Arylpropionic acid compound, preparation method therefor, and use thereof

Abstract

The present invention relates to a novel arylpropionic acid compound, or a salt, a solvate, a stereoisomer, or a tautomer thereof. The compound is capable of inhibiting plasma lipoprotein(a) levels. The present invention further relates to a pharmaceutical composition thereof, a preparation method therefor, and a therapeutic use thereof.

Description

Arylpropionic acid compounds, methods for preparing the same and uses thereof TECHNICAL FIELD

[0001] The present application belongs to the field of medicine, and particularly relates to an arylpropionic acid compound, a preparation method and uses thereof. The present application provides the novel compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, and the use in a medicine for preventing and / or treating diseases or disorders related to elevated Lp(a) plasma levels.

[0002] BACKGROUND

[0003] Lipoprotein(a) [Lp(a)] is composed of apolipoprotein a [Apo(a)] and low-density lipoprotein (LDL)-like particles, which are covalently bound by disulfide bonds. Unlike LDL, Lp(a) cannot be converted from very low-density lipoprotein (VLDL) and cannot be converted into other lipoproteins, and is an independent lipoprotein synthesized by the liver. Among them, Apo(a) is a highly glycosylated hydrophilic protein with 10 homologous kringle IV (K IV) domains, and the similar ring cake in the second K IV domain has a copy number of 2-40, and the others have only one copy number, which determines the molecular weight of Lp(a) and the large difference in plasma Lp(a) levels among different individuals; the LDL-like particle contains about 30-46% cholesterol, apolipoprotein B100 (ApoB100) and oxidized phospholipid (OxPL).

[0004] The concentration of Lp(a) is largely determined by genetic factors, so it is difficult to control through diet, exercise and other lifestyle changes. Current research suggests that Lp(a) is an independent risk factor for atherosclerotic cardiovascular disease (ASCVD), and there are various treatment options for elevated LDL-C, low HDL-C and elevated triglycerides (TG), but there is currently no approved drug treatment for patients with elevated Lp(a) concentration.

[0005] Lp(a) inhibitors have urgent clinical needs and broad application prospects. There are some related literature and patents that have disclosed Lp(a) inhibitors, for example, WO2020247429, WO2023146785 and WO2023078333 reported a class of pyrrolidine lipoprotein inhibitors, but there is no marketed drug approved for clinical application, and there is still an urgent need to develop new compounds with Lp(a) inhibitory effect. SUMMARY

[0006] The present application provides a compound with Lp(a) inhibitory effect and a preparation method and uses thereof.

[0007] The present application provides a compound of formula (K)

[0008] or salts, solvates, stereoisomers, or tautomers thereof, wherein:

[0009] each ring Cy is independently a N-containing five- or six-membered heterocyclyl;

[0010] each ring Ar is independently phenyl or a six-membered N-containing heteroaryl, which is substituted with 0-3 R a optionally substituted phenyl or a six-membered N-containing heteroaryl;

[0011] R a each independently is H, halo, or C 1-6 alkyl;

[0012] each J is independently absent or CH2;

[0013] w is 1 or 2;

[0014] R 1 each independently is H or C 1-6 alkyl;

[0015] R 2 each independently is H, halo, hydroxy, C 1-6 alkyl, or C 1-6 haloalkyl;

[0016] R 3 each independently is H, halo, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, or C 1-6 haloalkoxy;

[0017] L is selected from the group consisting of:

[0018] ring A is phenyl or a monocyclic heteroaryl containing 1-3 N atoms;

[0019] ring B is phenyl or a monocyclic or bicyclic heteroaryl or heterocyclyl containing 1-3 N atoms;

[0020] L 1 is a single bond, C 1-10 alkylene, or C 1-10 alkyleneoxy, which alkylene or alkyleneoxy is optionally substituted with 0-2 R L ; preferably is C 1-6 alkylene, or C 1-6 alkyleneoxy, more preferably is C 1-4 alkylene, or C 1-4 alkyleneoxy;

[0021] R L each independently is H, oxo, halo, or C1-6 alkyl, or two R L form, together with the atom to which they are attached, a cycloalkyl, which cycloalkyl is optionally substituted with 0-1 halo or C 1-6 alkyl;

[0022] R 4 and R 5 each independently is H, C 1-6 alkyl or C 1-6 alkoxy, which alkyl or alkoxy is optionally substituted with 0-1 -P(=0)(OR’)2;

[0023] R 6 each independently is H, halo, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 cycloalkyl, pyrrolidinyl, piperidinyl, or -COOH, which alkyl, alkoxy, or cycloalkyl is optionally substituted with 0-3 halo, C 1-6 alkyl, C 1-6 cycloalkyl, pyrrolidinyl, piperidinyl, -COOH, -P(=0)(OR’)2, or ;

[0024] each R’ independently is H or C 1-6 alkyl, or two R’ form, together with the atom to which they are attached, a heterocyclyl, which heterocyclyl is optionally substituted with 0-1 halo-substituted phenyl;

[0025] each n independently is 0, 1, or 2;

[0026] m is an integer selected from 0-3;

[0027] and, L is not

[0028] In some embodiments, the compound has the chemical structure of Formula (I):

[0029] wherein:

[0030] w is 1 or 2;

[0031] each R 1 each independently is H or C 1-6 alkyl, preferably H or methyl, more preferably H;

[0032] each R 2 each independently is H, halo, hydroxyl, C 1-6 alkyl or C 1-6 haloalkyl, preferably H or methyl, more preferably H;

[0033] R 3 each independently H, halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl or C 1-6 haloalkoxy, preferably H or methyl, more preferably H;

[0034] L is selected from the group consisting of:

[0035] Ring A is phenyl or a monocyclic heteroaryl containing 1-3 N atoms;

[0036] Ring B is phenyl or a monocyclic or bicyclic heteroaryl or heterocyclyl containing 1-3 N atoms;

[0037] L 1 is a single bond or C 1-10 alkylene, preferably C 1-6 alkylene, more preferably C 1-4 alkylene, which alkylene is optionally substituted with 0-2 R L ;

[0038] R L each independently H, oxo, halogen or C 1-6 alkyl, or two of R L , together with the atom to which they are attached, form a cycloalkyl, which cycloalkyl is optionally substituted with 0-1 halogen or C 1-6 alkyl;

[0039] R 4 and R 5 each independently H, C 1-6 alkyl or C 1-6 alkoxy, which alkyl or alkoxy is optionally substituted with 0-1 -P(=O)(OR’)2;

[0040] R 6 each independently H, halogen, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 cycloalkyl, pyrrolidinyl, piperidinyl or -COOH, which alkyl, alkoxy or cycloalkyl is optionally substituted with 0-3 halogen, C 1-6 alkyl, C 1-6 cycloalkyl, pyrrolidinyl, piperidinyl, -COOH, -P(=O)(OR’)2 or ;

[0041] each R’ independently is H or C 1-6alkyl, or two of R' taken together with the atom to which they are attached form heterocyclyl, which is optionally substituted with 0-1 halo-substituted phenyl;

[0042] each n is independently 0, 1, or 2;

[0043] m is an integer selected from 0-3;

[0044] and L is not

[0045] In some embodiments, the compound has the specified stereochemical structure of Formula (IIa) or Formula (IIb):

[0046] In some embodiments, w is 1; L is Ring A is phenyl.

[0047] In some embodiments, w is 2;

[0048] L is selected from the group consisting of:

[0049] m is 1 or 2.

[0050] In some embodiments, L is

[0051] Ring B is

[0052] R 6 each independently is H, C 1-6 alkyl, pyrrolidinyl, or -COOH, which alkyl is optionally substituted with pyrrolidinyl or -COOH;

[0053] m is 2.

[0054] In some embodiments, L is

[0055] Ring B is phenyl;

[0056] R 6 each independently is H, halo, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, or C 1-6 cycloalkyl, which alkyl, alkoxy, or cycloalkyl is optionally substituted with 0-3 halo, C 1-6 alkyl, C 1-6 cycloalkyl, -P(=O)(OR')2, or .

[0057] In some embodiments, L1 -C(=O)- or -CR L R L -; wherein R L each independently is H or C 1-6 alkyl, or two of R L form a cycloalkyl group together with the atom to which they are attached;

[0058] R 6 each independently is H, halogen, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy or C 1-6 cycloalkyl, said alkyl, alkoxy or cycloalkyl optionally can be substituted with 0-3 halogen, C 1-6 alkyl or -P(=O)(OR')2;

[0059] R' each independently is H or C 1-6 alkyl, preferably H or ethyl; m is 2.

[0060] In some embodiments, L is

[0061] L 1 -C(=O)- or -CR L R L -; wherein R L each independently is H or C 1-6 alkyl, or two of R L form a cycloalkyl group together with the atom to which they are attached;

[0062] B 1 , B 2 , B 3 or B 4 each independently is N or CR 6b ;

[0063] R 6a is C 1-6 alkyl, said alkyl optionally can be substituted with pyrrolidinyl, piperidinyl or -COOH;

[0064] R 6b is H, halogen, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy or C 1-6 cycloalkyl, said alkyl, alkoxy or cycloalkyl optionally can be substituted with 0-3 halogen or C 1-6 alkyl.

[0065] In some embodiments, R 6a is ethyl or propyl, said ethyl or propyl optionally can be substituted with pyrrolidinyl, piperidinyl or -COOH; R6b is H, fluoro, chloro, hydroxy, methyl, methoxy, or cyclopropyl, which methyl, methoxy, or cyclopropyl is optionally substituted with 0-3 fluoro, chloro, or methyl.

[0066] In some embodiments, the compound has the chemical structure of Formula (III):

[0067] wherein:

[0068] ring Cy 1 , Cy 2 , or Cy 3 each independently is pyrrolidinyl or piperidinyl;

[0069] ring Ar 1 , or Ar 2 each independently is phenyl optionally substituted with 1-3 R a , or a six-membered heteroaryl containing 1-3 N atoms;

[0070] R a each independently is H, C 1-6 1-6 alkyl, or halo;

[0071] ring B 1 is phenyl optionally substituted with 1-2 R 6 , or a six-membered heteroaryl containing 1-3 N atoms;

[0072] R 6 each independently is H, halo, hydroxy, C 1-6 1-6 alkyl, C 1-6 1-6 alkoxy, or C 1-6 3-6 cycloalkyl, which alkyl, alkoxy, or cycloalkyl is optionally substituted with 0-3 halo or C 1-6 1-6 alkyl;

[0073] J 1 , J 2 , or J 3 each independently is absent or CH2, and at least one of J 1 , J 2 , or J 3 is CH2;

[0074] Preferably, R 6 each independently is H, halo, C 1-6 1-6 alkyl, or C 1-6 1-6 alkoxy, which alkyl or alkoxy is optionally substituted with 0-3 halo.

[0075] In some embodiments, the compound has the chemical structure of Formula (IIIa):

[0076] In some embodiments, the compound has the chemical structure of Formula (IIIa): in:

[0077] Cy 1 Cy 2 or Cy 3 Each is independently a pyrrolidinyl group;

[0078] Ring Ar 1 Or Ar 2 Each is independently controlled by 1-3 Rs a Optional substitutions include phenyl, pyridinyl, pyridinyl, pyrazinyl, or triazinyl;

[0079] Ring B 1 It is by 1-2 Rs 6 Optional substitutions include phenyl, pyridinyl, pyridinyl, pyrazinyl, or triazinyl;

[0080] Preferably, ring Ar 1 Ar 2 Or ring B 1 Each is either phenyl or pyridyl.

[0081] In some specific embodiments, the compound has the chemical structure of formula (IV):

[0082] in:

[0083] Cy 1 Cy 2 or Cy 3 Each is independently either pyrrolidinyl or piperidinyl;

[0084] Ring Ar 1 Or Ar 2 Each is independently controlled by 1-3 Rs a Optionally substituted phenyl groups or six-membered heteroaryl groups containing 1-3 N atoms;

[0085] R a H and C are independent of each other. 1-6 Alkyl or halogen;

[0086] Ring B 1 It is by 1-2 Rs 6 Optionally substituted phenyl groups or six-membered heteroaryl groups containing 1-3 N atoms;

[0087] R 6 Each is independently H, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Cycloalkyl groups, wherein the alkyl, alkoxy, or cycloalkyl group may optionally be 0-3 halogens or C atoms. 1-6 Alkyl groups are substituted;

[0088] J 1 J 2 or J 3 Each of them either does not exist independently or is CH2;

[0089] And, when R a and R 6 When both are H, the ring Ar 1 Ar 2 Or ring B 1 Not both are phenyl;

[0090] Preferably, R 6 Each is independently H, halogen, C 1-6 Alkyl or C 1-6 Alkoxy groups, wherein the alkyl or alkoxy group may optionally be replaced by 0-3 halogens.

[0091] In some specific embodiments, the compound has the chemical structure of formula (IVa):

[0092] in:

[0093] Ring Ar 1 Or Ar 2 Each is independently controlled by 1-3 Rs a Optional substitutions include phenyl, pyridinyl, pyridinyl, pyrazinyl, or triazinyl;

[0094] Ring B 1 It is by 1-2 Rs 6 Optional substitutions include phenyl, pyridyl, pyridinyl, pyrazinyl, or triazinyl.

[0095] In some specific embodiments, the compound has the chemical structure of formula (IVb):

[0096] in:

[0097] Z 1 Z 2 or Z 3 Each is either N or CH independently;

[0098] R a or R 6 As described in claim 14;

[0099] Preferably, Z 3 It is N.

[0100] In some specific embodiments, the compound has the chemical structure of formula (V):

[0101] wherein:

[0102] ring Cy 1 , Cy 2 or Cy 3 each independently is pyrrolidinyl or piperidinyl;

[0103] ring Ar 1 or Ar 2 each independently is phenyl optionally substituted with 1-3 R a or a six-membered heteroaryl containing 1-3 N atoms;

[0104] R a each independently is H, C 1-6 alkyl or halogen;

[0105] ring B 1 is phenyl optionally substituted with 1-2 R 6 or a six-membered heteroaryl containing 1-3 N atoms;

[0106] R 6 each independently is H, halogen, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy or C 1-6 cycloalkyl, said alkyl, alkoxy or cycloalkyl optionally can be substituted with 0-3 halogen or C 1-6 alkyl;

[0107] J 1 , J 2 or J 3 each independently is absent or CH2;

[0108] n is an integer selected from 0-3.

[0109] In some embodiments, wherein the compound has the chemical structure of Formula (Va):

[0110] wherein:

[0111] ring Ar 1 or Ar 2 each independently is phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or triazinyl optionally substituted with 1-3 R a .

[0112] ring B 1 is phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or triazinyl optionally substituted with 1-2 R 6 .

[0113] In some embodiments, wherein the compound has the chemical structure of Formula (Vb): wherein:

[0114] Z 1 , Z 2 or Z 3 each independently is N or CH;

[0115] R a or R 6 each independently is H, C 1-6 alkyl or halogen; preferably H or halogen; n is 0 or 1.

[0116] In another aspect, the present application provides specific compounds comprising, but not limited to, the following compounds:

[0117] The present application includes all pharmaceutically acceptable salt forms of the compounds. Such salts can be prepared using commercially available reagents according to conventional organic chemistry methods, and include, but are not limited to, hydrochloride, hydrobromide, hydroiodide, phosphate, sulfate, nitrate, formate, acetate, succinate, benzenesulfonate, citrate, glucuronate, lactate, mesylate, tosylate, pamoate, and tartrate salts.

[0118] The present application is intended to include all isotopes of atoms occurring in the present compounds. Isotopically-labeled compounds of the present application can generally be prepared by conventional techniques known to those skilled in the art, or by processes analogous to those described herein, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent employed.

[0119] For stereoisomers, the compounds of the present application can have chiral centers and occur as racemates, racemic mixtures, and as individual enantiomers or diastereomers, any of which can be

[0120] The present application is intended to include all tautomers of the compounds. Tautomers refer to the shift of a proton from one atom of a molecule to another atom of the same molecule, non-limiting examples of which include keto-enol pairs, amide-imine pairs, lactam-lactim pairs, amide-imidic acid pairs, enamine-imine pairs, and the like.

[0121] In addition, certain crystal forms of the compounds of the present application can exist as polymorphs, which are also included in the present application. In addition, some of the compounds can also form solvates with water or other organic solvents, which are likewise included in the scope of the present application.

[0122] In another aspect, the present application provides a method of preparing a compound of formula (I):

[0123] General Method One:

[0124] wherein X is selected from halogen, carboxyl, aldehyde; n = 0-9;

[0125] General Formula I is converted to General Formula II or General Formula III by condensation reaction or substitution reaction or reductive amination reaction, and General Formula II or General Formula III is converted to General Formula IV or General Formula V by deprotection reaction.

[0126] General Method Two:

[0127] wherein X is selected from halogen, carboxyl, aldehyde; n = 0-9;

[0128] General Formula I is converted to General Formula II or General Formula III by condensation reaction or substitution reaction or reductive amination reaction, and General Formula II or General Formula III is converted to General Formula IV or General Formula V by deprotection reaction.

[0129] General Method Three:

[0130] wherein X is selected from halogen, hydroxyl, p-nitrophenoxy; n = 0-3; A1, A2, A3, A4 are independently C or N.

[0131] General Formula I is converted to General Formula II by condensation reaction or substitution reaction, and General Formula II is converted to General Formula III by deprotection reaction.

[0132] In another aspect, the present application provides a pharmaceutical formulation suitable for use in human patients, comprising any of the compounds shown above (e.g., a compound of the present application, such as a compound of Formula (I)), together with one or more pharmaceutically acceptable excipients. In certain embodiments, the pharmaceutical formulation can be used to treat or prevent a disorder or disease described herein.

[0133] In another aspect, the present application discloses the use of the compounds in the manufacture of a medicament for lowering Lp(a) level.

[0134] In another aspect, the present application discloses the use of the compounds in the manufacture of a medicament for preventing and / or treating a disease or disorder associated with elevated Lp(a) plasma level.

[0135] In another aspect, the present application discloses the use of the compounds in the manufacture of a medicament for preventing and / or treating a cardiovascular disease.

[0136] The compounds of the present application have inhibitory activity against Lp(a), for example, the compounds of the present application inhibit Lp(a) assembly with an IC50of less than 100 μM, preferably less than 50 μM, more preferably less than 10 μM, and most preferably less than 1 μM, according to the assay method described below. 50values less than 500 nM; in some embodiments, the compounds of the application inhibit Lp(a) assembly with an IC50 50 values less than 100 nM; in some embodiments, the compounds of the application inhibit Lp(a) assembly with an IC50 50 values less than 50 nM; in some embodiments, the compounds of the application inhibit Lp(a) assembly with an IC50 50 values less than 20 nM; in some embodiments, the compounds of the application inhibit Lp(a) assembly with an IC50 50 values less than 10 nM; in some embodiments, the compounds of the application inhibit Lp(a) assembly with an IC50 50 values less than 1 nM; in some embodiments, the compounds of the application inhibit Lp(a) assembly with an IC50 50 values less than 0.1 nM.

[0137] Glossary of Terms

[0138] Alkyl or alkane is a fully saturated straight chain or branched non-aromatic hydrocarbon. In general, unless otherwise defined, straight chain or branched alkyl groups have from 1 to about 20 carbon atoms, preferably from 1 to about 10 carbon atoms. Examples of straight chain and branched alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl, pentyl, hexyl, pentyl and octyl. C1-6straight chain or branched alkyl groups are also referred to as "lower alkyl."

[0139] Also, as used throughout the specification, examples and claims, the term "alkyl" (or "lower alkyl") is intended to include both "unsubstituted alkyl" and "substituted alkyl", the latter referring to alkyl moieties having substituents replacing one or more of the hydrogens on the hydrocarbon backbone. Such substituents can include, for example, halogen, hydroxyl, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl (such as thioester, thioformate, or thioacetate), alkoxyl, phosphoryl, phosphine, phosphonate, phosphinate, amino, amide, imide, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonamide, sulfamoyl, sulfonate, sulfonyl, heterocyclyl, aralkyl, or aromatic or heteroaromatic moieties. One of skill in the art will appreciate that the moieties substituted on the hydrocarbon chain can themselves be substituted if appropriate. For example, substituted alkyl groups can include substituted and unsubstituted forms of aminos, azidos, imines, amides, phosphines, phosphonyls (including phosphonates and phosphinates), sulfonamides, sulfamoyls, sulfonates, sulfonyls, and silyls, as well as substituted and unsubstituted forms of ethers, alkylthios, carbonyls (including ketones, aldehydes, carboxyls, and esters), -CF3, -CN, and the like.

[0140] Alkylene by itself or as part of another substituent refers to a straight or branched saturated bivalent hydrocarbon moiety derived from a chain alkane having the number of carbon atoms indicated in the prefix. C1-6alkylene includes, for example, methylene, ethylene, propylene, 2-methylpropylene, pentylene, hexylene, and the like, C1-4alkylene includes, for example, methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), isopropylene [e.g., -CH(CH3)CH2-, -CH2CH(CH3)-], and butylene [e.g., -CH2-(CH2)2CH2-, -CH2-CH(CH3)CH2-, -CH2-C(CH3)2-, -CH2-CH2CH(CH3)-], and the like. Alkylene can be further substituted with alkyl, alkenyl, alkoxy, alkylthio, aminoalkyl, carbonyl-substituted alkyl, -CF3, -CN, and the like.

[0141] Cycloalkyl preferably has 3 to 7 ring carbon atoms and can be in substituted and unsubstituted form. Cycloalkyl is, for example, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, or methylcyclopentyl. Cycloalkyl can be further substituted with alkyl, alkenyl, alkoxy, alkylthio, aminoalkyl, carbonyl-substituted alkyl, -CF3, -CN, and the like.

[0142] Aryl denotes a monocyclic or bicyclic, fused ring aromatic group having 5 to 10 carbon atoms, for example phenyl, 1-naphthyl or 2-naphthyl; or a partially saturated bicyclic, fused ring containing a phenyl moiety, for example indanyl, dihydro- or tetrahydronaphthyl.

[0143] Heteroaryl denotes an aromatic group containing at least one heteroatom selected from nitrogen, oxygen and sulfur and is monocyclic or bicyclic. Monocyclic heteroaryl groups include 5- to 8-membered heteroaryl groups containing 1, 2, 3 or 4 heteroatoms selected from nitrogen, sulfur and oxygen. Bicyclic heteroaryl groups include 9- or 10-membered fused ring heteroaryl groups. Heteroaryl is, for example, pyrrolyl, thienyl, furanyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, and benzo-fused derivatives of such monocyclic heteroaryls such as indolyl, benzimidazolyl or benzofuranyl, quinolinyl, isoquinolinyl, quinazolinyl or purinyl.

[0144] In the optionally substituted heteroaryl group, the substituents are preferably lower alkyl, lower alkoxy, lower alkoxy-lower alkoxy, halo-lower alkyl, amino, lower alkoxy-lower alkyl, halogen or nitro, optionally substituted with 1 to 3 substituents selected from lower alkyl, lower alkenyl and alkylcarbonyl.

[0145] Heterocyclyl preferably denotes a saturated, partially saturated or unsaturated monocyclic or bicyclic ring containing 4 to 10 atoms, including 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, which can be carbon- or nitrogen-bonded, wherein the ring nitrogen atoms can optionally be substituted by radicals selected from lower alkyl, amino-lower alkyl, aryl, aryl-lower alkyl and acyl, and the ring carbon atoms can be substituted by lower alkyl, amino-lower alkyl, aryl, aryl-lower alkyl, heteroaryl, lower alkoxy, hydroxy or oxo. Heterocyclyl is for example pyrrolidinyl, oxazolidinyl, thiazolidinyl, piperidinyl, morpholinyl, piperazinyl, dioxolanyl or tetrahydropyranyl.

[0146] Alkenyl contains one or more, for example two or three, double bonds and is preferably lower alkenyl, for example 1- or 2-butenyl, 1-propenyl, allyl or vinyl.

[0147] Alkynyl is preferably lower alkynyl, for example propargyl or ethynyl.

[0148] In optionally substituted alkenyl or alkynyl, the substituents are preferably lower alkyl, lower alkoxy, halo or di(lower alkyl)amino and are attached to a saturated carbon atom of the alkenyl or alkynyl group or to an unsaturated carbon atom of the alkenyl group.

[0149] Acyl for example denotes alkylcarbonyl, cyclohexylcarbonyl, arylcarbonyl, aryl-lower alkylcarbonyl or heteroarylcarbonyl. Lower acyl is preferably lower alkylcarbonyl, in particular propionyl or acetyl.

[0150] Hydroxyalkyl denotes alkyl substituted by at least one hydroxy group, preferably hydroxy-lower alkyl, for example hydroxymethyl, 2-hydroxyethyl, 2-hydroxy-n-propyl, hydroxyisopropyl.

[0151] Cyanoalkyl denotes alkyl substituted by at least one cyano group, preferably cyano-lower alkyl, for example cyanomethyl or cyanoethyl.

[0152] Haloalkyl denotes alkyl substituted by at least one halogen, preferably halo-lower alkyl, for example monofluoromethyl, difluoromethyl, trifluoromethyl, 3,3,3-trifluoroethyl or pentafluoroethyl.

[0153] Halogen is fluorine, chlorine, bromine or iodine.

[0154] Lower alkoxy is in particular methoxy, ethoxy, isopropoxy or tert-butoxy.

[0155] Arylalkyl comprises aryl and alkyl as defined above and is for example benzyl, 1-phenylethyl or 2-phenylethyl.

[0156] Heteroarylalkyl comprises a heteroaryl group and an alkyl group as defined above and is for example 2-, 3- or 4-pyridylmethyl, 1- or 2-pyrrolylmethyl, 1-pyrazolylmethyl, 1-imidazolylmethyl, 2-(1-imidazolyl)ethyl or 3-(1-imidazolyl)propyl.

[0157] Two adjacent substituents which can form together with the atoms of the aryl or heteroaryl group a 5- or 6-membered carbocyclic or heterocyclic ring are for example propylene, 1- or 2-oxopropylene, 1- or 2-oxapropylene, 1-oxapropylidene, methylenedioxy, difluoro-methylenedioxy, 1- or 2-azapropylene, 1- or 2-azapropylidene, 1,2- or 1,3-diazapropylidene, 1,3-diaz-2-oxopropylene, butylene, 1- or 2-oxabutylene, ethylenedioxy, 1- or 2-azabutylene or 1- or 2-azabutadienyl or such groups carrying further substituents as defined above. BRIEF DESCRIPTION OF DRAWINGS

[0158] Figure 1 Change from baseline in Lp(a) levels in cynomolgus monkeys for compounds of the present application DETAILED DESCRIPTION

[0159] Synthesis Examples

[0160] In order that the present application can be more clearly understood, the following examples will further set forth the present application. It should be understood that these examples are for illustration only and are not to be construed as limiting the scope of the present application. Further, specific experimental methods are not mentioned in the following examples, but are performed according to conventional methods.

[0161] The abbreviations used herein have the following meanings: Abbreviation Meaning ACN acetonitrile DAST diethylaminosulfur trifluoride DCM dichloromethane DIPEA N,N-diisopropylethylamine DMF N,N-dimethylformamide DMSO dimethyl sulfoxide DMP 2,2-dimethoxypropane EA ethyl acetate PE petroleum ether THF tetrahydrofuran IPA isopropyl alcohol TEA triethylamine TFA trifluoroacetic acid SEMCl 2-(trimethylsilyl)ethoxymethyl chloride LiHMDS lithium bis(trimethylsilyl)amide LiBH4 lithium borohydride NaBH3CN sodium cyanoborohydride NBS N-bromosuccinimide NCS N-chlorosuccinimide NMI N-methylimidazole TMSCF3 (trifluoromethyl)trimethylsilane TBAF tetrabutylammonium fluoride NMI N-methylimidazole TCFH N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate HATU O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate TsCl p-toluenesulfonyl chloride DIPEA N,N-diisopropylethylamine DCC N,N'-dicyclohexylcarbodiimide DMAP 4-dimethylaminopyridine PMBCl 4-methoxychlorobenzene BINAP 1,1'-binaphthalene-2,2'-bisphosphine t-BuXPhos 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl Xant-phos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene Pd2(dba)3 tri(dibenzylidene-BASE acetone) palladium Pd(dppf)Cl2 1,1-bis(diphenylphosphino) ferrocene dichloropalladium Pd(dtbpf)Cl2 [1,1'-bis(di-tert-butylphosphino) ferrocene] dichloropalladium Prep-HPLC preparative high performance liquid chromatography SFC supercritical fluid chromatography HPLC high performance liquid chromatography LCMS liquid chromatography-mass spectrometry,

[0162] The structures of the compounds described in the following examples were confirmed by nuclear magnetic resonance spectroscopy (H-NMR) or mass spectrometry (MS). 1 H-NMR) or mass spectrometry (MS).

[0163] 1 The measuring instrument of H-NMR was Bruker 400MHz nuclear magnetic resonance instrument, and the measuring solvent was deuterated methanol (CD3OD), deuterated chloroform (CDCl3) or hexadeuterated dimethyl sulfoxide (DMSO-d6), and the internal standard was tetramethylsilane (TMS). The chemical shift (δ) was given in units of parts per million (ppm).

[0164] The measuring instrument of mass spectrometry (MS) was Agilent (ESI) mass spectrometer, model Agilent 6120B.

[0165] Thin layer chromatography (TLC) was performed using aluminum plates (20x20cm) produced by Merck, and thin layer preparation chromatography was performed using GF254 (0.4-0.5mm) silica gel plates.

[0166] The monitoring of the reaction was performed using thin layer chromatography (TLC) or liquid chromatography-mass spectrometry (LC-MS), and the developing agent system used included dichloromethane and methanol system, n-hexane and ethyl acetate system, and petroleum ether and ethyl acetate system. The developing agent system was adjusted (by adjusting the volume ratio of the solvents or adding triethylamine, etc.) according to the polarity of the compound to be separated.

[0167] Unless otherwise specified, the reaction temperature was room temperature (20-30°C).

[0168] Indicates a single bond of a single chiral isomer.

[0169] The reagents used in the examples were purchased from Acros Organics, Aldrich Chemical Company, Shanghai Tebo Chemical Technology Co., Ltd., etc.

[0170] Preparation of common intermediates

[0171] Preparation of Intermediate A:

[0172] Step 1: Preparation of A-2

[0173] In a three-necked flask, A-1 (43.0 g, 187.8 mmol) was dissolved in tetrahydrofuran (700 mL), the reaction was placed in an ice-water bath under nitrogen protection, triethylamine (47.4 g, 469.5 mmol) and SM-2 (28.2 g, 234.8 mmol) were added successively, the reaction was stirred in the ice-water bath for 1 h. In another single-necked flask, SM-1 (33.2 g, 187.8 mmol) and lithium chloride (11.8 g, 281.7 mmol) were dissolved in tetrahydrofuran (200 mL) and stirred uniformly, then the solution was added to the reaction solution in the previous step, the ice-water bath was removed, and the reaction was stirred at room temperature overnight. After the reaction was completed, water (1000 mL) was added to quench the reaction, and extraction was performed with ethyl acetate (1000 mL x 2), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to remove the solvent, the crude product was purified by silica gel column chromatography [petroleum ether: methyl tert-butyl ether (v / v) = (100:0-27:73)] to obtain a light yellow solid A-2 (62.0 g, yield: 85%, purity: >99%). LCMS (method C), Rt = 0.987 min; MS Calcd.: 388.2; MS Found: 333.0 [M-56+H]+.

[0174] Step 2: Preparation of A-3

[0175] In a three necked flask, was charged with A-2 (58.0 g, 149.5 mmol) and tetrahydrofuran (500 mL), the reaction was placed in an ice water bath under nitrogen protection, LiHMDS (194.4 mL, 194.4 mmol, 1 mol / L in tetrahydrofuran) was added dropwise slowly, the reaction was stirred in the ice water bath for 1 h. SM-3 (48.2 g, 194.4 mmol) was dissolved in tetrahydrofuran (200 mL) and added to the above reaction at 0 °C, the ice water bath was removed, the reaction was stirred at room temperature overnight. After the reaction was completed, saturated ammonium chloride solution (500 mL) was added to quench the reaction, and extracted with ethyl acetate (800 mL x 2), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure, the crude product was purified by silica gel column chromatography [petroleum ether: methyl tert-butyl ether (v / v) = (100:0-53:47)], to give a light yellow oil A-3 (68.0 g, yield: 73.5%, purity: 89.70%). LCMS (method C), Rt = 1.174 min; MS Calcd.: 556.2; MS Found: 500.7 [M-56+H]+.

[0176] Step 3: Preparation of A-4

[0177] In a three necked flask, was charged with A-3 (68.0 g, 122.3 mmol) and tetrahydrofuran (600 mL), the reaction was placed in an ice water bath under nitrogen protection, 2 mol / L lithium hydroxide aqueous solution (122.3 mL, 244.6 mmol) and hydrogen peroxide (55.4 g, 489.2 mmol, 30 wt% aqueous solution) were added dropwise slowly, then the ice water bath was removed, the reaction was stirred at room temperature overnight. After the reaction was completed, water (500 mL) and n-hexane (500 mL) were added, the aqueous phase was separated, the aqueous phase was adjusted to pH 4-5 with dilute hydrochloric acid, and extracted with ethyl acetate (600 mL x 2), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure, the crude product was purified by silica gel column chromatography [petroleum ether: methyl tert-butyl ether (v / v) = (100:0-69:31)], to give a light yellow oil A-4 (45.0 g, yield: 91%, purity: 88.06%). LCMS (method D), Rt = 0.634 min; MS Calcd.: 397.1; MS Found: 341.8 [M-56+H]+.

[0178] Step 4: Preparation of A-5

[0179] In a single reaction flask, A-5 (11.0 g, 24.3 mmol), SM-5 (4.9 g, 36.4 mmol), Pd(dppf)Cl2(1.4 g, 1.9 mmol) and potassium carbonate (6.7 g, 48.6 mmol) were dissolved in 1,4-dioxane (100 mL) and water (20 mL), and the reaction was stirred at 100 °C overnight under nitrogen protection. After the reaction was completed, the reaction solution was filtered through celite to remove solid impurities, and the filtrate was evaporated under reduced pressure to remove the solvent. The crude product was purified by silica gel column chromatography [petroleum ether: methyl tert-butyl ether (v / v) = (100:0-70:30)] to obtain A-6 (8.0 g, yield: 82%, purity: >99%) as a transparent oil. LCMS (method C), Rt= 1.220 min; MS Calcd.: 401.3; MS Found: 290.3 [M-112+H]+.

[0180] Step 5: Preparation of A-6

[0181] In a single reaction flask, A-5 (11.0 g, 24.3 mmol), SM-5 (4.9 g, 36.4 mmol), Pd(dppf)Cl2(1.4 g, 1.9 mmol) and potassium carbonate (6.7 g, 48.6 mmol) were dissolved in 1,4-dioxane (100 mL) and water (20 mL), and the reaction was stirred at 100 °C overnight under nitrogen protection. After the reaction was completed, the reaction solution was filtered through celite to remove solid impurities, and the filtrate was evaporated under reduced pressure to remove the solvent. The crude product was purified by silica gel column chromatography [petroleum ether: methyl tert-butyl ether (v / v) = (100:0-70:30)] to obtain A-6 (8.0 g, yield: 82%, purity: >99%) as a transparent oil. LCMS (method C), Rt= 1.220 min; MS Calcd.: 401.3; MS Found: 290.3 [M-112+H]+.

[0182] Step 6: Preparation of A-7

[0183] In a single-necked reaction flask, A-6 (8.0 g, 20.0 mmol), NaIO4(12.8 g, 60.0 mmol) and K2OsO4(736 mg, 2.0 mmol) were dissolved in tetrahydrofuran (75 mL) and water (25 mL), the reaction was stirred at room temperature overnight under nitrogen protection. After the reaction was completed, saturated aqueous sodium thiosulfate solution (80 mL) was added to quench the reaction, saturated sodium bicarbonate solution was used to adjust the pH to 8-9, and extracted with ethyl acetate (100 mL x 3), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to remove the solvent, and the crude product was purified by silica gel column chromatography [petroleum ether: methyl tert-butyl ether (v / v) = (100:0-65:35)] to obtain colorless oil A-7 (6.2 g, yield: 75%, purity: 97.52%). LCMS (method C), Rt= 1.096 min; MS Calcd.: 403.2; MS Found: 304.3 [M-Boc+H]+.

[0184] Step 7: Preparation of A-8

[0185] In a single-necked reaction flask, A-7 (3.0 g, 7.4 mmol) and aqueous hydroxylamine solution (977 mg, 14.8 mmol, 50 wt%) were dissolved in ethanol (30 mL), the reaction was stirred at 60°C for 1 hour under nitrogen protection. After the reaction was completed, the reaction solution was evaporated under reduced pressure to remove the solvent to obtain the crude product as a light yellow oil A-8 (3.1 g, yield: 90%, purity: 92.74%), which was directly used in the next step reaction. LCMS (method C), Rt= 1.043 min; MS Calcd.: 418.3; MS Found: 319.3 [M-Boc+H]+.

[0186] Step 8: Preparation of A-9

[0187] In a single-necked reaction flask, A-8 (3.1 g, 7.4 mmol), Raney Ni (350 mg) and tetrahydrofuran (100 mL) were added, and the gas was replaced with a hydrogen balloon for three times, and the reaction was stirred at room temperature overnight under hydrogen atmosphere. After the reaction was completed, the reaction solution was filtered with diatomite to remove solid impurities, and the filtrate was evaporated under reduced pressure to remove the solvent, and the crude product was purified by silica gel column chromatography [petroleum ether: methyl tert-butyl ether (v / v) = (100:0-60:40)] to obtain a light yellow oil A-9 (2.6 g, yield: 82%, purity: >99%). LCMS (method C), Rt= 1.093 min; MS Calcd.: 404.3; MS Found: 405.0 [M+H]+.

[0188] Step 9: Preparation of Intermediate A

[0189] In a single necked reaction flask, A-9 (2.6 g, 6.4 mmol), A-7 (2.6 g, 6.4 mmol) were dissolved in methanol (30 mL) and cooled with ice water bath, then 2 drops of glacial acetic acid was added into the reaction solution, after 1 minute stirring, sodium cyanoborohydride (605 mg, 9.6 mmol) was added, the reaction was stirred at room temperature overnight under nitrogen protection. After the reaction was completed, the reaction was quenched by adding saturated sodium bicarbonate solution (40 mL), the solvent methanol was removed by reduced pressure evaporation, ethyl acetate was added for extraction (40 mL x 3), the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was evaporated by reduced pressure to remove the solvent, the crude product was purified by silica gel column chromatography [petroleum ether: methyl tert-butyl ether (v / v) = (100:0-40:60)] to obtain yellowish oil A (3.5 g, yield: 74%, purity: 91.71%). LCMS (method G), Rt = 1.806 min; MS Calcd.: 791.5; MS Found: 792.5 [M+H]+.

[0190] Example 1:

[0191] Step 1: Preparation of 1-a

[0192] In a single necked reaction flask, A-5 (250 mg, 0.55 mmol) was dissolved in ethanol (7 mL), then potassium acetate (110 mg, 1.12 mmol) and Pd(dppf)Cl2(40 mg, 0.06 mmol) were added, the gas was replaced with a carbon monoxide balloon for three times, the reaction was stirred at 80 °C overnight under carbon monoxide atmosphere. After the reaction was completed, the reaction was evaporated by reduced pressure to remove the solvent, the obtained crude product was purified by silica gel column chromatography [petroleum ether: ethyl acetate (v / v) = (100:0-80:20)] to obtain yellowish liquid 1-a (210 mg, yield: 85%, purity: 82.47%). LCMS (method C), Rt = 1.188 min; MS Calcd.: 447.3; MS Found: 348.0 [M-Boc+H] + .

[0193] Step 2: Preparation of 1-b

[0194] In a single-necked reaction flask, 1-a (210 mg, 0.47 mmol) was dissolved in methanol (2 mL), then 2 mol / L aqueous sodium hydroxide solution (0.3 mL, 0.60 mmol) was added, and stirred at room temperature under nitrogen protection overnight. After the reaction was completed, the reaction solution was adjusted to pH 5-6 by adding 2 mol / L dilute hydrochloric acid dropwise, and the methanol was removed under reduced pressure. The aqueous phase was extracted with ethyl acetate (15 mL x 3), and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to obtain a yellow liquid 1-b (170 mg, yield: 69%, purity: 79.44%). LCMS (method C), Rt = 0.736 min; MS Calcd.: 419.2; MS Found: 320.3 [M-Boc+H] + .

[0195] Step 3: Preparation of 1-c

[0196] In a single-necked reaction flask, 1-b (170 mg, 0.32 mmol) was dissolved in N,N-dimethylformamide (3 mL), then A (253 mg, 0.32 mmol), N-methylimidazole (50 mg, 0.64 mmol), and N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (134 mg, 0.48 mmol) were added, and stirred at room temperature under nitrogen protection for 2 hours. After the reaction was completed, the reaction solution was quenched with water (6 mL) and extracted with ethyl acetate (15 mL x 3), and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to obtain a white solid 1-c (300 mg, yield: 78%, purity: >99%). LCMS (method G), Rt = 2.582 min; MS Calcd.: 1192.7; MS Found: 1093.5 [M+H] + .

[0197] Step 4: Preparation of compound 1

[0198] In a single-necked reaction flask, 1-c (300 mg, 0.25 mmol) was dissolved in 2 mol / L hydrochloric acid in acetic acid solution (3 mL), and stirred at room temperature under nitrogen protection for 2 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, and the obtained crude product was purified by preparative high performance liquid chromatography to obtain compound 1. LCMS (method E), Rt = 1.187 min; MS Calcd.: 724.4; MS Found: 725.3 [M+H] +HPLC (method J), Rt = 3.999 min; MS Calcd.: 724.4; MS Found: no mass response.

[0199] 1 HNMR (400 MHz, CD3OD) δ: 7.36-7.38 (m, 4H), 7.35-7.26 (m, 2H), 7.21 (d, J = 6.4 Hz, 3H), 7.16 (d, J = 7.6 Hz, 1H), 7.04 (s, 1H), 6.96 (d, J = 8 Hz, 1H), 4.66 (dd, J = 24.0, 14.8 Hz, 2H), 4.40 (s, 2H), 3.57-3.46 (m, 3H), 3.40-3.36 (m, 3H), 3.29-3.19 (m, 3H), 3.15-3.03 (m, 3H), 3.00-2.88 (m, 6H), 2.80-2.68 (m, 3H), 2.60-2.51 (m, 3H), 2.22-2.13 (m, 3H), 1.88-1.79 (m, 3H).

[0200] Example 2:

[0201] Step 1: Preparation of 2-b

[0202] In a single-necked reaction flask, tert-butyl phosphineoxyacetic acid (2.54 g, 10.07 mmol) was dissolved in anhydrous N,N-dimethylformamide (35 mL). With an ice water bath for cooling, sodium hydride (403 mg, 10.07 mmol, 60 wt%) was added in batches under nitrogen protection, and reacted in an ice water bath for 0.5 h, followed by the addition of 2-a (2.00 g, 10.07 mmol), and stirred at room temperature overnight under nitrogen protection. After the reaction was completed, saturated aqueous ammonium chloride solution (50 mL) was added to quench the reaction, and extracted with ethyl acetate (40 mL x 3), and the organic phase was combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography [petroleum ether: methyl tert-butyl ether (v / v) = (100:0-50:50)] to obtain colorless oil 2-b (3.70 g, yield: 28%, purity: 31.82%). LCMS (method C), Rt = 0.994 min; MS Calcd.: 414.2; MS Found: 359.2 [M-56+H] + .

[0203] Step 2: Preparation of 2-c

[0204] In a single necked flask, 2-b (3.60 g, 2.69 mmol, 31.82% purity) was dissolved in dry N,N-dimethylformamide (40 mL). The reaction flask was cooled with an ice water bath, sodium hydride (162 mg, 4.03 mmol, 60 wt%) was added portion wise under nitrogen atmosphere, the reaction was stirred for 0.5 h in an ice water bath, then SM-6 (554 mg, 2.78 mmol) was added, the reaction was stirred at room temperature overnight under nitrogen atmosphere. After completion of the reaction, the reaction was quenched with saturated aqueous ammonium chloride solution (50 mL) and extracted with ethyl acetate (40 mL x 3), the organic layers were combined and washed with saturated brine solution (30 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was evaporated under reduced pressure to get the crude product which was purified by silica gel column chromatography [petroleum ether: methyl-tert-butyl ether (v / v) = (100:0-36:64)] to get 2-c as colorless oil (250 mg, yield: 20%, purity: 63.62%). LCMS (method C), Rt = 1.207 min; MS Calcd.: 459.3; MS Found: 360.3 [M-100+H] + .

[0205] Step 3: Preparation of 2-d

[0206] In a single necked flask, 2-c (210 mg, 0.46 mmol) and 10% Pd / C (30 mg) were dissolved in isopropyl alcohol (10 mL). The reaction flask was purged with hydrogen gas balloon for three times and stirred at 60 °C under hydrogen atmosphere overnight. After completion of the reaction, the reaction was filtered through celite, the filtrate was evaporated under reduced pressure to get the crude product which was purified by silica gel column chromatography [petroleum ether: methyl-tert-butyl ether (v / v) = (100:0-90:10)] to get 2-d as colorless oil (150 mg, yield: 71%, purity: >99%). LCMS (method B), Rt = 2.199 min; MS Calcd.: 461.1; MS Found: 362.3 [M-100+H] + .

[0207] Step 4: Preparation of 2-e

[0208] In a single necked reaction flask, 2-d (150 mg, 0.32 mmol) and 2 mol / L sodium hydroxide aqueous solution (0.4 mL, 0.80 mmol) were dissolved in ethanol (2 mL). Stirring at room temperature for 6 hours. After the reaction was completed, the pH of the reaction solution was adjusted to 5-6 with 1 mol / L dilute hydrochloric acid, and extracted with ethyl acetate (10 mL x 3), the combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to obtain a colorless oil 2-e (128 mg, yield: 91%, purity: 86.67%) as a crude product. LCMS (method C), Rt= 0.747 min; MS Calcd.: 433.2; MS Found: 322.2 [M-56-56+H] + .

[0209] Step 5: Preparation of 2-f

[0210] In a single necked reaction flask, 2-e (116 mg, 0.27 mmol) and triethylamine (55 mg, 0.54 mmol) were dissolved in tetrahydrofuran (10 mL). Under ice water bath, isobutyl chloroformate (55 mg, 0.40 mmol) was added, stirring at room temperature for 1 hour under nitrogen protection, in another single necked reaction flask, sodium borohydride (31 mg, 0.81 mmol) and water (5 mL) were added, and the tetrahydrofuran solution of the active ester synthesized in the previous step was slowly added dropwise under ice water bath, and the reaction was allowed to warm to room temperature and stirred for 2 hours. After the reaction was completed, water (15 mL) was added to quench the reaction, and extracted with ethyl acetate (20 mL x 3), the combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography [petroleum ether: methyl tert-butyl ether (v / v) = (100:0-60:40)] to obtain 2-f (80 mg, yield: 72%, purity: 91.08%) as a colorless oil. LCMS (method C), Rt= 1.059 min; MS Calcd.: 419.3; MS Found: 320.4 [M-100+H] + .

[0211] Step 6: Preparation of 2-g

[0212] In a single necked flask, 2-f (80 mg, 0.19 mmol) and (chloromethylidene)dimethylammonium chloride (49 mg, 0.38 mmol) were dissolved in dichloromethane (5 mL). The reaction mixture was stirred at room temperature for 1 h under nitrogen atmosphere. After completion of the reaction, the reaction mixture was quenched with saturated aqueous sodium bicarbonate solution (6 mL) and extracted with dichloromethane (10 mL x 3), the organic layers were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was evaporated under reduced pressure to obtain the crude 2-g (90 mg, yield: 95%, purity: 88.25%) as colorless oil which was used as such in the next step. LCMS (method C), Rt = 1.223 min; MS Calcd. for C26H26F3N3O4: 437.2; MS Found: 326.2 [M-56-56+H] + .

[0213] Step 7: Preparation of 2-h

[0214] In a single necked flask, 2-g (110 mg, 0.25 mmol), A (198 mg, 0.25 mmol), potassium iodide (41 mg, 0.25 mmol) and potassium carbonate (69 mg, 0.50 mmol) were dissolved in N,N-dimethylformamide (3 mL). The reaction mixture was stirred at 80 °C for 2 h under nitrogen atmosphere. After completion of the reaction, the reaction mixture was quenched with saturated ammonium chloride (6 mL) and extracted with ethyl acetate (15 mL x 3), the organic layers were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was evaporated under reduced pressure to obtain the crude which was purified by silica gel column chromatography [petroleum ether: methyl tert-butyl ether (v / v) = (100:0-60:40)] to afford 2-h (100 mg, yield: 33%, purity: 89.19%) as colorless oil. LCMS (method G), Rt = 1.905 min; MS Calcd. for C62H73F3N6O8: 1192.8; MS Found: 1194.6 [M+H] + .

[0215] Step 8: Preparation of compound 2

[0216] In a single necked flask, 2-h (100 mg, 0.08 mmol) was dissolved in hydrochloric acid in acetic acid (3 mL, 2 mol / L hydrochloric acid in acetic acid). The reaction mixture was stirred at room temperature for 3 h under nitrogen atmosphere. After completion of the reaction, the reaction mixture was evaporated under reduced pressure to obtain the crude which was purified by preparative high performance liquid chromatography, evaporated under reduced pressure, dried to obtain compound 2 as hydrochloride salt. LCMS (method A) Rt = 1.184 min; MS Calcd. for C36H35F3N6O8: 724.4; MS Found: 725.5 [M+H] +HPLC (method I) Rt = 4.383 min; MS Calcd.: 724.4; MS Found: 725.3 [M+H] + .

[0217] 1 HNMR (400 MHz, CD3OD) δ: 7.52 (br, 3H), 7.42-7.37 (m, 9H), 4.33-4.25 (m, 6H), 3.64-3.53 (m, 3H), 3.45-3.40 (m, 2H), 3.31-3.23 (m, 4H), 3.15 (t, J = 6.0 Hz, 2H), 3.04-2.96 (m, 7H), 2.92-2.86 (m, 2H), 2.63-2.57 (m, 2H), 2.26-2.16 (m, 3H), 2.09-1.95 (m, 4H), 1.90-1.80 (m, 2H), 1.71-1.61 (m, 1H).

[0218] Example 3:

[0219] Step 1: Preparation of 3-a

[0220] In a single-necked reaction flask, 2-e (80 mg, 0.18 mmol), A (143 mg, 0.18 mmol), N,N,N',N'-tetramethylchloroformamidium hexafluorophosphate (76 mg, 0.27 mmol) and N-methylimidazole (44 mg, 0.54 mmol) were dissolved in N,N-dimethylformamide (5 mL). Stirring was carried out at room temperature for 3 hours under nitrogen protection. After the reaction was completed, water (10 mL) was added to quench the reaction, and the organic phase was extracted with ethyl acetate (15 mL x 3), washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography [petroleum ether: methyl tert-butyl ether (v / v) = (100:0-40:60)] to obtain colorless oil 3-a (140 mg, yield: 63%, purity: 80.26%). LCMS (method G), Rt = 2.689 min; MS Calcd.: 1206.7; MS Found: no mass response.

[0221] Step 2: Preparation of compound 3

[0222] In a single-necked flask, 3-a (140 mg, 0.12 mmol) was dissolved in hydrochloric acid in acetic acid (4 mL, 2 mol / L hydrochloric acid in acetic acid). Stirring was carried out at room temperature for 4 hours under nitrogen protection. After the reaction was completed, the solvent was removed by evaporation under reduced pressure, and the crude product was purified by preparative high performance liquid chromatography, the solvent was removed by evaporation under reduced pressure, water was removed, and the hydrochloride salt of compound 3 was obtained. LCMS (method E) Rt = 1.225 min; MS Calcd.: 738.4; MS Found: 739.3 [M+H] + .HPLC (method J) Rt = 4.190 min; MS Calcd.: 738.4; MS Found: no mass response.

[0223] 1 HNMR (400 MHz, CD3OD) δ: 7.39-7.37 (m, 4H), 7.33-7.26 (m, 2H), 7.20-7.15 (m, 4H), 7.04 (s, 1H), 6.97 (d, J = 7.6 Hz, 1H), 4.18-4.57 (m, 2H), 4.44 (s, 2H), 3.59-3.49 (m, 3H), 3.41-3.39 (m, 2H), 3.27-3.22 (m, 4H), 3.13-2.98 (m, 4H), 2.95-2.90 (m, 4H), 2.83-2.75 (m, 3H), 2.63-2.52 (m, 2H), 2.23-2.15 (m, 3H), 2.08-1.81 (m, 3H), 1.65-1.55 (m, 1H).

[0224] Example 4:

[0225] Step 1: Preparation of 4-b

[0226] In a three-necked reaction flask, was placed 4-b (1.00 g, 1.79 mmol) and tetrahydrofuran (18 mL), the reaction was placed in an ice-water bath under nitrogen protection, 2 mol / L lithium hydroxide aqueous solution (2.0 mL, 4.00 mmol) and hydrogen peroxide (610 mg, 5.37 mmol, 30 wt% aqueous solution) were added slowly in turn, then the ice-water bath was removed, and the reaction was stirred at room temperature overnight. After the reaction was completed, water (20 mL) and n-hexane (15 mL) were added, the aqueous phase was separated, the aqueous phase was adjusted to pH 6-7 with dilute hydrochloric acid, and extracted with ethyl acetate (20 mL x 2), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure, the crude product was purified by silica gel column chromatography [petroleum ether: methyl tert-butyl ether (v / v) = (100:0-50:50)] to obtain 4-c (520 mg, yield: 73%, purity: 85.80%) as a light yellow oil. LCMS (method C), Rt = 0.589 min; MS Calcd.: 398.1; MS Found: 343.1 [M-56+H] + .

[0227] Step 2: Preparation of 4-c

[0228] In a three-necked reaction flask, was placed 4-b (1.00 g, 1.79 mmol) and tetrahydrofuran (18 mL), the reaction was placed in an ice-water bath under nitrogen protection, 2 mol / L lithium hydroxide aqueous solution (2.0 mL, 4.00 mmol) and hydrogen peroxide (610 mg, 5.37 mmol, 30 wt% aqueous solution) were added slowly in turn, then the ice-water bath was removed, and the reaction was stirred at room temperature overnight. After the reaction was completed, water (20 mL) and n-hexane (15 mL) were added, the aqueous phase was separated, the aqueous phase was adjusted to pH 6-7 with dilute hydrochloric acid, and extracted with ethyl acetate (20 mL x 2), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure, the crude product was purified by silica gel column chromatography [petroleum ether: methyl tert-butyl ether (v / v) = (100:0-50:50)] to obtain 4-c (520 mg, yield: 73%, purity: 85.80%) as a light yellow oil. LCMS (method C), Rt = 0.589 min; MS Calcd.: 398.1; MS Found: 343.1 [M-56+H] + .

[0229] Step 3: Preparation of 4-d

[0230] In a single necked flask, 4-c (520 mg, 1.30 mmol), SM-4 (261 mg, 1.30 mmol) and tetrahydrofuran (13 mL) were added. The reaction was stirred at 70 °C for 2 h under nitrogen protection, then SM-4 (515 mg, 2.57 mmol) was added, the reaction was stirred at 70 °C overnight. After the reaction was completed, the filtrate was evaporated to remove the solvent under reduced pressure, and the crude product was purified by silica gel column chromatography [petroleum ether: methyl tert-butyl ether (v / v) = (100:0-68:42)] to obtain 4-d (380 mg, yield: 64%, purity: >99%) as a transparent oil. LCMS (method C), Rt= 1.103 min; MS Calcd.: 454.1; MS Found: 399.0 [M-56+H] + .

[0231] Step 4: Preparation of 4-e

[0232] In a single necked flask, 4-d (380 mg, 0.83 mmol), Pd(dppf)Cl2(59 g, 0.08 mmol), potassium acetate (244 mg, 2.49 mmol) and ethanol (10 mL) were added, replaced with carbon monoxide balloon three times, then the reaction was stirred at 90 °C overnight under the atmosphere of carbon monoxide gas. After the reaction was completed, the filtrate was evaporated to remove the solvent under reduced pressure, and the crude product was purified by silica gel column chromatography [petroleum ether: methyl tert-butyl ether (v / v) = (100:0-29:71)] to obtain 4-e (330 mg, yield: 88%, purity: >99%) as a transparent oil. LCMS (method C), Rt= 0.998 min; MS Calcd.: 448.3; MS Found: 449.4 [M+H] + .

[0233] Step 5: Preparation of 4-f

[0234] In a single necked flask, 4-e (200 mg, 0.44 mmol) and 2 mol / L sodium hydroxide aqueous solution (0.4 mL, 0.80 mmol) were dissolved in ethanol (5 mL). Stirring at room temperature for 5 h. After the reaction was completed, the pH of the reaction solution was adjusted to 6-7 with 1 mol / L dilute hydrochloric acid, and extracted with ethyl acetate (15 mL x 3), the organic phase was combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to remove the solvent under reduced pressure to obtain the crude product as a light yellow oil 4-f (180 mg, yield: 96%, purity: 80.90%), which was directly used in the next step reaction. LCMS (method C), Rt= 0.683 min; MS Calcd.: 420.2; MS Found: 421.3 [M+H] +.

[0235] Step 6: Preparation of 4-g

[0236] In a single-necked flask, 4-f (180 mg, 0.43 mmol), A (340 mg, 0.43 mmol), N,N,N',N'-tetramethylchloroformamidium hexafluorophosphate (181 mg, 0.64 mmol) and N-methylimidazole (71 mg, 0.86 mmol) were dissolved in N,N-dimethylformamide (6 mL). The reaction was stirred at room temperature for 5 hours under nitrogen protection. After the reaction was completed, the reaction was quenched by adding water (15 mL) and extracted with ethyl acetate (20 mL x 3), the organic phase was combined and washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was evaporated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography [petroleum ether: methyl tert-butyl ether (v / v) = (100:0-48:52)] to obtain 4-g (230 mg, yield: 45%, purity: >99%) as a colorless oil. LCMS (method G), Rt = 2.429 min; MS Calcd.: 1193.7; MS Found: 1194.5 [M+H] + .

[0237] Step 7: Preparation of compound 4

[0238] In a single-necked flask, 4-g (230 mg, 0.19 mmol) was dissolved in hydrochloric acid in acetic acid solution (5 mL, 2 mol / L hydrochloric acid in acetic acid solution). The reaction was stirred at room temperature for 3 hours under nitrogen protection. After the reaction was completed, the reaction was evaporated under reduced pressure to obtain a crude product, which was purified by preparative high performance liquid chromatography, evaporated under reduced pressure, dried to obtain the hydrochloride salt of compound 4. LCMS (method E) Rt = 1.163 min; MS Calcd.: 725.4; MS Found: 726.3 [M+H] + HPLC (method I) Rt = 4.513 min; MS Calcd.: 725.4; MS Found: no mass response.

[0239] 1HNMR (400 MHz, CD3OD) δ: 8.73 (d, J = 6.0 Hz, 1H), 8.02 (s, 1H), 7.96 (d, J = 6.4 Hz, 1H), 7.33-7.26 (m, 2H), 7.25-7.21 (m, 4H), 7.03 (s, 1H), 6.94 (d, J = 7.2 Hz, 1H), 4.88-4.75 (m, 2H), 4.55 (s, 2H), 3.56-3.46 (m, 3H), 3.44-3.41 (m, 3H), 3.30-3.22 (m, 3H), 3.20-3.11 (m, 6H), 2.98-2.2.90 (m, 3H), 2.89-2.78 (m, 3H), 2.63-2.58 (m, 3H), 2.21-2.18 (m, 3H), 1.89-1.81 (m, 3H).

[0240] Example 5:

[0241] Step 1: Preparation of 5-b

[0242] In a three-necked flask, A-2 (3.00 g, 7.73 mmol) and tetrahydrofuran (50 mL) were added, and the reaction was placed in an ice water bath under nitrogen protection. Lithium bis(trimethylsilyl)amide (10 mL, 10 mmol, 1 mol / L tetrahydrofuran solution) was slowly added, and the reaction was stirred in the ice water bath for 1 hour. 5-a (2.69 g, 10.1 mmol) was dissolved in tetrahydrofuran (15 mL) and added to the above reaction solution at 0°C. The ice water bath was removed, and the reaction was stirred at room temperature overnight. After the reaction was completed, saturated ammonium chloride solution (20 mL) was added to quench the reaction, and extracted with ethyl acetate (40 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure. The crude product was purified by silica gel column chromatography [petroleum ether: methyl tert-butyl ether (v / v) = (100:0-53:47)] to obtain 5-b (2.60 g, yield: 52%, purity: 88.38%) as a light yellow oil. LCMS (method C), Rt = 1.181 min; MS Calcd.: 574.2; MS Found: 519.1 [M-56+H] + .

[0243] Step 2: Preparation of 5-c

[0244] In a single-necked flask, 5-b (2.6 g, 4.00 mmol) was dissolved in tetrahydrofuran (20 mL), the reaction was placed in an ice-water bath, and hydrogen peroxide (2.27 g, 20.00 mmol, 30 wt%) and 2 mol / L aqueous lithium hydroxide solution (6 mL, 12.00 mmol) were slowly added. The reaction was stirred at room temperature overnight under nitrogen protection. After the reaction was completed, the reaction solution was adjusted to pH 5-6 by dropwise addition of 2 mol / L dilute hydrochloric acid, extracted with ethyl acetate (30 mL x 3), and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to obtain a white liquid 5-c (1.30 g, yield: 56%, purity: 71.99%). LCMS (method C), Rt= 0.688 min; MS Calcd.: 415.1; MS Found: 360.1 [M-56+H] + .

[0245] Step 3: Preparation of 5-d

[0246] In a two-necked flask, 5-c (1.3 g, 2.26 mmol) was dissolved in tetrahydrofuran (14 mL), and SM-4 (678 mg, 3.39 mmol) was added. The reaction was stirred at 70°C overnight under nitrogen protection, followed by the addition of SM-4 (339 mg, 1.70 mmol). After stirring at 70°C for 1 h, SM-4 (339 mg, 1.70 mmol) was added again, and the reaction was stirred at 70°C for 1 h. After the reaction was completed, the solvent was evaporated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography [petroleum ether: ethyl acetate (v / v) = (100:0-93:7)] to obtain a yellowish liquid 5-d (1.00 g, yield: 90%, purity: 95.74%). LCMS (method C), Rt= 1.220 min; MS Calcd.: 471.2; MS Found: 360.1 [M-56-56+H] + .

[0247] Step 4: Preparation of 5-e

[0248] In a single-necked reaction flask, 5-d (580 mg, 0.57 mmol) was dissolved in ethanol (15 mL), then potassium acetate (112 mg, 1.14 mmol) and Pd(dppf)Cl2(40 mg, 0.06 mmol) were added, the reaction was replaced with carbon monoxide balloon three times of gas, and the reaction was stirred at 80 °C overnight under the protection of carbon monoxide gas. After the reaction was completed, the solvent was removed by evaporation under reduced pressure, and the obtained crude product was purified by silica gel column chromatography [petroleum ether: ethyl acetate (v / v) = (100:0-90:10)] to obtain a yellowish liquid 5-e (500 mg, yield: 91%, purity: >99%). LCMS (method C), Rt = 1.201 min; MS Calcd.: 465.3; MS Found: 366.3 [M-Boc+H] + .

[0249] Step 5: Preparation of 5-f

[0250] In a single-necked reaction flask, 5-e (250 mg, 0.54 mmol) was dissolved in tetrahydrofuran (10 mL), then 2 mol / L aqueous lithium hydroxide solution (0.3 mL, 0.60 mmol) was added, and the reaction was stirred at room temperature overnight under nitrogen protection. After the reaction was completed, the reaction solution was adjusted to pH 5-6 by dropwise addition of 2 mol / L dilute hydrochloric acid, then extracted with ethyl acetate (20 mL x 3), the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to obtain a white solid 5-f (207 mg, yield: 87%, purity: 98.72%). LCMS (method A), Rt = 1.626 min; MS Calcd.: 437.2; MS Found: 338.2 [M-Boc+H] + .

[0251] Step 6: Preparation of 5-g

[0252] In a single-necked flask, 5-f (200 mg, 0.45 mmol) was dissolved in N,N- dimethylformamide (5 mL), followed by the addition of A (356 mg, 0.45 mmol), N- methylimidazole (73 mg, 0.90 mmol) and N,N,N',N'-tetramethylchloroformamidium hexafluorophosphate (189 mg, 0.65 mmol). The reaction was stirred at room temperature for 2 hours under nitrogen protection. After the reaction was completed, the reaction solution was quenched with water (10 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was evaporated under reduced pressure to obtain a crude product which was purified by silica gel column chromatography [petroleum ether: ethyl acetate (v / v) = (100:0-70:30)] to obtain 5-g (310 mg, yield: 56.7%, purity: >99%) as a white solid. LCMS (method G), Rt = 2.539 min; MS Calcd.: 1210.7; MS Found: no mass response.

[0253] Step 7: Preparation of 5

[0254] In a single-necked flask, 5-g (310 mg, 0.26 mmol) was dissolved in hydrochloric acid in acetic acid solution (5 mL, 2 mol / L hydrochloric acid in acetic acid solution) and stirred at room temperature for 2 hours under nitrogen protection. After the reaction was completed, the solvent was evaporated under reduced pressure and the obtained crude product was purified by preparative high performance liquid chromatography to obtain compound 5. LCMS (method E), Rt = 1.217 min; MS Calcd.: 742.4; MS Found: 743.3 [M+H] + .HPLC (method J), Rt = 4.123 min; MS Calcd.: 724.4; MS Found: no mass response.

[0255] 1HNMR (400 MHz, CD3OD) δ: 7.33-7.26 (m, 2H), 7.22-7.19 (m, 4H), 7.17-7.15 (m, 1H), 7.13-7.10 (m, 2H), 7.03 (s, 1H), 6.96 (d, J = 6.8 Hz, 1H), 4.66 (dd, J = 26, 15.2 Hz, 2H), 4.39 (s, 2H), 3.57-3.47 (m, 3H), 3.44-3.37 (m, 3H), 3.29-3.20 (m, 3H), 3.15-3.01 (m, 3H), 2.98-2.92 (m, 6H), 2.82-2.78 (m, 2H), 2.73-2.67 (m, 1H), 2.61-2.50 (m, 3H), 2.21-2.13 (m, 3H), 1.89-1.78 (m, 3H).

[0256] Example 6:

[0257] Step 1: Preparation of 6-b

[0258] In a single-necked reaction flask, 6-a (6.00 g, 30.14 mmol) was dissolved in tetrahydrofuran (40 mL) and methanol (10 mL), the reaction was placed in an ice water bath under nitrogen protection, sodium borohydride (1.37 g, 36.17 mmol) was added in batches, the reaction was stirred in the ice water bath for 1 hour. After the reaction was completed, 0.5 mol / L dilute hydrochloric acid aqueous solution (40 mL) was added to quench the reaction, and extracted with ethyl acetate (40 mL x 3), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to obtain a light yellow oil 6-b (5.30 g, yield: 88%, purity: >99%), which was directly used in the next step reaction.

[0259] 1 HNMR (400 MHz, CD3OD) δ: 7.33-7.26 (m, 2H), 7.22-7.19 (m, 4H), 7.17-7.15 (m, 1H), 7.13-7.10 (m, 2H), 7.03 (s, 1H), 6.96 (d, J = 6.8 Hz, 1H), 4.66 (dd, J = 26, 15.2 Hz, 2H), 4.39 (s, 2H), 3.57-3.47 (m, 3H), 3.44-3.37 (m, 3H), 3.29-3.20 (m, 3H), 3.15-3.01 (m, 3H), 2.98-2.92 (m, 6H), 2.82-2.78 (m, 2H), 2.73-2.67 (m, 1H), 2.61-2.50 (m, 3H), 2.21-2.13 (m, 3H), 1.89-1.78 (m, 3H).

[0260] Step 2: Preparation of 6-c

[0261] In a single-necked flask, was charged with 6-b (5.30 g, 26.36 mmol) and dichloromethane (50 mL), the reaction was placed in an ice-water bath under nitrogen protection, phosphorus tribromide (7.11 g, 26.36 mmol) was added slowly, then the ice-water bath was removed, the reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction was poured into ice water to quench, the aqueous phase was separated and extracted with dichloromethane (30 mL x 2), the organic phase was washed with saturated sodium bicarbonate aqueous solution (30 mL x 2), saturated brine (30 mL) successively, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to obtain a light yellow solid 6-c (4.30 g, yield: 62%, purity: >95%), which was sublimed, and the crude product was directly used in the next step.

[0262] 1 HNMR (400 MHz, CDC13) δ: 7.34 (s, 1H), 7.26 (s, 1H), 7.12 (s, 1H), 4.39 (s, 2H), 2.33 (s, 3H).

[0263] Step 3: Preparation of 6-d

[0264] In a three-necked flask, was charged with A-2 (4.21 g, 10.86 mmol) and anhydrous tetrahydrofuran (60 mL), the reaction was placed in an ice-water bath under nitrogen protection, lithium bis(trimethylsilyl)amide (16.3 mL, 16.30 mmol, 1 mol / L tetrahydrofuran solution) was added dropwise slowly, the reaction was stirred in the ice-water bath for 1 hour. Then 6-c (4.30 g, 16.29 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL) and added to the above reaction solution at 0°C, the ice-water bath was removed, and the reaction was stirred at room temperature overnight. After the reaction was completed, saturated ammonium chloride aqueous solution (60 mL) was added to quench the reaction, and extracted with ethyl acetate (60 mL x 3), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to obtain a light yellow oil 6-d (3.80 g, yield: 61%, purity: 73.58%). LCMS (method C), Rt = 1.189 min; MS Calcd.: 570.2; MS Found: 515.2 [M-56+H] + .

[0265] Step 4: Preparation of 6-e

[0266] In a single necked reaction flask, was charged with 6-d (3.80 g, 6.65 mmol) and tetrahydrofuran (40 mL), the reaction was placed in an ice water bath under nitrogen protection, 2 mol / L lithium hydroxide aqueous solution (7.0 mL, 14.00 mmol) and hydrogen peroxide (2.26 g, 19.95 mmol, 30 wt% aqueous solution) were added slowly one by one, then the ice water bath was removed, the reaction was stirred at room temperature overnight. After the reaction was completed, water (50 mL) and n-hexane (50 mL) were added, the aqueous phase was separated, the aqueous phase was adjusted to pH 4-5 with dilute hydrochloric acid, and extracted with ethyl acetate (30 mL x 3), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure, the crude product was purified by silica gel column chromatography [petroleum ether: methyl tert-butyl ether (v / v) = (100:0-75:25)] to give 6-e (2.20 g, yield: 80%, purity: 93.34%) as a light yellow oil. LCMS (method C), Rt = 0.710 min; MS Calcd.: 411.1; MS Found: 356.1 [M-56+H] + .

[0267] Step 5: Preparation of 6-f

[0268] In a single necked reaction flask, was charged with 6-e (2.20 g, 5.34 mmol), SM-4 (1.07 g, 5.34 mmol) and tetrahydrofuran (27 mL), the reaction was stirred at 70 °C for 8 hours under nitrogen protection, then SM-4 (1.07 g, 5.34 mmol) was added, the reaction was stirred at 70 °C for 22 hours. After the reaction was completed, the filtrate was evaporated under reduced pressure, the crude product was purified by silica gel column chromatography [petroleum ether: methyl tert-butyl ether (v / v) = (100:0-80:20)] to give 6-f (1.60 g, yield: 64%, purity: >99%) as a transparent oil. LCMS (method C), Rt = 1.270 min; MS Calcd.: 467.2; MS Found: 356.1 [M-112+H] + .

[0269] Step 6: Preparation of 6-g

[0270] In a single-necked reaction flask, 6-f (1.00 g, 2.13 mmol), Pd(dppf)Cl2(154 mg, 0.21 mmol), potassium acetate (417 mg, 4.26 mmol) and ethanol (22 mL) were added, and the flask was replaced with carbon monoxide gas three times, and then the reaction was stirred at 90 °C overnight under the atmosphere of carbon monoxide gas. After the reaction was completed, the filtrate was evaporated under reduced pressure to remove the solvent, and the crude product was purified by silica gel column chromatography [petroleum ether: methyl tert-butyl ether (v / v) = (100:0-78:22)] to obtain 6-g (900 mg, yield: 91%, purity: >99%) as a transparent oil. LCMS (method C), Rt = 1.221 min; MS Calcd.: 461.3; MS Found: 362.4 [M-Boc+H] + .

[0271] Step 7: Preparation of 6-h

[0272] In a single-necked reaction flask, 6-g (300 mg, 0.65 mmol) and 2 mol / L sodium hydroxide aqueous solution (0.6 mL, 1.20 mmol) were dissolved in ethanol (5 mL) at room temperature and stirred for 5 hours. After the reaction was completed, the reaction solution was adjusted to pH 6-7 with 1 mol / L dilute hydrochloric acid, and extracted with ethyl acetate (15 mL x 3), and the organic phase was combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to obtain the crude product 6-h (260 mg, yield: 92%, purity: 91.43%) as a colorless oil, which was directly used in the next reaction. LCMS (method C), Rt = 0.758 min; MS Calcd.: 433.2; MS Found: 334.3 [M+H] + .

[0273] Step 8: Preparation of 6-i

[0274] In a single-necked reaction flask, 6-h (260 mg, 0.60 mmol), A (475 mg, 0.60 mmol), N,N,N',N'-tetramethylchloroformamidium hexafluorophosphate (585 mg, 0.90 mmol) and N-methylimidazole (99 mg, 1.20 mmol) were dissolved in N,N-dimethylformamide (8 mL). After stirring at room temperature overnight under nitrogen protection, water (15 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to give a crude product, which was purified by silica gel column chromatography [petroleum ether: methyl tert-butyl ether (v / v) = (100:0-48:52)] to give 6-i (160 mg, yield: 22%, purity: 62.97%) as a light yellow oil. LCMS (method G), Rt = 2.673 min; MS Calcd.: 1206.7; MS Found: no mass response.

[0275] Step 9: Preparation of 6

[0276] In a single-necked reaction flask, 6-i (260 mg, 0.13 mmol) was dissolved in hydrochloric acid in acetic acid solution (4 mL, 2 mol / L hydrochloric acid in acetic acid). After stirring at room temperature for 3 hours under nitrogen protection, the reaction mixture was evaporated under reduced pressure to remove the solvent. The crude product was purified by preparative high-performance liquid chromatography, evaporated under reduced pressure to remove the solvent, and dried to give the hydrochloride salt of compound 6. LCMS (method E) Rt = 1.217 min; MS Calcd.: 738.4; MS Found: 739.3 [M+H] + .HPLC (method I) Rt = 4.827 min; MS Calcd.: 738.4; MS Found: 739.3 [M+H] + .

[0277] 1HNMR (400 MHz, CD3OD) δ: 7.31-7.26 (m, 2H), 7.21 (d, J = 6.8 Hz, 3H), 7.16 (d, J = 6.8 Hz, 4H), 7.04 (s, 1H), 6.95 (d, J = 6.8 Hz, 1H), 4.64 (d, J = 7.2 Hz, 2H), 4.39 (s, 2H), 3.54-3.44 (m, 3H), 3.41-3.37 (m, 3H), 3.27-3.21 (m, 3H), 3.13-3.01 (m, 3H), 2.99-2.87 (m, 6H), 2.80-2.69 (m, 3H), 2.59-2.52 (m, 3H), 2.32 (s, 3H), 2.01-2.17 (m, 3H), 1.89-1.81 (m, 3H).

[0278] Example 7:

[0279] Step 1: Preparation of 7-b

[0280] In a three-necked flask, A-2 (3.00 g, 7.72 mmol) and tetrahydrofuran (40 mL) were added, the reaction was placed in an ice water bath under nitrogen protection, lithium bis(trimethylsilyl)amide (11.5 mL, 11.50 mmol, 1 mol / L tetrahydrofuran solution) was added dropwise slowly, the reaction was stirred in the ice water bath for 1 hour. Then 7-a (2.70 g, 8.50 mmol) was dissolved in tetrahydrofuran (8 mL) and added to the above reaction solution at 0°C, the ice water bath was removed, and the reaction was stirred at room temperature overnight. After the reaction was completed, saturated aqueous ammonium chloride solution (40 mL) was added to quench the reaction, and extracted with ethyl acetate (30 mL x 2), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure, and the crude product was purified by silica gel column chromatography [petroleum ether: methyl tert-butyl ether (v / v) = (100:0-58:42)] to give 7-b (2.00 g, yield: 41%, purity: 62.75%) as a light yellow oil. LCMS (method C), Rt = 1.213 min; MS Calcd.: 624.1; MS Found: 569.1 [M-56+H] + .

[0281] Step 2: Preparation of 7-c

[0282] In a three-necked reaction flask, was charged with 7-b (1.90 g, 3.04 mmol) and tetrahydrofuran (15 mL), the reaction was placed in an ice-water bath under nitrogen protection, 2 mol / L lithium hydroxide aqueous solution (3.0 mL, 6.00 mmol) and hydrogen peroxide (1.03 g, 9.11 mmol, 30 wt% aqueous solution) were added slowly in turn, then the ice-water bath was removed, the reaction was stirred at room temperature overnight. After the reaction was completed, water (30 mL) and n-hexane (20 mL) were added, the aqueous phase was separated, the aqueous phase was adjusted to pH 4-5 with dilute hydrochloric acid, and extracted with ethyl acetate (30 mL x 2), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure, the crude product was purified by silica gel column chromatography [petroleum ether: methyl tert-butyl ether (v / v) = (100:0-70:30)] to give 7-c (1.20 g, yield: 85%, purity: 88.06%) as a light yellow oil. LCMS (method C), Rt= 0.736 min; MS Calcd.: 465.1; MS Found: 410.0 [M-56+H] + .

[0283] Step 3: Preparation of 7-d

[0284] In a single-necked reaction flask, was charged with 7-c (1.20 g, 2.57 mmol), SM-4 (515 mg, 2.57 mmol) and tetrahydrofuran (25 mL), the reaction was stirred at 70 °C for 2 hours under nitrogen protection, then SM-4 (515 mg, 2.57 mmol) was added, the reaction was stirred at 70 °C overnight. After the reaction was completed, the filtrate was evaporated under reduced pressure, the crude product was purified by silica gel column chromatography [petroleum ether: methyl tert-butyl ether (v / v) = (100:0-84:16)] to give 7-d (1.20 g, yield: 89%, purity: 76.48%) as a transparent oil. LCMS (method C), Rt= 1.274 min; MS Calcd.: 521.1; MS Found: 410.1 [M-112+H] + .

[0285] Step 4: Preparation of 7-e

[0286] In a single-necked reaction flask, 7-d (600 mg, 1.15 mmol), Pd(dppf)Cl2(84 mg, 0.11 mmol), potassium acetate (226 mg, 2.30 mmol) and ethanol (20 mL) were added, replaced with carbon monoxide balloon three times, then the reaction was stirred at 90 °C overnight under the atmosphere of carbon monoxide. After the reaction was completed, the filtrate was evaporated under reduced pressure to remove the solvent, and the crude product was purified by silica gel column chromatography [petroleum ether: methyl tert-butyl ether (v / v) = (100:0-62:38)] to obtain 7-e (400 mg, yield: 67%, purity: 95.83%) as a transparent oil. LCMS (method C), Rt= 1.229 min; MS Calcd.: 515.2; MS Found: 416.3 [M-Boc+H] + .

[0287] Step 5: Preparation of 7-f

[0288] In a single-necked reaction flask, 7-e (200 mg, 0.39 mmol) and 2 mol / L sodium hydroxide aqueous solution (0.4 mL, 0.80 mmol) were dissolved in ethanol (2 mL) at room temperature and stirred for 5 hours. After the reaction was completed, the reaction solution was adjusted to pH 5-6 with 1 mol / L dilute hydrochloric acid, and extracted with ethyl acetate (10 mL x 3), the organic phase was combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to obtain the crude product 7-f (180 mg, yield: 95%, purity: 91.72%) as a colorless oil, which was directly used in the next step reaction. LCMS (method C), Rt= 0.783 min; MS Calcd.: 487.2; MS Found: 376.1 [M-112+H] + .

[0289] Step 6: Preparation of 7-g

[0290] In a single-necked reaction flask, 7-f (180 mg, 0.37 mmol), 1006-9 (292 mg, 0.37 mmol), N,N,N',N'-tetramethylchloroformamidium hexafluorophosphate (155 mg, 0.55 mmol) and N-methylimidazole (61 mg, 0.74 mmol) were dissolved in N,N-dimethylformamide (8 mL). After stirring for 5 hours at room temperature under nitrogen protection, water (15 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phase was combined and washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography [petroleum ether: methyl tert-butyl ether (v / v) = (100:0-44:56)] to obtain 7-g (270 mg, yield: 58%, purity: 80.26%) as a colorless oil. LCMS (method G), Rt = 2.639 min; MS Calcd.: 1187.7; MS Found: no mass response.

[0291] Step 7: Preparation of 7

[0292] In a single-necked reaction flask, 7-g (270 mg, 0.21 mmol) was dissolved in hydrochloric acid in acetic acid solution (6 mL, 2 mol / L hydrochloric acid in acetic acid solution). After stirring for 3 hours at room temperature under nitrogen protection, the reaction mixture was evaporated under reduced pressure to obtain a crude product, which was purified by preparative high-performance liquid chromatography, evaporated under reduced pressure, and dried to obtain the hydrochloride salt of compound 7. LCMS (method E) Rt = 1.296 min; MS Calcd.: 792.4; MS Found: 793.3 [M+H] + .HPLC (method J) Rt = 4.622 min; MS Calcd.: 792.4; MS Found: no mass response.

[0293] 1HNMR (400 MHz, CD3OD) δ: 7.65 (s, 1H), 7.61 (s, 2H), 7.32-7.18 (m, 6H), 7.03 (s, 1H), 6.93 (d, J = 7.2 Hz, 1H), 4.71 (dd, J = 42.0, 14.4 Hz, 2H), 4.38 (s, 2H), 3.56-3.49 (m, 3H), 3.44-3.39 (m, 3H), 3.30-3.21 (m, 3H), 3.15-3.05 (m, 3H), 3.00-2.95 (m, 2H), 2.94-2.2.91 (m, 3H), 2.86 (s, 2H), 2.83-2.77 (m, 1H), 2.71-2.68 (m, 1H), 2.61-2.54 (m, 3H), 2.19-2.14 (m, 3H), 1.89-1.78 (m, 3H).

[0294] Example 8:

[0295] Step 1: Preparation of 8-b

[0296] In a three-necked flask, 8-a (9.0 g, 37.0 mmol) was dissolved in tetrahydrofuran (140 mL), the reaction was placed in an ice-water bath under nitrogen protection, and triethylamine (9.3 g, 92.5 mmol) and SM-2 (5.6 g, 46.3 mmol) were added successively. The reaction was stirred in the ice-water bath for 1 h. In another single-necked flask, SM-1 (6.6 g, 37.0 mmol) and lithium chloride (1.9 g, 46.3 mmol) were dissolved in tetrahydrofuran (40 mL) and stirred uniformly, and then the solution was added to the reaction solution in the previous step. The ice-water bath was removed, and the reaction was stirred at room temperature overnight. After the reaction was completed, water (200 mL) was added to quench the reaction, and extraction was performed with ethyl acetate (200 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to remove the solvent. The crude product was purified by silica gel column chromatography [petroleum ether: methyl tert-butyl ether (v / v) = (100:0-32:68)] to obtain 8-b (13.0 g, yield: 87%, purity: >99%) as a light yellow oil. LCMS (method C), Rt = 1.008 min; MS Calcd.: 402.2; MS Found: 347.2 [M-56+H] + .

[0297] Step 2: Preparation of 8-c

[0298] In a three-necked reaction flask, was charged with 8-b (3.0 g, 7.46 mmol) and tetrahydrofuran (30 mL), the reaction was placed in an ice-water bath under nitrogen protection, lithium bis(trimethylsilyl)amide (11.2 mL, 11.2 mmol, 1 mol / L tetrahydrofuran solution) was added dropwise slowly, the reaction was stirred in the ice-water bath for 1 hour. SM-3 (2.8 g, 11.2 mmol) was dissolved in tetrahydrofuran (10 mL) and added to the above reaction solution at 0 °C, the ice-water bath was removed, and the reaction was stirred at room temperature overnight. After the reaction was completed, the reaction was quenched by adding saturated ammonium chloride solution (50 mL), and extracted with ethyl acetate (50 mL x 2), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure, the crude product was purified by silica gel column chromatography [petroleum ether: methyl tert-butyl ether (v / v) = (100:0-47:53)] to obtain 8-c (2.5 g, yield: 50.9%, purity: 86.62%) as a light yellow solid. LCMS (method C), Rt = 1.200 min; MS Calcd.: 570.2; MS Found: 515.2 [M-56+H] + .

[0299] Step 3: Preparation of 8-d

[0300] In a three-necked reaction flask, was charged with 8-c (2.5 g, 4.4 mmol) and tetrahydrofuran (20 mL), the reaction was placed in an ice-water bath under nitrogen protection, 2 mol / L lithium hydroxide aqueous solution (4.4 mL, 8.8 mmol) and hydrogen peroxide (2.0 g, 17.6 mmol, 30 wt% aqueous solution) were added dropwise slowly, then the ice-water bath was removed, and the reaction was stirred at room temperature overnight. After the reaction was completed, water (20 mL) and n-hexane (20 mL) were added, the aqueous phase was separated, the aqueous phase was adjusted to pH 4-5 with dilute hydrochloric acid, and extracted with ethyl acetate (25 mL x 2), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure, the crude product was purified by silica gel column chromatography [petroleum ether: methyl tert-butyl ether (v / v) = (100:0-52:48)] to obtain 8-d (1.5 g, yield: 91%, purity: >99%) as a light yellow oil. LCMS (method C), Rt = 0.708 min; MS Calcd.: 411.1; MS Found: 356.1 [M-56+H] + .

[0301] Step 4: Preparation of 8-e

[0302] In a single reaction flask, 8-e (1.2 g, 2.57 mmol), Pd(dppf)Cl2(190 mg, 0.26 mmol) and potassium acetate (756 mg, 7.71 mmol) were dissolved in ethanol (200 mL) and stirred at 90 °C under carbon monoxide overnight. After completion of the reaction, the reaction was filtered through celite to remove the solid impurities and the filtrate was evaporated under reduced pressure to remove the solvent. The crude product was purified by silica gel column chromatography [petroleum ether: methyl-tert-butyl ether (v / v) = (100:0-80:20)] to obtain 8-f (1.0 g, yield: 85%, purity: >99%) as a light yellow oil. LCMS (method C), Rt= 1.215 min; MS Calcd.: 461.3; MS Found: 362.3 [M-Boc+H] + .

[0303] Step 5: Preparation of 8-f

[0304] In a single reaction flask, 8-e (1.2 g, 2.57 mmol), Pd(dppf)Cl2(190 mg, 0.26 mmol) and potassium acetate (756 mg, 7.71 mmol) were dissolved in ethanol (200 mL) and stirred at 90 °C under carbon monoxide overnight. After completion of the reaction, the reaction was filtered through celite to remove the solid impurities and the filtrate was evaporated under reduced pressure to remove the solvent. The crude product was purified by silica gel column chromatography [petroleum ether: methyl-tert-butyl ether (v / v) = (100:0-80:20)] to obtain 8-f (1.0 g, yield: 85%, purity: >99%) as a light yellow oil. LCMS (method C), Rt= 1.215 min; MS Calcd.: 461.3; MS Found: 362.3 [M-Boc+H] + .

[0305] Step 6: Preparation of 8-g

[0306] In a single necked reaction flask, 8-f (250 mg, 0.54 mmol) and tetrahydrofuran (8 mL) were taken and the reaction was kept in ice water bath under nitrogen atmosphere, lithium borohydride (1.1 mL, 2.16 mmol, 2 mol / L in tetrahydrofuran) was added drop wise slowly, ice water bath was removed and the reaction was stirred at room temperature overnight. After completion of the reaction, saturated ammonium chloride solution (10 mL) was added to quench the reaction and extracted with ethyl acetate (10 mL x 2), the organic layer was dried over anhydrous sodium sulphate, filtered and the filtrate was evaporated under reduced pressure to get the crude product which was purified by silica gel column chromatography [petroleum ether: methyl tert-butyl ether (v / v) = (100:0-58:42)] to get 8-g (190 mg, yield: 75%, purity: 90.80%) as a light yellow oil. LCMS (method C), Rt= 1.050 min; MS Calcd.: 419.3; MS Found: 290.3 [M-56-56-18+H] + .

[0307] Step 7: Preparation of 8-h

[0308] In a single necked reaction flask, 8-g (190 mg, 0.45 mmol) and (chloromethylidene)dimethylammonium chloride (87 mg, 0.68 mmol) were taken in dichloromethane (5 mL) and the reaction was stirred at room temperature for 1 h under nitrogen atmosphere. After completion of the reaction, saturated sodium bicarbonate solution (6 mL) was added to quench the reaction and extracted with dichloromethane (5 mL x 2), the organic layer was dried over anhydrous sodium sulphate, filtered and the filtrate was evaporated under reduced pressure to get the crude product as a light yellow oil 8-h (180 mg, yield: 78%, purity: 77.05%) which was taken as such for the next reaction. LCMS (method C), Rt= 1.215 min; MS Calcd.: 437.2; MS Found: 326.2 [M-56-56+H] + .

[0309] Step 8: Preparation of 8-i

[0310] In a single necked flask, 8-h (180 mg, 0.41 mmol), A (314 mg, 0.41 mmol), cesium carbonate (267 mg, 0.82 mmol) and potassium iodide (88 mg, 0.53 mmol) were dissolved in N,N-dimethylformamide (4 mL) and the reaction was stirred at 70 °C overnight under nitrogen protection. After the reaction was completed, the reaction was quenched by the addition of saturated NH4CI solution (5 mL) and extracted with ethyl acetate (6 mL x 3), the organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was evaporated under reduced pressure. The crude product was purified by silica gel column chromatography [petroleum ether: methyl tert-butyl ether (v / v) = (100:0-64:36)] to give 8-i (200 mg, yield: 49%, purity: 92.61%) as a light yellow oil. LCMS (method G), Rt = 1.871 min; MS Calcd.: 1192.8; MS Found: 1194.6 [M+H] + .

[0311] Step 9: Preparation of 8

[0312] In a single necked flask, 8-i (200 mg, 0.17 mmol) was dissolved in hydrochloric acid in acetic acid solution (3 mL, 2 mol / L hydrochloric acid in acetic acid solution) and stirred at room temperature for 5 hours under nitrogen protection. After the reaction was completed, the solvent was evaporated under reduced pressure to give the crude product which was purified by preparative high performance liquid chromatography. The solvent was evaporated under reduced pressure, water was added and the hydrochloride salt of compound 8 was obtained. LCMS (method A) Rt = 1.189 min; MS Calcd.: 724.4; MS Found: 725.5 [M+H] + HPLC (method H) Rt = 4.849 min; MS Calcd.: 724.4; MS Found: 363.5 [1 / 2M+H] + .

[0313] 1HNMR (400 MHz, CD3OD) δ: 7.51 (s, 2H), 7.46 (s, 1H), 7.42-7.32 (m, 9H), 4.29 (q, J = 12.0 Hz, 6H), 3.56 (q, J = 8.0 Hz, 2H), 3.48-3.39 (m, 4H), 3.29-3.23 (m, 2H), 3.15 (t, J = 10.0 Hz, 2H), 3.05-2.97 (m, 7H), 2.96-2.83 (m, 2H), 2.72-2.67 (m, 1H), 2.60 (q, J = 8.4 Hz, 2H), 2.24-2.11 (m, 3H), 1.97 (d, J = 12.8 Hz, 2H), 1.90-1.82 (m, 2H), 1.70 (t, J = 12.0 Hz, 2H).

[0314] Example 9:

[0315] Step 1: Preparation of 9-b

[0316] In a single-necked reaction flask, 9-a (5.0 g, 24.63 mmol), SM-7 (4.97 g, 29.56 mmol), Pd(dppf)Cl2(1.8 g, 2.46 mmol) and potassium carbonate (6.8 g, 49.26 mmol) were dissolved in 1,4-dioxane (100 mL) and water (20 mL), and the reaction was stirred at 100 °C under nitrogen protection overnight. After the reaction was completed, the reaction liquid was filtered with diatomite to remove solid impurities, and the filtrate was evaporated under reduced pressure to remove the solvent. The crude product was purified by silica gel column chromatography [petroleum ether: methyl tert-butyl ether (v / v) = (100:0-77:23)] to obtain 9-b (3.5 g, yield: 86%, purity: >99%) as a light yellow oil.

[0317] 1 HNMR (400 MHz, CD3OD) δ: 7.51 (s, 2H), 7.46 (s, 1H), 7.42-7.32 (m, 9H), 4.29 (q, J = 12.0 Hz, 6H), 3.56 (q, J = 8.0 Hz, 2H), 3.48-3.39 (m, 4H), 3.29-3.23 (m, 2H), 3.15 (t, J = 10.0 Hz, 2H), 3.05-2.97 (m, 7H), 2.96-2.83 (m, 2H), 2.72-2.67 (m, 1H), 2.60 (q, J = 8.4 Hz, 2H), 2.24-2.11 (m, 3H), 1.97 (d, J = 12.8 Hz, 2H), 1.90-1.82 (m, 2H), 1.70 (t, J = 12.0 Hz, 2H).

[0318] Step 2: Preparation of 9-c

[0319] In a single-necked reaction flask, 9-b (3.5 g, 21.34 mmol) was dissolved in tetrahydrofuran (70 mL) and the reaction was placed in an ice-water bath under nitrogen protection. Sodium borohydride (1.63 g, 42.68 mmol) was added in portions and the reaction was stirred in the ice-water bath for 1 hour. After the reaction was completed, 0.5 mol / L dilute hydrochloric acid aqueous solution (40 mL) was added to quench the reaction, and extracted with ethyl acetate (100 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to obtain a light yellow oil 9-c (3.3 g, yield: 88%, purity: >99%), which was used directly in the next step.

[0320] 1 HNMR (400 MHz, CDC13) δ: 7.23 (s, 1H), 7.07 (dd, J = 6.4 Hz, 1H), 6.99 (d, J = 9.2 Hz, 1H), 5.40 (s, 1H), 5.14 (t, J = 1.2 Hz, 1H), 4.70 (s, 2H), 2.14 (s, 3H).

[0321] Step 3: Preparation of 9-d

[0322] In a single-necked reaction flask, 9-c (3.3 g, 19.88 mmol), TBSCl (5.97 g, 39.76 mmol) and imidazole (4.06 g, 59.64 mmol) were dissolved in dichloromethane (100 mL) and the reaction was stirred at room temperature overnight under nitrogen protection. After the reaction was completed, water (120 mL) was added to quench the reaction, and extracted with dichloromethane (100 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure. The crude product was purified by silica gel column chromatography [petroleum ether: methyl tert-butyl ether (v / v) = (100:0-70:30)] to obtain a light yellow oil 9-d (4.0 g, yield: 72%, purity: >99%).

[0323] 1 HNMR (400 MHz, CDC13) δ: 7.23 (s, 1H), 7.07 (dd, J = 6.4 Hz, 1H), 6.99 (d, J = 9.2 Hz, 1H), 5.40 (s, 1H), 5.14 (t, J = 1.2 Hz, 1H), 4.70 (s, 2H), 2.14 (s, 3H).

[0324] Step 4: Preparation of 9-e

[0325] In a single necked reaction flask, 9-d (1.0 g, 3.57 mmol), chloroiodomethane (6.28 g, 35.70 mmol) and diethylzinc (17.9 mL, 17.85 mmol, 1 mol / L in n-hexane) were dissolved in dichloromethane (20 mL) in an ice water bath under nitrogen protection. The reaction was stirred at room temperature overnight. After the reaction was completed, the reaction was quenched by adding saturated ammonium chloride solution (25 mL), and extracted with dichloromethane (20 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure. The crude product was purified by silica gel column chromatography [petroleum ether: methyl tert-butyl ether (v / v) = (100:0-78:22)] to give 9-e (1.0 g, yield: 95%, purity: >99%) as a light yellow oil.

[0326] 1 HNMR (400 MHz, DMSO-d6) δ: 6.92 (s, 1H), 6.80 (s, 1H), 6.78 (s, 1H), 4.62 (s, 2H), 1.29 (s, 3H), 0.83 (s, 9H), 0.80-0.75 (m, 2H), 0.73-0.69 (m, 2H), 0.01 (s, 6H).

[0327] Step 5: Preparation of 9-f

[0328] In a single necked reaction flask, 9-e (1.0 g, 3.40 mmol) and tetrabutylammonium fluoride (6.8 mL, 6.80 mmol, 1 mol / L in tetrahydrofuran) were dissolved in tetrahydrofuran (15 mL) under nitrogen protection. The reaction was stirred at room temperature overnight. After the reaction was completed, the reaction was evaporated under reduced pressure. The crude product was purified by silica gel column chromatography [petroleum ether: methyl tert-butyl ether (v / v) = (100:0-80:20)] to give 9-f (550 mg, yield: 90%, purity: >99%) as a light yellow oil. LCMS (method C), Rt = 0.855 min; MS Calcd.: 180.1; MS Found: no mass response.

[0329] Step 6: Preparation of 9-g

[0330] In a single necked reaction flask, 9-f (550 mg, 3.06 mmol) and Dess-Martin Oxidizing reagent (1.95 g, 4.59 mmol) were dissolved in dichloromethane (15 mL) and the reaction was stirred at room temperature overnight under nitrogen atmosphere. After completion of the reaction, saturated aqueous sodium thiosulfate solution (20 mL) was added to quench the reaction, the pH was adjusted to 8-9 using saturated NaHC03solution and extracted with dichloromethane (20 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered and the filtrate was evaporated under reduced pressure to obtain a yellowish oil. The crude product was purified by silica gel column chromatography [petroleum ether: methyl-tert-butyl ether (v / v) = (100:0-70:30)] to obtain 9-g (400 mg, yield: 73%, purity: >99%) as a yellowish oil.

[0331] 1 HNMR (400 MHz, CDC13) δ: 9.95 (d, J = 1.2 Hz, 1H), 7.53 (t, J = 1.2 Hz, 1H), 7.37-7.34 (m, 1H), 7.21-7.17 (m, 1H), 1.45 (s, 3H), 0.94-0.91 (m, 2H), 0.87-0.83 (m, 2H).

[0332] Step 7: Preparation of 9-h

[0333] In a single necked reaction flask, 9-g (70 mg, 0.39 mmol), A (240 mg, 0.30 mmol) were dissolved in methanol (3 mL) and cooled using an ice water bath. Subsequently, 1 drop of glacial acetic acid was added to the reaction mixture, followed by the drop wise addition of sodium cyanoborohydride (38 mg, 0.60 mmol) after stirring for 2 minutes. The reaction was stirred at room temperature overnight under nitrogen atmosphere. After completion of the reaction, saturated sodium bicarbonate solution (4 mL) was added to quench the reaction and the methanol was evaporated under reduced pressure. The reaction mixture was extracted with ethyl acetate (5 mL x 3) and the organic layer was dried over anhydrous sodium sulfate, filtered and the filtrate was evaporated under reduced pressure. The crude product was purified by silica gel column chromatography [petroleum ether: methyl-tert-butyl ether (v / v) = (100:0-60:40)] to obtain 9-h (150 mg, yield: 37%, purity: 69.82%) as a yellowish oil. LCMS (method G), Rt = 1.982 min; MS Calcd.: 953.6; MS Found: 955.1 [M+H] + .

[0334] Step 8: Preparation of 9

[0335] In a single necked flask, 9-h (150 mg, 0.16 mmol) was dissolved in acetic acid solution of hydrochloric acid (3 mL, 2 mol / L of hydrochloric acid in acetic acid). The reaction was stirred at room temperature for 3 hours under nitrogen protection. After the reaction was completed, the reaction solution was evaporated under reduced pressure to remove the solvent, the crude product was purified by preparative high performance liquid chromatography, the solvent was evaporated under reduced pressure, and the water was removed to obtain the hydrochloride salt of compound 9. LCMS (method E) Rt = 1.501 min; MS Calcd.: 641.4; MS Found: 642.3 [M+H] + .HPLC (method I) Rt = 8.255 min; MS Calcd.: 641.4; MS Found: 642.3 [M+H] + .

[0336] 1 HNMR (400 MHz, CD3OD) δ: 7.51 (s, 2H), 7.42-7.35 (m, 4H), 7.31 (d, J = 7.2 Hz, 2H), 7.20 (s, 1H), 7.09 (d, J = 1.2 Hz, 1H), 7.06 (d, J = 1.2 Hz, 1H), 4.37-4.26 (m, 6H), 3.55 (q, J = 8.0 Hz, 2H), 3.45-3.39 (m, 2H), 3.28-3.23 (m, 2H), 3.15 (t, J = 11.2 Hz, 2H), 2.96 (d, J = 7.2 Hz, 4H), 2.88-2.82 (m, 2H), 2.65-2.54 (m, 2H), 2.24-2.16 (m, 2H), 1.94-1.80 (m, 2H), 1.42 (s, 3H), 0.94-0.90 (m, 2H), 0.88-0.81 (m, 2H).

[0337] Example 10:

[0338] Step 1: Preparation of 10-b

[0339] In a single necked flask, 10-a (600 mg, 3.01 mmol) and dichloromethane (15 mL) were added, the reaction was placed in an ice water bath under nitrogen protection, diethylamine sulfide (581 mg, 3.61 mmol) was added, then the ice water bath was removed, and the reaction was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was poured into ice water to quench the reaction, and extracted with dichloromethane (20 mL x 3), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to remove the solvent, and the crude product was purified by silica gel column chromatography [petroleum ether: methyl tert-butyl ether (v / v) = (100:0-90:10)] to obtain 10-b (510 mg, yield: 77%, purity: >95%) as a colorless oil.

[0340] 1 HNMR (400 MHz, CDC13) δ: 7.45 (d, J = 4.8 Hz, 2H), 7.24 (s, 1H), 6.56 (t, J = 56.4 Hz, 1H).

[0341] Step 2: Preparation of 10-c

[0342] In a three-necked flask equipped with a thermometer, 10-b (510 mg, 2.31 mmol) was dissolved in anhydrous tetrahydrofuran (15 mL) and cooled to -70 °C with dry ice acetone bath. n-Butyllithium (1.4 mL, 3.46 mmol, 2.5 mol / L in n-hexane) was added dropwise under nitrogen protection. The reaction was stirred at -70 °C for 30 min. Then anhydrous N,N-dimethylformamide (505 mg, 6.93 mmol) was added and the reaction was slowly warmed to room temperature and stirred for 2 h. After the reaction was completed, the reaction was quenched by saturated aqueous solution of ammonium chloride (20 mL) and extracted with ethyl acetate (20 mL x 3). The organic phase was washed with saturated aqueous solution of sodium chloride (20 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was evaporated under reduced pressure to give a crude product which was purified by silica gel column chromatography [petroleum ether: methyl tert-butyl ether (v / v) = (100:0-82:18)] to give 10-c (300 mg, yield: 76%, purity: >95%) as a colorless oil.

[0343] 1 HNMR (400 MHz, CDC13) δ: 7.45 (d, J = 4.8 Hz, 2H), 7.24 (s, 1H), 6.56 (t, J = 56.4 Hz, 1H).

[0344] Step 3: Preparation of 10-d

[0345] In a single-necked reaction flask, 10-c (30 mg, 0.18 mmol) was dissolved in methanol (3 mL), then A (142 mg, 0.18 mmol) and one drop of glacial acetic acid were added, the reaction was stirred at room temperature for 10 minutes, then sodium cyanoborohydride (23 mg, 0.36 mmol) was added, the reaction was stirred at room temperature overnight under nitrogen protection. After the reaction was completed, the reaction solution was quenched with saturated aqueous sodium bicarbonate solution (8 mL), the solvent was removed under reduced pressure, the aqueous phase was extracted with ethyl acetate (15 mL x 3), the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a colorless oil 10-d (120 mg, yield: 40%, purity: 55.16%). LCMS (method G), Rt= 1.884 min; MS Calcd.: 945.6; MS Found: 946.8 [M+H] + .

[0346] Step 4: Preparation of 10

[0347] In a single-necked reaction flask, 10-d (120 mg, 0.13 mmol) was dissolved in 2 mol / L hydrochloric acid in acetic acid solution (3 mL), the reaction was stirred at room temperature overnight under nitrogen protection. After the reaction was completed, the solvent was removed under reduced pressure, and the obtained crude product was purified by preparative high performance liquid chromatography to give the hydrochloride salt of compound 10. LCMS (method E), Rt= 1.274 min; MS Calcd.: 633.3; MS Found: 634.3 [M+H] + HPLC (method I), Rt= 5.186 min; MS Calcd.: 633.3; MS Found: 634.2 [M+H] + .

[0348] 1 HNMR (400 MHz, CD3OD) δ: 7.51 (s, 2H), 7.45-7.43 (m, 3H), 7.41-7.33 (m, 6H), 6.77 (t, J = 56.0 Hz, 1H), 4.39-4.28 (m, 6H), 3.56 (dd, J = 11.6, 8.0 Hz, 2H), 3.45-3.39 (m, 2H), 3.30-3.23 (m, 2H), 3.15 (t, J = 10.0 Hz, 2H), 2.96 (d, J = 7.6 Hz, 4H), 2.91-2.84 (m, 2H), 2.63-2.56 (m, 2H), 2.41 (s, 3H), 2.23-2.16 (m, 2H), 1.90-1.81 (m, 2H).

[0349] Example 11:

[0350] Step 1: Preparation of 11-b

[0351] In a three-necked flask equipped with a thermometer, 11-a (1.00 g, 6.62 mmol) was dissolved in anhydrous tetrahydrofuran (60 mL) and cooled to -70 °C with dry ice acetone bath. Tetraisopropyl titanate (2.24 g, 7.94 mmol) and ethyl magnesium bromide (4.4 mL, 13.24 mmol, 3 mol / L in ethyl ether) were added dropwise successively under nitrogen protection. The reaction was stirred at -70 °C for 2 h. Then boron trifluoride etherate (1.88 g, 13.24 mmol) was added and the reaction was slowly warmed to room temperature and stirred overnight. After the reaction was completed, the reaction solution was cooled with ice water bath and quenched by dropwise addition of water (10 mL). After stirring at room temperature for half an hour, the reaction solution was filtered with diatomite and the filter cake was washed with ethyl acetate (20 mL x 3). The solvent was removed from the filtrate under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography [petroleum ether: methyl tert-butyl ether (v / v) = (100:0-80:20)] to obtain 11-b (600 mg, yield: 50%, purity: >99%) as a light yellow solid. LCMS (method D), Rt = 0.730 min; MS Calcd.: 181.1; MS Found: 182.1 [M+H] + .

[0352] Step 2: Preparation of 11-c

[0353] In a single-necked flask, A-7 (133 mg, 0.33 mmol) was dissolved in methanol (3 mL), followed by the addition of 11-b (60 mg, 0.33 mmol) and a drop of glacial acetic acid. The reaction was stirred at room temperature for 10 min, followed by the addition of sodium cyanoborohydride (42 mg, 0.66 mmol). The reaction was stirred at room temperature overnight under nitrogen protection. After the reaction was completed, the reaction solution was quenched by the addition of saturated aqueous sodium bicarbonate solution (8 mL), and the solvent was removed under reduced pressure. The aqueous phase was extracted with ethyl acetate (15 mL x 3), and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography [petroleum ether: methyl tert-butyl ether (v / v) = (100:0-52:48)] to obtain 11-c (100 mg, yield: 53%, purity: 71.12%) as a colorless oil. LCMS (method G), Rt = 1.687 min; MS Calcd.: 568.3; MS Found: 569.0 [M+H] + .

[0354] Step 3: Preparation of 11-d

[0355] In a single-necked flask, A-7 (71 mg, 0.17 mmol) was dissolved in methanol (3 mL), then 11-c (100 mg, 0.17 mmol) and one drop of glacial acetic acid were added, the reaction was stirred at room temperature for 10 minutes, then sodium cyanoborohydride (22 mg, 0.34 mmol) was added, the reaction was stirred at room temperature overnight under nitrogen protection. After the reaction was completed, the reaction solution was quenched with saturated aqueous sodium bicarbonate solution (8 mL), the solvent was removed under reduced pressure, the aqueous phase was extracted with ethyl acetate (15 mL x 3), the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography [petroleum ether: methyl tert-butyl ether (v / v) = (100:0-52:48)] to obtain 11-d (130 mg, yield: 77%, purity: 64.68%) as a colorless oil. LCMS (method G), Rt = 2.279 min; MS Calcd.: 955.6; MS Found: 956.9 [M+H] + .

[0356] Step 4: Preparation of 11

[0357] In a single-necked flask, 11-d (130 mg, 0.13 mmol) was dissolved in 2 mol / L hydrochloric acid in acetic acid solution (3 mL), the reaction was stirred at room temperature overnight under nitrogen protection. After the reaction was completed, the solvent was removed under reduced pressure to obtain a crude product, which was purified by preparative high performance liquid chromatography to obtain the hydrochloride salt of compound 11. LCMS (method E), Rt = 1.428 min; MS Calcd.: 643.3; MS Found: 644.3 [M+H] + HPLC (method I), Rt = 6.179 min; MS Calcd.: 643.3; MS Found: 644.3 [M+H] + .

[0358] 1HNMR (400 MHz, CD3OD) δ: 7.50 (s, 2H), 7.36-7.33 (m, 6H), 7.18-7.17 (m, 2H), 6.96 (d, J = 10.4 Hz, 1H), 4.80-4.78 (m, 1H), 4.66-4.64 (m, 1H), 4.29 (s, 2H), 3.91 (s, 3H), 3.54 (dd, J = 11.6, 8.4 Hz, 2H), 3.45-3.39 (m, 2H), 3.30-3.22 (m, 2H), 3.15 (t, J = 10.0 Hz, 2H), 2.97-2.91 (m, 4H), 2.88-2.84 (m, 2H), 2.61-2.55 (m, 2H), 2.23-2.15 (m, 2H), 1.90-1.82 (m, 2H), 1.80-1.76 (m, 1H), 1.70-1.67 (m, 1H), 1.31-1.24 (m, 2H).

[0359] Example 12:

[0360] Step 1: Preparation of 12-b

[0361] In a single-necked reaction flask, 12-a (28 mg, 0.16 mmol) was dissolved in N,N- dimethylformamide (3 mL), then A (130 mg, 0.16 mmol), HATU (122 mg, 0.32 mmol) and N,N- diisopropylethylamine (62 mg, 0.48 mmol) were added, and stirred at room temperature under nitrogen protection overnight. After the reaction was completed, the reaction solution was quenched with water (6 mL), extracted with ethyl acetate (15 mL x 3), the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography [petroleum ether: methyl tert-butyl ether (v / v) = (100:0-55:45)] to obtain colorless oil 12-b (130 mg, yield: 84%, purity: 84.57%). LCMS (method D), Rt= 1.332 min; MS Calcd.: 943.5; MS Found: 944.7 [M+H] + .

[0362] Step 2: Preparation of 12

[0363] In a single-necked reaction flask, 12-b (130 mg, 0.14 mmol) was dissolved in 2 mol / L hydrochloric acid in acetic acid solution (3 mL) and stirred at room temperature for 4 hours under nitrogen protection. After the reaction was completed, the solvent was removed by evaporation under reduced pressure, and the obtained crude product was purified by preparative high performance liquid chromatography to obtain compound 12. LCMS (method E), Rt = 1.437 min; MS Calcd.: 631.3; MS Found: 632.3 [M+H] + .HPLC (method I), Rt = 5.642 min; MS Calcd.: 631.3; MS Found: 632.3 [M+H] + .

[0364] 1 HNMR (400 MHz, CD3OD) δ: 7.30 (d, J = 8.0 Hz, 2H), 7.21-7.19 (m, 3H), 7.13 (d, J = 7.2 Hz, 1H), 7.05 (s, 1H), 7.00 (d, J = 6.4 Hz, 1H), 6.83-6.77 (m, 3H), 4.67 (dd, J = 33.6, 14.4 Hz, 2H), 4.41 (d, J = 3.6 Hz, 2H), 3.74 (s, 3H), 3.56-3.47 (m, 2H), 3.44-3.36 (m, 2H), 3.31-3.21 (m, 2H), 3.13-3.08 (m, 2H), 3.06-2.91 (m, 4H), 2.79-2.77 (m, 2H), 2.62-2.53 (m, 2H), 2.20-2.18 (m, 2H), 1.91-1.80 (m, 2H).

[0365] Example 13:

[0366] Step 1: Preparation of 13-b

[0367] In a single-necked reaction flask, 13-a (2.02 g, 10.0 mmol) was dissolved in ethanol (50 mL), then potassium acetate (2.94 g, 30.0 mmol) and Pd(dppf)Cl2(727 mg, 1.0 mmol) were added, and the gas was replaced three times with a carbon monoxide balloon. The reaction was stirred at 90 °C overnight under a carbon monoxide atmosphere. After the reaction was completed, the solvent was removed by evaporation under reduced pressure, and the obtained crude product was purified by silica gel column chromatography [petroleum ether: ethyl acetate (v / v) = (100:0-82:18)] to obtain yellow liquid 13-b (1.78 g, yield: 91%, purity: >99%).

[0368] 1HNMR (400 MHz, CDC13) δ: 10.05 (d, J = 2 Hz, 1H), 8.34 (s, 1H), 7.99 (dd, J = 8.8, 1.6 Hz, 1H), 7.77 (dd, J = 7.2, 1.2 Hz, 1H), 4.44 (q, J = 14.0, 6.8 Hz, 2H), 1.43 (t, J = 7.2 Hz, 3H).

[0369] Step 2: Preparation of 13-c

[0370] In a single-necked reaction flask, 13-b (1.62 g, 8.27 mmol) was dissolved in methanol (33 mL), then sodium borohydride (628 mg, 16.6 mmol) was added, and the reaction was stirred at room temperature for 1 hour under nitrogen protection. After the reaction was completed, 2 mol / L dilute hydrochloric acid (15 mL) was added dropwise to quench the reaction, and the solvent was removed under reduced pressure. The product was extracted with ethyl acetate (20 mL x 3), and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a yellow solid 13-c (1.60 g, yield: 98%, purity: >99%).

[0371] 1 HNMR (400 MHz, CDC13) δ: 10.05 (d, J = 2 Hz, 1H), 8.34 (s, 1H), 7.99 (dd, J = 8.8, 1.6 Hz, 1H), 7.77 (dd, J = 7.2, 1.2 Hz, 1H), 4.44 (q, J = 14.0, 6.8 Hz, 2H), 1.43 (t, J = 7.2 Hz, 3H).

[0372] Step 3: Preparation of 13-d

[0373] In a single-necked reaction flask, 13-c (4.0 g, 20.20 mmol) was dissolved in dichloromethane (100 mL), and the reaction was cooled with an ice water bath, followed by the addition of phosphorus tribromide (8.21 g, 30.30 mmol). The reaction was stirred at room temperature for 3 hours under nitrogen protection. After the reaction was completed, the reaction was quenched with ice water, extracted with dichloromethane (120 mL x 3), and the combined organic phase was washed with saturated sodium bicarbonate solution (120 mL) and saturated brine (120 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a yellow solid 13-d (3.5 g, yield: 67%, purity: >95%), which was used directly in the next step.

[0374] 1HNMR (400 MHz, CDC13) δ: 7.86 (t, J = 1.6 Hz, 1H), 7.68-7.64 (m, 1H), 7.32-7.29 (m, 1H), 4.48 (s, 2H), 4.43-4.37 (m, 2H), 1.40 (t, J = 7.2 Hz, 3H).

[0375] Step 4: Preparation of 13-e

[0376] In a single-necked reaction flask, 13-d (2.10 g, 8.08 mmol) was dissolved in toluene (20 mL), and triethyl phosphite (2.01 g, 12.12 mmol) was added. The reaction was stirred at 130 °C overnight under nitrogen protection. After the reaction was completed, the solvent was removed by evaporation under reduced pressure, and the obtained crude product was purified by silica gel column chromatography [dichloromethane:methanol (v / v) = (100:0-93:7)] to give 13-e (1.20 g, yield: 36%, purity: 67.17%) as a yellowish liquid. LCMS (method C), Rt= 0.854 min; MS Calcd.: 318.1; MS Found: 319.0 [M+H] + .

[0377] Step 5: Preparation of 13-f

[0378] In a single-necked reaction flask, 12-e (1.1 g, 2.66 mmol) was dissolved in tetrahydrofuran (11 mL), and the reaction was cooled with an ice-water bath, followed by the addition of lithium borohydride (2.7 mL, 2.70 mmol, 1 mol / L tetrahydrofuran solution). The reaction was stirred at room temperature for 1 hour under nitrogen protection. After the reaction was completed, 0.5 mol / L dilute hydrochloric acid aqueous solution was added for quenching, and extracted with ethyl acetate (20 mL x 3), and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to give the crude product, which was purified by silica gel column chromatography [dichloromethane:methanol (v / v) = (100:0-87:13)] to give 13-f (490 mg, yield: 48%, purity: 71.84%) as a yellow liquid. LCMS (method C), Rt= 0.651 min; MS Calcd.: 276.1; MS Found: 277.0 [M+H] + .

[0379] Step 6: Preparation of 13-g

[0380] In a single-necked flask, 13-f (490 mg, 1.28 mmol) was dissolved in dichloromethane (12 mL), the reaction was cooled with ice-water bath, then 2,2-dimethoxypropane (1.08 g, 2.55 mmol) was added, the reaction was stirred at room temperature overnight under nitrogen protection. After the reaction was completed, the reaction was quenched by saturated aqueous sodium thiosulfate solution (20 mL), then the solution was adjusted to basic with saturated aqueous sodium bicarbonate solution, extracted with dichloromethane (20 mL x 3), the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to obtain a colorless oil 13-g (280 mg, yield: 49%, purity: 61.72%). LCMS (method C), Rt= 0.726 min; MS Calcd.: 274.1; MS Found: 274.9 [M+H] + .

[0381] Step 7: Preparation of 13-h

[0382] In a single-necked flask, 13-g (70 mg, 0.16 mmol) was dissolved in methanol (3 mL), then A (127 mg, 0.16 mmol) and a drop of glacial acetic acid were added, the reaction was stirred at room temperature for 10 minutes, then sodium cyanoborohydride (20 mg, 0.32 mmol) was added, the reaction was stirred at room temperature for 2 hours under nitrogen protection. After the reaction was completed, the reaction was quenched by saturated aqueous sodium bicarbonate solution (8 mL), the solvent was evaporated under reduced pressure, the aqueous phase was extracted with ethyl acetate (15 mL x 3), the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure, the obtained crude product was purified by silica gel column chromatography [dichloromethane:methanol (v / v) = (100:0-95:5)] to obtain white solid 13-h (80 mg, yield: 27%, purity: 56.24%).

[0383] LCMS (method G), Rt= 1.818 min; MS Calcd.: 1049.6; MS Found: 1050.8 [M+H] + .

[0384] Step 8: Preparation of 13

[0385] In a single necked flask, 13-h (80 mg, 0.04 mmol) was dissolved in 2 Molar hydrochloric acid in acetic acid (2 mL) and stirred at room temperature under nitrogen overnight. After completion of the reaction, the solvent was evaporated under reduced pressure and the crude obtained was purified by preparative HPLC to give the hydrochloride salt of compound 13. LCMS (method E), Rt = 1.258 min; MS Calcd.: 737.4; MS Found: 738.3 [M+H] + .HPLC (method I), Rt = 5.180 min; MS Calcd.: 737.4; MS Found: 738.2 [M+H] + .

[0386] 1 HNMR (400 MHz, CD3OD) δ: 7.52 (s, 2H), 7.43-7.36 (m, 4H), 7.34-7.32 (m, 2H), 7.28-7.26 (m, 2H), 7.23-7.20 (m, 1H), 4.38-4.27 (m, 6H), 4.10-4.04 (m, 4H), 3.56 (dd, J = 7.6, 3.6 Hz, 2H), 3.35-3.34 (m, 2H), 3.36 (d, J = 22.0 Hz, 2H), 3.30-3.23 (m, 2H), 3.13 (t, J = 6.8 Hz, 2H), 2.97 (d, J = 7.2 Hz, 4H), 2.88-2.84 (m, 2H), 2.63-2.57 (m, 2H), 2.22-2.17 (m, 2H), 1.88-1.82 (m, 2H), 1.26 (td, J = 7.2, 2.4 Hz, 6H).

[0387] Example 14:

[0388] Step 1: Preparation of 14

[0389] In a single necked flask, 13 (20 mg, 0.03 mmol) was dissolved in concentrated hydrochloric acid (2 mL) and stirred at 100 °C under nitrogen overnight. After completion of the reaction, the solvent was evaporated under reduced pressure and the crude obtained was purified by preparative HPLC to give compound 14. LCMS (method A), Rt = 1.144 min; MS Calcd.: 681.3; MS Found: 682.5 [M+H] + .HPLC (method I), Rt = 4.397 min; MS Calcd.: 681.3; MS Found: 682.2 [M+H] + .

[0390] 1 HNMR (400 MHz, CD3OD) δ: 7.49 (s, 2H), 7.44-7.37 (m, 4H), 7.33 (d, J = 6.8 Hz, 2H), 7.22-7.14 (m, 3H), 4.34 (dd, J = 13.2, 3.2 Hz, 4H), 4.27 (d, J = 4.8 Hz, 2H), 3.56 (dd, J = 11.6, 8.0 Hz, 2H), 3.48-3.47 (m, 2H), 3.28-3.27 (m, 2H), 3.25 (s, 1H), 3.22 (s, 1H), 3.17-3.11 (m, 2H), 2.97 (d, J = 7.6 Hz, 4H), 2.84 (dd, J = 16.8, 8.4 Hz, 2H), 2.61 (d, J = 12, 8 Hz, 2H), 2.23-2.17 (m, 2H), 1.87-1.81 (m, 2H).

[0391] Example 15:

[0392] Step 1: Preparation of 15-b

[0393] In a single-mouth reaction flask, phosphorus trichloride (2.64 g, 19.25 mmol) was dissolved in dichloromethane (50 mL) and cooled to -20 °C; in another single-mouth reaction flask, 15-a (3.0 g, 16.04 mmol) and pyridine (2.54 g, 32.08 mmol) were dissolved in dichloromethane (30 mL) and slowly dropped into the former reaction solution, which was stirred at -20 °C for 1 h under nitrogen protection. After the reaction was completed, water (100 mL) was added to quench the reaction, and dichloromethane (100 mL x 3) was used to extract the organic phase, which was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to remove the solvent. The crude product was purified by silica gel column chromatography [dichloromethane:methanol (v / v) = (100:0-98:2)] to obtain colorless oil 15-b (2.8 g, yield: 62%, purity: 83.02%). LCMS (method C), Rt= 0.702 min; MS Calcd.: 232.0; MS Found: 250.1 [M+NH4] + .

[0394] Step 2: Preparation of 15-c-P1 & P2

[0395] In a single-necked flask, 13-d (2.60 g, 10.01 mmol), 15-b (2.34 g, 10.01 mmol) and potassium carbonate (2.77 g, 20.02 mmol) were dissolved in acetonitrile (60 mL) and the reaction was stirred at room temperature overnight under nitrogen protection. After the reaction was completed, the reaction solution was filtered with celite to remove solid impurities, and the filtrate was evaporated under reduced pressure to remove the solvent. The crude product was purified by silica gel column chromatography [dichloromethane:methanol (v / v) = (100:0-96:4-90:10)] to obtain 15-c-P1 (500 mg, yield: 12%, purity: >99%) as a light yellow oil and 15-c-P2 (460 mg, yield: 11%, purity: 95.91%) as a light yellow oil.

[0396] 15-c-P1: LCMS (method C), Rt = 0.937 min; MS Calcd.: 412.1; MS Found: 430.2 [M+NH4] + .

[0397] 1 HNMR (400 MHz, CDC13) δ: 7.80 (t, J = 1.2 Hz, 1H), 7.70-7.66 (m, 1H), 7.32-7.28 (m, 2H), 7.26-7.22 (m, 1H), 7.09 (s, 1H), 7.07-7.04 (m, 1H), 5.59 (q, J = 5.2 Hz, 1H), 4.73-4.65 (m, 1H), 4.43-4.35 (m, 2H), 4.31-4.21 (m, 1H), 3.42 (s, 1H), 3.36 (s, 1H), 1.95-1.89 (m, 2H), 1.39 (t, J = 7.2 Hz, 3H).

[0398] 15-c-P2: LCMS (method C), Rt = 0.912 min; MS Calcd.: 412.1; MS Found: 430.1 [M+NH4] + .

[0399] 1HNMR (400 MHz, CDC13) δ: 7.79 (s, 1H), 7.67 (dd, J = 7.6 Hz, 1H), 7.35 (s, 1H), 7.33-7.31 (m, 2H), 7.30-7.27 (m, 2H), 5.14-5.10 (m, 1H), 4.51-4.42 (m, 1H), 4.38 (q, J = 7.2 Hz, 2H), 4.25-4.17 (m, 1H), 3.41 (d, J = 21.6 Hz, 2H), 2.43-2.33 (m, 1H), 1.99-1.92 (m, 1H), 1.38 (t, J = 7.2 Hz, 3H).

[0400] Step 3: Preparation of 15-d-P1&P2

[0401] In a single-necked reaction flask, 15-c-P1 (500 mg, 1.21 mmol) was dissolved in tetrahydrofuran (10 mL), the reaction was placed in an ice-water bath under nitrogen protection, lithium borohydride (2.4 mL, 4.84 mmol, 2 mol / L tetrahydrofuran solution) was added dropwise slowly, the ice-water bath was removed, and the reaction was stirred at room temperature overnight. After the reaction was completed, saturated ammonium chloride solution (10 mL) was added to quench the reaction, and extracted with ethyl acetate (10 mL x 3), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to remove the solvent. The crude product was purified by silica gel column chromatography [dichloromethane:methanol (v / v) = (100:0-98:2)] to obtain 15-d-P1 (240 mg, yield: 50%, purity: 94.16%) as a colorless oil. LCMS (method C), Rt = 0.765 min; MS Calcd.: 370.1; MS Found: 371.1 [M+H] + .

[0402] In a single-necked reaction flask, 15-c-P2 (460 mg, 1.12 mmol) was dissolved in tetrahydrofuran (10 mL), the reaction was placed in an ice-water bath under nitrogen protection, lithium borohydride (2.3 mL, 4.48 mmol, 2 mol / L tetrahydrofuran solution) was added dropwise slowly, the ice-water bath was removed, and the reaction was stirred at room temperature overnight. After the reaction was completed, saturated ammonium chloride solution (10 mL) was added to quench the reaction, and extracted with ethyl acetate (10 mL x 3), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to remove the solvent. The crude product was purified by silica gel column chromatography [dichloromethane:methanol (v / v) = (100:0-97:3)] to obtain 15-d-P2 (220 mg, yield: 53%, purity: >99%) as a colorless oil. LCMS (method C), Rt = 0.753 min; MS Calcd.: 370.1; MS Found: 371.0 [M+H] +.

[0403] Step 4: Preparation of 15-e-P1 & P2

[0404] In a single-necked reaction flask, 15-d-P1 (150 mg, 0.41 mmol) and (chloromethylidene)dimethylammonium chloride (78 mg, 0.62 mmol) were dissolved in dichloromethane (5 mL). Stirring was carried out at room temperature for 1 h under nitrogen protection. After the reaction was completed, saturated aqueous sodium bicarbonate solution (6 mL) was added to quench the reaction, and extracted with dichloromethane (10 mL x 3), the organic phase was combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to obtain the crude product 15-e-P1 (150 mg, yield: 75%, purity: 78.84%) as a colorless oil, which was directly used in the next step. LCMS (method C), Rt= 0.928 min; MS Calcd.: 388.0; MS Found: 389.0 [M+H] + .

[0405] In a single-necked reaction flask, 15-d-P2 (150 mg, 0.41 mmol) and (chloromethylidene)dimethylammonium chloride (78 mg, 0.62 mmol) were dissolved in dichloromethane (5 mL). Stirring was carried out at room temperature for 1 h under nitrogen protection. After the reaction was completed, saturated aqueous sodium bicarbonate solution (6 mL) was added to quench the reaction, and extracted with dichloromethane (10 mL x 3), the organic phase was combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to obtain the crude product 15-e-P2 (150 mg, yield: 85%, purity: 88.63%) as a light yellow oil, which was directly used in the next step. LCMS (method C), Rt= 0.902 min; MS Calcd.: 388.0; MS Found: 389.0 [M+H] + .

[0406] Step 5: Preparation of 15-f-P1 & P2

[0407] In a single-necked reaction flask, 15-e-P1 (150 mg, 0.39 mmol), A (306 mg, 0.39 mmol), potassium iodide (84 mg, 0.51 mmol) and cesium carbonate (254 mg, 0.78 mmol) were dissolved in N,N-dimethylformamide (4 mL). It was stirred at 70 °C overnight under nitrogen protection. After the reaction was completed, saturated ammonium chloride (6 mL) was added to quench the reaction, and extracted with ethyl acetate (15 mL x 3), the organic phase was combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography [dichloromethane:methanol (v / v) = (100:0-98:2)] to obtain 15-f-P1 (190 mg, yield: 40%, purity: 74.00%) as a light yellow oil. LCMS (method G), Rt= 1.817 min; MS Calcd.: 1143.6; MS Found: 1144.4 [M+H] + .

[0408] In a single-necked reaction flask, 15-e-P2 (150 mg, 0.39 mmol), A (306 mg, 0.39 mmol), potassium iodide (84 mg, 0.51 mmol) and cesium carbonate (254 mg, 0.78 mmol) were dissolved in N,N-dimethylformamide (4 mL). It was stirred at 70 °C overnight under nitrogen protection. After the reaction was completed, saturated ammonium chloride (6 mL) was added to quench the reaction, and extracted with ethyl acetate (15 mL x 3), the organic phase was combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography [dichloromethane:methanol (v / v) = (100:0-97:3)] to obtain 15-f-P2 (180 mg, yield: 29%, purity: 62.44%) as a light yellow oil. LCMS (method G), Rt= 1.821 min; MS Calcd.: 1143.6; MS Found: 1145.4 [M+H] + .

[0409] Step 6: Preparation of 15-P1 & P2

[0410] In a single-necked flask, 15-f-P2 (180 mg, 0.16 mmol) was dissolved in trifluoroacetic acid (1 mL) and dichloromethane (5 mL). It was stirred at room temperature for 5 hours under nitrogen protection. After the reaction was completed, the solvent was removed by evaporation under reduced pressure, and the crude product was purified by preparative high performance liquid chromatography, the solvent was removed by evaporation under reduced pressure, and water was removed to obtain the trifluoroacetate salt of compound 15-P2. LCMS (method E) Rt = 1.403 min; MS Calcd.: 831.3; MS Found: 832.2 [M+H] + .HPLC (method I) Rt = 5.669 min; MS Calcd.: 831.3; MS Found: 832.2 [M+H] + .

[0411] 1 HNMR (400 MHz, CD3OD) δ: 7.37-7.18 (m, 14H), 7.13 (d, J = 8.8 Hz, 1H), 5.61 (t, J = 6.0 Hz, 1H), 4.71-4.61 (m, 1H), 4.39-4.30 (m, 1H), 4.06 (t, J = 12.4 Hz, 6H), 3.57-3.47 (m, 4H), 3.43-3.37 (m, 2H), 3.27-3.20 (m, 2H), 3.08 (t, J = 10.0 Hz, 2H), 2.99-2.87 (m, 4H), 2.81-2.75 (m, 2H), 2.60-2.51 (m, 2H), 2.22-2.15 (m, 2H), 2.05 (s, 2H), 1.90-1.80 (m, 2H).

[0412] In a single-necked flask, 15-f-P2 (180 mg, 0.16 mmol) was dissolved in trifluoroacetic acid (1 mL) and dichloromethane (5 mL). It was stirred at room temperature for 5 hours under nitrogen protection. After the reaction was completed, the solvent was removed by evaporation under reduced pressure, and the crude product was purified by preparative high performance liquid chromatography, the solvent was removed by evaporation under reduced pressure, and water was removed to obtain the trifluoroacetate salt of compound 15-P2. LCMS (method E) Rt = 1.403 min; MS Calcd.: 831.3; MS Found: 832.2 [M+H] + .HPLC (method I) Rt = 5.669 min; MS Calcd.: 831.3; MS Found: 832.2 [M+H] + .

[0413] 1HNMR (400 MHz, CD3OD) δ: 7.43 (s, 1H), 7.37-7.29 (m, 10H), 7.25-7.19 (m, 3H), 7.08 (d, J = 8.8 Hz, 1H), 5.72 (d, J = 11.2 Hz, 1H), 4.69 (t, J = 11.6 Hz, 1H), 4.57-4.48 (m, 1H), 4.00 (s, 6H), 3.64 (d, J = 7.6 Hz, 2H), 3.54-3.47 (m, 2H), 3.44-3.36 (m, 2H), 3.26-3.19 (m, 2H), 3.10 (t, J = 10.4 Hz, 2H), 3.00-2.89 (m, 4H), 2.85-2.76 (m, 2H), 2.62-2.50 (m, 2H), 2.36-2.25 (m, 1H), 2.22-2.10 (m, 3H), 1.89-1.79 (m, 2H).

[0414] Example 16:

[0415] Step 1: Preparation of 16-a

[0416] In a single-necked reaction flask, 13-e (90 mg, 0.28 mmol) and 2 mol / L aqueous lithium hydroxide solution (0.3 mL, 0.60 mmol) were dissolved in tetrahydrofuran (3 mL). Stirring at room temperature overnight under nitrogen protection. After the reaction was completed, the solvent was removed by evaporation under reduced pressure, the residue was adjusted to pH 5-6 with 2 mol / L dilute hydrochloric acid, and extracted with ethyl acetate (10 mL x 3), the organic phase was combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to obtain a colorless oil 16-a (80 mg, yield: 97%, purity: 79.41%) as a crude product. LCMS (method C), Rt= 0.494 min; MS Calcd.: 290.0; MS Found: 291.2 [M+H] + .

[0417] Step 2: Preparation of 16-b

[0418] In a single-necked flask, 16-a (80 mg, 0.27 mmol) was dissolved in N,N- dimethylformamide (4 mL), then A (218 mg, 0.27 mmol), HATU (154 mg, 0.40 mmol) and N,N-diisopropyl ethylamine (105 mg, 0.81 mmol) were added, and stirred at room temperature overnight under nitrogen protection. After the reaction was completed, the reaction solution was quenched with water (8 mL), extracted with ethyl acetate (15 mL x 3), the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography [petroleum ether: methyl tert-butyl ether (v / v) = (100:0-12:88)] to obtain 16-b (130 mg, yield: 44%, purity: >95%) as a colorless oil. LCMS (method G), Rt = 2.223 min; MS Calcd.: 1063.6; MS Found: 965.0 [M-Boc+H] + .

[0419] Step 3: Preparation of 16

[0420] In a single-necked flask, 16-b (130 mg, 0.12 mmol) was dissolved in 2 mol / L hydrochloric acid in acetic acid solution (3 mL), and stirred at room temperature for 4 hours under nitrogen protection. After the reaction was completed, the solvent was evaporated under reduced pressure to obtain a crude product, which was purified by preparative high performance liquid chromatography to obtain the hydrochloride salt of compound 16. LCMS (method E), Rt = 1.381 min; MS Calcd.: 751.3; MS Found: 752.3 [M+H] + HPLC (method I), Rt = 6.106 min; MS Calcd.: 751.3; MS Found: 752.2 [M+H] + .

[0421] 1HNMR (400 MHz, CD3OD) δ: 7.32-7.25 (m, 3H), 7.25-7.13 (m, 6H), 7.04 (s, 1H), 6.96 (d, J = 7.2 Hz, 1H), 4.70 (d, J = 15.2 Hz, 1H), 4.58 (d, J = 14.8 Hz, 1H), 4.40 (d, J = 8.8 Hz, 2H), 4.06-3.96 (m, 4H), 3.54-3.48 (m, 2H), 3.43-3.37 (m, 4H), 3.30-3.21 (m, 2H), 3.11-3.03 (m, 2H), 2.97-2.86 (m, 4H), 2.78-2.71 (m, 2H), 2.59-2.53 (m, 2H), 2.23-2.15 (m, 2H), 1.91-1.81 (m, 2H), 1.21 (q, J = 7.2 Hz, 6H).

[0422] Example 17:

[0423] Step 1: Preparation of 17-a

[0424] In a single-necked reaction flask, 13-f (550 mg, 2.00 mmol) was dissolved in dichloromethane (20 mL), then imidazole (408 mg, 4.00 mmol) and tert-butyldiphenylsilyl chloride (825 mg, 3.00 mmol) were added, and the reaction was stirred at room temperature overnight. After the reaction was completed, the reaction solution was quenched with saturated water (20 mL), extracted with dichloromethane (20 mL x 3), and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography [petroleum ether: methyl tert-butyl ether (v / v) = (100:0-60:40)] to obtain colorless oil 17-a (650 mg, yield: 63%, purity: >99%). LCMS (method C), Rt = 1.256 min; MS Calcd.: 514.2; MS Found: 532.3 [M+NH4] + .

[0425] Step 2: Preparation of 17-c

[0426] In a single-necked reaction flask, 17-a (650 mg, 1.26 mmol) was dissolved in thionyl chloride (10 mL), and the reaction was stirred at 75 °C for 4 hours under nitrogen protection. After the reaction was completed, the reaction solution was evaporated under reduced pressure to obtain a crude product, which was a light yellow oil 17-b (700 mg, yield: 100%, purity: >85%), which was directly used in the next step reaction.

[0427] In a single-necked reaction flask, SM-8 (256 mg, 1.52 mmol), N,N- diisopropylethylamine (975 mg, 7.56 mmol) and dichloromethane (15 mL) were added and cooled with ice water bath, then a solution of 17-b in dichloromethane (8 mL) was added, the reaction was stirred at 0 °C for 1 h. After the reaction was completed, the solvent was removed by evaporation under reduced pressure, the crude product was purified by silica gel column chromatography [petroleum ether: methyl tert-butyl ether (v / v) = (100:0-42:58)] to give 17-c (360 mg, yield: 47%, purity: 92.10%) as a yellow oil. LCMS (method C), Rt= 1.267 min; MS Calcd.: 599.3; MS Found: 600.3 [M+H] + .

[0428] Step 3: Preparation of 17-d

[0429] In a single-necked reaction flask, 17-c (360 mg, 0.60 mmol) was dissolved in tetrahydrofuran (10 mL) and cooled with ice water bath, then tetrabutylammonium fluoride (0.6 mL, 0.60 mmol, 1 mol / L tetrahydrofuran solution) was added, the reaction was stirred at 0 °C for 1 h. After the reaction was completed, the solvent was removed by evaporation under reduced pressure, the crude product was purified by silica gel column chromatography [dichloromethane: methanol (v / v) = (100:0-83:17)] to give 17-d (150 mg, yield: 70%, purity: 39.10%) as a yellow oil. LCMS (method C), Rt= 0.731 min; MS Calcd.: 361.1; MS Found: 362.2 [M+H] + .

[0430] Step 4: Preparation of 17-e

[0431] In a single-necked reaction flask, 17-d (140 mg, 0.39 mmol) and N,N- diisopropylethylamine (100 mg, 0.78 mmol) were dissolved in dichloromethane (5 mL) and cooled with ice water bath, then methylsulfonyl chloride (50 mg, 0.43 mmol) was added, the reaction was stirred at 0 °C for 1 h under nitrogen protection. After the reaction was completed, the reaction was quenched with water (10 mL), extracted with dichloromethane (10 mL x 3), the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to give the crude product 17-e (150 mg, yield: 88%, purity: 71.17%) as a yellow oil, which was used directly in the next step. LCMS (method C), Rt= 0.810 min; MS Calcd.: 439.1; MS Found: 440.2 [M+H] + .

[0432] Step 5: Preparation of 17-f

[0433] In a single-necked reaction flask, 17-e (150 mg, 0.34 mmol), A (269 mg, 0.34 mmol), potassium iodide (56 mg, 0.34 mmol) and potassium carbonate (70 mg, 0.51 mmol) were dissolved in N,N-dimethylformamide (3 mL). The reaction was stirred at 70 °C for 2 h under nitrogen protection. After the reaction was completed, saturated ammonium chloride (6 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (15 mL x 3), and the organic phase was combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography [dichloromethane:methanol (v / v) = (100:0-87:13)] to obtain 17-f (180 mg, yield: 46%, purity: 57.29%) as a colorless oil. LCMS (method G), Rt= 1.813 min; MS Calcd.: 1134.6; MS Found: 1135.5 [M+H] + .

[0434] Step 6: Preparation of 17

[0435] In a single-necked reaction flask, 17-f (90 mg, 0.08 mmol) and zinc bromide (90 mg, 0.40 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for two days under nitrogen protection. After the reaction was completed, the solvent was evaporated under reduced pressure to obtain a crude product, which was purified by preparative high performance liquid chromatography to obtain compound 17. LCMS (method A), Rt= 1.466 min; MS Calcd.: 822.4; MS Found: 823.0 [M+H] + HPLC (method H), Rt= 6.609 min; MS Calcd.: 822.4; MS Found: 822.9 [M+H] + .

[0436] 1HNMR (400 MHz, CD3OD) δ: 7.31 (s, 2H), 7.24-7.22 (m, 4H), 7.15-7.13 (m, 3H), 7.09 (d, J = 12.8 Hz, 1H), 6.96 (t, J = 13.2 Hz, 1H), 4.96-4.89 (m, 1H), 4.07-3.93 (m, 2H), 3.82-3.69 (m, 1H), 3.52 (s, 2H), 3.49 (m, 3H), 3.48-3.46 (m, 1H), 3.28-3.11 (m, 5H), 3.09-3.00 (m, 4H), 2.80-2.70 (m, 4H), 2.53 (dd, J = 14.8, 7.2 Hz, 2H), 2.39 (dd, J = 16.4, 8.0 Hz, 2H), 2.14-2.06 (m, 2H), 1.88-1.78 (m, 2H), 1.29 (dd, J = 17.2, 10.4 Hz, 2H), 1.23 (d, J = 8.8 Hz, 2H), 1.21-1.18 (m, 7H), 1.12 (dd, J = 7.2 Hz, 2H).

[0437] Example 18:

[0438] Step 1: Preparation of 18

[0439] In a single-necked flask, 16 (17 mg, 0.02 mmol) was dissolved in concentrated hydrochloric acid (2 mL) and the reaction was stirred at 100 °C under nitrogen overnight. After the reaction was completed, the solvent was evaporated under reduced pressure and the crude product was purified by preparative high performance liquid chromatography to give the hydrochloride salt of compound 18. LCMS (method A), Rt = 0.997 min; MS Calcd.: 695.3; MS Found: 696.5 [M+H] + .HPLC (method I), Rt = 3.831 min; MS Calcd.: 695.3; MS Found: no mass response.

[0440] 1HNMR (400 MHz, CD3OD) δ: 7.35 (s, 1H), 7.31-7.19 (m, 6H), 7.12 (d, J = 7.6 Hz, 2H), 7.02 (s, 1H), 6.95 (d, J = 7.2 Hz, 1H), 4.71 (d, J = 14.4 Hz, 1H), 4.56 (d, J = 14.8 Hz, 1H), 4.48 (dd, J = 17.2, 14.8 Hz, 2H), 3.53-3.48 (m, 2H), 3.43-3.37 (m, 2H), 3.30-3.16 (m, 4H), 3.07 (t, J = 10.4 Hz, 2H), 2.98-2.91 (m, 4H), 2.81-2.75 (m, 2H), 2.21-2.17 (m, 2H), 1.91-1.81 (m, 2H), 1.21 (q, J = 7.2 Hz, 2H).

[0441] Example 19:

[0442] Step 1: Preparation of A-10

[0443] In a single necked reaction flask, A-7 (300 mg, 0.74 mmol) was dissolved in tetrahydrofuran (5 mL) and methanol (1 mL), the reaction was placed in ice water bath under nitrogen protection, sodium borohydride (56 mg, 1.48 mmol) was added, the reaction was stirred in ice water bath for 1 hour. After the reaction was completed, saturated aqueous ammonium chloride solution (5 mL) was added to quench the reaction, and extracted with ethyl acetate (10 mL x 3), the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was evaporated under reduced pressure to obtain a light yellow oil A-10 (280 mg, yield: 93%, purity: 72.70%), the crude product was directly used in the next step reaction. LCMS (method B), Rt = 1.865 min; MS Calcd.: 405.2; MS Found: 294.3 [M-112+H] + .

[0444] Step 2: Preparation of A-11

[0445] In a single-necked reaction flask, A-10 (110 mg, 0.27 mmol) and (chloromethylene)dimethylammonium chloride (69 mg, 0.54 mmol) were dissolved in dichloromethane (5 mL). Stirring was carried out at room temperature for 1 hour under nitrogen protection. After the reaction was completed, saturated aqueous sodium bicarbonate solution (6 mL) was added to quench the reaction, and extracted with dichloromethane (10 mL x 3), the combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to obtain the crude product as colorless oil A-11 (110 mg, yield: 96%, purity: >99%), which was directly used in the next step. LCMS (method C), Rt= 1.187 min; MS Calcd.: 423.2; MS Found: 312.2 [M-112+H] + .

[0446] Step 3: Preparation of 19-b

[0447] In a single-necked reaction flask, 3-fluoro-5-methoxyphenylacetonitrile (19-a, 3.00 g, 18.16 mmol) and sodium hydroxide (1.45 g, 36.32 mmol) were dissolved in methanol (45 mL) and water (15 mL). Stirring was carried out at 65 °C for 4 hours under nitrogen protection. After the reaction was completed, the solvent was evaporated under reduced pressure, the residue was adjusted to pH 5-6 with 2 mol / L dilute hydrochloric acid, and extracted with ethyl acetate (40 mL x 3), the combined organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to obtain the crude product as light yellow solid 19-b (3.10 g, yield: 93%, purity: 93.94%). LCMS (method C), Rt= 0.407 min; MS Calcd.: 184.1; MS Found: 202.3 [M+NH4] + .

[0448] Step 4: Preparation of 19-c

[0449] In a single-necked flask, 19-b (3.10 g, 16.83 mmol), benzyl bromide (3.45 g, 20.20 mmol) and potassium carbonate (3.49 g, 25.24 mmol) were dissolved in N,N-dimethylformamide (50 mL). The reaction was stirred at room temperature for 4 h under nitrogen protection. After the reaction was completed, the reaction was quenched by adding water (60 mL) and extracted with ethyl acetate (40 mL x 3), the organic phase was combined and washed with saturated aqueous ammonium chloride solution (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography [petroleum ether: methyl tert-butyl ether (v / v) = (100:0-90:10)] to give 19-c (4.00 g, yield: 93%, purity: 60.89%) as a colorless oil. LCMS (method C), Rt= 1.014 min; MS Calcd.: 274.1; MS Found: 292.3 [M+NH4] + .

[0450] Step 5: Preparation of 19-d

[0451] In a single-necked flask, 19-c (4.00 g, 14.58 mmol) was dissolved in anhydrous N,N-dimethylformamide (50 mL). The reaction was cooled with an ice water bath, and sodium hydride (1.75 g, 36.45 mmol, 60 wt%) was added portionwise. The reaction was stirred at room temperature for 0.5 h under nitrogen protection, followed by the addition of iodomethane (5.03 g, 36.45 mmol). The reaction was stirred at room temperature overnight under nitrogen protection. After the reaction was completed, the reaction was quenched by adding saturated aqueous ammonium chloride solution (80 mL) and extracted with ethyl acetate (50 mL x 3), the organic phase was combined and washed with saturated aqueous ammonium chloride solution (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography [petroleum ether: methyl tert-butyl ether (v / v) = (100:0-92:8)] to give 19-d (4.00 g, yield: 32%, purity: 36.92%) as a colorless oil. LCMS (method C), Rt= 1.095 min; MS Calcd.: 302.1; MS Found: 320.3 [M+NH4] + .

[0452] Step 6: Preparation of 19-e

[0453] In a single necked reaction flask, 19-d (2.70 g, 8.93 mmol) and 10% palladium on carbon (300 mg) were dissolved in methanol (50 mL). The reaction was stirred at room temperature under hydrogen atmosphere for 6 h after three times of gas replacement with hydrogen balloon. After completion of the reaction, the reaction was filtered through celite and the filtrate was evaporated under reduced pressure to get the crude product as colorless oil 19-e (1.30 g, yield: 69%, purity: 87.81%) which was used as such for the next step. LC MS (method C), Rt = 0.504 min; MS Calcd.: 212.1; MS Found: 230.3 [M+NH4] + .

[0454] Step 7: Preparation of 19-f

[0455] In a single necked reaction flask, 19-e (1.30 g, 6.13 mmol), benzyl alcohol (1.99 g, 18.39 mmol), triethylamine (3.10 g, 30.65 mmol) and diphenyl phosphorazide (5.06 g, 18.39 mmol) were dissolved in toluene (60 mL). The reaction was stirred at reflux under nitrogen atmosphere overnight. After completion of the reaction, the reaction was evaporated under reduced pressure to get the crude product which was purified by silica gel column chromatography [petroleum ether: methyl-tert-butyl ether (v / v) = (100:0-72:28)] to get colorless oil 19-f (1.80 g, yield: 93%, purity: 70.66%). LC MS (method C), Rt = 0.994 min; MS Calcd.: 317.1; MS Found: 318.3 [M+NH4] + .

[0456] Step 8: Preparation of 19-g

[0457] In a single necked reaction flask, 19-f (1.80 g, 5.67 mmol) and 10% palladium on carbon (250 mg) were dissolved in isopropyl alcohol (40 mL). The reaction was stirred at room temperature under hydrogen atmosphere overnight after three times of gas replacement with hydrogen balloon. After completion of the reaction, the reaction was filtered through celite and the filtrate was evaporated under reduced pressure to get the crude product as colorless oil 19-g (900 mg, yield: 87%, purity: >95%) which was used as such for the next step.

[0458] 1 HNMR (400 MHz, DMSO-d6) δ: 6.92-6.88 (m, 2H), 6.63-6.59 (m, 1H), 3.75 (s, 3H), 1.89 (s, 2H), 1.32 (m, 6H).

[0459] Step 9: Preparation of 19-h

[0460] In a single necked flask, A-7 (222 mg, 0.55 mmol) was dissolved in methanol (6 mL), followed by the addition of 19-g (100 mg, 0.55 mmol) and a drop of glacial acetic acid. The reaction was stirred at room temperature for 10 minutes, followed by the addition of sodium cyanoborohydride (69 mg, 1.10 mmol). The reaction was stirred at room temperature overnight under nitrogen protection. After the completion of the reaction, the reaction was quenched by the addition of saturated aqueous sodium bicarbonate solution (8 mL). The solvent was removed under reduced pressure. The aqueous phase was extracted with ethyl acetate (15 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give a crude product. Purification of the crude product by column chromatography on silica gel [petroleum ether: methyl-tert-butyl ether (v / v) = (100:0-42:58)] gave 19-h (170 mg, yield: 56%, purity: 87.76%) as a colorless oil. LCMS (method G), Rt= 1.345 min; MS Calcd.: 570.3; MS Found: 571.4 [M+H] + .

[0461] Step 10: Preparation of 19-i

[0462] In a single necked flask, 19-h (150 mg, 0.26 mmol), A-11 (110 mg, 0.26 mmol), potassium iodide (41 mg, 0.26 mmol) and potassium carbonate (70 mg, 0.52 mmol) were dissolved in N,N-dimethylformamide (3 mL). The reaction was stirred at 70 °C overnight under nitrogen protection. After the completion of the reaction, the reaction was quenched by the addition of saturated ammonium chloride (6 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give a crude product. Purification of the crude product by column chromatography on silica gel [petroleum ether: methyl-tert-butyl ether (v / v) = (100:0-60:40)] gave 19-i (50 mg, yield: 20%, purity: 57.29%) as a colorless oil. LCMS (method G), Rt= 1.808 min; MS Calcd.: 957.6; MS Found: 958.5 [M+H] + .

[0463] Step 11: Preparation of 19

[0464] In a single-necked reaction flask, 19-i (50 mg, 0.05 mmol) was dissolved in 2 mol / L hydrochloric acid in acetic acid solution (2 mL), and the reaction was stirred at room temperature under nitrogen protection overnight. After the reaction was completed, the solvent was removed by evaporation under reduced pressure to obtain the crude product, which was purified by preparative high performance liquid chromatography to obtain the hydrochloride salt of compound 19. LCMS (method E), Rt = 1.286 min; MS Calcd.: 645.4; MS Found: 646.3 [M+H] + .HPLC(method I),Rt=5.323min;MS Calcd.:645.4;MS Found:646.3[M+H] + .

[0465] 1 HNMR (400 MHz, CD3OD) δ: 7.41 (s, 1H), 7.36 (d, J = 10.4 Hz, 1H), 7.21 (t, J = 8.8 Hz, 2H), 7.12 (t, J = 7.6 Hz, 2H), 6.93-6.91 (m, 1H), 6.82-6.80 (m, 2H), 6.67 (dd, J = 17.6, 7.2 Hz, 2H), 4.61 (d, J = 12.8 Hz, 2H), 4.30 (d, J = 6.8 Hz, 2H), 3.86 (s, 3H), 3.52-3.47 (m, 2H), 3.44-3.39 (m, 2H), 3.30-3.21 (m, 2H), 3.14-3.04 (m, 2H), 2.84-2.72 (m, 6H), 2.56-2.48 (m, 2H), 2.21-2.14 (m, 2H), 2.08-2.07 (m, 6H), 1.90-1.79 (m, 2H).

[0466] Example 20:

[0467] Step 1: Preparation of 20-a

[0468] In a single-necked reaction flask, 1-a (330 mg, 0.74 mmol) was dissolved in methanol (10 mL), and then hydrazine hydrate (463 mg, 7.40 mmol, 80 wt%) was added. The reaction was stirred at 70°C under nitrogen protection for 5 hours. After the reaction was completed, the solvent was removed by evaporation under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography [dichloromethane:methanol (v / v) = (100:0-93:7)] to obtain colorless oil 20-a (260 mg, yield: 63%, purity: 77.07%). LCMS (method C), Rt = 0.905 min; MS Calcd.: 433.2; MS Found: 334.3 [M-Boc+H]+ .

[0469] Step 2: Preparation of 20-b

[0470] In a single-necked reaction flask, 20-a (260 mg, 0.46 mmol), 1-b (170 mg, 0.32 mmol), HATU (262 mg, 0.69 mmol) and diisopropylethylamine (124 mg, 0.96 mmol) were dissolved in N,N-dimethylformamide (5 mL). The reaction was stirred at room temperature overnight under nitrogen protection. After the reaction was completed, saturated aqueous ammonium chloride solution (10 mL) was slowly added to the reaction solution, and extracted with ethyl acetate (15 mL x 3), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography [petroleum ether: methyl tert-butyl ether (v / v) = (100:0-70:30)] to obtain yellow solid 20-b (150 mg, yield: 43%, purity: 76.79%). LCMS (method G), Rt= 1.989 min; MS Calcd.: 834.2; MS Found: 735.0 [M-Boc+H] + .

[0471] Step 3: Preparation of 20-c

[0472] In a single-necked reaction flask, 20-b (150 mg, 0.14 mmol) and triethylamine (71 mg, 0.70 mmol) were dissolved in dichloromethane (10 mL), the reaction was placed in an ice water bath, and p-toluenesulfonyl chloride (40 mg, 0.21 mmol) was added. After the reaction was completed, the reaction solution was evaporated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography [petroleum ether: methyl tert-butyl ether (v / v) = (100:0-65:35)] to obtain colorless oil 20-c (164 mg, yield: 85%, purity: 58.17%). LCMS (method G), Rt= 2.271 min; MS Calcd.: 816.2; MS Found: 717.0 [M-Boc+H] + .

[0473] Step 4: Preparation of 20

[0474] In a single necked flask, 20-c (164 mg, 0.11 mmol) was dissolved in 2 mol / L hydrochloric acid in acetic acid (2 mL) and stirred at room temperature under nitrogen overnight. After completion of the reaction, the solvent was evaporated under reduced pressure to give the crude product which was purified by preparative high performance liquid chromatography to give the hydrochloride salt of compound 20. LCMS (method E), Rt = 1.248 min; MS Calcd.: 504.2; MS Found: 505.3 [M+H] + .HPLC (method I), Rt = 4.986 min; MS Calcd.: 504.2; MS Found: 505.3 [M+H] + .

[0475] 1 HNMR (400 MHz, CD3OD) δ: 8.07 (s, 2H), 8.04-8.01 (m, 2H), 7.57-7.53 (m, 4H), 3.56 (dd, J = 11.6, 8.0 Hz, 2H), 3.46-3.39 (m, 2H), 3.31-3.22 (m, 2H), 3.17-3.12 (m, 2H), 3.11-3.00 (m, 4H), 2.86 (s, 2H), 2.65-2.58 (m, 2H), 2.26-2.18 (m, 2H), 1.93-1.83 (m, 2H).

[0476] Example 21:

[0477] Step 1: Preparation of 21-a

[0478] In a single necked flask, A-5 (200 mg, 0.44 mmol), thiophene-2,5-diboronic acid pinacol ester (177 mg, 0.53 mmol), Pd(PPh3)4 (51 mg, 0.044 mmol) and NaHCO3 (111 mg, 1.32 mmol) were dissolved in 1,4-dioxane (5 mL) and water (1 mL) and stirred at 85 °C under nitrogen for 35 minutes. After completion of the reaction, the reaction was filtered through celite to remove solid impurities and the filtrate was evaporated under reduced pressure to give the crude product which was purified by silica gel column chromatography [petroleum ether: methyl-tert-butyl ether (v / v) = (100:0-70:30)] to give 21-a (80 mg, yield: 15%, purity: 70.91%) as a yellowish oil. LCMS (method A), Rt = 2.783 min; MS Calcd.: 830.5; MS Found: 730.7 [M-100+H] + .

[0479] 1H NMR (400 MHz, DMSO-d6) δ: 7.55-7.50 (m, 5H), 7.33 (t, J = 7.6 Hz, 2H), 7.15 (d, J = 7.6 Hz, 2H), 3.58-3.50 (m, 2H), 3.39-3.33 (m, 2H), 3.22-3.11 (m, 2H), 3.03 (t, J = 9.2 Hz, 2H), 2.85-2.70 (m, 4H), 2.62-2.54 (m, 2H), 2.33-2.24 (m, 2H), 1.88-1.83 (m, 2H), 1.65-1.53 (m, 2H), 1.40 (s, 18H), 1.22 (m, 18H).

[0480] Step 2: Preparation of 21

[0481] In a single-necked flask, 21-a (80 mg, 0.068 mmol) was dissolved in a solution of hydrochloric acid in dioxane (3 mL, 4 mol / L hydrochloric acid in dioxane). The reaction was stirred at room temperature for 2 hours under nitrogen protection. After the reaction was completed, the solvent was removed by evaporation under reduced pressure, and the crude product was purified by preparative high-performance liquid chromatography. The acetonitrile was removed by evaporation under reduced pressure, and the water was removed to obtain the hydrochloride salt of compound 21. LCMS (method A) Rt = 1.184 min; MS Calcd.: 518.2; MS Found: 519.2 [M+H] + HPLC (method J) Rt = 4.994 min; MS Calcd.: 518.2; MS Found: no mass response.

[0482] 1 H NMR (400 MHz, DMSO-d6 + CF3COOD) δ: 7.57-7.52 (m, 6H), 7.39 (t, J = 7.6 Hz, 2H), 7.20 (d, J = 7.6 Hz, 2H), 3.48 (dd, J = 11.6, 8.0 Hz, 2H), 3.34-3.28 (m, 2H), 3.21-3.17 (m, 2H), 3.06-3.01 (m, 2H), 2.95-2.86 (m, 4H), 2.78-2.73 (m, 2H), 2.51-2.46 (m, 2H), 2.10-2.05 (m, 2H), 1.75-1.69 (m, 2H).

[0483] Example 22:

[0484] Step 1: Preparation of 22-a

[0485] In a single necked flask, 22-a (270 mg, 0.46 mmol) and 10% palladium on carbon (30 mg) were dissolved in isopropyl alcohol (5 mL), replaced three times of gas with hydrogen balloon, the reaction was stirred at room temperature overnight under hydrogen atmosphere. After the reaction was completed, the reaction was filtered with celite to remove solid impurities, the filtrate was evaporated under reduced pressure to remove the solvent, to obtain a light yellow oil 22-b (200 mg, yield: 95%, purity: >99%), the crude product was directly used in the next step reaction. LCMS (method C), Rt = 0.999 min; MS Calcd.: 459.3; MS Found: 460.0 [M+H] + .

[0486] Step 2: Preparation of 22-b

[0487] In a single necked flask, 22-a (270 mg, 0.46 mmol) and 10% palladium on carbon (30 mg) were dissolved in isopropyl alcohol (5 mL), replaced three times of gas with hydrogen balloon, the reaction was stirred at room temperature overnight under hydrogen atmosphere. After the reaction was completed, the reaction was filtered with celite to remove solid impurities, the filtrate was evaporated under reduced pressure to remove the solvent, to obtain a light yellow oil 22-b (200 mg, yield: 95%, purity: >99%), the crude product was directly used in the next step reaction. LCMS (method C), Rt = 0.999 min; MS Calcd.: 459.3; MS Found: 460.0 [M+H] + .

[0488] Step 3: Preparation of 22-c

[0489] In a single-necked flask, 22-b (200 mg, 0.44 mmol), A-5 (197 mg, 0.44 mmol), Pd2(dba)3(40 mg, 0.044 mmol), Xant-phos (51 mg, 0.088 mmol) and potassium tert-butoxide (99 mg, 0.88 mmol) were dissolved in 1,4-dioxane (5 mL) and the reaction was stirred at 110 °C overnight under nitrogen protection. After the reaction was completed, the reaction solution was filtered with diatomite to remove solid impurities, and the filtrate was evaporated under reduced pressure to remove the solvent. The crude product was purified by silica gel column chromatography [petroleum ether: methyl tert-butyl ether (v / v) = (100:0-55:45)] to obtain 22-c (80 mg, yield: 86%, purity: 68.59%) as a light yellow oil. LCMS (method D), Rt = 1.385 min; MS Calcd.: 832.5; MS Found: 832.8 [M+H] + .

[0490] Step 4: Preparation of 22

[0491] In a single-necked flask, 22-c (80 mg, 0.10 mmol) was dissolved in hydrochloric acid in acetic acid solution (2 mL, 2 mol / L hydrochloric acid in acetic acid solution). It was stirred at room temperature for 2 days under nitrogen protection. After the reaction was completed, the reaction solution was evaporated under reduced pressure to remove the solvent, and the crude product was purified by preparative high performance liquid chromatography. Acetonitrile was evaporated under reduced pressure, and water was removed to obtain the hydrochloride salt of compound 22. LCMS (method E) Rt = 1.281 min; MS Calcd.: 520.3; MS Found: 521.3 [M+H] + HPLC (method H) Rt = 4.366 min; MS Calcd.: 520.3; MS Found: 520.6 [M+H] + .

[0492] 1 HNMR (400 MHz, CD3OD) δ: 7.26 (t, J = 8.0 Hz, 2H), 7.08 (s, 4H), 6.86 (d, J = 7.2 Hz, 2H), 3.47 (s, 8H), 3.42-3.36 (m, 1H), 3.31-3.22 (m, 3H), 3.15-3.08 (m, 2H), 2.97-2.87 (m, 2H), 2.85-2.75 (m, 4H), 2.73-2.67 (m, 2H), 2.51-2.34 (m, 2H), 2.19-2.15 (m, 1H), 2.04-2.00 (m, 1H), 1.71-1.62 (m, 2H).

[0493] Example 23:

[0494] Step 1: Preparation of 23-b

[0495] In a single-necked reaction flask, was added 23-a (660 mg, 3.06 mmol), triethyl phosphite (761 mg, 4.58 mmol) and toluene (15 mL), and the reaction was carried out at 130 °C overnight under nitrogen protection. After the reaction was completed, the solvent was removed by evaporation under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography [petroleum ether: methyl tert-butyl ether (v / v) = (100:0-40:60)] to obtain yellow oil 23-b (620 mg, yield: 74%, purity: >99%). LCMS (method C), Rt= 0.758 min; MS Calcd.: 273.1; MS Found: 274.0 [M+H] + .

[0496] Step 2: Preparation of 23-c

[0497] In a single-necked reaction flask, was added 23-b (620 mg, 2.27 mmol), 10% palladium carbon (100 mg) and isopropanol (20 mL), and the reaction was carried out at room temperature overnight under hydrogen atmosphere. After the reaction was completed, the reaction mixture was filtered with diatomite, and the filtrate was evaporated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography [petroleum ether: methyl tert-butyl ether (v / v) = (100:0-20:80)] to obtain yellow oil 23-c (450 mg, yield: 81%, purity: >99%). LCMS (method C), Rt= 0.629 min; MS Calcd.: 243.1; MS Found: 244.0 [M+H] + .

[0498] Step 3: Preparation of 23-d

[0499] In a single-necked flask, 23-c (90 mg, 0.37 mmol), A-7 (149 mg, 0.37 mmol) were dissolved in methanol (6 mL) and cooled with an ice-water bath, then 1 drop of glacial acetic acid was added into the reaction solution, after stirring for 2 minutes, sodium cyanoborohydride (34 mg, 0.56 mmol) was added, and the reaction was stirred at room temperature overnight under nitrogen protection. After the reaction was completed, the reaction was quenched by adding saturated sodium bicarbonate solution (15 mL), and the solvent methanol was removed by reduced pressure evaporation. Ethyl acetate (15 mL x 3) was added for extraction, and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated by reduced pressure to remove the solvent. Purification was performed by silica gel column chromatography [petroleum ether: methyl tert-butyl ether (v / v) = (100:0-20:80)], and yellow oil 23-d (170 mg, yield: 68%, purity: 93.68%) was obtained. LCMS (method A), Rt = 2.223 min; MS Calcd.: 630.3; MS Found: 631.0 [M+H] + .

[0500] Step 4: Preparation of 23

[0501] In a single-necked flask, 23-d (100 mg, 0.16 mmol) was dissolved in hydrochloric acid in acetic acid solution (2 mL, 2 mol / L hydrochloric acid in acetic acid), and stirred at room temperature under nitrogen protection for two days. After the reaction was completed, the solvent was evaporated by reduced pressure, and the crude product was purified by reverse phase [water: acetonitrile (v / v) = (100:0-50:50)]. The acetonitrile was evaporated by reduced pressure, and water was removed to obtain the hydrochloride salt of compound 23. LCMS (method A) Rt = 1.390 min; MS Calcd.: 474.2; MS Found: 238.3 [1 / 2M+H] + , 475.0 [M+H] + HPLC (method I) Rt = 5.779 min; MS Calcd.: 474.2; MS Found: 238.3 [1 / 2M+H] + , 475.2 [M+H] + .

[0502] 1HNMR (400 MHz, CD3OD) δ: 7.50-7.47 (m, 2H), 7.42 (s, 2H), 7.35-7.32 (m, 3H), 7.25-7.24 (m, 1H), 4.91 (s, 1H), 4.59 (s, 2H), 4.11-4.03 (m, 4H), 3.51 (t, J = 8.0 Hz, 1H), 3.44-3.38 (m, 2H), 3.28-3.23 (m, 1H), 3.10 (t, J = 10.0 Hz, 1H), 2.99-2.89 (m, 2H), 2.80-2.49 (m, 1H), 2.58-2.56 (m, 1H), 2.20-2.19 (m, 1H), 1.85 (t, J = 8.0 Hz, 1H), 1.28 (t, J = 6.8 Hz, 6H).

[0503] Example 24:

[0504] Step 1: Preparation of 24-b

[0505] Into a three-necked flask, 24-a (5.0 g, 16.78 mmol) and tetrahydrofuran (80 mL) were added, the reaction was placed in an ice-water bath under nitrogen protection, sodium hydride (738 mg, 18.46 mmol, 60 wt%) was slowly added, the reaction was stirred in an ice-water bath for 1 hour. Bromomethyl methyl ether (2.1 g, 16.78 mmol) was dissolved in tetrahydrofuran (20 mL) and added to the above reaction solution at 0°C, the ice-water bath was removed, and the reaction was stirred at room temperature overnight. After the reaction was completed, saturated ammonium chloride solution (100 mL) was added to quench the reaction, and extracted with ethyl acetate (120 mL x 2), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure. The crude product was purified by silica gel column chromatography [petroleum ether: methyl tert-butyl ether (v / v) = (100:0-65:35)] to obtain yellowish oil 24-b (5.5 g, yield: 96%, purity: >99%).

[0506] 1 HNMR (400 MHz, CDCl3) δ: 7.50 (t, J = 1.6 Hz, 1H), 7.33 (t, J = 1.2 Hz, 1H), 7.18 (t, J = 2.0 Hz, 1H), 5.13 (s, 2H), 3.46 (s, 3H).

[0507] Step 2: Preparation of 24-c

[0508] In a single-necked flask, 24-b (5.0 g, 14.53 mmol), isopropenylboronic acid pinacol ester (2.95 g, 17.44 mmol), Pd(dppf)Cl2(1.06 g, 1.45 mmol) and potassium carbonate (4.01 g, 29.06 mmol) were dissolved in 1,4-dioxane (60 mL) and water (10 mL), and the reaction was stirred at 80 °C overnight under nitrogen protection. After the reaction was completed, the reaction solution was filtered with diatomite to remove solid impurities, and the filtrate was evaporated under reduced pressure to remove the solvent. The crude product was purified by silica gel column chromatography [petroleum ether: methyl tert-butyl ether (v / v) = (100:0-93:7)] to obtain 24-c (3.0 g, yield: 80%, purity: >99%) as a light yellow oil.

[0509] 1 HNMR (400 MHz, CDC13) δ: 7.24 (s, 1H), 7.13 (t, J = 1.6 Hz, 1H), 7.04 (t, J = 1.6 Hz, 1H), 5.36 (s, 1H), 5.16 (s, 2H), 5.11 (s, 1H), 3.49 (t, J = 2.0 Hz, 3H), 2.10 (s, 3H).

[0510] Step 3: Preparation of 24-d

[0511] In a three-necked flask, 24-c (1.5 g, 5.86 mmol) and anhydrous tetrahydrofuran (30 mL) were added, and the reaction was placed in a dry ice acetone bath under nitrogen protection. N-butyllithium (3.52 mL, 8.79 mmol, 2.5 mol / L in n-hexane) was slowly added at -70 °C, and the reaction was stirred at -70 °C for 1 hour. Then N,N-dimethylformamide (1.28 g, 17.58 mmol) was added, the dry ice acetone bath was removed, and the reaction was stirred at room temperature for 16 hours. After the reaction was completed, saturated aqueous ammonium chloride solution (50 mL) was added to quench the reaction, and extraction was performed with ethyl acetate (50 mL x 2). The organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to remove the solvent. The crude product was purified by silica gel column chromatography [petroleum ether: methyl tert-butyl ether (v / v) = (100:0-73:27)] to obtain 24-d (1.2 g, yield: 98%, purity: >99%) as a light yellow oil.

[0512] 1HNMR (400 MHz, CDC13) δ: 9.98 (s, 1H), 7.63 (s, 1H), 7.46 (t, J = 1.6 Hz, 1H), 7.38 (t, J = 2.0 Hz, 1H), 5.46 (s, 1H), 5.24 (t, J = 3.2 Hz, 2H), 5.19 (s, 1H), 3.50 (t, J = 2.4 Hz, 3H), 2.18 (s, 3H).

[0513] Step 4: Preparation of 24-e

[0514] In a single-necked reaction flask, 24-d (1.2 g, 5.83 mmol) was dissolved in tetrahydrofuran (30 mL), the reaction was placed in an ice water bath under nitrogen protection, sodium borohydride (332 mg, 8.74 mmol) was added in portions, the reaction was stirred at room temperature for 1 hour. After the reaction was completed, 0.5 mol / L dilute hydrochloric acid aqueous solution (20 mL) was added to quench the reaction, and extracted with ethyl acetate (30 mL x 3), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to obtain a light yellow oil 24-e (800 mg, yield: 66%, purity: >99%), which was used directly in the next step reaction.

[0515] 1 HNMR (400 MHz, CDC13) δ: 7.12 (d, J = 1.2 Hz, 1H), 7.06 (t, J = 2.0 Hz, 1H), 6.98 (d, J = 2.0 Hz, 1H), 5.37 (d, J = 0.8 Hz, 1H), 5.20 (s, 2H), 5.10 (t, J = 1.2 Hz, 1H), 4.68 (s, 2H), 3.49 (s, 3H), 2.18 (q, J = 0.8 Hz, 3H).

[0516] Step 5: Preparation of 24-f

[0517] In a single-necked reaction flask, 24-e (800 mg, 3.85 mmol), tert-butyldimethylsilyl chloride (1.73 g, 11.55 mmol) and imidazole (1.05 g, 15.40 mmol) were dissolved in dichloromethane (20 mL), the reaction was stirred at room temperature overnight under nitrogen protection. After the reaction was completed, water (25 mL) was added to quench the reaction, and extracted with dichloromethane (25 mL x 3), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure, the crude product was purified by silica gel column chromatography [petroleum ether: methyl tert-butyl ether (v / v) = (100:0-68:32)], to obtain a light yellow oil 24-f (1.0 g, yield: 81%, purity: >99%).

[0518] 1HNMR (400 MHz, CDC13) δ: 6.98 (s, 1H), 6.90 (t, J = 2.0 Hz, 1H), 6.85 (s, 1H), 5.36 (s, 1H), 5.07 (d, J = 3.2 Hz, 2H), 4.97 (t, J = 1.6 Hz, 1H), 4.62 (s, 2H), 3.37 (t, J = 2.0 Hz, 3H), 2.03 (s, 3H), 0.84 (t, J = 2.8 Hz, 9H), 0.01 (t, J = 2.8 Hz, 6H).

[0519] Step 6: Preparation of 24-g

[0520] In a single-necked reaction flask, 24-f (1.0 g, 3.11 mmol) and chloroiodomethane (5.47 g, 31.10 mmol) were dissolved in dichloromethane (20 mL), the reaction was placed in an ice-water bath under nitrogen protection, diethyl zinc (15.6 mL, 15.55 mmol, 1 mol / L in n-hexane) was added, then the ice-water bath was removed, and the reaction was stirred at room temperature overnight. After the reaction was completed, saturated ammonium chloride solution (25 mL) was added to quench the reaction, and dichloromethane (30 mL x 3) was used for extraction, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to remove the solvent, and the crude product was purified by silica gel column chromatography [petroleum ether: methyl tert-butyl ether (v / v) = (100:0-60:40)] to obtain 24-g (900 mg, yield: 86%, purity: >95%) as a light yellow oil.

[0521] 1 HNMR (400 MHz, CDC13) δ: 6.75 (d, J = 8.8 Hz, 2H), 6.70 (t, J = 2.0 Hz, 1H), 5.07 (d, J = 7.2 Hz, 2H), 4.61 (d, J = 12.0 Hz, 2H), 3.39 (t, J = 3.6 Hz, 3H), 1.29 (s, 3H), 0.85 (s, 9H), 0.77-0.74 (m, 2H), 0.62-0.60 (m, 2H), 0.01 (d, J = 2.0 Hz, 6H).

[0522] Step 7: Preparation of 24-h

[0523] In a single-necked reaction flask, 24-g (900 mg, 2.68 mmol) and tetrabutylammonium fluoride (5.4 mL, 5.36 mmol, 1 mol / L in tetrahydrofuran) were dissolved in tetrahydrofuran (5 mL), the reaction was stirred at room temperature overnight under nitrogen protection. After the reaction was completed, the solvent was removed by evaporation under reduced pressure, and the crude product was purified by silica gel column chromatography [petroleum ether: methyl tert-butyl ether (v / v) = (100:0-60:40)] to obtain 24-h (480 mg, yield: 54%, purity: 66.69%) as a light yellow oil. LCMS (method C), Rt= 0.827 min; MS Calcd.: 222.1; MS Found: 223.3 [M+H] + .

[0524] Step 8: Preparation of 24-i

[0525] In a single-necked reaction flask, 24-h (480 mg, 2.16 mmol) and Dess-Martin oxidizing agent (1.65 g, 3.89 mmol) were dissolved in dichloromethane (15 mL), the reaction was stirred at room temperature overnight under nitrogen protection. After the reaction was completed, saturated aqueous sodium thiosulfate solution (20 mL) was added to quench the reaction, followed by adjusting the pH to 8-9 with saturated NaHCO3 solution and extracting with dichloromethane (20 mL x 3), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to remove the solvent. The crude product was purified by silica gel column chromatography [petroleum ether: methyl tert-butyl ether (v / v) = (100:0-65:35)] to obtain 24-i (340 mg, yield: 59%, purity: 55.55%) as a light yellow oil. LCMS (method C), Rt= 0.962 min; MS Calcd.: 220.1; MS Found: 221.3 [M+H] + .

[0526] Step 9: Preparation of 24-j

[0527] In a single-necked reaction flask, 24-i (44 mg, 0.20 mmol) was dissolved in hydrochloric acid in dioxane solution (1 mL, 4 mol / L in dioxane), the reaction was stirred at room temperature for 1 hour under nitrogen protection. After the reaction was completed, the solvent was removed by evaporation under reduced pressure, and the crude product was purified by silica gel column chromatography [petroleum ether: methyl tert-butyl ether (v / v) = (100:0-70:30)] to obtain 24-j (15 mg, yield: 77%, purity: >95%) as a light yellow oil.

[0528] 1HNMR (400 MHz, CDC13) δ: 9.92 (s, 1H), 7.33 (t, J = 1.2 Hz, 1H), 7.12 (q, J = 1.6 Hz, 1H), 7.00 (q, J = 2.0 Hz, 1H), 1.43 (s, 3H), 0.90 (t, J = 6.4 Hz, 2H), 0.80 (q, J = 4.0 Hz, 2H).

[0529] Step 10: Preparation of 24-k

[0530] In a single-necked reaction flask, 24-j (15 mg, 0.085 mmol), A (67 mg, 0.085 mmol) were dissolved in methanol (1 mL) and cooled with an ice-water bath, then 1 drop of glacial acetic acid was added dropwise into the reaction solution, after stirring for 2 minutes, sodium cyanoborohydride (11 mg, 0.17 mmol) was added, and the reaction was stirred at room temperature overnight under nitrogen protection. After the reaction was completed, the reaction was quenched by adding saturated sodium bicarbonate solution (3 mL), and the solvent methanol was removed under reduced pressure, and extracted with ethyl acetate (3 mL x 3), and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography [petroleum ether: methyl tert-butyl ether (v / v) = (100:0-65:35)] to obtain yellowish oil 24-k (30 mg, yield: 30%, purity: 81.97%). LCMS (method G), Rt = 1.686 min; MS Calcd.: 951.6; MS Found: 953.1 [M+H] + .

[0531] Step 11: Preparation of 24

[0532] In a single-necked reaction flask, 24-k (30 mg, 0.032 mmol) was dissolved in hydrochloric acid in acetic acid solution (1 mL, 2 mol / L hydrochloric acid in acetic acid solution). Stirring at room temperature for 3 hours under nitrogen protection. After the reaction was completed, the solvent was removed under reduced pressure, and the crude product was purified by preparative high performance liquid chromatography, and the acetonitrile was removed under reduced pressure, and the water was removed to obtain the hydrochloride salt of compound 24. LCMS (method E) Rt = 1.321 min; MS Calcd.: 639.4; MS Found: 640.3 [M+H] + HPLC (method I) Rt = 5.463 min; MS Calcd.: 639.4; MS Found: 640.3 [M+H] + .

[0533] 1HNMR (400 MHz, CD3OD) δ: 7.02 (d, J = 6.4 Hz, 3H), 7.39-7.36 (m, 3H), 7.27 (d, J = 5.2 Hz, 2H), 6.81 (d, J = 11.2 Hz, 2H), 6.71 (s, 1H), 4.30 (q, J = 6.0 Hz, 4H), 4.19 (d, J = 6.8 Hz, 2H), 3.55 (q, J = 8.0 Hz, 2H), 3.45-3.38 (m, 2H), 3.27-3.22 (m, 2H), 3.13 (t, J = 11.2 Hz, 2H), 2.96 (d, J = 7.2 Hz, 4H), 2.85 (d, J = 8.0 Hz, 2H), 2.58 (d, J = 8.8 Hz, 2H), 2.22-2.16 (m, 2H), 1.92-1.82 (m, 2H), 1.39 (s, 3H), 0.86 (t, J = 6.4 Hz, 2H), 0.76 (t, J = 3.6 Hz, 2H).

[0534] Example 25:

[0535] Step 1: Preparation of 25

[0536] In a single-necked flask, 23 (25.00 mg, 0.052 mmol) was dissolved in concentrated hydrochloric acid (2 mL) under nitrogen protection, the reaction was stirred at 100 °C overnight. After the reaction was completed, the solvent was removed by evaporation under reduced pressure, and the obtained crude product was purified by preparative high performance liquid chromatography to obtain compound 25 hydrochloride. LCMS (method A) Rt = 0.326 min, 0.956 min; MS Calcd.: 418.2; MS Found: 419.2 [M+H] + .HPLC (method I) Rt = 1.836 min, 4.028 min; MS Calcd.: 418.2; MS Found: 419.2 [M+H] + .

[0537] 1HNMR (400 MHz, CD3OD) δ: 7.46-7.43 (m, 2H), 7.41 (s, 1H), 7.337-7.34 (m, 2H), 7.33-7.29 (m, 2H), 7.23-7.21 (m, 1H), 4.57 (s, 2H), 3.51-3.47 (m, 1H), 3.43-3.38 (m, 1H), 3.26-3.18 (m, 3H), 3.06 (t, J = 10.4 Hz, 1H), 2.98-2.87 (m, 2H), 2.77-2.72 (m, 1H), 2.57-2.53 (m, 1H), 2.21-2.17 (m, 1H), 1.87-1.81 (m, 1H).

[0538] Example 26:

[0539] Step 1: Preparation of 26-a

[0540] In a single-necked reaction flask, A-7 (90 mg, 0.37 mmol), (aminomethyl)phosphonic acid diethyl ester (75 mg, 0.45 mmol) were dissolved in MeOH (6 mL) and cooled with an ice-water bath, then 2 drops of glacial acetic acid were added dropwise to the reaction solution, and after stirring for 1 min, sodium cyanoborohydride (34 mg, 0.56 mmol) was added. The reaction was stirred at room temperature overnight under nitrogen protection. After the reaction was completed, the reaction was quenched by adding aqueous sodium bicarbonate solution (20 mL), and extracted with ethyl acetate (20 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography [petroleum ether: methyl tert-butyl ether (v / v) = (100:0-40:60)] to obtain yellow oil 26-a (180 mg, yield: 72%, purity: 83.39%). LCMS (method G), Rt= 1.442 min; MS Calcd.: 554.3; MS Found: 555.4 [M+H] + .

[0541] Step 2: Preparation of 26-b

[0542] In a single-necked flask, 26-a (180 mg, 0.32 mmol), A-7 (131 mg, 0.32 mmol) were dissolved in MeOH (6 mL) with ice water bath cooling, then 2 drops of glacial acetic acid was added into the reaction, after 1 min stirring, sodium cyanoborohydride (30 mg, 0.48 mmol) was added, the reaction was stirred at room temperature overnight under nitrogen protection. After the reaction was completed, the reaction was quenched by adding aqueous sodium bicarbonate solution (20 mL), extracted with ethyl acetate (20 mL x 3), the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was evaporated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography [petroleum ether: methyl tert-butyl ether (v / v) = (100:0-40:60)] to obtain yellow oil 26-b (200 mg, yield: 65%, purity: >99%). LCMS (method G), Rt = 2.048 min; MS Calcd.: 941.6; MS Found: 942.5 [M+H] + .

[0543] Step 3: Preparation of 26

[0544] In a single-necked flask, 26-b (200 mg, 0.21 mmol) was dissolved in 2 mol / L hydrochloric acid in acetic acid solution (2 mL), the reaction was stirred at room temperature overnight under nitrogen protection. After the reaction was completed, the solvent was evaporated under reduced pressure to obtain a crude product, which was purified by preparative high performance liquid chromatography, by evaporating acetonitrile under reduced pressure, and water was removed to obtain the hydrochloride salt of compound 26. LCMS (method E) Rt = 1.263 min; MS Calcd.: 629.3; MS Found: 315.8 [1 / 2M+H] + , 630.3 [M+H] + HPLC (method I) Rt = 5.173 min; MS Calcd.: 629.3; MS Found: 315.8 [1 / 2M+H] + , 630.3 [M+H] + .

[0545] 1HNMR (400 MHz, CD3OD) δ: 7.57 (s, 2H), 7.45-7.39 (m, 6H), 4.55 (s, 4H), 4.25-4.16 (m, 4H), 3.59-3.51 (m, 4H), 3.45-3.39 (m, 2H), 3.26-3.23 (m, 2H), 3.17-3.12 (m, 2H), 2.98 (d, J = 7.6 Hz, 4H), 2.88-2.82 (m, 2H), 2.63-2.57 (m, 2H), 2.24-2.16 (m, 2H), 1.90-1.79 (m, 2H), 1.37-1.32 (m, 6H).

[0546] Example 27:

[0547] Step 1: Preparation of 27

[0548] In a single-necked flask, 26 (50 mg, 0.08 mmol) was dissolved in concentrated hydrochloric acid (2 mL) and the reaction was stirred at 100 °C overnight under nitrogen protection. After the reaction was completed, the solvent was removed by evaporation under reduced pressure to give a crude product, which was purified by preparative high performance liquid chromatography. The hydrochloride salt of compound 27 was obtained by removing acetonitrile under reduced pressure, and then removing water. LCMS (method E) Rt = 1.043 min; MS Calcd.: 573.3; MS Found: 287.7 [1 / 2 M+H] + , 574.3 [M+H] + HPLC (method I) Rt = 3.993 min; MS Calcd.: 573.3; MS Found: 287.8 [1 / 2 M+H] + , 574.2 [M+H] + .

[0549] 1 HNMR (400 MHz, CD3OD) δ: 7.55 (s, 2H), 7.45-7.41 (m, 6H), 4.56 (s, 4H), 3.58-3.53 (m, 2H), 3.43-3.39 (m, 2H), 3.34-3.31 (m, 2H), 3.28-3.23 (m, 2H), 3.13 (t, J = 9.6 Hz, 2H), 2.99 (d, J = 6.8 Hz, 4H), 2.87-2.84 (m, 2H), 2.59-2.58 (m, 2H), 2.21-2.19 (m, 2H), 1.87-1.81 (m, 2H).

[0550] Example 28:

[0551] Step 1: Preparation of 28-b

[0552] In a single-necked reaction flask, 3-bromo-5-fluorobenzaldehyde (28-a, 3.0 g, 14.86 mmol), malonic acid (3.09 g, 29.71 mmol) and tetrahydro-pyrrole (106 mg, 1.49 mmol) were dissolved in pyridine (50 mL) and the reaction was stirred at 120 °C for 1 h under nitrogen protection. After the reaction was completed, the solvent was removed by evaporation under reduced pressure, then the pH was adjusted to 4-5 with 2 mol / L dilute hydrochloric acid, and extracted with ethyl acetate (50 mL x 3). The organic phase was evaporated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography [petroleum ether: ethyl acetate (v / v) = (100:0-70:30)] to obtain white solid 28-b (3.2 g, yield: 88%, purity: >99%).

[0553] 1 HNMR (400 MHz, CDC13) δ: 7.66 (d, J = 16.0 Hz, 1H), 7.48 (s, 1H), 7.30 (dt, J = 7.6, 2.0 Hz, 1H), 7.19 (dt, J = 8.8, 1.6 Hz, 1H), 6.44 (d, J = 16.0 Hz, 1H).

[0554] Step 2: Preparation of 28-c

[0555] In a single-necked reaction flask, 28-b (3.2 g, 13.11 mmol) was dissolved in ethyl acetate (130 mL), then platinum dioxide (298 mg, 1.31 mmol) was added, and the gas was replaced with hydrogen three times. The reaction was stirred at room temperature under hydrogen protection overnight. After the reaction was completed, the reaction liquid was filtered with diatomite, and the filtrate was dried with anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure to obtain white solid 28-c (2.8 g, yield: 87%, purity: >99%).

[0556] 1 HNMR (400 MHz, CDC13) δ: 7.16 (s, 1H), 7.11 (dt, J = 8.0, 2.0 Hz, 1H), 6.88 (d, J = 9.2 Hz, 1H), 2.93 (t, J = 7.6 Hz, 2H), 2.68 (t, J = 7.6 Hz, 2H).

[0557] Step 3: Preparation of 28-d

[0558] In a single-necked reaction flask, 28-c (2.8 g, 11.38 mmol), hydroxylamine hydrochloride (1.11 g, 11.38 mmol), HATU (6.49 g, 17.07 mmol) and diisopropylethylamine (7.34 g, 56.90 mmol) were dissolved in N,N-dimethylformamide (55 mL) and the reaction was stirred at room temperature for 2 hours under nitrogen atmosphere. After the reaction was completed, the reaction was quenched by adding water (100 mL) and extracted with ethyl acetate (40 mL x 3), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure. The crude product was purified by silica gel column chromatography [petroleum ether: methyl tert-butyl ether (v / v) = (100:0-75:25)] to give 28-d (3.5 g, yield: 74%, purity: 60.65%) as a light yellow oil. LCMS (method C), Rt= 0.907 min; MS Calcd.: 289.0; MS Found: 290.1 [M+H] + .

[0559] Step 4: Preparation of 28-e

[0560] In a three-necked reaction flask, 28-d (3.5 g, 7.35 mmol) was dissolved in tetrahydrofuran (70 mL) and the reaction was placed in a dry ice-acetone bath to control the reaction temperature below -20 °C under nitrogen atmosphere. A solution of lithium aluminum hydride (5.5 mL, 11.00 mmol, 2 mol / L in tetrahydrofuran) was added dropwise, and then stirred at -20 °C for 30 minutes. After the reaction was completed, the reaction was quenched by adding sodium sulfate decahydrate (15 g) and stirred at room temperature for 30 minutes. Then the reaction was filtered with celite, and the tetrahydrofuran solution of 28-e was directly used in the next reaction.

[0561] Step 5: Preparation of 28-f

[0562] In a single-necked reaction flask, tert-butyl phosphine acid diethyl ester (2.23 g, 8.82 mmol) was dissolved in tetrahydrofuran (25 mL) and sodium hydride (382 mg, 9.56 mmol, 60 wt%) was added under nitrogen atmosphere. The reaction was stirred in an ice water bath for 30 minutes, and then the tetrahydrofuran solution of 28-e was added. The ice water bath was removed and the reaction was stirred at room temperature for 2 hours. After the reaction was completed, the reaction was quenched by adding aqueous ammonium chloride solution (50 mL) and extracted with ethyl acetate (60 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure. The crude product was purified by silica gel column chromatography [petroleum ether: methyl tert-butyl ether (v / v) = (100:0-57:43)] to give 28-f (2.5 g, yield: 93%, purity: >95%) as a light yellow oil.

[0563] 1 HNMR (400 MHz, CDC13) δ: 7.15-7.11 (m, 1H), 7.10-6.91 (m, 1H), 6.90-6.85 (m, 1H), 6.84-6.80 (m, 1H), 5.80-5.74 (m, 1H), 2.78-2.71 (m, 2H), 2.51-2.44 (m, 2H), 1.48 (s, 9H).

[0564] Step 6: Preparation of 28-g

[0565] In a single-necked reaction flask, 28-f (2.5 g, 6.86 mmol) was dissolved in ethyl acetate (65 mL), then platinum dioxide (233 mg, 1.03 mmol) was added, and the gas was replaced with hydrogen three times. The reaction was stirred at room temperature overnight under a hydrogen atmosphere. After the reaction was completed, the reaction solution was filtered with diatomite, and the filtrate was dried with anhydrous sodium sulfate. After filtering again, the filtrate was evaporated to remove the solvent under reduced pressure to obtain yellow oil 28-g (2.1 g, yield: 67%, purity: >95%).

[0566] 1 HNMR (400 MHz, CDC13) δ: 7.15-7.11 (m, 1H), 7.10-6.91 (m, 1H), 6.90-6.85 (m, 1H), 6.84-6.80 (m, 1H), 5.80-5.74 (m, 1H), 2.78-2.71 (m, 2H), 2.51-2.44 (m, 2H), 1.48 (s, 9H).

[0567] Step 7: Preparation of 28-h

[0568] In a single-necked reaction flask, 28-g (2.1 g, 4.61 mmol) was dissolved in dichloromethane (25 mL), and trifluoroacetic acid (5 mL) was added. The reaction was stirred at room temperature overnight under nitrogen protection. After the reaction was completed, the reaction solution was evaporated to remove the solvent under reduced pressure, then water (20 mL) was added to quench, and extracted with ethyl acetate (30 mL x 3). The organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was evaporated to remove the solvent under reduced pressure. The crude product was purified by silica gel column chromatography [petroleum ether: methyl tert-butyl ether (v / v) = (100:0-40:60)] to obtain yellow oil 28-h (1.6 g, yield: 96%, purity: >95%).

[0569] 1HNMR (400 MHz, CDC13) δ: 7.12 (s, 1H), 7.07 (dt, J = 8.0, 2.4 Hz, 1H), 6.83 (dt, J = 7.6, 1.6 Hz, 1H), 2.63-2.59 (m, 2H), 2.41-2.37 (m, 2H), 1.69-1.65 (m, 4H).

[0570] Step 8: Preparation of 28-i

[0571] In a three-necked flask, 28-h (1.6 g, 4.42 mmol), 4-dimethylaminopyridine (54 mg, 0.44 mmol) and hydrogen peroxide (631 mg, 5.58 mmol, 30 wt%) were dissolved in dichloromethane (20 mL), the reaction was placed in dry ice acetone bath under nitrogen protection, the reaction temperature was controlled below -15 °C, stirred for 15 minutes, then the temperature was controlled below 0 °C, and N,N'-dicyclohexyl carbodiimide (1.0 g, 4.86 mmol) was added, then the reaction was stirred at 0 °C for 2 hours. After the reaction was completed, the reaction solution was filtered, the filtrate was dried with anhydrous sodium sulfate, and after filtration, the solvent was removed under reduced pressure to obtain the crude intermediate, which was directly used in the next step reaction.

[0572] In a three-necked flask, copper trifluoromethanesulfonate (160 mg, 0.44 mmol), 2,2'-dipyridyl (69 mg, 0.44 mmol), diethyl phosphite (779 g, 5.64 mmol) and triethylamine (570 g, 5.64 mmol) were dissolved in ethylene glycol dimethyl ether (10 mL), the reaction was stirred at 60 °C for 5 minutes under argon protection, then the ethylene glycol dimethyl ether (10 mL) solution of the intermediate was added to the reaction, and stirred at 60 °C for 1 hour. After the reaction was completed, the solvent was removed under reduced pressure, and the crude product was purified by silica gel column chromatography [petroleum ether: methyl tert-butyl ether (v / v) = (100:0-17:83)] to obtain 28-i (150 mg, yield: 6%, purity: 68.01%) as a light yellow oil. LCMS (method B), Rt = 1.824 min; MS Calcd.: 366.2; MS Found: 367.1 [M+H] + .

[0573] Step 9: Preparation of 28-j

[0574] In a single-necked reaction flask, 28-i (150 mg, 0.28 mmol), vinylpotassium trifluoroborate (75 mg, 0.56 mmol), Pd(dppf)Cl2(20 mg, 0.028 mmol) and sodium bicarbonate (71 mg, 0.84 mmol) were added to a mixture of dioxane (6 mL) and water (2 mL). The reaction was stirred at 85 °C overnight under nitrogen protection after being purged with nitrogen three times. After the reaction was completed, the reaction solution was filtered, the filtrate was evaporated under reduced pressure to remove the solvent, and the crude product was purified by silica gel column chromatography [dichloromethane:methanol (v / v) = (100:0-93:7)] to obtain yellow oil 28-j (100 mg, yield: 83%, purity: 72.23%). LCMS (method D), Rt= 0.911 min; MS Calcd.: 314.2; MS Found: 315.3 [M+H] + .

[0575] Step 10: Preparation of 28-k

[0576] In a single-necked reaction flask, 28-j (100 mg, 0.23 mmol) was dissolved in a mixture of acetone (6 mL) and water (2 mL), and potassium osmate (7 mg, 0.023 mmol) and sodium periodate (149 mg, 0.69 mmol) were added sequentially. The reaction was stirred at room temperature overnight under nitrogen protection. After the reaction was completed, the reaction solution was quenched with water (10 mL) and then extracted with ethyl acetate (15 mL x 3), and the organic phase filtrate was evaporated under reduced pressure to remove the solvent. The crude product was purified by silica gel column chromatography [dichloromethane:methanol (v / v) = (100:0-93:7)] to obtain yellow oil 28-k (162 mg, yield: 91%, purity: 40.79%). LCMS (method D), Rt= 0.792 min; MS Calcd.: 316.2; MS Found: 317.1 [M+H] + .

[0577] Step 11: Preparation of 28-l

[0578] In a single-necked flask, 28-k (162 mg, 0.21 mmol) was dissolved in methanol (4 mL), followed by the addition of A (165 mg, 0.21 mmol) and 1 drop of glacial acetic acid. After stirring at room temperature for 10 minutes, sodium cyanoborohydride (26 mg, 0.42 mmol) was added and the reaction was stirred at room temperature for 2 hours under nitrogen protection. After the reaction was completed, the reaction solution was quenched with saturated aqueous sodium bicarbonate solution (6 mL), and the solvent was removed under reduced pressure. The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography [dichloromethane:methanol (v / v) = (100:0-94:6)] to give 28-l (80 mg, yield: 35%, purity: >99%) as a white solid. LCMS (method G), Rt = 1.832 min; MS Calcd.: 1191.6; MS Found: 1093.1 [M-100+H] + .

[0579] Step 12: Preparation of 28

[0580] In a single-necked flask, 28-l (80 mg, 0.067 mmol) was dissolved in 2 mol / L hydrochloric acid in acetic acid solution (1 mL), and the reaction was stirred at room temperature overnight under nitrogen protection. After the reaction was completed, the solvent was removed under reduced pressure, and the crude product was purified by preparative high-performance liquid chromatography to give the hydrochloride salt of compound 28. LCMS (method A), Rt = 1.513 min; MS Calcd.: 779.4; MS Found: 780.0 [M+H] + HPLC (method H), Rt = 6.882 min; MS Calcd.: 779.4; MS Found: 780.0 [M+H] + .

[0581] 1HNMR (400 MHz, CD3OD) δ: 7.52 (s, 2H), 7.42-7.32 (m, 6H), 7.18 (s, 1H), 7.11 (t, J = 4.8 Hz, 2H), 4.37-4.26 (m, 6H), 4.09-4.01 (m, 4H), 3.58-3.54 (m, 2H), 3.45-3.39 (m, 2H), 3.30-3.23 (m, 2H), 3.17-3.12 (m, 2H), 2.96 (d, J = 7.6 Hz, 4H), 2.85 (q, J = 16.0, 8.0 Hz, 2H), 2.70 (t, J = 7.2 Hz, 2H), 2.63-2.56 (m, 2H), 2.22-2.17 (m, 2H), 1.88-1.74 (m, 6H), 1.62-1.58 (m, 2H), 1.28 (t, J = 6.8 Hz, 6H).

[0582] Example 29:

[0583] Step 1: Preparation of 29

[0584] In a single-necked flask, 28 (26 mg, 0.03 mmol) was dissolved in concentrated hydrochloric acid (2 mL) and the reaction was stirred at 100 °C under nitrogen overnight. After the reaction was completed, the solvent was evaporated under reduced pressure and the crude product was purified by preparative high performance liquid chromatography to give the hydrochloride salt of compound 29. LCMS (method A), Rt = 1.278 min; MS Calcd.: 723.3; MS Found: 723.9 [M+H] + HPLC (method H), Rt = 5.304 min; MS Calcd.: 723.3; MS Found: 723.9 [M+H] + .

[0585] 1HNMR (400 MHz, CD3OD) δ: 7.51 (s, 2H), 7.42-7.33 (m, 6H), 7.15 (s, 1H), 7.09 (d, J = 9.2 Hz, 2H), 4.33-4.28 (m, 6H), 3.56 (dd, J = 11.6, 8.0 Hz, 2H), 3.45-3.39 (m, 2H), 3.29-3.25 (m, 2H), 3.14 (dd, J = 11.2, 10.0 Hz, 2H), 2.96 (d, J = 7.6 Hz, 4H), 2.85 (q, J = 16.0, 7.2 Hz, 2H), 2.70 (t, J = 7.2 Hz, 2H), 2.61-2.56 (m, 2H), 2.22-2.17 (m, 2H), 1.88-1.82 (m, 2H), 1.78-1.70 (m, 4H), 1.66-1.58 (m, 2H).

[0586] Example 30:

[0587] Step 1: Preparation of 30-b

[0588] In a single-necked reaction flask, 3-fluoro-5-hydroxybenzaldehyde (30-a, 2.50 g, 17.84 mmol) was dissolved in tetrahydrofuran (60 mL), the reaction was placed in an ice-water bath, sodium borohydride (881 mg, 23.19 mmol) was added in portions, then the ice-water bath was removed, the reaction was stirred at room temperature overnight. After the reaction was completed, saturated aqueous ammonium chloride solution (50 mL) was added to quench the reaction, and extracted with ethyl acetate (30 mL x 3), the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to give the crude product 30-b (2.30 g, yield: 91%, purity: >99%) as a colorless oil, which was used directly in the next step. LCMS (method C), Rt= 0.482 min; MS Calcd.: 142.0; MS Found: no mass response.

[0589] Step 2: Preparation of 30-c

[0590] In a single-necked reaction flask, 30-b (2.30 g, 16.18 mmol), iodo methyl phosphonic acid diethyl ester (4.95 g, 17.80 mmol) and cesium carbonate (5.80 g, 17.80 mmol) were dissolved in N,N-dimethylformamide (50 mL), the reaction was stirred at 80 °C overnight under nitrogen protection. After the reaction was completed, saturated aqueous ammonium chloride solution (60 mL) was added to quench the reaction, and extracted with ethyl acetate (50 mL x 3), the combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography [petroleum ether: methyl tert-butyl ether (v / v) = (100:0 = 20:80)] to obtain 30-c (1.80 g, yield: 38%, purity: 50.44%) as a light yellow oil. LCMS (method C), Rt= 0.687 min; MS Calcd.: 292.1; MS Found: 293.2 [M+H] + .

[0591] Step 3: Preparation of 30-d

[0592] In a single-necked reaction flask, 30-c (300 mg, 1.03 mmol) and (chloromethylene)dimethylammonium chloride (198 mg, 1.54 mmol) were dissolved in dichloromethane (10 mL). Stirring at room temperature for 1 hour under nitrogen protection. After the reaction was completed, saturated aqueous sodium bicarbonate solution (10 mL) was added to quench the reaction, and extracted with dichloromethane (15 mL x 3), the combined organic phase was washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to obtain a crude product as colorless oil 30-d (300 mg, yield: 94%, purity: 85.61%), which was directly used in the next step reaction. LCMS (method C), Rt= 0.876 min; MS Calcd.: 310.0; MS Found: 311.1 [M+H] + .

[0593] Step 4: Preparation of 30-e

[0594] In a single-necked flask, 30-d (300 mg, 0.97 mmol), A (611 mg, 0.77 mmol), potassium iodide (161 mg, 0.97 mmol) and cesium carbonate (348 mg, 1.07 mmol) were dissolved in N,N-dimethylformamide (10 mL). The reaction was stirred at 80 °C overnight under nitrogen protection. After the reaction was completed, saturated ammonium chloride (20 mL) was added to quench the reaction, and extracted with ethyl acetate (20 mL x 3), the organic phase was combined and washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography [dichloromethane:methanol (v / v) = (100:0-91:9)] to obtain 30-e (300 mg, yield: 36%, purity: 59.02%) as a light yellow oil. LCMS (method G), Rt= 1.807 min; MS Calcd.: 1065.6; MS Found: 1067.4 [M+H] + .

[0595] Step 5: Preparation of 30

[0596] In a single-necked flask, 30-e (80 mg, 0.08 mmol) was dissolved in 2 mol / L hydrochloric acid in acetic acid solution (2 mL), and the reaction was stirred at room temperature overnight under nitrogen protection. After the reaction was completed, the solvent was evaporated under reduced pressure to obtain a crude product, which was purified by preparative high performance liquid chromatography to obtain the hydrochloride salt of compound 30. LCMS (method A), Rt= 1.437 min; MS Calcd.: 753.4; MS Found: 755.0 [M+H] + HPLC (method H), Rt= 6.418 min; MS Calcd.: 753.4; MS Found: 754.8 [M+H] + .

[0597] 1H NMR (400 MHz, CD3OD) δ: 7.54 (s, 2H), 7.40-7.34 (m, 6H), 7.07 (s, 1H), 6.95-6.92 (m, 2H), 4.48 (d, J = 10.0 Hz, 2H), 4.34-4.29 (m, 4H), 4.28-4.25 (m, 2H), 4.23-4.20 (m, 2H), 3.58-3.54 (m, 2H), 3.46-3.39 (m, 2H), 3.30-3.25 (m, 2H), 3.17-3.12 (m, 2H), 2.98-2.95 (m, 4H), 2.86 (q, J = 8.0 Hz, 2H), 2.62 (q, J = 8.0 Hz, 2H), 2.23-2.16 (m, 2H), 1.89-1.80 (m, 2H), 1.36 (t, J = 7.2 Hz, 6H).

[0598] Example 31:

[0599] Step 1: Preparation of 31

[0600] In a single-necked flask, 30-e (120 mg, 0.11 mmol) was dissolved in concentrated hydrochloric acid (4 mL) and the reaction was stirred at 95 °C under nitrogen overnight. After the reaction was completed, the solvent was evaporated under reduced pressure to give the crude product which was purified by preparative high performance liquid chromatography to give the hydrochloride salt of compound 31. LCMS (method E), Rt = 1.130 min; MS Calcd.: 697.3; MS Found: 698.2 [M+H] + HPLC (method J), Rt = 4.742 min; MS Calcd.: 697.3; MS Found: no mass response.

[0601] 1 H NMR (400 MHz, CD3OD) δ: 7.54 (s, 2H), 7.42-7.33 (m, 6H), 7.06 (s, 1H), 6.91 (dd, J = 9.2, 1.2 Hz, 2H), 4.38-4.34 (m, 4H), 4.30-4.28 (m, 4H), 3.59-3.54 (m, 2H), 3.45-3.39 (m, 2H), 3.30-3.25 (m, 2H), 3.14-3.11 (m, 2H), 2.97-2.86 (m, 4H), 2.87 (q, J = 8.0 Hz, 2H), 2.60 (q, J = 8.4 Hz, 2H), 2.22-2.18 (m, 2H), 1.88-1.82 (m, 2H).

[0602] Example 32:

[0603] Step 1: Preparation of 32-b

[0604] In a single-necked reaction flask, 3-fluoro-5-hydroxybenzoic acid (32-a, 4.50 g, 28.83 mmol) was dissolved in ethanol (60 mL), the reaction was placed in an ice water bath, and thionyl chloride (343 mg, 2.88 mmol) was added dropwise slowly, then the ice water bath was removed, and the reaction was stirred at 80 °C overnight. After the reaction was completed, the solvent was removed by evaporation under reduced pressure, and the crude product was purified by silica gel column chromatography [petroleum ether: methyl tert-butyl ether (v / v) = (100:0 = 85:15)] to obtain colorless oil 32-b (5.00 g, yield: 94%, purity: >95%).

[0605] 1 HNMR (400 MHz, CDC13) δ: 7.42 (t, J = 1.6 Hz, 1H), 7.31-7.28 (m, 1H), 6.82-6.78 (m, 1H), 6.12 (s, 1H), 4.39 (q, J = 6.8 Hz, 2H), 1.40 (t, J = 7.2 Hz, 3H).

[0606] Step 2: Preparation of 32-c

[0607] In a single-necked reaction flask, 32-b (3.00 g, 16.29 mmol), iodo methyl phosphonic acid diethyl ester (4.98 g, 17.92 mmol), and cesium carbonate (5.84 g, 17.92 mmol) were dissolved in N,N-dimethylformamide (50 mL), and the reaction was stirred at 70 °C for 5 hours under nitrogen protection. After the reaction was completed, saturated aqueous ammonium chloride solution (60 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (50 mL x 3), the organic phase was combined and washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography [petroleum ether: methyl tert-butyl ether (v / v) = (100:0 = 60:40)] to obtain yellowish oil 32-c (2.00 g, yield: 37%, purity: 60.39%). LCMS (method C), Rt = 0.883 min; MS Calcd.: 334.1; MS Found: 335.2 [M+H] + .

[0608] Step 3: Preparation of 32-d

[0609] In a single-necked reaction flask, 32-c (2.00 g, 5.98 mmol) was dissolved in dichloromethane (60 mL), the reaction was placed in an ice-water bath under nitrogen protection, pyridine (9.44 g, 119.60 mmol) and trimethylsilyl bromide (9.20 g, 59.80 mmol) were added dropwise successively, the ice-water bath was removed, and the reaction was stirred at room temperature overnight. After the reaction was completed, 1 mol / L dilute hydrochloric acid was added to adjust the reaction pH to 2-3, and extracted with ethyl acetate (50 mL x 3), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to remove the solvent. The crude product was purified by preparative high performance liquid chromatography, evaporated under reduced pressure to remove acetonitrile, and freeze-dried to remove water to obtain white solid 32-d (1.20 g, yield: 72%, purity: 97.07%). LCMS (method C), Rt = 0.467 min; MS Calcd.: 278.0; MS Found: 279.2 [M+H] + .

[0610] Step 4: Preparation of 32-e

[0611] In a single-necked reaction flask, 32-d (1.10 g, 3.95 mmol), (S)-1-(3-chlorophenyl)-1,3- propanediol (1.10 g, 5.93 mmol), N,N'-dicyclohexylcarbodiimide (3.26 g, 15.80 mmol) and pyridine (1.87 g, 23.70 mmol) were dissolved in anhydrous N,N-dimethylformamide (40 mL), the reaction was stirred at room temperature overnight under nitrogen protection. After the reaction was completed, saturated ammonium chloride solution (40 mL) was added to quench the reaction, and extracted with ethyl acetate (30 mL x 3), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to remove the solvent. The crude product was purified by silica gel column chromatography [dichloromethane:methanol (v / v) = (100:0-93:7)] to obtain colorless oil 32-e (1.00 g, yield: 58%, purity: >99%). LCMS (method C), Rt = 0.962 min; MS Calc d.: 428.1; MS Found: 446.1 [M+NH4] + .

[0612] Step 5: Preparation of 32-f

[0613] In a single necked flask, 32-e (500 mg, 1.17 mmol) was dissolved in tetrahydrofuran (15 mL), the reaction was placed in an ice water bath under nitrogen protection, lithium borohydride (1.2 mL, 2.40 mmol, 2 mol / L in tetrahydrofuran) was added dropwise slowly, the ice water bath was removed, the reaction was stirred at room temperature overnight. After the reaction was completed, saturated ammonium chloride solution (10 mL) was added to quench the reaction, and extracted with ethyl acetate (15 mL x 3), the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was evaporated under reduced pressure, the crude product was purified by silica gel column chromatography [dichloromethane:methanol (v / v) = (100:0-90:10)], to give colorless oil 32-f (380 mg, yield: 84%, purity: 68.46%). LCMS (method C), Rt = 0.570 min and 0.580 min; MS Calcd.: 386.1; MS Found: 387.1 [M+H] + .

[0614] Step 6: Preparation of 32-g

[0615] In a single necked flask, 32-f (300 mg, 0.78 mmol) and N,N-diisopropylethylamine (201 mg, 1.56 mmol) were dissolved in tetrahydrofuran (10 mL), cooled with ice water bath, then methyl sulfonyl chloride (100 mg, 0.86 mmol) was added, the reaction was stirred at 0 °C for 1 hour under nitrogen protection. After the reaction was completed, the reaction was quenched with water (10 mL), extracted with ethyl acetate (10 mL x 3), the combined organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was evaporated under reduced pressure, to give the crude product as a light yellow oil 32-g (288 mg, yield: 80%, purity: 57.76%), which was used directly in the next step reaction. LCMS (method C), Rt = 0.640 min and 0.669 min; MS Calcd.: 464.0; MS Found: 465.0 [M+H] + .

[0616] Step 7: Preparation of 32-h

[0617] In a single-necked reaction flask, 32-g (288 mg, 0.62 mmol), A (490 mg, 0.62 mmol), potassium iodide (102 mg, 0.62 mmol) and cesium carbonate (263 mg, 0.81 mmol) were dissolved in N,N-dimethylformamide (8 mL). Stirring was carried out at 70 °C for 2 hours under nitrogen protection. After the reaction was completed, saturated ammonium chloride (10 mL) was added to quench the reaction, and extracted with ethyl acetate (15 mL x 3), the organic phase was combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography [dichloromethane:methanol (v / v) = (100:0-91:9)] to obtain 32-h (140 mg, yield: 20%, purity: 52.78%) as a light yellow oil. LCMS (method G), Rt = 1.808 min; MS Calcd.: 1159.5; MS Found: 1160.4 [M+H] + .

[0618] Step 8: Preparation of 32

[0619] In a single-necked reaction flask, 32-h (140 mg, 0.12 mmol) was dissolved in trifluoroacetic acid (1 mL) and dichloromethane (3 mL). Stirring was carried out at room temperature for 3 hours under nitrogen protection. After the reaction was completed, the reaction was evaporated under reduced pressure to obtain a crude product, which was purified by preparative high performance liquid chromatography, evaporated under reduced pressure to remove acetonitrile, and dried to obtain a trifluoroacetate salt of compound 32. LCMS (method E) Rt = 1.427 min; MS Calcd.: 847.3; MS Found: 848.2 [M+H] + HPLC (method I) Rt = 5.708 min and 5.184 min; MS Calcd.: 847.3; MS Found: 848.1 [M+H] + .

[0620] 1HNMR (400 MHz, CD3OD) δ: 7.44-7.26 (m, 12H), 6.98-6.82 (m, 3H), 5.85-5.75 (m, 1H), 4.89-4.88 (m, 1H), 4.71 (d, J = 9.6 Hz, 1H), 4.63-4.56 (m, 1H), 4.01-3.88 (m, 5H), 3.53-3.45 (m, 3H), 3.42-3.36 (m, 3H), 3.26-3.19 (m, 2H), 3.10-3.04 (m, 2H), 2.99-2.89 (m, 4H), 2.80-2.75 (m, 2H), 2.61-2.50 (m, 2H), 2.42-2.13 (m, 4H), 1.89-1.79 (m, 2H).

[0621] Example 33:

[0622] Step 1: Preparation of 33-a

[0623] In a single-necked reaction flask, A-1 (1.50 g, 6.54 mmol), O-tert-butyl-N,N'- diisopropylisourea (1.31 g, 6.54 mmol) and tetrahydrofuran (33 mL) were added and the reaction was stirred at 70 °C for 2 h under nitrogen protection, then O-tert-butyl-N,N'- diisopropylisourea (1.31 g, 6.54 mmol) was added and the reaction was stirred at 70 °C overnight. After the reaction was completed, the filtrate was evaporated under reduced pressure to remove the solvent, and the crude product was purified by silica gel column chromatography [petroleum ether: methyl tert-butyl ether (v / v) = (100:0-32:68)] to obtain 33-a (900 mg, yield: 48%, purity: 61.07%) as a transparent oil. LCMS (method C), Rt = 1.038 min; MS Calcd.: 285.2; MS Found: 174.3 [M-112+H] + .

[0624] Step 2: Preparation of 33-c-P1 & P2

[0625] In a three-necked flask, was charged with 33-a (300 mg, 1.05 mmol) and anhydrous tetrahydrofuran (15 mL), the reaction was placed under nitrogen protection, and was put in dry ice acetone bath, lithium bis(trimethylsilyl)amide (1.5 mL, 1.50 mmol, 1 mol / L tetrahydrofuran solution) was added dropwise slowly, the reaction was stirred at -70 °C for 1 hour. Then 33-b (397 mg, 1.58 mmol) was dissolved in anhydrous tetrahydrofuran (8 mL) and was added to the above reaction solution at -70 °C, the dry ice acetone bath was removed, and the reaction was stirred at room temperature for 2 hours. After the reaction was completed, saturated aqueous ammonium chloride solution (20 mL) was added to quench the reaction, and extracted with ethyl acetate (15 mL x 3), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to remove the solvent, and the crude product was purified by silica gel column chromatography [petroleum ether: methyl tert-butyl ether (v / v) = (100:0-42:58-30:70)] to obtain yellowish oil 33-c-P1 (110 mg, yield: 23%, purity: 81.62%) and yellowish oil 33-c-P2 (200 mg, yield: 42%, purity: 74.57%).

[0626] 33-c-P1: LCMS (method C), Rt = 1.112 min; MS Calcd.: 455.1; MS Found: 344.1 [M-112+H] + .

[0627] 1 HNMR (400 MHz, CDC13) δ: 8.58 (d, J = 1.6 Hz, 1H), 8.21 (d, J = 0.8 Hz, 1H), 3.66-3.61 (m, 1H), 3.54-3.49 (m, 1H), 3.30-3.23 (m, 1H), 3.11-3.02 (m, 2H), 2.89-2.84 (m, 1H), 2.77-2.71 (m, 1H), 2.44-2.38 (m, 1H), 2.02-1.95 (m, 1H), 1.74-1.68 (m, 1H), 1.46 (s, 9H), 1.34 (s, 9H).

[0628] 33-c-P2: LCMS (method C), Rt = 1.108 min; MS Calcd.: 455.1; MS Found: 344.1 [M-112+H] + .

[0629] 1HNMR (400 MHz, CDC13) δ: 8.58 (d, J = 1.2 Hz, 1H), 8.22 (d, J = 1.2 Hz, 1H), 3.58-3.50 (m, 2H), 3.30-3.23 (m, 1H), 3.13-3.05 (m, 2H), 2.97-2.92 (m, 1H), 2.77-2.71 (m, 1H), 2..43-2.37 (m, 1H), 2.13-2.07 (m, 1H), 1.70-1.60 (m, 1H), 1.46 (s, 9H), 1.34 (s, 9H).

[0630] Step 3: Preparation of 33-d-P1 & P2

[0631] In a single necked reaction flask, was taken 33-c-P1 (110 mg, 0.24 mmol), Pd(dppf)Cl2(14 mg, 0.02 mmol), potassium acetate (47 mg, 0.48 mmol) and ethanol (6 mL), replaced the gas three times with a carbon monoxide balloon, then the reaction was stirred at 90 °C overnight under an atmosphere of carbon monoxide gas. After completion of the reaction, the filtrate was evaporated under reduced pressure to remove the solvent, the crude product was purified by silica gel column chromatography [petroleum ether: methyl-tert-butyl ether (v / v) = (100:0 - 29:71)] to get 33-d-P1 (86 mg, yield: 79%, purity: 93.07%) as a clear oil. LCMS (method C), Rt= 1.040 min; MS Calcd.: 449.2; MS Found: 394.3 [M-56+H] + .

[0632] In a single necked reaction flask, was taken 33-c-P2 (200 mg, 0.44 mmol), Pd(dppf)Cl2(28 mg, 0.04 mmol), potassium acetate (86 mg, 0.88 mmol) and ethanol (10 mL), replaced the gas three times with a carbon monoxide balloon, then the reaction was stirred at 90 °C overnight under an atmosphere of carbon monoxide gas. After completion of the reaction, the filtrate was evaporated under reduced pressure to remove the solvent, the crude product was purified by silica gel column chromatography [petroleum ether: methyl-tert-butyl ether (v / v) = (100:0 - 29:71)] to get 33-d-P2 (160 mg, yield: 81%, purity: 85.16%) as a clear oil. LCMS (method C), Rt= 1.031 min; MS Calcd.: 449.2; MS Found: 338.2 [M-112+H] + .

[0633] Step 4: Preparation of 33-e-P1 & P2

[0634] In a single-necked reaction flask, 33-d-P1 (86 mg, 0.19 mmol) and 2 mol / L aqueous sodium hydroxide solution (0.2 mL, 0.40 mmol) were dissolved in ethanol (2 mL). Stirring at room temperature for 5 hours. After the reaction was completed, the reaction solution was adjusted to pH 6-7 with 1 mol / L dilute hydrochloric acid, and extracted with ethyl acetate (10 mL x 3), the combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to obtain a crude product as a light yellow oil 33-e-P1 (75 mg, yield: 93%, purity: 81.88%), which was directly used in the next step reaction. LCMS (method C), Rt= 0.671 min; MS Calcd.: 421.2; MS Found: 310.1 [M-112+H] + .

[0635] In a single-necked reaction flask, 33-d-P2 (160 mg, 0.36 mmol) and 2 mol / L aqueous sodium hydroxide solution (0.4 mL, 0.80 mmol) were dissolved in ethanol (5 mL). Stirring at room temperature for 6 hours. After the reaction was completed, the reaction solution was adjusted to pH 6-7 with 1 mol / L dilute hydrochloric acid, and extracted with ethyl acetate (15 mL x 3), the combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to obtain a crude product as a light yellow oil 33-e-P2 (140 mg, yield: 93%, purity: 86.21%), which was directly used in the next step reaction. LCMS (method C), Rt= 0.654 min; MS Calcd.: 421.2; MS Found: 310.2 [M-112+H] + .

[0636] Step 5: Preparation of 33-f-P1 & P2

[0637] In a single-necked flask, 33-e-P1 (75 mg, 0.18 mmol), A (142 mg, 0.18 mmol), N,N,N',N'-tetramethylchloroformamidium hexafluorophosphate (76 mg, 0.27 mmol) and N-methylimidazole (45 mg, 0.54 mmol) were dissolved in N,N-dimethylformamide (3 mL). After stirring at room temperature overnight under nitrogen protection, water (6 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phase was combined and washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography [petroleum ether: methyl tert-butyl ether (v / v) = (100:0-50:50)] to give 33-f-P1 (120 mg, yield: 56%, purity: 82.33%) as a colorless oil. LCMS (method G), Rt= 2.705 min; MS Calcd.: 1194.7; MS Found: no mass response.

[0638] In a single-necked flask, 33-e-P2 (140 mg, 0.33 mmol), A (261 mg, 0.33 mmol), N,N,N',N'-tetramethylchloroformamidium hexafluorophosphate (141 mg, 0.50 mmol) and N-methylimidazole (55 mg, 0.66 mmol) were dissolved in DMF (8 mL). After stirring at room temperature overnight under nitrogen protection, water (10 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (15 mL x 3). The organic phase was combined and washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography [petroleum ether: methyl tert-butyl ether (v / v) = (100:0-50:50)] to give 33-f-P2 (200 mg, yield: 50%, purity: 83.40%) as a colorless oil. LCMS (method G), Rt= 2.683 min; MS Calcd.: 1194.7; MS Found: no mass response.

[0639] Step 6: Preparation of 33-P1 & P2

[0640] In a single necked flask, 33-f-P1 (120 mg, 0.10 mmol) was dissolved in hydrochloric acid in acetic acid (3 mL, 2 mol / L hydrochloric acid in acetic acid). Stirring at room temperature for 4 hours under nitrogen protection. After the reaction was completed, the solvent was removed by reduced pressure evaporation, and the crude product was purified by prep-HPLC, acetonitrile was removed by reduced pressure evaporation, and water was removed to obtain the hydrochloride of compound 33-P1. LCMS (method E) Rt = 1.175 min; MS Calcd.: 726.4; MS Found: 727.3 [M+H] + .HPLC (method I) Rt = 4.737 min; MS Calcd.: 726.4; MS Found: 727.3 [M+H] + .

[0641] 1 HNMR (400 MHz, CD3OD) δ: 8.81 (d, J = 1.2 Hz, 1H), 8.58 (d, J = 0.8 Hz, 1H), 7.33-7.28 (m, 1H), 7.25-7.16 (m, 5H), 7.12 (s, 1H), 7.04 (d, J = 7.2 Hz, 1H), 4.66 (d, J = 2.8 Hz, 2H), 4.55 (s, 2H), 3.61-3.56 (m, 1H), 3.55-3.48 (m, 2H), 3.46-3.38 (m, 3H), 3.30-3.23 (m, 3H), 3.20-3.03 (m, 6H), 2.98-2.88 (m, 4H), 2.82-2.74 (m, 2H), 2.64-2.53 (m, 3H), 2.26-2.18 (m, 3H), 1.89-1.82 (m, 3H).

[0642] In a single necked flask, 33-f-P2 (200 mg, 0.17 mmol) was dissolved in hydrochloric acid in acetic acid (4 mL, 2 mol / L hydrochloric acid in acetic acid). Stirring at room temperature for 3 hours under nitrogen protection. After the reaction was completed, the solvent was removed by reduced pressure evaporation, and the crude product was purified by prep-HPLC, acetonitrile was removed by reduced pressure evaporation, and water was removed to obtain the hydrochloride of compound 33-P2. LCMS (method E) Rt = 1.194 min; MS Calcd.: 726.4; MS Found: 727.3 [M+H] + .HPLC (method I) Rt = 4.759 min; MS Calcd.: 726.4; MS Found: 364.4 [1 / 2M+H] + .

[0643] 1HNMR (400 MHz, CD3OD) δ: 8.80 (d, J = 1.2 Hz, 1H), 8.56 (d, J = 1.2 Hz, 1H), 7.33-7.27 (m, 1H), 7.25-7.16 (m, 5H), 7.12 (s, 1H), 7.04 (d, J = 7.2 Hz, 1H), 4.66 (d, J = 3.6 Hz, 2H), 4.55 (s, 2H), 3.55-3.47 (m, 3H), 3.46-3.37 (m, 3H), 3.30-3.18 (m, 5H), 3.14-3.03 (m, 4H), 2.99-2.88 (m, 4H), 2.81-2.72 (m, 2H), 2.66-2.50 (m, 3H), 2.37-2.29 (m, 1H), 2.23-2.18 (m, 2H), 1.91-1.77 (m, 3H).

[0644] Example 34:

[0645] Step 1: Preparation of 34-b

[0646] In a single-necked reaction flask, 2-b (4.40 g, 3.38 mmol) was dissolved in anhydrous N,N-dimethylformamide (50 mL). The reaction flask was cooled with an ice-water bath, and sodium hydride (176 mg, 4.39 mmol, 60 wt%) was added portionwise under nitrogen protection. The reaction was stirred for 0.5 h in an ice-water bath, and then 34-a (2.02 g, 10.13 mmol) was added. The reaction was stirred overnight at room temperature under nitrogen protection. After the reaction was completed, the reaction was quenched by the addition of saturated aqueous ammonium chloride solution (50 mL), and extracted with ethyl acetate (40 mL x 3). The organic phase was combined and washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography [petroleum ether: methyl tert-butyl ether (v / v) = (100:0-36:64)] to obtain 34-b (1.40 g, yield: 20%, purity: 93.10%) as a colorless oil. LCMS (method C), Rt = 1.185 min; MS Calcd.: 459.3; MS Found: 348.3 [M-112+H] + .

[0647] Step 2: Preparation of 34-c

[0648] In a single-necked reaction flask, 34-b (1.40 g, 3.05 mmol) and 10% Pd / C (140 mg) were dissolved in isopropanol (30 mL). The gas was replaced with a hydrogen balloon for three times and stirred at 60 °C overnight under hydrogen atmosphere. After the reaction was completed, the reaction solution was filtered with celite, and the filtrate was evaporated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography [petroleum ether: methyl tert-butyl ether (v / v) = (100:0-90:10)] to obtain 34-c (1.25 g, yield: 89%, purity: >99%) as a colorless oil. LCMS (method C), Rt = 1.225 min; MS Calcd.: 461.1; MS Found: 306.3 [M-156+H] + .

[0649] Step 3: Preparation of 34-d

[0650] In a single-necked reaction flask, 34-c (1.20 g, 2.60 mmol) and 2 mol / L aqueous sodium hydroxide solution (2.6 mL, 5.20 mmol) were dissolved in ethanol (10 mL), and the reaction was stirred at room temperature for 3 hours. After the reaction was completed, the pH of the reaction solution was adjusted to 5-6 with 1 mol / L dilute hydrochloric acid, and extracted with ethyl acetate (30 mL x 3), and the combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to obtain a crude product as a colorless oil 34-d (1.10 g, yield: 98%, purity: >99%), which was directly used in the next reaction. LCMS (method C), Rt = 0.757 min; MS Calcd.: 433.2; MS Found: 322.2 [M-112+H] + .

[0651] Step 4: Preparation of 34-e

[0652] In a single-necked reaction flask, 34-d (900 mg, 2.08 mmol) and triethylamine (273 mg, 2.70 mmol) were dissolved in tetrahydrofuran (20 mL). The reaction was cooled with an ice-water bath, then isobutyl chloroformate (312 mg, 2.28 mmol) was added. The reaction was stirred at room temperature for 1 h under nitrogen protection. In another single-necked reaction flask, sodium borohydride (158 mg, 4.16 mmol) and water (5 mL) were added and the reaction was cooled with an ice-water bath. The tetrahydrofuran solution of the active ester synthesized in the previous step was added dropwise slowly. The reaction was stirred at room temperature overnight. After the reaction was completed, water (20 mL) was added to quench the reaction and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phase was combined and washed with saturated brine (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography [petroleum ether: methyl tert-butyl ether (v / v) = (100:0-60:40)] to give 34-e (600 mg, yield: 69%, purity: >95%) as a colorless oil. LCMS (method C), Rt= 1.059 min; MS Calcd.: 419.3; MS Found: 320.4 [M-100+H] + .

[0653] Step 5: Preparation of 34-f

[0654] In a single-necked reaction flask, 34-e (200 mg, 0.47 mmol) and (chloromethylene)dimethylammonium chloride (121 mg, 0.94 mmol) were dissolved in dichloromethane (10 mL). The reaction was stirred at room temperature for 1 h under nitrogen protection. After the reaction was completed, saturated aqueous sodium bicarbonate solution (10 mL) was added to quench the reaction and the mixture was extracted with dichloromethane (15 mL x 3). The organic phase was combined and washed with saturated brine (10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product 34-f (210 mg, yield: 67%, purity: 66.92%) as a colorless oil. The crude product was used directly in the next step. LCMS (method C), Rt= 1.222 min; MS Calcd.: 437.2; MS Found: 326.2 [M-112+H] + .

[0655] Step 6: Preparation of 34-g

[0656] In a single-necked reaction flask, 34-f (210 mg, 0.47 mmol), A (297 mg, 0.38 mmol), potassium iodide (77 mg, 0.47 mmol), and cesium carbonate (306 mg, 0.94 mmol) were dissolved in N,N-dimethylformamide (10 mL). The reaction was stirred at 80 °C for 1 h under nitrogen protection. After the reaction was completed, the reaction was cooled to room temperature and water (20 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (30 mL x 3). The organic phase was combined and washed with saturated brine (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography [petroleum ether: methyl tert-butyl ether (v / v) = (100:0-60:40)] to give 34-g (100 mg, yield: 34%, purity: 100%) as a colorless oil. LCMS (method C), Rt= 1.222 min; MS Calcd.: 437.2; MS Found: 326.2 [M-112+H]

[0657] N,N-dimethylformamide (6 mL). Stirring at 70 °C overnight under nitrogen protection. After the reaction was completed, saturated ammonium chloride (10 mL) was added to quench the reaction, and extracted with ethyl acetate (15 mL x 3), the organic phase was combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography [petroleum ether: methyl tert-butyl ether (v / v) = (100:0-60:40)] to obtain colorless oil 34-g (170 mg, yield: 37%, purity: 89.19%). LCMS (method G), Rt = 1.878 min; MS Calcd.: 1192.8; MS Found: 1194.6 [M+H] + .

[0658] Step 7: Preparation of 34

[0659] In a single-mouth reaction bottle, 34-g (170 mg, 0.14 mmol) was dissolved in hydrochloric acid acetic acid solution (4 mL, 2 mol / L hydrochloric acid acetic acid solution). Stirring at room temperature for 3 hours under nitrogen protection. After the reaction was completed, the reaction was evaporated under reduced pressure to obtain a crude product, which was purified by preparative high performance liquid chromatography, evaporated under reduced pressure to remove acetonitrile, and dried to obtain hydrochloride of compound 34. LCMS (method A) Rt = 1.190 min; MS Calcd.: 724.4; MS Found: 363.6 [1 / 2M+H] + HPLC (method J) Rt = 4.312 min; MS Calcd.: 724.4; MS Found: no mass response.

[0660] 1 HNMR (400 MHz, CD3OD) δ: 7.53 (br, 3H), 7.41-7.37 (m, 9H), 4.34-4.26 (m, 6H), 3.64-3.53 (m, 3H), 3.45-3.39 (m, 2H), 3.30-3.23 (m, 4H), 3.15 (t, J = 10.4 Hz, 2H), 3.07-2.96 (m, 6H), 2.92-2.86 (m, 3H), 2.65-2.55 (m, 2H), 2.26-2.12 (m, 3H), 2.07-1.95 (m, 3H), 1.90-1.80 (m, 3H), 1.69-1.59 (m, 1H).

[0661] Example 35:

[0662] Step 1: Preparation of 35-a

[0663] Take a reaction flask, add A-5 (1.0 g, 1.0 eq), dioxane (10 mL), H20 (8 mL), KOH (0.45 g, 4.0 eq), tris(dibenzylideneacetone)dipalladium (0.091 g, 0.05 eq) and 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (0.085 g, 0.1 eq) in sequence, replace with nitrogen ball for 3 times, stir the reaction at 80 °C for 6 hours. Monitor the reaction completion by LCMS, add 20 mL water to the reaction, then separate the liquid, extract the water phase with ethyl acetate (3*15 mL), wash the combined organic phase with saturated NaCl solution (3*20 mL), dry, filter and rotary evaporate, purify the crude product by normal phase flash preparative liquid chromatography to obtain 35-a (0.75 g, yield: 87%, purity: 100%) as brown oil. LCMS: 35-a (Rt = 3.089 min, MS Found: 392 [M+H] + )

[0664] Step 2: Preparation of 35-c

[0665] Take a reaction flask, add 35-a (0.75 g, 1.0 eq), 35-b (0.43 g, 1.1 eq) and dichloromethane (10 mL) in sequence, then add triethylamine (0.48 g, 2.5 eq), stir the reaction at room temperature for 1 hour. Monitor the reaction completion by LCMS, directly load the reaction liquid on silica gel, purify by normal phase flash preparative liquid chromatography to obtain 35-c (0.50 g, yield: 41%, purity: 93%) as white solid. LCMS: 35-c (Rt = 3.500 min, MS Found: 578.76 [M+Na] + )

[0666] Step 3: Preparation of 35-d

[0667] Take a reaction flask, add 35-c (0.50 g, 1.0 eq), A (0.78 g, 1.1 eq), N-methylpyrrolidone (10 mL) in sequence, react at room temperature overnight. Monitor the reaction completion by LCMS, add 20 mL water to the reaction, then separate the liquid, extract the water phase with ethyl acetate (3*15 mL), wash the combined organic phase with saturated NaCl solution (3*20 mL), dry, filter and rotary evaporate, purify the crude product by normal phase flash preparative liquid chromatography to obtain 35-d (1.2 g, yield: 93%, purity: 85%) as brown oil. LCMS: 35-d (Rt = 9.824 min, MS Found: 1231.92 [M+Na] + )

[0668] Step 3: Preparation of 35

[0669] Take a reaction bottle, add 35-d (0.30 g, 1.0 eq) and hydrochloric acid acetic acid solution (4 mL, 2 mol / L hydrochloric acid acetic acid solution) in turn, stir at room temperature for 2 hours, monitor the reaction completion by LCMS, directly prepare the reaction liquid for purification, freeze-drying to obtain compound 35. LCMS: 35 (Rt = 1.588 min, MS Found: 741.22 [M+H] + )

[0670] 1 HNMR (400 MHz, CD3OD) δ: 7.33-7.24 (m, 3H), 7.21-7.11 (m, 7H), 7.06 (t, J = 2.0 Hz, 1H), 7.01-6.97 (m, 1H), 4.55 (s, 2H), 4.48 (s, 2H), 3.54-3.43 (m, 3H), 3.42-3.33 (m, 3H), 3.26-3.16 (m, 3H), 3.09-2.92 (m, 6H), 2.91-2.85 (m, 3H), 2.84-2.71 (m, 3H), 2.61-2.45 (m, 3H), 2.21-2.11 (m, 3H), 1.89-1.74 (m, 3H).

[0671] Example 36:

[0672] Step 1: Preparation of 36-b

[0673] In a 100 ml round-bottom flask, 4-d (4.0 g, 8.8 mmol), 36-a (2.0 g, 26.4 mmol) and K2CO3 (6.1 g, 44.0 mmml) were dissolved in dimethyl sulfoxide (20 mL) and reacted at 80 °C for 12 hours. The reaction was quenched by adding water (50 mL x 2) and extracted with ethyl acetate (100 mL x 3). The combined organic phase was washed with saturated brine, dried and concentrated. The residue was purified by reverse phase column (0.1% HCO2H in H2O: CH3CN (v / v) = (90:10-10:90)) to obtain white solid 36-b (640.3 mg, yield: 19%, purity: 97%). LCMS: Rt = 2.527 min; MS Calcd.: 392.23; MS Found: 414.99 [M+Na] + .

[0674] Step 2: Preparation of 36-c

[0675] In a 50 ml round-bottom flask, 36-b (244.9 mg, 0.62 mmol), 36-c (480.2 mg, 0.56 mmol) and cesium carbonate (230.4 mg, 0.71 mmol) were dissolved in CH3CN (20 mL), and the temperature was raised to 60 °C, and the reaction was allowed to proceed for 60 h. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel [petroleum ether: ethyl acetate (v / v) = (80:20-50:50)] to give 36-d (315.2 mg, yield: 47%, purity: 95%) as a white solid. LCMS: Rt = 8.698 min; MS Calcd.: 1209.72; MS Found: 1232.83 [M+Na] + .

[0676] Step 3: Preparation of 36-d

[0677] In a 50 ml round-bottom flask, 36-b (244.9 mg, 0.62 mmol), 36-c (480.2 mg, 0.56 mmol) and cesium carbonate (230.4 mg, 0.71 mmol) were dissolved in CH3CN (20 mL), and the temperature was raised to 60 °C, and the reaction was allowed to proceed for 60 h. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel [petroleum ether: ethyl acetate (v / v) = (80:20-50:50)] to give 36-d (315.2 mg, yield: 47%, purity: 95%) as a white solid. LCMS: Rt = 8.698 min; MS Calcd.: 1209.72; MS Found: 1232.83 [M+Na] + .

[0678] Step 4: Preparation of 36

[0679] In a 25 mL round-bottom flask, 36-d (310 mg, 0.26 mmol) was dissolved in hydrochloric acid in acetic acid solution (4 mL, 2 mol / L hydrochloric acid in acetic acid solution). The reaction was stirred at room temperature for 3 h under nitrogen protection. After the reaction was completed, the solvent was removed under reduced pressure, and the crude product was purified by preparative high-performance liquid chromatography. The acetonitrile was removed under reduced pressure, and the water was removed by freeze-drying to obtain the hydrochloride salt of compound 36. LCMS: Rt = 2.040 min; MS Calcd.: 741.37; MS Found: 742.04 [M+H] + .

[0680] 1HNMR (400 MHz, CD3OD) δ: 8.49 (d, J = 6.8 Hz, 1H), 7.70-7.64 (m, 2H), 7.34-7.19 (m, 8H), 4.63 (s, 2H), 4.53 (s, 2H), 3.60-3.50 (m, 3H), 3.48-3.34 (m, 3H), 3.28-3.09 (m, 13H), 2.84-2.77 (m, 2H), 2.66-2.56 (m, 3H), 2.27-2.15 (m, 3H), 1.94-1.80 (m, 3H).

[0681] Example 37:

[0682] Step 1: Preparation of 37-a

[0683] In a single-necked reaction flask, 37-a (248 mg) was dissolved in methanol (2 mL), then lithium hydroxide (0.5 mL, 2 mol / L aqueous solution) was added, and stirred at room temperature overnight under nitrogen protection. After the reaction was completed, the PH of the reaction solution was adjusted to 5 with dilute hydrochloric acid, then extracted with EA, and the organic phase was evaporated under vacuum to obtain the crude product, which was purified by silica gel column chromatography [petroleum ether: ethyl acetate (v / v) = (100:0-48:52)] to obtain transparent oil 37-b (210 mg, yield: 88%, purity: 64.46%). LCMS (method D), Rt= 0.662 min; MS Calcd.: 449.2; MS Found: 338.2 [M+56-56+H] + .

[0684] Step 2: Preparation of 37-b

[0685] In a single-necked reaction flask, 37-a (248 mg) was dissolved in methanol (2 mL), then lithium hydroxide (0.5 mL, 2 mol / L aqueous solution) was added, and stirred at room temperature overnight under nitrogen protection. After the reaction was completed, the PH of the reaction solution was adjusted to 5 with dilute hydrochloric acid, then extracted with EA, and the organic phase was evaporated under vacuum to obtain the crude product, which was purified by silica gel column chromatography [petroleum ether: ethyl acetate (v / v) = (100:0-48:52)] to obtain transparent oil 37-b (210 mg, yield: 88%, purity: 64.46%). LCMS (method D), Rt= 0.662 min; MS Calcd.: 449.2; MS Found: 338.2 [M+56-56+H] + .

[0686] Step 3: Preparation of 37-c

[0687] In a single-necked reaction flask, 37-b (240 mg) was dissolved in N,N- dimethylformamide (4 mL), then A (340 mg), N,N,N',N'-tetramethylchloroformamidium hexafluorophosphate (228 mg) and N-methyl imidazole (90 mg) were added successively, and stirred at room temperature overnight under nitrogen protection. After the reaction was completed, the reaction solution was quenched with aqueous ammonium chloride solution, then extracted with EA, and the organic phase was evaporated under vacuum to obtain a crude product which was purified by silica gel column chromatography [petroleum ether: methyl tert-butyl ether (v / v) = (100:0-16:84)] to obtain transparent oil liquid 37-c (597 mg, yield: 91%, purity: 70.33%). LCMS (method G), Rt= 2.784 min.

[0688] Step 4: Preparation of 37

[0689] In a single-necked reaction flask, 37-c (617 mg) was dissolved in dioxane (3 mL), then concentrated hydrochloric acid (3 mL) was added under ice water bath, and stirred at room temperature overnight under nitrogen protection. After the reaction was completed, the solvent was evaporated under reduced pressure to obtain a crude product which was purified by preparative high performance liquid chromatography to obtain compound 37. LCMS (method A), Rt= 1.062 min; MS Calcd.: 754.4; MS Found: 755.3 [M+H] + .

[0690] 1 HNMR (400 MHz, CD3OD) δ: 7.30 (t, J = 8.0 Hz, 1H), 7.25 (t, J = 7.6 Hz, 1H), 7.23-7.16 (m, 3H), 7.11 (s, 2H), 7.10-7.05 (m, 2H), 6.88 (d, J = 7.6 Hz, 1H), 6.84 (s, 1H), 6.77 (dd, J = 8.0, 2.0 Hz, 1H), 4.91 (s, 2H), 4.62-4.55 (m, 4H), 3.60-3.35 (m, 6H), 3.26-3.19 (m, 3H), 3.10-2.99 (m, 3H), 2.97-2.81 (m, 6H), 2.80-2.72 (m, 3H), 2.55-2.49 (m, 3H), 2.20-2.13 (m, 3H), 1.86-1.79 (m, 3H).

[0691] Example 38:

[0692] Step 1: Preparation of 38-a

[0693] In a single-necked flask, 2-f (600 mg) was dissolved in dichloromethane (10 mL), and Dess-Martin Oxidizing Agent (1.09 g) was added at 0 °C, and the reaction was protected by nitrogen. After stirring at room temperature overnight, the reaction was quenched by adding an aqueous solution of sodium thiosulfate (10 mL) and an aqueous solution of sodium bicarbonate (10 mL), and the reaction was extracted with dichloromethane (15 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography [petroleum ether: methyl tert-butyl ether (v / v) = (100:0-75:25)] to obtain 38-a (160 mg, yield: 26%, purity: >99%) as a yellowish oil. LCMS (method C), Rt= 1.051 min; MS Calcd.: 417.3; MS Found: 306.3 [M-56-56+H] + .

[0694] Step 2: Preparation of 38-b

[0695] In a single-necked flask, 38-a (140 mg) and ammonium acetate (310 mg) were dissolved in methanol (4 mL), and the reaction was stirred for 1 min after cooling with an ice water bath. Sodium triacetoxyborohydride (570 mg) was added, and the reaction was stirred at room temperature overnight under nitrogen protection. After the reaction was completed, the reaction was quenched by adding a saturated NaHCO3 solution (5 mL), and the methanol was removed under reduced pressure. The reaction was extracted with ethyl acetate (10 mL x 3), and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography [petroleum ether: methyl tert-butyl ether (v / v) = (100:0-43:57)] to obtain 38-b (60 mg, yield: 42%, purity: 95.96%) as a yellowish oil. LCMS (method G), Rt= 1.785 min; MS Calcd.: 819.4; MS Found: 820.5 [M+H] + .

[0696] Step 3: Preparation of 38-c

[0697] In a single-necked reaction flask, 38-b (50 mg), 2-g (40 mg), cesium carbonate (60 mg) and potassium iodide (10 mg) were dissolved in N,N-dimethylformamide (2 mL). After stirring for 2 hours at 70 °C under nitrogen protection. After the reaction was completed, the reaction solution was quenched by adding an aqueous solution of ammonium chloride (4 mL), and extracted with ethyl acetate (5 mL x 3), the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography [petroleum ether: methyl tert-butyl ether (v / v) = (100:0-58:42)] to obtain 38-c (50 mg, yield: 49%, purity: 86.39%) as a yellowish oil. LCMS (method G), Rt= 1.971 min; MS Calcd.: 1220.8; MS Found: 1222.7 [M+H] + .

[0698] Step 4: Preparation of 38

[0699] In a single-necked reaction flask, 38-c (50 mg) was dissolved in a hydrochloric acid solution in dioxane (5 mL, 6 mol / L hydrochloric acid in dioxane). After stirring for 3 hours at room temperature under nitrogen protection, the reaction solution was evaporated under reduced pressure to remove the solvent, and the crude product was purified by preparative high performance liquid chromatography, evaporated under reduced pressure to remove acetonitrile, and freeze-dried to remove water to obtain the hydrochloride salt of compound 38. LCMS (method A), Rt= 1.317 min; MS Calcd.: 752.5; MS Found: 377.3 [M / 2+H] + .

[0700] 1 HNMR (400 MHz, CD3OD) δ: 7.55 (s, 3H), 7.38 (d, J = 9.6 Hz, 9H), 4.31 (s, 6H), 3.62-3.58 (m, 3H), 3.28 (s, 6H), 3.06-2.87 (m, 9H), 2.24-2.17 (m, 3H), 2.15-1.87 (m, 12H), 1.69-1.60 (m, 3H).

[0701] Example 39:

[0702] Step 1: Preparation of 39-a

[0703] In a single-necked reaction flask, 4-f (800 mg) and N,N-diisopropylethylamine (490 mg) were dissolved in tetrahydrofuran (8 mL), isobutyl chloroformate (395 mg) was added at 0 °C, stirred at room temperature for 1 hour, then the solid impurities were filtered off with diatomite to obtain a tetrahydrofuran solution of the intermediate; NaBH4(290 mg) was dissolved in ice water (5 mL) and the tetrahydrofuran solution of the intermediate was added, stirred at room temperature overnight. After the reaction was completed, 2 mL of water was added, and extracted with ethyl acetate (3 mL x 3), the organic phase was washed twice with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to obtain a crude product, which was purified by column. The crude product was purified by silica gel column chromatography [dichloromethane:methanol (v / v) = (100:0-93:7)], to obtain 39-a (510 mg, yield: 41%, purity: 64.55%) as a light yellow solid. LCMS (method C), Rt = 1.010 min; MS Calcd.: 406.3; MS Found: 407.4 [M+H] + .

[0704] Step 2: Preparation of 39-b

[0705] In a single-necked reaction flask, 39-a (510 mg) was dissolved in dichloromethane (7 mL), and Dess-Martin oxidant (960 mg) was added at 0 °C, protected by nitrogen replacement, stirred at room temperature overnight. After the reaction was completed, aqueous sodium thiosulfate solution (10 mL) and aqueous sodium bicarbonate solution (10 mL) were added to quench the reaction, and extracted with dichloromethane (15 mL x 3), the organic phase was washed twice with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography [petroleum ether:methyl tert-butyl ether (v / v) = (100:0-22:78)], to obtain 39-b (410 mg, yield: 68%, purity: 85.66%) as a light yellow oil. LCMS (method C), Rt = 1.084 min; MS Calcd.: 404.2; MS Found: 405.2 [M+H] + .

[0706] Step 3: Preparation of 39-c

[0707] In a single-necked reaction flask, 39-b (370 mg) and ammonium acetate (850 mg) were dissolved in methanol (4 mL), and the solution was cooled with an ice water bath. After stirring for 1 min, sodium triacetoxyborohydride (1.56 g) was added, and the reaction was stirred at room temperature overnight under nitrogen protection. After the reaction was completed, the reaction was quenched by adding saturated NaHCO3solution (5 mL), and methanol was removed by evaporation under reduced pressure. Ethyl acetate (10 mL x 3) was added to extract the organic phase, which was dried over anhydrous sodium sulfate, filtered, and concentrated by evaporation under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography [dichloromethane:methanol (v / v) = (100:0-93:7)] to obtain 39-c (80 mg, yield: 9%, purity: 89.28%) as a yellowish oil. LCMS (method C), Rt= 1.105 min; MS Calcd.: 793.5; MS Found: 794.5 [M+H] + .

[0708] Step 4: Preparation of 39-d

[0709] In a single-necked reaction flask, 39-c (70 mg), 4-f (40 mg), N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (38 mg), and N-methylimidazole (15 mg) were dissolved in N,N-dimethylformamide (3 mL). The reaction was stirred at room temperature overnight under nitrogen protection. After the reaction was completed, the reaction was quenched by adding an aqueous ammonium chloride solution (4 mL) and extracted with ethyl acetate (5 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated by evaporation under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography [dichloromethane:methanol (v / v) = (100:0-95:5)] to obtain 39-d (110 mg, yield: 91%, purity: >99%) as a yellowish oil. LCMS (method G), Rt= 1.799 min; MS Calcd.: 1195.7; MS Found: 1197.3 [M+H] + .

[0710] Step 5: Preparation of 39

[0711] In a single-necked reaction flask, 39-d (100 mg) was dissolved in a hydrochloric acid solution in dioxane (3 mL, 6 mol / L hydrochloric acid in dioxane). The reaction was stirred at room temperature for 3 hours under nitrogen protection. After the reaction was completed, the reaction was concentrated by evaporation under reduced pressure, and the crude product was purified by preparative high-performance liquid chromatography. The acetonitrile was removed by evaporation under reduced pressure, and the water was removed by lyophilization to obtain a hydrochloride salt of compound 39. LCMS (method E), Rt= 0.982 min; MS Calcd.: 727.4; MS Found: 728.4 [M+H] + .

[0712] 1 HNMR (400 MHz, CD3OD) δ: 8.90 (d, J = 6.0 Hz, 1H), 8.74 (d, J = 6.0 Hz, 1H), 8.49 (d, J = 5.2 Hz, 1H), 8.25 (s, 1H), 8.15 (s, 1H), 8.04 (s, 1H), 8.00 (d, J = 5.6 Hz, 1H), 7.95 (d, J = 5.6 Hz, 1H), 7.58 (d, J = 4.4 Hz, 1H), 5.37 (s, 2H), 5.13 (s, 2H), 3.62-3.54 (m, 4H), 3.49-3.40 (m, 4H), 3.38-3.30 (m, 3H), 3.29-3.21 (m, 3H), 3.19-3.06 (m, 6H), 2.97-2.92 (m, 1H), 2.28-2.19 (m, 3H), 1.96-1.83 (m, 3H).

[0713] Biological Examples

[0714] Biological Example 1: In vitro compound inhibition of Lp(a) assembly assay

[0715] Test Procedure: Wild type HepG2 cells (source of endogenously expressed ApoB) and HEK293 stable cell line expressing human Apo(a) protein containing 17 Kringle repeats were incubated at 37°C and 5% CO2 to 90% confluency, respectively, and then conditioned media was collected. Gradient diluted compounds were added to 96 well plates, HEK293 conditioned media was added to 96 well plates and centrifuged at 1000 rpm for 1 min, HepG2 conditioned media was added to 96 well plates and centrifuged at 1000 rpm for 1 min, 96 well plates were incubated at 37°C for 2 hours, 6-aminohexanoic acid (EACA) was added to a final concentration of 150 mM, the reaction was stopped and equilibrated to room temperature. The stop reaction was transferred to Lp(a) capture antibody (anti-Apo(a) antibody) coated 96 well plates, incubated at 25°C for 1 hour, the plate was shaken and washed three times with wash buffer for 1 min each, HRP conjugated anti-ApoB detection antibody was added, incubated at 25°C for 1 hour, the plate was shaken and washed three times with wash buffer for 1 min each, TMB was added for color development, after 20 min incubation at 25°C, 1 N sulfuric acid was used for stopping. The signal at 450 nm absorbance was read on Envision 2104. The test results are shown in the table below.

[0716] Table 1

[0717] Biological Example 2: In vitro compound inhibition of Lp(a) assembly assay

[0718] Reference 1 Prepared according to WO2020247429A1 specification example 2.

[0719] Reference 2 Prepared according to WO2023078333A1 specification example 6.

[0720] Test procedure: Wild type HepG2 cells (source of endogenously expressed ApoB) and HEK293 stable cell line expressing human Apo(a) protein containing 17 Kringle repeats were incubated at 37°C and 5% CO2 to 90% confluency, then conditioned media was collected respectively. Gradient diluted compound was added to 96-well plate, HEK293 conditioned media was added to 96-well plate and centrifuged at 1000 rpm for 1 min, HepG2 conditioned media was added to 96-well plate and centrifuged at 1000 rpm for 1 min, 96-well plate was incubated at 37°C for 2 hours, 6-aminohexanoic acid (EACA) was added to a final concentration of 150 mM, the reaction was terminated, and equilibrated to room temperature. The termination reaction solution was transferred to a Lp(a) capture antibody (anti-Apo(a) antibody) coated 96-well plate, incubated at 25°C for 1 hour, the plate was shaken and washed with wash buffer for three times, 1 min each time, HRP conjugated anti-ApoB detection antibody was added, incubated at 25°C for 1 hour, the plate was shaken and washed with wash buffer for three times, 1 min each time, TMB was added, after incubation at 25°C for 20 min, 1N sulfuric acid was used for termination. The absorbance at 450 nm was read on Envision 2104. The test results are shown in the following table.

[0721] Table 2

[0722] Biological Example 3: In vivo pharmacokinetic test in mice

[0723] The pharmacokinetics of the compound of the present disclosure in mice was studied by determining the compound concentration in the plasma of mice at different time points after a single oral administration of the compound of the present disclosure to mice as the test animals using LC / MS / MS method.

[0724] Test animals: CD-1 mice (3, male, 7 weeks old, body weight 20.0-24.0 g).

[0725] Drug preparation: A certain amount of compound was weighed and dissolved in normal saline to prepare a colorless and clear solution of 1 mg / mL.

[0726] Dosing: Oral gavage administration after fasting, the dose of reference 1 and compounds 1, 4, 5 is 10 mg / kg.

[0727] Operation: Collect the plasma at 0.25, 0.5, 1, 2, 4, 6, 8, 24 hours after administration, first remove 5 μL of plasma sample in 96-well plate, add 200 μL of internal standard acetonitrile solution to precipitate protein, vortex mixing at 1000 rpm for 5 minutes, then centrifuge at 3220 g, 4℃ for 10 minutes; after taking the supernatant, the LC-MS / MS analysis method is used for quantitative analysis of blood drug concentration.

[0728] After analyzing the blood drug concentration, the WinNonlin 8.3.5 software is used to calculate the pharmacokinetic parameters by non-compartment model. The mouse pharmacokinetic parameters of the compounds of the present disclosure are as follows.

[0729] Table 3

[0730] Biological Example 4: Rat in vivo pharmacokinetic test

[0731] Using rats as test animals, the LC / MS / MS method is used to determine the compound concentration in the plasma of rats at different times after a single oral administration of the compounds of the present disclosure, and the pharmacokinetics of the compounds of the present disclosure in rats is studied.

[0732] Test animals: SD rats (3, male, 6 weeks old, body weight 180-210 g).

[0733] Drug preparation: A certain amount of compound is weighed and added to physiological saline to prepare a colorless and clear solution of 1 mg / mL.

[0734] Dosing: Oral gavage administration after fasting, the dose of reference 1 and compound 4 is 10 mg / kg.

[0735] Operation: Collect the plasma at 0.25, 0.5, 1, 2, 4, 6, 8, 24 hours after administration, first remove 10 μL of plasma sample in 96-well plate, add 800 μL of internal standard acetonitrile solution to precipitate protein, vortex mixing at 800 rpm for 10 minutes, then centrifuge at 3220 g, 4℃ for 15 minutes; after taking the supernatant, the LC-MS / MS analysis method is used for quantitative analysis of blood drug concentration.

[0736] After analyzing the blood drug concentration, the WinNonlin 8.3.5 software is used to calculate the pharmacokinetic parameters by non-compartment model. The rat pharmacokinetic parameters of the compounds of the present disclosure are as follows.

[0737] Table 4

[0738] Bio Example 5: Protein surface plasmon resonance assay of compounds with human Apo(a), human plasminogen in vitro

[0739] The data collection for surface plasmon resonance assay was performed on a BIAcore™ S200 instrument, and the data collection temperature was set at 25℃. The study immobilized human Apo(a) (Acro) or human plasminogen protein (Plasminogen, PLG) with His-tag on the surface of Series S Chip CM5 chip (Cytiva) by amino coupling, and the operation was strictly in accordance with the standard S series CM5 sensor chip instruction. The protein was diluted to a concentration of 20-40 ug / mL using sodium acetate coupling buffer solution pH 4.0-4.5, and the injection time was set to 500-800 s, and the final chip surface density reached 2600-3000 response values. The compound with a certain dilution ratio was injected through the CM5 sensor chip surface of the amino-coupled protein at a flow rate of 30 uL / min, the binding time was set to 90 s, and the dissociation time was set to 150 s. The running buffer for the study of compound binding was HBS-EP (Cytiva). All data were double-docked to exclude the influence of buffer and reference channel. The data were processed and analyzed by BIAcore™ S200 evaluation software version 1.1, and the affinity constant KD was confirmed by 1:1 binding model fitting. Apo(a) has a high similarity to plasminogen, containing multiple kringle domains and an inactive protease domain, and Apo(a) can competitively inhibit the binding of plasminogen to fibrin, thereby interfering with the fibrinolysis process and increasing the risk of thrombosis. The binding affinity constant KD of the compound with Apo(a) and plasminogen was determined by protein surface plasmon resonance assay, and the KD ratio of the compound to plasminogen and Apo(a) was calculated, so as to screen the ideal drug with Apo(a) selectivity significantly higher than that of plasminogen (PLG) with large KD ratio. The experimental results are as follows.

[0740] Table 5

[0741] Bio Example 6: Solubility determination in water

[0742] Experimental procedure: Accurately measure the volume (0.5 mL) of pure water, and add the over-saturated accurate weight of the sample to be tested (2 mg) to it respectively, and prepare three parallel samples for each sample. Place the sample in a constant temperature air bath shaker (37℃, 180r / min rotation mode vibration), and record the start time. After 24h of vibration, take out and record the time of taking out, and observe whether the sample is completely dissolved. If it is completely dissolved, continue to add the sample and shake until the sample reaches over-saturation. After taking out, place it at room temperature, filter, and detect the content by HPLC and calculate the average solubility. The experimental results are as follows.

[0743] Table 6

[0744] Biological Example 7: In vivo cynomolgus monkey Lp(a) assembly inhibition experiment

[0745] Male cynomolgus monkeys were housed in cages under standard light cycle (12 hours light, 12 hours dark) at room temperature 20-26 °C with relative humidity between 30-70%, and provided with drinking water ad libitum and twice daily with feed. Before the study, 51 cynomolgus monkeys were pre-screened for baseline Lp(a) level, and the monkeys were randomly divided into groups according to body weight and baseline serum Lp(a) concentration, with 3 monkeys in each group. The dosing was calculated according to the body weight of the animals on the day, and the volume was calculated at 5 mL / kg, and the continuous dosing was performed for 7 days, and the different dosing groups were orally gavaged once a day at a fixed time, and the solvent was normal saline. The blood sampling time of each dose group was before dosing, day 1, day 4, and day 7 after dosing for 6 hours; 1.8 mL of whole blood was collected at each time point, and the serum was separated by centrifugation at 2-8 °C and 3000 rpm for 15 minutes after being placed at room temperature for 60 minutes, and was used for detection of Lp(a) level. The serum Lp(a) level was detected by using a fully automatic biochemical analyzer, and the reduction percentage of Lp(a) in each group was determined by (dosing-pre dose) / pre dose*100%. The ratio of the change of the Lp(a) level in cynomolgus monkeys in vivo of the compound of the present application to the baseline is shown in FIG. 1; and the reduction percentage of Lp(a) in cynomolgus monkeys in vivo is shown in the following table.

[0746] Table 7

[0747] Biological Example 8: In vitro 3T3 fibroblast neutral red uptake test

[0748] 1. Cell line and medium

[0749] Cells: BALB / c 3T3 mouse fibroblast cell line. Medium: DMEM high glucose containing 10% FBS, 1x penicillin-streptomycin mixture, 1x non-essential amino acids (NEAA) and 1% Hepes.

[0750] 2. Cell seeding

[0751] Cells were incubated at 37°C in a humidified atmosphere of 5% CO2. The culture medium was aspirated from the flask and the cells were washed twice with 8-10 mL of PBS; 3-5 mL of trypsin-EDTA was added to the flask and incubated at 37°C for 3-5 minutes. Once the cells were detached, a 3-fold volume of growth medium containing 10% FBS was added to the flask to neutralize the trypsin. The cell suspension was transferred to a conical tube, the cells were pelleted by centrifugation at 150 g for 5 minutes, the supernatant was removed, and the cells were resuspended in the cell pellet with medium. The cell density was adjusted to 1.0*105cells / mL; 100 μL of the cell suspension was seeded into each well of a 96-well plate; the plate was incubated at 37°C, 95% humidity, and 5% CO2for 24 hours.

[0752] 3. Compound formulation and administration

[0753] i. Compound dilution series

[0754] Stock solutions of the compounds (10 mg / mL) were serially diluted 2-fold over 8 doses using H2O as solvent; stock solutions of hexachlorophene (10 mg / mL) and chloφromazine (10 mg / mL) were serially diluted 8 times with a dilution factor of 3.16 using DMSO as solvent. Working solutions of the test compounds, hexachlorophene, and chloφromazine were prepared by adding 4 μL of the stock solution to 396 μL of Hanks Balanced Salt Solution (HBSS); mixed well; DMSO was used as a solvent control.

[0755] ii. Compound administration

[0756] The culture medium was removed from the plate wells, and 100 μL of the working solution was added to the corresponding wells. The cells were incubated at 37°C in a humidified atmosphere of 5% CO2for one hour. After 60 minutes of incubation at 37°C, one plate was exposed to a dose of 5 J / cm2, while the other plate was simultaneously placed in the dark at room temperature. After irradiation, the working solution was decanted, the wells were washed twice with PBS, and the plates were incubated at 37°C, 5% CO2for 24 hours with 100 μL of culture medium (without test chemicals) added to each well.

[0757] 4. Assay

[0758] i. Prepare 50 pg / mL Neutral Red in unsupplemented DMEM working solution. ii. Remove media from the plate wells, then add 100 pL / well of Neutral Red media and incubate for 3 hours under standard culture conditions. iii. Remove the Neutral Red media and wash twice with 150 pL / well PBS, then add 100 uL / well of Neutral Red destarch (acetic acid: water: ethanol = 1 :49:50) solution and shake at 500 rpm for 10 minutes to extract the Neutral Red. Read the plate at 540 nM wavelength. And calculate the photostimulation factor (PIF) and mean photic effect (MPE) according to the formula.

[0759] Test results and conclusions: Example 4 in vitro 3T3 mouse fibroblast phototoxicity results were negative.

[0760] Table 9

Claims

1. A compound of formula (K) or a salt, solvate, stereoisomer, or tautomer thereof, wherein: each ring Cy is independently a N-containing five- or six-membered heterocyclyl; Each ring Ar is independently controlled by 0-3 R. a Optionally substituted phenyl or six-membered N-containing heteroaryl group; R a each independently H, halogen, or C 1-6 alkyl; each J is independently absent or CH2; w is 1 or 2; R 1 each independently is H or C 1-6 alkyl; R 2 each independently H, halogen, hydroxyl, C 1-6 alkyl or C 1-6 haloalkyl; R 3 each independently H, halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl or C 1-6 haloalkoxy; L is selected from the group consisting of: ring A is phenyl or a monocyclic heteroaryl containing 1-3 N atoms; ring B is phenyl or a monocyclic or bicyclic heteroaryl or heterocyclyl containing 1-3 N atoms; L 1 is a single bond, C 1-10 alkylene or C 1-10 alkyleneoxy, which alkylene or alkyleneoxy can optionally be substituted with 0-2 R L ; preferably C 1-6 alkylene or C 1-6 alkyleneoxy, more preferably C 1-4 alkylene or C 1-4 alkyleneoxy; R L each independently is H, oxo, halogen, or C 1-6 alkyl, or R L two of which together with the atom to which they are attached form a cycloalkyl, which optionally can be substituted with 0-1 halogen or C 1-6 alkyl; R 4 and R 5 each independently is H, C 1-6 alkyl or C 1-6 alkoxy, which alkyl or alkoxy can optionally be substituted with 0-1 -P(=0)(OR’)2; R 6 each independently H, halogen, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 cycloalkyl, pyrrolidinyl, piperidinyl, or -COOH, said alkyl, alkoxy, or cycloalkyl optionally can be substituted with 0-3 halogen, C 1-6 alkyl, C 1-6 cycloalkyl, pyrrolidinyl, piperidinyl, -COOH, -P(=0)(OR’)2, or substituted; R' are each independently H or C 1-6 alkyl, or two of R' together with the atom to which they are attached form a heterocyclyl, which is optionally substituted with 0-1 phenyl substituted with 0-1 halo; each n is independently 0, 1, or 2; m is an integer selected from 0-3; Also, L is not 2. The compound according to claim 1, or a salt, solvate, stereoisomer, or tautomer thereof, wherein the compound has the chemical structure of formula (I): ###0001### (I) wherein: w is 1 or 2; R 1 each independently is H or C 1-6 alkyl, preferably H or methyl, more preferably H; R 2 each independently is H, halogen, hydroxyl, C 1-6 alkyl or C 1-6 haloalkyl, preferably H or methyl, more preferably H; R 3 each independently H, halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl or C 1-6 haloalkoxy, preferably H or methyl, more preferably H; L is selected from the group consisting of: ring A is phenyl or a monocyclic heteroaryl containing 1-3 N atoms; ring B is phenyl or a monocyclic or bicyclic heteroaryl or heterocyclyl containing 1-3 N atoms; L 1 is a single bond or C 1-10 alkylene, preferably C 1-6 alkylene, more preferably C 1-4 alkylene, which alkylene is optionally substituted with 0-2 R L ; R L each independently is H, oxo, halogen, or C 1-6 alkyl, or R L two of which together with the atom to which they are attached form a cycloalkyl, which optionally can be substituted with 0-1 halogen or C 1-6 alkyl; R 4 and R 5 each independently is H, C 1-6 alkyl or C 1-6 alkoxy, which alkyl or alkoxy can optionally be substituted with 0-1 -P(=0)(OR’)2; R 6 each independently H, halogen, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 cycloalkyl, pyrrolidinyl, piperidinyl, or -COOH, said alkyl, alkoxy, or cycloalkyl optionally can be substituted with 0-3 halogen, C 1-6 alkyl, C 1-6 cycloalkyl, pyrrolidinyl, piperidinyl, -COOH, -P(=0)(OR’)2, or substituted; R' are each independently H or C 1-6 alkyl, or two of R' together with the atom to which they are attached form a heterocyclyl, which is optionally substituted with 0-1 phenyl substituted with 0-1 halo; each n is independently 0, 1, or 2; m is an integer selected from 0-3; Also, L is not 3. The compound of claim 2 or a salt, solvate, stereoisomer, or tautomer thereof, wherein the compound has a specified stereochemical structure of formula (IIa) or (IIb):

4. The compound according to any one of the preceding claims or a salt, solvate, stereoisomer, or tautomer thereof, wherein: w is 1; L is ring A is phenyl.

5. The compound according to any one of the preceding claims or a salt, solvate, stereoisomer, or tautomer thereof, wherein: w is 2; L is selected from the group consisting of: m is 1 or 2.

6. The compound according to any one of the preceding claims or a salt, solvate, stereoisomer, or tautomer thereof, wherein: L is Ring B is R 6 each independently H, C 1-6 alkyl, pyrrolidinyl or -COOH, said alkyl optionally can be substituted with pyrrolidinyl or -COOH; m is 2.

7. The compound according to any one of the preceding claims or a salt, solvate, stereoisomer, or tautomer thereof, wherein: L is ring B is phenyl; R 6 each independently H, halogen, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, or C 1-6 cycloalkyl, said alkyl, alkoxy, or cycloalkyl optionally can be substituted with 0-3 halogen, C 1-6 alkyl, C 1-6 cycloalkyl, -P(=O)(OR’)2, or substituted.

8. The compound according to any one of the preceding claims or a salt, solvate, stereoisomer, or tautomer thereof, wherein: L 1 is -C(=O)- or -CR L R L -, wherein R L each independently is H or C 1-6 alkyl, or two of R L form together with the atom to which they are attached a cycloalkyl; R 6 each independently H, halogen, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, or C 1-6 cycloalkyl, said alkyl, alkoxy, or cycloalkyl optionally substituted with 0-3 halogen, C 1-6 alkyl, or -P(=O)(OR’)2; R' are each independently H or C 1-6 alkyl, preferably H or ethyl; m is 2.

9. The compound according to any one of the preceding claims or a salt, solvate, stereoisomer, or tautomer thereof, wherein: L is ring B is phenyl or a monocyclic six-membered heteroaryl containing 1-2 N atoms; R 6 is H, halogen, hydroxyl, C 1-6 alkyl or C 1-6 alkoxy, said alkyl or alkoxy optionally substituted with 0-3 halogen, pyrrolidinyl, piperidinyl, or -COOH.

10. The compound according to any one of the preceding claims or a salt, solvate, stereoisomer, or tautomer thereof, wherein: L is L 1 is -C(=O)- or -CR L R L -, wherein R L each independently is H or C 1-6 alkyl, or two of R L form, together with the atom to which they are attached, a cycloalkyl; B 1 , B 2 , B 3 or B 4 each independently is N or CR 6b ; R 6a is C 1-6 alkyl, which alkyl is optionally substituted by pyrrolidinyl, piperidinyl or -COOH; R 6b is H, halogen, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy or C 1-6 cycloalkyl, said alkyl, alkoxy or cycloalkyl optionally substituted with 0-3 halogen or C 1-6 alkyl.

11. The compound according to any one of the preceding claims or a salt, solvate, stereoisomer, or tautomer thereof, wherein: R 6a is ethyl or propyl, which is optionally substituted by pyrrolidinyl, piperidinyl or -COOH; R 6b is H, fluorine, chlorine, hydroxyl, methyl, methoxy or cyclopropyl, which methyl, methoxy or cyclopropyl is optionally substituted with 0-3 fluorine, chlorine or methyl.

12. The compound according to any one of the preceding claims or a salt, solvate, stereoisomer, or tautomer thereof, wherein the compound has the chemical structure of Formula (III): wherein: Cy 1 Cy 2 or Cy 3 Each is independently either pyrrolidinyl or piperidinyl; the ring Ar 1 or Ar 2 each independently is optionally substituted phenyl or a six-membered heteroaryl containing 1-3 N atoms; a each independently is optionally substituted phenyl or a six-membered heteroaryl containing 1-3 N atoms; R a each independently H, C 1-6 alkyl or halogen; Ring B 1 is phenyl optionally substituted with 1-2 R 6 groups; or a six-membered heteroaryl group containing 1-3 N atoms; R 6 each independently H, halogen, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, or C 1-6 cycloalkyl, said alkyl, alkoxy, or cycloalkyl optionally substituted with 0-3 halogen or C 1-6 alkyl; J 1 , J 2 , J 3 each independently is absent or CH2, and J 1 , J 2 , J 3 at least one of J R is preferably H, halogen, C 6 each independently H, halogen, C 1-6 alkyl or C 1-6 alkoxy, said alkyl or alkoxy optionally substituted with 0-3 halogen.

13. The compound according to any one of the preceding claims or a salt, solvate, stereoisomer, or tautomer thereof, wherein the compound has the chemical structure of Formula (Ilia): wherein: ring Cy 1 , Cy 2 or Cy 3 each independently is pyrrolidinyl; Ring Ar 1 Or Ar 2 Each is independently controlled by 1-3 Rs a Optional substitutions include phenyl, pyridinyl, pyridinyl, pyrazinyl, or triazinyl; Ring B 1 is phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or triazinyl optionally substituted with 1-2 R 6 groups; Preferably, ring Ar 1 , Ar 2 or ring B 1 is each independently phenyl or pyridyl; R a , R 6 , J 1 or J 2 as in claim 12.

14. The compound according to any one of the preceding claims or a salt, solvate, stereoisomer, or tautomer thereof, wherein the compound has the chemical structure of Formula (IV): wherein: Cy 1 Cy 2 or Cy 3 Each is independently either pyrrolidinyl or piperidinyl; the ring Ar 1 or Ar 2 each independently is optionally substituted phenyl or a six-membered heteroaryl containing 1-3 N atoms; a each independently is optionally substituted phenyl or a six-membered heteroaryl containing 1-3 N atoms; R a each independently H, C 1-6 alkyl or halogen; Ring B 1 is phenyl optionally substituted with 1-2 R 6 groups; or a six-membered heteroaryl group containing 1-3 N atoms; R 6 each independently H, halogen, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy or C 1-6 cycloalkyl, said alkyl, alkoxy or cycloalkyl optionally substituted with 0-3 halogen or C 1-6 alkyl; J 1 , J 2 or J 3 each independently is absent or CH2; and when R a 6 are both H, ring Ar 1 , Ar 2 or ring B 1 is not phenyl;​ R is preferably H, halogen, C 6 each independently H, halogen, C 1-6 alkyl or C 1-6 alkoxy, said alkyl or alkoxy optionally substituted with 0-3 halogen.

15. The compound according to any one of the preceding claims or a salt, solvate, stereoisomer, or tautomer thereof, wherein the compound has the chemical structure of Formula (IVa): wherein: Ring Ar 1 Or Ar 2 Each is independently controlled by 1-3 Rs a Optional substitutions include phenyl, pyridinyl, pyridinyl, pyrazinyl, or triazinyl; Ring B 1 is phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or triazinyl optionally substituted with 1-2 R 6 substituents; R a or R 6 As in claim 14.

16. The compound according to any one of the preceding claims or a salt, solvate, stereoisomer, or tautomer thereof, wherein the compound has the chemical structure of Formula (IVb): wherein: Z 1 , Z 2 or Z 3 each independently is N or CH; R a or R 6 As in claim 14; Preferably, Z 3 is N.

17. The compound according to any one of the preceding claims, or a salt, solvate, stereoisomer, or tautomer thereof, wherein the compound has the chemical structure of Formula (V): wherein: Cy is 1 Cy is 2 Cy is 3 each independently pyrrolidinyl or piperidinyl; the ring Ar 1 or Ar 2 each independently is optionally substituted phenyl or six-membered heteroaryl containing 1-3 N atoms; a atoms; each R R a each independently H, C 1-6 alkyl or halogen; Ring B 1 is phenyl optionally substituted with 1-2 R 6 groups; or a six-membered heteroaryl group containing 1-3 N atoms; R 6 each independently H, halogen, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy or C 1-6 cycloalkyl, said alkyl, alkoxy or cycloalkyl optionally substituted with 0-3 halogen or C 1-6 alkyl; J 1 , J 2 or J 3 each independently is absent or CH2; n is an integer selected from 0-3.

18. The compound according to any one of the preceding claims, or a salt, solvate, stereoisomer, or tautomer thereof, wherein the compound has the chemical structure of Formula (Va): wherein: Ring Ar 1 Or Ar 2 Each is independently controlled by 1-3 Rs a Optional substitutions include phenyl, pyridinyl, pyridinyl, pyrazinyl, or triazinyl; Ring B 1 is phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or triazinyl optionally substituted with 1-2 R 6 groups; R a , R 6 or n are as described in claim 17.

19. The compound according to any one of the preceding claims, or a salt, solvate, stereoisomer, or tautomer thereof, wherein the compound has the chemical structure of Formula (Vb): wherein: Z 1 , Z 2 or Z 3 each independently is N or CH; R a or R 6 each independently is H, C 1-6 alkyl or halogen; preferably H or halogen; n is 0 or 1.

20. The compound according to claim 1, or a salt, solvate, stereoisomer, or tautomer thereof, wherein the compound is selected from:

21. The compound according to claim 1, or a salt, solvate, stereoisomer, or tautomer thereof, wherein the compound is selected from:

22. A pharmaceutical composition comprising a compound according to any one of the preceding claims, or a salt, solvate, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier.

23. Use of a compound according to any one of claims 1-21, or a salt, solvate, stereoisomer, or tautomer thereof, or a pharmaceutical composition of claim 22, for the manufacture of a medicament for lowering Lp(a) levels.

24. Use of a compound according to any one of claims 1-21, or a salt, solvate, stereoisomer, or tautomer thereof, or a pharmaceutical composition of claim 22, for the manufacture of a medicament for the prevention and / or treatment of a disease or disorder associated with elevated Lp(a) plasma levels.

25. Use of a compound according to any one of claims 1-21, or a salt, solvate, stereoisomer, or tautomer thereof, or a pharmaceutical composition of claim 22, for the manufacture of a medicament for the prevention and / or treatment of a cardiovascular disease.

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