Cathepsin c inhibitor compound and use thereof

Abstract

The present invention provides a compound of formula (X) or a pharmaceutically acceptable salt thereof, an isotopic variant thereof, a tautomer thereof, a stereoisomer thereof, an ester thereof, a polymorph thereof, or a hydrate thereof. The present invention further provides a preparation method for the compound, a pharmaceutical composition comprising same, and use thereof for treating and / or preventing diseases related to the inhibition of cathepsin C.

Description

Cathepsin C inhibitor compounds and uses thereof

[0001] This application claims priority to Chinese Patent Application No. 202410850881.X, filed on June 27, 2024, which is incorporated by reference herein in its entirety. TECHNICAL FIELD

[0002] The present application belongs to the field of pharmaceutical technology, and specifically relates to a new cathepsin C inhibitor compound and the use thereof for treating neutrophil-dominant inflammatory diseases. BACKGROUND

[0003] Cathepsin C (CTSC), also known as dipeptidyl peptidase 1 (DPP1), is the only member of the papain family that functions as a tetramer and has a unique “exclusive” domain to recognize and anchor specific catalytic substrates, and is an important lysosomal cysteine protease. Cathepsin C is a key enzyme for activating granule serine peptidases (elastase (NE), cathepsin G (Cat G), proteinase 3 (PR3) and neutrophil serine protease (NSP4), etc.) in inflammatory cells. Once these related enzymes are activated, they can degrade various extracellular matrix components, thereby causing tissue damage and chronic inflammation.

[0004] Therefore, cathepsin C inhibitors can be used as potential therapeutic drugs for treating neutrophil-dominant inflammatory diseases. SUMMARY

[0005] In one aspect, the present application provides a compound of Formula (X), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, ester, polymorph, or hydrate thereof:

[0006] wherein,

[0007] is a single or double bond;

[0008] X is O, S, NR X1 or C(R X2 )(R X3 ), wherein R X1 , R X2 and R X3 are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl and 3-8 membered heterocyclyl;

[0009] L is a bond, C 1-6 alkylene, C 1-6haloalkylene, -C(O)-, -OC(O)-, -C(O)O-, -S(O)-, or -S(O)2-;

[0010] m is 0, 1, or 2;

[0011] R 1 is selected from H, deuterium, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl;

[0012] R 2 is selected from H, deuterium, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl;

[0013] or R 1 and R 2 together with the atom to which they are attached form a 3-10 membered heterocyclyl group, which is optionally substituted with 1, 2, 3, or 4 R B ;

[0014] each R B is independently selected from H, deuterium, halogen, -CN, -O-R a , -S-R a , -N(R b )(R c ), -C(O)-R a , -OC(O)-R a , -C(O)O-R a , -C(O)-N(R b )(R c ), -N(R b )C(O)-R c , -S(O)R a , -S(O)2-R a , -S(O)2NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, and 3-8 membered heterocyclyl, wherein the above groups are optionally substituted with 1, 2, 3, or 4 R*;

[0015] and / or, two R B attached on non-adjacent atoms form a C 1-3 alkylene group;

[0016] and / or, two R on adjacent atoms B together with the atoms between them form C 3-7 cycloalkyl or 3-8 membered heterocyclyl, wherein the above groups are optionally substituted with 1, 2, 3, or 4 R*;

[0017] and / or, two R on the same carbon atom B together with the carbon atom form C 3-7 cycloalkyl or oxo;

[0018] R 3 is selected from H, deuterium, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein the above groups are optionally substituted with 1, 2, 3, or 4 R 3a ;

[0019] R 3a is selected from H, deuterium, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein the above groups are optionally substituted with 1, 2, 3, or 4 R*;

[0020] or, R 2 , R 3 together with the atoms between them form a 3-8 membered heterocyclyl, which is optionally substituted with 1, 2, 3, or 4 R*;

[0021] R 4 is selected from H and C 1-6 alkyl;

[0022] R 5 is selected from H and C 1-6 alkyl;

[0023] Ring A is selected from C 3-8 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein the above groups are optionally substituted with 1, 2, 3, or 4 R A ;

[0024] each R A is independently selected from H, deuterium, halogen, -CN, -O-R a , -S-R a , -N(R b )(R c ), -C(O)-R a , -OC(O)-R a , -C(O)O-Ra -C(O)-N(R) b (R) c ), -N(R b )C(O)-R c -S(O)R a -S(O)2-R a -S(O)2NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups, wherein the above groups are optionally substituted by 1, 2, 3 or 4 R*;

[0025] And / or, two R atoms on the same carbon atom A Together with this carbon atom, they form C 3-7 cycloalkyl or oxo, wherein the C 3-7 The cycloalkyl group is optionally substituted with 1, 2, 3 or 4 R*;

[0026] And / or, two R atoms on adjacent carbon atoms A Together with the carbon atoms between them and optionally the hydrogen atoms on those carbon atoms, they form C 3- 8-cycloalkyl, 3-8 membered heterocyclic, C 6-10 Aryl or 5-10 heteroaryl, wherein the above groups are optionally surrounded by 1, 2, 3 or 4 R groups. A5 replace;

[0027] Each R A5 Independently selected from H, deuterium, halogen, -OH, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups, wherein the above groups are optionally substituted by 1, 2, 3 or 4 R*;

[0028] And / or, two R atoms on the same carbon atom A5 Together with this carbon atom, they form C 3-7 Cycloalkyl, 3-8 membered heterocyclic or oxo, wherein the C 3-7 The cycloalkyl or 3-8 membered heterocyclic group is optionally substituted with 1, 2, 3 or 4 R*;

[0029] R a R b and R c Each is independently selected from H, halogen, -OH, -CN, C 1-6 Alkyl, C 1-6haloalkyl, C 3-7 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein the above groups are optionally substituted with 1, 2, 3, or 4 R*;

[0030] each R* is independently selected from H, deuterium, -CN, -NO2, halogen, -O-R* a , -S-R* a , -N(R* b )(R* c ), -C(O)-R* a , -OC(O)-R* a , -C(O)O-R* a , -C(O)-N(R* b )(R* c ), -N(R* b )C(O)-R* c , -S(O)R* a , -S(O)2-R* a , -S(O)2NR* b R* c , C 1- 6alkyl and C 1-6 haloalkyl;

[0031] R* a , R* b and R* c are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, 3-7 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl; or R b , R c and the N atom to which they are attached together form a 3-7 membered heterocyclyl.

[0032] In another aspect, the present application relates to a pharmaceutical composition containing a compound of the present application, or a pharmaceutically acceptable salt, isotopologue, tautomer, stereoisomer, ester, polymorph, or hydrate thereof, and a pharmaceutically acceptable excipient.

[0033] In another aspect, the present application relates to the use of a compound of the present application, or a pharmaceutically acceptable salt, isotopologue, tautomer, stereoisomer, ester, polymorph, or hydrate thereof, or a pharmaceutical composition of the present application, in the manufacture of a medicament for the treatment and / or prevention of a disease associated with the inhibition of Cathepsin C.

[0034] DETAILED DESCRIPTION

[0035] Definitions

[0036] As used in the present disclosure, the following terms, phrases and symbols are generally intended to have the meanings set forth below, unless the context of their use indicates otherwise.

[0037] Chemical Definitions

[0038] The definitions of specific functional groups and chemical terms are described in more detail below.

[0039] A dash ("-") that is not between two letters or symbols is used to indicate a point of attachment for substituents. For example, -CONH2is attached through the carbon atom. A dash either preceding or following a chemical group is used to indicate that the chemical group can be drawn with or without the dash without losing its ordinary meaning. A wavy line drawn through a line in a structure indicates the point of attachment of a group. Unless otherwise required by chemical or structural necessity, the order of writing or naming of chemical groups does not indicate or imply directionality. A solid line out of the center of a ring indicates that the point of attachment of the substituent on the ring can be on any ring atom. For example, R a may be attached to any one of the five carbon ring atoms, or R a may replace the hydrogen attached to the nitrogen ring atom:

[0040] When a numerical range is listed, it is intended to include each value and sub-range within the range. For example, "C 1-6 "alkyl" includes C1, C2, C3, C4, C5, C6, C 1-6 , C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-5 , C 2-4 , C 2-3 , C 3-6 , C 3-5 , C 3-4 , C 4-6 , C 4-5 and C 5-6 alkyl groups.

[0041] "C 1-6 alkyl" means a straight or branched chain saturated hydrocarbon group having from 1 to 6 carbon atoms. In some embodiments, C 1-4 alkyl groups are preferred. In some embodiments, C 1-2 alkyl groups are preferred. C 1-6Examples of alkyl groups include: methyl (Ci), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), t-butyl (C4), sec-butyl (C4), i-butyl (C4), n-pentyl (C5), 3-pentyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butyl (C5), t-amyl (C5), and n-hexyl (C6). The term "C 1-6 Alkyl" also includes heteroalkyl, wherein one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by a heteroatom (e.g., oxygen (O), sulfur (S), nitrogen (N), boron (B), silicon (Si), phosphorus (P)). Alkyl groups can be optionally substituted by one or more substituents, e.g., by 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. Conventional alkyl abbreviations include: Me (-CH3), Et (-CH2CH3), iPr (-CH(CH3)2), nPr (-CH2CH2CH3), n-Bu (-CH2CH2CH2CH3), or i-Bu (-CH2CH(CH3)2).

[0042] "Halo" or "halogen" refers to fluoro (F), chloro (CI), bromo (Br), and iodo (I).

[0043] Thus, "C 1-6 Haloalkyl" refers to "C 1-6 Alkyl" groups that are substituted with one or more halo groups. In some embodiments, C 1-3 Haloalkyl is particularly preferred, more preferably C 1-2 Haloalkyl. Exemplary haloalkyl groups include, but are not limited to: -CF3, -CH2F, -CHF2, -CHFCH2F, -CH2CHF2, -CF2CF3, -CCI3, -CH2CI, -CHCI2, 2,2,2-trifluoro- 1,1-dimethyl-ethyl, and the like. Haloalkyl groups can be substituted at any available point of attachment, e.g., by 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0044] "C 2-6 Alkenyl" refers to a straight or branched chain hydrocarbon group having from 2 to 6 carbon atoms and one or more carbon-carbon double bonds (e.g., 1, 2, or 3 carbon-carbon double bonds). The one or more carbon-carbon double bonds can be internal (e.g., in 2-butenyl) or terminal (e.g., in 1-butenyl). In some embodiments, C 2-4Alkenyl groups are particularly preferred. Examples of alkenyl groups include, but are not limited to, ethenyl (C2), 1- propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Each of the alkenyl groups is independently optionally substituted, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent, with suitable substituents defined below, regardless of whether the alkenyl group is modified with "substituted" or not.

[0045] "C 2-6 Alkynyl" refers to a straight or branched chain hydrocarbon group having 2 to 6 carbon atoms, one or more carbon-carbon triple bonds (e.g., 1, 2, or 3 carbon-carbon triple bonds), and optionally one or more carbon-carbon double bonds (e.g., 1, 2, or 3 carbon-carbon double bonds). In some embodiments, the C 2- Alkynyl groups are particularly preferred. In some embodiments, the alkynyl group does not contain any double bonds. The one or more carbon triple bonds can be internal (e.g., in 2-butylyne) or terminal (e.g., in 1-butylyne). Examples of alkynyl groups include, but are not limited to, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butylyl (C4), 2-butylyl (C4), pentynyl (C5), hexynyl (C6), and the like. Each of the alkynyl groups is independently optionally substituted, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent, with suitable substituents defined below, regardless of whether the alkynyl group is modified with "substituted" or not.

[0046] "C 1-6 Alkylene", "C 2-6 Alkenylene" and "C 2-6 Alkynylene" refer to divalent groups formed by the removal of two hydrogen atoms from a "C 1-6 Alkyl", "C 2-6 Alkenyl" and "C 2-6 Alkynyl".

[0047] "C 3-7 Cycloalkyl" refers to a non-aromatic cyclic hydrocarbon group having 3 to 7 ring carbon atoms and zero heteroatoms. Within this term includes cycloalkenyl (i.e., the cyclic group has at least one double bond). In some embodiments, the C 3-6 Cycloalkyl groups are preferred, C 4-6 Cycloalkyl groups are particularly preferred, more preferably C 5-6Cycloalkyl. Cycloalkyl also includes ring systems in which the above cycloalkyl ring is fused with one or more aryl or heteroaryl rings, where the point of attachment is on the cycloalkyl ring, and in such cases the number of carbons continues to designate the number of carbons in the cycloalkyl ring system. Exemplary cycloalkyl groups include, but are not limited to: cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptyl (C7), bicyclo[2.2.2]octyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-lH-indenyl (C9), decahydronaphthyl (C 10 ), spiro[4.5]decyl (C 10 ), bornyl, adamantyl, and the like. Each cycloalkyl group is independently optionally substituted, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent, with suitable substituents as defined below, whether or not preceded by the term "substituted."

[0048] "3-8 membered heterocyclyl" refers to a group having a non-aromatic ring system of 3 to 8 ring members which are carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon. In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. In some embodiments, 3-7 membered heterocyclyl is preferred, which is a non-aromatic ring system of 3 to 7 ring members which are carbon atoms and 1 to 4 ring heteroatoms; in some embodiments, 3-6 membered heterocyclyl is particularly preferred, which is a non-aromatic ring system of 3 to 6 ring members which are carbon atoms and 1 to 3 ring heteroatoms; more preferred is 5-6 membered heterocyclyl, which is a non-aromatic ring system of 5 to 6 ring members which are carbon atoms and 1 to 3 ring heteroatoms. Heterocyclyl also includes ring systems in which the above heterocyclyl ring is fused with one or more cycloalkyl, aryl, or heteroaryl rings, where the point of attachment is on the heterocyclyl ring; and in such cases the number of ring members continues to designate the number of ring members in the heterocyclyl ring system. Each heterocyclyl group is independently optionally substituted, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent, with suitable substituents as defined below, whether or not preceded by the term "substituted."

[0049] Exemplary 3-membered heterocyclic groups containing one heteroatom include, but are not limited to: azircyclopropane, oxacyclopropane, and thiorenyl. Exemplary 4-membered heterocyclic groups containing one heteroatom include, but are not limited to: azircyclobutane, oxacyclobutane, and thiorenyl. Exemplary 5-membered heterocyclic groups containing one heteroatom include, but are not limited to: tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolidinyl, and pyrrolidin-2,5-diketone. Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to: dioxasulfuranyl, oxasulfuranyl, disulfuranyl, and... 2-oxazolidinone. Exemplary 5-membered heterocyclic groups comprising three heteroatoms include, but are not limited to: triazolinyl, Diazolinyl and thiadiazolinyl. Exemplary 6-membered heterocyclic groups containing one heteroatom include, but are not limited to: piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to: piperazinyl, morpholinyl, dithianyl, and di... Alkyl groups. Exemplary 6-membered heterocyclic groups containing three heteroatoms include, but are not limited to, triazinanyl. Exemplary 7-membered heterocyclic groups containing one heteroatom include, but are not limited to, azirheptanyl, oxeheptanyl, and thioheptanyl. Exemplary 8-membered heterocyclic groups containing one heteroatom include, but are not limited to, azirheptanyl, oxeheptanyl, and thioheptanyl. Exemplary 5-membered heterocyclic groups fused with a C6 aryl ring (also referred to herein as 5,6-bicyclic heterocyclic groups) include, but are not limited to, dihydroindolyl, isodihydroindolyl, dihydrobenzofuranyl, dihydrobenzothiophene, and benzo[…]. Azolinone group, etc. Exemplary 6-membered heterocyclic groups fused with a C6 aryl ring (also referring to 6,6-bicyclic heterocyclic groups herein) include, but are not limited to: tetrahydroquinolinyl, tetrahydroisoquinolinyl, etc.

[0050] “C 6-10 "Aryl" refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6 or 10 shared π electrons arranged in a ring) having 6-10 ring carbon atoms and zero heteroatoms. In some embodiments, the aryl group has six ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, the aryl group has ten ring carbon atoms ("C... 10 "Aryl"; for example, naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, C 6-10Aryl is particularly preferred, more preferably C6 aryl. Aryl also includes ring systems in which the above aryl ring is fused to one or more cycloalkyl or heterocyclyl rings, with the point of attachment being on the aryl ring, in which case the number of carbon atoms designates the number of carbon atoms in the aryl ring system. Each aryl group is independently optionally substituted, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent, as defined below, whether or not modified by "substituted."

[0051] "5-10 membered heteroaryl" refers to a radical of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur. In heteroaryl groups containing one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valence permits. Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings. Heteroaryl also includes ring systems in which the above heteroaryl ring is fused to one or more cycloalkyl or heterocyclyl rings, with the point of attachment being on the heteroaryl ring, in which case the number of carbon atoms designates the number of carbon atoms in the heteroaryl ring system. In some embodiments, 5-6 membered heteroaryl is particularly preferred, which is a 5-6 membered monocyclic or bicyclic 4n+2 aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms. In some embodiments, 5 membered heteroaryl is particularly preferred, which is a 5 membered monocyclic or bicyclic 4n+2 aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms. Each heteroaryl group is independently optionally substituted, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent, as defined below, whether or not modified by "substituted."

[0052] Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzoimidazolyl, benzoxazolyl, benzoisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0053] In the present application, the term "optionally" or "optional" generally means that the subsequently described event or circumstance can or can not occur, and this description includes situations where the event or circumstance occurs and situations where it does not. For example, "heterocyclyl optionally substituted with alkyl" means that alkyl can or can not be present, and this description can include situations where the heterocyclyl group is substituted with alkyl and situations where the heterocyclyl group is not substituted with alkyl.

[0054] Exemplary substituents on carbon atoms include, but are not limited to: halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR aa , -ON(R bb )2, -N(R bb )2, -N(R bb )3 + X - , -N(OR cc )R bb , -SH, -SR aa , -SSR cc , -C(=O)R aa , -CO2H, -CHO, -C(OR cc )2, -CO2R aa , -OC(=O)R aa , -OCO2R aa、-C(=O)N(R bb )2、-OC(=O)N(R bb )2、-NR bb C(=O)R aa 、-NR bb CO2R aa 、-NR bb C(=O)N(R bb )2、-C(=NR bb )R aa 、-C(=NR bb )OR aa 、-OC(=NR bb )R aa 、-OC(=NR bb )OR aa 、-C(=NR bb )N(R bb )2、-OC(=NR bb )N(R bb )2、-NR bb C(=NR bb )N(R bb )2、-C(=O)NR bb SO2R aa 、-NR bb SO2R aa 、-SO2N(R bb )2、-SO2R aa 、-SO2OR aa 、-OSO2R aa 、-S(=O)R aa 、-OS(=O)R aa 、-Si(R aa )3、-OSi(R aa )3、-C(=S)N(R bb )2、-C(=O)SR aa 、-C(=S)SR aa 、-SC(=S)SR aa 、-SC(=O)SR aa 、-OC(=O)SR aa 、-SC(=O)OR aa 、-SC(=O)R aa 、-P(=O)2R aa 、-OP(=O)2R aa 、-P(=O)(R aa )2、-OP(=O)(R aa )2、-OP(=O)(OR cc )2、-P(=O)2N(Rbb )2, -P(=O)2N(R bb )2, -P(=O)(NR bb )2, -OP(=O)(NR bb )2, -NR bb P(=O)(OR cc )2, -NR bb P(=O)(NR bb )2, -P(R cc )2, -P(R cc )3, -OP(R cc )2, -OP(R cc )3, -B(R aa )2, -B(OR cc )2, -BR aa (OR cc ), alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups;

[0055] or two geminal hydrogens on a carbon atom are replaced with a group =O, =S, =NN(R bb )2, =NNR bb C(=O)R aa , =NNR bb C(=O)OR aa , =NNR bb S(=O)2R aa , =NR bb , or =NOR cc ;

[0056] each R aa is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl, or two R aa groups are combined to form a heterocyclyl or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups;

[0057] each R bb is independently selected from: hydrogen, -OH, -OR aa , -N(R cc )2, -CN, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NRcc )OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , -P(=O)2R aa , -P(=O)(R aa )2, -P(=O)2N(R cc )2, -P(=O)(NR cc )2, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl, or two R bb groups are joined to form a heterocyclyl or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups;

[0058] R cc each is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl, or two R cc groups are joined to form a heterocyclyl or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups;

[0059] R dd each is independently selected from: halo, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR ee , -ON(R ff )2, -N(R ff )2, -N(R ff )3 + X - , -N(OR ee )R ff , -SH, -SR ee , -SSR ee , -C(=O)R ee , -CO2H, -CO2R ee , -OC(=O)R ee , -OCO2R ee , -C(=O)N(R ff )2, -OC(=O)N(Rff )2, -NR ff C(=O)R ee , -NR ff CO2R ee , -NR ff C(=O)N(R ff )2, -C(=NR ff )OR ee , -OC(=NR ff )R ee , -OC(=NR ff )OR ee , -C(=NR ff )N(R ff )2, -OC(=NR ff )N(R ff )2, -NR ff C(=NR ff )N(R ff )2, -NR ff SO2R ee , -SO2N(R ff )2, -SO2R ee , -SO2OR ee , -OSO2R ee , -S(=O)R ee , -Si(R ee )3, -OSi(R ee )3, -C(=S)N(R ff )2, -C(=O)SR ee , -C(=S)SR ee , -SC(=S)SR ee , -P(=O)2R ee , -P(=O)(R ee )2, -OP(=O)(R ee )2, -OP(=O)(OR ee )2, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R gg groups, or two geminal R dd substituents can be combined to form =O or =S;

[0060] R ee is independently selected from the group consisting of alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, aryl, heterocyclyl, and heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, aryl, heterocyclyl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R gg groups;

[0061] R ff each R ff is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl, or two R gg groups combine to form a heterocyclyl or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R gg groups;

[0062] R 1-6 each R 1-6 is independently: halo, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC 1-6 alkyl, -ON(C 1-6 alkyl)2, -N(C + alkyl)2, -N(C - alkyl)3 1-6 X + , -NH(C - alkyl)2 1-6 X + , -NH2(C - alkyl) + X - , -N(OC 1-6 alkyl)(C 1-6 alkyl), -N(OH)(C 1-6 alkyl), -NH(OH), -SH, -SC 1-6 alkyl, -SS(C 1-6 alkyl), -C(=O)(C 1-6 alkyl), -CO2H, -CO2(C 1-6 alkyl), -OC(=O)(C 1-6 alkyl), -OCO2(C 1-6 alkyl), -C(=O)NH2, -C(=O)N(C 1-6 alkyl)2, -OC(=O)NH(C 1-6 alkyl), -NHC(=O)(C 1-6 alkyl), -N(C 1-6 alkyl)C(=O)(C 1-6 alkyl), -NHCO2(C 1-6 alkyl), -NHC(=O)N(C 1-6 alkyl)2, -NHC(=O)NH(C 1-6 alkyl), -NHC(=O)NH2, -C(=NH)O(C 1-6 alkyl), -OC(=NH)(C 1-6alkyl), -OC(=NH)OC 1-6 alkyl, -C(=NH)N(C 1-6 alkyl)2, -C(=NH)NH(C 1-6 alkyl), -C(=NH)NH2, -OC(=NH)N(C 1-6 alkyl)2, -OC(NH)NH(C 1-6 alkyl), -OC(NH)NH2, -NHC(NH)N(C 1-6 alkyl)2, -NHC(=NH)NH2, -NHSO2(C 1-6 alkyl), -SO2N(C 1-6 alkyl)2, -SO2NH(C 1-6 alkyl), -SO2NH2, -SO2C 1-6 alkyl, -SO2OC 1-6 alkyl, -OSO2C 1-6 alkyl, -SOC 1-6 alkyl, -Si(C 1-6 alkyl)3, -OSi(C 1-6 alkyl)3, -C(=S)N(C 1-6 alkyl)2, C(=S)NH(C 1-6 alkyl), C(=S)NH2, -C(=O)S(C 1-6 alkyl), -C(=S)SC 1-6 alkyl, -SC(=S)SC 1-6 alkyl, -P(=O)2(C 1-6 alkyl), -P(=O)(C 1- 6alkyl)2, -OP(=O)(C 1-6 alkyl)2, -OP(=O)(OC 1-6 alkyl)2, C 1-6 alkyl, C 1-6 haloalkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C7carbocyclyl, C6-C 10 aryl, C3-C7heterocyclyl, C5-C 10 heteroaryl; or two geminal R gg substituents can combine to form =O or =S; wherein X - is a counterion.

[0063] Exemplary substituents on a nitrogen atom include, but are not limited to: hydrogen, -OH, -OR aa , -N(R cc )2, -CN, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2Raa , -C(=NR bb )R aa , -C(=NR cc )OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , -P(=O)2R aa , -P(=O)(R aa )2, -P(=O)2N(R cc )2, -P(=O)(NR cc )2, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl, or two R cc groups attached to a nitrogen atom are combined to form a heterocyclyl or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd , R aa , R bb , R cc , and R dd are as described above.

[0064] As used herein, the term "compounds of the present application" refers to the compounds of the present application. This term also includes various pharmaceutically acceptable salts, stereoisomers, enantiomers, diastereomers, mesomers, racemates, or tautomers of the compounds of the present application.

[0065] Other Definitions

[0066] In the present application, the term "comprising" generally means including, but not limited to, the specified features. The terms "above", "below" generally mean including the number itself.

[0067] In the present application, the term "about" generally means a variance within a range of 0.5-10% above or below the specified numerical value, such as a variance within a range of 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, or 10% above or below the specified numerical value.

[0068] The term "pharmaceutically acceptable salt" as used herein refers to an acid addition salt or a base addition salt of a compound of the present application which is within the scope of sound medical judgment to be suitable for use in contact with the tissues of a patient without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit / risk ratio, effective for their intended use, including, where appropriate, two-ionic forms of the compounds of the present application.

[0069] The pharmaceutically acceptable salt can be an inorganic salt prepared from inorganic acids, or an organic acid salt prepared from organic acids.

[0070] The pharmaceutically acceptable salt can include a metal salt formed based on a cation of an alkali metal and an alkaline earth metal, or an amino acid salt formed with an amino acid or the like. The present application also includes isotopically-labeled compounds (isotopic variants) which are equivalent to those described herein but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be heteroatoms in the compounds of this application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, and chlorine, for example 2 H, 3 H, 13 C, 11 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 Cl. The present application also includes the compounds of the present application, prodrugs thereof, and pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes or other isotopes of other atoms present in the compounds. Certain isotopically-labeled compounds of this application, for example those into which radioactive isotopes such as 3 H, and 14 C) are useful in drug and / or substrate tissue distribution assays. Tritiated, i.e., 3 H, and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e., 2 H, can afford certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements. Isotopically labeled compounds of this application and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the Schemes and / or in the Examples and Preparations below, by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.

[0071] The compounds of the present application include one or more asymmetric centers and can thus occur as individual enantiomers, diastereomers, or as mixtures of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers can be separated by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or the preferred isomer can be prepared by asymmetric synthesis.

[0072] "tautomer" refers to an isomer of a compound in which a functional group changes its structure to become an isomer of the compound, and rapidly interconverts with the two isomers in a dynamic equilibrium, the two isomers being referred to as tautomers.

[0073] The term "hydrate" refers to a compound in combination with water. Typically, the ratio of the number of water molecules to the number of molecules of the compound in a hydrate of the compound is defined. Thus, a hydrate of a compound can be represented, for example, by the general formula R-x H2O, where R is the compound, and x is a number greater than zero. A given compound can form more than one type of hydrate, including, for example, monohydrates (x is 1), lower hydrates (x is a number greater than zero and less than 1, for example, hemihydrates (R-0.5 H2O)), and polyhydrates (x is a number greater than 1, for example, dihydrates (R-2 H2O) and hexahydrates (R-6 H2O)).

[0074] The compounds of the present application can be in amorphous or crystalline form (crystal form or polymorph). Furthermore, each of the component compounds of the present application can exist in one or more crystalline forms. Thus, the present application includes within its scope all amorphous or crystalline forms of each of the component compounds of the present application. The term "polymorph" refers to a crystalline form of a compound (or a salt, hydrate, or solvate thereof) of a particular crystal packing arrangement. All polymorphs have the same elemental composition. Different crystalline forms often have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility. The recrystallization solvent, the rate of crystallization, storage temperature, and other factors can cause one crystalline form to dominate over another. Various polymorphs of a compound can be prepared by crystallization under different conditions.

[0075] In the present application, the term "pharmaceutical composition" generally refers to a mixture of one or more of the compounds described herein, or physiologically / pharmaceutically acceptable salts or prodrugs thereof, with other chemical components, such as physiologically / pharmaceutically acceptable carriers and excipients. The pharmaceutical composition may

[0076] In the present application, the term "pharmaceutically acceptable carrier" generally refers to a carrier for administration of a therapeutic agent, such as an antibody or polypeptide, a gene, and other therapeutic agents. The term refers to any pharmaceutically acceptable carrier, which does not itself induce the production of antibodies to the individual receiving the composition, and which can be administered without undue toxicity. For example, a pharmaceutically acceptable carrier can be distinguished from a nucleic acid vector used in genetic engineering to contain a gene. Suitable carriers can be large, slowly metabolized macromolecules such as proteins, polysaccharides, polylactic acids, polyglycolic acids, polymeric amino acids, amino acid copolymers, lipid aggregates, and inactivated virus particles. These carriers are well known to those skilled in the art. The pharmaceutically acceptable carrier in the therapeutic composition can include liquids such as water, saline, glycerol, and ethanol. Auxiliary substances such as wetting or emulsifying agents, pH buffering substances, and the like can also be present in these carriers.

[0077] In the present application, the term "effective amount" generally refers to an amount of a therapeutic agent that treats, ameliorates, or prevents a target disease or condition, or an amount that shows a detectable therapeutic or prophylactic effect. The precise effective amount for a subject depends on the size and health of the subject, the nature and extent of the condition, and the therapeutic agent selected for administration and / or the combination of therapeutic agents. Therefore, it is not useful to specify the exact effective amount in advance. However, for a given condition, the effective amount can be determined by routine experimentation, and a clinician is able to judge.

[0078] The term "patient" includes mammals and non-mammals. Examples of mammals include, but are not limited to, any member of the mammalian class: humans, non-human primates such as chimpanzees and other apes and monkey species; farm animals such as cows, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents such as rats, mice and guinea pigs, and the like, and includes in utero mammals. Examples of non-mammals include, but are not limited to, birds, fish, and the like.

[0079] The term "patient" includes diagnosed patients, but the "patient" does not require any special identity to a hospital, clinic, or research facility (e.g., as a diagnosed patient, a research participant, etc.). Specific Embodiments

[0080] As used herein, "compounds of the application" refers to compounds of Formula (X), Formula (X-1), and Formula (I) through Formula (I-5), pharmaceutically acceptable salts, isotopologues, tautomers, stereoisomers, esters, polymorphs, or hydrates thereof.

[0081] As used herein, compounds are named using standard nomenclature. Compounds having asymmetric centers should be understood to include all optical isomers and mixtures thereof, unless otherwise indicated. In addition, unless otherwise indicated, all isomeric compounds of the application are included in the present application in Z and E form, where the carbon-carbon double bond can occur. Where compounds exist in different tautomeric forms, one of the compounds is not limited to any particular tautomer, but is intended to cover all tautomeric forms.

[0082] In one aspect, the present application provides a compound of Formula (X), or a pharmaceutically acceptable salt, isotopologue, tautomer, stereoisomer, ester, polymorph, or hydrate thereof:

[0083] wherein the variables are as defined herein.

[0084] In one embodiment, is a single bond. In another embodiment, is a double bond.

[0085] X, R X1 , R X2 , and R X3

[0086] In one embodiment, X is O. In another embodiment, X is S. In another embodiment, X is NR X1 . In another embodiment, X is C(R X2 )(R X3 ).

[0087] In one embodiment, R X1 , R X2 , and R X3 are independently H. In another embodiment, R X1 , R X2 , and R X3 are independently C 1-6 alkyl. In another embodiment, R X1 , R X2 , and R X3 are independently C 1-6 haloalkyl. In another embodiment, R X1 , R X2 , and R X3 are independently C3-7 Cycloalkyl. In another embodiment, R X1 R X2 and R X3 It is an independent 3-8 membered heterocyclic group.

[0088] In one specific implementation, X is NH. In another specific implementation, X is CH2.

[0089] L

[0090] In one implementation, L is a key. In another implementation, L is a C. 1-6 In another embodiment, L is C. 1-6 Alkyl halide. In another embodiment, L is -C(O)-. In another embodiment, L is -OC(O)-. In another embodiment, L is -C(O)O-. In another embodiment, L is -S(O)-. In another embodiment, L is -S(O)2-.

[0091] m

[0092] In one implementation, m is 0. In another implementation, m is 1. In yet another implementation, m is 2.

[0093] R 1

[0094] In one implementation, R 1 For H. In another implementation, R 1 C 1-6 Alkyl group. In another embodiment, R 1 C 1-6 Halogenated alkyl group. In another embodiment, R 1 C 3-7 Cycloalkyl. In another embodiment, R 1 It is a 3-8 membered heterocyclic group. In another embodiment, R 1 C 6-10 Aryl. In another embodiment, R 1 It is a 5-10 quinone heteroaryl group. In another embodiment, R 1 R 2 Together with the atoms between them, they form 3-10 membered heterocyclic groups, which are optionally surrounded by 1, 2, 3 or 4 R atoms. B replace.

[0095] R 2

[0096] In one implementation, R 2 For H. In another implementation, R 2For deuterium. In another implementation, R 2 C 1-6 Alkyl group. In another embodiment, R 2 C 1-6 Halogenated alkyl group. In another embodiment, R 2 C 3-7 Cycloalkyl. In another embodiment, R 2 It is a 3-8 membered heterocyclic group. In another embodiment, R 2 C 6-10 Aryl. In another embodiment, R 2 It is a 5-10 quinone heteroaryl group. In another embodiment, R 1 R 2 Together with the atoms between them, they form 3-10 membered heterocyclic groups, which are optionally surrounded by 1, 2, 3 or 4 R atoms. B replace.

[0097] R B

[0098] In one implementation scheme, each R B Independently for H, in another implementation, each R B Independently for deuterium. In another implementation, each R B Independently halogenated. In another embodiment, each R B Independently for -CN. In another implementation, each R B Independently for -OR a In another implementation, each R B Independently for -SR a In another implementation, each R B Independently -N(R) b (R) c In another implementation, each R B Independently -C(O)-R a In another implementation, each R B Independently -OC(O)-R a In another implementation, each R B Independently -C(O)OR a In another implementation, each R B Independently -C(O)-N(R) b (R) c In another implementation, each R B Independently -N(R) b )C(O)-R c In another implementation, each RB Independently for -S(O)R a In another implementation, each R B Independently -S(O)2-R a In another implementation, each R B Independently -S(O)2NR b R c In another implementation, each R B Independently for C 1-6 Alkyl group. In another embodiment, each R B Independently for C 1-6 Halogenated alkyl groups. In another embodiment, each R B Independently for C 3-7 Cycloalkyl. In another embodiment, each R B Independently for C 6-10 Aryl. In another embodiment, each R B Independently, it is a 5-10 member heteroaryl group. In another embodiment, each R B It is independently a 3-8 membered heterocyclic group. The above groups are optionally substituted by 1, 2, 3 or 4 R*.

[0099] In one implementation, two R atoms on non-adjacent atoms B Connect to form C 1-3 Alkylene. In one specific embodiment, two R atoms on non-adjacent atoms... B They are linked together to form an ethylene group. In another specific embodiment, two R atoms on non-adjacent atoms... B They connect to form methylene groups.

[0100] In one implementation, two R atoms on adjacent atoms B Together with the atoms between them, they form C 3-7 Cycloalkyl. In another embodiment, two R atoms on adjacent atoms B Together with the atoms between them, they form 3-8 membered heterocyclic groups. In one specific embodiment, two R atoms on adjacent atoms... B Together with the atoms between them, they form a cyclopropyl group. In another specific embodiment, the two R atoms on adjacent atoms... B Together with the atoms between them, they form a cyclopentyl group. In another specific embodiment, the two R atoms on adjacent atoms... B Together with the atoms between them, they form a tetrahydrofuran group. The above groups are optionally substituted with 1, 2, 3, or 4 R* atoms.

[0101] In one implementation, two R atoms on the same carbon atom Btogether with the carbon atom form a C 3-7 cycloalkyl. In a specific embodiment, two R B together with the carbon atom form a cyclobutyl. In another specific embodiment, two R B together with the carbon atom form an oxo.

[0102] R 3 and R 3a

[0103] In one embodiment, R 3 is H. In another embodiment, R 3 is deuterium. In another embodiment, R 3 is C 1-6 alkyl. In another embodiment, R 3 is C 1-6 haloalkyl. In another embodiment, R 3 is C 3-7 cycloalkyl. In another embodiment, R 3 is 3-8 membered heterocyclyl. In another embodiment, R 3 is C 6-10 aryl. In another embodiment, R 3 is 5-10 membered heteroaryl. In a specific embodiment, R 3 is methyl. The above groups are optionally substituted with 1, 2, 3, or 4 R 3a .

[0104] In one embodiment, R 3a is H. In another embodiment, R 3a is deuterium. In another embodiment, R 3a is C 3- 8cycloalkyl. In another embodiment, R 3a is 3-8 membered heterocyclyl. In another embodiment, R 3a is C 6-10 aryl. In another embodiment, R 3a is 5-10 membered heteroaryl. In a specific embodiment, R 3a is 5 membered heteroaryl. In a specific embodiment, R 3a is thienyl. The above groups are optionally substituted with 1, 2, 3, or 4 R

[0105] In one embodiment, R 2 , R 3 together with the atoms between them form a 3-8 membered heterocyclyl. In a specific embodiment, R 2 , R3 Together with the atoms between them, they form a 6-membered heterocyclic group. In another specific embodiment, R 2 R 3 Together with the atoms between them, they form a tetrahydropyranyl group. The above groups are optionally substituted with 1, 2, 3, or 4 R* atoms.

[0106] R 4

[0107] In one implementation, R 4 For H. In another implementation, R 4 C 1-6 Alkyl group. In one specific embodiment, R 4 It is methyl. In another specific embodiment, R 4 It is an ethyl group.

[0108] R 5

[0109] In one implementation, R 5 For H. In another implementation, R 5 C 1-6 Alkyl group. In one specific embodiment, R 5 It is methyl. In another specific embodiment, R 5 It is an ethyl group.

[0110] Rings A and R A and R A5

[0111] In one implementation, ring A is C. 3-8 Cycloalkyl. In another embodiment, ring A is a 3-10 membered heterocyclic group. In another embodiment, ring A is C. 6-10 Aryl group. In another embodiment, ring A is a 5-10 membered heteroaryl group. The above group is optionally surrounded by 1, 2, 3, or 4 R groups. A replace;

[0112] In one implementation scheme, each R A H is independent. In another implementation, each R A Independently for deuterium. In another implementation, each R A Independently halogenated. In another embodiment, each R A Independently for -CN. In another implementation, each R A Independently for -OR a In another implementation, each R A Independently for -SR a In another implementation, each R Aindependently -N(R b )(R c ). In another embodiment, each R A is independently -C(O)-R a . In another embodiment, each R A is independently -OC(O)-R a . In another embodiment, each R A is independently -C(O)O-R a . In another embodiment, each R A is independently -C(O)-N(R b )(R c ). In another embodiment, each R A is independently -N(R b )C(O)-R c . In another embodiment, each R A is independently -S(O)R a . In another embodiment, each R A is independently -S(O)2-R a . In another embodiment, each R A is independently -S(O)2NR b R c . In another embodiment, each R A is independently C 1-6 alkyl. In another embodiment, each R A is independently C 1-6 haloalkyl. In another embodiment, each R A is independently C 3-7 cycloalkyl. In another embodiment, each R A is independently 3-8 membered heterocyclyl. In another embodiment, each R A is independently C 6-10 aryl. In another embodiment, each R A is independently 5-10 membered heteroaryl. The above groups are optionally substituted with 1, 2, 3, or 4 R*;

[0113] In one embodiment, two R A on the same carbon atom, together with the carbon atom, form a C 3-7 cycloalkyl, which is optionally substituted with 1, 2, 3, or 4 R*. In another embodiment, two R A on the same carbon atom, together with the carbon atom, form an oxo.

[0114] In one embodiment, two R Awith the carbon atom therebetween and optionally a hydrogen atom on the carbon atom forms C 3-8 cycloalkyl. In another embodiment, two R A with the carbon atom therebetween and optionally a hydrogen atom on the carbon atom forms 3-8 membered heterocyclyl. In another embodiment, two R A with the carbon atom therebetween and optionally a hydrogen atom on the carbon atom forms C 6-10 aryl. In another embodiment, two R A with the carbon atom therebetween and optionally a hydrogen atom on the carbon atom forms 5-10 membered heteroaryl. The above groups are optionally substituted with 1, 2, 3, or 4 R A5 ;

[0115] In one embodiment, each R A5 is independently H. In another embodiment, each R A5 is independently deuterium. In another embodiment, each R A5 is independently halogen. In another embodiment, each R A5 is independently -OH. In another embodiment, each R A5 is independently -CN. In another embodiment, each R A5 is independently C 1-6 alkyl. In another embodiment, each R A5 is independently C 1-6 haloalkyl. In another embodiment, each R A5 is independently C 3-7 cycloalkyl. In another embodiment, each R A5 is independently 3-8 membered heterocyclyl. In another embodiment, each R A5 is independently C 6- 10 aryl. In another embodiment, each R A5 is independently 5-10 membered heteroaryl. The above groups are optionally substituted with 1, 2, 3, or 4 R

[0116] In one specific embodiment, ring A is cycloalkenyl. In another specific embodiment, ring A is 6 membered heterocyclyl. In another specific embodiment, ring A is phenyl.

[0117] In one specific embodiment, ring A is In another specific embodiment, ring member Y 1 , Y 2 , Y 3 , and Y 4each independently C, N, or O atom. In another specific embodiment, Y 1 and Y 2 , Y 2 and Y 3 , Y 3 and Y 4 the bond between Y 1 , Y 2 , Y 3 and Y 4 together with the other ring members form a phenyl, 6-membered heterocyclyl, or 6-membered heteroaryl. In another specific embodiment, ring A is optionally substituted with R A .

[0118] In one specific embodiment, ring A is In another specific embodiment, ring A is In another specific embodiment, ring A is In another specific embodiment, ring A is In another specific embodiment, ring A is In another specific embodiment, ring A is In another specific embodiment, ring A is phenyl. The above group is optionally substituted with 1, 2, 3, or 4 R A . In another specific embodiment, R A1 and R A4 each independently H. In another specific embodiment, R A1 and R A4 each independently C 1-6 alkyl. In another specific embodiment, R A1 and R A4 each independently C 3-7 cycloalkyl. In another specific embodiment, R A2 and R A3 independently H. In another specific embodiment, R A2 and R A3 independently halogen. In another specific embodiment, R A2 and R A3 independently C 1-6 alkyl. In another specific embodiment, R A2 , R A3 together with the carbon atom to which they are attached form C 3-6 cycloalkyl.

[0119] In one specific embodiment, ring A is In another specific embodiment, Ring A is In another specific embodiment, Ring A is In another specific embodiment, Ring A is In another specific embodiment, Ring A is In another specific embodiment, Ring A is In another specific embodiment, Ring A is In another specific embodiment, Ring A is In another specific embodiment, Ring A is In another specific embodiment, Ring A is. In another specific embodiment, Ring A is In another specific embodiment, Ring A is In another specific embodiment, Ring A is In another specific embodiment, Ring A is In another specific embodiment, Ring A is In another specific embodiment, Ring A is In another specific embodiment, Ring A is In another specific embodiment, Ring A is In another specific embodiment, Ring A is In another specific embodiment, Ring A is In another specific embodiment, Ring A is In another specific embodiment, Ring A is In another specific embodiment, Ring A is In another specific embodiment, Ring A is In another specific embodiment, Ring A is In another specific embodiment, Ring A is In another specific embodiment, Ring A is In another specific embodiment, Ring A is In another specific embodiment, Ring A is In another specific embodiment, Ring A is In another specific embodiment, Ring A is In another specific embodiment, Ring A is

[0120] R a , R b , and R c

[0121] In one embodiment, R a , R b , and R c are each independently H. In another embodiment, R a , R b , and R c are each independently halogen. In another embodiment, R a , R b , and R c are each independently -OH. In another embodiment, R a , R b , and R c are each independently -CN. In another embodiment, R a , R b , and R c are each independently C 1-6 alkyl. In another embodiment, R a , R b , and R c are each independently C 1-6 haloalkyl. In another embodiment, R a , R b , and R c are each independently C 3-7 cycloalkyl. In another embodiment, R a , R b , and R c are each independently 3-8 membered heterocyclyl. In another embodiment, R a , R b , and R c are each independently C 6-10 aryl and 5-10 membered heteroaryl. The above groups are optionally substituted with 1, 2, 3, or 4 R*;

[0122] R*

[0123] In one embodiment, each R* is independently H. In another embodiment, each R* is independently deuterium. In another embodiment, each R* is independently -CN. In another embodiment, each R* is independently -NO2. In another embodiment, each R* is independently halogen. In another embodiment, each R* is independently -O-R a . In another embodiment, each R* is independently -S-R a . In another embodiment, each R* is independently -N(R b )(R c ). In another embodiment, each R* is independently -C(O)-R a .In another embodiment, each R* is independently -OC(O)-R a In another embodiment, each R* is independently -C(O)O-R a In another embodiment, each R* is independently -C(O)-N(R b )(R c ). In another embodiment, each R* is independently -N(R b )C(O)-R c In another embodiment, each R* is independently -S(O)R a In another embodiment, each R* is independently -S(O)2-R a In another embodiment, each R* is independently -S(O)2NR b R c In another embodiment, each R* is independently C 1-6 alkyl. In another embodiment, each R* is independently C 1-6 haloalkyl.

[0124] R a , R b , and R c

[0125] In one embodiment, R a , R b , and R c are each independently H. In another embodiment, R a , R b , and R c are each independently C 1-6 alkyl. In another embodiment, R a , R b , and R c are each independently C 1-6 haloalkyl. In another embodiment, R a , R b , and R c are each independently C 2-6 alkenyl. In another embodiment, R a , R b , and R c are each independently C 2-6 alkynyl. In another embodiment, R a , R b , and R c are each independently C 3-7 cycloalkyl. In another embodiment, R a、R* b and R* c Each is independently a 3-7 membered heterocyclic group. In another embodiment, R* a 、R* b and R* c Each independently is C 6-10 Aryl. In another embodiment, R* a 、R* b and R* c Each is independently a 5-10 member heteroaryl group. In another embodiment, R* b 、R* c Together with the N atoms attached to them, they form 3-7 membered heterocyclic groups.

[0126] In another aspect, the present invention provides a compound of formula (X-1), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, ester, polymorph, or hydrate thereof:

[0127] The variables are defined as described in this paper.

[0128] In another aspect, the present invention provides compounds of formula (I), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, esters, polymorphs, or hydrates thereof:

[0129] The variables are defined as described in this paper.

[0130] In another aspect, the present invention provides compounds of formula (I-1), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, esters, polymorphs, or hydrates thereof:

[0131] The variables are defined as described in this paper.

[0132] Z

[0133] In one implementation, Z is -C(R) B1 (R) B2 In another implementation, Z is -NR. B3 - In another embodiment, Z is -O-. In yet another embodiment, Z is -S-.

[0134] In one implementation, R B R B1 R B2 and R B3 Each is independently represented by H. In another implementation, R... B R B1 RB2 and R B3 each independently is halogen. In another embodiment, R B , R B1 , R B2 and R B3 each independently is -CN. In another embodiment, R B , R B1 , R B2 and R B3 each independently is -O-R a . In another embodiment, R B , R B1 , R B2 and R B3 each independently is -S-R a . In another embodiment, R B , R B1 , R B2 and R B3 each independently is -N(R b )(R c ). In another embodiment, R B , R B1 , R B2 and R B3 each independently is -C(O)-R a . In another embodiment, R B , R B1 , R B2 and R B3 each independently is -OC(O)-R a . In another embodiment, R B , R B1 , R B2 and R B3 each independently is -C(O)O-R a . In another embodiment, R B , R B1 , R B2 and R B3 each independently is -C(O)-N(R b )(R c ). In another embodiment, R B , R B1 , R B2 and R B3 each independently is -N(R b )C(O)-R c . In another embodiment, R B , R B1 , R B2 and R B3each independently -S(O)R a In another embodiment, R B , R B1 , R B2 , and R B3 each independently -S(O)2-R a In another embodiment, R B , R B1 , R B2 , and R B3 each independently -S(O)2NR b R c In another embodiment, R B , R B1 , R B2 , and R B3 each independently C 1-6 alkyl. In another embodiment, R B , R B1 , R B2 , and R B3 each independently C 1-6 haloalkyl. In another embodiment, R B , R B1 , R B2 , and R B3 each independently C 3-7 cycloalkyl. In another embodiment, R B , R B1 , R B2 , and R B3 each independently 3-8 membered heterocyclyl. In another embodiment, R B , R B1 , R B2 , and R B3 each independently C 6-10 aryl. In another embodiment, R B , R B1 , R B2 , and R B3 each independently 5-10 membered heteroaryl. The above groups are optionally substituted with 1, 2, 3, or 4 R*;

[0135] In one embodiment, two of R B , R B1 , R B2 , or R B3 on adjacent atoms are joined to form a C 1-3 alkylene;

[0136] In one embodiment, two of R B , R B1 , RB2 or R B3 two of R 3-7 cycloalkyl. In another embodiment, two of R B , R B1 , R B2 or R B3 form, together with the atoms between them, a 3-8 membered heterocyclyl. The above groups are optionally substituted with 1, 2, 3, or 4 R*;

[0137] In one embodiment, R B1 , R B2 form, together with the carbon atom, a C 3-7 cycloalkyl. In another embodiment, R B1 , R B2 form, together with the carbon atom, an oxo.

[0138] q

[0139] In one embodiment, q is 1. In another embodiment, q is 2. In another embodiment, q is 3. In another embodiment, q is 4. In another embodiment, q is 5.

[0140] p

[0141] In one embodiment, p is 0. In another embodiment, p is 1. In another embodiment, p is 2. In another embodiment, p is 3. In another embodiment, p is 4. In another embodiment, p is 5.

[0142] In one embodiment, the moiety is selected from the following:

[0143] In another aspect, the present application provides a compound of Formula (I-2), or a pharmaceutically acceptable salt, isotopically enriched variant, tautomer, stereoisomer, ester, polymorph, or hydrate thereof:

[0144] wherein each variable is as defined herein.

[0145] In another aspect, the present application provides a compound of Formula (I-3), or a pharmaceutically acceptable salt, isotopically enriched variant, tautomer, stereoisomer, ester, polymorph, or hydrate thereof:

[0146] wherein each variable is as defined herein.

[0147] In another aspect, the present application provides a compound of Formula (I-4), or a pharmaceutically acceptable salt, isotopologue, tautomer, stereoisomer, ester, polymorph, or hydrate thereof:

[0148] wherein each variable is as defined herein.

[0149] In another aspect, the present application provides a compound of Formula (I-5), or a pharmaceutically acceptable salt, isotopologue, tautomer, stereoisomer, ester, polymorph, or hydrate thereof:

[0150] wherein each variable is as defined herein.

[0151] In another aspect, the present application provides the following specific technical solutions:

[0152] Technical Solution 1. A compound of Formula (X), or a pharmaceutically acceptable salt, isotopologue, tautomer, stereoisomer, ester, polymorph, or hydrate thereof:

[0153] wherein,

[0154] is a single or double bond;

[0155] X is O, S, NR X1 or C(R X2 )(R X3 ), wherein R X1 , R X2 and R X3 are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, and 3-8 membered heterocyclyl;

[0156] L is a bond, C 1-6 alkylene, C 1-6 haloalkylene, -C(O)-, -OC(O)-, -C(O)O-, -S(O)-, or -S(O)2-;

[0157] m is 0, 1, or 2;

[0158] R 1 is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl;

[0159] R 2 is selected from H, deuterium, C1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl;

[0160] or R 1 , R 2 and the atoms bound thereto form a 3-10 membered heterocyclyl, which is optionally substituted with 1, 2, 3, or 4 R B ;

[0161] each R B is independently selected from H, deuterium, halogen, -CN, -O-R a , -S-R a , -N(R b )(R c ), -C(O)-R a , -OC(O)-R a , -C(O)O-R a , -C(O)-N(R b )(R c ), -N(R b )C(O)-R c , -S(O)R a , -S(O)2-R a , -S(O)2NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl and 3-8 membered heterocyclyl, wherein the above groups are optionally substituted with 1, 2, 3, or 4 R*;

[0162] and / or, two R B on non-adjacent atoms are joined to form a C 1-3 alkylene;

[0163] and / or, two R B on adjacent atoms are joined to form a C 3-7 cycloalkyl or 3-8 membered heterocyclyl, wherein the above groups are optionally substituted with 1, 2, 3, or 4 R*;

[0164] and / or, two R B on the same carbon atom are joined to the carbon atom to form a C 3-7 cycloalkyl or oxo;

[0165] R 3 is selected from H, deuterium, C 1-6 alkyl, C1-6 Haloalkyl, C 3-7 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl groups, wherein the above groups are optionally surrounded by 1, 2, 3 or 4 R groups. 3a replace;

[0166] R 3a Selected from H, deuterium, and C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups, wherein the above groups are optionally substituted by 1, 2, 3 or 4 R*;

[0167] Or, R 2 R 3 Together with the atoms between them, they form 3-8 membered heterocyclic groups, which are optionally substituted with 1, 2, 3 or 4 R*.

[0168] R 4 Selected from H and C 1-6 alkyl;

[0169] R 5 Selected from H and C 1-6 alkyl;

[0170] Ring A is selected from C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl groups, wherein the above groups are optionally surrounded by 1, 2, 3 or 4 R groups. A replace;

[0171] Each R A Independently selected from H, deuterium, halogen, -CN, -OR a -SR a -N(R) b (R) c -C(O)-R a -OC(O)-R a -C(O)OR a -C(O)-N(R) b (R) c ), -N(R b )C(O)-R c -S(O)R a -S(O)2-R a -S(O)2NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10aryl and 5-10 membered heteroaryl, wherein said groups are optionally substituted with 1, 2, 3, or 4 R*;

[0172] and / or, two R A on the same carbon atom, together with the carbon atom, form a C 3-7 cycloalkyl or oxo, wherein said C 3-7 cycloalkyl is optionally substituted with 1, 2, 3, or 4 R*;

[0173] and / or, two R A on adjacent atoms, together with the carbon atoms between them and optionally the hydrogen atoms on the carbon atoms, form a C 3- 8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, wherein said groups are optionally substituted with 1, 2, 3, or 4 R A5 ;

[0174] each R A5 is independently selected from H, deuterium, halogen, -OH, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein said groups are optionally substituted with 1, 2, 3, or 4 R*;

[0175] and / or, two R A5 on the same carbon atom, together with the carbon atom, form a C 3-7 cycloalkyl, 3-8 membered heterocyclyl, or oxo, wherein said C 3-7 cycloalkyl or 3-8 membered heterocyclyl is optionally substituted with 1, 2, 3, or 4 R*;

[0176] R a , R b , and R c are each independently selected from H, halogen, -OH, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein said groups are optionally substituted with 1, 2, 3, or 4 R*;

[0177] each R* is independently selected from H, deuterium, -CN, -NO2, halogen, -O-R* a , -S-R* a , -N(R* b )(R* c ), -C(O)-R* a , -OC(O)-R*a -C(O)OR* a -C(O)-N(R*) b (R*) c -N(R*) b )C(O)-R* c -S(O)R* a -S(O)2-R* a -S(O)2NR* b R* c C 1- 6-alkyl and C 1-6 Halogenated alkyl groups;

[0178] R* a 、R* b and R* c Each is independently selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 cycloalkyl, 3-7 membered heterocyclic, C 6-10 Aryl and 5-10 heteroaryl groups; or R* b 、R* c Together with the N atoms attached to them, they form 3-7 membered heterocyclic groups.

[0179] Technical Solution 2. The compound according to Technical Solution 1, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, ester, polymorph, or hydrate thereof, wherein X is O, S, or NR. X1 or C(R) X2 (R) X3 ), where R X1 R X2 and R X3 Independently selected from H and C 1-6 Alkyl group; preferably, X is O, S, NH or CH2; preferably, X is O or NH; preferably, X is O.

[0180] Technical Solution 3. The compound according to Technical Solution 1 or 2, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, ester, polymorph or hydrate thereof, wherein L is a bond or -C(O)-; preferably, L is a bond.

[0181] Technical Solution 4. The compound according to any one of Technical Solutions 1-3, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, ester, polymorph or hydrate thereof, wherein m is 0 or 1.

[0182] TECHNICAL SOLUTION 5. The compound of any one of TECHNICAL SOLUTIONS 1-4, or a pharmaceutically acceptable salt, isotopolog, tautomer, stereoisomer, ester, polymorph, or hydrate thereof, wherein R 1 is H.

[0183] TECHNICAL SOLUTION 6. The compound of any one of TECHNICAL SOLUTIONS 1-5, or a pharmaceutically acceptable salt, isotopolog, tautomer, stereoisomer, ester, polymorph, or hydrate thereof, wherein R 2 is H.

[0184] TECHNICAL SOLUTION 7. The compound of any one of TECHNICAL SOLUTIONS 1-4, or a pharmaceutically acceptable salt, isotopolog, tautomer, stereoisomer, ester, polymorph, or hydrate thereof, wherein R 1 , R 2 and the atoms therebetween form a 3-10 membered heterocyclyl; preferably, a 5-7 membered heterocyclyl; which is optionally substituted with 1, 2, 3, or 4 R B .

[0185] TECHNICAL SOLUTION 8. The compound of TECHNICAL SOLUTION 7, or a pharmaceutically acceptable salt, isotopolog, tautomer, stereoisomer, ester, polymorph, or hydrate thereof, wherein each R B is independently selected from H, -OH, and C 1-6 alkyl; preferably, each R B is independently selected from -OH; wherein the C 1-6 alkyl is optionally substituted with 1, 2, 3, or 4 R*;

[0186] and / or, two R B on non-adjacent atoms are joined to form a C 1-3 alkylene; preferably, ethylene and methylene; preferably, methylene;

[0187] and / or, two R B on adjacent atoms are joined with the atoms therebetween to form a C 3-7 cycloalkyl or 3-8 membered heterocyclyl; preferably, cyclopropyl, cyclopentyl, or tetrahydrofuranyl;

[0188] and / or, two R B on the same carbon atom are joined with the carbon atom to form a C 3-7 cycloalkyl; preferably, cyclobutyl.

[0189] TECHNICAL SOLUTION 9. The compound of any one of TECHNICAL SOLUTIONS 1-8, or a pharmaceutically acceptable salt, isotopolog, tautomer, stereoisomer, ester, polymorph, or hydrate thereof, wherein R 3 is selected from H and C 1-6alkyl; preferably, the C 1-6 alkyl is methyl; wherein the C 1-6 alkyl is substituted with one R 3a .

[0190] Technical solution 10. The compound of technical solution 9, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, ester, polymorph, or hydrate thereof, wherein R 3a is selected from 5-10 membered heteroaryl; preferably, 5 membered heteroaryl; preferably, thienyl; wherein the above groups are optionally substituted with 1, 2, 3, or 4 R*.

[0191] Technical solution 11. The compound of any one of technical solutions 1-10, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, ester, polymorph, or hydrate thereof, wherein R 2 , R 3 and the atom therebetween together form a 3-8 membered heterocyclyl; preferably, 6 membered heterocyclyl; preferably, tetrahydropyranyl.

[0192] Technical solution 12. The compound of any one of technical solutions 1-11, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, ester, polymorph, or hydrate thereof, wherein ring A is selected from C 3-8 cycloalkenyl, 3-8 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl; preferably, cyclohexenyl, 6 membered heterocyclyl, phenyl, and 5-10 membered heteroaryl, wherein the above groups are optionally substituted with 1, 2, 3, or 4 R A .

[0193] Technical solution 13. The compound of technical solution 12, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, ester, polymorph, or hydrate thereof, wherein each R A is independently selected from H, -OH, halogen, -CN, -S(O)2-R a , C 1-6 alkyl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, and 3-8 membered heterocyclyl, wherein the C 1-6 alkyl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, and 3-8 membered heterocyclyl are optionally substituted with 1, 2, 3, or 4 R*; wherein R a is selected from 3-8 membered heterocyclyl, which is optionally substituted with 1, 2, 3, or 4 R*;

[0194] and / or, two R A on the same carbon atom together with the carbon atom form an oxo;

[0195] and / or, two R A with the carbon atom therebetween and optionally the hydrogen atom on the carbon atom, form a 5-6 membered heterocyclyl or 6 membered heteroaryl, wherein the above groups are optionally substituted with 1, 2, 3, or 4 R A5 substituents.

[0196] Technical solution 14. The compound of technical solution 13, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, ester, polymorph, or hydrate thereof, wherein each R A5 is independently selected from H, halogen, -OH, C 1-6 alkyl, C 3-7 cycloalkyl, 3-8 membered heterocyclyl, and 5-10 membered heteroaryl;

[0197] and / or, two R A5 on the same carbon atom, together with the carbon atom, form a C 3-7 cycloalkyl, 3-8 membered heterocyclyl, or oxo, wherein the C 3-7 cycloalkyl or 3-8 membered heterocyclyl is optionally substituted with 1, 2, 3, or 4 R*.

[0198] Technical solution 15. The compound of any one of technical solutions 1-14, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, ester, polymorph, or hydrate thereof, wherein ring A is wherein ring members Y 1 , Y 2 , Y 3 , and Y 4 are each independently C, N, or O atoms, and the ring A is optionally substituted with R A ;

[0199] Y 1 and Y 2 , Y 2 and Y 3 , Y 3 and Y 4 the bond between Y 1 , Y 2 , Y 3 and Y 4 is a single or double bond, or Y 1 , Y 2 , Y 3 and Y 4 together with the other ring members form a phenyl, 6 membered heterocyclyl, or 6 membered heteroaryl.

[0200] Technical solution 16. The compound of any one of technical solutions 1-15, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, ester, polymorph, or hydrate thereof, wherein ring A is selected from phenyl, 6 membered heteroaryl, wherein the above groups are optionally substituted with 1, 2, 3, or 4 RA replace.

[0201] Technical Solution 17. The compound according to Technical Solution 15 or 16, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, ester, polymorph, or hydrate thereof, wherein each R A Independently selected from H, halogen, -CN, C 1-6 Alkyl, C 3-7 Cycloalkyl, 5-10-membered heteroaryl and 3-8-membered heterocyclic groups;

[0202] And / or, two R atoms on adjacent carbon atoms A Together with the carbon atoms between them and optionally the hydrogen atoms on those carbon atoms, they form a 5-6 membered heterocyclic group or a 6-membered heteroaryl group, wherein the above group is optionally surrounded by 1, 2, 3 or 4 R atoms. A5 replace.

[0203] Technical Solution 18. The compound according to Technical Solution 17, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, ester, polymorph, or hydrate thereof, wherein each R A5 Independently selected from H and C 1-6 Alkyl, C 3-7 Cycloalkyl and 5-10 heteroaryl groups.

[0204] Technical Solution 19. The compound according to any one of Technical Solutions 1-18, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, ester, polymorph, or hydrate thereof, wherein ring A is selected from... and phenyl, wherein the above groups are optionally surrounded by 1, 2, 3 or 4 R... A replace;

[0205] R A1 and R A4 Each is independently selected from H and C. 1-6 Alkyl and C 3-7 cycloalkyl;

[0206] R A2 and R A3 Independently selected from H, halogens and C 1-6 Alkyl, or R A2 R A3 Together with the carbon atoms attached to them, they form C 3- 6-Cycloalkyl.

[0207] Technical Solution 20. The compound according to Technical Solution 19, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, ester, polymorph, or hydrate thereof, wherein each R Aindependently selected from H, halogen, -CN, C 1-6 alkyl, 5-10 membered heteroaryl, and 3-8 membered heterocyclyl.

[0208] Technical solution 21. The compound of any one of technical solutions 1-20, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, ester, polymorph, or hydrate thereof, wherein ring A is selected from and phenyl, wherein the above groups are optionally substituted with 1, 2, 3, or 4 R A substituents;

[0209] R A1 is selected from H and C 1-6 alkyl;

[0210] R A2 and R A3 are independently selected from H, halogen, and C 1-6 alkyl, or R A2 , R A3 together with the carbon atom to which they are attached form a C 3- 6cycloalkyl.

[0211] Technical solution 22. The compound of technical solution 21, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, ester, polymorph, or hydrate thereof, wherein each R A is independently selected from H, halogen, -CN, and C 1-6 alkyl.

[0212] Technical solution 23. The compound of any one of technical solutions 1-22, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, ester, polymorph, or hydrate thereof, wherein ring A is selected from wherein the above groups are optionally substituted with 1, 2, 3, or 4 R A substituents;

[0213] R A1 is selected from H and C 1-6 alkyl.

[0214] Technical solution 24. The compound of technical solution 23, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, ester, polymorph, or hydrate thereof, wherein each R A is independently selected from H and C 1-6 alkyl.

[0215] Technical solution 25. The compound of any one of technical solutions 1-24, or a pharmaceutically acceptable salt, isotopically enriched variant, tautomer, stereoisomer, ester, polymorph, or hydrate thereof, wherein ring A is selected from

[0216] Technical solution 26. The compound of any one of technical solutions 1-25, or a pharmaceutically acceptable salt, isotopically enriched variant, tautomer, stereoisomer, ester, polymorph, or hydrate thereof, wherein R 4 is H or methyl, R 5 is H; preferably; R 4 is H, and R 5 is H.

[0217] Technical solution 27. The compound of any one of technical solutions 1-26, or a pharmaceutically acceptable salt, isotopically enriched variant, tautomer, stereoisomer, ester, polymorph, or hydrate thereof, wherein the compound has the structure of Formula (X-1):

[0218] wherein the variables are as defined in any one of technical solutions 1-26.

[0219] Technical solution 28. The compound of any one of technical solutions 1-27, or a pharmaceutically acceptable salt, isotopically enriched variant, tautomer, stereoisomer, ester, polymorph, or hydrate thereof, wherein the compound has the structure of Formula (I):

[0220] wherein,

[0221] is a single or double bond; preferably, a double bond;

[0222] X is O, S, NR X1 or C(R X2 )(R X3 ), wherein R X1 , R X2 and R X3 are independently selected from H, C 1-6 alkyl and C 1-6 haloalkyl; preferably, X is O, S, NH or CH2; preferably, X is O or NH; preferably, X is O;

[0223] L is a bond or -C(O)-; preferably, L is a bond;

[0224] m is 0 or 1;

[0225] R 1 is H;

[0226] R 2 For H;

[0227] Or, R 1 R 2 Together with the atoms between them, they form 3-10 membered heterocyclic groups; preferably, 5-7 membered heterocyclic groups; which are optionally surrounded by 1, 2, 3 or 4 R atoms. B replace;

[0228] Each R B Independently selected from H, -OH and C 1-6 Alkyl; preferably, each R B Independently selected from -OH; wherein the C 1-6 Alkyl groups may optionally be substituted with 1, 2, 3 or 4 R*;

[0229] And / or, two R atoms on non-adjacent atoms B Connect to form C 1-3 Alkylene; preferably, ethylene and methylene; preferably, methylene;

[0230] And / or, two R atoms on adjacent atoms B Together with the atoms between them, they form C 3-7 Cycloalkyl or 3-8 membered heterocyclic groups; preferably cyclopropyl, cyclopentyl or tetrahydrofuranyl; wherein the above groups are optionally substituted by 1, 2, 3 or 4 R*;

[0231] And / or, two R atoms on the same carbon atom B Together with this carbon atom, they form C 3-7 cycloalkyl; preferably, cyclobutyl;

[0232] R 3 Selected from H and C 1-6 Alkyl, preferably, the C 1-6 The alkyl group is methyl; wherein the C 1-6 Alkyl group is formed by an R 3a replace;

[0233] R 3a Selected from 5-10-membered heteroaryl groups; preferably, 5-membered heteroaryl groups; preferably, thiophene groups; wherein the above groups are optionally substituted by 1, 2, 3 or 4 R* groups;

[0234] Or, R 2 R 3 Together with the atoms between them, they form 3-8 membered heterocyclic groups; preferably, 6 membered heterocyclic groups; preferably, tetrahydropyranyl groups;

[0235] Ring A is selected from C 3-8 Cycloalkenyl, 3-8 membered heterocyclic groups, C 6-10aryl and 5-10 membered heteroaryl; preferably cycloalkenyl, 6 membered heterocyclyl, phenyl and 5-10 membered heteroaryl, wherein the above mentioned groups are optionally substituted with 1, 2, 3 or 4 R A substituted;

[0236] each R A is independently selected from H, -OH, halogen, -CN, -S(O)2-R a , C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, C 6-10 aryl and 3-8 membered heterocyclyl, wherein the above mentioned groups are optionally substituted with 1, 2, 3 or 4 R a is selected from 3-8 membered heterocyclyl, which is optionally substituted with 1, 2, 3 or 4 R

[0237] and / or, two R A on the same carbon atom together form oxo;

[0238] and / or, two R A on adjacent carbon atoms together with the carbon atoms between them and optionally the hydrogen atom on the carbon atom form a 5-6 membered heterocyclyl or 6 membered heteroaryl, wherein the above mentioned groups are optionally substituted with 1, 2, 3 or 4 R A5 substituted;

[0239] each R A5 is independently selected from H, halogen, -OH, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, 3-8 membered heterocyclyl, C 6- 10 aryl and 5-10 membered heteroaryl;

[0240] and / or, two R A5 on the same carbon atom together form C 3-7 cycloalkyl, 3-8 membered heterocyclyl or oxo, wherein the C 3-7 cycloalkyl or 3-8 membered heterocyclyl is optionally substituted with 1, 2, 3 or 4 R

[0241] R a , R b and R c are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein the above mentioned groups are optionally substituted with 1, 2, 3 or 4 R

[0242] each R* is independently selected from H, -CN, -NO2, halogen, -O-R* a , -S-R* a , -N(R* b )(R* c ), -C(O)-R* a , -OC(O)-R* a , -C(O)O-R* a , -C(O)-N(R* b )(R* c ), -N(R* b )C(O)-R* c , -S(O)R* a , -S(O)2-R* a , -S(O)2NR* b R* c , C 1- 6alkyl and C 1-6 haloalkyl;

[0243] R* a , R* b and R* c are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, 3-7 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl; or R* b , R* c and the N atom to which they are attached form a 3-7 membered heterocyclyl.

[0244] Technical solution 29. The compound of technical solution 1, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, ester, polymorph, or hydrate thereof, wherein the compound has the structure of formula (I-1):

[0245] wherein,

[0246] is a single or double bond;

[0247] X is O, S, NR X1 or C(R X2 )(R X3 ), wherein R X1 , R X2 and R X3 are independently selected from H, C 1-6 alkyl, Chaloalkyl and C 3-7 cycloalkyl;

[0248] L is a bond or -C(O)-;

[0249] Z is -C(R B1 )(R B2 )-, -NR B3 -, -O- or -S-;

[0250] m is 0 or 1 ;

[0251] q is 1, 2, 3, 4 or 5;

[0252] p is 0, 1, 2, 3, 4 or 5;

[0253] R B , R B1 , R B2 and R B3 are each independently selected from H, halogen, -CN, -O-R a , -S-R a , -N(R b )(R c ), -C(O)-R a , -OC(O)-R a , -C(O)O-R a , -C(O)-N(R b )(R c ), -N(R b )C(O)-R c , -S(O)R a , -S(O)2-R a , -S(O)2NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein the above groups are optionally substituted with 1, 2, 3 or 4 R*;

[0254] and / or, two of R B , R B1 , R B2 or R B3 on adjacent atoms are joined to form a C 1-3 alkylene group;

[0255] and / or, two of R B , R B1 , R B2 or R B3 on adjacent atoms are joined to form a C 3-7 alkylene group.two of which, together with the atoms between them, form C 3-7 cycloalkyl or 3-8 membered heterocyclyl, wherein the above groups are optionally substituted with 1, 2, 3, or 4 R*;

[0256] and / or, R B1 and R B2 together with the carbon atom form C 3-7 cycloalkyl or oxo;

[0257] R 3 is selected from H and C 1-6 alkyl;

[0258] Ring A is selected from C 3-8 cycloalkenyl, 3-10 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein the above groups are optionally substituted with 1, 2, 3, or 4 R A ;

[0259] each R A is independently selected from H, halogen, -CN, -O-R a , -S-R a , -N(R b )(R c ), -C(O)-R a , -OC(O)-R a , -C(O)O-R a , -C(O)-N(R b )(R c ), -N(R b )C(O)-R c , -S(O)R a , -S(O)2-R a , -S(O)2NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein the above groups are optionally substituted with 1, 2, 3, or 4 R*;

[0260] and / or, two R A on the same carbon atom together with the carbon atom form C 3-7 cycloalkyl or oxo, wherein the C 3-7 cycloalkyl is optionally substituted with 1, 2, 3, or 4 R*;

[0261] and / or, two R Awith the carbon atom and optionally the hydrogen atom on the carbon atom together forming C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, wherein the above groups are optionally substituted with 1, 2, 3, or 4 R A5 substituents;

[0262] each R A5 is independently selected from the group consisting of H, halogen, -OH, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, 3-8 membered heterocyclyl, C 6- 10 aryl and 5-10 membered heteroaryl, wherein the above groups are optionally substituted with 1, 2, 3, or 4 R

[0263] and / or, two R A5 on the same carbon atom together with the carbon atom form C 3-7 cycloalkyl, 3-8 membered heterocyclyl, or oxo, wherein the C 3-7 cycloalkyl or 3-8 membered heterocyclyl is optionally substituted with 1, 2, 3, or 4 R

[0264] R a , R b , and R c are each independently selected from the group consisting of H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein the above groups are optionally substituted with 1, 2, 3, or 4 R

[0265] each R* is independently selected from the group consisting of H, -CN, -NO2, halogen, -O-R* a , -S-R* a , -N(R* b )(R* c ), -C(O)-R* a , -OC(O)-R* a , -C(O)O-R* a , -C(O)-N(R* b )(R* c ), -N(R* b )C(O)-R* c , -S(O)R* a , -S(O)2-R* a , -S(O)2NR* b R* c , C 1- 6alkyl and C1-6 Halogenated alkyl groups;

[0266] R* a 、R* b and R* c Each is independently selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 Cycloalkyl, 3-7 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups; or R* b 、R* c Together with the N atoms attached to them, they form 3-7 membered heterocyclic groups.

[0267] Technical Solution 30. The compound of formula (I-1) according to Technical Solution 29, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, ester, polymorph, or hydrate thereof, wherein,

[0268] It can be a single bond or a double bond;

[0269] X represents O, S, and NR. X1 or C(R) X2 (R) X3 ), where R X1 R X2 and R X3 Independently selected from H and C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 3-7 cycloalkyl;

[0270] L represents a bond or -C(O)-;

[0271] Z is -C(R) B1 (R) B2 - or -O-;

[0272] m is 0 or 1;

[0273] q is 1, 2, 3, or 4;

[0274] p is 0, 1, 2, 3, 4 or 5;

[0275] R B R B1 R B2 and R B3 Each is independently selected from H, halogen, -OH and C. 1-6 alkyl;

[0276] And / or, R on non-adjacent atoms B RB1 or R B2 are both attached to form a C 1-3 alkylene;

[0277] and / or, R B , R B1 or R B2 on adjacent atoms are taken together with their intervening atoms to form a C 3-7 cycloalkyl or 3-8 membered heterocyclyl;

[0278] and / or, R B1 , R B2 on the same carbon atom are taken together with the carbon atom to form a C 3-7 cycloalkyl;

[0279] R 3 is H;

[0280] Ring A is selected from C 3-8 cycloalkenyl, 3-10 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein the foregoing rings are optionally substituted with 1, 2, 3, or 4 R A ;

[0281] each R A is independently selected from H, halogen, -CN, -O-R a , -S-R a , -N(R b )(R c ), -C(O)-R a , -OC(O)-R a , -C(O)O-R a , -C(O)-N(R b )(R c ), -N(R b )C(O)-R c , -S(O)R a , -S(O)2-R a , -S(O)2NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein the foregoing rings are optionally substituted with 1, 2, 3, or 4 R*;

[0282] and / or, two R A on the same carbon atom are taken together with the carbon atom to form a C 3-7 cycloalkyl or oxo, wherein the C 3-7cycloalkyl is optionally substituted with 1, 2, 3, or 4 R*;

[0283] and / or, two R A together with the carbon atom between them and optionally a hydrogen atom on the carbon atom form a C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, wherein the above groups are optionally substituted with 1, 2, 3, or 4 R A5 ;

[0284] each R A5 is independently selected from H, halogen, -OH, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, 3-8 membered heterocyclyl, C 6- 10 aryl and 5-10 membered heteroaryl, wherein the above groups are optionally substituted with 1, 2, 3, or 4 R*;

[0285] and / or, two R A5 on the same carbon atom together with the carbon atom form a C 3-7 cycloalkyl, 3-8 membered heterocyclyl, or oxo, wherein the C 3-7 cycloalkyl is optionally substituted with 1, 2, 3, or 4 R*;

[0286] R a , R b , and R c are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein the above groups are optionally substituted with 1, 2, 3, or 4 R*;

[0287] each R* is independently selected from H, -CN, -NO2, halogen, -O-R* a , -S-R* a , -N(R* b )(R* c ), -C(O)-R* a , -OC(O)-R* a , -C(O)O-R* a , -C(O)-N(R* b )(R* c ), -N(R* b )C(O)-R* c , -S(O)R* a , -S(O)2-R*a -S(O)2NR* b R* c C 1- 6-alkyl and C 1-6 Halogenated alkyl groups;

[0288] R* a 、R* b and R* c Each is independently selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 Cycloalkyl, 3-7 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups; or R* b 、R* c Together with the N atoms attached to them, they form 3-7 membered heterocyclic groups.

[0289] Technical Solution 31. The compound according to Technical Solution 1, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, ester, polymorph, or hydrate thereof, wherein the compound has the structure of formula (I-2):

[0290] in,

[0291] It can be a single bond or a double bond;

[0292] X represents O, S, and NR. X1 or C(R) X2 (R) X3 ), where R X1 R X2 and R X3 Independently selected from H and C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 3-7 cycloalkyl;

[0293] L represents a bond or -C(O)-;

[0294] Ring A is selected from C 3-8 Cycloalkenyl, 3-10 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl groups, wherein the above groups are optionally surrounded by 1, 2, 3 or 4 R groups. A replace;

[0295] Each R A Independently selected from H, halogen, -CN, -OR a -SR a -N(R) b (R)c -C(O)-R a -OC(O)-R a -C(O)OR a -C(O)-N(R) b (R) c ), -N(R b )C(O)-R c -S(O)R a -S(O)2-R a -S(O)2NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups, wherein the above groups are optionally substituted by 1, 2, 3 or 4 R*;

[0296] And / or, two R atoms on the same carbon atom A Together with this carbon atom, they form C 3-7 cycloalkyl or oxo, wherein the C 3-7 The cycloalkyl group is optionally substituted with 1, 2, 3 or 4 R*;

[0297] And / or, two R atoms on adjacent carbon atoms A Together with the carbon atoms between them and optionally the hydrogen atoms on those carbon atoms, they form C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl, wherein the above groups are optionally surrounded by 1, 2, 3 or 4 R groups. A5 replace;

[0298] Each R A5 Independently selected from H, halogens, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, 3-8 membered heterocyclic groups, C 6- 10 Aryl and 5-10 heteroaryl groups, wherein the above groups are optionally substituted by 1, 2, 3 or 4 R*;

[0299] And / or, two R atoms on the same carbon atom A5 Together with this carbon atom, they form C 3-7 Cycloalkyl, 3-8 membered heterocyclic or oxo, wherein the C 3-7 The cycloalkyl or 3-8 membered heterocyclic group is optionally substituted with 1, 2, 3 or 4 R*;

[0300] R a Rb and R c each independently is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein the above groups are optionally substituted with 1, 2, 3, or 4 R*;

[0301] each R* is independently selected from H, -CN, -NO2, halogen, -O-R* a , -S-R* a , -N(R* b )(R* c ), -C(O)-R* a , -OC(O)-R* a , -C(O)O-R* a , -C(O)-N(R* b )(R* c ), -N(R* b )C(O)-R* c , -S(O)R* a , -S(O)2-R* a , -S(O)2NR* b R* c , C 1- 6alkyl and C 1-6 haloalkyl;

[0302] R* a , R* b and R* c each independently is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, 3-7 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl; or R b , R c and the N atom to which they are attached form a 3-7 membered heterocyclyl group;

[0303] n is 1 or 2.

[0304] Technical solution 32. The compound of formula (I-2) according to technical solution 31, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, ester, polymorph, or hydrate thereof, wherein,

[0305] is a single or double bond;

[0306] X is O, S, NR X1 or C(R X2 )(R X3 ), wherein R X1 , R X2 and R X3 are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl and C 3-7 cycloalkyl;

[0307] L is a bond or -C(O)-;

[0308] Ring A is selected from C 3-8 cycloalkenyl, 3-10 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein the above groups are optionally substituted with 1, 2, 3 or 4 R A ;

[0309] each R A is independently selected from H, halogen, -CN, -OH, C 1-6 alkyl and C 3-7 cycloalkyl;

[0310] and / or, two R A on adjacent carbon atoms, together with the carbon atoms therebetween and optionally the hydrogen atoms on said carbon atoms, form a C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, wherein the above groups are optionally substituted with 1, 2, 3 or 4 R A5 ;

[0311] each R A5 is independently selected from H, halogen, -OH, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, 3-8 membered heterocyclyl, C 6- 10 aryl and 5-10 membered heteroaryl, wherein the above groups are optionally substituted with 1, 2, 3 or 4 R*;

[0312] and / or, two R A5 on the same carbon atom, together with the carbon atom, form a C 3-7 cycloalkyl, 3-8 membered heterocyclyl or oxo, wherein said C 3-7 cycloalkyl or 3-8 membered heterocyclyl is optionally substituted with 1, 2, 3 or 4 R*;

[0313] each R* is independently selected from H, -CN, -NO2, halogen, -O-R* a , -S-R* a , -N(R* b(R c )-C(O)-R a , -OC(O)-R a , -C(O)O-R a , -C(O)-N(R b )(R c ), -N(R b )C(O)-R c , -S(O)R a , -S(O)2-R a , -S(O)2NR b R c , C 1- 6alkyl, and C 1-6 haloalkyl;

[0314] R a , R b , and R c are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, 3-7 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl; or R b , R c , and the N atom to which they are attached form a 3-7 membered heterocyclyl;

[0315] n is 1 or 2.

[0316] Technical solution 33. The compound of technical solution 1, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, ester, polymorph, or hydrate thereof, wherein the compound has the structure of formula (I-3):

[0317] wherein,

[0318] is a double bond;

[0319] X is O or NR X1 , wherein R X1 is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, and C 3-7 cycloalkyl;

[0320] Ring A is phenyl, optionally substituted with 1, 2, 3, or 4 R A ;

[0321] each R Aindependently selected from H, halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, 3-8 membered heterocyclyl, C 6- 10 aryl and 5-10 membered heteroaryl, wherein the above groups are optionally substituted with 1, 2, 3 or 4 R*;

[0322] and / or, two R A on adjacent carbon atoms, together with the carbon atoms they are attached to and optionally the hydrogen atoms on the carbon atoms, form a C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, wherein the above groups are optionally substituted with 1, 2, 3 or 4 R A5 ;

[0323] each R A5 is independently selected from H, halogen, -OH, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, 3-8 membered heterocyclyl, C 6- 10 aryl and 5-10 membered heteroaryl, wherein the above groups are optionally substituted with 1, 2, 3 or 4 R*;

[0324] and / or, two R A5 on the same carbon atom, together with the carbon atom, form a C 3-7 cycloalkyl, 3-8 membered heterocyclyl or oxo, wherein the C 3-7 cycloalkyl or 3-8 membered heterocyclyl is optionally substituted with 1, 2, 3 or 4 R*;

[0325] each R* is independently selected from H, -CN, -NO2, halogen, -O-R* a , -S-R* a , -N(R* b )(R* c ), -C(O)-R* a , -OC(O)-R* a , -C(O)O-R* a , -C(O)-N(R* b )(R* c ), -N(R* b )C(O)-R* c , -S(O)R* a , -S(O)2-R* a , -S(O)2NR* b R* c , C 1- 6alkyl and C1-6 Halogenated alkyl groups;

[0326] R* a 、R* b and R* c Each is independently selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 Cycloalkyl, 3-7 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups; or R* b 、R* c Together with the N atoms attached to them, they form 3-7 membered heterocyclic groups;

[0327] n is 1 or 2.

[0328] Technical Solution 34. The compound of formula (I-3) according to Technical Solution 33, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, ester, polymorph, or hydrate thereof, wherein,

[0329] It is a double bond;

[0330] X is O or NR X1 , where R X1 Selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 3-7 cycloalkyl;

[0331] Ring A is a phenyl group, optionally surrounded by 1, 2, 3, or 4 R groups. A replace;

[0332] Each R A Independently selected from H, -CN and C 1-6 alkyl;

[0333] And / or, two R atoms on adjacent carbon atoms A Together with the carbon atoms between them and optionally the hydrogen atoms on those carbon atoms, they form 5-10-membered heteroaryl groups or 3-8-membered heterocyclic groups, wherein the above groups are optionally surrounded by 1, 2, 3 or 4 R groups. A5 replace;

[0334] Each R A5 Independently selected from H and C 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0335] And / or, two R atoms on the same carbon atom A5 Together with the carbon atom, it forms a 3-8 membered heterocyclic group or an oxo group;

[0336] n is 1 or 2;

[0337] Preferably,

[0338] is a double bond;

[0339] X is O or NR X1 wherein R X1 is selected from H, C 1-6 alkyl and C 1-6 haloalkyl;

[0340] Ring A is selected from and phenyl, wherein the aforementioned groups are optionally substituted with 1, 2, 3 or 4 R A substituents;

[0341] each R A is independently selected from H, -CN and C 1-6 alkyl;

[0342] R A1 is selected from H and C 1-6 alkyl;

[0343] n is 1 ;

[0344] Preferably,

[0345] is a double bond;

[0346] X is O or NH;

[0347] Ring A is selected from

[0348] n = 1 ;

[0349] Preferably,

[0350] is a double bond;

[0351] X is O;

[0352] Ring A is selected from and phenyl, wherein the aforementioned groups are optionally substituted with 1, 2, 3 or 4 R A substituents;

[0353] each R A is independently selected from H, -CN and C 1-6 alkyl;

[0354] R A1 is selected from H and C 1-6 alkyl;

[0355] n is 1 ;

[0356] Preferably,

[0357] is a double bond;

[0358] X is O;

[0359] Ring A is

[0360] n = 1.

[0361] Technical solution 35. The compound of technical solution 1, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, ester, polymorph, or hydrate thereof, wherein the compound has the structure of formula (I-4):

[0362] wherein,

[0363] is a single or double bond;

[0364] X is O, S, NR X1 or C(R X2 )(R X3 ), wherein R X1 , R X2 and R X3 are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl and C 3-7 cycloalkyl;

[0365] Ring A is selected from C 3-8 cycloalkenyl, 3-10 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein the above groups are optionally substituted with 1, 2, 3 or 4 R A ;

[0366] each R A is independently selected from H, halogen, -CN, -O-R a , -S-R a , -N(R b )(R c ), -C(O)-R a , -OC(O)-R a , -C(O)O-R a , -C(O)-N(R b )(R c ), -N(R b )C(O)-R c , -S(O)R a , -S(O)2-R a , -S(O)2NR b R c , C1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein the above groups are optionally substituted with 1, 2, 3, or 4 R*;

[0367] and / or, two R A on the same carbon atom, together with the carbon atom, form a C 3-7 cycloalkyl or oxo, wherein the C 3-7 cycloalkyl is optionally substituted with 1, 2, 3, or 4 R*;

[0368] and / or, two R A on adjacent carbon atoms, together with the carbon atoms between them and the hydrogen atoms optionally present on the carbon atoms, form a C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, wherein the above groups are optionally substituted with 1, 2, 3, or 4 R A5 ;

[0369] each R A5 is independently selected from H, halogen, -OH, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, 3-8 membered heterocyclyl, C 6- 10 aryl and 5-10 membered heteroaryl, wherein the above groups are optionally substituted with 1, 2, 3, or 4 R*;

[0370] and / or, two R A5 on the same carbon atom, together with the carbon atom, form a C 3-7 cycloalkyl or oxo, wherein the C 3-7 cycloalkyl is optionally substituted with 1, 2, 3, or 4 R*;

[0371] R a , R b and R c are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein the above groups are optionally substituted with 1, 2, 3, or 4 R*;

[0372] each R* is independently selected from H, -CN, -NO2, halogen, -O-R* a , -S-R* a , -N(R* b )(R*c -C(O)-R* a -OC(O)-R* a -C(O)O-R* a -C(O)-N(R* b )(R* c -N(R* b )C(O)-R* c -S(O)R* a -S(O)2-R* a -S(O)2NR* b R* c C 1- 6alkyl and C 1-6 haloalkyl;

[0373] R* a , R* b and R* c are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, 3-7 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl; or R b , R c and the N atom to which they are attached form a 3-7 membered heterocyclyl.

[0374] Technical solution 36. The compound of Formula (I-4) according to technical solution 35, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, ester, polymorph, or hydrate thereof, wherein,

[0375] is a single or double bond;

[0376] X is O, S, NR X1 or C(R X2 )(R X3 ), wherein R X1 , R X2 and R X3 are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl and C 3-7 cycloalkyl;

[0377] Ring A is selected from C 3-8 cycloalkenyl, 3-10 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein the aforementioned groups are optionally substituted with 1, 2, 3 or 4 R A .

[0378] each R A is independently selected from H, halogen, -CN, -O-R a , -C(O)O-R a , -C(O)-N(R b )(R c ), C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein the above groups are optionally substituted with 1, 2, 3, or 4 R*;

[0379] and / or, two R A on the same carbon atom, together with the carbon atom, form a C 3-7 cycloalkyl or oxo, wherein the C 3-7 cycloalkyl is optionally substituted with 1, 2, 3, or 4 R*;

[0380] and / or, two R A on adjacent carbon atoms, together with the carbon atoms between them and optionally the hydrogen atoms on the carbon atoms, form a C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, wherein the above groups are optionally substituted with 1, 2, 3, or 4 R A5 ;

[0381] each R A5 is independently selected from H, halogen, -OH, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, 3-8 membered heterocyclyl, C 6- 10 aryl and 5-10 membered heteroaryl, wherein the above groups are optionally substituted with 1, 2, 3, or 4 R*;

[0382] and / or, two R A5 on the same carbon atom, together with the carbon atom, form a C 3-7 cycloalkyl or oxo, wherein the C 3-7 cycloalkyl is optionally substituted with 1, 2, 3, or 4 R*;

[0383] R a , R b and R c are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, C 6-10aryl and 3-8 membered heterocyclyl, wherein the above groups are optionally substituted with one or more R*;

[0384] each R* is independently selected from H, -CN, -NO2, halogen, -O-R* a , -S-R* a , -N(R* b )(R* c ), -C(O)-R* a , -OC(O)-R* a , -C(O)O-R* a , -C(O)-N(R* b )(R* c ), -N(R* b )C(O)-R* c , -S(O)R* a , -S(O)2-R* a , -S(O)2NR* b R* c , C 1- 6alkyl and C 1-6 haloalkyl;

[0385] each R* is independently selected from H, -CN, -NO2, halogen, -O-R* a , -S-R* b , -N(R* c )(R* 1-6 , C 1-6 alkyl, C 2-6 haloalkyl, C 2-6 alkenyl, C 3-7 alkynyl, C 6-10 cycloalkyl, 3-7 membered heterocyclyl, C b aryl and 5-10 membered heteroaryl; or R c , R X1 and the N atom to which they are attached together form a 3-7 membered heterocyclyl.

[0386] Technical Solution 37. The compound of Technical Solution 1, or a pharmaceutically acceptable salt, isotopically enriched variant, tautomer, stereoisomer, ester, polymorph, or hydrate thereof, wherein the compound has the structure of Formula (I-5):

[0387] wherein,

[0388] is a single or double bond;

[0389] X is O, S, or NR X1 , preferably O or NR X1 ; wherein R X1 is selected from H, C 1-6 alkyl, C 1-6 haloalkyl.Halogenated alkyl groups and C 3-7 cycloalkyl;

[0390] Ring A is selected from C 3-8 Cycloalkenyl, 3-10 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl groups, wherein the above groups are optionally surrounded by 1, 2, 3 or 4 R groups. A replace;

[0391] Each R A Independently selected from H, halogen, -CN, -OR a -C(O)OR a -C(O)-N(R) b (R) c C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, C 6-10 Aryl and 6-8 membered heterocyclic groups, wherein the above groups are optionally substituted by 1, 2, 3 or 4 R*;

[0392] R a R b and R c Each is independently selected from H and C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0393] And / or, two R atoms on the same carbon atom A Together with this carbon atom, they form C 3-7 cycloalkyl or oxo, wherein the C 3-7 The cycloalkyl group is optionally substituted with 1, 2, 3 or 4 R*; preferably, two R* on the same carbon atom. A Together with the carbon atom, it forms an oxo group; and / or, two R atoms on adjacent carbon atoms... A Together with the carbon atoms between them and optionally the hydrogen atoms on those carbon atoms, they form C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl, wherein the above groups are optionally surrounded by 1, 2, 3 or 4 R groups. A5 replace;

[0394] Each R A5 Independently selected from H, halogens, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, 3-8 membered heterocyclic groups, C 6- 10 Aryl and 5-10 heteroaryl groups, wherein the above groups are optionally substituted by 1, 2, 3 or 4 R*;

[0395] and / or two R groups on the same carbon atom are taken together to form a C A5 and together with the carbon atom form a C 3-7 cycloalkyl or oxo, wherein the C 3-7 cycloalkyl is optionally substituted with 1, 2, 3, or 4 R*;

[0396] each R* is independently selected from the group consisting of H, -CN, -NO2, halogen, -O-R* a , -S-R* a , -N(R* b )(R* c ), -C(O)-R* a , -OC(O)-R* a , -C(O)O-R* a , -C(O)-N(R* b )(R* c ), -N(R* b )C(O)-R* c , -S(O)R* a , -S(O)2-R* a , -S(O)2NR* b R* c , C 1- 6alkyl and C 1-6 haloalkyl;

[0397] R* a , R* b and R* c are each independently selected from the group consisting of H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, 3-7 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl; or R b , R c and the N atom to which they are attached form a 3-7 membered heterocyclyl;

[0398] preferably,

[0399] is a single or double bond;

[0400] X is O, S or NH, preferably O or NH;

[0401] Ring A is selected from

[0402] Technical solution 38. The compound of formula (I-5) according to technical solution 37, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, ester, polymorph, or hydrate thereof, wherein,

[0403] is a single or double bond;

[0404] X is O, S, or NR X1 , preferably O or NR X1 ; wherein R X1 is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, and C 3-7 cycloalkyl;

[0405] Ring A is wherein the ring members Y 1 , Y 2 , Y 3 , and Y 4 are each independently C, N, or O atoms, and said ring A is optionally substituted with R A ;

[0406] the bond between Y 1 and Y 2 , Y 2 and Y 3 , Y 3 and Y 4 is a single or double bond, or Y 1 , Y 2 , Y 3 and Y 4 together with the other ring members form a phenyl, 6-membered heterocyclyl, or 6-membered heteroaryl;

[0407] each R A is independently selected from H, halogen, -CN, -O-R a , C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, C 6-10 aryl, and 6-8 membered heterocyclyl, wherein the aforementioned groups are optionally substituted with 1, 2, 3, or 4 R*;

[0408] R a is selected from H, C 1-6 alkyl, and C 1-6 haloalkyl;

[0409] and / or, two R A on adjacent carbon atoms, together with the carbon atoms therebetween and optionally the hydrogen atoms on the carbon atoms, form a C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl or 5-10 membered heteroaryl, wherein the above groups are optionally substituted with 1, 2, 3, or 4 R A5 substituents;

[0410] each R A5 is independently selected from the group consisting of H, halogen, -OH, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, 3-8 membered heterocyclyl, C 6- 10 aryl and 5-10 membered heteroaryl, wherein the above groups are optionally substituted with 1, 2, 3, or 4 R

[0411] and / or, two R A5 on the same carbon atom together with the carbon atom form a C 3-7 cycloalkyl or oxo, wherein the C 3-7 cycloalkyl is optionally substituted with 1, 2, 3, or 4 R

[0412] each R is independently selected from the group consisting of H, -CN, -NO2, halogen, -O-R a , -S-R a , -N(R b )(R c ), -C(O)-R a , -OC(O)-R a , -C(O)O-R a , -C(O)-N(R b )(R c ), -N(R b )C(O)-R c , -S(O)R a , -S(O)2-R a , -S(O)2NR b R c , C 1- 6alkyl and C 1-6 haloalkyl;

[0413] R a , R b and R c are each independently selected from the group consisting of H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, 3-7 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl; or R b , R cand together with the N atom to which they are attached form a 3-7 membered heterocyclyl;

[0414] Preferably,

[0415] is a single or double bond;

[0416] X is O or NH;

[0417] Ring A is selected from

[0418] Technical solution 39. The compound of formula (I-5) according to technical solution 38, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, ester, polymorph, or hydrate thereof, wherein,

[0419] is a single or double bond;

[0420] X is O, S, or NR X1 , preferably O or NR X1 ; wherein R X1 is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, and C 3-7 cycloalkyl;

[0421] Ring A is selected from phenyl, 6-membered heteroaryl, wherein the aforementioned groups are optionally substituted with 1, 2, 3, or 4 R A ;

[0422] each R A is independently selected from H, halogen, -CN, -O-R a , C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, 5-6 membered heteroaryl, C 6-10 aryl, and 6-8 membered heterocyclyl, wherein the aforementioned groups are optionally substituted with 1, 2, 3, or 4 R*;

[0423] R a is selected from H and C 1-6 alkyl;

[0424] and / or, two R A on adjacent carbon atoms, together with the carbon atoms therebetween and optionally the hydrogen atoms on the carbon atoms, form a C 6-10 aryl, 5-6 membered heteroaryl, or 3-8 membered heterocyclyl; preferably, 5-10 membered heteroaryl or 3-8 membered heterocyclyl; wherein the aforementioned groups are optionally substituted with 1, 2, 3, or 4 R A5 ;

[0425] Each R A5 Independently selected from H, halogens, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, 3-8 membered heterocyclic groups, C 6- 10 Aryl and 5-10 heteroaryl; preferably, H, C 1-6 Alkyl, C 3-7 Cycloalkyl and 5-10 heteroaryl groups; wherein the above groups are optionally substituted by 1, 2, 3 or 4 R*;

[0426] And / or, two R atoms on the same carbon atom A5 Together with this carbon atom, they form C 3-7 cycloalkyl or oxo, wherein the C 3-7 The cycloalkyl group is optionally substituted with 1, 2, 3 or 4 R*;

[0427] Each R* is independently selected from H, -CN, -NO2, halogen, -OR* a -SR* a -N(R*) b (R*) c -C(O)-R* a -OC(O)-R* a -C(O)OR* a -C(O)-N(R*) b (R*) c -N(R*) b )C(O)-R* c -S(O)R* a -S(O)2-R* a -S(O)2NR* b R* c C 1- 6-alkyl and C 1-6 Halogenated alkyl groups;

[0428] R* a 、R* b and R* c Each is independently selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 cycloalkyl, 3-7 membered heterocyclic, C 6-10 Aryl and 5-10 heteroaryl groups; or R* b 、R* c Together with the N atoms attached to them, they form 3-7 membered heterocyclic groups;

[0429] Preferably,

[0430] is a single or double bond;

[0431] X is O or NH;

[0432] Ring A is selected from

[0433] Technical solution 40. The compound of formula (I-5) according to technical solution 39, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, ester, polymorph, or hydrate thereof, wherein,

[0434] is a single or double bond;

[0435] X is O, S, or NR X1 , preferably O or NR X1 ; wherein R X1 is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, and C 3-7 cycloalkyl;

[0436] Ring A is selected from and phenyl, wherein the aforementioned groups are optionally substituted with 1, 2, 3, or 4 R A ;

[0437] Each R A is independently selected from H, halogen, -CN, -O-R a , C 1-6 alkyl, C 1-6 haloalkyl, 5-6 membered heteroaryl, and 6-8 membered heterocyclyl, wherein the aforementioned groups are optionally substituted with 1, 2, 3, or 4 R*;

[0438] R a is selected from H, C 1-6 alkyl, and C 1-6 haloalkyl;

[0439] R A1 and R A4 are each independently selected from H, C 1-6 alkyl, and C 3-7 cycloalkyl, optionally substituted with 1, 2, 3, or 4 R*;

[0440] R A2 and R A3 are independently selected from H, halogen, and C 1-6 alkyl, or R A2 , R A3 together with the carbon atom to which they are attached form a C3- 6 cycloalkyl;

[0441] each R* is independently selected from H, -CN, -NO2, halogen, -O-R* a , -S-R* a , -N(R* b )(R* c ), -C(O)-R* a , -OC(O)-R* a , -C(O)O-R* a , -C(O)-N(R* b )(R* c ), -N(R* b )C(O)-R* c , -S(O)R* a , -S(O)2-R* a , -S(O)2NR* b R* c , C 1- 6 alkyl and C 1-6 haloalkyl; preferably, each R* is independently selected from H, -OH and C 1-6 alkyl;

[0442] R* a , R* b and R* c are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, 3-7 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl; or R b , R c and the N atom to which they are attached form a 3-7 membered heterocyclyl;

[0443] preferably,

[0444] is a single or double bond;

[0445] X is O or NH;

[0446] Ring A is selected from

[0447] Technical solution 41. The compound of formula (I-5) according to technical solution 40, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, ester, polymorph, or hydrate thereof, wherein,

[0448] is a single or double bond;

[0449] X is O, S or NR X1 , preferably O or NR X1 ; wherein R X1 is selected from H, C 1-6 alkyl, C 1-6 haloalkyl and C 3-7 cycloalkyl;

[0450] Ring A is selected from and phenyl, wherein the above mentioned groups are optionally substituted with 1, 2, 3 or 4 R A ;

[0451] each R A is independently selected from H, halogen, -CN and C 1-6 alkyl;

[0452] R A1 is selected from H and C 1-6 alkyl;

[0453] R A2 and R A3 are independently selected from H, halogen and C 1-6 alkyl, or R A2 , R A3 together with the carbon atom to which they are attached form a C 3-6 cycloalkyl;

[0454] Preferably,

[0455] is a single or double bond;

[0456] X is O or NH;

[0457] Ring A is selected from

[0458] Technical solution 42. The compound of formula (I-5) according to technical solution 41, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, ester, polymorph, or hydrate thereof, wherein,

[0459] is a double bond;

[0460] X is O, S or NR X1 , preferably O or NR X1 ; wherein R X1 is selected from H, C 1-6 alkyl and C 1-6 haloalkyl; preferably, X is O or NH;

[0461] Ring A is selected from wherein the above groups are optionally substituted with 1, 2, 3, or 4 R A substituted;

[0462] each R A is independently selected from H and C 1-6 alkyl;

[0463] R A1 is selected from H and C 1-6 alkyl, preferably C 1-6 alkyl;

[0464] preferably,

[0465] is a double bond;

[0466] X is O or NH;

[0467] Ring A is selected from

[0468] TECHNICAL SOLUTION 43. The compound of any one of TECHNICAL SOLUTIONS 1-42, or a pharmaceutically acceptable salt, isotopically enriched variant, tautomer, stereoisomer, ester, polymorph, or hydrate thereof, wherein the compound is selected from:

[0469] TECHNICAL SOLUTION 44. A pharmaceutical composition comprising the compound of any one of TECHNICAL SOLUTIONS 1-43, or a pharmaceutically acceptable salt, isotopically enriched variant, tautomer, stereoisomer, ester, polymorph, or hydrate thereof, and a pharmaceutically acceptable excipient.

[0470] TECHNICAL SOLUTION 45. Use of the compound of any one of TECHNICAL SOLUTIONS 1-43, or a pharmaceutically acceptable salt, isotopically enriched variant, tautomer, stereoisomer, ester, polymorph, or hydrate thereof, or the pharmaceutical composition of TECHNICAL SOLUTION 44, in the manufacture of a medicament for the treatment and / or prevention of a disease associated with the inhibition of Cathepsin C.

[0471] TECHNICAL SOLUTION 46. The compound of any one of TECHNICAL SOLUTIONS 1-43, or a pharmaceutically acceptable salt, isotopically enriched variant, tautomer, stereoisomer, ester, polymorph, or hydrate thereof, or the pharmaceutical composition of TECHNICAL SOLUTION 42, for use in the treatment and / or prevention of a disease associated with the inhibition of Cathepsin C.

[0472] Technical solution 47. A method of treating and / or preventing a disease associated with inhibiting cathepsin C in a subject, comprising administering to the subject a compound of any one of technical solutions 1-43, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, ester, polymorph, or hydrate thereof, or the pharmaceutical composition of technical solution 44.

[0473] Technical solution 48. The use of technical solution 45 or the use of the compound of technical solution 46 or the method of technical solution 47, wherein the disease associated with inhibiting cathepsin C is a neutrophil-dominant inflammatory disease.

[0474] Technical solution 49. The use or the use of the compound or the method of technical solution 48, wherein the disease is a respiratory disease.

[0475] Technical solution 50. The use or the use of the compound or the method of technical solution 48, wherein the disease is bronchiectasis.

[0476] Examples

[0477] In order to make the technical solutions of the present application clearer and more explicit, the present application is further described in detail by the following examples. The following examples are only used to illustrate the specific embodiments of the present application, so that those skilled in the art can understand the present application, but not used to limit the protection scope of the present application. In the specific embodiments of the present application, the technical means or methods not specifically described are the conventional technical means or methods in the art. The materials, reagents, etc. used in the examples, if not specifically described, can be obtained from commercial channels.

[0478] Synthesis of key intermediates:

[0479] Key intermediate A

[0480] Synthesis of compound A:

[0481] Weigh SM-A (5.0 g, 1 eq) into a 125 ml reaction bottle, add 50 ml (5.0 eq) of 7M ammonia methanol solution, then add TMSCN (3.32 g, 1.5 eq), tetraethyl titanate (5.1 g, 1.0 eq) in turn, warm to 45℃, react for 2h, monitor the reaction by LC-MS, and when SM-A basically disappears, the reaction liquid is cooled to room temperature, 50 ml of dichloromethane is added, the reaction liquid is poured into 5% sodium carbonate aqueous solution, filtered, layered in a separatory funnel, the aqueous phase is extracted with dichloromethane three times, the combined organic phase is washed with saturated brine once, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (PE / EA=30%), to obtain A (2.4 g, yield: 42.10%). MS: [M+H] 233, 235.

[0482] Key intermediate B

[0483] Synthesis of compound pro-SM-B:

[0484] Compound SM-B (2 g, 8.92 mmol) was dissolved in dichloromethane, Boc20 (2.91 g, 1.5 eq), triethylamine (2.72 g, 3 eq) were added, the reaction was carried out at room temperature overnight, LC-MS detection, after the reaction was completed, concentrated under reduced pressure, the residue was purified by column chromatography to obtain compound pro-SM-B (1.7 g).

[0485] Synthesis of compound B:

[0486] Compound pro-SM-B (1.7 g, 5.26 mmol) was weighed into a reaction bottle, 7M ammonia methanol solution (5 mL, 35 mmol) was added for dissolution, then TMSCN (781 mg, 1.5 eq), tetraethyl titanate (1.19 g, 1 eq) were added in turn, the temperature was raised to 45°C, and the reaction was carried out for 2h, LC-MS was used to monitor the reaction, and when SM-A basically disappeared, the reaction liquid was cooled to room temperature, 50 ml of dichloromethane was added, the reaction liquid was poured into 5% sodium carbonate aqueous solution, filtered, and separated by a separatory funnel, the aqueous phase was extracted with dichloromethane three times, the organic phase was combined, washed with saturated brine once, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain compound B (400 mg).

[0487] Key intermediate C

[0488] Synthesis of compound C:

[0489] Compound SM-C (1 g, 4.14 mmol) was dissolved in 7M ammonia methanol solution (3 mL, 21 mmol), then TMSCN (616 mg, 6.21 mmol) and Ti(OEt)4 (943 mg, 4.14 mmol) were added at room temperature, the temperature was raised to 40°C, and the reaction was stirred for 2h, LC-MS was used to monitor the reaction, and after the reaction was completed, the reaction solvent was evaporated under reduced pressure, and the residue was purified by column chromatography to obtain compound C (400 mg). MS: [M-NH2] 250, 252.

[0490] Key intermediate D

[0491] Step 1: Compound D-SM2 (50.0 g, 0.2487 mol) was taken in a reaction flask, dissolved in DMF (500 mL), then bromoethyl acetate (57.07 g, 0.3730 mol), potassium carbonate (103.12 g, 0.7461 mol) were added at room temperature, heated to 130 °C, stirred for 5 h, monitored by TLC, after completion of reaction, the reaction mixture was poured into ice-cold water, extracted with ethyl acetate, the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, purified by column chromatography to get white solid compound D-N1 (40.0 g, yield: 60%). 1 H NMR (400 MHz, CDCl3) δ 7.77 (s, 1H), 7.54 (d, J = 8.4 Hz, 1H), 7.49 (s, 1H), 7.43 (dd, J = 8.4, 1.6 Hz, 1H), 4.45 (q, J = 7.2 Hz, 2H), 1.43 (t, J = 7.2 Hz, 3H).

[0492] Step 2: Compound D-N1 (30.0 g, 0.1115 mol) was taken in a reaction flask, dissolved in ethanol, then NaBH4 (8.43 g, 0.223 mol) was added under ice bath, the temperature of the reaction mixture was controlled at 0-25 °C for 16 h, monitored by TLC, after completion of reaction, the reaction mixture was concentrated to remove most of the ethanol, then poured into ice-cold water, extracted with dichloromethane, the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, purified by column chromatography to get white solid compound D-N2 (20.0 g, yield: 79%). 1 H NMR (400 MHz, CDCl3) δ 7.60 (s, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.32 (dd, J = 8.4, 1.6 Hz, 1H), 6.60 (d, J = 0.8 Hz, 1H), 4.72 (s, 2H).

[0493] Step 3: Compound D-N2 (20.0 g, 0.0881 mol) was taken in a reaction flask, dissolved in dichloromethane, then Dess-Martin oxidizing agent (56.05 g, 0.1321 mol) was added under ice bath, the temperature was raised to room temperature, stirred for 5 h, monitored by TLC, after completion of reaction, the reaction mixture was filtered, concentrated, purified by column chromatography to get yellow solid compound D-N3 (13.0 g, yield: 66%). 1 H NMR (400 MHz, DMSO) δ 9.87 (s, 1H), 8.08 (s, 1H), 7.98 (d, J = 0.8 Hz, 1H), 7.85 (d, J = 8.4 Hz, 1H), 7.55 (dd, J = 8.4, 1.6 Hz, 1H).

[0494] Step 4: Compound D-N3 (13 g, 0.0578 mol) was weighed into a reaction flask, 7M ammonia in methanol (70 mL) was added, stirred at room temperature for 1 h, then TMSCN (8.60 g, 0.0867 mol) was added, and the reaction was continued to stir at room temperature for 1 h. TLC monitoring, after the reaction was completed, the reaction solution was concentrated, and the residue was purified by column chromatography to obtain yellow solid compound D (7.63 g, 53%). MS: [M-NH2] 234.0 / 235.0; 1 H NMR (400 MHz, DMSO) δ 7.92 (s, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.44 (dd, J = 8.4, 1.6 Hz, 1H), 6.97 (s, 1H), 5.38 (s, 1H), 3.02 (s, 2H).

[0495] Example 1: Synthesis of compound 001

[0496] Step 1: Compound A (1.0 g, 1.0 eq) and compound SM-1 (976 mg, 1.0 eq) were weighed into a reaction flask, dissolved in 25 ml of super dry dichloromethane, DIPEA (1.0 g, 2.0 eq) and T3P (3.8 g, 1.5 eq) were added, and the reaction was carried out at room temperature for 1 h. TLC monitoring, after compound A was basically disappeared, the reaction solution was poured into ice water, ammonia was added to adjust the pH to 9-10, extracted with dichloromethane three times, then the organic phase was washed with saturated ammonium chloride and saturated brine in turn, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain A1 crude product (1.9 g). MS: [M+H] 422, 424. Without purification, the next step was directly carried out.

[0497] Step 2: A1 (1.0 g 1 eq) and 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazol-2(3H)-one (580 mg, 1 eq) were weighed into a reaction flask, dissolved in dimethyltetrahydrofuran / water (20 / 2) ml, and then nitrogen was flowed for 2 min. Sodium bicarbonate (380 mg, 2.0 eq), Pd(dppf)Cl2 (330 mg, 0.2 eq) were added, and the reaction was heated to 80°C for 2 h. LC-MS monitoring, after A1 basically disappeared, the reaction solution was cooled to room temperature, poured into saturated brine, extracted with ethyl acetate (20, 20, 10) ml, and the organic phase was combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain A1-01 (650 mg). MS: [M+H] 491.

[0498] Step 3: Put A1-01 in a reaction flask, add 5 ml formic acid, heat to 45 °C for 20 min, TLC monitoring, until A1-01 is almost disappeared, drop the reaction solution into ice ammonia water, extract with ethyl acetate, dry the combined organic phase with anhydrous sodium sulfate, filter, concentrate, purify by column chromatography to obtain compound 001, white solid. MS: [M+H] 447. 1 H NMR (400 MHz, DMSO-d6) δ 9.30 (t, J = 7.8 Hz, 1H), 7.99 - 7.96 (m, 1H), 7.74 - 7.66 (m, 2H), 7.61 (s, 1H), 7.43 - 7.41 (m, 2H), 7.08 - 7.02 (m, 1H), 6.53 - 6.45 (m, 1H), 4.16 - 4.08 (m, 1H), 3.97 - 3.82 (m, 1H), 3.80 - 3.71 (m, 1H), 3.42 (s, 3H), 3.24 - 3.16 (m, 1H), 2.88 - 2.67 (m, 4H), 1.84 - 1.72 (m, 2H).

[0499] Example 2: Synthesis of compound 002

[0500] The synthesis method of compound 002 is shown in 001. Compound B and SM-1 were reacted, and then coupled with 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazol-2(3H)-one, and deprotected to obtain compound 002. Compound 002 is a white solid. MS: [M+H] 446; 1 H NMR (400 MHz, DMSO-d6) δ 9.30 (t, J = 7.8 Hz, 1H), 7.99 - 7.96 (m, 1H), 7.74 - 7.66 (m, 2H), 7.61 (s, 1H), 7.43 - 7.41 (m, 2H), 7.08 - 7.02 (m, 1H), 6.53 - 6.45 (m, 1H), 4.16 - 4.08 (m, 1H), 3.97 - 3.82 (m, 1H), 3.80 - 3.71 (m, 1H), 3.42 (s, 3H), 3.24 - 3.16 (m, 1H), 2.88 - 2.67 (m, 4H), 1.84 - 1.72 (m, 2H).

[0501] Example 3: Synthesis of compound 003

[0502] Method for synthesizing compound 003, see 001. Compound C and SM-1 were reacted, then coupled with 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazol-2(3H)-one, deprotection to give compound 003. Compound 003 was a white solid. MS: [M+H] 463; 1 H NMR (400 MHz, DMSO-d6) δ 9.43 (t, J = 8.8 Hz, 1H), 8.23 (d, J = 2.0 Hz, 1H), 8.07 (d, J = 8.8 Hz, 1H), 7.77 - 7.70 (m, 1H), 7.66 (d, J = 2.0 Hz, 1H), 7.59 (s, 1H), 7.53 - 7.46 (m, 1H), 7.43 (d, J = 8.4 Hz, 1H), 6.59 - 6.48 (m, 1H), 4.18 - 4.09 (m, 1H), 3.98 - 3.87 (m, 1H), 3.82 - 3.70 (m, 1H), 3.42 (s, 3H), 3.31 - 3.18 (m, 1H), 2.93 - 2.79 (m, 2H), 2.79 - 2.70 (m, 1H), 1.93 - 1.76 (m, 2H).

[0503] Example 4: Synthesis of compound 009

[0504] Method for synthesizing compound 009, see 001. Compound A and SM-1 were reacted, then coupled with (2-methylbenzo[d]oxazol-6-yl)boronic acid in the presence of potassium carbonate, deprotection to give compound 009. Compound 009 was a white solid. MS: [M+H] 431; 1 H NMR (400 MHz, DMSO-d6) δ 9.43 (t, J = 8.8 Hz, 1H), 8.23 (d, J = 2.0 Hz, 1H), 8.07 (d, J = 8.8 Hz, 1H), 7.77 - 7.70 (m, 1H), 7.66 (d, J = 2.0 Hz, 1H), 7.59 (s, 1H), 7.53 - 7.46 (m, 1H), 7.43 (d, J = 8.4 Hz, 1H), 6.59 - 6.48 (m, 1H), 4.18 - 4.09 (m, 1H), 3.98 - 3.87 (m, 1H), 3.82 - 3.70 (m, 1H), 3.42 (s, 3H), 3.31 - 3.18 (m, 1H), 2.93 - 2.79 (m, 2H), 2.79 - 2.70 (m, 1H), 1.93 - 1.76 (m, 2H).

[0505] Example 5: Synthesis of compound 010

[0506] The synthetic method of compound 010 is described in 001. Compound A reacts with SM-1, and then is coupled with 2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxazolo[4,5-b]pyridine in the presence of potassium carbonate, and deprotection to obtain compound 010. Compound 010 is a white solid. MS: [M+H] 432; 1 H NMR (400 MHz, DMSO-d6) δ 9.31 (t, J = 7.4 Hz, 1H), 8.80 (d, J = 2.1 Hz, 1H), 8.45 (d, J = 2.1 Hz, 1H), 8.08 (s, 1H), 7.77 (d, J = 1.8 Hz, 2H), 7.07 (d, J = 2.6 Hz, 1H), 6.50 (dd, J = 8.6, 4.8 Hz, 1H), 4.16 - 4.08 (m, 1H), 3.97 - 3.89 (m, 1H), 3.80 - 3.70 (m, 1H), 3.23 - 3.15 (m, 1H), 2.89 - 2.78 (m, 2H), 2.77 - 2.69 (m, 4H), 1.86 - 1.68 (m, 2H).

[0507] Example 6: Synthesis of compound 011

[0508] The synthetic method of compound 011 is described in 001. Compound A reacts with SM-1, and then is coupled with 3-methyl-6-pinacol boronate benz[d]oxazol-2(3H)-one in the presence of potassium carbonate, and deprotection to obtain compound 011. Compound 011 is a white solid. MS: [M+H] 447; 1 H NMR (400 MHz, DMSO-d6) δ 9.33 (t, J = 7.2 Hz, 1H), 7.95 (d, J = 2.0 Hz, 1H), 7.75 - 7.61 (m, 3H), 7.59 - 7.53 (m, 1H), 7.34 (d, J = 8.0 Hz, 1H), 7.07 - 7.02 (m, 1H), 6.53 - 6.45 (m, 1H), 4.20 - 4.11 (m, 1H), 3.98 - 3.88 (m, 1H), 3.81 - 3.70 (m, 1H), 3.38 (s, 3H), 3.28 - 3.17 (m, 1H), 2.92 - 2.81 (m, 2H), 2.81 - 2.70 (m, 1H), 1.89 - 1.68 (m, 2H), 1.38 - 1.21 (m, 1H).

[0509] Example 7: Synthesis of compound 014

[0510] Method for synthesizing compound 014, see 001. Compound A and SM-1 were reacted, then coupled with (2-methylbenzo[D]oxazol-5-yl)boronic acid in the presence of potassium carbonate, deprotection to give compound 014. Compound 014 was a white solid. MS: [M+H] 431; 1 H NMR (400 MHz, DMSO-d6) δ 9.39 - 9.28 (m, 1H), 8.01 (t, J = 1.1 Hz, 1H), 7.95 (d, J = 2.0 Hz, 1H), 7.79 - 7.63 (m, 4H), 7.11 - 7.04 (m, 1H), 6.51 (dd, J = 7.4, 4.0 Hz, 1H), 4.33 (t, J = 5.5 Hz, 1H), 4.23 - 4.10 (m, 1H), 4.00 - 3.90 (m, 1H), 3.83 - 3.71 (m, 1H), 3.26 - 3.18 (m, 1H), 2.90 - 2.81 (m, 2H), 2.80 - 2.71 (m, 1H), 2.66 (s, 3H), 1.91 - 1.68 (m, 2H).

[0511] Example 8: Synthesis of compound 015

[0512] Method for synthesizing compound 015, see 001. Compound A and SM-1 were reacted, then coupled with 3-(4-methylpiperazin-1-yl)benzeneboronic acid in the presence of potassium carbonate, deprotection to give compound 015. Compound 015 was a white solid. MS: [M+H] 473; 1 H NMR (400 MHz, DMSO-d6) δ 9.28 (t, J = 8.0 Hz, 1H), 7.93 (s, 1H), 7.71 - 7.59 (m, 2H), 7.30 (t, J = 7.9 Hz, 1H), 7.17 (d, J = 2.3 Hz, 1H), 7.13 - 7.00 (m, 2H), 6.94 (d, J = 8.6 Hz, 1H), 6.51 - 6.44 (m, 1H), 4.37 - 4.27 (m, 1H), 4.16 - 4.08 (m, 1H), 3.96 - 3.89 (m, 1H), 3.80 - 3.71 (m, 1H), 3.26 - 3.19 (m, 4H), 2.87 - 2.78 (m, 2H), 2.75 - 2.68 (m, 1H), 2.50 - 2.45 (m, 4H), 2.23 (s, 3H), 1.84 - 1.70 (m, 2H).

[0513] Example 9: Synthesis of compound 016

[0514] Method for synthesizing compound 016, see 001. Compound A and SM-1 were reacted, and then coupled with 5'-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-indol]-2'-one under the action of potassium carbonate, and deprotected to obtain compound 015. Compound 015 was a white solid. MS: [M+H] 457; 1 H NMR (400 MHz, DMSO-d6) δ 10.62 (s, 1H), 9.32 (t, J = 7.6 Hz, 1H), 7.88 (d, J = 1.8 Hz, 1H), 7.66 (d, J = 8.7 Hz, 1H), 7.60 (dd, J = 8.7, 1.9 Hz, 1H), 7.47 (dd, J = 8.0, 1.9 Hz, 1H), 7.32 (d, J = 1.8 Hz, 1H), 7.04 - 6.95 (m, 2H), 6.52 - 6.44 (m, 1H), 4.20 - 4.11 (m, 1H), 3.98 - 3.87 (m, 1H), 3.81 - 3.70 (m, 1H), 3.27 - 3.19 (m, 1H), 2.93 - 2.81 (m, 2H), 2.81 - 2.70 (m, 1H), 1.86 - 1.73 (m, 2H), 1.72 - 1.64 (m, 2H), 1.53 - 1.46 (m, 2H).

[0515] Example 10: Synthesis of compound 018

[0516] Step 1: 4-bromophenylhydrazine (1 g, 1 eq) and methyl acetoacetate (620 mg, 1 eq) were added to a 10 ml reaction bottle, acetic acid (1 ml) was added, heated at 100 °C for 2 hours, and LC-MS was monitored. After the reaction was completed, it was concentrated and purified by column chromatography to obtain 018-A (500 mg), a brownish solid. MS: [M+H] 253. 1 H NMR (400 MHz, DMSO-d6) δ 11.79 - 11.58 (m, 1H), 7.72 - 7.67 (m, 2H), 7.62 - 7.57 (m, 2H), 5.37 (s, 1H), 2.11 (d, J = 2.1 Hz, 3H).

[0517] Step 2: Compound 018-A (500 mg, 1 eq), Pin2B2 (554 mg, 1.1 eq), Pd(dppf)Cl2 (145 mg, 0.1 eq) and KOAc (487 mg, 2.5 eq) were added to a 40 ml reaction bottle, protected by nitrogen, 10 ml of DMF was added, then heated at 80 °C overnight. LC-MS monitoring. After the reaction was completed, the reaction solution was added to water to quench, extracted with ethyl acetate, washed with saturated aqueous sodium chloride solution, dried, concentrated, and purified by column chromatography to obtain 018-B (350 mg) as a light yellow oil. MS: [M+H] 301.

[0518] Step 3: 018-B (387 mg, 1.0 eq), compound A1 (292 mg, 1.2 eq), KOAc (238.8 mg, 3 eq) and Pd(dppf)Cl2 (59.4 mg, 0.1 eq) were added to a 40 ml reaction bottle, protected by nitrogen, 7 ml of DMF and 0.7 ml of water were added, heated at 80 °C for 1 hour, LC-MS monitoring. After the reaction was completed, the reaction solution was added to water to quench, extracted with ethyl acetate, washed with saturated aqueous sodium chloride solution, dried, concentrated, and the residue was purified by column chromatography to obtain 018-C (130 mg) as a light yellow solid. MS: [M+H] 572.

[0519] Step 4: 018-C was added to a reaction bottle, 1 ml of formic acid was added, then heated to 40 °C, stirred for 20 min, LC-MS monitoring. After the reaction was completed, the reaction solution was slowly dropped into 10 ml of ammonia water under ice water bath, then extracted with dichloromethane, dried, concentrated, and purified by column chromatography to obtain compound 018 (30 mg) as a light yellow solid. MS: [M+H] 471; 1 H NMR (400 MHz, DMSO-d6) δ 9.34 (dd, J = 8.0, 5.8 Hz, 1H), 7.97 (d, J = 1.8 Hz, 1H), 7.88 (d, J = 8.5 Hz, 2H), 7.75 - 7.64 (m, 4H), 7.06 (d, J = 1.8 Hz, 1H), 6.49 (dd, J = 8.1, 3.2 Hz, 1H), 5.29 (s, 1H), 4.22 - 4.11 (m, 1H), 3.99 - 3.87 (m, 1H), 3.80 - 3.71 (m, 1H), 3.31 - 3.17 (m, 2H), 3.14 (s, 1H), 2.94 - 2.81 (m, 2H), 2.81 - 2.71 (m, 1H), 2.12 (s, 3H), 1.90 - 1.67 (m, 2H).

[0520] Example 11: Synthesis of compound 019

[0521] The synthetic method of compound 019 was described in 001. Compound A reacted with SM-1, then coupled with 4-cyanophenylboronic acid pinacol ester in the presence of potassium carbonate, deprotection to give compound 019. Compound 019 was a white solid. MS: [M+H] 401. 1 H NMR (400 MHz, DMSO) δ 9.34 - 9.26 (m, 1H), 8.06 (s, 1H), 7.96 - 7.91 (m, 4H), 7.80 - 7.70 (m, 2H), 7.07 (d, J = 2.2 Hz, 1H), 6.53 - 6.46 (m, 1H), 4.16 - 4.07 (m, 1H), 3.96 - 3.87 (m, 1H), 3.76 (d, J = 8.5 Hz, 1H), 3.39 (d, J = 2.6 Hz, 1H), 3.24 - 3.13 (m, 1H), 2.86 - 2.79 (m, 2H), 2.76 - 2.69 (m, 1H), 1.78 (s, 1H), 1.23 (s, 1H).

[0522] Example 12: Synthesis of compound 022

[0523] The synthetic method of compound 022 was described in 001. Compound A reacted with SM-1, then coupled with 1-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrrolidine in the presence of potassium carbonate, deprotection to give compound 022. Compound 022 was a white solid. MS: [M+H] 459; 1 H NMR (400 MHz, Methanol-d4) δ 7.90 (d, J = 1.9 Hz, 1H), 7.71 - 7.61 (m, 2H), 7.61 - 7.55 (m, 2H), 7.46 (t, J = 7.7 Hz, 1H), 7.38 - 7.32 (m, 1H), 7.08 (s, 1H), 4.64 - 4.55 (m, 1H), 4.20 - 4.08 (m, 1H), 3.93 - 3.72 (m, 4H), 3.70 - 3.59 (m, 2H), 3.50 - 3.34 (m, 4H), 3.03 (s, 3H), 2.65 - 2.53 (m, 1H), 2.39 - 2.24 (m, 1H), 2.21 - 2.08 (m, 2H).

[0524] Example 13: Synthesis of compound 024

[0525] Method for synthesizing compound 024, see 001. Compound A and SM-1 were reacted, then coupled with 1-methyl-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester in the presence of potassium phosphate, and deprotected to give compound 024. Compound 024 was a light yellow solid. MS: [M+H] 395; 1 H NMR (400 MHz, Methanol-d4) δ 7.66 (s, 1H), 7.46 (s, 2H), 6.97 (d, J = 2.8 Hz, 1H), 6.11 (s, 1H), 4.26 - 4.15 (m, 1H), 4.10 - 3.99 (m, 1H), 3.87 - 3.75 (m, 1H), 3.40 - 3.33 (m, 1H), 3.20 - 3.08 (m, 2H), 3.00 - 2.80 (m, 3H), 2.79 - 2.62 (m, 4H), 2.41 (s, 3H), 2.00 - 1.79 (m, 2H).

[0526] Example 14: Synthesis of compound 025

[0527] Method for synthesizing compound 025, see 001. Compound A and SM-1 were reacted, then coupled with 4,4-dimethylcyclohexen-1-yl boronic acid in the presence of potassium fluoride, and deprotected to give compound 025. Compound 024 was a white solid. MS: [M+H] 408; 1 H NMR (400 MHz, Methanol-d4) δ 7.66 (s, 1H), 7.46 (s, 2H), 6.97 (d, J = 2.8 Hz, 1H), 6.11 (s, 1H), 4.26 - 4.15 (m, 1H), 4.10 - 3.99 (m, 1H), 3.87 - 3.75 (m, 1H), 3.40 - 3.33 (m, 1H), 3.20 - 3.08 (m, 2H), 3.00 - 2.80 (m, 3H), 2.79 - 2.62 (m, 4H), 2.41 (s, 3H), 2.00 - 1.79 (m, 2H).

[0528] Example 15: Synthesis of compound 026

[0529] Method for synthesizing compound 026, see 001. Compound A reacted with SM-1, then coupled with 2-(4,4-difluorocyclohex-1-en-1-yl)boronic acid pinacol ester in the presence of potassium carbonate, deprotection to give compound 026. Compound 026 is a white solid. MS: [M+H] 416; 1 H NMR (400 MHz, Methanol-d4) δ 7.64 (s, 1H), 7.44 (d, J = 3.0 Hz, 2H), 6.99 (s, 1H), 5.93 (t, J = 3.6 Hz, 1H), 4.49 - 4.39 (m, 1H), 4.15 - 4.04 (m, 1H), 3.90 - 3.78 (m, 1H), 3.65 - 3.55 (m, 1H), 3.28 - 3.07 (m, 3H), 2.79 - 2.63 (m, 4H), 2.25 - 2.13 (m, 2H), 2.11 - 1.97 (m, 2H).

[0530] Example 16: Synthesis of compound 028

[0531] Method for synthesizing compound 028, see 001. Compound A reacted with SM-1, then coupled with 3,6-dihydro-2H-pyran-4-boronic acid in the presence of potassium carbonate, deprotection to give compound 028. Compound 028 is a white solid. MS: [M+H] 382; 1 H NMR (400 MHz, DMSO-d6) δ 9.42 (dd, J = 8.1, 3.5 Hz, 1H), 7.71 (d, J = 1.9 Hz, 1H), 7.58 (d, J = 8.7 Hz, 1H), 7.48 (dd, J = 8.7, 1.9 Hz, 1H), 7.00 (s, 1H), 6.47 (d, J = 7.7 Hz, 1H), 6.24 (dd, J = 3.2, 1.6 Hz, 1H), 4.30 - 4.21 (m, 3H), 3.98 - 3.88 (m, 1H), 3.84 (t, J = 5.5 Hz, 2H), 3.81 - 3.71 (m, 1H), 3.37 - 3.29 (m, 1H), 3.06 - 2.83 (m, 3H), 2.54 - 2.44 (m, 2H), 1.92 - 1.81 (m, 2H).

[0532] Example 17: Synthesis of compound 029

[0533] Method for synthesizing compound 029, see 001. Compound A reacted with SM-1, then coupled with 4-(4-methylpiperazin-1-ylsulfonyl)phenylboronic acid in the presence of potassium carbonate, deprotection to give compound 029. Compound 029 is a white solid. MS: [M+H] 538; 1H NMR (400 MHz, DMSO-d6) δ 9.62 (s, 1H), 8.07 (s, 1H), 7.97 (d, J = 8.2 Hz, 2H), 7.82 (d, J = 8.1 Hz, 2H), 7.79 - 7.72 (m, 2H), 7.11 (s, 1H), 6.51 (s, 1H), 4.32 (d, J = 8.6 Hz, 1H), 3.99 - 3.88 (m, 1H), 3.83 - 3.72 (m, 1H), 3.39 - 3.29 (m, 1H), 3.07 - 2.81 (m, 7H), 2.42 - 2.35 (m, 4H), 2.15 (s, 3H), 1.94 - 1.79 (m, 2H).

[0534] Example 18: Synthesis of compound 034

[0535] The synthetic method of compound 034 was described in 001. Compound A reacted with SM-1, then coupled with (4-hydroxy-3, 5-dimethoxyphenyl)boronic acid in the presence of potassium carbonate, deprotection to get compound 034. Compound 034 was a white solid. MS: [M+H] 452; 1 H NMR (400 MHz, DMSO-d6) δ 9.62 (s, 1H), 8.07 (s, 1H), 7.97 (d, J = 8.2 Hz, 2H), 7.82 (d, J = 8.1 Hz, 2H), 7.79 - 7.72 (m, 2H), 7.11 (s, 1H), 6.51 (s, 1H), 4.32 (d, J = 8.6 Hz, 1H), 3.99 - 3.88 (m, 1H), 3.83 - 3.72 (m, 1H), 3.39 - 3.29 (m, 1H), 3.07 - 2.81 (m, 7H), 2.42 - 2.35 (m, 4H), 2.15 (s, 3H), 1.94 - 1.79 (m, 2H).

[0536] Example 19: Synthesis of compound 039

[0537] The synthetic method of compound 039 was described in 001. Compound A reacted with SM-1, then coupled with 3, 4-difluorophenylboronic acid in the presence of potassium carbonate, deprotection to get compound 039. Compound 039 was a white solid. MS: [M+H] 412; 1H NMR (400 MHz, DMSO-d6) δ 9.44 (dd, J = 8.2, 3.7 Hz, 1H), 7.98 (d, J = 1.9 Hz, 1H), 7.84 - 7.76 (m, 1H), 7.74 - 7.65 (m, 2H), 7.57 - 7.51 (m, 2H), 7.06 (s, 1H), 6.51 (dd, J = 7.9, 2.6 Hz, 1H), 4.32 - 4.23 (m, 1H), 3.98 - 3.89 (m, 1H), 3.82 - 3.72 (m, 1H), 3.37 - 3.29 (m, 1H), 3.02 - 2.84 (m, 3H), 1.90 - 1.80 (m, 2H).

[0538] Example 20: Synthesis of compound 005

[0539] Step 1: Compound A (650 mg, 1.0 eq) and compound SM-2 (625 mg, 1.0 eq) were weighed into a reaction flask, dissolved in anhydrous dichloromethane, then T3P 50 WT% EA solution (2.47 g, 1.5 eq) and DIPEA (1.0 g, 3.0 eq) were added. The reaction was stirred at room temperature for 1 h. TLC monitoring, when compound A was basically disappeared, the reaction was poured into ice water, ammonia was added to adjust PH 9-10, extracted with dichloromethane three times, the organic phase was combined, then the organic phase was washed with saturated ammonium chloride and saturated brine in turn, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give intermediate A2 (520 mg), yellowish solid. MS: [M+H] 474, 476.

[0540] Step 2: A2 (1 eq) and 4-cyanophenylboronic acid pinacol ester (1 eq) were weighed into a reaction flask, dissolved in dimethyltetrahydrofuran / water (6 / 1), and then purged with nitrogen flow for 2 min. Potassium carbonate (2 eq), Pd(dppf)Cl2(0.2 eq) were added, and the reaction was heated to 80°C for 2 h, and LC-MS monitoring. After the reaction was completed, the reaction was cooled to room temperature, poured into saturated brine, and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give A2-05 (88 mg), yellow oil.

[0541] Step 3: A2-05 was placed in a reaction flask, 3 ml of formic acid was added, and the reaction was heated to 45°C for 20 min, TLC monitoring. After the reaction was completed, the reaction was dropped into ice ammonia water, extracted with ethyl acetate, and the organic phase was combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give compound 005, white solid. MS: [M+H] 397; 1H NMR (400 MHz, DMSO-d6) δ 9.18 (s, 1H), 8.07 (s, 1H), 7.95 - 7.91 (m, 4H), 7.79 - 7.70 (m, 2H), 7.05 (s, 1H), 6.47 (t, J = 8.0 Hz, 1H), 3.45 - 3.38 (m, 1H), 3.21 (d, J = 4.2 Hz, 1H), 2.57 - 2.52 (m, 1H), 2.05 - 1.94 (m, 1H), 1.70 - 1.49 (m, 3H), 1.49 - 1.37 (m, 3H).

[0542] Example 21: Synthesis of compound 006

[0543] The synthetic method of compound 006 was described in 005. Compound B and SM-2 were reacted, then coupled with 4-cyanophenylboronic acid in the presence of potassium carbonate, and deprotected to give compound 006. Compound 006 was a white solid, MS: [M+H] 396; 1 H NMR (400 MHz, DMSO-d6) δ 9.18 (s, 1H), 8.07 (s, 1H), 7.95 - 7.91 (m, 4H), 7.79 - 7.70 (m, 2H), 7.05 (s, 1H), 6.47 (t, J = 8.0 Hz, 1H), 3.45 - 3.38 (m, 1H), 3.21 (d, J = 4.2 Hz, 1H), 2.57 - 2.52 (m, 1H), 2.05 - 1.94 (m, 1H), 1.70 - 1.49 (m, 3H), 1.49 - 1.37 (m, 3H).

[0544] Example 22: Synthesis of compound 008

[0545] Step 1:008-SM (500 mg) was weighed into a single-mouth bottle, 4M HCl solution in dioxane (5 ml) was added, and the reaction was stirred at room temperature for 1 h. After the reaction was completed, the reaction solution was concentrated and dried to give white solid 008-A (608 mg), which was used directly in the next step without purification. MS: [M+H] 316.

[0546] Step 2: 008-A (608 mg, 1 eq) was added to a reaction bottle, dissolved with methanol, then 37% aqueous formaldehyde solution (6 g, 10 eq) was added, stirred at 50 °C for 30 min, then reduced to room temperature to react with sodium triacetyl borohydride (400 mg, 4 eq), LC-MS monitoring, after the reaction was completed, the reaction solution was added with ethyl acetate, then washed with water, saturated brine, dried with anhydrous sodium sulfate, filtered, concentrated and purified by column chromatography to obtain 008-B (280 mg) as a light yellow solid. MS: [M+H] 330.

[0547] Step 3: Compound 008-B (1 eq) and A2 (1 eq) were weighed into a reaction bottle, dissolved with dimethyltetrahydrofuran / water (5 / 1), and then passed through a nitrogen stream for 2 min. Potassium carbonate (4.0 eq), Pd(dppf)Cl2(0.2 eq) were added, heated to 80 °C, reacted for 2 h, LC-MS monitoring, after the reaction was completed, the reaction solution was poured into saturated brine, extracted with ethyl acetate, the combined organic phase was dried with anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain 008-C (167 mg) as a yellow oil. MS: [M+H] 597.

[0548] Step 4: 008-C was placed in a reaction bottle, 5 ml of formic acid was added, heated to 45 °C and reacted for 20 min, TLC monitoring, and then the reaction solution was dropped into ice ammonia water, extracted with ethyl acetate, the combined organic phase was dried with anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain compound 008 (68 mg) as a white solid. MS: [M+H] 496; 1 H NMR (400 MHz, DMSO-d6) δ 9.17 (s, 1H), 8.03-7.94 (m, 1H), 7.69-7.66 (m, 1H), 7.60-7.52 (m, 3H), 7.36 (d, J = 7.8 Hz, 1H), 7.02 (s, 1H), 6.46 (t, J = 8.9 Hz, 1H), 5.01 (s, 2H), 3.44-3.37 (m, 1H), 3.20 (d, J = 4.9 Hz, 1H), 2.74-2.66 (m, 3H), 2.56-2.53 (m, 1H), 2.32-2.25 (m, 2H), 2.23 (s, 3H), 2.08-1.97 (m, 3H), 1.69-1.62 (m, 3H), 1.44-1.41 (m, 1H), 1.25-1.22 (m, 1H), 1.18-1.11 (m, 1H).

[0549] Example 23: Synthesis of compound 012

[0550] Method for synthesizing compound 012, see 005. Compound A and SM-2 reacted, then coupled with 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazol-2(3H)-one, deprotection to give compound 012. Compound 012 is a white solid, MS: [M+H] 423; 1 H NMR (400 MHz, DMSO-d6) δ 9.19 (d, J = 8.2 Hz, 1H), 7.98 (d, J = 1.9 Hz, 1H), 7.77 - 7.65 (m, 2H), 7.61 (d, J = 1.5 Hz, 1H), 7.42 (d, J = 2.2 Hz, 2H), 7.03 (s, 1H), 6.46 (t, J = 8.8 Hz, 1H), 3.45 - 3.39 (m, 4H), 3.22 (d, J = 4.5 Hz, 1H), 2.57 - 2.52 (m, 1H), 1.63 - 1.49 (m, 2H), 1.46 - 1.27 (m, 3H), 1.19 - 1.09 (m, 1H).

[0551] Example 24: Synthesis of compound 017

[0552] Method for synthesizing compound 017, see 005. Compound A and SM-2 reacted, then coupled with 2-methylbenzo[D]oxazole-6-boronic acid, deprotection to give compound 017. Compound 017 is a white solid, MS: [M+H] 427; 1 H NMR (400 MHz, DMSO-d6) δ 9.34 (s, 1H), 8.03 - 8.00 (m, 1H), 7.97 (d, J = 1.6 Hz, 1H), 7.75 - 7.70 (m, 3H), 7.65 (dd, J = 8.3, 1.7 Hz, 1H), 7.06 (s, 1H), 6.49 (t, J = 7.2 Hz, 1H), 3.57 - 3.48 (m, 1H), 2.64 (s, 3H), 2.61 - 2.56 (m, 1H), 1.68 - 1.17 (m, 8H).

[0553] Example 25: Synthesis of compound 021

[0554] Method for synthesizing compound 021, see 005. Compound A and SM-2 reacted, then coupled with (2-methylbenzo[D]oxazol-5-yl)boronic acid in the presence of potassium fluoride, deprotection to give compound 021. Compound 021 is a white solid, MS: [M+H] 427; 1H NMR (400 MHz, DMSO-d6) δ 9.86 (s, 1H), 8.01 (s, 1H), 7.93 (d, J = 1.9 Hz, 1H), 7.78 - 7.70 (m, 3H), 7.65 (d, J = 8.5 Hz, 1H), 7.13 (s, 1H), 6.58 (d, J = 7.1 Hz, 1H), 3.93 - 3.78 (m, 1H), 3.77 - 3.62 (m, 1H), 3.10 - 3.04 (m, 1H), 2.77 - 2.65 (m, 1H), 2.64 (s, 3H), 1.73 - 1.61 (m, 3H), 1.51 - 1.40 (m, 3H).

[0555] Example 26: Synthesis of compound 033

[0556] The synthetic method of compound 033 was described in '005'. Compound A reacted with SM-2, then coupled with 1-cyclopropylpyrazole-4-boronic acid pinacol ester in the presence of potassium carbonate, deprotection to give compound 033. Compound 033 was a white solid. MS: [M+H] 402; 1 H NMR (400 MHz, Methanol-d4) δ 8.03 (s, 1H), 7.83 - 7.76 (m, 2H), 7.55 (dd, J = 8.6, 1.8 Hz, 1H), 7.49 (d, J = 8.6 Hz, 1H), 6.98 (s, 1H), 3.72 - 3.64 (m, 1H), 3.63 - 3.55 (m, 1H), 3.37 - 3.34 (m, 1H), 2.69 - 2.60 (m, 1H), 1.76 - 1.61 (m, 2H), 1.54 - 1.48 (m, 2H), 1.32 - 1.25 (m, 2H), 1.16 - 1.10 (m, 2H), 1.10 - 1.04 (m, 2H).

[0557] Example 27: Synthesis of compound 036

[0558] The synthetic method of compound 036 was described in '005'. Compound A reacted with SM-2, then coupled with (2-methylimidazo[l,2-A]pyridin-6-yl)boronic acid in the presence of potassium fluoride, deprotection to give compound 036. Compound 036 was a white solid. MS: [M+H] 426; 1H NMR (400 MHz, Methanol-d4) δ 8.62 (s, 1H), 7.91 (s, 1H), 7.68 - 7.57 (m, 4H), 7.51 (d, J = 9.3 Hz, 1H), 7.11 (s, 1H), 3.89 (d, J = 8.9 Hz, 1H), 3.68 (d, J = 6.5 Hz, 1H), 2.83 - 2.70 (m, 1H), 2.42 (s, 3H), 1.85 - 1.72 (m, 2H), 1.68 - 1.57 (m, 3H), 1.53 - 1.48 (m, 1H).

[0559] Example 28: Synthesis of compound 038

[0560] The synthetic method of compound 038 was described in 005. The compound A reacted with SM-2, then coupled with 4,4-difluorocyclohex-l-enylboronic acid pinacol ester in the presence of potassium carbonate, deprotection to give compound 038. Compound 038 was a white solid. MS: [M+H] 412; 1 H NMR (400 MHz, Methanol-d4) δ 8.62 (s, 1H), 7.91 (s, 1H), 7.68 - 7.57 (m, 4H), 7.51 (d, J = 9.3 Hz, 1H), 7.11 (s, 1H), 3.89 (d, J = 8.9 Hz, 1H), 3.68 (d, J = 6.5 Hz, 1H), 2.83 - 2.70 (m, 1H), 2.42 (s, 3H), 1.85 - 1.72 (m, 2H), 1.68 - 1.57 (m, 3H), 1.53 - 1.48 (m, 1H).

[0561] Example 29: Synthesis of compound 040

[0562] The synthetic method of compound 040 was described in 005. The compound A reacted with SM-2, then coupled with 1-methylindazole-5-boronic acid pinacol ester in the presence of potassium carbonate, deprotection to give compound 040. Compound 040 was a white solid. MS: [M+H] 426; 1H NMR (400 MHz, Methanol-d4) δ 8.05 (d, J = 0.9 Hz, 1H), 7.98 (d, J = 1.4 Hz, 1H), 7.89 (d, J = 1.9 Hz, 1H), 7.78 - 7.71 (m, 1H), 7.71 - 7.56 (m, 3H), 7.06 (s, 1H), 4.10 (s, 3H), 3.63 - 3.55 (m, 1H), 3.39 - 3.34 (m, 1H), 2.68 - 2.62 (m, 1H), 1.78 - 1.61 (m, 2H), 1.55 - 1.50 (m, 2H), 1.34 - 1.30 (m, 2H).

[0563] Example 30: Synthesis of compound 041

[0564] The synthetic method of compound 041 was shown in 005. Compound A reacted with SM-2, then coupled with 3,4-difluorophenylboronic acid in the presence of potassium carbonate and deprotection to give compound 041. Compound 041 was a white solid. MS: [M+H] 408; 1 H NMR (400 MHz, DMSO-d6) δ 9.91 - 8.82 (m, 1H), 7.99 (s, 1H), 7.84 - 7.75 (m, 1H), 7.75 - 7.63 (m, 2H), 7.58 - 7.47 (m, 2H), 7.04 (d, J = 2.4 Hz, 1H), 6.47 (d, J = 7.1 Hz, 1H), 3.52 - 3.45 (m, 1H), 3.32 (d, J = 7.9 Hz, 1H), 2.60 - 2.52 (m, 1H), 1.62 - 1.16 (m, 6H).

[0565] Example 31: Synthesis of compound 043

[0566] Step 1: Compound A2 (500 mg, 1 eq) was dissolved in 1,4-dioxane (10 ml), then pinacol diboronic acid (403 mg, 1.5 eq) was added, and then the reaction was stirred under a stream of nitrogen for 2 min. AcOK (312 mg, 3 eq) and Pd(dppf)Cl2 (233 mg, 0.3 eq) were added, and the reaction was heated to 85°C. LC-MS monitoring was performed until A2 was substantially consumed. The reaction was cooled to room temperature, and then an appropriate amount of sodium sulfate and ethyl acetate were added. The mixture was stirred for 10 min, and then filtered under suction. The filter cake was washed with ethyl acetate, and then the filtrate was concentrated to dryness under reduced pressure at 40°C. The residue was subjected to flash column chromatography to give compound 043-A (470 mg, yield: 85.34%, purity: 95.22%). MS: [M+H] 422.

[0567] Step 2: Take 043-A (420 mg, 1 eq) into a reaction bottle, dissolve with dimethyltetrahydrofuran / water (6 / 1), then add 6-bromoisoquinoline-1,3(2H,4H)-dione (290 mg, 1.5 eq), after flowing nitrogen for 2 min, add potassium fluoride (282 mg, 6 eq), Pd(dppf)Cl2(177 mg, 0.3 eq), heat to 85°C, and react, monitor by LC-MS. After the reaction is completed, cool to room temperature, pour the reaction liquid into saturated brine, extract with ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate, and purify by column chromatography to obtain 043-B (214 mg, yield: 47.67%, purity: 97.55%). MS: [M+H] 455.

[0568] Step 3: Take compound 043-B (210 mg) and add to 2 ml of formic acid, stir and heat to 45°C, monitor by TLC, and when 043-B is substantially disappeared, drop the reaction liquid into ice ammonia water, extract with DCM / MeOH (10 / 1) for 3 times, combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate, and purify by column chromatography to obtain compound 043, white solid. MS: [M+H] 455; 1 H NMR (400 MHz, DMSO-d6) δ 11.32 (s, 1H), 10.17 (d, J = 6.8 Hz, 1H), 8.10 (d, J = 8.3 Hz, 2H), 7.82 - 7.73 (m, 4H), 7.21 (d, J = 1.8 Hz, 1H), 6.62 (d, J = 6.5 Hz, 1H), 4.12 (s, 2H), 4.03 - 3.98 (m, 1H), 3.94 - 3.89 (m, 1H), 2.86 - 2.71 (m, 1H), 1.87 - 1.78 (m, 1H), 1.76 - 1.63 (m, 2H), 1.60 - 1.39 (m, 4H).

[0569] Example 32: Synthesis of compound 004

[0570] Step 1: Compound 004-SM (2.00 g, 7.00 mmol) was dissolved in dichloromethane (30 mL), then diisobutylaluminum hydride (14 mL, 1.0 M in toluene) was slowly added at -70°C. The reaction was stirred at this temperature for 2 hours. After the reaction was completed, the reaction liquid was slowly poured into 1 N hydrochloric acid (50 mL) in an ice bath, extracted with dichloromethane for 3 times, combined the organic phases, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain 004-A (1.00 g, yield: 63.0%) as a white solid. MS: [M+H] 227, 229.

[0571] Step 2: Compound 004-A (600 mg, 2.64 mmol) was dissolved in a reaction flask, 7M ammonia in methanol (15 mL) and tetraethyl titanate (1.13 g, 3.96 mmol) were added, stirred at room temperature for 1 h, then TMSCN (393.2 mg, 3.96 mmol) was added, the reaction was continued to stir for 1 h, LC-MS monitoring, after the reaction was completed, the reaction was reduced to room temperature, ethyl acetate (20 mL) was added, the reaction was poured into 5% aqueous sodium carbonate solution, filtered, and the layers were separated with a separatory funnel, the aqueous phase was extracted with ethyl acetate three times, the organic phase was combined and washed with saturated brine once, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain white solid 004-B (200 mg). MS: [M+H] 253.0, 255.

[0572] Step 3: Compound 004-B (190.0 mg, 0.75 mmol) and 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazol-2(3H)-one (268.5 mg, 0.98 mmol) were dissolved in dimethyl ether / water (4 / 1, 5 mL), and a nitrogen stream was passed for 2 min, then K3PO4 (398.4 mg, 1.88 mmol) and Pd(dppf)Cl2 (54.9 mg, 0.08 mmol) were added, and the mixture was heated to 70°C and stirred for 1 h. After the reaction was completed, the reaction solvent was removed by reduced pressure concentration, then water (20 mL) and ethyl acetate (20 mL) were added to separate the layers, the aqueous phase was extracted with ethyl acetate twice, the organic phase was combined, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure, and then purified by column chromatography to obtain white solid 004-C (44.66 mg). MS: [M+H] 322; 1 H NMR (400 MHz, DMSO) δ 7.56 (s, 1H), 7.51 (s, 1H), 7.43 (d, J = 8.3 Hz, 1H), 7.39-7.28 (m, 2H), 6.89 (d, J = 8.3 Hz, 1H), 5.05-4.90 (m, 1H), 4.16 (d, J = 3.9 Hz, 1H), 3.39 (s, 3H), 3.28 (m, 2H).

[0573] Step 4: Compound 004-C (44 mg) was dissolved in DMF, SM-1 (50.3 mg) was added, HATU (92.5 mg), DIPEA (72.3 mg), and the mixture was reacted at room temperature for half an hour, then water and ethyl acetate were added, extracted, the organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain compound 004-D (54 mg).

[0574] Step 5: Compound 004-D (54 mg) was dissolved in formic acid (2 mL) and reacted at room temperature for 1 h. After the reaction was completed, the reaction solution was slowly dropped into 0 °C ammonia water, extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain compound 004. White solid. MS: [M+H] 449; 1 H NMR (400 MHz, DMSO-d6) δ 8.67 (s, 1H), 7.60 - 7.54 (m, 1H), 7.50 (dd, J = 4.1, 1.7 Hz, 1H), 7.47 - 7.43 (m, 1H), 7.37 - 7.30 (m, 2H), 6.91 (dd, J = 8.3, 2.3 Hz, 1H), 5.30 - 5.13 (m, 2H), 4.11 - 4.04 (m, 1H), 3.80 - 3.62 (m, 2H), 3.49 - 3.41 (m, 1H), 3.39 (s, 3H), 3.26 - 3.09 (m, 3H), 2.83 - 2.66 (m, 2H), 1.85 - 1.46 (m, 2H).

[0575] Example 33: Synthesis of compound 007

[0576] Step 1: Compound 007-SM1 (500 mg, 1 eq) and compound A (535 mg, 1 eq) were placed in a reaction bottle, dissolved in super dry dichloromethane 20 ml, then DIPEA (510 mg, 2.0 eq), T3P (2.3 g, 1.5 eq) were added in turn, and reacted at room temperature for 1 h. TLC monitoring, the raw material basically disappeared, the reaction solution was added to saturated brine, extracted with dichloromethane for 3 times, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain brown solid 007-A (640 mg). MS: [M+H-Boc] 404; 406.

[0577] Step 2: Compound 007-A (120 mg, 1 eq) and 007-SM2 (110 mg, 1.2 eq) were placed in a reaction bottle, dissolved in dimethyltetrahydrofuran and water (6 / 1), then passed through a nitrogen stream for 2 min, then added sodium bicarbonate (60 mg, 3.0 eq), Pd(PPh3)2Cl2, heated to 80 °C and reacted for 2 h. LC-MS monitoring, after the reaction was completed, the reaction solution was evaporated, and 007-B (118 mg) was obtained by column chromatography purification. MS: [M+H] 625.

[0578] Step 3: Put 007-B in a reaction flask, add 5 ml formic acid, heat to 45 °C for 25 min, TLC monitoring, until 007-B is basically disappeared, drop the reaction solution into ice ammonia water, extract with ethyl acetate for 3 times, combine the organic phase, dry over anhydrous sodium sulfate, filter, concentrate, purify by column chromatography to give compound 007. Off-white solid. MS: [M+H] 525; 1 H NMR (400 MHz, Methanol-d4) δ 7.86 (d, J = 1.9 Hz, 1H), 7.67 - 7.62 (m, 1H), 7.58 (d, J = 8.5 Hz, 1H), 7.42 (dd, J = 7.6, 3.6 Hz, 2H), 7.34 - 7.28 (m, 1H), 7.25 - 7.13 (m, 1H), 7.04 - 6.88 (m, 2H), 6.84 - 6.79 (m, 1H), 3.72 (t, J = 6.5 Hz, 1H), 3.46 (s, 3H), 3.28 - 3.15 (m, 2H).

[0579] Example 34: Synthesis of compound 037

[0580] Synthesis method of compound 037, see compound 007. Compound A and 007-SM1 were reacted, and then coupled with 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazol-2(3H)-one under the action of potassium fluoride, and deprotected to give compound 037. Compound 037 is a light yellow solid, MS: [M+H] 473; 1 H NMR (400 MHz, Methanol-d4) δ 7.86 (d, J = 1.9 Hz, 1H), 7.67 - 7.62 (m, 1H), 7.58 (d, J = 8.5 Hz, 1H), 7.42 (dd, J = 7.6, 3.6 Hz, 2H), 7.34 - 7.28 (m, 1H), 7.25 - 7.13 (m, 1H), 7.04 - 6.88 (m, 2H), 6.84 - 6.79 (m, 1H), 3.72 (t, J = 6.5 Hz, 1H), 3.46 (s, 3H), 3.28 - 3.15 (m, 2H).

[0581] Example 35: Synthesis of compound 013

[0582] Step 1 : Compound A (1.0 g) was dissolved in dichloromethane (20 ml), then SM-013 (1.11 g) DIPEA (1.55 g) was added with stirring, and 50% T3P ethyl acetate solution (3.82 g) was added dropwise slowly. After the addition was completed, the reaction was stirred at room temperature, and LC-MS was monitored. After the reaction was completed, water (20 ml) was added, and the mixture was separated. The aqueous phase was extracted with dichloromethane (20 ml) again. The combined organic phases were concentrated to dryness under reduced pressure at 40°C. The residue was purified by reversed-phase column chromatography, and freeze-dried to obtain compound 013-B (1.82 g). MS: [M+H] 364, 366.

[0583] Step 2: Compound 013-B (500 mg) was dissolved in dimethyltetrahydrofuran / water (6 / 1), and 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazol-2(3H)-one (891 mg) was added. Nitrogen was flowed for 2 min, and then KF (376 mg) and Pd(dppf)Cl2(238 mg) were added. The reaction was heated to 85°C, and LC-MS was monitored. After the reaction was completed, water (20 ml) was added, and the mixture was stirred and separated. The aqueous phase was extracted with ethyl acetate, and the combined organic phases were concentrated to dryness under reduced pressure at 40°C. The residue was purified by column chromatography to obtain compound 013-C (172 mg). MS: [M+H-Boc] 433.

[0584] Step 3: Compound 013-C (170 mg) was added to 2 ml of formic acid, and the mixture was stirred and heated to 45°C for 20 min, and LC-MS was monitored. After the reaction was completed, the reaction solution was added dropwise into ice ammonia water, and the mixture was extracted with dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain compound 013 as a white solid. MS: [M+H] 433; 1 H NMR (400 MHz, DMSO-d6) δ 9.60 (s, 1H), 8.00 (d, J = 1.8 Hz, 1H), 7.81-7.68 (m, 2H), 7.63 (s, 1H), 7.49-7.39 (m, 2H), 7.14 (s, 1H), 6.57 (t, J = 7.8 Hz, 1H), 5.09-4.94 (m, 1H), 4.31-4.20 (m, 1H), 4.05-3.88 (m, 1H), 3.44 (s, 3H), 2.99-2.84 (m, 1H), 2.40-2.26 (m, 1H), 1.94-1.75 (m, 1H).

[0585] Example 36: Synthesis of compound 020

[0586] Step 1 : Compound A (1.5 g) was dissolved in dichloromethane (20 ml), then SM-020 (1.66 g) and DIPEA (2.33 g) were added with stirring, and a 50% T3P solution in ethyl acetate (5.73 g) was added dropwise. The reaction was stirred at room temperature, and LC-MS was used for monitoring. After the reaction was completed, water (20 ml) was added, and the mixture was separated. The aqueous phase was extracted with dichloromethane (20 ml), and the combined organic phase was concentrated to dryness under reduced pressure at 40°C. The residue was purified by reversed-phase column chromatography, and freeze-drying was performed to obtain compound 020-B (2.26 g). MS: [M+H] 364, 366.

[0587] Step 2: Compound 020-B (1 g) was dissolved in dichloromethane (20 ml), and diethylamine sulfide (DAST, 418 mg) was added with stirring. The reaction was stirred at room temperature, and LC-MS was used for monitoring. After the reaction was completed, the reaction solution was added dropwise into saturated aqueous ammonium bicarbonate solution, and the mixture was stirred for 10 min. The aqueous phase was extracted with dichloromethane, and the combined organic phase was concentrated to dryness under reduced pressure at 40°C to obtain compound 020-C (957 mg). MS: [M+H] 366, 368.

[0588] Step 3: Compound 020-C (500 mg) was dissolved in dimethyltetrahydrofuran / water (6 / 1), and 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazol-2(3H)-one (887 mg) was added. Nitrogen was passed for 2 min, and then KF (376 mg) and Pd(dppf)Cl2(238 mg) were added. The reaction was heated to 85°C, and LC-MS was used for monitoring. After the reaction was completed, water (20 ml) was added, and the mixture was stirred and separated. The aqueous phase was extracted with ethyl acetate, and the combined organic phase was concentrated to dryness under reduced pressure at 40°C. The residue was purified by column chromatography to obtain compound 020-D (153 mg). MS: [M+H] 435.

[0589] Step 4: Compound 020-D (150 mg) was added to 2 ml of formic acid, and the mixture was heated to 45°C with stirring for 20 min. LC-MS was used for monitoring. After the reaction was completed, the reaction solution was added dropwise into ice water, and dichloromethane was added for extraction. The combined organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain compound 020, a white solid. MS: [M+H] 435; 1H NMR (400 MHz, DMSO-d6) δ 9.51 - 9.41 (m, 1H), 8.00 (d, J = 1.8 Hz, 1H), 7.77 - 7.68 (m, 2H), 7.64 (d, J = 1.7 Hz, 1H), 7.47 - 7.42 (m, 2H), 7.06 (d, J = 8.5 Hz, 1H), 6.53 (t, J = 8.7 Hz, 1H), 5.36 - 5.17 (m, 1H), 3.93 - 3.86 (m, 1H), 3.44 (s, 3H), 3.25 - 3.08 (m, 2H), 2.40 - 2.14 (m, 2H).

[0590] Example 37: Synthesis of compound 027

[0591] The synthetic method of compound 027 was referred to compound 001. The compound A reacted with SM-027, then coupled with 3-methyl-5-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl)benzo[d]oxazol-2(3H)-one, deprotection to obtain compound 027. Compound 027 was a white solid, MS: [M+H] 457; 1 H NMR (400 MHz, Methanol-d4) δ 7.90 (s, 1H), 7.69 - 7.56 (m, 2H), 7.43 (d, J = 8.8 Hz, 2H), 7.32 (d, J = 8.2 Hz, 1H), 7.11 (d, J = 8.0 Hz, 1H), 3.98 - 3.93 (m, 1H), 3.46 (s, 3H), 2.22 - 2.07 (m, 1H), 2.07 - 1.52 (m, 9H).

[0592] Example 38: Synthesis of compound 035

[0593] The synthetic method of compound 035 was referred to compound 001. The compound A reacted with 035-SM, then coupled with 3-methyl-5-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl)benzo[d]oxazol-2(3H)-one, deprotection to obtain compound 035. Compound 035 was a light yellow solid, MS: [M+H] 429; 1H NMR (400 MHz, Methanol-d4) δ 7.88 (d, J = 1.8 Hz, 1H), 7.65 - 7.56 (m, 2H), 7.42 (d, J = 7.9 Hz, 2H), 7.31 (d, J = 8.3 Hz, 1H), 7.05 (s, 1H), 3.52 - 3.47 (m, 1H), 3.46 (s, 3H), 2.94 - 2.87 (m, 1H), 2.34 - 2.26 (m, 1H), 1.51 - 1.44 (m, 1H), 1.36 - 1.26 (m, 3H).

[0594] Example 39: Synthesis of compound 044

[0595] The synthetic method of compound 044 was described in compound 001. The reaction of compound A and 044-SM, followed by coupling with 3-methyl-5-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl)benzo[d]oxazol-2(3H)-one, deprotection gave compound 044. Compound 044 was white solid, MS: [M+H] 457; 1 H NMR (400 MHz, Methanol-d4) δ 7.88 (d, J = 1.8 Hz, 1H), 7.65 - 7.56 (m, 2H), 7.42 (d, J = 7.9 Hz, 2H), 7.31 (d, J = 8.3 Hz, 1H), 7.05 (s, 1H), 3.52 - 3.47 (m, 1H), 3.46 (s, 3H), 2.94 - 2.87 (m, 1H), 2.34 - 2.26 (m, 1H), 1.51 - 1.44 (m, 1H), 1.36 - 1.26 (m, 3H).

[0596] Example 40: Synthesis of compound 030

[0597] The synthetic method of compound 030 was described in compound 001. The reaction of compound D and SM1, followed by coupling with 3-methyl-5-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl)benzo[d]oxazol-2(3H)-one in the presence of potassium fluoride, deprotection gave compound 030. Compound 030 was white solid, MS: [M+H] 447; 1H NMR (400 MHz, Methanol-d4) δ 7.77 (s, 1H), 7.70 (d, J = 8.2 Hz, 1H), 7.58 (dd, J = 8.2, 1.6 Hz, 1H), 7.47 - 7.41 (m, 2H), 7.31 (d, J = 8.8 Hz, 1H), 7.04 (t, J = 1.2 Hz, 1H), 4.60 - 4.51 (m, 1H), 4.17 - 4.09 (m, 1H), 3.92 - 3.85 (m, 1H), 3.79 - 3.70 (m, 1H), 3.45 (s, 3H), 3.44 - 3.38 (m, 1H), 3.38 - 3.32 (m, 2H), 2.22 - 2.07 (m, 2H).

[0598] Example 41: Synthesis of compound 031

[0599] The synthetic method of compound 031 was described in compound 001. The compound D and SM1 were reacted, then coupled with 4-cyanophenylboronic acid pinacol ester in the presence of potassium fluoride, deprotection to give compound 031. Compound 031 was white solid, MS: [M+H] 401; 1 H NMR (400 MHz, Methanol-d4) δ 7.77 (s, 1H), 7.70 (d, J = 8.2 Hz, 1H), 7.58 (dd, J = 8.2, 1.6 Hz, 1H), 7.47 - 7.41 (m, 2H), 7.31 (d, J = 8.8 Hz, 1H), 7.04 (t, J = 1.2 Hz, 1H), 4.60 - 4.51 (m, 1H), 4.17 - 4.09 (m, 1H), 3.92 - 3.85 (m, 1H), 3.79 - 3.70 (m, 1H), 3.45 (s, 3H), 3.44 - 3.38 (m, 1H), 3.38 - 3.32 (m, 2H), 2.22 - 2.07 (m, 2H).

[0600] Example 42: Synthesis of compound 032

[0601] The synthetic method of compound 032 was described in compound 005. The compound D and SM2 were reacted, then coupled with 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazol-2(3H)-one in the presence of potassium fluoride, deprotection to give compound 032. Compound 032 was white solid, MS: [M+H] 443; 1H NMR (400 MHz, Methanol-d4) δ 7.78 (d, J = 6.5 Hz, 1H), 7.71 (dd, J = 8.2, 2.5 Hz, 1H), 7.63 - 7.55 (m, 1H), 7.48 - 7.40 (m, 2H), 7.31 (dd, J = 8.8, 2.1 Hz, 1H), 7.08 (s, 1H), 4.05 - 3.99 (m, 1H), 3.83 (d, J = 6.7 Hz, 1H), 3.45 (s, 3H), 2.89 - 2.75 (m, 1H), 1.88 - 1.69 (m, 4H), 1.66 - 1.55 (m, 2H).

[0602] Example 43: Synthesis of compound 042

[0603] Step 1: Compound 042-SM (9.00 g, 45.68 mmol) was dissolved in phosphorus oxychloride (30 mL), heated to 80 °C with stirring, then DMF (26.71 g, 0.37 mol) was added dropwise, after the addition was completed, the reaction was continued to stir for 16 h. After the reaction was completed, the reaction liquid was concentrated under reduced pressure, the residue was added with water (100 mL), extracted with ethyl acetate, the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain yellow solid compound 042-A (4.0 g). 1 H NMR (400 MHz, DMSO-d6) δ 9.88 (s, 1H), 8.11 (s, 1H), 8.00 (d, J = 0.8 Hz, 1H), 7.87 (d, J = 8.4 Hz, 1H), 7.58 (dd, J = 8.4, 1.7 Hz, 1H).

[0604] Step 2: Compound 042-A (3.00 g, 13.33 mmol) was placed in a reaction bottle, dissolved with 7M ammonia methanol solution (20 mL) and stirred at room temperature for 1 h. Then TMSCN (2.0 g, 20.0 mmol) was added, and stirring was continued at room temperature for 1 h. After the reaction was completed, the reaction liquid was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain light yellow solid compound 042-B (1.11 g). MS: [M-NH2] 234.0, 236.1; 1 H NMR (400 MHz, DMSO-d6) δ 9.88 (s, 1H), 8.11 (s, 1H), 8.00 (d, J = 0.8 Hz, 1H), 7.87 (d, J = 8.4 Hz, 1H), 7.58 (dd, J = 8.4, 1.7 Hz, 1H).

[0605] Step 3: Refer to the synthetic method of Step 1 of Compound 005. Amide condensation of 042-B with SM-2 to give 042-C.

[0606] Step 4: Refer to the synthetic method of Step 2 of Compound 005. Coupling of 042-C with 3-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzo[d]oxazol-2(3H)-one to give 042-D.

[0607] Step 5: Refer to the synthetic method of Step 3 of Compound 005. Boc deprotection of 042-D in formic acid to give Compound 042. Compound 042 is a off-white solid. MS: [M+H] 443; 1 H NMR (400 MHz, Methanol-d4) δ 7.80 (s, 1H), 7.71 (d, J = 8.2 Hz, 1H), 7.60 (d, J = 8.1 Hz, 1H), 7.45 (d, J = 6.9 Hz, 2H), 7.32 (d, J = 8.6 Hz, 1H), 7.04 (s, 1H), 3.78 - 3.70 (m, 1H), 3.53 (d, J = 5.4 Hz, 1H), 3.46 (s, 3H), 2.76 - 2.67 (m, 1H), 1.81 - 1.67 (m, 2H), 1.64 - 1.50 (m, 3H), 1.45 - 1.37 (m, 1H).

[0608] Example 44: Synthesis of Compound 023

[0609] Step 1: Compound 023-SM (2 g, 8.92 mmol) was dissolved in dichloromethane, Boc20 (2.91 g, 1.5 eq), triethylamine (2.72 g, 3 eq) were added, and the reaction was allowed to proceed at room temperature overnight. After the reaction was completed, it was concentrated under reduced pressure, and the residue was purified by column chromatography to give Compound 023-A (1.8 g).

[0610] Step 2: Compound 023-A (1.7 g, 5.26 mmol) was weighed into a reaction bottle, 7M ammonia in methanol solution (5 mL, 35 mmol) was added for dissolution, and then TMSCN (781 mg, 1.5 eq), tetraethyl titanate (1.19 g, 1 eq) were added in sequence. The reaction was warmed to 45°C and allowed to proceed for 2 h. The reaction was monitored by LC-MS. After SM-A was substantially consumed, the reaction was allowed to cool to room temperature, 50 mL of dichloromethane was added, and the reaction was poured into 5% aqueous sodium carbonate solution. The mixture was filtered, and the layers were separated in a separatory funnel. The aqueous phase was extracted with dichloromethane three times, and the combined organic phase was washed with saturated brine once, dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by column chromatography gave Compound 023-B (490 mg).

[0611] Step 3: Compound 023-B (450 mg, 1.0 eq) and compound SM-1 (1.0 eq) were weighed into a reaction flask, dissolved in 25 ml of super dry dichloromethane, DIPEA (2.0 eq) and T3P (1.5 eq) were added, and the reaction was carried out at room temperature for 1 h, TLC monitoring, and when compound 023-B was basically disappeared, the reaction solution was poured into ice water, ammonia water was added to adjust the pH to 9-10, extracted with dichloromethane three times, the organic phase was combined, and then the organic phase was washed with saturated ammonium chloride and saturated brine in turn, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 023-C crude. The next step reaction was carried out directly without purification.

[0612] Step 4: Compound 023-C (1 eq) and 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazol-2(3H)-one (1 eq) were placed in a reaction flask, dissolved in dimethyltetrahydrofuran / water (20 / 2) ml, and then nitrogen was flowed for 2 min, sodium bicarbonate (380 mg, 2.0 eq), Pd(dppf)Cl2(330 mg, 0.2 eq) were added, heated to 80°C, and the reaction was carried out for 2 h, LC-MS monitoring, and when 023-C was basically disappeared, the reaction solution was cooled to room temperature, and the reaction solution was poured into saturated brine, extracted with ethyl acetate, the organic phase was combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain compound 023-D (60 mg). MS: [M+H] 646.

[0613] Step 5: Compound 023-D was placed in a reaction flask, 5 ml of formic acid was added, heated to 45°C and reacted for 20 min, TLC monitoring, and when 023-D was basically disappeared, the reaction solution was dropped into ice ammonia water, extracted with ethyl acetate, the organic phase was combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain compound 023, a white solid. MS: [M+H] 446; 1 H NMR (400 MHz, Methanol-d4) δ 7.81 (s, 1H), 7.46 (s, 2H), 7.43-7.39 (m, 2H), 7.32-7.26 (m, 1H), 6.73-6.69 (m, 1H), 4.44-4.38 (m, 1H), 4.13-4.04 (m, 1H), 3.89-3.80 (m, 1H), 3.62-3.48 (m, 2H), 3.46 (s, 3H), 3.15-3.08 (m, 2H), 2.11-1.92 (m, 2H).

[0614] Biological Example 1: In vitro DPP1 cell activity experiment

[0615] Table 1, experimental materials

[0616] Experimental procedure

[0617] After the recovery of THP-1 cells, they were subcultured for 2-3 passages to restore normal growth. The cells in the logarithmic growth phase were centrifuged at 150g for 5 min, and the supernatant was discarded. The cells were resuspended by gentle blowing with PBS buffer solution and the density was adjusted to 1.0 x 106 / mL. 60 μL of the above density cells were added to a 96-well black plate, and 100 μL of PBS buffer solution was added to the edge of the 96-well plate to prevent evaporation of the liquid during incubation. The weighed compounds were dissolved in DMSO to prepare a 10 mM stock solution. 5 μL of the 10 mM compound stock solution was added to 495 μL of PBS buffer solution to prepare a 100 μM stock solution. 25 μL of the 100 μM stock solution was added to 975 μL of PBS buffer solution to prepare a working solution with an initial concentration of 2500 nM. After 3-fold gradient dilution to 8 points, the compound was added to the above 96-well plate containing the cells. After 60 min of incubation, 500 μM Gly-Phe-AFC substrate working solution was added. Then the above 96-well plate was placed in a BioTek enzyme marker, and the fluorescence value was obtained by reading at Ex400 nm & Em505 nm wavelength. The data were processed by four-parameter curve fitting. The sample dilution concentration gradient was used as the x-axis, and the fluorescence value was used as the y-axis. Four-parameter fitting was performed, and the EC50 value was obtained according to the fitting curve.

[0618] Table 2, activity data

Claims

1. A compound of formula (X), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, ester, polymorph, or hydrate thereof: in, It can be a single bond or a double bond; X represents O, S, and NR. X1 or C(R) X2 (R) X3 ), where R X1 R X2 and R X3 Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 cycloalkyl and 3-8 membered heterocyclic groups; L stands for bond, C 1-6 Alkylene, C 1-6 Alkyl halide, -C(O)-, -OC(O)-, -C(O)O-, -S(O)- or -S(O)2-; m is 0, 1, or 2; R 1 Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups; R 2 Selected from H, deuterium, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups; Or R 1 R 2 Together with the atoms between them, they form 3-10 membered heterocyclic groups, which are optionally surrounded by 1, 2, 3 or 4 R atoms. B replace; Each R B Independently selected from H, deuterium, halogen, -CN, -OR a -SR a -N(R) b (R) c -C(O)-R a -OC(O)-R a -C(O)OR a -C(O)-N(R) b (R) c ), -N(R b )C(O)-R c -S(O)R a -S(O)2-R a -S(O)2NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 cycloalkyl, C 6-10 Aryl, 5-10-membered heteroaryl and 3-8-membered heterocyclic groups, wherein the above groups are optionally substituted by 1, 2, 3 or 4 R*; And / or, two R atoms on non-adjacent atoms B Connect to form C 1-3 Alkylene; And / or, two R atoms on adjacent atoms B Together with the atoms between them, they form C 3-7 Cycloalkyl or 3-8 membered heterocyclic groups, wherein the above groups are optionally substituted by 1, 2, 3 or 4 R*; And / or, two R atoms on the same carbon atom B Together with this carbon atom, they form C 3-7 Cycloalkyl or oxo; R 3 Selected from H, deuterium, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl groups, wherein the above groups are optionally surrounded by 1, 2, 3 or 4 R groups. 3a replace; R 3a Selected from H, deuterium, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups, wherein the above groups are optionally substituted by 1, 2, 3 or 4 R*; Or, R 2 R 3 Together with the atoms between them, they form 3-8 membered heterocyclic groups, which are optionally substituted with 1, 2, 3 or 4 R*. R 4 Selected from H and C 1-6 alkyl; R 5 Selected from H and C 1-6 alkyl; Ring A is selected from C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl groups, wherein the above groups are optionally surrounded by 1, 2, 3 or 4 R groups. A replace; Each R A Independently selected from H, deuterium, halogen, -CN, -OR a -SR a -N(R) b (R) c -C(O)-R a -OC(O)-R a -C(O)OR a -C(O)-N(R) b (R) c ), -N(R b )C(O)-R c -S(O)R a -S(O)2-R a -S(O)2NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups, wherein the above groups are optionally substituted by 1, 2, 3 or 4 R*; And / or, two R atoms on the same carbon atom A Together with this carbon atom, they form C 3-7 cycloalkyl or oxo, wherein the C 3-7 The cycloalkyl group is optionally substituted with 1, 2, 3 or 4 R*; And / or, two R atoms on adjacent carbon atoms A Together with the carbon atoms between them and optionally the hydrogen atoms on those carbon atoms, they form C 3- 8-cycloalkyl, 3-8 membered heterocyclic, C 6-10 Aryl or 5-10 heteroaryl, wherein the above groups are optionally surrounded by 1, 2, 3 or 4 R groups. A5 replace; Each R A5 Independently selected from H, deuterium, halogen, -OH, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups, wherein the above groups are optionally substituted by 1, 2, 3 or 4 R*; And / or, two R atoms on the same carbon atom A5 Together with this carbon atom, they form C 3-7 Cycloalkyl, 3-8 membered heterocyclic or oxo, wherein the C 3-7 The cycloalkyl or 3-8 membered heterocyclic group is optionally substituted with 1, 2, 3 or 4 R*; R a R b and R c Each is independently selected from H, halogen, -OH, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups, wherein the above groups are optionally substituted by 1, 2, 3 or 4 R*; Each R* is independently selected from H, deuterium, -CN, -NO2, halogen, -OR* a -SR* a -N(R*) b (R*) c -C(O)-R* a -OC(O)-R* a -C(O)OR* a -C(O)-N(R*) b (R*) c -N(R*) b )C(O)-R* c -S(O)R* a -S(O)2-R* a -S(O)2NR* b R* c C 1- 6-alkyl and C 1-6 Halogenated alkyl groups; R* a 、R* b and R* c Each is independently selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 Cycloalkyl, 3-7 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups; or R* b 、R* c Together with the N atoms attached to them, they form 3-7 membered heterocyclic groups.

2. The compound according to claim 1, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, ester, polymorph, or hydrate thereof, wherein, X represents O, S, and NR. X1 or C(R) X2 (R) X3 ), where R X1 R X2 and R X3 Independently selected from H and C 1-6 Alkyl group; preferably, X is O, S, NH or CH2; preferably, X is O or NH; preferably, X is O.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, ester, polymorph, or hydrate thereof, wherein, L is a bond or -C(O)-; preferably, L is a bond.

4. The compound according to any one of claims 1-3, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, ester, polymorph, or hydrate thereof, wherein, m is 0 or 1.

5. The compound according to any one of claims 1-4, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, ester, polymorph, or hydrate thereof, wherein, R 1 For H.

6. The compound according to any one of claims 1-5, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, ester, polymorph, or hydrate thereof, wherein, R 2 For H.

7. The compound according to any one of claims 1-4, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, ester, polymorph, or hydrate thereof, wherein, R 1 R 2 Together with the atoms between them, they form 3-10 membered heterocyclic groups; preferably, 5-7 membered heterocyclic groups; which are optionally surrounded by 1, 2, 3 or 4 R atoms. B replace.

8. The compound according to claim 7, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, ester, polymorph, or hydrate thereof, wherein, Each R B Independently selected from H, -OH and C 1-6 Alkyl; preferably, each R B Independently selected from -OH; wherein the C 1-6 Alkyl groups may optionally be substituted with 1, 2, 3 or 4 R*; And / or, two R atoms on non-adjacent atoms B Connect to form C 1-3 Alkylene; preferably, ethylene and methylene; preferably, methylene; And / or, two R atoms on adjacent atoms B Together with the atoms between them, they form C 3-7 Cycloalkyl or 3-8 membered heterocyclic groups; preferably cyclopropyl, cyclopentyl, or tetrahydrofuranyl; And / or, two R atoms on the same carbon atom B Together with this carbon atom, they form C 3-7 Cycloalkyl; preferably, cyclobutyl.

9. The compound according to any one of claims 1-8, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, ester, polymorph, or hydrate thereof, wherein, R 3 Selected from H and C 1-6 Alkyl; preferably, the C 1-6 The alkyl group is methyl; wherein the C 1-6 Alkyl group is formed by an R 3a replace.

10. The compound according to claim 9, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, ester, polymorph, or hydrate thereof, wherein, R 3a Selected from 5-10-membered heteroaryl groups; preferably, 5-membered heteroaryl groups; preferably, thiophene groups; wherein the above groups are optionally substituted by 1, 2, 3 or 4 R* groups.

11. The compound according to any one of claims 1-10, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, ester, polymorph, or hydrate thereof, wherein, R 2 R 3 Together with the atoms between them, they form 3-8 membered heterocyclic groups; preferably, 6 membered heterocyclic groups; preferably, tetrahydropyranyl groups.

12. The compound according to any one of claims 1-11, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, ester, polymorph, or hydrate thereof, wherein, Ring A is selected from C 3-8 Cycloalkenyl, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-10-membered heteroaryl; preferably, cyclohexenyl, 6-membered heterocyclic, phenyl and 5-10-membered heteroaryl, wherein the above groups are optionally surrounded by 1, 2, 3 or 4 R... A replace.

13. The compound according to claim 12, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, ester, polymorph, or hydrate thereof, wherein, Each R A Independently selected from H, -OH, halogens, -CN, -S(O)2-R a C 1-6 Alkyl, C 3-7 Cycloalkyl, 5-10-membered heteroaryl and 3-8-membered heterocyclic, wherein the C 1-6 Alkyl, C 3-7 The cycloalkyl, 5-10-membered heteroaryl, and 3-8-membered heterocyclic groups are optionally substituted with 1, 2, 3, or 4 R* groups; wherein, R... a Selected from 3-8 membered heterocyclic groups, which are optionally replaced by 1, 2, 3 or 4 R*; And / or, two R atoms on the same carbon atom A Together with the carbon atom, it forms an oxygen atom; And / or, two R atoms on adjacent carbon atoms A Together with the carbon atoms between them and optionally the hydrogen atoms on those carbon atoms, they form a 5-6 membered heterocyclic group or a 6-membered heteroaryl group, wherein the above groups are optionally surrounded by 1, 2, 3 or 4 R groups. A5 replace.

14. The compound according to claim 13, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, ester, polymorph, or hydrate thereof, wherein, Each R A5 Independently selected from H, halogens, -OH, C 1-6 Alkyl, C 3-7 Cycloalkyl, 3-8 membered heterocyclic and 5-10 membered heteroaryl; And / or, two R atoms on the same carbon atom A5 Together with this carbon atom, they form C 3-7 Cycloalkyl, 3-8 membered heterocyclic or oxo, wherein the C 3-7 The cycloalkyl or 3-8 membered heterocyclic group is optionally substituted with 1, 2, 3 or 4 R*.

15. The compound according to any one of claims 1-14, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, ester, polymorph, or hydrate thereof, wherein, Ring A is Among them, ring member Y 1 Y 2 Y 3 and Y 4 Each atom is independently C, N, or O, and the ring A is optionally surrounded by R. A replace; Y 1 and Y 2 Y 2 and Y 3 Y 3 and Y 4 The bond between them is a single bond or a double bond, or Y. 1 Y 2 Y 3 and Y 4 Together with other ring members, it forms phenyl, 6-membered heterocyclic or 6-membered heteroaryl groups.

16. The compound according to any one of claims 1-15, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, ester, polymorph, or hydrate thereof, wherein, Ring A is selected from phenyl, 6-membered heteroaryl, The above-mentioned groups are optionally surrounded by 1, 2, 3 or 4 R groups. A replace.

17. The compound according to claim 15 or 16, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, ester, polymorph, or hydrate thereof, wherein, Each R A Independently selected from H, halogen, -CN, C 1-6 Alkyl, C 3-7 Cycloalkyl, 5-10-membered heteroaryl and 3-8-membered heterocyclic groups; And / or, two R atoms on adjacent carbon atoms A Together with the carbon atoms between them and optionally the hydrogen atoms on those carbon atoms, they form a 5-6 membered heterocyclic group or a 6-membered heteroaryl group, wherein the above groups are optionally surrounded by 1, 2, 3 or 4 R groups. A5 replace.

18. The compound of claim 17, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, ester, polymorph, or hydrate thereof, wherein, Each R A5 Independently selected from H and C 1-6 Alkyl, C 3-7 Cycloalkyl and 5-10 heteroaryl groups.

19. The compound according to any one of claims 1-18, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, ester, polymorph, or hydrate thereof, wherein, Ring A is selected from and phenyl, wherein the above groups are optionally surrounded by 1, 2, 3 or 4 R... A replace; R A1 and R A4 Each is independently selected from H and C. 1-6 Alkyl and C 3-7 cycloalkyl; R A2 and R A3 Independently selected from H, halogens and C 1-6 Alkyl, or R A2 R A3 Together with the carbon atoms attached to them, they form C 3- 6-Cycloalkyl.

20. The compound of claim 19, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, ester, polymorph, or hydrate thereof, wherein, Each R A Independently selected from H, halogen, -CN, C 1-6 Alkyl, 5-10 membered heteroaryl and 3-8 membered heterocyclic groups.

21. The compound according to any one of claims 1-20, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, ester, polymorph, or hydrate thereof, wherein, Ring A is selected from and phenyl, wherein the above groups are optionally surrounded by 1, 2, 3 or 4 R... A replace; R A1 Selected from H and C 1-6 alkyl; R A2 and R A3 Independently selected from H, halogens and C 1-6 Alkyl, or R A2 R A3 Together with the carbon atoms attached to them, they form C 3- 6-Cycloalkyl.

22. The compound of claim 21, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, ester, polymorph, or hydrate thereof, wherein, Each R A Independently selected from H, halogens, -CN and C 1-6 alkyl.

23. The compound according to any one of claims 1-22, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, ester, polymorph, or hydrate thereof, wherein, Ring A is selected from The above-mentioned groups are optionally surrounded by 1, 2, 3 or 4 R groups. A replace; R A1 Selected from H and C 1-6 alkyl.

24. The compound of claim 23, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, ester, polymorph, or hydrate thereof, wherein, Each R A Independently selected from H and C 1-6 alkyl.

25. The compound according to any one of claims 1-24, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, ester, polymorph, or hydrate thereof, wherein, Ring A is selected from 26. The compound according to any one of claims 1-25, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, ester, polymorph, or hydrate thereof, wherein, R 4 H or methyl, R 5 H; preferably; R 4 Let H be the number of 'R', and R be the number of 'R'. 5 For H.

27. The compound according to any one of claims 1-26, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, ester, polymorph, or hydrate thereof, wherein, The compound has the structure of formula (X-1): Each of the variables is defined as described in any one of claims 1-26.

28. The compound according to any one of claims 1-27, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, ester, polymorph, or hydrate thereof, wherein the compound has the structure of formula (I): in, It can be a single bond or a double bond; preferably, it is a double bond. X represents O, S, and NR. X1 or C(R) X2 (R) X3 ), where R X1 R X2 and R X3 Independently selected from H and C 1-6 Alkyl and C 1-6 Halogenated alkyl group; preferably, X is O, S, NH or CH2; preferably, X is O or NH; preferably, X is O; L is a bond or -C(O)-; preferably, L is a bond; m is 0 or 1; R 1 For H; R 2 For H; Or, R 1 R 2 Together with the atoms between them, they form 3-10 membered heterocyclic groups; preferably, 5-7 membered heterocyclic groups; which are optionally surrounded by 1, 2, 3 or 4 R atoms. B replace; Each R B Independently selected from H, -OH and C 1-6 Alkyl; preferably, each R B Independently selected from -OH; wherein the C 1-6 Alkyl groups may optionally be substituted with 1, 2, 3 or 4 R*; And / or, two R atoms on non-adjacent atoms B Connect to form C 1-3 Alkylene; preferably, ethylene and methylene; preferably, methylene; And / or, two R atoms on adjacent atoms B Together with the atoms between them, they form C 3-7 Cycloalkyl or 3-8 membered heterocyclic groups; preferably cyclopropyl, cyclopentyl or tetrahydrofuranyl; wherein the above groups are optionally substituted by 1, 2, 3 or 4 R*; And / or, two R atoms on the same carbon atom B Together with this carbon atom, they form C 3-7 cycloalkyl; preferably, cyclobutyl; R 3 Selected from H and C 1-6 Alkyl, preferably, the C 1-6 The alkyl group is methyl; wherein the C 1-6 Alkyl group is formed by an R 3a replace; R 3a Selected from 5-10-membered heteroaryl groups; preferably, 5-membered heteroaryl groups; preferably, thiophene groups; wherein the above groups are optionally substituted by 1, 2, 3 or 4 R* groups; Or, R 2 R 3 Together with the atoms between them, they form 3-8 membered heterocyclic groups; preferably, 6 membered heterocyclic groups; preferably, tetrahydropyranyl groups; Ring A is selected from C 3-8 Cycloalkenyl, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-10-membered heteroaryl; preferably, cyclohexenyl, 6-membered heterocyclic, phenyl and 5-10-membered heteroaryl, wherein the above groups are optionally surrounded by 1, 2, 3 or 4 R... A replace; Each R A Independently selected from H, -OH, halogens, -CN, -S(O)2-R a C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, C 6-10 Aryl and 3-8 membered heterocyclic groups, wherein the above groups are optionally substituted by 1, 2, 3 or 4 R*; wherein R a Selected from 3-8 membered heterocyclic groups, which are optionally replaced by 1, 2, 3 or 4 R*; And / or, two R atoms on the same carbon atom A Together with the carbon atom, it forms an oxygen atom; And / or, two R atoms on adjacent carbon atoms A Together with the carbon atoms between them and optionally the hydrogen atoms on those carbon atoms, they form a 5-6 membered heterocyclic group or a 6-membered heteroaryl group, wherein the above groups are optionally surrounded by 1, 2, 3 or 4 R groups. A5 replace; Each R A5 Independently selected from H, halogens, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, 3-8 membered heterocyclic groups, C 6- 10 Aryl and 5-10 heteroaryl groups; And / or, two R atoms on the same carbon atom A5 Together with this carbon atom, they form C 3-7 Cycloalkyl, 3-8 membered heterocyclic or oxo, wherein the C 3-7 The cycloalkyl or 3-8 membered heterocyclic group is optionally substituted with 1, 2, 3 or 4 R*; R a R b and R c Each is independently selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups, wherein the above groups are optionally substituted by 1, 2, 3 or 4 R*; Each R* is independently selected from H, -CN, -NO2, halogen, -OR* a -SR* a -N(R*) b (R*) c -C(O)-R* a -OC(O)-R* a -C(O)OR* a -C(O)-N(R*) b (R*) c -N(R*) b )C(O)-R* c -S(O)R* a -S(O)2-R* a -S(O)2NR* b R* c C 1- 6-alkyl and C 1-6 Halogenated alkyl groups; R* a 、R* b and R* c Each is independently selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 Cycloalkyl, 3-7 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups; or R* b 、R* c Together with the N atoms attached to them, they form 3-7 membered heterocyclic groups.

29. The compound of claim 1, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, ester, polymorph, or hydrate thereof, wherein the compound has the structure of formula (I-1): in, It can be a single bond or a double bond; X represents O, S, and NR. X1 or C(R) X2 (R) X3 ), where R X1 R X2 and R X3 Independently selected from H and C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 3-7 cycloalkyl; L represents a bond or -C(O)-; Z is -C(R) B1 (R) B2 )-、-NR B3 -、-O- or -S-; m is 0 or 1; q is 1, 2, 3, 4, or 5; p is 0, 1, 2, 3, 4 or 5; R B R B1 R B2 and R B3 Each is independently selected from H, halogen, -CN, -OR a -SR a -N(R) b (R) c -C(O)-R a -OC(O)-R a -C(O)OR a -C(O)-N(R) b (R) c ), -N(R b )C(O)-R c -S(O)R a -S(O)2-R a -S(O)2NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups, wherein the above groups are optionally substituted by 1, 2, 3 or 4 R*; And / or, R on non-adjacent atoms B R B1 R B2 or R B3 The two are connected to form C 1-3 Alkylene; And / or, R on adjacent atoms B R B1 R B2 or R B3 The two atoms in the middle, together with the atoms between them, form C. 3-7 Cycloalkyl or 3-8 membered heterocyclic groups, wherein the above groups are optionally substituted by 1, 2, 3 or 4 R*; And / or, R on the same carbon atom B1 R B2 Together with this carbon atom, they form C 3-7 Cycloalkyl or oxo; R 3 Selected from H and C 1-6 alkyl; Ring A is selected from C 3-8 Cycloalkenyl, 3-10 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl groups, wherein the above groups are optionally surrounded by 1, 2, 3 or 4 R groups. A replace; Each R A Independently selected from H, halogen, -CN, -OR a -SR a -N(R) b (R) c -C(O)-R a -OC(O)-R a -C(O)OR a -C(O)-N(R) b (R) c ), -N(R b )C(O)-R c -S(O)R a -S(O)2-R a -S(O)2NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups, wherein the above groups are optionally substituted by 1, 2, 3 or 4 R*; And / or, two R atoms on the same carbon atom A Together with this carbon atom, they form C 3-7 cycloalkyl or oxo, wherein the C 3-7 The cycloalkyl group is optionally substituted with 1, 2, 3 or 4 R*; And / or, two R atoms on adjacent carbon atoms A Together with the carbon atoms between them and optionally the hydrogen atoms on those carbon atoms, they form C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl, wherein the above groups are optionally surrounded by 1, 2, 3 or 4 R groups. A5 replace; Each R A5 Independently selected from H, halogens, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, 3-8 membered heterocyclic groups, C 6- 10 Aryl and 5-10 heteroaryl groups, wherein the above groups are optionally substituted by 1, 2, 3 or 4 R*; And / or, two R atoms on the same carbon atom A5 Together with this carbon atom, they form C 3-7 Cycloalkyl, 3-8 membered heterocyclic or oxo, wherein the C 3-7 The cycloalkyl or 3-8 membered heterocyclic group is optionally substituted with 1, 2, 3 or 4 R*; R a R b and R c Each is independently selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups, wherein the above groups are optionally substituted by 1, 2, 3 or 4 R*; Each R* is independently selected from H, -CN, -NO2, halogen, -OR* a -SR* a -N(R*) b (R*) c -C(O)-R* a -OC(O)-R* a -C(O)OR* a -C(O)-N(R*) b (R*) c -N(R*) b )C(O)-R* c -S(O)R* a -S(O)2-R* a -S(O)2NR* b R* c C 1- 6-alkyl and C 1-6 Halogenated alkyl groups; R* a 、R* b and R* c Each is independently selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 Cycloalkyl, 3-7 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups; or R* b 、R* c Together with the N atoms attached to them, they form 3-7 membered heterocyclic groups.

30. The compound of formula (I-1) according to claim 29, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, ester, polymorph, or hydrate thereof, wherein, It can be a single bond or a double bond; X represents O, S, and NR. X1 or C(R) X2 (R) X3 ), where R X1 R X2 and R X3 Independently selected from H and C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 3-7 cycloalkyl; L represents a bond or -C(O)-; Z is -C(R) B1 (R) B2 - or -O-; m is 0 or 1; q is 1, 2, 3, or 4; p is 0, 1, 2, 3, 4 or 5; R B R B1 R B2 and R B3 Each is independently selected from H, halogen, -OH and C. 1-6 alkyl; And / or, R on non-adjacent atoms B R B1 or R B2 The two are connected to form C 1-3 Alkylene; And / or, R on adjacent atoms B R B1 or R B2 The two atoms in the middle, together with the atoms between them, form C. 3-7 cycloalkyl or 3-8 membered heterocyclic groups; And / or, R on the same carbon atom B1 R B2 Together with this carbon atom, they form C 3-7 cycloalkyl; R 3 For H; Ring A is selected from C 3-8 Cycloalkenyl, 3-10 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl groups, wherein the above groups are optionally surrounded by 1, 2, 3 or 4 R groups. A replace; Each R A Independently selected from H, halogen, -CN, -OR a -SR a -N(R) b (R) c -C(O)-R a -OC(O)-R a -C(O)OR a -C(O)-N(R) b (R) c ), -N(R b )C(O)-R c -S(O)R a -S(O)2-R a -S(O)2NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups, wherein the above groups are optionally substituted by 1, 2, 3 or 4 R*; And / or, two R atoms on the same carbon atom A Together with this carbon atom, they form C 3-7 cycloalkyl or oxo, wherein the C 3-7 The cycloalkyl group is optionally substituted with 1, 2, 3 or 4 R*; And / or, two R atoms on adjacent carbon atoms A Together with the carbon atoms between them and optionally the hydrogen atoms on those carbon atoms, they form C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl, wherein the above groups are optionally surrounded by 1, 2, 3 or 4 R groups. A5 replace; Each R A5 Independently selected from H, halogens, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, 3-8 membered heterocyclic groups, C 6- 10 Aryl and 5-10 heteroaryl groups, wherein the above groups are optionally substituted by 1, 2, 3 or 4 R*; And / or, two R atoms on the same carbon atom A5 Together with this carbon atom, they form C 3-7 Cycloalkyl, 3-8 membered heterocyclic or oxo, wherein the C 3-7 The cycloalkyl group is optionally substituted with 1, 2, 3 or 4 R*; R a R b and R c Each is independently selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups, wherein the above groups are optionally substituted by 1, 2, 3 or 4 R*; Each R* is independently selected from H, -CN, -NO2, halogen, -OR* a -SR* a -N(R*) b (R*) c -C(O)-R* a -OC(O)-R* a -C(O)OR* a -C(O)-N(R*) b (R*) c -N(R*) b )C(O)-R* c -S(O)R* a -S(O)2-R* a -S(O)2NR* b R* c C 1- 6-alkyl and C 1-6 Halogenated alkyl groups; R* a 、R* b and R* c Each is independently selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 Cycloalkyl, 3-7 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups; or R* b 、R* c Together with the N atoms attached to them, they form 3-7 membered heterocyclic groups.

31. The compound according to claim 1, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, ester, polymorph, or hydrate thereof, wherein the compound has the structure of formula (I-2): in, It can be a single bond or a double bond; X represents O, S, and NR. X1 or C(R) X2 (R) X3 ), where R X1 R X2 and R X3 Independently selected from H and C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 3-7 cycloalkyl; L represents a bond or -C(O)-; Ring A is selected from C 3-8 Cycloalkenyl, 3-10 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl groups, wherein the above groups are optionally surrounded by 1, 2, 3 or 4 R groups. A replace; Each R A Independently selected from H, halogen, -CN, -OR a -SR a -N(R) b (R) c -C(O)-R a -OC(O)-R a -C(O)OR a -C(O)-N(R) b (R) c ), -N(R b )C(O)-R c -S(O)R a -S(O)2-R a -S(O)2NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups, wherein the above groups are optionally substituted by 1, 2, 3 or 4 R*; And / or, two R atoms on the same carbon atom A Together with this carbon atom, they form C 3-7 cycloalkyl or oxo, wherein the C 3-7 The cycloalkyl group is optionally substituted with 1, 2, 3 or 4 R*; And / or, two R atoms on adjacent carbon atoms A Together with the carbon atoms between them and optionally the hydrogen atoms on those carbon atoms, they form C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl, wherein the above groups are optionally surrounded by 1, 2, 3 or 4 R groups. A5 replace; Each R A5 Independently selected from H, halogens, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, 3-8 membered heterocyclic groups, C 6- 10 Aryl and 5-10 heteroaryl groups, wherein the above groups are optionally substituted by 1, 2, 3 or 4 R*; And / or, two R atoms on the same carbon atom A5 Together with this carbon atom, they form C 3-7 Cycloalkyl, 3-8 membered heterocyclic or oxo, wherein the C 3-7 The cycloalkyl or 3-8 membered heterocyclic group is optionally substituted with 1, 2, 3 or 4 R*; R a R b and R c Each is independently selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups, wherein the above groups are optionally substituted by 1, 2, 3 or 4 R*; Each R* is independently selected from H, -CN, -NO2, halogen, -OR* a -SR* a -N(R*) b (R*) c -C(O)-R* a -OC(O)-R* a -C(O)OR* a -C(O)-N(R*) b (R*) c -N(R*) b )C(O)-R* c -S(O)R* a -S(O)2-R* a -S(O)2NR* b R* c C 1- 6-alkyl and C 1-6 Halogenated alkyl groups; R* a 、R* b and R* c Each is independently selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 Cycloalkyl, 3-7 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups; or R* b 、R* c Together with the N atoms attached to them, they form 3-7 membered heterocyclic groups; n is 1 or 2.

32. The compound of formula (I-2) according to claim 31, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, ester, polymorph, or hydrate thereof, wherein, It can be a single bond or a double bond; X represents O, S, and NR. X1 or C(R) X2 (R) X3 ), where R X1 R X2 and R X3 Independently selected from H and C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 3-7 cycloalkyl; L represents a bond or -C(O)-; Ring A is selected from C 3-8 Cycloalkenyl, 3-10 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl groups, wherein the above groups are optionally surrounded by 1, 2, 3 or 4 R groups. A replace; Each R A Independently selected from H, halogens, -CN, -OH, C 1-6 Alkyl and C 3-7 cycloalkyl; And / or, two R atoms on adjacent carbon atoms A Together with the carbon atoms between them and optionally the hydrogen atoms on those carbon atoms, they form C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl, wherein the above groups are optionally surrounded by 1, 2, 3 or 4 R groups. A5 replace; Each R A5 Independently selected from H, halogens, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, 3-8 membered heterocyclic groups, C 6- 10 Aryl and 5-10 heteroaryl groups, wherein the above groups are optionally substituted by 1, 2, 3 or 4 R*; And / or, two R atoms on the same carbon atom A5 Together with this carbon atom, they form C 3-7 Cycloalkyl, 3-8 membered heterocyclic or oxo, wherein the C 3-7 The cycloalkyl or 3-8 membered heterocyclic group is optionally substituted with 1, 2, 3 or 4 R*; Each R* is independently selected from H, -CN, -NO2, halogen, -OR* a -SR* a -N(R*) b (R*) c -C(O)-R* a -OC(O)-R* a -C(O)OR* a -C(O)-N(R*) b (R*) c -N(R*) b )C(O)-R* c -S(O)R* a -S(O)2-R* a -S(O)2NR* b R* c C 1- 6-alkyl and C 1-6 Halogenated alkyl groups; R* a 、R* b and R* c Each is independently selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 Cycloalkyl, 3-7 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups; or R* b 、R* c Together with the N atoms attached to them, they form 3-7 membered heterocyclic groups; n is 1 or 2.

33. The compound according to claim 1, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, ester, polymorph, or hydrate thereof, wherein the compound has a structure of formula (I-3): in, It is a double bond; X is O or NR X1 , where R X1 Selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 3-7 cycloalkyl; Ring A is a phenyl group, optionally surrounded by 1, 2, 3, or 4 R groups. A replace; Each R A Independently selected from H, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, 3-8 membered heterocyclic groups, C 6- 10 Aryl and 5-10 heteroaryl groups, wherein the above groups are optionally substituted by 1, 2, 3 or 4 R*; And / or, two R atoms on adjacent carbon atoms A Together with the carbon atoms between them and optionally the hydrogen atoms on those carbon atoms, they form C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl, wherein the above groups are optionally surrounded by 1, 2, 3 or 4 R groups. A5 replace; Each R A5 Independently selected from H, halogens, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, 3-8 membered heterocyclic groups, C 6- 10 Aryl and 5-10 heteroaryl groups, wherein the above groups are optionally substituted by 1, 2, 3 or 4 R*; And / or, two R atoms on the same carbon atom A5 Together with this carbon atom, they form C 3-7 Cycloalkyl, 3-8 membered heterocyclic or oxo, wherein the C 3-7 The cycloalkyl or 3-8 membered heterocyclic group is optionally substituted with 1, 2, 3 or 4 R*; Each R* is independently selected from H, -CN, -NO2, halogen, -OR* a -SR* a -N(R*) b (R*) c -C(O)-R* a -OC(O)-R* a -C(O)OR* a -C(O)-N(R*) b (R*) c -N(R*) b )C(O)-R* c -S(O)R* a -S(O)2-R* a -S(O)2NR* b R* c C 1- 6-alkyl and C 1-6 Halogenated alkyl groups; R* a 、R* b and R* c Each is independently selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 Cycloalkyl, 3-7 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups; or R* b 、R* c Together with the N atoms attached to them, they form 3-7 membered heterocyclic groups; n is 1 or 2.

34. The compound of formula (I-3) according to claim 33, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, ester, polymorph, or hydrate thereof, wherein, It is a double bond; X is O or NR X1 , where R X1 Selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 3-7 cycloalkyl; Ring A is a phenyl group, optionally surrounded by 1, 2, 3, or 4 R groups. A replace; Each R A Independently selected from H, -CN and C 1-6 alkyl; And / or, two R atoms on adjacent carbon atoms A Together with the carbon atoms between them and optionally the hydrogen atoms on those carbon atoms, they form 5-10-membered heteroaryl groups or 3-8-membered heterocyclic groups, wherein the above groups are optionally surrounded by 1, 2, 3 or 4 R groups. A5 replace; Each R A5 Independently selected from H and C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; And / or, two R atoms on the same carbon atom A5 Together with the carbon atom, it forms a 3-8 membered heterocyclic group or an oxo group; n is 1 or 2; Preferably, It is a double bond; X is O or NR X1 , where R X1 Selected from H, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; Ring A is selected from and phenyl, wherein the above groups are optionally surrounded by 1, 2, 3 or 4 R... A replace; Each R A Independently selected from H, -CN and C 1-6 alkyl; R A1 Selected from H and C 1-6 alkyl; n is 1; Preferably, It is a double bond; X is either O or NH; Ring A is selected from n＝1； Preferably, It is a double bond; X is O; Ring A is selected from and phenyl, wherein the above groups are optionally surrounded by 1, 2, 3 or 4 R... A replace; Each R A Independently selected from H, -CN and C 1-6 alkyl; R A1 Selected from H and C 1-6 alkyl; n is 1; Preferably, It is a double bond; X is O; Ring A is n＝1。 35. The compound of claim 1, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, ester, polymorph, or hydrate thereof, wherein the compound has a structure of formula (I-4): in, It can be a single bond or a double bond; X represents O, S, and NR. X1 or C(R) X2 (R) X3 ), where R X1 R X2 and R X3 Independently selected from H and C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 3-7 cycloalkyl; Ring A is selected from C 3-8 Cycloalkenyl, 3-10 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl groups, wherein the above groups are optionally surrounded by 1, 2, 3 or 4 R groups. A replace; Each R A Independently selected from H, halogen, -CN, -OR a -SR a -N(R) b (R) c -C(O)-R a -OC(O)-R a -C(O)OR a -C(O)-N(R) b (R) c ), -N(R b )C(O)-R c -S(O)R a -S(O)2-R a -S(O)2NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups, wherein the above groups are optionally substituted by 1, 2, 3 or 4 R*; And / or, two R atoms on the same carbon atom A Together with this carbon atom, they form C 3-7 cycloalkyl or oxo, wherein the C 3-7 The cycloalkyl group is optionally substituted with 1, 2, 3 or 4 R*; And / or, two R atoms on adjacent carbon atoms A Together with the carbon atoms between them and optionally the hydrogen atoms on those carbon atoms, they form C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl, wherein the above groups are optionally surrounded by 1, 2, 3 or 4 R groups. A5 replace; Each R A5 Independently selected from H, halogens, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, 3-8 membered heterocyclic groups, C 6- 10 Aryl and 5-10 heteroaryl groups, wherein the above groups are optionally substituted by 1, 2, 3 or 4 R*; And / or, two R atoms on the same carbon atom A5 Together with this carbon atom, they form C 3-7 cycloalkyl or oxo, wherein the C 3-7 The cycloalkyl group is optionally substituted with 1, 2, 3 or 4 R*; R a R b and R c Each is independently selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups, wherein the above groups are optionally substituted by 1, 2, 3 or 4 R*; Each R* is independently selected from H, -CN, -NO2, halogen, -OR* a -SR* a -N(R*) b (R*) c -C(O)-R* a -OC(O)-R* a -C(O)OR* a -C(O)-N(R*) b (R*) c -N(R*) b )C(O)-R* c -S(O)R* a -S(O)2-R* a -S(O)2NR* b R* c C 1- 6-alkyl and C 1-6 Halogenated alkyl groups; R* a 、R* b and R* c Each is independently selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 Cycloalkyl, 3-7 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups; or R* b 、R* c Together with the N atoms attached to them, they form 3-7 membered heterocyclic groups.

36. The compound of formula (I-4) according to claim 35, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, ester, polymorph, or hydrate thereof, wherein, It can be a single bond or a double bond; X represents O, S, and NR. X1 or C(R) X2 (R) X3 ), where R X1 R X2 and R X3 Independently selected from H and C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 3-7 cycloalkyl; Ring A is selected from C 3-8 Cycloalkenyl, 3-10 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl groups, wherein the above groups are optionally surrounded by 1, 2, 3 or 4 R groups. A replace; Each R A Independently selected from H, halogen, -CN, -OR a -C(O)OR a -C(O)-N(R) b (R) c C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups, wherein the above groups are optionally substituted by 1, 2, 3 or 4 R*; And / or, two R atoms on the same carbon atom A Together with this carbon atom, they form C 3-7 cycloalkyl or oxo, wherein the C 3-7 The cycloalkyl group is optionally substituted with 1, 2, 3 or 4 R*; And / or, two R atoms on adjacent carbon atoms A Together with the carbon atoms between them and optionally the hydrogen atoms on those carbon atoms, they form C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl, wherein the above groups are optionally surrounded by 1, 2, 3 or 4 R groups. A5 replace; Each R A5 Independently selected from H, halogens, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, 3-8 membered heterocyclic groups, C 6- 10 Aryl and 5-10 heteroaryl groups, wherein the above groups are optionally substituted by 1, 2, 3 or 4 R*; And / or, two R atoms on the same carbon atom A5 Together with this carbon atom, they form C 3-7 cycloalkyl or oxo, wherein the C 3-7 The cycloalkyl group is optionally substituted with 1, 2, 3 or 4 R*; R a R b and R c Each is independently selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, C 6-10 Aryl and 3-8 membered heterocyclic groups, wherein the above groups are optionally substituted by one or more R*; Each R* is independently selected from H, -CN, -NO2, halogen, -OR* a -SR* a -N(R*) b (R*) c -C(O)-R* a -OC(O)-R* a -C(O)OR* a -C(O)-N(R*) b (R*) c -N(R*) b )C(O)-R* c -S(O)R* a -S(O)2-R* a -S(O)2NR* b R* c C 1- 6-alkyl and C 1-6 Halogenated alkyl groups; R* a 、R* b and R* c Each is independently selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 Cycloalkyl, 3-7 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups; or R* b 、R* c Together with the N atoms attached to them, they form 3-7 membered heterocyclic groups.

37. The compound of claim 1, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, ester, polymorph, or hydrate thereof, wherein the compound has a structure of formula (I-5): in, It can be a single bond or a double bond; X is O, S, or NR X1 Preferably O or NR X1 ;where R X1 Selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 3-7 cycloalkyl; Ring A is selected from C 3-8 Cycloalkenyl, 3-10 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl groups, wherein the above groups are optionally surrounded by 1, 2, 3 or 4 R groups. A replace; Each R A Independently selected from H, halogen, -CN, -OR a -C(O)OR a -C(O)-N(R) b (R) c C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, C 6-10 Aryl and 6-8 membered heterocyclic groups, wherein the above groups are optionally substituted by 1, 2, 3 or 4 R*; R a R b and R c Each is independently selected from H and C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups; And / or, two R atoms on the same carbon atom A Together with this carbon atom, they form C 3-7 cycloalkyl or oxo, wherein the C 3-7 The cycloalkyl group is optionally substituted with 1, 2, 3 or 4 R*; preferably, two R* on the same carbon atom. A Together with the carbon atom, it forms an oxygen atom; And / or, two R atoms on adjacent carbon atoms A Together with the carbon atoms between them and optionally the hydrogen atoms on those carbon atoms, they form C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl, wherein the above groups are optionally surrounded by 1, 2, 3 or 4 R groups. A5 replace; Each R A5 Independently selected from H, halogens, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, 3-8 membered heterocyclic groups, C 6- 10 Aryl and 5-10 heteroaryl groups, wherein the above groups are optionally substituted by 1, 2, 3 or 4 R*; And / or, two R atoms on the same carbon atom A5 Together with this carbon atom, they form C 3-7 cycloalkyl or oxo, wherein the C 3-7 The cycloalkyl group is optionally substituted with 1, 2, 3 or 4 R*; Each R* is independently selected from H, -CN, -NO2, halogen, -OR* a -SR* a -N(R*) b (R*) c -C(O)-R* a -OC(O)-R* a -C(O)OR* a -C(O)-N(R*) b (R*) c -N(R*) b )C(O)-R* c -S(O)R* a -S(O)2-R* a -S(O)2NR* b R* c C 1- 6-alkyl and C 1-6 Halogenated alkyl groups; R* a 、R* b and R* c Each is independently selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 Cycloalkyl, 3-7 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups; or R* b 、R* c Together with the N atoms attached to them, they form 3-7 membered heterocyclic groups; Preferably, It can be a single bond or a double bond; X is O, S, or NH, with O or NH being preferred; Ring A is selected from 38. The compound of formula (I-5) according to claim 37, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, ester, polymorph, or hydrate thereof, wherein, It can be a single bond or a double bond; X is O, S, or NR X1 Preferably O or NR X1 ;where R X1 Selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 3-7 cycloalkyl; Ring A is Among them, ring member Y 1 Y 2 Y 3 and Y 4 Each atom is independently C, N, or O, and the ring A is optionally surrounded by R. A replace; Y 1 and Y 2 Y 2 and Y 3 Y 3 and Y 4 The bond between them is a single bond or a double bond, or Y. 1 Y 2 Y 3 and Y 4 Together with other ring members, they can form phenyl, 6-membered heterocyclic or 6-membered heteroaryl groups; Each R A Independently selected from H, halogen, -CN, -OR a C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, C 6-10 Aryl and 6-8 membered heterocyclic groups, wherein the above groups are optionally substituted by 1, 2, 3 or 4 R*; R a Selected from H, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; And / or, two R atoms on adjacent carbon atoms A Together with the carbon atoms between them and optionally the hydrogen atoms on those carbon atoms, they form C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl, wherein the above groups are optionally surrounded by 1, 2, 3 or 4 R groups. A5 replace; Each R A5 Independently selected from H, halogens, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, 3-8 membered heterocyclic groups, C 6- 10 Aryl and 5-10 heteroaryl groups, wherein the above groups are optionally substituted by 1, 2, 3 or 4 R*; And / or, two R atoms on the same carbon atom A5 Together with this carbon atom, they form C 3-7 cycloalkyl or oxo, wherein the C 3-7 The cycloalkyl group is optionally substituted with 1, 2, 3 or 4 R*; Each R* is independently selected from H, -CN, -NO2, halogen, -OR* a -SR* a -N(R*) b (R*) c -C(O)-R* a -OC(O)-R* a -C(O)OR* a -C(O)-N(R*) b (R*) c -N(R*) b )C(O)-R* c -S(O)R* a -S(O)2-R* a -S(O)2NR* b R* c C 1- 6-alkyl and C 1-6 Halogenated alkyl groups; R* a 、R* b and R* c Each is independently selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 Cycloalkyl, 3-7 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups; or R* b 、R* c Together with the N atoms attached to them, they form 3-7 membered heterocyclic groups; Preferably, It can be a single bond or a double bond; X is either O or NH; Ring A is selected from 39. The compound of formula (I-5) according to claim 38, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, ester, polymorph, or hydrate thereof, wherein, It can be a single bond or a double bond; X is O, S, or NR X1 Preferably O or NR X1 ;where R X1 Selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 3-7 cycloalkyl; Ring A is selected from phenyl, 6-membered heteroaryl, The above-mentioned groups are optionally surrounded by 1, 2, 3 or 4 R groups. A replace; Each R A Independently selected from H, halogen, -CN, -OR a C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 cycloalkyl, 5-6 membered heteroaryl, C 6-10 Aryl and 6-8 membered heterocyclic groups, wherein the above groups are optionally substituted by 1, 2, 3 or 4 R*; R a Selected from H and C 1-6 alkyl; And / or, two R atoms on adjacent carbon atoms A Together with the carbon atoms between them and optionally the hydrogen atoms on those carbon atoms, they form C 6-10 Aryl, 5-6 membered heteroaryl, or 3-8 membered heterocyclic group; preferably, 5-10 membered heteroaryl or 3-8 membered heterocyclic group; wherein the above groups are optionally surrounded by 1, 2, 3, or 4 R groups. A5 replace; Each R A5 Independently selected from H, halogens, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, 3-8 membered heterocyclic groups, C 6- 10 Aryl and 5-10 heteroaryl; preferably, H, C 1-6 Alkyl, C 3-7 Cycloalkyl and 5-10 heteroaryl groups; wherein the above groups are optionally substituted by 1, 2, 3 or 4 R*; And / or, two R atoms on the same carbon atom A5 Together with this carbon atom, they form C 3-7 cycloalkyl or oxo, wherein the C 3-7 The cycloalkyl group is optionally substituted with 1, 2, 3 or 4 R*; Each R* is independently selected from H, -CN, -NO2, halogen, -OR* a -SR* a -N(R*) b (R*) c -C(O)-R* a -OC(O)-R* a -C(O)OR* a -C(O)-N(R*) b (R*) c -N(R*) b )C(O)-R* c -S(O)R* a -S(O)2-R* a -S(O)2NR* b R* c C 1- 6-alkyl and C 1-6 Halogenated alkyl groups; R* a 、R* b and R* c Each is independently selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 Cycloalkyl, 3-7 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups; or R* b 、R* c Together with the N atoms attached to them, they form 3-7 membered heterocyclic groups; Preferably, It can be a single bond or a double bond; X is either O or NH; Ring A is selected from 40. The compound of formula (I-5) according to claim 39, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, ester, polymorph, or hydrate thereof, wherein, It can be a single bond or a double bond; X is O, S, or NR X1 Preferably O or NR X1 ;where R X1 Selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 3-7 cycloalkyl; Ring A is selected from and phenyl, wherein the above groups are optionally surrounded by 1, 2, 3 or 4 R... A replace; Each R A Independently selected from H, halogen, -CN, -OR a C 1-6 Alkyl, C 1-6 Haloalkyl, 5-6-membered heteroaryl and 6-8-membered heterocyclic groups, wherein the above groups are optionally substituted by 1, 2, 3 or 4 R*; R a Selected from H, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; R A1 and R A4 Each is independently selected from H and C. 1-6 Alkyl and C 3-7 Cycloalkyl groups, which are optionally substituted with 1, 2, 3 or 4 R*s; R A2 and R A3 Independently selected from H, halogens and C 1-6 Alkyl, or R A2 R A3 Together with the carbon atoms attached to them, they form C 3- 6-cycloalkyl; Each R* is independently selected from H, -CN, -NO2, halogen, -OR* a -SR* a -N(R*) b (R*) c -C(O)-R* a -OC(O)-R* a -C(O)OR* a -C(O)-N(R*) b (R*) c -N(R*) b )C(O)-R* c -S(O)R* a -S(O)2-R* a -S(O)2NR* b R* c C 1- 6-alkyl and C 1-6 Haloalkyl; preferably, each R* is independently selected from H, -OH and C. 1-6 alkyl; R* a 、R* b and R* c Each is independently selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 Cycloalkyl, 3-7 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl groups; or R b R c Together with the N atoms attached to them, they form 3-7 membered heterocyclic groups; Preferably, It can be a single bond or a double bond; X is either O or NH; Ring A is selected from 41. The compound of formula (I-5) according to claim 40, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, ester, polymorph, or hydrate thereof, wherein, It can be a single bond or a double bond; X is O, S, or NR X1 Preferably O or NR X1 ;where R X1 Selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 3-7 cycloalkyl; Ring A is selected from and phenyl, wherein the above groups are optionally surrounded by 1, 2, 3 or 4 R... A replace; Each R A Independently selected from H, halogens, -CN and C 1-6 alkyl; R A1 Selected from H and C 1-6 alkyl; R A2 and R A3 Independently selected from H, halogens and C 1-6 Alkyl, or R A2 R A3 Together with the carbon atoms attached to them, they form C 3-6 cycloalkyl; Preferably, It can be a single bond or a double bond; X is either O or NH; Ring A is selected from 42. The compound of formula (I-5) according to claim 41, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, ester, polymorph, or hydrate thereof, wherein, It is a double bond; X is O, S, or NR X1 Preferably O or NR X1 ;where R X1 Selected from H, C 1-6 Alkyl and C 1-6 Haloalkyl; preferably, X is O or NH; Ring A is selected from The above-mentioned groups are optionally surrounded by 1, 2, 3 or 4 R groups. A replace; Each R A Independently selected from H and C 1-6 alkyl; R A1 Selected from H and C 1-6 Alkyl, preferably C 1-6 alkyl; Preferably, It is a double bond; X is either O or NH; Ring A is selected from 43. A compound according to any one of claims 1-42, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, ester, polymorph, or hydrate thereof, wherein the compound is selected from:

44. A pharmaceutical composition comprising the compound of any one of claims 1-43, or a pharmaceutically acceptable salt, isotope variant, tautomer, stereoisomer, ester, polymorph or hydrate thereof, and a pharmaceutically acceptable excipient.

45. The use of any compound of claims 1-43, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, ester, polymorph, or hydrate thereof, or the pharmaceutical composition of claim 44, in the preparation for the treatment and / or prevention of diseases associated with inhibition of cathepsin C.

46. ​​The compound of any one of claims 1-43, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, ester, polymorph or hydrate thereof, or the pharmaceutical composition of claim 44, for the treatment and / or prevention of diseases associated with inhibition of cathepsin C.

47. A method of treating and / or preventing a disease associated with inhibition of cathepsin C in a subject, comprising administering to the subject a compound of any one of claims 1-43, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, ester, polymorph, or hydrate thereof, or a pharmaceutical composition of claim 44.

48. The use of the compound of claim 45 or the method of claim 47, wherein the disease associated with inhibition of cathepsin C is a neutrophil-dominated inflammatory disease.

49. The use or method of the compound according to claim 48, wherein the disease is a respiratory disease.

50. The use or method of the compound according to claim 48, wherein the disease is bronchiectasis.

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