Cyclic peptide analog and preparation method therefor and use thereof

Abstract

Provided is a compound represented by formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof. The compound has the activity of treating cardiovascular diseases related to dyslipidemia, and significantly antagonizing PCSK9 in a subject.

Description

Cyclic peptide analogs, methods of making and uses thereof

[0001] Cross-reference to related applications

[0002] This application claims priority to and the benefit of Chinese Patent Application No. 202411074013.3, filed August 6, 2024, and Chinese Patent Application No. 202510796091.2, filed June 13, 2025, in the China National Intellectual Property Office, the disclosures of which are incorporated herein in their entireties by reference. TECHNICAL FIELD

[0003] The present application relates to the field of medicine, in particular, to a class of polypeptide derivatives, a preparation method thereof, and a pharmaceutical use. BACKGROUND

[0004] High levels of low-density lipoprotein cholesterol (LDL-C) are a major risk factor for atherosclerosis and coronary heart disease. The first-line drug for reducing LDL-C is currently statins, however, statins also have patient intolerance or do not achieve the desired effect at the accepted dose. Non-statin drugs such as cholesterol inhibitors ezetimibe combined with statins can further reduce LDL-C by 15-20%. Literature shows that PCSK9 inhibitors combined with statins have a more significant effect on reducing LDL-C, and can also overcome common side effects of statins such as muscle pain.

[0005] PCSK9, full name Proprotein Convertase Subtilisin / Kexin type 9, is a protein closely related to cholesterol regulation. It was first reported in 2003. PCSK9 is mainly synthesized in the liver and contains three unique domains that play an important role in the biological function and intracellular transport of PCSK9. The expression of PCSK9 is regulated by various factors, such as SREBP2, etc. The interaction of PCSK9 with low-density lipoprotein receptor (LDLR) is one of its main functions. It promotes its degradation in liver cells by binding to LDLR, thereby reducing the number of LDLR on the surface of liver cells, affecting the clearance of LDL-C, and possibly leading to an increase in LDL-C levels in the blood, increasing the risk of cardiovascular disease. In addition to affecting LDLR, PCSK9 can also regulate other proteins related to LDLR family members, such as ApoER2 and VLDLR, as well as other cell surface proteins, such as CD36 and ACE2, etc.

[0006] PCSK9 can play a key role in a variety of diseases, including cardiovascular disease, liver disease (such as non-alcoholic fatty liver disease NAFLD / NASH), infectious and autoimmune diseases, and neurocognitive disorders and cancer. In particular, in cardiovascular disease, PCSK9 increases the risk of disease by affecting cholesterol uptake. In addition, PCSK9 levels are significantly correlated with cholesterol, oxidized low-density lipoprotein (ox-LDL), triglycerides, and the like.

[0007] Since PCSK9 was discovered in 2003, a variety of PCSK9 inhibitors have been developed and approved, including monoclonal antibodies (such as Evolocumab, Alirocumab, and Tafolecimab) and siRNA (such as Inclisiran). These inhibitors reduce LDL-C levels in the blood by reducing PCSK9 levels, increasing the number of LDLR on the surface of liver cells, and improving the clearance rate of LDL-C, thereby exhibiting the potential to significantly reduce LDL-C and possibly reduce the risk of cardiovascular events. So far, there is no small molecule inhibitor of PCSK9 on the market, and the two products with relatively active clinical progress (MK-0616 and AZD0780) are the main products. Other small molecule products have not disclosed important clinical data in the past three years. Therefore, the development of PCSK9 inhibitors with oral properties has great research value and application prospects. SUMMARY

[0008] In a first aspect, the present application provides a compound as shown in formula (I), or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, having the following structure:

[0009] wherein,

[0010] Ring A is

[0011] X1, X2, X3, X4, X5, X 11 each independently selected from hydrogen, deuterium, halogen, nitro, amino, hydroxyl, carboxyl, cyano, alkylsulfonyl, alkyl ester, alkyl phosphine, C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-12 membered heterocyclyl, said amino, C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 The cycloalkyl group and the 3-12 membered heterocyclic group are optionally selected from one or more of the following groups: deuterium, halogen, nitro, hydroxyl, amino, hydroxyl, oxo, thio, carboxyl, cyano, alkylsulfonyl, alkyl ester, alkylphosphono, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Substituted with cycloalkyl or 3-12 membered heterocyclic groups;

[0012] Or X2, X3, together with the atoms they are attached to, form C. 3-6 cycloalkyl, C 3-6 Heterocyclic, phenyl, 5-6 membered heteroaryl, wherein the cycloalkyl, heterocyclic, phenyl, and heteroaryl groups are optionally selected from one or more groups selected from deuterium, halogen, nitro, amino, hydroxyl, oxo, thio, carboxyl, cyano, sulfonyl, ester, phosphono, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Substituents of cycloalkyl groups and 3-6 membered heterocyclic groups;

[0013] X6 is independently selected from H, -C(O)-, and -CH(R). a )C(O)-、-CH(R a )OC(O)-、-C(O)O-、 The "*" terminal indicates connection to terminal O, and the "#" terminal indicates connection to terminal X7; when X6 is H, X7 and X8 do not exist;

[0014] X7 and X9 are each independently selected from: key, -[(CHR d ) p1 OC(O)] p2 -、-[(CHR d ) p1 O] p2 -、-[(CHR d ) p1 OC(O)O] p2 -、-[(CHR d )p1 C(O)O] p2 -[(CHR d ) p O] p3 -、-[(CHR d ) p1 C(O)O] p2 -[(CHR d ) p1 OC(O)O] p3 -、-[(CHR d ) p1 OP(O)(OR e )O] p2 -、-[(CHR d ) p1 OP(O)(OR e )O] p2 -[(CHR d ) p1 OC(O)] p3 -、-[(CR d =CR d ) p3 C(O)O] p2 -[(CHR d ) p1 O] p3 -、-[(CR d =CR d ) p3 C(O)O] p2 -[(CHR d ) p1 OC(O)O] p2 -;

[0015] X8independently selected from hydrogen, C 1-6 alkyl, C 3-6 carbocyclyl, 3-6 membered heterocyclyl, said C 1-6 alkyl, C 3-6 carbocyclyl and 3-6 membered heterocyclyl optionally substituted with one or more substituents selected from R b ;

[0016] X 10 is independently selected from hydrogen, C 1-6 alkyl, said C 1-6 alkyl optionally substituted with one or more substituents selected from R c ;

[0017] p1, p2and p3are each independently selected from 0, 1, 2, 3, 4, 5;

[0018] R dIndependently selected from hydrogen, halogen, amino, cyano, nitro, hydroxyl, mercapto, C 1-6 Alkyl, C 3-6 cycloalkyl, the C 1-6 Alkyl and C 3-6 cycloalkyl groups are optionally selected from one or more of R f The substituents are replaced;

[0019] R e Independently selected from hydrogen, C 1-6 Alkyl, benzyl, the C 1-6 Alkyl and benzyl groups are optionally selected from one or more of R g The substituents are replaced;

[0020] R a R b R c R f R g Each is independently selected from hydrogen, halogen, amino, cyano, nitro, hydroxyl, mercapto, C 1-6 Alkyl, benzyl;

[0021] R1 and R2 are each independently selected from hydrogen, deuterium, and -L 1 m1 -L 2 m2 -L 3 m3 -L 4 m4 -L 5 m5 -L 6 m6 -R3, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 3-12 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 The cycloalkyl group and the 3-12 membered heterocyclic group are optionally selected from one or more of deuterium, halogen, hydroxyl, amino, hydroxyl, oxo, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-6 Substituents of cycloalkyl groups and 3-6 membered heterocyclic groups;

[0022] L 1 L 2 L 3 L 4 L 5 L 6each independently selected from: -O-, -N(R8)-, -S-, -C(O)-, -C(O)O-, -N(R8)C(O)-, -SO-, -SO2-, -SO2N(R8)-, -N(R8)C(O)O-, -OC(O)O-, -N(R8)C(O)N(R8)-, -N(R8)S(O)2N(R8)-, -S(O)(NR8)-, -S(O)(NR8)N(R8)-, C 1-6 alkylene, C 2-8 alkenylene, C 2-8 alkynylene, C 2-6 heteroalkylene, C 3-10 cycloalkylene, 4-10 membered heterocyclylene, C 6-10 arylene, 5-10 membered heteroarylene; said C 1-6 alkylene, C 2-8 alkenylene, C 2-8 alkynylene, 2-6 membered heteroalkylene, C 3-10 cycloalkylene, 4-10 membered heterocyclylene, C 6-10 arylene and 5-10 membered heteroarylene are optionally substituted with 1 to 3 substituents selected from Z1;

[0023] m1, m2, m3, m4, m5, m6 are each independently selected from 0, 1, 2, 3, and the sum of m1+m2+m3+m4+m5+m6 is less than 6;

[0024] Z1is independently selected from oxo, halo, amino, hydroxyl, nitro, cyano, -OR9, -C(O)R9, -C(O)OR9, -C(O)N(R9)2, -N(R9)2, -N(R9)C(O)R9, -N(R9)C(O)OR9, -N(R9)C(O)N(R9)2, -N(R9)S(O)2(R9), -NR9, S(O)2N(R9)2, -NR9S(O)2, O(R9), -OC(O)R9, -OC(O)OR9, -OC(O)N(R9)2, -SR9, -S(O)R9, -SF5, -S(O)(NR9)R9, -S(O)2R9, -S(O)2N(R9)2, -C(O)N(R9)S(O)2R9, -S(O)2N(R9)CR9, C 1-8 alkyl, C 1-6 alkoxy, C 2-8 alkenyl, C 2-8 alkynyl, C 3-10 cycloalkyl, 4-10 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl; said C 1-8 alkyl, C 1-6 alkoxy, C 2-8 alkenyl, C2-8 alkynyl group, C 3-10 Cycloalkyl, 4-10 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups are optionally selected from Zn, with 1 to 3 of them chosen from Zn. 1a The substituents replace it; or any two Z1 atoms together with the atoms they are attached to form C. 3-6 cycloalkyl, C 3-6 Heterocyclic groups, phenyl groups, and 5-6 membered heteroaryl groups;

[0025] Z 1a Independently selected from halogen, amino, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy;

[0026] R8 and R9 are each independently selected from hydrogen, deuterium, and C. 1-6 Alkyl, C 1-6 Alkoxy;

[0027] R3 is independently selected from -NH2, -N + H3, -N + (C 1-3 Alkyl) 3, -NH-C(O)-L 1 m1 -L 2 m2 -L 3 m3 -L 4 m4 -L 5 m5 -L 6 m6 -R4, where R4 is independently selected from -NH2, -N + H3, -N + (C 1-3 alkyl)3 or n is independently selected from 1 and 2;

[0028] R5 is independently selected from hydrogen, deuterium, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 cycloalkyl groups, 3-12 membered heterocyclic groups;

[0029] Alternatively, R2 and R5, together with the carbon atom they are attached to, can optionally be formed by one or more elements selected from deuterium, halogen, amino, hydroxyl, cyano, C. 1-6 Alkyl, C 1-6 The C substituent of the alkoxy group 3-6 cycloalkyl or C 3-6 Heterocyclic groups;

[0030] provided that when X1is H, X2is halogen, X3is H, X4is methoxy, X5is H, X6is H, X7and X8are absent, R4is hydrogen, ring A is 1 2

[0031] a) H;

[0032] b) -(CH2) z -R 1a , wherein z is an integer from 1 to 6, and R 1a

[0033] i) -H, -NH2, -N + H3, or -N + (CH3)3;

[0034] ii) -NH-C(O)-[(CH2)2-O-]2-(CH2)2R 1B , wherein R 1B + + (CH3)3;

[0035] iii) -NH-C(O)-[(CH2) y1 -O-]2-(CH2) y2 R 1B , wherein y1, y2are each independently an integer from 2 to 4, and are not both 2; R 1B + + (CH3)3;

[0036] iv) -NH-C(O)-(CH2) y R 1C , wherein y is an integer from 1 to 6; R 1C za -N + (CH3)3, wherein za is an integer from 2 to 4;

[0037] c) -(CR 1D ) zb NR-C(O)-(CR 1D ) zb [O(CR 1D ) n ] zc -N + (CH3)3, wherein R 1D 1-6 ​​​​​​​​​​Alkyl groups, zb is an integer from 1 to 6, zc is an integer from 0 to 4;

[0038] Unless otherwise stated, the heteroatoms in the above heterocyclic groups and heteroaryl groups are independently selected from O, N or S, and the number of heteroatoms is 1, 2, 3 or 4.

[0039] In some implementations, ring A is

[0040] In some implementations, ring A is

[0041] In some implementations, ring A is "**" indicates a connection to the methylene end, and "##" indicates a connection to the ethylidene end.

[0042] In some implementations, ring A is

[0043] In some implementation schemes, X1, X2, X3, X4, X5, X 11 Each is independently selected from hydrogen, deuterium, halogens, and carbon. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, 3-6 membered heterocyclic groups, wherein C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 The cycloalkyl group and the 3-6 membered heterocyclic group are optionally selected from one or more of the following groups: deuterium, halogen, nitro, hydroxyl, amino, hydroxyl, oxo, thio, carboxyl, cyano, sulfonyl, ester, phosphono, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 3-6 Substituents include cycloalkyl groups and 3-6 membered heterocyclic groups.

[0044] In some implementations, X1 is independently selected from hydrogen, deuterium, halogen, and C. 1-6 Alkyl, C 1-6alkyl, further preferably X1is located at the meta position on the phenyl ring.

[0045] In some embodiments, X1is independently selected from hydrogen, halogen, C 1-3 alkyl, further preferably X1is located at the meta position on the phenyl ring.

[0046] In some embodiments, X1is independently selected from hydrogen, fluorine, chlorine, methyl.

[0047] In some embodiments, X1is hydrogen.

[0048] In some embodiments, X1is located at the meta position on the phenyl ring, X1is fluorine, chlorine, or methyl.

[0049] In some embodiments, X2is independently selected from hydrogen, deuterium, halogen; preferably halogen; more preferably fluorine.

[0050] In some embodiments, X3is independently selected from hydrogen, deuterium, halogen; preferably hydrogen, halogen; more preferably hydrogen, fluorine, chlorine.

[0051] In some embodiments, X3is independently selected from hydrogen, fluorine.

[0052] In some embodiments, X2is fluorine and X3is hydrogen; or X2is fluorine and X3is fluorine.

[0053] In some embodiments, X4is independently selected from hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy.

[0054] In some embodiments, X4is independently selected from halogen, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy (preferably C 1- 6fluoroalkoxy).

[0055] In some embodiments, X4is independently selected from C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy (preferably C 1-6 fluoroalkoxy).

[0056] In some embodiments, X4is independently selected from C 1-3 alkoxy, C 1-3 deuteroalkoxy, C 1-3 haloalkoxy (preferably C 1-3 fluoroalkoxy).

[0057] In some embodiments, X4is independently selected from -OCH3, -OCD3, -OCF3, -OCHF2; preferably -OCH3.

[0058] In some embodiments, X4is independently selected from -OCH3, -OCD3, -OCF3, -OCHF2, Cl.

[0059] In some embodiments, X5is independently selected from hydrogen, deuterium, halogen; preferably hydrogen.

[0060] In some embodiments, X4is independently selected from -OCH3, -OCD3, -OCF3, -OCHF2, Cl, and X5is hydrogen.

[0061] In some embodiments, X4is -OCH3, and X5is hydrogen.

[0062] In some embodiments, X 11 is independently selected from hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, 3-6 membered heterocyclyl.

[0063] In some embodiments, X 11 is independently selected from hydrogen, halogen, C 1-3 alkyl (e.g., methyl), C 3-4 cycloalkyl (e.g., cyclopropyl).

[0064] In some embodiments, X 11 is independently selected from hydrogen, fluorine, chlorine, methyl, cyclopropyl; preferably hydrogen.

[0065] In some embodiments, X6is independently selected from H, -C(O)-, -CH(R a )OC(O)-, “*” end represents the connection to O end, and “#” end represents the connection to X7end; when X6is H, X7, X8are not present.

[0066] In some embodiments, X7, X9are independently selected from: bond, -[(CHR d ) p1 OC(O)O] p2 -, d ) p1 C(O)O] p2 -, d =CR d ) p3 C(O)O] p2 -.

[0067] In some embodiments, X7, X9are each independently selected from the group consisting of: a bond, -(CHR d ) p1 OC(O)O-, -(CHR d ) p1 C(O)O-, -(CR d =CR d ) p3 C(O)O-.

[0068] In some embodiments, X7is a bond, -CH2OC(O)O-, -CH=CHC(O)O-, or -CH2CH2C(O)O-.

[0069] In some embodiments, X9is a bond or -CH2OC(O)O-.

[0070] In some embodiments, X8is independently selected from the group consisting of hydrogen, C 1-6 alkyl; preferably hydrogen, C 1-4 alkyl.

[0071] In some embodiments, X8is independently selected from the group consisting of hydrogen, methyl, -C(CH3)3, -CH(CH3)2.

[0072] In some embodiments, X8is methyl.

[0073] In some embodiments, X 10 is independently selected from the group consisting of hydrogen, C 1-4 alkyl; preferably hydrogen, methyl, -C(CH3)3, -CH(CH3)2.

[0074] In some embodiments, X 10 is hydrogen or -CH(CH3)2.

[0075] In some embodiments, X6is H, X7, X8are absent.

[0076] In some embodiments, p1, p2, and p3 are each independently selected from 0, 1, 2.

[0077] In some embodiments, p1is 1, 2, p2is 1, and p3is 0, 1.

[0078] In some embodiments, R a is independently selected from the group consisting of hydrogen, C 1-6 alkyl; preferably hydrogen, C 1-2 alkyl; more preferably hydrogen, methyl.

[0079] In some embodiments, R d is independently selected from the group consisting of hydrogen, C 1-6 alkyl; preferably hydrogen, C 1-3alkyl; more preferably hydrogen.

[0080] In some embodiments, independently selected from hydrogen, -C(O)CH3, -CH2OC(O)CH3, 1-6 alkyl, -CH(R a )OC(O)C 1-6 alkyl, -C(O)-CH=CH-C(O)OC 1-6 alkyl, -C(O)-(CH2) p1 -C(O)OC 1-6 alkyl, -P(O)(OH)2, -CH2-P(O)[O(CH2) 1-6 alkylene-P(O)[O(CHR d ) p1 OC(O)OC 1-6 alkyl]2, wherein R a is selected from hydrogen, C 1-6 alkyl, R d is selected from hydrogen, C 1-6 alkyl, and pi is 1, 2, 3, 4, 5.

[0081] In some embodiments, independently selected from hydrogen, -C(O)CH3, -CH2OC(O)CH3, 1-3 alkyl, -CH(R a )OC(O)C 1-3 alkyl, -C(O)-CH=CH-C(O)OC 1-3 alkyl, -C(O)-(CH2) p1 -C(O)OC 1-3 alkyl, -P(O)(OH)2, -CH2-P(O)[O(CH2) p1 OC(O)OC 1-6 alkyl]2, wherein R a is selected from hydrogen, C 1-3 alkyl, and pi is 1, 2, 3, 4, 5.

[0082] In some embodiments, independently selected from hydrogen, -C(O)CH3, -CH2OC(O)CH3,

[0083] In some embodiments, is hydrogen.

[0084] In some embodiments, R1is independently selected from -L 1 m1 -L 2m2 -L 3 m3 -L 4 m4 -L 5 m5 -L 6 m6 -R3;

[0085] L 1 , L 2 , L 3 , L 4 , L 5 , L 6 each independently selected from: -O-, -N(R8)-, -C(O)-, -C(O)O-, -N(R8)C(O)-, -C(O)N(R8)-, C 1-6 alkylene, C 2-6 alkenylene, C 2-6 alkynylene, C 2-6 heteroalkylene, C 3-6 cycloalkylene, 4-6 membered heterocyclyl ene, phenyl, 5-6 membered heteroarylene; said C 1-6 alkylene, C 2-6 alkenylene, C 2-6 alkynylene, C 2-6 heteroalkylene, C 3-6 cycloalkylene, 4-6 membered heterocyclyl ene, phenyl, and 5-6 membered heteroarylene are optionally substituted with 1 to 3 substituents selected from Z1;

[0086] m1, m2, m3, m4, m5, m6 are each independently selected from 0, 1, 2, 3, and the sum of m1+m2+m3+m4+m5+m6 is less than 6;

[0087] Z1is independently selected from halo, amino, hydroxyl, cyano, -OR9, -C(O)R9, -C(O)OR9, -C(O)N(R9)2, -N(R9)2, -N(R9)C(O)R9, -S(O)2R9, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 4-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl; or any two Z1together with the atom(s) to which they are attached form a C 3-6 cycloalkyl, C 3-6 heterocyclyl, phenyl, 5-6 membered heteroaryl;

[0088] R8, R9are each independently selected from hydrogen, deuterium, C 1-6 alkyl;

[0089] R3is independently selected from -NH2, -N + H3, -N + (CH3)3, n is independently selected from 1, 2.

[0090] In some embodiments, R1is independently selected from -C 1-6 alkylene-R3, -CH2NHC(O)-(C 1-6 alkylene) m R3, -CH2C(O)NH-(C 1- 6alkylene) m R3, -CH2NHC(O)-[(C 1-6 alkylene) m -O- 1-4 -(C 1-6 alkylene) m R3, -CH2NHC(O)-(C 1-6 alkylene) m -C 3-6 cycloalkylene-(C 1-6 alkylene) m -R3, -CH2NHC(O)-(C 1-6 alkylene) m -4-6 membered heterocyclylene-(C 1-6 alkylene) m -R3, -CH2NHC(O)-(C 1-6 alkylene) m -phenyl-(C 1-6 alkylene) m -R3, -CH2NHC(O)-(C 1-6 alkylene) m -5-6 membered heteroarylene-(C 1-6 alkylene) m -R3, -CH2NHC(O)-(C 1-6 alkylene) m -O-(C 1-6 alkylene) m -C 3-6 cycloalkylene-(C 1-6 alkylene) m -R3, -CH2NHC(O)N(C 1-3 alkyl)-(C 1-6 alkylene) m -R3, -CH2NHC(O)NH-(C 1-6 alkylene) m -R3, -CH2NHC(O)-(C 1-6 alkylene) m -C 3-6Cycloalkylene-O-(C 1- 6alkylene) m -R3, -CH2NHC(O)-(C 1-6 alkylene) m -NHCO-(C 1-6 alkylene) m -R3, -CH2NHS(O)2-(C 1-6 alkylene) m R3, -CH2S(O)2NH-(C 1-6 alkylene) m R3, -CH2NHS(O)2-[(C 1-6 alkylene) m -O-] 1-4 -(C 1-6 alkylene) m R3, -CH2NHS(O)2-(C 1- 6alkylene) m -C 3-6 Cycloalkylene-(C 1-6 alkylene) m -R3, -CH2NHS(O)2-(C 1-6 alkylene) m -4-6 membered heterocyclylene-(C 1-6 alkylene) m -R3, -CH2NHS(O)2-(C 1-6 alkylene) m -Phenyl-(C 1-6 alkylene) m -R3, -CH2NHS(O)2-(C 1-6 alkylene) m -5-6 membered heteroarylene-(C 1-6 alkylene) m -R3, -CH2NHS(O)2-(C 1-6 alkylene) m -O-(C 1-6 alkylene) m -C 3-6 Cycloalkylene-(C 1-6 alkylene) m -R3, -CH2NHS(O)2N(C 1-3 alkylene)-(C 1-6 alkylene) m -R3, -CH2NHS(O)2NH-(C 1-6 alkylene) m -R3, -CH2NHS(O)2-(C 1-6 alkylene) m -C 3-6Cycloalkylene-O-(C 1-6 Alkylene m -R3, -CH2NHS(O)2-(C 1-6 Alkylene m -NHS(O)2-(C 1-6 Alkylene m -R3, said alkylene, cycloalkylene, heteroarylene being optionally substituted with 1 to 3 substituents selected from Z1;

[0091] R3is independently selected from -NH2, -N + H3, -N + (CH3)3, m is independently selected from 0, 1, n is independently selected from 1, 2;

[0092] Z1is independently selected from halo, amino, hydroxy, cyano, -S(O)2R9, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 4-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl; or any two Z1together with the atom(s) to which they are attached form a C 3-6 cycloalkyl, C 3-6 heterocyclyl, phenyl, 5-6 membered heteroaryl;

[0093] R9is independently selected from hydrogen, C 1-6 alkyl.

[0094] In some embodiments, R1is independently selected from -C 1-6 alkylene-R3, -CH2NHC(O)-(C 1-6 Alkylene m R3, -CH2C(O)NH-(C 1- 6Alkylene m R3, -CH2NHC(O)-[(C 1-3 Alkylene m -O- 1-2 -(C 1-3 Alkylene m R3, -CH2NHC(O)-(C 1-3 Alkylene m -C 3-6 Cycloalkylene-(C 1-3 Alkylene m -R3, -CH2NHC(O)-(C 1-3 Alkylene m -4-6 membered heterocyclylene-(C 1-3 Alkylene m-R3、-CH2NHC(O)-(C 1-3 Alkylene) m -phenyl-(C 1-3 Alkylene) m -R3、-CH2NHC(O)-(C 1-3 Alkylene) m -5-6-membered heteroaryl-(C 1-3 Alkylene) m -R3、-CH2NHC(O)-(C 1-3 Alkylene) m -O-(C 1-3 Alkylene) m -C 3-6 Cycloalkylene-(C 1-3 Alkylene) m -R3、-CH2NHC(O)N(C 1-3 alkyl)-(C 1-3 Alkylene) m -R3、-CH2NHC(O)NH-(C 1-3 Alkylene) m -R3、-CH2NHC(O)-(C 1-3 Alkylene) m -C 3-6 Cycloalkyl-O-(C 1- 3-alkylene) m -R3、-CH2NHC(O)-(C 1-3 Alkylene) m -NHCO-(C 1-3 Alkylene) m -R3、-CH2NHS(O)2-(C 1-6 Alkylene) m R3、-CH2S(O)2NH-(C 1-6 Alkylene) m R3、-CH2NHS(O)2-[(C 1-3 Alkylene) m -O-] 1-2 -(C 1-3 Alkylene) m R3、-CH2NHS(O)2-(C 1- 3-alkylene) m -C 3-6 Cycloalkylene-(C 1-3 Alkylene) m -R3、-CH2NHS(O)2-(C 1-3 Alkylene) m -4-6-membered heterocyclic group-(C 1-3 Alkylene) mR3, -CH2NHS(O)2-(C 1-3 alkylene m -phenyl-(C 1-3 alkylene m R3, -CH2NHS(O)2-(C 1-3 alkylene m -5-6 membered heteroarylene-(C 1-3 alkylene m R3, -CH2NHS(O)2-(C 1-3 alkylene m -O-(C 1-3 alkylene m -C 3-6 cycloalkylene-(C 1-3 alkylene m R3, -CH2NHS(O)2N(C 1-3 alkylene)-(C 1-3 alkylene m R3, -CH2NHS(O)2NH-(C 1-3 alkylene m R3, -CH2NHS(O)2-(C 1-3 alkylene m -C 3-6 cycloalkylene-O-(C 1-3 alkylene m R3, -CH2NHS(O)2-(C 1-3 alkylene m -NHS(O)2-(C 1-3 alkylene m R3, R1 is preferably -CH2NHC(O)-(C 1-6 alkylene m R3, -CH2NHS(O)2-(C 1-6 alkylene m R3; said alkylene, cycloalkylene, heteroarylene groups being optionally substituted by one to three substituents selected from Z1;

[0095] R3is independently selected from -NH2, -N + H3, -N + (CH3)3, m is independently selected from 0, 1, n is independently selected from 1, 2;

[0096] Z1is independently selected from halo (e.g. fluorine, chlorine, bromine), amino, hydroxyl, cyano, -S(O)2R9, C 1-3 alkyl (e.g. methyl, ethyl), C 1-3 alkoxy (e.g. methoxy, ethoxy), C 2-4alkenyl (e.g., -CH=CH2, -CH2CH=CH2), C 2-4 alkynyl, C 3-6 cycloalkyl (e.g., cyclopropane, cyclobutane, cyclopentane, cyclohexane), 4-6 membered heterocyclyl (e.g., ), phenyl, 5-6 membered heteroaryl (e.g., pyridinyl); or any two Z1together with the atom to which they are attached form a C 3-6 cycloalkyl (e.g., cyclopropane, cyclobutane, cyclopentane, cyclohexane), 4-6 membered heterocyclyl (e.g., “.” denotes the point of attachment), phenyl, 5-6 membered heteroaryl;

[0097] R9is independently selected from hydrogen, C 1-3 alkyl (e.g., methyl, ethyl).

[0098] In some embodiments, R1is independently selected from -C 1-6 alkylene-R3, -CH2NHC(O)-(C 1-6 alkylene) m R3, -CH2NHC(O)-(C 1- alkylene) m -O- 1-4 -(C 1-6 alkylene) m R3, -CH2NHC(O)-(C 1-6 alkylene) m -C 3-6 cycloalkylene-(C 1-6 alkylene) m -R3, -CH2NHC(O)-(C 1-6 alkylene) m -4-6 membered heterocyclylene-(C 1-6 alkylene) m -R3, -CH2NHC(O)-(C 1-6 alkylene) m -phenyl-(C 1-6 alkylene) m -R3, -CH2NHC(O)-(C 1-6 alkylene) m -5-6 membered heteroarylene-(C 1-6 alkylene) m -R3, -CH2NHC(O)-(C 1-6 alkylene) m -O-(C 1-6 alkylene) m -C 3-6 cycloalkylene-(C 1-6 alkylene) m-R3, -CH2NHC(O)N(C 1-3 alkyl)-(C 1-6 alkylene) m -R3, -CH2NHC(O)NH-(C 1-6 alkylene) m -R3, -CH2NHC(O)-(C 1-6 alkylene) m -C 3-6 cycloalkylene-O-(C 1-6 alkylene) m -R3, -CH2NHC(O)-(C 1-6 alkylene) m -NHCO-(C 1-6 alkylene) m -R3, wherein R3is independently selected from -NH2, -N + H3, -N + (CH3)3, m is independently selected from 0, 1, n is independently selected from 1, 2; said C 1-6 alkylene, C 1-3 alkylene is optionally substituted with 1 to 3 substituents selected from Z1;

[0099] Z1is independently selected from halo, amino, hydroxyl, cyano, -S(O)2R9, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 4-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl; or any two Z1together with the atom(s) to which they are attached form a C 3-6 cycloalkyl, C 3-6 heterocyclyl, phenyl, 5-6 membered heteroaryl;

[0100] R8, R9are each independently selected from hydrogen, C 1-6 alkyl.

[0101] In some embodiments, R1is independently selected from -CH2NHC(O)-(C 1-6 alkylene) m R3, -CH2NHC(O)-(C 1-6 alkylene) m -C 3-6 cycloalkylene-(C 1-6 alkylene) m -R3, -CH2NHC(O)-(C 1-6 alkylene) m -4-6 membered heterocyclylene-(C 1-6 alkylene)m -R3, -CH2NHC(O)-(C 1-6 alkylene) m -5-6 membered heteroaryl-(C 1-6 alkylene) m -R3, -CH2NHC(O)-(C 1-6 alkylene) m -O-(C 1-6 alkylene) m -C 3-6 cycloalkylene-(C 1-6 alkylene) m -R3, -CH2NHC(O)N(C 1-3 alkyl)-(C 1-6 alkylene) m -R3, -CH2NHC(O)-(C 1-6 alkylene) m -C 3- 6cycloalkylene-O-(C 1-6 alkylene) m -R3, -CH2NHC(O)-(C 1-6 alkylene) m -NHCO-(C 1-6 alkylene) m -R3or -CH2NHS(O)2-(C 1-6 alkylene) m R3, wherein R3is independently selected from -N + H3, -N + (CH3)3, m is independently selected from 0 or 1, n is independently selected from 1 or 2; said C 1-6 alkylene, C 1-3 alkyl is optionally substituted with 1 to 3 substituents selected from Z1;

[0102] Z1is independently selected from halo, amino, hydroxyl, cyano, -S(O)2R9, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, 4-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl; or any two Z1together with the atom(s) to which they are attached form a C 3-6 cycloalkyl, C 3-6 heterocyclyl;

[0103] R9is each independently selected from hydrogen or C 1-6 alkyl.

[0104] In some embodiments, R1is independently selected from -CH2NHC(O)-(C 1-6 alkylene)R3, -CH2NHC(O)-(C1-3 alkylene)-C 3-6 cycloalkylene-(C 1-3 alkylene)-R3, -CH2NHC(O)-C 3-6 cycloalkylene-(C 1-6 alkylene)-R3, -CH2NHC(O)-(C 1-3 alkylene)-4-6 membered heterocyclylene-(C 1-3 alkylene)-R3, -CH2NHC(O)-5-6 membered heteroarylene-(C 1-6 alkylene)-R3, -CH2NHC(O)-(C 1-3 alkylene)-O-(C 1-3 alkylene)-R3, -CH2NHC(O)-(C 1-3 alkylene)-O-(C 1-3 alkylene)-C 3-6 cycloalkylene-R3, -CH2NHC(O)-(C 1-3 alkylene)-O-(C 1-3 alkylene)-C 3-6 cycloalkylene-(C 1-3 alkylene)-R3, -CH2NHC(O)N(C 1-3 alkyl)-(C 1-6 alkylene)-R3, -CH2NHC(O)NH-(C 1-6 alkylene)-R3, -CH2NHC(O)-C 3-6 cycloalkylene-O-(C 1-6 alkylene)-R3, -CH2NHC(O)-(C 1-3 alkylene)-NHCO-(C 1-3 alkylene)-R3or -CH2NHS(O)2-(C 1-6 alkylene)R3, wherein R3is independently selected from -N + H3, -N + (CH3)3, n is independently selected from 1 or 2; the C 1-6 alkylene, C 1-3 alkylene is optionally substituted with 1, 2, or 3 substituents selected from Z1;

[0105] Z1is independently selected from halo, amino, hydroxyl, cyano, -S(O)2R9, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, phenyl, 5-6 membered heteroaryl; or any two Z1together with the atom(s) to which they are attached form a C 3-6 cycloalkyl or C 3-6 heterocyclyl;

[0106] R9is selected from hydrogen or C 1-6 alkyl.

[0107] In some embodiments, Z1is independently selected from -S(O)2R9, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, phenyl, or 5-6 membered heteroaryl; R9is selected from hydrogen or C 1-6 alkyl.

[0108] In some embodiments, Z1is independently selected from -CH3, -OCH3, -CH2CH=CH2, phenyl, pyridyl, -S(O)2CH3; or any two Z1together with the atom to which they are attached form a C 3-6 cycloalkyl (e.g., ) or C 3-6 heterocyclyl (e.g. ).

[0109] In some embodiments, R1is selected from -CH2NHC(O)-(CH2) m7 -R3, -CH2NHS(O)2-(CH2) m8 -R3, m7, m8 are each independently 4, 5, 6, or 7, wherein 1 or adjacent 2 -(CH2)- are optionally replaced by any one of the following: C 3-6 cycloalkyl, C 3-6 heterocyclyl, phenyl, 5-6 membered heteroaryl, -C(O)NH-, or -N(CH3)- (more preferably -C(O)NH-, or -N(CH3)-); optionally, further another -(CH2)- is replaced by -O-; R3is independently selected from -N + H3, -N + (CH3)3, n is independently selected from 1 or 2; said -(CH2) m7 -, -(CH2) m8 - is optionally substituted with 1 or 2 substituents selected from Z1, Z1is independently selected from -S(O)2R9, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, phenyl, or 5-6 membered heteroaryl; R9is selected from hydrogen or C 1-6 alkyl.

[0110] In some embodiments, R1is selected from -CH2NHC(O)-(CH2) m7 -R3, m7 is 4, 5, 6, or 7, wherein 1 or adjacent 2 -(CH2)- are optionally replaced by any one of the following: -C(O)NH- or -N(CH3)-; optionally, further, another -(CH2)- is replaced by -O-; R3is independently selected from -N + H3, -N + (CH3)3, n is independently selected from 1 or 2; said -(CH2) m7 - is optionally substituted with 1 or 2 substituents selected from Z1, Z1is independently selected from -S(O)2R9, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, phenyl or 5-6 membered heteroaryl; R9is selected from hydrogen or C 1-6 alkyl.

[0111] In some embodiments, R1is selected from -CH2NHS(O)2-(CH2) m8 -R3, m8 is 4, 5 or 6; R3is independently selected from -N + H3, -N + (CH3)3, n is independently selected from 1 or 2.

[0112] In some embodiments, R1is independently selected from the following groups:

[0113] In some embodiments, R1is independently selected from the following groups:

[0114] In some embodiments, R1is independently selected from the following groups:

[0115] each of the above embodiments of R1contains A - In some embodiments, A - is independently selected from Cl - , CH3COO - , HCOO - , C 10 H 19 O2 - , C9H 18 O2 - , CF3COO - In some embodiments, A - is Cl - or CF3COO - In some embodiments, A - is Cl - .

[0116] In some embodiments, R1is independently selected from the following groups:

[0117] In some embodiments, R3is independently selected from -NH2, -N + H3, -N + (CH3)3, -NH-C(O)-L 1 m1 -L 2 m2 -L 3 m3 -L 4 m4 -L 5 m5 -L 6 m6 -R4, wherein R4is independently selected from -NH2, -N + H3, -N + (CH3)3, or n is independently selected from 1, 2; preferably, R3is -NH2, -N + H3, -N + (CH3)3, n is 1, 2.

[0118] In some embodiments, -L 1 m1 -L 2 m2 -L 3 m3 -L 4 m4 -L 5 m5 -L 6 m6 - is independently selected from: -CH2NHC(O)-(C 1-6 alkylene) m -, -CH2C(O)NH-(C 1-6 alkylene) m -, -CH2NHC(O)-(C 1-6 alkylene) m -(R6) m -(C 1-6 alkylene) m -, -CH2NHC(O)-[(C 1-6 alkylene) m -O-] 1-4 -(C 1-6 alkylene) m -(R6) m -(C 1-6 alkylene) m -, -CH2NHC(O)N(R8)-(C 1-6 alkylene)m -CH2NHC(O)-(C 1- 6alkylene) m -(R6) m -NHCO-(C 1-6 alkylene) m ] 1-2 -CH2NHC(O)-(C 1-6 alkylene) m -(R6) m -NHCO-(C 1-6 alkylene) m -CH2NHS(O)2-(C 1-6 alkylene) m -CH2S(O)2NH-(C 1-6 alkylene) m -CH2NHS(O)2-(C 1-6 alkylene) m -(R6) m -(C 1-6 alkylene) m -CH2NHS(O)2-[(C 1-6 alkylene) m -O-] 1-4 -(C 1-6 alkylene) m -(R6) m -(C 1-6 alkylene) m -CH2NHS(O)2N(R8)-(C 1-6 alkylene) m -CH2NHS(O)2-(C 1-6 alkylene) m -(R6) m -[-O-(C 1-6 alkylene) m ] 1-2 -CH2NHS(O)2-(C 1-6 alkylene) m -(R6) m -NHCO-(C 1-6 alkylene) m -; wherein R6is independently selected from the group consisting of C 3-6 cycloalkylene, 4-6 membered heterocyclylene, phenyl, 5-6 membered heteroarylene; said alkylene, cycloalkylene, heterocyclylene, phenyl and heteroarylene are optionally substituted with 1 to 3 substituents selected from Z1;

[0119] Z1is independently selected from halo (e.g. fluoro, chloro, bromo), amino, hydroxyl, cyano, -OR9, -C(O)R9, -C(O)OR9, -C(O)N(R9)2, -N(R9)2, -N(R9)C(O)R9, -S(O)2R9, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 4-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl; or any two Z1together with the atom(s) to which they are attached form a C 3-6 cycloalkyl, C 3-6 heterocyclyl, phenyl, 5-6 membered heteroaryl;

[0120] R8, R9are each independently selected from hydrogen, deuterium, C 1-6 alkyl; preferably, R8, R9are each independently selected from hydrogen, deuterium, methyl, ethyl;

[0121] m is independently selected from 0, 1, 2, 3; preferably, m is independently selected from 0, 1.

[0122] In some embodiments, -L 1 m1 -L 2 m2 -L 3 m3 -L 4 m4 -L 5 m5 -L 6 m6 - is independently selected from: -CH2NHC(O)-(C 1-6 alkylene) m -, -CH2C(O)NH-(C 1-6 alkylene) m -, -CH2NHC(O)-(C 1-3 alkylene) m -(R6) m -(C 1-3 alkylene) m -, -CH2NHC(O)-[(C 1-3 alkylene) m -O-] 1-2 -(C 1-3 alkylene) m -(R6) m -(C 1-3 alkylene) m -, -CH2NHC(O)N(R8)-(C 1-3 alkylene) m-CH2NHC(O)-(C1-C6alkylene) 1- 3alkylene) m -(R6) m -[-O-(C1-C6alkylene) 1-3 alkylene) m ] 1-2 -CH2NHC(O)-(C1-C6alkylene) 1-3 alkylene) m -(R6) m -NHCO-(C1-C6alkylene) 1-3 alkylene) m -CH2NHS(O)2-(C1-C6alkylene) 1-6 alkylene) m -CH2S(O)2NH-(C1-C6alkylene) 1-6 alkylene) m -CH2NHS(O)2-(C1-C6alkylene) 1-3 alkylene) m -(R6) m -(C1-C6alkylene) 1-3 alkylene) m -CH2NHS(O)2-[(C1-C6alkylene) 1-3 alkylene) m -O-] 1-2 -(C1-C6alkylene) 1-3 alkylene) m -(R6) m -(C1-C6alkylene) 1-3 alkylene) m -CH2NHS(O)2N(R8)-(C1-C6alkylene) 1-3 alkylene) m -CH2NHS(O)2-(C1-C6alkylene) 1-3 alkylene) m -(R6) m -[-O-(C1-C6alkylene) 1-3 alkylene) m ] 1-2 -CH2NHS(O)2-(C1-C6alkylene) 1-3 alkylene) m -(R6) m -NHCO-(C1-C6alkylene) 1-3 alkylene) m -; wherein R6is independently selected from the group consisting of C 3-6 cycloalkylene, 4-6 membered heterocyclylene, phenyl, 5-6 membered heteroarylene; said alkylene, cycloalkylene, heterocyclylene, phenyl and heteroarylene are optionally substituted with 1 to 3 substituents selected from Z1;

[0123] Z1is independently selected from halo (e.g., fluorine, chlorine, bromine), amino, hydroxyl, cyano, -C(O)R9, -C(O)OR9, -C(O)N(R9)2, -N(R9)2, -N(R9)C(O)R9, -S(O)2R9, C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 4-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl; or any two Z1together with the atom(s) to which they are attached form a C 3-6 cycloalkyl, C 3-6 heterocyclyl, phenyl, 5-6 membered heteroaryl;

[0124] R8, R9are each independently selected from hydrogen, deuterium, C 1-3 alkyl; preferably, R8, R9are each independently selected from hydrogen, deuterium, methyl, ethyl;

[0125] m is independently selected from 0, 1.

[0126] In some embodiments, -L 1 m1 -L 2 m2 -L 3 m3 -L 4 m4 -L 5 m5 -L 6 m6 - is independently selected from: -CH2NHC(O)-(C 1-6 alkylene) m -, -CH2NHC(O)-(C 1-6 alkylene) m -(R6) m -(C 1-6 alkylene) m -, -CH2NHC(O)-[(C 1-6 alkylene) m -O-] 1-4 -(C 1-6 alkylene) m -(R6) m -(C 1-6 alkylene) m -, -CH2NHC(O)N(R8)-(C 1-6 alkylene) m -, -CH2NHC(O)-(C 1-6 alkylene) m -(R6) m -[-O-(C1-6 alkylene m ] 1-2 -CH2NHC(O)-(C 1-6 alkylene m -(R6) m -NHCO-(C 1-6 alkylene m -; wherein R6is independently selected from the group consisting of: C 3-6 cycloalkylene, 4-6 membered heterocyclylene, phenyl, 5-6 membered heteroarylene; said C 1-6 alkylene, C 3-6 cycloalkylene, 4-6 membered heterocyclylene, phenyl, and 5-6 membered heteroarylene is optionally substituted with 1 to 3 substituents selected from Z1;

[0127] Z1is independently selected from halo, amino, hydroxyl, cyano, -OR9, -C(O)R9, -C(O)OR9, -C(O)N(R9)2, -N(R9)2, -N(R9)C(O)R9, -S(O)2R9, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 4-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl; or any two Z1together with the atom(s) to which they are attached form a C 3-6 cycloalkyl, C 3-6 heterocyclyl, phenyl, 5-6 membered heteroaryl;

[0128] R8, R9are each independently selected from hydrogen, deuterium, C 1-6 alkyl; m is independently selected from 0, 1, 2, 3.

[0129] In some embodiments, -L 1 m1 -L 2 m2 -L 3 m3 -L 4 m4 -L 5 m5 -L 6 m6 - is independently selected from the group consisting of:

[0130] In some embodiments, R6is independently selected from cyclopropyl, cyclobutane, cyclopentane, cyclohexane, phenyl, imidazolyl, pyrazolyl.

[0131] In some embodiments, R6is independently selected from

[0132] In some embodiments, Z1is independently selected from halo (e.g., fluorine, chlorine, bromine), amino, hydroxyl, cyano, -C(O)CH3, -C(O)OCH3, -C(O)NH2, -C(O)N(CH3)2, -NH(CH3), -N(CH3)2, -NHC(O)CH3, -S(O)2CH3, methyl, ethyl, methoxy, -CH=CH2, -CH2CH=CH2, ethynyl, cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexanyl, 1-3 alkyl, -C(O)OC 1-3 alkyl, -C(O)NH2, -C(O)N(C 1-3 alkyl)2, -N(C 1-3 alkyl)2, -NHC(O)C 1-3 alkyl, -S(O)2C 1-3 alkyl, C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 4-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl; or any two Z1together with the atom(s) to which they are attached form a C 3-6 cycloalkyl, 4-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl.

[0133] In some embodiments, Z1is independently selected from halo (e.g., fluorine, chlorine, bromine), amino, hydroxyl, cyano, -C(O)CH3, -C(O)OCH3, -C(O)NH2, -C(O)N(CH3)2, -NH(CH3), -N(CH3)2, -NHC(O)CH3, -S(O)2CH3, methyl, ethyl, methoxy, -CH=CH2, -CH2CH=CH2, ethynyl, cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexanyl, phenyl, pyridyl; or any two Z1together with the atom(s) to which they are attached form a wherein “.” indicates the site of attachment.

[0134] In some embodiments, A - is independently selected from Cl - , CH3COO - , HCOO - , C 10 H 19 O2 - , C9H 18 O2 - , CF3COO - In some embodiments, A - is Cl - or CF3COO - In some embodiments, A - is Cl - .

[0135] In some embodiments, R2is independently selected from C 1-6 alkyl, C 1-6alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, said C 1-6 alkyl, C 1-6 alkyl, C 3-6 cycloalkyl and 3-6 membered heterocyclyl are optionally substituted with one or more substituents selected from halogen.

[0136] In some embodiments, R2is independently selected from C 1-2 alkyl, C 3-4 cycloalkyl.

[0137] In some embodiments, R2is independently selected from methyl, cyclopropyl.

[0138] In some embodiments, R5is independently selected from hydrogen.

[0139] In some embodiments, R2, R5together with the carbon atom to which they are attached form C 3-6 cycloalkyl or C 3-6 heterocyclyl.

[0140] In some embodiments, R2, R5together with the carbon atom to which they are attached form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; preferably cyclopropyl.

[0141] In some embodiments, the carbon atom to which R2and R5are attached is in S configuration.

[0142] In some embodiments, ring A is “**” indicates attachment to the methylene end, and “##” indicates attachment to the ethylene end; X1is meta to the phenyl ring and is independently selected from hydrogen, fluorine, chlorine, methyl; X2is fluorine and X3is hydrogen; or X2is fluorine and X3is fluorine; X4is independently selected from -OCH3, -OCD3, -OCF3, -OCHF2, Cl, X5is hydrogen; R2is independently selected from methyl, cyclopropyl, R5is hydrogen, or R2, R5together with the carbon atom to which they are attached form cyclopropyl. In some embodiments, X6is H and X7, X8are absent.

[0143] In some embodiments, X1is hydrogen, X2is halogen (e.g. fluorine), X3is hydrogen, X4is C 1-3 alkoxy (e.g. -OCH3) or C 1-3 haloalkoxy (e.g. C 1-3 fluoroalkoxy, e.g. -OCF3), X5is hydrogen, and / or ring A is and X 11 is hydrogen or halogen (e.g. fluorine).

[0144] In some embodiments, X1is hydrogen, X2is fluorine, X3is hydrogen, X4is -OCH3or -OCF3, X5is hydrogen, and / or ring A is and X 11 is hydrogen or fluorine.

[0145] In some embodiments, X1is hydrogen, X2is fluorine, X3is hydrogen, X4is -OCH3, X5is hydrogen, and / or ring A is

[0146] In some embodiments, R1is -CH2NHC(O)-C 1-6 alkylene-R3, -CH2NHS(O)2-C 1-6 alkylene-R3, R3is independently selected from -N + H3, -N + (CH3)3, n is independently selected from 1 or 2; the C 1-6 alkylene is optionally substituted with 1, 2, or 3 substituents selected from Z1; any two Z1together with the atoms to which they are attached form a C 3-6 cycloalkyl (e.g., cyclopropyl, cyclobutyl), or C 3-6 heterocyclyl.

[0147] In some embodiments, R1is -CH2NHC(O)-(CH2) m7 -R3, -CH2NHS(O)2-(CH2) m8 -R3, m7, m8 are each independently 4, 5, 6, or 7, wherein 1 or adjacent 2 -(CH2)- are optionally replaced with any of C 3-6 cycloalkyl (preferably ), C 3-6 heterocyclyl (preferably ); R3is independently selected from -N + H3, -N + (CH3)3, n is independently selected from 1 or 2.

[0148] In some embodiments, R1is

[0149] In some embodiments, R1is

[0150] In some embodiments, R2is C 1-6 alkyl (preferably C 1-4 alkyl, more preferably C 1-2 alkyl) or C 3-6 cycloalkyl (preferably C 3-4 cycloalkyl), R5is hydrogen, X6is hydrogen, and X7and X8are absent.

[0151] In some embodiments, R2 is methyl or cyclopropyl, R5 is hydrogen, X6 is hydrogen, and X7 and X8 are absent.

[0152] In some implementations, R2 is methyl, R5 is hydrogen, X6 is hydrogen, and X7 and X8 are absent.

[0153] In some embodiments, X1 is hydrogen, X2 is fluorine, X3 is hydrogen, X4 is -OCH3 or -OCF3, X5 is hydrogen, and ring A is... "**" indicates a connection to the methylene end, "##" indicates a connection to the ethylene end; R2 is methyl or cyclopropyl, R5 is hydrogen, X6 is hydrogen, and X7 and X8 are not present.

[0154] In some embodiments, X1 is hydrogen, X2 is fluorine, X3 is hydrogen, X4 is -OCH3, X5 is hydrogen, and ring A is... "**" indicates a connection to the methylene terminus, "##" indicates a connection to the ethyl terminus; R2 is methyl, R5 is hydrogen, X6 is hydrogen, and X7 and X8 are absent; R1 is -CH2NHC(O)-(C 5-6 (alkylene)R3、-CH2NHC(O)-C 3-6 Cycloalkylene-(C 4-5 (alkylene)-R3, where R3 is -N + (CH3)3、 n is 1; (preferably R1 is -CH2NHC(O)-(CH2)5-R3, -CH2NHC(O)-cyclopropyl-(CH2)4-R3, and R3 is -N + (CH3)3、 n is 1; more preferably R1 is... ).

[0155] In the above implementation scheme, when R1 or R3 contains a cation, it must also contain A. - A - It is a pharmaceutically acceptable anion. For example, when R3 contains -N + H3, -N + (CH3)3 or When n is 1 or 2, R3 is -N. + H3A - -N + (CH3)3A - or A - n is 1 or 2.

[0156] Based on common knowledge in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of this application.

[0157] Preferably, the present application provides a compound or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein the compound has the following structure:

[0158] ; wherein A - is a pharmaceutically acceptable anion.

[0159] In some embodiments, A - is independently selected from the group consisting of Cl - , CH3COO - , HCOO - , C 10 H 19 O2 - , C9H 18 O2 - , CF3COO - ; preferably Cl - , CF3COO - .

[0160] Preferably, the present application provides a compound or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein the compound has the following structure:

[0161] The present application also provides a pharmaceutical composition comprising a compound described herein or a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

[0162] Further, the present application provides a pharmaceutical composition comprising a compound described herein or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0163] The compounds described herein or a stereoisomer thereof or a pharmaceutically acceptable salt thereof can be administered in pure form or in an appropriate pharmaceutical composition. The pharmaceutical compositions of the present application can be prepared by combining a compound described herein with an appropriate pharmaceutically acceptable excipient. The pharmaceutical compositions of the present application can be formulated into preparations in solid, semi-solid, liquid or gaseous forms. In general, the pharmaceutical compositions described above can be prepared by conventional techniques, e.g., by mixing, granulating, confectioning, dissolving or lyophilizing processes.

[0164] Another aspect of the application also provides the use of a compound described herein, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, in the manufacture of a medicament for antagonizing the activity of PCSK9 in a subject.

[0165] In another aspect, the application provides a method for antagonizing the activity of PCSK9 in a subject, comprising administering to the subject a therapeutically effective amount of a PCSK9 specific antagonist described herein (i.e., a compound described herein, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein).

[0166] In another aspect, the application provides a compound described herein, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, for use in antagonizing the activity of PCSK9 in a subject.

[0167] In another aspect, the application provides the use of a compound described herein, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, in antagonizing the activity of PCSK9 in a subject.

[0168] In some embodiments, the methods for antagonizing PCSK9 function are used for the treatment of a PCSK9-associated disease, disorder, or condition, as defined herein, or alternatively, for providing therapy in a disease, disorder, or condition that can benefit from the effects of a PCSK9 antagonist.

[0169] Accordingly, the application encompasses the use of a PCSK9 specific antagonist described herein in various therapeutic methods in which antagonizing PCSK9 function is desired. As used herein, the term "therapeutic method" relates to a process of actions that results in a change of at least one symptom of a disease state that can be prophylactic or therapeutic in nature.

[0170] Another aspect of the application also provides the use of a compound described herein, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, in the manufacture of a medicament for treating a condition associated with PCSK9 activity.

[0171] In another aspect, the application provides a method of treating a condition associated with PCSK9 activity, comprising administering to the subject a therapeutically effective amount of a compound described herein, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.

[0172] In another aspect, the application provides a compound described herein, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, for use in treating a condition associated with PCSK9 activity.

[0173] In yet another aspect, the present application provides the use of a compound described herein, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, in the treatment of a condition associated with PCSK9 activity.

[0174] In some embodiments, the condition associated with PCSK9 activity is a cardiovascular disease related to dyslipidemia, preferably atherosclerosis, hypercholesterolemia, coronary heart disease, metabolic syndrome, acute coronary syndrome, or related cardiovascular and cardiometabolic conditions.

[0175] In some embodiments, the present application relates to a method for the treatment of a condition associated with PCSK9 activity, or a method for the treatment of a condition caused by PCSK9 activity, or a method for the treatment of a condition for which the function of PCSK9 is contraindicated for a particular individual. The method comprises administering to the individual a therapeutically effective amount of a PCSK9 antagonist compound of Formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, the condition is a cardiovascular disease related to dyslipidemia, preferably atherosclerosis, hypercholesterolemia, coronary heart disease, metabolic syndrome, acute coronary syndrome, or related cardiovascular and cardiometabolic conditions.

[0176] The method of treatment according to the present application comprises administering to the individual a therapeutically (or prophylactically) effective amount of a PCSK9 specific antagonist according to the present application. The term "therapeutically effective" or "prophylactically effective" with reference to an amount used means the amount necessary to achieve the intended therapeutic and / or prophylactic effect for the desired period of time. The desired effect can be, for example, the alleviation, reduction, decrease or cessation of at least one symptom associated with the condition being treated.

[0177] In some embodiments, the PCSK9 antagonist compounds of the present application are preferably administered in the form of a pharmaceutical composition as described herein.

[0178] The present application also provides in another aspect a pharmaceutical composition comprising a compound described herein, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, and another, two or more compounds having the same or similar indications.

[0179] Definitions

[0180] C herein m-n means that the moiety has an integer number of carbon atoms in the given range. For example, "C 1-6 " means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms.

[0181] When any variable (e.g. R d) more than one time in the composition or structure of a compound, each instance is defined independently. Thus, for example, if a group, a site, or an atom is substituted with two R d groups, each R d group has independent options.

[0182] The term "plurality" means 2-10, e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10, preferably 2, 3, 4, 5, 6, 7, 8; preferably 2, 3, 4, 5, 6; more preferably 2, 3.

[0183] The terms "optionally," "optional," "arbitrarily," or "arbitrarily" mean that the event or circumstance described subsequently can, but need not, occur, and the description includes the case where the event or circumstance occurs and the case where it does not.

[0184] The term "oxo" means two hydrogen atoms at the same substitution site are replaced with the same oxygen atom to form a double bond (i.e., =0).

[0185] When a group is present with two attachment bonds, it does not imply an order of attachment, except where specifically indicated. For example, L 1 is selected from -N(R8)C(O)-, -SO2N(R8)-, represents L 1 is selected from -N(R8)C(O)-, -C(O)N(R8)-, -SO2N(R8)-, -N(R8)SO2-.

[0186] The term "alkyl," unless otherwise specified, refers to a monovalent saturated aliphatic hydrocarbon group including straight-chain or branched-chain groups, preferably containing 1-20 carbon atoms (i.e., C 1-10 alkyl), further preferably containing 1-8 carbon atoms (i.e., C 1-8 alkyl), more preferably containing 1-6 carbon atoms (i.e., C 1-6 alkyl), or containing 1-4 carbon atoms (i.e., C 1-4 alkyl), or containing 1-3 carbon atoms (i.e., C 1-3 alkyl), for example "C 1-6 alkyl" means that the group is an alkyl group and the number of carbon atoms in the carbon chain is between 1 and 6 (specifically 1, 2, 3, 4, 5, or 6). Examples include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, sec-butyl, n-pentyl, neopentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, n-heptyl, n-octyl, and the like.

[0187] The term "alkylene," unless specified otherwise, refers to a divalent alkyl group as defined above, comprising a straight-chain or branched-chain group of 1-20 carbon atoms, preferably comprising 1-10 carbon atoms (i.e., C 1-10 alkylene), further preferably comprising 1-8 carbon atoms (i.e., C 1-8 alkylene), more preferably comprising 1-6 carbon atoms (i.e., C 1-6 alkylene), or comprising 1-4 carbon atoms (i.e., C 1-4 alkylene), or comprising 1-3 carbon atoms (i.e., C 1-3 alkylene), for example "C 1- 6alkylene" means that the group is an alkylene group and the number of carbon atoms in the carbon chain is between 1-6 (specifically 1, 2, 3, 4, 5, or 6). Examples include, but are not limited to, methylene, ethylene, n-propylene, n-pentylene, n-hexylene, and the like.

[0188] The term "alkenyl," unless specified otherwise, refers to a straight-chain or branched-chain unsaturated aliphatic hydrocarbon group having at least one double bond, consisting of carbon and hydrogen atoms. Alkenyl groups can contain 2-20 carbon atoms, preferably 2-10 carbon atoms (i.e., C 2-10 alkenyl), further preferably comprising 2-8 carbon atoms (i.e., C 2-8 alkenyl), more preferably comprising 2-6 carbon atoms (i.e., C 2-6 alkenyl), 2-5 carbon atoms (i.e., C 2-5 alkenyl), 2-4 carbon atoms (i.e., C 2-4 alkenyl), 2-3 carbon atoms (i.e., C 2-3 alkenyl), 2 carbon atoms (i.e., C2alkenyl), for example "C 2-6 alkenyl" means that the group is an alkenyl group and the number of carbon atoms in the carbon chain is between 2-6 (specifically 2, 3, 4, 5, or 6). Non-limiting examples of alkenyl groups include, but are not limited to, ethenyl, 1- propenyl, 2-propenyl, 1-butenyl, isobutenyl, and 1,3-buten-2-yl, and the like.

[0189] The term "alkynyl," unless specified otherwise, refers to a straight-chain or branched-chain unsaturated aliphatic hydrocarbon group having at least one triple bond, consisting of carbon and hydrogen atoms. Alkynyl groups can contain 2-20 carbon atoms, preferably 2-10 carbon atoms (i.e., C 2-10 alkynyl), further preferably comprising 2-8 carbon atoms (i.e., C 2-8 alkynyl), more preferably comprising 2-6 carbon atoms (i.e., C 2-6 alkynyl), 2-5 carbon atoms (i.e., C 2-5 alkynyl), 2-4 carbon atoms (i.e., C 2- 4alkynyl), 2-3 carbon atoms (i.e., C 2-3 alkynyl), 2 carbon atoms (i.e., C2alkynyl), for example "C2-6 "Alkynyl" means that the group is an alkynyl group and the number of carbon atoms in the carbon chain is between 2 and 6 (specifically 2, 3, 4, 5, or 6). Non-limiting examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, and 1-butynyl, and the like.

[0190] The term "alkoxy," unless otherwise specified, means -O-alkyl, the alkyl group being defined as above, i.e., containing 1 to 20 carbon atoms, preferably, 1 to 10 carbon atoms, more preferably 1 to 8 carbon atoms, and even more preferably 1 to 6 carbon atoms (specifically 1, 2, 3, 4, 5, or 6, i.e., C 1- 6alkoxy) or 1 to 3 carbon atoms (i.e., C 1-3 Alkoxy). Representative examples include, but are not limited to, methoxy, ethoxy, propyloxy, isopropoxy, butoxy, 1-methylpropyloxy, 2-methylpropyloxy, t-butoxy, pentyloxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 1,1-dimethylpropyloxy, 1,2-dimethylpropyloxy, 2,2-dimethylpropyloxy, 1-ethylpropyloxy, and the like.

[0191] The terms "alkylene," "alkynylene," "cycloalkylene," "heterocyclylene," "arylene," "heteroarylene," unless otherwise specified, mean a divalent radical that is formed by removing two hydrogen atoms from the corresponding molecule.

[0192] The term "heteroalkylene," unless otherwise specified, means an alkylene residue in which one or more carbons (and their associated hydrogens) are replaced by a heteroatom. For example, "oxaalkylene," "thiaalkylene," "azaalkylene." The heteroatom is preferably O, N, or S, and the number of heteroatoms is preferably 1, 2, or 3. The term "oxaalkylene" means an alkylene residue in which one or more carbons (and their associated hydrogens) are replaced by oxygen, such as "alkoxy," "alkoxyalkyl." For example, a C3oxaalkylene group includes -OC 1-3 CH2CH2OCH3, and the like. Examples include methoxy, ethoxy, propyloxy, methoxypropyl, and the like. The term oxaalkyl is understood in the art [see Chemical Abstracts Service Nomenclature and Index System for Chemical Substances, published by the American Chemical Society, 1967, but not limited to, 127(a)], i.e., it refers to compounds in which oxygen is bonded to its adjacent atom by a single bond (forming an ether linkage); it does not refer to the double-bonded oxygen found in carbonyl groups. The term "thiaalkylene" is analogous to "oxaalkylene." The term "azaalkylene" means an alkylene group that contains the atom group "NH," for example, a C3azaalkylene group includes -NHCH2CH2CH3, -CH2NHCH2CH3, -CH2CH2NHCH3, and the like.

[0193] The term "halogen" or "halo" means F, CI, Br, I, unless otherwise specified. The term "haloalkyl" means an alkyl group as defined above in which one, two, or multiple hydrogen atoms, or all hydrogen atoms, are replaced by halogen. Representative examples of haloalkyl include CCI3, CF3, CHF2, CH2F, CHCI2, CH2CI, CH2Br, CH2I, CH2CF3, CF2CF3, and the like.

[0194] The term "cycloalkyl" means, unless otherwise specified, a monocyclic saturated aliphatic radical having the particular number of carbon atoms designated, preferably containing 3-12 carbon atoms (i.e., C 3-12 cycloalkyl), more preferably 3-10 carbon atoms (C 3-10 cycloalkyl), even more preferably 3-8 carbon atoms (C 3-8 cycloalkyl), still more preferably 3-6 carbon atoms (C 3-6 cycloalkyl), and even more preferably 5-6 carbon atoms (C 5-6 cycloalkyl). Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclopropyl, 2-ethyl-cyclopentyl, dimethylcyclobutyl, and the like.

[0195] The term "carbocyclyl" means, unless otherwise specified, a non-aromatic cyclic hydrocarbon group having from 3 to 14 ring carbon atoms ("C 3-14 carbocyclyl") and having no heteroatoms in the non-aromatic ring system. In some embodiments, a carbocyclyl group has 3-8 ring carbon atoms ("C 3-8 carbocyclyl"), or 3-6 ring carbon atoms ("C 3-6 carbocyclyl"), or 5 to 8 ring carbon atoms ("C 5-8 carbocyclyl"). In some embodiments, a carbocyclyl group has 5 to 6 ring carbon atoms ("C 5-6 carbocyclyl"). Exemplary C 3-6 carbocyclyl 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), and the like. Exemplary C 5-8 carbocyclyl groups include, but are not limited to, the aforementioned C 3-6carbocyclyl groups are monocyclic ("monocyclic carbocyclyl") or a fused (fused-cyclyl), bridged (bridged-cyclyl), or spiro-fused (spiro-cyclyl) ring system, such as a bicyclic ring system ("bicyclic carbocyclyl"), and can be saturated or can be partially unsaturated. "Carbocyclyl" also includes ring systems in which the carbocyclyl ring as defined above is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the carbocyclyl ring, and in such cases the member count for the carbocyclyl ring system is the number of carbons in the carbocyclyl system after fusion. In certain embodiments, each instance of a carbocyclyl group is independently optionally substituted, e.g., unsubstituted (an "unsubstituted carbocyclyl") or substituted with one or more substituents (a "substituted carbocyclyl"). In certain embodiments, the carbocyclyl group is an unsubstituted C 5-8 carbocyclyl group is a substituted C 5-8 carbocyclyl group is a substituted C

[0196] The term "heterocyclyl" or "heterocycle" means, unless otherwise specified, a saturated or partially unsaturated monocyclic or polycyclic ring-containing nonaromatic substituent having ring carbon atoms and from one to four ring heteroatoms, comprising from 3 to 20 ring atoms, of which one, two, three or more ring atoms are selected from N, O, or S, with the remainder of the ring atoms being C, wherein one or more S ring atoms, if present, and / or one or more N ring atoms, if present, can be optionally oxidized, wherein one or more carbon ring atoms can be optionally oxidized (i.e., form an oxo group). Preferably comprising from 3 to 10 ring atoms (3-10 membered heterocyclyl), further preferably comprising from 3 to 8 ring atoms (3-8 membered heterocyclyl), or from 3 to 6 ring atoms (3-6 membered heterocyclyl), or from 4 to 6 ring atoms (4-6 membered heterocyclyl), from 5 to 8 ring atoms (5-8 membered heterocyclyl), or from 5 to 6 ring atoms (5-6 membered heterocyclyl). The heteroatoms are preferably from 1 to 4, more preferably from 1 to 3 (i.e., 1, 2, or 3). Examples of monocyclic heterocyclyl groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, dihydropyrrolyl, piperidinyl, piperazinyl, pyranyl, and the like. Polycyclic heterocyclyl groups include spiro, fused, and bridged heterocyclyl groups. The "heterocyclyl" can be monocyclic ("monocyclic heterocyclyl") or a fused ("fused heterocyclyl" or "heterofused cyclyl"), bridged ("heterobridged cyclyl" or "bridged heterocyclyl"), or spiro-fused ("heterospirocyclyl" or "spiroheterocyclyl") ring system, such as a bicyclic ring system ("bicyclic heterocyclyl"), and can be saturated or can be partially unsaturated. The "heterocyclyl" also includes ring systems in which the heterocyclyl ring as defined above is fused with one or more carbocyclyl groups, with the point of attachment being on the carbocyclyl or heterocyclyl ring, or the "heterocyclyl" also includes ring systems in which the heterocyclyl ring as defined above is fused with one or more aryl or heteroaryl groups, or ring systems in which the cycloalkyl ring as defined above is fused with one or more heteroaryl groups, with the point of attachment being on the heterocyclyl or cycloalkyl ring, and in such cases the member count of the heterocyclyl ring system is the number of atoms in the fused ring system. In certain embodiments, each instance of heterocyclyl is independently optionally substituted, e.g., unsubstituted (an "unsubstituted heterocyclyl") or substituted with one or more substituents (a "substituted heterocyclyl"). Exemplary 3-membered heterocyclyl groups containing 1 heteroatom include, but are not limited to, azirdinyl, oxiranyl (oxirane), and thiorenyl (thiirane). Exemplary 4-membered heterocyclyl groups containing 1 heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing 1 heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione.Exemplary 5-membered heterocyclyl groups containing 2 heteroatoms include, but are not limited to, dioxolanyl, oxathiolanyl, dithiolanyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing 3 heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing 1 heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing 2 heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing 3 heteroatoms include, but are not limited to, triazinanyl, oxadiazinanyl, thiadiazinanyl, oxathiazinanyl, and dioxazinanyl. Exemplary 7-membered heterocyclyl groups containing 1 heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclyl groups containing 1 heteroatom include, but are not limited to, azocanyl, oxecanyl, and thieocanyl. Exemplary 5-membered heterocyclyl groups fused to a C6 aryl ring (also referred to herein as a 5,6-bicyclic heterocyclic ring) include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl groups fused to an aryl ring (also referred to herein as a 6,6-bicyclic heterocyclic ring) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

[0197] Unless otherwise specified, "heterocyclic alkyl" refers to a monocyclic, saturated "heterocyclic group" or "heterocycle" as defined above, with the same definition of ring atoms, i.e., containing 3 to 20 ring atoms ("3-20-membered heterocyclic alkyl"), and the number of heteroatoms is 1 to 4 (1, 2, 3 or 4), preferably 1 to 3 (1, 2 or 3), wherein each heteroatom is independently selected from N, O or S. One or more S ring atoms (if present) and / or one or more N ring atoms (if present) may optionally be oxidized, and one or more carbocyclic atoms may optionally be oxidized (i.e., forming an oxo group). Preferably containing 3 to 12 ring atoms ("3-12-membered heterocyclic alkyl"), more preferably containing 3 to 10 ring atoms ("3-10-membered heterocyclic alkyl"), even more preferably containing 3 to 8 ring atoms ("3-8-membered heterocyclic alkyl"), and even more preferably containing 3 to 4 ring atoms ("3-4-membered heterocyclic alkyl"). In some embodiments, each example of a heterocyclic alkyl group is independently optionally substituted, for example, unsubstituted (an “unsubstituted heterocyclic alkyl”) or substituted with one or more substituents (an “substituted heterocyclic alkyl”). The “heterocyclic group” or “heterocyclic” section above has given some exemplary examples of “heterocyclic alkyl”, and also includes, but is not limited to, azirropropyl, oxacyclopropyl, thiocyclopropyl, azirrobutyl, oxacyclobutyl, thiocyclobutyl, tetrahydrofuranyl, oxacyclohexyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, oxathiohexyl, oxazolyl, dioxyl, dithiohexyl, thiazolyl, pyrroliyl, pyrazolyl, imidazolinidine, etc.

[0198] Unless otherwise specified, the term "aryl" or "aromatic cycloyl" refers to a monocyclic, bicyclic, or tricyclic aromatic carbocyclic system containing 6-16 carbon atoms, or 6-14 carbon atoms, or 6-12 carbon atoms, preferably 6-10 carbon atoms. The term "aryl" may be used interchangeably with the term "aromatic cycloyl". Examples of aryl groups may include, but are not limited to, phenyl, naphthyl, anthraceneyl, phenanthryl, or pyrene.

[0199] The term "heteroaryl" or "heteroaromatic" means, unless otherwise specified, an aromatic monocyclic or polycyclic ring system containing 5-14 members, or preferably 5-10 members, or preferably 5-8 members, more preferably 5-6 members, wherein 1, 2, 3, or more ring atoms are heteroatoms and the remaining atoms are carbon, the heteroatoms being independently selected from O, N, or S, the number of heteroatoms preferably being 1, 2, or 3. Examples of heteroaryl groups include, but are not limited to, furanyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiadiazolyl, triazinyl, phtalazinyl, quinolinyl, isoquinolinyl, pteridinyl, purinyl, indolyl, isoindolyl, indazolyl, benzofuranyl, benzothienyl, benzopyridyl, benzopyrimidyl, benzopyrazinyl, benzimidazolyl, benzophthalazinyl, pyrrolo[2,3-b]pyridyl, imidazo[l,2-a]pyridyl, pyrazolo[l,5-a]pyridyl, pyrazolo[l,5-a]pyrimidyl, imidazo[l,2-b]pyridazinyl, [l,2,4]triazolo[4,3-b]pyridazinyl, [l,2,4]triazolo[l,5-a]pyrimidyl, [l,2,4]triazolo[l,5-a]pyridyl, and the like.

[0200] The term "salt" or "pharmaceutically acceptable salt" includes, unless otherwise specified, any of the following: acid salts, base salts, zwitterions, and quaternary ammonium complexes with inorganic and / or organic acids and bases. Salts of the compounds of the present application can be formed by methods known to those of ordinary skill in the art, for example, by reacting a compound of the present application with an amount of acid or base, such as an equivalent amount of acid or base, in a medium such as a salt precipitating medium or aqueous medium, followed by lyophilization.

[0201] The compounds of the present application contain a tricoordinate nitrogen atom, for example, a primary, secondary, or tertiary amino moiety, wherein, as is known, the lone pair of electrons present on the nitrogen atom can be protonated under appropriate reaction conditions with an appropriate acid or alkylated with an appropriate reagent, for example, an alkyl bromide, to provide a tetracoordinate charged nitrogen stabilized by the anion produced in the process, for example, a halide ion or a conjugate base. Thus, the compounds of the present application can be prepared in the form of a free base, or isolated in the form of a quaternary complex or salt complex. In some cases, where it is possible for an appropriate acid to protonate the basic nitrogen of the zwitterionic complex to form. When the term is employed herein, salts of the compounds of the present application include, whether acid salts with inorganic and / or organic acids, base salts with inorganic and / or organic bases, salts formed including zwitterionic properties (for example, where a compound contains both a basic moiety, for example, but not limited to, a nitrogen atom, for example, an amine, pyridine, or imidazole; and an acidic moiety, for example, but not limited to, a carboxylic acid), and quaternary ammonium complexes, within the scope of the compounds of the present application described herein.

[0202] Thus, structural representations of the compounds of the application, whether in free base form, salt form, zwitterion formation, or quaternary ammonium form, also encompass all other forms of such compounds discussed above. Accordingly, one aspect of the application is to provide the compounds of the application in the form of a pharmaceutically acceptable salt, zwitterion complex, or quaternary ammonium complex. Those skilled in the art will recognize examples of the compounds of the application that can form such complexes, including examples in which a tetra-coordinated nitrogen can be quaternized or protonated and the charged nitrogen form stabilized by an associated anion. The term "pharmaceutically acceptable salt" refers to salts (including quaternary ammonium complexes and internal salts such as zwitterion complexes) that possess similar or greater effectiveness than the free base form of the compound and are not biologically or otherwise undesirable (e.g., neither toxic nor otherwise deleterious to the recipient thereof).

[0203] The application encompasses both the free base form and all available salts of the compounds of the application, including salts that are generally considered safe and effective for the preparation of pharmaceutical formulations, as well as those that can be formed within the skill of the art at the present time and later classified as "generally recognized as safe" for the preparation of pharmaceutical formulations, referred to herein as "pharmaceutically acceptable salts." It is understood that the free base compounds can be prepared by controlling the conditions of isolation of the compounds during synthesis or by neutralization and ion exchange from salt forms of the compounds of the application.

[0204] Examples of pharmaceutically acceptable acid salts include, but are not limited to, acetate (including trifluoroacetate), adipate, alginate, ascorbate, aspartate, benzoate, besylate, bisulfate, borate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, methylsulfate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfate, sulfonate (such as those mentioned herein), tartrate, thiocyanate, toluenesulfonate (also known as tosylate), undecanoate, and the like.

[0205] The compounds of the present application also include "isotopically-labeled" derivatives thereof unless otherwise specified. The term "isotopically-labeled" means that the compounds of the present application can exist with one or more atoms replaced by an isotope of that atom, the atom having an atomic mass or mass number different from the atomic mass or mass number most commonly found in nature. The isotopes can be radioactive or non-radioactive. Isotopes that are commonly used as labels are: 2 H and 3 H; carbon isotopes: 13 C and 14 C; chlorine isotopes: 35 Cl and 37 Cl; fluorine isotopes: 18 F; iodine isotopes: 123 I and 125 I; nitrogen isotopes: 13 N and 15 N; oxygen isotopes: 15 O, 17 O and 18 O and sulfur isotopes 35 S. These isotopically-labeled compounds are useful in metabolic studies relating to the distribution of the pharmaceutical molecule within an organism. Isotopically-labeled compounds of this invention can generally be prepared by carrying out the procedures disclosed in the schemes and examples below, by either: 3 H and 13 C, are more readily available and are often simpler and easier to handle using standard synthetic procedures. Substitution of heavier isotopes, such as 2 H, for example, affords products that are useful in metabolic studies (including human

[0206] The compounds of the present application also include "solvates" thereof unless otherwise specified. The term "solvate" means a physical association of one or more solvent molecules with one or more of the compounds of the present application. This physical association can include hydrogen bonding. In certain instances, the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. Solvate molecules are in general capable of movement in the solvate structure. Solvates are generally identified by the solvent used in the solvation. For example, hydrates are solvates where water is the solvent. Non-limiting examples of solvates include but are not limited to ethanolates, methanolates and isopropanolates. Methods for solvation are generally known. The term "hydrate" means a compound having one or more water molecules in or on the crystalline structure of the compound. The compounds of the present application can exist in one or more tautomeric forms. The present application encompasses all tautomeric forms of the compounds of the present application.

[0207] The term "stereoisomers" means compounds which have identical chemical constitution, but differ in the arrangement of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers), geometric isomers (cis / trans), atropisomers, and the like. Any mixture of stereoisomers can be separated into their individual components by well-known techniques used by those skilled in the art, such as, for example, chromatographic and / or fractional crystallization techniques. Unless otherwise stated, the term "geometric isomers (cis / trans) isomers" can contain carbon-carbon double bonds or carbon-nitrogen double bonds in the E or Z configuration, wherein the term "E" represents the higher order substitution of the carbon-carbon or carbon-nitrogen double bond on opposite sides, and the term "Z" represents the higher order substitution of the carbon-carbon or carbon-nitrogen double bond on the same side (determined using the Cahn-Ingold Prelog priority rules). The compounds of the present application can also exist as mixtures of "E" and "Z" isomers.

[0208] Unless otherwise specified, the compounds of the present application also include "prodrugs" thereof. The term "prodrug" means a drug which is converted into the parent drug in vivo. Prodrugs are often useful because, in some situations, they can be easier to administer than the parent drug. Solubility or bioavailability properties of a prodrug can also be enhanced over the parent drug. For example, a prodrug can be designed to undergo rapid metabolic cleavage to release the parent drug, thereby permitting the use of lower dosages of the prodrug compared to the parent drug. A prodrug can also have improved physical properties, such as improved hpid or water solubility, over the parent drug. Examples of prodrugs can be any of the compounds of the present application which are administered as an ester (the "prodrug") to facilitate transport across a cell membrane, where water solubility is detrimental to mobility, but once inside the cell, is metabolically hydrolyzed to the carboxylic acid, the active entity. Another example of a prodrug can be a short peptide (polyamino acid) attached to the acid group, where the peptide is metabolized to reveal the active moiety.

[0209] Unless otherwise specified, the term "treatment" encompasses any treatment of a disease, disorder, and condition of a patient, and includes: (a) inhibiting the disease, disorder, and condition, i.e., arresting its development; or (b) relieving the disease, disorder, and condition, i.e., causing the disease or symptoms to regress; or (c) ameliorating or eliminating the disease, disorder, and condition or one or more symptoms associated with the disease.

[0210] A therapeutically effective amount of the present application means an amount sufficient to provide a pharmacological effect as measured by any suitable pharmacological endpoint. The term "pharmacological effect" means an effect on a biological system that is measurable by a pharmacological endpoint.

[0211] The abbreviations used in the Preparations, Examples, Test Examples, and elsewhere herein are:

[0212] Mg: milligram; mL: milliliter; g: gram; h: hour; °C: degree Celsius; NMR: nuclear magnetic resonance; DMF: N,N-dimethylformamide; DMSO: dimethyl sulfoxide; LC-MS: high performance liquid chromatography-mass spectrometry; Pd / C: palladium-carbon. Beneficial effects:

[0213] The present application has one or more of the following beneficial effects:

[0214] (1) The compound of the present application is a high-selectivity, high-activity PCSK9 inhibitor with oral absorption characteristics;

[0215] (2) The compound of the present application can effectively reduce the LDL-C level in serum;

[0216] (3) The compound of the present application can significantly improve the LDL uptake capacity of HepG2 cells;

[0217] (4) The compound of the present application can be used for treating cardiovascular diseases related to dyslipidemia;

[0218] (5) SPR test shows that the compound of the present application has high affinity for PCSK9 protein;

[0219] (6) The compound of the present application has good in vivo pharmacokinetic properties;

[0220] (7) The compound of the present application has excellent oral administration performance;

[0221] (8) The compound of the present application has no obvious inhibitory effect on hERG channel and has low cardiotoxicity risk;

[0222] (9) The present application studies a specific synthesis method, the synthesis method of the compound of the present application is simple in process and convenient to operate, which is beneficial to large-scale industrial production and application. BRIEF DESCRIPTION OF DRAWINGS

[0223] Figure 1 is a mass spectrum of the compound obtained in Example 1-1.

[0224] Figure 2 is a mass spectrum of the compound obtained in Example 2-1.

[0225] Figure 3 is a mass spectrum of the compound obtained in Example 3-1.

[0226] Figure 4 is a mass spectrum of the compound obtained in Example 4-1.

[0227] Figure 5 is a mass spectrum of the compound obtained in Example 7-1. DETAILED DESCRIPTION

[0228] The application will be further described in conjunction with specific examples. It should be understood that these examples are only used to illustrate the application and not intended to limit the scope of the application. The experimental methods in the following examples, if not otherwise specified, are usually carried out under conventional conditions or according to the conditions recommended by the manufacturers. Unless otherwise defined, all the professional and scientific terms used herein have the same meaning as understood by the skilled person in the art. In addition, any method and material similar or equivalent to those described herein can be applied to the methods of the application. The preferred methods and materials shown herein are only used for demonstration.

[0229] The structure of the compounds of the application is determined by nuclear magnetic resonance (NMR) or / and liquid chromatography-mass spectrometry (LC-MS) or / and high performance liquid chromatography (HPLC). The NMR determination uses a Bruker AVANCE III 600MHz instrument, the LC-MS uses an Agilent Technologies 6120 Quadrupole LC / MS and LCMS WATERS ACQUITY UPLC H-Class PLUS or / and SQD2; the HPLC uses a WATERS e2695_2998 or / and Agilent 1100.

[0230] The starting materials in the examples of the application are known and commercially available or can be synthesized using or according to methods known in the art.

[0231] The following are preparation examples of exemplary compounds of the application.

[0232] Synthesis of intermediate Int1:

[0233] Step 1: Preparation of intermediate 2

[0234] (2S,3S)-3-hydroxypyrrolidine-2-carboxylic acid (10.6 g) was dissolved in a mixture of tetrahydrofuran (50 mL) and water (50 mL), sodium bicarbonate (20.4 g) was added under stirring, the temperature was controlled at 0°C, and benzyl chloroformate (15.2 g) was slowly added dropwise. After the dropwise addition was completed, the temperature was raised to 20°C and the reaction was allowed to proceed for 1 h, and LC-MS detection showed that the reaction was complete. Tetrahydrofuran was removed under reduced pressure, and a 30% isopropyl alcohol and dichloromethane mixture was used for extraction, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain intermediate 2 (18 g), LC-MS: (M+H) + : 266.09.

[0235] Step 2: Preparation of intermediate 3

[0236] Intermediate 2 (18 g) was dissolved in methanol (100 mL), and trimethylsilyldiazomethane (50 mL) was added dropwise slowly. The reaction was stirred at room temperature for 2 h, and LC-MS was used to monitor the reaction. Acetic acid (1 mL) was added to quench the reaction. The reaction was concentrated, and the product was purified by silica gel column to give intermediate 3 (9.5 g). LC-MS: (M+H) + : 280.11. 1 H NMR (400 MHz, DMSO-d6) δ: 7.44-7.21 (m, 5H), 5.57 (t, 1H), 5.15-4.93 (m, 2H), 4.35-4.21 (m, 1H), 4.11 (d, J = 8.63 Hz, 1H), 3.65 (s, 2H), 3.58 (s, 1H), 3.56-3.42 (m, 2H), 1.92 (m, 1H), 1.86-1.74 (m, 1H).

[0237] Step 3: Preparation of intermediate 4

[0238] A 100 mL Schlenk flask was charged with intermediate 3 (9.0 g), dichloromethane (200 mL), and nitrogen was bubbled through for 10 min. Rhodium (II) acetate dimer (2.8 g) was added. The reaction mixture was cooled to 0 °C, and tert-butyl azide (6.9 g) was added dropwise slowly. The reaction was stirred for 2 h, and LC-MS was used to monitor the reaction. Water (100 mL) was added to quench the reaction, and dichloromethane was used to extract the product. The organic phase was combined, dried over anhydrous sodium sulfate, and concentrated. The product was purified by reverse phase preparative column to give intermediate 4. LC-MS: (M+H) + : 394.18.

[0239] Step 4: Preparation of intermediate Int1

[0240] Intermediate 4 (6.1 g) was dissolved in methanol, and 10% Pd / C (0.61 g) was added. The reaction mixture was bubbled through with hydrogen for 3 times, and the reaction was stirred at room temperature for 2 h. LC-MS was used to monitor the reaction. The reaction was filtered, and the filtrate was concentrated to give intermediate Int1. LC-MS: (M+H) + : 260.14.

[0241] Synthesis of intermediate Int2:

[0242] Step 1: Preparation of 6-(tert-butoxy)-N,N,N-trimethyl-6-oxohexan-1-aminidum bromide

[0243] 6-bromo-n-hexyl tert-butyl ester (2.5 g) was dissolved in acetonitrile (10 mL), 3-methyl-1-aminopropyl chloride hydrochloride (1.5 g) was added dropwise, and the mixture was stirred at 50°C for 12 h. The reaction was complete according to LC-MS. The reaction solution was removed under reduced pressure, and concentrated to dryness to obtain 6-(tert-butoxy)-N,N,N-trimethyl-6-oxohexan-1-aminium bromide (3.4 g). LC-MS: (M) + : 231.21.

[0244] Step 2: Preparation of intermediate Int2

[0245] 6-(tert-butoxy)-N,N,N-trimethyl-6-oxohexan-1-aminium bromide (3.4 g) was dissolved in dichloromethane (10 mL), and 2 mol / L hydrochloric acid in dioxane (30 mL) was added dropwise. The mixture was stirred at 20°C for 4 h. The reaction was complete according to LC-MS. The reaction solution was removed under reduced pressure, and concentrated to dryness to obtain intermediate Int2 (2.5 g). LC-MS: (M) + : 174.15.

[0246] Synthesis of intermediate Int3:

[0247] The preparation method was the same as that of intermediate Int2, except that 3-methyl-1-aminopropyl chloride hydrochloride was replaced by 1-methylpyrrolidine in step 1 to obtain intermediate Int3 (2.5 g). LC-MS: (M) + : 200.15.

[0248] Synthesis of intermediate Int4:

[0249] 2.5M lithium bis(trimethylsilyl)amide in n-hexane (21.2 mL) was added to a reaction bottle, which was cooled to -78°C. A solution of tert-butyl cyclopropylcarboxylate (5.0 g) and 1,4-dibromo-n-butane (15.2 g) in anhydrous tetrahydrofuran was slowly added, and the mixture was slowly warmed to room temperature and stirred for 5 h. The reaction was complete according to LC-MS. The reaction solution was poured into saturated ammonium chloride solution, extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, and separated by silica gel column chromatography. The eluent was concentrated under reduced pressure to obtain intermediate Int4 (10.5 g). LC-MS: (M+H) + : 277.07.

[0250] Synthesis of intermediate Int5:

[0251] The preparation method was the same as that of intermediate Int2, except that 6-bromo-n-hexyl tert-butyl ester was replaced by intermediate Int4 in step 1 to obtain intermediate Int5 (2.0 g). LC-MS: (M) + : 200.16.

[0252] Synthesis of intermediate 10:

[0253] Step 1: Preparation of intermediate 5

[0254] (S)-2-amino-3-(5-fluoro-lH-indol-3-yl)propionic acid (25 g) was dissolved in a mixed solvent of dioxane (150 mL) and water (150 mL), sodium bicarbonate (18.9 g) was added under stirring, and the temperature was controlled at 0 °C. Di-tert-butyl dicarbonate (27 g) was slowly added dropwise. After the dropwise addition was completed, the temperature was increased to 20 °C, and the reaction was allowed to proceed for 1 h. LC-MS detection showed that the reaction was complete. Dioxane was removed under reduced pressure, and dichloromethane was used for extraction. The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain intermediate 5 (31 g). LC-MS: (M+H) + : 323.13.

[0255] Step 2: Preparation of intermediate 6

[0256] Intermediate 5 (30 g) was dissolved in DMF (150 mL), and potassium carbonate (25.7 g) was added under stirring. The temperature was controlled at 0 °C, and methyl iodide (14.5 g) was slowly added dropwise. After the dropwise addition was completed, the temperature was increased to 20 °C, and the reaction was allowed to proceed for 2 h. LC-MS detection showed that the reaction was complete. Water (200 mL) was added to quench the reaction, and dichloromethane was used for extraction. The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain intermediate 6 (26 g). LC-MS: (M+H) + : 337.15.

[0257] Step 3: Preparation of intermediate 7

[0258] Intermediate 6 (25 g) was dissolved in DMSO (100 mL), and sodium hydroxide (5.9 g) was added under stirring. The temperature was controlled at 0 °C, and 3-bromopropene (9.8 g) was slowly added dropwise. After the dropwise addition was completed, the temperature was increased to 20 °C, and the reaction was allowed to proceed for 2 h. LC-MS detection showed that the reaction was complete. Water (200 mL) was added to quench the reaction, and dichloromethane was used for extraction. The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain intermediate 7 (22 g). LC-MS: (M+H) + : 363.16. 1H NMR (400 MHz, DMSO-d6) δ 12.6 (s, 1H), 7.38 (dd, J = 8.9 and 4.4 Hz, 1H), 7.31 (dd, J = 10.0 and 2.4 Hz, 1H), 7.22 (s, 1H), 6.90 (m, 2H), 5.95 (m, 1H), 5.12 (m, 1H), 4.99 (m, 1H), 4.77 (d, J = 5.3 Hz, 2H), 3.10 (m, 1H), 2.95 (m, 1H), 1.32 (s, 9H) 1.20 (br s, 1H);

[0259] Step 4: Preparation of Intermediate 8

[0260] Intermediate 7 (21 g) was dissolved in DMF (150 mL), potassium carbonate (16.0 g) was added under stirring, temperature was controlled at 0 °C, iodomethane (9.8 g) was added dropwise slowly. After the addition was completed, the temperature was increased to 20 °C and reacted for 2 h, LC-MS detection showed that the reaction was complete. The reaction was quenched by adding water (200 mL), extracted with dichloromethane, the combined organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain intermediate 8 (18 g), LC-MS: (M+H) + : 377.18.

[0261] Step 5: Preparation of Intermediate 9

[0262] Intermediate 8 (18 g) was dissolved in dichloromethane (100 mL), trifluoroacetic acid (20 mL) was added under stirring, after the addition was completed, the reaction was carried out at 20 °C for 1 h, LC-MS detection showed that the reaction was complete. The reaction solution was removed under reduced pressure, dichloromethane (100 mL) and water (100 mL) were added to the residue, the pH of the aqueous phase was adjusted to 9 with sodium carbonate, extracted, the combined organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain intermediate 9 (12 g), LC-MS: (M+H) + : 277.31.

[0263] Step 6: Preparation of Intermediate 10

[0264] Intermediate 9 (12 g) was dissolved in DMF (100 mL), (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)propanoic acid (22.3 g), 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (18.1 g), and diisopropylethylamine (15 mL) were added in sequence, the reaction was carried out at room temperature for 3 h, LC-MS detection showed that the reaction was complete. Dichloromethane (100 mL) and water (100 mL) were added to the reaction solution, extracted, the combined organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain intermediate 10 (12 g), LC-MS: (M+H) +:775.34.

[0265] Synthesis of intermediate 15:

[0266] Step 1: Preparation of intermediate 11

[0267] Intermediate 10 (12 g) was dissolved in methanol (100 mL), lithium hydroxide (1.9 g) was added under stirring, and the mixture was reacted at room temperature for 1 h. LC-MS detection showed that the reaction was complete. 1 mol / L hydrochloric acid (80 mL) was added to adjust the pH, and dichloromethane was used for extraction. The combined organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain intermediate 11 (11 g). LC-MS: (M+H) + :761.33.

[0268] Step 2: Preparation of intermediate 12

[0269] Intermediate 11 (11 g) and intermediate Int1 (3.7 g) were dissolved in DMF (50 mL), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (5.7 g) and diisopropyl ethylamine (5 mL) were added in sequence. The mixture was reacted at room temperature for 3 h. LC-MS detection showed that the reaction was complete. Dichloromethane (100 mL) and water (100 mL) were added to the reaction solution, and the mixture was extracted. The combined organic phase was dried over anhydrous sodium sulfate and separated by silica gel column preparation. The eluent was concentrated under reduced pressure to obtain intermediate 12 (10 g). LC-MS: (M+H) + :1002.46.

[0270] Step 3: Preparation of intermediate 13

[0271] Intermediate 12 (10 g) was dissolved in dichloromethane (100 mL), and trifluoroacetic acid (20 mL) was added under stirring. After the dropwise addition was completed, the mixture was reacted at 20°C for 1 h. LC-MS detection showed that the reaction was complete. The reaction solution was removed under reduced pressure, and dichloromethane (100 mL) and water (100 mL) were added to the residue. The pH of the aqueous phase was adjusted to 9 with sodium carbonate, and the mixture was extracted. The combined organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain intermediate 13 (6 g). LC-MS: (M+H) + :846.34.

[0272] Step 4: Preparation of intermediate 14

[0273] Intermediate 13 (6 g) was dissolved in DMF (50 mL), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (2.7 g), diisopropylethylamine (2.4 mL) were added successively, and the reaction was carried out at room temperature for 3 h. The reaction was complete according to LC-MS. The reaction solution was extracted with dichloromethane (100 mL) and water (100 mL), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain intermediate 14 (4 g), LC-MS: (M+H) + : 828.33.

[0274] Step 5: Preparation of intermediate 15

[0275] Intermediate 14 (2 g) was dissolved in tetrahydrofuran (30 mL) and water (30 mL), and the internal temperature was controlled at 0 °C. Sodium hydroxide (0.34 g) was slowly added under stirring. The reaction was carried out at 0 °C for 10 h. The reaction was complete according to LC-MS. 1 mol / L hydrochloric acid (15 mL) was added to adjust the pH, and the tetrahydrofuran solvent was spin-dried. The internal temperature was controlled at 0 °C, and acetone (30 mL), sodium carbonate (0.42 g), and 9-fluorenylmethyl-N-succinimidyl carbonate (0.98 g) were added. The reaction was carried out at 0 °C for 6 h. The reaction was complete according to LC-MS. The organic solvent was removed under reduced pressure, the water phase was adjusted to pH 4, and extracted with 30% isopropyl alcohol and dichloromethane solution. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification was performed by silica gel column separation to obtain intermediate 15 (2.2 g), LC-MS: (M+H) + : 814.32. 1 H NMR (400 MHz, DMSO-d6) δ 7.90 (d, J = 7.4 Hz, 2H), 7.79-7.67 (m, 2H), 7.48-7.28 (m, 8H), 7.17 (t, J = 7.6 Hz, 1H), 7.13-7.03 (m, 3H), 7.02-6.94 (m, 1H), 6.93-6.88 (m, 1H), 5.96-5.75 (m, 1H), 5.10-4.93 (m, 2H), 4.74-4.51 (m, 3H), 4.42-4.20 (m, 5H), 4.18-4.10 (m, 2H), 4.06-3.93 (m, 3H), 3.13-2.74 (m, 5H), 2.71-2.64 (m, 1H), 1.90-1.83 (m, 1H), 1.80-1.66 (m, 1H).

[0276] Synthesis of intermediate 21:

[0277] Step 1: Preparation of intermediate 16

[0278] The starting materials (S)-2-((tert-butoxycarbonyl)amino)-3-(4-methoxyphenyl)propionic acid (10 g) and (S)-2-methylpyrrolidine-2-carboxylic acid methyl ester hydrochloride (6.1 g) were dissolved in DMF (50 mL). 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (12.9 g) and diisopropylethylamine (11.8 mL) were added sequentially at 0 °C, and the reaction was allowed to proceed to room temperature for 4 h. LC-MS analysis confirmed the reaction was complete. Dichloromethane (100 mL) and water (100 mL) were added to the reaction mixture, and the mixture was extracted. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain intermediate 16 (11 g). LC-MS: (M+H) + :421.22.

[0279] Step 2: Preparation of Intermediate 17

[0280] Intermediate 16 (11 g) was dissolved in dioxane (50 mL), and dioxane hydrochloric acid solution (2 mol / L, 30 mL) was added dropwise with stirring. After the addition was complete, the reaction was carried out at 20 °C for 4 h, and the reaction was confirmed to be complete by LC-MS. The reaction solution was removed under reduced pressure, and dichloromethane (100 mL) and water (100 mL) were added to the residue. The pH of the aqueous phase was adjusted to 9 with sodium carbonate, and the mixture was extracted. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain intermediate 17 (7 g). LC-MS: (M+H) + :321.17.

[0281] Step 3: Preparation of Intermediate 18

[0282] Intermediate 17 (7.0 g) and N-((benzyloxy)carbonyl)-O-(tert-butyl)-L-threonine (6.7 g) were dissolved in DMF (100 mL). 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (8.4 g) and diisopropylethylamine (7.6 mL) were added sequentially, and the mixture was reacted at 0 °C for 4 h. LC-MS analysis confirmed the reaction was complete. Dichloromethane (100 mL) and water (200 mL) were added to the reaction mixture, and the mixture was extracted three times. The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain intermediate 18 (12 g). LC-MS: (M+H) + :612.32.

[0283] Step 4: Preparation of Intermediate 19

[0284] Intermediate 18 (9.5 g) was dissolved in methanol, and 10% Pd / C (1.0 g) was added. The reaction mixture was purged three times under a hydrogen atmosphere and reacted at room temperature for 2 h. The reaction was confirmed to be complete by LC-MS. The mixture was filtered, and the filtrate was collected and concentrated to obtain intermediate 19 (7.0 g). LC-MS: (M+H) + :478.28.

[0285] Step 5: Preparation of intermediate 20

[0286] Intermediate 19 (7.0 g) was dissolved in tetrahydrofuran (50 mL) and water (50 mL), lithium hydroxide (1.8 g) was added under stirring, the reaction was carried out at 45 °C for 24 h, LC-MS was used to monitor the reaction. The organic solvent was removed under reduced pressure, 1 mol / L hydrochloric acid (80 mL) was added to adjust the pH, dichloromethane was used to extract, the organic phase was combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain intermediate 20 (6 g), LC-MS: (M+H) + : 464.27.

[0287] Step 6: Preparation of intermediate 21

[0288] Intermediate 20 (6 g) was dissolved in tetrahydrofuran (30 mL) and water (30 mL), the internal temperature was controlled to 0 °C, sodium bicarbonate (2.2 g) and 9-fluorenylmethyl-N-succinimidyl carbonate (4.4 g) were added, the temperature was increased to 20 °C and the reaction was continued for 2 h, LC-MS was used to monitor the reaction. The organic solvent was removed under reduced pressure, the water phase was adjusted to pH 4, 30% isopropyl alcohol and dichloromethane solution was used to extract, the organic phase was combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated and purified by silica gel column to obtain intermediate 21 (6 g), LC-MS: (M+H) + : 686.33. 1 H NMR (400 MHz, DMSO-d6) δ 8.05 (d, J = 8.4 Hz, 1H), 7.89 (d, J = 7.6 Hz, 2H), 7.72 (t, J = 6.8 Hz, 2H), 7.42 (t, J = 7.5 Hz, 2H), 7.32 (t, J = 7.4 Hz, 2H), 7.19 - 7.13 (m, 2H), 6.84 - 6.73 (m, 3H), 4.66 (td, J = 8.2, 5.6 Hz, 1H), 4.39 - 4.18 (m, 3H), 3.94 (dd, J = 9.2, 4.9 Hz, 1H), 3.82 - 3.70 (m, 2H), 3.67 (s, 3H), 3.51 - 3.40 (m, 1H), 2.93 (dd, J = 13.9, 5.6 Hz, 1H), 2.63 (dd, J = 14.0, 8.2 Hz, 1H), 2.11 - 1.98 (m, 1H), 1.91 (s, 5H), 1.86 - 1.76 (m, 1H), 1.38 (s, 3H), 1.06 (s, 9H).

[0289] Synthesis of intermediate 25:

[0290] Step 1: Preparation of intermediate 22

[0291] Intermediate 22 (12 g) was dissolved in methanol, 10% Pd / C (1.2 g) was added, the reaction mixture was replaced with hydrogen atmosphere for 3 times, and the reaction was carried out at room temperature for 2 h. LC-MS detection showed that the reaction was complete. Filtration was performed, and the filtrate was concentrated to obtain intermediate 23 (6.0 g). LC-MS: (M+H) + : 353.15.

[0292] Step 2: Preparation of intermediate 23

[0293] Intermediate 22 (12 g) was dissolved in methanol, 10% Pd / C (1.2 g) was added, the reaction mixture was replaced with hydrogen atmosphere for 3 times, and the reaction was carried out at room temperature for 2 h. LC-MS detection showed that the reaction was complete. Filtration was performed, and the filtrate was concentrated to obtain intermediate 23 (6.0 g). LC-MS: (M+H) + : 219.13.

[0294] Step 3: Preparation of intermediate 24

[0295] Intermediate 23 (6.0 g) was dissolved in DMF (50 mL), ((9H-fluoren-9-yl)methoxy)carbonyl)-L-alanine (8.5 g), 1-hydroxybenzotriazole (4.0 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (5.7 g), and diisopropylethylamine (10.7 mL) were added in sequence, and the reaction was carried out at room temperature for 3 h. LC-MS detection showed that the reaction was complete. Dichloromethane (100 mL) and water (200 mL) were added to the reaction solution, extraction was performed, the organic phases were combined, saturated brine was added for washing, anhydrous sodium sulfate was added for drying, column chromatography was performed for separation, and the eluent was concentrated under reduced pressure to obtain intermediate 24 (7.0 g). LC-MS: (M+H) + : 512.23.

[0296] Step 4: Preparation of intermediate 25

[0297] Intermediate 24 (7.0 g) was dissolved in isopropanol (50 mL) and water (50 mL), sodium hydroxide (2.7 g) and calcium chloride (7.5 g) were added with stirring, and the reaction was carried out at 20°C for 3 h. LC-MS detection showed that the reaction was complete. The organic solvent was removed under reduced pressure, 1 mol / L hydrochloric acid (80 mL) was added to adjust the pH, extraction was performed with dichloromethane, the organic phases were combined, anhydrous sodium sulfate was added for drying, and concentration was performed under reduced pressure to obtain intermediate 25 (4.8 g). LC-MS: (M+H) + : 498.21.

[0298] Synthesis of intermediate 29:

[0299] Step 1: Preparation of intermediate 26

[0300] Bromobenzaldehyde (3.5 g), potassium (2-((tert-butoxycarbonyl)amino)ethyl)trifluoroborate (4.7 g), 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (0.68 g) and cesium carbonate (12.21 g) were placed in a round bottom flask, replaced with nitrogen for 3 times, added 1,4-dioxane (60 mL) and water (15 mL), heated to 100 °C for 3 h, LC-MS detection reaction was complete. Filtered, removed the organic solvent under reduced pressure, extracted with dichloromethane, combined the organic phase, dried over anhydrous sodium sulfate, column chromatography separation, eluent reduced pressure concentration to obtain intermediate 26 (3.5 g), LC-MS: (M+H) + : 250.13.

[0301] Step 2: Preparation of intermediate 27

[0302] Intermediate 26 (3.0 g) and pentenylamine (1.9 mL) were dissolved in dichloromethane (50 mL), reduced to 0 °C, acetic acid (0.69 mL) and sodium triacetylborohydride (7.6 g) were slowly added in turn, heated to 20 °C for 3 h, LC-MS detection reaction was complete. Added 1 mol / L hydrochloric acid (1 mL) to quench the reaction, added water, extracted with dichloromethane, combined the organic phase, dried over anhydrous sodium sulfate, column chromatography separation, eluent reduced pressure concentration to obtain intermediate 27 (3.1 g), LC-MS: (M+H) + : 319.23.

[0303] Step 3: Preparation of intermediate 28

[0304] Intermediate 27 (3.0 g) was dissolved in DMF (50 mL), monomethyl butyrate (1.4 g), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (4.3 g), diisopropylethylamine (3.9 mL), room temperature reaction for 3 h, LC-MS detection reaction was complete. Added dichloromethane (100 mL) and water (100 mL) to the reaction solution, extracted, combined the organic phase, dried over anhydrous sodium sulfate, separated by silica gel column, eluent reduced pressure concentration to obtain intermediate 28 (2.3 g), LC-MS: (M+H) + : 433.26.

[0305] Step 4: Preparation of intermediate 29

[0306] Intermediate 28 (2.3 g) was dissolved in dioxane (10 mL), hydrochloric acid dioxane solution (2 mol / L, 10 mL) was added under stirring, and the mixture was stirred at 20 °C for 4 h after the dropwise addition was completed. The reaction was detected by LC-MS. The reaction solution was removed under reduced pressure, and concentrated to obtain intermediate 29 (1.8 g). LC-MS: (M+H) + : 333.17. 1 H NMR (600 MHz, DMSO-d6) δ 8.10-8.01 (m, 3H), 7.08 (d, J = 7.8 Hz, 1H), 7.03-6.99 (m, 2H), 6.96 (d, J = 8.1 Hz, 1H), 5.64-5.53 (m, 1H), 4.86-4.70 (m, 2H), 4.37 (s, 1H), 4.29 (s, 1H), 3.39 (d, J = 12.7 Hz, 3H), 3.06-2.99 (m, 2H), 2.85-2.66 (m, 4H), 2.41-2.29 (m, 4H), 1.84-1.72 (m, 2H), 1.46-1.29 (m, 2H).

[0307] Synthesis of intermediate 39 hydrochloride:

[0308] Step 1: Preparation of intermediate 30

[0309] Intermediate 21 (3.0 g) was dissolved in DMF (50 mL), and intermediate 29 (1.8 g), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.9 g), and diisopropylethylamine (3.4 mL) were added sequentially at 0 °C. The mixture was stirred at room temperature for 3 h, and the reaction was detected by LC-MS. Ethyl acetate (100 mL) and water (100 mL) were added to the reaction solution, and the organic phase was extracted, dried over anhydrous sodium sulfate, and separated by column chromatography. The concentrated under reduced pressure to obtain intermediate 30 (3.0 g). LC-MS: (M+H) + : 1000.53.

[0310] Step 2: Preparation of intermediate 31

[0311] Intermediate 30 (3.5 g) was dissolved in acetonitrile (50 mL), and piperidine (1.5 g) was added at 0 °C. The mixture was stirred at room temperature for 3 h, and the reaction was detected by LC-MS. The reaction solution was concentrated under reduced pressure, and dichloromethane was added again. The mixture was concentrated and dried to obtain crude intermediate 31 (2.7 g). LC-MS: (M+H) + : 778.47.

[0312] Step 3: Preparation of intermediate 32

[0313] Intermediate 31 (2.3 g) and intermediate 15 (2.5 g) were dissolved in DMF (50 mL), n-propylphosphonic anhydride (1.0 g) and diisopropylethylamine (1.1 mL) were added at 0 °C, the reaction was allowed to warm to room temperature and stirred for 3 h. LC-MS indicated the reaction was complete. The reaction was diluted with dichloromethane (100 mL) and water (100 mL), the organic phase was extracted, washed with saturated sodium chloride, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give intermediate 32 (2.3 g). LC-MS: (M+H) + : 1573.77.

[0314] Step 4: Preparation of intermediate 33

[0315] A 100 mL Schlenk flask was charged with intermediate 32 (1.9 g), dichloromethane (20 mL) and glacial acetic acid (20 mL), and purged with nitrogen for 30 min. Grubbs second generation catalyst (0.51 g) was added. The reaction was allowed to warm to 50 °C and stirred under nitrogen. LC-MS indicated the reaction was complete after 5 h. The reaction was filtered and the filtrate was concentrated. The residue was purified by column chromatography to give intermediate 33. LC-MS: (M+H) + : 1545.7.

[0316] Step 5: Preparation of intermediate 34

[0317] Intermediate 33 (1.5 g) was dissolved in acetonitrile (50 mL), piperidine (0.43 g) was added at 0 °C, and the reaction was allowed to warm to room temperature and stirred for 2 h. LC-MS indicated the reaction was complete. The reaction was concentrated under reduced pressure, dichloromethane was added, and the reaction was concentrated and dried to give a crude product. The crude product was dissolved in DMF, intermediate 25 (0.49 g) was added, n-propylphosphonic anhydride (0.32 g) and diisopropylethylamine (0.35 mL) were added at 0 °C, and the reaction was allowed to warm to room temperature and stirred for 3 h. LC-MS indicated the reaction was complete. The reaction was diluted with dichloromethane (100 mL) and water (100 mL), the organic phase was extracted, washed with saturated sodium chloride, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give intermediate 34 (1.3 g). LC-MS: (M+H) + : 1802.88.

[0318] Step 6: Preparation of intermediate 35

[0319] Intermediate 34 (0.89 g) was dissolved in DMF (10 mL), piperidine (2.0 mL) was added at 0 °C, and the reaction was allowed to warm to room temperature and stirred for 3 h. LC-MS indicated the reaction was complete. The reaction was concentrated under reduced pressure, dichloromethane was added, and the reaction was concentrated and dried to give a crude product, intermediate 35 (0.61 g). LC-MS: (M+H) + : 1580.81.

[0320] Step 7: Preparation of intermediate 36

[0321] Intermediate 35 (0.61 g) was dissolved in tetrahydrofuran (5 mL) and water (5 mL), lithium hydroxide (96 mg) was added under stirring, the reaction was carried out at 0 °C for 2 h, LC-MS was used to monitor the reaction. The organic solvent was removed under reduced pressure, 1 mol / L hydrochloric acid (4 mL) was added to the water phase to adjust the pH to 5, the residue was lyophilized, and the trifluoroacetate salt of intermediate 36 was separated by C18 preparative column (0.51 g). The trifluoroacetate salt was dissolved in a mixed solvent of acetonitrile and water, 0.1 mol / L hydrochloric acid solution was slowly added, the reaction was carried out at 0 °C for 10 min, and the hydrochloride salt of intermediate 36 was obtained by lyophilization (0.50 g). LC-MS: (M+H) + :1566.79.

[0322] Step 8: Preparation of intermediate 37

[0323] The hydrochloride salt of intermediate 36 (0.50 g) was dissolved in DMF (25 mL) and dichloromethane (25 mL), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.13 g), diisopropyl ethylamine (0.11 mL) were added under stirring, the reaction was carried out at room temperature for 18 h, LC-MS was used to monitor the reaction. The organic solvent was removed under reduced pressure, dichloromethane, saturated brine were added, extraction, anhydrous sodium sulfate was used for drying, and intermediate 37 was separated by C 18 preparative column (0.37 g). LC-MS: (M+H) + :1548.78.

[0324] Step 9: Preparation of intermediate 38

[0325] Intermediate 37 (0.31 g) was dissolved in tetrahydrofuran, 10% Pd / C (0.03 g) was added, the reaction mixture was replaced with hydrogen atmosphere for 3 times, the reaction was carried out at room temperature for 8 h, LC-MS was used to monitor the reaction. Filtration was performed, the filtrate was collected, and column chromatography was used for separation, and intermediate 38 was obtained by concentration. LC-MS: (M+H) + :1550.80.

[0326] Step 10: Preparation of intermediate 39 hydrochloride

[0327] Intermediate 16 (0.25 g) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (20 mL) was added with stirring, dropwise, and the reaction was allowed to proceed at 20 °C for 1 h. The reaction was monitored by LC-MS. The reaction was concentrated under reduced pressure, dichloromethane (10 mL) and toluene (10 mL) were added to the residue, and the mixture was concentrated under reduced pressure. The residue was dissolved in dichloromethane, 2 mol / L hydrochloric acid in dioxane (2 mL) was added slowly, and the reaction was allowed to proceed at 20 °C for 1 h. The reaction was monitored by LC-MS. The reaction was concentrated under reduced pressure to give intermediate 39 hydrochloride (0.1 g), LC-MS: (M+H) + : 1394.69.

[0328] Synthesis of intermediate 40:

[0329] The preparation method was the same as that of intermediate 25, except that ((9H-fluoren-9-yl)methoxy)carbonyl)-L-cyclopropylalanine was used instead of ((9H-fluoren-9-yl)methoxy)carbonyl)-L-alanine in step 3, to give intermediate 40 (150 mg), LC-MS: (M+H) + : 524.23.

[0330] Synthesis of intermediate 41:

[0331] The preparation method was the same as that of intermediate 39, except that intermediate 40 was used instead of intermediate 25 in step 5, to give intermediate 41 (53.1 mg), LC-MS: (M+H) + : 1420.70.

[0332] Synthesis of intermediate 42:

[0333] The preparation method was the same as that of intermediate 29, except that 4-bromo-2-fluorobenzaldehyde was used instead of p-bromobenzaldehyde, to give intermediate 42 (160 mg), LC-MS: (M+H) + : 352.20.

[0334] Synthesis of intermediate 43:

[0335] The preparation method was the same as that of intermediate 39, except that intermediate 42 was used instead of intermediate 25 in step 5, to give intermediate 43 (59.4 mg), LC-MS: (M+H) + : 1412.70.

[0336] Synthesis of intermediate 44:

[0337] Preparation method same as intermediate 21, only the raw material p-Boc-4-methoxy-L-phenylalanine is replaced by Boc-4-trifluoromethoxy-L-phenylalanine to obtain intermediate 44 (160 mg), LC-MS: (M+H) + : 740.30.

[0338] Synthesis of intermediate 45:

[0339] Preparation method same as intermediate 39, only intermediate 25 in step 5 is replaced by intermediate 44 to obtain intermediate 45 (59.4 mg), LC-MS: (M+H) + : 1448.66.

[0340] Synthesis of intermediate 45:

[0341] Step 1: Synthesis of intermediate 46-2

[0342] Compound 46-1 (15 g) was dissolved in 25 mL water and 25 mL ethanol at room temperature, and sodium sulfite (2.79 g) was added. Stirring was carried out at 100°C for 16 hours. After the reaction was completed, the organic phase was concentrated under reduced pressure. Filtration, purification by reverse phase MPLC on C 18 18 column, eluted with 0.1% TFA in water / acetonitrile (1:1) to obtain intermediate 46-2 (0.7 g). LC-MS: m / z = 229 / 231 [M-1] + .

[0343] Step 2: Synthesis of intermediate 46-3

[0344] Intermediate 46-2 (0.7 g) was dissolved in 10 mL acetonitrile at room temperature. Trimethylamine (3 mL) was added to the reaction system, and the reaction was carried out at 60°C for 16 hours. After the reaction was completed, it was concentrated under reduced pressure to obtain intermediate 46-3 (0.8 g, crude product).

[0345] Step 3: Synthesis of intermediate 46

[0346] Intermediate 46-3 (0.4 g) was dissolved in 10 mL DCM at room temperature, SOCl2 (0.34 g) was added to the reaction system, and finally DMF (1 drop) was added. After 4 hours of reaction, intermediate 46 (crude product) was obtained, which was used directly in the next step without purification.

[0347] Example 1-1 (compound 11):

[0348] Intermediate 39 hydrochloride (0.10 g) and intermediate Int 3 (18.0 mg) were dissolved in DMF (10 mL) and water (1 mL), 2-(7-azobenzotriazol)-N,N,N',N'- tetramethyluronium hexafluorophosphate (30.4 mg), diisopropylethylamine (25.1 μL) were added under stirring, the reaction was carried out at room temperature for 6 h, the reaction was checked by LC-MS. The organic solvent was removed under reduced pressure, dichloromethane was added, saturated brine was extracted, dried over anhydrous sodium sulfate, and the target compound (0.05 g) was obtained by using C 18 Preparative column separation gave example 1-1 trifluoroacetate salt, using AG MP-1 (chloride type) exchange resin, 20% acetonitrile water as mobile phase, to obtain the target compound (0.05 g). LC-MS: (M) + : 1576.7.

[0349] Example 2-1 (compound 47):

[0350] Intermediate 39 hydrochloride (0.10 g) and intermediate Int 5 (14.7 mg) were dissolved in DMF (10 mL) and water (1 mL), 2-(7-azobenzotriazol)-N,N,N',N'- tetramethyluronium hexafluorophosphate (30.4 mg), diisopropylethylamine (25.1 μL) were added under stirring, the reaction was carried out at room temperature for 6 h, the reaction was checked by LC-MS. The organic solvent was removed under reduced pressure, dichloromethane was added, saturated brine was extracted, dried over anhydrous sodium sulfate, and the target compound (0.05 g) was obtained by using C 18 Preparative column separation gave example 2-1 trifluoroacetate salt, using AG MP-1 (chloride type) exchange resin, 20% acetonitrile water as mobile phase, to obtain the target compound (0.05 g). LC-MS: (M) + : 1576.8.

[0351] Example 3-1 (compound 73):

[0352] The preparation method is the same as example 2-1, only intermediate 39 is replaced by intermediate 41, to obtain the target compound (15.1 mg), LC-MS: (M) + : 1575.7.

[0353] Example 4-1 (compound 8):

[0354] The preparation method is the same as example 2-1, only intermediate 39 is replaced by intermediate 43, to obtain the target compound (19.7 mg), LC-MS: (M) + : 1568.8.

[0355] Example 5-1 (compound 18):

[0356] The preparation method is the same as in Example 1-1, except that intermediate 39 is replaced by intermediate 45, to obtain the target compound (23.7 mg). LC-MS: (M) + : 1603.8.

[0357] Example 6-1 (compound 37):

[0358] The preparation method is the same as in Example 1-1, except that intermediate 39 is replaced by intermediate 43, to obtain the target compound (15.1 mg). LC-MS: (M) + : 1594.7.

[0359] Example 7-1 (compound 76):

[0360] Intermediate 39 (200 mg), DMAP (1.75 mg) and triethylamine (43 mg) were added to a DCM (10 mL) solution at room temperature. Intermediate 46 (dissolved in 5 mL DCM) was slowly added dropwise to the reaction solution at 0°C, and stirred at 0°C for 2 hours. After the reaction was completed, it was concentrated under reduced pressure, purified by reverse phase MPLC on C 18 to obtain the target compound (7.6 mg). LC-MS: (M) + : 1585.5.

[0361] The following are the effect tests and data of the compounds in this application.

[0362] Test Example 1: HepG2 cell in vitro LDL uptake test

[0363] 1. HepG2 cells were cultured in MEM medium containing 10% FBS, and incubated at 37°C, 5% CO2. 100 μL of cells were added to a poly-D-lysine coated 96-well culture plate at a density of 20,000 cells per well. The cell plate was incubated at 37°C, 5% CO2 overnight;

[0364] 2. The HepG2 cells were starved with MEM medium without FBS. The cell plate was incubated at 37°C, 5% CO2 overnight.

[0365] 3. After a series of concentrations of compounds and PCSK9 protein were pre-incubated for 1 h, the starved cell culture medium was removed, and a certain volume of pre-incubation solution was added to each well to make the final concentration of PCSK9 protein 5 μg / mL. The cell plate was incubated at 37°C, 5% CO2 for 23 h;

[0366] 4. Remove the supernatant of the cell plate, add a certain volume of BODIPY™ FL LDL (ThermoFisher) to each well to make its final concentration 10 μg / mL, avoid light incubation for 4 h;

[0367] 5. Remove the supernatant of the cell plate, wash each well with 200 μL of PBS for 2 times, read with a microplate reader (bottom reading), excitation wavelength is 480 nm, emission wavelength is 530 nm.

[0368] The test results show that the compound of the present application can significantly improve the LDL uptake capacity of HepG2 cells. The test results of the exemplary compounds are shown in the following table.

[0369] Note: A represents EC 50 <200nΜ, B represents 200nM≤EC 50 <300nΜ, C represents EC 50 ≥300nΜ.

[0370] The structure of the control compound is as follows, and its preparation method refers to the preparation method of compound 1 in patent WO2023023245:

[0371] Test Example 2: PCSK9 in vitro binding test

[0372] The ability of different compounds to bind to PCSK9 protein was detected by a conventional surface plasmon resonance (SPR) method.

[0373] Test parameters

[0374] 1) Protein: PCSK9, Acro

[0375] 2) Chip: SA chip

[0376] 3) Experimental temperature: 25℃

[0377] 4) Experimental flow rate: 30 uL / min

[0378] 5) Fixing method: tag capture method

[0379] 6) Binding determination mode: multi-cycle kinetics

[0380] 7) Buffer:

[0381] a) Protein fixation: HBSP + 0.1 mM CaCL2, pH 7.4

[0382] b) Compound analysis: HBSP + 0.1 mM CaCL2, pH 7.4, 4% DMSO

[0383] Protein fixation

[0384] 1) The PCSK9 (Acro) protein is immobilized on the SA chip by biotin-SA tag capture, and after immobilization, the channel is blocked.

[0385] 2) The reference channel is blocked.

[0386] Analysis test

[0387] 1) Compound analysis buffer (HBSP + 0.1 mM CaCL2, pH 7.4, 4% DMSO) is configured and filtered with a 0.22 μm filter membrane.

[0388] 2) A series of concentration gradients of the compound are configured, a total of 8 concentrations, and multi-cycle detection is performed.

[0389] Data analysis

[0390] The final binding dissociation curve is obtained after subtracting the reference channel and buffer blank control from the experimental channel signal value, and the affinity data is obtained by fitting according to the 1:1 binding mode kinetics method.

[0391] The test results show that the compound has a high affinity for PCSK9 protein (all less than 1 nM, preferably the compound K D value is less than 500 pM, more preferably the compound K D value is less than 20 pM), and the test results of the exemplary compounds are shown below.

[0392] Note: A represents K D <20 pM, B represents 20 pM ≤ K D <500 pM. The structures of the control compounds are as follows:

[0393] Test Example 3: Mouse PK test

[0394] Male ICR mice are given the compound by gavage at 10 mg / kg (combined with 400 mg / kg sodium decanoate) or intravenous administration at 1 mg / kg, and at different time points after administration (gavage group: 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 8 h, 24 h; intravenous group: 0.083 h, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 8 h, 24 h), 100 μL of blood is taken from the mouse orbit and placed in an EDTA-K2 anticoagulant tube, and within 2 h, 3000 g centrifugation for 10 min to obtain mouse plasma samples. The drug concentration in the mouse plasma after administration is determined by HPLC-MS / MS method, the drug-time curve is drawn, and the pharmacokinetic parameters are calculated. The pharmacokinetic behavior of the compound in mice after administration is described by non-compartment model statistical moment parameters.

[0395] The test results show that the compounds of the present application have good in vivo pharmacokinetic properties and excellent oral administration performance. Exemplary compounds are shown in the following table.

[0396] Main pharmacokinetic parameters in plasma after intravenous administration

[0397] Main pharmacokinetic parameters in plasma after intragastric administration

[0398] Note: The structure of the control compound is as follows:

[0399] Test Example 4: In vitro inhibition test on human potassium ion channel (hERG)

[0400] Experimental equipment: The electrophysiological detection was performed using a full-automatic patch clamp QPatch 48X (Sophion) device.

[0401] Experimental procedure: The prepared cells were placed on the centrifuge of the Qpatch workbench, and the cells were washed using the multiple centrifugation / suspension method, and the cell culture medium was replaced with an extracellular solution. A MTP-96 plate was taken out and then placed in the position of the MTP source. The QPlate chip was taken out and then placed in the Qplate source position. The mechanical arm scanned the MTP-96 plate and the QPlate chip bar code, and grabbed to the measurement station. The intracellular and extracellular solutions were taken from the liquid pool and added to the intracellular solution pool and the cell and test substance pool of the QPlate chip, respectively. In the measurement station, all measurement sites on the QPlate were subjected to initial quality control. The quality control process included taking the cell suspension from the cell container of the centrifuge, and positioning the cells on the chip hole through the pressure controller, establishing a high resistance seal, and forming a whole cell recording mode. Once a stable control current baseline was obtained, the test substance was applied to the cells in a concentration gradient from the test substance MTP-96 plate. The current detected in each cell in the extracellular solution without the compound served as its own control group, and two cells were independently detected. All Qpatch electrophysiological tests were performed at 24°C.

[0402] Compound treatment: The compound dilution gradient was 0.3, 1, 3, 10, 30 μM gradient

[0403] Data processing: IC values were calculated using GraphPad Prism software. 50

[0404] The test results show that the compounds of the present application have no obvious inhibition effect on the hERG channel within the detection concentration range of the present test, indicating that the compounds of the present application have a lower cardiotoxicity risk. ​

[0405] Test Example 5: Pharmacodynamic test of B6-hPCSK9-CDS mouse hyperlipidemia animal model

[0406] Male B6-hPCSK9-CDS transgenic C57 mice, after the animals arrived at the barrier system, adapt for 2-10 days, start to feed Western Diets feed, after a period of time, collect mouse blood from the eye socket into an EP tube, stand at room temperature for 30 min, then centrifuge at 8000 rpm for 10 min to collect mouse serum samples, use a full-automatic blood biochemical instrument to detect the LDL-C level in the serum, according to the LDL-C level of the mice, randomly group, oral administration, the detection index during the test is the LDL-C level in the serum. The change rate of LDL-C is calculated by the following formula.

[0407] LDL-C change rate = [(LDL-C after administration) - (LDL-C on the day of administration)] / (LDL-C on the day of administration) x 100%

[0408] The test results show that the compound of the application can effectively reduce the LDL-C level in the serum.

Claims

A compound as shown in formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, having the following structure: wherein Ring A is X1, X2, X3, X4, X5, X 11 each independently selected from hydrogen, deuterium, halogen, nitro, amino, hydroxyl, carboxyl, cyano, alkylsulfonyl, alkylester, alkylphosphonyl, C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-12 membered heterocyclyl, said amino, C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl and 3-12 membered heterocyclyl are optionally substituted with one or more substituents selected from deuterium, halogen, nitro, hydroxyl, amino, hydroxyl, oxo, thioxo, carboxyl, cyano, alkylsulfonyl, alkylester, alkylphosphonyl, C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl and 3-12 membered heterocyclyl are optionally substituted with one or more substituents selected from deuterium, halogen, nitro, hydroxyl, amino, hydroxyl, oxo, thioxo, carboxyl, cyano, alkylsulfonyl, alkylester, alkylphosphonyl, C or X2, X3 together with the atoms to which they are attached form C 3-6 cycloalkyl, C 3-6 heterocyclyl, phenyl, 5-6 membered heteroaryl, said cycloalkyl, heterocyclyl, phenyl and heteroaryl optionally substituted with one or more substituents selected from deuterium, halogen, nitro, amino, hydroxyl, oxo, thioxo, carboxyl, cyano, sulfonyl, ester, phosphine, C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, said cycloalkyl and heterocyclyl optionally substituted with one or more substituents selected from deuterium, halogen, nitro, amino, hydroxyl, oxo, thioxo, carboxyl, cyano, sulfonyl, ester, phosphine, C X6is independently selected from H, -C(O)-, -CH(R a )C(O)-, -CH(R a )OC(O)-, -C(O)O-, "*" end represents the connection with O end, "#" end represents the connection with X7 end; when X6 is H, X7, X8 are not present; X7, X9are each independently selected from the group consisting of: a bond, -[(CHR d ) p1 OC(O)] p2 -, -[(CHR d ) p1 O] p2 -, -[(CHR d ) p1 OC(O)O] p2 -, -[(CHR d ) p1 C(O)O] p2 -[(CHR d ) p O] p3 -, -[(CHR d ) p1 C(O)O] p2 -[(CHR d ) p1 OC(O)O] p3 -, -[(CHR d ) p1 OP(O)(OR e )O] p2 -, -[(CHR d ) p1 OP(O)(OR e )O] p2 -[(CHR d ) p1 OC(O)] p3 -, -[(CR d =CR d ) p3 C(O)O] p2 -[(CHR d ) p1 O] p3 -, -[(CR d =CR d ) p3 C(O)O] p2 -[(CHR d ) p1 OC(O)O] p2 - ; X8is independently selected from hydrogen, C 1-6 alkyl, C 3-6 carbocyclyl, 3-6 membered heterocyclyl, said C 1-6 alkyl, C 3-6 carbocyclyl and 3-6 membered heterocyclyl are optionally substituted with one or more substituents selected from R b ; X 10 independently selected from hydrogen, C 1-6 alkyl, said C 1-6 alkyl is optionally substituted with one or more substituents selected from the group consisting of R c ; p1, p2 and p3 are each independently selected from 0, 1, 2, 3, 4, 5; R d independently selected from hydrogen, halogen, amino, cyano, nitro, hydroxy, thioxy, C 1-6 alkyl, C 3-6 cycloalkyl, said C 1-6 alkyl and C 3-6 cycloalkyl are optionally substituted with one or more substituents selected from R f ; R e independently selected from hydrogen, C 1-6 alkyl, benzyl, said C 1-6 alkyl and benzyl are optionally substituted with one or more substituents selected from R g ; R a , R b , R c , R f , R g are each independently selected from the group consisting of hydrogen, halogen, amino, cyano, nitro, hydroxy, thio, C 1-6 alkyl, benzyl; R1, R2are each independently selected from the group consisting of hydrogen, deuterium, -L 1 m1 -L 2 m2 -L 3 m3 -L 4 m4 -L 5 m5 -L 6 m6 -R3, C 1-6 alkyl, C 1-6 alkoxy, C 3-10 cycloalkyl, 3-12 membered heterocyclyl, said C 1-6 alkyl, C 1-6 alkoxy, C 3-10 cycloalkyl and 3-12 membered heterocyclyl are optionally substituted with one or more substituents selected from the group consisting of deuterium, halogen, hydroxyl, amino, hydroxyl, oxo, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-6 cycloalkyl, 3-6 membered heterocyclyl; L 1 、L 2 、L 3 、L 4 、L 5 、L 6 each independently is selected from: -O-, -N(R8)-, -S-, -C(O)-, -C(O)O-, -N(R8)C(O)-, -SO-, -SO2-, -SO2N(R8)-, -N(R8)C(O)O-, -OC(O)O-, -N(R8)C(O)N(R8)-, -N(R8)S(O)2N(R8)-, -S(O)(NR8)-, -S(O)(NR8)N(R8)-, C 1-6 alkylene, C 2-8 alkenylene, C 2-8 alkynylene, C 2-6 heteroalkylene, C 3-10 cycloalkylene, 4-10 membered heterocyclyl ene, C 6-10 arylene, 5-10 membered heteroarylene; said C 1-6 alkylene, C 2-8 alkenylene, C 2-8 alkynylene, 2-6 membered heteroalkylene, C 3-10 cycloalkylene, 4-10 membered heterocyclyl ene, C 6-10 arylene and 5-10 membered heteroarylene are optionally substituted with 1 to 3 substituents selected from Z1; m1, m2, m3, m4, m5, m6 are each independently selected from 0, 1, 2, 3, and the sum of m1+m2+m3+m4+m5+m6 is less than 6; Z1is independently selected from oxo, halo, amino, hydroxyl, nitro, cyano, -OR9, -C(O)R9, -C(O)OR9, -C(O)N(R9)2, -N(R9)2, -N(R9)C(O)R9, -N(R9)C(O)OR9, -N(R9)C(O)N(R9)2, -N(R9)S(O)2(R9), -NR9, S(O)2N(R9)2, -NR9S(O)2, O(R9), -OC(O)R9, -OC(O)OR9, -OC(O)N(R9)2, -SR9, -S(O)R9, -SF5, -S(O)(NR9)R9, -S(O)2R9, -S(O)2N(R9)2, -C(O)N(R9)S(O)2R9, -S(O)2N(R9)CR9, C 1-8 alkyl, C 1-6 alkoxy, C 2-8 alkenyl, C 2-8 alkynyl, C 3-10 cycloalkyl, 4-10 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl; said C 1-8 alkyl, C 1-6 alkoxy, C 2-8 alkenyl, C 2-8 alkynyl, C 3-10 cycloalkyl, 4-10 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl are optionally substituted with 1 to 3 substituents selected from Z 1a ; or any two Z1together with the atom(s) to which they are attached form a C 3-6 cycloalkyl, C 3-6 heterocyclyl, phenyl, 5-6 membered heteroaryl; Z 1a independently selected from halogen, amino, cyano, hydroxy, C 1-6 alkyl, C 1-6 alkoxy; R8, R9are each independently selected from the group consisting of hydrogen, deuterium, C 1-6 alkyl, C 1-6 alkoxy; R3is independently selected from -NH2, -N + H3, -N + (C 1-3 alkyl)3, -NH-C(O)-L 1 m1 -L 2 m2 -L 3 m3 -L 4 m4 -L 5 m5 -L 6 m6 -R4, wherein R4is independently selected from -NH2, -N + H3, -N + (C 1-3 alkyl)3or n is independently selected from 1, 2; R5is independently selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 alkoxy, C 3-10 cycloalkyl, 3-12 membered heterocyclyl; Alternatively, R2 and R5, together with the carbon atom they are attached to, can optionally be formed by one or more elements selected from deuterium, halogen, amino, hydroxyl, cyano, C. 1-6 Alkyl, C 1-6 The C substituent of the alkoxy group 3-6 cycloalkyl or C 3-6 Heterocyclic groups; with the proviso that when X1is H, X2is halogen, X3is H, X4is methoxy, X5is H, X6is H, X7and X8are absent, R4is hydrogen, ring A is at the time, R 1 or R 2 is not: a) H; b) - (CH2) z - R 1a , wherein z is an integer from 1 to 6, and R 1a is: ii) -H, -NH2, -N + H3or -N + (CH3)3; ii) -NH-C(O)-[(CH2)2-O-]2-(CH2)2R 1B wherein R 1B is -NH2, -N + H3, -N(CH3)2or -N + (CH3)3; iii) -NH-C(O)-[(CH2) y1 -O-]2-(CH2) y2 R 1B wherein y1, y2 are each independently an integer from 2 to 4, and are not both 2; R 1B is -NH2, -N + H3, -N(CH3)2 or -N + (CH3)3; iv) -NH-C(O)-(CH2) y R 1C wherein y is an integer from 1 to 6; R 1C is -O-(CH2) za -N + (CH3)3, wherein za is an integer from 2 to 4; c) -(CR 1D ) zb NR-C(O)-(CR 1D ) zb [O(CR 1D ) n ] zc -N + (CH3)3, wherein R 1D is H or C 1-6 alkyl, zb is an integer from 1 to 6, and zc is an integer from 0 to 4; Unless otherwise specified, the heteroatoms in the above heterocyclyl, heteroaryl are independently selected from O, N or S, and the number of heteroatoms is 1, 2, 3 or 4. The compound according to claim 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: Ring A is and / or, X 11 independently selected from hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, 3-6 membered heterocyclyl; or X 11 independently selected from hydrogen, halogen, C 1-3 alkyl, C 3-4 cycloalkyl; or X 11 is independently selected from hydrogen, fluorine, chlorine, methyl, cyclopropyl; preferably hydrogen; or Ring A is or Ring A is "**" represents the connection with methylene end, "##" represents the connection with ethylene end. The compound according to any one of claims 1-2, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: X1is independently selected from hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 alkoxy; or X1is independently selected from hydrogen, halogen, C 1-3 alkyl; or X1 is independently selected from hydrogen, fluorine, chlorine, methyl; and / or, X2 is independently selected from hydrogen, deuterium, halogen; preferably halogen; more preferably fluorine; and / or, X3 is independently selected from hydrogen, deuterium, halogen; preferably hydrogen, halogen; more preferably hydrogen, fluorine, chlorine; or X3 is independently selected from hydrogen, fluorine; and / or, X4is independently selected from hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy; or X4is independently selected from halogen, C 1-6 alkyl, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy; X4is independently selected from C 1-6 alkyl, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy; or X4is independently selected from C 1-3 alkyl, C 1-3 deuteroalkoxy, C 1-3 haloalkoxy; or X4 is independently selected from -OCH3, -OCD3, -OCF3, -OCHF2, Cl; or X4 is independently selected from -OCH3, -OCD3, -OCF3, -OCHF2; preferably -OCH3; and / or, X5 is independently selected from hydrogen, deuterium, halogen; preferably hydrogen. The compound according to any one of claims 1 to 3, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: X6is independently selected from H, -C(O)-, -CH(R a )OC(O)-, "*" end represents the connection with O end, "#" end represents the connection with X7 end; when X6 is H, X7, X8 are not present; and / or, X7, X9are independently selected from the group consisting of: a bond, -[(CHR d ) p1 OC(O)O] p2 -、-[(CHR d ) p1 C(O)O] p2 -、-[(CR d =CR d ) p3 C(O)O] p2 -; or X7, X9are each independently selected from the group consisting of: a bond, -(CHR d ) p1 OC(O)O-, -(CHR d ) p1 C(O)O-, -(CR d =CR d ) p3 C(O)O-; and / or, X7 is a bond, -CH2OC(O)O-, -CH=CHC(O)O- or -CH2CH2C(O)O-; and / or, X9 is a bond or -CH2OC(O)O-; and / or, X8is independently selected from the group consisting of hydrogen, C 1-6 alkyl; preferably hydrogen, C 1-4 alkyl; or X8 is independently selected from hydrogen, methyl, -C(CH3)3, -CH(CH3)2; and / or, X 10 independently selected from hydrogen, C 1-4 alkyl; preferably hydrogen, methyl, -C(CH3)3, -CH(CH3)2; or X 10 is hydrogen or -CH(CH3)2; or X6 is H, X7, X8 are not present; and / or, p1, p2 and p3 are each independently selected from 0, 1, 2; or p1 is 1, 2, p2 is 1, p3 is 0, 1; and / or, R a independently selected from hydrogen, C 1-6 alkyl; preferably hydrogen, C 1-2 alkyl; more preferably hydrogen, methyl; and / or, R d independently selected from hydrogen, C 1-6 alkyl; preferably hydrogen, C 1-3 alkyl; more preferably hydrogen; and / or, independently selected from hydrogen, -C(O)C 1-6 alkyl, -CH(R a )OC(O)C 1-6 alkyl, -C(O)-CH=CH-C(O)OC 1-6 alkyl, -C(O)-(CH2) p1 -C(O)OC 1-6 alkyl, -P(O)(OH)2, -C 1-6 alkylene-P(O)[O(CHR d ) p1 OC(O)OC 1-6 alkyl]2, wherein R a is selected from hydrogen, C 1-6 alkyl, R d is selected from hydrogen, C 1-6 alkyl, and pi is 1, 2, 3, 4, 5; or independently selected from hydrogen, -C(O)C 1-3 alkyl, -CH(R a )OC(O)C 1-3 alkyl, -C(O)-CH=CH-C(O)OC 1-3 alkyl, -C(O)-(CH2) p1 -C(O)OC 1-3 alkyl, -P(O)(OH)2, -CH2-P(O)[O(CH2) p1 OC(O)OC 1-6 alkyl]2, wherein R a is selected from hydrogen, C 1-3 alkyl, p1 is 1, 2, 3, 4, 5; or independently selected from the group consisting of hydrogen, -C(O)CH3, -CH2OC(O)CH3, -CH(CH3)OC(O)CH3, -C(O)-CH=CH-C(O)OCH3, -C(O)CH2CH2C(O)OCH3, -P(O)(OH)2, The compound according to any one of claims 1-4, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R1is independently selected from -C 1-6 alkylene-R3, -CH2NHC(O)-(C 1-6 alkylene) m R3, -CH2C(O)NH-(C 1-6 alkylene) m R3, -CH2NHC(O)-[(C 1-3 alkylene) m -O-] 1-2 -(C 1-3 alkylene) m R3, -CH2NHC(O)-(C 1-3 alkylene) m -C 3-6 cycloalkylene-(C 1-3 alkylene) m -R3, -CH2NHC(O)-(C 1-3 alkylene) m -4-6 membered heterocyclylene-(C 1-3 alkylene) m -R3, -CH2NHC(O)-(C 1-3 alkylene) m -phenyl-(C 1-3 alkylene) m -R3, -CH2NHC(O)-(C 1-3 alkylene) m -5-6 membered heteroarylene-(C 1-3 alkylene) m -R3, -CH2NHC(O)-(C 1-3 alkylene) m -O-(C 1-3 alkylene) m -C 3-6 cycloalkylene-(C 1-3 alkylene) m -R3, -CH2NHC(O)N(C 1-3 alkyl)-(C 1-3 alkylene) m -R3, -CH2NHC(O)NH-(C 1-3 alkylene) m -R3, -CH2NHC(O)-(C 1-3 alkylene) m -C 3-6 cycloalkylene-O-(C 1-3 alkylene) m -R3, -CH2NHC(O)-(C 1-3 alkylene) m -NHCO-(C 1-3 alkylene) m R3, -CH2NHS(O)2-(C 1-6 alkylene) m R3, -CH2S(O)2NH-(C 1-6 alkylene) m R3, -CH2NHS(O)2-[(C 1-3 alkylene) m -O-] 1-2 -(C 1-3 alkylene) m R3, -CH2NHS(O)2-(C 1-3 alkylene) m -C 3- 6cycloalkylene-(C 1-3 alkylene) m R3, -CH2NHS(O)2-(C 1-3 alkylene) m -4-6 membered heterocyclylene-(C 1-3 alkylene) m R3, -CH2NHS(O)2-(C 1-3 alkylene) m -phenyl-(C 1-3 alkylene) m R3, -CH2NHS(O)2-(C 1-3 alkylene) m -5-6 membered heteroarylene-(C 1-3 alkylene) m R3, -CH2NHS(O)2-(C 1-3 alkylene) m -O-(C 1-3 alkylene) m -C 3-6 cycloalkylene-O-(C 1-3 alkylene) m R3, -CH2NHS(O)2N(C 1-3 alkylene)-(C 1-3 alkylene) m R3, -CH2NHS(O)2NH-(C 1-3 alkylene) m R3, -CH2NHS(O)2-(C 1-3 alkylene) m -C 3-6 cycloalkylene-O-(C 1-3 alkylene) m R3, -CH2NHS(O)2-(C 1-3 alkylene) m -NHS(O)2-(C 1-3 alkylene) m R3, R1preferably -CH2NHC(O)-(C 1-6 alkylene) m R3, -CH2NHS(O)2-(C 1-6 alkylene) m R3; the alkylene, cycloalkylene, heteroarylene groups are optionally substituted by one to three substituents selected from Z1; R3is independently selected from -NH2, -N + H3, -N + (CH3)3, m is independently selected from 0, 1, n is independently selected from 1, 2; Z1is independently selected from halo (e.g. fluorine, chlorine, bromine), amino, hydroxyl, cyano, -S(O)2R9, C 1-3 alkyl (e.g. methyl, ethyl), C 1-3 alkoxy (e.g. methoxy, ethoxy), C 2-4 alkenyl (e.g. -CH=CH2, -CH2CH=CH2), C 2-4 alkynyl, C 3-6 cycloalkyl (e.g. cyclopropane, cyclobutane, cyclopentane, cyclohexane), 4-6 membered heterocyclyl (e.g. ), phenyl, 5-6 heteroaryl (e.g., pyridyl); or any two Z1 atoms together with the atoms they are attached to form C 3-6 Cycloalkyl (e.g., cyclopropane, cyclobutane, cyclopentane, cyclohexane), 4-6 membered heterocyclic groups (e.g.) "." represents the connection site), phenyl, 5-6 membered heteroaryl; R9is independently selected from hydrogen, C 1-3 alkyl (e.g., methyl, ethyl); or R1is independently selected from -CH2NHC(O)-(C 1-6 alkylene) m R3, -CH2NHC(O)-(C 1-6 alkylene) m -C 3-6 cycloalkylene-(C 1-6 alkylene) m -R3, -CH2NHC(O)-(C 1-6 alkylene) m -4-6 membered heterocyclyl-(C 1-6 alkylene) m -R3, -CH2NHC(O)-(C 1-6 alkylene) m -5-6 membered heteroaryl-(C 1-6 alkylene) m -R3, -CH2NHC(O)-(C 1-6 alkylene) m -O-(C 1-6 alkylene) m -C 3-6 cycloalkylene-(C 1-6 alkylene) m -R3, -CH2NHC(O)N(C 1-3 alkyl)-(C 1-6 alkylene) m -R3, -CH2NHC(O)-(C 1-6 alkylene) m -C 3-6 cycloalkylene-O-(C 1- 6alkylene) m -R3, -CH2NHC(O)-(C 1-6 alkylene) m -NHCO-(C 1-6 alkylene) m -R3or -CH2NHS(O)2-(C 1-6 alkylene) m R3, wherein R3is independently selected from -N + H3, -N + (CH3)3、 m is independently selected from 0 or 1, and n is independently selected from 1 or 2; said C 1-6 alkylene, C 1-3 alkyl is optionally substituted with one to three substituents selected from Z1; Z1is independently selected from halo, amino, hydroxyl, cyano, -S(O)2R9, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, 4-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl; or any two Z1together with the atom to which they are attached form a C 3-6 cycloalkyl, C 3-6 heterocyclyl; each R9is independently selected from hydrogen or C 1-6 alkyl; or R1is independently selected from -CH2NHC(O)-(C 1-6 alkylene)R3, -CH2NHC(O)-(C 1-3 alkylene)-C 3-6 cycloalkylene-(C 1-3 alkylene)-R3, -CH2NHC(O)-C 3-6 cycloalkylene-(C 1-6 alkylene)-R3, -CH2NHC(O)-(C 1-3 alkylene)-4-6 membered heterocyclyl-(C 1-3 alkylene)-R3, -CH2NHC(O)-5-6 membered heteroaryl-(C 1-6 alkylene)-R3, -CH2NHC(O)-(C 1-3 alkylene)-O-(C 1-3 alkylene)-R3, -CH2NHC(O)-(C 1-3 alkylene)-O-(C 1-3 alkylene)-C 3-6 cycloalkylene-R3, -CH2NHC(O)-(C 1-3 alkylene)-O-(C 1-3 alkylene)-C 3-6 cycloalkylene-(C 1-3 alkylene)-R3, -CH2NHC(O)N(C 1-3 alkyl)-(C 1-6 alkylene)-R3, -CH2NHC(O)NH-(C 1-6 alkylene)-R3, -CH2NHC(O)-C 3-6 cycloalkylene-O-(C 1-6 alkylene)-R3, -CH2NHC(O)-(C 1-3 alkylene)-NHCO-(C 1-3 alkylene)-R3or -CH2NHS(O)2-(C 1-6 alkylene)R3, wherein R3is independently selected from -N + H3, -N + (CH3)3, n is independently selected from 1 or 2; said C 1-6 alkylene, C 1-3 alkylene is optionally substituted with 1, 2, or 3 substituents selected from Z1; Z1is independently selected from halo, amino, hydroxyl, cyano, -S(O)2R9, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, phenyl, 5-6 membered heteroaryl; or any two Z1together with the atom to which they are attached form a C 3-6 cycloalkyl or C 3-6 heterocyclyl; R9is selected from hydrogen or C 1-6 alkyl; or R1is selected from -CH2NHC(O)-(CH2) m7 -R3, -CH2NHS(O)2-(CH2) m8 -R3, each m7, m8 is independently 4, 5, 6 or 7, wherein 1 or adjacent 2 -(CH2)- are optionally replaced by any of the following substituents: C 3-6 cycloalkyl, C 3-6 heterocyclyl, phenyl, 5-6 membered heteroaryl, -C(O)NH- or -N(CH3)- (more preferably -C(O)NH- or -N(CH3)-); optionally, further, another -(CH2)- is replaced by -O-; R3is independently selected from -N + H3, -N + (CH3)3, n is independently selected from 1 or 2; said -(CH2) m7 - -(CH2) m8 - is optionally substituted with 1 or 2 substituents selected from Z1, Z1is independently selected from -S(O)2R9, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, phenyl or 5-6 membered heteroaryl; R9is selected from hydrogen or C 1-6 alkyl; or R1is independently selected from the following groups: or R1is independently selected from the following groups: and / or, R3is independently selected from -NH2, -N + H3, -N + (CH3)3, -NH-C(O)-L 1 m1 -L 2 m2 -L 3 m3 -L 4 m4 -L 5 m5 -L 6 m6 -R4, where R4is independently selected from -NH2, -N + H3, -N + (CH3)3or n is independently selected from 1, 2; preferably, R3is -NH2, -N + H3, -N + (CH3)3, n is 1, 2; and / or, -L 1 m1 -L 2 m2 -L 3 m3 -L 4 m4 -L 5 m5 -L 6 m6 - are independently selected from the group consisting of: and / or, Z1 is independently selected from halogen groups (e.g., fluorine, chlorine, bromine), amino, hydroxyl, cyano, -C(O)CH3, -C(O)OCH3, -C(O)NH2, -C(O)N(CH3)2, -NH(CH3), -N(CH3)2, -NHC(O)CH3, -S(O)2CH3, methyl, ethyl, methoxy, -CH=CH2, -CH2CH=CH2, ethynyl, cyclopropane, cyclobutane, cyclopentane, cyclohexane, phenyl, pyridyl; or any two Z1together with the atoms to which they are attached form a wherein "." represents the connection site. The compound according to any one of claims 1 to 5, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R2is independently selected from C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, said C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl and 3-6 membered heterocyclyl are optionally substituted with one or more substituents selected from halogen; or R2is independently selected from C 1-2 alkyl, C 3-4 cycloalkyl; or R2 is independently selected from methyl, cyclopropyl; and / or, R5 is independently selected from hydrogen; and / or, R2, R5together with the carbon atom to which they are attached form C 3-6 cycloalkyl or C 3-6 heterocyclyl; or R2, R5 together with the carbon atom to which they are attached form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; preferably cyclopropyl. The compound according to claim 1, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein: The compound is selected from: A pharmaceutical composition comprising the compound according to any one of claims 1-7, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. Use of a compound according to any one of claims 1 to 7, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 8, for the manufacture of a medicament for antagonizing the activity of PCSK9 in a subject; preferably, the condition is a cardiovascular disease associated with dyslipidemia; preferably atherosclerosis, hypercholesterolemia, coronary heart disease, metabolic syndrome, acute coronary syndrome or related cardiovascular and cardiovascular metabolic conditions. A pharmaceutical composition comprising a compound according to any one of claims 1 to 7, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 8, and another, two or more compounds having the same or similar indications.

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