CN114891013A - Derivatives of cephalotaxine compounds, preparation method, pharmaceutical composition and application thereof - Google Patents

Abstract

The invention relates to a derivative of a harringtonine compound, a pharmaceutical composition thereof and its use in preparing a medicine, and belongs to the field of medicine. Specifically, the compound of the present invention has the structure represented by formula (I), or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof. . The compounds of the present invention and their pharmaceutical compositions can be used to prepare medicines for preventing, treating or alleviating cancer.

Description

Derivatives of harringtonine compounds and their preparation methods, pharmaceutical compositions and uses

technical field

The invention belongs to the field of medicine, in particular to derivatives of harringtonine compounds and their preparation methods, pharmaceutical compositions and uses.

Background technique

Chronic myeloid leukemia (CML) is a malignant tumor formed by the clonal proliferation of bone marrow hematopoietic stem cells, which is characterized by the production of a large number of immature leukocytes, which accumulate in the bone marrow and inhibit the normal hematopoiesis of the bone marrow; The blood spreads throughout the body, causing the patient to develop anemia, easy bleeding, infection, and organ infiltration. Clinically, it can be divided into chronic phase, accelerated phase and blast phase according to its symptoms.

The emergence of Bcr-Abl fusion protein is the main pathogenic mechanism of CML. In 2001, the first Bcr-Abl kinase inhibitor imatinib was approved by the US FDA for the treatment of chronic myeloid leukemia and acute lymphoblastic leukemia. Toxic side effects and good in vivo properties have brought a breakthrough in the clinical treatment of CML. However, with the large-scale clinical use of imatinib, more and more clinical patients show different degrees of drug resistance. Studies on the pathological mechanism of drug-resistant patients have shown that the acquired point mutation of Bcr-Abl kinase is the main cause of drug resistance, and more than 100 types of point mutations have been discovered one after another. In response to the problem of imatinib resistance caused by acquired point mutations, second-generation small-molecule drugs such as dasatinib, nilotinib, and bosutinib have been approved for marketing. Compared with imatinib, these compounds showed stronger Bcr-AblWT inhibitory activity, and also had good curative effect on drug-resistant patients caused by various acquired point mutations. Although second-generation CML inhibitors are effective against a variety of point mutations, they are still ineffective against a few mutations, especially the Bcr-AblT315I mutation. The 315th threonine (Thr), as the "gatekeeper" amino acid residue of Bcr-Abl protein, plays a key activity regulation role in the ATP binding domain. For CML patients in the accelerated phase or blast phase, once Bcr-Abl occurs The Abl T315I mutation can lead to a sharp deterioration of the disease due to the absence of drugs.

Therefore, the prior art still has the following technical problems:

(1) The first-line drugs (such as imatinib) have poor activity and have no obvious effect on drug-resistant cell lines.

(2) It does not have broad-spectrum antitumor activity.

Therefore, there is an urgent need to find more efficient leukemia therapeutic drugs with better activity and good drug resistance, and have broad-spectrum anti-tumor activity.

SUMMARY OF THE INVENTION

To solve the above problems, a compound and its pharmaceutical composition, use and preparation method are provided.

In a first aspect, there is provided a compound or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof.

A compound represented by formula (I) or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof,

in,

Ring A is C _6-14 aryl or 5-12 membered heteroaryl;

R ¹ is H, C _1-6 alkyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 1,2-dichloroethyl, 2-fluoropropyl or 3-fluoropropyl;

R ² is H, D, F, Cl, Br, I, OH, CN, NO ₂ , NH ₂ , COOH, CF ₃ , -OBn, -N(H)-Boc, -N(CH ₃ ) ₂ , - S(=O) ₂ CH ₃ , -OCH ₃ , C _1-6 alkyl, C _1-6 haloalkyl or C _1-6 alkoxy;

*The indicated site is in R configuration or S configuration.

In some embodiments, the A ring is a C _6-14 aryl group (eg: C ₆ aryl, C ₇ aryl, C ₈ aryl, C ₉ aryl, C ₁₀ aryl, C ₁₁ aryl, C ₁₂ aryl, C ₁₃ aryl or C ₁₄ aryl).

In some embodiments, the A ring is phenyl or naphthyl.

In some embodiments, the R ¹ is C _1-6 alkyl.

In some embodiments, the C _1-6 alkyl group includes a C ₁ alkyl group, a C ₂ alkyl group, a C ₃ alkyl group, a C ₄ alkyl group, a C ₅ alkyl group, or a C ₆ alkyl group.

The C _1-6 alkyl group may include selected from methyl, ethyl, n-propyl, isopropyl or tert-butyl.

The C _1-6 haloalkyl may include selected from C _1-6 fluoroalkyl, C _1-6 chloroalkyl or C _1-6 bromoalkyl.

In some embodiments, the compound comprises a structure selected from the group consisting of:

In a second aspect, a pharmaceutical composition is provided.

A pharmaceutical composition comprising the compound of the first aspect or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof, and Optionally pharmaceutically acceptable excipients.

A third aspect provides a compound of the first aspect or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug or second Use of the pharmaceutical composition of the aspects.

A compound of the first aspect or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof, or a drug of the second aspect A composition for use in the manufacture of a medicament for preventing, treating or alleviating cancer.

The cancer may include: lymphoma or leukemia. In some embodiments, the cancer comprises: chronic myeloid leukemia, T351 I-mutated chronic myeloid leukemia, lymphocytic leukemia, lymphoma, or promyelocytic leukemia.

A fourth aspect provides a compound of the one aspect or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of the formula ( I) Method for the compounds shown.

A compound of formula (I) in the preparation of the compound described in the first aspect or its stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof. A method of displaying a compound, comprising:

The compound of formula (II) and the compound of formula (III) are reacted in solvent a in the presence of catalyst A, a condensing agent and a base to obtain the compound of formula (I), the site marked by * is R configuration or S configuration .

*The indicated site can be in R configuration or S configuration.

The catalyst A may include at least one selected from 4-dimethylaminopyridine and HATU and TBTU.

The condensing agent may include at least one selected from 2-chloro-1-methylpyridinium iodide (CMPI) and PyBop.

The base may include at least one selected from triethylamine and N,N-diisopropylethylamine.

The solvent a may include at least one selected from toluene and N,N-dimethylformamide.

In some embodiments, R ² is H, D, F, Cl, Br, I, OH, CN, NO ₂ , NH ₂ , COOH, CF ₃ , -OBn, -N(H)-Boc, -N( CH ₃ ) ₂ , -S(=O) ₂ CH ₃ , -OCH ₃ , C _1-6 alkyl, C _1-6 haloalkyl or C _1-6 alkoxy.

In some embodiments, the A ring is a C _6-14 aryl group (eg: C ₆ aryl, C ₇ aryl, C ₈ aryl, C ₉ aryl, C ₁₀ aryl, C ₁₁ aryl, C ₁₂ aryl, C ₁₃ aryl or C ₁₄ aryl).

In some embodiments, the A ring is phenyl or naphthyl.

In some embodiments, the R ¹ is C _1-6 alkyl.

In some embodiments, the C _1-6 alkyl group includes a C ₁ alkyl group, a C ₂ alkyl group, a C ₃ alkyl group, a C ₄ alkyl group, a C ₅ alkyl group, or a C ₆ alkyl group.

The C _1-6 alkyl group may include selected from methyl, ethyl, n-propyl, isopropyl or tert-butyl.

The C _1-6 haloalkyl may include selected from C _1-6 fluoroalkyl, C _1-6 chloroalkyl or C _1-6 bromoalkyl.

The substitution position of the R ² substituent may be that any hydrogen of the A ring in the compound of formula (I) is replaced by R ² .

In some embodiments of the present invention, a kind of method for preparing compound represented by formula (IA-8), it comprises:

The compound of formula (II) and the compound of formula (IA-6) are reacted in a solvent in the presence of a catalyst, a resolution reagent and an acid or a base to obtain a compound of formula (I), the resolution reagent is CMPI, * The indicated sites are in the R configuration or the S configuration.

In some embodiments, R ² is H, D, F, Cl, Br, I, OH, CN, NO ₂ , NH ₂ , COOH, CF ₃ , -OBn, -N(H)-Boc, -N( CH ₃ ) ₂ , -S(=O) ₂ CH ₃ , -OCH ₃ , C _1-6 alkyl, C _1-6 haloalkyl or C _1-6 alkoxy.

The substitution position of the R ² substituent may be that any hydrogen in the benzene ring in the compound of formula (IA-6) or the compound of formula (IA-8) is replaced by R ² .

A fifth aspect, a use of Ru[(S)-DTBM-SegPhos](OAc) ₂ or Ru[(R)-DTBM-SegPhos](OAc) ₂ .

Use of Ru[(S)-DTBM-SegPhos](OAc) ₂ or Ru[(R)-DTBM-SegPhos](OAc) ₂ in catalyzing the asymmetric hydrogenation of a compound containing carbon-carbon double bonds.

When the Ru[(S)-DTBM-SegPhos](OAc) ₂ or Ru[(R)-DTBM-SegPhos](OAc) ₂ catalyzes the asymmetric hydrogenation of compounds containing carbon-carbon double bonds, other groups (such as ketone, aldehyde or imine, etc.) is not affected, has high selectivity, and has high product yield and high chiral purity.

A sixth aspect provides a method for preparing a compound of formula (V).

A preparation method of a compound of formula (V), comprising:

In the presence of catalyst B and solvent b, the compound of formula (IV) reacts with hydrogen under certain pressure and temperature to obtain the compound of formula (V);

Wherein, the site indicated by * is R configuration or S configuration;

Ring A is C _6-14 aryl or 5-12 membered heteroaryl;

R ² is H, D, F, Cl, Br, I, OH, CN, NO ₂ , NH ₂ , COOH, CF ₃ , -OBn, -N(H)-Boc, -N(CH ₃ ) ₂ , - S(=O) ₂ CH ₃ , -OCH ₃ , C _1-6 alkyl, C _1-6 haloalkyl or C _1-6 alkoxy.

In some embodiments, the catalyst is Ru[(S)-DTBM-SegPhos](OAc) ₂ , and the site indicated by * is in the R configuration. In some embodiments, the catalyst is Ru[(R)-DTBM-SegPhos](OAc) ₂ , and the site indicated by * is in the S configuration.

The substitution position of the R ² substituent may be that any hydrogen of the A ring in the compound of formula (I) is replaced by R ² .

The solvent b includes at least one selected from methanol, dichloromethane and toluene.

The certain air pressure may be 10-30 standard atmospheric pressure. In some embodiments, the certain air pressure is 20 standard atmospheres.

The certain temperature may be 10-50°C. In some embodiments, the certain temperature is 10-45°C. In some embodiments, the certain temperature is 15-40°C. In some embodiments, the certain temperature is 15-35°C. In some embodiments, the certain temperature is 20-35°C.

In some embodiments, the A ring is a C _6-14 aryl group (eg: C ₆ aryl, C ₇ aryl, C ₈ aryl, C ₉ aryl, C ₁₀ aryl, C ₁₁ aryl, C ₁₂ aryl, C ₁₃ aryl or C ₁₄ aryl).

In some embodiments, the A ring is phenyl or naphthyl.

In some embodiments, the R ¹ is C _1-6 alkyl.

In some embodiments, the C _1-6 alkyl group includes a C ₁ alkyl group, a C ₂ alkyl group, a C ₃ alkyl group, a C ₄ alkyl group, a C ₅ alkyl group, or a C ₆ alkyl group.

The C _1-6 alkyl group may include selected from methyl, ethyl, n-propyl, isopropyl or tert-butyl.

The C _1-6 haloalkyl may include selected from C _1-6 fluoroalkyl, C _1-6 chloroalkyl or C _1-6 bromoalkyl.

In some embodiments of the present invention, a kind of method for preparing compound represented by formula (IA-6), it comprises:

Compound (IA-1) and compound (IA-2) are refluxed in a solvent (eg methanol) under the action of sodium methoxide to obtain compound (IA-3);

Compound (IA-3) is hydrolyzed in a solvent (eg methanol) under basic conditions (eg, sodium hydroxide) to obtain compound (IA-4);

Compound (IA-4) is reacted in methanol under the action of SOCl ₂ to obtain compound (IA-5);

Compound (IA-5) is asymmetrically hydrogenated with hydrogen at 10°C to 50°C in solvent b (e.g. methanol) at 20 standard atmospheres in the presence of catalyst B to give compound (IA-6). In some embodiments, the catalyst B is

Ru[(S)-DTBM-SegPhos](OAc) ₂ , the site indicated by * is in R configuration. In some embodiments, the catalyst B is Ru[(R)-DTBM-SegPhos](OAc) ₂ , and the site indicated by * is in the S configuration.

beneficial effect

Compared with the prior art, an embodiment of the present invention has at least one of the following beneficial effects:

(1) Compared with first-line drugs (eg, imatinib), the compound of formula (I) provided by the present invention has better activity and is effective against drug-resistant cell lines. (2) The compound of formula (I) provided by the present invention has broad-spectrum antitumor activity.

(3) The preparation method of the compound of formula (I) provided by the present invention is simple in operation, high in product yield and high in chiral purity.

(4) The present invention adopts Ru[(S)-DTBM-SegPhos](OAc) ₂ or Ru[(R)-DTBM-SegPhos](OAc) ₂ as a catalyst for asymmetric hydrogenation, other groups (such as ketone, aldehydes or imines, etc.) are not affected, with high selectivity, high product yield and high chiral purity.

Glossary

In the present invention, "room temperature" refers to ambient temperature, which is from about 10°C to about 40°C. In some embodiments, "room temperature" refers to a temperature from about 20°C to about 30°C; in other embodiments, "room temperature" refers to a temperature from about 25°C to about 30°C; in still other embodiments Among them, "room temperature" refers to 10°C, 15°C, 20°C, 25°C, 30°C, 35°C, 40°C, and the like.

"Compound of the present invention" means the compound represented by formula I or its pharmaceutically acceptable salts, tautomers, polymorphs, isomers and solvates. Likewise, the phrase "a compound of formula I" means a compound of that formula and pharmaceutically acceptable salts, tautomers, polymorphs, isomers and solvates thereof.

_IC50 represents the half inhibitory concentration.

The term "T315I mutation" refers to the mutation of threonine 315 to isoleucine in the ABL kinase domain in the Bcr-Abl fusion protein.

The term "asymmetric hydrogenation" refers to the asymmetric addition reaction of a reducing agent (such as hydrogen) to the sp ² carbon to form the sp ³ orbital (tetrahedral) carbon in the synthesis of chiral drug molecules and related compounds. .

In the present invention, expressions such as "compound I" and "compound represented by formula I" refer to the same compound.

In the present invention, the meaning of each atom in the compound structure: F represents fluorine, Cl represents chlorine, and Br represents bromine.

In the present invention, the meaning of each abbreviated group in the compound structure: Me represents methyl group, and Et represents ethyl group.

The term "V:V" denotes a volume ratio.

The term "HATU" means "2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate".

The term "TBTU" means "O-benzotriazole-N,N,N',N'-tetramethylurea tetrafluoroboric acid".

The term "PyBop" means "benzotriazol-1-yl-oxytripyrrolidinophosphorus hexafluorophosphate".

In the above description of the invention, all numbers disclosed herein are approximations, whether or not the words "about" or "about" are used. Based on the published figures, the numerical value of each figure may vary by less than ±10% or a reasonable difference considered by those in the art, such as ±1%, ±2%, ±3%, ±4% or ±5% difference.

"Alkyl" is a hydrocarbon containing normal, secondary, tertiary, or ring carbon atoms. For example, an alkyl group can have 1 to 10 carbon atoms (ie, a _C1 - _C10 alkyl group), 1 to ₈ carbon atoms (ie, a _C1 -C8 alkyl group), or 1 to 6 carbon atoms (ie, a C1-C8 alkyl group). , C ₁ -C ₆ alkyl). Examples of suitable alkyl groups include, but are not limited to, methyl (Me, _-CH3 ), ethyl (Et, -CH2CH3), ₁ -propyl (i-Pr, i-propyl, _{-CH2 )} CH ₂ CH ₃ ), 2-propyl (i-Pr, i-propyl, -CH(CH ₃ ) ₂ ), 1-butyl (n-Bu, n-butyl, -CH ₂ CH ₂ CH ₂ CH ₃ ), 2-methyl-1-propyl (i-Bu, i-butyl, -CH ₂ CH(CH ₃ ) ₂ ), 2-butyl (s-Bu, s-butyl, -CH (CH ₃ )CH ₂ CH ₃ ), 2-methyl-2-propyl (t-Bu, t-butyl, -C(CH ₃ ) ₃ ), 1-pentyl (n-pentyl, -CH 2CH2CH2CH2CH3), ₂ -pentyl (-CH( _{CH3 ) CH2CH2CH3 )} , _{3 -} pentyl (-CH( _{CH2CH3 ) 2 )} , ₂ -methyl -2-Butyl (-C(CH ₃ ) ₂ CH ₂ CH ₃ ), 3-methyl-2-butyl (-CH(CH ₃ )CH(CH ₃ ) ₂ ), 3-methyl-1-butane (-CH ₂ CH ₂ CH(CH ₃ ) ₂ ), 2-methyl-1-butyl (-CH ₂ CH(CH ₃ )CH ₂ CH ₃ ), 1-hexyl (-CH ₂ CH ₂ CH _{2 CH2CH2CH3} ), ₂ -hexyl (-CH( _CH3 ) _{CH2CH2CH2CH3 )} , _{3 -} hexyl (-CH( _{CH2CH3 ) ( CH2CH2CH3 ) )} , 2-Methyl-2-pentyl (-C(CH ₃ ) ₂ CH ₂ CH ₂ CH ₃ ), 3-methyl-2-pentyl (-CH(CH ₃ )CH(CH ₃ )CH ₂ CH ₃ ), 4-methyl-2-pentyl (-CH(CH ₃ )CH ₂ CH(CH ₃ ) ₂ ), 3-methyl-3-pentyl (-C(CH ₃ )(CH ₂ CH ₃ ) ₂ ), 2-methyl-3-pentyl (-CH(CH ₂ CH ₃ )CH(CH ₃ ) ₂ ), 2,3-dimethyl-2-butyl (-C(CH ₃ ) ₂ CH ( _CH3 ) ₂ ), 3,3-dimethyl-2-butyl (-CH( _CH3 )C( _CH3 ) ₃ , and octyl ( _- ( _CH2 ) _7CH3 ).

"Aryl" means an aromatic hydrocarbon group derived by removing one hydrogen atom from a single carbon atom of a parent aromatic ring system. For example, an aryl group can have 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 10 carbon atoms. Typical aryl groups include, but are not limited to, groups derived from benzene (eg, phenyl), substituted benzene, naphthalene, anthracene, biphenyl, and the like, and the like.

The terms "substituted" and the like refer to alkyl, aryl, arylalkyl, heterocyclyl, heteroaryl, carbocyclyl, etc., such as "substituted _C1 - _C10 alkyl", "substituted C ₆ -C ₂₀ aryl", "substituted arylalkyl", "substituted C ₁ -C ₂₀ heterocycle" and "substituted carbocyclyl" respectively mean that one or more hydrogen atoms are each independently C ₁ -C ₁₀ alkyl, C ₆ -C ₂₀ aryl, arylalkyl, C ₁ -C ₂₀ heterocycle, alkylamino, carbocyclyl substituted with non-hydrogen substituents. "C _1-6 haloalkyl" means a C ₁ -C ₆ alkyl group in which one or more hydrogen atoms are each independently replaced by a halogen atom, unless otherwise indicated, when the term "substituted" is used with two When groups of one or more moieties such as arylalkyl are used in combination, the substituents may be attached to the aryl moiety, the alkyl moiety, or both.

"Heteroaryl" refers to an aromatic heterocyclic group having at least one heteroatom in the ring. Non-limiting examples of suitable heteroatoms that may be included on the aromatic ring include oxygen, sulfur, and nitrogen. Non-limiting examples of heteroaryl rings include all those aromatic rings listed in the definition of "heterocyclyl", including pyridyl, pyrrolyl, oxazolyl, indolyl, isoindolyl, purinyl, furan base, thienyl, benzofuranyl, benzothienyl, carbazolyl, imidazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, quinolinyl, isoquinolinyl, pyridazinyl , pyrimidinyl, pyrazolyl, etc.

"Prodrug" refers to a labile functional group that is isolated from an active inhibitory compound during metabolism, systemically, intracellularly, by hydrolysis, enzymatic cleavage, or by some other process (Bundgaard, Hans, "Design and Application of Prodrugs" in Textbook of Drug Design and Development (1991), P. Krogsgaard-Larsen and H. Bundgaard, Eds. Harwood Academic Publishers, pp. 113-191). Prodrugs can be used to enhance solubility, absorption, and lipophilicity to optimize drug delivery, bioavailability, and efficacy.

Prodrugs can include active metabolites or the drug itself.

The compounds of formula I, or pharmaceutically acceptable salts thereof, may exist as different polymorphs or pseudopolymorphs. Crystal polymorphism, as used herein, refers to the ability of a crystalline compound to exist in different crystal structures. Crystal polymorphism can arise from differences in crystal packing (packing polymorphism) or packing differences between different conformers of the same molecule (conformational polymorphism). Crystal pseudopolymorphism, as used herein, refers to the ability of a hydrate or solvate of a compound to exist in different crystal structures. The pseudopolymorphs of the present invention may exist due to differences in crystal packing (packing pseudopolymorphism) or due to differences in packing between different conformers of the same molecule (conformational pseudopolymorphism). The present invention encompasses all polymorphs and pseudopolymorphs of the compounds of formulae I-III and their pharmaceutically acceptable salts.

The compound of formula I or a pharmaceutically acceptable salt thereof may also exist as an amorphous solid. As used herein, an amorphous solid is one in which no long-range order exists in the positions of atoms in the solid. This definition also applies when the crystal size is 2 nanometers or less. Additives, including solvents, can be used to create the amorphous form of the present invention. The present invention encompasses all amorphous forms of the compounds of formulae I-III and their pharmaceutically acceptable salts.

The term "treating" as used herein, unless otherwise indicated, means reversing, alleviating, alleviating, inhibiting, or one or more of the condition or disorder to which the term applies or one or more symptoms of such a disorder or disorder The progression of a symptom or the prevention of the condition or disorder or one or more symptoms thereof. The term "treatment" as used herein refers to the act of treatment, as "treatment" is defined immediately above.

The compounds described herein also include reference to their physiologically acceptable salts, examples including salts derived from suitable bases such as alkali or alkaline earth metals (eg, Na ⁺ , Li ⁺ , K ⁺ , Ca ⁺² and Mg ⁺² ), ammonium and NR ₄ ⁺ (wherein R is as defined herein). Physiologically acceptable salts of nitrogen atoms or amino groups include: (a) acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, etc. (b) salts with organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, maleic acid, fumaric acid, gluconic acid, citric acid, malic acid, ascorbic acid, benzoic acid, isethionate acid, lactobionic acid, tannic acid, palmitic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, polygalacturonic acid, malonic acid , sulfosalicylic acid, glycolic acid, 2-hydroxy-3-naphthoate, pamoate, salicylic acid, stearic acid, phthalic acid, mandelic acid, lactic acid, ethanesulfonic acid, lysate amino acids, arginine, glutamic acid, glycine, serine, threonine, alanine, isoleucine, leucine, etc.; and (c) salts formed with elemental anions such as, Chlorine, Bromine and Iodine. Physiologically acceptable salts of hydroxy compounds include the anion of the compound in combination with a suitable cation such as Na ⁺ and NR4 ₊ ^.

For therapeutic use, the salts of the active ingredients of the compounds of the present invention are physiologically acceptable, ie they are salts derived from physiologically acceptable acids or bases. However, salts of acids or bases that are not physiologically acceptable can also be used, for example, in the preparation or purification of physiologically acceptable compounds. All salts, whether derived from physiologically acceptable acids or bases, are within the scope of this invention.

The compounds of this invention are formulated with conventional carriers and excipients, which will be selected in accordance with conventional practice. Although the active ingredients can be administered alone, they are preferably formulated into pharmaceutical formulations. The formulations of the present invention, whether for veterinary or human application, comprise at least one active ingredient as defined above together with one or more acceptable carriers therefor, and optionally other therapeutic ingredients, especially Additional therapeutic ingredients such as those disclosed herein. The carrier must be "acceptable" in the meaning of being compatible with the other components of the formulation and not physiologically injurious to its recipient.

Formulations include those suitable for the above-mentioned routes of administration. The formulations may conveniently be presented in unit dosage form and by any of the methods well known in the art of pharmacy. Techniques and formulations can generally be found in Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, PA.). Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately mixing the active ingredient with liquid carriers or finely divided solid carriers, or both, and then, if desired, shaping the product.

The terms "optional", "optional" or "optionally" mean that the subsequently described event or circumstance may but need not occur. For example, "optional surfactant" means that the surfactant may or may not be present.

The term "and/or" should be understood to mean any one of the alternatives or a combination of any two or more of the alternatives.

The term "atm" means standard atmospheric pressure, ie 101.325 kPa. The term "mol%" means mole percent.

The term "Pd-C" means palladium on carbon.

As used herein, the term "treatment" refers to a clinical intervention intended to alter the natural course of disease in an individual being treated. Desired therapeutic effects include, but are not limited to, preventing disease occurrence or recurrence, reducing symptoms, reducing any direct or indirect pathological consequences of disease, preventing metastasis, reducing the rate of disease progression, ameliorating or alleviating disease state, and relieving or improving prognosis.

In the description of this specification, description with reference to the terms "one embodiment," "some embodiments," "example," "specific example," or "some examples", etc., mean specific features described in connection with the embodiment or example , structure, material or feature is included in at least one embodiment or example of the present invention. In this specification, schematic representations of the above terms are not necessarily directed to the same embodiment or example. Furthermore, the particular features, structures, materials or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, those skilled in the art may combine and combine the different embodiments or examples described in this specification, as well as the features of the different embodiments or examples, without conflicting each other.

As used herein, "compositions" may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. Generally, the compositions are prepared by uniformly and thoroughly bringing into association the active compound with liquid carriers, finely divided solid carriers, or both.

The abbreviation structure of the compound of the present invention:

Detailed ways

In order to make those skilled in the art better understand the technical solutions of the present invention, some non-limiting embodiments are further disclosed below to further illustrate the present invention in detail.

The reagents used in the present invention can be purchased from the market or can be prepared by the method described in the present invention.

Example 1: Synthesis of Compound 1

Step 1: Preparation of Compound 1a

Dimethyl succinate (5.0 mL, 38.2 mmol), tert-butyl 4-formylphenylcarbamate (6.9 g, 31.0 mmol) and sodium methoxide (1.7 g, 31.0 mmol) were added to 100 mL of methanol, 65 ℃ reaction 6h. Cool to room temperature, spin dry the solvent, adjust pH=5 with 1 mol/L HCl, extract three times with ethyl acetate, combine the organic layers, wash once with saturated aqueous sodium chloride solution, dry over anhydrous sodium sulfate, spin off the organic solution, and use the residue Silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=8:1) obtained 4.2 g of compound 1a (yield 40%). ¹ H NMR (400 MHz, Chloroform-d) δ 7.86(s, 1H), 7.41(d, J=8.4Hz, 2H), 7.33(d, J=8.6Hz, 2H), 3.84(s, 3H) ,3.60(s, 2H),1.53(s,9H).

Step 2: Preparation of Compound 1b

Compound 1a (4.0 g, 12.0 mmol) was dissolved in 20 mL of methanol, added to 40 mL of 15% aqueous sodium hydroxide solution, and reacted at room temperature for 2 h. Spin dry ethanol, adjust pH=5 with 1 mol/L HCl, extract three times with ethyl acetate, combine the organic layers, wash with saturated aqueous sodium chloride solution once, dry with anhydrous sodium sulfate, spin off the organic solvent, use petroleum ether and ethyl acetate Recrystallization gave 3.48 g of compound 1b (yield 90%). ¹ H NMR (600MHz,Methanol-d4)δ7.84(s,1H),7.49(d,J=8.5Hz,2H),7.37-7.31(m,2H),3.54(s,2H),1.54(s ,9H).

Step 3: Preparation of Compound 1c

Compound 1b (3.0 g, 9.3 mmol) and SOCl ₂ (thionyl chloride) (40 μL) were added to 30 mL of methanol, reacted at room temperature for 12 h, the organic solvent was removed, and the residue was subjected to silica gel column chromatography (petroleum ether: ethyl acetate) (V:V)=5:1) to obtain 2.2 g of compound 1c (yield 70.5%). ¹ H NMR(400MHz, Chloroform-d)δ7.95(s,1H),7.42(d,J=8.5Hz,2H),7.33(d,J=8.7Hz,2H),3.75(s,3H), 3.59(s, 2H), 1.53(s, 9H).

Step 4: Preparation of Compound 1d and Compound 1e

(1) Preparation of compound 1d

In an argon-filled glove box, compound 1c (0.335 g, 1 mmol) and catalyst Ru[(R)-DTBM-SegPhos](OAc) ₂ (0.2 mol%) were charged into an ampoule, and 1 mL of degassed was added of methanol, transferred the vial to the autoclave, then filled the autoclave with hydrogen at 20 atm, stirred at room temperature for 12 h, slowly released hydrogen in a well-ventilated fume hood, and concentrated to obtain 0.332 g of compound 1d (yield 99%). ), ee=99%. ¹ H NMR (400MHz, Chloroform-d) δ 7.26 (s, 2H), 7.09 (d, J=8.0 Hz, 2H), 3.65 (s, 3H), 3.08 (dt, J=31.9, 7.3 Hz, 2H ),2.76(dd,J＝13.8,8.3Hz,1H),2.64(dd,J＝17.0,8.9Hz,1H),2.40(dd,J＝16.7,4.9Hz,1H),1.51(s,9H) .HRMS-ESI(m/z): [M+H] ⁺ 338.1531.

(2) Preparation of compound 1e

In an argon-filled glove box, compound 1c (0.335 g, 1 mmol) and catalyst Ru[(S)-DTBM-SegPhos](OAc) ₂ (0.2 mol%) were charged into an ampoule, and 1 mL of degassed was added of methanol, transferred the vial to the autoclave, then filled the autoclave with hydrogen at 20 atm, stirred at room temperature for 12 h, slowly released hydrogen in a well-ventilated fume hood, and concentrated to obtain 0.331 g of compound 1e (yield 99%). ), ee=99%. Hydrogen spectrum: ¹ H NMR (400MHz, Chloroform-d) δ 7.26 (s, 2H), 7.09 (d, J=8.0 Hz, 2H), 3.65 (s, 3H), 3.08 (dt, J=31.9, 7.3 Hz, 2H), 2.76(dd, J＝13.8, 8.3Hz, 1H), 2.64(dd, J＝17.0, 8.9Hz, 1H), 2.40(dd, J＝16.7, 4.9Hz, 1H), 1.51(s , 9H). Mass spectrum: HRMS-ESI (m/z): [M+H] ⁺ 338.1531.

Step 5: Preparation of Compound 1 and Compound 1f

(1) Preparation of compound 1:

Take compound 1d (202 mg, 0.6 mmol), compound of formula (II) (158 mg, 0.5 mmol), DMAP (p-dimethylaminopyridine) (61 mg, 0.5 mmol), triethylamine (208 μL, 1.5 mmol) and CMPI (255 mg) , 1.0 mmol) was added to 5 mL of toluene under argon protection. The reaction was carried out at room temperature for 12h. 20 mL of water was added, extracted three times with ethyl acetate, the organic layers were combined, washed once with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, the organic solvent was spun off, and the residue was subjected to silica gel column chromatography (petroleum ether:ethyl acetate (V: V)=2:1～1:1) 303 mg of compound 1 were purified (yield 95%). Take compound 1 to detect hydrogen spectrum and mass spectrum, and the results are as follows:

Hydrogen spectrum: ¹ H NMR (400 MHz, Chloroform-d) δ 7.21 (d, J=8.1 Hz, 2H), 6.88 (d, J=8.2 Hz, 2H), 6.59 (d, J=3.0 Hz, 2H) ,6.52(s,1H),5.88(d,J＝9.6Hz,1H),5.82(d,J＝1.6Hz,1H),5.77(d,J＝1.6Hz,1H), 5.04(s,1H) , 3.78(d, J=9.6Hz, 1H), 3.71(s, 3H), 3.55(s, 3H), 3.31–3.19(m, 1H), 3.12–3.04(m, 1H), 2.94(td, J =11.6,7.0Hz,1H),2.74(tt,J=9.7,5.3Hz,1H),2.66–2.54(m,2H),2.39(dd,J=14.3,6.9 Hz,1H),2.29(dd, J=13.9, 5.2Hz, 1H), 2.22 (dd, J=16.9, 8.7Hz, 1H), 2.08–1.98 (m, 3H), 1.94–1.86 (m, 1H), 1.79–1.70 (m, 2H) ,1.49(s,9H).

Mass spectrum: HRMS-ESI (m/z): [M+H] ⁺ , [C ₃₅ H ₄₃ N ₂ O ₉ ] ⁺ found 635.2956.

(2) Preparation of compound 1f

Compound 1e (202 mg, 0.6 mmol), compound of formula (II) (158 mg, 0.5 mmol), DMAP (61 mg, 0.5 mmol), triethylamine (208 μL, 1.5 mmol) and CMPI (255 mg, 1.0 mmol) were added to 5 mL In toluene, argon protection. The reaction was carried out at room temperature for 12 h. 20 mL of water was added, extracted three times with ethyl acetate, the organic layers were combined, washed with saturated sodium chloride solution once, dried over anhydrous sodium sulfate, the organic solution was spun off, and the residue was subjected to silica gel column chromatography (petroleum ether:ethyl acetate (V: V)=2:1～1:1) and purified to obtain 289 mg of compound 1f (yield 91%).

Hydrogen spectrum: ¹ H NMR (400 MHz, Chloroform-d) δ 7.16 (d, J=8.1 Hz, 2H), 6.86 (d, J=8.2 Hz, 2H), 6.40 (d, J= 3.0 Hz, 2H) ,6.58(s,1H),5.8(d,J＝9.6Hz,1H),5.82(d,J＝1.6Hz,1H),5.77(d,J＝1.6Hz,1H),5.11(s,1H) , 3.78(d, J＝9.6Hz, 1H), 3.74(s, 3H), 3.50(s, 3H), 3.32–3.20(m, 1H), 3.13–3.02(m, 1H), 2.94(td, J =11.6,7.0 Hz,1H),2.81(tt,J=9.7,5.1Hz,1H),2.69(p,J=8.7Hz,2H),2.45–2.30(m,2H),2.20(dd,J= 16.8, 8.8Hz, 1H), 2.11–1.97 (m, 3H), 1.97–1.85 (m, 1H), 1.80–1.69 (m, 2H), 1.52 (s, 9H).

Mass spectrum: HRMS-ESI (m/z): [M+H] ⁺ , [C ₃₅ H ₄₃ N ₂ O ₉ ] ⁺ found 635.2956.

Example 2: Synthesis of Compound 2

Take 190 mg of compound 1 (0.3 mmol), add 1 mL of trifluoroacetic acid (TFA) and 5 mL of DCM (dichloromethane), and react at room temperature for 10 h. Adjust the pH to 8 with 1 mol/L NaOH, add 10 mL of water, extract three times with DCM, combine the organic layers, wash with saturated sodium chloride solution once, dry with anhydrous sodium sulfate, spin off the organic solution, and use silica gel column chromatography (petroleum) for the residue. Ether:ethyl acetate (V:V)=1:2) was purified to obtain 150 mg of compound 2 (94% yield). The obtained compound 2 was taken to detect the hydrogen spectrum and mass spectrum, and the results were as follows: hydrogen spectrum: ¹ H NMR (600MHz, Chloroform-d)δ6.74(d,J=7.7Hz,2H),6.60(d,J=6.2Hz,2H ),6.55(d,J＝7.8Hz,2H),5.89(d,J＝9.7Hz,1H),5.83(d,J＝1.6Hz,1H),5.77(d,J＝1.6Hz,1H), 5.04(s,1H),3.79(d,J=9.7Hz,1H),3.71(s,3H),3.55(s,3H),3.26(td,J=13.1,7.8Hz,1H),3.09(td , J=8.9, 4.5Hz, 1H), 2.95 (td, J=11.7, 7.4 Hz, 1H), 2.74–2.68 (m, 1H), 2.64–2.56 (m, 2H), 2.39 (dd, J=14.4 ,7.0Hz,1H),2.27–2.19(m,2H), 2.09–2.01(m,2H),1.94–1.86(m,2H),1.80–1.70(m,2H).

Mass spectrum: HRMS-ESI (m/z): [M+H] ⁺ calcd for [C ₃₀ H ₃₅ N ₂ O ₇ ] ⁺ , found 535.2435.

Example 3: Synthesis of Compound 3

The synthetic method refers to the synthetic method of compound 1 in Example 1, replaces tert-butyl 4-formylphenylcarbamate (31.0 mmol) with compound 3-1 (31.0 mmol), and the rest of the operations refer to Example 1 to obtain compound 3 . The obtained compound 3 was taken to detect the hydrogen spectrum and mass spectrum, and the results were as follows: ¹ H NMR (400MHz, Chloroform-d)δ7.81-7.69(m,3H),7.50-7.36(m,3H),7.11(dd,J=8.4 , 1.8Hz,1H),6.63(s,2H),5.92(d,J＝9.6Hz,1H),5.82(d,J＝1.6Hz,1H),5.74(d,J＝1.6Hz,1H), 5.07(s,1H),3.82(d,J=9.6Hz,1H),3.72(s,3H),3.52(s,3H),3.36–3.26(m,1H),3.16–3.06(m,1H) ,3.03-2.86(m,2H),2.72-2.58(m,2H),2.52(dd,J＝13.9,5.2Hz,1H),2.43(dd,J＝14.3,6.9Hz,1H),2.33-2.21 (m, 2H), 2.13–2.04 (m, 2H), 1.99–1.90 (s, 1H), 1.82–1.72 (m, 2H). Mass spectrum: HRMS-ESI (m/z): [M+H] ⁺ calcd for [C ₃₄ H ₃₆ NO ₇ ] ⁺ , found 570.2480.

Example 4: Synthesis of Compound 4

The synthetic method refers to the synthetic method of compound 1 in Example 1, and replaces tert-butyl 4-formylphenylcarbamate (31.0 mmol) with compound 4-1 (31.0 mmol), and other operations refer to Example 1 to obtain compound 4 . The obtained compound 4 was taken to detect hydrogen spectrum and mass spectrum, and the results were as follows: ¹ H NMR (400MHz, Chloroform-d)δ7.44-7.30(m,5H),6.91-6.81(m,4H),6.61(d,J=2.9 Hz, 2H), 5.90(d, J＝9.6Hz, 1H), 5.83(d, J＝1.6Hz, 1H), 5.77(d, J＝1.6Hz, 1H), 5.06(s, 1H), 5.02( s, 2H), 3.80(d, J=9.6Hz, 1H), 3.72(s, 3H), 3.56(s, 3H), 3.32-3.23(m, 1H), 3.14-3.04(m, 1H), 2.96 (td, J=11.6, 7.0Hz, 1H), 2.76 (ddt, J=10.6, 9.0, 4.3Hz, 1H), 2.68–2.56 (m, 2H), 2.41 (dd, J=14.3, 6.9Hz, 1H) ), 2.33 (dd, J=14.0, 5.3Hz, 1H), 2.25 (dd, J=16.8, 8.7Hz, 1H), 2.10–2.00 (m, 3H), 1.96–1.88 (m, 1H), 1.81– 1.72 (m, 2H). Mass spectrum: HRMS-ESI (m/z): [M+H] ⁺ calcd for [C ₃₇ H ₄₀ NO ₈ ] ⁺ , found 626.2741.

Example 5: Synthesis of Compound 5

Compound 4 (0.15 mmol) was taken, 20 mg of Pd-C and 5 mL of methanol were added, and the reaction was carried out under 1 atm hydrogen at room temperature for 10 h. The solid was removed by suction filtration, the organic solution was spun off, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain 78 mg of compound 5 (yield 97%). The obtained compound 5 was taken to detect the hydrogen spectrum and mass spectrum, and the results were as follows: ¹ H NMR (400MHz, Chloroform-d) δ6.76(d, J=8.0Hz, 2H), 6.60(d, J=13.0Hz, 4H), 5.89 (d, J＝9.6Hz, 1H), 5.75(s, 2H), 5.05(s, 1H), 3.80(d, J＝9.6 Hz, 1H), 3.71(s, 3H), 3.55(s, 3H) ,3.33-3.20(m,1H),3.13-3.05(m,1H),2.98(td,J=11.6,7.0Hz,1H),2.78-2.69(m,1H),2.67-2.57(m,2H) , 2.41(dd, J=14.3, 6.9Hz, 1H), 2.31–2.17 (m, 2H), 2.10– 1.89 (m, 4H), 1.82–1.71 (m, 2H). Mass spectrum: HRMS-ESI (m/ z): [M+H] ⁺ calcd for [C ₃₀ H ₃₄ NO ₈ ] ⁺ , found 536.2273.

Example 6: Synthesis of Compound 6

The synthetic method refers to the synthetic method of compound 1 in Example 1, and tert-butyl 4-formylphenylcarbamate (31.0 mmol) is replaced with compound 6-1 (31.0 mmol), and the rest operations refer to Example 1 to obtain compound 6 . The obtained compound 6 was taken to detect hydrogen spectrum and mass spectrum, and the results are as follows: ¹ H NMR (400MHz, Chloroform-d)δ7.29-7.18(m, 3H), 7.03-6.97(m, 2H), 6.64(d, J=2.7 Hz, 2H), 5.93(d, J＝9.6Hz, 1H), 5.86(d, J＝1.6Hz, 1H), 5.80(d, J＝1.6Hz, 1H), 5.09(s, 1H), 3.83( d, J = 9.6Hz, 1H), 3.75(s, 3H), 3.58(s, 3H), 3.35-3.25(m, 1H), 3.16-3.09(m, 1H), 3.02-2.93(m, 1H) , 2.86–2.77 (m, 1H), 2.69–2.58 (m, 2H), 2.47–2.37 (m, 2H), 2.29 (dd, J=16.8, 8.7Hz, 1H), 2.11–2.04 (m, 3H) , 1.97–1.90 (m, 1H), 1.83–1.73 (m, 2H). Mass spectrum: HRMS-ESI (m/z): [M+H] ⁺ calcd for

[ _{C30H34NO7 ]} ⁺ , found _520.2324 .

Example 7: Synthesis of Compound 7

Synthesis method Refer to the synthesis method of compound 1f in Example 1, replace tert-butyl 4-formylphenylcarbamate (31.0 mmol) with compound 6-1 (31.0 mmol), and replace the catalyst Ru[(R)-DTBM- SegPhos](OAc) ₂ was replaced with Ru[(S)-DTBM-SegPhos](OAc) ₂ , and the remaining operations were referred to in Example 1 to obtain compound 7. The obtained compound 7 was taken to detect hydrogen spectrum and mass spectrum, and the results were as follows: ¹ H NMR (600MHz, Chloroform-d)δ7.23(t, J=7.5Hz, 2H), 7.17(t, J=7.4Hz, 1H), 7.02 (d, J＝7.4Hz, 2H), 6.66(s, 1H), 6.59(s, 1H), 5.87(d, J＝9.6Hz, 1H), 5.86(d, J＝2.1Hz, 1H), 5.82 (d, J=2.1Hz, 1H), 5.03(s, 1H), 3.78 (d, J=9.6Hz, 1H), 3.67(s, 3H), 3.56(s, 3H), 3.22–3.15(m, 1H), 3.13–3.05 (m, 1H), 2.96 (td, J=11.6, 7.0Hz, 1H), 2.80–2.70 (m, 2H), 2.66–2.57 (m, 2H), 2.39 (dd, J= 14.5, 7.0Hz, 1H), 2.15–2.06 (m, 2H), 2.05–1.97 (m, 2H), 1.95–1.88 (m, 1H), 1.81–1.72 (m, 2H). Mass spectrum: HRMS-ESI ( m/z): [M+H] ⁺ calcd for [C ₃₀ H ₃₄ NO ₇ ] ⁺ , found 520.2325.

Example 8: Synthesis of Compound 8

The synthetic method refers to the synthetic method of compound 1 in Example 1, and replaces tert-butyl 4-formylphenylcarbamate (31.0 mmol) with compound 8-1 (31.0 mmol), and other operations refer to Example 1 to obtain compound 8 . The obtained compound 8 was taken to detect the hydrogen spectrum and mass spectrum, and the results were as follows: ¹ H NMR (400MHz, Chloroform-d)δ6.95-6.88(m, 4H), 6.59(d, J=5.0Hz, 2H), 5.89(d, J＝9.6 Hz, 1H), 5.83(d, J＝1.5Hz, 1H), 5.79(d, J＝1.5Hz, 1H), 5.06(s, 1H), 3.79(d, J＝9.6Hz, 1H) , 3.71(s, 3H), 3.57(s, 3H), 3.25(ddd, J=14.1, 12.2, 7.8Hz, 1H), 3.09(td, J=8.5, 5.1Hz, 1H), 2.95(td, J ＝11.6, 7.0Hz, 1H), 2.80-2.71(m,1H), 2.65-2.54(m,2H), 2.44-2.34(m,2H), 2.27-2.20(m,1H), 2.16-2.08(m ,1H),2.07–1.99(m,2H),1.94–1.86(m,1H),1.80–1.69(m,2H).Mass spectrum: HRMS-ESI(m/z):[M+H] ⁺ calcd for[ _{C30H33FNO7 ]} ⁺ , found _538.2231 .

Example 9: Synthesis of Compound 9

Synthesis method Referring to the synthesis method of compound 1f in Example 1, tert-butyl 4-formylphenylcarbamate (31.0 mmol) was replaced with compound 8-1 (31.0 mmol), and the catalyst Ru[(R)-DTBM- SegPhos](OAc) ₂ was replaced with Ru[(S)-DTBM-SegPhos](OAc) ₂ , and the remaining operations were referred to in Example 1 to obtain compound 9. The obtained compound 9 was taken to detect the hydrogen spectrum and mass spectrum, and the results were as follows: ¹ H NMR (400MHz, Chloroform-d)δ7.02-6.97(m,2H),6.95-6.88(m,2H),6.64(s,1H), 6.58(s, 1H), 5.86(d, J＝1.6Hz, 1H), 5.85(d, J＝9.5Hz, 1H), 5.83(d, J＝1.6Hz, 1H), 5.03(s, 1H), 3.77(d, J=9.5Hz, 1H), 3.67(s, 3H), 3.58(s, 3H), 3.22–3.06(m, 2H), 3.00–2.90(m, 1H), 2.77–2.54(m, 4H), 2.38 (dd, J=14.3, 6.9Hz, 1H), 2.22 (dd, J=13.6, 7.7Hz, 1H), 2.09–1.88 (m, 4H), 1.80–1.71 (m, 2H). MS : HRMS-ESI(m/z): [M +H] ⁺ calcd for [C ₃₀ H ₃₃ FNO ₇ ] ⁺ , found 538.2231.

Example 10: Synthesis of Compound 10

The synthetic method refers to the synthetic method of compound 1 in Example 1, and tert-butyl 4-formylphenylcarbamate (31.0 mmol) is replaced with compound 10-1 (31.0 mmol), and the rest operations refer to Example 1 to obtain compound 10 . The obtained compound 10 was taken to detect the hydrogen spectrum and mass spectrum, and the results were as follows: ¹ H NMR (600MHz, Chloroform-d)δ7.45-7.41(m, 2H), 7.41-7.37(m, 2H), 7.35-7.31(m, 1H) ),7.15(t,J=7.9Hz,1H),6.82-6.77(m,1H),6.63(t,J=2.1Hz,1H),6.61-6.57(m,3H),5.90(d,J= 9.6Hz, 1H), 5.83(d, J=1.6Hz, 1H), 5.77(d, J=1.6Hz, 1H), 5.06(s, 1H), 5.03(s, 2H), 3.80(d, J= 9.6 Hz, 1H), 3.71 (s, 3H), 3.57 (s, 3H), 3.30–3.23 (m, 1H), 3.12–3.07 (m, 1H), 2.95 (td, J=11.7, 7.1Hz, 1H) ), 2.82–2.76 (m, 1H), 2.64–2.56 (m, 2H), 2.39 (dd, J=14.3, 7.0Hz, 1H), 2.33 (dd, J=13.8, 5.1Hz, 1H), 2.25 ( dd, J=16.9, 8.9Hz, 1H), 2.09–1.98 (m, 3H), 1.94–1.88 (m, 1H), 1.80–1.71 (m, 2H). Mass spectrum: HRMS-ESI (m/z): [M+H] ⁺ calcd for [C ₃₇ H ₄₀ NO ₈ ] ⁺ , found 626.2741.

Example 11: Synthesis of Compound 11

Compound 10 (0.15 mmol) was taken, 20 mg of Pd-C and 5 mL of methanol were added, and the reaction was carried out at room temperature under 1 atm hydrogen for 10 h. The solid was removed by suction filtration, the organic solution was spun off, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain compound 11. The obtained compound 11 was taken to detect the hydrogen spectrum and mass spectrum, and the results were as follows: ¹ H NMR (400MHz, Chloroform-d)δ7.06(t, J=7.8Hz, 1H), 6.65 -6.58(m, 3H), 6.49(d, J=7.5Hz, 1H), 6.39(t, J=2.0Hz, 1H), 5.89(d, J=9.6Hz, 1H), 5.79(s, 2H), 5.06(s, 1H), 3.81(d, J=9.6Hz, 1H), 3.72(s, 3H), 3.56(s, 3H), 3.32-3.21(m, 1H), 3.14-3.06(m, 1H), 2.97(td, J=11.6, 7.1Hz , 1H), 2.81–2.73 (m, 1H), 2.67–2.58 (m, 2H), 2.41 (dd, J=14.3, 6.9Hz, 1H), 2.35–2.20 (m, 2H), 2.12–1.89 (m , 4H), 1.82-1.72 (m, 2H). Mass spectrum: HRMS-ESI (m/z): [M+H] ⁺ calcd for [C ₃₀ H ₃₄ NO ₈ ] ⁺ , found 536.2275.

Example 12: Synthesis of Compound 12

The synthetic method refers to the synthetic method of compound 1 in Example 1, replaces tert-butyl 4-formylphenylcarbamate (31.0 mmol) with compound 12-1 (31.0 mmol), and the rest operations refer to Example 1 to obtain compound 12 . The obtained compound 12 was taken to detect the hydrogen spectrum and mass spectrum, and the results were as follows: ¹ H NMR (400MHz, Chloroform-d) δ7.19 (td, J=7.9, 6.0Hz, 1H), 6.90-6.83 (m, 1H), 6.76 ( dt, J＝7.6,1.2Hz,1H),6.72(dt,J＝9.7,2.1Hz,1H),6.60(d,J＝7.1Hz,2H),5.89(d,J＝9.6Hz,1H), 5.84(d,J＝1.6Hz,1H),5.79(d,J＝1.6Hz,1H),5.06(s,1H),3.79(d,J＝9.6Hz,1H),3.72(s,3H), 3.57 (s, 3H), 3.30–3.20 (m, 1H), 3.12–3.05 (m, 1H), 2.95 (td, J=11.6, 7.0Hz, 1H), 2.82–2.74 (m, 1H), 2.66– 2.55 (m, 2H), 2.44–2.34 (m, 2H), 2.26–2.11 (m, 2H), 2.06–1.98 (m, 2H), 1.95–1.86 (m, 1H), 1.80– 1.70 (m, 2H) ). Mass spectrum: HRMS-ESI (m/z): [M+H] ⁺ calcd for [C ₃₀ H ₃₃ FNO ₇ ] ⁺ , found 538.2228.

Example 13: Synthesis of Compound 13

Synthetic method Referring to the synthesis method of compound 1 in Example 1, tert-butyl 4-formylphenylcarbamate (31.0 mmol) was replaced with compound 13-1 (31.0 mmol), and methanol in step 3 was replaced with ethanol , and other operations refer to Example 1 to obtain compound 13. The obtained compound 13 was taken to detect the hydrogen spectrum and mass spectrum, and the results were as follows: ¹ H NMR (400MHz, Chloroform-d)δ7.45-7.30(m,5H),6.92-6.81(m,4H),6.61(s,2H), 5.91(d,J＝9.6Hz,1H),5.82(d,J＝1.5Hz,1H),5.76(d,J＝1.5Hz,1H), 5.06(s,1H),5.02(s,2H), 4.05-3.97(m, 2H), 3.80(d, J=9.6Hz, 1H), 3.71(s, 3H), 3.34-3.23(m, 1H), 3.14-3.05(m, 1H), 2.96(td, J=11.6, 7.1Hz, 1H), 2.81–2.71 (m, 1H), 2.69–2.56 (m, 2H), 2.41 (dd, J=14.2, 6.9Hz, 1H), 2.34–2.21 (m, 2H) ,2.09-1.99(m,3H),1.95-1.88(m,1H),1.81-1.71(m,2H), 1.18(t,J=7.1Hz,3H).Mass Spectrum: HRMS-ESI(m/z) :[M+H] ⁺ calcd for [C ₃₈ H ₄₂ NO ₈ ] ⁺ , found 640.2896.

Example 14: Synthesis of Compound 14

Take compound 13 (0.15 mmol), add 20 mg of Pd-C and 5 mL of methanol, and react at room temperature for 10 h under 1 atm hydrogen. The solid was removed by suction filtration, the organic solvent was spun off, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain compound 14. The obtained compound 14 was taken to detect the hydrogen spectrum and mass spectrum, and the results were as follows: ¹ H NMR (400MHz, Chloroform-d) δ6.77(d, J=8.3Hz, 2H), 6.64-6.53(m, 4H), 5.89(d, J=9.6Hz, 1H), 5.75(q, J=1.6Hz, 2H), 5.05(s, 1H), 4.06–3.96(m, 2H), 3.80(d, J=9.6Hz, 1H), 3.70( s, 3H), 3.32–3.22 (m, 1H), 3.12–3.04 (m, 1H), 2.97 (td, J=11.5, 7.0Hz, 1H), 2.78–2.68 (m, 1H), 2.66–2.56 ( m, 2H), 2.41 (dd, J=14.3, 6.9 Hz, 1H), 2.30–2.18 (m, 2H), 2.08– 2.02 (m, 2H), 1.98–1.88 (m, 2H), 1.82–1.69 ( m, 2H), 1.17 (t, J=7.1 Hz, 3H). Mass spectrum: HRMS-ESI (m/z): [M+H] ⁺ calcd for [C ₃₁ H ₃₆ NO ₈ ] ⁺ , found 550.2430.

Example 15: Synthesis of Compound 15

The synthetic method refers to the synthetic method of compound 1 in Example 1, and replaces tert-butyl 4-formylphenylcarbamate (31.0 mmol) with compound 15-1 (31.0 mmol), and the rest operations refer to Example 1 to obtain compound 15 . The obtained compound 15 was taken to detect the hydrogen spectrum and mass spectrum, and the results were as follows: ¹ H NMR (400MHz, Chloroform-d)δ7.21(d, J=8.2Hz, 1H), 7.13(t, J=7.8Hz, 1H), 6.95 (s, 1H), 6.62 (dd, J=10.0, 7.2Hz, 3H), 6.51 (s, 1H), 5.89 (d, J=9.6Hz, 1H), 5.82 (d, J=1.5Hz, 1H) ,5.79(d,J＝1.6Hz,1H),5.05(s,1H),3.79(d,J＝9.6Hz,1H),3.71(s,3H),3.55(s,3H),3.32–3.20( m, 1H), 3.13–3.03 (m, 1H), 2.94 (td, J=11.6, 7.0Hz, 1H), 2.78 (tt, J=9.7, 5.1Hz, 1H), 2.61 (p, J=8.7Hz) , 2H), 2.45–2.31 (m, 2H), 2.24 (dd, J=16.8, 8.8Hz, 1H), 2.10–1.97 (m, 3H), 1.95–1.85 (m, 1H), 1.80–1.69 (m , 2H), 1.51 (s, 9H). Mass spectrum: HRMS-ESI (m/z): [M+H] ⁺ calcd for [C ₃₅ H ₄₃ N ₂ O ₉ ] ⁺ , found 635.2953.

Example 16: Synthesis of Compound 16

The synthetic method refers to the synthetic method of compound 1 in Example 2, and tert-butyl 4-formylphenylcarbamate (31.0 mmol) is replaced with compound 16-1 (31.0 mmol), and the remaining operations refer to Example 1 to obtain compound 16 . The obtained compound 16 was taken to detect the hydrogen spectrum and mass spectrum, and the results were as follows: ¹ H NMR (400MHz, Chloroform-d) δ7.00 (t, J=7.7Hz, 1H), 6.61 (d, J=4.2Hz, 2H), 6.49 (dd, J＝7.8, 2.3Hz, 1H), 6.36 (d, J＝7.5Hz, 1H), 6.28 (t, J＝2.0Hz, 1H), 5.89 (d, J＝9.6Hz, 1H), 5.83 (d,J＝1.6Hz,1H),5.79(d,J＝1.6Hz,1H),5.05(s,1H),3.80(d,J＝9.6Hz,1H),3.72(s,3H),3.56 (s, 3H), 3.42–3.20 (m, 3H), 3.14–3.04 (m, 1H), 2.95 (td, J=11.6, 7.1Hz, 1H), 2.75 (tt, J=9.8, 4.9Hz, 1H) ), 2.65–2.55 (m, 2H), 2.40 (dd, J=14.3, 6.9Hz, 1H), 2.33–2.19 (m, 2H), 2.14–1.99 (m, 2H), 1.95–1.86 (m, 2H ), 1.80–1.71 (m, 2H). Mass spectrum: HRMS-ESI (m/z): [M+H] ⁺ calcd for [C ₃₀ H ₃₅ N ₂ O ₇ ] ⁺ , found 535.2433.

Example 17: Synthesis of Compound 17

The synthetic method refers to the synthetic method of compound 1 in Example 1, and tert-butyl 4-formylphenylcarbamate (31.0 mmol) is replaced with compound 17-1 (31.0 mmol), and the remaining operations refer to Example 1 to obtain compound 17 . The obtained compound 17 was taken to detect the hydrogen spectrum and mass spectrum, and the results were as follows: ¹ H NMR (400MHz, Chloroform-d)δ7.48-7.30(m, 5H), 7.15(td, J=7.7, 1.8Hz, 1H), 6.96 ( dd, J=7.6, 1.8Hz, 1H), 6.89–6.81(m, 2H), 6.62(s, 1H), 6.54(s, 1H), 5.91(d, J=9.6Hz, 1H), 5.81(d , J＝1.6Hz, 1H), 5.72(d, J＝1.6Hz, 1H), 5.07(s, 3H), 3.81(d, J＝9.6Hz, 1H), 3.73(s, 3H), 3.49(s , 3H), 3.28–3.18 (m, 1H), 3.13–3.00 (m, 2H), 2.91 (td, J=11.6, 7.0Hz, 1H), 2.64–2.47 (m, 3H), 2.33–2.14 (m ,3H),2.12–1.99(m,2H),1.96–1.88(m,1H),1.82–1.72(m,2H).Mass spectrum: HRMS-ESI(m/z):[M+H] ⁺ calcdfor[ _{C37H40NO8 ]} ⁺ , found _626.2741 .

Example 18: Synthesis of Compound 18

The synthetic method refers to the synthetic method of compound 1 in Example 1, and tert-butyl 4-formylphenylcarbamate (31.0 mmol) is replaced with compound 18-1 (31.0 mmol), and the remaining operations refer to Example 1 to obtain compound 18 . The obtained compound 18 was taken to detect the hydrogen spectrum and mass spectrum, and the results were as follows: ¹ H NMR (400MHz, Chloroform-d) δ7.04 (td, J=7.7, 1.7Hz, 1H), 6.88 (d, J=7.9Hz, 1H) , 6.75(d,J＝6.9Hz,2H),6.59(d,J＝7.8Hz,2H),5.88(d,J＝9.4Hz,1H),5.82(d,J＝1.5Hz,1H),5.80 (d, J=1.5Hz, 1H), 5.06(s, 1H), 3.80(d, J=9.4Hz, 1H), 3.72(s, 3H), 3.59(s, 3H), 3.32–3.21(m, 1H), 3.17–3.00 (m, 2H), 2.80 (p, J=6.9Hz, 1H), 2.72–2.60 (m, 2H), 2.51–2.39 (m, 2H), 2.32–2.22 (m, 2H) ,2.17–2.05(m,2H),1.98–1.90(m,1H),1.84–1.74(m,2H).Mass spectrum: HRMS-ESI(m/z):[M+H] ⁺

calcd for [C ₃₀ H ₃₄ NO ₈ ] ⁺ , found 536.2275.

Example 19: Synthesis of Compound 19

The synthetic method refers to the synthetic method of compound 1 in Example 1, and replaces tert-butyl 4-formylphenylcarbamate (31.0 mmol) with compound 19-1 (31.0 mmol), and the rest operations refer to Example 1 to obtain compound 19 . The obtained compound 19 was taken to detect the hydrogen spectrum and mass spectrum, and the results were as follows: ¹ H NMR (400MHz, Chloroform-d)δ7.34(d, J=8.1Hz, 2H), 6.84(d, J=8.1Hz, 2H), 6.59 (d, J＝1.9Hz, 2H), 5.88(d, J＝9.6Hz, 1H), 5.83(d, J＝1.5Hz, 1H), 5.79(d, J＝1.5Hz, 1H), 5.05(s ,1H), 3.79(d,J＝9.6Hz,1H),3.71(s,3H),3.56(s,3H),3.24(ddd,J＝14.0,12.3,7.7Hz,1H),3.09(td, J=8.9, 5.5Hz, 1H), 2.98 (td, J=11.6, 7.0Hz, 1H), 2.80–2.72 (m, 1H), 2.66–2.54 (m, 2H), 2.42–2.30 (m, 2H) , 2.23(dd,J＝16.9,8.1Hz,1H),2.15-2.04(m,2H),2.03-2.98(m,1H),1.94-1.87(m,1H),1.81-1.70(m,2H) . Mass spectrum: HRMS-ESI (m/z): [M+H] ⁺ calcd for [C ₃₀ H ₃₃ BrNO ₇ ] ⁺ , found 598.1429.

Example 20: Synthesis of Compound 20

The synthetic method refers to the synthetic method of compound 1 in Example 1, replaces tert-butyl 4-formylphenylcarbamate (31.0 mmol) with compound 20-1 (31.0 mmol), and the rest of the operations refer to Example 1 to obtain compound 20 . The obtained compound 20 was taken to detect the hydrogen spectrum and mass spectrum, and the results were as follows: ¹ H NMR (400MHz, Chloroform-d)δ7.47(d, J=7.5Hz, 1H), 7.16 (t, J=7.4Hz, 1H), 7.08 – 6.98(m, 2H), 6.60(d, J=6.7Hz, 2H), 5.88(d, J=9.6Hz, 1H), 5.82(d, J=1.6Hz, 1H), 5.79(d, J= 1.6 Hz, 1H), 5.05(s, 1H), 3.79(d, J=9.6Hz, 1H), 3.71(s, 3H), 3.53(s, 3H), 3.30–3.20(m, 1H), 3.11– 3.05 (m, 1H), 3.00–2.88 (m, 2H), 2.66–2.48 (m, 3H), 2.40 (dd, J=14.3, 7.0Hz, 1H), 2.35–2.22 (m, 2H), 2.10– 1.98(m,2H),1.94–1.86(m,1H),1.79–1.69(m,2H).Mass spectrum: HRMS-ESI(m/z):[M+H] ⁺ calcd for [C ₃₀ H ₃₃ BrNO ₇ ] ⁺ , found 598.1429.

Example 21: Synthesis of Compound 21

The synthetic method refers to the synthetic method of compound 1 in Example 1, and replaces tert-butyl 4-formylphenylcarbamate (31.0 mmol) with compound 21-1 (31.0 mmol), and the remaining operations refer to Example 1 to obtain compound 21 . The obtained compound 21 was taken to detect the hydrogen spectrum and mass spectrum, and the results were as follows: ¹ H NMR (600MHz, Chloroform-d)δ7.31(d, J=8.0Hz, 1H), 7.19-7.15(m, 1H), 7.10(t, J＝7.8Hz,1H),6.91(d,J＝7.6Hz,1H),6.60(d,J＝10.6Hz,2H),5.88(d,J＝9.6Hz,1H),5.84(d,J＝ 1.6 Hz, 1H), 5.79(d, J=1.6Hz, 1H), 5.06(s, 1H), 3.79(d, J=9.6Hz, 1H), 3.73(s, 3H), 3.57(s, 3H) , 3.28– 3.20 (m, 1H), 3.09 (td, J=9.0, 4.7Hz, 1H), 2.95 (td, J=11.6, 7.1Hz, 1H), 2.81–2.74 (m, 1H), 2.66– 2.56 (m, 2H), 2.40 (dd, J=14.4, 7.0Hz, 1H), 2.36–2.32 (m, 1H), 2.22 (dd, J=16.8, 8.1Hz, 1H), 2.10 (dd, J=14.0 ,9.2Hz,1H),2.06–1.99(m,2H),1.94–1.88(m,1H),1.80–1.70(m,2H).Mass Spectrum: HRMS-ESI(m/z):[M+H] ⁺ calcd for [C ₃₀ H ₃₃ BrNO ₇ ] ⁺ , found 598.1428.

Example 22: Cell proliferation inhibition experiment

1. Detection method

The inhibitory effect of compounds on cell proliferation was detected with CCK-8 cell counting kit (Dojindo). Specific steps are as follows:

1) Cell seeding: inoculate K562 cells (human chronic myeloid leukemia cells) and HL60 cells (pro-leukemia cells) at the same density in different 96-well plates (3000-10000 cells/100 μl/well). Myeloid cells), U937 cells (human histiocytic lymphoma cells), K562 (T315I) cells (T351I mutant human chronic myeloid leukemia cells) and other tumor cells.

2) Working solution preparation: take the corresponding medium required for cell culture as the dilution of the vehicle control group (with or without the vehicle DMSO, and without test compounds and control compounds); take the corresponding medium required for cell culture as the dilution (with or without vehicle DMSO), dilute the test compound and reference compound stock solution to obtain the working solution of the dosing experimental group with a series concentration of 2 times the final concentration, the content of the vehicle DMSO in each concentration group is compared with the vehicle group consistent.

3) Co-incubation:

Dosing experimental group: After 24 hours of inoculation, the working solution of the dosing experimental group with a series of compound concentrations was added to the 96-well plate in an amount of 100 μl/well, and the mixture was mixed for 72 hours. All groups have at least 3 duplicate wells, each compound has 6 concentrations, to obtain drug-added experimental groups of each compound and each concentration.

Vehicle control group (that is, adding medium and cells, without adding drugs): 24 hours after inoculation, add the dilution of the vehicle control group to the 96-well plate in an amount of 100 μl/well, at least 3 duplicate wells, and co-culture after mixing. 72h, as the vehicle control group.

Blank control group: only medium, no cells and drugs, to exclude the interference of medium contrast color.

4) Absorbance measurement: after sucking the medium from the 96-well plate, add 10 μl of CCK-8 solution to each well, after co-cultivation for 4 hours, fully shake to make it uniform, and use 450 nm as the detection wavelength on the microplate reader and 650 nm as the reference. Absorbance was measured by wavelength.

5) Data processing: The cell viability of each treated well is obtained by the obtained absorbance value (the calculation method is as follows); then the cell viability data and the corresponding compound concentration are input into the GraphPad Prism 8.0Demo software, and the nonlinear regression model is used to calculate _IC50 values of compounds against different cells.

Calculation of cell viability: cell viability (%)=[(As-Ac)/(Ab-Ac)]×100%] (As: absorbance of the wells in the drug-added experimental group; Ab: wells in the vehicle control group The absorbance value of ; Ac: the absorbance value of the wells of the blank control group).

2. Experimental results

The experimental results are shown in Table 1 and Table 2.

Table 1: Anti-leukemia cell activity data for compounds

Table 2: Compound activity data on K562(T315I) cells

Compound number IC₅₀(μM)-K562(T315I) Compound 2 0.246±0.037 Imatinib 12.2±2.1

The above-mentioned compounds are respectively selected from the compounds prepared in Examples 1-21, and are represented by numbers in Table 1 and Table 2.

3. Experimental conclusion

From the data in Table 1 and Table 2, we can see that the compounds of the experimental examples of the present invention have good inhibitory effects on three leukemia cells, and their activities are significantly better than imatinib in HL60 cells and U937 cells. Compounds 2, 4, 5, 6, and 12 were more active than imatinib in K562 cells, with an IC ₅₀ of less than 0.135 μM, showing potential therapeutic effects. The mutation of T315I is an important reason for the failure of clinical imatinib treatment. K562 cells with T351 I mutation are resistant to imatinib. Compound 2 inhibits this cell with an IC ₅₀ of 0.246 μM, which has the potential to treat imatinib resistance. The therapeutic effect of drugs in chronic myeloid leukemia.

The method of the present invention has been described through the preferred embodiments, and it is obvious that relevant persons can modify or appropriately change and combine the methods and applications described herein within the content, spirit and scope of the present invention to realize and apply the technology of the present invention . Those skilled in the art can refer to the content of this document to appropriately improve the process parameters to achieve. It should be particularly pointed out that all similar substitutions and modifications apparent to those skilled in the art are deemed to be included in the present invention.

Claims (11)

1. The compound represented by formula (I) or its stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof,

in, Ring A is C _6-14 aryl or 5-12 membered heteroaryl; R ¹ is H, C _1-6 alkyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 1,2-dichloroethyl, 2-fluoropropyl or 3-fluoropropyl; R ² is H, D, F, Cl, Br, I, OH, CN, NO ₂ , NH ₂ , COOH, CF ₃ , -OBn, -N(H)-Boc, -N(CH ₃ ) ₂ , - S(=O) ₂ CH ₃ , -OCH ₃ , C _{1-6 alkyl, C 1-6 haloalkyl or C 1-6 alkoxy ;} *The indicated site is in R configuration or S configuration. 2. The compound according to claim 1 or its stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein the A ring is C _6-14 aryl; and/or The A ring is phenyl or naphthyl; and/or Said R ¹ is C _1-6 alkyl; and/or The C _1-6 alkyl group is selected from methyl, ethyl, n-propyl, isopropyl or tert-butyl; and/or The C _1-6 haloalkyl group is selected from the group consisting of C _1-6 fluoroalkyl group, C _1-6 chloroalkyl group or C _1-6 bromoalkyl group. 3. The compound according to any one of claims 1-2 or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein The compounds include structures selected from the group consisting of:

4. A pharmaceutical composition comprising the compound of any one of claims 1-3 or its stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable Salts or prodrugs thereof, and optionally pharmaceutically acceptable excipients. 5. A compound according to any one of claims 1-3 or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof, Or the use of the pharmaceutical composition of claim 4 in the preparation of a medicament for preventing, treating or alleviating cancer. 6. The use according to claim 5, wherein the cancer comprises: lymphoma or leukemia; or the cancer comprises: chronic myeloid leukemia, T3511 mutated chronic myeloid leukemia, lymphocytic leukemia, lymphoma or promyelocyst myeloid leukemia. 7. A compound for preparing any one of claims 1-3 or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof The method for the compound shown in formula (I) in, it comprises:

The compound of formula (II) and the compound of formula (III) are reacted in solvent a in the presence of catalyst A, a condensing agent and a base to obtain the compound of formula (I), the site marked by * is R configuration or S configuration . 8. The method according to claim 7, wherein the catalyst A comprises at least one selected from the group consisting of 4-dimethylaminopyridine, HATU and TBTU; and/or The condensing agent comprises at least one selected from 2-chloro-1-methylpyridinium iodide and PyBop; and/or The base comprises at least one selected from triethylamine and N,N-diisopropylethylamine; and/or The solvent a includes at least one selected from toluene and N,N-dimethylformamide. 9. Use of Ru[(S)-DTBM-SegPhos](OAc) ₂ or Ru[(R)-DTBM-SegPhos](OAc) ₂ in catalyzing asymmetric hydrogenation of a compound containing a carbon-carbon double bond. 10. A preparation method of a compound of formula (V), comprising:

In the presence of catalyst B and solvent b, the compound of formula (IV) reacts with hydrogen under certain pressure and temperature to obtain the compound of formula (V); Wherein, the site indicated by * is R configuration or S configuration; Ring A is C _6-14 aryl or 5-12 membered heteroaryl; R ² is H, D, F, Cl, Br, I, OH, CN, NO ₂ , NH ₂ , COOH, CF ₃ , -OBn, -N(H)-Boc, -N(CH ₃ ) ₂ , - S(=O) ₂ CH ₃ , -OCH ₃ , C _1-6 alkyl, C _1-6 haloalkyl or C _1-6 alkoxy. 11. The preparation method according to claim 9, wherein the catalyst is Ru[(S)-DTBM-SegPhos](OAc) ₂ , and the site marked by * is R configuration; or The catalyst is Ru[(R)-DTBM-SegPhos](OAc) ₂ , and the site indicated by * is S configuration; and/or The solvent b comprises at least one selected from methanol, dichloromethane and toluene; and/or The certain pressure is 10-30 standard atmospheres; or the certain pressure is 20 standard atmospheres; and/or The certain temperature is 10-50°C.