Novel Compounds as PCSK9 Inhibitors

Abstract

The present invention discloses compounds of formula (I), wherein the variables are defined herein, pharmaceutical compositions containing the compounds, and methods and uses of the compounds or compositions in the treatment of diseases mediated by PCSK9, such as cardiovascular disease. TIFF2023512617000075.tif3888

Description

Background Art

[0001] In developed countries, patients with high levels of low-density lipoprotein cholesterol (LDL-C) have cardiovascular disease as the leading cause of death. An increase in LDL-C levels is considered a major risk factor for the development of coronary artery disease (CAD) and atherosclerotic plaques in arteries. Also, when LDL-C decreases, the cardiovascular risk decreases.

[0002] Loss-of-function mutations in the low-density lipoprotein receptor (LDLR) gene in patients with familial hypercholesterolemia (FH) are associated with high plasma LDL-C values and early-onset CAD that develops from childhood. LDLR located on the cell membrane reduces plasma LDL-C concentration by the receptor-mediated uptake of LDL-C into cells.

[0003] One of the greatest advances in the lipid-lowering field over the past decade has been the development of lipid-modulating therapies that target proprotein convertase subtilisin / kexin type 9 (also called PCSK9, which binds to LDLR and targets its lysosomal degradation). This is because when statin drugs are used, the transcription of both PCSK9 and LDLR increases, reducing the lipid-lowering effect of statin drugs.

[0004] Therefore, by inhibiting the production of PCSK9 or inhibiting the function of PCSK9, it is expected that the amount of LDLR can be increased, and as a result, the blood LDL cholesterol level will decrease.

[0005] From this perspective, research has been conducted to inhibit the function of PCSK9 or suppress the production of PCSK9. For example, attempts such as using monoclonal antibodies targeting PCSK9 to inhibit its function and inhibiting the production of PCSK9 by RNA interference have been reported. However, for patients with cardiovascular disease, a potent small molecule inhibitor for inhibiting the function of PCSK9 is needed.

Summary of the Invention

[0006] An object of the present invention is to provide a novel compound having an action of reducing blood LDL cholesterol and useful as an active ingredient of a pharmaceutical. More specifically, the present disclosure provides a method for downregulating the function of PCSK9.

[0007] In one aspect, the present invention relates to a compound represented by the general formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotope variant thereof, and mixtures thereof. [Chemical formula] However, Ring A is selected from the group consisting of C 3-7 cycloalkyl, 3- to 7-membered heterocyclyl, or C 6-10 aryl; Ring B is selected from the group consisting of C 3-7 cycloalkyl, 3- to 7-membered heterocyclyl, C 6-10 aryl, or 5- to 10-membered heteroaryl; L1 is selected from the group consisting of a bond, -O-, -C(O)-, -CR’R’’-, -CR’R’’-CR’R’’- or -CR’R’’-CR’R’’-CR’R’’-; L2 is selected from the group consisting of a bond, -C(O)-, -CR’R’’-, -CR’R’’-CR’R’’- or -CR’R’’-CR’R’’-CR’R’’-; Y is selected from the group consisting of O, S, NH or CH2; R1 is H, -C(O)R a , -C(O)OR a , -C(O)NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, 3- to 7-membered heterocyclyl, C 6-10 aryl, or 5- to 10-membered heteroaryl; R2 is H, C 1-6 alkyl, or C1-6 selected from the group consisting of haloalkyl; R s1 is H, halogen, -CN, -NO2, -OR a -SR a -NR b R c -C(O)R a -C(O)OR a -C(O)NR b R c C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, 3- to 7-membered heterocyclyl, C 6-10 aryl, or 5- to 10-membered heteroaryl; R s2 is H, halogen, -CN, -NO2, -OR a -SR a -NR b R c -C(O)R a -C(O)OR a -C(O)NR b R c C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, 3- to 7-membered heterocyclyl, C 6-10 aryl, or 5- to 10-membered heteroaryl; R s3 is H, halogen, -CN, -NO2, -OR a -SR a -NR b R c -C(O)R a -C(O)OR a -C(O)NR b R c C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7Cycloalkyl, 3- to 7-membered heterocyclyl, C 6-10 selected from the group consisting of aryl, or 5- to 10-membered heteroaryl; R s4 is H, halogen, -CN, -NO2, -OR a , -SR a , -NR b R c , -C(O)R a , -C(O)OR a , -C(O)NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 selected from the group consisting of cycloalkyl, 3- to 7-membered heterocyclyl, C 6-10 aryl, or 5- to 10-membered heteroaryl; m = 0, 1, 2, 3, 4 or 5; n = 0, 1, 2, 3 or 4; p = 0, 1, 2, 3, 4, 5, 6, 7 or 8; q = 0, 1, 2, 3, 4 or 5; wherein R' and R'' are each independently H, halogen, -OR a , -SR a , -NR b R c , -C(O)R a , -C(O)OR a , -C(O)NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, or C 2-6 selected from the group consisting of alkynyl; R a is independently H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 selected from the group consisting of cycloalkyl, 3- to 7-membered heterocyclyl, C 6-10selected from the group consisting of aryl or 5- to 10-membered heteroaryl; R b and R c are each independently H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, 3- to 7-membered heterocyclyl, C 6-10 aryl, or 5- to 10-membered heteroaryl; or R b , R c together with the N atom form a 3- to 7-membered heterocyclyl; wherein Y, R1, R2, R s1 , R s2 , R s3 and R s4 each may be substituted with one, two or three R groups, where R is independently H, -OH, halogen, -NO2, carbonyl, -L-CN, -L-OR a , -L-SR a , -L-NR b R c , -L-C(O)R a , -L-C(S)R a , -L-C(O)OR a , -L-C(S)OR a , -L-C(O)-NR b R c , -L-C(S)-NR b R c , -L-O-C(O)R a , -L-O-C(S)R a , -L-N(R b )-C(O)-R a , -L-N(R b )-C(S)-R a , -L-S(O) x R a , -L-S(O) x OR a , -L-S(O) x NR b R c , -L-N(R b )-S(O) x -R a, -L-N(R b )-S(O) x -NR b R c , -L-N(R b )-C(O)OR a , -L-N(R b )-C(S)OR a , -L-O-C 1-6 alkylene-OR a , -L-C(O)-C 1-6 alkylene-NR b R c , -L-N(R b )-C(O)-NR b R c , -L-N(R b )-C(S)-NR b R c , -L-O-C(O)-NR b R c , -L-O-C(S)-NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -L-C 3-7 cycloalkyl, -L-3- to 7-membered heterocyclyl, -L-C 6-10 aryl, or -L-5- to 10-membered heteroaryl, selected from the group consisting of; wherein said C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -L-C 3-7 cycloalkyl, -L-3- to 7-membered heterocyclyl, -L-C 6-10 aryl, or -L-5- to 10-membered heteroaryl, respectively, -L-CN, -NO2, carbonyl, -L-OR a , -L-SR a , -L-NR b R c , -L-C(O)R a , -L-C(S)R a , -L-C(O)OR a , -L-C(S)OR a , -L-C(O)-NR bR c 、 -L-C(S)-NR b R c 、 -L-O-C(O)R a 、 -L-O-C(S)R a 、 -L-N(R b )-C(O)-R a 、 -L-N(R b )-C(S)-R a 、 -L-S(O) x R a 、 -L-S(O) x OR a 、 -L-S(O) x NR b R c 、 -L-N(R b )-S(O) x -R a 、 -L-N(R b )-S(O) x -NR b R c 、 -L-N(R b )-C(O)OR a 、 -L-N(R b )-C(S)OR a 、 -L-O-C 1-6 alkylene-OR a 、 -L-C(O)-C 1-6 alkylene-NR b R c 、 -L-N(R b )-C(O)-NR b R c 、 -L-N(R b )-C(S)-NR b R c 、 -L-O-C(O)-NR b R c 、 or -L-O-C(S)-NR b R c and may be further substituted by one or more groups selected from the group consisting of; L is selected from the group consisting of a chemical bond, -C 1-6 alkylene-, -C 2-6 alkenylene- or -C 2-6 alkynylene-; x = 0, 1 or 2.

[0008] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable excipient.

[0009] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable excipient, further comprising another therapeutic agent, for example, a statin drug.

[0010] In another aspect, the present invention provides the use of a compound of the present invention in the preparation of a medicament for treating and / or preventing a disease mediated by PCSK9.

[0011] In another aspect, the present invention provides a method for treating and / or preventing a disease mediated by PCSK9 in a subject, comprising administering to the subject a compound of the present invention or the composition of the present invention.

[0012] In another aspect, the present invention provides a compound or composition of the present invention for treating and / or preventing a disease mediated by PCSK9.

[0013] In certain embodiments, the diseases described herein include atherosclerosis, dyslipidemia, hypertriglyceridemia, hypertension, heart failure, arrhythmia, low HDL level, high LDL level, sudden death, stable angina, coronary artery disease, acute myocardial infarction, secondary prevention of myocardial infarction, cardiomyopathy, endocarditis, type 2 diabetes, insulin resistance, impaired glucose tolerance, hypercholesterolemia (including heterozygous and homozygous familial hypercholesterolemia), stroke, hyperlipidemia, hyperlipoproteinemia, chronic kidney disease, intermittent claudication, hyperphosphatemia, carotid atherosclerosis, peripheral artery disease, diabetic nephropathy, hypercholesterolemia in HIV infection, acute coronary syndrome (ACS), non-alcoholic fatty liver disease, obstructive arterial disease, cerebral arteriosclerosis, cerebrovascular disease, myocardial ischemia, non-alcoholic fatty liver disease (NLLD), non-alcoholic steatohepatitis (NASH), and diabetic autonomic neuropathy.

[0014] Other objects and advantages of the present invention will become apparent to those skilled in the art from the following specific embodiments, examples, and claims.

[0015] Definitions Chemical Definitions Hereinafter, the definitions of specific functional groups and chemical terms will be described in more detail.

[0016] When a numerical range is recited, it includes each value and sub-range within that range. For example, "C 1-6 alkyl group" 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 , C 5-6 alkyl groups.

[0017] "C 1-6 alkyl group" refers to a straight-chain or branched-chain saturated hydrocarbon group having 1 to 6 carbon atoms. In some embodiments, C 1-4 alkyl groups are preferred. Exemplary C 1-6 alkyl groups include methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentyl (C5), pentyl (C5), neopentyl (C5), 3-methyl-2-butyl (C5), tert-pentyl (C5), n-hexyl (C6), and the like. "C 1-6The term "alkyl group" also includes heteroalkyl groups in which one or more (e.g., 1, 2, 3, or 4) carbon atoms are substituted with heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). The alkyl group may be substituted with one or more substituents, such as 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. Usually, abbreviations for alkyl include Me (-CH3), Et (-CH2CH3), iPr (-CH(CH3)2), nPr (-CH2CH2CH3), n-Bu (-CH2CH2CH2CH3), or i-Bu (-CH2CH(CH3)2).

[0018] "C 2-6 The term "alkenyl group" refers to a straight-chain or branched-chain hydrocarbon group having 2 to 6 carbon atoms and at least one carbon-carbon double bond. In some embodiments, C 2-4 alkenyl groups are preferred. Exemplary C 2-6 alkenyl groups include vinyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. The term "C 1-6 alkenyl group" also includes heteroalkenyl groups in which one or more (e.g., 1, 2, 3, or 4) carbon atoms are substituted with heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). The alkenyl group may be substituted with one or more substituents, such as 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0019] "C 2-6 The term "alkynyl group" refers to a straight-chain or branched-chain hydrocarbon group having 2 to 6 carbon atoms, at least one carbon-carbon triple bond, and optionally one or more carbon-carbon double bonds. In some embodiments, C 2-4 alkynyl groups are preferred. Exemplary C 2-6Examples of the alkynyl group include, but are not limited to, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), hexynyl (C6), etc. "C 2-6 The term "alkynyl group" also includes a heteroalkynyl group in which one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). The alkynyl group may be substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0020] "C 1-6 alkylene, C 2-6 alkenylene or C 2-6 alkynylene" refers to a divalent group of "C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl" as defined above.

[0021] "C 1-6 alkylene" refers to a divalent group obtained by removing another hydrogen from a C 1-6 alkyl group, which may be substituted or unsubstituted. In some embodiments, C 1-4 alkylene is particularly preferred. Examples of unsubstituted alkylene include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), pentylene (-CH2CH2CH2CH2CH2-), hexylene (-CH2CH2CH2CH2CH2CH2-), etc. Typical substituted alkylene includes, for example, substituted methylene (-CH(CH3)-, -C(CH3)2-), substituted ethylene (-CH(CH3)CH2-, -CH2CH(CH3)-, -C(CH3)2CH2-, -CH2C(CH3) 2-) Examples of the alkylene substituted with one or more alkyl (methyl) groups such as substituted propylene (-CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH(CH3)-, -C(CH3)2CH2CH2-, -CH2C(CH3)2CH2-, -CH2CH2C(CH3)2-) are included, but not limited thereto.

[0022] “C 2-6 alkenylene” refers to a divalent group obtained by removing another hydrogen from C 2-6 alkenyl, which may be substituted or unsubstituted. In some embodiments, C 2-4 alkenylene is particularly preferred. Exemplary unsubstituted alkenylene groups include, but are not limited to, ethenylene (-CH=CH-) and propenylene (e.g., -CH=CHCH2-, -CH2-CH=CH-). Exemplary substituted alkenylene groups include, for example, alkenylene substituted with one or more alkyl groups, such as substituted ethenylene (-C(CH3)=CH-, -CH=C(CH3)-), substituted propenylene (-C(CH3)=CHCH2-, -CH=C(CH3)CH2-, -CH=CHCH(CH3)-, -CH=CHC(CH3)2-, -CH(CH3)-CH=CH-, -C(CH3)2-CH=CH-, -CH2-C(CH3)=CH-, -CH2-CH=C(CH3)-), etc., but are not limited thereto.

[0023] “C 2-6 alkynylene” refers to a divalent group obtained by removing another hydrogen from C 2-6 alkynyl, which may be substituted or unsubstituted. In some embodiments, C 2-4 alkynylene is particularly preferred. Exemplary alkynylene groups include, but are not limited to, ethynylene (-C≡C-), substituted or unsubstituted propynylene (-C≡CCH2-), etc.

[0024] “Halogenated” or “halogen” means fluorine (F), chlorine (Cl), bromine (Br), and iodine (I).

[0025] "C 1-6 "Haloalkyl" refers to the above-mentioned "C 1-6 alkyl" substituted with one or more halogen groups. Examples include mono-halogenated, di-halogenated, and poly-halogenated (including per-halogenated) alkyls. A mono-halogen substituent may have one iodine, bromine, chlorine, or fluorine atom in the group. Di-halogen substituents and poly-halogen substituents may have two or more identical halogen atoms or a combination of different halogens. Examples of preferred haloalkyl groups include monofluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, and dichloropropyl. The haloalkyl group is substituted at any available bonding site with, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0026] "C 3-7 "Cycloalkyl group" refers to a non-aromatic cyclic hydrocarbon group having 3 to 7 ring carbon atoms and 0 heteroatoms. In some embodiments, the C 3-6 cycloalkyl group is particularly preferred, and the C 5-6A cycloalkyl group is more preferred. The cycloalkyl group further includes a ring system in which the cycloalkyl ring is condensed with one or more aryl groups or heteroaryl groups, where the connection point is located on the cycloalkyl ring, and in such a case, the number of carbon atoms still indicates the number of carbon atoms in the cycloalkyl 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), cycloheptatrieneyl (C7), etc. The cycloalkyl group may be substituted with one or more substituents such as, for example, 1 to 5 substituents, 1 to 3 substituents or 1 substituent.

[0027] "3- to 11-membered heterocyclyl group" is a 3- to 11-membered non-aromatic ring system group having ring carbon atoms and 1 to 5 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon. In a heterocyclyl group containing one or more nitrogen atoms, as long as the valence is acceptable, the linking site may be a carbon or nitrogen atom. In some embodiments, a 3- to 9-membered heterocyclyl group, which is a 3- to 9-membered non-aromatic ring system having ring carbon atoms and 1 to 5 ring heteroatoms, is preferred. In some embodiments, a 3- to 7-membered heterocyclyl group, which is a 3- to 7-membered non-aromatic ring system group having ring carbon atoms and 1 to 4 ring heteroatoms, is preferred. A 3- to 6-membered heterocyclyl group, which is a 3- to 6-membered non-aromatic ring system group having ring carbon atoms and 1 to 3 ring heteroatoms, is preferred. A 4- to 6-membered heterocyclyl group, which is a 4- to 6-membered non-aromatic ring system group having ring carbon atoms and 1 to 3 ring heteroatoms, is preferred. A 5- to 6-membered heterocyclyl group, which is a 5- to 6-membered non-aromatic ring system group having ring carbon atoms and 1 to 3 ring heteroatoms, is more preferred. Further, the heterocyclyl group includes a ring system in which the heterocyclyl group ring is condensed with one or more cycloalkyl groups, where the linking point is located on the cycloalkyl ring; or the heterocyclyl ring includes a ring system in which the heterocyclyl ring is condensed with one or more aryl groups or heteroaryl groups, and among them, the linking point is located on the heterocyclyl ring. And in such a situation, the ring member number still indicates the ring member number of the heterocyclyl group ring. Exemplary 3-membered heterocyclyls containing one heteroatom include, but are not limited to, aziridinyl, oxiranyl, thiorenyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrol-2,5-dione.Exemplary 5-membered heterocyclyls containing two heteroatoms include, but are not limited to, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyls containing three heteroatoms include, but are not limited to, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 5-membered heterocyclyl groups (also referred to herein as 5,6-bicyclic heterocyclyls) fused to a C6 aryl include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl groups (also referred to herein as 6,6-bicyclic heterocyclyl groups) fused to a C6 aryl ring include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like. The heterocyclyl group may be substituted with one or more substituents, such as, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0028] The 3- to 11-membered heterocyclyl group includes a spiroheterocyclyl group, i.e., a group in which two rings (e.g., heterocyclyl and carbocyclyl) share one carbon atom, where at least one ring is the heterocyclyl group defined above. More specifically, the spiroheterocyclyl group is a spiro ring formed by two 4-membered rings, two 5-membered rings, two 6-membered rings, one 4-membered ring and one 5-membered ring, one 4-membered ring and one 6-membered ring, or one 5-membered ring and one 6-membered ring, where at least one ring is the 4- to 6-membered heterocyclyl group defined above. A 4- to 6-membered heterocyclyl group containing one, two or three heteroatoms O, N or S is preferred.

[0029] Specific examples of preferred heterocyclic groups include pyrrolinyl, imidazolidinyl, pyrazolidinyl, tetrahydropyranyl, dihydropyranyl, dihydrofuranyl, thiazolidinyl, dihydrothiazolyl, 2,3-dihydro-benzo[1,4]dioxolyl, indolinyl, isoindolinyl, dihydrobenzothiophene, dihydrobenzofuranyl, isodihydrobenzopyranyl, dihydrobenzopyranyl, 1,2-dihydroisoquinoline, 1,2,3,4-tetrahydroisoquinoline, 1,2,3,4-tetrahydroquinoline, 2,3,4,4a,9,9a-hexahydro-1H-3-azafluorene, 5,6,7-trihydro-1,2,4-triazolo[3,4-a]isoquinolyl, 3,4-dihydro-2H-benzo[1,4]oxazinyl, benzo[1,4]dioxolyl, 2,3-dihydro-1H-lk’-benzo[d]isothiazol-6-yl, 2,3-di-benzo[1,4]dioxinyl, dihydrobenzofuran, 2-oxoaziridin-1-yl, 2-oxoazetidin-1-yl, 2-oxopyrrolidin-1-yl, 2-oxopiperidin-1-yl, 2-oxoazepan-1-yl, 2-oxoazocan-1-yl, 2-oxoazonan-1-yl, 2-oxoazecan-1-yl, aziridine, azetidine, pyrrolidinyl, piperidine, azepane, azocane, azonane, azecane, piperidyl, piperazinyl, morpholinyl, diazaspiro[3.3]heptane, diazaspiro[3.4]octane, diazaspiro[3.5]nonane, diazaspiro[4.4]nonane, diazaspiro[4.5]decane, diazaspiro[5.5]undecane.

[0030] "C 6-10 An "aryl group" refers to a group of a monocyclic or polycyclic (e.g., bicyclic) 4n+2 aromatic ring system having 6 to 10 ring carbon atoms and 0 heteroatoms (e.g., having 6 or 10 π electrons shared in a cyclic arrangement). In some embodiments, the aryl group has 6 ring carbon atoms ("C6 aryl"; e.g., phenyl group). In some embodiments, the aryl group has 10 ring carbon atoms ("C 10"Aryl"; for example, naphthyl such as 1-naphthyl, 2-naphthyl, etc.). The aryl group further includes a ring system in which the aryl ring is condensed with one or more cycloalkyl or heterocyclyl groups, and the linking site is located on the aryl ring. In this case, the number of carbon atoms still indicates the number of carbon atoms in the aryl ring system. The aryl group may be substituted with one or more substituents such as, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0031] "5- to 10-membered heteroaryl group" refers to a group having a 5- to 10-membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons shared in a cyclic arrangement) with ring carbon atoms and 1 to 4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur. In a heteroaryl group containing one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom as long as the valence is allowed. The heteroaryl bicyclic ring system can contain one or more heteroatoms in one or both rings. The heteroaryl group further includes a ring system in which the heteroaryl ring is fused with one or more cycloalkyl groups or heterocyclyl groups, and the connecting site is located on the heteroaryl ring, in which case the number of carbon atoms still indicates the number of carbon atoms in the heteroaryl ring system. In some embodiments, a 5- to 6-membered heteroaryl group, which is a 5- to 6-membered monocyclic or bicyclic 4n+2 aromatic ring system group having ring carbon atoms and 1 to 4 ring heteroatoms, is particularly preferred. 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 (e.g., 1,2,4-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-fused bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-fused bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. The heteroaryl group may be substituted with one or more substituents such as, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0032] Examples of preferred heteroaryl groups include pyrrolyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl (4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl), pyranyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, oxazolyl, isoxazolyl, oxazolyl (1,2,4-oxazolyl, 1,3,4-oxazolyl, 1,2,5-oxazolyl), thiazolyl, thiadiazolyl (1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl).

[0033] "Carbonyl", whether used alone or in combination with other terms (e.g., aminocarbonyl), is represented by -C(O)-.

[0034] The alkyl, alkenyl, alkynyl, carbocyclic, heterocyclyl, aryl, and heteroaryl groups as defined herein may be optionally substituted.

[0035] Exemplary carbon atom substituents include 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)Raa ,-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(R bb )2,-OP(=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, carbocyclic group, heterocyclyl group, aryl, and heteroaryl are included, but not limited thereto, where alkyl, alkenyl, alkynyl, carbocyclic group, heterocyclyl group, aryl, and heteroaryl are each independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups;

[0036] or, two geminal hydrogens on a carbon atom are =O, =S, =NN(R bb )2, =NNR bb C(=O)R aa , =NNRbb C(=O)OR aa 、 =NNR bb S(=O)2R aa 、 =NR bb or =NOR cc substituted with a group;

[0037] Each R aa is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, carbocyclic group, heterocyclyl group, aryl, and heteroaryl, or two R aa groups are linked to form a heterocyclyl group or heteroaryl ring, where alkyl, alkenyl, alkynyl, carbocyclic group, heterocyclyl group, aryl, and heteroaryl are each independently substituted with 0, 1, 2, 3, 4 or 5 R dd groups;

[0038] Each R bb is independently hydrogen, -OH, -OR aa , -N(R cc )2, -CN, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R 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, carbocyclic group, heterocyclyl group, aryl, and heteroaryl, or two R bbThe groups are linked to form a heterocyclyl group or heteroaryl ring, where alkyl, alkenyl, alkynyl, carbocyclic group, heterocyclyl group, aryl, and heteroaryl are each independently substituted with 0, 1, 2, 3, 4 or 5 R dd groups;

[0039] Each R cc is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclic group, heterocyclyl group, aryl, and heteroaryl, or two R cc groups are linked to form a heterocyclyl group or heteroaryl ring, where alkyl, alkenyl, alkynyl, carbocyclic group, heterocyclyl group, aryl, and heteroaryl are each independently substituted with 0, 1, 2, 3, 4 or 5 R dd groups;

[0040] Each R dd is independently halogen, -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(R ff )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, carbocyclic group, heterocyclyl group, aryl, heteroaryl, wherein the alkyl, alkenyl, alkynyl, carbocyclic group, heterocyclyl group, aryl, and heteroaryl are each independently substituted with 0, 1, 2, 3, 4 or 5 R gg groups, or two geminal R dd substituents may be linked to form =O or =S;

[0041] 0]]Each R ee is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, carbocyclic group, aryl, heterocyclyl group, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, carbocyclic group, heterocyclyl group, aryl, and heteroaryl are each independently substituted with 0, 1, 2, 3, 4 or 5 R gg groups;

[0042] Each R ff is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclic group, heterocyclyl group, aryl, and heteroaryl, or two R ff groups are linked to form a heterocyclyl group or a heteroaryl ring, wherein alkyl, alkenyl, alkynyl, carbocyclic group, heterocyclyl group, aryl, and heteroaryl are each independently substituted with 0, 1, 2, 3, 4 or 5 R gg groups;

[0043] Each R gg is independently halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC 1-6 alkyl group, -ON(C 1-6 alkyl group)2, -N(C 1-6 alkyl group)2, -N(C 1-6 alkyl group)3 + X - , -NH(C 1-6 alkyl group)2 + X - , -NH2(C 1-6 alkyl group) + X - , -NH3 + X - , -N(OC 1-6 alkyl group)(C 1-6 alkyl group), -N(OH)(C 1-6 alkyl group), -NH(OH), -SH, -SC 1-6 alkyl group, -SS(C 1-6 alkyl group), -C(=O)(C 1-6 alkyl group), -CO2H, -CO2(C 1-6 alkyl group), -OC(=O)(C 1-6 alkyl group), -OCO2(C 1-6 alkyl group), -C(=O)NH2, -C(=O)N(C 1-6 alkyl group)2, -OC(=O)NH(C 1-6 alkyl group), -NHC(=O)(C 1-6 alkyl group), -N(C 1-6 alkyl group)C(=O)(C 1-6(alkyl group), -NHCO2(C 1-6 (alkyl group), -NHC(=O)N(C 1-6 (alkyl group)2, -NHC(=O)NH(C 1-6 (alkyl group), -NHC(=O)NH2, -C(=NH)O(C 1-6 (alkyl group), -OC(=NH)(C 1-6 (alkyl group), -OC(=NH)OC 1-6 (alkyl group, -C(=NH)N(C 1-6 (alkyl group)2, -C(=NH)NH(C 1-6 (alkyl group), -C(=NH)NH2, -OC(=NH)N(C 1-6 (alkyl group)2, -OC(NH)NH(C 1-6 (alkyl group), -OC(NH)NH2, -NHC(NH)N(C 1-6 (alkyl group)2, -NHC(=NH)NH2, -NHSO2(C 1-6 (alkyl group), -SO2N(C 1-6 (alkyl group)2, -SO2NH(C 1-6 (alkyl group), -SO2NH2, -SO2C 1-6 (alkyl group, -SO2OC 1-6 (alkyl group, -OSO2C 1-6 (alkyl group, -SOC 1-6 (alkyl group, -Si(C 1-6 (alkyl group)3, -OSi(C 1-6 (alkyl group)3, -C(=S)N(C 1-6 (alkyl group)2, C(=S)NH(C 1-6 (alkyl group), C(=S)NH2, -C(=O)S(C 1-6 (alkyl group), -C(=S)SC 1-6 (alkyl group, -SC(=S)SC 1-6 (alkyl group, -P(=O)2(C 1-6 (alkyl group), -P(=O)(C 1-6 (alkyl group)2, -OP(=O)(C 1-6 (alkyl group)2, -OP(=O)(OC 1-6 (alkyl group)2, C 1-6 (alkyl group, C 1-6 (haloalkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, C3-C7 carbocyclic group, C6-C 10an aryl group, a C3-C7 heterocyclyl group, a C5-C 10 heteroaryl group; or two geminal R gg substituents may be linked to form =O or =S; wherein X - is a counterion.

[0044] Exemplary substituents on the nitrogen atom include hydrogen, -OH, -OR aa , -N(R cc )2, -CN, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -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, carbocyclic group, heterocyclyl group, aryl, and heteroaryl are included, but not limited thereto, or two R cc groups bonded to the nitrogen atom may be linked to form a heterocyclyl group or a heteroaryl ring, wherein alkyl, alkenyl, alkynyl, carbocyclic group, heterocyclyl group, aryl, and heteroaryl are each independently substituted with 0, 1, 2, 3, 4 or 5 R dd groups, wherein R aa , R bb , R cc and R dd are as defined above.

[0045] Other definitions As used herein, the term "treatment" relates to the progression, reversal, or alleviation of a disorder or condition to which the term applies, or one or more symptoms of such a disorder or condition, or the prevention thereof. The noun "treatment" as used herein relates to the act of treating, which is a verb and is as defined above.

[0046] As used herein, the term "pharmaceutically acceptable salt" represents carboxylate salts and amino acid salt addition salts of the present invention. They are suitable for use in contact with the tissues of a patient without undue toxicity, irritation, allergic response, etc., within the scope of sound medical judgment, commensurate with a reasonable benefit / risk ratio, effective for their desired applications, and, if possible, include zwitterionic forms of the compounds of the present invention.

[0047] The term "salt" means relatively non-toxic addition salts of the compounds of the present invention combined with inorganic and organic acids. These salts are prepared in situ at the final isolation and purification stages of the compound, or by reacting a purified compound in free base form separately with a suitable organic or inorganic acid and isolating the resulting salt. As long as the compounds of the present invention are basic compounds, they can form multiple different salts with various inorganic and organic acids. Such salts need to be pharmaceutically acceptable for administration to animals, but in practice, after first isolating the pharmaceutically unacceptable salt of the basic compound from the reaction mixture, it is treated with a basic reagent to simply convert it to the free base compound, and subsequently the free base is converted to a pharmaceutically acceptable acid addition salt. Acid addition salts of basic compounds are prepared by contacting the free base form in a conventional manner with a sufficient amount of acid to form the salt. The free base is regenerated by contacting the salt form with a base in a conventional manner and isolating the free base again. The physical properties of the free base form, such as solubility in polar solvents, differ somewhat depending on the respective salt form, but for the purposes of the present invention, the salts are equivalent to their respective free bases.

[0048] Pharmaceutically acceptable base addition salts are formed with metals or amines such as, for example, hydroxides of alkali metals and alkaline earth metals or organic amines. Examples of metals used as cations include sodium, potassium, magnesium, calcium and the like. Examples of preferred amines include N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine and procaine.

[0049] Base addition salts of acidic compounds can be prepared by contacting the free acid form with a sufficient amount of the required base in a conventional manner to form the salt. The free acid is regenerated by contacting the salt form with an acid in a conventional manner and isolating the free acid again. The free acid form has somewhat different physical properties, such as solubility in polar solvents, from those of the respective salt forms. However, for the purposes of the present invention, the salts are equivalent to the respective free acids.

[0050] The salts may be sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides and iodides, which are prepared from inorganic acids. Examples of the acids include hydrochloric acid, nitric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphoric acid and the like. Representative salts include hydrobromides, hydrochlorides, sulfates, bisulfates, nitrates, acetates, oxalates, valerates, oleates, palmitates, stearates, laurates, borates, benzoates, lactates, phosphates, tosylates, citrates, maleates, fumarates, succinates, tartrates, naphthalates, methanesulfonates, glucoheptanoates, lactobionates, lauryl sulfonates, and isethionates. The salts may be aliphatic monocarboxylic acids and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc., which are prepared from organic acids. Representative salts include acetates, propionates, octanoates, isobutyrates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, naphthoates, besylates, tosylates, phenylacetates, citrates, lactates, maleates, tartrates, methanesulfonates and the like. Pharmaceutically acceptable salts include cations derived from alkali metals and alkaline earth metals such as sodium, lithium, potassium, calcium, magnesium, etc., and non-toxic ammonium, quaternary ammonium, and amine cations including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, etc. Further, salts of amino acids such as, for example, arginine salts, gluconates, galacturonates, etc. are also included (see, for example, Berge S.M. et al., "Pharmaceutical Salts." J.Pharm.Sci., 1977;66:1-19).

[0051] Examples of pharmaceutically acceptable non-toxic esters of the compounds of the present invention include C1-C6 alkyl esters in which the alkyl group is straight-chain or branched-chain. Acceptable esters also include C5-C7 cycloalkyl esters and arylalkyl esters (e.g., but not limited to, benzyl esters). C1-C4 alkyl esters are preferred. The esters of the compounds of the present invention can be prepared according to conventional methods, for example, as described in March’s Advanced Organic Chemistry, 5 Edition, M.B. Smith & J. March, John Wiley & Sons, 2001.

[0052] Examples of pharmaceutically acceptable non-toxic amides of the compounds of the present invention include amides derived from ammonia, primary C1-C6 alkylamines, and secondary C1-C6 dialkylamines, where the alkyl group is straight-chain or branched-chain. In the case of secondary amines, the amine may be in the form of a 5- or 6-membered heterocycle containing one nitrogen atom. Amides derived from ammonia, C1-C3 alkyl primary amines, and C1-C2 dialkyl secondary amines are preferred. The amides of the compounds of the present invention can be prepared according to conventional methods, for example, as described in March’s Advanced Organic Chemistry, 5 Edition, M.B. Smith & J. March, John Wiley & Sons, 2001.

[0053] The “subjects” to be administered include humans (i.e., males or females of any age group, such as pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or elderly adults)) and / or non-human animals, such as mammals (e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys), cows, pigs, horses, sheep, goats, rodents, cats, and / or dogs), but are not limited thereto. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal. The terms “human,” “patient,” and “subject” are used interchangeably herein.

[0054] The terms "disease", "disorder" and "condition" are used interchangeably herein.

[0055] Unless otherwise specified, the term "treatment" as used herein is contemplated to be an act (a "therapeutic treatment") that occurs while a subject is suffering from a particular disease, disorder or condition and that reduces the severity of, or delays or slows the progression of, that disease, disorder or condition, and also an act (a "preventive treatment") that occurs before a subject begins to suffer from a particular disease, disorder or condition.

[0056] Generally, an "effective amount" of a compound refers to an amount sufficient to elicit a desired biological response. As will be understood by those skilled in the art, the effective amount of a compound of the present invention can vary depending on factors such as the desired biological goal, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, health and condition of the subject. An effective amount includes a therapeutically effective amount and a prophylactically effective amount.

[0057] Unless otherwise specified, a "therapeutically effective amount" of a compound as used herein is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder or condition or to delay or minimize one or more symptoms associated with that disease, disorder or condition. A therapeutically effective amount of a compound means the amount of the therapeutic agent, alone or in combination with other therapies, that provides a therapeutic benefit in the treatment of that disease, disorder or condition. The term "therapeutically effective amount" includes an amount that improves the overall treatment, reduces or avoids the symptoms or causes of a disease or condition, or enhances the therapeutic effect of another therapeutic agent.

[0058] Unless otherwise specified, the "prophylactically effective amount" of a compound as used herein is an amount sufficient to prevent a disease, disorder or medical condition, or one or more symptoms associated with that disease, disorder or medical condition, or to prevent its recurrence. The prophylactically effective amount of a compound means the amount of a therapeutic agent that provides a prophylactic benefit in preventing the disease, disorder or medical condition, either alone or in combination with other agents. The term "prophylactically effective amount" includes an amount that improves prophylaxis overall or enhances the prophylactic effect of another prophylactic agent.

[0059] "Combination" and related terms mean the administration of a compound of the invention and another therapeutic agent either simultaneously or sequentially. For example, a compound of the invention can be administered simultaneously or sequentially with another therapeutic agent in separate unit formulations or simultaneously with another therapeutic agent in a single unit formulation.

Best Mode for Carrying Out the Invention

[0060] As used herein, the term "compound of the invention" refers to a compound represented by the following formula (I), formula (II-1), etc., or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotope variant thereof, and mixtures thereof.

[0061] In this specification, compounds are generally named using standard nomenclature. For compounds having asymmetric centers, it should be understood that all optical isomers and mixtures thereof are included unless otherwise specified. Further, all isomeric compounds and carbon-carbon double bonds included in the present invention may appear in the Z and E forms unless otherwise specified. For compounds existing in different tautomeric forms, the compounds are not limited to a specific tautomer and are intended to include all tautomeric forms.

[0062] In one embodiment, the present invention relates to a compound represented by formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotope variant thereof, and mixtures thereof.

Chemical formula

[0063] Ring A In one embodiment, ring A is C 3-7 In another embodiment, Ring A is a 3- to 7-membered heterocyclyl; in another embodiment, Ring A is C 6-10 It is aryl.

[0064] Ring B In one embodiment, Ring B is C 3-7 cycloalkyl; in another embodiment, Ring B is a 3- to 7-membered heterocyclyl; in another embodiment, Ring B is C 6-10 aryl; in another embodiment, Ring B is a 5- to 10-membered heteroaryl.

[0065] L1 In one embodiment, L1 is a bond; in another embodiment, L1 is -O-; in another embodiment, L1 is -C(O)-; in another embodiment, L1 is -CR’R’’-; in another embodiment, L1 is -CR’R’’-CR’R’’-; in another embodiment, L1 is -CR’R’’-CR’R’’-CR’R’’-.

[0066] L2 In one embodiment, L2 is a bond; in another embodiment, L2 is -C(O)-; in another embodiment, L2 is -CR’R’’-; in another embodiment, L2 is -CR’R’’-CR’R’’-; in another embodiment, L2 is -CR’R’’-CR’R’’-CR’R’’-.

[0067] Y In one embodiment, Y is O; in another embodiment, Y is S; in another embodiment, Y is NH; in another embodiment, Y is CH2.

[0068] R1 In one embodiment, R1 is H; in another embodiment, R1 is -C(O)R a ; in another embodiment, R1 is -C(O)OR a ; in another embodiment, R1 is -C(O)NR b R c ; in another embodiment, R1 is C 1-6 alkyl; in another embodiment, R1 is C 1-6is haloalkyl; in another embodiment, R1 is C 3-7 is cycloalkyl; in another embodiment, R1 is 3- to 7-membered heterocyclyl; in another embodiment, R1 is C 6-10 is aryl; in another embodiment, R1 is 5- to 10-membered heteroaryl.

[0069] R2 In one embodiment, R2 is H; in another embodiment, R2 is C 1-6 is alkyl; in another embodiment, R2 is C 1-6 is haloalkyl.

[0070] R s1 In one embodiment, R s1 is H; in another embodiment, R s1 is halogen; in another embodiment, R s1 is -CN; in another embodiment, R s1 is -NO2; in another embodiment, R s1 is -OR a ; in another embodiment, R s1 is -SR a ; in another embodiment, R s1 is -NR b R c ; in another embodiment, R s1 is -C(O)R a ; in another embodiment, R s1 is -C(O)OR a ; in another embodiment, R s1 is -C(O)NR b R c ; in another embodiment, R s1 is C 1-6 is alkyl; in another embodiment, R s1 is C 1-6 is haloalkyl; in another embodiment, R s1 is C 2-6 is alkenyl; in another embodiment, R s1 is C2-6 is alkynyl; in another embodiment, R s1 is C 3-7 is cycloalkyl; in another embodiment, R s1 is 3- to 7-membered heterocyclyl; in another embodiment, R s1 is C 6-10 is aryl; in another embodiment, R s1 is 5- to 10-membered heteroaryl.

[0071] R s2 In one embodiment, R s2 is H; in another embodiment, R s2 is halogen; in another embodiment, R s2 is -CN; in another embodiment, R s2 is -NO2; in another embodiment, R s2 is -OR a ; in another embodiment, R s2 is -SR a ; in another embodiment, R s2 is -NR b R c ; in another embodiment, R s2 is -C(O)R a ; in another embodiment, R s2 is -C(O)OR a ; in another embodiment, R s2 is -C(O)NR b R c ; in another embodiment, R s2 is C 1-6 alkyl; in another embodiment, R s2 is C 1-6 haloalkyl; in another embodiment, R s2 is C 2-6 alkenyl; in another embodiment, R s2 is C 2-6 alkynyl; in another embodiment, R s2 is C 3-7 cycloalkyl; in another embodiment, Rs2 is a 3- to 7-membered heterocyclyl; in another embodiment, R s2 is C 6-10 aryl; in another embodiment, R s2 is a 5- to 10-membered heteroaryl.

[0072] R s3 In one embodiment, R s3 is H; in another embodiment, R s3 is halogen; in another embodiment, R s3 is -CN; in another embodiment, R s3 is -NO2; in another embodiment, R s3 is -OR a ; in another embodiment, R s3 is -SR a ; in another embodiment, R s3 is -NR b R c ; in another embodiment, R s3 is -C(O)R a ; in another embodiment, R s3 is -C(O)OR a ; in another embodiment, R s3 is -C(O)NR b R c ; in another embodiment, R s3 is C 1-6 alkyl; in another embodiment, R s3 is C 1-6 haloalkyl; in another embodiment, R s3 is C 2-6 alkenyl; in another embodiment, R s3 is C 2-6 alkynyl; in another embodiment, R s3 is C 3-7 cycloalkyl; in another embodiment, R s3 is a 3- to 7-membered heterocyclyl; in another embodiment, R s3 is C 6-10 aryl; in another embodiment, Rs3 is a 5- to 10-membered heteroaryl.

[0073] R s4 In one embodiment, R s4 is H; in another embodiment, R s4 is halogen; in another embodiment, R s4 is -CN; in another embodiment, R s4 is -NO2; in another embodiment, R s4 is -OR a ; in another embodiment, R s4 is -SR a ; in another embodiment, R s4 is -NR b R c ; in another embodiment, R s4 is -C(O)R a ; in another embodiment, R s4 is -C(O)OR a ; in another embodiment, R s4 is -C(O)NR b R c ; in another embodiment, R s4 is C 1-6 alkyl; in another embodiment, R s4 is C 1-6 haloalkyl; in another embodiment, R s4 is C 2-6 alkenyl; in another embodiment, R s4 is C 2-6 alkynyl; in another embodiment, R s4 is C 3-7 cycloalkyl; in another embodiment, R s4 is a 3- to 7-membered heterocyclyl; in another embodiment, R s4 is C 6-10 aryl; in another embodiment, R s4 is a 5- to 10-membered heteroaryl.

[0074] m In one embodiment, m = 0; in another embodiment, m = 1; in another embodiment, m = 2; in another embodiment, m = 3; in another embodiment, m = 4; in another embodiment, m = 5.

[0075] n In one embodiment, n = 0; in another embodiment, n = 1; in another embodiment, n = 2; in another embodiment, n = 3; in another embodiment, n = 4.

[0076] p In one embodiment, p = 0; in another embodiment, p = 1; in another embodiment, p = 2; in another embodiment, p = 3; in another embodiment, p = 4; in another embodiment, p = 5; in another embodiment, p = 6; in another embodiment, p = 7; in another embodiment, p = 8.

[0077] q In one embodiment, q = 0; in another embodiment, q = 1; in another embodiment, q = 2; in another embodiment, q = 3; in another embodiment, q = 4; in another embodiment, q = 5.

[0078] Any one technical configuration or any combination thereof in the above specific embodiments can be combined with any one technical configuration or any combination thereof in the above specific embodiments. For example, any technical configuration or any combination thereof regarding ring A can be combined with any technical configuration or any combination thereof such as ring B, L1, L2, Y, R1, R2, R s1 -R s4 , m, n, p, and q. The present invention includes all combinations of such technical configurations, but they are not listed here.

[0079] In a more specific embodiment, the present invention provides a technical configuration 1 which is a compound represented by formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotope variant thereof, and mixtures thereof.

Chemical formula

[0080] In a more specific embodiment, the present invention provides Technical Configuration 2 which is a compound represented by the formula (I) of Technical Configuration 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotope variant thereof, and mixtures thereof, wherein R2 is H.

[0081] In a more specific embodiment, the present invention provides Technical Configuration 3 which is a compound represented by the formula (I) of Technical Configuration 1 or 2, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotope variant thereof, and mixtures thereof, wherein R1 is a group other than H.

[0082] In a more specific embodiment, the present invention provides Technical Configuration 4 which is a compound represented by the formula (I) of any one of Technical Configurations 1 to 3, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotope variant thereof, and mixtures thereof, wherein q = 1, 2, 3, 4 or 5, and at least one of R s4 is selected from the group consisting of halogen or C l-6 haloalkyl.

[0083] In a more specific embodiment, the present invention provides Technical Configuration 5 which is a compound represented by the formula (I) of any one of Technical Configurations 1 to 4, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotope variant thereof, and mixtures thereof, wherein m = 0, 1, 2 or 3, and R s1 is H, halogen, -CN, -NO2, -OR a , -SR a , -NR b R c , -C(O)R a , -C(O)OR a , -C(O)NR b R c , C 1-6 alkyl, or C 1-6It is selected from the group consisting of haloalkyl.

[0084] In a more specific embodiment, the present invention provides Technical Configuration 6 which is a compound represented by formula (I) according to any one of Technical Configurations 1 to 5, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotope variant thereof, and mixtures thereof, where p = 0, 1 or 2, and R s3 is H, halogen, -CN, -NO2, -OR a -SR a -NR b R c -C(O)R a -C(O)OR a -C(O)NR b R c C 1-6 alkyl, or C 1-6 is selected from the group consisting of haloalkyl.

[0085] In a more specific embodiment, the present invention provides Technical Configuration 7 which is a compound represented by formula (I) according to any one of Technical Configurations 1 to 6, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotope variant thereof, and mixtures thereof, where Y is O.

[0086] In a more specific embodiment, the present invention provides Technical Configuration 8 which is a compound represented by formula (I) according to any one of Technical Configurations 1 to 7, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotope variant thereof, and mixtures thereof, where L2 is -C(O)-.

[0087] In a more specific embodiment, the present invention provides Technical Configuration 9 which is a compound represented by the formula (I) according to any one of Technical Configurations 1 to 8, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotope variant thereof, and mixtures thereof, wherein ring A is

Chemical formula

[0088] In a more specific embodiment, the present invention provides Technical Configuration 10 which is a compound represented by the formula (I) according to any one of Technical Configurations 1 to 9, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotope variant thereof, and mixtures thereof, wherein ring B is

Chemical formula

Chemical formula

[0089] In a more specific embodiment, the present invention provides Technical Configuration 11 which is a compound represented by the formula (I) according to any one of Technical Configurations 1 to 10, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotope variant thereof, and mixtures thereof, wherein the above compound is a compound represented by the formulas (II-1) to (II-4).

Chemical formula

Chemical formula

[0090] In a more specific embodiment, the present invention provides Technical Configuration 12, which is a compound represented by the formula (I) of any one of Technical Configurations 1 to 10, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotope variant thereof, and mixtures thereof, wherein the compound is a compound represented by the formulas (III-1) to (III-3).

Chemical formula

[0091] In a more specific embodiment, the present invention provides Technical Configuration 13, which is a compound represented by the formula (I) of any one of Technical Configurations 1 to 10, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotope variant thereof, and mixtures thereof, wherein the compound is a compound represented by the formulas (IV-1) to (IV-3).

Chemical formula

[0092] In a more specific embodiment, the present invention provides Technical Configuration 14 which is a compound represented by the formula (I) of any one of Technical Configurations 1 to 10, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotope variant thereof, and mixtures thereof, wherein the compound is a compound represented by the formula (III-1).

Chemical Formula

Chemical formula

[0093] In a more specific embodiment, the present invention provides Technical Configuration 15 which is a compound represented by the formula (I) of any one of Technical Configurations 1 to 10, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotope variant thereof, and mixtures thereof, wherein the compound is a compound represented by the formula (III-2).

Chemical formula

Chemical formula

Chemical formula

[0094] In a more specific embodiment, the present invention provides Technical Configuration 16 which is a compound represented by formula (I) of any one of Technical Configurations 1 to 10, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotope variant thereof, and mixtures thereof, wherein the compound is a compound represented by formula (III-3).

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0095] In a more specific embodiment, the present invention provides Technical Configuration 17 which is a compound represented by formula (I) according to any one of Technical Configurations 1 to 10, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotope variant thereof, and mixtures thereof, wherein the said compound is a compound represented by formula (IV-1).

Chemical formula

[0096] In a more specific embodiment, the present invention provides Technical Configuration 18 which is a compound represented by the formula (I) according to any one of Technical Configurations 1 to 10, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotope variant thereof, and a mixture thereof, wherein the compound is a compound represented by the formula (IV-2).

Chemical formula

[0097] In a more specific embodiment, the present invention provides Technical Configuration 19 which is a compound represented by formula (I) of any one of Technical Configurations 1 to 10, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotope variant thereof, and mixtures thereof, wherein the said compound is a compound represented by formula (IV-3).

Chemical formula

[0098] Since the compounds of the present invention may contain one or more asymmetric centers, they may exist as various isomers, for example, enantiomers and / or diastereomers. For example, the compounds of the present invention may be in the form of individual enantiomers, diastereomers or geometric isomers (e.g., cis and trans isomers), or in the form of a mixture of stereoisomers (including racemic mixtures and mixtures rich in one or more stereoisomers). The isomers can be isolated from the mixture by methods known to those skilled in the art (including chiral high performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts); or the preferred isomers can be prepared by asymmetric synthesis.

[0099] Those skilled in the art can understand that an organic compound can react in a solvent or precipitate or crystallize from a solvent to form a complex with the solvent. These complexes are called "solvates". When the solvent is water, the complex is called a "hydrate". The present invention includes all solvates of the compounds of the present invention.

[0100] The term "solvate" generally refers to a compound or a salt thereof combined with a solvent, formed by solvolysis reaction. This physical association includes hydrogen bonding. Common solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, etc. The compounds of the present invention can be prepared, for example, as crystals and can be solvated. Suitable solvates include pharmaceutically acceptable solvates, and further include stoichiometric solvates and non-stoichiometric solvates. In certain embodiments, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid, the solvate is isolated. "Solvate" includes solvates separable from the solvate in solution state. Representative solvates include hydrates, ethanolates, and methanolates.

[0101] The term "hydrate" refers to a compound combined with water. Usually, the ratio of the number of water molecules contained in the hydrate of a compound to the number of compound molecules in the hydrate is constant. Thus, the hydrate of a compound is represented, for example, by the general formula R x ·xH2O. Here, R is the compound and x is a number greater than 0. A given compound may form multiple types of hydrates. For example, monohydrate (x is 1), lower hydrate (x is a number greater than 0 and less than 1, for example, hemihydrate (R 0.5 ·1 / 2H2O)), and polyhydrate (x is a number greater than 1, for example, dihydrate (R2H2O) and hexahydrate (R6H2O)) can be mentioned.

[0102] The compounds of the present invention may be in either amorphous or crystalline (crystal polymorph) form. Also, the compounds of the present invention may exist as one or more crystals. Accordingly, the present invention includes all amorphous or crystalline forms of the compounds of the present invention within its scope. The term "crystal polymorph" refers to the crystal form (or its salt, hydrate or solvate) of a compound in which specific crystals are deposited and arranged. All polymorphs have the same elemental composition. Different crystal forms usually have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystal shapes, photoelectric properties, stability, and solubility. Depending on the recrystallization solvent, crystallization rate, storage temperature, and other factors, a dominant crystal form may occur. The various polymorphs of a compound can be prepared by crystallization under different conditions.

[0103] The present invention also includes isotopically labeled compounds equivalent to those described in formula (I), wherein one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number typically found in nature. Examples of isotopes that can be introduced into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as 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 compounds of the present invention, their prodrugs, and pharmaceutically acceptable salts of the foregoing compounds or prodrugs containing the above isotopes and / or other isotopes of other atoms are included within the scope of the present invention. Some isotopically labeled compounds of the present invention, such as those incorporating radioactive isotopes (e.g., 3 H and 14 C), are used for measurements regarding the tissue distribution of drugs and / or substrates. Tritium (i.e., 3 H) and carbon-14 (i.e., 14The isotopes of (C) are particularly preferred because they are easy to produce and detect. Furthermore, substitution with heavier isotopes such as deuterium, i.e., 2 substitution with 2 H, is advantageous for treatment because of its excellent metabolic stability. For example, it can extend the half-life in vivo and reduce the dosage, so it may be preferentially considered depending on the situation. Usually, the isotopically labeled compounds of formula (I) of the present invention and their prodrugs can be prepared by using readily available isotopically labeled reagents instead of non-isotopically labeled reagents when the processes disclosed in the following schemes and / or examples and preparation examples are carried out.

[0104] Furthermore, prodrugs are also included in the specification of the present invention. As used herein, the term "prodrug" refers to a compound that is converted in vivo, for example, by hydrolysis in blood, into an active form having a medical effect. Pharmaceutically acceptable prodrugs are described in T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, A.C.S. Symposium Series Vol. 14, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, and D. Fleisher, S. Ramon and H. Barbra "Improved oral drug delivery: solubility limitations overcome by the use of prodrugs", Advanced Drug Delivery Reviews (1996) 19(2) 115-130, which are hereby incorporated by reference herein, respectively.

[0105] A prodrug is any covalently bonded compound of the invention that, when administered to a patient, releases the parent compound in vivo. Prodrugs are typically prepared by modifying a functional group so that it can be cleaved, either by normal manipulation or in vivo, to yield the parent compound. Prodrugs include, for example, compounds of the invention in which a hydroxyl group, an amino group, or a mercapto group is bonded to any group, and when administered to a patient, can be cleaved to form a hydroxyl group, an amino group, or a mercapto group. Thus, representative examples of prodrugs include, but are not limited to, acetate / acetamide, formate / formamide, and benzoate / benzamide derivatives of compounds of formula (I) with a hydroxyl group, an amino group, or a mercapto group. In the case of carboxylic acid (-COOH), esters such as methyl ester and ethyl ester can be used. The ester itself may have activity and / or may be hydrolyzed under conditions in the human body. Suitable pharmaceutically acceptable in vivo hydrolyzable ester groups include groups that are readily decomposed in the human body to release the parent acid or its salt.

[0106] The present invention also provides a pharmaceutical preparation comprising a therapeutically effective amount of a compound of formula (I) or a therapeutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient. All of these forms are included in the present invention.

[0107] Preferred compounds of the present invention include, but are not limited to, the following compounds, or their pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, solvates, hydrates, polymorphs, prodrugs, or isotope variants, and mixtures thereof.

Chemical formula

Chemical formula

Chemical formula

[0108] Pharmaceutical Compositions, Preparations, and Kits In other aspects, the present invention provides a pharmaceutical composition comprising a compound of the present invention (also referred to as the "active ingredient") and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises an effective amount of the compound of the present invention. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the compound of the present invention. In some embodiments, the pharmaceutical composition comprises a prophylactically effective amount of the compound of the present invention.

[0109] The pharmaceutically acceptable excipients of the present invention refer to non-toxic carriers, adjuvants, or vehicles that do not inactivate the pharmacological activity of the compound being formulated. Pharmaceutically acceptable carriers, adjuvants, or vehicles that can be used in the compositions of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum albumin (e.g., human serum albumin), buffering substances (e.g., phosphates), glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (e.g., protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and lanolin.

[0110] The present invention further includes kits (e.g., pharmaceutical packs). The kits provided include the compound of the present invention, other therapeutic agents, and first and second containers (e.g., vials, ampoules, bottles, syringes, and / or dispensing packages, or other suitable containers) containing the compound of the present invention and other therapeutic agents. In some embodiments, the kits provided may also have a third container containing a pharmaceutically acceptable excipient for diluting or suspending the compound of the present invention and / or other therapeutic agents. In some embodiments, the compound of the present invention in the first and second containers is combined with other therapeutic agents to form and provide unit dosage forms.

[0111] Administration The pharmaceutical composition provided by the present invention can be administered by various methods such as oral administration, parenteral administration, inhalation administration, topical administration, rectal administration, nasal administration, oral cavity administration, vaginal administration, administration by implant or other administration methods, but is not limited thereto. For example, parenteral administration used in the present invention includes subcutaneous administration, intradermal administration, intravenous administration, intramuscular administration, intra-articular administration, intra-arterial administration, intra-synovial cavity administration, intrasternal administration, intrathecal administration, intralesional administration, intracranial injection and infusion techniques.

[0112] Generally, the compound provided by the present invention is administered in an effective amount. The amount of the compound actually administered is determined by a physician according to circumstances including the medical condition to be treated, the administration method selected, the compound actually administered, the age, weight and reaction of the patient, and the severity of the patient's symptoms.

[0113] When used to prevent the medical conditions described in this specification, the compound provided by the present invention is administered to a subject at risk of developing the above-mentioned medical conditions, and typically is administered at the above dosage levels based on the recommendation of a physician. Subjects at risk of developing a particular medical condition typically include subjects with a family history of the above-mentioned medical condition, or subjects who are likely to develop the above-mentioned medical condition by genetic testing or screening.

[0114] The pharmaceutical composition provided by the present invention ( "long-term administration") can also be administered long-term. Long-term administration refers to the ability to administer a compound or its pharmaceutical composition over a long period of time, such as 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or to be administered continuously indefinitely for the rest of the subject's life. For example, in some embodiments, long-term administration is intended to provide a certain level of the above compound in the blood over a long period of time, for example, within a treatment window.

[0115] The pharmaceutical composition of the present invention can be further delivered using various administration methods. For example, in some embodiments, the pharmaceutical composition can be administered by bolus injection, for example, to increase the concentration of the compound in the blood to an effective level. The placement of the bolus dose depends on the desired systemic level of the active ingredient through the body. For example, an intramuscular or subcutaneous bolus dose allows for a slow release of the active ingredient, while a bolus delivered directly into the vein (e.g., by IV infusion) allows for a faster delivery, which rapidly raises the concentration of the active ingredient in the blood to an effective level. In other embodiments, this pharmaceutical composition can be administered as a continuous infusion, for example, by IV infusion, to provide maintenance of a steady-state concentration of the active ingredient within the subject's body.

[0116] Compositions for oral administration can take the form of bulk liquid solutions or suspensions or bulk powders. However, generally, the compositions are provided in unit doses in order to be able to administer the composition in precise dosages. The term "unit dosage form" refers to physically discrete units suitable as unit doses for human subjects and other mammals, each unit containing a predetermined quantity of the active ingredient calculated to produce the desired therapeutic effect, together with a suitable pharmaceutical excipient. Typical unit dosage forms include pre-measured and pre-filled ampoules or syringes of liquid compositions, or in the case of solid compositions, pills, tablets, capsules, etc. In such compositions, the compound is usually a minor component (about 0.1 to about 50 wt%, or preferably about 1 to about 40 wt%), and the remainder are various carriers or excipients and processing aids useful in forming the desired dosage form.

[0117] For oral administration, oral dosages of 1 to 5 times per day, particularly 2 to 4 times per day, and typically 3 times per day are representative regimens. When using these dosing patterns, each dose provides from about 0.01 to about 20 mg / kg of the compound of the present invention, and preferred doses provide from about 0.1 to about 10 mg / kg, particularly from about 1 to about 5 mg / kg, respectively.

[0118] The transdermal dosage is generally selected to provide blood levels similar to or lower than those achieved using injectable dosages, and is generally in the range of about 0.01% to about 20% by weight, preferably about 0.1% to about 20% by weight, preferably about 0.1% to about 10% by weight, and more preferably about 0.5% to about 15% by weight.

[0119] The dosage levels of the injectable are in the range of about 0.1 mg / kg / hour to at least 10 mg / kg / hour, all over about 1 to about 120 hours, particularly 24 to 96 hours. A preloading bolus of about 0.1 mg / kg to about 10 mg / kg or more may also be administered to achieve an appropriate steady state level. The maximum total dosage does not exceed about 2 g / day for a human patient of 40 - 80 kg.

[0120] Liquid forms suitable for oral administration may contain suitable aqueous or non-aqueous carriers including buffering agents, suspending and dispensing agents, coloring agents, flavorings, etc. Solid forms may contain, for example, any of the following ingredients or compounds of similar nature: binders (e.g., microcrystalline cellulose, tragacanth gum or gelatin); excipients (e.g., starch or lactose), disintegrants (e.g., alginic acid, Primogel or corn starch); lubricants (e.g., magnesium stearate); lubricants (e.g., colloidal silicon dioxide); sweetening agents (e.g., sucrose or saccharin); or flavoring agents (e.g., peppermint, methyl salicylate or orange flavor).

[0121] Injectable compositions are typically based on injectable sterile saline or phosphate buffered saline or other injectable excipients known in the art. Conventionally, the active compound in such compositions is typically a minor component, often about 0.05 - 10% by weight, and the remainder is, for example, an injectable excipient.

[0122] Transdermal compositions are typically formulated as topical ointments or creams containing the active ingredient(s). When formulated as an ointment, the active ingredient is typically mixed with a paraffin ointment base or a water-miscible ointment base. Alternatively, the active ingredient may be formulated as a cream, for example, containing an oil-in-water cream base. Such transdermal formulations are well known in the art and generally include additional ingredients that enhance the skin penetration or stability of the active ingredient or the formulation. All such known transdermal formulations and ingredients are included within the scope provided by the present invention.

[0123] The compounds of the present invention can also be administered by transdermal devices. Thus, transdermal administration can be achieved using a reservoir type or a porous membrane type or a solid matrix type patch.

[0124] In orally administrable, injectable, or topically administrable compositions, the components described above are merely representative. Other materials as well as processing techniques, etc. are shown in Part 8 of Remington’s Pharmaceutical Sciences, 17th Edition, 1985, Mack Publishing Company, Easton, Pennsylvania (incorporated herein by reference).

[0125] The compounds of the present invention can also be administered in a sustained release form or from a sustained release drug delivery system. Descriptions of representative sustained release materials can be found in Remington’s Pharmaceutical Sciences.

[0126] The present invention also relates to a pharmaceutically acceptable formulation of the compounds of the present invention. In one embodiment, the formulation comprises water. In another embodiment, the formulation comprises a cyclodextrin derivative. The most common cyclodextrins are α-, β- and γ-cyclodextrins, each consisting of 6, 7 and 8 α-1,4-linked glucose units, respectively, with one or more substituents (including, but not limited to, methylation, hydroxyalkylation, acylation and sulfoalkyl ether substitution) as required on the linked sugar moieties. In certain specific embodiments, the cyclodextrin is a sulfoalkyl ether β-cyclodextrin, such as sulfobutyl ether β-cyclodextrin, also known as Captisol. See, for example, U.S. Patent No. 5,376,645. In some embodiments, the formulation comprises hexapropyl-β-cyclodextrin (e.g., 10-50% in water).

[0127] Combination therapy Also, the compounds of the present invention are administered in combination with other therapeutic agents (e.g., cholesterol lowering agents, fibrate drugs and lipid lowering agents, anti-diabetic agents, anti-hypertensive agents and angiotensin converting enzyme (ACE) inhibitors, etc.).

[0128] In some embodiments, the other therapeutic agent is a cholesterol lowering agent. Examples of cholesterol lowering agents include, but are not limited to, atorvastatin, cerivastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin, ezetimibe, and combinations of ezetimibe / simvastatin (Vytorin®).

[0129] In some embodiments, the other therapeutic agent is a fibrate or lipid-lowering agent. Examples of fibrates or lipid-lowering agents include, but are not limited to, acifran, acipimox, bezafibrate, ciprofibrate, clofibrate, colesevelam, gemfibrozil, fenofibrate, melinamide, niacin, and ronafibrate.

[0130] In some embodiments, the other therapeutic agent is a DPP-IV inhibitor as an anti-diabetic agent. Examples of DPP-IV inhibitors as anti-diabetic agents include, but are not limited to, sitagliptin, saxagliptin, vildagliptin, linagliptin, dutogliptin, gemigliptin, and alogliptin.

[0131] In some embodiments, the other therapeutic agent is an anti-diabetic agent other than a DPP-IV inhibitor. Examples of anti-diabetic agents include, but are not limited to, acarbose, epalrestat, exenatide, glimepiride, liraglutide, metformin, miglitol, mitiglinide, nateglinide, pioglitazone, pramlintide, repaglinide, rosiglitazone, tolrestat, troglitazone, and voglibose.

[0132] In some embodiments, the other therapeutic agent is an antihypertensive agent. Examples of antihypertensive agents include, but are not limited to, alacepril, alfuzosin, aliskiren, amlodipine besylate, amosulalol, aranidipine, arotinolol hydrochloride, azelnidipine, bambidipine hydrochloride, benazepril hydrochloride, benidipine hydrochloride, betaxolol hydrochloride, bevantolol hydrochloride, bisoprolol fumarate, bopindolol, bosentan, budralazine, bunazosin hydrochloride, candesartan, captopril, carvedilol, celiprolol hydrochloride, cicletanine, cilazapril, cinildipine, clevidipine, delapril, dilevalol, doxazosin mesylate, efonidipine, enalapril maleate, enalaprilat, eplerenone, eprosartan, felodipine, fenoldopam mesylate, fosinopril sodium, guanadrel sulfate, imidapril hydrochloride, irbesartan, isradipine, ketanserin, lacidipine, lercanidipine, lisinopril, losartan, manidipine hydrochloride, mibefradil hydrochloride, moxonidine, nebivolol, nilvadipine, nipradilol, nisoldipine, olmesartan medoxomil, perindopril, pinacidil, quinapril, ramipril, rilmenidine, spirapril hydrochloride, telmisartan, temocarpil, terazosin hydrochloride, tertatolol hydrochloride, thiamenidine hydrochloride, tilisolol hydrochloride,trandolapril, treprostinil sodium, trimazosin hydrochloride, valsartan, and zofenopril calcium.

[0133] In some embodiments, suitable angiotensin-converting enzyme (ACE) inhibitors for use in the above combination therapies include, but are not limited to, enalapril, ramipril, quinapril, perindopril, lisinopril, imidapril, zofenopril,trandolapril, fosinopril, and captopril.

[0134] Examples The following examples are provided to give those skilled in the art a complete disclosure and description of how to implement, prepare, and evaluate the methods and compounds claimed herein. They are for illustrative purposes only and are not intended to limit the scope of the invention.

[0135] The preparation protocols for the compounds disclosed herein are shown below. Scheme 1: General synthetic scheme for the preparation of monoamide intermediates:

Chemical formula

[0136] According to Scheme 1, after converting N-BOC-imino diacetic acid in situ to anhydride 1 (1 equivalent of EDCI, in DMF solution), monoamide A is obtained by treating it with an amine (1 equivalent, in DMF solution).

[0137] Scheme 2: General synthetic scheme for the preparation of diamide intermediates

Chemical formula

[0138] According to Scheme 2, monoamide A is treated with an amine, EDCI, and HOBT to obtain diamide intermediate B.

[0139] Scheme 3: Deprotection of the diamide intermediate

Chemical formula

[0140] According to Scheme 3, the hydrochloride salt of amine C is obtained by performing N-Boc deprotection on diamide B using 4N HCl-dioxane at room temperature.

[0141] Scheme 4: General synthetic scheme for preparing the compounds of the present invention

Chemical formula

[0142] According to Scheme 4, the compounds of the present invention are prepared by reacting a certain compound (where X can be halogen, aldehyde and carboxylic acid) with a diamide intermediate in the presence of EDCI and HOBT.

[0143] General synthetic process for the preparation of monoamide intermediate: At 25 °C, a solution of N-((tert-butyloxy)carbonyl)iminodiacetic acid (2.33 g, 10 mmol) in DCM (30 mL) was treated with EDCI (1.98 g, 10.3 mmol). The mixture was stirred at 25 °C for 1 h, then an amine (12 mmol) was added and the solution was stirred at 25 °C for 20 h. The reaction mixture was poured into 10% HCl (aq) (100 mL) and extracted with DCM (100 mL × 2). 10% HCl (aq) (80 mL × 2) and saturated NaCl (aq) (100 mL × 2) to wash the organic phase, dried (MgSO4), filtered, concentrated in vacuo to obtain pure N-((tert-butyloxy)carbonyl)iminodiacetic acid monoamide.

[0144] General process for the preparation of diamide intermediate: N-((tert-butyloxy)carbonyl)iminodiacetic acid monoamide (4.8 mmol) was dissolved in DCM (15 mL). This solution was treated with an amine (1 equiv), EDCI (1.2 equiv), HOBt (1.2 equiv) and Et3N (1.5 equiv). The solution was stirred at 25 °C for 20 h. The mixture was poured into H2O and extracted with DCM (40 mL × 2). The organic phase was washed with saturated NaCl (aq) (50 mL × 2), dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by MPLC to obtain pure diamide.

[0145] General process for Boc-deprotected diamide intermediate N'-((tert-Butyloxy)carbonyl)-N,N-disubstitutediminodiacetic acid diamide (2.88 mmol) was dissolved in 4N HCl-dioxane, and the mixture was stirred at 25 °C for 1 h. The solvent was removed in vacuo, and the residue was purified by MPLC to obtain the desired product.

[0146] According to the above process, the following diamide intermediates were prepared.

Table 1

[0147] General process for preparing the compounds of the present invention A solution of diamide (0.25 mmol), carboxylic acid (0.25 mmol), EDCI (0.30 mol), HOBt (0.3 mol), Et3N (0.05 mL) and DMF (2 mL) was stirred at 25 °C for 20 h. The mixture was poured into 10% HCl (aq) and extracted with EtOAc. The organic phase was washed with saturated NaCl (aq) and the organic phase was dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by MPLC to obtain the desired product.

[0148] Preparation of compounds 201-29

Chemical formula

[0149] Other partial compounds were prepared according to the synthesis process of Compound 201-29, except that different carboxylic acids and diamide intermediates were used.

Table 2-1

Table 2-2

[0150] Preparation of Compound 201-65

Chemical formula

Table 3-1

Table 3-2

[0151] Preparation of Compound 201-74

Chemical formula

Table 4-1

Table 4-2

Table 4-3

Table 4-4

[0152] Preparation of Compound 201-5

Chemical formula

Table 5-1

Table 5-2

[0153] Another general process for preparing the compounds of the present invention Aldehydes (2 mmol) were added to a solution of amine (2 mmol) in DCE (5 mL), and the mixture was stirred at room temperature for 15 min. After adding NaBH(OAc)3 (2.5 mmol) to the resulting mixture, the mixture was stirred at room temperature until TLC showed complete disappearance of the starting aldehyde. The reaction mixture was quenched with water (10 mL) and extracted with CH2Cl2 (3 × 10 mL). The combined extracts were dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by MPLC to obtain the desired product.

[0154] Preparation of Compound 201-135

Chemical formula

Table 6

[0155] Preparation of Compound 201-255 [Chemical] Compound 201-255 was prepared according to the general process for preparing the compounds of the present invention. In addition, some other compounds were prepared according to the synthetic process of Compound 201-255, except that different aldehyde and diamide intermediates were used. [Table 7]

[0156] Biological assay Materials and methods: Cell culture: HepG2 cells (ATCC, Cat.: HB-8065) were maintained in Eagle's Minimum Essential Medium (Corning, 10-010-CVR), 10% FBS (Gibco, 10099-141), penicillin (100 units / mL), and streptomycin (100 μg / mL), which is a growth medium. The HepG2 cells were incubated at 37 °C under 5% CO2 conditions.

[0157] Cell viability assay HepG2 cells were plated at 40,000 cells / well in 100 μL of growth medium in black clear-bottom 96-well plates (Corning, 3063). After incubation overnight, the medium was replaced with 90 μL / well of serum-free OptiMEM medium (Gibco, 31985-062). Medium, PF-06446846 hydrochloride, berberine, or the test compound was added to the medium at 10 μL / well. After 24 hours, the ATP level of the cells was measured using the CellTiter-Glo® 2.0 Assay (Promega, G9242).

[0158] ELISA assay HepG2 cells were plated at 40,000 cells / well in a flat-bottom 96-well plate (Corning, 3599) with 100 μL of growth medium. After overnight incubation, the medium was replaced with serum-free OptiMEM medium (Gibco, 31985-062) at 90 μL / well. Medium, PF-06446846 hydrochloride, berberine, or the test compound was added to the culture medium at 10 μL / well. After 24 hours, the medium was collected and 10 μL of the medium was subjected to PCSK9 ELISA (R&D Systems, SPC900).

[0159] RNA extraction and quantitative reverse transcription PCR (RT-Q-PCR) analysis Cells were cultured in growth medium and treated with medium, berberine, or the test compound for 24 hours according to the above method. RNA was extracted using the Total RNA mini Kit (Tiangen, Beijing, China) according to the manufacturer's instructions. Reverse transcription was performed using the High-Capacity cDNA Reverse Transcription Kit (Thermo Fisher Scientific). Quantitative real-time PCR was performed using a reaction mixture containing cDNA, specific primers [PCSK9, 5'-GCTGAGCTGCTCCAGTTTCT-3' (forward) and 5'-AATGGCGTAGACACCCTCAC-3' (reverse); GAPDH, 5'-CATGAGAAGTATGACAACAGCCT-3' (forward) and 5'-AGTCCTTCCACGATACCAAAGT-3' (reverse)], and Maxima SYBR Green / ROX qPCR Master Mix (Thermo Fisher Scientific). PCR amplification was performed on a real-time PCR system. The conditions for real-time PCR were 37°C for 10 min; 95°C for 10 min; 95°C for 15 s, 60°C for 30 s, 72°C for 30 s, for 40 cycles. The amount of mRNA in the same sample was normalized to the GAPDH level.

Table 8-1

Table 8-2

[0160] Measurement of Dil-LDL uptake HepG2 cells were maintained in MEM supplemented with 10% FBS. Cells were seeded in black 96-well plates at a density of 1×10 4 cells per well and grown to 70 - 80% confluence. Subsequently, the cells were switched to serum-free Opti-MEM for 1 hour and then incubated with 10 μM berberine or the compound of the present invention for 20 hours. Next, 20 μg / mL of Dil-LDL was added and the incubation was continued for an additional 4 hours at 37°C in the dark. The cells were washed three times with PBS and LDL uptake was measured with a fluorescence plate reader at an excitation wavelength of 520 nm and an emission wavelength of 580 nm. [Table 9]

[0161] Although the present invention has been described in detail with reference to preferred embodiments, the specific embodiments of the present invention are not limited to these descriptions. Those skilled in the art will understand that various simple deductions or substitutions can be made without departing from the spirit of the present invention, and these should also be considered to be within the scope of the present invention.

Claims

1. A compound represented by formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate or isotope variant thereof, and mixtures thereof, provided that 【Chemical 1】 where Ring A is C ３－７ cycloalkyl, 3- to 7-membered heterocyclyl, or C ６－１０ selected from the group consisting of aryl; Ring B is C ３－７ cycloalkyl, 3- to 7-membered heterocyclyl, C ６－１０ aryl, or 5- to 10-membered heteroaryl, and is selected from the group consisting of; L １ is selected from the group consisting of a bond, -O-, -C(O)-, -CR'R''-, -CR'R''-CR'R''- or -CR'R''-CR'R''-CR'R''-; L ２ is selected from the group consisting of a bond, -C(O)-, -CR'R''-, -CR'R''-CR'R''- or -CR'R''-CR'R''-CR'R''-; Y is selected from the group consisting of O, S, NH or CH ２ and is selected from the group consisting of; R １ is selected from the group consisting of H, -C(O)R ａ , -C(O)OR ａ , -C(O)NR ｂ R ｃ , C １－６ alkyl, C １－６ haloalkyl, C ３－７ cycloalkyl, 3- to 7-membered heterocyclyl, C ６－１０ aryl, or 5- to 10-membered heteroaryl; R ２ is selected from the group consisting of H, C １－６ alkyl, or C １－６ haloalkyl; R ｓ１ is selected from the group consisting of H, halogen, -CN, -NO ２ , -OR ａ , -SR ａ , -NR ｂ R ｃ , -C(O)R ａ , -C(O)OR ａ , -C(O)NR ｂ R ｃ , C １－６ alkyl, C １－６ haloalkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ３－７ cycloalkyl, 3- to 7-membered heterocyclyl, C ６－１０ aryl, or 5- to 10-membered heteroaryl; R ｓ２ is selected from the group consisting of H, halogen, -CN, -NO ２ , -OR ａ , -SR ａ , -NR ｂ R ｃ , -C(O)R ａ , -C(O)OR ａ , -C(O)NR ｂ R ｃ , C １－６ alkyl, C １－６ haloalkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ３－７ cycloalkyl, 3- to 7-membered heterocyclyl, C ６－１０ aryl, or 5- to 10-membered heteroaryl; R ｓ３ is selected from the group consisting of H, halogen, -CN, -NO ２ , -OR ａ , -SR ａ , -NR ｂ R ｃ , -C(O)R ａ , -C(O)OR ａ , -C(O)NR ｂ R ｃ , C １－６ alkyl, C １－６ haloalkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ３－７ cycloalkyl, 3- to 7-membered heterocyclyl, C ６－１０ aryl, or 5- to 10-membered heteroaryl; R ｓ４ is selected from the group consisting of H, halogen, -CN, -NO ２ , -OR ａ , -SR ａ , -NR ｂ R ｃ , -C(O)R ａ , -C(O)OR ａ , -C(O)NR ｂ R ｃ , C １－６ alkyl, C １－６ haloalkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ３－７ cycloalkyl, 3- to 7-membered heterocyclyl, C ６－１０ aryl, or 5- to 10-membered heteroaryl; m = 0, 1, 2, 3, 4 or 5; n = 0, 1, 2, 3 or 4; p = 0, 1, 2, 3, 4, 5, 6, 7 or 8; q = 0, 1, 2, 3, 4 or 5; here R' and R'' are each independently H, halogen, -OR ａ , -SR ａ , -NR ｂ R ｃ , -C(O)R ａ , -C(O)OR ａ , -C(O)NR ｂ R ｃ , C １－６ alkyl, C １－６ haloalkyl, C ２－６ alkenyl, or C ２－６ alkynyl selected from the group consisting of; R ａ is 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- to 7-membered heterocyclyl, C ６－１０ aryl, or 5- to 10-membered heteroaryl; 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- to 7-membered heterocyclyl, C ６－１０ aryl, or 5- to 10-membered heteroaryl; or, R ｂ , R ｃ together with the N atom form a 3- to 7-membered heterocyclyl; Here, Y, R １ , R ２ , R ｓ１ , R ｓ２ , R ｓ３ and R ｓ４ each may be substituted with 1, 2 or 3 R groups, where R is independently H, -OH, halogen, -NO ２ , carbonyl, -L-CN, -L-OR ａ , -L-SR ａ , -L-NR ｂ R ｃ , -L-C(O)R ａ , -L-C(S)R ａ , -L-C(O)OR ａ , -L-C(S)OR ａ , -L-C(O)-NR ｂ R ｃ , -L-C(S)-NR ｂ R ｃ , -L-O-C(O)R ａ , -L-O-C(S)R ａ , -L-N(R ｂ )-C(O)-R ａ , -L-N(R ｂ )-C(S)-R ａ , -L-S(O) ｘ R ａ , -L-S(O) ｘ OR ａ , -L-S(O) ｘ NR ｂ R ｃ , -L-N(R ｂ )-S(O) ｘ -R ａ , -L-N(R ｂ )-S(O) ｘ -NR ｂ R ｃ , -L-N(R ｂ )-C(O)OR ａ , -L-N(R ｂ )-C(S)OR ａ , -L-O-C １－６ alkylene-OR ａ , -L-C(O)-C １－６ alkylene-NR ｂ R ｃ , -L-N(R ｂ )-C(O)-NR ｂ R ｃ 、 -L-N(R ｂ )-C(S)-NR ｂ R ｃ 、 -L-O-C(O)-NR ｂ R ｃ 、 -L-O-C(S)-NR ｂ R ｃ 、 C １－６ alkyl, C １－６ haloalkyl, C ２－６ alkenyl, C ２－６ alkynyl, -L-C ３－７ cycloalkyl, -L-3- to 7-membered heterocyclyl, -L-C ６－１０ aryl, or -L-5- to 10-membered heteroaryl, selected from the group consisting of; wherein said C １－６ alkyl, C １－６ haloalkyl, C ２－６ alkenyl, C ２－６ alkynyl, -L-C ３－７ cycloalkyl, -L-3- to 7-membered heterocyclyl, -L-C ６－１０ aryl, or -L-5- to 10-membered heteroaryl are each, -L-CN, -NO ２ , carbonyl, -L-OR ａ , -L-SR ａ , -L-NR ｂ R ｃ , -L-C(O)R ａ , -L-C(S)R ａ , -L-C(O)OR ａ , -L-C(S)OR ａ , -L-C(O)-NR ｂ R ｃ , -L-C(S)-NR ｂ R ｃ , -L-O-C(O)R ａ , -L-O-C(S)R ａ , -L-N(R ｂ ), -C(O)-R ａ , -L-N(R ｂ ), -C(S)-R ａ , -L-S(O) ｘ R ａ , -L-S(O) ｘ OR ａ , -L-S(O) ｘ NR ｂ R ｃ , -L-N(R ｂ ), -S(O) ｘ -R ａ , -L-N(R ｂ ), -S(O) ｘ -NR ｂ R ｃ , -L-N(R ｂ ), -C(O)OR ａ , -L-N(R ｂ ), -C(S)OR ａ , -L-O-C １－６ alkylene-OR ａ , -L-C(O)-C １－６ alkylene-NR ｂ R ｃ , -L-N(R ｂ ), -C(O)-NR ｂ R ｃ , -L-N(R ｂ ), -C(S)-NR ｂ R ｃ , -L-O-C(O)-NR ｂ R ｃ , or -L-O-C(S)-NR ｂ R ｃ optionally further substituted by one or more groups selected from the group consisting of; L is selected from the group consisting of a chemical bond, -C １－６ alkylene-, -C ２－６ alkenylene- or -C ２－６ alkynylene-; x = 0, 1 or 2, A compound represented by formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate or isotope variant thereof, and mixtures thereof.

2. The compound is a compound represented by formula (II-1) to (II-4), where [Chemical Formula 2] here X is O, S, NH or CH ２ selected from the group consisting of; R ３ is selected from the group consisting of H, halogen, -CN, -NO ２ , -OR ａ , -SR ａ , -NR ｂ R ｃ , -C(O)R ａ , -C(O)OR ａ , -C(O)NR ｂ R ｃ , C １－６ alkyl, C １－６ haloalkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ３－７ cycloalkyl, 3- to 7-membered heterocyclyl, C ６－１０ aryl, or 5- to 10-membered heteroaryl; R ４ is selected from the group consisting of H, halogen, -CN, -NO ２ , -OR ａ , -SR ａ , -NR ｂ R ｃ , -C(O)R ａ , -C(O)OR ａ , -C(O)NR ｂ R ｃ , C １－６ alkyl, C １－６ haloalkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ３－７ cycloalkyl, 3- to 7-membered heterocyclyl, C ６－１０ aryl, or 5- to 10-membered heteroaryl; Alternatively, R ３ and R ４ are linked to form C ３－７ cycloalkyl, 3- to 7-membered heterocyclyl, C ６－１０ aryl, or 5- to 10-membered heteroaryl; R ５ is selected from the group consisting of H, halogen, -CN, -NO ２ , -OR ａ , -SR ａ , -NR ｂ R ｃ , C １－６ alkyl, C １－６ haloalkyl, C ２－６ alkenyl, or C ２－６ alkynyl; R ６ is selected from the group consisting of H, halogen, -CN, -NO ２ , -OR ａ , -SR ａ , -NR ｂ R ｃ , C １－６ alkyl, C １－６ haloalkyl, C ２－６ alkenyl, or C ２－６ alkynyl; Alternatively, R ５ and R ４ are linked to form C ３－７ cycloalkyl, 3- to 7-membered heterocyclyl, C ６－１０ aryl, or 5- to 10-membered heteroaryl; the other variables are as defined in claim 1, The compound represented by formula (I) according to claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate or isotope variant thereof, and mixtures thereof.

3. The compound is a compound represented by formula (III-1) to (III-3), where 【Chemical Formula 3】 the variables are as defined in claim 1, The compound represented by formula (I) according to claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate or isotope variant thereof, and mixtures thereof.

4. The compound is a compound represented by formula (IV-1) to (IV-3), where 【Chemical 4】 here X is selected from the group consisting of O, S or NH; R ４ is selected from the group consisting of H, halogen, -CN, -NO ２ , -OR ａ , -SR ａ , -NR ｂ R ｃ , -C(O)R ａ , -C(O)OR ａ , -C(O)NR ｂ R ｃ , C １－６ alkyl, C １－６ haloalkyl, C ２－６ alkenyl, or C ２－６ alkynyl; R ５ is selected from the group consisting of H, halogen, -CN, -NO ２ , -OR ａ , -SR ａ , -NR ｂ R ｃ , C １－６ alkyl, C １－６ haloalkyl, C ２－６ alkenyl, or C ２－６ alkynyl; R ６ is selected from the group consisting of H, halogen, -CN, -NO ２ , -OR ａ , -SR ａ , -NR ｂ R ｃ , C １－６ alkyl, C １－６ haloalkyl, C ２－６ alkenyl, or C ２－６ alkynyl; Alternatively, R ５ and R ４ are linked to form C ６－１０ aryl, or 5- to 10-membered heteroaryl; the other variables are as defined in claim 1, The compound represented by formula (I) according to claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate or isotope variant thereof, and mixtures thereof.

5. The compound is a compound represented by the following general formula (III-1), where 【Chemical Formula 5】 here ring B is a 5- to 10-membered heteroaryl; L １ is a bond; L ２ is selected from the group consisting of a bond, -C(O)- or -CR'R''-; Y is selected from the group consisting of O, S or NH; R １ is selected from the group consisting of H, C １－６ alkyl, or C １－６ haloalkyl; R ２ is selected from the group consisting of H, C １－６ alkyl, or C １－６ haloalkyl; R ｓ１ is selected from the group consisting of H, halogen, -CN, -NO ２ , -OR ａ , -SR ａ , -NR ｂ R ｃ , C １－６ alkyl, or C １－６ haloalkyl; R ｓ２ is selected from the group consisting of H, halogen, -CN, -NO ２ , -OR ａ , -SR ａ , -NR ｂ R ｃ , C １－６ alkyl, or C １－６ haloalkyl; R ｓ３ is selected from the group consisting of H, halogen, -CN, -NO ２ , -OR ａ , -SR ａ , -NR ｂ R ｃ , C １－６ alkyl, or C １－６ haloalkyl; R ｓ４ is selected from the group consisting of H, halogen, -CN, -NO ２ , -OR ａ , -SR ａ , -NR ｂ R ｃ , C １－６ alkyl, or C １－６ haloalkyl; m = 0, 1, 2 or 3; n = 0, 1, 2 or 3; p = 0, 1, 2 or 3; q = 0, 1, 2 or 3; R’ and R’’ are each independently selected from the group consisting of H, halogen, C １－６ alkyl, or C １－６ haloalkyl; R ａ is 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- to 7-membered heterocyclyl, C ６－１０ aryl, or 5- to 10-membered heteroaryl; 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- to 7-membered heterocyclyl, C ６－１０ aryl, or 5- to 10-membered heteroaryl; or, R ｂ , R ｃ together with the N atom form a 3- to 7-membered heterocyclyl; or ring B is 【Chemical Formula 6】 selected from the group consisting of L １ is a bond; L ２ is -C(O)-; Y is O; R １ is selected from the group consisting of H, C １－６ alkyl, or C １－６ haloalkyl; R ２ is H; R ｓ１ is selected from the group consisting of H, halogen, C １－６ alkyl, or C １－６ haloalkyl; R ｓ２ is H; R ｓ３ is H; R ｓ４ is H; m = 0, 1 or 2; n = 0, 1 or 2; p = 0, 1 or 2; q = 0, 1 or 2. The compound represented by formula (I) according to claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate or isotope variant thereof, and mixtures thereof.

6. The compound is a compound represented by formula (III-2), 【Chemical Formula 7】 wherein ring B is a 5- to 10-membered heteroaryl; L １ is a bond; L ２ is selected from the group consisting of a bond, -C(O)- or -CR'R''-; Y is selected from the group consisting of O, S or NH; R １ is selected from the group consisting of H, C １－６ alkyl, or C １－６ haloalkyl; R ２ is selected from the group consisting of H, C １－６ alkyl, or C １－６ haloalkyl; R ｓ１ is selected from the group consisting of H, halogen, -CN, -NO ２ , -OR ａ , -SR ａ , -NR ｂ R ｃ , C １－６ alkyl, or C １－６ haloalkyl; R ｓ２ is selected from the group consisting of H, halogen, -CN, -NO ２ , -OR ａ , -SR ａ , -NR ｂ R ｃ , C １－６ alkyl, or C １－６ haloalkyl; R ｓ３ is selected from the group consisting of H, halogen, -CN, -NO ２ , -OR ａ , -SR ａ , -NR ｂ R ｃ , C １－６ alkyl, or C １－６ haloalkyl; R ｓ４ is selected from the group consisting of H, halogen, -CN, -NO ２ , -OR ａ , -SR ａ , -NR ｂ R ｃ , C １－６ alkyl, or C １－６ haloalkyl; m = 0, 1, 2 or 3; n = 0, 1, 2 or 3; p = 0, 1, 2 or 3; q = 0, 1, 2 or 3; R' and R'' are each independently selected from the group consisting of H, halogen, C １－６ alkyl, or C １－６ haloalkyl; R ａ is 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- to 7-membered heterocyclyl, C ６－１０ aryl, or 5- to 10-membered heteroaryl; 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- to 7-membered heterocyclyl, C ６－１０ aryl, or 5- to 10-membered heteroaryl; or, R ｂ , R ｃ together with the N atom form a 3- to 7-membered heterocyclyl; or ring B is [Chemical 8] selected from the group consisting of L １ is a bond; L ２ is -C(O)-; Y is O; R １ is selected from the group consisting of H, C １－６ alkyl, or C １－６ haloalkyl; R ２ is selected from the group consisting of H, C １－６ alkyl, or C １－６ haloalkyl; R ｓ１ is selected from the group consisting of H or halogen; R ｓ２ is H; R ｓ３ is H; R ｓ４ is H; m = 0, 1 or 2; n = 0, 1 or 2; p = 0, 1 or 2; q = 0, 1 or 2; or ring B is a 5- to 6-membered heteroaryl; L １ is a bond; L ２ is selected from the group consisting of a bond, -C(O)- or -CR'R''-; Y is selected from the group consisting of O, S or NH; R １ is C １－６ alkyl, or C １－６ haloalkyl; R ２ is H; R ｓ１ is selected from the group consisting of H, halogen, -CN, -NO ２ , -OR ａ , -SR ａ , -NR ｂ R ｃ , C １－６ alkyl, or C １－６ haloalkyl; R ｓ２ is selected from the group consisting of H, halogen, -CN, -NO ２ , -OR ａ , -SR ａ , -NR ｂ R ｃ , C １－６ alkyl, or C １－６ haloalkyl; R ｓ３ is selected from the group consisting of H, halogen, -CN, -NO ２ , -OR ａ , -SR ａ , -NR ｂ R ｃ , C １－６ alkyl, or C １－６ haloalkyl; R ｓ４ is selected from the group consisting of H, halogen, -CN, -NO ２ , -OR ａ , -SR ａ , -NR ｂ R ｃ , C １－６ alkyl, or C １－６ haloalkyl; m = 0, 1, 2 or 3; n = 0, 1, 2 or 3; p = 0, 1, 2 or 3; q = 0, 1, 2 or 3; R ａ is 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- to 7-membered heterocyclyl, C ６－１０ aryl, or 5- to 10-membered heteroaryl; 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- to 7-membered heterocyclyl, C ６－１０ aryl, or 5- to 10-membered heteroaryl; or R ｂ , R ｃ forms a 3- to 7-membered heterocyclyl together with the N atom; or ring B is: 【Chemical Formula 9】 selected from the group consisting of L １ is a bond; L ２ is -C(O)-; Y is O; R １ is C １－６ alkyl, or C １－６ haloalkyl; R ２ is H; R ｓ１ is selected from the group consisting of H or halogen; R ｓ２ is H; R ｓ３ is H; R ｓ４ is H; m = 0, 1 or 2; n = 0, 1 or 2; p = 0, 1 or 2; q = 0, 1 or 2, The compound represented by formula (I) according to claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate or isotope variant thereof, and mixtures thereof.

7. The compound is a compound represented by (III-3), 【Chemical formula 10】 wherein ring B is a 5- to 10-membered heteroaryl; L １ is -CR'R''-, -CR'R''-CR'R''- or -CR'R''-CR'R''-CR'R''-; L ２ is selected from the group consisting of a bond, -C(O)- or -CR'R''-; Y is selected from the group consisting of O, S or NH; R １ is selected from the group consisting of H, C １－６ alkyl, or C １－６ haloalkyl; R ２ is selected from the group consisting of H, C １－６ alkyl, or C １－６ haloalkyl; R ｓ１ is selected from the group consisting of H, halogen, -CN, -NO ２ , -OR ａ , -SR ａ , -NR ｂ R ｃ , C １－６ alkyl, or C １－６ haloalkyl; R ｓ２ is selected from the group consisting of H, halogen, -CN, -NO ２ , -OR ａ , -SR ａ , -NR ｂ R ｃ , C １－６ alkyl, or C １－６ haloalkyl; R ｓ３ is selected from the group consisting of H, halogen, -CN, -NO ２ , -OR ａ , -SR ａ , -NR ｂ R ｃ , C １－６ alkyl, or C １－６ haloalkyl; R ｓ４ is selected from the group consisting of H, halogen, -CN, -NO ２ , -OR ａ , -SR ａ , -NR ｂ R ｃ , C １－６ alkyl, or C １－６ haloalkyl; m = 0, 1, 2 or 3; n = 0, 1, 2 or 3; p = 0, 1, 2 or 3; q = 0, 1, 2 or 3; R' and R'' are each independently selected from the group consisting of H, halogen, C １－６ alkyl, or C １－６ haloalkyl; R ａ is 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- to 7-membered heterocyclyl, C ６－１０ aryl, or 5- to 10-membered heteroaryl; 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- to 7-membered heterocyclyl, C ６－１０ aryl, or 5- to 10-membered heteroaryl; or, R ｂ , R ｃ together with the N atom form a 3- to 7-membered heterocyclyl; or ring B is 【Chemical 11】 selected from the group consisting of L １ is -CR'R''-; L ２ is -C(O)-; Y is O; R １ is selected from the group consisting of H, C １－６ alkyl, or C １－６ haloalkyl; R ２ is selected from the group consisting of H, C １－６ alkyl, or C １－６ haloalkyl; R ｓ１ is selected from the group consisting of H, halogen, C １－６ alkyl, or C １－６ haloalkyl; R ｓ２ is H; R ｓ３ is H or halogen; R ｓ４ is H; m = 0, 1 or 2; n = 0, 1 or 2; p = 0, 1 or 2; q = 0, 1 or 2; R' and R'' are each independently selected from the group consisting of H or halogen; or ring B is a 5- to 10-membered heteroaryl; L １ is a bond; L ２ is selected from the group consisting of a bond, -C(O)- or -CR'R''-; Y is selected from the group consisting of O, S or NH; R １ is H; R ２ is H; R ｓ１ is selected from the group consisting of H, halogen, -CN, -NO ２ , -OR ａ , -SR ａ , -NR ｂ R ｃ , C １－６ alkyl, or C １－６ haloalkyl; R ｓ２ is selected from the group consisting of H, halogen, -CN, -NO ２ , -OR ａ , -SR ａ , -NR ｂ R ｃ , C １－６ alkyl, or C １－６ haloalkyl; R ｓ３ is selected from the group consisting of H, halogen, -CN, -NO ２ , -OR ａ , -SR ａ , -NR ｂ R ｃ , C １－６ alkyl, or C １－６ haloalkyl; R ｓ４ is selected from the group consisting of H, halogen, -CN, -NO ２ , -OR ａ , -SR ａ , -NR ｂ R ｃ , C １－６ alkyl, or C １－６ haloalkyl; m = 0, 1, 2 or 3; n = 0, 1, 2 or 3; p = 0, 1, 2 or 3; q = 0, 1, 2 or 3; R ａ is 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- to 7-membered heterocyclyl, C ６－１０ aryl, or 5- to 10-membered heteroaryl; 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- to 7-membered heterocyclyl, C ６－１０ aryl, or 5- to 10-membered heteroaryl; or, R ｂ , R ｃ together with the N atom form a 3- to 7-membered heterocyclyl; or ring B is 【Chemical Formula 12】 selected from the group consisting of L １ is a bond; L ２ is -C(O)-; Y is O; R １ is H; R ２ is H; R ｓ１ is selected from the group consisting of H, halogen, -CN, -NO ２ , -OR ａ , -SR ａ , -NR ｂ R ｃ , C １－６ alkyl, or C １－６ haloalkyl; R ｓ２ is H; R ｓ３ is H; R ｓ４ is H; m = 0, 1 or 2; n = 0, 1 or 2; p = 0, 1 or 2; q = 0, 1 or 2; R ａ is independently selected from the group consisting of H, C １－６ alkyl, or C １－６ haloalkyl; R ｂ and R ｃ are each independently selected from the group consisting of H, C １－６ alkyl, or C １－６ haloalkyl; or ring B is a 5- or 6-membered heteroaryl; L １ is -CR'R''-, -CR'R''-CR'R''- or -CR'R''-CR'R''-CR'R''-; L ２ is selected from the group consisting of a bond, -C(O)- or -CR'R''-; Y is selected from the group consisting of O, S or NH; R １ is C １－６ alkyl, or C １－６ haloalkyl; R ２ is H; R ｓ１ is selected from the group consisting of H, halogen, -CN, -NO ２ , -OR ａ , -SR ａ , -NR ｂ R ｃ , C １－６ alkyl, or C １－６ haloalkyl; R ｓ２ is selected from the group consisting of H, halogen, -CN, -NO ２ , -OR ａ , -SR ａ , -NR ｂ R ｃ , C １－６ alkyl, or C １－６ haloalkyl; R ｓ３ is selected from the group consisting of H, halogen, -CN, -NO ２ , -OR ａ , -SR ａ , -NR ｂ R ｃ , C １－６ alkyl, or C １－６ haloalkyl; R ｓ４ is selected from the group consisting of H, halogen, -CN, -NO ２ , -OR ａ , -SR ａ , -NR ｂ R ｃ , C １－６ alkyl, or C １－６ haloalkyl; m = 0, 1, 2 or 3; n = 0, 1, 2 or 3; p = 0, 1, 2 or 3; q = 0, 1, 2 or 3; R' and R'' are each independently selected from the group consisting of H, halogen, C １－６ alkyl, or C １－６ haloalkyl; R ａ is 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- to 7-membered heterocyclyl, C ６－１０ aryl, or 5- to 10-membered heteroaryl; 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- to 7-membered heterocyclyl, C ６－１０ aryl, or 5- to 10-membered heteroaryl; or, R ｂ , R ｃ together with the N atom form a 3- to 7-membered heterocyclyl; or ring B is selected from the group consisting of 【Chemical 13】 Y is O; L １ is -CR'R''-; L ２ is -C(O)-; m = 0, 1 or 2; R １ is C １－６ alkyl, or C １－６ haloalkyl; R ２ is H; R ｓ１ is selected from the group consisting of H or halogen; R ｓ２ is H; R ｓ３ is H or halogen; R ｓ４ is H; n = 0, 1 or 2; p = 0, 1 or 2; q = 0, 1 or 2; R' and R'' are each independently selected from the group consisting of H or halogen, a compound represented by formula (I) according to claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate or isotope variant thereof, and mixtures thereof.

8. the compound is a compound represented by formula (IV-1), where 【Chemical Formula 14】 X is selected from the group consisting of O, S or NH; m = 0, 1, 2 or 3; R ４ 、 R ５ and R ６ are linked to the atoms to which they are attached to form a C ６－１０ aryl, or 5- to 10-membered heteroaryl; L １ is a bond; R １ is C １－６ alkyl, or C １－６ haloalkyl; R ｓ１ is selected from the group consisting of H, halogen, -CN, -NO ２ , -OR ａ , -SR ａ , -NR ｂ R ｃ , C １－６ alkyl, or C １－６ haloalkyl; R ｓ２ is selected from the group consisting of H, halogen, -CN, -NO ２ , -OR ａ , -SR ａ , -NR ｂ R ｃ , C １－６ alkyl, or C １－６ haloalkyl; R ｓ３ is selected from the group consisting of H, halogen, -CN, -NO ２ , -OR ａ , -SR ａ , -NR ｂ R ｃ , C １－６ alkyl, or C １－６ haloalkyl; R ｓ４ is selected from the group consisting of H, halogen, -CN, -NO ２ , -OR ａ , -SR ａ , -NR ｂ R ｃ , C １－６ alkyl, or C １－６ haloalkyl; n = 0, 1, 2 or 3; p = 0, 1, 2 or 3; q = 0, 1, 2 or 3; or R ａ is 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- to 7-membered heterocyclyl, C ６－１０ aryl, or 5- to 10-membered heteroaryl; 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- to 7-membered heterocyclyl, C ６－１０ aryl, or 5- to 10-membered heteroaryl; or R ｂ , R ｃ together with the N atom form a 3- to 7-membered heterocyclyl; X is NH; m = 0, 1 or 2; R ４ 、 R ５ and R ６ are linked to the atoms to which they are attached to form phenyl; L １ is a bond; R １ is C １－６ alkyl, or C １－６ haloalkyl; R ｓ１ is selected from the group consisting of H or halogen; R ｓ２ is H; R ｓ３ is H; R ｓ４ is H; n = 0, 1 or 2; p = 0, 1 or 2; q = 0, 1 or 2; or X is selected from the group consisting of O, S or NH; m = 0, 1, 2 or 3; L １ is a bond; R １ is H; R ４ is selected from the group consisting of H, halogen, -CN, -NO ２ , -OR ａ , -SR ａ , -NR ｂ R ｃ , C １－６ alkyl, or C １－６ haloalkyl; R ５ is selected from the group consisting of H, halogen, -CN, -NO ２ , -OR ａ , -SR ａ , -NR ｂ R ｃ , C １－６ alkyl, or C １－６ haloalkyl; R ６ is selected from the group consisting of H, halogen, -CN, -NO ２ , -OR ａ , -SR ａ , -NR ｂ R ｃ , C １－６ alkyl, or C １－６ haloalkyl; R ｓ１ is selected from the group consisting of H, halogen, -CN, -NO ２ , -OR ａ , -SR ａ , -NR ｂ R ｃ , C １－６ alkyl, or C １－６ haloalkyl; R ｓ２ is selected from the group consisting of H, halogen, -CN, -NO ２ , -OR ａ , -SR ａ , -NR ｂ R ｃ , C １－６ alkyl, or C １－６ haloalkyl; R ｓ３ is selected from the group consisting of H, halogen, -CN, -NO ２ , -OR ａ , -SR ａ , -NR ｂ R ｃ , C １－６ alkyl, or C １－６ haloalkyl; R ｓ４ is selected from the group consisting of H, halogen, -CN, -NO ２ , -OR ａ , -SR ａ , -NR ｂ R ｃ , C １－６ alkyl, or C １－６ haloalkyl; n = 0, 1, 2 or 3; p = 0, 1, 2 or 3; q = 0, 1, 2 or 3; or R ａ is 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- to 7-membered heterocyclyl, C ６－１０ aryl, or 5- to 10-membered heteroaryl; 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- to 7-membered heterocyclyl, C ６－１０ aryl, or 5- to 10-membered heteroaryl; or R ｂ , R ｃ together with the N atom form a 3- to 7-membered heterocyclyl; X is NH; m = 0, 1 or 2; L １ is a bond; R １ is H; R ４ is selected from the group consisting of H or halogen; R ５ is selected from the group consisting of H or halogen; R ６ is selected from the group consisting of H or halogen; R ｓ１ is selected from the group consisting of H, halogen, C １－６ alkyl, or C １－６ haloalkyl; R ｓ２ is H; R ｓ３ is H; R ｓ４ is H; n = 0, 1 or 2; p = 0, 1 or 2; q = 0, 1 or 2 a compound represented by formula (I) according to claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate or isotope variant thereof, and mixtures thereof.

9. the compound is a compound represented by formula (IV-2), X is selected from the group consisting of O, S or NH; 【Chemical Formula 15】 m = 0, 1, 2 or 3; R ４ 、 R ５ and R ６ are linked to the atoms to which they are attached to form C ６－１０ aryl, or 5- to 10-membered heteroaryl; L １ is a bond; R １ is selected from the group consisting of H, C １－６ alkyl, or C １－６ haloalkyl; or R １ is H; R ｓ１ is selected from the group consisting of H, halogen, -CN, -NO ２ , -OR ａ , -SR ａ , -NR ｂ R ｃ , C １－６ alkyl, or C １－６ haloalkyl; R ｓ２ is selected from the group consisting of H, halogen, -CN, -NO ２ , -OR ａ , -SR ａ , -NR ｂ R ｃ , C １－６ alkyl, or C １－６ haloalkyl; R ｓ３ is selected from the group consisting of H, halogen, -CN, -NO ２ , -OR ａ , -SR ａ , -NR ｂ R ｃ , C １－６ alkyl, or C １－６ haloalkyl; R ｓ４ is selected from the group consisting of H, halogen, -CN, -NO ２ , -OR ａ , -SR ａ , -NR ｂ R ｃ , C １－６ alkyl, or C １－６ haloalkyl; n = 0, 1, 2 or 3; p = 0, 1, 2 or 3; q = 0, 1, 2 or 3; or R ａ is 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- to 7-membered heterocyclyl, C ６－１０ aryl, or 5- to 10-membered heteroaryl; 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- to 7-membered heterocyclyl, C ６－１０ aryl, or 5- to 10-membered heteroaryl; or R ｂ , R ｃ together with the N atom form a 3- to 7-membered heterocyclyl; X is NH; m = 0, 1 or 2; R ４ 、 R ５ and R ６ are linked to the atoms to which they are attached to form phenyl; L １ is a bond; R １ is selected from the group consisting of H, C １－６ alkyl, or C １－６ haloalkyl; or R １ is H; R ｓ１ is selected from the group consisting of H or halogen; R ｓ２ is H; R ｓ３ is H; R ｓ４ is H; n = 0, 1 or 2; p = 0, 1 or 2; q = 0, 1 or 2; or X is selected from the group consisting of O, S or NH; m = L １ is a bond; R １ is C １－６ alkyl, or C １－６ haloalkyl; R ４ is selected from the group consisting of H, halogen, -CN, -NO ２ , -OR ａ , -SR ａ , -NR ｂ R ｃ , C １－６ alkyl, or C １－６ haloalkyl; R ５ is selected from the group consisting of H, halogen, -CN, -NO ２ , -OR ａ , -SR ａ , -NR ｂ R ｃ , C １－６ alkyl, or C １－６ haloalkyl; R ６ is selected from the group consisting of H, halogen, -CN, -NO ２ , -OR ａ , -SR ａ , -NR ｂ R ｃ , C １－６ alkyl, or C １－６ haloalkyl; R ｓ１ is selected from the group consisting of H, halogen, -CN, -NO ２ , -OR ａ , -SR ａ , -NR ｂ R ｃ , C １－６ alkyl, or C １－６ haloalkyl; R ｓ２ is selected from the group consisting of H, halogen, -CN, -NO ２ , -OR ａ , -SR ａ , -NR ｂ R ｃ , C １－６ alkyl, or C １－６ haloalkyl; R ｓ３ is selected from the group consisting of H, halogen, -CN, -NO ２ , -OR ａ , -SR ａ , -NR ｂ R ｃ , C １－６ alkyl, or C １－６ haloalkyl; R ｓ４ is selected from the group consisting of H, halogen, -CN, -NO ２ , -OR ａ , -SR ａ , -NR ｂ R ｃ , C １－６ alkyl, or C １－６ haloalkyl; ​ ​ p = 0, 1, 2 or 3; q = 0, 1, 2 or 3; R ａ is 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- to 7-membered heterocyclyl, C ６－１０ aryl, or 5- to 10-membered heteroaryl; 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- to 7-membered heterocyclyl, C ６－１０ aryl, or 5- to 10-membered heteroaryl; or R ｂ , R ｃ forms a 3- to 7-membered heterocyclyl together with the N atom; or X is O; L １ is a bond; R １ is C １－６ alkyl, or C １－６ haloalkyl; R ４ is selected from the group consisting of H or halogen; R ５ is selected from the group consisting of H or halogen; R ６ is selected from the group consisting of H or a halogen; R ｓ１ is selected from the group consisting of H or halogen; R ｓ２ is H; R ｓ３ is H; R ｓ４ is H; m = 0, 1 or 2; n = 0, 1 or 2; p = 0, 1 or 2; q = 0, 1 or 2, a compound represented by formula (I) according to claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate or isotope variant thereof, and mixtures thereof.

10. the compound is a compound represented by formula (IV-3), 【Chemical 16】 where X is selected from the group consisting of O, S or NH; R ４ 、 R ５ and R ６ are linked to the atoms to which they are attached to form C ６－１０ aryl, or 5- to 10-membered heteroaryl; L １ is -CR'R''-, -CR'R''-CR'R''- or -CR'R''-CR'R''-CR'R''-; R １ is H, C １－６ alkyl, or C １－６ haloalkyl; R ｓ１ is selected from the group consisting of H, halogen, -CN, -NO ２ , -OR ａ , -SR ａ , -NR ｂ R ｃ , C １－６ alkyl, or C １－６ haloalkyl; R ｓ２ is selected from the group consisting of H, halogen, -CN, -NO ２ , -OR ａ , -SR ａ , -NR ｂ R ｃ , C １－６ alkyl, or C １－６ haloalkyl; R ｓ３ is selected from the group consisting of H, halogen, -CN, -NO ２ , -OR ａ , -SR ａ , -NR ｂ R ｃ , C １－６ alkyl, or C １－６ haloalkyl; R ｓ４ is selected from the group consisting of H, halogen, -CN, -NO ２ , -OR ａ , -SR ａ , -NR ｂ R ｃ , C １－６ alkyl, or C １－６ haloalkyl; m = 0, 1, 2 or 3; n = 0, 1, 2 or 3; p = 0, 1, 2 or 3; q = 0, 1, 2 or 3; R' and R'' are each independently selected from the group consisting of H, halogen, C １－６ alkyl, or C １－６ haloalkyl; R ａ is 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- to 7-membered heterocyclyl, C ６－１０ aryl, or 5- to 10-membered heteroaryl; 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- to 7-membered heterocyclyl, C ６－１０ aryl, or 5- to 10-membered heteroaryl; or, R ｂ , R ｃ together with the N atom form a 3- to 7-membered heterocyclyl; or X is NH; R ４ , R ５ and R ６ are linked to the atoms to which they are attached to form phenyl; L １ is -CR'R''-; R １ is H, C １－６ alkyl, or C １－６ haloalkyl; R ｓ１ is selected from the group consisting of H, halogen, C １－６ alkyl, or C １－６ haloalkyl; R ｓ２ is H; R ｓ３ is H or halogen; R ｓ４ is H; m = 0, 1 or 2; n = 0, 1 or 2; p = 0, 1 or 2; q = 0, 1 or 2; R’ and R’’ are each independently selected from the group consisting of H or halogen; or X is selected from the group consisting of O, S or NH; L １ is a bond; R １ is H; R ４ is selected from the group consisting of H, halogen, -CN, -NO ２ , -OR ａ , -SR ａ , -NR ｂ R ｃ , C １－６ alkyl, or C １－６ haloalkyl; R ５ is selected from the group consisting of H, halogen, -CN, -NO ２ , -OR ａ , -SR ａ , -NR ｂ R ｃ , C １－６ alkyl, or C １－６ haloalkyl; R ６ is selected from the group consisting of H, halogen, -CN, -NO ２ , -OR ａ , -SR ａ , -NR ｂ R ｃ , C １－６ alkyl, or C １－６ haloalkyl; Alternatively, R ４ , R ５ and R ６ are linked to the atoms to which they are attached to form a C ６－１０ aryl, or 5- to 10-membered heteroaryl; R ｓ１ is selected from the group consisting of H, halogen, -CN, -NO ２ , -OR ａ , -SR ａ , -NR ｂ R ｃ , C １－６ alkyl, or C １－６ haloalkyl; R ｓ２ is selected from the group consisting of H, halogen, -CN, -NO ２ , -OR ａ , -SR ａ , -NR ｂ R ｃ , C １－６ alkyl, or C １－６ haloalkyl; R ｓ３ is selected from the group consisting of H, halogen, -CN, -NO ２ , -OR ａ , -SR ａ , -NR ｂ R ｃ , C １－６ alkyl, or C １－６ haloalkyl; R ｓ４ is selected from the group consisting of H, halogen, -CN, -NO ２ , -OR ａ , -SR ａ , -NR ｂ R ｃ , C １－６ alkyl, or C １－６ haloalkyl; m = 0, 1, 2 or 3; n = 0, 1, 2 or 3; p = 0, 1, 2 or 3; q = 0, 1, 2 or 3; R ａ is 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- to 7-membered heterocyclyl, C ６－１０ aryl, or 5- to 10-membered heteroaryl; 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- to 7-membered heterocyclyl, C ６－１０ aryl, or 5- to 10-membered heteroaryl; or, R ｂ , R ｃ together with the N atom form a 3- to 7-membered heterocyclyl; or X is NH; L １ is a bond; R １ is H; R ４ is selected from the group consisting of H or halogen; R ５ is selected from the group consisting of H or halogen; R ６ is selected from the group consisting of H or halogen; Alternatively, R ４ , R ５ and R ６ are linked to the atoms to which they are attached to form phenyl; R ｓ１ is selected from the group consisting of H, halogen, -CN, -NO ２ , -OR ａ , -SR ａ , -NR ｂ R ｃ , C １－６ alkyl, or C １－６ haloalkyl; R ｓ２ is H; R ｓ３ is H; R ｓ４ is H; m = 0, 1 or 2; n = 0, 1 or 2; p = 0, 1 or 2; q = 0, 1 or 2; R ａ is independently selected from the group consisting of H, C １－６ alkyl, or C １－６ haloalkyl; R ｂ and R ｃ are each independently selected from the group consisting of H, C １－６ alkyl, or C １－６ haloalkyl; or X is selected from the group consisting of O, S or NH; L １ is -CR'R''-, -CR'R''-CR'R''- or -CR'R''-CR'R''-CR'R''-; R １ is C １－６ alkyl, or C １－６ haloalkyl; R ４ is selected from the group consisting of H, halogen, -CN, -NO ２ , -OR ａ , -SR ａ , -NR ｂ R ｃ , C １－６ alkyl, or C １－６ haloalkyl; R ５ is selected from the group consisting of H, halogen, -CN, -NO ２ , -OR ａ , -SR ａ , -NR ｂ R ｃ , C １－６ alkyl, or C １－６ haloalkyl; R ６ is selected from the group consisting of H, halogen, -CN, -NO ２ , -OR ａ , -SR ａ , -NR ｂ R ｃ , C １－６ alkyl, or C １－６ haloalkyl; R ｓ１ is selected from the group consisting of H, halogen, -CN, -NO ２ , -OR ａ , -SR ａ , -NR ｂ R ｃ , C １－６ alkyl, or C １－６ haloalkyl; R ｓ２ is selected from the group consisting of H, halogen, -CN, -NO ２ , -OR ａ , -SR ａ , -NR ｂ R ｃ , C １－６ alkyl, or C １－６ haloalkyl; R ｓ３ is selected from the group consisting of H, halogen, -CN, -NO ２ , -OR ａ , -SR ａ , -NR ｂ R ｃ , C １－６ alkyl, or C １－６ haloalkyl; R ｓ４ is selected from the group consisting of H, halogen, -CN, -NO ２ , -OR ａ , -SR ａ , -NR ｂ R ｃ , C １－６ alkyl, or C １－６ haloalkyl; m = 0, 1, 2 or 3; n = 0, 1, 2 or 3; p = 0, 1, 2 or 3; q = 0, 1, 2 or 3; R' and R'' are each independently selected from the group consisting of H, halogen, C １－６ alkyl, or C １－６ haloalkyl; R ａ is 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- to 7-membered heterocyclyl, C ６－１０ aryl, or 5- to 10-membered heteroaryl; 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- to 7-membered heterocyclyl, C ６－１０ aryl, or 5- to 10-membered heteroaryl; or, R ｂ , R ｃ together with the N atom form a 3- to 7-membered heterocyclyl; or X is O; L １ is -CR'R''-; R １ is C １－６ alkyl, or C １－６ haloalkyl; R ４ is selected from the group consisting of H or halogen; R ５ is selected from the group consisting of H or halogen; R ６ is selected from the group consisting of H or halogen; R ｓ１ is selected from the group consisting of H or halogen; R ｓ２ is H; R ｓ３ is H or halogen; R ｓ４ is H; m = 0, 1 or 2; n = 0, 1 or 2; p = 0, 1 or 2; q = 0, 1 or 2; R’ and R’’ are each independently selected from the group consisting of H or halogen, a compound represented by formula (I) according to claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate or isotope variant thereof, and mixtures thereof.

11. the compound is 【Chemical 17】 【Chemical 18】 【Chemical 19】 selected from the group consisting of a compound represented by formula (I) according to claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate or isotope variant thereof, and mixtures thereof.

12. A pharmaceutical composition comprising the compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate or isotope variant thereof, and a pharmaceutically acceptable excipient.

13. A pharmaceutical composition according to claim 12, further comprising one or more other therapeutic agents.

14. A pharmaceutical composition for treating and / or preventing a disease mediated by PCSK9, A pharmaceutical composition comprising the compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate or isotope variant thereof.

15. The pharmaceutical composition according to claim 14, wherein the disease mediated by PCSK9 is selected from the group consisting of atherosclerosis, dyslipidemia, hypertriglyceridemia, hypertension, heart failure, arrhythmia, low HDL level, high LDL level, sudden death, stable angina, coronary artery disease, acute myocardial infarction, secondary prevention of myocardial infarction, cardiomyopathy, endocarditis, type 2 diabetes, insulin resistance, impaired glucose tolerance, hypercholesterolemia (including heterozygous and homozygous familial hypercholesterolemia), stroke, hyperlipidemia, hyperlipoproteinemia, chronic kidney disease, intermittent claudication, hyperphosphatemia, carotid atherosclerotic disease, peripheral arterial disease, diabetic nephropathy, hypercholesterolemia in HIV infection, acute coronary syndrome (ACS), non-alcoholic fatty liver disease, obstructive arterial disease, cerebral arteriosclerosis, cerebrovascular disease, myocardial ischemia, non-alcoholic fatty liver disease (NLLD), non-alcoholic steatohepatitis (NASH) and diabetic autonomic neuropathy.

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