WO2019154261A1

WO2019154261A1 - Pyridine derivative related to kmd5 pathway

Info

Publication number: WO2019154261A1
Application number: PCT/CN2019/074144
Authority: WO
Inventors: 杨亚讯; 江志赶; 贺海鹰; 龚珍; 黎健; 陈曙辉
Original assignee: 南京明德新药研发股份有限公司
Priority date: 2018-02-09
Filing date: 2019-01-31
Publication date: 2019-08-15

Abstract

Disclosed is a class of pyridine derivatives, and specifically disclosed are compounds as shown in formula (Ⅲ) and pharmaceutically acceptable salts thereof.

Description

Pyridine derivatives associated with the KMD5 pathway

Reference to related application

This application claims the following priority:

CN201810136955.8, application date 2018-02-09;

CN201810312269.1, application date 2018-04-09;

CN201810639113.4, application date 2018-06-20;

CN201811466305.6, application date 2018-12-03.

Technical field

The present invention relates to a class of pyridine derivatives, and in particular to compounds of formula (III) and pharmaceutically acceptable salts thereof.

Background technique

The regulation of epigenetic binding to DNA damage repair is an effective way to treat some malignant tumors, and there is a good prospect for good synergy. Members of the KMD5 family have abnormalities in breast cancer and have great market potential. About 15% of breast cancer patients have KDM5A gene amplification; KMD5B is abnormally expressed in luminal subtype breast cancer (about 60% of breast cancer). KMD5A and KMD5B are abnormally highly expressed in non-small cell lung cancer (accounting for more than 80% of the total lung cancer). The global R&D investment in NSCLC is large, and the market space is large. KDM5C plays a role in neuronal development, while KDM5D encoded by the Y chromosome is widely expressed and involved in spermatogenesis.

WO2016168349 reports that the compound is GS-5801.

Summary of the invention

The present invention provides a compound of the formula (III) or a pharmaceutically acceptable salt thereof,

among them,

Y is selected from O and S;

R _{1 is} selected from H and C _1-6 alkyl, wherein said C _1-6 alkyl is optionally substituted by 1, 2 or 3 R _a ;

R _{a is} independently selected from the group consisting of F, Cl, Br, I, OH, NH ₂ and CF ₃ ;

R _{2 is} selected from H and C _1-6 alkyl, wherein said C _1-6 alkyl is optionally substituted by 1, 2 or 3 R _b ;

R _{b is} independently selected from the group consisting of F, Cl, Br, I, OH, NH ₂ and CF ₃ ;

Alternatively, R ₁ and R _{2 are} bonded together to form a benzene ring, a 5- to 6-membered heteroaryl ring or a C _3-6 cycloalkyl group, wherein the benzene ring and the 5- to 6-membered heteroaryl ring are optionally 1, 2 Or 3 R ₃ substitutions;

R _{3 is} independently selected from the group consisting of H, F, Cl, Br, I, OH, NH ₂ and CF ₃ ;

R _{4 is} selected from the group consisting of OH and C _1-3 alkoxy;

R _{5 is} selected from the group consisting of H and C _1-3 alkyl;

R _{6 is} selected from the group consisting of H and C _1-3 alkyl;

Alternatively, R ₁ and R _{5 are} joined together to form a C _3-6 cycloalkyl group;

Alternatively, R ₂ and R _{6 are} joined together to form a C _3-6 cycloalkyl group;

And, when R ₁ and R _{2 are} bonded together to form a benzene ring or a 5- to 6-membered heteroaryl ring, R ₅ and R ₆ are empty;

R _{7 is} selected from H and C _1-5 alkyl, wherein said C _1-5 alkyl is optionally substituted by 1, 2 or 3 R _c ;

R _{8 is} selected from H and C _1-5 alkyl, wherein said C _1-5 alkyl is optionally substituted by 1, 2 or 3 R _c ;

Alternatively, R ₇ , R ₈ and the N atoms to which they are attached are joined together to form

Said

Optionally substituted by 1, 2 or 3 R _c ;

R _{c is} independently selected from the group consisting of F, Cl, Br, I, OH, NH ₂ and CF ₃ ;

The 5- to 6-membered heteroaryl ring contains 1, 2 or 3 heteroatoms and heteroatoms independently selected from the group consisting of -O-, -S-, -NH- and N.

The present invention provides a compound of the formula (II) or a pharmaceutically acceptable salt thereof,

among them,

Y is selected from O and S;

Alternatively, R ₁ and R _{2 are} bonded together to form a benzene ring, a 5- to 6-membered heteroaryl ring or a C _3-6 cycloalkyl group, wherein the benzene ring and the 5- to 6-membered heteroaryl ring are optionally 1. 2 or 3 R ₃ substitutions;

R _{4 is} selected from the group consisting of OH and C _1-3 alkoxy;

R _{5 is} selected from the group consisting of H and C _1-3 alkyl;

R _{6 is} selected from the group consisting of H and C _1-3 alkyl;

In some embodiments of the invention, the above R _{1 is} selected from the group consisting of H and C _1-3 alkyl, wherein the C _1-3 alkyl group is optionally substituted by 1, 2 or 3 R _a , and other variables are as defined in the present invention .

In some aspects of the invention, R ₁ above is selected from the group consisting of H, Me, and Et, and other variables are as defined herein.

In some embodiments of the invention, the above R _{2 is} selected from the group consisting of H and C _1-3 alkyl, wherein the C _1-3 alkyl group is optionally substituted by 1, 2 or 3 R _b , and other variables are as defined in the present invention .

In some aspects of the invention, the above R _{2 is} selected from the group consisting of H, Me, and Et, and other variables are as defined herein.

In some embodiments of the invention, R ₁ and R _{2 are} bonded together to form a benzene ring, cyclopropyl or pyridine ring, wherein the benzene ring and the pyridine ring are optionally substituted by 1, 2 or 3 R ₃ , Other variables are as defined by the present invention.

In some embodiments of the invention, R ₁ and R _{2 are} bonded together to form a benzene ring, a cyclopropyl group and a pyridine ring, and the benzene ring, cyclopropyl group and pyridine are optionally substituted by R ₃ , and other variables are The invention is defined.

In some aspects of the invention, the structural unit

Selected from

Other variables are as defined by the present invention.

In some embodiments of the invention, the above R _{4 is} selected from the group consisting of OH,

Other variables are as defined by the present invention.

In some embodiments of the invention, R ₁ and R _{5 are} joined together to form a cyclopropyl group, and other variables are as defined herein.

In some embodiments of the invention, R ₂ and R _{6 are} joined together to form a cyclopropyl group, and other variables are as defined herein.

In some embodiments of the invention, the above R _{7 is} selected from the group consisting of H and C _1-3 alkyl, wherein the C _1-3 alkyl group is optionally substituted by 1, 2 or 3 R _c , and other variables are as defined in the present invention .

In some embodiments of the invention, R ₇ above is selected from the group consisting of H, Me, CH ₂ F, CHF ₂ , CF ₃ , CH ₂ CF ₃ , CHFCH ₂ F, and Et, and other variables are as defined herein.

In some embodiments of the invention, the above R _{8 is} selected from the group consisting of H and C _1-3 alkyl, wherein the C _1-3 alkyl group is optionally substituted by 1, 2 or 3 R _c , and other variables are as defined in the present invention .

In some aspects of the invention, the structural unit

Selected from

Other variables are as defined by the present invention.

The present invention provides a compound of the formula (I) or a pharmaceutically acceptable salt thereof,

among them,

Y is selected from O and S;

Or R ₁ and R _{2 are} bonded together to form a benzene ring or a 5- to 6-membered heteroaryl ring, wherein the benzene ring and the 5- to 6-membered heteroaryl ring are optionally substituted by 1, 2 or 3 R ₃ ;

R _{4 is} selected from C _1-3 alkoxy;

In some embodiments of the invention, R ₁ and R _{2 are} bonded together to form a benzene ring or a pyridine ring, wherein the benzene ring and the pyridine ring are optionally substituted by 1, 2 or 3 R ₃ , and other variables such as The invention is defined.

In some embodiments of the invention, R ₁ and R _{2 are} joined together to form a benzene or pyridine ring, and other variables are as defined herein.

In some embodiments of the invention, the above R _{4 is} selected from

Other variables are as defined by the present invention.

In some embodiments of the invention, the above compound or a pharmaceutically acceptable salt thereof, selected from the group consisting of

among them,

R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ and Y are as defined in the present invention.

Still other aspects of the invention are arbitrarily combined from the above variables.

The present invention provides a compound of the formula: or a pharmaceutically acceptable salt thereof,

The present invention also provides the use of the above compound or a pharmaceutically acceptable salt thereof for the preparation of a medicament for treating a disease associated with the KDM5 pathway.

In some aspects of the invention, the above-described diseases associated with the KDM5 pathway are tumors and hepatitis B.

In some aspects of the invention, the tumor is breast cancer, gastric cancer, colorectal cancer, lung cancer, and liver cancer.

Technical effect

The compound of the present invention has a 4'-carboxylic acid pyridine heterocyclic ring as a mother nucleus, and a different substituent is attached to the heterocyclic ring, so that the compound of the present invention has a significant inhibitory effect on the demethylation of histone (KDM5), and the chromosome is maintained. Methylation of the histone residue H3K4me2/3, thereby silencing or eliminating replication of cccDNA.

The compound of the present invention has a remarkable inhibitory effect on KDM5A. The compounds of the invention can significantly increase the single or partial index of pharmacokinetics in mice. Compound 1 inhibited the five CYP isoenzymes to a lesser extent, and the compound was not cardiotoxic.

Definition and description

Unless otherwise stated, the following terms and phrases as used herein are intended to have the following meanings. A particular term or phrase should not be considered undefined or unclear without a particular definition, but should be understood in the ordinary sense. When a trade name appears in this document, it is intended to refer to its corresponding commodity or its active ingredient. The term "pharmaceutically acceptable" as used herein is intended to mean that those compounds, materials, compositions and/or dosage forms are within the scope of sound medical judgment and are suitable for use in contact with human and animal tissues. Without excessive toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.

The term "pharmaceutically acceptable salt" refers to a salt of a compound of the invention prepared from a compound having a particular substituent found in the present invention and a relatively non-toxic acid or base. When a relatively acidic functional group is contained in the compound of the present invention, a base addition salt can be obtained by contacting a neutral amount of such a compound with a sufficient amount of a base in a neat solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts. When a relatively basic functional group is contained in the compound of the present invention, an acid addition salt can be obtained by contacting a neutral form of such a compound with a sufficient amount of an acid in a neat solution or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, hydrogencarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and an organic acid salt, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Similar acids such as fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid; and salts of amino acids (such as arginine, etc.) And salts of organic acids such as glucuronic acid. Certain specific compounds of the invention contain both basic and acidic functional groups which can be converted to any base or acid addition salt.

The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing an acid group or a base by conventional chemical methods. In general, such salts are prepared by reacting these compounds in water or an organic solvent or a mixture of the two via a free acid or base form with a stoichiometric amount of a suitable base or acid.

The compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up the compound. For example, radiolabeled compounds can be used, such as tritium ⁽³ H), iodine -125 ⁽¹²⁵ I) or ^C-14 (14 C). For another example, hydrogen can be replaced by heavy hydrogen to form a deuterated drug. The bond composed of barium and carbon is stronger than the bond composed of common hydrogen and carbon. Compared with undeuterated drugs, deuterated drugs have reduced side effects and increased drug stability. Enhance the efficacy and prolong the biological half-life of the drug. Alterations of all isotopic compositions of the compounds of the invention, whether radioactive or not, are included within the scope of the invention. "Optional" or "optionally" means that the subsequently described event or condition may, but is not necessarily, to occur, and that the description includes instances in which the event or condition occurs and instances in which the event or condition does not occur.

The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, and may include variants of heavy hydrogen and hydrogen, as long as the valence of the particular atom is normal and the substituted compound is stable. of. When the substituent is oxygen (ie, =0), it means that two hydrogen atoms are substituted. Oxygen substitution does not occur on the aromatic group. The term "optionally substituted" means that it may or may not be substituted, and unless otherwise specified, the kind and number of substituents may be arbitrary on the basis of chemically achievable.

When any variable (eg, R) occurs more than once in the composition or structure of a compound, its definition in each case is independent. Thus, for example, if a group is substituted with 0-2 R, the group may optionally be substituted with at most two R, and each case has an independent option. Furthermore, combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.

When the number of one linking group is 0, such as -(CRR) ₀ -, it indicates that the linking group is a single bond.

When one of the variables is selected from a single bond, it means that the two groups to which it is attached are directly linked. For example, when L represents a single bond in A-L-Z, the structure is actually A-Z.

When a substituent is vacant, it means that the substituent is absent. For example, when X is vacant in A-X, the structure is actually A. When the listed substituents are not indicated by which atom is attached to the substituted group, such a substituent may be bonded through any atom thereof, for example, a pyridyl group as a substituent may be passed through any one of the pyridine rings. A carbon atom is attached to the substituted group.

When the listed linking group does not indicate its direction of attachment, its connection direction is arbitrary, for example,

The medium linking group L is -MW-, and at this time, -MW- can be connected in the same direction as the reading order from left to right to form ring A and ring B.

It is also possible to connect the ring A and the ring B in a direction opposite to the reading order from left to right.

Combinations of the linking groups, substituents and/or variants thereof are permissible only if such combinations result in stable compounds.

Unless otherwise specified, "ring" means substituted or unsubstituted cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aryl or heteroaryl. The ring includes a single ring, and also includes a bicyclic or polycyclic ring system such as a spiro ring, a ring and a bridge ring. The number of atoms on the ring is usually defined as the number of elements of the ring. For example, "5 to 7-membered ring" means 5 to 7 atoms arranged in a circle. Unless otherwise specified, the ring optionally contains from 1 to 3 heteroatoms. Thus, the "5-7 membered ring" includes, for example, phenyl, pyridyl and piperidinyl; on the other hand, the term "5-7 membered heterocycloalkyl" includes pyridyl and piperidinyl, but does not include phenyl. The term "ring" also includes ring systems containing at least one ring, each of which "ring" independently conforms to the above definition.

Unless otherwise specified, the term "alkyl" is used to mean a straight or branched saturated hydrocarbon group, and in some embodiments, the alkyl group is a C _1-12 alkyl group; in other embodiments The alkyl group is a C _1-6 alkyl group; in other embodiments, the alkyl group is a C _1-3 alkyl group. It may be monosubstituted (such as -CH ₂ F) or polysubstituted (such as -CF ₃ ), and may be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine). . Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, s-butyl) And t-butyl), pentyl (including n-pentyl, isopentyl and neopentyl), hexyl and the like.

Unless otherwise specified, the term "heteroalkyl", by itself or in conjunction with another term, denotes a stable straight or branched alkyl radical or a combination thereof consisting of a number of carbon atoms and at least one heteroatom or heteroatom. Things. In some embodiments, the heteroatoms are selected from the group consisting of B, O, N, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen heteroatoms are optionally quaternized. In other embodiments, the heteroatom group is selected from the group consisting of -C(=O)O-, -C(=O)-, -C(=S)-, -S(=O), -S(=O) ₂ -, -C(=O)N(H)-, -N(H)-, -C(=NH)-, -S(=O) ₂ N(H)- and -S(=O)N( H)-. In some embodiments, the heteroalkyl group is a _C1-6 heteroalkyl group; in other embodiments, the heteroalkyl group is a _C1-3 heteroalkyl group. A heteroatom or heteroatom can be located at any internal position of a heteroalkyl group, including the position at which the alkyl group is attached to the rest of the molecule, but the terms "alkoxy", "alkylamino" and "alkylthio" (or thioalkyl) Oxyl) is a conventional expression and refers to those alkyl groups which are attached to the remainder of the molecule through an oxygen atom, an amino group or a sulfur atom, respectively. Examples of heteroalkyl groups include, but are not limited to, -OCH ₃ , -OCH ₂ CH ₃ , -OCH ₂ CH ₂ CH ₃ , -OCH ₂ (CH ₃ ) ₂ , -CH ₂ -CH ₂ -O-CH ₃ , -NHCH ₃ , -N(CH ₃ ) ₂ , -NHCH ₂ CH ₃ , -N(CH ₃ )(CH ₂ CH ₃ ), -CH ₂ -CH ₂ -NH-CH ₃ , -CH ₂ -CH ₂ -N ( CH ₃ )-CH ₃ , -SCH ₃ , -SCH ₂ CH ₃ , -SCH ₂ CH ₂ CH ₃ , -SCH ₂ (CH ₃ ) ₂ , -CH ₂ -S-CH ₂ -CH ₃ , -CH ₂ - CH ₂ , -S(=O)-CH ₃ , -CH ₂ -CH ₂ -S(=O) ₂ -CH ₃ , -CH=CH-O-CH ₃ , -CH ₂ -CH=N-OCH ₃ And -CH=CH-N(CH ₃ )-CH ₃ . Up to two heteroatoms may be consecutive, for example, -CH ₂ -NH-OCH _3.

Unless otherwise specified, "cycloalkyl" includes any stable cyclic alkyl group including monocyclic, bicyclic or tricyclic systems wherein the bicyclic and tricyclic systems include spiro, co and ring. In some embodiments, the cycloalkyl group is a C _3-8 cycloalkyl group; in other embodiments, the cycloalkyl group is a C _3-6 cycloalkyl group; in other embodiments, the The cycloalkyl group is a C _5-6 cycloalkyl group. It may be monosubstituted or polysubstituted, and may be monovalent, divalent or multivalent. Examples of such cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, [2.2.2]bicyclooctane, [4.4.0] Dicyclodecane and the like.

Unless otherwise specified, "cycloalkenyl" includes any stable cyclic alkenyl group containing one or more unsaturated carbon-carbon double bonds at any position of the group, including monocyclic, bicyclic or tricyclic The system wherein the bicyclic and tricyclic systems include spiro, parallel and bridged rings, but any ring of this system is non-aromatic. In some embodiments, the cycloalkenyl group is a C _3-8 cycloalkenyl group; in other embodiments, the cycloalkenyl group is a C _3-6 cycloalkenyl group; in other embodiments, the The cycloalkenyl group is a C _5-6 cycloalkenyl group. It may be monosubstituted or polysubstituted, and may be monovalent, divalent or multivalent. Examples of such cycloalkenyl groups include, but are not limited to, cyclopentenyl, cyclohexenyl, and the like.

Unless otherwise specified, "cycloalkynyl" includes any stable cyclic alkynyl group containing one or more carbon-carbon triple bonds at any position of the group, including monocyclic, bicyclic or tricyclic systems, wherein Bicyclic and tricyclic systems include spiro, parallel and bridging rings. It may be monosubstituted or polysubstituted, and may be monovalent, divalent or multivalent.

Unless otherwise specified, the term "heterocycloalkyl", by itself or in conjunction with other terms, denotes a cyclized "heteroalkyl", respectively, which includes monocyclic, bicyclic, and tricyclic systems, wherein the bicyclic and tricyclic systems include spiro rings, And ring and bridge ring. Further, in the case of the "heterocycloalkyl group", a hetero atom may occupy a position where a heterocycloalkyl group is bonded to the rest of the molecule. In some embodiments, the heterocycloalkyl group is a 4-6 membered heterocycloalkyl group; in other embodiments, the heterocycloalkyl group is a 5-6 membered heterocycloalkyl group. Examples of heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, thioheterobutyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophene) -2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxoalkyl , dithiaalkyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl, homopiperazinyl, homopiperidinyl or oxygen Heterocyclic heptane.

The above-described alkyl groups having the specified number of carbon atoms, "alkoxy" represents attached through an oxygen bridge, unless otherwise specified, C _1-6 alkoxy groups include _{_{_{C 1, C 2, C 3}}} , C 4, C 5 , and C ₆ alkoxy groups. In some embodiments, the alkoxy group is a C _1-3 alkoxy group. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy, and S- Pentyloxy.

Unless otherwise specified, the terms "aromatic ring" and "aryl" are used interchangeably and the term "aryl ring" or "aryl" means a polyunsaturated carbocyclic ring system which may be monocyclic, bicyclic or poly A ring system in which at least one ring is aromatic, and each ring in the bicyclic and polycyclic ring system is fused together. It may be mono- or poly-substituted, may be monovalent, divalent or multivalent, in some embodiments, the aryl is a C _6-12 aryl; in other embodiments, the aryl It is a C _6-10 aryl group. Examples of aryl groups include, but are not limited to, phenyl, naphthyl (including 1-naphthyl and 2-naphthyl, and the like). Substituents for any of the above aryl ring systems are selected from the group of acceptable substituents described herein.

Unless otherwise specified, the terms "heteroaryl ring" and "heteroaryl" are used interchangeably and the term "heteroaryl" means 1, 2, 3 or 4 independently selected from B, N, O and An aryl (or aromatic ring) of a hetero atom of S, which may be a monocyclic, bicyclic or tricyclic ring system in which the nitrogen atom may be substituted or unsubstituted (ie, N or NR, wherein R is H or has been herein Other substituents are defined, and are optionally quaternized, and the nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O) _p , p is 1 or 2). A heteroaryl group can be attached to the remainder of the molecule through a heteroatom. In some embodiments, the heteroaryl is a 5-10 membered heteroaryl; in other embodiments, the heteroaryl is a 5-6 membered heteroaryl. Examples of the heteroaryl group include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl, and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl, etc.) , imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5-oxazolyl, etc.) , triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl and 4H-1,2,4- Triazolyl, etc.), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl and 5-isoxazolyl, etc.), thiazolyl (including 2-thiazolyl, 4-thiazole And 5-thiazolyl, etc.), furyl (including 2-furyl and 3-furyl, etc.), thienyl (including 2-thienyl and 3-thienyl, etc.), pyridyl (including 2-pyridyl, 3-pyridyl and 4-pyridyl, etc., pyrazinyl, pyrimidinyl (including 2-pyrimidinyl and 4-pyrimidinyl, etc.), benzothiazolyl (including 5-benzothiazolyl, etc.), fluorenyl, Benzimidazolyl (including 2-benzimidazolyl, etc.), fluorenyl (including 5-indenyl, etc.), isoquinolyl (including 1-isoquinolinyl and 5-isoquinolinyl, etc.), Quinoxalinyl (including 2-quinoxalinyl and 5-quinoxalinyl, etc.), Quinolinyl (including 3-quinolyl and 6-quinolinyl, etc.), pyrazinyl, fluorenyl, phenyloxazolyl. Substituents for any of the above heteroaryl ring systems are selected from the group of acceptable substituents described herein.

Unless otherwise specified, C _n-n+m or C _n -C _n+m includes any one of n to n+m carbons, for example, C _1-12 includes C ₁ , C ₂ , C ₃ , C ₄ , C ₅ , C ₆ , C ₇ , C ₈ , C ₉ , C ₁₀ , C ₁₁ , and C ₁₂ , also including any range of n to n+m, for example, C _1-12 includes C _1-3 , C _1-6 , C _1-9 , C _3-6 , C _3-9 , C _3-12 , C _6-9 , C _6-12 , and C _{9-12 ,} etc.; similarly, n to n The +m element indicates that the number of atoms on the ring is n to n+m, for example, the 3-12 element ring includes a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, a 7-membered ring, an 8-membered ring, and a 9-membered ring. a 10-membered ring, a 11-membered ring, and a 12-membered ring, and includes any one of n to n+m, for example, a 3-12-membered ring including a 3-6-membered ring, a 3-9-membered ring, and a 5-6-membered ring. Ring, 5-7 membered ring, 6-7 membered ring, 6-8 membered ring, and 6-10 membered ring.

The compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments set forth below, combinations thereof with other chemical synthetic methods, and those well known to those skilled in the art. Equivalent alternatives, preferred embodiments include, but are not limited to, embodiments of the invention.

The solvent used in the present invention is commercially available. The present invention employs the following abbreviations: aq for water; HATU for O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate ; EDC stands for N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride; m-CPBA stands for 3-chloroperoxybenzoic acid; eq stands for equivalent, equivalent; CDI stands for Carbonyldiimidazole; DCM stands for dichloromethane; PE stands for petroleum ether; DIAD stands for diisopropyl azodicarboxylate; DMF stands for N,N-dimethylformamide; DMSO stands for dimethyl sulfoxide; EtOAc stands for acetic acid Esters; EtOH for ethanol; MeOH for methanol; CBz for benzyloxycarbonyl, an amine protecting group; BOC for t-butoxycarbonyl is an amine protecting group; HOAc for acetic acid; NaCNBH ₃ for sodium cyanoborohydride ; rt stands for room temperature; O/N stands for overnight; THF stands for tetrahydrofuran; Boc ₂ O stands for di-tert-butyl dicarbonate; TFA stands for trifluoroacetic acid; DIPEA stands for diisopropylethylamine; SOCl ₂ stands for chloride sulfone; CS ₂ on behalf of the carbon disulfide; Representative TsOH p-toluenesulfonic acid; NFSI Representative fluoro-N- -N- (phenylsulfonyl) benzenesulfonamide; n-Bu ₄ NF representative of tetrabutylammonium fluoride; iPrOH represents 2-propanol mp stands for melting point; LDA lithium diisopropylamide Representative; Ti (i-PrO) ₄ titanium tetraisopropoxide Representative; n-BuLi represents n-butyl lithium; Et ₃ N triethylamine Representative; T ₃ P represents a propionyl Phosphoric acid anhydride; LiOH·H ₂ O represents lithium hydroxide monohydrate; DIBAL- represents diisobutylaluminum hydride; TBDPS represents tert-butyldimethylsilyl; M represents mol/L.

The crude product of the present invention is subjected to a preparative HPLC purification method which is a neutral system.

Compound by hand or

Software naming, commercially available compounds using the supplier catalog name.

Detailed ways

The invention is described in detail below by the examples, but is not intended to limit the invention. The present invention has been described in detail herein, the embodiments of the present invention are disclosed herein, and various modifications and changes may be made to the embodiments of the present invention without departing from the spirit and scope of the invention. It will be obvious.

Reference Example 1: Fragment BB-1

Step 1: BB-1-2 synthesis

BB-1-1 (2 g, 11.97 mmol) and TsOH.H ₂ O (4.55 g, 23.94 mmol) were dissolved in anhydrous toluene (30 mL) in a pre-dried 100 mL three-necked flask at 25 ° C and heated to Anhydrous ethanol (5.51 g, 119.68 mmol) was slowly added dropwise to the system at 110 ° C, and the mixture was stirred at this temperature for 12 h. The reaction solution was cooled to room temperature, 20 mL ethyl acetate was added, and a saturated sodium carbonate aqueous solution was added to adjust the pH to 7. The mixture was separated and EtOAc (EtOAc) (EtOAc) ¹ H NMR (400 MHz, CDCl ₃ ) δ: 8.84 (brd, J = 4.63 Hz, 1H), 8.57 (s, 1H), 7.97 (dd, J = 3.42, 1.21 Hz, 1H), 4.26-4.52 (m) , 4H), 1.30-1.48 (m, 6H). MS m/z: 224 [M + H] ⁺ .

Step 2: BB-1 synthesis

BB-1-2 and solvent anhydrous tetrahydrofuran (12 mL) were added to a pre-dried 50 mL three-necked flask, followed by DIBAL-H (1 M, 6.72 mL) dropwise at -78 ° C, and the reaction was carried out at -78 ° C. 2h, the reaction solution was poured into a mixed solution of iced acetic acid (3mL) and water (18mL), and the mixture was stirred for 10min, then was adjusted to pH 8 with saturated sodium bicarbonate solution (10mL) 2×50 mL), and the organic layer was combined, evaporated, evaporated, evaporated MS m/z: 180 [M + H] ⁺ .

Reference Example 2: Fragment BB-2

Step 1: BB-2 synthesis

Raw material BB-2-1 (1 g, 4.67 mmol) and solvent DMF (20 mL) were added to a pre-dried 50 mL vial, and NaH (466.68 mg, 11.68 mmol, 60% purity) was added to the system at 0 °C. After stirring at 0 ° C for 0.5 h, 2-chloro-N,N-dimethyl-ethylamine hydrochloride ( 739.95 mg, 5.14 mmol) was added to the system, and the mixture was stirred at 25 ° C for 12 h. To the system, 10 mL of a saturated ammonium chloride solution was added, and the mixture was extracted with ethyl acetate (3×50 mL). . MS m/z: 286 [M + H] ⁺ .

Reference Example 3: Fragment BB-3

Step: BB-3 synthesis

Raw materials BB-3-1 (5 g, 29.90 mmol, 4.50 mL) and tetrahydrofuran (125 mL) were added to a pre-dried single-mouth bottle, followed by the addition of triethylamine (9.08 g, 89.71 mmol, 12.49 mL) to the system, BB -3-2 (4.57g, 29.90mmol, 2.82mL), reacted at 70 ° C for 1h, the system was cooled to room temperature, the solid was directly filtered, and the filtrate was concentrated under reduced pressure to give a crude product. :ethyl acetate = 1:1-1:2) purified to give BB-3, ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 7.10 (d, J = 8.00 Hz, 1H), 6.30-6.50 (m, 2H), 3.75-3.81 (m, 6H), 3.72 (s, 2H), 3.65-3.69 (m, 3H), 3.37 (s, 2H). MS m/z: 240 [M+H] ⁺ .

Reference Example 4: Fragment BB-4

Step 1: Synthesis of Compound BB-4

Starting material BB-4-1 (10 g, 80.02 mmol, 5.68 mL) was added to anhydrous dichloromethane (200 mL), followed by reagent imidazole (8.17 g, 120.03 mmol) and tert-butyldiphenylchlorosilane (22.00 g). , 80.02 mmol, 20.56 mL), stirring at 25 ° C for 1 hour, adding 30 mL of water to the system, separating the liquid, extracting the aqueous phase with dichloromethane (100 mL × 3), combining the organic phase, washing with 20 mL of saturated brine. Dry over anhydrous sodium sulfate, filtered and concentrated under reduced vacuo to afford EtOAc. ^{_{1 H NMR (400MHz, CDCl 3}} ) δppm 7.63-7.72 (m, 4H), 7.32-7.49 (m, 6H), 3.92 (t, J = 6.40Hz, 2H), 3.42 (t, J = 6.40Hz, 2H ), 1.07 (s, 9H).

Reference Example 5: Fragment BB-5

Step 1: Synthesis of BB-5-1

Raw material BB-2-1 (2 g, 9.33 mmol) and solvent dimethyl sulfoxide (30 mL) were added to a pre-dried single-mouth bottle, and NaH (746.75 mg, 18.67 mmol, 60) was added to the system at 25 °C. % purity), reacting at 25 ° C for 0.5 hours, then adding BB-4 (4.41 g, 12.13 mmol), stirring at 40 ° C for 12 hours, adding 30 mL of water to the system, extracting with ethyl acetate (100 mL × 3 The organic phase was combined and washed with brine (10 mL×3). Purified to give BB-5-1. MS m/z: 497 [M + H] ⁺ .

Step 2: BB-5-2 synthesis

Add raw material BB-5-1 (3 g, 6.04 mmol) and anhydrous tetrahydrofuran (50 mL) to a pre-dried single-mouth bottle, and add tetrabutylammonium fluoride (1 M, 18.12 mL) to the system at 25 °C. The reaction was carried out at 25 ° C for 0.5 hours, and concentrated under reduced pressure. To the system was added 10 mL of water, ethyl acetate (50 mL×3), and the organic phase was combined, washed with 5 mL of brine, dried over anhydrous sodium sulfate Concentration by pressure gave the crude product which was purified by flash column chromatography (dichloromethanol:methanol = 20:1:1:1). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 3.99-4.23 (m, 2H), 3.73 (t, J = 5.20 Hz, 2H), 3.49-3.57 (m, 4H), 3.42-3.48 (m, 2H), 1.80 -1.91 (m, 2H), 1.43 (s, 9H).

Step 3: BB-5 Synthesis

Add raw material BB-5-2 (0.5 g, 1.94 mmol) and anhydrous dichloromethane (10 mL) to a pre-dried single-mouth bottle, and add Dess-Martin oxidant (1.23 g, to the system at 25 ° C, 2.90mmol), at 25 ° C, the reaction was carried out for 2 hours, 10mL saturated sodium thiosulfate aqueous solution was added to the system, stirred for 10 minutes, the starch potassium iodide test paper was detected unchanged blue, 10mL saturated sodium bicarbonate aqueous solution was added to the system, and stirred 20 The mixture was extracted with ethyl acetate (50 mL×3). MS m/z: 201 [M+H] ⁺ .

Reference Example 6: Fragment BB-6

Step 1: Synthesis of Compound BB-6

Substrate BB-6-1 (30 g, 260.67 mmol) and solvent acetone (150 mL), water (150 mL) were added to a vial, and sodium carbonate (13.81 g, 130.34 mmol), benzyl chloroformate was added to the system at 0 °C. (44.47 g, 260.67 mmol), slowly warmed to 22 ° C and stirred for 2 h. A conical flask was taken, 80 mL of water was added, and the reaction mixture was poured, and the mixture was extracted three times with ethyl acetate (80 mL).

Example 1: Compound 1

Step 1: Synthesis of Compound 1-1

BB-2 (2g, 7.01mmol) and reagent HCl/MeOH (4M, 10mL) were added to a pre-dried 50mL single-mouth bottle, and stirred at 25 ° C for 1.5h, the reaction gradually produced a white solid, and the solid was filtered. Compound 1-1. MS m/z: 186 [M + H] ⁺ .

Step 2: Compound 1-2 Synthesis

In a pre-dried single-mouth bottle, the starting compound 1-1 (149.32 mg, 673.46 μmol, HCl), solvent MeOH (0.4 mL) and DCE (2 mL), reagent N,N-diisopropylethylamine (87.04 mg) , 673.46 μmol, 117.30 μL), stirred at 25 ° C for 10 min, then added BB-1, stirred at 25 ° C for 20 min, then added sodium triacetoxyborohydride (178.42 mg, 841.82 μmol), stirred at 25 ° C 1h, 5mL of water was added to the system, ethyl acetate was extracted (50mL × 3), the organic phase was combined, washed with saturated brine (10mL × 1), dried over anhydrous sodium sulfate, filtered, Purification by HPLC gave Compound 1-2. ¹ H NMR (400 MHz, D ₂ O) δ: 8.75 (d, J = 5.52 Hz, 1H), 7.85-8.08 (m, 2H), 4.57 (s, 2H), 4.36 (q, J = 7.36 Hz, 2H) ), 4.11 (s, 2H), 3.79 (br t, J = 6.02 Hz, 2H), 3.63 - 3.73 (m, 2H), 3.53 (br t, J = 5.77 Hz, 2H), 3.30 (t, J = 6.27 Hz, 2H), 2.85 (s, 6H), 2.11 (br s, 2H), 1.30 (t, J = 7.28 Hz, 3H). MS m/z: 349[M+H] ⁺

Step 3: Compound 1 Synthesis

Compound 1-2 (0.02 g, 57.40 μmol) and solvent H ₂ O (1 mL) were added to a pre-dried single-mouth bottle, and LiOH.H ₂ O (9.63 mg, 229.60 μmol) was added to the system at 25 ° C. The mixture was stirred at 25 ° C for 0.25 h, and the reaction mixture was adjusted to pH 6 with aqueous hydrochloric acid (2 mol / L), and the reaction mixture was evaporated to dryness. ^{_{1 H NMR (400MHz, D 2}} O) δ: 8.42 (d, J = 5.02Hz, 1H), 7.36-7.70 (m, 2H), 3.73 (s, 2H), 3.63 (br t, J = 5.77Hz, 2H), 3.41 (br s, 4H), 3.14 (br t, J = 5.77 Hz, 2H), 2.79 (br s, 2H), 2.72 (s, 6H), 1.71 (br s, 2H). MS m/z: 321 [M+H] ⁺ .

Example 2: Compound 2

Step 1: Synthesis of Compound 2-1

BB-2 (0.3 g, 1.05 mmol) and solvent toluene (5 mL) were added to the pre-dried single-mouth bottle, and 2,4-bis(p-methoxyphenyl)-1,3-disulfide was added to the system. Diphosphetane-2,4 sulfide (297.63 mg, 735.86 μmol), stirred at 120 ° C for 12 h, 5 mL water was added to the system, ethyl acetate was extracted (3×50 mL), and the organic phase was combined, 5 mL The mixture was washed with EtOAc (EtOAc m. MS m/z: 302 [M + H] ⁺ .

Step 2: Synthesis of Compound 2-2

Compound 2-1 (0.07 g, 232.21 μmol) and reagent HCl/MeOH (4M, 10 mL) were added to a pre-dried 50 mL vial, and stirred at 25 ° C for 1 h. 2. MS m/z: 202 [M+H] ⁺ .

Step 3: Compound 2-3 Synthesis

Compound 2-2 (48.04 mg, 202.04 μmol, HCl), solvent MeOH (0.4 mL), DCE (2 mL) and N,N-diisopropylethylamine (26.11 mg, 202.04) were added to the pre-dried vial. Μmol), stirred at 25 ° C for 10 min, then BB-1 and HOAc (1.01 mg, 16.84 μmol) were added and stirred at 25 ° C for 20 min, followed by sodium triacetoxyborohydride (53.52 mg, 252.55 μmol). After stirring at 25 ° C for 1 h, 5 mL of water was added, and ethyl acetate (50 mL × 3) was evaporated. Compound 2-3 was obtained as MS m/z: 365 [M+H] ⁺ .

Step 4: Compound 2 Synthesis

Compound 2-3 (0.01 g, 27.43 μmol) and solvent H ₂ O (1 mL) were added to the pre-dried single-mouth bottle, and LiOH.H ₂ O (4.61 mg, 109.74 μmol) was added to the system at 25 ° C. After stirring at 0.25 ° C, the reaction solution was adjusted to pH 6 with aqueous hydrochloric acid (2 mol / L), and the reaction mixture was evaporated to dryness. The crude product was purified by preparative HPLC to give compound 2, ¹ H NMR (400 MHz, D ₂ O) δ: 8.52 (d, J = 5.02 Hz, 1H), 7.74 (s, 1H), 7.63 (br d, J = 5.02 Hz, 1H), 4.32 (br t, J = 6.78 Hz, 2H), 4.01 (s, 2H) ), 3.88 (br s, 4H), 3.36 (br t, J = 7.03 Hz, 2H), 2.88 (br s, 1H), 2.83 (s, 6H), 1.82 (br s, 2H). MS m/z: 337 [M+H] ⁺ .

Example 3: Compound 3

Step 1: Synthesis of Compound 3-2

Compound 3-1 (20 g, 92.58 mmol), DIEA (35.89 g, 277.74 mmol, 48.38 mL) and DMF (200 mL) were then added to the reaction flask, then 2-aminoacetic acid methyl ester hydrochloride (17.44 g, 138.87 mmol) The reaction solution was stirred at 25 ° C for 16 hours. After adding 1000 mL of water to the reaction mixture, ethyl acetate (200 mL × 5) was evaporated. The crude product was purified by column chromatography (gradient elution: petroleum ether: ethyl acetate = 50:1 to 10:1) to afford compound 3-2. ¹ H NMR (400 MHz, CDCl ₃ ) δ=7.98-7.84 (m, 1H), 7.64-7.48 (m, 2H), 7.36 (t, J = 7.6 Hz, 1H), 4.03 (s, 2H), 3.65 (s) , 3H), 3.39 (s, 2H). MS m/z: 225 [M + H] ⁺ .

Step 2: Synthesis of Compound 3-3

Compound 3-2 (20.7 g, 92.32 mmol), DCM (300 mL), TEA (28.03 g, 276.97 mmol), DMAP (563.96 mg, 4.62 mmol) and Boc ₂ O (30.22 g, 138.48 mmol) were added to the reaction flask. The reaction solution was stirred at 25 ° C for 16 hours. After 200 mL of water was added to the reaction mixture, the mixture was evaporated. The crude product was purified by column chromatography (gradient elution: petroleum ether: ethyl acetate = 1:0 to 5:1) to afford compound 3-3. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.01 (t, J = 8.7 Hz, 1H), 7.69 - 7.51 (m, 2H), 7.43 (q, J = 7.5 Hz, 1H), 4.86 (d, J = 19.1) Hz, 2H), 4.04-3.90 (m, 1H), 3.92 (s, 1H), 3.73 (s, 3H), 1.47-1.36 (m, 9H). MS m/z: 225 [M - 100 + H] ⁺ .

Step 3: Compound 3-4 Synthesis

Compound 3-3 (21 g, 64.75 mmol), Pd/C (10 g, 64.75 mmol) and MeOH (100 mL) were added to the reaction flask, and the reaction mixture was replaced with hydrogen three times, then stirred at 25 ° C and H ₂ (15 psi). 4 hours. The reaction solution was filtered through celite, and washed with methanol (300 <RTIgt; ¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.11 (t, J = 7.2 Hz, 1H), 6.96 (d, J = 6.7 Hz, 1H), 6.73-6.60 (m, 2H), 4.46 (s, 2H), 3.80 (br s, 2H), 3.70 (s, 3H), 1.56-1.39 (m, 9H). MS m/z: 295 [M + 1] ⁺ .

Step 4: Compound 3-5 Synthesis

3-4 (1.5 g, 5.10 mmol) and toluene (20 mL) were added to the reaction flask, then HOBT (550.86 mg, 4.08 mmol) was added, and the reaction mixture was stirred at 110 ° C for 16 hours. After the reaction mixture was cooled, EtOAc (EtOAc m.) The crude product was purified by column chromatography (gradient elution: petroleum ether: ethyl acetate = 1:0 to 10:1) to afford compound 3-5. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.22 (br s, 1H), 7.18 (br s, 1H), 7.19-6.96 (m, 1H), 6.88 (d, J = 7.8 Hz, 1H), 4.55 - 4.16 (m, 4H), 1.43 - 1.25 (m, 9H). MS m/z: 207 [M-55] ⁺ .

Step 5: Compound 3-6 Synthesis

Add compound 3-5 (1.0g, 3.81mmol) and DMF (20mL) to the reaction flask, add NaH (457.49mg, 11.44mmol) to the reaction mixture at 0 °C for 0.5 hour, then add 2-chloro-N,N- Methyl ethylamine hydrochloride (823.72 mg, 5.72 mmol), and the final reaction mixture was stirred at 40 ° C for 48 hours. The reaction mixture was poured into aq. EtOAc (EtOAc m. The crude product was purified by preparative EtOAc (EtOAc:EtOAc:EtOAc MS m/z: 334 [M + 1] ⁺ .

Step 6: Synthesis of Compound 3-7

Compound 3-6 (0.26 g, 779.79 μmol) and EtOAc (10 mL) were added to the reaction mixture, then HCl/EtOAc (4M, 10 mL) was added and the reaction mixture was reacted at 15 ° C for 0.5 hour. The reaction mixture was concentrated under reduced pressure to give Compound Compound 3-7 Compound Compound MS m/z: 234 [M + 1] ⁺ .

Step 7: Synthesis of compound 3-8

Compound 3-7 (90.34 mg, 334.87 μmol) and DCM (2 mL) were added to the reaction flask, then TEA (56.48 mg, 558.12 μmol) was added, and after stirring for 0.5 hour, BB-1 (50 mg, 279.06 μmol) was added in that order. NaBH(OAc) ₃ (118.29 mg, 558.12 μmol) and HOAc (0.2 mL), and the mixture was stirred at 15 ° C for 16 hours. A saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture until pH=7, and the mixture was partitioned, and the aqueous phase was extracted with methylene chloride (10 mL × 3). The crude product was isolated and purified by preparative HPLC to give compound 3-8. MS m/z: 397 [M + 1] ⁺ .

Step 8: Compound 3 Synthesis

Compound 3-8 (30 mg, 75.67 μmol) and H ₂ O (1 mL) were added to the reaction mixture, then LiOH.H ₂ O (3.81 mg, 90.80 μmol) was added, and the reaction mixture was stirred at 15 ° C for 20 minutes. A 1 M aqueous HCl solution was added to the reaction mixture until pH = 6. The reaction solution was separated and purified by preparative HPLC to give Compound 3. ¹ H NMR (400 MHz, D ₂ O) δ = 8.54 (d, J = 5.1 Hz, 1H), 7.74 (s, 1H), 7.65 (dd, J = 1.4, 5.1 Hz, 1H), 7.53-7.42 (m, 1H), 7.39-7.27 (m, 3H), 4.19 (br t, J = 7.2 Hz, 2H), 3.93 (s, 2H), 3.60 (s, 2H), 3.23 (br t, J = 7.3 Hz, 2H) ), 3.14 (s, 2H), 2.78 (s, 6H). MS m/z: 369 [M + 1] ⁺ .

Example 4: Compound 4

Step 1: Synthesis of Compound 4-2

Compound 4-1 (10 g, 58.28 mmol) and solvent CCl ₄ (110 mL) were added to the reaction flask, followed by reagent AIBN (1.91 g, 11.66 mmol) and NBS (11.41 g, 64.11 mmol), and the reaction was carried out at 80 ° C. 12 hours. The reaction solution was filtered, and the filtrate was dried on a water pump to give a crude material. Purification by flash column chromatography (petroleum ether: ethyl acetate = 50:1) gave compound 4-2. ^{_{1 H NMR (400MHz, CDCl 3}} ) δ: 7.87 (dd, J = 8.4,7.2Hz, 1H), 7.71 (dd, J = 8.0,1.2Hz, 1H), 7.44 (t, J = 8.0Hz, 1H) , 4.89 (s, 2H).

Step 2: Synthesis of Compound 4-3

Compound 4-2 (3.5 g, 13.97 mmol), methyl glycate hydrochloride (2.63 g, 20.96 mmol) and solvent DMF (35 mL) were added to the reaction flask, followed by the reagent DIPEA (5.42 g, 41.92 mmol). The reaction was carried out at 25 ° C for 12 hours. The reaction was washed with 10mL H ₂ O and diluted with 10mL EtOAc, the aqueous phase was extracted with EtOAc (10mL × 2), 10mL of saturated brine, dried over anhydrous sodium sulfate, filtered, organic phase was concentrated to give crude product. Purification by flash column chromatography (petroleum ether: ethyl acetate = 10:1) gave compound 4-3. ^{_{1 H NMR (400MHz, CDCl 3}} ) δ: 7.71 (d, J = 8.4Hz, 1H), 7.64 (d, J = 8.4Hz, 1H), 7.37 (t, J = 8.0Hz, 1H), 4.14 (s , 2H), 3.73 (s, 3H), 3.49 (s, 2H).

Step 3: Synthesis of Compound 4-4

Was added compound 4-3 (3.5g, 13.53mmol) and a solvent THF (40mL) added to the reaction flask, H ₂ O (10mL), followed by addition of reagent _{(Boc) 2 O (4.43g,} 20.30mmol) and NaHCO ₃ (2.27 g, 27.06 mmol), the reaction was carried out at 35 ° C for 12 hours. The reaction solution was added 20mL H ₂ O, and extracted with EtOAc (20mL × 2), 20mL of saturated brine, dried over anhydrous sodium sulfate, filtered, organic phase was concentrated to give crude product. Purification by flash column chromatography (petroleum ether: ethyl acetate = 5:1) gave compound 4-4.

Step 4: Synthesis of Compound 4-5

4-4 (4.3g, 11.99mmol), and the solvent EtOH (40mL) was added to the reaction flask compound, H ₂ O (20mL), followed by addition of reagent Fe (2.01g, 35.96mmol) and NH ₄ Cl (641.09mg, 11.99 (mmol), the reaction was carried out at 75 ° C for 2 hours. The reaction was filtered, the filtrate added 20mL H ₂ O and 20mL EtOAc, separated, the aqueous phase was extracted with EtOAc (20mL × 2), 20mL of saturated brine, dried over anhydrous sodium sulfate, filtered, organic phase was concentrated to give crude product. Purification by flash column chromatography (petroleum ether: ethyl acetate = 5:1) gave compound 4-5. ^{_{1 H NMR (400MHz, CDCl 3}} ) δ: 6.99 (t, J = 8.0Hz, 1H), 6.69 (d, J = 8.8Hz, 1H), 6.54 (d, J = 8.0Hz, 1H), 4.72 (s , 3H), 3.90 (s, 2H), 3.71 (s, 3H), 1.45 (s, 9H).

Step 5: Synthesis of Compound 4-6

Compound 4-5 (3.5 g, 10.65 mmol) and solvent toluene (35 mL) were added to the reaction flask, followed by the addition of AlMe ₃ (2M, 6.92 mL), and the mixture was stirred under vacuum for three times and then reacted at 110 ° C for 12 hours. The reaction mixture was quenched with 30 mL of a mixture of KHSO ₄ and NaHCO ₃ (pH = 5-6), filtered through celite, and the filtrate was extracted with EtOAc (30 mL × 2) Filtration and concentration of the organic phase gave compound 4-6. ¹ H NMR (400 MHz, CDCl ₃ ) δ: 7.18 (d, J = 6.4 Hz, 2H), 6.91 (brd, J = 6.4 Hz, 1H), 4.77 (d, J = 32.4 Hz, 2H), 4.43 ( Br s, 1H), 4.26 (br s, 1H), 1.41-1.48 (m, 9H).

Step 6: Synthesis of Compound 4-7

Compound 4-6 (0.5 g, 1.68 mmol) and solvent DMF (5 mL) were added to the reaction flask, then NaH (269.59 mg, 6.74 mmol, purity 60%) was added at 0 ° C, and reagent N was added after 0.5 hour. N-dimethylaminochloroethane hydrochloride (485.40 mg, 3.37 mmol, HCl) was reacted at 35 ° C for 12 hours. The reaction was quenched with 5mL H ₂ O, and extracted with EtOAc (10mL × 2), 10mL of saturated brine, dried over anhydrous sodium sulfate, filtered, organic phase was concentrated to give crude product. Purification by flash column chromatography (dichloromethane:methanol = 30:1) gave compound 4-7.

Step 7: Synthesis of compound 4-8

Compound 4-7 (0.5 g, 1.36 mmol) and solvent HCl / EtOAc (4M) (10 mL) were added to the reaction mixture, and then the reaction was reacted at 25 ° C for 2 hours. The reaction solution was dried on a water pump to give Compound 4-8.

Step 8: Synthesis of compound 4-9

Compound 4-8 (240.00 mg, 788.92 μmol) and DCM (2 mL) were added to the reaction flask, followed by TEA (79.83 mg, 788.92 μmol), and after stirring for 0.5 hour, BB-1 (117.79 mg, 657.43 μmol) was added in sequence. HOAc (0.1 mL), after 2 hours of reaction, NaBH(OAc) ₃ (278.67 mg, 1.31 mmol) was added, and the reaction mixture was reacted at 25 ° C for 12 hours. The reaction was quenched with 5mL H ₂ O, with EtOAc (10mL × 2) the aqueous phase was extracted, washed with 10 mL of water and saturated brine The organic phase was dried over anhydrous sodium sulfate, filtered, organic phase was concentrated to give crude product. Purification by preparative HPLC gave compound 4-9. ^{1 H NMR (400MHz, DMSO-} d 6) δ: 10.70 (br s, 1H), 8.83 (d, J = 5.2Hz, 1H), 8.07 (s, 1H), 7.86 (d, J = 5.2Hz, 1H ), 7.54 - 7.59 (m, 3H), 4.38 (q, J = 6.8 Hz, 4H), 4.22-4.26 (m, 3H), 3.40 (br s, 2H), 3.31 (br s, 2H), 2.78 ( d, J = 4.8 Hz, 6H), 1.34 (t, J = 7.2 Hz, 3H).

MS m/z: 431, 433 [M+H] ⁺ .

Step 9: Compound 4 Synthesis

Compound 4-9 (0.03 g, 69.62 μmol) and solvent H ₂ O (2 mL) were added to the reaction mixture, followed by the reagent LiOH·H ₂ O (5.84 mg, 139.23 μmol), and the reaction was carried out at 25 ° C for 0.5 hour. The reaction solution was filtered and purified by preparative HPLC to give Compound 4. ^{_{1 H NMR (400MHz, D 2}} O) δ: 8.84 (d, J = 5.2Hz, 1H), 8.11 (s, 1H), 8.07 (d, J = 1.6Hz, 1H), 7.45-7.60 (m, 2H ), 7.44 (d, J = 5.2 Hz, 1H), 4.62 (s, 2H), 4.49 (br s, 2H), 4.29 (t, J = 7.2 Hz, 2H), 3.71 (s, 2H), 3.49 ( Br t, J = 6.8 Hz, 2H), 2.94 (s, 6H). MS m/z: 403, 405 [M+H] ⁺ .

Example 5: Compound 5

Step 1: Synthesis of Compound 5-2

5-1 (20 g, 116.56 mmol) and CCl ₄ (200 mL), followed by reagent AIBN (11.48 g, 69.94 mmol) and NBS (31.12 g, 174.84 mmol), and the reaction mixture was reacted at 85 ° C for 16 hours. The reaction mixture was cooled and filtered through celite. The crude product was purified by an automatic column chromatography COMBI-FLASH (gradient elution: petroleum ether: ethyl acetate = 1:0 to 50:1) to afford product 5-2.

Step 2: Synthesis of compound 5-3

5-2 (5.6 g, 22.36 mmol), DIEA (8.67 g, 67.07 mmol, 11.68 mL) and DMF (50 mL) were added to the reaction flask, followed by the addition of glycine methyl ester hydrochloride (4.21 g, 33.54 mmol). The solution was stirred at 25 ° C for 16 hours. 500 mL of water was added to the reaction mixture, and ethyl acetate (100 mL × 5) was evaporated. The crude product was concentrated under reduced pressure. The crude product was purified by an automatic column chromatography COMBI-FLASH (gradient elution: petroleum ether: ethyl acetate = 1:0 to 1:1) to afford product 5-3. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.94 (d, J = 8.8 Hz, 1H), 7.72 (d, J = 2.0 Hz, 1H), 7.36-7.39 (dd, J = 2.0, 8.8 Hz, 1H), 4.10 (s, 2H), 3.73 (s, 3H), 3.45 (s, 2H), 2.10 (s, 1H). MS m/z: 259 [M+H] ⁺ .

Step 3: Synthesis of Compound 5-4

5-3 (4.0 g, 15.46 mmol), DCM (40 mL), DIEA (6.00 g, 46.39 mmol, 8.08 mL), DMAP (94.46 mg, 773.22 μmol) and Boc ₂ O (13.50 g, 61.86 mmol, 14.21 mL), and the reaction solution was stirred at 40 ° C for 16 hours. After 200 mL of water was added to the reaction mixture, the mixture was evaporated. The crude product was purified by an automatic column chromatography COMBI-FLASH (gradient elution: petroleum ether: ethyl acetate = 1:0 to 5:1) to afford product 5-4. MS m/z: 259 [M-99] ⁺ .

Step 4: Synthesis of compound 5-5

5-4 (4.0 g, 11.15 mmol), Fe (1.87 g, 33.45 mmol), NH ₄ Cl (2.39 g, 44.60 mmol, 1.56 mL), EtOH (60 mL) and H ₂ O (20 mL) The reaction solution was purged with nitrogen three times and then stirred at 70 ° C for 6 hours. The reaction mixture was filtered over EtOAc (EtOAc)EtOAc. Concentration under reduced pressure gave the product 5-5 as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 6.96-7.07 (m, 2H), 6.60 (brd, J = 1.6 Hz, 1H), 4.42 (br s, 2H), 3.82 (br s, 2H), 3.73 ( Br s, 3H), 1.47 (br s, 9H). MS m/z: 329 [M + H] ⁺ .

Step 5: Synthesis of compound 5-6

Was added 5-5 (3.60g, 10.95mmol) added to the reaction flask, THF (30mL) and H ₂ O (5mL), followed by addition of NaOH (656.95mg, 16.42mmol), The reaction was stirred at 15 ℃ 5 hours. 1 M hydrochloric acid was added to the reaction mixture until pH = 5-6, and ethyl acetate (3 mL) was evaporated. MS m/z: 315 [M + H] ⁺ .

Step 6: Synthesis of compound 5-7

Was added 5-6 (2.0g, 6.35mmol) and EtOAc (20mL) added to the reaction flask, followed by addition of DIEA (2.46g, 19.06mmol, 3.32mL) and _{T 3 P (8.09g, 12.71mmol,} 7.56mL, 50% Purity), the reaction solution was stirred at 15 ° C for 0.25 hours, and a large amount of white solid was formed. After 100 mL of water was added to the reaction mixture, the mixture was separated and evaporated, evaporated, evaporated, evaporated, evaporated The crude product was slurried with ethyl acetate and petroleum ether and filtered to give product 5-7. MS m/z: 241 [M-55] ⁺ . Step 7: Synthesis of compound 5-8

5-7 (1.8 g, 3.40 mmol) and DMF (20 mL) were added to the reaction flask, NaH (543.49 mg, 13.59 mmol, 60% purity) was added at 0 ° C, and the reaction solution was stirred at 15 ° C for 1 hour, and then reacted to the reaction. N,N-dimethylaminochloroethane hydrochloride (978.57 mg, 6.79 mmol) was added to the flask, and the mixture was stirred at 40 ° C for 16 hours under nitrogen atmosphere. After the reaction was cooled, the reaction mixture was poured into EtOAc EtOAc. The crude product was purified by automatic column chromatography COMBI-FLASH (gradient elution: dichloromethane:methanol = 1:0 to 10:1) to afford product 5-8. ¹ H NMR (400 MHz, CDCl ₃ ) δ=8.01 (s, 1H), 7.41-7.31 (m, 2H), 7.25 (s, 1H), 4.50 (br s, 2H), 3.98 (brt, J = 6.0 Hz) , 2H), 3.92 (br s, 2H), 2.36-2.39 (br t, J = 6.4 Hz, 2H), 2.13 (s, 6H), 1.47 (br s, 9H). MS m/z: 368 [M + H] ⁺ .

Step 8: Synthesis of compound 5-9

5-8 (1.6 g, 4.35 mmol) and EtOAc (20 mL) were added to the reaction mixture, then HCl/EtOAc (4M, 16.98 mL) was added to the reaction mixture, and the reaction mixture was stirred at 25 ° C for 0.5 hour. A white solid is formed. The reaction solution was concentrated under reduced pressure to give the product 5-9.

Step 9: Compound 5-10 Synthesis

5-9 (305.62 mg, 1.00 mmol) and DCM (3 mL) were added to the reaction flask, then TEA (169.43 mg, 1.67 mmol, 233.05 μL) was added, and after stirring for 1 hour, BB-1 (150 mg, 837.18 μmol) was sequentially added. And HOAc (0.1 mL), the reaction mixture was stirred for 2 hr, then sodium borohydride (354.87 mg, 1.67 mmol) was added, and the reaction mixture was stirred at 15 ° C for 16 hours. A saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture until pH=7, and the aqueous layer was separated and evaporated with methylene chloride (10 mL×3). The product was isolated by HPLC () and purified to give product 5-10. MS m/z: 431 [M + H] ⁺ .

Step 10: Synthesis of Compound 5

5-10 (80 mg, 185.65 μmol) and H ₂ O (2 mL) were added to the reaction mixture, then LiOH·H ₂ O (9.35 mg, 222.78 μmol) was added, and the reaction mixture was stirred at 15 ° C for 20 minutes. 1 M HCl was added to the reaction solution until pH = 6. The reaction solution was separated by HPLC (column: Waters Xbridge 150×25 mm 5 um; mobile phase: [water (10 mM NH ₄ HCO ₃ )-ACN]; B%: 5%-30%, 12 min), and purified to give product 5. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.57 (d, J = 5.2 Hz, 1H), 7.76 (s, 1H), 7.68 (brd, J = 5.2 Hz, 1H), 7.48 (brd, J = 8.8 Hz, 1H), 7.33-7.35 (dd, J=3.2, 5.2 Hz, 2H), 4.18-4.21 (br t, J=6.8 Hz, 2H), 3.94 (s, 2H), 3.62 (s, 2H), 3.28-3.32 (br t, J = 7.2 Hz, 2H), 3.19 (s, 2H), 2.85 (s, 6H). MS m/z: 403 [M + H] ⁺ .

Example 6: Compound 6

Step 1: Synthesis of Compound 6-2

Compound 6-1 (10 g, 58.28 mmol) and solvent CCl ₄ (110 mL) were added to the reaction flask, followed by reagents AIBN (1.91 g, 11.66 mmol) and NBS (11.41 g, 64.11 mmol), at 80 ° C Reaction for 12 hours. The reaction solution was filtered, and the filtrate was dried on a water pump to give a crude material. Purification by flash column chromatography (petroleum ether: ethyl acetate = 50:1) gave compound 6-2. ^{_{1 H NMR (400MHz, CDCl 3}} ) δ: 8.05 (d, J = 2.0Hz, 1H), 7.58-7.62 (m, 1H), 7.57 (d, J = 14.8Hz, 1H), 4.80 (s, 2H) .

Step 2: Synthesis of compound 6-3

Compound 6-2 (4.2 g, 16.77 mmol), methyl glycinate hydrochloride (3.16 g, 25.15 mmol) and solvent DMF (40 mL) were added to the reaction flask, followed by reagent DIPEA (6.50 g, 50.30 mmol). The reaction was carried out at 25 ° C for 12 hours. The reaction was washed with 10mL H ₂ O and diluted with 10mL EtOAc, the aqueous phase was extracted with EtOAc (10mL × 2), 10mL of saturated brine, dried over anhydrous sodium sulfate, filtered, organic phase was concentrated to give crude product. Purification by flash column chromatography (petroleum ether: ethyl acetate = 10:1) gave compound 6-3. ^{_{1 H NMR (400MHz, CDCl 3}} ) δ: 7.96 (d, J = 2.0Hz, 1H), 7.57-7.63 (m, 1H), 7.55 (d, J = 2.0Hz, 1H), 4.08 (s, 2H) , 3.73 (s, 3H), 3.44 (s, 2H).

Step 3: Synthesis of Compound 6-4

To the reaction flask was added compound 6-3 (4.30g, 16.62mmol), the solvent THF (40mL) and H ₂ O (10mL), followed by addition of reagent _{(Boc) 2 O (5.44g,} 24.94mmol) and NaHCO ₃ (2.79 g, 33.25 mmol), and the reaction solution was reacted at 35 ° C for 12 hours. The reaction solution was added 10mL H ₂ O, and extracted with EtOAc (10mL × 2), 10mL of saturated brine, dried over anhydrous sodium sulfate, filtered, organic phase was concentrated to give crude product. Purification by flash column chromatography (petroleum ether: ethyl acetate = 5:1) gave compound 6-4.

Step 4: Synthesis of compound 6-5

To the reaction flask was added compound 6-4 (4.8g, 13.38mmol), the solvent EtOH (50mL) and H ₂ O (25mL), followed by addition of reagent Fe (2.24g, 40.14mmol) and NH ₄ Cl (858.77mg, 16.05 (mmol), the reaction was carried out at 78 ° C for 2 hours. The reaction was filtered, the filtrate added 20mL H ₂ O and 20ml EtOAc, separated, the aqueous phase was extracted with EtOAc (20mL × 2), 20mL of saturated brine, dried over anhydrous sodium sulfate, filtered, organic phase was concentrated to give crude product. Purification by flash column chromatography (petroleum ether: ethyl acetate = 5:1) gave compound 6-5. ^{_{1 H NMR (400MHz, CDCl 3}} ) δ: 6.86 (d, J = 8.0Hz, 1H), 6.61-6.64 (m, 2H), 4.40 (s, 2H), 3.78 (s, 2H), 3.70 (s, 3H), 1.45 (br s, 9H).

Step 5: Synthesis of compound 6-6

Compound 6-5 (3.5 g, 10.65 mmol) and solvent toluene (35 mL) were added to the reaction mixture, followed by the addition of AlMe ₃ (2M, 6.92 mL), and the mixture was stirred under vacuum for three times and then reacted at 110 ° C for 12 hours. The reaction mixture was quenched with 30 mL of a mixture of KHSO ₄ and NaHCO ₃ (pH = 5-6), filtered through celite, and the filtrate was extracted with EtOAc (30 mL × 2) Filtration and concentration of the organic phase gave compound 6-6.

Step 6: Synthesis of compound 6-7

Compound 6-6 (0.5 g, 1.68 mmol) and solvent DMF (5 mL) were added to the reaction flask, then NaH (269.59 mg, 6.74 mmol, purity 60%) was added at 0 ° C, and the reagent was added after 0.5 hour of reaction. -Dimethylaminochloroethane hydrochloride (485.40 mg, 3.37 mmol, HCl), and the reaction was carried out at 35 ° C for 12 hours. The reaction was quenched with 5mL H ₂ O, and extracted with EtOAc (10mL × 2), 10mL of saturated brine, dried over anhydrous sodium sulfate, filtered, organic phase was concentrated to give crude product. Purification by flash column chromatography (dichloromethane:methanol = 30:1) gave compound 6-7.

Step 7: Synthesis of compound 6-8

Compound 6-7 (0.4 g, 1.09 mmol) and solvent HCl / EtOAc (4M, 10 mL) were added to the reaction mixture, and then the reaction was reacted at 25 ° C for 2 hours. The reaction solution was dried on a water pump to give Compound 6-8.

Step 8: Synthesis of compound 6-9

Compound 6-8 (240.00 mg, 788.92 μmol) and DCM (2 mL) were added to the reaction flask, followed by TEA (79.83 mg, 788.92 μmol), and after stirring for 0.5 hour, BB-1 (117.79 mg, 657.43 μmol) was added in that order. HOAc (0.1 mL), after 2 hours of reaction, NaBH(OAc) ₃ (278.67 mg, 1.31 mmol) was added, and the reaction mixture was reacted at 25 ° C for 12 hours. The reaction was quenched with 5mL H ₂ O, with EtOAc (10mL × 2) the aqueous phase was extracted, washed with 10 mL of water and saturated brine The organic phase was dried over anhydrous sodium sulfate, filtered, organic phase was concentrated to give crude product. Purification by preparative HPLC gave compound 6-9. ^{1 H NMR (400MHz, DMSO-} d 6) δ: 10.80 (br s, 1H), 8.88 (d, J = 5.2Hz, 1H), 8.13 (s, 1H), 7.91 (d, J = 1.6Hz, 1H ), 7.75 (d, J = 1.6 Hz, 1H), 7.53-7.57 (m, 1H), 7.47-7.50 (m, 1 H), 4.55 (br s, 3H) 4.39 (q, J = 7.2 Hz, 2H) ), 4.34 - 4.43 (m, 1H), 4.21-4.32 (m, 4H), 3.58 (br s, 2H), 3.33 (br s, 2H), 2.79 (d, J = 4.8 Hz, 6H), 1.35 ( t, J = 7.2 Hz, 3H). MS m/z: 431, 433 [M+H] ⁺ .

Step 9: Synthesis of Compound 6

Compound 6-9 (0.03 g, 69.62 μmol) and solvent H ₂ O (2 mL) were added to the reaction mixture, followed by the reagent LiOH·H ₂ O (5.84 mg, 139.23 μmol), and the reaction solution was reacted at 25 ° C for 0.5 hour. The reaction solution was filtered and purified by preparative HPLC to give Compound 6. ^{_{1 H NMR (400MHz, D 2}} O) δ: 8.82 (d, J = 5.6Hz, 1H), 8.08 (s, 1H), 8.03 (d, J = 5.2Hz, 1H), 7.59 (s, 1H), 7.50 (s, 2H), 4.62 (s, 2H), 4.26-4.36 (m, 4H), 3.77 (s, 2H), 3.49 (br, J = 7.2 Hz, 2H), 2.95 (s, 6H).

MS m/z: 403, 405 [M+H] ⁺ .

Example 7: Compound 7

Step 1: Synthesis of Compound 7-2

Compound 7-1 (5 g, 29.1 mmol) was dissolved in CCl ₄ (50 mL), and NBS (10.4 g, 58.28 mmol) and AIBN (2.87 g, 17.48 mmol) were added to the reaction solution at 80 ° C. Reaction for 16 h. The reaction solution was cooled to 15 ° C and concentrated under reduced vacuo. The crude product was separated by column chromatography and the polar range was: petroleum ether: ethyl acetate = 1:1 to 0:1. The fraction was concentrated under reduced pressure to give Compound 7-2.

Step 2: Synthesis of Compound 7-3

Compound 7-2 (11.5 g, 45.91 mmol) and glycine methyl ester hydrochloride (8.65 g, 68.87 mmol) were dissolved in DMF (15 mL) The reaction mixture was diluted with EtOAc EtOAc. The crude product was separated by column chromatography, the polar range: petroleum ether: ethyl acetate = 10: 1-5: 1-1: 1 - 0:1. Concentrated to give compound _{7-3.1H NMR (400MHz, CDCl 3)} δppm 7.38-7.52 (m, 3H) 3.85 (s, 2H) 3.75 (s, 3H) 3.49 (s, 1H) 3.39 (s fraction under reduced pressure, 2H ).

Step 3: Synthesis of Compound 7-4

Compound 7-3 (4.5g, 17.40mmol) was dissolved in DCM (50mL) in the reaction solution were successively added _{Boc 2 O (7.59g, 34.79mmol)} , DMAP (106.27mg, 869.87μmol) and DIEA (4.50g , 34.79 mmol), stirred at 40 ° C for 16 h. The reaction mixture was cooled to room temperature and diluted with water (20 mL). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 7.28-7.44 (m, 3H) 4.44 (d, J = 12 Hz, 2H) 3.89 (s, 1H), 3.76 (s, 1H), 3.66 (s, 3H) 1.36 ( d, J = 16 Hz, 9H).

Step 4: Synthesis of compound 7-5

Compound 7-4 (3 g, 8.36 mmol) and NH ₄ Cl (536.74 mg, 10.03 mmol) were dissolved in a solvent mixture of EtOH (30 mL) and H ₂ O (15 mL) and stirred at 70 ° C for 2 h. The reaction mixture was diluted with water (100 mL) and evaporated. ^{1 H NMR (400MHz, MeOD)} δppm 7.20 (dd, J = 8,1.19Hz, 1H) 6.99 (d, J = 4Hz, 1H) 6.61 (m, 1H) 4.47 (s, 2H) 3.86 (s, 2H) 3.68 (s, 3H) 1.48 (s, 9H). MS m/z: 329 [M + H] ⁺ .

Step 5: Synthesis of Compound 7-6

Compound 7-5 (2.7 g, 8.21 mmol) and LiOH·H ₂ O (1.03 g, 24.64 mmol) were dissolved in THF (60 mL) and H ₂ O (12 mL) and stirred at 15 ° C for 5 h. The reaction solution was concentrated under reduced pressure at 50 °C. The crude product was taken up in methanol (20 mL) x 2 to give compound 7-6. ^{1 H NMR (400MHz, MeOD)} δppm 7.06 (dd, J = 8.0,1.38Hz, 1H) 6.82 (d, J = 8Hz, 1H) 6.49 (m, 1H) 4.79 (s, 2H) 4.36 (s, 2H) 1.38 (s, 9H). MS m/z: 315 [M+H] ⁺

Step 6: Synthesis of Compound 7-7

Compound 7-6 (2.4 g, 7.62 mmol), T ₃ P (7.28 g, 11.44 mmol, 6.80 mL, 50% purity) was dissolved in a mixture of EA (60 mL) and DMF (60 mL) at 15 ° C Stir for 12 h. The reaction mixture was diluted with EtOAc (EtOAc) (EtOAc) MS m/z: 241 [M-56+H] ⁺

Step 7: Synthesis of compound 7-8

Compound 7-7 (2.1 g, 7.08 mmol) was dissolved in DMF (50 mL) and NaH (l. The reaction liquid was stirred at 15 ° C for 0.5 h, and dimethylaminochloroethane hydrochloride (2.04 g, 14.15 mmol) was added to the reaction mixture in portions and reacted at 40 ° C for 12 h. The reaction was quenched with EtOAc EtOAc m. The crude product was separated by column chromatography, the polar range: petroleum ether: ethyl acetate = 10:1 to 0:1, and the fractions were concentrated under reduced pressure to give compound 7-8.

Step 8: Synthesis of compound 7-9

Compound 7-8 (0.75 g, 2.04 mmol) was dissolved in EtOAc (EtOAc)EtOAc. The reaction mixture was poured into aq. EtOAc (EtOAc) Filtration and concentration of the filtrate under reduced pressure gave compound 7-9. MS m/z: 268 [M+H] ⁺ .

Step 9: Synthesis of Compound 7-10

Compound 7-9 (0.37 g, 1.38 mmol) was dissolved in DCM (5 mL), EtOAc (EtOAc, EtOAc, EtOAc. ), pH = 6 was adjusted with glacial acetic acid, and stirred at 15 ° C for 0.5 h. Further, NaBH(OAc) ₃ (585.75 mg, 2.76 mmol) was added to the reaction system. Stirring was continued for 15 h at 15 °C. The reaction was quenched with EtOAc (EtOAc m. MS m/z: 431 [M + H] ⁺ .

Step 10: Synthesis of Compound 7

Compound 7-10 (0.05 g, 116.03 μmol) and LiOH·H ₂ O (9.74 mg, 232.06 μmol) were dissolved in MeOH (1 mL) and stirred at 20 ° C for 0.2 h. The reaction solution was directly filtered and separated by preparative HPLC. Post-treatment gave the compound 7. 1H NMR (400 MHz, DMSO) δ ppm 8.47 (d, J = 4.0 Hz, 1H) 7.66 (s, 1H) 7.58 (d, J = 4.0 Hz, 1H) 7.49 (d, J = 8.00 Hz ,1H)7.28(t,J=8.00Hz,1H)7.18-7.23(m,1H)4.05-4.13(m,1H)3.95-4.02(m,1H)3.86-3.89(d,J=12.00Hz,1H ) 3.76-3.79 (d, J=12.00 Hz, 1H) 3.67-3.70 (d, J=12.00 Hz, 1H) 3.47-3.50 (m, 2H) 3.34 (m, 1H) 3.06 (s, 2H) 2.82 (s) , 6H).

Example 8: Compound 8

Step 1: Synthesis of Compound 8-2

8-1 (20 g, 85.46 mmol), DIEA (33.14 g, 256.39 mmol, 44.66 mL) and DMF (200 mL) were added to the reaction flask, followed by the addition of glycine methyl ester hydrochloride (16.10 g, 128.19 mmol,). The solution was stirred at 25 ° C for 16 hours. After 100 mL of water was added to the reaction mixture, the mixture was evaporated. The crude product was purified by an automatic column chromatography (COMBI-FLASH) (gradient elution: petroleum ether: ethyl acetate = 50:1 to 1:1) to afford product 8-2 as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.71 - 7.73 (m, 1H), 7.40 - 7.42 (m, 1H), 7.32 - 7.38 (m, 1H), 4.06 (d, J = 1.6 Hz, 2H), 3.68 (s, 3H), 3.45 (s, 2H), 2.19-2.31 (m, 1H). MS m/z: 243 [M+H] ⁺ .

Step 2: Synthesis of Compound 8-3

8-2 (20.7, 85.47 mmol), DCM (200 mL), DIEA (33.14 g, 256.40 mmol, 44.66 mL), DMAP (522.07 mg, 4.27 mmol) and Boc ₂ O (37.31 g, 170.93) were added to the reaction flask. After the reaction mixture was heated to 40 ° C for 16 hours, Boc ₂ O (18.65 g, 85.47 mmol, 19.63 mL) was added to the reaction mixture, and the mixture was stirred at 40 ° C for 16 hours. After 200 mL of water was added to the reaction mixture, the mixture was evaporated. The crude product was purified by an automatic column chromatography (COMBI-FLASH) (gradient elution: petroleum ether: ethyl acetate = 1:0 to 5:1) to afford product 8-3 as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.62 (br t, J = 7.6 Hz, 1H), 7.43 (brt, J = 5.6 Hz, 1H), 7.30-7.35 (m, 1H), 4.80 (s, 2H) ), 3.90-3.99 (m, 2H), 3.71 (s, 3H), 1.38 (br s, 9H). MS m/z: 243 [M-99] ⁺ .

Step 3: Synthesis of Compound 8-4

8-3 (17.6 g, 51.41 mmol), Pd/C (5 g, 51.41 mmol, 5% purity) and EA (300 mL) were added to the reaction flask, and the reaction liquid was replaced with hydrogen three times, then at 25 ° C and H 2 (15 psi). Stir under effect for 11 hours. The reaction mixture was filtered with EtOAc (EtOAc)EtOAc. MS m/z: 313 [M + H] ⁺ .

Step 4: Synthesis of compound 8-5

8-4 was added to the reaction flask (5g, 16.01mmol) and toluene (50mL), was then added AlMe ₃ (2M, 12.01mL), the reaction was stirred at 110 ℃ 16 hours. The reaction mixture was cooled and poured into aq. EtOAc EtOAc EtOAc. MS m/z: 225 [M-55] ⁺ .

Step 5: Synthesis of compound 8-6

8-5 (2.5 g, 7.14 mmol) and DMF (20 mL) were added to the reaction flask, and NaH (1.14 g, 28.54 mmol, 60% purity) was added at 0 ° C for 1 hour at 15 ° C, then to the reaction flask. N,N-dimethylaminochloroethane hydrochloride (2.06 g, 14.27 mmol) was added, and the resulting reaction mixture was stirred at 40 ° C for 16 hours under nitrogen atmosphere. After the reaction was cooled, the reaction mixture was evaporated, evaporated, evaporated, evaporated The crude product was purified by an auto-column separation of COMBI-FLASH (gradient elution: dichloromethane:methanol = 1:0 to 10:1) to afford product 8-6 as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.33 - 7.37 (dt, J = 1.6, 7.2 Hz, 1H), 7.12 (d, J = 8.0 Hz, 1H), 7.00 - 7.04 (t, J = 8.4 Hz, 1H) ), 4.65 (br s, 2H), 4.13 (t, J = 1.2 Hz, 2H), 3.99-4.03 (t, J = 6.4 Hz, 2H), 3.90 (s, 2H), 2.31-2.41 (t, J = 6.4 Hz, 2H), 2.14 (s, 6H), 1.49 (s, 9H). MS m/z: 352 [M + H] ⁺ .

Step 6: Synthesis of compound 8-7

8-6 (1.7 g, 4.84 mmol) and EtOAc (10 mL) were added to the reaction mixture and then HCl/EtOAc (4M, 18.89 mL) The reaction solution was concentrated under reduced pressure to give product 8-7. MS m/z: 252 [M+H] ⁺ .

Step 7: Synthesis of compound 8-8

8-7 (250.54 mg, 870.67 μmol) and DCM (1 mL) were added to the reaction flask, then TEA (146.84 mg, 1.45 mmol, 201.98 μL) was added, and after stirring for 0.5 hour, BB-1 (130 mg, 725.56 μmol) was sequentially added. , 1 eq), sodium borohydride (307.55 mg, 1.45 mmol, 2 eq) and HOAc (0.1 mL), and the mixture was stirred at 15 ° C for 16 hours. A saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture until pH=7, and the aqueous layer was separated and extracted with dichloromethane (10 mL×3), and the organic phase was combined and dried over anhydrous sodium sulfate. -8. ¹ H NMR (400 MHz, DMSP-d6) δ = 11.24 (m, 1H), 8.88 (d, J = 4.8 Hz, 1H), 8.15 (s, 1H), 7.90-7.92 (dd, J = 1.6, 5.2 Hz, 1H), 7.64-7.65 (m, 1H), 7.49 (d, J = 8.4 Hz, 1H), 7.28-7.33 (m, 1H), 4.65 (br s, 2H), 4.36-4.42 (q, J = 7.2) Hz, 4H), 4.28 (br t, J = 7.2 Hz, 2H), 3.62 (s, 2H), 3.29-3.34 (m, 2H), 2.77-2.79 (m, 6H), 1.35 (t, J = 6.8 Hz, 3H). MS m/z: 415 [M + H] ⁺ .

Step 8: Synthesis of Compound 8

8-8 (100 mg, 241.27 μmol) and H ₂ O (4 mL) were added to the reaction mixture, then LiOH.H ₂ O (12.15 mg, 289.52 μmol) was added, and the reaction mixture was stirred at 15 ° C for 20 minutes. 1 M HCl was added to the reaction solution until pH = 6. The reaction solution was separated by HPLC and purified to give product 8. ¹ H NMR (400 MHz, DMSP-d6) δ = 8.62 (d, J = 5.2 Hz, 1H), 7.90 (s, 1H), 7.67-7.68 (dd, J = 1.6, 5.2 Hz, 1H), 7.45-7.47 ( m, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.17 (t, J = 8.8 Hz, 1H), 3.99 (br t, J = 6.0 Hz, 2H), 3.82 (s, 2H), 3.77 (s, 2H), 2.99 (s, 2H), 2.36 (t, J = 6.4 Hz, 2H), 2.12 (s, 6H). MS m/z: 387 [M + H] ⁺ .

Example 9: Compound 9

Step 1: Synthesis of Compound 9-2

Compound 9-1 (5 g, 32.23 mmol) and solvent CCl ₄ (100 mL) were added to the reaction flask, followed by reagents AIBN (2.12 g, 12.89 mmol) and NBS (7.46 g, 41.90 mmol), and the reaction was carried out at 80 ° C. 12 hours. The reaction solution was filtered, and the filtrate was dried on a water pump to give a crude material. Purification by flash column chromatography (petroleum ether: ethyl acetate = 50:1) gave compound 9-2. ^{_{1 H NMR (400MHz, CDCl 3}} ) δ: 8.12 (dd, J = 8.8,5.2Hz, 1H), 7.30 (dd, J = 8.8,2.8Hz, 1H), 7.12-7.19 (m, 1H), 4.81 ( s, 2H).

Step 2: Synthesis of compound 9-3

Compound 9-2 (4.2 g, 17.95 mmol), glycine methyl ester hydrochloride (3.38 g, 26.92 mmol) and solvent DMF (35 mL) were added to the reaction flask, followed by reagent DIPEA (6.96 g, 53.84 mmol). The reaction was carried out at 25 ° C for 12 hours. The reaction solution was 20mL H ₂ O and diluted with 20mL EtOAc, the aqueous phase was extracted with EtOAc (20mL × 2), 10mL of saturated brine, dried over anhydrous sodium sulfate, filtered, organic phase was concentrated to give crude product. Purification by flash column chromatography (petroleum ether: ethyl acetate = 10:1) gave compound 9-3.

Step 3: Synthesis of Compound 9-4

Was added compound 9-3 (4.2g, 17.34mmol) and a solvent THF (45mL) added to the reaction flask, H ₂ O (15mL), followed by addition of reagent _{(Boc) 2 O (5.68g,} 26.01mmol) and NaHCO ₃ (2.91 g, 34.68 mmol), the reaction was carried out at 35 ° C for 12 hours. The reaction solution was added 20ml H ₂ O, and extracted with EtOAc (30mL × 2), 20mL of saturated brine, dried over anhydrous sodium sulfate, filtered, organic phase was concentrated to give crude product. Purification by flash column chromatography (petroleum ether: ethyl acetate = 5:1) gave compound 9-4. ^{_{1 H NMR (400MHz, CDCl 3}} ) δ: 8.13-8.16 (m, 1H), 7.30-7.38 (m, 1H), 7.07-7.16 (m, 1H), 4.91 (s, 1H), 4.85 (s, 1H ), 4.05 (s, 1H), 3.96 (s, 1H), 3.76 (d, J = 2.0 Hz, 3H), 1.36-1.50 (m, 9H).

Step 4: Synthesis of compound 9-5

Was added compound 9-4 (4.4g, 12.85mmol), and the solvent EtOH (40mL) added to the reaction flask, H ₂ O (20mL), followed by addition of reagent Fe (2.15g, 38.56mmol) and NH ₄ Cl (825.04mg, 15.42 (mmol), the reaction was carried out at 78 ° C for 2 hours. The reaction was filtered, the filtrate added 30mL H ₂ O and 50ml EtOAc, separated, the aqueous phase was extracted with EtOAc (30mL × 2), 30mL of saturated brine, dried over anhydrous sodium sulfate, filtered, organic phase was concentrated to give crude product. Purification by flash column chromatography (petroleum ether: ethyl acetate = 5:1) gave compound 9-5. ¹ H NMR (400 MHz, CDCl ₃ ) δ: 6.81-6.85 (m,, 1H), 6.73 (d, J = 5.2 Hz, 1H), 6.71 (dd, J = 2.8 Hz, 1H), 4.43 (s, 2H) ), 3.81 (br s, 2H), 3.71 (s, 3H), 1.46 (br s, 9H).

Step 5: Synthesis of compound 9-6

Compound 9-5 (3.3 g, 10.57 mmol) and solvent toluene (30 mL) were added to the reaction mixture, followed by the addition of AlMe ₃ (2M, 6.87 mL), and the mixture was stirred under vacuum for three times and then reacted at 110 ° C for 12 hours. The reaction mixture was quenched with 30 mL of a mixture of KHSO ₄ and NaHCO ₃ (pH = 5-6), filtered through celite, and the filtrate was extracted with EtOAc (30 mL × 2) Filtration and concentration of the organic phase gave compound 9-6.

Step 6: Synthesis of compound 9-7

Compound 9-6 (0.5 g, 1.78 mmol) and solvent DMF (5 mL) were added to the reaction flask, then NaH (285.41 mg, 7.14 mmol, purity 60%) was added at 0 ° C, and reagent N was added after 0.5 hour. N-dimethylaminochloroethane hydrochloride (513.90 mg, 3.57 mmol, HCl) was reacted at 35 ° C for 12 hours. The reaction was quenched with 5mL H ₂ O, and extracted with EtOAc (10mL × 2), 10mL of saturated brine, dried over anhydrous sodium sulfate, filtered, organic phase was concentrated to give crude product. Purification by flash column chromatography (dichloromethane:methanol = 30:1) gave compound 9-7. ^{_{1 H NMR (400MHz, CDCl 3}} ) δ: 7.30 (br dd, J = 8.4,4.8Hz, 1H), 7.08-7.13 (m, 2H), 4.52 (br s, 2H), 3.95-4.04 (m, 1H ), 3.84-4.05 (m, 3H), 2.62 (s, 1H), 2.39 (t, J = 6.4 Hz, 2H), 2.15 (s, 6H), 1.48 (br s, 9H).

Step 7: Synthesis of compound 9-8

Compound 9-7 (0.45 g, 1.28 mmol) and solvent HCl / EtOAc (4M) (5 mL) were added to the reaction mixture, and then the reaction was reacted at 25 ° C for 2 hours. The reaction solution was dried on a water pump to give Compound 9-8.

Step 8: Synthesis of compound 9-9

Compound 9-8 (0.22 g, 764.53 μmol) and DCM (2 mL) were added to the reaction flask, then TEA (77.36 mg, 764.53 μmol) was added, and after stirring for 0.5 hour, BB-1 (105.37 mg, 588.10 μmol) was sequentially added. HOAc (0.1 mL), after 2 hours of reaction, NaBH(OAc) ₃ (249.28 mg, 1.18 mmol) was added, and the reaction was allowed to react at 25 ° C for 12 hours. The reaction was quenched by 5mL H ₂ O, with EtOAc (10mL × 2) the aqueous phase was extracted, washed with 10 mL saturated sodium chloride aqueous organic phases were combined, dried over anhydrous sodium sulfate, filtered, organic phase was concentrated to give crude product. Purification by preparative HPLC gave compound 9-9. ^{1 H NMR (400MHz, DMSO-} d 6) δ: 11.07 (br s, 1H), 8.88 (d, J = 5.2Hz, 1H), 8.16 (s, 1H), 7.91 (d, J = 5.2Hz, 1H ), 7.67-7.90 (m,,1H), 7.42-7.48 (m, 2H), 4.59 (br s, 2H), 4.39 (q, J = 6.8 Hz, 2H), 4.33 (br s, 2H), 4.24 (br t, J = 7.6 Hz, 2H), 3.59 (br s, 2H), 3.32 (br s, 2H), 2.79 (d, J = 4.4 Hz, 6H), 1.35 (t, J = 6.8 Hz, 3H) ).

Step 9: Synthesis of Compound 9

Compound 9-9 (0.05 g, 110.88 μmol) and solvent H ₂ O (2 mL) were added to the reaction flask, followed by the reagent LiOH.H ₂ O (9.31 mg, 221.76 μmol), and the reaction was allowed to react at 25 ° C for 0.5 hour. The reaction solution was filtered and purified by preparative HPLC to give Compound 9. ^{_{1 H NMR (400MHz, D 2}} O) δ: 8.84 (d, J = 5.2Hz, 1H), 8.11 (s, 1H), 8.07 (d, J = 5.2Hz, 1H), 7.54 (dd, J = 8.8 , 4.8 Hz, 1H), 7.40-7.46 (m, 1H), 7.34 (d, J = 3.2 Hz, 1H), 4.60 (s, 2H), 4.27-4.33 (m, 4H), 3.72 (s, 2H) , 3.49 (t, J = 7.6 Hz, 2H), 2.96 (s, 6H). MS m/z: 387 [M + H] ⁺ .

Example 10: Compound 10

Step 1: Synthesis of Compound 10-2

10-1 (25 g, 106.83 mmol), DIEA (41.42 g, 320.48 mmol, 55.82 mL) and DMF (100 mL) were added to the reaction flask, followed by the addition of glycine methyl ester hydrochloride (20.12 g, 160.24 mmol). Stir at 25 ° C for 16 hours. 500 mL of water was added to the reaction mixture, and ethyl acetate (100 mL × 5) was evaporated. The crude product was concentrated under reduced pressure. The crude product was purified by an automatic column-column COMBI-FLASH (gradient elution: petroleum ether: ethyl acetate = 1:0 to 1:1) to obtain a pure product. A yellow oily product 10-2 was obtained. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.61 - 7.66 (m, 2H), 7.28 (dt, J = 2.7, 8.0 Hz, 1H), 4.03 (s, 2H), 3.68 (s, 3H), 3.40 (s) , 2H), 2.08 (s, 1H). MS m/z: 243 [M+H] ⁺ .

Step 2: Synthesis of Compound 10-3

10-2 (24 g, 99.09 mmol), DCM (250 mL), DIEA (38.42 g, 297.27 mmol, 51.78 mL), DMAP (605.29 mg, 4.95 mmol) and Boc2O (64.88 g, 297.27 mmol, 68.29 mL), the reaction solution was stirred at 25 ° C for 16 hours. The reaction solution was warmed to 40 ° C and stirring was continued for 16 hours. Thin layer chromatography (PLATE 1, petroleum ether: ethyl acetate = 3:1, new point Rf = 0.6) showed that the starting material disappeared and a new product was formed. After 200 mL of water was added to the mixture, the mixture was evaporated. The crude product was purified by an automatic column-column COMBI-FLASH (gradient elution: petroleum ether: ethyl acetate = 1:0 to 5:1) to afford 10-3.

¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.71 - 7.76 (m, 1H), 7.64 - 7.66 (m, 1H), 7.36 (q, J = 6.8 Hz, 1H), 4.81 (d, J = 15.3 Hz, 2H) ), 4.11 - 4.16 (m, 2H), 3.74 (s, 3H), 1.46 (s, 5H), 1.38 (s, 4H). MS m/z: 243 [M-99] ⁺ .

Step 3: Synthesis of Compound 10-4

To the reaction flask was added 10-3 (31 g, 90.56 mmol), Pd / C (5 g, 90.56 mmol, 5% purity) and MeOH (400 mL), and the reaction solution was replaced with hydrogen three times, then at 25 ° C and H 2 (15 psi) After stirring for 16 hours, the reaction mixture was filtered through Celite, and washed with methanol (300 mL).

Step 4: Synthesis of compound 10-5

To the reaction flask was added 10-4 (5g, 16.01mmol) and toluene (50mL), was then added AlMe ₃ (2M, 12.01mL), the reaction was stirred at 110 ℃ 16 hours. After the reaction mixture was cooled, EtOAc (EtOAc m.) The crude product was purified by automated cross-column COMBI-FLASH (gradient elution: petroleum ether: ethyl acetate = 1:0 to 10:1) to afford product 10-5. ¹ H NMR (400 MHz, CDCl ₃ ) δ=8.44-8.64 (m, 1H), 7.07 (br s, 1H), 6.61-6.73 (m, 2H), 4.25-4.43 (m, 4H), 1.31-1.37 (m) , 9H). MS m/z: 225 [M-55] ⁺ .

Step 5: Compound 10-6 Synthesis

Add 10-5 (2.3 g, 4.60 mmol) and DMF (20 mL) to the reaction flask, and add NaH (735.23 mg, 18.38 mmol, 60% purity) to the reaction mixture at 0 ° C for 1 hour at 15 ° C, then to the reaction flask N,N-Dimethylaminochloroethane hydrochloride (1.32 g, 9.19 mmol) was added, and the resulting mixture was stirred at 40 ° C for 16 hours under nitrogen. After the reaction was cooled, the reaction mixture was evaporated, evaporated, evaporated, evaporated The crude product was purified by auto-column separation by COMBI-FLASH (gradient elution: dichloromethane:methanol = 1:0 to 10:1) to afford 10-6. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.31 (br d, J = 3.2 Hz, 1H), 7.08-7.11 (dd, J = 2.0, 9.6 Hz, 1H), 6.96-6.99 (dt, J = 2.8, 4.8 Hz, 1H), 4.50 (br s, 2H), 3.95-3.99 (t, J = 6.4 Hz, 2H), 3.90 (s, 2H), 2.42 (t, J = 6.4 Hz, 2H), 2.16 (s, 6H), 1.39-1.48 (m, 9H). MS m/z: 352 [M + H] ⁺ .

Step 6: Synthesis of Compound 10-7

To the reaction flask were added 10-6 (640 mg, 1.82 mmol) and EtOAc (2 mL). Thin layer chromatography (PLATE 1, dichloromethane: methanol = 10:1, Rf = 0) showed that the starting material disappeared and a new product was formed. The reaction solution was concentrated under reduced pressure to give 10-7. MS m/z: 252 [M+H] ⁺ .

Step 7: Synthesis of compound 10-8

10-7 (250.54 mg, 870.67 μmol) and DCM (1 mL) were added to the reaction flask, then TEA (146.84 mg, 1.45 mmol, 201.98 μL) was added, and after stirring for 1 hour, BB-1 (130 mg, 725.56 μmol) was sequentially added. And HOAc (0.1 mL), the reaction mixture was stirred for 2 hr, then sodium borohydride (307.55 mg, 1.45 mmol) was added, and the reaction mixture was stirred at 15 ° C for 16 hours. A saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture until pH=7, and the aqueous portion was separated and extracted with dichloromethane (10 mL×3). The organic phase was combined and dried over anhydrous sodium sulfate. Product. The product obtained after lyophilization was separated by HPLC and purified to give the product 10-8. ¹ H NMR (400 MHz, DMSO-d) δ=11.09-11.12 (m, 1H), 8.89 (d, J = 5.2 Hz, 1H), 8.18 (s, 1H), 7.92 (d, J = 5.2 Hz, 1H) , 7.57-7.62 (m, 2H), 7.28-7.31 (dt, J = 2.4, 8.4 Hz, 1H), 4.62 (br s, 2H), 4.37-4.42 (m, 4H), 4.27 (br t, J = 7.2 Hz, 2H), 3.65 (s, 2H), 3.31-3.33 (m, 2H), 2.79 (d, J = 4.8 Hz, 6H), 1.35 (t, J = 6.8 Hz, 3H). MS m/z: 415 [M + H] ⁺ .

Step 8: Synthesis of Compound 10

10-8 (100 mg, 241.27 μmol) and H 2 O (4 mL) were added to the reaction mixture, then LiOH.H ₂ O (12.15 mg, 289.52 μmol) was added, and the reaction mixture was stirred at 15 ° C for 20 minutes. 1 M HCl was added to the reaction solution until pH = 6. The reaction solution was separated by HPLC and purified to give the product 10. ¹ H NMR (400 MHz, DMSO-d6) δ = 8.62 (d, J = 5.2 Hz, 1H), 7.78 (s, 1H), 7.67-7.68 (m, 1H), 7.36-7.46 (m, 2H), 7.10 ( Dt, J = 2.4, 1H), 3.97 (br t, J = 6.4 Hz, 2H), 3.82 (s, 2H), 3.66 (s, 2H), 2.98 (s, 2H), 2.35 (t, J = 6.4) Hz, 2H), 2.12 (s, 6H). MS m/z: 387 [M + H] ⁺ .

Example 11: Compound 11

Step 1: Synthesis of Compound 11-2

Compound 11-1 (15 g, 96.70 mmol) and solvent CCl ₄ (150 mL) were added to the reaction flask, followed by reagents AIBN (11.11 g, 67.69 mmol) and NBS (30.98 g, 174.05 mmol), and the reaction was carried out at 80 ° C. 24 hours. The reaction solution was filtered, and the filtrate was dried on a water pump to give a crude material. Purification by flash column chromatography (petroleum ether: ethyl acetate = 50:1) gave Compound 11-2. ¹ H NMR (400 MHz, CDCl ₃ ) δ: 7.41 - 7.44 (m, 1H), 7.26 (d, J = 8.0 Hz, 1H), 7.14-7.20 (m, 1H), 4.48 (s, 2H).

Step 2: Synthesis of Compound 11-3

Compound 11-2 (4.7 g, 20.08 mmol), glycine methyl ester hydrochloride (3.78 g, 30.13 mmol) and solvent DMF (50 mL) were added to the reaction flask, followed by the reagent DIPEA (7.79 g, 60.25 mmol). The reaction was carried out at 25 ° C for 12 hours. The reaction solution was 30mL H ₂ O and diluted with 30mL EtOAc, the aqueous phase was extracted with EtOAc (30mL × 2), 30mL of saturated brine, dried over anhydrous sodium sulfate, filtered, organic phase was concentrated to give crude product. Purification by flash column chromatography (petroleum ether: ethyl acetate = 10:1) gave Compound 11-3.

Step 3: Synthesis of Compound 11-4

Reaction flask was added Compound 11-3 (5.2g, 21.47mmol) and a solvent _{THF (50mL), H 2 O} (17mL), followed by addition of reagent _{(Boc) 2 O (7.03g,} 32.20mmol) and NaHCO ₃ (3.61 g, 42.94 mmol), the reaction was carried out at 35 ° C for 12 hours. The reaction solution was added 20mL H ₂ O, and extracted with EtOAc (20mL × 2), 20mL of saturated brine, dried over anhydrous sodium sulfate, filtered, organic phase was concentrated to give crude product. Purification by flash column chromatography (petroleum ether: ethyl acetate = 5:1) gave compound 11-4. ¹ H NMR (400 MHz, CDCl ₃ ) δ: 7.46-7.54 (m, 1H), 7.36 (brd, J = 8.0 Hz, 1H), 7.19-7.27 (m, 1H), 4.59 (d, J = 13.2 Hz) , 2H), 3.99 (s, 1H), 3.87 (s, 1H), 3.73-3.77 (m, 3H), 1.40-1.46 (m, 9H).

Step 4: Synthesis of Compound 11-5

Was added compound 11-4 (7g, 20.45mmol) added to the reaction flask, and the solvent EtOH (70mL) and H ₂ O (35mL), followed by addition of reagent Fe (3.43g, 61.35mmol) and NH ₄ Cl (1.31g, 24.54mmol The reaction was allowed to react at 78 ° C for 2 hours. The reaction was filtered, the filtrate added 30mL H ₂ O and 50ml EtOAc, separated, the aqueous phase was extracted with EtOAc (50mL × 2), 50mL of saturated brine, dried over anhydrous sodium sulfate, filtered, organic phase was concentrated to give crude product. Purification by flash column chromatography (petroleum ether: ethyl acetate = 5:1) gave Compound 11-5. ¹ H NMR (400 MHz, CDCl ₃ ) δ: 6.93-6.97 (m, 1H), 6.76 (d, J = 7.6 Hz, 1H), 6.56 (br s, 1H), 4.56 (br s, 1H), 4.48 ( s, 2H), 3.80 (s, 2H), 3.70 (s, 3H), 1.46 (s, 9H).

Step 5: Synthesis of Compound 11-6

To the reaction flask were added Compound 11-5 (6.2 g, 19.85 mmol) and solvent toluene (60 mL), followed by AlMe ₃ (2M, 12.90 mL), and the mixture was stirred under vacuum for three times and then reacted at 110 ° C for 12 hours. The reaction mixture was quenched with 30 mL of a mixture of KHSO ₄ and NaHCO ₃ (pH = 5-6), filtered through celite, and the filtrate was extracted with EtOAc (30 mL × 2) Filtration and concentration of the organic phase gave compound 11-6.

Step 6: Synthesis of compound 11-7

Compound 11-6 (0.5 g, 1.78 mmol) and solvent DMF (5 mL) were added to the reaction flask, then NaH (285.41 mg, 7.14 mmol, purity 60%) was added at 0 ° C, and reagent N was added after 0.5 hour of reaction. N-dimethylaminochloroethane hydrochloride (513.90 mg, 3.57 mmol, HCl) was reacted at 35 ° C for 12 hours. The reaction was quenched with 5mL H ₂ O, and extracted with EtOAc (10mL × 2), 10mL of saturated brine, dried over anhydrous sodium sulfate, filtered, organic phase was concentrated to give crude product. Purification by flash column chromatography (dichloromethane:methanol = 30:1) gave compound 11-7.

Step 7: Synthesis of compound 11-8

Compound 11-7 (0.5 g, 1.42 mmol,) and solvent HCl / EtOAc (4M, 5 mL) were then added to the reaction mixture, and then the reaction was reacted at 25 ° C for 2 hours. The reaction solution was dried on a water pump to give Compound 11-8.

Step 8: Synthesis of compound 11-9

Compound 11-8 (0.5 g, 1.74 mmol) and DCM (2 mL) were added to the reaction mixture, then TEA (175.82 mg, 1.74 mmol) was added, and after stirring for 0.5 hour, BB-1 (207.55 mg, 1.16 mmol) and HOAc (0.1 mL), after 2 hours of reaction, NaBH(OAc) ₃ (491.01 mg, 2.32 mmol) was added, and the reaction was allowed to react at 25 ° C for 12 hours. The reaction was quenched with 5mL H ₂ O, with EtOAc (10mL × 2) the aqueous phase was extracted, washed with 10 mL of water and saturated brine The organic phase was dried over anhydrous sodium sulfate, filtered, organic phase was concentrated to give crude product. Purification by preparative HPLC gave compound 11-9.

Step 9: Synthesis of Compound 11

Compound 11-9 (0.05 g, 120.64 μmol) and solvent H ₂ O (2 mL) were added to the reaction flask, followed by the reagent LiOH·H ₂ O (10.12 mg, 242.77 μmol), and the reaction was allowed to react at 25 ° C for 0.5 hour. The reaction solution was filtered and purified by preparative HPLC to give Compound 11. ^{_{1 H NMR (400MHz, D 2}} O) δ: 8.85 (d, J = 5.2Hz, 1H), 8.11 (s, 1H), 8.02 (d, J = 1.6Hz, 1H), 7.41-7.52 (m, 2H ), 7.38 (d, J = 7.2 Hz, 1H), 4.65 (q, J = 35.6 Hz, 2H), 4.32-4.41 (m, 3H), 3.81-3.84 (m, 1H), 3.74 - 3.81 (m, 1H), 3.71-3.73 (m, 1H), 3.59-3.62 (m, 2H), 2.93 (d, J 11.6 Hz, 6H). MS m/z: 387 [M + H] ⁺ .

Example 12: Compound 12

synthetic route:

Step 1:12-2 Synthesis

Raw material 12-1 (0.15 g, 1.09 mmol) and solvent dioxane (4 mL) were added to a pre-dried single-mouth bottle, and selenium dioxide (132.55 mg, 1.19 mmol) was added to the system, and the reaction was carried out at 100 ° C. After 12h, 5mL of water was added to the system, and the mixture was combined with ethyl acetate (20mL×3). (eluent petroleum ether: ethyl acetate = 1:1) gave 12-2. ^{_{1 H NMR (400MHz, CDCl 3}} ) δ: 10.27 (s, 1H), 8.98 (d, J = 4.40Hz, 1H), 8.25 (d, J = 8.00Hz, 1H), 7.70 (dd, J = 8.40, 4.80 Hz, 1H). MS m/z: 153 [M+H] ⁺ .

Step 2: 12-3 Synthesis

Starting material 12-2 (1 g, 6.57 mmol) and anhydrous dichloromethane (10 mL) were added to a pre-dried single-mouth bottle, followed by BB-3 (1.57 g, 6.57 mmol), HOAc (39.48 mg, 657.43 μmol, 37.60 μL), stirring at 25 ° C for 0.5 h, then adding NaBH(OAc) ₃ (2.79 g, 13.15 mmol), stirring at 25 ° C for 0.5 h, adding 10 mL of water to the system, dichloromethane The mixture was extracted (50 mL×3). MS m/z: 376 [M + H] ⁺ .

Step 3: 12-4 Synthesis

Add raw material 12-3 (1.8 g, 4.80 mmol) and 20 mL of ethyl acetate to a pre-dried single-mouth bottle, and add Pd/C (2 g, 5% purity) to H ₂ (15 psi) in the system. The reaction was carried out at 25 ° C for 0.5 h, the catalyst was filtered, and the filtrate was concentrated under reduced pressure to give 12-4. MS m/z: 346 [M + H] ⁺ .

Step 4: 12-5 Synthesis

Add 12-4 (0.2g, 579.05μmol) and 5mL anhydrous toluene to the pre-dried single-mouth bottle, add trimethylaluminum (2M, 579.05μL) to the system, react at 110 ° C for 12h, add to the system 5 mL of water, ethyl acetate (50 mL×3), EtOAc (EtOAc m. Methanol = 20: 1-10: 1) Purification afforded 12-5. ^{_{1 HNMR (400MHz, CDCl 3)}} δ: 9.01 (s, 1H), 8.23 (dd, J = 4.40,0.80Hz, 1H), 7.27 (dd, J = 8.00,0.80Hz, 1H), 7.12 (dd, J = 8.00, 4.80 Hz, 1H), 7.04-7.06 (m, 1H), 6.36 (dq, J = 6.00, 2.80 Hz, 2H), 4.19 (s, 2H), 3.72 (s, 5H), 3.67-3.68 ( m, 5H). MS m/z: 314 [M + H] ⁺ .

Step 5: 12-6 synthesis

Add material 12-5 (1000.00 mg, 3.19 mmol) and 20 mL DMF to a pre-dried single-mouth bottle, and add NaH (382.96 mg, 9.57 mmol, 60% purity) to the system at 0 ° C at 0 ° C. After reacting for 0.5 h, 2-chloro-N,N-dimethyl-ethylamine hydrochloride (689.53 mg, 4.79 mmol, HCl) was added, and the reaction was carried out at 40 ° C for 12 h, and 5 mL of water, acetic acid was added to the system. Ethyl acetate (50 mL × 3), EtOAc (EtOAc m. 1-5:1) Purification affords 12-6. MS m/z: 385 [M + H] ⁺ .

Step 6: 12-7 Synthesis

12-6 (0.1 g, 260.10 μmol, 1 eq) and solvent TFA (1 mL) were added to a pre-dried single-mouth bottle, and reacted at 40 ° C for 1 h. The system was concentrated under reduced pressure and the system was adjusted with saturated aqueous sodium hydrogen carbonate. The pH was 7, and ethyl acetate was extracted (3×10 mL). The aqueous phase was concentrated under reduced pressure and evaporated to ethyl acetate. MS m/z: 235 [M + H] ⁺ .

Step 7: 12-8 Synthesis

12-7 (0.04 g, 223.25 μmol) and 3 mL of anhydrous methanol were added to a pre-dried single-mouth bottle, and BB-1, HOAc (1.34 mg, 22.32 μmol, 1.28 μL) was added to the system at 25 ° C. Stir for 0.5 h, then add NaBH ₃ CN (28.06 mg, 446.50 μmol), stir at 25 ° C for 12 h, add 5 mL of water to the system, extract with ethyl acetate (50 mL × 3), combine the organic phase, 5 mL of saturated brine Washed, dried over anhydrous sodium sulfate, filtered, and then evaporated. MS m/z: 398 [M + H] ⁺ .

Step 8:12 Synthesis

Adding raw materials 12-8 and 1 mL of H ₂ O to a pre-dried single-mouth bottle, adding LiOH·H ₂ O (966.97 ug, 23.05 μmol) to the system at 25 ° C, and reacting at 25 ° C for 5 min, the reaction was carried out. A 1 M aqueous HCl solution was added to the solution until pH = 6. The reaction solution was separated and purified by preparative HPLC to give Compound 12. ¹ H NMR (400 MHz, D ₂ O) δ: 8.44 (brd, J = 4.80 Hz, 1H), 8.30 (brd, J = 4.40 Hz, 1H), 7.73 (br d, J = 8.40 Hz, 1H) , 7.64 (s, 1H), 7.54 (br d, J = 4.40 Hz, 1H), 7.41 - 7.46 (m, 1H), 4.07 (br t, J = 6.80 Hz, 2H), 3.85 (s, 2H), 3.73 (s, 2H), 3.07-3.14 (m, 4H), 2.66 (s, 6H). MS m/z: 370 [M + H] ⁺ .

Example 13: Compound 13

synthetic route:

Step 1:13-2 Synthesis

Raw material 13-1 (3.00 g, 24.17 mmol) and 20 mL of SOCl _{2 were} added to a pre-dried single-mouth flask, and reacted at 80 ° C for 2 h, and the system was directly concentrated under reduced pressure to give 13-2. MS m/z: 143 [M + H] ⁺ .

Step 2: 13-3 Synthesis

Into a pre-dried single-mouth bottle was added raw material 13-2 and solvent DMF (10 mL), followed by N,N-diisopropylethylamine (1.80 g, 13.92 mmol, 2.42 mL), BB-3 ( 1.44g, 6.03mmol), stirring at 25 ° C for 12h, adding 5mL of water to the system, ethyl acetate extraction (30mL × 3), the organic phase was combined, washed with 5mL of saturated brine, dried over anhydrous sodium sulfate, filtered. The filtrate was concentrated under reduced pressure to give a crude material. MS m/z: 346 [M + H] ⁺ .

Step 3: 13-4 Synthesis

Add 13-3 (0.15g, 434.29μmol) and anhydrous toluene (3mL) to the pre-dried single-mouth bottle, add trimethyl aluminum (2M, 434.29μL) to the system, and react at 110 ° C for 12h, 5 mL of water was added to the system, and the mixture was extracted with ethyl acetate (30 mL×3). :Methanol = 20:1-10:1) Purification afforded 13-4. MS m/z: 314 [M + H] ⁺ .

Step 4: 13-5 Synthesis

In a pre-dried single-mouth bottle, raw materials 13-4 (0.1 g, 319.13 μmol) and solvent DMF (2 mL) were added, and at 0 ° C, NaH (38.30 mg, 957.39 μmol, 60%) was added to the system at 0 The reaction was carried out at ° C for 0.5 h, then 2-chloro-N,N-dimethyl-ethylamine hydrochloride (68.95 mg, 478.70 μmol, HCl) was added, and reacted at 40 ° C for 24 h, 5 mL of water, acetic acid was added to the system. Ethyl acetate extraction (50 mL × 3), EtOAc (EtOAc m. :1) Purification affords 13-5. ^{_{1 H NMR (400MHz, CDCl 3}} ) δ: 8.50 (d, J = 5.60Hz, 1H), 8.43 (s, 1H), 7.26 (d, J = 7.60Hz, 1H), 7.12 (d, J = 5.20Hz , 1H), 6.41-6.44 (m, 2H), 3.94 (t, J = 6.40 Hz, 2H), 3.76 (d, J = 7.60 Hz, 6H), 3.67 (s, 2H), 3.61 (s, 2H) , 3.14 (s, 2H), 2.40 (t, J = 6.80 Hz, 2H), 2.12 (s, 6H).

MS m/z: 385 [M + H] ⁺ .

Step 5: 13-6 synthesis

The raw material 13-5 (0.1 g, 260.10 μmol) and the solvent TFA (1 mL) were added to the pre-dried single-mouth bottle at 40 ° C for 1 h, the system was concentrated, and the pH of the system was adjusted to 7 with a saturated aqueous solution of sodium hydrogen carbonate. The mixture was extracted with ethyl acetate (20 mL×1). MS m/z: 235 [M + H] ⁺ .

Step 6: 13-7 Synthesis

Raw material BB-1 (0.04 g, 223.25 μmol) and solvent MeOH (3 mL) were added to a pre-dried single-mouth bottle, followed by addition of 13-6 (52.31 mg, 223.25 μmol), HOAc (1.34 mg, 22.32 μmol, 1.28 μL). The mixture was stirred at 25 ° C for 0.25 h, then NaBH ₃ CN (28.06 mg, 446.50 μmol) was added, and stirred at 25 ° C for 0.25 h, 5 mL of water was added to the system, and ethyl acetate was extracted (30 mL×3). The organic phase was combined, washed with EtOAc EtOAc EtOAcjjjjjjjj MS m/z: 398 [M + H] ⁺ .

Step 7: 13 Synthesis

13-7 (0.01 g, 23.05 μmol, HCl) and solvent H ₂ O (1 mL) were added to the pre-dried single-mouth bottle, and LiOH·H ₂ O (966.97 ug, 23.05 μmol) was added to the system at 25 ° C. The mixture was stirred at 25 ° C for 5 min, and the reaction mixture was adjusted to pH 6 with aqueous hydrochloric acid (2 mol/L), and the reaction mixture was evaporated to dryness. ^{_{1 HNMR δ (400MHz, D 2}} O): 8.52 (t, J = 5.60Hz, 2H), 8.38 (s, 1H), 7.72 (s, 1H), 7.63 (d, J = 5.20Hz, 1H), 7.35 (d, J = 5.60 Hz, 1H), 4.21 (t, J = 6.40 Hz, 2H), 3.96 (s, 2H), 3.67 (s, 2H), 3.31 (t, J = 7.20 Hz, 2H), 3.21. (s, 2H), 2.84 (s, 6H). MS m/z: 370 [M + H] ⁺ .

Example 14: Compound 14

Step 1: Synthesis of Compound 14-2

Compound 14-1 (10 g, 72.40 mmol) and solvent xylene (50 mL) were added to the reaction flask. After heating to 140 ° C, the reagent selenium dioxide (12.05 g, 108.60 mmol) was added in portions under reflux. The reaction was carried out at ° C for 12 hours. The reaction solution was filtered, and the filtrate was concentrated on a water. Purification by flash column chromatography (petroleum ether: ethyl acetate = 1:1) gave compound 14-2. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 10.56 (s, 1H), 9.45 (s, 1H), 9.09 (d, J = 4.8 Hz, 1H), 7.77 (d, J = 4.8 Hz, 1H).

Step 2: Synthesis of compound 14-3

Add compound 14-2 (1.9 g, 12.49 mmol) and compound BB-3 (1.69 g, 14.99 mmol) and solvent dichloromethane (20 mL) and methanol (10 mL) to a reaction flask, and add a few drops of acetic acid to adjust the solution pH= 5-6, after 0.5 hour of reaction, the reagent NaBH(OAc) ₃ (5.29 g, 24.98 mmol) was added, and the reaction was allowed to react at 25 ° C for 2 hours. The reaction was quenched with 20mL H ₂ O, and extracted with ethyl acetate (20ml × 2), 20ml saturated brine, dried over anhydrous sodium sulfate, filtered, organic phase was concentrated to give the crude product by flash column chromatography (petroleum ether: Purification of ethyl acetate = 5: 1-3: 1) gave compound 14-3.

Step 3: Synthesis of Compound 14-4

To the reaction flask was added compound 14-3 (1.8 g, 4.80 mmol) and solvent ethanol (20 mL) and water (10 mL), followed by reagent Fe (803.44 mg, 14.39 mmol) and NH ₄ Cl (307.79 mg, 5.75 mmol) The reaction was allowed to react at 78 ° C for 2 hours. The reaction solution was filtered, and the filtrate was concentrated on a water pump to remove most of the solvent. 30 mL of H2O and 30 ml of ethyl acetate were added, and the mixture was separated, ethyl acetate (20 ml × 2) was evaporated. MS m/z: 346 [M + H] ⁺ .

Step 4: Synthesis of compound 14-5

Compound 14-4 (1.2 g, 3.47 mmol) and solvent toluene (12 mL) were added to the reaction mixture, followed by trimethylaluminum (2M, 2.26 mL), and the mixture was stirred under vacuum for three times and then reacted at 110 ° C for 12 hours. The reaction solution was quenched with 20 mL of saturated KHSO ₄ solution, and the solution was adjusted to pH = 7-8 with 10 mL of saturated NaHCO 3 solution. After insolubles were filtered off, the aqueous phase was extracted with ethyl acetate (30 mL×2), and washed with 20 mL of brine. The phase was dried over anhydrous sodium sulfate, and the organic layer was filtered to afford compound 14-5. MS m/z: 314 [M + H] ⁺ .

Step 5: Synthesis of compound 14-6

Compound 14-5 (0.9 g, 4.79 mmol) and DMF (10 mL) were added to the reaction flask, then NaH (765.91 mg, 19.15 mmol, 60% purity) was added at 0 ° C, and the reagent N, N was added after 0.5 hour. - Dimethylaminochloroethane hydrochloride (1.38 g, 9.57 mmol), and the reaction was carried out at 25 ° C for 12 hours. After adding 10 ml of H ₂ O, it was extracted with ethyl acetate (10 mL × 2), washed with 10 mL of brine, dried over anhydrous sodium sulfate. Purification by flash column chromatography (dichloromethane:methanol = 50:1) gave compound 14-6. ^{_{1 H NMR (400MHz, CDCl 3}} ) δppm 8.61 (s, 1H), 8.44 (d, J = 4.8Hz, 1H), 7.32 (d, J = 8.0Hz, 1H), 7.23 (d, J = 4.8Hz, 1H), 6.46-6.53 (m, 2H), 4.05 (t, J = 6.4 Hz, 2H), 3.83 (d, J = 4.4 Hz, 6H), 3.72 (d, J = 3.6 Hz, 4H), 3.19 ( s, 2H), 2.50 (t, J = 6.8 Hz, 2H), 2.19 (s, 6H). MS m/z: 385 [M + H] ⁺ .

Step 6: Synthesis of Compound 14-7

Compound 14-6 (0.34 g, 1.30 mmol) and solvent trifluoroacetic acid (3 mL) were added to the reaction mixture, followed by reaction at 40 ° C for 2 hours. The reaction solution was concentrated on a water pump to give a crude product. The pH was adjusted to 7-8 with 10 ml of saturated sodium bicarbonate solution and concentrated on water to give a crude material. The crude product was soaked in 20 mL of a mixed solution of dichloromethane:methanol = 3:1, filtered, and the filtrate was concentrated on a water pump to give compound 14-7. MS m/z: 235 [M + H] ⁺ .

Step 7: Synthesis of Compound 14-8

Compound 14-7 (706.14 mg, 3.01 mmol) and compound BB-1 (0.3 g, 1.67 mmol) and methanol (10 mL) were added to the reaction flask, pH was adjusted to 5-6 with acetic acid, and the reagent NaBH was added after 2 hours of reaction. ₃ CN (210.43 mg, 3.35 mmol), and the reaction was carried out at 25 ° C for 1.5 hours. The reaction solution was quenched with 10mL H ₂ O, extracted with ethyl acetate (10mL × 2) the aqueous phase was extracted, washed with 10 mL saturated sodium chloride aqueous organic phases were combined, dried over anhydrous sodium sulfate, filtered, organic phase was concentrated to give a crude product which was purified by preparative HPLC Compound 14-8 was obtained. MS m/z: 398 [M + H] ⁺ .

Step 8: Synthesis of Compound 14

Compound 14-8 (0.05 g, 125.80 μmol) and solvent H ₂ O (2 mL) were added to the reaction flask, followed by the addition of the reagent lithium hydroxide monohydrate (10.56 mg, 251.59 μmol), and the reaction was carried out at 25 ° C for 0.5 hour. The reaction solution was purified by preparative HPLC to give Compound 14. ^{_{1 H NMR (400MHz, CDCl 3}} ) δppm 8.54-8.58 (m, 2H), 8.42 (d, J = 5.2Hz, 1H), 7.75 (s, 1H), 7.66 (d, J = 5.2Hz, 1H), 7.39 (d, J = 5.2 Hz, 1H), 4.24 (t, J = 7.2 Hz, 2H), 3.97 (s, 2H), 3.71 (s, 2H), 3.37 (t, J = 7.2 Hz, 2H), 3.22 (s, 2H), 2.88 (s, 6H). MS m/z: 370 [M + H] ⁺ .

Example 15: Compound 15

Step 1: Synthesis of Compound 15-2

To the reaction flask were added the compound thionyl chloride (5.75 g, 48.33 mmol) and the solvent tetrahydrofuran (150 mL). After the reaction was cooled to 0 ° C, a solution of compound 15-1 (5 g, 40.28 mmol) in tetrahydrofuran (50 mL) was slowly added dropwise. It was then slowly warmed to 25 ° C and reacted for 3 hours. Filtration and filtration of the filter cake on a water pump gave compound 15-2. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 8.26 (br s, 2H), 8.10 (dd, J = 7.4, 1.2 Hz, 1H), 8.04 (dd, J = 8.0, 1.6 Hz, 1H), 6.91 (t, J = 6.8 Hz, 1H), 4.85 (s, 2H). MS m/z: 143, 145 [M+H] ⁺ .

Step 2: Synthesis of compound 15-3

Compound 15-2 (3.8 g, 26.65 mmol) and compound BB-3 (3.64 g, 31.98 mmol) and N,N-dimethylformamide (40 mL) were added to the reaction flask, followed by reagent N, N-di Isopropylethylamine (10.33 g, 79.95 mmol) was reacted at 25 ° C for 12 hours. After adding 25 mL of H ₂ O and 30 mL of ethyl acetate, the mixture was separated, and the aqueous layer was combined with ethyl acetate (20 mL × 2), and the organic phase was washed with 25 mL of brine. Purification by flash column chromatography (dichloromethane:methanol = 30:1) gave compound 15-3.

Step 3: Synthesis of Compound 15-4

Compound 15-3 (3.5 g, 10.13 mmol) and solvent toluene (40 ml) were added to the reaction mixture, followed by trimethylaluminum (2M, 6.59 mL), and the mixture was stirred under vacuum for three times and then reacted at 110 ° C for 12 hours. The reaction solution was quenched with 10 mL of a mixed solution of KHSO ₄ and NaHCO ₃ (pH=5-6), filtered through celite, and the filtrate was extracted with ethyl acetate (20 ml×2), and washed with 20 mL of brine. The sodium is dried, filtered and the organic phase is concentrated to give compound 15-4.

Step 4: Synthesis of compound 15-5

Compound 15-4 (1 g, 5.23 mmol) and solvent N,N-dimethylformamide (10 mL) were added to the reaction mixture, followed by NaH (837.54 mg, 20.94 mmol, 60% purity) at 0 ° C. After 0.5 hours, N,N-dimethylaminochloroethane hydrochloride (1.51 g, 10.47 mmol) was added, and the reaction was allowed to react at 25 ° C for 12 hours. After adding 10 ml of H ₂ O, the aqueous phase was extracted with ethyl acetate (10 mL × 2) Purification by flash column chromatography (dichloromethane:methanol = 50:1) gave compound 15-5. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 8.41 (dd, J = 6.4, 1.6 Hz, 1H), 7.63 (dd, J = 7.6, 1.6 Hz, 1H), 7.35 (d, J = 8.0 Hz, 1H), 7.10 (dd, J = 7.6, 4.8 Hz, 1H), 6.46-6.52 (m, 2H), 4.26 (t, J = 6.6 Hz, 2H), 3.83 (d, J = 6.0 Hz, 7H), 3.77 (s) , 2H), 3.64 (s, 2H), 3.24 (s, 2H), 2.57 (br t, J = 6.8 Hz, 2H), 2.20 (s, 6H). MS m/z: 385 [M + H] ⁺ .

Step 5: Synthesis of compound 15-6

Compound 15-5 (0.3 g, 1.14 mmol) and trifluoroacetic acid (3 mL) were added to the reaction mixture, followed by reaction at 40 ° C for 2 hours. The reaction solution was concentrated on a water pump to give a crude product. The pH was adjusted to 7-8 with 10 ml of saturated sodium bicarbonate solution and concentrated on water to give a crude material. The crude product was soaked in 20 mL of a mixed solution of dichloromethane:methanol = 3:1, filtered, and the filtrate was concentrated on a water pump to give compound 15-6. MS m/z: 235 [M + H] ⁺ .

Step 6: Synthesis of compound 15-7

Compound 15-6 (0.25 g, 1.07 mmol), BB-1 (159.32 mg, 889.19 μmol) and methanol (3 mL) were added to the reaction flask, pH was adjusted to 5-6 with acetic acid, and cyano boron was added after 2 hours. Sodium hydride (111.75 mg, 1.78 mmol) was reacted at 25 ° C for 1.5 hours. The reaction was quenched with 10mL H ₂ O, extracted with ethyl acetate (10ml × 2) the aqueous phase was extracted, washed with 10 mL saturated sodium chloride aqueous organic phases were combined, dried over anhydrous sodium sulfate, filtered, organic phase was concentrated to give crude product. Purification by preparative HPLC gave compound 15-7. MS m/z: 398 [M + H] ⁺ .

Step 7: Synthesis of Compound 15

Compound 15-7 (0.03 g, 75.48 μmol) and solvent water (2 mL) were added to the reaction flask, followed by the addition of the reagent lithium hydroxide monohydrate (6.33 mg, 150.95 μmol), and the reaction was carried out at 25 ° C for 10 minutes. The reaction solution was concentrated and purified by preparative HPLC to give Compound 15. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 8.56 (d, J = 5.2 Hz, 1H), 8.44 (dd, J = 5.2, 1.6 Hz, 1H), 7.81 (d, J = 7.6 Hz, 1H), 7.75 ( s, 1H), 7.66 (d, J = 5.2 Hz, 1H), 7.34 (dd, J = 7.6, 5.2 Hz, 1H), 4.22 (t, J = 5.2 Hz, 2H), 4.00 (s, 2H), 3.69 (s, 2H), 3.44 (br t, J = 5.6 Hz, 2H), 3.28 (s, 2H), 2.96 (s, 6H). MS m/z: 370 [M + H] ⁺ .

Example 16: Compound 16

Step 1: Synthesis of Compound 16-2

Compound 16-1 (2.45 g, 28.12 mmol) and solvent tetrahydrofuran (30 mL) and water (10 mL) were added to the reaction mixture, followed by the reagent sodium hydrogencarbonate (9.45 g, 112.49 mmol), (Boc) ₂ O (9.21 g) , 42.18 mmol), the reaction was carried out at 25 ° C for 12 hours. After adding 10 mL of H ₂ O, it was extracted with ethyl acetate (10 mL × 2), dried over anhydrous sodium sulfate. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 5.06 (br s, 1H), 3.60 (d, J = 5.2 Hz, 2H), 1.45 (s, 10H), 0.84 (m, 4H).

Step 2: Synthesis of Compound 16-3

Compound 16-2 (3.5 g, 18.69 mmol) and solvent dichloromethane (40 mL) were added to the reaction flask, followed by the reagent triphenylphosphine (6.62 g, 25.24 mmol) and carbon tetrabromide (8.37 g, 25.24 mmol). The reaction was allowed to react at 25 ° C for 12 hours. The reaction mixture was concentrated on a water-purified water to afford crude crystals (yield: petroleum ether: ethyl acetate = 5:1). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 5.14 (br s, 1H), 3.59 (br s, 2H), 1.46 (s, 9H), 1.05-1.10 (m, 2H), 0.89-0.94 (m, 2H) ).

Step 3: Synthesis of Compound 16-4

Compound 16-3 (1.4 g, 5.60 mmol) and solvent dimethyl sulfoxide (15 ml) were added to the reaction flask, followed by the reagent KI (92.91 mg, 559.70 μmol) and NaCN (1.37 g, 27.99 mmol). The reaction was carried out at 25 ° C for 12 hours. The reaction was diluted with H ₂ O was added 10mL, extracted with ethyl acetate (10ml × 2), 10ml saturated brine, dried over anhydrous sodium sulfate, filtered, organic phase was concentrated to give the crude product by flash column chromatography (petroleum ether: acetic acid Ethyl ester = 3:1) was purified to give compound 16-4.

Step 4: Synthesis of Compound 16-5

Compound 16-4 (0.8 g, 4.08 mmol) and solvent ethanol (30 mL) and aqueous ammonia (10 mL) were added to the reaction flask, then Raney nickel (1 g) was added under argon atmosphere, 30 psi under a hydrogen atmosphere, 30 ° C Reaction for 6 hours. The reaction solution was filtered through celite, and the filtrate was concentrated on water. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 4.93 (s, 1H), 2.82 - 2.86 (t, J = 7.2 Hz, 2H), 1.62-1.64 (t, J = 7.2 Hz), 1.43 (s, 9H), 0.77 (s, 2H), 0.64 (s, 2H).

Step 5: Synthesis of Compound 16-6

Compound 16-5 (0.4 g, 2.00 mmol) and N,N-dimethylformamide (10 mL) were added to the reaction mixture, followed by N,N-diisopropylethylamine (180.69 mg, 1.40 mmol). A solution of ethyl bromoacetate (266.83 mg, 1.60 mmol) in N,N-diisopropylethylamine (2 mL) was slowly added, and the mixture was reacted at 25 ° C for 10 minutes. After adding 10 mL of H ₂ O, it was extracted with ethyl acetate (10 mL × 2), washed with 10 mL of brine, dried over anhydrous sodium sulfate 3:1) Purification afforded compound 16-6. ^{_{1 H NMR (400MHz, CDCl 3}} ) δppm 4.20 (q, J = 7.2Hz, 2H), 3.39 (s, 2H), 2.74 (t, J = 7.2Hz, 2H), 1.83 (s, 2H), 1.71 ( Br t, J=6.6 Hz, 1H), 1.64-1.76 (m, 1H), 1.43 (br s, 9H), 1.26-1.31 (m, 3H), 0.78 (br s, 2H), 0.61-0.67 (m) , 2H).

Step 6: Synthesis of Compound 16-7

Compound 16-6 (0.16 g, 558.73 μmol) and solvent HCl/ethyl acetate (4M, 2 mL) were added to the reaction mixture, and the reaction was allowed to react at 25 ° C for 2 hours. The reaction solution was concentrated on a water pump to give Compound 16-7. MS m/z: 187 [M + H] ⁺ .

Step 7: Synthesis of Compound 16-8

Compound 16-7 (0.1 g, 536.91 μmol) and solvent methanol (20 mL) were added to the reaction flask, followed by the reagent sodium methoxide (174.02 mg, 3.22 mmol), and the reaction was allowed to react at 75 ° C for 12 hours. The reaction mixture was quenched with 5 mL of H ₂ O and concentrated directly to afford compound 16-8. MS m/z: 141 [M + H] ⁺ .

Step 8: Synthesis of Compound 16-9

Compound 16-8 (0.07 g, 499.35 μmol) and solvent methanol (10 mL) were added to the reaction flask, and compound BB-1 (89.47 mg, 499.35 μmol) was added thereto, and the pH was adjusted to 5-6 with acetic acid, and the reaction was carried out for 0.5 hour. Sodium cyanoborohydride (62.76 mg, 998.70 μmol) was reacted at 25 ° C for 2 hours. The reaction mixture was quenched with 5 mL of H ₂ O and then evaporated. MS m/z: 304 [M + H] ⁺ .

Step 9: Synthesis of Compound 16

Compound 16-8 (0.05 g, 164.82 μmol) and solvent N,N-dimethylformamide (2 mL) were added to the reaction flask, followed by NaH (19.78 mg, 494.46 μmol, 60% purity), and the reaction was at 0 ° C. After 0.5 hours, N,N-dimethylaminochloroethane hydrochloride (28.68 mg, 247.23 μmol) was added, and the reaction was allowed to react at 25 ° C for 12 hours. Add 3ml H ₂ O quench the reaction, followed by the water pump to give the crude product is directly concentrated to give compound 16 was purified by preparative HPLC. ^{1 H NMR (400MHz, D2O)} δ: 8.79 (d, J = 5.2Hz, 1H), 8.02 (s, 1H), 7.98 (d, J = 4.8Hz, 1H), 4.61 (s, 2H), 4.25 ( Br s, 2H), 3.81 (t, J = 6.8 Hz, 2H), 3.54 (br t, J = 5.4 Hz, 2H), 3.21-3.29 (m, 2H), 2.03 (br s, 2H), 1.22 ( Br s, 2H), 1.11 (br s, 2H). MS m/z: 347 [M+H] ⁺ .

Example 17: Compound 17

synthetic route:

Step 1: 17-2 Synthesis

The raw material 17-1 (5 g, 31.62 mmol, 4.35 mL) and the reagent NH ₃ / MeOH (7M, 50 mL) were added to the previously dried septic tank, and the mixture was stirred at 50 ° C for 24 hours, and the system was concentrated under reduced pressure to give 17 -2, MS m/z: 129 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ δ δ δ δ δ δ δ δ δ δ δ δ 。。。。。。。。。。。。。。。。。。。。。。。。

Step 2: 17-3 Synthesis

The reagent lithium aluminum hydride (4.44 g, 117.07 mmol) and anhydrous tetrahydrofuran (100 mL) were added to a pre-dried single-mouth bottle, and at 0 ° C, the starting material 17-2 (5 g, 39.02 mmol) was then added, Stir at 60 ° C for 12 h, add 4.5 mL of water to the system, then add 4.5 mL of 15% aqueous sodium hydroxide solution, then add 13.5 mL of water, precipitate a large amount of white solid, directly filter, leave the filtrate, get 17-3 directly to the next step , MS m/z: 101 [M+H] ⁺ .

Step 3: 17-4 Synthesis

To the pre-dried flask, the treatment liquid of the 17-3 obtained in the previous reaction (3.91 g, 39.04 mmol) and the reagent (Boc) ₂ O (5.11 g, 23.42 mmol, 5.38 mL) were stirred at 25 ° C for 4 h. The mixture was washed with aq. : 1-1:1) Obtained 17-4, MS m/z: 201 [M+H] ⁺ , ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 4.86 (br s, 1H), 2.74 (d, J = 6.0) Hz, 2H), 2.22 (s, 2H), 1.53 (br s, 2H), 1.08 (s, 9H), 0.34 (m, 4H).

Step 4: 17-5 Synthesis

The raw material 17-4 (575 mg, 2.87 mmol) and the solvent DMF (10 mL) were added to a pre-dried single-mouth flask, and N,N-diisopropylethylamine (742.12 mg, 5.74 mmol, 1.00 mL) was added to the system. Methyl bromoacetate (439.19 mg, 2.87 mmol, 271.11 uL) was reacted at 25 ° C for 12 h, 100 mL of ethyl acetate was added to the system, and washed with saturated brine (30 ml × 3). sulfate, filtered, and concentrated under reduced pressure to give 17-5, MS m / z: 273 [m + H] +.

Step 5: 17-6 synthesis

The raw material 17-5 (0.5 g, 1.84 mmol) and anhydrous dichloromethane (5 mL) were added to a pre-dried single-mouth flask, and N,N-diisopropylethylamine (237.28 mg, 1.84 mmol) was added to the system. , 319.79uL), benzyl chloroformate (375.84mg, 2.20mmol, 313.20uL), reacted at 25 ° C for 0.5h, added 50mL of dichloromethane to the system, washed with saturated saline (20mL × 3), organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 17-6,307 [M ⁺ H] +.

Step 6: 17-7 Synthesis

In a pre-dried single-mouth bottle, raw materials 17-6 (0.4 g, 984.08 μmol) and dichloromethane (4 mL) were added, followed by the addition of trifluoroacetic acid (1 mL), and reacted at 25 ° C for 3 h, adding 20 mL of saturation to the system. aqueous sodium bicarbonate, extracted with dichloromethane (50mL × 3), the organic phases were combined, washed with 5 mL saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, to give 17-7,307 [M ⁺ H] + concentrated under reduced pressure.

Step 7: 17-8 Synthesis

Raw materials 17-7 (0.3 g, 979.25 μmol) and anhydrous toluene (10 mL) were added to a pre-dried single-mouth bottle, and trimethylaluminum (1 M, 1.96 mL) was added to the system, and the reaction was carried out at 100 ° C for 2 h. 5 mL of 1N potassium hydrogen sulfate solution was added to the system, and the mixture was extracted with ethyl acetate (50 mL × 3), washed with 5 mL of brine, dried over anhydrous sodium sulfate Purification with methyl chloride:methanol = 40:1 - 20:1) affords 17-8, 275 [M+H] ⁺ .

Step 8: 17-9 Synthesis

Add 17-8 (0.12 g, 437.45 μmol) and solvent ethyl acetate (5 mL) to the pre-dried flask, followed by reagent Pd/C (0.1 g, 5% purity) in H ₂ (15 psi) environment. After stirring at 25 ° C for 1 h, the catalyst was filtered and the filtrate was concentrated to give 17-9, 141 [M+H] ⁺ .

Step 9: 17-10 Synthesis

Raw materials 17-9 (0.05 g, 279.06 μmol) and anhydrous methanol (3 mL) were added to the pre-dried flask, and the starting material BB-1 (39.12 mg, 279.06 μmol), reagent glacial acetic acid (1.68 mg, 27.91 μmol, 1.60uL), stirring at 25 ° C for 1 h, then adding sodium cyanoborohydride (35.07 mg, 558.12 μmol), stirring at 25 ° C for 0.25 h, adding 1 mL of water to the system, and directly concentrating under reduced pressure to give a crude product. The crude material was purified by preparative HPLC to afford 17-10,304 [M+H] ⁺ . ^{_{1 H NMR (400MHz, CDCl 3}} ) δppm 8.70 (d, J = 5.20Hz, 1H), 7.97 (s, 1H), 7.72 (dd, J = 5.20,1.60Hz, 1H), 5.93 (s, 1H), 4.42 (q, J = 7.20 Hz, 2H), 4.07 (s, 2H), 3.67 (s, 2H), 3.10 (br s, 2H), 2.81 (s, 2H), 1.42 (t, J = 6.80 Hz, 3H), 0.486 (m, 4H)

Step 10:17 Synthesis

Raw materials 17-10 (0.02 g, 65.93 μmol) and solvent DMF (1 mL) were added to the pre-dried flask, and NaH (7.91 mg, 197.79 μmol, 60% purity) was added to the system at 0 ° C. After stirring at ° C for 0.5 h, 2-chloro-N,N-dimethyl-ethylamine hydrochloride (14.24 mg, 98.89 μmol) was added and stirred at 25 ° C for 12 h. 1mL saturated ammonium chloride aqueous solution was added to the system, concentrated under reduced pressure to give the crude product, the crude product to give Compound 17,347 [M + H] ⁺ purified by preparative HPLC. ¹ H NMR (399 MHz, D ₂ O) δ ppm 8.46 (d, J = 5.20 Hz, 1H), 7.63 (s, 1H), 7.57 (dd, J = 5.20, 1.60 Hz, 1H), 3.86 (s, 2H) , 3.70 (br s, 2H), 3.56 (br s, 2H), 3.21 (m, 2H), 3.09 (s, 1H), 2.83 (s, 6H), 2.34 (s, 1H), 0.52 (s, 2H) ), 0.42 (s, 2H)

Example 18: Compound 18

Step 1: Synthesis of Compound 18-2

18-1 (15 g, 125.43 mmol) and dioxane (200 mL) were added to a reaction flask, then NaOH (1M, 250.85 mL) and Boc ₂ O (54.75 g, 250.85 mmol) were added, and the reaction mixture was stirred at 25 ° C for 3 hours. After the reaction was completed, a saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the mixture was evaporated to dryness. To the rough product. The crude product was used directly in the next step without purification. Compound 18-2 was obtained.

Step 2: Synthesis of Compound 18-3

Was added 18-2 (15g, 81.86mmol) added to the reaction flask, ethyl acetate (300 mL) and H ₂ O (300mL), followed by addition of NaIO ₄ (70.03g, 327.43mmol) and RuCl ₃ (509.39mg, 2.46mmol) The reaction was stirred at 25 ° C for 2 hours. Isopropanol (300 mL) was added to the reaction mixture, and after stirring for 0.5 hr, a large amount of brown solid was formed, which was filtered through Celite and washed with ethyl acetate. The organic phase was combined and dried over anhydrous sodium sulfate. The crude product was purified by an automatic column-column COMBI-FLASH (gradient elution: petroleum ether: ethyl acetate = 1:0 to 1:1) to obtain a pure product. Compound 18-3 was obtained. 1H NMR (400 Hz, CDCl3) δ = 7.94 (d, J = 8.8 Hz, 1H), 7.72 (d, J = 2.0 Hz, 1H), 7.36-7.39 (dd, J = 6.0 Hz, 2.0 Hz, 2H), 4.10 (s, 2H), 3.73 (s, 3H), 3.45 (s, 2H), 2.10 (s, 1H). MS m/z: 142 [M-55] ⁺ .

Step 3: Synthesis of Compound 18-4

Was added 18-3 (20g, 101.40mmol) added to the reaction flask, THF (200mL) and H ₂ O (100mL), then was added LiOH.H at _{0 ℃ 2 O (1M, 101.40mL} ), the reaction was stirred at 25 ℃ 16 hour. To the reaction mixture, 5% citric acid was added until pH = 3, then ethyl acetate (200 mL×3), and the organic phase was combined and dried over anhydrous sodium sulfate. Used directly in the next step without purification. Compound 18-4 was obtained.

Step 4: Synthesis of Compound 18-5

18-4 (15 g, 69.69 mmol) and Toluene (150 mL) were added to the reaction flask, then TEA (17.63 g, 174.22 mmol) and DPPA (28.77 g, 104.53 mmol) were added, and the reaction was stirred at 110 ° C under nitrogen atmosphere. After an hour, BnOH (15.07 g, 139.38 mmol) was then added and the reaction was stirred at 110 ° C under nitrogen for 1 hour. After the reaction mixture was cooled to room temperature, water (300 mL) was evaporated, and then ethyl acetate (150 mL) was evaporated. The crude product was separated and purified by an automatic column-column COMBI-FLASH to obtain a pure product. Compound 18-5 was obtained.

_{1H NMR (400MHz, CDCl 3)} δ = 6.99-7.08 (m, 5H), 5.60 (br, 1H), 4.80-5.02 (m, 3H), 3.35 (br, 1H), 2.35-2.39 (m, 2H) , 1.18 (br s, 10H), 0.96-0.99 (m, 1H), 0.65-0.67 (m, 1H), 0.02-0.04 (m, 1H). MS m/z: 221 [Ms-100+1] ⁺

Step 5: Synthesis of Compound 18-6

18-5 (9.3 g, 29.03 mmol) and ethyl acetate (60 mL) were added to the reaction mixture, then HCl / ethyl acetate (4M, 160 mL) was added and the mixture was stirred at 25 ° C for 2 hours. The reaction was concentrated under reduced pressure to give a crude material. The crude product was used in the next step without purification. The compound 18-6 was obtained. 1H NMR (400 MHz, EtOAc) δ= 7.30-7.36 (m, 5H), 5.09-5.16 (m, 2H), 3.03 (br s, 1H), 2.74-2.84 (m, 2H), 1.13-1.28 (m, 1H), 1.07-1.11 (m, 1H), 0.57-0.59 (m, 1H). MS m/z: 221Ms+H] ⁺

Step 6: Synthesis of Compound 18-7

18-6 (3 g, 11.69 mmol), TEA (2.36 g, 23.37 mmol) and dichloromethane (30 mL) were added to the reaction flask, and ethyl glyoxylate (2.39 g, 11.69 mmol) and HOAc were added at 25 ° C ( After the reaction was stirred at 25 ° C for 2 hours, NaBH(OAc) ₃ (4.95 g, 23.37 mmol, 2 eq) was added, and the final reaction was stirred at 25 ° C for 16 hours. Water (100 ml) was added to the mixture and the mixture was evaporated. Used directly in the next step without purification. Compound 18-7 was obtained. MS m/z: 307 [Ms + H] ⁺ .

Step 7: Synthesis of compound 18-8

18-7 (3.58 g, 11.69 mmol), DIEA (3.02 g, 23.37 mmol) and dichloromethane (40 mL) were added to the reaction flask, then Boc ₂ O (3.83 g, 17.53 mmol) was added and the reaction was stirred at 25 ° C. 16 hours. The reaction solution was concentrated under reduced pressure to give a crude material. The crude product was separated and purified by an automatic column-column COMBI-FLASH to obtain a pure product. The compound 18-8 was obtained. 1H NMR (400 MHz, CDC3) δ=7.19-7.32 (m, 5H), 6.66 (br s, 1H), 4.99-5.11 (m, 2H), 4.04-4.15 (m, 2H), 3.86(s,2H), 3.25-3.40(m,2H), 2.60(br s,1H), 1.43(s,9H),1.17-1.19(m,3H),1.08(br s,1H),0.94( Br s, 1H), 0.29 (br s, 1H).

Step 8: Synthesis of compound 18-9

18-8 (0.5 g, 1.23 mmol), Pd/C (0.3 g, 1.23 mmol) and THF (50 mL) were added to the reaction flask, and then hydrogen was replaced three times, and then stirred at H 2 and 25 ° C for 0.25 hours. The reaction mixture was filtered through EtOAc (EtOAc)EtOAc. The compound 18-9 was obtained. 1H NMR (400MHz, CDCl3) δ=4.43-4.48 (m, 1H), 4.17-4.20 (m, 3H), 4.02-4.05 (m, 2H), 3.34-3.35 (m, 2H) , 1.48 (s, 9H), 1.26-1.29 (m, 4H), 1.00-1.02 (m, 1H), 0.73-0.99 (m, 1H), 0.51 - 0.52 (m, 1H). MS m/z: 273 [Ms + H] ⁺ .

Step 9: Synthesis of Compound 18-10

18-9 (0.33 g, 1.21 mmol), CH ₃ ONa (392.74 mg, 7.27 mmol) and MeOH (20 mL) were added to the reaction mixture, and the mixture was stirred at 70 ° C for 16 hours. The reaction solution was filtered and concentrated under reduced pressure to give a crude material. The crude product was separated and purified by an automatic column-column COMBI-FLASH to obtain a pure product. Compound 18-10 was obtained. MS m/z: 171 [Ms-55] ⁺ .

Step 10: Synthesis of compound 18-11

18-10 (110 mg, 486.14 μmol) and DMF (2 mL) were added to the reaction flask, NaH (77.78 mg, 1.94 mmol) was added at 0 ° C, and stirred for 0.5 hour, then N,N-dimethylamine chloride hydrochloride was added. (140.05 mg, 972.28 μmol), and the reaction was stirred at 40 ° C for 3 hours. A saturated aqueous solution of ammonium chloride (20 mL) was added, and ethyl acetate (5 mL) was evaporated. The crude product was separated by an automatic column-column COMBI-FLASH (purification to give the product pure product. Compound 18-11 was obtained.

Step 11: Synthesis of compound 18-12

18-11 (60 mg, 201.75 μmol) and ethyl acetate (5 mL) were added to a reaction mixture, then HCl/ethyl acetate (4M, 5 mL) was added and the mixture was stirred at 25 ° C for 1 hour. The reaction solution was concentrated under reduced pressure to give a crude material. The crude product was used in the next step without purification. Compound 18-12 was obtained. MS m/z: 198 [Ms + H] ⁺ .

Step 12: Synthesis of Compound 18-13

18-12 (48 mg, 205.36 μmol), TEA (20.78 mg, 205.36 μmol) and dichloromethane (2 mL) were added to the reaction flask, followed by addition of BB-1 (36.79 mg, 205.36 μmol) and AcOH (0.05). After stirring at 25 ° C for 1 hour, NaBH(OAc) ₃ (65.29 mg, 308.04 μmol) was added, and the final reaction was stirred at 25 ° C for 0.5 hour. A saturated aqueous solution of sodium hydrogencarbonate was added to the mixture until pH = 7 and dichloromethane was evaporated under reduced vacuo. The residue was purified by preparative hp~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ 5.2, 1.6 Hz, 1H), 4.79-4.83 (m, 1H), 4.65 - 4.66 (m, 2H), 4.43-4.47 (m, 1H), 4.33-4.42 (m, 1H), 3.72 (d, J = 12.8 Hz, 1H), 3.41-3.44 (m, 2H), 3.33-3.40 (m, 1H), 2.93-2.96 (m, 7H), 1.83-1.84 (m, 1H), 1.32-1.41 (m, 4H) , 0.94 (dt, J = 4.2, 6.0 Hz, 1H). MS m/z: 361 [Ms + 1] ⁺ .

Step 13: Synthesis of Compound 18

18-13 (25 mg, 69.36 μmol) and H ₂ O (1 mL) were added to the reaction flask, then LiOH.H ₂ O (5.82 mg, 138.72 μmol) was added, and the reaction was stirred at 25 ° C for 0.5 hour. A 1 M aqueous hydrochloric acid solution was added to the reaction until pH = 6. The crude product was purified by preparative HPLC to afford compound 18. ^{1 H NMR (400MHz, DMSO-} d6) δ = 8.55 (d, J = 5.2Hz, 1H), 7.87 (s, 1H), 7.61-7.62 (m, 1H), 4.13 (d, J = 12.8Hz, 1H ), 4.03 (br s, 1H), 3.84 (d, J = 14.0 Hz, 1H), 3.63 (d, J = 14.0 Hz, 1H), 3.37 (br d, J = 4.8 Hz, 1H), 3.34 (br d, J = 4.2 Hz, 1H), 3.06 (br s, 1H), 2.91-2.95 (m, 1H), 2.84 (br d, J = 13.2 Hz, 1H), 2.67 (br s, 1H), 2.40 ( Br s,6H), 1.84 (t, J = 12.0 Hz, 1H), 1.40 (br dd, J = 5.2, 5.6 Hz, 1H), 0.86 (br dd, J = 1.6, 6.4 Hz, 1H), 0.53 ( Br d, J = 4.0 Hz, 1H). MS m/z: 333 [Ms + H] ⁺ .

Example 19: Preparation of Compound 19

synthetic route:

Step 1: Synthesis of Compound 19-1

Raw material BB-2-1 (0.4 g, 1.87 mmol) and solvent N,N-dimethylformamide (10 mL) were added to a pre-dried single-mouth bottle, and NaH (298.70 mg) was added to the system at 0 °C. , 7.47 mmol, 60% purity), reacted at 0 ° C for 0.5 h, then added N,N-diethylaminochloroethane hydrochloride (481.92 mg, 2.80 mmol), stirred at 40 ° C for 12 h, to system Add 10 mL of water, extract with ethyl acetate (50 mL×3), EtOAc (EtOAc) =10:1-3:1) Purification afforded 19-1. MS m/z: 314 [M + H] ⁺ .

Step 2: Synthesis of Compound 19-2

Raw material 19-1 (0.1 g, 319.05 μmol) and reagent HCl/MeOH (4M, 5 mL) were added to a pre-dried one-necked flask, and stirred at 25 ° C for 1 hour, and the system was concentrated under reduced pressure to give 19-2. MS m/z: 214 [M + H] ⁺ .

Step 3: Synthesis of Compound 19-3

In a pre-dried single-mouth bottle, raw material 19-2 (0.1 g, 400.35 μmol, HCl), BB-1 (68.32 mg, 381.29 μmol) and anhydrous dichloromethane (4 mL) were added, followed by the addition of reagents N, N- Diisopropylethylamine (59.13 mg, 457.55 μmol, 79.69 μL), glacial acetic acid (1.14 mg, 19.06 μmol, 1.09 μL), adjusted system pH to 6, stirred at 25 ° C for 0.5 hours, then added triacetoxy Sodium borohydride (161.62 mg, 762.58 μmol) was stirred at 25 ° C for 0.5 h, 5 mL of water was added, and the mixture was extracted with dichloromethane (3×30 mL). The organic phase was combined and washed with 5 mL of brine. The organic layer was dried (Na2SO4). MS m/z: 375 [M + H] ⁺ .

Step 4: Synthesis of Compound 19

Add 19-3 (0.05 g, 132.81 μmol) and water (2 mL) to a pre-dried single-mouth bottle, and add LiOH.H ₂ O (27.86 mg, 664.03 μmol) to the system at 25 ° C at 25 ° C. After stirring for 10 minutes, the pH of the system was adjusted to 7 with 1M aqueous hydrochloric acid. ¹ H NMR (400 MHz, D ₂ O) δ ppm 8.43 (d, J = 4.80 Hz, 1H), 7.60 (s, 1H), 7.54 (dd, J = 5.20, 1.60 Hz, 1H), 3.74 (s, 2H) , 3.66 (br t, J = 6.40 Hz, 2H), 3.40-3.54 (m, 4H), 3.07-3.22 (m, 6H), 2.81 (br s, 2H), 1.73 (br s, 2H), 1.09- 1.21 (t, 6H). MS m/z: 349 [M+H] ⁺ .

Example 20: Compound 20

synthetic route:

Step 1: Synthesis of Compound 20-1

Raw material BB-2-1 (0.4 g, 1.87 mmol) and solvent N,N-dimethylformamide (10 mL) were added to a pre-dried single-mouth bottle, and NaH (298.70 mg) was added to the system at 0 °C. , 7.47 mmol, 60% purity), reacted at 0 ° C for 0.5 h, then added 1-(2-chloroethyl)pyrrolidine hydrochloride (476.28 mg, 2.80 mmol), and stirred at 40 ° C for 12 h. To the system, 10 mL of water was added, and ethyl acetate (50 mL×3) was evaporated. :Methanol = 10:1-3:1) Purification afforded 20-1. MS m/z: 312 [M + H] ⁺ .

Step 2: Synthesis of Compound 20-2

Raw material 20-1 (0.1 g, 321.11 μmol) and reagent HCl/MeOH (4M, 5 mL) were added to a pre-dried single-mouth flask, and the mixture was reacted at 25 ° C for 1 hour, and the system was directly concentrated under reduced pressure to give 20-2. MS m/z: 212 [M + H] ⁺ .

Step 3: Synthesis of Compound 20-3

Into a pre-dried single-mouth bottle was added raw material 20-2 (0.1 g, 403.61 μmol), BB-1 (68.87 mg, 384.39 μmol) and anhydrous dichloromethane (4 mL), followed by the addition of reagent N, N-diisopropyl Ethylethylamine (59.61 mg, 461.27 μmol, 80.34 μL), glacial acetic acid (1.15 mg, 19.22 μmol, 1.10 μL), adjust the pH of the system to 6, and stir at 25 ° C for 0.5 hours, followed by the addition of triacetoxyborohydride Sodium (162.94 mg, 768.78 μmol) was reacted at 25 ° C for 0.5 hours. After adding 5 mL of water, the system was extracted with dichloromethane (3×50 mL). The organic layer was evaporated. Dichloromethane:methanol = 10:1-5:1) Purification afforded 20-3. MS m/z: 375 [M + H] ⁺ .

Step 4: Synthesis of Compound 20

Add 20-3 (0.05 g, 133.52 μmol) and water (2 mL) to a pre-dried single-mouth bottle, and add LiOH.H ₂ O (28.01 mg, 667.60 μmol) to the system at 25 ° C at 25 ° C. After stirring for 10 minutes, the pH of the system was adjusted to 7 with 1M aqueous hydrochloric acid, and then concentrated under reduced pressure to give a crude product. ¹ H NMR (400 MHz, D ₂ O) δ ppm 8.44 (d, J = 5.20 Hz, 1H), 7.60 (s, 1H), 7.55 (dd, J = 5.20, 1.20 Hz, 1H), 3.75 (s, 2H) , 3.66 (t, J = 6.00 Hz, 2H), 3.40-3.53 (m, 4H), 3.26 (br t, J = 6.00 Hz, 6H), 2.81 (br s, 2H), 1.91 (br s, 4H) , 1.73 (br s, 2H). MS m/z: 347 [M+H] ⁺ .

Example 21: Compound 21

synthetic route:

Step 1: Synthesis of Compound 21-1

Raw material BB-2-1 (0.4 g, 1.87 mmol) and N,N-dimethylformamide (10 mL) were added to a pre-dried single-mouth bottle, and NaH (298.70 mg, was added to the system at 0 ° C, 7.47mmol, 60% purity), reacted at 0 ° C for 0.5 hours, then added 2-chloroethyl methyl ether (264.74 mg, 2.80 mmol, 254.56 μL), stirred at 40 ° C for 12 hours, added to the system After 10 mL of water and ethyl acetate (50 mL × 3), EtOAc (EtOAc) MS m/z: 217 [M + H] ⁺ .

Step 2: Synthesis of Compound 21-2

Raw material 21-1 (0.2 g, 734.38 μmol) and reagent HCl/MeOH (4M, 5 mL) were added to a pre-dried one-necked flask, and reacted at 25 ° C for 0.5 hour, and the system was directly concentrated under reduced pressure to give 21-2. MS m/z: 173 [M+H] ⁺ .

Step 3: Synthesis of Compound 21-3

Add 21-2 (0.15g, 718.79μmol, HCl), BB-1 (122.65mg, 684.56μmol) and anhydrous dichloromethane (4mL) to the pre-dried single-mouth bottle, then add the reagent N, N-diiso Propylethylamine (106.17 mg, 821.47 μmol, 143.88 μL), glacial acetic acid (2.06 mg, 34.23 μmol, 1.96 μL), adjust the pH of the system to 6, and stir at 25 ° C for 0.5 hours, followed by the addition of triacetoxy boron Sodium hydride (290.17 mg, 1.37 mmol) was reacted for 5 hours at 25 ° C, 5 mL of water was added, and the mixture was extracted with dichloromethane (3×50 mL). The organic phase was combined and washed with 5 mL of brine Drying, filtration, concentrating the organic phase <RTI ID=0.0> MS m/z: 336 [M+H] ⁺ .

Step 4: Synthesis of Compound 21

Into a pre-dried single-mouth bottle, raw materials 21-3 (0.05 g, 134.46 μmol) and water (1 mL) were added, and at 25 ° C, LiOH.H ₂ O (28.21 mg, 672.30 μmol) was added to the system at 25 The reaction was carried out for 5 minutes at rt. ¹ H NMR (400 MHz, D ₂ O) δ ppm 8.39 (d, J = 5.20 Hz, 1H), 7.55 (s, 1H), 7.49 (d, J = 5.20 Hz, 1H), 3.71 (s, 2H), 3.37 -3.50 (m, 8H), 3.21 (s, 3H), 2.76 (br s, 2H), 1.68 (br s, 2H). MS m/z: 308 [M + H] ⁺ .

Example 22: Preparation of Compound 22

synthetic route:

Step 1: 22-1 Synthesis

In a pre-dried single-mouth bottle, raw material BB-5 (0.3 g, 1.17 mmol), 4,4-difluoropiperidine hydrochloride (221.35 mg, 1.40 mmol) and anhydrous dichloromethane (10 mL) were added, followed by addition. Reagent glacial acetic acid (3.51 mg, 58.53 μmol, 3.35 μL), adjust system pH=6, stir at 25 ° C for 0.5 h, then add sodium triacetoxyborohydride (496.16 mg, 2.34 mmol) at 25 ° C The reaction was carried out for 0.5 hours, and 5 mL of water was added to the mixture. The mixture was extracted with dichloromethane (3×50 mL). Purification by flash column chromatography (dichloromethane:methanol = 10:1-5:1) afforded 22-1. MS m/z: 362 [M + H] ⁺ .

Step 2: 22-2 Synthesis

Raw material 22-1 (0.2 g, 553.36 μmol) and reagent HCl/MeOH (4M, 10.00 mL) were added to a pre-dried single-mouth bottle, and the reaction was carried out at 25 ° C for 1 hour, and the system was directly concentrated under reduced pressure to give 22-2. . MS m/z: 262 [M+H] ⁺ .

Step 3: 22-3 Synthesis

In a pre-dried vial, feed 22-2 (0.16 g, 537.32 umol, HCl) and anhydrous dichloromethane were added followed by N,N-diisopropylethylamine (79.36 mg, 614.09 μmol, 106.96 μL) , BB-1 (91.69 mg, 511.44 μmol), glacial acetic acid (1.54 mg, 25.59 μmol, 1.46 μL), adjusting system pH=6, stirring at 25 ° C for 0.5 hours, followed by the addition of sodium triacetoxyborohydride ( 216.92 mg, 1.02 mmol), stirred at 25 ° C for 0.5 h, 5 mL of water was added, the system was extracted with dichloromethane (3×50 mL), and the combined organic phases were washed with 5 mL of brine The organic phase was concentrated under reduced pressure to give crude crystals. MS m/z: 425 [M+H] ⁺ .

Step 4: 22 Synthesis

The raw material 22-3 (0.05 g, 117.79 μmol) and water (1 mL) were added to a pre-dried single-mouth bottle, followed by the reagent LiOH.H ₂ O (28.21 mg, 1.18 mmol), and stirred at 25 ° C for 5 minutes. The pH of the system was adjusted to 7 with 1M aqueous HCl. ¹ H NMR (400 MHz, D ₂ O) δ ppm 8.44 (d, J = 4.80 Hz, 1H), 7.60 (s, 1H), 7.54 (dd, J = 5.20, 1.60 Hz, 1H), 3.76 (s, 2H) , 3.51 (t, J = 6.80 Hz, 2H), 3.45 (s, 4H), 2.79 (br s, 6H), 2.71 (br d, J = 6.40 Hz, 2H), 1.89-2.11 (m, 4H), 1.73 (br s, 2H). FNMR (400 MHz, D ₂ O) δ ppm 122.211. MS m/z: 425 [M+H] ⁺ .

Example 23: Preparation of Compound 23

synthetic route:

Step 1: Synthesis of 23-1

In a pre-dried single-mouth bottle, raw material BB-5 (0.5 g, 1.95 mmol), azetidine hydrochloride (167.07 mg, 2.93 mmol, 197.49 μL) and anhydrous dichloromethane (4 mL) were added, followed by addition. Reagent glacial acetic acid (5.86 mg, 97.54 μmol, 5.58 μL), adjust system pH=6, stir at 25 ° C for 0.5 h, then add sodium triacetoxyborohydride (826.93 mg, 3.90 mmol) at 25 ° C The reaction was carried out for 0.5 hour, 10 mL of water was added, and the mixture was extracted with dichloromethane (3×50 mL). Purification by chromatography (dichloromethane:methanol = 10: 1-5:1) afforded 23-1. MS m/z: 298 [M + H] ⁺ .

Step 2: 23-2 Synthesis

Raw material 23-1 (0.1 g, 336.26 μmol) and reagent HCl/MeOH (4M, 10 mL) were added to a pre-dried single-mouth flask, and the mixture was reacted at 25 ° C for 0.5 hour, and the system was directly concentrated under reduced pressure to give 23-2. MS m/z: 198 [M + H] ⁺ .

Step 3: 22-3 Synthesis

Into a pre-dried single-mouth bottle, raw material 23-2 (0.1 g, 427.83 μmol), BB-1 (73.01 mg, 407.46 μmol) and anhydrous dichloromethane (4 mL) were added, followed by the addition of the reagent N,N-diisopropyl Ethylethylamine (63.19 mg, 488.95 μmol, 85.16 μL), glacial acetic acid (1.22 mg, 20.37 μmol, 1.17 μL), adjusted system pH=6, stirred at 25 ° C for 0.5 hours, followed by triacetoxyborohydride Sodium (172.71 mg, 814.91 μmol) was reacted at 25 ° C for 0.5 hours, and concentrated under reduced pressure to give a crude material which was purified by flash column chromatography (dichloromethane:methanol = 10:1:1:1) 3. MS m/z: 361 [M + H] ⁺ .

Step 4:23 Synthesis

Raw material 23-3 (50.00 mg, 138.72 μmol) and solvent water (1 mL) were added to a pre-dried vial, followed by the reagent LiOH.H ₂ O (16.61 mg, 693.58 μmol), and stirred at 25 ° C for 5 minutes. The pH of the system was adjusted to 7 with 1M aqueous HCl. ¹ H NMR (400 MHz, D ₂ O) δ ppm 8.45 (d, J = 5.20 Hz, 1H), 7.61 (s, 1H), 7.55 (dd, J = 4.80, 1.20 Hz, 1H), 4.00 (brt, J = 8.40 Hz, 4H), 3.75 (s, 2H), 3.52 (t, J = 5.20 Hz, 2H), 3.42 (s, 4H), 3.26 (t, J = 5.20 Hz, 2H), 2.81 (br s, 2H), 2.26-2.42 (m, 2H), 1.72 (br s, 2H)

Example 24: Preparation of Compound 24

Step 1: Synthesis of Compound 24-2

Compound 24-1 (2 g, 19.39 mmol) was dissolved in water (5 mL) and tetrahydrofuran (30 mL), sodium hydrogen carbonate (2.44 g, 29.08 mmol), and finally BB-6 (5.80 g, 23.26 mmol), 22 Stir at °C for 14 h. A conical flask was taken, 50 mL of water was added, and the reaction mixture was poured. The fraction was concentrated under reduced pressure. Purification by flash column chromatography (petroleum ether: ethyl acetate = 10:1 to 1:1) afforded compound 24-2. ^{_{1 H NMR (400MHz, CDCl 3}} ) δppm 7.29-7.38 (m, 5H), 5.37 (br s, 1H), 5.01 (s, 2H), 3.71-3.77 (m, 2H), 2.77 (s, 1H), 1.84 (t, J = 6.4 Hz, 2H), 1.33 (s, 6H).

MS m/z: 238 [M + H] ⁺ .

Step 2: Synthesis of Compound 24-3

Compound 24-2 (10 g, 42.14 mmol) was dissolved in dichloromethane <RTI ID=0.0>(50</RTI><RTIgt;</RTI><RTIgt;</RTI><RTIgt;</RTI><RTIgt;</RTI><RTIgt; A conical flask was taken, 40 mL of water was added, the reaction mixture was poured, and the mixture was extracted three times with 40 mL of dichloromethane. The organic phase was combined, dried over anhydrous sodium sulfate, filtered, MS m/z: 236 [M + H] ⁺ .

Step 3: Synthesis of Compound 24-4

In a pre-dried round bottom single-mouth flask, compound 24-3 (6.53 g, 73.32 mmol) was added, dissolved in dichloromethane (100 mL), then triethylamine (7.42 g, 73.32 mmol) was added, and glacial acetic acid (293.51) was added dropwise. Mg, 4.89 mmol), adjusted to pH = 7, stirred for 0.5 h, then sodium borohydride (20.72 g, 97.76 mmol). Stir at 15 ° C for 2 h. A conical flask was taken, 60 mL of water was added, the reaction mixture was poured, and the mixture was extracted three times with 60 mL of dichloromethane. The crude product was purified through a silica gel column ( petroleum ether: ethyl acetate = 10:1, 5:1, 3:1, 1:1), and the fractions were concentrated under reduced pressure to afford compound 24-4. MS m/z: 309 [M + H] ⁺ . ^{_{1 H NMR (400MHz, CDCl 3}} ) δppm 8.05-7.75 (m, 3H), 7.35-7.32 (m, 2H), 5.01 (s, 2H), 3.72 (s, 3H), 2.89-2.83 (m, 1H) , 2.04–1.93 (m, 3H), 1.43–1.25 (m, 6H).

Step 4: Synthesis of compound 24-5

Compound 24-4 (5.3 g, 17.19 mmol) was dissolved in tetrahydrofuran (60 mL) and water (15 mL), and sodium hydrogen carbonate (5.78 g, 68.75 mmol) and Boc ₂ O (4.50 g, 20.62 mmol), 15 Stir at °C for 5 h. The reaction solution was concentrated under reduced pressure to give Compound 24-5. MS m/z: 409 [M + H] ⁺ .

Step 5: Compound 24-6 Synthesis

Compound 24-5 (0.5 g, 1.22 mmol) was dissolved in EtOAc (5 mL)EtOAc. The round bottom flask was taken up, filtered through Celite, and the fraction was concentrated under reduced pressure to give a residue. The crude product was purified by silica gel column ( petroleum ether: ethyl acetate = 10:1, 5:1, 3:1, 1:1), fraction Concentration under reduced pressure gave Compound 24-6. MS m/z: 275 [M+H] ⁺ .

Step 6: Synthesis of Compound 24-7

Compound 24-6 (1.4g, 5.10mmol) was dissolved in anhydrous toluene (30mL) was added _{AlMe 3 (735.73mg, 10.21mmol),} 15 ℃ reaction 2h. 1 mL of water was added to the reaction mixture, and the mixture was directly dried, and then the product was directly soaked with 20 mL of dichloromethane:methanol = 20:1, and then filtered over Celite, The crude product was purified through silica gel column (dichloromethane:methanol = 20:1). Compound 24-7 was obtained. MS m/z: 243 [M+H] ⁺ .

Step 7: Synthesis of Compound 24-8

Compound 24-7 (237.78 mg, 1.65 mmol) was dissolved in DMF (5 mL). sodium hydride (198.07 mg, 3.30 mmol) was added to the reaction mixture at 0 ° C, N,N-dimethyl Chloroethylamine hydrochloride (237.78 mg, 1.65 mmol) was added to the reaction mixture and stirred at 40 ° C for 12 h. A conical flask was taken, and 20 mL of a saturated ammonium chloride solution was added thereto, and the reaction mixture was poured. The crude product was purified through silica gel column (dichloromethane:methanol = 20:1). MS m/z: 314 [M + H] ⁺ .

Step 8: Synthesis of compound 24-9

Compound 24-8 (0.2 g, 638.09 μmol) was dissolved in EtOAc / MeOH (4M, 5 mL). The reaction solution was directly concentrated under reduced pressure to give Compound 24-9. MS m/z: 214 [M + H] ⁺ .

Step 9: Compound 24-10 Synthesis

Compound 24-9 (0.2 g, 800.70 μmol) was dissolved in dichloromethane (3 mL), BB-1 (143.46 mg, 800.70 μmol) was added, and triethylamine (81.02 mg, 800.70 μmol) was added to the reaction solution. The mixture was adjusted to pH 7 with glacial acetic acid (9.62 mg, 160.14 μmol), and stirred at 25 ° C for 0.5 h, then sodium borohydride (339.40 mg, 1.60 mmol) was added to the reaction mixture and stirred at 15 ° C for 2 h. An Erlenmeyer flask was taken, 20 mL of water was added, and the reaction mixture was poured, and the mixture was extracted three times with 20 mL of ethyl acetate. MS m/z: 377 [M + H] ⁺ .

Step 10: Compound 24 Synthesis

Compound 24-10 (0.1 g, 265.61 μmol) was dissolved in water (2 mL), and lithium hydroxide (11.15 mg, 265.61 μmol) was added to the reaction mixture and stirred at 15 ° C for 0.5 h. The reaction solution was concentrated under reduced pressure to give a residue. Compound 24 was obtained by preparative HPLC. MS m/z: 349 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.52 (d, J = 4.8 Hz, 1H), 8.06 (s, 1H), 7.71 (d, J = 4.8 Hz, 1H), 3.81 (s, 2H), 3.73 -3.79(m,2H),3.53(s,2H),3.15-3.21(m,2H),2.81(s,6H),2.53-2.60(m,2H),1.91(m,2H), 1.32(s , 6H).

Example 25: Preparation of Compound 25

Step 1: Synthesis of Compound 25-2

Compound 25-1 (10.00 g, 97.87 mmol) and HCl (12M, 8.16 mL) were dissolved in MeOH (400 mL), (Boc) ₂ O (21.36 g, 97.87 mmol) dissolved in MeOH (400 mL) Add to the reaction solution. The reaction was stirred at 10 ° C for 12 h. The reaction was quenched with EtOAc EtOAc (EtOAc)EtOAc.

Step 2: Synthesis of Compound 25-3

Compound 25-2 (5.00 g, 24.72 mmol) and diisopropylethylamine (6.39 g, 49.43 mmol) were dissolved in DMF (100 mL) and ethyl bromoacetate (1.65 g, 9. Into the reaction system, and stirred at 10 ° C for 12 h. The reaction mixture was stirred with EtOAc EtOAc EtOAc. The crude product was directly concentrated to give product 25-3 as a colorless oil. No further purification was used in the next step, MS m/z: 289 [M+H] ⁺ .

Step 3: Synthesis of Compound 25-4

Compound 25-3 (10.00g, 34.68mmol) and NaHCO ₃ (2.91g, 34.68mmol) was dissolved in THF (120mL) and water (30mL), the compound at 0 ℃ BB-6 (7.35g, 29.48mmol) It was added to the reaction system and the reaction was stirred at 15 ° C for 12 h. The reaction was quenched with EtOAc (EtOAc)EtOAc. The crude product by flash column chromatography to give 25-4 as a yellow oil, MS m / z: 423 [ M + H] +. ^{_{1 H NMR (400MHz, CDCl 3}} ) δppm 7.21-7.42 (m, 5H), 5.128 (s, 2H), 4.09 (d, J = 8Hz, 2H), 3.15 (s, 2H), 2.83-2.99 (m, 4H), 1.45 (s, 9H), 1.17 (t, J = 7.2 Hz, 3H), 0.897 (s, 6H).

Step 4: Synthesis of compound 25-5

Compound 25-4 (5.00 g, 11.83 mmol) was dissolved in EtOAc (EtOAc)EtOAc. The reaction mixture was concentrated to give a crude product under reduced pressure to yield directly the compound 25-5, MS m / z: 322 [M + H] +.

Step 5: Synthesis of compound 25-6

Compound 25-5 (3.00 g, 8.36 mmol, HCl) was dissolved in EtOH (50 mL). Et.sub.2 (1. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj M+H] ⁺ .

Step 6: Synthesis of Compound 25-7

Compound 25-6 (0.3 g, 1.09 mmol) was dissolved in DMF (10 mL), NaH (173.69 mg, 4.34 mmol, purity: 60%) was added to the reaction system at 0 ° C, and the reaction was stirred at 0 ° C. After 0.5 h, N,N-dimethylaminochloroethane hydrochloride (116.80 mg, 1.09 mmol) was added to the reaction mixture and the reaction was stirred at 40 ° C for 12 h. The reaction was quenched with EtOAc EtOAc. The crude product obtained was purified by flash column chromatography (ethyl acetate) of compound 25-7 as a yellow oil, MS m / z: 348 [ M + H] +.

Step 7: Synthesis of compound 25-8

Compound 25-7 (0.2 g, 575.62 μmol) and Pd/C (0.2 g, 5% purity) were dissolved in ethyl acetate (5 mL) and stirred under H ₂ (15 Psi) for 0.5 h. filtered through celite, ethyl acetate (50mL) was washed cake and the filtrate concentrated under reduced pressure to give compound 25-8 as a yellow oil, MS m / z: 214 [ m + H] +.

Step 8: Synthesis of compound 25-9

Compound BB-1 (16.80 mg, 93.76 μmol) and compound 25-8 (0.02 g, 93.76 μmol, HCl) were dissolved in DCM (1 mL), and triethylamine (9.49 mg, 93.76 μmol) was added to the reaction system. To pH is alkaline, then adjust the pH to 6-7 with glacial acetic acid, the reaction is stirred at 15 ° C for 1 h, then NaBH(OAc) ₃ (39.74 mg, 187.51 μmol) is added to the reaction system and stirring is continued for 3 h. . A few drops of water were added to the reaction mixture and concentrated under reduced pressure. The crude product obtained by preparative HPLC to yield compound 25-9 as a yellow oil, MS m / z: 377 [ M + H] +.

Step 9: Synthesis of Compound 25

Compound 25-9 (0.07 g, 185.93 μmol) was dissolved in water (1 mL), then LiOH.H ₂ O (15.60 mg, 371.85 μmol) was added to the reaction system, and the reaction was stirred at 15 ° C for 0.1 h. The reaction solution was directly filtered, and then purified by preparative HPLC to afford compound 25, MS m/z: 349 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.47-8.52 (m, 1H), 8.02 (s, 1H), 7.73 (dd, J = 5.2, 1.6 Hz, 1H), 3.89 (s, 2H), 3.43 (s) , 2H), 3.33 (dt, J = 3.2, 1.6 Hz, 4H), 2.64 (t, J = 6.8 Hz, 2H), 2.51 (br s, 2H), 2.42 (s, 6H), 0.96 (s, 6H) ).

Test Example 1: Evaluation: Inhibition of KDM5A by a compound:

1 experimental materials:

1.1 Reagents:

KDM5A (Active Motif-63RMT000C31831)

Histone H3(1-21)lysine 4tri-methylated biotinchemical peptide (GL Biochem-561488)

2OG (Sigma-75892)

L-ascorbic acid (Sigma-795437)

Ammonium iron sulfate hexahydrate (Sigma-203505)

Mab Anti histone H3K4 Me2-Eu(K)(Cisbio-61KA2KAD)

Streptavidin-XL665 (Cisbio-610SAXLB)

1.3 consumables and instruments:

384-well plate (Greiner-784075)

96 pointed bottom plate (Haimen-FPT019)

384-LDV board (LABCYTE-LP-0200)

Liquid handler: Echo(LABCYTE-Echo550)

Small tube metal tip dispensing cassette(Thermo-24073290)

Multidrop Combi (Thermo)

Centrifuge (Thermo Centrifuge ST 40R)

Microplate reader (TECAN-SPARK 10M)

Incubator (Grant-bio Thermo-shaker PHMP)

2 experimental steps and methods:

2.1 On the day of the experiment, prepare a fresh reagent solution, L-ascorbic acid, 2OG and Ammonium iron sulfate hexahydrate, and then prepare a reaction buffer.

2.2 The concentration of the four compounds was first prepared in DMSO, 4000 μM, 148.15 μM, 5.49 μM and 0.2 μM, respectively, and the four concentrations of the compound were transferred from 8 μL to 384 LDV plates. Then transfer to 384 analytical plate with Echo 550 to obtain 10 concentration points, 3 times dilution, and two duplicate wells.

2.3 Prepare KDM5A enzyme solution, add 5μL to 384ml plate per well, add reaction buffer to replace the enzyme for each well. Centrifuge at 1000 rpm for 1 min. Incubate in a 25 degree incubator for 20 min.

2.4 Prepare H3K4Me3 (biotin) (histone third subunit tetra-lysine trimethylated peptide) (biotin label), add 5 μL per well to the assay plate using an automatic dispenser (negative control well, or no Add the enzyme to the well. Centrifuge at 1000 rpm for 1 min. Incubate for 60 min in a 25-degree incubator.

2.5 Preparation of H3K4 me2-Eu(K)Ab铕-labeled histone third subunit lysine bismethylated polypeptide antibody and streptavidin XL665 streptavidin XL665 detection solution to ensure streptavidin Xl665 and peptide-biotin The ratio is 1:4. After the enzyme reaction for 60 min, 10 μL of the above test solution per well was added. Centrifuge at 1000 rpm for 1 min. Incubate overnight in a 4 degree refrigerator.

2.6 On the second day, HTRF 340 nm excitation light, 665 nm and 612 nm emission light, and 665 nm/612 nm were read by TECAN Spark 10M microplate reader to calculate the original signal value of IC ₅₀ .

3 data analysis:

3.1 Calculation of inhibition percentage: % inhibition rate = 100-100 x (average signal value of signal value - min) / (average signal value of max - average signal value of min).

3.2 calculated IC _50: calculated using the XLfit software 50% KDM5A compound inhibitory concentrations (IC ₅₀₎ values.

4 experimental results:

Table 1 IC ₅₀ test results of KDM5 in TR-FRET format test

Conclusion: The compounds of the present invention have a significant inhibitory effect on KDM5A.

Test Example 2: Compound pharmacokinetic evaluation

Objective: To test the pharmacokinetics of compounds in Male CD-1 mice

Experimental Materials:

Male CD-1 mice, 25-30g, 7-10 weeks old, Shanghai Xipuer-Beikai Experimental Animal Co., Ltd.

Experimental operation:

The compounds were tested by standard protocol for intravenous injection of 0.2 mg/ml in saline and orally administered with 2 mg/ml in saline. The candidate compounds were formulated into a clear solution and administered to mice in a single intravenous injection. Oral administration. The intravenous and oral vehicles are a certain proportion of physiological saline solution. Collect whole blood samples within 24 hours, centrifuge at 3000g for 15 minutes, separate the supernatant to obtain plasma samples, add 4 times volume of acetonitrile solution containing internal standard to precipitate protein, centrifuge to remove the supernatant, add equal volume of water and centrifuge to remove the supernatant. The LC-MS/MS analysis method was used to quantitatively analyze the plasma concentration, and the pharmacokinetic parameters such as peak concentration, peak time, clearance rate, half-life, area under the curve of the drug, and bioavailability were calculated.

The experimental results are shown in Table 2:

Table 2 Pharmacokinetic test results

Conclusion: The compounds of the present invention can significantly increase the single or partial index of pharmacokinetics in mice.

Test Example 3: Human liver microsome CYP inhibition experiment

The aim of the study was to evaluate the inhibitory effect of the test article on human liver microsomal cytochrome P450 isoenzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4) using a 5-in-1 probe substrate of CYP isoenzyme.

Mixed human liver microsomes (HLM) were purchased from Corning Inc. (Steuben, New York, USA) or XenoTech, LLC (Lenexa, KS, USA) or other suppliers and stored at temperatures below -70 °C prior to use. under.

The diluted serial concentration of 10 mM, 5 mM, 1.5 mM, 0.5 mM, 0.15 mM, 0.05 mM, 0.015 mM test solution was added to the incubation system containing cofactors of human liver microsomes, probe substrate and circulation system. Among them, a control containing no solvent and containing a solvent was used as an enzyme activity control (100%). The concentration of the metabolite produced by the probe substrate in the sample was determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Non-linear regression analysis was performed on the average percent activity versus concentration of the test article using SigmaPlot (V.11). The IC ₅₀ value (μM) was calculated by a three-parameter or four-parameter recursive logarithmic equation. The test results are shown in Table 3:

table 3

测试化合物Test compound	CYP1A2CYP1A2	CYP2C9CYP2C9	CYP2C19CYP2C19	CYP2D6CYP2D6	CYP3A4CYP3A4
实施例1Example 1	>50>50	>50>50	>50>50	>50>50	>50>50

Conclusion: Compound 1 inhibited the inhibition of five CYP isoenzymes.

Test Example 4: Inhibition test of hERG potassium channel

1. Experimental purpose:

The effect of Example 1 on the hERG potassium ion channel was examined by a fully automated patch clamp method.

2. Experimental methods

2.1. Cell culture

The cells stably expressing the hERG potassium channel used in the experiment were obtained from CHO-hERE of Aviva Biosciences, and CHO-hERG was cultured in a 5% CO ₂ atmosphere at 37 °C. CHO hERG culture solution is shown in Table 4.

Table 4 CHO hERG medium

ReagentReagent	SupplierSupplier	Catalog NumberCatalog Number	Volume(mL)Volume(mL)
F12HamsF12Hams	InvitrogenInvitrogen	31765-09231765-092	500500
FBSFBS	InvitrogenInvitrogen	10099-14110099-141	5050
G418/GeneticinG418/Geneticin	InvitrogenInvitrogen	10131-02710131-027	11
Hygromycin BHygromycin B	InvitrogenInvitrogen	10687-01010687-010	11

2.2. Preliminary preparation of cells

The CHO-hERG cells prepared for the experiment were cultured for at least two days, and the cell density reached 75% or more. Prior to the start of the experiment, cells were digested with TrypLE and then resuspended in extracellular fluid to collect the cells.

2.3. Preparation of intracellular and extracellular fluids

The extracellular fluid needs to be prepared once a month. The intracellular fluid must be frozen at -20 °C. The internal and external fluid components are shown in Table 5.

Table 5 Intracellular and extracellular fluid components

组成成分Composition	细胞外液(mM)Extracellular fluid (mM)	细胞内液(mM)Intracellular fluid (mM)
NaClNaCl	145145	--
KClKCl	44	120120
KOHKOH	--	31.2531.25
CaCl ₂ CaCl ₂	22	5.3745.374
MgCl ₂ MgCl ₂	11	1.751.75
葡萄糖glucose	1010	--
Na ₂ATP Na ₂ ATP	--	44
两性离子缓冲液Zwitterionic buffer	1010	1010
螯合剂Chelating agent	--	1010
pHpH	7.4(NaOH调节)7.4 (NaOH adjustment)	7.2(KOH调节)7.2 (KOH adjustment)
渗透压Osmotic pressure	295mOsm295mOsm	285mOsm285mOsm

2.4. Compound preparation

The test compound is dissolved in DMSO into a certain concentration of the stock solution, and then diluted according to different gradients, and finally added to the extracellular fluid in a certain ratio, and diluted to a concentration to be measured. Visual inspection was performed to see if there was any precipitation before the start of the experiment. Finally, the concentration of DMSO in the test solution and the positive control Amitriptyline should not exceed 0.3%.

2.5. Voltage stimulation scheme

Keep the clamping potential at -80mv, first give a voltage stimulation of -50mv for 80ms to record the cell leakage current value, then depolarize to +20mv, maintain 4800ms, open the channel of hERG, then repolarize to -50mv for 5000ms , the hERG tail current is drawn and recorded. Finally, the voltage is restored to the clamping potential of -80 mv for 3100 ms. The above voltage stimulation is repeated every 15000ms.

2.6.QPatch ^HTX Whole Cell Patch Clamp Record

The hERG QPatch ^HTX experiment was performed at room temperature. A whole cell protocol, a voltage stimulation protocol and a compound detection protocol were established on the software of QPatch Assay Software 5.2 (Sophion Bioscience).

First, 30 repeated set voltage stimulations were performed, which was the baseline area for subsequent analysis, followed by the addition of 5 μl of extracellular fluid, three times. The concentration of each compound added in sequence was repeated three times in a volume of 5 μl. Incubate the cells for at least 5 mins at each test concentration. During the entire recording process, the indicators need to meet the data analysis acceptance criteria. If the standard is not met, the cells will not be included in the analysis scope, and the compounds will be re-tested. The above recording process is automatically operated by Qpatch analysis software. The test concentration of each compound was 0.24 μM, 1.20 μM, 6.00 μM, 30.00 μM, and at least two cells were repeated for each concentration.

2.7. Data Analysis

In each complete current record, based on the percentage of peak current in the negative control, the percent inhibition of the concentration of each compound can be calculated. The dose-effect relationship curve is obtained by fitting the standard Greek equation. The specific equation is as follows:

I _(C) = I _b + (I _{fr -} I _b ) × c ⁿ / (IC ₅₀ ⁿ + c ⁿ )

C is the compound test concentration, n is the slope

The curve fitting and inhibition rate calculations were all analyzed by Qpatch analysis software. If the inhibition rate exceeds half of the inhibition at the lowest concentration or the inhibition rate does not reach half the inhibition at the highest concentration, the corresponding IC _{50 of} the compound is lower than the lowest concentration or IC ₅₀ value. Greater than the highest concentration.

2.8. Test results

The results of the hERG IC ₅₀ values for the example compounds are shown in Table 6.

Table 6 Example compound hERG IC ₅₀ value results

供试样品Test sample	hERG IC ₅₀(nM) hERG IC ₅₀ (nM)	测试次数Testing frequency
实施例1Example 1	>30>30	N＝2N=2

Conclusion: This compound is not cardiotoxic.

Claims

a compound of the formula (III) or a pharmaceutically acceptable salt thereof,

among them,

Y is selected from O and S;

R 1 is selected from H and C 1-6 alkyl, wherein said C 1-6 alkyl is optionally substituted by 1, 2 or 3 R a ;

R a is independently selected from the group consisting of F, Cl, Br, I, OH, NH 2 and CF 3 ;

R 2 is selected from H and C 1-6 alkyl, wherein said C 1-6 alkyl is optionally substituted by 1, 2 or 3 R b ;

R b is independently selected from the group consisting of F, Cl, Br, I, OH, NH 2 and CF 3 ;

Alternatively, R 1 and R 2 are bonded together to form a benzene ring, a 5- to 6-membered heteroaryl ring or a C 3-6 cycloalkyl group, wherein the benzene ring and the 5- to 6-membered heteroaryl ring are optionally 1, 2 Or 3 R 3 substitutions;

R 3 is independently selected from the group consisting of H, F, Cl, Br, I, OH, NH 2 and CF 3 ;

R 4 is selected from the group consisting of OH and C 1-3 alkoxy;

R 5 is selected from the group consisting of H and C 1-3 alkyl;

R 6 is selected from the group consisting of H and C 1-3 alkyl;

Alternatively, R 1 and R 5 are joined together to form a C 3-6 cycloalkyl group;

Alternatively, R 2 and R 6 are joined together to form a C 3-6 cycloalkyl group;

And, when R 1 and R 2 are bonded together to form a benzene ring or a 5- to 6-membered heteroaryl ring, R 5 and R 6 are empty;

R 7 is selected from H and C 1-5 alkyl, wherein said C 1-5 alkyl is optionally substituted by 1, 2 or 3 R c ;

R 8 is selected from H and C 1-5 alkyl, wherein said C 1-5 alkyl is optionally substituted by 1, 2 or 3 R c ;

Alternatively, R 7 , R 8 and the N atoms to which they are attached are joined together to form
Said

Optionally substituted by 1, 2 or 3 R c ;

R c is independently selected from the group consisting of F, Cl, Br, I, OH, NH 2 and CF 3 ;

The 5- to 6-membered heteroaryl ring contains 1, 2 or 3 heteroatoms and heteroatoms independently selected from the group consisting of -O-, -S-, -NH- and N.
A compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of

among them,

Y is selected from O and S;

R 1 is selected from H and C 1-6 alkyl, wherein said C 1-6 alkyl is optionally substituted by 1, 2 or 3 R a ;

R a is independently selected from the group consisting of F, Cl, Br, I, OH, NH 2 and CF 3 ;

R 2 is selected from H and C 1-6 alkyl, wherein said C 1-6 alkyl is optionally substituted by 1, 2 or 3 R b ;

R b is independently selected from the group consisting of F, Cl, Br, I, OH, NH 2 and CF 3 ;

Alternatively, R 1 and R 2 are bonded together to form a benzene ring, a 5- to 6-membered heteroaryl ring or a C 3-6 cycloalkyl group, wherein the benzene ring and the 5- to 6-membered heteroaryl ring are optionally 1, 2 Or 3 R 3 substitutions;

R 3 is independently selected from the group consisting of H, F, Cl, Br, I, OH, NH 2 and CF 3 ;

R 4 is selected from the group consisting of OH and C 1-3 alkoxy;

R 5 is selected from the group consisting of H and C 1-3 alkyl;

R 6 is selected from the group consisting of H and C 1-3 alkyl;

Alternatively, R 1 and R 5 are joined together to form a C 3-6 cycloalkyl group;

Alternatively, R 2 and R 6 are joined together to form a C 3-6 cycloalkyl group;

And, when R 1 and R 2 are bonded together to form a benzene ring or a 5- to 6-membered heteroaryl ring, R 5 and R 6 are empty;

The 5- to 6-membered heteroaryl ring contains 1, 2 or 3 heteroatoms and heteroatoms independently selected from the group consisting of -O-, -S-, -NH- and N.
The compound according to claim 1 or 2, wherein R 1 is selected from H and C 1-3 alkyl, wherein the C 1-3 alkyl group is optionally 1, 2 or 3, or a pharmaceutically acceptable salt thereof Replace with R a .
The compound according to claim 3 or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group consisting of H, Me and Et.
The compound according to any one of claims 1 to 2, wherein R 2 is selected from the group consisting of H and C 1-3 alkyl, wherein the C 1-3 alkyl group is optionally substituted with 1, or a pharmaceutically acceptable salt thereof. 2 or 3 R b substitutions.
The compound according to claim 5 or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from the group consisting of H, Me and Et.
The compound according to any one of claims 1 to 2, wherein R 1 and R 2 are bonded together to form a benzene ring, a cyclopropyl group or a pyridine ring, wherein the benzene ring and pyridine are formed, or a pharmaceutically acceptable salt thereof. The ring is optionally substituted with 1, 2 or 3 R 3 .
The compound according to any one of claims 1 to 2, or a pharmaceutically acceptable salt thereof, wherein the structural unit
Selected from
The compound according to any one of claims 1 to 2, wherein R 4 is selected from OH, or a pharmaceutically acceptable salt thereof
The compound according to any one of claims 1 to 2, wherein R 1 and R 5 are bonded together to form a cyclopropyl group, or a pharmaceutically acceptable salt thereof.
The compound according to any one of claims 1 to 2, wherein R 2 and R 6 are bonded together to form a cyclopropyl group, or a pharmaceutically acceptable salt thereof.
The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 7 is selected from the group consisting of H and C 1-3 alkyl, wherein said C 1-3 alkyl group is optionally 1, 2 or 3 R c replaced.
The compound according to claim 12, or a pharmaceutically acceptable salt thereof, wherein R 7 is selected from the group consisting of H, Me, CH 2 F, CHF 2 , CF 3 , CH 2 CF 3 , CHFCH 2 F and Et.
The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 8 is selected from the group consisting of H and C 1-3 alkyl, wherein said C 1-3 alkyl group is optionally 1, 2 or 3 R c replaced.
The compound according to claim 14 or a pharmaceutically acceptable salt thereof, wherein R 7 is selected from the group consisting of H, Me, CH 2 F, CHF 2 , CF 3 , CH 2 CF 3 , CHFCH 2 F and Et.
The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the structural unit
Selected from
The compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of

among them,

R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and Y are as defined in any one of claims 1 to 11;

R 7 and R 8 are as defined in any one of claims 1, 2 and 12 to 16.
a compound of the formula: or a pharmaceutically acceptable salt thereof,
Use of a compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating a disease associated with the KDM5 pathway.
The use according to claim 19, wherein the disease associated with the KDM5 pathway is a tumor and hepatitis B.
According to the use of claim 20, the tumor is breast cancer, gastric cancer, colorectal cancer, lung cancer and liver cancer.