EA044333B1 - PYRAZOLOPYRIDINE COMPOUNDS AS SELECTIVE BTK KINASE INHIBITORS - Google Patents

Description

This application claims priority under CN 201910919180.6 with a filing date of 26 September

2019; CN 202010330226.3 with a filing date of April 24, 2020.

Field of technology

The invention relates to a class of compounds that are BTK kinase (Bruton's tyrosine kinase) inhibitors and are characterized by high activity and high selectivity, as well as their use in the preparation of a drug for the treatment of diseases associated with targeting BTK. In particular, the present invention relates to the compound represented by formula (I), an isomer thereof, or a pharmaceutically acceptable salt thereof.

State of the art

BTK is a key kinase in the antigen recognition B cell receptor (BCR) signaling pathway. Irreversible BTK inhibitors inhibit BTK activity by covalently binding to the active site of Cys-481 kinase, thereby effectively inhibiting excessive B cell proliferation and providing antitumor or anti-inflammatory effects.

Among the drugs currently on the market, ibrutinib, an irreversible BTK inhibitor jointly developed by Pharmacyclics and Johnson & Johnson, has been approved by the Food and Drug Administration (FDA) for the treatment of mantle cell lymphoma, chronic lymphocytic leukemia, Waldenström's macroglobulinemia, chronic graft-versus-host disease, etc. However, in addition to BTK, ibrutinib also has potent inhibitory effects on other kinases, especially kinases such as EGFR, ITK and TEC, which can lead to serious adverse reactions such as rash, diarrhea and bleeding. Therefore, there is a need in the art to develop a new class of BTK inhibitors having high potency and proper selectivity for the treatment of related diseases.

Contents of the present invention

The present invention provides a compound represented by formula (I), an isomer thereof or a pharmaceutically acceptable salt thereof

(I) where T ₁ is independently selected from N and CH;

R ₂ is independently selected from H, C _1-6 αlkyl, C ₂ . ₆ alkenyl and C ₂ - ₆ alkynyl, wherein each of C _1-6 alkyl, C ₂ - ₆ alkenyl and C ₂ - ₆ alkynyl is independently and optionally substituted with 1, 2 or 3 Ra;

ring A is selected from phenyl and 5-6 membered heteroaryl;

M is independently selected from C ₃ - ₆ cycloalkyl and 3-6 membered heterocycloalkyl, wherein each of C ₃ - ₆ cycloalkyl and 3-6 membered heterocycloalkyl is independently and optionally substituted with 1, 2 or 3 R _b ;

R1 and R3 are each independently selected from F, Cl, Br, I, OH, NH2, CN;

each of n and m is independently selected from 0, 1,2 or 3 and n and m are not simultaneously equal to 0;

each of L1 and L2 is independently selected from -CH2-, -CH2CH2-, -O-, -C(=O)- and -C(=O)-NH-;

Ra is independently selected from H, F, Cl, Br, I, OH, NH ₂ , CN, C _1-3 alkyl, C _1-3 alkoxy and C _1-3 alkylamino, each of C _1-3 αlkyl, C _1-3 alkoxy and C _1-3 αlkylamino are independently and optionally substituted with 1, 2 or 3 R;

R _b is selected from F, Cl, Br, I, CH ₃ ;

R is selected from H, F, Cl, Br, I;

each of the 5-6 membered heteroaryl and 3-6 membered heterocycloalkyl independently contains 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from -NH-, -O-, -S-, -C(=O) -, -S(=O)- and N.

The present invention provides a compound represented by formula (I), an isomer thereof or a pharmaceutically acceptable salt thereof

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where T ₁ is independently selected from N and CH;

R2 is independently selected from H, C _1-6 alkyl, C _2-6 alkenyl and C _2-6 alkynyl, wherein each of C _1-6 alkyl, C _2-6 alkenyl and C _2-6 alkynyl is independently and optionally substituted with 1 , 2 or 3 R _a ;

ring A is selected from phenyl and 5-6 membered heteroaryl;

M is independently selected from C _3-6 cycloalkyl and 3-6 membered heterocycloalkyl, wherein each of C _3-6 cycloalkyl and 3-6 membered heterocycloalkyl is independently and optionally substituted with 1, 2 or 3 R _b ;

R1 and R3 are each independently selected from F, Cl, Br, I, OH, NH2, CN;

n and m are equal to 0, 1, 2 or 3 and n and m are not equal to 0 at the same time;

each of L1 and L2 is independently selected from -CH2-, -CH2CH2-, -O-, -C(O)- and -C(O)NH-;

R _a is selected from H, F, Cl, Br, I, OH, NH2, CN, C _1-3 alkyl, C _1-3 alkoxy and C _1-3 alkylamino, each of C _1-3 alkyl, C _{1 -3} αlkoxy and C _1-3 alkylamino are independently and optionally substituted with 1, 2 or 3 R;

R _b is selected from F, Cl, Br, I, CH ₃ ;

R is selected from H, F, Cl, Br, I.

each of the 5-6 membered heteroaryl and 3-6 membered heterocycloalkyl independently contains 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from -NH-, -O-, -S-, -C(=O) -, -S(=O)- and N.

In some embodiments of the present invention, the above R _a is independently selected from H, F, Cl, Br, I, OH, NH2, CN, _CH3 , _OCH3 , NH( _CH3 ) and N( _CH3 )2, and other variables are as defined in the present invention.

In some embodiments of the present invention, the above R2 is independently selected from H, C _1-3 alkyl, C _2-4 alkenyl, and C _2-4 alkynyl, each of C _1-3 alkyl, C _2-4 alkenyl, and C ₂ . ₄ alkynyl is independently and optionally substituted with 1, 2 or 3 R _a and other variables are as defined in the present invention.

In some embodiments of the present invention, the above R ₂ is independently selected from H, CH ₃ , vinyl and propynyl, and other variables are as defined in the present invention.

In some embodiments of the present invention, the above M is independently selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, piperidyl, and morpholinyl, wherein each of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, piperidyl, morpholinyl is independently and optionally substituted 1, 2 or 3 Rb, and other variables are as defined in the present invention.

In some embodiments of the present invention, the above M is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, piperidyl, and morpholinyl, wherein each of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, piperidyl, morpholinyl is independently and optionally substituted with 1 , 2 or 3 R _b and other variables are as defined in the present invention.

In some embodiments of the present invention, the above M is independently selected from piperidyl and morpholinyl, and other variables are as defined in the present invention.

In some embodiments of the present invention, the above M is selected from piperidyl and morpholinyl, and other variables are as defined in the present invention.

In some embodiments of the present invention, the above L1 is selected from -O- and -C(O)NH-, and the other variables are as defined in the present invention.

In some embodiments of the present invention, the above L ₁ is selected from -O- and -C(=O)-NH-, and other variables are as defined in the present invention.

In some embodiments of the present invention, the above L ₂ is selected from -C(=O)- and -C(=O)-NH-, and other variables are as defined in the present invention.

In some embodiments of the present invention, the above L2 is selected from -C(O)- and -C(O)NH-, and other variables are as defined in the present invention.

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In some embodiments of the present invention, the above ring A is selected from phenyl and pyridyl, and other variables are as defined in the present invention.

In some embodiments of the present invention, the above structural unit is selected from

and other variables are as defined in the present invention.

In some embodiments of the present invention, the above structural unit

selected from

and other variables are as defined in the present invention.

Other embodiments of the present invention are created by any combination of the above variables.

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

where n, m, R1, R2, _R3 , L1, L2 are as defined in the present invention.

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

where n, m, R1, R2, _R3 , L1, L2 are as defined in the present invention.

The present invention also provides a compound represented by the following formulas, an isomer thereof, or a pharmaceutically acceptable salt thereof,

F

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

The present invention also provides a pharmaceutical composition containing a therapeutically effective amount of the above compound, an isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient and a pharmaceutically acceptable carrier.

In some embodiments, the present invention provides the use of the above compound, an isomer thereof, or a pharmaceutically acceptable salt thereof or the above pharmaceutical composition in the preparation of a BTK inhibitor-related drug.

In some embodiments of the present invention, the above use is characterized in that the BTK inhibitor-related drug is a drug for treating a hematological tumor and an autoimmune disease.

In some embodiments of the present invention, the above use is characterized in that the BTK inhibitor-related drug is for the treatment of diffuse large B cell lymphoma.

Technical effects.

The compounds of the present invention, as a class of BTK kinase inhibitors having high activity and high selectivity, have great prospects for use in the treatment of tumors and demonstrate good tumor inhibition effect in the treatment of cancer. The compounds of the present invention exhibit better kinase inhibitory activity, and preferably the compounds have strong kinase inhibitory activity (IC50 < 100 nM). The compounds of the present invention exhibit better selectivity for EGFR kinase, ITK and TEC. The compounds of the present invention are characterized by a short half-life, widespread distribution outside the blood plasma and moderate bioavailability.

Definition and Description

Unless otherwise specified, the following terms and phrases used herein have the following meanings. A particular term or expression, in the absence of a specific definition, should not be considered vague or unclear, but should be understood in accordance with its generally accepted meaning. Where a trade name appears herein, it is intended to refer to the applicable product or its active ingredient.

As used herein, the term pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms that are medically acceptable

- 5 044333 are suitable for use in contact with human and animal tissue and are not associated with excessive toxicity, irritation, allergic reactions or other problems or complications that are commensurate with a reasonable benefit/risk ratio.

The term pharmaceutically acceptable salt refers to a salt of a compound of the present invention that is derived from a compound containing the specific substituents provided by the present invention and relatively non-toxic acids or bases. If the compounds of the present invention contain relatively acidic functional groups, then base addition salts can be prepared by contacting such compounds with a sufficient amount of base, either in pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or the like. If the compounds of the present invention contain relatively basic functional groups, then acid addition salts can be prepared by contacting such compounds with a sufficient amount of acid, either in pure solution or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include salts of inorganic acids, which include, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid and phosphoric acid; and salts of organic acids, which include, for example, acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, ptoluenesulfonic acid acid, citric acid, tartaric acid and methanesulfonic acid; and also include salts of amino acids (such as arginine) and salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain basic and acidic functional groups and thus can be converted into any base addition salt or acid addition salt.

The pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from a starting compound containing acid radicals or basic radicals. In general, the process for preparing such salts involves reacting such compounds in free acid or free base forms, either in water or an organic solvent, or a mixture of both, with a stoichiometric amount of a suitable base or acid to produce the salts.

When applied to a drug or pharmacologically active agent, the term effective amount or therapeutically effective amount refers to a non-toxic but sufficient amount of the drug or agent to achieve the desired effect. For oral dosage forms of the present invention, the effective amount of one active agent in the composition refers to the amount necessary to achieve the desired effect when used in combination with another active agent in the composition. The determination of the effective amount varies for each individual subject depending on the age and general condition of the receptors, as well as depending on the specific active substances, and the appropriate effective amount in an individual case can be determined by one skilled in the art based on routine experimentation.

The term active ingredient, therapeutic agent, active substance or active agent refers to a chemical compound that can effectively treat the target disorder, disease or condition.

The structure of the compound of the present invention can be confirmed using conventional methods well known to one skilled in the art. If the present invention relates to an absolute connection configuration, the absolute configuration can be confirmed using conventional techniques in the art. For example, single crystal X-ray diffraction (SXRD) uses a Bruker D8 Venture diffractometer with a CuKa light source and a scanning mode of φ/ω scanning to collect diffraction intensity data from a cultured single crystal. After collecting relevant data, a direct method (Shelxs97) is further applied to refine the crystal structure so that the absolute configuration can be confirmed.

The compounds of the present invention may be in the forms of a particular geometric isomer or stereoisomer. The present invention contemplates all such compounds, including cis- and trans-isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereoisomers, (D)-isomers, (L)- isomers, as well as racemic mixtures and other mixtures thereof, such as enantiomerically or diastereoisomerically enriched mixtures, all of which are included within the scope of the present invention. Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers and mixtures thereof are included within the scope of the present invention.

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

Unless otherwise specified, the term cis/trans isomer or geometric isomer is defined by the inability of the double bonds or single bonds of the carbon atoms forming the ring to rotate freely.

Unless otherwise specified, the term diastereoisomer refers to stereoisomers whose molecules have two or more chiral centers and are not mirror images of each other.

Unless otherwise noted, (+) means right rotation, (-) means left rotation, and (±) means racemate.

Unless otherwise indicated, the wedge-shaped solid link 1' and the wedge-shaped dotted link represent the absolute configuration of the stereoscopic center; the straight solid link and the straight dotted link (' ) represent the relative configuration of the stereoscopic center; a wavy line) represents a wedge-shaped solid bond (or a wedge-shaped dotted bond (') or a wavy line () represents a straight solid bond () or a straight dotted bond (').

direct dotted connection ' >.

Unless otherwise specified, the term enriched with one isomer, enriched with an isomer, enriched with one enantiomer, or enantiomerically enriched means the content of one of the isomers or enantiomers is less than 100% and the content of the isomer or enantiomer is greater than or equal to 60%, or greater than or equal to 70 %, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or greater than or equal to 96%, or greater than or equal to 97%, or greater than or equal to 98%, or greater than or equal to 99% , or greater than or equal to 99.5%, or greater than or equal to 99.6%, or greater than or equal to 99.7%, or greater than or equal to 99.8%, or greater than or equal to 99.9%.

Unless otherwise specified, the term isomer excess or enantiomeric excess refers to the difference in the relative percentages of two isomers or two enantiomers. For example, if the content of one isomer or enantiomer is 90%, and the content of another isomer or enantiomer is 10%, then the excess of the isomer or enantiomer (ee value) is 80%.

Optically active (R)- and (S)-isomers and D- and L-isomers can be prepared using chiral synthesis, or chiral reagents, or other conventional techniques. If a specific enantiomer of a compound of the present invention is desired, it can be obtained by asymmetric synthesis or derivatization using a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary groups are cleaved to obtain the pure desired enantiomers. Alternatively, if the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), diastereomeric salts can be formed using a suitable optically active acid or base, followed by separation of the diastereoisomers using conventional methods well known in the art, and further recovery of pure enantiomers. In addition, separation of enantiomers and diastereoisomers is often accomplished by chromatography using chiral stationary phases, optionally in combination with chemical derivatization techniques (eg, formation of carbamates from amines).

The compounds of the present invention may contain unnatural atomic isotope ratios at one or more of the atoms that make up the compound. For example, compounds can be radiolabeled with radioactive isotopes such as tritium ( ^3H ), iodine-125 ( ^125I ), or C-14 ( ^14C ). In another example, hydrogen may be replaced by heavy hydrogen to form deuterated drugs. The bond formed by deuterium and carbon is stronger than the bond formed by light hydrogen and carbon. Compared with non-deuterated drugs, deuterated drugs have less pronounced toxic side effects, higher drug stability, increased efficacy, prolonged biological half-life of drugs, etc. It is intended that all isotopic variants of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.

The term optional or optional means that the event or circumstance described after it may be realized, but is not required, and that the description includes cases where the specified event or circumstance is realized and cases where the specified event or circumstance is not realized.

The term substituted means that any one or more hydrogen atoms at a particular atom are replaced by a substituent, which may include heavy hydrogen and hydrogen variants, provided

- 7 044333 that the valence state of a particular atom is normal and the substituted compound is stable. If the substituent is an oxygen atom (ie =O), then this means that two hydrogen atoms are substituted. Substitution with an oxygen atom does not occur with aromatic groups. The term optionally substituted means that the object may be substituted or may be unsubstituted. Unless otherwise indicated, the type and number of substituents may be arbitrary, provided that this can be achieved using chemical methods.

If any variable (such as R) is present more than once in the composition or structure of a compound, its definition in each case is independent. Thus, for example, if a group is substituted with 0-2 R's, then the group may optionally be substituted with no more than two R's, with R having independent variants in each case. In addition, combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.

If the number of linker groups is 0, for example -(CRR) ₀ -, this means that the linker group is a single bond.

If the number of substituents is 0, this means that there is no substituent. For example, -A-(R) ₀ means that the structure is actually -A.

If the proxy is not specified, it means that the proxy is missing. For example, if X is not listed in A-X, this means that the structure is actually A.

If one of the variables is selected from a single relationship, this means that the two groups it is associated with are directly related. For example, if L represents a single bond in A-L-Z, this means that the structure is actually A-Z.

If the bond of the substituent can be cross-linked to more than two atoms on the ring, the substituent can be bonded to any atom on the ring, for example, a structural unit or indicates that the substituent R can be substituted at any position on cyclohexyl or cyclohexadiene. If the listed substituents do not indicate by which atom they are attached to the substituted group, then such substituents can be connected through any of its atoms, for example, pyridyl as a substituent can be connected to the substituted group through any of the carbon atoms in the pyridine ring.

If the listed linker group does not indicate the direction of binding, then the direction of binding is arbitrary, for example, if the linker group L is -M-W- then in this situation -M-W- can link ring A and ring B in the direction corresponding to the reading order from left to right , to form and can also link ring A and ring B in the direction opposite to the reading order from left to right, to form

W-M

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

Unless otherwise specified, when a group contains one or more connecting sites, any one or more sites in the group can be connected to other groups through chemical bonds. If the type of compound of the chemical bond is not established, and there is an H atom in the attached site, the number of H atoms in the specified site will correspondingly decrease by the number of chemical bonds being added, and in the case of the addition of a chemical bond, the group becomes the corresponding valence. Chemical bonds between sites and other groups can be represented by a straight solid bond ', a straight dotted bond b 7 or a wavy line ' L For example, a straight solid bond in -OSH ₃ means that the group is attached to other groups through an atom oxygen in the group; direct dotted connection in

means that the group is attached to other groups at either end of the nitrogen atom in the group; wavy line in

means that the group is attached to other groups through 1 and 2 carbon atoms in the phenyl group;

means that any attachment site in piperidinyl can be attached to other groups through a single chemical bond, including at least four types of connection

still includes the group with the compound type even if the H atom is shown at -N-,

but the number of H in the specified site will correspondingly decrease by one, and in the case of addition of a chemical bond, piperidinyl becomes correspondingly monovalent.

Unless otherwise stated, the number of atoms in a ring is usually defined as the number of ring members. For example, a 5-7 membered ring means a ring containing 5-7 atoms arranged in a circle.

Unless otherwise specified, the term C _1-6 αlkyl is used to designate a linear or branched saturated hydrocarbon group consisting of 1-6 carbon atoms. C _1-6 alkyl includes C1. ₅ -, C _1-4 -, C _1-3 -, C _1-2 -, C _2-6 -, C _2-4 -, C ₆ - and C ₅ alkyl and can be monovalent (such as methyl), divalent (such as methylene) or multivalent (such as methine). Examples of C _1-6 alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, sec-butyl and tert-butyl), pentyl (including n-pentyl, isopentyl and neopentyl) and hexyl.

Unless otherwise specified, the term C _1-3 αlkyl is used to designate a linear or branched saturated hydrocarbon group consisting of 1-3 carbon atoms. C _1-3 alkyl includes C _1-2 alkyl, C _2-3 alkyl and the like; and it may be monovalent (such as methyl), divalent (such as methylene) or multivalent (such as methine). Examples of C _1-3 alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.

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

Unless otherwise specified, C _3-6 cycloalkyl means a saturated cyclic hydrocarbon group of 3-6 carbon atoms, which contains a monocyclic and bicyclic ring system, where the carbon atoms may optionally be oxidized (ie, C=O). _C3-6 cycloalkyl includes _C3-5 cycloalkyl, _C4-5 cycloalkyl, _C5-6 cycloalkyl and the like; and it may be monovalent, divalent or multivalent. Examples of C _3-6 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.

Unless otherwise specified, _C2-6 alkenyl is used to denote a straight or branched hydrocarbon group of 2-6 carbon atoms and containing at least one carbon-carbon double bond, wherein the carbon-carbon double bond can be at any position in the group . C2-6alkenyl includes C2-4alkenyl, C2-3alkenyl, C4alkenyl, C3alkenyl, C2alkenyl and the like; and it may be monovalent, divalent or multivalent. Examples of C2 ₆ alkenyl include, but are not limited to, vinyl, propenyl, butenyl, pentenyl, hexenyl, butadienyl, piperylene, hexadienyl and the like.

Unless otherwise specified, _C2-4 alkenyl is used to denote a straight or branched hydrocarbon group of 2-4 carbon atoms and containing at least one carbon-carbon double bond, wherein the carbon-carbon double bond can be at any position in the group . C _2-4 alkenyl includes C _2-3 alkenyl, C ₄ alkenyl, C ₃ alkenyl, C ₂ alkenyl and the like; and the C2-4 alkenyl may be monovalent, divalent or multivalent. Examples of C2-4 alkenyl include, but are not limited to, vinyl, propenyl, butenyl, butadienyl and the like.

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Unless otherwise specified, _C2-6 alkynyl is used to denote a straight or branched hydrocarbon group of 2-6 carbon atoms and containing at least one carbon-carbon triple bond, where the carbon-carbon triple bond can be at any position in the group. C _2-6 alkynyl includes C _2-4 alkynyl, C _2-3 alkynyl, C ₄ alkynyl, C ₃ alkynyl, C ₂ alkynyl and the like; and it may be monovalent, divalent or multivalent. Examples of C _2-6 alkynyl include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl and the like.

Unless otherwise specified, _C2-4 alkynyl is used to denote a straight or branched hydrocarbon group of 2-4 carbon atoms and containing at least one carbon-carbon triple bond, wherein the carbon-carbon triple bond can be at any position in the group . C ₂ - ₄ alkynyl includes C ₂ - ₃ alkynyl, C ₄ alkynyl, C ₃ alkynyl, C ₂ alkynyl and the like; and it may be monovalent, divalent or multivalent. Examples of C2-4 alkynyl include, but are not limited to, ethynyl, propynyl, butynyl and the like.

Unless otherwise noted, the term is C ₁ . ₃ αlkoxy means those alkyl groups containing 1-3 carbon atoms which are attached to the rest of the molecule by one oxygen atom. C ₁ . ₃ alkoxy includes _C1-2 alkoxy, C _{2 -3} alkoxy, C ₃ alkoxy, C ₂ alkoxy and the like. Examples C ₁ . ₃ alkoxy includes, but is not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.

Unless otherwise noted, the term is C ₁ . ₃ alkylamino means those alkyl groups containing 1-3 carbon atoms which are attached to the rest of the molecule by an amino group. C ₁₃ alkylamino includes C1-2-, C ₃ -, C ₂ alkylamino and the like. Examples of C _{1_3 alkylamino} include, but are not limited to -NHCH ₃ , -N(CH ₃ ) ₂ , -NHCH2CH3 , -N(CH ₃ )CH ₂ CH ₃ , -NHCH ₂ CH ₂ CH ₃ , -NHCH ₂ (CH ₃ ) ₂ , etc.

Unless otherwise specified, the term 3-6 membered heterocycloalkyl, alone or in combination with other terms, appropriately designates a saturated cyclic group consisting of 3-6 ring atoms, of which 1, 2, 3 or 4 ring atoms are heteroatoms, independently selected from O, S and N, and the remainder being carbon atoms, where the nitrogen atom is optionally quaternized, and the heteroatoms being nitrogen and sulfur may be optionally oxidized (i.e. NO and S(O)p, where p equals 1 or 2). It contains a monocyclic and a bicyclic ring system, with the bicyclic system including a spiro ring, a fused ring, and a bridged ring. Additionally, in the case of a 3- to 6-membered heterocycloalkyl, the heteroatom may occupy a position where the heterocycloalkyl is attached to the rest of the molecule. 3-6 membered heterocycloalkyl includes 4-6 membered, 5-6 membered, 4 membered, 5 membered, 6 membered heterocycloalkyl and the like. Examples of 3-6 membered heterocycloalkyl include, but are not limited to, azetidinyl, oxetanyl, thiatanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl (including tetrahydrothien-2-yl, tetrahydrothien-3-yl and the like), 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 and the like), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2thiazinyl, hexahydropyridazinyl, homopiperazinyl or homopiperidinyl.

Unless otherwise specified, the terms 5-6 membered heteroaryl ring and 5-6 membered heteroaryl of the present invention may be used interchangeably, and the term 5-6 membered heteroaryl refers to a monocyclic group containing a conjugated π electron system and consisting of 5- 6 ring atoms, of which 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, and the rest are carbon atoms, where the nitrogen atom is optionally quaternized, and carbon and heteroatoms representing nitrogen and sulfur may optionally be oxidized (ie, C=O, NO and S(O)p, where p is 1 or 2). The 5-6 membered heteroaryl may be attached to the rest of the molecule via a heteroatom or carbon atom. 5-6 membered heteroaryl includes 5 membered and 6 membered heteroaryl. Examples of 5-6 membered heteroaryl include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl and the like), pyrazolyl (including 2-pyrazolyl, 3-pyrazolyl and the like), imidazolyl (including N -imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, etc.), triazolyl (1H-1,2,3- triazolyl, 2H-1,2,3-triαzolyl, 1H-1,2,4-triazolyl, 4H-1,2,4-triαzolyl, etc.), tetrazolyl, isoxazolyl (including 3-isoxazolyl, 4-isoxazolyl , 5-isoxazolyl, etc.), thiazolyl (including 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, etc.), furyl (including 2-furanyl, 3-furanyl, etc.), thienyl (including 2-thienyl, 3-thienyl and the like), pyridyl (including 2-pyridyl, 3-pyridyl, 4-pyridyl and the like), pyrazinyl or pyrimidinyl (including 2-pyrimidyl, 4-pyrimidyl and the like. ).

The compounds of the present invention can be prepared by various synthetic routes well known to one skilled in the art, including the specific embodiments listed below, embodiments formed by combination with other chemical synthesis routes, and equivalent alternative embodiments well known to one skilled in the art. of the art, where preferred embodiments include, without limitation, examples from the present disclosure.

The solvents used in the present invention are commercially available.

In the present invention the following abbreviations are used: aq. denotes aquatic; eq. denotes equivalent; DCM stands for dichloromethane; PE stands for petroleum ether; DMF stands for 10 044333 N,N-dimethylformamide; DMSO stands for dimethyl sulfoxide; EtOAc stands for ethyl acetate;

EtOH means ethanol; MeOH stands for methanol; Cbz stands for benzyloxycarbonyl, which is an amine protecting group; Voe denotes tert-butoxycarbonyl, which is an amine protecting group; HOAc stands for acetic acid; THF stands for tetrahydrofuran; LDA stands for lithium diisopropylamide.

Compounds are named according to traditional nomenclature principles in the art or using ChemDraw® software, and commercially available compounds are named using supplier catalog names.

Detailed Description of the Preferred Embodiment

The present invention will be described in detail with the help of the following examples, but no unfavorable limitations of the present invention are intended. The present invention has been described in detail herein, and specific embodiments thereof have also been disclosed. All variations and improvements made with respect to specific embodiments of the present invention, without departing from the spirit and scope of the present invention, will be apparent to one skilled in the art.

Example 1.

The path of synthesis.

Obtaining connection 1-10.

To a solution of phenol (8.18 g, 86.92 mmol, 7.64 mL, 1 eq.) in tetrahydrofuran (100 mL) was added potassium tert-butoxide (11.70 g, 104.27 mmol, 1.2 eq. ) and compound 1-9 (10 g, 86.90 mmol, 7.94 ml, 1 eq.). The resulting reaction solution was reacted at room temperature (30°C) for 6 hours. The reaction solution was slowly poured into water (150 ml) and extracted with ethyl acetate (100 ml-3). The organic phase was washed successively with 1N. aqueous sodium hydroxide solution (150 ml) and saturated saline solution (200 ml), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and then the residue was separated and purified by column chromatography to obtain compound 1-10. 1H NMR (400 MHz, DMSO-d ₆ ) δ 8.02 (q, J=8.0 Hz, 1H), 7.50-7.41 (m, 2H), 7.31-7.24 (m , 1H), 7.21-7.14 (m, 2H), 6.90 (ddd, J=1.8, 7.8, 14.2 Hz, 2H). LCMS: MS(ESI) mass/charge (M+H)+: 190.3.

Obtaining connection 1-6.

At -78°C under a protective nitrogen atmosphere, n-butyllithium (2.5 M, 1 .6 ml, 1.13 eq.). The resulting reaction solution was reacted at -78°C for 1 hour. Triisopropyl borate (866 mg, 4.60 mmol, 1.06 ml, 1.3 eq.) was then added and the mixture was reacted at -78°C C for 1 hour. A saturated aqueous ammonium chloride solution (30 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 ml-3). The organic phase was washed with brine (30 ml), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and then the residue was separated and purified by column chromatography to obtain compound 1-6. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.15 (t, J=8.5 Hz, 1H), 7.52-7.39 (m, 2H), 7.32-7.22 ( m, 1H), 7.17 (brd, J=7.8 Hz, 2H), 6.87 (dd, J=1.6, 7.9 Hz, 1H), 1.36-1.14 (m , 1H), 0.87-0.55 (m, 1H). LCMS: MS(ESI) mass/charge (M+H)+: 234.1.

Obtaining connection 1-3.

Preparation of LDA solution: Under a protective nitrogen atmosphere at -78°C, nbutyllithium ( 2.5 M, 7.04 ml, 1.1 eq.). The resulting mixture was heated to 0°C, reacted for 0.5 hours and cooled again to -78°C for subsequent use.

At -78°C, under a protective nitrogen atmosphere, the above LDA solution was added dropwise to a solution of compound 1-1 (1.84 g, 15.99 mmol, 1 eq.) in anhydrous tetrahydrofuran (5 ml). The resulting mixture was reacted at -78°C for 1 hour. A solution of compound 1-2 (3.41 g, 15.99 mmol, 1 eq.) in anhydrous tetrahydrofuran (5 ml) was added dropwise to the reaction solution. The resulting mixture was gradually warmed to room temperature (24°C) and reacted for another 16 hours. A saturated ammonium chloride solution was added to the system and ethyl acetate (20 ml) was added. The liquid was separated and extracted. The organic phase was washed with brine (10 ml), then dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and then the residue was separated and purified by column chromatography to obtain compound 1-3. LCMS: Ms(eSI) mass/charge (M-56+H)+: 272.9.

Preparation of compounds 1-4.

At 0°C, Dess-Martin periodinane (7.84 g, 18.47 mmol, 5.72 mL, 1.2 eq.) was added to a solution of compound 1-3 (5.07 g, 15.44 mmol, 1 eq. .) in anhydrous dichloromethane (300 ml). The mixture was gradually warmed to room temperature (26°C) and reacted for 3 hours. Saturated sodium hydrogen carbonate solution (200 ml) and dichloromethane (400 ml) were added to the system. The mixture was filtered and the filtrate was separated. The organic phase was washed with brine (100 ml), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain compound 1-4. LCMS: MS(ESI) mass/charge (M-56+H)+: 270.9.

Preparation of compounds 1-5.

Sodium hydrogen carbonate (1.72 g, 20.51 mmol, 797.50 µl, 1.13 eq.) and hydrazine hydrate (2.32 g, 45.35 mmol, 2.25 ml, 2.49 eq.). The resulting mixture was heated to 75° C. and reacted for 16 hours. The reaction solution was concentrated under reduced pressure, suspended with dichloromethane/methanol (110 ml, v/v = 10/1) and filtered. The filtrate was concentrated under reduced pressure and then the residue was separated and purified by column chromatography to obtain compound 1-5. LCMS: MS(ESI) mass/charge (M+H)+: 321.4.

Obtaining connection 1-7.

Copper acetate (600 mg, 3.30 mmol, 2.12 eq.), pyridine (600 mg, 7.59 mmol, 612.24 µl, 4.86 eq.) and 4 A molecular sieves (500 mg). The atmosphere of the resulting mixture was replaced three times with oxygen and it was heated to 70°C and reacted for 40 hours in an oxygen atmosphere in a cylinder. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. Dichloromethane (100 ml), water (20 ml) and aqueous ammonia (30% purity, 15 ml) were added. The liquid was separated and extracted. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and then the residue was separated and purified by column chromatography to obtain compound 1-7. LCMS: MS(ESI) mass/charge (M+H)+: 508.1.

Obtaining connection 1-8.

To compound 1-7 (250 mg, 492.58 µmol, 1 eq) in dichloromethane (4 ml) was added trifluoroacetic acid (1.54 g, 13.51 mmol, 1 ml, 27.42 eq). The resulting mixture was reacted at room temperature (31 °C) for 0.5 h. The reaction solution was concentrated under reduced pressure to give compound 1-8 (crude, trifluoroacetate). LCMS: MS(ESI) mass/charge (M+H)+: 408.0.

Preparation of compounds 1A and 1B.

To compound 1-8 (200 mg, 383.55 µmol, 1 eq., trifluoroacetate) and sodium carbonate (200 mg, 1.89 mmol, 4.92 eq.) in tetrahydrofuran (3 ml) and water (3 ml) acryloyl chloride (40 mg, 441.95 µmol, 36.04 µl, 1.15 eq) in tetrahydrofuran (0.1 ml) was added. The resulting mixture was subjected to the reaction

- 12 044333 at room temperature (31 °C) for 10 minutes. Dichloromethane (50 ml) was added to the reaction solution. The liquid was separated and extracted. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and then the residue was separated and purified sequentially using column chromatography and high performance liquid chromatography (alkaline); the product was determined using supercritical fluid chromatography (chromatography column: Chiralcel OJ-3, 150x4.6 mm I.D, 3 μm; mobile phase: A: supercritical carbon dioxide, B: 0.05% diethylamine in ethanol; gradient: B 5 to 40% over 5 min, hold at 40% for 2.5 min, back to 5% and equilibrate within 2.5 min; flow rate: 2.5 ml/min; column temperature: 35° C; wavelength: 220 nm) and analyzed as a racemic compound, which was separated to give chiral isomers: compound 1A and compound 1B with retention times of 5.091 and 5.687 min, respectively.

Compound 1A: 1H NMR (400 MHz, DMSO-d6) δ 9.43-9.42 (m, 1H), 8.51-8.49 (m, 1H), 7.51-7.47 (m, 4H), 7.31-7.25 (m, 3H), 6.85-6.83 (m, 1H), 6.13-6.08 (m, 1H), 5.68-5.63 ( m, 1H), 4.62-4.58 (m, 1H), 4.32-3.95 (m, 2H), 3.65-3.55 (m, 1H), 2.30-2, 20 (m, 1H), 2.05-1.80 (m, 3H), 1.60-1.50 (m, 1H). LCMS: MS(ESI) mass/charge (M+H)+: 462.2.

Compound 1B: 1H NMR (400 MHz, DMSO- _d6 ) δ 9.43-9.41(m, 1H), 8.49 (s, 1H), 7.51-7.47 (m, 4H), 7.32-7.25 (m, 3H), 6.85-6.83 (m, 1H), 6.12-6.08 (m, 1H), 5.70-5.64 (m, 1H ), 4.61-4.58 (m, 1H), 4.29-3.95 (m, 2H), 3.65-3.55 (m, 1H), 2.28-2.20 (m , 1H), 2.05-1.80 (m, 3H), 1.60-1.50 (m, 1H). LCMS: MS(ESI) mass/charge (M+H) ⁺ : 462.0.

Example 2.

The path of synthesis.

Obtaining connection 2-3.

Compound 2-2 (30 g, 149.38 mmol, 2.16 eq) was added to a solution of compound 2-1 (9 g, 69.18 mmol, 1 eq) in dichloroethane (500 ml) and then pyridine was added sequentially (17.64 g, 223.01 mmol, 18.00 mL, 3.22 eq.), 4 A molecular sieves (9 g), and copper acetate (25.20 g, 138.74 mmol, 2. 01 eq.). The atmosphere of the mixture was replaced three times with oxygen and it was heated to 60°C and reacted for 16 hours in an oxygen atmosphere in a cylinder. The reaction solution was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and then the residue was separated and purified by column chromatography to obtain compound 2-3.

Obtaining connection 2-4.

bis-(Pinacolato)diboron (9.79 g, 38.55 mmol, 2 eq.), potassium acetate (3.78 g, 38.56 mmol, 2 eq.) and [1,1'bis(diphenylphosphino)ferrocene ]dichloropalladium (1.43 g, 1.95 mmol, 1.01 e-1 eq.) successively to

- 13044333 was added to compound 2-3 (5.5 g, 19.29 mmol, 1 eq.) in anhydrous 1,4-dioxane (150 ml). The mixture was heated to 110°C and reacted for 16 hours under a protective nitrogen atmosphere. The reaction solution was cooled to room temperature and then filtered. The filtrate was concentrated under reduced pressure and then the residue was separated and purified by column chromatography to obtain compound 2-4. 1H NMR (400 MHz, CDCI3) δ 7.78-7.76 (m, 2H), 7.16-7.14 (m, 1H), 7.04-7.01 (m, 2H), 6, 99-6.91 (m, 2H), 1.33 (s, 12H).

Obtaining connection 2-5.

Compound 2-4 (2 g, 6.02 mmol, 1 eq.) was dissolved in tetrahydrofuran (40 ml) and water (10 ml) and then sodium periodate (3.86 g, 18.06 mmol, 1.00 ml) was added , 3 eq.). The mixture was reacted at room temperature (26°C) for 0.5 h and then hydrochloric acid (2 M, 2.00 ml, 6.64 e-1 eq.) was added. The mixture was reacted at room temperature (26°C) for another 16 hours. Ethyl acetate (20 ml-3) was added to the reaction solution. The liquid was separated and extracted. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and then the residue was separated and purified by column chromatography to obtain compound 2-5. 1H NMR (400 MHz, DMSO-d ₆ ) δ 8.16-8.14 (m, 2H), 7.71-7.69 (m, 1H), 7.21-7.18 (m, 1H) , 7.07-6.96 (m, 3H).

Obtaining connection 2-6.

Compound 1-5 (400 mg, 1.25 mmol, 1 eq.) was added to a solution of compound 2-5 (624.31 mg, 2.50 mmol, 2 eq.) in dichloroethane (15 ml) and pyridine (321, 44 mg, 4.06 mmol, 328 µl, 3.25 eq.) 4 A molecular sieves (500 mg) and copper acetate (468 mg, 2.58 mmol, 2.06 eq.) were added sequentially. The atmosphere of the mixture was replaced three times with oxygen and it was heated to 60°C and reacted for 16 hours in an oxygen atmosphere in a cylinder. The reaction solution was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure, and dissolved in dichloromethane (5 ml), and water (3 ml) was added. The liquid was separated and extracted. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and then the residue was separated and purified by column chromatography to obtain compound 2-6. LCMS: MS(ESI) mass/charge (M+H)+: 525.3.

Obtaining connection 2-7.

Add trifluoroacetic acid (4.62 g, 40.52 mmol, 3.00 mL, 70.84 eq.) to a solution of compound 2-6 (300 mg, 571.94 μmol, 1 eq.) in anhydrous dichloromethane (2 mL ). The mixture was reacted at room temperature (25°C) for 0.5 hours. The reaction solution was directly concentrated under reduced pressure. The residue was dissolved by adding dichloromethane (20 ml) and then concentrated again under reduced pressure to give compound 2-7 (crude, trifluoroacetate). LCMS: MS(ESI) mass/charge (M+H)+: 425.0.

Preparation of compounds 2A and 2B.

Compound 2-7 (200 mg, 371.44 µmol, 1 equiv, trifluoroacetate) was dissolved in tetrahydrofuran (2 ml) and water (2 ml); added sodium carbonate (50.00 mg, 471.74 µmol, 1.27 eq.) and added dropwise a solution of acryloyl chloride (26 mg, 287.27 µmol, 23.42 µl, 7.73 e-1 eq.) in anhydrous tetrahydrofuran (0.5 ml). The mixture was reacted at room temperature (26°C) for 10 minutes.

The reaction solution was adjusted to pH 7 with hydrochloric acid (1 M) and then water (5 ml), dichloromethane (10 ml) and methanol (1 ml) were added. The liquid was separated and extracted. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and then the residue was separated and purified using high performance liquid chromatography (alkaline); the product was determined using supercritical fluid chromatography (chromatographic column: Chiralpak AD-3, 50 x 3 mm I.D, 3 μm; mobile phase: A: supercritical carbon dioxide, B: 0.05% diethylamine in ethanol; gradient: B 5% to 40% in 2.5 min, hold at 40% for 0.35 min, back to 5% and equilibrate in 0.15 min; flow rate: 2.8 mL/min; column temperature : 40°C; wavelength: 220 nm) and analyzed as a racemic compound, which was separated to give chiral isomers: compound 2A and compound 2B with retention times of 2.205 and 2.504 min, respectively.

Compound 2A: 1H NMR (400 MHz, DMSO-d ₆ ) δ 8.94(s, 1H), 8.21-8.19 (m, 1H), 7.64-7.62 (m, 2H), 7.22-7.05 (m, 5H), 6.69-6.62 (m, 1H), 6.30-6.26 (m, 1H), 5.70-5.65 (m, 1H ), 5.01-4.98 (m, 0.5H), 4.65-4.62 (m, 0.5H), 4.33-4.30 (m, 0.5H), 4.09 -4.06 (m, 0.5H), 3.52-3.41 (m, 1.5H), 3.20-3.17 (m, 1H), 2.89-2.86 (m, 0.5H), 2.35-2.32 (m, 1H), 2.07-2.04 (m, 2H), 1.96-1.70 (m, 1H). LCMS: MS mass/charge (M+H)+: 479.5.

Compound 2B: 1H NMR (400 MHz, DMSO-d6) δ 8.94(s, 1H), 8.21-8.19 (m, 1H), 7.64-7.62 (m, 2H), 7 .22-7.05 (m, 5H), 6.68-6.62 (m, 1H), 6.30-6.26 (m, 1H), 5.73-5.65 (m, 1H) , 5.01-4.98 (m, 0.5N), 4.65-4.62 (m, 0.5N), 4.33-4.30 (m, 0.5N), 4.09- 4.06 (m, 0.5H), 3.54-3.41 (m, 1.5H), 3.21-3.17 (m, 1H), 2.92-2.89 (m, 0 ,5H), 2.35-2.32 (m, 1H), 2.07-2.03 (m, 2H), 1.96-1.70 (m, 1H). LCMS: MS mass/charge (M+H)+: 479.1.

- 14 044333

Example 3.

The path of synthesis.

Preparation of compound 3-9.

Cesium carbonate (46.25 g, 141.95 mmol, eq.) was added to a solution of compound 3-8 (10 g,

70.87 mmol, 7.52 mL, 1 eq.) and compound 2-2 (11.25 g, 86.48 mmol, 1.22 eq.) in anhydrous N,Ndimethylformamide (500 mL). The mixture was reacted at 140°C for 16 hours. The reaction solution was cooled to room temperature and then concentrated under reduced pressure to remove the solvent; the residue was dissolved by adding ethyl acetate (500 ml) and then water (200 ml) was added. The solution was separated. The organic phase was washed with brine (200 ml), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and then the residue was separated and purified by column chromatography to obtain compound 3-9.

Preparation of compound 3-10.

Add wet palladium on carbon (4.5 g, 10% purity) to compound 3-9 (9 g, 35.83 mmol, 1 eq) in anhydrous methanol (250 ml). The atmosphere of the mixture was changed to hydrogen three times and it was reacted at room temperature (15° C.) under a hydrogen atmosphere in a balloon for 3 hours. The reaction solution was filtered (through celite) and the filtrate was concentrated under reduced pressure to give compound 3-10. LCMS: MS(ESI) mass/charge (M+H)+: 221.7.

Obtaining connection 3-4.

Hydrochloric acid (600 mL, concentrated hydrochloric acid) was added to compound 3-10 (19 g, 85.89 mmol, 1 eq.) and the mixture was cooled to 0°C. To the above reaction solution, a solution of sodium nitrite (11.85 g, 171.79 mmol, 2 eq.) in water (200 ml) was added dropwise. The mixture was reacted at 0°C for 1 hour and a mixture of tin chloride dihydrate (79.47 g, 352.17 mmol, 4.1 eq.) and hydrochloric acid (200 ml, concentrated chloride) was added dropwise.

- 15 044333 hydric acid). After the dropwise addition was completed, the mixture was reacted at 0° C. for 3 hours. The reaction solution was adjusted to pH 12 with sodium hydroxide (6 M) and dichloromethane (2000 ml) was added. The liquid was separated. The organic phase was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain compound 3-4. 1H NMR (400 MHz, CDC13) δ 7.27(s, 1H), 7.11-7.00 (m, 2H), 6.98-6.90 (m, 2H), 6.88-6, 76 (m, 2H), 5.08 (s, 1H), 3.56 (s, 2H).

Obtaining connection 3-2.

To a solution of compound 3-1 (10 g, 43.24 mmol, 1 eq.) in dichloromethane (120 mL) was added N,Ncarbonyldiimidazole (7.71 g, 47.57 mmol, 1.1 eq.). The resulting reaction solution was reacted at 10°C for 1 hour, and N,Ο-dimethylhydroxylamine hydrochloride (4.72 g, 48.37 mmol, 1.12 eq.) was added. The resulting reaction solution was reacted at 10°C for 16 hours. Dichloromethane (100 ml) and water (60 ml) were added to the reaction solution. The liquid was separated and extracted. The organic phase was washed successively with 1N. aqueous solution of hydrochloric acid (50 ml), 1N. aqueous sodium hydroxide solution (50 ml) and saturated saline solution (80 ml), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain compound 3-2. LCMS: MS(ESI) mass/charge (M-56+H)+: 218.9.

Obtaining connection 3-3.

Preparation of LDA solution: At -78°C under a protective atmosphere of nitrogen, nbutyllithium ( 2.5 M, 6.0 ml, 1.65 eq.). The resulting mixture was heated to 0°C, reacted for 0.5 hours and cooled again to -78°C for subsequent use.

At -78°C, under a protective nitrogen atmosphere, a solution of compounds 1-1 (2.5 g, 9.11 mmol, 1 eq.) and 3-2 (1.26 g, 10.94 mmol) was added dropwise to the above LDA solution , 2.98 ml, 1.2 eq.) in anhydrous tetrahydrofuran (20 ml). The resulting mixture was gradually warmed to room temperature (15°C) and reacted for another 16 hours. The reaction was quenched by adding saturated ammonium chloride solution (100 ml). Then, most of the solvent in the mixed solution was rotary evaporated under reduced pressure, and the liquid was separated and extracted with ethyl acetate (150 ml). The organic phase was washed with brine (150 ml), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and then the residue was separated and purified by column chromatography to give compound 33. LCMS: MS(ESI) wt/charge (M+H)+: 328.9.

Preparation of compound 3-5.

At 10°C, a mixed solution of compound 3-3 (270 mg, 822.39 µmol, 1 eq.), compound 3-4 (540.00 mg, 2.29 mmol, 2.78 eq.), acetic acid (2 .10 g, 34.97 mmol, 2 mL, 42.52 eq.) and ethanol (10 mL) were reacted for 1 hour. The reaction solution was concentrated under reduced pressure to give compound 3-5. LCMS: MS(ESI) mass/charge (M-56+H)+: 491.0.

Preparation of compound 3-6.

Compound 3-5 (720 mg, 1.32 mmol, 1 eq), cesium carbonate (1.29 g, 3.96 mmol, 3 eq) and N,Ndimethylformamide ( 1.5 ml). The resulting reaction solution was heated to 150°C and reacted for 30 min under microwave radiation. The reaction solution was filtered. The filtrate was concentrated under reduced pressure and then the residue was separated and purified by column chromatography to obtain compound 3-6. LCMS: MS(ESI) mass/charge (M+H)+: 527.1.

Getting connection 3-7

Trifluoroacetic acid (3.08 g, 27.01 mmol, 2 mL, 35.56 eq) was added to a solution of compound 3-6 (0.4 g, 759.73 μmol, 1 eq.) in dichloromethane (8 mL). . The resulting reaction solution was reacted at 10°C for 0.5 hours. The reaction solution was concentrated under reduced pressure to obtain compound 3-7 (crude, trifluoroacetate). LCMS: MS(ESI) mass/charge (M+H)+: 427.0.

Preparation of compounds 3A and 3B.

To a solution of compound 3-7 (420 mg, 985.01 µmol, 1 eq., trifluoroacetate) in tetrahydrofuran (8 ml) was added sodium carbonate (521 mg, 4.92 mmol, 4.99 eq.) and water (4 ml ); then a solution of acryloyl chloride (180 mg, 1.99 mmol, 162.16 µl, 2.02 eq) in tetrahydrofuran (0.2 ml) was added dropwise. The resulting reaction solution was reacted at 10°C for 0.5 hours. A dichloromethane/methanol mixture (50 ml, 10/1) and water (50 ml) were added to the reaction solution. The liquid was separated. The organic phase was washed with brine (50 ml), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and then the residue was separated and purified by column chromatography; the product was determined using supercritical fluid chromatography (chromatography column: Chiralpak AD-3, 50 x 4.6 mm I.D, 3 μm; mobile phase: A: supercritical carbon dioxide, B: 0.05% diethylamine in ethanol; gradient : B from 5% to 40% in 2 min, hold at 40% for 1.2 min, back to 5% and equilibrate in 0.8 min; flow rate: 4 ml/min; column temperature: 35 °C; length

- 16 044333 wavelength: 220 nm) and analyzed as a racemic compound, which was separated to give chiral isomers: compound 3A and compound 3B with retention times of 1.979 and 2.083 min, respectively.

Compound 3A: Ή NMR (400 MHz, DMSO-d ₆ ) δ 9.11 (brs, 1H), 8.37 (brs, 1H), 7.85 (brd, J=8.5 Hz, 2H), 7 ,51-7.33 (m, 3H), 7.22 (brd, J=8.5 Hz, 2H), 6.88 (brdd, J=10.3, 16.6 Hz, 1H), 6, 18 (brt, J=13.3 Hz, 1H), 5.835.66 (m, 1H), 5.10-4.91 (m, 1H), 4.67 (brd, J=13.1 Hz, 0 ,5H), 4.42-4.21 (m, 1H), 4.18-3.92 (m, 2H), 3.86-3.63 (m, 2H), 3.09 (brs, 0 ,5H). LCMS: MS(ESI) mass/charge (M+H)+: 481.1.

Compound 3B: Ή NMR (400 MHz, DMSO-d ₆ ) δ 9.15 (brs, 1H), 8.41 (brs, 1H), 7.89 (brd, J=8.8 Hz, 2H), 7 ,54-7.37 (m, 3H), 7.25 (brd, J=8.8 Hz, 2H), 6.91 (brdd, J=10.7, 16.4 Hz, 1H), 6, 29-6.14 (m, 1H), 5.85-5.68 (m, 1H), 5.12-4.95 (m, 1H), 4.71 (brd, J=12.8 Hz, 0.5H), 4.46-4.23 (m, 1H), 4.22-3.91 (m, 2H), 3.90-3.67 (m, 2H), 3.14 (brd, J=10.8 Hz, 0.5H). LCMS: MS(ESI) mass/charge (M+H)+: 481.1.

Example 4.

The path of synthesis.

Preparation of connection 4-2.

Cesium carbonate (14.78 g, 45.36 mmol, 2 eq.) was added to a solution of compound 3-8 (3.2 g, 22.68 mmol, 2.41 ml, 1 eq.) and compound 4-1 ( 4 g, 27.01 mmol, 1.19 eq.) in anhydrous N,N dimethylformamide (100 ml). The mixture was reacted at 100°C for 2.5 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved by adding ethyl acetate (200 ml) and then water (200 ml) was added. The solution was separated. The organic phase was washed with brine (100 ml), then dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain compound 4-2.

Getting connection 4-3.

Add wet palladium on carbon (4 g, 10% purity) to compound 4-2 (4 g, 14.86 mmol, 1 eq) in anhydrous methanol (150 ml). The atmosphere of the mixture was changed to hydrogen three times and it was reacted at room temperature (10° C.) under a hydrogen atmosphere in a cylinder (15 psi) for 16 hours. The reaction solution was filtered (through celite) and the filtrate was concentrated under reduced pressure to obtain compound 4-3. LCMS: MS(ESI) mass/charge (M+H)+: 239.8.

Getting connection 4-4.

Hydrochloric acid (200 mL, concentrated hydrochloric acid) was added to compound 4-3 (6.5 g, 27.17 mmol, 1 eq.) and the mixture was cooled to 0°C. To the above reaction solution, a solution of sodium nitrite (3.75 g, 54.35 mmol, 2 eq.) in water (70 ml) was added dropwise.

- 17 044333

The mixture was reacted at 0°C for 1 hour, then a mixture of tin chloride dihydrate (24.53 g, 108.70 mmol, 4 eq.) and hydrochloric acid (70 ml, concentrated hydrochloric acid) was added dropwise. After the dropwise addition was complete, the mixture was reacted at 0°C for 3 hours, gradually warmed to room temperature (10°C) and reacted for another 16 hours. The pH was adjusted to approximately 12 with sodium hydroxide (6 M) and dichloromethane (500 ml-3) was added. The liquid was separated and extracted. The organic phase was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain compound 4-4. LCMS: MS(ESI) mass/charge (M+H)+: 255.0.

Obtaining connection 4-5.

To a solution of compound 1-5 (0.5 g, 1.53 mmol, 1 eq.) and compound 4-4 (1.00 g, 3.93 mmol, 2.57 eq.) in ethanol (15 ml) was added acetic acid (3.15 g, 52.38 mmol, 3 ml, 34.24 eq.). The mixture was reacted at room temperature (20°C) for 16 hours. The reaction solution was concentrated under reduced pressure to obtain compound 4-5. LCMS: MS(ESI) mass/charge (M-56+H)+: 507.3.

Obtaining connection 4-6.

Cesium carbonate (2.76 g, 8.48 mmol, 3 equiv) was added to a solution of compound 4-5 (1.59 g, 2.83 mmol, 1 eq.) in N,N-dimethylformamide (20 mL). The mixture was heated to 135°C and reacted for 1.5 hours. The reaction solution was filtered (through Celite) and the filter cake was washed with N,Ndimethylformamide (20 ml). The combined filtrate was concentrated under reduced pressure and then the residue was separated and purified by column chromatography to give compound 46. LCMS: MS(ESI) wt/charge (M+H)+: 543.3.

Obtaining connection 4-7.

Trifluoroacetic acid (1.54 g, 13.51 mmol, 1 mL, 68.59 eq) was added to a solution of compound 4-6 (110 mg, 196.92 μmol, 1 eq.) in dichloromethane (4 mL). The mixture was reacted at room temperature (20°C) for 0.5 hours. The reaction solution was concentrated under reduced pressure to give compound 4-7 (crude, trifluoroacetate). LCMS: MS(ESI) mass/charge (M+H)+: 443.1.

Preparation of compounds 4A and 4B.

To a solution of compound 4-7 (677 mg, 1.22 mmol, 1 eq., trifluoroacetate) in tetrahydrofuran (10 mL) and water (10 mL) was added sodium carbonate (1 g, 9.43 mmol, 7.75 eq. ) and a solution of acryloyl chloride (63 mg, 696.07 µmol, 56.76 µl, 5.72 e-1 eq.) in tetrahydrofuran (1 ml) was added dropwise to the reaction solution. The mixture was reacted at room temperature (25°C) for 1 hour and supplemented with a solution of acyl chloride (35 mg, 386.71 µmol, 31.53 µl, 3.18 e-1 eq.) in tetrahydrofuran (1 ml) and the resulting the solution was reacted at room temperature (25°C) for an additional 0.5 hours. The reaction solution was adjusted to pH approximately 5 with 1N. hydrochloric acid and extracted with dichloromethane (10 ml-3). The combined organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and then the residue was separated and purified by column chromatography; the product was determined using supercritical fluid chromatography (chromatographic column: Chiralpak AD-3 50 x 4.6 mm I.D, 3 μm; mobile phase: A: supercritical carbon dioxide, B: 0.05% diethylamine solution in methanol; gradient: B 5% to 40% in 2 min, hold at 40% for 1.2 min, back to 5% and equilibrate in 0.8 min; flow rate: 4 ml/min; column temperature: 35° C; wavelength: 220 nm) and analyzed as a racemic compound, which was separated to give chiral isomers: compound 4A and compound 4B with retention times of 2.134 and 2.518 min, respectively.

Compound 4A: ^1H NMR (400 MHz, DMSO-d6) δ 9.11 (s, 1H), 8.34 (s, 1H), 7.87 (d, J=8.8 Hz, 2H), 7.487 .39 (m, 1H), 7.35 (d, J=8.8 Hz, 2H), 7.14-7.03 (m, 1H), 6.94-6.75 (m, 1H), 6.09 (t, J=16.3 Hz, 1H), 5.73-5.55 (m, 1H), 4.72 (d, J=12.0 Hz, 0.5H), 4.31 (t, J=14.8 Hz, 1H), 4.08 (d, J=13.3 Hz, 0.5H), 3.55-3.43 (m, 0.5H), 3.32- 3.13 (m, 1.5H), 3.13-2.90 (m, 1H), 2.27-2.17 (m, 1H), 2.06-1.81 (m, 2H), 1.65-1.49 (m, 1H). LCMS: MS(ESI) mass/charge (M+H)+: 497.2.

Compound 4B: 1H NMR (400 MHz, DMSO-d6) δ 9.12 (s, 1H), 8.36 (s, 1H), 7.89 (d, J=8.8 Hz, 2H), 7.527, 40 (m, 1H), 7.37 (d, J=9.0 Hz, 2H), 7.16-7.06 (m, 1H), 6.94-6.74 (m, 1H), 6 .10 (t, J=16.6 Hz, 1H), 5.75-5.56 (m, 1H), 4.73 (d, J=11.5 Hz, 0.5H), 4.32 ( t, J=15.1 Hz, 1H), 4.10 (d, J=13.1 Hz, 0.5H), 3.58-3.44 (m, 0.5H), 3.32-3 .13 (m, 1.5H), 3.15-2.92 (m, 1H), 2.27-2.17 (m, 1H), 2.09-1.82 (m, 2H), 1 .65-1.49 (m, 1H). LCMS: MS(ESI) mass/charge (M+H)+: 497.2.

- 18 044333

Example 5.

The path of synthesis.

Preparation of compound 5-2.

Mixed solution of compound 3-8 (5.16 g, 36.57 mmol, 3.88 mL, 1 eq.), compound 5-1 (5.32 g, 40.89 mmol, 7.54 mL, 1.12 eq.), cesium carbonate (23.83 g, 73.14 mmol, 2 eq.) and N,N-dimethylformamide (60 ml) were heated to 80°C and stirred for 2 hours. The reaction solution was concentrated under reduced pressure, and then the residue was separated and purified by column chromatography to obtain compound 5-2. 1H NMR (400 MHz, CDCl ₃ ) δ 8.24-8.26 (m, 2H), 6.99-7.17 (m, 5H).

Preparation of compound 5-3.

To a solution of compound 5-2 (4.5 g, 17.92 mmol, 1 eq.) in methanol (60 ml) was added wet palladium on carbon (2.3 g, 10% purity). The mixture atmosphere was changed to hydrogen three times and then stirred at 15° C. in a hydrogen atmosphere in a balloon for 16 hours. The reaction solution was filtered (through celite). The filtrate was concentrated under reduced pressure and then the residue was separated and purified by column chromatography to obtain compound 5-3. 1H NMR (400 MHz, CDCl ₃ ) δ 6.796.83 (m, 4H), 6.64-6.53 (m, 3H), 3.54 (brs, 2H). LCMS: MS(ESI) mass/charge (M+H)+: 222.1.

Preparation of compound 5-4.

At 0°C, to a solution of compound 5-3 (5.5 g, 24.86 mmol, 1 eq.) in hydrochloric acid (150 ml, concentrated hydrochloric acid) was added dropwise a solution of sodium nitrite (3.43 g, 49. 73 mmol, 2 equiv) in water (50 ml) and the mixture was reacted at 0°C for 1 hour. Then, a solution of tin chloride dihydrate (23.00 g, 101.94 mmol, 4.00) was added dropwise to the reaction solution. 1 eq.) in hydrochloric acid (50 ml, concentrated hydrochloric acid) and the mixture was reacted at 0°C for 3 hours. The reaction solution was adjusted to pH approximately 13 with sodium hydroxide solution (6 N) and extracted with dichloromethane (200 ml-3). The combined organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain compound 5-4. LCMS: MS(ESI) mass/charge (M+H)+: 237.1.

Obtaining connection 5-5.

To a solution of compound 1-5 (500 mg, 1.53 mmol, 1 eq.) and compound 5-4 (1.00 g, 4.23 mmol, 2.76 eq.) in ethanol (25 ml) was added acetic acid (5.25 g, 87.43 mmol, 5 ml, 57.06 eq.) and the mixture was reacted at room temperature (25°C) for 16 hours. The reaction solution was concentrated under reduced pressure to obtain compound 5-5. LCMS: MS(ESI) mass/charge (M-56+H)+: 489.1.

- 19 044333

Obtaining connection 5-6.

To a solution of compound 5-5 (1.9 g, 3.49 mmol, 1 eq.) in N,N-dimethylformamide (30 mL) was added cesium carbonate (3.45 g, 10.57 mmol, 3.03 eq. ). The mixture was heated to 135°C and reacted for 1 hour. The reaction solution was filtered (through Celite) and the filter cake was washed with N,Ndimethylformamide (30 ml). The filtrate was concentrated under reduced pressure and then the residue was separated and purified by column chromatography to obtain compound 5-6. LCMS: MS(ESI) mass/charge (M+H)+: 525.3.

Obtaining connection 5-7.

To compound 5-6 (585 mg, 1.12 mmol, 1 eq.) in dichloromethane (16 ml) was added dropwise trifluoroacetic acid (6.16 g, 54.02 mmol, 4 ml, 48.44 eq.) and the mixture was reacted at room temperature (30°C) for 0.5 hours. The reaction solution was concentrated under reduced pressure to obtain compound 5-7 (crude, trifluoroacetate). LCMS: MS(ESI) mass/charge (M+H)+: 425.2.

Preparation of compounds 5A and 5B.

Sodium carbonate (1.15 g, 10.85 mmol, 4 .30 eq.) and a solution of acryloyl chloride (130 mg, 1.44 mmol, 117.12 µl, 5.69 e-1 eq.) in tetrahydrofuran (1 ml) was added dropwise to the reaction solution. The mixture was reacted at room temperature (25°C) for 1 hour. The reaction solution was adjusted to pH approximately 5 with 1N. hydrochloric acid and extracted with dichloromethane (10 ml-3). The combined organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and then the residue was separated and purified by column chromatography; the product was determined using supercritical fluid chromatography (chromatography column: Cellulose 2, 150 x 4.6 mm I.D, 5 μm; mobile phase: A: supercritical carbon dioxide, B: 0.05% diethylamine in ethanol; gradient: B 5% to 40% in 5 min, hold at 40% for 2.5 min, back to 5% and equilibrate in 2.5 min; flow rate: 2.5 mL/min; column temperature: 35 °C; wavelength: 220 nm) and analyzed as a racemic compound, which was separated to give chiral isomers: compound 5A and compound 5B with retention times of 6.616 and 6.971 min, respectively.

Compound 5A: Ή NMR (400 MHz, DMSO4) δ 9.09 (s, 1H), 8.33 (s, 1H), 7.85 (d, J=9.0 Hz, 2H), 7.397.22 ( m, 4H), 7.16-7.05 (m, 1H), 6.92-6.76 (m, 1H), 6.09 (t, J=16.1 Hz, 1H), 5.72 -5.57 (m, 1H), 4.72 (d, J=12.3 Hz, 0.5H), 4.31 (t, J=13.7 Hz, 1H), 4.17-4, 00 (m, 0.5N), 3.53-3.44 (m, 0.5N), 3.33-3.14 (m, 1.5N), 3.123.02 (m, 0.5N), 3.01-2.89 (m, 0.5H), 2.27-2.16 (m, 1H), 2.05-1.80 (m, 2H), 1.66-1.46 (m , 1H). LCMS: MS(ESI) mass/charge (M+H)+: 479.2.

Compound 5B: ^1H NMR (400 MHz, DMSO-d6) δ 9.09 (s, 1H), 8.33 (s, 1H), 7.85 (d, J=8.8 Hz, 2H), 7.407 .23 (m, 4H), 7.14-7.04 (m, 1H), 6.94-6.75 (m, 1H), 6.10 (t, J=16.1 Hz, 1H), 5.72-5.52 (m, 1H), 4.73 (d, J=12.5 Hz, 0.5H), 4.32 (t, J=12.7 Hz, 1H), 4.09 (d, J=13.1 Hz, 0.5H), 3.57-3.44 (m, 0.5H), 3.33-3.15 (m, 1.5H), 3.12-3 .03 (m, 0.5H), 3.03-2.88 (m, 0.5H), 2.27-2.16 (m, 1H), 2.05-1.79 (m, 2H) , 1.68-1.49 (m, 1H). LCMS: MS(ESI) mass/charge (M+H)+: 479.2.

Example 6.

6A or 6V

6B or 6A

- 20 044333

The path of synthesis.

Preparation of compound 6-2.

To a solution of compound 6-1 (19 g, 134.66 mmol, 14.29 ml, 1 eq.) and compound 3-8 (20.22 g, 155.43 mmol, 1.15 eq.) in N,N -dimethylformamide (400 ml) was added cesium carbonate (84 g, 257.81 mmol, 1.91 eq.). The mixture was heated to 80°C and reacted for 16 hours. The reaction solution was filtered (through Celite) and the filter cake was washed with N,N-dimethylformamide (30 ml). The combined filtrate was poured into 2 L of water under reaction conditions. The mixture was then reacted at room temperature (20°C) for another 10 minutes and then filtered.

The filter cake was washed with water (20 ml·5) and the resulting filter cake was dissolved in 150 ml of dichloromethane. The solution was washed with 20 ml of saturated saline. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain compound 6-2. ^1H NMR (400 MHz, DMSO- _d6 ) δ 8.28-8.25 (m, 2H), 7.56-7.52 (m, 1H), 7.45-7.30 (m, 1H ), 7.25-7.19 (m, 3H).

Preparation of compound 6-3.

To a solution of compound 6-2 (8 g, 31.85 mmol, 1 eq.) in methanol (90 ml) was added wet palladium on carbon (4 g, 10% purity). The atmosphere of the mixture was changed to hydrogen three times and it was reacted at room temperature (25°C) under a hydrogen atmosphere in a cylinder (15 psi) for 16 hours. The reaction solution was filtered (through celite) and the filtrate was concentrated under reduced pressure to obtain compound 6-3. LCMS: MS(ESI) mass/charge (M+H)+: 222.1.

Preparation of compound 6-4.

At 0°C, to a solution of compound 6-3 (6.00 g, 27.12 mmol, 1 eq.) in hydrochloric acid (180 ml, concentrated hydrochloric acid) was added dropwise a solution of sodium nitrite (3.74 g, 54, 25 mmol, 2 equiv) in water (60 ml) and the mixture was reacted at 0°C for 1 hour. Then, a solution of tin chloride dihydrate (25.09 g, 111.21 mmol, 4, 1 eq.) in hydrochloric acid (60 ml, concentrated hydrochloric acid) and the mixture was reacted at 0°C for 5 hours. The reaction solution was adjusted to pH approximately 12 with 6 N. sodium hydroxide solution and extracted with dichloromethane (150 μλ·3). The combined organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain compound 6-4. LCMS: MS(ESI) mass/charge (M+H)+: 237.1.

Preparation of compound 6-5.

Acetic acid (4 .20 g, 69.94 mmol, 4 ml, 45.65 eq.). The mixture was reacted at room temperature (25°C) for 16 hours. The reaction solution was concentrated under reduced pressure to obtain compound 6-5. LCMS: MS(ESI) mass/charge (M-56+H)+: 489.3.

Obtaining connection 6-6.

Cesium carbonate (1.5 g, 4.60 mmol, 3.13 eq) was added to a solution of compound 6-5 (800 mg, 1.47 mmol, 1 eq.) in N,N-dimethylformamide (15 mL). The mixture was heated to 150°C under microwave conditions and reacted for 0.5 hours. The reaction solution was filtered (through Celite) and the filter cake was washed with K,K-dimethylformamide (20 ml). The combined filtrate was concentrated under reduced pressure, and then the residue was separated and purified by column chromatography to give compound 6-6. LCMS: MS(ESI) mass/charge (M+H)+: 525.3.

Obtaining connection 6-7.

Trifluoroacetic acid (3.08 g, 27.01 mmol, 2 mL, 42.94 eq) was added to a solution of compound 6-6 (330 mg, 629.13 μmol, 1 eq.) in dichloromethane (8 mL). The mixture was reacted at room temperature (25°C) for 0.5 hours. The reaction solution was concentrated under reduced pressure to give compound 6-7 (crude, trifluoroacetate). LCMS: MS(ESI) mass/charge (M+H)+: 425.2.

Preparation of compounds 6A and 6B.

To a solution of compound 6-7 (780 mg, 1.45 mmol, 1 eq., trifluoroacetate) in tetrahydrofuran (10 ml) and water (10 ml) was added sodium carbonate (1.19 g, 11.23 mmol, 7.75 eq.) and a solution of acryloyl chloride (70 mg, 773.41 µmol, 63.06 µl, 5.34 e-1 eq.) in tetrahydrofuran (1 ml) was added dropwise. The mixture was reacted at room temperature (25°C) for 1 hour. The reaction solution was adjusted to pH approximately 5 with 1N. hydrochloric acid and extracted with dichloromethane (10 ml-3). The combined organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and then the residue was separated and purified by column chromatography; the product was determined using supercritical fluid chromatography (chromatography column: Chiralpak IG-3 50 x 4.6 mm I.D, 3 μm; mobile phase: A: supercritical carbon dioxide, B: 0.05% diethylamine in ethanol; gradient: B 5% to 40% in 2 min, hold at 40% for 1.2 min, back to 5% and equilibrate in 0.8 min; flow rate: 4 ml/min; column temperature: 35° C; wavelength: 220 nm) and analyzed as a racemic compound, which was separated to give chiral isomers: compound 6A and compound 6B with retention times of 2.820 and 3.128 min, respectively.

Compound 6A: 1H NMR (400 MHz, DMSO-d6) δ 9.10 (s, 1H), 8.34 (s, 1H), 7.85 (d, J=8.8 Hz, 2H), 7.567, 47 (m, 1H), 7.31-7.20 (m, 3H), 7.19-7.11 (m, 1H), 6.92-6.74 (m, 1H), 6.09 ( t, J=16.2 Hz, 1H), 5.75-5.58 (m, 1H), 4.73 (d, J=12.0 Hz, 0.5H), 4.41-4.23 (m, 1H), 4.09 (d, J=13.1 Hz, 0.5H), 3.54-3.44 (m, 0.5H), 3.34-2.90 (m, 2 ,5H), 2.30-2.16 (m, 1H), 2.07-1.81 (m, 2H), 1.67-1.48 (m, 1H). LCMS: MS(ESI) mass/charge (M+H) ⁺ : 479.3.

Compound 6B: 1H NMR (400 MHz, DMSO4) δ 9.10 (s, 1H), 8.35 (s, 1H), 7.86 (d, J=8.8 Hz, 2H), 7.567.47 ( m, 1H), 7.35-7.23 (m, 3H), 7.19-7.11 (m, 1H), 6.93-6.74 (m, 1H), 6.10 (t, J=16.3 Hz, 1H), 5.76-5.57 (m, 1H), 4.73 (d, J=12.5 Hz, 0.5H), 4.32 (t, J=14 ,1 Hz, 1H), 4.10 (d, J=13.1 Hz, 0.5H), 3.55-3.45 (m, 0.5H), 3.342.88 (m, 2.5H) , 2.30-2.16 (m, 1H), 2.07-1.82 (m, 2H), 1.68-1.46 (m, 1H). LCMS: MS(ESI) mass/charge (M+H) ⁺ : 479.3.

Reference Example 7

7A or 7B 7B or 7A

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Synthesis path

Preparation of compound 7-2.

To compound 7-1 (6.47 g, 28.22 mmol, 1 eq.) in dichloromethane (90 ml) was added N,N'-carbonyldiimidazole (5.64 g, 34.78 mmol, 1.23 eq.) . The resulting mixture was stirred at room temperature (25°C) for 1 hour and N,O-dimethylhydroxylamine hydrochloride (3.12 g, 31.99 mmol, 1.13 eq.) was added. The mixture was stirred at room temperature (25°C) for 16 hours. The reaction solution was washed successively with 1 M hydrochloric acid (80 ml) and saturated sodium hydrogen carbonate solution (80 ml), and the liquid was separated and extracted. The organic phase was washed with brine (50 ml), then dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure to give compound 7-2. LCMS: MS(ESI) mass/charge (M-56+H)+: 217.1.

Preparation of compound 7-4.

At -65°C, under a protective nitrogen atmosphere, n-butyllithium (2.5 M, 11 ml, 1.46 eq.) and the mixture was reacted at -65°C for 1 hour. Then a solution of compound 7-2 (5.12 g, 18.80 mmol, 1 eq.) in THF (40 ml) was added ) and the mixture was reacted at -65 °C for 2 hours, slowly warmed to normal temperature (25 °C) and then reacted for another 16 hours. The reaction was quenched by adding dropwise saturated ammonium chloride solution (15 ml) to the reaction solution and it was concentrated to dryness under reduced pressure. The resulting concentrated residue was diluted with ethyl acetate (150 ml) and water (40 ml) and the liquid was separated and extracted. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure, and then the residue was purified using a silica gel column to obtain compound 7-4. LCMS: MS(ESI) mass/charge (M-56+H)+: 287.1.

Preparation of compound 7-5.

To a mixed solution of compound 7-4 (7.43 g, 21.67 mmol, 1 eq.) in 1,4-dioxane (56 ml) and ethanol (28 ml) was added sequentially sodium carbonate (1.83 g, 21. 78 mmol, 847.22 µl, 1 eq.) and hydrazine hydrate (1.51 g, 25.57 mmol, 1.46 ml, 1.18 eq., 85% purity). The mixture was heated to 70°C and reacted for 16 hours. The reaction solution was concentrated to dryness, and then the residue was purified using a silica gel column to obtain compound 7-5. LCMS: MS(ESI) mass/charge (M+H)+: 337.2.

Preparation of compound 7-7.

To a suspension of dichloromethane (100 ml) and 4 A molecular sieves (4.86 g) was added compound 7-5 (4.78 g, 14.19 mmol, 1 eq.), compound 7-6 (4.88 g, 22.80 mmol, 1.61 eq.), copper acetate (3.78 g) and pyridine (2.25 g, 28.50 mmol, 2.3 ml, 2.01 eq.). The atmosphere of the resulting mixture was replaced three times with oxygen, it was heated to 60°C and reacted for 16 hours in an oxygen atmosphere in a cylinder, supplemented with 7-6 (4.88 g, 22.80 mmol, 1.61 eq. ) and then reacted at 60°C in

- 23 044333 oxygen atmosphere for another 16 hours. The reaction solution was filtered and the filtrate was concentrated to dryness under reduced pressure. Ethyl acetate (200 ml) and water (60 ml) were added and the liquid was separated and extracted. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure. The residue was then purified using a silica gel column to obtain compound 7-7. LCMS: MS(ESI) mass/charge (M+H)+: 505.3.

Preparation of compound 7-9.

To compound 7-8 (7.77 g, 46.47 mmol, 7 mL, 14.21 eq.) was added compound 7-7 (1.65 g, 3.27 mmol, 1 eq.) and sodium carbonate (540 mg, 6.43 mmol, 250.00 µl, 1.97 eq.). The mixture was reacted at 130°C for 16 hours. Water (40 ml) was added to the reaction solution, and the liquid was separated and extracted with ethyl acetate (50 ml-2). The combined organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure. The residue was then purified using a silica gel column to obtain compound 7-9. LCMS: MS(ESI) mass/charge (M+H)+: 636.5.

Preparation of compound 7-10.

Dichloromethane (35 mL) and trifluoroacetic acid (5.39 g, 47.27 mmol, 3.50 mL, 37.33 eq.) were added to compound 7-9 (805 mg, 1.27 mmol, 1 eq.). The mixture was reacted at 0° C. for 0.5 h. The reaction solution was concentrated to dryness under reduced pressure to obtain compound 7-10 (crude, trifluoroacetate). LCMS: MS(ESI) mass/charge (M+H)+: 536.4.

Getting connection 7-11.

At 0°C to a solution of compound 7-10 (1.15 g, 1.77 mmol, 1 eq., TFA) and sodium carbonate (625 mg, 5.90 mmol, 3.33 eq.) in tetrahydrofuran (30 ml ) and water (30 mL), acryloyl chloride (307 mg, 3.39 mmol, 276.58 μL, 1.92 eq.) was added dropwise. The mixture was reacted at 0° C. for another 0.5 hour. Dichloromethane (50 ml) and water (20 ml) were added to the reaction solution, and the liquid was separated and extracted. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure to give compound 7-11. LCMS: MS(ESI) mass/charge (M+H)+: 590.4.

Obtaining connection 7-12.

Compound 7-11 (511.16 mg, 866.84 μmol, 1 eq.) was added to TFA (15 mL). The mixture was stirred at 60°C for 2 hours. The reaction solution was concentrated to dryness under reduced pressure, and then the residue was separated and purified sequentially by column chromatography and high performance liquid chromatography to obtain compound 7-12. LCMS: MS(ESI) mass/charge (M+H)+: 440.3.

Preparation of compounds 7A and 7B.

Compound 7-12 (44 mg, 100.11 µmol, 1 eq.) was determined using SFC (chromatography column: Chiralpak AD-350 x 4.6 mm I.D., 3 µm; mobile phase: A: supercritical carbon dioxide, B: 0.05% diethylamine in isopropanol; gradient: 40% B; flow rate: 4 ml/min; column temperature: 35°C; wavelength: 220 nm) and it showed more than one configuration. The product was subjected to chiral resolution to yield compounds 7A and 7B with retention times of 1.199 and 2.095 min, respectively.

Compound 7A: 1H NMR (400 MHz, DMSO-d6) δ 7.70-7.68 (m, 1H), 7.52-7.43 (m, 2H), 7.45-7.43 (m, 2H), 7.21-7.16 (m, 5H), 6.86-6.84 (m, 2H), 6.15-6.08 (m, 1H), 5.71-5.68 ( m, 2H), 5.02-5.64 (m, 1H), 4.22-4.11 (m, 1H), 3.52-3.44 (m, 1H), 3.24-3, 21 (m, 2H), 3.18-2.90 (m, 1H), 2.15-2.11 (m, 1H), 1.93-1.86 (m, 2H), 1.561.52 ( m, 1H). LCMS: MS(ESI) mass/charge (M+H)+: 440.3.

Compound 7B: 1H NMR (400 MHz, DMSO-T) δ 7.70-7.68 (m, 1H), 7.52-7.43 (m, 2H), 7.47-7.45 (m, 2H), 7.22-7.15 (m, 5H), 6.87-6.83 (m, 2H), 6.14-6.08 (m, 1H), 5.73-5.69 ( m, 2H), 5.02-5.65 (m, 1H), 4.23-4.12 (m, 1H), 3.51-3.44 (m, 1H), 3.24-3, 20 (m, 2H), 3.19-2.90 (m, 1H), 2.16-2.13 (m, 1H), 1.94-1.87 (m, 2H), 1.571.54 ( m, 1H). LCMS: MS(ESI) mass/charge (M+H)+: 440.2.

Experimental Example 1 Test against BTK kinase.

1. Reaction conditions:

Buffer conditions: 20 mM HEPES (pH 7.5), 10 mM MgCl ₂ , 1 mM EGTA, 0.02% Brij35, 0.02 mg/ml BSA, 0.1 mM Na ₃ VO ₄ , 2 mM DTT, 1% DMSO.

2. Reaction procedure.

2.1. Preparation of indicator substrate in freshly prepared reaction buffer.

2.2. Delivery of the required cofactor to the above substrate solution.

2.3. Delivery of the specified kinase to the substrate solution and their careful mixing.

2.4. Delivery of compounds in DMSO into the kinase reaction mixture using acoustic technology (Echo550).

2.5. Initiate the reaction (final ATP concentration: 5 µM) by delivering ³³ P-ATP (final specific activity: 0.01 µCi/µL) to the reaction mixture.

2.6. Incubation of the reaction mixture with kinase at room temperature for 120 minutes.

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2.7. Record the reaction progress on P81 grade ion exchange chromatography paper (Whatman No. 3698-915).

2.8. Intensive rinsing of the filter with 0.75% phosphoric acid.

2.9. Measurement of the amount of radioactive phosphorylated substrate remaining on the filter paper.

3. Data analysis.

Kinase activity data were expressed as a percentage of the remaining kinase activity in the test sample compared to the vehicle reaction (dimethyl sulfoxide), and IC ₅₀ values were obtained and curve fitted using Prism4 software (GraphPad).

4. Conclusion of experiments: the results are shown in table. 1.

Table 1

BTK kinase inhibitory activity

Connection no. VTK (1C _50> nM) Connection no. VTK (1C ₅₀ , nM) 2B 5.27 5A 31.8 BEHIND 9.58 5V 2.16 ZV 2.7 6A 9.58

4A eleven 6V 140 4B 98.1

Conclusion: The compounds of the present invention exhibit better kinase inhibitory activity and preferably these compounds have strong kinase inhibitory activity (IC ₅₀ < 100 nM).

Experimental Example 2 Test against EGFR, ITK and TEC kinases.

1. Reaction conditions.

Buffer conditions: 20 mM HEPES (pH 7.5), 10 mM MgCl ₂ , 1 mM EGTA, 0.02% Brij35, 0.02 mg/ml BSA, 0.1 mM Na ₃ VO ₄ , 2 mM DTT, 1% DMSO.

2. Reaction procedure.

2.1. Preparation of indicator substrate in freshly prepared reaction buffer.

2.2. Delivery of the required cofactor to the above substrate solution.

2.3. Delivery of the specified kinase to the substrate solution and their careful mixing.

2.4. Delivery of compounds in DMSO into the kinase reaction mixture using acoustic technology (Echo550).

2.5. Initiate the reaction (final ATP concentration: 2 μM, 5 μM, and 5 μM, respectively) by delivering ³³ P-ATP (final specific activity: 0.01 μCi/μL) to the reaction mixture.

2.6. Incubation of the reaction mixture with kinase at room temperature for 120 minutes.

2.7. Record the reaction progress on P81 grade ion exchange chromatography paper (Whatman No. 3698-915).

2.8. Intensive rinsing of the filter with 0.75% phosphoric acid.

2.9. Measurement of the amount of radioactive phosphorylated substrate remaining on the filter paper.

3. Data Analysis: Kinase activity data were expressed as a percentage of the remaining kinase activity in the test sample compared to the vehicle reaction (dimethyl sulfoxide), and IC ₅₀ values were obtained and curve fitting was performed using Prism4 software (GraphPad).

4. Conclusion of experiments: the results are shown in table. 2.

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table 2

Comparison of inhibitory activity values for EGFR, ITK, and TEC, and BTK kinases

Connection no. EGFR OSanM) PC (1C5o,nM) TES (IC50, nM) VTK (IC50, nM) Correlation of activity values for EGFR, ITK, TEC and BTK 2B 344 8910 42 5.27 65x, 1690x, 7x 4A 2020 > 10 µM 169 eleven 183x, >909x, 15x 5V 829 5430 74.8 2.16 383x, 2513x, 34x 6A 812 7320 43.2 9.58 84x, 764x, 4x 7A 14.5 42.2 3.39 0.73 19x,57x,4.6x 7V 33.3 1450 3.74 0.93 35x, 1559x, 4x

Conclusion: The compounds of the present invention exhibit better selectivity for EGFR, ITK and TEC kinases.

Experimental Example 3: Pharmacokinetic study of the compounds of the present invention.

1. Brief description of the pharmacokinetic study of the compounds of the present invention.

1.1. Male CD-1 mice are used as experimental animals; The LC/MS/MS method is used to determine drug concentrations in the blood plasma of mice at different time points after intravenous and intragastric administration of test compounds. The pharmacokinetic behavior of the compounds in mice was studied and their pharmacokinetic characteristics were assessed.

2. Experimental design.

2.1. Experimental drugs: compounds being tested.

2.2. Experimental Animals: 4 healthy adult male CD-I mice, divided into 2 groups according to the principle of similar body weight, with 2 mice in each group. Animals were purchased from Shanghai Xipuer-Bikai Experimental Animal Co., Ltd.

2.3. Composition of the medicinal product.

A suitable number of samples was weighed out; a solvent was added and the mixture was stirred under sonication conditions until a clear state was achieved and then used for intravenous administration.

A suitable number of samples was weighed out; a solvent was added and the mixture was stirred under sonication until an approximately clear solution appeared and then used for intragastric administration.

2.4 Introduction.

male CD-1 mice were divided into 2 groups and fasted overnight. One group received intravenous administration and the other group received intragastric administration.

3. Carrying out the test.

After intravenous administration of test compounds to male CD-1 mice, 30 μl of blood was collected at 0.0830, 0.25, 0.5, 1, 2, 4, 8, and 24 h, respectively, and placed into commercial tubes containing EDTA-K2. After intragastric administration of test compounds to other mice, 30 μl of blood was collected at 0.25, 0.5, 1, 2, 4, 6, 8, and 24 h, respectively, and placed into commercial tubes containing EDTA-K2. Test tubes were centrifuged at 3000 g for 15 min to separate blood plasma and stored at -60°C. 2 hours after administration, the animals were allowed to eat.

After intravenous and intragastric administration, the content of the compounds to be tested in the blood plasma of mice was determined using the LC/MS/MS method. The linear range of the method was from 2.00 to 6000 nmol/L; Blood plasma samples were analyzed after protein treatment and precipitation with acetonitrile.

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4. Results regarding pharmacokinetic parameters.

Table 3

Brief description of data in the form of pharmacokinetic parameters

Method of administration Dozir sheep The concentration of the drug in the blood Time to peak Half-life Every day volume of distribution Elimination rate The area is crooked? (0-t) Area along a curve (O-inf) Biodostability Stach (nM) Ttah (h.) T1/2 (h.) Vdss (l/kg) C1 (ml/min/kg) AUCO-n donkey (nmch.) ALJCO-i nf (nmch.) F (%)

2B, intravenous administration 1 mg/k G - - 1.21 0.954 13.3 2697 2720 - 2B, intragastric administration 2 mg/k G 400 0.25 4.88 - - 1259 1777 23 5B, intravenous administration 1 mg/k G - - 1.5 1.45 19.3 1821 1847 - 5B, intragastric administration 2 mg/k G 135 0.25 ND - - 620 ND 17

Note: --: no data available;

ND: not defined.

Conclusion: The compounds of the present invention are characterized by a short half-life, wide distribution outside the blood plasma and moderate bioavailability.

Experimental Example 4: Study of the effectiveness of the compounds of the present invention against a human lymphoma model derived from a subcutaneous xenograft of TMD-8 cells in CB-17 SCID mice.

Experimental Objective: The antitumor effects of the compounds were assessed in this experiment by using a subcutaneous xenograft model of TMD8 cells in CB-17 SCID mice.

Experimental procedures.

(1) Cell culture.

Human TMD-8 lymphoma cells were cultured in a monolayer configuration in vitro with the following culture conditions: RMPI-1640 medium supplemented with 10% fetal bovine serum, 100 U/ml penicillin and 100 μg/ml streptomycin and a 37°C incubator, 5% CO2. Conventional cell detachment treatment was carried out using Pancreatin-EDTA for passaging twice a week. When cell saturation was between 80% and 90% and the number reached the required level, the cells were collected, counted and inoculated.

(2) Inoculation of tumor cells.

0.2 ml (1 x 10 ⁷ cells) TMD-8 cells (supplemented with Matrigel in a 1:1 volume ratio) were subcutaneously inoculated into the right dorsum of each mouse. Grouping and administration began when the average tumor volume reached approximately 113 mm ³ .

(3) Obtaining test samples.

Test Compound Administration Group: A specified amount of test compound was weighed into a brown dosing bottle and an appropriate volume of solvent was added. The mixture was then vortex-mixed to obtain a homogeneous suspension or clear solution.

Tumor diameter was measured twice a week using vernier calipers. The formula for calculating tumor volume was as follows: V = 0.5a x b ² , where a and b represent the long and short diameters of the tumor, respectively.

The antitumor efficacy of the compound was assessed using TGI (%) or relative tumor growth rate T/C (%). Relative tumor growth rate T/C (%) = Tr _TV /Cr _TV x 100% (T _RTV : RTV treatment group; C _RTV : RTV negative control group). Relative tumor volume (RTV) was calculated according to tumor measurements. The formula for calculation was

-

Claims (18)

as follows: RTV = Vt/V ₀ where V ₀ was the average tumor volume measured at the start of grouping and administration (ie, D0), and V _t was the average tumor volume at certain measurements. T _RTV and C _RTV were obtained from data on the same day. The TGI value (%) reflects the degree of tumor growth suppression. TGI (%). at the beginning of administration in the control group receiving the solvent)] x 100%. At the end of the experiment, the weight of the tumor can be determined, and the percentage T/C _weight can be calculated, where T _weight and C _weight represent the weight of the tumor in the administration group and the vehicle control group, respectively. Statistical analysis. Statistical analysis was performed using SPSS software based on RTV data at the end of the experiment. Comparisons between three or more groups were analyzed using one-way ANOVA. If homogeneity of variance was observed (F-value was not significantly different), Tukey's test was used for analysis. If heterogeneity of variance was observed (F value was significantly different), the Games-Howell test was used. p < 0.05 was considered a significant difference. Conclusion of the experiments: the results are shown in table. 4. Table 4 Effects of the compounds of the invention on human lymphoma models derived from subcutaneous TMD-8 cell xenograft Compound no. Dosage (mg/kg) TGI (%) t/s P-value 2B 50, once a day 102 7.7% <0.05 5V 50, once a day 101 3.6% 0.008 Conclusion: The compounds of the present invention exhibit significant antitumor effects compared with the vehicle control group. CLAIM 1. The compound represented by formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof ( . where T 1 is independently selected from N and CH; R2 is independently selected from H, C ₁ . ₆ alkyl, C ₂ . ₆ alkenyl and C ₂ . ₆ alkynyl, with each of the C ₁ . ₆ alkyl, C ₂ . ₆ alkenyl and C ₂ . ₆ alkynyl is independently and optionally substituted with 1, 2 or 3 R _a ; ring A is selected from phenyl and 5-6 membered heteroaryl; M is independently selected from C3. ₆ cycloalkyl and 3-6-membered heterocycloalkyl, with each of C3. ₆ cycloalkyl and 3-6 membered heterocycloalkyl independently and optionally substituted with 1, 2 or 3 Rb; R1 and R3 are each independently selected from F, Cl, Br, I, OH, NH2, CN; each of n and m is independently selected from 0, 1, 2 or 3 and n and m are not simultaneously equal to 0; each of L1 and L2 is independently selected from -CH2-, -CH2CH2-, -O-, -C(=O)- and -C(=O)-NH-; R _{a is} independently selected from H, F, Cl, Br, I, OH, NH2, CN, C ₁ . ₃ alkyl, C ₁ . ₃ alkoxy and C ₁ . ₃ alkylamino, with each of C ₁ . ₃ alkyl, C ₁ . ₃ alkoxy and C ₁ . ₃ alkylamino is independently and optionally substituted with 1, 2 or 3 R; Rb is selected from F, Cl, Br, I, CH ₃ ; - 28 044333 R is selected from H, F, Cl, Br, I; each of the 5-6 membered heteroaryl and 3-6 membered heterocycloalkyl independently contains 1, 2, 3 or 4 heteroatoms or heteroatomic groups independently selected from -NH-, -O-, -S-, -C(=O)-, -S(=O)- and N. 2. The compound represented by formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to claim 1, wherein R _a is independently selected from H, F, Cl, Br, I, OH, NH ₂ , CN, CH ₃ , OCH ₃ , NH(CH ₃ ) and N(CH3)2. 3. The compound represented by formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to claim 2, wherein R2 is independently selected from H, C _1-3 alkyl, C _2-4 alkenyl, and C _2-4 alkynyl, each of C _1-3 alkyl, C _2-4 alkenyl and C _2-4 alkynyl independently and optionally substituted with 1, 2 or 3 R _a . 4. The compound represented by formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to claim 3, wherein R2 is independently selected from H, _CH3 , vinyl and propynyl. 5. The compound represented by formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to claim 1, wherein M is independently selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, piperidyl and morpholinyl, each of cyclopropyl, cyclobutyl , cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, piperidyl and morpholinyl, independently and optionally substituted with 1, 2 or 3 Rb. 6. The compound represented by formula (I), its stereoisomer or salt according to claim 5, wherein M is independently selected from piperidyl and morpholinyl. it is pharmaceutically acceptable 7. The compound represented by formula (I), its stereoisomer, salt according to claim 1, wherein L1 is selected from -O- and -C(=O)-NH-. 8. The compound represented by formula (I), its stereoisomer and salt according to claim 1, wherein L2 is selected from -C(=O)- and -C(=O)-NH-. 9. The compound represented by formula (I), its stereoisomer, the salt according to claim 1, wherein ring A is selected from phenyl and pyridyl. or or or 10. The compound represented by formula (I), its stereoisomeric salt according to claim 9, where the structural unit is selected from his his his pharmaceutically acceptablelepharmaceutically acceptablelepharmaceutically acceptableor his pharmaceutically accepted his pharmaceutically accepted selected from 11. The compound represented by formula (I), its stereoisomeric salt according to claim 10, where the structural unit 12. The compound represented by formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, selected from - 29 044333 where R1 and R ₃ are as defined in claim 1; each of n and m is independently selected from 0, 1, 2 or 3 and n and m are not simultaneously equal to 0; R ₂ is as defined in any one of paragraphs. 1, 3 or 4; L1 is as defined in claim 1 or 7; L ₂ is as defined in claim 1 or 8. 13. The compound represented by formula (I), or a pharmaceutically acceptable salt thereof according to claim 12, selected from where n, m, R1, R ₂ , R ₃ , L1, L ₂ are as defined in paragraph 12. 14. A compound represented by the following formulas, a stereoisomer thereof or a pharmaceutically acceptable salt thereof: - 30 044333 15. A compound, a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to claim 14, selected from 16. A pharmaceutical composition containing a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 15 as an active ingredient and a pharmaceutically acceptable carrier. 17. Use of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 15 or a pharmaceutical composition according to and. 16 in obtaining a medicament for the treatment of a hematological tumor and an autoimmune disease. 18. Use according to claim 17, wherein the disease is diffuse large B-cell lymphoma. Eurasian Patent Organization, EAPO Russia, 109012, Moscow, Maly Cherkassky lane, 2