CN114555574B

CN114555574B - Chromans targeting aldehyde ketone reductase 1C3

Info

Publication number: CN114555574B
Application number: CN202080071652.8A
Authority: CN
Inventors: 蔡哲; 孙飞; 丁照中; 陈曙辉
Original assignee: Shenzhen Yangli Pharmaceutical Technology Co ltd
Current assignee: Shenzhen Yangli Pharmaceutical Technology Co ltd
Priority date: 2019-10-12
Filing date: 2020-10-12
Publication date: 2024-04-12
Anticipated expiration: 2040-10-12
Also published as: CN114555574A; WO2021068952A1

Abstract

Disclosed are novel-structure chroman compounds targeting AKR1C3 enzyme (aldehyde ketone reductase 1C 3), and specifically discloses compounds shown in a formula (II), pharmaceutically acceptable salts or isomers thereof.

Description

Chromans targeting aldehyde ketone reductase 1C3

The present application claims priority as follows:

CN201910969224.6, filing date 2019, 10, 12;

CN202010884517.7, filing date 2020, 28 th 08 th month.

Technical Field

The invention relates to a chroman compound of a novel structure of a targeting AKR1C3 enzyme (aldehyde ketone reductase 1C 3), in particular to a compound shown in a formula (II), pharmaceutically acceptable salts or isomers thereof and a medicinal composition containing the compound, and application of the compound shown in the formula (II), the pharmaceutically acceptable salts, isomers and the medicinal composition containing the compound in the treatment of malignant tumors.

Background

Malignant tumor is a serious disease that seriously threatens human life and health. The existing treatment means mainly comprise operation treatment, chemical treatment, targeted treatment and the like. Chemotherapy is a therapeutic method for killing tumor cells and inhibiting the growth of tumor cells by using chemical drugs, and is a systemic therapeutic method. Chemotherapy remains an important method of treating tumors due to the heterogeneity of malignant tumors. However, it is this systemic treatment that results in chemotherapy with significant side effects. There is a great unmet clinical need to develop chemotherapeutic agents with targeted effects.

Aldehyde ketone reductase 1C3 (AKR 1C 3) is a member of the aldehyde ketone reductase family, mainly involved in hormone synthesis and toxin clearance. AKR1C3 may be induced to be overexpressed by factors such as smoking, alcohol, hepatitis b or hepatitis C infection. AKR1C3 is overexpressed in a variety of refractory cancers, such as liver, lung, stomach, esophagus, colorectal, prostate, acute lymphoblastic leukemia, especially liver, with a high surface ratio of above 60%.

At present, AKR1C3 inhibitor medicines are developed clinically, but no good progress is made. Threshold pharmaceutical Inc. reported a targeting AKR1C3 enzyme compound TH3424.TH3424 is a selective prodrug, releases a strong DNA alkylating agent in tumor cells which highly express AKR1C3 enzyme, selectively kills the tumor cells which highly express AKR1C3, and ensures that the chemical drug has obvious targeting effect.

The current research of this target is still in an early stage, only TH-3424 enters clinical stage one, and indications are mainly hepatocellular carcinoma (HCC) and castration prostate cancer (CRPC), and its effectiveness and safety are still under verification. There is a need for further exploration and research in this area.

Disclosure of Invention

In one aspect, the present invention provides a compound of formula (II), a pharmaceutically acceptable salt or isomer thereof,

Wherein R is _w Is that

R ₁ H, C of a shape of H, C _1-6 Alkyl, C _3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl or phenyl, wherein said C _1-6 Alkyl, C _3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl and phenyl are optionally substituted by 1, 2 or 3R ^a Substituted;

each R is ^a Is independently H, F, cl, br, I, -CN, -OH, C _1-3 Alkoxy or C _1-3 An alkyl group;

R ₂ is H or C _1-6 An alkyl group;

or R is ₁ And R is ₂ Are linked together to form, together with the N atom to which they are attached, a 4-6 membered heterocycloalkyl, wherein said 4-6 membered heterocycloalkyl is optionally substituted with 1, 2 or 3R ^b Substituted;

each R is ^b Is independently H, F, cl, br, I, -CN, -OH, -NH ₂ 、-OCH ₃ 、-OCH ₂ CH ₃ 、-CH ₃ or-CH ₂ CH ₃ ；

R ₃ Is H, F, cl, br, I, -OH, -NH ₂ 、C _1-3 Alkoxy or C _1-3 An alkyl group;

or R is ₂ And R is ₃ ConnectionTogether to form a structural unitIs->

T ₁ Is- (CR) ^c R ^d ) _m -or- (CR) ^c R ^d ) _n -O-；

m is 1, 2 or 3;

n is 1 or 2;

T ₂ is N or CH;

R ^c and R is ^d Each independently H, F, C _1-3 Alkyl or C _1-3 An alkoxy group;

R ₄ 、R ₅ and R is ₆ Each independently H, F, cl, br, I, C _1-3 Alkyl or C _1-3 An alkoxy group;

t is N or CH;

R ₇ and R is ₈ Each independently H, F, cl, br or I;

R ₉ and R is ₁₀ Each independently is H, F, cl, br, I, -CN or

The 4-6 membered heterocycloalkyl and 5-6 membered heteroaryl each contain 1, 2, 3 or 4 heteroatoms independently selected from N, -O-and-S-.

In another aspect, the present invention provides a compound of formula (I), a pharmaceutically acceptable salt or isomer thereof,

wherein R is ₁ H, C of a shape of H, C _1-6 Alkyl, C _3-6 Cycloalkyl, 4-6 membered heterogeniesCycloalkyl, 5-6 membered heteroaryl or phenyl, wherein said C _1-6 Alkyl, C _3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl and phenyl are optionally substituted by 1, 2 or 3R ^a Substituted;

R ₂ is H or C _1-6 An alkyl group;

or R is ₂ And R is ₃ Are connected together to form a structural unitIs->

T ₁ Is- (CR) ^c R ^d ) _m -or- (CR) ^c R ^d ) _n -O-；

m is 1, 2 or 3;

n is 1 or 2;

T ₂ is N or CH;

In some embodiments of the invention, the above-described compounds have a structure represented by formula (II-1) or formula (II-2):

wherein the carbon atoms with "+" are chiral carbon atoms, either in the form of (R) or (S) single enantiomers or enriched in one enantiomer; r is R ₇ 、R ₈ 、R ₉ And R is ₁₀ As defined herein.

In some embodiments of the invention, the above-described compounds have the structure of formula (I-1):

wherein the carbon atoms with "+" are chiral carbon atoms, either in the form of (R) or (S) single enantiomers or enriched in one enantiomer; r is R ₁ 、R ₂ 、R ₃ 、R ₄ 、R ₅ And R is ₆ As defined herein.

In some embodiments of the invention, the above-described compounds have a structure represented by formula (II-3) or formula (II-4):

In some aspects of the invention, R is as defined above ₂ Is H or-CH ₃ The other variables are as defined herein.

In some aspects of the invention, R is as defined above ₁ And R is ₂ Are linked together to form, together with the N atom to which they are linked Wherein said-> Optionally by 1, 2 or 3R ^b Substituted, R ^b And other variables are as defined herein.

In some aspects of the invention, R is as defined above ₁ And R is ₂ Are linked together to form, together with the N atom to which they are linked R ^b And other variables are as defined herein.

In some aspects of the invention, R is as defined above ₁ And R is ₂ Are linked together to form, together with the N atom to which they are linked The other variables are as defined herein.

In some aspects of the invention, R is as defined above ₂ And R is ₃ Are connected together to form a structural unitIs that R ₁ 、R ₄ 、R ₅ And R is ₆ And other variables are as defined herein.

In some aspects of the invention, R is as defined above ₂ And R is ₃ Are connected together to form a structural unitIs that The other variables are as defined herein.

In some aspects of the invention, the structural units described aboveIs-> The other variables are as defined herein.

In some aspects of the invention, R is as defined above ^c And R is ^d Each independently is H, F or-CH ₃ The other variables are as defined herein.

In some aspects of the invention, T is as described above ₁ is-CH ₂ -、-CH ₂ -CH ₂ -、-CH ₂ -CH ₂ -CH ₂ -、-CH ₂ -O-、-O-CH ₂ -or-CH ₂ -CH ₂ -O-, other variables are as defined herein.

In some embodiments of the invention, the compounds have structures represented by any of formulas (I-2) to (I-7):

wherein T is ₂ 、R ₁ 、R ₃ 、R ₄ 、R ₅ And R is ₆ As defined herein.

In some embodiments of the invention, the compounds have structures represented by any of formulas (I-8) to (I-13):

Wherein the carbon atoms with "+" are chiral carbon atoms, either in the form of (R) or (S) single enantiomers or enriched in one enantiomer; t (T) ₂ 、R ₁ 、R ₃ 、R ₄ 、R ₅ And R is ₆ As defined herein.

In some aspects of the invention, each R is ^a Is independently H, F, cl, br, I, -CN, -OH, -OCH ₃ or-CH ₃ The other variables are as defined herein.

In some aspects of the invention, R is as defined above ₁ Is H, -CH ₃ 、-CH ₂ CH ₃ Cyclopropyl, cyclopentyl, cyclohexyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyridinyl or phenyl, wherein said-CH ₃ 、-CH ₂ CH ₃ Optionally substituted with 1, 2 or 3R groups, cyclopropyl, cyclopentyl, cyclohexyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyridinyl and phenyl ^a Substituted, R ^a And other variables are as defined herein.

In some aspects of the invention, R is as defined above ₁ Is H, -CH ₃ 、-CH ₂ CH ₃ 、 Wherein the-CH ₃ 、-CH ₂ CH ₃ 、/> Optionally by 1, 2 or 3R ^a Substituted, R ^a And other variables are as defined herein.

In some aspects of the invention, R is as defined above ₁ Is H, -CH ₃ 、-CH ₂ CH ₃ 、 R ^a And other variables are as defined herein.

In some aspects of the invention, R is as defined above ₁ Is H, -CH ₃ 、-CH ₂ CH ₃ 、 The other variables are as defined herein.

In some aspects of the invention, R is as defined above ₃ Is H, F, cl, br, I, -OH, -NH ₂ 、-OCH ₃ or-CH ₃ Other variables such as the presentThe invention is defined.

In some aspects of the invention, R is as defined above ₄ 、R ₅ And R is ₆ Each independently is H, F, cl, br, I or-CH ₃ The other variables are as defined herein.

Still other embodiments of the present invention are derived from any combination of the variables described above.

In some embodiments of the invention, the above compounds are:

in some embodiments of the invention, the above compounds are:

in another aspect, the invention also provides a pharmaceutical composition comprising a therapeutically effective amount of the above compound, a pharmaceutically acceptable salt or isomer thereof, and a pharmaceutically acceptable carrier.

The invention also provides application of the compound, pharmaceutically acceptable salt or isomer thereof and the pharmaceutical composition in preparing drugs targeting AKR1C3 enzyme.

Technical effects

The invention provides a compound targeting AKR1C3 with a novel structure. The compound has excellent antiproliferative activity on tumor cells with high expression of AKR1C3, has weak activity on tumor cells with low expression of AKR1C3, and shows excellent selectivity.

Definition of the definition

The following terms and phrases used herein are intended to have the following meanings unless otherwise indicated. A particular term or phrase, unless otherwise specifically defined, should not be construed as being ambiguous or otherwise clear, but rather should be construed in a generic sense. When trade names are presented herein, it is intended to refer to their corresponding commercial products or active ingredients thereof. The term "pharmaceutically acceptable" as used herein is intended to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention prepared from the compounds of the present invention which have the specified substituents found herein with relatively non-toxic acids or bases. When the compounds of the present invention contain relatively acidic functional groups, base addition salts may be obtained by contacting neutral forms of such compounds with a sufficient amount of a base in pure solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts. When the compounds of the present invention contain relatively basic functional groups, the acid addition salts may be obtained by contacting the neutral form of such compounds with a sufficient amount of an acid in pure solution or in 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, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, and the like; and organic acid salts including acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid; also included are salts of amino acids (e.g., arginine, etc.), and salts of organic acids such as glucuronic acid. Certain specific compounds of the invention contain basic and acidic functionalities that can be converted to either base or acid addition salts.

Pharmaceutically acceptable salts of the invention can be synthesized from the parent compound containing an acid or base by conventional chemical methods. In general, the preparation of such salts is as follows: prepared via reaction of these compounds in free acid or base form with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of both.

For a drug or pharmacologically active agent, the term "effective amount" or "therapeutically effective amount" refers to a sufficient amount of the drug or agent that is non-toxic but achieves the desired effect. For the purposes of the present oral dosage form, an "effective amount" of one active agent in a composition refers to that amount which is required to achieve the desired effect when used in combination with another active agent in the composition. Determination of an effective amount varies from person to person, depending on the age and general condition of the recipient, and also on the particular active substance, a suitable effective amount in an individual case can be determined by one skilled in the art according to routine experimentation.

In addition to salt forms, the compounds provided herein exist in prodrug forms. Prodrugs of the compounds described herein readily undergo chemical changes under physiological conditions to convert to the compounds of the invention. In addition, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an in vivo environment.

Certain compounds of the invention may exist in unsolvated forms or solvated forms, including hydrated forms. In general, solvated forms, which are equivalent to unsolvated forms, are intended to be encompassed within the scope of the present invention.

The compounds of the invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-) -and (+) -pairs of enantiomers, (R) -and (S) -enantiomers, diastereomers, (D) -isomers, (L) -isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included within the scope of the present invention.

Unless otherwise indicated, the term "enantiomer" or "optical isomer" refers to stereoisomers that are mirror images of each other.

Unless otherwise indicated, the term "cis-trans isomer" or "geometric isomer" is caused by the inability of a double bond or a single bond of a ring-forming carbon atom to rotate freely.

Unless otherwise indicated, the term "diastereoisomer" refers to stereoisomers of a molecule having two or more chiral centers and having a non-mirror relationship between the molecules.

Unless otherwise stated, "(D)" or "(+)" means right-handed, "(L)" or "(-)" means left-handed, "(DL)" or "(±)" means racemic.

Unless otherwise indicated, with solid wedge bondsAnd wedge-shaped dotted bond->Representing the absolute structure of a stereogenic centerBy straight solid line key->And straight dotted bond->Representing the relative configuration of the stereo centers, using wavy lines +.>Representing a wedge solid key +.>Or wedge-shaped dotted bond->Or by wave lines->Representing a straight solid line key->And straight dotted bond->

The compounds of the invention may be present in particular. Unless otherwise indicated, the term "tautomer" or "tautomeric form" refers to the fact that at room temperature, different functional group isomers are in dynamic equilibrium and are capable of rapid interconversion. If tautomers are possible (e.g., in solution), chemical equilibrium of the tautomers can be reached. For example, proton tautomers (also known as proton tautomers) (prototropic tautomer) include interconversions by proton transfer, such as keto-enol isomerisation and imine-enamine isomerisation. Valence isomer (valance tautomer) includes the interconversion by recombination of some of the bond-forming electrons. A specific example of where keto-enol tautomerization is the interconversion between two tautomers of pentane-2, 4-dione and 4-hydroxypent-3-en-2-one.

Unless otherwise indicated, the terms "enriched in one isomer", "enriched in one enantiomer" or "enantiomerically enriched" mean that the content of one isomer or enantiomer is less than 100% and the content of the isomer or enantiomer is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or greater than or equal to 96%, or greater than or equal to 97%, or greater than or equal to 98%, or greater than or equal to 99%, or greater than or equal to 99.5%, or greater than or equal to 99.6%, or greater than or equal to 99.7%, or greater than or equal to 99.8%, or greater than or equal to 99.9%.

Unless otherwise indicated, the term "isomer excess" or "enantiomeric excess" refers to the difference between the relative percentages of two isomers or enantiomers. For example, where one isomer or enantiomer is present in an amount of 90% and the other isomer or enantiomer is present in an amount of 10%, the isomer or enantiomer excess (ee value) is 80%.

Optically active (R) -and (S) -isomers and D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the invention is desired, it may be prepared by asymmetric synthesis or derivatization with chiral auxiliary wherein the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (e.g., amino) or an acidic functional group (e.g., carboxyl), a diastereomeric salt is formed with an appropriate optically active acid or base, and then the diastereomeric resolution is carried out by conventional methods well known in the art, and then the pure enantiomer is recovered. Furthermore, separation of enantiomers and diastereomers is typically accomplished by the use of chromatography employing a chiral stationary phase, optionally in combination with chemical derivatization (e.g., carbamate formation from amine). The compounds of the present invention may contain non-natural proportions of atomic isotopes on one or more of the atoms comprising the compounds. For example, compounds can be labeled with a radioisotope Such as tritium @, for example ³ H) Iodine-125% ¹²⁵ I) Or C-14% ¹⁴ C) A. The invention relates to a method for producing a fibre-reinforced plastic composite For example, deuterium can be substituted for hydrogen to form a deuterated drug, and the bond between deuterium and carbon is stronger than the bond between normal hydrogen and carbon, so that the deuterated drug has the advantages of reducing toxic and side effects, increasing the stability of the drug, enhancing the curative effect, prolonging the biological half-life of the drug and the like compared with the non-deuterated drug. All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention. "optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

The term "substituted" means that any one or more hydrogen atoms on a particular atom is substituted with a substituent, and may include deuterium and variants of hydrogen, provided that the valence of the particular atom is normal and the substituted compound is stable. When the substituent is oxygen (i.e., =o), it means that two hydrogen atoms are substituted. Oxygen substitution does not occur on the aromatic group. The term "optionally substituted" means that the substituents may or may not be substituted, and the types and numbers of substituents may be arbitrary on the basis that they can be chemically achieved unless otherwise specified.

When any variable (e.g., 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 to 2R, the group may optionally be substituted with up to two R's, and R's in each case have independent options. Furthermore, combinations of substituents and/or variants thereof are only permissible if such combinations result in stable compounds.

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

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

When a substituent is absent, it is meant that the substituent is absent, e.g., X in A-X is absent, meaning that the structure is actually A. When the listed substituents do not indicate which atom is attached to the substituted group, such substituents may be bonded through any atom thereof, for example, a pyridyl group may be attached to the substituted group as a substituent through any carbon atom on the pyridine ring.

When the exemplified linking group does not indicate its linking direction, its linking direction is arbitrary, for example,the linking group L is-M-W-, in which case-M-W-may be a group in which the linking rings A and B are linked in the same direction as the reading order from left to right>It is also possible to connect the ring A and the ring B in the opposite direction to the reading order from left to right>Combinations of such linking groups, substituents and/or variants thereof are permissible only if such combinations result in stable compounds.

Unless otherwise specified, when a group has one or more bondable sites, any one or more of the sites of the group may be bonded to other groups by chemical bonds. The chemical bond of the site and other groups can be a straight solid line bondStraight dotted line key->Or wave line->And (3) representing. For example-OCH ₃ The straight solid bonds in (a) represent the oxygen atom in the group and othersThe groups are connected; />The straight dashed bonds in (a) represent the attachment to other groups through both ends of the nitrogen atom in the group; />The wavy line in (2) represents the attachment to other groups through carbon atoms at positions 1 and 2 in the phenyl group.

Unless otherwise specified, the number of atoms on a ring is generally defined as the number of ring elements, e.g., "5-7 membered ring" refers to a "ring" of 5-7 atoms arranged around a ring.

Unless otherwise specified, the term "C _1-6 Alkyl "is used to denote a straight or branched saturated hydrocarbon group consisting of 1 to 6 carbon atoms. The C is _1-6 Alkyl includes C _1-5 、C _1-4 、C _1-3 、C _1-2 、C _2-6 、C _2-4 、C ₆ And C ₅ Alkyl groups, etc.; it may be monovalent (e.g., methyl), divalent (e.g., methylene), or multivalent (e.g., methine). C (C) _1-6 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 "C _1-3 Alkyl "is used to denote a straight or branched saturated hydrocarbon group consisting of 1 to 3 carbon atoms. The C is _1-3 Alkyl includes C _1-2 And C _2-3 Alkyl groups, etc.; it may be monovalent (e.g., methyl), divalent (e.g., methylene), or multivalent (e.g., methine). C (C) _1-3 Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.

Unless otherwise specified, the term "C _1-3 Alkoxy "means those alkyl groups containing 1 to 3 carbon atoms that are attached to the remainder of the molecule through one oxygen atom. The C is _1-3 Alkoxy includes C _1-2 、C _2-3 、C ₃ And C ₂ Alkoxy groups, and the like. C (C) _1-3 Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.

Unless otherwise specified, "C _3-6 Cycloalkyl "means a saturated cyclic hydrocarbon group consisting of 3 to 6 carbon atoms, which is a monocyclic and bicyclic ring system, said C _3-6 Cycloalkyl includes C _3-5 、C _4-5 And C _5-6 Cycloalkyl groups, and the like; it may be monovalent, divalent or multivalent. C (C) _3-6 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

Unless otherwise specified, the term "4-6 membered heterocycloalkyl" alone or in combination with other terms, refers to a saturated cyclic group consisting of 4 to 6 ring atoms, 1,2, 3 or 4 of which are heteroatoms independently selected from O, S and N, the remainder being carbon atoms, wherein the nitrogen atom is optionally quaternized and the nitrogen and sulfur heteroatoms may be optionally oxidized (i.e., NO and S (O) _p P is 1 or 2). It includes monocyclic and bicyclic ring systems, wherein the bicyclic ring system includes spiro, fused and bridged rings. In addition, in the case of the "4-6 membered heterocycloalkyl" group, the heteroatom may occupy the position of attachment of the heterocycloalkyl group to the remainder of the molecule. The 4-6 membered heterocycloalkyl group includes 5-6 membered, 4 membered, 5 membered and 6 membered heterocycloalkyl groups and the like. Examples of 4-6 membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl, 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl, 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1, 2-oxazinyl, 1, 2-thiazinyl, hexahydropyridazinyl, homopiperazinyl, homopiperidinyl, etc.

The terms "5-6 membered heteroaryl ring" and "5-6 membered heteroaryl" are used interchangeably herein, unless otherwise specified, and the term "5-6 membered heteroaryl" means a ring composed of 5 to 6 ring atoms having a conjugated piA monocyclic group of an electronic system, wherein 1,2,3 or 4 ring atoms are heteroatoms independently selected from O, S and N, the remainder being carbon atoms. Wherein the nitrogen atom is optionally quaternized and the nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., NO and S (O) _p P is 1 or 2). The 5-6 membered heteroaryl group may be attached to the remainder of the molecule through a heteroatom or carbon atom. The 5-6 membered heteroaryl groups include 5-and 6-membered heteroaryl groups. Examples of the 5-6 membered heteroaryl group include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl, 3-pyrazolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, etc.), triazolyl (1H-1, 2, 3-triazolyl, 2H-1,2, 3-triazolyl, 1H-1,2, 4-triazolyl, 4H-1,2, 4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, etc.), thiazolyl (including 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, etc.), furanyl (including 2-furanyl, 3-furanyl, etc.), thienyl (including 2-thienyl, 3-thienyl, etc.), pyridyl (including 2-pyridyl, 4-pyrimidyl, etc.), pyrimidyl (including 2-pyridyl, 4-pyrimidyl, etc.), pyrimidyl, etc.

Unless otherwise specified, the term "C" in the present invention _6-10 Aromatic rings "and" C _6-10 Aryl "may be used interchangeably, the term" C _6-10 Aromatic ring "or" C _6-10 Aryl "means a cyclic hydrocarbon group consisting of 6 to 10 carbon atoms with a conjugated pi electron system, which may be a monocyclic, fused bicyclic or fused tricyclic ring system, wherein each ring is aromatic. It may be monovalent, divalent or multivalent, C _6-10 Aryl groups include C _6-9 、C ₉ 、C ₁₀ And C ₆ Aryl, and the like. C (C) _6-10 Examples of aryl groups include, but are not limited to, phenyl, naphthyl (including 1-naphthyl, 2-naphthyl, and the like).

Unless otherwise specified, C _n-n+m Or C _n -C _n+m Comprising any one of the specific cases of n to n+m carbons, e.g. C _1-12 Comprises 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 included is any one of the ranges n to n+m, e.g. C _1-12 Comprises 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-membered to n+m-membered means that the number of atoms on the ring is n to n+m, for example, 3-12 membered ring includes 3-membered ring, 4-membered ring, 5-membered ring, 6-membered ring, 7-membered ring, 8-membered ring, 9-membered ring, 10-membered ring, 11-membered ring, and 12-membered ring, and any one of n to n+m is also included, for example, 3-12-membered ring includes 3-6-membered ring, 3-9-membered ring, 5-6-membered ring, 5-7-membered ring, 6-8-membered ring, 6-10-membered ring, and the like.

The term "leaving group" refers to a functional group or atom that may be substituted with another functional group or atom by a substitution reaction (e.g., a nucleophilic substitution reaction). For example, representative leaving groups include triflate; chlorine, bromine, iodine; sulfonate groups such as methanesulfonate, toluenesulfonate, p-bromophenylsulfonate, p-toluenesulfonate and the like; acyloxy groups such as acetoxy, trifluoroacetoxy, and the like.

The term "protecting group" includes, but is not limited to, "amino protecting group", "hydroxy protecting group" or "mercapto protecting group". The term "amino protecting group" refers to a protecting group suitable for preventing side reactions at the amino nitrogen position. Representative amino protecting groups include, but are not limited to: a formyl group; acyl groups such as alkanoyl (e.g., acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl groups such as t-butoxycarbonyl (Boc); arylmethoxycarbonyl groups such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl groups such as benzyl (Bn), trityl (Tr), 1-bis- (4' -methoxyphenyl) methyl; silyl groups such as Trimethylsilyl (TMS) and t-butyldimethylsilyl (TBS), and the like. The term "hydroxy protecting group" refers to a protecting group suitable for use in preventing side reactions of a hydroxy group. Representative hydroxyl protecting groups include, but are not limited to: alkyl groups such as methyl, ethyl and t-butyl; acyl groups such as alkanoyl (e.g., acetyl); arylmethyl groups such as benzyl (Bn), p-methoxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (benzhydryl, DPM); silyl groups such as Trimethylsilyl (TMS) and t-butyldimethylsilyl (TBS), and the like.

The compounds of the present invention may be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments set forth below, embodiments formed by combining with other chemical synthetic methods, and equivalent alternatives well known to those skilled in the art, preferred embodiments including but not limited to the examples of the present invention.

The invention adopts the following abbreviations:

Pd/C	Pd/C catalyst with palladium content of 10w%
		DCM	Dichloromethane (dichloromethane)
THF	Tetrahydrofuran (THF)
		EtOAc	Acetic acid ethyl ester
TBME	Tert-butyl methyl ether
		DMF	N, N-dimethylformamide
IV	Intravenous injection
		QW	Once a week
TFA	Trifluoroacetic acid
		PE	Petroleum ether
DMSO	Dimethyl sulfoxide
		EtOH	Ethanol
MeOH	Methanol
		HOAc	Acetic acid
DIPEA	Diisopropylethylamine
		EDTA	Ethylenediamine tetraacetic acid
SiO ₂	100-200 mesh silica gel powder for column chromatography
		psi	Pound force per square inch, pressure unit
p-HPLC	Preparation of high performance liquid chromatography for purification of Compounds

The compounds of the invention are either according to the nomenclature conventional in the art or are usedSoftware naming, commercial compounds are referred to by vendor catalog names.

The solvents used in the present invention are commercially available and do not require further purification. The reaction is generally carried out under inert nitrogen in an anhydrous solvent. Proton nuclear magnetic resonance data were recorded on a Bruker Avance III 400 (400 MHz) spectrometer with chemical shifts expressed in (ppm) at the high field of tetramethylsilane. LC/MS or Shimadzu MS contains one DAD: SPD-M20A (LC) and Shimadzu Micromass 2020 detectors. Mass spectrometers are equipped with an electrospray ion source (ESI) that operates in either a positive or negative mode.

The compounds of the present invention may be structured by conventional methods well known to those skilled in the art, and if the present invention relates to the absolute configuration of a compound, the absolute configuration may be confirmed by conventional means in the art. For example, single crystal X-ray diffraction (SXRD), the grown single crystal is collected from diffraction intensity data using a Bruker D8 vent diffractometer, and the light source is cukα radiation, scanning:after scanning and collecting the relevant data, the absolute configuration can be confirmed by further analyzing the crystal structure by a direct method (Shellxs 97).

With Shimadzu SIL-20A autosampler and Shimadzu DAD: the Shimadzu LC20AB system of SPD-M20A detector was subjected to high performance liquid chromatography using an Xtimate C18 (3 μm packing, specification 2.1X100 mn) column. Method of 0-60AB_6 min: the elution was started with 100% a (a as 0.0675% tfa in water) and ended with 60% B (B as 0.0625% tfa in MeCN) using a linear gradient for 4.2 minutes and then with 60% B for 1 minute. The column was re-equilibrated for 0.8 min to 100:0 with a total run time of 6 min. Method of 10-80AB_6 min: the elution was started with 90% a (a as 0.0675% tfa in water) and ended with 80% B (B as 0.0625% tfa in acetonitrile) using a linear gradient for 4.2 minutes followed by 1 minute with 80% B. The column was re-equilibrated for 0.8 min to 90:10 with a total run time of 6 min. The column temperature was 50℃and the flow rate was 0.8mL/min. The diode array detector scans at a wavelength of 200-400nm.

Thin Layer Chromatography (TLC) on Sanpont-group silica gel GF254, spot detection by UV light irradiation is common, and in some cases other methods are also used, in which case the spots are detected with iodine (10 g silica gel with about 1g iodine added and thoroughly mixed), vanillin (dissolved about 1g vanillin in 100mL 10% H) ₂ SO ₄ Obtained from Aldrich), ninhydrin (commercially available from Aldrich) or a special developer (25 g (NH) ₄ )6Mo ₇ O ₂₄ ·4H ₂ O、5g(NH ₄ )2Ce(IV)(NO ₃ )6、450mL H ₂ O and 50mL of concentrated H ₂ SO ₄ And made) the thin-layer plate was unfolded and inspected for compounds. Stills, w.c.; kahn, m.; and Mitra, M.journal of Organic Chemistry,1978, 43, 2923-2925. A similar method to the technique disclosed in Silicicle, flash column chromatography on 40-63 μm (230-400 mesh) silica gel. Typical solvents for flash column chromatography or thin layer chromatography are mixtures of dichloromethane/methanol, etOAc/methanol and petroleum ether/EtOAc.

Preparative chromatography was performed on a Gilson-281 Prep LC 322 system using a Gilson UV/VIS-156 detector using columns Agella Venusil ASB Prep C (5 μm packing, 150X 21.2 mm gauge), phenomenex Gemini C18 (5 μm packing, 150X 30mm gauge), boston Symmetrix C18 (5 μm packing, 150X 30mm gauge) or Phenomenex Synergi C18 (4 μm packing, 150X 30mm gauge). At a flow rate of about 25mL/min, the compound was eluted with a low gradient of acetonitrile/water (10 mM ammonium bicarbonate in water) for a total run time of 8-15 minutes.

Drawings

FIG. 1 is a graph showing tumor growth curves of HepG2 in situ xenograft tumor model tumor-bearing mice after administration of sorafenib, compound 4A, and Compound 8.

FIG. 2 shows the change in body weight of HepG2 xenograft model tumor-bearing mice during the administration of sorafenib, compound 4A and Compound 8.

Detailed Description

The present invention is described in detail below by way of examples, but is not meant to be limiting in any way. The present invention has been described in detail herein, and specific embodiments thereof are also disclosed, it will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the invention without departing from the spirit and scope of the invention.

Synthesis of intermediates

Synthesis of intermediate compounds 1-5:

step A: sodium hydrogen (8.43 g, 210.87 mmol, 60% purity) was dissolved in DMF (260 ml) and compound 1-1 (13 g, 84.35 mmol) was added. The mixture was stirred at 25℃for 1 hour under nitrogen. Benzyl bromide (14.43 g, 84.35 mmol) was then added and the mixture stirred at 25 degrees celsius for 5 hours, and benzyl bromide (2.89 g, 16.87 mmol) was added and the mixture stirred at 25 degrees celsius for 2 hours. The reaction mixture was added with water (1000 ml), and hydrochloric acid (250 ml, 1 mol/l) was added to adjust the pH to 1-3. EtOAc (800 ml×2) was added again for extraction, and the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO ₂ PE: etOAc=5:1 to 1:1) to give compounds 1-2. ¹ H NMR(400MHz，CDCl ₃ )：δ10.87-11.06(m，1H)，8.08(s，1H)，7.54(dd，J＝1.4，8.1Hz，1H)，7.43-7.49(m，2H)，7.29-7.34(m，1H)，7.36-7.41(m，2H)，7.09(dd，J＝1.4，8.0Hz，1H)，6.76-6.83(m，1H)，5.19(s，2H)。

And (B) step (B): compound 1-2 (18.8 g, 55.42 mmol) was dissolved in a mixture of pyridine (35 ml) and anhydrous DCM (150 ml) and cooled to 0-5 ℃. Triphosgene (11.02 g, 37.13 mmol) was dissolved in anhydrousDCM (80 ml) was added slowly dropwise to the mixture containing compounds 1-2. After the dripping is finished, the reaction solution is continuously stirred for 14 hours at the temperature of 25-30 ℃. Then, to the reaction solution was added methylamine hydrochloride (19.10 g, 277.16 mmol), triethylamine (28.62 g, 277.16 mmol), anhydrous DCM (150 ml). The mixture was stirred at 25 degrees celsius for 16 hours under nitrogen blanket. The reaction was added water (400 ml) and DCM (100 ml), and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO ₂ PE: etOAc=6:1-4.5:1) to give compounds 1-3. ¹ H NMR(400MHz，CDCl ₃ )：δ11.57-11.77(m，1H)，7.44-7.47(m，2H)，7.36-7.41(m，2H)，7.30-7.35(m，1H)，7.09(dd，J＝1.3，8.1Hz，1H)，7.00(dd，J＝1.2，8.1Hz，1H)，6.73-6.78(m，1H)，5.15-5.19(m，2H)，3.02(d，J＝4.89Hz，3H)，1.27(s，1H)。

Step C: compounds 1-3 (4.6 g, 17.88 mmol) were dissolved in chloroform (30 ml), paraformaldehyde (6.44 g, 71.52 mmol) was added, followed by concentrated sulfuric acid (175.36 mg, 1.79 mmol). The mixture was stirred at 70 degrees celsius for 12 hours under nitrogen protection. The reaction was added water (50 ml) and extracted with DCM (50 ml×2) and the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give compounds 1-4.

Step D: compounds 1-4 (4.81 g, 17.86 mmol) were dissolved in anhydrous MeOH (400 mL) and Pd/C (10% purity, 100 mg, 17.86 mmol) was added. The mixture was stirred at 25℃for 3 hours under a hydrogen atmosphere. The filtrate after filtration was concentrated under reduced pressure to obtain intermediate compounds 1-5. ¹ H NMR(400MHz，CDCl ₃ )：δ3.13(s，3H)，5.24(s，2H)，5.58(s，1H)，6.96-7.05(m，1H)，7.05-7.14(m，1H)，7.43-7.57(m，1H)。

Synthesis of intermediate compounds 2-7:

step A: to compound 2-1 (25 g, 137.23 mmol)) To a mixture of cesium carbonate (49.18 g, 150.96 mmol) in DMF (250 ml) was added 2-2 (33.83 g, 150.96 mmol). The mixture is stirred for 12 hours at 15-28 ℃. The reaction was poured into water (1000 ml) and TBME (800 ml) and separated. The organic phase was washed with saturated brine (20 ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 2-3. ¹ H NMR(DMSO-d ₆ ，400MHz)δ7.32-7.10(m，3H)，6.82-6.71(m，1H)，3.94(t，J＝6.1Hz，2H)，3.83(m，6H)，3.26(q，J＝6.0Hz，2H)，1.39(s，9H)。

And (B) step (B): compound 2-3 (44 g, 135.24 mmol) was dissolved in dioxane (250 ml) and dioxane hydrochloride solution (4 m,220 ml) was added. The mixture was stirred at 30 degrees celsius for 2 hours. The reaction solution was concentrated under reduced pressure to obtain compounds 2-4.

Step C: compound 2-4 (35.91 g, 137.22 mmol) was added to toluene (600 ml) followed by sodium methoxide (16.31 g, 301.88 mmol). The mixture was stirred at 120 degrees celsius for 12 hours. The reaction solution was concentrated under reduced pressure to remove the solvent. The residue was taken up in aqueous ammonium chloride (60 ml) and extracted with DCM/isopropanol (3:1, 200 ml. Times.3). The combined organic phases were washed with saturated brine (60 ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compounds 2-5. ¹ H NMR(DMSO-d ₆ ，400MHz)δ8.30(br s，1H)，7.24-7.04(m，3H)，4.21(t，J＝5.3Hz，2H)，3.79(s，3H)，3.22(q，J＝5.4Hz，2H)。

Step D: to DMF (100 ml) of compound 2-5 (18 g, 93.17 mmol) at 0 degrees celsius was added sodium hydrogen (4.84 g, 121.12 mmol, 60% purity). The mixture was stirred at 0 degrees celsius for 10 minutes. Methyl iodide (19.84 g, 139.75 mmol) was then added. The mixture was stirred at 10 degrees celsius for 2 hours. The reaction was added to water at 0℃and extracted with DCM/isopropanol (3:1, 200 ml. Times.3). The combined organic phases were washed with saturated brine (20 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give compounds 2-6. ¹ H NMR(DMSO-d ₆ ，400MHz)δ7.19-7.08(m，3H)，4.29(t，J＝5.3Hz，2H)，3.79(s，3H)，3.46(t，J＝5.4Hz，2H)，3.09(s，3H)。

Step E: compound 2-6 (9 g, 43.43 mmol) was dissolved in DCM (100 ml) and boron tribromide (21.76 g, 86.86 mmol) was added at 0 degrees celsius. The reaction solution was stirred at 0 degrees celsius for 2 hours. The reaction was quenched with slow addition of water (50 ml) at 0℃and then extracted with DCM/isopropanol (3:1, 30 ml. Times.3). The combined organic phases were washed with saturated brine (20 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give compounds 2-7. ¹ H NMR(DMSO-d ₆ ，400MHz)δ7.01-6.91(m，3H)，4.30(t，J＝5.4Hz，2H)，3.45(t，J＝5.4Hz，2H)，3.08(s，3H)。

Synthesis of intermediate compounds 3-7:

step A: compound 3-1 (100 g, 657.26 mmol) was dissolved in THF (300 ml) and triethylamine (106.69 g, 1.05 mol) was added. Triphosgene (29.53 g, 99.50 mmol) was dissolved in DCM (200 ml) and added dropwise to the reaction solution at zero degrees celsius. The mixture was stirred at zero degrees celsius for 20 minutes and at 25 degrees celsius for 16 hours. The reaction was quenched by pouring into saturated aqueous sodium bicarbonate (400 ml), extracted with DCM (200 ml×2) and the combined organic phases were washed with saturated brine (200 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The concentrated residue was added to TBME: pe=1:1 (80 ml) at 25 degrees celsius, stirred for 1 hour, and filtered to give compound 3-2. ¹ H NMR(400MHz，CDCl ₃ )δ8.06(dd，J＝1.6，7.8Hz，2H)，7.67-7.59(m，2H)，7.45-7.35(m，4H)，3.97(s，6H)。

And (B) step (B): compound 3-3 (15.00 g, 99.20 mmol) was dissolved in THF (150 ml) and compound 3-2 (31.37 g, 99.20 mmol) was added. The mixture was stirred at 25 degrees celsius for 1 hour. The reaction mixture was concentrated under reduced pressure and dried by spin drying, and the residue was added to TBME: pe=1:1 (30 ml) and stirred for 1 hour at 25 degrees celsius, and filtered to give compound 3-4. ¹ H NMR(400MHz，CDCl ₃ )δ7.98(dd，J＝1.5，7.8Hz，1H)，7.54(dt，J＝1.7，7.8Hz，1H)，7.33-7.29(m，1H)，7.28-7.22(m，2H)，7.16(d，J＝8.2Hz，1H)，6.99-6.88(m，2H)，3.88(s，3H)，3.84(s，3H)，3.55(q，J＝6.7Hz，2H)，2.95(t，J＝6.8Hz，2H)。

Step C: compound 3-4 (30.29 g, 91.97 mmol) was dissolved in DCM (460 ml) and triflic acid (138.03 g, 919.70 mmol) was added dropwise at zero degrees celsius. The mixture was stirred at 20 degrees celsius for 1.5 hours. The reaction was quenched by addition of ice water (500 ml) with stirring and extracted with DCM (300 ml×2). The combined organic phases were washed successively with 1 mol/l aqueous sodium hydroxide solution (500 ml×2) and saturated brine (200 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was added to TBME: pe=1:1 (15 ml) and stirred for 1h, then filtered and dried to give compound 3-5. ¹ H NMR(400MHz，CDCl ₃ )δ7.70(d，J＝7.2Hz，1H)，7.32(t，J＝8.0Hz，1H)，7.03(dd，J＝0.7，8.2Hz，1H)，6.82-6.65(m，1H)，3.88(s，3H)，3.55(dt，J＝2.9，6.8Hz，2H)，2.98(t，J＝6.7Hz，2H)。

Step D: compound 3-5 (3.3 g, 18.62 mmol) was dissolved in DMF (33 ml) and sodium hydrogen (1.49 g, 37.25 mmol) was added in portions at zero degrees celsius. The mixture was stirred at zero degrees celsius for 15 minutes and methyl iodide (5.82 g, 40.97 mmol) was added. The mixture was stirred at 25 degrees celsius for 1 hour. The reaction was quenched by addition of ice water (60 ml) with stirring and extracted with DCM (60 ml×2). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. EtOAc (60 ml) and saturated brine (20 ml) were added, the solution was separated, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give compounds 3-6.

Step E: compound 3-6 (4.10 g, 21.44 mmol) was dissolved in DCM (41 ml) and boron tribromide (6.45 g, 25.73 mmol) was added dropwise at zero degrees celsius. The mixture was stirred at 20 degrees celsius for 1 hour. The reaction was cooled to zero degrees celsius, quenched by dropwise addition of MeOH (40 ml) and concentrated under reduced pressure. The residue was stirred at 25 degrees celsius with EtOAc: pe=1:3 (15 ml) for 1 hour and filtered to give compounds 3-7.

Synthesis of intermediate compound 5-4:

step A: compound 5-1 (25 g, 149.56 mmol) was dissolved in DMF (500 ml) and carbonyldiimidazole (23.76 g, 146.53 mmol) was added. The reaction solution was stirred under nitrogen at 70 degrees celsius for 1 hour. Then, ammonia (3.36 mol, 518.16 ml, purity 25%) was added to the reaction solution. The reaction solution was stirred under nitrogen at 70 degrees celsius for 16 hours. The reaction was partitioned between water (2.5L) and EtOAc (2L). The organic phase was washed with saturated brine (1000 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give crude compound 5-2. ¹ H NMR(DMSO-d ₆ ，400MHz)δ：7.73(br s，1H)，7.24-7.17(m，1H)，7.10(br s，1H)，6.89(d，J＝7.8Hz，1H)，6.48(t，J＝8.0Hz，1H)，6.28(br s，2H)，3.79(s，3H)。

And (B) step (B): compound 5-2 (22.5 g, 135.40 mmol) and N, N-dimethyl methylal (48.40 g, 406.19 mmol) were added to DMF (500 ml). The reaction solution was stirred at 140 degrees celsius for 16 hours. The reaction solution was concentrated under reduced pressure. The crude product was added to EtOAc/TBME (100 mL) and stirred for 1 hour and filtered to give compound 5-3. ¹ H NMR(DMSO-d ₆ ，400MHz)δ：8.32(s，1H)，7.70(dd，J＝1.1，8.0Hz，1H)，7.47(t，J＝8.0Hz，1H)，7.36(dd，J＝1.0，8.0Hz，1H)，3.91(s，3H)，3.50(s，3H)。

Step C: compound 5-3 (7 g, 36.80 mmol) was dissolved in DCM (100 ml) and boron tribromide (18.44 g, 73.61 mmol) was added at 0 degrees celsius. The reaction solution was stirred at 0℃for 2 hours. The reaction was quenched by slow addition of MeOH (20 ml) at 0-10℃and concentrated under reduced pressure. The crude product was added to MeOH (50 ml) and stirred for 1 hour and filtered to give compound 5-4. ¹ H NMR(DMSO-d ₆ ，400MHz)δ9.92(br s，1H)，9.10(s，1H)，7.63(d，J＝7.9Hz，1H)，7.51(t，J＝8.0Hz，1H)，7.39(d，J＝7.9Hz，1H)，3.59(s，3H)。

Synthesis of intermediate compound 6-3:

step A: compound 6-1 (4.00 g, 18.60 mmol) was dissolved in DMSO (36 ml), magnesium sulfate (2.24 g, 18.60 mmol), 1' -bis (diphenylphosphine) ferrocene (206.24 mg, 372.02 μmol), palladium acetate (83.52 mg, 372.02 μmol), hydrazine methyl sulfate (2.68 g, 18.60 mmol) and 1, 8-diazabicyclo undec-7-ene (8.50 g, 55.80 mmol) were added. The suspension was replaced 3 times with carbon monoxide and stirred at 100 degrees celsius for 16 hours in a carbon monoxide (45 Psi) atmosphere. The reaction was added to water (30 ml), extracted with EtOAc (30 ml), and the organic phase was washed with water (30 ml) and saturated brine (15 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column purification (SiO ₂ PE: etOAc=8:1-3:1) and then added to TBME (10 ml) and stirred for 1 hour, and filtered to give compound 6-2. ¹ H NMR(CDCl ₃ ，400MHz)δ8.51(s，1H)，8.00(d，1H，J＝8.1Hz)，7.70(t，1H，J＝8.1Hz)，7.19(d，1H，J＝8.1Hz)，4.01(s，3H)，3.88(s，3H)。

And (B) step (B): compound 6-2 (390 mg, 2.05 mmol) was dissolved in DCM (5 ml) and boron tribromide (1.03 g, 4.10 mmol) was added dropwise at zero degrees celsius. The mixture was stirred at 25 degrees celsius for 16 hours. The reaction was quenched by dropwise addition of MeOH (20 ml) at zero degrees Celsius with stirring and concentrated under reduced pressure to give compound 6-3.

Synthesis of intermediate compound 7-4:

step A: compound 3-5 (5.70 g, 32.17 mmol) was dissolved in DCM (57 ml) and boron tribromide (12.09 g, 48.25 mmol) was added dropwise at zero degrees celsius. The mixture was stirred at 20 degrees celsius for 2 hours. The reaction solution was stirred at zero degrees celsiusMeOH (40 ml) was added dropwise for quenching and concentrated under reduced pressure. The crude product was added to MeOH: H ₂ O=1:1 (14 ml) for 1 hour, and compound 7-1 was obtained by filtration.

And (B) step (B): compound 7-1 (1.8 g, 11.03 mmol) was dissolved in acetone (180 ml) and potassium carbonate (4.57 g, 33.09 mmol) and benzyl bromide (3.77 g, 22.06 mmol) were added. The mixture was stirred at 60 degrees celsius for 16 hours. The reaction was concentrated under reduced pressure, water (100 ml) was added, DCM (100 ml×2) was extracted, and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was added to PE: tbme=1:1 (15 ml) and filtered with stirring to give compound 7-2. ¹ H NMR(400MHz，DMSO-d ₆ )δ＝7.91(br s，1H)，7.51-7.45(m，3H)，7.41(t，J＝7.3Hz，2H)，7.37-7.32(m，1H)，7.29(d，J＝7.7Hz，1H)，7.27-7.22(m，1H)，5.17(s，2H)，3.37(br d，J＝2.8Hz，2H)，2.87(t，J＝6.7Hz，2H)。

Step C: compound 7-2 (1.8 g, 7.11 mmol) was dissolved in DMF (40 ml) and sodium hydrogen (852.68 mg, 21.32 mmol) was added in portions at zero degrees celsius. The mixture was stirred at 25 degrees celsius for 0.5 hour. 3-iodooxetane (1.96 g, 10.66 mmol) was added. The mixture was stirred at 100 degrees celsius for 16 hours. The reaction was extracted with water (50 ml), etOAc (60 ml×2), and the combined organic phases were washed with saturated brine (30 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO ₂ PE: etOAc=10:1-3:1) to give compound 7-3.

Step D: compound 7-3 (0.9 g, 2.91 mmol) was dissolved in MeOH (10 ml) and Pd/C (0.1 g) was added under nitrogen. The mixture was replaced 3 times with hydrogen and stirred at 25 degrees celsius for 16 hours under an atmosphere of hydrogen (15 psi). Filtering and concentrating under reduced pressure to obtain compound 7-4. ¹ H NMR(400MHz，DMSO-d ₆ )δ10.45-9.22(m，1H)，7.34(dd，J＝0.8，7.6Hz，1H)，7.14(t，J＝7.8Hz，1H)，6.99(dd，J＝1.0，8.1Hz，1H)，5.44(m，，1H)，4.80-4.66(m，4H)，3.65(t，J＝6.6Hz，2H)，2.90(t，J＝6.5Hz，2H)。

Example 1

Step A: compounds 1-6 (40.0 g, 169.49 mmol) were dissolved in dioxane (600 ml) and bis (triphenylphosphine) palladium dichloride (4.0 g, 5.7 mmol) and tributyl (1-ethoxyethylene) tin (57.3 ml, 169.49 mmol) were added. The mixture was stirred at 60 degrees celsius for 16 hours under nitrogen blanket. The reaction was poured into saturated aqueous potassium fluoride (200 ml) and EtOAc (200 ml), stirred for 1 hour, filtered, the filter cake was washed with EtOAc, and the organic phase was separated and dried over anhydrous sodium sulfate. Concentrating under reduced pressure to obtain compounds 1-7.

And (B) step (B): compounds 1-7 (38 g, 167.26 mmol) were dissolved in THF (400 ml) and a 2 mol/l hydrochloric acid solution (400 ml) was added and reacted at 25℃for 2 hours. Extracted with EtOAc (200 ml×3), the combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO ₂ PE: etOAc=10:1-5:1) to give compounds 1-8. ¹ H NMR(400MHz，CDCl ₃ )δ11.96(s，1H)，7.66(d，J＝10.4Hz，1H)，7.61(d，J＝6.1Hz，1H)，2.70(s，3H)。

Step C: to a solution of compounds 1-8 (10.1 g, 50.72 mmol) in ethyl formate (151.5 ml, 1.88 mol) at 0-5 degrees celsius, sodium hydrogen (12.17 g, 304.32 mmol, purity 60%) was added in portions. The reaction solution is stirred for 20 minutes at the temperature of 0-5 ℃, and then heated to the temperature of 20-30 ℃ and stirred for 2 hours. MeOH (21 ml) and concentrated hydrochloric acid (63 ml) were added sequentially at 10 degrees celsius and the reaction stirred for an additional 2 hours at 20-30 degrees celsius. The reaction solution was dissolved in EtOAc (300 ml), washed with water (200 ml) and saturated brine (200 ml), and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiO ₂ PE: etOAc=7:1-3:1) to afford compounds 1-9. ¹ H NMR(400MHz，CDCl ₃ )δ8.21(d，J＝5.6Hz，1H)，8.10(d，J＝10.0Hz，1H)，7.96(d，J＝6.1Hz，1H)，6.44(d，J＝6.1Hz，1H)。

Step D: the compound is prepared1-9 (500 mg, 2.39 mmol), compounds 1-5 (449.79 mg, 2.51 mmol), potassium carbonate (991.29 mg, 7.17 mmol) in DMF (10 ml) was stirred at 40 degrees celsius for 14 hours. The reaction solution was poured into water (50 ml) and stirred for 0.5 hours, filtered, and the filter cake was rinsed with TBME (5 ml×2) and dried under reduced pressure to give compounds 1-10. ¹ H NMR(400MHz，DMSO-d ₆ )δ8.56(s，1H)，8.42(d，J＝6.0Hz，1H)，7.77(dd，J＝1.5，7.8Hz，1H)，7.52(dd，J＝1.6，8.1Hz，1H)，7.34(s，1H)，7.25(t，J＝7.9Hz，1H)，6.43(d，J＝6.1Hz，1H)，5.27(s，2H)，2.96(s，3H)。

Step E: to a solution of compounds 1-10 (170 mg, 461.58 μmol) in THF (6 ml) at 0 degrees celsius was added sodium borohydride (52.39 mg, 1.38 mmol) in portions. The reaction solution was stirred at 20-30℃for 4 hours. The reaction was poured into saturated ammonium chloride solution (80 ml), extracted with EtOAc (50 ml×2), and the combined organic phases were washed with saturated brine (40 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by thin layer chromatography (developer: DCM: etOAc=1:10) to give compounds 1-11. ¹ H NMR(400MHz，CDCl ₃ )δ7.72(dd，J＝1.7，7.6Hz，1H)，7.46(s，1H)，7.12-7.01(m，3H)，5.25-5.14(m，2H)，4.82-4.71(m，1H)，4.40-4.24(m，2H)，3.08(s，3H)，2.26-2.00(m，2H)。

Step F: compounds 1-11 (70 mg, 188.01. Mu. Mol) were dissolved in THF (5 ml) and LiHMDS (1 mol/l, 282.01. Mu.l) was added at-60℃and the mixture stirred at-60℃for 15 min. A mixture of phosphorus oxychloride (57.65 mg, 376.01. Mu. Mol) in THF (0.2 ml) was added. The reaction solution was stirred at-60 degrees celsius for 10 minutes. 2-Bromoethylamine hydrobromide (308.17 mg, 1.5 mmol) and DIPEA (194.38 mg, 1.5 mmol) were added sequentially, vigorously stirred and warmed to 0℃and stirred for 30 min. The reaction was poured into water (20 ml), extracted with EtOAc (20 ml×2), and the combined organic phases were washed with brine (20 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by thin layer chromatography (developer: etOAc: acetone=3:1) to give compounds 1-12. ¹ H NMR(400MHz，CDCl ₃ )δ7.78(dd，J＝2.6，6.8Hz，1H)，7.47(s，1H)，7.16(s，1H)，7.12-7.03(m，2H)，5.44-5.36(m，1H)，5.23(s，2H)，4.41-4.24(m，2H)，3.75(ddd，J＝2.6，4.1，6.5Hz，2H)，3.48-3.44(m，2H)，3.36-3.27(m，4H)，3.12(s，3H)，3.10-3.05(m，2H)，2.32-2.21(m，2H)。

Step G: compounds 1-12 (80 mg, 120.44 μmol) were dissolved in THF (6 ml) and silver oxide (279.11 mg, 1.2 mmol) was added. The mixture was stirred at 60 degrees celsius for 14 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by high performance liquid chromatography (separation column: waters Xridge (specification: C18X 50mM, particle size: 10 μm); mobile phase: [ water (10 mM ammonium bicarbonate) -acetonitrile ]; elution gradient: 17% -47%,10 min.) to give compound 1.

¹ H NMR(400MHz，CDCl ₃ )δ7.79(dd，J＝1.7，7.7Hz，1H)，7.47(s，1H)，7.15-7.11(m，2H)，7.09-7.05(m，1H)，5.55-5.48(m，1H)，5.21(s，2H)，4.39-4.26(m，2H)，3.12(s，3H)，2.32-2.24(m，2H)，2.17-2.13(m，1H)，2.12-2.09(m，1H)，2.08-1.97(m，6H)。

Example 2

Synthesis of compound 2 reference compound 1. In the synthetic route of compound 1, intermediate 1-5 may be replaced with intermediate 2-7. ¹ H NMR(400MHz，CDCl ₃ )δ7.58(dd，J＝2.4，7.2Hz，1H)，7.45(s，1H)，7.19-7.11(m，2H)，7.06(s，1H)，5.54-5.48(m，1H)，4.39-4.29(m，4H)，3.52(t，J＝5.3Hz，2H)，3.21(s，3H)，2.31-2.23(m，2H)，2.15-2.12(m，1H)，2.11-2.08(m，1H)，2.08-1.99(m，6H)。

Example 3

Method for synthesizing reference compound 1 of compound 3. In the synthetic route of compound 1, intermediate 1-5 may be replaced with intermediate 3-7. ¹ H NMR(400MHz，CDCl ₃ )δ＝7.94-7.89(m，1H)，7.47(s，1H)，7.31-7.27(m，1H)，7.12(s，1H)，6.95(dd，J＝1.0，8.2Hz，1H)，5.57-5.50(m，1H)，4.39-4.28(m，2H)，3.59(t，J＝6.8Hz，2H)，3.17(s，3H)，3.04(t，J＝6.7Hz，2H)，2.33-2.26(m，2H)，2.17-2.15(m，1H)，2.13-2.11(m，1H)，2.09-2.00(m，6H)。

Example 4

Method for synthesizing reference compound 1 of compound 4. In the synthetic route of the compound 1, the intermediate 1-5 is replaced by 3-hydroxy-N, N-dimethylbenzamide. ¹ H NMR(400MHz，CDCl ₃ )δ7.46(s，1H)，7.39-7.34(m，1H)，7.28(s，1H)，7.13(td，J＝1.1，7.6Hz，1H)，7.02(ddd，J＝0.9，2.6，8.3Hz，1H)，6.97(dd，J＝1.5，2.3Hz，1H)，5.60-5.52(m，1H)，4.40-4.29(m，2H)，3.08(s，3H)，2.96(s，3H)，2.34-2.26(m，2H)，2.20-2.07(m，8H)。

Compound 4 was isolated by SFC preparation (separation column: DAICEL CHIRALPAK AD-H (specification: AD-H250 mm x 30mm, particle size: 5 μm); mobile phase: [ isopropanol ]; elution gradient: 35% -35%,5 min) to give single configuration compound 4A (retention time=1.784) and compound 4B (retention time= 1.911).

Compound 4A: ¹ H NMR(400MHz，CDCl ₃ )δ7.46(s，1H)，7.39-7.34(m，1H)，7.28(s，1H)，7.13(td，J＝1.1，7.6Hz，1H)，7.02(ddd，J＝0.9，2.5，8.3Hz，1H)，6.97(dd，J＝1.5，2.4Hz，1H)，5.58-5.52(m，1H)，4.41-4.28(m，2H)，3.08(s，3H)，2.95(s，3H)，2.34-2.25(m，2H)，2.20-2.06(m，8H)。

compound 4B: ¹ H NMR(400MHz，CDCl ₃ )δ7.45(s，1H)，7.39-7.33(m，1H)，7.28(s，1H)，7.13(td，J＝1.1，7.5Hz，1H)，7.02(ddd，J＝0.8，2.5，8.2Hz，1H)，6.96(dd，J＝1.5，2.4Hz，1H)，5.59-5.52(m，1H)，4.40-4.28(m，2H)，3.07(s，3H)，2.95(s，3H)，2.32-2.26(m，2H)，2.19-2.06(m，8H)。

example 5

Method of synthesizing reference compound 1 of compound 5. In the synthetic route of compound 1, intermediate 1-5 is replaced with intermediate 5-4. ¹ H NMR(CD ₃ CN，400MHz)δ7.82-7.76(m，2H)，7.28-7.15(m，3H)，6.74(s，1H)，5.15-5.05(m，1H)，4.10-4.03(m，1H)，3.99-3.91(m，1H)，3.22(s，3H)，1.71-1.64(m，6H)，1.62-1.51(m，4H)。

Example 6

Method for synthesizing reference compound 1 of compound 6. In the synthetic route of the compound 1, the intermediate 1-5 is replaced by the intermediate 6-3. ¹ H NMR(400MHz，CDCl ₃ )δ8.57(s，1H)，8.15(d，J＝7.9Hz，1H)，7.66-7.55(m，2H)，7.41(s，1H)，7.01(d，J＝8.1Hz，1H)，5.66-5.56(m，1H)，4.48-4.32(m，2H)，3.90(s，3H)，2.40-2.29(m，2H)，2.22-2.06(m，8H)。

Example 7

Method for synthesizing reference compound 1 of compound 7. In the synthetic route of compound 1, intermediate 1-5 may be replaced with intermediate 7-4. ¹ H NMR(400MHz，CDCl ₃ )δ7.88(dd，J＝1.0，7.8Hz，1H)，7.50(s，1H)，7.32-7.28(m，1H)，7.19(s，1H)，6.95(dd，J＝1.0，8.1Hz，1H)，5.78-5.68(m，1H)，5.58-5.52(m，1H)，5.02-4.94(m，2H)，4.80(dt，J＝2.3，6.8Hz，2H)，4.45-4.25(m，2H)，3.81(t，J＝6.5Hz，2H)，3.14(t，J＝6.5Hz，2H)，2.31(td，J＝4.5，6.2Hz，2H)，2.21-2.01(m，8H)。

Example 8

Step A: a solution of compound 8-1 (1 g, 8.84 mmol), compound 1-9 (1.85 g, 8.84 mmol), potassium carbonate (3.67 g, 26.53 mmol) in acetonitrile (15 ml) was stirred at 50 degrees celsius for 12 hours. The reaction solution was concentrated under reduced pressure, and the crude product was purified by column chromatography (SiO 2, PE: etoac=5:1 to 1:1) to give compound 8-2. ¹ H NMR(400MHz，CDCl ₃ )δ8.09-8.01(m，2H)，7.90-7.84(m，1H)，7.61-7.48(m，2H)，7.27-7.15(m，2H)，6.32(d，J＝6.1Hz，1H)。

And (B) step (B): to a solution of compound 8-2 (900 mg, 2.98 mmol) in THF (10 ml) at 0 degrees celsius was added dropwise an aqueous solution of sodium borohydride (112.67 mg, 2.98 mmol) (1 ml). The reaction solution was stirred at 0℃for 0.5 hours. The reaction solution was poured into water (3 ml) and quenched, and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO ₂ PE: etOAc=5:1-1:2) to give compound 8-3. ¹ H NMR(400MHz，CDCl ₃ )δ7.97-7.91(m，1H)，7.49(s，1H)，7.31(ddd，J＝1.6，7.9，9.7Hz，1H)，7.18-7.11(m，2H)，4.80(br d，J＝4.4Hz，1H)，4.40-4.28(m，2H)，2.25-2.15(m，1H)，2.13-2.05(m，1H)。

Step C: compound 8-3 (650 mg, 2.12 mmol) was dissolved in THF (20 ml) and lithium bis (trimethylsilyl) amide (1 mol/l, 3.18 ml) was added at-60 ℃ and the mixture stirred for 15 min at-60 ℃. THF (3 ml) of phosphorus oxychloride (650.13 mg, 394.02 micromole) was added in one portionIs a mixed solution of (a) and (b). The reaction solution was stirred at-60 degrees celsius for 15 minutes. 2-Bromoethylamine hydrobromide (2.10 g, 16.96 mmol) and DIPEA (2.19 g, 16.96 mmol) were added sequentially and the reaction stirred at-60℃for 30 min. The reaction was poured into ice water (50 ml), extracted with EtOAc (100 ml×2), and the combined organic phases were washed with brine (100 ml), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The crude product was purified by column chromatography (SiO ₂ PE: etOAc=3:1-1:2) to afford compound 8-4.

Step D: compound 8-4 (500 mg, 835.91 μmol) was dissolved in THF (10 ml) and silver oxide (3.87 g, 1.2 mmol) was added. The mixture was stirred at 70 degrees celsius for 12 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (SiO ₂ PE: etOAc=5:1 to 1:4) to afford compound 8. ¹ H NMR(400MHz，CDCl ₃ )δ7.98(td，J＝1.6，4.8Hz，1H)，7.50(s，1H)，7.37(ddd，J＝1.6，7.9，9.7Hz，1H)，7.23(s，1H)，7.17(ddd，J＝0.6，4.9，7.9Hz，1H)，5.60-5.51(m，1H)，4.44-4.27(m，2H)，2.34-2.25(m，2H)，2.21-2.06(m，8H)。

Compound 8 was isolated by SFC preparation (separation column: cellulose-2 (size: 50×4.6mm, particle size: 3 μm; mobile phase: [ isopropanol ]; elution gradient: 40% -40%, flow rate: 3 mL/min) to give single configuration compound 8A (retention time=0.864 min) and compound 8B (retention time=1.102 min).

Compound 8A: ¹ H NMR(400MHz，CDCl ₃ )δ7.99(td，J＝1.5，4.8Hz，1H)，7.51(s，1H)，7.38(ddd，J＝1.6，7.9，9.7Hz，1H)，7.23(s，1H)，7.20-7.14(m，1H)，5.58-5.51(m，1H)，4.42-4.29(m，2H)，2.33-2.26(m，2H)，2.22-2.06(m，8H)。

compound 8B: ¹ H NMR(400MHz，CDCl ₃ )δ7.99(td，J＝1.5，4.8Hz，1H)，7.51(s，1H)，7.38(ddd，J＝1.7，7.9，9.7Hz，1H)，7.23(s，1H)，7.20-7.14(m，1H)，5.61-5.49(m，1H)，4.46-4.27(m，2H)，2.33-2.26(m，2H)，2.21-2.06(m，8H)。

example 9

Step A: compounds 1-9 (8.00 g, 38.25 mmol) were dissolved in tetrahydrofuran (160 ml) and methanol (16 ml) and sodium borohydride (1.45 g, 38.25 mmol) was added at 0deg.C and the reaction stirred at 0deg.C for 1 hour. Adding acetone (80 ml) into the reaction solution, quenching, adding concentrated hydrochloric acid (12 mol/L) to adjust pH to 8, concentrating under reduced pressure to obtain crude product, purifying by column chromatography (SiO) ₂ PE/EtOAc=7.5:1 to 3:1) to give compound 9-1. ¹ H NMR(400MHz，DMSO-d6)：δ7.55-7.38(m，2H)，5.83(d，J＝5.5Hz，1H)，4.70(q，J＝5.4Hz，1H)，4.34-4.16(m，2H)，2.16-2.02(m，1H)，1.98-1.76(m，1H)。

And (B) step (B): compound 9-1 (4.00 g, 9.38 mmol) was dissolved in tetrahydrofuran (60 ml), lithium bis (trimethylsilyl) amide (1 mol/l, 14.07 ml, 14.07 mmol) was added dropwise at-60 ℃ and then reacted under stirring at-60 ℃ for 15 minutes. To the reaction solution was added phosphorus oxychloride (2.16 g, 14.07 mmol) at one time, and after continuing the stirring reaction at-60 ℃ for 15 minutes, 2-bromoethylamine hydrobromide (9.61 g, 46.90 mmol) and DIPEA (6.06 g, 46.90 mmol) were added in this order, and the reaction solution was stirred at-60 ℃ for 90 minutes. The reaction solution was slowly poured into ice water (160 ml), extracted with ethyl acetate (300 ml×1), and the combined organic phases were washed with saturated brine (100 ml×1), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography (SiO) ₂ PE/EtOAc=3:1-0:1) to give compound 9-2. ¹ H NMR(400MHz，CDCl ₃ )δ7.51-7.42(m，2H)，5.51-5.41(m，1H)，4.39-4.31(m，1H)，4.31-4.22(m，1H)，3.53-3.46(m，2H)，3.45-3.40(m，2H)，3.40-3.32(m，4H)，3.24(br s，2H)，2.28-2.22(m，2H)。

Step C: compound 9-2 (3.00 g, 5.94 mmol) was dissolved in tetrahydrofuran (54 ml), silver oxide (3 g, 178.19 mmol) was added, and the reaction solution was heated to 70 ℃ and stirred for reaction for 12 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to give compound 9-3. ¹ H NMR(400MHz，CDCl ₃ )δ7.54-7.49(m，1H)，7.46-7.40(m，1H)，5.63-5.54(m，1H)，4.42-4.25(m，2H)，2.31-2.19(m，10H)。

Step D: compound 9-3 (100 mg, 291.34 micromolar) was dissolved in acetonitrile (3 ml), potassium carbonate (80.53 mg, 582.67 micromolar) and 4-fluorophenol (35.93 mg, 320.47 micromolar) were added, and the reaction solution was warmed to 55 degrees celsius and stirred for reaction for 12 hours. The reaction solution was filtered and concentrated under reduced pressure to give a crude product. Purification by preparative thin layer silica gel chromatography (SiO ₂ : PE/etoac=0/1) followed by p-HPLC (column: welch Ultimate XB-SiOH; model: 250X 50mm X10 μm; fluidity: [ n-hexane-isopropyl alcohol ]]The method comprises the steps of carrying out a first treatment on the surface of the Isopropyl alcohol%: 15% -55%,15 min) and purifying to obtain the compound 9.

¹ H NMR(400MHz，CDCl ₃ )δ7.46-7.39(m，1H)，7.20-7.16(m，1H)，7.09-6.92(m，4H)，5.58-5.48(m，1H)，4.42-4.23(m，2H)，2.33-2.24(m，2H)，2.19-2.01(m，8H)。

Example 10

Method for synthesizing reference compound 9 of compound 10. In the synthetic route of the compound 9, the intermediate 4-fluorophenol is replaced by the intermediate 3-hydroxypyridine.

¹ H NMR(400MHz，CDCl ₃ )δ8.38(br d，J＝9.5Hz，2H)，7.49(s，1H)，7.32-7.28(m，3H)，5.56(td，J＝4.1，8.0Hz，1H)，4.45-4.26(m，2H)，2.38-2.25(m，2H)，2.22-2.05(m，8H)。

Example 11

Method for synthesizing reference compound 9 of compound 11. In the synthetic route of compound 9, intermediate 4-fluorophenol is replaced

The intermediate 3-hydroxy-6-fluoropyridine is obtained.

¹ H NMR(400MHz，CDCl ₃ )δ7.89(dd，J＝1.5，2.9Hz，1H)，7.49(s，1H)，7.44(ddd，J＝3.1，6.2，9.0Hz，1H)，7.31(s，1H)，6.93(dd，J＝3.5，8.9Hz，1H)，5.61-5.53(m，1H)，4.43-4.29(m，2H)，2.34-2.26(m，2H)，2.24-2.06(m，8H)。

Example 12

Method for synthesizing reference compound 9 of compound 12. In the synthetic route of the compound 9, the intermediate 4-fluorophenol is replaced by the intermediate 3-hydroxy-5-fluoropyridine.

¹ H NMR(400MHz，CDCl ₃ )δ8.26(d，J＝2.4Hz，1H)，8.18(d，J＝2.3Hz，1H)，7.53(s，1H)，7.41(s，1H)，7.01(td，J＝2.4，9.5Hz，1H)，5.63-5.54(m，1H)，4.47-4.30(m，2H)，2.35-2.29(m，2H)，2.24-2.10(m，8H)。

Biological activity

Experimental example 1: antiproliferative activity of the compounds of the invention on NCI-H460 cell lines

Experimental materials:

RPMI-1640 medium, penicillin/streptomycin antibiotics were purchased from Vison's Tex, and fetal bovine serum from Biosera. CellTiter-Glo (cell viability chemiluminescent detection reagent) reagent was purchased from Promega. The NCI-H460 cell line was purchased from Nanjac Bai Biotechnology Co. Nivo Multi-labelling Analyzer (Perkinelmer).

The experimental method comprises the following steps:

NCI-H460 cells were seeded in white 96-well plates, 80. Mu.L of cell suspension per well, containing 4000 NCI-H460 cells. Cell plates were placed in a carbon dioxide incubator overnight for culture. The test compounds were diluted 3-fold to the 8 th concentration, i.e. from 200 μm to 92nM, using a row gun and a double multiplex well experiment was set up. 78. Mu.L of medium was added to the intermediate plate, and 2. Mu.L of the gradient diluted compound per well was transferred to the intermediate plate at the corresponding position, and 20. Mu.L of the gradient diluted compound per well was transferred to the cell plate after mixing. The concentration of compound transferred into the cell plate ranged from 1. Mu.M to 0.46nM. The cell plates were placed in a carbon dioxide incubator for 2 hours, after which the drug-containing medium was removed, the cell plates were rinsed once with fresh medium, and 100 μl of fresh medium without drug was added to each well for further 70 hours. A cell plate was also prepared and the signal value read on the day of dosing as the maximum value (Max value in the following equation) was used in the data analysis. To this plate, 25. Mu.L of cell viability chemiluminescent detection reagent was added per well and incubated at room temperature for 10 minutes to stabilize the luminescent signal. Multiple marker analyzer readings were used. To the cell plate, 25. Mu.L of a cell viability chemiluminescent detection reagent per well was added, and the luminescent signal was stabilized by incubation at room temperature for 10 minutes. Multiple marker analyzer readings were used.

Data analysis:

converting the raw data into inhibition rate, IC, using the equation (Sample-Min)/(Max-Min) 100% ₅₀ The values of (a) can be obtained by curve fitting with four parameters (obtained in the "log (inhibitor) vs. response-Variable slope" mode in GraphPad Prism). Table 1 provides the inhibitory activity of the compounds of the present invention on NCI-H460 cell proliferation.

TABLE 1 antiproliferative activity data of the inventive example compounds on NCI-H460 cell line

Numbering of compounds	IC ₅₀ (nM)	Numbering of compounds	IC ₅₀ (nM)
				Compound 1	26.36	Compound 7	5.62
Compound 2	16.51	Compound 8	40.3
				Compound 3	3.10	Compound 8A	30.6
Compound 4	5.09	Compound 8B	31.0
				Compound 4A	2.88	Compound 9	50.0
Compound 4B	7.22	Compound 10	58.1
				Compound 5	37.3	Compound 11	70.4
Compound 6	7.82	Compound 12	24.0

Conclusion: the compounds of the present invention have excellent antiproliferative activity against NCI-H460, which highly expresses AKR1C3 enzyme.

Experimental example 2: antiproliferative activity of compounds of the invention on Hep3B cell lines

Experimental materials:

EMEM (Eagle's Minimum Essential Medium, eagle minimal basal medium) medium, penicillin/streptomycin antibiotics were purchased from Vison's, and fetal bovine serum from Biosera. CellTiter-Glo (cell viability chemiluminescent detection reagent) reagent was purchased from Promega. Hep3B cell lines were purchased from the cell bank of the national academy of sciences. Nivo Multi-labelling Analyzer (Perkinelmer).

The experimental method comprises the following steps:

hep3B cells were seeded in white 96-well plates, 80 μl of cell suspension per well, containing 3000 Hep3B cells. Cell plates were placed in a carbon dioxide incubator overnight for culture. The test compounds were diluted 5-fold to the 9 th concentration, i.e. from 2mM to 5.12nM, using a row gun and a double multiplex well experiment was set up. 78. Mu.L of medium was added to the intermediate plate, and 2. Mu.L of the gradient diluted compound per well was transferred to the intermediate plate at the corresponding position, and 20. Mu.L of the gradient diluted compound per well was transferred to the cell plate after mixing. The concentration of compound transferred into the cell plate ranged from 10. Mu.M to 0.0256nM. The cell plates were placed in a carbon dioxide incubator for 3 days. A cell plate was also prepared and the signal value read on the day of dosing as the maximum value (Max value in the following equation) was used in the data analysis. To this plate, 25. Mu.L of cell viability chemiluminescent detection reagent was added per well and incubated at room temperature for 10 minutes to stabilize the luminescent signal. Multiple marker analyzer readings were used. To the cell plate, 25. Mu.L of a cell viability chemiluminescent detection reagent per well was added, and the luminescent signal was stabilized by incubation at room temperature for 10 minutes. Multiple marker analyzer readings were used.

Data analysis:

raw data was converted to inhibition ratio, IC, using the equation (Sample-Min)/(Max-Min) ×100% ₅₀ The values of (a) can be obtained by curve fitting with four parameters (obtained in the "log (inhibitor) vs. response-Variable slope" mode in GraphPad Prism). Table 2 provides the inhibitory activity of the compounds of the invention on Hep3B cell proliferation.

TABLE 2 antiproliferative activity data of the inventive example compounds on Hep3B cell lines

Numbering of compounds	IC ₅₀ (nM)
		Compound 4A	＞10,000
Compound 4B	＞10,000
		Compound 8A	＞10,000
Compound 8B	＞10,000

Conclusion: the compounds of the invention show no antiproliferative activity on Hep3B with low expression of AKR1C3 and very high selectivity.

Experimental example 3: antiproliferative activity of the compounds of the invention on HepG2 cell lines

Experimental materials:

DMEM medium, penicillin/streptomycin antibiotics were purchased from visnit and fetal bovine serum from Biosera. CellTiter-Glo (cell viability chemiluminescent detection reagent) reagent was purchased from Promega. HepG2 cell lines were purchased from the cell bank of the national academy of sciences. Nivo Multi-labelling Analyzer (Perkinelmer).

The experimental method comprises the following steps:

HepG2 cells were seeded in white 384-well plates, 25. Mu.M cell suspension per well, containing 1000 HepG2 cells. Cell plates were placed in a carbon dioxide incubator overnight for culture. The test compounds were diluted 3-fold to the 9 th concentration, i.e. from 200 μm to 30nM, using a row gun and a double multiplex well experiment was set up. 99. Mu.M medium was added to the intermediate plate, and then 1. Mu.M of the gradient diluted compound per well was transferred to the intermediate plate at the corresponding position, and after mixing, 25. Mu.M per well was transferred to the cell plate. The concentration of compound transferred into the cell plate ranged from 1. Mu.M to 0.15nM. The cell plates were placed in a carbon dioxide incubator for 5 days. A cell plate was also prepared and the signal value read on the day of dosing as the maximum value (Max value in the following equation) was used in the data analysis. To each well of this plate, 20. Mu.M of cell viability chemiluminescent detection reagent was added and incubated at room temperature for 10 minutes to stabilize the luminescent signal. Multiple marker analyzer readings were used. To the cell plate, 20. Mu.M of a cell viability chemiluminescent detection reagent per well was added, and the luminescent signal was stabilized by incubation at room temperature for 10 minutes. Multiple marker analyzer readings were used.

Data analysis:

raw data was converted to inhibition ratio, IC, using the equation (Sample-Min)/(Max-Min) ×100% ₅₀ The values of (a) can be obtained by curve fitting with four parameters (obtained in the "log (inhibitor) vs. response-Variable slope" mode in GraphPad Prism). Table 3 provides the inhibitory activity of the compounds of the invention on HepG2 cell proliferation.

TABLE 3 antiproliferative activity data of the inventive compounds on HepG2 cell lines

Conclusion: the compounds of the present invention have excellent antiproliferative activity on HepG2 highly expressing AKR1C 3.

Experimental example 4: in vivo pharmacodynamics research of compound of the invention on in-situ transplantation tumor model of human liver cancer HepG2 nude mice

The purpose of the experiment is as follows:

the test uses a HepG2 in situ xenograft tumor nude mouse model to evaluate the anti-tumor effect of the compounds.

Experimental materials:

female Balb/C nude mice, 6-8 weeks old, 18-22 g weight, fetal bovine serum (PBS), medium EMEM (30-2003), phosphate buffer, double antibody (15240-062), matrigel, pancreatin.

The experimental steps are as follows:

experimental methods and procedures

1. Cell culture preparation: hepG2-luc cells were cultured in vitro as a monolayer by adding 10% heat-inactivated fetal bovine serum to EMEM medium at 37deg.C with 5% CO ₂ Culturing in an incubator. The passages were digested twice a week with pancreatin-EDTA. Cells were digested with pancreatin-EDTA, counted, resuspended in PBS and matrigel (PBS: matrigel=1:1) at a density of 166.67 ×10 when the cell saturation was 80% -90% ⁶ Individual cells/mL.

2. Tumor cell inoculation grouping: the animals were anesthetized by intramuscular injection of 60mg/kg sultai 50+1.5mg/kg tolylthiazine, and when the animals had reached deep anesthesia, the animals were suitably fixed, the abdominal skin was cleaned with 75% alcohol cotton balls, the wound was surgically cut off by approximately 10mm, 0.03mL (PBS: matrigl=1:1) of HpG-luc cells were inoculated in situ on the left lobe of the liver of each mouse, and then the muscle layer wound was sutured with absorbable intestinal lines, and the skin wound was sutured with a stapler. The animal after the operation is placed on a heat insulation blanket for heat insulation until the animal wakes up. To reduce pain in animals, 2mg/kg of meloxicam (administered subcutaneously once a day) was administered 3 consecutive days after surgery. The 15 animals were randomly selected to detect signal growth, and when the signal began to rise, the signals were randomly grouped according to the bioluminescence signal values, and the dosing treatment was started, with the detailed treatment schedule shown in table 4.

Table 4 experimental animal grouping and dosing regimen

3. Experimental index

The experimental index is whether the tumor growth can be delayed or whether the tumor can be cured. Bioluminescence signals and animal body weight were measured 1 time per week after tumor inoculation and continued until the end of the observation period. The bioluminescence signal value can be used to calculate T/C (where T is the dosing group and C is the average intensity value of bioluminescence over a set time period for the blank). Tumor inhibition TGI calculation formula: TGI (%) = [1- (T) _i -T ₀ )/(V _i -V ₀ )]X 100, where T _i The mean intensity of bioluminescence for the treatment group at the set time; t (T) ₀ The mean intensity of bioluminescence, which is the starting point of administration. V (V) _i Bioluminescence mean intensity at a set time for a blank; v (V) ₀ The mean intensity of bioluminescence was used as the starting point for administration.

4. Inhibition effect of compound on growth of subcutaneous transplantation tumor of HepG2 liver cancer nude mice

The efficacy of compound 4A and compound 8 in HepG2 liver cancer in situ xenograft tumor models was evaluated in this experiment, with sorafenib as reference. At 20 days of administration, each of compound 4A and compound 8 had significant tumor growth inhibition at 1.5mg/kg of administration, with p < 0.05 compared to the vehicle control group. Sorafenib treated group T/c= 47.46%, tgi=57.23%, p=0.436 compared to the solvent control, with no significant tumor inhibition. See fig. 1 and tables 5,6,7 for details.

TABLE 5 tumor inhibiting effect of the inventive compounds on HepG2 in situ xenograft tumor models

Note that: a. mean ± SEM, n=6.

TABLE 6 p-values for Relative Tumor Volume (RTV) comparisons between groups of HepG2 xenograft tumor models

Group of	1	2	3	4
					1	N/A	0.436	0.000	0.000
2	0.436	N/A	0.815	0.684
					3	0.004	0.992	0.881	0.542
4	0.000	0.684	0.997	N/A

Note that: the p-value was obtained by analysis of tumor volume relative values (RTV) using one-way ANOVA.

Table 7 tumor volumes at various time points for each group

Note that: a. mean ± SEM, n=6

5. Weight change condition

In this model, the weight of sorafenib treated animals had a large fluctuation, the average of the overall animal weight was reduced by more than 5%, the weight of animals in compound 4A and compound 8 groups were better, no significant reduction was found, and the animal tolerance was good. See figure 2 for details.

Claims

1. A compound represented by the formula (II), a pharmaceutically acceptable salt thereof or a stereoisomer thereof,

wherein R is _w Is that

R ₁ H, C of a shape of H, C _1-6 Alkyl, C _3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl or phenyl, wherein said C _1-6 Alkyl, C _3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl andphenyl is optionally substituted with 1, 2 or 3R ^a Substituted;

R ₂ is H or C _1-6 An alkyl group;

or R is ₂ And R is ₃ Are connected together to form a structural unitIs->

T ₁ Is- (CR) ^c R ^d ) _m -or- (CR) ^c R ^d ) _n -O-；

m is 1, 2 or 3;

n is 1 or 2;

T ₂ is N or CH;

t is N or CH;

R ₇ and R is ₈ Each independently H, F, cl, br or I;

R ₉ and R is ₁₀ Each independently is H, F, cl, br, I, -CN or

2. The compound of claim 1, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein the compound has a structure of formula (I), formula (II-1), or formula (II-2):

wherein R is ₁ 、R ₂ 、R ₃ 、R ₄ 、R ₅ 、R ₆ 、R ₇ 、R ₈ 、R ₉ And R is ₁₀ As defined in claim 1.

3. The compound of claim 1, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein the compound has a structure of formula (I-1), formula (II-3), or formula (II-4):

wherein the carbon atoms with "+" are chiral carbon atoms, either in the form of (R) or (S) single enantiomers or enriched in one enantiomer;

R ₁ 、R ₂ 、R ₃ 、R ₄ 、R ₅ 、R ₆ 、R ₇ 、R ₈ 、R ₉ And R is ₁₀ As defined in claim 1.

4. A compound according to any one of claims 1 to 3, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein R ₂ Is H or-CH ₃ 。

5. A compound according to any one of claims 1 to 3, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein R ₁ And R is ₂ Are linked together to form, together with the N atom to which they are linked Wherein said->Optionally by 1, 2 or 3R ^b Substituted.

6. The compound according to claim 5, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein R ₁ And R is ₂ Are linked together to form, together with the N atom to which they are linked

7. The compound of claim 6, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein R ₁ And R is ₂ Are linked together to form, together with the N atom to which they are linked

8. A compound according to any one of claims 1 to 3, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein R ₂ And R is ₃ Are connected together to form a structural unitIs->

9. The compound of claim 8, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein R ₂ And R is ₃ Are connected together to form a structural unitIs->

10. A compound according to any one of claims 1 to 3, a pharmaceutically acceptable salt thereof or a stereoisomer thereof, wherein the structural unit Is->

11. The compound of claim 1, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein R ^c And R is ^d Each independently is H, F or-CH ₃ 。

12. The compound according to claim 1 or 11, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein T ₁ is-CH ₂ -、-CH ₂ -CH ₂ -、-CH ₂ -CH ₂ -CH ₂ -、-CH ₂ -O-、-O-CH ₂ -or-CH ₂ -CH ₂ -O-。

13. The compound of claim 1, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein the compound has a structure according to any one of the formulae (I-2) to (I-7):

wherein T is ₂ 、R ₁ 、R ₃ 、R ₄ 、R ₅ And R is ₆ As defined in claim 1.

14. The compound of claim 13, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein the compound has a structure according to any one of formulas (I-8) to (I-13):

wherein the carbon atoms with "+" are chiral carbon atoms, either in the form of (R) or (S) single enantiomers or enriched in one enantiomer; t (T) ₂ 、R ₁ 、R ₃ 、R ₄ 、R ₅ And R is ₆ As defined in claim 13.

15. The compound of claim 1, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein each R ^a Is independently H, F, cl, br, I, -CN, -OH, -OCH ₃ or-CH ₃ 。

16. The compound according to any one of claims 1 to 3 or 13 to 15, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein R ₁ Is H, -CH ₃ 、-CH ₂ CH ₃ Cyclopropyl, cyclopentyl, cyclohexyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyridinyl or phenyl, wherein said-CH ₃ 、-CH ₂ CH ₃ Optionally substituted with 1, 2 or 3R groups, cyclopropyl, cyclopentyl, cyclohexyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyridinyl and phenyl ^a Substituted.

17. The compound of claim 16, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein R ₁ Is H, -CH ₃ 、-CH ₂ CH ₃ 、 Wherein the-CH ₃ 、-CH ₂ CH ₃ 、/> Optionally by 1, 2 or 3R ^a Substituted.

18. The compound of claim 17, pharmaceutically acceptable thereofA salt or stereoisomer thereof, wherein R ₁ Is H, -CH ₃ 、-CH ₂ CH ₃ 、

19. The compound of claim 18, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein R ₁ Is H, -CH ₃ 、-CH ₂ CH ₃ 、

20. The compound according to any one of claims 1 to 3, 13 or 14, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein R ₃ Is H, F, cl, br, I, -OH, -NH ₂ 、-OCH ₃ or-CH ₃ 。

21. The compound according to any one of claims 1 to 3, 13 or 14, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein R ₄ 、R ₅ And R is ₆ Each independently is H, F, cl, br, I or-CH ₃ 。

22. A compound according to any one of claims 1 to 3, a pharmaceutically acceptable salt thereof or a stereoisomer thereof, wherein the structural unitIs->

23. A compound of the formula, a pharmaceutically acceptable salt thereof or a stereoisomer thereof,

24. a compound of the formula:

25. a pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 24, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, and a pharmaceutically acceptable carrier.

26. Use of a compound according to any one of claims 1 to 24, a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a pharmaceutical composition according to claim 25 for the preparation of a medicament for targeting AKR1C3 enzyme.