WO2019101144A1 - Selective mcl-1 inhibitor and preparation and use thereof - Google Patents

Abstract

The present invention provides a selective Mcl-1 inhibitor and a preparation and use thereof. The present invention also provides a series of compounds represented by general formula (I), pharmaceutically acceptable salt, solvate, polymorphs, or prodrugs thereof, pharmaceutical compositions comprising the compounds, and methods of treating a disease induced or aggravated by overexpressed or dysfunctional MCL-1 protein by using the compounds.

Description

Mcl-1 selective inhibitor and preparation and use thereof

cross reference

This application claims the Chinese patent application No. 201711189194.4 filed on November 23, 2017, entitled "Mcl-1 selective inhibitor and its preparation and use" and the patent name submitted on May 8, 2018 is "Mcl- The priority of the Chinese Patent Application No. 201101, 425, 427, the entire disclosure of which is incorporated herein by reference.

Technical field

The present invention relates to compounds which selectively inhibit the activity of Mcl-1 anti-apoptotic proteins, to the preparation of these compounds and to the use of the same.

Background technique

Apoptosis is an autonomous and ordered process of death of cells controlled by multiple genes. It involves the activation, expression and regulation of a range of genes (J. Cell Mol Life Sci, 2008, 66(8): 1326-1336). The Bcl-2 family plays an important regulatory role in the process of apoptosis. Mcl-1, an important member of the anti-apoptotic protein in the Bcl-2 family, plays an important role in early embryogenesis and maintenance of lymphocytes, nerve cells, fibroblasts, and liver stem cells (J.Cell D eath D Iffer, 2013, 20 (11): 1475-1484.). Studies have shown that many malignant tumor cells can overexpress Mcl-1 protein (J. Cell death & disease, 2010.1 (5): pe 40.), resulting in an imbalance between the anti-apoptotic members and pro-apoptotic members, leading to Malignant proliferation of tumor cells. In recent years, genetic variation of Mcl-1 has been detected in different cell lines of central nervous system tumors, breast cancer, colon cancer, lung cancer, ovarian cancer, prostate cancer, and melanoma (J. Bioorg Med Chem, 2013, 21 (21): 6642-6649.). Mcl-1 is involved in the correlation of tumor cell survival and drug resistance (J. Proc Natl Acad Sci USA, 2007, 104(49): 19512-19517). Whether it is a single application of Mcl-1 small molecule inhibitors, or a combination of other anti-tumor drugs, it has a better therapeutic effect, providing a new way for Mcl-1 targeted therapy to treat tumors.

In the past 10 years, small molecule inhibitors against anti-apoptotic proteins have emerged, such as the polyphenol derivative AT-101 (J. Thorac. Oncol, 2011, 6(10): 1757-1760) and APOG2. The treatment of a variety of tumors has achieved good results and is currently in Phase II/III clinical research. However, this compound has limited clinical application due to numerous adverse reactions. Several known sulfonamide protein inhibitors include BH3 mimicking proteins (ABT-737), (ABT-263) and (ABT-199) and the like. However, several studies have shown that excessive over-regulation of Mcl-1 inhibits the activity of sulfonamide-like protein inhibitors in a variety of tumor treatments, and that ABT-263 alone is not ideal for tumor therapy (J. Clin. Oncol, 2011, 29(7): 909-916.). At present, inhibition of over-expressed Mcl-1 protein has become an important research direction in the field of cancer therapy, especially Mcl-1 small molecule inhibitors, which can effectively overcome the problem of drug resistance in cancer treatment, so it is necessary to continue to develop new, more active Mcl-1 inhibitors with high drug resistance and clinical side effects are used in clinical treatment.

Summary of the invention

The present invention provides a Mcl-1 selective inhibitor which is a compound represented by the formula (I) or a pharmaceutically acceptable salt, solvate, polymorph or prodrug thereof. The present invention also provides a series of compounds represented by the general formula (I), and pharmaceutically acceptable salts, solvates, polymorphs or prodrugs thereof, pharmaceutical compositions comprising the same, and the use of such compounds A method of treating a disease caused or aggravated by over-expressed or dysregulated MCL-1 protein.

The present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, solvate, polymorph or prodrug thereof, as described below:

among them,

X is O, NH or S;

a and b are each independently a single bond or a double bond, and at most one of a and b may be a double bond;

R _{1 is} selected from H and a 5-8 membered heteroaryl group, which may be optionally C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 ring Alkyla, C _1-6 alkyl-O-, or 6-10 membered aryl, the C _1-6 alkyl group may be optionally substituted with 1-3 halo, and the 6-10 member aryl The base may be optionally substituted with from _{1 to 3} groups independently selected from C _1-6 alkyl and C _1-6 alkyl-O-;

When both a and b are a single bond, R ₂ and R ₃ are each independently selected from H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl. , halogen and cyano, or R ₂ , R ₃ together with the carbon atom to which they are attached form a 3-8 membered cycloalkyl group, and R ² and R ^{3 may} not be hydrogen at the same time;

When a is a double bond, R ₃ does not exist, and R ₂ is

When b is a double bond, R ₃ is absent, and R _{2 is} selected from the group consisting of H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, halogen and cyanide. base;

R ₄ each independently is halogen, C _1-6 alkyl, C _1-6 alkyl-O-, or cyano;

R _{5 is} selected from phenyl and 5-8 membered heteroaryl, and the phenyl and 5-8 membered heteroaryl are optionally substituted with from 1 to 3 groups selected from halogen and C _1-6 alkyl;

R _{6 is} selected from a 3-8 membered heterocyclic group optionally substituted by C _1-6 alkyl, -C _1-6 alkylene-OP(=O)(OH) ₂ , C _{1- 6} alkyl-O-substituted;

R ₇ and R ₈ are each independently selected from H and C _1-6 alkyl;

p and q are each independently 1, 2, 3, 4, 5 and 6;

m is 0, 1, 2, 3, or 4.

In some embodiments of the invention, R _{1 is} selected from H and a 5-8 membered heteroaryl, which may be optionally C _1-6 alkyl, C _1-6 alkyl-O-, Or a 6-10 membered aryl group, the C _1-6 alkyl group may be optionally substituted with 1-3 halo, and the 6-10 membered aryl group may be optionally independently selected from 1 to 3 Substituted from a C _1-6 alkyl group and a C _1-6 alkyl-O- group;

In some embodiments of the invention, R _{1 is} selected from H and a 5-8 membered heteroaryl, which may be optionally C _1-6 alkyl, C _2-6 alkenyl, C _{2 - 6} alkynyl, C _3-8 cycloalkyl, C _1-6 alkyl-O-, or 6-10 membered aryl substituted, said C _1-6 alkyl optionally substituted by 1-3 halo And the 6-10 membered aryl group may be optionally substituted with 1 to 3 groups independently selected from C _1-6 alkyl and C _1-6 alkyl-O-;

In some embodiments of the invention, R _{1 is} selected from H and a 5-8 membered heteroaryl, which may be optionally C _1-6 alkyl, C _1-6 alkyl-O-, Or a 6-10 membered aryl group, the C _1-6 alkyl group may be optionally substituted with 1-3 halo, and the 6-10 membered aryl group may be optionally independently selected from 1 to 3 Substituted from a C _1-6 alkyl group and a C _1-6 alkyl-O- group;

In some embodiments of the invention, R _{1 is} selected from the group consisting of H, pyrazolyl, and pyrimidinyl, and said pyrazolyl and pyrimidinyl are optionally C _1-6 alkyl, C _1-6 alkyl-O - or a 6-10 membered aryl group, the C _1-6 alkyl group may be optionally substituted with 1 to 3 halogens, and the 6-10 membered aryl group may be optionally 1-3 independently a group substituted with a C _1-6 alkyl group and a C _1-6 alkyl-O- group;

In some embodiments of the invention, a is a single bond or a double bond, and b is a single bond;

When both a and b are a single bond, R ₂ and R ₃ are each independently selected from H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl. , halogen and cyano, or R ₂ , R ₃ together with the carbon atom to which they are attached form a 3-8 membered cycloalkyl group, and R ₂ and R _{3 may} not be hydrogen at the same time;

In some embodiments of the invention, when both a and b are a single bond, R ₂ and R ₃ are each independently selected from H, C _1-6 alkyl, halo and cyano, or R ₂ , R ₃ and The carbon atoms attached thereto form a 3-8 membered cycloalkyl group, and R ₂ and R ₃ cannot simultaneously be hydrogen;

In some embodiments of the invention, when both a and b are a single bond, R ₂ and R ₃ are each independently selected from H, C _1-6 alkyl, or halogen, or R ₂ , R ₃ and The linked carbon atoms together form a 3-8 membered cycloalkyl group, and R ₂ and R ₃ cannot simultaneously be hydrogen;

In some embodiments of the invention, when both a and b are a single bond, R ₂ and R ₃ are each independently selected from H, C _1-6 alkyl, or halogen, or R ₂ , R ₃ and The linked carbon atoms together form a 3-6 membered cycloalkyl group, and R ₂ and R ₃ cannot simultaneously be hydrogen;

When a is a double bond, R ₃ does not exist, and R ₂ is

Wherein R ₇ and R ₈ are hydrogen;

In some embodiments of the invention, R _{5 is} selected from the group consisting of phenyl and furanyl, which are optionally substituted with from 1 to 3 groups selected from halo and C _1-6 alkyl;

In some embodiments of the invention, R ₆ is piperazinyl, and the piperazinyl is optionally substituted with C _1-6 alkyl;

In some embodiments of the invention, p is 1, 2, or 3, preferably 1 or 2, more preferably 1;

In some embodiments of the invention, q is 1, 2, 3, or 4, preferably 1 or 2, more preferably 2;

In some embodiments of the invention, m is 0, 1, or 2;

In a preferred embodiment of the invention, in the compound of formula (I), X is O, and the structural formula is as shown in the following formula (II):

The present invention provides a compound of formula (II), or a pharmaceutically acceptable salt, solvate, polymorph or prodrug thereof, as described above;

among them,

a and b are each independently a single bond or a double bond, and at most one of a and b may be a double bond;

R _{1 is} selected from H and a 5-8 membered heteroaryl group, which may be optionally C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 ring Alkyla, C _1-6 alkyl-O-, or 6-10 membered aryl, the C _1-6 alkyl group may be optionally substituted with 1-3 halo, and the 6-10 member aryl The base may be optionally substituted with from _{1 to 3} groups independently selected from C _1-6 alkyl and C _1-6 alkyl-O-;

When both a and b are a single bond, R ₂ and R ₃ are each independently selected from H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl. , halogen and cyano, or R ₂ , R ₃ together with the carbon atom to which they are attached form a 3-8 membered cycloalkyl group, and R ² and R ^{3 may} not be hydrogen at the same time;

When a is a double bond, R ₃ does not exist, and R ₂ is

When b is a double bond, R ₃ is absent, and R _{2 is} selected from the group consisting of H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, halogen and cyanide. base;

R ₄ each independently is halogen or C _1-6 alkyl;

R _{5 is} selected from phenyl and 5-8 membered heteroaryl, and the phenyl and 5-8 membered heteroaryl are optionally substituted with from 1 to 3 groups selected from halogen and C _1-6 alkyl;

R _{6 is} selected from a 3-8 membered heterocyclic group, which is optionally substituted by a C _1-6 alkyl group;

R ₇ and R ₈ are each independently selected from H and C _1-6 alkyl;

p and q are each independently 1, 2, 3, 4, 5 and 6;

m is 0, 1, 2, 3, or 4.

In some embodiments of the invention, R _{1 is} selected from H and a 5-8 membered heteroaryl, which heteroaryl group can be optionally substituted with a C _1-6 alkyl group or a 6-10 membered aryl group. The C _1-6 alkyl group may be optionally substituted by 1 to 3 halogens, which may be optionally 1-3 independently selected from C _1-6 alkyl and C _1-6 a group substituted with an alkyl-O- group;

Preferably, R _{1 is} selected from the group consisting of H, pyrazolyl and pyrimidinyl; the pyrazolyl and pyrimidinyl may be optionally C _1-6 alkyl, C _1-6 alkyl-O-, or 6-10 Substituted by a aryl group, the C _1-6 alkyl group may be optionally substituted with from 1 to 3 halogens, and the 6-10 membered aryl group may be optionally selected from 1-3 independently from C _1- Substituted by a group of ₆ alkyl and C _1-6 alkyl-O-.

In some embodiments of the invention, R _{1 is} selected from H, pyrazolyl, pyrimidinyl, and the pyrazolyl may be optionally substituted by C _1-6 alkyl, the C _1-6 alkyl optionally substituted with 1-3 halogens, the pyrimidinyl may be optionally substituted 6-10 membered aryl, 6-10-membered aryl optionally substituted with 1-3 substituents independently selected from C ₁ Substituted with a group of _-6 alkyl and C _1-6 alkyl-O-;

In some embodiments of the invention, when both a and b are a single bond, R ₂ and R ₃ are each independently selected from H, C _1-6 alkyl, halo and cyano, or R ₂ , R ₃ and The carbon atoms attached thereto form a 3-8 membered cycloalkyl group, and R ² and R ³ cannot simultaneously be hydrogen;

When a is a double bond, R ₃ does not exist, and R ₂ is

Wherein R ₇ and R ₈ are hydrogen;

When b is a double bond, R ₃ is absent, and R _{2 is} selected from the group consisting of H, C _1-6 alkyl, halogen and cyano;

In some embodiments of the invention, R _{5 is} selected from the group consisting of phenyl and furanyl, which are optionally substituted with from 1 to 3 groups selected from halo and C _1-6 alkyl;

In some embodiments of the invention, R ₆ is piperazinyl, and the piperazinyl is optionally substituted with C _1-6 alkyl;

In some embodiments of the invention, p is 1, 2, or 3, preferably 1 or 2, more preferably 1;

In some embodiments of the invention, p is 1, 2, 3, or 4, preferably 1 or 2, more preferably 2;

In some embodiments of the invention, the compound of the invention is selected from the group consisting of

Or a pharmaceutically acceptable salt, solvate, isomer, or prodrug thereof.

The present invention also provides a series of compounds represented by the general formula (I), and pharmaceutically acceptable salts, solvates, polymorphs or prodrugs thereof, pharmaceutical compositions comprising the same, and the use of such compounds A method of treating a disease caused or aggravated by over-expressed or dysregulated MCL-1 protein.

The compounds of the invention may be used in the treatment of a disease caused or exacerbated by overexpressed or dysregulated MCL-1 protein; in some embodiments, the disease is cancer. In some embodiments, the disease is a cancer that is resistant to chemotherapy or radiation; in some embodiments, the cancer is selected from the group consisting of: bladder cancer, brain cancer, breast cancer and uterine cancer, chronic lymphocytic leukemia, colon Cancer, esophageal cancer and liver cancer, lymphoblastic leukemia, acute myeloid leukemia, lymphoma, ovarian cancer, or non-small cell lung cancer.

Another aspect of the invention also relates to a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein, and a pharmaceutically acceptable carrier.

In another aspect, the invention provides a method of treating a condition caused or exacerbated by an overexpressed or dysregulated MCL-1 protein, comprising administering to a subject in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable compound thereof Salts, solvates, polymorphs, isomers or prodrugs or combinations thereof. In some embodiments, the disease is cancer. In some embodiments, the disease is a cancer that is resistant to chemotherapy or radiation; in some embodiments, the cancer is selected from the group consisting of: bladder cancer, brain cancer, breast cancer and uterine cancer, chronic lymphocytic leukemia, colon Cancer, esophageal cancer and liver cancer, lymphoblastic leukemia, acute myeloid leukemia, lymphoma, ovarian cancer, or non-small cell lung cancer.

In some embodiments of the invention, the subject matter of the invention is a mammal comprising a human.

In another aspect, the invention provides a compound of formula (I), or a pharmaceutically acceptable salt, solvate, polymorph, isomer or prodrug thereof, for use in the treatment of MCL-overexpressed or dysregulated Use of a drug for a protein-induced or aggravated disease. In some embodiments, the disease is cancer. In some embodiments, the disease is a cancer that is resistant to chemotherapy or radiation; in some embodiments, the cancer is selected from the group consisting of: bladder cancer, brain cancer, breast cancer and uterine cancer, chronic lymphocytic leukemia, colon Cancer, esophageal cancer and liver cancer, lymphoblastic leukemia, acute myeloid leukemia, lymphoma, ovarian cancer, non-small cell lung cancer, multiple myeloma, acute lymphocytic leukemia, or myelodysplastic syndrome.

In another aspect, the invention provides a compound of formula (I), or a pharmaceutically acceptable salt, solvate, polymorph, isomer or prodrug thereof, for use in the treatment of MCL-overexpressed or dysregulated Use of a drug for a protein-induced or aggravated disease. In some embodiments, the disease is cancer. In some embodiments, the disease is a cancer that is resistant to chemotherapy or radiation; in some embodiments, the cancer is selected from the group consisting of: bladder cancer, brain cancer, breast cancer and uterine cancer, chronic lymphocytic leukemia, colon Cancer, esophageal cancer and liver cancer, lymphoblastic leukemia, acute myeloid leukemia, lymphoma, ovarian cancer, or non-small cell lung cancer.

Detailed description of the invention

Exemplary embodiments utilizing the principles of the invention are set forth in the Detailed Description of the Invention. The features and advantages of the present invention will become more apparent from the <RTIgt;

It is to be understood that the scope of the present invention is defined by the scope of the claims, and the scope of the appended claims.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning meaning meaning All patents, patent applications, and publications cited herein are hereby incorporated by reference in their entirety in their entirety in their entirety herein.

The above description and the following detailed description are intended to be illustrative and not restrictive. Unless otherwise specified, the use of the singular forms also includes the plural. Unless otherwise stated, the use of "or" or "or" means "and/or". In addition, the terms "comprises" and "comprising", "include", "include", and "include" are not limiting.

Certain chemical terms

The term "optional,""optional," or "optionally" means that the subsequently described event or circumstance may or may not occur, the description including the occurrence of the event or condition and the occurrence of the event or condition. For example, "optionally substituted alkyl" means "unsubstituted alkyl" or "substituted alkyl". Also, the optionally substituted group may be unsubstituted (for example: -CH ₂ CH ₃ ), fully substituted (for example: -CF ₂ CF ₃ ), monosubstituted (for example: -CH ₂ CH ₂ F) or Any level between single and complete substitutions (eg, -CH ₂ CHF ₂ , -CF ₂ CH ₃ , -CFHCHF _{2 ,} etc.). It will be understood by those skilled in the art that for any group containing one or more substituents, no substitution or substitution pattern that is sterically impossible to exist and/or which cannot be synthesized is introduced.

Unless otherwise stated, conventional methods within the skill of the art, such as mass spectrometry, nuclear magnetic, high performance liquid chromatography, infrared and ultraviolet/visible spectroscopy, and pharmacological methods are employed. Unless specifically defined, the terms and experimental procedures and techniques herein for analytical chemistry, organic synthetic chemistry, and pharmaceutical and pharmaceutical chemistry are known in the art. Standard techniques can be used in chemical synthesis, chemical analysis, pharmaceutical preparation, formulation and delivery, and treatment of patients. For example, the reaction can be carried out and purified using the manufacturer's instructions for use of the kit, or in a manner well known in the art or as described in the present invention. The above techniques and methods can generally be carried out according to conventional methods well known in the art, as described in the various summaries and more specific references cited and discussed in this specification. In the present specification, the group and its substituents can be selected by those skilled in the art to provide stable structural moieties and compounds.

When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes the chemically equivalent substituent obtained when the structural formula is written from right to left. For example, -CH ₂ O- is equivalent to -OCH ₂ -.

The term "group", "chemical group" as used herein, refers to a specific moiety or functional group of a molecule. Chemical groups are often recognized as chemical entities embedded or attached to a molecule.

Some of the chemical groups named here can indicate the total number of carbon atoms with a short mark. For example, a C ₁ -C ₆ alkyl group describes an alkyl group, as defined below, having a total of from 1 to 6 carbon atoms. The total number of carbon atoms indicated by the abbreviations does not include the carbon atoms on the possible substituents.

The term "halogen", "halo" or "halide" means bromo, chloro, fluoro or iodo.

The terms "aromatic", "aromatic ring", "aromatic", "aromatic", "aromatic ring" as used herein, mean a ring portion of a ring or rings of a plane having 4n+2 An electronic delocalized electronic conjugate system in which n is an integer. The aromatic ring may be formed of 5, 6, 7, 8, 9, or 9 or more atoms. The aromatic compound may be optionally substituted and may be a monocyclic or fused ring polycyclic ring. The term aromatic compound includes all carbocyclic rings (such as benzene rings) and rings containing one or more heteroatoms (such as pyridine).

The term "heteroatom" or "hetero" as used herein, alone or as part of another ingredient, refers to an atom other than carbon and hydrogen. The heteroatoms are independently selected from the group consisting of oxygen, nitrogen, sulfur, phosphorus, silicon, selenium, and tin, but are not limited to these atoms. In embodiments where two or more heteroatoms are present, the two or more heteroatoms may be identical to each other, or some or all of the two or more heteroatoms may be different from each other.

The term "thick" or "fused ring" as used herein, alone or in combination, refers to a cyclic structure in which two or more rings share one or more bonds.

The term "spiro" or "spiro" as used herein, alone or in combination, refers to a cyclic structure in which two or more rings share one or more atoms.

The term "alkyl" as used herein alone or as part of another component (eg, monoalkylamino) refers to an optionally substituted straight or optionally substituted branched monovalent saturated hydrocarbon having from 1 to 12 a carbon atom, preferably 1-8 carbon atoms, more preferably 1-6 carbon atoms, linked to other moieties of the molecule by a single bond, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, Isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, n-octyl, n-decyl, n-decyl and the like.

The term "alkylene" refers to a divalent group formed by the removal of one hydrogen from an alkyl group as defined above.

The term "alkenyl" refers to a class of alkyl groups wherein the first two atoms of the alkyl group form a double bond which is not part of the aryl group. That is, an alkenyl group begins with -C(R)=C(R)-R, wherein R refers to the remainder of the alkenyl group, and each R may be the same or different. The alkenyl group may have 2 to 10 carbon atoms. The alkenyl group may also be a "lower alkenyl group" having 2 to 6 carbon atoms.

The term "alkynyl" refers to a class of alkyl groups wherein the first two atoms of the alkyl group form a triple bond. That is, an alkynyl group begins with the atom -C≡C-R, where R refers to the remainder of the alkynyl group. The "R" moiety in the alkynyl moiety can be branched, straight chain or cyclic. An alkynyl group can have 2 to 10 carbon atoms. The alkynyl group may also be a "lower alkyl group" having 2 to 6 carbon atoms.

The term "cycloalkyl" as used herein, alone or as part of another ingredient, refers to a stable, monovalent, non-aromatic monocyclic or polycyclic hydrocarbon group containing only carbon and hydrogen atoms, and may include fused rings, spiro rings or bridges. A ring system comprising from 3 to 15 ring-forming carbon atoms, preferably from 3 to 10 ring-forming carbon atoms, more preferably from 3 to 8 ring-forming carbon atoms, either saturated or unsaturated, through a single bond to the rest of the molecule Connected. Non-limiting examples of "cycloalkyl" include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.

The terms "heterocyclyl", "heterocycloalkyl", "heterocycle" as used herein, alone or as part of another ingredient, refers to a stable 3-18 membered monovalent non-aromatic ring, including 2-12 carbon atoms, 1 -6 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. Unless otherwise specified, a heterocyclic group can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system which may contain a fused ring, spiro ring or bridged ring system, and nitrogen, carbon or sulfur on the heterocyclic group may be optionally Oxidized, the nitrogen atom can be selectively quaternized, and the heterocyclic group can be partially or fully saturated. The heterocyclic group may be bonded to the remainder of the molecule through a single bond through a carbon atom or a hetero atom on the ring. The heterocyclic group containing a fused ring may contain one or more aromatic or heteroaromatic rings as long as it is attached to the remainder of the molecule to an atom on the non-aromatic ring. For the purposes of the present application, the heterocyclic group is preferably a stable 4-11 membered monovalent non-aromatic monocyclic or bicyclic ring containing from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably a stable A 4-8 membered monovalent non-aromatic monocyclic ring containing from 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. Non-limiting examples of heterocyclic groups include azepanyl, azetidinyl, decahydroisoquinolinyl, dihydrofuranyl, indanyl, dioxopentyl, 1,1 -dioxy-thiomorpholinyl, imidazolidinyl, imidazolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindenyl, octahydroisodecyl, oxazinyl, Oxazolidinyl, 1-oxo-thiomorpholinyl, 2-oxopyrazinyl, 2-oxopyridinyl, 2-oxopyrrolidinyl, phthalimido, piperazinyl, piperidinyl, 4-piperidinone, pyranyl, pyrazolyl, pyrrolidinyl, quinazinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydropyranyl, thiazolidinyl, thiophene [1,3] Dithiaalkyl, thiomorpholinyl, trithylalkyl and the like.

The term "heteroaryl" as used herein, alone or as part of another ingredient, refers to a 5-16 membered ring system comprising from 1 to 15 carbon atoms, preferably from 1 to 10 carbon atoms, from one to four selected from a hetero atom of nitrogen, oxygen and sulfur, at least one aromatic ring. Unless otherwise specified, a heteroaryl group can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system which may contain a fused ring or bridged ring system as long as the point of attachment to the rest of the molecule is an aromatic ring atom. The nitrogen, carbon and sulfur atoms on the heteroaromatic ring can be selectively oxidized, and the nitrogen atom can be selectively quaternized. For the purposes of the present invention, the heteroaryl group is preferably a stable 4-11 membered monoaromatic ring comprising from 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, more preferably a stable 5-8 membered single. An aromatic ring comprising from 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. Non-limiting examples of heteroaryl groups include acridinyl, azaftyl, benzimidazolyl, benzindenyl, 1,4-benzodioxanyl, benzo[6][1,4 Dioxepane, benzodioxanyl, benzodioxanyl, benzofuranone, benzofuranyl, benzo[4,6]imidazo[1,2-a]pyridyl , benzonaphthofuranyl, benzopyranone, benzopyranyl, benzopyrazolyl, benzothiadiazolyl, benzothiazolyl, benzothienyl, benzotriazolyl, Benzooxazolyl, carbazolyl, carbolinyl, o-naphthylnaphthyl, dibenzofuranyl, dibenzothiophenyl, furanone, furyl, imidazolyl, oxazolyl, indoline Base, pyridazinyl, fluorenyl, isoxazolyl, isoindoline, isodecyl, isoquinolinyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, Oxytriazolyl, oxazolyl, 1-oxopyrazinyl, 1-oxooxazinyl, 1-oxopyridinyl, 1-oxopyrimidinyl, oxiranyl, 2-oxoza Zhuoji, oxopyridinyl, phenanthryl, phenanthroline, phenazinyl, phenothiazine, phenoxazinyl, 1-phenyl-1H -pyrrolyl, diazepine, acridinyl, fluorenyl, pyrazinyl, pyrazolyl, pyridazinyl, 1H-pyridin-2-yl, 1H-pyridin-4-yl, 1H-pyridine-2 -keto-4-yl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, quinuclyl, tetrahydroquinolyl, 4,5,6,7-tetrahydro Benzo[b]thienyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazinyl, triazolyl and the like. In the present application, the heteroaryl group is preferably a 5-8 membered heteroaryl group containing from 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, more preferably pyridyl, pyrimidinyl, thiazolyl, oxo Pyridyl, 1H-pyridin-2-one-4-yl or thienyl.

The term "cyano" refers to the group -CN.

The term "polymorph" or "polymorph (phenomenon)" as used herein means that the compound of the invention has a plurality of lattice forms. Some of the compounds of the invention may have more than one crystalline form, and the invention encompasses all polymorphic forms or mixtures thereof.

Intermediate compounds of the compounds of the invention and polymorphs thereof are also within the scope of the invention.

Unless otherwise specified, the olefinic double bonds contained in the compounds of the present invention include the E and Z isomers.

It will be understood that the compounds of the invention may contain asymmetric centers. These asymmetric centers can be independently R or S configurations. Some of the compounds of the invention may also exhibit cis-trans isomerism, as will be apparent to those skilled in the art. It will be understood that the compounds of the invention include their individual geometric isomers and stereoisomers, as well as mixtures thereof, including racemic mixtures. These isomers may be separated from their mixtures by carrying out or modifying known methods, such as chromatographic techniques and recrystallization techniques, or they may be prepared separately from the appropriate isomers of their intermediates.

The term "pharmaceutically acceptable salt" as used herein includes both acid addition salts and base salts.

"Pharmaceutically acceptable acid addition" means those biological properties and properties which retain the free base of the compound, are not biologically or otherwise undesirable, and are inorganic acids such as, but not limited to, hydrochloric acid, hydrogen Bromo acid, sulfuric acid, nitric acid, phosphoric acid, etc., or an organic acid such as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid, citric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclaic acid, lauryl sulfate, ethane-1,2- Disulfonic acid, ethyl sulfonic acid, 2-hydroxy oxalic acid, formic acid, fumaric acid, galactonic acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid Acid, 2-oxo-glutaric acid, glycerophosphate glycolic acid, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methyl Sulfonic acid, mucic acid, naphthalene-1,5-naphthalene disulfonic acid, naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, Oxalic acid, palmitic acid, palmitic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid tartaric acid, thiocyanic acid, p-toluene a salt formed from sulfonic acid, trifluoroacetic acid, undecylenic acid or the like. "Pharmaceutically acceptable base salt" refers to those salts which retain the biological effectiveness and properties of the free acid of the compound, which are not biologically or otherwise undesirable. These salts are prepared by reacting a free acid with an inorganic or organic base. Salts formed by reaction with inorganic bases include, but are not limited to, sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, aluminum salts, and the like. Preferred inorganic salts are ammonium, sodium, potassium, calcium, and manganese salts.

Salt-forming organic bases include, but are not limited to, primary, secondary, tertiary, substituted amines (including naturally occurring substituted amines), cyclic amines, and basic ion exchange resins such as ammonia, isopropylamine, trimethylamine, Diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, dimethylamine ethanol, 2-dimethylethanolamine, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histamine Acid, caffeine, procaine, baibamin penicillin, choline, betaine, phenylethylamine, benzathine, ethylenediamine, glucosamine, meglumine, theobromine, triethanolamine, tromethamine Alcohol, hydrazine, piperazine, piperidine, N-ethylpiperidine, polyamine resin, and the like. Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine.

Crystallization often produces solvates of the compounds of the invention. The term "solvate" as used herein, refers to a combination of one or more molecules of the compound of the invention and one or more solvent molecules.

The solvent may be water, in which case the solvate is a hydrate. It may also be an organic solvent. Thus, the compounds of the invention may exist as hydrates, including monohydrates, dihydrates, hemihydrates, trihydrates, tetrahydrates, and the like, as well as the corresponding solvated forms. The compounds of the invention may be true solvates, but in other instances, the compounds of the invention may also simply retain water or a mixture of water and some other solvent. The compound of the present invention can be reacted in a solvent or precipitated or crystallized in a solvent. Solvates of the compounds of the invention are also included within the scope of the invention.

Prodrugs of the compounds of the invention are also contemplated by the present invention. "Prodrug" means a compound of the invention which can be converted to a biologically active compound under physiological conditions or solvation. Thus, the term "prodrug" refers to a pharmaceutically acceptable metabolic precursor of a compound of the invention which may be inactive when administered to a subject in need thereof, but which will be converted in vivo to an active compound of the invention. Prodrugs are typically rapidly converted to the parent compound of the invention in vivo, for example, by hydrolysis in the blood. Prodrugs often have advantages in solubility, tissue compatibility, or extended release in mammalian organisms. Prodrugs include an amino protecting group and a carboxy protecting group, all of which are well known to those skilled in the art. For the preparation of specific prodrugs, for example, Saulnier, MG, et al., Bioorg. Med. Chem. Lett. 1994, 4, 1985-1990; Greenwald, RB, et al., J. Med. .2000, 43,475.

The term "pharmaceutical composition" as used herein refers to a preparation in which a compound of the present invention is mixed with a medium which is generally accepted in the art for delivering a biologically active compound to a mammal such as a human. This medium contains all pharmaceutically acceptable carriers.

As used herein, the term "acceptable" in connection with a formulation, composition or ingredient means that there is no sustained deleterious effect on the overall health of the subject.

The term "pharmaceutically acceptable" as used herein, refers to a substance (such as a carrier or diluent) that does not affect the biological activity or properties of the compound of the invention, and is relatively non-toxic, ie, the substance can be administered to an individual without causing undesirable organisms. The reaction or in an undesirable manner interacts with any of the components contained in the composition.

"Pharmaceutically acceptable carrier" includes, but is not limited to, adjuvants, carriers, excipients, auxiliaries, deodorants, diluents, preservatives, which can be used in humans and domesticated animals, which have been approved by the relevant government administration. Dyes/colorants, flavor enhancers, surfactants and wetting agents, dispersing agents, suspending agents, stabilizers, isotonic agents, solvents, or emulsifiers.

The term "subject," "patient," or "individual" as used herein, refers to an individual, including a mammal, and a non-mammal, having a disease, disorder, or condition. Examples of mammals include, but are not limited to, any member of the mammalian class: humans, non-human primates (eg, chimpanzees and other mites and monkeys); livestock, such as cattle, horses, sheep, goats, pigs; domestic animals For example, rabbits, dogs and cats; laboratory animals, including rodents such as rats, mice and guinea pigs. Examples of non-human mammals include, but are not limited to, birds and fish, and the like. In one embodiment of the methods and compositions provided herein, the mammal is a human.

The term "treating" as used herein refers to the treatment of a disease or condition associated with a mammal, particularly a human, including

(i) preventing a mammal, particularly a mammal that has previously been exposed to a disease or condition but has not been diagnosed with the disease or condition, producing a corresponding disease or condition;

(ii) inhibiting the disease or condition, ie controlling its development;

(iii) alleviating the disease or condition, even if the disease or condition subsides;

(iv) alleviating the symptoms caused by the disease or condition.

The terms "disease" and "condition" as used herein may be substituted for each other or may mean different meanings, since certain specific diseases or conditions have no known causative factors (so the cause of the disease is not known), so it cannot be considered as The disease can only be seen as an undesired condition or syndrome that has more or less specific symptoms that have been confirmed by clinical researchers.

The term "effective amount," "therapeutically effective amount," or "pharmaceutically effective amount," as used herein, refers to at least one agent or compound that, after administration, is sufficient to alleviate one or more symptoms of the disease or condition being treated to some extent. The amount. The result can be a reduction and/or alleviation of signs, symptoms or causes, or any other desired change in the biological system. For example, an "effective amount" for treatment is an amount of a composition comprising a compound disclosed herein that is required to provide a significant conditional relief effect in the clinic. An effective amount suitable for any individual case can be determined using techniques such as dose escalation testing.

The terms "administering," "administering," "administering," and the like, as used herein, refers to a method of delivering a compound or composition to a desired site for biological action. These methods include, but are not limited to, oral routes, duodenal routes, parenteral injections (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical administration, and rectal administration. In a preferred embodiment, the compounds and compositions discussed herein are administered orally.

In general, a compound of the invention, or a pharmaceutically acceptable salt thereof, can be administered by forming a suitable pharmaceutical composition with one or more pharmaceutically acceptable carriers. The pharmaceutical compositions of the present invention can be formulated into solid, semi-solid, liquid or gaseous forms such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants, gels, microspheres and aerosols. .

The pharmaceutical composition of the present invention can be produced by using a method well known in pharmacy. For example, a pharmaceutical composition for administration by injection can be prepared by combining a compound of the present invention with sterile, distilled water to form a solution. Surfactants can be added to help form a homogeneous solution or suspension. The actual methods of preparing these dosage forms are known or apparent to those skilled in the art.

Typical routes for administering these pharmaceutical compositions include, but are not limited to, oral, topical, transdermal, inhalation, parenteral, sublingual, rectal, vaginal and intranasal. For example, suitable dosage forms for oral administration include capsules, tablets, granules, and syrups. The compound of the present invention encompassed by these dosage forms may be a solid powder or granule; a solution or suspension in an aqueous or non-aqueous solvent; an oil-drop type in water, a drip-type emulsion in oil, and the like. The dosage forms mentioned above may be prepared from the active compound and one or more carriers or adjuvants by conventional methods of administration. The carrier should be compatible with the active compound or other adjuvant. For solid preparations, non-toxic carriers commonly used include, but are not limited to, mannitol, lactose, starch, magnesium stearate, cellulose, glucose, sucrose, and the like. Liquid formulation carriers include, but are not limited to, water, physiological saline, dextrose, ethylene glycol, aqueous polyethylene glycol solutions, and the like. The active compound may form a solution or a suspension with the above carrier. The particular route of administration and dosage form will depend on the physical/chemical characteristics of the compound itself and the severity of the condition being treated, and can be conventionally determined by those skilled in the art.

Detailed ways

Preparation of the compounds of the invention

The following schemes show the preparation of the compounds of the invention.

It should be understood that in the following description, the substituent groups and/or the variables of the formula are allowed to be combined only in the case of forming a stable compound.

It will also be appreciated by those skilled in the art that in the schemes described below, the functional groups of the intermediate compounds may need to be protected by suitable protecting groups. These functional groups include a hydroxyl group, an amino group, a thiol group, and a carboxyl group. Suitable hydroxy protecting groups include trialkylsilyl or diarylalkylsilyl (eg, tert-butylmethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl, Benzyl and the like. Suitable amino, sulfhydryl and hydrazine protecting groups include t-butoxycarbonyl, benzyloxycarbonyl and the like. Suitable protecting groups for the indenyl group include -C(O)-R" (R" represents an alkyl, aryl or arylalkyl group), p-methoxybenzyl, trityl and the like. Suitable carboxy protecting groups include alkyl, aryl or arylalkyl esters. The protecting group can be added or removed by standard techniques known to those skilled in the art.

Example

The following non-limiting examples are merely illustrative and are not intended to limit the invention in any way.

Unless otherwise stated, the temperature is Celsius. The reagents were purchased from commercial suppliers such as Sinopharm Chemical Reagent Beijing Co., Ltd., Alfa Aesar, or Beijing Belling Technology Co., Ltd., and these reagents can be used directly without further purification unless otherwise stated.

Unless otherwise stated, the following reactions were carried out at room temperature, in an anhydrous solvent, under a positive pressure of nitrogen or argon or using a drying tube; a reaction vessel was fitted with a rubber septum to add substrate and reagents via a syringe; glassware was dried and / or heat dry.

Unless otherwise stated, the column chromatography was performed using 200-300 mesh silica gel from Qingdao Ocean Chemical Plant; the thin layer chromatography was performed using a thin layer chromatography silica gel prefabricated plate (HSGF254) produced by Yantai Chemical Industry Research Institute; the measurement of MS was performed by Thermo LCQ Fleet. Type (ESI) liquid chromatography-mass spectrometer; optical rotation measurement using SGW-3 automatic polarimeter, Shanghai Shenguang Instrument Co., Ltd.

Nuclear magnetic data ( ¹ H NMR) was run at 400 MHz using a Varian device. The solvent used for the nuclear magnetic data is CDCl ₃ , CD ₃ OD, D ₂ O, DMSO-d6, etc., based on tetramethylsilane (0.00 ppm) or based on residual solvent (CDCl ₃ : 7.26 ppm; CD ₃ OD: 3.31 ppm; D ₂ O: 4.79 ppm; d6-DMSO: 2.50 ppm). When the peak shape diversity is indicated, the following abbreviations indicate different peak shapes: s (single peak), d (double peak), t (triplet), q (quadruple), m (multiple peak), br (wide peak) ), dd (double doublet), dt (double triplet). If a coupling constant is given, it is in Hertz (Hz).

Abbreviations:

TBSCl	Tert-butyldimethylchlorosilane
NaBH 4	Sodium borohydride
TBAF	Tetrabutylammonium fluoride
PPh 3	Triphenylphosphine
Pd(dppf)Cl 2	1,1'-bisdiphenylphosphinoferrocene palladium dichloride
TMSCN	Trimethylcyanosilane
TEA	Triethylamine
CBr 4	Carbon tetrabromide
DMF	N,N-dimethylformamide
DMSO	Dimethyl sulfoxide

DIBAL-H	Diisobutylaluminum hydride
NaOAc	Sodium acetate
Et 2 O	Ether
Toluene	Toluene
LDA	Lithium diisopropylamide
TFAA	Trifluoroacetic anhydride
H 2 SO4	sulfuric acid
K 2 CO 3	Potassium carbonate
N-Acetylglycine	N-acetylglycine
CH 3 I	Methyl iodide
NaOEt	Sodium ethoxide
Rt	Room temperature
DIAD	Diisopropyl azodicarboxylate
TEA	Triethylamine
MsCl	Methanesulfonyl chloride
LAH	Lithium tetrahydroaluminum
Pd(PPh 3 ) 4	Tetratriphenylphosphine palladium
Cs 2 CO 3	Barium carbonate
Dioxane	1,4-dioxane
KOH	Potassium hydroxide
NaH	Sodium hydride

Intermediate 1: 2-hydroxy-3-methyl-3-(2-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)methoxy)phenyl Synthesis of methyl butyrate

Step 1: 2-((tert-Butyldimethylsilyl)oxy)benzaldehyde

Imidazole (36.7 g) was added to a solution of salicylaldehyde (24.4 g) and tert-butyldimethylsilyl chloride (36.2 g) in DMF (300 mL) at room temperature, stirred at room temperature for 2 hours, and poured into 500 mL of water. The organic phase was washed with brine, dried over anhydrous sodium sulfate and evaporated to dryness.

Step 2: 2-((tert-Butyldimethylsilyl)oxy)benzyl alcohol

The crude 2-((tert-butyldimethylsilyl)oxy)benzaldehyde obtained in the previous step was dissolved in 300 mL of methanol, and sodium borohydride (7.6 g) was slowly added at 0 ° C, and the temperature was raised to room temperature after the addition. And the mixture was stirred at room temperature for 30 minutes, and the reaction mixture was poured into aq. 47.6 g, used without purification, was used directly in the next reaction.

Step 3: 2-((tert-Butyldimethylsilyl)oxy)benzyl bromide

The crude 2-((tert-butyldimethylsilyl)oxy)benzyl alcohol obtained in the previous step was dissolved in 500 mL of dichloromethane, and triphenylphosphine (62.8 g) and carbon tetrabromide were sequentially added thereto at room temperature. The title compound (59.0 g) was purified by silica gel column chromatography eluting ).

Step 4: 2-((tert-Butyldimethylsilyl)oxy)phenylacetonitrile

2-((tert-Butyldimethylsilyl)oxy)benzyl bromide was dissolved in 500 mL of acetonitrile at room temperature, and trimethylcyanosilane (29.1 g) and potassium carbonate (54.2 g) were added and heated to 60 ° C. After stirring overnight, the reaction mixture was poured into water, ethyl acetate was evaporated, EtOAcjjjjjjjjjjjjj The title compound (30.2 g) was obtained after purification.

Step 5: 2-(2-((tert-Butyldimethylsilyl)oxy)phenyl)-2-methylpropanenitrile

A solution of lithium diisopropylamide in tetrahydrofuran (1 M, 300 mL) was added dropwise to 2-((tert-butyldimethylsilyl)oxy)phenylacetonitrile (25 g) in tetrahydrofuran (300 mL). The solution was stirred for 30 minutes, and kept at -78 ° C, and methyl iodide (42.6 g) was added dropwise to the solution, stirred for 30 minutes, and then allowed to warm to room temperature. The reaction mixture was poured into aq. aq. The title compound (25.4 g) was obtained after purification.

Step 6: 2-(2-((tert-Butyldimethylsilyl)oxy)phenyl)-2-methylpropanal

A solution of diisobutylaluminum hydride in toluene (1 M, 300 mL) was added dropwise at -78 ° C to 2-(2-((tert-butyldimethylsilyl)oxy)phenyl)-2-methyl A solution of propionitrile (25.0 g) in tetrahydrofuran (300 mL) was stirred for 30 min then warmed to room temperature. The mixture was poured into saturated aqueous ammonium chloride (500 mL). The title compound (22.1 g) was obtained.

Step 7: 3-(2-((tert-Butyldimethylsilyl)oxy)phenyl)-3-methyl-2-((trimethylsilyl)oxy)butyronitrile

Trimethylcyanosilane (15.9 g) and triethylamine (16.2 g) were separately added to 2-(2-((tert-butyldimethylsilyl)oxy)phenyl)-2-methyl at room temperature A solution of propylacetone (22 g) in acetonitrile (300 mL) was stirred at room temperature for 1 hour. The reaction mixture was poured into water and ethyl acetate was evaporated. The eluent: petroleum ether: ethyl acetate = 30:1 (V:V)

Step 8: 2-Hydroxy-3-(2-hydroxyphenyl)-3-methylbutyronitrile

Tetrabutylammonium fluoride (2.8 g) was added to 3-(2-((tert-butyldimethylsilyl)oxy)phenyl)-3-methyl-2-((trimethyl) at room temperature A solution of the group of silyl)oxy)butyronitrile (2 g) in dichloromethane (200 mL) was stirred at room temperature for 5 min. The title compound (0.63 g) was obtained.

Step 9: 2-Methyl-2-(2-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)methoxy)phenyl)propanal

Methyl (1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)methanesulfonate (1.35 g) and potassium carbonate (0.97 g) were added to 2- at room temperature A solution of hydroxy-3-(2-hydroxyphenyl)-3-methylbutyronitrile (0.63 g) in DMF (20 mL) After cooling to room temperature, the reaction mixture was poured into water, and ethyl acetate was evaporated. EtOAcjjjjjjjjjjjjj (V: V)) The title compound (0.30 g) was obtained.

Step 10: 3-Methyl-3-(2-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)methoxy)phenyl)-2-( (trimethylsilyl)oxy)butyronitrile

The title compound (0.30 g) was obtained according

Step 11: 2-Hydroxy-3-methyl-3-(2-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)methoxy)phenyl) Butyric acid

3-methyl-3-(2-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)methoxy)phenyl)-2-() at room temperature (Trimethylsilyl)oxy)butyronitrile (0.30g) was dissolved in 30mL concentrated hydrochloric acid, heated to 110 ° C, stirred for 6 hours, cooled to room temperature, the reaction solution was poured into water, ethyl acetate extraction, organic The extract was washed with brine, dried over anhydrous sodium sulfate

Step 12: 2-Hydroxy-3-methyl-3-(2-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)methoxy)phenyl) Methyl butyrate

Add 3 mL of concentrated sulfuric acid to 2-hydroxy-3-methyl-3-(2-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)) at room temperature A solution of oxy)phenyl)butyric acid (0.30 g) in methanol (50 mL) was heated to 60 ° C and stirred for 2 hours. After cooling, the reaction mixture was poured into water, ethyl acetate was evaporated, and the organic phase was washed with brine. The title compound (0.23 g) was obtained.

¹ H NMR (400 MHz, CDCl 3 ) δ 7.61 (d, J = 1.6 Hz, 1H), 7.23 - 7.28 (m, 2H), 6.87 - 7.01 (m, 2H), 6.46 (d, J = 2.0 Hz, 1H) ), 5.16 (s, 2H), 4.82-4.88 (m, 3H), 3.50 (s, 3H), 2.78 (d, J = 7.6 Hz, 1H), 1.41 (s, 3H), 1.35 (s, 3H) .

Intermediate 2: Synthesis of ethyl 2-hydroxy-2-(1-(2-methoxyphenyl)cyclopropyl)acetate

Step 1: (Z)-4-(2-Methoxybenzylidene)-2-methyloxazole-5(4H)-one

N-acetylglycine (19.6 g) and sodium acetate (22.9 g) were separately added to a solution of 2-methoxybenzaldehyde (13.6 g) in acetic anhydride (300 mL), heated to 130 ° C for 2 hours, cooled to room temperature. After that, it was poured into ice water, filtered and washed with water.

Step 2: 2-methoxyphenylpyruvate

Add the crude (Z)-4-(2-methoxybenzylidene)-2-methyloxazole-5(4H)-one of the previous step to 400 mL of hydrochloric acid (4M) and heat to 110 °C. The mixture was stirred for 2 hours. After cooling to room temperature, the reaction mixture was poured into EtOAc EtOAc. , used directly in the next reaction.

Step 3: 2-(1-(2-Methoxyphenyl)cyclopropyl)-2-oxoacetic acid

Potassium hydroxide (3.4g) and 1,2-dibromoethane (5.8g) were separately added to a mixed solution of p- 2-methoxyphenylpyruvate (3g) in 100mL tetrahydrofuran: water = 1:1, room temperature After stirring for 5 hours, the reaction mixture was poured into water, EtOAc was evaporated,jjjjjjjjjjjjjjjjj One step reaction.

Step 4: 2-(1-(2-Methoxyphenyl)cyclopropyl)-2-oxoethylacetate

10 mL of concentrated sulfuric acid was added to a solution of 2-(1-(2-methoxyphenyl)cyclopropyl)-2-oxoacetic acid (1.0 g) in ethanol (50 mL), heated to 60 ° C, and stirred for 2 hours. After cooling, the reaction mixture was poured into water, ethyl acetate was evaporated, and the organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated to silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 10:1 (V) :V)) The title compound (0.80 g) was obtained.

Step 5: Ethyl 2-hydroxy-2-(1-(2-methoxyphenyl)cyclopropyl)acetate

2-(1-(2-Methoxyphenyl)cyclopropyl)-2-oxoacetate (0.80 g) was dissolved in 50 mL of methanol, cooled to 0 ° C, and sodium borohydride (0.12 g) was slowly added. The mixture was stirred at room temperature for 30 minutes, and the reaction mixture was poured into EtOAc EtOAc. Deliquoring: petroleum ether: ethyl acetate = 5:1 (V:V))

Synthesis of intermediate 3: ethyl 2-hydroxy-2-(1-(2-methoxyphenyl)cyclobutyl)acetate

Step 1: 2-(1-(2-Methoxyphenyl)cyclobutyl)-2-oxoacetic acid

The title compound was obtained according to the procedure of Intermediate 3 Step 3.

Step 2: 2-(1-(2-Methoxyphenyl)cyclobutyl)-2-oxoethylacetate

The title compound was obtained according to the procedure of Intermediate 4 Step 4.

Step 3: Ethyl 2-hydroxy-2-(1-(2-methoxyphenyl)cyclobutyl)acetate

The title compound was obtained according to the procedure of Intermediate 2 Step 5.

Intermediate 4: 2-hydroxy-3-(2-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)methoxy)phenyl)but-3- Synthesis of ethyl enoate:

Intermediate 5: 2-hydroxy-2-(1-(2-(2-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)methoxy)phenyl)) Synthesis of propyl)ethyl acetate:

Step 1: (1-(2,2,2-Trifluoroethyl)-1H-pyrazol-3-yl)methyl methanesulfonate

To (1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)methanol (10.0 g) and triethylamine (11.2 g) in dichloromethane (150 mL) Methanesulfonyl chloride (9.58 g) was slowly added dropwise to the solution, and after completion of the dropwise addition, it was allowed to warm to room temperature and stirring was continued for 2 h. The reaction mixture was poured into EtOAc (EtOAc m.

Step 2: 1-(2-((1-(2,2,2-Trifluoroethyl)-1H-pyrazol-5-yl)methoxy)phenyl)ethan-1-one

To o-hydroxyacetophenone (7.07 g) and (1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)methyl methanesulfonate (10.3 g) at room temperature Potassium carbonate powder (14.4 g) was added to the DMF (100 mL) solution, and after the addition, the mixture was stirred at 65 ° C for 12 h. The reaction mixture was poured into water and extracted with ethyl acetate. EtOAc was evaporated. 3:1 (V:V)).

Step 3: 3-Methyl-3-(2-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)methoxy)phenyl)oxirane Ethyl 2-carboxylate

Add sodium metal (2g) to anhydrous ethanol (40mL) in batches at 0 °C, add to the room temperature and stir until completely dissolved, then cool to -20 °C with ice salt bath, 1-(2) -((1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)methoxy)phenyl)ethan-1-one (13.0 g) and ethyl chloroacetate (10.8 The toluene (10 mL) solution of g) was slowly added dropwise to the above sodium ethoxide solution, and after the addition, the temperature was raised to room temperature and stirred for 15 hours, and the reaction liquid was poured into a mixed solvent of AcOH:H ₂ O (1:100) (450 mL). The mixture was extracted with EtOAc (EtOAc m.) The title compound (15.8 g) was purified.

Step 4: 2-Hydroxy-3-(2-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)methoxy)phenyl)but-3-ene Ethyl acetate

To a 3-methyl-3-(2-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)methoxy)phenyl) ring at 0 °C Concentrated sulfuric acid (3.90 g) was slowly added dropwise to a solution of ethyl oxy-2-carboxylate (13.8 g) in diethyl ether (150 mL). The reaction solution was poured into water, and the sodium hydrogencarbonate powder was adjusted to pH. The mixture was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. Deliquoring: petroleum ether: ethyl acetate = 5:1 (V:V))

^{1 H NMR (400MHz, CDCl3)} δ7.54 (d, J = 2.0Hz, 1H), 7.30 (td, J = 8.0Hz, 1.6Hz, 1H), 7.14 (dd, J = 7.2Hz, 1.6Hz, 1H ), 7.01 (t, J = 8.4 Hz, 1H), 6.95 (d, J = 8.4 Hz, 1H), 6.37 (d, J = 2.0 Hz, 1H), 5.60 (s, 1H), 5.27 (s, 1H) ), 5.14 (d, J = 12.4 Hz, 1H), 5.10 (d, J = 12.4 Hz, 1H), 4.99 (d, J = 7.2 Hz, 1H), 4.82-4.87 (m, 2H), 3.96-4.06 (m, 2H), 3.14 (d, J = 7.2 Hz, 1H), 1.05 (t, J = 7.2 Hz, 3H).

Step 5: 2-Hydroxy-2-(1-(2-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)methoxy)phenyl)cyclopropane Ethyl acetate

To 2-hydroxy-3-(2-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)methoxy)phenyl) butyl at -20 °C A solution of ethyl 3-enoate (1.5 g) in anhydrous dichloromethane (30 mL) was slowly added dropwise diethylzinc (1.0M solution in n-hexane, 23.5 mL), then di-dichloromethane (1.96 mL). After the addition, the mixture was slowly warmed to room temperature and stirred for 30 hours. The reaction mixture was poured into a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate The title compound (130 mg) was obtained.

¹ H NMR (400 MHz, CDCl 3 ) δ 7.59 (d, J = 2.0 Hz, 1H), 7.23 - 7.29 (m, 2H), 6.94-6.98 (m, 2H), 6.44 (d, J = 1.6 Hz, 1H) ), 5.16 (s, 2H), 4.90-5.09 (m, 2H), 4.03-4.11 (m, 1H), 3.90-3.98 (m, 2H), 2.98 (d, J = 7.6 Hz, 1H), 1.19- 1.26 (m, 1H), 1.12 (t, J = 7.6 Hz, 3H), 0.99-1.03 (m, 1H), 0.80-0.85 (m, 2H).

Intermediate 6: 2-hydroxy-2-(1-(2-methoxyphenyl)cyclopropyl)acetate

Step 1: Ethyl 3-(2-methoxyphenyl)-3-methyloxirane-2-carboxylate

The title compound was obtained according to the procedure of Intermediate 3 Step 3.

Step 2: Ethyl 2-hydroxy-3-(2-methoxyphenyl)but-3-enoate

The title compound was obtained according to the procedure of Intermediate 4 Step 4.

^{1 H NMR (400MHz, CDCl3)} δ7.28 (td, J = 7.2Hz, 1.6Hz, 1H), 7.13 (d, J = 7.2Hz, 1.6Hz, 1H), 6.93 (t, J = 7.2Hz, 1H ), 6.87 (d, J = 8.4 Hz, 1H), 5.60 (s, 1H), 5.33 (s, 1H), 5.08 (d, J = 7.2, Hz, 1H), 4.07 - 4.13 (m, 2H), 3.82 (s, 3H), 3.39 (d, J = 7.2 Hz, 1H), 1.09 (t, J = 7.2 Hz, 3H).

Intermediate 7: Synthesis of ethyl 2-hydroxy-3-(2-methoxyphenyl)-3-methylbutanoate:

Step 1: 3-(2-Methoxyphenyl)-3-methyl-2-oxobutanoic acid

3-(2-methoxyphenyl)-2-oxopropionic acid (1.95 g) was dissolved in a mixed solution of tetrahydrofuran (50 mL) and 5N aqueous sodium hydroxide (10 mL) at 0 ° C, and slowly added Methyl iodide (4.23 g). The reaction solution was heated to 50 ° C and stirred for 12 hours. After cooling to room temperature, the reaction liquid was poured into ice water (100 mL), and the reaction mixture was neutralized with dilute hydrochloric acid to make it weakly acidic (pH=5). The mixture was extracted with methylene chloride. EtOAc (EtOAc)

Step 2: Ethyl 3-(2-methoxyphenyl)-3-methyl-2-oxobutanoate

Concentrated sulfuric acid (0.50 g) was slowly added dropwise to a solution of 3-(2-methoxyphenyl)-3-methyl-2-oxobutanoic acid (0.50 g) in ethanol (15 mL). After the completion of the dropwise addition, the temperature was raised to 80 ° C and stirring was continued for 1 hour. After cooling to room temperature, the reaction solution was poured into ice water, and the sodium hydrogencarbonate powder was adjusted to pH. The mixture was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. Column chromatography (eluent: petroleum ether: ethyl acetate = 10:1 (V:V))

Step 3: Synthesis of ethyl 2-hydroxy-3-(2-methoxyphenyl)-3-methylbutanoate

To a solution of ethyl 3-(2-methoxyphenyl)-3-methyl-2-oxobutanoate (0.30 g) in dry methanol (10 mL) After the addition, the mixture was slowly warmed to room temperature and stirred for 1 hour. The reaction mixture was poured into cold water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate, filtered, The title compound (130 mg) was obtained.

^{1 H NMR (400MHz, CDCl3)} δ7.18-7.24 (m, 2H), 6.88-6.91 (m, 2H), 4.99 (d, J = 8.0Hz, 1H), 3.88-3.89 (m, 2H), 3.87 (s, 3H), 3.01 (d, J = 8.0 Hz, 1H), 1.48 (s, 3H), 1.37 (s, 3H), 0.93 (t, J = 7.2 Hz, 3H).

Intermediate 8: Synthesis of ethyl 2-hydroxy-3-(2-methoxyphenyl)butanoate

Step 1: 3-(2-Methoxyphenyl)-2-oxobutanoic acid

3-(2-methoxyphenyl)-2-oxopropionic acid (1.95 g) was dissolved in a mixed solution of tetrahydrofuran (50 mL) and 5N aqueous sodium hydroxide (10 mL) at 0 ° C, and slowly added Methyl iodide (2.0 g). The reaction solution was stirred at 50 ° C for 12 hours. After cooling to room temperature, the reaction liquid was poured into ice water (100 mL), and the reaction mixture was neutralized with dilute hydrochloric acid to make it weakly acidic (pH=5). The mixture was extracted with methylene chloride. EtOAc (EtOAc)

Step 2, Step 3: According to the synthesis method of Intermediate 7, the title compound is obtained.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.22 (dd, J = 7.6 Hz, 1H), 7.44 (td, J = 7.6 Hz, 1.6 Hz, 1H), 6.90 (d, J = 8.0 Hz, 1H) ), 6.84 (t, J = 7.6 Hz, 1H), 5.30 (d, J = 6.0 Hz, 1H), 4.23 (t, J = 6.8 Hz, 1H), 3.98 (dd, J = 7.2 Hz, 2H), 3.74 (s, 3H), 3.44 - 3.50 (m, 1H), 1.12 (d, J = 7.2 Hz, 3H), 1.07 (t, J = 7.2 Hz, 3H).

Synthesis of intermediate 9: ethyl 3,3-difluoro-2-hydroxy-3-(2-methoxyphenyl)propanoate

Step 1: 2,2-Difluoro-2-(2-methoxyphenyl)acetate

2-Iodoanisole (4.68 g), copper powder (6.4 g), ethyl 2-bromo-2,2-difluoroacetate (8.12 g) and DMSO (100 mL) were sequentially added to a 250 mL reaction flask. The reaction solution was heated to 80 ° C and stirred for 3 hours. After cooling to room temperature, 200 mL of water was added, and the mixture was filtered over Celite. The organic layer was dried over anhydrous sodium

Step 2: 2,2-Difluoro-2-(2-methoxyphenyl)acetamide

To a solution of 2,2-difluoro-2-(2-methoxyphenyl)acetate (3.0 g) in methanol (50 mL) was added concentrated aqueous ammonia (20 mL) at 0° C. Stir at 0 ° C for 5 hours. The reaction mixture was concentrated under reduced pressure and the organic solvent was evaporated, evaporated, evaporated, evaporated, evaporated, evaporated. Deliquoring: petroleum ether: ethyl acetate = 1:1 (V:V).

Step 3: 2,2-Difluoro-2-(2-methoxyphenyl)acetonitrile

2,2-Difluoro-2-(2-methoxyphenyl)acetamide (2.0 g) was dissolved in tetrahydrofuran (50 mL) and triethylamine (3 mL) and trifluoroacetic acid anhydride were added at 0 °C 2mL). The reaction solution was stirred at 0 ° C for 1 hour, and then poured into ice water (100 mL). The mixture was extracted with methylene chloride. EtOAc (EtOAc)

Step 4: 2,2-Difluoro-2-(2-methoxyphenyl)acetaldehyde

Lithium aluminum hydride (0.4 g) was slowly added to a solution of 2,2-difluoro-2-(2-methoxyphenyl)acetonitrile (1.5 g) in tetrahydrofuran (50 mL) at 0 ° C. Stirring was continued for 1 hour at 0 °C. Then, the reaction was quenched by the dropwise addition of 10 mL of 1M hydrochloric acid, and the mixture was poured into cold water and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. Deliquoring: petroleum ether: ethyl acetate = 2:1 (V:V))

Step 5: 3,3-Difluoro-2-hydroxy-3-(2-methoxyphenyl)propanenitrile

To a solution of 2,2-difluoro-2-(2-methoxyphenyl)acetaldehyde (0.50 g) in acetonitrile (10 mL) was slowly added triethylamine (1 mL) and trimethylcyanosilane at 20 °C (0.5 mL). After the addition, the mixture was stirred at room temperature for 1 hour, and the reaction mixture was poured into EtOAc EtOAc. The title compound (0.40 g) was obtained.

Step 6: Ethyl 3,3-difluoro-2-hydroxy-3-(2-methoxyphenyl)propanoate

To a solution of 3,3-difluoro-2-hydroxy-3-(2-methoxyphenyl)propanenitrile (0.40 g) in ethanol (10 mL), slowly dry dry hydrogen chloride gas at 0 ° C, Stirring was maintained for 5 hours. The reaction solution was poured into 100 mL of cold water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated, and the residue was applied to silica gel column chromatography (eluent: petroleum ether: acetic acid Purification of the title compound (0.20 g)

_{^{1 H NMR (400MHz, CDCl 3}} ) δ7.39 (dd, J = 7.6Hz, 1.6Hz, 1H), 7.34 (t, J = 7.6Hz, 1H), 6.91 (t, J = 7.6Hz, 1H), 6.88 (d, J = 7.6 Hz, 1H), 4.94 - 5.03 (m, 1H), 3.79 - 4.16 (m, 2H), 3.81 (s, 3H), 3.29 (d, J = 7.2 Hz, 1H), 1.05 (t, J = 7.2 Hz, 3H).

Intermediate 10: 4-chloro-5-(3-chloro-2-methyl-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6-(5- Synthesis of fluorofuran-2-yl)thieno[2,3-d]pyrimidine

The target compound was synthesized by referring to the synthesis methods on pages 31 and 42 of the patent WO2016/207226.

^{1 H NMR (400MHz, DMSO-} d 6) δ8.93 (s, 1H), 7.25 (d, J = 8.8Hz, 1H), 7.17 (d, J = 8.4Hz, 1H), 5.92 (dd, J = 6.8 Hz, 3.6 Hz, 1H), 5.69 (t, J = 3.2 Hz, 1H), 4.24 - 4.26 (m, 2H), 2.80-3.30 (m, 10H), 2.73 (s, 3H), 2.04 (s, 3H).

Intermediate 11: 4-Chloro-5-(3-chloro-2-methyl-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6-(furan- Synthesis of 2-yl)thieno[2,3-d]pyrimidine

The target compound was synthesized by referring to the synthesis method on page 192 of Patent WO2015/97123.

Intermediate 12: 4-Chloro-5-(3-chloro-2-methyl-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6-(4- Synthesis of fluorophenyl)thieno[2,3-d]pyrimidine

4-Chloro-5-(3-chloro-2-methyl-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6-iodothiophene[2] , 3-d] pyrimidine (synthesized by the synthetic method on page 191 of patent WO2015/97123) (563 mg), 4-fluorophenylboronic acid (140 mg), tetrakistriphenylphosphine palladium (11 mg) and cesium carbonate (65 mg) The mixture was dissolved in dioxane (20 mL) and water (10 mL) in a glass sealed tube, and heated to 90 ° C under nitrogen atmosphere. After 3 hours, the reaction solution was cooled to room temperature and poured into ice water with dichloro The methane was extracted, and the extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated, and the residue was purified by thin layer chromatography (diluent: methylene chloride:methanol = 10:1 (V:V)) The title compound (100 mg).

Intermediate 13: (R)-2-hydroxy-3-methyl-3-(2-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)methoxy) Methyl)phenyl)butyrate and intermediate 14: (S)-2-hydroxy-3-methyl-3-(2-((1-(2,2,2-trifluoroethyl)-1H) Synthesis of methyl pyrazol-5-yl)methoxy)phenyl)butanoate:

Step 1: (R)-2-((R)-2-Methoxy-2-phenylacetoxy)-3-methyl-3-(2-((1-(2,2,2-) Methyl trifluoroethyl)-1H-pyrazol-5-yl) methoxy)phenyl)butanoate and (S)-2-((R)-2-methoxy-2-phenyl Acetoxy)-3-methyl-3-(2-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)yl)methoxy)phenyl) Methyl butyrate

(R)-(-)-α-methoxyphenylacetic acid (1.66 g) was dissolved in 50 mL of dichloromethane at 0 ° C, and 5 drops of DMF and oxalyl chloride (2.54 g) were sequentially added with stirring. The reaction was allowed to warm to room temperature and stirred for 1 hour. The reaction solution was concentrated under reduced pressure to give (R)-2-methoxy-2-phenylacetyl chloride. Intermediate 1 (1.93 g) was dissolved in 50 mL of dry pyridine and the acid chloride was slowly added at room temperature and stirring was continued for one hour. The organic layer was concentrated under reduced pressure. EtOAc (EtOAc)EtOAc. The organic phase was dried over anhydrous sodium sulfate (MgSO4), filtered, evaporated. -((R)-2-methoxy-2-phenylacetoxy)-3-methyl-3-(2-((1-(2,2,2-trifluoroethyl)-1H- Methyl pyrazol-5-yl) methoxy)phenyl)butanoate (0.90 g);

_{^{1 H NMR (400MHz, CDCl 3}} ) δ7.56 (d, J = 2.0Hz, 1H), 7.23-7.31 (m, 7H), 6.99 (t, J = 8.8Hz, 1H), 6.92 (d, J = 8.8 Hz, 1H), 6.41 (d, J = 1.6 Hz, 1H), 5.85 (s, 1H), 5.07 (d, J = 11.6 Hz, 1H), 4.99 (d, J = 11.6 Hz, 1H), 4.76 - 4.88 (m, 2H), 4.67 (s, 1H), 3.42 (s, 3H), 3.36 (s, 3H), 1.38 (s, 3H), 1.36 (s, 3H).

(S)-2-((R)-2-methoxy-2-phenylacetoxy)-3-methyl-3-(2-((1-(2,2,2-trifluoroethyl) Methyl-1)-pyrazol-5-yl)yl)methoxy)phenyl)butanoate (0.80 g).

_{^{1 H NMR (400MHz, CDCl 3}} ) δ7.57 (d, J = 2.0Hz, 1H), 7.13-7.27 (m, 7H), 6.91 (t, J = 8.8Hz, 1H), 6.81 (d, J = 8.8 Hz, 1H), 6.37 (d, J = 1.6 Hz, 1H), 5.80 (s, 1H), 4.98 (d, J = 12.4 Hz, 1H), 4.75 - 4.86 (m, 3H), 4.73 (s, 1H), 3.52 (s, 3H), 3.33 (s, 3H), 1.35 (s, 3H), 1.17 (s, 3H).

Step 2: (R)-2-Hydroxy-3-methyl-3-(2-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)methoxy) Phenyl)methyl butyrate and (S)-2-hydroxy-3-methyl-3-(2-((1-(2,2,2-trifluoroethyl)-1H-pyrazole-5) Methyl-methoxy)phenyl)butyrate

(R)-2-((R)-2-Methoxy-2-phenylacetoxy)-3-methyl-3-(2-((1-) obtained in step 1 at 0 °C Methyl (2,2,2-trifluoroethyl)-1H-pyrazol-5-yl) methoxy)phenyl)butanoate (0.90 g) was dissolved in 30 mL of methanol, and sodium methoxide powder was slowly added. (100 mg) and stirring was continued for 1 h. The reaction solution was poured into a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. EtOAc was evaporated. Ether: ethyl acetate = 5:1 (V: V)) purified (R)-2-hydroxy-3-methyl-3-(2-((1-(2,2,2-trifluoroethyl) Methyl-1H-pyrazol-5-yl)methoxy)phenyl)butanoate (0.50 g).

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.61 (d, J = 1.6 Hz, 1H), 7.23 - 7.28 (m, 2H), 6.87 - 7.01 (m, 2H), 6.46 (d, J = 2.0 Hz, 1H), 5.16 (s, 2H), 4.82-4.88 (m, 3H), 3.50 (s, 3H), 2.78 (d, J = 7.6 Hz, 1H), 1.41 (s, 3H), 1.35 (s, 3H) ).

Hydrolysis of (S)-2-((R)-2-methoxy-2-phenylacetoxy)-3-methyl-3-(2-((1-(2)) with sodium methoxide according to the above procedure Methyl (2,2-trifluoroethyl)-1H-pyrazol-5-yl) methoxy)phenyl)butanoate (0.80 g) gave (S)-2-hydroxy-3-methyl Methyl 3-(2-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)methoxy)phenyl)butanoate (0.40 g).

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.61 (d, J = 1.6 Hz, 1H), 7.23 - 7.28 (m, 2H), 6.87 - 7.01 (m, 2H), 6.46 (d, J = 2.0 Hz, 1H), 5.16 (s, 2H), 4.82-4.88 (m, 3H), 3.50 (s, 3H), 2.78 (d, J = 7.6 Hz, 1H), 1.41 (s, 3H), 1.35 (s, 3H) ).

Intermediate 15: (R)-2-hydroxy-2-(1-(2-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)methoxy)) Phenyl)cyclopropyl)acetate and intermediate 16: (S)-2-hydroxy-2-(1-(2-(2-(2,2,2-trifluoroethyl)-1H-) Synthesis of pyrazol-5-yl)methoxy)phenyl)cyclopropyl)acetate:

Step 1: (R)-2-Methoxy-2-phenylacetic acid ((R)-2-ethoxy-2-oxo-1-(1-(2-((1-(2,2, 2-Trifluoroethyl)-1H-pyrazol-5-yl)methoxy)phenyl)cyclopropyl))ethyl ester and (S)-2-methoxy-2-phenylacetic acid ((R) -2-ethoxy-2-oxo-1-(1-(2-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)methoxy)) Phenyl)cyclopropyl))ethyl ester

Referring to the first step of the synthesis of intermediate 13 and intermediate 14, substituting intermediate 5 for intermediate 1 gives (R)-2-methoxy-2-phenylacetic acid ((R)-2-ethoxy-2- Oxo-1-(1-(2-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)methoxy)phenyl)cyclopropyl)) Ester (0.40 g);

_{^{1 H NMR (400MHz, CDCl 3}} ) δ7.55 (d, J = 2.0Hz, 1H), 7.24-7.36 (m, 7H), 6.90-6.96 (m, 2H), 6.40 (d, J = 2.0Hz, 1H), 5.12 (s, 2H), 5.02 (s, 1H), 4.88 (q, J = 8.4 Hz, 2H), 4.71 (s, 1H), 3.79-3.92 (m, 2H), 3.38 (s, 3H) ), 1.10 - 1.13 (m, 1H), 0.99 - 1.03 (m, 1H), 0.93 (t, J = 7.2 Hz, 3H), 0.80 - 0.83 (m, 2H).

(S)-2-methoxy-2-phenylacetic acid ((R)-2-ethoxy-2-oxo-1-(1-(2-((1-(2,2,2-3) Fluoroethyl)-1H-pyrazol-5-yl)methoxy)phenyl)cyclopropyl))ethyl ester (0.30 g).

_{^{1 H NMR (400MHz, CDCl 3}} ) δ7.55 (d, J = 1.6Hz, 1H), 7.32-7.36 (m, 5H), 7.20-7.25 (m, 1H), 7.04 (dd, J = 7.6Hz, 1.6 Hz, 1H), 6.83-6.88 (m, 2H), 6.37 (d, J = 2.0 Hz, 1H), 5.11 (d, J = 12.8 Hz, 1H), 5.06 (d, J = 12.8 Hz, 1H) , 5.07(s,1H), 4.80-4.87(m,2H), 4.78(s,1H),3.86-4.23(m,2H),3.36(s,3H),1.04(t,J=7.2Hz,3H ), 0.92-0.94 (m, 2H), 0.72-0.76 (m, 1H), 0.65-0.68 (m, 1H).

Step 2: (R)-2-Hydroxy-2-(1-(2-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)methoxy)benzene Ethyl propyl)acetate and (S)-2-hydroxy-2-(1-(2-((1-(2,2,2-trifluoroethyl)-1H-pyrazole-5-) Methoxy)phenyl)cyclopropyl)acetate

The second step of the synthesis of intermediate 13 and intermediate 14 is carried out by hydrolysis of (R)-2-methoxy-2-phenylacetic acid ((R)-2-ethoxy-2-oxo-1-) with sodium ethoxide, respectively. (1-(2-((1-(2,2,2-Trifluoroethyl)-1H-pyrazol-5-yl)methoxy)phenyl)cyclopropyl))ethyl ester (0.40 g) And (S)-2-methoxy-2-phenylacetic acid ((R)-2-ethoxy-2-oxo-1-(1-(2-((1-(2,2,2-) Trifluoroethyl)-1H-pyrazol-5-yl)methoxy)phenyl)cyclopropyl))ethyl ester (0.30 g) gave (R)-2-hydroxy-2-(1-(2- ((1-(2,2,2-Trifluoroethyl)-1H-pyrazol-5-yl)methoxy)phenyl)cyclopropyl)acetate (0.30 g);

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.59 (d, J = 2.0 Hz, 1H), 7.23 - 7.29 (m, 2H), 6.94 - 6.98 (m, 2H), 6.44 (d, J = 1.6 Hz, (1), 5. - 1.26 (m, 1H), 1.12 (t, J = 7.6 Hz, 3H), 0.99 - 1.03 (m, 1H), 0.80 - 0.85 (m, 2H).

(S)-2-hydroxy-2-(1-(2-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)methoxy)phenyl)) Propyl)ethyl acetate (0.20 g);

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.59 (d, J = 2.0 Hz, 1H), 7.23 - 7.29 (m, 2H), 6.94 - 6.98 (m, 2H), 6.44 (d, J = 1.6 Hz, (1), 5. - 1.26 (m, 1H), 1.12 (t, J = 7.6 Hz, 3H), 0.99 - 1.03 (m, 1H), 0.80 - 0.85 (m, 2H).

Intermediate 17: (R)-2-hydroxy-2-(1-(2-((2-(2-methoxyphenyl)pyrimidin-4-yl)methoxy)phenyl)cyclopropyl) Synthesis of ethyl acetate:

Step 1: (2-(2-Methoxyphenyl)pyrimidin-4-yl)methylmethanesulfonate

The title compound was prepared according to the procedure of Intermediate 5 Step 1.

Step 2: 1-(2-((2-(2-methoxyphenyl)pyrimidin-4-yl)methoxy)phenyl)ethan-1-one

The title compound was obtained according to the procedure of Intermediate 5 Step 2.

Step 3: Ethyl 3-(2-((2-(2-methoxyphenyl)pyrimidin-4-yl)methoxy)phenyl)-3-methyloxirane-2-carboxylate

The title compound was obtained according to the procedure of Intermediate 3 Step 3.

Step 4: Ethyl 2-hydroxy-3-(2-((2-(2-methoxyphenyl)pyrimidin-4-yl)methoxy)phenyl)but-3-enoate

The title compound was obtained according to the procedure of Intermediate 4 Step 4.

Step 5: Ethyl 2-(2-(2-(2-(2-methoxyphenyl)pyrimidin-4-yl)methoxy)phenyl)cyclopropyl)acetate

The title compound was obtained according to the procedure of Intermediate 5 Step 5.

Step 6: (R)-2-Methoxy-2-phenylacetic acid ((R)-2-ethoxy-1-(1-(2-(2-(2-methoxyphenyl))pyrimidine) 4-yl)methoxy)phenyl)cyclopropyl)-2-oxo)ethyl ester

The title compound was obtained according to the procedure of Intermediate 13 Step 1.

Step 7: (R)-2-Hydroxy-2-(1-(2-((2-(2-methoxyphenyl)pyrimidin-4-yl)methoxy)phenyl)cyclopropyl)acetic acid Ethyl ester

The title compound was obtained according to the procedure of Intermediate 13 Step 2.

Intermediate 18: (R)-2-hydroxy-3-(2-((2-(2-methoxyphenyl)pyrimidin-4-yl)methoxy)phenyl)-3-methylbutanoic acid Synthesis of methyl ester:

Step 1: 2-(2-((2-(2-methoxyphenyl)pyrimidin-4-yl)methoxy)phenyl)-2-methylpropanal

The title compound was obtained according to the procedure of Intermediate 1 Step 9.

Step 2: 2-Hydroxy-3-(2-((2-(2-methoxyphenyl)pyrimidin-4-yl)methoxy)phenyl)-3-methylbutyronitrile

The title compound was obtained according to the procedure of Intermediate 1 Step 10.

Step 3: (2-((2-(2-methoxyphenyl)pyrimidin-4-yl)methoxy)phenyl)-3-methylbutanoic acid

The title compound was obtained according to the procedure of Intermediate 1 Step 11.

Step 4: Methyl 2-hydroxy-3-(2-((2-(2-methoxyphenyl)pyrimidin-4-yl)methoxy)phenyl)-3-methylbutanoate

The title compound was obtained according to the procedure of Intermediate 12 Step 12.

Step 5: (R)-2-((R)-2-Methoxy-2-phenylacetoxy)-3-(2-((2-(2-methoxyphenyl)pyrimidine-4) Methyl-methoxy)phenyl)-3-methylbutanoate

The title compound was obtained according to the procedure of Intermediate 13 Step 1.

Step 6: (R)-2-Hydroxy-3-(2-((2-(2-methoxyphenyl)pyrimidin-4-yl)methoxy)phenyl)-3-methylbutanoic acid ester

The title compound was obtained according to the procedure of Intermediate 13 Step 2.

Intermediate 19: Synthesis of ethyl 2-amino-2-(1-(2-methoxyphenyl)cyclopropyl)acetate

Step 1: 2-azido-2-(1-(2-methoxyphenyl)cyclopropyl)acetate

Methanesulfonyl chloride (172 mg) was slowly added dropwise to a solution of Intermediate 2 (250 mg) and triethylamine (202 mg) in dichloromethane (15 mL). The reaction mixture was poured into water, and the mixture was evaporated. The oil was dissolved in 5 mL of DMF and sodium azide (130 mg) was added and allowed to react at room temperature for 12 hours. The reaction mixture was poured into water and extracted with ethyl acetate. EtOAc was evaporated. 2:1 (V:V))

Step 2: Ethyl 2-amino-2-(1-(2-methoxyphenyl)cyclopropyl)acetate

The solid obtained in the first step was dissolved in a mixed solvent of THF (5 mL) and water (5 mL), and triphenylphosphine (500 mg) was added, and the mixture was heated to reflux for 2 hours and cooled to room temperature. The reaction mixture was poured into ice water and extracted with dichloromethane. EtOAc was evaporated. = 1:1 (V: V)) Intermediate 19 (102 mg) was obtained.

Example 1: 2-((5-(3-Chloro-2-methyl-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6-(4- Fluorophenyl)thieno[2,3-d]pyrimidin-4-yloxy-3-methyl-3-(2-((1-(2,2,2-trifluoroethyl)-1H-) Pyrazol-5-yl)methoxy)phenyl)butyric acid

Step 1: 2-((5-(3-Chloro-2-methyl-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6-(4-fluoro) Phenyl)thieno[2,3-d]pyrimidin-4-yloxy-3-methyl-3-(2-((1-(2,2,2-trifluoroethyl)-1H-pyridyl) Methyl oxazol-5-yl)methoxy)phenyl)butanoate

To 4-chloro-5-(3-chloro-2-methyl-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6-( at 0 ° C) 4-fluorophenyl)thieno[2,3-d]pyrimidine (110 mg) (Intermediate 12) and 2-hydroxy-3-methyl-3-(2-((1-(2,2,2-) Add sodium hydride (11 mg) to a solution of methyl trifluoroethyl)-1H-pyrazol-5-yl)methoxy)phenyl)butanoate (80 mg) ( Intermediate 1) in THF (10 mL) After that, the mixture was stirred at room temperature for 2 hours. The reaction solution was poured into a saturated aqueous solution of ammonium chloride (50 mL), and the mixture was evaporated. Purification of the title compound (m.

Step 2: 2-((5-(3-Chloro-2-methyl-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6-(4-fluoro) Phenyl)thieno[2,3-d]pyrimidin-4-yloxy-3-methyl-3-(2-((1-(2,2,2-trifluoroethyl)-1H-pyridyl) Zyrid-5-yl)methoxy)phenyl)butyric acid

To 2-((5-(3-chloro-2-methyl-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6-(4-) Fluorophenyl)thieno[2,3-d]pyrimidin-4-yloxy-3-methyl-3-(2-((1-(2,2,2-trifluoroethyl)-1H-) Methyl pyrazole-5-yl)methoxy)phenyl)butanoate A solution of lithium hydroxide solid (22 mg) was added to a solution of 1,4-dioxane and water (1:1) (6 mL). After stirring at room temperature for 12 hours, the reaction mixture was poured into water, the pH was adjusted to 3-4 with dilute hydrochloric acid (2M), and dichloromethane was evaporated. The extract was washed with brine, dried over anhydrous sodium sulfate The title compound (1.5 mg) was obtained from m. m.

^{1 H NMR (400MHz, DMSO-} d 6) δ8.61 (s, 1H), 7.52 (d, J = 1.6Hz, 1H), 7.16-7.26 (m, 5H), 7.07 (d, J = 8.4Hz, 1H), 6.96 (d, J = 8.8 Hz, 1H), 6.86-6.88 (m, 3H), 6.49 (s, 1H), 6.20 (s, 1H), 5.17-5.21 (m, 4H), 4.11-4.22 (m, 2H), 2.77 (t, J = 5.2 Hz, 2H), 2.32 - 2.64 (m, 8H), 2.24 (s, 3H), 2.20 (s, 3H), 1.01 (s, 3H), 0.81 ( s, 3H).

Example 2: 2-((5-(3-Chloro-2-methyl-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6-(4- Fluorophenyl)thieno[2,3-d]pyrimidin-4-yloxy-2-(1-(2-(2,2,2-trifluoroethyl)-1H-pyrazole -5-yl)methoxy)phenyl)cyclopropyl)acetic acid

Step 1: 2-((5-(3-Chloro-2-methyl-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6-(4-fluoro) Phenyl)thieno[2,3-d]pyrimidin-4-yloxy-2-(1-(2-(2,2,2-trifluoroethyl)-1H-pyrazole- 5-yl)methoxy)phenyl)cyclopropyl)acetate

The title compound (80 mg) was obtained from the title compound (yield).

Step 2: 2-((5-(3-Chloro-2-methyl-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6-(5-fluoro) Furan-2-yl)thieno[2,3-d]pyrimidin-4-yl)oxy)-2-(1-(2(-((1-(2,2,2-trifluoroethyl))) -1H-pyrazol-5-yl)methoxy)phenyl)cyclopropyl)acetic acid

Referring to the method of Step 2 in Example 1, 2-((5-(3-chloro-2-methyl-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl) -6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-oxy)-2-(1-(2-((1-(2,2,2-trifluoroethyl)) -1H-pyrazol-5-yl)methoxy)phenyl)cyclopropyl)acetate in place of 2-((5-(3-chloro-2-methyl-4-(2-(4-) Methyl piperazin-1-yl)ethoxy)phenyl)-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yloxy)-3-methyl-3- (2-((1-(2,2,2-Trifluoroethyl)-1H-pyrazol-5-yl)methoxy)phenyl)butanoate, taking the polar isomer The title compound (1.91 mg) was obtained.

¹ H NMR (400 MHz, CD 3 OD) δ 8.45 (s, 1H), 7.50 (d, J = 2.0 Hz, 1H), 7.45 (d, J = 8.8 Hz, 1H), 7.24 - 7.28 (m, 2H), 7.12-7.16 (m, 2H), 6.99-7.05 (m, 3H), 6.76 (t, J = 7.6 Hz, 1H), 6.53 (d, J = 1.6 Hz, 1H), 6.46 (d, J = 6.0 Hz) , 1H), 5.64 (s, 1H), 5.21-5.28 (m, 2H), 5.09-5.17 (m, 2H), 4.30-4.36 (m, 2H), 3.10-3.20 (m, 4H), 3.03 (t , J=5.2 Hz, 2H), 2.88-3.02 (m, 4H), 2.74 (s, 3H), 1.92 (s, 3H), 0.84-0.92 (m, 1H), 0.63-0.72 (m, 1H), 0.42-0.48 (m, 1H), 0.36-0.42 (m, 1H).

Example 3: 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-(2-methoxyphenyl)but-3-enoic acid

Step 1: 2-((5-(3-Chloro-2-methyl-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6-(4-fluoro) Phenyl) thieno[2,3-d]pyrimidin-4-yl)oxy)-3-(2-methoxyphenyl)but-3-enoate

The title compound (24 mg) was obtained from m.

Step 2: 2-((5-(3-Chloro-2-methyl-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6-(4-fluoro) Phenyl)thieno[2,3-d]pyrimidin-4-yl)oxy)-3-(2-methoxyphenyl)but-3-enoic acid

Referring to the method of Step 2 in Example 1, 2-((5-(3-chloro-2-methyl-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl) Ethyl 6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl)oxy)-3-(2-methoxyphenyl)but-3-enoate instead of 2 -((5-(3-chloro-2-methyl-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6-(4-fluorophenyl)thiophene And [2,3-d]pyrimidin-4-oxy)-3-methyl-3-(2-((1-(2,2,2-trifluoroethyl)-1H-pyrazole-5-) Ethyl methoxy)phenyl)butanoate, the more polar isomer was obtained to give the title compound (2.87 mg).

^{1 H NMR (400MHz, DMSO-} d 6) δ8.68 (s, 1H), 7.18-7.32 (m, 5H), 6.77-6.94 (m, 5H), 6.12 (s, 1H), 4.94 (s, 1H ), 4.72 (s, 1H), 4.06-4.19 (m, 2H), 3.66 (s, 3H), 2.74 (t, J = 6.0 Hz, 2H), 2.33-2.60 (m, 8H), 2.28 (s, 3H), 2.19 (s, 3H).

Example 4: 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)-2-(1-(2-methoxyphenyl)cyclopropyl)acetic acid

Step 1: 2-((5-(3-Chloro-2-methyl-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6-(4-fluoro) Phenyl) thieno[2,3-d]pyrimidin-4-yl)oxy)-2-(1-(2-methoxyphenyl)cyclopropyl)acetate

The title compound (60 mg) was obtained from m.

Step 2: 2-((5-(3-Chloro-2-methyl-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6-(4-fluoro) Phenyl)thieno[2,3-d]pyrimidin-4-yl)oxy)-2-(1-(2-methoxyphenyl)cyclobutyl)acetic acid

Referring to the method of Step 2 in Example 1, 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)-2-(1-(2-methoxyphenyl)cyclopropyl)acetate Instead of 2-((5-(3-chloro-2-methyl-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6-(4-fluorophenyl) Thieno[2,3-d]pyrimidin-4-yloxy-3-methyl-3-(2-((1-(2,2,2-trifluoroethyl)-1H-pyrazole-) Ethyl 5-amino)methoxy)phenyl)butanoate, the title compound (20 mg) was obtained.

^{1 H NMR (400MHz, DMSO-} d 6) δ8.59 (s, 1H), 7.18-7.28 (m, 6H), 7.13 (td, J = 8.8Hz, 1.6Hz, 1H), 6.85 (d, J = 7.6 Hz, 1H), 6.66 (t, J = 7.6 Hz, 1H), 6.29 (dd, J = 7.6 Hz, 1.6 Hz, 1H), 5.36 (s, 1H), 4.20 - 4.316 (m, 2H), 3.76 (s, 3H), 2.81 (t, J = 5.2 Hz, 2H), 2.49-2.70 (m, 8H), 2.29 (s, 3H), 1.95 (s, 3H), 0.78-0.85 (m, 1H), 0.66-0.73 (m, 1H), 0.44-0.52 (m, 1H), 0.36-0.43 (m, 1H).

Example 5: 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)-2-(1-(2-methoxyphenyl)cyclobutyl)acetic acid

Step 1: 2-((5-(3-Chloro-2-methyl-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6-(4-fluoro) Phenyl) thieno[2,3-d]pyrimidin-4-yl)oxy)-2-(1-(2-methoxyphenyl)cyclobutyl)acetate

The title compound (40 mg) was obtained from m.

Step 2: 2-((5-(3-Chloro-2-methyl-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6-(4-fluoro) Phenyl)thieno[2,3-d]pyrimidin-4-yl)oxy)-2-(1-(2-methoxyphenyl)cyclobutyl)acetic acid

Referring to the method of Step 2 in Example 1, 2-((5-(3-chloro-2-methyl-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl) Ethyl 6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl)oxy)-2-(1-(2-methoxyphenyl)cyclobutyl)acetate Instead of 2-((5-(3-chloro-2-methyl-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6-(4-fluorophenyl) Thieno[2,3-d]pyrimidin-4-yloxy-3-methyl-3-(2-((1-(2,2,2-trifluoroethyl)-1H-pyrazole-) Ethyl 5-methyl)methoxy)phenyl)butanoate, the title compound (15 mg) was obtained.

^{1 H NMR (400MHz, DMSO-} d 6) δ8.66 (s, 1H), 7.18-7.21 (m, 5H), 7.06-7.10 (m, 2H), 6.85 (d, J = 8.0Hz, 1H), 6.67 (t, J = 7.2 Hz, 1H), 6.39 (d, J = 7.2 Hz, 1H), 5.43-5.52 (m, 1H), 5.40 (d, J = 4.0 Hz, 1H), 4.89 (d, J) =6.0 Hz, 1H), 4.85 (s, 1H), 4.11-4.16 (m, 1H), 3.94-3.99 (m, 1H), 3.72 (s, 3H), 3.59-3.68 (m, 1H), 2.67 ( t, J = 5.2 Hz, 2H), 2.38-2.58 (m, 8H), 2.27 (s, 3H), 2.13 (s, 3H), 1.96-2.08 (m, 2H).

Example 6: 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-(2-methoxyphenyl)-3-methylbutyric acid

Step 1: 2-((5-(3-Chloro-2-methyl-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6-(4-fluoro) Phenyl) thieno[2,3-d]pyrimidin-4-yl)oxy)-3-(2-methoxyphenyl)-3-methylbutanoic acid ethyl ester

The title compound (30 mg) was obtained from m.

Step 2: 2-((5-(3-Chloro-2-methyl-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6-(4-fluoro) Phenyl)thieno[2,3-d]pyrimidin-4-yl)oxy)-3-(2-methoxyphenyl)-3-methylbutyric acid

Referring to the method of Step 2 in Example 1, 2-((5-(3-chloro-2-methyl-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl) Ethyl-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl)oxy)-3-(2-methoxyphenyl)-3-methylbutanoate 2-((5-(3-Chloro-2-methyl-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6-(4-fluorophenyl) Thieno[2,3-d]pyrimidin-4-yloxy-3-methyl-3-(2-((1-(2,2,2-trifluoroethyl)-1H-pyrazole-5) Ethyl methoxy)phenyl)butanoate, the more polar isomer was taken to give the title compound (5 mg).

^{1 H NMR (400MHz, DMSO-} d 6) δ8.63 (s, 1H), 7.07-7.25 (m, 7H), 6.88 (d, J = 8.0Hz, 1H), 6.76-6.82 (m, 2H), 6.20(s,1H), 4.22-4.26(m,1H),4.11-4.17(m,1H), 3.74(s,3H), 2.79(t,J=5.2Hz,2H), 2.48-2.72(m, 8H), 2.27 (s, 3H), 1.76 (s, 3H), 0.97 (s, 3H), 0.83 (s, 3H).

Example 7: 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-(2-methoxyphenyl)-3-methylbutyric acid

Step 1: 2-((5-(3-Chloro-2-methyl-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6-(4-fluoro) Phenyl) thieno[2,3-d]pyrimidin-4-yl)oxy)-3-(2-methoxyphenyl)butanoic acid ethyl ester

The title compound (10 mg) was obtained from the title compound (m.

Step 2: 2-((5-(3-Chloro-2-methyl-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6-(4-fluoro) Phenyl)thieno[2,3-d]pyrimidin-4-yl)oxy)-3-(2-methoxyphenyl)butanoic acid

Referring to the method of Step 2 in Example 1, 2-((5-(3-chloro-2-methyl-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl) Ethyl-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl)oxy)-3-(2-methoxyphenyl)butanoate instead of 2-((5) -(3-chloro-2-methyl-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6-(4-fluorophenyl)thieno[2, 3-d]pyrimidin-4-yloxy-3-methyl-3-(2-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)methoxy) Ethyl phenyl) butyrate, the more polar isomer was taken to give the title compound (2 mg).

^{1 H NMR (400MHz, DMSO-} d 6) δ8.66 (s, 1H), 7.27-7.31 (m, 2H), 7.21 (t, J = 8.8Hz, 2H), 7.09-7.15 (m, 2H), 7.05 (d, J = 8.8 Hz, 1H), 6.88 (d, J = 8.0 Hz, 1H), 6.71 (t, J = 7.2 Hz, 1H), 6.56 (d, J = 8.0 Hz, 1H), 5.38 ( d, J = 4.8 Hz, 1H), 4.12-4.16 (m, 1H), 4.02-4.06 (m, 1H), 3.75 (s, 3H), 3.46-3.52 (m, 1H), 2.68 (t, J = 5.6 Hz, 2H), 2.33 - 2.58 (m, 8H), 2.22 (s, 3H), 2.09 (s, 3H), 0.85 (d, J = 7.2 Hz, 3H).

Example 8: 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)-3,3-difluoro-3-(2-methoxyphenyl)propionic acid

Step 1: 2-((5-(3-Chloro-2-methyl-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6-(4-fluoro) Ethyl phenyl)thieno[2,3-d]pyrimidin-4-yl)oxy)-3,3-difluoro-3-(2-methoxyphenyl)propanoate

The title compound (30 mg) was obtained from the title compound (yield).

Step 2: 2-((5-(3-Chloro-2-methyl-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6-(4-fluoro) Phenyl)thieno[2,3-d]pyrimidin-4-yl)oxy)-3,3-difluoro-3-(2-methoxyphenyl)propionic acid

Referring to the method of Step 2 in Example 1, 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)-3,3-difluoro-3-(2-methoxyphenyl)propanoic acid Ester instead of 2-((5-(3-chloro-2-methyl-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6-(4-fluorobenzene) Thio[2,3-d]pyrimidin-4-yloxy-3-methyl-3-(2-((1-(2,2,2-trifluoroethyl)-1H-pyrazole) Ethyl 5-methoxy)phenyl)butanoate, the more polar isomer was obtained to give the title compound (5 mg).

^{1 H NMR (400MHz, DMSO-} d 6) δ8.66 (s, 1H), 7.31-7.35 (m, 1H), 7.14-7.24 (m, 4H), 6.96 (d, J = 8.0Hz, 1H), 6.78-6.83 (m, 2H), 6.72 (t, J = 8.0 Hz, 1H), 6.62 (t, J = 8.0 Hz, 1H), 6.04-6.11 (m, 1H), 4.10-4.20 (m, 2H) , 3.70 (s, 3H), 2.84 (t, J = 5.2 Hz, 2H), 2.60-2.83 (m, 8H), 2.40 (s, 3H), 2.32 (s, 3H).

Example 9: 2-((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-(2-((1-(2,2,2-trifluoroethyl)-1H-) Pyrazol-5-yl)methoxy)phenyl)but-3-enoic acid

Step 1: 2-((5-(3-Chloro-2-methyl-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6-(5-fluoro) Furan-2-yl)thieno[2,3-d]pyrimidin-4-yl)oxy)-3-(2-((1-(2,2,2-trifluoroethyl)-1H-pyridyl) Ethyl-5-yl)methoxy)phenyl)but-3-enoate

The title compound (2.55 mg) was obtained from the title compound.

Step 2: 2-((5-(3-Chloro-2-methyl-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6-(5-fluoro) Furan-2-yl)thieno[2,3-d]pyrimidin-4-yl)oxy)-3-(2-((1-(2,2,2-trifluoroethyl)-1H-pyridyl) Oxazol-5-yl)methoxy)phenyl)but-3-enoic acid

Referring to the method of Step 2 in Example 1, 2-((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-(2-((1-(2,2,2-trifluoro)) Ethyl ethyl-1H-pyrazol-5-yl)methoxy)phenyl)but-3-enoate ethyl ester instead of 2-((5-(3-chloro-2-methyl-4-(2-) (4-methylpiperazin-1-yl)ethoxy)phenyl)-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yloxy-3-methyl Ethyl 3-(2-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)methoxy)phenyl)butanoate as the title compound (2.55mg ).

¹ H NMR (400 MHz, CD ₃ OD) δ 8.70 (s, 1H), 8.50 (s, 1H), 7.49 (s, 1H), 7.34 (d, J = 1.6 Hz, 1H), 7.25-7.33 (m) , 2H), 7.09 (t, J = 8.0 Hz, 2H), 6.89-6.96 (m, 2H), 6.32 (s, 1H), 6.19 (s, 1H), 5.63 (t, J = 3.6 Hz, 1H) , 5.55 (dd, J = 6.8 Hz, 4.0 Hz, 1H), 5.17 (s, 2H), 4.84 - 4.94 (m, 2H), 4.30 (t, J = 4.8 Hz, 2H), 2.90 - 3.300 (m, 10H), 2.83 (s, 3H), 1.93 (s, 3H).

Example 10: 2-((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)-2-(1-(2-((1-(2,2,2-trifluoroethyl))) -1H-pyrazol-5-yl)methoxy)phenyl)cyclopropyl)acetic acid

Step 1: 2-((5-(3-Chloro-2-methyl-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6-(5-fluoro) Furan-2-yl)thieno[2,3-d]pyrimidin-4-yl)oxy)-2-(1-(2(-((1-(2,2,2-trifluoroethyl))) -1H-pyrazol-5-yl)methoxy)phenyl)cyclopropyl)acetate

Referring to the procedure of Step 1 in Example 1, Intermediate 5 was used instead of Intermediate 1 and Intermediate 10 was taken to the title compound (12 mg).

Step 2: 2-((5-(3-Chloro-2-methyl-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6-(5-fluoro) Furan-2-yl)thieno[2,3-d]pyrimidin-4-yl)oxy)-2-(1-(2(-((1-(2,2,2-trifluoroethyl))) -1H-pyrazol-5-yl)methoxy)phenyl)cyclopropyl)acetic acid

Referring to the method of Step 2 in Example 1, 2-((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)-2-(1-(2(-((1-(2,2, 2-((3-(3-chloro-2-methyl-4-)-(2-(3-chloro-2-methyl-4-)-4-yl-pyridyl-5-yl)methoxy)phenyl)cyclopropyl)acetate (2-(4-Methylpiperazin-1-yl)ethoxy)phenyl)-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yloxy)-3 -ethyl 3-(2-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)methoxy)phenyl)butanoate, polar The larger isomer gave the title compound (4.50 mg).

^{1 H NMR (400MHz, CD3OD)} δ8.43 (s, 1H), 7.51 (d, J = 2.0Hz, 1H), 7.36 (d, J = 8.4Hz, 1H), 7.22 (d, J = 8.8Hz, 1H), 7.17 (td, J = 7.6 Hz, 1.6 Hz, 1H), 7.02 (d, J = 8.0 Hz, 1H), 6.84 (t, J = 7.6 Hz, 1H), 6.58 (dd, J = 7.6 Hz) , 1.6 Hz, 1H), 6.54 (d, J = 1.6 Hz, 1H), 5.63 (s, 1H), 5.60 (t, J = 3.2 Hz, 1H), 5.56 (dd, J = 6.4 Hz, 3.6 Hz, 1H), 5.27 (d, J = 13.2 Hz, 1H), 5.24 (d, J = 13.2 Hz, 1H), 5.03-5.18 (m, 2H), 4.34 - 4.42 (m, 2H), 3.12-3.22 (m , 4H), 3.06 (t, J = 4.8 Hz, 2H), 2.90-3.05 (m, 4H), 2.77 (s, 3H), 2.07 (s, 3H), 0.87-0.92 (m, 1H), 0.61 0.68 (m, 1 H), 0.42-0.48 (m, 1 H), 0.34-0.42 (m, 1H).

Example 11: 2-((5-(3-Chloro-2-methyl-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6-(furan- 2-yl)thieno[2,3-d]pyrimidin-4-yl)oxy)-2-(1-(2-((1-(2,2,2-trifluoroethyl)-1H-) Pyrazol-5-yl)methoxy)phenyl)cyclopropyl)acetic acid

Step 1: 2-((5-(3-Chloro-2-methyl-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6-(furan-2) -yl)thieno[2,3-d]pyrimidin-4-yl)oxy)-2-(1-(2-(2-(2,2,2-trifluoroethyl)-1H-pyridyl) Ethyl-5-yl)methoxy)phenyl)cyclopropyl)acetate

Referring to the procedure of Step 1 in Example 1, Intermediate 5 was used instead of Intermediate 1 and Intermediate 11 was taken to the title compound (40 mg).

Step 2: 2-((5-(3-Chloro-2-methyl-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6-(furan-2) -yl)thieno[2,3-d]pyrimidin-4-yl)oxy)-2-(1-(2-(2-(2,2,2-trifluoroethyl)-1H-pyridyl) Oxazol-5-yl)methoxy)phenyl)cyclopropyl)acetic acid

Referring to the method of Step 2 in Example 1, 2-((5-(3-chloro-2-methyl-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl) -6-(furan-2-yl)thieno[2,3-d]pyrimidin-4-yl)oxy)-2-(1-(2-((1-(2,2,2-trifluoro)) Ethyl)-1H-pyrazol-5-yl)methoxy)phenyl)cyclopropyl)acetate in place of 2-((5-(3-chloro-2-methyl-4-(2-) 4-methylpiperazin-1-yl)ethoxy)phenyl)-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yloxy-3-methyl- Ethyl 3-(2-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)methoxy)phenyl)butanoate, taking a more polar The title compound (1.91 mg) was obtained.

^{1 H NMR (400MHz, CD3OD)} δ8.43 (s, 1H), 7.54 (d, J = 1.6Hz, 1H), 7.52 (d, J = 2.0Hz, 1H), 7.34 (d, J = 8.8Hz, 1H), 7.22 (d, J = 8.4 Hz, 1H), 7.18 (d, J = 8.0 Hz, 1H), 7.03 (d, J = 8.4 Hz, 1H), 6.86 (t, J = 7.6 Hz, 1H) , 6.60 (d, J = 7.2 Hz, 1H), 6.54 (s, 1H), 6.38 (dd, J = 3.2 Hz, 2.0 Hz, 1H), 5.65 (s, 1H), 5.62 (d, J = 7.2 Hz) , 1H), 5.30 (d, J = 13.2 Hz, 1H), 5.24 (d, J = 13.2 Hz, 1H), 5.07-5.17 (m, 2H), 4.32-4.47 (m, 2H), 3.12-3.30 ( m, 4H), 3.08 (t, J = 5.2 Hz, 2H), 2.90-3.07 (m, 4H), 2.80 (s, 3H), 2.05 (s, 3H), 0.84-0.93 (m, 1H), 0.61 -0.69 (m, 1H), 0.44-0.52 (m, 1H), 0.36 - 0.42 (m, 1H).

Example 12: 2-((5-(3-Chloro-2-methyl-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6-(furan- 2-yl)thieno[2,3-d]pyrimidin-4-yloxy-3-methyl-3-(2-((1-(2,2,2-trifluoroethyl)-1H-) Pyrazol-5-yl)methoxy)phenyl)butyric acid

Step 1: 2-((5-(3-Chloro-2-methyl-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6-(furan-2) -yl)thieno[2,3-d]pyrimidin-4-yloxy-3-methyl-3-(2-((1-(2,2,2-trifluoroethyl)-1H-pyridyl) Methyl oxazol-5-yl)methoxy)phenyl)butanoate

The title compound (60 mg) was obtained from m.

Step 2: 2-((5-(3-Chloro-2-methyl-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6-(furan-2) -yl)thieno[2,3-d]pyrimidin-4-yloxy-3-methyl-3-(2-((1-(2,2,2-trifluoroethyl)-1H-pyridyl) Zyrid-5-yl)methoxy)phenyl)butyric acid

Referring to the method of Step 2 in Example 1, 2-((5-(3-chloro-2-methyl-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl) -6-(furan-2-yl)thieno[2,3-d]pyrimidin-4-yloxy-3-methyl-3-(2-((1-(2,2,2-trifluoro)) Methyl ethyl 1H-pyrazol-5-yl)methoxy)phenyl)butanoate instead of 2-((5-(3-chloro-2-methyl-4-(2-(4-) Piperazin-1-yl)ethoxy)phenyl)-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-oxy)-3-methyl-3-( Ethyl 2-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)methoxy)phenyl)butanoate, obtained from the more polar isomer The title compound (15 mg).

^{1 H NMR (400MHz, DMSO-} d 6) δ8.58 (s, 1H), 7.77 (s, 1H), 7.56 (d, J = 2.0Hz, 1H), 7.17-7.25 (m, 3H), 7.09 ( d, J = 8.0 Hz, 1H), 6.85-6.95 (m, 2H), 6.55 (s, 1H), 6.48-6.50 (m, 1H), 6.24 (s, 1H), 5.48 (d, J = 3.2 Hz) , 1H), 5.18-5.25 (m, 4H), 4.22-4.36 (m, 2H), 2.85 (t, J = 5.2 Hz, 2H), 2.45-2.78 (m, 8H), 2.33 (s, 3H), 1.80 (s, 3H), 0.99 (s, 3H), 0.85 (s, 3H).

Example 13: 2-((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-methyl-3-(2-((1-(2,2,2-trifluoroethyl) -1H-pyrazol-5-yl)methoxy)phenyl)butyric acid

Step 1: 2-((5-(3-Chloro-2-methyl-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6-(5-fluoro) Furan-2-yl)thieno[2,3-d]pyrimidin-4-yl)oxy)-3-methyl-3-(2-((1-(2,2,2-trifluoroethyl)) )-1H-pyrazol-5-yl)methoxy)phenyl)butyric acid methyl ester

The title compound (20 mg) was obtained from the title compound.

Step 2: 2-((5-(3-Chloro-2-methyl-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6-(5-fluoro) Furan-2-yl)thieno[2,3-d]pyrimidin-4-yl)oxy)-3-methyl-3-(2-((1-(2,2,2-trifluoroethyl)) )-1H-pyrazol-5-yl)methoxy)phenyl)butyric acid

Referring to the method of Step 2 in Example 1, 2-((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-methyl-3-(2-((1-(2,2) Methyl 2-(2-trifluoroethyl)-1H-pyrazol-5-yl)methoxy)phenyl)butanoate instead of 2-((5-(3-chloro-2-methyl-4-(2) -(4-methylpiperazin-1-yl)ethoxy)phenyl)-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yloxy-3-yl Ethyl 3-(2-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)methoxy)phenyl)butanoate, which is more polar The isomer gave the title compound (5 mg).

^{1 H NMR (400MHz, DMSO-} d 6) δ8.58 (s, 1H), 7.56 (d, J = 1.6Hz, 1H), 7.17-7.24 (m, 3H), 7.09 (d, J = 8.0Hz, 1H), 6.93 (t, J = 7.2 Hz, 1H), 6.87 (d, J = 8.0 Hz, 1H), 6.. 55 (d, J = 1.6 Hz, 1H), 6.24 (s, 1H), 5.85 (dd, J = 7.2 Hz, 3.6 Hz, 1H), 5.51 (t, J = 7.2 Hz, 1H), 5.17-5.25 (m, 4H), 4.21-4.33 (m, 2H), 2.83 (t, J = 5.2 Hz, 2H), 2.34 - 2.74 (m, 8H), 2.28 (s, 3H), 1.81 (s, 3H), 0.98 (s, 3H), 0.85 (s, 3H).

Example 14: (2R)-2-(((5Sa)-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-(2-((1-(2,2,2) -trifluoroethyl)-1H-pyrazol-5-yl)methoxy)phenyl)butyric acid

Step 1: (2R)-2-(((5Sa)-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-methyl-3-(2-((1-(2, Methyl 2,2-trifluoroethyl)-1H-pyrazol-5-yl)methoxy)phenyl)butanoate

The title compound (20 mg) was obtained from the title compound.

Step 2: (2R)-2-(((5Sa)-5--(3-chloro-2-methyl-4-(2-(4-methylpiperazin-1-yl)ethoxy)benzene) 6-(5-fluorofuran-2-yl)thieno[2,3-d]pyrimidin-4-yl)oxy)-3-(2-((1-(2,2,2-) Trifluoroethyl)-1H-pyrazol-5-yl)methoxy)phenyl)butyric acid

Referring to the method of Step 2 in Example 1, (2R)-2-(((5Sa)-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-methyl-3-(2- Methyl ((1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)methoxy)phenyl)butanoate instead of 2-((5-(3-chloro-2) -methyl-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6-(4-fluorophenyl)thieno[2,3-d]pyrimidine-4 -oxy)-3-methyl-3-(2-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)methoxy)phenyl)butanoic acid The ethyl ester was taken to give the title compound (3 mg).

^{1 H NMR (400MHz, DMSO-} d 6) δ8.58 (s, 1H), 7.56 (d, J = 1.6Hz, 1H), 7.17-7.24 (m, 3H), 7.09 (d, J = 8.0Hz, 1H), 6.93 (t, J = 7.2 Hz, 1H), 6.87 (d, J = 8.0 Hz, 1H), 6.. 55 (d, J = 1.6 Hz, 1H), 6.24 (s, 1H), 5.85 (dd, J = 7.2 Hz, 3.6 Hz, 1H), 5.51 (t, J = 7.2 Hz, 1H), 5.17-5.25 (m, 4H), 4.21-4.33 (m, 2H), 2.83 (t, J = 5.2 Hz, 2H), 2.34 - 2.74 (m, 8H), 2.28 (s, 3H), 1.81 (s, 3H), 0.98 (s, 3H), 0.85 (s, 3H).

Example 15: (2R)-2-(((5Sa)-5-(3-chloro-2-methyl-4-(2-(4-methylpiperazin-1-yl)ethoxy)benzene) 6-(5-fluorofuran-2-yl)thieno[2,3-d]pyrimidin-4-yl)oxy)-2-(1-(2-((1-(2,2) ,2-trifluoroethyl)-1H-pyrazol-5-yl)methoxy)phenyl)cyclopropyl)acetic acid

Step 1: (2R)-2-(((5Sa)-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)-2-(1-(2(-((1-(2,2) ,2-trifluoroethyl)-1H-pyrazol-5-yl)methoxy)phenyl)cyclopropyl)acetate

Referring to the procedure of Step 1 in Example 1, Intermediate 15 was used instead of Intermediate 1 and Intermediate 10 was used instead of Intermediate 12 to give the title compound (10 mg).

Step 2: (2R)-2-(((5Sa)-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)-2-(1-(2(-((1-(2,2) ,2-trifluoroethyl)-1H-pyrazol-5-yl)methoxy)phenyl)cyclopropyl)acetic acid

Referring to the method of Step 2 in Example 1, (2R)-2-(((5Sa)-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)-2-(1-(2(-( (1-(2,2,2-Trifluoroethyl)-1H-pyrazol-5-yl)methoxy)phenyl)cyclopropyl)acetate in place of 2-((5-(3-chloro) -2-methyl-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6-(4-fluorophenyl)thieno[2,3-d]pyrimidine -4-oxy)-3-methyl-3-(2-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)methoxy)phenyl) Ethyl butyrate, the more polar isomer was taken to give the title compound (5 mg).

_{^{1 H NMR (400MHz, CD 3}} OD) δ8.43 (s, 1H), 7.51 (d, J = 2.0Hz, 1H), 7.36 (d, J = 8.4Hz, 1H), 7.22 (d, J = 8.8 Hz, 1H), 7.17 (td, J = 7.6 Hz, 1.6 Hz, 1H), 7.02 (d, J = 8.0 Hz, 1H), 6.84 (t, J = 7.6 Hz, 1H), 6.58 (dd, J = 7.6 Hz, 1.6 Hz, 1H), 6.54 (d, J = 1.6 Hz, 1H), 5.63 (s, 1H), 5.60 (t, J = 3.2 Hz, 1H), 5.56 (dd, J = 6.4 Hz, 3.6 Hz, 1H), 5.27 (d, J = 13.2 Hz, 1H), 5.24 (d, J = 13.2 Hz, 1H), 5.03-5.18 (m, 2H), 4.34 - 4.42 (m, 2H), 3.12-3.22 (m, 4H), 3.06 (t, J = 4.8 Hz, 2H), 2.90-3.05 (m, 4H), 2.77 (s, 3H), 2.07 (s, 3H), 0.87-0.92 (m, 1H), 0.61-0.68 (m, 1H), 0.42-0.48 (m, 1H), 0.34-0.42 (m, 1H).

Example 16: 2-((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)amino)-2-(1-(2-methoxyphenyl)cyclopropyl)acetic acid

Step 1: 2-((5-(3-Chloro-2-methyl-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6-(5-fluoro) Furan-2-yl)thieno[2,3-d]pyrimidin-4-yl)amino)-2-(1-(2-methoxyphenyl)cyclopropyl)acetate

The title compound (20 mg) was obtained from the title compound.

Step 2: 2-((5-(3-Chloro-2-methyl-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6-(5-fluoro) Furan-2-yl)thieno[2,3-d]pyrimidin-4-yl)amino)-2-(1-(2-methoxyphenyl)cyclopropyl)acetic acid

Referring to the method of Step 2 in Example 1, 2-((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)amino)-2-(1-(2-methoxyphenyl)cyclopropyl)acetic acid Ethyl ester instead of 2-((5-(3-chloro-2-methyl-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6-(4-fluoro) Phenyl)thieno[2,3-d]pyrimidin-4-yloxy-3-methyl-3-(2-((1-(2,2,2-trifluoroethyl)-1H-pyridyl) Ethylzol-5-yl)methoxy)phenyl)butanoate gave the title compound (5 mg).

^{1 H NMR (400MHz, DMSO-} d 6) δ8.32 (s, 1H), 7.33-7.38 (m, 2H), 7.18 (t, J = 8.0Hz, 1H), 6.89 (d, J = 7.6Hz, 1H), 6.78 (t, J = 8.0 Hz, 1H), 6.48 (d, J = 7.6 Hz, 1H), 5.84 (dd, J = 6.8 Hz, 3.6 Hz, 1H), 5.62 (t, J = 3.6 Hz) , 1H), 5.26 (d, J = 8.4 Hz, 1H), 4.71 (d, J = 8.4 Hz, 1H), 4.31-4.34 (m, 2H), 3.75 (s, 3H), 2.89-2.95 (m, 2H), 2.60-2.85 (m, 8H), 2.44 (s, 3H), 2.02 (s, 3H), 0.84-0.89 (m, 1H), 0.51-0.60 (m, 2H), 0.38-0.43 (m, 1H).

Example 17: (2R)-2-(((5Sa)-5-(3-chloro-2-methyl-4-(2-(4-methylpiperazin-1-yl)ethoxy)benzene) 6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl)oxy)-3-(2-((2-(2-methoxyphenyl)pyrimidine) 4-yl)methoxy)phenyl)-3-methylbutyric acid

Step 1: (2R)-2-(((5Sa)-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-(2-((2-(2-methoxyphenyl)pyrimidine)- Methyl 4-yl)methoxy)phenyl)-3-methylbutanoate

The title compound (20 mg) was obtained from the title compound (yield).

Step 2: (2R)-2-(((5Sa)-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-(2-((2-(2-methoxyphenyl)pyrimidine)- 4-yl)methoxy)phenyl)-3-methylbutyric acid

Referring to the method of Step 2 in Example 1, using (2R)-2-((5Sa)-5-(3-chloro-2-methyl-4-(2-(4-methylpiperazin-1-) Ethyl)phenyl)-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl)oxy)-3-(2-((2-(2-) Methyl methoxyphenyl)pyrimidin-4-yl)methoxy)phenyl)-3-methylbutanoate instead of 2-((5-(3-chloro-2-methyl-4-(2-) (4-methylpiperazin-1-yl)ethoxy)phenyl)-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yloxy-3-methyl Ethyl 3-(2-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)methoxy)phenyl)butanoate, which is more polar The title compound (4 mg) was obtained.

^{1 H NMR (400MHz, DMSO-} d 6) δ8.80 (d, J = 4.8Hz, 1H), 8.52 (s, 1H), 7.54 (d, J = 5.6Hz, 1H), 7.43-7.49 (m, 2H), 7.11-7.28 (m, 9H), 6.97-7.02 (m, 2H), 6.89 (d, J = 4.0 Hz, 1H), 6.44 (s, 1H), 5.25 (d, J = 15.2 Hz, 1H) ), 5.24 (d, J = 15.2 Hz, 1H), 4.26-4.28 (m, 1H), 4.16-4.19 (m, 1H), 3.77 (s, 3H), 2.60-2.90 (m, 10H), 2.44 ( s, 3H), 1.76 (s, 3H), 1.07 (s, 3H), 0.99 (s, 3H).

Example 18: (2R)-2-(((5Sa)-5-(3-chloro-2-methyl-4-(2-(4-methylpiperazin-1-yl)ethoxy)benzene) 6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl)oxy)-2-(1-(2-((2-(2-methoxybenzene)) Pyrimidin-4-yl)methoxy)phenyl)cyclopropyl)acetic acid

Step 1: (2R)-2-(((5Sa)-5-(3-Chloro-2-methyl-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl) - 6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl)oxy)-2-(1-(2-(2-(2-methoxyphenyl) Pyrimidine-4-yl)methoxy)phenyl)cyclopropyl)acetate

The title compound (90 mg) was obtained from the title compound (yield).

Step 2: (2R)-2-(((5Sa)-5-(3-chloro-2-methyl-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl) - 6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl)oxy)-2-(1-(2-(2-(2-methoxyphenyl) Pyrimidin-4-yl)methoxy)phenyl)cyclopropyl)acetic acid

Referring to the method of Step 2 in Example 1, (2R)-2-(((5Sa)-5-(3-chloro-2-methyl-4-(2-(4-methylpiperazin-1-yl) Ethoxy)phenyl)-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl)oxy)-2-(1-(2-((2-) 2-((2-(3-chlorophenyl)pyrimidin-4-yl)methoxy)phenyl)cyclopropyl)acetate in place of 2-((5-(3-chloro-2-methyl-4-(2-) (4-methylpiperazin-1-yl)ethoxy)phenyl)-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yloxy-3-methyl Ethyl 3-(2-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)methoxy)phenyl)butanoate, which is more polar The title compound (45 mg) was obtained.

^{1 H NMR (400MHz, CDCl3)} δ8.78 (d, J = 5.6Hz, 1H), 8.44 (s, 1H), 7.98 (d, J = 4.8Hz, 1H), 7.66 (dd, J = 7.6Hz, 1.6 Hz, 1H), 7.40-7.45 (m, 2H), 7.02-7.14 (m, 5H), 6.89-6.97 (m, 3H), 6.78 (d, J = 8.0 Hz, 1H), 6.74 (d, J) = 7.6 Hz, 1H), 6.36 (d, J = 7.6 Hz, 1H), 5.78 (s, 1H), 5.22 (d, J = 15.2 Hz, 1H), 5.15 (d, J = 15.2 Hz, 1H), 4.32-4.39 (m, 2H), 3.85 (s, 3H), 2.61-3.13 (m, 10H), 2.47 (s, 3H), 1.96 (s, 3H), 0.90-0.99 (m, 1H), 0.81 0.89 (m, 1H), 0.60-0.69 (m, 1H), 0.51 - 0.59 (m, 1H).

Example 19: (R)-4-(2-(4-(4-(carboxy)(1-(2-(2-(2-methoxyphenyl)pyrimidin-4-yl)methoxy)) Phenyl)cyclopropyl)methoxy)-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-5-yl)-2-chloro-3-methylphenoxy) 1-methyl-1-((phosphonooxy)methyl)piperazine-1-pyrene

Step 1: (2R)-2-(((5Sa)-5-(3-Chloro-2-methyl-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl) - 6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl)oxy)-2-(1-(2-(2-(2-methoxyphenyl) Pyrimidin-4-yl)methoxy)phenyl)cyclopropyl)acetic acid (4-methoxy)benzyl ester

To (2R)-2-((5Sa)-5-(3-chloro-2-methyl-4-(2-(4-methylpiperazin-1-yl)ethoxy)benzene at room temperature 6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl)oxy)-2-(1-(2-((2-(2-methoxybenzene)) a solution of (meth)pyrimidin-4-yl)methoxy)phenyl)cyclopropyl)acetic acid (75 mg), (4-methoxy)benzyl alcohol (23 mg) and triphenylphosphine (55 mg) in toluene (10 mL) DIAD (37 mg) was added dropwise, and after the addition, the temperature was raised to 50 ° C and stirred for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. EtOAc was evaporated. The title compound (60 mg) was obtained after purification.

Step 2: (R)-4-(2-(2-Chloro-4-(6-(4-fluorophenyl)-4-(2-(4-methoxybenzyl)oxy)-1) -(1-(2-((2-(2-methoxyphenyl)pyrimidin-4-yl)methoxy)phenyl)cyclopropyl)-2-oxoethoxy)thiophene [2 ,3-d]pyrimidin-5-yl)-3-methylphenoxy)ethyl)-1-(((di-tert-butoxyphosphoryl)oxy)methyl)-1-methylpiperazine -1-鎓

To (2R)-2-((5Sa)-5-(3-chloro-2-methyl-4-(2-(4-methylpiperazin-1-yl)ethoxy)benzene at room temperature 6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl)oxy)-2-(1-(2-((2-(2-methoxybenzene)) (4-methoxy)phenyl)cyclopropyl)acetic acid (4-methoxy)benzyl ester (60 mg), sodium iodide (26 mg) and sodium bicarbonate (15 mg) in acetone (10 mL) Di-tert-butyl chloromethyl phosphate (45 mg) was added dropwise to the solution, and the mixture was stirred at room temperature for 1 hour. The reaction solution was filtered, and the solid was dried and used directly for the next reaction.

Step 3: (R)-4-(2-(4-(4-(carboxy)(1-(2-(2-)2-methoxyphenyl)pyrimidin-4-yl)methoxy)benzene Cyclopropyl)methoxy)-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-5-yl)-2-chloro-3-methylphenoxy)ethyl )-1-methyl-1-((phosphonooxy)methyl)piperazine-1-pyrene

To (R)-4-(2-(2-chloro-4-(6-(4-fluorophenyl)-4-(2-(4-methoxybenzyl))oxy)-) 1-(1-(2-(2-(2-methoxyphenyl)pyrimidin-4-yl)methoxy)phenyl)cyclopropyl)-2-oxoethoxy)thieno[ 2,3-d]pyrimidin-5-yl)-3-methylphenoxy)ethyl)-1-(((di-tert-butoxyphosphoryl)oxy)methyl)-1-methylper Trifluoroacetic acid (3 mL) was added dropwise to aq. The reaction solution is concentrated, and the residue is subjected to a preparative column to isolate the target compound 10 (mg).

¹ H NMR (400 MHz, CD ₃ OD) δ 8.80 (d, J = 5.6 Hz, 1H), 8.41 (s, 1H), 8.1 (d, J = 5.2 Hz, 1H), 7.68 (dd, J = 7.2 Hz, 1.6 Hz, 1H), 7.49 (td, J = 8.0 Hz, 1.2 Hz, 1H), 7.33 (d, J = 8.4 Hz, 1H), 7.22 - 7.26 (m, 2H), 7.13 - 7.17 (m, 3H), 6.99-7.06 (m, 3H), 6.93 (d, J = 8.4 Hz, 1H), 6.77 (t, J = 7.2 Hz, 1H), 6.43 (dd, J = 7.6 Hz, 1.6 Hz, 1H) , 5.63 (s, 1H), 5.29 (d, J = 15.6 Hz, 1H), 5.22 (d, J = 15.6 Hz, 1H), 4.89 (d, J = 8.4 Hz, 2H), 4.32 (t, J = 4.4 Hz, 2H), 3.85 (s, 3H), 3.12-3.60 (m, 8H), 3.07-3.10 (m, 2H), 3.05 (s, 3H), 1.99 (s, 3H), 0.99-1.06 (m) , 1H), 0.84-0.92 (m, 1H), 0.56-0.71 (m, 2H).

Biological activity experiment

1. Determination of in vitro protein activity of compounds:

A screening method for protein activity of Mcl-1 was established by fluorescence polarization method. The basic principle is that the small molecule compound competes with the fluorophore FITC-labeled short peptide (FITC-Noxa) for its binding site to Mcl-1. When FITC-Noxa is combined with the macromolecular substance Mcl-1, the fluorescent substance FITC is irradiated by a single plane of blue-polarized light (485 nm), and the absorbed light energy jumps into the excited state, then returns to the ground state, and emits a single plane of polarized fluorescence. (525nm). Conversely, if FITC-Noxa fails to bind to the macromolecular substance Mcl-1, the small molecule rotates or flips faster, and the emitted light will be depolarized relative to the plane of the excitation light. That is to say, when the compound is competitively bound to Mcl-1, FITC-Noxa will exist in a free state and its polarization value will decrease. Therefore, the binding ability of the compound to Mcl-1 can be reflected by the change in the polarization value.

The specific procedure was as follows: First, 10 mM of the compound stock solution was diluted to 1 mM with DMSO, followed by 3-fold gradient dilution with DMSO. 4 μL of the serially diluted compound was transferred to 96 μL of reaction buffer (PBS, pH 7.4; 50 mM NaCl; 0.01% NP40 and 2 mM dithiothreitol (DTT)), and then this further diluted compound was added to 384- Hole black round bottom plate

Then, a protein solution containing 10 nM of Mcl-1 prepared by adding 8 μL of the reaction buffer was added. The test mixture was then incubated at 23 ° C for 30 minutes with shaking, after which 4 μL of reaction buffer containing 10 nM FITC-Noxa was added and incubation was continued for 120 minutes at room temperature. The polarization value was measured by EnVision under Ex 485/Em530. The data was processed by the data analysis software Prism and the IC50 value of the compound was obtained.

2. Determination of cell proliferation activity of the compound:

Using Promega

The detection reagent establishes a screening method for suspension cell proliferation inhibition.

Human leukemia cell MV-411 and human myeloma cell NCI-H929 supplemented with 10% (MV-411) and 20% (NCI-H929) fetal bovine serum

of

The culture medium is cultured at 37 ° C, 95% air and 5% CO 2 , and cultured in a 25 cm 2 or 75 cm 2 plastic tissue culture flask.

In the middle, subculture is carried out 2 to 3 times a week.

The cells were seeded at a density of 8×10 3 cells/well (MV-411) and 1×10 4 cells/well (NCI-H929) in a 96-well cell culture plate.

Medium, 195 μL/well, and cultured at 37 ° C, 95% air and 5% CO 2 . Add the test compound after 24 hours: start the compound from 10 mM (dissolved in DMSO) with 3-fold gradient dilution with DMSO, add 4 μL of each concentration to 96 μL of serum-free medium, and finally dilute with 5 μL of medium. The compound is added to the culture plate inoculated with the cells. The final concentration of DMSO in the cell culture medium was 0.1%, and the final concentration of the test compound was 0.3 nM to 10 μM. The above cells were incubated at 37 ° C for 3 days.

After 3 days, the cell viability assay was performed by the Cell Titer-Blue (Promega) kit, and finally the semi-inhibitory concentration of the compound on cell proliferation, i.e., the IC50 value, was calculated by the Prism program.

Biological data of selected compounds

Selected compounds prepared above were analyzed according to the biological methods described herein. The results are shown in the table below:

Protein activity data

Cytological data

Industrial applicability

The present invention provides a Mcl-1 selective inhibitor and its preparation and use. The present invention also provides a series of compounds represented by the general formula (I), and pharmaceutically acceptable salts, solvates, polymorphs or prodrugs thereof, pharmaceutical compositions comprising the same, and the use of such compounds A method of treating a disease caused or aggravated by over-expressed or dysregulated MCL-1 protein. The Mcl-1 selective inhibitor provided by the invention has high activity, strong drug resistance and small clinical side effects, and can effectively overcome the problem of tumor treatment resistance, and has good economic value and application prospect.

Claims (10)

1. a compound of formula (I), or a pharmaceutically acceptable salt, solvate, isomer, or prodrug thereof,

   

   among them,

   X is O, NH or S;

   a and b are each independently a single bond or a double bond, and at most one of a and b may be a double bond;

   R _{1 is} selected from H and a 5-8 membered heteroaryl group, which may be optionally C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 ring Alkyla, C _1-6 alkyl-O-, or 6-10 membered aryl, the C _1-6 alkyl group may be optionally substituted with 1-3 halo, and the 6-10 member aryl The base may be optionally substituted with from _{1 to 3} groups independently selected from C _1-6 alkyl and C _1-6 alkyl-O-;

   When both a and b are a single bond, R ₂ and R ₃ are each independently selected from H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl. , halogen and cyano, or R ₂ , R ₃ together with the carbon atom to which they are attached form a 3-8 membered cycloalkyl group, and R ₂ and R _{3 may} not be hydrogen at the same time;

   When a is a double bond, R ₃ does not exist, and R ₂ is

   

   When b is a double bond, R ₃ is absent, and R _{2 is} selected from the group consisting of H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, halogen and cyanide. base;

   R ₄ each independently is halogen, C _1-6 alkyl, C _1-6 alkyl-O-, or cyano;

   R _{5 is} selected from phenyl and 5-8 membered heteroaryl, and the phenyl and 5-8 membered heteroaryl are optionally substituted with from 1 to 3 groups selected from halogen and C _1-6 alkyl;

   R _{6 is} selected from a 3-8 membered heterocyclic group optionally substituted by C _1-6 alkyl, -C _1-6 alkylene-OP(=O)(OH) ₂ , C _{1- 6} alkyl-O-substituted;

   R ₇ and R ₈ are each independently selected from H and C _1-6 alkyl;

   p and q are each independently 1, 2, 3, 4, 5 and 6;

   m is 0, 1, 2, 3, or 4.
2. The compound according to claim 1 or a pharmaceutically acceptable salt, solvate, isomer or prodrug thereof, wherein X is O; and the structural formula is as shown in the following formula (II):

   

   among them,

   a and b are each independently a single bond or a double bond, and at most one of a and b may be a double bond;

   R _{1 is} selected from H and a 5-8 membered heteroaryl group, which may be optionally C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 ring Alkyla, C _1-6 alkyl-O-, or 6-10 membered aryl, the C _1-6 alkyl group may be optionally substituted with 1-3 halo, and the 6-10 member aryl The base may be optionally substituted with from _{1 to 3} groups independently selected from C _1-6 alkyl and C _1-6 alkyl-O-;

   When both a and b are a single bond, R ₂ and R ₃ are each independently selected from H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl. , halogen and cyano, or R ₂ , R ₃ together with the carbon atom to which they are attached form a 3-8 membered cycloalkyl group, and R ₂ and R _{3 may} not be hydrogen at the same time;

   When a is a double bond, R ₃ does not exist, and R ₂ is

   

   When b is a double bond, R ₃ is absent, and R _{2 is} selected from the group consisting of H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, halogen and cyanide. base;

   R ₄ each independently is halogen or C _1-6 alkyl;

   R _{5 is} selected from phenyl and 5-8 membered heteroaryl, and the phenyl and 5-8 membered heteroaryl are optionally substituted with from 1 to 3 groups selected from halogen and C _1-6 alkyl;

   R _{6 is} selected from a 3-8 membered heterocyclic group, which is optionally substituted by a C _1-6 alkyl group;

   R ₇ and R ₈ are each independently selected from H and C _1-6 alkyl;

   p and q are each independently 1, 2, 3, 4, 5 and 6;

   m is 0, 1, or 2.
3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, solvate, isomer or prodrug thereof, wherein R _{1 is} selected from H and a 5-8 membered heteroaryl; the heteroaryl group Optionally substituted with C _1-6 alkyl, C _1-6 alkyl-O-, or 6-10 membered aryl; the C _1-6 alkyl group may be optionally substituted with 1-3 halogens And the 6-10 membered aryl group may be optionally substituted with 1 to 3 groups independently selected from C _1-6 alkyl and C _1-6 alkyl-O-;

   Preferably, R _{1 is} selected from the group consisting of H, pyrazolyl and pyrimidinyl; the pyrazolyl and pyrimidinyl may be optionally C _1-6 alkyl, C _1-6 alkyl-O-, or 6-10 Substituted by a aryl group, the C _1-6 alkyl group may be optionally substituted with from 1 to 3 halogens, and the 6-10 membered aryl group may be optionally selected from 1-3 independently from C _1- Substituted by a group of ₆ alkyl and C _1-6 alkyl-O-.

   Preferably, R _{1 is} selected from H, pyrazolyl, pyrimidinyl, said pyrazolyl may be optionally substituted with C _1-6 alkyl, said C _1-6 alkyl may be optionally substituted with 1-3 Substituted by a halogen, the pyrimidinyl group may be optionally substituted by a 6-10 membered aryl group, which may optionally be independently selected from 1-3 independently selected from _C1-6 alkyl and C Substituted by a group of _1-6 alkyl-O-.
4. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, solvate, isomer, or prodrug thereof, wherein

   When both a and b are a single bond, R ₂ and R ₃ are each independently selected from H, C _1-6 alkyl, halogen and cyano, or R ₂ , R ₃ and the carbon atom to which they are attached form 3 -8 membered cycloalkyl, R ₂ and R _{3 may} not be hydrogen at the same time;

   When a is a double bond, R ₃ does not exist, and R ₂ is

   

   Wherein R ₇ and R ₈ are hydrogen;

   When b is a double bond, R ₃ is absent, and R _{2 is} selected from the group consisting of H, C _1-6 alkyl, halogen and cyano;
5. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, solvate, isomer or prodrug thereof, wherein R _{5 is} selected from the group consisting of phenyl and furyl, optionally phenyl and furanyl The ground is substituted with 1-3 groups selected from halogen and C _1-6 alkyl.
6. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, solvate, isomer or prodrug thereof, wherein p is 1, q is 2;
7. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, solvate, isomer or prodrug thereof, wherein the compound is selected from the group consisting of:

   
8. A pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt, solvate, isomer, or prodrug thereof, and a pharmaceutically acceptable carrier.
9. The compound of any of claims 1-7, or a pharmaceutically acceptable salt, solvate, isomer, or prodrug thereof, for use in the manufacture of a disease caused or aggravated by overexpressed or dysregulated MCL-1 protein Use in medicine.
10. The compound of any of claims 1-7, or a pharmaceutically acceptable salt, solvate, isomer, or prodrug thereof, for use in the treatment of bladder cancer, brain cancer, breast and uterine cancer, chronic lymphocytic leukemia, Use in colon cancer, esophageal cancer and liver cancer, lymphoblastic leukemia, acute myeloid leukemia, lymphoma, ovarian cancer, non-small cell lung cancer, multiple myeloma, acute lymphoblastic leukemia, or myelodysplastic syndrome.