WO2023134751A1 - 微管蛋白-Src双靶点抑制剂和用途 - Google Patents

微管蛋白-Src双靶点抑制剂和用途 Download PDF

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WO2023134751A1
WO2023134751A1 PCT/CN2023/072140 CN2023072140W WO2023134751A1 WO 2023134751 A1 WO2023134751 A1 WO 2023134751A1 CN 2023072140 W CN2023072140 W CN 2023072140W WO 2023134751 A1 WO2023134751 A1 WO 2023134751A1
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alkyl
compound
ring
pharmaceutically acceptable
formula
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PCT/CN2023/072140
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French (fr)
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张学军
臧杨
杨辉
雷四军
魏文军
吴智强
刘勇
高振兴
钱丽娜
李莉娥
杨俊�
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武汉人福创新药物研发中心有限公司
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    • C07F7/22—Tin compounds
    • C07F7/2208—Compounds having tin linked only to carbon, hydrogen and/or halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/04—Systems containing only non-condensed rings with a four-membered ring
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention belongs to the field of medicine, in particular, the invention relates to a tubulin-Src dual-target inhibitor and its application.
  • Microtubules are an important part of the cytoskeleton in eukaryotic cells and play an important role in maintaining cell shape, signal transmission, organelle transport, cell movement, cell division and mitosis and other cellular functions (Jordan M A et al. Nature Reviews Cancer, 2004, 4(4):253-265.).
  • Microtubules are composed of two types of tubulin subunits, ⁇ -tubulin and ⁇ -tubulin, which form tubulin heterodimers and are microtubule The basic unit of assembly.
  • Microtubule-targeting agents can destroy the dynamic stability and structure of microtubules, interfere with the formation of mitotic spindle, induce cell cycle arrest in G2/M phase, and promote cell apoptosis (Shuai W et al. Journal of Medicinal Chemistry, 2021, 64(12).).
  • Microtubules are involved in many important cellular processes and have become one of the most important drug targets for the treatment of hyperproliferative diseases.
  • dual-target inhibitors can overcome drug resistance and improve therapeutic effects, and have become research hotspots, such as: tubulin-SRC dual-target inhibitors, tubulin-receptor tyrosine Kinase (receptor tyrosine kinases inhibitor, RTK) dual-target inhibitor, tubulin-histone deacetylase (histone deacetylases inhibitor, HDAC) dual-target inhibitors, etc.
  • tubulin-SRC dual-target inhibitors tubulin-receptor tyrosine Kinase (receptor tyrosine kinases inhibitor, RTK) dual-target inhibitor
  • tubulin-histone deacetylase histone deacetylases inhibitor, HDAC
  • Actinic keratosis a skin disorder associated with prolonged exposure to UV light
  • AK Actinic keratosis
  • SCC cutaneous squamous cell carcinoma
  • the tubulin-SRC dual-target inhibitor Tirbanibulin has a significant clinical effect in the local treatment of AK (NCT03285477), and has been approved by the FDA for marketing, which indicates that the development of new tubulin-SRC dual-target inhibitors with better efficacy locally Treatment of AK may be a potential direction.
  • the object of the present invention is to provide a compound used as a dual-target inhibitor of tubulin-Src kinase. It can also be used as a single tubulin polymerization inhibitor or Src kinase inhibitor.
  • X is selected from O, S, NH or N(C 1 -C 6 alkyl);
  • ring A When ring A exists, Y does not exist; said ring A is selected from C 3 -C 8 cycloalkyl;
  • Y is selected from C 1 -C 6 alkyl substituted by R 1 , or Wherein, the ring B is selected from 3-6 membered cycloalkyl or 4-8 membered heterocycloalkyl;
  • the R 1 is C 1 -C 6 alkyl
  • Each of said L 1 and L 2 independently does not exist or is selected from C 1 -C 6 alkylene;
  • Z is selected from C 3 -C 8 cycloalkyl, 3-11 membered heterocycloalkyl, wherein, the C 3 -C 8 cycloalkyl, 3-11 membered heterocycloalkyl is optionally substituted by R 2 ;
  • Q is selected from an unsubstituted or substituted 6-10 membered aryl group, an unsubstituted or substituted 5-10 membered heteroaryl group by R3 ;
  • the heteroatom of the heteroaryl group is N, O or S , the number of heteroatoms is 1-3;
  • the R 3 is substituted by one or more substitutions, and each of the R 3 is independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkoxy; or, when R 3 is multiple, substituted 6-10 membered aryl or 5-10 membered heteroaryl together with R 3 form an O-containing saturated heterocycle ;
  • n, p, and q are 0, 1, 2, or 3 each independently.
  • X is selected from O
  • ring A When ring A exists, Y does not exist; said ring A is selected from C 3 -C 8 cycloalkyl;
  • Y is selected from C 1 -C 6 alkyl substituted by R 1 ;
  • the R 1 is C 1 -C 6 alkyl
  • Z is selected from 3-11 membered heterocycloalkyl groups that are unsubstituted or substituted by 1 or more C 1 -C 6 alkyl groups;
  • the C 1 -C 6 alkyl is substituted with methyl
  • Q is selected from unsubstituted 6-10 membered aryl groups
  • R a is halogen, cyano or C 1 -C 6 alkyl
  • n 1;
  • p is 0 or 1;
  • the C 3 -C 8 cycloalkyl group is a 3-6 membered cycloalkyl group.
  • the C 3 -C 8 cycloalkyl is a monocyclic ring, a parallel ring, a bridged ring or a spiro ring.
  • the C 3 -C 8 cycloalkyl is a saturated ring.
  • the C 3 -C 8 cycloalkyl is cyclobutyl or cyclopropyl, more preferably Further optimization
  • said C 1 -C 6 alkyl group is preferably a C 1 -C 3 alkylene group, more preferably -CH 2 -, -CH 2 CH 2 - or - CH2CH2CH2- .
  • said C 1 -C 6 alkyl group is preferably methyl or ethyl.
  • said Y is further preferred Its left end is connected with Z.
  • the 3-11 membered heterocycloalkyl is 4-10 membered heterocycloalkyl, preferably, the 3-11 membered heterocycloalkyl is 4 -6 membered heterocycloalkyl.
  • said 3-11 membered heterocycloalkyl is a monocyclic ring, a double ring, a bridged ring or a spiro ring.
  • said 3-11 membered heterocycloalkyl is a saturated ring.
  • the heteroatoms in said 3-11 membered heterocycloalkyl are N and/or O.
  • the heteroatoms in said 3-11 membered heterocycloalkyl are N and O.
  • said 3-11 membered heterocycloalkyl is connected to Y or A through an N atom.
  • said 3-11 membered heterocycloalkyl is
  • said 6-10 membered aryl group is phenyl
  • said halogen is fluorine or chlorine.
  • said C 1 -C 6 alkyl group is methyl or ethyl.
  • Y is selected from C 1 -C 6 alkyl substituted by methyl, or
  • the ring B is cyclopropyl; the L 1 and L 2 are independently absent or selected from C 1 - C 6 alkylene.
  • Z is selected from unsubstituted or 3-11 membered saturated heterocycles substituted by R 2 , wherein R 2 is selected from C 1 -C 6 alkyl, and the substitution is 1 1 or 2; the 3-11 membered saturated heterocyclic ring further has 1 to 3 heteroatoms selected from N, O, S.
  • Z is selected from 5-10 membered saturated heterocycles that are unsubstituted or substituted by R 2 ; wherein, the 5-10 membered saturated heterocycles are monocyclic, parallel, spiro or bridge ring.
  • Z is selected from 5-8 membered monocyclic rings, 6-10 membered spiro rings, 6-10 membered bridge rings, 8-10 membered monocyclic rings, 8-10 membered monocyclic rings that are unsubstituted or substituted by R 2 ring.
  • Z is selected from
  • Q is selected from unsubstituted or substituted by R 3 phenyl, unsubstituted or substituted by R 5-6 membered heteroaryl; the heteroatom of the heteroaryl is N, O or S, the number of heteroatoms is 1-3; the R 3 is substituted with one or more substitutions, and the R 3 are each independently selected from hydrogen, halogen, hydroxyl, nitro, cyano , C 1 -C 6 alkyl, C 1 -C 6 alkoxy; or, when R 3 is more than one, substituted phenyl or 5-6 membered heteroaryl together with R 3 form O-containing saturated hetero ring.
  • said Q is selected from
  • the compound shown in formula I has a structure shown in formula II:
  • X, ring A, Y, Z, m, n are as defined in the first aspect of the present invention.
  • R 6 and R 7 are independently absent or methyl, ethyl, fluorine, chlorine, respectively.
  • the compound shown in formula I has a structure shown in formula III:
  • X, ring A, Y, Z, m, n are as defined in the first aspect of the present invention.
  • R 6 and R 7 are independently absent or methyl, ethyl, fluorine, chlorine, respectively.
  • X, ring A, Y, Z, m, n are as defined in the first aspect of the present invention.
  • R 6 and R 7 are independently absent or methyl, ethyl, fluorine, chlorine, respectively.
  • the compound shown in formula I has a structure shown in formula III:
  • X, ring A, Y, Z, m, n are as defined in the first aspect of the present invention.
  • R 6 and R 7 are independently absent or methyl, ethyl, fluorine, chlorine, respectively.
  • said R 6 is identical to R b
  • R 7 is identical to R a .
  • the compound shown in formula I has a structure shown in formula IV-1:
  • the compound shown in formula I has a structure shown in formula IV-2:
  • the compound shown in formula I has a structure shown in formula IV-3:
  • the compound shown in formula I has a structure shown in formula IV-4:
  • the compound shown in formula I has a structure shown in formula IV-5:
  • the compound shown in formula I has a structure shown in formula IV-6:
  • the compound shown in formula I has a structure shown in formula IV-7:
  • the compound shown in formula I has a structure shown in formula IV-8:
  • the compound shown in formula I has a structure shown in formula IV-9:
  • the compound shown in formula I has a structure shown in formula IV-10:
  • the compound shown in formula I has a structure shown in formula IV-11:
  • the compound shown in formula I has a structure shown in formula IV-12:
  • the compound shown in formula I is selected from any of the following compounds:
  • a compound or a salt thereof is provided, which is selected from any of the following structures:
  • the third aspect of the present invention provides a pharmaceutical composition, said pharmaceutical composition comprising: the compound shown in formula I as described in the first aspect of the present invention, its tautomer, stereoisomer, solvent compound (such as hydrate), pharmaceutically acceptable salt or prodrug; and pharmaceutically acceptable carrier.
  • the fourth aspect of the present invention provides the compound represented by formula I as described in the first aspect of the present invention, its tautomers, stereoisomers, solvates (such as hydrates), and pharmaceutically acceptable salts Or the use of prodrug, or the use of the pharmaceutical composition described in the third aspect of the present invention, said use includes: inhibiting tubulin polymerization and/or Src kinase; and/or, preventing and/or treating tubulin polymerization mediate and/or Src kinase-related diseases; and/or, preparation for inhibiting tubulin polymerization and/or Src kinase, and/or, preparation for the prevention and/or treatment of tubulin polymerization-mediated and/or Src kinase-related A drug, pharmaceutical composition or preparation for a disease.
  • the drug is an external preparation.
  • the drug is a drug for transdermal administration.
  • tubulin polymerization-mediated or Src kinase-related diseases include: one, two or more of tumors, skin diseases and/or other diseases.
  • the tumors include, but are not limited to: solid tumors, sarcomas, hematological cancers, subtypes include breast cancer, ovarian cancer, prostate cancer, cervical cancer, testicular cancer, colon cancer, colorectal cancer, liver cancer, Small cell lung cancer, squamous cell carcinoma, small cell lung cancer, gastric cancer, gastrointestinal stromal tumor, pancreatic cancer, bladder cancer, germ cell tumor, mast cell tumor, mastocytosis, glioblastoma, neuroblastoma astrocytoma, melanoma, B-cell lymphoma, T-cell lymphoma, indolent lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, acute myeloid leukemia, acute lymphoblastic leukemia, Chronic myeloid leukemia, chronic lymphocytic leukemia, myeloma, and/or myelodysplastic syndrome
  • the skin diseases include but not limited to: actinic keratosis, psoriasis, atopic dermatitis, psoriasis, vitiligo, roseola and/or systemic lupus erythematosus.
  • the other diseases include but are not limited to: autoimmune diabetes, diabetic retinopathy, liver fibrosis, pulmonary fibrosis (including idiopathic pulmonary fibrosis, etc.), renal fibrosis, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, spinocerebellar degeneration, atherosclerosis, anemia, sickle cell anemia, thalassemia, osteoarthritis, rheumatoid arthritis, malaria, cone protozoa, helminthiasis, protozoan infection, multiple sclerosis, lupus, asthma, allergic rhinitis, and/or inflammatory bowel disease.
  • the fifth aspect of the present invention provides the compound as described in any one of the first aspect, its tautomer, stereoisomer, solvate (such as hydrate), pharmaceutically acceptable salt or prodrug
  • At least one of or the pharmaceutical composition described in the third aspect of the present invention is used to treat or prevent tumors and/or skin Use for skin diseases.
  • a method for inhibiting tubulin polymerization and/or Src kinase, or preventing and/or treating diseases related to microtubule oligomerization and/or Src kinase comprising the steps of: giving to a subject in need Administration of the compound represented by formula I according to the first aspect of the present invention, its tautomers, stereoisomers, solvates (eg hydrates), pharmaceutically acceptable salts or prodrugs.
  • a method for inhibiting Src kinase, or preventing and/or treating Src kinase-related (or mediated) diseases comprising the steps of: administering to a subject in need as described in the first aspect of the present invention
  • the above compound, its tautomer, stereoisomer, solvate (such as hydrate), pharmaceutically acceptable salt or prodrug, or the pharmaceutical composition as described in the third aspect of the present invention comprising the steps of: administering to a subject in need as described in the first aspect of the present invention
  • a method for inhibiting tubulin, or preventing and/or treating tubulin-related (or mediated) diseases comprising the steps of: administering to a subject in need as described in the first aspect of the present invention
  • the compound described in one aspect, its tautomer, stereoisomer, solvate (such as hydrate), pharmaceutically acceptable salt or prodrug, or the pharmaceutical composition as described in the third aspect of the present invention comprising the steps of: administering to a subject in need as described in the first aspect of the present invention
  • reactions and purifications can be carried out using the manufacturer's instructions for the kit, or by methods known in the art or as described herein.
  • the techniques and methods described above can generally be performed according to conventional methods well known in the art as described in various general and more specific documents that are cited and discussed in this specification.
  • groups and substituents thereof can be selected by those skilled in the art to provide stable moieties and compounds.
  • substituents When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes chemically equivalent substituents obtained when the structural formula is written from right to left. For example, CH2O is equivalent to OCH2 .
  • R 1 ", “R1” and “R 1 " have the same meaning and can be substituted for each other. For other symbols such as R 2 , similar definitions have the same meanings.
  • a number from 1 to 10 should be understood as not only recording each integer of 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10, but also at least recording each of the integers with Sum of 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9.
  • substitution means that the hydrogen atom in the molecule is replaced by other different atoms or groups, or the lone pair of electrons of atoms in the molecule is replaced by other atoms or groups, for example, the lone pair of electrons on the S atom can be replaced by O atomic substitution formation
  • halogen alone or as part of another substituent, means fluorine, chlorine, bromine, iodine; preferably fluorine or chlorine.
  • alkyl means consisting solely of carbon and hydrogen atoms, free of unsaturated bonds, having, for example, 1 to 6 carbon atoms and attached to the rest of the molecule by a single bond straight-chain or branched hydrocarbon chain groups.
  • alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, and hexyl.
  • alkyl groups may also be isotopomers of naturally abundant alkyl groups that are rich in carbon and/or hydrogen isotopes (ie, deuterium or tritium).
  • alkenyl means an unbranched or branched monovalent hydrocarbon chain containing one or more carbon-carbon double bonds.
  • alkynyl refers to an unbranched or branched monovalent hydrocarbon chain containing one or more carbon-carbon triple bonds.
  • C 1 -C 6 alkyl alone or as part of another substituent is understood to mean a linear or branched saturated monovalent hydrocarbon radical having 1, 2, 3, 4, 5 or 6 carbon atoms.
  • the alkyl group is for example methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl base, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl , 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethyl Butyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,
  • alkylene means an alkyl group further substituted by one hydrogen atom
  • C 1 -C 6 alkylene means an alkylene group having 1 to 6 carbon atoms group.
  • methylene means -CH 2 -
  • ethylene means -(CH 2 ) 2 -
  • alkylene groups include straight and branched chain hydrocarbon groups, for example, "propylene” can be exemplified by the structure:
  • dimethylbutylene can be exemplified by any of the following structures:
  • cycloalkyl by itself or as part of another substituent means a cyclic alkyl group having carbon atoms and no ring heteroatoms and having a single ring or multiple rings (including fused, bridged) A saturated or partially saturated cyclic group.
  • mn-membered cycloalkyl or " Cm - Cncycloalkyl” is understood to mean a saturated, unsaturated or partially saturated carbocycle having m to n atoms.
  • 3-15 membered cycloalkyl or “C 3 -C 15 cycloalkyl” refers to a cyclic alkyl group containing 3 to 15, 3 to 9, 3 to 6 or 3 to 5 carbon atoms, which May contain 1 to 4 rings.
  • 3-10 membered cycloalkyl contains 3-10 carbon atoms. Including monocyclic, bicyclic, tricyclic, spiro or bridged rings.
  • unsubstituted cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and adamantyl, or bicyclic hydrocarbon groups such as a decahydronaphthalene ring. Cycloalkyl groups may be substituted with one or more substituents.
  • the term "cycloalkyl” is used interchangeably with the terms "carbocyclyl” and "cycloalkane”.
  • heterocycloalkyl by itself or as part of another substituent, refers to a cycloalkyl group in which one or more (in some embodiments, 1 to 3) carbon atoms are replaced by a heteroatom which Atoms are such as, but not limited to, N, O, S, and P.
  • mn-membered heterocycloalkyl is understood to mean a saturated, unsaturated or partially saturated ring having m to n atoms, wherein the hetero ring atoms are selected from N, O, S, P, is preferably selected from N, O or S.
  • the term "4-8 membered heterocycloalkyl” or “C 4 -C 8 heterocycloalkyl” is understood to mean a saturated, unsaturated or partially saturated ring having 4 to 8 atoms, wherein 1, 2 , 3, or 4 ring atoms are selected from N, O, S, P, preferably selected from N, O or S.
  • "4-10 membered heterocyclic group” means a saturated, unsaturated or partially saturated ring having 4 to 10 atoms. When a prefix such as 4-8 membered or 4-10 membered is used to indicate heterocycloalkyl, the number of carbons is also meant to include heteroatoms. Including monocyclic, bicyclic, tricyclic, spiro or bridged rings.
  • heterocycloalkyl groups are: pyrrolidinyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydropyridyl, tetrahydropyrrolyl, azetidinyl, thiazolidinyl, oxazolidinyl , piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, azepanyl, diazepanyl, oxazepanyl, etc.
  • heterocycloalkyl is used interchangeably with the terms “heteroalkane", “heterocycle”, “heterocycloalkane”.
  • alkenyl by itself or as part of another substituent refers to a straight or branched chain monovalent hydrocarbon group of two to forty carbon atoms having at least one carbon-carbon sp2 double bond (for example C2- C 6 alkenyl, another example is C 2 -C 4 alkenyl), and includes groups with "cis” and “trans” orientations or "E” and “Z” orientations.
  • alkenyl groups include, but are not limited to, vinyl and allyl.
  • alkynyl by itself or as part of another substituent refers to a straight or branched chain monovalent hydrocarbon radical (e.g. C2 - C6 ) of two to forty carbon atoms having at least one carbon-carbon sp triple bond.
  • alkynyl another example is C 2 -C 4 alkynyl).
  • alkynyl include, but are not limited to, ethynyl and propynyl.
  • alkoxy by itself or as part of another substituent, refers to the group -ORx , wherein Rx is "alkyl" as defined above.
  • oxo by itself or as part of another substituent, means that two hydrogens on a methylene group are replaced by oxygen, ie a methylene group is replaced by a carbonyl group.
  • aryl by itself or as part of another substituent means a monocyclic or polycyclic carbocyclic ring having from 6 to 20 carbon atoms, at least one of which is aromatic. When one of the rings is a non-aromatic ring, the group can be attached through an aromatic ring or through a non-aromatic ring. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthrenyl, anthracenyl, and acenaphthyl.
  • heteromatic ring means a monocyclic or polycyclic carbocyclic ring in which at least one ring atom is a heteroatom independently selected from oxygen, sulfur and nitrogen, and the remaining ring atoms are C, wherein at least one ring is aromatic.
  • the group may be a carbon group or a heteroatom group (ie it may be C-attached or N-attached, wherever this is possible).
  • the group can be attached through an aromatic ring or through a non-aromatic ring.
  • heteroaryl groups include, but are not limited to: imidazolyl, acridinyl, carbazolyl, cinnolinyl, quinoxalinyl, pyrazolyl, indolyl, benzotriazolyl, furyl, thienyl, Benzothienyl, benzofuryl, quinolinyl, isoquinolyl, oxazolyl, isoxazolyl, indolyl, pyrazinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, N - methylpyrrolyl and tetrahydroquinoline.
  • heteroaryl may be used interchangeably with the terms “heteroaromatic", “heteroaryl” or "heteroaryl”.
  • heteroalkene ring refers to a monocyclic group with heteroatoms (the monocyclic group has a double bond, but is not aromatic), preferably containing 1, 2 or a monocyclic ring of 3 ring heteroatoms independently selected from N, O and S.
  • heterocycloalkenyl groups are: dihydrofuryl, dihydrothienyl, dihydropyrrolyl, dioxolyl, dihydroimidazolyl, dihydropyrazolyl, dihydrothiazolyl, dihydroiso Thiazolyl, dihydrooxadiazolyl, dihydrothiadiazolyl, dihydrotriazolyl, dihydrotetrazolyl, tetrahydropyridyl, 3,4-dihydro-2H-pyran, pyranyl, Thipyryl, dihydropyridyl, dihydropyrazinyl, dihydropyrimidinyl, oxazinyl, dihydrotetrazolyl and the like.
  • heteroalkenyl may be used interchangeably with the term “heterocycloalkenyl”.
  • merged ring refers to a cyclic hydrocarbon in which any two rings in the compound share two directly connected carbon atoms, and can be divided into bicyclic hydrocarbons, tricyclic hydrocarbons, tetracyclic hydrocarbons, etc. according to the number of rings.
  • Non-limiting examples include:
  • spirocycle refers to a polycyclic group that shares one carbon atom (called a spiro atom) between monocyclic rings, which may contain one or more double bonds, but none of the rings has a fully conjugated ⁇ -electron system. Preferably it is 6 to 12 yuan, more preferably 7 to 8 yuan. According to the number of spiro atoms shared between the ring and the ring, spirocycloalkyl is divided into single spirocycloalkyl, double spirocycloalkyl or polyspirocycloalkyl, preferably single spirocycloalkyl and double spirocycloalkyl alkyl.
  • spirocycloalkyl groups include:
  • spirocycloalkyls in which a single spirocycloalkyl shares a spiro atom with a heterocycloalkyl, non-limiting examples include:
  • bridged ring refers to a cyclic hydrocarbon in which any two rings in a compound share two carbon atoms that are not directly connected, and can be divided into bicyclic hydrocarbons, tricyclic hydrocarbons, tetracyclic hydrocarbons, etc.
  • Non-limiting examples include:
  • haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl.
  • the compounds provided herein, including intermediates useful in the preparation of the compounds provided herein, contain reactive functional groups (such as, but not limited to, carboxyl, hydroxyl, and amino moieties), and also include protected derivatives thereof.
  • "Protected derivatives” are those compounds in which one or more reactive sites are blocked by one or more protecting groups (also known as protecting groups).
  • Suitable protecting groups for the carboxyl moiety include benzyl, tert-butyl, etc., and isotopes, etc.
  • Suitable amino and amido protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl, benzyloxycarbonyl and the like.
  • Suitable hydroxy protecting groups include benzyl and the like. Other suitable protecting groups are well known to those of ordinary skill in the art.
  • optionally or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes both the occurrence and non-occurrence of the event or circumstance.
  • optionally substituted aryl means that the aryl is substituted or unsubstituted, and the description also includes substituted Substituted aryl and unsubstituted aryl.
  • salt or “pharmaceutically acceptable salt” includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissues without excessive Toxicity, irritation, allergic reaction, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • “Pharmaceutically acceptable acid addition salt” refers to a salt formed with an inorganic or organic acid that retains the biological effectiveness of the free base without other side effects.
  • “Pharmaceutically acceptable base addition salt” refers to a salt formed with an inorganic base or an organic base that can maintain the biological effectiveness of the free acid without other side effects.
  • other salts are contemplated by the present invention. They may serve as intermediates in the purification of compounds or in the preparation of other pharmaceutically acceptable salts or may be useful in the identification, characterization or purification of compounds of the invention.
  • amine salt refers to the product obtained by neutralizing an alkyl primary, secondary or tertiary amine with an acid.
  • the acid includes an inorganic acid or an organic acid as described in this application.
  • stereoisomer refers to isomers resulting from differences in the arrangement of atoms in a molecule in space, including cis-trans isomers, enantiomers, diastereoisomers and conformers.
  • the compounds according to the invention may exist as one of the possible isomers or as mixtures thereof, for example as pure optical isomers, or as mixtures of isomers, for example as racemic and non- A mixture of enantiomers, depending on the number of asymmetric carbon atoms.
  • the prefixes D and L or R and S are used to denote the absolute configuration of the molecule with respect to the chiral center (or centers) in the molecule.
  • the prefixes D and L or (+) and (-) are symbols used to designate the rotation of plane polarized light by a compound, where (-) or L indicates that the compound is levorotatory.
  • Compounds prefixed with (+) or D are dextrorotatory.
  • tautomer refers to isomers of functional groups resulting from the rapid movement of an atom in a molecule between two positions.
  • the compounds of the present invention may exhibit tautomerism.
  • Tautomeric compounds can exist in two or more interconvertible species.
  • Prototropic tautomers result from the migration of a covalently bonded hydrogen atom between two atoms.
  • Tautomers generally exist in equilibrium and attempts to isolate a single tautomer usually result in a mixture whose physicochemical properties are consistent with the mixture of compounds. The position of equilibrium depends on the chemical properties within the molecule.
  • the keto form predominates
  • the enol form predominates.
  • the present invention encompasses all tautomeric forms of the compounds.
  • solvate means that the compound of the present invention or its salt includes a stoichiometric or non-stoichiometric solvent bonded by intermolecular non-covalent forces, and when the solvent is water, it is a hydrate.
  • prodrug refers to a compound of the invention that can be converted to biological activity under physiological conditions or by solvolysis.
  • the prodrugs of the present invention are prepared by modifying functional groups in the compounds which can be removed routinely or in vivo to yield the parent compound.
  • Prodrugs include compounds formed by linking a hydroxyl or amino group in the compound of the present invention to any group. When the prodrug of the compound of the present invention is administered to a mammalian individual, the prodrug is split to form free hydroxyl, free of amino.
  • a "pharmaceutical composition” refers to a formulation of a compound of the present invention with a vehicle generally accepted in the art for the delivery of a biologically active compound to a mammal (eg, a human).
  • the medium includes a pharmaceutically acceptable carrier.
  • the purpose of the pharmaceutical composition is to promote the administration of the organism, facilitate the absorption of the active ingredient and thus exert its biological activity.
  • pharmaceutically acceptable carrier includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener approved by the relevant government regulatory agency as acceptable for human or livestock use , diluent, preservative, dye/colorant, flavoring agent, surfactant, wetting agent, dispersing agent, suspending agent, stabilizing agent, isotonic agent, solvent or emulsifying agent.
  • excipient refers to a pharmaceutically acceptable inert ingredient.
  • examples of categories of the term “excipient” include, but are not limited to, binders, disintegrants, lubricants, glidants, stabilizers, fillers, diluents, and the like. Excipients can enhance the handling characteristics of a pharmaceutical formulation, ie make the formulation more suitable for direct compression by increasing flow and/or cohesiveness.
  • treatment refers to therapeutic therapy.
  • treatment means: (1) amelioration of one or more biological manifestations of the disease or condition, (2) interference with (a) one or more points in the biological cascade leading to or causing the condition or (b ) one or more biological manifestations of the disorder, (3) amelioration of one or more symptoms, effects or side effects associated with the disorder, or one or more symptoms, effects or side effects associated with the disorder or its treatment, Or (4) slowing the development of the disorder or one or more biological manifestations of the disorder.
  • prevention refers to a reduction in the risk of acquiring or developing a disease or disorder.
  • patient refers to any animal, preferably a mammal, that is about to or has received the administration of the compound or composition according to the embodiments of the present invention.
  • mammal includes any mammal. Examples of mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc., preferably humans.
  • terapéuticaally effective amount refers to an amount of a compound which, when administered to a patient, is sufficient to effectively treat a disease or condition described herein.
  • the “therapeutically effective amount” will vary depending on the compound, the disorder and its severity, and the age of the patient to be treated, and can be adjusted as necessary by those skilled in the art.
  • the reaction temperature can be appropriately selected according to the solvent, starting material, reagent, etc.
  • the reaction time can also be appropriately selected according to the reaction temperature, solvent, starting material, reagent, etc.
  • the target compound can be separated and purified from the reaction system according to common methods, such as filtration, extraction, recrystallization, washing, silica gel column chromatography and other methods. Without affecting the next step reaction, the target compound can also directly enter the next step reaction without separation and purification.
  • the present invention provides a compound represented by formula I or a pharmaceutically acceptable salt thereof.
  • the compound of formula I can obviously inhibit the polymerization of tubulin monomer, and has better inhibitory activity than positive compounds.
  • the compound of the present invention can obviously inhibit cell proliferation.
  • the compound of the present invention exhibits pharmacokinetic properties in line with topical skin administration, fast metabolism in vivo, low potential toxicity and good druggability. It has a good therapeutic effect on actinic keratosis; it has good p-SRC inhibitory activity and can block the downstream signaling pathway of SRC.
  • the invention provides a method and an intermediate for preparing the compound shown in I or a pharmaceutically acceptable salt thereof.
  • the method is simple in operation, high in yield and high in purity, and can be used in industrialized production of medicine.
  • Figure 1 shows the results of the compound's inhibition of tubulin polymerization.
  • IC 50 half inhibitory concentration, which refers to the concentration at which half of the maximum inhibitory effect is achieved
  • n-butyllithium 14.56mL, 29.1mmol, 2.5M n-hexane solution
  • DIAD diisopropyl azodicarboxylate
  • the first step the preparation of 2-(5-bromopyridin-2-yl)acetonitrile
  • the raw material acetonitrile (19.6g, 477mmol) was added to anhydrous tetrahydrofuran (500mL) at room temperature, cooled to -78°C, and n-butyllithium (170mL, 426mmol, 2.5M) was slowly added dropwise, and the reaction solution was heated at -78°C Stir for 1 h, then dropwise add the raw material 5-bromo-2-fluoropyridine (30 g, 170 mmol) in tetrahydrofuran (100 mL), slowly warm up to room temperature after the dropwise addition, and continue stirring for 2 h.
  • reaction solution was poured into saturated ammonium chloride solution/ethyl acetate (300mL/300mL), separated, and the aqueous phase was extracted with ethyl acetate (200mL ⁇ 3), and the organic phase was combined.
  • the phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified with a thin-layer silica gel plate to obtain compound A1-2 (22.5 g, yield 67%).
  • the second step the preparation of 2-(5-bromopyridin-2-yl) methyl acetate
  • the raw material compound A1-2 (30 g, 152 mmol) was added into anhydrous methanol (200 mL) at room temperature, and concentrated sulfuric acid (25 mL, 457 mmol) was slowly added dropwise, then heated to reflux and stirred for 24 h. point board supervisor After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove methanol, the residue was dissolved in dichloromethane (500 mL), and the organic phase was washed with water (200 mL), saturated sodium bicarbonate solution (200 mL) and saturated brine (200 mL) successively. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated, and the residue was separated and purified on a thin-layer silica gel plate to obtain compound A1-3 (31 g, yield 88%).
  • the third step the preparation of N-benzyl-2-(5-bromopyridin-2-yl)acetamide
  • Embodiment 1 Preparation of N-benzyl-2-(5-(4-((1-morpholinoprop-2-yl)oxy)phenyl)pyridin-2-yl)acetamide
  • the first step the preparation of 4-(2-(4-bromophenoxy)propyl)morpholine
  • the third step the preparation of N-benzyl-2-(5-(4-((1-morpholinoprop-2-yl)oxy)phenyl)pyridin-2-yl)acetamide
  • Step 1 Preparation of ((1r,3r)-3-(4-bromophenoxy)cyclobutyl)carbamate tert-butyl ester
  • the third step the preparation of 4-((1r,3r)-3-(4-bromophenoxy)cyclobutyl)morpholine
  • Step 5 Preparation of N-benzyl-2-(5-(4-((1r,3r)-3-morpholinocyclobutoxy)phenyl)pyridin-2-yl)acetamide
  • reaction solution was cooled to room temperature, diluted with water (10 mL), extracted with dichloromethane (10 mL ⁇ 3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the residue was purified by preparative liquid chromatography to obtain compound 2 (150 mg, yield rate of 79%).
  • Step 1 Preparation of ((1s,3s)-3-(4-bromophenoxy)cyclobutyl)carbamate tert-butyl ester
  • the third step the preparation of 4-((1s,3s)-3-(4-bromophenoxy)cyclobutyl)morpholine
  • Step 4 Preparation of N-benzyl-2-(5-(4-((1s,3s)-3-morpholinocyclobutoxy)phenyl)pyridin-2-yl)acetamide
  • Embodiment 4 Preparation of N-benzyl-2-(5-(4-(2-morpholinopropoxy)phenyl)pyridin-2-yl)acetamide
  • the first step the preparation of 1-(4-bromophenoxy)propan-2-one
  • reaction solution was poured into saturated aqueous sodium sulfite (50 mL), extracted with ethyl acetate (50 mL ⁇ 3), dried over Concentrate by filtration to give a brown oil.
  • the yellow solid was purified by column chromatography to obtain compound 4-2 (yellow oil, 4.5 g, yield 68.0%), which was directly used in the next step.
  • the second step the preparation of 4-(1-(4-bromophenoxy)propan-2-yl)morpholine
  • the third step the preparation of N-benzyl-2-(5-(4-(2-morpholinopropoxy)phenyl)pyridin-2-yl)acetamide
  • the second step the preparation of N-benzyl-2-(5-(2-fluoro-4-hydroxyphenyl)pyridin-2-yl)acetamide
  • the fourth step 2-(5-(4-((1r,3r)-3-aminocyclobutoxy)-2-fluorophenyl)pyridin-2-yl)-N-benzylacetamide hydrochloride preparation of
  • Step 5 Preparation of N-benzyl-2-(5-(2-fluoro-4-((1r,3r)-3-morpholinecyclobutoxy)phenyl)pyridin-2-yl)acetamide
  • Step 1 Preparation of ((1r,3r)-3-(4-bromo-3-methylphenoxy)cyclobutyl)carbamate tert-butyl ester
  • the third step the preparation of 4-((1r,3r)-3-(4-bromo-3-methylphenoxy)cyclobutyl)morpholine
  • the fourth step 4-((1r,3r)-3-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- Preparation of 2-yl)phenoxy)cyclobutyl)morpholine
  • the fifth step N-benzyl-2-(5-(2-methyl-4-((1r,3r)-3-morpholinocyclobutoxy)phenyl)pyridin-2-yl)acetamide preparation of
  • Step 1 Preparation of ((1r,3r)-3-(4-bromo-3-cyanophenoxy)cyclobutyl)carbamate tert-butyl ester
  • the second step preparation of 5-((1r,3r)-3-aminocyclobutoxy)-2-bromobenzonitrile hydrochloride
  • the third step the preparation of 2-bromo-5-((1r,3r)-3-morpholinocyclobutoxy)benzonitrile
  • the fourth step 5-((1r,3r)-3-morpholinocyclobutoxy)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborine Preparation of pentane-2-yl)benzonitrile
  • the fifth step N-benzyl-2-(5-(2-cyano-4-((1r,3r)-3-morpholinocyclobutoxy)phenyl)pyridin-2-yl)acetamide preparation of
  • the racemate compound 4 (50mg) was separated by SFC, the separation method is: column type: Column: Chiralcel OD-3 50 ⁇ 4.6mm ID, 3um, mobile phase: mobile phase A is CO 2 , mobile phase B is 50% Ethanol (containing 0.05% diethylamine); Gradient elution: 40% ethanol (containing 0.05% diethylamine) in CO ; Flow rate: 3ml/min; Wavelength: 220nm; Column temperature: 35 °C; 100 Bar.
  • the racemate compound 4 (50mg) was separated by SFC, the separation method is: column type: Column: Chiralcel OD-3 50 ⁇ 4.6mm ID, 3um, mobile phase: mobile phase A is CO 2 , mobile phase B is 50% Ethanol (containing 0.05% diethylamine); Gradient elution: 40% ethanol (containing 0.05% diethylamine) in CO ; Flow rate: 3ml/min; Wavelength: 220nm; Column temperature: 35 °C; 100 Bar.
  • the racemate compound 1 (50mg) was separated by SFC, the separation method is: column type: Column: Chiralcel OD-3 50 ⁇ 4.6mm ID, 3um, mobile phase: mobile phase A is CO 2 , mobile phase B is 50% Ethanol (containing 0.05% diethylamine); Gradient elution: 40% ethanol (containing 0.05% diethylamine) in CO ; Flow rate: 3ml/min; Wavelength: 220nm; Column temperature: 35 °C; 100 Bar.
  • the racemate compound 1 (50mg) was separated by SFC, the separation method is: column type: Column: Chiralcel OD-3 50 ⁇ 4.6mm ID, 3um, mobile phase: mobile phase A is CO 2 , mobile phase B is 50% Ethanol (containing 0.05% diethylamine); Gradient elution: 40% ethanol (containing 0.05% diethylamine) in CO ; Flow rate: 3ml/min; Wavelength: 220nm; Column temperature: 35 °C; 100 Bar.
  • the synthetic route is as follows:
  • the third step 4-((1r,3r)-3-(4-bromo-3-chlorophenoxy)cyclobutyl)morpholine
  • the fourth step 4-((1r,3r)-3-(3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2 -yl)phenoxy)cyclobutyl)morpholine
  • the positive compound I (trade name Tirbanibulin) in the test example of the present invention is a dual-action Src kinase and tubulin polymerization inhibitor, which has been approved by the FDA and the European Union for local treatment of actinic keratosis of the face or scalp treat.
  • the preparation of the positive compound I refers to the patent WO2008/082637A1, and the structure of the positive compound I is as follows:
  • the Tubulin Polymerization Assay Kit (cytoskeleton, Cat.#BK011P) was used to carry out the compound inhibition of tubulin monomer polymerization test.
  • Human skin squamous cell carcinoma cell A-431 (ATCC, CRL-1555) and human embryonic kidney epithelial cell 293T (China Center for Type Culture Collection, GDC0187) proliferation assay were used to detect the inhibitory effect of small molecule compounds on cell proliferation.
  • A-431 cells and 293T cells were cultured in DMEM medium containing 10% fetal bovine serum at 37°C in a 5% CO 2 incubator.
  • the logarithmic phase cells were inoculated into 96-well cell culture plates at 1000 cells/well, 100 ⁇ l per well, and cultured overnight at 37°C in a 5% CO 2 incubator.
  • Add 100 ⁇ l of gradient diluted 2 ⁇ test compound solution to each well DMSO was used as a positive control, and 10 ⁇ M staurosporine (Aladdin, S102392) was set as a negative control group, and the culture plate after adding the compound was continued at 37°C. , and incubate for 4 days in a 5% CO 2 incubator.
  • Inhibition% (signal of positive control group - signal of test well) / (signal of positive control group - signal of negative control group) * 100
  • mice For the mouse pharmacokinetics test, three male ICR mice, 20-25g in weight, were fasted overnight and injected into the tail vein (1 mg/kg or 5 mg/kg). Blood was collected before administration, 15, 30min and 1, 2, 4, 8, 24h after administration. The blood samples were centrifuged at 6800g at 2-8°C for 6 minutes, and the plasma was collected and stored at -80°C. Take the plasma at each time point, add 3-5 times the amount of acetonitrile solution containing the internal standard and mix, vortex mix for 1 min, centrifuge at 4°C for 10 min at 13,000 rpm, take the supernatant and add 3 times the amount of water to mix, and take an appropriate amount of the mixture LC-MS/MS analysis was performed. The main pharmacokinetic parameters were analyzed by WinNonlin7.0 software non-compartmental model.
  • mice pharmacokinetic test show that the compound of the present invention exhibits pharmacokinetic properties conforming to topical skin administration, fast metabolism in vivo, low potential toxicity and good druggability.
  • the stability test of human liver microsomes was detected by incubating the compound with human liver microsomes in vitro. Firstly, the compound to be tested was prepared as a 10 mM stock solution in DMSO solvent, and then the compound was diluted to 0.5 mM with acetonitrile. Use PBS to dilute human liver microsomes (Corning) into a microsome/buffer solution, and use this solution to dilute 0.5 mM compound to become a working solution. The concentration of the compound in the working solution is 1.5 ⁇ M, and the concentration of human liver microsomes is 0.75 mg/ml .
  • the results of the stability test of human liver microsomes show that the compound of the present invention exhibits pharmacokinetic properties conforming to topical skin administration, fast metabolism of liver microsomes, low potential toxicity and good druggability.

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Abstract

本发明公开了一种微管蛋白-Src双靶点抑制剂和用途。本发明提供了一种式I所示化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药；该化合物具有较好的微管蛋白聚合抑制作用。

Description

微管蛋白-Src双靶点抑制剂和用途
本申请要求申请日为2022年1月14日的中国专利申请2022100440006和申请日为2022年4月15日的中国专利申请2022103993985的优先权。本申请引用上述中国专利申请的全文。
技术领域
本发明属于医药领域，具体地，本发明涉及到一种微管蛋白-Src双靶点抑制剂及其用途。
背景技术
微管是真核细胞中细胞骨架的重要组成部分，在维持细胞形态、信号传递、细胞器运输、细胞运动、细胞分裂和有丝分裂等多种细胞功能中发挥着重要作用(Jordan M A et al.Nature Reviews Cancer,2004,4(4):253-265.)。
微管由两种类型的微管蛋白亚基，即α-微管蛋白和β-微管蛋白组成，α-微管蛋白和β-微管蛋白形成微管蛋白异二聚体，是微管装配的基本单位。微管靶向剂(Microtubule-targeting agents，MTAs)能破坏微管的动力学稳定性和结构，干扰有丝分裂纺锤体的形成，诱导细胞周期阻滞于G2/M期，促使细胞凋亡(Shuai W et al.Journal of Medicinal Chemistry,2021,64(12).)。
微管参与很多重要的细胞过程，已成为治疗过度增殖性疾病最重要的药物靶点之一，美国FDA批准的几种微管靶向剂如长春花碱和紫杉烷类化合物被广泛用于治疗多实体肿瘤和血液系统恶性肿瘤，但微管靶向药物的耐药性和剂量限制性毒性限制了其临床疗效。双靶点抑制剂与单靶点药物相比克服了耐药性，可以改善治疗效果，已成为研究热点，如：微管蛋白-SRC双靶点抑制剂、微管蛋白-受体酪氨酸激酶(receptor tyrosine kinases inhibitor，RTK)双靶点抑制剂、微管蛋白-组蛋白去乙酰化酶(histone deacetylases inhibitor， HDAC)双靶点抑制剂等(Shuai W et al.Journal of Medicinal Chemistry,2021,64(12).)。
光化性角化病(Actinic keratosis，AK)是一种与长时间暴露在紫外线下有关的皮肤病，在美国AK是皮肤科医生第二常见的疾病，特征是突变的角质形成细胞不受控制的增殖，其被认为是一种癌前病变，如果不及时治疗，20％的病例可能会发展为皮肤鳞状细胞癌(SCC)。目前微管蛋白-SRC双靶点抑制剂Tirbanibulin临床上局部治疗AK效果显著(NCT03285477)，已被FDA批准上市，这表明开发新的具有更好效果的微管蛋白-SRC双靶点抑制剂局部治疗AK可能是一个有潜力的方向。
目前开发新的可抑制微管蛋白聚合或Src激酶的化合物对于包括光化性角化病在内的众多疾病的治疗具有积极意义。
发明内容
本发明的目的是提供一种化合物，用作微管蛋白-Src激酶双靶点抑制剂。亦可作为单独的微管蛋白聚合抑制剂或Src激酶抑制剂使用。
在本发明的第一方面，提供了式I所示化合物、其互变异构体、立体异构体、溶剂化物(例如水合物)、药学上可接受的盐或前药：
其中，
X选自O、S、NH或N(C1-C6烷基)；
当环A存在时，Y不存在；所述环A选自C3-C8环烷基；
当环A不存在时，Y选自被R1所取代的C1-C6烷基，或 其中，所述环B选自3-6元环烷基或4-8元杂环烷基；
所述R1为C1-C6烷基；
所述L1、L2各自独立地不存在或选自C1-C6亚烷基；
Z选自C3-C8环烷基、3-11元杂环烷基，其中，所述C3-C8环烷基、3-11元杂环烷基任选地被R2所取代；
R2选自卤素、羟基、氨基、氰基、羰基、氧代(＝O)、羧基、C1-C6烷基、C2-C6烯基、C2-C6炔基、卤代C1-C6烷基、羟基C1-C6烷基、C1-C6烷基羰基、C1-C6烷基氰基、C1-C6烷氧基、卤代C1-C6烷氧基、C1-C6烷氧羰基、C1-C6烷氧基C1-C6烷基、C1-C6烷氧羰基C1-C6烷基、C3-C8环烷基、C3-C8环烷基羰基、C3-C8环烷氧基，任选具有1或2个C1-C6烷基基团的氨基羰基基团，C1-C6烷基磺酰基基团，任选具有1或2个C1-C6烷基基团的氨基磺酰基，C1-C6烷基磺酰基氨基基团和任选具有1或2个C1-C6烷基基团的氨基；
Q选自未取代或被R3所取代的6-10元芳基、未取代或被R3所取代的5-10元杂芳基；所述杂芳基的杂原子为N、O或S，杂原子个数为1-3个；所述的R3取代为一个或多个取代，所述的R3各自独立地选自氢、卤素、羟基、硝基、氰基、C1-C6烷基、C1-C6烷氧基；或者，当R3为多个时，被取代的6-10元芳基或5-10元杂芳基与R3一起形成含O饱和杂环；
Ra和Rb不存在，或分别独立地为卤素、羟基、氨基、氰基、羰基、氧代(＝O)、羧基、C2-C6烯基、C1-C6烷基、C1-C6氘代烷基、C2-C6炔基、卤代C1-C6烷基、羟基C1-C6烷基、C1-C6烷基羰基、C1-C6烷氧基、卤代C1-C6烷氧基、-COO-C1-C6烷基、-C(O)NR4R5；其中，所述R4和R5各自独立地为氢、C1-C6烷基；
m、n、p、q分别独立地为0、1、2或3。
在本发明中，所述的如式I所示的化合物中某些取代基的定义可如下所述，未提及的取代基的定义均如上任一方案所述(以下简称“在本发明一优选实施方案中”)。
在本发明一优选实施方案中，X选自O；
当环A存在时，Y不存在；所述环A选自C3-C8环烷基；
当环A不存在时，Y选自被R1所取代的C1-C6烷基；
所述R1为C1-C6烷基；
Z选自未取代或被1个或多个C1-C6烷基取代的3-11元杂环烷基；
所述C1-C6烷基取代为甲基；
Q选自未取代的6-10元芳基；
Ra为卤素、氰基或C1-C6烷基；
m为1；
p为0或1；
q为0。
在本发明一优选实施方案中，所述的环A里，所述的C3-C8环烷基为3-6元环烷基。
在本发明一优选实施方案中，所述的环A里，所述的C3-C8环烷基为单环、并环、桥环或螺环。
在本发明一优选实施方案中，所述的环A里，所述的C3-C8环烷基为饱和环。
在本发明一优选实施方案中，所述的环A里，所述的C3-C8环烷基为环丁基或环丙基，进一步优选更进一步优选
在本发明一优选实施方案中，所述的Y里，所述的C1-C6烷基优选C1-C3亚烷基，进一步优选-CH2-、-CH2CH2-或-CH2CH2CH2-。
在本发明一优选实施方案中，所述的R1里，所述的C1-C6烷基优选甲基或乙基。
在本发明一优选实施方案中，所述的Y为进一步优选 其左端与Z连接。
在本发明一优选实施方案中，所述的Z里，所述的3-11元杂环烷基为4-10元杂环烷基，较佳地，3-11元杂环烷基为4-6元杂环烷基。
在本发明一优选实施方案中，所述的Z里，所述的3-11元杂环烷基为单环、并环、桥环或螺环。
在本发明一优选实施方案中，所述的Z里，所述的3-11元杂环烷基为饱和环。
在本发明一优选实施方案中，所述的Z里，所述的3-11元杂环烷基中的杂原子为N和/或O。
在本发明一优选实施方案中，所述的Z里，所述的3-11元杂环烷基中的杂原子为N和O。
在本发明一优选实施方案中，所述的Z里，所述的3-11元杂环烷基通过N原子与Y或A连接。
在本发明一优选实施方案中，所述的Z里，所述的3-11元杂环烷基为
在本发明一优选实施方案中，所述的Q里，所述的6-10元芳基为苯基。
在本发明一优选实施方案中，所述的Ra里，所述的卤素为氟或氯。
在本发明一优选实施方案中，所述的Ra里，所述的C1-C6烷基为甲基或乙基。
在本发明一优选实施方案中，Y选自被甲基取代的C1-C6烷基，或所述环B为环丙基；所述L1、L2各自独立地不存在或选自C1- C6亚烷基。
在本发明一优选实施方案中，Z选自未取代或者被R2所取代的3-11元饱和杂环，其中，所述R2选自C1-C6烷基，所述取代为1个或2个；所述3-11元饱和杂环进一步具有1至3个选自N、O、S的杂原子。
在本发明一优选实施方案中，Z选自未取代或者被R2所取代的5-10元饱和杂环；其中，所述5-10元饱和杂环为单环、并环、螺环或桥环。
在本发明一优选实施方案中，Z选自未取代或者被R2所取代的单环的5-8元单环、6-10元螺环、6-10元桥环、8-10元并环。
在本发明一优选实施方案中，Z选自
在本发明一优选实施方案中，Q选自未取代或被R3所取代的苯基、未取代或被R3所取代的5-6元杂芳基；所述杂芳基的杂原子为N、O或S，杂原子个数为1-3个；所述的R3取代为一个或多个取代，所述的R3各自独立地选自氢、卤素、羟基、硝基、氰基、C1-C6烷基、C1-C6烷氧基；或者，当R3为多个时，被取代的苯基或5-6元杂芳基与R3一起形成含O饱和杂环。
在本发明一优选实施方案中，所述Q选自
在本发明一优选实施方案中，所述的如式I所示的化合物具有式II所示结构：
其中，R6、R7各自独立地不存在或为卤素、羟基、氨基、硝基、氰基、羰基、氧代(＝O)、羧基、C1-C6烷基、C1-C6氘代烷基、C2-C6炔基、卤代C1-C6烷基、羟基C1-C6烷基、C1-C6烷基羰基、C1-C6烷氧基、卤代C1-C6烷氧基；X、环A、Y、Z、m、n的定义如本发明第一方面中所述。在本发明一优选实施方案中，R6、R7分别独立地为不存在或为甲基、乙基、氟、氯。
在本发明一优选实施方案中，所述的如式I所示的化合物具有式III所示结构：
其中，R6、R7各自独立地不存在或为卤素、羟基、氨基、硝基、氰基、羰基、氧代(＝O)、羧基、C1-C6烷基、C1-C6氘代烷基、C2-C6炔基、卤代C1-C6烷基、羟基C1-C6烷基、C1-C6烷基羰基、C1-C6烷氧基、卤代C1-C6烷氧基；X、环A、Y、Z、m、n的定义如本发明第一方面中所述。在本发明一优选实施方案中，R6、R7分别独立地为不存在或为甲基、乙基、氟、氯。
在本发明一优选实施方案中，所述的如式I所示的化合物具有式II所示 结构：
其中，R6、R7各自独立地为卤素、羟基、氨基、硝基、氰基、羰基、氧代(＝O)、羧基、C1-C6烷基、C1-C6氘代烷基、C2-C6炔基、卤代C1-C6烷基、羟基C1-C6烷基、C1-C6烷基羰基、C1-C6烷氧基、卤代C1-C6烷氧基；X、环A、Y、Z、m、n的定义如本发明第一方面中所述。在本发明一优选实施方案中，R6、R7分别独立地为不存在或为甲基、乙基、氟、氯。
在本发明一优选实施方案中，所述的如式I所示的化合物具有式III所示结构：
其中，R6、R7各自独立地为卤素、羟基、氨基、硝基、氰基、羰基、氧代(＝O)、羧基、C1-C6烷基、C1-C6氘代烷基、C2-C6炔基、卤代C1-C6烷基、羟基C1-C6烷基、C1-C6烷基羰基、C1-C6烷氧基、卤代C1-C6烷氧基；X、环A、Y、Z、m、n的定义如本发明第一方面中所述。在本发明一优选实施方案中，R6、R7分别独立地为不存在或为甲基、乙基、氟、氯。
在本发明一优选实施方案中，所述R6与Rb等同，R7与Ra等同。
在本发明一优选实施方案中，所述的如式I所示的化合物具有式IV-1所示结构：
其中，Z的定义如本发明第一方面中所述。
在本发明一优选实施方案中，所述的如式I所示的化合物具有式IV-2所示结构：
其中，Z的定义如本发明第一方面中所述。
在本发明一优选实施方案中，所述的如式I所示的化合物具有式IV-3所示结构：
其中，Z的定义如本发明第一方面中所述。
在本发明一优选实施方案中，所述的如式I所示的化合物具有式IV-4所示结构：
其中，Z的定义如本发明第一方面中所述。
在本发明一优选实施方案中，所述的如式I所示的化合物具有式IV-5所示结构：
其中，Z的定义如本发明第一方面中所述。
在本发明一优选实施方案中，所述的如式I所示的化合物具有式IV-6所示结构：
其中，Z的定义如本发明第一方面中所述。
在本发明一优选实施方案中，所述的如式I所示的化合物具有式IV-7所示结构：
其中，Z的定义如本发明第一方面 中所述。
在本发明一优选实施方案中，所述的如式I所示的化合物具有式IV-8所示结构：
其中，Z的定义如本发明第一方面中所述。
在本发明一优选实施方案中，所述的如式I所示的化合物具有式IV-9所示结构：
其中，Z的定义如本发明第一方面中所述。
在本发明一优选实施方案中，所述的如式I所示的化合物具有式IV-10所示结构：
其中，Z的定义如本发明第一方面中所述。
在本发明一优选实施方案中，所述的如式I所示的化合物具有式IV-11所示结构：
其中，Z的定义如本发明第一方面中所述。
在本发明一优选实施方案中，所述的如式I所示的化合物具有式IV-12所示结构：
其中，Z的定义如本发明第一方面中所述。
在本发明一优选实施方案中，所述的如式I所示的化合物选自下列任一化合物：





在本发明的第二方面，提供了一种化合物或其盐，其选自如下任一结构：

本发明第三方面，提供一种药物组合物，所述的药物组合物包括：如本发明第一方面中所述的式I所示化合物、其互变异构体、立体异构体、溶剂化物(例如水合物)、药学上可接受的盐或前药；和药学上可接受的载体。
本发明第四方面，提供了如本发明第一方面中所述的式I所示化合物、其互变异构体、立体异构体、溶剂化物(例如水合物)、药学上可接受的盐或前药的用途，或本发明第三方面所述的药物组合物的用途，所述用途包括：抑制微管蛋白聚合和/或Src激酶；和/或，预防和/或治疗微管蛋白聚合介导 和/或Src激酶相关的疾病；和/或，制备用于抑制微管蛋白聚合和/或Src激酶，和/或，制备预防和/或治疗微管蛋白聚合介导和/或Src激酶相关的疾病的药物、药物组合物或制剂。
较佳地，所述药物为外用制剂。
较佳地，所述药物为经皮给药的药物。
较佳的，所述微管蛋白聚合介导或Src激酶相关的疾病包括：肿瘤、皮肤疾病和/或其它疾病的一种、两种或更多种。
较佳地，所述肿瘤包括但不限于：实体瘤、肉瘤、血液系统癌症，亚型有乳腺癌、卵巢癌、前列腺癌、子宫颈癌、睾丸癌、结肠癌、结肠直肠癌、肝癌、非小细胞肺癌、鳞状细胞癌、小细胞肺癌、胃癌、胃肠道间质瘤、胰腺癌、膀胱癌、生殖细胞瘤、肥大细胞瘤、肥大细胞增多症、胶质母细胞瘤、神经母细胞瘤、星形细胞瘤、黑色素瘤、B细胞淋巴瘤、T细胞淋巴瘤、缓慢进展淋巴瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、急性髓细胞性白血病、急性淋巴细胞性白血病、慢性髓细胞性白血病、慢性淋巴细胞性白血病、骨髓瘤和/或骨髓增生异常综合症
较佳地，所述皮肤疾病包括但不限于：光化性角化病、银屑病、异位性皮炎、牛皮癣、白癜风、玫瑰疹和/或系统性红斑狼疮。
较佳地，所述其他疾病包括但不限于：自身免疫型糖尿病、糖尿病视网膜病变、肝纤维化、肺纤维化(包括特发性肺纤维化等)、肾纤维化、阿尔茨海默病、帕金森病、亨廷顿舞蹈症、肌萎缩侧索硬化、脊髓小脑退行性病变、动脉粥样硬化、贫血、镰刀形红细胞贫血症、地中海贫血症、骨关节炎、类风湿性关节炎、疟疾、锥形虫病、蠕虫病、原虫感染、多发性硬化症、狼疮、哮喘、过敏性鼻炎和/或炎性肠病。
本发明第五方面，提供了如第一方面中任一所述的化合物、其互变异构体、立体异构体、溶剂化物(例如水合物)、药学上可接受的盐或前药中的至少一种或本发明第三方面所述的药物组合物用于治疗或者预防肿瘤和/或皮 肤疾病的用途。
在本发明第六方面，提供一种抑制微管蛋白聚合和/或Src激酶，或预防和/或治疗微管寡聚化和/或Src激酶相关的疾病的方法，包括步骤：给需要的对象施用本发明第一方面所述的式I所示化合物、其互变异构体、立体异构体、溶剂化物(例如水合物)、药学上可接受的盐或前药。
在本发明第七方面，提供了一种抑制Src激酶，或预防和/或治疗Src激酶相关的(或介导的)疾病的方法，包括步骤：给需要的对象使用如本发明第一方面所述的化合物、其互变异构体、立体异构体、溶剂化物(例如水合物)、药学上可接受的盐或前药，或如本发明第三方面所述的药物组合物。
在本发明第八方面，提供了一种抑制微管蛋白，或预防和/或治疗与微管蛋白相关的(或介导的)疾病的方法，包括步骤：给需要的对象使用如本发明第一方面所述的化合物、其互变异构体、立体异构体、溶剂化物(例如水合物)、药学上可接受的盐或前药，或如本发明第三方面所述的药物组合物。
本发明的附加方面和优点将在下面的描述中部分给出，部分将从下面的描述中变得明显，或通过本发明的实践了解到。
术语和定义
除非另有说明，本申请说明书和权利要求书中记载的基团和术语定义，包括其作为实例的定义、示例性的定义、优选的定义、表格中记载的定义、实施例中具体化合物的定义等，可以彼此之间任意组合和结合。这样的组合和结合后的基团定义及化合物结构，应当属于本申请说明书记载的范围内。
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。如果本文对术语有多个定义，以本章的定义为准。
应理解，上述简述和下文的详述为示例性且仅用于解释，而不对本发明主题作任何限制。在本申请中，除非另有具体说明，否则使用单数时也包括 复数。必须注意，除非文中另有清楚的说明，否则在本说明书和权利要求书中所用的单数形式包括所指事物的复数形式。还应注意，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。
可在参考文献(包括Carey and Sundberg"ADVANCED ORGANIC CHEMISTRY 4THED."Vols.A(2000)and B(2001),Plenum Press,New York)中找到对标准化学术语的定义。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、NMR、IR和UV/VIS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药物化学的有关描述中采用的术语是本领域已知的。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，CH2O等同于OCH2。如本文所用，表示基团的连接位点。如本文所用，“R1”、“R1”和“R1”的含义相同，可相互替换。对于R2等其它其他符号，类似定义的含义相同。
本文所用的章节标题仅用于组织文章的目的，而不应被解释为对所述主题的限制。本申请中引用的所有文献或文献部分包括但不限于专利、专利申请、文章、书籍、操作手册和论文，均通过引用方式整体并入本文。
除前述以外，当用于本申请的说明书及权利要求书中时，除非另外特别指明，否则以下术语具有如下所示的含义。
本申请说明书和权利要求书记载的数值范围，当该数值范围被理解为 “整数”时，应当理解为记载了该范围的两个端点以及该范围内的每一个整数。例如，“1～6的整数”应当理解为记载了0、1、2、3、4、5和6的每一个整数。当该数值范围被理解为“数”时，应当理解为记载了该范围的两个端点以及该范围内的每一个整数以及该范围内的每一个小数。例如，“1～10的数”应当被理解为不仅记载了1、2、3、4、5、6、7、8、9和10的每一个整数，还至少记载了其中每一个整数分别与0.1、0.2、0.3、0.4、0.5、0.6、0.7、0.8、0.9的和。
“取代”是指分子中的氢原子被其它不同的原子或基团所替换，或者是分子中原子的孤对电子被其它的原子或基团替换，例如S原子上的孤对电子可被O原子取代形成
“任选地被取代”或“可进一步被取代”是指“取代”可以但不必须发生，该说明包括发生或不发生的情形。
在本申请中，在单独或作为其他取代基一部分时，术语“卤素”是指氟、氯、溴、碘；优选氟或氯。
在单独或作为其他取代基一部分时，术语“烷基”意指仅由碳原子和氢原子组成、不含不饱和键、具有例如1至6个碳原子且通过单键与分子的其余部分连接的直链或支链的烃链基团。烷基的实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基，叔丁基，戊基，异戊基，新戊基和己基。烷基也可以是富含碳和/或氢的同位素(即氘或氚)的天然丰度烷基的同位素异构体。如本文所用，术语“烯基”表示无支链或支链的单价烃链，其含有一个或多个碳-碳双键。如本文所用，术语“炔基”是指无支链或支链的一价烃链，其含有一个或多个碳-碳三键。
在单独或作为其他取代基一部分时，术语“C1-C6烷基”应理解为表示具有1、2、3、4、5或6个碳原子的直链或支链饱和一价烃基。所述烷基是例如甲基、乙基、丙基、丁基、戊基、己基、异丙基、异丁基、仲丁基、叔丁 基、异戊基、2-甲基丁基、1-甲基丁基、1-乙基丙基、1,2-二甲基丙基、新戊基、1,1-二甲基丙基、4-甲基戊基、3-甲基戊基、2-甲基戊基、1-甲基戊基、2-乙基丁基、1-乙基丁基、3,3-二甲基丁基、2,2-二甲基丁基、1,1-二甲基丁基、2,3-二甲基丁基、1,3-二甲基丁基或1,2-二甲基丁基等或它们的异构体。特别地，所述基团具有1、2或3个碳原子(“C1-C3烷基”)，例如甲基、乙基、正丙基或异丙基。
在单独或作为其他取代基一部分时，术语“亚烷基”是指烷基的一个氢原子进一步被取代，C1-C6亚烷基是指具有1-6个碳原子的亚烷基基团。例如：“亚甲基”指-CH2-、“亚乙基”指-(CH2)2-等。亚烷基基团包括直链和支链烃基基团，例如，“亚丙基”可以通过结构例举：同样地，术语“二甲基亚丁基”可以通过下列任一结构例举：
在单独或作为其他取代基一部分时，术语“环烷基”是指一种环状烷基，其具有碳原子且没有环杂原子且具有单个环或多个环(包括稠和、桥连)的饱和或部分饱和的环状基团。术语“m-n元环烷基”或者“Cm-Cn环烷基”应理解为表示具有m至n个原子的饱和、不饱和或部分饱和的碳环。例如，“3-15元环烷基”或者“C3-C15环烷基”是指含有3至15，3至9，3至6或3至5个碳原子的环状烷基，它可能包含1至4个环。“3-10元环烷基”则含有3-10个碳原子。包括单环、二环、三环、螺环或桥环。未取代的环烷基的实例包括但不限于环丙基、环丁基、环戊基、环己基和金刚烷基，或者是双环烃基如十氢化萘环。环烷基可以被一个或多个取代基取代。术语“环烷基”可以和术语“碳环基”、“环烷烃”交换使用。
在单独或作为其他取代基一部分时，术语“杂环烷基”是指其中一个或多个(在一些实施方案中为1至3个)碳原子被杂原子取代的环烷基，所述杂原子例如但不限于N、O、S和P。术语“m-n元杂环烷基”应理解为表示具有m至n个原子的饱和、不饱和或部分饱和的环，其中杂环原子选自N、O、S、 P，优选地选自N、O或S。例如，术语“4-8元杂环烷基”或者“C4-C8杂环烷基”应理解为表示具有4至8个原子的饱和、不饱和或部分饱和的环，其中1、2、3、或4个环原子选自N、O、S、P，优选地选自N、O或S。“4-10元杂环基”则是表示具有4至10个原子的饱和、不饱和或部分饱和的环。当诸如4-8元或4-10元的前缀用于表示杂环烷基时，碳的数目也意味着包括杂原子。包括单环、二环、三环、螺环或桥环。杂环烷基的示例为：吡咯烷基、四氢呋喃基、四氢吡喃基、四氢噻吩基、四氢吡啶基、四氢吡咯基、氮杂环丁烷基、噻唑烷基、唑烷基、哌啶基、吗啉基、硫代吗啉基、哌嗪基、氮杂环庚烷基、二氮杂环庚烷基、氧氮杂环庚烷基等。术语“杂环烷基”可以和术语“杂烷环”、“杂环”、“杂环环烷烃”交换使用。
在单独或作为其他取代基一部分时，术语“烯基”是指指具有至少一个碳-碳sp2双键的二到四十个碳原子的直链或支链的一价烃基(例如C2-C6烯基，又例如C2-C4烯基)，并且包括具有“顺式”和“反式”取向或者“E”和“Z”取向的基团。烯基的实例包括但不限于乙烯基和烯丙基。
在单独或作为其他取代基一部分时，术语“炔基”是指具有至少一个碳-碳sp三键的二到四十个碳原子的直链或支链的单价烃基(例如C2-C6炔基，又例如C2-C4炔基)。炔基的实例包括但不限于乙炔基和丙炔基。
在单独或作为其他取代基一部分时，术语“烷氧基”是指基团-O-RX，其中，RX为如上文所定义的“烷基”。
在单独或作为其他取代基一部分时，术语“氧代”是指亚甲基上的两个氢被氧取代，也即亚甲基被羰基替代。
在单独或作为其他取代基一部分时，术语“芳基”是指具有6到20个碳原子的单环或多环碳环，其中至少一个环是芳香环。当其中一个环是非芳香环时，该基团可通过芳香环连接，也可通过非芳香环连接。芳基的实例包括但不限于：苯基、萘基、四氢萘基、2,3-二氢化茚基、联苯基、菲基、蒽基和苊基。
在单独或作为其他取代基一部分时，术语“杂芳环”是指单环或多环碳环，其中至少一个环原子为独立地选自氧、硫和氮的杂原子，其余的环原子为C，其中至少一个环是芳香环。该基团可为碳基团或杂原子基团(也即其可为C-连接的或N-连接的，只要其是可能的即可)。当其中一个环是非芳香环时，该基团可通过芳香环连接，也可通过非芳香环连接。杂芳基的实例包括但不限于：咪唑基、吖啶基、咔唑基、噌啉基、喹喔啉基、吡唑基、吲哚基、苯并三唑基、呋喃基、噻吩基、苯并噻吩基、苯并呋喃基、喹啉基、异喹啉基、噁唑基、异噁唑基、吲哚基、吡嗪基、哒嗪基、吡啶基、嘧啶基、吡咯基、N-甲基吡咯基和四氢喹啉。术语“杂芳环”可以和术语“杂芳香环”、“杂芳基”或“杂芳环基”交换使用。
在单独或作为其他取代基一部分时，术语“杂烯环”是指具有杂原子的单环基团(该单环基团具有双键、但不具有芳香性)，优选含有1个、2个或3个独立选自N、O和S的环杂原子的单环。杂环烯基的示例为：二氢呋喃基、二氢噻吩基、二氢吡咯基、二氧杂环戊烯基、二氢咪唑基、二氢吡唑基、二氢噻唑基、二氢异噻唑基、二氢噁二唑基、二氢噻二唑基、二氢三唑基、二氢四唑基、四氢吡啶基、3,4-二氢-2H-吡喃、吡喃基、噻喃基、二氢吡啶基、二氢吡嗪基、二氢嘧啶基、噁嗪基、二氢四唑基等。术语“杂烯环”可以和术语“杂环烯基”交换使用。
术语“并环”是指化合物中的任意两个环共用两直接相连的碳原子的环烃，根据组成环的数目分为二环烃、三环烃、四环烃等。非限制性实例包括：
术语“螺环”指单环之间共用一个碳原子(称螺原子)的多环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至12元，更优选为7至8元。根据环与环之间共用螺原子的数目将螺环烷基分为单螺环烷基、双螺环烷基或多螺环烷基，优选为单螺环烷基和双螺环 烷基。更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺环烷基。螺环烷基的非限制性实例包括：
也包含单螺环烷基与杂环烷基共用螺原子的螺环烷基，非限制性实例包括：
术语“桥环”是指化合物中的任意两个环共用两不直接相连的碳原子的环烃,根据组成环的数目分为二环烃、三环烃、四环烃等。非限制性实例包括：
在单独或作为其他取代基一部分时，“卤代烷基”指包括具有特定数目的碳原子、被一或多个卤素取代的支链和直链的饱和脂族烃基(如-CvFw，其中v＝1至3，w＝1至(2v+1))。卤代烷基的实例包括，但不限于三氟甲基、三氯甲基、五氟乙基、五氯乙基、2,2,2-三氟乙基、七氟丙基和七氯丙基。
本文提供的化合物，包括可用于制备本文提供的化合物的中间体，其含有反应性官能团(例如但不限于羧基，羟基和氨基部分)，还包括其保护的衍生物。“受保护的衍生物”是其中一个或多个反应性位点被一个或多个保护基团(也称为保护基团)封闭的那些化合物。合适的羧基部分保护基包括苄基，叔丁基等，以及同位素等。合适的氨基和酰氨基保护基包括乙酰基，三氟乙酰基，叔丁氧基羰基，苄氧基羰基等。合适的羟基保护基包括苄基等。其他合适的保护基团是本领域普通技术人员所熟知的。
在本申请中，“任选的”或“任选地”表示随后描述的事件或状况可能发生也可能不发生，且该描述同时包括该事件或状况发生和不发生的情况。例如，“任选地被取代的芳基”表示芳基被取代或未被取代，且该描述同时包括被取 代的芳基与未被取代的芳基。
在本申请中，术语“盐”或“药学上可接受的盐”，包括药学上可接受的酸加成盐和药学上可接受的碱加成盐。术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。
“药学上可接受的酸加成盐”是指能够保留游离碱的生物有效性而无其它副作用的，与无机酸或有机酸所形成的盐。“药学上可接受的碱加成盐”是指能够保持游离酸的生物有效性而无其它副作用的、与无机碱或有机碱所形成的盐。除了药学可接受的盐外，本发明还考虑其他盐。它们可以在化合物纯化中或在制备其它药学上课接受的盐中充当中间体或可用于本发明化合物的鉴别、表征或纯化。
术语“胺盐”是指用酸中和烷基伯胺、仲胺或叔胺得到的产物。所述酸包括本申请中所述的无机酸或有机酸。
术语“立体异构体”是指由分子中原子在空间上排列方式不同所产生的异构体，包括顺反异构体、对映异构体、非对应异构体和构象异构体。
依据原料和方法的选择，本发明化合物可以以可能的异构体中的一个或它们的混合物的形式存在，例如作为纯旋光异构体，或作为异构体混合物，如作为外消旋和非对映异构体混合物，这取决于不对称碳原子的数量。当描述具有光学活性的化合物时，使用前缀D和L或R和S来表示就分子中的手性中心(或多个手性中心)而言分子的绝对构型。前缀D和L或(+)和(–)是用于指定化合物所致平面偏振光旋转的符号，其中(–)或L表示化合物是左旋的。前缀为(+)或D的化合物是右旋的。
当将本发明式中与手性碳的键描写直成线时，应当理解为，手性碳的(R)和(S)两种构型和由此产生的其对映体纯的化合物和混合物两者包括在该通式范围内。本文中消旋体或者对映体纯的化合物的图示法来自Maehr， J.Chem.Ed.1985，62:114-120。用楔形键和虚线键表示一个立体中心的绝对构型。
术语“互变异构体”是指因分子中某一原子在两个位置迅速移动而产生的官能团异构体。本发明化合物可表现出互变异构现象。互变异构的化合物可以存在两种或多种可相互转化的种类。质子移变互变异构体来自两个原子之间共价键合的氢原子的迁移。互变异构体一般以平衡形式存在，尝试分离单一互变异构体时通常产生一种混合物，其理化性质与化合物的混合物是一致的。平衡的位置取决于分子内的化学特性。例如，在很多脂族醛和酮如乙醛中，酮型占优势；而在酚中，烯醇型占优势。本发明包含化合物的所有互变异构形式。
术语“溶剂化物”指本发明化合物或其盐包括以分子间非共价力结合的化学计量或非化学计量的溶剂，当溶剂为水时，则为水合物。
术语“前药”是指可以在生理条件下或者通过溶剂解转化为具有生物活性的本发明化合物。本发明的前药通过修饰在该化合物中的功能基团来制备，该修饰可以按常规的操作或者在体内被除去，而得到母体化合物。前药包括本发明化合物中的一个羟基或者氨基连接到任何基团上所形成的化合物，当本发明化合物的前药被施予哺乳动物个体时，前药被割裂而分别形成游离的羟基、游离的氨基。
在本申请中，“药物组合物”是指本发明化合物与本领域通常接受的用于将生物活性化合物输送至哺乳动物(例如人)的介质的制剂。该介质包括药学上可接受的载体。药物组合物的目的是促进生物体的给药，利于活性成分的吸收进而发挥生物活性。
在本申请中，“药学上可接受的载体”包括但不限于任何被相关的政府管理部门许可为可接受供人类或家畜使用的佐剂、载体、赋形剂、助流剂、增甜剂、稀释剂、防腐剂、染料/着色剂、矫味剂、表面活性剂、润湿剂、分散剂、助悬剂、稳定剂、等渗剂、溶剂或乳化剂。
术语“辅料”是指可药用惰性成分。术语“赋形剂”的种类实例非限制性地包括粘合剂、崩解剂、润滑剂、助流剂、稳定剂、填充剂和稀释剂等。赋形剂能增强药物制剂的操作特性，即通过增加流动性和/或粘着性使制剂更适于直接压缩。
术语“治疗”指治疗性疗法。涉及具体病症时，治疗指：(1)缓解疾病或者病症的一种或多种生物学表现，(2)干扰(a)导致或引起病症的生物级联中的一个或多个点或(b)病症的一种或多种生物学表现，(3)改善与病症相关的一种或多种症状、影响或副作用，或者与病症或其治疗相关的一种或多种症状、影响或副作用，或(4)减缓病症或者病症的一种或多种生物学表现发展。
术语“预防”是指获得或发生疾病或障碍的风险降低。
术语“患者”是指根据本发明的实施例，即将或已经接受了该化合物或组合物给药的任何动物，哺乳动物为优。术语“哺乳动物”包括任何哺乳动物。哺乳动物的实例包括但不限于牛、马、羊、猪、猫、狗、小鼠、大鼠、家兔、豚鼠、猴、人等，以人类为优。
术语“治疗有效量”是指在给予患者时，足以有效治疗本文所述的疾病或病症的化合物的量。“治疗有效量”将根据化合物、病症及其严重度、以及欲治疗患者的年龄而变化，可由本领域技术人员根据需要进行调整。
各步骤的反应，反应温度可因溶剂、起始原料、试剂等适宜选择，反应时间也可因反应温度、溶剂、起始原料、试剂等适宜选择。各步骤反应结束后，目标化合物可按常用方法自反应体系中进行分离、提纯等步骤，如过滤、萃取、重结晶、洗涤、硅胶柱层析等方法。在不影响下一步反应的情况下，目标化合物也可不经过分离、纯化直接进入下一步反应。
在不违背本领域常识的基础上，上述各优选条件，可任意组合，即得本发明各较佳实例。
有益效果
本发明人经过广泛而深入地研究，意外地开发了一种化合物或其药学上可接受的盐及制备方法和用途。
本发明提供了式I所示化合物或其药学上可接受的盐，所述式I化合物能明显抑制微管蛋白单体的聚合，与阳性化合物相比，抑制活性更优。通过细胞增殖抑制试验，本发明化合物能明显抑制细胞增殖。此外，经过小鼠药代动力学试验，本发明化合物表现出符合皮肤局部给药的药代动力学性质，体内代谢快，潜在毒性小，成药性良好。对光化性角化病具有很好的治疗作用；具有很好的p-SRC抑制活性，能阻断SRC下游信号通路。
本发明提供了制备I所示化合物或其药学上可接受的盐的方法及中间体，所述方法操作简单、收率高、纯度高，可用于医药工业化生产。
附图说明
图1为化合物对微管蛋白聚合抑制试验结果。
具体实施方式
本申请具有如下定义：
符号或单位：
IC50：半数抑制浓度，指达到最大抑制效果一半时的浓度
M：mol/L，例如正丁基锂(14.56mL，29.1mmol，2.5M的正己烷溶液)表示摩尔浓度为2.5mol/L的正丁基锂的正己烷溶液
N：当量浓度，例如2N盐酸表示2mol/L盐酸溶液
试剂：
DIAD：偶氮二甲酸二异丙酯；
DME：乙二醇二甲醚
DMP：戴斯马丁氧化剂
DCM：二氯甲烷
中间体A1：N-苄基-2-(5-溴吡啶-2-基)乙酰胺的制备
中间体A1的合成路线如下：
第一步：2-(5-溴吡啶-2-基)乙腈的制备
室温下将原料乙腈(19.6g，477mmol)加入到无水四氢呋喃中(500mL)，冷却到-78℃,缓慢滴加正丁基锂(170mL，426mmol，2.5M)，反应液在-78℃下搅拌1h，然后滴加原料5-溴-2-氟吡啶(30g，170mmol)的四氢呋喃中(100mL)，滴加完成后缓慢升温到室温，再继续搅拌2h。点板检测反应完成后，将反应液倒入饱和氯化铵溶液/乙酸乙酯(300mL/300mL)中，分液，水相再用乙酸乙酯(200mL×3)萃取，合并有机相，有机相用无水硫酸钠干燥，过滤，浓缩，残留物用薄层硅胶板分离纯化得化合物A1-2(22.5g，产率67％)。
第二步：2-(5-溴吡啶-2-基)乙酸甲酯的制备
室温下将原料化合物A1-2(30g，152mmol)加入到无水甲醇(200mL)中，缓慢滴加浓硫酸(25mL，457mmol)，然后加热回流搅拌24h。点板监 测反应完成后，将反应液减压浓缩除去甲醇，残留物用二氯甲烷(500mL)溶解，有机相依次用水(200mL)，饱和碳酸氢钠溶液(200mL)和饱和食盐水(200mL)洗涤，有机相用无水硫酸钠干燥，过滤，浓缩，残留物用薄层硅胶板分离纯化得化合物A1-3(31g，产率88％)。
第三步：N-苄基-2-(5-溴吡啶-2-基)乙酰胺的制备
室温下向化合物A1-3(28g，122mmol)中加入苄胺(39.1g，365mmol)，然后加热到125℃搅拌15h，点板检测反应完成后，将反应液冷却到室温，在搅拌状态下缓慢加入乙酸乙酯/石油醚(100mL/100mL)，析出的固体过滤，得化合物A1(28.5g，产率77％)。
1H NMR(400MHz,DMSO-d6):δ8.66–8.53(m,2H),7.97(dd,J＝8.3,2.5Hz,1H),7.38–7.19(m,6H),4.26(d,J＝5.9Hz,2H),3.66(s,2H).
LC-MS,M/Z(ESI):306.9[M+H]+
中间体A2：N-苄基-2-(5-(三丁基甲锡烷基)吡啶-2-基)乙酰胺的制备
中间体A2的合成路线如下：
室温下将中间体A1(15g，49.2mmol)加入到1,4-二氧六环(300mL)中，然后加入氯化锂(6.2g，147mmol)，氮气保护下加入1,1,1,2,2,2-六丁基二锡烷(29.8mL，59.0mmol)和四(三苯基膦)钯(2.84g，2.46mmol)，然后加热到110℃搅拌15h。点板检测反应完成后，将反应液冷却到室温，减压浓缩掉溶剂，加入水(500mL)稀释，用乙酸乙酯(200mL×3)萃取，分液，合并有机相，有机相用无水硫酸钠干燥，过滤，浓缩，残留物用薄层硅胶板分离纯化(石油醚:乙酸乙酯(V/V)＝5:1)得中间体A2(10.5g，产率41.5％)。
1H NMR(400MHz,CDCl3):δ8.01(s,3H),7.71(dd,J＝7.5,1.6Hz,1H),7.31–7.26(m,2H),7.24–7.20(m,3H),4.47(d,J＝5.8Hz,2H),3.74(s,2H),1.56–1.47(m,5H),1.31(ddd,J＝22.6,14.9,7.3Hz,7H),1.08(dd,J＝9.5,6.8Hz,6H),0.87(t,J＝7.3Hz,9H).
LC-MS,M/Z(ESI):517.3[M+H]+
实施例1：N-苄基-2-(5-(4-((1-吗啉代丙-2-基)氧基)苯基)吡啶-2-基)乙酰胺的制备
第一步：4-(2-(4-溴苯氧基)丙基)吗啉的制备
室温下将1-吗啉丙-2-醇(1.01g，6.94mmol)和4-溴苯酚(1g，5.78mmol)，三苯基膦(2.27g，8.67mmol)加入到无水四氢呋喃中(20mL)，冷却到0℃,滴加偶氮二甲酸二异丙酯(1.75g，8.67mmol)，室温搅拌16h。加入饱和食盐水(20mL)稀释，用乙酸乙酯(20mL×3)萃取，分液，合并有机相。有机相用无水硫酸钠干燥，过滤，浓缩，残留物用薄层硅胶板分离纯化得化合物1-3(1.1g，产率63.4％)。
第二步：4-(2-(4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯氧基)丙基)吗啉的制备
室温下将化合物1-3(0.5g，1.67mmol)和联硼酸频那醇酯(1.27g，5.0mmol)加入到1,4-二氧六环(10mL)中,然后加入醋酸钾(0.49g，5.0mmol)，氮气保护下加入1,1'-二(二苯膦基)二茂铁二氯化钯(II)(61mg，0.083mmol)，加热至100℃，搅拌6h。冷却至室温，加入水(50mL)稀释，用乙酸乙酯(50mL×3)萃取，分液，合并有机相。有机相用无水硫酸钠干燥，过滤，浓缩，残留物用薄层硅胶板分离纯化(石油醚:乙酸乙酯(V/V)＝5:1)，得化合物1-4(350mg，产率60.5％)。
第三步：N-苄基-2-(5-(4-((1-吗啉代丙-2-基)氧基)苯基)吡啶-2-基)乙酰胺的制备
室温下将化合物1-4(171mg，0.49mmol)和中间体A1(100mg，0.33mmol)加入到乙二醇二甲醚(5mL)中，然后加入碳酸钠水溶液(2M，0.49mL)，氮气保护下加入四(三苯基膦)钯(20mg，0.016mmol)，加热到90℃搅拌10h。冷却至室温，加入水(50mL)稀释，用乙酸乙酯(20mL×3)萃取，分液，合并有机相。有机相用无水硫酸钠干燥，过滤，浓缩，残留物经制备高效液相色谱纯化得到化合物1(12.3mg，产率9.3％)。
1H NMR(400MHz,CDCl3)δ8.68(d,J＝2.2Hz,1H),8.21(s,1H),7.85(dd,J＝8.1,2.4Hz,1H),7.65(s,1H),7.52–7.46(m,2H),7.41(d,J＝8.1Hz,1H),7.34–7.27(m,2H),7.26–7.21(m,2H),7.01(d,J＝8.7Hz,2H),4.83–4.73(m,1H),4.48(d,J＝5.8Hz,2H),3.84(s,2H),3.77(t,J＝4.7Hz,4H),2.93–2.68(m,6H),1.34(t,J＝6.5Hz,3H)
LC-MS,M/Z(ESI):446.2[M+H]+
实施例2：N-苄基-2-(5-(4-((1r,3r)-3-吗啡啉代环丁氧)苯基)吡啶-2-基)乙酰胺的制备
第一步：((1r,3r)-3-(4-溴苯氧基)环丁基)氨基甲酸叔丁酯的制备
向反式-3-羟基环丁基氨基甲酸叔丁酯(3.0g，16.02mmol)和4-溴苯酚(3.33g，19.23mmol)的四氢呋喃(50mL)溶液中加入三苯基膦(5.04g，19.23mmol)。然后在0℃下向混合物中逐滴加入偶氮二甲酸二异丙酯(3.89g，19.23mmol)，反应液逐渐升至25℃搅拌16h。浓缩混合物得到粗产物。粗产物通过柱层析法(石油醚/乙酸乙酯(V/V)＝1/0-1/1)纯化得到化合物2-2(白色固体，4.5g，产率82％)。LC-MS,M/Z(ESI):286.0[M-56+H]+。
第二步：(1r,3r)-3-(4-溴苯氧基)环丁胺盐酸盐的制备
向化合物2-2(4.5g，13.15mmol)的1,4-二氧六环(20mL)溶液中加入盐酸(13mL，4mol/L的二氧六环溶液)，并在25℃下搅拌12h。然后将反应液浓缩,残留物用乙酸乙酯(20mL)于室温下打浆2h，过滤收集滤饼，干燥后得到化合物2-3(白色固体，2.3g，产率62.8％)。
第三步：4-((1r,3r)-3-(4-溴苯氧基)环丁基)吗啉的制备
向化合物2-3(1g，3.59mmol)和乙腈(15mL)混合溶液中加入1-溴-2-(2-溴乙氧基)乙烷(0.916g，3.95mmol)和碳酸钾(1.240g，8.97mmol)，然后在90℃下搅拌16h。将混合物过滤并浓缩得到粗产物。粗产物经柱层析(石油醚/乙酸乙酯(V/V)＝1/0-1/2)纯化得到化合物2-5(白色固体，0.75g,产率66.9％)。
第四步：4-((1r,3r)-3-(4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯氧)环丁基)吗啡啉的制备
化合物2-5(200mg，0.641mmol)溶于干燥的1,4-二氧六环(3mL)中，依次加入联硼酸频那醇酯(244mg，0.961mmol)，乙酸钾(189mg，1.922mmol)和1,1'-双二苯基膦二茂铁二氯化钯(46.88mg，0.064mmol)。氮气置换三次，升温至90℃搅拌16h。反应液加入水(10mL)，乙酸乙酯萃取(10mL×3)，合并有机相。有机相用无水硫酸钠干燥，过滤后浓缩，得到化合物2-6(粗品，220mg，产率96％)。
第五步：N-苄基-2-(5-(4-((1r,3r)-3-吗啡啉代环丁氧)苯基)吡啶-2-基)乙酰胺的制备
化合物2-6(180mg，0.501mmol)溶于1,4-二氧六环(1mL)和水(0.7mL)中，依次加入中间体A1(127mg，0.418mmol)，碳酸钾(115mg，0.835mmol)和1,1'-双二苯基膦二茂铁二氯化钯(30.5mg，0.042mmol)。氮气置换三次，升温至100℃搅拌12h。反应液冷却至室温，加入水(10mL)稀释，二氯甲烷萃取(10mL×3)，合并有机相，无水硫酸钠干燥，浓缩，残余物用制备液相色谱纯化得到化合物2(150mg，产率79％)。
1H NMR(400MHz,DMSO-d6):δ8.73(d,J＝2.5Hz,1H),8.66–8.58(m,1H),7.95(dd,J＝8.1,2.5Hz,1H),7.63(d,J＝8.8Hz,2H),7.39(d,J＝8.1Hz,1H),7.35–7.20(m,5H),6.93(d,J＝8.9Hz,2H),4.85–4.76(m,1H),4.30(d,J＝6.1Hz,2H),3.71(s,2H),3.60(t,J＝4.7Hz,4H),2.97–2.87(m,1H),2.41(dt,J ＝12.5,6.7Hz,2H),2.30(s,4H),2.19–2.10(m,2H).
LC-MS,M/Z(ESI):458.3[M+H]+
实施例3：N-苄基-2-(5-(4-((1s,3s)-3-吗啉代环丁氧基)苯基)吡啶-2-基)乙酰胺的制备
第一步：((1s,3s)-3-(4-溴苯氧基)环丁基)氨基甲酸叔丁酯的制备
向顺式-3-羟基环丁基氨基甲酸叔丁酯(2.0g，10.68mmol)和4-溴苯酚(2.77g，16.02mmol)的四氢呋喃(20mL)溶液中加入三苯基膦(5.60g，21.36mmol)，然后在0℃下向混合物中逐滴加入偶氮二甲酸二异丙酯(4.32g，21.36mmol)，随后反应液在25℃搅拌16h。浓缩反应液得到粗产物。粗产物通过柱层析法(石油醚/乙酸乙酯(V/V)＝1/0-1/1)纯化得到化合物3-2(白色固体，2.3g，产率62.9％)。
LC-MS,M/Z(ESI):343.1[M+H]+
第二步：(1s,3s)-3-(4-溴苯氧基)环丁胺盐酸盐的制备
向化合物3-2(2.3g，6.72mmol)的二氧六环(20mL)溶液中加入盐 酸(20mL，4mol/L的二氧六环溶液)，并在25℃搅拌16h。然后将反应液浓缩得到化合物3-3(白色固体，盐酸盐，1.0g，产率61.5％)。
LC-MS,M/Z(ESI):243.3[M+H]+
第三步：4-((1s,3s)-3-(4-溴苯氧基)环丁基)吗啉的制备
向化合物3-3(1g，4.13mmol)的乙腈(15mL)溶液中加入1-溴-2-(2-溴乙氧基)乙烷(1.149g，4.96mmol)和碳酸钾(1.427g，10.33mmol)，然后在90℃下搅拌18h。将混合物加入到水(100mL)中，用乙酸乙酯(30mL×3)萃取。有机层用饱和食盐水(10mL×2)洗涤，用无水硫酸钠干燥，过滤并浓缩得到粗产物。粗产物经柱层析(石油醚/乙酸乙酯(V/V)＝1/0-1/2)纯化得到化合物3-4(黄色固体，500mg,产率38.8％)。
LC-MS,M/Z(ESI)：312.0[M+H]+
第四步：N-苄基-2-(5-(4-((1s,3s)-3-吗啉代环丁氧基)苯基)吡啶-2-基)乙酰胺的制备
向化合物3-4(150mg，0.480mmol)的二氧六环(2mL)溶液中加入中间体A2(297mg，0.577mmol)和二三苯基磷二氯化钯(33.7mg，0.048mmol)。反应液置换3次氮气并在氮气环境下于90℃搅拌18h。将混合物加入水(10mL)并用乙酸乙酯(10mL×2)萃取。有机层用无水硫酸钠干燥，过滤并浓缩得到粗产物。粗产物通过制备薄层色谱(DCM/MeOH(V/V)＝10/1)纯化得到化合物3(17.7mg，产率8.05％)。
1H NMR(400MHz,DMSO-d6):δ8.73(d,J＝2.2Hz,1H),8.61(t,J＝5.9 Hz,1H),7.95(dd,J＝8.1,2.5Hz,1H),7.62(d,J＝8.8Hz,2H),7.39(d,J＝8.1Hz,1H),7.34-7.17(m,4H),6.97(d,J＝8.8Hz,2H),4.54(dt,J＝14.2,7.1Hz,1H),4.29(d,J＝6.0Hz,2H),3.70(s,2H),3.58-3.52(m,4H),2.66(dt,J＝9.3,6.8Hz,2H),2.52(s,1H),2.38(s,1H),2.27(s,3H),1.92-1.76(m,2H),1.23(s,2H)
LC-MS,M/Z(ESI):458.3[M+H]+
实施例4：N-苄基-2-(5-(4-(2-吗啉代丙氧基)苯基)吡啶-2-基)乙酰胺的制备
第一步：1-(4-溴苯氧基)丙烷-2-酮的制备
把化合物1-2(5.00g，28.9mmol)溶于水(10mL)中，在0℃下，加入氢氧化钠(1.39g，34.6mmol)，再缓慢滴加2-甲基环氧乙烷(3.36g，57.8mmol)。于25℃反应12h。反应结束后，将反应液倒入到水(50mL)中，乙酸乙酯(50mL×3)萃取，干燥过滤浓缩得到棕色油状物。将浓缩物溶于干燥的二氯甲烷(50mL)中，降温至0℃，并分批加入戴斯马丁氧化剂(12.2g，28.9mmol)，于25℃反应1h。反应结束后，将反应液倒入到饱和的亚硫酸钠水溶液(50mL)中，乙酸乙酯(50mL×3)萃取，干燥过 滤浓缩得到棕色油状物。黄色固体经柱层析纯化后得到得化合物4-2(黄色油状物，4.5g，产率68.0％)，直接用于下一步。
第二步：4-(1-(4-溴苯氧基)丙烷-2-基)吗啉的制备
把化合物4-2(1.50g，6.55mmol)，吗啉(741mg，8.51mmol)，溶于二氯甲烷(10mL)中。氮气置换三次，于0℃滴加氯(三异丙氧基)钛(1M，13.1mL)，反应2h。再向反应液中加入氰基硼氢化钠(1.03g，16.3mmol)，反应12h。反应结束后，将反应液倒入到水(20mL)中，乙酸乙酯(15mL×3)萃取，干燥过滤浓缩得到棕色油状物。得到的油状物经柱层析(乙酸乙酯：石油醚＝200:1-2:1)纯化后得到化合物4-4(黄色油状物，1.93g，6.33mmol，产率96.6％)。
1H NMR(400MHz,CDCl3)δ7.44-7.31(m,2H),6.87-6.72(m,2H),4.03(m,9.4Hz,1H),3.91-3.81(m,1H),3.80-3.66(m,4H),3.03-2.89(m,1H),2.79-2.43(m,4H),1.19(m,3H)
第三步：N-苄基-2-(5-(4-(2-吗啉代丙氧基)苯基)吡啶-2-基)乙酰胺的制备
室温下将化合物4-4(100mg，0.33mmol)和中间体A2(210mg，0.4mmol)加入到甲苯(3mL)中，氮气保护下加入四(三苯基膦)钯(20mg，0.017mmol)，加热到100℃搅拌10h。冷却至室温，加入水(50mL)稀释，用乙酸乙酯(20mL×3)萃取，分液，合并有机相，有机相用无水硫酸钠干燥， 过滤，浓缩，残留物经制备高效液相色谱纯化得到化合物4(12.3mg，产率9.3％)。
1H NMR(400MHz,DMSO-d6)δ8.74(d,1H),8.60(t,1H),7.95(dd,1H),7.62(t,2H),7.39(d,1H),7.34–7.17(m,5H),7.06(d,2H),4.29(d,2H),4.11(dd,1H),3.91(dd,1H),3.70(s,2H),3.56(t,4H),2.96–2.87(m,1H),2.64–2.51(m,4H),1.08(t,3H)
LC-MS,M/Z(ESI):446.2[M+H]+
实施例28：N-苄基-2-(5-(2-氟-4-((1r,3r)-3-吗啉环丁氧基)苯基)吡啶-2-基)乙酰胺的制备
第一步：3-氟-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯酚的制备
室温下将化合物4-溴-3-氟苯酚(5.0g,24.10mmol)，醋酸钾(9.99g,72.3mmol)和联硼酸频那醇酯(12.24g,48.2mmol)，1,1'-二(二苯膦基)二茂铁二氯化钯(II)(1.76g，2.41mmol)加入到二氧六环(80mL)中，氮气保护下85℃搅拌12h。待反应完全，加入水(100mL)稀释，用乙酸乙酯(50mL×3)萃取， 分液，合并有机相，有机相用无水硫酸钠干燥，过滤，浓缩，残留物用层析柱分离纯化(石油醚:乙酸乙酯(V/V)＝2:3)得到化合物28-2(白色固体，3.8g,产率60.1％)。
第二步：N-苄基-2-(5-(2-氟-4-羟基苯基)吡啶-2-基)乙酰胺的制备
将化合物28-2(2.1g,8.25mmol)，中间体A1(2.77g,9.08mmol)，碳酸钾(3.42g,24.75mmol)和1,1-双(二苯基膦)二茂铁二氯化钯(II)(0.065g，0.089mmol)加入到二氧六环(30mL)中，置换氮气，升温至85℃搅拌10h。加入水(100mL)稀释，用乙酸乙酯(30mL×3)萃取，分液，合并有机相。有机相用无水硫酸钠干燥，过滤，浓缩，残留物用层析柱分离纯化(石油醚:乙酸乙酯(V/V)＝3:2)得到化合物28-3(白色固体，2.6g,产率42.4％)。
LC-MS,M/Z(ESI):337.3[M+H]+
第三步：叔丁基((1r,3r)-3-(4-(6-(2-(苄基氨基)-2-氧乙基)吡啶-3-基)-3-氟苯氧基)环丁基)氨基甲酸酯的制备
室温下将化合物28-3(1.078g,3.20mmol)，((1s,3s)-3-羟基环丁基)氨基甲酸叔丁酯(0.50g,2.67mmol),三苯基磷(0.84g,3.20mmol)加入到四氢呋喃(8.0mL)中，将反应体系降温至0℃，然后将偶氮二甲酸二异丙酯(0.647g, 3.20mmol)滴加到反应体系中，氮气保护下25℃搅拌12h。待反应完全，加入水(30mL)稀释，用乙酸乙酯(20mL×3)萃取，分液，合并有机相，有机相用无水硫酸钠干燥，过滤，浓缩，残留物用层析柱分离纯化(石油醚:乙酸乙酯(V/V)＝2:3)得到化合物28-4(白色固体，0.7g,产率51.8％)。
第四步：2-(5-(4-((1r,3r)-3-氨基环丁氧基)-2-氟苯基)吡啶-2-基)-N-苄基乙酰胺盐酸盐的制备
将化合物28-4(0.7g,1.385mmol)溶于二氧六环中(7mL)，再向其中加入盐酸二氧六环溶液(4mol/L，6mL)，25℃搅拌10h。反应完毕后，将反应液旋干，残留物加入乙酸乙酯(10mL)，室温搅拌1h，过滤收集滤饼，干燥后得到化合物28-5(0.4g,产率71.3％)。
第五步：N-苄基-2-(5-(2-氟-4-((1r,3r)-3-吗啉环丁氧基)苯基)吡啶-2-基)乙酰胺的制备
将原料化合物28-5(0.4g,0.987mmol)，1-溴-2-(2-溴乙氧基)乙烷(0.252g,1.085mmol)和碳酸钾(0.341g,2.466mmol)置于乙腈(5mL)中,升温至85℃搅拌12h。反应液冷至室温，加入水(5mL)稀释，用乙酸乙酯(5mL×3)萃取， 分液，合并有机相。有机相用无水硫酸钠干燥，过滤，浓缩，残留物经制备高效液相色谱纯化得到化合物28(0.091g，产率19.4％)。
1H NMR(400MHz,CDCl3)δ8.65(s,1H),7.84–7.77(m,1H),7.63(s,1H),7.36–7.27(m,4H),7.26–7.23(m,2H),6.70(dd,1H),6.62(dd,1H),4.80(tt,1H),4.49(d,2H),3.83(s,2H),3.75(t,4H),3.10–3.00(m,1H),2.48–2.36(m,6H),2.32(m,2H).
LC-MS,M/Z(ESI):476.5[M+H]+
实施例29：N-苄基-2-(5-(2-甲基-4-((1r,3r)-3-吗啉代环丁氧基)苯基)吡啶-2-基)乙酰胺的制备
第一步：((1r,3r)-3-(4-溴-3-甲基苯氧基)环丁基)氨基甲酸叔丁酯的制备
室温下将化合物4-溴-3-甲基苯酚(1.27g,6.41mmol)，((1s,3s)-3-羟基环丁基)氨基甲酸叔丁酯(1.0g,5.34mmol),三苯基磷(1.68g,6.41mmol)加入到四氢呋喃(17.0mL)中，0℃将偶氮二甲酸二异丙酯(1.30g,6.41mmol)滴加到反应液中，氮气保护下25℃搅拌12h。反应液加入水(30mL)，用乙酸乙酯(20mL×3)萃取，分液，合并有机相，有机相用无水硫酸钠干燥，过滤，浓 缩，残留物用层析柱分离纯化(石油醚:乙酸乙酯(V/V)＝2:3)得化合物29-2(白色固体，1.2g,产率61.8％)。
第二步：(1r,3r)-3-(4-溴-3-甲基苯氧基)环丁烷-1-胺盐酸盐的制备
将化合物化合物29-2(1.2g,3.27mmol)溶于二氧六环中(5mL)，向其中加入盐酸二氧六环溶液(4mol/L,5mL)，反应液于25℃搅拌10h。将反应液浓缩，得到残留物于乙酸乙酯(10mL)中室温搅拌1h，上述悬浊液过滤，收集滤饼并干燥，得到化合物29-3(0.8g,产率91.3％)。
第三步：4-((1r,3r)-3-(4-溴-3-甲基苯氧基)环丁基)吗啉的制备
将化合物29-3(0.5g,1.647mmol)，1-溴-2-(2-溴乙氧基)乙烷(0.420g,1.812mmol)和碳酸钾(0.569g,4.12mmol)置于乙腈(5mL)中，升温至85℃搅拌12h。反应液加入水(5mL)，用乙酸乙酯(5mL×3)萃取，分液，合并有机相。有机相用无水硫酸钠干燥，过滤，浓缩，残留物用层析柱分离纯化(石油醚:乙酸乙酯(V/V)＝2:3)得化合物29-4(白色固体，0.52g,产率94％)。
第四步：4-((1r,3r)-3-(3-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯氧基)环丁基)吗啉的制备
室温下将化合物29-4(0.3g,0.890mmol)，醋酸钾(0.262g,2.67mmol)和联硼酸频那醇酯(0.339g,1.334mmol)，1,1'-双(二苯基膦)二茂铁二氯化钯(II) 二氯甲烷络合物(0.065g，0.889mmol)加入到二氧六环(5.0mL)中，氮气保护下85℃搅拌12h。待反应完全，加入水(10mL)稀释，用乙酸乙酯(5mL×3)萃取，分液，合并有机相，有机相用无水硫酸钠干燥，过滤，浓缩，残留物用层析柱分离纯化(石油醚:乙酸乙酯(V/V)＝2:3)得到化合物29-5(白色固体，0.21g,产率61.4％)。
第五步：N-苄基-2-(5-(2-甲基-4-((1r,3r)-3-吗啉代环丁氧基)苯基)吡啶-2-基)乙酰胺的制备
室温下将化合物29-5(0.21g,0.520mmol)，碳酸钾(0.216g,1.561mmol)和中间体A1(0.175g,0.573mmol)，1,1'-双(二苯基膦)二茂铁二氯化钯(II)(0.038g，0.052mmol)加入到二氧六环(5.0mL)中，氮气保护下85℃搅拌12h。待反应完全，加入水(10mL)稀释，用乙酸乙酯(5mL×3)萃取，分液，合并有机相，有机相用无水硫酸钠干燥，过滤，浓缩，残留物经制备高效液相色谱纯化得到化合物29(0.09g,产率23.75％)。
1H NMR(400MHz,CDCl3)δ8.46(s,1H),7.67(s,1H),7.61(d,1H),7.31(dd,3H),7.27(s,3H),7.11(d,1H),6.77–6.65(m,2H),4.81(s,1H),4.50(d,2H),3.83(s,2H),3.76(s,4H),3.05(dt,1H),2.40(s,6H),2.33(dd,2H),2.24(s,3H).
LC-MS,M/Z(ESI):472.3[M+H]+
实施例30：N-苄基-2-(5-(2-氰基-4-((1r,3r)-3-吗啉代环丁氧基)苯基)吡啶-2-基)乙酰胺的制备
第一步：((1r,3r)-3-(4-溴-3-氰基苯氧基)环丁基)氨基甲酸叔丁酯的制备
室温下将化合物2-溴-5-羟基苄腈(1.27g,6.41mmol)，((1s,3s)-3-羟基环丁基)氨基甲酸叔丁酯(1.0g,5.34mmol)和三苯基磷(1.68g,6.41mmol)溶于四氢呋喃(17.0mL)中，0℃下将偶氮二甲酸二异丙酯(1.30g,6.41mmol)滴加到上述反应液中，氮气保护下25℃搅拌12h。待反应完全，加入水(30mL)稀释，用乙酸乙酯(20mL×3)萃取，分液，合并有机相，有机相用无水硫酸钠干燥，过滤，浓缩，残留物用层析柱分离纯化(石油醚:乙酸乙酯(V/V)＝2:3)得到化合物30-2(1.2g,产率61.8％)。
第二步：5-((1r,3r)-3-氨基环丁氧基)-2-溴苄腈盐酸盐的制备
将化合物30-2(1.2g,3.27mmol)溶入到二氧六环中(5mL)，向反应液中加入盐酸二氧六环(4mol/L，5mL)，25℃搅拌10h。反应完毕后，将反应液旋干，残留物中加入乙酸乙酯(5mL)，室温搅拌1h，过滤，收集滤饼并干燥得到化合物30-3(0.8g,产率91.3％)。
第三步：2-溴-5-((1r,3r)-3-吗啉代环丁氧基)苄腈的制备
将化合物30-3(0.5g,1.647mmol)，1-溴-2-(2-溴乙氧基)乙烷(0.420g,1.812mmol)和碳酸钾(0.569g,4.12mmol)溶于乙腈(5mL)中，反应液升温至85℃搅拌12h。加入水(5mL)稀释，用乙酸乙酯(5mL×3)萃取，分液，合并有机相。有机相用无水硫酸钠干燥，过滤，浓缩，残留物用柱层析纯化(石油醚:乙酸乙酯(V/V)＝2:3)得到化合物30-4(白色固体，0.52g,产率94％)。
第四步：5-((1r,3r)-3-吗啉代环丁氧基)-2-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苄腈的制备
室温下将化合物30-4(0.3g,0.890mmol)，醋酸钾(0.262g,2.67mmol)和联硼酸频那醇酯(0.339g,1.334mmol)，1,1'-二(二苯膦基)二茂铁二氯化钯(II)(0.065g，0.889mmol)溶于二氧六环(5.0mL)中，氮气保护下85℃搅拌12h。待反应完全，加入水(10mL)稀释，用乙酸乙酯(5mL×3)萃取，分液，合并有机相，有机相用无水硫酸钠干燥，过滤，浓缩，残留物用层析柱分离纯化(石油醚:乙酸乙酯(V/V)＝2:3)得到化合物30-5(0.21g,产率61.4％)。
第五步：N-苄基-2-(5-(2-氰基-4-((1r,3r)-3-吗啉代环丁氧基)苯基)吡啶-2-基)乙酰胺的制备
室温下将化合物30-5(0.21g,0.520mmol)，碳酸钾(0.216g,1.561mmol)和中间体A1(0.175g,0.573mmol)，1,1'-二(二苯膦基)二茂铁二氯化钯(II)(0.038g，0.052mmol)加入到二氧六环(5.0mL)中，氮气保护下85℃搅拌12h。待反应完全，加入水(10mL)稀释，用乙酸乙酯(5mL×3)萃取，分液，合并有机相，有机相用无水硫酸钠干燥，过滤，浓缩，残留物经高效液相色谱制备分离纯化得到化合物30(0.02g,产率7.96％)。
1H NMR(400MHz,CDCl3)δ8.65(s,1H),7.86(d,1H),7.59(s,1H),7.43–7.37(m,2H),7.35–7.29(m,2H),7.27(d,3H),7.13(dd,2H),4.86–4.79(m,1H),4.50(d,2H),3.86(s,2H),3.80–3.69(m,4H),3.06(dt,1H),2.44(dd,6H),2.33(dd,2H).
LC-MS,M/Z(ESI):483.2[M+H]+
实施例31：(R)-N-苄基-2-(5-(4-(2-吗啉代丙氧基)苯基)吡啶-2-基)乙酰胺的制备
将消旋体化合物4(50mg)通过SFC分离，分离方法为：柱型：Column:Chiralcel OD-3 50×4.6mm I.D.,3um，流动相：流动相A为CO2，流动相B为50％乙醇(含0.05％二乙胺)；梯度洗脱：在CO2中的40％乙醇(含0.05％二乙胺)；流速：3ml/min；波长：220nm；柱温：35℃；背压：100Bar。
得到单一的异构体(R)-N-苄基-2-(5-(4-(2-吗啉代丙氧基)苯基)吡啶-2-基)乙酰胺(化合物31)(13.1mg,99.21％ee,保留时间：1.014min)。
1H NMR(400MHz,DMSO-d6)δ8.74(d,1H),8.60(t,1H),7.95(dd,1H),7.62(t,2H),7.39(d,1H),7.34–7.17(m,5H),7.06(d,2H),4.29(d,2H),4.11 (dd,1H),3.91(dd,1H),3.70(s,2H),3.56(t,4H),2.96–2.87(m,1H),2.64–2.51(m,4H),1.08(t,3H)。
LC-MS,M/Z(ESI):446.2[M+H]+
实施例32：(S)-N-苄基-2-(5-(4-(2-吗啉代丙氧基)苯基)吡啶-2-基)乙酰胺的制备
将消旋体化合物4(50mg)通过SFC分离，分离方法为：柱型：Column:Chiralcel OD-3 50×4.6mm I.D.,3um，流动相：流动相A为CO2，流动相B为50％乙醇(含0.05％二乙胺)；梯度洗脱：在CO2中的40％乙醇(含0.05％二乙胺)；流速：3ml/min；波长：220nm；柱温：35℃；背压：100Bar。
得到单一的异构体(S)-N-苄基-2-(5-(4-(2-吗啉代丙氧基)苯基)吡啶-2-基)乙酰胺(化合物32)(16.1mg,98.12％ee,保留时间：1.292min)。
1H NMR(400MHz,DMSO-d6)δ8.75(d,1H),8.61(t,1H),7.96(dd,1H),7.62(t,2H),7.39(d,1H),7.34–7.17(m,5H),7.06(d,2H),4.29(d,2H),4.12(dd,1H),3.91(dd,1H),3.70(s,2H),3.56(t,4H),2.96–2.87(m,1H),2.64–2.52(m,4H),1.09(t,3H)。
LC-MS,M/Z(ESI):446.2[M+H]+
实施例33：(R)-N-苄基-2-(5-(4-((1-吗啉代丙-2-基)氧基)苯基)吡啶-2-基)乙酰胺的制备
将消旋体化合物1(50mg)通过SFC分离，分离方法为：柱型：Column:Chiralcel OD-3 50×4.6mm I.D.,3um，流动相：流动相A为CO2，流动相B为50％乙醇(含0.05％二乙胺)；梯度洗脱：在CO2中的40％乙醇(含0.05％二乙胺)；流速：3ml/min；波长：220nm；柱温：35℃；背压：100Bar。
得到单一的异构体(R)-N-苄基-2-(5-(4-((1-吗啉代丙-2-基)氧基)苯基)吡啶-2-基)乙酰胺(化合物33)(14.5mg,88.1％ee,保留时间：0.848min)。
1H NMR(400MHz,CDCl3)δ8.68(d,1H),8.21(s,1H),7.85(dd,1H),7.65(s,1H),7.52–7.46(m,2H),7.41(d,1H),7.34–7.27(m,2H),7.26–7.21(m,2H),7.01(d,2H),4.83–4.73(m,1H),4.48(d,2H),3.84(s,2H),3.77(t,4H),2.93–2.68(m,6H),1.34(t,3H)
LC-MS,M/Z(ESI):446.2[M+H]+
实施例34：(S)-N-苄基-2-(5-(4-((1-吗啉代丙-2-基)氧基)苯基)吡啶-2-基)乙酰胺的制备
将消旋体化合物1(50mg)通过SFC分离，分离方法为：柱型：Column:Chiralcel OD-3 50×4.6mm I.D.,3um，流动相：流动相A为CO2，流动相B为50％乙醇(含0.05％二乙胺)；梯度洗脱：在CO2中的40％乙醇(含0.05％二乙胺)；流速：3ml/min；波长：220nm；柱温：35℃；背压：100Bar。
得到单一的异构体(S)-N-苄基-2-(5-(4-((1-吗啉代丙-2-基)氧基)苯基)吡啶-2-基)乙酰胺(化合物34)(21.1mg,93.23％ee,保留时间：1.065min)。
1H NMR(400MHz,CDCl3)δ8.69(d,1H),8.22(s,1H),7.85(dd,1H),7.66(s,1H),7.52–7.47(m,2H),7.42(d,1H),7.34–7.27(m,2H),7.26–7.21(m,2H),7.01(d,2H),4.83–4.73(m,1H),4.48(d,2H),3.85(s,2H),3.77(t,4H),2.93–2.69(m,6H),1.35(t,3H)
LC-MS,M/Z(ESI):446.2[M+H]+
实施例35：N-苄基-2-(5-(2-氯-4-((1r,3r)-3-吗啉代环丁氧基)苯基)吡啶-2-基)乙酰胺
合成路线如下所示：
第一步：((1r,3r)-3-(4-溴-3-氯苯氧基)环丁基)氨基甲酸叔丁酯
室温下将化合物4-溴-3-氯苯酚(2g,9.64mmol)，((1s,3s)-3-羟基环丁基)氨基甲酸叔丁酯(2.71g,14.5mmol)和三苯基膦(5.06g,19.3mmol)加入到四氢呋喃(50mL)中，然后缓慢滴加偶氮二甲酸二异丙基酯(2.9g,19.3mmol)，氮气保护下将混合物加热回流18小时。反应液冷至室温，减压浓缩，残留物用柱层析硅胶纯化(石油醚：乙酸乙酯(V/V)＝10:1)，得到化合物35-2(3.2g,产率88％)。
第二步：(1r,3r)-3-(4-溴-3-氯苯氧基)环丁烷-1-胺
室温下将化合物35-2(3.2g,8.5mmol)加入到二氯甲烷(15mL)中，然后加入三氟乙酸(15mL)，氮气保护下室温搅拌10h，然后减压浓缩得到粗品化合物35-3(3.32g,产率100％)。
第三步：4-((1r,3r)-3-(4-溴-3-氯苯氧基)环丁基)吗啉
室温下将粗品化合物35-3(3.32g,8.45mmol)和碳酸钾(4.67g,33.8mmol)加入到无水乙腈中(30mL)，然后加入1-溴-2-(2-溴乙氧基)乙烷(2.94g,12.67mmol)，加热到85℃搅拌10h，反应完成后冷却到室温，减压浓缩除去 溶剂，粗品用硅胶柱分离纯化(二氯乙烷：甲醇(V/V)＝95:5)得到化合物35-4(2.1g,产率71.7％).
第四步：4-((1r,3r)-3-(3-氯-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯氧基)环丁基)吗啉
室温下将化合物35-4(1g,2.88mmol)，醋酸钾(0.43g,4.33mmol)、联硼酸频那醇酯(0.81g,3.17mmol)和1,1'-二(二苯膦基)二茂铁二氯化钯(II)(106mg,0.144mmol)加入到反应瓶中，以氮气置换三次，然后加入溶剂二氧六环(10mL)，加热至80℃搅拌10h，反应完成后冷却到室温，减压浓缩除去溶剂，残留物用乙酸乙酯(100mL)溶解，依次用水(50mL)和饱和食盐水(50mL)洗涤，再用无水硫酸钠干燥，减压浓缩得到化合物35-5粗品(1.14g,产率100％)，直接用于下一步。
第五步：N-苄基-2-(5-(2-氯-4-((1r,3r)-3-吗啉代环丁氧基)苯基)吡啶-2-基)乙酰胺
室温下将中间体A1(0.2g,0.66mmol)，化合物35-5(0.39g,0.98mmol)、碳酸钠(0.21g,1.97mmol)和1,1'-二(二苯膦基)二茂铁二氯化钯(II)(24mg,0.033mmol)加入到反应瓶中，然后加入二氧六环/水(3mL/0.3mL)，氮气保护下加热至90℃搅拌10h，反应完成后将反应液冷却到室温，减压浓缩除去溶剂，粗品用柱层析纯化(石油醚/乙酸乙酯(V/V＝1:1))，得到N-苄基-2- (5-(2-氯-4-((1r,3r)-3-吗啉代环丁氧基)苯基)吡啶-2-基)乙酰胺(化合物35)(0.61g,产率19％)。
1H NMR(400MHz,DMSO-d6)δ8.66(t,1H),8.49(d,1H),7.78(dd,1H),7.42(d,1H),7.37(d,1H),7.34–7.16(m,5H),7.03(d,1H),6.93(dd,1H),4.82(td,1H),4.30(d,2H),3.73(s,2H),3.59(t,4H),2.91(td,1H),2.45–2.38(m,2H),2.29(s,4H),2.19–2.10(m,2H).
LC-MS,M/Z(ESI):492.2[M+H]+
其它化合物的合成操作如上，只是更改参与反应相应的起始原料，结果展示如下：





本发明测试例中的阳性化合物I(商品名Tirbanibulin)是一种双重作用的Src激酶和微管蛋白聚合抑制剂，已被FDA和欧盟获批用于面部或头皮光化性角化病的局部治疗。阳性化合物I的制备参考专利WO2008/082637A1，阳性化合物I结构如下：
测试例1：抑制微管蛋白单体聚合试验
采用Tubulin Polymerization Assay Kit(cytoskeleton，Cat.#BK011P)开展化合物抑制微管蛋白单体聚合试验。
试验前先将试剂盒配套的96孔板(Corning Costar，Cat.#3686)放置于酶标仪(MD，SpectraMax M5)中加热至37℃，维持10min，取出96孔 板，加入5μl的12.5μM的化合物溶液或空白溶液，再将96孔板放入酶标仪37℃孵育1min，使化合物溶液升温至37℃，取出96孔板于每孔迅速加入按照供应商说明书配置的反应混合物50μl，1min内完成加样并避免产生气泡，然后立即将96孔板放入酶标仪，震荡5s，使用Kinetic mode在激发光360nm、发射光420nm条件下，37℃连续检测30min-60min，每30s检测一次，以检测时间为X轴，荧光信号值为Y轴得到微管蛋白单体聚合曲线。如附图1所示，聚合曲线的Vmax值越大和最大荧光信号值越高代表化合物抑制效率越低。
表1测试化合物对微管蛋白聚合抑制试验结果
化合物对微管蛋白聚合抑制试验结果如图1和表1所示，结果表明本发明化合物对应的聚合曲线的最大荧光信号值明显更小，说明其能明显抑制微管蛋白单体的聚合，与阳性化合物I相比，抑制活性更优。
测试例2：抑制细胞增殖试验
采用人皮肤鳞状细胞癌细胞A-431(ATCC，CRL-1555)、人胚胎肾上皮细胞293T(中国典型培养物保藏中心，GDC0187)增殖试验检测小分子化合物对细胞增殖抑制作用。
A-431细胞、293T细胞培养于含10％胎牛血清的DMEM培养基中，于37℃，5％CO2培养箱中生长。将对数期细胞按照1000个细胞/孔，每孔100μl接种于96孔细胞培养板，置于37℃，5％CO2培养箱培养过夜。第二天每孔再加入100μl梯度稀释的2×待测化合物溶液，DMSO作为阳性对照，另设置10μM十字孢碱(阿拉丁，S102392)作为阴性对照组，加完化合物的培养板继续于37℃，5％CO2培养箱中孵育4天。孵育完成后使用Steady-luciferase assay system(Promega，G9243)并按照供应商提供的说明书 在Envision 2104Multilabel Reader上测定荧光信号值。通过以下公式计算抑制率，然后以抑制剂的浓度Log值为X轴，抑制率为Y轴绘制曲线，用Graphpad 8.0计算得出IC50。
Inhibition％＝(阳性对照组信号-测试孔信号)/(阳性对照组信号-阴性对照组信号)*100
表2测试化合物对A431细胞增殖活性抑制结果
表3测试化合物对293T细胞增殖活性抑制结果

化合物对细胞增殖抑制试验结果如表2和表3所示，结果表明，本发明中的化合物能明显抑制细胞增殖。
测试例3：药代动力学试验
小鼠药代动力学试验，使用3只雄性ICR小鼠，20-25g，禁食过夜，尾静脉注射给药(1mg/kg或5mg/kg)。在给药前和给药后15、30min以及1、2、4、8、24h采血。血液样品于转速6800g、2-8℃条件下离心6分钟，收集血浆，于-80℃保存。取各时间点血浆，加入3-5倍量含内标的乙腈溶液混合，涡旋混合1min，13000转/min下于4℃离心10min，取上清液加入3倍量水混合，取适量混合液进行LC-MS/MS分析。主要药代动力学参数用WinNonlin7.0软件非房室模型分析。
表4小鼠药代动力学试验结果
表5小鼠药代动力学试验结果-2

小鼠药代动力学试验结果表明，本发明化合物表现出符合皮肤局部给药的药代动力学性质，体内代谢快，潜在毒性小，成药性良好。
测试例4：人肝微粒体稳定性试验
人肝微粒体稳定性试验采用化合物与人肝微粒体体外共孵育进行检测。首先将待测化合物在DMSO溶剂中配制成10mM的储备液，随后使用乙腈将化合物稀释至0.5mM。使用PBS稀释人肝微粒体(Corning)成微粒体/缓冲液溶液，并使用该溶液稀释0.5mM的化合物成为工作溶液，工作溶液中化合物浓度为1.5μM，人肝微粒体浓度为0.75mg/ml。取深孔板，每孔加入30μL工作溶液，然后加入15μL预热好的6mM NADPH溶液启动反应，37℃孵育。在孵育的0、5、15、30、45分钟时，加入135μL乙腈至相应的孔中终止反应。在最后45分钟时间点用乙腈终止反应后，深孔板涡旋振动10分钟(600rpm/min)，然后离心15分钟。离心后取上清，1:1加入纯化水后进行LC-MS/MS检测，获得每个时间点化合物峰面积与内标峰面积比值，将5、15、30、45分钟时化合物的峰面积比值与0分钟时的峰面积比值进行比较，计算每个时间点化合物的剩余百分比，使用Graphpad 5软件计算T1/2。
表6人肝微粒体稳定性试验结果

人肝微粒体稳定性试验结果表明，本发明化合物表现出符合皮肤局部给药的药代动力学性质，肝微粒体代谢快，潜在毒性小，成药性良好。
尽管上面已经示出和描述了本发明的实施例，可以理解的是，上述实施例是示例性的，不能理解为对本发明的限制，本领域的普通技术人员在本发明的范围内可以对上述实施例进行变化、修改、替换和变型。

Claims (28)

  1. 一种如式I所示化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药：

    其中，
    X选自O、S、NH或N(C1-C6烷基)；
    当环A存在时，Y不存在；所述环A选自C3-C8环烷基；
    当环A不存在时，Y选自被R1所取代的C1-C6烷基，或其中，所述环B选自3-6元环烷基或4-8元杂环烷基；
    所述R1为C1-C6烷基；
    所述L1、L2各自独立地不存在或选自C1-C6亚烷基；
    Z选自C3-C8环烷基、3-11元杂环烷基，其中，所述C3-C8环烷基、3-11元杂环烷基任选地被R2所取代；
    R2选自卤素、羟基、氨基、氰基、羰基、氧代(＝O)、羧基、C1-C6烷基、C2-C6烯基、C2-C6炔基、卤代C1-C6烷基、羟基C1-C6烷基、C1-C6烷基羰基、C1-C6烷基氰基、C1-C6烷氧基、卤代C1-C6烷氧基、C1-C6烷氧羰基、C1-C6烷氧基C1-C6烷基、C1-C6烷氧羰基C1-C6烷基、C3-C8环烷基、C3-C8环烷基羰基、C3-C8环烷氧基，任选具有1或2个C1-C6烷基基团的氨基羰基基团，C1-C6烷基磺酰基基团，任选具有1或2个C1-C6烷基基团的氨基磺酰基，C1-C6烷基磺酰基氨基基团和任选具有1或2个C1-C6烷基基团的氨基；
    Q选自未取代或被R3所取代的6-10元芳基、未取代或被R3所取代的5- 10元杂芳基；所述杂芳基的杂原子为N、O或S，杂原子个数为1-3个；所述的R3取代为一个或多个取代，所述的R3各自独立地选自氢、卤素、羟基、硝基、氰基、C1-C6烷基、C1-C6烷氧基；或者，当R3为多个时，被取代的6-10元芳基或5-10元杂芳基与R3一起形成含O饱和杂环；
    Ra和Rb不存在，或分别独立地为卤素、羟基、氨基、氰基、羰基、氧代(＝O)、羧基、C2-C6烯基、C1-C6烷基、C1-C6氘代烷基、C2-C6炔基、卤代C1-C6烷基、羟基C1-C6烷基、C1-C6烷基羰基、C1-C6烷氧基、卤代C1-C6烷氧基、-COO-C1-C6烷基、-C(O)NR4R5；其中，所述R4和R5各自独立地为氢、C1-C6烷基；
    m、n、p、q分别独立地为0、1、2或3。
  2. 如权利要求1所述的式I所示的化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药，其特征在于，所述Y选自被甲基取代的C1-C6烷基，或所述环B为环丙基；所述L1、L2各自独立地不存在或选自C1-C6亚烷基。
  3. 如权利要求1所述的式I所示的化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药，其特征在于，所述Z选自未取代或者被R2所取代的3-11元饱和杂环，其中，所述R2选自C1-C6烷基，所述取代为1个或2个；所述3-11元饱和杂环进一步具有1至3个选自N、O、S的杂原子。
  4. 如权利要求3所述的式I所示的化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药，其特征在于，所述Z选自未取代或者被R2所取代的5-10元饱和杂环；其中，所述5-10元饱和杂环为单环、并环、螺环或桥环。
  5. 如权利要求4所述的式I所示的化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药，其特征在于，所述Z选自未取代或者 被R2所取代的单环的5-8元单环、6-10元螺环、6-10元桥环、8-10元并环。
  6. 如权利要求5所述的式I所示的化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药，其特征在于，所述Z选自
  7. 如权利要求1所述的式I所示的化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药，其特征在于，所述Q选自未取代或被R3所取代的苯基、未取代或被R3所取代的5-6元杂芳基；所述杂芳基的杂原子为N、O或S，杂原子个数为1-3个；所述的R3取代为一个或多个取代，所述的R3各自独立地选自氢、卤素、羟基、硝基、氰基、C1-C6烷基、C1-C6烷氧基；或者，当R3为多个时，被取代的苯基或5-6元杂芳基与R3一起形成含O饱和杂环。
  8. 如权利要求7所述的式I所示的化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药，其特征在于，所述Q选自
  9. 如权利要求1所述的式I所示的化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药，其特征在于，所述化合物选自如下结 构：
    其中，R6、R7各自独立地不存在或为卤素、羟基、氨基、硝基、氰基、羰基、氧代(＝O)、羧基、C1-C6烷基、C1-C6氘代烷基、C2-C6炔基、卤代C1-C6烷基、羟基C1-C6烷基、C1-C6烷基羰基、C1-C6烷氧基、卤代C1-C6烷氧基；
    X、环A、Y、Z、m、n具有权利要求1所述的定义。
  10. 如权利要求9所述的式I所示的化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药，其特征在于，所述R6、R7分别独立地为不存在或为甲基、乙基、氟、氯。
  11. 如权利要求1所述的式I所示的化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药，其特征在于，所述化合物选自如下结构：
    其中，R6、R7各自独立地不存在或为卤素、羟基、氨基、硝基、氰基、羰基、氧代(＝O)、羧基、C1-C6烷基、C1-C6氘代烷基、C2-C6炔基、卤代C1-C6烷基、羟基C1-C6烷基、C1-C6烷基羰基、C1-C6烷氧基、卤代C1-C6烷氧基；
    X、环A、Y、Z、m、n具有权利要求1所述的定义。
  12. 如权利要求11所述的式I所示的化合物、其互变异构体、立体异构 体、溶剂化物、药学上可接受的盐或前药，其特征在于，所述R6、R7分别独立地不存在，或为甲基、乙基、氟、氯。
  13. 如权利要求1所述的式I所示的化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药，其特征在于，其如下述任一方案所述：
    a)所述X选自O；
    b)当环A存在时，所述Y不存在；所述环A选自C3-C8环烷基；当环A不存在时，所述Y选自被R1所取代的C1-C6烷基；所述R1为C1-C6烷基；
    c)所述Z选自未取代或被一个或多个C1-C6烷基取代的3-11元杂环烷基；
    d)所述Q选自未取代的6-10元芳基；所述m为1；
    e)所述Ra为卤素、氰基或C1-C6烷基；所述p为0或1；
    f)所述q为0。
  14. 如权利要求1所述的式I所示的化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药，其特征在于，所述X选自O；
    当环A存在时，Y不存在；所述环A选自C3-C8环烷基；
    当环A不存在时，所述Y选自被R1所取代的C1-C6烷基；
    所述R1为C1-C6烷基；
    所述Z选自未取代或被一个或多个甲基取代的3-11元杂环烷基；
    所述Q选自未取代的6-10元芳基；
    所述Ra为卤素、氰基或C1-C6烷基；
    所述m为1；
    所述p为0或1；
    所述q为0。
  15. 如权利要求1所述的式I所示的化合物、其互变异构体、立体异构 体、溶剂化物、药学上可接受的盐或前药，其特征在于，其如下述任一方案所述：
    g)所述的环A里，所述的C3-C8环烷基为3-6元环烷基；
    h)所述的环A里，所述的C3-C8环烷基为单环、并环、桥环或螺环；
    i)所述的环A里，所述的C3-C8环烷基为饱和环；
    j)所述的Y里，所述的C1-C6烷基优选C1-C3亚烷基，进一步优选-CH2-、-CH2CH2-或-CH2CH2CH2-；
    k)所述的R1里，所述的C1-C6烷基优选甲基或乙基；
    l)所述的Y为进一步优选其左端与Z连接；
    m)所述的Z里，所述的3-11元杂环烷基为4-6元杂环烷基；
    n)所述的Z里，所述的3-11元杂环烷基为单环、并环、桥环或螺环；
    o)所述的Z里，所述的3-11元杂环烷基为饱和环；
    p)所述的Z里，所述的3-11元杂环烷基中的杂原子为N和/或O；
    q)所述的Z里，所述的3-11元杂环烷基中的杂原子为N和O；
    r)所述的Z里，所述的3-11元杂环烷基通过N原子与Y或A连接；
    s)所述的Z里，所述的3-11元杂环烷基为
    t)所述的Q里，所述的6-10元芳基为苯基；
    u)所述的Ra里，所述的卤素为氟或氯；
    v)所述的Ra里，所述的C1-C6烷基为甲基或乙基。
  16. 如权利要求1所述的式I所示的化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药，其特征在于，所述的环A里，所述的C3-C8环烷基为环丁基或环丙基，进一步优选更进一 步优选
  17. 如权利要求1所述的式I所示的化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药，其特征在于，所述化合物选自如下结构：

    其中，Z具有权利要求1所述的定义。
  18. 如权利要求1所述的式I所示的化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药，其特征在于，所述化合物包括：



  19. 一种化合物或其盐，其选自如下任一结构：

  20. 一种药物组合物，其特征在于，所述药物组合物包括：如权利要求1-18中任一所述的式I所示化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药；和药学上可接受的载体。
  21. 一种如权利要求1-18中任一所述的式I所示化合物、其互变异构体、 立体异构体、溶剂化物、药学上可接受的盐或前药的用途，或权利要求20所述的药物组合物的用途，所述用途包括：
    抑制微管蛋白聚合或Src激酶；
    和/或，预防和/或治疗微管蛋白聚合介导或Src激酶相关的疾病；
    和/或，制备用于抑制微管蛋白聚合或Src激酶，和/或预防和/或治疗微管蛋白聚合介导或Src激酶相关的疾病的药物、药物组合物或制剂。
  22. 如权利要求21所述的用途，其特征在于，所述微管蛋白聚合介导或Src激酶相关的疾病包括：肿瘤、皮肤疾病和/或其它疾病的一种、两种或更多种；
    和/或，所述药物为外用制剂；
    和/或，所述药物为经皮给药的药物。
  23. 如权利要求21所述的用途，其特征在于，所述肿瘤包括：实体瘤、肉瘤、血液系统癌症，亚型有乳腺癌、卵巢癌、前列腺癌、子宫颈癌、睾丸癌、结肠癌、结肠直肠癌、肝癌、非小细胞肺癌、鳞状细胞癌、小细胞肺癌、胃癌、胃肠道间质瘤、胰腺癌、膀胱癌、生殖细胞瘤、肥大细胞瘤、肥大细胞增多症、胶质母细胞瘤、神经母细胞瘤、星形细胞瘤、黑色素瘤、B细胞淋巴瘤、T细胞淋巴瘤、缓慢进展淋巴瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、急性髓细胞性白血病、急性淋巴细胞性白血病、慢性髓细胞性白血病、慢性淋巴细胞性白血病、骨髓瘤和/或骨髓增生异常综合症。
  24. 如权利要求21所述的用途，其特征在于，所述皮肤疾病包括：光化性角化病、银屑病、异位性皮炎、牛皮癣、白癜风、玫瑰疹和/或系统性红斑狼疮。
  25. 如权利要求21所述的用途，其特征在于，所述其他疾病包括：自身免疫型糖尿病、糖尿病视网膜病变、肝纤维化、肺纤维化、肾纤维化、阿尔茨海默病、帕金森病、亨廷顿舞蹈症、肌萎缩侧索硬化、脊髓小脑退行性病变、动脉粥样硬化、贫血、镰刀形红细胞贫血症、地中海贫血症、骨关节炎、 类风湿性关节炎、疟疾、锥形虫病、蠕虫病、原虫感染、多发性硬化症、狼疮、哮喘、过敏性鼻炎和/或炎性肠病。
  26. 如权利要求1-18中任一所述的式I所示化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药，或如权利要求20所述的药物组合物用于治疗或者预防肿瘤和/或皮肤疾病的用途。
  27. 一种抑制Src激酶，或预防和/或治疗Src激酶相关的疾病的方法，包括步骤：给需要的对象使用如权利要求1-18中任一所述的化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药，或如权利要求20所述的药物组合物。
  28. 一种抑制微管蛋白，或预防和/或治疗与微管蛋白相关的疾病的方法，包括步骤：给需要的对象使用如权利要求1-18中任一所述的化合物或其药学上可接受的盐，或如权利要求20所述的药物组合物。
PCT/CN2023/072140 2022-01-14 2023-01-13 微管蛋白-Src双靶点抑制剂和用途 WO2023134751A1 (zh)

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