CN116102564A

CN116102564A - Preparation method of azole compound and application of azole compound as antibacterial agent

Info

Publication number: CN116102564A
Application number: CN202211387744.4A
Authority: CN
Inventors: 邓刚; 李中尧; 戴明; 张琼; 彭建彪
Original assignee: Shanghai Jiyu Pharmaceutical Technology Co ltd
Current assignee: Shanghai Jiyu Pharmaceutical Technology Co ltd
Priority date: 2021-11-09
Filing date: 2022-11-07
Publication date: 2023-05-12

Abstract

The invention discloses a preparation method of an azole compound and application of the azole compound as an antibacterial agent, and in particular discloses a compound shown in a formula (I) and pharmaceutically acceptable salts thereof, and antifungal application of the compound.

Description

Preparation method of azole compound and application of azole compound as antibacterial agent

Technical Field

The invention relates to a preparation method of azole compounds and application of azole compounds as antibacterial agents. The invention also relates to a compound shown in the formula (I) and pharmaceutically acceptable salts thereof, and antifungal application of the compound.

Background

In recent years, with the long-term widespread use of broad-spectrum antibiotics, the increase of chemoradiotherapy, the popularization of bone marrow and organ transplantation operations, the increase of immunosuppressant use, the development of interventional treatments such as heart valve implantation, and the like, the incidence and mortality of clinical invasive fungal infections caused by candida, aspergillus, cryptococcus neoformans, and the like have been remarkably increased. Tens of millions of people with fungal infections worldwide, at least 150 tens of people die from deep invasion of fungi.

The present clinically used antifungal infection medicines comprise azoles, polyenes, echinocandins and the like. The azole antifungal drug is the largest of various antifungal drugs, is also the most common antifungal drug in clinic, has wide antibacterial spectrum and smaller toxicity, and has better tolerance compared with amphotericin B, so the application is the most extensive.

Despite the wide clinical use, these azole antifungal agents still have some drawbacks and limitations, respectively. For example, ketoconazole has great toxic and side effects and is basically used as local medicine at present. Fluconazole has limited activity as a first-line drug for the treatment of localized and deep fungal infections and develops severe resistance due to prolonged use. Itraconazole has poor water solubility and low bioavailability, and cyclodextrin contained in the oral liquid can cause osmotic diarrhea, so that the itraconazole has great harm to patients with renal insufficiency. Posaconazole is a strong CYP3A4 inhibitor, and the clinical application of the posaconazole is limited by the strong drug-drug interaction (DDI), and the physical and chemical properties and the metabolic properties of the posaconazole are also quite unsatisfactory, so that the curative effect stability of the posaconazole is greatly reduced. Ai Shakang oxazole is a moderate-intensity CYP3A4 inhibitor and still presents the problem of drug DDI.

Voriconazole is considered to be the most successful fluconazole derivative, has stronger activity on deep pathogenic fungi including fluconazole-resistant strains such as candida krusei, candida parapsilosis and the like, and is the most optimal medicine for treating fungal infection, especially invasive mycosis caused by aspergillus at present. The disadvantage is that the CYP2C19 is metabolized in the body, and the blood concentration is too high due to individual differences of CYP2C19 metabolism, so that adverse reactions are particularly easy to cause for Chinese people. Side effects such as abnormal visual response, liver dysfunction, etc. after voriconazole administration have also been reported successively.

In view of the defects and limitations of the existing antifungal medicines of the conazole, the novel efficient, broad-spectrum and low-toxicity CYP51 inhibitor antifungal medicines with activity, metabolism, medicine interaction and the like superior to the existing medicines are developed, the limitations and defects of the existing clinical medicines are overcome, the resistance to the fluconazole and the like is overcome, and the novel efficient, broad-spectrum and low-toxicity CYP51 inhibitor antifungal medicines have great clinical value in treating and preventing various fungal infections, especially deep infections caused by candida and aspergillus, and reducing the mortality rate of clinical invasive fungal infections.

Disclosure of Invention

Based on the findings of the problems, the invention provides a series of compounds with brand-new azole structures, compared with the existing clinical therapeutic drugs, the compounds have better or equivalent candida infection resistance activity, overcome the limitations and defects of the existing clinical drugs, and can be used clinically to reduce the death rate of invasive fungal infection.

In a first aspect of the present invention, the present invention provides a compound of formula (I), optical isomers, tautomers and pharmaceutically acceptable salts thereof,

wherein,,

ring a is selected from 5-6 membered heteroaryl;

ring B is selected from phenyl, 5-6 membered heteroaryl and C _5-6 Cycloalkyl;

ring C, ring E are each independently selected from phenyl and 5-6 membered heteroaryl, said phenyl or 5-6 membered heteroaryl optionally substituted with 1, 2 or 3 Rx; ring D is selected from C _4-8 Cycloalkyl and 4-8 membered heterocyclyl, said C _4-8 Cycloalkyl or 4-8 membered heterocyclyl is optionally substituted with 1, 2 or 3R _Y Substitution;

R ₃ selected from OH, NH ₂ 、-OSi(R ₉ ) ₃ 、F、Cl、Br、I、CN、C _1-6 Alkyl, C _1-6 Heteroalkyl group,

The C is _1-6 Alkyl or C _1-6 Heteroalkyl is optionally substituted with 1, 2 or 3 NH ₂ Substitution;

R ₂ 、R ₄ 、R ₅ 、R _X 、R _Y are respectively and independently selected from H, CN, OH, F, cl, br, I, C _1-6 Alkyl, C _1-6 Heteroalkyl, SF ₃ 、SF ₆ 、SCN、SO ₃ H and SO ₂ R ₇ The C is _1-6 Alkyl or C _1-6 Heteroalkyl is optionally substituted with 1, 2 or 3 CN, OH, F, cl, br, I or C _1-6 Alkyl substitution;

R ₇ 、R ₉ independently selected from NH ₂ 、C _1-6 Alkyl, phenyl and 5-6 membered heteroaryl, said phenyl or 5-6 membered heteroaryl optionally being substituted with 1, 2 or 3 CN, OH, F, cl, br, I or C _1-6 Alkyl substitution;

n is independently selected from 0, 1, 2 or 3;

L ₁ selected from single bonds, C _1-6 Alkyl, C _2-6 Alkynyl, phenyl and 5-6 membered heteroaryl groups, said C _1-6 Alkyl, C _2-6 Alkynyl, phenyl or 5-6 membered heteroaryl groups are optionally substituted by 1, 2 or 3 CN, OH, F, cl, br, I or C _1-6 Alkyl substitution;

L ₂ selected from single bonds, O, S, NH, C _1-6 Alkyl, C _1-6 Heteroalkyl, 3-6 membered heterocyclyl, C _3-6 Cycloalkyl and phenyl-O-C _1-6 Alkyl-, said C _1-6 Alkyl, C _1-6 Heteroalkyl, 3-6 membered heterocyclyl, C _3-6 Cycloalkyl or phenyl-O-C _1-6 Alkyl-optionally substituted by 1, 2 or 3 CN, OH, F, cl, br, I or C _1-6 Alkyl substitution;

L ₃ selected from single bond, -C (=O) -, -C (=O) NH-, C _1-6 Alkyl, 3-6 membered heterocyclyl, C _3-6 Cycloalkyl, phenyl and 5-6 membered heteroaryl, said C _1-6 Alkyl, 3-6 membered heterocyclyl, C _3-6 Cycloalkyl, phenyl or 5-6 membered heteroaryl groups are optionally substituted by 1, 2 or 3 CN, OH, F, cl, br, I or C _1-6 Alkyl substitution;

L ₄ selected from H, F, cl, br, I, OH, CN, NH ₂ 、COOH、SF ₃ 、SF ₆ 、SCN、SO ₂ R ₇ 、C _1-6 Alkyl, C _1-6 Heteroalkyl, C _3-6 Cycloalkyl, 4-6 membered heterocyclyl, C _1-6 Alkyl-5-6 membered heterocyclyl, 5-6 membered heteroaryl and benzo 4-6 membered heterocyclyl, said C _1-6 Alkyl, C _1-6 Heteroalkyl, C _3-6 Cycloalkyl, 4-6 membered heterocyclyl, C _1-6 Alkyl-5-6 membered heterocyclyl, 5-6 membered heteroaryl or benzo 5-6 membered heterocyclyl optionally substituted with 1, 2, 3, 4 or 5R _L Substitution;

R _L selected from CN, OH, F, cl, br, I, NH ₂ 、C _1-6 Alkyl and C _1-6 Heteroalkyl, said, C _1-6 Alkyl or C _1-6 Heteroalkyl is optionally substituted with 1, 2 or 3 CN, OH, NH ₂ F, cl, br, I or C _1-6 Alkyl substitution;

the C is _1-6 Heteroalkyl, 5-6 membered heterocyclyl or 5-6 membered heteroaryl comprises 1, 2, 3 or 4 groups independently selected from-O-, -NH-, -N=, -S-, -C (=O) O-, -S (=O) ₂ -and N.

In a second aspect of the present invention, there is provided a compound of formula (I), optical isomers, tautomers and pharmaceutically acceptable salts thereof,

Wherein,,

X ₁ 、X ₂ are each independently selected from C (R) _X ) And N;

X ₃ 、X ₄ are each independently selected from C (R) _Y ) ₂ And O;

ring a is selected from 5-6 membered heteroaryl;

ring B is selected from phenyl, 5-6 membered heteroaryl and C _5-6 Cycloalkyl;

R ₃ selected from OH, NH ₂ 、-OSi(R ₉ ) ₃ 、F、Cl、Br、I、CN、C _1-6 Alkyl, C _1-6 Heteroalkyl, -C (=o) alkyl, -OC (=o) C _1-6 Alkyl, -NHC (=o) C _1-6 Alkyl group,

the-C (=o) alkyl is optionally substituted with 1, 2 or 3 NH ₂ Substitution;

n, m are each independently selected from 0, 1, 2 or 3;

L ₁ selected from single bonds, C _1-6 Alkyl, C _2-6 Alkynyl, phenyl and 5-6 membered heteroaryl groups, said C _1-6 Alkyl, C _2-6 Alkynyl, phenyl or 5-6 membered heteroaryl groups are optionally substituted by 1, 2 or 3 CN, OH, F, cl,Br, I or C _1-6 Alkyl substitution;

R _L selected from CN, OH, F, cl, br, I, NH ₂ 、C _1-6 Alkyl and C _1-6 Heteroalkyl group, C _1-6 Alkyl or C _1-6 Heteroalkyl is optionally substituted with 1, 2 or 3 CN, OH, NH ₂ F, cl, br, I or C _1-6 Alkyl substitution;

In some aspects of the invention, R is as defined above ₂ 、R ₄ 、R ₅ 、R _X 、R _Y Are respectively and independently selected from H, CN, OH, F, cl, br, I, C _1-6 Alkyl, C _1-6 Alkylthio, -OR ₇ R ₉ 、-NR ₇ R ₉ 、-C(＝O)R ₇ R ₉ 、-C(O)OH、-C(O)OR ₇ 、-C(O)NR ₇ R ₉ 、SF ₃ 、SF ₆ 、SCN、SO ₃ H and SO ₂ R ₇ The C is _1-6 Alkyl or C _1-6 Alkylthio is optionally substituted by 1, 2 or 3 CN, OH, F, cl, br, I or C _1-6 Alkyl substitution, the remaining variables are as defined herein.

In some embodiments of the invention, ring a is selected from tetrazolyl, triazolyl, oxazolyl, pyrimidinyl, thiazolyl, or pyrazolyl, with the remaining variables being as defined herein.

In some embodiments of the invention, the ring A is selected from

The remaining variables are as defined herein.

In some embodiments of the invention, ring B is selected from phenyl and pyridyl, and the remaining variables are as defined herein.

In some aspects of the invention, the structural units described above

Selected from the group consisting of

The remaining variables are as defined herein.

In some aspects of the invention, R is as described above ₃ Selected from OH, NH ₂ 、C _1-3 Alkyl, C _1-3 Alkoxy, C _1-3 Alkylamino, C _1-3 Alkylthio, -OC (=o) C _1-3 Alkyl and-NHC (=o) C _1-3 Alkyl, the remaining variables are as defined herein.

In some aspects of the invention, R is as defined above ₃ Selected from OH, F, cl, br, NH ₂ 、OCH ₃ 、

The remaining variables are as defined herein.

In some embodiments of the invention, the above-mentioned rings C and E are each independently selected from phenyl and pyridyl, optionally substituted with 1, 2 or 3 Rx, the remaining variables being as defined herein.

In some embodiments of the invention, the aforementioned rings D are each independently selected from the group consisting of cyclopentyl, cyclohexyl, tetrahydrofuranyl, and tetrahydropyranyl, the cyclopentyl, cyclohexyl, tetrahydrofuranyl, or tetrahydropyranyl being optionally substituted with 1, 2, or 3R _Y Instead, the remaining variables are as defined herein.

In some aspects of the invention, L as described above ₁ Selected from single bonds, C _1-3 Alkyl, C _2-3 Alkynyl, phenyl, pyridyl, thienyl and oxazolyl groups, said C _1-3 Alkyl, C _2-3 Alkynyl, phenyl, pyridinyl, thienyl or oxazolyl are optionally substituted with 1, 2 or 3 CN, OH, F, cl, br, I or C _1-6 Alkyl substitution, the remaining variables are as defined herein.

In some aspects of the invention, L as described above ₁ Selected from single bonds, CH ₂ 、

The remaining variables are as defined herein.

In some aspects of the invention, L as described above ₂ Selected from single bonds, O, S, C _1-3 Alkyl, NH, -NC _1-3 Alkyl, 5-6 membered heterocyclyl, C _5-6 Cycloalkyl and phenyl-O-C _1-3 Alkyl-, said C _1-3 Alkyl, 5-6 membered heterocyclyl, C _5-6 Cycloalkyl or phenyl-O-C _1-3 Alkyl-optionally substituted with 1, 2 or 3 CN, OH,F. Cl, br, I or C _1-6 Alkyl substitution, the remaining variables are as defined herein.

In some aspects of the invention, L as described above ₂ Selected from single bonds, O, S, CH ₂ 、NH、-NCH ₃ 、

The remaining variables are as defined herein.

In some aspects of the invention, L as described above ₃ Selected from single bonds, 5-6 membered heterocyclic groups, C _5-6 Cycloalkyl, phenyl and pyridyl, said 5-6 membered heterocyclyl, C _5-6 Cycloalkyl, phenyl or pyridinyl are optionally substituted with 1,2 or 3 CN, OH, F, cl, br, I or C _1-3 Alkyl substitution, the remaining variables are as defined herein.

In some aspects of the invention, L as described above ₃ Selected from single bonds, CH ₂ 、CH ₂ CH ₂ 、-C(＝O)-、-C(＝O)NH-、

The remaining variables are as defined herein.

In some aspects of the invention, L as described above ₄ Selected from H, F, cl, br, I, OH, CN, NH ₂ 、COOH、

C(＝O)C _1-3 Alkyl, C (=o) NHC _1-3 Alkyl, C (=O) N (C) _1-3 Alkyl group ₂ 、C _1-3 Alkyl, C _1-3 Alkoxy, C _1-3 Alkylthio, C _1-3 Alkylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 24-dihydro-3H-1, 2, 4-triazol-3-one, piperazinyl, benzo-1, 3-methylenedioxy pentacyclic, pyridinyl, thiazolyl, 1,2, 4-oxadiazolyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, azetidinyl, morpholinyl and 1, 3-dioxolan-2-one, said C (=O) C _1-3 Alkyl, C (=o) NHC _1-3 Alkyl, C (=O) N (C) _1-3 Alkyl group ₂ 、C _1-3 Alkyl, C _1-3 Alkoxy, C _1-3 Alkylthio, C _1-3 Alkylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2, 4-dihydro-3H-1, 2, 4-triazol-3-one, piperazinyl, benzo-1, 3-methylenedioxy pentacyclo-yl, pyridinyl, thiazolyl, 1,2, 4-oxadiazolyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, azetidinyl, morpholinyl or 1, 3-dioxolan-2-one optionally being substituted with 1,2, 3, 4 or 5R _L Instead, the remaining variables are as defined herein.

In some aspects of the invention, R is as defined above _L Selected from CN, OH, F, cl, br, I, NH ₂ 、C(＝O)C _1-3 Alkyl, C (=o) NHC _1-3 Alkyl, C (=O) N (C) _1-3 Alkyl group ₂ 、C _1-3 Alkyl, C _1-3 Alkoxy, C _1-3 Alkylthio and C _1-3 Alkylamino, said C (=o) C _1-3 Alkyl, C (=o) NHC _1-3 Alkyl, C (=O) N (C) _1-3 Alkyl group ₂ 、C _1-3 Alkyl, C _1-3 Alkoxy, C _1-3 Alkylthio or C _1-3 Alkylamino is optionally substituted with 1, 2 or 3 CN, OH, NH ₂ F, cl, br, I or C _1-6 Alkyl substitution, the remaining variables are as defined herein.

In some aspects of the invention, L as described above ₄ Selected from H, F, cl, br, I, OH, CN, NH ₂ 、CHF ₂ 、CF ₃ 、OCH ₃ 、OCF ₃ 、OCHF ₂ 、OCH ₂ CH ₃ 、COOH、CONHMe、CONMe ₂ 、NMe ₂ 、

/>

The remaining variables are as defined herein.

In some aspects of the invention, the structural units described above

Selected from H, I, CN, OH, CF ₃ 、COOH、CONHMe、CONMe ₂ 、

/>

/>

The remaining variables are as defined herein.

In some aspects of the invention, the structural units described above

The remaining variables are as defined herein.

In another aspect of the invention, the invention also provides a compound of the formula, optical isomers, tautomers, and pharmaceutically acceptable salts thereof, selected from

In another aspect of the invention, the invention also provides a compound of the formula and pharmaceutically acceptable salts thereof, selected from

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.

As used herein, the phrase "at least one" when referring to a list of one or more elements is understood to mean at least one element selected from any one or more of the elements in the list of elements, but does not necessarily include at least one of each element specifically listed within the list of elements, and does not exclude any combination of elements in the list of elements. This definition also allows that elements other than the specifically identified elements within the list of elements referred to by the phrase "at least one" may optionally be present, whether related or unrelated to those elements specifically identified.

The term "pharmaceutically acceptable" as used herein is intended to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention prepared from the compounds of the present invention which have the specified substituents found herein with relatively non-toxic acids or bases. When the compounds of the present invention contain relatively acidic functional groups, base addition salts may be obtained by contacting neutral forms of such compounds with a sufficient amount of a base in pure solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts. When the compounds of the present invention contain relatively basic functional groups, the acid addition salts may be obtained by contacting the neutral form of such compounds with a sufficient amount of an acid in 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, trifluoroacetic 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, methanesulfonic acid, and the like; 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.

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. For example, the number of the cells to be processed,

can be selected from->

Etc.

The short dash ("-") that is not between two letters or symbols represents the attachment site for a substituent. For example, C _1-6 Alkylcarbonyl-refers to C attached to the remainder of the molecule through a carbonyl group _1-6 An alkyl group. However, "-" may be omitted when the attachment site for the substituent is apparent to those skilled in the art, for example, a halogen substituent.

With broken lines at the valencies of the radicals

When, for example, in->

The dotted line represents the point of attachment of the group to the rest of the molecule. When a single bond is provided with->

When, for example, in->

In which the dotted line represents a single bond or is absent, also meaning +.>

Represents a single bond->

Or double bond->

The term "substituted" or "substituted with …" means that any one or more hydrogen atoms on a particular atom are substituted with substituents, and may include heavy hydrogens and variants of hydrogens, provided that the valence of the particular atom is normal and the substituted compound is stable. The term "optionally substituted" or "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 of being chemically realizable unless otherwise indicated.

When one of the variables is selected from single bonds, the two groups representing their attachment are directly linked, e.g

Middle L ₁ Representing a single bond means that the structure is actually +.>

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-CH ₂ O-, in this case-CH ₂ O-can be connected in the same direction as the reading sequence from left to rightPhenyl and cyclopentyl group>

The phenyl group and the cyclopentyl group may be linked in the opposite direction to the reading order from left to right to form +.>

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

Unless otherwise specified, the number of atoms on a ring is generally defined as the number of ring elements, e.g., "3-6 membered ring" refers to a "ring" of 3-6 atoms arranged around a ring.

Unless otherwise specified, the term "C _1-6 Alkyl "is used to denote a straight or branched saturated hydrocarbon group consisting of 1 to 6 carbon atoms. The C is _1-6 Alkyl includes C _1-5 、C _1-4 、C _1-3 、C _1-2 、C _2-6 、C _2-4 、C ₆ And C ₅ Alkyl groups, etc.; which may be monovalent (e.g. CH ₃ ) Divalent (-CH) ₂ (-) or multivalent (e.g. inferior)

)。C _1-6 Examples of alkyl groups include, but are not limited to CH ₃ 、

Etc.

Unless otherwise specified, the term "C _1-4 Alkyl "is used to denote a straight or branched saturated hydrocarbon group consisting of 1 to 4 carbon atoms. The C is _1-4 Alkyl includes C _1-2 、C _1-3 、C _3-4 And C _2-3 Alkyl groups, etc.; which is a kind of Can be monovalent (e.g. CH ₃ ) Divalent (-CH) ₂ (-) or multivalent (e.g. inferior)

)。C _1-4 Examples of alkyl groups include, but are not limited to CH ₃ 、

Etc.

Unless otherwise specified, "C _2-6 Alkynyl "is used to denote a straight or branched hydrocarbon group consisting of 2 to 6 carbon atoms containing at least one carbon-carbon triple bond, which may be located at any position of the group. It may be monovalent, divalent or multivalent. The C is _2-6 Alkynyl includes C _2-3 、C _2-4 、C _2-5 、C _3-4 、C _3-5 、C _3-6 、C _4-5 、C _4-6 、C _5-6 、C ₆ 、C ₅ 、C ₄ 、C ₃ And C ₂ Alkynyl groups. C (C) _2-6 Examples of alkynyl groups include, but are not limited to

Etc.

Unless otherwise specified, "C _2-3 Alkynyl "is used to denote a straight or branched hydrocarbon group consisting of 2 to 3 carbon atoms containing at least one carbon-carbon triple bond, which may be located at any position of the group. It may be monovalent, divalent or multivalent. The C is _2-3 Alkynyl includes C ₃ And C ₂ Alkynyl groups. C (C) _2-3 Examples of alkynyl groups include, but are not limited to

Etc.

The term "heteroalkyl", by itself or in combination with another term, means a stable, straight or branched chain alkyl radical or combination thereof, consisting of a number of carbon atoms and at least one heteroatom or group of heteroatoms. In some embodiments, the heteroatoms are selected from B, O, N and S, wherein the nitrogen and sulfur atoms are optionally Oxidized and optionally quaternized. In other embodiments, the heteroatom is selected from-C (=o) O-, -C (=o) -, -C (=s) -, -S (=o) ₂ -、-C(＝O)N(H)-、-N(H)-、-C(＝NH)-、-S(＝O) ₂ N (H) -and-S (=o) N (H) -. In some embodiments, the heteroalkyl is C _1-6 A heteroalkyl group; in other embodiments, the heteroalkyl is C _1-3 A heteroalkyl group. The heteroatom or heteroatom group may be located in any internal position of the heteroalkyl group, including where the alkyl group is attached to the remainder of the molecule, although the term "alkoxy" is used interchangeably and refers to those alkyl groups attached to the remainder of the molecule through an oxygen atom. Examples of heteroalkyl groups include, but are not limited to, -OCH ₃ 、-OCH ₂ CH ₃ 、-OCH ₂ CH ₂ CH ₃ 、-OCH ₂ (CH ₃ ) ₂ 、-CH ₂ -CH ₂ -O-CH ₃ 、-NHCH ₃ 、-N(CH ₃ ) ₂ 、-NHCH ₂ CH ₃ 、-N(CH ₃ )(CH ₂ CH ₃ )、-CH ₂ -CH ₂ -NH-CH ₃ 、-CH ₂ -CH ₂ -N(CH ₃ )-CH ₃ 、-SCH ₃ 、-SCH ₂ CH ₃ 、-SCH ₂ CH ₂ CH ₃ 、-SCH ₂ (CH ₃ ) ₂ 、-CH ₂ -S-CH ₂ -CH ₃ 、-CH ₂ -CH ₂ 、-S(＝O)-CH ₃ 、-CH ₂ -CH ₂ -S(＝O) ₂ -CH ₃ And up to two heteroatoms may be contiguous, e.g. -CH ₂ -NH-OCH ₃ 。

Unless otherwise specified, the term "C _1-6 Alkoxy "means those alkyl groups containing 1 to 6 carbon atoms that are attached to the remainder of the molecule through one oxygen atom. The C is _1-6 Alkoxy includes C _1-4 、C _1-3 、C _1-2 、C _2-6 、C _2-4 、C ₆ 、C ₅ 、C ₄ And C ₃ Alkoxy groups, and the like. C (C) _1-6 Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxyAnd isopropoxy), butoxy (including n-butoxy, isobutoxy, s-butoxy and t-butoxy), pentoxy (including n-pentoxy, isopentoxy and neopentoxy), hexoxy, 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 _1-3 、C _1-2 、C _2-3 、C ₁ 、C ₂ And C ₃ 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, the term "C _1-6 Alkylamino "means those alkyl groups containing 1 to 6 carbon atoms that are attached to the remainder of the molecule through an amino group. The C is _1-6 Alkylamino includes C _1-4 、C _1-3 、C _1-2 、C _2-6 、C _2-4 、C ₆ 、C ₅ 、C ₄ 、C ₃ And C ₂ Alkylamino, and the like. C (C) _1-6 Examples of alkylamino groups include, but are not limited to, -NHCH ₃ 、-N(CH ₃ ) ₂ 、-NHCH ₂ CH ₃ 、-N(CH ₃ )CH ₂ CH ₃ 、-N(CH ₂ CH ₃ )(CH ₂ CH ₃ )、-NHCH ₂ CH ₂ CH ₃ 、-NHCH ₂ (CH ₃ ) ₂ 、-NHCH ₂ CH ₂ CH ₂ CH ₃ Etc.

Unless otherwise specified, the term "C _1-3 Alkylamino "means those alkyl groups containing 1 to 3 carbon atoms attached to the remainder of the molecule through an amino group. The C is _1-3 Alkylamino includes C _1-3 、C _1-2 、C _2-3 、C ₁ 、C ₂ And C ₃ Alkylamino, and the like. C (C) _1-3 Examples of alkylamino groups include, but are not limited to, -NHCH ₃ 、-N(CH ₃ ) ₂ 、-NHCH ₂ CH ₃ 、-N(CH ₃ )CH ₂ CH ₃ 、-NHCH ₂ CH ₂ CH ₃ 、-NHCH ₂ (CH ₃ ) ₂ Etc.

Unless otherwise specified, the term "C _1-6 Alkylthio "means those alkyl groups containing 1 to 6 carbon atoms which are attached to the remainder of the molecule through a sulfur atom. The C is _1-6 Alkylthio includes C _1-4 、C _1-3 、C _1-2 、C _2-6 、C _2-4 、C ₆ 、C ₅ 、C ₄ 、C ₃ And C ₂ Alkylthio, and the like. C (C) _1-6 Examples of alkylthio groups include, but are not limited to, -SCH ₃ 、-SCH ₂ CH ₃ 、-SCH ₂ CH ₂ CH ₃ 、-SCH ₂ (CH ₃ ) ₂ Etc.

Unless otherwise specified, the term "C _1-3 Alkylthio "means those alkyl groups containing 1 to 3 carbon atoms which are attached to the remainder of the molecule through a sulfur atom. The C is _1-3 Alkylthio includes C _1-3 、C _1-2 、C _2-3 、C ₁ 、C ₂ And C ₃ Alkylthio, and the like. C (C) _1-3 Examples of alkylthio groups include, but are not limited to, -SCH ₃ 、-SCH ₂ CH ₃ 、-SCH ₂ CH ₂ CH ₃ 、-SCH ₂ (CH ₃ ) ₂ Etc.

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 heterocyclyl" by itself or in combination with other terms, denotes 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 atoms are optionally quaternized and the nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., NO and S (O) _p P is 1 or 2). It comprises a monocyclic and bicyclic ring systemWherein the bicyclic ring system includes spiro, fused and bridged rings. In addition, with respect to the "3-6 membered heterocyclic group", the heteroatom may occupy the position of attachment of the heterocyclic group to the remainder of the molecule. The 3-6 membered heterocyclic group includes 4-6 membered, 5-6 membered, 4 membered, 5 membered, 6 membered heterocyclic groups and the like. Examples of 3-6 membered heterocyclyl 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 "5-6 membered heterocyclyl" alone or in combination with other terms, denotes a saturated cyclic group consisting of 5 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 atoms are optionally quaternized and the nitrogen and sulfur heteroatoms may optionally be 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 "5-6 membered heterocyclic group", the heteroatom may occupy the position of attachment of the heterocyclic group to the remainder of the molecule. The 5-6 membered heterocyclic group includes 5-membered and 6-membered heterocyclic groups and the like. Examples of 5-6 membered heterocyclyl groups include, but are not limited to, 1, 3-dioxolane,

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, isothiazole Alkyl, 1, 2-oxazinyl, 1, 2-thiazinyl, hexahydropyridazinyl, homopiperazinyl, homopiperidinyl, and the like.

The terms "5-6 membered heteroaryl ring" and "5-6 membered heteroaryl" are used interchangeably herein unless otherwise specified, the term "5-6 membered heteroaryl" meaning a monocyclic group having a conjugated pi-electron system consisting of 5 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 optionally be oxidized (i.e., NO and S (O) _p P is 1 or 2). The 5-6 membered heteroaryl group may be attached to the remainder of the molecule through a heteroatom or carbon atom. The 5-6 membered heteroaryl groups include 5-and 6-membered heteroaryl groups. Examples of the 5-6 membered heteroaryl group include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl, 3-pyrazolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, etc.), triazolyl (1H-1, 2, 3-triazolyl, 2H-1,2, 3-triazolyl, 1H-1,2, 4-triazolyl, 4H-1,2, 4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, etc.), thiazolyl (including 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, etc.), furanyl (including 2-furanyl, 3-furanyl, etc.), thienyl (including 2-thienyl, 3-thienyl, etc.), pyridyl (including 2-pyridyl, 4-pyrimidyl, etc.), pyrimidyl (including 2-pyridyl, 4-pyrimidyl, etc.), pyrimidyl, etc.

Unless otherwise specified, C _n-n+m Or C _n -C _n+m Comprising any one of the specific cases of n to n+m carbons, e.g. C _1-12 Comprises C ₁ 、C ₂ 、C ₃ 、C ₄ 、C ₅ 、C ₆ 、C ₇ 、C ₈ 、C ₉ 、C ₁₀ 、C ₁₁ And C ₁₂ Also included is any one of the ranges n to n+m, e.g. C _1-12 Comprises C _1-3 、C _1-6 、C _1-9 、C _3-6 、C _3-9 、C _3-12 、C _6-9 、C _6-12 And C _9-12 Etc.; as same asBy n-membered to n+m-membered means that the number of atoms on the ring is n to n+m, for example, 3-12 membered ring includes 3-membered ring, 4-membered ring, 5-membered ring, 6-membered ring, 7-membered ring, 8-membered ring, 9-membered ring, 10-membered ring, 11-membered ring, and 12-membered ring, and any one of n to n+m is also included, for example, 3-12 membered ring includes 3-6-membered ring, 3-9-membered ring, 5-6-membered ring, 5-7-membered ring, 5-10-membered ring, 6-7-membered ring, 6-8-membered ring, 6-9-membered ring, 6-10-membered ring, and the like.

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

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

It will be appreciated by those skilled in the art that some compounds of formula (I) may contain one or more chiral centers and thus two or more stereoisomers may be present. Thus, the compounds of the invention may exist as individual stereoisomers (e.g. enantiomers, diastereomers) and mixtures thereof in any proportion, e.g. racemates, and, where appropriate, as tautomers and geometric isomers thereof.

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 claimed invention.

The term "stereoisomer" as used herein refers to a compound that has the same chemical constitution but differs in the spatial arrangement of atoms or groups. Stereoisomers include enantiomers, diastereomers, conformational isomers and the like.

The term "enantiomer" as used herein refers to two stereoisomers of a compound that are non-superimposable mirror images of each other.

The term "diastereoisomer" as used herein refers to stereoisomers which have two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting point, boiling point, spectral properties, or biological activity. Mixtures of diastereomers can be separated using high resolution analytical methods such as electrophoresis and chromatography such as HPLC.

Stereochemical definitions and conventions can follow the edition s.p. parker, mcGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, new York; and Eliel, e. And Wilen, s., "Stereochemistry of Organic Compounds", john Wiley & Sons, inc., new York,1994. Many organic compounds exist in optically active form, i.e., they have the ability to rotate the plane of plane polarized light. In describing optically active compounds, the prefixes D and L or R and S are used to represent the absolute configuration of the molecule with respect to its chiral center. The prefix d and l or (+) and (-) is used to denote the sign of the compound rotating plane polarized light, where (-) or l indicates that the compound is left-handed. The compound with the prefix (+) or d is dextrorotatory. These stereoisomers are identical for a given chemical structure, except that they are mirror images of each other. Certain stereoisomers may also be referred to as enantiomers, and mixtures of such isomers are generally referred to as enantiomeric mixtures. The 50:50 mixture of enantiomers is referred to as a racemic mixture or racemate, which may occur in the absence of stereoselectivity or stereospecificity in a chemical reaction or process. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomers that are not optically active.

The racemic mixture may be used as such or resolved into individual isomers. The resolution can be carried out to obtain a stereochemically pure compound or a mixture enriched in one or more isomers. Methods for separating isomers are well known (see Allinger n.l. and Eliel e.l. "Topics in Stereochemistry", volume 6, wiley Interscience, 1971), and include physical methods such as chromatography using chiral adsorbents. Individual isomers of chiral form can be prepared from chiral precursors. Alternatively, one or both of the isomers substantially free of the other isomer, i.e., the desired stereoisomer having an optical purity of, for example, at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 99.5% by weight, can be obtained by chemical separation of the individual isomers from the mixture by formation of diastereomeric salts with chiral acids (e.g., individual enantiomers of 10-camphorsulfonic acid, camphoric acid, α -bromocamphoric acid, tartaric acid, diacetyltartaric acid, malic acid, pyrrolidone-5-carboxylic acid, etc.), fractional crystallization of said salts, and then liberating one or both of the resolved bases, optionally repeating this process. Alternatively, the racemate may be covalently linked to a chiral compound (adjunct) to provide the diastereoisomers, as is well known to those skilled in the art.

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

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 variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.

"optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

The 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 solvent used in the present invention is commercially available.

Compounds are either prepared according to the general nomenclature of the art or are used

Software naming, commercial compounds are referred to by vendor catalog names.

The disclosed compounds may have one or more chiral centers, each having an R configuration or an S configuration independently of the other. The chiral centers of some of the compounds disclosed herein are labeled R, S, R, or S, indicating that the absolute configuration of the chiral center of the compound has not been identified, but that the compound has been chiral resolved and the chiral center is a single configuration chiral center, that the compound is a single configuration enantiomer monomer, or a single configuration diastereomer monomer, or a single diastereomer mixture of the chiral center configurations (e.g., other chiral center configurations have not been resolved). When the chiral center of the compound disclosed by the invention is unidentified in absolute configuration (R configuration or S configuration), the compound can be prepared according to the retention time (R) corresponding to the chiral center under the corresponding chromatographic column conditions (such as chromatographic column model, chromatographic column filling, chromatographic column size, flow equality) _T ) Confirm it.

The present invention is more specifically explained in the following examples. It should be understood, however, that these examples are intended to illustrate the invention and are not intended to limit the scope of the invention in any way. The experimental procedures in the following examples, without specifying the specific conditions, are generally carried out according to the conventional conditions for such reactions, or according to the conditions recommended by the manufacturer. Percentages and parts are weight percentages and parts unless otherwise indicated. Unless otherwise specified, the ratio of liquids is the volume ratio.

Technical and scientific terms used herein have the meaning commonly understood by one of ordinary skill in the art to which this invention belongs.

Detailed Description

The present application is described in detail below by way of examples, but is not meant to be limiting in any way. The present application 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 present application without departing from the spirit and scope of the application.

The experimental materials and reagents used in the following examples were obtained from commercial sources unless otherwise specified.

In all of the embodiments described herein, the present invention, ¹ H-NMR, ¹³ C-NMR ¹⁹ The F-NMR spectra were recorded using a Bruker Assend 400mHz Nuclear magnetic resonance apparatus, the spectra were processed using Topspin software, and deuterated solvents were used as internal deuterium locks. Wherein the method comprises the steps of ¹³ C-NMR ¹⁹ F-NMR pair ¹ H decoupling. Partitioning is performed according to a defined chemical shift/coupling pattern, or according to 2D Cosy,HMBC,HSQC or NOESY experiments. The multiplicity of peaks is defined as s singlet, d doublet, t triplet, q quartet, m multiplet, br broad, br.s broad singlet; the coupling constant (J) is accurate to 0.1Hz. Mass spectra were recorded using an Agilent1260 (ESI) or Shimadzu LC-MS-2020 (ESI) type or Agilent 6215 (ESI) type mass spectrometer; reversed phase preparative HPLC separation is a full-automatic purification system guided by Agilent 1290 ultraviolet rays

Prep C18OBDTM 21.2×250mm 10 μm column) or a fully automated purification system (% guided by Gilson GX281 uv light>

Prep C18OBDTM 19X 250mm 10 μm column) or Waters QDa-directed fully automated purification System (>

Prep C18OBD 29 x 250mm 10 μm column). Unless otherwise specified, sepaFlash was used for separation, a normal phase silica gel column (national pharmaceutical systems and chemicals Co., ltd.) was preloaded, and the ratio of eluents was volume ratio in TLC analysis plate (smoke stage Jiang You silica gel development Co., ltd., model: HSGF254, specification: 2.5X15 cm).

Wherein, the Chinese names of the reagents represented by chemical formulas or English letter abbreviations are as follows:

CD ₃ OD represents deuterated methanol; DMSO-d6 represents deuterated dimethyl sulfoxide; chloroform-d or CDCl ₃ Represents deuterated chloroform; acOH represents acetic acid; alCl ₃ Represents aluminum trichloride; aq represents an aqueous solution; n (N) ₂ Represents nitrogen; ar represents argon; b (B) ₂ Pin ₂ Represents a bisboronic acid pinacol ester; BBr (BBr) ₃ Represents boron tribromide; BH (BH) ₃ Represents borane; (Boc) ₂ O represents di-tert-butyl dicarbonate; et (Et) ₃ SiH represents triethylsilane; HATU stands for 1- [ bis (dimethylamino) methylene]-1H-1,2, 3-triazolo [4,5-b]Pyridinium 3-oxide hexafluorophosphate; HOBt represents 1-hydroxybenzotriazole; k (K) ₂ CO ₃ Represents potassium carbonate; KOAc represents potassium acetate; meONa stands for sodium methoxide; LDA represents lithium diisopropylamide; liHMDS represents lithium bis (trimethylsilyl) amide; liOH represents lithium hydroxide; m-CPBA represents m-chloroperoxybenzoic acid; na (Na) ₂ CO ₃ Represents sodium carbonate; naBH ₄ Represents sodium borohydride; naCl represents sodium chloride; naHCO (NaHCO) ₃ Represents sodium bicarbonate; naOH represents sodium hydroxide; na (Na) ₂ SO ₄ Represents sodium sulfate; NBS represents N-bromosuccinimide; n-BuLi represents n-butyllithium; NH (NH) ₄ Cl represents ammonium chloride; NMP represents N-methyl-2-pyrrolidone; PBr (PBr) ₃ Represents phosphorus tribromide; pd (dppf) Cl ₂ Or PdCl ₂ (dppf) represents 1,1' -bis (diphenylphosphino) ferrocene palladium dichloride; pd (OAc) ₂ Represents palladium acetate; conc represents concentration; (COCl) ₂ Represents oxalyl chloride; cs (cells) ₂ CO ₃ Represents cesium carbonate; cuCl stands for cuprous chloride; cuI stands for cuprous iodide; DCM represents dichloromethane; dioxane or 1,4-Dioxane represents 1, 4-Dioxane; meCN, ACN or CH ₃ CN represents acetonitrile; meOH or methanol represents methanol; etOH or ethanol represents ethanol; DEA represents diethylamine; DIPEA or DIEA represents N, N-diisopropylethylamine; DMAP represents 4-dimethylaminopyridine; DMF represents N, N-dimethylformamide; DMSO represents dimethyl sulfoxide; EA or EtOAc represents ethyl acetate; PE represents petroleum ether; THF represents tetrahydrofuran; tolene or tol represents Toluene; SOCl ₂ Represents thionyl chloride; t (T)FA represents trifluoroacetic acid; FA represents formic acid; TMSCN represents trimethylsilane cyanide; h ₂ O represents water; HCl represents hydrogen chloride gas; HCl aq. represents aqueous hydrochloric acid; DEG C represents DEG C; RT or RT represents room temperature; h represents hours; min represents minutes; g represents g; mg represents mg; mL represents mL; mmol represents mmol; m represents a mole; cm represents cm; mm represents millimeters; μm represents micrometers; nm represents nanometers; mL/min represents mL/min; hz stands for hertz; MHz stands for megahertz; bar represents the pressure unit bar; psi stands for pressure units pounds per square inch; n (N) ₂ Represents nitrogen; HPLC means high performance liquid chromatography; I.D. represents the inner diameter; LCMS or LC-MS represents liquid chromatography-mass spectrometry combined; m/z represents mass to charge ratio; ESI stands for electrospray ionization; CO ₂ Represents carbon dioxide; TLC stands for thin layer chromatography; UV stands for ultraviolet.

Example 1 preparation of Compounds 1A and 1B

Preparation of Compounds 1-2

Compound 1-1 (10 g,49.7 mmol), CF ₃ CH ₂ I(20.89g,99.49mmol),K ₂ CO ₃ (13.75 g,99.49 mmol) was dissolved in DMF (150 mL). The reaction system was stirred for 12 hours at 110℃in a sealed tube. After the reaction system was cooled, the reaction mixture was quenched with water, and extracted with ethyl acetate (20 mL. Times.3). The crude product was purified by column chromatography (biotage, 330g, silica gel column, UV254, PE: ea=0-100%) to give the title compound 1-2 (13.0 g, 92% yield).

Preparation of Compounds 1-3

Compound 1-2 (25 g, 88.33 mmol) was dissolved in ethanol (250 mL), sodium borohydride (1.67 g,44.16 mmol) was slowly added at 0deg.C, and the mixture was stirred at room temperature for 2 hours. LCMS detected complete reaction. The reaction was quenched by the addition of saturated aqueous ammonium chloride (250 mL) and extracted with ethyl acetate (100 mL. Times.3). The organic phases were combined and washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and dried by spin to give crude title compound 1-3 (25 g, yield 100%). The crude product was directly subjected to the next reaction without purification, LC-MS (ESI): m/z 266.9[ [ M-H ₂ O+H] ⁺ 。

Preparation of Compounds 1-4

Compounds 1-3 (25 g,87.7 mmol) were dissolved in DMF (125 mL) and NaH (60%, 3.86g,96.47 mmol) was added at 0deg.C. After 0.5 hour of reaction, methyl iodide (13.69 g,96.47 mmol) was added. After stirring at room temperature for 2 hours, TLC monitored complete reaction, quenched with saturated aqueous ammonium chloride (500 mL) and extracted with ethyl acetate (250 mL. Times.3.) the organic phases were combined and dried by spin-drying, and the crude product was purified by column chromatography (biotage, 330g, silica gel column, UV254, PE: EA=0-100%) to give the title compound 1-4 (25 g, 95% yield).

Preparation of Compounds 1-5

Compounds 1-4 (15 g,50.15 mmol), pinacol diboron ester (14 g,55.17 mol mL), pdCl ₂ dppf (3.65 g,5.01 mmol) was dissolved in 1, 4-dioxane (100 mL) and reacted at 110℃for 16 hours under nitrogen, and the disappearance of starting material was detected by TLC. The obtained reaction solution was directly used for the next reaction.

Preparation of Compounds 1-6

K is added into the 1-5 reaction solution ₂ CO ₃ (20.76 g,150.45 mmol), 5-bromo-4-methoxypyridin-2-amine (10.13 g,50.15 mmol), pdCl ₂ dppf (3.65 g,5.01 mmol) and water (25 mL), 110℃under nitrogen for 16h, LCMS showed complete reaction. Quench by addition of saturated aqueous ammonium chloride (500 mL) and extract with ethyl acetate (250 mL. Times.3). The organic phases were combined and dried by spin-drying and the crude product was purified by column chromatography (biotage, 330g, silica gel column, UV254, PE: ea=0-100%) to give the title compounds 1-6 (8.2 g, yield: 48%). LC-MS (ESI) m/z 343.2[ M+H ] ⁺ . ¹ H NMR(400MHz,Chloroform-d)δ7.74(s,1H),7.16–7.10(m,2H),6.90(dd,J＝8.4,2.9Hz,1H),6.06(s,1H),4.57(s,2H),4.40(q,J＝8.2Hz,2H),4.24(s,2H),3.75(s,3H),3.30(s,3H).

Preparation of Compounds 1-8

Compounds 1-6 (5.5 g,16.07 mmol) were added to BBr ₃ 1, 2-dichloroethane (1:2, 25 mL) was reacted at 100℃for 16 hours and then cooled to room temperature to give crude compounds 1-7.

The crude reaction solution of the above compounds 1-7 was slowly added dropwise to a saturated potassium carbonate solution (100 mL) at 0deg.C, stirred at room temperature for 2 hours, and the reaction was complete by LCMS. Dichloro methylThe organic phases were combined by extraction with alkane (250 ml×3) and dried by spin-drying, and the crude product was purified by column chromatography (biotage, 330g, silica gel column, UV254, PE: ea=0-100%) to give the title compound 1-8 (3.5 g, 73% yield). LC-MS (ESI) m/z 297.1[ M+H ]] ⁺ , ¹ H NMR(400MHz,DMSO-d6)δ8.39(s,1H),7.73(d,J＝8.6Hz,1H),7.04(dd,J＝8.6,2.8Hz,1H),6.96(d,J＝2.7Hz,1H),6.09(s,2H),6.01(s,1H),5.09(s,2H),4.76(q,J＝8.9Hz,2H).

Preparation of Compounds 1-9

Compounds 1 to 8 (7 g,23.63 mmol) were dissolved in diiodomethane (50 mL), tert-butyl nitrite (3.65 g,35.44 mmol) was added and stirred for 10 min, and cuprous iodide (2.25 g,11.81 mmol) and iodinated species (6 g,23.63 mmol) were added. Stirring was performed under nitrogen for 16 hours, and LCMS was complete. Sodium hydroxide (5 g) and water (50 mL) were added, and after stirring for 5 minutes, a saturated aqueous sodium sulfite solution was added, and after spinning-drying under reduced pressure, water (50 mL), methylene chloride (50 ml×3) was added, the organic phases were combined, and the crude product after spinning-drying was purified by column chromatography (biotage, 50g, silica gel column, UV254, PE: ea=0 to 100%) to give the title compound 1-9 (4.0 g, yield: 42%). LC-MS (ESI) m/z 408.0[ M+H ] ] ⁺ 。

Preparation of Compounds 1-10

Compounds 1-9 (3.5 g,8.6 mmol) were dissolved in DMSO (70 mL) and copper powder (1.37 g,21.49 mmol) was added, ethyl difluorobromoacetate (2.62 g,12.9 mmol). Under the protection of nitrogen, the temperature is raised to 60 ℃ and stirred for 16 hours. Saturated aqueous ammonium chloride (50 mL) was added and extracted with ethyl acetate (50 ml×3), the organic phases were combined and dried by spin, and the crude product was purified by column chromatography (biotage, 50g, silica gel column, UV254, PE: ea=0-100%) to give the title compound 1-10 (650 mg, yield: 18%). LC-MS (ESI) m/z 403.8[ M+H ]] ⁺ 。

Preparation of Compounds 1-11

Compounds 1-10 (600 mg,1.49 mmol) were dissolved in morpholine (2 mL). Stirred at 80℃for 4 hours. TLC detection reaction was complete. Saturated aqueous ammonium chloride (50 mL) was added and extracted with ethyl acetate (50 ml×3), the organic phases were combined and dried by spin, and the crude product was purified by column chromatography (biotage, 10g, silica gel column, UV254, PE: ea=0-100%) to give the title compound 1-11 (640 mg, 96% yield).

Preparation of Compounds 1-12

Will be combined1-11 (540 mg,1.22 mmol) were dissolved in tetrahydrofuran. 2, 4-difluorophenylmagnesium bromide (1M, 1.82 mL) was added dropwise at-78deg.C under nitrogen. After slowly warming to room temperature, stirring for 2 hours, TLC detection reaction was complete. Saturated aqueous ammonium chloride (5 mL) was added and extracted with ethyl acetate (5 ml×3), the organic phases were combined and dried by spin, and the crude product was purified by column chromatography (biotage, 10g, silica gel column, UV254, PE: ea=0-100%) to give the title compound 1-12 (400 mg, yield: 70%). ¹ H NMR(400MHz,DMSO-d6)δ9.01(s,1H),7.99(dd,J＝7.7,3.1Hz,2H),7.51(s,1H),7.46(ddd,J＝11.7,9.3,2.5Hz,1H),7.29(d,J＝2.4Hz,1H),7.15(dd,J＝8.7,2.8Hz,1H),7.07(d,J＝2.6Hz,1H),5.38(s,2H),4.85(q,J＝8.8Hz,2H).

Preparation of Compounds 1-13

Compounds 1-12 (300 mg,0.63 mmol), sodium hydroxide (38.19 mg,0.95 mmol), trimethylsulfoxide iodide (140 mg,0.63 mmol) were dissolved in dichloromethane (5 mL) and water (1 mL). Stirring is carried out for 2 hours under the protection of nitrogen. LCMS detected complete reaction. Water (5 mL) was added and extracted with dichloromethane (5 ml×3), the organic phases were combined and dried by spin, and the crude product was purified by column chromatography (biotage, 10g, silica gel column, UV254, PE: ea=0-100%) to give the title compound 1-13 (200 mg, yield: 64%). LC-MS (ESI) m/z 486.2[ M+H ]] ⁺ 。

Preparation of Compound 1

Compound 1-13 (150 mg,0.31 mmol) was dissolved in DMF (3 mL), 1H-tetrazole (43.3 mg,0.62 mmol), potassium carbonate (85.4 mg,0.62 mmol) was added, the reaction was heated to 80℃and stirred for 16 hours, after cooling the reaction system, the crude product was filtered and purified by preparative separation (preparation method: column: agilent 10Prep-C18 250x21.2mm; mobile phase: A:0.1% aqueous formic acid; B: acetonitrile; column temperature: 25 ℃ C.; gradient: 60% -80% acetonitrile in 12min; flow rate: 30 mL/min) to give title compound 1 (90 mg, yield: 52%) and corresponding regioisomer compound 1-14 (30 mg, yield: 17%).

Compound 1 LC-MS (ESI) m/z 556.2[ M+H ]] ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ )δ9.16(s,1H),9.04(s,1H),8.03(d,J＝8.7Hz,1H),7.38–7.27(m,2H),7.27–7.12(m,2H),7.07(d,J＝2.7Hz,1H),7.00(s,1H),6.93(td,J＝8.5,2.6Hz,1H),5.66(d,J＝14.7Hz,1H),5.32(s,2H),5.19–5.00(m,1H),4.85(q,J＝8.8Hz,2H).

Compounds 1-14 LC-MS (ESI) m/z 556.2[ M+H ]] ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ )δ9.02(s,1H),8.77(s,1H),8.03(d,J＝8.8Hz,1H),7.38–7.13(m,4H),7.07(d,J＝2.7Hz,1H),7.04(s,1H),6.92–6.91(m,1H),5.84(d,J＝14.3Hz,1H),5.40(d,J＝14.3Hz,1H),5.33(s,2H),4.85(q,J＝8.8Hz,2H).

Preparation of Compounds 1A and 1B

SFC chiral preparation resolution of Compound 1 (90 MG) (preparation separation method, instrument model: MG II preparation SFC (SFC-1), column model: chiralPak AD, 250X 30mm I.D.,10 μm, mobile phase: A for CO) ₂ and B for Ethanol(0.1％NH ₃ H ₂ O); elution gradient: B40%; the flow rate is 70mL/min; column pressure 100bar; column temperature is 38 ℃; the detection wavelength is 220nm; period: -4 min) gave the title compound 1A (45 mg) and 1B (42 mg).

Chiral analysis method for Compound 1A (column model: chiralPak AD, 150X 4.6mm I.D.,3 μm; mobile phase: A for CO) ₂ and B for Ethanol (0.05% dea); elution gradient: B40%; the flow rate is 2.5mL/min; column temperature is 35 ℃; column pressure 100bar; the detection wavelength is 220nm; rt= 2.341 min). ChiralPak AD, 250X 30mm I.D.,10 μm. LC-MS (ESI) m/z 556.2[ M+H ]] ⁺ , ¹ H NMR(400MHz,DMSO-d ₆ )δ9.16(s,1H),9.04(s,1H),8.03(d,J＝8.7Hz,1H),7.38–7.27(m,2H),7.27–7.12(m,2H),7.07(d,J＝2.7Hz,1H),7.00(s,1H),6.93(td,J＝8.5,2.6Hz,1H),5.66(d,J＝14.7Hz,1H),5.32(s,2H),5.19–5.00(m,1H),4.85(q,J＝8.8Hz,2H).

Chiral analysis method for Compound 1B (column model: chiralPak AD, 150X 4.6mm I.D.,3 μm; mobile phase: A for CO) ₂ and B for Ethanol (0.05% dea); elution gradient: B40%; the flow rate is 2.5mL/min; column temperature is 35 ℃; column pressure 100bar; the detection wavelength is 220nm; rt= 1.787 min). ChiralPak AD, 250X 30mm I.D.,10 μm. LC-MS (ESI) m/z 556.2[ M+H ]] ⁺ , ¹ H NMR(400MHz,DMSO-d ₆ )δ9.16(s,1H),9.04(s,1H),8.03(d,J＝8.7Hz,1H),7.38–7.27(m,2H),7.27–7.12(m,2H),7.07(d,J＝2.7Hz,1H),7.00(s,1H),6.93(td,J＝8.5,2.6Hz,1H),5.66(d,J＝14.7Hz,1H),5.32(s,2H),5.19–5.00(m,1H),4.85(q,J＝8.8Hz,2H).

EXAMPLE 2 preparation of Compound 2

Preparation of Compound 2-2

Compound 2-1 (25 g,116.25 mmol) was dissolved in ethanol (250 mL) and sodium borohydride (2.2 g,58.13 mmol) was added at 0deg.C. The reaction was completed by TLC at room temperature for 2 hours, saturated aqueous ammonium chloride (250 mL) was added and extracted with ethyl acetate (100 mL. Times.3), and the organic phases were combined and washed with 15% sodium chloride solution (20 mL), dried over anhydrous sodium sulfate and dried by spin to give the crude title compound 2-2 (25 g, yield 99%). The crude compound was used directly in the next reaction without purification.

Preparation of Compounds 2-3

The crude compound 2-2 (25 g,115.17 mmol) was dissolved in DMF (125 mL) and NaH (60%, 5.07g,126.69 mmol) was added at 0deg.C. After half an hour of reaction, methyl iodide (17.98 g,126.69 mmol) was added and stirred at room temperature for 2 hours, TLC monitored for completion of the reaction, saturated aqueous ammonium chloride solution (500 mL) was added to quench and extract with ethyl acetate (250 mL. Times.3), the organic phases were combined and dried by spinning, and the crude product was purified by column chromatography (biotage, 330g, silica gel column, UV254, PE: EA=0 to 100%) to give the title compound 2-3 (25 g, yield 94%).

Preparation of Compounds 2-4

Compound 2-3 (25 g,108.18 mmol), pinacol diboron ester (30.22 g,119 mole mL), pdCl ₂ dppf (3.79 g,5.41 mmol), KOAc (31.85 g,324.55 mmol) was dissolved in 1, 4-dioxane (250 mL) and reacted at 110℃for 16 h under nitrogen protection, and TLC detected the disappearance of starting material. Saturated aqueous ammonium chloride (500 mL) was added and extracted with ethyl acetate (250 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate and spin-dried to give crude title compound 2-4 (28 g) which was used in the next reaction without purification.

Preparation of Compounds 2-5

Crude compound 2-4 (28 g,100.66 mmol), K ₂ CO ₃ (41.74 g,301.99 mmol) and the compound 5-bromo-4-methoxypyridin-2-amine (20.44 g,100.66 mmol), pdCl ₂ dppf (3.52 g,5.03 mmol) was dissolved in dioxane (250 mL), and finally water (25 mL) was added and reacted at 110℃for 16 hours under nitrogen, LCMS showed completion of the reaction. Saturated aqueous ammonium chloride (500 mL) was added and extracted with ethyl acetate (250 ml×3), the organic phases were combined and spin-dried, and the crude product was purified by column chromatography (biotage, 330g, silica gel column, UV254, PE: ea=0-100%) to give the title compound 2-5 (16.3 g, yield 59%), LC-MS (ESI): m/z 275.2[ m+h] ⁺ 。

Preparation of Compounds 2-6

Compound 2-5 (13 g,47.39 mmol) was dissolved in diiodomethane (100 mL), tert-butyl nitrite (7.33 g,71.08 mmol) was added, followed by stirring at room temperature for 10 minutes, and cuprous iodide (4.51 g,23.69 mmol) and iodized particles (12.03 g,47.39 mmol) were added. After stirring at room temperature for 16 hours, LCMS detects completion of the reaction. Water (100 mL) and sodium hydroxide (10 g) were added separately to the system. After stirring for 5 minutes, a saturated aqueous sodium sulfite solution was added. And spin-drying to obtain a crude compound. The crude compound was added with water (50 mL) and extracted with dichloromethane (100 ml×3), the organic phases were combined and spin-dried, and the crude product was purified by column chromatography (biotage, 220g, silica gel column, UV254, PE: ea=0-100%) to give the title compound 2-6 (6.8 g, yield 37%). LC-MS (ESI) m/z 386.0[ M+H ]] ⁺ 。

Preparation of Compounds 2-8

Compounds 2-6 (6.8 g,17.65 mmol) were added to BBr ₃ (18 mL) and 1, 2-dichloroethane (36 mL), sealing the tube, reacting for 16 hours at 100 ℃, and cooling to room temperature to obtain the crude compound 2-7.

The crude compound 2-7 was added dropwise to saturated potassium carbonate solution (100 mL) at 0deg.C, stirred at room temperature for 2 hours, and the reaction was complete by LCMS. Dichloromethane extraction (250 ml×3), combining the organic phases and spin-drying, and purifying the crude product by column chromatography (biotage, 330g, silica gel column, UV254, PE: ea=0-100%) to give the title compound 2-8 (4.2 g, two-step reaction yield 73%), LC-MS (ESI): m/z 326.0[ m+h ]] ⁺ 。

Preparation of Compounds 2-9

Compound 2-8 (4.2 g,12.92 mmol) was dissolved in DMF (20 mL) and NaH (60%, 568.3mg,14.21 mmol) was added at 0deg.C. After half an hour of reaction, bromoethane (1.55 g,14.21 mmol) was added. After stirring at room temperature for 2 hours, TLC monitored complete reaction, quenched with saturated aqueous ammonium chloride (50 mL) and extracted with ethyl acetate (50 mL. Times.3), the organic phases were combined and dried by spin, and the crude product was purified by column chromatography (biotage, 80g, silica gel column, UV254, PE: EA 0-100%) to give the title compound 2-9 (2.2 g, yield 48%).

Preparation of Compounds 2-10

Compounds 2-9 (2 g,5.7 mmol) were dissolved in DMSO (400 mL) and copper powder (1.1 g,17.0 mmol) was added, ethyl difluorobromoacetate (1.71 g,8.5 mmol). Under the protection of nitrogen, the temperature is raised to 60 ℃ and stirred for 16 hours. The reaction was quenched with saturated aqueous ammonium chloride (50 mL) and extracted with ethyl acetate (50 mL. Times.3), the organic phases were combined and dried by spin-drying, and the crude product was purified by column chromatography (biotage, 50g, silica gel column, UV254, PE: EA 0-100%) to give the title compound 2-10 (700 mg, yield 38%). LC-MS (ESI) m/z 322.2[ M+H ] ] ⁺ 。

Preparation of Compounds 2-11

Compounds 2-10 (700 mg,2.18 mmol) were dissolved in dichloromethane (7 mL). Oxalyl chloride (553.06 mg,4.36 mmol) was added and 2 drops of DMF were added dropwise. Stirring at room temperature for 2 hours until no bubbles were generated. After spinning to dryness, methylene chloride (7 mL) was added and dissolved, and then, morpholine (1 mL) was added at 0℃and stirred for 1 hour. TLC detection reaction was complete. The reaction was quenched with saturated aqueous ammonium chloride (50 mL), extracted with ethyl acetate (50 mL. Times.3), the organic phases combined and dried by spin, and the crude product was purified by column chromatography (biotage, 10g, silica gel column, UV254, PE: EA 0-100%) to give the title compound 2-11 (500 mg, yield 59%).

Preparation of Compounds 2-12

Compound 2-11 (400 mg,1.02 mmol) was dissolved in tetrahydrofuran (50 mL). 2,4 difluorophenylmagnesium bromide (1M, 1.54 mL) was added dropwise under nitrogen. Stirring was carried out at room temperature for 2 hours and LCMS detected complete reaction. Saturated aqueous ammonium chloride (5 mL) was added and extracted with ethyl acetate (5 mL. Times.3), the organic phases were combined and dried by spin-drying, and the crude product was purified by column chromatography (biotage, 10g, silica gel column, UV254, PE: EA 0-100%) to give the title compound 2-12 (150 mg, yield 35%). LC-MS (ESI) m/z 418.2[ M+H ]] ⁺ 。

Preparation of Compounds 2-13

Compound 2-12 (110 mg,0.36 mmol), sodium hydroxide (22 mg,0.54 mmol), trimethylsulfoxide iodide (118 mg,0.54 mmol) were dissolved in dichloromethane (5 mL) and water (1 mL) ) Is a kind of medium. Stirring is carried out for 16 hours under the protection of nitrogen. LCMS detected complete reaction. Water (5 mL) was added and extracted with dichloromethane (5 mL. Times.3), the organic phases were combined and spin-dried, and the crude product was purified by column chromatography (biotage, 10g, silica gel column, UV254, PE: EA 0-100%) to give the title compound 2-13 (110 mg, 71% yield), LC-MS (ESI): m/z 432.2[ M+H ]] ⁺ 。

Preparation of Compound 2

Compound 2-13 (110 mg,0.25 mmol) was dissolved in DMF (3 mL), 1H-tetrazole (54 mg,0.76 mmol) was added, the reaction was heated to 80℃and stirred for 16 hours, after cooling the reaction, the reaction mixture was filtered and the crude filtrate was isolated and purified by preparative separation (preparation method: column: agilent 10Prep-C18 250x21.2mm; mobile phase: A:0.1% aqueous formic acid; B: acetonitrile; column temperature: 25℃gradient: 60% -80% acetonitrile in 12min; flow rate: 30 mL/min) to give title compound 2 (30 mg, yield 23%) and corresponding regioisomer compound 2-14 (15 mg, yield 12%).

Compound 2 LC-MS (ESI) m/z 502.2[ M+H ]] ⁺ , ¹ H NMR(400MHz,DMSO-d ₆ )δ9.15(s,1H),9.00(s,1H),7.95(d,J＝8.6Hz,1H),7.39–7.14(m,3H),7.07–6.84(m,4H),5.65(d,J＝14.7Hz,1H),5.30(s,2H),5.09(d,J＝14.7Hz,1H),4.09(q,J＝6.9Hz,2H),1.35(t,J＝6.9Hz,3H).

Compounds 2-14 LC-MS (ESI) m/z 502.2[ M+H ]] ⁺ , ¹ H NMR(400MHz,DMSO-d ₆ )δ8.99(s,1H),8.78(s,1H),7.96(d,J＝8.6Hz,1H),7.38–7.15(m,3H),7.01(d,J＝8.8Hz,2H),6.98–6.81(m,2H),5.85(d,J＝14.3Hz,1H),5.40(d,J＝14.5Hz,1H),5.32(s,2H),2.56–2.48(m,2H),1.37(t,J＝6.9Hz,3H).

EXAMPLE 3 preparation of Compounds 3A and 3B

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Preparation of Compound 3-1

Compound 2-8 (2.89 g,8.9 mmol) was dissolved in DMF (10 mL), and potassium carbonate (2.45 g,17.8 mmol) and 2, 2-trifluoroethyl trifluoromethane sulfonate (4.13 mg,17.8 mmol) were added and reacted for 16 hours at 65℃in an oil bath. After cooling, etOAc (2) 5mL×3) and the organic phases were combined, dried and concentrated to give the crude product, which was purified by normal phase silica gel column (EtOAc/PE=0-5%) to give the title compound 3-1 (3 g, 55% yield), LC-MS (ESI): m/z 408.0[ M+H)] ⁺ 。

Preparation of Compound 3-2

Compound 3-1 (2.7 g,6.6 mmol) was dissolved in DMSO (15 mL) and copper powder (1.06 g,16.6 mmol) and ethyl difluorobromoacetate (2 g,10 mmol) were added. Under the protection of nitrogen, the reaction is carried out for 3 hours at 65 ℃ in an oil bath. After cooling, pouring into ice water, extracting with EtOAc (25 mL. Times.3), combining the organic phases, drying and concentrating to give the crude product, and isolating and purifying the crude product by normal phase silica gel column (EtOAc: PE=0-15%) to give the title compound 3-2 (1.51 g, 53% yield), LC-MS (ESI): m/z 404.2[ M+H)] ⁺ 。

Preparation of Compound 3-3

2, 4-difluorobromobenzene (0.93 g,4.8 mmol) was added to a three-necked flask and replaced with nitrogen three times. Anhydrous diethyl ether (15 mL) was added to the three-necked flask, and n-butyllithium (2.5M, 1.9mL,4.8 mmol) was added dropwise at-78deg.C. After the reaction system was stirred at-78℃for 45 minutes, an anhydrous diethyl ether solution (10 mL) in which compound 3-2 (1.3 g,3.2 mmol) was dissolved was added dropwise and the reaction was continued with stirring for 1 hour. After the completion of the reaction, the reaction mixture was quenched with saturated ammonium chloride solution (5 mL), extracted with EtOAc (20 mL. Times.3), the organic phases were combined, dried and concentrated to give the crude product, which was purified by normal phase silica gel column (PE: etOAc=0-20%) to give the title compound 3-3 (0.71 g, 47% yield), LC-MS (ESI): m/z 472.2[ M+H ] ⁺ 。

Preparation of Compounds 3-4

Compound 3-3 (710 mg,1.5 mmol) was dissolved in THF (10 mL), 2-methylpropyl-2-thiamine (547 mg,4.5 mmol) and tetraethyltitanate (1.72 g,7.5 mmol) were added, the tube was capped at 80℃for 16 h, distilled water (2 mL) was added after cooling to room temperature to quench the reaction, the solvent was spun dry, the residue was dissolved in DCM (10 mL), the filtrate was concentrated to give the crude product, and the title compound 3-4 (480 mg, yield 55%) was isolated and purified by a normal phase silica gel column (EtOAc: PE=0-20%) with LC-MS (ESI): m/z 575.2[ M+H ]] ⁺ 。

Preparation of Compounds 3-5

Compound 3-4 (480 mg,0.84 mmol) was dissolved in nitromethane (2.5 mL), nitrogen blanketed, and added dropwise at 0deg.CTetrabutylammonium fluoride (1M, 1.67mL,1.67 mmol) was reacted at room temperature for 16 hours after the completion of the dropping. Water (20 mL) was added and the combined organic phases were extracted with EtOAc (20 mL. Times.3) and concentrated to give the crude product which was purified by separation on a normal phase silica gel column (EtOAc: PE=0-100%) to give the title compound 3-5 (204 mg, 38% yield, containing a pair of enantiomers), LC-MS (ESI): m/z 636.4[ M+H)] ⁺ 。

Preparation of Compounds 3-6

Compound 3-5 (204 mg,0.32 mmol) was dissolved in EtOAc (5 mL), raney-Ni (100 mg) was added, and after three hydrogen substitutions, the reaction was carried out at room temperature for 3 hours. After completion of the reaction, it was filtered through celite and concentrated to give the crude title compound 3-6 (160 mg) which was used directly in the next step, LC-MS (ESI): m/z 606.2[ M+H ] ] ⁺ 。

Preparation of Compounds 3-7

Compound 3-6 (160 mg,0.26 mmol) was dissolved in AcOH (5 mL) in a microwave tube, and trimethyl orthoformate (140 mg,1.3 mmol), sodium acetate (26 mg,0.32 mmol) and TMSN were added thereto ₃ (304 mg,2.6 mmol), microwave tube sealed, and reacted at 75℃for 16 hours. After cooling, the organic phases were combined by extraction with EtOAc (100 mL. Times.3), dried and concentrated to give the crude product, which was purified by separation on a normal phase silica gel column (EtOAc/PE=0-100%) to give the title compound 3-7 (100 mg, yield 57%, pair of enantiomers), LC-MS (ESI): m/z 659.2[ M+H)] ⁺ 。

Preparation of Compound 3

Compound 3-7 (100 mg,0.15 mmol) was dissolved in methanol (3 mL), stirred at 0deg.C, then dioxane solution (4M, 2 mL) of hydrochloric acid was added dropwise, and the reaction was stirred at 0deg.C for 4 hours. Saturated NaHCO is added into the reaction system dropwise ₃ The reaction was quenched with aqueous (5 mL), extracted with EtOAc, the organic phase solvent was concentrated, filtered with methanol and the crude filtrate was isolated and purified by preparative separation (preparation method: chromatography column: agilent 10Prep-C18 250X21.2mm; column temperature: 25 ℃ C.; mobile phase: water (0.1% TFA) -acetonitrile; mobile phase acetonitrile ratio 55% -75% in 12min; flow rate 30 mL/min) to give the title compound 3 (25 mg, yield 30% of one enantiomer). LC-MS (ESI) m/z 555.2[ M+H ]] ⁺ , ¹ H NMR(400MHz,DMSO-d ₆ )δ9.23(s,1H),9.07(s,1H),8.04(d,J＝8.6Hz,1H),7.41–7.32(m,1H),7.20–7.12(m,2H),7.06(d,J＝2.8Hz,1H),6.99(s,1H),6.93(td,J＝8.6,2.8Hz,1H),5.67(d,J＝14.4Hz,1H),5.30(s,2H),4.94–4.77(m,3H),2.97(s,2H).

Preparation of Compounds 3A and 3B

Chiral preparation resolution of Compound 3 (25 MG) by SFC (preparation separation method, apparatus model: MG II preparation SFC (SFC-14), column model: chiralPak AD, 250X 30mm I.D.,10 μm, mobile phase: A for CO) ₂ and B for Ethanol(0.1％NH ₃ H ₂ O); elution gradient: B40%; the flow rate is 80mL/min; column pressure 100bar; column temperature is 38 ℃; the detection wavelength is 220nm; period: -7 min) to give the title compound 3A (13 mg) and 3B (8 mg).

Compound 3A LC-MS (ESI): 555.2[ M+H ]] ⁺ 。 ¹ H NMR(400MHz,DMSO-d ₆ )δ9.23(s,1H),9.08(s,1H),8.04(d,J＝8.6Hz,1H),7.41–7.31(m,1H),7.21–7.12(m,2H),7.06(d,J＝2.8Hz,1H),7.00(s,1H),6.93(td,J＝8.4,2.8Hz,1H),5.67(d,J＝14.4Hz,1H),5.30(s,2H),4.93–4.78(m,3H),2.98(s,2H).

Compound 3B LC-MS (ESI): 555.2[ M+H ]] ⁺ 。 ¹ H NMR(400MHz,DMSO-d ₆ )δ9.23(s,1H),9.08(s,1H),8.04(d,J＝8.6Hz,1H),7.41–7.30(m,1H),7.23–7.12(m,2H),7.06(d,J＝2.8Hz,1H),7.00(s,1H),6.93(td,J＝8.6,2.8Hz,1H),5.67(d,J＝14.4Hz,1H),5.30(s,2H),4.92–4.78(m,3H),2.98(s,2H).

EXAMPLE 4 preparation of Compounds 4A and 4B

Preparation of Compound 4-3

Compound 4-1 (10 g,43.5 mmol), K ₂ CO ₃ (17.94 g,129.84 mmol), compound 4-2 (10.82 g,43.28 mmol), pdCl ₂ dppf (3.17 g,4.33 mmol) was dissolved in 1, 4-dioxane (100 mL) solvent and water (20 mL) was added and reacted at 110℃for 16 h under nitrogen, LCMS showed complete reaction. The reaction was quenched with saturated aqueous ammonium chloride (200 mL) and extracted with ethyl acetate (100 ml×3), the organic phases were combined and dried by spin-drying, and the crude product was purified by column chromatography (biotage, 220g, silica gel column, UV254, PE: ea=0-100%) to give the title compound4-3 (3.6 g, yield 15%), LC-MS (ESI): m/z 357.2[ M+H ]] ⁺ 。

Preparation of Compounds 4-4

Compound 4-3 (3.4 g,9.54 mmol) was dissolved in dichloromethane. BBr is added at 0 DEG C ₃ Is slowly warmed to room temperature and stirred for 1 hour. LCMS detected complete reaction. The reaction solution was added dropwise to saturated sodium bicarbonate solution (100 mL) at 0 ℃. After stirring at room temperature for 2 hours. Dichloromethane extraction (50 ml×3), combining the organic phases and spin-drying, and purification of the crude product by column chromatography (biotage, 50g, silica gel column, UV254, PE: ea=0-100%) gave the title compound 4-4 (2.8 g, 95% yield), LC-MS (ESI): m/z 311.2[ m+h] ⁺ 。

Preparation of Compounds 4-5

Compound 4-4 (3.11 g,10.02 mmol) was dissolved in ethanol (30 mL), slowly added sodium borohydride (618 mg,15.10 mmol) at 0deg.C, stirred at room temperature for 16 h, quenched by the addition of saturated aqueous ammonium chloride (250 mL), extracted with ethyl acetate (100 mL. Times.3), combined with the organic phase, washed with saturated aqueous sodium chloride (100 mL), dried over anhydrous sodium sulfate, and the organic phase was spun dry to give crude title compound 4-5 (25 g, 96% yield) LC-MS (ESI) m/z 315.2[ M+H ]] ⁺ 。

Preparation of Compounds 4-6

Compound 4-5 (3 g,9.55 mmol), triphenylphosphine (2.5 g,9.55 mmol) was dissolved in tetrahydrofuran (30 mL), and DEAD (1.99 g,11.46 mmol) was added dropwise after cooling to 0deg.C. After the reaction was slowly warmed to room temperature and stirred for 2 hours, LCMS detected completion of the reaction. Water (50 mL) was added to the reaction, extraction was performed with ethyl acetate (50 mL. Times.3), the organic phases were combined and spin-dried, and the crude product was purified by column chromatography (biotage, 40g, silica gel column, UV254, PE: EA=0-100%) to give the title compound 4-6 (2.6 g, yield 91%), LC-MS (ESI): m/z 297.2[ M+H ] ] ⁺ 。

Preparation of Compounds 4-7

Compound 4-6 (200 mg,0.68 mmol) was dissolved in diiodomethane (1.5 mL), tert-butyl nitrite (104 mg,1.01 mmol), cuprous iodide (64 mg,0.34 mmol) and iodized particles (171mg, 0.68 mmol) were added at room temperature. The reaction was stirred under nitrogen at room temperature for 16 hours and LCMS monitoring showed complete reaction. Sodium hydroxide (2 g) and water (2) are respectively added into the systemmL). After stirring for 5 minutes, saturated aqueous sodium sulfite solution (2 mL) was added. Dichloromethane extraction (3 ml×3), combining the organic phases and spin-drying, and purification of the crude product by column chromatography (biotage, 4g, silica gel column, UV254, PE: ea=0-100%) gave the title compound 4-7 (83 mg, 30% yield), LC-MS (ESI): m/z 408.0[ m+h ]] ⁺ 。

Preparation of Compounds 4-8

Compound 4-7 (83 mg,0.2 mmol) was dissolved in DMSO (2 mL), copper powder (32 mg,0.51 mmol) and ethyl difluorobromoacetate (203 mg,0.31 mmol) were added, the mixture was stirred for 16 h under nitrogen protection, warmed to 60℃and stirred, saturated aqueous ammonium chloride (50 mL) was added and extracted with ethyl acetate (10 mL. Times.3), the organic phases were combined and spin-dried, and the crude product was purified by column chromatography (biotage, 4g, silica gel column, UV254, PE: EA=0-100%) to give title compound 4-8 (35 mg, yield 42%), LC-MS (ESI): m/z 404.2[ M+H ]] ⁺ 。

Preparation of Compounds 4-9

Compounds 4-8 (600 mg,1.49 mmol) were dissolved in morpholine (2 mL). Stirred at 80℃for 4 hours. TLC detection reaction was complete. Saturated aqueous ammonium chloride (50 mL) was added, extraction was performed with ethyl acetate (50 mL. Times.3), the combined organic phases were spun dry and the crude product was purified by column chromatography (biotage, 10g, silica gel column, UV254, PE: EA=0-100%) to give the title compound 4-9 (640 mg, 96% yield), LC-MS (ESI): m/z 445.2[ M+H ] ] ⁺ 。

Preparation of Compounds 4-10

Compound 4-9 (400 mg,1.02 mmol) was dissolved in tetrahydrofuran (50 mL). 2, 4-difluorophenylmagnesium bromide (1M, 1.54 mL) was added dropwise under nitrogen. Stirring was carried out at room temperature for 2 hours and LCMS detected complete reaction. Saturated aqueous ammonium chloride (5 mL) was added and extracted with ethyl acetate (5 ml×3), the organic phases were combined and spin-dried and purified by column chromatography (biotage, 10g, silica gel column, UV254, PE: ea=0-100%) to give the title compound 4-10 (150 mg, yield 35%), LC-MS (ESI): m/z 472.0[ m+h ]] ⁺ 。

Preparation of Compounds 4-11

Compounds 4-10 (150 mg,0.31 mmol), sodium hydroxide (20 mg,0.43 mmol), trimethylsulfoxide iodide (70 mg,0.31 mmol) were dissolved in dichloromethane (5 mL) and water (1 mL). Stirring is carried out for 2 hours under the protection of nitrogen. LCMS detected complete reaction. Water (5 mL) was added and extracted with dichloromethane (15 mL. Times.3) and combinedThe crude product was purified by column chromatography (biotage, 10g, silica gel column, UV254, PE: EA=0-100%) to give the title compound 4-11 (100 mg, yield 64%), LC-MS (ESI): m/z 486.0[ M+H ]] ⁺ 。

Preparation of Compound 4

Compound 4-11 (100 mg,0.2 mmol) was dissolved in DMF (3 mL) and 1H-tetrazole (27 mg,0.8 mmol) and potassium carbonate (28 mg,0.8 mmol) were added, respectively. The reaction system was stirred at 80℃for 16 hours, after the reaction system was cooled, filtered and spin-dried, and the crude product was isolated and purified by preparative separation (preparation method: column chromatography: agilent 10 Prep-C18X 21.2mm; mobile phase: A:0.1% aqueous formic acid; B: acetonitrile; column temperature: 25 ℃ C.; gradient: 60% -80% acetonitrile in 12min; flow rate: 30 mL/min) to give the title compound 4 (50 mg, yield 43%) and the corresponding regioisomer compound 4-12 (10 mg, yield 9%).

Compound 4 LC-MS (ESI) m/z 556.2[ M+H ]] ⁺ , ¹ H NMR(400MHz,DMSO-d ₆ )δ9.15(s,1H),9.04(s,1H),8.04(d,J＝8.7Hz,1H),7.43(s,1H),7.33–7.15(m,3H),6.97–6.88(m,1H),6.88–6.81(m,1H),6.78(d,J＝2.6Hz,1H),5.65(d,J＝14.7Hz,1H),5.24(d,J＝1.8Hz,2H),5.14–5.06(m,1H),4.84(q,J＝8.9Hz,2H).

Compounds 4-12 LC-MS (ESI) m/z 556.2[ M+H ]] ⁺ , ¹ H NMR(400 MHz,DMSO-d ₆ )δ9.03(s,1H),8.78(s,1H),8.04(s,1H),7.37(d,J＝73.2Hz,4H),7.03–6.57(m,3H),5.85(d,J＝14.5Hz,1H),5.33(d,J＝66.7Hz,3H),4.85(s,2H).

Preparation of Compounds 4A and 4B

SFC chiral preparation resolution of Compound 4 (50 MG) (preparation separation method, apparatus model: MG II preparation SFC (SFC-14), column model: chiralPak AD, 250X 30mm I.D.,10 μm, mobile phase: A for CO) ₂ and B for Ethanol; elution gradient: B30%; the flow rate is 70mL/min; column pressure 100 bar; column temperature is 38 ℃; a detection wavelength of 220 nm; period: -7 min) to give the title compound 4A (16 mg) and 4B (16 mg).

Compound 4A: chiral analysis method (column model: chiralPak AD, 150X 4.6mm I.D.,3 μm; mobile phase: A for CO) ₂ and B for Ethanol (0.05% dea); elution gradient: B40%; the flow rate is 2.5mL/min; column temperature:35 ℃; column pressure 100 bar; a detection wavelength of 220 nm; rt=2.312 min). LC-MS (ESI) m/z 556.2[ M+H ]] ⁺ 。 ¹ H NMR(400 MHz,DMSO-d ₆ )δ9.15(s,1H),9.04(s,1H),8.04(d,J＝8.7Hz,1H),7.43(s,1H),7.33–7.15(m,3H),6.97–6.88(m,1H),6.88–6.81(m,1H),6.78(d,J＝2.6Hz,1H),5.65(d,J＝14.7Hz,1H),5.24(d,J＝1.8Hz,2H),5.14–5.06(m,1H),4.84(q,J＝8.9Hz,2H). ¹⁹ F NMR(376 MHz,DMSO-d ₆ )δ-72.46(m,3F),-100.78–-104.59(m,1F),-105.80–-108.39(m,1F),-109.76(m,2F).

Chiral analysis method for Compound 4B (column model: chiralPak AD, 150X 4.6mm I.D.,3 μm; mobile phase: A for CO) ₂ and B for Ethanol (0.05% dea); elution gradient: B40%; the flow rate is 2.5mL/min; column temperature is 35 ℃; column pressure 100 bar; a detection wavelength of 220 nm; rt=1.753 min). LC-MS (ESI) m/z 556.2[ M+H ]] ⁺ 。 ¹ H NMR(400 MHz,DMSO-d ₆ )δ9.15(s,1H),9.04(s,1H),8.04(d,J＝8.7Hz,1H),7.43(s,1H),7.33–7.15(m,3H),6.97–6.88(m,1H),6.88–6.81(m,1H),6.78(d,J＝2.6Hz,1H),5.65(d,J＝14.7Hz,1H),5.24(d,J＝1.8Hz,2H),5.14–5.06(m,1H),4.84(q,J＝8.9Hz,2H). ¹⁹ F NMR(376 MHz,DMSO-d ₆ )δ-72.46(m,3F),-100.78–-104.59(m,1F),-105.80–-108.39(m,1F),-109.76(m,2F).

EXAMPLE 5 preparation of Compound 5

Preparation of Compound 5-2

Compound 5-1 (25 g,123.13 mmol) was added to the autoclave followed by DMF (250 mL), trifluoroiodoethane (28.43 g,135.44 mmol) and potassium carbonate (25.53 g,184.70 mmol) in sequence. The reaction system was reacted at 110℃for 16 hours under nitrogen protection. Ethyl acetate (500 mL), saturated sodium hydrogencarbonate (150 ml×3) and dried over anhydrous sodium sulfate were added, and the crude product was purified by normal phase column chromatography (PE: ea=0 to 100%) to give the title compound 5-2 as a colorless liquid (27 g, yield 77%). ¹ H NMR(400 MHz,CDCl ₃ )δ7.44(dd,J＝8.7,1.0Hz,1H),6.56(d,J＝2.6Hz,1H),6.39(dd, j=8.6, 2.5hz, 1H), 4.33 (q, j=8.1 hz, 2H), 3.88 (s, 3H). Preparation of compound 5-3

Compound 5-2 (27 g,94.72 mmol), 1, 4-dioxane (250 mL), potassium acetate (13.94 mg,142.08 mmol), pinacol ester of biboronate (28.86 g,113.66 mmol) were added sequentially to a single-necked flask, the system replaced nitrogen, and reacted at 110℃for 16 hours. Water (20 mL) was added, extracted with ethyl acetate (100 mL. Times.3), washed with saturated brine, dried, filtered, and concentrated to give the crude title compound 5-3 (18 g) as a pale yellow solid, which was used in the next step without purification.

Preparation of Compounds 5-5

Compound 5-3 (10 g,30.11 mmol), 1, 4-dioxane (200 mL), water (20 mL), compound 5-4 (7.5 g,36.13 mmol), potassium carbonate (6.2 g,45.10 mmol), pd (dppf) Cl ₂ (2.1 g,3.0 mmol) was added to a single-port flask, after nitrogen substitution, the reaction was carried out at 110℃for 16 hours, extracted with ethyl acetate (250 mL. Times.3), washed with saturated brine (250 mL), dried over anhydrous sodium sulfate and concentrated, and the crude product was purified by normal phase column chromatography (PE: EA=0 to 100%) to give the title compound 5-5 as a white solid (7 g, yield 70%), LCMS (ESI): m/z=333.0 [ M+H ]] ⁺ 。

Preparation of Compounds 5-6

Compound 5-5 (7 g,21.04 mmol) and dichloromethane (100 mL) were sequentially added into a three-necked flask, the system was slowly added dropwise with boron tribromide (1M, 105.20 mmol) after 0 ℃ and reacted at room temperature for 3 hours, methanol was added to quench the reaction, the mixture was dried under reduced pressure, ethyl acetate (100 mL) was added, saturated sodium bicarbonate water (30 mL) was used for washing, anhydrous sodium sulfate was dried, dried over spin, and the crude product was purified by normal phase column chromatography (PE: EA=0-100%) to give the title compound 5-6 (5.2 g, yield 78%) as a pale yellow solid, LCMS (ESI): m/z=319.0 [ M+H ]] ⁺ 。

Preparation of Compounds 5-7

Compounds 5-6 (5.2 g,16.32 mmol), DMF (100 mL) and cesium carbonate (7.97 g,24.48 mmol) were added sequentially to a single-necked flask. The reaction was reacted at 120℃for 3 hours, extracted with ethyl acetate (100 mL), washed with saturated brine (30 mL), dried over anhydrous sodium sulfate and spin-dried, and the crude product was purified by normal phase column chromatography (PE: EA=0 to 100%) to give the title compound 5-7 (3.9 g, yield 84%) as a pale yellow solid, LCMS (ESI): m/z=283.0 [ M+H ] ⁺ 。

Preparation of Compounds 5-8

Compound 5-7 (3.9 g,13.82 mmol), diiodomethane (50 mL), elemental iodine (3.15 g,13.82 mmol), cuprous iodide (526.36 mg,2.76 mmol), tert-butyl nitrite (1.85 g,17.96 mmol) were sequentially added to a single-port flask, reacted at room temperature for 16 hours, dried under reduced pressure, ethyl acetate (100 mL) was added, washed with water (100 mL), and the crude product after concentration was purified by normal phase column chromatography (PE: EA=0-100%) to give the title compound 5-8 (2.4 g, yield 48%) as a pale yellow solid. ¹ H NMR(400MHz,DMSO-d6)δ9.13(d,J＝0.6Hz,1H),8.29(d,J＝0.6Hz,1H),8.18(d,J＝8.6Hz,1H),7.58(d,J＝2.2Hz,1H),7.23(dd,J＝8.6,2.3Hz,1H),4.92(q,J＝8.8Hz,2H).

Preparation of Compounds 5-9

Compound 5-8 (2.4 g,6.11 mmol), DMSO (50 mL), ethyl difluorobromoacetate (1.49 g,7.33 mmol), active copper powder (426.76 mg,6.72 mmol) were sequentially added to a single-necked flask, reacted at room temperature under nitrogen protection for 16 hours, ethyl acetate (100 mL) was added, water (100 mL) was used for washing, concentrated and purified by normal phase column chromatography (PE: EA=0-100%) to give compound 5-9 (0.5 g, yield 21%) as a white solid, LCMS (ESI) m/z=390.1 [ M+H ]] ⁺ 。

Preparation of Compounds 5-10

2, 4-Difluorobromobenzene (272.67 mg,1.41 mmol), diethyl ether (10 mL) was added to a single-necked flask, the temperature was lowered to-78℃after nitrogen substitution, and n-butyllithium (0.7 mL,1.67 mmol) was slowly added dropwise, and the reaction was continued for 1 hour after the dropwise addition was completed. An MTBE (2 mL) solution containing compound 5-9 (500 mg,1.28 mmol) was slowly added dropwise to the reaction system. The reaction was continued for 3 hours. Saturated ammonium chloride (15 mL) was added to quench, ethyl acetate was extracted (30 ml×3), the organic phases were combined, concentrated and subjected to normal phase column chromatography (PE: ea=0 to 100%) to give the title compound 5-10 (170 mg, yield 29%) as a pale yellow solid. LCMS (ESI) m/z=458.0 [ m+h ] ] ⁺ 。

Preparation of Compounds 5-11

Trimethylsulfoxide iodide (90 mg,0.41 mmol), THF (6 mL), DMSO (4 mL), potassium tert-butoxide (50 mg, 0.458 mmol) were added sequentially to a single-necked flask, and reacted at room temperature for 1 hour, and cooled to 0 ℃. The reaction system was slowly dropped with THF (3 mL) containing 5-10 (170 mg,0.371 mmol) of the compound dissolved therein, and the reaction was continued for 3 hours. Ethyl acetate (20)ml×3), washed with water, dried, and concentrated, and the crude product was purified by normal phase column chromatography (PE: ea=0 to 100%) to give the title compound 5-11 (143 mg, yield 82%) as a pale yellow solid. LCMS (ESI) m/z=472.0 [ m+h ]] ⁺ 。

Preparation of Compound 5

Compound 5-11 (143 mg,0.303 mmol), tetrazole (31.88 mg, 0.266 mmol), THF (2 mL), and potassium carbonate (83.86 mg,0.606 mmol) were each added to a microwave tube and reacted at 70℃for 16 hours. Quench with water and extract with ethyl acetate (20 mL. Times.3). The crude product was concentrated by drying and prepared by reverse phase chromatography to give the title compound 5 (38 mg) and the corresponding regioisomer compounds 5-12 (29 mg).

Compound 5 LC-MS m/z 542.1[ M+H ]] ⁺ , ¹ H NMR(400MHz,DMSO-d6)δ9.36(s,1H),9.15(s,1H),8.27(d,J＝8.6Hz,1H),7.86(s,1H),7.65(d,J＝2.2Hz,1H),7.34(s,1H),7.31–7.24(m,2H),7.19(ddd,J＝11.8,9.1,2.5Hz,1H),6.92–6.85(m,1H),5.69(d,J＝14.7Hz,1H),5.13(d,J＝14.8Hz,1H),4.95(q,J＝8.8Hz,2H).

Compounds 5-12 LC-MS: m/z 542.2[ M+H ]] ⁺ , ¹ H NMR(400MHz,DMSO-d6)δ9.33(s,1H),8.76(s,1H),8.26(d,J＝8.6Hz,1H),7.86(s,1H),7.64(d,J＝2.2Hz,1H),7.34–7.08(m,4H),6.86(t,J＝7.1Hz,1H),5.88(d,J＝14.4Hz,1H),5.41(d,J＝14.3Hz,1H),4.95(q,J＝8.8Hz,2H).

Test example 1 minimum inhibitory concentration (Minimal Inhibitory Concentration, MIC) test of Compounds against fungal growth

(1) The main reagent comprises:

RPMI1640 medium, gibco, cat# 31800-014

Saccharum dextrose agar (Sabouraud dextrose agar, SDA) brand of Haibo, cat# HB0253-81

Voriconazole brand name Adamas, cat No. 22105A

Amphotericin B brand Abcam, cat# ab141199

(2) The fungal strains are shown in Table 1 below:

TABLE 1

(3) The testing method comprises the following steps:

MIC testing was performed according to guidelines and requirements of CLSI M27 (for yeast) and M38 (for aspergillus).

Strain preparation the strain was streaked onto SDA plates 1 day in advance with glycerol strain stored at-80 ℃. Culturing at 35 deg.C under 40-60% humidity for 18-24 hr. Aspergillus fumigatus, cryptococcus neoformans, respectively, require streaking inoculation 3 days and 2 days in advance.

Culture medium and compound preparation liquid culture medium RPMI was prepared with pure water, and 0.165mol/L MOPS was added and pH was adjusted to 7.0, and after filtration sterilization with a filter of 0.22 μm filter membrane, it was stored at 4℃for not more than 3 months. 0.85% physiological saline is sterilized at 121 ℃ for 30 minutes and then stored at room temperature (not more than 1 week). The compound was dissolved in DMSO at 12.8mg/mL and stored at-20 ℃.

For yeast, 3-5 colonies were picked from the SDA plate on the day of the test, and fully suspended in 5mL of sterilized 0.85% physiological saline. The turbidity of the bacterial liquid is measured by a turbidity meter, and the turbidity is adjusted to about 0.2. The bacterial solutions were diluted 50-fold and 20-fold (1000-fold total) in sequence with RPMI1640 medium as inoculum. The final inoculum concentration was 500-2500CFU/mL.

For Aspergillus, 5mL of physiological saline was used to cover the mycelium, spores were gently scraped off with a spreader, and the spore suspension was transferred to a sterile tube. Appropriate amounts of spore suspension were aspirated and counted under a microscope using a hemocytometer. Spore concentration was adjusted to about 0.4-5x10 with RPMI1640 medium ⁴ spores/mL。

The compound was diluted with DMSO up to 800 μg/mL (or 400 μg/mL) and 10 2-fold gradient dilutions were performed for a total of 11 concentrations. Transfer 2. Mu.L of the gradient diluted compound to the corresponding well of the 96-well plate and transfer 198. Mu.L of the inoculum to the test plate, incubate at 35℃for 24 hours (Aspergillus fumigatus and Cryptococcus neoformans for 48 and 72 hours, respectively).

(4) MIC assessment:

after the incubation, the fungal growth was visually observed, and the point of minimum compound concentration at which the inhibition of yeast growth was not less than 50% (100% inhibition of aspergillus) was defined as the minimum inhibitory concentration MIC (μg/mL). MIC determination can be aided with a magnifying glass or reading OD530 nm. The test board photographs the record file. The results are shown in Table 2 below.

TABLE 2 results of in vitro antifungal Activity of partially preferred Compounds MIC (μg/mL)

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Claims

1. A compound shown in a formula (I), optical isomer, tautomer and pharmaceutically acceptable salt thereof,

wherein,,

ring a is selected from 5-6 membered heteroaryl;

ring B is selected from phenyl, 5-6 membered heteroaryl and C _5-6 Cycloalkyl;

ring C, ring E are each independently selected from phenyl and 5-6 membered heteroaryl, said phenyl or 5-6 membered heteroaryl optionally substituted with 1, 2 or 3 Rx;

ring D is selected from C _4-8 Cycloalkyl and 4-8 membered heterocyclyl, said C _4-8 Cycloalkyl or 4-8 membered heterocyclyl is optionally substituted with 1, 2 or 3R _Y Substitution;

n is independently selected from 0, 1, 2 or 3;

L ₄ selected from H, F, cl, br, I, OH, CN, NH ₂ 、COOH、SF ₃ 、SF ₆ 、SCN、SO ₂ R ₇ 、C _1-6 Alkyl, C _1-6 Heteroalkyl, C _3-6 Cycloalkyl, 4-6 membered heterocyclyl, C _1-6 Alkyl-5-6 membered heterocyclyl, 5-6 membered heteroaryl and benzo 4-6 membered heterocyclyl, said C _1-6 Alkyl, C _1-6 Heteroalkyl, C _3-6 Cycloalkyl, 4-6 membered heterocyclyl, C _1-6 Alkyl-5-6 membered heterocyclyl, 5-6 membered heteroaryl or benzo 5-6 membered heterocyclyl optionally substituted with 1,2. 3, 4 or 5R _L Substitution;

2. A compound shown in a formula (I), optical isomer, tautomer and pharmaceutically acceptable salt thereof,

wherein,,

X ₁ 、X ₂ are each independently selected from C (R) _X ) And N;

X ₃ 、X ₄ are each independently selected from C (R) _Y ) ₂ And O;

ring a is selected from 5-6 membered heteroaryl;

ring B is selected from phenyl, 5-6 membered heteroaryl and C _5-6 Cycloalkyl;

R ₂ 、R ₄ 、R ₅ 、R _X 、R _Y are respectively and independently selected from H, CN, OH, F, cl, br, I, C _1-6 Alkyl, C _1-6 HeteroalkanesBase, SF ₃ 、SF ₆ 、SCN、SO ₃ H and SO ₂ R ₇ The C is _1-6 Alkyl or C _1-6 Heteroalkyl is optionally substituted with 1, 2 or 3 CN, OH, F, cl, br, I or C _1-6 Alkyl substitution;

n, m are each independently selected from 0, 1, 2 or 3;

L ₄ selected from H, F, cl, br, I, OH, CN, NH ₂ 、COOH、SF ₃ 、SF ₆ 、SCN、SO ₂ R ₇ 、C _1-6 Alkyl, C _1-6 Heteroalkyl, C _3-6 Cycloalkyl, 4-6 membered heterocyclyl, C _1-6 Alkyl-5-6 membered heterocyclyl, 5-6 membered heteroaryl and benzo 4-6 membered heterocyclyl, said C _1-6 Alkyl, C _1-6 Heteroalkyl group、C _3-6 Cycloalkyl, 4-6 membered heterocyclyl, C _1-6 Alkyl-5-6 membered heterocyclyl, 5-6 membered heteroaryl or benzo 5-6 membered heterocyclyl optionally substituted with 1, 2, 3, 4 or 5R _L Substitution;

R _L selected from CN, OH, F, cl, br, I, NH ₂ 、C _1-6 Alkyl and C _1-6 Heteroalkyl group, C (=O) C _1-6 Alkyl, C _1-6 Alkyl or C _1-6 Heteroalkyl is optionally substituted with 1, 2 or 3 CN, OH, NH ₂ F, cl, br, I or C _1-6 Alkyl substitution;

3. The compound according to claim 1 or 2, optical isomers, tautomers and pharmaceutically acceptable salts thereof, wherein ring a is selected from tetrazolyl, triazolyl, oxazolyl, pyrimidinyl, thiazolyl or pyrazolyl.

4. The compound according to claim 1 or 2, optical isomers, tautomers and pharmaceutically acceptable salts thereof, wherein ring a is selected from the group consisting of

5. The compound according to claim 1 or 2, optical isomers, tautomers and pharmaceutically acceptable salts thereof, wherein ring B is selected from phenyl and pyridyl.

6. The compound according to claim 1 or 2, optical isomers, tautomers and pharmaceutically acceptable salts thereof, wherein the structural unit

Selected from->

7. The compound of claim 1 or 2, optical isomers, tautomers, and pharmaceutically acceptable salts thereof, wherein R ₃ Selected from OH, NH ₂ 、C _1-3 Alkyl, C _1-3 Alkoxy, C _1-3 Alkylamino, C _1-3 Alkylthio, -OC (=o) C _1-3 Alkyl and-NHC (=o) C _1-3 An alkyl group.

8. The compound of claim 1, optical isomers, tautomers, and pharmaceutically acceptable salts thereof, wherein ring C and ring E are each independently selected from phenyl and pyridinyl, said phenyl or pyridinyl optionally substituted with 1, 2, or 3 Rx.

9. The compound of claim 1, optical isomers, tautomers, and pharmaceutically acceptable salts thereof, wherein ring D is each independently selected from the group consisting of cyclopentyl, cyclohexyl, tetrahydrofuranyl, and tetrahydropyranyl, said cyclopentyl, cyclohexyl, tetrahydrofuranyl, or tetrahydropyranyl being optionally substituted with 1, 2, or 3R _Y And (3) substitution.

10. The compound according to claim 1 or 2, optical isomers, tautomers and pharmaceutically acceptable salts thereof, wherein L ₁ Selected from single bonds, CH ₂ 、

11. The compound according to claim 1 or 2, optical isomers, tautomers and pharmaceutically acceptable salts thereof, wherein L ₂ Selected from single bonds, O, S, CH ₂ 、NH、NCH ₃ 、

12. The compound according to claim 1 or 2, optical isomers, tautomers and pharmaceutically acceptable salts thereof, wherein L ₃ Selected from single bonds, CH ₂ 、CH ₂ CH ₂ 、-C(＝O)-、-C(＝O)NH-、

13. The compound according to claim 1 or 2, optical isomers, tautomers and pharmaceutically acceptable salts thereof, wherein L ₄ Selected from H, F, cl, br, I, OH, CN, NH ₂ 、CHF ₂ 、CF ₃ 、OCH ₃ 、OCF ₃ 、OCHF ₂ 、OCH ₂ CH ₃ 、COOH、CONHMe、CONMe ₂ 、NMe ₂ 、