Polycyclic compound, pharmaceutical composition thereof, and use thereof

Abstract

The present invention provides a polycyclic compound, a pharmaceutical composition thereof, and a use thereof. The polycyclic compound of the present invention has a structure as shown in formula A, wherein the definitions of R1-R6, ring A-ring E, L, n, m, q, and t are as described herein. The compound of the present application is an RIPK1 inhibitor, which can be used for treating an RIPK1-related disease.

Description

A polycyclic compound, its pharmaceutical composition and use thereof Technical Field

[0001] The present disclosure belongs to the field of biomedicine, and specifically relates to a Ripk1 inhibitor, a pharmaceutical composition thereof, and uses thereof. Background Art

[0002] Receptor-interacting protein kinase 1 (Ripk1) is a key mediator of multiple signaling pathways activated by the death receptor family and pattern recognition receptors. Ripk1 comprises an N-terminal kinase domain, a C-terminal death domain (DD), and an intermediate domain containing the RIP homotypic interaction motif (RHIM). In TNFα-stimulated cells, Ripk1 kinase exerts pro-cell death and pro-inflammatory activities by activating Ripk1-dependent apoptosis and pyroptosis. The resulting complex triggers multiple cellular responses, including cytokine release, microglial activation, and necroptosis (a regulated form of cell death). The early role of Ripk1 in this signaling cascade has led to the hypothesis that inhibiting Ripk1 signaling may be beneficial in diseases characterized by excessive cell death and inflammation. Indeed, inhibition of Ripk1 activity has been shown to have protective effects. A growing body of research suggests that the development of highly active and selective inhibitors targeting Ripk1 could provide new avenues for the treatment of inflammatory diseases, neurological disorders, cancer, sepsis, and other diseases.

[0003] Necroptosis can be triggered by many mechanisms, including TNF receptor activation, Toll-like receptor engagement, genotoxic stress, and viral infection. Downstream of various stimuli, the signaling pathway leading to necroptosis depends on the activity of Ripk1 and Ripk3 kinases. (He et al., (2009) Cell 137: 1100-1111; Cho et al., (2009) Cell 137: 1112-1123; Zhang et al., (2009) Science 325: 332-336). Dysregulation of the necroptosis signaling pathway has been associated with inflammatory diseases such as macrophage necrosis in the development of atherosclerosis, virus-induced inflammation, systemic inflammatory response syndrome, and ethanol-induced liver damage; and neurodegeneration such as retinal detachment, ischemia, amyotrophic lateral sclerosis (ALS), and Gaucher's disease (Trichonas et al., (2010) Proc. Natl. Acad. Sci. 107, 21695-21700; Lin et al., (2013) Cell Rep. 3, 200-210; Cho et al., (2009) Cell, 137, 1112-1123).

[0004] Nec-1s is the first Ripk1-specific inhibitor discovered through phenotypic screening. GlaxoSmithKline has reported a series of benzoxazepinone compounds, including GSK'481 and GSK'772 in clinical trials, as well as dihydropyrazole compounds GSK'547 and GSK'963. R552 is a once-daily oral Ripk1 inhibitor that has previously completed Phase I safety testing in healthy people. In preclinical studies, R552 has been shown to prevent joint and skin inflammation in mice. Currently known indications include autoimmune diseases and inflammatory diseases. Summary of the Invention

[0005] The present disclosure aims to provide a Ripk1 inhibitor. The present disclosure also provides a method for preparing the inhibitor, a pharmaceutical composition containing the inhibitor, and its use in treating or preventing Ripk1-mediated diseases.

[0006] In a first aspect of the present disclosure, there is provided a compound of formula A, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph, prodrug or metabolite thereof, having the structure shown in the following formula:

[0007] in:

[0008] Ring A is selected from: substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, wherein the heterocyclyl or heteroaryl contains 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P;

[0009] L is selected from: C 1-10 Alkylene, or chemical bond;

[0010] When L is or C 1-10 When alkylene, ring B is selected from: substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, wherein the heterocyclyl or heteroaryl contains 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P; Ring C and Ring D are each independently selected from the group consisting of substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic group, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 5-10 membered heteroaryl or absent, said heterocyclyl or heteroaryl containing 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P;

[0011] When L is a chemical bond, ring E is directly connected to ring B through the chemical bond, and ring B, ring C and ring D are each independently selected from: substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, wherein the heterocyclyl or heteroaryl contains 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P;

[0012] R1 is selected from H, halogen, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, cyano, -NO2, -OH, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic group, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted 3-8 membered heterocyclyl, spiro 3-8 membered heterocyclyl, substituted or unsubstituted 3-8 membered heterocyclyl, 3-8 membered heterocyclyl, substituted or unsubstituted C 3-8 Cycloalkylspiro C 3-8 Cycloalkyl, substituted or unsubstituted C 3-8 Cycloalkyl C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic group and C 6-10 Aryl, substituted or unsubstituted 3-8 membered heterocyclic group and 5-10 membered heteroaryl, substituted or unsubstituted C 3-8 Cycloalkyl C 6-10 Aryl, substituted or unsubstituted C 3-8 Cycloalkyl and 5-10 membered heteroaryl, wherein the heterocyclic group or heteroaryl contains 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P;

[0013] R2 is selected from H, oxo (=O), substituted or unsubstituted C 1-6 Alkoxy, halogen, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 1-6 Alkyl, cyano, -NO2, -OH, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic group, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, said heterocyclic group or heteroaryl group containing 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P;

[0014] R3 is selected from H, oxo, substituted or unsubstituted C 1-6 Alkoxy, halogen, substituted or unsubstituted C 2-6Alkynyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 1-6 Alkyl, cyano, -NO2, -OH, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic group, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, said heterocyclic group or heteroaryl group containing 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P;

[0015] R4 is selected from H, oxo, substituted or unsubstituted C 1-6 Alkoxy, halogen, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 1-6 Alkyl, cyano, -NO2, -OH, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic group, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, said heterocyclic group or heteroaryl group containing 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P;

[0016] R5 is selected from H, halogen, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, cyano, -NO2, -OH, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic group, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, said heterocyclic group or heteroaryl group containing 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P;

[0017] R6 is selected from H, halogen, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, cyano, -NO2, -OH, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic group, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, said heterocyclic group or heteroaryl group containing 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P;

[0018] n, m, q and t are each independently any integer of 0, 1, 2 and 3;

[0019] The substitution refers to that one or more hydrogen atoms on the group are replaced by a substituent selected from the group consisting of halogen, -OH, -NO2, -NH2, -NH (unsubstituted or halogenated C 1-6 Alkyl), -N(unsubstituted or halogenated C 1-6 Alkyl)2, -CN, unsubstituted or substituted by halogen or hydroxyl C 1-8 Alkyl, unsubstituted or halogenated C 1-8 Alkoxy, unsubstituted or halogenated C 1-8 Alkoxy-C 1- 8 alkyl, unsubstituted or halogenated C 3-8 Cycloalkyl-C 1-8 Alkyl, unsubstituted or halogenated C 1-6 Alkylcarbonyl, unsubstituted or halogenated C 1-6 Alkoxycarbonyl, hydroxamate, unsubstituted or halogenated C 1-6 Alkylthio, -S(O)2N(unsubstituted or halogenated C 1-6 Alkyl)2, -S(O)2 unsubstituted or halogenated C 1-6 Alkyl, -N (unsubstituted or halogenated C 1-6 Alkyl)S(O)2N(unsubstituted or halogenated C 1-6 Alkyl)2, -S(O)N(unsubstituted or halogenated C 1-6 Alkyl)2, -S(O)(unsubstituted or halogenated C 1-6 Alkyl), -N(unsubstituted or halogenated C 1-6 Alkyl)S(O)N(unsubstituted or halogenated C 1-6 Alkyl)2, -N (unsubstituted or halogenated C 1-6 Alkyl)S(O)(unsubstituted or halogenated C 1-6 Alkyl), unsubstituted or halogenated C 5-10 Aryl, unsubstituted or halogenated 5-10 membered heteroaryl, unsubstituted or halogenated C 3-8 Cycloalkyl and unsubstituted or halogenated 3-8 membered heterocyclyl, said heterocyclyl and heteroaryl containing 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O or S;

[0020] This represents a connection to the rest of the molecule via a chemical bond.

[0021] The second aspect of the present disclosure provides a pharmaceutical composition comprising: (a) as an active ingredient the compound of formula A described in the first aspect of the present disclosure, or a pharmaceutically acceptable salt thereof, or a solvate, isotope substitution, polymorph, prodrug or metabolite thereof, and (b) a pharmaceutically acceptable carrier or excipient.

[0022] The third aspect of the present disclosure provides a use of the compound of formula A described in the first aspect of the present disclosure, or a pharmaceutically acceptable salt thereof, or a solvate, isotope-substituted product, polymorph, prodrug or metabolite thereof in the preparation of a medicament for treating or preventing Ripk1-related diseases. DETAILED DESCRIPTION

[0023] The following specific embodiments are provided to enable those skilled in the art to more clearly understand the content of the present disclosure. It should be noted that these embodiments are recorded for illustrative purposes only and are not intended to limit the scope of protection of this application.

[0024] To help those skilled in the art understand the features and effects of this disclosure, the following provides a general description and definition of terms and expressions used in the specification and claims. Unless otherwise indicated, all technical and scientific terms used herein have the ordinary meanings understood by those skilled in the art with respect to this disclosure. In the event of conflict, the definitions in this specification shall prevail.

[0025] The theories or mechanisms described and disclosed herein, whether correct or incorrect, should not limit the scope of the present disclosure in any way, that is, the technical solutions of the present disclosure can be implemented without being restricted by any specific theory or mechanism.

[0026] Herein, “comprising,” “including,” “containing” and similar terms encompass the meanings of “consisting essentially of” and “consisting of,” for example, when “A comprises B and C” is disclosed herein, “A consists essentially of B and C” and “A consists of B and C” should be deemed to have been disclosed herein.

[0027] Throughout this document, all features, such as values, amounts, amounts, and concentrations, specified in numerical ranges or percentage ranges are provided for simplicity and convenience only. Accordingly, the description of numerical ranges or percentage ranges should be considered to encompass and specifically disclose all possible subranges and individual values ​​within those ranges (including integers and fractions).

[0028] In this document, unless otherwise specified, percentage refers to mass percentage and ratio refers to mass ratio.

[0029] When describing embodiments or examples herein, it should be understood that they are not intended to limit the present disclosure to these embodiments or examples. On the contrary, all alternatives, modifications, and equivalents of the methods and materials described in the technical solutions of the present disclosure are within the scope defined by the claims.

[0030] In this document, for the sake of brevity, not all possible combinations of the various technical features in each embodiment or example are described. Therefore, as long as there are no contradictions in the combination of these technical features, the various technical features in each embodiment or example can be combined in any way, and all possible combinations should be considered to be within the scope of this specification.

[0031] the term

[0032] Unless otherwise defined, all technical and scientific terms herein have the same meanings as commonly understood by those skilled in the art to which the subject matter of the claims pertains. Unless otherwise indicated, all patents, patent applications, and publications cited herein are incorporated herein by reference in their entirety.

[0033] It should be understood that the above brief description and the detailed description below are exemplary and are only used for explanation, and do not impose any restrictions on the subject matter of the present disclosure. In this application, unless otherwise specifically stated, the use of the singular also includes the plural. It must be noted that, unless otherwise clearly stated in the text, the singular forms used in this specification and claims include the plural forms of the things referred to. It should also be noted that, unless otherwise stated, the use of "or" and "or" means "and / or". In addition, the use of the term "comprise" and other forms, such as "comprises", "contains" and "containing" are not restrictive, and can be open, semi-closed and closed. In other words, the term also includes the meaning of "essentially consisting of..." or "consisting of..."

[0034] Definitions of standard chemical terms can be found in the literature (including Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY 4TH ED." Vols. A (2000) and B (2001), Plenum Press, New York). Unless otherwise indicated, conventional methods within the skill of the art, such as mass spectrometry, NMR, IR and UV / VIS spectroscopy, and pharmacological methods, are employed. Unless specifically defined, the terms used herein in the descriptions of analytical chemistry, organic synthetic chemistry, and pharmaceutical and medicinal chemistry are those known in the art. Standard techniques can be used in chemical syntheses, chemical analyses, pharmaceutical preparation, formulation, and delivery, and treatment of patients. For example, reactions and purifications can be performed using the manufacturer's instructions for kits, or as described in the present disclosure. The techniques and methods described above can generally be performed according to conventional methods well known in the art, as described in the various general and more specific references cited and discussed in this specification. In the present specification, groups and substituents thereof can be selected by one skilled in the art to provide stable structural moieties and compounds.

[0035] When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes chemically equivalent substituents that would result if the formula were written from right to left. For example, -CH2O- is equivalent to -OCH2-.

[0036] The section headings used herein are for organizational purposes only and should not be construed as limitations on the subject matter described. All documents or portions of documents cited in this application, including but not limited to patents, patent applications, articles, books, manuals, and papers, are incorporated herein by reference in their entirety.

[0037] Certain chemical groups defined in this disclosure are preceded by a shorthand notation to indicate the total number of carbon atoms present in the group. For example, C 1-6 Alkyl refers to an alkyl group as defined below having a total of 1 to 6 carbon atoms. The total number of carbon atoms in the shorthand notation does not include carbons that may be present in substituents of the group being described.

[0038] When a variable is referred to in the present disclosure as "selected from: ...", it means that the variable is selected from any one of the options listed after the colon, or, if possible, it means that the variable is selected from one or more of the options listed after the colon.

[0039] All numerical ranges mentioned in this disclosure are intended to include both endpoints of the range, all integers within the range, and sub-ranges formed by these integers.

[0040] In addition to the foregoing, when used in the specification and claims of the present disclosure, the following terms have the meanings indicated below unless otherwise specifically stated.

[0041] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0042] "Hydroxy" refers to an -OH group.

[0043] "Hydroxyalkyl" refers to an alkyl group, as defined below, substituted with a hydroxy (-OH) group.

[0044] "Carbonyl" refers to a -C(=O)- group.

[0045] "Cyano" refers to -CN.

[0046] "Oxo" refers to =0.

[0047] "Thio" refers to a =S group.

[0048] "Nitro" refers to -NO2.

[0049] "Amino" refers to -NH2.

[0050] "Substituted amino" refers to an amino group substituted with one or two alkyl groups, alkylcarbonyl groups, aralkyl groups, aryl groups, heteroaryl groups, heterocyclyl groups, heteroaralkyl groups as defined below, for example, monoalkylamino, dialkylamino, alkylcarbonylamino, aralkylamino, heteroaralkylamino, heterocyclylamino, heteroarylamino and arylamino groups. In some embodiments herein, "substituted amino" is represented by -NR'R", wherein R' and R" are each independently selected from H, C1-C4 alkyl, C1-C4 alkyl-S(O)2- and halo-C1-C4 alkyl (provided that at least one of R' and R" is not H).

[0051] "Carboxyl" refers to -COOH.

[0052] "Amino" refers to -NH2.

[0053] In the present disclosure, the term "Ci-Cj" refers to a range of carbon atoms, wherein i and j are integers, and the range of carbon atoms includes the endpoints (i.e., i and j) and each integer point between the endpoints, wherein j is greater than i. For example, C1-C6 refers to a range of 1 to 6 carbon atoms, including 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, and 6 carbon atoms. For another example, the term "C1-C12" refers to 1 to 12, particularly 1 to 10, particularly 1 to 8, particularly 1 to 6, particularly 1 to 5, particularly 1 to 4, particularly 1 to 3, or particularly 1 to 2 carbon atoms.

[0054] In this disclosure, the term "alkyl" as a group or as part of another group (e.g., as used in groups such as alkyl groups substituted with halogens (e.g., fluorine, chlorine, bromine, or iodine)) refers to a fully saturated straight or branched hydrocarbon chain group consisting solely of carbon and hydrogen atoms connected to the remainder of the molecule by a single bond. In some embodiments, the alkyl group has 1 to 12 carbon atoms. In some embodiments, the alkyl group contains 1 to 11 carbon atoms. In some embodiments, the alkyl group contains 1 to 10 carbon atoms, 1 to 9 carbon atoms, 1 to 8 carbon atoms, 1 to 7 carbon atoms, 1 to 6 carbon atoms, 1 to 5 carbon atoms, 1 to 4 carbon atoms, 1 to 3 carbon atoms, or 1 to 2 carbon atoms. Non-limiting examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, tert-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, n-octyl, n-nonyl, n-decyl, n-undecyl, and n-dodecyl. For purposes of this disclosure, the term "alkyl" refers to an alkyl group containing 1 to 6 carbon atoms. Unless otherwise specifically provided in this specification, an alkyl group may be optionally substituted.

[0055] In this disclosure, the term "alkenyl," as a group or part of another group, means a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing at least one double bond, connected to the rest of the molecule by a single bond. In some embodiments, an alkenyl group contains 2 to 20 carbon atoms. In some embodiments, an alkenyl group contains 2 to 19 carbon atoms. In some embodiments, an alkenyl group contains 2 to 18 carbon atoms. In some embodiments, an alkenyl group contains 2 to 17 carbon atoms. In some embodiments, an alkenyl group contains 2 to 16 carbon atoms. In some embodiments, an alkenyl group contains 2 to 17 carbon atoms. In some embodiments, an alkenyl group contains 2 to 16 carbon atoms. In some embodiments, an alkenyl group contains 2 to 15 carbon atoms. In some embodiments, an alkenyl group contains 2 to 14 carbon atoms. In some embodiments, an alkenyl group contains 2 to 13 carbon atoms. In some embodiments, an alkenyl group contains 2 to 12 carbon atoms. In some embodiments, an alkenyl group contains 2 to 11 carbon atoms. In some embodiments, an alkenyl group contains 2 to 10 carbon atoms. In some embodiments, the alkenyl group contains 2 to 9 carbon atoms. In some embodiments, the alkenyl group contains 2 to 8 carbon atoms. In some embodiments, the alkenyl group contains 2 to 7 carbon atoms. In some embodiments, the alkenyl group contains 2 to 6 carbon atoms. In some embodiments, the alkenyl group contains 2 to 5 carbon atoms. In some embodiments, the alkenyl group contains 2 to 4 carbon atoms. In some embodiments, the alkenyl group contains 2 to 3 carbon atoms. In some embodiments, the alkenyl group contains 2 carbon atoms. Non-limiting examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, allyl, butenyl, but-1-enyl, but-2-enyl, pentenyl, pent-1-enyl, pentadienyl, pent-1,4-dienyl, and the like. Unless otherwise specifically provided in this specification, alkenyl groups may be optionally substituted.

[0056] In this disclosure, the term "alkynyl," as a group or part of another group, refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms with one or more carbon-carbon triple bonds (-C≡C-) connected to the rest of the molecule by a single bond. In some embodiments, the alkynyl group contains 2 to 20 carbon atoms. In some embodiments, the alkynyl group contains 2 to 19 carbon atoms. In some embodiments, the alkynyl group contains 2 to 18 carbon atoms. In some embodiments, the alkynyl group contains 2 to 17 carbon atoms. In some embodiments, the alkynyl group contains 2 to 16 carbon atoms. In some embodiments, the alkynyl group contains 2 to 17 carbon atoms. In some embodiments, the alkynyl group contains 2 to 16 carbon atoms. In some embodiments, the alkynyl group contains 2 to 15 carbon atoms. In some embodiments, the alkynyl group contains 2 to 14 carbon atoms. In some embodiments, the alkynyl group contains 2 to 13 carbon atoms. In some embodiments, the alkynyl group contains 2 to 12 carbon atoms. In some embodiments, the alkynyl group contains 2 to 11 carbon atoms. In some embodiments, the alkynyl group contains 2 to 10 carbon atoms. In some embodiments, the alkynyl group contains 2 to 9 carbon atoms. In some embodiments, the alkynyl group contains 2 to 8 carbon atoms. In some embodiments, the alkynyl group contains 2 to 7 carbon atoms. In some embodiments, the alkynyl group contains 2 to 6 carbon atoms. In some embodiments, the alkynyl group contains 2 to 5 carbon atoms. In some embodiments, the alkynyl group contains 2 to 4 carbon atoms. In some embodiments, the alkynyl group contains 2 to 3 carbon atoms. In some embodiments, the alkynyl group contains 2 carbon atoms. Non-limiting examples of alkynyl groups include ethynyl, 1-propynyl, 1-methyl-2-propynyl, 2-propynyl, 1-butynyl, and 2-butynyl, etc. Unless otherwise specifically provided in this specification, the alkynyl group may be optionally substituted.

[0057] In this disclosure, the term "alkylene" as a group or part of another group refers to a group that is the same as an alkyl group but has a divalent radical. In some embodiments, an alkylene group has 1 to 20 carbon atoms. For example, C 1-10 Alkylene, C 1-6 Alkylene, C 1-4 Alkylene. Examples of the alkylene group include methylene (—CH2—), ethylene (—CH2CH2—), propylene (—CH2CH2CH2—), butylene (—CH2CH2CH2CH2—), and the like.

[0058] In this disclosure, the term "alkoxy" as a group or part of another group refers to a "-O-alkyl" group, wherein alkyl has the meaning described above. In some embodiments, alkoxy is C 1-20 Alkoxy, C 1-19 Alkoxy, C 1-18 Alkoxy, C 1-17 Alkoxy, C1-16 Alkoxy, C 1-15 Alkoxy, C 1-14 Alkoxy, C 1-13 Alkoxy, C 1-12 Alkoxy, C 1-11 In some embodiments, the alkoxy group is C 1-10 In some embodiments, the alkoxy group is C 1-8 In some embodiments, the alkoxy group is C 1-6 In some embodiments, the alkoxy group is C 1-4 Alkoxy, C 1-3 Alkoxy or C 1-2 Alkoxy. Non-limiting examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, and the like. Alkenyloxy refers to "alkenyl-O-," wherein alkenyl has the meaning described above. Alkynyloxy refers to "alkynyl-O-," wherein alkynyl has the meaning described above. "Substituted alkoxy" refers to substituted alkyl-O-.

[0059] In this disclosure, the term "haloalkyl" as a group or part of another group refers to an alkyl group substituted by one or more halogens, wherein alkyl has the meaning given above and the number of halogens can be up to the same number of substitutable hydrogens on the alkyl group.

[0060] In the present disclosure, the term "acyl" as a group or as part of another group refers to a monovalent radical remaining after removing the hydroxyl group from an aliphatic carboxylic acid, and can be represented by the general formula "GC(=O)-", where G represents H or an alkyl, alkenyl, or alkynyl group as described above. For example, specific examples of C1-C4 acyl groups include, but are not limited to, formyl, acetyl, propionyl, butyryl, and the like.

[0061] In the present disclosure, as a group or part of another group, the term "cycloalkyl" refers to a saturated or partially unsaturated non-aromatic monocyclic or polycyclic hydrocarbon group or moiety (moiety, representing a structural fragment of an organic molecule) consisting only of carbon atoms and hydrogen atoms and optionally having one or more carbon-carbon double bonds (-C=C-) or carbon-carbon triple bonds (-C≡C-), which can be connected to the rest of the molecule through any suitable carbon atom and includes "cycloalkyl", "cycloalkenyl" and "cycloalkynyl". In some embodiments, the cycloalkyl group contains 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 ring carbon atoms. Non-limiting examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, and cyclooctynyl. Unless otherwise specifically noted in this specification, the carbon atoms in the cycloalkyl may be optionally oxidized (thereby forming an oxo (=O) group), and the cycloalkyl may be optionally substituted.

[0062] In the present disclosure, as a group or part of other groups, the term "cycloalkyl" refers to a saturated non-aromatic monocyclic or polycyclic alkyl group or moiety consisting only of carbon atoms and hydrogen atoms, which can be connected to the rest of the molecule via any suitable carbon atom. In some embodiments, the cycloalkyl group may include a fused ring system, a bridged ring system, or a spirocyclic ring system. In some embodiments, the cycloalkyl group contains 3 to 15 carbon atoms, 3 to 14 carbon atoms, 3 to 13 carbon atoms, 3 to 12 carbon atoms, 3 to 11 carbon atoms, 3 to 10 carbon atoms, 3 to 9 carbon atoms, 3 to 8 carbon atoms. In some embodiments, the cycloalkyl group has 3, 4, 5, 6, 7 or 8 carbon atoms. Unless otherwise specifically indicated in this specification, the carbon atoms in the cycloalkyl group may be optionally oxidized. Non-limiting examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, 1H-indenyl, 2,3-dihydroindanyl, 1,2,3,4-tetrahydro-naphthyl, 5,6,7,8-tetrahydro-naphthyl, 8,9-dihydro-7H-benzocyclohepten-6-yl, 6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl, 5,6,7,8,9,10-hexahydro-benzocyclohepten- cyclopenta-1,1-dihydro-4,7-methylene-1H-indenyl, octahydro-2,5-methylene-1H-indenyl, and octahydro-2,5-methylene-1H-indenyl.

[0063] In the present disclosure, as a group or part of other groups, the term "cycloalkenyl" refers to a partially unsaturated non-aromatic monocyclic or polycyclic hydrocarbon group or portion consisting only of carbon atoms and hydrogen atoms and having one or more carbon-carbon double bonds (-C=C-), which can be connected to the rest of the molecule via any suitable carbon atom. In some embodiments, the cycloalkenyl group contains 5 to 12 ring carbon atoms, 5 to 10 ring carbon atoms, 5 to 9 ring carbon atoms, 5 to 8 ring carbon atoms, 5 to 7 ring carbon atoms, 5 to 6 ring carbon atoms. Non-limiting examples of cycloalkenyl groups include cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl, etc. Unless otherwise specifically indicated in this specification, the carbon atoms in the cycloalkenyl group can be optionally oxidized (thereby forming an oxo (=O) group), and the cycloalkenyl group can be optionally substituted.

[0064] In the present disclosure, as a group or part of other groups, the term "cycloalkynyl" refers to a partially unsaturated non-aromatic monocyclic or polycyclic hydrocarbon group or portion consisting only of carbon atoms and hydrogen atoms and having one or more carbon-carbon triple bonds (-C=C-), which can be connected to the rest of the molecule via any suitable carbon atom. In some embodiments, the cycloalkynyl contains 8 to 12 ring carbon atoms, 8 to 11 ring carbon atoms, 8 to 10 ring carbon atoms, 8 to 9 ring carbon atoms. Non-limiting examples of cycloalkynyl include cyclooctynyl and the like. Unless otherwise specifically indicated in this specification, the carbon atoms in the cycloalkynyl group can be optionally oxidized (thereby forming an oxo (=O) group), and the cycloalkynyl group can be optionally substituted.

[0065] In the present disclosure, as a group or part of other groups, the term "spirocyclyl" or "spiro ring" refers to a ring system consisting of multiple (e.g., two, three or more) rings, wherein at least two rings are cycloalkyl rings that are combined with each other to share a carbon atom. In some embodiments, the spirocyclyl contains 6 to 12 ring carbon atoms, 6 to 11 ring carbon atoms, 6 to 10 ring carbon atoms, 6 to 9 ring carbon atoms, 6 to 8 ring carbon atoms, 6 to 7 ring carbon atoms. Non-limiting examples of spirocyclyl include, but are not limited to, spiro [5.5] undecyl, spiro-pentadienyl, spiro [3.6] decyl, etc. Unless otherwise specifically provided in this specification, spirocyclyl may be optionally substituted.

[0066] In the present disclosure, the term "paracyclyl" or "paracyclyl (also known as "fused ring"), as a group or part of another group, refers to a cycloalkyl ring system consisting of multiple (e.g., two, three or more) rings, at least two of which are linked to each other by sharing two adjacent carbon atoms (i.e., the at least two rings share a covalent bond such that the bridgehead atoms are directly connected). In some embodiments, the paracyclyl contains 5 to 12 ring carbon atoms, 5 to 11 ring carbon atoms, 5 to 10 ring carbon atoms, 5 to 9 ring carbon atoms, 5 to 8 ring carbon atoms, 5 to 7 ring carbon atoms, or 5 to 6 ring carbon atoms. Non-limiting examples of cyclyl groups include, but are not limited to, 2,3-dihydroindanyl, 1,2,3,4-tetrahydro-naphthyl, 5,6,7,8-tetrahydro-naphthyl, 8,9-dihydro-7H-benzocyclohepten-6-yl, 6,7,8,9-tetrahydro-5H-benzocycloheptenyl, 5,6,7,8,9,10-hexahydro-benzocyclooctenyl, etc. Unless specifically stated otherwise in the specification, cyclyl groups may be optionally substituted.

[0067] In the present disclosure, the term "bridged ring group" or "bridged ring" as a group or part of another group refers to a ring system consisting of multiple (e.g., two, three, or more) rings, wherein at least two of the rings are cycloalkyl groups that are connected to each other by sharing three or more carbon atoms (the at least two rings are separated by two bridgehead atoms by a bridge containing at least one atom). In some embodiments, the bridged ring group contains 8 to 12 ring carbon atoms, 8 to 11 ring carbon atoms, 8 to 10 ring carbon atoms, or 8 to 9 ring carbon atoms. Non-limiting examples of bridged ring groups include, but are not limited to, bicyclo[1.1.1]pentenyl, bicyclo[2.2.1]heptenyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.2.1]octenyl, bicyclo[3.3.1]nonyl, bicyclo[3.3.3]undecyl, adamantyl, and the like. Unless stated otherwise specifically in the specification, a bridged ring group may be optionally substituted.

[0068] In the present disclosure, the term "heterocyclyl" or "heterocycle" as a group or part of another group refers to a stable saturated or partially unsaturated 3- to 20-membered non-aromatic cyclic group or moiety consisting of 2 to 14 carbon atoms (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 carbon atoms) and 1 to 6 heteroatoms (e.g., 1, 2, 3, 4, 5, or 6 heteroatoms) selected from nitrogen, phosphorus, oxygen, and sulfur. In some embodiments, the heterocyclyl group can be a 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-, 13-, 14-, 15-, 16-, 17-, 18-, 19-, or 20-membered heterocyclyl group, such as a 3- to 20-membered heterocyclyl group, a 3- to 19-membered heterocyclyl group, a 3- to 18-membered heterocyclyl group, a 3- to 17-membered heterocyclyl group, a 3- to 16-membered heterocyclyl group, a 3- to 15-membered heterocyclyl group, a 4- to 12-membered heterocyclyl group, a 4- to 10-membered heterocyclyl group, a 4- to 9-membered heterocyclyl group, a 4- to 8-membered heterocyclyl group, a 4- to 7-membered heterocyclyl group, a 4- to 6-membered heterocyclyl group, or a 4- to 5-membered heterocyclyl group. Unless otherwise specifically indicated in this specification, the heterocyclic group can be a monocyclic, bicyclic, tricyclic or more ring system, which may include a fused / annular system (i.e., an annular heterocyclic group, such as a 4-9 member annular heterocyclic group), a bridged ring system (i.e., a bridged heterocyclic group, such as a 6-12 member bridged heterocyclic group) or a spiro ring system (i.e., a spiro heterocyclic group, such as a 6-12 member spiro heterocyclic group). An annular heterocyclic group refers to a ring system of a heterocyclic group consisting of multiple (e.g., two, three or more) rings, wherein at least two rings are combined to share two adjacent atoms (i.e., the at least two rings share a covalent bond, so that the bridgehead atoms are directly connected). In some embodiments, the heterocyclic group is a bicyclic annular heterocyclic group. A bridged heterocyclic group refers to a ring system of a heterocyclic group consisting of multiple (e.g., two, three or more) rings, wherein at least two rings are combined to share three or more atoms (the at least two rings are separated by a bridge containing at least one atom, such as two bridgehead atoms). Spiroheterocyclyl refers to a ring system consisting of multiple (e.g., two, three or more) rings, at least two of which are heterocyclic rings that are bound to each other by a common carbon atom. The nitrogen, carbon or sulfur atoms in the heterocyclic group may be optionally oxidized; the nitrogen atom may be optionally quaternized; and the heterocyclic group may be partially or completely saturated. The heterocyclic group may be connected to the rest of the molecule via a carbon atom or a heteroatom and by a single bond. In some cases, the heterocyclic group may be carbon-linked, nitrogen-linked or sulfur-linked. In some embodiments, the heterocyclic group is carbon-linked. In some embodiments, the heterocyclic group is nitrogen-linked. In some embodiments, the heterocyclic group is sulfur-linked. Unless otherwise specifically provided in this specification, the heterocyclic group may be optionally substituted. Unless otherwise specifically provided in this specification, the heterocyclic group may be optionally substituted.

[0069] Heterocyclyl also includes groups in which a heterocyclyl group is fused to a saturated, partially unsaturated, or fully unsaturated (i.e., aromatic) cycloalkyl, aryl, heterocyclyl, or heteroaryl group. In heterocyclyl groups comprising fused rings, one or more rings may be aryl or heteroaryl as defined below. Examples of fused heterocyclic groups include, but are not limited to, phenyl-fused heterocyclic groups or pyridyl-fused heterocyclic groups, as well as quinolinyl, isoquinolinyl, quinoxalinyl, quinolizinyl, quinazolinyl, azaindolizinyl, pteridinyl, chromenyl, isochromenyl, indolyl, isoindolyl, indolizinyl, indazolyl, purinyl, benzofuranyl, isobenzofuranyl, benzimidazolyl, benzothiophenyl, benzothiazolyl, carbazolyl, phenazinyl, phenothiazinyl, phenanthridinyl, imidazo[1,2-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, [1,2,3]triazolo[4,3-a]pyridinyl-fused heterocyclic groups, and the like.

[0070] In some embodiments, the heterocyclyl group is a stable 3- to 12-membered, 4- to 11-membered, 5- to 12-membered, 6- to 10-membered, 4- to 10-membered, 4- to 9-membered, or 3- to 8-membered non-aromatic monocyclic, bicyclic, bridged, or spirocyclic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the heterocyclyl group is a stable 3- to 10-membered (e.g., 3- to 8-membered, 5- to 10-membered, or 4- to 9-membered) non-aromatic monocyclic, bicyclic, tricyclic, or higher ring group (including fused, bridged, or spirocyclic groups) containing 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur. Non-limiting examples of heterocyclic groups include, but are not limited to, pyrrolidinyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, thiomorpholinyl, 2,7-diaza-spiro[3.5]nonan-7-yl, 2-oxa-6-aza-spiro[3.3]heptane-6-yl, 2-oxa-6-aza-spiro[3.4]octan-7-yl, 8-oxa-2-aza-spiro[4.5]decane-6-yl, 2,5-diaza-bicyclo[2.2.1]heptane-2-yl, azetidinyl, oxetanyl, thietanyl, thio heterocyclopentyl, pyranyl, tetrahydropyranyl, thiopyranyl, tetrahydrofuranyl, oxazinyl, dioxolane, tetrahydroisoquinolinyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, quinolizinyl, thiazolidinyl, isothiazolidinyl, isoxazolidinyl, dihydroindole, octahydroindole, octahydroisoindole, pyrrolidinyl, pyrazolidinyl, phthalimido, dioxothiomorpholinyl, dioxothiolane, dioxothietane, thiahexyl, dioxothiocyclohexyl, thiomorpholinyl, 1,4-oxathiahexyl, and the like.

[0071] In the present disclosure, the term "aryl" or "aromatic ring" as a group or part of another group refers to a conjugated hydrocarbon ring system group or part having 6 to 18 carbon atoms (e.g., 6 to 14 carbon atoms or 6 to 10 carbon atoms, such as 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms). For the purposes of this disclosure, an aryl group can be a monocyclic, bicyclic, tricyclic or more ring system, and can also be fused to a cycloalkyl or heterocyclic group as defined above. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthrenyl, fluorenyl, 2,3-dihydro-1H-isoindolyl, 2-benzoxazolinone, 2H-1,4-benzoxazine-3(4H)-one-7-yl, and the like. Unless otherwise specifically provided in this specification, an aryl group may be optionally substituted.

[0072] In the present disclosure, the term "heteroaryl" or "heteroaromatic ring" as a group or part of another group refers to a conjugated ring system radical or portion having carbon atoms (e.g., 1 to 15 carbon atoms, 1 to 14 carbon atoms, 1 to 13 carbon atoms, 1 to 12 carbon atoms, 1 to 11 carbon atoms, 1 to 10 carbon atoms, such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms) and heteroatoms selected from nitrogen, oxygen and sulfur (e.g., 1 to 6 heteroatoms, such as 1, 2, 3, 4, 5 or 6 heteroatoms) within the ring. In some embodiments, the heteroaryl group may contain 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 ring-forming atoms, such as 5 to 20 ring-forming atoms, 5 to 19 ring-forming atoms, 5 to 18 ring-forming atoms, 5 to 17 ring-forming atoms, 5 to 16 ring-forming atoms, 5 to 15 ring-forming atoms, 5 to 14 ring-forming atoms, 5 to 13 ring-forming atoms, 5 to 12 ring-forming atoms, 5 to 10 ring-forming carbon atoms, 5 to 9 ring-forming atoms, 5 to 8 ring-forming atoms, 5 to 7 ring-forming atoms, or 5 to 6 ring-forming atoms. Unless otherwise specified in the specification, the heteroaryl group may be a monocyclic, bicyclic, tricyclic, or higher ring system, and may further be fused with a cycloalkyl, aryl, or heterocyclyl group as defined above. Examples of heteroaryl fused to aryl include, but are not limited to, benzopyridyl, benzopyrazolyl, benzimidazolyl, benzopyrrolyl, etc. The nitrogen, carbon or sulfur atom in the heteroaryl group may be optionally oxidized; the nitrogen atom may be optionally quaternized. For the purposes of this disclosure, in some embodiments, the heteroaryl group is a stable 5- to 12-membered aromatic group comprising 1 to 5 (e.g., 1, 2, 3, 4, or 5) heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl group is a stable 5- to 10-membered aromatic group comprising 1 to 4 (e.g., 1, 2, 3, or 4) heteroatoms selected from nitrogen, oxygen, and sulfur, or a 5- to 6-membered aromatic group comprising 1, 2, or 3 heteroatoms selected from nitrogen, oxygen, and sulfur. Unless otherwise specifically provided in this specification, the heteroaryl group may be optionally substituted.

[0073] Non-limiting examples of heteroaryl groups include, but are not limited to, thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzimidazolyl, benzopyrazolyl, indolyl, furanyl, pyrrolyl, triazolyl, tetrazolyl, triazinyl, indolizinyl, isoindolyl, indazolyl, isoindazolyl, purinyl, quinolyl, isoquinolyl, naphthazinyl, naphthyridinyl, quinoxalinyl, pteridinyl, carbazolyl, carbolinyl, phenanthridinyl, phenanthrolinyl, acridinyl, phenazinyl, isothiazolyl, benzothiazolyl, benzothiophenyl, oxatriol, oxazolyl, cinnolinyl, quinazolinyl, indolizinyl, o-phenanthroline, isoxazolyl, phenoxazinyl, phenothiazinyl, 4,5,6,7-tetrahydrobenzo[b]thienyl, naphthopyridinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[4,3-a]pyrazinyl, [1,2,4]triazolo[4,3-c]pyrimidinyl, [1,2,4]triazolo[4,3-a]pyridinyl, imidazo[1,2-a]pyridinyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrazinyl, and the like.

[0074] In the present disclosure, as a group or part of other groups, the term "heterocyclyl spiroheterocyclic radical" or "heterocyclyl spiroheterocycle" refers to a fully saturated 5 to 20-membered (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20-membered) polycyclic ring sharing a carbon atom (called spiro atom) between heterocyclyls, and one or more ring atoms in the polycyclic ring are selected from the heteroatoms (e.g., 1 or 2 heteroatoms) of sulfur, silicon, phosphorus, oxygen and / or nitrogen, and the remaining ring atoms are carbon atoms. Spiro heterocycle is divided into single spiro heterocycle, double spiro heterocycle or multiple spiro heterocycles according to the number of shared spiro atoms between rings. In some embodiments, heterocyclyl spiroheterocyclic radical is single spiro heterocycle or double spiro heterocycle. In some embodiments, the heterocyclyl spiroheterocyclyl is a 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered monospiroheterocyclic ring. Non-limiting examples of heterocycles include

[0075] In the present disclosure, all cyclic groups may exist as substituents on a parent core, or may themselves exist as part of a chain (including straight chain and branched) structure, a parent core or a portion of a parent core.

[0076] In this disclosure, the term "heteroarylalkyl" or "heteroaralkyl" refers to an alkyl group as defined above substituted with a heteroaryl group as defined above.

[0077] In the present disclosure, "optionally" or "optionally" means that the subsequently described event or circumstance may or may not occur, and the description includes both cases where the event or circumstance occurs and cases where it does not occur. For example, "optionally substituted aryl" means that the aryl group is substituted or unsubstituted, and the description includes both substituted aryl groups and unsubstituted aryl groups. The "optionally" substituents described in the claims and description of the present disclosure are selected from alkyl, alkenyl, alkynyl, alkoxy, halogen, haloalkyl, haloalkenyl, haloalkynyl, cyano, hydroxy, nitro, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, and optionally substituted heterocyclyl.

[0078] In the present disclosure, the term "substituted", whether or not preceded by the term "optionally" (i.e., equivalent to substituted or unsubstituted), refers to the replacement of one or more hydrogens of a specified group or portion by a "suitable substituent". Herein, the number of substituents may be one or more, i.e., 1, 2, 3, 4, 5, or 6 or more, depending on the group being substituted and the nature of the substituent. For example, when the substituent of an ethyl group is a halogen, the group may be substituted by 1, 2, 3, 4, or 5 substituents, such as trifluoroethyl, pentafluoroethyl, etc., depending on the structure of the substituted group. In some embodiments, the number of the substituents is 1, 2, or 3. In some embodiments, the number of the substituents is 1 or 2. In some embodiments, the number of the substituents is 1. It will be understood that "substituted" or "substituted by..." includes implicit conditions, i.e., such replacement is carried out according to the allowed valence of the substituted atom, and the replacement produces a stable or chemically feasible compound, such as a compound that will not spontaneously transform, such as by rearrangement, cyclization, elimination, etc. Unless otherwise indicated, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituents may be the same or different at each position. It will be understood by those skilled in the art that the substituents themselves may be substituted if appropriate. Unless specifically indicated as "unsubstituted," reference to chemical moieties herein is understood to include substituted variants. For example, reference to an "aryl" group or moiety implicitly includes both unsubstituted aryl groups and substituted variants.

[0079] Throughout this application, the “suitable substituents” mentioned above are understood to include, but are not limited to, the alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, cyano, hydroxy, amino, monoalkylamino, dialkylamino, nitro, aryl, heteroaryl, cycloalkyl (e.g., cycloalkyl, cycloalkenyl, etc.), heterocyclyl, etc. described herein; these groups as substituents, including alkyl, alkenyl, alkynyl, alkyl in haloalkyl, alkenyl in haloalkenyl, alkynyl in haloalkynyl, alkoxy, alkyl in monoalkylamino, alkyl in dialkylamino, aryl, heteroaryl, cycloalkyl and heterocyclyl themselves are also optionally substituted, for example, they may be optionally substituted with one or more groups selected from alkyl, halogen, haloalkyl, alkoxy, hydroxy, amino, monoalkylamino, dialkylamino, nitro, aryl, heteroaryl, cycloalkyl and heterocyclyl.

[0080] In some embodiments, the "suitable substituent" is selected from hydroxy, halogen, C1-C4 alkoxy optionally substituted by halogen, C1-C4 alkoxycarbonyl, cyano, -S(O)2-C1-C4 alkyl optionally substituted by halogen, C1-C4 alkyl optionally substituted by halogen, -NR'R", -S(O)2-NR'R", -S(O)2-NH2, -C(O)-C1-C4 alkyl, -NR'-C(O)-C1-C4 alkyl, C3-C8 cycloalkyloxy and optionally 1 , 6-14 membered aryl, 5-10 membered heteroaryl, C3-C8 cycloalkyl and 4-9 membered heterocyclyl substituted with 2 or 3 substituents selected from C1-C4 alkyl, halo-substituted C1-C4 alkyl, C1-C4 alkoxy, halo-substituted C1-C4 alkoxy, halogen, cyano, C1-C4 alkyl-S(O)2-, hydroxyl, carboxyl, -NR'R", 6-14 membered aryl, 5-10 membered heteroaryl, C3-C8 cycloalkyl and 4-9 membered heterocyclyl, wherein R' and R" are each independently selected from H and C1-C4 alkyl. In some embodiments, the "suitable substituents" are hydroxyl, amino, halogen, substituted or unsubstituted alkyl, -NR'R" and substituted or unsubstituted alkoxy, wherein R' and R" are each independently selected from H, C1-C4 alkyl, C1-C4 alkyl-S(O)2- and halo-substituted C1-C4 alkyl. In some embodiments, the "suitable substituent" is selected from deuterium, hydroxyl, cyano, C1-C4 alkyl, halogen and C1-C4 alkoxy. In some embodiments, the "suitable substituent" is deuterium, hydroxyl, methyl, F and methoxy. In some embodiments, the "suitable substituent" is selected from hydroxyl, halogen, C1-C4 alkoxy, cyano and -S(O)2-C1-C4 alkyl. In some embodiments, the "suitable substituent" is selected from halogen, hydroxyl, cyano, -S(O)2-C1-C4 alkyl, C1-C4 alkyl and C1-C4 alkoxy. In some embodiments, the "suitable substituent" is selected from hydroxyl, C1-C4 alkyl, C1-C4 alkoxy and cyano. In some embodiments, the "suitable substituent" is F, hydroxyl and cyano.

[0081] As used herein, the terms "moiety," "moiety," "chemical moiety," "group," and "chemical group" refer to specific segments or functional groups in a molecule. A chemical moiety is generally considered to be a chemical entity embedded in or attached to a molecule.

[0082] Those skilled in the art will also appreciate that in the methods described below, the intermediate compound functional groups may need to be protected by appropriate protecting groups. Such functional groups include hydroxyl, amino, amidino, guanidino, sulfhydryl and carboxyl. Suitable hydroxy protecting groups include trialkylsilyl or diarylalkylsilyl (e.g., tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl, benzyl, etc. Suitable protecting groups for amino, amidino and guanidino include tert-butyloxycarbonyl, benzyloxycarbonyl, etc. Suitable sulfhydryl protecting groups include -C (O) -R X (where R X is alkyl, aryl or aralkyl), p-methoxybenzyl, trityl, etc. Suitable carboxyl protecting groups include alkyl esters, aryl esters or aralkyl esters.

[0083] "Stereoisomers" refer to compounds composed of the same atoms, bonded by the same bonds, but having different three-dimensional structures. The present disclosure is intended to encompass various stereoisomers and mixtures thereof.

[0084] When the compounds of the present disclosure contain olefinic double bonds, and unless specified otherwise, it is intended that the compounds of the present disclosure include both E- and Z- geometric isomers.

[0085] "Tautomer" refers to an isomer formed by a proton shift from one atom of a molecule to another atom of the same molecule. All tautomeric forms of the compounds of the present disclosure are intended to be encompassed within the scope of the present disclosure.

[0086] The compounds of the present invention or their pharmaceutically acceptable salts may contain one or more chiral carbon atoms and may therefore produce enantiomers, diastereomers and other stereoisomeric forms. Each chiral carbon atom can be defined as (R)- or (S)- based on stereochemistry. The present disclosure is intended to include all possible isomers, as well as racemates and optically pure forms thereof. The compounds of the present invention may be prepared using racemates, diastereomers or enantiomers as starting materials or intermediates. Optically active isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as crystallization and chiral chromatography.

[0087] Unless otherwise indicated, "(D)" or "(+)" indicates dextrorotatory, "(L)" or "(-)" indicates levorotatory, and "(DL)" or "(±)" indicates racemic.

[0088] Unless otherwise specified, use a solid wedge key. and dotted wedge key Indicates the absolute configuration of a stereocenter.

[0089] Conventional techniques for preparing / isolating individual isomers include chiral synthesis from appropriate optically pure precursors, or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high performance liquid chromatography, see, for example, Gerald Gübitz and Martin G. Schmid (Eds.), Chiral Separations, Methods and Protocols, Methods in Molecular Biology, Vol. 243, 2004; A.M. Stalcup, Chiral Separations, Annu. Rev. Anal. Chem. 3: 341-63, 2010; Fumiss et al. (eds.), VOGEL'S ENCYCLOPEDIA OF PRACTICAL ORGANIC CHEMISTRY 5.sup.TH ED., Longman Scientific and Technical Ltd., Essex, 1991, 809-816; Heller, Acc. Chem. Res. 1990, 23, 128, the disclosures of which are incorporated herein by reference in their entirety.

[0090] The compounds of the present disclosure also include all suitable isotopic substitutions (or isotopic variants) of their pharmaceutically acceptable salts. Isotopic variants of the compounds of the present disclosure or their pharmaceutically acceptable salts are defined as those in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass commonly found in nature. Isotopes that can be incorporated into the compounds of the present disclosure and their pharmaceutically acceptable salts include, but are not limited to, isotopes of H, C, N, and O, for example 2 H. 3 H. 11 C. 13 C. 14 C. 15 N. 17 O. 18 O. 35 S. 18 F. 36 Cl and 125 I. Isotopic variations of the compounds of the present disclosure or pharmaceutically acceptable salts thereof can be prepared by conventional techniques using appropriate isotopic variations of suitable reagents.

[0091] Herein, unless otherwise specified, the wavy line on each structural formula or group generally indicates the position where the structural formula or group is connected to other parts in the compound.

[0092] As used herein, "solvate" refers to a solvent containing a stoichiometric or non-stoichiometric amount, and it is often formed during the crystallization process. Solvate comprises an aggregate of one or more molecules of the disclosed compounds and one or more solvent molecules. Hydrates are formed when the solvent is water, or the solvent can be an organic solvent (e.g., alcoholates are formed when the solvent is an alcohol). Therefore, the disclosed compounds can exist as hydrates, including monohydrates, dihydrates, hemihydrates, sesquihydrates, trihydrates, tetrahydrates, etc., as well as as corresponding solvated forms. The disclosed compounds can be true solvates, while in other cases, the disclosed compounds can only retain adventitious water or a mixture of water plus some adventitious solvent.

[0093] As used herein, the term "polymorph" refers to different crystal packing arrangements (all having the same elemental composition) of a compound (or its salt, solvate, or other derivative such as a prodrug or metabolite). Polymorphs typically have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical or electrical properties, stability, and solubility. Various factors such as recrystallization solvent, crystallization rate, and storage temperature can cause a single crystalline form to predominate.

[0094] In the present disclosure, the term "pharmaceutically acceptable salt" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0095] "Pharmaceutically acceptable acid addition salts" refer to salts formed with inorganic or organic acids that retain the biological effectiveness of the free base without the side effects. Inorganic acid salts include, but are not limited to, hydrochlorides, hydrobromides, sulfates, nitrates, and phosphates; organic acid salts include, but are not limited to, formate, acetate, 2,2-dichloroacetate, trifluoroacetate, propionate, hexanoate, octanoate, decanoate, undecylenate, glycolate, gluconate, lactate, sebacate, adipate, glutarate, malonate, oxalate, maleate, succinate, fumarate, tartrate, citrate, palmitate, stearate, oleate, cinnamate, laurate, malate, glutamate, pyroglutamate, aspartate, benzoate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, alginate, ascorbate, salicylate, 4-aminosalicylate, and naphthalene disulfonate. These salts can be prepared by methods known in the art.

[0096] "Pharmaceutically acceptable base addition salts" refer to salts formed with inorganic or organic bases that retain the biological effectiveness of the free acid without other side effects. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Preferred inorganic salts are ammonium, sodium, potassium, calcium, and magnesium salts. The salt derived from organic base includes but is not limited to following salt: primary amines, secondary amines and tertiary amines, substituted amines, including natural substituted amines, cyclic amines and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins etc. Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine. These salts can be prepared by methods known in the art.

[0097] As used herein, the term "prodrug" refers to compounds that are metabolized (i.e., converted in vivo) into pharmacologically active compounds of the present disclosure after administration. When the compounds of the present disclosure themselves are poorly absorbed from the gastrointestinal tract, their bioavailability can be improved by preparing them into prodrugs. Examples of prodrugs of the compounds of the present disclosure may include simple esters of compounds containing carboxyl groups (e.g., esters obtained by condensation with C1-C4 alcohols according to methods known in the art); esters of compounds containing hydroxyl groups (e.g., esters obtained by condensation with C1-C4 monocarboxylic acids, C3-C6 dicarboxylic acids, or anhydrides thereof, such as succinic anhydride or fumaric anhydride according to methods known in the art); imines of compounds containing amino groups (e.g., imines obtained by condensation with C1-C4 aldehydes or ketones according to methods known in the art); carbamates of compounds containing amino groups, such as those described by Leu et al. (J. Med. Chem., 42:3623-3628 (1999)) and Greenwald et al. (J. Med. Chem., 42:3657-3667 (1999)); acetals or ketals of compounds containing hydroxyl groups (e.g., those obtained by condensation with chloromethyl methyl ether or chloromethyl ethyl ether according to methods known in the art).

[0098] In the present disclosure, "pharmaceutical composition" refers to a preparation of a compound of the present disclosure or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotope-substituted product, polymorph, prodrug or metabolite thereof and a medium generally accepted in the art for delivering a biological (pharmacological) active compound to a mammal (e.g., a human). The medium includes a pharmaceutically acceptable carrier or excipient. The purpose of the pharmaceutical composition is to promote administration to an organism, facilitate the absorption of the active ingredient, and thus exert biological (pharmacological) activity. In general, the pharmaceutical composition of the present disclosure contains 0.1% by weight to 99.5% by weight of the active pharmaceutical ingredient (i.e., a compound of the present disclosure or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotope-substituted product, polymorph, prodrug or metabolite thereof). In some embodiments, the pharmaceutical compositions of the present disclosure contain 0.5% to 90% by weight, e.g., 1%, 1.5%, 2%, 5%, 10%, 15%, 20%, 25%, 30% or 50% by weight of the pharmaceutically active ingredient.

[0099] As used herein, the term "pharmaceutically acceptable" refers to a substance (such as a carrier or diluent) that does not affect the biological activity or properties of the disclosed compounds and is relatively non-toxic, i.e., the substance can be administered to a subject without causing an adverse biological response or interacting in an adverse manner with any components included in the composition.

[0100] In the present disclosure, "pharmaceutically acceptable excipients" include, but are not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye / colorant, flavoring, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier approved by the relevant governmental regulatory authorities as acceptable for human or veterinary use.

[0101] As used herein, the terms "prophylactic," "prevent," and "prevent" include reducing the likelihood of a disease or condition developing or worsening in a patient. "Prophylactic," "prevent," and "prevent" refer to preventing the disease or condition from occurring in a mammal, preferably a human, particularly when the mammal is susceptible to the condition but has not yet been diagnosed with the condition, or preventing a disease or condition that has been cured from recurring in a mammal, preferably a human.

[0102] As used herein, the term "treatment" encompasses the treatment of a disease or condition of interest in a mammal, preferably a human, suffering from the disease or condition of interest, including one or more of the following:

[0103] (i) inhibiting a disease or condition, i.e., arresting its development;

[0104] (ii) alleviate the disease or condition, that is, cause regression of the disease or condition; or

[0105] (iii) Alleviation of symptoms caused by the disease or condition, i.e., relief of pain without resolving the underlying disease or condition.

[0106] As used herein, the terms "effective amount," "therapeutically effective amount," or "pharmaceutically effective amount" refer to an amount of at least one agent or compound sufficient to provide some relief to some degree from one or more symptoms of the disease or condition being treated. This can result in a reduction and / or alleviation of signs, symptoms, or causes of disease, or any other desired change in a biological system. For example, a therapeutically effective amount is the amount of a composition comprising a compound disclosed herein that provides a clinically significant alleviation of symptoms. Techniques such as dose escalation studies can be used to determine the effective amount appropriate for any individual case.

[0107] As used herein, the terms "administer," "administer," "dosing," and the like refer to methods by which a compound or pharmaceutical composition can be delivered to the desired site for biological action. Methods of administration known in the art can be used in the present disclosure. These methods include, but are not limited to, oral administration, intraduodenal administration, parenteral injection (including intrapulmonary, intranasal administration; intrathecal, intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical administration, and rectal administration. Those skilled in the art are familiar with administration techniques that can be used for the compounds and methods described herein, such as those discussed in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa. In preferred embodiments, the compounds discussed herein, their pharmaceutically acceptable salts, enantiomers, diastereomers, tautomers, solvates, isotopically substituted products, polymorphs, prodrugs or metabolites, or pharmaceutical compositions thereof, are administered orally.

[0108] As used herein, the terms "pharmaceutical combination," "pharmaceutical composition," "combination," "drug combination," "administration in combination," "administration of another therapy," "administration of another therapeutic agent," and the like refer to a pharmaceutical therapy obtained by mixing or combining more than one active ingredient, and include both fixed and non-fixed combinations of the active ingredients. The term "fixed combination" means that at least one compound described herein and at least one other active ingredient are administered to a patient simultaneously as a single entity or single dosage form. The term "non-fixed combination" means that at least one compound described herein and at least one other active ingredient are administered to a patient simultaneously, in combination, or sequentially at variable intervals as separate entities. This also applies to cocktail therapies, e.g., administration of three or more active ingredients.

[0109] Those skilled in the art will also appreciate that in the methods described below, the functional groups of the intermediate compounds may need to be protected by appropriate protecting groups. Such functional groups include hydroxyl, amino, sulfhydryl, and carboxylic acid. Suitable hydroxy protecting groups include trialkylsilyl or diarylalkylsilyl (e.g., tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or trimethylsilyl), tetrahydropyranyl, benzyl, etc. Suitable protecting groups for amino, amidino, and guanidino include tert-butyloxycarbonyl, benzyloxycarbonyl, etc. Suitable sulfhydryl protecting groups include -C(O)-R" (wherein R" is alkyl, aryl, or aralkyl), p-methoxybenzyl, trityl, etc. Suitable carboxyl protecting groups include alkyl, aryl, or aralkyl esters.

[0110] Protecting groups can be introduced and removed according to standard techniques known to those skilled in the art and as described herein. The use of protecting groups is described in detail in Greene, TW and PGM Wuts, Protective Groups in Organi Synthesis, (1999), 4th Ed., Wiley. Protecting groups can also be polymeric resins.

[0111] Compound of formula A

[0112] The present disclosure provides a compound of formula A, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph, prodrug or metabolite thereof, having a structure shown in the following formula:

[0113] in,

[0114] Ring A is selected from: substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, wherein the heterocyclyl or heteroaryl contains 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P;

[0115] L is selected from: C 1-10 Alkylene, or chemical bond;

[0116] When L is or C 1-10 When alkylene, ring B is selected from: substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, wherein the heterocyclyl or heteroaryl contains 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P; Ring C and Ring D are each independently selected from the group consisting of substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic group, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 5-10 membered heteroaryl or absent, said heterocyclyl or heteroaryl containing 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P;

[0117] When L is a chemical bond, ring E is directly connected to ring B through the chemical bond, and ring B, ring C and ring D are each independently selected from: substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, wherein the heterocyclyl or heteroaryl contains 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P;

[0118] R1 is selected from H, halogen, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, cyano, -NO2, -OH, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic group, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted 3-8 membered heterocyclyl, spiro 3-8 membered heterocyclyl, substituted or unsubstituted 3-8 membered heterocyclyl, 3-8 membered heterocyclyl, substituted or unsubstituted C 3-8 Cycloalkylspiro C 3-8 Cycloalkyl, substituted or unsubstituted C 3-8 Cycloalkyl C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic group and C 6-10 Aryl, substituted or unsubstituted 3-8 membered heterocyclic group and 5-10 membered heteroaryl, substituted or unsubstituted C 3-8 Cycloalkyl C 6-10 Aryl, substituted or unsubstituted C 3-8Cycloalkyl and 5-10 membered heteroaryl, wherein the heterocyclic group or heteroaryl contains 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P;

[0119] R2 is selected from H, oxo (=O), substituted or unsubstituted C 1-6 Alkoxy, halogen, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 1-6 Alkyl, cyano, -NO2, -OH, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic group, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, said heterocyclic group or heteroaryl group containing 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P;

[0120] R3 is selected from H, oxo, substituted or unsubstituted C 1-6 Alkoxy, halogen, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 1-6 Alkyl, cyano, -NO2, -OH, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic group, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, said heterocyclic group or heteroaryl group containing 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P;

[0121] R4 is selected from H, oxo, substituted or unsubstituted C 1-6 Alkoxy, halogen, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 1-6 Alkyl, cyano, -NO2, -OH, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic group, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, said heterocyclic group or heteroaryl group containing 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P;

[0122] R5 is selected from H, halogen, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, cyano, -NO2, -OH, substituted or unsubstituted C 3-8Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic group, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, said heterocyclic group or heteroaryl group containing 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P;

[0123] R6 is selected from H, halogen, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, cyano, -NO2, -OH, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic group, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, said heterocyclic group or heteroaryl group containing 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P;

[0124] n, m, q and t are each independently any integer of 0, 1, 2 and 3;

[0125] The substitution refers to that one or more hydrogen atoms on the group are replaced by a substituent selected from the group consisting of halogen, -OH, -NO2, -NH2, -NH (unsubstituted or halogenated C 1-6 Alkyl), -N(unsubstituted or halogenated C 1-6 Alkyl)2, -CN, unsubstituted or substituted by halogen or hydroxyl C 1-8 Alkyl, unsubstituted or halogenated C 1-8 Alkoxy, unsubstituted or halogenated C 1-8 Alkoxy-C 1- 8 alkyl, unsubstituted or halogenated C 3-8 Cycloalkyl-C 1-8 Alkyl, unsubstituted or halogenated C 1-6 Alkylcarbonyl, unsubstituted or halogenated C 1-6 Alkoxycarbonyl, hydroxamate, unsubstituted or halogenated C 1-6 Alkylthio, -S(O)2N(unsubstituted or halogenated C 1-6 Alkyl)2, -S(O)2 unsubstituted or halogenated C 1-6 Alkyl, -N (unsubstituted or halogenated C 1-6 Alkyl)S(O)2N(unsubstituted or halogenated C 1-6 Alkyl)2, -S(O)N(unsubstituted or halogenated C 1-6 Alkyl)2, -S(O)(unsubstituted or halogenated C 1-6 Alkyl), -N(unsubstituted or halogenated C 1-6 Alkyl)S(O)N(unsubstituted or halogenated C1-6 Alkyl)2, -N (unsubstituted or halogenated C 1-6 Alkyl)S(O)(unsubstituted or halogenated C 1-6 Alkyl), unsubstituted or halogenated C 5-10 Aryl, unsubstituted or halogenated 5-10 membered heteroaryl, unsubstituted or halogenated C 3-8 Cycloalkyl and unsubstituted or halogenated 3-8 membered heterocyclyl, said heterocyclyl and heteroaryl containing 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O or S;

[0126] This represents a connection to the rest of the molecule via a chemical bond.

[0127] In some embodiments, Ring A is a substituted or unsubstituted aryl group. Ring A is a 6-14 membered aryl group, a 6-12 membered aryl group, a 6-10 membered aryl group, or a 6-8 membered aryl group. In certain embodiments, Ring A is a phenyl group or a naphthyl group. In certain embodiments, Ring A is a phenyl group.

[0128] In some embodiments, Ring A is a substituted or unsubstituted heteroaryl. In some embodiments, Ring A is selected from a 5-14 membered heteroaryl, a 5-12 membered heteroaryl, a 5-10 membered heteroaryl, a 5-8 membered heteroaryl, or a 5-6 membered heteroaryl. In certain embodiments, Ring A is selected from a thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, furanyl, pyrrolyl, triazolyl, triazinyl, imidazolyl, pyrazolyl, pyrrolyl, pyridinyl, pyrimidinyl, or pyrazinyl. In certain embodiments, Ring A is pyridinyl.

[0129] In some embodiments, Ring B is a substituted or unsubstituted heterocyclyl. Ring B is selected from 5-14 membered heterocyclyl, 5-12 membered heterocyclyl, 5-10 membered heterocyclyl, 5-8 membered heterocyclyl, and 5-6 membered heterocyclyl. In certain embodiments, Ring B is selected from pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and pyranyl. In certain embodiments, Ring B is piperidinyl.

[0130] In some embodiments, Ring B is a substituted or unsubstituted heteroaryl. In certain embodiments, Ring B is a 5-14 membered heteroaryl, a 5-12 membered heteroaryl, a 5-10 membered heteroaryl, a 5-8 membered heteroaryl, or a 5-6 membered heteroaryl. In certain embodiments, Ring B is selected from thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, oxazinyl, furanyl, pyrrolyl, triazolyl, triazinyl, or pyridonyl. In certain embodiments, Ring B is pyrazolyl or pyridinyl.

[0131] In some embodiments, Ring C is a substituted or unsubstituted heteroaryl. In certain embodiments, Ring C is a 5-14 membered heteroaryl, a 5-12 membered heteroaryl, a 5-10 membered heteroaryl, a 5-8 membered heteroaryl, or a 5-6 membered heteroaryl. In certain embodiments, Ring C is selected from thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, oxazinyl, furanyl, pyrrolyl, triazolyl, triazinyl, or pyridonyl. In certain embodiments, Ring C is pyrazolyl.

[0132] In some embodiments, Ring C is a substituted or unsubstituted heterocyclyl. Ring C is selected from 5-14 membered heterocyclyl, 5-12 membered heterocyclyl, 5-10 membered heterocyclyl, 5-8 membered heterocyclyl, 5-6 membered heterocyclyl. In certain embodiments, Ring C is selected from pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl. In certain embodiments, Ring C is pyrrolidinyl.

[0133] In some embodiments, ring D is a substituted or unsubstituted heterocyclyl. Ring D is selected from 5-14 membered heterocyclyl, 5-12 membered heterocyclyl, 5-10 membered heterocyclyl, 5-8 membered heterocyclyl, 5-6 membered heterocyclyl. In certain embodiments, ring D is selected from pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, or oxazepine. In certain embodiments, ring D is pyrrolidinyl or 1,3-oxazepine. In certain embodiments, ring D is pyrrolidinyl. In certain embodiments, ring D is 1,3-oxazepine or morpholinyl. In certain embodiments, ring D is 1,3-oxazepine.

[0134] In some embodiments, R1 is selected from H, halogen, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 2- 6 alkenyl, substituted or unsubstituted C 1-6 Alkoxy, cyano, substituted or unsubstituted 3-8 membered heterocyclyl spiro 3-8 membered heterocyclyl, the heterocyclyl containing 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S. In certain embodiments, R1 is selected from H, halogen, substituted or unsubstituted C 2-5 Alkynyl, substituted or unsubstituted C 1-3 Alkoxy, cyano, substituted or unsubstituted 5-6 membered heterocyclyl spiro 4-6 membered heterocyclyl, wherein the heterocyclyl contains 1 or 2 heteroatoms selected from the group consisting of N, O, and S. In certain embodiments, the C 2-5 Alkynyl, C 1-3Alkoxy, and 5-6 membered heterocyclyl spiro 4-6 membered heterocyclyl are selected from C 1-6 Alkyl, 3-5 membered cycloalkyl, 4-6 membered heterocyclic group, hydroxyl C 2-5 In certain embodiments, the C 2-5 Alkynyl, C 1-3 The alkoxy, and 5-6 membered heterocyclyl, spiro 4-6 membered heterocyclyl are substituted by a substituent selected from cyclopropyl, pyranyl, hydroxyisopropyl.

[0135] In certain embodiments, R1 is selected from the group consisting of:

[0136] H. methoxy, cyano, chlorine and bromine.

[0137] In some embodiments, R2 is selected from H, oxo (=O), substituted or unsubstituted C 1-6 Alkoxy, halogen, substituted or unsubstituted C 1-6 Alkyl, cyano, -NO2, -OH, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-14 membered heteroaryl, said heteroaryl containing 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P. In certain embodiments, said C 1-6 Alkoxy and C 1-6 The alkyl groups are each independently substituted with oxo (=O), C 6-10 In certain embodiments, R2 is selected from H, oxo (=O), optionally substituted by C 6-10 Aryl-substituted C 1-6 Alkoxy, halogen, substituted or unsubstituted 5-10 membered heteroaryl, said heteroaryl containing 1, 2 or 3 heteroatoms selected from the group consisting of N, O and S. In certain embodiments, R2 is H, oxo, C 6-10 Aryl-substituted C 1-4 Alkoxy, benzopyrazolyl.

[0138] In some embodiments, R3 is selected from: H, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted C 1-6 Alkoxy, halogen, cyano, -NO2, -OH, in certain embodiments, the C 1-6 Alkoxy and C 1-6 Each alkyl group is independently substituted with oxo (=O), -OH, cyano or -NO2. In certain embodiments, R3 is H or C 6-10 Aryl.

[0139] In some embodiments, R4 is selected from H, substituted or unsubstituted C 1-6 Alkoxy, halogen, substituted or unsubstituted C 1-6Alkyl, cyano, -NO2, -OH, substituted or unsubstituted 3-8 membered heterocyclic group, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 5-10 membered heteroaryl, wherein the heterocyclic group or heteroaryl group contains 1, 2 or 3 heteroatoms selected from the group consisting of N, O and S. In certain embodiments, the C 1-6 Alkoxy, C 1-6 Alkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl are each independently substituted by 1, 2 or 3 groups selected from H, halogen, -OH, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-8 In certain embodiments, t is 1 or 2.

[0140] In certain embodiments, R4 is selected from halogen, difluoropropyl, phenyl, benzyl, difluorophenyl, tolyl, methoxyphenyl and pyridyl. In certain embodiments, R4 is selected from: and halogens.

[0141] In certain embodiments, R4 is selected from:

[0142] and F.

[0143] In some embodiments, R5 is selected from H, substituted or unsubstituted C 1-6 Alkoxy, halogen, substituted or unsubstituted C 1-6 In certain embodiments, R5 is selected from unsubstituted C 1-6 In certain embodiments, R5 is methyl.

[0144] In some embodiments, R6 is selected from H, substituted or unsubstituted C 1-6 Alkoxy, halogen, substituted or unsubstituted C 1-6 In certain embodiments, R6 is H.

[0145] In some embodiments, the compound of Formula A provided herein, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph, prodrug or metabolite thereof, has the structure shown in Formula I below:

[0146] In Formula 1:

[0147] Ring A, Ring B, Ring C and Ring D are each independently selected from: substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic group, substituted or unsubstituted C 6-10Aryl, substituted or unsubstituted 5-10 membered heteroaryl, said heterocyclic group or heteroaryl group containing 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P;

[0148] R1 is selected from: H, halogen, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, cyano, -NO2, -OH, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic group, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted 3-8 membered heterocyclyl, spiro 3-8 membered heterocyclyl, substituted or unsubstituted 3-8 membered heterocyclyl, 3-8 membered heterocyclyl, substituted or unsubstituted C 3-8 Cycloalkylspiro C 3-8 Cycloalkyl, substituted or unsubstituted C 3-8 Cycloalkyl C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic group and C 6-10 Aryl, substituted or unsubstituted 3-8 membered heterocyclic group and 5-10 membered heteroaryl, substituted or unsubstituted C 3-8 Cycloalkyl C 6-10 Aryl, substituted or unsubstituted C 3-8 Cycloalkyl and 5-10 membered heteroaryl, wherein the heterocyclic group or heteroaryl contains 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P;

[0149] R2, R3, R4, R5 and R6 are each independently selected from the group consisting of: H, oxo (=O), substituted or unsubstituted C 1-6 Alkoxy, halogen, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 1-6 Alkyl, cyano, -NO2, -OH, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic group, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, said heterocyclic group or heteroaryl group containing 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P;

[0150] n, m, q and t are each independently an integer of 0, 1, 2 or 3;

[0151] The substitution refers to that one or more hydrogen atoms on the group are replaced by a substituent selected from the group consisting of halogen, -OH, -NO2, -NH2, -NH (unsubstituted or halogenated C1-6 Alkyl), -N(unsubstituted or halogenated C 1-6 Alkyl)2, -CN, unsubstituted or substituted by halogen or hydroxyl C 1-8 Alkyl, unsubstituted or halogenated C 1-8 Alkoxy, unsubstituted or halogenated C 1-8 Alkoxy-C 1- 8 alkyl, unsubstituted or halogenated C 3-8 Cycloalkyl-C 1-8 Alkyl, unsubstituted or halogenated C 1-6 Alkylcarbonyl, unsubstituted or halogenated C 1-6 Alkoxycarbonyl, hydroxamate, unsubstituted or halogenated C 1-6 Alkylthio, -S(O)2N(unsubstituted or halogenated C 1-6 Alkyl)2, -S(O)2 unsubstituted or halogenated C 1-6 Alkyl, -N (unsubstituted or halogenated C 1-6 Alkyl)S(O)2N(unsubstituted or halogenated C 1-6 Alkyl)2, -S(O)N(unsubstituted or halogenated C 1-6 Alkyl)2, -S(O)(unsubstituted or halogenated C 1-6 Alkyl), -N(unsubstituted or halogenated C 1-6 Alkyl)S(O)N(unsubstituted or halogenated C 1-6 Alkyl)2, -N (unsubstituted or halogenated C 1-6 Alkyl)S(O)(unsubstituted or halogenated C 1-6 Alkyl), unsubstituted or halogenated C 5-10 Aryl, unsubstituted or halogenated 5-10 membered heteroaryl, unsubstituted or halogenated C 3-8 Cycloalkyl and unsubstituted or halogenated 3-8 membered heterocyclyl, said heterocyclyl and heteroaryl containing 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O and S.

[0152] In some embodiments, Ring A is selected from: substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, wherein the heteroaryl contains 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P.

[0153] In some embodiments, Ring B is selected from: substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic group, said heterocyclic group containing 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P.

[0154] In some embodiments, Ring C is selected from: substituted or unsubstituted C 6-10Aryl, substituted or unsubstituted 5-10 membered heteroaryl, wherein the heteroaryl contains 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P.

[0155] In some embodiments, Ring D is selected from: substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic group, said heterocyclic group containing 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P.

[0156] In some embodiments, R1 is selected from: H, halogen, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 2- 6 alkenyl, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, cyano, -NO2, -OH, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic group, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted 3-8 membered heterocyclyl, spiro 3-8 membered heterocyclyl, substituted or unsubstituted 3-8 membered heterocyclyl, 3-8 membered heterocyclyl, substituted or unsubstituted C 3-8 Cycloalkylspiro C 3-8 Cycloalkyl, substituted or unsubstituted C 3-8 Cycloalkyl C 3-8 Cycloalkyl, the heterocyclic or heteroaryl group contains 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P. In some embodiments, R1 is selected from the group consisting of H, halogen, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, cyano, -NO2, -OH, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclyl, substituted or unsubstituted 3-8 membered heterocyclyl spiro 3-8 membered heterocyclyl, substituted or unsubstituted 3-8 membered heterocyclyl and 3-8 membered heterocyclyl, substituted or unsubstituted C3-8 cycloalkyl spiro C 3-8 Cycloalkyl, the heterocyclic group contains 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P. In certain embodiments, R1 is selected from the group consisting of H, halogen, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6Alkoxy, cyano, -NO2, -OH, substituted or unsubstituted 3-8 membered heterocyclyl, substituted or unsubstituted 3-8 membered heterocyclylspiro 3-8 membered heterocyclyl, wherein the heterocyclyl contains 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P.

[0157] In some embodiments, R2, R3, R4, R5 and R6 are each independently selected from: H, oxo (=O), substituted or unsubstituted C 1-6 Alkoxy, halogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic group, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 5-10 membered heteroaryl, wherein the heterocyclic group or heteroaryl contains 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P. In some embodiments, R2, R3, R4, R5 and R6 are each independently selected from the group consisting of H, oxo (=O), substituted or unsubstituted C 1-6 Alkoxy, halogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 5-10 membered heteroaryl, said heteroaryl containing 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P. In certain embodiments, R2, R3, R4, R5 and R6 are each independently selected from the group consisting of H, oxo (=O), halogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, wherein the heteroaryl contains 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P.

[0158] In some embodiments, Ring A is a substituted or unsubstituted aryl group. Ring A is a 6-14 membered aryl group, a 6-12 membered aryl group, a 6-10 membered aryl group, or a 6-8 membered aryl group. In certain embodiments, Ring A is a phenyl group or a naphthyl group. In certain embodiments, Ring A is a phenyl group.

[0159] In some embodiments, Ring A is a substituted or unsubstituted heteroaryl. In some embodiments, Ring A is selected from a 5-14 membered heteroaryl, a 5-12 membered heteroaryl, a 5-10 membered heteroaryl, a 5-8 membered heteroaryl, or a 5-6 membered heteroaryl. In certain embodiments, Ring A is selected from a thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, furanyl, pyrrolyl, triazolyl, triazinyl, imidazolyl, pyrazolyl, pyrrolyl, pyridinyl, pyrimidinyl, or pyrazinyl. In certain embodiments, Ring A is pyridinyl.

[0160] In some embodiments, Ring B is a substituted or unsubstituted heterocyclyl. Ring B is selected from 5-14 membered heterocyclyl, 5-12 membered heterocyclyl, 5-10 membered heterocyclyl, 5-8 membered heterocyclyl, and 5-6 membered heterocyclyl. In certain embodiments, Ring B is selected from pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and pyranyl. In certain embodiments, Ring B is piperidinyl.

[0161] In some embodiments, Ring C is a substituted or unsubstituted heteroaryl. In certain embodiments, Ring C is a 5-14 membered heteroaryl, a 5-12 membered heteroaryl, a 5-10 membered heteroaryl, a 5-8 membered heteroaryl, or a 5-6 membered heteroaryl. In certain embodiments, Ring C is selected from thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, oxazinyl, furanyl, pyrrolyl, triazolyl, triazinyl, or pyridonyl. In certain embodiments, Ring C is pyrazolyl.

[0162] In some embodiments, ring D is a substituted or unsubstituted heterocyclyl. Ring D is selected from 5-14 membered heterocyclyl, 5-12 membered heterocyclyl, 5-10 membered heterocyclyl, 5-8 membered heterocyclyl, 5-6 membered heterocyclyl. In certain embodiments, ring D is selected from pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, or oxazepine. In certain embodiments, ring D is pyrrolidinyl or 1,3-oxazepine. In certain embodiments, ring D is pyrrolidinyl. In certain embodiments, ring D is 1,3-oxazepine or morpholinyl. In certain embodiments, ring D is 1,3-oxazepine.

[0163] In some embodiments, R1 is selected from H, halogen, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 2- 6 alkenyl, substituted or unsubstituted C 1-6 Alkoxy, cyano, substituted or unsubstituted 3-8 membered heterocyclyl spiro 3-8 membered heterocyclyl, the heterocyclyl containing 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S. In certain embodiments, R1 is selected from H, halogen, substituted or unsubstituted C 2-5 Alkynyl, substituted or unsubstituted C 1-3 Alkoxy, cyano, substituted or unsubstituted 5-6 membered heterocyclyl spiro 4-6 membered heterocyclyl, wherein the heterocyclyl contains 1 or 2 heteroatoms selected from the group consisting of N, O, and S. In certain embodiments, the C 2-5 Alkynyl, C 1-3Alkoxy, and 5-6 membered heterocyclyl spiro 4-6 membered heterocyclyl are selected from C 1-6 Alkyl, 3-5 membered cycloalkyl, 4-6 membered heterocyclic group, hydroxyl C 2-5 In certain embodiments, the C 2-5 Alkynyl, C 1-3 The alkoxy, and 5-6 membered heterocyclyl, spiro 4-6 membered heterocyclyl are substituted by a substituent selected from cyclopropyl, pyranyl, hydroxyisopropyl.

[0164] In certain embodiments, R1 is selected from the group consisting of:

[0165] H. methoxy, cyano, chlorine and bromine.

[0166] In some embodiments, R2 is selected from H, oxo (=O), substituted or unsubstituted C1-6 alkoxy, halogen, substituted or unsubstituted C 1-6 Alkyl, cyano, -NO2, -OH, in certain embodiments, the C 1-6 Alkoxy and C 1-6 Each alkyl group is independently substituted with oxo (=O), -OH, cyano, or -NO 2. In certain embodiments, R 2 is oxo.

[0167] In some embodiments, R3 is selected from: H, substituted or unsubstituted C 1-6 Alkoxy, halogen, cyano, -NO2, -OH, in certain embodiments, the C 1-6 Alkoxy and C 1-6 Each alkyl group is independently substituted with oxo (=O), -OH, cyano, or -NO 2 . In certain embodiments, R 3 is H.

[0168] In some embodiments, R4 is selected from H, substituted or unsubstituted C 1-6 Alkoxy, halogen, substituted or unsubstituted C 1-6 Alkyl, cyano, -NO2, -OH, substituted or unsubstituted 3-8 membered heterocyclic group, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 5-10 membered heteroaryl, wherein the heterocyclic group or heteroaryl group contains 1, 2 or 3 heteroatoms selected from the group consisting of N, O and S. In certain embodiments, the C 1-6 Alkoxy, C 1-6 Alkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl are each independently substituted by 1, 2 or 3 groups selected from H, halogen, -OH, C 1-6 Alkyl, halogenated C 1-6 Alkyl and C 1-8 In certain embodiments, t is 1 or 2.

[0169] In certain embodiments, R4 is selected from halogen, tolyl, difluoropropyl, phenyl, benzyl, difluorophenyl, methoxyphenyl and pyridyl. In certain embodiments, R4 is selected from: and halogens.

[0170] In certain embodiments, R4 is selected from:

[0171] and F.

[0172] In some embodiments, R5 is selected from H, substituted or unsubstituted C 1-6 Alkoxy, halogen, substituted or unsubstituted C 1-6 In certain embodiments, R5 is selected from unsubstituted C 1-6 In certain embodiments, R5 is methyl.

[0173] In some embodiments, R6 is selected from H, substituted or unsubstituted C 1-6 Alkoxy, halogen, substituted or unsubstituted C 1-6 In certain embodiments, R6 is H.

[0174] In some embodiments, n, m, q, and t are each independently any integer of 0, 1, or 2. In some embodiments, n, m, q, and t are each independently any integer of 0 or 1.

[0175] In some embodiments, the compound of Formula A provided herein, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph, prodrug or metabolite thereof, has the structure shown in Formula II below:

[0176] In Formula II:

[0177] Ring A, Ring B and Ring C are each independently selected from: substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic group, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, said heterocyclic group or heteroaryl group containing 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P;

[0178] L is selected from: and C 1-10 alkylene;

[0179] R1 is selected from: H, halogen, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 1-6Alkyl, substituted or unsubstituted C 1-6 Alkoxy, cyano, -NO2, -OH, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic group, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted 3-8 membered heterocyclyl, spiro 3-8 membered heterocyclyl, substituted or unsubstituted 3-8 membered heterocyclyl, 3-8 membered heterocyclyl, substituted or unsubstituted C 3-8 Cycloalkylspiro C 3-8 Cycloalkyl, substituted or unsubstituted C 3-8 Cycloalkyl C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic group and C 6-10 Aryl, substituted or unsubstituted 3-8 membered heterocyclic group and 5-10 membered heteroaryl, substituted or unsubstituted C 3-8 Cycloalkyl C 6-10 Aryl, substituted or unsubstituted C 3-8 Cycloalkyl and 5-10 membered heteroaryl, wherein the heterocyclic group or heteroaryl contains 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P;

[0180] R2, R3, R5 and R6 are each independently selected from: H, oxo (=O), substituted or unsubstituted C 1-6 Alkoxy, halogen, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 1-6 Alkyl, cyano, -NO2, -OH, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic group, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, said heterocyclic group or heteroaryl group containing 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P;

[0181] n, m and q are each independently an integer of 0, 1, 2 or 3;

[0182] The substitution refers to that one or more hydrogen atoms on the group are replaced by a substituent selected from the group consisting of halogen, -OH, -NO2, -NH2, -NH (unsubstituted or halogenated C 1-6 Alkyl), -N(unsubstituted or halogenated C 1-6 Alkyl)2, -CN, unsubstituted or substituted by halogen or hydroxyl C 1-8 Alkyl, unsubstituted or halogenated C 1-8 Alkoxy, unsubstituted or halogenated C 1-8 Alkoxy-C 1- 8 alkyl, unsubstituted or halogenated C 3-8Cycloalkyl-C 1-8 Alkyl, unsubstituted or halogenated C 1-6 Alkylcarbonyl, unsubstituted or halogenated C 1-6 Alkoxycarbonyl, hydroxamate, unsubstituted or halogenated C 1-6 Alkylthio, -S(O)2N(unsubstituted or halogenated C 1-6 Alkyl)2, -S(O)2 unsubstituted or halogenated C 1-6 Alkyl, -N (unsubstituted or halogenated C 1-6 Alkyl)S(O)2N(unsubstituted or halogenated C 1-6 Alkyl)2, -S(O)N(unsubstituted or halogenated C 1-6 Alkyl)2, -S(O)(unsubstituted or halogenated C 1-6 Alkyl), -N(unsubstituted or halogenated C 1-6 Alkyl)S(O)N(unsubstituted or halogenated C 1-6 Alkyl)2, -N (unsubstituted or halogenated C 1-6 Alkyl)S(O)(unsubstituted or halogenated C 1-6 Alkyl), unsubstituted or halogenated C 5-10 Aryl, unsubstituted or halogenated 5-10 membered heteroaryl, unsubstituted or halogenated C 3-8 Cycloalkyl, unsubstituted or halogenated 3-8 membered heterocyclyl, said heterocyclyl and heteroaryl containing 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O or S.

[0183] In some embodiments, Ring A is selected from: substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, wherein the heteroaryl contains 1, 2 or 3 heteroatoms selected from the group consisting of N, O and S.

[0184] In some embodiments, Ring B is selected from: substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, said heteroaryl containing 1, 2 or 3 heteroatoms selected from the group consisting of N, O and S

[0185] In some embodiments, Ring C is selected from: substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic group, wherein the heterocyclic group contains 1, 2 or 3 heteroatoms selected from the group consisting of N, O and S.

[0186] In some embodiments, L is selected from: and C 1-10 In some embodiments, L is selected from: In certain embodiments, L is

[0187] In some embodiments, R1 is selected from: H, halogen, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 2- 6 alkenyl, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, cyano, -NO2, -OH, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic group, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 5-10 membered heteroaryl, wherein the heterocyclic group or heteroaryl group contains 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P. In some embodiments, R1 is selected from the group consisting of H, halogen, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 In certain embodiments, R1 is selected from the group consisting of: H, halogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, cyano, -NO2, -OH.

[0188] In some embodiments, R2, R3, R5 and R6 are each independently selected from: H, oxo (=O), substituted or unsubstituted C 1-6 Alkoxy, halogen, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 1-6 Alkyl, cyano, -NO2, -OH, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 5-10 membered heteroaryl, said heteroaryl containing 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P. In some embodiments, R3, R4, R5 and R6 are each independently selected from the group consisting of H, oxo (=O), substituted or unsubstituted C 1-6 Alkoxy, halogen, substituted or unsubstituted C 1-6 Alkyl, cyano, -NO2, -OH, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 5-10 membered heteroaryl, said heteroaryl containing 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P. In certain embodiments, R3, R4, R5 and R6 are each independently selected from the group consisting of H, oxo (=O), substituted or unsubstituted C 1-6 Alkoxy, halogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 6-10 Aryl.

[0189] In some embodiments, n, m, and q are each independently any integer of 0, 1, or 2. In some embodiments, n, q, and t are each independently any integer of 0 or 1.

[0190] In some embodiments, the compound of formula A provided herein, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph, prodrug or metabolite thereof, has the structure shown in the following formula III:

[0191] In formula III:

[0192] Ring A and Ring B are each independently selected from: substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic group, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, said heterocyclic group or heteroaryl group containing 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P;

[0193] L is selected from: and C 1-10 alkylene;

[0194] R1 is selected from: H, halogen, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, cyano, -NO2, -OH, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic group, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted 3-8 membered heterocyclyl, spiro 3-8 membered heterocyclyl, substituted or unsubstituted 3-8 membered heterocyclyl, 3-8 membered heterocyclyl, substituted or unsubstituted C 3-8 Cycloalkylspiro C 3-8 Cycloalkyl, substituted or unsubstituted C 3-8 Cycloalkyl C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic group and C 6-10 Aryl, substituted or unsubstituted 3-8 membered heterocyclic group and 5-10 membered heteroaryl, substituted or unsubstituted C 3-8 Cycloalkyl C 6-10 Aryl, substituted or unsubstituted C 3-8 Cycloalkyl and 5-10 membered heteroaryl, wherein the heterocyclic group or heteroaryl contains 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P;

[0195] R2, R5 and R6 are each independently selected from: H, oxo (=O), substituted or unsubstituted C 1-6 Alkoxy, halogen, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 1-6 Alkyl, cyano, -NO2, -OH, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic group, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, said heterocyclic group or heteroaryl group containing 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P;

[0196] n and m are each independently an integer of 0, 1, 2 or 3;

[0197] The substitution refers to that one or more hydrogen atoms on the group are replaced by a substituent selected from the group consisting of halogen, -OH, -NO2, -NH2, -NH (unsubstituted or halogenated C 1-6 Alkyl), -N(unsubstituted or halogenated C 1-6 Alkyl)2, -CN, unsubstituted or substituted by halogen or hydroxyl C 1-8 Alkyl, unsubstituted or halogenated C 1-8 Alkoxy, unsubstituted or halogenated C 1-8 Alkoxy-C1-8 alkyl, unsubstituted or halogenated C 3-8 Cycloalkyl-C 1-8 Alkyl, unsubstituted or halogenated C 1-6 Alkylcarbonyl, unsubstituted or halogenated C 1-6 Alkoxycarbonyl, hydroxamate, unsubstituted or halogenated C 1-6 Alkylthio, -S(O)2N(unsubstituted or halogenated C 1-6 Alkyl)2, -S(O)2 unsubstituted or halogenated C 1-6 Alkyl, -N (unsubstituted or halogenated C 1-6 Alkyl)S(O)2N(unsubstituted or halogenated C 1-6 Alkyl)2, -S(O)N(unsubstituted or halogenated C 1-6 Alkyl)2, -S(O)(unsubstituted or halogenated C 1-6 Alkyl), -N(unsubstituted or halogenated C 1-6 Alkyl)S(O)N(unsubstituted or halogenated C 1-6 Alkyl)2, -N (unsubstituted or halogenated C 1-6 Alkyl)S(O)(unsubstituted or halogenated C 1-6 Alkyl), unsubstituted or halogenated C 5-10Aryl, unsubstituted or halogenated 5-10 membered heteroaryl, unsubstituted or halogenated C 3-8 Cycloalkyl, unsubstituted or halogenated 3-8 membered heterocyclyl, said heterocyclyl and heteroaryl containing 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O or S.

[0198] In some embodiments, Ring A and Ring B are each independently selected from: substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, wherein the heteroaryl contains 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P.

[0199] In some embodiments, L is selected from and C 1-10 In some embodiments, L is selected from: In certain embodiments, L is selected from:

[0200] In some embodiments, R1 is selected from: H, halogen, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 2- 6 alkenyl, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, cyano, -NO2, -OH, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic group, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted 3-8 membered heterocyclyl, spiro 3-8 membered heterocyclyl, substituted or unsubstituted 3-8 membered heterocyclyl and 3-8 membered heterocyclyl, wherein the heterocyclyl or heteroaryl contains 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P. In some embodiments, R1 is selected from the group consisting of H, halogen, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, cyano, -NO2, -OH, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclyl, substituted or unsubstituted 3-8 membered heterocyclyl spiro 3-8 membered heterocyclyl, substituted or unsubstituted 3-8 membered heterocyclyl and 3-8 membered heterocyclyl, wherein the heterocyclyl contains 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P. In certain embodiments, R1 is selected from the group consisting of H, halogen, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted 3-8 membered heterocyclyl, substituted or unsubstituted 3-8 membered heterocyclylspiro 3-8 membered heterocyclyl, wherein the heterocyclyl contains 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P.

[0201] In some embodiments, R2, R5 and R6 are each independently selected from: H, oxo (=O), substituted or unsubstituted C 1-6 Alkoxy, halogen, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 1-6 Alkyl, cyano, -NO2, -OH, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 5-10 membered heteroaryl, said heteroaryl containing 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P. In some embodiments, R2, R5 and R6 are each independently selected from the group consisting of H, oxo (=O), substituted or unsubstituted C 1-6 Alkoxy, halogen, substituted or unsubstituted C 1-6 Alkyl, cyano, -NO2, -OH, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 5-10 membered heteroaryl, said heteroaryl containing 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P. In certain embodiments, R2, R5 and R6 are each independently selected from the group consisting of H, oxo (=O), substituted or unsubstituted C 1-6 Alkoxy, halogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted 5-10 membered heteroaryl, said heteroaryl containing 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P.

[0202] In some embodiments, n and m are each independently any integer of 0, 1, or 2. In some embodiments, n and m are each independently any integer of 0 or 1.

[0203] In some embodiments, the compound of Formula A provided herein, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph, prodrug or metabolite thereof, has the structure shown in the following Formula I-1:

[0204] In formula I-1:

[0205] A1, A2, A3 and A4 are each independently selected from: CR1 or N;

[0206] B1, B2, B3 and B4 are each independently selected from: C(R2) mor N(R2) m ;

[0207] C1, C2 and C3 are each independently selected from: C(R3) q or N(R3) q ;

[0208] Ring B, Ring C and Ring D are each independently selected from: substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic group, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, said heterocyclic group or heteroaryl group containing 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P;

[0209] R1 is selected from: H, halogen, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, cyano, -NO2, -OH, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic group, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted 3-8 membered heterocyclyl, spiro 3-8 membered heterocyclyl, substituted or unsubstituted 3-8 membered heterocyclyl, 3-8 membered heterocyclyl, substituted or unsubstituted C 3-8 Cycloalkylspiro C 3-8 Cycloalkyl, substituted or unsubstituted C 3-8 Cycloalkyl C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic group and C 6-10 Aryl, substituted or unsubstituted 3-8 membered heterocyclic group and 5-10 membered heteroaryl, substituted or unsubstituted C 3-8 Cycloalkyl C 6-10 Aryl, substituted or unsubstituted C 3-8 Cycloalkyl and 5-10 membered heteroaryl, wherein the heterocyclic group or heteroaryl contains 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P;

[0210] R2, R3, R4, R5 and R6 are each independently selected from the group consisting of: H, oxo (=O), substituted or unsubstituted C 1-6 Alkoxy, halogen, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 1-6 Alkyl, cyano, -NO2, -OH, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic group, substituted or unsubstituted C6-10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, said heterocyclic group or heteroaryl group containing 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P;

[0211] m, q and t are each independently an integer of 0, 1, 2 or 3;

[0212] The substitution refers to that one or more hydrogen atoms on the group are replaced by a substituent selected from the group consisting of halogen, -OH, -NO2, -NH2, -NH (unsubstituted or halogenated C 1-6 Alkyl), -N(unsubstituted or halogenated C 1-6 Alkyl)2, -CN, unsubstituted or substituted by halogen or hydroxyl C 1-8 Alkyl, unsubstituted or halogenated C 1-8 Alkoxy, unsubstituted or halogenated C 1-8 Alkoxy-C1-8 alkyl, unsubstituted or halogenated C 3-8 Cycloalkyl-C 1-8 Alkyl, unsubstituted or halogenated C 1-6 Alkylcarbonyl, unsubstituted or halogenated C 1-6 Alkoxycarbonyl, hydroxamate, unsubstituted or halogenated C 1-6 Alkylthio, -S(O)2N(unsubstituted or halogenated C 1-6 Alkyl)2, -S(O)2 unsubstituted or halogenated C 1-6 Alkyl, -N (unsubstituted or halogenated C 1-6 Alkyl)S(O)2N(unsubstituted or halogenated C 1-6 Alkyl)2, -S(O)N(unsubstituted or halogenated C 1-6 Alkyl)2, -S(O)(unsubstituted or halogenated C 1-6 Alkyl), -N(unsubstituted or halogenated C 1-6 Alkyl)S(O)N(unsubstituted or halogenated C 1-6 Alkyl)2, -N (unsubstituted or halogenated C 1-6 Alkyl)S(O)(unsubstituted or halogenated C 1-6 Alkyl), unsubstituted or halogenated C 5-10 Aryl, unsubstituted or halogenated 5-10 membered heteroaryl, unsubstituted or halogenated C 3-8 Cycloalkyl and unsubstituted or halogenated 3-8 membered heterocyclyl, said heterocyclyl and heteroaryl containing 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O or S.

[0213] In some embodiments, Ring B is selected from: substituted or unsubstituted C 3-8Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclyl, the heterocyclyl containing 1, 2, or 3 heteroatoms selected from the group consisting of N, O, S, and P. In some embodiments, Ring B is a substituted or unsubstituted 3-8 membered heterocyclyl, the heterocyclyl containing 1, 2, or 3 heteroatoms selected from the group consisting of N, O, and S. In some embodiments, Ring B is a substituted or unsubstituted 3-7 membered heterocyclyl, a substituted or unsubstituted 4-7 membered heterocyclyl, a substituted or unsubstituted 4-6 membered heterocyclyl, or a substituted or unsubstituted 5- or 6 membered heterocyclyl. In some embodiments, Ring B is a substituted or unsubstituted 5-7 membered heterocyclyl. In some embodiments, Ring B contains 1 or 2 nitrogen atoms.

[0214] In certain embodiments, Ring B is selected from pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl. In certain embodiments, Ring B is piperidinyl.

[0215] In some embodiments, Ring C is selected from: substituted or unsubstituted C 6-10 In some embodiments, ring C is a substituted or unsubstituted 5-10 membered heteroaryl group, a substituted or unsubstituted 5-10 membered heteroaryl group, the heteroaryl group containing 1, 2, or 3 heteroatoms selected from the group consisting of N, O, S, and P. In some embodiments, ring C is a substituted or unsubstituted 5-9 membered heteroaryl group, a 5-8 membered heteroaryl group, a 5-7 membered heteroaryl group, or a 5-6 membered heteroaryl group. In some embodiments, ring C is a substituted or unsubstituted 5-10 membered heteroaryl group, in certain embodiments, the heteroaryl group contains 1, 2, or 3 heteroatoms selected from the group consisting of N, O, S, and P. In some embodiments, ring C is a substituted or unsubstituted 5-7 membered heteroaryl group. In some embodiments, ring C contains 1, 2, or 3 nitrogen atoms, and in certain embodiments, ring C contains 1 or 2 nitrogen atoms. In certain embodiments, ring C is selected from thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, azinyl, furanyl, pyrrolyl, triazolyl, triazinyl, pyridonyl. In certain embodiments, ring C is pyrazolyl.

[0216] In some embodiments, Ring D is selected from: substituted or unsubstituted C 3-8Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclyl, the heterocyclyl containing 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P. In some embodiments, ring D is a substituted or unsubstituted 3-8 membered heterocyclyl, the heterocyclyl containing 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P. In some embodiments, ring D is selected from the group consisting of 5-10 membered heterocyclyl, 5-9 membered heterocyclyl, 5-8 membered heterocyclyl, 5-6 membered heterocyclyl. In some embodiments, ring D is a substituted or unsubstituted 5-7 membered heterocyclyl. In some embodiments, ring D contains 1 or 2 nitrogen atoms. In certain embodiments, ring D is selected from pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, or oxazepine. In certain embodiments, ring D is pyrrolidinyl or 1,3-oxazepine. In certain embodiments, ring D is pyrrolidinyl. In certain embodiments, ring D is 1,3-oxazepine or morpholinyl. In certain embodiments, ring D is 1,3-oxazepine.

[0217] In some embodiments, the structure composed of Ring B, Ring C, and Ring D is selected from the group consisting of:

[0218] In some embodiments, the structure composed of Ring B, Ring C, and Ring D is selected from the group consisting of:

[0219] In some embodiments, the structure composed of Ring B, Ring C, and Ring D is selected from the group consisting of:

[0220] In some embodiments, the structure composed of Ring B, Ring C, and Ring D is selected from the group consisting of:

[0221] In some embodiments, A1 and A2 are each independently selected from: CR1 or N; A3 and A4 are C.

[0222] In some embodiments, B1 is N(R2) m In some embodiments, B2 is C(R2) m In some embodiments, B3 is C(R2) m In some embodiments, B4 is C(R2) m .

[0223] In some embodiments, C1 is N(R3) qIn some embodiments, C2 is N(R3) q .

[0224] In some embodiments, R1 is selected from: H, halogen, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, cyano, -NO2, -OH, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclyl, substituted or unsubstituted 3-8 membered heterocyclyl, spiro 3-8 membered heterocyclyl, substituted or unsubstituted 3-8 membered heterocyclyl, 3-8 membered heterocyclyl, substituted or unsubstituted C 3-8 Cycloalkylspiro C 3-8 Cycloalkyl, substituted or unsubstituted C 3-8 Cycloalkyl C 3-8 Cycloalkyl, the heterocyclic group contains 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P. In some embodiments, R1 is selected from the group consisting of H, halogen, substituted or unsubstituted C 2- 6Alkynyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, cyano, -NO2, -OH, substituted or unsubstituted 3-8 membered heterocyclyl, substituted or unsubstituted 3-8 membered heterocyclyl spiro 3-8 membered heterocyclyl, the heterocyclyl containing 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P. In some embodiments, R1 is selected from the group consisting of H, halogen, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 1-6 Alkoxy, cyano, substituted or unsubstituted 3-8 membered heterocyclyl, substituted or unsubstituted 3-8 membered heterocyclyl spiro 3-8 membered heterocyclyl, wherein the heterocyclyl contains 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P. In some embodiments, R1 is selected from the group consisting of H, halogen, substituted or unsubstituted C 2-6 Alkynyl, C 1-6 Alkoxy, cyano, substituted or unsubstituted 3-8 membered heterocyclic group, substituted or unsubstituted 3-8 membered heterocyclic group spiro 3-8 membered heterocyclic group, the C 2-6 The alkynyl group is optionally replaced by C 3-8 Cycloalkyl, C 1-6 Alkyl, hydroxy substituted C 1-6 alkyl, 3-8 membered heterocyclic group, said heterocyclic group containing 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P. In some embodiments, R1 is selected from the group consisting of H, halogen, substituted or unsubstituted C 2-5 Alkynyl, substituted or unsubstituted C 1-3Alkoxy, cyano, substituted or unsubstituted 5-6 membered heterocyclyl spiro 4-6 membered heterocyclyl, wherein the heterocyclyl contains 1 or 2 heteroatoms selected from the group consisting of N, O, and S. In certain embodiments, the C 2-5 Alkynyl, C 1-3 Alkoxy, and 5-6 membered heterocyclyl spiro 4-6 membered heterocyclyl are selected from C 1-6 Alkyl, 3-5 membered cycloalkyl, 4-6 membered heterocyclic group, hydroxyl C 2-5 In certain embodiments, the C 2-5 Alkynyl, C 1-3 The alkoxy, and 5-6 membered heterocyclyl, spiro 4-6 membered heterocyclyl are substituted by a substituent selected from cyclopropyl, pyranyl, hydroxyisopropyl.

[0225] In certain embodiments, R1 is selected from the group consisting of: H, methoxy, cyano, chlorine and bromine.

[0226] In some embodiments, R2 and R3 are each independently selected from: H, oxo (=O), substituted or unsubstituted C 1-6 Alkoxy, halogen, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 1-6 In some embodiments, R2 and R3 are each independently selected from: H, oxo, substituted or unsubstituted C 1-6 Alkoxy, halogen, substituted or unsubstituted C 1-6 Alkyl, cyano, -NO2, -OH. In some embodiments, R2 and R3 are each independently selected from: H and oxo (=O).

[0227] In some embodiments, R2 is selected from H, oxo (=O), substituted or unsubstituted C 1-6 Alkoxy, halogen, substituted or unsubstituted C 1-6 In certain embodiments, the C 1-6 Alkoxy and C 1-6 Each alkyl group is independently substituted with oxo (=O), -OH, cyano, or -NO 2. In certain embodiments, R 2 is oxo.

[0228] In some embodiments, R3 is selected from: H, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Alkyl, halogen, cyano, -NO2, -OH, in certain embodiments, the C 1-6 Alkoxy and C 1-6Each alkyl group is independently substituted with oxo (=O), -OH, cyano, or -NO 2 . In certain embodiments, R 3 is H.

[0229] In some embodiments, R4 is selected from: H, oxo (=O), substituted or unsubstituted C 1-6 Alkoxy, halogen, substituted or unsubstituted C 1-6 Alkyl, cyano, -NO2, -OH, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic group, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 5-10 membered heteroaryl, wherein the heterocyclic group or heteroaryl group contains 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P. In some embodiments, R4 is selected from the group consisting of H, substituted or unsubstituted C 1-6 Alkoxy, halogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic group, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 5-10 membered heteroaryl, wherein the heterocyclic group or heteroaryl group contains 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P. In some embodiments, R4 is selected from the group consisting of H, halogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, said heteroaryl containing 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P. In some embodiments, said substitution refers to one or more hydrogen atoms on the group being replaced by a substituent selected from the group consisting of halogen, C 1-8 Alkyl and C 1-8 In some embodiments, R4 is selected from H, substituted or unsubstituted C 1-6 Alkoxy, halogen, substituted or unsubstituted C 1-6 Alkyl, cyano, -NO2, -OH, substituted or unsubstituted 3-8 membered heterocyclic group, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 5-10 membered heteroaryl, wherein the heterocyclic group or heteroaryl group contains 1, 2 or 3 heteroatoms selected from the group consisting of N, O and S. In certain embodiments, the C 1-6 Alkoxy, C 1-6 Alkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl are each independently substituted by 1, 2 or 3 groups selected from H, halogen, -OH, C 1- 6 alkyl, halogenated C 1-6 Alkyl and C 1-8 In certain embodiments, t is 1 or 2.

[0230] In certain embodiments, R4 is selected from halogen, tolyl, difluoropropyl, phenyl, benzyl, difluorophenyl, methoxyphenyl and pyridyl. In certain embodiments, R4 is selected from: and halogens.

[0231] In certain embodiments, R4 is selected from:

[0232] and F.

[0233] In some embodiments, R5 and R6 are each independently selected from: H, oxo (=O), substituted or unsubstituted C 1-6 Alkoxy, halogen, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 1-6 In some embodiments, R5 and R6 are each independently selected from: H, oxo (=O), substituted or unsubstituted C 1-6 Alkoxy, halogen, substituted or unsubstituted C 1-6 In some embodiments, R5 and R6 are each independently selected from: H, substituted or unsubstituted C 1-6 Alkoxy, halogen, substituted or unsubstituted C 1- In some embodiments, R5 and R6 are each independently selected from: H, C 1-6 In some embodiments, R5 is selected from H, substituted or unsubstituted C 1-6 Alkoxy, halogen, substituted or unsubstituted C 1-6 In certain embodiments, R5 is selected from unsubstituted C 1-6 In certain embodiments, R5 is methyl.

[0234] In some embodiments, R6 is selected from H, substituted or unsubstituted C 1-6 Alkoxy, halogen, substituted or unsubstituted C 1-6 In certain embodiments, R6 is H.

[0235] In some embodiments, m is any integer of 0, 1, or 2. In some embodiments, m is 1.

[0236] In some embodiments, q is any integer of 0, 1, or 2. In some embodiments, q is any integer of 0 to 1. In some embodiments, q is 0.

[0237] In some embodiments, t is any integer of 0, 1, or 2. In some embodiments, t is 1 or 2.

[0238] In some embodiments, the compound of Formula A provided herein, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph, prodrug or metabolite thereof, has the structure shown in the following Formula II-1:

[0239] In formula II-1:

[0240] A1, A2, A3 and A4 are each independently selected from: CR1 or N;

[0241] B1, B2, B3 and B4 are each independently selected from: C(R2) m or N(R2) m ;

[0242] Ring B and Ring C are each independently selected from: substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic group, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, said heterocyclic group or heteroaryl group containing 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P;

[0243] L is selected from: and C 1-10 alkylene;

[0244] R1 is selected from: H, halogen, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, cyano, -NO2, -OH, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic group, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted 3-8 membered heterocyclyl, spiro 3-8 membered heterocyclyl, substituted or unsubstituted 3-8 membered heterocyclyl, 3-8 membered heterocyclyl, substituted or unsubstituted C 3-8 Cycloalkylspiro C 3-8 Cycloalkyl, substituted or unsubstituted C 3-8 Cycloalkyl C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic group and C 6-10 Aryl, substituted or unsubstituted 3-8 membered heterocyclic group and 5-10 membered heteroaryl, substituted or unsubstituted C 3-8 Cycloalkyl C 6-10 Aryl, substituted or unsubstituted C 3-8Cycloalkyl and 5-10 membered heteroaryl, wherein the heterocyclic group or heteroaryl contains 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P;

[0245] R2, R3, R5 and R6 are each independently selected from: H, oxo (=O), substituted or unsubstituted C 1-6 Alkoxy, halogen, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 1-6 Alkyl, cyano, -NO2, -OH, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic group, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, said heterocyclic group or heteroaryl group containing 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P;

[0246] m and q are each independently an integer of 0, 1, 2 or 3;

[0247] The substitution refers to that one or more hydrogen atoms on the group are replaced by a substituent selected from the group consisting of halogen, -OH, -NO2, -NH2, -NH (unsubstituted or halogenated C 1-6 Alkyl), -N(unsubstituted or halogenated C 1-6 Alkyl)2, -CN, unsubstituted or substituted by halogen or hydroxyl C 1-8 Alkyl, unsubstituted or halogenated C 1-8 Alkoxy, unsubstituted or halogenated C 1-8 Alkoxy-C 1- 8 alkyl, unsubstituted or halogenated C 3-8 Cycloalkyl-C 1-8 Alkyl, unsubstituted or halogenated C 1-6 Alkylcarbonyl, unsubstituted or halogenated C 1-6 Alkoxycarbonyl, hydroxamate, unsubstituted or halogenated C 1-6 Alkylthio, -S(O)2N(unsubstituted or halogenated C 1-6 Alkyl)2, -S(O)2 unsubstituted or halogenated C 1-6 Alkyl, -N (unsubstituted or halogenated C 1-6 Alkyl)S(O)2N(unsubstituted or halogenated C 1-6 Alkyl)2, -S(O)N(unsubstituted or halogenated C 1-6 Alkyl)2, -S(O)(unsubstituted or halogenated C 1-6 Alkyl), -N(unsubstituted or halogenated C 1-6 Alkyl)S(O)N(unsubstituted or halogenated C 1-6 Alkyl)2, -N (unsubstituted or halogenated C1-6 Alkyl)S(O)(unsubstituted or halogenated C 1-6 Alkyl), unsubstituted or halogenated C 5-10 Aryl, unsubstituted or halogenated 5-10 membered heteroaryl, unsubstituted or halogenated C 3-8 Cycloalkyl and unsubstituted or halogenated 3-8 membered heterocyclyl, said heterocyclyl and heteroaryl containing 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O and S.

[0248] In some embodiments, A1, A2, A3 and A4 are C.

[0249] In some embodiments, B1 and B4 are C(R2) m , B2 and B3 are N(R2) m .

[0250] In some embodiments, Ring B is a substituted or unsubstituted C 6-10 In some embodiments, ring B is a substituted or unsubstituted 5-10 membered heteroaryl group, a substituted or unsubstituted 5-10 membered heteroaryl group, the heteroaryl group containing 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P. In some embodiments, ring B is a substituted or unsubstituted 5-10 membered heteroaryl group, the heteroaryl group containing 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P. In some embodiments, ring B is a substituted or unsubstituted 5-7 membered heteroaryl group, the heteroaryl group containing 1, 2 or 3 nitrogen atoms.

[0251] In some embodiments, Ring C is a substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclyl, said heterocyclyl containing 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P. In some embodiments, ring C is a substituted or unsubstituted 3-8 membered heterocyclyl, said heterocyclyl containing 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P. In some embodiments, ring C is a substituted or unsubstituted 5-7 membered heterocyclyl, said heterocyclyl containing 1, 2 or 3 nitrogen atoms.

[0252] In some embodiments, L is selected from: In some embodiments, L is selected from: In some embodiments, L is

[0253] In some embodiments, R1 is selected from: H, halogen, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 2- 6 alkenyl, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6In some embodiments, R1 is selected from: H, halogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 In some embodiments, R1 is selected from: H, halogen, substituted or unsubstituted C 1-6 In some embodiments, R1 is selected from the group consisting of: H and halogen.

[0254] In some embodiments, R2 and R3 are each independently selected from: H, substituted or unsubstituted C 1-6 Alkoxy, halogen, substituted or unsubstituted C 1-6 Alkyl, cyano, -NO2, -OH, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic group, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 5-10 membered heteroaryl, wherein the heterocyclic group or heteroaryl group contains 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P. In some embodiments, R2 and R3 are each independently selected from the group consisting of H, halogen, substituted or unsubstituted C 1-6 Alkyl, cyano, -NO2, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 5-10 membered heteroaryl, said heteroaryl containing 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P. In some embodiments, R2 and R3 are each independently selected from the group consisting of H, halogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 6-10 In some embodiments, R2 and R3 are each independently selected from: H, C 1-6 Alkyl and C 6-10 Aryl.

[0255] In some embodiments, R5 and R6 are each independently selected from: H, oxo (=O), substituted or unsubstituted C 1-6 Alkoxy, halogen, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 1-6 In some embodiments, R5 and R6 are each independently selected from: H, oxo (=O), substituted or unsubstituted C 1-6 Alkoxy, halogen, substituted or unsubstituted C 1-6 In some embodiments, R5 and R6 are each independently selected from: H, oxo (=O), substituted or unsubstituted C 1-6 In some embodiments, R5 and R6 are each independently selected from: H and C 1-6 alkyl.

[0256] In some embodiments, m is any integer of 0, 1, or 2. In some embodiments, m is 0 or 1. In some embodiments, m is 0.

[0257] In some embodiments, q is any integer of 0, 1, or 2. In some embodiments, q is 0 or 1. In some embodiments, q is 1.

[0258] In some embodiments, the structure composed of Ring B and Ring C is selected from the group consisting of: In some embodiments, the structure composed of Ring B and Ring C is For example In some embodiments, the structure composed of Ring B and Ring C is selected from the group consisting of:

[0259] In some embodiments, the compound of Formula A provided herein, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph, prodrug or metabolite thereof, has the structure shown in the following Formula III-1:

[0260] In formula III-1:

[0261] A1, A2, A3 and A4 are each independently selected from: CR1 or N;

[0262] Ring B is selected from: substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic group, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, said heterocyclic group or heteroaryl group containing 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P;

[0263] L is selected from: and C 1-10 alkylene;

[0264] R1 is selected from: H, halogen, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, cyano, -NO2, -OH, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic group, substituted or unsubstituted C 6-10Aryl, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted 3-8 membered heterocyclyl, spiro 3-8 membered heterocyclyl, substituted or unsubstituted 3-8 membered heterocyclyl, 3-8 membered heterocyclyl, substituted or unsubstituted C 3-8 Cycloalkylspiro C 3-8 Cycloalkyl, substituted or unsubstituted C 3-8 Cycloalkyl C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic group and C 6-10 Aryl, substituted or unsubstituted 3-8 membered heterocyclic group and 5-10 membered heteroaryl, substituted or unsubstituted C 3-8 Cycloalkyl C 6-10 Aryl, substituted or unsubstituted C 3-8 Cycloalkyl and 5-10 membered heteroaryl, wherein the heterocyclic group or heteroaryl contains 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P;

[0265] R2, R5 and R6 are each independently selected from: H, oxo (=O), substituted or unsubstituted C 1-6 Alkoxy, halogen, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 1-6 Alkyl, cyano, -NO2, -OH, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic group, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, said heterocyclic group or heteroaryl group containing 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P;

[0266] m is any integer of 0, 1, 2 or 3;

[0267] The substitution refers to that one or more hydrogen atoms on the group are replaced by a substituent selected from the group consisting of halogen, -OH, -NO2, -NH2, -NH (unsubstituted or halogenated C 1-6 Alkyl), -N(unsubstituted or halogenated C 1-6 Alkyl)2, -CN, unsubstituted or substituted by halogen or hydroxyl C 1-8 Alkyl, unsubstituted or halogenated C 1-8 Alkoxy, unsubstituted or halogenated C 1-8 Alkoxy-C 1- 8 alkyl, unsubstituted or halogenated C 3-8 Cycloalkyl-C 1-8 Alkyl, unsubstituted or halogenated C 1-6 Alkylcarbonyl, unsubstituted or halogenated C 1-6 Alkoxycarbonyl, hydroxamate, unsubstituted or halogenated C 1-6Alkylthio, -S(O)2N(unsubstituted or halogenated C 1-6 Alkyl)2, -S(O)2 unsubstituted or halogenated C 1-6 Alkyl, -N (unsubstituted or halogenated C 1-6 Alkyl)S(O)2N(unsubstituted or halogenated C 1-6 Alkyl)2, -S(O)N(unsubstituted or halogenated C 1-6 Alkyl)2, -S(O)(unsubstituted or halogenated C 1-6 Alkyl), -N(unsubstituted or halogenated C 1-6 Alkyl)S(O)N(unsubstituted or halogenated C 1-6 Alkyl)2, -N (unsubstituted or halogenated C 1-6 Alkyl)S(O)(unsubstituted or halogenated C 1-6 Alkyl), unsubstituted or halogenated C 5-10 Aryl, unsubstituted or halogenated 5-10 membered heteroaryl, unsubstituted or halogenated C 3-8 Cycloalkyl and unsubstituted or halogenated 3-8 membered heterocyclyl, said heterocyclyl and heteroaryl containing 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O or S.

[0268] In some embodiments, A1, A2, A3 and A4 are C.

[0269] In some embodiments, Ring B is a substituted or unsubstituted C 6-10 In some embodiments, Ring B is a substituted or unsubstituted 5-10 membered heteroaryl group containing 1, 2, or 3 heteroatoms selected from the group consisting of N, O, S, and P. In some embodiments, Ring B is a substituted or unsubstituted 5-10 membered heteroaryl group containing 1, 2, or 3 heteroatoms selected from the group consisting of N, O, S, and P. In some embodiments, Ring B is a substituted or unsubstituted 5-7 membered heteroaryl group containing 1, 2, or 3 nitrogen atoms. In some embodiments, Ring B is selected from the group consisting of pyridyl, imidazolyl, pyrrolyl, pyrazolyl, pyrimidinyl, pyrazinyl, triazolyl, and triazinyl. In some embodiments, Ring B is pyridyl.

[0270] In some embodiments, L is selected from In some embodiments, L is selected from:

[0271] In some embodiments, R1 is selected from: H, halogen, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 2- 6 alkenyl, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, cyano, -NO2, -OH, substituted or unsubstituted C3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclyl, substituted or unsubstituted 3-8 membered heterocyclyl, spiro 3-8 membered heterocyclyl, substituted or unsubstituted 3-8 membered heterocyclyl, 3-8 membered heterocyclyl, substituted or unsubstituted C 3-8 Cycloalkylspiro C 3-8 Cycloalkyl, substituted or unsubstituted C 3-8 Cycloalkyl C 3-8 Cycloalkyl, the heterocyclic group contains 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P. In some embodiments, R1 is selected from the group consisting of H, halogen, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted 3-8 membered heterocyclyl, substituted or unsubstituted 3-8 membered heterocyclylspiro 3-8 membered heterocyclyl, the heterocyclyl containing 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P. In some embodiments, R1 is selected from the group consisting of H, halogen, unsubstituted or C 3-8 Cycloalkyl substituted C 2-6 Alkynyl, substituted or unsubstituted 3-8 membered heterocyclyl, substituted or unsubstituted 3-8 membered heterocyclylspiro 3-8 membered heterocyclyl, the heterocyclyl containing 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P. In some embodiments, R1 is selected from the group consisting of H, halogen, substituted or unsubstituted C 2-6 Alkynyl, C 1-6 Alkoxy, cyano, substituted or unsubstituted 3-8 membered heterocyclic group, substituted or unsubstituted 3-8 membered heterocyclic group spiro 3-8 membered heterocyclic group, the C 2-6 The alkynyl group is optionally replaced by C 3-8 Cycloalkyl, C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl, 3-8 membered heterocyclic group, said heterocyclic group containing 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P.

[0272] In some embodiments, R2 is selected from: H, oxo (=O), substituted or unsubstituted C 1-6 Alkoxy, halogen, substituted or unsubstituted C 1-6 Alkyl, cyano, -NO2, -OH, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 5-10 membered heteroaryl, said heteroaryl containing 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P. In some embodiments, R2 is selected from the group consisting of H, substituted or unsubstituted C 1-6 Alkoxy, halogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 6-10aryl, substituted or unsubstituted 5-10 membered heteroaryl, said heteroaryl containing 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P. In some embodiments, R2 is selected from the group consisting of: H, optionally substituted by C 6-10 Aryl-substituted C 1-6 Alkoxy, substituted or unsubstituted 7-10 membered heteroaryl, said heteroaryl containing 1, 2 or 3 nitrogen atoms.

[0273] In some embodiments, R5 and R6 are each independently selected from: H, oxo (=O), substituted or unsubstituted C 1-6 Alkoxy, halogen, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 1-6 In some embodiments, R5 and R6 are each independently selected from: H, oxo (=O), substituted or unsubstituted C 1-6 Alkoxy, halogen, substituted or unsubstituted C 1-6 In some embodiments, R5 and R6 are each independently selected from: H, oxo (=O), substituted or unsubstituted C 1-6 alkyl.

[0274] In some embodiments, m is any integer of 0, 1, or 2. In some embodiments, m is 0 or 1. In some embodiments, m is 1.

[0275] In some embodiments, the compound of formula A has the structure shown in the following formula A':

[0276] wherein R1-R6, Ring A-Ring E, L, n, m, q and t are as described in any of the above embodiments.

[0277] In some embodiments, the compound of formula A has the structure shown in the following formula A":

[0278] wherein R1-R6, Ring A-Ring E, L, n, m, q and t are as described in any of the above embodiments.

[0279] In some embodiments, the compound of formula A has the structure shown in the following formula I':

[0280] wherein R1-R6, Ring A-Ring E, L, n, m, q and t are as described in any of the above embodiments.

[0281] In some embodiments, the compound of formula A has the structure shown in the following formula I":

[0282] wherein R1-R6, Ring A-Ring E, L, n, m, q and t are as described in any of the above embodiments.

[0283] In some embodiments, the compound of formula A has the structure shown in the following formula II':

[0284] wherein R1-R3, R5-R6, Ring A-Ring C, Ring E, L, n, m and q are as described in any of the above embodiments.

[0285] In some embodiments, the compound of formula A has the structure shown in the following formula II":

[0286] wherein R1-R3, R5-R6, Ring A-Ring C, Ring E, L, n, m and q are as described in any of the above embodiments.

[0287] In some embodiments, the compound of formula A has the structure shown in the following formula III':

[0288] wherein R1-R2, R5-R6, Ring A, Ring B, Ring E, L, n and m are as described in any of the above embodiments.

[0289] In some embodiments, the compound of formula A has the structure shown in the following formula III":

[0290] wherein R1-R2, R5-R6, Ring A, Ring B, Ring E, L, n and m are as described in any of the above embodiments.

[0291] In some embodiments, the compound of formula A has the structure shown in the following formula I'-1:

[0292] wherein A1-A4, B1-B4, C1-C3, R2-R6, Ring A-Ring E, m, q and t are as described in any of the above embodiments.

[0293] In some embodiments, the compound of formula A has the structure shown in the following formula I"-1:

[0294] wherein A1-A4, B1-B4, C1-C3, R2-R6, Ring A-Ring E, m, q and t are as described in any of the above embodiments.

[0295] In some embodiments, the compound of formula A has the structure shown in the following formula II'-1:

[0296] wherein A1-A4, B1-B4, R2-R3, R5-R6, Ring A, Ring B, Ring C, Ring E, L, m and q are as described in any of the above embodiments.

[0297] In some embodiments, the compound of formula A has the structure shown in the following formula II'-2:

[0298] wherein A1-A4, B1-B4, R2-R3, R5-R6, Ring A, Ring B, Ring C, Ring E, L, m and q are as described in any of the above embodiments.

[0299] In some embodiments, the compound of formula A has the structure shown in the following formula III'-1:

[0300] wherein A1-A4, R2, R5-R6, Ring A, Ring B, Ring E, L and m are as described in any of the above embodiments.

[0301] In some embodiments, the compound of formula A has the structure shown in the following formula III'-2:

[0302] wherein A1-A4, R2, R5-R6, Ring A, Ring B, Ring E, L and m are as described in any of the above embodiments.

[0303] In some embodiments, the compound of formula A provided herein, or a pharmaceutically acceptable salt thereof, or a solvate, isotope substitution, polymorph, prodrug or metabolite thereof, is selected from the following structures:

[0304] Pharmaceutical composition

[0305] The present disclosure provides a pharmaceutical composition comprising a compound of formula A described in any embodiment herein or any sub-formula thereof (including but not limited to a compound of formula I, a compound of formula II, a compound of formula III) or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph, prodrug or metabolite thereof, and a pharmaceutically acceptable excipient or carrier.

[0306] The pharmaceutical compositions described herein may comprise 0.01-99% w (weight percent), 0.05-80% w, 0.10-70% w, and / or even 0.10-50% w of a compound of Formula A or any subformula thereof (including but not limited to a compound of Formula I, a compound of Formula II, a compound of Formula III) or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph, prodrug or metabolite thereof as an active ingredient (e.g., the sole active ingredient), based on the weight of the total composition, depending on the mode of administration.

[0307] In another aspect, the present disclosure further provides a method for preparing a pharmaceutical composition of the present disclosure, comprising mixing a compound of formula A described in any embodiment herein or any sub-formula thereof (including but not limited to a compound of formula I, a compound of formula II, a compound of formula III) or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph, prodrug or metabolite thereof with a pharmaceutically acceptable excipient or carrier.

[0308] Herein, the pharmaceutical composition can be administered topically (e.g., to the skin or lungs and / or airways), for example, in the form of creams, solutions, suspensions, hexafluoroethane aerosols, and dry powder formulations; or systemically, for example, orally in the form of tablets, capsules, syrups, powders, or granules; or gastrointestinal in the form of solutions or suspensions; or subcutaneously; or rectally in the form of suppositories; or transdermally.

[0309] The compositions of the present disclosure can be obtained by conventional methods using conventional pharmaceutical excipients well known in the art. Thus, pharmaceutical compositions intended for oral use may contain, for example, one or more coloring agents, sweeteners, flavoring agents and / or preservatives.

[0310] Suitable pharmaceutically acceptable excipients for tablet preparation include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate; granulating and disintegrants such as corn starch or algenic acid; binders such as starch; lubricants such as magnesium stearate, stearic acid or talc; preservatives such as ethyl or propyl paraben, and antioxidants such as ascorbic acid. Tablets may be uncoated or coated using conventional coating materials and methods well known in the art to improve disintegration and subsequent absorption of the active ingredient in the gastrointestinal tract, or to improve stability and / or appearance.

[0311] Compositions for oral administration may be in the form of hard gelatin capsules wherein the active ingredient is mixed with an inert organic diluent such as calcium carbonate, calcium phosphate or kaolin; or in the form of soft gelatin capsules wherein the active ingredient is mixed with water, or an oil such as peanut oil, liquid paraffin or olive oil.

[0312] Aqueous suspensions generally contain the active ingredient in finely divided powder form and one or more suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum arabic; a dispersing or wetting agent such as lecithin or a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), or a condensation product of ethylene oxide with a long-chain fatty alcohol (e.g., heptadecanethoxycetanol), or a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol (e.g., polyoxyethylene sorbitan monooleate), or a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol acid (e.g., polyoxyethylene sorbitan monooleate). The aqueous suspension may also contain one or more preservatives (eg, ethyl or propyl paraben, antioxidants (eg, ascorbic acid), coloring agents, flavoring agents, and / or sweetening agents (eg, sucrose, saccharin, or aspartame)).

[0313] Oily suspensions can be prepared by suspending the active ingredient in a vegetable oil (e.g., peanut oil, olive oil, sesame oil, or coconut oil) or a mineral oil (e.g., liquid paraffin). Oily suspensions may also contain thickeners such as beeswax, hard paraffin, or cetyl alcohol. Sweeteners and flavorings such as those listed above may be added to obtain a palatable oral formulation. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid.

[0314] Dispersible powders and granules suitable for preparing an aqueous suspension by the addition of water typically comprise the active ingredient and a dispersing or wetting agent, a suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those mentioned above. Other excipients such as sweeteners, flavorings and coloring agents may also be present.

[0315] In some embodiments, pharmaceutical composition of the present disclosure can also be in the form of oil-in-water emulsion.The oil phase can be vegetable oil such as olive oil or peanut oil, or mineral oil such as liquid paraffin, or any mixture of these.Suitable emulsifying agent can be for example naturally occurring gum such as gum arabic or tragacanth, naturally occurring phospholipids such as soybean lecithin, lecithin, ester derived from fatty acid and hexitol anhydride or partial ester (such as sorbitan monooleate) and the condensation product of described partial ester and ethylene oxide such as polyoxyethylene sorbitan monooleate.Emulsion can also comprise sweetener, flavoring agent and preservative.

[0316] Syrups and elixirs may be formulated with sweetening agents such as glycerol, propylene glycol, sorbitol, aspartame or sucrose, and may also contain a demulcent, a preservative, a flavoring and / or a coloring agent.

[0317] The pharmaceutical compositions described herein can also be in the form of sterile injectable aqueous or oily suspensions, which can be prepared using one or more of the above-mentioned suitable dispersants or wetting agents and suspending agents according to known methods. Sterile injectable preparations can also be sterile injectable solutions or suspensions in toxins, parenteral-acceptable diluents or solvents (e.g., solutions in 1,3-butanediol).

[0318] Suppositories can be prepared by mixing the active ingredient with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Suitable excipients include, for example, cocoa butter and polyethylene glycols.

[0319] Topical preparations such as creams, ointments, gels or aqueous or oily solutions or suspensions are generally formulated with the active ingredient and conventional, topically acceptable excipients or diluents using conventional methods well known in the art.

[0320] Compositions for insufflation can be administered as a finely divided powder, e.g., having an average particle size of 30 μm or less, containing the active ingredient alone or diluted with one or more physiologically acceptable carriers, such as lactose. The powder for insufflation is then conveniently placed in a capsule containing, e.g., 1-50 mg of the active ingredient, and used with a turbo-inhaler device, e.g., for insufflation of the known drug sodium cromolyn.

[0321] Compositions for administration by inhalation may be in the form of conventional pressurized aerosols which dispense the active ingredient into an aerosol containing finely divided solid or liquid droplets. Conventional aerosol propellants such as volatile fluorinated hydrocarbons or hydrocarbons may be used and the aerosol device allows for convenient measurement of the amount of active ingredient.

[0322] According to well-known medical principles, the size of the dose of the disclosed compounds for therapeutic purposes will naturally vary depending on the nature and severity of the condition, the age and sex of the animal or patient and the route of administration.

[0323] In general, the compound of formula A described in any embodiment herein or any sub-formula thereof (including but not limited to the compound of formula I, the compound of formula II, the compound of formula III) or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph, prodrug or metabolite thereof is administered so as to obtain a daily dose of, for example, 0.1 mg to 1000 mg of active ingredient / kg body weight, which may also be administered in divided doses if necessary. However, the daily dose must vary depending on the host being treated, the specific route of administration, and the severity of the disease being treated. Therefore, the optimal dose can be determined by the physician treating any specific patient. In general, the dose is lower when a non-gastrointestinal route is used. Thus, for example, for intravenous administration, a dose of, for example, 0.1 mg to 30 mg of active ingredient / kg body weight will typically be used. Similarly, for inhalation administration, a dose of, for example, 0.1 mg to 25 mg of active ingredient / kg body weight will typically be used. However, oral administration is preferred. For example, a formulation intended for oral administration to humans will typically contain 0.1 mg to 2 g of active ingredient.

[0324] For information on other formulations, routes of administration, and dosage regimens, reference is made to the publication of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board).

[0325] The pharmaceutical composition of the present disclosure can be administered alone or in combination with other pharmaceutically acceptable compounds (such as Ripk1 inhibitors).

[0326] The disclosed treatment methods can be used alone or in combination with other treatments or therapeutic drugs.

[0327] use

[0328] The compound of formula A disclosed herein or any subformula thereof (including but not limited to the compound of formula I, the compound of formula II, the compound of formula III) or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph, prodrug or metabolite thereof is a Ripk1 inhibitor. Therefore, the compound of formula A disclosed herein or any subformula thereof (including but not limited to the compound of formula I, the compound of formula II, the compound of formula III) or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph, prodrug or metabolite thereof can be used to treat or prevent diseases or conditions related to Ripk1, or for the preparation of a medicament for treating or preventing diseases or conditions related to Ripk1.

[0329] Therefore, the present disclosure provides a method for treating or preventing a disease or condition associated with Ripk1 in a subject, comprising administering to the subject a therapeutically effective amount of a compound of formula A or any subformula thereof (including but not limited to a compound of formula I, a compound of formula II, a compound of formula III) or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph, prodrug or metabolite thereof, or a pharmaceutical composition of the present disclosure.

[0330] The present disclosure also provides the use of a compound of Formula A or any sub-formula thereof (including but not limited to a compound of Formula I, a compound of Formula II, a compound of Formula III) or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph, prodrug or metabolite thereof, or a pharmaceutical composition thereof in the preparation of a medicament for treating or preventing a disease or condition associated with Ripk1.

[0331] The present disclosure also provides a compound of formula A or any subformula thereof (including but not limited to a compound of formula I, a compound of formula II, a compound of formula III) or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph, prodrug or metabolite or pharmaceutical composition thereof for use in treating or preventing a disease or condition associated with Ripk1.

[0332] Herein, "associated with Ripk1" means that Ripk1 plays a role in the occurrence and / or development of the disease. The diseases or conditions associated with Ripk1 described herein may also be referred to as Ripk1-mediated diseases or conditions.

[0333] In some embodiments, the Ripk1-mediated diseases described herein include inflammatory diseases and diseases associated with necrotic cell death.

[0334] In some embodiments, the Ripk1-mediated disease includes stroke, inflammatory bowel disease, ulcerative colitis, Crohn's disease, psoriasis, rheumatoid arthritis, NASH, and heart failure.

[0335] In some embodiments, the diseases or conditions associated with Pipk1 include, but are not limited to, inflammatory diseases (e.g., Crohn's disease and ulcerative colitis, inflammatory bowel disease, asthma, graft-versus-host disease, chronic obstructive pulmonary disease), inflammatory skin diseases (e.g., psoriasis, eczema), autoimmune diseases (e.g., Graves' disease, rheumatoid arthritis, systemic lupus erythematosus, psoriasis; destructive bone diseases, such as bone resorption diseases, osteoarthritis, osteoporosis, multiple myeloma-related bone disease); proliferative diseases (leukemia, such as myeloid leukemia, including granulocytic leukemia, lymphocytic leukemia, monocytic leukemia); , erythroleukemia, further including acute myeloid leukemia, chronic myeloid leukemia), angiogenesis disorders (such as angiogenesis disorders, including solid tumors, ocular neovascularization and infantile hemangioma), infectious diseases (such as sepsis, septic shock and shigellosis); neurodegenerative diseases (such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, cerebral ischemia or neurodegenerative diseases caused by traumatic injury), tumors and viral diseases (such as metastatic melanoma, Kaposi's sarcoma, multiple myeloma, fibroblastoma, lymphocytoma, HIV infection and CMV retinitis, AIDS).

[0336] In some embodiments, the diseases or conditions associated with Ripk1 include but are not limited to pancreatitis (acute or chronic), asthma, allergies, adult respiratory distress syndrome, chronic obstructive pulmonary disease, glomerulonephritis, rheumatoid arthritis, systemic lupus erythematosus, scleroderma, chronic thyroiditis, Graves' disease, autoimmune gastritis, diabetes, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, atopic dermatitis, chronic active hepatitis, myasthenia gravis, amyotrophic lateral sclerosis, sclerosis, multiple sclerosis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, psoriasis, graft-versus-host disease, endotoxin-induced inflammatory reactions, tuberculosis, atherosclerosis, muscle degeneration, cachexia, psoriatic arthritis, Reiter's syndrome, gout, traumatic arthritis, rubella arthritis, acute synovitis, pancreatic beta-cell disease; diseases characterized by massive neutrophil infiltration; rheumatoid spondylitis, gouty arthritis and other arthritic conditions, cerebral malaria, chronic lung inflammation, silicosis, pulmonary sarcoidosis, bone resorption disease, allograft rejection, fever and myalgia caused by infection, cachexia secondary to infection, corpus luteum formation, scar tissue formation, ulcerative colitis, fever, influenza, osteoporosis, osteoarthritis, acute myeloid leukemia, chronic myeloid leukemia, metastatic melanoma, Kaposi's sarcoma, multiple myeloma, sepsis, septic shock, and shigellosis; Alzheimer's disease, Parkinson's disease, neurodegenerative diseases caused by cerebral ischemia or traumatic injury; angiogenesis disorders including solid tumors, ocular neoplasia ducts and infantile hemangiomas; viral diseases including acute hepatitis infection (including hepatitis A, B, and C), HIV infection and CMV retinitis, AIDS, ARC or malignant tumors and herpes; stroke, myocardial ischemia, stroke heart attack, organ ischemia, vascular proliferation, cardiac and renal reperfusion injury, thrombosis, cardiac hypertrophy, thrombin-induced platelet aggregation, endotoxemia and / or toxic shock syndrome, conditions related to prostaglandin endoperoxidase synthase-2, and pemphigus vulgaris.

[0337] In some embodiments, the disease or condition associated with Ripk1 is selected from the group consisting of stroke, inflammatory bowel disease, Crohn's disease and ulcerative colitis, allogeneic transplant rejection, rheumatoid arthritis, psoriasis, ankylosing spondylitis, psoriatic arthritis and pemphigus vulgaris. Alternatively, the disease or condition is selected from the group consisting of ischemia-reperfusion injury, including cerebral ischemia-reperfusion injury caused by stroke and myocardial ischemia-reperfusion injury caused by myocardial infarction.

[0338] In some embodiments, the present disclosure also provides a method for treating an inflammatory skin disease in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of formula A of the present disclosure or any sub-formula thereof (including but not limited to a compound of formula I, a compound of formula II, a compound of formula III) or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph, prodrug or metabolite or pharmaceutical composition thereof. The present disclosure also provides a compound of formula A of the present disclosure or any sub-formula thereof (including but not limited to a compound of formula I, a compound of formula II, a compound of formula III) or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph, prodrug or metabolite or pharmaceutical composition thereof in the preparation of a medicament for treating or preventing an inflammatory skin disease.

[0339] In some embodiments, the disclosure further provides a method for treating subject eczema, atopic eczema, hand eczema or radiation dermatitis, the method comprising administering to the subject a therapeutically effective amount of a compound of formula A of the present disclosure or any sub-formula thereof (including but not limited to a compound of formula I, a compound of formula II, a compound of formula III) or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph, prodrug or metabolite or pharmaceutical composition thereof. The disclosure further provides a compound of formula A of the present disclosure or any sub-formula thereof (including but not limited to a compound of formula I, a compound of formula II, a compound of formula III) or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph, prodrug or metabolite or pharmaceutical composition thereof in the preparation of a medicament for treating, preventing and / or alleviating contact eczema, atopic eczema, hand eczema and radiation dermatitis.

[0340] In the above methods and uses, the drug can be administered in a suitable manner, such as topically (e.g., to the skin or lungs and / or airways), such as in the form of creams, solutions, suspensions, hexafluoroethane aerosols and dry powder formulations; or systemically, such as oral administration in the form of tablets, capsules, syrups, powders or granules; or gastrointestinal administration in the form of solutions or suspensions; or subcutaneous administration; or rectal administration in the form of suppositories; or transdermal administration.

[0341] The present disclosure will be further described below with reference to specific examples. It should be understood that these examples are intended to illustrate the present invention only and are not intended to limit the scope of the present invention. The experimental methods in the following examples, for which specific conditions are not specified, are generally based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0342] The starting materials used in the following examples can be purchased from chemical distributors such as Aldrich, TCI, Alfa Aesar, Bidrich, and Anergy, or can be synthesized by known methods.

[0343] Example 1: Synthesis of Compound 1'

[0344] (3S)-7-(Cyclopropylethynyl)-5-methyl-3-(1-oxo-7-phenyl-4,5,6,7-tetrahydro-1H-pyrrolo[1′,2′:1,5]pyrazolo[3,4-c]pyridin-2(3H)-yl)-2,3-dihydrobenzo[b][1,4]oxepin-4(5H)-one

[0345] Step 1: To a suspension of sodium hydride (60% dispersion in mineral oil, 18.2 g, 454.5 mmol) in DMF (400 mL) at 0°C under argon was added a solution of A-SM-2 (46.6 g, 227.3 mmol) in DMF (100 mL) dropwise. The mixture was stirred at 0°C for 1 hour. A solution of A-SM-1 (50.0 g, 227.3 mmol) in DMF (50 mL) was added dropwise. The reaction was allowed to react at room temperature overnight. The reaction solution was poured into saturated aqueous ammonium chloride solution and extracted with ethyl acetate (3 × 800 mL). The organic phases were combined, washed with water (3 × 1.5 L), washed with saturated brine (2 × 1.5 L), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (dichloromethane / methanol = 10 / 1) to obtain A-1 (35.0 g, yield: 38.0%) as a yellow oil. LCMS: m / z: 304.7 [M-100+H] + .

[0346] Step 2: Zinc powder (28.1 g, 432.0 mmol) was added in batches to a suspension of A-1 (35.0 g, 86.4 mmol) and ammonium chloride (46.2 g, 863.7 mmol) in ethanol (350 mL) and water (70 mL) under an ice-water bath, and the temperature did not exceed 30°C. Stir at room temperature for 3 hours. Filter, concentrate the filtrate under reduced pressure to remove ethanol, add water (100 mL) and ethyl acetate (300 mL), separate the liquids, extract the aqueous phase with ethyl acetate (2×250 mL), combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate to obtain a yellow oil A-2 (25.0 g, yield: 77.1%). The crude product was used directly in the next step. LCMS: m / z=376.8[M+H] + .

[0347] Step 3: Under argon protection, N,N,N′,N′-tetramethylchloroformamidine hexafluorophosphate (20.6 g, 73.4 mmol) was added to a solution of A-2 (25.0 g, 66.6 mmol) and N-methylimidazole (11.4 g, 140.0 mmol) in acetonitrile (400 mL). The reaction was allowed to react at room temperature for 30 minutes. The reaction solution was poured into water and extracted with ethyl acetate (3×300 mL). The organic phases were combined, washed with saturated brine (500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain a white solid A-3 (13.0 g, yield: 54.6%). LCMS: m / z = 300.7 [M+H-56] + .

[0348] 1 H NMR (400MHz, DMSO-d6) δppm: 10.04 (s, 1H), 7.30~7.26 (m, 2H), 7.15 (d, J=8.0Hz, 1H), 7.09 (d, J=8.4Hz, 1H), 4.37~4.27 (m, 3H), 1.37 (s, 9H).

[0349] Step 4: To a solution of A-3 (9.2 g, 25.76 mmol) in dry DMF (100 mL) was added potassium carbonate (10.7 g, 77.27 mmol) and iodomethane (11.0 g, 77.27 mmol) at 0°C under argon. The reaction was allowed to react overnight at room temperature. The reaction solution was poured into water and extracted with ethyl acetate (3×150 mL). The organic phases were combined, washed with water (3×300 mL), washed with saturated brine (2×300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 20 / 1) to obtain a white solid A-4 (8.4 g, yield: 87.9%). LCMS: m / z = 315.0 [M+H-56] + .

[0350] 1 H NMR (400MHz, DMSO-d6) δppm: 7.74 (d, J=2.4Hz, 1H), 7.46~7.43 (m, 1H), 7.20 (d, J =8.4Hz, 1H), 7.17 (d, J = 8.4Hz, 1H), 4.40~4.26 (m, 3H), 3.28 (s, 3H), 1.35 (s, 9H).

[0351] Step 5: Trifluoroacetic acid (7 mL) was added dropwise to a solution of A-4 (3.5 g, 9.43 mmol) in dichloromethane (35 mL) at 0°C. The mixture was allowed to react at room temperature for 1 hour. The reaction solution was slowly poured into a saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate (3×200 mL), and the organic phases were combined, washed with saturated brine (400 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (dichloromethane / methanol = 20 / 1) to obtain a white solid A (2.5 g, yield: 97.8%). LCMS: m / z = 271.1 [M+H] + .

[0352] 1 H NMR (400MHz, DMSO-d6) δppm: 7.67 (d, J=2.4Hz, 1H), 7.41~7.38 (m, 1H), 7.13 (d, J=8.4Hz, 1H), 4.26~4.24(m, 1H), 4.03~3.98(m, 1H), 3.65~3.60(m, 1H), 3.29(s, 3H), 1.73(s, 2H).

[0353] ee%=100%.

[0354] Step 6: Add propargyl alcohol (45 g, 0.79 mol) to a toluene solution of 1'-SM-1 (100 g, 0.87 mol). Stir and react at 110°C for 5 hours. Cool the reaction mixture to room temperature and concentrate under reduced pressure. Add petroleum ether and ethyl acetate to the residue and filter to obtain a white solid 1'-1 as a mixture (82 g, yield: 60.0%). LCMS: m / z 171.1 [M+H] + .

[0355] Step 7: Add 2-(trimethylsilyl)ethoxymethyl chloride (132 g, 0.79 mol) to an acetone solution of 1′-1 (68 g, 0.40 mol) and cesium carbonate (390 g, 1.20 mmol). Stir and react at room temperature for 5 hours. Filter the reaction solution, and concentrate the filtrate to dryness under reduced pressure. The crude product is purified by silica gel column chromatography to obtain a yellow oily liquid 1′-2, a mixture (85 g, yield: 70.8%). LCMS: m / z 300.2 [M+H] + .

[0356] Step 8: Add Dess-Martin periodinane (212 g, 0.50 mol) to a solution of 1′-2 (75 g, 0.25 mol) in dichloromethane. Stir the reaction at room temperature for 3 hours. Filter the reaction solution, and concentrate the filtrate to dryness under reduced pressure. The crude product is purified by silica gel column chromatography to obtain 1′-3 as a yellow oil (12 g, yield: 16.1%). LCMS: m / z 298.3 [M+H] + .

[0357] 1 H NMR (400MHz, CDCl3) δppm: 10.01 (s, 1H), 7.51 (s, 1H), 5.92 (s, 2H), 4.48 (q, J=7.2Hz, 2H), 3.66 (t, J=8.0Hz, 2H), 1.46 (t, J=7.2Hz, 3H), 0.93 (t, J=8.0Hz, 2H), 0.01 (s, 9H).

[0358] Step 9: Add titanium tetrachloride (3.84 g, 20.2 mmol) to a dichloromethane solution of 1′-3 (2.98 g, 10.0 mmol) and trimethyl((1-phenylvinyl)oxy)silane (2.59 g, 13.5 mmol). React at 40°C for 48 hours. Dilute the reaction solution with water and extract with ethyl acetate. Combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The crude product is purified by silica gel chromatography (petroleum ether / ethyl acetate = 3:1) to obtain a yellow solid 1′-4 (1.0 g, yield: 37.0%). LCMS: m / z 271.1 [M+H] + .

[0359] Step 10: To a methanol solution of 1′-4 (270 mg, 1.0 mmol) was added palladium on carbon (10%, 50 mg) and aqueous ammonia (2 drops). The air was replaced with hydrogen three times. The reaction was stirred at room temperature for 2 hours. The mixture was filtered and the filtrate was concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography to obtain a yellow oil 1′-5 (168 mg, yield: 61.3%). LCMS: m / z 275.1 [M+H] + .

[0360] Step 11: To a solution of 1′-5 (850 mg, 3.1 mmol) in acetonitrile, add thionyl chloride (357 mg, 9.3 mmol). Stir the reaction at 50°C for 5 hours. Concentrate the reaction mixture to dryness under reduced pressure. Dilute the residue with ethyl acetate and saturated aqueous sodium bicarbonate. Collect the organic phase and concentrate it to dryness under reduced pressure. The crude product is purified by silica gel column chromatography to obtain a yellow solid 1′-6 (680 mg, yield: 75.0%). LCMS: m / z 293.1 [M+H] + .

[0361] Step 12: Add cesium carbonate (978 mg, 3.0 mmol) to a solution of 1′-6 (292 mg, 1.0 mmol) in acetonitrile. Stir the reaction at room temperature for 2 hours. Filter, and concentrate the filtrate to dryness under reduced pressure. The crude product is purified by silica gel column chromatography to obtain a yellow solid 1′-7 (155 mg, yield: 60.5%). LCMS: m / z 257.2 [M+H] + .

[0362] Step 13: To a solution of 1′-7 (2.56 g, 10.0 mmol) in acetonitrile, add liquid bromine (3.2 g, 20.0 mmol). Stir the reaction at 25°C for 15 hours. Dilute the reaction solution with ethyl acetate and saturated aqueous sodium sulfite. Collect the organic phase, dry over anhydrous sodium sulfate, and concentrate to dryness under reduced pressure. The crude product is purified by silica gel column chromatography to obtain a yellow solid 1′-8 (2.8 g, yield: 83.6%). LCMS: m / z 335.1 / 337.1 [M+H] + .

[0363] 1 H NMR (400MHz, CDCl3) δppm: 7.36~7.29(m, 3H), 7.03~7.01(m, 2H), 5.54~5.50(m, 1H) ), 4.42-4.35(m, 2H), 3.14-2.91(m, 3H), 2.57-2.51(m, 1H), 1.37(t, J=7.2Hz, 3H).

[0364] Step 14: To a solution of 1′-8 (2.6 g, 7.8 mmol) and (E)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.1 g, 15.5 mmol) in ethylene glycol dimethyl ether and water, potassium carbonate (2.14 g, 15.5 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (568 mg, 0.78 mmol) were added. The reaction was stirred at 90°C under argon for 15 hours. The reaction solution was diluted with ethyl acetate and water, and the organic phase was collected, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography to obtain 1′-9 (1.62 g, yield: 64.0%) as a white solid. LCMS: m / z 327.2 [M+H] + .

[0365] Step 15: To a solution of ethyl 1'-9 (2.4 g, 7.36 mmol) in tetrahydrofuran, add aqueous hydrochloric acid (6 M, 7 mL). Stir at room temperature for 1 hour. Add additional aqueous hydrochloric acid (6 M, 8 mL). Stir at room temperature for 1 hour and then react at 60°C for 0.5 hours. The reaction solution was diluted with ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic phase was collected, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography to obtain a yellow oil 1'-10 (1.3 g, yield: 59.1%). LCMS: m / z 299.1 [M+H] + .

[0366] Step 16: To a methanol solution of 1′-10 (298 mg, 1.0 mmol) was added A (406 mg, 1.5 mmol) and acetic acid (1 drop). Stir at room temperature for 0.1 hour. Sodium cyanoborohydride (125 mg, 2 mmol) was added. Stir at room temperature for 15 hours. The reaction solution was diluted with ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic phase was collected, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography to obtain a colorless oil 1′-11 (380 mg, yield: 68.8%). LCMS: m / z 553.1 / 555.1 [M+H] + .

[0367] Step 17: To a toluene solution of 1′-11 (100 mg, 0.18 mmol) was added a toluene solution of trimethylaluminum (1.0 M, 0.54 mL, 0.54 mmol). The reaction was stirred at 110°C for 15 hours. The reaction solution was diluted with ethyl acetate and water, and the organic phase was collected, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography to obtain a white solid 1′-12 (50 mg, yield: 54.5%). LCMS: m / z 507.1 / 509.1 [M+H] + .

[0368] Step 18: To a solution of 1′-12 (50.7 mg, 0.1 mmol), cyclopropyl acetylene (66 mg, 1.0 mmol), cuprous iodide (4 mg, 0.02 mmol), and N,N-diisopropylethylamine (38 mg, 0.3 mmol) in N,N-dimethylformamide (20 mL) was added bis(triphenylphosphine)palladium dichloride (14 mg, 0.02 mmol). Stir at 80°C under argon for 15 hours. The reaction mixture was diluted with ethyl acetate and water, and the organic phase was collected, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The crude product was purified by Prep-HPLC to obtain 1′ (2 mg, yield: 24.4%) as a white solid. LCMS: m / z 493.2 [M+H] + .

[0369] 1H NMR (400MHz, MeOD-d4) δppm: 7.37~7.21(m, 5H), 7.12~7.07(m, 3H), 5.73~5.68(m, 1H), 5.47~5.43(m, 1H), 4.84~4.81(m, 1H), 4.41~4.36(m, 1H), 4.18~4.12(m, 1H), 3 .66~3.61(m,1H), 3.36(s,3H), 3.13~3.10(m,1H), 3.04~2.93(m,3H), 2.82~2.81(m , 1H), 2.55~2.51(m, 1H), 1.48~1.44(m, 1H), 0.90~0.86(m, 2H), 0.75~0.71(m, 2H).

[0370] Example 2: Synthesis of Compounds 1" and 1"'

[0371] (S)-7-(cyclopropylethynyl)-5-methyl-3-((R)-1-oxo-7-phenyl-4,5,6,7-tetrahydro-1H-pyrrolo[1′,2′:1,5]pyrazolo[3,4-c]pyridin-2(3H)-yl)-2,3-dihydrobenzo[b][1,4]oxepin-4(5H)-one and

[0372] (S)-7-(Cyclopropylethynyl)-5-methyl-3-((S)-1-oxo-7-phenyl-4,5,6,7-tetrahydro-1H-pyrrolo[1′,2′:1,5]pyrazolo[3,4-c]pyridin-2(3H)-yl)-2,3-dihydrobenzo[b][1,4]oxepin-4(5H)-one

[0373] Step 1: 1′ (35 mg, 0.07 mmol) was purified by SFC to give two white solids 1″ (peak 1, 8 mg, yield: 22.9%) and 1″′ (peak 2, 8 mg, yield: 22.9%).

[0374] 1”(peak 1):

[0375] LCMS: m / z 493.3 [M+H] + ;

[0376] 1H NMR (400MHz, MeOD-d4) δppm: 7.37~7.28(m, 4H), 7.23~7.21(m, 1H), 7.12~7.07(m, 3H), 5.71~5.68 (m, 1H), 5.47~5.43 (m, 1H), 4.84~4.81 (m, 1H), 4.41~4.36 (m, 1H), 4.18~4.12 (m, 1H), 3.66~3.61 (m, 1H), 3.35 (s, 3H), 3.14~3.10 (m, 1H), 3.04~2.93 (m, 3H), 2.82~2. 81(m, 1H), 2.55~2.49(m, 1H), 1.48~1.44(m, 1H), 0.90~0.86(m, 2H), 0.75~0.71(m, 2H).

[0377] de%=100%.

[0378] 1"'(peak2):

[0379] LCMS: m / z 493.3 [M+H] + ;

[0380] 1 H NMR (400MHz, DMSO-d6) δppm: 7.48 (d, J=1.6Hz, 1H), 7.36~7.29 (m, 3H), 7.26~7.24 (m, 1H), 7.18~7 .16 (m, 1H), 7.11 (s, 1H), 7.09 (s, 1H), 5.56~5.46 (m, 2H), 4.83 (t, J=10.4Hz, 1H), 4.32 (t, J=10.4 Hz, 1H), 3.99~3.96(m, 1H), 3.60~3.56(m, 1H), 3.27(s, 3H), 3.08~3.04(m, 1H), 2.96~2.81(m, 3H) , 2.74~2.72(m, 1H), 2.44~2.39(m, 1H), 1.58~1.52(m, 1H), 0.91~0.86(m, 2H), 0.75~0.71(m, 2H).

[0381] de%=100%.

[0382] Example 3: Synthesis of Compounds 2' and 2"

[0383] (S)-7-bromo-5-methyl-3-((R)-1-oxo-7-phenyl-4,5,6,7-tetrahydro-1H-pyrrolo[1′,2′:1,5]pyrazolo[3,4-c]pyridin-2(3H)-yl)-2,3-dihydrobenzo[b][1,4]oxepin-4(5H)-one and

[0384] (S)-7-Bromo-5-methyl-3-((S)-1-oxo-7-phenyl-4,5,6,7-tetrahydro-1H-pyrrolo[1′,2′:1,5]pyrazolo[3,4-c]pyridin-2(3H)-yl)-2,3-dihydrobenzo[b][1,4]oxepin-4(5H)-one

[0385] Step 1: 1'-12 (25 mg, 0.05 mmol) was purified by SFC to give two white solids 2' (peak 1, 7 mg, yield: 28.0%) and 2" (peak 2, 7 mg, yield: 28.0%).

[0386] 2'(peak 1):

[0387] LCMS: m / z 509.2 [M+H] + ;

[0388] 1 H NMR (400MHz, MeOD-d4) δppm: 7.60 (d, J=2.4Hz, 1H), 7.42~7.39 (m, 1H), 7.36~7 .26(m, 3H), 7.15~7.06(m, 3H), 5.74~5.68(m, 1H), 5.47~5.43(m, 1H), 4.87~4.8 2(m, 1H), 4.42~4-38(m, 1H), 4.18~4.12(m, 1H), 3.66~3.61(m, 1H), 3.35(s, 3H ), 3.15~3.11(m, 1H), 3.04~2.93(m, 3H), 2.82~2.81(m, 1H), 2.55~2.49(m, 1H).

[0389] de%=100%.

[0390] 2”(peak2):

[0391] LCMS: m / z 509.2 [M+H] + ;

[0392] 1H NMR (400MHz, MeOD-d4) δppm: 7.60 (d, J=2.4Hz, 1H), 7.42~7.38 (m, 1H), 7.35~7 .26(m, 3H), 7.15~7.06(m, 3H), 5.74~5.68(m, 1H), 5.49~5.46(m, 1H), 4.87~4.8 2(m, 1H), 4.43~4.39(m, 1H), 4.18~4.11(m, 1H), 3.66~3.62(m, 1H), 3.35(s, 3H ), 3.15~3.11(m, 1H), 3.04~2.93(m, 3H), 2.81~2.79(m, 1H), 2.54~2.51(m, 1H).

[0393] de%=98.8%.

[0394] Example 4: Synthesis of Compounds 3' and 3"

[0395] (S)-5-methyl-4-oxo-3-((R)-1-oxo-7-phenyl-4,5,6,7-tetrahydro-1H-pyrrolo[1′,2′:1,5]pyrazolo[3,4-c]pyridin-2(3H)-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxirane-7-carbonitrile and

[0396] ((S)-5-methyl-4-oxo-3-((S)-1-oxo-7-phenyl-4,5,6,7-tetrahydro-1H-pyrrolo[1′,2′:1,5]pyrazolo[3,4-c]pyridin-2(3H)-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxirane-7-carbonitrile

[0397] Step 1: Zinc cyanide (9.1 mg, 0.08 mmol) was added to a solution of 1'-12 (30 mg, 0.06 mmol) in tetrahydrofuran (5.0 mL) and water (2.0 mL). The air was replaced with argon three times. Methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium (II) (5 mg, 0.006 mmol) was added. The air was replaced with argon three times under vacuum. The reaction was carried out at 70°C for 18 hours. The reaction solution was slowly poured into ice water (10 mL), extracted with ethyl acetate (3×10 mL), and the insoluble matter was removed by filtration. The organic phases were combined, washed with saturated brine (2×50 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by Prep-HPLC to give 3 (18 mg, yield: 67.1%) as a light yellow solid.

[0398] LCMS: m / z 454.2 [M+H]+ .

[0399] Step 2: 3 (18 mg) was purified by SFC to give 3' (peak 1, 5 mg, yield: 27.8%) and 3" (peak 2, 8 mg, yield: 44.4%).

[0400] 3'(peak 1):

[0401] LCMS: m / z 454.2 [M+H] + ;

[0402] 1 H NMR (400MHz, MeOD-d4) δppm: 7.85 (d, J=2.4Hz, 1H), 7.64~7.62 (m, 1H), 7.37~7 .27(m, 4H), 7.10~7.08(m, 2H), 5.71-5.66(m, 1H), 5.47~5.43(m, 1H), 4.89~4.8 4(m, 1H), 4.51~4.47(m, 1H), 4.15~4.10(m, 1H), 3.66~3.61(m, 1H), 3.35(s, 3H ), 3.14~3.11(m, 1H), 3.04~2.93(m, 3H), 2.82~2.81(m, 1H), 2.55~2.49(m, 1H).

[0403] de%=100%.

[0404] 3”(peak2):

[0405] LCMS: m / z 454.2 [M+H] + ;

[0406] 1 H NMR (400MHz, MeOD-d4) δppm: 7.85 (d, J=2.4Hz, 1H), 7.65~7.62 (m, 1H), 7.37~7 .27(m, 4H), 7.08~7.06(m,2H), 5.71~5.66(m, 1H), 5.49~5.46(m, 1H), 4.99~4.9 4(m, 1H), 4.51~4.47(m, 1H), 4.15~4.10(m, 1H), 3.68~3.63(m, 1H), 3.35(s, 3H ), 3.17~3.12(m, 1H), 3.04~2.94(m, 3H), 2.85~2.82(m, 1H), 2.55~2.51(m, 1H).

[0407] de%=100%.

[0408] Example 5: Synthesis of Compounds 4' and 4"

[0409] (S)-7-chloro-5-methyl-3-((R)-1-oxo-7-phenyl-4,5,6,7-tetrahydro-1H-pyrrolo[1′,2′:1,5]pyrazolo[3,4-c]pyridin-2(3H)-yl)-2,3-dihydrobenzo[b][1,4]oxepin-4(5H)-one and

[0410] ((S)-5-methyl-4-oxo-3-((S)-1-oxo-7-phenyl-4,5,6,7-tetrahydro-1H-pyrrolo[1′,2′:1,5]pyrazolo[3,4-c]pyridin-2(3H)-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxirane-7-carbonitrile

[0411] Step 1: Under nitrogen at 0°C, add dropwise a solution of Boc-L-serine (11.7 g, 56.97 mmol) in DMF (30 mL) to a solution of sodium hydride (60% dispersion in oil, 2.9 g, 72.5 mmol) in DMF (70 mL). Stir and react at 0°C for 1.5 hours. Add dropwise a solution of 4-SM-1 (10.0 g, 56.97 mmol) in DMF (20 mL). Allow to react at room temperature for 4 hours. Pour the reaction solution into water (600 mL) and adjust the pH to 6 with 1M hydrochloric acid. Extract with ethyl acetate (3 x 150 mL). The organic phases are combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product is separated by column chromatography (dichloromethane:methanol = 10:1) to afford 4-1 (5.2 g, 25.2% yield) as a gray solid. LCMS: m / z 302.1 [M-56+H]. + .

[0412] Step 2: To a solution of 4-1 (5.8 g, 16.1 mmol) in ethanol (30 mL) and water (6 mL) at 0°C, add ammonium chloride (8.6 g, 160.7 mmol). Add zinc powder (5.3 g, 80.4 mmol) under nitrogen. Warm to 25°C and react overnight. Filter the reaction mixture, and extract the filtrate with ethyl acetate (2×200 mL). The organic phases are combined, washed with water, brine, dried, and concentrated to give 4-2 (4.8 g, yield: 90.3%). The crude product is directly used in the next step. LCMS: m / z 275.0 [M-56+H] + .

[0413] Step 3: Under nitrogen, N-methylimidazole (2.5 g, 30.5 mmol) and N,N,N′,N′-tetramethylchloroformamidine hexafluorophosphate (4.5 g, 16.0 mmol) were added to a solution of 4-2 (4.8 g, 14.5 mmol) in acetonitrile (20 mL). The mixture was allowed to react at room temperature for 30 minutes. The reaction solution was poured into water and extracted with ethyl acetate (2×200 mL). The organic phases were combined, washed with water and brine, and concentrated. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain 4-3 (2.3 g, yield: 50.7%). LCMS: m / z 257.0 [M-56+H] + .

[0414] Step 4: To a solution of 4-3 (2.3 g, 7.35 mmol) in dry N,N-dimethylformamide (10 mL) at 0°C, iodomethane (5.2 g, 36.77 mmol) and potassium carbonate (4.1 g, 29.42 mmol) were added. The reaction was allowed to react overnight at room temperature. The reaction solution was poured into water, filtered, and the filter cake was purified by column chromatography (dichloromethane / methanol = 20 / 1) to obtain 4-4 (1.4 g, yield: 58.3%). LCMS: m / z 271.1 [M-56+H] + .

[0415] Step 5: To a solution of 4-4 (1.4 g, 4.28 mmol) in dry dichloromethane (10 mL) was added trifluoroacetic acid (3 mL) at 0°C. The mixture was reacted at room temperature for 2 hours. The mixture was cooled to 0°C and slowly poured into a saturated aqueous sodium bicarbonate solution. The mixture was extracted with dichloromethane (2 x 50 mL). The organic phases were combined, washed with water and brine, dried, and concentrated to afford 4-5 (800 mg, yield: 82.4%). LCMS: m / z 227.3 [M+H] + .

[0416] Step 6: To a solution of 4-5 (410 mg, 1.81 mmol) and ethyl 3-(2-oxoethyl)-6-phenyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylate (270 mg, 0.91 mmol) in methanol (10 mL) were added acetic acid (543 mg, 9.05 mmol) and anhydrous magnesium sulfate (545 mg, 4.53 mmol). The mixture was reacted at room temperature for 30 min. Sodium cyanoborohydride (114 mg, 1.81 mmol) was added. The mixture was reacted at room temperature overnight. Dichloromethane / methanol (V / V=10 / 1, 10 mL) was added, filtered, and the filtrate was concentrated. The residue was purified by C18 to give 4-6 (120 mg, yield: 13.0%). LCMS: m / z 509.3 [M+H] + .

[0417] Step 7: To a solution of 4-6 (100 mg, 0.20 mmol) in methanol (10 mL) and water (4 mL) was added lithium hydroxide (47 mg, 2.0 mmol). The reaction was allowed to react at 45°C for 3 hours. The reaction solution was poured into water and the pH was adjusted to 4 with 1M hydrochloric acid. The mixture was extracted with dichloromethane (2 x 50 mL). The organic phases were combined, washed with water and brine, dried, and concentrated to afford 4-7 (85 mg, yield: 90.0%). LCMS: m / z 481.5 [M+H] + .

[0418] Step 8: Under nitrogen, N-methylimidazole (31 mg, 0.37 mmol) and N,N,N′,N′-tetramethylchloroformamidine hexafluorophosphate (55 mg, 0.19 mmol) were added to a solution of 4-7 (85 mg, 0.18 mmol) in acetonitrile (8 mL). The mixture was allowed to react at room temperature for 30 minutes. The reaction solution was poured into water and extracted with ethyl acetate (2×50 mL). The organic phases were combined, washed with water and brine, and concentrated. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain 4 (82 mg, yield: 95%). LCMS: m / z 463.1 [M+H] + .

[0419] Step nine: 4 (82 mg, 0.18 mmol) was purified by SFC to give two white solids 4′ (peak 1, 26.16 mg, yield: 31.9%) and 4″ (peak 2, 19.53 mg, yield: 23.8%).

[0420] 4′(1):

[0421] 1 H NMR (400MHz, CDCl3) δppm: 7.31~7.26 (m, 3H), 7.21 (d, J=2.0Hz, 1H), 7.18~7.15 (m, 1H), 7.1 0~7.08 (m, 1H), 7.00 (d, J=6.8Hz, 2H), 5.97 (dd, J=11.2, 8.0Hz, 1H), 5.45~5.43 (m, 1H), 4.65 ~4.60 (m, 1H), 4.41 (t, J = 8.8Hz, 1H), 4.26 ~ 4.21 (m, 1H), 3.60 ~ 3.55 (m, 1H), 3.36 (s, 3H), 3.1 4~3.07(m,2H), 3.00~2.92(m,1H), 2.89~2.83(m,1H), 2.73~2.69(m,1H), 2.55~2.50(m,1H).

[0422] de%=100%.

[0423] 4″(peak2):

[0424] 1 H NMR (400MHz, CDCl3) δppm: 7.29~7.26(m, 3H), 7.21~7.15(m, 2H), 7.09~7.07(m, 1H ), 7.04 (d, J=6.0Hz, 2H), 5.96 (dd, J=10.8, 8.0Hz, 1H), 5.45~5.43 (m, 1H), 4.65~4 .60(m, 1H), 4.39(t, J=8.4Hz, 1H), 4.24~4.21(m, 1H), 3.60~3.55(m, 1H), 3.36(s, 3H), 3.14~3.09(m, 2H), 2.97~2.89(m, 2H), 2.74~2.70(m, 1H), 2.56~2.51(m, 1H).

[0425] de%=100%.

[0426] Reference compound AA: Reference compound AA was synthesized according to the method of patent (WO2014125444, Example 45).

[0427] Test Example 1: Binding Assay Based on Fluorescence Polarization

[0428] Mouse fibroblast L929 cells were cultured in DMEM supplemented with 10% fetal bovine serum, 100 units / mL penicillin, and 100 μg / mL streptomycin. Human histiocytic lymphoma U937 cells and human T-lymphocytic leukemia FADD- / - Jurkat cells were cultured in RMPI1640 medium supplemented with 10% fetal bovine serum, 100 units / mL penicillin, and 100 μg / mL streptomycin.

[0429] Cells in the logarithmic growth phase were harvested, digested, centrifuged, and resuspended in fresh cell culture medium to obtain a cell suspension. Count the cells and seed 45 μL of culture medium per well into a 384-well plate, with each well containing 5,000 L929 cells, 10,000 U937 cells, or 10,000 FADD- / - Jurkat cells. The cells were then cultured in a 37°C, 5% CO2 incubator for 24 hours.

[0430] Dissolve the test compound in 100% DMSO to obtain a 20 mM stock solution. Serially dilute the test compound in 100% DMSO at a 1:3 ratio starting at 10 mM in a 384-well plate, for a total of 12 concentrations. Add 100 nl of the diluted compound to the 384-well plate seeded with cells.

[0431] A 10X TNFα / SM1164 or 10X TNFα / Z-VAD solution was prepared in culture medium, and 5 μl of drug-containing medium was added to each well, resulting in a final concentration of 10 ng / ml TNFα and 40 nM SM-164 in L929 cells; 40 ng / ml TNFα and 25 nM SM-164 in FADD- / - Jurkat cells; and 100 ng / ml TNFα and 25 μM Z-VAD in U937 cells. The cells were incubated in a 37°C, 5% CO2 incubator for 24 hours. 15 μl CTG was added to each well, and the cells were incubated at room temperature for 10 minutes in the dark. Fluorescence signals were detected using a PerkinElmer EnVision plate reader, and the half-maximal inhibitory activity (IC50) values ​​for each test compound were fitted using GraphPad Prism, a professional graphics and analysis software. The results are shown in Table 1.

[0432] Table 1: TNFα-induced L929 and U937 cell proliferation inhibitory activity

[0433] The experimental results showed that this series of compounds had good proliferation inhibitory activity on L929 and U937 cells.

[0434] Test Example 2: Enzyme activity test

[0435] The Promega ADP-GLO kinase assay was used to detect the inhibitory effect of the compounds on Ripk1 enzyme activity.

[0436] Dissolve the test compound in 100% DMSO to obtain a 20mM stock solution. Further dilute the compound with DMSO to 100 times the test concentration. Add 100nL of the diluted test compound to the 384-well plate. Then, add the diluted human Ripk1, substrate MBP and ATP to the 348-well plate to which the test compound has been added, in sequence, to the reaction wells to a final concentration of 1.25ng / μL, 0.125ng / ml and 12.5μM, respectively. The 348-well plate containing the test compound is incubated at room temperature for 3 hours. After incubation, 10μL of Promega ADP-GLO reagent is added to stop the reaction and remove the remaining ATP. The mixture after the reaction is stopped is incubated at room temperature for 10 minutes. Then, 20μL of Promega ADP-GLO kinase assay reagent is added to convert the ADP produced by the kinase reaction into ATP. After reacting at room temperature for 30-60 minutes, the fluorescence signal was detected using a PerkinElmer EnVision plate reader, and the half-maximal inhibitory activity (IC50) of each test compound was fitted using the professional graph analysis software GraphPad Prism. The results are shown in Table 2.

[0437] Table 2: ADP GLO enzyme activity

[0438] Experimental results show that this series of compounds has a good inhibitory effect on Ripk1 activity.

Claims

1. A compound of formula A, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph, prodrug or metabolite thereof, has the structure shown by the following formula: In the formula: Ring A is selected from: substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted 3- to 8-membered heterocyclic group, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, said heterocyclic group or heteroaryl containing 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P; L is selected from: C 1-10 an alkylene group, or a chemical bond; When L is or C 1-10 When the alkylene group is present, ring B is selected from: substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted 3- to 8-membered heterocyclic group, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, wherein the heterocyclic group or heteroaryl contains 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P; ring C and ring D are each independently selected from: substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted 3- to 8-membered heterocyclic group, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 5- to 10-membered heteroaryl or absent, wherein the heterocyclic group or heteroaryl contains 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P; When L is a chemical bond, ring E is directly connected to ring B through this chemical bond, and ring B, ring C and ring D are each independently selected from: substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and the heterocyclic group or heteroaryl contains 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P; R1 is selected from H, halogen, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 1-6 alkoxy, cyano, -NO2, -OH, substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted 3- to 8-membered heterocyclic group, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, substituted or unsubstituted 3- to 8-membered heterocyclic group spiro 3- to 8-membered heterocyclic group, substituted or unsubstituted 3- to 8-membered heterocyclic group fused to 3- to 8-membered heterocyclic group, substituted or unsubstituted C 3-8 cycloalkyl spiro C 3-8 cycloalkyl, substituted or unsubstituted C 3-8 cycloalkyl fused to C 3-8 cycloalkyl, substituted or unsubstituted 3- to 8-membered heterocyclic group fused to C 6-10 aryl, substituted or unsubstituted 3- to 8-membered heterocyclic group fused to 5- to 10-membered heteroaryl, substituted or unsubstituted C 3-8 cycloalkyl fused to C 6-10 aryl, substituted or unsubstituted C 3-8 cycloalkyl fused to 5- to 10-membered heteroaryl, wherein the heterocyclic group or heteroaryl contains 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P; R2 is selected from H, oxo (=O), substituted or unsubstituted C 1-6 alkoxy, halogen, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 1-6 alkyl, cyano, -NO2, -OH, substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic group, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 5-10 membered heteroaryl, said heterocyclic group or heteroaryl containing 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P; R3 is selected from H, oxo, substituted or unsubstituted C 1-6 alkoxy, halogen, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 1-6 alkyl, cyano, -NO2, -OH, substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic group, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 5-10 membered heteroaryl, said heterocyclic group or heteroaryl containing 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P; R4 is selected from H, oxo, substituted or unsubstituted C 1-6 alkoxy, halogen, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 1-6 alkyl, cyano, -NO2, -OH, substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic group, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 5-10 membered heteroaryl, said heterocyclic group or heteroaryl containing 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P; R5 is selected from H, halogen, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 1-6 alkoxy, cyano, -NO2, -OH, substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted 3- to 8-membered heterocyclic group, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, wherein the heterocyclic group or heteroaryl contains 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P; R6 is selected from H, halogen, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 1-6 alkoxy, cyano, -NO2, -OH, substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted 3- to 8-membered heterocyclic group, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, wherein the heterocyclic group or heteroaryl contains 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P; n, m, q, and t are each independently any integer among 0, 1, 2, and 3; The substitution means that one or more hydrogen atoms on the group are substituted by substituents selected from the following group: halogen, -OH, -NO2, -NH2, -NH(unsubstituted or halogenated C 1-6 alkyl), -N(unsubstituted or halogenated C 1-6 alkyl)2, -CN, C 1-8 alkyl which is unsubstituted or substituted by halogen or hydroxyl, C 1-8 alkoxy which is unsubstituted or halogenated, C 1-8 alkoxy-C1-8 alkyl, C 3-8 cycloalkyl-C 1-8 alkyl, C 1-6 alkylcarbonyl which is unsubstituted or halogenated, C 1-6 alkoxycarbonyl, hydroxamic acid group, C 1-6 alkylthio which is unsubstituted or halogenated, -S(O)2N(unsubstituted or halogenated C 1-6 alkyl)2, -S(O)2 unsubstituted or halogenated C 1-6 alkyl, -N(unsubstituted or halogenated C 1-6 alkyl)S(O)2N(unsubstituted or halogenated C 1-6 alkyl)2, -S(O)N(unsubstituted or halogenated C 1-6 alkyl)2, -S(O)(unsubstituted or halogenated C 1-6 alkyl), -N(unsubstituted or halogenated C 1-6 alkyl)S(O)N(unsubstituted or halogenated C 1-6 alkyl)2, -N(unsubstituted or halogenated C 1-6 alkyl)S(O)(unsubstituted or halogenated C 1-6 alkyl), C 5-10 aryl, 5-10 membered heteroaryl which is unsubstituted or halogenated, C 3-8 cycloalkyl and 3-8 membered heterocyclic group which is unsubstituted or halogenated, and the heterocyclic group and heteroaryl contain 1, 2, 3 or 4 heteroatoms selected from the following group: N, O or S; represents being connected to other parts of the molecule here through a chemical bond.

2. The compound shown by formula A according to claim 1, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph, prodrug, or metabolite thereof, characterized in that Ring A is a substituted or unsubstituted C 6-14 aryl or a substituted or unsubstituted 5- to 14-membered heteroaryl; Ring A is a substituted or unsubstituted C 6-10 aryl or a substituted or unsubstituted 5- to 10-membered heteroaryl; Preferably, Ring A is pyridyl or phenyl; Ring B is a substituted or unsubstituted 5- to 14-membered heterocyclic group or a substituted or unsubstituted 5- to 14-membered heteroaryl group; Ring B is a substituted or unsubstituted 5- to 10-membered heterocyclic group or a substituted or unsubstituted 5- to 10-membered heteroaryl group; Preferably, Ring B is a piperidinyl group, a pyrazolyl group, or a pyridinyl group; Ring C is a substituted or unsubstituted 5- to 14-membered heterocyclic group or a substituted or unsubstituted 5- to 14-membered heteroaryl group; Ring C is a substituted or unsubstituted 5- to 10-membered heterocyclic group or a substituted or unsubstituted 5- to 10-membered heteroaryl group; Preferably, Ring C is a pyrazolyl group or a pyrrolidinyl group; Ring D is a substituted or unsubstituted 5- to 14-membered heterocyclic group; Preferably, Ring D is selected from a pyrrolidinyl group, an imidazolidinyl group, a tetrahydrofuranyl group, a tetrahydrothienyl group, a dihydroimidazolyl group, a dihydrofuranyl group, a dihydropyrazolyl group, a dihydropyrrolyl group, a piperidinyl group, a piperazinyl group, a morpholinyl group, a thiomorpholinyl group, a homopiperazinyl group, a pyranyl group, or an oxazepanyl group; Preferably, Ring D is a pyrrolidinyl group or a 1,3-oxazepanyl group; R1 is selected from H, halogen, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 1-6 alkoxy, cyano, substituted or unsubstituted 3- to 8-membered heterocyclic spiro 3- to 8-membered heterocyclic group, said heterocyclic group containing 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S; preferably, R1 is selected from H, halogen, substituted or unsubstituted C 2-5 alkynyl, substituted or unsubstituted C 1-3 alkoxy, cyano, substituted or unsubstituted 5- to 6-membered heterocyclic spiro 4- to 6-membered heterocyclic group, said C 2-5 alkynyl, C 1-3 alkoxy, and 5- to 6-membered heterocyclic spiro 4- to 6-membered heterocyclic group are substituted by substituents selected from C 1-6 alkyl, 3- to 5-membered cycloalkyl, 4- to 6-membered heterocyclic group, hydroxy C 2-5 alkyl; preferably, said C 2-5 alkynyl, C 1-3 alkoxy, and 5- to 6-membered heterocyclic spiro 4- to 6-membered heterocyclic group are substituted by substituents selected from cyclopropyl, pyranyl, hydroxyisopropyl; preferably, R1 is selected from the group consisting of H, Methoxy, cyano, chlorine, and bromine; R2 is selected from H, oxo (=O), substituted or unsubstituted C 1-6 alkoxy, halogen, substituted or unsubstituted C 1-6 alkyl, cyano, -NO2, -OH, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 5- to 14-membered heteroaryl, said heteroaryl containing 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P, the C 1-6 alkoxy and C 1-6 alkyl are each independently substituted by oxo (=O), C 6-10 aryl, -OH, cyano or -NO2; preferably, R2 is selected from H, oxo (=O), optionally C 6-10 aryl-substituted C 1-6 alkoxy, halogen, substituted or unsubstituted 5- to 10-membered heteroaryl; preferably, R2 is H, oxo, C 6-10 aryl-substituted C 1-4 alkoxy, benzopyrazolyl; R3 is selected from: H, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted C 1-6 alkoxy, halogen, cyano, -NO2, -OH, wherein the C 1-6 alkoxy is substituted by oxo (=O), -OH, cyano or -NO2; preferably, R3 is H or C 6- 10 aryl; R4 is selected from H, substituted or unsubstituted C 1-6 alkoxy, halogen, substituted or unsubstituted C 1-6 alkyl, cyano, -NO2, -OH, substituted or unsubstituted 3-8 membered heterocyclic group, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 5-10 membered heteroaryl, the heterocyclic group or heteroaryl containing 1, 2 or 3 heteroatoms selected from the group consisting of N, O and S, the C 1-6 alkoxy, C 1-6 alkyl, 3-8 membered heterocyclic group, C 6-10 aryl, 5-10 membered heteroaryl are each independently substituted by 1, 2 or 3 substituents selected from H, halogen, -OH, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-8 alkoxy; preferably, R4 is selected from halogen, difluoropropyl, phenyl, benzyl, difluorophenyl, tolyl, methoxyphenyl and pyridyl; preferably, R4 is selected from: and halogen; Preferably, R4 is selected from: and F; t is 1 or 2; R5 is selected from H, substituted or unsubstituted C 1-6 alkoxy, halogen, substituted or unsubstituted C 1-6 alkyl; preferably, R5 is selected from unsubstituted C 1-6 alkyl; preferably, R5 is methyl; R6 is selected from H, substituted or unsubstituted C 1-6 alkoxy, halogen, substituted or unsubstituted C 1-6 alkyl; preferably, R6 is H.

3. The compound of formula A as claimed in claim 1, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph, prodrug or metabolite thereof, which has the structure shown in formula I below: In formula I: Ring A, Ring B, Ring C and Ring D are each independently selected from: substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted 3- to 8-membered heterocyclic group, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, said heterocyclic group or heteroaryl containing 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P; R1 is selected from: H, halogen, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 1-6 alkoxy, cyano, -NO2, -OH, substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted 3- to 8-membered heterocyclic group, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, substituted or unsubstituted 3- to 8-membered heterocyclic group spiro 3- to 8-membered heterocyclic group, substituted or unsubstituted 3- to 8-membered heterocyclic group fused to 3- to 8-membered heterocyclic group, substituted or unsubstituted C 3-8 cycloalkyl spiro C 3-8 cycloalkyl, substituted or unsubstituted C 3-8 cycloalkyl fused to C 3-8 cycloalkyl, substituted or unsubstituted 3- to 8-membered heterocyclic group fused to C 6-10 aryl, substituted or unsubstituted 3- to 8-membered heterocyclic group fused to 5- to 10-membered heteroaryl, substituted or unsubstituted C 3-8 cycloalkyl fused to C 6-10 aryl, substituted or unsubstituted C 3-8 cycloalkyl fused to 5- to 10-membered heteroaryl, wherein the heterocyclic group or heteroaryl contains 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P; R2, R3, R4, R5 and R6 are each independently selected from: H, oxo(=O), substituted or unsubstituted C 1-6 alkoxy, halogen, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 1-6 alkyl, cyano, -NO2, -OH, substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic group, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 5-10 membered heteroaryl, said heterocyclic group or heteroaryl containing 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P; n, m, q, and t are each independently any integer among 0, 1, 2, and 3; The substitution means that one or more hydrogen atoms on the group are substituted by substituents selected from the following group: halogen, -OH, -NO2, -NH2, -NH(unsubstituted or halogenated C 1-6 alkyl), -N(unsubstituted or halogenated C 1-6 alkyl)2, -CN, C 1-8 alkyl which is unsubstituted or substituted by halogen or hydroxyl, unsubstituted or halogenated C 1-8 alkoxy, unsubstituted or halogenated C 1-8 alkoxy-C 1- 8alkyl, unsubstituted or halogenated C 3-8 cycloalkyl-C 1-8 alkyl, unsubstituted or halogenated C 1-6 alkylcarbonyl, unsubstituted or halogenated C 1-6 alkoxycarbonyl, hydroxamic acid group, unsubstituted or halogenated C 1-6 alkylthio, -S(O)2N(unsubstituted or halogenated C 1-6 alkyl)2, -S(O)2unsubstituted or halogenated C 1-6 alkyl, -N(unsubstituted or halogenated C 1-6 alkyl)S(O)2N(unsubstituted or halogenated C 1-6 alkyl)2, -S(O)N(unsubstituted or halogenated C 1-6 alkyl)2, -S(O)(unsubstituted or halogenated C 1-6 alkyl), -N(unsubstituted or halogenated C 1-6 alkyl)S(O)N(unsubstituted or halogenated C 1-6 alkyl)2, -N(unsubstituted or halogenated C 1-6 alkyl)S(O)(unsubstituted or halogenated C 1-6 alkyl), unsubstituted or halogenated C 5-10 aryl, unsubstituted or halogenated 5-10-membered heteroaryl, unsubstituted or halogenated C 3-8 cycloalkyl and unsubstituted or halogenated 3-8-membered heterocyclic group, and the heterocyclic group and heteroaryl contain 1, 2, 3 or 4 heteroatoms selected from the following group: N, O and S.

4. The compound of formula A according to claim 3, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph, prodrug or metabolite thereof, characterized in that, In formula I: Ring A is a substituted or unsubstituted C 6-14 aryl or a substituted or unsubstituted 5- to 14-membered heteroaryl; Ring A is a substituted or unsubstituted C 6-10 aryl or a substituted or unsubstituted 5- to 10-membered heteroaryl; Preferably, Ring A is pyridyl or phenyl; Ring B is a substituted or unsubstituted 5- to 14-membered heterocyclic group; Ring B is a substituted or unsubstituted 5- to 10-membered heterocyclic group; Preferably, Ring B is a piperidinyl group; Ring C is a substituted or unsubstituted 5- to 14-membered heteroaryl group; Ring C is a substituted or unsubstituted 5- to 10-membered heteroaryl group; Preferably, Ring C is a pyrazolyl group; Ring D is a substituted or unsubstituted 5- to 14-membered heterocyclic group; Preferably, Ring D is selected from a pyrrolidinyl group, an imidazolidinyl group, a tetrahydrofuranyl group, a tetrahydrothienyl group, a dihydroimidazolyl group, a dihydrofuranyl group, a dihydropyrazolyl group, a dihydropyrrolyl group, a piperidinyl group, a piperazinyl group, a morpholinyl group, a thiomorpholinyl group, a homopiperazinyl group, a pyranyl group, or an oxazepanyl group; Preferably, Ring D is a pyrrolidinyl group or a 1,3-oxazepanyl group; R1 is selected from H, halogen, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 1-6 alkoxy, cyano, substituted or unsubstituted 3- to 8-membered heterocyclic spiro 3- to 8-membered heterocyclic group, the heterocyclic group containing 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S; preferably, R1 is selected from H, halogen, substituted or unsubstituted C 2-5 alkynyl, substituted or unsubstituted C 1-3 alkoxy, cyano, substituted or unsubstituted 5- to 6-membered heterocyclic spiro 4- to 6-membered heterocyclic group, the C 2-5 alkynyl, C 1-3 alkoxy, and 5- to 6-membered heterocyclic spiro 4- to 6-membered heterocyclic group are substituted by substituents selected from C 1-6 alkyl, 3- to 5-membered cycloalkyl, 4- to 6-membered heterocyclic group, hydroxy C 2-5 alkyl; preferably, the C 2-5 alkynyl, C 1-3 alkoxy, and 5- to 6-membered heterocyclic spiro 4- to 6-membered heterocyclic group are substituted by substituents selected from cyclopropyl, pyranyl, hydroxyisopropyl; preferably, R1 is selected from the group consisting of H, Methoxy, cyano, chlorine, and bromine; R2 is selected from H, oxo (=O), substituted or unsubstituted C 1-6 alkoxy, halogen, substituted or unsubstituted C 1-6 alkyl, cyano, -NO2, -OH, wherein said C 1-6 alkoxy and C 1-6 alkyl are each independently substituted by oxo (=O), -OH, cyano or -NO2; preferably, R2 is oxo; R3 is selected from: H, substituted or unsubstituted C 1-6 alkoxy, halogen, cyano, -NO2, -OH, wherein the C 1-6 alkoxy is substituted by oxo(=O), -OH, cyano or -NO2; preferably, R3 is H; R4 is selected from H, substituted or unsubstituted C 1-6 alkoxy, halogen, substituted or unsubstituted C 1-6 alkyl, cyano, -NO2, -OH, substituted or unsubstituted 3-8 membered heterocyclic group, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 5-10 membered heteroaryl, said heterocyclic group or heteroaryl containing 1, 2 or 3 heteroatoms selected from the group consisting of N, O and S, said C 1-6 alkoxy, C 1-6 alkyl, 3-8 membered heterocyclic group, C 6-10 aryl, 5-10 membered heteroaryl are each independently substituted by 1, 2 or 3 substituents selected from H, halogen, -OH, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-8 alkoxy; preferably, R4 is selected from halogen, difluoropropyl, phenyl, benzyl, difluorophenyl, tolyl, methoxyphenyl and pyridyl; preferably, R4 is selected from: and halogen; Preferably, R4 is selected from: and F; R5 is selected from H, substituted or unsubstituted C 1-6 alkoxy, halogen, substituted or unsubstituted C 1-6 alkyl; preferably, R5 is selected from unsubstituted C 1-6 alkyl; preferably, R5 is methyl; R6 is selected from H, substituted or unsubstituted C 1-6 alkoxy, halogen, substituted or unsubstituted C 1-6 alkyl; preferably, R6 is H; n, m, q, and t are each independently any integer among 0, 1, or 2; Preferably, n, m, q, and t are each independently any integer among 0 or 1.

5. The compound of formula A according to claim 3, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph, prodrug or metabolite thereof, having the structure shown in formula I-1 below: In formula I-1: A1, A2, A3, and A4 are each independently selected from: CR1 or N; Preferably, A1 and A2 are each independently selected from: CR1 or N; A3 and A4 are C; B1, B2, B3, and B4 are each independently selected from: C(R2) m or N(R2) m ; preferably, B1 is N(R2) m ; preferably, B2 is C(R2) m ; preferably, B3 is C(R2) m ; preferably, B4 is C(R2) m ; C1, C2, and C3 are each independently selected from: C(R3) q or N(R3) q ; preferably, C1 is N(R3) q ; preferably, C2 is N(R3) q ; preferably, C3 is C(R3) q .

6. The compound of formula A according to claim 3 or 5, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph, prodrug or metabolite thereof, characterized in that, The structure formed by Ring B, Ring C and Ring D is selected from the following group: Preferably, the structure formed by Ring B, Ring C and Ring D is selected from the following group: Preferably, the structure formed by Ring B, Ring C and Ring D is selected from the following group: Preferably, the structure formed by Ring B, Ring C and Ring D is selected from the following group:

7. The compound of formula A according to claim 1, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph, prodrug or metabolite thereof, which has the structure shown in formula II below: In formula II: Ring A, Ring B and Ring C are each independently selected from: substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted 3- to 8-membered heterocyclic group, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, said heterocyclic group or heteroaryl containing 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P; L is selected from: and C 1-10 alkylene; R1 is selected from: H, halogen, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 1-6 alkoxy, cyano, -NO2, -OH, substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic group, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted 3-8 membered heterocyclic group spiro 3-8 membered heterocyclic group, substituted or unsubstituted 3-8 membered heterocyclic group fused to 3-8 membered heterocyclic group, substituted or unsubstituted C 3-8 cycloalkyl spiro C 3-8 cycloalkyl, substituted or unsubstituted C 3-8 cycloalkyl fused to C 3-8 cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic group fused to C 6-10 aryl, substituted or unsubstituted 3-8 membered heterocyclic group fused to 5-10 membered heteroaryl, substituted or unsubstituted C 3-8 cycloalkyl fused to C 6-10 aryl, substituted or unsubstituted C 3-8 cycloalkyl fused to 5-10 membered heteroaryl, wherein the heterocyclic group or heteroaryl contains 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P; R2, R3, R5 and R6 are each independently selected from: H, oxo (=O), substituted or unsubstituted C 1-6 alkoxy, halogen, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 1-6 alkyl, cyano, -NO2, -OH, substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic group, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 5-10 membered heteroaryl, said heterocyclic group or heteroaryl containing 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P; n, m, and q are each independently any integer among 0, 1, 2, and 3; The substitution means that one or more hydrogen atoms on the group are substituted by substituents selected from the following group: halogen, -OH, -NO2, -NH2, -NH(unsubstituted or halogenated C 1-6 alkyl), -N(unsubstituted or halogenated C 1-6 alkyl)2, -CN, C 1-8 alkyl which is unsubstituted or substituted by halogen or hydroxyl, unsubstituted or halogenated C 1-8 alkoxy, unsubstituted or halogenated C 1-8 alkoxy-C 1- 8alkyl, unsubstituted or halogenated C 3-8 cycloalkyl-C 1-8 alkyl, unsubstituted or halogenated C 1-6 alkylcarbonyl, unsubstituted or halogenated C 1-6 alkoxycarbonyl, hydroxamic acid group, unsubstituted or halogenated C 1-6 alkylthio, -S(O)2N(unsubstituted or halogenated C 1-6 alkyl)2, -S(O)2 unsubstituted or halogenated C 1-6 alkyl, -N(unsubstituted or halogenated C 1-6 alkyl)S(O)2N(unsubstituted or halogenated C 1-6 alkyl)2, -S(O)N(unsubstituted or halogenated C 1-6 alkyl)2, -S(O)(unsubstituted or halogenated C 1-6 alkyl), -N(unsubstituted or halogenated C 1-6 alkyl)S(O)N(unsubstituted or halogenated C 1-6 alkyl)2, -N(unsubstituted or halogenated C 1-6 alkyl)S(O)(unsubstituted or halogenated C 1-6 alkyl), unsubstituted or halogenated C 5-10 aryl, unsubstituted or halogenated 5-10-membered heteroaryl, unsubstituted or halogenated C 3-8 cycloalkyl, unsubstituted or halogenated 3-8-membered heterocyclic group, and the heterocyclic group and heteroaryl contain 1, 2, 3 or 4 heteroatoms selected from the following group: N, O or S.

8. The compound of formula A according to claim 7, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph, prodrug or metabolite thereof, characterized in that, In formula II: Ring A is selected from: substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, said heteroaryl containing 1, 2 or 3 heteroatoms selected from the group consisting of N, O and S; preferably, Ring A is phenyl; Ring B is selected from: substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, said heteroaryl containing 1 or 2 heteroatoms selected from the group consisting of N, O and S; preferably, ring B is a substituted or unsubstituted 5- to 10-membered heteroaryl; preferably, ring B is pyrazolyl; Ring C is selected from: substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted 3- to 8-membered heterocyclic group, said heterocyclic group containing 1, 2 or 3 heteroatoms selected from the group consisting of N, O and S; preferably, ring C is a substituted or unsubstituted 3- to 8-membered heterocyclic group; preferably, ring C is pyrrolidinyl; L is selected from: and C 1-10 an alkylene group; preferably, L is selected from: Preferably, L is R1 is selected from: H, halogen, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 1-6 alkyl, cyano, -NO2, -OH, substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic group, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 5-10 membered heteroaryl, said heterocyclic group or heteroaryl containing 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P; preferably, R1 is selected from: H, halogen, cyano, -NO2, -OH; preferably, R1 is selected from: H or halogen; R2 is selected from: H, substituted or unsubstituted C 1-6 alkoxy, halogen, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 1-6 alkyl, cyano, -NO2, -OH; preferably, R2 is selected from: H, halogen, cyano, -NO2, -OH; preferably, R2 is H; R3 is selected from: H, oxo (=O), substituted or unsubstituted C 1-6 alkoxy, halogen, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 1-6 alkyl, cyano, -NO2, -OH, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, said heteroaryl containing 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P; preferably, R3 is selected from: H, halogen, substituted or unsubstituted C 1-6 alkyl, cyano, -NO2, -OH, substituted or unsubstituted C 6-10 aryl; preferably, R3 is selected from: H or C 6-10 aryl; R5 is selected from H, substituted or unsubstituted C 1-6 alkoxy, halogen, substituted or unsubstituted C 1-6 alkyl; preferably, R5 is selected from unsubstituted C 1-6 alkyl; preferably, R5 is methyl; R6 is selected from H, substituted or unsubstituted C 1-6 alkoxy, halogen, substituted or unsubstituted C 1-6 alkyl; preferably, R6 is H; n, m, and q are each independently any integer among 0, 1, or 2; Preferably, n, m, and q are each independently any integer among 0 or 1.

9. The compound of formula A according to claim 7, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph, prodrug or metabolite thereof, which has the structure shown in formula II-1 below: In formula II-1: A1, A2, A3, and A4 are each independently selected from: CR1 or N; Preferably, A1, A2, A3, and A4 are all C; B1, B2, B3, and B4 are each independently selected from: C(R2) m or N(R2) m ; preferably, B1 is C(R2) m ; preferably, B2 is N(R2) m ; preferably, B3 is N(R2) m ; preferably, B4 is C(R2) m .

10. The compound of formula A according to claim 1, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph, prodrug or metabolite thereof, has the structure shown in formula III below: In formula III: Ring A and Ring B are each independently selected from: substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted 3- to 8-membered heterocyclic group, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, said heterocyclic group or heteroaryl containing 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P; L is selected from: and C 1-10 alkylene; R1 is selected from: H, halogen, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 1-6 alkoxy, cyano, -NO2, -OH, substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted 3-8-membered heterocyclic group, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 5-10-membered heteroaryl, substituted or unsubstituted 3-8-membered heterocyclic group spiro 3-8-membered heterocyclic group, substituted or unsubstituted 3-8-membered heterocyclic group fused to 3-8-membered heterocyclic group, substituted or unsubstituted C 3-8 cycloalkyl spiro C 3-8 cycloalkyl, substituted or unsubstituted C 3-8 cycloalkyl fused to C 3-8 cycloalkyl, substituted or unsubstituted 3-8-membered heterocyclic group fused to C 6-10 aryl, substituted or unsubstituted 3-8-membered heterocyclic group fused to 5-10-membered heteroaryl, substituted or unsubstituted C 3-8 cycloalkyl fused to C 6-10 aryl, substituted or unsubstituted C 3-8 cycloalkyl fused to 5-10-membered heteroaryl, wherein the heterocyclic group or heteroaryl contains 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P; R2, R5, and R6 are each independently selected from: H, oxo (=O), substituted or unsubstituted C 1-6 alkoxy, halogen, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 1-6 alkyl, cyano, -NO2, -OH, substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic group, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 5-10 membered heteroaryl, said heterocyclic group or heteroaryl containing 1, 2, or 3 heteroatoms selected from the group consisting of N, O, S, and P; n and m are each independently any integer of 0, 1, 2 or 3; The substitution means that one or more hydrogen atoms on the group are substituted by substituents selected from the following group: halogen, -OH, -NO2, -NH2, -NH(unsubstituted or halogenated C 1-6 alkyl), -N(unsubstituted or halogenated C 1-6 alkyl)2, -CN, C 1-8 alkyl which is unsubstituted or substituted by halogen or hydroxyl, unsubstituted or halogenated C 1-8 alkoxy, unsubstituted or halogenated C 1-8 alkoxy-C 1- 8alkyl, unsubstituted or halogenated C 3-8 cycloalkyl-C 1-8 alkyl, unsubstituted or halogenated C 1-6 alkylcarbonyl, unsubstituted or halogenated C 1-6 alkoxycarbonyl, hydroxamic acid group, unsubstituted or halogenated C 1-6 alkylthio, -S(O)2N(unsubstituted or halogenated C 1-6 alkyl)2, -S(O)2 unsubstituted or halogenated C 1-6 alkyl, -N(unsubstituted or halogenated C 1-6 alkyl)S(O)2N(unsubstituted or halogenated C 1-6 alkyl)2, -S(O)N(unsubstituted or halogenated C 1-6 alkyl)2, -S(O)(unsubstituted or halogenated C 1-6 alkyl), -N(unsubstituted or halogenated C 1-6 alkyl)S(O)N(unsubstituted or halogenated C 1-6 alkyl)2, -N(unsubstituted or halogenated C 1-6 alkyl)S(O)(unsubstituted or halogenated C 1-6 alkyl), unsubstituted or halogenated C 5-10 aryl, unsubstituted or halogenated 5-10 membered heteroaryl, unsubstituted or halogenated C 3-8 cycloalkyl, unsubstituted or halogenated 3-8 membered heterocyclic group, and the heterocyclic group and heteroaryl contain 1, 2, 3 or 4 heteroatoms selected from the following group: N, O or S.

11. The compound of formula A according to claim 10, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph, prodrug or metabolite thereof, characterized in that, In formula III: Ring A is selected from: substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, said heteroaryl containing 1, 2 or 3 heteroatoms selected from the group consisting of N, O and S; preferably, Ring A is phenyl; Ring B is selected from: substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, said heteroaryl containing 1 or 2 heteroatoms selected from the group consisting of N, O and S; preferably, Ring B is a substituted or unsubstituted 5- to 10-membered heteroaryl; preferably, Ring B is pyridyl; L is selected from: and C 1-10 an alkylene group; preferably, L is selected from: Preferably, L is selected from: R1 is selected from H, halogen, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 1-6 alkoxy, cyano, substituted or unsubstituted 3-8 membered heterocyclic spiro 3-8 membered heterocyclic group, said heterocyclic group containing 1, 2 or 3 heteroatoms selected from the group consisting of: N, O, S; preferably, R1 is selected from H, halogen, substituted or unsubstituted C 2-5 alkynyl, substituted or unsubstituted C 1-3 alkoxy, cyano, substituted or unsubstituted 5-6 membered heterocyclic spiro 4-6 membered heterocyclic group, said C 2-5 alkynyl, C 1-3 alkoxy, and 5-6 membered heterocyclic spiro 4-6 membered heterocyclic group are substituted by substituents selected from C 1-6 alkyl, 3-5 membered cycloalkyl, 4-6 membered heterocyclic group, hydroxy C 2-5 alkyl; preferably, said C 2-5 alkynyl, C 1-3 alkoxy, and 5-6 membered heterocyclic spiro 4-6 membered heterocyclic group are substituted by substituents selected from cyclopropyl, pyranyl, hydroxyisopropyl; preferably, R1 is selected from the group consisting of: H, methoxy, cyano, chloro and bromo; R2 is selected from H, oxo (=O), substituted or unsubstituted C 1-6 alkoxy, halogen, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 1-6 alkyl, cyano, -NO2, -OH, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 5- to 14-membered heteroaryl, said heteroaryl containing 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P; preferably, R2 is selected from H, oxo (=O), optionally substituted by C 6-10 aryl-substituted C 1-6 alkoxy, halogen, substituted or unsubstituted C 1-6 alkyl, cyano, -NO2, -OH, substituted or unsubstituted 5- to 10-membered heteroaryl; preferably, R2 is selected from H, optionally substituted by C 6-10 aryl-substituted C 1-6 alkoxy, halogen, 5- to 10-membered heteroaryl; R5 is selected from H, substituted or unsubstituted C 1-6 alkoxy, halogen, substituted or unsubstituted C 1-6 alkyl; preferably, R5 is selected from unsubstituted C 1-6 alkyl; preferably, R5 is methyl; R6 is selected from H, substituted or unsubstituted C 1-6 alkoxy, halogen, substituted or unsubstituted C 1-6 alkyl; preferably, R6 is H; n and m are each independently any integer of 0, 1 or 2; preferably, n and m are each independently any integer of 0 or 1.

12. The compound of formula A according to claim 10, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph, prodrug or metabolite thereof, characterized in that, Has the structure shown in Formula III-1 below: In the formula, A1, A2, A3 and A4 are each independently selected from CR1 or N; preferably, A1, A2, A3 and A4 are C.

13. The compound of formula A as claimed in claim 1, or a pharmaceutically acceptable salt thereof, or a solvate, isotope-substituted compound, polymorph, prodrug or metabolite thereof, selected from the following structures:

14. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises: (a) a compound of formula A as described in any one of claims 1-13 as an active ingredient, or a pharmaceutically acceptable salt thereof, or a solvate, isotope-substituted product, polymorph, prodrug or metabolite thereof, and (b) a pharmaceutically acceptable carrier or excipient.

15. The pharmaceutical composition according to claim 14, wherein The pharmaceutical composition further comprises (c) a second active ingredient, and the second active ingredient is a Ripk1 inhibitor.

16. Use of a compound of formula A as described in any one of claims 1-13, or a pharmaceutically acceptable salt thereof, or a solvate, isotope-substituted product, polymorph, prodrug or metabolite thereof in the preparation of a drug for treating or preventing Ripk1-related diseases.

17. The application according to claim 16, wherein The Ripk1-related diseases are selected from inflammatory diseases (such as Crohn's disease and ulcerative colitis, inflammatory bowel disease, asthma, graft-versus-host disease, chronic obstructive pulmonary disease), inflammatory skin diseases (such as psoriasis, eczema), autoimmune diseases (such as Graves' disease, rheumatoid arthritis, systemic lupus erythematosus, psoriasis; destructive bone diseases, such as bone resorption diseases, osteoarthritis, osteoporosis, multiple myeloma-related bone diseases); proliferative diseases (such as acute myeloid leukemia, chronic myeloid leukemia), angiogenesis disorders (such as angiogenesis disorders, including solid tumors, ocular neovascularization and infantile hemangioma), infectious diseases (such as sepsis, septic shock and shigellosis); neurodegenerative diseases (such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, cerebral ischemia or neurodegenerative diseases caused by traumatic injury), tumors and viral diseases (such as metastatic melanoma, Kaposi's sarcoma, multiple myeloma, fibroblastoma, lymphocytoma, HIV infection and CMV retinitis, AIDS); preferably, the inflammatory skin diseases are selected from contact eczema, atopic eczema, hand eczema and radiodermatitis.

18. The application according to claim 16, wherein The Ripk1-related diseases are selected from pancreatitis (acute or chronic), asthma, allergy, adult respiratory distress syndrome, chronic obstructive pulmonary disease, glomerulonephritis, rheumatoid arthritis, systemic lupus erythematosus, scleroderma, chronic thyroiditis, Graves' disease, autoimmune gastritis, diabetes, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, atopic dermatitis, chronic active hepatitis, myasthenia gravis, amyotrophic lateral sclerosis, multiple sclerosis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, psoriasis, graft-versus-host disease, endotoxin-induced inflammatory response, tuberculosis, atherosclerosis, muscle degeneration, cachexia, ankylosing spondylitis, psoriatic arthritis, Reiter's syndrome, gout, traumatic arthritis, rubella arthritis, acute synovitis, pancreatic beta cell disease; Diseases characterized by massive neutrophil infiltration; Rheumatoid spondylitis, gouty arthritis and other arthritic conditions, cerebral malaria, chronic pulmonary inflammation, silicosis, pulmonary sarcoidosis, bone resorption diseases, allograft rejection, infection-induced fever and myalgia, cachexia secondary to infection, luteoid formation, scar tissue formation, ulcerative colitis, fever, influenza, osteoporosis, osteoarthritis, acute myeloid leukemia, chronic myeloid leukemia, metastatic melanoma, Kaposi's sarcoma, multiple myeloma, sepsis, septic shock and shigellosis; Alzheimer's disease, Parkinson's disease, neurodegenerative diseases caused by cerebral ischemia or traumatic injury; angiogenesis disorders including solid tumors, ocular neovascularization and infantile hemangioma; viral diseases including acute hepatitis infections (including hepatitis A, hepatitis B and hepatitis C), HIV infection and CMV retinitis, AIDS, ARC or malignancy and herpes; stroke, myocardial ischemia, stroke heart attack, organ ischemia, vascular hyperplasia, cardiac and renal reperfusion injury, thrombosis, cardiac hypertrophy, thrombin-induced platelet aggregation, endotoxemia and / or toxic shock syndrome, conditions related to prostaglandin endoperoxide synthase-2 and pemphigus vulgaris; NASH, inflammatory diseases, diseases related to necrotic cell death, heart failure; Preferably, the Ripk1-related diseases are selected from ischemic reperfusion injury, including cerebral ischemic reperfusion injury caused by stroke and myocardial ischemic reperfusion injury caused by myocardial infarction.

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