WO2019101144A1 - Inhibiteur sélectif de mcl-1, préparation et utilisation associées - Google Patents

Inhibiteur sélectif de mcl-1, préparation et utilisation associées 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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alkyl
phenyl
group
methyl
methoxy
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PCT/CN2018/117014
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English (en)
Chinese (zh)
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
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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/fr

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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

La présente invention concerne un inhibiteur sélectif de Mcl-1, ainsi qu'une préparation et une utilisation associées. La présente invention concerne également une série de composés représentés par la formule générale (I), un sel, un solvate, des polymorphes ou des promédicaments pharmaceutiquement acceptables de ceux-ci, des compositions pharmaceutiques comprenant les composés, et des méthodes de traitement d'une maladie induite ou aggravée par une protéine MCL-1 surexprimée ou dysfonctionnelle à l'aide des composés.
PCT/CN2018/117014 2017-11-23 2018-11-22 Inhibiteur sélectif de mcl-1, préparation et utilisation associées WO2019101144A1 (fr)

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CN113024578A (zh) * 2019-12-09 2021-06-25 首药控股(北京)有限公司 一种mcl1选择性抑制剂的多晶型物及其制备方法

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WO2016207217A1 (fr) * 2015-06-23 2016-12-29 Les Laboratoires Servier Nouveaux dérivés bicycliques, leur procédé de préparation, et compositions pharmaceutiques les contenant
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