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WO2019101144A1 - Mcl-1选择性抑制剂及其制备和用途 - Google Patents

Mcl-1选择性抑制剂及其制备和用途 Download PDF

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Publication number
WO2019101144A1
WO2019101144A1 PCT/CN2018/117014 CN2018117014W WO2019101144A1 WO 2019101144 A1 WO2019101144 A1 WO 2019101144A1 CN 2018117014 W CN2018117014 W CN 2018117014W WO 2019101144 A1 WO2019101144 A1 WO 2019101144A1
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WIPO (PCT)
Prior art keywords
alkyl
phenyl
group
methyl
methoxy
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PCT/CN2018/117014
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English (en)
French (fr)
Inventor
刘志华
陈坤成
袁保昆
焦楠
解博闻
闵汪洋
许新合
刘希杰
孙莹
徐枫
孙颖慧
Original Assignee
北京赛林泰医药技术有限公司
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Priority claimed from CN201711189194.4A external-priority patent/CN109824690A/zh
Priority claimed from CN201810425784.0A external-priority patent/CN110452253A/zh
Application filed by 北京赛林泰医药技术有限公司 filed Critical 北京赛林泰医药技术有限公司
Priority to CN201880075917.4A priority Critical patent/CN111372936B/zh
Publication of WO2019101144A1 publication Critical patent/WO2019101144A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • 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.
  • 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.
  • 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.
  • 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.
  • 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:
  • 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-;
  • 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;
  • 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 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;
  • n 0, 1, 2, 3, or 4.
  • 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;
  • 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-;
  • 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;
  • 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;
  • a is a single bond or a double bond, and b is 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;
  • 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;
  • 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;
  • 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;
  • R 3 When a is a double bond, R 3 does not exist, and R 2 is Wherein R 7 and R 8 are hydrogen;
  • 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;
  • R 6 is piperazinyl, and the piperazinyl is optionally substituted with C 1-6 alkyl;
  • p is 1, 2, or 3, preferably 1 or 2, more preferably 1;
  • q is 1, 2, 3, or 4, preferably 1 or 2, more preferably 2;
  • n 0, 1, or 2;
  • the present invention provides a compound of formula (II), or a pharmaceutically acceptable salt, solvate, polymorph or prodrug thereof, as described above;
  • 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-;
  • 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;
  • 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;
  • n 0, 1, 2, 3, or 4.
  • 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;
  • 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-.
  • 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-;
  • 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;
  • R 3 When a is a double bond, R 3 does not exist, and R 2 is Wherein R 7 and R 8 are hydrogen;
  • R 3 is absent, and R 2 is selected from the group consisting of H, C 1-6 alkyl, halogen and cyano;
  • 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;
  • R 6 is piperazinyl, and the piperazinyl is optionally substituted with C 1-6 alkyl;
  • p is 1, 2, or 3, preferably 1 or 2, more preferably 1;
  • p is 1, 2, 3, or 4, preferably 1 or 2, more preferably 2;
  • the compound of the invention is selected from the group consisting of
  • 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.
  • 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
  • a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein, and a pharmaceutically acceptable carrier.
  • 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.
  • the disease is cancer.
  • 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.
  • the subject matter of the invention is a mammal comprising a human.
  • 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.
  • the disease is cancer.
  • 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.
  • 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.
  • the disease is cancer.
  • 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.
  • optionally substituted alkyl means “unsubstituted alkyl” or "substituted alkyl”.
  • 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.
  • substituent 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.
  • substituent -CH 2 O- is equivalent to -OCH 2 -.
  • group 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.
  • 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.
  • halogen means bromo, chloro, fluoro or iodo.
  • aromatic means 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.
  • aromatic compound includes all carbocyclic rings (such as benzene rings) and rings containing one or more heteroatoms (such as pyridine).
  • heteroatom 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.
  • 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.
  • 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.
  • 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.
  • alkyl 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.
  • alkylene refers to a divalent group formed by the removal of one hydrogen from an alkyl group as defined above.
  • 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.
  • 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.
  • 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.
  • cycloalkyl 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.
  • heterocyclyl 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.
  • 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.
  • 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.
  • 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,
  • heteroaryl 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.
  • 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.
  • 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.
  • 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
  • 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.
  • cyano refers to the group -CN.
  • 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.
  • the olefinic double bonds contained in the compounds of the present invention include the E and Z isomers.
  • 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.
  • pharmaceutically acceptable salt 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
  • “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 isopropy
  • solvate 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.
  • 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.
  • 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.
  • composition 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.
  • 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.
  • pharmaceutically acceptable 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.
  • subject refers to an individual, including a mammal, and a non-mammal, having a disease, disorder, or condition.
  • 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.
  • non-human mammals include, but are not limited to, birds and fish, and the like.
  • the mammal is a human.
  • treating refers to the treatment of a disease or condition associated with a mammal, particularly a human, including
  • 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.
  • an "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.
  • 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.
  • administering 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • reaction vessel was fitted with a rubber septum to add substrate and reagents via a syringe; glassware was dried and / or heat dry.
  • 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.
  • 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).
  • 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
  • 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.
  • 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 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)
  • Tetrabutylammonium fluoride (2.8 g) was added to 3-(2-((tert-butyldimethylsilyl)oxy)phenyl)-3-methyl-2-((trimethyl) at room temperature
  • 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
  • Step 10 3-Methyl-3-(2-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)methoxy)phenyl)-2-( (trimethylsilyl)oxy)butyronitrile
  • Step 11 2-Hydroxy-3-methyl-3-(2-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)methoxy)phenyl) Butyric acid
  • Step 12 2-Hydroxy-3-methyl-3-(2-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)methoxy)phenyl) Methyl butyrate
  • 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 1-(2-((1-(2,2,2-Trifluoroethyl)-1H-pyrazol-5-yl)methoxy)phenyl)ethan-1-one
  • Step 4 2-Hydroxy-3-(2-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)methoxy)phenyl)but-3-ene Ethyl acetate
  • Step 3 Synthesis of ethyl 2-hydroxy-3-(2-methoxyphenyl)-3-methylbutanoate
  • Step 2 According to the synthesis method of Intermediate 7, the title compound is obtained.
  • the target compound was synthesized by referring to the synthesis methods on pages 31 and 42 of the patent WO2016/207226.
  • the target compound was synthesized by referring to the synthesis method on page 192 of Patent WO2015/97123.
  • 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
  • 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
  • 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
  • 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.
  • (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
  • Step 3 Ethyl 3-(2-((2-(2-methoxyphenyl)pyrimidin-4-yl)methoxy)phenyl)-3-methyloxirane-2-carboxylate
  • Step 4 Ethyl 2-hydroxy-3-(2-((2-(2-methoxyphenyl)pyrimidin-4-yl)methoxy)phenyl)but-3-enoate
  • Step 5 Ethyl 2-(2-(2-(2-(2-(2-(2-(2-(2-methoxyphenyl)pyrimidin-4-yl)methoxy)phenyl)cyclopropyl)acetate
  • 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
  • Step 7 (R)-2-Hydroxy-2-(1-(2-((2-(2-methoxyphenyl)pyrimidin-4-yl)methoxy)phenyl)cyclopropyl)acetic acid Ethyl ester
  • Step 4 Methyl 2-hydroxy-3-(2-((2-(2-methoxyphenyl)pyrimidin-4-yl)methoxy)phenyl)-3-methylbutanoate
  • Step 5 (R)-2-((R)-2-Methoxy-2-phenylacetoxy)-3-(2-((2-(2-methoxyphenyl)pyrimidine-4) Methyl-methoxy)phenyl)-3-methylbutanoate
  • Step 6 (R)-2-Hydroxy-3-(2-((2-(2-methoxyphenyl)pyrimidin-4-yl)methoxy)phenyl)-3-methylbutanoic acid ester
  • Step 1 2-azido-2-(1-(2-methoxyphenyl)cyclopropyl)acetate
  • Step 2 Ethyl 2-amino-2-(1-(2-methoxyphenyl)cyclopropyl)acetate
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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- ⁇
  • 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
  • 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.
  • FITC-Noxa fluorophore FITC-labeled short peptide
  • Mcl-1 macromolecular substance
  • 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).
  • 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.
  • test mixture was then incubated at 23 ° C for 30 minutes with shaking, after which 4 ⁇ L 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.
  • the detection reagent establishes a screening method for suspension cell proliferation inhibition.
  • 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 ⁇ L/well, and cultured at 37 ° C, 95% air and 5% CO 2 .
  • 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 ⁇ M.
  • the above cells were incubated at 37 ° C for 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.
  • 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.

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Abstract

本发明提供了Mcl-1选择性抑制剂及其制备和用途；本发明同时提供了一系列由通式(I)所表示的化合物及其药学上可接受的盐、溶剂化物、多晶型物或前药、包含这些化合物的药物组合物，以及用此类化合物治疗由过度表达或失调的MCL-1蛋白引起的或加重的疾病的方法。

Description

Mcl-1选择性抑制剂及其制备和用途
交叉引用
本申请要求2017年11月23日提交的专利名称为“Mcl-1选择性抑制剂及其制备和用途”的第201711189194.4号中国专利申请和2018年5月8日提交的专利名称为“Mcl-1选择性抑制剂及其制备和用途”的201810425784.0号中国专利申请的优先权，其全部公开内容通过引用整体并入本文。
技术领域
本发明涉及选择性抑制Mcl-1抗凋亡蛋白活性的化合物，还涉及这些化合物的制备方法和及其药物组合物的用途。
背景技术
细胞凋亡(Apoptosis)是由多种基因控制的细胞自主有序的死亡过程。它涉及一系列基因的激活、表达以及调控(J.Cell Mol Life Sci,2008,66(8):1326-1336).。Bcl-2家族在细胞凋亡过程中起着重要的调控作用。Mcl-1作为Bcl-2家族中抗凋亡蛋白重要的一员，在早期胚胎形成及淋巴细胞、神经细胞、纤维母细胞及肝脏干细胞的功能维持中发挥重要的作用(J.Cell D eath D iffer,2013,20(11)：1475-1484.)。经研究表明，诸多恶性肿瘤细胞都能过度表达Mcl-1蛋白(J.Cell death&disease,2010.1(5):p.e 40.)，导致抗凋亡成员与促凋亡成员之间的相互作用失衡，引发肿瘤细胞恶性增殖。近年来，在中枢神经系统肿瘤，乳腺癌，结肠癌，肺癌，卵巢癌，前列腺癌，黑色素瘤不同的细胞系中均检测出Mcl-1的基因遗传变异(J.Bioorg Med Chem,2013,21(21):6642-6649.)。Mcl-1参与肿瘤细胞的存活和耐药性的相关作用(J.Proc Natl Acad Sci USA,2007,104(49):19512-19517)。不管是单一应用Mcl-1小分子抑制剂，还是与其他抗肿瘤药物合用均呈现较好的治疗作用，为Mcl-1靶向疗法治疗肿瘤提供了新的途径。
近10年来，针对抗凋亡蛋白的小分子抑制剂不断涌现，如多酚类衍生物AT-101(J.Thorac.Oncol,2011,6(10):1757-1760)和APOG2，研究表明对多种肿瘤的治疗已取得较好疗效，目前处于Ⅱ/Ⅲ期临床研究阶段。但该化合物由于不良反应众多使其临床应用受限。已知的几种磺酰胺类蛋白抑制剂包括BH3的模拟蛋白物(ABT-737)、(ABT-263)和(ABT-199)等。但多项研究证明，Mcl-1的过度上调抑制了磺酰胺类蛋白抑制剂在多种肿瘤治疗中的活性，且ABT-263等单独应用于肿瘤治疗的效果不甚理想.(J.Clin.Oncol,2011,29(7)：909-916.)。目前，抑制过度表达的Mcl-1蛋白已成为肿瘤治疗领域 的重要研究方向，特别是Mcl-1小分子抑制剂，可有效克服肿瘤治疗耐药性问题，所以有必要继续开发新的、活性更高、耐药性强、临床副作用更小的Mcl-1抑制剂应用于临床治疗。
发明内容
本发明提供了一种Mcl-1选择性抑制剂，其为通式(I)所表示的化合物或其药学上可接受的盐、溶剂化物、多晶型物或前药。本发明同时提供了一系列由通式(I)所表示的化合物及其药学上可接受的盐、溶剂化物、多晶型物或前药、包含这些化合物的药物组合物，以及用此类化合物治疗由过度表达或失调的MCL-1蛋白引起的或加重的疾病的方法。
本发明提供了如下所述的式(I)化合物或其药学上可接受的盐、溶剂化物、多晶形物或前药：
Figure PCTCN2018117014-appb-000001
其中，
X为O、NH或S；
a和b各自独立地为单键或双键，且a和b中最多只有一个可以为双键；
R 1选自H和5-8元杂芳基，所述杂芳基可任选地被C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、C 1-6烷基-O-、或6-10元芳基取代，所述C 1-6烷基可任选地被1-3个卤素取代，并且所述6-10元芳基可任选地被1-3个独立地选自C 1-6烷基和C 1-6烷基-O-的基团取代；
当a和b均为单键时，R 2和R 3各自独立地选自H、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、卤素和氰基，或者R 2、R 3和与之相连的碳原子一起形成3-8元环烷基，R 2和R 3不能同时为氢；
当a为双键时，R 3不存在，R 2为
Figure PCTCN2018117014-appb-000002
当b为双键时，R 3不存在，R 2选自H、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、卤素和氰基；
R 4各自独立地为卤素、C 1-6烷基、C 1-6烷基-O-、或氰基；
R 5选自苯基和5-8元杂芳基，所述苯基和5-8元杂芳基任选地被1-3个选自卤素和C 1-6烷基的基团取代；
R 6选自3-8元杂环基，所述杂环基任选地被C 1-6烷基、-C 1-6亚烷基-O-P(＝O)(OH) 2、C 1-6烷基-O-取代；
R 7和R 8各自独立地选自H和C 1-6烷基；
p和q各自独立地为1、2、3、4、5和6；
m为0、1、2、3、或4。
在本发明的一些实施方案中，R 1选自H和5-8元杂芳基，所述杂芳基可任选地被C 1-6烷基、C 1-6烷基-O-、或6-10元芳基取代，所述C 1-6烷基可任选地被1-3个卤素取代，并且所述6-10元芳基可任选地被1-3个独立地选自C 1-6烷基和C 1-6烷基-O-的基团取代；
在本发明的一些实施方案中，R 1选自H和5-8元杂芳基，所述杂芳基可任选地被C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、C 1-6烷基-O-、或6-10元芳基取代，所述C 1-6烷基可任选地被1-3个卤素取代，并且所述6-10元芳基可任选地被1-3个独立地选自C 1-6烷基和C 1-6烷基-O-的基团取代；
在本发明的一些实施方案中，R 1选自H和5-8元杂芳基，所述杂芳基可任选地被C 1-6烷基、C 1-6烷基-O-、或6-10元芳基取代，所述C 1-6烷基可任选地被1-3个卤素取代，并且所述6-10元芳基可任选地被1-3个独立地选自C 1-6烷基和C 1-6烷基-O-的基团取代；
在本发明的一些实施方案中，R 1选自H、吡唑基和嘧啶基，所述吡唑基和嘧啶基可任选地被C 1-6烷基、C 1-6烷基-O-、或6-10元芳基取代，所述C 1-6烷基可任选地被1-3个卤素取代，并且所述6-10元芳基可任选地被1-3个独立地选自C 1-6烷基和C 1-6烷基-O-的基团取代；
在本发明的一些实施方案中，a为单键或双键，b为单键；
当a和b均为单键时，R 2和R 3各自独立地选自H、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、卤素和氰基，或者R 2、R 3和与之相连的碳原子一起形成3-8元环烷基，R 2和R 3不能同时为氢；
在本发明的一些实施方案中，当a和b均为单键时，R 2和R 3各自独立地选自H、C 1-6烷基、卤素和氰基，或者R 2、R 3和与之相连的碳原子一起形成3-8元环烷基，R 2和R 3 不能同时为氢；
在本发明的一些实施方案中，当a和b均为单键时，R 2和R 3各自独立地选自H、C 1-6烷基、或卤素，或者R 2、R 3和与之相连的碳原子一起形成3-8元环烷基，R 2和R 3不能同时为氢；
在本发明的一些实施方案中，当a和b均为单键时，R 2和R 3各自独立地选自H、C 1-6烷基、或卤素，或者R 2、R 3和与之相连的碳原子一起形成3-6元环烷基，R 2和R 3不能同时为氢；
当a为双键时，R 3不存在，R 2为
Figure PCTCN2018117014-appb-000003
其中R 7和R 8为氢；
在本发明的一些实施方案中，R 5选自苯基和呋喃基，所述苯基和呋喃基任选地被1-3个选自卤素和C 1-6烷基的基团取代；
在本发明的一些实施方案中，R 6为哌嗪基，所述哌嗪基任选地被C 1-6烷基取代；
在本发明的一些实施方案中，p为1、2、或3，优选为1或2，更优选为1；
在本发明的一些实施方案中，q为1、2、3、或4，优选为1或2，更优选为2；
在本发明的一些实施方案中，m为0、1、或2；
在本发明的一个优选的实施方案中，在式(I)化合物中，X为O，其结构式如下式(II)所示：
Figure PCTCN2018117014-appb-000004
本发明提供了如上所述的式(II)化合物或其药学上可接受的盐、溶剂化物、多晶形物或前药；
其中，
a和b各自独立地为单键或双键，且a和b中最多只有一个可以为双键；
R 1选自H和5-8元杂芳基，所述杂芳基可任选地被C 1-6烷基、C 2-6烯基、C 2-6炔基、 C 3-8环烷基、C 1-6烷基-O-、或6-10元芳基取代，所述C 1-6烷基可任选地被1-3个卤素取代，并且所述6-10元芳基可任选地被1-3个独立地选自C 1-6烷基和C 1-6烷基-O-的基团取代；
当a和b均为单键时，R 2和R 3各自独立地选自H、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、卤素和氰基，或者R 2、R 3和与之相连的碳原子一起形成3-8元环烷基，R 2和R 3不能同时为氢；
当a为双键时，R 3不存在，R 2为
Figure PCTCN2018117014-appb-000005
当b为双键时，R 3不存在，R 2选自H、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、卤素和氰基；
R 4各自独立地为卤素或C 1-6烷基；
R 5选自苯基和5-8元杂芳基，所述苯基和5-8元杂芳基任选地被1-3个选自卤素和C 1-6烷基的基团取代；
R 6选自3-8元杂环基，所述杂环基任选地被C 1-6烷基取代；
R 7和R 8各自独立地选自H和C 1-6烷基；
p和q各自独立地为1、2、3、4、5和6；
m为0、1、2、3、或4。
在本发明的一些实施方案中，R 1选自H和5-8元杂芳基，所述杂芳基可任选地被C 1-6烷基或6-10元芳基取代，所述C 1-6烷基可任选地被1-3个卤素取代，所述6-10元芳基可任选地被1-3个独立地选自C 1-6烷基和C 1-6烷基-O-的基团取代；
优选地，R 1选自H、吡唑基和嘧啶基；所述吡唑基和嘧啶基可任选地被C 1-6烷基、C 1-6烷基-O-、或者6-10元芳基取代，所述C 1-6烷基可任选地被1-3个卤素取代，并且所述6-10元芳基可任选地被1-3个独立地选自C 1-6烷基和C 1-6烷基-O-的基团取代。
在本发明的一些实施方案中，R 1选自H、吡唑基、嘧啶基，所述吡唑基可任选地被C 1-6烷基取代，所述C 1-6烷基可任选地被1-3个卤素取代，所述嘧啶基可任选地被6-10元芳基取代，所述6-10元芳基可任选地被1-3个独立地选自C 1-6烷基和C 1-6烷基-O-的基团取代；
在本发明的一些实施方案中，当a和b均为单键时，R 2和R 3各自独立地选自H、C 1-6烷基、卤素和氰基，或者R 2、R 3和与之相连的碳原子一起形成3-8元环烷基，R 2和R 3不能同时为氢；
当a为双键时，R 3不存在，R 2为
Figure PCTCN2018117014-appb-000006
其中R 7和R 8为氢；
当b为双键时，R 3不存在，R 2选自H、C 1-6烷基、卤素和氰基；
在本发明的一些实施方案中，R 5选自苯基和呋喃基，所述苯基和呋喃基任选地被1-3个选自卤素和C 1-6烷基的基团取代；
在本发明的一些实施方案中，R 6为哌嗪基，所述哌嗪基任选地被C 1-6烷基取代；
在本发明的一些实施方案中，p为1、2、或3，优选为1或2，更优选为1；
在本发明的一些实施方案中，p为1、2、3、或4，优选为1或2，更优选为2；
在本发明的一些实施方案中，本发明化合物选自：
Figure PCTCN2018117014-appb-000007
或其药学上可接受的盐、溶剂化物、异构体、或前药。
本发明同时提供了一系列由通式(I)所表示的化合物及其药学上可接受的盐、溶剂化物、多晶型物或前药、包含这些化合物的药物组合物，以及用此类化合物治疗由过度表达或失调的MCL-1蛋白引起的或加重的疾病的方法。
本发明化合物可以用于治疗治疗由过度表达或失调的MCL-1蛋白引起的或加重的疾病；在一些实施方式中，所述疾病为癌症。在一些实施方式中，所述疾病为对化疗或放疗具有抗性的癌症；在一些实施方式中，所述癌症选自：膀胱癌、脑癌、乳腺癌和子宫癌、慢性淋巴性白血病、结肠癌、食道癌和肝癌、成淋巴细胞白血病、急性髓性白血病、淋巴 瘤、卵巢癌、或非小细胞肺癌。
本发明另一方面还涉及药物组合物，其包含本发明所定义的式(I)化合物或其药学上可接受的盐和药学上可接受的载体。
在另一方面，本发明提供了治疗由过度表达或失调的MCL-1蛋白引起的或加重的疾病的方法，其包括给所需对象施用有效量的式(I)化合物或其药学上可接受的盐、溶剂化物、多晶型物、异构体或前药或上述组合物。在一些实施方式中，所述疾病为癌症。在一些实施方式中，所述疾病为对化疗或放疗具有抗性的癌症；在一些实施方式中，所述癌症选自：膀胱癌、脑癌、乳腺癌和子宫癌、慢性淋巴性白血病、结肠癌、食道癌和肝癌、成淋巴细胞白血病、急性髓性白血病、淋巴瘤、卵巢癌、或非小细胞肺癌。
在本发明的一些实施方式中，本发明涉及的所述对象为包括人类的哺乳动物。
在另一方面，本发明提供了式(I)化合物或其药学上可接受的盐、溶剂化物、多晶型物、异构体或前药在制备用于治疗由过度表达或失调的MCL-1蛋白引起的或加重的疾病的药物中的用途。在一些实施方式中，所述疾病为癌症。在一些实施方式中，所述疾病为对化疗或放疗具有抗性的癌症；在一些实施方式中，所述癌症选自：膀胱癌、脑癌、乳腺癌和子宫癌、慢性淋巴性白血病、结肠癌、食道癌和肝癌、成淋巴细胞白血病、急性髓性白血病、淋巴瘤、卵巢癌、非小细胞肺癌、多发性骨髓瘤、急性淋巴白血病、或骨髓增生异常综合征。
在另一方面，本发明提供了式(I)化合物或其药学上可接受的盐、溶剂化物、多晶型物、异构体或前药在制备用于治疗由过度表达或失调的MCL-1蛋白引起的或加重的疾病的药物中的用途。在一些实施方式中，所述疾病为癌症。在一些实施方式中，所述疾病为对化疗或放疗具有抗性的癌症；在一些实施方式中，所述癌症选自：膀胱癌、脑癌、乳腺癌和子宫癌、慢性淋巴性白血病、结肠癌、食道癌和肝癌、成淋巴细胞白血病、急性髓性白血病、淋巴瘤、卵巢癌、或非小细胞肺癌。
发明详述
在下文的发明详述中陈述了利用本发明原理的示例性实施方式。通过参考以下发明内容可更好地理解本发明的特征和优点。
应理解本发明各个方面的保护范围由权利要求书决定，并且这些权利要求范围内的方法和结构以及其等价的方法和结构均在本权利要求书涵盖的范围之内。
除非另有定义，否则本文所有科技术语具有的涵义与权利要求主题所属领域技术人员通常理解的涵义相同。除非另有说明，本文全文引用的所有专利、专利申请、公开材料通 过引用方式整体并入本文。
应理解，上述简述和下文的详述都是示例性的、解释性的，而不是对任何本发明主题的限制。除非另有具体说明，否则使用单数形式时也包括复数。除非另有说明，否则所用“或”、“或者”表示“和/或”。此外，所用术语“包括”以及其它形式，例如“包含”、“含”和“含有”并非限制性。
某些化学术语
术语“任选”、“任选的”或“任选地”是指随后描述的事件或情况可能发生也可能不发生，该描述包括发生所述事件或情况和不发生所述事件或情况。例如，“任选取代的烷基”表示“未取代的烷基”或“取代的烷基”。并且，任选取代的基团可以是未取代的(例如：-CH 2CH 3)、完全取代的(例如：-CF 2CF 3)、单取代的(例如：-CH 2CH 2F)或者介于单取代和完全取代之间的任意层级(例如：-CH 2CHF 2、-CF 2CH 3、-CFHCHF 2等)。本领域技术人员可理解，对于包含一个或多个取代基的任何基团，不会引入任何在空间上不可能存在和/或不能合成的取代或取代模式。
除非另有说明，否则采用本领域技术范围内的常规方法，如质谱、核磁、高效液相色谱、红外和紫外/可见光谱法和药理学方法。除非提出具体定义，否则本文在分析化学、有机合成化学以及药物和医药化学的有关术语以及实验步骤和技术是本领域已知的。可在化学合成、化学分析、药物制备、制剂和递送、以及对患者的治疗中使用标准技术。例如，可利用厂商对试剂盒的使用说明，或者按照本领域公知的方式或本发明的说明来实施反应和进行纯化。通常可根据本说明书中引用和讨论的多个概要性和较具体的文献中的描述，按照本领域熟知的常规方法实施上述技术和方法。在本说明书中，可由本领域技术人员选择基团及其取代基以提供稳定的结构部分和化合物。
当通过从左向右书写的常规化学式描述取代基时，该取代基也同样包括从右向左书写结构式时所得到的在化学上等同的取代基。举例而言，-CH 2O-等同于-OCH 2-。
本文所用术语“基团”、“化学基团”是指分子的一个特定的部分或官能团。化学基团经常被认作为嵌入或附加到一个分子中的化学实体。
一些在此命名的化学基团可以用简略记号表示碳原子的总个数。例如，C 1-C 6烷基描述了一个烷基团，如下定义的那样，具有总共1到6个碳原子。简略记号所示碳原子总个数不包括可能的取代基上的碳原子。
术语“卤素”、“卤代”或“卤化物”是指溴、氯、氟或碘。
本文使用的术语“芳香”、“芳香环”、“芳香的”、“芳香性的”、“芳香环的”是指平面的 一个环或多个环的环部分，其具有含4n+2个电子的离域化电子共扼体系，其中n为整数。芳环可由5、6、7、8、9或9个以上的原子形成。芳族化合物可被任选地取代，并可为单环或稠合环的多环。术语芳族化合物包括所有碳环(如苯环)和含一个或多个杂原子的环(如吡啶)。
本文单独或作为其它成分的一部分使用的术语“杂原子”或“杂”是指除碳和氢之外的原子。杂原子独立地选自氧、氮、硫、磷、硅、硒和锡，但不限于这些原子。在出现两个或更多杂原子的实施方案中，所述两个或更多杂原子可彼此相同，或者所述两个或更多杂原子中的一些或全部彼此不同。
本文单独或组合使用的术语“稠”或“稠环”是指两个或更多个环共享一个或更多个键的环状结构。
本文单独或组合使用的术语“螺”或“螺环”是指两个或更多个环共享一个或更多个原子的环状结构。
本文单独或作为其它组分的一部分(比如：单烷基氨基)使用的术语“烷基”是指任选取代的直链或任选取代的支链的一价饱和烃，其具有1-12个碳原子，优选1-8个碳原子，更优选1-6个碳原子，通过单键与分子的其它部分相连，例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、正己基、正庚基、2-甲基己基、3甲基己基、正辛基，正壬基、正癸基等。
术语“亚烷基”是指由以上所定义的烷基去掉一个氢形成的二价基团。
术语“烯基”是指一类烷基，其中烷基的起始的两个原子形成双键，该双键不是芳香基的组成部分。也就是说，烯基始于–C(R)＝C(R)-R，其中R是指烯基的其余部分，各R可以相同或不同。烯基可以具有2-10个碳原子。烯基也可以是具有2-6个碳原子的“低级烯基”。
术语“炔基”是指一类烷基，其中烷基的起始的两个原子形成三键。也就是说，炔基始于原子-C≡C-R，其中R是指炔基其余部分。炔基部分中的“R”部分可以是支链、直链或环状的。炔基可以具有2-10个碳原子。炔基也可以是具有2-6个碳原子的“低级烷基”。
本文单独或作为其它成分的一部分使用的术语“环烷基”是指稳定的单价非芳香单环或多环碳氢基团，只包含碳原子和氢原子，可能包括稠环、螺环或桥环系统，包含3-15个成环碳原子，优选包含3-10个成环碳原子，更优选包含3-8个成环碳原子，可饱和也可不饱和，通过单键与分子的其它部分相连。“环烷基”的非限制性实例包括但不限于环丙基、环丁基、环戊基、环己基和环庚基等。
本文单独或作为其它成分的一部分使用的术语“杂环基”、“杂环烷基”、“杂环”是指稳定的3-18元单价非芳香环，包括2-12个碳原子，1-6个选自氮、氧和硫的杂原子。除非另作说明，杂环基团可以是单环、双环、三环或四环系统，其可能包含稠环、螺环或桥环系统，杂环基上的氮、碳或硫可选择性的被氧化，氮原子可选择性的被季铵化，杂环基可以部分或完全饱和。杂环基可以通过环上的碳原子或杂原子与分子的其余部分通过一个单键连接。包含稠环的杂环基中可以包含一个或多个芳环或杂芳环，只要与分子的其余部分连接的是非芳香环上的原子。为了本申请，杂环基优选的是一个稳定的4-11元单价非芳香单环或二环，其包含1-3个选自氮、氧和硫的杂原子，更优选的是一个稳定的4-8元单价非芳香单环，其包含1-3个选自氮、氧和硫的杂原子。杂环基的的非限制性实例包括氮杂环庚烷基、氮杂环丁基、十氢异喹啉基、二氢呋喃基、二氢吲哚基、二氧戊烷基、1,1-二氧-硫代吗啉基、咪唑烷基、咪唑啉基、异噻唑烷基、异恶唑烷基、吗啉基、八氢吲哚基、八氢异吲哚基、恶嗪基、恶唑烷基、1-氧-硫代吗啉基、2-氧哌嗪基、2-氧哌啶基、2-氧吡咯烷基、苯二酰亚氨基、哌嗪基、哌啶基、4-哌啶酮基、吡喃基、吡唑烷基、吡咯烷基、喹嗪基、奎宁环基、四氢呋喃基、四氢异喹啉基、四氢吡喃基、噻唑烷基、噻吩[1,3]二噻烷基、硫代吗啉基、三噻烷基等。
本文单独或作为其它成分的一部分使用的术语“杂芳基”是指5-16元环状系统，其包含1-15个碳原子，优选的1-10个碳原子，1-4个选自氮、氧和硫的杂原子，至少一个芳香环。除非另作说明，杂芳基可以是单环、双环、三环或四环系统，其可能包含稠环或桥环系统，只要与分子其它部分的连接点为芳环原子。杂芳环上的氮原子、碳原子和硫原子可以选择性的被氧化，氮原子可选择性的被季铵化。为了本发明，杂芳基优选的为稳定的4-11元单芳香环，其包含1-3个选自选自氮、氧和硫的杂原子，更优选的为稳定的5-8元单芳香环，其包含1-3个选自选自氮、氧和硫的杂原子。杂芳基的非限定性实例包括吖啶基、氮杂卓基、苯并咪唑基、苯并吲哚基、1,4-苯并二氧六环基、苯并[6][1,4]二氧杂环庚基、苯并二氧芑基、苯并二噁茂基、苯并呋喃酮基、苯并呋喃基、苯并[4,6]咪唑并[1,2-a]吡啶基、苯并萘并呋喃基、苯并吡喃酮基、苯并吡喃基、苯并吡唑基、苯并噻二唑基、苯并噻唑基、苯并噻吩基、苯并三唑基、苯并恶唑基、咔唑基、卡啉基、邻二氮萘基、二苯并呋喃基、二苯并噻吩基、呋喃酮基、呋喃基、咪唑基、吲唑基、二氢吲哚基、吲嗪基、吲哚基、异吲唑基、异二氢吲哚基、异吲哚基、异喹啉基、异噻唑基、异恶唑基、萘啶基、恶二唑基、恶三唑基、恶唑基、1-氧代吡嗪基、1-氧代哒嗪基、1-氧代吡啶基、1-氧代嘧啶基、环氧乙烷基、2-氧氮杂卓基、氧代吡啶基、菲啶基、菲咯啉基、吩嗪基、吩噻 嗪基、吩恶嗪基、1-苯基-1H-吡咯基、二氮杂萘基、喋啶基、嘌呤基、吡嗪基、吡唑基、哒嗪基、1H-吡啶-2-基、1H-吡啶-4-基、1H-吡啶-2-酮-4-基、吡啶基、嘧啶基、吡咯基、喹唑啉基、喹啉基、喹恶啉基、奎宁基、四氢喹啉基、4,5,6,7-四氢苯并[b]噻吩基、四唑基、噻二唑基、噻唑基、噻吩基、三嗪基、三唑基等。本申请中，杂芳基优选为5-8元杂芳基，其包含1-3个选自选自氮、氧和硫的杂原子，更优选为吡啶基、嘧啶基、噻唑基、氧代吡啶基、1H-吡啶-2-酮-4-基或噻吩基。
术语“氰基”是指基团-CN。
本发明使用的术语“多晶型物”或“多晶型(现象)”是指本发明的化合物具有多种晶格形态。本发明的一些化合物可能有一个以上的晶体形式，本发明涵盖所有的多晶型态或其混合物。
本发明化合物的中间体化合物及其多晶形物也在本发明的范围内。
除非另有指定，本发明化合物所含有的烯烃双键包括E和Z异构体。
应理解，本发明化合物可能含有不对称中心。这些不对称中心可以独立的为R或S构型。一些本发明化合物也可显示出顺-反异构现象，这对于本领域技术人员而言是显而易见的。应理解，本发明化合物包括它们的单独的几何异构体和立体异构体以及它们的混合物，包括外消旋混合物。通过实施或修改已知方法，例如层析技术和重结晶技术可以从它们的混合物中分离这些异构体，或者可以由它们的中间体的合适的异构体分别制备它们。
本文所用术语“药学上可接受的盐”既包括加酸盐，也包括加碱盐。
“药学上可接受的加酸盐”是指那些保留了化合物的游离碱的生物效力和特性、在生物学上或其它方面并非不合需要、跟无机酸，例如但是不限于，氢氯酸、氢溴酸、硫酸、硝酸、磷酸等，或有机酸，例如但不限于，乙酸、2,2-二氯乙酸、己二酸、海藻酸、抗坏血酸、天冬氨酸、苯磺酸、苯甲酸、4-乙酰氨基苯甲酸、樟脑酸、樟脑-10-磺酸、癸酸、己酸、辛酸、碳酸、肉桂酸、柠檬酸、环拉酸、十二烷基硫酸、乙烷-1，2-二磺酸、乙基磺酸、2-羟基乙二酸、蚁酸、富马酸、半乳糖二酸、龙胆酸、葡庚糖酸、葡萄糖酸、葡萄糖醛酸、谷氨酸、戊二酸、2-氧代-戊二酸、甘油磷酸酯乙醇酸，马尿酸、异丁酸、乳酸、乳糖酸、月桂酸、顺丁烯二酸、苹果酸、丙二酸、扁桃酸、甲基磺酸、黏酸、萘-1，5-萘二磺酸、萘-2-磺酸、1-羟基-2-萘甲酸、烟酸、油酸、乳清酸、草酸、棕榈酸、帕莫酸、丙酸、焦谷氨酸、丙酮酸、水杨酸、4-氨基水杨酸、癸二酸、硬脂酸、丁二酸酒石酸，硫氰酸，对甲苯磺酸、三氟乙酸，十一烯酸等形成的盐。“药学上可接受的加碱盐”是指那些 保留了化合物的游离酸的生物效力和特性、在生物学上或其它方面并非不合需要的盐。这些盐通过游离酸跟无机碱或有机碱反应制备。通过跟无机碱反应生成的盐包括，但不限于，钠盐、钾盐、锂盐、铵盐、钙盐、镁盐、铁盐、锌盐、铜盐、锰盐、铝盐等。优选的无机盐为铵盐、钠盐、钾盐、钙盐、和锰盐。
形成盐的有机碱包括，但不限于，伯胺、仲胺、叔胺、取代胺(包括自然界发生的取代的胺)、环胺和基本的离子交换树脂，例如氨、异丙胺、三甲胺、二乙胺、三乙胺、三丙胺、二乙醇胺、乙醇胺、二甲胺乙醇、2-二甲基乙醇胺、2-二乙氨基乙醇、二环己胺、赖氨酸、精氨酸、组氨酸、咖啡因、普鲁卡因、海巴明青霉素、胆碱、甜菜碱、苯乙苄胺、苄星青霉素、乙二胺、氨基葡萄糖、葡甲胺、可可碱、三乙醇胺、氨丁三醇、嘌呤、哌嗪、哌啶，N-乙基哌啶、多胺树脂等。特别优选的有机碱为异丙胺、二乙胺、乙醇胺、三甲胺、二环己胺、胆碱和咖啡因
结晶经常产生本发明化合物的溶剂化物。本文所用术语“溶剂化物”是指由一个或多个本发明化合物分子和一个或多个溶剂分子组合而成的合体。
溶剂可以是水，这种情况下，溶剂化物是水合物。另外还可以是有机溶剂。因此，本发明化合物可作为水合物存在，包括一水合物、二水合物、半水合物、三水合物、四水合物等，以及相应的溶剂化形态。本发明化合物可以是真溶剂化物，但在其它一些情况下，本发明化合物也可能只是偶然保留了水或水跟一些其它溶剂的混合物。本发明化合物可在一种溶剂中反应或在一种溶剂中沉淀或结晶。本发明化合物的溶剂化物也包括在本发明的范围内。
本发明也考虑本发明化合物的前药。“前药”是指一个化合物可以在生理学状态下或溶剂化作用下被转化成具有生物活性作用的本发明化合物。因此，术语“前药”指本发明化合物药学上可接受的代谢前体，前药在给所需主体施用时可能是没有活性的，但是会在体内转化成有活性的本发明化合物。前药通常在体内，例如，通过在血液中水解，迅速转化成本发明的母化合物。前药经常在溶解性、组织兼容性、或在哺乳动物有机体内的延释方面具有优势。前药包括氨基保护基团和羧基保护基团，这些保护基团均为本领域人员所熟知的。用来制备具体前药的方法可参考，例如，Saulnier,M.G.,et al.,Bioorg.Med.Chem.Lett.1994,4,1985-1990；Greenwald,R.B.,et al.,J.Med.Chem.2000,43,475。
本文所用术语“药物组合物”是指混合有本发明化合物和通常在本领域被接受的用来将具有生物活性的化合物传送给哺乳动物(比如人类)的介质的制剂。这种介质包含所有药学上可接受的载体。
本文所用的跟制剂、组合物或成分相关的术语“可接受的”是指对治疗主体的总体健康没有持续的有害影响。
本文所用术语“药学上可接受的”是指不影响本发明化合物的生物活性或性质的物质(如载体或稀释剂)，并且相对无毒，即该物质可施用于个体而不造成不良的生物反应或以不良方式与组合物中包含的任意组分相互作用。
“药学上可接受的载体”包括但不限于已经被相关政府行政部门批准的可以被用于人类和驯养动物的佐剂、载体、赋形剂、助剂、脱臭剂、稀释剂、保鲜剂、染料/着色剂、风味增强剂、表面活性剂和润湿剂、分散剂、悬浮剂、稳定剂、等渗剂、溶剂、或乳化剂。
本文所用术语“主体”、“患者”或“个体”是指患有疾病、紊乱或病症等的个体，包括哺乳动物和非哺乳动物。哺乳动物的实例包括但不限于哺乳动物纲的任何成员：人，非人的灵长类动物(例如黑猩猩和其它猿类和猴)；家畜，例如牛、马、绵羊、山羊、猪；家养动物，例如兔、狗和猫；实验室动物，包括啮齿类动物，例如大鼠、小鼠和豚鼠等。非人哺乳动物的实例包括但不限于鸟类和鱼类等。在本文提供的一个有关方法和组合物的实施方案中，所述哺乳动物为人。
本文所用术语“治疗”是指对哺乳动物特别是人类的相关疾病或病症的治疗，包括
(i)预防哺乳动物，特别是之前已经暴漏在某个疾病或病症下但尚未被诊断患有该疾病或病症的哺乳动物，产生相应的疾病或病症；
(ii)抑制疾病或病症，即控制其发展；
(iii)缓解疾病或病症，即使疾病或病症消退；
(iv)缓解疾病或病症引起的症状。
本文所用术语“疾病”和“病症”可以互相替代，也可以是不同意思，因为某些特定疾病或病症还没有已知的致病因子(所以发病原因尚不清楚)，所以还不能被认作疾病而只能被看做不想要的状况或综合症，所述综合症或多或少有一些具体症状已经被临床研究人员证实。
本文所使用术语“有效量”、“治疗有效量”或“药学有效量”是指服用后足以在某种程度上缓解所治疗的疾病或病症的一个或多个症状的至少一种药剂或化合物的量。其结果可以为迹象、症状或病因的消减和/或缓解，或生物系统的任何其它所需变化。例如，用于治疗的“有效量”是在临床上提供显著的病症缓解效果所需的包含本文公开化合物的组合物的量。可使用诸如剂量递增试验的技术测定适合于任意个体病例中的有效量。
本文所用术语“服用”、“施用”、“给药”等是指能够将化合物或组合物递送到进行生物 作用的所需位点的方法。这些方法包括但不限于口服途径、经十二指肠途径、胃肠外注射(包括静脉内、皮下、腹膜内、肌内、动脉内注射或输注)、局部给药和经直肠给药。在优选的实施方案中，本文讨论的化合物和组合物通过口服施用。
通常，本发明的化合物，或者其药学上可接受的盐，可通过与药学上可接受的一个或多个载体形成适当的药物组合物来施用。本发明的药物组合物可以形成固体、半固体、液体或气体形态的制备物，比如片剂、胶囊、粉末、颗粒剂、软膏、溶液、栓剂、注射剂、吸入剂、凝胶、微球和气溶胶。
本发明的药物组合物可以通过使用在药物学上熟知的方法来制备。例如，施用方式为注射的药物组合物可以通过将本发明化合物跟无菌、蒸馏水结合来形成溶液的方式来制备。可以加入表面活性剂来帮助形成均相溶液或悬浮液。对于熟悉本领域技术的人员来说，制备这些剂型的实际方法是已知的或显而易见的。
典型的施用这些药物组合物的路径包括，但不限于，口服、外用、透皮吸收、吸入、肠外、舌下、直肠、阴道和鼻内。例如，用来口服的合适的剂量形式包括胶囊、片剂、颗粒剂和糖浆。这些剂量形式所包括的的本发明化合物可以是固体粉末或颗粒；在水溶剂或非水溶剂中的溶液或悬浊液；水中油滴型、油中滴水型乳剂等。以上提到的剂量形式可以从活性化合物和一个或多个载体或助剂通过常用药学方法制备。载体应该与活性化合物或其它助剂兼容。对于固体制剂来说，通常使用的非毒性载体包括，但不限于，甘露醇、乳糖、淀粉、硬脂酸镁、纤维素、葡萄糖、蔗糖等。液体制剂载体包括，但不限于，水、生理盐水、葡萄糖、乙二醇、聚乙二醇水溶液等。活性化合物可以与以上载体形成一个溶液或一个悬浊液。具体的施用路径和剂量形式要根据化合物自身的物理/化学特性以及要治疗的疾病的严重程度，并且可被本领域技术人员按常规来决定。
具体实施方式
本发明化合物的制备
以下反应路线式显示了制备本发明化合物的方法。
应了解，以下描述中，只有在形成稳定化合物的情况下才允许取代基团和/或所述分子式的变量进行组合。
本领域的技术人员也应了解，在以下所述流程中，中间体化合物的官能团可能需要被合适的保护基团保护。这些官能团包括羟基、氨基、巯基和羧基。合适的羟基保护基团包括三烷基硅基或二芳基烷基硅基(例如叔丁基甲基硅基、叔丁基二苯基硅基或三甲基硅基)、四氢吡喃基、苄基等。合适的氨基、脒基和胍保护基团包括叔丁氧羰基、苄氧羰基 等。巯基的合适保护基团包括-C(O)-R"(R"表示烷基、芳基或芳基烷基)、对甲氧基苄基、三苯甲基等。合适的羧基保护基团包括烷基、芳基或芳基烷基酯。保护基团可以通过本领域技术人员知道的标准技术方法加上或去掉。
实施例
下述非限制性实施例仅仅是说明性的，不以任何方式限制本发明。
除非另有说明，温度是摄氏温度。试剂购自国药集团化学试剂北京有限公司，阿法埃莎(Alfa Aesar)，或北京百灵威科技有限公司等商业供应商，并且这些试剂可直接使用无需进一步纯化，除非另有说明。
除非另有说明，下列反应在室温、无水溶剂中、氮气或氩气的正压下或使用干燥管进行；反应瓶上装有橡胶隔膜，以便通过注射器加入底物和试剂；玻璃器皿烘干和/或加热干燥。
除非另有说明，柱色谱纯化使用青岛海洋化工厂的200-300目硅胶；制备薄层色谱使用烟台市化学工业研究所生产的薄层色谱硅胶预制板(HSGF254)；MS的测定用Thermo LCQ Fleet型(ESI)液相色谱-质谱联用仪；旋光测定使用SGW-3自动旋光仪,上海申光仪器仪表有限公司。
核磁数据( 1H NMR)使用Varian设备于400MHz运行。核磁数据使用的溶剂有CDCl 3、CD 3OD、D 2O、DMSO-d6等，以四甲基硅烷(0.00ppm)为基准或以残留溶剂为基准(CDCl 3:7.26ppm；CD 3OD:3.31ppm；D 2O:4.79ppm；d6-DMSO:2.50ppm)。当标明峰形多样性时，以下简写表示不同峰形：s(单峰)、d(双重峰)、t(三重峰)、q(四重峰)、m(多重峰)、br(宽峰)、dd(双双重峰)、dt(双三重峰)。如果给出了耦合常数，则以Hertz(Hz)为单位。
缩略语：
TBSCl 叔丁基二甲基氯硅烷
NaBH 4 硼氢化钠
TBAF 四丁基氟化铵
PPh 3 三苯基膦
Pd(dppf)Cl 2 1,1'-双二苯基膦二茂铁二氯化钯
TMSCN 三甲基氰硅烷
TEA 三乙胺
CBr 4 四溴化碳
DMF N,N-二甲基甲酰胺
DMSO 二甲基亚砜
DIBAL-H 二异丁基氢化铝
NaOAc 乙酸钠
Et 2O 乙醚
Toluene 甲苯
LDA 二异丙基氨基锂
TFAA 三氟乙酸酐
H 2SO4 硫酸
K 2CO 3 碳酸钾
N-Acetylglycine N-乙酰甘氨酸
CH 3I 碘甲烷
NaOEt 乙醇钠
rt 室温
DIAD 偶氮二甲酸二异丙酯
TEA 三乙胺
MsCl 甲磺酰氯
LAH 四氢铝锂
Pd(PPh 3) 4 四三苯基膦钯
Cs 2CO 3 碳酸铯
dioxane 1,4-二氧六环
KOH 氢氧化钾
NaH 氢化钠
中间体1：2-羟基-3-甲基-3-(2-((1-(2,2,2-三氟乙基)-1H-吡唑-5-基)甲氧基)苯基)丁酸甲酯的合成
Figure PCTCN2018117014-appb-000008
步骤1：2-((叔丁基二甲基硅烷基)氧基)苯甲醛
室温下，将咪唑(36.7g)加入到水杨醛(24.4g)和叔丁基二甲基氯硅烷(36.2g)的DMF(300mL)溶液中，室温搅拌2小时，倒入500mL水中，用300mL乙酸乙酯萃取两次，有机相用饱和食盐水洗涤，无水硫酸钠干燥，减压蒸干得粗产品47.2g，无需纯化，直接用于下一步反应。
步骤2：2-((叔丁基二甲基硅烷基)氧基)苯甲醇
将上一步所得的粗品2-((叔丁基二甲基硅烷基)氧基)苯甲醛溶于300mL甲醇中，0℃下，缓慢加入硼氢化钠(7.6g)，加完后升至室温，并于室温下搅拌30分钟，将反应液倒入(400mL)饱和氯化铵水溶液中，乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，减压蒸干得粗产品47.6g，无需纯化，直接用于下一步反应。
步骤3：2-((叔丁基二甲基硅烷基)氧基)苄溴
将上一步所得的粗品2-((叔丁基二甲基硅烷基)氧基)苯甲醇溶于500mL二氯甲烷中，室温下依次加入三苯基膦(62.8g)和四溴化碳(79.6g)，室温搅拌1小时，减压蒸干溶剂，残余物用硅胶柱色谱法(洗脱液：石油醚:乙酸乙酯＝50:1(V:V))纯化得标题化合物(59.0g)。
步骤4：2-((叔丁基二甲基硅烷基)氧基)苯乙腈
室温下，将2-((叔丁基二甲基硅烷基)氧基)苄溴溶于500mL乙腈中，加入三甲基氰硅烷(29.1g)和碳酸钾(54.2g)，加热至60℃搅拌过夜，反应液倒入水中，乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，硅胶柱色谱法(洗脱液：石油醚:乙酸乙酯＝30:1(V:V))纯化得标题化合物(30.2g)。
步骤5：2-(2-((叔丁基二甲基硅烷基)氧基)苯基)-2-甲基丙腈
-78℃下，将二异丙基胺基锂的四氢呋喃溶液(1M，300mL)滴加到2-((叔丁基二甲基硅烷基)氧基)苯乙腈(25g)的四氢呋喃(300mL)溶液中，搅拌30分钟，继续保持-78℃，向溶液中滴加碘甲烷(42.6g)，搅拌30分钟，然后升至室温。将反应液倒入饱和氯化铵水溶液(500mL)中，乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，用硅胶柱色谱法(洗脱液：石油醚:乙酸乙酯＝30:1(V:V))纯化得标题化合物(25.4g)。
步骤6：2-(2-((叔丁基二甲基硅烷基)氧基)苯基)-2-甲基丙醛
-78℃下，将二异丁基氢化铝的甲苯溶液(1M，300mL)滴加到2-(2-((叔丁基二甲基硅烷基)氧基)苯基)-2-甲基丙腈(25.0g)的四氢呋喃(300mL)溶液中，搅拌30分钟，然后升至室温，将反应液倒入饱和氯化铵水溶液(500mL)中，乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，用硅胶柱色谱法(洗脱液：石油醚:乙酸乙酯＝50:1(V:V))纯化得标题化合物(22.1g)。
步骤7：3-(2-((叔丁基二甲基硅烷基)氧基)苯基)-3-甲基-2-((三甲基甲硅烷基)氧基)丁腈
室温下，将三甲基氰硅烷(15.9g)和三乙胺(16.2g)分别加入到2-(2-((叔丁基二甲基硅烷基)氧基)苯基)-2-甲基丙醛(22g)的乙腈(300mL)溶液中，室温搅拌1小时，反应液倒入水中，乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，用硅胶柱色谱法(洗脱液：石油醚:乙酸乙酯＝30:1(V:V))纯化得标题化合物(21.2g)。
步骤8：2-羟基-3-(2-羟基苯基)-3-甲基丁腈
室温下，将四丁基氟化铵(2.8g)加入到3-(2-((叔丁基二甲基硅烷基)氧基)苯基)-3-甲基-2-((三甲基甲硅烷基)氧基)丁腈(2g)的二氯甲烷(200mL)溶液中，室温搅拌5分钟，将反应液倒入饱和氯化铵水溶液(200mL)中，乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，用硅胶柱色谱法(洗脱液：石油醚:乙酸乙酯＝10:1(V:V))纯化得标题化合物(0.63g)。
步骤9：2-甲基-2-(2-((1-(2,2,2-三氟乙基)-1H-吡唑-5-基)甲氧基)苯基)丙醛
室温下，将(1-(2,2,2-三氟乙基)-1H-吡唑-5-基)甲磺酸甲酯(1.35g)和碳酸钾(0.97g)分别加入到2-羟基-3-(2-羟基苯基)-3-甲基丁腈(0.63g)的DMF(20mL)溶液中，加热至60℃搅拌过夜。冷却到室温后将反应液倒入水中，乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，用硅胶柱色谱法(洗脱液：石油醚:乙酸乙酯＝5:1(V:V))纯化得标题化合物(0.30g)。
步骤10：3-甲基-3-(2-((1-(2,2,2-三氟乙基)-1H-吡唑-5-基)甲氧基)苯基)-2-((三甲基甲硅烷基)氧基)丁腈
按照中间体1步骤7的方法实施制得标题化合物(0.30g)。
步骤11：2-羟基-3-甲基-3-(2-((1-(2,2,2-三氟乙基)-1H-吡唑-5-基)甲氧基)苯基)丁酸
室温下，3-甲基-3-(2-((1-(2,2,2-三氟乙基)-1H-吡唑-5-基)甲氧基)苯基)-2-((三甲基甲硅烷基)氧基)丁腈(0.30g)溶于30mL浓盐酸中，加热至110℃，搅拌6小时，冷却至室温后将反应液倒入水中，乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，减压蒸干得标题化合物粗产品(0.30g)无需纯化，直接用于下一步反应。
步骤12：2-羟基-3-甲基-3-(2-((1-(2,2,2-三氟乙基)-1H-吡唑-5-基)甲氧基)苯基)丁酸甲酯
室温下，将3mL浓硫酸加入到2-羟基-3-甲基-3-(2-((1-(2,2,2-三氟乙基)-1H-吡唑-5-基)甲氧基)苯基)丁酸(0.30g)的甲醇(50mL)溶液中，加热至60℃，搅拌2小时，冷却后反应液倒入水中，乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，用硅胶柱色谱法(洗脱液：石油醚:乙酸乙酯＝4:1(V:V))纯化得标题化合物(0.23g)。
1H NMR(400MHz,CDCl3)δ7.61(d,J＝1.6Hz,1H),7.23-7.28(m,2H),6.87-7.01(m,2H),6.46(d,J＝2.0Hz,1H),5.16(s,2H),4.82-4.88(m,3H),3.50(s,3H),2.78(d,J＝7.6Hz,1H),1.41(s,3H),1.35(s,3H)。
中间体2：2-羟基-2-(1-(2-甲氧基苯基)环丙基)乙酸乙酯的合成
Figure PCTCN2018117014-appb-000009
步骤1：(Z)-4-(2-甲氧基亚苄基)-2-甲基恶唑-5(4H)-酮
将N-乙酰甘氨酸(19.6g)和乙酸钠(22.9g)分别加入到2-甲氧基苯甲醛(13.6g)的乙酸酐(300mL)溶液中，加热至130℃搅拌2小时，冷却到室温后倒入冰水中，过滤并用水洗涤 得标题化合物粗品，无须纯化直接用于下一步反应。
步骤2：2-甲氧基苯丙酮酸
将上一步的(Z)-4-(2-甲氧基亚苄基)-2-甲基恶唑-5(4H)-酮粗品全部加入到400mL盐酸(4M)溶液中，加热至110℃，搅拌2小时，冷却到室温后反应液倒入水中，乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，减压蒸干得标题化合物粗产品(20.0g)，无需纯化，直接用于下一步反应。
步骤3：2-(1-(2-甲氧基苯基)环丙基)-2-氧代乙酸
将氢氧化钾(3.4g)和1,2-二溴乙烷(5.8g)分别加入倒2-甲氧基苯丙酮酸(3g)的100mL四氢呋喃：水＝1：1的混合溶液中，室温搅拌5小时，反应液倒入水中，乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，减压蒸干得标题化合物粗产品(1.0g)，无需纯化，直接用于下一步反应。
步骤4：2-(1-(2-甲氧基苯基)环丙基)-2-氧代乙酸乙酯
将10mL浓硫酸加入到2-(1-(2-甲氧基苯基)环丙基)-2-氧代乙酸(1.0g)的乙醇(50mL)溶液中，加热至60℃，搅拌2小时，冷却后反应液倒入水中，乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，用硅胶柱色谱法(洗脱液：石油醚:乙酸乙酯＝10:1(V:V))纯化得标题化合物(0.80g)。
步骤5：2-羟基-2-(1-(2-甲氧基苯基)环丙基)乙酸乙酯
将2-(1-(2-甲氧基苯基)环丙基)-2-氧代乙酸乙酯(0.80g)溶于50mL甲醇中，冷却至0℃，缓慢加入硼氢化钠(0.12g)，升至室温搅拌30分钟，将反应液倒入饱和氯化铵水溶液(50mL)中，乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，用硅胶柱色谱法(洗脱液：石油醚:乙酸乙酯＝5:1(V:V))纯化得标题化合物(0.50g)。
中间体3：2-羟基-2-(1-(2-甲氧基苯基)环丁基)乙酸乙酯的合成
Figure PCTCN2018117014-appb-000010
步骤1：2-(1-(2-甲氧基苯基)环丁基)-2-氧代乙酸
按照中间体2步骤3的方法实施制得标题化合物。
步骤2：2-(1-(2-甲氧基苯基)环丁基)-2-氧代乙酸乙酯
按照中间体2步骤4的方法实施制得标题化合物。
步骤3：2-羟基-2-(1-(2-甲氧基苯基)环丁基)乙酸乙酯
按照中间体2步骤5的方法实施制得标题化合物。
中间体4：2-羟基-3-(2-((1-(2,2,2-三氟乙基)-1H-吡唑-5-基)甲氧基)苯基)丁-3-烯酸乙酯的合成：
中间体5：2-羟基-2-(1-(2-((1-(2,2,2-三氟乙基)-1H-吡唑-5-基)甲氧基)苯基)环丙基)乙酸乙酯的合成：
Figure PCTCN2018117014-appb-000011
步骤1：(1-(2,2,2-三氟乙基)-1H-吡唑-3-基)甲基甲磺酸酯
在0℃下，向(1-(2,2,2-三氟乙基)-1H-吡唑-3-基)甲醇(10.0g)和三乙胺(11.2g)的二氯甲烷(150mL)溶液中缓慢滴加甲磺酰氯(9.58g)，滴加完毕后升至室温并继续搅拌2h。将反应液倒入水中，二氯甲烷萃取，萃取液用饱和食盐水洗，无水硫酸钠干燥，过滤，滤液浓缩得标题化合物(10.3g)。
步骤2：1-(2-((1-(2,2,2-三氟乙基)-1H-吡唑-5-基)甲氧基)苯基)乙-1-酮
室温下，向邻羟基苯乙酮(7.07g)和(1-(2,2,2-三氟乙基)-1H-吡唑-3-基)甲基甲磺酸酯(10.3g)的DMF(100mL)溶液中加入碳酸钾粉末(14.4g)，加毕后升至65℃搅拌12h。将反应液倒入水中，乙酸乙酯萃取，萃取液用饱和食盐水洗，无水硫酸钠干燥，过滤，滤液浓缩，将残留物用硅胶柱色谱法(洗脱液：石油醚:乙酸乙酯＝3:1(V:V))纯化得标题化合物(13.0g)。
步骤3：3-甲基-3-(2-((1-(2,2,2-三氟乙基)-1H-吡唑-5-基)甲氧基)苯基)环氧乙烷-2-羧酸乙酯
在0℃下，向无水乙醇(40mL)中分批次加入金属钠(2g)，加毕后升至室温搅拌至全溶，然后用冰盐浴冷至-20℃，将1-(2-((1-(2,2,2-三氟乙基)-1H-吡唑-5-基)甲氧基)苯基)乙-1-酮 (13.0g)和氯乙酸乙酯(10.8g)的甲苯(10mL)溶液缓慢滴加至上述乙醇钠溶液中，加毕后升至室温并搅拌15h，将反应液倒入AcOH:H 2O(1:100)(450mL)混合溶剂中，二氯甲烷萃取，萃取液用饱和食盐水洗，无水硫酸钠干燥，过滤，滤液浓缩，将残留物用硅胶柱色谱法(洗脱液：石油醚:乙酸乙酯＝5:1(V:V))纯化得标题化合物(15.8g)。
步骤4：2-羟基-3-(2-((1-(2,2,2-三氟乙基)-1H-吡唑-5-基)甲氧基)苯基)丁-3-烯酸乙酯
在0℃下，向3-甲基-3-(2-((1-(2,2,2-三氟乙基)-1H-吡唑-5-基)甲氧基)苯基)环氧乙烷-2-羧酸乙酯(13.8g)的乙醚(150mL)溶液中缓慢滴加浓硫酸(3.90g)，滴加完毕后升至室温并继续搅拌12h。将反应液倒入水中，碳酸氢钠粉末调节pH至中性，乙酸乙酯萃取，萃取液用饱和食盐水洗，无水硫酸钠干燥，过滤，滤液浓缩，将残留物用硅胶柱色谱法(洗脱液：石油醚:乙酸乙酯＝5:1(V:V))纯化得标题化合物(5.8g)。
1H 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＝8.4Hz,1H),6.95(d,J＝8.4Hz,1H),6.37(d,J＝2.0Hz,1H),5.60(s,1H),5.27(s,1H),5.14(d,J＝12.4Hz,1H),5.10(d,J＝12.4Hz,1H),4.99(d,J＝7.2Hz,1H),4.82-4.87(m,2H),3.96-4.06(m,2H),3.14(d,J＝7.2Hz,1H),1.05(t,J＝7.2Hz,3H)。
步骤5：2-羟基-2-(1-(2-((1-(2,2,2-三氟乙基)-1H-吡唑-5-基)甲氧基)苯基)环丙基)乙酸乙酯
在-20℃下，向2-羟基-3-(2-((1-(2,2,2-三氟乙基)-1H-吡唑-5-基)甲氧基)苯基)丁-3-烯酸乙酯(1.5g)的无水二氯甲烷(30mL)溶液缓慢滴加二乙基锌(1.0M的正己烷溶液，23.5mL)，然后加入二碘甲烷(1.96mL)，加毕后缓慢升至室温并搅拌30小时，将反应液倒入饱和氯化铵水溶液中，乙酸乙酯萃取，萃取液用饱和食盐水洗，无水硫酸钠干燥，过滤，滤液浓缩，将残留物用硅胶柱色谱法(洗脱液：石油醚:乙酸乙酯＝4:1(V:V))纯化得标题化合物(130mg)。
1H NMR(400MHz,CDCl3)δ7.59(d,J＝2.0Hz,1H),7.23-7.29(m,2H),6.94-6.98(m,2H),6.44(d,J＝1.6Hz,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＝7.6Hz,1H),1.19-1.26(m,1H),1.12(t,J＝7.6Hz,3H),0.99-1.03(m,1H),0.80-0.85(m,2H)。
中间体6：2-羟基-2-(1-(2-甲氧基苯基)环丙基)乙酸乙酯
Figure PCTCN2018117014-appb-000012
步骤1：3-(2-甲氧基苯基)-3-甲基环氧乙烷-2-羧酸乙酯
按照中间体4步骤3的方法实施制得标题化合物。
步骤2：2-羟基-3-(2-甲氧基苯基)丁-3-烯酸乙酯
按照中间体4步骤4的方法实施制得标题化合物。
1H 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＝8.4Hz,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＝7.2Hz,1H),1.09(t,J＝7.2Hz,3H)。
中间体7：2-羟基-3-(2-甲氧基苯基)-3-甲基丁酸乙酯的合成：
Figure PCTCN2018117014-appb-000013
步骤1：3-(2-甲氧基苯基)-3-甲基-2-氧代丁酸
在0℃下，将3-(2-甲氧基苯基)-2-氧代丙酸(1.95g)溶于四氢呋喃(50mL)和5N氢氧化钠水溶液(10mL)的混合溶液中，缓慢加入碘甲烷(4.23g)。将此反应液加热至50℃搅拌12小时。冷却至室温后将反应液倒入冰水(100mL)中，用稀盐酸中和反应液使其呈弱酸性(pH＝5)。混合液用二氯甲烷萃取，萃取液用饱和食盐水洗，无水硫酸钠干燥，过滤，滤液浓缩得标题化合物(0.80g)。
步骤2：3-(2-甲氧基苯基)-3-甲基-2-氧代丁酸乙酯
在0℃下，向3-(2-甲氧基苯基)-3-甲基-2-氧代丁酸(0.50g)的乙醇(15mL)溶液中缓慢滴加浓硫酸(0.50g)，滴加完毕后升至80℃继续搅拌1小时。冷却至室温后将反应液倒入冰水中，碳酸氢钠粉末调节pH至中性，乙酸乙酯萃取，萃取液用饱和食盐水洗，无水硫酸钠干燥，过滤，滤液浓缩，将残留物用硅胶柱色谱法(洗脱液：石油醚:乙酸乙酯＝10:1(V:V))纯化得标题化合物(0.50g)。
步骤3：2-羟基-3-(2-甲氧基苯基)-3-甲基丁酸乙酯的合成
在-0℃下，向3-(2-甲氧基苯基)-3-甲基-2-氧代丁酸乙酯(0.30g)的无水甲醇(10mL)溶液缓慢加入硼氢化钠(20mg)，加毕后缓慢升至室温并搅拌1小时，将反应液倒入冷水中， 乙酸乙酯萃取，萃取液用饱和食盐水洗，无水硫酸钠干燥，过滤，滤液浓缩，将残留物用硅胶柱色谱法(洗脱液：石油醚:乙酸乙酯＝4:1(V:V))纯化得标题化合物(130mg)。
1H 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＝8.0Hz,1H),1.48(s,3H),1.37(s,3H),0.93(t,J＝7.2Hz,3H)。
中间体8：2-羟基-3-(2-甲氧基苯基)丁酸乙酯的合成
Figure PCTCN2018117014-appb-000014
步骤1：3-(2-甲氧基苯基)-2-氧代丁酸
在0℃下，将3-(2-甲氧基苯基)-2-氧代丙酸(1.95g)溶于四氢呋喃(50mL)和5N氢氧化钠水溶液(10mL)的混合溶液中，缓慢加入碘甲烷(2.0g)。将此反应液50℃搅拌12小时。冷却至室温后将反应液倒入冰水(100mL)中，用稀盐酸中和反应液使其呈弱酸性(pH＝5)。混合液用二氯甲烷萃取，萃取液用饱和食盐水洗，无水硫酸钠干燥，过滤，滤液浓缩得标题化合物(1.0g)。
步骤2，步骤3按照中间体7的合成方法实施制得标题化合物
1H NMR(400MHz,DMSO-d 6)δ7.22(dd,J＝7.6Hz,1H),7.44(td,J＝7.6Hz,1.6Hz,1H),6.90(d,J＝8.0Hz,1H),6.84(t,J＝7.6Hz,1H),5.30(d,J＝6.0Hz,1H),4.23(t,J＝6.8Hz,1H),3.98(dd,J＝7.2Hz,2H),3.74(s,3H)，3.44-3.50(m,1H),1.12(d,J＝7.2Hz,3H),1.07(t,J＝7.2Hz,3H)。
中间体9：3,3-二氟-2-羟基-3-(2-甲氧基苯基)丙酸乙酯的合成
Figure PCTCN2018117014-appb-000015
步骤1：2,2-二氟-2-(2-甲氧基苯基)乙酸乙酯
在250mL反应瓶中依次加入 2-碘苯甲醚(4.68g)、铜粉(6.4g)、2-溴-2,2-二氟乙酸乙酯(8.12g)和DMSO(100mL)。将此反应液加热至80℃搅拌3小时。冷却至室温后，加入200mL水，用硅藻土过滤，滤液用乙酸乙酯萃取，有机相用饱和食盐水洗涤。有机相用无水硫酸钠干燥，过滤，滤液浓缩，将残留物用硅胶柱色谱法真空干燥得到标题化合物(3.0g)。
步骤2：2,2-二氟-2-(2-甲氧基苯基)乙酰胺
0℃下，向装有2,2-二氟-2-(2-甲氧基苯基)乙酸乙酯(3.0g)的甲醇(50mL)溶液中加入浓氨水(20mL)，将此反应液在0℃下搅拌5小时。减压浓缩反应液除去有机溶剂，然后加入100mL冷水，用乙酸乙酯萃取，萃取液萃取液用饱和食盐水洗，无水硫酸钠干燥，过滤，滤液浓缩，将残留物用硅胶柱色谱法(洗脱液：石油醚:乙酸乙酯＝1:1(V:V))纯化得标题化合物(2.0g)。
步骤3：2,2-二氟-2-(2-甲氧基苯基)乙腈
将2,2-二氟-2-(2-甲氧基苯基)乙酰胺(2.0g)溶于四氢呋喃(50mL)中，在0℃下加入三乙胺(3mL)和三氟乙酸酐(2mL)。将此反应液在0℃下搅拌1小时，将反应液倒入冰水(100mL)中。混合液用二氯甲烷萃取，萃取液萃取液用饱和食盐水洗，无水硫酸钠干燥，过滤，滤液浓缩得标题化合物(1.5g)。
步骤4：2,2-二氟-2-(2-甲氧基苯基)乙醛
在0℃下，向2,2-二氟-2-(2-甲氧基苯基)乙腈(1.5g)的四氢呋喃(50mL)溶液中缓慢加入氢化铝锂(0.4g)，滴加完毕后在0℃下继续搅拌1小时。然后滴加10mL 1M盐酸淬灭反应，反应液倒入冷水中用乙酸乙酯萃取，萃取液用饱和食盐水洗，无水硫酸钠干燥，过滤，滤液浓缩，将残留物用硅胶柱色谱法(洗脱液：石油醚:乙酸乙酯＝2:1(V:V))纯化得标题化合物(0.50g)。
步骤5：3,3-二氟-2-羟基-3-(2-甲氧基苯基)丙腈
在20℃下，向2,2-二氟-2-(2-甲氧基苯基)乙醛(0.50g)的乙腈(10mL)溶液缓慢加入三乙胺(1mL)和三甲基氰硅烷(0.5mL)。加毕后室温搅拌1小时，将反应液倒入饱和氯化铵水溶液中，乙酸乙酯萃取，萃取液用饱和食盐水洗，无水硫酸钠干燥，过滤，滤液浓缩，将残留物用硅胶柱色谱法(洗脱液：石油醚:乙酸乙酯＝2:1(V:V))纯化得标题化合物(0.40g)。
步骤6：3,3-二氟-2-羟基-3-(2-甲氧基苯基)丙酸乙酯
在0℃下，向3,3-二氟-2-羟基-3-(2-甲氧基苯基)丙腈(0.40g)的乙醇(10mL)溶液中缓慢持续通入干燥的氯化氢气体，并维持搅拌5小时。将反应液倒入100mL冷水中，乙酸乙酯萃取，萃取液用饱和食盐水洗，无水硫酸钠干燥，过滤，滤液浓缩，将残留物用硅胶柱 色谱法(洗脱液：石油醚:乙酸乙酯＝4:1(V:V))纯化得标题化合物(0.20g)。
1H 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＝7.6Hz,1H),4.94-5.03(m,1H),3.79-4.16(m,2H),3.81(s,3H),3.29(d,J＝7.2Hz,1H),1.05(t,J＝7.2Hz,3H)。
中间体10：4-氯-5-(3-氯-2-甲基-4-(2-(4-甲基哌嗪-1-基)乙氧基)苯基)-6-(5-氟呋喃-2-基)噻吩并[2,3-d]嘧啶的合成
Figure PCTCN2018117014-appb-000016
参照专利WO2016/207226中第31页和第42页的合成方法合成目标化合物。
1H 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＝6.8Hz,3.6Hz,1H),5.69(t,J＝3.2Hz,1H),4.24-4.26(m,2H),2.80-3.30(m,10H),2.73(s,3H),2.04(s,3H)。
中间体11：4-氯-5-(3-氯-2-甲基-4-(2-(4-甲基哌嗪-1-基)乙氧基)苯基)-6-(呋喃-2-基)噻吩并[2,3-d]嘧啶的合成
Figure PCTCN2018117014-appb-000017
参照专利WO2015/97123中第192页的合成方法合成目标化合物。
中间体12：4-氯-5-(3-氯-2-甲基-4-(2-(4-甲基哌嗪-1-基)乙氧基)苯基)-6-(4-氟苯基)噻吩并[2,3-d]嘧啶的合成
Figure PCTCN2018117014-appb-000018
将4-氯-5-(3-氯-2-甲基-4-(2-(4-甲基哌嗪-1-基)乙氧基)苯基)-6-碘代噻吩并[2,3-d]嘧啶(参照专利WO2015/97123中第191页的合成方法合成)(563mg)、4-氟苯硼酸(140mg)、四三苯基膦钯(11mg)和碳酸铯(65mg)的混合物一起溶于玻璃封管中的二氧六环(20mL)和水(10mL)中，在氮气保护下加热至90℃，3小时后将反应液冷却至室温并倒入冰水中，用二氯甲烷萃取，萃取液用饱和食盐水洗，无水硫酸钠干燥，过滤，滤液浓缩，将残留物用薄层色谱法(展开剂：二氯甲烷:甲醇＝10:1(V:V))纯化得标题化合物(100mg)。
中间体13：(R)-2-羟基-3-甲基-3-(2-((1-(2,2,2-三氟乙基)-1H-吡唑-5-基)甲氧基)苯基)丁酸甲酯以及中间体14：(S)-2-羟基-3-甲基-3-(2-((1-(2,2,2-三氟乙基)-1H-吡唑-5-基)甲氧基)苯基)丁酸甲酯的合成：
Figure PCTCN2018117014-appb-000019
步骤1：(R)-2-((R)-2-甲氧基-2-苯基乙酰氧基)-3-甲基-3-(2-((1-(2,2,2-三氟乙基)-1H-吡唑-5-基)基)甲氧基)苯基)丁酸甲酯和(S)-2-((R)-2-甲氧基-2-苯基乙酰氧基)-3-甲基-3-(2-((1-(2,2,2-三氟乙基)-1H-吡唑-5-基)基)甲氧基)苯基)丁酸甲酯
在0℃下，将(R)-(-)-α-甲氧基苯乙酸(1.66g)溶于50mL二氯甲烷中，搅拌下依次加入5滴DMF和草酰氯(2.54g)。将此反应液升至室温搅拌1小时。反应液减压浓缩得(R)-2-甲氧基-2-苯基乙酰氯。将中间体1(1.93g)溶于50mL干燥的吡啶中，于室温下缓慢加入上述酰氯并继续搅拌1小时。减压浓缩，残余物用水稀释后用乙酸乙酯萃取，萃取液分别用稀盐酸(2M)和饱和食盐水洗涤。有机相用无水硫酸钠干燥，过滤，滤液浓缩，将残留物用硅胶柱色谱法(洗脱液：石油醚:乙酸乙酯＝10:1(V:V))纯化得(R)-2-((R)-2-甲氧基-2-苯基乙酰氧基)-3-甲基-3-(2-((1-(2,2,2-三氟乙基)-1H-吡唑-5-基)基)甲氧基)苯基)丁酸甲酯(0.90g)；
1H 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＝8.8Hz,1H),6.41(d,J＝1.6Hz,1H),5.85(s,1H),5.07(d,J＝11.6Hz,1H), 4.99(d,J＝11.6Hz,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-甲氧基-2-苯基乙酰氧基)-3-甲基-3-(2-((1-(2,2,2-三氟乙基)-1H-吡唑-5-基)基)甲氧基)苯基)丁酸甲酯(0.80g)。
1H 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＝8.8Hz,1H),6.37(d,J＝1.6Hz,1H),5.80(s,1H),4.98(d,J＝12.4Hz,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)。
步骤2：(R)-2-羟基-3-甲基-3-(2-((1-(2,2,2-三氟乙基)-1H-吡唑-5-基)甲氧基)苯基)丁酸甲酯和(S)-2-羟基-3-甲基-3-(2-((1-(2,2,2-三氟乙基)-1H-吡唑-5-基)甲氧基)苯基)丁酸甲酯
在0℃下，将步骤1得到的(R)-2-((R)-2-甲氧基-2-苯基乙酰氧基)-3-甲基-3-(2-((1-(2,2,2-三氟乙基)-1H-吡唑-5-基)基)甲氧基)苯基)丁酸甲酯(0.90g)溶于30mL甲醇中，缓慢加入甲醇钠粉末(100mg)并继续搅拌1h。将反应液倒入饱和氯化铵水溶液中，乙酸乙酯萃取，萃取液用饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液浓缩，将残留物用硅胶柱色谱法(洗脱液：石油醚:乙酸乙酯＝5:1(V:V))纯化得(R)-2-羟基-3-甲基-3-(2-((1-(2,2,2-三氟乙基)-1H-吡唑-5-基)甲氧基)苯基)丁酸甲酯(0.50g)。
1H NMR(400MHz,CDCl 3)δ7.61(d,J＝1.6Hz,1H),7.23-7.28(m,2H),6.87-7.01(m,2H),6.46(d,J＝2.0Hz,1H),5.16(s,2H),4.82-4.88(m,3H),3.50(s,3H),2.78(d,J＝7.6Hz,1H),1.41(s,3H),1.35(s,3H)。
参照上述操作，用甲醇钠水解(S)-2-((R)-2-甲氧基-2-苯基乙酰氧基)-3-甲基-3-(2-((1-(2,2,2-三氟乙基)-1H-吡唑-5-基)基)甲氧基)苯基)丁酸甲酯(0.80g)得到(S)-2-羟基-3-甲基-3-(2-((1-(2,2,2-三氟乙基)-1H-吡唑-5-基)甲氧基)苯基)丁酸甲酯(0.40g)。
1H NMR(400MHz,CDCl 3)δ7.61(d,J＝1.6Hz,1H),7.23-7.28(m,2H),6.87-7.01(m,2H),6.46(d,J＝2.0Hz,1H),5.16(s,2H),4.82-4.88(m,3H),3.50(s,3H),2.78(d,J＝7.6Hz,1H),1.41(s,3H),1.35(s,3H)。
中间体15：(R)-2-羟基-2-(1-(2-((1-(2,2,2-三氟乙基)-1H-吡唑-5-基)甲氧基)苯基)环丙基)乙酸乙酯以及中间体16：(S)-2-羟基-2-(1-(2-((1-(2,2,2-三氟乙基)-1H-吡唑-5-基)甲氧基)苯基)环丙基)乙酸乙酯的合成：
Figure PCTCN2018117014-appb-000020
步骤1：(R)-2-甲氧基-2-苯乙酸((R)-2-乙氧基-2-氧代-1-(1-(2-((1-(2,2,2-三氟乙基)-1H-吡唑-5-基)甲氧基)苯基)环丙基))乙酯和(S)-2-甲氧基-2-苯乙酸((R)-2-乙氧基-2-氧代-1-(1-(2-((1-(2,2,2-三氟乙基)-1H-吡唑-5-基)甲氧基)苯基)环丙基))乙酯
参考中间体13和中间体14的步骤一合成方法，用中间体5代替中间体1得(R)-2-甲氧基-2-苯乙酸((R)-2-乙氧基-2-氧代-1-(1-(2-((1-(2,2,2-三氟乙基)-1H-吡唑-5-基)甲氧基)苯基)环丙基))乙酯(0.40g)；
1H 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＝8.4Hz,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＝7.2Hz,3H),0.80-0.83(m,2H)。
(S)-2-甲氧基-2-苯乙酸((R)-2-乙氧基-2-氧代-1-(1-(2-((1-(2,2,2-三氟乙基)-1H-吡唑-5-基)甲氧基)苯基)环丙基))乙酯(0.30g)。
1H 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,1.6Hz,1H),6.83-6.88(m,2H),6.37(d,J＝2.0Hz,1H),5.11(d,J＝12.8Hz,1H),5.06(d,J＝12.8Hz,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)。
步骤2：(R)-2-羟基-2-(1-(2-((1-(2,2,2-三氟乙基)-1H-吡唑-5-基)甲氧基)苯基)环丙基)乙酸乙酯和(S)-2-羟基-2-(1-(2-((1-(2,2,2-三氟乙基)-1H-吡唑-5-基)甲氧基)苯基)环丙基)乙酸乙酯
参考中间体13和中间体14的步骤二合成方法分别用乙醇钠水解(R)-2-甲氧基-2-苯乙酸((R)-2-乙氧基-2-氧代-1-(1-(2-((1-(2,2,2-三氟乙基)-1H-吡唑-5-基)甲氧基)苯基)环丙基))乙酯(0.40g)和(S)-2-甲氧基-2-苯乙酸((R)-2-乙氧基-2-氧代-1-(1-(2-((1-(2,2,2-三氟乙基)-1H-吡唑-5-基)甲氧基)苯基)环丙基))乙酯(0.30g)得到(R)-2-羟基-2-(1-(2-((1-(2,2,2-三氟乙基)-1H-吡唑-5-基)甲氧基)苯基)环丙基)乙酸乙酯(0.30g)；
1H NMR(400MHz,CDCl 3)δ7.59(d,J＝2.0Hz,1H),7.23-7.29(m,2H),6.94-6.98(m,2H),6.44(d,J＝1.6Hz,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＝7.6Hz,1H),1.19-1.26(m,1H),1.12(t,J＝7.6Hz,3H),0.99-1.03(m,1H),0.80-0.85(m,2H)。
(S)-2-羟基-2-(1-(2-((1-(2,2,2-三氟乙基)-1H-吡唑-5-基)甲氧基)苯基)环丙基)乙酸乙酯 (0.20g)；
1H NMR(400MHz,CDCl 3)δ7.59(d,J＝2.0Hz,1H),7.23-7.29(m,2H),6.94-6.98(m,2H),6.44(d,J＝1.6Hz,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＝7.6Hz,1H),1.19-1.26(m,1H),1.12(t,J＝7.6Hz,3H),0.99-1.03(m,1H),0.80-0.85(m,2H)。
中间体17：(R)-2-羟基-2-(1-(2-((2-(2-甲氧基苯基)嘧啶-4-基)甲氧基)苯基)环丙基)乙酸乙酯的合成：
Figure PCTCN2018117014-appb-000021
步骤1：(2-(2-甲氧基苯基)嘧啶-4-基)甲基甲磺酸酯
按照中间体5步骤1的方法实施制得标题化合物。
步骤2：1-(2-((2-(2-甲氧基苯基)嘧啶-4-基)甲氧基)苯基)乙-1-酮
按照中间体5步骤2的方法实施制得标题化合物。
步骤3：3-(2-((2-(2-甲氧基苯基)嘧啶-4-基)甲氧基)苯基)-3-甲基环氧乙烷-2-羧酸乙酯
按照中间体5步骤3的方法实施制得标题化合物。
步骤4：2-羟基-3-(2-((2-(2-甲氧基苯基)嘧啶-4-基)甲氧基)苯基)丁-3-烯酸乙酯
按照中间体5步骤4的方法实施制得标题化合物。
步骤5：2-羟基-2-(1-(2-((2-(2-甲氧基苯基)嘧啶-4-基)甲氧基)苯基)环丙基)乙酸乙酯
按照中间体5步骤5的方法实施制得标题化合物。
步骤6：(R)-2-甲氧基-2-苯乙酸((R)-2-乙氧基-1-(1-(2-((2-(2-甲氧基苯基)嘧啶-4-基)甲氧基)苯基)环丙基)-2-氧代)乙酯
按照中间体13步骤1的方法实施制得标题化合物。
步骤7：(R)-2-羟基-2-(1-(2-((2-(2-甲氧基苯基)嘧啶-4-基)甲氧基)苯基)环丙基)乙酸乙酯
按照中间体13步骤2的方法实施制得标题化合物。
中间体18：(R)-2-羟基-3-(2-((2-(2-甲氧基苯基)嘧啶-4-基)甲氧基)苯基)-3-甲基丁酸甲酯的合成：
Figure PCTCN2018117014-appb-000022
步骤1：2-(2-((2-(2-甲氧基苯基)嘧啶-4-基)甲氧基)苯基)-2-甲基丙醛
按照中间体1步骤9的方法实施制得标题化合物。
步骤2：2-羟基-3-(2-((2-(2-甲氧基苯基)嘧啶-4-基)甲氧基)苯基)-3-甲基丁腈
按照中间体1步骤10的方法实施制得标题化合物。
步骤3：(2-((2-(2-甲氧基苯基)嘧啶-4-基)甲氧基)苯基)-3-甲基丁酸
按照中间体1步骤11的方法实施制得标题化合物。
步骤4：2-羟基-3-(2-((2-(2-甲氧基苯基)嘧啶-4-基)甲氧基)苯基)-3-甲基丁酸甲酯
按照中间体1步骤12的方法实施制得标题化合物。
步骤5：(R)-2-((R)-2-甲氧基-2-苯基乙酰氧基)-3-(2-((2-(2-甲氧基苯基)嘧啶-4-基)甲氧基)苯基)-3-甲基丁酸甲酯
按照中间体13步骤1的方法实施制得标题化合物。
步骤6：(R)-2-羟基-3-(2-((2-(2-甲氧基苯基)嘧啶-4-基)甲氧基)苯基)-3-甲基丁酸甲酯
按照中间体13步骤2的方法实施制得标题化合物。
中间体19：2-氨基-2-(1-(2-甲氧基苯基)环丙基)乙酸乙酯的合成
Figure PCTCN2018117014-appb-000023
步骤1：2-叠氮基-2-(1-(2-甲氧基苯基)环丙基)乙酸乙酯
在0℃下，向中间体2(250mg)和三乙胺(202mg)的二氯甲烷(15mL)溶液中缓慢滴加甲磺酰氯(172mg)，滴加完毕后升至室温并继续搅拌1h。将反应液倒入水中，二氯甲烷萃取两次，萃取液用饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液浓缩得到褐色油状物。将油状物溶于5mL DMF中并加入叠氮化钠(130mg),与室温反应12小时。将反应液倒入水中，乙酸乙酯萃取，萃取液用饱和食盐水洗，无水硫酸钠干燥，过滤，滤液浓缩，将残留物用硅胶柱色谱法(洗脱液：石油醚:乙酸乙酯＝2:1(V:V))纯化得标题化合物(190mg)。
步骤2：2-氨基-2-(1-(2-甲氧基苯基)环丙基)乙酸乙酯
将步骤一中所得固体溶于THF(5mL)与水(5mL)的混合溶剂中，添加三苯基膦(500mg)然后加热回流2小时并冷却至室温。将反应液倒入冰水中，二氯甲烷萃取，萃取液用饱和食盐水洗，无水硫酸钠干燥，过滤，滤液浓缩，将残留物用硅胶柱色谱法(洗脱液：石油醚:乙酸乙酯＝1:1(V:V))纯化得中间体19(102mg)。
实施例1：2-((5-(3-氯-2-甲基-4-(2-(4-甲基哌嗪-1-基)乙氧基)苯基)-6-(4-氟苯基)噻吩并[2,3-d]嘧啶-4-氧基)-3-甲基-3-(2-((1-(2,2,2-三氟乙基)-1H-吡唑-5-基)甲氧基)苯基)丁酸
Figure PCTCN2018117014-appb-000024
步骤1：2-((5-(3-氯-2-甲基-4-(2-(4-甲基哌嗪-1-基)乙氧基)苯基)-6-(4-氟苯基)噻吩并[2,3-d]嘧啶-4-氧基)-3-甲基-3-(2-((1-(2,2,2-三氟乙基)-1H-吡唑-5-基)甲氧基)苯基)丁酸甲酯
在0℃下，向4-氯-5-(3-氯-2-甲基-4-(2-(4-甲基哌嗪-1-基)乙氧基)苯基)-6-(4-氟苯基)噻吩并[2,3-d]嘧啶(110mg)(中间体12)和2-羟基-3-甲基-3-(2-((1-(2,2,2-三氟乙基)-1H-吡唑-5-基)甲氧基)苯基)丁酸甲酯(80mg)(中间体1)的THF(10mL)溶液中加入氢化钠(11mg)，加 毕后升至室温搅拌2小时。将反应液倒入饱和氯化铵水溶液(50mL)中，二氯甲烷萃取，萃取液用饱和食盐水洗，无水硫酸钠干燥，过滤，滤液浓缩，将残留物用薄层色谱法(展开剂：二氯甲烷:甲醇＝10:1(V:V))纯化得标题化合物(80mg)。
步骤2：2-((5-(3-氯-2-甲基-4-(2-(4-甲基哌嗪-1-基)乙氧基)苯基)-6-(4-氟苯基)噻吩并[2,3-d]嘧啶-4-氧基)-3-甲基-3-(2-((1-(2,2,2-三氟乙基)-1H-吡唑-5-基)甲氧基)苯基)丁酸
室温下，向2-((5-(3-氯-2-甲基-4-(2-(4-甲基哌嗪-1-基)乙氧基)苯基)-6-(4-氟苯基)噻吩并[2,3-d]嘧啶-4-氧基)-3-甲基-3-(2-((1-(2,2,2-三氟乙基)-1H-吡唑-5-基)甲氧基)苯基)丁酸甲酯在1,4-二氧六环和水(1:1)(6mL)中的溶液中加入氢氧化锂固体(22mg)，室温搅拌12小时，将反应液倒入水中，用稀盐酸(2M)调节pH至3-4，二氯甲烷萃取，萃取液用饱和食盐水洗，无水硫酸钠干燥，过滤，滤液浓缩，将残留物用薄层色谱法(展开剂：二氯甲烷:甲醇＝4:1(V:V))纯化，取极性较大的异构体得标题化合物(1.5mg)。
1H 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＝8.8Hz,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＝5.2Hz,2H),2.32-2.64(m,8H),2.24(s,3H),2.20(s,3H),1.01(s,3H),0.81(s,3H)。
实施例2：2-((5-(3-氯-2-甲基-4-(2-(4-甲基哌嗪-1-基)乙氧基)苯基)-6-(4-氟苯基)噻吩并[2,3-d]嘧啶-4-氧基)-2-(1-(2-((1-(2,2,2-三氟乙基)-1H-吡唑-5-基)甲氧基)苯基)环丙基)乙酸
Figure PCTCN2018117014-appb-000025
步骤1：2-((5-(3-氯-2-甲基-4-(2-(4-甲基哌嗪-1-基)乙氧基)苯基)-6-(4-氟苯基)噻吩并[2,3-d]嘧啶-4-氧基)-2-(1-(2-((1-(2,2,2-三氟乙基)-1H-吡唑-5-基)甲氧基)苯基)环丙基)乙酸乙酯
参照实施例1中步骤1的方法，用中间体5代替中间体1，得到标题化合物(80mg)。
步骤2：2-((5-(3-氯-2-甲基-4-(2-(4-甲基哌嗪-1-基)乙氧基)苯基)-6-(5-氟呋喃-2-基)噻吩并[2,3-d]嘧啶-4-基)氧基)-2-(1-(2(-((1-(2,2,2-三氟乙基)-1H-吡唑-5-基)甲氧基)苯基)环丙基)乙酸
参照实施例1中步骤2的方法，2-((5-(3-氯-2-甲基-4-(2-(4-甲基哌嗪-1-基)乙氧基)苯 基)-6-(4-氟苯基)噻吩并[2,3-d]嘧啶-4-氧基)-2-(1-(2-((1-(2,2,2-三氟乙基)-1H-吡唑-5-基)甲氧基)苯基)环丙基)乙酸乙酯代替2-((5-(3-氯-2-甲基-4-(2-(4-甲基哌嗪-1-基)乙氧基)苯基)-6-(4-氟苯基)噻吩并[2,3-d]嘧啶-4-氧基)-3-甲基-3-(2-((1-(2,2,2-三氟乙基)-1H-吡唑-5-基)甲氧基)苯基)丁酸乙酯，取极性较大的异构体得到标题化合物(1.91mg)。
1H NMR(400MHz,CD3OD)δ8.45(s,1H),7.50(d,J＝2.0Hz,1H),7.45(d,J＝8.8Hz,1H),7.24-7.28(m,2H),7.12-7.16(m,2H),6.99-7.05(m,3H),6.76(t,J＝7.6Hz,1H),6.53(d,J＝1.6Hz,1H),6.46(d,J＝6.0Hz,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＝5.2Hz,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)。
实施例3：2-((5-(3-氯-2-甲基-4-(2-(4-甲基哌嗪-1-基)乙氧基)苯基)-6-(4-氟苯基)噻吩并[2,3-d]嘧啶-4-基)氧基)-3-(2-甲氧基苯基)丁-3-烯酸
Figure PCTCN2018117014-appb-000026
步骤1：2-((5-(3-氯-2-甲基-4-(2-(4-甲基哌嗪-1-基)乙氧基)苯基)-6-(4-氟苯基)噻吩并[2,3-d]嘧啶-4-基)氧基)-3-(2-甲氧基苯基)丁-3-烯酸乙酯
参照实施例1中步骤1的方法，中间体6代替中间体1，得到标题化合物(24mg)。
步骤2：2-((5-(3-氯-2-甲基-4-(2-(4-甲基哌嗪-1-基)乙氧基)苯基)-6-(4-氟苯基)噻吩并[2,3-d]嘧啶-4-基)氧基)-3-(2-甲氧基苯基)丁-3-烯酸
参照实施例1中步骤2的方法，2-((5-(3-氯-2-甲基-4-(2-(4-甲基哌嗪-1-基)乙氧基)苯基)-6-(4-氟苯基)噻吩并[2,3-d]嘧啶-4-基)氧基)-3-(2-甲氧基苯基)丁-3-烯酸乙酯代替2-((5-(3-氯-2-甲基-4-(2-(4-甲基哌嗪-1-基)乙氧基)苯基)-6-(4-氟苯基)噻吩并[2,3-d]嘧啶-4-氧基)-3-甲基-3-(2-((1-(2,2,2-三氟乙基)-1H-吡唑-5-基)甲氧基)苯基)丁酸乙酯，取极性较大的异构体得到标题化合物(2.87mg)。
1H 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＝6.0Hz,2H),2.33-2.60(m,8H),2.28(s,3H),2.19(s,3H)。
实施例4：2-((5-(3-氯-2-甲基-4-(2-(4-甲基哌嗪-1-基)乙氧基)苯基)-6-(4-氟苯基)噻吩并 [2,3-d]嘧啶-4-基)氧基)-2-(1-(2-甲氧基苯基)环丙基)乙酸
Figure PCTCN2018117014-appb-000027
步骤1：2-((5-(3-氯-2-甲基-4-(2-(4-甲基哌嗪-1-基)乙氧基)苯基)-6-(4-氟苯基)噻吩并[2,3-d]嘧啶-4-基)氧基)-2-(1-(2-甲氧基苯基)环丙基)乙酸乙酯
参照实施例1中步骤1的方法，中间体2代替中间体1，得到标题化合物(60mg)。
步骤2：2-((5-(3-氯-2-甲基-4-(2-(4-甲基哌嗪-1-基)乙氧基)苯基)-6-(4-氟苯基)噻吩并[2,3-d]嘧啶-4-基)氧基)-2-(1-(2-甲氧基苯基)环丁基)乙酸
参照实施例1中步骤2的方法，2-((5-(3-氯-2-甲基-4-(2-(4-甲基哌嗪-1-基)乙氧基)苯基)-6-(4-氟苯基)噻吩并[2,3-d]嘧啶-4-基)氧基)-2-(1-(2-甲氧基苯基)环丙基)乙酸乙酯代替2-((5-(3-氯-2-甲基-4-(2-(4-甲基哌嗪-1-基)乙氧基)苯基)-6-(4-氟苯基)噻吩并[2,3-d]嘧啶-4-氧基)-3-甲基-3-(2-((1-(2,2,2-三氟乙基)-1H-吡唑-5-基)甲氧基)苯基)丁酸乙酯，取极性较大的异构体得到标题化合物(20mg)。
1H 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＝7.6Hz,1H),6.66(t,J＝7.6Hz,1H),6.29(dd,J＝7.6Hz,1.6Hz,1H),5.36(s,1H),4.20-4.316(m,2H),3.76(s,3H),2.81(t,J＝5.2Hz,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)。
实施例5：2-((5-(3-氯-2-甲基-4-(2-(4-甲基哌嗪-1-基)乙氧基)苯基)-6-(4-氟苯基)噻吩并[2,3-d]嘧啶-4-基)氧基)-2-(1-(2-甲氧基苯基)环丁基)乙酸
Figure PCTCN2018117014-appb-000028
步骤1：2-((5-(3-氯-2-甲基-4-(2-(4-甲基哌嗪-1-基)乙氧基)苯基)-6-(4-氟苯基)噻吩并[2,3-d]嘧啶-4-基)氧基)-2-(1-(2-甲氧基苯基)环丁基)乙酸乙酯
参照实施例1中步骤1的方法，中间体3代替中间体1，得到标题化合物(40mg)。
步骤2：2-((5-(3-氯-2-甲基-4-(2-(4-甲基哌嗪-1-基)乙氧基)苯基)-6-(4-氟苯基)噻吩并 [2,3-d]嘧啶-4-基)氧基)-2-(1-(2-甲氧基苯基)环丁基)乙酸
参照实施例1中步骤2的方法，2-((5-(3-氯-2-甲基-4-(2-(4-甲基哌嗪-1-基)乙氧基)苯基)-6-(4-氟苯基)噻吩并[2,3-d]嘧啶-4-基)氧基)-2-(1-(2-甲氧基苯基)环丁基)乙酸乙酯代替2-((5-(3-氯-2-甲基-4-(2-(4-甲基哌嗪-1-基)乙氧基)苯基)-6-(4-氟苯基)噻吩并[2,3-d]嘧啶-4-氧基)-3-甲基-3-(2-((1-(2,2,2-三氟乙基)-1H-吡唑-5-基)甲氧基)苯基)丁酸乙酯，取极性较大的异构体得到标题化合物(15mg)。
1H 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＝7.2Hz,1H),6.39(d,J＝7.2Hz,1H),5.43-5.52(m,1H),5.40(d,J＝4.0Hz,1H),4.89(d,J＝6.0Hz,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＝5.2Hz,2H),2.38-2.58(m,8H),2.27(s,3H),2.13(s,3H),1.96-2.08(m,2H)。
实施例6：2-((5-(3-氯-2-甲基-4-(2-(4-甲基哌嗪-1-基)乙氧基)苯基)-6-(4-氟苯基)噻吩并[2,3-d]嘧啶-4-基)氧基)-3-(2-甲氧基苯基)-3-甲基丁酸
Figure PCTCN2018117014-appb-000029
步骤1：2-((5-(3-氯-2-甲基-4-(2-(4-甲基哌嗪-1-基)乙氧基)苯基)-6-(4-氟苯基)噻吩并[2,3-d]嘧啶-4-基)氧基)-3-(2-甲氧基苯基)-3-甲基丁酸乙酯
参照实施例1中步骤1的方法，中间体7代替中间体1，得到标题化合物(30mg)。
步骤2：2-((5-(3-氯-2-甲基-4-(2-(4-甲基哌嗪-1-基)乙氧基)苯基)-6-(4-氟苯基)噻吩并[2,3-d]嘧啶-4-基)氧基)-3-(2-甲氧基苯基)-3-甲基丁酸
参照实施例1中步骤2的方法，2-((5-(3-氯-2-甲基-4-(2-(4-甲基哌嗪-1-基)乙氧基)苯基)-6-(4-氟苯基)噻吩并[2,3-d]嘧啶-4-基)氧基)-3-(2-甲氧基苯基)-3-甲基丁酸乙酯代替2-((5-(3-氯-2-甲基-4-(2-(4-甲基哌嗪-1-基)乙氧基)苯基)-6-(4-氟苯基)噻吩并[2,3-d]嘧啶-4-氧基)-3-甲基-3-(2-((1-(2,2,2-三氟乙基)-1H-吡唑-5-基)甲氧基)苯基)丁酸乙酯，取极性较大的异构体得到标题化合物(5mg)。
1H 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)。
实施例7：2-((5-(3-氯-2-甲基-4-(2-(4-甲基哌嗪-1-基)乙氧基)苯基)-6-(4-氟苯基)噻吩并[2,3-d]嘧啶-4-基)氧基)-3-(2-甲氧基苯基)-3-甲基丁酸
Figure PCTCN2018117014-appb-000030
步骤1：2-((5-(3-氯-2-甲基-4-(2-(4-甲基哌嗪-1-基)乙氧基)苯基)-6-(4-氟苯基)噻吩并[2,3-d]嘧啶-4-基)氧基)-3-(2-甲氧基苯基)丁酸乙酯
参照实施例1中步骤1的方法，中间体8代替中间体1，得到标题化合物(10mg)。
步骤2：2-((5-(3-氯-2-甲基-4-(2-(4-甲基哌嗪-1-基)乙氧基)苯基)-6-(4-氟苯基)噻吩并[2,3-d]嘧啶-4-基)氧基)-3-(2-甲氧基苯基)丁酸
参照实施例1中步骤2的方法，2-((5-(3-氯-2-甲基-4-(2-(4-甲基哌嗪-1-基)乙氧基)苯基)-6-(4-氟苯基)噻吩并[2,3-d]嘧啶-4-基)氧基)-3-(2-甲氧基苯基)丁酸乙酯代替2-((5-(3-氯-2-甲基-4-(2-(4-甲基哌嗪-1-基)乙氧基)苯基)-6-(4-氟苯基)噻吩并[2,3-d]嘧啶-4-氧基)-3-甲基-3-(2-((1-(2,2,2-三氟乙基)-1H-吡唑-5-基)甲氧基)苯基)丁酸乙酯，取极性较大的异构体得到标题化合物(2mg)。
1H 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＝8.8Hz,1H),6.88(d,J＝8.0Hz,1H),6.71(t,J＝7.2Hz,1H),6.56(d,J＝8.0Hz,1H),5.38(d,J＝4.8Hz,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＝5.6Hz,2H),2.33-2.58(m,8H),2.22(s,3H),2.09(s,3H),0.85(d,J＝7.2Hz,3H)。
实施例8：2-((5-(3-氯-2-甲基-4-(2-(4-甲基哌嗪-1-基)乙氧基)苯基)-6-(4-氟苯基)噻吩并[2,3-d]嘧啶-4-基)氧基)-3,3-二氟-3-(2-甲氧基苯基)丙酸
Figure PCTCN2018117014-appb-000031
步骤1：2-((5-(3-氯-2-甲基-4-(2-(4-甲基哌嗪-1-基)乙氧基)苯基)-6-(4-氟苯基)噻吩并[2,3-d]嘧啶-4-基)氧基)-3,3-二氟-3-(2-甲氧基苯基)丙酸乙酯
参照实施例1中步骤1的方法，中间体9代替中间体1，得到标题化合物(30mg)。
步骤2：2-((5-(3-氯-2-甲基-4-(2-(4-甲基哌嗪-1-基)乙氧基)苯基)-6-(4-氟苯基)噻吩并[2,3-d]嘧啶-4-基)氧基)-3,3-二氟-3-(2-甲氧基苯基)丙酸
参照实施例1中步骤2的方法，2-((5-(3-氯-2-甲基-4-(2-(4-甲基哌嗪-1-基)乙氧基)苯基)-6-(4-氟苯基)噻吩并[2,3-D]嘧啶-4-基)氧基)-3,3-二氟-3-(2-甲氧基苯基)丙酸乙酯代替2-((5-(3-氯-2-甲基-4-(2-(4-甲基哌嗪-1-基)乙氧基)苯基)-6-(4-氟苯基)噻吩并[2,3-d]嘧啶-4-氧基)-3-甲基-3-(2-((1-(2,2,2-三氟乙基)-1H-吡唑-5-基)甲氧基)苯基)丁酸乙酯，取极性较大的异构体得到标题化合物(5mg)。
1H 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＝8.0Hz,1H),6.62(t,J＝8.0Hz,1H),6.04-6.11(m,1H),4.10-4.20(m,2H),3.70(s,3H),2.84(t,J＝5.2Hz,2H),2.60-2.83(m,8H),2.40(s,3H),2.32(s,3H)。
实施例9：2-((5-(3-氯-2-甲基-4-(2-(4-甲基哌嗪-1-基)乙氧基)苯基)-6-(5-氟呋喃-2-基)噻吩并[2,3-d]嘧啶-4-基)氧基)-3-(2-((1-(2,2,2-三氟乙基)-1H-吡唑-5-基)甲氧基)苯基)丁-3-烯酸
Figure PCTCN2018117014-appb-000032
步骤1：2-((5-(3-氯-2-甲基-4-(2-(4-甲基哌嗪-1-基)乙氧基)苯基)-6-(5-氟呋喃-2-基)噻吩并[2,3-d]嘧啶-4-基)氧基)-3-(2-((1-(2,2,2-三氟乙基)-1H-吡唑-5-基)甲氧基)苯基)丁-3-烯酸乙酯
参照实施例1中步骤1的方法，中间体4替中间体1，中间体10代替中间体12，得标题化合物(2.55mg)。
步骤2：2-((5-(3-氯-2-甲基-4-(2-(4-甲基哌嗪-1-基)乙氧基)苯基)-6-(5-氟呋喃-2-基)噻吩并[2,3-d]嘧啶-4-基)氧基)-3-(2-((1-(2,2,2-三氟乙基)-1H-吡唑-5-基)甲氧基)苯基)丁-3-烯酸
参照实施例1中步骤2的方法，2-((5-(3-氯-2-甲基-4-(2-(4-甲基哌嗪-1-基)乙氧基)苯基)-6-(5-氟呋喃-2-基)噻吩并[2,3-d]嘧啶-4-基)氧基)-3-(2-((1-(2,2,2-三氟乙基)-1H-吡唑-5-基)甲氧基)苯基)丁-3-烯酸乙酯代替2-((5-(3-氯-2-甲基-4-(2-(4-甲基哌嗪-1-基)乙氧基)苯基)-6-(4-氟苯基)噻吩并[2,3-d]嘧啶-4-氧基)-3-甲基-3-(2-((1-(2,2,2-三氟乙基)-1H-吡唑-5-基)甲氧基)苯基)丁酸乙酯，得标题化合物(2.55mg)。
1H NMR(400MHz,CD 3OD)δ8.70(s,1H),8.50(s,1H),7.49(s,1H),7.34(d,J＝1.6Hz,1H),7.25-7.33(m,2H),7.09(t,J＝8.0Hz,2H),6.89-6.96(m,2H),6.32(s,1H),6.19(s,1H),5.63(t,J＝3.6Hz,1H),5.55(dd,J＝6.8Hz,4.0Hz,1H),5.17(s,2H),4.84-4.94(m,2H),4.30(t,J＝4.8Hz,2H),2.90-3.300(m,10H),2.83(s,3H),1.93(s,3H)。
实施例10：2-((5-(3-氯-2-甲基-4-(2-(4-甲基哌嗪-1-基)乙氧基)苯基)-6-(5-氟呋喃-2-基)噻吩并[2,3-d]嘧啶-4-基)氧基)-2-(1-(2-((1-(2,2,2-三氟乙基)-1H-吡唑-5-基)甲氧基)苯基)环丙基)乙酸
Figure PCTCN2018117014-appb-000033
步骤1：2-((5-(3-氯-2-甲基-4-(2-(4-甲基哌嗪-1-基)乙氧基)苯基)-6-(5-氟呋喃-2-基)噻吩并[2,3-d]嘧啶-4-基)氧基)-2-(1-(2(-((1-(2,2,2-三氟乙基)-1H-吡唑-5-基)甲氧基)苯基)环丙基)乙酸乙酯
参照实施例1中步骤1的方法，中间体5代替中间体1，中间体10代替中间体12，得到标题化合物(12mg)。
步骤2：2-((5-(3-氯-2-甲基-4-(2-(4-甲基哌嗪-1-基)乙氧基)苯基)-6-(5-氟呋喃-2-基)噻吩并[2,3-d]嘧啶-4-基)氧基)-2-(1-(2(-((1-(2,2,2-三氟乙基)-1H-吡唑-5-基)甲氧基)苯基)环丙基)乙酸
参照实施例1中步骤2的方法，2-((5-(3-氯-2-甲基-4-(2-(4-甲基哌嗪-1-基)乙氧基)苯基)-6-(5-氟呋喃-2-基)噻吩并[2,3-d]嘧啶-4-基)氧基)-2-(1-(2(-((1-(2,2,2-三氟乙基)-1H-吡唑-5-基)甲氧基)苯基)环丙基)乙酸乙酯代替2-((5-(3-氯-2-甲基-4-(2-(4-甲基哌嗪-1-基)乙氧基)苯基)-6-(4-氟苯基)噻吩并[2,3-d]嘧啶-4-氧基)-3-甲基-3-(2-((1-(2,2,2-三氟乙基)-1H-吡唑-5-基)甲氧基)苯基)丁酸乙酯，取极性较大的异构体得到标题化合物(4.50mg)。
1H 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＝7.6Hz,1.6Hz,1H),7.02(d,J＝8.0Hz,1H),6.84(t,J＝7.6Hz,1H),6.58(dd,J＝7.6Hz,1.6Hz,1H),6.54(d,J＝1.6Hz,1H),5.63(s,1H),5.60(t,J＝3.2Hz,1H),5.56(dd,J＝6.4Hz,3.6Hz,1H),5.27(d,J＝13.2Hz,1H),5.24(d,J＝13.2Hz,1H),5.03-5.18(m,2H),4.34-4.42(m,2H),3.12-3.22(m,4H),3.06(t,J＝4.8Hz,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)。
实施例11：2-((5-(3-氯-2-甲基-4-(2-(4-甲基哌嗪-1-基)乙氧基)苯基)-6-(呋喃-2-基)噻吩并[2,3-d]嘧啶-4-基)氧基)-2-(1-(2-((1-(2,2,2-三氟乙基)-1H-吡唑-5-基)甲氧基)苯基)环丙基)乙酸
Figure PCTCN2018117014-appb-000034
步骤1：2-((5-(3-氯-2-甲基-4-(2-(4-甲基哌嗪-1-基)乙氧基)苯基)-6-(呋喃-2-基)噻吩并[2,3-d]嘧啶-4-基)氧基)-2-(1-(2-((1-(2,2,2-三氟乙基)-1H-吡唑-5-基)甲氧基)苯基)环丙基)乙酸乙酯
参照实施例1中步骤1的方法，中间体5代替中间体1，中间体11代替中间体12，得到标题化合物(40mg)。
步骤2：2-((5-(3-氯-2-甲基-4-(2-(4-甲基哌嗪-1-基)乙氧基)苯基)-6-(呋喃-2-基)噻吩并[2,3-d]嘧啶-4-基)氧基)-2-(1-(2-((1-(2,2,2-三氟乙基)-1H-吡唑-5-基)甲氧基)苯基)环丙基)乙酸
参照实施例1中步骤2的方法，2-((5-(3-氯-2-甲基-4-(2-(4-甲基哌嗪-1-基)乙氧基)苯基)-6-(呋喃-2-基)噻吩并[2,3-d]嘧啶-4-基)氧基)-2-(1-(2-((1-(2,2,2-三氟乙基)-1H-吡唑-5-基)甲氧基)苯基)环丙基)乙酸乙酯代替2-((5-(3-氯-2-甲基-4-(2-(4-甲基哌嗪-1-基)乙氧基)苯基)-6-(4-氟苯基)噻吩并[2,3-d]嘧啶-4-氧基)-3-甲基-3-(2-((1-(2,2,2-三氟乙基)-1H-吡唑-5-基)甲氧基)苯基)丁酸乙酯，取极性较大的异构体得到标题化合物(1.91mg)。
1H 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＝8.4Hz,1H),7.18(d,J＝8.0Hz,1H),7.03(d,J＝8.4Hz,1H),6.86(t,J＝7.6Hz,1H),6.60(d,J＝7.2Hz,1H),6.54(s,1H),6.38(dd,J＝3.2Hz,2.0Hz,1H),5.65(s,1H),5.62(d,J＝7.2Hz,1H),5.30(d,J＝13.2Hz,1H),5.24(d,J＝13.2Hz,1H),5.07-5.17(m,2H),4.32-4.47(m,2H),3.12-3.30(m,4H),3.08(t,J＝5.2Hz,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)。
实施例12：2-((5-(3-氯-2-甲基-4-(2-(4-甲基哌嗪-1-基)乙氧基)苯基)-6-(呋喃-2-基)噻吩并[2,3-d]嘧啶-4-氧基)-3-甲基-3-(2-((1-(2,2,2-三氟乙基)-1H-吡唑-5-基)甲氧基)苯基)丁酸
Figure PCTCN2018117014-appb-000035
步骤1：2-((5-(3-氯-2-甲基-4-(2-(4-甲基哌嗪-1-基)乙氧基)苯基)-6-(呋喃-2-基)噻吩并[2,3-d]嘧啶-4-氧基)-3-甲基-3-(2-((1-(2,2,2-三氟乙基)-1H-吡唑-5-基)甲氧基)苯基)丁酸甲酯
参照实施例1中步骤1的方法，中间体11代替中间体12，得到标题化合物(60mg)。
步骤2：2-((5-(3-氯-2-甲基-4-(2-(4-甲基哌嗪-1-基)乙氧基)苯基)-6-(呋喃-2-基)噻吩并[2,3-d]嘧啶-4-氧基)-3-甲基-3-(2-((1-(2,2,2-三氟乙基)-1H-吡唑-5-基)甲氧基)苯基)丁酸
参照实施例1中步骤2的方法，2-((5-(3-氯-2-甲基-4-(2-(4-甲基哌嗪-1-基)乙氧基)苯基)-6-(呋喃-2-基)噻吩并[2,3-d]嘧啶-4-氧基)-3-甲基-3-(2-((1-(2,2,2-三氟乙基)-1H-吡唑-5-基)甲氧基)苯基)丁酸甲酯代替2-((5-(3-氯-2-甲基-4-(2-(4-甲基哌嗪-1-基)乙氧基)苯基)-6-(4-氟苯基)噻吩并[2,3-d]嘧啶-4-氧基)-3-甲基-3-(2-((1-(2,2,2-三氟乙基)-1H-吡唑-5-基)甲氧基)苯基)丁酸乙酯，取极性较大的异构体得到标题化合物(15mg)。
1H 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＝8.0Hz,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＝3.2Hz,1H),5.18-5.25(m,4H),4.22-4.36(m,2H),2.85(t,J＝5.2Hz,2H),2.45-2.78(m,8H),2.33(s,3H),1.80(s,3H),0.99(s,3H),0.85(s,3H)。
实施例13：2-((5-(3-氯-2-甲基-4-(2-(4-甲基哌嗪-1-基)乙氧基)苯基)-6-(5-氟呋喃-2-基)噻吩并[2,3-d]嘧啶-4-基)氧基)-3-甲基-3-(2-((1-(2,2,2-三氟乙基)-1H-吡唑-5-基)甲氧基)苯基)丁酸
Figure PCTCN2018117014-appb-000036
步骤1：2-((5-(3-氯-2-甲基-4-(2-(4-甲基哌嗪-1-基)乙氧基)苯基)-6-(5-氟呋喃-2-基)噻吩并[2，3-d]嘧啶-4-基)氧基)-3-甲基-3-(2-((1-(2,2,2-三氟乙基)-1H-吡唑-5-基)甲氧基)苯基)丁 酸甲酯
参照实施例1中步骤1的方法，中间体10代替中间体12，得到标题化合物(20mg)。
步骤2：2-((5-(3-氯-2-甲基-4-(2-(4-甲基哌嗪-1-基)乙氧基)苯基)-6-(5-氟呋喃-2-基)噻吩并[2,3-d]嘧啶-4-基)氧基)-3-甲基-3-(2-((1-(2,2,2-三氟乙基)-1H-吡唑-5-基)甲氧基)苯基)丁酸
参照实施例1中步骤2的方法，2-((5-(3-氯-2-甲基-4-(2-(4-甲基哌嗪-1-基)乙氧基)苯基)-6-(5-氟呋喃-2-基)噻吩并[2，3-d]嘧啶-4-基)氧基)-3-甲基-3-(2-((1-(2,2,2-三氟乙基)-1H-吡唑-5-基)甲氧基)苯基)丁酸甲酯代替2-((5-(3-氯-2-甲基-4-(2-(4-甲基哌嗪-1-基)乙氧基)苯基)-6-(4-氟苯基)噻吩并[2,3-d]嘧啶-4-氧基)-3-甲基-3-(2-((1-(2,2,2-三氟乙基)-1H-吡唑-5-基)甲氧基)苯基)丁酸乙酯，取极性较大的异构体得到标题化合物(5mg)。
1H 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＝7.2Hz,1H),6.87(d,J＝8.0Hz,1H),6..55(d,J＝1.6Hz,1H),6.24(s,1H),5.85(dd,J＝7.2Hz,3.6Hz,1H),5.51(t,J＝7.2Hz,1H),5.17-5.25(m,4H),4.21-4.33(m,2H),2.83(t,J＝5.2Hz,2H),2.34-2.74(m,8H),2.28(s,3H),1.81(s,3H),0.98(s,3H),0.85(s,3H)。
实施例14：(2R)-2-(((5Sa)-5--(3-氯-2-甲基-4-(2-(4-甲基哌嗪-1-基)乙氧基)苯基)-6-(5-氟呋喃-2-基)噻吩并[2,3-d]嘧啶-4-基)氧基)-3-(2-((1-(2,2,2-三氟乙基)-1H-吡唑-5-基)甲氧基)苯基)丁酸
Figure PCTCN2018117014-appb-000037
步骤1：(2R)-2-(((5Sa)-5-(3-氯-2-甲基-4-(2-(4-甲基哌嗪-1-基)乙氧基)苯基)-6-(5-氟呋喃-2-基)噻吩并[2，3-d]嘧啶-4-基)氧基)-3-甲基-3-(2-((1-(2,2,2-三氟乙基)-1H-吡唑-5-基)甲氧基)苯基)丁酸甲酯
参照实施例1中步骤1的方法，中间体13代替中间体12，得到标题化合物(20mg)。
步骤2：(2R)-2-(((5Sa)-5--(3-氯-2-甲基-4-(2-(4-甲基哌嗪-1-基)乙氧基)苯基)-6-(5-氟呋喃-2-基)噻吩并[2,3-d]嘧啶-4-基)氧基)-3-(2-((1-(2,2,2-三氟乙基)-1H-吡唑-5-基)甲氧基)苯基)丁酸
参照实施例1中步骤2的方法，(2R)-2-(((5Sa)-5-(3-氯-2-甲基-4-(2-(4-甲基哌嗪-1-基)乙氧基)苯基)-6-(5-氟呋喃-2-基)噻吩并[2，3-d]嘧啶-4-基)氧基)-3-甲基-3-(2-((1-(2,2,2-三氟乙基)-1H-吡唑-5-基)甲氧基)苯基)丁酸甲酯代替2-((5-(3-氯-2-甲基-4-(2-(4-甲基哌嗪-1-基)乙氧基)苯基)-6-(4-氟苯基)噻吩并[2,3-d]嘧啶-4-氧基)-3-甲基-3-(2-((1-(2,2,2-三氟乙基)-1H-吡唑-5-基)甲氧基)苯基)丁酸乙酯，取极性较大的异构体得到标题化合物(3mg)。
1H 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＝7.2Hz,1H),6.87(d,J＝8.0Hz,1H),6..55(d,J＝1.6Hz,1H),6.24(s,1H),5.85(dd,J＝7.2Hz,3.6Hz,1H),5.51(t,J＝7.2Hz,1H),5.17-5.25(m,4H),4.21-4.33(m,2H),2.83(t,J＝5.2Hz,2H),2.34-2.74(m,8H),2.28(s,3H),1.81(s,3H),0.98(s,3H),0.85(s,3H)。
实施例15：(2R)-2-(((5Sa)-5-(3-氯-2-甲基-4-(2-(4-甲基哌嗪-1-基)乙氧基)苯基)-6-(5-氟呋喃-2-基)噻吩并[2,3-d]嘧啶-4-基)氧基)-2-(1-(2-((1-(2,2,2-三氟乙基)-1H-吡唑-5-基)甲氧基)苯基)环丙基)乙酸
Figure PCTCN2018117014-appb-000038
步骤1：(2R)-2-(((5Sa)-5-(3-氯-2-甲基-4-(2-(4-甲基哌嗪-1-基)乙氧基)苯基)-6-(5-氟呋喃-2-基)噻吩并[2,3-d]嘧啶-4-基)氧基)-2-(1-(2(-((1-(2,2,2-三氟乙基)-1H-吡唑-5-基)甲氧基)苯基)环丙基)乙酸乙酯
参照实施例1中步骤1的方法，中间体15代替中间体1，中间体10代替中间体12，得到标题化合物(10mg)。
步骤2：(2R)-2-(((5Sa)-5-(3-氯-2-甲基-4-(2-(4-甲基哌嗪-1-基)乙氧基)苯基)-6-(5-氟呋喃-2-基)噻吩并[2,3-d]嘧啶-4-基)氧基)-2-(1-(2(-((1-(2,2,2-三氟乙基)-1H-吡唑-5-基)甲氧基)苯基)环丙基)乙酸
参照实施例1中步骤2的方法，(2R)-2-(((5Sa)-5-(3-氯-2-甲基-4-(2-(4-甲基哌嗪-1-基)乙氧基)苯基)-6-(5-氟呋喃-2-基)噻吩并[2,3-d]嘧啶-4-基)氧基)-2-(1-(2(-((1-(2,2,2-三氟乙基)-1H-吡唑-5-基)甲氧基)苯基)环丙基)乙酸乙酯代替2-((5-(3-氯-2-甲基-4-(2-(4-甲基哌嗪-1-基)乙氧基)苯基)-6-(4-氟苯基)噻吩并[2,3-d]嘧啶-4-氧基)-3-甲基-3-(2-((1-(2,2,2-三氟乙 基)-1H-吡唑-5-基)甲氧基)苯基)丁酸乙酯，取极性较大的异构体得到标题化合物(5mg)。
1H NMR(400MHz,CD 3OD)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＝7.6Hz,1.6Hz,1H),7.02(d,J＝8.0Hz,1H),6.84(t,J＝7.6Hz,1H),6.58(dd,J＝7.6Hz,1.6Hz,1H),6.54(d,J＝1.6Hz,1H),5.63(s,1H),5.60(t,J＝3.2Hz,1H),5.56(dd,J＝6.4Hz,3.6Hz,1H),5.27(d,J＝13.2Hz,1H),5.24(d,J＝13.2Hz,1H),5.03-5.18(m,2H),4.34-4.42(m,2H),3.12-3.22(m,4H),3.06(t,J＝4.8Hz,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)。
实施例16：2-((5-(3-氯-2-甲基-4-(2-(4-甲基哌嗪-1-基)乙氧基)苯基)-6-(5-氟呋喃-2-基)噻吩并[2,3-d]嘧啶-4-基)氨基)-2-(1-(2-甲氧基苯基)环丙基)乙酸
Figure PCTCN2018117014-appb-000039
步骤1：2-((5-(3-氯-2-甲基-4-(2-(4-甲基哌嗪-1-基)乙氧基)苯基)-6-(5-氟呋喃-2-基)噻吩并[2,3-d]嘧啶-4-基)氨基)-2-(1-(2-甲氧基苯基)环丙基)乙酸乙酯
参照实施例1中步骤1的方法，中间体19替中间体1，中间体10代替中间体12，得标题化合物(20mg)。
步骤2：2-((5-(3-氯-2-甲基-4-(2-(4-甲基哌嗪-1-基)乙氧基)苯基)-6-(5-氟呋喃-2-基)噻吩并[2,3-d]嘧啶-4-基)氨基)-2-(1-(2-甲氧基苯基)环丙基)乙酸
参照实施例1中步骤2的方法，2-((5-(3-氯-2-甲基-4-(2-(4-甲基哌嗪-1-基)乙氧基)苯基)-6-(5-氟呋喃-2-基)噻吩并[2,3-d]嘧啶-4-基)氨基)-2-(1-(2-甲氧基苯基)环丙基)乙酸乙酯代替2-((5-(3-氯-2-甲基-4-(2-(4-甲基哌嗪-1-基)乙氧基)苯基)-6-(4-氟苯基)噻吩并[2,3-d]嘧啶-4-氧基)-3-甲基-3-(2-((1-(2,2,2-三氟乙基)-1H-吡唑-5-基)甲氧基)苯基)丁酸乙酯，得标题化合物(5mg)。
1H 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＝8.0Hz,1H),6.48(d,J＝7.6Hz,1H),5.84(dd,J＝6.8Hz,3.6Hz,1H),5.62(t,J＝3.6Hz,1H),5.26(d,J＝8.4Hz,1H),4.71(d,J＝8.4Hz,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)。
实施例17：(2R)-2-(((5Sa)-5-(3-氯-2-甲基-4-(2-(4-甲基哌嗪-1-基)乙氧基)苯基)-6-(4-氟苯基)噻吩并[2,3-d]嘧啶-4-基)氧基)-3-(2-((2-(2-甲氧基苯基)嘧啶-4-基)甲氧基)苯基)-3-甲基丁酸
Figure PCTCN2018117014-appb-000040
步骤1：(2R)-2-(((5Sa)-5-(3-氯-2-甲基-4-(2-(4-甲基哌嗪-1-基)乙氧基)苯基)-6-(4-氟苯基)噻吩并[2,3-d]嘧啶-4-基)氧基)-3-(2-((2-(2-甲氧基苯基)嘧啶-4-基)甲氧基)苯基)-3-甲基丁酸甲酯
参照实施例1中步骤1的方法，用中间体18代替中间体1，得到标题化合物(20mg)。
步骤2：(2R)-2-(((5Sa)-5-(3-氯-2-甲基-4-(2-(4-甲基哌嗪-1-基)乙氧基)苯基)-6-(4-氟苯基)噻吩并[2,3-d]嘧啶-4-基)氧基)-3-(2-((2-(2-甲氧基苯基)嘧啶-4-基)甲氧基)苯基)-3-甲基丁酸
参照实施例1中步骤2的方法，用(2R)-2-(((5Sa)-5-(3-氯-2-甲基-4-(2-(4-甲基哌嗪-1-基)乙氧基)苯基)-6-(4-氟苯基)噻吩并[2,3-d]嘧啶-4-基)氧基)-3-(2-((2-(2-甲氧基苯基)嘧啶-4-基)甲氧基)苯基)-3-甲基丁酸甲酯代替2-((5-(3-氯-2-甲基-4-(2-(4-甲基哌嗪-1-基)乙氧基)苯基)-6-(4-氟苯基)噻吩并[2,3-d]嘧啶-4-氧基)-3-甲基-3-(2-((1-(2,2,2-三氟乙基)-1H-吡唑-5-基)甲氧基)苯基)丁酸乙酯，取极性较大的异构体得到标题化合物(4mg)。
1H 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＝4.0Hz,1H),6.44(s,1H),5.25(d,J＝15.2Hz,1H),5.24(d,J＝15.2Hz,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)。
实施例18：(2R)-2-(((5Sa)-5-(3-氯-2-甲基-4-(2-(4-甲基哌嗪-1-基)乙氧基)苯基)-6-(4-氟苯基)噻吩并[2，3-d]嘧啶-4-基)氧基)-2-(1-(2-((2-(2-甲氧基苯基)嘧啶-4-基)甲氧基)苯基)环丙基)乙酸
Figure PCTCN2018117014-appb-000041
步骤1：(2R)-2-(((5Sa)-5-(3-氯-2-甲基-4-(2-(4-甲基哌嗪-1-基)乙氧基)苯基)-6-(4-氟苯基)噻吩并[2，3-d]嘧啶-4-基)氧基)-2-(1-(2-((2-(2-甲氧基苯基)嘧啶-4-基)甲氧基)苯基)环丙基)乙酸乙酯
参照实施例1中步骤1的方法，用中间体17代替中间体1，得到标题化合物(90mg)。
步骤2：(2R)-2-(((5Sa)-5-(3-氯-2-甲基-4-(2-(4-甲基哌嗪-1-基)乙氧基)苯基)-6-(4-氟苯基)噻吩并[2，3-d]嘧啶-4-基)氧基)-2-(1-(2-((2-(2-甲氧基苯基)嘧啶-4-基)甲氧基)苯基)环丙基)乙酸
参照实施例1中步骤2的方法，(2R)-2-(((5Sa)-5-(3-氯-2-甲基-4-(2-(4-甲基哌嗪-1-基)乙氧基)苯基)-6-(4-氟苯基)噻吩并[2，3-d]嘧啶-4-基)氧基)-2-(1-(2-((2-(2-甲氧基苯基)嘧啶-4-基)甲氧基)苯基)环丙基)乙酸乙酯代替2-((5-(3-氯-2-甲基-4-(2-(4-甲基哌嗪-1-基)乙氧基)苯基)-6-(4-氟苯基)噻吩并[2,3-d]嘧啶-4-氧基)-3-甲基-3-(2-((1-(2,2,2-三氟乙基)-1H-吡唑-5-基)甲氧基)苯基)丁酸乙酯，取极性较大的异构体得到标题化合物(45mg)。
1H 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,1.6Hz,1H),7.40-7.45(m,2H),7.02-7.14(m,5H),6.89-6.97(m,3H),6.78(d,J＝8.0Hz,1H),6.74(d,J＝7.6Hz,1H),6.36(d,J＝7.6Hz,1H),5.78(s,1H),5.22(d,J＝15.2Hz,1H),5.15(d,J＝15.2Hz,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)。
实施例19：(R)-4-(2-(4-(4-(羧基(1-(2-((2-(2-甲氧基苯基)嘧啶-4-基)甲氧基)苯基)环丙基)甲氧基)-6-(4-氟苯基)噻吩并[2,3-d]嘧啶-5-基)-2-氯-3-甲基苯氧基)乙基)-1-甲基-1-((膦酰氧基)甲基)哌嗪-1-鎓
Figure PCTCN2018117014-appb-000042
步骤1：(2R)-2-(((5Sa)-5-(3-氯-2-甲基-4-(2-(4-甲基哌嗪-1-基)乙氧基)苯基)-6-(4-氟苯基)噻吩并[2，3-d]嘧啶-4-基)氧基)-2-(1-(2-((2-(2-甲氧基苯基)嘧啶-4-基)甲氧基)苯基)环丙基)乙酸(4-甲氧基)苄酯
室温下，向(2R)-2-(((5Sa)-5-(3-氯-2-甲基-4-(2-(4-甲基哌嗪-1-基)乙氧基)苯基)-6-(4-氟苯基)噻吩并[2,3-d]嘧啶-4-基)氧基)-2-(1-(2-((2-(2-甲氧基苯基)嘧啶-4-基)甲氧基)苯基)环丙基)乙酸(75mg)、(4-甲氧基)苄醇(23mg)和三苯基膦(55mg)的甲苯(10mL)溶液中滴加DIAD(37mg)，加毕后升至50℃搅拌1小时。将反应液倒入水中，乙酸乙酯萃取，萃取液用饱和食盐水洗，无水硫酸钠干燥，过滤，滤液浓缩，将残留物用硅胶柱色谱法(洗脱液：二氯甲烷:甲醇＝15:1(V:V))纯化得标题化合物(60mg)。
步骤2：(R)-4-(2-(2-氯-4-(6-(4-氟苯基)-4-(2-((4-甲氧基苄基)氧基)-1-(1-(2-((2-(2-甲氧基苯基)嘧啶-4-基)甲氧基)苯基)环丙基)-2-氧代乙氧基)噻吩并[2,3-d]嘧啶-5-基)-3-甲基苯氧基)乙基)-1-(((二叔丁氧基磷酰基)氧基)甲基)-1-甲基哌嗪-1-鎓
室温下，向(2R)-2-(((5Sa)-5-(3-氯-2-甲基-4-(2-(4-甲基哌嗪-1-基)乙氧基)苯基)-6-(4-氟苯基)噻吩并[2，3-d]嘧啶-4-基)氧基)-2-(1-(2-((2-(2-甲氧基苯基)嘧啶-4-基)甲氧基)苯基)环丙基)乙酸(4-甲氧基)苄酯(60mg)、碘化钠(26mg)和碳酸氢钠(15mg)的丙酮(10mL)溶液中滴加二叔丁基氯甲基磷酸酯(45mg)，加毕后室温搅拌1小时。将反应液过滤，固体烘干直接用于下一步反应。
步骤3：(R)-4-(2-(4-(4-(羧基(1-(2-((2-(2-甲氧基苯基)嘧啶-4-基)甲氧基)苯基)环丙基)甲氧基)-6-(4-氟苯基)噻吩并[2,3-d]嘧啶-5-基)-2-氯-3-甲基苯氧基)乙基)-1-甲基-1-((膦酰氧基)甲基)哌嗪-1-鎓
室温下，向(R)-4-(2-(2-氯-4-(6-(4-氟苯基)-4-(2-((4-甲氧基苄基)氧基)-1-(1-(2-((2-(2-甲氧基苯基)嘧啶-4-基)甲氧基)苯基)环丙基)-2-氧代乙氧基)噻吩并[2,3-d]嘧啶-5-基)-3-甲基苯氧基)乙基)-1-(((二叔丁氧基磷酰基)氧基)甲基)-1-甲基哌嗪-1-鎓的二氯甲烷(4mL)溶液中滴加三氟乙酸(3mL)，加毕后室温搅拌12小时。将反应液浓缩，残余物经制备柱分离的目标化合物10(mg).
1H NMR(400MHz,CD 3OD)δ8.80(d,J＝5.6Hz,1H),8.41(s,1H),8.01(d,J＝5.2Hz,1H),7.68(dd,J＝7.2Hz,1.6Hz,1H),7.49(td,J＝8.0Hz,1.2Hz,1H),7.33(d,J＝8.4Hz,1H),7.22-7.26(m,2H),7.13-7.17(m,3H),6.99-7.06(m,3H),6.93(d,J＝8.4Hz,1H),6.77(t,J＝7.2Hz,1H),6.43(dd,J＝7.6Hz,1.6Hz,1H),5.63(s,1H),5.29(d,J＝15.6Hz,1H),5.22(d,J＝15.6Hz,1H),4.89(d,J＝8.4Hz,2H),4.32(t,J＝4.4Hz,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).
生物活性实验
1.化合物的体外蛋白活性测定：
采用荧光偏振方法建立了Mcl-1的蛋白活性筛选方法。其基本原理是：小分子化合物与荧光基团FITC标记的短肽(FITC-Noxa)竞争其与Mcl-1的结合位点。当FITC-Noxa与大分子物质Mcl-1结合之后，荧光物质FITC经单一平面的蓝偏振光(485nm)照射后，吸收光能跃入激发态，随后回复至基态，并发出单一平面的偏振荧光(525nm)。相反，如果FITC-Noxa未能与大分子物质Mcl-1结合，小分子旋转或翻转速度快，发射光相对于激发光平面将去偏振化。也就是说当化合物竞争性的与Mcl-1结合之后，FITC-Noxa便会以游离状态存在，其偏振值降低。因此，通过偏振值的变化可以反映化合物与Mcl-1的结合能力。
具体操作如下：首先将10mM的化合物储存液用DMSO稀释至1mM，之后用DMSO进行3倍梯度稀释。取4μL梯度稀释的化合物转移到96μL反应缓冲液中(PBS,pH 7.4；50mM NaCl；0.01％NP40和2mM二硫代苏糖醇(DTT))，而后将这种进一步稀释的化合物加入到384-孔黑色圆底板
Figure PCTCN2018117014-appb-000043
中，接着添加8μL反应缓冲液配制的含有10nM Mcl-1的蛋白溶液。然后将上述测试混合物在23℃摇晃孵育30分钟，之后添加4μL含有10nM FITC-Noxa的反应缓冲液并继续室温孵育120分钟。通过EnVision在Ex 485/Em530下进行偏振光值测定。通过数据分析软件Prism处理数据并得到该化合物的IC50值。
2.化合物的细胞增殖活性测定：
采用Promega公司的
Figure PCTCN2018117014-appb-000044
检测试剂建立了悬浮细胞增殖抑制筛选方法。
人白血病细胞MV-411以及人骨髓瘤细胞NCI-H929用补充有10％(MV-411)和20％(NCI-H929)胎牛血清
Figure PCTCN2018117014-appb-000045
的
Figure PCTCN2018117014-appb-000046
培养基进行培养，培养条件是37℃，95％空气和5％的CO2，培养于25cm2或75cm2塑料组织培养瓶
Figure PCTCN2018117014-appb-000047
中，一周传代培养2～3次。
将细胞分别以8×103细胞/孔(MV-411)和1×104细胞/孔(NCI-H929)的密度接种在96-孔细胞培养板
Figure PCTCN2018117014-appb-000048
中，195μL/孔，并在37℃，95％空气和5％的CO2中进行培养。24小时后加入待测化合物：将化合物从10mM(溶于DMSO中)开始用DMSO进行3倍梯度稀释，每个浓度取4μL加入到96μL的无血清培养基中，最后取5μL培养基稀释后的化合物加入到接种有细胞的培养版中。细胞培养液中DMSO的终浓度为0.1％，所试化 合物的终浓度是0.3nM～10μM。将上述细胞37℃温育3天。
3天后，通过Cell Titer-Blue(Promega)试剂盒进行细胞活力测定，最后通过Prism程序计算化合物对细胞增殖的半抑制浓度，即IC50值。
所选的部分化合物的生物学数据
根据本文所述的生物学方法对上述制备的所选化合物进行分析。其结果显示于下表：
蛋白活性数据
Figure PCTCN2018117014-appb-000049
细胞学数据
Figure PCTCN2018117014-appb-000050
Figure PCTCN2018117014-appb-000051
工业实用性
本发明提供一种Mcl-1选择性抑制剂及其制备和用途。本发明同时提供了一系列由通式(I)所表示的化合物及其药学上可接受的盐、溶剂化物、多晶型物或前药、包含这些化合物的药物组合物，以及用此类化合物治疗由过度表达或失调的MCL-1蛋白引起的或加重的疾病的方法。本发明提供的Mcl-1选择性抑制剂的活性高、耐药性强、临床副作用小，可有效克服肿瘤治疗耐药性问题，具有较好的经济价值和应用前景。

Claims (10)

  1. 式(I)化合物，或其药学上可接受的盐、溶剂化物、异构体、或前药，
    Figure PCTCN2018117014-appb-100001
    其中，
    X为O、NH或S；
    a和b各自独立地为单键或双键，且a和b中最多只有一个可以为双键；
    R 1选自H和5-8元杂芳基，所述杂芳基可任选地被C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、C 1-6烷基-O-、或6-10元芳基取代，所述C 1-6烷基可任选地被1-3个卤素取代，并且所述6-10元芳基可任选地被1-3个独立地选自C 1-6烷基和C 1-6烷基-O-的基团取代；
    当a和b均为单键时，R 2和R 3各自独立地选自H、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、卤素和氰基，或者R 2、R 3和与之相连的碳原子一起形成3-8元环烷基，R 2和R 3不能同时为氢；
    当a为双键时，R 3不存在，R 2为
    Figure PCTCN2018117014-appb-100002
    当b为双键时，R 3不存在，R 2选自H、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、卤素和氰基；
    R 4各自独立地为卤素、C 1-6烷基、C 1-6烷基-O-、或氰基；
    R 5选自苯基和5-8元杂芳基，所述苯基和5-8元杂芳基任选地被1-3个选自卤素和C 1-6烷基的基团取代；
    R 6选自3-8元杂环基，所述杂环基任选地被C 1-6烷基、-C 1-6亚烷基-O-P(＝O)(OH) 2、 C 1-6烷基-O-取代；
    R 7和R 8各自独立地选自H和C 1-6烷基；
    p和q各自独立地为1、2、3、4、5和6；
    m为0、1、2、3、或4。
  2. 根据权利要求1所述的化合物或其药学上可接受的盐、溶剂化物、异构体、或前药，其中X为O；其结构式如以下式(II)所示：
    Figure PCTCN2018117014-appb-100003
    其中，
    a和b各自独立地为单键或双键，且a和b中最多只有一个可以为双键；
    R 1选自H和5-8元杂芳基，所述杂芳基可任选地被C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、C 1-6烷基-O-、或6-10元芳基取代，所述C 1-6烷基可任选地被1-3个卤素取代，并且所述6-10元芳基可任选地被1-3个独立地选自C 1-6烷基和C 1-6烷基-O-的基团取代；
    当a和b均为单键时，R 2和R 3各自独立地选自H、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、卤素和氰基，或者R 2、R 3和与之相连的碳原子一起形成3-8元环烷基，R 2和R 3不能同时为氢；
    当a为双键时，R 3不存在，R 2为
    Figure PCTCN2018117014-appb-100004
    当b为双键时，R 3不存在，R 2选自H、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、卤素和氰基；
    R 4各自独立地为卤素或C 1-6烷基；
    R 5选自苯基和5-8元杂芳基，所述苯基和5-8元杂芳基任选地被1-3个选自卤素和C 1-6烷基的基团取代；
    R 6选自3-8元杂环基，所述杂环基任选地被C 1-6烷基取代；
    R 7和R 8各自独立地选自H和C 1-6烷基；
    p和q各自独立地为1、2、3、4、5和6；
    m为0、1、或2。
  3. 根据权利要求1或2所述的化合物或其药学上可接受的盐、溶剂化物、异构体、或前药，其中R 1选自H和5-8元杂芳基；所述杂芳基可任选地被C 1-6烷基、C 1-6烷基-O-、或者6-10元芳基取代；所述C 1-6烷基可任选地被1-3个卤素取代，并且所述6-10元芳基可任选地被1-3个独立地选自C 1-6烷基和C 1-6烷基-O-的基团取代；
    优选地，R 1选自H、吡唑基和嘧啶基；所述吡唑基和嘧啶基可任选地被C 1-6烷基、C 1-6烷基-O-、或者6-10元芳基取代，所述C 1-6烷基可任选地被1-3个卤素取代，并且所述6-10元芳基可任选地被1-3个独立地选自C 1-6烷基和C 1-6烷基-O-的基团取代。
    优选地，R 1选自H、吡唑基、嘧啶基，所述吡唑基可任选地被C 1-6烷基取代，所述C 1-6烷基可任选地被1-3个卤素取代，所述嘧啶基可任选地被6-10元芳基取代，所述6-10元芳基可任选地被1-3个独立地选自C 1-6烷基和C 1-6烷基-O-的基团取代。
  4. 根据权利要求1或2所述的化合物或其药学上可接受的盐、溶剂化物、异构体、或前药，其中
    当a和b均为单键时，R 2和R 3各自独立地选自H、C 1-6烷基、卤素和氰基，或者R 2、R 3和与之相连的碳原子一起形成3-8元环烷基，R 2和R 3不能同时为氢；
    当a为双键时，R 3不存在，R 2为
    Figure PCTCN2018117014-appb-100005
    其中R 7和R 8为氢；
    当b为双键时，R 3不存在，R 2选自H、C 1-6烷基、卤素和氰基；
  5. 根据权利要求1或2所述的化合物或其药学上可接受的盐、溶剂化物、异构体、或前药，其中R 5选自苯基和呋喃基，所述苯基和呋喃基任选地被1-3个选自卤素和C 1-6烷基的基团取代。
  6. 根据权利要求1或2所述的化合物或其药学上可接受的盐、溶剂化物、异构体、或前药，其中p为1，q为2；
  7. 根据权利要求1或2所述的化合物或其药学上可接受的盐、溶剂化物、异构体、或前药，其中所述化合物选自：
    Figure PCTCN2018117014-appb-100006
  8. 一种药物组合物，其包含式(I)化合物或其药学上可接受的盐、溶剂化物、异构体、或前药，以及药学上可接受的载体。
  9. 权利要求1-7所述的化合物或其药学上可接受的盐、溶剂化物、异构体、或前药在制备用于治疗由过度表达或失调的MCL-1蛋白引起的或加重的疾病的药物中的用途。
  10. 权利要求1-7所述的化合物或其药学上可接受的盐、溶剂化物、异构体、或前药在制备用于治疗膀胱癌、脑癌、乳腺癌和子宫癌、慢性淋巴性白血病、结肠癌、食道癌和肝癌、成淋巴细胞白血病、急性髓性白血病、淋巴瘤、卵巢癌、非小细胞肺癌、多发性骨髓瘤、急性淋巴白血病、或骨髓增生异常综合征的药物中的用途。
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