CN114846001B

CN114846001B - Benzo condensed ring compound

Info

Publication number: CN114846001B
Application number: CN202080089752.3A
Authority: CN
Inventors: 李鹏; 杨亚讯; 张建臣; 贺海鹰; 刘金鑫; 胡国平; 黎健; 陈曙辉
Original assignee: Medshine Discovery Inc
Current assignee: Medshine Discovery Inc
Priority date: 2019-12-27
Filing date: 2020-12-25
Publication date: 2024-01-23
Anticipated expiration: 2040-12-25
Also published as: WO2021129827A1; CN114846001A

Abstract

Disclosed are compounds represented by formula (IV), isomers thereof, and pharmaceutically acceptable salts thereof. The compounds can be used for preparing medicines for treating THR-beta agonist related diseases.

Description

Benzo condensed ring compound

The present application claims priority as follows

CN201911379378.6, filing date: 2019-12-27

CN202010070530.9, filing date: 2020-01-21

CN202010152655.6, filing date: 2020-03-06

CN202010198251.0, filing date: 2020-03-19

CN202010302096.2, filing date: 2020-04-16

CN202010565413.X, filing date: 2020-06-19

CN202010581064.0, filing date: 2020-06-23

CN20201068790. X, application day: 2020-07-15

Cn202011054149.X, filing date: 2020-09-29

CN202011146814.8, filing date: 2020-10-23

CN202011326523.7, filing date: 2020-11-23

Technical Field

The present invention relates to a class of benzo-fused ring compounds. In particular to a compound shown in a formula (IV), an isomer and a pharmaceutically acceptable salt thereof.

Background

Thyroid Hormone (TH) is produced by the thyroid gland and secreted into the circulatory system (hypothalamus/pituitary/thyroid system) in two different forms: 3,5,3',5' -tetraiodo-L-thyronine (T4) and 3,5,3' -triiodo-L-thyronine (T3). While T4 is the predominant form secreted by the thyroid gland, T3 is the more physiologically active form. T4 is converted to T3 by a tissue-specific deiodinase that is present in all tissues but is primarily in the liver and kidney.

The physiological activity of thyroid hormones is mediated by Thyroid Receptors (TRs). TRs are encoded by different genes α and β located on human chromosomes 17 and 3, respectively, and produce different protein subtypes upon selective cleavage of the primary transcript, each gene producing two subtypes, namely trα1, trα2, trβ1, trβ2.TR β1 and TR β2 are differentially expressed from the promoter, with the two subtypes differing only at the amino terminus. The trα1 and trα2 are spliced from the difference in pre-mRNA, mainly at the carboxy terminus. Wherein, trα1, trβ1 and trβ2 bind thyroid hormone. It has been shown that thyroid hormone receptor subtypes may differ in the contribution of a particular physiological response. Trβ1 plays an important role in the liver in regulating the action of the thyroid stimulating hormone nucleus in regulating thyroid hormone; trβ2 plays a major role in regulating thyroid stimulating hormone.

Thyroid hormone has the effect of lowering serum Low Density Lipoprotein (LDL). Hyperthyroidism is associated with low total serum cholesterol due to thyroid hormones increasing hepatic LDL receptor expression and stimulating cholesterol metabolism to bile acids. Thyroid hormone can also reduce the risk of atherosclerosis and other cardiovascular diseases. Thyroid hormone has a beneficial effect on obese patients by increasing metabolic rate, oxygen consumption and heat release, thereby reducing body weight and improving co-morbidity associated with obesity. While avoiding the adverse effects of hyperthyroidism and hypothyroidism, thyroid analogs that maintain the beneficial effects of thyroid hormones would open a new way to treat: metabolic diseases such as obesity, hyperlipidemia, hypercholesterolemia, diabetes and other conditions such as steatosis and nonalcoholic steatohepatitis (NASH), atherosclerosis and the like.

Disclosure of Invention

The present invention provides a compound of formula (IV), an isomer thereof, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

wherein,

R ₁ selected from H, halogen, OH, NHR _a 、C _1-3 Alkyl and C _1-3 Alkoxy group, the C _1-3 Alkyl and C _1-3 Alkoxy is optionally substituted with 1, 2 or 3 halogens;

R ₂ selected from H, halogen, OH, NHR _a 、C _1-3 Alkyl, C _1-3 Alkoxy and C _3-6 Cycloalkyl group, the C _1-3 Alkyl, C _1-3 Alkoxy and C _3-6 Cycloalkyl is optionally substituted with 1, 2 or 3 halogens;

R ₃ 、R ₄ and R is ₅ Each independently selected from H, halogen, OH, NHR _a 、C _1-3 Alkyl, C _1-3 Alkoxy, C _3-6 Cycloalkyl and 4-6 membered heterocycloalkyl, said C _1-3 Alkyl, C _1-3 Alkoxy, C _3-6 Cycloalkyl and 4-6 membered heterocycloalkyl are optionally substituted with 1, 2 or 3R;

each R is independently selected from halogen or C _1-3 An alkyl group;

L ₁ selected from- (CR) _b R _c ) _m -、-NH(CR _b R _c ) _m -、-O(CR _b R _c ) _m -、C _3-6 Cycloalkyl and 3-6 membered heterocycloalkyl;

E ₁ and E is ₂ Are independently selected from- (CR) _b R _c ) _n -、NR _a And O;

R _a selected from H, C _1-3 Alkyl, -COCH ₃ and-SO ₂ R’；

R _b And R is _c Are respectively and independently selected from H, C _1～3 Alkyl and C _1-3 Alkoxy group, the C _1-3 Alkyl and C _1-3 Alkoxy is optionally substituted with 1, 2 or 3 halogens; alternatively, R ₁ And R is R _b Or R is _c And the carbon atoms that are commonly attached form cyclopropyl;

alternatively, R _b And R is R _c And the carbon atoms that are commonly attached form cyclopropyl;

r' is selected from C _1～3 Alkyl, said C _1～3 Alkyl is optionally substituted with 1, 2 or 3 halogens;

Each m is independently selected from 0, 1 and 2;

n is selected from 1 and 2;

x is selected from-PO (OH) ₂ 、-P(O)[-OC(R _d ) ₂ OC(O)R _e ] ₂ 、-P(O)[-OC(R _d ) ₂ OC(O)OR _e ] ₂ 、-P(O)[-N(H)C(R _d ) ₂ C(O)OR _e ][-OR _e ]、-P(O)[-N(H)C(R _d ) ₂ C(O)OR _e ] ₂ And

v is selected from C _6-10 Aryl and 5-to 10-membered heteroaryl, said C _6-10 Aryl and 5-to 10-membered heteroaryl optionally substituted with 1, 2 or 3 halogens;

each R is _d Independently selected from R _e And H;

each R is _e Independently selected from C _1-4 Alkyl and C _6-10 Aryl, said C _1-4 Alkyl and C _6-10 Aryl is optionally substituted with 1, 2 or 3 halogens;

the "hetero" comprises 1, 2 or 3 heteroatoms or groups of heteroatoms independently selected from-O-, -NH-, -S-, and N.

In some aspects of the invention, R is as described above ₁ Selected from H, F, OH, NH ₂ 、C _1-3 Alkyl and C _1-3 Alkoxy group, the C _1-3 Alkyl and C _1-3 Alkoxy is optionally substituted with 1, 2 or 3 halogens, and the other variables are as defined herein.

In some aspects of the invention, R is as described above ₁ Selected from H, F, OH, NH ₂ And CH (CH) ₃ The other variables are as defined herein.

In some aspects of the invention, R is as described above ₂ Selected from H, F, cl, br, NH ₂ 、C _1～3 Alkyl and cyclopropyl, said C _1～3 Alkyl is optionally substituted with 1, 2 or 3F, with the other variables being as defined herein.

In some aspects of the invention, R is as described above ₂ Selected from Cl, br, CH ₃ 、CF ₃ And cyclopropyl, the other variables are as defined herein.

In some embodiments of the invention, each R is independently selected from F and CH ₃ The other variables are as defined herein.

In some aspects of the invention, R is as described above ₃ 、R ₄ And R is ₅ Each independently selected from H, halogen, OH, NH ₂ 、C _1-3 Alkyl, C _3-6 Cycloalkyl and 4-6 membered heterocycloalkyl, said C _1-3 Alkyl, C _3-6 Cycloalkyl and 4-6 membered heterocycloalkyl are optionally substituted with 1, 2 or 3R, the other variables being as defined herein.

In some aspects of the invention, R is as described above ₃ 、R ₄ And R is ₅ Each independently selected from H, F, cl, OH, CH ₃ 、CH ₂ CH ₃ 、CH(CH ₃ ) ₂ 、The other variables are as defined herein.

In some aspects of the invention, L as described above ₁ Selected from- (CH) ₂ ) _m -、-NH(CH ₂ ) _m -and-O (CH) ₂ ) _m -, the other variables are as defined herein.

In some aspects of the invention, L as described above ₁ Selected from-CH ₂ -、-(CH ₂ ) ₂ -、-NHCH ₂ -and-OCH ₂ -, the other variables are as defined herein.

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

In some embodiments of the invention, V is selected from phenyl optionally substituted with 1, 2 or 3 halogens, and the other variables are as defined herein.

In some embodiments of the invention, V is selected fromThe other variables are as defined herein.

In some aspects of the invention, R is as described above _e Selected from-CH ₃ 、-CH ₂ CH ₃ 、-CH(CH ₃ ) ₂ 、-C(CH ₃ ) ₃ And phenyl, the other variables being as defined herein.

In some embodiments of the invention, the X is selected from the group consisting of-PO (OH) ₂ 、-P(O)[-OCH ₂ OC (O) -tert-butyl] ₂ 、-P(O)[-OCH ₂ OC (O) O-isopropyl] ₂ 、-P(O)[-N(H)CH(CH ₃ )C(O)OCH ₂ CH ₃ ] ₂ 、-P(O)[-N(H)C(CH ₃ ) ₂ C(O)OCH ₂ CH ₃ ] ₂ 、 The other variables are as defined herein.

In some embodiments of the invention, the X is selected from the group consisting of-PO (OH) ₂ 、The other variables are as defined herein.

The present invention provides a compound of formula (I), an isomer thereof, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

wherein,

R ₂ selected from H, halogen, OH, NHR _a 、C _1-3 Alkyl and C _1-3 Alkoxy group, the C _1-3 Alkyl and C _1-3 Alkoxy is optionally substituted with 1, 2 or 3 halogens;

R ₃ 、R ₄ and R is ₅ Each independently selected from H, halogen, OH, NHR _a 、C _1-3 Alkyl and C _1-3 Alkoxy group, the C _1-3 Alkyl and C _1-3 Alkoxy is optionally substituted with 1, 2 or 3 halogens;

L ₁ selected from- (CR) _b R _c ) _m -、-NH(R _b R _c ) _m -、-O(R _b R _c ) _m -、C _3-6 Cycloalkyl and 3-6 membered heterocycloalkyl;

E ₁ and E is ₂ Each independently selected from-CR _b R _c -、NR _a And O;

R _a selected from H, C _1-3 Alkyl, -COCH ₃ and-SO ₂ R；

R _b And R is _c Each independently selected from H, C _1～3 Alkyl and C _1-3 Alkoxy group, the C _1-3 Alkyl and C _1-3 Alkoxy is optionally substituted with 1, 2 or 3 halogens;

r is selected from C _1～3 Alkyl, said C _1～3 Alkyl is optionally substituted with 1, 2 or 3 halogens;

m is selected from 0, 1 and 2;

x is selected from-PO (OH) ₂ 、-P(O)[-OC(R _d ) ₂ OC(O)R _e ] ₂ 、-P(O)[-OC(R _d ) ₂ OC(O)OR _e ] ₂ 、-P(O)[-N(H)C(R _d ) ₂ C(O)OR _e ] ₂ And

each R is _d Independently selected from R _e And H;

the "hetero" comprises 1, 2 or 3 heteroatoms independently selected from O, S and N.

In some aspects of the invention, R is as described above ₂ Selected from H, halogen and C _1～3 Alkyl, said C _1～3 Alkyl is optionally substituted with 1, 2 or 3 halogens, and the other variables are as defined herein.

In some aspects of the invention, R is as described above ₂ Selected from H, F, cl, br and C _1～3 Alkyl, other variables are as defined herein.

In some aspects of the invention, R is as described above ₃ 、R ₄ And R is ₅ Each independently selected from H, halogen, OH and C _1-3 Alkyl, said C _1-3 Alkyl is optionally substituted with 1, 2 or 3 halogens, and the other variables are as defined herein.

In some aspects of the invention, R is as described above ₃ 、R ₄ And R is ₅ Each independently selected from H, F, cl, OH, CH ₃ 、CH ₂ CH ₃ And CH (CH) ₃ ) ₂ The other variables are as defined herein.

In some aspects of the invention, E as described above ₁ And E is ₂ Each independently selected from-CH ₂ -, NH and O, the other variables being as defined herein.

In some aspects of the invention, E as described above ₁ And E is ₂ Each independently selected from-CH ₂ -, the other variables are as defined herein.

In some embodiments of the invention, the X is selected from the group consisting of-PO (OH) ₂ 、-P(O)[-OCH ₂ OC (O) -tert-butyl] ₂ 、-P(O)[-OCH ₂ OC (O) O-isopropyl] ₂ 、-P(O)[-N(H)CH(CH ₃ )C(O)OCH ₂ CH ₃ ] ₂ 、-P(O)[-N(H)C(CH ₃ ) ₂ C(O)OCH ₂ CH ₃ ] ₂ Andthe other variables are as defined herein.

In some embodiments of the invention, the X is selected from the group consisting of-PO (OH) ₂ Andthe other variables are as defined herein.

The present invention provides a compound of the formula, an isomer thereof, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

wherein,

E ₁ and E is ₂ Each independently selected from- (CR) _b R _c ) _n -、NR _a And O;

R _a selected from H, C _1-3 Alkyl, -COCH ₃ and-SO ₂ R；

m is selected from 0, 1 and 2;

n is selected from 1 and 2;

each R is _d Independently selected from R _e And H;

In some aspects of the invention, R is as described above ₂ Selected from H, F, cl, br and C _1～3 Alkyl groupThe other variables are as defined herein.

In some aspects of the invention, R is as described above ₂ Selected from methyl groups, and the other variables are as defined herein.

In some aspects of the invention, E as described above ₁ And E is ₂ Each independently selected from-CH ₂ -、-CH ₂ CH ₂ -, NH and O, the other variables being as defined herein.

In some aspects of the invention, E as described above ₁ And E is ₂ Each independently selected from-CH ₂ -and-CH ₂ CH ₂ -, the other variables are as defined herein.

wherein,

R ₃ 、R ₄ and R is ₅ Each independently selected from H, halogen, OH, NHR _a 、C _1-3 Alkyl, C _1-3 Alkoxy and C _3-6 Cycloalkyl group, the C _1-3 Alkyl, C _1-3 Alkoxy and C _3-6 Cycloalkyl is optionally substituted with 1, 2 or 3 halogens;

R _a selected from H, C _1-3 Alkyl, -COCH ₃ and-SO ₂ R；

each m is independently selected from 0, 1 and 2;

n is selected from 1 and 2;

each R is _d Independently selected from R _e And H;

In some aspects of the invention, R is as described above ₂ Selected from H, F, cl, br and C _1～3 Alkyl, said C _1～3 Alkyl is optionally substituted with 1, 2 or 3F, with the other variables being as defined herein.

In some aspects of the invention, R is as described above ₂ Selected from Cl, br, CH ₃ And CF (compact F) ₃ The other variables are as defined herein.

In some aspects of the invention, R is as described above ₃ 、R ₄ And R is ₅ Each independently selected from H, halogen, OH, NH ₂ 、C _1-3 Alkyl and C _3-6 Cycloalkyl group, the C _1-3 Alkyl and C _3-6 Cycloalkyl groups are optionally substituted with 1, 2 or 3 halogens, with the other variables being as defined herein.

In some aspects of the invention, the aboveE ₁ And E is ₂ Each independently selected from-CH ₂ -and-CH ₂ CH ₂ -, the other variables are as defined herein.

wherein,

R ₃ 、R ₄ and R is ₅ Each independently selected from H, halogen, OH, NHR _a 、C _1-3 Alkyl, C _1-3 Alkoxy and C _3-6 Cycloalkyl group, the C _1-3 Alkyl, C _1-3 Alkoxy and C _3-6 Cycloalkyl optionally substituted with 1, 2 or 3 halogens or C _1-3 Alkyl substitution;

R _a selected from H, C _1-3 Alkyl, -COCH ₃ and-SO ₂ R；

each m is independently selected from 0, 1 and 2;

n is selected from 1 and 2;

each R is _d Independently selected from R _e And H;

In some aspects of the invention, R is as described above ₃ 、R ₄ And R is ₅ Each independently selected from H, halogen, OH, NH ₂ 、C _1-3 Alkyl and C _3-6 Cycloalkyl group, the C _1-3 Alkyl and C _3-6 Cycloalkyl is optionally substituted with 1, 2 or 3F or methyl, the other variables being as defined herein.

In some embodiments of the invention, the X is selected from the group consisting of-PO (OH) ₂ 、-P(O)[-OCH ₂ OC (O) -tert-butyl] ₂ 、-P(O)[-OCH ₂ OC (O) O-isopropyl] ₂ 、-P(O)[-N(H)CH(CH ₃ )C(O)OCH ₂ CH ₃ ] ₂ 、-P(O)[-N(H)C(CH ₃ ) ₂ C(O)OCH ₂ CH ₃ ] ₂ 、 The other variables are as defined herein. />

Wherein,

R ₃ 、R ₄ and R is ₅ Each independently selected from H, halogen, OH, NHR _a 、C _1-3 Alkyl, C _1-3 Alkoxy and C _3-6 Cycloalkyl group, the C _1-3 Alkyl, C _1-3 Alkoxy and C _3-6 Cycloalkyl is optionally substituted with 1, 2 or 3R;

each R is independently selected from halogen or C _1-3 An alkyl group;

R _a selected from H, C _1-3 Alkyl, -COCH ₃ and-SO ₂ R；

R _b And R is _c Each independently selected from H, C _1～3 Alkyl and C _1-3 Alkoxy group, the C _1-3 Alkyl and C _1-3 Alkoxy is optionally substituted with 1, 2 or 3 halogens; alternatively, R ₁ And R is R _b Or R is _c And the carbon atoms that are commonly attached form cyclopropyl;

each m is independently selected from 0, 1 and 2;

n is selected from 1 and 2;

Each R is _d Independently selected from R _e And H;

In some aspects of the invention, R is as described above ₂ Selected from H, halogen, C _1～3 Alkyl and cyclopropyl, said C _1～3 Alkyl and cyclopropyl are optionally substituted with 1, 2 or 3 halogens, and the other variables are as defined herein.

In some aspects of the invention, R is as described above ₂ Selected from H, F, cl, br, C _1～3 Alkyl and cyclopropyl, said C _1～3 Alkyl optionally substituted with 1, 2 or 3F, other variables being as in the present inventionIs clearly defined.

In some aspects of the invention, E as described above ₁ And E is ₂ Each independently selected from-CH ₂ -、-CH ₂ CH ₂ -and O, the other variables being as defined herein.

wherein,

each R is independently selected from halogen or C _1-3 Alkyl group；

R _a selected from H, C _1-3 Alkyl, -COCH ₃ and-SO ₂ R’；

R _b And R is _c Are respectively and independently selected from H, C _1～3 Alkyl and C _1-3 Alkoxy group, the C _1-3 Alkyl and C _1-3 Alkoxy is optionally substituted with 1, 2 or 3 halogens;

alternatively, R ₁ And R is R _b Or R is _c And the carbon atoms that are commonly attached form cyclopropyl;

each m is independently selected from 0, 1 and 2;

n is selected from 1 and 2;

Each R is _d Independently selected from R _e And H;

In some aspects of the invention, R is as described above ₃ 、R ₄ And R is ₅ Each independently selected from H, halogen, OH, NH ₂ 、C _1-3 Alkyl and C _3-6 Cycloalkyl group, the C _1-3 Alkyl and C _3-6 Cycloalkyl is optionally substituted with 1, 2 or 3R, the other variables being as defined herein.

The inventionIn some aspects of the invention, R is _e Selected from-CH ₃ 、-CH ₂ CH ₃ 、-CH(CH ₃ ) ₂ 、-C(CH ₃ ) ₃ And phenyl, the other variables being as defined herein.

In some embodiments of the invention, the above compound, an isomer thereof, or a pharmaceutically acceptable salt thereof is selected from

Wherein,

R ₁ 、R ₂ 、R ₃ 、R ₄ 、R ₅ and L ₁ As defined herein.

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

The invention also provides the following compounds, isomers or pharmaceutically acceptable salts thereof:

/>

the present invention also provides the above compound, an isomer thereof or a pharmaceutically acceptable salt thereof, which is selected from

/>

The invention also provides application of the compound, the isomer or the pharmaceutically acceptable salt thereof in preparing medicaments for treating THR-beta agonist related diseases.

In some embodiments of the invention, the above-described THR- β agonist-related agent is an agent for non-alcoholic steatohepatitis (NASH).

Definition and description

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 such compounds with a sufficient amount of 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 such compounds with a sufficient amount of 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.

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 "3-6 membered heterocycloalkyl" alone or in combination with other terms, refers to a saturated cyclic group consisting of 3 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, with respect to the "3-6 membered heterocycloalkyl" group, the heteroatom may occupy the position of attachment of the heterocycloalkyl group to the remainder of the molecule. The 3-6 membered heterocycloalkyl group includes 4-6 membered and 5-)6-membered, 4-membered, 5-membered, 6-membered heterocycloalkyl, and the like. Examples of 3-6 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.

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.

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).

The terms "5-10 membered heteroaryl ring" and "5-10 membered heteroaryl" are used interchangeably herein unless otherwise specified, the term "5-10 membered heteroaryl" being a cyclic group consisting of 5 to 10 ring atoms with a conjugated pi electron system, 1,2,3 or 4 of which are heteroatoms independently selected from O, S and N, the remainder being carbon atoms. It may be a monocyclic, fused bicyclic or fused tricyclic ring system, wherein each ring is aromatic. 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 5-10 membered heteroaryl group may be attached to the remainder of the molecule through a heteroatom or carbon atom. The 5-10 membered heteroaryl group includes 5-8 membered, 5-7 membered, 5-6 membered, 5 membered, 6 membered heteroaryl, and the like. Examples of the 5-10 membered heteroaryl group include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl and the like), pyrazolyl (including 2-pyrazolyl, 3-pyrazolyl and the like), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl and the like), oxazolyl (including 2-oxazolyl, 4-oxazolyl, 5-oxazolyl and the like), triazolyl (1H-1, 2, 3-triazolyl, 2H-1,2, 3-triazolyl, 1H-1,2, 4-triazolyl, 4H-1,2, 4-triazolyl and the like), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl and 5-isoxazolyl and the like), thiazolyl (including 2-thiazolyl, 4-thiazolyl and 5-thiazolyl and the like), furanyl (including 2-furanyl and 3-furanyl and the like), thienyl (including 2-thienyl and the like), pyridyl (including 2-pyridyl and the 3-pyridyl, and the like), pyrimidyl (including the 2-pyridyl, 4-pyridyl, the like), and the pyrimidyl (including the 2-pyridyl, the 4-pyridyl, the 5-pyridyl, the like), the pyrimidyl, and the like Indolyl (including 5-indolyl and the like), isoquinolyl (including 1-isoquinolyl and 5-isoquinolyl and the like), quinoxalinyl (including 2-quinoxalinyl and 5-quinoxalinyl and the like), or quinolinyl (including 3-quinolyl and 6-quinolyl and the like).

Unless otherwise specified, the term "halo" or "halogen" by itself or as part of another substituent means a fluorine, chlorine, bromine or iodine atom.

Unless otherwise indicated, the term "isomer" is intended to include geometric isomers, cis-trans isomers, stereoisomers, enantiomers, optical isomers, diastereomers and tautomers.

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 (+) -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 indicated, "(+)" means dextrorotation, "(-)" means levorotatory, "(±)" means racemization.

Unless otherwise indicated, with solid wedge bondsAnd wedge-shaped dotted bond->Representing the absolute configuration of a solid centre, using straight solid keys +.>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->Or straight dotted line key

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).

Unless otherwise indicated, a "x" carbon atom in the structure is a chiral carbon atom, either in the form of a single enantiomer of (R) or (S) or enriched in one enantiomer.

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 radioisotopes, 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 composition of the compounds of the present inventionAnd variations of (2), whether radioactive or not, are included within the scope of the present invention.

The term "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 the number of a substituent is 0, this indicates that the substituent is absent, such as-A- (R) ₀ Indicating that the structure is actually-a.

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 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 bonds of one substituent are crossedWhen more than two atoms are attached to a ring, such substituents may be bonded to any atom on the ring, e.g. building blocks It means that the substituent R may be substituted at any position on the cyclohexyl or cyclohexadiene. 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. When the connection mode of the chemical bond is not positioned and the H atoms exist in the connectable site, the number of the H atoms of the site can be correspondingly reduced to be changed into the corresponding valence group along with the number of the connected chemical bond when the chemical bond is connected. The chemical bond of the site and other groups can be a straight solid line bond Straight dotted line key->Or wave line->And (3) representing. For example-OCH ₃ The straight solid line bond in (a) represents the connection to other groups through the oxygen atom in the group; />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 means that the carbon atoms at positions 1 and 2 in the phenyl group are attached to other groups;it means that any of the ligatable sites on the piperidinyl group may be attached to other groups by 1 chemical bond, including at least These 4 connection modes, even though H atom is drawn on-N-, areStill include->The group of this linkage is only when 1 chemical bond is linked, the H at this site will be correspondingly reduced by 1 to the corresponding monovalent piperidinyl 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.

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 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:scanningAfter collecting the relevant data, the absolute configuration can be confirmed by further analyzing the crystal structure by direct method (Shellxs 97).

The solvent used in the present invention is commercially available.

The invention adopts the following abbreviations: aq represents water; HATU represents O- (7-azabenzotriazol-1-yl) -N, N-tetramethyluronium hexafluorophosphine salt; eq represents equivalent, equivalent; ACN represents acetonitrile; DCM represents dichloromethane; PE represents petroleum ether; DMSO represents dimethylsulfoxide; etOAc represents ethyl acetate; etOH stands for ethanol; meOH represents methanol; cbz represents benzyloxycarbonyl, an amine protecting group; boc represents that t-butoxycarbonyl is an amine protecting group; MOM represents methoxymethyl; DEA represents diethylamine; r.t. stands for room temperature; O/N stands for overnight; THF represents tetrahydrofuran; boc ₂ O represents di-tert-butyl dicarbonate; TFA represents trifluoroacetic acid; DIPEA stands for diisopropylethylamine; iPrOH or IPA stands for isopropanol; TBS represents t-butyldimethylsilyl; bn represents benzyl; et represents ethyl; mp represents the melting point; prep-HPLC stands for preparative high performance liquid chromatography; TLC stands for thin layer chromatography; DEG C stands for degrees Celsius.

Compounds are either prepared according to the general nomenclature of the art or are usedSoftware naming, commercial compounds are referred to by vendor catalog names.

Technical effects

The compound has stronger agonistic activity to thyroid receptor beta. The compound has better bioavailability, higher exposure in the liver, lower exposure in the blood plasma and the heart and better targeting to the liver. For DIO+CCl ₄ The non-alcoholic fatty liver disease activity score of the model mice was significantly improved.

Drawings

Fig. 1: ellipsometry of the molecular steric structure of acetonide of compound 6.

Fig. 2: unit cell packing diagram of acetonide of compound 6 along the b-axis direction.

Fig. 3: absolute configuration diagram of the compound of compound 6 acetonide.

Fig. 4a and 4b: HFD-CCl administration of Compound 6 ₄ Induced liver weight changes and liver volume ratios in NASH model mice are schematically represented (note: NASH group is used as control, data are shown as mean ± standard deviation..number represents statistical differences, p < 0.001, p < 0.01, p < 0.05).

Fig. 5a and 5b: HFD-CCl administration of Compound 6 ₄ Liver histopathological analysis of induced NASH model mice (note: NASH group as control, data shown as mean ± standard deviation..the statistical differences are indicated by the numbers p < 0.001, p < 0.01, p < 0.05).

Fig. 6a and 6b: HFD-CCl administration of Compound 6 and Compound 36 ₄ Schematic representation of liver weight changes and liver volume ratios in induced NASH model mice

Fig. 7a and 7b: HFD-CCl administration of Compound 6 and Compound 36 ₄ Schematic representation of liver histopathological analysis of induced NASH model mice

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.

Example 1

The synthetic route is as follows:

step 1: synthesis of Compounds 1-2

Compound 1-1 (0.2 g,1.3 mmol), malonic acid (0.21 g,2 mmol) was added to pyridine (2 mL), piperidine (0.018 g,0.3mmol,0.02 mL) was added, and the mixture was stirred at 120℃for 1.5 hours. TLC showed the starting material disappeared and product was present. Cooling to 24 ℃, adding 2mL of water for dilution, carefully adjusting the pH to be less than 3 by 12NHCl, and precipitating. Filtering, and collecting residue without purification. Compound 1-2 was obtained.

¹ H NMR(400MHz,CDCl ₃ )δ＝2.29(s,3H),3.77(s,3H),6.52(d,J＝16.18Hz,1H),6.82(s,1H),7.07(d,J＝8.59Hz,2H),7.51(d,J＝15.85Hz,1H)。

Step 2: synthesis of Compounds 1-3

Compound 1-2 (6.06 g,32 mmol) was added to tetrahydrofuran (120 mL), 5% palladium on carbon (0.6 g) was added and stirred at 24℃for 18 hours. TLC showed the starting material disappeared and product was present. The mixture was filtered through celite and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate=5:1-2:1) to give compounds 1-3.

¹ H NMR(400MHz,CDCl ₃ )δ＝2.24(s,3H),2.50(m,2H),2.74(t,J＝7.70Hz,2H),3.71(s,3H),6.55-6.63(m,3H)。

Step 3: synthesis of Compounds 1-4

Compounds 1-3 (0.24 g,1.2 mmol) were added to polyphosphoric acid (3 g), and the mixture was stirred for 1 hour at 80 ℃. TLC showed the starting material disappeared and product was present. Cooling to 24 ℃, diluting with 30mL of ice water, extracting with ethyl acetate (10 ml×3), washing with saturated sodium bicarbonate water (10 ml×2), and washing with saturated brine (10 mL). Dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by column chromatography on silica gel (petroleum ether: ethyl acetate=2:1) gives compounds 1-4.

¹ H NMR(400MHz,CDCl ₃ )δ＝2.49-2.51(m,3H),2.54-2.57(m,2H),2.97-3.03(m,2H)3.83,(s,3H),6.72(d,J＝0.55Hz,1H),6.90(s,1H)。

Step 4: synthesis of Compounds 1-5

Compounds 1-4 (2.4 g,13.6 mmol) were added to a solution of boron tribromide in methylene chloride (1M, 20 mL). Cooling to 0 ℃ and stirring for 0.5 hour, heating to 40 ℃ and reacting for 18 hours, wherein TLC shows that the raw materials disappear, and products are generated. Concentrating under reduced pressure, and purifying by silica gel column chromatography (dichloromethane/methanol=50:1) to obtain compounds 1-5.

¹ H NMR(400MHz,CDCl ₃ )δ＝2.45(s,3H),2.51-2.54(m,2H),2.91-2.96(m,2H),6.54(s,1H),6.67(d,J＝1.28Hz,1H),10.34(s,1H)。

Step 5: synthesis of Compound BB-1

Compounds 1-5 (0.14 g,0.86 mmol) were added to dichloromethane (3 mL) and N, N-dimethyl-4 pyridine (0.2 g,1.5 mmol) and t-butyldimethylsilyl chloride (0.2 g,1.3 mmol) were added. Stirred at 20℃for 24 hours. TLC showed the starting material disappeared and product was present. 10mL of saturated ammonium chloride water was added thereto, and the mixture was extracted with methylene chloride (3X 10 mL) and washed with saturated brine (10 mL). Dried over anhydrous sodium sulfate and concentrated under reduced pressure. Silica gel column chromatography (petroleum ether/ethyl acetate=1:0-30:1) gives compound BB-1.

¹ H NMR(400MHz,CDCl ₃ )δ＝0.23(s,6H),0.96(s,9H),2.46-2.49(m,3H),2.53-2.58(m,2H),2.93-3.00(m,2H),6.60-6.64(m,1H),6.75-6.82(m,1H)。

Step 6: synthesis of Compounds 1-7

Compounds 1-6 (5 g,36.71 mmol) were added to acetonitrile (50 mL), cooled to 0deg.C, N-bromosuccinimide (6.86 g,38.55 mmol) was added slowly in portions, the temperature was controlled at 0-5deg.C, after completion, the temperature was raised to 20deg.C and stirring continued for 3 hours, and the reaction solution was concentrated under reduced pressure. Ethyl acetate (50 mL) was added, the mixture was washed with a half-saturated sodium chloride solution (30 mL. Times.3), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Compounds 1-7 were obtained. Identified by H-NMR.

¹ H NMR(400MHz,CDCl ₃ )δ＝7.29(d,J＝2.4Hz,1H),7.19-7.13(m,1H),6.67-6.61(m,1H),3.24-3.12(m,1H),1.27-1.22(m,6H)。

Step 7: synthesis of Compounds 1-8

Compounds 1-7 (2 g,9.30 mmol) were added to acetonitrile (20 mL), cesium carbonate (4.54 g,13.95 mmol) and benzyl bromide (1.91 g,11.16 mmol) were added and the temperature was raised to 70℃and stirring continued for 5 hours. TLC (petroleum ether: ethyl acetate=10:1) showed the disappearance of starting material and the creation of new spots. The reaction solution was concentrated under reduced pressure. Ethyl acetate (50 mL) was added, the mixture was washed with a half-saturated sodium chloride solution (30 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 on silica gel (petroleum ether: ethyl acetate=10:1) to give compounds 1-8. Identified by H-NMR.

¹ H NMR(400MHz,CDCl ₃ )δ＝7.46-7.34(m,5H),7.34-7.32(m,1H),7.26-7.22(m,1H),6.78(d,J＝8.6Hz,1H),5.09-5.04(m,2H),3.45-3.30(m,1H),1.26-1.19(m,6H)。

Step 8: synthesis of Compounds 1-9

Compound 1-8 (500.00 mg,1.64 mmol) was dissolved in tetrahydrofuran (10 mL), cooled to-78 ℃, n-butyllithium (2.5M, 982.93. Mu.L) was added dropwise, the reaction was stirred at-78℃for 0.5 hours, a solution of raw BB-1 (452.88 mg,1.64 mmol) in tetrahydrofuran (5 mL) was added dropwise, and the temperature was slowly raised to 20℃and stirred for 0.5 hours. The reaction solution was added to ethyl acetate (30 mL) and saturated ammonium chloride solution (10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate=5:1) to give compounds 1-9.

¹ H NMR(400MHz,CDCl ₃ )δ＝7.51-7.39(m,4H),7.38-7.30(m,1H),7.25-7.23(m,1H),7.16-7.11(m,1H),6.94-6.91(m,1H),6.89-6.86(m,1H),6.55-6.51(m,1H),6.24-6.19(m,1H),5.16-5.05(m,2H),3.51-3.41(m,1H),3.40-3.35(m,2H),2.01-1.96(m,2H),1.58-1.50(m,3H),1.28-1.23(m,6H),1.04-0.97(m,9H),0.22(s,6H)。

Step 9: synthesis of Compounds 1-10

Compounds 1-9 (0.16 g, 318.24. Mu. Mol) were dissolved in methylene chloride (2 mL), trifluoroacetic acid (54.43 mg, 477.37. Mu. Mol), triethylsilane (111.02 mg, 954.73. Mu. Mol) was added dropwise, and the mixture was stirred at 20℃for 1 hour. The reaction solution was concentrated under reduced pressure. To obtain the compound 1-10, which is directly used for the next reaction.

Step 10: synthesis of Compounds 1-11

Compounds 1-10 (0.4 g, 821.76. Mu. Mol) were dissolved in methanol (8 mL) and tetrahydrofuran (8 mL), and ammonium fluoride (304.36 mg,8.22 mmol) was added thereto, and stirred at 50℃for 3 hours. TLC (petroleum ether: ethyl acetate=3:1) showed the disappearance of starting material and the creation of new spots. The reaction mixture was concentrated under reduced pressure, washed with ethyl acetate (50 mL), washed with a half-saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate=3:1) to give compounds 1-11, which were identified by LCMS.

[M+1] ⁺ ＝373.3

Step 11: synthesis of Compounds 1-12

Compounds 1 to 11 (0.3 g, 805.37. Mu. Mol) were dissolved in dimethylformamide (2 mL), cesium carbonate (393.61 mg,1.21 mmol) was added, methyl diethylphospholipid triflate (265.94 mg, 885.91. Mu. Mol) was added dropwise at 0℃and the mixture was gradually warmed to 20℃and stirred for 16 hours. Ethyl acetate (50 mL) was added to the reaction mixture, which was washed with a half-saturated sodium chloride solution (30 mL. Times.4), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate=1:3) to give compounds 1-12.

¹ H NMR(400MHz,CDCl ₃ )δ＝7.47-7.30(m,5H),6.96(d,J＝2.0Hz,1H),6.79-6.73(m,2H),6.72-6.68(m,1H),6.61-6.57(m,1H),5.05-5.00(m,2H),4.28-4.24(m,4H),3.42-3.31(m,1H),3.09-2.99(m,1H),2.97-2.89(m,3H),2.87-2.78(m,1H),2.63-2.51(m,1H),2.06-1.96(m,1H),1.95-1.90(m,3H),1.39(t,J＝7.2Hz,6H),1.22-1.16(m,6H)。

Step 12:1-13 synthesis

Compounds 1 to 12 (0.1 g, 191.35. Mu. Mol) were dissolved in methanol (3 mL), palladium on carbon (0.1 g, 191.35. Mu. Mol, palladium content 5%) was added, hydrogen was replaced three times, and stirred at 20℃and 15psi for 1 hour. The reaction was filtered to remove palladium on carbon, and the filtrate was concentrated under reduced pressure. To obtain the compounds 1-13, which are directly used for the next reaction. [ M+1 ]] ⁺ ＝433.2

Step 13: synthesis of Compound 1

Compounds 1-13 (0.08 g, 184.98. Mu. Mol) were dissolved in dichloromethane (5 mL), cooled to 0deg.C, and trimethylsilicon bromide (283.18 mg,1.85 mmol) was added and gradually warmed to 20deg.C and stirred for 16 hours. The reaction mixture was concentrated under reduced pressure, washed with a half-saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by prep-HPLC (column: phenomenex luna C80 mm. Times.40 mm. Times.3 μm; mobile phase: [ H) ₂ O (0.04% HCl) -acetonitrile]The method comprises the steps of carrying out a first treatment on the surface of the B (ACN)% (acetonitrile) 32% -52%,7 min). Compound 1 was obtained.

[M-1] ⁺ ＝375.2

¹ H NMR(400MHz,CD ₃ OD)δ＝6.82-6.80(m,1H),6.78-6.76(m,1H),6.62-6.56(m,3H),4.24(dd,J＝3.8,8.6Hz,1H),4.19(d,J＝10.4Hz,2H),3.26-3.15(m,1H),3.00(td,J＝8.1,16.0Hz,1H),2.80(ddd,J＝4.3,8.8,15.9Hz,1H),2.52(qd,J＝8.5,12.6Hz,1H),1.97-1.91(m,1H),1.89(s,3H),1.18-1.09(m,6H)。

Examples 2, 3, 4, 5, 6 and 7

The synthetic route is as follows:

the absolute configuration of compounds 2, 3, 4, 5, 7 is deduced from the configuration of compound 6.

Step 1: synthesis of Compounds 2-1 and 2-2

Compounds 1 to 13 (500 mg,1.16 mmol) were subjected to SFC isolation. SFC (column: DAICEL CHIRALPAK AD (250 mm. Times.30 mm,10 μm); mobile phase: [ Neu-EtOH)]33% -33%,6 min) to obtain compounds 2-1 and 2-2. The analytical method comprises the steps of (a) measuring Thar analytical SFC by an instrument, (b) measuring ChiralpakAD-3 by 50mm, measuring 4.6mm, and measuring 3 mu m by a mobile phase (A) and (CO) ₂ And B: etOH (0.05% ipam), gradient: B: a=5% -50%, 4min, flow rate: 4.0mL/min, column temperature: 35 ℃, wavelength: 220nm, column pressure: 100bar. Retention time of compound 2-1: 1.26min. Retention time of compound 2-2: 1.42min.

Step 2: synthesis of Compound 2

Compound 2-1 (212 mg, 490.19. Mu. Mol) was dissolved in methylene chloride (5 mL), cooled to 0℃and trimethylsilicon bromide (750.43 mg,4.90 mmol) was added thereto, and the mixture was gradually warmed to 30℃and stirred for 5 hours. Concentrating under reduced pressure, adding ethyl acetate30 mL), half-saturated sodium chloride solution (20 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by prep-HPLC (column: phenomenex luna C, 250 mm. Times.50 mm. Times.10 μm; mobile phase: [ H) ₂ O(0.05％HCl)-ACN]The method comprises the steps of carrying out a first treatment on the surface of the B (ACN)% > 30% -60% and 10 min). Compound 2 was obtained.

[M+1] ⁺ ＝377.1

¹ H NMR(400MHz,CD ₃ OD)δ＝6.83-6.75(m,2H),6.63-6.53(m,3H),4.24(dd,J＝3.7,8.6Hz,1H),4.19(d,J＝10.5Hz,2H),3.21(td,J＝7.0,13.7Hz,1H),3.05-2.95(m,1H),2.86-2.75(m,1H),2.53(qd,J＝8.6,12.7Hz,1H),1.97-1.91(m,1H),1.90(s,3H),1.13(t,J＝7.2Hz,6H)。

Step 3: synthesis of Compound 4, compound 5

Compound 2 (65.9 mg, 175.09. Mu. Mol) was dissolved in dimethylformamide (5 mL), and Compound BB-2 (65.36 mg,350.18 mmol), dicyclohexylimine (108.38 mg, 525.26. Mu. Mol) and pyridine (332.39 mg,4.20 mmol) were added thereto, followed by stirring at 70℃for 16 hours. Filtering, collecting filtrate, adding ethyl acetate (100 mL) and water (100 mL), separating, collecting organic phase, washing with saturated saline (100 mL×3), drying the organic phase over anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure to obtain crude product. The crude product was subjected to prep-HPLC (column: waters Xbridge Prep OBD C: 150 mm. Times.40 mm. Times.10 μm; mobile phase: [ H.) ₂ O(10mM NH ₄ HCO ₃ )-ACN]The method comprises the steps of carrying out a first treatment on the surface of the B (ACN)% > 45% -65%,8 min). Compound 4, compound 5, was obtained. The analysis method comprises the following steps: column type: x-bridge Shield RP182.1mm 50mm 5 μm mobile phase: a:10mmol/L NH ₄ HCO ₃ And B: acetonitrile, gradient: 10-80% B (3.00 min), 80% B for 0.9min, then 80-10% B (0.03 min), and finally 10% B for 0.57min (flow rate: 0.01-3.91min:0.8mL/min;3.92-4.50min:1.2 mL/min), monitoring method: diode Array Detector (DAD). Retention time of compound 4: 3.116min, retention time of compound 5: 3.165min. The configuration of the phosphate positions of compounds 4 and 5 was confirmed by NOE.

Compound 4: [ M+1 ]] ⁺ ＝527.3； ¹ H NMR(400MHz,CDCl ₃ )δ＝7.43(s,1H),7.35-7.28(m,2H),7.27-7.23(m,1H),6.93(s,1H),6.75(s,1H),6.66-6.55(m,3H),5.64(br d,J＝11.3Hz,1H),5.67-5.60(m,1H),4.75-4.65(m,1H),4.51(dddd,J＝2.3,4.8,11.2,16.4Hz,1H),4.44(d,J＝9.7Hz,2H),4.29(dd,J＝3.9,8.8Hz,1H),3.24-3.12(m,1H),3.09-2.97(m,1H),2.90-2.77(m,1H),2.64-2.42(m,2H),2.01(tdd,J＝4.1,8.4,12.7Hz,1H),1.93(s,3H),1.22(dd,J＝4.8,6.8Hz,6H)。

Compound 5: [ M+1 ]] ⁺ ＝527.3； ¹ H NMR(400MHz,CDCl ₃ )δ＝7.42(s,1H),7.36-7.28(m,3H),6.93(s,1H),6.75(s,1H),6.64-6.56(m,3H),5.90(br d,J＝11.0Hz,1H),4.98(br t,J＝11.7Hz,1H),4.63-4.52(m,3H),4.30(dd,J＝4.0,8.6Hz,1H),3.17(td,J＝6.9,13.8Hz,1H),3.11-2.98(m,1H),2.89-2.80(m,1H),2.64-2.52(m,1H),2.50-2.38(m,1H),2.18-2.10(m,1H),2.02(tdd,J＝4.4,8.4,12.6Hz,1H),1.95(s,3H),1.23(dd,J＝5.5,6.7Hz,6H)。

Step 4: synthesis of Compound 3

Raw material 2-2 (0.27 g, 624.29. Mu. Mol) was dissolved in dichloromethane (5 mL), cooled to 0℃and trimethylsilicon bromide (955.75 mg,6.24 mmol) was added and the reaction was raised to 20℃and stirring continued for 8 hours. The reaction mixture was concentrated under reduced pressure, ethyl acetate (50 mL) was added, the mixture was washed with a half-saturated sodium chloride solution (30 mL), and the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by prep-HPLC (column: phenomenex luna C, 250 mm. Times.50 mm. Times.10 μm; mobile phase: [ H) ₂ O(0.05％HCl)-ACN]The method comprises the steps of carrying out a first treatment on the surface of the B (ACN)% > 20% -60% and 10 min) to obtain compound 3.

¹ H NMR(400MHz,CD ₃ OD)δ＝6.81(d,J＝1.6Hz,1H),6.79-6.76(m,1H),6.63-6.55(m,3H),4.27-4.22(m,1H),4.19(d,J＝10.4Hz,2H),3.25-3.16(m,1H),3.05-2.93(m,1H),2.86-2.75(m,1H),2.58-2.46(m,1H),1.97-1.91(m,1H),1.90-1.88(m,3H),1.13(t,J＝7.4Hz,6H)。

Step 5: synthesis of Compound 6 and Compound 7

Compound 3 (60 mg, 159.41. Mu. Mol) was dissolved in dimethylformamide (2.5 mL) and pyridine (0.25 mL), dicyclohexylcarbodiimide (98.67 mg, 478.24. Mu. Mol) and compound BB-2 (29.75 mg, 159.41. Mu. Mol) were added, and the reaction was allowed to stand at 70℃for further stirring for 16 hours. Ethyl acetate (50 mL) and a half-saturated sodium chloride solution (30 mL) are added into the reaction solution for washing, and the reaction solution is organicThe layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by prep-HPLC (column: waters Xbridge Prep OBD C150 mm 40mm 10 μm; mobile phase: [ H.) ₂ O(10mM NH ₄ HCO ₃ )-ACN]The method comprises the steps of carrying out a first treatment on the surface of the B (ACN)%: 25% -55%,8 min) to obtain crude products of the compound 6 and the compound 7. Separating by SFC method (column type DAICEL CHIRALPAKAS (250 mm. Times.30 mm. Times.10 μm), and mobile phase [ neutral-methanol ] ]33% -33% of the total weight of the composition is in the range of min), and compound 6 and compound 7 are obtained. The analysis method comprises the following steps: column type ChiralpakAS-3,50mm 4.6mm 3 μm mobile phase A: CO ₂ Methanol (0.05% DEA), gradient from 5% to 50% in 1.2 min for phase B, decrease to 5% in 0.8 min, flow rate 3.4mL/min, column temperature 35℃and ABPR 1500psi. Retention time of compound 6: 1.450min, retention time of compound 7: 1.311min. The configuration of the phosphate positions of compounds 6 and 7 was confirmed by NOE.

Compound 6:

¹ H NMR(400MHz,CDCl ₃ )δ＝7.43(s,1H),7.35-7.28(m,2H),7.26-7.22(m,1H),6.93(s,1H),6.76-6.73(m,1H),6.62(s,2H),6.60-6.57(m,1H),5.68-5.60(m,1H),4.75-4.64(m,2H),4.58-4.39(m,3H),4.29(br dd,J＝3.6,8.5Hz,1H),3.24-3.13(m,1H),3.04(td,J＝8.1,16.1Hz,1H),2.90-2.77(m,1H),2.65-2.40(m,2H),2.20-2.08(m,1H),2.01(ddd,J＝4.1,8.3,12.5Hz,1H),1.96-1.89(m,3H),1.22(t,J＝6.4Hz,6H)。

compound 7:

¹ H NMR(400MHz,CDCl ₃ )δ＝7.42(s,1H),7.37-7.29(m,3H),6.93(s,1H),6.77-6.74(m,1H),6.63-6.60(m,2H),6.60-6.57(m,1H),5.93-5.86(m,1H),5.02-4.94(m,1H),4.70-4.66(m,1H),4.63-4.52(m,3H),4.33-4.26(m,1H),3.24-3.12(m,1H),3.09-3.00(m,1H),2.91-2.81(m,1H),2.64-2.53(m,1H),2.50-2.37(m,1H),2.18-2.10(m,1H),2.07-1.97(m,1H),1.97-1.92(m,3H),1.22(dd,J＝4.8,6.8Hz,6H)。

single crystal X-ray diffraction detection analysis of compound 6

The crystal of the compound 6 is obtained by culturing at room temperature for 5 days under the condition of acetone by using a solvent volatilization method, the size of the crystal for diffraction is 0.08x0.12x0.20mm, the crystal belongs to monoclinic system, and the space group is P2 ₁ Unit cell parameters: a=11.8483(3)，b＝9.3533(3)， α=γ=90°, β= 109.013 (2) °, unit cell volume +.>The number of asymmetric units z=2 in the unit cell.

Diffraction intensity data were collected using a Bruker D8 Venture Photon II diffractometer with a light source of CuK _α Radiation, scanning mode:scanning, wherein the total diffraction points are 16909, the independent diffraction points are 5938, and the observable points (I/sigma is more than or equal to 2) are 3601.

Analyzing the crystal structure by direct method (Shellxs 97) to obtain all 40 non-hydrogen atom positions, correcting structural parameters and discriminating atom types by least square method, obtaining all hydrogen atom positions by geometric calculation method and difference Fourier method, and refining R ₁ ＝0.0585，wR ₂ ＝0.1812(w＝1/σ|F| ² ) S=1.035. The final stoichiometry is defined as C ₂₉ H ₃₂ ClO ₅ P·C ₃ H ₆ O, calculated molecular weight 585.04, calculated crystal density 1.224g/cm ³ 。

Single crystal results showed that: the molecular alignment in the crystalline state belongs to the first space group, the compound should have optical activity, and the Flack coefficient is 0.047 (15), and the absolute configuration of the compound in the crystal can be determined. The hydrogen bond connection exists among molecules in the crystalline state, and the stable arrangement of the molecules in space is maintained by the hydrogen bond and Van der Waals force.

The stereoellipsoidal diagram of the acetonide of the compound 6, the unit cell stacking diagram along the b-axis direction and the absolute configuration diagram of the compound are shown in figures 1, 2 and 3. The data and parameters for the acetonide crystal structure of compound 6 are shown in tables 1, 2, 3, 4 and 5.

Table 1 crystal structure refinement information table

Table 2: atomic coordinates of crystals (. Times.10) ⁴ ) And equivalent isotropic shift parameter/>

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TABLE 3 bond length of bond atomsAnd bond angle (°)>

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TABLE 5 Hydrogen bond List

Symmetrical transformation for generating equivalent atoms #1x, y, z+1

Example 8

The synthetic route is as follows:

step 1: synthesis of Compound 8-2

Compound 8-1 (3.00 g,11.58 mmol) was dissolved in tetrahydrofuran (50 mL), cooled to-78deg.C, n-butyllithium solution (2.5M, 6.95 mL) was added dropwise, the reaction was stirred at-78deg.C for 30 min, a solution of compound BB-1 (3.20 g,11.58 mmol) in tetrahydrofuran (20 mL) was added dropwise, and the temperature was slowly raised to 20deg.C and stirred for 16 h. To the reaction mixture was added a saturated ammonium chloride solution (50 mL), followed by extraction with ethyl acetate (200 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate=5:1) to give compound 8-2.

[M-17] ⁺ ＝439.3

Step 2: synthesis of Compound 8-3

Compound 8-2 (1 g,2.19 mmol) was added to dichloromethane (20 mL), triethylsilane (763.85 mg,6.57 mmol) was added, the temperature was reduced to 0deg.C, trifluoroacetic acid (299.60 mg,2.63 mmol) was added dropwise, and the reaction was gradually warmed to 20deg.C and stirred for 16 hours. Dichloromethane (50 mL) was added to the reaction solution, half-saturated sodium bicarbonate solution (30 mL) was washed, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate=5:1) to give compound 8-3.

¹ H NMR(400MHz,CDCl ₃ )δ＝6.91-6.87(m,2H),6.74-6.69(m,1H),6.64-6.60(m,1H),6.48-6.45(m,1H),5.18-5.14(m,2H),4.30-4.25(m,1H),3.49(s,3H),3.35-3.24(m,1H),3.03-2.93(m,1H),2.83-2.74(m,1H),2.61-2.50(m,1H),2.02-1.94(m,1H),1.91-1.87(m,3H),1.19-1.15(m,6H),1.00(s,9H),0.24-0.19(m,6H)。

Step 3: synthesis of Compound 8-4

Compound 8-3 (1.26 g,2.86 mmol) was added to methanol (30 mL) and tetrahydrofuran (30 mL), ammonium fluoride (1.06 g,28.59 mmol) was added and the reaction stirred at 20℃for 16 h. The reaction solution was concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate=5:1) to give compound 8-4.

¹ H NMR(400MHz,CDCl ₃ )δ＝6.93(d,J＝2.1Hz,1H),6.92-6.89(m,1H),6.74-6.70(m,1H),6.63-6.60(m,1H),6.47-6.44(m,1H),5.17(s,2H),4.55-4.51(m,1H),4.31-4.24(m,1H),3.51-3.47(m,3H),3.35-3.25(m,1H),3.06-2.94(m,1H),2.86-2.75(m,1H),2.64-2.49(m,1H),2.04-1.95(m,1H),1.93-1.89(m,3H),1.21-1.16(m,6H)。

Step 4: synthesis of Compound 8-5

Compound 8-4 (1.05 g,3.22 mmol) was added to dichloromethane (20 mL) and N, N-lutidine (1.57 g,12.87 mmol), cooled to 0deg.C, triflic anhydride (1.36 g,4.82 mmol) was added and the reaction was gradually warmed to 20deg.C and stirred for 2 hours. The reaction solution was concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate=5:1) to give compound 8-5.

¹ H NMR(400MHz,CDCl ₃ )δ＝7.05-7.02(m,1H),6.93(d,J＝8.3Hz,1H),6.90(d,J＝2.2Hz,1H),6.88-6.83(m,1H),6.70-6.64(m,1H),5.20-5.14(m,2H),4.36-4.30(m,1H),3.48(d,J＝2.6Hz,3H),3.35-3.25(m,1H),3.14-3.04(m,1H),2.95-2.85(m,1H),2.69-2.55(m,1H),2.11-2.06(m,1H),1.99-1.96(m,3H),1.18(t,J＝6.8Hz,6H)。

Step 5: synthesis of Compound 8-6

Compound 8-5 (0.1 g, 218.11. Mu. Mol) was added to dimethylformamide (2 mL), triethylamine (55.18 mg, 545.27. Mu. Mol), ditriphenylphosphine palladium dichloride (15.31 mg, 21.81. Mu. Mol), vinyl diethyl phosphate (39.38 mg, 239.92. Mu. Mol) was added, and the reaction was stirred for 16 hours at 80℃under a sealed tube with nitrogen substitution three times. Ethyl acetate (50 mL) was added to the reaction mixture, which was washed with a half-saturated sodium chloride solution (30 mL. Times.4), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate=5:1 to petroleum ether: ethyl acetate=1:1) according to TLC (petroleum ether: ethyl acetate=0:1, rf=0.55) to give compound 8-6.

¹ H NMR(400MHz,CDCl ₃ )δ＝7.31-7.28(m,1H),7.12-7.08(m,1H),6.93(d,J＝2.1Hz,1H),6.91(d,J＝8.3Hz,1H),6.71-6.66(m,1H),6.37-6.31(m,1H),6.20-6.17(m,1H),5.20-5.13(m,2H),4.34(dd,J＝3.8,8.7Hz,1H),4.20-4.13(m,4H),3.50-3.48(m,3H),3.35-3.22(m,1H),3.07(td,J＝8.2,16.1Hz,1H),2.94-2.81(m,1H),2.63-2.51(m,1H),2.10-1.99(m,1H),1.98-1.94(m,3H),1.39-1.36(m,6H),1.22-1.14(m,6H)。

Step 6: synthesis of Compound 8-7

Compound 8-6 (0.11 g, 232.78. Mu. Mol) was added to methanol (3 mL), palladium on carbon (0.1 g, 21.16. Mu. Mol, palladium content 5%) was added, hydrogen was replaced three times, and the reaction was stirred at 20℃and 15psi for 16 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to give compound 8-7.

¹ H NMR(400MHz,CDCl ₃ )δ＝6.99-6.97(m,1H),6.96-6.93(m,1H),6.91-6.87(m,1H),6.79(s,1H),6.71-6.66(m,1H),5.18-5.13(m,2H),4.10-4.04(m,4H),3.50-3.46(m,3H),3.35-3.24(m,1H),3.09-2.97(m,1H),2.96-2.83(m,4H),2.61-2.49(m,1H),2.07-1.96(m,3H),1.95-1.90(m,3H),1.37-1.34(m,6H),1.22-1.18(m,6H)。

Step 7: synthesis of Compound 8

Compound 8-7 (0.09 g, 189.65. Mu. Mol) was added to dichloromethane (6 mL), cooled to 0deg.C, trimethylbromosilane (290.33 mg,1.90 mmol) was added and the reaction was gradually raised to 20deg.C and stirred for 5 hours. Dichloromethane (50 mL) was added to the reaction solution, which was washed with water (30 ml×2), and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by prep-HPLC (column: welchXtimate C18.25 mm.5 μm; mobile phase: [ water (0.04% HCl) -acetonitrile ]; acetonitrile%: 30% -60%,8 min). Compound 8 was obtained.

¹ H NMR(400MHz,CD ₃ OD)δ＝7.00-6.95(m,1H),6.84-6.80(m,1H),6.80-6.78(m,1H),6.61-6.58(m,1H),6.58-6.54(m,1H),4.31-4.22(m,1H),3.25-3.16(m,1H),3.05-2.95(m,1H),2.90-2.74(m,3H),2.58-2.43(m,1H),2.03-1.91(m,3H),1.90(s,3H),1.13(t,J＝7.4Hz,6H)。

Examples 9 and 10

The synthetic route is as follows:

step 1: synthesis of Compound 9-2

To a solution of compound 9-1 (3 g,11.80 mmol) in tetrahydrofuran (50 mL) was added vinylmagnesium bromide (1M, 11.80 mL) at 0deg.C, and the mixture was reacted at 20deg.C for 12 hours. The reaction solution was poured into a saturated ammonium chloride solution, extracted with ethyl acetate (50 ml×3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The crude product was separated by column chromatography on silica gel (petroleum ether: ethyl acetate=10:1) to give compound 9-2.

¹ H NMR(400MHz,DMSO-d ₆ )δ＝7.37-7.46(m,4H),7.28-7.35(m,1H),7.17(d,J＝1.96Hz,1H),7.07(dd,J＝8.44,1.96Hz,1H),6.97(d,J＝8.31Hz,1H),5.93(ddd,J＝17.06,10.33,5.75Hz,1H),5.32(d,J＝4.52Hz,1H),5.21(dt,J＝17.12,1.71Hz,1H),5.10(s,2H),4.94-5.04(m,2H),3.25-3.31(m,1H),1.17(d,J＝6.72Hz,6H).

Step 2: synthesis of Compound 9-3

To a solution of compound 9-11 (2.19 g,6.37 mmol) in N, N-dimethylformamide (15 mL) was added diacetonitrile palladium chloride (137.81 mg, 531.21. Mu. Mol), tris (o-methylphenyl) phosphine (161.68 mg, 531.21. Mu. Mol), N, N-dicyclohexylmethylamine (1.56 g,7.97mmol,1.69 mL), and compound 9-2 (1.5 g,5.31 mmol) and reacted at 90℃for 12 hours. The reaction solution was filtered through celite, ethyl acetate (100 mL) was added to the filtrate to dilute, water (100 mL) was added, the organic phase was washed with saturated brine (100 mL. Times.2), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The crude product was separated by column chromatography on silica gel (petroleum ether: ethyl acetate=20:1) to give compound 9-3.MS m/z 545[ M+1 ] ] ⁺ 。

Step 3: synthesis of Compound 9-4

To tetrahydrofuran (10 mL) of Compound 9-3 (0.8 g,1.47 mmol) was added methyllithium (1.6M, 1.10 mL) at-78deg.C, and the reaction was allowed to spontaneously recover to 20deg.C for 2 hours. The reaction solution was poured into a saturated ammonium chloride solution, ethyl acetate (50 mL) was added, the aqueous phase was extracted with ethyl acetate (50 ml×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The crude product was separated by column chromatography on silica gel (petroleum ether: ethyl acetate=20:1) to give compound 9-4.

¹ H NMR(400MHz,CDCl ₃ )δ＝7.46-7.52(m,2H),7.40-7.45(m,2H),7.32-7.38(m,2H),7.27(d,J＝2.4Hz,1H),7.25(d,J＝2.4Hz,1H),6.92(d,J＝8.5Hz,1H),6.53(d,J＝8.4Hz,2H),6.48(s,1H),5.11(s,2H),3.46(spt,J＝6.9Hz,1H),2.46-2.56(m,1H),2.35-2.45(m,1H),2.26(s,3H),2.08-2.16(m,2H),1.61(s,3H),1.27-1.30(m,6H),1.20-1.27(m,3H),1.09-1.13(m,18H).MS m/z:543[M-17] ⁺ 。

Step 4: synthesis of Compound 9-5

To dichloromethane (2 mL) of compound 9-4 (0.85 g,1.52 mmol) was added trifluoroacetic acid (518.38 mg,4.55mmol, 336.61. Mu.L) at 0deg.C, and the reaction was carried out at 20deg.C for 2 hours. The reaction solution was poured into a saturated sodium bicarbonate solution, methylene chloride (50 mL) was added, the aqueous phase was extracted with methylene chloride (50 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 9-5.

Step 5: synthesis of Compound 9-6

To tetrahydrofuran (2 mL) of Compound 9-5 (0.8 g,1.47 mmol) was added tetrabutylammonium fluoride solution (1M, 1.77 mL) and reacted at 20℃for 1 hour. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was separated by column chromatography on silica gel (petroleum ether: ethyl acetate=5:1) to give compound 9-6.

¹ H NMR(400MHz,CDCl ₃ )δ＝7.44-7.49(m,2H),7.40(t,J＝7.4Hz,2H),7.30-7.37(m,1H),7.09(d,J＝2.4Hz,1H),6.98(dd,J＝8.4,2.4Hz,1H),6.82(d,J＝8.4Hz,1H),6.60(d,J＝1.8Hz,1H),6.42(d,J＝1.5Hz,1H),5.07(s,2H),3.39(spt,J＝6.9Hz,1H),2.80-2.96(m,2H),2.22-2.34(m,1H),2.11-2.20(m,1H),1.78(s,3H),1.65(s,3H),1.19ppm(t,J＝6.8Hz,6H).

Step 6: synthesis of Compound 9-7

Cesium carbonate (505.77 mg,1.55 mmol) was added to N, N-dimethylformamide (5 mL) of compound 9-6 (0.5 g,1.29 mmol) at 0℃and diethyl tosyloxymethyl phosphonate (970.80 mg,3.23 mmol) was reacted at 20℃for 12 hours. The reaction mixture was poured into saturated brine, extracted with ethyl acetate (30 mL. Times.3), and the organic phases were combined, washed with saturated brine (100 mL. Times.3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The crude product was separated by column chromatography on silica gel (petroleum ether: ethyl acetate=2:1) to give compound 9-7.

¹ H NMR(400MHz,CDCl ₃ )δ＝7.43-7.49(m,2H),7.36-7.42(m,2H),7.30-7.36(m,1H),7.07(d,J＝2.4Hz,1H),6.95(dd,J＝8.4,2.4Hz,1H),6.81(d,J＝8.4Hz,1H),6.72(d,J＝2.0Hz,1H),6.55(d,J＝2.0Hz,1H),5.06(s,2H),4.19-4.31(m,6H),3.37(spt,J＝6.9Hz,1H),2.79-2.99(m,2H),2.22-2.33(m,1H),2.11-2.21(m,1H),1.78(s,3H),1.64(s,3H),1.38(t,J＝7.0Hz,6H),1.18ppm(t,J＝7.1Hz,6H).MS m/z:537[M+1] ⁺ 。

Step 7:9-8 Synthesis

To methanol (5 mL) of compound 9-7 (0.35 g, 652.21. Mu. Mol) was added palladium on carbon (0.1 g, palladium content 5%) and reacted under a hydrogen atmosphere (15 psi) at 20℃for 2 hours. The reaction solution was filtered with celite, and the filtrate was concentrated under reduced pressure to give a crude product. The crude product was separated by column chromatography on silica gel (petroleum ether: ethyl acetate=1:1) to give compounds 9-8.

¹ H NMR(400MHz,DMSO-d ₆ )δ＝9.02(s,1H),6.88(d,J＝2.0Hz,1H),6.71-6.80(m,2H),6.62-6.68(m,1H),6.56(s,1H),4.35(d,J＝9.7Hz,2H),4.06-4.17(m,4H),3.05-3.20(m,1H),2.71-2.94(m,2H),2.03-2.20(m,2H),1.69(s,3H),1.52(s,3H),1.25(t,J＝7.1Hz,6H),1.07ppm(t,J＝6.6Hz,6H).

Step 8: synthesis of Compounds 9-9 and 9-10

Compounds 9-8 (1 g,2.24 mmol) were SFC isolated. SFC (column: DAICEL CHIRALPAK AD (250 mm. Times.30 mm,10 μm); mobile phase: [0.1% NH) ₃ H ₂ O IPA]35% -35%,7 min) to obtain compounds 9-9 and 9-10. The analysis method comprises the following steps: instrument: thar analytical SFC column: chiralpakAD-3, 50mm x 4.6mm x 3 μm, mobile phase: a is CO ₂ And B: IPA (0.05% DEA), gradient: B: A=5% -50%, 3min, flow rate: 3.4mL/min, column temperature: 35 ℃, wavelength: 220nm, column pressure: 1800psi. Retention time of compound 9-9: 1.136min. Retention time of compounds 9-10: 1.211min.

Step 9: synthesis of Compound 9

To compound 9-9 (0.39 g, 873.43. Mu. Mol) in methylene chloride (10 mL) was added trimethylbromosilane (1.34 g,8.73mmol,1.13 mL) at 0deg.C, and the mixture was reacted at 20deg.C for 12 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. Separation was performed by pre-HPLC (column type: phenomenex luna C18, 250, 50mm, 10 μm; mobile phase: water (0.04% HCl) -ACN; gradient: B (ACN)%: 30% -60%,10 min). Compound 9 was obtained.

¹ H NMR(400MHz,CD ₃ OD)δ＝6.94(d,J＝2.3Hz,1H),6.81(dd,J＝8.3,2.4Hz,1H),6.74(d,J＝1.8Hz,1H),6.63(d,J＝8.3Hz,1H),6.56(d,J＝1.8Hz,1H),4.18(d,J＝10.4Hz,2H),3.15-3.27(m,1H),2.79-2.95(m,2H),2.06-2.27(m,2H),1.76(s,3H),1.59(s,3H),1.11ppm(t,J＝6.9Hz,6H).

Step 10: synthesis of Compound 10

To dichloromethane (2 mL) of compounds 9-10 (40 mg, 88.32. Mu. Mol) was added trimethylbromosilane (135.21 mg, 883.18. Mu. Mol, 114.58. Mu.L) at 0deg.C, and the mixture was reacted at 20deg.C for 12 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. The compound 10 was obtained by separation by pre-HPLC (column: welch Xtimate C18X 25mm X5 μm; mobile phase: water (0.04% HCl) -ACN; gradient: B (ACN): 40% -65%,8 min). ¹ H NMR(400MHz,CD ₃ OD)δ＝6.88-6.94(m,1H),6.81(dd,J＝8.8,2.1Hz,2H),6.52-6.61(m,2H),4.34(dd,J＝8.7,2.8Hz,1H),4.21(d,J＝10.4Hz,2H),3.14-3.25(m,1H),2.99-3.12(m,1H),2.87(ddd,J＝16.1,8.9,2.9Hz,1H),2.54(dq,J＝12.6,9.0Hz,1H),1.91-2.02(m,1H),1.13(t,J＝6.8Hz,6H).

Examples 11 and 12

The synthetic route is as follows:

step 1:11-2 Synthesis

N-butyllithium (2.5M, 1.14 mL) was added to tetrahydrofuran (10 mL) of compound 1-8 (868.75 mg,2.85 mmol) at-78℃and compound 11-1 (0.65 g,2.19 mmol) was added after 1 hour, and after 1 hour of reaction, the reaction was carried out at 20℃for 2 hours. The reaction solution was poured into a saturated ammonium chloride solution, ethyl acetate (100 mL) was added to the solution, the aqueous phase was extracted with ethyl acetate (100 ml×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The crude product was isolated by column chromatography on silica gel (petroleum ether/ethyl acetate=20:1) to give compound 11-2.MS m/z 505[ M-17 ] ] ⁺ 。

Step 2:11-3 Synthesis

Triethylsilahydrogen (466.74 mg,4.01mmol, 641.13. Mu.L) and trifluoroacetic acid (228.83 mg,2.01mmol, 148.59. Mu.L, 1.5 eq) were added to dichloromethane (20 mL) of compound 11-2 (0.7 g,1.34 mmol) at 0deg.C and reacted for 2 hours at 20deg.C. The reaction solution was poured into saturated sodium bicarbonate solution, dichloromethane (50 mL) was added, the aqueous phase was extracted with dichloromethane (50 ml×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The crude product was isolated by column chromatography on silica gel (petroleum ether/ethyl acetate=50:1) to give compound 11-3.

Step 3:11-4 Synthesis

To tetrahydrofuran (10 mL) of Compound 11-3 (0.56 g,1.10 mmol) was added a tetrahydrofuran solution (1M, 1.32 mL) of tetrabutylammonium fluoride, and the mixture was reacted at 20℃for 1 hour. The reaction solution was concentrated under reduced pressure to obtain a crude product. Separation by silica gel column chromatography (petroleum ether/ethyl acetate=5:1) gives compound 11-4.

¹ H NMR(DMSO-d ₆ ,400MHz)δ＝9.68(s,1H),7.42-7.47(m,2H),7.37-7.42(m,2H),7.29-7.35(m,1H),6.93(d,J＝2.1Hz,1H),6.88(d,J＝8.5Hz,1H),6.64-6.71(m,2H),6.58(d,J＝1.8Hz,1H),5.04(s,2H),4.31(dd,J＝8.6,2.6Hz,1H),3.23(spt,J＝6.9Hz,1H),2.91-3.03(m,1H),2.74-2.87(m,1H),1.81-1.94(m,1H),1.22-1.39(m,1H),1.12ppm(dd,J＝6.7,5.5Hz,6H).

Step 4:11-5 Synthesis

To compound 11-4 (0.45 g,1.15 mmol) in N, N-dimethylformamide (5 mL) was added cesium carbonate (559.73 mg,1.72 mmol), diethyl tosyloxymethyl phosphonate (442.97 mg,1.37 mmol), and the mixture was reacted at 50℃for 3 hours. The reaction solution was poured into a saturated sodium chloride solution, ethyl acetate (50 mL) was added, the aqueous phase was extracted with ethyl acetate (50 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The crude product was isolated by column chromatography on silica gel (petroleum ether/ethyl acetate=1:1) to give compound 11-5.

¹ H NMR(CDCl ₃ ,400MHz)δ＝7.42-7.47(m,2H),7.39(t,J＝7.5Hz,2H),7.29-7.35(m,1H),6.99(d,J＝2.0Hz,1H),6.83(s,1H),6.78(d,J＝8.6Hz,2H),6.68-6.73(m,1H),5.04(s,2H),4.43(dd,J＝8.7,2.9Hz,1H),4.21-4.31(m,6H),3.31-3.42(m,1H),3.10(dt,J＝16.5,8.4Hz,1H),2.88(ddd,J＝16.2,8.8,3.1Hz,1H),2.59(dq,J＝12.8,8.9Hz,1H),2.06(s,1H),1.39(t,J＝7.0Hz,6H),1.21(dd,J＝6.8,5.1Hz,6H).

Step 5:11-6 Synthesis

To ethanol (10 mL) of compound 11-5 (0.22 g, 405.13. Mu. Mol) was added platinum dioxide (110.00 mg, 484.42. Mu. Mol), and the mixture was reacted under hydrogen atmosphere (15 psi) at 20℃for 12 hours. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure to give a crude product. The crude product was isolated by column chromatography on silica gel (petroleum ether/ethyl acetate=1:1) to give compound 11-6.

Step 6:11-7 and 11-8 Synthesis

Compound 11-6 (0.13 g,0.29 mmol) was subjected to SFC isolation. SFC (column: DAICEL CHIRALPAK AD (250 mm. Times.30 mm,10 μm); mobile phase: [0.1% NH) ₃ H ₂ O IPA]40% -40%,8 min) to obtain compounds 11-7 and 11-8. The analysis method comprises the steps of (a) measuring Thar analytical SFC by an instrument, (a) measuring Chiralpak AD-3 by 50mm, measuring 4.6mm, and measuring 3 mu m by a mobile phase (A) and (CO) ₂ And B: IPA (0.05% DEA), gradient: B: A=5% -50%, 3min, flow rate: 3.4mL/min, column temperature: 35 ℃, wavelength: 220nm, column pressure: 1800psi. Retention time of compound 11-7: 1.171min. Retention time of compound 11-8: 1.306min.

Step 7: synthesis of Compound 11

To dichloromethane (2 mL) of Compound 11-7 (40 mg, 88.32. Mu. Mol) was added trimethylbromosilane (135.21 mg, 883.18. Mu. Mol) at 0deg.C, and the mixture was reacted at 20deg.C for 12 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. prep-HPLC (column: welch Xtime C18X 25mm X5 μm; mobile phase: water (0.04% HCl) -acetonitrile; gradient: B (ACN): 40% -65%,8 min) was used for separation. Compound 11 was obtained.

¹ H NMR(CD ₃ OD,400MHz)δ＝6.88-6.94(m,1H),6.81(dd,J＝8.8,2.1Hz,2H),6.52-6.61(m,2H),4.34(dd,J＝8.7,2.8Hz,1H),4.21(d,J＝10.4Hz,2H),3.14-3.25(m,1H),2.99-3.12(m,1H),2.87(ddd,J＝16.1,8.9,2.9Hz,1H),2.54(dq,J＝12.6,9.0Hz,1H),1.91-2.02(m,1H),1.13ppm(t,J＝6.8Hz,6H).

Step 8: synthesis of Compound 12

To dichloromethane (2 mL) of Compound 11-8 (40 mg, 88.32. Mu. Mol) was added trimethylbromosilane (135.21 mg, 883.18. Mu. Mol) at 0deg.C, and the mixture was reacted at 20deg.C for 12 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. prep-HPLC (column: welch Xtimate C18X 25mm X5 μm; mobile phase: water (0.04% HCl) -acetonitrile; gradient: B (ACN): 40% -65%,8 min) was used to give compound 12.

¹ H NMR(CD ₃ OD,400MHz)δ＝6.92(s,1H),6.82(dd,J＝9.0,1.9Hz,2H),6.53-6.61(m,2H),4.35(dd,J＝8.7,2.8Hz,1H),4.22(d,J＝10.4Hz,2H),3.15-3.27(m,1H),3.00-3.12(m,1H),2.83-2.94(m,1H),2.55(dq,J＝12.7,9.0Hz,1H),1.91-2.05(m,1H),1.14ppm(t,J＝6.8Hz,6H)

Examples 13 and 14

The synthetic route is as follows:

step 1: synthesis of Compound 13-2

Compound 13-1 (13 g,64.66 mmol) was dissolved in tetrahydrofuran (130 mL), cooled to-78deg.C, n-butyllithium (2.5M, 28.45 mL) was added, stirred at-78deg.C for 1 hour, dimethylformamide (6.14 g,84.05 mmol) was added dropwise, and the reaction was stirred at-78deg.C for 1 hour. The reaction solution was added to a mixture of ammonium chloride solution (150 mL) and ethyl acetate (150 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Compound 13-2 is obtained.

¹ H NMR(400MHz,CDCl ₃ )δ＝9.97-9.90(m,1H),7.29(s,1H),7.21(s,1H),7.02-6.98(m,1H),3.89-3.82(m,3H),2.45-2.39(m,3H)。

Step 2: synthesis of Compound 13-3

Compound 13-2 (9.5 g,63.26 mmol), 2-carboxyethyltriphenylphosphine bromide (26.27 g,63.26 mmol) was added to dichloromethane (100 mL), the temperature was reduced to 0deg.C, potassium tert-butoxide (1M, 145.50 mL) was added, and the reaction was gradually warmed to 20deg.C and stirred for 16 h. The reaction mixture was concentrated under reduced pressure, ethyl acetate (200 mL) and water (200 mL) were added, the organic phase was washed with saturated sodium carbonate solution (50 mL. Times.2), the aqueous phase was combined, extracted with ethyl acetate (100 mL), the organic phase was discarded, ethyl acetate (200 mL) was added to the aqueous phase, stirred, pH was adjusted to about 5 by adding 12M hydrochloric acid, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (dichloromethane: ethanol=10:1) to give compound 13-3.

¹ H NMR(400MHz,CDCl ₃ )δ＝11.61-10.76(m,1H),6.83-6.79(m,1H),6.75-6.71(m,1H),6.63(s,1H),6.50-6.42(m,1H),6.32-6.23(m,1H),3.82-3.80(m,3H),3.33-3.27(m,2H),2.34-2.30(m,3H)。

Step 3: synthesis of Compound 13-4

Compound 13-3 (9 g,43.64 mmol) was added to methanol (100 mL), palladium on carbon (3 g, 5% palladium) was added, the hydrogen was replaced three times, and the reaction was stirred at 20℃and 15psi for 16 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. Compound 13-4 is obtained.

¹ H NMR(400MHz,CD ₃ OD)δ＝6.59(s,1H),6.57-6.52(m,2H),3.77-3.73(m,3H),2.61-2.53(m,2H),2.32-2.23(m,5H),1.94-1.82(m,2H)。

Step 4: synthesis of Compound 13-5

Compound 13-4 (5.2 g,24.97 mmol) was added to 1, 2-dichloroethane (100 mL), cooled to 0deg.C, trifluoroacetic anhydride (6.29 g,29.96 mmol) was added dropwise and the reaction was gradually raised to 20deg.C and stirred for 16 hours. To the reaction mixture was added a mixture of saturated sodium hydrogencarbonate solution (100 mL) and methylene chloride (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 on silica gel (petroleum ether: ethyl acetate=5:1) to give compound 13-5.

¹ H NMR(400MHz,CDCl ₃ )δ＝6.61(s,1H),6.60-6.58(m,1H),3.87-3.80(m,3H),2.96-2.88(m,2H),2.66-2.63(m,3H),2.63-2.58(m,2H),2.10-2.01(m,2H)。

Step 5: synthesis of Compound 13-6

Compound 13-5 (4.50 g,23.65 mmol) was added to dichloromethane (50 mL), cooled to-78deg.C, and boron tribromide (11.85 g,47.31mmol,4.56 mL) was added dropwise and the reaction was gradually warmed to 20deg.C and stirred for 16 hours. The reaction solution was added to a mixture of water (50 mL) and methylene chloride (50 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 on silica gel (petroleum ether: ethyl acetate=5:1) to give compound 13-6.

¹ H NMR(400MHz,CDCl ₃ )δ＝6.58(s,2H),5.92-5.87(m,1H),2.90(t,J＝6.1Hz,2H),2.67-2.58(m,5H),2.09-2.00(m,2H)。

Step 6: synthesis of Compound 13-7

Compound 13-6 (3.6 g,20.43 mmol) was added to tetrahydrofuran (70 mL), imidazole (2.78 g,40.86 mmol) was added, the temperature was reduced to 0℃and tert-butyldimethylchlorosilane (4.00 g,26.56 mmol) was added and the reaction was gradually warmed to 20℃and stirred for 16 hours. To the reaction mixture was added a mixture of a half-saturated sodium chloride solution (100 mL) and ethyl acetate (100 mL), the mixture was separated, and the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate=5:1) to give compound 13-7.

¹ H NMR(400MHz,CDCl ₃ )δ＝6.54(d,J＝1.8Hz,2H),2.89(t,J＝6.1Hz,2H),2.63-2.55(m,5H),2.10-1.97(m,2H),1.01-0.98(m,9H),0.26-0.21(m,6H)。

Step 7: synthesis of Compound 13-8

Compound 1-8 (4.98 g,12.40 mmol) was added to tetrahydrofuran (30 mL), cooled to-78deg.C, n-butyllithium (2.5M, 4.55 mL) was added dropwise, the reaction was continued for 0.5 hr, a solution of compound 13-7 (3 g,10.33 mmol) in tetrahydrofuran (10 mL) was slowly added dropwise, and the reaction was gradually raised to 20deg.C and stirred for 2 hr. The reaction solution was added to a mixture of ammonium chloride solution (50 mL) and ethyl acetate (50 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 on silica gel (petroleum ether: ethyl acetate=5:1) to give compound 13-8.

¹ H NMR(400MHz,CDCl ₃ )δ＝7.40-7.30(m,5H),7.08-7.07(m,1H),7.05-7.01(m,1H),6.88-6.85(m,1H),6.60-6.58(m,1H),6.47-6.45(m,1H),6.10-6.06(m,1H),5.10(s,2H),3.41-3.34(m,1H),2.90-2.86(m,1H),2.66(br d,J＝7.6Hz,1H),2.62-2.57(m,4H),2.24-2.20(m,2H),2.15-2.07(m,2H),1.23-1.19(m,6H),1.00(s,9H),0.24(s,6H)。

Step 8: synthesis of Compound 13-9

Compound 13-8 (4.8 g,9.29 mmol) was added to dichloromethane (100 mL), cooled to 0deg.C, triethylsilane (3.24 g,27.86 mmol) was added dropwise, and trifluoroacetic acid (1.59 g,13.93 mmol) was added and the reaction was gradually warmed to 20deg.C and stirred for 16 h. To the reaction solution were added saturated sodium hydrogencarbonate solution (10 mL) and methylene chloride (50 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 on silica gel (petroleum ether: ethyl acetate=5:1) to give compound 13-9.

¹ H NMR(400MHz,CDCl ₃ )δ＝7.47-7.29(m,5H),6.91-6.88(m,1H),6.74(d,J＝8.2Hz,1H),6.63-6.59(m,1H),6.53-6.50(m,1H),6.49(d,J＝2.0Hz,1H),5.04-4.99(m,2H),4.14-4.08(m,1H),3.39-3.29(m,1H),2.82-2.75(m,2H),2.10-2.00(m,1H),1.97-1.90(m,1H),1.59(br d,J＝6.2Hz,1H),1.24-1.11(m,6H),1.00(s,9H),0.26-0.19(m,6H)。

Step 9: synthesis of Compound 13-10

Compound 13-9 (3.35 g,6.69 mmol) was added to methanol (30 mL) and tetrahydrofuran (30 mL), ammonium fluoride (2.48 g,66.89 mmol) was added, and the reaction was gradually raised to 20℃and stirred for 16 hours. The reaction mixture was concentrated under reduced pressure, ethyl acetate (50 mL) was added, the mixture was washed with a half-saturated sodium chloride solution (30 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 on silica gel (petroleum ether: ethyl acetate=3:1) to give compound 13-10.

¹ H NMR(400MHz,CDCl ₃ )δ＝7.46-7.30(m,5H),6.94(d,J＝2.2Hz,1H),6.74(d,J＝8.4Hz,1H),6.59(dd,J＝2.3,8.3Hz,1H),6.52(d,J＝2.3Hz,1H),6.50-6.47(m,1H),5.02(s,2H),4.48(s,1H),4.11(br t,J＝3.8Hz,1H),3.42-3.30(m,1H),2.85-2.73(m,2H),2.05-1.91(m,2H),1.90(s,3H),1.68-1.58(m,2H),1.23-1.15(m,6H)。

Step 10: synthesis of Compound 13-11

Compound 13-10 (1.8 g,4.66 mmol) was added to dimethylformamide (18 mL), diethyl p-toluenesulfonyloxymethylphosphonate (1.43 g,4.42 mmol) and cesium carbonate (2.28 g,6.99 mmol) was added and the reaction was gradually warmed to 50deg.C and stirred for 16 hours. Ethyl acetate (100 mL) was added to the reaction mixture, the mixture was washed with a half-saturated sodium chloride solution (50 mL. Times.4), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate=1:1 to 1:2) to give compound 13-11.

¹ H NMR(400MHz,CDCl ₃ )δ＝7.46-7.29(m,5H),6.95-6.91(m,1H),6.75-6.71(m,1H),6.63-6.60(m,2H),6.56(dd,J＝2.2,8.3Hz,1H),5.04-5.00(m,2H),4.31-4.21(m,6H),4.12-4.10(m,1H),3.41-3.31(m,1H),2.86-2.78(m,2H),2.05-1.94(m,2H),1.94-1.90(m,3H),1.68-1.59(m,2H),1.58(s,1H),1.39(t,J＝7.0Hz,6H),1.19(dd,J＝6.9,10.1Hz,6H)。

Step 11: synthesis of Compounds 13-12

Compounds 13-11 (2 g,3.73 mmol) were added to methanol (10 mL), palladium on carbon (0.3 g, 5% palladium) was added, hydrogen was replaced three times, and the reaction was stirred at 20℃and 15psi for 16 hours. The reaction solution was filtered and concentrated under reduced pressure. Obtaining the compound 13-12.

¹ H NMR(400MHz,CDCl ₃ )δ＝6.87(d,J＝2.0Hz,1H),6.61(s,2H),6.59(d,J＝8.2Hz,1H),6.48(dd,J＝2.1,8.2Hz,1H),4.84-4.80(m,1H),4.30-4.21(m,6H),4.09(dd,J＝2.3,5.1Hz,1H),3.21-3.11(m,1H),2.84-2.76(m,2H),2.07-1.93(m,2H),1.92-1.89(m,3H),1.65-1.59(m,2H),1.38(t,J＝7.0Hz,6H),1.21(dd,J＝6.9,10.4Hz,6H)。

Step 12: synthesis of Compounds 13-13 and Compounds 13-14

Compounds 13-12 (1.30 g,2.91 mmol) were SFC isolated. Purification by SFC (column: DAICEL CHIRALPAK AD (250 mm. Times.30 mm,10 μm), mobile phase: [0.1% NH ] ₃ H ₂ O-IPA]42-42% for min) to obtain compounds 13-13, 13-14. The analysis method comprises the following steps: column type ChiralpakAD-3, 50X4.6mm, I.D,3 μm. Mobile phase A and CO ₂ IPA (0.05% DEA). Gradient from 5% to 50% in 1.2 minutes for phase B, decreasing to 5% in 0.8 minutes for 1 minute, flow rate 3.4mL/min. Column temperature 35 ℃. CABPR 1800psi. Obtaining the compound 13-13 and the compound 13-14. Retention time of compounds 13-13: 1.163min, retention time of Compounds 13-14: 1.300min.

Step 13: synthesis of Compound 13

Compounds 13-13 (0.07 g, 156.77. Mu. Mol) were dissolved in methylene chloride (2 mL) and trimethylbromosilane (240.00 mg,1.57 mmol) was added and the reaction stirred at 20℃for 16 hours. The reaction mixture was concentrated under reduced pressure, ethyl acetate (30 mL) was added, the mixture was washed with water (10 mL. Times.2), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. prep-HPLC purification (column: welchXtimate C18.25 mm.5 μm; mobile phase: [ water (0.04% HCl) -ACN ]; B (ACN)%: 30% -60%,8 min) afforded Compound 13.

¹ H NMR(400MHz,CD ₃ OD)δ＝6.78-6.72(m,1H),6.67-6.60(m,2H),6.60-6.53(m,1H),6.50-6.43(m,1H),4.18(br d,J＝10.3Hz,2H),4.10-4.04(m,1H),3.25-3.13(m,1H),2.89-2.72(m,2H),2.06-1.90(m,2H),1.89(s,3H),1.69-1.51(m,2H),1.16-1.04(m,6H)。

Step 14: synthesis of Compound 14

Compounds 13-14 (70.00 mg, 156.77. Mu. Mol) were dissolved in dichloromethane (2 mL) and trimethylbromosilane (240.00 mg,1.57 mmol) was added and the reaction stirred at 20℃for 16 h. The reaction mixture was concentrated under reduced pressure, ethyl acetate (30 mL) was added, the mixture was washed with water (10 mL. Times.2), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. prep-HPLC purification (column: welchXtimate C18.25 mm.5 μm; mobile phase: [ water (0.04% HCl) -ACN ]; B (ACN)%: 30% -60%,8 min) afforded Compound 14.

¹ H NMR(400MHz,CD ₃ OD)δ＝6.79-6.73(m,1H),6.69-6.61(m,2H),6.59-6.54(m,1H),6.51-6.44(m,1H),4.26-4.14(m,2H),4.12-4.04(m,1H),3.24-3.13(m,1H),2.89-2.72(m,2H),2.03-1.82(m,5H),1.70-1.53(m,2H),1.19-1.03(m,6H)。

Examples 15 and 16

The synthetic route is as follows:

step 1: synthesis of Compound 15-2

Will be combinedThe 15-1 (3.00 g,11.58 mmol) was dissolved in tetrahydrofuran (50 mL), cooled to-78deg.C, n-butyllithium (2.5M, 6.95 mL) was added dropwise, the reaction was stirred at-78deg.C for 30 min, a solution of compound BB-1 (3.20 g,11.58 mmol) in tetrahydrofuran (20 mL) was added dropwise, and the temperature was slowly raised to 20deg.C and stirred for 16 h. To the reaction mixture was added a saturated ammonium chloride solution (50 mL), followed by extraction with ethyl acetate (200 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate=5:1) to give compound 15-2.[ M-17 ]] ⁺ ＝439.3

Step 2: synthesis of Compound 15-3

Compound 15-2 (1 g,2.19 mmol) was added to dichloromethane (20 mL), triethylsilane (763.85 mg,6.57 mmol) was added, cooled to 0deg.C, TFA (299.60 mg,2.63 mmol) was added dropwise, and the reaction was gradually warmed to 20deg.C and stirred for 16 hours. Dichloromethane (50 mL) was added, half-saturated sodium bicarbonate solution (30 mL) was washed, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate=5:1) to give compound 15-3.

Step 3: synthesis of Compound 15-4

Compound 15-3 (1.26 g,2.86 mmol) was added to methanol (30 mL) and tetrahydrofuran (30 mL), ammonium fluoride (1.06 g,28.59 mmol) was added and the reaction stirred at 20℃for 16 h. The reaction solution was concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate=5:1) to give compound 15-4.

Step 4: synthesis of Compound 15-5

Compound 15-4 (1.05 g,3.22mmol,1 eq) was added to dichloromethane (20 mL) and 4-dimethylaminopyridine (1.57 g,12.87 mmol), cooled to 0deg.C, triflic anhydride (1.36 g,4.82 mmol) was added and the reaction was gradually warmed to 20deg.C and stirred for 2 hours. The reaction solution was concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate=5:1) to give compound 15-5.

Step 5: synthesis of Compound 15-6

Compound 15-5 (0.4 g, 872.43. Mu. Mol,1 eq) was added to dimethylformamide (5 mL), triethylamine (176.56 mg,1.74 mmol), 1, 3-bis (diphenylphosphine) propane (35.98 mg, 87.24. Mu. Mol), methanol (559.05 mg,17.45 mmol), palladium acetate (19.59 mg), carbon monoxide (9.78. Mu.L) was replaced three times, and the reaction was stirred at 70℃under 50psi for 16 hours. Ethyl acetate (50 mL) was added to the reaction mixture, the mixture was washed with a half-saturated sodium chloride solution (30 mL. Times.4), and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate=5:1) to give compound 15-6.

¹ H NMR(400MHz,CDCl ₃ )δ＝7.81(s,1H),7.70-7.61(m,1H),6.94-6.89(m,2H),6.73-6.66(m,1H),5.19-5.12(m,2H),4.37(dd,J＝3.8,8.8Hz,1H),3.92(s,3H),3.49(s,3H),3.34-3.23(m,1H),3.17-3.04(m,1H),2.96-2.85(m,1H),2.66-2.53(m,1H),2.10-2.02(m,1H),2.02-1.98(m,3H),1.17(t,J＝7.1Hz,6H)。

Step 6: synthesis of Compound 15-7

Compound 15-6 (0.26 g, 705.63. Mu. Mol) was added to methanol (10 mL), p-toluenesulfonic acid (364.53 mg,2.12 mmol) was added and the reaction stirred at 20℃for 16 h. The reaction mixture was added with 3 equivalents of sodium hydrogencarbonate, ethyl acetate (50 mL), washed with water (50 mL) and the organic phaseAfter drying over anhydrous sodium sulfate, filtration was performed, and the filtrate was concentrated under reduced pressure. Compound 15-7 is obtained. [ M+1 ]] ⁺ ＝325.1

Step 7: synthesis of Compound 15-8

Compound 15-7 (0.22 g, 678.15. Mu. Mol) was added to acetonitrile (5 mL), cesium carbonate (441.91 mg,1.36 mmol) was added, benzyl bromide (173.98 mg,1.02 mmol) and the reaction was stirred at 20℃for 16 hours. The reaction solution was concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate=5:1) to give compound 15-8.[ M+1 ] ] ⁺ ＝415.3

Step 8: synthesis of Compound 15-9

Compound 15-8 (0.25 g, 603.09. Mu. Mol) was added to tetrahydrofuran (5 mL), cooled to 0deg.C, lithium aluminum hydride (45.77 mg,1.21 mmol) was added, and the reaction was gradually raised to 20deg.C and stirred for 2 hours. To the reaction solution was added a saturated ammonium chloride solution (20 mL), which was extracted with ethyl acetate (30 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Compound 15-9 is obtained. [ M-17 ]] ⁺ ＝369.4

Step 9: synthesis of Compounds 15-10

Compound 15-9 (180 mg, 465.69. Mu. Mol) was added to dichloromethane (5 mL), cooled to 0deg.C, triphenylphosphine (183.22 mg, 698.53. Mu. Mol) and carbon tetrabromide (231.65 mg, 698.53. Mu. Mol) was added, and the reaction was gradually warmed to 20deg.C and stirred for 2 hours. The reaction solution was concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate=5:1) to give compounds 15-10.

¹ H NMR(400MHz,CDCl ₃ )δ＝7.47-7.30(m,5H),7.18(s,1H),7.02-6.96(m,2H),6.80-6.75(m,1H),6.72-6.66(m,1H),5.04(s,2H),4.52(s,2H),4.33(dd,J＝4.0,8.6Hz,1H),3.42-3.31(m,1H),3.11-3.00(m,1H),2.92-2.82(m,1H),2.64-2.52(m,1H),2.08-1.99(m,1H),1.98-1.93(m,3H),1.21(dd,J＝5.3,6.9Hz,6H)。

Step 10: synthesis of Compound 15-11

Diethyl phosphite (110.62 mg, 801.03. Mu. Mol), cesium carbonate (260.99 mg, 801.03. Mu. Mol), tetrabutylammonium iodide (147.94 mg, 400.51. Mu. Mol) were added to dimethylformamide (4 mL), stirred at 20℃for 1 hour, compounds 15-10 (0.18 g, 400.51. Mu. Mol) were added, and the reaction was stirred at 20℃for 16 hours. Ethyl acetate (50 mL) was added, the mixture was washed with a half-saturated sodium chloride solution (30 mL. Times.4), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by column chromatography on silica gel (pure petroleum ether to petroleum ether: ethyl acetate=1:1) gives compounds 15-11.

¹ H NMR(400MHz,CDCl ₃ )δ＝7.46-7.30(m,5H),7.11-7.05(m,1H),6.94(d,J＝2.2Hz,1H),6.89(s,1H),6.79-6.75(m,1H),6.73-6.69(m,1H),5.06-5.00(m,2H),4.35-4.29(m,1H),4.10-3.96(m,4H),3.41-3.30(m,1H),3.17-3.10(m,2H),3.09-2.99(m,1H),2.90-2.79(m,1H),2.61-2.49(m,1H),2.05-1.96(m,1H),1.95-1.91(m,3H),1.30-1.23(m,6H),1.20-1.14(m,6H)。

Step 11: synthesis of Compounds 15-12

Compounds 15-11 (200 mg, 394.78. Mu. Mol) were added to methanol (10 mL), palladium on carbon (0.2 g,5% palladium content) was added, hydrogen was displaced three times, and the reaction was stirred at 50℃under 50psi for 16 hours. Filtering, and concentrating the filtrate under reduced pressure. Obtaining the compound 15-12.[ M+1 ]] ⁺ ＝417.3

Step 12: synthesis of Compounds 15-13

Compounds 15-12 (0.19 g, 456.19. Mu. Mol) were resolved by SFC. SFC (column: DAICEL CHIRALPAK AD (250 mm. Times.30 mm,10 μm); mobile phase: [0.1% NH) ₃ H ₂ O IPA]35% -35%,6 min). The compounds 15-13, 15-14 are obtained. The analysis method comprises the following steps: column-type ChiralpakAD-3, 50X 4.6mm, I.D.,3 μm. Mobile phase A and CO ₂ IPA (0.05% DEA). Gradient from 5% to 50% in 1.2 minutes for phase B, decreasing to 5% in 0.8 minutes for 1 minute, flow rate 3.4mL/min. Column temperature 35 ℃. ABPR 1800psi. Retention time of compounds 15-13: 1.142min. Retention time of compounds 15-14: 1.211min.

Step 13: synthesis of Compound 15

Compounds 15-13 (60.00 mg, 144.06. Mu. Mol) were dissolved in dichloromethane (3 mL) and trimethylbromosilane (220.55 mg,1.44 mmol) was added and the reaction stirred at 20℃for an additional 16 h. The reaction mixture was concentrated under reduced pressure, washed with ethyl acetate (20 mL), water (10 mL. Times.2), separated, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification was performed by prep-HPLC (column: welch Xtimate C18X 25mm X5 μm; mobile phase: [ Water (0.04% HCl) -ACN ]; B (ACN): 40% -65%,8 min). Compound 15 was obtained.

¹ H NMR(400MHz,CD ₃ OD)δ＝7.07(s,1H),6.88(s,1H),6.86(d,J＝1.8Hz,1H),6.60-6.54(m,2H),4.30-4.24(m,1H),3.21(td,J＝7.0,13.8Hz,1H),3.12-3.03(m,2H),3.03-2.93(m,1H),2.87-2.74(m,1H),2.57-2.44(m,1H),1.98-1.91(m,1H),1.90(s,3H),1.14(t,J＝7.0Hz,6H)。

Step 14: synthesis of Compound 16

Compounds 15-14 (60.00 mg, 144.06. Mu. Mol) were dissolved in dichloromethane (3 mL) and trimethylbromosilane (220.55 mg,1.44 mmol) was added and the reaction stirred at 20℃for an additional 16 h. The reaction mixture was concentrated under reduced pressure, washed with ethyl acetate (20 mL), water (10 mL. Times.2), separated, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. prep-HPLC (column: welch Xtime C18.25 mm.5 μm; mobile phase: [ water (0.04% HCl) -ACN ]; B (ACN)%: 40% -65%,8 min) afforded Compound 16.

¹ H NMR(400MHz,CD ₃ OD)δ＝7.07(s,1H),6.90-6.87(m,1H),6.87-6.84(m,1H),6.60-6.53(m,2H),4.30-4.23(m,1H),3.21(td,J＝6.9,13.8Hz,1H),3.12-3.04(m,2H),3.03-2.96(m,1H),2.87-2.77(m,1H),2.57-2.44(m,1H),1.98-1.92(m,1H),1.90(s,3H),1.14(t,J＝7.0Hz,6H)。

Examples 17 and 18

The synthetic route is as follows:

step 1:17-2 Synthesis

17-1 (2 g,6.19 mmol) and tetrahydrofuran (60 mL) were added to a dry and clean three-necked flask, stirring was started, the temperature was controlled to-70 ℃, n-butyllithium (2.5M, 2.97 mL) was slowly added dropwise, the reaction was continued for 30min, the temperature was controlled to-70 ℃, BB-1 (1.71 g,6.19 mmol) was added, and the reaction was continuedSaturated ammonium chloride solution (100 mL) was slowly added dropwise under nitrogen protection, followed by extraction with ethyl acetate (100 mL) to give an organic phase, which was dried over anhydrous sodium sulfate and spun-dried to give compound 17-2.[ M-17 ]] ⁺ ＝503.4

Step 2:17-3 Synthesis

To a thumb flask was added 17-2 (3.6 g,3.46 mmol) and dichloromethane (35 mL), stirring was turned on, ethyl acetate (591.18 mg,5.18 mmol) was added followed by triethylsilane (1.21 g,10.37mmol,1.66 mL) and reacted at 20℃for 2 hours. To the reaction system, a saturated sodium carbonate solution (80 mL) was added and stirred for 10min, followed by addition (40 mL) of an extract to obtain an organic phase, drying over anhydrous sodium sulfate, and spin-drying to obtain compound 17-3.

¹ H NMR(400MHz,CDCl ₃ )δ＝7.44(dd,J＝1.1,3.7Hz,5H),7.23-7.19(m,2H),6.50-6.47(m,2H),5.03(s,2H),4.57(dd,J＝3.5,8.8Hz,1H),3.42-3.31(m,2H),3.03-2.95(m,1H),2.88-2.80(m,1H),2.01-1.97(m,1H),1.91(s,3H),1.24(s,6H),1.22(s,6H),1.01(s,9H)。

Step 3:17-4 Synthesis

To a dry clean thumb flask was added 17-3 (1.6 g,3.17 mmol), followed by methanol (16 mL) and tetrahydrofuran (16 mL), stirring was turned on, ammonium fluoride (1.17 g,31.70 mmol) was added, and the mixture was reacted at 50℃for 2 hours; spin drying to obtain a crude product; purifying by silica gel column chromatography (petroleum ether: ethyl acetate=10:1-3:1) to obtain the compound 17-4.

¹ H NMR(400MHz,CDCl ₃ )δ＝7.46-7.42(m,5H),7.22-7.14(m,2H),6.66-6.63(m,2H),5.07(s,2H),5.04(s,1H),4.56(dd,J＝3.9,8.8Hz,1H),3.41-3.19(m,2H),3.04-2.95(m,1H),2.90-2.79(m,1H),2.66-2.54(m,1H),1.24(s,3H),1.22(s,3H)。

Step 4:17-5 Synthesis

17-4 (1.2 g,3.07 mmol) and N, N-dimethylformamide (7 mL) were added to the thumb flask, stirring was turned on, cesium carbonate (2.00 g,6.15 mmol) was added, followed by diethyl p-toluenesulfonyloxymethylphosphonate (891.43 mg,2.77mmol, 713.15. Mu.L) and the temperature was controlled at 50deg.C for 3 hours; ethyl acetate (50 mL) was added to the reaction system, followed by extraction with water (50 mL) and saturated brine (50 mL) in this order, and an organic phase was separated, dried over anhydrous sodium sulfate, and spun-dried to obtain the target crude product; purification by silica gel column chromatography (petroleum ether: ethyl acetate=10:1-3:1) afforded compound 17-5.

[M+1] ⁺ :541.3

Step 5: synthesis of Compound 17-6

To a thumb flask were added compound 17-5 (1 g,1.85 mmol) and ethyl acetate (28 mL), stirring was turned on, followed by palladium on carbon (1.3 g,1.85mmol, 5%) and reacted for 1 hour at 20℃under a hydrogen balloon 15psi atmosphere; the reaction system was filtered through a five-hole funnel of 2g of celite, and washed twice with ethyl acetate (25 ml×2), the filtrate was spin-dried to give a crude product, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate=10:1 to 1:1) to give compound 17-6.

¹ H NMR(400MHz,CDCl ₃ )δ＝6.74(s,1H),6.62-6.56(m,2H),6.47(d,J＝8.8Hz,1H),4.52(dd,J＝4.0,8.8Hz,1H),4.33-4.24(m,6H),3.16-2.95(m,2H),2.88-2.78(m,1H),2.54(qd,J＝8.5,12.8Hz,1H),2.00(tdd,J＝4.3,8.4,12.7Hz,1H),1.91(s,3H),1.39(t,J＝7.1Hz,6H),1.07(dd,J＝6.9,10.4Hz,6H)。

F NMR(400MHz,CDCl ₃ )δppm-121.571。

Step 6: resolution to obtain 17-7 and 17-8

This step was used for intermediate 17-6 resolution via chiral separation: pillar DAICEL CHIRALPAKAD (250 mm. Times.30 mm,10 μm); mobile phase [0.1% NH ] ₃ .H ₂ O IPA]The method comprises the steps of carrying out a first treatment on the surface of the B (ACN)% > is 20% -20%, min, and resolving to obtain compounds 17-7, 17-8. The analysis method comprises the following steps: column-type ChiralpakAD-3, 50X 4.6mm, I.D.,3 μm. Mobile phase A and CO ₂ IPA (0.05% DEA). Gradient from 5% to 50% in 1.2 minutes for phase B, decreasing to 5% in 0.8 minutes for 1 minute, flow rate 3.4mL/min. Column temperature 35 ℃. ABPR 1800psi. Retention time of compound 17-7: 1.046min. Retention time of compound 17-7: 1.115min.

Step 7:17 synthesis

17-7 (215.00 mg, 477.27. Mu. Mol) and methylene chloride (4 mL) were added to the thumb flask and stirring was turned on; cooling to 0 ℃, adding trimethyl bromosilane (730.65 mg,4.77mmol,619.20 mu L), slowly heating to 20 ℃, and reacting for 16 hours; spin drying the reaction system to obtain a target crude product; purification by prep-HPLC (column: phenomenex Luna C: 100 x 30mm x 5 μm; mobile phase: [ water (0.04% HCl) -ACN ]; B (ACN)%: 30% -65%,10 min) gave compound 17.

¹ H NMR(400MHz,DMSO)δ＝9.54(s,1H),6.77(s,1H),6.60(s,1H),6.52(d,J＝11.9Hz,1H),6.44(d,J＝9.2Hz,1H),4.42(br dd,J＝4.1,8.5Hz,1H),4.04(br d,J＝10.2Hz,2H),3.10-2.89(m,4H),2.83-2.74(m,1H),1.84(s,3H),0.97(dd,J＝7.1,8.8Hz,6H)。

F NMR(400MHz,DMSO)δppm-121.434。

³¹ P NMR(400MHz,DMSO)δppm 14.922。

Step 8: synthesis of Compound 18

17-8 (200.00 mg,443.97 mu mol) and methylene dichloride (4 mL) are added into a thumb bottle, stirring is started, the temperature is reduced to 0 ℃, trimethylbromosilane (679.68 mg,4.44mmol,576.00 mu L) is added, the temperature is slowly increased to 20 ℃, the reaction is carried out for 16 hours, and the crude product is obtained after the reaction system is dried by spinning; compound 18 was obtained by purification by prep-HPLC (column: phenomenex Luna C, 100X 30mm X5 μm; mobile phase: [ water (0.04% HCl) -ACN ]; B (ACN)%: 30% -65%,10 min).

¹ H NMR(400MHz,DMSO-d ₆ )δ＝9.54(br s,1H),6.77(s,1H),6.60(s,1H),6.53(d,J＝11.9Hz,1H),6.44(d,J＝9.0Hz,1H),4.42(br dd,J＝4.1,8.5Hz,1H),4.04(d,J＝10.3Hz,2H),3.10-2.71(m,5H),1.84(s,3H),0.97(dd,J＝7.0,9.0Hz,6H)。

Examples 19 and 20

The synthetic route is as follows:

step 1:19-2 Synthesis

N-butyllithium (2.5M, 16.55 mL) was added to tetrahydrofuran (100 mL) of compound 19-1 (10 g,37.60 mmol) at-78℃and after 0.5 hour, N-dimethylformamide (3.30 g,45.12mmol,3.47 mL) was added and reacted for 1 hour. The reaction solution was poured into a saturated ammonium chloride solution, ethyl acetate (50 mL) was added to the solution, the aqueous phase was extracted with ethyl acetate (50 ml×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. Isolation by silica gel column chromatography (petroleum ether/ethyl acetate=20:1) gives compound 19-2.

¹ H NMR(400MHz,CDCl ₃ )δ＝9.91(s,1H),7.59(t,J＝1.5Hz,1H),7.33(q,J＝2.1Hz,2H),3.87ppm(s,3H).

Step 2:19-3 synthesis

To pyridine (120 mL) of compound 19-2 (11.2 g,52.08 mmol) was added malonic acid (8.13 g,78.12mmol,8.13 mL), piperidine (886.96 mg,10.42mmol,1.03 mL), and the mixture was reacted at 120℃for 1.5 hours. Diluting with 80mL of water, carefully adjusting the pH to less than 3 with 12N HCl, precipitating out a precipitate, filtering, and collecting a filter cake. The crude product was not further purified to give compound 19-3.

¹ H NMR(400MHz,DMSO-d ₆ )δ＝7.48-7.54(m,2H),7.27-7.30(m,1H),7.18(t,J＝2.0Hz,1H),6.63(d,J＝16.0Hz,1H),3.80ppm(s,3H).

Step 3:19-4 synthesis

To ethanol (10 mL) of compound 19-3 (11.2 g,43.57 mmol) was added platinum dioxide (2.28 g,10.02 mmol) and reacted for 2 hours at 20℃and 15psi under hydrogen atmosphere. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure to give a crude product. The crude product was not purified to give compound 19-4.

Step 4:19-5 Synthesis

Polyphosphoric acid (120 mL) was added to a reaction flask containing compound 19-4 (11 g,25.47mmol, 60%) and reacted at 95℃for 12 hours. Slowly pouring the reaction solution into ice water for dilution, precipitating yellow solid for filtration, and collecting a filter cake. The crude product was not further purified to give compound 19-5.

¹ H NMR(400MHz,CDCl ₃ )δ＝7.08(d,J＝2.1Hz,1H),6.83-6.90(d,1H),3.88(s,3H),2.98-3.09(m,2H),2.68-2.77ppm(m,2H).

Step 5:19-6 synthesis

To a reaction flask containing compound 19-5 (1.7 g,4.58mmol, 65%) was added aqueous hydrobromic acid (16.46 g,97.67mmol,11.05mL, 48%) and reacted at 130℃for 2 hours. Ethyl acetate (50 mL) was added to the mixture to separate a liquid, and the aqueous phase was extracted with ethyl acetate (50 mL. Times.3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The mixture was purified by beating with petroleum ether and ethyl acetate at room temperature (10:1, 5 mL) and filtered to give compound 19-6.

¹ H NMR(400MHz,DMSO-d ₆ )δ＝10.85(br s,1H),6.96(d,J＝1.9Hz,1H),6.87(s,1H),2.90-2.99(m,2H),2.54-2.63ppm(m,2H).

Step 6:19-7 synthesis

To compound 19-6 (1.2 g,5.29 mmol) in dichloromethane (20 mL) was added 4-dimethylaminopyridine (1.16 g,9.51 mmol), triisopropylchlorosilane (917.07 mg,4.76mmol,1.02 mL) and reacted at 20℃for 2 hours. The reaction solution was poured into a saturated sodium chloride solution, dichloromethane (50 mL) was added to separate the solution, the aqueous phase was extracted with dichloromethane (50 ml×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. Purification by column chromatography on silica gel (petroleum ether/ethyl acetate=50:1) gives compound 19-7.

Step 7:19-8 synthesis

To a solution of compound 19-17 (1.93 g,6.46 mmol) in tetrahydrofuran (20 mL) was added n-butyllithium (2.5M, 2.41 mL), and after 0.5 hour at-78℃compound 19-7 (1.65 g,4.30 mmol) was added and the reaction was allowed to proceed naturally back to 20℃for 2 hours. The reaction solution was poured into a saturated ammonium chloride solution, ethyl acetate (50 mL) was added to separate the solution, the aqueous phase was extracted with ethyl acetate (50 ml×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give a crude product, which was separated by silica gel column chromatography (petroleum ether/ethyl acetate=20:1) to give compound 19-8.

Step 8:19-9 Synthesis

Triethylsilahydrogen (548.94 mg,4.72mmol, 754.04. Mu.L.) and trifluoroacetic acid (269.14 mg,2.36mmol, 174.76. Mu.L) were added to dichloromethane (10 mL) of compound 19-8 (1.9 g,1.57mmol, 50%) at 0℃and reacted at 20℃for 2 hours. The reaction solution was poured into a saturated sodium bicarbonate solution, dichloromethane (50 mL) was added to the solution, the aqueous phase was extracted with dichloromethane (50 ml×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. Isolation by silica gel column chromatography (petroleum ether/ethyl acetate=20:1) gives compound 19-9.

Step 9:19-10 synthesis

Triethylsilahydrogen (469.96 mg,4.04mmol, 645.54. Mu.L) and trifluoroacetic acid (230.42 mg,2.02mmol, 149.63. Mu.L) were added to dichloromethane (2 mL) of Compound 19-9 (0.7 g,1.35 mmol) at 0℃and reacted at 20℃for 2 hours. The reaction solution was concentrated under reduced pressure to give a crude product, which was separated by silica gel column chromatography (petroleum ether/ethyl acetate=50:1) to give compound 19-10.

¹ H NMR(400MHz,CDCl ₃ )δ＝6.83-6.95(m,2H),6.77(s,1H),6.55-6.70(m,2H),4.52(s,1H),4.30-4.40(m,1H),2.99-3.22(m,2H),2.86(ddd,J＝16.0,8.9,2.5Hz,1H),2.58(dq,J＝12.6,9.1Hz,1H),1.98-2.05(m,1H),1.26-1.30(m,3H),1.20(dd,J＝6.8,5.2Hz,6H),1.12ppm(d,J＝7.3Hz,18H).

Step 10:19-11 synthesis

To dichloromethane (10 mL) of compound 19-10 (0.7 g,1.39 mmol) was added pyridine p-toluenesulfonate (34.93 mg, 139.00. Mu. Mol), 2, 3-dihydropyran (140.31 mg,1.67mmol, 152.51. Mu.L), and the mixture was reacted at 20℃for 12 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. Isolation by silica gel column chromatography (petroleum ether/ethyl acetate=50:1) gives compounds 19-11.

¹ H NMR(400MHz,CDCl ₃ )δ＝6.97(dd,J＝8.3,6.8Hz,1H),6.82-6.92(m,2H),6.64-6.78(m,2H),5.38(t,J＝3.0Hz,1H),4.36(br d,J＝7.5Hz,1H),3.86-3.99(m,1H),3.61(br d,J＝11.4Hz,1H),3.22-3.35(m,1H),3.00-3.15(m,1H),2.80-2.91(m,1H),2.57(dq,J＝12.6,9.1Hz,1H),1.96-2.06(m,2H),1.86(dt,J＝7.4,3.6Hz,2H),1.58-1.77(m,3H),1.25-1.30(m,3H),1.14-1.21(m,6H),1.12ppm(d,J＝7.2Hz,18H).

Step 11:19-12 synthesis

Tetrabutylammonium fluoride (1M, 1.43 mL) was added to tetrahydrofuran (20 mL) of compound 19-11 (0.7 g,1.19 mmol), and reacted at 20℃for 2 hours. To the reaction solution was added water (20 mL) and quenched, ethyl acetate (50 mL) was added to the mixture, the aqueous phase was extracted with ethyl acetate (50 mL. Times.3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. Separation by silica gel column chromatography (petroleum ether/ethyl acetate=3:1) gives compounds 19-12.

¹ H NMR(400MHz,CDCl ₃ )δ＝6.87-7.01(m,2H),6.84(d,J＝2.1Hz,1H),6.63-6.75(m,2H),5.38(t,J＝3.1Hz,1H),4.35(br d,J＝6.9Hz,1H),3.86-3.97(m,1H),3.56-3.66(m,1H),3.23-3.35(m,1H),3.01-3.16(m,1H),2.80-2.92(m,1H),2.46-2.65(m,2H),1.95-2.03(m,1H),1.86(dt,J＝7.4,3.7Hz,2H),1.56-1.76(m,3H),1.18-1.24ppm(m,6H).

Step 12:19-13 synthesis

To N, N-dimethylformamide (2 mL) of Compound 19-12 (0.4 g, 927.30. Mu. Mol) was added cesium carbonate (453.20 mg,1.39 mmol), diethyl tosyloxymethylphosphonate (298.88 mg, 927.30. Mu. Mol, 239.10. Mu.L), and the mixture was reacted at 50℃for 3 hours. The reaction solution was poured into a saturated sodium chloride solution, 50mL of ethyl acetate was added to separate the solution, the aqueous phase was extracted with ethyl acetate (50 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. Separation by silica gel column chromatography (petroleum ether/ethyl acetate=1:1) gives compounds 19-13.

Step 13:19-14 synthesis

To methanol (1 mL) of compound 19-13 (0.35 g, 601.92. Mu. Mol) was added pyridine p-toluenesulfonate (15.13 mg, 60.19. Mu. Mol), and the mixture was reacted at 50℃for 5 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. Separation by silica gel column chromatography (petroleum ether/ethyl acetate=1:1) gives compounds 19-14.

Step 14:19-15 and 19-16

Compounds 19-14 (0.13 g,0.29 mmol) were isolated by SFC. SFC (column: DAICEL CHIRALPAK AD-3, (250 mm. Times.30 mm,10 μm), mobile phase: [0.1% NH ] ₃ H ₂ O-IPA]40% -40%,8 min) to obtain the compounds 19-15 and 19-16. The analysis method comprises the steps of (a) measuring Thar analytical SFC by an instrument, (a) measuring Chiralpak AD-3 by 50mm, measuring 4.6mm, and measuring 3 mu m by a mobile phase (A) and (CO) ₂ And B: IPA (0.05% DEA), gradient: B: A=5% -50%, 3min, flow rate: 3.4mL/min, column temperature: 35 ℃, wavelength: 220nm, column pressure: 1800psi. Retention time of compounds 19-15: 1.206And (3) minutes. Retention time of compounds 19-16: 1.332 minutes.

Step 15:19 synthesis

To dichloromethane (2 mL) of compounds 19-15 (20 mg, 40.21. Mu. Mol) was added trimethylbromosilane (61.56 mg, 402.12. Mu. Mol, 52.17. Mu.L) at 0deg.C, and the mixture was reacted at 20deg.C for 12 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. Separation was performed by pre-HPLC (column type: phenomenex luna C, 18, 80, 40mm, 3 μm; mobile phase: water (0.04% HCl) -acetonitrile; gradient: B (acetonitrile): 35% -55%,7 min). Compound 19 was obtained.

¹ H NMR(400MHz,CD ₃ OD)δ＝6.97(br d,J＝15.6Hz,2H),6.78(d,J＝1.6Hz,1H),6.47-6.62(m,2H),4.29(dd,J＝8.7,2.2Hz,1H),4.20(d,J＝10.4Hz,2H),3.14-3.24(m,1H),3.07(dt,J＝16.7,8.3Hz,1H),2.81-2.95(m,1H),2.45-2.60(m,1H),1.88-2.03(m,1H),1.12ppm(t,J＝6.5Hz,6H).

Step 16:20 synthesis

To dichloromethane (2 mL) of compounds 19-16 (20 mg, 40.21. Mu. Mol) was added trimethylbromosilane (61.56 mg, 402.12. Mu. Mol, 52.17. Mu.L) at 0deg.C, and the mixture was reacted at 20deg.C for 12 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. Separation was performed by pre-HPLC (column type: phenomenex luna C, 18, 80, 40mm, 3 μm; mobile phase: water (0.04% HCl) -acetonitrile; gradient: B (acetonitrile): 38% -56%,7 min). Compound 20 was obtained.

¹ H NMR(400MHz,CD ₃ OD)δ＝6.99(br d,J＝15.8Hz,2H),6.81(d,J＝2.0Hz,1H),6.51-6.65(m,2H),4.31(dd,J＝8.8,2.4Hz,1H),4.23(d,J＝10.5Hz,2H),3.22(dt,J＝13.9,7.0Hz,1H),3.02-3.15(m,1H),2.84-2.97(m,1H),2.56(dq,J＝12.7,9.0Hz,1H),1.91-2.08(m,1H),1.15ppm(dd,J＝6.8,6.1Hz,6H).

Examples 21 and 22

The synthetic route is as follows:

step 1: synthesis of Compound 21-2

21-1 (5 g,15.89 mmol) was dissolved in acetonitrile (50 mL), benzyl bromide (2.72 g,15.89 mmol) was added, cesium carbonate (7.77 g,23.84 mmol) was reacted at 15℃for 12 hours, ethyl acetate (100 mL), water (100 mL), extracted, the organic phase was collected, the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate concentrated under reduced pressure, and the crude product was separated by column chromatography (petroleum ether: ethyl acetate=5:1) to give compound 21-2.

¹ H NMR(400MHz,CDCl ₃ )δ＝7.94(d,J＝2.3Hz,1H),7.54-7.32(m,6H),6.72(d,J＝8.8Hz,1H),5.12(s,2H)

Step 2: synthesis of Compound 21-3

Compound 21-2 (6.18 g,15.89 mmol), cyclobutanone (1.67 g,23.83 mmol) was dissolved in tetrahydrofuran (60 mL), n-butyllithium (2.5M, 7.63 mL) was slowly added dropwise at-68℃and stirred for 0.5 h, transferred to 30℃and stirred for 2.5 h, and saturated ammonium chloride (20 mL) was added to quench the reaction. Ethyl acetate (100 mL), water (50 mL), extracts, collects the organic phase, dries the organic phase over anhydrous sodium sulfate, filters, and the filtrate is concentrated under reduced pressure. Compound 21-3 is obtained.

¹ H NMR(400MHz,CDCl ₃ )δ＝7.47-7.32(m,7H),6.86(d,J＝8.7Hz,1H),5.11(s,2H),3.48(br s,1H),2.62-2.47(m,2H),2.41-2.28(m,2H),1.72-1.57(m,2H)。

Step 3: synthesis of Compound 21-4

Compound 21-3 (3 g,9.00 mmol) was dissolved in dichloromethane (30 mL) and trifluoroacetic acid (1.54 g,13.50 mmol) was added at 0deg.C, triethylsilane (3.14 g,27.01 mmol) and the reaction was carried out at 15deg.C for 12 hours. Concentrated under reduced pressure, and the crude product was isolated by column chromatography (petroleum ether: ethyl acetate=5:1) to give compound 21-4.

¹ H NMR(400MHz,CDCl ₃ )δ＝7.33-7.19(m,6H),7.17-7.10(m,1H),6.63(d,J＝8.7Hz,1H),4.92(s,2H),3.66(quin,J＝8.8Hz,1H),2.28-2.18(m,2H),2.07-1.84(m,3H),1.77-1.66(m,1H)。

Step 4: synthesis of Compound 21-5

Compound 21-4 (2.2 g,6.94 mmol) was dissolved in tetrahydrofuran (30 mL), nitrogen was displaced 3 times, n-butyllithium (2.5M, 3.33 mL) was slowly added dropwise at-68℃and the reaction was carried out at-68℃for 0.5 hours. BB-1 (1.92 g,6.94 mmol) was added at-68℃and the reaction was carried out at 15℃for 1 hour. To the reaction mixture was added a saturated aqueous ammonium chloride solution (10 mL) to quench the reaction. Ethyl acetate (100 mL), water (100 mL), extraction, collection of the organic phase, drying of the organic phase over anhydrous sodium sulfate, filtration, and concentration of the filtrate under reduced pressure, gave compound 21-5.

Step 5: synthesis of Compound 21-6

Compound 21-5 (3.57 g,2.98 mmol) was dissolved in dichloromethane (20 mL), triethylsilane (1.04 g,8.95 mmol) was added, and the reaction was carried out at 15℃for 12 hours with the addition of trifluoroacetic acid (510.04 mg,4.47 mmol) at 0 ℃. Concentrating under reduced pressure to obtain compound 21-6.

Step 6: synthesis of Compound 21-7

Compound 21-6 (1.21 g,2.43 mmol) was dissolved in a mixed solvent of methanol (15 mL) and tetrahydrofuran (15 mL), and ammonium fluoride (899.25 mg,24.28 mmol) was added thereto, and the reaction was carried out at 15℃for 12 hours. Ethyl acetate (100 mL), water (100 mL), extraction, collection of an organic phase, washing of the organic phase with supersaturated saline (100 mL. Times.3), drying of the organic phase over anhydrous sodium sulfate, filtration, concentration of the filtrate under reduced pressure, and separation of the crude product by column chromatography (petroleum ether: ethyl acetate 5:1) to give compound 21-7.

¹ H NMR(400MHz,CDCl ₃ )δ＝7.49-7.29(m,5H),6.98(s,1H),6.78-6.68(m,2H),6.63(br s,1H),6.47(s,1H),5.01(s,2H),4.54(s,1H),4.31(br dd,J＝3.2,8.4Hz,1H),3.78(quin,J＝8.7Hz,1H),3.10-2.93(m,1H),2.89-2.73(m,1H),2.58(qd,J＝8.7,12.5Hz,1H),2.30(q,J＝8.2Hz,2H),2.17-1.96(m,4H),1.94(s,3H),1.85-1.74(m,1H)。

Step 7: synthesis of Compound 21-8

Compound 21-7 (800 mg,2.08 mmol) was dissolved in dimethylformamide (10 mL), cesium carbonate (1.02 g,3.12 mmol) was added, and the reaction was carried out for 2 hours at 50℃with diethyl tosyloxymethylphosphonate (670.41 mg,2.08 mmol). Ethyl acetate (100 mL), water (100 mL), extraction, collection of organic phase, supersaturation of organic phaseThe organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product. The crude product was separated by column chromatography (petroleum ether: ethyl acetate 1:1) to give compound 21-8.[ M+1 ] ] ⁺ ＝535.2

Step 8: synthesis of Compound 21-9

Compound 21-8 (0.9 g,1.68 mmol) was dissolved in methanol (5 mL), wet palladium on carbon (0.05 g palladium content: 5%) was added, hydrogen was introduced and the reaction was performed 3 times at 15psi 15℃for 2 hours. Filtering, and concentrating the filtrate under reduced pressure to obtain compound 21-9.

[M-17] ⁺ ＝445.3

Step 9: synthesis of Compounds 21-10, 21-11

SFC resolution of Compound 21-9 (0.7 g,1.57 mmol). SFC (column type: DAICEL CHIRALPAK AD (250 mm. Times.50 mm. Times.10 μm), mobile phase: [ Neu-IPA ]]40% -40%,8 min). The compound 21-10, 21-11 was obtained. The analysis method comprises the following steps: column-type ChiralpakAD-3, 50X 4.6mm, I.D.,3 μm. Mobile phase A and CO ₂ IPA (0.05% DEA). Gradient from 5% to 50% in 1.2 minutes for phase B, decreasing to 5% in 0.8 minutes for 1 minute, flow rate 3.4mL/min. Column temperature 35 ℃. ABPR 1800psi. Retention time of compound 21-10: 1.271min. Retention time of compounds 21-11: 1.416min.

Step 10: synthesis of Compound 21

Compounds 21-10 (130 mg, 292.46. Mu. Mol) were dissolved in dichloromethane (5 mL) and trimethylbromosilane (223.87 mg,1.46 mmol) was added at 0deg.C and the reaction was carried out at 30deg.C for 12 hours. Concentrating under reduced pressure, ethyl acetate (10 mL), water (10 mL), extracting, collecting an organic phase, washing the organic phase with half-saturated saline (10 mL. Times.3), drying the organic phase with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, and obtaining a crude product. By prep-HPLC (column: phenomenex luna C, 80X 40mm X3 μm; mobile phase: [ H) ₂ O(0.04％HCl)-ACN]The method comprises the steps of carrying out a first treatment on the surface of the B (ACN)% > 32% -62%,7 min). Compound 21 was obtained.

¹ H NMR(400MHz,CD ₃ OD)δ＝6.80(br d,J＝17.8Hz,2H),6.63-6.54(m,3H),4.26(dd,J＝3.6,8.6Hz,1H),4.19(d,J＝10.5Hz,2H),3.75-3.60(m,1H),3.01(td,J＝8.2,16.0Hz,1H),2.86-2.76(m,1H),2.54(qd,J＝8.6,12.5Hz,1H),2.31-2.19(m,2H),2.08-1.92(m,4H),1.91(s,3H),1.82-1.72(m,1H)。

Step 11: synthesis of Compound 22

Compounds 21-11 (240 mg, 539.93. Mu. Mol) were dissolved in dichloromethane (5 mL) and trimethylbromosilane (413.29 mg,2.70 mmol) was added at 0deg.C and the reaction was carried out at 30deg.C for 12 hours. Concentrating under reduced pressure to obtain crude product.

Ethyl acetate (10 mL), water (10 mL), extraction, collection of organic phase, washing of the organic phase with supersaturated saline (10 ml×3), drying of the organic phase over anhydrous sodium sulfate, filtration, concentration of the filtrate under reduced pressure, and obtaining crude product. By prep-HPLC (column: phenomenex luna C, 80X 40mm X3 μm; mobile phase: [ H) ₂ O(0.04％HCl)-ACN]The method comprises the steps of carrying out a first treatment on the surface of the B (ACN)% > 35% -62%,7 min) to give compound 22.

¹ H NMR(400MHz,CD ₃ OD)δ＝6.82(br d,J＝17.9Hz,2H),6.69-6.53(m,3H),4.28(dd,J＝3.6,8.7Hz,1H),4.21(d,J＝10.4Hz,2H),3.75-3.61(m,1H),3.03(td,J＝8.2,16.0Hz,1H),2.90-2.77(m,1H),2.55(qd,J＝8.6,12.5Hz,1H),2.35-2.21(m,2H),2.10-1.94(m,4H),1.93(s,3H),1.83-1.75(m,1H)。

Examples 23 and 24

The synthetic route is as follows:

step 1: synthesis of Compound 23-1

Compound 23-1 (5 g,24.49 mmol) was added to pyridine (50 mL), malonic acid (3.82 g,36.74mmol,3.82 mL) and piperidine (417.09 mg,4.90mmol, 483.75. Mu.L) were added and the reaction was stirred at 90℃for 16 hours. After the reaction, 4M hydrochloric acid was added to the reaction mixture to adjust the pH to about 4, about 50mL of ethyl acetate was added, the mixture was separated, the aqueous phase was extracted once with 50mL of ethyl acetate, the ethyl acetate was combined, the organic phase was washed once with saturated sodium chloride (50 mL), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Compound 23-2 is obtained.

¹ H NMR(400MHz,CDCl ₃ )δ＝7.78-7.71(m,1H),7.38-7.36(m,1H),7.22-7.19(m,1H),7.17-7.13(m,1H),6.49(d,J＝16.0Hz,1H),3.90-3.86(m,3H)。

Step 2: synthesis of Compound 23-3

Compound 23-2 (6 g,24.37 mmol) was added to tetrahydrofuran (50 mL), palladium on carbon (1 g,24.37mmol, palladium content 5%) was added, and H was vented ₂ The reaction was stirred at 25℃for 18 hours. After the completion of the reaction, the reaction solution was filtered through celite, washed 3 times with tetrahydrofuran, and the filtrate was collected and concentrated under reduced pressure. Compound 23-3 is obtained.

¹ H NMR(400MHz,CDCl ₃ )δ＝7.09-7.05(m,1H),7.00-6.97(m,1H),6.95-6.93(m,1H),3.86-3.83(m,3H),2.99(t,J＝7.7Hz,2H),2.75-2.68(m,2H)。

Step 3: synthesis of Compound 23-4

Compound 23-3 (3 g,12.09 mmol) was added to polyphosphoric acid (10 g), heated to 90℃and stirred for 16 hours. After the reaction, saturated sodium bicarbonate was added to the reaction solution to adjust the pH to about 8, ethyl acetate (20 mL) was added, extraction was performed, the organic phase was collected, washed once with saturated sodium chloride (20 mL), then dried over anhydrous sodium sulfate, filtered, the filtrate was added with about 15mL of chromatography silica gel, the mixture was dried, and the crude product was purified by chromatography (petroleum ether: ethyl acetate=90%: 10% to petroleum ether: ethyl acetate=80%: 20%) to give compound 23-4.

¹ H NMR(400MHz,CDCl ₃ )δ＝7.22-7.20(m,1H),7.06-7.03(m,1H),3.94(s,3H),3.17-3.11(m,2H),2.77-2.72(m,2H)。

Step 4: synthesis of Compound 23-5

Compound 23-4 (8.5 g,36.93 mmol) was added to hydrobromic acid (70 mL, 48% strength) and the reaction was stirred at 130 ℃ under reflux for 16 hours. After the reaction, saturated sodium hydrogencarbonate was added to the reaction mixture to adjust the pH to neutral, ethyl acetate (50 mL) was added, stirred, the mixture was separated, the aqueous phase was extracted once with ethyl acetate (50 mL), ethyl acetate was combined, washed once with saturated sodium chloride (50 mL), the separated solution was collected, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. After concentration, the mixture was slurried at room temperature (petroleum ether: ethyl acetate=10:1, total 20 mL) to give compound 23-5.

¹ H NMR(400MHz,CDCl ₃ )δ＝7.18-7.15(m,1H),7.07-7.02(m,1H),3.17-3.09(m,2H),2.78-2.73(m,2H)。

Step 5: synthesis of Compound 23-6

Compound 23-5 (3 g,13.88 mmol) was added to dichloromethane (30 mL), 4-dimethylaminopyridine (2.97 g,24.29 mmol) was added, tert-butyldimethylchlorosilane (3.14 g,20.82mmol,2.55 mL) was added and the reaction stirred at 25℃for 16 h. After the reaction was completed, the methylene chloride solution was concentrated under reduced pressure, saturated ammonium chloride (20 mL) and ethyl acetate (20 mL) were added, stirring was performed, the mixture was separated, saturated ammonium chloride was extracted once with ethyl acetate (10 mL), the separated liquid was combined with the organic phase, the organic phase was washed once with saturated sodium chloride (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was added to about 15mL of silica gel, stirred and dried, and purified by column chromatography (petroleum ether: ethyl acetate=90%: 10% to petroleum ether: ethyl acetate=70%: 30%) to give compound 23-6.

¹ H NMR(400MHz,CDCl ₃ )δ＝7.18-7.11(m,2H),7.11-7.06(m,1H),6.98(dt,J＝1.7,7.7Hz,1H),6.81-6.72(m,3H),6.70-6.66(m,1H),6.64-6.58(m,1H),2.60-2.48(m,2H),2.44-2.30(m,1H),1.12-1.04(m,11H),0.99(t,J＝6.4Hz,6H),0.88-0.81(m,9H)。

Step 6: synthesis of Compound 23-7

Cooling to-68 ℃, adding 1-8 (3.81 g,12.48 mmol) of compound to tetrahydrofuran (30 mL), slowly adding n-butyllithium (2.5M, 5.99 mL), reacting for 0.5 hours, adding 23-6 (3.3 g,9.99 mmol) of compound, slowly heating to 25 ℃ and stirring for 3 hours. After the reaction, the reaction mixture was slowly added to saturated ammonium chloride (20 mL), stirred, ethyl acetate (10 mL) was added, the mixture was separated, the organic phase was collected, washed with saturated sodium chloride (10 mL), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, the filtrate was added to about 20mL of silica gel chromatography, the mixture was dried, and the column was purified (petroleum ether: ethyl acetate =90%: 10%), giving compound 23-7.[ M-17 ]] ⁺ ＝539.3

Step 7: synthesis of Compound 23-8

Cooling to 0deg.C, compound 23-7 (5 g,8.98 mmol) was added to dichloromethane (50 mL), triethylsilane (3.13 g,26.94mmol,4.30 mL) was added, trifluoroacetic acid (1.54 g,13.47mmol, 997.44. Mu.L) was added, and the temperature was slowly raised to 25deg.C and stirring was continued for 16 hours. After the completion of the reaction, the mixture was concentrated under reduced pressure to remove the dichloromethane solution, ethyl acetate (20 mL) and saturated sodium hydrogencarbonate (20 mL) were added, stirred, separated, ethyl acetate was washed with saturated sodium chloride (20 mL), the separated solution was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Compound 23-8 is obtained. [ M-1 ]] ⁺ ＝539.3

Step 8: synthesis of Compound 23-9

Compound 23-8 (3.92 g,7.25 mmol) was added to tetrahydrofuran (40 mL), cooled to 0deg.C, tetrabutylammonium fluoride (1M, 7.25mmol,7.25 mL) was added and the reaction was gradually warmed to 20deg.C and stirred for 2 hours. After the reaction was completed, a saturated ammonium chloride solution (20 mL) was added to the reaction solution, extraction was performed with ethyl acetate (30 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was added with about 15mL of silica gel, dried with stirring, and purified with a column chromatography (petroleum ether: ethyl acetate=90%: 10%), to obtain compound 23-9.

¹ H NMR(400MHz,CDCl ₃ )δ＝7.46-7.29(m,5H),7.47-7.27(m,2H),7.00-6.92(m,1H),6.84(d,J＝2.1Hz,1H),6.77-6.71(m,1H),6.59(dd,J＝2.2,8.3Hz,2H),5.03-5.00(m,1H),4.65-4.50(m,1H),4.19-4.07(m,1H),3.39-3.30(m,1H),3.09-2.96(m,1H),2.84-2.75(m,1H),2.06(s,3H),1.60-1.55(m,1H),1.31-1.24(m,3H)。

Step 9: synthesis of Compound 23-10

Compound 23-9 (1.7 g,3.99 mmol) was added to N, N-dimethylformamide (20 mL), cesium carbonate (1.95 g,5.98 mmol) was added, diethyl p-toluenesulfonyloxymethyl phosphonate (1.28 g,3.99mmol,1.03 mL) was added and the reaction stirred at 50℃for 16 hours. After the completion of the reaction, ethyl acetate (20 mL) was added to the reaction mixture, which was then extracted with half-saturated sodium chloride (20 mL. Times.4), the mixture was separated, the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was added with about 10mL of silica gel chromatography and dried with stirring. Purification by column chromatography (petroleum ether: ethyl acetate=90%: 10%) gives compound 23-10.

¹ H NMR(400MHz,CDCl ₃ )δ＝7.45-7.30(m,5H),7.15-7.10(m,1H),7.08-7.04(m,1H),6.86-6.83(m,1H),6.74(d,J＝8.4Hz,1H),6.59-6.53(m,1H),5.02(s,2H),4.36-4.23(m,6H),3.39-3.29(m,1H),3.13-3.01(m,1H),2.88-2.78(m,1H),2.63-2.51(m,1H),1.43-1.37(m,6H),1.27(t,J＝7.2Hz,2H),1.17(dd,J＝7.0,8.7Hz,6H)。

Step 10: synthesis of Compound 23-11

Compound 23-10 (2 g,3.47 mmol) was added to methanol (5 mL), palladium on carbon (1 g, 5% palladium) was added, hydrogen gas (3 times replaced with hydrogen gas) was introduced, and the reaction was stirred at 25℃for 2 hours. After the completion of the reaction, the reaction mixture was filtered through celite (palladium/carbon removal), and the filtrate was collected and concentrated under reduced pressure to give compound 23-11.

¹ H NMR(400MHz,CDCl ₃ )δ＝7.10(s,1H),7.07-7.04(m,1H),6.79(d,J＝1.9Hz,1H),6.61-6.56(m,1H),6.51-6.45(m,1H),4.36-4.22(m,6H),3.22-2.99(m,2H),2.88-2.77(m,1H),2.63-2.50(m,1H),1.39(t,J＝7.0Hz,6H),1.33(t,J＝7.0Hz,1H),1.27(t,J＝7.2Hz,2H),1.19(dd,J＝7.1,8.1Hz,6H)。

Step 11: synthesis of Compounds 23-12, 23-13

Compound 23-11 (1.4 g,2.88 mmol) was resolved by SFC. The separation method comprises the following steps: pillar DAICEL CHIRALPAK AD (250 mm. Times.30 mm. Times.10 μm); mobile phase [ Neu-IPA ]]30-30 percent for 6min to obtain the compounds 23-12 and 23-13. The analysis method comprises the following steps: column type ChiralpakAD-3, 50X 4.6mm, I.D.,3 μm, mobile phase A: CO ₂ IPA (0.05% DEA), gradient from 5% to 50% in 1.2 min for phase B, decrease to 5% in 0.8 min, flow rate 3.4mL/min, column temperature 35℃and ABPR 1800ps. Retention time of compound 23-12: 1.081min. Retention time of compound 23-13: 1.136min.

Step 12: synthesis of Compound 23

Compound 23-12 (0.5 g,1.031 mmol) was dissolved in dichloromethane (5 mL) and trimethylbromosilane (1.57 g,10.28 mmol) was added and the reaction stirred at 25℃for an additional 16 h. Concentrating the reaction solution under reduced pressureEthyl acetate (10 mL) was added, washed with water (10 mL. Times.2), the mixture was separated, and the ethyl acetate layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. prep-HPLC (column: welch Xtime C18.multidot.25 mm.multidot.5 μm; mobile phase: [ H) ₂ O(0.04％HCl)-ACN]The method comprises the steps of carrying out a first treatment on the surface of the ACN%:30% -60%,8 min). Compound 23 was obtained.

¹ H NMR(400MHz,CD ₃ OD)δ＝7.26-7.20(m,1H),7.12-7.06(m,1H),6.68-6.65(m,1H),6.58-6.54(m,1H),6.47-6.42(m,1H),4.56-4.48(m,1H),4.32-4.23(m,1H),4.36-4.18(m,2H),3.23-3.13(m,1H),3.07-2.96(m,1H),2.88-2.78(m,1H),2.58-2.46(m,1H),2.00(br dd,J＝7.8,11.5Hz,1H),1.14-1.05(m,6H)。

Step 13: synthesis of Compound 24

Compound 23-13 (0.48 g, 986.72. Mu. Mol) was dissolved in dichloromethane (5 mL) and trimethylbromosilane (1.51 g,9.87 mmol) was added and the reaction stirred at 25℃for an additional 16 h. The reaction mixture was concentrated under reduced pressure, washed with ethyl acetate (10 mL), water (10 mL. Times.2), separated, and the ethyl acetate layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. prep-HPLC (column: welch Xtime C18.multidot.25 mm.multidot.5 μm; mobile phase: [ H) ₂ O(0.04％HCl)-ACN]The method comprises the steps of carrying out a first treatment on the surface of the B (ACN)% > 30% -60% and 8 min). Compound 24 was obtained.

¹ H NMR(400MHz,CD ₃ OD)δ＝7.31-7.16(m,1H),7.09(br s,1H),6.70-6.62(m,1H),6.56(br d,J＝7.9Hz,1H),6.48-6.38(m,1H),4.57-4.47(m,1H),4.44-4.10(m,2H),3.22-3.15(m,1H),3.08-2.92(m,1H),2.87-2.76(m,1H),2.60-2.44(m,1H),2.04-1.89(m,1H),1.15-1.05(m,6H)。

Examples 25 and 26

The synthetic route is as follows:

step 1:25-2 Synthesis

To a dry and clean three-necked flask, 25-1 (1.6 g,5.28 mmol) and tetrahydrofuran (60 mL) were added, stirring was started, the temperature was controlled to-70℃and n-butyllithium (2.5M, 2.53 mL) was slowly added dropwise thereto for 30 minutes, the temperature was controlled to-70℃and BB-1 (1.46 g,5.28 mmol) was added thereto, and the reaction was continued for 2 hours. Under the protection of nitrogen, saturated ammonium chloride solution (100 mL) is slowly added dropwise, ethyl acetate (100 mL) is added for extraction, and the organic phase anhydrous sodium sulfate is obtained for drying, and then the compound 25-2 is obtained through spin drying.

¹ H NMR(400MHz,CDCl ₃ )δ＝7.52(d,J＝7.3Hz,2H),7.41(br d,J＝8.1Hz,2H),7.35(br d,J＝3.8Hz,1H),7.10(dd,J＝2.1,8.2Hz,1H),6.92(d,J＝8.3Hz,1H),6.84-6.83(m,1H),6.52(d,J＝1.6Hz,1H),6.19-6.14(m,1H),5.16(s,2H),3.03-2.91(m,1H),2.84-2.70(m,1H),2.43-2.38(m,1H),2.35-2.29(m,1H),2.27-2.17(m,1H),1.96(s,3H),1.01(s,15H),0.96-0.93(m,2H),0.70-0.67(m,2H)。

Step 2:25-3 Synthesis

To a dry, clean 50mL single-necked flask was added 25-2 (1 g,2.00 mmol) and methylene chloride (10 mL), and stirring was turned on; trifluoroacetic acid (683.11 mg,5.99mmol, 443.58. Mu.L) was added followed by triethylsilane (696.65 mg,5.99mmol, 956.93. Mu.L) and reacted at 20℃for 2 hours. Saturated sodium carbonate solution (80 mL) was added and stirred for 10min, followed by extraction with dichloromethane (40 mL) to give an organic phase, drying over anhydrous sodium sulfate and spin-drying to give compound 25-3.[ M+1 ]] ⁺ ＝485.4

Step 3:25-4 Synthesis

To a dry clean thumb flask was added 25-3 (0.9 g,1.86 mmol), followed by methanol (15 mL) and tetrahydrofuran (15 mL), and stirring was turned on; ammonium fluoride (687.71 mg,18.57 mmol) was added and reacted at 50℃for 2h. The reaction system was spin-dried to give crude product, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate=1:0 to petroleum ether: ethyl acetate=10:1) to give compound 25-4.

¹ H NMR(400MHz,CDCl ₃ )δ＝7.47(d,J＝7.5Hz,2H),7.41-7.37(m,2H),7.35-7.31(m,1H),6.79-6.75(m,1H),6.72-6.67(m,1H),6.61(d,J＝2.0Hz,1H),6.59(d,J＝2.2Hz,1H),6.45(d,J＝1.8Hz,1H),5.07(s,2H),4.24(dd,J＝3.6,8.7Hz,1H),2.98(td,J＝8.2,16.1Hz,1H),2.86-2.72(m,1H),2.54(qd,J＝8.7,12.6Hz,1H),2.29-2.16(m,1H),1.96(ddd,J＝4.2,8.3,12.5Hz,1H),1.90(s,3H),0.99-0.91(m,2H),0.64-0.57(m,2H)。

Step 4:25-5 Synthesis

To a thumb flask were added 25-4 (650 mg,1.75 mmol) and N, N-dimethylformamide (8 mL), and stirring was turned on; cesium carbonate (1.14 g,3.51 mmol) was added followed by diethyl p-toluenesulfonyloxymethylphosphonate (537.21 mg,1.67mmol, 429.77. Mu.L) and reacted for 3h at 50 ℃. Ethyl acetate (50 mL) was added, followed by extraction with water (50 mL) and saturated brine (50 mL) in this order, the organic phase was separated, dried over anhydrous sodium sulfate, and spin-dried to give a crude product, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate=1:0 to petroleum ether: ethyl acetate=10:1) to give compound 25-5.[ M+1 ]] ⁺ ＝521.2

Step 5:25-6 Synthesis

To the thumb flask was added 25-5 (800 mg,1.54 mmol) and ethyl acetate (4 mL), and stirring was turned on; pd/C (0.2 g, 5% palladium) was then added and reacted for 1 hour at 20℃under a hydrogen balloon atmosphere of 15 psi. Filtration through a 5-well funnel of 2g celite and washing twice with ethyl acetate (25 mL x 2) gave the crude filtrate which was spin-dried and purified by silica gel column chromatography (petroleum ether: ethyl acetate=10:1 to petroleum ether: ethyl acetate=1:1) to give compound 25-6.[ M+1 ]] ⁺ ＝431.3

Step 6: resolution to 25-7 and 25-8

The step is 25-6 resolution, chiral separation: column type: DAICEL CHIRALPAKAD (250 mm. Times.30 mm. Times.10 μm); mobile phase [0.1% NH ] ₃ .H ₂ O-IPA]The method comprises the steps of carrying out a first treatment on the surface of the IPA accounts for 40% -40%, and 25-7 and 25-8 are obtained after 8 min. The analysis method comprises the following steps: pillar DAICEL CHIRALPAKAD, 50X 4.6mm, I.D.,3 μm. Mobile phase A and CO ₂ IPA (0.05% DEA). Gradient from 5% to 50% in 1.2 minutes for phase B, decreasing to 5% in 0.8 minutes for 1 minute, flow rate 3.4mL/min. Column temperature 35 ℃. Column pressure 1800psi. Retention time of compound 25-7: 1.232min. Retention time of compound 25-8: 1.350min.

25-7： ¹ H NMR(400MHz,DMSO-d ₆ )δ＝9.06(s,1H),6.85-6.73(m,1H),6.66-6.55(m,2H),6.49(dd,J＝2.0,8.1Hz,1H),6.43(d,J＝1.8Hz,1H),4.36(d,J＝9.8Hz,2H),4.17(dd,J＝3.6,8.6Hz,1H),4.11(quin,J＝7.3Hz,4H),2.99-2.86(m,1H),2.81-2.69(m,1H),2.47-2.38(m,1H),2.06-1.92(m,1H),1.86-1.75(m,4H),1.25(t,J＝7.1Hz,6H),0.87-0.74(m,2H),0.53-0.38(m,2H)。

³¹ P NMR(400MHz,DMSO-d ₆ )δppm20.010。

25-8： ¹ H NMR(400MHz,DMSO-d ₆ )δ＝9.06(s,1H),6.84-6.74(m,1H),6.64-6.57(m,2H),6.49(dd,J＝2.0,8.1Hz,1H),6.44(d,J＝1.6Hz,1H),4.36(d,J＝9.8Hz,2H),4.17(dd,J＝3.6,8.6Hz,1H),4.15-4.07(m,4H),3.34(s,4H),2.93(td,J＝8.1,16.1Hz,1H),2.80-2.70(m,1H),2.48-2.38(m,1H),2.11-1.93(m,1H),1.83(s,3H),1.26(t,J＝7.0Hz,6H),0.91-0.73(m,2H),0.56-0.39(m,2H)。

³¹ P NMR(400MHz,DMSO-d ₆ )δppm20.010。

Step 7:25 synthesis

To the thumb flask was added 25-7 (80.00 mg, 185.84. Mu. Mol) and dichloromethane (1 mL) and stirring was turned on; cooled to 0 ℃, trimethylbromosilane (284.51 mg,1.86mmol,241.11 μl) was added, and the temperature was slowly raised to 20 ℃ for 16h. Dichloromethane (20 mL) and water (20 mL) are added into the reaction system for extraction, an organic phase is obtained, anhydrous sodium sulfate is dried, a crude product is obtained by spin drying, and prep-HPLC (column: xtime C18 x 30mm x 3 μm; mobile phase: [ H) ₂ O(0.2％FA)-ACN]The method comprises the steps of carrying out a first treatment on the surface of the B (ACN)% > 23% -53%,9 min) to obtain compound 25.

¹ H NMR(400MHz,DMSO-d ₆ )δ＝9.05(br s,1H),6.74(s,1H),6.61(d,J＝8.2Hz,1H),6.56(s,1H),6.49(dd,J＝1.9,8.2Hz,1H),6.44(d,J＝1.9Hz,1H),4.16(br dd,J＝3.6,8.6Hz,1H),4.03(d,J＝10.2Hz,2H),2.96-2.87(m,1H),2.80-2.71(m,1H),2.46-2.39(m,1H),2.05-1.95(m,1H),1.85-1.76(m,4H),0.80(d,J＝8.4Hz,2H),0.47(br dd,J＝5.7,7.5Hz,2H).

³¹ P NMR(400MHz,DMSO-d ₆ )δppm 15.007.

Step 8:26 synthesis

To the thumb flask was added 25-8 (60 mg, 139.38. Mu. Mol) and dichloromethane (1 mL) and stirring was turned on; cooling to 0 ℃, and adding trimethyl bromosilane (213).38mg,1.39mmol, 180.83. Mu.L), slowly warmed to 20℃and reacted for 16h. Dichloromethane (20 mL) and saturated brine (20 mL) were added to the reaction system, and the organic phase was obtained by extraction, dried over anhydrous sodium sulfate and spun-dried to obtain a crude product. prep-HPLC column: phenomnex Luna80mm 30mm 3 μm; mobile phase [ H ] ₂ O(0.04％HCl)-ACN]The method comprises the steps of carrying out a first treatment on the surface of the B (ACN)% > 30% -60%, purifying for 7min to obtain compound 26.

¹ H NMR(400MHz,DMSO-d ₆ )δ＝9.04(s,1H),6.74(s,1H),6.62(d,J＝8.1Hz,1H),6.56(s,1H),6.49(br d,J＝8.3Hz,1H),6.44(s,1H),4.16(br dd,J＝3.5,8.5Hz,1H),4.03(d,J＝10.1Hz,2H),2.92(td,J＝8.2,16.2Hz,1H),2.80-2.69(m,1H),2.47-2.37(m,1H),2.06-1.95(m,1H),1.88-1.71(m,4H),0.80(br d,J＝8.4Hz,2H),0.47(br t,J＝6.3Hz,2H).

³¹ P NMR(400MHz,DMSO-d ₆ )δppm 15.010.

Examples 27 and 28

The synthetic route is as follows:

step 1: synthesis of Compound 27-2

To a mixture of dioxane (120 mL) and water (12 mL) was added compound 27-1 (12.5 g,41.82 mmol), pinacol isopropenylborate (8.43 g,50.18 mmol) was added, potassium carbonate (8.67 g,62.73 mmol) was added, and finally [1, 1-bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane (1.71 g,2.09 mmol) was added, nitrogen substitution was performed 3 times, an oxygen-free environment was ensured, and the temperature was slowly raised to 60℃and stirred for 3hr. After the reaction was completed, the reaction mixture was distilled off under reduced pressure (dioxane solvent was removed), ethyl acetate (50 mL) and water (50 mL) were added, stirred, separated, and the organic phase was collected, washed with saturated sodium chloride (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Column purification (petroleum ether to petroleum ether: ethyl acetate=95%: 5%). Compound 27-2 was obtained.

¹ H NMR(400MHz,CDCl ₃ )δ＝7.29-7.23(m,2H),6.84-6.80(m,1H),5.45-5.41(m,1H),5.17-5.14(m,1H),2.11-2.09(m,3H)

Step 2: synthesis of Compound 27-3

Compound 27-2 (8.85 g,41.54 mmol) was added to acetonitrile (85 mL), benzyl bromide (5.68 g,33.23 mmol) was added, cesium carbonate (27.07 g,83.07 mmol) was added, and stirred at 25℃for 16hr. After the completion of the reaction, water (20 mL) and ethyl acetate (20 mL) were added to the reaction mixture, the mixture was stirred, the organic phase was collected, washed with saturated sodium chloride (20 mL), the mixture was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Purification by column chromatography (petroleum ether=100%) afforded compound 27-3.

¹ H NMR(400MHz,CDCl ₃ )δ＝7.39-7.34(m,4H),7.33-7.30(m,2H),7.28-7.23(m,1H),6.76-6.75(m,1H),6.79-6.75(m,1H),5.17-5.14(m,1H),5.10-5.08(m,1H),5.06(s,2H),2.12-2.09(m,3H)。

Step 3: synthesis of Compound 27-4

Cooling to-40 ℃, adding diethyl zinc toluene solution (1M, 131.93 mL) to dichloromethane (40 mL), slowly adding diiodomethane (35.34 g,131.93 mmol), stirring at-40 ℃ for 0.5h, finally adding dichloromethane (40 mL) solution of compound 27-3 (4 g,13.19 mmol), slowly raising the temperature to 25 ℃ and continuing the reaction for 12h. After the completion of the reaction, the reaction solution was slowly added to stirred saturated ammonium chloride (30 mL), then dichloromethane (10 mL) was added, the solution was separated, the dichloromethane phase was collected, washed once with saturated sodium chloride (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Then, purification by chromatography (petroleum ether=100%) gave compound 27-4.

¹ H NMR(400MHz,CDCl ₃ )δ＝7.51-7.46(m,2H),7.45-7.38(m,3H),7.37-7.32(m,1H),7.28-7.24(m,1H),6.80-6.73(m,1H),5.13(s,2H),1.37-1.33(m,3H),0.81-0.75(m,2H),0.72-0.67(m,2H)。

Step 4: synthesis of Compound 27-5

Cooling to-68 ℃, adding compound 27-4 (3.5 g,11.03 mmol) to tetrahydrofuran (35 mL),n-butyllithium (2.5M, 4.85 mL) was slowly added, and after 0.5hr of reaction, a solution of compound BB-1 (3.66 g,13.24 mmol) in tetrahydrofuran (35 mL) was added, and the temperature was slowly raised to 25℃and stirred for 3hr. After the reaction, the reaction solution was slowly added to saturated ammonium chloride (30 mL), stirred, ethyl acetate (30 mL) was added, the solution was separated, the organic phase was collected, washed with saturated sodium chloride solution (20 ml×2), the solution was separated, the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Purification by column chromatography (petroleum ether to petroleum ether: ethyl acetate=90%: 10%) gives compound 27-5.[ M-17 ] ] ⁺ ＝497.3

Step 5: synthesis of Compound 27-6

Cooling to 0 ℃, compound 27-5 (4.25 g,8.26 mmol) was added to dichloromethane (40 mL), triethylsilane (2.88 g,24.77 mmol) and trifluoroacetic acid (1.41 g,12.38 mmol) were added, and the temperature was slowly raised to 25 ℃ and stirred for 16h. After the completion of the reaction, the mixture was concentrated under reduced pressure to remove methylene chloride, ethyl acetate (30 mL) was added, the mixture was washed with saturated sodium bicarbonate (30 mL), the organic phase was washed with saturated sodium chloride (30 mL), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Compound 27-6 was obtained. [ M+1 ]] ⁺ ＝499.4

Step 6: synthesis of Compound 27-7

Compound 27-6 (3.5 g,7.02 mmol) was added to tetrahydrofuran (30 mL), tetrabutylammonium fluoride (1M, 7.02 mL) was added and reacted at 20℃for 2h. After the completion of the reaction, the reaction mixture was quenched by adding water (50 mL), ethyl acetate (50 mL), stirring, separating the mixture, extracting the aqueous phase with ethyl acetate (50 mL. Times.3), mixing the organic phases, drying over anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (petroleum ether to petroleum ether: ethyl acetate=90%: 10%) to give compound 27-7.

Step 7: synthesis of Compound 27-8

Compound 27-7 (1.2 g,3.12 mmol) was added to N, N-dimethylformamide (10 mL), cesium carbonate (1.53 g,4.68 mmol) was added, diethyl p-toluenesulfonyloxymethyl phosphonate (1.01 g,3.12 mmol) was added and the reaction stirred at 50℃for 16hr. After the completion of the reaction, ethyl acetate (20 mL), saturated sodium chloride (20 ml×4) was added to the reaction solution, the solution was separated, the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the crude product was purified by chromatography (petroleum ether to petroleum ether: ethyl acetate=90%: 10%) to give compound 27-8.

¹ H NMR(400MHz,CDCl ₃ )δ＝7.50(d,J＝7.2Hz,2H),7.40(t,J＝7.5Hz,2H),7.34-7.29(m,1H),7.01(d,J＝1.5Hz,1H),6.76-6.71(m,3H),6.59(d,J＝1.8Hz,1H),5.09(s,2H),4.31-4.21(m,7H),3.03(td,J＝8.2,16.3Hz,1H),2.88-2.77(m,1H),2.61-2.52(m,1H),2.03-1.96(m,1H),1.92(s,3H),1.39(t,J＝7.1Hz,6H),1.33(s,3H),0.73(br d,J＝2.6Hz,2H),0.65-0.61(m,2H)。

Step 8: synthesis of Compound 27-9

Compound 27-8 (1.51 g,2.82 mmol) was added to methanol (15 mL), palladium on carbon (150 mg, palladium content: 5%) was added, and the mixture was reacted at 25℃for 2 hours under 15psi of hydrogen. After the reaction, palladium carbon is removed by filtration through celite, and the filtrate is collected and concentrated under reduced pressure to give compound 27-9.[ M+1 ]] ⁺ ＝445.2

Step 9: synthesis of Compounds 27-10 and 27-11

Compound 27-9 (0.7 g,1.57 mmol) was subjected to SFC resolution, resolution method: pillar DAICEL CHIRALPAK AD (250 mm. Times.30 mm,10 μm); mobile phase [ Neu-IPA ]]38-38%. Compound 27-10 and compound 27-11 were obtained. The analysis method comprises the following steps: column-type ChiralpakAD-3, 50X 4.6mm, I.D.,3 μm. Mobile phase A and CO ₂ IPA (0.05% DEA). Gradient from 5% to 50% in 1.2min, 50% maintained at 1min, and from 50% to 5% in 0.8 min. The flow rate was 3.4mL/min. Column temperature 35 ℃. ABPR 1800psi. Retention time of compound 27-10: 1.148min. Retention time of compound 27-11: 1.272min.

Step 10: synthesis of Compound 27

Cooled to 0 ℃, 27-10 (358.25 mg,922.39 μmol) was slowly added to dichloromethane (5 mL), trimethylbromosilane (1.41 g,9.22 mmol) was added, and the temperature was slowly raised to 25 ℃ and stirred for 16hr. After the completion of the reaction, ethyl acetate (15 mL) was added to the reaction mixture, followed by washing with half-saturated sodium chloride (10X 4 mL), separating the solution, drying the organic phase over anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure. The crude product is purified by machine separation, and the purification method comprises the following steps: column type Phenomenex Gemini-NX 150 x 30mm x 5 μm; mobile phase [ water (0.04% hcl) -ACN ]; ACN is 30% -60%,8min. Compound 27 was obtained.

¹ H NMR(400MHz,CD ₃ OD)δ＝6.82(d,J＝1.5Hz,1H),6.77-6.61(m,3H),6.59-6.53(m,1H),4.25-4.18(m,1H),4.02(d,J＝10.4Hz,2H),3.01-2.93(m,1H),2.83-2.74(m,1H),2.55-2.48(m,1H),1.95-1.84(m,6H),1.41-1.35(m,1H),1.26(s,3H),0.66-0.54(m,4H)。

Step 11: synthesis of Compound 28

Cooling to 0deg.C, compounds 27-11 (320 mg, 719.91. Mu. Mol) were slowly added to dichloromethane (5 mL), trimethylbromosilane (1.10 g,7.20 mmol) was added, and the temperature was slowly raised to 25deg.C and stirred for 16hr. After the completion of the reaction, ethyl acetate (15 mL) was added to the reaction mixture, followed by washing with half-saturated sodium chloride (10X 4 mL), separating the solution, drying the organic phase over anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure. The crude product is purified by machine separation, and the purification method comprises the following steps: column type Phenomenex Gemini-NX 150 x 30mm x 5 μm; mobile phase [ water (0.04% hcl) -ACN ]; ACN is 30% -60%,8min. Compound 28 was obtained.

Examples 29 and 30

The synthetic route is as follows:

step 1: synthesis of Compound 29-2

29-1 (1 g,3.61 mmol) and tetrahydrofuran (25 mL) are added into a dry and clean three-port bottle, stirring is started, the temperature is controlled to be-70 ℃, n-butyllithium (2.5M, 1.73 mL) is slowly added dropwise for reaction for 30min, the temperature is controlled to be-70 ℃, 11-1 (1.07 g,3.61 mmol) is added for continuous reaction for 2h, saturated ammonium chloride solution (100 mL) is slowly added dropwise under the protection of nitrogen, ethyl acetate (100 mL) is then added for extraction, an organic phase is obtained, anhydrous sodium sulfate is dried, the mixture is dried in a spinning manner, a crude product of a target compound is obtained, and the compound 29-2 is obtained through purification of silica gel column chromatography (petroleum ether: ethyl acetate=1:0-10:1).

¹ H NMR(400MHz,CDCl ₃ )δ＝7.11(d,J＝9.4Hz,1H),6.79(d,J＝13.2Hz,1H),6.69(d,J＝0.9Hz,2H),5.20-5.14(m,2H),3.50-3.48(m,3H),3.34-3.19(m,1H),3.10-2.96(m,1H),2.88-2.79(m,1H),2.73-2.59(m,1H),2.57-2.47(m,1H),1.01-0.99(m,9H),0.24-0.21(m,6H)。

F NMR(400MHz,CDCl ₃ )δppm-114.175。

Step 2: synthesis of Compound 29-3

To a dry clean thumb flask was added 29-2 (600 mg,1.21 mmol), followed by dichloromethane (3 mL) and trifluoroacetic acid (394.13 mg,3.46 mmol), stirring was turned on, triethylsilane (422.75 mg,3.64 mmol) was added, and the reaction was carried out at 20℃for 2h. Dichloromethane (100 mL), saturated sodium carbonate (50 mL) and water (100 mL) were added to the reaction system, and the organic phase was separated, dried over anhydrous sodium sulfate and spin-dried to give compound 29-3.

¹ H NMR(400MHz,CDCl ₃ )δ＝6.81(d,J＝12.0Hz,1H),6.69(d,J＝3.1Hz,2H),6.48(d,J＝8.9Hz,1H),5.21-5.13(m,2H),4.65(dd,J＝3.3,8.8Hz,1H),3.51-3.48(m,3H),3.17(quin,J＝6.9Hz,1H),3.07-2.95(m,1H),2.91-2.81(m,1H),2.57(qd,J＝8.8,12.9Hz,1H),2.02(br dd,J＝4.0,8.0Hz,1H),1.06(dd,J＝4.3,6.9Hz,6H),1.02-0.98(m,15H)

F NMR(400MHz,CDCl ₃ )δppm-119.936。

Step 3: synthesis of Compound 29-4

To a dry and clean thumb flask was added compound 29-3 (550 mg), followed by methanol (3 mL) and tetrahydrofuran (3 mL), stirring was turned on, ammonium fluoride (425.22 mg,11.48 mmol) was added, the reaction was carried out at 50 ℃ for 2 hours, the reaction system was spin-dried to obtain a crude product of the objective compound, and purification was carried out by silica gel column chromatography (petroleum ether: ethyl acetate=1:0 to 3:1) to obtain compound 29-4.

¹ H NMR(400MHz,CDCl ₃ )δ＝6.79(d,J＝12.1Hz,1H),6.70-6.65(m,2H),6.53-6.48(m,1H),5.14(d,J＝4.2Hz,2H),4.64-4.52(m,1H),3.47-3.46(m,3H),3.21-3.10(m,1H),3.06-2.96(m,1H),2.89-2.79(m,1H),2.60-2.50(m,1H),2.06-1.94(m,1H),1.07-1.03(m,6H)。

F NMR(400MHz,CDCl ₃ )δppm-119.927。

Step 4: synthesis of Compound 29-5

To a thumb flask were added compound 29-4 (360 mg, 986.74. Mu. Mol) and N, N-dimethylformamide (2.5 mL), stirring was turned on, cesium carbonate (643.00 mg,1.97 mmol) was added, followed by diethyl tosyloxymethylphosphonate (318.04 mg, 986.74. Mu. Mol), and the temperature was controlled at 50℃for 3h. Ethyl acetate (50 mL), water (50 mL) and saturated brine (50 mL) were added to the reaction system, the organic phase was separated, dried over anhydrous sodium sulfate, spin-dried and purified by silica gel column chromatography (petroleum ether: ethyl acetate=10:1-1:1) to give compound 29-5.

¹ H NMR(400MHz,CDCl ₃ )δ＝6.85-6.78(m,3H),6.53(d,J＝8.9Hz,1H),5.19-5.13(m,2H),4.64(dd,J＝3.6,9.0Hz,1H),4.31-4.23(m,6H),3.52-3.47(m,3H),3.24-3.13(m,1H),3.12-3.01(m,1H),2.90(ddd,J＝4.0,8.9,16.2Hz,1H),2.59(qd,J＝8.8,12.9Hz,1H),2.09-2.06(m,1H),1.39(t,J＝7.0Hz,6H),1.08(dd,J＝3.9,6.9Hz,6H)。

F NMR(400MHz,CDCl ₃ )δppm-119.831。

Step 5: synthesis of Compound 29-6

29-5 (230 mg, 446.65. Mu. Mol) and methanol (2 mL) were added to the thumb flask, stirring was turned on, hydrochloric acid (6M, 200.00. Mu.L) was then added, the temperature was raised to 50℃and the reaction was continued for 2 hours. Saturated sodium bicarbonate solution (50 mL) was added to the reaction system, stirred for 10min, followed by extraction twice with ethyl acetate (50 ml×2), the organic phase was separated, dried over anhydrous sodium sulfate, dried by spin, and purified by silica gel column chromatography (petroleum ether: ethyl acetate=10:1 to 1:1) to give compound 29-6.

¹ H NMR(400MHz,DMSO-d ₆ )δ＝9.57(s,1H),6.98(s,1H),6.92(d,J＝2.1Hz,1H),6.52(d,J＝12.0Hz,1H),6.45(d,J＝9.0Hz,1H),4.51-4.48(m,1H),4.16-4.06(m,4H),4.05-4.00(m,2H),3.10-2.96(m,2H),2.94-2.84(m,1H),2.60-2.52(m,1H),1.90(tdd,J＝4.1,8.3,12.5Hz,1H),1.25(t,J＝7.1Hz,6H),1.07-0.93(m,6H)。

F NMR(400MHz,DMSO-d ₆ )δppm-121.326。

³¹ P NMR(400MHz,DMSO-d ₆ )δppm 19.467。

Step 6: synthesis of Compounds 29-7 and 30-7

Compound 29-6 was isolated via chiral separation column form DAICEL CHIRALPAKAD (250 mm x 30mm,10 μm); mobile phase [0.1% NH ] ₃ H ₂ O IPA]35-35% and resolving for 8min to obtain compounds 29-7 and 30-7. The analysis method comprises the following steps: column-type ChiralpakAD-3, 50X 4.6mm, I.D.,3 μm. Mobile phase A and CO ₂ IPA (0.05% DEA). Gradient from 5% to 50% in 1.2min, 50% maintained at 1min, and from 50% to 5% in 0.8 min. The flow rate was 3.4mL/min. Column temperature 35 ℃. Column pressure 1800psi. Retention time of compound 29-7: 1.084min. Retention time of compound 30-7: 1.208min.

Step 7: synthesis of Compound 29

29-7 (70 mg, 148.65. Mu. Mol) and dichloromethane (1 mL) were added to the thumb flask, stirring was turned on, cooling to 0deg.C, trimethylbromosilane (227.57 mg,1.49 mmol) was added, and the temperature was slowly raised to 20deg.C for 16h. The reaction system was spin-dried and purified by prep-HPLC (column: xtimate C18X 30mm X3 μm; mobile phase: [ water (0.04% HCl) -ACN ]; ACN%:26% -56%,9 min) to give compound 29.

¹ H NMR(400MHz,DMSO-d ₆ )δ＝9.56(br s,1H),6.96(s,1H),6.87(d,J＝2.1Hz,1H),6.53(d,J＝11.9Hz,1H),6.46(d,J＝9.0Hz,1H),4.50(dd,J＝3.7,8.9Hz,1H),4.12(d,J＝10.1Hz,2H),3.09-2.97(m,2H),2.95-2.83(m,1H),2.60-2.53(m,1H),1.90(tdd,J＝4.1,8.3,12.5Hz,1H),1.00(dd,J＝7.1,7.9Hz,6H)。

F NMR(400MHz,DMSO)δppm-121.358。

³¹ P NMR(400MHz,DMSO)δppm 14.358。

Step 8: synthesis of Compound 30

30-7 (70 mg, 148.65. Mu. Mol) and dichloromethane (1 mL) were added to the thumb flask, stirring was turned on, cooling to 0deg.C, trimethylbromosilane (227.57 mg,1.49 mmol) was added, and the temperature was slowly raised to 20deg.C for 16h. The reaction system was spin-dried and purified by prep-HPLC (column: xtimate C18X 30mm X3 μm; mobile phase: [ water (0.04% HCl) -ACN ]; B%:26% -56%,9 min) to give compound 30.

¹ H NMR(400MHz,DMSO-d ₆ )δ＝9.55(br s,1H),6.95(s,1H),6.86(d,J＝2.1Hz,1H),6.52(d,J＝12.0Hz,1H),6.45(d,J＝9.0Hz,1H),4.49(dd,J＝3.8,8.9Hz,1H),4.11(d,J＝10.1Hz,2H),3.08-2.95(m,2H),2.94-2.83(m,1H),2.57-2.52(m,1H),1.90(tt,J＝4.1,8.4Hz,1H),1.06-0.91(m,6H)。

F NMR(400MHz,DMSO-d ₆ )δppm-121.358。

³¹ P NMR(400MHz,DMSO-d ₆ )δppm 14.340。

Example 31

The synthetic route is as follows:

step 1: synthesis of Compound 31-2

Compound 31-1 (30 g,149.24 mmol) was added to N, N-dimethylformamide (150 mL), potassium carbonate (24.75 g,179.09 mmol) was added, benzyl bromide (25.52 g,149.24 mmol) was added, and the reaction was gradually warmed to 50℃and stirred for 16 hours. Ethyl acetate (500 mL) was added to the reaction solution, the solution was washed with saturated sodium chloride solution (300 mL. Times.4), and the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Compound 31-2 is obtained.

¹ H NMR(400MHz,CDCl ₃ )δ＝10.53-10.43(m,1H),8.02-7.92(m,1H),7.67-7.59(m,1H),7.46-7.34(m,5H),7.01-6.91(m,1H),5.25-5.14(m,2H)。

Step 2: synthesis of Compound 31-3

Triphenylphosphine (58.65 g,223.60 mmol) and potassium iodide (17.68 g,106.48 mmol) were added to acetonitrile (300 mL), heated to 70 ℃, compound 31-2 (31 g,106.48 mmol) was added, stirred for 30 minutes, a solution of methyl fluorosulfonyl difluoroacetate (40.91 g,212.96 mmol) in acetonitrile (30 mL) was added and the reaction stirred at 70℃for 3 hours. The reaction mixture was concentrated under reduced pressure, ethyl acetate (200 mL) was added, and the mixture was washed with saturated sodium chloride solution (100 mL), and the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate=1:0) to give compound 31-3.

¹ H NMR(400MHz,CDCl ₃ )δ＝7.50-7.46(m,1H),7.27(br s,5H),7.19-7.12(m,1H),6.67(br d,J＝8.8Hz,1H),5.59-5.48(m,1H),4.96-4.88(m,2H)。

Step 3: synthesis of Compound 31-4

Trimethylsulfoxide iodide (16.92 g,76.89 mmol) was added to dimethylsulfoxide (50 mL), potassium tert-butoxide (1M, 67.66 mL) was added, heated to 50deg.C and stirred for 1 hour, followed by a solution of compound 31-3 (10 g,30.76 mmol) in dimethylsulfoxide (10 mL) and the reaction was stirred at 50deg.C for an additional 16 hours. Ethyl acetate (300 mL) was added to the reaction solution, the solution was washed with saturated sodium chloride solution (100 mL. Times.4), and the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The compound was purified by silica gel column chromatography (petroleum ether: ethyl acetate=1:0) to give compound 31-4.

¹ H NMR(400MHz,CDCl ₃ )δ＝7.46-7.39(m,4H),7.37-7.32(m,2H),7.24(d,J＝2.3Hz,1H),6.84-6.79(m,1H),5.12(d,J＝3.1Hz,2H),2.95-2.81(m,1H),1.83-1.75(m,1H),1.65-1.57(m,1H)。

Step 4: synthesis of Compound 31-5

Compound 31-4 (0.85 g,2.51 mmol) was added to tetrahydrofuran (10 mL), cooled to-78deg.C, and n-butyllithium (2.5M, 1.20 mL) was added dropwise, and the reaction was continued for 0.5 hDuring this time, compound BB-1 (692.80 mg,2.51 mmol) was slowly added dropwise to tetrahydrofuran (5 mL), and the reaction was gradually raised to 20℃and stirred for 2 hours. The reaction solution was added to a mixture of saturated ammonium chloride solution (50 mL) and ethyl acetate (50 mL), and the ethyl acetate layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Compound 31-5 is obtained. [ M-17 ]] ⁺ ＝519.3。

Step 5: synthesis of Compound 31-6

Compound 31-5 (1.35 g,2.52 mmol) was added to dichloromethane (20 mL), cooled to 0deg.C, triethylsilane (877.40 mg,7.55 mmol) was added dropwise, trifluoroacetic acid (430.20 mg,3.77 mmol) was slowly added dropwise, and the reaction was gradually raised to 20deg.C and stirred for 16 hours. To the reaction solution were added saturated sodium hydrogencarbonate (20 mL) and DCM (20 mL), and trifluoroacetic acid was neutralized with stirring, and the dichloromethane layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Compound 31-6 is obtained. [ M+1 ] ] ⁺ ＝521.3。

Step 6: synthesis of Compound 31-7

Compound 31-6 (1.31 g,2.52 mmol) was added to methanol (10 mL) and tetrahydrofuran (10 mL), ammonium fluoride (931.75 mg,25.16 mmol) was added, and the reaction was gradually raised to 50℃and stirred for 3 hours. The reaction solution was concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate=5:1) to give compound 31-7.

¹ H NMR(400MHz,CDCl ₃ )δ＝7.48-7.44(m,2H),7.39(t,J＝7.5Hz,2H),7.34(br d,J＝7.2Hz,1H),6.87-6.76(m,3H),6.65-6.59(m,1H),6.49-6.43(m,1H),5.13-5.03(m,2H),4.57-4.47(m,1H),4.27(br dd,J＝3.2,9.0Hz,1H),3.05-2.75(m,3H),2.62-2.48(m,1H),2.01-1.93(m,1H),1.91-1.86(m,3H),1.80-1.68(m,1H),1.57-1.48(m,1H)。

Step 7: synthesis of Compound 31-8

Compound 31-7 (0.34 g, 836.48. Mu. Mol) was added to N, N-dimethylformamide (5 mL), cesium carbonate (408.81 mg,1.25 mmol) was added, and diethyl tosyloxymethyl phosphonate (242.65 mg, 752.84. Mu. Mol) and the reaction stirred at 50℃for 16 hours. Ethyl acetate (50 mL) was added to the reaction mixture, which was washed with a saturated sodium chloride solution (30 mL. Times.4), and the ethyl acetate layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate=1:1) to give compound 31-8.

¹ H NMR(400MHz,CDCl ₃ )δ＝7.46-7.32(m,5H),6.83-6.74(m,3H),6.73-6.67(m,1H),6.55(br s,1H),5.11-4.95(m,2H),4.29-4.12(m,7H),3.06-2.90(m,1H),2.87-2.73(m,1H),2.90-2.73(m,1H),2.60-2.44(m,1H),1.98-1.81(m,4H),1.76-1.64(m,1H),1.55-1.43(m,1H),1.40-1.28(m,6H)。

Step 8: synthesis of Compound 31-9

Compound 31-8 (130 mg, 233.57. Mu. Mol) was dissolved in methylene chloride (2 mL), and boron trichloride (1M, 1.40 mL) was added dropwise, and the reaction was carried out at 10℃for 12 hours. Ethyl acetate (50 mL), water (50 mL) and saturated brine (50 mL) were added to the reaction mixture, the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was separated by column chromatography (petroleum ether: ethyl acetate=1:1) to give compounds 31-9.

[M+1] ⁺ ＝467.1

Step 9: synthesis of Compound 31

Compound 31-9 (57 mg, 122.20. Mu. Mol) was dissolved in dichloromethane (2 mL), and trimethylbromosilane (187.08 mg,1.22 mmol) was added and the reaction was carried out at 30℃for 12 hours. Concentrating under reduced pressure to obtain crude product. Separation by prep-HPLC (column type: phenomenex luna C, 18, 80, 40mm, 3 μm; mobile phase: [ water (0.04% HCl) -acetonitrile ]; acetonitrile%: 33% -60%,7 min) gives compound 31.

[M+1] ⁺ ＝411.1。

¹ H NMR(400MHz,CD ₃ OD)δ＝6.80-6.58(m,5H),4.25(br dd,J＝3.4,8.3Hz,1H),4.19(d,J＝10.4Hz,2H),3.05-2.94(m,1H),2.86-2.75(m,2H),2.53(qd,J＝8.6,12.6Hz,1H),1.92(br dd,J＝4.0,8.3Hz,1H),1.88(d,J＝3.1Hz,3H),1.77-1.66(m,1H),1.52-1.39(m,1H)。

Example 32

The synthetic route is as follows:

/>

step 1:32 synthesis

1-methyl-2-pyrrolidone (0.5 mL), compound 3 (20 mg, 53.14. Mu. Mol) and triethylamine (26.88 mg, 265.69. Mu. Mol) were added to a thumb flask, warmed to 60℃and reacted for 0.5h, followed by iodomethyl pivalate (64.31 mg, 265.69. Mu. Mol) and reacted for 5h, followed by prep-HPLC (column type: phenomenex Gemini-NX C18 75. Mu.30 mM. Times.3. Mu.m; mobile phase: [ water (10 mM NH) ₄ HCO ₃ )-ACN]The method comprises the steps of carrying out a first treatment on the surface of the ACN%:56% -76%,6 min) to obtain compound 32.

¹ H NMR(400MHz,CDCl ₃ )δ＝6.89(s,1H),6.70(s,1H),6.65-6.58(m,2H),6.55(s,1H),5.88-5.71(m,4H),4.35(d,J＝10.0Hz,2H),4.26(dd,J＝3.8,8.7Hz,1H),3.17(spt,J＝6.9Hz,1H),3.07-2.94(m,1H),2.89-2.74(m,1H),2.56(qd,J＝8.5,12.6Hz,1H),1.98(tdd,J＝4.1,8.3,12.6Hz,1H),1.91(s,3H),1.22(s,18H),1.22-1.18(m,6H)。

³¹ P NMR(400MHz,DMSO)δppm 19.938。

Example 33

The synthetic route is as follows:

step 1:33-1 Synthesis

To a thumb flask was added 2-2 (200 mg, 462.44. Mu. Mol), followed by acetonitrile (4 mL), stirring was turned on, followed by cesium carbonate (226.01 mg, 693.66. Mu. Mol) and benzyl bromide (94.91 mg, 554.93. Mu. Mol), heating to 70 ℃, reacting for 5 hours, filtering the reaction system, adding water (50 mL) and dichloromethane (50 mL. Times.2), extracting, separating an organic phase, drying over anhydrous sodium sulfate, spin-drying, and purifying by silica gel column chromatography (petroleum ether: ethyl acetate=10:0 to 1:2) to obtain compound 33-1.

¹ H NMR(400MHz,CDCl ₃ )δ＝7.48-7.29(m,5H),6.96(d,J＝2.0Hz,1H),6.81-6.73(m,2H),6.72-6.66(m,1H),6.60(s,1H),5.04(s,2H),4.34-4.21(m,8H),3.47-3.29(m,1H),3.03(td,J＝8.3,16.1Hz,1H),2.92-2.76(m,1H),2.57(qd,J＝8.5,12.8Hz,1H),2.05-1.97(m,1H),1.93(s,3H),1.39(t,J＝7.0Hz,6H),1.20(dd,J＝5.5,6.8Hz,6H)。

Step 2:33-2 Synthesis

To the thumb flask was added 33-1 (210 mg, 401.83. Mu. Mol) and dichloromethane (3 mL), stirring was turned on, cooling to 0deg.C, trimethylbromosilane (615.16 mg,4.02 mmol) was added, and the temperature was slowly raised to 20deg.C for 16h. Spin-drying the reaction system to obtain a compound 33-2.

¹ H NMR(400MHz,CDCl ₃ )δ＝7.52-7.29(m,5H),7.06-6.89(m,1H),6.84-6.66(m,3H),6.61-6.51(m,1H),5.03(s,2H),4.35-4.16(m,3H),3.37(td,J＝6.8,13.8Hz,1H),3.12-2.92(m,1H),2.91-2.70(m,1H),2.62-2.48(m,1H),2.06-1.97(m,1H),1.96-1.88(m,3H),1.20(t,J＝6.0Hz,6H)。

Step 3:33-3 synthesis

A dry, clean 50mL single-necked flask was charged with 33-2 (120 mg, 257.23. Mu. Mol) and N, N-dimethylformamide (1 mL), stirring was turned on, and pyridine (203.47 mg,2.57 mmol) and dicyclohexylcarbodiimide (265.37 mg,1.29 mmol) were then added, phenol (24.21 mg, 257.23. Mu. Mol) was added, the temperature was raised and the reaction was controlled at 50℃for 2 hours. Ethyl acetate (50 mL) was added to the reaction system, followed by sequential addition of water (50 mL), extraction with saturated brine (50 ml×2), separation of an organic phase, drying over anhydrous sodium sulfate, spin-drying to give a crude product of the objective product, and purification by silica gel column chromatography (petroleum ether: ethyl acetate=3:1 to 1:1) to give compound 33-3.

¹ H NMR(400MHz,DMSO-d ₆ )δ＝7.46-7.37(m,5H),7.28-7.12(m,5H),6.97-6.84(m,3H),6.67(br d,J＝7.5Hz,2H),5.59(br d,J＝7.7Hz,1H),5.04(s,2H),4.24(br d,J＝6.1Hz,1H),3.85(br s,1H),3.27-3.16(m,1H),2.89(br s,1H),2.74(br s,1H),1.86(s,1H),1.81(br s,3H),1.49(br s,1H),1.23(s,3H),1.11(br s,3H)。

Step 4:33-4 Synthesis

Adding 33-3 (100.00 mg,184.30 mu mol) into a dry and clean thumb bottle, then adding thionyl chloride (0.5 mL), stirring at 70 ℃ for 2h, and spin-drying the reaction system to obtain brown oily substance for later use; another thumb flask, L-alanine isopropyl ester hydrochloride (37.07 mg, 221.16. Mu. Mol) was dissolved in methylene chloride (0.5 mL), potassium bicarbonate (44.28 mg, 442.31. Mu. Mol) was added, stirred at 20℃for 1 hour, dried over anhydrous sodium sulfate and filtered to give a filtrate, which was then added dropwise to a brown oil ready for use, monitored by pH paper and adjusted to pH between 4 and 7 with triethylamine (22.38 mg, 221.16. Mu. Mol), and reacted at 20℃for 2 hours. The reaction system was spin-dried and purified by silica gel column chromatography (petroleum ether: ethyl acetate=3:1 to 1:1) to give compound 33-4.

¹ H NMR(400MHz,CDCl ₃ )δ＝7.47-7.27(m,9H),7.22-7.12(m,1H),6.97(d,J＝2.1Hz,1H),6.82-6.67(m,3H),6.62-6.54(m,1H),5.04(s,2H),4.98(td,J＝6.2,12.4Hz,1H),4.42-4.28(m,3H),4.21(s,1H),3.79-3.62(m,1H),3.44-3.26(m,1H),3.03(td,J＝8.0,16.1Hz,1H),2.91-2.73(m,1H),2.66-2.51(m,1H),2.01(br d,J＝4.4Hz,1H),1.94(s,3H),1.38(d,J＝7.0Hz,3H),1.23-1.17(m,12H)。

³¹ P NMR(400MHz,CDCl ₃ )δppm20.852。

Step 5:33 synthesis

A dry clean thumb flask was taken, 33-4 (30 mg, 45.75. Mu. Mol) was dissolved in ethyl acetate (2 mL), pd/C (0.2 g, palladium content: 5%) and trifluoroacetic acid (15.65 mg, 137.25. Mu. Mol) were then added, the reaction was carried out at 20℃for 16H under a hydrogen balloon atmosphere of 15psi, the reaction system was filtered through celite, and dried by spin to give crude product, which was purified by prep-HPLC (column form: waters Xbridge BEH C: 100X 30 mm. Mu.m; mobile phase: [ H) ₂ O(10mM NH ₄ HCO ₃ )-ACN]The method comprises the steps of carrying out a first treatment on the surface of the ACN%:45% -75%,8 min) to give compound 33.

¹ H NMR(400MHz,CDCl ₃ )δ＝7.36-7.27(m,3H),7.25-7.23(m,1H),7.19-7.13(m,1H),6.92(s,1H),6.73(s,1H),6.62(s,2H),6.58(s,1H),5.05-4.90(m,1H),4.54(br s,1H),4.40-4.30(m,2H),4.29-4.26(m,1H),4.25-4.18(m,1H),3.72-3.57(m,1H),3.23-3.11(m,1H),3.09-2.95(m,1H),2.83(br s,1H),2.57(dd,J＝8.4,12.5Hz,1H),2.05-1.95(m,1H),1.93(s,3H),1.38(d,J＝7.2Hz,3H),1.25-1.18(m,12H)。

³¹ P NMR(400MHz,CDCl ₃ )δppm 20.828。

Examples 34 and 35

The synthetic route is as follows:

step 1:34 synthesis

To a solution of raw material 12 (0.39 g, 982.86. Mu. Mol) in N, N-dimethylformamide (20 mL) was added pyridine (2 mL), dicyclohexylcarbodiimide (608.37 mg,2.95 mmol), BB-2 (183.44 mg, 982.86. Mu. Mol), and the mixture was reacted at 50℃for 16hr. Ethyl acetate (200 mL), 10% citric acid (100 mL. Times.2) and a half-saturated sodium chloride solution (100 mL. Times.2) were added to the reaction mixture, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. According to TLC (petroleum ether: ethyl acetate=1:2, rf of compound 34=0.3, rf of compound 35=0.6), the crude product was separated by column chromatography on silica gel (petroleum ether/ethyl acetate=1:1 to 0:1) and then by prep-HPLC (column form: phenomenex Gemini-NX C18 75 x 30mm x 3 μm mobile phase: [ water (10 mnnh ₄ HCO ₃ ) -acetonitrile]The method comprises the steps of carrying out a first treatment on the surface of the Acetonitrile%: 45% -65%,6 min) to obtain compound 34 and compound 35. The configuration of the phosphorus atom position of compound 34 was confirmed by NOE.

Compound 34:

[M+1] ⁺ ＝547.1。

¹ H NMR(400MHz,CDCl ₃ )δ＝7.39(s,1H),7.28-7.36(m,2H),7.20-7.25(m,1H),6.95(s,1H),6.80(br d,J＝9.7Hz,2H),6.63(s,2H),5.65(br d,J＝11.3Hz,1H),4.65-4.78(m,1H),4.38-4.57(m,4H),3.06-3.21(m,2H),2.88(ddd,J＝16.3,8.9,3.2Hz,1H),2.56-2.63(m,1H),2.38-2.50(m,1H),2.11-2.18(m,1H),2.06(td,J＝8.5,4.1Hz,1H),1.20-1.25ppm(m,6H)。

compound 35: [ M+1 ]] ⁺ ＝547.1

Examples 36 and 37

The synthetic route is as follows:

step 1: synthesis of Compound 36

A dry clean thumb flask was taken, compound 18 (50 mg, 126.78. Mu. Mol) and N, N-dimethylformamide (2 mL) were added, stirring was turned on, dicyclohexylcarbodiimide (156.96 mg, 760.70. Mu. Mol, 153.88. Mu.L) and pyridine (150.43 mg,1.90 mmol) were then added, compound BB-2 (28.39 mg, 152.14. Mu. Mol) was added, the temperature was raised and the reaction was controlled at 60℃for 16h. The reaction system was filtered to give a filtrate, ethyl acetate (30 mL) was added, followed by washing with water (30 mL), saturated brine (30 mL. Times.2) to give an organic phase, which was spin-dried to give a crude product of the desired product, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate=3:1 to 0:1) according to TLC (petroleum ether: ethyl acetate=1:2, rf of compound 36=0.3, rf of compound 37=0.6) to give a crude product of the desired product, followed by prep-HPLC (column: waters Xbridge BEH C18.0X105 mm. Times.10 μm; mobile phase: [ H) ₂ O(10mM NH ₄ HCO ₃ ) -acetonitrile]The method comprises the steps of carrying out a first treatment on the surface of the Acetonitrile%: 40% -70%,6 min) to obtain crude products of the compound 36 and the compound 37. Crude compound 36 was purified by prep-HPLC (column: waters Xbridge BEH C, 100X 30mM X10 μm; mobile phase: [ water (10 mM NH) ₄ HCO ₃ ) -acetonitrile]The method comprises the steps of carrying out a first treatment on the surface of the Acetonitrile%: 40% -70%,6 min) to obtain compound 36. The configuration of the phosphorus atom position of compound 36 was confirmed by NOE.

Compound 36: ¹ H NMR(400MHz,DMSO-d ₆ )δ＝9.57(br s,1H),7.50(s,1H),7.44-7.38(m,2H),7.38-7.34(m,1H),6.84(s,1H),6.65(s,1H),6.58-6.50(m,1H),6.45(d,J＝9.0Hz,1H),5.76(br d,J＝11.1Hz,1H),4.67-4.54(m,1H),4.49(d,J＝9.5Hz,2H),4.44-4.38(m,1H),3.03(quin,J＝6.9Hz,1H),2.97-2.87(m,1H),2.85-2.74(m,1H),2.70-2.65(m,1H),2.36-2.31(m,1H),2.26-2.16(m,2H),1.94-1.86(m,1H),1.85(s,3H),0.97(dd,J＝6.9,11.8Hz,6H).

¹⁹ F NMR(400MHz,DMSO-d ₆ )δppm-121.411.

³¹ P NMR(400MHz,DMSO-d ₆ )δppm 14.285.

compound 37 [ M-1 ]] ^- ＝543.1.

Example 38

The synthetic route is as follows:

step 1:38-1 synthesis

Raw material 11-1 (3.7 g,12.46 mmol) and cyclopropylboronic acid (2.68 g,31.16 mmol) were dissolved in toluene (40 mL) and water (4 mL), potassium phosphate (10.58 g,49.85 mmol), palladium acetate (279.82 mg,1.25 mmol) was added, nitrogen was replaced three times, tricyclohexylphosphine (699.03 mg,2.49 mmol) was added, and stirring was continued in an oil bath at 110℃after nitrogen replacement for 12 hours. The reaction mixture was extracted with 50mL of water and ethyl acetate (50 mL. Times.3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. The crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate=3:1). Compound 38-1 is obtained.

¹ H NMR(400MHz,DMSO-d ₆ )δppm 6.69-6.73(m,1H),6.15-6.19(m,1H),3.16-3.26(m,1H),2.93-2.99(m,2H),2.54-2.61(m,2H),0.99-1.06(m,2H),0.90-0.96(m,9H),0.64-0.72(m,2H),0.17-0.23(m,6H)。

Step 2:38-2 synthesis

Compound 1-8 (3.8 g,12.45 mmol) was dissolved in tetrahydrofuran (35 mL), n-butyllithium (2.5M, 5.98 mL) was added dropwise at-65℃and stirring was continued for 1 hour, and a solution of compound 38-1 (3.01 g,9.96 mmol) in tetrahydrofuran (20 mL) was added and stirring was continued for 3 hours. The temperature was raised to-10℃and the reaction solution was poured into 25mL of saturated ammonium chloride solution, stirred, extracted with ethyl acetate (20 mL. Times.) 3) Dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. Compound 38-2 is obtained. [ M-17 ]] ⁺ ＝511.2

Step 3:38-3 synthesis

Compound 38-2 (5.19 g,9.81 mmol) was dissolved in dichloromethane (50 mL), cooled to 0deg.C, boron trifluoride diethyl ether (2.09 g,14.72 mmol) was added dropwise, triethylsilane (3.42 g,29.44 mmol) was warmed naturally to 20deg.C and stirring continued for 2 hours. The reaction mixture was added with saturated aqueous sodium bicarbonate, ph=8, and extracted with dichloromethane (15 ml×3), and the solvent was removed by concentration under reduced pressure. Compound 38-3 is obtained. [ Ms+1 ]] ⁺ ＝513.3

Step 4:38-4 synthesis

Compound 38-3 (5.00 g,9.75 mmol) was dissolved in tetrahydrofuran (25 mL) and methanol (25 mL), and ammonium fluoride (2.90 g,78.30 mmol) was added and stirring was continued in an oil bath at 50℃for 12 hours. The reaction solution was cooled to room temperature and filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. Separated by column chromatography on silica gel (petroleum ether: ethyl acetate=1:1). Compound 38-4 is obtained.

¹ H NMR(400MHz,DMSO-d ₆ )δppm 8.98-9.03(m,1H),7.42-7.48(m,2H),7.37-7.42(m,2H),7.29-7.34(m,1H),6.91-6.95(m,1H),6.87-6.91(m,1H),6.72-6.78(m,1H),6.47-6.51(m,1H),6.03-6.06(m,1H),5.02-5.07(m,2H),4.35-4.42(m,1H),3.19-3.28(m,1H),2.82-2.93(m,1H),2.66-2.75(m,1H),2.42-2.49(m,1H),1.82-1.91(m,1H),1.38-1.47(m,1H),1.06-1.13(m,6H),0.65-0.74(m,1H),0.41-0.51(m,2H),0.31-0.38(m,1H)。

Step 5:38-5 synthesis

Compound 38-4 (1.41 g,3.54 mmol) was dissolved in N, N-dimethylformamide (15 mL), cesium carbonate (1.73 g,5.31 mmol) was added, and diethyl tosyloxymethylphosphonate (1.25 g,3.89 mmol) was stirred in an oil bath at 50deg.C for an additional 12 hours. The reaction solution was cooled to room temperature, poured into 40mL of water, extracted with ethyl acetate (25 mL. Times.3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. The crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate=1:1). Compound 38-5 is obtained.

¹ H NMR(400MHz,DMSO-d ₆ )δppm 7.42-7.46(m,2H),7.36-7.42(m,2H),7.28-7.34(m,1H),6.92-6.95(m,1H),6.87-6.91(m,1H),6.72-6.76(m,1H),6.74(m,1H),6.25-6.29(m,1H),5.03-5.07(m,2H),4.41-4.47(m,1H),4.33-4.39(m,2H),4.06-4.15(m,4H),3.19-3.28(m,1H),2.88-3.00(m,1H),2.72-2.82(m,1H),2.51-2.57(m,1H),1.85-1.94(m,1H),1.41-1.51(m,1H),1.22-1.29(m,6H),1.08-1.13(m,6H),0.67-0.76(m,1H),0.53-0.61(m,1H),0.42-0.52(m,2H)。

Step 6:38-6 synthesis

Compound 38-5 (1.1 g,2.00 mmol) was dissolved in dichloromethane (12 mL), boron trichloride (1M, 12.03 mL) was added at 0deg.C, and stirring was continued at 20deg.C for 1 hour under nitrogen. The reaction mixture was poured into a saturated aqueous sodium hydrogencarbonate solution (20 mL), extracted with methylene chloride (30 mL. Times.3), and the solvent was removed by concentration under reduced pressure. The crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate=1:1). Compound 38-6 is obtained. [ Ms+1 ]] ⁺ ＝459.3

Step 7:38-7 synthesis

SFC analysis method: column type ChiralpakAD-3, 50X 4.6mm I.D.,3 μm mobile phase A: CO ₂ IPA (0.05% IPAm, v/v), gradient: timeA% -B%,0-2.2min, B phase from 0% to 50%,2.2-3.0min, B phase from 50% to 5%, flow rate: 3.4mL/min, column temperature: 35 ℃, ABPR:1800psi, retention time: 1.229min. Compound 38-6 was resolved by chiral separation (column: DAICEL CHIRALPAK AD (250 mm. Times.30 mm,10 μm); mobile phase: [ Neu-IPA)]The method comprises the steps of carrying out a first treatment on the surface of the IPA%:35% -35%,7 min). Compound 38-7 is obtained. [ Ms+1 ]] ⁺ ＝459.3

Step 8:38 synthesis

38-7 (47.5 mg,103.59 mmol) was dissolved in dichloromethane (1.5 mL) and trimethylbromosilane (158.59 mg,1.04 mmol) was added and stirring was continued at 20℃for 5 hours at room temperature. The reaction solution was concentrated under reduced pressure to remove the solvent. The crude product was purified by preparative HPLC (column: phenomenex Gemini-NX C18X 75X 30mm X3 μm; mobile phase: [ H ] ₂ O(0.05％NH ₃ H ₂ O+10mM NH ₄ HCO ₃ )-ACN]The method comprises the steps of carrying out a first treatment on the surface of the B (ACN)% > 5% -30%,8 min) to give compound 38.

1H NMR(400MHz,CD ₃ OD)δ＝6.84-6.80(m,2H),6.64(d,J＝2.1Hz,1H),6.61(s,1H),6.61-6.57(m,1H),5.73-5.60(m,1H),4.86-4.78(m,2H),4.32-4.25(m,1H),4.08-4.00(m,2H),3.27-3.17(m,1H),3.08-2.91(m,3H),2.86-2.73(m,1H),2.60-2.44(m,1H),1.98-1.88(m,1H),1.15(dd,J＝7.0,9.3Hz,6H)

Example 39

The synthetic route is as follows:

step 1:39-1 Synthesis

Compounds 1-9 (0.9 g,1.79 mmol) were dissolved in toluene (10 mL) and pyridine p-toluenesulfonate (224.93 mg, 895.06. Mu. Mol) was added and refluxed at 110℃for 3 hours. The reaction mixture was extracted with ethyl acetate (30 mL. Times.3), and the solvent was removed by concentration under reduced pressure. The crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate=10:1). Compound 39-1 was obtained.

¹ H NMR(400MHz,CDCl ₃ )δ＝7.54-7.49(m,2H),7.47-7.42(m,2H),7.40-7.36(m,1H),7.27(s,1H),7.19-7.15(m,1H),6.97-6.93(m,1H),6.92-6.88(m,1H),6.58-6.55(m,1H),6.25-6.22(m,1H),5.19-5.12(m,2H),3.54-3.46(m,1H),3.43-3.39(m,2H),2.04-2.00(m,3H),1.31-1.26(m,6H),1.06-1.02(m,9H),0.27-0.24(m,6H)

Step 2:39-2 Synthesis

To a clean flask was added dichloromethane (25 mL), diethyl zinc (1M, 30.94 mL), diiodomethane (8.29 g,30.94 mmol) was added slowly at 10deg.C, stirring was continued for 1 hour, until a white solid had evolved, compound 39-1 (3 g,6.19 mmol) dichloromethane (25 mL) was added and stirring was continued for 2 hours at 20deg.C. The reaction mixture was poured into 50mL of saturated aqueous ammonium chloride, extracted with methylene chloride (80 mL. Times.2), and the solvent was removed by concentration under reduced pressure. The crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate=5:1). Compound 39-2 is obtained. [ Ms+1 ]] ⁺ ＝499.3

Step 3:39-3 Synthesis

Compound 39-2 (2.7 g,5.41 mmol) was dissolved in methanol (25 mL) and tetrahydrofuran (25 mL), and ammonium fluoride (1.60 g,43.31 mmol) was added and stirring was continued for 12 hours at 50℃in an oil bath. The reaction solution was concentrated under reduced pressure to remove the solvent. Purification by column chromatography on silica gel (petroleum ether: ethyl acetate=1:1). Compound 39-3 is obtained.

¹ H NMR(400MHz,CDCl ₃ )δppm 7.44-7.49(m,2H),7.37-7.43(m,2H),7.31-7.36(m,1H),7.15-7.20(m,1H),7.04-7.10(m,1H),6.82-6.87(m,1H),6.51-6.54(m,1H),6.34-6.38(m,1H),5.05-5.10(m,2H),4.54-4.60(m,1H),3.33-3.44(m,2H),2.84-2.92(m,1H),1.75-1.82(m,3H),1.75-1.78(m,1H),1.19-1.24(m,6H),0.48-0.53(m,1H)。

Step 4:39-4 Synthesis

Compound 39-3 (0.57 g,1.48 mmol) was dissolved in N, N-dimethylformamide (6 mL), cesium carbonate (723.32 mg,2.22 mmol) was added, and dibenzyl p-toluenesulfonyloxymethyl phosphonate (726.82 mg,1.63 mmol) was stirred in an oil bath at 50℃for an additional 12 hours. 15mL of water was added, the mixture was extracted with ethyl acetate (20 mL. Times.2), dried over anhydrous sodium sulfate, and the solvent was removed by concentration under reduced pressure. The crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate=1:1). Compound 39-4 is obtained.

¹ H NMR(400MHz,CDCl ₃ )δ＝7.49-7.43(m,1H),7.44-7.39(m,1H),7.43-7.39(m,1H),7.43-7.39(m,1H),7.38-7.31(m,12H),7.18-7.15(m,1H),7.08-7.02(m,1H),6.87-6.81(m,1H),6.61-6.57(m,1H),6.45-6.42(m,1H),5.18-5.12(m,4H),5.09-5.06(m,2H),4.29-4.22(m,2H),4.18-4.10(m,1H),3.43-3.33(m,2H),2.07-2.05(m,1H),2.07-2.04(m,1H),1.75-1.66(m,1H),1.63-1.59(m,2H),1.21(t,J＝6.9Hz,6H)

Step 5:39-5 Synthesis

SFC analysis method: column type, chiralcel OJ-3, 50X 4.6mm I.D.,3 μm, mobile phase A: CO ₂ EtOH (0.05% IPAm, v/v), gradient from 5% to 50% in 1 min for phase B, decrease to 5% in 0.8 min, flow rate 3.4mL/min, column temperature 35℃and ABPR 1800psi. Retention time of compound 39-5: 1.478min. Compound 39-4 was chiral resolved (column: DAICEL CHIRALCEL OJ (250 mm. Times.30 mm,10 μm); mobile phase: [0.1% NH) ₃ H ₂ O EtOH]45% -45%,10 min). Compound 39-5 was obtained.

Step 6:39 synthesis

Compound 39-5 (0.1 g, 151.80. Mu. Mol) was dissolved in methanol (1 mL) and wet palladium on carbon (15 mg, 151.80. Mu. Mol, palladium content: 10%) was added under a pressure of 15psi, H ₂ Stirring was continued for 5 hours at 20℃under protection. The reaction solution was filtered, and the solvent was removed by concentration under reduced pressure. By preparative HPLC (column type: phenomenex Gemini-NX 150. Times.30 mm. Times.5 μm; mobile phase: [ H) ₂ O(10mM NH ₄ HCO ₃ )-ACN]The method comprises the steps of carrying out a first treatment on the surface of the B (ACN)% > is 10% -30%, and 7 min) separating and purifying. Compound 39 was obtained.

¹ H NMR(400MHz,CD ₃ OD)δppm 7.04-7.07(m,1H),6.86-6.90(m,1H),6.64-6.68(m,2H),6.48-6.50(m,1H),3.94-3.99(m,2H),3.34-3.38(m,1H),3.20-3.28(m,1H),2.82-2.88(m,1H),1.76-1.77(m,3H),1.72-1.76(m,1H),1.54-1.60(m,1H),1.13-1.18(m,6H),0.36-0.40(m,1H)。

Example 40

The synthetic route is as follows:

step 1: synthesis of Compound 40-2

Raw material 40-1 (5 g,20.75 mmol) was added to dichloromethane (50 mL), trifluoromethanesulfonic acid (15.57 g,103.73 mmol) and isopropanol (2.49 g,41.49 mmol) and the reaction was stirred at 20℃for 16 h. Ethyl acetate (100 mL) was added to the reaction mixture, which was washed with a saturated sodium chloride solution (50 mL. Times.4), and the ethyl acetate layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate=1:0). Compound 40-2 was obtained.

¹ H NMR(400MHz,CDCl ₃ )δ＝7.50-7.45(m,2H),5.51(q,J＝3.4Hz,1H),3.31-3.22(m,1H),1.26(d,J＝6.8Hz,6H)。

Step 2: synthesis of Compound 40-3

Compound 40-2 (5.43 g,19.18 mmol) was added to N, N-dimethylformamide (50 mL), potassium carbonate (5.30 g,38.36 mmol) and benzyl bromide (2.95 g,17.26 mmol) were added and the reaction was stirred for 16 hours at 60 ℃. Ethyl acetate (50 mL) was added to the reaction mixture, which was washed with a saturated sodium chloride solution (30 mL. Times.4), and the ethyl acetate layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate=1:0). Compound 40-3 was obtained.

¹ H NMR(400MHz,CDCl ₃ )δ＝7.63-7.58(m,2H),7.52-7.35(m,5H),4.90(s,2H),3.44-3.32(m,1H),1.26(d,J＝6.8Hz,6H)。

Step 3: synthesis of Compound 40-4

Raw material 40-3 (4.4 g,11.79 mmol) was dissolved in tetrahydrofuran (40 mL), replaced with nitrogen for 3 times, n-butyllithium (2.5M, 5.66 mL) was slowly added dropwise at-68℃and the reaction was carried out at-68℃for 0.5 hours, BB-1 (3.26 g,11.79 mmol) was added at-68℃and the reaction was carried out at 25℃for 12 hours. To the reaction mixture was added a saturated aqueous ammonium chloride solution (10 mL) to quench the reaction. Ethyl acetate (200 mL), water (200 mL) and the organic phase were collected, dried over anhydrous sodium sulfate, filtered and the filtrate concentrated under reduced pressure to give compound 40-4.[ Ms-17 ] ] ⁺ = 553.1. Step 4: synthesis of Compound 40-5

Raw material 40-4 (6.86 g,12.02 mmol) was dissolved in dichloromethane (30 mL), triethylsilane (4.19 g,36.06 mmol) was added, trifluoroacetic acid (2.06 g,18.03 mmol) was added at 0deg.C, and the reaction was carried out at 25deg.C for 12 hours. Concentrating under reduced pressure to obtain compound 40-5.[ Ms+1 ]] ⁺ ＝555.1。

Step 5: synthesis of Compound 40-6

Raw material 40-5 (6.67. G12.02 mmol) was dissolved in a mixed solvent of methanol (30 mL) and tetrahydrofuran (30 mL), and ammonium fluoride (4.54 g,120.23 mmol) was added thereto, and the reaction was carried out at 25℃for 12 hours. Concentrated under reduced pressure, and the crude product was isolated by column chromatography (petroleum ether: ethyl acetate=3:1) to give compound 40-6.

¹ H NMR(400MHz,CDCl ₃ )δ＝7.54-7.49(m,2H),7.46-7.40(m,2H),7.40-7.34(m,1H),7.20-7.13(m,2H),6.67(s,1H),6.51(s,1H),4.91(s,2H),4.36(dd,J＝3.8,8.6Hz,1H),3.40(spt,J＝6.9Hz,1H),3.10-2.97(m,1H),2.91-2.80(m,1H),2.62(qd,J＝8.6,12.7Hz,1H),2.01(tdd,J＝4.2,8.4,12.7Hz,1H),1.90(s,3H),1.24-1.17(m,6H)。

Step 6: synthesis of Compound 40-7

Raw material 40-6 (1.75 g,3.97 mmol) was dissolved in dimethylformamide (10 mL), cesium carbonate (1.02 g,3.12 mmol) was added, and diethyl tosyloxymethylphosphonate (1.28 g,3.97 mmol) was reacted at 50℃for 2 hours. Ethyl acetate (100 mL), water (100 mL) were extracted, the organic phase was collected, washed with supersaturated brine (100 mL. Times.3) and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product. The crude product was isolated by column chromatography (petroleum ether: ethyl acetate=1:1) to give compound 40-7.[ Ms+1 ] ] ⁺ = 591.1. Step 7: synthesis of Compound 40-8

Raw material 40-7 (1.6 g,2.71 mmol) was dissolved in methanol (5 mL), wet palladium on carbon (0.8 g, palladium content: 5%) was added, hydrogen was introduced and the reaction was carried out at 15psi at 25℃for 12 hours, 3 times of displacement. Filtering, concentrating the filtrate under reduced pressure to obtain a crude product. Compound 40-8 is obtained. [ Ms+1 ]] ⁺ ＝501.1。

Step 8: synthesis of Compound 40-9

SFC resolution of starting material 40-8 (0.7 g,1.57 mmol). SFC (column: DAICEL CHIRALPAK AD (250 mm. Times.50 mm,10 μm); mobile phase: [0.1% NH) ₃ H ₂ O/IPA]20% -20%,4.5 min). Compound 40-9 is obtained. The analysis method comprises the following steps: column-type ChiralpakAD-3, 50X 4.6mm, I.D.,3 μm. Mobile phase A and CO ₂ IPA (0.05% IPAm, v/v. Gradient: phase B rising from 5% to 50% in 1 minute, maintaining for 1 minute, decreasing to 5% in 0.8 minute. Flow rate: 3.4mL/min. Column temperature: 35 ℃ C. ABPR:1800psi. Compound 40-9 retention time: 1.011min.

Step 9: synthesis of Compound 40

Raw material 40-9 (348 mg, 683.34. Mu. Mol) was dissolved in methylene chloride (3 mL), and trimethylbromosilane (1.05 g,6.783 mmol) was added at 0deg.C and the reaction was carried out at 30deg.C for 12 hours. Concentrating under reduced pressure to obtain crude product, extracting with ethyl acetate (10 mL) and water (10 mL), collecting organic phase, washing with supersaturated saline (10 mL×3) and allowing the organic phase to pass through without Drying with sodium sulfate, filtering, and concentrating the filtrate under reduced pressure to obtain crude product. By preparative HPLC (column type Phenomenex luna C, 80X 40mm X3 μm; mobile phase: [ H) ₂ O(0.04％HCl)-ACN]The method comprises the steps of carrying out a first treatment on the surface of the B (ACN)% > 45% -70%, and 7 min) to obtain compound 40.

¹ H NMR(400MHz,CD ₃ OD)δ＝7.10(s,1H),6.96(s,1H),6.83(s,1H),6.66(s,1H),4.36(br dd,J＝3.6,8.7Hz,1H),4.22(br d,J＝10.4Hz,2H),3.30-3.25(m,1H),3.02(td,J＝8.2,16.0Hz,1H),2.93-2.81(m,1H),2.69-2.53(m,1H),1.98-1.89(m,4H),1.17(dd,J＝6.9,9.7Hz,6H)。

Example 41

The synthetic route is as follows:

step 1:41-2 Synthesis

To a solution of starting material 41-1 (10 g,43.65 mmol) in 1, 4-dioxane (50 mL) was added boron dipicolinate (12.19 g,48.02 mmol), 4 '-di-tert-butyl-2, 2' -bipyridine (234.34 mg, 873.09. Mu. Mol), 1, 5-cyclooctadiene iridium chloride dimer (293.23 mg, 436.55. Mu. Mol), and the mixture was reacted at 85℃for 16 hours. The reaction solution was concentrated under reduced pressure, diluted with ethyl acetate (100 mL), washed with 10% aqueous citric acid (100 mL. Times.2), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The crude product was directly taken to the next step without purification. Compound 41-2 is obtained.

¹ H NMR(400MHz,CDCl ₃ )δ＝7.87(d,J＝0.9Hz,1H),7.75(d,J＝0.9Hz,1H),3.93(s,3H),2.46(s,3H),1.35(s,12H)。

Step 2:41-3 Synthesis

To a solution of starting material 41-2 (15.5 g,43.66 mmol) in tetrahydrofuran (150 mL) and water (50 mL) was added sodium perborate (20.15 g,130.97 mmol), and the mixture was reacted at 20℃for 4 hours. The reaction was added to ethyl acetate (100 mL), saturated chlorineThe mixture was washed with sodium chloride solution (100 mL. Times.2), and the ethyl acetate layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was directly taken to the next step without purification. Compound 41-3 is obtained. [ Ms+1 ] ] ⁺ ＝244.9。

Step 3:41-4 Synthesis

N, N-diisopropylethylamine (11.29 g,87.32 mmol) was added to a solution of starting material 41-3 (10.7 g,43.66 mmol) in methylene chloride (150 mL) at 0℃and bromomethoxymethyl ether (6.55 g,52.39 mmol) was reacted at 20℃for 12 hours. The reaction solution was poured into saturated sodium hydrogencarbonate solution (100 mL), dichloromethane (50 mL) was added to separate the solution, the aqueous phase was extracted with dichloromethane (50 ml×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The crude product was isolated by column chromatography on silica gel (petroleum ether: ethyl acetate=10:1). Compound 41-4 is obtained.

¹ H NMR(400MHz,CDCl ₃ )δ＝7.17(d,J＝2.6Hz,1H),7.05(d,J＝2.6Hz,1H),5.16(d,J＝0.9Hz,2H),3.93(d,J＝0.9Hz,3H),3.47(d,J＝1.1Hz,3H),2.43(s,3H)。

Step 4:41-5 Synthesis

To a solution of starting material 41-4 (9 g,31.13 mmol) in tetrahydrofuran (90 mL), methanol (30 mL) and water (45 mL) was added lithium hydroxide monohydrate (3.92 g,93.39 mmol), and the mixture was reacted at 70℃for 4 hours. The reaction solution was concentrated under reduced pressure, the pH was adjusted to 3 by adding 2M hydrochloric acid solution, and the cake was collected by filtration. The crude product was directly taken to the next step without purification. Compound 41-5 is obtained.

¹ H NMR(400MHz,CDCl ₃ )δ＝7.40(d,J＝2.9Hz,1H),7.12(d,J＝2.9Hz,1H),5.19(s,2H),3.49(s,3H),2.49-2.42(m,3H)。

Step 5:41-6 Synthesis

To a solution of starting material 41-5 (3 g,10.91 mmol) in tetrahydrofuran (180 mL) was added n-butyllithium (2.5M, 15.27 mL) at-78℃and after 2 hours a solution of 4-benzyloxy-3-isopropylbenzaldehyde (5.55 g,21.81 mmol) in tetrahydrofuran (80 mL) was added and after 0.5 hour the reaction was carried out, the reaction was carried out at 20℃for 12 hours. The reaction solution was poured into a saturated ammonium chloride solution (50 mL), ethyl acetate was added to the solution (100 mL), the aqueous phase was extracted with ethyl acetate (100 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The crude product was isolated by column chromatography on silica gel (petroleum ether: ethyl acetate=5:1). Compound 41-6 is obtained.

¹ H NMR(400MHz,DMSO-d ₆ )δ＝7.50-7.45(m,2H),7.45-7.39(m,2H),7.37-7.31(m,2H),7.23(d,J＝1.5Hz,1H),7.18(d,J＝2.1Hz,1H),7.07(d,J＝8.5Hz,1H),6.93(dd,J＝2.2,8.5Hz,1H),6.60(s,1H),5.38-5.27(m,2H),5.13(s,2H),3.42(s,3H),3.30-3.22(m,1H),1.96(s,3H),1.15(dd,J＝6.0,6.7Hz,6H)。

Step 6:41-7 synthesis

To a solution of starting material 41-6 (5.5 g,12.21 mmol) in tetrahydrofuran (40 mL) was added lithium aluminum hydride (926.70 mg,24.42 mmol) at 0deg.C, and the reaction was carried out for 1 hour. The reaction mixture was quenched by slowly adding sodium sulfate decahydrate, filtered through celite, the filtrate was extracted with ethyl acetate (50 ml×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The crude product was isolated by column chromatography on silica gel (petroleum ether: ethyl acetate=3:1). Compound 41-7 is obtained.

¹ H NMR(400MHz,CDCl ₃ )δ＝7.47-7.31(m,5H),7.14(d,J＝2.0Hz,1H),6.94(dd,J＝2.2,8.3Hz,1H),6.88-6.78(m,2H),6.73(s,1H),6.06(s,1H),5.24(dd,J＝2.3,12.3Hz,1H),5.19(s,2H),5.09(s,1H),5.07(s,2H),3.52(s,3H),3.43-3.30(m,1H),1.89(s,3H),1.21(t,J＝7.1Hz,6H)。

Step 7:41-8 Synthesis

To a solution of starting material 41-7 (4.5 g,10.31 mmol) in toluene (120 mL) was added p-toluenesulfonyl chloride (2.36 g,12.37 mmol) and reacted at 90℃for 12 hours. The reaction solution was poured into saturated sodium hydrogencarbonate solution (50 mL), ethyl acetate (50 mL) was added to the mixture to separate the mixture, the aqueous phase was extracted with ethyl acetate (50 mL. Times.3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The crude product was isolated by column chromatography on silica gel (petroleum ether: ethyl acetate=10:1). Compound 41-8 is obtained.

¹ H NMR(400MHz,CDCl ₃ )δ＝7.47-7.30(m,5H),7.15(d,J＝2.0Hz,1H),6.94(dd,J＝2.2,8.3Hz,1H),6.88-6.79(m,2H),6.73(s,1H),6.07(s,1H),5.24(dd,J＝2.4,12.3Hz,1H),5.20(s,2H),5.11-5.05(m,3H),3.52(s,3H),3.44-3.34(m,1H),1.90(s,3H),1.22(t,J＝7.1Hz,6H)。

Step 8:41-9 Synthesis

To a solution of starting material 41-8 (1.6 g,3.82 mmol) in methanol (16 mL) was added p-toluenesulfonic acid (1.97 g,11.47 mmol) and reacted at 50℃for 4 hours. The reaction solution was poured into 20mL of water, ethyl acetate (50 mL) was added thereto, and the organic phase was washed with saturated sodium hydrogencarbonate (20 ml×3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The crude product was directly taken to the next step without purification. Compound 41-9 is obtained.

¹ H NMR(400MHz,CDCl ₃ )δ＝7.49-7.30(m,5H),7.13(d,J＝1.5Hz,1H),7.02-6.79(m,2H),6.62-6.44(m,2H),6.06(s,1H),5.28-5.01(m,4H),3.45-3.30(m,1H),1.85(s,3H),1.20(t,J＝7.5Hz,6H)。

Step 9:41-10 synthesis

SFC (column type: REGIS (S, S) WHELK-O1 (250 mm. Times.25 mm,10 μm) of raw material 41-9 (1.9 g,5.07 mmol) was carried out, mobile phase: [ Neu-EtOH ]]60% -60%,8 min). Compound 41-10 is obtained. The analysis method comprises the following steps: column (S, S) -WHELK-O1, 50X 4.6mm I.D.,3.5 μm. Mobile phase A and CO ₂ IPA (0.05% IPAm, v/v. Gradient: phase B rising from 5% to 50% in 1 minute, maintaining for 1 minute, decreasing to 5% in 0.8 minute, flow rate: 3.4mL/min. Column temperature: 35 ℃ C. ABPR:1800psi. Compound 41-10 retention time: 1.624min.

Step 10:41-11 Synthesis

To a solution of raw material 41-10 (0.3 g, 801.13. Mu. Mol) in N, N dimethylformamide (5 mL) was added cesium carbonate (391.54 mg,1.20 mmol), BB-2 (536.50 mg,1.20 mmol), and the mixture was reacted at 60℃for 12 hours. The reaction solution was poured into a saturated sodium chloride solution, ethyl acetate was added to the solution (50 mL), the aqueous phase was extracted with ethyl acetate (50 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The crude product was isolated by column chromatography on silica gel (petroleum ether: ethyl acetate=2:1). Compound 41-11 is obtained.

¹ H NMR(400MHz,CDCl ₃ )δ＝7.47-7.35(m,15H),7.13(d,J＝1.8Hz,1H),6.96-6.79(m,2H),6.63(br d,J＝17.8Hz,2H),6.07(s,1H),5.25-5.06(m,8H),4.29(d,J＝9.9Hz,2H),3.40(td,J＝6.9,13.8Hz,1H),1.88(s,3H),1.22(t,J＝7.5Hz,6H)。

Step 11:41 synthesis

To a solution of raw materials 41 to 11 (250.00 mg, 385.37. Mu. Mol) in ethyl acetate (10 mL) was added palladium on carbon (0.2 g, palladium content: 5%), and the mixture was reacted under a hydrogen atmosphere at 15psi at 20℃for 2 hours. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure to give a crude product. The crude product was purified by preparative HPLC (column: phenomenex Gemini-NX 150X 30mM X5 μm; mobile phase: [ water (10 mM NH) ₄ HCO ₃ )-ACN]The method comprises the steps of carrying out a first treatment on the surface of the B (ACN)% > 5% -45% and 10 min). Compound 41 was obtained.

¹ H NMR(400MHz,CD ₃ OD)δ＝7.00(d,J＝2.1Hz,1H),6.84-6.75(m,2H),6.73-6.63(m,2H),6.01(s,1H),5.18(dd,J＝2.4,12.2Hz,1H),5.01(d,J＝12.0Hz,1H),4.05(d,J＝10.3Hz,2H),3.28-3.17(m,1H),1.83(s,3H),1.15(dd,J＝6.9,8.5Hz,6H)。

Examples 42 and 43

The synthetic route is as follows:

step 1:42-2 Synthesis

To a reaction flask containing starting material 42-1 (2 g,10.47 mmol) was added sulfuric acid solution (10 mL, 80%) followed by isopropanol (1.26 g,20.94 mmol) and reacted at 80℃for 4 hours. The reaction solution was poured into ice water, extracted with ethyl acetate (50 ml×2), the organic phases were combined, washed with saturated sodium bicarbonate solution (100 ml×2), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The crude product was isolated by column chromatography on silica gel (petroleum ether/ethyl acetate=20:1). Compound 42-2 was obtained. [ M+1 ]] ⁺ ＝233.1。

Step 2:42-3 Synthesis

To a solution of raw material 42-2 (7.3 g,31.32 mmol) in tetrahydrofuran (120 mL) was added cesium carbonate (15.31 g,46.98 mmol), benzyl bromide (5.36 g,31.32 mmol), and the mixture was reacted at 70℃for 4 hours. The reaction solution was poured into a saturated sodium chloride solution, ethyl acetate was added to the solution (100 mL), the aqueous phase was extracted with ethyl acetate (100 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The crude product was directly put into the next step without further purification. Compound 42-3 is obtained.

Step 3:42-4 Synthesis

To a solution of raw material 42-3 (2 g,6.19 mmol) (60 mL) was added n-butyllithium (2.5M, 2.60 mL) at-68℃and after 0.5 hour, a solution of intermediate BB-1 (1.71 g,6.19 mmol) in tetrahydrofuran (60 mL) was added, and after 1 hour of reaction, the temperature was naturally raised to 20℃and the reaction was carried out for 0.5 hour. The reaction solution was poured into a saturated ammonium chloride solution (100 mL), 100mL of ethyl acetate was added, the solution was separated, the aqueous phase was extracted with ethyl acetate (100 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The crude product was isolated by column chromatography on silica gel (petroleum ether: ethyl acetate=20:1). Compound 42-4 was obtained. [ Ms-17 ] ] ⁺ ＝503.3。

Step 4:42-5 Synthesis

Triethylsilane (1.00 g,8.64 mmol), trifluoroacetic acid (492.65 mg,4.32 mmol) was added to a solution of starting material 42-4 (1.5 g,2.88 mmol) in dichloromethane (50 mL) at 0deg.C, and reacted at 20deg.C for 2 hours. The reaction solution was poured into saturated sodium hydrogencarbonate solution (50 mL), dichloromethane (50 mL) was added to separate the solution, the aqueous phase was extracted with dichloromethane (50 ml×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The crude product was directly put into the next step without further purification. Compound 42-5 was obtained.

Step 5:42-6 Synthesis

To a solution of raw material 42-5 (1 g,1.98 mmol) in tetrahydrofuran (10 mL) was added a tetrahydrofuran solution of tetrabutylammonium fluoride (1M, 2.38 mL), and the mixture was reacted at 20℃for 1 hour. The reaction solution was concentrated under reduced pressure to obtain a crude product. Separation by column chromatography on silica gel (petroleum ether: ethyl acetate=5:1). Compound 42-6 was obtained. [ Ms+1 ]] ⁺ ＝389.3。

Step 6:42-7 Synthesis

To a solution of raw material 42-6 (0.5 g,1.28 mmol) in N, N-dimethylformamide (5 mL) was added cesium carbonate (625.79 mg,1.92 mmol), diethyl tosyloxymethyl phosphonate (412.71 mg,1.28 mmol), and the mixture was reacted at 60℃for 3 hours. The reaction solution was poured into a saturated sodium chloride solution (30 mL), ethyl acetate was added to the solution (50 mL), the aqueous phase was extracted with ethyl acetate (50 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The crude product was isolated by column chromatography on silica gel (petroleum ether: ethyl acetate=1:1). Compound 42-7 was obtained.

¹ H NMR(400MHz,DMSO-d ₆ )δ＝7.44-7.39(m,4H),7.38-7.33(m,1H),6.83(br d,J＝3.9Hz,2H),6.68-6.55(m,2H),4.99(s,2H),4.41-4.37(m,2H),4.34(dd,J＝3.7,8.7Hz,1H),4.16-4.08(m,4H),4.07-3.96(m,1H),3.25-3.14(m,1H),3.00(td,J＝8.1,16.4Hz,1H),2.88-2.75(m,1H),1.96-1.89(m,1H),1.87(s,3H),1.27(t,J＝7.1Hz,6H),1.05(dd,J＝5.0,6.9Hz,6H)。[Ms+1] ⁺ ＝541.2。

Step 7:42-8 Synthesis

To a solution of raw material 42-7 (0.6 g,1.11 mmol) in ethyl acetate (20 mL) was added palladium on carbon (0.3 g, palladium content: 5%), and the mixture was reacted under hydrogen atmosphere at 15psi at 20℃for 2 hours. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure to give a crude product. The crude product was directly taken to the next step without further purification. Compound 42-8 was obtained. [ Ms-1 ]] ^- ＝449.2。

Step 8:42-9 Synthesis

SFC (column: DAICEL CHIRALPAKAD (250 mm. Times.30 mm,10 μm): mobile phase: [0.1% NH) was carried out on starting material 42-8 (0.45 g, 998.94. Mu. Mol) ₃ H ₂ O IPA]38% -38%,5 min). Compound 42-9 was obtained. The analysis method comprises the following steps: column-type Chiralpak AD-3, 50X 4.6mm I.D.,3 μm. Mobile phase A: CO 2B: IPA (0.05% IPAm, v/v. Gradient: phase B rising from 5% to 50% in 1 min, maintaining for 1 min, decreasing to 5% in 0.8 min, flow rate: 3.4mL/min. Column temperature: 35 ℃ C. ABPR:1800psi. Compound 42-9 retention time: 1.258min.

Step 9:42 synthesis

To a solution of raw material 42-9 (50 mg, 110.99. Mu. Mol) in methylene chloride (2 mL) at 0℃was added trimethylbromosilane (169.92 mg,1.11 mmol), and the mixture was reacted at 20℃for 12 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. Separation was performed by preparative HPLC (column type Phenomenex luna C, 18, 80, 40mm, 3 μm; mobile phase: [ water (0.04% HCl) -ACN ]; B (ACN)%: 40% -62%,7 min). Compound 42 was obtained.

¹ H NMR(400MHz,CD ₃ OD)δ＝6.79(s,1H),6.65(br d,J＝11.3Hz,2H),6.41(dd,J＝1.8,11.7Hz,1H),4.26(br dd,J＝3.4,8.6Hz,1H),4.20(d,J＝10.4Hz,2H),3.28-3.21(m,1H),3.06-2.92(m,1H),2.87-2.75(m,1H),2.54(qd,J＝8.6,12.7Hz,1H),1.99-1.89(m,4H),1.15(t,J＝6.6Hz,6H)。[Ms+1] ⁺ ＝395.2。

Step 10:43 synthesis

To a solution of raw material 42 (0.11 g, 278.92. Mu. Mol) in N, N-dimethylformamide (4 mL) was added pyridine (0.4 mL), dicyclohexylcarbodiimide (172.65 mg, 836.77. Mu. Mol), BB-2 (57.26 mg, 306.82. Mu. Mol), and the mixture was reacted at 50℃for 16 hours. Ethyl acetate (200 mL), 10% citric acid (100 mL. Times.2) and a half-saturated sodium chloride solution (100 mL. Times.2) were added to the reaction mixture, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by column chromatography on silica gel (petroleum ether: ethyl acetate=1:1 to 0:1) to give crude product of the target compound as colourless oil, which was separated by preparative HPLC (column form: waters Xbridge BEH C100 x 30mM x 10 μm; mobile phase: [ water (10 mM NH ₄ HCO ₃ )-ACN]The method comprises the steps of carrying out a first treatment on the surface of the B (ACN)% > 50% -80%,8 min). Compound 43 was obtained.

¹ H NMR(400MHz,CDCl ₃ ):δ＝7.39(s,1H),7.28-7.36(m,2H),7.20-7.25(m,1H),6.95(s,1H),6.80(br d,J＝9.7Hz,2H),6.63(s,2H),5.65(br d,J＝11.3Hz,1H),4.65-4.78(m,1H),4.38-4.57(m,4H),3.06-3.21(m,2H),2.88(ddd,J＝16.3,8.9,3.2Hz,1H),2.56-2.63(m,1H),2.38-2.50(m,1H),2.11-2.18(m,1H),2.06(td,J＝8.5,4.1Hz,1H),1.99(s,3H),1.20-1.25ppm(m,6H)。

Example 44

The synthetic route is as follows:

step 1:44 synthesis

Compound 14 (90.47 mg, 231.72. Mu. Mol) was dissolved in dimethylformamide (5 mL) and pyridine (0.5 mL), dicyclohexylcarbodiimide (143.43 mg, 695.17. Mu. Mol) was added, BB-2 (43.25 mg, 231.72. Mu. Mol) and the reaction was stirred at 70℃for 16 hours. Ethyl acetate (50 mL), 10% citric acid (25 mL. Times.2) and a half-saturated sodium chloride solution (25 mL. Times.2) were added to the reaction mixture, and the ethyl acetate layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purifying the crude product by silica gel column chromatography (petroleum ether: ethyl acetate=1:1, eluting other impurities, petroleum ether: ethyl acetate=3:7 to obtain compound 44 crude product), and subjecting the crude product to preparative HPLC (column: waters Xbridge BEH C: 100×30mm×10 μm; mobile phase: [ H.) ₂ O(10mMNH ₄ HCO ₃ )-ACN]The method comprises the steps of carrying out a first treatment on the surface of the B (ACN)% > 50% -80%, and purifying for 10 min. Compound 44 was obtained.

¹ H NMR(400MHz,CDCl ₃ )δ＝7.43(s,1H),7.35-7.29(m,2H),7.26-7.22(m,1H),6.88(d,J＝1.6Hz,1H),6.61(s,2H),6.58(d,J＝8.1Hz,1H),6.52-6.47(m,1H),5.68-5.61(m,1H),4.76(s,1H),4.73-4.65(m,1H),4.56-4.46(m,1H),4.43(d,J＝9.4Hz,2H),4.14-4.08(m,1H),3.21-3.11(m,1H),2.88-2.74(m,2H),2.56-2.42(m,1H),2.17-2.10(m,1H),2.09-1.99(m,1H),1.95(br s,1H),1.92(s,3H),1.66(br d,J＝3.0Hz,2H),1.21(dd,J＝6.9,11.4Hz,6H)。

Example 45

The synthetic route is as follows:

step 1:45 synthesis

Compound 28 (80 mg, 205.98. Mu. Mol) was dissolved in N, N-dimethylformamideTo (4 mL) and pyridine (0.4 mL) was added dicyclohexylcarbodiimide (212.50 mg,1.03 mmol), BB-2 (38.44 mg, 205.98. Mu. Mol), and the reaction was stirred at 70℃for 16 hours. Ethyl acetate (50 mL), 10% citric acid (25 mL. Times.2) and a half-saturated sodium chloride solution (25 mL. Times.2) were added to the reaction mixture, and the ethyl acetate layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purifying the crude product by silica gel column chromatography (petroleum ether: ethyl acetate=1:1, eluting other impurities, petroleum ether: ethyl acetate=3:7) to obtain crude product of compound 45, and subjecting the crude product to preparative HPLC (column: waters Xbridge BEH C: 100 x 30mm x 10 μm; mobile phase: [ H.) ₂ O(10mM NH ₄ HCO ₃ )-ACN]The method comprises the steps of carrying out a first treatment on the surface of the B (ACN)% > 50% -80%, and purifying for 10 min. Compound 45 was obtained.

¹ H NMR(400MHz,CDCl ₃ )δ＝7.45-7.41(m,1H),7.35-7.28(m,2H),7.26-7.23(m,1H),6.93(s,1H),6.74(s,3H),6.61-6.57(m,1H),5.67-5.61(m,1H),5.53-5.44(m,1H),4.75-4.65(m,1H),4.56-4.46(m,1H),4.44(d,J＝9.6Hz,2H),4.27(dd,J＝3.8,8.6Hz,1H),3.09-2.97(m,1H),2.89-2.78(m,1H),2.62-2.43(m,2H),2.14(br dd,J＝2.3,14.8Hz,1H),2.03-1.95(m,1H),1.92(s,3H),1.31(s,3H),0.75(s,4H)。

Example 46

The synthetic route is as follows:

step 1:46-1 synthesis

39-1 (1 g,2.06 mmol) was dissolved in tetrahydrofuran (10 mL), nitrogen was replaced 3 times, lithium diisopropylamide (2M, 4.13 mL) was slowly added dropwise at 20℃and reacted for 0.5h; then, a solution of methyl iodide (1.46 g,10.31 mmol) in tetrahydrofuran (0.5 mL) was slowly added dropwise thereto, the reaction was continued for 15.5 hours, and under the protection of nitrogen, a saturated solution of ammonium chloride (50 mL) was slowly added dropwise thereto to quench the reaction, and an organic phase was separated by extraction with ethyl acetate (50 mL), dried over anhydrous sodium sulfate and dried to give compound 46-1.

[Ms+1] ⁺ ＝513.3

Step 2:46-2 synthesis

46-1 (500 mg, 975.05. Mu. Mol) was dissolved in methanol (10 mL), stirring was started, ammonium fluoride (361.13 mg,9.75 mmol) was added, the temperature was raised to 50 ℃, the reaction was carried out for 2 hours, methylene chloride (20 mL) and water (20 mL) were added to the reaction system for extraction, an organic phase was obtained by separation, dried over anhydrous sodium sulfate and spin-dried, and crude compound was obtained by purification through silica gel column chromatography (petroleum ether: ethyl acetate=10:1 to 5:1), chiral separation: pillar DAICEL CHIRALPAKAD (250 mm. Times.30 mm,10 μm); mobile phase [0.1% NH ] ₃ H ₂ O EtOH]33% -33%, obtaining compound 46-2 after 11min, and determining the structure of the compound by HNMR. Analysis method of chiral separation: column-type ChiralpakAD-3, 50X 4.6mm I.D.,3 μm. Mobile phase A and CO ₂ EtOH (0.05% IPAm, v/v). Gradient from 5% to 50% in 1.2 minutes for phase B and 5% in 0.8 minutes for 1 minute. The flow rate was 3.4mL/min. Column temperature 35 ℃. ABPR 1800psi. Retention time of compound 46-2: 1.249min.

¹ H NMR(400MHz,CDCl ₃ )δ＝7.42-7.24(m,5H),7.14(d,J＝2.2Hz,1H),7.05(dd,J＝2.1,8.2Hz,1H),6.83(d,J＝8.3Hz,1H),6.65(d,J＝2.3Hz,1H),6.38(d,J＝2.0Hz,1H),5.96(s,1H),5.06-5.01(m,2H),4.58(br s,1H),3.38(spt,J＝7.0Hz,1H),1.93-1.87(m,3H),1.27(s,6H),1.18(s,3H),1.16(s,3H)。

Step 3:46-3 synthesis

46-2 (160 mg, 401.47. Mu. Mol) was dissolved in N, N-dimethylformamide (0.6 mL), stirring was started, cesium carbonate (261.61 mg, 802.94. Mu. Mol) and diethyl p-toluenesulfonyloxymethylphosphonate (129.40 mg, 401.47. Mu. Mol) were added, the temperature was raised to 50℃for 3 hours, methylene chloride (10 mL) and water (10 mL) were added for extraction, an organic phase was separated, dried over anhydrous sodium sulfate, and dried by spin-drying to give a crude compound, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate=10:1 to 3:1) to give a compound 46-3.

¹ H NMR(400MHz,CDCl ₃ )δ＝7.53-7.32(m,5H),7.21(d,J＝2.0Hz,1H),7.12(dd,J＝2.1,8.3Hz,1H),6.92(d,J＝8.3Hz,1H),6.86(d,J＝2.1Hz,1H),6.59(d,J＝2.0Hz,1H),6.08(s,1H),5.13(s,2H),4.37-4.23(m,6H),3.46(spt,J＝6.8Hz,1H),2.00(s,3H),1.39(t,J＝7.1Hz,6H),1.35(s,6H),1.25(d,J＝7.0Hz,6H)。

³¹ P NMR(400MHz,CDCl ₃ )δppm 19.669

Step 4:46-4 synthesis

To a solution of 46-3 (20 mg, 36.45. Mu. Mol) in ethyl acetate (0.8 mL) was added Pd/C (20 mg,5% palladium content), the stirring was turned on, and the mixture was reacted under a hydrogen balloon atmosphere at 15psi for 1.5 hours at 25℃and the reaction system was filtered through celite, and the filtrate was spin-dried to give compound 46-4.

¹ H NMR(400MHz,CDCl ₃ )δ＝6.93(d,J＝1.9Hz,1H),6.79-6.63(m,3H),6.57(d,J＝2.1Hz,1H),4.34-4.22(m,7H),3.19(spt,J＝6.9Hz,1H),2.45(dd,J＝8.5,12.8Hz,1H),1.89(dd,J＝6.9,12.8Hz,1H),1.80(s,3H),1.38(t,J＝7.1Hz,6H),1.27(s,3H),1.23-1.18(m,9H)。

³¹ P NMR(400MHz,CDCl ₃ )δppm 19.874。

Step 5:46-5 synthesis

This procedure was used for resolution of intermediate 46-4, via chiral separation (column: DAICEL CHIRALPAKAD (250 mm. Times.30 mm,10 μm); mobile phase: [ Neu-IPA)]30% -30%,10 min) to obtain compound 46-5, and determining the structure of the compound by HNMR and PNMR. The analysis method comprises the following steps: column-type ChiralpakAD-3, 50X 4.6mm, I.D.,3 μm. Mobile phase A and CO ₂ IPA (0.05% ethyl acetate D). Gradient from 5% to 50% in 1.2 minutes for phase B and 5% in 0.8 minutes for 1 minute. The flow rate was 3.4mL/min. Column temperature 35 ℃. ABPR 1800psi. Retention time of compound 46-5: 1.149min.

¹ H NMR(400MHz,CDCl ₃ )δ＝6.93(d,J＝1.8Hz,1H),6.74-6.66(m,2H),6.64(d,J＝2.3Hz,1H),6.57(d,J＝2.0Hz,1H),4.35-4.18(m,7H),3.21(spt,J＝6.9Hz,1H),2.45(dd,J＝8.5,12.8Hz,1H),1.89(dd,J＝6.9,12.8Hz,1H),1.81(s,3H),1.38(t,J＝7.0Hz,6H),1.27(s,3H),1.24-1.17(m,9H)。

³¹ P NMR(400MHz,CDCl ₃ )δppm 19.870。

Step 8:46 synthesis

46-5 (25.00 mg, 54.28. Mu. Mol) was dissolved in methylene chloride (0.5 mL), stirring was turned on, trimethylbromosilane (83.10 mg, 542.84. Mu. Mol, 70.43. Mu.L) was added, the reaction was carried out at 25℃for 16 hours, the reaction system was dried by spinning, and then anhydrous methylene chloride (2 mL. Times.2) was added and dried by spinning twice to obtain a crude compound, which was dissolved in acetonitrile (30 mL) and water (30 mL) to obtain a compound 46.

¹ H NMR(400MHz,CD ₃ OD)δ＝6.83(s,1H),6.73-6.54(m,4H),4.25(br t,J＝7.5Hz,1H),4.20(br d,J＝10.4Hz,2H),3.26-3.18(m,1H),2.42(dd,J＝8.5,12.8Hz,1H),1.84(br dd,J＝6.6,12.8Hz,1H),1.79(s,3H),1.27(s,3H),1.21(s,3H),1.13(dd,J＝1.9,6.8Hz,6H)。

³¹ P NMR(400MHz,CD ₃ OD)δppm 18.000。

Example 47

The synthetic route is as follows:

step 1:47-1 Synthesis

39-1 (1.7 g,3.51 mmol) is dissolved in tetrahydrofuran (8 mL), nitrogen is replaced for 3 times, the temperature is reduced to-70 ℃, lithium diisopropylamide (2M, 5.26 mL) is slowly added dropwise for reaction for 1h, then a solution of 1, 2-dibromoethane (3.29 g,17.54mmol,1.32 mL) in tetrahydrofuran (0.7 mL) is slowly added dropwise for reaction for 2h, saturated solution of ammonium chloride (10 mL) is slowly added dropwise for quenching reaction under the protection of nitrogen, ethyl acetate (10 mL) is added for extraction to obtain an organic phase, anhydrous sodium sulfate is dried, and a crude compound is obtained by spin drying; purification by column chromatography on silica gel (petroleum ether: ethyl acetate=1:0) gives compound 47-1.

¹ H NMR(400MHz,CDCl ₃ )δ＝7.53-7.32(m,5H),7.29(d,J＝2.1Hz,1H),7.18(dd,J＝2.1,8.2Hz,1H),6.93(d,J＝8.3Hz,1H),6.50(d,J＝2.0Hz,1H),6.32(d,J＝2.0Hz,1H),5.93(s,1H),5.13(s,2H),3.47(spt,J＝6.9Hz,1H),2.03(s,3H),1.69-1.64(m,2H),1.54-1.51(m,2H),1.25(d,J＝6.9Hz,6H),1.00(s,8H),0.24-0.18(m,6H)。

Step 2:47-2 Synthesis

47-1 (1 g,1.96 mmol) was dissolved in methanol (9 mL), stirring was started, ammonium fluoride (725.10 mg,19.58 mmol) was added, the temperature was raised to 50℃and the reaction was carried out for 2 hours, water (100 mL) and methylene chloride (100 mL. Times.2) were added for extraction, an organic phase was separated, dried over anhydrous sodium sulfate, and dried by spin-drying to give a crude compound, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate=1:0 to 10:1) to give compound 47-2.

¹ H NMR(400MHz,CDCl ₃ )δ＝7.51-7.34(m,5H),7.28(d,J＝2.1Hz,1H),7.22-7.13(m,1H),6.93(d,J＝8.3Hz,1H),6.49(d,J＝1.9Hz,1H),6.36(d,J＝2.1Hz,1H),5.92(s,1H),5.13(s,2H),4.87(s,1H),3.47(spt,J＝6.9Hz,1H),2.04(s,3H),1.73-1.65(m,2H),1.57-1.50(m,2H),1.26(s,3H),1.24(s,3H)。

Step 3:47-3 Synthesis

47-2 (0.7 g,1.77 mmol) was dissolved in N, N-dimethylformamide (7 mL) and stirring was turned on; cesium carbonate (1.15 g,3.53 mmol) and diethyl p-toluenesulfonyloxymethylphosphonate (540.54 mg,1.68mmol, 432.43. Mu.L) were added, heated to 50deg.C, reacted for 3 hours, ethyl acetate (100 mL) and water (50 mL. Times.2) were added to the reaction system to extract, the organic phases were combined and dried by spin to give crude compound, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate=10:1 to 3:1) to give compound 47-3.

¹ H NMR(400MHz,CDCl ₃ )δ＝7.58-7.31(m,5H),7.16(dd,J＝2.1,8.3Hz,1H),6.93(d,J＝8.3Hz,1H),6.63(d,J＝2.0Hz,1H),6.47(d,J＝2.3Hz,1H),5.96(s,1H),5.13(s,2H),4.36-4.20(m,6H),3.56-3.36(m,1H),2.11-2.03(m,3H),1.75-1.66(m,2H),1.57-1.52(m,2H),1.38(t,J＝7.1Hz,6H),1.25(d,J＝6.9Hz,6H)。

Step 4:47-4 Synthesis

47-3 (200 mg, 365.88. Mu. Mol) was added to a Pd/C (60 mg,5% palladium content) solution of ethyl acetate (6 mL), stirring was turned on, and the mixture was reacted under hydrogen balloon atmosphere at 15psi at 25℃for 1.5 hours, the reaction system was filtered through celite, and the filtrate was spin-dried to give a crude compound, which was then prepared into a liquid phase (column: waters Xbridge BEH C: 100X 25 mm. Mu.m; mobile phase: H) ₂ O(10mM NH ₄ HCO ₃ )-ACN]The method comprises the steps of carrying out a first treatment on the surface of the B (ACN)%: 50% -80%, purifying for 10min to obtain compound 47-4, and determining the structure of the compound by HNMR and PNMR.

¹ H NMR(400MHz,CD ₃ OD)δ＝6.75(d,J＝2.3Hz,1H),6.69(d,J＝2.0Hz,1H),6.51-6.41(m,3H),6.04(d,J＝1.8Hz,1H),4.27(d,J＝2.0Hz,1H),4.13(d,J＝10.4Hz,2H),3.09(td,J＝6.8,13.8Hz,1H),2.53-2.36(m,2H),1.86(s,3H),1.16(t,J＝7.4Hz,3H),1.01(dd,J＝6.0,6.8Hz,7H),0.00(s,1H)。

³¹ P NMR(400MHz,CD ₃ OD)δppm 18.094

Step 5:47-5 Synthesis

This procedure was used for resolution of intermediate 47-4, via chiral separation (column: DAICEL CHIRALPAKAD (250 mm. Times.30 mm,10 μm); mobile: [0.1% NH) ₃ .H ₂ O IPA]20% -20%,10 min) to obtain compound 47-5, and determining the structure of the compound by HNMR and PNMR. The analysis method comprises the following steps: column-type ChiralpakAD-3, 50X 4.6mm, I.D.,3 μm. Mobile phase A and CO ₂ IPA (0.05% IPAm, v/v). Gradient from 5% to 50% in 1.2 minutes for phase B and 5% in 0.8 minutes for 1 minute. The flow rate was 3.4mL/min. Column temperature 35 ℃. ABPR 1800psi. Retention time of compound 47-5: 1.230min.

¹ H NMR(400MHz,CDCl ₃ )δ＝7.00(d,J＝2.1Hz,1H),6.76(dd,J＝2.1,8.2Hz,1H),6.66(d,J＝8.0Hz,1H),6.50(d,J＝1.9Hz,1H),6.16(d,J＝2.3Hz,1H),4.31(dd,J＝3.5,9.1Hz,1H),4.28-4.19(m,6H),3.20(spt,J＝6.9Hz,1H),2.76(dd,J＝9.2,12.8Hz,1H),1.96-1.87(m,4H),1.37(t,J＝7.1Hz,6H),1.21(dd,J＝6.9,9.9Hz,6H),1.03-0.86(m,4H)。

³¹ P NMR(400MHz,CDCl ₃ )δppm 19.790。

Step 6:47 synthesis

47-5 (25 mg, 54.52. Mu. Mol) was dissolved in methylene chloride (0.5 mL), stirring was started, trimethylbromosilane (83.47 mg, 545.23. Mu. Mol) was added, the reaction system was dried by spinning at 25℃for 16 hours, and then anhydrous methylene chloride (2 mL. Times.2) was added and dried by spinning twice to obtain a crude compound, which was dissolved in acetonitrile (30 mL) and water (30 mL) to obtain compound 47.

¹ H NMR(400MHz,CD ₃ OD)δ＝6.85(s,1H),6.80(s,1H),6.62-6.52(m,3H),6.15(s,1H),4.39(br s,1H),4.33-4.11(m,3H),3.23-3.12(m,1H),2.61-2.47(m,2H),1.97(s,3H),1.32-1.20(m,4H),1.13(t,J＝6.4Hz,6H)。

³¹ P NMR(400MHz,CD ₃ OD)δppm 18.013。

Example 48

The synthetic route is as follows:

step 1:48 synthesis

A dry clean thumb flask was taken, 46 (15.00 mg, 37.09. Mu. Mol) and N, N-dimethylformamide (0.5 mL) were added, stirring was turned on, dicyclohexylcarbodiimide (45.92 mg, 222.53. Mu. Mol, 45.01. Mu.L) and pyridine (44.01 mg, 556.33. Mu. Mol, 44.90. Mu.L) were then added, BB-2 (8.31 mg, 44.51. Mu. Mol) was added, and the reaction was carried out at 55℃for 16h. Ethyl acetate (10 mL) and H were added to the reaction system ₂ O (10 mL. Times.3) extraction, separation of organic phase, anhydrous sodium sulfate drying, spin drying to obtain crude compound. Compound 48 had an Rf value of 0.4 according to thin layer chromatography (petroleum ether: ethyl acetate=1:2), and was purified by silica gel thin layer chromatography (petroleum ether: ethyl acetate=1:2) to give a crude compound, which was further purified by silica gel column chromatography (petroleum ether: ethyl acetate=5:1 to 1:1) to give compound 48.

¹ H NMR(400MHz,CDCl ₃ )δ＝7.44(s,1H),7.36-7.28(m,3H),6.94(d,J＝1.9Hz,1H),6.74(dd,J＝2.1,8.1Hz,1H),6.65(d,J＝8.1Hz,2H),6.59(s,1H),5.65(br d,J＝11.0Hz,1H),4.69(br d,J＝11.5Hz,2H),4.45(br d,J＝9.6Hz,2H),4.30(br t,J＝7.6Hz,1H),3.18(td,J＝6.8,13.7Hz,1H),2.54-2.40(m,2H),2.14(br d,J＝14.6Hz,1H),1.97-1.79(m,4H),1.27(br d,J＝5.8Hz,6H),1.23(d,J＝2.4Hz,3H),1.21-1.20(m,3H)。

³¹ P NMR(400MHz,CDCl ₃ )δppm 15.833。

Example 49

The synthetic route is as follows:

step 1: synthesis of Compound 49

A dry, clean 50mL single-necked flask was charged with 30 (280 mg, 675.04. Mu. Mol) and N, N-dimethylformamide (8.5 mL), stirring was turned on, and dicyclohexylcarbodiimide (835.68 mg,4.05mmol, 819.30. Mu.L) and pyridine (800.93 mg,10.13mmol, 817.28. Mu.L) were then added, BB-2 (151.18 mg, 810.05. Mu. Mol,1.2 eq) was added, the temperature was raised and the reaction was controlled at 55℃for 16 hours. Ethyl acetate (10 mL) and saturated brine (10 ml×3) were added to the reaction system to extract, an organic phase was separated, dried over anhydrous sodium sulfate, and spin-dried to give a crude compound, which was purified by thin layer chromatography (petroleum ether: ethyl acetate=1:2, r _f =0.4), followed by purification by silica gel column chromatography (petroleum ether: ethyl acetate=5:1-1:1) to give crude compound, which was purified by preparative HPLC (column form: kromasil C18 (250×50mm×10 μm); mobile phase [ H ] ₂ O(10mM NH ₄ HCO ₃ )-ACN]The method comprises the steps of carrying out a first treatment on the surface of the ACN%:45% -85%,10 mm) to give compound 49.

¹ H NMR(400MHz,CD ₃ OD)δ＝7.47(s,1H),7.40-7.26(m,3H),6.96(d,J＝1.9Hz,1H),6.88(d,J＝2.1Hz,1H),6.55-6.36(m,2H),5.82-5.69(m,1H),4.72(tt,J＝3.2,11.6Hz,1H),4.64-4.46(m,4H),3.17-3.00(m,2H),2.96-2.83(m,1H),2.56(qd,J＝8.8,12.8Hz,1H),2.46-2.32(m,1H),2.28-2.19(m,1H),2.08-1.94(m,1H),1.02(dd,J＝7.0,10.1Hz,6H).

¹⁹ F NMR(400MHz,DMSO)δppm-123.731.

³¹ P NMR(400MHz,DMSO)δppm 16.331.

Example 50

The synthetic route is as follows:

step 1: synthesis of Compound 50-2

Compound 50-1 (15 g,47.67mmol,95% purity) was dissolved in acetonitrile (150 mL), benzyl bromide (8.15 g,47.67 mmol) was added, cesium carbonate (23.30 g,71.51 mmol) was reacted at 70℃for 12 hours, cooled to room temperature, ethyl acetate (200 mL) was added, water (150 mL) was extracted, the organic phase was collected, the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was separated by column chromatography (petroleum ether: ethyl acetate=5:1) to give compound 50-2.

¹ H NMR(400MHz,CDCl ₃ )δ＝7.92(d,J＝2.4Hz,1H),7.51-7.46(m,2H),7.45-7.32(m,4H),6.72(d,J＝8.8Hz,1H),5.14(s,2H)

Step 2: synthesis of Compound 50-3

Compound 50-2 (19 g,48.84 mmol) was dissolved with diethyl malonate (15.65 g,97.68 mmol), cesium carbonate (23.87 g,73.26 mmol) in dioxane (190 mL), stirred for 15 min, purged 3 times with nitrogen, cuprous iodide (1.40 g,7.33 mmol) and 2-picolinic acid (1.20 g,9.77 mmol) were added and the reaction was carried out at 105℃for 15 hours. Cooled to room temperature, ethyl acetate (100 mL. Times.2) was added, 100mL of water was used for extraction, the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product. The crude product was isolated by column chromatography (petroleum ether: ethyl acetate=5:1) to give compound 50-3.

¹ H NMR(400MHz,CDCl ₃ )δ＝7.47(d,J＝2.4Hz,1H),7.40-7.29(m,6H),6.85-6.77(m,1H),5.12-5.02(m,3H),4.22-4.20(m,4H),3.40-3.31(m,2H),1.27(br t,J＝3.5Hz,6H)

Step 3: synthesis of Compound 50-4

Lithium aluminum hydride (4.87 g,128.18 mmol) was dissolved in tetrahydrofuran (90 mL), and a solution of 50-3 (18 g,42.73 mmol) in tetrahydrofuran (90 mL) was slowly added dropwise at-10℃and the reaction was carried out at 25℃for 3 hours. The reaction solution was poured into a 10% aqueous solution of potassium bisulfate to quench the reaction, ethyl acetate (200 mL. Times.3) was added, 200mL of water was used for extraction, and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product. The crude product was isolated by column chromatography (petroleum ether: ethyl acetate=1:1) to give compound 50-4.

¹ H NMR(400MHz,CDCl ₃ )δ＝7.33-7.19(m,6H),7.17-7.10(m,1H),6.63(d,J＝8.7Hz,1H),4.92(s,2H),3.66(quin,J＝8.8Hz,1H),2.28-2.18(m,2H),2.07-1.84(m,3H),1.77-1.66(m,1H)

Step 4: synthesis of Compound 50-5

50-4 (6.9 g,20.46 mmol) was dissolved in tetrahydrofuran (70 mL), cooled to-68℃and lithium diisopropylamide (2M, 10.23 mL) was slowly added dropwise, the reaction was carried out at-68℃for 15 minutes, the temperature was raised to 10℃and stirred for 0.5 hours, a solution of p-toluenesulfonyl chloride (4.29 g,22.51 mmol) in tetrahydrofuran (8 mL) was slowly added dropwise, the temperature was cooled to-20℃and stirred for 0.5 hours, the reaction was carried out at 25℃and quenched by adding 20mL of saturated aqueous ammonium chloride solution to the reaction solution. Ethyl acetate (200 mL), water (100 mL) were extracted, the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product. The crude product was separated by column chromatography to give compound 50-5.

Step 5: synthesis of Compound 50-6

50-5 (6 g,12.21 mmol) was dissolved in N, N dimethylformamide (240 mL), sodium hydrogen (1.47 g,36.63 mmol) was added at 0deg.C, the reaction was carried out at 25deg.C for 12 hours, and the reaction solution was poured into 200mL of water. Ethyl acetate (300 mL) was added, water (100 mL) was extracted, and the organic phase was collected, washed with supersaturated brine (100 ml×3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product. The crude product was isolated by column chromatography (petroleum ether: ethyl acetate=3:1) to give compound 50-6.[ Ms+1 ]] ⁺ ＝320.1

Step 6: synthesis of Compound 50-7

50-6 (694 mg,2.17 mmol) was dissolved in tetrahydrofuran (5 mL), n-butyllithium (2M, 1.30 mL) was added at-68℃and the reaction was carried out at-68℃for 0.5 hours, a solution of BB-1 (601.06 mg,2.17 mmol) in tetrahydrofuran (5 mL) was added, the reaction was carried out at 20℃for 1 hour, 10mL of saturated aqueous ammonium chloride solution was added to quench the reaction solution, ethyl acetate (50 mL) was added, water (100 mL) was extracted, the organic phase was collected, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated by column chromatography (petroleum ether: ethyl acetate=3:1) to give compound 50-7.[ Ms-18 ] ] ⁺ ＝499.2

Step 7: synthesis of Compound 50-8

50-7 (327 mg, 632.81. Mu. Mol) was dissolved in methylene chloride (2 mL), triethylsilane (220.74 mg,1.90 mmol) was added at 0deg.C, and the reaction was performed with trifluoroacetic acid (108.23 mg, 949.22. Mu. Mol) at 25deg.C for 12 hours. Concentrating under reduced pressure to obtain compound 50-8.[ Ms+1 ]] ⁺ ＝501.2

Step 8: synthesis of Compound 50-9

50-8 (335 mg, 669.01. Mu. Mol) was dissolved in a mixed solvent of methanol (2 mL) and tetrahydrofuran (2 mL), and ammonium fluoride (247.78 mg,6.69 mmol) was added thereto, and the reaction was carried out at 25℃for 12 hours. Concentrating under reduced pressure to obtain crude product. The crude product was separated by column chromatography (petroleum ether: ethyl acetate=1:1) to give compound 50-9.[ Ms+1 ]] ⁺ ＝385.1

Step 9: synthesis of Compounds 50-10

50-9 (70 mg, 181.12. Mu. Mol) was dissolved in N, N-dimethylformamide (5 mL), cesium carbonate (88.52 mg, 271.68. Mu. Mol) was added, and dibenzyl p-toluenesulfonyloxymethyl phosphonate (80.86 mg, 181.12. Mu. Mol) was reacted at 50℃for 12 hours. Cooled to room temperature, ethyl acetate (20 mL) was added, water (20 mL) was used for extraction, the organic phase was collected, the organic phase was washed with supersaturated brine (20 mL. Times.3), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product. The crude product was isolated by column chromatography (petroleum ether: ethyl acetate=1:1) to give compounds 50-10.[ Ms+1 ] ] ⁺ ＝683.2

Step 10: synthesis of Compound 50-11

SFC resolution of 50-10 (40 mg, 60.54. Mu. Mol). SFC (column: DAICEL CHIRALPAKAD (250 mm. Times.30 mm,10 μm); mobile phase: [ Neu-IPA)]50% -50%,15 min). Obtaining the compound 50-11. The analysis method comprises the following steps: column type: chiralcel OJ-3, 50X 4.6mm I.D.,3 μm. Mobile phase A and CO ₂ EtOH (0.05% IPAm, v/v. Gradient: phase B rising from 5% to 50% in 1 min, maintaining for 1 min, decreasing to 5% in 0.8 min. Flow rate: 3.4mL/min. Column temperature: 35 ℃ C. ABPR:1800psi. Compound 50-11 retention time: 1.593min.

Step 11: synthesis of Compound 50

50-11 (8 mg, 12.11. Mu. Mol) was dissolved in methanol (3 mL), wet palladium on carbon (10 mg,5% palladium content) was added, and the reaction was carried out at 15psi,15℃for 3 hours by passing hydrogen gas. The reaction solution is filtered, and the filtrate is decompressed and concentrated to obtain a crude product. The crude product was purified by preparative HPLC (column: phenomenex Gemini-NXC1875X100 mm. Times.3μm; mobile phase: [ H ] ₂ O(10mM NH ₄ HCO ₃ )-ACN]The method comprises the steps of carrying out a first treatment on the surface of the ACN%:10% -30%,8 min) to give compound 50.[ Ms+1 ]] ⁺ ＝391.1

Biological test data

Experimental example 1: determination of Biochemical Activity of thyroid hormone receptor-beta agonists

Experimental materials:

thyroid receptor protein beta coactivation kit: thermoFisher Cat#PV4686

Fluorescent peptide segment SCR2-2terbium marked anti GST antibody

Experimental steps and methods:

the agonist compound screening is carried out by using a thyroid receptor protein beta coactivation experimental kit by utilizing the time-resolved fluorescence resonance energy transfer principle, and is briefly described as follows:

1) DMSO-dissolved compounds were transferred to 384 well plates using an ECHO liquid workstation, 10 gradient concentrations of each compound, 3-fold dilution, double-multiplexed wells.

2) mu.L of Buffer C solution was added to each well, followed by 10. Mu.L of a mixture of fluorescent SCR2-2 peptide, terbium-labeled anti-GST antibody and thyroreceptor protein beta.

3) After 2 hours incubation at normal temperature. The relevant signal values of the energy transfer were read at 340nm excitation, 495nm and 520 nm.

Data analysis:

the GraphPad Prism of the mapping software is used for fitting a curve according to the ratio of the concentration of the compound to the 520nm signal and the 495nm signal, calculating 50% effective activation concentration, and obtaining the compound EC ₅₀ In each experiment, the reference compound triiodothyronine (T3) was used as a positive control for the experiment. Calculation of the Z factor (greater than 0.5) will be used to monitor the stability of each experiment. The experimental results are shown in Table 6.

TABLE 6 determination of Biochemical Activity of thyroid hormone receptor-beta agonists

Conclusion: the compound has stronger agonistic activity to thyroid receptor beta.

Experimental example 2 pharmacokinetic test of rat

SD male rat test animals are selected for this study, and the drug concentration in plasma of test compound 6 at various time points of oral administration to rats is quantitatively determined using LC/MS/MS method to evaluate the pharmacokinetic profile of the test drug in the rat.

The clarified solution of test compound was injected into SD rats via the tail vein (overnight fast, 7-10 weeks old) and the test compound was administered parenterally to SD rats (overnight fast, 7-10 weeks old). Animals were bled from the jugular or caudal vein at 0.0833,0.25,0.5,1,2,4,6,8 and 24 hours post-administration with about 200 μl and placed in an anticoagulant tube with EDTA-K2 added, and plasma was collected by centrifugation at 3200g for 10min at 4 ℃. The LC-MS/MS method is adopted to measure the blood concentration, and Phoenix WinNonlin 6.3.3 pharmacokinetic software is used to calculate the relevant pharmacokinetic parameters by a non-atrioventricular model linear logarithmic trapezoidal method. The experimental results are shown in Table 7.

TABLE 7 pharmacokinetic parameters of the compounds of the invention in rats

Note that: 3 represents herein that compound 3 is an in vivo metabolite of compound 6; N/A represents either not measured or not obtained.

Conclusion of experiment: the bioavailability of the compound of the invention is better.

Experimental example 3 tissue distribution test of mice

The study selects C57BL/6J male mouse test animals, and the drug concentration of the test compound in the plasma, liver and heart at different time points of oral administration of the mice is quantitatively measured by using LC/MS/MS method to evaluate the pharmacokinetic characteristics of the test drug in the mice.

The test compound solution was administered to mice by gavage (overnight fast, 6-8 weeks of age). Animals were bled 40 μl from the saphenous vein of mice 1, 2 and 8 hours after dosing, placed in an anticoagulant tube with EDTA-K2 added, plasma was collected by centrifugation at 3200g for 10min at 4 ℃, and liver and heart tissue were collected from the dead animals at 1, 2 and 8 hours. After treatment, plasma samples were assayed for plasma concentration using LC-MS/MS. After liver and heart tissues are homogenized, the drug concentration in the tissues is measured. The experimental results are shown in Table 8.

TABLE 8 pharmacokinetic parameters of the compounds of the invention in mice

Note that: 3 represents where compound 3 is an in vivo metabolite of compound 6, 18 represents where compound 18 is an in vivo metabolite of compound 36; ND indicates not detected.

Conclusion of experiment: the compound has higher exposure in the liver, lower exposure in the blood plasma and the heart and better targeting to the liver.

Experimental example 4 Using HFD-CCl ₄ (high fat diet-carbon tetrachloride) induced mouse NASH model test for detecting in vivo efficacy of the Compounds of the present invention

The experiment uses high-fat feed to feed induced DIO mice in the early stage, and uses the high-fat feed to feed while injecting CCl intraperitoneally ₄ A NASH model is induced in which the test compounds are tested for their anti-NASH efficacy.

Normal control animals, i.e. animals injected with physiological saline and orally administered compound vehicle as control, mice given the group were given 25% cci i.e. twice weekly ₄ Solution, CCl ₄ The injection time of (2) was 1 day, 4 days, 8 days, 11 days, 15 days, 18 days, 22 days and 26 days, the NASH model was induced, and the corresponding dose of the compound was orally administered. At the end of the experiment, animals were sacrificed, liver weight and liver-body ratio were tested, and liver histopathological analysis was performed. HFD-CCl for administration of a compound ₄ Induced liver weight changes and liver volume ratios in NASH model mice are shown in figures 4a, 4b, 6a and 6b. HFD-CCl for administration of a compound ₄ Liver histopathological analysis of induced NASH model mice is shown in fig. 5a, 5b and 7a, 7 b.

Conclusion of experiment: for dio+ccl the compounds of the invention ₄ The liver weight of model mice decreased significantly for DIO+CCl ₄ The non-alcoholic fatty liver disease activity score of the model mice is obviously improved, and a more obvious dose-drug effect relationship exists.

Claims

1. A compound of formula (IV), an isomer thereof, or a pharmaceutically acceptable salt thereof, selected from:

wherein,

R ₁ selected from H, C _1-3 Alkyl, said C _1-3 Alkyl optionally substituted with 1, 2 or 3 halogensSubstitution;

R ₂ selected from halogen, C _1-3 Alkyl, C _1-3 Alkoxy and C _3-6 Cycloalkyl group, the C _1-3 Alkyl, C _1-3 Alkoxy and C _3-6 Cycloalkyl is optionally substituted with 1, 2 or 3 halogens;

each R is independently selected from halogen or C _1-3 An alkyl group;

L ₁ selected from- (CR) _b R _c ) _m -、-NH(CR _b R _c ) _m -、-O(CR _b R _c ) _m -；

R _a selected from H, C _1-3 Alkyl, -COCH ₃ and-SO ₂ R’；

Each m is independently selected from 0, 1 and 2;

n is selected from 1 and 2;

x is selected from-PO (OH) ₂ 、-P(O)[-OC(R _d ) ₂ OC(O)R _e ] ₂ 、

-P(O)[-N(H)C(R _d ) ₂ C(O)OR _e ][-OR _e ]And (d) sum

each R is _d Independently selected from R _e And H;

2. The compound of claim 1, an isomer thereof, or a pharmaceutically acceptable salt thereof, wherein R ₁ Selected from H and CH ₃ 。

3. The compound of claim 1, an isomer thereof, or a pharmaceutically acceptable salt thereof, wherein R ₂ Selected from F, cl, br, C _1～3 Alkyl and cyclopropyl, said C _1～3 The alkyl group is optionally substituted with 1, 2 or 3F.

4. A compound according to claim 3, an isomer, or a pharmaceutically acceptable salt thereof, wherein R ₂ Selected from Cl, CH ₃ Cyclopropyl.

5. The compound of claim 1, an isomer thereof, or a pharmaceutically acceptable salt thereof, wherein each R is independently selected from F and CH ₃ 。

6. The compound of claim 1, an isomer thereof, or a pharmaceutically acceptable salt thereof, wherein R ₃ 、R ₄ And R is ₅ Each independently selected from H, halogen, OH, NH ₂ 、C _1-3 Alkyl, C _3-6 Cycloalkyl and 4-6 membered heterocycloalkyl, said C _1-3 Alkyl, C _3-6 Cycloalkyl and 4-6 membered heterocycloalkyl are optionally substituted with 1, 2 or 3R.

7. The compound of claim 6, an isomer, or a pharmaceutically acceptable salt thereof, wherein R ₃ 、R ₄ And R is ₅ Each independently selected from H, F, cl, OH, CH ₃ 、CF ₃ 、CH ₂ CH ₃ 、CH(CH ₃ ) ₂ 、

8. The compound of claim 1, an isomer thereof, or a pharmaceutically acceptable salt thereof, wherein L ₁ Selected from- (CH) ₂ ) _m -and-O (CH) ₂ ) _m -。

9. The compound of claim 8, an isomer, or a pharmaceutically acceptable salt thereof, wherein L ₁ Selected from-CH ₂ -、-(CH ₂ ) ₂ -and-OCH ₂ -。

10. The compound of claim 1, an isomer thereof, or a pharmaceutically acceptable salt thereof, wherein the structural unitSelected from->

11. The compound of claim 10, an isomer thereof, or a pharmaceutically acceptable salt thereof, wherein the structural unitSelected from->

12. The compound of claim 1, an isomer, or a pharmaceutically acceptable salt thereof, wherein V is selected from phenyl, said phenyl optionally substituted with 1, 2, or 3 halogens.

13. The compound of claim 12, an isomer, or a pharmaceutically acceptable salt thereof, wherein V is selected from the group consisting of

14. The compound of claim 1, an isomer thereof, or a pharmaceutically acceptable salt thereof, wherein R _e Selected from-CH ₃ 、-CH ₂ CH ₃ 、-CH(CH ₃ ) ₂ 、-C(CH ₃ ) ₃ And phenyl.

15. The compound of claim 1, an isomer thereof, or a pharmaceutically acceptable salt thereof, wherein X is selected from-PO (OH) ₂ 、-P(O)[-OCH ₂ OC (O) -tert-butyl] ₂ 、-P(O)[-N(H)CH(CH ₃ )C(O)OCH ₂ CH ₃ ] ₂ 、

16. The compound of claim 15, an isomer thereof, or a pharmaceutically acceptable salt thereof, wherein X is selected from-PO (OH) ₂ 、

17. A compound according to any one of claims 1 to 10, an isomer thereof or a pharmaceutically acceptable salt thereof, which is selected from

Wherein,

R ₁ 、R ₂ 、R ₃ 、R ₄ 、R ₅ and L ₁ As defined in any one of claims 1 to 10.

18. A compound of the formula:

19. the compound of claim 18, or a pharmaceutically acceptable salt thereof, selected from:

20. use of a compound according to any one of claims 1 to 19, an isomer thereof or a pharmaceutically acceptable salt thereof for the manufacture of a THR- β agonist-related medicament.

21. The use according to claim 20, wherein the THR- β agonist-related drug is a drug for non-alcoholic steatohepatitis (NASH).