CN111187277B

CN111187277B - Thienopyrimidine derivative, preparation method and medical application thereof

Info

Publication number: CN111187277B
Application number: CN201911104283.3A
Authority: CN
Inventors: 张国宝; 胡伟民; 贺峰; 陶维康
Original assignee: Jiangsu Hengrui Medicine Co Ltd; Shanghai Hengrui Pharmaceutical Co Ltd
Current assignee: Jiangsu Hengrui Medicine Co Ltd; Shanghai Hengrui Pharmaceutical Co Ltd
Priority date: 2018-11-14
Filing date: 2019-11-13
Publication date: 2022-04-12
Anticipated expiration: 2039-11-13
Also published as: CN111187277A

Abstract

The invention relates to a thienopyrimidine derivative, a preparation method thereof and application thereof in medicines. Specifically, the invention relates to a thienopyrimidine derivative shown in a general formula (I), a preparation method thereof, a pharmaceutical composition containing the derivative and application of the derivative as a therapeutic agent, especially as an MCL-1 inhibitor, wherein each substituent in the general formula (I) is defined as the specification.

Description

Thienopyrimidine derivative, preparation method and medical application thereof

Technical Field

The invention belongs to the field of medicines, and relates to a thienopyrimidine derivative shown in a general formula (I), a preparation method thereof, a pharmaceutical composition containing the derivative, and application of the thienopyrimidine derivative as a therapeutic agent, especially as an MCL-1 inhibitor.

Background

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

BCL-2 family proteins are mainly present on mitochondrial membranes and can be classified into two major classes, anti-apoptotic proteins and pro-apoptotic proteins, according to their function. 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, a polymer cavity is formed, which increases the permeability of the mitochondrial membrane of cells, promotes the release of cytochrome C and the like into the cytoplasm, and leads to cell death. The BH3-only protein comprises the BH3 domain only. In the state of cell survival, BH3-only proteins (e.g., Bim) bind to anti-apoptotic proteins. When the cell is stressed, the combination balance is broken, BH3-only protein is released to combine with BAX on mitochondria, BAX/BAK is promoted to form polymer, cytochrome C and SMAC are promoted to be released into cytoplasm, and downstream apoptosis pathway is activated.

Current 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 the multiple myeloma sample, MCL-1 expression is obviously improved along with the increase of the cancer deterioration degree, but BCL-2 expression is not changed. Furthermore, the expression level of MCL-1 is inversely correlated with the survival rate of the patients. High MCL-1 expression was observed with lower survival in both breast cancer and multiple myeloma patients. Therefore, MCL-1 is an important target for tumor treatment.

Novartis, Amgen and AstraZeneca have developed small molecule inhibitors against MCL-1, but are now in clinical stage, so further development of MCL-1 inhibitor drugs is needed. Patents for MCL-1 inhibitors that have been disclosed are WO2015097123, WO2016207226, WO2016207225, WO2018078064, WO2018126898, and the like.

Disclosure of Invention

The invention aims to provide a compound shown in a general formula (I), or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, a mixture thereof or a pharmaceutically acceptable salt thereof:

wherein:

g is C, CH or N;

l is- (CR)⁸R⁹)_s-；

R¹The same or different, and each is independently selected from a hydrogen atom, halogen, alkyl, alkoxy, deuterated alkyl, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl or heterocyclyl;

R²selected from the group consisting of hydrogen atoms, halogens, alkyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, hydroxyl groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups, wherein said alkyl groups, alkoxy groups, haloalkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups are optionally selected from the group consisting of alkyl groups, haloalkyl groups, halogen groups, amino groups, nitro groups, cyano groups, hydroxyl groups, alkoxy groups, haloalkoxy groups, hydroxyalkyl groups, -R^aCycloalkyl, heterocyclyl, aryl and heteroaryl;

R³selected from hydrogen atoms, alkyl groups, deuterated alkyl groups, haloalkyl groups, cycloalkyl groups, heterocyclic groups, aryl groups, heteroaryl groups, arylalkyl groups or heteroarylalkyl groups;

R⁴selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, -S-alkyl, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl, -O-Cy₁-alkylene-Cy₁Wherein said alkyl, alkoxy, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally selected from the group consisting of alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, -NR¹⁰R¹¹Cycloalkyl, heterocyclyl, aryl and heteroaryl;

R⁵selected from the group consisting of hydrogen, halogen, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl;

R⁶identical or different and are each independently selected from the group consisting of hydrogen atom, halogen, alkyl, deuterated alkyl, alkyl halideA group, alkoxy, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl or heterocyclyl;

R⁷selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -alkylene-Cy₂or-alkenylene-Cy₂(ii) a Wherein said alkyl, alkoxy, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of alkyl, halo, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R⁸and R⁹Are the same or different and are each independently selected from a hydrogen atom, a hydroxyl group or an alkyl group;

R¹⁰and R¹¹Are the same or different and are each independently selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group; wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of alkyl, alkoxy, halogen, amino, cyano, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

or, said R¹⁰And R¹¹Together with the nitrogen atom to which they are attached form a heterocyclyl or heteroaryl group, wherein said heterocyclyl and heteroaryl groups optionally contain 1 to 2 identical or different heteroatoms selected from N, O and S in addition to 1 nitrogen atom, and said heterocyclyl and heteroaryl groups are optionally substituted with one or more substituents selected from alkyl, alkoxy, halogen, amino, cyano, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups;

R^ais-Cy₃or-Cy₃-Cy₄；

Cy₁、Cy₂、Cy₃And Cy₄Are the same or different and are each independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl, and heteroaryl; wherein the ringEach of the alkyl, heterocyclyl, aryl and heteroaryl groups is independently optionally substituted with one or more substituents selected from the group consisting of alkyl, alkoxy, halogen, amino, cyano, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

n is 0 or 1;

m is 0, 1 or 2; and

s is 0 or 1.

In a preferred embodiment of the present invention, the compound of formula (I), or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is⁴Is an alkoxy group, said alkoxy group being optionally substituted by one or more-NR groups¹⁰R¹¹Substitution; is preferably-O (CH)₂)_q-NR¹⁰R¹¹Q is an integer of 0 to 6, R¹⁰And R¹¹As defined in formula (I).

In a preferred embodiment of the present invention, the compound represented by the general formula (I), or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound represented by the general formula (II), or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

，

wherein

R¹～R³、R⁵～R¹¹N and m are as defined in formula (I).

In a preferred embodiment of the present invention, the compound of formula (I), or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is²Is alkoxy, wherein said alkoxy is optionally substituted with one or more R^aSubstitution; is preferably-O (CH)₂)_p-R^aP is 0, 1,2 or 3, R^aAs defined in formula (I).

In a preferred embodiment of the present invention, the compound of formula (I), or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is³Is a hydrogen atom or an alkyl group.

In a preferred embodiment of the present invention, the compound represented by the general formula (I), or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound represented by the general formula (III), or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein

R¹⁰And R¹¹Together with the nitrogen atom to which they are attached form a heterocyclyl or heteroaryl group, wherein said heterocyclyl and heteroaryl groups optionally contain 1 to 2 identical or different heteroatoms selected from N, O and S in addition to 1 nitrogen atom, and said heterocyclyl and heteroaryl groups are optionally substituted with one or more substituents selected from alkyl, alkoxy, halogen, amino, cyano, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups;

R^ais-Cy₃or-Cy₃-Cy₄；

Cy₃And Cy₄Are the same or different and are each independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl, and heteroaryl; wherein said cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of alkyl, alkoxy, halogen, amino, cyano, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroarylIs substituted with one or more substituents of (1);

R¹、R⁵～R⁷n and m are as defined in formula (I).

In a preferred embodiment of the present invention, the compound of formula (I), or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is⁶Is halogen.

In a preferred embodiment of the present invention, the compound represented by the general formula (I), or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound represented by the general formula (IV), or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein:

R⁶is halogen;

R^ais-Cy₃or-Cy₃-Cy₄；

Cy₃And Cy₄Are the same or different and are each independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl, and heteroaryl; wherein said cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of alkyl, alkoxy, halogen, amino, cyano, halogen, or a substituted aryl, substituted,Nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R¹、R⁵、R⁷and n is as defined in formula (I).

In a preferred embodiment of the present invention, the compound of formula (I), or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is^ais-Cy₃-Cy₄；Cy₃And Cy₄Are the same or different and are each independently aryl or heteroaryl; wherein said aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of alkyl, alkoxy, halogen, amino, cyano, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl.

In a preferred embodiment of the present invention, the compound of formula (I), or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is¹Is a hydrogen atom or an alkyl group.

In a preferred embodiment of the present invention, the compound of formula (I), or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is⁵Is an alkyl group.

In a preferred embodiment of the present invention, the compound of formula (I), or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is⁷Is aryl or heteroaryl, wherein said aryl and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of alkyl, halogen, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl.

In a preferred embodiment of the present invention, the compound of formula (I), or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is¹⁰And R¹¹Together with the nitrogen atom to which they are attached form a heterocyclic group, wherein said heterocyclic group optionally contains 1 to 2 identical or different heteroatoms selected from N, O and S in addition to 1 nitrogen atom, and said heterocyclic group is optionally substituted with one or more alkyl groups.

In a preferred embodiment of the present invention, the compound represented by the general formula (I), or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound represented by the general formula (V), or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein:

R¹is a hydrogen atom or an alkyl group;

R⁵is an alkyl group;

R⁶is halogen;

R⁷is aryl or heteroaryl, wherein said aryl and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of alkyl, halogen, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R¹⁰and R¹¹Together with the nitrogen atom to which they are attached form a heterocyclic group, wherein said heterocyclic group optionally contains 1 to 2 of the same or different heteroatoms selected from N, O and S in addition to 1 nitrogen atom, and said heterocyclic group is optionally substituted with one or more alkyl groups;

Cy₃and Cy₄Same or differentAnd each is independently aryl or heteroaryl; wherein said aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of alkyl, alkoxy, halogen, amino, cyano, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

n is 0 or 1.

Typical compounds of the invention include, but are not limited to:

or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof.

Another aspect of the present invention relates to a compound of formula (IA), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein:

x is halogen;

R^bis an alkyl group;

R¹、R²、R⁷l and n are as defined in formula (I).

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

Another aspect of the present invention relates to a method of preparing a compound of formula (I), the method comprising:

carrying out coupling reaction on the compound of the general formula (IA) and the compound of the general formula (IB) to obtain the compound of the general formula (I),

wherein:

x is halogen;

R^bis an alkyl group;

m is

R³Is a hydrogen atom;

R¹、R²、R⁴～R⁷l, G, n and m are as defined in formula (I).

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

the compound of the general formula (IIA) and the compound of the general formula (IIB) are subjected to coupling reaction to obtain a compound of a general formula (II),

wherein:

x is halogen;

R^bis an alkyl group;

m is

R³Is a hydrogen atom;

R¹、R²、R⁵～R¹¹n and m are as defined in formula (II).

Another aspect of the present invention relates to a method of preparing a compound of formula (III), comprising:

the compound of the general formula (IIIA) and the compound of the general formula (IIB) are subjected to coupling reaction to obtain a compound of a general formula (III),

wherein:

x is halogen;

R^bis an alkyl group;

m is

R¹、R^a、R⁵～R⁷、R¹⁰、R¹¹N and m are as defined in formula (III).

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

the compound of the general formula (VA) and the compound of the general formula (VB) are subjected to coupling reaction to obtain the compound of the general formula (V),

wherein:

x is halogen;

R^bis an alkyl group;

m is

R¹、R⁵～R⁷、R¹⁰、R¹¹、Cy₃、Cy₄And n is as defined in formula (V).

Another aspect of the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) of the present invention, or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or mixture thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

The invention further relates to the use of a compound of formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for the manufacture of a medicament for the treatment or prevention of a MCL-1 mediated disease.

The invention further relates to the use of a compound of formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for the preparation of a medicament for inhibiting MCL-1.

The invention further relates to the use of a compound of general formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for the preparation of a medicament for the treatment of tumors, autoimmune diseases and immune system disorders; wherein said tumor is preferably selected from the group consisting of bladder cancer, brain tumor, breast cancer, uterine cancer, cervical cancer, endometrial cancer, ovarian cancer, leukemia (such as chronic myeloid leukemia, chronic lymphoid leukemia, lymphoblastic leukemia, or acute myeloid leukemia), renal 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, glioma, sarcoma, lung cancer (such as non-small cell lung cancer or small cell lung cancer), thyroid cancer, and prostate cancer.

The present invention also relates to a method of inhibiting MCL-1 comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

The present invention also relates to a method for treating or preventing MCL-1 mediated diseases, which comprises administering to a patient in need thereof a therapeutically effective amount of a compound represented by the general formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

The present invention also relates to a method for the treatment of tumors, autoimmune diseases and diseases of the immune system, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising same; wherein said tumor is preferably selected from the group consisting of bladder cancer, brain tumor, breast cancer, uterine cancer, cervical cancer, endometrial cancer, ovarian cancer, leukemia (such as chronic myeloid leukemia, chronic lymphoid leukemia, lymphoblastic leukemia, or acute myeloid leukemia), renal 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, glioma, sarcoma, lung cancer (such as non-small cell lung cancer or small cell lung cancer), thyroid cancer, and prostate cancer.

The invention further relates to a compound of general formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a medicament.

The invention also relates to a compound shown in the general formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the compound, which is used as the MCL-1 inhibitor.

The invention also relates to a compound shown in the general formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the compound, which treats or prevents MCL-1 mediated diseases.

The invention also relates to a compound shown in the general formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture form thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the compound, which is used for treating tumors, autoimmune diseases and immune system diseases; wherein said tumor is preferably selected from the group consisting of bladder cancer, brain tumor, breast cancer, uterine cancer, cervical cancer, endometrial cancer, ovarian cancer, leukemia (such as chronic myeloid leukemia, chronic lymphoid leukemia, lymphoblastic leukemia, or acute myeloid leukemia), renal 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, glioma, sarcoma, lung cancer (such as non-small cell lung cancer or small cell lung cancer), thyroid cancer, and prostate cancer.

The active compound may be formulated so as to be suitable for administration by any suitable route, preferably in unit dose form, or in such a way that the patient may self-administer it in a single dose. The unit dose of a compound or composition of the invention may be expressed in the form of a tablet, capsule, cachet, bottle, powder, granule, lozenge, suppository, reconstituted powder or liquid.

The dosage of the compound or composition used in the methods of treatment of the present invention 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 may be 0.1 to 1000 mg.

The pharmaceutical compositions of the invention may contain, in addition to the active compound, one or more adjuvants selected from the following: fillers (diluents), binders, wetting agents, disintegrants, excipients, and the like. Depending on the method of administration, the compositions may contain from 0.1 to 99% by weight of active compound.

The pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Oral compositions may be prepared according to any method known in the art for preparing pharmaceutical compositions, and such compositions may contain one or more ingredients selected from the group consisting of: sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide a pleasant to the eye and palatable pharmaceutical preparation. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.

Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. The aqueous suspensions may also contain one or more preservatives, for example ethyl or n-propyl paraben, one or more coloring agents, one or more flavoring agents and one or more sweetening agents.

Oil suspensions may be formulated by suspending the active ingredient in a vegetable oil. The oil suspension may contain a thickener. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable preparation.

Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent or one or more preservatives. Suitable dispersing or wetting agents and suspending agents are illustrative of the examples given above. Other excipients, for example sweetening, flavoring and coloring agents, may also be present. These compositions are preserved by the addition of an antioxidant such as ascorbic acid.

The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions.

The pharmaceutical compositions may be in the form of a sterile injectable aqueous solution. Among the acceptable vehicles or solvents that may be employed are 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 the oil phase. For example, the active ingredient is dissolved in a mixture of soybean oil and lecithin. The oil solution is then treated to form a microemulsion by adding to a mixture of water and glycerol. The injection solution or microemulsion may be injected into the bloodstream of a patient by local bulk injection. Alternatively, it may be desirable to administer the solutions and microemulsions in a manner that maintains a constant circulating concentration of the compounds of the present invention. To maintain such a constant concentration, a continuous intravenous delivery device may be used. An example of such a device is an intravenous pump model Deltec CADD-PLUS. TM.5400.

The pharmaceutical compositions may be in the form of sterile injectable aqueous or oleaginous suspensions for intramuscular and subcutaneous administration. The suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a parenterally-acceptable, non-toxic diluent or solvent. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium.

The compounds of the present invention may 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 which is solid at ordinary temperatures but liquid in the rectum and therefore will melt in the rectum to release the drug. Such materials include cocoa butter, glycerogelatin, hydrogenated vegetable oils, polyethylene glycols of various molecular weights and mixtures of fatty acid esters of polyethylene glycols.

As is well known to those skilled in the art, the dosage of a drug administered depends on a variety of factors, including, but not limited to: the activity of the particular compound employed, the age of the patient, the weight of the patient, the health condition of the patient, the behavior of the patient, the diet of the patient, the time of administration, the mode of administration, the rate of excretion, the combination of drugs, and the like; in addition, the optimal treatment regimen, such as the mode of treatment, the daily amount of compound (I) of the formula or the type of pharmaceutically acceptable salt, can be verified according to conventional treatment protocols.

Detailed description of the invention

Unless stated to the contrary, terms used in the specification and claims have 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 an alkyl group containing 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 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-dimethylpentyl, 3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2, 3-dimethylhexyl, 2, 4-dimethylhexyl, 2, 5-dimethylhexyl, 2-dimethylhexyl, 3-dimethylhexyl, 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-dimethylpentyl, 2-dimethylhexyl, 3-dimethylpentyl, 2-ethylhexyl, 3-dimethylhexyl, 2-ethylhexyl, 2-dimethylhexyl, 2-ethylhexyl, 2-dimethylhexyl, 2-dimethylhexyl, 2-dimethylhexyl, 2-ethylhexyl, 2-ethyl, 2-2, 2-2, 2-2, or, 2, 2-diethylpentyl, n-decyl, 3-diethylhexyl, 2-diethylhexyl, and various branched isomers thereof. More preferred are lower alkyl groups having 1 to 6 carbon atoms, non-limiting examples of which include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl and the like. The alkyl group may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any available point of attachment, preferably independently optionally substituted with one or more substituents selected from H atom, D atom, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl.

The term "alkylene" refers to a saturated straight or branched chain aliphatic hydrocarbon group having 2 residues derived from the parent alkane by removal of two hydrogen atoms from the same carbon atom or two different carbon atoms, and is a straight or branched chain group containing 1 to 30 carbon atoms, preferably an alkylene group containing 1 to 18 carbon atoms, more preferably 1 to 12 carbon atoms, and most preferably an alkylene group containing 1 to 6 carbon atoms. Non-limiting examples of alkylene groups include, but are not limited to, methylene (-CH)₂-), 1-ethylidene (-CH (CH)₃) -), 1, 2-ethylene (-CH)₂CH₂-), 1-propylene (-CH (CH)₂CH₃) -), 1, 2-propylene (-CH)₂CH(CH₃) -), 1, 3-propylene (-CH)₂CH₂CH₂-) 1, 4-butylene (-CH₂CH₂CH₂CH₂-)、-(CH₂)₉-、-(CH₂)₁₇-and the like. Alkylene groups may be substituted OR unsubstituted, and when substituted, substituents may be substituted at any available point of attachment, preferably independently optionally selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, -OR⁵、-C(O)R⁵、-S(O)_mR⁵、-NR⁶R⁷and-C (O) NR⁶R⁷Is substituted with one or more substituents.

The term "alkenyl" refers to an alkene moleculeA hydrocarbon group having one or more hydrogen atoms in the molecule. The alkenyl group may be substituted OR unsubstituted, and when substituted, the substituent is preferably one OR more groups independently selected from hydrogen atom, alkyl group, alkoxy group, halogen, haloalkyl group, hydroxyl group, hydroxyalkyl group, cyano group, amino group, nitro group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group, -OR⁵、-C(O)R⁵、-S(O)_mR⁵、-NR⁶R⁷and-C (O) NR⁶R⁷Is substituted with one or more substituents of (1);

the term "alkynyl" refers to a hydrocarbon containing a carbon-carbon triple bond in the molecule. Alkynyl groups may be substituted OR unsubstituted, and when substituted, the substituents are preferably one OR more groups independently selected from hydrogen, alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR⁵、-C(O)R⁵、-S(O)_mR⁵、-NR⁶R⁷and-C (O) NR⁶R⁷Is substituted with one or more substituents.

The term "alkoxy" refers to-O- (alkyl) and-O- (unsubstituted cycloalkyl), wherein alkyl is as defined 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, and when substituted, the substituent is preferably one or more groups substituted with one or more substituents independently selected from H atom, D atom, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl.

The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing from 3 to 20 carbon atoms, preferably from 3 to 12 carbon atoms, preferably from 3 to 8 carbon atoms, more preferably from 3 to 6 carbon atoms (which may be, for example, 3, 4,5 or 6 carbon atoms). Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups.

The term "spirocycloalkyl" refers to a 5 to 20 membered polycyclic group sharing one carbon atom (referred to as a spiro atom) between monocyclic rings, which may contain one or more double bonds, but none of the rings have a completely conjugated pi-electron system. Preferably 6 to 14, more preferably 7 to 10 (e.g.7, 8, 9 or 10). Spirocycloalkyl groups are classified into a single spirocycloalkyl group, a double spirocycloalkyl group or a multi spirocycloalkyl group, preferably a single spirocycloalkyl group and a double spirocycloalkyl group, according to the number of spiro atoms shared between rings. More preferably 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered. Non-limiting examples of spirocycloalkyl groups include:

the term "fused cyclic alkyl" refers to a 5 to 20 membered all carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or more double bonds, but none of the rings has a completely conjugated pi-electron system. Preferably 6 to 14, more preferably 7 to 10. They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused ring alkyls according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 5-or 6-membered bicycloalkyl. Non-limiting examples of fused ring alkyl groups include:

the term "bridged cycloalkyl" refers to a 5 to 20 membered all carbon polycyclic group in which any two rings share two carbon atoms not directly attached, which may contain one or more double bonds, but none of the rings have a completely conjugated pi-electron system. Preferably 6 to 14, more preferably 7 to 10. They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups according to the number of constituent rings, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include:

the cycloalkyl ring includes a cycloalkyl ring (including monocyclic, spiro, fused and bridged rings) fused to an aryl, heteroaryl or heterocycloalkyl ring as described above, wherein the rings attached to the parent structure are cycloalkyl, non-limiting examples of which include indanyl, tetrahydronaphthyl, benzocycloheptanyl, and the like; preferably phenyl and cyclopentyl, tetrahydronaphthyl.

Cycloalkyl groups may be substituted or unsubstituted, and when substituted, substituents may be substituted at any available point of attachment, preferably independently optionally substituted with one or more substituents selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl.

The term "heterocyclyl" refers to a saturated or partially unsaturated mono-or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 ring atoms wherein one or more of the ring atoms is selected from nitrogen, oxygen, or S (O)_m(wherein m is an integer from 0 to 2) but excludes the ring moiety of-O-O-, -O-S-, or-S-S-, the remaining ring atoms being carbon. Preferably 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably 3 to 8 ring atoms, wherein 1-3 is a heteroatom; more preferably 3 to 6 ring atoms (which may for example be 3, 4,5 or 6 ring atoms), of which 1-3 are heteroatoms; most preferably 5 or 6 ring atoms, of which 1 to 3 are heteroatoms. Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, tetrahydropyranyl, 1, 2.3.6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like. Polycyclic heterocyclic groups include spiro, fused and bridged heterocyclic groups.

Polycyclic heterocyclic groups include spiro, fused and bridged heterocyclic groups.

The term "spiro-heteroCyclo "refers to a 5 to 20 membered polycyclic heterocyclic group wherein one atom (referred to as a spiro atom) is shared between monocyclic rings and wherein one or more ring atoms is selected from nitrogen, oxygen, or S (O)_m(wherein m is an integer of 0 to 2) and the remaining ring atoms are carbon. It may contain one or more double bonds, but no ring has a completely conjugated pi-electron system. Preferably 6 to 14, more preferably 7 to 10. The spiro heterocyclic group is classified into a mono-spiro heterocyclic group, a di-spiro heterocyclic group or a multi-spiro heterocyclic group, preferably a mono-spiro heterocyclic group and a di-spiro heterocyclic group, according to the number of spiro atoms shared between rings. More preferred are 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered mono spiroheterocyclic groups. Non-limiting examples of spiro heterocyclic groups include:

the term "fused heterocyclyl" refers to a 5 to 20 membered polycyclic heterocyclic group in which 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 bonds, but none of the rings has a fully conjugated pi-electron system in which one or more ring atoms is selected from nitrogen, oxygen or S (O)_m(wherein m is an integer of 0 to 2) and the remaining ring atoms are carbon. Preferably 6 to 14, more preferably 7 to 10. They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 5-or 6-membered bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclic groups include:

the term "bridged heterocyclyl" refers to a 5 to 14 membered polycyclic heterocyclic group in which any two rings share two atoms not directly attached which may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system in which one or more of the ring atoms is selected from nitrogen, oxygen or S (O)_m(wherein m is an integer of 0 to 2),the remaining ring atoms are carbon. Preferably 6 to 14, more preferably 7 to 10. They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups according to the number of constituent rings, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:

the heterocyclyl ring includes a heterocyclyl (including monocyclic, spiroheterocyclic, fused heterocyclic and bridged heterocyclic) fused to an aryl, heteroaryl or cycloalkyl ring as described above, wherein the ring to which the parent structure is attached is a heterocyclyl, non-limiting examples of which include:

the heterocyclyl group may be substituted or unsubstituted and when substituted, the substituents may be substituted at any available point of attachment, preferably independently optionally substituted with one or more substituents selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl.

The term "aryl" refers to a 6 to 14 membered all carbon monocyclic or fused polycyclic (fused polycyclic is a ring sharing adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably 6 to 10 membered, such as phenyl and naphthyl. Such aryl rings include those wherein the aryl ring as described above is fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring, non-limiting examples of which include:

aryl groups may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any available point of attachment, preferably independently optionally substituted with one or more substituents selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl.

The term "heteroaryl" refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. Heteroaryl is preferably 5 to 10 membered, more preferably 5 or 6 membered, for example furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl and the like. The heteroaryl ring includes a heteroaryl fused to an aryl, heterocyclyl or cycloalkyl ring as described above, wherein the ring joined together with the parent structure is a heteroaryl ring, non-limiting examples of which include:

heteroaryl groups may be substituted or unsubstituted, and when substituted, substituents may be substituted at any available point of attachment, preferably independently optionally substituted with one or more substituents selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl.

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

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

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

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

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

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

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

The term "amino" refers to the group-NH₂。

The term "cyano" refers to — CN.

The term "nitro" means-NO₂。

The term "carbonyl" refers to C ═ O.

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

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

The invention also includes various deuterated forms of the compounds of formula (I). Each available hydrogen atom attached to a carbon atom may be independently replaced by a deuterium atom. The person skilled in the art is able to synthesize the deuterated forms of the compounds of the formula (I) with reference to the relevant literature. Commercially available deuterated starting materials can be used in preparing the deuterated forms of the compounds of formula (I), or they can be synthesized using conventional techniques using deuterated reagents including, but not limited to, deuterated boranes, trideuteroborane tetrahydrofuran solutions, deuterated lithium aluminum hydrides, deuterated iodoethanes, deuterated iodomethanes, and the like.

"optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs or does not. For example, "a heterocyclic group optionally substituted with an alkyl" means that an alkyl may, but need not, be present, and the description includes the case where the heterocyclic group is substituted with an alkyl and the heterocyclic group is not substituted with an alkyl.

"substituted" means that one or more, preferably up to 5, more preferably 1 to 3, hydrogen atoms in the group are independently substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and that the person skilled in the art is able to determine (experimentally or theoretically) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable in combination with carbon atoms having unsaturated (e.g., olefinic) bonds.

"pharmaceutical composition" means a mixture containing one or more compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof in admixture with other chemical components, as well as other components such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate administration to an organism, facilitate absorption of the active ingredient and exert biological activity.

"pharmaceutically acceptable salts" refers to salts of the compounds of the present invention which are safe and effective for use in the body of a mammal and which possess the requisite biological activity.

The invention develops an MCL-1 inhibitor which has stronger binding capacity with MCL-1 protein and can well inhibit the binding of MCL-1 and Bim protein, the pyrazole group in the general formula (I) has obvious influence on the activity, and the applicant finds that the biological activity of the compound is obviously reduced after the pyrazole group in the general formula (I) is replaced by the pyrrole group or the triazole group, and specific examples are shown in example 4

Same as in example 5

The structural difference is only that the position of pyrazolyl is replaced by pyrrolyl and triazolyl respectively, but the activity of the compounds is obviously different.

Synthesis of the Compounds of the invention

In order to achieve the purpose of the invention, the invention adopts the following technical scheme:

scheme one

The invention relates to a method for preparing a compound shown as a general formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereoisomer or a mixture form thereof, or a pharmaceutically acceptable salt form thereof, which comprises the following steps:

carrying out coupling reaction on the compound of the general formula (IA) and the compound of the general formula (IB) under alkaline conditions and in the presence of a catalyst to obtain a compound of the general formula (I),

wherein:

x is halogen;

R^bis an alkyl group;

m is

R³Is a hydrogen atom;

R¹、R²、R⁴～R⁷l, G, n and m are as defined in formula (I).

The reagents that provide basic conditions include organic bases including, but not limited to, triethylamine, N-diisopropylethylamine, N-butyllithium, lithium diisopropylamide, lithium bistrimethylsilylamide, potassium acetate, sodium t-butoxide, potassium t-butoxide, and sodium N-butoxide, and inorganic bases including, but not limited to, sodium bicarbonate, potassium bicarbonate, sodium hydride, potassium phosphate, sodium carbonate, potassium acetate, cesium carbonate, sodium hydroxide, and lithium hydroxide; preferably cesium carbonate;

the catalyst includes, but is not limited to, palladium on carbon, tetrakis-triphenylphosphine palladium, palladium dichloride, palladium acetate, bis (dibenzylideneacetone) palladium, dichlorobis [ di-t-butyl- (4-dimethylaminophenyl) phosphine ] palladium (II), chloro (2-dicyclohexylphosphino-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) [2- (2 '-amino-1, 1' -biphenyl) ] palladium, [1,1 '-bis (diphenylphosphino) ferrocene ] dichloropalladium, 1' -bis (dibenzylphosphine) dichloropentairon palladium or tris (dibenzylideneacetone) dipalladium, preferably dichlorobis [ di-t-butyl- (4-dimethylaminophenyl) phosphine ] palladium (II);

the above reaction is preferably carried out in a solvent including, but not limited to: acetic acid, methanol, ethanol, N-butanol, tert-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, N-hexane, dimethyl sulfoxide, 1, 4-dioxane, ethylene glycol dimethyl ether, water or N, N-dimethylformamide, and mixtures thereof.

Scheme two

The invention relates to a method for preparing a compound shown as a general formula (II) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, which comprises the following steps:

wherein:

x is halogen;

R^bis an alkyl group;

m is

R³Is a hydrogen atom;

R¹、R²、R⁵～R¹¹n and m are as defined in formula (II).

Scheme three

The invention relates to a method for preparing a compound shown as a general formula (III) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, which comprises the following steps:

wherein:

x is halogen;

R^bis an alkyl group;

m is

Scheme four

The invention relates to a method for preparing a compound shown as a general formula (IV) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, which comprises the following steps:

the compound of the general formula (IVA) and the compound of the general formula (IVB) are subjected to coupling reaction to obtain the compound of the general formula (IV),

wherein:

x is halogen;

R^bis an alkyl group;

m is

R¹、R^a、R⁵～R⁷、R¹⁰、R¹¹And n is as defined in formula (IV).

Scheme five

The invention relates to a method for preparing a compound shown as a general formula (V) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, which comprises the following steps:

wherein:

x is halogen;

R^bis an alkyl group;

m is

R¹、R⁵～R⁷、R¹⁰、R¹¹、Cy₃、Cy₄And n is as defined in formula (IV).

Detailed Description

The present invention will be further described with reference to the following examples, which are not intended to limit the scope of the present invention.

Examples

The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or Mass Spectrometry (MS). NMR was measured using a Bruker AVANCE-400 NMR spectrometer using deuterated dimethyl sulfoxide (DMSO-d6) and deuterated chloroform (CDCl)₃) Deuterated methanol (CD)₃OD), internal standard Tetramethylsilane (TMS), chemical shift is 10^-6(ppm) is given as a unit.

MS was determined using a FINNIGAN LCQAD (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantage MAX).

HPLC was carried out using an Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18150X 4.6mm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18150X 4.6mm column).

High Performance liquid preparation A preparative chromatograph was used from Waters2767, Waters 2767-SQ Detector 2, Shimadzu LC-20AP and Gilson-281.

The thin layer chromatography silica gel plate adopts HSGF254 of tobacco yellow sea or GF254 of Qingdao, the specification of the silica gel plate used by Thin Layer Chromatography (TLC) is 0.15 mm-0.2 mm, and the specification of the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm.

The column chromatography generally uses 200-300 mesh silica gel of Taiwan yellow sea as a carrier.

Known starting materials of the present invention can be synthesized by or according to methods known in the art, or can be purchased from companies such as ABCR GmbH & Co.KG, Acros Organnics, Aldrich Chemical Company, Shao Yuan Chemical technology (Accela ChemBio Inc), Darri Chemicals, and the like.

In the examples, the reaction was carried out under an argon atmosphere or a nitrogen atmosphere unless otherwise specified.

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

The hydrogen atmosphere refers to a reaction flask connected with a hydrogen balloon with a volume of about 1L.

The pressure hydrogenation reaction used a hydrogenation apparatus of Parr 3916EKX type and a hydrogen generator of Qinglan QL-500 type or a hydrogenation apparatus of HC2-SS type.

The hydrogenation reaction was usually evacuated and charged with hydrogen and repeated 3 times.

The microwave reaction was carried out using a CEM Discover-S908860 type microwave reactor.

In the examples, the solution in the reaction is an aqueous solution unless otherwise specified.

In the examples, the reaction temperature was room temperature unless otherwise specified.

The room temperature is the optimum reaction temperature, and the temperature range is 20-30 ℃.

The progress of the reaction in the examples was monitored by Thin Layer Chromatography (TLC) using a developing solvent system of: a: dichloromethane and methanol system, B: n-hexane and ethyl acetate, and the volume ratio of the solvent is adjusted according to the polarity of the compound.

The system of eluents for column chromatography and developing agents for thin layer chromatography used for purifying compounds include: a: dichloromethane and methanol system, B: the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of triethylamine, an acidic or basic reagent and the like can be added for adjustment.

Example 1

(R) -1- (2- (((S) -5- (3-chloro-2-methyl-4- (2- (4-methylpiperazin-1-yl) ethoxy) phenyl) -6- (4-fluorophenyl) thieno [2,3-d ] pyrimidin-4-yl) oxy) -3- (5- ((2- (2-methoxyphenyl) pyrimidin-4-yl) methoxy) -3-methyl-1H-pyrazol-1-yl) propanoic acid

First step of

2- (2-methoxyphenyl) -4- (((5-methyl-1H-pyrazol-3-yl) oxy) methyl) pyrimidine 1c

5-methyl-1H-pyrazol-3-ol 1a (1.00g, 10.19mmol, Shaoyuan), triphenylphosphine (3.60g,13.7mmol) and (2- (2-methoxyphenyl) pyrimidin-4-yl) methanol 1b (2.00g, 9.25mmol, prepared by the method disclosed in the patent application 'WO 201715224') were dissolved in 30mL tetrahydrofuran, and di-tert-butyl azodicarboxylate (3.20g, 13.9mmol) was added to the reaction solution, and the reaction solution was heated to 45 ℃ and stirred for 16 hours. The reaction was cooled to room temperature and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title product 1c (1.90g), yield: and 69 percent.

MS m/z(ESI):297.2[M+1]

Second step of

(R) -2-hydroxy-3- (5- ((2- (2-methoxyphenyl) pyrimidin-4-yl) methoxy) -3-methyl-1H-pyrazol-1-yl) propionic acid methyl ester 1e

1c (1.90g, 6.41mmol) and (R) -oxetane-2-carboxylic acid methyl ester 1d (1.31g, 12.83mmol) were dissolved in 20mL of ethanol, and the reaction mixture was heated to 80 ℃ and stirred for reaction for 48 hours. The reaction was cooled to room temperature, concentrated under reduced pressure to remove the solvent, and the resulting residue was purified by silica gel column chromatography with eluent system a to give the title product 1e (650mg), yield: 25 percent.

MS m/z(ESI):399.1[M+1]

The third step

(R) -methyl 2- ((5-bromo-6- (4-fluorophenyl) thieno [2,3-d ] pyrimidin-4-yl) oxy) -3- (5- ((2- (2-methoxyphenyl) pyrimidin-4-yl) methoxy) -3-methyl-1H-pyrazol-1-yl) propionate 1g

1e (430mg, 1.08mmol), 5-bromo-4-chloro-6- (4-fluorophenyl) thieno [2,3-d ] pyrimidine 1f (200mg, 0.58mmol, prepared by the method disclosed in patent application "WO 201715224") and cesium carbonate (300mg, 0.92mmol) were placed in a 50mL round-bottomed flask, 10mL of t-butanol was added, and the reaction was heated to 40 ℃ and stirred for 16 hours. The reaction solution was cooled to room temperature, filtered, the filter cake was washed with ethyl acetate, the filtrate 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 give the title product 1g (310mg), yield: 75 percent.

MS m/z(ESI):706.2[M+1]

The fourth step

1g (100mg, 0.14mmol), 1- (2- (2-chloro-3-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenoxy) ethyl) -4-methylpiperazine 1h (100mg, 0.25mmol), cesium carbonate (140mg,0.43mmol) and dichlorobis [ di-tert-butyl- (4-dimethylaminophenyl) phosphine ] palladium (II) (15mg,0.02mmol) were dissolved in 2.0mL dioxane and 0.5mL water, replaced with argon three times, and the reaction solution was heated to 100 ℃ under an argon atmosphere and stirred for 16 hours. The reaction solution was cooled to room temperature, the solvent was removed by concentration under reduced pressure, and the obtained residue was purified by high performance liquid chromatography (waters2767, eluent: 0.1% trifluoroacetic acid, water, acetonitrile) to obtain the title product 1(6.2mg), yield: 5 percent. MS M/z (ESI) 879.5[ M +1]

¹H NMR(400MHz,CD₃OD):δ8.83(d,1H),8.58(s,1H),7.67(d,1H),7.53(t,1H),7.32(d,1H),7.26-7.19(m,3H),7.13-7.07(m,2H),7.04-6.99(m,2H),6.91(d,1H),5.58(t,1H),5.54(s,1H),5.17(s,2H),4.33-4.20(m,4H),3.86(s,3H),3.38-3.25(m,6H),3.14-3.05(m,4H),2.86(s,3H),2.12(s,3H),2.00(s,3H).

Example 2

(R) -2- (((S) -5- (3-chloro-2-methyl-4- (2- (4-methylpiperazin-1-yl) ethoxy) phenyl) -6- (5-fluorofuran-2-yl) thieno [2,3-d ] pyrimidin-4-yl) oxy) -3- (5- ((2- (2-methoxyphenyl) pyrimidin-4-yl) methoxy) -3-methyl-1H-pyrazol-1-yl) propanoic acid 2

First step of

(R) -methyl 2- ((5-bromo-6- (5-fluorofuran-2-yl) thieno [2,3-d ] pyrimidin-4-yl) oxy) -3- (5- ((2- (2-methoxyphenyl) pyrimidin-4-yl) methoxy) -3-methyl-1H-pyrazol-1-yl) propionate 2b

1e (360mg, 0.90mmol), 5-bromo-4-chloro-6- (5-fluoro-furan-2-yl) thieno [2,3-d ] pyrimidine 2a (350mg, 1.05mmol, prepared by the method disclosed in patent application "EP 2886545A 1") and cesium carbonate (450mg, 1.38mmol) were placed in a 50mL round-bottomed flask, 10mL of t-butanol was added, and the reaction was heated to 40 ℃ and stirred for 16 hours. The reaction was cooled to room temperature, filtered, the filter cake was washed with ethyl acetate, the filtrate 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 give the title product 2B (220mg), yield: 30 percent.

MS m/z(ESI):696.0[M+1]

Second step of

2b (170mg, 0.24mmol), 1h (150mg, 0.38mmol), cesium carbonate (240mg, 0.74mmol) and dichlorobis [ di-tert-butyl- (4-dimethylaminophenyl) phosphine ] palladium (II) (20mg, 0.03mmol) were dissolved in 2.5mL of dioxane and 0.5mL of water, replaced with argon three times, and the reaction mixture was heated to 80 ℃ under argon atmosphere and stirred for 16 hours. The reaction solution was cooled to room temperature, the solvent was removed by concentration under reduced pressure, and the obtained residue was purified by high performance liquid chromatography (waters2767, eluent: 0.1% trifluoroacetic acid, water, acetonitrile) to obtain the title product 2(11mg), yield: 5 percent of

MS m/z(ESI):869.3[M+1]

¹H NMR(400MHz,CD₃OD):δ8.85(d,1H),8.54(s,1H),7.68(d,1H),7.53(t,1H),7.37(d,1H),7.20-7.17(m,2H),7.10-7.04(m,2H),5.66-5.56(m,4H),5.20(s,2H),4.29-4.24(m,4H),3.87(s,3H),3.38-3.11(m,10H),2.87(s,3H),2.12(s,3H),2.03(s,3H).

Example 3

(R) -2- (((S) -5- (3-chloro-2-methyl-4- (2- (4-methylpiperazin-1-yl) ethoxy) phenyl) -6- (5-chlorofuran-2-yl) thieno [2,3-d ] pyrimidin-4-yl) oxy) -3- (5- ((2- (2-methoxyphenyl) pyrimidin-4-yl) methoxy) -3-methyl-1H-pyrazol-1-yl) propanoic acid 3

First step of

(R) -methyl 2- ((5-bromo-6- (5-chlorofuran-2-yl) thieno [2,3-d ] pyrimidin-4-yl) oxy) -3- (5- ((2- (2-methoxyphenyl) pyrimidin-4-yl) methoxy) -3-methyl-1H-pyrazol-1-yl) propionate 3b

1e (300mg, 0.75mmol), 5-bromo-4-chloro-6- (5-chlorofuran-2-yl) thieno [2,3-d ] pyrimidine 3a (180mg, 0.51mmol, prepared by the method disclosed in patent application "WO 201597123 (A1)") and cesium carbonate (340mg, 1.04mmol) were placed in a 50mL round-bottomed flask, 3.0mL of t-butanol was added, and the reaction was heated to 50 ℃ and stirred for reaction for 3 hours. Water (10mL), ethyl acetate (10mL × 2) extraction, concentration of the filtrate under reduced pressure to remove the solvent, and purification of the resulting residue by thin layer chromatography with developer system B to give the title product 3B (150mg), yield: 41 percent.

MS m/z(ESI):711.1[M+1]

Second step of

3b (150mg, 0.21mmol), 1h (120mg, 0.30mmol), cesium carbonate (140mg,0.43mmol) and dichlorobis [ di-tert-butyl- (4-dimethylaminophenyl) phosphine ] palladium (II) (15mg,0.02mmol) were dissolved in 3.0mL of tetrahydrofuran and 1.0mL of water, replaced with argon three times, the reaction mixture was stirred at room temperature under an argon atmosphere for 24 hours, lithium hydroxide monohydrate (80mg, 1.9mmol) was added, and the mixture was stirred at room temperature for 2 hours. Ethyl acetate (10 mL. times.2) was extracted, the solvent was removed by concentration under reduced pressure, and the resulting residue was purified by high performance liquid chromatography (waters2767, eluent: 0.1% trifluoroacetic acid, water, acetonitrile) to give the title product 3(40mg), yield: 21 percent.

MS m/z(ESI):885.1[M+1]

¹H NMR(400MHz,CD₃OD):δ8.85(d,1H),8.56(s,1H),7.65(d,1H),7.52(t,1H),7.34(d,1H),7.18(t,2H),7.08(t,1H),7.03(d,1H),6.25(d,1H),5.69(d,1H),5.63-5.60(m,1H),5.56(s,1H),5.19(s,2H),4.31-4.19(m,4H),3.87(s,3H),3.38-3.12(m,8H),2.99(t,2H),2.85(s,3H),2.13(s,3H),2.02(s,3H).

Example 4

(R) -2- (((S) -5- (3-chloro-2-methyl-4- (2- (4-methylpiperazin-1-yl) ethoxy) phenyl) -6- (4-fluorophenyl) thieno [2,3-d ] pyrimidin-4-yl) oxy) -3- (1H-pyrazol-1-yl) propionic acid 4

First step of

(R) -2-hydroxy-3- (1H-pyrazol-1-yl) propionic acid methyl ester 4b

Pyrazole 4a (500mg,7.34mmol) and 1d (425mg,4.16mmol) were dissolved in 5.0mL of ethanol, and the reaction mixture was heated to 80 ℃ and stirred for 16 hours. The reaction was cooled to room temperature, concentrated under reduced pressure to remove the solvent, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title product 4B (550mg), yield: 78 percent.

¹H NMR(400MHz,CDCl₃):δ7.56(d,1H),7.48(d,1H),6.30(dd,1H),4.60(m,1H),4.54-4.52(m,2H),4.37-4.29(m,2H),3.83(s,3H).

Second step of

(R) -methyl 2- ((5-bromo-6- (4-fluorophenyl) thieno [2,3-d ] pyrimidin-4-yl) oxy) -3- (1H-pyrazol-1-yl) propionate 4c

4b (150mg, 0.88mmol), 1f (200mg, 0.58mmol) and cesium carbonate (400mg, 1.23mmol) were placed in 5.0mL of t-butanol, and the reaction solution was heated to 50 ℃ and stirred for 2 hours. The reaction solution was cooled to room temperature, water (10mL), ethyl acetate (10mL × 4) was added, the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate 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 give the title product 4c (201mg), yield: 72 percent.

MS m/z(ESI):477.0[M+1]

The third step

4c (150mg, 0.31mmol), 1h (190mg, 0.48mmol), cesium carbonate (310mg,0.95mmol) and dichlorobis [ di-tert-butyl- (4-dimethylaminophenyl) phosphine ] palladium (II) (23mg, 0.03mmol) were placed in 5.0mL of dioxane and 1.0mL of water, replaced with argon three times, and the reaction solution was heated to 90 ℃ under argon atmosphere and stirred for reaction for 3.0 hours. The reaction was cooled to room temperature, concentrated under reduced pressure to remove the solvent, and the resulting residue was purified by high performance liquid chromatography (waters2767, eluent: 10mmol/L ammonium bicarbonate, water, acetonitrile) to give the title product 4(3.2mg), yield: 1.6 percent.

MS m/z(ESI):652.1[M+1]

¹H NMR(400MHz,CD₃OD):δ8.52(s,1H),7.54(d,1H),7.34(s,1H),7.28-7.26(m,2H),7.11(d,1H),7.05-7.01(m,2H),6.47(s,1H),6.03(s,1H),5.64(d,1H),4.56(d,1H),4.34-4.26(m,2H),4.04(m,1H),3.31(m,6H),3.01-2.98(m,4H),2.67(s,3H),1.86(s,3H).

Example 5 (comparative example 1)

(R) -2- (((S) -5- (3-chloro-2-methyl-4- (2- (4-methylpiperazin-1-yl) ethoxy) phenyl) -6- (4-fluorophenyl) thieno [2,3-d ] pyrimidin-4-yl) oxy) -3- (1H-pyrrol-1-yl) propionic acid 5

First step of

(R) -2-hydroxy-3- (1H-pyrrol-1-yl) propionic acid 5c

(R) -3-amino-2-hydroxypropionic acid 5a (440mg, 4.19mmol, available from Shuya) and sodium acetate (344mg, 4.20mmol) were dissolved in 2.5mL of acetic acid and 10mL of water, the reaction was heated to 80 deg.C, 2, 5-methoxytetrahydrofuran 5b (554mg, 4.19mmol, available from Adamas) was added dropwise to the reaction, and the reaction was stirred at 80 deg.C for 2.5 hours. The reaction was cooled to room temperature, and the solvent was removed by concentration under reduced pressure to give the title product 5c (650mg), yield: 100 percent. The product was directly subjected to the next reaction without purification.

Second step of

(R) -2-hydroxy-3- (1H-pyrrol-1-yl) propionic acid methyl ester 5d

Crude product 5c (650mg, 4.19mmol) was dissolved in 20mL of methanol, the reaction solution was cooled to 0 ℃ and thionyl chloride (2.00g, 16.8mmol) was added dropwise to the reaction solution, and the reaction solution was stirred at room temperature for reaction for 72 hours. The reaction solution was concentrated under reduced pressure to remove the solvent, and the residue was added to 50mL of a saturated sodium bicarbonate solution, extracted with ethyl acetate (50mL × 4), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent to give the title product 5d (500mg), yield: 70 percent.

MS m/z(ESI):170.1[M+1]

The third step

(R) -methyl 2- ((5-bromo-6- (4-fluorophenyl) thieno [2,3-d ] pyrimidin-4-yl) oxy) -3- (1H-pyrrol-1-yl) propionate 5e

5d (500mg, 2.96mmol), 1f (210mg, 0.61mmol) and cesium carbonate (840mg, 2.58mmol) were placed in 10.0mL of t-butanol, and the reaction was heated to 40 ℃ and stirred for 16 hours. The reaction solution was cooled to room temperature, water (10mL), ethyl acetate (10mL × 4) was added, the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate 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 give the title product 5e (210mg), yield: 72 percent.

MS m/z(ESI):477.0[M+1]

The fourth step

5e (175mg, 0.37mmol), 1h (200mg, 0.51mmol), cesium carbonate (360mg,1.11mmol) and dichlorobis [ di-tert-butyl- (4-dimethylaminophenyl) phosphine ] palladium (II) (30mg, 0.04mmol) were placed in 4.0mL of dioxane and 1.0mL of water, replaced with argon three times, and the reaction solution was heated to 90 ℃ under argon atmosphere and stirred for reaction for 3.0 hours. The reaction solution was cooled to room temperature, the solvent was removed by concentration under reduced pressure, and the obtained residue was purified by high performance liquid chromatography (waters2767, eluent: 0.1% trifluoroacetic acid, water, acetonitrile) to obtain the title product 5(66.0mg), yield: 28 percent.

MS m/z(ESI):651.2[M+1]

¹H NMR(400MHz,CD₃OD):δ8.58(s,1H),7.38(d,1H),7.34-7.30(m,2H),7.13-7.06(m,3H),6.05(s,2H),5.90(d,2H),5.61(dd,1H),4.36-4.26(m,3H),4.01(m,1H),3.26-3.05(m,10H),2.86(s,3H),2.04(s,3H).

Example 6 (comparative example 2)

(R) -2- (5- (3-chloro-2-methyl-4- (2- (4-methylpiperazin-1-yl) ethoxy) phenyl) -6- (4-fluorophenyl) thieno [2,3-d ] pyrimidin-4-yl) oxy) -3- (1H-1,2, 4-triazol-1-yl) propionic acid 6

First step of

(R) -2-hydroxy-3- (1H-1,2, 4-triazol-1-yl) propionic acid ethyl ester 6b

1H-1,2, 4-triazole 6a (130mg,1.88mmol) and 1d (200mg, 1.96mmol) were dissolved in 3.0mL of ethanol, and the reaction mixture was heated to 80 ℃ and stirred for reaction for 16 hours. The reaction was cooled to room temperature and concentrated under reduced pressure to remove the solvent to give the title product 6b (260mg, crude), yield: 74 percent.

MS m/z(ESI):186.2[M+1]

Second step of

(R) -ethyl 2- ((5-bromo-6- (4-fluorophenyl) thieno [2,3-d ] pyrimidin-4-yl) oxy) -3- (1H-1,2, 4-triazol-1-yl) propionate 6c

6b (250mg, 1.35mmol), 1f (300mg, 0.87mmol, prepared by the method disclosed in patent application "WO 201715224") and cesium carbonate (570mg, 1.75mmol) were placed in a 50mL round bottom flask, 5.0mL t-butanol was added, and the reaction was heated to 50 ℃ and stirred for 2 hours. The reaction solution was cooled to room temperature, water (10mL), ethyl acetate (10mL × 2) was added thereto, the solvent was removed by concentration of the filtrate under reduced pressure, and the obtained residue was purified by column chromatography using developer system B to give the title product 6c (200mg), yield: 46 percent.

MS m/z(ESI):492.0[M+1]

The third step

6c (110mg, 0.22mmol), 1h (130mg, 0.33mmol), cesium carbonate (150mg,0.46mmol) and dichlorobis [ di-tert-butyl- (4-dimethylaminophenyl) phosphine ] palladium (II) (16mg, 0.02mmol) were dissolved in 1.5mL of dioxane and 0.5mL of water, replaced with argon three times, and the reaction mixture was heated to 100 ℃ under argon atmosphere and stirred for 2 hours. The reaction solution was cooled to room temperature, the solvent was removed by concentration under reduced pressure, and the obtained residue was purified by high performance liquid chromatography (waters2767, eluent: 0.1% trifluoroacetic acid, water, acetonitrile) to obtain the title product 6(20mg), yield: 13 percent.

MS m/z(ESI):652.1[M+1]

¹H NMR(400MHz,CD₃OD):δ8.61(d,1H),7.87(s,1H),7.32-7.21(m,4H),7.07-7.02(m,3H),5.90(d,1H),4.54-4.49(m,2H),4.37-4.29(m,2H),3.34-3.25(m,8H),3.14-3.05(m,2H),2.88(s,3H),2.02(s,3H).

Test example:

biological evaluation

Test example 1 binding assay of the compounds of the present invention to MCL-1 protein.

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

first, experimental material and instrument

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

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

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

4. Affinity streptomycin linkage XL665(cisbio, 611SAXLA)

5. Binding buffer (cisbio, 62DLBDDF)

6. Detection buffer (cisbio, 62DB1FDG)

7. Enzyme mark instrument (BMG, PHERASta)

Second, the experimental procedure

MCL-1 inhibitors bind to the MCL-1 protein to prevent binding of MCL-1 to the Bim protein. This experiment evaluates the binding capacity of MCL-1 inhibitors to the MCL-1 protein by detecting the binding of MCL-1 and Bim proteins by means of HTRF, and the activity of the compounds is evaluated on the basis of the Ki size.

His and biotin are respectively marked on the peptide segments of the human recombinant protein MCL-1 (sequence 171-327) and Bim (sequence 51-76). 0.1nM His-MCL-1, 2.5nM bio-Bim and different concentrations of small molecule compounds (first 10uM, 3 fold gradient diluted 11 concentrations in binding buffer) were mixed and incubated at room temperature for 2 hours, followed by addition of 0.5nM europium cryptate anti-6 His antibody and 1.25nM affinity streptomycin linked to 665 XL (diluted in assay buffer). After 2 hours incubation at room temperature, fluorescence signals at 620nm and 665nm were detected using PHERAStar. Data were processed using GraphPad software.

Third, experimental data

The binding capacity of the compounds of the invention to the MCL-1 protein can be determined by the above assay and the Ki values determined are shown in Table 1.

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

Example numbering	Ki/nM	Max Inhibition(％)
			1	0.81	94
2	0.07	100
			3	0.65	98
4	26	80
			5 (comparative example 1)	102	72
6 (comparative example 2)	769	63

And (4) conclusion: the compound has stronger binding capacity with MCL-1 protein, and can well inhibit the binding of MCL-1 and Bim protein. Comparing the data of example 4 with those of examples 5 and 6, it can be seen that the influence of the pyrazole group in the structure of the compound of the present invention on the activity is significant.

Claims

1. A compound of formula (II), or a tautomer thereof, or a pharmaceutically acceptable salt thereof:

wherein:

R¹is a hydrogen atom or C_1-6An alkyl group;

R²is a hydrogen atom or-O (CH)₂)_p-R^aP is 1;

R³is a hydrogen atom or C_1-6An alkyl group;

R⁵is a hydrogen atom or C_1-6An alkyl group;

R⁶are the same or different and are each independently a hydrogen atom or a halogen;

R⁷is phenyl or 5-membered heteroaryl; wherein said phenyl or 5-membered heteroaryl is each independently optionally selected from C_1-6Alkyl and halogen;

R⁸and R⁹Is a hydrogen atom;

R¹⁰and R¹¹Together with the nitrogen atom to which they are attached form a 3-to 6-membered heterocyclic group, wherein said 3-to 6-membered heterocyclic group optionally contains, in addition to 1 nitrogen atom, 1 to 2 identical or different heteroatoms selected from N, O and S, and said 3-to 6-membered heterocyclic group is optionally substituted with one or more C_1-6Alkyl substituted;

R^ais-Cy₃-Cy₄；

Cy₃And Cy₄Are the same or different and are each independently phenyl or 6-membered heteroaryl; wherein said phenyl or 6-membered heteroaryl is each independently optionally selected from C_1-6Alkyl and C_1-6Substituted with one or more substituents of alkoxy;

n is 0 or 1; and

m is 0, 1 or 2.

2. The compound represented by the general formula (II), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, according to claim 1, which is a compound represented by the general formula (III), or a tautomer thereof, or a pharmaceutically acceptable salt thereof:

wherein

R¹⁰、R¹¹、R^a、R¹、R⁵To R⁷N and m are as defined in claim 1.

3. The compound of formula (II), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, according to claim 1, wherein R is⁶Is halogen.

4. The compound represented by the general formula (II), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, according to claim 1, which is a compound represented by the general formula (IV), or a tautomer thereof, or a pharmaceutically acceptable salt thereof,

wherein:

R⁶is halogen;

R¹⁰、R¹¹、R^a、R¹、R⁵、R⁷and n is as defined in claim 1.

5. The compound of formula (II), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, according to claim 1, wherein R is⁵Is C_1-6An alkyl group.

6. The compound represented by the general formula (II), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, according to claim 1, which is a compound represented by the general formula (V), or a tautomer thereof, or a pharmaceutically acceptable salt thereof,

wherein:

R¹is a hydrogen atom or C_1-6An alkyl group;

R⁵is C_1-6An alkyl group;

R⁶is halogen;

R⁷is phenyl or 5-membered heteroaryl, wherein said phenyl or 5-membered heteroaryl is optionally selected from C_1-6Alkyl and halogen;

R¹⁰and R¹¹Together with the nitrogen atom to which they are attached form a 3-to 6-membered heterocyclic group, wherein said 3-to 6-membered heterocyclic group optionally contains, in addition to 1 nitrogen atom, 1 to 2 identical or different heteroatoms selected from N, O and S, and said 3-to 6-membered heterocyclic group is optionally substituted with one or more C_1-6Substituted by alkyl radicals；

Cy₃And Cy₄Are the same or different and are each independently phenyl or 6-membered heteroaryl; wherein said phenyl or 6-membered heteroaryl is each independently optionally substituted by one or more C_1-6Alkoxy substituted;

n is 0 or 1.

7. A compound of formula (II), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, according to claim 1, selected from the group consisting of:

8. a compound represented by the general formula (IIA), or a tautomer thereof, or a pharmaceutically acceptable salt thereof,

wherein:

x is halogen;

R^bis C_1-6An alkyl group;

R¹、R²、R⁷、R⁸、R⁹and n is as defined in claim 1.

9. A compound of formula (IIA) according to claim 8, which is selected from:

10. a process for preparing a compound of formula (II), the process comprising:

wherein:

x is halogen;

R^bis C_1-6An alkyl group;

m is

R³Is a hydrogen atom;

R¹、R²、R⁵to R¹¹N and m are as defined in claim 1.

11. A pharmaceutical composition comprising a therapeutically effective amount of a compound of general formula (II) according to any one of claims 1 to 7, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

12. Use of a compound of general formula (II) according to any one of claims 1 to 7 or a tautomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 11, for the preparation of a medicament for inhibiting MCL-1.

13. Use of a compound of general formula (II) according to any one of claims 1 to 7 or a tautomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 11, for the preparation of a medicament for the treatment or prevention of a MCL-1 mediated disease.

14. Use of a compound of general formula (II) according to any one of claims 1 to 7 or a tautomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 11 for the preparation of a medicament for the treatment of tumors, autoimmune diseases and immune system diseases.

15. The use according to claim 14, wherein the tumor is selected from the group consisting of bladder cancer, brain tumor, breast cancer, cervical cancer, endometrial cancer, ovarian cancer, leukemia, renal cancer, colorectal cancer, esophageal cancer, liver cancer, gastric cancer, head and neck cancer, skin cancer, lymphoma, pancreatic cancer, melanoma, myeloma, bone cancer, neuroblastoma, glioma, sarcoma, lung cancer, thyroid cancer, and prostate cancer.