Kinase inhibitors and uses thereof

Abstract

The present disclosure relates generally to compounds and compositions, intermediates, processes for their preparation and their use as kinase inhibitors.

Description

This application is a divisional application of the Chinese patent application No. 201880047293.5 (application date: May 17, 2018, invention name: kinase inhibitors and their uses). CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 62 / 507,698, filed May 17, 2017, and U.S. Provisional Patent Application No. 62 / 664,895, filed April 30, 2018, which are hereby incorporated by reference in their entireties. Background Art Although inflammation serves as a protective mechanism in response to harmful stimuli, such as pathogen invasion and tissue damage, chronic inflammation is an important underlying factor in many human diseases, such as neurodegenerative diseases, rheumatoid arthritis, autoimmune and inflammatory diseases, and cancer. Similarly, activation of cell death pathways, such as necrosis and apoptosis, is useful for eliminating infected or damaged cells and is an important underlying mechanism in human diseases, including acute and chronic neurodegenerative diseases. Receptor-interacting protein kinase 1 (UniProtKB Q13546) is a key regulator of inflammation, apoptosis, and necroptosis. Receptor-interacting protein kinase 1 plays an important role in regulating the inflammatory response mediated by nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). Recent studies have shown that its kinase activity controls necroptosis, a form of necrotic cell death that has traditionally been considered passive and unregulated and has distinct morphological features. Furthermore, receptor-interacting protein kinase 1 is part of a pro-apoptotic complex, suggesting its activity in regulating apoptosis. Receptor-interacting protein kinase 1 undergoes an intricate regulatory mechanism involving ubiquitination, deubiquitination, and phosphorylation. These regulatory events collectively determine whether a cell will survive and activate an inflammatory response, or die through apoptosis or necroptosis. Dysregulation of receptor-interacting protein kinase 1 signaling can lead to excessive inflammation or cell death. Conversely, studies have shown that inhibiting receptor-interacting protein kinase 1 is an effective treatment for diseases involving inflammation or cell death. Summary of the Invention In one aspect, provided herein are compounds useful as inhibitors of receptor-interacting protein kinase 1. In another aspect, provided herein are methods for preparing the compounds and their intermediates. In a related aspect, provided herein are pharmaceutical compositions comprising a compound as described herein and a pharmaceutically acceptable excipient. In another aspect, provided herein are methods of inhibiting receptor-interacting protein kinase 1. Further provided herein are methods of treating a disease or condition mediated by receptor-interacting protein kinase 1, comprising administering to a subject in need thereof a therapeutically effective amount of a compound or pharmaceutical composition as described herein. The present disclosure also provides the use of the compound or composition thereof in the preparation of a medicament for treating a disease, condition, or illness mediated (or at least partially mediated) by receptor-interacting protein kinase. I. Definition As used herein, the term "alkyl" by itself or as part of another substituent refers to a straight or branched chain, saturated aliphatic group having the indicated carbon atoms. Alkyl groups may include any number of carbon atoms, such as C 1-2 、C 1-3 、C 1-4 、C 1-5 、C 1-6 、C 1-7 、C 1-8 、C 1-9 、C 1-10 、C 2-3 、C 2-4 、C 2-5 、C 2-6 、C 3-4 、C 3-5 、C 3-6 、C 4-5 、C 4-6 and C 5-6 For example, C 1-6 Alkyl includes, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, etc. Alkyl can also refer to an alkyl group having up to 20 carbon atoms, such as, but not limited to, heptyl, octyl, nonyl, decyl, etc. Alkyl groups can be substituted or unsubstituted. Unless otherwise indicated, a "substituted alkyl" group can be substituted with one or more halogen, hydroxyl, amino, alkylamino, amido, acyl, nitro, cyano, and / or alkoxy groups. The term "alkoxy," as used herein, by itself or as part of another substituent, refers to a group having the formula -OR, where R is alkyl. As used herein, the term "cycloalkyl" by itself or as part of another substituent refers to a saturated or partially unsaturated, monocyclic, fused bicyclic or bridged polycyclic ring assembly containing from 3 to 12 ring atoms or the indicated carbon atoms. Cycloalkyl groups may include any number of carbon atoms, such as C 3-6 、C 4-6 、C 5-6 、C 3-8 、C 4-8 、C 5-8 、C 6-8、C 3-9 、C 3-10 、C 3-11 and C 3-12 . Saturated monocyclic cycloalkyl rings include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl. Saturated bicyclic and polycyclic cycloalkyl rings include, for example, norbornane, [2.2.2]bicyclooctane, decalin, and adamantane. Cycloalkyl groups may also be partially unsaturated, having one or more double or triple bonds in the ring. Representative partially unsaturated cycloalkyl groups include, but are not limited to, cyclobutene, cyclopentene, cyclohexene, cyclohexadiene (1,3- and 1,4-isomers), cycloheptene, cycloheptadiene, cyclooctene, cyclooctadiene (1,3-, 1,4-, and 1,5-isomers), norbornene, and norbornadiene. When the cycloalkyl group is a saturated monocyclic C 3-8 When cycloalkyl is a saturated monocyclic C 3-6 When cycloalkyl, exemplary groups include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Cycloalkyl groups can be substituted or unsubstituted. Unless otherwise indicated, "substituted cycloalkyl" groups can be substituted with one or more halogen, hydroxyl, amino, alkylamino, acylamino, acyl, nitro, cyano and / or alkoxy groups. The term "low cycloalkyl" refers to a cycloalkyl group with 3 to 7 carbon atoms, including, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. As used herein, the term "heteroalkyl" by itself or as part of another substitution refers to an alkyl group of any suitable length having 1 to 3 heteroatoms, such as N, O, and S, provided that the attachment of the substituent is located on a carbon atom. For example, heteroalkyl can include ethers, thioethers, and alkyl-amines. Other heteroatoms may also be useful, including but not limited to B, Al, Si, and P. Heteroatoms can be oxidized to form moieties, such as, but not limited to -S(O)- and -S(O)2-. The heteroatom portion of the heteroalkyl can replace the hydrogen of the alkyl group to form a hydroxyl, thio, or amino group. Alternatively, the heteroatom portion can be inserted between two carbon atoms. As used herein, the term "alkenyl" by itself or as part of another substituent refers to a straight or branched chain hydrocarbon having at least 2 carbon atoms and at least one double bond. Alkenyl groups may include any number of carbon atoms, such as C2, C 2-3 、C 2-4 、C 2-5 、C 2-6 、C 2-7 、C 2-8 、C 2-9 、C 2-10 , C3, C 3-4 、C 3-5 、C3-6 , C4, C 4-5 、C 4-6 , C5, C 5-6 and C6. Alkenyl groups may have any suitable number of double bonds, including but not limited to 1, 2, 3, 4, 5 or more. Examples of alkenyl groups include but are not limited to ethenyl, propenyl, isopropenyl, 1-butenyl, 2-butenyl, isobutenyl, butadienyl, 1-pentenyl, 2-pentenyl, isopentenyl, 1,3-pentadienyl, 1,4-pentadienyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1,3-hexadienyl, 1,4-hexadienyl, 1,5-hexadienyl, 2,4-hexadienyl, or 1,3,5-hexatrienyl. Alkenyl groups may be substituted or unsubstituted. Unless otherwise indicated, "substituted alkenyl" groups may be substituted with one or more halogen, hydroxyl, amino, alkylamino, amido, acyl, nitro, cyano, and / or alkoxy groups. As used herein, the term "alkynyl" by itself or as part of another substituent refers to a straight or branched chain hydrocarbon having at least 2 carbon atoms and at least one triple bond. Alkynyl groups may include any number of carbon atoms, such as C2, C 2-3 、C 2-4 、C 2-5 、C 2-6 、C 2-7 、C 2-8 、C 2-9 、C 2-10 , C3, C 3-4 、C 3-5 、C 3-6 , C4, C 4-5 、C 4-6 , C5, C 5-6 and C6. Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, 1-butynyl, 2-butynyl, isobutynyl, sec-butynyl, butadiynyl, 1-pentynyl, 2-pentynyl, isopentenyl, 1,3-pentadiynyl, 1,4-pentadiynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 1,3-hexadiynyl, 1,4-hexadiynyl, 1,5-hexadiynyl, 2,4-hexadiynyl, or 1,3,5-hexatriynyl. Alkynyl groups may be substituted or unsubstituted. Unless otherwise indicated, a "substituted alkynyl" group may be substituted with one or more halogen, hydroxy, amino, alkylamino, amido, acyl, nitro, cyano, and / or alkoxy groups.

[00146] The terms "halo" and "halogen," as used herein, by themselves or as part of another substituent, refer to a fluorine, chlorine, bromine, or iodine atom. As used herein, the term "haloalkyl" by itself or as part of another substituent refers to an alkyl group in which some or all of the hydrogen atoms are replaced by halogen atoms. As with alkyl groups, a haloalkyl group can have any suitable number of carbon atoms, for example, C 1-6 For example, haloalkyl includes trifluoromethyl, fluoromethyl, and the like. In some cases, the term "perfluoro" may be used to define a compound or group in which all hydrogens are replaced by fluorine. For example, perfluoromethyl refers to 1,1,1-trifluoromethyl. As used herein, the term "aryl" by itself or as part of another substituent refers to an aromatic ring system having any suitable number of carbon ring atoms and any suitable number of rings. Aryl groups may include any suitable number of carbon ring atoms, for example, C6, C7, C8, C9, C 10 、C 11 、C 12 、C 13 、C 14 、C 15 or C 16 and C 6-10 、C 6-12 or C 6-14 . The aryl group can be monocyclic, fused to form a bicyclic (e.g., benzocyclohexyl) or tricyclic group, or formed into a biaryl group through a bond. Representative aryl groups include phenyl, naphthyl, and biphenyl. Other aryl groups include benzyl with a methylene linker. Some aryl groups have 6 to 12 ring members, such as phenyl, naphthyl, or biphenyl. Other aryl groups have 6 to 10 ring members, such as phenyl or naphthyl. Some other aryl groups have 6 ring members, such as phenyl. The aryl group can be substituted or unsubstituted. Unless otherwise indicated, a "substituted aryl" group can be substituted with one or more halogen, hydroxyl, amino, alkylamino, acylamino, acyl, nitro, cyano, and / or alkoxy groups. As used herein, the term "heteroaryl" by itself or as part of another substituent refers to a monocyclic or fused bicyclic or tricyclic aromatic ring assembly containing 5 to 16 ring atoms, of which 1 to 5 ring atoms are heteroatoms, such as N, O, or S. Additional heteroatoms may also be useful, including but not limited to B, Al, Si, and P. The heteroatoms may be oxidized to form moieties such as, but not limited to, -S(O)- and -S(O)2-. A heteroaryl group may include any number of ring atoms, such as C 5-6 、C 3-8 、C 4-8 、C 5-8 、C 6-8 、C 3-9 、C 3-10 、C 3-11 or C 3-12, wherein at least one carbon atom is replaced by a heteroatom. Any suitable number of heteroatoms may be included in a heteroaryl group, for example, 1, 2, 3, 4; or 5, or 1 to 2, 1 to 3, 1 to 4, 1 to 5, 2 to 3, 2 to 4, 2 to 5, 3 to 4, or 3 to 5. For example, a heteroaryl group may be C 5-8 Heteroaryl, wherein 1 to 4 carbon ring atoms are replaced by heteroatoms; or C 5-8 Heteroaryl, wherein 1 to 3 carbon ring atoms are replaced by heteroatoms; or C 5-6 Heteroaryl, wherein 1 to 4 carbon ring atoms are replaced by heteroatoms; or C 5-6 Heteroaryl, wherein 1 to 3 carbon ring atoms are replaced by heteroatoms. The heteroaryl group may include groups such as pyrrole, pyridine, imidazole, pyrazole, triazole, tetrazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4- and 1,3,5-isomers), thiophene, furan, thiazole, isothiazole, oxazole and isoxazole. The heteroaryl group may also be fused to an aromatic ring system, such as a phenyl ring, to form a member, including but not limited to benzopyrroles such as indole and isoindole, benzopyridines such as quinoline and isoquinoline, benzopyrazine (quinoxaline), benzopyrimidine (quinazoline), benzopyridazine such as phthalazine and cinnoline, benzothiophene and benzofuran. Other heteroaryl groups include heteroaryl rings connected by bonds, such as bipyridine. The heteroaryl group may be substituted or unsubstituted. Unless otherwise indicated, a "substituted heteroaryl" group may be substituted with one or more halo, hydroxy, amino, alkylamino, amido, acyl, nitro, cyano, and / or alkoxy groups. The heteroaryl groups may be attached at any position on the ring. For example, pyrrole includes 1-, 2- and 3-pyrrole, pyridine includes 2-, 3- and 4-pyridine, imidazole includes 1-, 2-, 4- and 5-imidazole, pyrazole includes 1-, 3-, 4- and 5-pyrazole, triazole includes 1-, 4- and 5-triazole, tetrazole includes 1- and 5-tetrazole, pyrimidine includes 2-, 4-, 5- and 6-pyrimidine, pyridazine includes 3- and 4-pyridazine, 1,2,3-triazine includes 4- and 5-triazine, 1,2,4-triazine includes 3-, 5- and 6-triazine, 1,3,5-triazine includes 2-triazine, thiophene includes 2- and 3-thiophene, furan includes 2- and 3-furan, thiazole includes 2-, 4- and 5-thiazole, isothiazole includes 3-, 4- and 5-isothiazole, oxazole includes 2-, 4- and 5-oxazole, isoxazole includes 3-, 4- and 5-isoxazole, indole includes 1-, 2- and 3-indole, isoindole includes 1- and 2-isoindole, quinoline includes 2-, 3- and 4-quinoline, isoquinoline includes 1-, 3- and 4-isoquinoline, quinazoline includes 2- and 4-quinazoline, cinnoline includes 3- and 4-cinnoline, benzothiophene includes 2- and 3-benzothiophene, and benzofuran includes 2- and 3-benzofuran. Some heteroaryl groups include those having 5 to 10 ring members and 1 to 3 ring atoms including N, O or S, such as pyrrole, pyridine, imidazole, pyrazole, triazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4- and 1,3,5-isomers), thiophene, furan, thiazole, isothiazole, oxazole, isoxazole, indole, isoindole, quinoline, isoquinoline, quinoxaline, quinazoline, phthalazine, cinnoline, benzothiophene and benzofuran. Other heteroaryl groups include those having 5 to 8 ring members and 1 to 3 heteroatoms, such as pyrrole, pyridine, imidazole, pyrazole, triazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4- and 1,3,5-isomers), thiophene, furan, thiazole, isothiazole, oxazole and isoxazole. Some other heteroaryl groups include those with 9 to 12 ring members and 1 to 3 heteroatoms, such as indole, isoindole, quinoline, isoquinoline, quinoxaline, quinazoline, phthalazine, cinnoline, benzothiophene, benzofuran and bipyridine. Other heteroaryl groups include those with 5 to 6 ring members and 1 to 2 ring atoms including N, O or S, such as pyrrole, pyridine, imidazole, pyrazole, pyrazine, pyrimidine, pyridazine, thiophene, furan, thiazole, isothiazole, oxazole and isoxazole. Some heteroaryl groups include 5 to 10 ring members and only nitrogen heteroatoms, such as pyrrole, pyridine, imidazole, pyrazole, triazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4-, and 1,3,5-isomers), indole, isoindole, quinoline, isoquinoline, quinoxaline, quinazoline, phthalazine, and cinnoline. Other heteroaryl groups include 5 to 10 ring members and only oxygen heteroatoms, such as furan and benzofuran. Some other heteroaryl groups include 5 to 10 ring members and only sulfur heteroatoms, such as thiophene and benzothiophene. Other heteroaryl groups include 5 to 10 ring members and at least two heteroatoms, such as imidazole, pyrazole, triazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4- and 1,3,5-isomers), thiazole, isothiazole, oxazole, isoxazole, quinoxaline, quinazoline, phthalazine and cinnoline. As used herein, the term "heterocyclyl" by itself or as part of another substituent refers to a saturated ring system having 3 to 12 ring members and 1 to 4 heteroatoms N, O and S. Additional heteroatoms may also be useful, including but not limited to B, Al, Si and P. The heteroatoms may be oxidized to form moieties such as, but not limited to, -S(O)- and -S(O)2-. A heterocyclyl group may include any number of ring atoms, for example, C 3-6 、C 4-6 、C 5-6 、C 3-8 、C 4-8 、C 5-8 、C 6-8 、C 3-9 、C3-10 、C 3-11 , or C 3-12 , wherein at least one carbon atom is replaced by a heteroatom. Any suitable number of carbon ring atoms can be replaced by heteroatoms in the heterocyclyl group, for example 1, 2, 3 or 4, or 1 to 2, 1 to 3, 1 to 4, 2 to 3, 2 to 4, or 3 to 4. The heterocyclyl group may include groups such as aziridine, azetidine, pyrrolidine, piperidine, azepane, azocyclooctane (azocane), quinuclidine, pyrazolidine, imidazolidine, piperazine (1,2-, 1,3- and 1,4-isomers), oxirane, oxetane, tetrahydrofuran, oxirane (tetrahydropyran), oxepane, thiirane, thietane, thiolane (tetrahydrothiophene), thiocyclohexanone (thiane) (tetrahydrothiopyran), oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, dioxolane, dithiolane, morpholine, thiomorpholine, dioxane or dithiane. The heterocyclyl group may also be fused to an aromatic or non-aromatic ring system to form a member, including but not limited to indole. The heterocyclyl group may be unsubstituted or substituted. Unless otherwise indicated, a "substituted heterocyclyl" group may be substituted with one or more halo, hydroxy, amino, oxo (=0), alkylamino, amido, acyl, nitro, cyano, and / or alkoxy groups. The heterocyclyl group may be attached at any position on the ring. For example, aziridine may be 1- or 2-aziridine, azetidine may be 1- or 2-azetidine, pyrrolidine may be 1-, 2- or 3-pyrrolidine, piperidine may be 1-, 2-, 3- or 4-piperidine, pyrazolidine may be 1-, 2-, 3- or 4-pyrazolidine, imidazolidine may be 1-, 2-, 3- or 4-imidazolidine, piperazine may be 1-, 2- , 3- or 4-piperazine, tetrahydrofuran may be 1- or 2-tetrahydrofuran, oxazolidine may be 2-, 3-, 4- or 5-oxazolidine, isoxazolidine may be 2-, 3-, 4- or 5-isoxazolidine, thiazolidine may be 2-, 3-, 4- or 5-thiazolidine, isothiazolidine may be 2-, 3-, 4- or 5-isothiazolidine, and morpholine may be 2-, 3- or 4-morpholine. When the heterocyclic group includes 3 to 8 ring members and 1 to 3 heteroatoms, representative members include, but are not limited to, pyrrolidine, piperidine, tetrahydrofuran, ethylene oxide, tetrahydrothiophene, thiocyclohexanone, pyrazolidine, imidazolidine, piperazine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, morpholine, thiomorpholine, dioxane, and dithiane. The heterocyclic group can also form a ring with 5 to 6 ring members and 1 to 2 heteroatoms, and its representative members include, but are not limited to, pyrrolidine, piperidine, tetrahydrofuran, tetrahydrothiophene, pyrazolidine, imidazolidine, piperazine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, and morpholine. The term "carbonyl," as used herein, by itself or as part of another substituent, refers to -C(O)-, ie, a carbon atom doubly bonded to oxygen and to two other groups having a carbonyl moiety. As used herein, the term "amino" refers to the moiety -NR2, wherein each R group is H or alkyl. The amino moiety can be ionized to form the corresponding ammonium cation. "Dialkylamino" refers to an amino moiety wherein each R group is alkyl. The term "hydroxy" as used herein refers to the moiety -OH. The term "cyano," as used herein, refers to a carbon atom triple-bonded to a nitrogen atom (ie, the moiety -C≡N). As used herein, the term "carboxyl" refers to the moiety -C(O)OH. The carboxyl moiety can ionize to form the corresponding carboxylate anion. As used herein, the term "amido" refers to the moiety -NRC(O)R or -C(O)NR2, wherein each R group is H or alkyl. The term "nitro" as used herein refers to the moiety -NO2. As used herein, the term "oxo" refers to an oxygen atom double-bonded to a compound (ie, O=). As used herein, the term "pharmaceutically acceptable excipient" refers to a substance that facilitates administration of an active agent to a subject. "Pharmaceutically acceptable" means that the excipient is compatible with the other ingredients of the formulation and is not deleterious to the recipient thereof. Pharmaceutical excipients that can be used in the present disclosure include, but are not limited to, binders, fillers, disintegrants, lubricants, glidants, coatings, sweeteners, flavorings, and pigments. As used herein, the term "salt" refers to an acidic or basic salt of a compound disclosed herein. Illustrative examples of pharmaceutically acceptable salts are salts of inorganic acids (hydrochloric acid, hydrobromic acid, phosphoric acid, etc.), organic acids (acetic acid, propionic acid, glutamic acid, citric acid, etc.), and quaternary ammonium salts (methyl iodide, ethyl iodide, etc.). It should be understood that the pharmaceutically acceptable salts are non-toxic. Pharmaceutically acceptable salts of the acidic compounds disclosed herein are salts formed with bases, i.e., cationic salts, such as alkali metal salts and alkaline earth metal salts, e.g., sodium, lithium, potassium, calcium, magnesium, and ammonium salts, such as ammonium, trimethyl-ammonium, diethylammonium and tris-(hydroxymethyl)-methyl-ammonium salts. Similarly, acid addition salts may also be provided, for example with inorganic acids, organic carboxylic acids and organic sulfonic acids, for example, hydrochloric acid, methanesulfonic acid, maleic acid, with a basic group, for example pyridyl, forming part of the structure. The neutral forms of the compounds can be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but for the purposes of this disclosure, the salts are equivalent to the parent form of the compound. In addition to salt forms, compounds described herein are in prodrug form. Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds described herein. Additionally, prodrugs can be converted to the compounds described herein by chemical or biochemical methods in an ex vivo environment. For example, when a prodrug is placed in a transdermal patch reservoir along with a suitable enzyme or chemical reagent, it can be slowly converted to the compounds described herein. Any compound or formula given herein is also intended to represent unlabeled forms as well as isotopically labeled forms (i.e., "isotopic analogs") of the compound. An isotopically labeled compound has a structure depicted by a formula given herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, for example, 2 H. 3 H. 11 C. 13 C. 14 C. 13 N. 15 N. 15 O. 17 O. 18 O. 31 P. 32 P. 35 S. 18 F. 36 Cl, 123 I and 125 I. Various isotopically labeled compounds of the present disclosure, for example, compounds into which radioactive isotopes (e.g. 3 H. 13 C and 14 Such isotopically labeled compounds are useful in metabolism studies, reaction kinetic studies, detection or imaging techniques, such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including drug or substrate tissue distribution assays, or in radiation therapy of patients. The present disclosure also includes "deuterated analogs" of the compounds described herein, in which 1 to n hydrogens attached to a carbon atom are replaced by deuterium, where n is the number of hydrogens in the molecule. Such compounds exhibit increased resistance to metabolism and, therefore, can be used to increase the half-life of any compound when administered to mammals, particularly humans. See, for example, Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism," Trends Pharmacol. Sci. 5(12):524-527 (1984). Such compounds are synthesized by methods well known in the art, for example, by employing starting materials in which one or more hydrogens have been replaced by deuterium. Deuterium-labeled or substituted therapeutic compounds of the present disclosure may have improved DMPK (drug metabolism and pharmacokinetics) properties, which are related to distribution, metabolism, and excretion (ADME). Substitution with heavier isotopes such as deuterium may provide certain therapeutic advantages due to greater metabolic stability, for example, increased half-life in vivo, reduced dosage requirements, and / or improved therapeutic index. 18 F. 3 H. 11 C-labeled compounds may be useful for PET or SPECT or other imaging studies. Isotopically labeled compounds of the present disclosure and their prodrugs can generally be prepared by the methods disclosed in the following schemes or examples and preparations by replacing non-isotopically labeled reagents with readily available isotopically labeled reagents. It should be understood that deuterium in this context is considered a substituent in the compounds described herein. The concentration of such heavier isotopes, particularly deuterium, can be defined by an isotopic enrichment factor. In the compounds described herein, any atom not specifically designated as a particular isotope represents any stable isotope of that atom. Unless otherwise indicated, when a position is specifically designated as "H" or "hydrogen," it is understood that the position has hydrogen in its natural abundance isotopic composition. Thus, in the compounds described herein, any atom specifically designated as deuterium (D) represents deuterium. "Treatment" or "treating" is an approach to obtaining beneficial or desired results, including clinical results. Beneficial or desired clinical results may include one or more of the following: a) inhibiting the disease or condition (e.g., alleviating one or more symptoms caused by the disease or condition, and / or reducing the extent of the disease or condition); b) slowing or arresting the development of one or more clinical symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, preventing or slowing the worsening or progression of the disease or condition, and / or preventing or slowing the spread of the disease or condition (e.g., metabolism)); and / or c) relieving the disease, i.e., causing regression of clinical symptoms (e.g., improving the disease state, partially or completely resolving the disease or condition, enhancing the effect of another drug, slowing the progression of the disease, improving quality of life, and / or prolonging survival). "Prevention" or "preventing" means any treatment of a disease or condition that results in the clinical symptoms of the disease or condition not developing. In some embodiments, the compound can be administered to a subject (including a human) who is at risk or has a family history of the disease or condition. "Subject" refers to an animal, such as a mammal (including a human) that is or will be the subject of treatment, observation, or experiment. The methods described herein can be useful in human therapy and / or veterinary applications. In some embodiments, the subject is a mammal. In one embodiment, the subject is a human. The term "therapeutically effective amount" or "effective amount" of a compound described herein, or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof, means an amount sufficient to achieve a therapeutic effect when administered to a subject, to provide a therapeutic benefit, such as improvement in symptoms or slowing of disease progression. For example, a therapeutically effective amount can be an amount sufficient to alleviate the symptoms of a disease or condition described herein. The therapeutically effective amount can vary depending on the subject and the disease or condition being treated, the subject's weight and age, the severity of the disease or condition, and the mode of administration, and can be readily determined by one of ordinary skill in the art. II. Kinase Inhibitors In one aspect, there is provided a compound of formula A: or a pharmaceutically acceptable salt, solvate, prodrug, isotopic analog or isomer thereof, in W 1 、W 2 、W 3 and W 4 are independently N or CR 7 ; R1a 、R 1b and R 1c are independently hydrogen, halogen, -CN, -N3, -NO2, -OH, -SF5, -SCF3, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Heteroalkyl, C 3-8 Cycloalkyl, C 1-8 Halogenated alkyl, C 1-8 Alkoxy, C 1-8 Haloalkoxy, 4 to 12 membered heterocyclic group, C 6-10 Aryl, 5- to 12-membered heteroaryl, -N(R 1d )2、-C(O)R 1e 、 -C(O)OR 1d 、-C(O)N(R 1d )2、-NR 1d C(O)R 1e 、-NR 1d C(O)N(R 1d )2. -NR 1d C(O)OR 1d 、-OC(O)N(R 1d )2. -OC(O)OR 1d 、-SR 1d 、 -S(O)R 1e 、-S(O)2R 1e 、-S(O)3R 1d 、-S(O)N(R 1d )2、-S(O)2N(R 1d )2. -NR 1d S(O)R 1e 、-NR 1d S(O)2R 1e 、-NR 1d S(O)N(R 1d )2 or -NR 1d S(O)2N(R 1d )2, where R 1a 、R 1b and R 1c each optionally and independently substituted with one or more (e.g., 1 to 8) R 5 And R 1a 、R 1b and R 1c At least one of is not hydrogen; or R 1b and R 1c Optionally together to form C 3-10 cycloalkyl or 4 to 12 membered heterocyclyl, each of which is optionally substituted with one or more (eg, 1 to 8) R 5 ;or R 1a 、R 1b and R 1c Optionally together to form C 5-10 cycloalkyl or 5- to 12-membered heterocyclyl, each of which is optionally substituted with one or more (eg, 1 to 8) R 5 ; or R 1a does not exist and R 1b and R 1c Together they form C 6-10 aryl or 5- to 12-membered heteroaryl or 5- to 12-membered heterocyclyl, each of which is optionally substituted with one or more (e.g., 1 to 8) R 5 ; R 1d are independently hydrogen, C 1-8 Alkyl, C 1-8 Halogenated alkyl, C 3-10 cycloalkyl or 4 to 12 membered heterocyclic group, or Two R on the same atom 1d Optionally together form a 4 to 8 membered heterocyclic group, which is optionally substituted by oxo, halogen or C 1-6 Alkyl substituted, wherein the alkyl is optionally substituted with one or more (e.g., 1 to 8) R 5 ; R 1e Each independently is C 1-8 Alkyl, C 1-8 Halogenated alkyl, C 3-10 cycloalkyl or 4- to 12-membered heterocyclic group; R 2a and R 2b are independently hydrogen, halogen, C 1-8 Alkyl, C 1-8 Halogenated alkyl, C 2-8 Alkenyl or C 2-8 Alkynyl, or R 2a and R 2b Optionally together to form C 3-6 cycloalkyl or 4 to 6 membered heterocyclyl, each of which is optionally substituted with one or more (eg, 1 to 8) R 6 ; R 3a and R 3b are independently hydrogen, halogen, C 1-8 Alkyl, C 2-8 Alkenyl, C2-8 Alkynyl, C 1-8 Halogenated alkyl, C 3-6 Cycloalkyl or 4 to 6 membered heterocyclyl, wherein the cycloalkyl and the heterocyclyl are optionally substituted with one or more (eg, 1 to 8) R 6 , or R 3a and R 3b Optionally together to form oxo, C 3-6 Cycloalkyl or 4 to 6 membered heterocyclyl, wherein the cycloalkyl and the heterocyclyl are optionally substituted with one or more (eg, 1 to 8) R 6 ; Y is O, C(O), S, S(O), S(O)2, CR 4a R 4b or NR 4c ; R 4a and R 4b are independently hydrogen, halogen, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Halogenated alkyl, C 3-6 Cycloalkyl or 4 to 6 membered heterocyclyl, wherein the cycloalkyl and the heterocyclyl are optionally substituted with one or more (eg, 1 to 8) R 6 , or R 4a and R 4b Optionally together to form C 3-6 Cycloalkyl or 4 to 6 membered heterocyclyl, wherein the cycloalkyl and the heterocyclyl are optionally substituted with one or more (eg, 1 to 8) R 6 ,or R 4a and R 1b Optionally taken together to form a 4- to 12-membered heterocyclyl, optionally substituted with one or more (eg, 1 to 8) R 6 ,or R 4a and R 3a Optionally together to form C 3-8 cycloalkyl or 4 to 12 membered heterocyclyl, each of which is optionally substituted with one or more (eg, 1 to 8) R 6 ,or R 4c For hydrogen, C 1-8 Alkyl, C 1-8 Halogenated alkyl, C 3-10 Cycloalkyl or 4 to 12-membered heterocyclic group; R 5 Each independently represents halogen, -CN, -OH, -SF5, -SCF3, C 1-8 Alkyl, C 2-8 ene Base, C 2-8 Alkynyl, C 1-8 Halogenated alkyl, C 1-8 Heteroalkyl, C 3-8 Cycloalkyl, C 1-8 Halogenated alkyl, C 1-8 Alkoxy, C 1-8 Haloalkoxy, 4 to 12 membered heterocyclic group, C 6-10 Aryl, 5- to 12-membered heteroaryl, (4- to 12-membered heterocyclic) (C 1-8 Heteroalkyl), (C 6-10 Aryl)(C 1-8 Heteroalkyl), (5 to 12 membered heteroaryl) (C 1-8 heteroalkyl), -N(R 5a )2. -C(O)R 5b 、-C(O)OR 5a 、-C(O)N(R 5a )2、-NR 5a C(O)R 5b 、 -NR 5a C(O)N(R 5a )2、-NR 5a C(O)OR 5a 、-OC(O)N(R 5a )2. -OC(O)OR 5a 、-SR 5a 、-S(O)R 5b 、-S(O)2R 5b 、-S(O)3R 5a 、 -S(O)N(R 5a )2、-S(O)2N(R 5a )2、-NR 5a S(O)R 5b 、-NR 5a S(O)2R 5b 、 -NR 5a S(O)N(R 5a )2, or –NR 5a S(O)2N(R 5a ) 2, each of which is optionally substituted with one or more (e.g., 1 to 8) R 5c ,or Two R's 5 optionally together forming an oxo group; R 5a are independently hydrogen, C 1-8 Alkyl, C 1-8 Halogenated alkyl, C3-10 a cycloalkyl group or a 4- to 12-membered heterocyclic group, and R 5b Each independently is C 1-8 Alkyl, C 1-8 Halogenated alkyl, C 3-10 cycloalkyl, 4- to 12-membered heterocyclyl, or 5- to 12-membered heteroaryl; R 5c are independently halogen, cyano, C 1-8 Halogenated alkyl, C 1-8 Alkyl, C 1-8 Alkoxy, C 1-8 Halogenated alkoxy, (C 1-8 Alkoxy) (C 1-8 Alkoxy), hydroxyl, SR 5d 、N(R 5d )2、N(R 5d )2(C 1-8 Alkoxy), C 3-10 Cycloalkyl and 4 to 12 membered heterocyclic group, or two R 5c optionally together forming an oxo group; R 5d are independently hydrogen, C 1-8 Alkyl or C 1-8 alkyl halide; R 6 Each is halogen, -CN, -OH, C 1-8 Alkyl, C 1-8 Heteroalkyl, C 3-8 Cycloalkyl, C 1-8 Halogenated alkyl, C 1-8 Alkoxy, 4 to 12 membered heterocyclic group, C 6-10 Aryl, 5- to 12-membered heteroaryl, -N(R 6a )2、-C(O)R 6b 、-C(O)N(R 6a )2 or -C(O)OR 6a , or two R 6 Together they form an oxo group; R 6a are independently hydrogen, C 1-8 Alkyl or C 1-8 Haloalkyl, or two R on the same atom 6a optionally taken together to form a 4- to 6-membered heterocyclyl; R 6b Each independently is C 1-8 Alkyl or C 1-8 alkyl halide; R 7 Each is independently hydrogen, halogen, -CN, -N3, -NO2, -SF5, -SCF3, C1-8 alkyl Base, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Heteroalkyl, C 3-8 Cycloalkyl, C 1-8 Haloalkyl, 4 to 12 membered heterocyclic group, C 6-10 Aryl, 5- to 12-membered heteroaryl, -OR 7a 、 -C(O)R 7b 、-N(R 7a )2、-C(O)OR 7a 、-C(O)N(R 7a )2、-NR 7a C(O)R 7b 、 -NR 7a C(O)N(R 7a )2、-NR 7a C(O)OR 7a 、-OC(O)N(R 7a )2. -OC(O)OR 7a 、-SR 7a 、-S(O)R 7b 、-S(O)2R 7b 、-S(O)3R 7a 、 -S(O)N(R 7a )2、-S(O)2N(R 7a )2、-NR 7a S(O)R 7b ,–NR 7a S(O)2R 7b 、 -NR 7a S(O)N(R 7a )2, or -NR 7a S(O)2N(R 7a ) 2, each of which is optionally and independently substituted with one or more (e.g., 1 to 8) R 8 ; R 7a are independently hydrogen, C 1-8 Alkyl, C 1-8 Halogenated alkyl, C 3-10 cycloalkyl or 4 to 12 membered heterocyclic group, or Two R on the same atom 7a Optionally together form a 4 to 8 membered heterocyclic group, which is optionally substituted by oxo, halogen or C 1-6Alkyl substituted, wherein the alkyl is optionally substituted with one or more (e.g., 1 to 8) R 8 ; R 7b Each independently is C 1-8 Alkyl, C 1-8 Halogenated alkyl, C 3-10 cycloalkyl or 4- to 12-membered heterocyclic group; R 8 Each is halogen, -CN, -OH, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Heteroalkyl, C 3-8 Cycloalkyl, C 1-8 Halogenated alkyl, C 1-8 Alkoxy, 4 to 12 membered heterocyclic group, C 6-10 Aryl, 5- to 12-membered heteroaryl, -N(R 8a )2、-C(O)R 8b or-C(O)OR 8a ,or Two R's 8 optionally together forming an oxo group; R 8a are independently hydrogen, C 1-8 Alkyl or C 1-8 alkyl halide; R 8b Each independently is C 1-8 Alkyl or C 1-8 alkyl halide; Z is C(R 9 )2, C(O), O, S, S(O), S(O)2, S(O)NR 9 or NR 9 ; R 9 are independently hydrogen, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Halogenated alkyl, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclyl, or –C(O)R 9a ;and R 9a C 1-8 Alkyl, C 1-8 Halogenated alkyl, C 3-8 Cycloalkyl or 4 to 12 membered heterocyclic group, or R 9 and R 3a Optionally together to form C 3-8cycloalkyl or 4 to 12 membered heterocyclyl, each of which is optionally substituted with one or more (eg, 1 to 8) R 6 . In one aspect, a compound of formula B is provided: or a pharmaceutically acceptable salt, solvate, prodrug, isotopic analog or isomer thereof, wherein W 1 、W 2 、W 3 and W 4 are independently N or CR 7 ; R 1a 、R 1b and R 1c are independently hydrogen, halogen, -CN, -N3, -NO2, -OH, -SF5, -SCF3, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Heteroalkyl, C 3-8 Cycloalkyl, C 1-8 Halogenated alkyl, C 1-8 Alkoxy, C 1-8 Haloalkoxy, 4 to 12 membered heterocyclic group, C 6-10 Aryl, 5- to 12-membered heteroaryl, -N(R 1d )2、-C(O)R 1e 、 -C(O)OR 1d 、-C(O)N(R 1d )2、-NR 1d C(O)R 1e 、-NR 1d C(O)N(R 1d )2. -NR 1d C(O)OR 1d 、-OC(O)N(R 1d )2. -OC(O)OR 1d 、-SR 1d 、 -S(O)R 1e 、-S(O)2R 1e 、-S(O)3R 1d 、-S(O)N(R 1d )2、-S(O)2N(R 1d )2. -NR 1d S(O)R 1e 、-NR 1dS(O)2R 1e 、-NR 1d S(O)N(R 1d )2 or -NR 1d S(O)2N(R 1d )2, where R 1a 、R 1b and R 1c each optionally and independently substituted with one or more (e.g., 1 to 8) R 5 And R 1a 、R 1b and R 1c At least one of is not hydrogen; or R 1b and R 1c Optionally together to form C 3-10 cycloalkyl or 4 to 12 membered heterocyclyl, each of which is optionally substituted with one or more (eg, 1 to 8) R 5 ;or R 1a 、R 1b and R 1c Optionally together to form C 5-10 Cycloalkyl, optionally substituted with one or more (eg, 1 to 8) R 5 ;or R 1a does not exist and R 1b and R 1c Together they form C 6-10 aryl or 5- to 12-membered heteroaryl, each of which is optionally substituted with one or more (e.g., 1 to 8) R 5 ; R 1d are independently hydrogen, C 1-8 Alkyl, C 1-8 Halogenated alkyl, C 3-10 Cycloalkyl or 4- to 12-membered heterocyclyl, or two R on the same atom 1d Optionally together form a 4 to 8 membered heterocyclic group, which is optionally substituted by oxo, halogen or C 1-6 Alkyl substituted, wherein the alkyl is optionally substituted with one or more (e.g., 1 to 8) R 5 ; R 1e Each independently is C 1-8 Alkyl, C 1-8 Halogenated alkyl, C 3-10 cycloalkyl or 4- to 12-membered heterocyclic group; R 2a and R 2b are independently hydrogen, halogen, C 1-8 Alkyl, C 1-8Halogenated alkyl, C 2-8 Alkenyl or C 2-8 Alkynyl, or R 2a and R 2b Optionally together to form C 3-6 cycloalkyl or 4 to 6 membered heterocyclyl, each of which is optionally substituted with one or more (eg, 1 to 8) R 6 ; R 3a and R 3b are independently hydrogen, halogen, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Halogenated alkyl, C 3-6 Cycloalkyl or 4 to 6 membered heterocyclyl, wherein the cycloalkyl and the heterocyclyl are optionally substituted with one or more (eg, 1 to 8) R 6 , or R 3a and R 3b Optionally together to form oxo, C 3-6 Cycloalkyl or 4 to 6 membered heterocyclyl, wherein the cycloalkyl and the heterocyclyl are optionally substituted with one or more (eg, 1 to 8) R 6 ; Y is O, C(O), S, S(O), S(O)2, CR 4a R 4b or NR 4c ; R 4a and R 4b are independently hydrogen, halogen, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Halogenated alkyl, C 3-6 Cycloalkyl or 4 to 6 membered heterocyclyl, wherein the cycloalkyl and the heterocyclyl are optionally substituted with one or more (eg, 1 to 8) R 6 , or R 4a and R 4b Optionally together to form C 3-6 Cycloalkyl or 4 to 6 membered heterocyclyl, wherein the cycloalkyl and the heterocyclyl are optionally substituted with one or more (eg, 1 to 8) R 6 ,or R 4a and R 1b Optionally taken together to form a 4- to 12-membered heterocyclyl, optionally substituted with one or more (eg, 1 to 8) R 6 ,or R 4a and R 3a Optionally together to form C3-8 cycloalkyl or 4 to 12 membered heterocyclyl, each of which is optionally substituted with one or more (eg, 1 to 8) R 6 ,or R 4c For hydrogen, C 1-8 Alkyl, C 1-8 Halogenated alkyl, C 3-10 Cycloalkyl or 4 to 12-membered heterocyclic group; R 5 Each is halogen, -CN, -OH, -SF5, -SCF3, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Heteroalkyl, C 3-8 Cycloalkyl, C 1-8 Halogenated alkyl, C 1-8 Alkoxy, 4 to 12 membered heterocyclic group, C 6-10 Aryl, 5- to 12-membered heteroaryl, -N(R 5a )2. -C(O)R 5b 、-C(O)OR 5a 、-C(O)N(R 5a )2、-NR 5a C(O)R 5b 、 -NR 5a C(O)N(R 5a )2、-NR 5a C(O)OR 5a 、-OC(O)N(R 5a )2. -OC(O)OR 5a 、-SR 5a 、-S(O)R 5b 、-S(O)2R 5b 、-S(O)3R 5a 、 -S(O)N(R 5a )2、-S(O)2N(R 5a )2、-NR 5a S(O)R 5b 、-NR 5a S(O)2R 5b 、 -NR 5a S(O)N(R 5a )2 or –NR 5a S(O)2N(R 5a ) 2, each of which is optionally substituted with one or more (e.g., 1 to 8) R 5c ,or Two R's5 optionally together forming an oxo group; R 5a are independently hydrogen, C 1-8 Alkyl, C 1-8 Halogenated alkyl, C 3-10 a cycloalkyl group or a 4- to 12-membered heterocyclic group, and R 5b Each independently is C 1-8 Alkyl, C 1-8 Halogenated alkyl, C 3-10 cycloalkyl or 4- to 12-membered heterocyclic group; R 5c are each independently halogen, C 1-8 Alkyl, C 1-8 Alkoxy, C 3-10 cycloalkyl and 4 to 12 membered heterocyclic group, or Two R's 5c optionally together forming an oxo group; R 6 Each is halogen, -CN, -OH, C 1-8 Alkyl, C 1-8 Heteroalkyl, C 3-8 Cycloalkyl, C 1-8 Halogenated alkyl, C 1-8 Alkoxy, 4 to 12 membered heterocyclic group, C 6-10 Aryl, 5- to 12-membered heteroaryl, -N(R 6a )2、-C(O)R 6b 、-C(O)N(R 6a )2 or -C(O)OR 6a , or two R 6 Together they form an oxo group; R 6a are independently hydrogen, C 1-8 Alkyl or C 1-8 Haloalkyl, or two R on the same atom 6a optionally taken together to form a 4- to 6-membered heterocyclyl; R 6b Each independently is C 1-8 Alkyl or C 1-8 alkyl halide; R 7 Each is independently hydrogen, halogen, -CN, -N3, -NO2, -SF5, -SCF3, C 1-8 alkyl Base, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Heteroalkyl, C 3-8 Cycloalkyl, C 1-8 Haloalkyl, 4 to 12 membered heterocyclic group, C6-10 Aryl, 5- to 12-membered heteroaryl, -OR 7a 、 -C(O)R 7b 、-N(R 7a )2、-C(O)OR 7a 、-C(O)N(R 7a )2、-NR 7a C(O)R 7b 、 -NR 7a C(O)N(R 7a )2、-NR 7a C(O)OR 7a 、-OC(O)N(R 7a )2. -OC(O)OR 7a 、-SR 7a 、-S(O)R 7b 、-S(O)2R 7b 、-S(O)3R 7a 、 -S(O)N(R 7a )2、-S(O)2N(R 7a )2、-NR 7a S(O)R 7b ,–NR 7a S(O)2R 7b 、 -NR 7a S(O)N(R 7a )2 or –NR 7a S(O)2N(R 7a ) 2, each of which is optionally and independently substituted with one or more (e.g., 1 to 8) R 8 ; R 7a are independently hydrogen, C 1-8 Alkyl, C 1-8 Halogenated alkyl, C 3-10 cycloalkyl or 4 to 12 membered heterocyclic group, or Two R on the same atom 7a Optionally together form a 4 to 8 membered heterocyclic group, which is optionally substituted by oxo, halogen or C 1-6 Alkyl substituted, wherein the alkyl is optionally substituted with one or more (e.g., 1 to 8) R 8 ; R 7b Each independently is C 1-8 Alkyl, C 1-8 Halogenated alkyl, C 3-10 cycloalkyl or 4- to 12-membered heterocyclic group; R8 Each is halogen, -CN, -OH, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Heteroalkyl, C 3-8 Cycloalkyl, C 1-8 Halogenated alkyl, C 1-8 Alkoxy, 4 to 12 membered heterocyclic group, C 6-10 Aryl, 5- to 12-membered heteroaryl, -N(R 8a )2、-C(O)R 8b or-C(O)OR 8a , or two R 8 optionally together forming an oxo group; R 8a are independently hydrogen, C 1-8 Alkyl or C 1-8 alkyl halide; R 8b Each independently is C 1-8 Alkyl or C 1-8 alkyl halide; Z is C(R 9 )2, C(O), O, S, S(O), S(O)2, S(O)NR 9 or NR 9 ; R 9 are independently hydrogen, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Halogenated alkyl, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclyl, or –C(O)R 9a ;and R 9a C 1-8 Alkyl, C 1-8 Halogenated alkyl, C 3-8 Cycloalkyl or 4 to 12 membered heterocyclic group, or R 9 and R 3a Optionally together to form C 3-8 cycloalkyl or 4 to 12 membered heterocyclyl, each of which is optionally substituted with one or more (eg, 1 to 8) R 6 . In one aspect, compounds of Formula I are provided: or a pharmaceutically acceptable salt, solvate, prodrug, isotopic analog or isomer thereof, wherein W 1 、W 3and W 4 CR 7 ; W 2 N or CR 7 ; The premise is that when W 2 CR 7 When a)W 4 C-CN or b)R 1a is not hydrogen, and R 1b and R 1c Together they form the warp (R 5 ) n a substituted piperidinyl ring and n is 0-9; R 1a 、R 1b and R 1c are independently hydrogen, halogen, -CN, -N3, -NO2, -OH, -SF5, -SCF3, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Heteroalkyl, C 3-8 Cycloalkyl, C 1-8 Halogenated alkyl, C 1-8 Alkoxy, C 1-8 Haloalkoxy, 4 to 12 membered heterocyclic group, C 6-10 Aryl, 5- to 12-membered heteroaryl, -N(R 1d )2、-C(O)R 1e 、 -C(O)OR 1d 、-C(O)N(R 1d )2、-NR 1d C(O)R 1e 、-NR 1d C(O)N(R 1d )2. -NR 1d C(O)OR 1d 、-OC(O)N(R 1d )2. -OC(O)OR 1d 、-SR 1d 、 -S(O)R 1e 、-S(O)2R 1e 、-S(O)3R 1d 、-S(O)N(R 1d )2、-S(O)2N(R 1d )2. -NR 1dS(O)R 1e 、-NR 1d S(O)2R 1e 、-NR 1d S(O)N(R 1d )2 or -NR 1d S(O)2N(R 1d )2, where R 1a 、R 1b and R 1c each optionally and independently substituted with 1 to 8 R 5 And R 1a 、R 1b and R 1c At least one of is not hydrogen; or R 1b and R 1c Optionally together to form C 3-10 cycloalkyl or 4 to 12 membered heterocyclyl, each of which is optionally substituted with 1 to 8 R 5 ;or R 1a 、R 1b and R 1c Optionally together to form C 5-10 cycloalkyl or 6 to 8 membered heterocyclyl, each of which is optionally substituted with 1 to 8 R 5 ;or R 1a does not exist and R 1b and R 1c Together they form C 6-10 aryl or 5- to 12-membered heteroaryl, each of which is optionally substituted with 1 to 8 R 5 ; R 1d are independently hydrogen, C 1-8 Alkyl, C 1-8 Halogenated alkyl, C 3-10 cycloalkyl or 4 to 12 membered heterocyclic group, or Two R on the same atom 1d Optionally together form a 4 to 8 membered heterocyclic group, which is optionally substituted by oxo, halogen or C 1-6 Alkyl substituted, wherein the alkyl is optionally substituted with 1 to 8 R 5 ; R 1e Each independently is C 1-8 Alkyl, C 1-8 Halogenated alkyl, C 3-10 cycloalkyl or 4- to 12-membered heterocyclic group; R 2a and R 2b are independently hydrogen, halogen, C 1-8 Alkyl, C 1-8Halogenated alkyl, C 2-8 Alkenyl or C 2-8 Alkynyl, or R 2a and R 2b Optionally together to form C 3-6 cycloalkyl or 4 to 6 membered heterocyclyl, each of which is optionally substituted with 1 to 8 R 6 ; R 3a and R 3b are independently hydrogen, halogen, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Halogenated alkyl, C 3-6 Cycloalkyl or 4 to 6 membered heterocyclyl, wherein the cycloalkyl and the heterocyclyl are optionally substituted with 1 to 8 R 6 ,or R 3a and R 3b Optionally together to form oxo, C 3-6 Cycloalkyl or 4 to 6 membered heterocyclyl, wherein the cycloalkyl and the heterocyclyl are optionally substituted with 1 to 8 R 6 ; Y is O, C(O), S, S(O), S(O)2, CR 4a R 4b or NR 4c ; R 4a and R 4b are independently hydrogen, halogen, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Halogenated alkyl, C 3-6 Cycloalkyl or 4 to 6 membered heterocyclyl, wherein the cycloalkyl and the heterocyclyl are optionally substituted with 1 to 8 R 6 ,or R 4a and R 4b Optionally together to form C 3-6 Cycloalkyl or 4 to 6 membered heterocyclyl, wherein the cycloalkyl and the heterocyclyl are optionally substituted with 1 to 8 R 6 ,or R 4a and R 1b optionally taken together to form a 4- to 12-membered heterocyclyl optionally substituted with 1 to 8 R 6 ,or R 4a and R 3a Optionally together to form C 3-8cycloalkyl or 4 to 12 membered heterocyclyl, each of which is optionally substituted with 1 to 8 R 6 ,or R 4c For hydrogen, C 1-8 Alkyl, C 1-8 Halogenated alkyl, C 3-10 Cycloalkyl or 4 to 12-membered heterocyclic group; R 5 Each independently represents halogen, -CN, -OH, -SF5, -SCF3, C 1-8 Alkyl, C 2-8 ene Base, C 2-8 Alkynyl, C 1-8 Heteroalkyl, C 3-8 Cycloalkyl, C 1-8 Alkoxy, 4 to 12 membered heterocyclic group, C 6-10 Aryl, 5- to 12-membered heteroaryl, (4- to 12-membered heterocyclyl)-(C 1-8 Heteroalkyl), (C 6-10 Aryl)(C 1-8 Heteroalkyl), (5 to 12 membered heteroaryl) (C 1-8 heteroalkyl), -N(R 5a )2、-C(O)R 5b 、-C(O)OR 5a 、-C(O)N(R 5a )2. -NR 5a C(O)R 5b 、-NR 5a C(O)N(R 5a )2、-NR 5a C(O)OR 5a 、 -OC(O)N(R 5a )2. -OC(O)OR 5a 、-SR 5a 、-S(O)R 5b 、-S(O)2R 5b 、 -S(O)3R 5a 、-S(O)N(R 5a )2、-S(O)2N(R 5a )2、-NR 5a S(O)R 5b 、 -NR 5a S(O)2R 5b 、-NR 5a S(O)N(R 5a )2 or –NR 5a S(O)2N(R 5a) 2, each of which is optionally substituted with 1 to 8 R 5c ,or Two R's 5 optionally together forming an oxo group; R 5a are independently hydrogen, C 1-8 Alkyl, C 1-8 Halogenated alkyl, C 3-10 a cycloalkyl group or a 4- to 12-membered heterocyclic group, and R 5b Each independently is C 1-8 Alkyl, C 1-8 Halogenated alkyl, C 3-10 cycloalkyl, 4- to 12-membered heterocyclyl, or 5- to 12-membered heteroaryl; R 5c are independently halogen, cyano, C 1-8 Halogenated alkyl, C 1-8 Alkyl, C 1-8 Alkoxy, C 1-8 Halogenated alkoxy, (C 1-8 Alkoxy) (C 1-8 Alkoxy), hydroxyl, SR 5d 、N(R 5d )2、N(R 5d )2(C 1-8 Alkoxy), C 3-10 Cycloalkyl or 4 to 12 membered heterocyclic group, or two R 5c optionally together forming an oxo group; R 5d are independently hydrogen, C 1-8 Alkyl or C 1-8 alkyl halide; R 6 Each is halogen, -CN, -OH, C 1-8 Alkyl, C 1-8 Heteroalkyl, C 3-8 Cycloalkyl, C 1-8 Halogenated alkyl, C 1-8 Alkoxy, 4 to 12 membered heterocyclic group, C 6-10 Aryl, 5- to 12-membered heteroaryl, -N(R 6a )2、-C(O)R 6b 、-C(O)N(R 6a )2 or -C(O)OR 6a , or two R 6 Together they form an oxo group; R 6a are independently hydrogen, C 1-8 Alkyl or C 1-8 Haloalkyl, or two R on the same atom 6aoptionally taken together to form a 4- to 6-membered heterocyclyl; R 6b Each independently is C 1-8 Alkyl or C 1-8 alkyl halide; R 7 Each is independently hydrogen, halogen, -CN, -N3, -NO2, -SF5, -SCF3, C 1-8 alkyl Base, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Heteroalkyl, C 3-8 Cycloalkyl, C 1-8 Haloalkyl, 4 to 12 membered heterocyclic group, C 6-10 Aryl, 5- to 12-membered heteroaryl, -OR 7a 、 -C(O)R 7b 、-N(R 7a )2、-C(O)OR 7a 、-C(O)N(R 7a )2、-NR 7a C(O)R 7b 、 -NR 7a C(O)N(R 7a )2、-NR 7a C(O)OR 7a 、-OC(O)N(R 7a )2. -OC(O)OR 7a 、-SR 7a 、-S(O)R 7b 、-S(O)2R 7b 、-S(O)3R 7a 、 -S(O)N(R 7a )2、-S(O)2N(R 7a )2、-NR 7a S(O)R 7b ,–NR 7a S(O)2R 7b 、 -NR 7a S(O)N(R 7a )2 or –NR 7a S(O)2N(R 7a ) 2, each of which is optionally and independently substituted with 1 to 8 R 8 ; R 7a are independently hydrogen, C 1-8 Alkyl, C 1-8Halogenated alkyl, C 3-10 cycloalkyl or 4 to 12 membered heterocyclic group, or Two R on the same atom 7a Optionally together form a 4 to 8 membered heterocyclic group, which is optionally substituted by oxo, halogen or C 1-6 Alkyl substituted, wherein the alkyl is optionally substituted with 1 to 8 R 8 ; R 7b Each independently is C 1-8 Alkyl, C 1-8 Halogenated alkyl, C 3-10 cycloalkyl or 4- to 12-membered heterocyclic group; R 8 Each is halogen, -CN, -OH, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Heteroalkyl, C 3-8 Cycloalkyl, C 1-8 Halogenated alkyl, C 1-8 Alkoxy, 4 to 12 membered heterocyclic group, C 6-10 Aryl, 5- to 12-membered heteroaryl, -N(R 8a )2、-C(O)R 8b or-C(O)OR 8a ,or Two R's 8 optionally together forming an oxo group; R 8a are independently hydrogen, C 1-8 Alkyl or C 1-8 alkyl halide; R 8b Each independently is C 1-8 Alkyl or C 1-8 alkyl halide; Z is C(R 9 )2, C(O), O, S, S(O), S(O)2, S(O)NR 9 or NR 9 ; The condition is that when Z is N, then R 3a and R 3b Not for oxygen generation; R 9 are independently hydrogen, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Halogenated alkyl, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclyl, or –C(O)R 9a ;and R 9a C 1-8 Alkyl, C 1-8 Halogenated alkyl, C 3-8 cycloalkyl or 4 to 12 membered heterocyclic group, or R 9 and R 3a Optionally together to form C 3-8 cycloalkyl or 4 to 12 membered heterocyclyl, each of which is optionally substituted with 1 to 8 R 6 . In some embodiments, when R 2a 、R 2b 、R 3a and R 3b is hydrogen and R 1a 、R 1b and R 1c When the two form a piperidinyl or pyrrolidinyl group in a compound of formula A, formula B or formula I, the piperidinyl or pyrrolidinyl group is substituted with at least one R 1d group. In some embodiments, when R 2a 、R 2b 、R 3a and R 3b When it is hydrogen, R 1a is an unsubstituted methyl group, R 1b is unsubstituted methyl, chloromethyl or unsubstituted ethyl, and R 1c is a methyl group in the compounds of formula A, formula B and formula I, wherein R 1c Substitute 1-3 R 1d . In some embodiments, when R 2a 、R 2b 、R 3a and R 3b When it is hydrogen, R 1a is unsubstituted aminomethyl or unsubstituted 2-aminopropan-2-yl, R 1b is an unsubstituted methyl group or an unsubstituted ethyl group, and R 1c is a methyl or ethyl group in the compounds of formula A, formula B and formula I, wherein R 1c Replace with 1-4 R 1d . In some embodiments, when R 3a or R 3b When R is a methyl group in the compounds of formula A, formula B and formula I, 1a 、R 1b and R 1c At least two of them are C 1-8 Alkyl, C 1-8 Heteroalkyl, C 3-8Cycloalkyl, C 6-10 aryl, 5- to 12-membered heterocyclyl, or 5- to 12-membered heteroaryl. In some embodiments, W 2 is N in the compounds of Formula A, Formula B and Formula I. In some embodiments, Z is O; Y is CR 4a R 4b ; R 2a 、R 2b 、R 3a 、R 3b 、R 4a and R 4b is H; and R 1a 、R 1b 、R 1c 、R 5 、R 7 and R 8 As defined for Formula I, Formula A or Formula B. In some embodiments, provided herein are compounds of Formula Ia in R 1a 、R 2a 、R 2b 、R 3a 、R 3b 、R 5 、R 7 、W 1 、W 2 、W 3 、W 4 , Y and Z are as defined for Formula I, Formula A or Formula B; and n is 0-9; The premise is that when W 1 、W 2 、W 3 and W 4 CR 7 When R 1a Not hydrogen. In some embodiments, provided herein are compounds of Formula Ia, wherein at least one R 5 is a 4- to 12-membered heterocyclyl or a 5- to 12-membered heteroaryl, each of which is optionally substituted with one or more (e.g., 1 to 8) R 5c In some embodiments, at least one R 5 is a 5- to 12-membered heteroaryl group, optionally substituted with one or more (e.g., 1 to 8) R 5c In some embodiments, at least one R 5 Attached to the piperidine nitrogen. In some embodiments, provided herein are compounds of Formula Ib where R 1a 、R 1b 、R 1c 、R 2a 、R 2b 、R 3a 、R 3b 、W 1 、W 2 、W 3 , Y and Z are as defined for Formula I, Formula A or Formula B. In some embodiments, W 2 is N in the compounds of Formula I, Formula Ia and Formula Ib, and W 1 、W 3 、W 4 CR 7 In some embodiments, W 2 is N in the compounds of Formula I, Formula Ia and Formula Ib, and W 3 In some embodiments, W 2 is N in the compounds of Formula I, Formula Ia and Formula Ib, and R 7 are independently hydrogen, halogen, cyano, C 1-8 Alkyl, C 1-8 Haloalkyl or C 1-8 In some embodiments, W 2 is CR in the compounds of Formula I, Formula Ia and Formula Ib 7 . In some embodiments, provided herein is a compound of Formula Ic, in R 1d 、R 1e 、R 2a 、R 2b 、R 3a 、R 3b 、R 4a 、R 5 、R 6 、W 1 、W 2 、W 3 、W 4 , Y and Z are as defined for Formula I, Formula A or Formula B; R 11a is a haloalkyl group; R 1b and R 1c are independently -CN, C 1-8 Alkyl, C 2-8Alkenyl, C 2-8 Alkynyl, C 3-8 Cycloalkyl, C 1-8 Halogenated alkyl, C 6-10 Aryl, 5- to 12-membered heteroaryl, -C(O)R 1e 、-C(O)OR 1d or -C(O)N(R 1d )2, where R 1b and R 1c are independently substituted with one or more (eg, 1 to 8) R 5 ;or R 1b and R 1c Optionally together to form C 3-10 Cycloalkyl, optionally substituted with one or more (eg, 1 to 8) R 5 ;or R 1b and R 4a Optionally taken together to form a 4- to 12-membered heterocyclyl, optionally substituted with one or more (eg, 1 to 8) R 6 ;and The premise is that the compound is not: In some embodiments, provided herein are compounds of Formula Ic, wherein W 1 、W 2 、W 3 or W 4 At least one of is nitrogen. In some embodiments, provided herein is a compound of Formula Ic, wherein R 11a It is difluoromethyl. In some embodiments, provided herein are compounds of Formula Id in R 1a 、R 1d 、R 1e 、R 2a 、R 2b 、R 3a 、R 3b 、R 4a 、R 5 、R 6 、W 1 、W 2 、W 3 、 W 4 , Y and Z are as defined for Formula I, Formula A or Formula B; W 1 、W 2 、W3 or W 4 At least one of which is nitrogen (e.g., W 1 、W 3 and W 4 CR 7 And W 2 N or CR 7 ); R 1b and R 1c are independently -CN, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-8 Cycloalkyl, C 1-8 Halogenated alkyl, C 6-10 Aryl, 5- to 12-membered heteroaryl, -C(O)R 1e 、 -C(O)OR 1d or -C(O)N(R 1d )2, where R 1b and R 1c are independently substituted with one or more (eg, 1 to 8) R 5 ;or R 1b and R 1c Optionally together to form C 3-10 Cycloalkyl, optionally substituted with one or more (eg, 1 to 8) R 5 ;or R 1b and R 4a Optionally taken together to form a 4- to 12-membered heterocyclyl, optionally substituted with one or more (eg, 1 to 8) R 6 ;or R 1a 、R 1b and R 1c Optionally together to form C 5-10 Cycloalkyl, optionally substituted with one or more (eg, 1 to 8) R 5 ;and With the proviso that the compound is not: In some embodiments, provided herein are compounds of Formula Id, wherein W 1 、W 2 、W 3 or W 4 Two or three of the CR 7 , where R 7 are independently hydrogen, halogen, -CN, -N3, -NO2, C 1-8 Alkyl, C2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Heteroalkyl, C 3-8 Cycloalkyl, C 1-8 Halogenated alkyl, C 6-10 Aryl, 5- to 12-membered heteroaryl, -OR 7a 、-C(O)R 7b 、-C(O)OR 7a 、-C(O)N(R 7a )2、-OC(O)N(R 7a )2OR-OC(O)OR 7a , each of which is optionally and independently substituted with one or more (e.g., 1 to 8) R 8 . In some embodiments, provided herein are compounds of Formula Id, wherein R 1a 、R 1b or R 1c One of them is difluoromethyl. In some embodiments, provided herein are compounds of Formula Id, wherein R 1a 、R 1b and R 1c One of them is cyclopropyl. In some embodiments, provided herein are compounds of Formula Ie in R 1b 、R 1c 、R 2a 、R 2b 、R 3a 、R 3b 、R 5 、R 7 、W 1 、W 2 、W 3 、W 4 , Y and Z are as defined for Formula I, Formula A or Formula B; Cy is C 3-8 Cycloalkyl, 4 to 12 membered heterocyclyl or 5 to 12 membered heteroaryl, wherein Cy is optionally substituted by 1 to 6 independently selected halogen, C 1-8 Alkyl and halogenated C 1-8 Substitution of alkyl groups; The premise is that when W 1 、W 2 、W 3 and W 4 CR 7 When Cy is cyclopropyl, R 1b or R 1c At least one of C1-8 Alkyl, optionally substituted with one or more (eg, 1 to 8) R 5 , and at least one R 7 Not hydrogen. In some embodiments, provided herein are compounds of Formula Ie, wherein W 1 、W 2 、W 3 or W 4 At least one of the carbon atoms is nitrogen. In some embodiments, provided herein are compounds of Formula Ie, wherein Cy is C 3-8 Cycloalkyl, optionally substituted with one or more (eg, 1 to 8) R 5 . In some embodiments, provided herein are compounds of Formula I, Formula A, Formula B, Formula Ia, Formula Ic, Formula Id, or Formula Ie, wherein W 1 Is N. In some embodiments, provided herein are compounds of Formula I, Formula A, Formula B, Formula Ia, Formula Ic, Formula Id, or Formula Ie, wherein W 2 Is N. In some embodiments, provided herein are compounds of Formula I, Formula A, Formula B, Formula Ia, Formula Ic, Formula Id, or Formula Ie, wherein W 3 Is N. In some embodiments, provided herein are compounds of Formula I, Formula A, Formula B, Formula Ia, Formula Ic, Formula Id, or Formula Ie, wherein W 3 and W 4 N and W 1 and W 2 CR 7 In some embodiments, provided herein are compounds of Formula I, Formula A, Formula B, Formula Ia, Formula Ic, Formula Id, or Formula Ie, wherein W 4 N and W 1 、W 2 and W 3 CR 7 . In some embodiments, provided herein are compounds of Formula I, wherein: W 2 is N; W 1 、W 3 and W 4 CR 7 ; Z is O; Y is CR 4a R 4b ; R 2a 、R 2b 、R 3a 、R 3b 、R 4a and R4b is H; and R 1a 、R 1b and R 1c 、R 5 、R 7 and R 8 As defined above. In some embodiments, provided herein are compounds of Formula I, Formula A, Formula B, Formula Ia, Formula Ib, Formula Ic, Formula Id, or Formula Ie, wherein R 7 are independently hydrogen, halogen, cyano, C 1-8 Alkyl, C 1-8 Haloalkyl or C 1-8 In some embodiments, at least one R 7 Halogen, C 1-6 Alkyl, C 1-6 In some embodiments, at least one R 7 is chloro, fluoro, methyl, methoxy, cyano, bromo, or triazolyl. 7 is 7-chloro, 7-methyl, 8-methoxy, 9-fluoro, 6-fluoro, 6-fluoro-9-cyano, 7-fluoro-9-cyano, 9-cyano, 6-cyano, 8-cyano, 7-fluoro-, 9-bromo-7-fluoro- or 9-triazol-2-yl. In some embodiments, at least one R 7 Halogen, C 1-6 Alkyl, C 1-6 In some embodiments, at least one R 7 is chloro, fluoro, methyl, methoxy, cyano or bromo. In some embodiments, one or two R 7 is 7-chloro, 7-methyl, 8-methoxy, 9-fluoro, 6-fluoro, 6-fluoro-9-cyano, 7-fluoro-9-cyano, 9-cyano, 6-cyano, 8-cyano, 7-fluoro- or 9-bromo-7-fluoro-. In some embodiments, provided herein are compounds of Formula If: in R 1d 、R 1e 、R 2a 、R 2b 、R 3a 、R 3b 、R 4a 、R 5 、R 6 、R 7a 、R 7b 、R 8, Y and Z are as defined for Formula I, Formula A or Formula B; R 1a 、R 1b and R 1c Independently C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Heteroalkyl, C 3-8 Cycloalkyl, C 1-8 Halogenated alkyl, C 1-8 Alkoxy, C 1-8 Halogenated alkoxy, C 6-10 Aryl, 5- to 12-membered heteroaryl, -C(O)R 1e or -C(O)N(R 1d ) 2, each of which is optionally and independently substituted with one or more (e.g., 1 to 8) R 5 ;or R 1b and R 1c Optionally together to form C 3-10 cycloalkyl or 4 to 12 membered heterocyclyl, each of which is optionally and independently substituted with one or more (eg, 1 to 8) R 5 ;or R 1b and R 4a Optionally taken together to form a 4- to 12-membered heterocyclyl, optionally substituted with one or more (eg, 1 to 8) R 6 ;or R 1a 、R 1b and R 1c Optionally together to form C 5-10 Cycloalkyl, optionally substituted with one or more (eg, 1 to 8) R 5 ;and R 7 Each independently represents hydrogen, halogen, -CN, -SF5, -SCF3, C 2-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-8 Cycloalkyl, C 1-8 Halogenated alkyl, 4 to 12 membered heterocyclic group, 5 to 12-membered heteroaryl, -C(O)R 7b 、-SR 7a 、-S(O)R 7b 、-S(O)2R 7b 、 -S(O)3R 7a 、-S(O)N(R 7a)2 or -S(O)2N(R 7a ) 2, each of which is optionally and independently substituted with one or more (e.g., 1 to 8) R 8 ; The premise is that at least one R 7 Not hydrogen. In some embodiments, provided herein is a compound of Formula If, wherein R 7 Each independently represents hydrogen, halogen, -CN, -SF5, -SCF3, C 2-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-8 Cycloalkyl, C 1-8 Haloalkyl, 5- to 12-membered heteroaryl, -C(O)R 7b 、-SR 7a 、-S(O)R 7b 、-S(O)2R 7b 、-S(O)3R 7a 、-S(O)N(R 7a )2 or -S(O)2N(R 7a ) 2, each of which is optionally and independently substituted with one or more (e.g., 1 to 8) R 8 . In some embodiments, provided herein are compounds of Formula If, wherein at least one R 7 is halogen, cyano or 5- to 12-membered heteroaryl. In some embodiments, provided herein are compounds of Formula If, wherein at least one R 7 It is chlorine, fluorine, methyl, methoxy, cyano, bromine, or triazolyl. In some embodiments, provided herein are compounds of Formula If, wherein one or both R 7 is 7-chloro, 7-methyl, 8-methoxy, 9-fluoro, 6-fluoro, 6-fluoro-9-cyano, 7-fluoro-9-cyano, 9-cyano, 6-cyano, 8-cyano, 7-fluoro-, 9-bromo-7-fluoro- or 9-triazol-2-yl. In some embodiments, provided herein are compounds wherein Z is CH2. In some embodiments, provided herein are compounds wherein Z is O. In some embodiments, provided herein are compounds wherein Y is CR 4a R 4b . In some embodiments, provided herein are compounds of Formula I, Formula A, or Formula B, wherein R 1a 、R 1b and R 1c are independently hydrogen, C1-8 Alkyl, C 1-8 Heteroalkyl, C 3-8 Cycloalkyl, C 6-10 aryl, 4- to 12-membered heterocyclyl, or 5- to 12-membered heteroaryl. In some embodiments, provided herein are compounds of Formula I, Formula A, or Formula B, wherein R 1a For hydrogen, C 1-8 Alkyl, C 1-8 Haloalkyl and C 3-8 Cycloalkyl, wherein C 1-8 Alkyl, C 1-8 Haloalkyl and C 3-8 Cycloalkyl is optionally substituted with halogen or -CN. In some embodiments, R 1a 、R 1b and R 1c At least one of the following is chloro, fluoro, methyl, -CD3, ethyl, difluoromethyl, cyanomethyl, cyclopropyl, cyclopropylmethyl, trifluoromethyl, methoxy, trifluoromethoxymethyl, 2,2,2-trifluoroethyl, 1,1-difluoroethyl, 2-fluoroethyl, trifluoromethoxy, 1-cyanoethyl, fluoromethyl, 1-hydroxycyclopropyl, difluoromethylcyclo-propyl, cyanocyclopropyl, 3,3-difluorocyclobutyl, 1,1,2,2,2-pentafluoroethyl, 1-methylethyl, methylsulfanyl, methoxymethyl, 5-fluoropyrimidin-2-ylsulfanyl, azetidin-3-yl, pyrrolidin-3-yl, cyano or hydroxy. In some embodiments, R 1a 、R 1b and R 1c At least one of is chloro, methyl, -CD3, ethyl, difluoromethyl, cyanomethyl, cyclopropyl, cyclopropylmethyl, trifluoromethyl, methoxy, trifluoromethoxymethyl, 2,2,2-trifluoroethyl or 1,1-difluoroethyl. In some embodiments, R 1a 、R 1b and R 1c Together they form bicyclo[1.1.1]pentane, azabicyclo[4.1.0]heptane, azepan-4-yl, 1,4-oxepan-7-yl, tetrahydropyran-2-yl, or 3,6-dihydro-2H-pyridin-4-yl. In some embodiments, R 1a 、R 1b and R 1c Together they form bicyclo[1.1.1]pentane. In some embodiments, R 1b and R 1c Together they form a 4- to 12-membered heterocyclyl, each of which is optionally substituted with one or more (e.g., 1 to 8) R 5 . R1b and R 1c Together they form a 4-, 5-, 6- or 7-membered heterocyclic group containing a nitrogen ring atom and optionally substituted with 1 to 8 R 5 In some embodiments, the heterocyclyl is substituted with 1 to 4 R 5 In some embodiments, at least one R 5 C 1-8 Alkyl, C 1-8 Haloalkyl, halogen, C 1-8 Halogenated alkyl, C 1-8 In some embodiments, at least one R 5 Methyl, ethyl, fluorine, chlorine, difluoromethyl, fluoromethyl, methoxy, hydroxyl, C 1-8 Haloalkyl, halogen, C 1-8 Halogenated alkyl, C 1-8 an alkoxy group or a cyano group. In some embodiments, at least one R 5 is a 4- to 12-membered heterocyclyl or a 5- to 12-membered heteroaryl, each of which is optionally substituted with 1 to 8 R 5c In some embodiments, at least one R 5 is a 5- to 12-membered heteroaryl group optionally substituted with 1 to 8 R 5c For example, R 5 It can be pyrimidin-2-yl, pyrimidin-4-yl, pyrazin-2-yl, [1,2,4]triazolo[1,5-a]pyrazin-8-yl, [1,2,4]triazolo[1,5-c]pyrimidin-5-yl, pyrazolo[1,5-a][1,3,5]triazin-4-yl, pyrazolo[1,5-a]pyrimidin-7-yl, pyridazin-4-yl, quinazolin-2-yl, imidazo[1,2-a]pyrazin-8-yl, pyrazolo[4,3-c]pyridin-6-yl, pyrrolo[3,2-d]pyrimidin-2-yl, imidazo[1,2- b] pyridazin-6-yl, pyrazolo[1,5-a]pyrimidin-7-yl, 6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl, pyridin-2-yl, pyridin-3-yl, methoxypyridazin-3-yl, 5,7-dihydrofuro[3,4-d]pyrimidin-2-yl, purin-2-yl, quinazolin-2-yl, quinoxalin-2-yl, isoquinolin-3-yl, quinolin-2-yl and 1,3,5-triazin-2-yl, or imidazo[2,1-f][1,2,4]triazin-4-yl, each of which may be optionally substituted with 1 to 8 R 5c In some embodiments, R 5 The heterocyclic group in the 5c In some embodiments, R 5cand alkyl, ... In some embodiments, R 1b and R 1c Together they form 2,2-difluorocyclobutyl, 3,3-difluorocyclobutyl, (5-fluoropyrimidin-2-yl)piperidin-4-yl, tetrahydropyran-4-yl, tetrahydropyran-3-yl, tetrahydrofuran-3-yl, cyclopropyl or cyclobutyl. Some embodiments provide a compound as described above, wherein R 1a In some embodiments, R 1a is chlorine, fluorine, methyl, ethyl, difluoromethyl, fluoromethyl, cyano or hydroxy. In some embodiments, provided herein are compounds of Formula I, Formula A, or Formula B, wherein R 2a is hydrogen and R 2b C 1-8 alkyl. In some embodiments, provided herein are compounds of Formula I, Formula A, or Formula B, wherein R 2a and R 2b For hydrogen. In some embodiments, provided herein are compounds of Formula I, Formula A, or Formula B, wherein Z is O, R 1b and R 1c C 1-8 Alkyl, C 1-8 Haloalkyl or C 3-8 Cycloalkyl, each of which is optionally substituted with halogen and / or -CN. In some embodiments, Z is CH2, R 1b and R 1c C 1-8 Alkyl, C 1-8 Haloalkyl or C 3-8 Cycloalkyl, each of which is optionally substituted with halogen and / or -CN. In some embodiments, provided herein are compounds of Formula I, Formula A, or Formula B, wherein Z is O; R 2a and R 2b is hydrogen; and R 1b and R 1c C 1-8 Alkyl, C 1-8 Haloalkyl or C 3-8 Cycloalkyl, each of which is optionally substituted with halogen and / or -CN. In some embodiments, Z is CH2; R 2a and R 2b is hydrogen; and R1b and R 1c C 1-8 Alkyl, C 1-8 Haloalkyl or C 3-8 Cycloalkyl, each of which is optionally substituted with halogen and / or -CN. In some embodiments, provided herein are compounds of Formula I, Formula A, or Formula B, wherein Z is O; R 2a is hydrogen; R 2b C 1-4 alkyl; and R 1b and R 1c C 1-8 Alkyl, C 1-8 Haloalkyl or C 3-8 Cycloalkyl, each of which is optionally substituted with halogen and / or -CN. In some such embodiments, R 2b In some embodiments, Z is CH2; R 2a is hydrogen; R 2b C 1-4 alkyl; and R 1b and R 1c C 1-8 Alkyl, C 1-8 Haloalkyl or C 3-8 Cycloalkyl, each of which is optionally substituted with halogen and / or -CN. In some such embodiments, R 2b It is a methyl group. In some embodiments, provided herein are compounds of Formula I, Formula A, or Formula B, wherein R 1b and R 1c Independently selected as C 1-8 Alkyl. For example, R 1b and R 1c R may independently be methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, branched pentyl, n-hexyl, branched hexyl, n-heptyl, branched heptyl, n-octyl or branched octyl. In some embodiments, R 1b and R 1c Independently selected as C 1-4 In some embodiments, R 1b and R 1c Each is a methyl group. In some embodiments, provided herein are compounds of Formula I, Formula A, or Formula B, wherein R 1b and R 1c Independently selected as C 1-4 Alkyl, and R 1a C 1-4 Alkyl, halo-C 1-4 Alkyl, cyano-C 1-4In some embodiments, R 1b and R 1c Independently selected as C 1-4 Alkyl, and R 1a is methyl, ethyl, difluoromethyl, cyanomethyl, 1,1-difluoroethyl, 2,2-difluoroethyl or cyclopropyl. In some embodiments, provided herein are compounds of Formula I, Formula A, or Formula B, wherein R 1b and R 1c Each is a methyl group, and R 1a C 1-4 Alkyl, halo-C 1-4 Alkyl, cyano-C 1-4 In some embodiments, R 1b and R 1c Each is a methyl group, and R 1a is methyl, ethyl, difluoromethyl, cyanomethyl, 1,1-difluoroethyl, 2,2-difluoroethyl or cyclopropyl. In some embodiments, provided herein are compounds of Formula I, Formula A, or Formula B, wherein R 1b and R 1c C 1-8 Haloalkyl or C 3-8 Cycloalkyl. For example, R 1b and R 1c R is independently chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trichloroethyl, 2,2,2-trifluoroethyl, pentachloroethyl, pentafluoroethyl, 1,1,1,3,3,3-hexachloropropyl, 1,1,1,3,3,3-hexafluoropropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl. 1b and R 1c Independently C 1-4 Haloalkyl or C 3-6 In some embodiments, R 1b and R 1c is trifluoromethyl or cyclopropyl. In some embodiments, provided herein are compounds of Formula I, Formula A, or Formula B, wherein R 1b and R 1c Independently C 1-4 Haloalkyl or C 3-6 Cycloalkyl, and R 1a In some embodiments, R 1b and R 1c is trifluoromethyl or cyclopropyl, and R 1a For hydrogen. In some embodiments, provided herein are compounds of Formula I, Formula A, or Formula B, wherein Z is O or CH2; R 2a and R 2b are independently hydrogen or C 1-4 Alkyl; R 1b and R 1c Independently selected as C 1-4 alkyl; and R 1a C 1-4 Alkyl, halo-C 1-4 Alkyl, cyano-C 1-4 In some such embodiments, Y is CR 4a R 4b ; and R 3a 、R 3b 、R 4a and R 4b are independently hydrogen or C 1-4 alkyl. In some embodiments, provided herein are compounds of Formula I, Formula A, or Formula B, wherein Z is O or CH2; R 2a and R 2b are independently hydrogen or C 1-4 Alkyl; R 1b and R 1c Independently selected as C 1-4 alkyl; and R 1a is methyl, ethyl, difluoromethyl, cyanomethyl, 1,1-difluoroethyl, 2,2-difluoroethyl or cyclopropyl. In some such embodiments, Y is CR 4a R 4b ; and R 3a 、R 3b 、R 4a and R 4b are independently hydrogen or C 1-4 alkyl. In some embodiments, provided herein are compounds of Formula I, Formula A, or Formula B, wherein Z is O or CH2; R 2a and R 2b are independently hydrogen or C 1-4 Alkyl; R 1b and R 1c Each is methyl; and R 1a C 1-4 Alkyl, halo-C 1-4 Alkyl, cyano-C 1-4 In some such embodiments, Y is CR 4a R 4b ; and R 3a 、R 3b 、R 4a and R 4bare independently hydrogen or C 1-4 alkyl. In some embodiments, provided herein are compounds of Formula I, Formula A, or Formula B, wherein Z is O or CH2; R 2a and R 2b are independently hydrogen or C 1-4 Alkyl; R 1b and R 1c Each is methyl; and R 1a is methyl, ethyl, difluoromethyl, cyanomethyl, 1,1-difluoroethyl, 2,2-difluoroethyl or cyclopropyl. In some such embodiments, Y is CR 4a R 4b ; and R 3a 、R 3b 、R 4a and R 4b are independently hydrogen or C 1-4 alkyl. In some embodiments, provided herein are compounds of Formula I, Formula A, or Formula B, wherein Z is O or CH2; R 2a and R 2b are independently hydrogen or C 1-4 Alkyl; R 1b and R 1c Independently C 1-4 Haloalkyl or C 3-6 cycloalkyl; and R 1a In some such embodiments, Y is CR 4a R 4b ; and R 3a 、R 3b 、R 4a and R 4b are independently hydrogen or C 1-4 alkyl. In some embodiments, provided herein are compounds of Formula I, Formula A, or Formula B, wherein Z is O or CH2; R 2a and R 2b are independently hydrogen or C 1-4 Alkyl; R 1b and R 1c is trifluoromethyl or cyclopropyl; and R 1a In some such embodiments, Y is CR 4a R 4b ; and R 3a 、R 3b 、R 4a and R 4b are independently hydrogen or C 1-4 alkyl. In some embodiments, provided herein are compounds of Formula I, Formula A, or Formula B, wherein R1b and R 1c Together they form a 4- to 12-membered heterocyclic group. In some embodiments, provided herein are compounds of Formula I, Formula A, or Formula B, wherein R 1a does not exist, and R 1b and R 1c Together they form C 6-10 aryl or 5- to 12-membered heteroaryl. In some embodiments, provided herein are compounds of Formula I, Formula A, or Formula B, wherein R 4a is hydrogen or methyl. In some embodiments, provided herein are compounds described by Formula I, Formula A, or Formula B, wherein Y is O. In some embodiments, provided herein are compounds of Formula I, Formula A, or Formula B, wherein R 3a and R 3b are independently hydrogen or methyl. In some embodiments, provided herein are compounds of Formula I, Formula A, or Formula B, wherein W 1 、W 2 、W 3 and W 4 CR 7 . In some embodiments, provided herein are compounds of Formula I, Formula A, or Formula B, wherein W 2 、W 3 and W 4 CR 7 ;W 2 、W 3 and W 4 At least one R 7 is hydrogen; and wherein W 1 CR 7 , where W 1 R in 7 Halogen, -CN, -N3, -NO2, -SF5, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Heteroalkyl, C 3-8 Cycloalkyl, C 1-8 Haloalkyl, 4 to 12 membered heterocyclic group, C 6-10 Aryl, 5- to 12-membered heteroaryl, -OR 7a 、-C(O)R 7b 、-N(R 7a )2、-C(O)OR 7a 、-C(O)N(R 7a )2、-NR 7a C(O)R7b 、-NR 7a C(O)N(R 7a )2、-NR 7a C(O)OR 7a 、-OC(O)N(R 7a )2. -OC(O)OR 7a 、-SR 7a 、-S(O)R 7b 、-S(O)2R 7b 、-S(O)3R 7a 、-S(O)N(R 7a )2、-S(O)2N(R 7a )2、-NR 7a S(O)R 7b ,–NR 7a S(O)2R 7b 、-NR 7a S(O)N(R 7a )2, or –NR 7a S(O)2N(R 7a ) 2, each of which is optionally and independently substituted with one or more (e.g., 1 to 8) R 8 In some such embodiments, W 1 R in 7 Halogen, -CN, -NO2, -SF5, C 1-8 Haloalkyl, -C(O)R 7b 、-C(O)OR 7a 、-S(O)R 7b 、-S(O)2R 7b or -S(O)3R 7a . In some embodiments, provided herein are compounds of Formula I, Formula A, or Formula B, wherein W 1 、W 3 and W 4 CR 7 ;W 1 、W 3 and W 4 At least one R 7 is hydrogen; and wherein W 2 CR 7 , where W 2 R in 7 Halogen, -CN, -N3, -NO2, -SF5, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Heteroalkyl, C 3-8 Cycloalkyl, C 1-8Haloalkyl, 4 to 12 membered heterocyclic group, C 6-10 Aryl, 5- to 12-membered heteroaryl, -OR 7a 、-C(O)R 7b 、-N(R 7a )2、-C(O)OR 7a 、-C(O)N(R 7a )2、-NR 7a C(O)R 7b 、-NR 7a C(O)N(R 7a )2、-NR 7a C(O)OR 7a 、-OC(O)N(R 7a )2. -OC(O)OR 7a 、-SR 7a 、-S(O)R 7b 、-S(O)2R 7b 、-S(O)3R 7a 、-S(O)N(R 7a )2、-S(O)2N(R 7a )2、-NR 7a S(O)R 7b ,–NR 7a S(O)2R 7b 、-NR 7a S(O)N(R 7a )2 or –NR 7a S(O)2N(R 7a ) 2, each of which is optionally and independently substituted with one or more (e.g., 1 to 8) R 8 In some such embodiments, W 2 R in 7 Halogen, -CN, -NO2, -SF5, C 1-8 Haloalkyl, -C(O)R 7b 、-C(O)OR 7a 、-S(O)R 7b 、-S(O)2R 7b or -S(O)3R 7a . In some embodiments, provided herein are compounds of Formula I, Formula A, or Formula B, wherein W 1 、W 2 and W 4 CR 7 ;W 1 、W 2 and W 4 At least one R 7 is hydrogen; and wherein W 3 CR7 , where W 3 R in 7 Halogen, -CN, -N3, -NO2, -SF5, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Heteroalkyl, C 3-8 Cycloalkyl, C 1-8 Haloalkyl, 4 to 12 membered heterocyclic group, C 6-10 Aryl, 5- to 12-membered heteroaryl, -OR 7a 、-C(O)R 7b 、-N(R 7a )2、-C(O)OR 7a 、-C(O)N(R 7a )2、-NR 7a C(O)R 7b 、-NR 7a C(O)N(R 7a )2、-NR 7a C(O)OR 7a 、-OC(O)N(R 7a )2. -OC(O)OR 7a 、-SR 7a 、-S(O)R 7b 、-S(O)2R 7b 、-S(O)3R 7a 、-S(O)N(R 7a )2、-S(O)2N(R 7a )2、-NR 7a S(O)R 7b ,–NR 7a S(O)2R 7b 、-NR 7a S(O)N(R 7a )2 or –NR 7a S(O)2N(R 7a ) 2, each of which is optionally and independently substituted with one or more (e.g., 1 to 8) R 8 In some such embodiments, W 3 R in 7 Halogen, -CN, -NO2, -SF5, C 1-8 Haloalkyl, -C(O)R 7b 、-C(O)OR 7a 、-S(O)R 7b 、-S(O)2R 7b or -S(O)3R 7a . In some embodiments, provided herein are compounds of Formula I, Formula A, or Formula B, wherein W 1 、W 2 and W 3 CR 7 ;W 1 、W 2 and W 3 At least one R 7 is hydrogen; and wherein W 4 CR 7 , where W 4 R in 7 Halogen, -CN, -N3, -NO2, -SF5, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Heteroalkyl, C 3-8 Cycloalkyl, C 1-8 Haloalkyl, 4 to 12 membered heterocyclic group, C 6-10 Aryl, 5- to 12-membered heteroaryl, -OR 7a 、-C(O)R 7b 、-N(R 7a )2、-C(O)OR 7a 、-C(O)N(R 7a )2、-NR 7a C(O)R 7b 、-NR 7a C(O)N(R 7a )2、-NR 7a C(O)OR 7a 、-OC(O)N(R 7a )2. -OC(O)OR 7a 、-SR 7a 、-S(O)R 7b 、-S(O)2R 7b 、-S(O)3R 7a 、-S(O)N(R 7a )2、-S(O)2N(R 7a )2、-NR 7a S(O)R 7b ,–NR 7a S(O)2R 7b 、-NR 7a S(O)N(R 7a )2 or –NR 7a S(O)2N(R 7a ) 2, each of which is optionally and independently substituted with one or more (e.g., 1 to 8) R 8 In some such embodiments, W 4 R in7 Halogen, -CN, -NO2, -SF5, C 1-8 Haloalkyl, -C(O)R 7b 、-C(O)OR 7a 、-S(O)R 7b 、-S(O)2R 7b or -S(O)3R 7a . In some embodiments, provided herein are compounds of Formula I, Formula A, or Formula B, wherein W 1 、W 2 、W 3 and W 4 CR 7 ;W 2 、W 3 and W 4 R in 7 Each independently represents hydrogen, halogen, -CN, -NO2, -SF5, C 1-8 Haloalkyl, -C(O)R 7b 、-C(O)OR 7a 、-S(O)R 7b 、-S(O)2R 7b or -S(O)3R 7a ; and wherein W 1 R in 7 Halogen, -CN, -NO2, -SF5, C 1-8 Haloalkyl, -C(O)R 7b 、-C(O)OR 7a 、-S(O)R 7b 、-S(O)2R 7b or -S(O)3R 7a . In some embodiments, provided herein are compounds of Formula I, Formula A, or Formula B, wherein W 1 、W 2 、W 3 and W 4 CR 7 ;W 1 、W 3 and W 4 R in 7 Each independently represents hydrogen, halogen, -CN, -NO2, -SF5, C 1-8 Haloalkyl, -C(O)R 7b 、-C(O)OR 7a 、-S(O)R 7b 、-S(O)2R 7b or -S(O)3R 7a ; and wherein W 2 R in7 Halogen, -CN, -NO2, -SF5, C 1-8 Haloalkyl, -C(O)R 7b 、-C(O)OR 7a 、-S(O)R 7b 、-S(O)2R 7b or -S(O)3R 7a . In some embodiments, provided herein are compounds of Formula I, Formula A, or Formula B, wherein W 1 、W 2 、W 3 and W 4 CR 7 ;W 1 、W 2 and W 4 R in 7 Each independently represents hydrogen, halogen, -CN, -NO2, -SF5, C 1-8 Haloalkyl, -C(O)R 7b 、-C(O)OR 7a 、-S(O)R 7b 、-S(O)2R 7b or -S(O)3R 7a ; and wherein W 3 R in 7 Halogen, -CN, -NO2, -SF5, C 1-8 Haloalkyl, -C(O)R 7b 、-C(O)OR 7a 、-S(O)R 7b 、-S(O)2R 7b or -S(O)3R 7a . In some embodiments, provided herein are compounds of Formula I, Formula A, or Formula B, wherein W 1 、W 2 、W 3 and W 4 CR 7 ;W 1 、W 2 and W 3 R in 7 Each independently represents hydrogen, halogen, -CN, -NO2, -SF5, C 1-8 Haloalkyl, -C(O)R 7b 、-C(O)OR 7a 、-S(O)R 7b 、-S(O)2R 7b or -S(O)3R 7a ; and wherein W 4 R in7 Halogen, -CN, -NO2, -SF5, C 1-8 Haloalkyl, -C(O)R 7b 、-C(O)OR 7a 、-S(O)R 7b 、-S(O)2R 7b or -S(O)3R 7a . In some embodiments, provided herein are compounds of Formula A or Formula B, wherein W 1 N and W 2 、W 3 and W 4 CR 7 In some such embodiments, W 2 、W 3 and W 4 R in 7 Each independently represents hydrogen, halogen, -CN, -NO2, -SF5, C 1-8 Haloalkyl, -C(O)R 7b 、-C(O)OR 7a 、-S(O)R 7b 、-S(O)2R 7b or -S(O)3R 7a . In some embodiments, provided herein are compounds of Formula I, Formula A, or Formula B, wherein W 2 N and W 1 、W 3 and W 4 CR 7 In some such embodiments, W 1 、W 3 and W 4 Each R 7 are independently hydrogen, halogen, -CN, -NO2, -SF5, C 1-8 Haloalkyl, -C(O)R 7b 、-C(O)OR 7a 、-S(O)R 7b 、-S(O)2R 7b or -S(O)3R 7a . In some embodiments, provided herein are compounds of Formula A or Formula B, wherein W 3 N and W 1 、W 2 and W 4 CR 7 In some such embodiments, W 1 、W 2 and W 4Each R 7 are independently hydrogen, halogen, -CN, -NO2, -SF5, C 1-8 Haloalkyl, -C(O)R 7b 、-C(O)OR 7a 、-S(O)R 7b 、-S(O)2R 7b or -S(O)3R 7a . In some embodiments, provided herein are compounds of Formula A or Formula B, wherein W 1 、W 2 and W 3 CR 7 And W 4 is N. In some such embodiments, W 1 、W 2 and W 3 Each R 7 are independently hydrogen, halogen, -CN, -NO2, -SF5, C 1-8 Haloalkyl, -C(O)R 7b 、-C(O)OR 7a 、-S(O)R 7b 、-S(O)2R 7b or -S(O)3R 7a . In some embodiments, provided herein are compounds of Formula A or Formula B, wherein W 4 CR 7 And W 4 R 7 Is CN or halogen. In some such embodiments, W 4 In some embodiments of this type, W 4 is C-CN, and W 2 is N. In some embodiments, W 4 C-CN, W 2 is N, and Z is O or S. In some embodiments, W 4 is CX, wherein X is halogen; and W 2 is N. In some embodiments, W 4 CX, wherein X is halogen; W 2 is N; and Z is O or S. In some such embodiments, Z is O. In some such embodiments, W 4 is C-CN; and W 2 Is CH or CX, wherein X is halogen. In some embodiments, W 4 C-CN, W 2is CH or CX, wherein X is halogen; and Z is O or S. In some embodiments, W 4 is CX, wherein X is halogen; and W 2 Is CH or CX, wherein X is halogen. In some embodiments, W 4 CX, wherein X is halogen; W 2 is CH or CX, wherein X is halogen; and Z is O or S. In some such embodiments, Z is O. In some embodiments, provided herein are compounds of Formula A or Formula B, wherein W 1 N; R 1a exists; and R 1a 、R 1b and R 1c At least two of them are not hydrogen. In some embodiments, provided herein are compounds of Formula I, wherein R 7 are independently hydrogen, halogen, cyano, C 1-8 Alkyl, C 1-8 Haloalkyl or C 1-8 Alkoxy. In some embodiments, provided herein is a compound selected from Table 1 or Examples 258-309, or a pharmaceutically acceptable salt, solvate, prodrug, isotopic analog, or isomer thereof. III. Synthesis of Compounds Compounds can be prepared using methods disclosed herein and conventional modifications thereof, which will be apparent in view of methods disclosed herein and well-known in the art. In addition to the teachings herein, conventional and well-known synthetic methods can be used. The synthesis of representative compounds as described herein can be carried out as described in the following examples. If feasible, reagents can be purchased commercially from, for example, SigmaAldrich or other chemical suppliers. It should be understood that, in the case of providing typical or preferred process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.), other process conditions may also be used unless otherwise indicated. Optimal reaction conditions may vary with the specific reactants or solvents used, but such conditions may be determined by conventional optimization procedures by those skilled in the art. In addition, it will be apparent to those skilled in the art that conventional protecting groups may be required to prevent certain functional groups from undergoing undesirable reactions. Suitable protecting groups for various functional groups and suitable conditions for protecting and deprotecting specific functional groups are well known in the art. For example, many protecting groups are described in Wuts, PGM, Greene, TW, & Greene, TW (2006). Greene's protective groups in organic synthesis. Hoboken, NJ, Wiley-Interscience and references cited therein. In addition, the compounds of the present invention may contain one or more chiral centers. Therefore, if desired, these compounds can be prepared or separated into pure stereoisomers, i.e., as individual enantiomers or diastereomers or mixtures enriched in stereoisomers. Unless otherwise indicated, all of these stereoisomers (and enriched mixtures) are included within the scope of this disclosure. For example, pure stereoisomers (or enriched mixtures) can be prepared using optically active starting materials or stereoselective reagents well known in the art. Alternatively, for example, a racemic mixture of such compounds can be separated using chiral column chromatography, chiral resolving agents, etc. The starting materials for the following reactions are generally known compounds or can be prepared by known methods or obvious modifications thereof. For example, many starting materials are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Bachem (Torrance, California, USA), Emka-Chemce or Sigma (St. Louis, Missouri, USA). Others can be prepared by procedures described in standard reference books, or obvious modifications thereof, such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15 (John Wiley, and Sons, 1991), Rodd's Chemistry of Carbon Compounds, Volumes 1-5, and Supplementals (Elsevier Science Publishers, 1989) Organic Reactions, Volumes 1-40 (John Wiley, and Sons, 1991), March's Advanced Organic Chemistry, (John Wiley, Sons, 5th Edition, 2001), and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989). The terms "solvent," "inert organic solvent," or "inert solvent" refer to solvents that are inert under the reaction conditions described in conjunction therewith (including, for example, benzene, toluene, acetonitrile, tetrahydrofuran ("THF"), dimethylformamide ("DMF"), chloroform, methylene chloride (or dichloromethane), diethyl ether, methanol, pyridine, etc.). Unless otherwise specified, the solvents used in the reactions of the present disclosure are inert organic solvents, and the reactions are carried out under an inert gas, preferably nitrogen. Scheme 1 shows the synthesis of compounds of Formula I, wherein Q is a hydroxyl group (ie, -OH) or a leaving group (eg, chloride) and W 1 、W 2 、W 3 、W 4 , Y, Z, R 1a 、R 1b 、R 1c 、R 2a 、R 2b 、R 3a and R 3bAs defined herein. Solution 1 Compounds of Formula I can be formed by contacting an appropriately substituted amine 1-a with compound 1-b under standard amide bond forming reaction conditions as shown in Scheme 1. When Q is hydroxy, an activating agent may be used to facilitate the reaction. Suitable coupling agents (or activators) are known in the art and include, for example, carbodiimides (e.g., N,N′-dicyclohexylcarbodiimide (DCC), N,N′-dicyclopentylcarbodiimide, N,N′-diisopropylcarbodiimide (DIC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), N-tert-butyl-N-methylcarbodiimide (BMC), N-tert-butyl-N-ethylcarbodiimide (BEC), 1,3-bis(2,2-dimethyl-1,3-dioxolan-4-ylmethyl)carbodiimide (BDDC), etc.), phosphonium salts (HOBt, PyBOP, HOAt, etc.), ammonium / uronium salts (e.g., tetramethylammonium salts, bispyrrolidino aminium salts, bispiperidino aminium salts), etc. salts), imidazolium uronium salts, pyrimidinium uronium salts, uronium salts derived from N,N,N′-trimethyl-N′-phenylurea, morpholinyl-based ammonium / uronium coupling reagents, antimonate uronium salts, etc.), or organophosphorus reagents (e.g., phosphinic acid and phosphoric acid derivatives), or organosulfur reagents (e.g., sulfonic acid derivatives), triazine coupling reagents (e.g., 2-chloro-4,6-dimethoxy-1,3,5-triazine, 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride, 4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methylmorpholinium chloride, oxazine-2-yl)-4-methylmorpholinium tetrafluoroborate, etc.), pyridinium coupling reagents (e.g., Mukaiyama reagent, pyridinium tetrafluoroborate coupling reagents, etc.), polymer-supported reagents (e.g., polymer-bound carbodiimide, polymer-bound TBTU, polymer-bound 2,4,6-trichloro-1,3,5-triazine, polymer-bound HOBt, polymer-bound HOSu, polymer-bound IIDQ, polymer-bound EEDQ, etc.), etc. (see, for example, El-Faham, et al. Chem. Rev., 2011, 111(11):6557–6602; Han, et al. Tetrahedron, 2004, 60:2447-2467).Carboxylic acids in which Q is -OH can also be converted to activated derivatives in which Q is a leaving group; activated derivatives include, but are not limited to, anhydrides (including symmetrical, mixed, or cyclic anhydrides), activated esters (e.g., p-nitrophenyl esters, pentafluorophenyl esters, N-succinimidyl esters, etc.), acylazoles (e.g., acyl imidazoles, which are prepared using carbonyldiimidazole, etc.), acyl azides, and acid halides (e.g., acid chlorides). Compounds of Formula 1-a and 1-b used in Scheme 1 can be obtained as described in the Schemes and Examples provided herein or from conventional synthetic methods known in the art using appropriate starting materials. and benzoxazepines Starting materials are commercially available and can be used in the methods described herein. Examples of such starting materials include, but are not limited to: 1,2,4,5-tetrahydro-3,2-benzoxazepine 2,3,4,5-Tetrahydro-1,4-benzoxazepine 2,3,4,5-Tetrahydro-1H-2-benzodiazepine 2,3,4,5-Tetrahydro-1,4-benzothiazepine 2,3,4,5-Tetrahydropyrido[3,4-f][1,4]oxazepine -9-carbonitrile; 2,3,4,5-tetrahydro-1,4-benzoxazepine -6-carbonitrile; 2,3,4,5-tetrahydro-1,4-benzoxazepine -9-carbonitrile; 2-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepine 3-Methyl-2,3,4,5-tetrahydro-1,4-benzoxazepine 4-Benzyl-9-bromo-6-fluoro-2,3-dihydro-1,4-benzoxazepine -5-ketone; 6-fluoro-2,3,4,5-tetrahydro-1,4-benzoxazepine 7-Chloro-2,3,4,5-tetrahydro-1,4-benzoxazepine 7-Fluoro-2,3,4,5-tetrahydro-1,4-benzoxazepine 7-Methyl-2,3,4,5-tetrahydro-1,4-benzoxazepine 8-Methoxy-2,3,4,5-tetrahydro-1,4-benzoxazepine 9-Bromo-7-fluoro-2,3,4,5-tetrahydro-1,4-benzoxazepine Hydrochloride; 9-Fluoro-2,3,4,5-tetrahydro-1,4-benzoxazepine and salts thereof (eg, hydrochloride, etc.). In some embodiments, the bicyclic amine used for acylation with compound 1-b is prepared as summarized in Scheme 2, wherein Q is a hydroxyl group (ie, -OH) or a leaving group (eg, chloride); V is hydrogen or an amine protecting group; Z 1 is the first reactive functional group; Z 2 is a second reactive functional group; and W 1 、W 2 、W 3 、W 4 , Y, Z, R 1a 、R 1b 、R 1c 、R 2a 、R 2b 、R 3a and R 3b As defined herein. Option 2 Compound 2-a (for example, Y is CR 4a R 4b A primary or secondary amine (e.g., a primary or secondary amine, or a hydroxylamine where Y is O) can be used for the reductive amination of ketone or aldehyde 2-b to provide amine 2-c, or compound 2-a can be used for acylation with compound 2-e to provide amide 2-f. The reductive amination to form amine 2-c is typically performed with sodium borohydride, sodium cyanoborohydride, or other suitable reducing agents. As described in Scheme 1, the acylation step to form amide 2-f can be performed with a carboxylic acid 2-e (where Q is OH) or an activated carboxylic acid derivative 2-e (where Q is a leaving group). The amide 2-f can then be reduced to amine 2-g using a reducing agent such as borane, lithium aluminum hydride, or a silane reagent (e.g., diethylsilane, 1,1,3,3-tetramethyldisiloxane, etc.) in the presence or absence of a suitable catalyst (e.g., zinc acetate, diethylzinc, tris(pentafluorophenyl)boron, etc.). Amines 2-c and 2-g contain complementary reactive groups Z 1 and Z 2 , which can react in a cyclization step to provide bicyclic amines 2-d and 2-h. For example, alcohol Z 1 The group can react with a halide Z in the presence of a base (such as sodium hydride, lithium diisopropylamide, etc.) 2 Those skilled in the art will appreciate that Z may be protected with a suitable protecting group (e.g. as a silyl ether such as TBSO) prior to the cyclization step. 1 groups to prevent unwanted reactions. 2The protecting group is removed before the cyclization step in Scheme 2 (e.g., with an acid such as HCl). Similarly, as shown in Scheme 1, amine 2-a may contain a protecting group V (e.g., benzyloxycarbonyl) to prevent undesirable reactions before acylation. The protecting group V may be removed before acylation with a carboxylic acid or an activated derivative thereof (e.g., by hydrogenation). By using conventional synthetic methods known in the art (e.g., by halogenation, reduction, oxidation, olefination, alkylation, etc.), before or after the cyclization step in Scheme 2, W 1 、W 2 、W 3 、W 4 , Y, R 3a and R 3 The desired functional groups are installed. In some embodiments, a method for preparing a compound of Formula A or a salt thereof is provided. The method comprises: The compound described by formula IIa and the compound described in formula IIb, contacting under conditions sufficient to form the compound of formula IIc Converting the compound of formula IIc into the compound of formula IId and the compound of formula IId and the compound of formula IIe contacting under conditions sufficient to form the compound described by Formula A; in: Z 1 is an optionally protected first reactive group; Z 2 is an optionally protected second reactive group; Q is -OH or a leaving group; and R 1a 、R 1b 、R 1c 、R 2a 、R 2b 、R 3a 、R 3b 、W 1 、W 2 、W 3 、W 4 , Y and Z are as defined above. In some embodiments, Z1 is an optionally protected alcohol. 2 is halogen. In some embodiments, the compound of Formula IIc is converted to the compound of Formula IId, comprising contacting the compound of Formula IIc with a base (e.g., sodium hydride, lithium diisopropylamide, potassium tert-butoxide, potassium carbonate, etc.). It will be understood by those skilled in the art that the method for preparing the compound of Formula A can also be used to prepare compounds of Formula B and / or Formula I. Also provided herein are intermediates for the synthesis of kinase inhibitors, including compounds of Formula IId as described above. In some embodiments, compounds of Formula IId are provided, wherein W 2 is N. In some such embodiments, W 1 、W 3 and W 4 CR 7 In some embodiments, W 2 N, W 1 CH, W 3 is CH, and W 4 CR 7 In some embodiments, a compound of Formula IId is provided, wherein W 2 N, W 1 CH, W 3 is CH, and W 4 is C(CN); in some such embodiments, Y is CH2 and Z is O. In some embodiments, the compound described by Formula IId is: or a salt thereof. In some embodiments, the salt is a hydrochloride salt. In some embodiments, the salt is a dihydrochloride salt. IV. Pharmaceutical Compositions The compounds provided herein are generally administered in the form of pharmaceutical compositions. Therefore, also provided herein are pharmaceutical compositions containing one or more compounds described herein or their pharmaceutically acceptable salts, tautomers, stereoisomers, mixtures of stereoisomers, prodrugs or deuterated analogs and one or more pharmaceutically acceptable vehicles, the vehicle being selected from carriers, adjuvants and excipients. Suitable pharmaceutically acceptable vehicles may include, for example, inert solid diluents and fillers, diluents (including sterile aqueous solutions and various organic solvents), penetration enhancers, solubilizers and adjuvants. Such compositions are prepared in a manner well known in the pharmaceutical field. The pharmaceutical compositions of the present disclosure can be specially formulated for administration in solid or liquid forms, including those suitable for the following routes: oral administration, for example, a drench (aqueous or non-aqueous solution or suspension), a tablet, for example, intended for oral, sublingual and systemic absorption, a bolus, a powder, a granule, a paste for application to the tongue; parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection, for example, a sterile solution or suspension or a sustained-release formulation; topical application, for example, to the skin in the form of a cream, ointment or controlled-release patch or spray; intravaginally or intrarectally, for example, in the form of a pessary, cream or foam; sublingually; ophthalmically; transdermally; or nasally, pulmonary and to other mucosal surfaces. As used herein, the phrase "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, or other problems or complications, and at a reasonable benefit / risk ratio. As used herein, the phrase "pharmaceutically acceptable carrier" means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, or solvent encapsulating material, that is involved in transferring or transporting the subject compound from one organ or part of the body to another organ or part of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of substances that can be used as pharmaceutically acceptable carriers include: sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; surfactants such as polysorbate 80 (i.e., Tween 80); powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol; polyols such as glycerol, sorbitol, mannitol, and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol; pH buffered solutions; polyesters, polycarbonates, and / or polyanhydrides; and other nontoxic, compatible substances employed in pharmaceutical formulations. Examples of such formulations include, but are not limited to, DMSO, 10 mM DMSO, 8% hydroxypropyl-β-cyclodextrin in PBS, propylene glycol, and the like. For example, in certain embodiments, the compounds of the present disclosure can be used as a 4 mM solution in 8% hydroxypropyl-β-cyclodextrin in PBS for parenteral administration. In certain other embodiments, the compounds of the present disclosure can be used as a suspension in 0.5% CMC aqueous solution containing 0.1% Tween 80. As described herein, some embodiments of the compounds of the present invention may include basic functional groups, such as amino or methylamino (NCH 3 ), so that pharmaceutically acceptable salts can be formed with pharmaceutically acceptable acid. In this respect, the term "pharmaceutically acceptable salt" refers to the relatively nontoxic inorganic and organic acid addition salts of the compounds of the present invention. These salts can be prepared in situ during administration of a drug delivery vehicle or dosage form manufacturing process, or by reacting the compounds of the present invention with a suitable organic or inorganic acid in the form of a free alkali after purification, and separating the formed salt in subsequent purification. Representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, toluenesulfonate, citrate, maleate, fumarate, succinate, tartrate, naphthoate, mesylate, glucoheptonate, lactobionate and laurylsulfonate etc. Pharmaceutically acceptable salts of the subject compounds include conventional non-toxic salts or quaternary ammonium salts of the compounds, for example, from non-toxic organic or inorganic acids. For example, such conventional non-toxic salts include salts derived from inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and the like; and salts prepared from organic acids, such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isosulfonic acid, and the like. In other cases, the compounds of the present disclosure may contain one or more acidic functional groups and are therefore capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable bases. In these cases, the term "pharmaceutically acceptable salt" refers to relatively non-toxic inorganic and organic base addition salts of the compounds of the present disclosure. These salts can also be prepared during the administration of a drug delivery vehicle or dosage form manufacturing process, or by reacting the purified free acid form of the compound with a suitable base (e.g., a hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation in situ), with ammonia or a pharmaceutically acceptable organic primary, secondary or tertiary amine, respectively. Representative alkali metal or alkaline earth metal salts include salts of lithium, sodium, potassium, calcium, magnesium and aluminum, etc. Representative organic amine salts for forming base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, etc. Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions. Examples of pharmaceutically acceptable antioxidants include: water-soluble antioxidants, such as ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, etc.; oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, α-tocopherol, etc.; and metal chelators, such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, etc. Preparations of the present disclosure include those suitable for oral, nasal, topical (including oral and sublingual), rectal, vaginal and / or parenteral administration. The preparations can be conveniently present in unit dosage form and can be prepared by any method known in the pharmaceutical field. The amount of the active ingredient that can be combined with a carrier material to produce a single dosage form will vary according to the host being treated, the specific mode of administration. The amount of the active ingredient that can be combined with a carrier material to produce a single dosage form will generally be the amount of the compound that produces the therapeutic effect. Typically, this amount is about 1% to about 99% of the active ingredient, preferably about 5% to about 70%, and most preferably about 10% to about 30%. In certain embodiments, the formulations of the present disclosure include one or more of the following: cyclodextrins, liposomes, micelle formers, e.g., bile acids, and polymeric carriers, e.g., polyesters and polyanhydrides; and compounds of the present disclosure. In certain embodiments, the formulations described above render the compounds of the present disclosure orally bioavailable. The method for preparing these preparations or compositions comprises the step of associating the compound of the present disclosure with a carrier and optionally one or more auxiliary ingredients. Generally, the preparation is prepared by uniformly and intimately associating the compound of the present disclosure with a liquid carrier or a finely divided solid carrier or both, and then shaping the product as desired. Formulations suitable for oral administration of the present invention may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored base, typically sucrose and acacia or tragacanth), powders, granules, or solutions or suspensions in aqueous or non-aqueous liquids, or as oil-in-water or water-in-oil liquid emulsions, or as elixirs or syrups or lozenges (using an inert base, such as gelatin and glycerin or sucrose and acacia), and / or as lotions, etc., each containing a predetermined amount of a compound of the present invention as the active ingredient. The compounds of the present invention may also be administered as a bolus, electuary, or paste. In the solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules, etc.) of the present disclosure, the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate and / or any of the following: fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol and / or silicic acid; binders, such as carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and / or acacia; humectants, such as glycerol; disintegrants, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; solution retarding agents, such as paraffin hydrocarbons; absorption accelerators, such as quaternary ammonium compounds; wetting agents, such as cetyl alcohol, glyceryl monostearate and nonionic surfactants; absorbents, such as kaolin and bentonite; lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate and mixtures thereof; and coloring agents. In the case of capsules, tablets and pills, the pharmaceutical compositions may also contain buffering agents.Solid compositions of a similar type may also be employed as fillers in soft and hard shell gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols. Tablets can be made by compression or molding, optionally with one or more auxiliary ingredients. Compressed tablets can be prepared using a binder (e.g., gelatin or hydroxypropyl methylcellulose), a lubricant, an inert diluent, a preservative, a disintegrant (e.g., sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), a surfactant, or a dispersant. Molded tablets can be prepared in a suitable machine in which a mixture of the powdered compound is moistened with an inert liquid diluent. Tablets and other solid dosage forms of the pharmaceutical compositions of the present disclosure, such as dragees, capsules, pills, and granules, may be optionally scored or prepared with coatings and shells, such as enteric coatings and other coatings well-known in the field of pharmaceutical formulations. For example, in order to provide slow or controlled release of the active ingredient therein, they may also be formulated using hydroxypropylmethylcellulose (to provide the desired release characteristics), other polymer matrices, liposomes, and / or microspheres in varying proportions. They may be formulated for rapid release, for example, by freeze drying. For example, they may be filtered through a filter that retains bacteria or sterilized by incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved in sterile water or some other sterile injection medium immediately before use. These compositions may also optionally contain an opacifier and may be compositions that release the active ingredient only or preferentially in certain parts of the gastrointestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. The active ingredient may also be in microencapsulated form, if appropriate, containing one or more of the above-mentioned excipients. Liquid dosage forms for oral administration of the compounds of the present disclosure include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active ingredient, the liquid dosage form may also contain inert diluents commonly used in the art, for example, water or other solvents, solubilizers, and emulsifiers, for example, ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofuranol, polyethylene glycol, and fatty acid esters of sorbitan and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents. Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof. Formulations of the pharmaceutical compositions of the present disclosure for rectal or vaginal administration may be presented as suppositories, which may be prepared by mixing one or more compounds of the present disclosure with one or more suitable non-irritating excipients or carriers including, for example, cocoa butter, polyethylene glycol, suppository waxes or salicylates, which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity to release the active compound. Formulations of the present disclosure suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate. Dosage forms for topical or transdermal administration of the compounds of the present disclosure include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compound can be mixed under sterile conditions with a pharmaceutically acceptable carrier and any preservatives, buffers or propellants that may be required. Ointments, pastes, creams and gels may contain, in addition to the active compounds of this disclosure, excipients such as animal and vegetable fats, oils, waxes, paraffin hydrocarbons, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof. Powders and sprays may contain, in addition to a compound of this disclosure, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate and polyamide powder, or mixtures of these substances. Sprays may also contain customary propellants, such as chlorofluorocarbons and volatile unsubstituted hydrocarbons, such as butane and propane. Transdermal patches have the additional advantage of controlling the delivery of the disclosed compounds to the body. Such dosage forms can be prepared by dissolving or dispersing the compound in a suitable medium. Absorption enhancers can also be used to increase the circulation of the compound through the skin. Providing a rate-controlling membrane or dispersing the compound in a polymer matrix or gel can control the rate of such circulation. Ophthalmic formulations, eye ointments, powders, solutions, etc. are also contemplated as being within the scope of this disclosure. Pharmaceutical compositions of the present disclosure suitable for parenteral administration comprise a combination of one or more compounds of the present disclosure and one or more pharmaceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders, which may be reconstituted into sterile injectable solutions or dispersions just before use and which may contain sugars, alcohols, antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient, or suspending or thickening agents. Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions of the present disclosure include water, ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, etc.) and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. Suitable fluidity can be maintained, for example, by the use of coating materials (e.g., lecithin), by maintaining the desired particle size in the case of dispersions, and by the use of surfactants. These compositions may also include adjuvants such as preservatives, wetting agents, emulsifiers, and dispersants. Various antibacterial and antifungal agents such as parabens, chlorobutanol, phenylsorbic acid, etc. may be added to ensure that the effects of microorganisms on the subject compound are prevented. It may also be necessary to include isotonic agents such as sugars, sodium chloride, etc., which are added to the composition. Additionally, the absorption of the injectable pharmaceutical form may be prolonged by including agents that delay absorption such as aluminum monostearate and gelatin. In some cases, to prolong the effect of a drug, it is necessary to slow the absorption of a drug injected subcutaneously or intramuscularly. This can be achieved by using a liquid suspension of a poorly water-soluble crystalline or amorphous substance. The drug's absorption rate then depends on its dissolution rate, which in turn depends on the size and crystalline form of the crystals. Alternatively, delayed absorption of parenteral drug forms can be achieved by dissolving or suspending the drug in an oily vehicle. Injectable storage forms are prepared by forming a microencapsulated matrix of the subject compound in a biodegradable polymer (e.g., polylactide-polyglycolide). According to the ratio of the drug to the polymer and the property of the specific polymer used, the release rate of the drug can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Injectable preparations for storage can also be prepared by entrapping the drug in a liposome or microemulsion compatible with body tissues. V. Treatment Methods In other embodiments, provided herein are methods for treating a disease or condition mediated by receptor-interacting protein kinase 1. The methods comprise administering to a subject in need thereof a therapeutically effective amount of a compound or pharmaceutical composition as described herein. In some embodiments, the disease or condition mediated by receptor-interacting protein kinase 1 is trauma, ischemia, stroke, myocardial infarction, infection, Gaucher disease, Krabbe disease, sepsis, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease, dementia associated with human immunodeficiency virus, retinal degenerative disease, glaucoma, age-related macular degeneration, rheumatoid arthritis, psoriasis, psoriatic arthritis, or inflammatory bowel disease. As used herein, the term "trauma" refers to any physical injury to the body caused by violence, accidents, fractures, etc. The term "ischemia" refers to a cardiovascular disease characterized by a low oxygen state or insufficient blood supply leading to tissue hypoxia, usually due to blockage of arterial blood supply. The term "stroke" refers to a cardiovascular disease caused by a blood clot or hemorrhage in the brain, most commonly caused by interruption of blood flow in the brain caused by a blood clot blocking a blood vessel, and in certain embodiments of the present disclosure, the term "stroke" refers to an ischemic stroke or a hemorrhagic stroke. The term "myocardial infarction" refers to a cardiovascular disease characterized by local necrosis caused by obstruction of blood supply. The methods described herein can be applied to cell populations in vivo or in vitro. "In vivo" means within a living individual, such as an animal or human. In this context, the methods described herein can be used therapeutically in an individual. "Ex vivo" means outside a living individual. Examples of ex vivo cell populations include in vitro cell cultures and biological samples, including fluid or tissue samples obtained from an individual. Such samples can be obtained by methods well known in the art. Exemplary biological fluid samples include blood, cerebrospinal fluid, urine, and saliva. In this context, the compounds and compositions described herein can be used for a variety of purposes, including therapeutic and experimental purposes. For example, for a given indication, cell type, individual, and other parameters, the compounds and compositions described herein can be used in vitro to determine the optimal dosing regimen and / or dosage of the compounds of the invention. The information collected from such use can be used for experimental purposes or in the clinic to set up in vivo treatment regimens. Other ex vivo uses for which the compounds and compositions described herein may be applicable are described below or will become apparent to those skilled in the art. Selected compounds can be further characterized to examine safety or tolerable doses in human or non-human subjects. These properties can be examined using methods well known to those skilled in the art. Experiments using knockout animal models and Necrostatin 1 (a receptor-interacting protein kinase 1 inhibitor) have demonstrated that receptor-interacting protein kinase 1 inhibition is effective in protecting tissues from inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), psoriasis, retinal detachment-induced photoreceptor necrosis, retinitis pigmentosa, cerulein-induced acute pancreatitis, and sepsis / systemic inflammatory response syndrome (SIRS), as well as ameliorating ischemic brain injury, retinal ischemia / reperfusion injury, Huntington's disease, renal ischemia-reperfusion injury, cisplatin-induced kidney damage, traumatic brain injury, blood and solid organ malignancies, bacterial and viral infections (e.g., tuberculosis and influenza), and lysosomal storage diseases. Therefore, the receptor-interacting protein kinase 1 inhibitors described in the present disclosure are effective in treating diseases and conditions mediated by receptor-interacting protein kinase 1, including but not limited to inflammatory diseases or disorders, necrotic cell diseases, neurodegenerative diseases, central nervous system (CNS) diseases, eye diseases, infections, and malignancies. In certain embodiments, the receptor-interacting protein kinase 1 inhibitors described herein can inhibit inflammation, protect tissues or cells from damage or unwanted cell death (e.g., necrosis or apoptosis), improve symptoms, and improve immune responses or neuronal function in patients with any specified disease or condition. In addition, the compounds may be suitable for treating immune-mediated diseases such as, but not limited to, allergic diseases, autoimmune diseases, and preventing transplant rejection. Provided herein are compounds and compositions for use in medicine. In certain embodiments, the compounds and compositions are used to treat a disease or condition mediated by receptor-interacting protein kinase 1. Also provided herein are methods of treating a disease or condition mediated by receptor-interacting protein kinase 1, comprising administering to a subject in need thereof a therapeutically effective amount of a compound or pharmaceutical composition described herein. In certain embodiments, the disease or condition is an inflammatory disease associated with the A20 SNP. A variety of specific diseases and conditions are described below. In certain embodiments, the disease or condition is necrotizing enterocolitis, tuberous sclerosis, hypoalphalipoproteinemia, Wohlman syndrome, inflammatory bowel disease, Crohn's disease, ulcerative colitis, psoriasis, retinal detachment, retinitis pigmentosa, macular degeneration, pancreatitis (e.g., acute pancreatitis), atopic dermatitis, rheumatoid arthritis, spondyloarthritis, gout, SoJIA, systemic lupus erythematosus, Sjögren's syndrome, systemic scleroderma, antiphospholipid syndrome, vasculitis, osteoarthritis, nonalcoholic fatty liver disease, alcoholic fatty liver disease, autoimmune hepatitis, autoimmune hepatobiliary disease, primary sclerosing cholangitis, nephritis, celiac disease, autoimmune ITP, transplant rejection, solid organ ischemia-reperfusion injury, sepsis, systemic inflammatory response syndrome, cerebrovascular accident, myocardial infarction, Huntington's disease, Alzheimer's disease, Parkinson's disease, allergic diseases, asthma, atopic dermatitis, multiple sclerosis, type I diabetes mellitus, Wegener's granulomatosis, pulmonary sarcoidosis, Behçet's disease, interleukin-1 converting enzyme associated fever syndrome, chronic obstructive pulmonary disease, tumor necrosis factor receptor-associated periodic syndrome, periodontitis, bacterial infection, staphylococcal infection, mycobacterial infection, retinitis pigmentosa, influenza, transplant rejection, burns, or hypoxia. In certain embodiments, the disease or condition is trauma, ischemia, stroke, myocardial infarction, infection, lysosomal storage disease, Niemann-Pick disease, Gaucher disease, Krabbe disease, sepsis, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS / Lou Gehrig's disease), Huntington's disease, human immunodeficiency virus-associated dementia, encephalopathy, retinal degenerative disease, glaucoma, age-related macular degeneration, rheumatoid arthritis, psoriasis, psoriatic arthritis, or inflammatory bowel disease. In certain embodiments, the disease or condition is Alzheimer's disease, ALS, Friedreich's ataxia, Huntington's disease, Lewy body disease, Parkinson's disease, Huntington's disease, multiple sclerosis, diabetic neuropathy, polyglutamine (polyQ) disease, stroke, Fahr's disease, Menke's disease, Wilson's disease, cerebral ischemia, lysosomal storage disease, or prion disease. In certain embodiments, the disease is ALS. In certain embodiments, the disease is Alzheimer's disease. In certain embodiments, the disease is a lysosomal storage disease. In certain embodiments, the disease is Parkinson's disease. In certain embodiments, the condition is an ischemic disease of an organ, including but not limited to the brain, heart, kidney, and liver.In some different embodiments, the disorder is an eye disorder, such as a retinal degenerative disease, glaucoma, or age-related macular degeneration. In some different embodiments, the disorder is a central nervous system (CNS) disorder. In certain embodiments, the compounds and compositions are useful for treating psoriasis. In certain embodiments, the condition is an inflammatory disease of the intestine, such as Crohn's disease or ulcerative colitis (both of which are generally referred to together as inflammatory bowel disease). In certain embodiments, the mammal is a primate, canine or feline subject. In certain embodiments, the mammal is a human subject. Although not wishing to be bound by theory, it is believed that the inhibition of receptor-interacting protein kinase 1 by the compounds described in this disclosure is at least in part the cause of its anti-inflammatory activity. Therefore, embodiments of the present disclosure also include methods for inhibiting receptor-interacting protein kinase 1 in vitro or in a subject in need thereof, the methods comprising contacting receptor-interacting protein kinase 1 with a compound disclosed herein. In some of these embodiments, inhibition of receptor-interacting protein kinase 1 effectively prevents (partially or completely) the release of inflammatory mediators (e.g., TNF and / or IL6). In certain embodiments, there is provided a method for treating rheumatoid arthritis, systemic onset juvenile idiopathic arthritis (SoJIA), spondyloarthritis, osteoarthritis, psoriasis, Crohn's disease, ulcerative colitis or multiple sclerosis, comprising administering a therapeutically effective amount of a compound as provided herein to a subject in need thereof. In certain embodiments, there is provided a method for treating autoimmune hepatitis, atherosclerosis, neutrophilic dermatosis or a rare disease caused by A20, NEMO and / or LUBAC mutations, comprising administering a therapeutically effective amount of a compound as provided herein to a subject in need thereof. In certain embodiments, the compound has Formula I (or any formula described herein or its tautomer), wherein A is a triazole. In certain embodiments, the compound has Formula V or Va. In certain embodiments, the method comprises administering Compound 42 or its tautomer. Inflammatory diseases or conditions The receptor interacting protein kinase 1 inhibitors described herein can be used to treat inflammatory diseases and disorders.Inflammatory diseases and disorders often manifest themselves in high levels of inflammation in connective tissues or degeneration of these tissues. Non-limiting examples of inflammatory diseases and disorders include Alzheimer's disease, ankylosing spondylitis, arthritis (including osteoarthritis, rheumatoid arthritis (RA)), psoriasis, asthma, atherosclerosis, Crohn's disease, colitis, dermatitis, diverticulitis, fibromyalgia, hepatitis, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), systemic lupus erythematosus (SLE), nephritis, Parkinson's disease, and ulcerative colitis. In certain embodiments, the compounds and compositions described herein are useful for treating autoimmune disorders, such as rheumatoid arthritis, psoriasis, psoriatic arthritis, encephalitis, allograft rejection, autoimmune thyroid disease (e.g., Graves' disease and Hashimoto's thyroiditis), autoimmune uveoretinitis, giant cell arteritis, inflammatory bowel disease (including Crohn's disease, ulcerative colitis, Crohn's disease, granulomatous enterocolitis, terminal ileitis, Crohn's disease, and terminal ileitis), insulin-dependent diabetes mellitus, multiple sclerosis, pernicious anemia, sarcoidosis, scleroderma, and systemic lupus erythematosus. In one embodiment, the receptor interacting protein kinase 1 inhibitors described herein are useful for treating autoimmune encephalitis. In certain embodiments, the compounds and compositions are useful for treating rheumatoid arthritis (RA). In certain embodiments, the compounds and compositions are useful for treating ulcerative colitis. In certain embodiments, the compounds and compositions are useful for treating psoriasis. In certain embodiments, the condition is an inflammatory disease of the intestine, such as Crohn's disease or ulcerative colitis (both of which are generally referred to together as inflammatory bowel disease). In certain embodiments, the mammal is a primate, canine or feline subject. In certain embodiments, the mammal is a human subject. Although not wishing to be bound by theory, it is believed that the inhibition of receptor-interacting protein kinase 1 by the compounds described in this disclosure is at least in part the cause of its anti-inflammatory activity. Therefore, embodiments of the present disclosure also include methods for inhibiting receptor-interacting protein kinase 1 in vitro or in a subject in need thereof, the methods comprising contacting receptor-interacting protein kinase 1 with a compound disclosed herein. In some of these embodiments, inhibition of receptor-interacting protein kinase 1 effectively prevents (partially or completely) the release of inflammatory mediators (e.g., TNF and / or IL6). Necrotic cell disease The compounds described herein can be used to treat diseases / conditions caused by or associated with cell necrosis. In particular, the present disclosure provides a method for preventing or treating a condition associated with cell necrosis in a mammal, comprising the step of administering to the mammal a therapeutically effective amount of a compound or composition described herein. The term "necrotic cell disease" refers to a disease associated with or caused by cell necrosis, such as trauma, ischemia, stroke, myocardial infarction, infection, Gaucher's disease, Krabbe's disease, sepsis, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease, dementia associated with human immunodeficiency virus, retinal degenerative disease, glaucoma, age-related macular degeneration, rheumatoid arthritis, psoriasis, psoriatic arthritis, or inflammatory bowel disease. The necrotic cell disease can be an acute disease, such as trauma, ischemia, stroke, myocardial infarction, septic shock caused by anthrax lethal toxin, sepsis, LPS-induced cell death, and HIV-induced T-cell death leading to immunodeficiency. In certain embodiments, the condition is an ischemic disease of an organ, including but not limited to the brain, heart, kidney, and liver. The necrotizing cell diseases also include chronic neurodegenerative diseases such as Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, Alzheimer's disease, transmissible encephalopathy, and dementia such as human immunodeficiency virus-associated dementia. In some different embodiments, the disorder is an eye disorder, such as a retinal degenerative disease, glaucoma, or age-related macular degeneration. In some different embodiments, the disorder is a central nervous system (CNS) disorder. Neurodegenerative and CNS diseases The receptor-interacting protein kinase 1 inhibitors described herein may also be used to treat neurodegenerative diseases. Neurodegenerative diseases can affect many bodily functions, such as balance, movement, speech, breathing, and heart function. Neurodegenerative diseases can be genetic or caused by medical conditions, such as alcoholism, tumors, stroke, toxins, chemicals, and viruses. Non-limiting examples of neurodegenerative diseases include Alzheimer's disease, amyotrophic lateral sclerosis (ALS), Friedreich's ataxia, Huntington's disease, Lewy body disease, Parkinson's disease, and spinal muscular atrophy. In certain embodiments, neurodegenerative diseases and CNS diseases include Niemann-Pick disease, type C1 (NPC1), Alzheimer's disease, amyotrophic lateral sclerosis (ALS), Friedreich's ataxia, Huntington's disease, Lewy body disease, Parkinson's disease, and spinal muscular atrophy. In certain embodiments, the receptor interacting protein kinase 1 inhibitors described herein can be used to treat NPC1 by inhibiting necroptosis that causes neuronal loss. In certain embodiments, the compounds and compositions described herein are useful for treating Alzheimer's disease. In certain embodiments, the compounds and compositions described herein are useful for treating Parkinson's disease. In certain embodiments, the compounds and compositions described herein are useful for treating amyotrophic lateral sclerosis (ALS). More generally, the receptor-interacting protein kinase 1 inhibitors described herein can be used to maintain neuronal viability and promote axonal growth and neural function in the central nervous system (CNS). Therefore, by maintaining neuronal viability and / or promoting axonal regeneration and / or neural function, the compounds can be used to reduce or even reverse the loss of cognitive, motor and sensory function associated with CNS diseases or disorders. Receptor-interacting protein kinase 1 inhibitors described herein can be used in methods for promoting axon regeneration in CNS neurons (e.g., CNS sensory neurons, motor neurons, cortical neurons, cerebellar neurons, hippocampal neurons, and midbrain neurons). Receptor-interacting protein kinase 1 inhibitors described herein can be used in methods for promoting neurological function or maintaining vitality after damaging CNS neurons. In another embodiment, these compounds can be used to promote the regeneration of axons in CNS neurons that have degenerated in CNS diseases or disorders. RIP receptor-interacting protein kinase 1 inhibitors can be administered by any conventional means, such as topically administered to neurons or applied in vitro before re-implantation. Therefore, in one aspect, the present disclosure provides a method for treating CNS disorders in a subject in need thereof, wherein the symptom of CNS disorders is axonal degeneration or damage in CNS neurons. The method includes administering an effective amount of a compound or composition as described herein to the subject, thereby promoting the regeneration of axons affected by CNS disorders in CNS neurons. After administration, neurological function can be measured, for example, as an indication of axonal regeneration. It is also contemplated that after administration of the compound or composition, the neuronal function of the CNS neurons is maintained or improved relative to the neuronal function before administration. Non-limiting examples of CNS diseases or disorders include brain injury, spinal cord injury, dementia, stroke, Alzheimer's disease, amyotrophic lateral sclerosis (ALS / Lou Gehrig's disease), Parkinson's disease, Huntington's disease, multiple sclerosis, diabetic neuropathy, polyglutamine (polyQ) disease, stroke, Fahr's disease, Menkes disease, Wilson's disease, cerebral ischemia, and prion diseases. In exemplary embodiments, the CNS disorder is brain injury or spinal cord injury. Also provided herein are methods of promoting neuronal survival and axonal regeneration in the CNS. CNS disorders characterized by impaired or failed axonal growth or axonal degeneration can result from injury to CNS neurons (e.g., trauma, surgery, nerve compression, nerve contusion, nerve transection, neurotoxicity, or other physical injury to the brain or spinal cord) or a neurodegenerative CNS disease, wherein a symptom of the disorder is axonal degeneration (e.g., Alzheimer's disease, amyotrophic lateral sclerosis (ALS / Lou Gehrig's disease), Parkinson's disease, multiple sclerosis, diabetic neuropathy, polyglutamine (polyQ) disease, stroke, Fahr's disease, Menkes disease, Wilson's disease, cerebral ischemia, prion diseases (e.g., Creutzfeldt-Jakob disease). In certain embodiments, the CNS disorder is brain injury (e.g., traumatic brain injury) or spinal cord injury (e.g., chronic, acute, or traumatic spinal cord injury). In certain embodiments, the CNS disorder affects the subject's basic vital functions, such as breathing, heartbeat, and blood pressure, e.g., brainstem injury or aneurysm. In certain embodiments, the CNS disease or condition affects the cognitive ability of the subject. In certain embodiments, the CNS disease or condition affects the movement and / or strength of the subject. In certain embodiments, the CNS disease or condition affects the coordination of the subject. In certain embodiments, the CNS disorder affects the subject's cognitive abilities, e.g., brain damage to the cerebral cortex or a neurodegenerative CNS disorder, e.g., Alzheimer's disease, frontotemporal dementia, dementia with Lewy bodies, corticobasal degeneration, progressive supranuclear palsy, and prion diseases. In certain embodiments, the CNS disorder affects the subject's movement and / or strength, such as an injury to the brain or spinal cord or a neurodegenerative CNS disorder, such as Parkinson's disease, frontotemporal dementia, dementia with Lewy bodies, corticobasal degeneration, progressive supranuclear palsy, Huntington's disease, multiple system atrophy, amyotrophic lateral sclerosis, and hereditary spastic paresis. In certain embodiments, the CNS disorder affects the subject's coordination, such as brain damage to the cerebellum or a neurodegenerative CNS disorder, such as spinocerebellar atrophy, Friedreich's ataxia, and prion diseases. In each of the foregoing methods, the CNS disorder includes, but is not limited to, brain injury, spinal cord injury, Alzheimer's disease, amyotrophic lateral sclerosis (ALS / Lou Gehrig's disease), Parkinson's disease, multiple sclerosis, diabetic neuropathy, polyglutamine (polyQ) disease, stroke, Fahr's disease, Menkes disease, Wilson's disease, cerebral ischemia, prion diseases (e.g., Creutzfeldt-Jakob disease), dementia (e.g., frontotemporal dementia, dementia with Lewy bodies), corticobasal degeneration, progressive supranuclear palsy, multiple system atrophy, hereditary spastic paraplegia, and spinocerebellar atrophy. Non-limiting examples of neurodegenerative diseases include Alzheimer's disease, lysosomal storage diseases, amyotrophic lateral sclerosis (ALS), Friedreich's ataxia, Huntington's disease, Lewy body diseases, Parkinson's disease, and spinal muscular atrophy. In certain embodiments, the compounds and compositions of the present disclosure are useful for treating Alzheimer's disease. In certain embodiments, the compounds and compositions of the present disclosure are useful for treating Parkinson's disease. In certain embodiments, the compounds and compositions of the present disclosure are useful for treating amyotrophic lateral sclerosis (ALS). In certain embodiments, the compounds and compositions of the present disclosure are useful for treating lysosomal storage diseases. In certain embodiments, the disorder is a brain disorder, such as, but not limited to, Alzheimer's disease, ALS, frontotemporal dementia, vascular dementia, Huntington's disease, Parkinson's disease, dementia with Lewy bodies, progressive supranuclear palsy, multiple sclerosis, neuromyelitis optica, ischemic brain injury (stroke), anoxic brain injury, traumatic brain injury, spinal cord injury, sepsis-induced brain injury, CNS infection, CNS abscess, glioblastoma multiforme, epilepsy, neuropathic pain, major depression, bipolar depression, schizophrenia, autism, Niemann-Pick disease, and neuro-Behcet's disease. In certain embodiments, a method for treating a CNS disease or condition is provided, comprising administering to a subject in need thereof a therapeutically effective amount of a compound as provided herein. In certain embodiments, the disease or condition is Alzheimer's disease or amyotrophic lateral sclerosis (ALS). In certain embodiments, the compound has Formula I (or any formula described herein), wherein A is not a triazole. In certain embodiments, the compound has Formula VI. Eye conditions The receptor-interacting protein kinase 1 inhibitors described herein may also be used to treat ocular conditions, for example, to reduce or prevent the loss of photoreceptor cell or retinal pigment epithelial cell viability. In certain embodiments, the present disclosure provides a method for maintaining the visual function of an eye of a subject having an ocular condition, wherein the symptom of the ocular condition is the loss of photoreceptor cell viability in the retina of the eye having the condition. The method comprises administering an effective amount of a compound or composition as described herein to the eye of the subject, thereby maintaining the viability of photoreceptor cells placed in the retina of the eye. Following administration, the visual function (e.g., visual acuity) of the eye can be maintained or improved relative to the visual function of the eye before administration. The eye condition can be age-related macular degeneration (AMD), retinitis pigmentosa (RP), macular edema, diabetic retinopathy, central reticular choroidal dystrophy, BEST disease, adult glassy disease, pattern dystrophy (pattern dystrophy), myopic degeneration, central serous chorioretinopathy, Stargardt disease, cone-rod dystrophy, North Carolina dystrophy (North Carolina dystrophy), infectious retinitis, inflammatory retinitis, uveitis, toxic retinitis or light-induced toxicity.AMD can be a neovascular form or a dry form of AMD.Retinal detachment can be rhegmatogenous, serous or tractional retinal detachment.In certain embodiments, the eye condition may be geographic atrophy, glaucoma or another ischemic eye disease. In certain embodiments, the present invention provides the method for the vitality of retinal pigment epithelial (RPE) cells in the retina of the subject with ocular conditions by administering the compound of the present invention.The subject being treated can have the loss of retinal pigment epithelial cells in the retina of the eyes with conditions, and ocular conditions can be age-related macular degeneration (AMD), BEST disease, myopic degeneration, Stargardt disease, uveitis, adult macular dystrophy (adultfoveomacular dystrophy), yellow dot fundus, multiple-transient white dot syndrome, serpentine choroidopathy, acute multifocal posterior papillary epitheliopathy (acute multifocal posterior placoid epitheliopathy) (AMPPE) or other uveitis conditions.In certain embodiments, methods described include compound as herein described or compositions administered to the eye of the subject with an effective amount, so as to maintain the vitality of retinal pigment epithelial cells. In another embodiment, provided is a method of maintaining the viability of photoreceptor cells placed in the retina of a subject suffering from age-related macular degeneration (AMD), retinitis pigmentosa (RP), macular edema, diabetic retinopathy, central reticular choroidal dystrophy, BEST disease, adult glassy disease, pattern dystrophy, myopic degeneration, central serous chorioretinopathy, Stargardt disease, cone-rod dystrophy, North Carolina dystrophy, infectious retinitis, inflammatory retinitis, uveitis, toxic retinitis or light-induced toxicity. Thus, in certain embodiments, the method comprises administering to the eye an effective amount of a compound or composition as described herein, thereby maintaining the viability of photoreceptor cells placed in the retina of a subject suffering from a condition. In another embodiment, provided is a method for maintaining the viability of photoreceptor cells placed in the retina of a mammalian eye after retinal detachment. The retinal detachment may be rhegmatogenous retinal detachment, tractional retinal detachment, or serous retinal detachment. In other embodiments, the retinal detachment may be caused by retinal tear, retinoblastoma, melanoma or other cancer, diabetic retinopathy, uveitis, choroidal neovascularization, retinal ischemia, pathological myopia, or trauma. In certain embodiments, the method comprises administering a compound or composition as described herein to an eye from which an area of ​​the retina has detached, in an amount sufficient to maintain the viability of photoreceptor cells placed in the detached retinal area. In another embodiment, provided is a method of maintaining visual function in an eye of a subject suffering from age-related macular degeneration (AMD), retinitis pigmentosa (RP), macular edema, central reticular choroidal dystrophy, retinal detachment, diabetic retinopathy, BEST disease, adult vitreous disease, pattern dystrophy, myopic degeneration, central serous chorioretinopathy, Stargardt disease, cone-rod dystrophy, North Carolina dystrophy, infectious retinitis, inflammatory retinitis, uveitis, toxic retinitis, or phototoxicity, wherein the symptom of the ocular condition is loss of photoreceptor cell viability in the retina of the eye, wherein the method comprises administering to the subject a compound or composition described herein to treat the subject. In another aspect, the present disclosure provides a method of maintaining visual function in an eye of a subject having an ocular condition, wherein a symptom of the ocular condition is loss of photoreceptor cell viability and / or RPE viability in the retina of the eye, wherein the method comprises administering to the subject a compound or composition described herein to treat the subject. In certain embodiments, a method of maintaining visual function in an eye of a subject suffering from an ocular condition is provided, wherein the symptom of the ocular condition is loss of viability of retinal ganglion cells in the retina of the eye suffering from the condition. The method comprises administering to the eye of the subject an effective amount of a compound or composition to maintain the viability of retinal ganglion cells disposed in the retina of the eye. Following administration of the compound or composition, the visual function of the eye can be maintained or improved relative to the visual function of the eye prior to administration. Furthermore, following administration, the maintained retinal ganglion cells are capable of supporting axonal regeneration. Non-limiting examples of symptoms associated with ocular conditions include loss of retinal ganglion cell activity in the retina of the eye, glaucoma, optic nerve damage, optic neuritis, optic neuropathy, diabetic retinopathy, central retinal artery occlusion, and central retinal vein occlusion. The compounds described herein can also be used to treat optic neuropathies, such as ischemic optic neuropathies (e.g., arterial or non-arteritic anterior ischemic neuropathy and posterior ischemic optic neuropathy), compressive optic neuropathies, infiltrative optic neuropathies, traumatic optic neuropathies, mitochondrial optic neuropathies (e.g., Leber's optic neuropathy), nutritional optic neuropathies, toxic optic neuropathies, and hereditary optic neuropathies (e.g., Leber's optic neuropathy, dominant optic atrophy, Bell's syndrome). Also disclosed herein are methods for maintaining visual function in an eye of a subject suffering from glaucoma, optic nerve damage, optic neuropathy, diabetic retinopathy, central retinal artery occlusion, or central retinal vein occlusion. The methods comprise administering to the eye of the subject an effective amount of a compound or composition described herein, thereby maintaining the viability of retinal ganglion cells within the retina of the eye and the visual function of the eye. In another aspect, disclosed herein is a method for maintaining the viability of retinal ganglion cells placed in the retina of a mammalian eye that is affected by, for example, glaucoma, optic nerve damage, optic neuritis, optic neuropathy, diabetic retinopathy, central retinal artery occlusion, and central retinal vein occlusion. The method comprises administering to the eye, wherein the retinal area has been affected, a compound or composition described herein in an amount sufficient to maintain the viability of retinal ganglion cells placed in the affected retinal area. The maintained retinal ganglion cells are capable of supporting axonal regeneration. Also disclosed are methods for promoting axon regeneration in the eye of a subject suffering from an ocular condition, wherein a symptom of the ocular condition is loss of retinal ganglion cell viability in the retina of the eye suffering from the condition. The method comprises administering to the eye of the subject an effective amount of a compound or composition described herein, thereby promoting axon regeneration of retinal ganglion cells in the retina of the eye. In each of the foregoing embodiments, it is understood that the methods and compositions described herein can be used to maintain viability and / or promote axonal regeneration of retinal ganglion cells during treatment of underlying conditions including, but not limited to, glaucoma, optic nerve damage, optic neuritis, optic neuropathy, diabetic retinopathy, central retinal artery occlusion, and central retinal vein occlusion. Tissue damage or destruction The ability of the compounds described herein to inhibit inflammation and cell death makes them suitable for alleviating tissue damage or damage. Tissue damage or damage may be the result of any of the above-mentioned diseases or conditions. For example, the compound can be used to improve brain tissue damage or damage after ischemic or traumatic brain injury, or for improving cardiac tissue damage or damage after myocardial infarction, or for improving brain tissue damage or damage associated with Huntington's disease, Alzheimer's disease or Parkinson's disease, or for improving liver tissue damage or damage associated with non-alcoholic fatty liver disease, alcoholic fatty liver disease, autoimmune hepatitis, autoimmune hepatobiliary disease or primary sclerosing cholangitis, or for improving liver tissue damage or damage associated with excessive use of acetaminophen, or for improving kidney tissue damage or damage after kidney transplantation or after administration of nephrotoxic drugs or substances. In certain embodiments, for example, the compound can be used to improve brain tissue damage or damage after lung injury or damage. Non-limiting examples of brain injury or damage include stroke (e.g., hemorrhagic and non-hemorrhagic), traumatic brain injury (TBI), cerebral hemorrhage, subarachnoid hemorrhage, intracranial hemorrhage secondary to cerebral arterial malformation, cerebral infarction, perinatal brain injury, non-traumatic brain injury, Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis, cerebral hemorrhage, brain infection, brain tumor, subclinical brain injury, spinal cord injury, hypoxic-ischemic brain injury, focal cerebral ischemia, global cerebral ischemia, and anoxic hypoxia. In one embodiment, the compounds and compositions described herein can be used to treat peritoneal tissue damage. Non-limiting examples of peritoneal tissue damage include peritoneal deterioration, peritoneal sclerosis, and peritoneal cancer. For example, the receptor interacting protein kinase 1 inhibitors described herein can be used to treat peritoneal damage caused by peritoneal dialysis fluid (PDF) and PD-related side effects. Liver damage and disease In one embodiment, the compounds and compositions described in the present disclosure can be used to treat liver damage and disease. Non-limiting examples of liver damage or injury include not only degeneration or necrosis of hepatocytes caused by damage due to certain factors, but also adverse phenomena caused by biological responses to damage, such as activity, infiltration, activation of Flesh cells, leukocytes, etc., fibrosis of liver tissue, etc. These reactions may occur alone or in combination. In certain embodiments, the receptor-interacting protein kinase 1 inhibitors described herein can be used to treat fatty liver disease and hepatocellular carcinoma by inhibiting hepatocyte receptor-interacting protein kinase 1 activity-dependent apoptosis and liver cancer. In one embodiment, the receptor-interacting protein kinase 1 inhibitors described herein can be used to treat alcoholic hepatitis, autoimmune hepatitis, fulminant hepatic failure, acute cholestasis, and liver damage. Kidney damage and disease In one embodiment, the compounds and compositions described in the present disclosure can be used to treat kidney damage and disease. Non-limiting examples of kidney disease include chronic kidney disease (CKD) (for example, glomerular disease, tubulointerstitial disease, obstruction, polycystic kidney disease), acute kidney injury (AKI), diabetic nephropathy, fibrosis, glomerulonephritis, focal glomerulosclerosis, immune complex nephropathy, crystalline nephropathy or lupus nephritis. Kidney disease can be caused by drug-induced kidney damage or renal transplant rejection. The characteristics of kidney disease can be nephrotic syndrome or renal insufficiency. In one embodiment, receptor interacting protein kinase 1 inhibitors as described herein can be used to treat kidney disease (for example, AKI) by suppressing the cell death pathway in kidney disease. In one embodiment, receptor interacting protein kinase 1 inhibitors as described herein can be used to treat patients with kidney stones by inhibiting necroptosis mediated by receptor interacting protein kinase 3-MLKL, and prevent crystal-induced cytotoxicity and acute kidney injury. Skin diseases In one embodiment, the compounds and compositions described herein can be used to treat dermal (or skin) diseases, including but not limited to, inflammatory skin diseases or neutrophilic skin diseases. Malignant tumors In one embodiment, the compounds and compositions of the present disclosure are useful for treating malignancies / cancers, such as carcinomas, sarcomas, melanomas, lymphomas, or leukemias. Non-limiting examples of malignancies that are suitably treated by the receptor interacting protein kinase 1 inhibitors described herein include lung cancer (e.g., non-small cell lung cancer, small cell lung cancer), hepatocellular carcinoma, melanoma, pancreatic cancer, urinary cancer, bladder cancer, colorectal cancer, colon cancer, breast cancer, prostate cancer, kidney cancer, thyroid cancer, gallbladder cancer, peritoneal cancer, ovarian cancer, cervical cancer, gastric cancer, endometrial cancer, esophageal cancer, head and neck cancer, neuroendocrine cancer, CNS cancer, brain tumors (e.g., neuropathy), ... glioma, anaplastic oligodendroglioma, adult glioblastoma, and adult anaplastic astrocytoma), bone cancer, soft tissue sarcoma, retinoblastoma, neuroblastoma, ascites, malignant pleural effusion, mesothelioma, Wilms' tumor, trophoblastic tumor, hemangiopericytoma, Kaposi's sarcoma, myxoid carcinoma, round cell carcinoma, squamous cell carcinoma, esophageal squamous cell carcinoma, oral cancer, vulvar cancer, adrenocortical carcinoma, ACTH-producing tumors, lymphoma, and leukemia. Infectious diseases In one embodiment, the compounds and compositions of the present disclosure can be used to treat infectious diseases caused by the presence of pathogens, including pathogenic viruses, pathogenic bacteria, fungi, protozoa, multicellular parasites, and abnormal proteins called prions. Non-limiting examples of infectious diseases appropriately treated by receptor-interacting protein kinase 1 inhibitors as described herein include viral infectious diseases and bacterial infectious diseases. Viral infectious diseases are not particularly limited, including, for example, infectious diseases with respiratory infectious viruses (for example, infectious diseases caused by respiratory infectious viruses, such as influenza virus, rhinovirus, coronavirus, parainfluenza virus, RS virus, adenovirus, reovirus, etc.), Staphylococcus aureus (MRSA) pneumonia, Serratia marcescens hemorrhagic pneumonia, herpes zoster caused by herpes virus, diarrhea caused by rotavirus, viral hepatitis, AIDS, etc. Bacterial infectious diseases are not particularly limited, for example, including infectious diseases caused by Bacillus cereus, Vibrio parahaemolyticus, enterohemorrhagic Escherichia coli, Staphylococcus aureus, MRSA, Salmonella, Clostridium botulinum, Candida, etc. Bone diseases In one embodiment, the compounds and compositions described herein can be used to treat bone diseases that may be caused by bone remodeling disorders, thereby changing the balance between bone formation and bone resorption. Non-limiting examples of bone remodeling disorders include osteoporosis, Paget's disease, osteoarthritis, rheumatoid arthritis, achondroplasia, osteochondritis, hyperparathyroidism, osteogenesis imperfecta, congenital hypophosphatemia, fibromatosis, fibrous dysplasia, multiple myeloma, abnormal bone turnover, osteolytic bone disease, and periodontal disease. Other examples of bone diseases that are appropriately treated by receptor-interacting protein kinase 1 inhibitors as described herein include bone fractures, bone trauma or bone deficiency associated with post-traumatic bone surgery, post-prosthetic joint surgery, post-orthopedic bone surgery, dental surgery, bone chemotherapy, or bone radiotherapy. Other examples of diseases that affect bones or bone joints that are appropriately treated by receptor-interacting protein kinase 1 inhibitors as described herein include metastatic bone cancer, rheumatic diseases, such as rheumatoid arthritis, osteoarthritis, and other inflammatory arthritis. In one embodiment, the receptor interacting protein kinase 1 inhibitors described herein can be used to treat postmenopausal osteoporosis by inhibiting osteocyte necroptosis and trabecular degeneration. cardiovascular disease In one embodiment, the compounds and compositions of the present disclosure can be used to treat cardiovascular diseases that may be associated with fragile plaque disorder, occlusive disease, and stenotic cardiovascular diseases. Non-limiting cardiovascular diseases include coronary artery disease and peripheral arterial disease, which include atherosclerosis, arterial occlusion, aneurysm formation, thrombosis, post-traumatic aneurysm formation, restenosis, and postoperative graft occlusion. Atherosclerosis is believed to be caused by maladaptive inflammation driven primarily by macrophages. Therefore, the compounds and compositions of the present disclosure can be used to treat atherosclerosis by inhibiting macrophage necroptosis. transplant In one embodiment, the compounds and compositions described in the present disclosure are useful for treating transplant patients. Non-limiting examples of transplant patients appropriately treated with the receptor-interacting protein kinase 1 inhibitors described herein include transplant patients of solid and non-solid organs and tissues, such as liver, heart, kidney, allogeneic and autologous bone marrow transplants. Typically, immunosuppressive therapy is used to avoid transplant rejection in solid organ transplant recipients. Bone marrow transplant recipients typically receive extensive irradiation and chemotherapy before transplantation. It is believed that receptor-interacting protein kinase 1 and NF-κB signaling in dying cells determine the cross-sensitization of CD8+T cells. Therefore, the receptor-interacting protein kinase 1 inhibitors described herein can be used to treat transplant patients and avoid transplant rejection by regulating the cross-sensitization of CD8+T cells. Other diseases and conditions Additional examples of diseases and conditions suitable for treatment by the receptor interacting protein kinase 1 inhibitors described herein include Gaucher's disease, organ failure, pancreatitis, atopic dermatitis, spondyloarthritis, gout, systemic onset juvenile idiopathic arthritis (SoJIA), systemic lupus erythematosus (SLE), Sjögren's syndrome, systemic scleroderma, antiphospholipid syndrome (APS), vasculitis, primary sclerosing cholangitis (PSC), acetaminophen poisoning, renal impairment / injury (nephritis, renal transplantation, surgery, administration of nephrotoxic drugs (e.g., cisplatin), acute kidney injury (AKI)), celiac disease, autoimmune idiopathic thrombocytopenic purpura (autoimmune ITP), cerebrovascular accident (CVA, stroke), myocardial infarction (MI) , allergic diseases (including asthma), diabetes mellitus, Wegener's granulomatosis, pulmonary sarcoidosis, Behçet's disease, interleukin-1 converting enzyme (ICE / caspase-1)-associated febrile syndrome, chronic obstructive pulmonary disease (COPD), tumor necrosis factor receptor-associated periodic syndrome (TRAPS), periodontitis, NEMO deficiency syndrome (essential regulator of F-κB (also known as IKKγ or IKKG) deficiency syndrome), HOIL-1 deficiency ((also known as RBCK1) heme oxidizing IRP2 ubiquitin ligase-1 deficiency), linear ubiquitin chain assembly complex (LUBAC) deficiency syndrome, hematological and solid organ malignancies, bacterial and viral infections (e.g., tuberculosis and influenza), and lysosomal storage diseases. Non-limiting examples of lysosomal storage diseases include Gaucher disease, GM2 gangliosidosis, mannosidosis, aspartylglucosaminuria, cholesterol ester storage disease, chronic hexosaminidase A deficiency, cystinosis, Danon disease, Fabry disease, Farber disease, fucose metabolism disease, galactosialidosis, GM1 gangliosidosis, mucopolysaccharidosis, infantile free sialic acid storage disease, juvenile hexosaminidase A deficiency, Krabbe disease, lysosomal acid lipase deficiency, metachromatic leukodystrophy, mucopolysaccharidosis, multiple sulfatase deficiency, Niemann-Pick disease, neuronal ceroid lipofuscinosis, Pompe disease, pycnodysostosis, Sandhoff disease, Schindler disease, sialic acid storage disease, Tay-Sachs disease, and Wolman disease. In certain embodiments, compounds and compositions for use in medicine are provided. In certain embodiments, the compounds and compositions are used to treat a disease or condition mediated by receptor-interacting protein kinase 1. Also provided herein are methods of treating a disease or condition mediated by receptor-interacting protein kinase 1, comprising administering to a subject in need thereof a therapeutically effective amount of a compound or pharmaceutical composition described herein. In another embodiment, the present disclosure provides a method for inhibiting receptor-interacting protein kinase 1. The method comprises contacting the receptor-interacting protein kinase 1 with an effective amount of a compound as described herein. Inhibiting the receptor-interacting protein kinase 1 generally comprises contacting the receptor-interacting protein kinase 1 with an amount of a compound sufficient to reduce the activity of the receptor-interacting protein kinase 1 (compared to the activity of the receptor-interacting protein kinase 1 in the absence of the compound). For example, contacting the receptor-interacting protein kinase 1 with a compound can result in about 1% to about 99% inhibition of the receptor-interacting protein kinase 1 (i.e., the activity of the inhibited enzyme is within the range of 99% to 1% of the activity of the enzyme in the absence of the compound). The level of inhibition of the receptor-interacting protein kinase 1 can range from about 1% to about 10%, or from about 10% to about 20%, or from about 20% to about 30%, or from about 30% to about 40%, or from about 40% to about 50%, or from about 50% to about 60%, or from about 60% to about 70%, or from about 70% to about 80%, or from about 80% to about 90%, or from about 90% to about 99%. The level of inhibition of the receptor-interacting protein kinase 1 can range from about 5% to about 95%, or from about 10% to about 90%, or from about 20% to about 80%, or from about 30% to about 70%, or from about 40% to about 60%. In some embodiments, contacting the receptor-interacting protein kinase 1 with a compound as described herein results in complete (i.e., 100%) inhibition. Drug administration As used herein, the phrases "parenteral administration" and "parenterally administered" mean modes of administration other than enteral and topical administration, usually by injection, and include, but are not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, intratracheal, subcutaneous, subcutaneous, intraarticular, subcapsular, subarachnoid, intraspinal, and intrasternal injection and infusion. As used herein, the phrases "systemic administration," "systemic administration," "peripheral administration," and "peripherally administered" refer to the administration of a compound, drug, or other substance other than directly into the central nervous system, thereby making it accessible throughout the patient's body and thereby susceptible to metabolism and other similar processes, e.g., subcutaneous administration. The compounds can be administered to humans and other animals for therapeutic purposes by any suitable route of administration, including orally, nasally, such as by spray, rectally, vaginally, parenterally, intracisternaly, and topically, such as by powders, ointments, or drops, including buccal and sublingual. Regardless of the route of administration selected, the compounds of the present disclosure and / or pharmaceutical compositions of the present disclosure, which can be used in a suitable hydrated form, are formulated into pharmaceutically acceptable dosage forms by conventional methods known to those skilled in the art. Actual dosage levels of the active ingredients in the pharmaceutical compositions of the present disclosure may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient. The selected dosage level will depend upon a variety of factors, including the activity of the particular compound of the disclosure employed, or its ester, salt, or amide, the route of administration, the time of administration, the rate of excretion or metabolism of the particular compound employed, the duration of the treatment, other drugs, compounds, and / or materials used in conjunction with the particular compound employed, the age, sex, weight, condition, general health, and prior medical history of the patient being treated, and similar factors well known in the medical arts. Daily, weekly, or monthly dosages (or other time intervals) may be used. A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the desired pharmaceutical composition. For example, a physician or veterinarian can start the dose of the compound of the present disclosure used in the pharmaceutical composition at a level lower than that required to achieve the desired therapeutic effect, and then gradually increase the dose until the desired effect is achieved. Typically, the daily dose of a compound of the present invention that is suitable will be the amount of the compound at the lowest dose that effectively produces a therapeutic effect (e.g., inhibiting necrosis). Typically, the effective dose will depend on the above factors. Typically, when used for the effects shown, the dosage of the compound of the present disclosure to the patient is from about 0.0001 to about 100 mg per kilogram of body weight per day. Preferably, the daily dose will be 0.001 to 50 mg of the compound per kilogram of body weight, even more preferably 0.01 to 10 mg of the compound per kilogram of body weight. If desired, the effective daily dose of active compound may be administered as two, three, four, five, six or more sub-doses administered at appropriate intervals throughout the day, optionally in unit dosage forms. In certain embodiments, the present disclosure relates to compounds for inhibiting cell death, wherein the compounds are represented by structure (I). In certain embodiments, the compounds of the present disclosure are inhibitors of cell death. In any case, the compounds of the present disclosure preferably exert their effect of inhibiting cell death at a concentration of less than about 50 micromolar, more preferably at a concentration of less than about 10 micromolar, and most preferably at a concentration of less than 1 micromolar. Compounds of the present disclosure can be tested in standard animal models of stroke and standard protocols such as described by Hara, H., et al. Proc. Natl. Acad. Sci. USA, 1997. 94(5):2007-12. When the compounds of the present disclosure are administered as pharmaceuticals to humans and animals, they can be administered per se or as pharmaceutical compositions containing, for example, 0.1% to 99.5% (more preferably 0.5% to 90%) active ingredients in combination with pharmaceutically acceptable carriers. The compounds of the present invention or their compositions can be administered once, twice, three times, or four times daily using any of the above-described suitable methods. Similarly, administration or treatment with these compounds can continue for several days; for example, typically a treatment cycle will continue for at least 7, 14, or 28 days of treatment. Treatment cycles are well known and often alternate between cycles for about 1 to 28 days, typically with a rest period of about 7 or about 14 days. In certain embodiments, treatment cycles can also be continuous. When administered orally, the total daily dose for a human subject can be 1 mg to 1,000 mg, about 1,000-2,000 mg / day, about 10-500 mg / day, about 50-300 mg / day, about 75-200 mg / day, or about 100-150 mg / day. The daily dose can also be described as the total amount of a compound described herein administered per dose or per day. The daily dose of a compound can be about 1 mg to 4,000 mg, about 2,000 to 4,000 mg / day, about 1 to 2,000 mg / day, about 1 to 1,000 mg / day, about 10 to 500 mg / day, about 20 to 500 mg / day, about 50 to 300 mg / day, about 75 to 200 mg / day, or about 15 to 150 mg / day. In certain embodiments, the method comprises administering to the subject an initial daily dose of about 1 to 800 mg of a compound described herein and increasing the dose in an incremental manner until clinical efficacy is achieved. The dose may be increased in increments of about 5, 10, 25, 50, or 100 mg. The dose may be increased daily, every other day, twice a week, or once a week. In certain embodiments, the compound or pharmaceutical formulation is administered orally. In certain embodiments, the compound or pharmaceutical formulation is administered intravenously. Alternative routes of administration include sublingual, intramuscular, and transdermal administration. The formulations of the present disclosure can be administered orally, parenterally, topically, or rectally. They are, of course, administered in a form suitable for each route of administration. For example, they can be administered in tablet or capsule form by injection, inhalation, eye drops, ointments, suppositories, etc., by injection, infusion, or inhalation; topically by lotion or ointment; and rectally by suppository. In certain embodiments, the administration is oral. VI. Examples All solvents used are commercially available and used without further purification. Reactions are typically carried out using anhydrous solvents under an inert atmosphere of nitrogen. Abbreviations: aq. (aqueous), EtOAc (ethyl acetate), DCM (dichloromethane), TFA (trifluoroacetic acid), HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate), TEA (triethylamine), DMF (dimethylformamide), THF (tetrahydrofuran), MeTHF (2-methyltetrahydrofuran), PE (petroleum ether), T3P (propylphosphonic anhydride), AcOH (acetic acid), hex (hexane), DIAD (diisopropyl azodicarboxylate), IPA (isopropyl alcohol), MTBE (methyl tert-butyl ether), MsCl (methanesulfonyl chloride), Boc2O (di-tert-butyl dicarbonate), DMSO (DMSO-HCl). P (Dess-Martin hypervalent iodide), LDA (lithium diisopropylamide), DAST ((diethylamino)sulfur trifluoride), i-PrOH (isopropyl alcohol), TBAF (tetrabutylammonium fluoride), DIEA (diisopropylethylamine), EtOH (ethanol), DMPU (1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone), BAST (bis(2-methoxyethyl)aminosulfur trifluoride), XPhos (2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl), BINAP ((2,2'-bis(diphenylphosphino)-1,1'-dinaphthyl), LHMDS (lithium bis(trimethylsilyl)amide), Select F (Selectfluor, 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate)), DCE (1,2-dichloroethane), TMSCF3 ((trifluoromethyl)trimethylsilane), ACN (acetonitrile, methyl cyanide), NaHMDS (sodium hexamethyldisilazide), NMI (N-methylimidazole), equiv. (equivalent), M (molar), mM (millimolar), μM (micromolar), h (hour), min. (minute), mm (millimeter), mL (milliliter), μL (micrometer), N (normal), RT (room temperature), mol (mole), mmol (millimolar), g (gram), mg (milligram), sat. (saturated), v / v (volume / volume), id (inner diameter), psi (pounds per square inch), LC-MS (liquid chromatography mass spectrometry), HPLC (high performance liquid chromatography), TLC (thin layer chromatography), SFC (supercritical fluid chromatography). NMR spectroscopy. 1H nuclear magnetic resonance (NMR) spectroscopy was performed using a Bruker Avance III equipped with a BBFO 300 MHz probe operating at 300 MHz or one of the following instruments: a Bruker Avance 400 equipped with a DUAL 400 MHz S1 probe, a Bruker Avance 500 equipped with a 6S1 400 MHz 5 mm 1 H- 13 A Bruker Avance 400 instrument with a CID probe, a Bruker Avance III 400 instrument with a nanobay equipped with a 5 mm direct broadband BBFO probe, and a Bruker Mercury Plus 400 NMR spectrometer equipped with a Bruker 400BBO probe were used, all operating at 400 MHz. All deuterated solvents typically contained 0.03% to 0.05% v / v tetramethylsiloxane as a reference signal (for 1 H and 13 C was set to δ 0.00. In some cases, unless otherwise stated, the solvents were used at around room temperature using a Bruker Advance 400 instrument (operating at 400 megahertz (MHz)). 1 H nuclear magnetic resonance (NMR) spectroscopy. In all cases, the NMR data were consistent with the proposed structure. To denote the major peaks, characteristic chemical shifts (δ) are expressed in parts per million using conventional abbreviations: for example, s, singlet; d, doublet; t, triplet; q, quartet; dd, doublet of a doublet; ddd, doublet of a doublet of a doublet, dt, doublet of a triplet; br, broad; m, multiplet. Chemical shifts are expressed in Hz (Hertz). Chromatography. Silica gel F254 (Merck) plates or plates from Manchester-Nagel were used. (Silica gel 60F254) is used for thin layer chromatography (TLC). Automatic flash chromatography system is used to carry out column chromatography on silica gel, eluting with typical solvents such as EtOAc / hexane or MeOH / DCM. Reverse phase HPLC is carried out using a C18 column, eluting with typical solvents (such as water and acetonitrile, wherein containing formic acid, TFA or HCl as additives). Liquid chromatography-mass spectrometry method A: The HPLC-MS / MS was carried out on a UPLC / MS Acquity HPLC system equipped with a PDA detector and coupled to a Waters single quadrupole mass spectrometer operating in alternating positive and negative electrospray ionization mode. TM Total ion current (TIC) and DAD UV chromatograms as well as peak-related MS and UV spectra were acquired on the system. [LC / MS-ES(+ / -): Using Acquity UPLC TMAnalysis was performed using a CSH C18 column (50×2.1 mm, 1.7 μm particle size), column temperature 40°C, mobile phase: A—water + 0.1% HCOOH / B—CH3CN + 0.1% HCOOH, flow rate: 1.0 mL / min, run time = 2.0 min, gradient: t=0 min 3% B, t=1.5 min 99.9% B, t=1.9 min 99.9% B, t=2.0 min 3% B, stop time 2.0 min. Positive ES 100-1000, negative ES 100-1000, UV detection DAD 210-350 nm. Liquid chromatography-mass spectrometry method B: HPLC-MS / MS was performed on a UPLC / MS Acquity HPLC system equipped with a PDA detector and coupled to a Waters single quadrupole mass spectrometer operating in alternating positive and negative electrospray ionization mode. TM Total ion current (TIC) and DAD UV chromatograms, as well as peak-related MS and UV spectra, were acquired on the system. The column used was a Cortecs UPLC C18, 1.6 μm, 2.1 × 50 mm. A linear gradient was applied, starting at 95% A (A: 0.1% formic acid in water) and ending at 95% B (B: 0.1% formic acid in MeCN) over 2 minutes, with a total run time of 2.5 minutes. The column temperature was 40°C, and the flow rate was 0.8 mL / min. Liquid chromatography-mass spectrometry method C: LCMS analysis was performed on a SHIMADZU LCMS consisting of a UFLC 20-AD and an LCMS2020MS detector. The diode array detector scanned at 190-400 nm. The mass spectrometer was equipped with an electrospray ionization source (ESI) operating in positive or negative mode. The mass spectrometer scanned between m / z 90-900 with a scan time of 0.5 to 1.0 s. The column used was a Shim-pack XR-ODS, 2.2 μm, 3.0×50 mm. A linear gradient was applied starting at 95% A (A: 0.05% TFA in water) and ending at 100% B (B: 0.05% TFA in MeCN) in 2.2 min, with a total run time of 2.6 min. The column temperature was 40° C. and the flow rate was 1.0 mL / min. Liquid chromatography-mass spectrometry method D: LCMS analysis was performed on a SHIMADZU LCMS consisting of a UFLC 20-AD and an LCMS2020MS detector. The diode array detector scanned at 190-400 nm. The mass spectrometer was equipped with an electrospray ionization source (ESI) operating in positive or negative mode. The mass spectrometer scanned between m / z 90-900 with a scan time of 0.5 to 1.0 s. The column used was a Kinetex EVO, 2.6 μm, 3.0×50 mm. A linear gradient was applied starting at 90% A (A: 0.05% NH4HCO3 in water) and ending at 95% B (B: MeCN) in 2.7 min, with a total run time of 3.0 min. The column temperature was 40°C and the flow rate was 1.3 mL / min. Liquid chromatography-mass spectrometry method E: LCMS analysis was performed on a SHIMADZU LCMS consisting of a UFLC 20-AD and an LCMS2020MS detector. The diode array detector scanned at 190-400 nm. The mass spectrometer was equipped with an electrospray ionization source (ESI) operating in positive or negative mode. The mass spectrometer scanned between m / z 90-900 with a scan time of 0.5 to 1.0 s. The column used was an Ascentis Express C18, 2.7 μm, 2.1×50 mm. A linear gradient was applied starting at 90% A (A: 0.1% formic acid in water) and ending at 100% B (B: 0.1% formic acid in MeCN) in 1.70 min, with a total run time of 2.0 min. The column temperature was 45°C and the flow rate was 1.0 mL / min. Liquid chromatography-mass spectrometry method F: LCMS analysis was performed on a SHIMADZU LCMS consisting of a UFLC 20-AD and an LCMS2020MS detector. The diode array detector scanned at 190-400 nm. The mass spectrometer was equipped with an electrospray ionization source (ESI) operating in positive or negative mode. The mass spectrometer scanned between m / z 90-900 with a scan time of 0.5 to 1.0 s. The column used was an Agilent Poroshell HPH-C18, 2.7 μm, 3.0×50 mm. A linear gradient was applied starting at 95% A (A: 0.05% NH4HCO3 in water) and ending at 95% B (B: 0.05% NH4HCO3 in MeCN) over 2.7 min, with a total run time of 3 min. The column temperature was 45°C, and the flow rate was 1.5 mL / min. Liquid chromatography-mass spectrometry method G: LCMS analysis was performed on a SHIMADZU LCMS consisting of a UFLC 20-AD and LCMS2020MS detector. The diode array detector scanned from 190 to 400 nm. The mass spectrometer was equipped with an electrospray ionization source (ESI) operating in positive or negative mode. The mass spectrometer scanned between m / z 90 and 900 with a scan time of 0.5 to 1.0 s. The column used was an Agilent Poroshell HPH-C18, 2.7 μm, 3.0 × 50 mm. A linear gradient was applied starting at 95% A (A: 0.05% NH4HCO3 in water) and ending at 95% B (B: 0.05% NH4HCO3 in MeCN) over 4.7 min, with a total run time of 5.0 min. The column temperature was 40°C, and the flow rate was 1.5 mL / min. Liquid chromatography-mass spectrometry method H: LCMS analysis was performed on a SHIMADZU LCMS consisting of a UFLC 20-AD and LCMS2020MS detector. The diode array detector scanned from 190 to 400 nm. The mass spectrometer was equipped with an electrospray ionization source (ESI) operating in positive or negative mode. The mass spectrometer scanned between m / z 90 and 900 with a scan time of 0.5 to 1.0 s. The column used was an Agilent Poroshell HPH-C18, 2.7 μm, 3.0 × 50 mm. A linear gradient was applied starting at 95% A (A: 0.05% NH4HCO3 in water) and ending at 95% B (B: 0.05% NH4HCO3 in MeCN) over 1.8 min, with a total run time of 2.0 min. The column temperature was 40°C, and the flow rate was 1.5 mL / min. Method A, T3P coupling: To a flask containing an amine (1.0 equivalent) and a carboxylic acid (2.0 equivalents) in a solvent (0.1 M) was added N-methylimidazole (2.0 equivalents), followed by a T3P solution (2.0 equivalents, 50% in EtOAc). The resulting reaction mixture was stirred at room temperature for 16 hours, at which point a 1 M NaOH solution was added followed by EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc (3 ×). The combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The crude reaction mixture was purified using silica gel flash chromatography or reverse phase preparative HPLC to give the desired product. Method B, HATU coupling: DMF (0.1 M) was added to a flask containing an amine (1.0 equivalent), a carboxylic acid (1.5 equivalents) and HATU (2.0 equivalents), followed by N,N-diisopropylethylamine (3-5 equivalents). The resulting reaction mixture was stirred overnight and diluted with brine and EtOAc. Layers were separated, and the aqueous layer was extracted with EtOAc (3×). The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The crude reaction mixture was purified using silica gel flash chromatography or reverse phase preparative HPLC to give the desired product. Method C, HATU coupling: TEA (5.0 equivalents) and DMF (0.15 M) were added to a vial containing an amine (1.0 equivalent), a carboxylic acid (1.5 equivalents) and HATU (2.0 equivalents). The resulting reaction mixture was stirred at room temperature for 16 hours, at which point water was added. The reaction mixture was diluted with EtOAc. The layers were separated, and the aqueous layer was extracted with EtOAc (3×). The combined organic layers were dried over anhydrous MgSO , filtered, and concentrated under reduced pressure. The crude reaction mixture was purified using silica gel flash chromatography or reverse phase preparative HPLC to give the desired product. Method D: when needing to prepare acyl chlorides, use SOCl Or the standard procedure of oxalyl chloride is prepared by corresponding acid.At room temperature, in THF (0.15M) solution of acyl chlorides (1.5 equivalents), add THF (0.15M) solution of triethylamine (5 equivalents) and amine (1 equivalent).Gained reaction mixture was stirred at room temperature 16 hours, now by mixture EtOAc and saturated NaHCO The aqueous solution was diluted.Layered and dried over sodium sulfate organic matter, filtered and concentrated under reduced pressure. Method E: Preparation of 9-fluoro-2,3,4,5-tetrahydropyrido[3,4-f][1,4]oxazepine 4-Chloro-5-fluoro-pyridine-3-carbaldehyde: To a solution of N-isopropylpropan-2-amine (9.23 g, 91.24 mmol) in THF (100 mL) was added n-butyllithium (2.5 M, 76.03 mmol, 36.49 mL) at -30 ° C over 15 minutes and stirred for 15 minutes. A solution of 4-chloro-3-fluoro-pyridine (10 g, 76.03 mmol) in THF (20 mL) was added dropwise at -78 ° C over 15 minutes, then stirred at -78 ° C for 6 hours, followed by the addition of DMF (7.02 mL, 91.24 mmol) and slowly warmed to 20 ° C. The reaction mixture was quenched by the addition of saturated NH4Cl (300 mL) at 0 ° C and extracted with EtOAc (3×300 mL). The organic layers were combined, washed with brine (3×50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc=100:1 to 4:1) to give the title compound (12 g, 99%) as a brown oil. 2-[(4-chloro-5-fluoro-3-pyridyl)methylamino]ethanol: To a mixture of 4-chloro-5-fluoro-pyridine-3-carboxaldehyde (2g, 12.54mmol) in MeOH (20mL), AcOH (1.51g, 25.07mmol) was added, followed by 2-aminoethanol (3.83g, 62.68mmol), and the reaction solution was stirred at 25°C for 3 hours. NaBH3CN (2.36g, 37.61mmol) was added and stirred at 25°C for 16 hours. The reaction mixture was quenched by adding water (50mL) at 0°C and extracted with DCM:i-PrOH (v:v=10:1, 3×50mL). The combined organic phase was washed with brine (50mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the title compound (1.46g, 57%) as a yellow oil. 9-Fluoro-2,3,4,5-tetrahydropyrido[3,4-f][1,4]oxazepine To a solution of 2-[(4-chloro-5-fluoro-3-pyridyl)methylamino]ethanol (1.4 g, 6.84 mmol) in DMF (20 mL) was added NaH (60% in mineral oil) (1.37 g, 34.21 mmol) and stirred at 25 ° C for 16 hours. The reaction mixture was diluted with water (30 mL). The mixture was extracted with DCM:i-PrOH (v:v=3:1, 3×30 mL), washed with water (30 mL) and brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the title compound (0.82 g, 71%) as a yellow oil. The following intermediates were prepared using similar methods as described above. Method F: Preparation of 1-(9-bromo-6-fluoro-3,5-dihydro-2H-1,4-benzoxazepine -4-yl)-3,3-difluoro-2,2-dimethyl-propan-1-one 4-Benzyl-9-bromo-6-fluoro-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine At room temperature, 4-benzyl-9-bromo-6-fluoro-2,3-dihydro-1,4-benzoxazepine was added. -5-ketone (1.0g, 2.9mmol) in THF (11.0mL) solution, add BH · SMe 2 (5.7mL, 11.4mmol). Heat the obtained reaction mixture at 60 ℃ for 2 hours, cool to 0 ℃ and slowly process with NaOH solution (25mL, 1M) and MeOH (10mL). The obtained mixture stirred for 15 minutes. Add EtOAc (50mL). Layer, and extract the water layer with EtOAc (3x 25mL). The organic layer merged is dried with anhydrous MgSO 4, filtered and concentrated under reduced pressure. Use flash chromatography on silica gel to purify (0-30% EtOAc / hexane) crude reaction mixture to obtain the desired product, which is a clear oil. 9-Bromo-6-fluoro-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine 4-Benzyl-9-bromo-6-fluoro-3,5-dihydro-2H-1,4-benzoxazepine (430mg, 1.28mmol) is dissolved in DCE (5.1mL) and treated with 1-chloroethyl chloroformate (0.28mL, 2.56mmol) at 90 ℃ for 1 hour.The reaction mixture is concentrated, and residue is dissolved in MeOH (10mL) and heated to 80 ℃ and continues for 2 hours.The concentrated solution is also added EtOAc (25mL) and NaOH solution (25mL).Layering, and water layer is extracted with EtOAc (3x 25mL).The organic layer merged is dried with anhydrous MgSO4, filtered and concentrated under reduced pressure.The crude reaction mixture is directly used without purification. 1-(9-Bromo-6-fluoro-3,5-dihydro-2H-1,4-benzoxazepine The title compound was prepared using General Procedure B employing 9-bromo-6-fluoro-2,3,4,5-tetrahydro-1,4-benzoxazepine in DMF (1 mL). (74 mg, 0.3 mmol), HATU (171 mg, 0.45 mmol), N,N-diisopropylethylamine (0.16 mL, 0.9 mmol) and 3,3-difluoro-2,2-dimethyl-propionic acid (62 mg, 0.45 mmol). Purification by column chromatography (0-40% EtOAc / hex) on combiflash followed by reverse phase HPLC gave the desired product as a brown solid. Method G: Preparation of 7-fluoro-2,3,4,5-tetrahydro-1,4-benzoxazepine -9-carbonitrile hydrochloride To a solution of 3-bromo-5-fluoro-2-hydroxy-benzaldehyde (240 mg, 1.1 mmol) in THF (1.0 mL) and ethanol (1.0 mL) was added ethanolamine (80 μL, 1.37 mmol) at room temperature. The reaction mixture was stirred at room temperature for 1 hour and cooled to 0°C. NaBH (17 mg, 0.44 mmol) was added, and the reaction mixture was warmed to room temperature and stirred for 4 hours. Water (5 mL) was added, and the two-phase mixture was stirred for 1 hour. NH4Cl solution (10 mL) and EtOAc (10 mL) were added, separated, and the aqueous layer was extracted with EtOAc (3 × 25 mL) and DCM (3 × 25 mL). The combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was suspended in THF (4.0 mL) and MeOH (1.0 mL) and cooled to 0°C. NEt3 (152 mg, 1.5 mmol) was added followed by Boc2O (218 mg, 1.0 mmol) and the resulting reaction mixture was stirred overnight. The reaction mixture was concentrated and purified using silica gel flash chromatography (25-75% EtOAc / hexanes) to give the desired product as a clear oil. 9-Bromo-7-fluoro-3,5-dihydro-2H-1,4-benzoxazepine To 4-hydroxy-4-carboxylic acid tert-butyl ester.By N-[(3-bromo-5-fluoro-2-hydroxy-phenyl) methyl]-N-(2-hydroxyethyl) carbamic acid tert-butyl ester (200mg, 0.55mmol) and PPh3(144mg, 0.55mmol) is dissolved in THF (2.0mL) and is cooled to 0 DEG C.DIAD (111mg, 0.55mmol) is added dropwise, and the reaction mixture is stirred overnight and is warmed to room temperature.The reaction mixture is concentrated, and flash chromatography on silica gel is used to purify (0-30% EtOAc / hexane), and required product is obtained, and it is clear oily matter. 9-Cyano-7-fluoro-3,5-dihydro-2H-1,4-benzoxazepine -4-carboxylic acid tert-butyl ester. -4-carboxylic acid tert-butyl ester (79mg, 0.23mmol) and Zn (CN) 2(26.8mg, 0.23mmol) flask, add DMF (2.0mL).With argon, solution was degassed 15 minutes, and tetrakis triphenylphosphine palladium (0) (26.4mg, 0.02mmol) was added. 100 ℃ of heated reaction mixtures were spent the night, cooled to room temperature and diluted with salt solution (10mL) and EtOAc (10mL). Layering, and EtOAc (3x 10mL) was used for water layer extraction, and the organic layer MgSO 4 merged was dried, filtered, and concentrated under reduced pressure. Use flash chromatography on silica gel to purify (0-50% EtOAc / hexane) crude reaction mixture, obtain required product, it is clarification oily matter. 7-Fluoro-2,3,4,5-tetrahydro-1,4-benzoxazepine -9-carbonitrile hydrochloride. 9-cyano-7-fluoro-3,5-dihydro-2H-1,4-benzoxazepine Tert-butyl-4-carboxylate (25 mg, 0.09 mmol) was dissolved in HCl solution (2.0 mL, 4 M in 1,4-dioxane) and stirred at room temperature for 1 hour. The resulting precipitate was collected and used directly. Method H: Preparation of 2,3,4,5-tetrahydro-1,4-benzoxazepine -8-carbonitrile hydrochloride 3-Hydroxy-4-[(2-hydroxyethylamino)methyl]benzonitrile. Ethanolamine (0.13mL, 2.12mmol) and 4-formyl-3-hydroxy-benzonitrile (250mg, 1.7mmol) were stirred in THF (2mL) and ethanol (2mL) overnight at room temperature. Sodium borohydride (64.3mg, 1.7mmol) was then added and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated to dryness, and the resulting residue was dissolved in EtOAc (25mL) and washed with 2x mL of water and then 1x mL of a saturated saline solution. The organic matter was then separated and dried (MgSO4), then concentrated to dryness. The crude product was used as is in the next step. LC-MS: m / z=193.01[M-Boc+H] + . N-[(4-cyano-2-hydroxy-phenyl) methyl]-N-(2-hydroxyethyl) carbamic acid tert-butyl ester.At 0 ℃, to 3-hydroxy-4-[(2-hydroxyethylamino) methyl] benzonitrile (235mg, 1.22mmol) THF (2mL) and methanol (2mL) solution, add triethylamine (0.26mL, 1.83mmol) and di-tert-butyl carbonate (266.83mg, 1.22mmol).Reaction mixture is slowly warmed to room temperature and stirred overnight.Concentrated reaction mixture, and use silica gel chromatography purification (0-60% EtOAc / hexane), obtain required product, it is colorless oil. 8-Cyano-3,5-dihydro-2H-1,4-benzoxazepine -4-carboxylic acid tert-butyl ester. N-[(4-cyano-2-hydroxy-phenyl)methyl]-N-(2-hydroxyethyl)carbamic acid tert-butyl ester (425 mg, 1.45 mmol) and triphenylphosphine (458 mg, 1.74 mmol) were dissolved in THF (10 mL) and cooled to 0 ° C. DIAD (0.31 mL, 1.6 mmol) was added dropwise and the reaction mixture was stirred overnight and warmed to room temperature. The reaction mixture was concentrated and purified using silica gel flash chromatography (0-30% gradient in ethyl acetate / hexane) to give the desired product as a clear oil. LC-MS: m / z=175.02[M–Boc+H] + . 2,3,4,5-Tetrahydro-1,4-benzoxazepine A 4 M solution of HCl in dioxane (2.55 mL, 10.21 mmol) was added to 8-cyano-3,5-dihydro-2H-1,4-benzoxazepine -tert-Butyl 4-carboxylate (280 mg, 1.02 mmol). After 20 minutes, the reaction mixture was diluted with ether and the white solid was collected by filtration to give the desired product. 1 H-NMR (400MHz, DMSO-d6): δ9.65-9.63 (m, 2H), 7.68-7.60 (m, 3H), 4.42 (s, 2H), 4.28 (dt, J=4.5, 2.3Hz, 2H), 3.52-3.49 (m, 2H). LC-MS: m / z=175.02[M+H] + . The following intermediates were prepared using similar methods as described above. Method I: Preparation of 2,3,4,5-tetrahydropyrido[3,4-f][1,4]oxazepine -9-carbonitrile dihydrochloride and 4-(3,3-difluoro-2,2-dimethyl-propionyl)-3,5-dihydro-2H-pyrido[3,4-f][1,4]oxazepine -9-carbonitrile 2-[(5-bromo-4-chloro-3-pyridinyl)methylamino]ethanol. 5-bromo-4-chloro-pyridine-3-carboxaldehyde (1 equivalent) was dissolved in dichloroethane (0.23 M). AcOH was added together with ethanolamine (2 equivalents) and the mixture was stirred for 10 minutes. Sodium triacetoxyborohydride (3 equivalents) was added and the mixture was stirred at room temperature overnight. Volatiles were removed under reduced pressure. The residue was treated with 1N NaOH until the pH was basic and extracted with DCM, dried over magnesium sulfate and concentrated under reduced pressure to give the desired substance as a white solid. 1 H-NMR (400MHz, CDCl3): δ8.70 (s, 1H), 8.54 (d, J = 0.6Hz, 1H), 4.03 (s, 2H), 3.75-3.70 (m, 2H), 2.88-2.85 (m, 2H). LCMS:m / z=266.87[M+H] + . 9-Bromo-3,5-dihydro-2H-pyrido[3,4-f][1,4]oxazepine -4-carboxylic acid tert-butyl ester. At 10 ° C, to a MeTHF (2.25M) solution of sodium tert-butoxide (3.0 equivalents), a MeTHF (0.38M) solution of 2- [(5-bromo-4-chloro-3-pyridyl) methylamino] ethanol (1.0 equivalent) was added while keeping the temperature below 15 ° C. The reaction mixture was stirred at 10-15 ° C for 1 hour and then quenched with a MeTHF (1.5M) solution of AcOH (2.0 equivalents). (Boc) O (1.0 equivalent) was added. The reaction mixture was stirred at 10-15 ° C for 3.5 hours and then diluted with water. Layering was performed, and the aqueous layer was extracted with MeTHF. The combined organics were washed with brine and concentrated in vacuo to give the title compound. 1 H-NMR (400MHz, CDCl3): δ 8.62-8.60 (m, 1H), 8.31-8.29 (m, 1H), 4.66-4.52 (m, 2H), 4.39-4.32 (m, 2H), 3.93-3.90 (m, 2H), 1.43 (dd, J=1.3, 0.7Hz, 9H). LCMS: m / z=330.40[M+H] + . 9-Formyl-3,5-dihydro-2H-pyrido[3,4-f][1,4]oxazepine -4-carboxylic acid tert-butyl ester. At 0 ° C, in an inert atmosphere, to 9-bromo-3,5-dihydro-2H-pyrido [3,4-f][1,4] oxazepine -4-carboxylic acid tert-butyl ester (1 equivalent) in THF (0.75M) solution, add i-PrMgCl-LiCl 1.3M THF (1.3 equivalent) solution, while keeping the temperature below 10 DEG C.Reaction mixture was stirred at 20 DEG C for 1 hour, was cooled to 10 DEG C, and DMF (1.5 equivalent) was added by addition funnel.Reaction mixture was stirred at 20 DEG C for 15 minutes, then concentrated in vacuo.Gained residue was distributed between water and EtOAc 1:1v / v.Layering and organic solution was concentrated in vacuo to obtain title compound, which was a yellow solid (95% yield). 1 H-NMR (400MHz, CDCl3): δ10.47 (s, 1H), 8.85 (s, 1H), 8.56-8.49 (m, 1H), 4.66-4.53 (m, 2H), 4.41 (br s, 2H), 3.91-3.89 (m, 2H), 1.40 (br s, 9H). LCMS: m / z=279[M+H] + . 9-cyano-3,5-dihydro-2H-pyrido[3,4-f][1,4]oxazepine -4-carboxylic acid tert-butyl ester. 9-Formyl-3,5-dihydro-2H-pyrido[3,4-f][1,4]oxazepine -4-carboxylic acid tert-butyl ester (1 equivalent), hydroxylamine hydrochloride (1.1 equivalents) and NEt (2 equivalents) in toluene (0.6M) was heated at 90 ° C for 30 minutes, then cooled to 50 ° C. Add 50% solution of T3P in EtOAc (2 equivalents), the reaction mixture was heated at 90 ° C for 30 minutes, then cooled to room temperature. The mixture was added to 10% K2CO3 and separated. The organic layer was washed with 10% K2CO3 aqueous solution and 5% KH2PO4 aqueous solution, then concentrated in vacuo to obtain the title compound as a yellow oil (78% yield). 1 H-NMR (CDCl3)=8.62 (brs, 1H), 8.45 (br s, 1H), 4.40-4.70 (m, 4H), 3.84-3.91 (m, 2H), 1.34-1.46 (m, 9H)ppm. LCMS: m / z=276.2[M+H] + . 2,3,4,5-Tetrahydropyrido[3,4-f][1,4]oxazepine -9-carbonitrile dihydrochloride. At 10 ° C to 9-cyano-3,5-dihydro-2H-pyrido [3,4-f] [1,4] oxazepine -4-carboxylic acid tert-butyl ester (1 equivalent) in toluene and IPA 1: 1v / v (0.5M) solution, add acetyl chloride (6 equivalents). The reaction mixture was stirred at room temperature for 3 hours. LCMS indicates that the reaction is not complete. Add additional acetyl chloride (3 equivalents) and stir the mixture overnight. The resulting precipitate is collected by vacuum filtration, and washed with MTBE to obtain the title compound (87% yield) as a white solid. 1 H-NMR (400MHz, CDCl3): δ10.17 (br s, 2H), 8.89 (s, 1H), 8.74 (s, 1H), 4.54-4.74 (m, 2H), 4.54 (s, 2H), 3.60 (s, 2H). LCMS: m / z=176[M+H] + . 4-(3,3-Difluoro-2,2-dimethyl-propionyl)-3,5-dihydro-2H-pyrido[3,4-f][1,4]oxazepine To a solution of 3,3-difluoro-2,2-dimethyl-propionic acid (1.3 eq) in CH3CN (1 M) was added N-methylimidazole (7 eq) followed by MsCl (1.3 eq). The reaction mixture was heated at 55°C for 90 min. The reaction mixture was cooled to 20°C and 2,3,4,5-tetrahydropyrido[3,4-f][1,4]oxazepine was added. -9-carbonitrile dihydrochloride (1 equivalent) was added and the reaction mixture was stirred for 45 minutes. 10% K2CO3 aqueous solution and DCM (1:1 v / v) were added and the layers were separated. The organic layer was washed with 10% K2CO3 aqueous solution and then concentrated in vacuo. The resulting solid was crystallized from IPA to give the title compound. 2-[(5-bromo-4-chloro-3-pyridyl)methylamino]ethanol. 5-bromo-4-chloro-pyridine-3-carboxaldehyde (600mg, 2.72mmol) was dissolved in dichloroethane (12mL). AcOH and ethanolamine (332mg, 5.44mmol) were added together and the mixture was stirred for 10 minutes. Sodium triacetoxyborohydride (1730mg, 8.16mmol) was added and the mixture was stirred at room temperature overnight. Volatiles were removed under reduced pressure. The residue was treated with 1N NaOH until the pH was alkaline and extracted with DCM (40mL), dried over magnesium sulfate and concentrated under reduced pressure to obtain the desired material as a white solid. 1 H-NMR (400 MHz, CDCl3): δ 8.70 (s, 1H), 8.54 (d, J = 0.6 Hz, 1H), 4.03 (s, 2H), 3.75-3.70 (m, 2H), 2.88-2.85 (m, 2H). LCMS (Method B): m / z [M+H] +=266.87,268.76. 9-Bromo-3,5-dihydro-2H-pyrido[3,4-f][1,4]oxazepine -4-carboxylic acid tert-butyl ester. To a DMF solution of 2-[(5-bromo-4-chloro-3-pyridyl)methylamino]ethanol (0.48 g, 1.81 mmol) was added NaH (0.36 g, 9.04 mmol). After stirring at room temperature overnight, the reaction was carefully treated with water at 0°C. The reaction mixture was diluted with EtOAc (30 mL). The organics were then separated and dried (MgSO4), then concentrated to dryness to give the desired cyclized intermediate (LCMS (Method B): m / z [M+H] + =228.95, 230.93). The crude product was then dissolved in DMF (10 mL) and treated with di-tert-butyl dicarbonate (0.79 g, 3.62 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was then diluted with water (20 mL) and EtOAc (20 mL). The organic matter was then separated and dried (MgSO4), and then concentrated to dryness. The crude product was then purified by flash column chromatography using 0-100% EtOAc / hexane as an eluent to give the desired product as a colorless oil. 1 H-NMR (400 MHz, CDCl3): δ 8.62-8.60 (m, 1H), 8.31-8.29 (m, 1H), 4.66-4.52 (m, 2H), 4.39-4.32 (m, 2H), 3.93-3.90 (m, 2H), 1.43 (dd, J = 1.3, 0.7 Hz, 9H). LC-MS (Method B): m / z = 330.40 [M+H] + . 9-cyano-3,5-dihydro-2H-pyrido[3,4-f][1,4]oxazepine -4-carboxylic acid tert-butyl ester. -4-carboxylic acid tert-butyl ester (230mg, 0.7mmol) and zinc cyanine (82mg, 0.7mmol) were added to a flask with DMF (5mL). The solution was sprayed with argon for 15 minutes, and then tetrakis (triphenylphosphine) palladium (0) (242mg, 0.21mmol) was added. The reaction mixture was heated at 100°C overnight, cooled to room temperature and diluted with water (10mL) and EtOAc (10mL). The organic matter was then separated and dried (MgSO4), and then concentrated to dryness. The crude product was then purified by flash column chromatography with 0-100% EtOAc / hexane elution to obtain the desired product as a colorless oil. LC-MS (method B): m / z=276.48[M+H] + . 2,3,4,5-Tetrahydropyrido[3,4-f][1,4]oxazepine -9-carbonitrile hydrochloride. 10 mL of 4M HCl / dioxane (40 mmol) was added to 9-cyano-3,5-dihydro-2H-pyrido[3,4-f][1,4]oxazepine -4-carboxylic acid tert-butyl ester (120 mg, 0.44 mmol). After 20 minutes, the reaction mixture was diluted with diethyl ether (10 mL) and the solid was collected by filtration to give the desired product as an orange solid. 1 H-NMR (400 MHz, DMSO-d6): δ 10.04-10.03 (m, 2H), 8.90 (s, 1H), 8.74 (s, 1H), 4.74-4.72 (m, 2H), 4.55-4.54 (m, 2H), 3.64-3.59 (m, 2H). LC-MS (Method B): m / z = 176.37 [M+H] + . 4-(3,3-Difluoro-2,2-dimethyl-propionyl)-3,5-dihydro-2H-pyrido[3,4-f][1,4]oxazepine -9-carbonitrile. General Procedure C was used with 2,3,4,5-tetrahydropyrido[3,4-f][1,4]oxazepine in DMF (1 mL). -9-carbonitrile hydrochloride (35 mg, 0.17 mmol), 3,3-difluoro-2,2-dimethyl-propionic acid (34 mg, 0.248 mmol), TEA (0.230 mL, 1.65 mmol) and HATU (125 mg, 0.33 mmol) were prepared. Purification by reverse phase HPLC gave the desired product as a white solid. 1H-NMR (400MHz, CDCl3): δ8.67 (s, 1H), 8.61 (s, 1H), 6.11 (t, J=56.5Hz, 1H), 4 .80 (s, 2H), 4.62-4.60 (m, 2H), 4.13 (t, J=5.0Hz, 2H), 1.39 (t, J=1.3Hz, 6H). LC-MS (Method B): m / z=296.29[M+H] + . Method J: Preparation of 2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine N-Benzyl-N-(2-(tert-butyldimethylsilyloxy)ethyl)-2-chloronicotinamide. To a mixture of 2-chloropyridine-3-carboxylic acid (1.0 g, 6.37 mmol) in N,N-dimethylformamide (15 mL) was added N-benzyl-2-(tert-butyldimethylsilyloxy)ethylamine (1.69 g, 6.37 mmol), 1-hydroxybenzotriazole (1.29 g, 9.55 mmol), and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (1.83 g, 9.55 mmol). After stirring at room temperature overnight, the reaction mixture was quenched by the addition of water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate / petroleum ether, 1 / 2) to give the title compound (2.2 g, 85%) as a yellow oil. LC-MS: m / z = 405.00 [M+H] + . N-Benzyl-2-(tert-butyldimethylsilyloxy)-N-((2-chloropyridin-3-yl)methyl)ethanamine. To a mixture of N-benzyl-N-(2-(tert-butyldimethylsilyloxy)ethyl)-2-chloronicotinamide (1.4 g, 3.46 mmol) in tetrahydrofuran (30 mL) was added a solution of borane in tetrahydrofuran (1 M, 17.3 mL). The resulting mixture was heated at 90° C. and stirred under nitrogen for 1 hour. After cooling to room temperature, the reaction mixture was quenched by the slow addition of methanol (20 mL) and concentrated in vacuo to give the title compound (1.7 g crude) as a white oil. LC-MS: m / z=391.15 [M+H] + . 2-(Benzyl((2-chloropyridin-3-yl)methyl)amino)ethanol. N-Benzyl-2-(tert-butyldimethylsilyloxy)-N-((2-chloropyridin-3-yl)methyl)ethanamine (1.7 g, 3.46 mmol) was added to hydrochloric acid (6N, 15 mL). The resulting mixture was heated at 90 ° C and stirred for 2 hours. After cooling to room temperature, the pH value of the reaction mixture was adjusted to 8 with aqueous sodium hydroxide solution (1 M, 15 mL). The resulting mixture was then extracted with ethyl acetate (3 x 20 mL). The combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give the title compound (550 mg, 57%, two-step yield) as a white oil. LC-MS: m / z = 277.05 [M + H] + . 4-Benzyl-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine Sodium hydride (96 mg, 4.0 mmol) was added to a stirred mixture of 2-(benzyl((2-chloropyridin-3-yl)methyl)amino)ethanol (550 mg, 1.99 mmol) in tetrahydrofuran (10 mL) at 0°C. The resulting mixture was then heated to 90°C and stirred for 1 hour. After cooling to room temperature, the reaction mixture was quenched by adding water (20 mL) and extracted with ethyl acetate (3 x 15 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative TLC (ethyl acetate) to give the title compound (470 mg, 98%) as a white oil. LC-MS: m / z=241.2[M+H] + . 2,3,4,5-Tetrahydropyrido[3,2-f][1,4]oxazepine 4-Benzyl-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine A mixture of (200 mg, 0.83 mmol) in methanol (5 mL) was hydrogenated in the presence of palladium hydroxide (20%, 120 mg) under a hydrogen atmosphere (2-3 atm). After stirring at room temperature overnight, the reaction mixture was filtered through celite. The filtrate was concentrated in vacuo to give the title compound (110 mg, 88%) as a white oil. LC-MS: m / z=150.88 [M+H] + . The following intermediates were prepared using similar methods as described above. Method K: Preparation of 2-cyclopropyl-3,3-difluoro-2-methyl-propionic acid: Ethyl 2-cyclopropylacetate: To a solution of 2-cyclopropylacetic acid (10.00 g, 99.88 mmol) in EtOH (40 mL) was added SOCl (17.82 g, 149.83 mmol) at 0° C. The reaction solution was stirred at 70° C. for 4 h and then directly concentrated to give the desired product (7 g, 55%) as a colorless oil. 1-tert-Butyl 3-ethyl 2-cyclopropylmalonate: At -78 ° C, under N2, to a solution of LDA (2M, 43.89 mL) in THF (10 mL) was added ethyl 2-cyclopropylacetate (4.50 g, 35.11 mmol) in THF (5 mL). The reaction solution was stirred at -78 ° C for 30 minutes and at 0 ° C for 30 minutes. Then, Boc2O (8.05 g, 36.87 mmol) was added dropwise at -78 ° C. The reaction solution was stirred at 25 ° C for 2 hours. The reaction mixture was quenched with saturated NH4Cl (30 mL) at 0 ° C and then extracted with EtOAc (3 × 30 mL). The combined organic layer was washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE:EtOAc=1:0 to 10:1) to give the title compound (5.55 g, 69%) as a colorless oil. 3-ethyl 2-cyclopropyl-2-methylmalonic acid 1-tert-butyl ester: NaH (1.46 g, 36.47 mmol, 60% purity) was slowly added to a stirred THF (100 mL) solution of 3-ethyl 2-cyclopropylmalonic acid 1-tert-butyl ester (5.55 g, 24.31 mmol) at 0 ° C. Mel (6.90 g, 48.62 mmol) was added after 30 minutes. The mixture was stirred at 25 ° C for 16 hours. The reaction solution was quenched with saturated NH4Cl (50 mL), extracted with EtOAc (3 × 50 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE: EtOAc = 50: 1) to give the title compound (3.6 g, 61%) as a yellow oil. 2-Cyclopropyl-3-hydroxy-2-methyl-propionic acid tert-butyl ester: A mixture of 1-tert-butyl 3-ethyl 2-cyclopropyl-2-methylmalonate (1.8 g, 7.43 mmol) and lithium tri-tert-butoxyaluminum hydride (1 M, 44.57 mmol) in THF (30 mL) was heated at reflux for 16 hours. The reaction was quenched with saturated NH4Cl solution (200 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4, filtered and concentrated to give the desired compound (1.3 g, crude product) as a yellow oil. 2-cyclopropyl-2-methyl-3-oxo-propionic acid tert-butyl ester: DMP (3.30g, 7.79mmol) is added to a DCM (20mL) solution of 2-cyclopropyl-3-hydroxy-2-methyl-propionic acid tert-butyl ester (1.3g, 6.5mmol) in stirring. The reaction mixture is stirred at 30°C for 3 hours, then quenched with saturated NaHCO (30mL). The mixture is extracted with EtOAc (3 × 20mL), and the combined organic layer is washed with brine (20mL), dried over anhydrous NaSO, filtered and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (PE: EtOAc = 50: 1 to 20: 1) to give the title compound (0.7g, 55%) as a yellow solid. 2-cyclopropyl-3,3-difluoro-2-methyl-propionic acid tert-butyl ester: DAST (610 mg, 3.78 mmol) was added to a stirred DCM (10 mL) solution of 2-cyclopropyl-2-methyl-3-oxo-propionic acid tert-butyl ester (0.3 g, 1.51 mmol) at -78 ° C. The mixture was stirred at 30 ° C for 16 hours. The reaction was quenched with saturated NaHCO solution (30 mL) and extracted with DCM (3 × 20 mL). The combined organic matter was washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated to give the title compound (0.31 g) as a yellow oil. 2-Cyclopropyl-3,3-difluoro-2-methyl-propionic acid: To a solution of tert-butyl 2-cyclopropyl-3,3-difluoro-2-methyl-propanoate (0.15 g, 0.68 mmol) in 1,4-dioxane (3 mL) was added concentrated HCl (1.5 mL). The reaction solution was stirred at 25 ° C for 5 hours, diluted with H2O (10 mL) (10 mL), and extracted with DCM (2×30 mL). The combined organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated to give the title compound (0.08 g) as a dark yellow oil, which was used directly without purification. LCMS: m / z=163.1 [MH] - . Method L: Preparation of 2-(difluoromethyl)-2-methylbutyryl chloride 2-Formyl-2-methyl-butyric acid ethyl ester: At -78 ° C, under N2, LDA (2M, 46.09 mL) was added dropwise to a solution of ethyl 2-methylbutyrate (10 g, 76.81 mmol) in THF (100 mL). The mixture was stirred at -78 ° C for 30 minutes. Ethyl formate (6.83 g, 92.18 mmol) was then added dropwise at -78 ° C. The mixture was stirred at 25 ° C for 2.5 hours, poured into water (100 mL), and extracted with EtOAc (3 × 80 mL). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated to give the title compound (7 g, 58%) as a yellow oil. 1 H NMR (400MHz, CDCl3): δ9.66 (s, 1H), 4.15-4.21 (m, 2H), 1.79-1.95 (m, 2H), 1.22-1.24 (m, 6H), 1.07-1.10 (m, 3H). 2-(Difluoromethyl)-2-methylbutanoic acid ethyl ester: DAST (1.02g, 6.32mmol) was added to a DCM (10mL) solution of 2-formyl-2-methyl-butanoic acid ethyl ester (0.5g, 3.16mmol) at 0°C. The reaction mixture was warmed to 25°C and stirred for 12 hours. The reaction mixture was quenched with saturated NaHCO (15mL) and extracted with EtOAc (3×10mL). The organic layer was washed with salt water (10mL), dried over anhydrous NaSO, filtered and concentrated to give the title compound (350mg, 61%), which was a yellow oil that was used in the next step without purification. 1 H NMR (400MHz, CDCl3): δ6.00 (t, J=56.0Hz, 1H), 4.23-4.12 (m, 2H), 1.82-1.77 (m, 1H), 1.62-1.58 (m, 1H), 1.30-1.23 (m, 6H), 0.92-0.88 (t, J=7.60Hz, 3H). 2-(Difluoromethyl)-2-methylbutanoic acid: At 0 ° C, to a solution of MeOH (3 mL) and H2O (1 mL) of 2-(difluoromethyl)-2-methyl-butyric acid ethyl ester (350 mg, 1.94 mmol) was added NaOH (233.07 mg, 5.83 mmol). The mixture was stirred at 25 ° C for 12 hours. The solvent was removed under reduced pressure and water (10 mL) was added. The aqueous phase was washed with EtOAc (3 × 10 mL), and the aqueous solution was adjusted to pH = 4 with 2N HCl and extracted with DCM:i-PrOH (3 × 10 mL, v: v = 3: 1). The combined organic layer was washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the title compound (150 mg, 51%), which was a yellow oil. The crude product was used in the next step without purification. 1 H NMR (400MHz, CDCl3): δ6.02 (t, J=56Hz, 1H), 1.97-1.82 (m, 1H), 1.69-1.64 (m, 1H), 1.28 (s, 3H), 1.00-0.96 (t, J=7.60Hz, 3H). 2-(Difluoromethyl)-2-methylbutanoyl chloride: A solution of 2-(difluoromethyl)-2-methyl-butanoic acid (100 mg, 657.29 μmol) in SOCl2 (4.37 g, 36.76 mmol) was stirred at 70 ° C for 2 hours. The reaction mixture was concentrated under reduced pressure to give the title compound (110 mg) as a yellow oil. The crude product was used in the next step without purification. Method M: Preparation of 8-chloro-2,3,4,5-tetrahydropyrido[3,4-f][1,4]oxazepine -9-carbonitrile 2-(1-ethoxyethylidene)propane dinitrile: at 20 DEG C, under N2, 1,1,1-triethoxyethane (134g, 826mmol) and AcOH (2.1g, 34.97mmol) are added successively to malononitrile (45.5g, 688.75mmol).The mixture is stirred and gently heated to 90 DEG C for 2 hours, thereby removing ethanol by distillation.Then the reaction is stirred additionally at 130 DEG C for 1 hour, to ensure that the reaction is complete.The reaction mixture is cooled to room temperature, and hexane (200mL) is added to the gained solid.The grinding solid is collected by filtration and the filter cake is washed with EtOH (50mL) to obtain the title compound (87g, 93%), which is a white solid. 2,4-dichloro-5-formyl-pyridine-3-carbonitrile: At 95 ° C, POCl3 (165.6 g, 1.08 mol) was slowly added dropwise to a solution of 2-(1-ethoxyethylidene)propane dinitrile (35 g, 257.07 mmol) in DMF (80 g, 1.08 mol). The mixture was stirred at 95 ° C for 2 days. The reaction mixture was diluted with DCM (1 L) and stirred for 1 hour, and then the solution was slowly poured into H2O (1 L) and continued to stir for 1 hour. The reaction mixture was extracted with DCM (3 × 600 mL). The organic layers were combined, washed with brine (800 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE: EtOAc = 20: 1 to 3: 1) to give the title compound (37 g, 36%) as a yellow solid. 2,4-dichloro-5-[(2-hydroxyethylamino)methyl]pyridine-3-carbonitrile: To a solution of 2,4-dichloro-5-formyl-pyridine-3-carbonitrile (5 g, 24.87 mmol) in DCE (50 mL) was added AcOH (3 g, 49.75 mmol) at 25 ° C, and the solution was stirred for 30 minutes. 2-Aminoethanol (1.7 g, 27.36 mmol) was added at 25 ° C and stirred at 25 ° C for 2 hours. NaBH (OAc) 3 (15.8 g, 74.62 mmol) was then added in portions. The reaction solution was stirred at 25 ° C for 2 hours. The reaction mixture was quenched by adding saturated NH 4 Cl (10 mL) at 0 ° C, and the aqueous phase was neutralized to pH = 7 with saturated NaHCO 3 and extracted with EtOAc (3 × 20 mL). The combined organic layers were dried over anhydrous Na 2 SO 4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc=1:1 to DCM:MeOH=1:1) to give the title compound (2.7 g, 44%) as a yellow solid. LCMS: m / z=246.1 [M+H] + . 8-Chloro-2,3,4,5-tetrahydropyrido[3,4-f][1,4]oxazepine -9-carbonitrile: To a solution of 2,4-dichloro-5-[(2-hydroxyethylamino)methyl]pyridine-3-carbonitrile (0.5 g, 2.03 mmol) in DMF (10 mL) was added NaH (60% in mineral oil) (163 mg, 4.06 mmol) at 0 ° C. The reaction mixture was stirred at 25 ° C for 4 hours. The reaction mixture was quenched by adding saturated NH4Cl (20 mL) at 0 ° C. and then extracted with EtOAc (4×10 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc=1:1 to EtOAc:MeOH=1:1) to give the title compound (230 mg, 54%) as a yellow solid. LCMS: m / z=210.1.1[M+H] + Method N: Preparation of 4-fluoro-2,2-dimethyl-butyric acid Sodium (4-hydroxy-2,2-dimethyl-butyryl) oxide: To a solution of 3,3-dimethyltetrahydrofuran-2-one (0.7 g, 6.13 mmol) in EtOH (6 mL) was added H O (3 mL) and NaOH (245.31 mg, 6.13 mmol). The reaction mixture was heated at 100 ° C and stirred for 3 hours. The mixture was concentrated to give the title compound (1.1 g) as a white solid, which was used directly in the next step. 4-hydroxy-2,2-dimethyl-butyric acid benzyl ester: bromomethylbenzene (1.28 g, 7.49 mmol) was added to a DMF (10 mL) solution of (4-hydroxy-2,2-dimethyl-butyryl) sodium oxyhydrate (1.1 g, 7.14 mmol) at 25 ° C. The solution was stirred at 25 ° C for 16 hours, then quenched with water (20 mL) at 0 ° C, and then extracted with EtOAc (3 × 20 mL). The combined organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative TLC (SiO2, PE: EtOAc = 3: 1) to give the title compound (254 mg, 16%) as a yellow oil. 2,2-dimethyl-4-methylsulfonyloxy-butyric acid benzyl ester: at 0 ° C, under N2, to a DCM (1 mL) solution of 4-hydroxy-2,2-dimethyl-butyric acid benzyl ester (0.09 g, 405 μmol) was added TEA (61.46 mg, 607 μmol, 85 μL) and MsCl (69.57 mg, 607 μmol, 47 μL). The mixture was stirred at 0 ° C for 1 hour. The mixture was diluted with DCM (10 mL), washed with water (3 mL) and brine (3 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated to give the title compound (0.12 g, 99%) as a colorless oil that was used directly in the next step. 4- fluoro-2,2-dimethyl-butyrate: TBAF (1M in THF, 4mL) solution of 2,2-dimethyl-4-methylsulfonyloxy-butyric acid benzyl ester (0.12g, 399μmol) was heated at 70 DEG C and stirred for 4 hours. The mixture was diluted with EtOAc (10mL) and washed with water (3mL) and brine (3mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated. The obtained residue was purified by preparative TLC (SiO2, PE:EtOAc=20:1) to give the title compound (0.07g, 78%) as a colorless oil. 4-Fluoro-2,2-dimethyl-butyric acid: To a solution of 4-fluoro-2,2-dimethyl-butyric acid benzyl ester (0.07 g, 312 μmol) in EtOAc (2 mL) was added 10% Pd / C (0.02 g) under N2. The suspension was degassed in vacuo and purged with H2 three times. The mixture was stirred at 25°C under H2 (50 psi) for 16 hours. The reaction mixture was filtered and the filtrate was concentrated to give the title compound (0.03 g, 72%) as a colorless oil which was used in the next step without purification. Method O: Preparation of 9-methyl-2,3,4,5-tetrahydropyrido[3,4-f][1,4]oxazepine dihydrochloride 9-Methyl-3,5-dihydro-2H-pyrido[3,4-f][1,4]oxazepine -4-carboxylic acid tert-butyl ester: to 9-bromo-3,5-dihydro-2H-pyrido[3,4-f][1,4]oxazepine -4-carboxylic acid tert-butyl ester (300mg, 911μmol) in THF (10mL) solution, add Pd (PPh3) 4 (105mg, 91μmol) and ZnMe2 (1M, 1.8mL), then under N2, stirred at 65 DEG C for 4 hours. By adding saturated NH4Cl (10mL) quenching the reaction mixture, and extracting with EtOAc (3 × 10mL). The combined organic layer is washed with brine (10mL), over anhydrous Na2SO4, dried, filtered and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (PE: EtOAc = 3: 1) to give the title compound (233mg, 73%), which is a yellow oil. 9-Methyl-2,3,4,5-tetrahydropyrido[3,4-f][1,4]oxazepine Dihydrochloride: 9-methyl-3,5-dihydro-2H-pyrido[3,4-f][1,4]oxazepine A solution of tert-butyl-4-carboxylate (230 mg, 765 μmol) in HCl / EtOAc (3 mL) was stirred at 25° C. for 12 hours. The reaction solution was concentrated under reduced pressure to give the title compound (72%) as a brown solid. Method P: Preparation of 8-(trifluoromethyl)-2,3,4,5-tetrahydropyrido[3,4-f][1,4]oxazepine 4-Chloro-6-(trifluoromethyl)pyridine-3-carboxylic acid: To a mixture of 2,2,6,6-tetramethylpiperidine (33.26 g, 235.47 mmol, 39.98 mL) in anhydrous THF (700 mL) was added n-butyl lithium (235.47 mmol, 2.5 M, 94.19 mL) dropwise at -78 ° C under N 2 . The mixture was stirred at -78 ° C for 30 minutes. The mixture was added dropwise to a solution of 6-(trifluoromethyl)pyridine-3-carboxylic acid (15 g, 78.49 mmol) in THF (700 mL) at -78 ° C. The mixture was stirred at -78 ° C for 1 hour and then added to a solution of hexachloroethane (37.16 g, 156.98 mmol, 17.78 mL) in THF (700 mL) and stirred at -78 ° C for 3 hours. The reaction mixture was quenched with saturated NH4Cl (500 mL) at -40 ° C and warmed to 25 ° C. The mixture was diluted with water (200 mL) and extracted with EtOAc (3×300 mL). The combined organics were washed with brine (200 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was triturated in MTBE (100 mL) to give the title compound (10 g, 27%) as a yellow solid. LCMS: m / z=225.9[M+H] + . [4-chloro-6-(trifluoromethyl)-3-pyridinyl] methanol: To a mixture of 4-chloro-6-(trifluoromethyl)pyridine-3-carboxylic acid (5 g, 22.17 mmol) in THF (50 mL) was added BH3.THF (66.50 mmol, 1 M, 66.50 mL) at 0 ° C under N2. The mixture was stirred at 25 ° C for 16 hours. The mixture was quenched with MeOH (10 mL) and poured into water (100 mL). The mixture was extracted with EtOAc (3×30 mL). The combined organics were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE: EtOAc = 20: 1 to 5: 1) to give the title compound (1.5 g, 32%) as a colorless oil. LCMS: m / z = 211.9 [M+H] + . 4-Chloro-6-(trifluoromethyl)pyridine-3-carbaldehyde: To a mixture of [4-chloro-6-(trifluoromethyl)-3-pyridinyl]methanol (700 mg, 3.31 mmol) in CHCl (20 mL) was added MnO (1.44 g, 16.54 mmol) at 25° C. under N2. The mixture was stirred at 70° C. for 16 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure to give the title compound (460 mg, 66%) as a yellow oil. 2-[(4-chloro-6-(trifluoromethyl)-3-pyridinyl)methylamino]ethanol: To a mixture of 4-chloro-6-(trifluoromethyl)pyridine-3-carboxaldehyde (460 mg, 2.20 mmol) and 2-aminoethanol (134 mg, 2.20 mmol) in DCE (25 mL) was added AcOH (264 mg, 4.39 mmol) at 25°C under N2. The mixture was stirred for 30 minutes at 25°C. NaBH(OAc)3 (1.40 g, 6.59 mmol) was then added and stirred for 16 hours. The mixture was poured into water (20 mL) and the organic phase was separated. The aqueous phase was adjusted to pH 7 with saturated NaHCO3 and extracted with DCM / i-PrOH (3×10 mL, v:v=3:1). The combined organic layers were dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to give the title compound (163 mg, 29%) as a colorless oil. 8-(Trifluoromethyl)-2,3,4,5-tetrahydropyrido[3,4-f][1,4]oxazepine To a mixture of 2-[(4-chloro-6-(trifluoromethyl)-3-pyridyl)methylamino]ethanol (163 mg, 640.13 μmol) in DMF (3 mL) was added NaH (64 mg, 1.60 mmol, 60% purity) at 0 ° C. under N2. The mixture was stirred at 25 ° C. for 16 hours. The mixture was poured into ice water (10 mL) and extracted with DCM / i-PrOH (3×5 mL, v:v=3:1). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by preparative TLC (SiO2, EtOAc) to give the title compound (34 mg, 24%) as a yellow oil. LCMS: m / z=219.1[M+H] + . Method Q: Preparation of 2-methyl-2-(trifluoromethoxy)propionic acid 2-(trifluoromethoxy)benzyl propionate: at 25 DEG C, under N2, to the mixture of AgOTf (12.83g, 49.94mmol), Selectfluor (8.85g, 24.97mmol) and KF (3.87g, 66.59mmol) in EtOAc (30mL), add 2-hydroxypropionic acid benzyl ester (3g, 16.65mmol).Then add 2-fluoropyridine (4.85g, 49.94mmol, 4.29mL) and TMSCF3 (7.1g, 49.94mmol).The mixture is stirred at 25 DEG C for 16 hours.The reaction mixture is filtered and the filtrate is concentrated.The crude product is purified by silica gel column chromatography (PE:EtOAc=100:1 to 10:1) to obtain title compound (1.7g, 41%), which is colorless oil. 2-Methyl-2-(trifluoromethoxy)benzyl propionate: at -78 ℃, under N 2, to a mixture of LiHMDS (1M, 12.09mL) in THF (5mL), HMPA (722mg, 4.03mmol, 708 μL) and 2-(trifluoromethoxy)benzyl propionate (1g, 4.03mmol) were added. The mixture was stirred at -78 ℃ for 5 minutes, then MeI (572mg, 4.03mmol) was added. The mixture was maintained at -78 ℃ and stirred for 2 hours. The mixture was quenched with saturated NH 4 Cl (50mL). The aqueous phase was extracted with EtOAc (3×15mL). The combined organic phase was washed with brine (10mL), dried over anhydrous Na 2 SO 4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc=100:1 to 50:1) to give the title compound (0.3 g, 28%) as a colorless oil. 2-Methyl-2-(trifluoromethoxy)propanoic acid: To a solution of benzyl 2-methyl-2-(trifluoromethoxy)propanoate (200 mg, 762.71 μmol) in EtOAc (5 mL) was added 10% Pd / C (0.07 g) under N. The suspension was degassed in vacuo and purged with H three times. The mixture was stirred at 25°C under H (50 psi) for 16 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure to give the title compound (0.12 g, 91%) as a colorless oil which was used directly in the next step. Method R: Preparation of 3-cyano-2,2-dimethylbutanoic acid 3-cyano-2,2-dimethylbutyric acid methyl ester: At -78 ° C, under N2, to a solution of LDA (2M, 3.50mL) in THF (15mL) was added dropwise 2-methylpropanoic acid methyl ester (0.65g, 6.36mmol). The mixture was stirred for 1 hour, and then 2-bromopropionitrile (1.02g, 7.64mmol) was added dropwise at -78 ° C. The resulting mixture was stirred for 10 hours at 25 ° C. The reaction mixture was quenched with HCl aqueous solution (3mL, 1N) at 0 ° C, then diluted with H2O (10mL) and extracted with EtOAc (2×15mL). The combined organics were washed with brine (30mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (0.84g, 85%) as a yellow oil that was used in the next step without purification. 3-Cyano-2,2-dimethylbutanoic acid: To a solution of 3-cyano-2,2-dimethyl-butyric acid methyl ester (400 mg, 2.58 mmol) in MeOH (3 mL) and H2O (1 mL) was added LiOH·H2O (433 mg, 10.31 mmol). The mixture was stirred at 25 ° C for 3 hours. The reaction mixture was concentrated under reduced pressure to remove MeOH. The residue was diluted with water (2 mL) and adjusted to pH = 4 with HCl aqueous solution (2N) and extracted with EtOAc (2×5 mL). The combined organics were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (270 mg, 74%) as a yellow oil that was used directly in the next step. LCMS: m / z=140.1[MH] - . The following intermediates were prepared using similar methods as described above. Method S: Preparation of 3,3-difluoro-2-methoxycarbonyl-2-methyl-butyric acid and 2-(difluoromethyl)-3-methoxy-2-methyl-3-oxo-propionic acid 1-tert-Butyl 3-methyl 2-(difluoro(trimethylsilyl)methyl)-2-methylmalonate and 1-tert-butyl 3-methyl 2-(difluoromethyl)-2-methylmalonate: At -78 ° C, under N2, LiHMDS (1M in THF, 106.26mL) was added to a solution of 1-tert-butyl 3-methyl 2-methylmalonate (20g, 106.26mmol) in THF (200mL). The mixture was stirred at -78 ° C for 30 minutes, and then MeLi (1M in THF, 106.26mL) was added. The mixture was stirred for 10 minutes, and then TMSCF3 (75.55g, 531.29mmol) was added. The reaction mixture was stirred for 16 hours and slowly warmed to 20 ° C. The mixture was slowly quenched with saturated NH4Cl aqueous solution (200mL). The organic phase was separated and the aqueous phase was extracted with MTBE (2×100mL). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to give the title compound (40 g, crude) as a colorless liquid. 1-tert-Butyl 3-Methyl 2-(1,1-Difluoroethyl)-2-methylmalonate and 1-tert-Butyl 3-Methyl 2-(difluoromethyl)-2-methylmalonate: KF (1.68 g, 28.99 mmol) was dried in vacuo and added to a mixture of 1-tert-butyl 3-methyl 2-(difluoro(trimethylsilyl)methyl)-2-methylmalonate and 1-tert-butyl 3-methyl 2-(difluoromethyl)-2-methylmalonate (3 g, 9.66 mmol) and MeI (4.12 g, 28.99 mmol, 1.80 mL) in DMF (20 mL) at 25 ° C under N2. The mixture was then heated to 80 ° C and stirred for 6 hours. This was done in 4 batches. The mixture was filtered through a celite pad and the filter cake was washed with MTBE (3×20 mL). The filtrate was poured into water (200 mL). The aqueous phase was extracted with MTBE (3 × 50 mL). The combined organic phase was washed with brine (50 mL), dried over Na2SO4, filtered and concentrated to give a residue. The residue was purified by silica gel column chromatography (PE: MTBE = 30: 1 to 10: 1) to give a mixture of 1-tert-butyl 3-methyl 2-(1,1-difluoroethyl)-2-methylmalonate and 1-tert-butyl 3-methyl 2-(difluoromethyl)-2-methylmalonate (6.5 g, 67%; ratio = 2: 3), which was a colorless liquid. 3,3-Difluoro-2-methoxycarbonyl-2-methyl-butanoic acid and 2-(difluoromethyl)-3-methoxy-2-methyl-3-oxo-propionic acid: To a mixture of 1-tert-butyl 3-methyl 2-(1,1-difluoroethyl)-2-methylmalonate and 1-tert-butyl 3-methyl 2-(difluoromethyl)-2-methylmalonate (2 g, 7.93 mmol) in DCM (20 mL) was added TFA (20 mL) at 25 ° C under N2. The reaction mixture was stirred at 25 ° C for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (20 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a mixture of 3,3-difluoro-2-methoxycarbonyl-2-methyl-butyric acid and 2-(difluoromethyl)-3-methoxy-2-methyl-3-oxo-propionic acid (2.7 g, crude product; ratio = 2:3) as a pale yellow oil. The residue was used without purification in the next step. Method T: Preparation of 3-fluoro-2,2-dimethyl-butyric acid and 2,2-dimethylbut-3-enoic acid 3-hydroxy-2,2-dimethyl-butyric acid benzyl ester: at -78 ° C, under N2, to a mixture of 2-methylpropionic acid benzyl ester (10.0 g, 56.11 mmol) in THF (200 mL) was added dropwise LDA (1 M, 56.11 mL). The mixture was stirred at -78 ° C for 1 hour. Acetaldehyde (3.0 g, 67.33 mmol) was then added dropwise to the mixture at -78 ° C while stirring, and the mixture was stirred at -78 ° C for 2 hours. The reaction mixture was quenched with saturated NH4Cl (150 mL) at 0 ° C, diluted with water (50 mL) and extracted with DCM (3 × 100 mL). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (PE: EtOAc = 1: 0 to 20: 1) to give the title compound (4 g, 32%) as a yellow oil. 3-Fluoro-2,2-dimethyl-butyric acid benzyl ester: at -78 ° C, under N2, DAST (1.74 g, 10.80 mmol) was added dropwise to a mixture of 3-hydroxy-2,2-dimethyl-butyric acid benzyl ester (2.00 g, 9.00 mmol) in DCM (40 mL). The mixture was stirred at -78 ° C for 2 hours. The reaction mixture was quenched with saturated NaHCO3 (40 mL) at 0 ° C, diluted with water (40 mL) and extracted with DCM (3 × 20 mL). The combined organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE: EtOAc = 100: 1 to 20: 1) to give the title compound (500 mg, 25%) as a yellow oil. 3-Fluoro-2,2-dimethyl-butyric acid and 2,2-dimethylbut-3-enoic acid: At 20 ° C, under N2, to a mixture of 3-fluoro-2,2-dimethyl-butyric acid benzyl ester (500 mg, 2.23 mmol) in THF (5 mL) and H2O (2 mL) was added KOH (375 mg, 6.69 mmol) at one time. The mixture was stirred at 20 ° C for 10 minutes, then heated to 70 ° C and stirred for 16 hours. The reaction mixture was diluted with water (14 mL) and extracted with EtOAc (5 mL). The organic phase was separated. The aqueous phase was adjusted to pH = 4-5 and extracted with DCM / i-PrOH (3 × 8 mL, v: v = 3 / 1). The combined organic layer was washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to obtain a mixture of the title compound (250 mg), which was a colorless oil. Method U: Preparation of 2-(1-hydroxycyclopropyl)-2-methylpropanoic acid Methyl 2-(1-hydroxycyclopropyl)-2-methylpropanoate: To a mixture of (1-ethoxycyclopropyloxy)-trimethyl-silane (5.0 g, 28.68 mmol) and (1-methoxy-2-methyl-prop-1-enyloxy)-trimethyl-silane (10.0 g, 57.37 mmol) in DCM (50 mL) was added BF3. Et2O (6.5 g, 45.89 mmol) at -78 °C. The mixture was slowly warmed to 25 °C over 5 hours. The reaction mixture was quenched at 0 °C with saturated NaHCO3 (20 mL), then diluted with DCM (20 mL) and extracted with DCM (2 x 25 mL). The combined organics were washed with brine (2 x 30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:MTBE=20:1 to 3:1) to give the title compound (3.0 g, 66%) as a yellow oil. 2-(1-Hydroxycyclopropyl)-2-methylpropanoic acid: To a solution of 2-(1-hydroxycyclopropyl)-2-methyl-propionic acid methyl ester (500 mg, 3.16 mmol) in MeOH (3 mL) and H2O (1 mL) was added LiOH·H2O (398 mg, 9.48 mmol). The mixture was stirred at 25°C for 3 hours. The reaction mixture was concentrated under reduced pressure to remove MeOH. The residue was diluted with H2O (2 mL) and extracted with EtOAc (2×3 mL). The aqueous phase was adjusted to pH=5 by adding 1N HCl and extracted with EtOAc (2×3 mL). The combined organics were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the title compound (240 mg, 42%) as a yellow oil. LCMS: m / z=143.1[MH] - . Method V: Preparation of (2,3-dihydrobenzo[f][1,4]oxazepine -4(5H)-yl)(1-(5-fluoropyrimidin-2-yl)piperidin-4-yl)methanone General procedure A was used with 2,3,4,5-tetrahydro-1,4-benzoxazepine To 4-nitro-1- methyl 4-thiazolyl ether (149mg, 1.0mmol), 1-tert-butoxycarbonylpiperidine-4-carboxylic acid (343mg, 1.5mmol), N-methylimidazole (246mg, 3.0mmol) and T3P (954mg, EtOAc (5mL) solution preparation title compound.Use flash chromatography on silica gel to purify (0-40% EtOAc / hexane), obtain the intermediate of required Boc-protection, it is white foam.This material is dissolved in HCl solution (4mL, 4M in dioxane).Stirring solution at room temperature 1 hour and concentrated, obtain the required compound for hydrochloride. The following intermediates were prepared using General Procedures A, B or C followed by deprotection with HCl. Method W: Nucleophilic Aromatic Substitution: A mixture of amine (1 equivalent), heteroaryl halide (2 equivalents) and CsCO (3 equivalents) in DMF (0.2M) was heated at 100°C until the reaction was complete. The reaction mixture was cooled to room temperature, and saturated NH4Cl was added followed by EtOAc. Layers were separated, and the aqueous layer was extracted 3 times with EtOAc. The combined organics were dried with MgSO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography or HPLC. In some cases, DIPEA, K2CO3, or NEt3 were used as bases, and acetonitrile, dioxane, or IPA were used as solvents. Method X: Preparation of 2-(2-(difluoromethyl)cyclopropyl)-2-methyl-propionic acid 2-(2-Ethoxy-1,1-dimethyl-2-oxo-ethyl)cyclopropanecarboxylic acid methyl ester: At -78 ° C, under N2, n-BuLi (2.5M, 89.53 mL) was added dropwise to a solution of i-Pr2NH (22.65 g, 223.83 mmol) in anhydrous THF (200 mL). The reaction mixture was warmed to 0 ° C and stirred for 30 minutes. Then, at -78 ° C, under N2, a solution of ethyl 2-methylpropanoate (20 g, 172.18 mmol) in anhydrous THF (50 mL) was added dropwise. The mixture was stirred for 30 minutes. Then, a solution of (E)-4-bromobut-2-enoic acid methyl ester (30.82 g, 172.18 mmol) in THF (50 mL) was added dropwise. The mixture was slowly warmed to 25 ° C and stirred for 3 hours. The mixture was quenched with saturated NH4Cl (200 mL). The mixture was diluted with water (100 mL) and extracted with EtOAc (3×200 mL). The combined organics were washed with brine (200 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to give the title compound (30 g, 81%) as a yellow oil. 2-(2-Ethoxy-1,1-dimethyl-2-oxo-ethyl)cyclopropanecarboxylic acid: To a mixture of methyl 2-(2-ethoxy-1,1-dimethyl-2-oxo-ethyl)cyclopropanecarboxylate (30 g, 140.02 mmol) in THF (100 mL), EtOH (100 mL) and H2O (100 mL) was added LiOH.H2O (11.75 g, 280.04 mmol) in one portion at 25°C. The mixture was stirred at 25°C for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (50 mL) and then with MTBE (25 mL). The organic phase was adjusted to pH 3-4 with aqueous HCl (1 N). The aqueous phase was extracted with EtOAc (3 x 30 mL). The combined organics were washed with brine (100 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to give the title compound (21 g, 75%) as a yellow oil. 2-(2-(Hydroxymethyl)cyclopropyl)-2-methyl-propionic acid ethyl ester: At 0 ° C, under N2, BH3.THF (1M, 149.83 mL) was added dropwise to a solution of 2-(2-ethoxy-1,1-dimethyl-2-oxo-ethyl)cyclopropanecarboxylic acid (10 g, 49.94 mmol) in THF (100 mL). The mixture was stirred at 0 ° C for 30 minutes, then warmed to 25 ° C and stirred for 3 hours. The reaction mixture was quenched with water (100 mL) and extracted with EtOAc (3×50 mL). The combined organics were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the title compound (6 g, 65%) as a yellow oil. 2-(2-Formylcyclopropyl)-2-methyl-propionic acid ethyl ester: At 0 ° C, under N2, DMP (1.37 g, 3.22 mmol) was added to a DCM (40 mL) solution of 2-(2-(hydroxymethyl)cyclopropyl)-2-methyl-propionic acid ethyl ester (0.5 g, 2.68 mmol). The reaction mixture was stirred at 25 ° C for 1 hour. The mixture was washed with saturated NaHCO3 (10 mL), Na2SO3 aqueous solution (10 mL, 10%) and brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (PE: EtOAc = 100 to 10: 1) to give the title compound (0.25 g, 51%) as a colorless oil. 2-(2-(Difluoromethyl)cyclopropyl)-2-methyl-propionic acid ethyl ester: At 0°C, under N2, DAST (328 mg, 2.04 mmol) was added dropwise to a mixture of 2-(2-formylcyclopropyl)-2-methyl-propionic acid ethyl ester (150 mg, 814.19 mmol) in DCM (2 mL). The mixture was stirred at 0°C for 30 minutes, then warmed to 25°C and stirred for 16 hours. The reaction mixture was slowly poured into an ice-cooled NaHCO3 solution and then extracted with EtOAc (3×10 mL). The combined organics were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the title compound (150 mg, 89%) as a yellow oil. 2-(2-(difluoromethyl)cyclopropyl)-2-methyl-propionic acid: At 25 ° C, to a mixture of ethyl 2-(2-(difluoromethyl)cyclopropyl)-2-methyl-propionic acid (150 mg, 727.35 μmol) in EtOH (2 mL) and H o (1 mL) was added LiOH.H o (183.13 mg, 4.36 mmol) at once. The mixture was stirred at 25 ° C for 30 minutes, then heated to 70 ° C and stirred for 16 hours. The mixture was cooled to 25 ° C and concentrated under reduced pressure. The residue was diluted with water (3 mL) and extracted with MTBE (5 mL). The aqueous phase was adjusted to pH = 3-4 with HCl aqueous solution (1 N) and extracted with EtOAc (3 × 5 mL). The combined organics were washed with brine (5 mL), dried over anhydrous Na SO , filtered and concentrated under reduced pressure to give the title compound (70 mg, 54%) as a yellow oil. Method Y: Preparation of 2-(2-cyanocyclopropyl)-2-methyl-propionic acid 2-(2-Carbamoylcyclopropyl)-2-methyl-propionic acid ethyl ester: At 25 ° C, to a solution of 2-(2-ethoxy-1,1-dimethyl-2-oxo-ethyl)cyclopropanecarboxylic acid (280 mg, 1.40 mmol) in DMF (2 mL) was added NH4Cl (449 mg, 8.39 mmol, 293.33 μL) and DIEA (1.08 g, 8.39 mmol, 1.46 mL) and stirred for 10 minutes. HATU (1.06 g, 2.80 mmol) was added at 25 ° C, and the mixture was stirred at 25 ° C for 2 hours. At 0 ° C, the reaction mixture was quenched with water (10 mL) and then extracted with EtOAc (3×10 mL). The combined organic layer was washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the title compound (220 mg, 79%) as a light yellow oil. 2-(2-Cyanocyclopropyl)-2-methyl-propionic acid ethyl ester: To a solution of 2-(2-carbamoylcyclopropyl)-2-methyl-propionic acid ethyl ester (0.22 g, 1.10 mmol) in EtOAc (2 mL) was added T3P (3.51 g, 5.52 mmol, 3.28 mL, 50% in EtOAc) at 25 ° C, and the solution was stirred at 75 ° C for 16 hours. The reaction mixture was quenched with water (10 mL) at 0 ° C, and then extracted with EtOAc (3×10 mL). The combined organic layer was washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE: EtOAc = 100: 1 to 5: 1) to give the title compound (220 mg, 55%) as a light yellow oil. LC-MS: m / z = 182.2 [M + H]+ . 2-(2-Cyanocyclopropyl)-2-methyl-propionic acid: To a solution of ethyl 2-(2-cyanocyclopropyl)-2-methyl-propanoate (50 mg, 275.89 μmol) in EtOH (2 mL) and H2O (2 mL) was added LiOH.H2O (46 mg, 1.10 mmol) at 25°C, and the solution was stirred at 25°C for 4 hours. The reaction mixture was washed with EtOAc (3×10 mL). The aqueous layer was adjusted to pH=4-5 by adding HCl (1 M) and then extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the title compound (40 mg, 95%) as a light yellow oil. Method Z: Preparation of 2-(3,3-difluorocyclobutyl)-2-methyl-propionic acid 2-(3-Hydroxycyclobutyl)-2-methyl-propionic acid ethyl ester: Under N2, 10% Pd / C (1 g) was added to a solution of 2-(3-benzyloxycyclobutyl)-2-methyl-propionic acid ethyl ester (3.2 g, 11.58 mmol) in EtOH (150 mL). The suspension was degassed under reduced pressure and purged with H2 several times. Under H2 (50 psi), the mixture was stirred at 50 ° C for 2 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure to give the title compound (2 g) as a yellow oil, which was used in the next step without purification. 2-Methyl-2-(3-oxocyclobutyl)ethyl propionate: at 0 ° C, under N2, to a mixture of 2-(3-hydroxycyclobutyl)-2-methyl-ethyl propionate (2g, 10.74mmol) in DCM (20mL), DMP (5.47g, 12.89mmol) was added. The mixture was stirred at 25 ° C for 1 hour. The mixture was diluted with DCM (60mL) and washed with saturated NaHCO3 (30mL), 10% Na2S2O3 aqueous solution (30mL), brine (30mL), and dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (PE: EtOAc = 20: 1 to 10: 1) to obtain the title compound (1g, 51%) as a colorless oil. 2-(3,3-difluorocyclobutyl)-2-methyl-ethyl propionate: At 0 ° C, under N2, DAST (787 mg, 4.89 mmol) was added to a DCM (3 mL) solution of 2-methyl-2-(3-oxocyclobutyl)ethyl propionate (0.3 g, 1.63 mmol). The reaction mixture was stirred at 25 ° C for 16 hours. The mixture was cooled to 0 ° C and poured into ice-water (30 mL). The aqueous phase was adjusted to pH = 8 with saturated NaHCO3 and extracted with MTBE (3 × 20 mL). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated. The resulting residue was purified by silica gel column chromatography (PE: MTBE = 30: 1 to 20: 1) to give the title compound (0.3 g, 89%) as a light yellow oil. 2-(3,3-difluorocyclobutyl)-2-methyl-propionic acid: At 25 ° C, under N2, to a solution of 2-(3,3-difluorocyclobutyl)-2-methyl-propionic acid ethyl ester (0.3 g, 1.45 mmol) in EtOH (4 mL) and H2O (2 mL) was added LiOH.H2O (366 mg, 8.73 mmol). The reaction mixture was heated at 50 ° C for 16 hours. The mixture was concentrated under reduced pressure to remove EtOH. The remaining aqueous phase was diluted with water (5 mL) and washed with MTBE (5 mL). The aqueous phase was adjusted to pH = 3-4 with HCl aqueous solution (2N) and extracted with EtOAc (3×10 mL). The combined organic phase was washed with brine (5 mL), dried over Na2SO4, filtered and concentrated to give the title compound (0.17 g, 66%) as a light yellow oil that was used without further purification. Method AA: Preparation of 2-[1-(5-fluoropyrimidin-2-yl)azetidin-3-yl]-2-methyl-propionic acid 2-[1-(5-fluoropyrimidin-2-yl)azetidin-3-yl]-2-methyl-propionic acid methyl ester: At 25 ° C, under N2, to a mixture of 2-(azetidin-3-yl)-2-methyl-propionic acid methyl ester trifluoroacetic acid (0.2 g, 737.37 μmol) and 2-chloro-5-fluoro-pyrimidine (195 mg, 1.47 mmol) in DMF (2 mL) was added K2CO3 (407 mg, 2.95 mmol). The reaction mixture was heated at 100 ° C for 4 hours. The reaction mixture was cooled to 25 ° C and poured into ice-water (60 mL). The aqueous phase was extracted with EtOAc (3×20 mL). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The obtained residue was purified by preparative TLC (SiO 2 , PE:EtOAc=10:1) to give the title compound (0.11 g, 59%) as a pale yellow oil. 2-[1-(5-fluoropyrimidin-2-yl)azetidin-3-yl]-2-methyl-propionic acid: To a solution of methyl 2-[1-(5-fluoropyrimidin-2-yl)azetidin-3-yl]-2-methyl-propanoate (0.11 g, 434.32 μmol) in MeOH (4 mL) and H2O (1 mL) was added LiOH.H2O (182 mg, 4.34 mmol) at 25°C under N2. The reaction mixture was stirred at 25°C for 16 hours. The reaction mixture was cooled to 0°C, adjusted to pH = 3-4 with aqueous HCl (2N), and concentrated to dryness under reduced pressure to give the title compound (0.103 g) as a yellow solid, which was used in the next step without purification. LC-MS: m / z = 240.2 [M+H] + . The following intermediates were prepared using methods similar to those described above. In some cases, the first step was performed using TEA or DIPEA as the base, EtOH as the solvent, and heating by microwave irradiation. Method AB: Preparation of 4-fluoro-1-(5-fluoropyrimidin-2-yl)piperidine-4-carboxylic acid hydrochloride 4-Fluoro-1-(5-fluoropyrimidin-2-yl)piperidine-4-carboxylic acid ethyl ester: To a solution of 4-fluoropiperidine-4-carboxylic acid ethyl ester hydrochloride (500 mg, 2.36 mmol) in DMF (5 mL) was added Cs2CO3 (1.54 g, 4.72 mmol) and 2-chloro-5-fluoro-pyrimidine (313 mg, 2.36 mmol). The reaction mixture was stirred at 50 ° C for 12 hours. The reaction mixture was diluted with H2O (5 mL) and extracted with EtOAc (3×5 mL). The combined organic layer was washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (SiO2, PE:EtOAc=10:1 to 0:1) to give the title compound (370 mg, 58%) as a yellow oil. LCMS: m / z=272.1[M+H] + . 4-Fluoro-1-(5-fluoropyrimidin-2-yl)piperidine-4-carboxylic acid hydrochloride: To a solution of ethyl 4-fluoro-1-(5-fluoropyrimidin-2-yl)piperidine-4-carboxylate (190 mg, 700.43 μmol) in 1,4-dioxane (2 mL) was added HCl (6 M, 2 mL). The reaction mixture was stirred at 60 ° C for 12 hours and then concentrated under reduced pressure to give the title compound (170 mg, 90%) as a white solid. LCMS: m / z = 244.1, [M + H] + . The following intermediates were prepared using similar methods as described above. Method AC: Preparation of cis-3-(5-fluoropyrimidin-2-yl)-3-azabicyclo[4.1.0]heptane-6-carboxylic acid Cis-3-Azabicyclo[4.1.0]heptane-6-carboxylic acid hydrochloride: A mixture of cis-3-tert-butoxycarbonyl-3-azabicyclo[4.1.0]heptane-6-carboxylic acid (100 mg, 414.45 μmol) in HCl / MeOH (1 mL, 4N) was heated at 60° C. for 4 hours. The reaction mixture was concentrated under reduced pressure to give the title compound (0.096 g) as a white solid which was used directly in the next step. Cis-3-(5-fluoropyrimidin-2-yl)-3-azabicyclo[4.1.0]heptane-6-carboxylic acid methyl ester: To a mixture of cis-3-azabicyclo[4.1.0]heptane-6-carboxylic acid methyl ester hydrochloride (0.09 g, 469.59 μmol) and 2-chloro-5-fluoro-pyrimidine (124 mg, 939.19 μmol) in DMF (4 mL) was added KCO (259 mg, 1.88 mmol). The reaction mixture was heated at 100° C. for 4 hours. The mixture was cooled to 25° C., poured into water (20 mL), and extracted with EtOAc (3×10 mL). The combined organic phases were washed with brine (10 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative TLC (SiO2, PE:EtOAc=9:1) to give the title compound (0.1 g, 85%) as a white solid. LC-MS: m / z=252.1 [M+H] + . Cis-3-(5-fluoropyrimidin-2-yl)-3-azabicyclo[4.1.0]heptane-6-carboxylic acid: At 25°C, under N2, to a mixture of cis-3-(5-fluoropyrimidin-2-yl)-3-azabicyclo[4.1.0]heptane-6-carboxylic acid methyl ester (0.1 g, 398.00 μmol) in MeOH (4 mL) was added NaOH (2N, 0.8 mL). The reaction mixture was stirred at 25°C for 16 hours and then at 50°C for 4 hours. The mixture was cooled to 25°C and concentrated under reduced pressure. The resulting residue was diluted with water (10 mL). The solution was adjusted to pH 3-4 with KHSO4 aqueous solution (1 N) and extracted with DCM (3×10 mL). The combined organic phases were washed with brine (10 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to afford the title compound (0.09 g, 95%) as a white solid which was used without further purification. Method AD: Preparation of 2-(1-(5-fluoropyrimidin-2-yl)pyrrolidin-3-yl)-2-methylpropanoic acid tert-Butyl 3-(2-methoxy-1-methyl-2-oxo-ethyl)pyrrolidine-1-carboxylate and tert-butyl 3-(2-methoxy-1,1-dimethyl-2-oxo-ethyl)pyrrolidine-1-carboxylate: To a mixture of DIPEA (645 mg, 6.37 mmol, 900 μL) in THF (5 mL) was added n-BuLi (2.5 M, 2.47 mL) at -40 ° C under N . The mixture was stirred at -40 ° C for 1 hour. The mixture was cooled to -78 ° C and then added dropwise to a solution of tert-butyl 3-(2-methoxy-2-oxo-ethyl)pyrrolidine-1-carboxylate (500 mg, 2.06 mmol) in THF (5 mL). The reaction mixture was stirred at -78 ° C for 1 hour. To the mixture was added MeI (1.75 g, 12.33 mmol, 768 μ L), and the reaction mixture was stirred at -78 ° C for 1 hour, then warmed to 25 ° C and stirred for 2 hours. The reaction mixture was diluted with H o (5 mL) and extracted with EtOAc (3 × 5 mL). The combined organic matter was washed with brine (10 mL), dried over Na sO , filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (PE: EtOAc = 10: 1 to 3: 1) to obtain a mixture of the title compound (0.5 g), which was a yellow oil. tert-Butyl 3-(2-methoxy-1,1-dimethyl-2-oxo-ethyl)pyrrolidine-1-carboxylate: To a mixture of DIPEA (610 mg, 6.02 mmol, 851 μL) in THF (5 mL) was added n-BuLi (2.5 M, 2.33 mL) at -40°C under N2. The mixture was stirred at -40°C for 1 hour. The mixture was cooled to -78°C and then added to a solution of tert-butyl 3-(2-methoxy-1,1-dimethyl-2-oxo-ethyl)pyrrolidine-1-carboxylate and tert-butyl 3-(2-methoxy-1,1-dimethyl-2-oxo-ethyl)pyrrolidine-1-carboxylate (0.50 g, 1.94 mmol) in THF (5 mL). The mixture was stirred at -78°C for 1 hour. To the mixture was added MeI (1.65 g, 11.66 mmol, 726 μ L), and the reaction mixture was stirred at -78 ° C for 30 minutes. The mixture was then warmed to 25 ° C and stirred for 2 hours. The reaction mixture was diluted with H o (5 mL) and extracted with EtOAc (3 × 5 mL). The combined organic matter was washed with brine (10 mL), dried over Na sO , filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (PE: EtOAc = 10: 1 to 3: 1) to obtain the title compound (0.2 g), which was a yellow oil. 2-Methyl-2-pyrrolidin-3-yl-propionic acid methyl ester trifluoroacetic acid: To a solution of tert-butyl 3-(2-methoxy-1,1-dimethyl-2-oxo-ethyl)pyrrolidine-1-carboxylate (0.2 g, 737 μmol) in DCM (6 mL) was added TFA (1 mL). The mixture was stirred at 25° C. for 4 hours and then concentrated under reduced pressure to give the title compound (390 mg) as a brown solid. 2-(1-(5-fluoropyrimidin-2-yl)pyrrolidin-3-yl)-2-methylpropanoic acid methyl ester: To a solution of 2-methyl-2-pyrrolidin-3-yl-propionic acid methyl ester trifluoroacetic acid (390 mg, 684 μmol) in DMF (5 mL) was added K2CO3 (380 mg, 2.73 mmol) and 2-chloro-5-fluoro-pyrimidine (181 mg, 1.37 mmol, 169 μL). The mixture was stirred at 100 ° C for 2 hours. The reaction mixture was diluted with water (5 mL) and extracted with EtOAc (3×5 mL). The combined organic layer was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative TLC (SiO2, PE:EtOAc=5:1) to give the title compound (140 mg) as a yellow oil. LCMS: m / z=268.1[M+H] + . 2-(1-(5-fluoropyrimidin-2-yl)pyrrolidin-3-yl)-2-methylpropanoic acid: To a solution of methyl 2-(1-(5-fluoropyrimidin-2-yl)pyrrolidin-3-yl)-2-methylpropanoate (140 mg, 524 μmol) in MeOH (4 mL) and H O (1 mL) was added LiOH.H O (659 mg, 15.71 mmol). The reaction mixture was stirred at 25 ° C for 20 hours. The reaction mixture was concentrated under reduced pressure. The resulting residue was diluted with H O (3 mL) and adjusted to pH = 4. The mixture was concentrated under reduced pressure to give the title compound (132 mg, 99%) as a white solid. Method AE: Preparation of 3-(((5-fluoropyrimidin-2-yl)oxy)methyl)bicyclo[1.1.1]-pentane-1-carboxylic acid 3-(((5-fluoropyrimidin-2-yl)oxy)methyl)bicyclo[1.1.1]pentane-1-carboxylic acid methyl ester: To a solution of 1-(hydroxymethyl)bicyclo[1.1.1]pentane-3-carboxylic acid methyl ester (300 mg, 1.92 mmol) and 2-chloro-5-fluoro-pyrimidine (254.6 mg, 1.92 mmol) in THF (10 mL) at 0° C. under nitrogen was added DMPU (984.8 mg, 7.68 mmol), Molecular sieves and NaH (153.7 mg, 3.84 mmol, 60% in mineral oil). The reaction mixture was stirred at 20 ° C for 3 hours. The mixture was filtered through a celite pad, and the filtrate was quenched by adding saturated NH4Cl (10 mL) at 0 ° C. The aqueous phase mixture was extracted with EtOAc (2 × 10 mL), and the combined organic layer was washed with brine (2 × 10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The obtained residue was purified by preparative TLC (SiO2, 3: 1PE / EtOAc) to give the title compound (60 mg, 13%) as a white solid. LCMS: m / z = 253.1 [M + H] + . 3-(((5-fluoropyrimidin-2-yl)oxy)methyl)bicyclo[1.1.1]pentane-1-carboxylic acid: To a solution of methyl 1-[(5-fluoropyrimidin-2-yl)oxymethyl]bicyclo[1.1.1]pentane-3-carboxylate (60 mg, 0.237 mmol) in MeOH (2 mL) and H2O (1 mL) was added LiOH.H2O (49.9 mg, 1.19 mmol). The mixture was stirred at 25°C for 12 hours. The reaction mixture was concentrated under reduced pressure to remove MeOH. The residue was diluted with H2O (3 mL) and adjusted to pH = 4 with HCl, then concentrated under reduced pressure to give the title compound (60 mg) as a white solid. LCMS: m / z = 239.1 [M+H] + . Method AF: Preparation of 4-(difluoromethyl)-1-(5-fluoropyrimidin-2-yl)piperidine-4-carboxylic acid 4-(Difluoromethyl)piperidine-1,4-dicarboxylic acid 1-tert-butyl 4-ethyl ester: At 0 ° C, under N2, BAST (2.05 g, 9.25 mmol, 2.03 mL) was added to a DCM (24 mL) solution of 4-formylpiperidine-1,4-dicarboxylic acid 1-tert-butyl 4-ethyl ester (1.2 g, 4.21 mmol). The reaction mixture was stirred at 25 ° C for 16 hours. The mixture was poured into ice-water (50 mL). The aqueous phase was adjusted to pH = 7-8 with saturated NaHCO3 aqueous solution. The organic phase was separated and the aqueous phase was extracted with DCM (30 mL). The combined organics were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE: EtOAc = 10: 1) to give the title compound (0.8 g, 62%) as a colorless oil. Ethyl 4-(difluoromethyl)piperidine-4-carboxylate hydrochloride: A mixture of 1-tert-butyl 4-ethyl 4-(difluoromethyl)piperidine-1,4-dicarboxylate (0.6 g, 1.95 mmol) in HCl / EtOAc (4 M, 10 mL) was stirred at 25 ° C for 1 hour. The reaction mixture was concentrated under reduced pressure to give the title compound (0.5 g) as a colorless oil, which was used directly in the next step. LC-MS: m / z = 208.1 [M+H] + . 4-(difluoromethyl)-1-(5-fluoropyrimidin-2-yl)piperidine-4-carboxylic acid ethyl ester: At 25 ° C, under N2, Cs2CO3 (2.67 g, 8.21 mmol) and 2-chloro-5-fluoro-pyrimidine (543 mg, 4.10 mmol) were added to a DMF (10 mL) solution of 4-(difluoromethyl)piperidine-4-carboxylic acid ethyl ester hydrochloride (0.5 g, 2.05 mmol). The reaction mixture was heated at 100 ° C for 2 hours. The mixture was cooled to 25 ° C and poured into ice-water (60 mL). The aqueous phase was extracted with EtOAc (3 × 20 mL). The combined organic phase was washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE: EtOAc = 10: 1) to give the title compound (0.52 g, 84%) as a colorless oil. LC-MS: m / z = 304.1 [M+H] + . 4-(Difluoromethyl)-1-(5-fluoropyrimidin-2-yl)piperidine-4-carboxylic acid: To a mixture of ethyl 4-(difluoromethyl)-1-(5-fluoropyrimidin-2-yl)piperidine-4-carboxylate (0.28 g, 0.92 mmol) in EtOH (4 mL) and H O (2 mL) was added NaOH (147.71 mg, 3.69 mmol) at 25 ° C under N . The mixture was stirred at 50 ° C for 2 hours. The mixture was cooled to 25 ° C and diluted with water (30 mL). The aqueous phase was washed with MTBE (10 mL) and the pH was adjusted to 3-4 with 2N KHSO aqueous solution. The aqueous phase was extracted with DCM (3×15 mL) and the combined organic phase was washed with brine (10 mL), dried over anhydrous Na SO , filtered and concentrated under reduced pressure to give the title compound (0.24 g, 95%) as a white solid, which was used directly in the next step. LC-MS: m / z = 276.3 [M+H] + . Method AG: Preparation of 4-fluoro-1-(pyridine-3-carbonyl)piperidine-4-carboxylic acid 4-Fluoro-1-(pyridine-3-carbonyl)piperidine-4-carboxylic acid ethyl ester: To a solution of 4-fluoropiperidine-4-carboxylic acid ethyl ester (200 mg, 0.94 mmol) and nicotinic acid (151 mg, 1.23 mmol) in DMF (10 mL) were added DIEA (366 mg, 2.83 mmol) and HATU (431 mg, 1.13 mmol). The reaction mixture was stirred at 20 ° C for 2 hours. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (2×10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by preparative TLC (SiO2, DCM:MeOH=20:1) to give the title compound (200 mg, 76%). LCMS: m / z=281.2[M+H] + . 4-Fluoro-1-(pyridine-3-carbonyl)piperidine-4-carboxylic acid: To a mixture of ethyl 4-fluoro-1-(pyridine-3-carbonyl)piperidine-4-carboxylate (45 mg, 0.16 mmol) in MeOH (2 mL) and H2O (1 mL) was added LiOH.H2O (34 mg, 0.80 mol). The reaction mixture was stirred at 20°C for 12 hours. The reaction mixture was adjusted to pH = 5 and concentrated under reduced pressure to give the title compound (38 mg) as a yellow oil, which was used in the next step without purification. LCMS: m / z = 253.2 [M+H] + . Method AH: Preparation of 3,3-difluoro-1-(5-fluoropyrimidin-2-yl)-4-methyl-piperidine-4-carboxylic acid 3,3-Difluoro-4-methylpiperidine-4-carboxylic acid ethyl ester hydrochloride: A solution of 1-tert-butyl 4-ethyl 3,3-difluoro-4-methyl-piperidine-1,4-dicarboxylate (200 mg, 0.65 mmol) in HCl / 1,4-dioxane (5 mL, 4N) was stirred at 20° C. for 1 hour. The mixture was concentrated under reduced pressure to give the title compound (150 mg) as a white solid. 3,3-Difluoro-1-(5-fluoropyrimidin-2-yl)-4-methyl-piperidine-4-carboxylic acid ethyl ester: To a mixture of 2-chloro-5-fluoro-pyrimidine (150 mg, 1.13 mmol) and 3,3-difluoro-4-methyl-piperidine-4-carboxylic acid ethyl ester hydrochloride (235 mg, 0.96 mmol) in MeCN (5 mL) was added DIEA (146 mg, 1.13 mmol) in one portion at 15 ° C. The mixture was heated at 120 ° C in a sealed tube and stirred for 16 hours. The mixture was concentrated under reduced pressure, and the resulting residue was purified by preparative TLC (SiO2, PE: EtOAc = 5: 1) to give the title compound (60 mg, 18%) as a light yellow oil. LCMS: m / z = 304.1 [M + H] + . 3,3-difluoro-1-(5-fluoropyrimidin-2-yl)-4-methyl-piperidine-4-carboxylic acid: To a mixture of 3,3-difluoro-1-(5-fluoropyrimidin-2-yl)-4-methyl-piperidine-4-carboxylic acid ethyl ester (60 mg, 198 μmol) in EtOH (2 mL) and H2O (0.4 mL) was added NaOH (32 mg, 0.79 mmol) at one time. The mixture was heated at 50 ° C for 4 hours. The mixture was concentrated under reduced pressure, and the resulting residue was dissolved in water (2 mL). The aqueous phase was adjusted to pH = 3 by adding HCl aqueous solution (2N). The aqueous phase was extracted with EtOAc (2×5 mL). The combined organics were washed with brine (5 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (50 mg, 92%) as a light yellow solid. The following intermediates were prepared using similar methods as described above. Method AI: Preparation of methyl 7,7-difluoro-3-azabicyclo[4.1.0]heptane-6-carboxylate Under N2, tetrabutylammonium bromide (33 mg, 0.10 mmol) was added to a solution of 1-tert-butyl 4-methyl 3,6-dihydro-2H-pyridine-1,4-dicarboxylate (500 mg, 2.07 mmol) in toluene (2.5 mL), and then [bromo(difluoro)methyl]-trimethyl-silane (842 mg, 4.14 mmol) was added dropwise under N2. The reaction mixture was heated at 110 ° C and stirred for 16 hours in a sealed tube. The residue was filtered and concentrated under reduced pressure to give the title compound (700 mg) as a brown oil, which was used in the next step without purification. LC-MS: m / z = 192.1 [M + H] + . Method AJ: Palladium-catalyzed coupling: A mixture of an amine (1 equivalent), a haloaryl (1 equivalent), XPhos (0.1 equivalent), Pd2(dba)3 (0.1 equivalent), and NaOt-Bu (4 equivalents) in 1,4-dioxane (0.2 M) was heated at 120°C for 120 minutes under microwave irradiation. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by chromatography. In some cases, BINAP was used as the ligand and the solvent was toluene, or RuPhos Pd G3 in THF was used as the solvent. Method AK: Preparation of 2-chloro-4-(2,2-difluoroethoxy)-5-fluoro-pyrimidine At 0 ° C, NaH (287 mg, 7.19 mmol, 60% in mineral oil) was added in batches to a solution of 2,4-dichloro-5-fluoro-pyrimidine (1 g, 5.99 mmol) and 2,2-difluoroethanol (540 mg, 6.59 mmol) in THF (20 mL). The mixture was warmed to 15 ° C and stirred for 1 hour. The mixture was quenched with saturated NH4Cl (20 mL) and extracted with EtOAc (2×10 mL). The organic layers were combined, washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the title compound (1.2 g, 94%) as a light yellow solid. LCMS: m / z=213.0[M+H] + . The following intermediates were prepared using similar methods as described above. Method AL: Preparation of 1-tert-butyl 4-ethyl 4-(fluoromethyl)piperidine-1,4-dicarboxylate 4-(Trifluoromethylsulfonyloxymethyl)piperidine-1,4-dicarboxylic acid tert-butyl 4-ethyl ester: Tf2O (324 mg, 1.15 mmol) was added to a DCM (3 mL) solution of 4-(hydroxymethyl)piperidine-1,4-dicarboxylic acid 1-tert-butyl 4-ethyl ester (300 mg, 1.04 mmol) and pyridine (248 mg, 3.13 mmol) at 0 ° C. The reaction mixture was stirred at 20 ° C for 2 hours. The mixture was poured into H2O (10 mL) and extracted with DCM (2 × 5 mL). The combined organic layer was washed with brine (15 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the title compound (340 mg, 78%) as a yellow oil. The product was used in the next step without purification. 4-(Fluoromethyl)piperidine-1,4-dicarboxylic acid 1-tert-butyl 4-ethyl ester: To a solution of 4-(trifluoromethylsulfonyloxymethyl)piperidine-1,4-dicarboxylic acid 1-tert-butyl 4-ethyl ester (300 mg, 0.72 mmol) in THF (10 mL) was added TBAF (1.07 mmol, 1 M in THF, 1.07 mL). The mixture was stirred at 20 ° C for 1 hour. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (PE: EtOAc = 10: 1) to give the title compound (180 mg, 87%) as a colorless oil. Method AM: Preparation of 4-chloro-(5-fluoropyrimidin-2-yl)piperidine-4-carboxylic acid 1-(5-fluoropyrimidine-2-yl)piperidine-4-carboxylic acid ethyl ester: to the round-bottom flask of dry piperidine-4-carboxylic acid ethyl ester (2.0g, 12.72mmol) and 2-chloro-5-fluoropyrimidine (1.57mL, 12.72mmol), add DIPEA (6.65mL, 38.17mmol).The reaction mixture is stirred at reflux overnight, then concentrated under reduced pressure.The crude reaction mixture is purified by silica gel chromatography (0-10% EtOAc / hexane) to obtain the required product as colorless oil. 4-Chloro-(5-fluoropyrimidin-2-yl)piperidine-4-carboxylic acid ethyl ester: LHMDS (2.02mL, 1M solution in THF) solution of 1-(5-fluoropyrimidin-2-yl)piperidine-4-carboxylic acid ethyl ester (426.0mg, 1.68mmol) was added dropwise at -78 ° C. Within 3 hours, the reaction mixture was warmed to 0 ° C from -78 ° C., now the reaction mixture was cooled to -78 ° C., and hexachloroethane (478mg, 2.02mmol) was added. The reaction mixture was warmed to room temperature from -78 ° C. overnight, now with saturated NH4Cl aqueous solution (20mL) and EtOAc (20mL) diluted reaction mixture. Layering, and water layer was extracted with EtOAc (3x 20mL). The organic layer merged was dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude reaction mixture was purified using silica gel flash chromatography (0-25% EtOAc / hexanes) to provide the desired product as a colorless oil. 4- chloro- (5- fluoropyrimidine -2- bases) piperidine -4- carboxylic acid: to 4- chloro- (5- fluoropyrimidine -2- bases) piperidine -4- carboxylic acid ethyl ester (81mg, 0.282mmol) in THF (1mL) and water (1mL) solution, add lithium hydroxide (67mg, 2.82mmol). The reaction mixture is stirred at room temperature overnight, then diluted with EtOAc (10mL). The organic layer is extracted with water (2x 10mL). The water layer is acidified to pH=1 with the 1M HCl aqueous solution, and extracted with EtOAc (3x 10mL). The organic layer anhydrous Na2SO4 of merging is dried, filtered, and concentrated under reduced pressure to obtain the desired product, which is a white solid that is directly used without further purification. Method AN: Preparation of 3,3,4-trifluoro-1-(5-fluoropyrimidin-2-yl)piperidine-4-carboxylic acid Ethyl 3-oxopiperidine-4-carboxylate hydrochloride: A solution of 1-tert-butyl 4-ethyl 3-oxopiperidine-1,4-dicarboxylate (2 g, 7.37 mmol) in HCl / EtOAc (4 M, 20 mL) was stirred for 1 hour at 20° C. The mixture was concentrated under reduced pressure to give the title compound (1.4 g, 91%) as a white solid. 1-(5-fluoropyrimidine-2-yl)-3-oxo-piperidine-4-carboxylic acid ethyl ester: At 20 ° C, under N2, to a mixture of 3-oxopiperidine-4-carboxylic acid ethyl ester hydrochloride (200 mg, 1.17 mmol) and 2-chloro-5-fluoro-pyrimidine (310 mg, 2.34 mmol) in DMF (5 mL) was added Cs2CO3 (1.14 g, 3.51 mmol). The reaction mixture was stirred at 80 ° C for 2.5 hours. The mixture was poured into water (20 mL) and extracted with EtOAc (3 × 10 mL). The combined organic phase was washed with brine (3 × 10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The obtained residue was purified by column chromatography (PE: EtOAc = 20: 1 to 10: 1) to give the title compound (330 mg, 15%) as a yellow oil. LCMS: m / z = 268.1 [M+H] + . 4-Fluoro-1-(5-fluoropyrimidin-2-yl)-3-oxo-piperidine-4-carboxylic acid ethyl ester: To a solution of 1-(5-fluoropyrimidin-2-yl)-3-oxo-piperidine-4-carboxylic acid ethyl ester (0.35 g, 1.31 mmol) in CHCN (20 mL) was added Selectfluor (464 mg, 1.31 mmol) at 0 ° C under N2. The reaction mixture was stirred at 25 ° C for 3 hours. The mixture was poured into ice-water (60 mL) and saturated NaHCO3 (3 mL) was added. The aqueous phase was extracted with EtOAc (3×20 mL), and the combined organic phases were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the title compound (0.37 g) as a light yellow oil. LCMS: m / z=286.0[M+H] + . 3,3,4-trifluoro-1-(5-fluoropyrimidin-2-yl)piperidine-4-carboxylic acid ethyl ester: At 25 ° C, under N2, DAST (418 mg, 2.59 mmol) was added to a DCM (5 mL) solution of 4-fluoro-1-(5-fluoropyrimidin-2-yl)-3-oxo-piperidine-4-carboxylic acid ethyl ester (0.37 g, 1.30 mmol). The reaction mixture was stirred at 25 ° C for 3 hours. The mixture was poured into ice-water (30 mL). The pH was adjusted to 7 with saturated NaHCO3 and extracted with EtOAc (3×20 mL). The combined organic phase was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the title compound (0.4 g) as a light yellow oil. LCMS: m / z=308.1[M+H] + . 3,3,4-Trifluoro-1-(5-fluoropyrimidin-2-yl)piperidine-4-carboxylic acid hydrochloride: To a solution of ethyl 3,3,4-trifluoro-1-(5-fluoropyrimidin-2-yl)piperidine-4-carboxylate (0.2 g, 651 μmol) in 1,4-dioxane (5 mL) was added 6N HCl (0.65 mmol, 10 mL) at 25 ° C under N2. The reaction mixture was heated at 60 ° C and stirred for 24 hours. The mixture was cooled to 25 ° C and concentrated under reduced pressure to give the title compound (0.18 g, 88%) as a red solid. LCMS: m / z = 280.2 [M + H] + . Method AO: Preparation of 1-(5-chloropyrimidin-2-yl)-3,3-difluoro-4-methylpiperidine-4-carbonyl chloride A solution of 3,3-difluoro-4-methyl-1-pyrimidin-2-yl-piperidine-4-carboxylic acid (140 mg, 0.55 mmol) in SOCl2 (6 mL) was heated and stirred at 70° C. for 2 h. The reaction mixture was concentrated under reduced pressure to give the title compound (75 mg, 44%) as a brown oil. Method AP: Preparation of 3-fluoro-1-(5-fluoropyrimidin-2-yl)-4-methyl-piperidine-4-carbonyl chloride 3-Fluoro-4-methyl-piperidine-1,4-dicarboxylic acid 1-tert-butyl 4-ethyl ester: To a solution of 5-fluoro-4-methyl-2,3-dihydropyridine-1,4-dicarboxylic acid 1-tert-butyl 4-ethyl ester (225 mg, 0.78 mmol) in EtOAc (3 mL) was added 10% Pd / C (100 mg). The suspension was degassed in vacuo and purged with H2 several times. The mixture was stirred at 20 ° C. under H2 (50 psi) for 2 hours. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure to give the title compound (220 mg, 97%) as a yellow oil. 3-Fluoro-4-methyl-piperidine-4-carboxylic acid ethyl ester hydrochloride: A solution of 1-tert-butyl 4-ethyl 3-fluoro-4-methyl-piperidine-1,4-dicarboxylate (380 mg, 1.31 mmol) in HCl / 1,4-dioxane (10 mL) was stirred at 10 ° C for 2 hours. The reaction solution was concentrated under reduced pressure to give the title compound (280 mg, 95%) as a white solid. The solid was used directly in the next step without purification. 3-Fluoro-1-(5-fluoropyrimidin-2-yl)-4-methyl-piperidine-4-carboxylic acid ethyl ester: DIEA (802 mg, 6.20 mmol, 1.08 mL) was added to a solution of 3-fluoro-4-methyl-piperidine-4-carboxylic acid ethyl ester hydrochloride (280 mg, 1.24 mmol) and 2-chloro-5-fluoro-pyrimidine (329 mg, 2.48 mmol) in MeCN (10 mL). The reaction mixture was heated at 120 ° C for 16 hours in a sealed tube. The reaction solution was then concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (PE: EtOAc = 20: 1 to 3: 1) to give the title compound (170 mg, 48%) as a yellow solid. 3-Fluoro-1-(5-fluoropyrimidin-2-yl)-4-methyl-piperidine-4-carboxylic acid: To a solution of 3-fluoro-1-(5-fluoropyrimidin-2-yl)-4-methyl-piperidine-4-carboxylic acid ethyl ester (170 mg, 0.59 mmol) in H O (2 mL) and EtOH (10 mL) was added NaOH (119 mg, 2.98 mmol) and the reaction solution was stirred at 50 ° C for 12 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was adjusted to pH = 3 with saturated KHSO solution. The aqueous solution was extracted with EtOAc (3×5 mL) and the combined organic layers were washed with brine (5 mL), dried over anhydrous Na SO , filtered and concentrated under reduced pressure to give the title compound (130 mg, 85%) as a yellow solid. 3-Fluoro-1-(5-fluoropyrimidin-2-yl)-4-methyl-piperidine-4-carbonyl chloride: A solution of 3-fluoro-1-(5-fluoropyrimidin-2-yl)-4-methyl-piperidine-4-carboxylic acid (112 mg, 0.44 mmol) in SOCl (155 mmol, 11 mL) was heated at 70° C. for 2 hours. The reaction mixture was concentrated under reduced pressure to give the title compound (120 mg, quantitative) as a yellow oil. Method AQ: Preparation of 7-chloro-3-fluoro-pyrazolo[1,5-a]pyrimidine and 3,7-dichloropyrazolo[1,5-a]pyrimidine 7-Chloro-3-fluoro-pyrazolo[1,5-a]pyrimidine and 3,7-dichloropyrazolo[1,5-a]pyrimidine: Selectfluor (554 mg, 1.56 mmol) was added to a mixture of 7-chloropyrazolo[1,5-a]pyrimidine (200 mg, 1.30 mmol) in MeCN (5 mL) at 20°C under N2. The mixture was stirred at 20°C for 16 hours. The mixture was poured into water (10 mL) and extracted with EtOAc (3×3 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (SiO2, PE:EtOAc=3:1) to give a mixture of 7-chloro-3-fluoro-pyrazolo[1,5-a]pyrimidine and 3,7-dichloropyrazolo[1,5-a]pyrimidine (110 mg, F:Cl=~5:2) as a yellow solid. Method AR: Preparation of spiro[4,5-dihydro-2H-pyrido[3,4-f][1,4]oxazepine -3,1'-cyclopropane]-9-carbonitrile [1-[(5-bromo-4-chloro-3-pyridinyl)methylamino]cyclopropyl]methanol: To a mixture of 5-bromo-4-chloro-pyridine-3-carboxaldehyde (3.5 g, 15.88 mmol) and (1-aminocyclopropyl)methanol HCl salt (2.94 g, 23.81 mmol) in DCE (150 mL) was added TEA (2.73 g, 26.99 mmol, 3.76 mL) at 0°C under N2. The mixture was stirred at 20°C for 1 hour, then AcOH (3.15 g, 52.39 mmol, 3 mL) was added and stirred for 1 hour. NaBH(OAc)3 (10.09 g, 47.63 mmol) was added to the mixture at 0°C and stirred at 20°C for 16 hours. The mixture was poured into saturated NaHCO3 (100 mL) and extracted with DCM:i-PrOH (3×30 mL, v:v=3:1). The combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the title compound (4.68 g) as a yellow gum. LCMS: m / z = 292.9 [M+H] + . 9-Bromospiro[4,5-dihydro-2H-pyrido[3,4-f][1,4]oxazepine -3,1'-cyclopropane]: To a mixture of [1-[(5-bromo-4-chloro-3-pyridyl)methylamino]cyclopropyl]methanol (4.6 g, 15.78 mmol) in THF (300 mL) was added t-BuOK (5.49 g, 48.91 mmol) at 0°C under N2. The mixture was stirred at 20°C for 16 hours. The mixture was poured into water (100 mL) and extracted with DCM:i-PrOH (3×30 mL, v:v=3:1). The combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the title compound (3.78 g, 93%) as a yellow oil. LCMS: m / z=255.0[M+H] + . 9-Bromospiro[2,5-dihydropyrido[3,4-f][1,4]oxazepine -3,1'-cyclopropane]-4-carboxylic acid tert-butyl ester: at 20 ° C, under N2, to 9-bromospiro [4,5-dihydro-2H-pyrido [3,4-f][1,4] oxazepine -3,1'-cyclopropane] (3.78 g, 14.82 mmol) and TEA (3 g, 29.63 mmol, 4.12 mL) in DCM (50 mL) was added Boc2O (4.85 g, 22.23 mmol, 5.11 mL). The reaction mixture was stirred at 20 ° C for 16 hours. The mixture was poured into water (50 mL) and extracted with DCM (3×20 mL). The combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE: EtOAc = 3: 1 to 1: 1) to give the title compound (1.7 g, 32%) as a yellow solid. LCMS: m / z = 355.0 [M + H] + . 9-Cyanspiro[2,5-dihydropyrido[3,4-f][1,4]oxazepine -3,1'-cyclopropane]-4-carboxylic acid tert-butyl ester: at 20 ° C, under N2, to 9-bromospiro [2,5-dihydropyrido [3,4-f][1,4] oxazepine -3,1'-cyclopropane]-4-carboxylic acid tert-butyl ester (1g, 2.82mmol) and Zn(CN)2 (331mg, 2.82mmol, 179μL) in DMF (15mL) were added Pd(PPh3)4 (325mg, 0.28mmol). The mixture was stirred at 110 ° C for 16 hours. The mixture was filtered and the filtrate was poured into water (50mL) and extracted with EtOAc (3×15mL). The combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (PE:EtOAc=3:1 to 1:1) to give the title compound (670mg, 79%) as a yellow oil. Spiro[4,5-dihydro-2H-pyrido[3,4-f][1,4]oxazepine -3,1'-cyclopropane]-9-carbonitrile dihydrochloride: 9-cyanospiro[2,5-dihydropyrido[3,4-f][1,4]oxazepine A solution of tert-butyl-3,1′-cyclopropane]-4-carboxylate (670 mg, 2.22 mmol) in HCl / EtOAc (60 mmol, 4 M, 15 mL) was stirred for 1 hour and then concentrated under reduced pressure to give the title compound (600 mg, 98%) as a white solid. Method AS: Preparation of 4-tert-Butoxycarbonyl-1,4-oxazepane-7-carboxylic acid tert-Butyl 7-(benzyloxymethyl)-1,4-oxazepane-4-carboxylate: To a solution of 7-(benzyloxymethyl)-1,4-oxazepane (3.2 g, 14.46 mmol) in THF (50 mL) was added Boc2O (3.79 g, 17.35 mmol, 3.99 mL) at 25 ° C under N2. The mixture was stirred at 25 ° C for 16 hours. The mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE: EtOAc = 10: 1 to 5: 1) to give the title compound (4.2 g, 90%) as a colorless oil. 7- (Hydroxymethyl) -1,4- oxazepane -4- carboxylic acid tert-butyl ester: Under N2, 10% Pd / C (2g) was added to a solution of 7- (benzyloxymethyl) -1,4- oxazepane -4- carboxylic acid tert-butyl ester (4.2g, 13.07mmol) in MeOH (84mL). The suspension was degassed under reduced pressure and purged with H2 three times. The mixture was stirred at 25 ° C under H2 (50psi) for 16 hours. The reaction mixture was filtered through a celite pad and the filtrate was concentrated under reduced pressure to give the title compound (2.9g, 96%) as a colorless oil. 4-tert-Butyloxycarbonyl-1,4-oxazepane-7-carboxylic acid: To a solution of tert-butyl 7-(hydroxymethyl)-1,4-oxazepane-4-carboxylate (0.5 g, 2.16 mmol) in DCM (4 mL), CH 3 CN (4 mL) and H 2 O (8 mL) was added NaIO 4 (1.39 g, 6.49 mmol, 359 μL) at 0° C. under N 2 . RuCl 3 .H 2 O (10 mg, 43 μmol) was added and the mixture was stirred at 25° C. for 2 hours. The mixture was cooled to 0° C. and saturated Na 2 S 2 O 3 was added. The mixture was adjusted to pH ~ 4-5 with 2N HCl and extracted with EtOAc (3×30 mL). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to give the title compound (0.32 g, 60%) as a gray oil. Method AT: Preparation of 3-fluoro-1-(5-fluoropyrimidin-2-yl)-4-hydroxy-piperidine-4-carboxylic acid 4- cyano -3- fluoro -4- hydroxy - piperidine -1- carboxylic acid tert-butyl ester: At room temperature, potassium cyanide (1.6 g, 25.3 mmol) and NaHCO (3.9 g, 46.0 mmol) in water (60 mL) solution was added dropwise to a vigorously stirred 3- fluoro -4- oxo - piperidine -1- carboxylic acid tert-butyl ester (5.0 g, 23.0 mmol) in ether (92 mL). The reaction mixture was stirred for 15 hours and separated. The aqueous layer was extracted with CH2Cl2 (3 x 100 mL) and the combined organic layer (MgSO4) was dried and concentrated under reduced pressure to give the title compound (4.9 g, 86% yield) as a colorless solid. LCMS: m / z=245.3 [M+H] + . 3-Fluoro-1-(5-fluoropyrimidin-2-yl)-4-hydroxy-piperidine-4-carbonitrile: 4-cyano-3-fluoro-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (2.2g, 9.01mmol) is dissolved in 4.0N HCl (20mL, 80mmol) in dioxane, and the mixture is stirred at room temperature for 2 hours. The reaction mixture is concentrated to dryness. MeCN (10mL) is added to the resulting residue, followed by 2-chloro-5-fluoropyrimidine (1.31g, 9.91mmol) and triethylamine (3.77mL, 27.0mmol). The mixture is heated at 80°C for 16 hours and then concentrated in vacuo to give a yellow solid. Purified by flash chromatography (0-20% methanol in dichloromethane) to give the title compound as a colorless solid (1.31g, 61% yield). LCMS: m / z=241.3[M+H] + . 3-Fluoro-1-(5-fluoropyrimidin-2-yl)-4-hydroxy-piperidine-4-carboxylic acid: 3-Fluoro-1-(5-fluoropyrimidin-2-yl)-4-hydroxy-piperidine-4-carbonitrile (350 mg, 1.46 mmol) was added to 6.0 N HCl (20 mL, 120 mmol) in water and the mixture was heated at 70 ° C for 6 hours. The mixture was concentrated to dryness and dissolved in water (50 mL). The pH was adjusted to 4.0 using aqueous sodium bicarbonate solution and extracted with ethyl acetate (50 mL×2). The organic layers were combined and concentrated to give the title compound, which was used directly in the next step. LC-MS: m / z=260.3[M+H] + . Method AU: Preparation of (3R)-3-methyl-2,3,4,5-tetrahydropyrido[3,4-f][1,4]oxazepine -9-carbonitrile (2R)-2-[(5-bromo-4-chloro-3-pyridinyl)methylamino]propan-1-ol: To a solution of 5-bromo-4-chloro-pyridine-3-carbaldehyde (5 g, 22.68 mmol) in DCE (100 mL) was added (2R)-2-aminopropan-1-ol (3.41 g, 45.36 mmol, 3.54 mL) at 25 ° C., followed by AcOH (2.72 g, 45.36 mmol, 2.59 mL), and the mixture was stirred for 10 minutes. NaBH(OAc) 3 (14.42 g, 68.04 mmol,) was added and the mixture was stirred at 25 ° C. for 12 hours. The reaction mixture was diluted with water (100 mL) and stirred for 20 minutes. The layers were separated and the aqueous layer was extracted with a mixture of i-PrOH / DCM (v:v=1:3, 3×50 mL). The aqueous layer was adjusted to pH=7-8 with saturated NaHCO 3. The aqueous layer was extracted with a mixture of i-PrOH:DCM (v:v=1:3; 3×100 mL). The combined organic layers were washed with brine (2×100 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to give the title compound (3.77 g, 59%) as a yellow solid. (3R)-9-Bromo-3-methyl-2,3,4,5-tetrahydropyrido[3,4-f][1,4]oxazepine To a solution of (2R)-2-[(5-bromo-4-chloro-3-pyridinyl)methylamino]propan-1-ol (3.4 g, 12.16 mmol,) in DMF (70 mL) was added NaH (486 mg, 12.16 mmol, 60% in mineral oil) at 0°C under N2, and the mixture was stirred at 25°C for 12 hours. The reaction mixture was quenched by the addition of saturated NH4Cl (50 mL) at 0°C and then extracted with i-PrOH:DCM (v:v=1:3; 3×50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the title compound (27 g, 82%) as a yellow oil. LCMS: m / z=243.1[M+H] + . (3R)-9-Bromo-3-methyl-3,5-dihydro-2H-pyrido[3,4-f][1,4]oxazepine -4-carboxylic acid tert-butyl ester: at 25 ° C, to (3R) -9-bromo-3-methyl-2,3,4,5-tetrahydropyrido [3,4-f][1,4] oxazepine To a solution of (27 g, 9.44 mmol,) in DMF (20 mL) was added Boc2O (4.12 g, 18.88 mmol, 4.34 mL) and the solution was stirred at 25 ° C for 2 hours. The reaction mixture was diluted with water (100 mL) at 25 ° C, and the aqueous phase was extracted with EtOAc (3×100 mL). The combined organic layer was washed with brine (2×50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE: EA = 10: 1 to 0: 1) to give the title compound (2.5 g, 77%) as a yellow oil. LCMS: m / z = 344.2 [M + H] + . (3R)-9-Cyano-3-methyl-3,5-dihydro-2H-pyrido[3,4-f][1,4]oxazepine -4-carboxylic acid tert-butyl ester: at 25 ° C, to (3R) -9-bromo-3-methyl-3,5-dihydro-2H-pyrido [3,4-f][1,4] oxazepine To a mixture of tert-butyl-4-carboxylate (2.5 g, 7.28 mmol) in DMF (50 mL) was added Pd(PPh3)4 (2.53 g, 2.19 mmol) and Zn(CN)2 (855 mg, 7.28 mmol), and the solution was stirred at 100 ° C for 12 hours. The reaction mixture was poured into H2O (50 mL). The mixture was extracted with EtOAc (3×20 mL). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE: EtOAc = 30: 1 to 0: 1) to give the title compound (2.19 g, 83%) as a yellow oil. LCMS: m / z = 290.0 [M+H] + . (3R)-3-Methyl-2,3,4,5-tetrahydropyrido[3,4-f][1,4]oxazepine -9-carbonitrile dihydrochloride: (3R)-9-cyano-3-methyl-3,5-dihydro-2H-pyrido[3,4-f][1,4]oxazepine A solution of tert-butyl-4-carboxylate (2.19 g, 6.06 mmol) in HCl / 1,4-dioxane (4 M, 23.36 mL) was stirred at 25° C. for 14 hours. The reaction mixture was filtered and washed with MTBE (50 mL) to give the title compound (1.2 g, 76%) as a white solid. Example 1: Preparation of (3,3-difluorocyclobutyl)(2,3-dihydrobenzo[f][1,4]oxazepine -4(5H)-methyl)methanone At 0 ° C, 2,3,4,5-tetrahydro-1,4-benzoxazepine (75 mg, 0.5 mmol) in THF (2.0 mL) was added i In the mixture of 4-difluoro-2-nitropropane-2-ol (100mg, 0.75mmol) and 4-difluoro-3-nitropropane-2-ol (100mg, 0.75mmol) in 4-nitropropane-2-ol (100mg, 0.75mmol) PrMgBr solution (183μM, 3M / THF).Solution is warmed to room temperature, and 3,3-difluorocyclobutanecarboxylic acid methyl esters (113mg, 0.75mmol) is added, and gained reaction mixture is stirred overnight.Add saturated NHThe Cl aqueous solution (10mL) is then added EtOAc (10mL).Layering, and water layer is extracted with EtOAc (3x 10mL).The organic layer anhydrous MgSO4 of merging is dried, filtered and concentrated under reduced pressure.The crude reaction mixture uses flash chromatography on silica gel to purify (0-100% EtOAc / hexane) to obtain required product, which is a clear oil. 1 H NMR (400MHz, CDCl3): δ7.39-7.02 (m, 4H), 4.68-4.51 (m, 2H), 4.13-3.79 (m, 4H), 3.25-2.83 (m, 3H), 2.81-2.61 (m, 2H). LC-MS: m / z=268.0[M+H] + . Example 2: Preparation of 4-(3,3-difluoro-2,2-dimethyl-propionyl)-6-fluoro-3,5-dihydro-2H-1,4-benzoxazepine -9-carbonitrile 4-(3,3-Difluoro-2,2-dimethyl-propionyl)-6-fluoro-3,5-dihydro-2H-1,4-benzoxazepine -9-carbonitrile. To the flask of 4- (4-yl) -3,3-difluoro-2,2-dimethyl-propan-1-one (43.0mg, 0.12mmol) and Zn (CN) 2 (13.8mg, 0.12mmol) was added DMF (1.0mL). The solution was degassed with argon for 15 minutes, and tetrakis (triphenylphosphine) palladium (0) (27.0mg, 0.02mmol) was added. The reaction mixture was heated to 100 ° C overnight, cooled to room temperature and diluted with salt solution (10mL) and EtOAc (10mL). Layered, and the water layer was extracted with EtOAc (3x 10mL). The combined organic layer was dried with MgSO 4, filtered, and concentrated under reduced pressure. The crude reaction mixture was purified using reversed-phase HPLC to obtain the desired product, which was a clear oil. 1H NMR (400MHz, CDCl3): δ7.50 (dd, J=8.7, 6.0Hz, 1H), 6.90 (t, J=8.7Hz, 1H), 6.12 (t, J=56.5Hz , 1H), 4.80 (s, 2H), 4.48 (dd, J=5.6, 4.4Hz, 2H), 4.09 (t, J=5.0Hz, 2H), 1.37 (t, J=1.3Hz, 6H). LC-MS: m / z=313.27[M+H] + . The compounds of Table 1 can be prepared according to the methods described herein. Table 1 Examples 258 and 259: Preparation of 4-[(2S)-2-cyclopropyl-3,3-difluoro-2-methyl-propionyl)]-3,5-dihydro-2H-pyrido[3,4-f][1,4]oxazepine -9-carbonitrile and 4-[(2R)-2-cyclopropyl-3,3-difluoro-2-methyl-propionyl)]-3,5-dihydro-2H-pyrido[3,4-f][1,4]oxazepine -9-carbonitrile Racemic 4-(2-cyclopropyl-3,3-difluoro-2-methyl-propionyl)-3,5-dihydro-2H-pyrido[3,4-f][1,4]oxazepine -9-Carbononitrile was separated by SFC under the following conditions: instrument: Thar SFC80 preparative SFC; column: Chiralpak AD-H 250×30 mm id5 μm; mobile phase A: CO2, mobile phase B: EtOH; gradient: B%=25%; flow rate: 65 g / min.; wavelength: 220 nm; column temperature: 40°C; system back pressure: 100 bar; two enantiomers were obtained. 4-(2-cyclopropyl-3,3-difluoro-2-methyl-propionyl)-3,5-dihydro-2H-pyrido[3,4-f][1,4]oxazepine -9-carbonitrile (first eluting peak, Example 258), isolated as a light yellow oil. LCMS: m / z = 322.3 [M+H] + . 4-(2-cyclopropyl-3,3-difluoro-2-methyl-propionyl)-3,5-dihydro-2H-pyrido[3,4-f][1,4]oxazepine -9-carbonitrile (second eluting peak, Example 259), isolated as a light yellow oil. LCMS: m / z = 322.3 [M+H] + . Examples 260 and 261: Preparation of 4-[(2S)-2-(difluoromethyl)-2-methylbutanoyl)]-2,3,4,5-tetrahydropyrido[3,4-f][1,4]oxazepine -9-carbonitrile and 4-[(2R)-2-(difluoromethyl)-2-methylbutanoyl)]-2,3,4,5-tetrahydropyrido[3,4-f][1,4]oxazepine -9-carbonitrile Racemic 4-(2-(difluoromethyl)-2-methylbutanoyl)-2,3,4,5-tetrahydropyrido[3,4-f][1,4]oxazepine -9-Carbononitrile was prepared by SFC column under the following conditions: instrument: Thar SFC80 preparative SFC; column: Chiralpak AD-H 250×30 mm id5 μm; mobile phase A: CO2, mobile phase B: EtOH; gradient: B%=35%; flow rate: 65 g / min.; wavelength: 220 nm; column temperature: 40°C; system back pressure: 100 bar, to obtain two enantiomers. 4-(2-(Difluoromethyl)-2-methylbutanoyl)-2,3,4,5-tetrahydropyrido[3,4-f][1,4]oxazepine -9-carbonitrile (first eluting peak, Example 260), isolated as a yellow oil. LCMS: m / z = 310.3 [M+H] + . 4-(2-(Difluoromethyl)-2-methylbutanoyl)-2,3,4,5-tetrahydropyrido[3,4-f][1,4]oxazepine -9-carbonitrile (second eluting peak, Example 261), isolated as a yellow oil. LCMS: m / z = 310.3 [M+H] + . Example 262: Preparation of 4-(3,3-difluoro-2,2-dimethyl-propionyl)-8-methyl-3,5-dihydro-2H-pyrido[3,4-f][1,4]oxazepine -9-carbonitrile To 8-chloro-4-(3,3-difluoro-2,2-dimethyl-propionyl)-3,5-dihydro-2H-pyrido[3,4-f][1,4]oxazepine To a mixture of -9-carbonitrile (30 mg, 0.091 mmol) in THF (3 mL) was added Pd(PPh 3 ) 4 (11 mg, 0.0091 mmol), followed by addition of Zn(Me) 2 (1 M, 91 μL) under N 2 , and the reaction mixture was stirred at 80° C. for 3 hours. The reaction mixture was then diluted with water (5 mL) and extracted with EtOAc (3×5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC using the following conditions: preparative HPLC (column: Nano-micro Kromasil C18 100×30 mm 5 μm; mobile phase: [A-TFA / H 2 O=0.075% v / v; B-ACN], gradient B%: 15%-40% in 10 minutes). The fractions containing the desired product were adjusted to pH 7 with saturated NaHCO₃ solution and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to afford the title compound as a white solid. LCMS: m / z=310.3 [M+H] + . Example 263: Preparation of 2,2,3,3-tetradeuterio-4-(3,3-difluoro-2,2-dimethyl-propionyl)-5H-pyrido[3,4-f][1,4]oxazepine -9-carbonitrile 9-Bromo-2,2,3,3-tetradeuterio-4,5-dihydropyrido[3,4-f][1,4]oxazepine The title compound was prepared using Method C employing 9-bromo-2,2,3,3-tetradeuterio-4,5-dihydropyrido[3,4-f][1,4]oxazepine (600 mg, 2.57 mmol) and 3,3-difluoro-2,2-dimethyl-propionic acid (391 mg, 2.83 mmol). The crude product was purified by silica gel column chromatography (PE:EtOAc=5:1 to 1:1) to give the title compound as a yellow syrup. LCMS: m / z=352.9 [M+H] + . 2,2,3,3-Tetradeuterio-4-(3,3-difluoro-2,2-dimethyl-propionyl)-5H-pyrido[3,4-f][1,4]oxazepine -9-carbonitrile: to 1-(9-bromo-2,2,3,3-tetradeuterio-5H-pyrido[3,4-f][1,4]oxazepine To a solution of 4-(4-yl)-3,3-difluoro-2,2-dimethyl-propan-1-one (500 mg, 1.42 mmol) in anhydrous DMF (20 mL) was added Pd(PPh3)4 (491 mg, 424.69 μmol) and Zn(CN)2 (183 mg, 1.56 mmol). The reaction mixture was heated to 100°C and stirred under N2 for 12 hours. The reaction mixture was diluted with EtOAc (20 mL), filtered and concentrated under reduced pressure. The filtrate was washed with water (40 mL) and brine (40 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc = 5:1 to 1:1) to give a crude product (92% HPLC purity). The crude product was further purified by preparative HPLC using the following conditions: Column: Xtimate C18 150×25 mm 5 μm; Mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 20%-50% over 10.5 minutes. The eluent was extracted with EtOAc (3×10 mL). The combined organics were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to provide the title compound as a white solid. 1 H NMR (400MHz, CDCl3): δ 8.65 (s, 1H), 8.59 (s, 1H), 6.09 (t, J = 56.0Hz, 1H), 4.78 (s, 2H), 1.38 (s, 6H). LCMS: m / z=300.3[M+H] + . Examples 264 and 265: Preparation of 4-[(2S)-2-(cyanomethyl)-2-methyl-butyryl]-3,5-dihydro-2H-pyrido[3,4-f][1,4]oxazepine -9-carbonitrile and 4-[(2R)-2-(cyanomethyl)-2-methyl-butyryl]-3,5-dihydro-2H-pyrido[3,4-f][1,4]oxazepine -9-carbonitrile Racemic 4-[2-(cyanomethyl)-2-methyl-butyryl]-3,5-dihydro-2H-pyrido[3,4-f][1,4]oxazepine -9-Carbononitrile was separated by SFC under the following conditions: instrument: Thar SFC80 preparative SFC; column: Chiralpak AD-H 250×30 mm id5 μm; mobile phase A: CO2, mobile phase B: MeOH; gradient: B% = 42%; flow rate: 70 g / min.; wavelength: 220 nm; column temperature: 40°C; system back pressure: 100 bar, to obtain two enantiomers. 4-[2-(Cyanomethyl)-2-methyl-butyryl]-3,5-dihydro-2H-pyrido[3,4-f][1,4]oxazepine -9-carbonitrile (first eluting peak, Example 264), isolated as a colorless oil. LCMS: m / z = 299.1, [M+H] + . 4-[2-(Cyanomethyl)-2-methyl-butyryl]-3,5-dihydro-2H-pyrido[3,4-f][1,4]oxazepine -9-carbonitrile (second eluting peak, Example 265), isolated as a colorless oil. LCMS: m / z = 299.1 [M+H] + . Examples 266 and 267: Preparation of 4-[3,3-difluoro-2-(fluoromethyl)-2-methyl-propionyl]-3,5-dihydro-2H-pyrido[3,4-f][1,4]oxazepine -9-carbonitrile (Example 266) and 4-[3,3-difluoro-2-(fluoromethyl)-2-methyl-butyryl]-3,5-dihydro-2H-pyrido[3,4-f][1,4]oxazepine -9-carbonitrile (Example 267) 2-(9-cyano-3,5-dihydro-2H-pyrido[3,4-f][1,4]oxazepine -4-carbonyl)-3,3-difluoro-2-methyl-butyric acid methyl ester and 2-(9-cyano-3,5-dihydro-2H-pyrido[3,4-f][1,4]oxazepine -4-carbonyl)-3,3-difluoro-2-methyl-propionic acid methyl ester: The title compound was prepared using Method D to give 2-(9-cyano-3,5-dihydro-2H-pyrido[3,4-f][1,4]oxazepine -4-carbonyl)-3,3-difluoro-2-methyl-butyric acid methyl ester and 2-(9-cyano-3,5-dihydro-2H-pyrido[3,4-f][1,4]oxazepine A mixture of methyl 2-(4-carbonyl)-3,3-difluoro-2-methyl-propionic acid ester (290 mg, 29%; ratio = 4:5) was prepared as a colorless oil. LC-MS: m / z = 340.3 [M+H] + ; m / z=354.3[M+H] + . 4-[3,3-difluoro-2-(hydroxymethyl)-2-methyl-butyryl]-3,5-dihydro-2H-pyrido[3,4-f][1,4]oxazepine -9-carbonitrile and 4-[3,3-difluoro-2-(hydroxymethyl)-2-methyl-propionyl]-3,5-dihydro-2H-pyrido[3,4-f][1,4]oxazepine -9-carbonitrile: at 25 ° C, under N2, to 2-(9-cyano-3,5-dihydro-2H-pyrido[3,4-f][1,4]oxazepine -4-carbonyl)-3,3-difluoro-2-methyl-butyric acid methyl ester and 2-(9-cyano-3,5-dihydro-2H-pyrido[3,4-f][1,4]oxazepine To a mixture of methyl tri-tert-butoxyaluminum hydride (0.29 g, 0.82 mmol) in THF (7 mL) was added a solution of lithium tri-tert-butoxyaluminum hydride (4.1 mmol, 4.1 mL, 1 M in THF). The mixture was then heated to 84 ° C and stirred for 16 hours. The mixture was cooled to 25 ° C, poured into an ice-cooled NH4Cl aqueous solution (20 mL) and filtered through a celite pad. The filter cake was washed with EtOAc (3×10 mL). The filtrate was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated in vacuo. The resulting residue was purified by preparative TLC (SiO2, PE:EtOAc=1:3) to give a mixture of the title compounds (100 mg, 38%; ratio=1:1), which was a colorless oil. LC-MS: m / z=312.0[M+H] + ; m / z=326.0[M+H] + . 4-[3,3-difluoro-2-(fluoromethyl)-2-methyl-butyryl]-3,5-dihydro-2H-pyrido[3,4-f][1,4]oxazepine -9-carbonitrile and 4-[3,3-difluoro-2-(fluoromethyl)-2-methyl-propionyl]-3,5-dihydro-2H-pyrido[3,4-f][1,4]oxazepine -9-carbonitrile: at -78 ° C, under N2, to 4-[3,3-difluoro-2-(hydroxymethyl)-2-methyl-butyryl]-3,5-dihydro-2H-pyrido[3,4-f][1,4]oxazepine -9-carbonitrile and 4-[3,3-difluoro-2-(hydroxymethyl)-2-methyl-propionyl]-3,5-dihydro-2H-pyrido[3,4-f][1,4]oxazepine To a mixture of 9-carbonitrile (80 mg, 0.25 mmol) in DCM (2 mL) was added DAST (198 mg, 1.23 mmol). The mixture was allowed to warm to 25°C and stirred for 1 hour. The mixture was diluted with DCM (20 mL) and adjusted to pH = 8 with saturated NaHCO3 at 0°C. The organic phase was separated, washed with brine (5 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC using the following conditions: column: Xtimate C18 150×25 mm×5 μm; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 25%-45% in 10.5 min. The title compound was obtained. 4-[3,3-difluoro-2-(fluoromethyl)-2-methyl-propionyl]-3,5-dihydro-2H-pyrido[3,4-f][1,4]oxazepine -9-carbonitrile (first eluting peak in HPLC, Example 266). Isolated as a colorless oil. LCMS: m / z = 314.3 [M+H] + . 4-[3,3-difluoro-2-(fluoromethyl)-2-methyl-butyryl]-3,5-dihydro-2H-pyrido[3,4-f][1,4]oxazepine -9-carbonitrile (second eluting peak in HPLC, Example 267). Isolated as a light yellow oil. LCMS: m / z = 328.3 [M+H] + . Examples 268 and 269: Pre...

Claims

1. Compounds of formula I: or a pharmaceutically acceptable salt, solvate, prodrug, isotopic analog or isomer thereof, wherein W 1 , W 3 and W 4 CR 7 ; W 2 N or CR 7 ; The premise is that when W 2 CR 7 When a)W 4 C-CN or b) R 1a is not hydrogen and R 1b and R 1c Together they form the 5 ) n substituted piperidinyl ring and n is 0-9; R 1a , R 1b and R 1c are independently hydrogen, halogen, -CN, -N3, -NO2, -OH, -SF5, -SCF3, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Heteroalkyl, C 3-8 Cycloalkyl, C 1-8 Haloalkyl, C 1-8 Alkoxy, C 1-8 Haloalkoxy, 4 to 12 membered heterocyclic group, C 6-10 Aryl, 5- to 12-membered heteroaryl, -N(R 1d )2. -C(O)R 1e 、-C(O)OR 1d , -C(O)N(R 1d )2、-NR 1d C(O)R 1e 、-NR 1d C(O)N(R 1d )2、-NR 1d C(O)OR 1d 、-OC(O)N(R 1d )2、-OC(O)OR 1d 、-SR 1d 、-S(O)R 1e 、-S(O)2R 1e 、 -S(O)3R 1d ,-S(O)N(R 1d )2、-S(O)2N(R 1d )2、-NR 1d S(O)R 1e 、 -NR 1d S(O)2R 1e 、-NR 1d S(O)N(R 1d )2 or -NR 1d S(O)2N(R 1d )2, where R 1a , R 1b and R 1c each optionally and independently substituted with 1 to 8 R 5 And R 1a , R 1b and R 1c At least one of is not hydrogen; or R 1b and R 1c Optionally together to form C 3-10 cycloalkyl or 4 to 12 membered heterocyclyl, each of which is optionally substituted with 1 to 8 R 5 ;or R 1a , R 1b and R 1c Optionally together to form C 5-10 cycloalkyl or 6 to 8 membered heterocyclyl, each of which is optionally substituted with 1 to 8 R 5 ;or R 1a does not exist and R 1b and R 1c Together they form C 6-10 aryl or 5 to 12 membered heteroaryl, each of which is optionally substituted with 1 to 8 R 5 ; R 1d are independently hydrogen, C 1-8 Alkyl, C 1-8 Haloalkyl, C 3-10 Cycloalkyl or 4 to 12 membered heterocyclic group, or Two R on the same atom 1d Optionally together form a 4- to 8-membered heterocyclic group, which is optionally substituted by oxo, halogen or C 1-6 Alkyl substituted, wherein the alkyl is optionally substituted with 1 to 8 R 5 ; R 1e Each independently is C 1-8 Alkyl, C 1-8 Haloalkyl, C 3-10 Cycloalkyl or 4- to 12-membered heterocyclic group; R 2a and R 2b are independently hydrogen, halogen, C 1-8 Alkyl, C 1-8 Haloalkyl, C 2-8 Alkenyl or C 2-8 Alkynyl, or R 2a and R 2b Optionally together to form C 3-6 cycloalkyl or 4 to 6 membered heterocyclyl, each of which is optionally substituted with 1 to 8 R 6 ; R 3a and R 3b are independently hydrogen, halogen, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Haloalkyl, C 3-6 cycloalkyl or 4 to 6 membered heterocyclyl, wherein the cycloalkyl and the heterocyclyl are optionally substituted with 1 to 8 R 6 ,or R 3a and R 3b Optionally together to form oxo, C 3-6 cycloalkyl or 4 to 6 membered heterocyclyl, wherein the cycloalkyl and the heterocyclyl are optionally substituted with 1 to 8 R 6 ; Y is O, C(O), S, S(O), S(O)2, CR 4a R 4b or NR 4c ; R 4a and R 4b are independently hydrogen, halogen, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Haloalkyl, C 3-6 cycloalkyl or 4 to 6 membered heterocyclyl, wherein the cycloalkyl and the heterocyclyl are optionally substituted with 1 to 8 R 6 ,or R 4a and R 4b Optionally together to form C 3-6 cycloalkyl or 4 to 6 membered heterocyclyl, wherein the cycloalkyl and the heterocyclyl are optionally substituted with 1 to 8 R 6 , or R 4a and R 1b Optionally together form a 4 to 12 membered heterocyclyl group, which is optionally substituted with 1 to 8 R 6 ,or R 4a and R 3a Optionally together to form C 3-8 cycloalkyl or 4 to 12 membered heterocyclyl, each of which is optionally substituted with 1 to 8 R 6 ,or R 4c For hydrogen, C 1-8 Alkyl, C 1-8 Haloalkyl, C 3-10 Cycloalkyl or 4 to 12 membered heterocyclic group; R 5 Each is independently halogen, -CN, -OH, -SF5, -SCF3, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Heteroalkyl, C 3-8 Cycloalkyl, C 1-8 Alkoxy, 4 to 12 membered heterocyclic group, C 6-10 Aryl, 5- to 12-membered heteroaryl, (4- to 12-membered heterocyclic) (C 1-8 Heteroalkyl), (C 6-10 Aryl) (C 1-8 Heteroalkyl), (5 to 12 membered heteroaryl) (C 1-8 heteroalkyl), -N(R 5a )2. -C(O)R 5b 、-C(O)OR 5a 、-C(O)N(R 5a )2. -NR 5a C(O)R 5b 、-NR 5a C(O)N(R 5a )2、-NR 5a C(O)OR 5a 、 -OC(O)N(R 5a )2、-OC(O)OR 5a 、-SR 5a 、-S(O)R 5b 、-S(O)2R 5b 、 -S(O)3R 5a ,-S(O)N(R 5a )2、-S(O)2N(R 5a )2、-NR 5a S(O)R 5b 、 -NR 5a S(O)2R 5b 、-NR 5a S(O)N(R 5a )2 or –NR 5a S(O)2N(R 5a ) 2, each of which is optionally substituted with 1 to 8 R 5c ,or Two R's 5 optionally together forming an oxo group; R 5a are independently hydrogen, C 1-8 Alkyl, C 1-8 Haloalkyl, C 3-10 cycloalkyl or 4- to 12-membered heterocyclic group, and R 5b Each independently is C 1-8 Alkyl, C 1-8 Haloalkyl, C 3-10 Cycloalkyl, 4- to 12-membered heterocyclyl, or 5- to 12-membered heteroaryl; R 5c are independently halogen, cyano, C 1-8 Haloalkyl, C 1-8 Alkyl, C 1-8 Alkoxy, C 1-8 Haloalkoxy, (C 1-8 Alkoxy) (C 1-8 Alkoxy), hydroxyl, SR 5d 、N(R 5d )2、N(R 5d )2(C 1-8 Alkoxy), C 3-10 Cycloalkyl or 4 to 12-membered heterocyclic group, or two R 5c optionally together forming an oxo group; R 5d are independently hydrogen, C 1-8 Alkyl or C 1-8 Haloalkyl; R 6 Each is halogen, -CN, -OH, C 1-8 Alkyl, C 1-8 Heteroalkyl, C 3-8 Cycloalkyl, C 1-8 Haloalkyl, C 1-8 Alkoxy, 4 to 12 membered heterocyclic group, C 6-10 Aryl, 5- to 12-membered heteroaryl, -N(R 6a )2. -C(O)R 6b 、-C(O)N(R 6a )2 or -C(O)OR 6a , or two R 6 Together they form an oxo group; R 6a are independently hydrogen, C 1-8 Alkyl or C 1-8 haloalkyl, or Two R on the same atom 6a optionally together form a 4- to 6-membered heterocyclyl; R 6b Each independently is C 1-8 Alkyl or C 1-8 Haloalkyl; R 7 Each is independently hydrogen, halogen, -CN, -N3, -NO2, -SF5, -SCF3, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Heteroalkyl, C 3-8 Cycloalkyl, C 1-8 haloalkyl, 4 to 12 membered heterocyclic group, C 6-10 Aryl, 5- to 12-membered heteroaryl, -OR 7a , -C(O)R 7b 、-N(R 7a )2、-C(O)OR 7a 、-C(O)N(R 7a )2、-NR 7a C(O)R 7b 、 -NR 7a C(O)N(R 7a )2、-NR 7a C(O)OR 7a 、-OC(O)N(R 7a )2、 -OC(O)OR 7a 、-SR 7a 、-S(O)R 7b 、-S(O)2R 7b 、-S(O)3R 7a 、 -S(O)N(R 7a )2、-S(O)2N(R 7a )2、-NR 7a S(O)R 7b 、–NR 7a S(O)2R 7b 、 -NR 7a S(O)N(R 7a )2 or –NR 7a S(O)2N(R 7a ) 2, each of which is optionally and independently substituted with 1 to 8 R 8 ; R 7a are independently hydrogen, C 1-8 Alkyl, C 1-8 Haloalkyl, C 3-10 Cycloalkyl or 4 to 12 membered heterocyclic group, or Two R on the same atom 7a Optionally together form a 4- to 8-membered heterocyclic group, which is optionally substituted by oxo, halogen or C 1-6 Alkyl substituted, wherein the alkyl is optionally substituted with 1 to 8 R 8 ; R 7b Each independently is C 1-8 Alkyl, C 1-8 Haloalkyl, C 3-10 Cycloalkyl or 4- to 12-membered heterocyclic group; R 8 Each is halogen, -CN, -OH, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Heteroalkyl, C 3-8 Cycloalkyl, C 1-8 Haloalkyl, C 1-8 Alkoxy, 4 to 12 membered heterocyclic group, C 6-10 Aryl, 5- to 12-membered heteroaryl, -N(R 8a )2. -C(O)R 8b or-C(O)OR 8a ,or Two R's 8 optionally together forming an oxo group; R 8a are independently hydrogen, C 1-8 Alkyl or C 1-8 Haloalkyl; R 8b Each independently is C 1-8 Alkyl or C 1-8 Haloalkyl; Z is C(R 9 )2, C(O), O, S, S(O), S(O)2, S(O)NR 9 or NR 9 ; The condition is that when Z is N, then R 3a and R 3b Not for oxygen generation; R 9 are independently hydrogen, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Haloalkyl, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclyl, or –C(O)R 9a ;and R 9a C 1-8 Alkyl, C 1-8 Haloalkyl, C 3-8 Cycloalkyl or 4 to 12 membered heterocyclic group, or R 9 and R 3a Optionally together to form C 3-8 cycloalkyl or 4 to 12 membered heterocyclyl, each of which is optionally substituted with 1 to 8 R 6 .

2. The compound according to claim 1, wherein W 2 is N.

3. The compound according to claim 2, wherein Z is O; Y is CR 4a R 4b ; R 2a , R 2b , R 3a , R 3b , R 4a and R 4b is H; and R 1a , R 1b , R 1c , R 5 , R 7 and R 8 As defined for Formula I.

4. The compound according to claim 1, which has formula Ia: in R 1a , R 2a , R 2b , R 3a , R 3b , R 5 , R 7 , W 1 , W 2 , W 3 , W 4 , Y and Z are as defined for Formula I; and n is 0-9; The premise is that when W 1 , W 2 , W 3 and W 4 CR 7 When R 1a Not hydrogen.

5. The compound according to claim 4, wherein at least one R 5 Attached to the nitrogen atom of piperidine.

6. The compound according to claim 1, which has the formula Ib: Where R 1a , R 1b , R 1c , R 2a , R 2b , R 3a , R 3b , W 1 , W 2 , W 3 , Y and Z are as defined for Formula I.

7. A compound according to any one of the preceding claims, wherein W 2 N and W 1 , W 3 , W 4 CR 7 .

8. A compound according to any one of the preceding claims, wherein W 2 N and W 3 For CH.

9. A compound according to any one of the preceding claims, wherein W 2 N and R 7 are independently hydrogen, halogen, cyano, C 1-8 Alkyl, C 1-8 Haloalkyl or C 1-8 Alkoxy.

10. A compound according to any one of the preceding claims, wherein W 2 CR 7 .

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