TW202106693A - A indole macrocyclic derivative, a preparation method thereof, and medical use thereof - Google Patents

Abstract

The present disclosure relates a indole macrocyclic derivative, a preparation method thereof, and medical use thereof. Specifically, the present disclosure relates to a indole macrocyclic derivative represented by general formula (I), a preparation method thereof, and a pharmaceutical composition containing the same, as well as its use as a therapeutic agent, particularly as an MCL-1 inhibitor, and its use for the treatment of tumors, autoimmune diseases or immune system diseases. The substituents of general formula (I) is the same as those defined in the description.

Description

Indole macrocyclic derivatives, preparation method thereof and application in medicine

The present disclosure belongs to the field of medicine, and relates to an indole macrocyclic derivative represented by general formula (I), a preparation method thereof, a pharmaceutical composition containing the derivative, and its use as a therapeutic agent, especially as an MCL-1 inhibitor And its use in the treatment of tumors, autoimmune diseases or immune system diseases.

An important feature that distinguishes tumor cells from normal cells is that apoptosis is inhibited, which gives them a greater survival advantage. Apoptosis is also called programmed death, which can be divided into exogenous apoptosis and endogenous apoptosis. Among them, endogenous apoptosis is an important barrier to the occurrence and development of cancer. BCL-2 family proteins are important regulators of endogenous apoptosis.

The BCL-2 family proteins mainly exist on the mitochondrial membrane, and can be divided into anti-apoptotic proteins and pro-apoptotic proteins according to their functions. Anti-apoptotic proteins include BCL-2, BCL-XL, BCL-w and MCL-1. Pro-apoptotic proteins include Bax, Bak and BH3-only proteins. When Bax and Bak are activated, they will form multimer cavities, increase the permeability of the cell mitochondrial membrane, promote the release of cytochrome C, etc. into the cytoplasm, leading to cell death. The BH3-only protein only contains the BH3 domain. In the state of cell survival, BH3-only protein (such as Bim) binds to anti-apoptotic protein Together. When cells are under external pressure, the balance of binding is broken, BH3-only protein is released and binds to Bax on mitochondria, promotes Bax/Bak to form multimers, promotes the release of cytochrome C and SMAC into the cytoplasm, and activates downstream apoptosis path.

Existing clinical data indicate that MCL-1 is overexpressed in a variety of tumors. For example, MCL-1 overexpression is detected in 55% of breast cancer and 84% of lung cancer samples. In multiple myeloma samples, as the degree of cancer progression increased, the expression of MCL-1 increased significantly, but the expression of BCL-2 did not change. In addition, the expression of MCL-1 is negatively correlated with the survival rate of patients. Both breast cancer and multiple myeloma patients have observed high expression of MCL-1 accompanied by lower survival rates. This shows that MCL-1 is an important tumor treatment target.

Novartis, Amgen, and AstraZeneca have all developed small molecule inhibitors for MCL-1, but they are still in the clinical stage, so further development of MCL-1 inhibitor drugs is needed.

The purpose of the present disclosure is to provide a compound represented by the general formula (I) or its tautomer, mesoisomer, racemate, enantiomer, diastereomer, or a mixture thereof Or its pharmaceutically acceptable salt,

among them:

R ^m , R ⁿ and R ^{w are the} same or different, and are each independently selected from a hydrogen atom, a halogen, an alkyl group, a deuterated alkyl group, an alkoxy group, a haloalkyl group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group , Nitro, cycloalkyl, cycloalkyloxy and heterocyclic groups;

Or R ^m and R ⁿ together with the connected carbon atoms form a cycloalkyl group, and R ^{w is} selected from hydrogen atom, halogen, deuterated alkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amine Group, nitro group, cycloalkyl group, cycloalkyloxy group and heterocyclic group;

Or R ⁿ and R ^w together with the connected carbon atoms form a cycloalkyl group, and R ^{m is} selected from hydrogen atom, halogen, deuterated alkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amine Group, nitro group, cycloalkyl group, cycloalkyloxy group and heterocyclic group;

Z is S atom, O atom or -CH ₂ -;

M is S atom, O atom or -NR ⁶ -;

R ^{1 is} selected from hydrogen atom, halogen, alkyl, deuterated alkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, cycloalkyloxy and Heterocyclic group;

R ^{2 are the} same or different, and are each selected from a hydrogen atom, a halogen, an alkyl group, a deuterated alkyl group, an alkoxy group, a haloalkyl group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amine group and a nitro group;

R ^{3 is} selected from hydrogen atom, halogen, alkyl, deuterated alkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amine and nitro;

R ^{4 is} selected from a hydrogen atom, an alkyl group, a deuterated alkyl group and a cycloalkyl group;

R ^{5 is} selected from a hydrogen atom, an alkyl group, a deuterated alkyl group and a cycloalkyl group;

R ^{6 is} selected from a hydrogen atom, an alkyl group and a cycloalkyl group;

n is 0, 1, 2 or 3.

In some preferred embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer ,or Its mixture form or its pharmaceutically acceptable salt is the compound represented by general formula (I-1) and general formula (I-2) or its tautomer, meso, racemate, enantiomer Conformers, diastereomers, or mixtures thereof or their pharmaceutically acceptable salts:

Wherein: R ^m , R ⁿ , R ^w , Z, M, R ¹ to R ⁵ and n are as defined in the compound of general formula (I).

In some preferred embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer , Or a mixture thereof or a pharmaceutically acceptable salt thereof, wherein: R ^m , R ⁿ and R ^{w are the} same or different, and are each independently selected from a hydrogen atom, a halogen and an alkyl group; or R ^m and R ⁿ are connected with The carbon atoms together form a cycloalkyl group, and R ^{w is} selected from a hydrogen atom, a halogen and an alkyl group; or R ⁿ and R ^w together with the connected carbon atoms form a cycloalkyl group, and R ^{m is} selected from a hydrogen atom, a halogen and an alkyl group .

In some preferred embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer , Or a mixture thereof or a pharmaceutically acceptable salt thereof, wherein: R ^m , R ⁿ and R ^{w are the} same or different, and are each independently selected from a hydrogen atom, a halogen and an alkyl group; or R ^m and R ⁿ are connected with The carbon atoms together form a C _4-6 cycloalkyl group, and R ^w is a hydrogen atom; or R ⁿ and R ^w together with the connected carbon atoms form a C _4-6 cycloalkyl group, and R ^m is a hydrogen atom.

選自：

、

和

；R^m、Rⁿ和R^w相同或不同，且各自獨立地選自氫 原子、鹵素和烷基；p為0、1或2；q為0、1或2。 In some preferred embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer , Or its mixture form or its pharmaceutically acceptable salt, wherein

Selected from:

,

with

; R ^m , R ⁿ and R ^{w are the} same or different, and are each independently selected from a hydrogen atom, a halogen, and an alkyl group; p is 0, 1, or 2; q is 0, 1, or 2.

選自：

、

、 In some preferred embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer , Or its mixture form or its pharmaceutically acceptable salt, wherein

Selected from:

,

,

In some preferred embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer , Or its mixture form or its pharmaceutically acceptable salt, which is a compound represented by the general formula (II), general formula (III) or general formula (IV) or its tautomer, meso form, exogenous Rotates, enantiomers, diastereomers, or mixtures thereof or their pharmaceutically acceptable salts:

among them:

p is 0, 1 or 2;

q is 0, 1 or 2;

R ^m , R ⁿ and R ^{w are the} same or different, and are each independently selected from a hydrogen atom, a halogen, and an alkyl group; and

Z, M and R ¹ to R ⁵ are as defined in the compound of general formula (I).

In some preferred embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer , Or a mixture form or a pharmaceutically acceptable salt thereof, wherein the Z is an S atom or an O atom.

In some preferred embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer , Or a mixture thereof or a pharmaceutically acceptable salt thereof, wherein the M is an S atom or -NR ⁶ -, and R ⁶ is a hydrogen atom or an alkyl group.

In some preferred embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer , Or a mixture form or a pharmaceutically acceptable salt thereof, wherein the R ¹ is a hydrogen atom or an alkyl group.

In some preferred embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer , Or a mixture form or a pharmaceutically acceptable salt thereof, wherein the R ² is halogen.

In some preferred embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer , Or a mixture thereof or a pharmaceutically acceptable salt thereof, wherein ^{each of R 3} and R ⁴ is an alkyl group.

In some preferred embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer , Or a mixture form or a pharmaceutically acceptable salt thereof, wherein the R ⁵ is an alkyl group.

Typical compounds of the present disclosure include but are not limited to:

Or its tautomers, mesosomes, racemates, enantiomers, diastereomers, or mixtures thereof or pharmaceutically acceptable salts thereof.

Another aspect of the present disclosure relates to a compound represented by general formula (IA) or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof Form or its pharmaceutically acceptable salt:

among them:

R ^a is an alkyl group;

R ^m , R ⁿ , R ^w , Z, M, R ¹ to R ⁵ and n are as defined in the compound of general formula (I).

In some preferred embodiments of the present disclosure, the compound represented by the general formula (IA) or its tautomer, meso, racemate, enantiomer, diastereomer , Or a mixture thereof or a pharmaceutically acceptable salt thereof, wherein: R ^m , R ⁿ and R ^{w are the} same or different, and are each independently selected from a hydrogen atom, a halogen and an alkyl group; or R ^m and R ⁿ are connected with The carbon atoms together form a cycloalkyl group, and R ^{w is} selected from a hydrogen atom, a halogen and an alkyl group; or R ⁿ and R ^w together with the connected carbon atoms form a cycloalkyl group, and R ^{m is} selected from a hydrogen atom, a halogen and an alkyl group .

In some preferred embodiments of the present disclosure, the compound represented by the general formula (IA) or its tautomer, meso, racemate, enantiomer, diastereomer , Or a mixture form or a pharmaceutically acceptable salt thereof, wherein: R ^m , R ⁿ and R ^{w are the} same or different, and are each independently selected from a hydrogen atom, a halogen and an alkyl group; R ^m and R ⁿ are connected to the carbon The atoms together form a C _4-6 cycloalkyl group, and R ^w is a hydrogen atom; or R ⁿ and R ^w together with the connected carbon atoms form a C _4-6 cycloalkyl group, and R ^m is a hydrogen atom.

選自：

、

和

；R^m、Rⁿ和R^w相同或不同，且各自獨立地選自氫 原子、鹵素和烷基；p為0、1或2；q為0、1或2。 In some preferred embodiments of the present disclosure, the compound represented by the general formula (IA) or its tautomer, meso, racemate, enantiomer, diastereomer , Or its mixture form or its pharmaceutically acceptable salt, wherein

Selected from:

,

with

; R ^m , R ⁿ and R ^{w are the} same or different, and are each independently selected from a hydrogen atom, a halogen, and an alkyl group; p is 0, 1, or 2; q is 0, 1, or 2.

選自：

、

、 In some preferred embodiments of the present disclosure, the compound represented by the general formula (IA) or its tautomer, meso, racemate, enantiomer, diastereomer , Or its mixture form or its pharmaceutically acceptable salt, wherein

Selected from:

,

,

Typical compounds of the general formula (IA) of the present disclosure include, but are not limited to:

Or its tautomers, mesosomes, racemates, enantiomers, diastereomers, or mixtures thereof or pharmaceutically acceptable salts thereof.

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (I), the method comprising:

Compounds of general formula (IA), removing the protecting group R ^a, to give a compound of formula (I), and

among them:

R ^a is an alkyl group;

R ^m , R ⁿ , R ^w , Z, M, R ¹ to R ⁵ and n are as defined in the compound of general formula (I).

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (I-1) or general formula (I-2), the method comprising:

The compound of general formula (IA) is chirally prepared to obtain the compound of general formula (IA-1) or the compound of general formula (IA-2);

Compounds of general formula (IA-1) or a compound of formula (IA-2) removing the protecting group of R ^a, of general formula (I-1) or the general formula (I-2) compound,

among them:

R ^a is an alkyl group;

R ^m , R ⁿ , R ^w , Z, M, R ¹ to R ⁵ and n are as defined in the compound of general formula (I).

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II), the method comprising:

Compounds of general formula (IIA) deprotection of R ^a, to give a compound of formula (II), and

among them:

R ^a is an alkyl group;

R ^m , R ⁿ , Z, M and R ¹ to R ⁵ are as defined in the compound of general formula (II).

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (III), the method comprising:

Compounds of general formula (IIIA) removing the protecting group of R ^a, to give a compound of formula (III), and

among them:

R ^a is an alkyl group;

R ^w , Z, M, R ¹ to R ⁵ and p are as defined in the compound of general formula (III).

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IV), the method comprising:

Compounds of general formula (IVA) removing the protecting group of R ^a, to give a compound of formula (IV), and

among them:

R ^a is an alkyl group;

R ^m , Z, M, R ¹ to R ⁵ and q are as defined in the compound of general formula (IV).

Another aspect of the present disclosure relates to a pharmaceutical composition containing a therapeutically effective amount of the compound represented by the general formula (I) of the present disclosure or its tautomer, meso form, racemate, and Enantiomers, diastereomers or mixtures thereof, or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

Another aspect of the present disclosure relates to a compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer or mixture thereof, or The use of its pharmaceutically acceptable salt or a pharmaceutical composition containing it in the preparation of a medicine for inhibiting MCL-1.

Another aspect of the present disclosure relates to the compound represented by the general formula (I) or its tautomer, mesoisomer, racemate, enantiomer, diastereomer or mixture thereof, The use of a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same in the preparation of a medicament for treating or preventing MCL-1 mediated diseases.

Another aspect of the present disclosure relates to a compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer or mixture thereof, or The use of its pharmaceutically acceptable salt or a pharmaceutical composition containing it in the preparation of a medicament for the treatment of tumors, autoimmune diseases or immune system diseases; wherein the tumor is preferably selected from bladder cancer, brain tumor, breast cancer, Uterine cancer, cervical cancer, endometrial cancer, ovarian cancer, leukemia (such as chronic myeloid leukemia, chronic lymphocytic leukemia, lymphoblastic leukemia, or acute myeloid leukemia), kidney cancer, colon cancer, rectal cancer, colorectal cancer , Esophageal cancer, liver cancer, gastric cancer, head and neck cancer, skin cancer, lymphoma, pancreatic cancer, melanoma, myeloma (such as multiple myeloma), bone cancer, neuroblastoma, glioma, sarcoma, lung cancer ( Such as non-small cell lung cancer or small cell lung cancer), thyroid cancer and prostate cancer.

Another aspect of the present disclosure relates to a method for inhibiting MCL-1, which comprises administering to a patient a therapeutically effective amount of a compound represented by the general formula (I) or its tautomers, mesosomes, racemates, Enantiomers, diastereomers or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing them.

Another aspect of the present disclosure relates to a method for treating or preventing MCL-1 mediated diseases, which comprises administering to a patient a therapeutically effective amount of a compound represented by general formula (I) or a tautomer or a mesoform thereof , Racemates, enantiomers, diastereomers or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing them.

Another aspect of the present disclosure relates to a method for the treatment of tumors, autoimmune diseases or immune system diseases, which comprises administering to a desired patient a therapeutically effective amount of a compound represented by general formula (I) or a tautomer, meso Forms of isomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing them; wherein the tumor is preferred Selected from bladder cancer, brain tumor, breast cancer, uterine cancer, cervical cancer, endometrial cancer, ovarian cancer, leukemia (such as chronic myeloid leukemia, chronic lymphocytic leukemia, lymphoblastic leukemia or acute myeloid leukemia), kidney Cancer, colon cancer, rectal cancer, colorectal cancer, esophageal cancer, liver cancer, stomach cancer, head and neck cancer, skin cancer, lymphoma, pancreatic cancer, melanoma, myeloma (such as multiple myeloma), bone cancer, neuroblastoma Tumor, glioma, sarcoma, lung cancer (such as non-small cell lung cancer or small cell lung cancer), thyroid cancer, and prostate cancer.

Another aspect of the present disclosure relates to a compound represented by general formula (I) or its tautomer, mesoisomer, racemate, enantiomer, diastereomer, or mixture thereof , Or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing the same, which is used as a medicine.

Another aspect of the present disclosure relates to a compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer or mixture thereof, or Its pharmaceutically acceptable salt, or a pharmaceutical composition containing it, is used as an MCL-1 inhibitor.

Another aspect of the present disclosure relates to a compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer or mixture thereof, or Its pharmaceutically acceptable salt, or a pharmaceutical composition containing it, is used to treat or prevent MCL-1 mediated diseases.

Another aspect of the present disclosure relates to a compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer or mixture thereof, or Its pharmaceutically acceptable salt, or a pharmaceutical composition containing it, is used to treat tumors, autoimmune diseases or immune system diseases; wherein the tumor is preferably selected from bladder cancer, brain tumor, breast cancer, uterine cancer, and cervical cancer , Endometrial cancer, ovarian cancer, leukemia (such as chronic myelogenous leukemia, chronic lymphocytic leukemia, lymphoblastic leukemia or acute myeloid leukemia), kidney cancer, colon cancer, rectal cancer, colorectal cancer, esophageal cancer, liver cancer , Stomach cancer, head and neck cancer, skin cancer, lymphoma, pancreatic cancer, black Pigmentoma, myeloma (such as multiple myeloma), bone cancer, neuroblastoma, glioma, sarcoma, lung cancer (such as non-small cell lung cancer or small cell lung cancer), thyroid cancer, and prostate cancer.

The active compound can be prepared in a form suitable for administration by any appropriate route, and the active compound is preferably in a unit dose form, or a form in which the patient can self-administer in a single dose. The unit dose of the compound or composition of the present disclosure can be expressed in the form of a tablet, capsule, cachet, bottled syrup, powder, granule, lozenge, suppository, rejuvenated powder or liquid preparation.

The dosage of the compound or composition used in the treatment methods of the present disclosure will generally vary with the severity of the disease, the weight of the patient, and the relative efficacy of the compound. However, as a general guide, a suitable unit dose can be 0.1 to 1000 mg.

In addition to the active compound, the pharmaceutical composition of the present disclosure may contain one or more excipients, which are selected from the following ingredients: fillers (diluents), binders, wetting agents, disintegrants or excipients, and the like. Depending on the method of administration, the composition may contain 0.1 to 99% by weight of the active compound.

The pharmaceutical composition containing the active ingredient may be in a form suitable for oral administration, such as tablets, dragees, lozenges, water or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or Elixirs. The oral composition may be prepared according to any method known in the art for preparing pharmaceutical compositions, and such composition may contain one or more ingredients selected from the group consisting of sweeteners, flavoring agents, coloring agents and preservatives to provide pleasing to the eye And delicious medicinal preparations. The tablet contains the active ingredient and non-toxic pharmaceutically acceptable excipients suitable for the preparation of tablets for mixing.

Aqueous suspensions contain the active substance and excipients suitable for the preparation of aqueous suspensions for mixing. The aqueous suspension may also contain one or more preservatives such as ethyl paraben or n-propyl paraben, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents.

Oil suspensions can be formulated by suspending the active ingredients in vegetable oils. The oil suspension may contain thickeners. The above-mentioned sweeteners and flavoring agents can be added to provide a palatable preparation.

By adding water, dispersible powders and granules suitable for preparing aqueous suspensions can be provided with active ingredients and dispersing or wetting agents for mixing, suspending agents or one or more preservatives. Suitable dispersing or wetting agents and suspending agents can illustrate the above examples. Other excipients such as sweeteners, flavoring agents and coloring agents may also be added. These compositions are preserved by adding antioxidants such as ascorbic acid.

The pharmaceutical composition of the present disclosure may also be in the form of an oil-in-water emulsion.

The pharmaceutical composition may be in the form of a sterile injectable aqueous solution. Acceptable solvents or solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solution. The sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in an oil phase. For example, the active ingredient is dissolved in a mixture of soybean oil and lecithin. Then the oil solution is added to the mixture of water and glycerin to form a microemulsion. The injection or microemulsion can be injected into the patient's bloodstream by local large-scale injection. Alternatively, it is best to administer the solution and microemulsion in a manner that can maintain a constant circulating concentration of the compound of the present disclosure. To maintain this constant concentration, a continuous intravenous delivery device can be used. An example of such a device is the Deltec CADD-PLUS.TM. 5400 intravenous pump.

The pharmaceutical composition may be in the form of a sterile injection water or oil suspension for intramuscular and subcutaneous administration. The suspension can be formulated according to known techniques using those suitable dispersing or wetting agents and suspending agents mentioned above. The sterile injection preparation may also be a sterile injection solution or suspension prepared in a parenterally acceptable non-toxic diluent or solvent. In addition, sterile fixed oil can be conveniently used as a solvent or suspending medium.

The compounds of the present disclosure can be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid in the rectum, and thus will melt in the rectum to release the drug. Such substances include cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, polyethylene glycols of various molecular weights and mixtures of fatty acid esters of polyethylene glycol.

As is well known to those skilled in the art, the dosage of the drug depends on many factors, including but not limited to the following factors: the activity of the specific compound used, the age of the patient, the weight of the patient, the health of the patient, the behavior of the patient, The patient’s diet, time of administration, mode of administration, rate of excretion, combination of drugs, etc.; in addition, the best treatment mode, such as the mode of treatment, the daily dosage of compound (I), or the type of pharmaceutically acceptable salt It can be verified according to the traditional treatment plan.

Definition of Terms

Unless stated to the contrary, the terms used in the specification and the scope of the patent application have It has the following meanings.

The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms, more preferably containing 1 to 6 carbon atoms. An alkyl group with three carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tertiary butyl, second butyl, n-pentyl, 1,1-dimethylpropyl , 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl- 2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1 ,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl , 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-di Methylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl , 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4 -Ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3 -Ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched isomers thereof. More preferred are lower alkyl groups containing 1 to 6 carbon atoms. Non-limiting examples include methyl Base, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tertiary butyl, second butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-di Methylpropyl, 2,2-Dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl , 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl Butyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, etc. The alkyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available attachment point. The substituent is preferably independently selected from the group consisting of H atom, D atom, halogen, and alkane. Is substituted by one or more substituents in the group, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

The term "alkoxy" refers to -O- (alkyl) and -O- (unsubstituted cycloalkyl), where the definition of alkyl is as described above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy. The alkoxy group may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are independently selected from H atom, D atom, halogen, alkyl, and alkoxy Substituted by one or more substituents in the group, haloalkyl, hydroxy, hydroxyalkyl, cyano, amine, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent. The cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, preferably 3 to 8 carbon atoms, more preferably 4 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene Groups, cyclooctyl, etc.; polycyclic cycloalkyls include spiro, fused, and bridged cycloalkyls.

The term "spirocycloalkyl" refers to a polycyclic group that shares one carbon atom (called a spiro atom) between monocyclic rings with 5 to 20 members. It may contain one or more double bonds, but none of the rings have complete Conjugated π electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members (for example, 7, 8, 9 or 10 members). According to the number of spiro atoms shared between the ring and the ring, the spirocycloalkyl group is classified into a single spirocycloalkyl group, a bispirocycloalkyl group or a polyspirocycloalkyl group, preferably a single spirocycloalkyl group and a bispirocycloalkyl group. . More preferably, it is 4 members/4 members, 4 members/5 members, 4 members/6 members, 5 members/5 members or 5 members/6 members monospirocycloalkyl. Non-limiting examples of spirocycloalkyl groups include:

The term "fused cycloalkyl" refers to an all-carbon polycyclic group consisting of 5 to 20 members. Each ring in the system shares an adjacent pair of carbon atoms with other rings in the system. One or more rings may contain one or Multiple double bonds, but none of the rings have a fully conjugated π-electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl groups, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic alkyl. Non-limiting examples of fused cycloalkyl groups include:

The term "bridged cycloalkyl" refers to a 5- to 20-member, all-carbon polycyclic group with any two rings sharing two carbon atoms that are not directly connected. It may contain one or more double bonds, but no ring has a complete Conjugated π electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyls, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include:

The cycloalkyl ring includes the cycloalkyl as described above (including monocyclic, spiro, fused and bridged rings) fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the parent structure is connected to The ring together is a cycloalkyl group, non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl, etc.; preferably phenylcyclopentyl, tetrahydronaphthyl.

Cycloalkyl groups can be substituted or unsubstituted. When substituted, the substituents can be substituted at any available attachment point. The substituents are preferably independently selected from hydrogen atoms, halogens, alkyl groups, Alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl are substituted by one or more substituents.

The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen or S(O) _m (wherein m is an integer of 0 to 2) heteroatoms, but does not include the ring part of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. It preferably contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably contains 3 to 8 ring atoms, of which 1-3 are heteroatoms; more preferably contains 3 to 6 ring atoms, of which 1- Three are heteroatoms; it preferably contains 5 or 6 ring atoms, of which 1-3 are heteroatoms. Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, tetrahydropyranyl, 1,2.3.6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homo Piperazinyl and so on. Polycyclic heterocyclic groups include spirocyclic, condensed, and bridged heterocyclic groups.

The term "spiroheterocyclic group" refers to a polycyclic heterocyclic group sharing one atom (called a spiro atom) between monocyclic rings of 5 to 20 members, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O ) _{Heteroatoms of m} (where m is an integer of 0 to 2), and the remaining ring atoms are carbon. It can contain one or more double bonds, but none of the rings have a fully conjugated π-electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members. According to the number of spiro atoms shared between the ring and the ring, the spiro heterocyclic group is classified into a single spiro heterocyclic group, a dispiro heterocyclic group or a polyspiro heterocyclic group, preferably a single spiro heterocyclic group and a dispiro heterocyclic group . More preferably, it is 4 members/4 members, 4 members/5 members, 4 members/6 members, 5 members/5 members or 5 members/6 members monospiroheterocyclic groups. Non-limiting examples of spiroheterocyclic groups include:

The term "fused heterocyclic group" refers to a polycyclic heterocyclic group with 5 to 20 members. Each ring in the system shares an adjacent pair of atoms with other rings in the system. One or more rings may contain one or more Double bond, but none of the rings have a fully conjugated π-electron system, where one or more of the ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) _m (where m is an integer from 0 to 2), and the rest of the ring The atom is carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic group . Non-limiting examples of fused heterocyclic groups include:

The term "bridged heterocyclic group" refers to a polycyclic heterocyclic group with 5 to 14 members, and any two rings share two atoms that are not directly connected. It may contain one or more double bonds, but none of the rings has a complete common A conjugated π-electron system in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen, or S(O) _m (where m is an integer of 0 to 2), and the remaining ring atoms are carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:

和

等。 The heterocyclyl ring includes the heterocyclic group as described above (including monocyclic, spiro heterocyclic, fused heterocyclic and bridged heterocyclic ring) fused on an aryl, heteroaryl or cycloalkyl ring, which is connected to the parent structure The rings connected together are heterocyclic groups, non-limiting examples of which include:

with

Wait.

The heterocyclyl ring includes the heterocyclic group as described above (including monocyclic, spiro heterocyclic, fused heterocyclic and bridged heterocyclic ring) fused on an aryl, heteroaryl or cycloalkyl ring, which is connected to the parent structure The rings connected together are heterocyclic groups, non-limiting examples of which include:

The heterocyclic group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment. The substituent is preferably independently selected from hydrogen atoms, halogens, alkyl groups, Alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl are substituted by one or more substituents.

The term "aryl" refers to a 6 to 14-membered all-carbon monocyclic or fused polycyclic (that is, rings sharing adjacent pairs of carbon atoms) group with a conjugated π-electron system, preferably 6 to 10 members, for example Phenyl and naphthyl. The aryl ring includes the aryl ring as described above fused to a heteroaryl, heterocyclic group or ring On the alkyl ring, where the ring connected to the parent structure is an aryl ring, non-limiting examples include:

The aryl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment. The substituent is preferably independently selected from the group consisting of hydrogen atom, halogen, alkyl, and alkane. One or more substituents of oxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amine, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl are substituted.

The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, where the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaryl group is preferably 5 to 10 members, more preferably 5 or 6 members, such as furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl , Imidazolyl, pyrazolyl, triazolyl, tetrazolyl, etc. The heteroaryl ring includes the above-mentioned heteroaryl group fused to an aryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, and non-limiting examples thereof include:

Heteroaryl groups can be substituted or unsubstituted. When substituted, the substituents can be substituted at any available attachment point. The substituents are preferably independently selected from hydrogen atoms, halogens, alkyl groups, Alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl are substituted by one or more substituents.

The term "cycloalkyloxy" refers to cycloalkyl-O-, where cycloalkyl is as defined above.

The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, where the alkyl group is as defined above.

The term "deuterated alkyl" refers to an alkyl group substituted with one or more deuterium atoms, where the alkyl group is as defined above.

The term "hydroxy" refers to the -OH group.

The term "hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, where the alkyl group is as defined above.

The term "halogen" refers to fluorine, chlorine, bromine or iodine.

The term "hydroxy" refers to the -OH group.

The term "amino" refers to -NH ₂ .

The term "cyano" refers to -CN.

The term "nitro" refers to -NO ₂ .

The term "carbonyl" refers to C=O.

The term "carboxy" refers to -C(O)OH.

The term "carboxylate group" refers to -C(O)O(alkyl) or -C(O)O(cycloalkyl), wherein alkyl and cycloalkyl are as defined above.

The present disclosure also includes compounds of formula (I) in various deuterated forms. Each available hydrogen atom connected to a carbon atom can be independently replaced by a deuterium atom. Those skilled in the art can refer to relevant literature to synthesize the deuterated form of the compound of formula (I). Commercially available deuterated starting materials can be used when preparing the deuterated form of the compound of formula (I), or they can be synthesized using conventional techniques using deuterated reagents. Deuterated reagents include, but are not limited to, deuterated borane and tri-deuterated. Borane tetrahydrofuran solution, deuterated lithium aluminum hydride, deuterated ethyl iodide and deuterated methyl iodide, etc.

"As needed" or "as needed" means that the event or environment described later can but need not occur, and the description includes the occasion where the event or environment occurs or does not occur. For example, "heterocyclic group substituted by an alkyl group as required" means that an alkyl group may but does not have to be present, and the description includes the case where the heterocyclic group is substituted by an alkyl group and the case where the heterocyclic group is not substituted by an alkyl group. .

"Substituted" refers to one or more hydrogen atoms in the group, preferably at most 5, and more preferably 1 to 3 hydrogen atoms are independently substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without too much effort. For example, an amine group or a hydroxyl group having free hydrogen may be unstable when combined with a carbon atom having an unsaturated (e.g., olefinic) bond.

"Pharmaceutical composition" means a mixture containing one or more of the compounds described herein or their physiologically/pharmaceutically acceptable salts or prodrugs and other chemical components, as well as other components such as physiological/pharmaceutically acceptable carriers And excipients. The purpose of the medicinal composition is to promote the administration to the organism, facilitate the absorption of the active ingredient and then exert the biological activity.

"Pharmaceutically acceptable salt" refers to the salt of the compound of the present disclosure. Such salt is safe and effective when used in mammals, and has due biological activity.

The compounds of the present disclosure may also include isotopic derivatives thereof. The term "isotopic derivative" refers to a compound that differs in structure only in the presence of one or more isotopically enriched atoms. For example, with the structure of the present disclosure, in addition to using "deuterium" or "tritium" instead of hydrogen, or using ¹⁸ F-fluorine label ( ¹⁸ F isotope) instead of fluorine, or using ¹¹ C-, ¹³ C-, or ¹⁴ C-rich Compounds in which a set of carbons ( ¹¹ C-, ¹³ C-, or ¹⁴ C-carbon labels; ¹¹ C-, ¹³ C-, or ¹⁴ C-isotopes) replace carbon atoms are within the scope of the present disclosure. Such compounds can be used, for example, as analytical tools or probes in biological assays, or as tracers for in vivo diagnostic imaging of diseases, or as tracers for pharmacodynamics, pharmacokinetics, or receptor studies. Deuterated compounds can generally retain the same activity as non-deuterated compounds, and when deuterated at certain specific sites, they can achieve better metabolic stability, thereby obtaining certain therapeutic advantages (such as increased in vivo half-life or reduced dosage requirements) ).

For drugs or pharmacologically active agents, the term "therapeutically effective amount" refers to a sufficient amount of a drug or agent that is non-toxic but can achieve the desired effect. The determination of the effective amount varies from person to person, and depends on the age and general conditions of the recipient, as well as the specific active substance. The appropriate effective amount in a case can be determined by those skilled in the art according to routine experiments.

Synthetic method of the compound of the present disclosure

In order to accomplish the purpose of the present disclosure, the present disclosure adopts the following technical solutions:

Option One

The compound represented by the general formula (I) of the present disclosure, or its tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmacologically The preparation method of the salt used includes the following steps:

Compounds of general formula (IA) is removed under basic conditions protective group R ^a, to give a compound of formula (I), and

among them:

R ^a is an alkyl group;

R ^m , R ⁿ , R ^w , Z, M, R ¹ to R ⁵ and n are as defined in the compound of general formula (I).

The reagents that provide alkaline conditions include organic bases and inorganic bases. The organic bases include, but are not limited to, triethylamine, N , N -diisopropylethylamine, n-butyllithium, lithium diisopropylamine, Lithium bistrimethylsilylamide, potassium acetate, potassium acetate, sodium tert-butoxide, potassium tert-butoxide and sodium n-butoxide. The inorganic bases include but are not limited to sodium bicarbonate, potassium bicarbonate, and sodium hydride , Potassium phosphate, sodium carbonate, potassium carbonate, potassium acetate, cesium carbonate, sodium hydroxide and lithium hydroxide and their hydrates; preferably lithium hydroxide monohydrate;

The above reaction is preferably carried out in a solvent. The solvents used include but are not limited to: acetic acid, methanol, ethanol, n-butanol, tertiary butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dichloromethane Methyl sulfenite, 1,4-dioxane, ethylene glycol dimethyl ether, water and N,N-dimethylformamide and mixtures thereof.

Option II

The compound represented by general formula (I-1) or general formula (I-2) of the present disclosure or its tautomer, meso, racemate, enantiomer, diastereomer , Or its mixture form, or its pharmaceutically acceptable salt preparation method, including the following steps:

The compound of general formula (IA) is chirally prepared to obtain the compound of general formula (IA-1) or the compound of general formula (IA-2);

Compounds of general formula (IA-1) or a compound of formula (IA-2) is removed under basic conditions protective group R ^a, of general formula (I-1) or the general formula (I-2) compound,

among them:

R ^a is an alkyl group;

R ^m , R ⁿ , R ^w , Z, M, R ¹ to R ⁵ and n are as defined in the compound of general formula (I).

The reagents that provide alkaline conditions include organic bases and inorganic bases. The organic bases include, but are not limited to, triethylamine, N , N -diisopropylethylamine, n-butyllithium, lithium diisopropylamine, Lithium bistrimethylsilylamide, potassium acetate, potassium acetate, sodium tert-butoxide, potassium tert-butoxide and sodium n-butoxide. The inorganic bases include but are not limited to sodium bicarbonate, potassium bicarbonate, and sodium hydride , Potassium phosphate, sodium carbonate, potassium carbonate, potassium acetate, cesium carbonate, sodium hydroxide and lithium hydroxide and their hydrates; preferably lithium hydroxide monohydrate;

The above reaction is preferably carried out in a solvent. The solvents used include but are not limited to: acetic acid, methanol, ethanol, n-butanol, tertiary butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dichloromethane Methyl sulfenite, 1,4-dioxane, ethylene glycol dimethyl ether, water and N,N-dimethylformamide and mixtures thereof.

third solution

The compound represented by the general formula (II) of the present disclosure, or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or its pharmacologically The preparation method of the salt used includes the following steps:

Compounds of general formula (IIA) is removed under basic conditions protective group R ^a, to give a compound of formula (II), and

among them:

R ^a is an alkyl group;

R ^m , R ⁿ , Z, M and R ¹ to R ⁵ are as defined in the compound of general formula (II).

The reagents that provide alkaline conditions include organic bases and inorganic bases. The organic bases include, but are not limited to, triethylamine, N , N -diisopropylethylamine, n-butyllithium, lithium diisopropylamine, Lithium bistrimethylsilylamide, potassium acetate, potassium acetate, sodium tert-butoxide, potassium tert-butoxide and sodium n-butoxide. The inorganic bases include but are not limited to sodium bicarbonate, potassium bicarbonate, and sodium hydride , Potassium phosphate, sodium carbonate, potassium carbonate, potassium acetate, cesium carbonate, sodium hydroxide and lithium hydroxide and their hydrates; preferably lithium hydroxide monohydrate;

The above reaction is preferably carried out in a solvent. The solvents used include but are not limited to: acetic acid, methanol, ethanol, n-butanol, tertiary butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dichloromethane Methyl sulfenite, 1,4-dioxane, ethylene glycol dimethyl ether, water and N,N-dimethylformamide and mixtures thereof.

Option Four

The compound represented by the general formula (III) of the present disclosure, or its tautomer, meso, racemate, enantiomer, diastereomer, or mixture form thereof, or its pharmacologically The preparation method of the salt used includes the following steps:

Compounds of general formula (IIIA) removing the protecting group of R ^a, to give a compound of formula (III), and

among them:

R ^a is an alkyl group;

R ^w , Z, M, R ¹ to R ⁵ and p are as defined in the compound of general formula (III).

The reagents that provide alkaline conditions include organic bases and inorganic bases. The organic bases include, but are not limited to, triethylamine, N , N -diisopropylethylamine, n-butyllithium, lithium diisopropylamine, Lithium bistrimethylsilylamide, potassium acetate, potassium acetate, sodium tert-butoxide, potassium tert-butoxide and sodium n-butoxide. The inorganic bases include but are not limited to sodium bicarbonate, potassium bicarbonate, and sodium hydride , Potassium phosphate, sodium carbonate, potassium carbonate, potassium acetate, cesium carbonate, sodium hydroxide and lithium hydroxide and their hydrates; preferably lithium hydroxide monohydrate;

The above reaction is preferably carried out in a solvent. The solvents used include but are not limited to: acetic acid, methanol, ethanol, n-butanol, tertiary butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dichloromethane Methyl sulfenite, 1,4-dioxane, ethylene glycol dimethyl ether, water and N,N-dimethylformamide and mixtures thereof.

Option Five

The compound represented by the general formula (IV) of the present disclosure, or its tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmacologically The preparation method of the salt used includes the following steps:

Compounds of general formula (IVA) removing the protecting group of R ^a, to give a compound of formula (IV), and

among them:

R ^a is an alkyl group;

R ^m , Z, M, R ¹ to R ⁵ and q are as defined in the compound of general formula (IV).

The reagents that provide alkaline conditions include organic bases and inorganic bases. The organic bases include, but are not limited to, triethylamine, N , N -diisopropylethylamine, n-butyllithium, lithium diisopropylamine, Lithium bistrimethylsilylamide, potassium acetate, potassium acetate, sodium tert-butoxide, potassium tert-butoxide and sodium n-butoxide. The inorganic bases include but are not limited to sodium bicarbonate, potassium bicarbonate, and sodium hydride , Potassium phosphate, sodium carbonate, potassium carbonate, potassium acetate, cesium carbonate, sodium hydroxide and lithium hydroxide and their hydrates; preferably lithium hydroxide monohydrate;

The above reaction is preferably carried out in a solvent. The solvents used include but are not limited to: acetic acid, methanol, ethanol, n-butanol, tertiary butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dichloromethane Methyl sulfenite, 1,4-dioxane, ethylene glycol dimethyl ether, water and N,N-dimethylformamide and mixtures thereof.

The following examples are used to further describe the present disclosure, but these examples do not limit the scope of the present disclosure.

Example

The structure of the compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS). The NMR shift (δ) is given in units of ^{10 -6 (ppm).} NMR was measured with Bruker AVANCE-400 nuclear magnetic instrument, and the solvent was deuterated dimethyl sulfoxide (DMSO- d ₆ ), deuterated chloroform (CDCl ₃ ), deuterated methanol (CD ₃ OD), and the internal standard was four Methyl Silane (TMS).

The measurement of MS uses Agilent 1200/1290 DAD-6110/6120 Quadrupole MS LC/MS (manufacturer: Agilent, MS model: 6110/6120 Quadrupole MS), waters ACQuity UPLC-QD/SQD (manufacturer: waters, MS Model: waters ACQuity Qda Detector/waters SQ Detector), THERMO Ultimate 3000-Q Exactive (manufacturer: THERMO, MS model: THERMO Q Exactive).

High performance liquid chromatography (HPLC) analysis uses Agilent HPLC 1200DAD, Agilent HPLC 1200VWD and Waters HPLC e2695-2489 high pressure liquid chromatograph.

Chiral HPLC analysis and determination used Agilent 1260 DAD high performance liquid chromatograph.

Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP and Gilson GX-281 preparative chromatographs were used for HPLC preparation.

For chiral preparation, Shimadzu LC-20AP preparative chromatograph was used.

CombiFlash rapid preparation instrument uses Combiflash Rf200 (TELEDYNE ISCO).

The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The size of the silica gel plate used in thin layer chromatography (TLC) is 0.15mm~0.2mm, and the size of thin layer chromatography separation and purification products is 0.4mm. ~0.5mm.

The silica gel column chromatography generally uses Yantai Huanghai silica gel 200~300 mesh silica gel as the carrier.

The average value of ₅₀ measured kinase inhibition rate and IC NovoStar using a microplate reader (BMG, Germany).

The known starting materials of the present disclosure can be synthesized by or according to methods known in the art, or can be purchased from ABCR GmbH & Co.KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Companies such as Darui Chemicals.

There is no special description in the examples, and the reaction can all be carried out under an argon atmosphere or a nitrogen atmosphere.

The argon atmosphere or nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon with a volume of about 1L.

The hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon with a volume of about 1L.

The pressure hydrogenation reaction uses Parr 3916EKX hydrogenator and Qinglan QL-500 hydrogen generator or HC2-SS hydrogenator.

The hydrogenation reaction is usually evacuated and filled with hydrogen, and the operation is repeated 3 times.

The microwave reaction uses a CEM Discover-S 908860 microwave reactor.

There is no special description in the examples, and the solution refers to an aqueous solution.

There are no special instructions in the examples, and the reaction temperature is room temperature, which is 20°C to 30°C.

The monitoring of the reaction progress in the examples adopts thin-layer chromatography (TLC), the developing reagent used in the reaction, the eluent system of column chromatography used to purify the compound, and the developing reagent system of thin-layer chromatography include: A : Dichloromethane/methanol system, B: n-hexane/ethyl acetate system. The volume ratio of the solvent is adjusted according to the polarity of the compound. A small amount of basic or acidic reagents such as triethylamine and acetic acid can also be added for adjustment.

Example 1

17-chloro-5,13,14,22-tetramethyl-28-oxa-2,9-dithia-5,6,12,13,22-pentaazaheptane [27.6.1.1 ^{4, 11,15} .0 ^16,21 .0 ^7.0 .0 ^{20, 24, 31, 35]} thirty-seven 1 (36), 4 (37), 6,11,14,16,18,20,23, 29,31(35)-Undecene-23-carboxylic acid 1

first step

( E )-3-(3-Bromo-5-methoxyphenyl)methyl acrylate 1b

Sodium hydrogen (1.34g, 34.97mmol, 60% purity) was dissolved in tetrahydrofuran (100mL), replaced with argon three times, and trimethylphosphoranyl acetate (6.35g, 34.87mmol) was added dropwise under an ice bath. After stirring for 30 minutes, a solution of 3-bromo-5-methoxybenzaldehyde 1a (5.00 g, 23.25 mmol) in tetrahydrofuran (30 mL) was added dropwise, and the reaction solution was stirred and reacted at room temperature for 1 hour. Under ice bath, add ethyl acetate (100mL) and water (100mL), separate the layers, wash the organic phase with saturated sodium chloride solution (30mL×2), dry the organic phase with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue obtained was purified by silica gel column chromatography with eluent system B to obtain the title compound 1b (6.20 g, yield: 98.4%).

MS m/z(ESI): 271.1 273.1[M+1]

Second step

Methyl 3-(3-bromo-5-methoxyphenyl)propionate 1c

Compound 1b (6.00 g, 22.1 mmol) was dissolved in methanol (75 mL) and tetrahydrofuran (75 mL) at room temperature, dry 5% rhodium carbon (600 mg) was added, and hydrogen was replaced three times. The reaction solution was stirred and reacted at room temperature for 90 minutes. The reaction solution was filtered and concentrated under reduced pressure to obtain the title compound 1c (6.04 g, yield: 99.3%).

MS m/z(ESI): 273.0 275.0[M+1]

third step

3-(3-Bromo-5-methoxyphenyl)propionic acid 1d

Dissolve compound 1c (6.20g, 22.7mmol) in methanol (30mL), tetrahydrofuran (30mL) and water (30mL) at room temperature, add lithium hydroxide monohydrate (2.86g, 68.2mmol), heat at 50℃ and stir. React for 1 hour. The reaction solution was concentrated under reduced pressure, water and dichloromethane (100mL) were added, the pH was adjusted to 2-3 with 1M hydrochloric acid, and the mixture was extracted with dichloromethane and methanol (V:V=10:1) (50mL). The organic phase was washed with water (30mL×3) and saturated sodium chloride solution (30mL×2) successively, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound 1d (5.80g, yield: 98.6%).

MS m/z(ESI): 257.2 259.2 [M-1]

the fourth step

7-Bromo-5-methoxy-2,3-dihydro-1 H -inden-1-one 1e-1

5-bromo-7-methoxy-2,3-dihydro-1 H -inden-1-one 1e-2

Compound 1d (5.50 g, 21.2 mmol) was weighed into a 100 mL reaction flask at room temperature, polyphosphoric acid (120 g, 35.5 mmol) was added, and the reaction was stirred at 95° C. for 1.5 hours. Pour into ice water, add dichloromethane (200mL), separate the layers, wash the organic phase with sodium bicarbonate, water and saturated sodium chloride each 30mL×3, dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and use silica gel The resulting residue was purified by column chromatography with eluent system B to obtain title compound 1e-1 (3.50 g, yield: 68.4%) and title compound 1e-2 (1.00 g, yield: 19.5%).

MS m/z(ESI): 241.1 243.1[M+1]

the fifth step

4-bromo-6-methoxy-2,3-dihydro-1 H -indene 1f

Compound 1e-1 (3.50g, 14.5mmol) was dissolved in trifluoroacetic acid (30ml) at room temperature, triethylsilane 3.37g, 29.0mmol) was added, and the reaction was stirred at 80°C for 1.5 hours. The reaction solution was concentrated under reduced pressure, ethyl acetate (50mL) and water (50mL) were added, and the layers were separated. The organic phase was washed with water and saturated sodium chloride each 30mL×3, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography with eluent system B to obtain the title compound 1f (2.70 g, yield: 81.9%).

Sixth step

7-bromo-2,3-dihydro-1 H -indene-5-phenol 1g

Compound 1f (2.70g, 11.9mmol) was dissolved in 30mL of dichloromethane at room temperature, 1M dichloromethane solution of boron tribromide (40mL, 40.0mmol) was added dropwise under ice bath, and the reaction was stirred at room temperature for 2 hours. The reaction solution was poured into ice water, extracted with dichloromethane (50mL×2), the organic phases were combined, washed with water (30mL), saturated sodium chloride solution (30mL), dried with anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was reduced Concentrate by pressure, and purify the residue obtained by silica gel column chromatography with eluent system B to obtain 1 g of the title compound (2.20 g, yield: 86.8%).

MS m/z(ESI): 211.0 213.0 [M-1]

Seventh step

3-((6-Hydroxy-2,3-dihydro- 1H -inden-4-yl)thio)propionic acid 2-ethylhexyl ester 1h

Compound 1g (800mg, 3.75mmol), 3-mercaptopropionic acid 2-ethylhexyl ester (984mg, 4.51mmol), N , N -diisopropylethylamine (971mg, 7.51mmol), tris( Dibenzylideneacetone) two palladium (172mg, 0.19mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (217mg, 0.38mmol) dissolved in 20mL dioxane , Replace argon three times, heat at 95°C and stir for 16 hours. Filtered through a pad of celite, the filtrate was concentrated under reduced pressure, and the residue obtained was purified by silica gel column chromatography with eluent system B to obtain the title compound 1h (450 mg, yield: 34.2%).

MS m/z(ESI): 351.1[M+1]

Eighth step

7-Mercapto-2,3-dihydro-1 H -indene-5-phenol 1i

Compound 1h (450 mg, 1.28 mmol) was dissolved in 4 mL of tetrahydrofuran under ice bath, argon was replaced three times, 1M potassium tert-butoxide (4.1 mL, 4.10 mmol) in tetrahydrofuran was added dropwise, and the reaction was stirred at room temperature for 2 hours. The title compound 1i is obtained, and the reaction solution is directly used in the next step.

Step 9

6-chloro-7-(3-((((5-(((6-hydroxy-2,3-dihydro-1 H -inden-4-yl)sulfanyl)methyl)-1-methyl- 1 H -pyrazol-3-yl)methyl)thio)methyl)-1,5-dimethyl-1 H -pyrazol-4-yl)-3-(3-methoxy-3- Pendant oxypropyl)-1-methyl-1 H -indole-2-carboxylic acid methyl ester 1k

Add 6-chloro-7-(3-((((5-(chloromethyl)-1-methyl-1 H -pyrazol-3-yl)methyl)thio)methyl)- 1,5-Dimethyl-1 H -pyrazol-4-yl)-3-(3-methoxy-3-oxopropyl)-1-methyl-1 H -indole-2- Methyl carboxylate 1j (150mg, 0.25mmol, prepared by the method disclosed in the patent application "WO2017182625 specification page 46 Intermediate 20") was dissolved in methanol (10mL) and tetrahydrofuran (3mL), and added dropwise under ice The reaction solution of the previous step was a 0.16 M compound 1i (2.4 mL, 0.38 mmol) in tetrahydrofuran solution, and the reaction was stirred at room temperature for 1 hour. The reaction solution was diluted with ethyl acetate (50mL), washed successively with water (30mL×3) and saturated sodium chloride solution (30mL×2), the organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and used a silica gel column. The residue obtained was purified by chromatography with the eluent system A to obtain the title compound 1k (200 mg, yield: 100%).

MS m/z(ESI): 722.0[M+1]

Tenth step

6-chloro-7-(3-((((5-(((6-hydroxy-2,3-dihydro-1 H -inden-4-yl)sulfanyl)methyl)-1-methyl- 1 H -pyrazol-3-yl)methyl)thio)methyl)-1,5-dimethyl-1 H -pyrazol-4-yl)-3-(3-hydroxypropyl)-1 -Methyl-1 H -indole-2-carboxylic acid methyl ester 1l

Compound 1k (200mg, 277μmol) was dissolved in tetrahydrofuran (3mL) at room temperature, the reaction solution was cooled to 0-5°C, 1.0M borane tetrahydrofuran solution (2.8mL) was slowly added dropwise, the reaction solution was warmed to room temperature, and continued The reaction was stirred for 16 hours. The reaction solution was cooled to 0-5°C, quenched with methanol, warmed to room temperature, stirred for 30 minutes, hydrochloric acid (3.2mL, 6.0N) was added, and stirring continued for 30 minutes. Dichloromethane and methanol (V:V=10:1) ) Extract with mixed solvent (30mL×3), combine the organic phases, wash with saturated sodium chloride solution (30mL), dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and use silica gel column chromatography to extract solvent system A The resulting residue was purified to obtain the title compound 11 (90 mg, yield: 46.8%).

MS m/z(ESI): 693.9 [M+1]

Eleventh step

17-chloro-5,13,14,22-tetramethyl-28-oxa-2,9-dithia-5,6,12,13,22-pentaazaheptane [27.6.1.1 ^{4, 11,15} .0 ^16,21 .0 ^7.0 .0 ^{20, 24, 31, 35]} thirty-seven 1 (36), 4 (37), 6,11,14,16,18,20,23, 29,31(35)-Undecene-23-carboxylic acid methyl ester 1m

Compound 1l (90mg, 130μmol) was dissolved in toluene (10mL) and tetrahydrofuran (5ml) at room temperature, tri-n-butylphosphine (131mg, 0.65mmol) was added, argon was replaced three times, and dipiperidine azodicarboxylate was added dropwise (163mg, 0.65mmol) in toluene solution (3mL), heated at 60°C and stirred for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue obtained was purified by silica gel column chromatography with eluent system A to obtain the title compound 1m (90 mg, yield: 100%).

MS m/z(ESI): 676.0[M+1]

Twelfth step

17-chloro-5,13,14,22-tetramethyl-28-oxa-2,9-dithia-5,6,12,13,22-pentaazaheptane [27.6.1.1 ^{4, 11,15} .0 ^16,21 .0 ^7.0 .0 ^{20, 24, 31, 35]} thirty-seven 1 (36), 4 (37), 6,11,14,16,18,20,23, 29,31(35)-Undecene-23-carboxylic acid 1

Compound 1m (90mg, 133μmol) was dissolved in 10mL of a mixed solution of tetrahydrofuran and methanol (V:V=1:1) at room temperature, and lithium hydroxide monohydrate (56mg, 1.33mmol) in water (2mL) was added , The reaction solution was heated to 50°C, and stirred for 1 hour. Cool to room temperature and dilute with water (15mL), concentrate under reduced pressure to remove most of the organic solvents, add dilute hydrochloric acid (1.0N) dropwise to pH=2-3, use dichloromethane and methanol (V:V=10:1) The mixed solvent (50mL×2) was extracted, the organic phases were combined, washed with water (30mL), saturated sodium chloride solution (30mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and purified by high performance liquid chromatography (Gilson GX-281, extraction system: H ₂ O (10 mmol NH ₄ OAc), ACN) to obtain the title compound 1 (20 mg, yield: 22.7%).

MS m/z(ESI): 662.0[M+1]

¹ H NMR (400MHz, CDCl ₃ ) δ 7.64-7.66 (m, 1H), 7.14-7.16 (m, 1H), 6.76 (s, 1H), 6.18 (s, 1H), 4.96 (s, 1H), 3.77 -3.89(m,5H),3.56-3.74(m,8H),3.43-3.55(m,2H),3.29-3.39(m,1H),3.09-3.20(m,2H),2.71-2.97(m, 5H), 2.11-2.37 (m, 2H), 1.96-2.11 (m, 5H).

Example 2

17-chloro-5,9,13,14,22-pentamethyl-28-oxa-2-thia-5,6,9,12,13,22-hexaazaheptane [27.6.1.1 ^{4 , 7.0 11,15} .0 ^16,21 .0 ^20,24 .0 ^31,35] thirty-seven 1 (36), 4 (37), 6,11,14,16,18,20,23 ,29,31(35)-Undecene-23-carboxylic acid 2

first step

1-(5-(((tert-butyldiphenylsilyl)oxy)methyl)-1-methyl-1 H -pyrazol-3-yl) -N -methylmethylamine 2b

The 5-(((tertiary butyldiphenylsilyl)oxy)methyl)-3-(chloromethyl)-1-methyl-1 H -pyrazole 2a (7g, 17.54mmol, patented Prepared by the method disclosed in “Intermediate 10 on page 39 of the specification of WO2017182625”) was dissolved in an ethanol solution of methylamine (~30wt%, 80mL), heated to 50°C, and stirred for 1 hour. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to obtain the title compound 2b (5.0 g, yield: 72.41%).

Second step

7-(3-((((5-(((tert-butyldiphenylsilyl)oxy)methyl)-1-methyl-1 H -pyrazol-3-yl)methyl)( (Methyl)amino)methyl)-1,5-dimethyl- 1H -pyrazol-4-yl)-6-chloro-3-(3-methoxy-3-oxopropyl) -1-Methyl-1 H -indole-2-carboxylic acid methyl ester 2d

Add 6-chloro-7-(3-(iodomethyl)-1,5-dimethyl- 1H -pyrazol-4-yl)-3-(3-methoxy-3-oxopropane Yl)-1-methyl-1 H -indole-2-carboxylic acid methyl ester 2c (4.8g, 8.83mmol, prepared by the method disclosed in the patent application "WO2017182625A1 specification page 44 Intermediate 17") N , N -dimethylformamide (50mL), potassium carbonate (3.7g, 26.77mmol, Titan) and 2b (4.2g, 10.67mmol) were added respectively, the reaction solution was heated to 60°C, and stirred for 1 hour . The reaction solution was cooled to room temperature, diluted with ethyl acetate (300mL), washed with water (100mL×2) and saturated sodium chloride solution (100mL×2), the organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure The residue obtained was purified by silica gel column chromatography with eluent system B to obtain the title compound 2d (5.0 g, yield: 70%).

MS m/z(ESI): 809.2[M+1]

third step

6-chloro-7-(3-((((5-(hydroxymethyl)-1-methyl-1 H -pyrazol-3-yl)methyl)(methyl)amino)methyl)- 1,5-Dimethyl-1 H -pyrazol-4-yl)-3-(3-methoxy-3-oxopropyl)-1-methyl-1 H -indole-2- Methyl carboxylate 2e

Compound 2d (4.8g, 5.93mmol) was dissolved in tetrahydrofuran (50mL) at room temperature, then tetra-n-butylammonium fluoride (6mL, 6.0mmol, 1M in tetrahydrofuran) was added dropwise, and the reaction solution was stirred at room temperature for reaction 1 hour. The reaction solution was concentrated under reduced pressure, the residue obtained was dissolved in ethyl acetate (200mL), washed with water (50mL×3) and saturated sodium chloride solution (50mL×2) successively, the organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate Concentrated under reduced pressure, and purified by silica gel column chromatography with eluent system A to obtain the title compound 2e (3.0 g, yield: 89%).

MS m/z(ESI): 571.2[M+1]

¹ H NMR (400MHz, CDCl ₃ ) δ 7.63 (d, 1H), 7.23 (d, 1H), 5.39 (s, 1H), 4.45 (s, 2H), 3.93 (s, 3H), 3.87 (s, 3H) ), 3.75(s, 3H), 3.63(s, 3H), 3.51(s, 3H), 3.50(bs, 1H), 3.47-3.42(m, 2H), 3.39-3.33(m, 2H), 3.27( d, 1H), 3.17 (d, 1H), 2.72-2.66 (m, 2H), 2.09 (s, 3H), 2.04 (s, 3H).

the fourth step

6-chloro-7-(3-((((5-(chloromethyl)-1-methyl-1 H -pyrazol-3-yl)methyl)(methyl)amino)methyl)- 1,5-Dimethyl-1 H -pyrazol-4-yl)-3-(3-methoxy-3-oxopropyl)-1-methyl-1 H -indole-2- Methyl carboxylate 2f

Compound 2e (3.0g, 5.25mmol) was dissolved in dichloromethane (30mL) at room temperature, the solution was cooled to 0-5°C, and sulfonium chloride (1.00mL, 13.78mmol) was slowly added dropwise to the reaction solution at room temperature The reaction was stirred for 30 minutes. The reaction solution was concentrated under reduced pressure to obtain the title compound 2f (3.0 g, yield: 97%), and the product was directly used in the next reaction without purification.

MS m/z(ESI): 589.2[M+1]

the fifth step

6-chloro-7-(3-((((5-(((6-hydroxy-2,3-dihydro-1 H -inden-4-yl)sulfanyl)methyl)-1-methyl- 1 H -pyrazol-3-yl)methyl)(methyl)amino)methyl)-1,5-dimethyl-1 H -pyrazol-4-yl)-3-(3-methoxy Group -3- pendant oxypropyl)-1-methyl-1 H -indole-2-carboxylic acid methyl ester 2g

Compound 2f (150mg, 0.25mmol) was dissolved in methanol (10mL) and tetrahydrofuran (3mL) at room temperature, and the reaction solution 0.16M 1i (2.4mL, 0.38mmol) in tetrahydrofuran was added dropwise under an ice bath. The reaction was stirred for 1 hour at warm temperature. The reaction solution was diluted with ethyl acetate (50mL), washed successively with water (30mL×3) and saturated sodium chloride solution (30mL×2), the organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and used a silica gel column. The residue obtained was purified by chromatography with the eluent system A to obtain the title compound 2g (130mg, yield: 71.0%).

MS m/z(ESI): 719.0[M+1]

Sixth step

6-chloro-7-(3-((((5-(((6-hydroxy-2,3-dihydro-1 H -inden-4-yl)sulfanyl)methyl)-1-methyl- 1 H -pyrazol-3-yl)methyl)(methyl)amino)methyl)-1,5-dimethyl-1 H -pyrazol-4-yl)-3-(3-hydroxypropane Base)-1-methyl-1 H -indole-2-carboxylic acid methyl ester 2h

Compound 2g (130mg, 181μmol) was dissolved in tetrahydrofuran (3mL) at room temperature, the reaction solution was cooled to 0-5°C, 1.0M borane tetrahydrofuran solution (1.8mL) was slowly added dropwise, the reaction solution was warmed to room temperature, and continued The reaction was stirred for 16 hours. The reaction solution was cooled to 0-5°C, quenched with methanol, warmed to room temperature, stirred for 30 minutes, hydrochloric acid (2.2mL, 6.0N) was added, and stirring was continued for 30 minutes, adjusted to pH=7 with sodium bicarbonate, dichloromethane and Extract with methanol (V:V=10:1) mixed solvent (30mL×3), combine the organic phases, wash with saturated sodium chloride solution (30mL), dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure with a silicone tube The resulting residue was purified by column chromatography with eluent system A to obtain the title compound 2h (40 mg, yield: 32.0%).

MS m/z(ESI): 691.0[M+1]

Seventh step

17-chloro-5,9,13,14,22-pentamethyl-28-oxa-2-thia-5,6,9,12,13,22-hexaazaheptane [27.6.1.1 ^{4 , 7.0 11,15} .0 ^16,21 .0 ^20,24 .0 ^31,35] thirty-seven 1 (36), 4 (37), 6,11,14,16 (21), 17, 19,23,29,31(35)-Undecene-23-carboxylic acid methyl ester 2i

Compound 2h (40mg, 58μmol) was dissolved in toluene (10mL) and tetrahydrofuran (5ml) at room temperature, tri-n-butylphosphine (58mg, 0.36mmol) was added, argon was replaced three times, and dipiperidine azodicarboxylate was added dropwise (73mg, 0.36mmol) in toluene solution (3mL), heated at 60°C and stirred for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue obtained was purified by silica gel column chromatography with eluent system A to obtain the title compound 2i (100 mg, yield: 100%).

MS m/z(ESI): 673.0[M+1]

Eighth step

17-chloro-5,9,13,14,22-pentamethyl-28-oxa-2-thia-5,6,9,12,13,22-hexaazaheptane [27.6.1.1 ^{4 , 7.0 11,15} .0 ^16,21 .0 ^20,24 .0 ^31,35] thirty-seven 1 (36), 4 (37), 6,11,14,16,18,20,23 ,29,31(35)-Undecene-23-carboxylic acid 2

Compound 2i (100mg, 149μmol) was dissolved in 10mL of a mixed solution of tetrahydrofuran and methanol (V:V=1:1) at room temperature, and lithium hydroxide monohydrate (62mg, 1.48mmol) in water (2mL) was added , The reaction solution was heated to 50°C, and stirred for 1 hour. Cool to room temperature and dilute with water (15mL), concentrate under reduced pressure to remove most of the organic solvents, add dilute hydrochloric acid (1.0N) dropwise to pH=6, mix with dichloromethane and methanol (V:V=10:1) Extract with solvent (50mL×2), combine the organic phases, wash with water (30mL), saturated sodium chloride solution (30mL), dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify by high performance liquid chromatography (Gilson GX- 281. Extraction system: H ₂ O (10 mmol NH ₄ OAc), ACN) to obtain the title compound 2 (20 mg, yield: 20.4%).

MS m/z(ESI): 659.0[M+1]

¹ H NMR (400MHz, CDCl ₃ ) δ 7.56-7.59 (m, 1H), 7.09-7.11 (m, 1H), 6.65 (s, 1H), 6.34 (s, 1H), 5.23 (s, 1H), 3.85 -4.00(m,5H),3.77-3.85(m,1H),3.59-3.76(m,5H),3.29-3.58(m,7H),3.15-3.26(m,1H),2.94-3.12(m, 2H), 2.65-2.92 (m, 4H), 1.93-2.34 (m, 8H).

Example 3

17-chloro-5,13,14,22-tetramethyl-28-oxa-2,9-dithia-5,6,12,13,22-pentaazaheptane [27.6.1.1 ^{4, 11,15} .0 ^16,21 .0 ^7.0 .0 ^{20,24 30,34]} thirty-seven 1 (36), 4 (37), 6,11,14,16,18,20,23, 29,34-Undecene-23-carboxylic acid 3

first step

6-Bromo-4-methoxy-2,3-dihydro-1 H -indene 3a

Compound 1e-2 (1.00 g, 4.15 mmol) was dissolved in trifluoroacetic acid (10 ml) at room temperature, triethyl silane (965 mg, 8.30 mmol) was added, and the mixture was heated at 80° C. and stirred for 1.5 hours. The reaction solution was concentrated under reduced pressure, ethyl acetate (50mL) and water (50mL) were added, and the layers were separated. The organic phase was washed with water and saturated sodium chloride each 30mL×3, dried over anhydrous sodium sulfate, filtered, concentrated to dryness, and used a silicone tube The resulting residue was purified by column chromatography with eluent system B to obtain the title compound 3a (880 mg, yield: 93.4%).

Second step

6-Bromo-2,3-dihydro-1 H -indene-4-phenol 3b

Compound 3a (900 mg, 3.96 mmol) was dissolved in 10 mL of dichloromethane at room temperature, and a 1M solution of boron tribromide (13.9 mL, 13.9 mmol) in dichloromethane was added dropwise under an ice bath, and the reaction was stirred at room temperature for 2 hours. The reaction solution was poured into ice water, extracted with dichloromethane (50mL×2), the organic phases were combined, washed with water (30mL), saturated sodium chloride solution (30mL), dried with anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was reduced Concentrate by pressure, and purify the residue obtained by silica gel column chromatography with eluent system B to obtain the title compound 3b (620 mg, yield: 73.4%).

MS m/z(ESI): 211.0 213.0 [M-1]

third step

3-((7-Hydroxy-2,3-dihydro-1 H -inden-5-yl)thio) 2-ethylhexyl propionate 3c

Compound 3b (620mg, 2.91mmol), 2-ethylhexyl 3-mercaptopropionate (762mg, 3.49mmol), N , N -diisopropylethylamine (752mg, 5.82mmol), tris( Dibenzylideneacetone) two palladium (133mg, 0.15mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (168mg, 0.29mmol) dissolved in 20mL dioxane , Replace with argon three times, heat at 95°C and stir for 16 hours. After filtering through a pad of Celite, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 3c (550 mg, yield: 53.9%).

MS m/z(ESI): 351.3[M+1]

the fourth step

6-Mercapto-2,3-dihydro-1 H -indene-4-phenol 3d

Compound 3c (550 mg, 1.57 mmol) was dissolved in 10 mL of tetrahydrofuran under ice bath, argon was replaced three times, 1M potassium tert-butoxide (5.0 mL, 5.0 mmol) in tetrahydrofuran was added dropwise, and the reaction was stirred at room temperature for 2 hours. The title compound 3d is obtained, and the reaction solution is directly in the next step.

the fifth step

6-chloro-7-(3-((((5-(((7-hydroxy-2,3-dihydro-1 H -inden-5-yl)sulfanyl)methyl)-1-methyl- 1 H -pyrazol-3-yl)methyl)thio)methyl)-1,5-dimethyl-1 H -pyrazol-4-yl)-3-(3-methoxy-3- Pendant oxypropyl)-1-methyl-1 H -indole-2-carboxylic acid methyl ester 3e

Dissolve compound 1j (150mg, 0.25mmol) in methanol (10mL) and tetrahydrofuran (3mL) at room temperature, add dropwise a step reaction solution of 0.16M compound 3d (1.6mL, 0.25mmol) in tetrahydrofuran under ice bath, The reaction was stirred at room temperature for 1 hour. The reaction solution was diluted with ethyl acetate (50mL), washed successively with water (30mL×3) and saturated sodium chloride solution (30mL×2), the organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and used a silica gel column. The residue obtained was purified by chromatography with the eluent system A to obtain the title compound 3e (150 mg, yield: 82.0%).

MS m/z(ESI): 721.9[M+1]

Sixth step

6-chloro-7-(3-((((5-(((7-hydroxy-2,3-dihydro-1 H -inden-5-yl)sulfanyl)methyl)-1-methyl- 1 H -pyrazol-3-yl)methyl)thio)methyl)-1,5-dimethyl-1 H -pyrazol-4-yl)-3-(3-hydroxypropyl)-1 -Methyl-1 H -indole-2-carboxylic acid methyl ester 3f

Compound 3e (150mg, 208μmol) was dissolved in tetrahydrofuran (3mL) at room temperature, the reaction solution was cooled to 0-5°C, 1.0M borane tetrahydrofuran solution (2.1mL) was slowly added dropwise, the reaction solution was warmed to room temperature, and continued The reaction was stirred for 16 hours. The reaction solution was cooled to 0-5°C, quenched with methanol, warmed to room temperature, stirred for 30 minutes, hydrochloric acid (3.2mL, 6.0N) was added, and stirring continued for 30 minutes. Dichloromethane and methanol (V:V=10:1) ) Extract with mixed solvent (30mL×3), combine the organic phases, wash with saturated sodium chloride solution (30mL), dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and use silica gel column chromatography to extract solvent system A The resulting residue was purified to obtain the title compound 3f (80 mg, yield: 55.5%).

MS m/z(ESI): 693.8[M+1]

Seventh step

17-chloro-5,13,14,22-tetramethyl-28-oxa-2,9-dithia-5,6,12,13,22-pentaazaheptane [27.6.1.1 ^{4, 11,15} .0 ^16,21 .0 ^7.0 .0 ^{20,24 30,34]} thirty-seven 1 (36), 4 (37), 6,11,14,16,18,20,23, 29,34-undecene-23-carboxylic acid methyl ester 3g

Compound 3f (80mg, 115μmol) was dissolved in toluene (10mL) and tetrahydrofuran (5mL) at room temperature, tri-n-butylphosphine (116mg, 0.57mmol) was added, argon was replaced three times, and dipiperidine azodicarboxylate was added dropwise (145mg, 0.58mmol) in toluene solution (3mL), heated at 60°C and stirred for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue obtained was purified by silica gel column chromatography with eluent system A to obtain 3 g of the title compound (50 mg, yield: 64.2%).

MS m/z(ESI): 676.0[M+1]

Eighth step

17-chloro-5,13,14,22-tetramethyl-28-oxa-2,9-dithia-5,6,12,13,22-pentaazaheptane [27.6.1.1 ^{4, 11,15} .0 ^16,21 .0 ^7.0 .0 ^{20,24 30,34]} thirty-seven 1 (36), 4 (37), 6,11,14,16,18,20,23, 29,34-Undecene-23-carboxylic acid 3

Compound 3g (50mg, 74μmol) was dissolved in 10mL of a mixed solution of tetrahydrofuran and methanol (V:V=1:1) at room temperature, and lithium hydroxide monohydrate (31mg, 0.74mmol) in water (2mL) was added , The reaction solution was heated to 50°C, and stirred for 1 hour. Cool to room temperature and dilute with water (15mL), concentrate under reduced pressure to remove most of the organic solvents, add dilute hydrochloric acid (1.0N) dropwise to pH=2-3, use dichloromethane and methanol (V:V=10:1) The mixed solvent (50mL×2) was extracted, the organic phases were combined, washed with water (30mL), saturated sodium chloride solution (30mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and purified by high performance liquid chromatography (Gilson GX-281, extraction system: H ₂ O (10 mmol NH ₄ OAc), ACN) to obtain the title compound 3 (10 mg, white solid, yield: 20.4%).

MS m/z(ESI): 662.0[M+1]

¹ H NMR (400MHz, CDCl ₃ ) δ 7.52-7.54 (m, 1H), 7.04-7.06 (m, 1H), 6.96 (s, 1H), 6.07 (s, 1H), 4.89 (s, 1H), 3.85 (s,3H),3.73-3.82(m,2H),3.62-3.72(m,7H),3.54-3.62(m,1H),3.38-3.52(m,2H),3.30-3.37(m,1H) , 3.03-3.18 (m, 2H), 2.80-3.03 (m, 4H), 2.51-2.63 (m, 1H), 2.19-2.30 (m, 1H), 2.01-2.17 (m, 6H).

Example 4

17-chloro-5,9,13,14,22-pentamethyl-28-oxa-2-thia-5,6,9,12,13,22-hexaazaheptane [27.6.1.1 ^{4 , 7.0 11,15} .0 ^16,21 .0 ^20,24 .0 ^30,34] thirty-seven 1 (36), 4 (37), 6,11,14,16,18,20,23 ,29,34-Undecene-23-carboxylic acid 4

first step

6-chloro-7-(3-((((5-(((7-hydroxy-2,3-dihydro-1 H -inden-5-yl)sulfanyl)methyl)-1-methyl- 1 H -pyrazol-3-yl)methyl)(methyl)amino)methyl)-1,5-dimethyl-1 H -pyrazol-4-yl)-3-(3-methoxy Propyl-3-oxopropyl)-1-methyl-1 H -indole-2-carboxylic acid methyl ester 4a

Dissolve compound 2f (150mg, 0.25mmol) in methanol (10mL) and tetrahydrofuran (3mL) at room temperature, add dropwise a reaction solution of 0.16M compound 3d (2.6 mL, 0.41mmol) in tetrahydrofuran under ice bath, The reaction was stirred at room temperature for 1 hour. The reaction solution was diluted with ethyl acetate (50mL), washed successively with water (30mL×3) and saturated sodium chloride solution (30mL×2), the organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and used a silica gel column. The resulting residue was purified by chromatography with eluent system A to obtain the title compound 4a (150 mg, yield: 82.0%).

MS m/z(ESI): 719.0[M+1]

Second step

6-chloro-7-(3-((((5-(((7-hydroxy-2,3-dihydro-1 H -inden-5-yl)sulfanyl)methyl)-1-methyl- 1 H -pyrazol-3-yl)methyl)(methyl)amino)methyl)-1,5-dimethyl-1 H -pyrazol-4-yl)-3-(3-hydroxypropane Yl)-1-methyl-1 H -indole-2-carboxylic acid methyl ester 4b

Compound 4a (150mg, 209μmol) was dissolved in tetrahydrofuran (3mL) at room temperature, the reaction solution was cooled to 0-5°C, 1.0M borane tetrahydrofuran solution (2.1mL) was slowly added dropwise, the reaction solution was warmed to room temperature, and continued The reaction was stirred for 16 hours. The reaction solution was cooled to 0-5°C, quenched with methanol, warmed to room temperature, stirred for 30 minutes, hydrochloric acid (3.2mL, 6.0N) was added, and stirring was continued for 30 minutes, adjusted to pH=7 with sodium bicarbonate, dichloromethane and Extract with methanol (V:V=10:1) mixed solvent (30mL×3), combine the organic phases, wash with saturated sodium chloride solution (30mL), dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure with a silicone tube The resulting residue was purified by column chromatography with eluent system A to obtain the title compound 4b (100 mg, yield: 69.4%).

MS m/z(ESI): 691.0[M+1]

third step

17-chloro-5,9,13,14,22-pentamethyl-28-oxa-2-thia-5,6,9,12,13,22-hexaazaheptane [27.6.1.1 ^{4 , 7.0 11,15} .0 ^16,21 .0 ^20,24 .0 ^30,34] thirty-seven 1 (36), 4 (37), 6,11,14,1618,20,23,29 ,34-Undecene-23-carboxylic acid methyl ester 4c

Compound 4b (100mg, 145μmol) was dissolved in toluene (10mL) and tetrahydrofuran (5ml) at room temperature, tri-n-butylphosphine (146mg, 0.72mmol) was added, argon was replaced three times, azodicarbazide was added dropwise A solution of pyridine (182mg, 0.72mmol) in toluene (3mL) was heated at 60°C and stirred for 2 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to obtain the title compound 4c (60 mg, yield: 61.6%).

MS m/z(ESI): 673.0[M+1]

the fourth step

17-chloro-5,9,13,14,22-pentamethyl-28-oxa-2-thia-5,6,9,12,13,22-hexaazaheptane [27.6.1.1 ^{4 , 7.0 11,15} .0 ^16,21 .0 ^20,24 .0 ^30,34] thirty-seven 1 (36), 4 (37), 6,11,14,16,18,20,23 ,29,34-Undecene-23-carboxylic acid 4

Compound 2i (60mg, 89μmol) was dissolved in 10mL of a mixed solution of tetrahydrofuran and methanol (V:V=1:1) at room temperature, and lithium hydroxide monohydrate (37mg, 0.88mmol) in water (2mL) was added , The reaction solution was heated to 50°C, and stirred for 1 hour. Cool to room temperature and dilute with water (15mL), concentrate under reduced pressure to remove most of the organic solvents, add dilute hydrochloric acid (1.0N) dropwise to pH=6, mix with dichloromethane and methanol (V:V=10:1) Extract with solvent (50mL×2), combine the organic phases, wash with water (30mL), saturated sodium chloride solution (30mL), dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify by high performance liquid chromatography (Gilson GX- 281. Extraction system: H ₂ O (10 mmol NH ₄ OAc), ACN) to obtain the title compound 4 (10 mg, yield: 17.0%).

MS m/z(ESI): 659.0[M+1]

¹ H NMR (400MHz, CDCl ₃ ) δ 7.52-7.54 (m, 1H), 7.06-7.09 (m, 1H), 6.84 (s, 1H), 6.27 (s, 1H), 5.26 (s, 1H), 3.77 -3.96(m,6H),3.64-3.75(m,4H),3.45-3.64(m,6H),3.37-3.45(m,3H),2.96-3.17(m,2H),2.76-2.96(m, 3H), 2.20.-3.34 (m, 3H), 1.99-2.20 (m, 6H).

Example 5

17-chloro-5,9,13,14,22-pentamethyl-28-oxa-2-thia-5,6,9,12,13,22-hexaazaheptane [27.7.1.1 ^{4 , 7.0 11,15} .0 ^16,21 .0 ^20,24 .0 ^30,35] thirty-eight 1 (37), 4 (38), 6,11,14,16,18,20,23 ,29,35-Undecene-23-carboxylic acid 5

first step

2-(4-Bromo-2-methoxyphenyl)ethanol 5b

4-Bromo-2-methoxyphenylacetic acid 5a (5.00g, 20.40mmol) was dissolved in tetrahydrofuran (50mL), the reaction solution was cooled to 0-5°C, and 1M borane tetrahydrofuran solution (27mL) was slowly added dropwise to react. The solution was warmed to room temperature, and the reaction was stirred for 16 hours. The reaction solution was cooled to 0-5°C, quenched with methanol (6mL), added water (12mL), stirred for 30 minutes, extracted with ethyl acetate (50mL×3), combined the organic phases, and used saturated sodium chloride solution (30mL) It was washed, dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound 5b (4.71 g, yield: 100%).

Second step

2-(4-Bromo-2-methoxyphenyl)acetaldehyde 5c

Compound 5b (3.70g, 16.01mmol) was dissolved in dichloromethane (50mL), and Dess-Martin oxidant (10.19g, 24.03mmol) was added in batches under ice bath. The reaction solution was raised to room temperature and stirred for 1 hour. . Under ice bath, add 50mL of water and dichloromethane, add saturated sodium thiosulfate and saturated sodium bicarbonate, separate the liquids, wash the organic phase with saturated sodium chloride solution three times, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure The residue obtained was purified by silica gel column chromatography with eluent system B to obtain the title compound 5c (3.00 g, yield: 81.8%).

third step

( E )-4-(4-Bromo-2-methoxyphenyl)but-2-enoic acid methyl ester 5d

Sodium hydride (753mg, 19.65mmol, 60% purity) was dissolved in tetrahydrofuran (30mL), replaced with argon three times, and trimethylphosphoranyl acetate (3.58g, 19.66mmol) was added dropwise under an ice bath. After stirring for 30 minutes, a solution of compound 5c in tetrahydrofuran (10 mL) was added dropwise, and the reaction solution was stirred and reacted at room temperature for 1 hour. Under ice bath, add ethyl acetate (100mL) and water (100mL), separate the layers, wash the organic phase with saturated sodium chloride solution (30mL×2), dry the organic phase with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue obtained was purified by silica gel column chromatography with eluent system B to obtain the title compound 5d (2.37 g, yield: 63.5%).

MS m/z(ESI): 285.0 287.0[M+1]

the fourth step

Methyl 4-(4-bromo-2-methoxyphenyl)butyrate 5e

Compound 5d (2.80 g, 9.82 mmol) was dissolved in methanol (50 mL) at room temperature, dry 5% rhodium carbon (280 mg) was added, and hydrogen was replaced three times. The reaction solution was stirred at room temperature for 60 minutes. The reaction solution was filtered and concentrated under reduced pressure to obtain the title compound 5e (2.50 g, yield: 88.7%).

MS m/z(ESI): 287.1 289.1 [M+1]

the fifth step

4-(4-Bromo-2-methoxyphenyl)butyric acid 5f

Dissolve crude product 5e (3.60g, 12.54mmol) in methanol (30mL), tetrahydrofuran (30mL) and water (30mL) at room temperature, add lithium hydroxide monohydrate (2.63g, 62.67mmol), heat at 50°C and stir React for 1 hour. The reaction solution was concentrated under reduced pressure, water and dichloromethane (100mL) were added, the pH was adjusted to 2-3 with 1M hydrochloric acid, and the mixture was extracted with dichloromethane and methanol (V:V=10:1) (50mL). The organic phase was washed successively with water (30mL×3) and saturated sodium chloride solution (30mL×2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound 5f (3.40g, yield: 99.3%).

MS m/z(ESI): 271.1 273.1[M-1]

Sixth step

7-bromo-5-methoxy-3,4-dihydronaphthalene-1( 2H )-one 5g

Compound 5f (3.40g, 12.45mmol) was weighed into a 100mL reaction flask at room temperature, polyphosphoric acid (60g, 17.75mmol) was added, and the reaction was stirred at 95°C for 1.5 hours. Pour into ice water, add dichloromethane (100mL), separate the liquids, wash the organic phase with sodium bicarbonate, water and saturated sodium chloride each 30mL×3, dry with anhydrous sodium sulfate, filter, filtrate decompression concentration, use silica gel The residue obtained was purified by column chromatography with eluent system B to obtain 5 g of the title compound (1.76 g, yield: 55.4%).

MS m/z(ESI): 255.1 257.1[M+1]

Seventh step

7-Bromo-5-methoxy-1,2,3,4-tetrahydronaphthalene 5h

Compound 5g (1.76g, 6.90mmol) was dissolved in trifluoroacetic acid (20ml) at room temperature, triethylsilane (1.60g, 13.76mmol) was added, and the reaction was stirred at 80°C for 1.5 hours. The reaction solution was concentrated under reduced pressure, ethyl acetate (50mL) and water (50mL) were added, and the layers were separated. The organic phase was washed with water and saturated sodium chloride each 30mL×3, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography with eluent system B to obtain the title compound 5h (1.60 g, yield: 96.2%).

Eighth step

3-bromo-5,6,7,8-tetralin-1-phenol 5i

Dissolve compound 5h (1.55g, 6.43mmol) in 20mL of dichloromethane at room temperature, add 1M boron tribromide (22.5mL, 22.5mmol) in dichloromethane solution dropwise under ice bath, stir and react at room temperature for 2 hours . The reaction solution was poured into ice water, extracted with dichloromethane (50mL×2), the organic phases were combined, washed with water (30mL), saturated sodium chloride solution (30mL), dried with anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was reduced It was concentrated under pressure, and the residue obtained was purified by silica gel column chromatography with eluent system B to obtain the title compound 5i (1.40 g, yield: 95.9%).

MS m/z(ESI): 225.0 227.0[M-1]

Step 9

3-((4-Hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)thio) 2-ethylhexyl propionate 5j

Compound 5i (500mg, 2.20mmol), 2-ethylhexyl 3-mercaptopropionate (577mg, 2.64mmol), N , N -diisopropylethylamine (569mg, 4.40mmol), tris( Dibenzylideneacetone) two palladium (101mg, 0.11mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (127mg, 0.22mmol) dissolved in 20mL dioxane , Replace with argon three times, heat at 95°C and stir for 16 hours. Filtered through a pad of celite, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 5j (800 mg, yield: 99.7%).

MS m/z(ESI): 365.3[M+1]

Tenth step

3-mercapto-5,6,7,8-tetralin-1-phenol 5k

Compound 5j (650 mg, 1.78 mmol) was dissolved in 20 mL of tetrahydrofuran under ice bath, argon was replaced three times, 1M potassium tert-butoxide (5.7 mL, 5.70 mmol) in tetrahydrofuran was added dropwise, and the reaction was stirred at room temperature for 2 hours. The title compound 5k was obtained, and the reaction solution was directly used for the next step.

Eleventh step

6-chloro-7-(3-((((5-(((4-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)thio)methyl)-1-methyl- 1 H -pyrazol-3-yl)methyl)(methyl)amino)methyl)-1,5-dimethyl-1 H -pyrazol-4-yl)-3-(3-methoxy Group -3- pendant oxypropyl)-1-methyl-1 H -indole-2-carboxylic acid methyl ester 5l

Compound 2f (309mg, 0.52mmol) was dissolved in methanol (20mL) and tetrahydrofuran (8mL) at room temperature, and a step reaction solution of 0.07M compound 5k (7.4mL, 0.52mmol) in tetrahydrofuran was added dropwise under an ice bath, The reaction was stirred at room temperature for 1 hour. The reaction solution was diluted with ethyl acetate (50mL), washed successively with water (30mL×3) and saturated sodium chloride solution (30mL×2), the organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and used a silica gel column. The residue obtained was purified by chromatography with eluent system A to obtain the title compound 51 (140 mg, yield: 36.4%).

MS m/z(ESI): 733.3[M+1]

Twelfth step

6-chloro-7-(3-((((5-(((4-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)thio)methyl)-1-methyl- 1 H -pyrazol-3-yl)methyl)(methyl)amino)methyl)-1,5-dimethyl-1 H -pyrazol-4-yl)-3-(3-hydroxypropane Base)-1-methyl-1 H -indole-2-carboxylic acid methyl ester 5m

Compound 5l (100mg, 136μmol) was dissolved in tetrahydrofuran (5mL) at room temperature, the reaction solution was cooled to 0-5°C, 1.0M borane tetrahydrofuran solution (1.4mL) was slowly added dropwise, the reaction solution was warmed to room temperature, and continued The reaction was stirred for 16 hours. The reaction solution was cooled to 0-5°C, quenched with methanol, warmed to room temperature, stirred for 30 minutes, hydrochloric acid (0.76mL, 6.0N) was added, and stirring continued for 30 minutes, adjusted to pH=7 with sodium bicarbonate, dichloromethane and Extract with methanol (V:V=10:1) mixed solvent (30mL×3), combine the organic phases, wash with saturated sodium chloride solution (30mL), dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure with a silicone tube The resulting residue was purified by column chromatography with eluent system A to obtain the title compound 5m (46 mg, yield: 47.8%).

MS m/z(ESI): 705.4[M+1]

Step 13

17-chloro-5,9,13,14,22-pentamethyl-28-oxa-2-thia-5,6,9,12,13,22-hexaazaheptane [27.7.1.1 ^{4 , 7.0 11,15} .0 ^16,21 .0 ^20,24 .0 ^30,35] thirty-eight 1 (37), 4 (38), 6,11,14,16,18,20,23 ,29,35-Undecene-23-carboxylic acid methyl ester 5n

Compound 5m (46mg, 65μmol) was dissolved in toluene (10mL) and tetrahydrofuran (1ml) at room temperature, tri-n-butylphosphine (66mg, 0.33mmol) was added, argon was replaced three times, and dipiperidine azodicarboxylate was added dropwise (83mg, 0.33mmol) in toluene solution (5mL), heated at 60°C and stirred for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue obtained was purified by silica gel column chromatography with eluent system A to obtain the title compound 5n (20 mg, yield: 44.6%).

MS m/z(ESI): 687.3[M+1]

Step Fourteen

17-chloro-5,9,13,14,22-pentamethyl-28-oxa-2-thia-5,6,9,12,13,22-hexaazaheptane [27.7.1.1 ^{4 , 7.0 11,15} .0 ^16,21 .0 ^20,24 .0 ^30,35] thirty-eight 1 (37), 4 (38), 6,11,14,16,18,20,23 ,29,35-Undecene-23-carboxylic acid 5

Compound 5n (20mg, 29μmol) was dissolved in 4mL of a mixed solution of tetrahydrofuran and methanol (V:V=1:1) at room temperature, and lithium hydroxide monohydrate (13mg, 0.31mmol) in water (2mL) was added , The reaction solution was heated to 50°C, and the reaction was stirred for 2 hours. Cool to room temperature and dilute with water (15mL), concentrate under reduced pressure to remove most of the organic solvents, add dilute hydrochloric acid (1.0N) dropwise to pH=6, mix with dichloromethane and methanol (V:V=10:1) Solvent (50mL×2) extraction, combined organic phases, washed with water (30mL), saturated sodium chloride solution (30mL), dried over anhydrous sodium sulfate, filtered to remove the desiccant, the filtrate was concentrated under reduced pressure, and purified by high performance liquid chromatography ( Gilson GX-281, extraction system: H ₂ O (10 mmol NH ₄ OAc), ACN), to obtain the title compound 5 (3 mg, yield: 15.3%).

MS m/z(ESI): 673.3[M+1]

¹ H NMR (400MHz, DMSO- d ₆ ) 8.34 (d, 1H), 7.72 (d, 1H), 6.95 (s, 1H), 6.06 (s, 1H), 5.86-5.74 (m, 1H), 4.66 4.58(m,1H),4.55-4.43(m,1H),4.32(s,3H),4.25-4.16(m,5H),4.12-3.97(m,5H),3.72-3.62(m,1H), 3.59-3.48 (m, 2H), 3.06-2.91 (m, 4H), 2.79-2.62 (m, 2H), 2.62-2.51 (m, 6H), 2.20-1.94 (m, 6H).

Example 6

17-Chloro-5,13,14,22,31-Pentamethyl-28-oxa-2,9-dithia-5,6,12,13,22-Pentazahexacyclo [27.3.1.1 ^4,7 .0 ^11,15 .0 ^{16,21.0 20,24} ] 34-1(33),4(34),6,11,14,16,18,20,23,29,31 -Undecene-23-carboxylic acid 6

first step

3-((3-Hydroxy-5-methylphenyl)thio)propionic acid 2-ethylhexyl ester 6c

Dissolve 3-bromo-5-methylphenol 6a (550mg, 2.94mmol, adamas) and 2-ethylhexyl 3-mercaptopropionate 6b ((800mg, 3.66mmol, TCI) in dioxane (10mL), Add N , N -diisopropylethylamine ((760mg, 5.88mmol), three (dibenzylidene indene acetone) two palladium ((140mg, 0.15mmol, adamas) and 4,5-bisdiphenylphosphine- 9,9-Dimethylxanthene ((190mg, 0.33mmol, Shaoyuan). Under the protection of nitrogen, the temperature was raised to 100°C and stirred for 3 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure with silica gel The resulting residue was purified by column chromatography with eluent system B to obtain the title compound 6c (620 mg, 65.98%).

MS m/z(ESI): 325.2[M+1

Second step

3-mercapto-5-methylphenol 6d

Dissolve metallic sodium (140mg, 6.09mmol, Sinopharm) in absolute ethanol (2mL). After the dissolution is complete, add this solution to the ethanol solution of compound 6c (400mg 6c is dissolved in 4.0mL ethanol) and stir at room temperature for 16 hours . After concentration, the solid was washed with dichloromethane, filtered, and the filter cake was collected and dried under vacuum to obtain the title compound 6d (120 mg, crude product), which was directly subjected to the next reaction without purification.

MS m/z(ESI): 140.2[M+1]

third step

6-chloro-7-(3-((((5-(chloromethyl)-1-methyl-1 H -pyrazol-3-yl)methyl)sulfanyl)methyl)-1,5- Dimethyl-1 H -pyrazol-4-yl)-3-(3-hydroxypropyl)-1-methyl-1 H -indole-2-carboxylic acid methyl ester 6e

Compound 1j (1.0g, 5.93mmol) was dissolved in tetrahydrofuran (10mL), and 1M borane tetrahydrofuran solution (10mL, adamas) was slowly added dropwise at 0°C. After adding to room temperature, the reaction was continued to stir for 6 hours. The reaction solution was cooled to 0-5°C, quenched with methanol, warmed to room temperature, stirred for 30 minutes, hydrochloric acid (10mL, 6.0N) was added, and stirring continued for 0.5 hours, water ((50mL), ethyl acetate (50mL×2) was added After extraction, the organic phases were combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue obtained was purified by silica gel column chromatography with eluent system A to obtain the title compound 6e (550mg, yield: 57.53%).

MS m/z(ESI): 564.2[M+1]

the fourth step

6-Chloro-7-(3-((((5-(((3-hydroxy-5-methylphenyl)thio)methyl)-1-methyl-1 H -pyrazol-3-yl )Methyl)sulfanyl)methyl)-1,5-dimethyl- 1H -pyrazol-4-yl)-3-(3-hydroxypropyl)-1-methyl- 1H -indole- Methyl 2-carboxylate 6f

Dissolve compound 6e (400mg, 0.71mmol) and compound 6d (120mg, 0.86mmol) in N , N -dimethylformamide (6.0mL), add potassium carbonate (490mg, 3.55mmol, Sinopharm) at room temperature The reaction was stirred for 10 hours. Add water (10 mL), extract with ethyl acetate (10 mL), concentrate, and purify the resulting residue with eluent system A using thin layer chromatography to obtain the title compound 6f (300 mg, yield: 63.35%).

MS m/z(ESI): 668.2[M+1]

the fifth step

17-Chloro-5,13,14,22,31-Pentamethyl-28-oxa-2,9-dithia-5,6,12,13,22-Pentazahexacyclo [27.3.1.1 ^4,7 .0 ^11,15 .0 ^{16,21.0 20,24} ] 34-1(33),4(34),6,11,14,16,18,20,23,29,31 -Undecene-23-carboxylic acid methyl ester 6g

Compound 6f (300mg, 0.49mmol) and tributylphosphine (400mg, 1.98mmol, adamas) were dissolved in toluene (20mL), argon was replaced three times, and dipiperidine azodicarboxylate (500mg, 1.98mmol, Shao Far), react at 60°C for 3 hours, add water (10mL), extract with ethyl acetate (10mL), concentrate, and purify the resulting residue by silica gel column chromatography with eluent system A to obtain the title compound 6g (150mg, yield : 51.37%).

MS m/z(ESI): 650.2[M+1]

Sixth step

17-Chloro-5,13,14,22,31-Pentamethyl-28-oxa-2,9-dithia-5,6,12,13,22-Pentazahexacyclo [27.3.1.1 ^4,7 .0 ^11,15 .0 ^{16,21.0 20,24} ] 34-1(33),4(34),6,11,14,16,18,20,23,29,31 -Undecene-23-carboxylic acid 6

Compound 6g (15mg, 23.11μmol) was dissolved in 1mL of a mixed solution of tetrahydrofuran and methanol (V:V=1:1) at room temperature, and lithium hydroxide monohydrate (10mg, 238.10μmol, Sinopharm) was added in water ( 0.3mL) solution, stirred and reacted at 50°C for 1 hour. Cool to room temperature, add dilute hydrochloric acid (1.0N) dropwise to pH=4-5, extract with ethyl acetate (5mL×2), filter, concentrate, and purify by high performance liquid chromatography (Gilson GX-281, extraction system : Water (10 mmol ammonium acetate, acetonitrile) to obtain the title compound 6 (3 mg, yield: 20.44%).

MS m/z(ESI): 636.2[M+1]

¹ H NMR (400MHz, CD ₃ OD) δ 7.73 (d, 1H), 7.16 (d, 1H), 6.76 (s, 1H), 6.67 (s, 1H), 6.34 (s, 1H), 4.86 (s, 1H), 4.07-3.95 (m, 2H), 3.84 (s, 3H), 3.73 (s, 3H), 3.71-3.63 (m, 5H), 3.49-3.46 (m, 2H), 3.33-3.32 (m, 1H), 3.15-3.11 (m, 2H), 2.78-2.75 (m, 1H), 2.25 (s, 3H), 2.22-2.10 (m, 2H), 2.15 (s, 3H).

Examples 6-1, 6-2

( Ra )-17-Chloro-5,13,14,22,31-Pentamethyl-28-oxa-2,9-dithia-5,6,12,13,22-Pentazahexacyclo ^{[27.3.1.1 4,7 .0 11,15 .0 16,21 .0} 20,24] thirty-four 1 (33), 4 (34), 6,11,14,16,18,20,23 ,29,31-Undecene-23-carboxylic acid 6-1

( Sa )-17-chloro-5,13,14,22,31-pentamethyl-28-oxa-2,9-dithia-5,6,12,13,22-pentaazahexacyclo ^{[27.3.1.1 4,7 .0 11,15 .0 16,21 .0} 20,24] thirty-four 1 (33), 4 (34), 6,11,14,16,18,20,23 ,29,31-Undecene-23-carboxylic acid 6-2

first step

( Ra )-17-Chloro-5,13,14,22,31-Pentamethyl-28-oxa-2,9-dithia-5,6,12,13,22-Pentazahexacyclo ^{[27.3.1.1 4,7 .0 11,15 .0 16,21 .0} 20,24] thirty-four 1 (33), 4 (34), 6,11,14,16,18,20,23 ,29,31-Undecene-23-carboxylic acid methyl ester 6g-1

( Sa )-17-chloro-5,13,14,22,31-pentamethyl-28-oxa-2,9-dithia-5,6,12,13,22-pentaazahexacyclo ^{[27.3.1.1 4,7 .0 11,15 .0 16,21 .0} 20,24] thirty-four 1 (33), 4 (34), 6,11,14,16,18,20,23 ,29,31-Undecene-23-carboxylic acid methyl ester 6g-2

The compound 6g (150mg, 0.23mmol) was chirally prepared (separation conditions: CHIRALPAK IF chiral preparation column, Prep 20*250mm; 5um; mobile phase: n-hexane/ethanol/diethylamine=70/30/0.1( V/V/V)), flow rate: 20 mL/min), collect the corresponding components, and concentrate under reduced pressure to obtain the title compound (70 mg, 70 mg).

Single configuration compound (shorter retention time)

MS m/z(ESI): 650.2[M+1]

Chiral HPLC analysis: retention time 6.214min, chiral purity: 100% (chromatographic column: CHIRALPAK IG 150*4.6mm, 5um; flow rate: 1.0ml/min; mobile phase: n-hexane/ethanol/trifluoroacetic acid=75 /25/0.1(v/v/v).

Single configuration compound (longer retention time)

MS m/z(ESI): 650.2[M+1]

Chiral HPLC analysis: retention time 10.652min, chiral purity: 100% (chromatographic column: CHIRALPAK IG 150*4.6mm, 5um; flow rate: 1.0ml/min; mobile phase: n-hexane/ethanol/trifluoroacetic acid=75 /25/0.1(v/v/v).

Second step

( Ra )-17-Chloro-5,13,14,22,31-Pentamethyl-28-oxa-2,9-dithia-5,6,12,13,22-Pentazahexacyclo ^{[27.3.1.1 4,7 .0 11,15 .0 16,21 .0} 20,24] thirty-four 1 (33), 4 (34), 6,11,14,16,18,20,23 ,29,31-Undecene-23-carboxylic acid 6-1

( Sa )-17-chloro-5,13,14,22,31-pentamethyl-28-oxa-2,9-dithia-5,6,12,13,22-pentaazahexacyclo ^{[27.3.1.1 4,7 .0 11,15 .0 16,21 .0} 20,24] thirty-four 1 (33), 4 (34), 6,11,14,16,18,20,23 ,29,31-Undecene-23-carboxylic acid 6-2

The compound obtained in the first step (70mg/70mg, 107.65μmol/107.65μmol) was dissolved in 2.5mL tetrahydrofuran/methanol/water (V:V:V=2:2:1) mixed solution at room temperature, and added Lithium hydroxide monohydrate (45mg/45mg, 1.07mmol/1.07mmol) was reacted at 50°C for 1 hour. Cool to room temperature, add dilute hydrochloric acid (1.0N) to pH=4~5, extract with EA (5mL×2), dry, concentrate, and purify by high performance liquid chromatography (Gilson GX-281, extraction system: water ( 10mmol ammonium acetate), acetonitrile) to obtain the title compound (40mg, 40mg) respectively.

Single configuration compound (shorter retention time)

MS m/z(ESI): 636.2[M+1]

Chiral HPLC analysis: retention time 6.208min, chiral purity: 100% (chromatographic column: CHIRALPAK IG 150*4.6mm, 5um; flow rate: 1.0ml/min; mobile phase: n-hexane/ethanol/trifluoroacetic acid=75 /25/0.1(v/v/v)).

¹ H NMR (400MHz, CD ₃ OD) δ 7.72 (d, 1H), 7.15 (d, 1H), 6.76 (s, 1H), 6.67 (s, 1H), 6.34 (s, 1H), 4.87 (s, 1H), 4.07-3.95 (m, 2H), 3.84 (s, 3H), 3.73 (s, 3H), 3.71-3.63 (m, 5H), 3.49-3.46 (m, 2H), 3.33-3.32 (m, 1H), 3.15-3.11 (m, 2H), 2.78-2.75 (m, 1H), 2.25 (s, 3H), 2.22-2.10 (m, 2H), 2.09 (s, 3H).

Single configuration compound (longer retention time)

MS m/z(ESI): 636.2[M+1]

Chiral HPLC analysis: retention time 10.649min, chiral purity: 95.2% (chromatographic column: CHIRALPAK IG 150*4.6mm, 5um; flow rate: 1.0ml/min; mobile phase: n-hexane/ethanol/trifluoroacetic acid=75 /25/0.1(v/v/v)).

¹ H NMR (400MHz, CD ₃ OD) δ 7.74 (d, 1H), 7.16 (d, 1H), 6.76 (s, 1H), 6.67 (s, 1H), 6.33 (s, 1H), 4.89 (s, 1H), 4.06-3.95 (m, 2H), 3.84 (s, 3H), 3.73 (s, 3H), 3.71-3.63 (m, 5H), 3.49-3.46 (m, 2H), 3.33-3.32 (m, 1H), 3.15-3.11 (m, 2H), 2.78-2.75 (m, 1H), 2.25 (s, 3H), 2.22-2.10 (m, 2H), 2.09 (s, 3H).

Example 7

17-Chloro-5,13,14,22,31-Pentamethyl-2,28-dioxa-9-thia-5,6,12,13,22-Pentazahexacyclo [27.3.1.1 ^4,7 .0 ^11,15 .0 ^{16,21.0 20,24} ] 34-1(33),4(34),6,11,14,16,18,20,23,29,31 -Undecene-23-carboxylic acid 7

first step

6-chloro-7-(3-((((5-(3-hydroxy-5-methylphenoxy)methyl)-1-methyl-1 H -pyrazol-3-yl)methyl) (Thio)methyl)-1,5-dimethyl- 1H -pyrazol-4-yl)-3-(3-hydroxypropyl)-1-methyl- 1H -indole-2-carboxy Methyl acid 7b

Compound 6e (100mg, 177.64μmol) and compound 7a (30mg, 241.67μmol, completed) were dissolved in N , N -dimethylformamide (1.5mL), potassium carbonate (100mg, 724.64μmol, National Medicine) was added, The reaction was stirred at room temperature for 10 hours. Water (10 mL) was added, extracted with ethyl acetate (10 mL), concentrated, and the resulting residue was purified with eluent system A using thin layer chromatography to obtain the title compound 7b (40 mg, yield: 34.62%).

MS m/z(ESI): 652.2[M+1]

Second step

17-Chloro-5,13,14,22,31-Pentamethyl-2,28-dioxa-9-thia-5,6,12,13,22-Pentazahexacyclo [27.3.1.1 ^4,7 .0 ^11,15 .0 ^{16,21.0 20,24} ] 34-1(33),4(34),6,11,14,16,18,20,23,29,31 -Undecene-23-carboxylic acid methyl ester 7c

Compound 7b (40mg, 61.33μmol) and tributylphosphine (62mg, 306.93μmol, adamas) were dissolved in toluene (2mL), replaced with argon three times, and dipiperidine azodicarboxylate (80mg, 317.46μmol, Shao Far), react at 60°C for 3 hours, add water (10 mL), extract with ethyl acetate (10 mL), concentrate the organic phase under reduced pressure, and purify the resulting residue by silica gel column chromatography with eluent system A to obtain the title compound 7c ( 30mg, yield: 77.13%).

MS m/z(ESI): 634.2[M+1]

third step

17-Chloro-5,13,14,22,31-Pentamethyl-2,28-dioxa-9-thia-5,6,12,13,22-Pentazahexacyclo [27.3.1.1 ^4,7 .0 ^11,15 .0 ^{16,21.0 20,24} ] 34-1(33),4(34),6,11,14,16,18,20,23,29,31 -Undecene-23-carboxylic acid 7

Compound 7c (30mg, 47.30μmol) was dissolved in 2.5mL of a mixed solution of tetrahydrofuran/methanol/water (V:V:V=2:2:1) at room temperature, and lithium hydroxide monohydrate (20mg, 476.19) was added. μmol) The reaction was stirred at 50°C for 1 hour. Cool to room temperature, add dilute hydrochloric acid (1.0N) dropwise to pH=4-5, extract with ethyl acetate (5mL×2), filter, concentrate, and purify the resulting residue with eluent system A by thin layer chromatography. The title compound 7 (10 mg, yield: 34.09%) was obtained.

MS m/z(ESI): 619.9[M+1]

¹ H NMR (400MHz, CD ₃ OD) δ 7.71 (d, 1H), 7.20 (d, 1H), 6.26 (s, 2H), 6.13 (s, 1H), 5.31 (s, 1H), 5.21-5.03 ( m, 2H), 3.85 (s, 3H), 3.77 (s, 3H), 3.77-3.70 (m, 2H), 3.62 (s, 3H), 3.56-3.42 (m, 4H), 3.22-3.04 (m, 2H), 2.17 (s, 3H), 2.15-2.10 (m, 2H), 2.06 (s, 3H).

Example 8

17-Chloro-5,13,14,22,30,31-hexamethyl-28-oxa-2,9-dithia-5,6,12,13,22-pentaazacyclo [27.3 .1.1 ^4,7 .0 ^11,15 .0 ^{16,21.0 20,24} ] 34-1(33),4(34),6,11,14,16,18,20,23,29 ,31-Undecene-23-carboxylic acid 8

first step

5-bromo-2,3-dimethylaniline 8b

Add 5-bromo-1,2-dimethyl-3-nitroaniline 8a (4.8g, 20.8mmol) to 80mL of ethanol and 30mL of water, add iron powder (9.3g, 167.0mmol) at room temperature, and chlorinate Ammonium (5.5 g, 104.0 mmol). The reaction was stirred at 80°C for 1 hour. The reaction solution was filtered, the filtrate was concentrated, 50mL of water and ethyl acetate were added, and the layers were separated. The aqueous phase was extracted with 50mL of ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue obtained was purified with the eluent system A to obtain the title compound 8b (4.0 g, yield: 96.4%).

MS m/z(ESI): 200.0[M+1]

Second step

5-bromo-2,3-dimethylphenol 8c

Compound 8b (4.3 g, 14.7 mmol) was dissolved in 50 mL of 50% sulfuric acid, sodium nitrite (1.8 g, 25.8 mmol) was added at 0°C, and the mixture was stirred at 0°C for 1 hour. The above reaction solution was added to 50 mL of a saturated copper sulfate solution at 100°C, and stirred at 100°C for 10 minutes. After the reaction solution was cooled, it was extracted twice with 50 mL of ethyl acetate. The organic phases were combined and washed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue obtained was purified by silica gel column chromatography with eluent system A to obtain the title compound 8c (820mg, product Rate: 19.0%).

MS m/z(ESI): 199.1[M-1]

third step

3-((3-hydroxy-4,5-dimethylphenyl)thio)propionic acid 2-ethylhexyl ester 8e

Compound 8c (770mg, 3.8mmol) was dissolved in 15mL dioxane, compound 8d (1.7g, 7.7mmol), tris(dibenzylideneacetone) two palladium (350.5mg, 0.38mmol), 4,5- Bis(diphenylphosphine)-9,9-dimethylxanthene (442.8mg, 0.77mmol), N , N -isopropylethylamine (990.0mg, 7.7mmol). Stir at 100°C overnight under argon protection. Add 50 mL each of water and ethyl acetate, separate the layers, extract the aqueous phase with ethyl acetate (50 mL), combine the organic phases and dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and use silica gel column chromatography to extract the eluent system The resulting residue was purified by A to obtain the title compound 8e (800 mg, yield: 61.7%).

MS m/z(ESI): 339.3[M+1]

the fourth step

5-mercapto-2,3-dimethylphenol 8f

Compound 8e (800 mg, 2.4 mmol) was dissolved in 20 mL of tetrahydrofuran, potassium tert-butoxide (795 mg, 7.1 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was neutralized with 2N hydrochloric acid to neutrality, extracted with ethyl acetate (50mL×2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound 8f (360mg, yield: 98.8%) , The product is directly subjected to the next reaction without purification.

MS m/z(ESI): 153.2[M-1]

the fifth step

6-Chloro-7-(3-((((5-(((3-hydroxy-4,5-dimethylphenyl)thio)methyl)-1-methyl-1 H -pyrazole- 3-yl)methyl)sulfanyl)methyl)-1,5-dimethyl- 1H -pyrazol-4-yl)-3-(3-methoxy-3-oxopropyl) -1-methyl-1 H -indole-2-carboxylic acid methyl ester 8g

Compound 1j (412mg, 0.7mmol) was dissolved in 8mL methanol, potassium carbonate (288.0mg, 2.1mmol) and compound 8f (322mg, 2.1mmol) were added and reacted at room temperature for 2 hours under argon protection. The reaction solution was concentrated under reduced pressure and most of the solvent was added. 50mL of water was added to the reaction solution, extracted with ethyl acetate (50mL×2), the organic phases were combined, washed with 30mL saturated sodium chloride solution, dried with anhydrous sodium sulfate, filtered, and the filtrate was reduced. After concentrating under pressure, the residue obtained was purified by silica gel column chromatography with eluent system B to obtain 8 g of the title compound (400 mg, yield: 81.0%).

MS m/z(ESI): 710.3[M+1]

Sixth step

6-Chloro-7-(3-((((5-(((3-hydroxy-4,5-dimethylphenyl)thio)methyl)-1-methyl-1 H -pyrazole- 3-yl)methyl)sulfanyl)methyl)-1,5-dimethyl- 1H -pyrazol-4-yl)-3-(3-hydroxypropyl)-1-methyl- 1H -Indole-2-carboxylic acid methyl ester 8h

Compound 8g (100mg, 0.14mmol) was dissolved in 1mL tetrahydrofuran, 1.0M borane tetrahydrofuran solution (0.14mL, 0.14mmol) was added dropwise under ice bath, and the reaction was stirred overnight at room temperature. Under ice bath, add 1 mL methanol and 1 mL 6N hydrochloric acid dropwise, stir under ice bath for 5 minutes, and 50°C for 30 minutes. The reaction solution was neutralized to neutrality with aqueous sodium bicarbonate solution, the organic phase was separated, and the aqueous phase was extracted twice with a mixed solvent of 50 mL of dichloromethane and methanol (V:V=10:1). The organic phases were combined and used 30 mL of saturated chlorine. Washed with sodium chloride solution, dried with anhydrous sodium sulfate, filtered to remove the desiccant, the filtrate was concentrated under reduced pressure, and the residue obtained was purified by silica gel column chromatography with eluent system B to obtain the title compound 8h (60mg, yield: 62.5%) .

MS m/z(ESI): 682.1[M+1]

Seventh step

17-Chloro-5,13,14,22,30,31-hexamethyl-28-oxa-2,9-dithia-5,6,12,13,22-pentaazacyclo [27.3 .1.1 ^4,7 .0 ^11,15 .0 ^{16,21.0 20,24} ] 34-1(33),4(34),6,11,14,16,18,20,23,29 ,31-Undecene-23-carboxylic acid methyl ester 8i

Compound 8h (60mg, 0.09mmol) was dissolved in 0.5mL of anhydrous tetrahydrofuran and 3mL of anhydrous toluene, tri-n-butylphosphine (89.0mg, 0.44mmol), dipiperidine azodicarboxylate (111mg, 0.44mmol) were added at room temperature ), protected by argon, reacted at 60°C for 3 hours. The reaction solution was concentrated under reduced pressure to remove the solvent, and the resulting residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 8i (40.0 mg, yield: 68.5%).

MS m/z(ESI): 664.2[M+1]

Eighth step

17-Chloro-5,13,14,22,30,31-hexamethyl-28-oxa-2,9-dithia-5,6,12,13,22-pentaazacyclo [27.3 .1.1 ^4,7 .0 ^11,15 .0 ^{16,21.0 20,24} ] 34-1(33),4(34),6,11,14,16,18,20,23,29 ,31-Undecene-23-carboxylic acid 8

Compound 8i (40.0 mg, 0.06 mmol) was dissolved in a mixed solvent of 1 mL methanol, 0.5 mL tetrahydrofuran and 0.5 mL water, lithium hydroxide monohydrate (51.0 mg, 1.2 mmol) was added, and the reaction was stirred at 50°C for 1 hour. The reaction solution was neutralized with 2N hydrochloric acid, concentrated under reduced pressure to remove most of the solvent, and prepared by reverse phase purification (Sharpsil-T C18 Column 21.2*150mm 5um, extraction system: 10mmoL/L ammonium acetate, water, acetonitrile) to obtain The title compound 8 (2.1 mg, yield: 5.1%).

MS m/z(ESI): 650.2[M+1]

1H NMR(400MHz,CD3OD)δ 7.68-7.66(d,1H), 7.14-7.12(d,1H,), 6.80(s,1H), 6.28(s,1H), 4.86(s,1H), 3.99- 3.84 (m, 5H), 3.70-3.44 (m, 11H), 3.27-3.06 (m, 3H), 2.70-2.67 (d, 1H), 2.23-2.05 (m, 10H).

Test case:

Biological evaluation

Test Example 1. The binding experiment of the compound of the present disclosure and MCL-1 protein.

The following method was used to determine the binding ability of the compounds of the present disclosure to MCL-1 protein. The experimental method is briefly described as follows:

1. Experimental materials and instruments

1. His-MCL-1 protein (Shanghai Hengrui Pharmaceutical Co., Ltd., NA)

2. Biotin labeled Bim protein (R&D, 3526/1)

3. Labeling Europium cryptate anti-6His antibody (cisbio, 61HI2KLA)

4. Affinity Streptomycin Link XL665 (cisbio, 611SAXLA)

5. Binding buffer (cisbio, 62DLBDDF)

6. Detection buffer (cisbio, 62DB1FDG)

7. Microplate reader (BMG, PHERAsta)

Second, the experimental steps

MCL-1 inhibitors can bind to MCL-1 protein to prevent the binding of MCL-1 to Bim protein. In this experiment, the HTRF method was used to detect the binding of MCL-1 and Bim protein to evaluate the binding ability of MCL-1 inhibitors and MCL-1 protein, and to evaluate the activity of the compound based on the Ki size.

The human recombinant protein MCL-1 (sequence 171-327) and Bim (sequence 51-76) peptides are labeled with His and biotin, respectively. 0.1nM His-MCL-1, 2.5nM bio-Bim and different concentrations of small molecule compounds (the first concentration is 10μM, the 3-fold dilution in 11 concentrations, diluted in binding buffer) are mixed and incubated for 2 hours at room temperature, then Add 0.5nM labeled europium cryptate anti-6His antibody and 1.25nM affinity streptomycin-linked XL665 (diluted in detection buffer). After incubating for 2 hours at room temperature, PHERAstar was used to detect the 620nm and 665nm fluorescence signals. Data is processed using GraphPad software.

3. Experimental data

The binding ability of the compound of the present disclosure and MCL-1 protein can be determined by the above test, and the measured Ki value is shown in Table 1.

Table 1 Ki of binding of compounds of the present disclosure to MCL-1 protein.

Conclusion: The compound of the present disclosure has a strong binding ability with MCL-1 protein, and can well inhibit the binding of MCL-1 with Bim protein. The optical activity has a certain influence on the activity of the compound.

Test Example 2: Cell Proliferation Experiment

By a method detection of intracellular ATP content, according to the size of the IC ₅₀ evaluation of compounds of the present application AMO-1 inhibitory effect on cell proliferation and MV-4-11 cells. The experimental method is briefly described as follows:

1. Experimental materials and instruments

1. AMO-1, human bone marrow plasmacytoma (Nanjing Kebai, CBP60242)

2. MV-4-11, human acute monocytic leukemia cells (ATCC, CRL-9591)

3. Fetal Bovine Serum (GIBCO, 10099)

4. RPMI1640 (GE, SH30809.01)

5. IMDM (Gibco, 12440053)

6.2-Mercaptoethanol (sigma, 60-24-2)

7. CellTite (Promega, G7573)

8.96-well cell culture plate (corning, 3903)

9. Trypan blue solution (Sigma, T8154-100ML)

10. Microplate reader (BMG, PHERAsta)

11. Cell counter (Shanghai Ruiyu Biotechnology Co., Ltd., IC1000)

Second, the experimental steps

AMO-1 cells were cultured in RPMI1640 medium containing 20% FBS, and MV-4-11 cells were cultured in IMDM medium containing 10% FBS for 2-3 times a week, with a subgeneration ratio of 1:4 or 1:6 . During subculture, the cells were transferred to a centrifuge tube, centrifuged at 1200 rpm for 3 minutes, the supernatant medium was discarded, and fresh medium was added to resuspend the cells. Add 90 μL of cell suspension to the 96-well cell culture plate at a density of 1.33×10 ⁵ cells/ml, and add only 100 μL of complete medium to the periphery of the 96-well plate. The culture plate was incubated in an incubator for 24 hours (37°C, 5% CO ₂ ).

Dilute the sample to be tested with DMSO to 20mM, and dilute to 9 concentrations sequentially by 4 times, and set blank and control wells. Take 5 μL of the test compound solution prepared as a gradient concentration and add it to 95 μL of fresh medium. Then add 10 μL of the above-mentioned drug-containing medium solution to the culture plate. Incubate the culture plate in an incubator for 3 days (37°C, 5% CO ₂ ). In a 96-well cell culture plate, add 50μL of CellTiter-Glo reagent to each well, keep it in the dark at room temperature for 5-10 minutes, read the chemiluminescence signal value in PHERAstar, and use GraphPad software to process the data.

3. Experimental data

The inhibition of the proliferation of AMO-1 and MV-4-11 cells by the compounds of the present disclosure can be determined by the above test. The measured IC ₅₀ values are shown in Table 2.

_{Table 2 The IC 50} values of the compounds of the present disclosure for inhibiting the proliferation of AMO-1 and MV-4-11 cells.

Conclusion: The compound of the present disclosure has a good cell proliferation inhibitory effect on both AMO-1 and MV-4-11.

Claims (18)

A compound represented by general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof or its pharmaceutically acceptable form salt,

among them: R ^m , R ⁿ and R ^{w are the} same or different, and are each independently selected from a hydrogen atom, a halogen, an alkyl group, a deuterated alkyl group, an alkoxy group, a haloalkyl group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group , Nitro, cycloalkyl, cycloalkyloxy and heterocyclic groups; Or R ^m and R ⁿ together with the connected carbon atoms form a cycloalkyl group, and R ^{w is} selected from hydrogen atom, halogen, deuterated alkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amine Group, nitro group, cycloalkyl group, cycloalkyloxy group and heterocyclic group; Or R ⁿ and R ^w together with the connected carbon atoms form a cycloalkyl group, and R ^{m is} selected from hydrogen atom, halogen, deuterated alkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amine Group, nitro group, cycloalkyl group, cycloalkyloxy group and heterocyclic group; Z is S atom, O atom or -CH ₂ -; M is S atom, O atom or -NR ⁶ -; R ^{1 is} selected from hydrogen atom, halogen, alkyl, deuterated alkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, cycloalkyloxy and Heterocyclic group; R ^{2 are the} same or different, and are each selected from a hydrogen atom, a halogen, an alkyl group, a deuterated alkyl group, an alkoxy group, a haloalkyl group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amine group and a nitro group; R ^{3 is} selected from hydrogen atom, halogen, alkyl, deuterated alkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amine and nitro; R ^{4 is} selected from a hydrogen atom, an alkyl group, a deuterated alkyl group and a cycloalkyl group; R ^{5 is} selected from a hydrogen atom, an alkyl group, a deuterated alkyl group and a cycloalkyl group; R ^{6 is} selected from a hydrogen atom, an alkyl group and a cycloalkyl group; n is 0, 1, 2 or 3. The compound represented by the general formula (I) as described in the first item of the scope of the patent application or its tautomer, meso, racemate, enantiomer, diastereomer, or In the form of a mixture or a pharmaceutically acceptable salt thereof, wherein: R ^m , R ⁿ and R ^{w are the} same or different, and are each independently selected from a hydrogen atom, a halogen and an alkyl group; or R ^m and R ⁿ are connected to a carbon atom Together to form a cycloalkyl group, and R ^{w is} selected from a hydrogen atom, a halogen, and an alkyl group; or R ⁿ and R ^w together with the attached carbon atom form a cycloalkyl group, and R ^{m is} selected from a hydrogen atom, a halogen, and an alkyl group. The compound represented by the general formula (I) or its tautomers, mesosomes, racemates, enantiomers, diastereomers as described in item 1 or 2 of the scope of the patent application , Or its mixture form or its pharmaceutically acceptable salt, wherein

Selected from:

,

with

; R ^m , R ⁿ and R ^{w are the} same or different, and are each independently selected from a hydrogen atom, a halogen, and an alkyl group; p is 0, 1, or 2; q is 0, 1, or 2. The compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, non-pair, as described in any one of items 1 to 3 in the scope of the patent application Enantiomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, which are compounds represented by general formula (II), general formula (III) or general formula (IV) or tautomers, meso Forms, racemates, enantiomers, diastereomers, or mixtures thereof or their pharmaceutically acceptable salts:

among them: p is 0, 1 or 2; q is 0, 1 or 2; R ^m , R ⁿ and R ^{w are the} same or different, and are each independently selected from a hydrogen atom, a halogen, and an alkyl group; and Z, M and R ¹ ~R ⁵ are as defined in item 1 of the scope of patent application. The compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, non-pair Enantiomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein the Z is a S atom or an O atom. The compound represented by the general formula (I) or its tautomers, mesosomes, racemates, enantiomers, and non-pairs as described in any one of the 1st to 5th items of the scope of patent application An enantiomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the M is an S atom or -NR ⁶ -, and R ⁶ is a hydrogen atom or an alkyl group. The compound represented by the general formula (I) or its tautomers, mesosomes, racemates, enantiomers, and non-pairs as described in any one of the 1st to 5th items of the scope of patent application An enantiomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the R ¹ is a hydrogen atom or an alkyl group. The compound represented by the general formula (I) or its tautomers, mesosomes, racemates, enantiomers, and non-pairs as described in any one of the 1st to 7th items of the scope of patent application An enantiomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the R ² is halogen. The compound represented by the general formula (I) or its tautomers, mesosomes, racemates, enantiomers, and non-pairs as described in any one of items 1 to 8 in the scope of the patent application An enantiomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ^{each of R 3} and R ⁴ is an alkyl group. The compound represented by the general formula (I) or its tautomers, mesosomes, racemates, enantiomers, and non-pairs as described in any one of the first to 9th items of the scope of patent application An enantiomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the R ⁵ is an alkyl group. The compound represented by the general formula (I) or its tautomers, mesosomes, racemates, enantiomers, and non-pairs as described in any one of items 1 to 10 in the scope of the patent application Enantiomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, which are selected from:

A compound represented by the general formula (IA) or its tautomer, meso, racemate, enantiomer, diastereomer, or its mixture form or its pharmaceutically acceptable salt,

among them: R ^a is an alkyl group; R ^m , R ⁿ , R ^w , Z, M, R ¹ to R ⁵ and n are as defined in item 1 of the scope of patent application. The compound represented by the general formula (IA) described in item 12 of the scope of the patent application or its tautomer, meso, racemate, enantiomer, diastereomer, or In the form of a mixture or a pharmaceutically acceptable salt thereof, it is selected from:

A method for preparing the compound represented by general formula (I) as described in item 1 of the scope of patent application, the method comprising:

Compounds of general formula (IA), removing the protecting group R ^a, to give a compound of formula (I), and among them: R ^a is an alkyl group; R ^m , R ⁿ , R ^w , Z, M, R ¹ to R ⁵ and n are as defined in item 1 of the scope of patent application. A pharmaceutical composition containing a therapeutically effective amount of the compound represented by the general formula (I) or its tautomers as described in any one of items 1 to 11 in the scope of the patent application Forms, meso, racemates, enantiomers, diastereomers, or mixtures thereof or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers and diluents Or excipients. A compound represented by the general formula (I) or its tautomers, mesosomes, racemates, enantiomers, and non-pairs according to any one of items 1 to 11 in the scope of patent application The enantiomers, or their mixture forms or their pharmaceutically acceptable salts, or the use of the pharmaceutical composition described in item 15 of the scope of the patent application, are used in the preparation of drugs for inhibiting MCL-1. A compound represented by the general formula (I) or its tautomers, mesosomes, racemates, enantiomers, and non-pairs according to any one of items 1 to 11 in the scope of patent application Enantiomers, or their mixture forms or their pharmaceutically acceptable salts or the use of the pharmaceutical composition described in item 15 of the scope of the patent application, which are used in the preparation of drugs for the treatment or prevention of MCL-1 mediated diseases . A compound represented by the general formula (I) or its tautomers, mesosomes, racemates, enantiomers, and non-pairs according to any one of items 1 to 11 in the scope of patent application Enantiomers, or their mixture forms or their pharmaceutically acceptable salts or the use of the pharmaceutical composition described in item 15 of the scope of the patent application, which are used in the preparation for the treatment of tumors, autoimmune diseases or immune system diseases drug, Preferably, the tumor is selected from bladder cancer, brain tumor, breast cancer, uterine cancer, cervical cancer, endometrial cancer, ovarian cancer, leukemia, kidney cancer, colon cancer, rectal cancer, colorectal cancer, esophageal cancer, liver cancer , Stomach cancer, head and neck cancer, skin cancer, lymphoma, pancreatic cancer, melanoma, myeloma, bone cancer, neuroblastoma, glioma, sarcoma, lung cancer, thyroid cancer and prostate cancer.