WO2023134753A1 - 微管蛋白-src双靶点抑制剂 - Google Patents

微管蛋白-src双靶点抑制剂 Download PDF

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WO2023134753A1
WO2023134753A1 PCT/CN2023/072144 CN2023072144W WO2023134753A1 WO 2023134753 A1 WO2023134753 A1 WO 2023134753A1 CN 2023072144 W CN2023072144 W CN 2023072144W WO 2023134753 A1 WO2023134753 A1 WO 2023134753A1
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ring
compound
alkyl
pharmaceutically acceptable
tautomer
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French (fr)
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张学军
臧杨
杨辉
魏文军
吴智强
高振兴
李群
李金平
李学强
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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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/56—Amides
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/443—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/04—Antipruritics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P35/02—Antineoplastic agents specific for leukemia
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/57—Nitriles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/34—One oxygen atom
    • C07D239/36—One oxygen atom as doubly bound oxygen atom or as unsubstituted hydroxy radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
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    • 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
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    • 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.
  • 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 Binases inhibitor, RTB) dual-target inhibitor, tubulin-histone deacetylase (histone deacetylases inhibitor, HDAC) dual-target inhibitors, etc. (Shuai W et al. Journal of Medicinal Chemistry, 2021, 64(12).).
  • Actinic Beratosis a skin disorder associated with prolonged exposure to UV light, is the second most common disease among dermatologists in the United States and is characterized by uncontrolled mutated keratinocytes Proliferation of the skin, which is considered a precancerous lesion, can develop into cutaneous squamous cell carcinoma (SCC) in 20% of cases if left untreated.
  • SCC cutaneous squamous cell carcinoma
  • the tubulin-SRC dual-target inhibitor TiRbanibulin has a significant clinical effect in the local treatment of AB (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 AB may be a potential direction.
  • the object of the present invention is to provide a dual-target inhibitor of tubulin-Src, said dual-target inhibitor has a structure as described in formula I in the present invention, which can be used as a dual-target inhibitor of tubulin and Src kinase It can also be used as a single tubulin or Src kinase inhibitor.
  • a compound represented by formula I having the structure:
  • W is selected from: -O-, -S-, -NH-, -N(C 1 -C 6 alkyl)-;
  • L 1 is C 1 -C 6 alkylene
  • L 2 and L 3 are each independently absent or C 1 -C 6 alkylene
  • Ring A is 3-6 membered cycloalkyl or 4-8 membered heterocyclic group
  • Ring B does not exist or is selected from: 3-8 membered cycloalkyl, 4-10 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl;
  • the L 1 , L 2 , L 3 are optionally substituted by one or more RL ; when there are multiple RL , the RL are the same or different;
  • R L , R b , R 1 , and R 2 are each independently selected from: halogen, hydroxyl, amino, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, -OC 1 -C 6 alkyl, -COO-C 1 -C 6 alkyl, -CO-C 1 - C 6 alkyl, -C(O)NR 11 R 12 ;
  • R 11 and R 12 are each independently hydrogen, C 1 -C 6 alkyl
  • R L , R b , R 1 , R 2 are optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxyl, amino, cyano, C 1 -C 6 alkyl, when the substituent is When multiple, the substituents are the same or different;
  • n 0, 1, 2 or 3; when R b is multiple, said R b is the same or different;
  • n 0, 1, 2 or 3; when there are multiple R 1s , the R 1s are the same or different;
  • p 0, 1, 2 or 3; when R 2 is multiple, said R 2 are the same or different.
  • W is selected from -O-;
  • L 1 is C 1 -C 6 alkylene
  • Ring B does not exist or is selected from: 3-8 membered cycloalkyl, 4-10 membered heterocyclic group;
  • R b and R 1 are each independently selected from: halogen, C 1 -C 6 alkyl;
  • n 0 or 1
  • n 0 or 1
  • L 1 is preferably C 1 -C 3 alkylene or More preferably -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 - or Its left end is connected with hydroxyl group or ring B.
  • the 3-8 membered cycloalkyl group is a 3-6 membered cycloalkyl group.
  • the 3-8 membered cycloalkyl group is a monocyclic ring, a parallel ring, a bridged ring or a spiro ring.
  • the 3-8 membered cycloalkyl is a saturated ring.
  • the 3-8 membered cycloalkyl is cyclopropyl.
  • the 3-8 membered cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
  • the 4-10 membered heterocyclic group is a 4-6 membered heterocyclic group.
  • the 4-10 membered heterocyclic group is a monocyclic ring, a parallel ring, a bridged ring or a spiro ring.
  • the 4-10 membered heterocyclic group is a saturated ring.
  • the heteroatom in the 4-10 membered heterocyclic group is N.
  • the heteroatoms in the 4-10 membered heterocyclic group are N or O.
  • the 4-10 membered heterocyclic group is connected to L1 through an N atom.
  • the 4-10 membered heterocyclic group is
  • said halogen is fluorine or chlorine.
  • said C 1 -C 6 alkyl group is methyl or ethyl.
  • said halogen is fluorine or chlorine.
  • said C 1 -C 6 alkyl group is methyl or ethyl.
  • W is selected from: -O-, -S-, -NH-; preferably, W is -O-.
  • L 1 is C 1 -C 3 alkylene
  • L 2 and L 3 are each independently absent or C 1 -C 3 alkylene
  • L 2 and L 3 are different and not exist.
  • ring A is 3-6 membered cycloalkyl or 4-6 membered heterocyclyl; L 1 , L 2 , L 3 are optionally substituted by one or more RL ; when RL is When there are multiple, the R Ls are the same or different;
  • the R L is selected from: halogen, hydroxyl, amino, cyano, C 1 -C 6 alkyl, -OC 1 -C 6 alkyl; the R L is optionally substituted by one or more selected from the following Group substitution: halogen, hydroxyl, amino, cyano, C 1 -C 6 alkyl; when there are multiple substituents, the substituents are the same or different;
  • the R L is selected from: C 1 -C 6 alkyl or C 1 -C 6 haloalkyl; preferably, ring A is 3-6 membered cycloalkyl; preferably, ring A is ring Propyl, cyclobutyl, cyclopentyl, cyclohexyl; preferably, The halogen is F.
  • ring B is selected from: 3-8 membered cycloalkyl, 4-10 membered heterocyclyl; preferably, ring B is selected from: 3-6 membered cycloalkyl, 4-6 membered heterocyclic Cyclic group; preferably, the ring B is a monocyclic ring, a ring, a bridging ring, a spiro ring; preferably, the 3-6 membered cycloalkyl group and the 4-6 membered heterocyclic group are monocyclic rings; relatively
  • the ring B has 1, 2 or 3 heteroatoms selected from N, O, S, P; preferably, the ring B has S heteroatoms, and the ring B has the structure
  • m is 0, 1 or 2;
  • R b is selected from: halogen, hydroxyl, amino, cyano, C 1 -C 3 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 Alkynyl, -OC 1 -C 3 alkyl, -COO-C 1 -C 3 alkyl, -CO-C 1 -C 3 alkyl, -C(O)NR 11 R 12 ;
  • R 11 and R 12 are each independently hydrogen, methyl, ethyl, propyl;
  • the R b is optionally substituted by one or more substituents selected from the following: halogen, hydroxyl, amino, cyano, C 1 -C 3 alkyl, when there are multiple substituents, the substituents are the same or different; or R b is selected from: halogen, hydroxyl, amino, cyano, C 1 -C 6 alkyl, -OC 1 -C 6 alkyl;
  • the R b is optionally substituted by one or more substituents selected from the following: halogen, C 1 -C 6 alkyl; when there are multiple substituents, the substituents are the same or different;
  • R b is selected from: C 1 -C 6 alkyl; said R b is optionally substituted by one or more halogens; when there are multiple halogens, said halogens are the same or different; preferably, R b is selected from: methyl, ethyl, propyl, isopropyl; said R b is optionally substituted by one or more halogens; when there are multiple halogens, said halogens are the same or different; preferably , the halogen is F.
  • n is 0 or 1;
  • R 1 is selected from: halogen, cyano, C 1 -C 6 alkyl;
  • R 1 is selected from: fluorine, cyano, methyl.
  • R 1 is selected from: fluorine, chlorine, cyano, methyl.
  • p is zero.
  • a pharmaceutical composition including the compound as described in any one of the first aspect, its tautomer, stereoisomer, solvate (such as hydrate), pharmaceutically acceptable Accepted salts or prodrugs.
  • a pharmaceutical composition comprising the compound as described in any one of the first aspect, its tautomer, stereoisomer, solvate (such as hydrate), pharmaceutically acceptable salt or prodrug, And pharmaceutically acceptable carrier and/or other active drugs.
  • any compound as described in the first aspect its tautomer, stereoisomer, solvate (such as hydrate), pharmaceutically acceptable salt or prodrug purposes, or the purposes of any pharmaceutical composition described in the second aspect, the purposes include:
  • the use includes: inhibiting tubulin polymerization; and/or, preventing and/or treating tubulin polymerization-related diseases; and/or, preparing tubulin polymerization inhibitors, and/or, preparing prophylactic And/or a medicament, pharmaceutical composition or preparation for treating a disease associated with tubulin polymerization.
  • the use includes: inhibiting Src kinase; and/or, preventing and/or treating diseases related to Src kinase; and/or, preparing a Src kinase inhibitor; and/or, preparing a method for preventing and/or treating diseases related to Src A medicament, pharmaceutical composition or preparation for a kinase-associated disease.
  • the drug is an external preparation.
  • the drug is a drug for transdermal administration.
  • the diseases related to tubulin polymerization and/or Src kinase include tumors and skin diseases.
  • the fourth 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 in Use in the preparation of medicines for treating tumors and/or skin diseases; or use of the pharmaceutical composition according to any one of the second aspect in the preparation of medicines for treating tumors and/or skin diseases.
  • the drug is an external preparation.
  • the drug is a drug for transdermal administration.
  • 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 to Use of at least one or the pharmaceutical composition described in the second aspect of the present invention for treating or preventing tumors and/or skin diseases.
  • the tumors include: solid tumors, sarcomas, and hematological cancers;
  • the tumors include: breast cancer, ovarian cancer, prostate cancer, cervical cancer, testicular cancer, colon cancer, colorectal cancer, liver cancer, non-small cell lung cancer, squamous cell carcinoma (such as squamous cell carcinoma of the skin) ), small cell lung cancer, gastric cancer, gastrointestinal stromal tumor, pancreatic cancer, bladder cancer, germ cell tumor, mastocytoma, mastocytoma, 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 Lymphoblastic leukemia, myeloma, and/or myelodysplastic syndrome.
  • squamous cell carcinoma such as squamous cell carcinoma of the
  • the skin diseases include: actinic keratosis, psoriasis, atopic dermatitis, psoriasis, vitiligo, roseola and/or systemic lupus erythematosus.
  • 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 second 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 second 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.
  • substituent 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.
  • CH2O is equivalent to OCH2 .
  • halogen means fluorine, chlorine, bromine, iodine alone or as part of another substituent.
  • alkyl alone or as part of another substituent, means consisting solely of carbon and hydrogen atoms, free of unsaturated bonds, having, for example, 1 to 6 carbon atoms, and is bonded to the molecule by a single bond. The rest are connected straight or branched hydrocarbon chain groups. Examples of 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, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl Base, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3
  • alkylene by itself or as part of another substituent, means a saturated divalent hydrocarbyl group obtained by removing two hydrogen atoms from a saturated straight or branched chain hydrocarbyl group.
  • alkylene groups include methylene (-CH 2 -), ethylene (including -CH 2 CH 2 - or -CH(CH 3 )-), isopropylidene (including -CH(CH 3 )CH 2 -or -C(CH 3 ) 2 -) and so on.
  • Carbocycle refers to a cyclic alkyl group.
  • mn-membered cycloalkyl or C m -C n cycloalkyl has the same definition and should be understood to mean a saturated, unsaturated or partially saturated carbocycle having m to n atoms.
  • a "3-8 membered cycloalkyl” contains 3-8 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 decahydronaphthalene rings. Cycloalkyl groups may be substituted with one or more substituents.
  • 3-6 membered cycloalkyl is understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3 to 6 carbon atoms, including fused or bridged polycyclic ring systems. For example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
  • unsubstituted cycloalkyl examples include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, and cyclohexadienyl.
  • the 3-15 membered cycloalkyl group is preferably a 3-10 membered cycloalkyl group; more preferably a 3-8 membered cycloalkyl group.
  • haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl.
  • C2 - C6 alkenyl is understood to mean a straight or branched monovalent hydrocarbon radical containing one or more double bonds and having 2, 3, 4, 5 or 6 carbon atoms, having 2 or 3 carbon atoms (ie, C2 - C3 alkenyl). It is understood that where the alkenyl group contains more than one double bond, the double bonds may be separated from each other or conjugated.
  • the alkenyl is, for example, vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)-but-2-enyl, (Z)- but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl.
  • C 2 -C 6 alkynyl is understood to mean a straight or branched monovalent hydrocarbon radical containing one or more triple bonds and having 2, 3, 4, 5 or 6 carbon atoms, having 2 or 3 carbon atoms (" C2 - C3alkynyl ").
  • the alkynyl group is, for example, ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl.
  • 6-10 membered aryl should be understood as a monovalent aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring with 6 to 10 carbon atoms, especially a ring with 6 carbon atoms (" C 6 aryl”), such as phenyl; or biphenyl, or a ring with 9 carbon atoms (“C 9 aryl”), such as indanyl or indenyl, or a ring with 10 carbon atoms ring (“C 10 aryl”), such as tetrahydronaphthyl, dihydronaphthyl or naphthyl.
  • C 6 -C 10 aryl When the C 6 -C 10 aryl is substituted, it may be monosubstituted or polysubstituted.
  • substitution site for example, it may be an ortho, para or meta substitution.
  • 5-10 membered heteroaryl is understood to mean a monovalent monocyclic, bicyclic or tricyclic aromatic ring having 5 to 10 ring atoms and containing 1 to 5 heteroatoms independently selected from N, O and S Groups, such as "5-14 membered heteroaryl".
  • the term "5-14 membered heteroaryl” is understood as having 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms - especially 5 or 6 or 9 or 10 carbon atoms - and it contains 1-5, preferably 1-3 - monovalent monocyclic, bicyclic or tricyclic aromatic ring groups of heteroatoms independently selected from N, O and S, and, additionally in each In this case it can be benzo-fused.
  • heteroaryl is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiazolyl, Diazolyl, etc.
  • benzo derivatives such as benzofuryl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl , indolyl, isoindolyl, etc.; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and their benzo derivatives, such as quinolinyl, quinazolinyl, iso Quinolinyl, etc.; or indolizinyl, purinyl, etc., and their benzo derivatives; or phthalazinyl, quinazolinyl, quinoxalinyl, etc.
  • heterocycle refers to any saturated, unsaturated or partially saturated monocyclic, bicyclic or tricyclic ring having 4 to 10 atoms, wherein 1, 2, 3, 4 or 5 ring atoms are selected from N, O, S and P (preferably selected from N, O, S); it is understood that when the total number of S atoms and O atoms in the heterocyclyl exceeds 1, these Atoms are not adjacent to each other. If the heterocyclyl is monocyclic, it must not be aromatic.
  • heterocyclic groups include, but are not limited to, piperidinyl, piperazinyl, azetidinyl, oxetanyl, morpholinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, dihydro Indolyl, tetrahydropyranyl, dihydro-2H-pyranyl, tetrahydrofuranyl, tetrahydrothiopyranyl.
  • 4-6 membered heterocyclic group should be understood as a saturated, unsaturated or partially saturated monocyclic ring having 4-6 atoms, of which 1, 2, 3 or 4 (preferably 1, 2 or 3 ) ring atoms are selected from N, O and S.
  • 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 rings, the spirocycloalkyl group can be divided into single spirocycloalkyl, double spirocycloalkyl or polyspirocycloalkyl, preferably single spirocycloalkyl and double spirocycloalkyl.
  • 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:
  • 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 Symbol used to designate 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.
  • 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.
  • 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 that can be converted under physiological conditions or by solvolysis into a biologically active compound. specific compounds of the present invention.
  • 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.
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compounds.
  • compounds can be labeled with radioactive isotopes, such as deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C). All changes in isotopic composition of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.
  • 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 and other similar synonyms include the following meanings:
  • the reagents and raw materials used in the present invention are all commercially available.
  • the method is simple in operation, high in yield and high in purity, and can be used in the industrial production of medicines.
  • the inventors unexpectedly developed a tubulin-SRC dual A target inhibitor, the dual target inhibitor has the structure as described in the first aspect of the present invention. It can be used as a dual-target inhibitor of tubulin and Src kinase, or as a single inhibitor of tubulin or Src kinase.
  • the inhibitor of the present invention can significantly inhibit the polymerization of tubulin monomers and inhibit cell proliferation; it has a good therapeutic effect on actinic keratosis; it conforms to the pharmacokinetic properties of topical skin administration ; The potential systemic toxicity is small, and the druggability is good; it has good p-SRC inhibitory activity and can block the downstream signaling pathway of SRC.
  • Figure 1 shows the results of the compound's inhibition of tubulin polymerization.
  • N-benzyl-2-(5-bromopyridin-2-yl)acetamide (2.0g, 6.55mmol), 4-(4,4,5,5-tetramethyl-1,3,2 -dioxaborolan-2-yl)phenol (1.73g, 7.86mmol), potassium fluoride (1.52g, 26.2mmol) and 1,1'-bis(diphenylphosphino)ferrocene dichloride Palladium(II)(II) (480mg, 0.66mmol) was added to the reaction flask, replaced with nitrogen three times, then the solvent dioxane (20mL) and water (2mL) were added, the reaction solution was stirred at 80°C for 10h, and the reaction was detected by TLC Cool to room temperature after completion, concentrate and rotate to evaporate The crude product was obtained from the solvent, and N-benzyl-2-(5-(4-hydroxyphenyl)pyridin-2-yl)acetamide (intermediate A1) (1.65 g, yield
  • the first step the preparation of 3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol
  • the second step the preparation of N-benzyl-2-(5-(2-chloro-4-hydroxyphenyl)pyridin-2-yl)acetamide
  • the first step the preparation of 4-(4-bromophenoxy)-2-methylbutan-2-ol
  • the third step the preparation of N-benzyl-2-(5-(4-(3-hydroxy-3-methylbutoxy)phenyl)pyridin-2-yl)acetamide
  • the first step the preparation of 1-(2-(4-bromophenoxy)ethyl)-4-methylpiperidin-4-ol
  • the second step 4-methyl-1-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy ) ethyl) preparation of piperidin-4-alcohol
  • the synthetic route is as follows:
  • the synthetic route is as follows:
  • the first step the preparation of 1-(2-bromoethyl) cyclopropan-1-ol
  • the second step the preparation of N-benzyl-2-(5-(4-(2-(1-hydroxycyclopropyl)ethoxy)phenyl)pyridin-2-yl)acetamide
  • N-benzyl-2-(5-(4-hydroxyphenyl)pyridin-2-yl)acetamide (0.2g, 0.63mmol) and potassium carbonate (0.26g, 1.89mmol) were added to anhydrous acetonitrile at room temperature (5mL), heated to 80°C and stirred for 1h, then added 1-(2-bromoethyl)cyclopropan-1-ol (0.11g, 0.94mmol), continued to heat and stirred at 80°C for 10h, TLC detected that the reaction was complete , the reaction solution was cooled to room temperature, concentrated and rotary evaporated to remove the solvent to obtain the crude product, Purified by preparative high-performance liquid chromatography to obtain compound N-benzyl-2-(5-(4-(2-(1-hydroxycyclopropyl) ethoxy) phenyl) pyridin-2-yl) acetamide (I -4) (126mg, yield 49%).
  • the synthetic route is as follows:
  • N-benzyl-2-(5-(2-chloro-4-hydroxyphenyl)pyridin-2-yl)acetamide (0.4g, 1.13mmol) and potassium carbonate (0.47g, 3.4mmol) were added at room temperature into anhydrous acetonitrile (15mL), heated to 85°C and stirred for 1h, then added 4-bromo-2-methylbutan-2-ol (0.57g, 3.40mmol), and continued to heat at 85°C Stir for 10 h, spot the plate to detect the completion of the reaction, cool to room temperature, concentrate and rotate to evaporate the solvent to obtain the crude product, and use silica gel column separation and purification to obtain the compound N-benzyl-2-(5-(2-chloro-4-(3-hydroxyl -3-Methylbutoxy)phenyl)pyridin-2-yl)acetamide (I-16) (0.34g, yield 68%).
  • control 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 face or scalp actinic keratosis treat.
  • the preparation of reference compound I refers to patent WO 2008/002676 A2, and the structure of reference 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 - negative pair Group signal)*100
  • Table 3 test compound inhibits the activity of different cell proliferation
  • 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. Blood samples were centrifuged at 6800g at 2-8°C for 6 minutes, 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 for 1 minute, centrifuge at 4°C at 13,000 rpm for 10 minutes, take the supernatant and add 3 times the amount of water to mix, take an appropriate amount and mix The liquid was analyzed by LC-MS/MS. The main pharmacokinetic parameters were analyzed by WinNonlin 7.0 software non-compartmental model.
  • mice pharmacokinetic test results are shown in Tables 4 and 5. The results show that the compound of the present invention has fast metabolism in vivo, 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。本发明提供了一种如式（I）所示化合物、其互变异构体、立体异构体、溶剂化物（例如水合物）、药学上可接受的盐或前药;其可以作为微管蛋白和Src激酶双靶点抑制剂,也可以作为单独的微管蛋白或Src激酶抑制剂使用，能明显抑制微管蛋白单体的聚合和抑制细胞增殖。

Description

微管蛋白-SRC双靶点抑制剂
本申请要求申请日为2022年1月14日的中国专利申请202210045140.5和申请日为2022年4月15日的中国专利申请202210399396.6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。
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 Binases inhibitor，RTB)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 Beratosis，AB)是一种与长时间暴露在紫外线下有关的皮肤病，在美国AB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AB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AB可能是一个有潜力的方向。
发明内容
本发明的目的是提供一种微管蛋白-SRC双靶点抑制剂，所述双靶点抑制剂具有如本发明中式I所述的结构，其可以作为微管蛋白和Src激酶双靶点抑制剂，也可以作为单独的微管蛋白或Src激酶抑制剂使用。
在本发明第一方面，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(例如水合物)、药学上可接受的盐或前药，具有结构：

其中，W选自：-O-、-S-、-NH-、-N(C1-C6烷基)-；
Q为
L1为C1-C6亚烷基；
L2、L3各自独立地为不存在或为C1-C6亚烷基；
且L2和L3不同时不存在；
环A为3-6元环烷基或4-8元杂环基；
环B不存在或选自：3-8元环烷基、4-10元杂环基、6-10元芳基、5-10元杂芳基；
所述L1、L2、L3任选地被一个或多个RL取代；当RL为多个时，所述RL相同或不同；
RL、Rb、R1、R2各自独立地选自：卤素、羟基、氨基、氰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、-O-C1-C6烷基、-COO-C1-C6烷基、-CO-C1-C6烷基、-C(O)NR11R12；
其中，R11、R12各自独立地为氢、C1-C6烷基；
所述RL、Rb、R1、R2任选地被一个或多个选自下列的取代基取代：卤素、羟基、氨基、氰基、C1-C6烷基，当取代基为多个时，所述取代基相同或不同；
m为0、1、2或3；当Rb为多个时，所述Rb相同或不同；
n为0、1、2或3；当R1为多个时，所述R1相同或不同；
p为0、1、2或3；当R2为多个时，所述R2相同或不同。
本发明中，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本申请中任一方案所述(以下简称“在一优选实施例中”、“在一优选实施方式中”或“在一优选实施方案中”)：
在一优选实施例中，W选自-O-；
Q为
L1为C1-C6亚烷基；
环B不存在或选自：3-8元环烷基、4-10元杂环基；
Rb、R1各自独立地选自：卤素、C1-C6烷基；
m为0或1；
n为0或1；
p为0。
在一优选实施例中，L1优选C1-C3亚烷基或进一步优选-CH2-、-CH2CH2-、-CH2CH2CH2-或其左端与羟基或环B相连。
在一优选实施例中，所述的环B里，所述的3-8元环烷基为3-6元环烷基。
在一优选实施例中，所述的环B里，所述的3-8元环烷基为单环、并环、桥环或螺环。
在一优选实施例中，所述的环B里，所述的3-8元环烷基为饱和环。
在一优选实施例中，所述的环B里，所述的3-8元环烷基为环丙基。
在一优选实施例中，所述的环B里，所述的3-8元环烷基为环丙基、环丁基、环戊基、环己基。
在一优选实施例中，所述的环B里，所述的4-10元杂环基为4-6元杂环基。
在一优选实施例中，所述的环B里，所述的4-10元杂环基为单环、并环、桥环或螺环。
在一优选实施例中，为
在一优选实施例中，所述的环B里，所述的4-10元杂环基为饱和环。
在一优选实施例中，所述的环B里，所述的4-10元杂环基中的杂原子为N。
在一优选实施例中，所述的环B里，所述的4-10元杂环基中的杂原子为N或O。
在一优选实施例中，所述的环B里，所述的4-10元杂环基通过N原子与L1连接。
在一优选实施例中，所述环B里，所述的4-10元杂环基为
在一优选实施例中，所述的Rb里，所述的卤素为氟或氯。
在一优选实施例中，所述的Rb里，所述的C1-C6烷基为甲基或乙基。
在一优选实施例中，所述的R1里，所述的卤素为氟或氯。
在一优选实施例中，所述的R1里，所述的C1-C6烷基为甲基或乙基。
在一优选实施例中，选自：
在一优选实施例中，选自：
在一优选实施例中，W选自：-O-、-S-、-NH-；较佳地，W为-O-。
在一优选实施例中，为
在一优选实施例中，L1为C1-C3亚烷基；L2、L3各自独立地为不存在或为C1-C3亚烷基；且L2和L3不同时不存在。
在一优选实施例中，环A为3-6元环烷基或4-6元杂环基；L1、L2、L3任选地被一个或多个RL取代；当RL为多个时，所述RL相同或不同；
所述RL选自：卤素、羟基、氨基、氰基、C1-C6烷基、-O-C1-C6烷基；所述RL任选地被一个或多个选自下列的取代基取代：卤素、羟基、氨基、氰基、C1-C6烷基；当取代基为多个时，所述取代基相同或不同；
较佳地，所述RL选自：C1-C6烷基或C1-C6卤代烷基；较佳地，环A为3-6元环烷基；较佳地，环A为环丙基、环丁基、环戊基、环己基；较佳地， 所述卤素为F。
在一优选实施例中，环B选自：3-8元环烷基、4-10元杂环基；较佳地，环B选自：3-6元环烷基、4-6元杂环基；较佳地，所述环B为单环、并环、桥环、螺环；较佳地，所述3-6元环烷基、4-6元杂环基为单环；较佳地，所述环B具有1、2或3选自N、O、S、P的杂原子；较佳地，所述环B具有S杂原子，所述环B具有结构
在一优选实施例中，m为0、1或2；Rb选自：卤素、羟基、氨基、氰基、C1-C3烷基、C2-C4烯基、C2-C4炔基、-O-C1-C3烷基、-COO-C1-C3烷基、-CO-C1-C3烷基、-C(O)NR11R12；
其中，R11、R12各自独立地为氢、甲基、乙基、丙基；
所述Rb任选地被一个或多个选自下列的取代基取代：卤素、羟基、氨基、氰基、C1-C3烷基，当取代基为多个时，所述取代基相同或不同；或Rb选自：卤素、羟基、氨基、氰基、C1-C6烷基、-O-C1-C6烷基；
所述Rb任选地被一个或多个选自下列的取代基取代：卤素、C1-C6烷基；当取代基为多个时，所述取代基相同或不同；
较佳地，Rb选自：C1-C6烷基；所述Rb任选地被一个或多个卤素取代；当卤素为多个时，所述卤素相同或不同；较佳地，Rb选自：甲基、乙基、丙基、异丙基；所述Rb任选地被一个或多个卤素取代；当卤素为多个时，所述卤素相同或不同；较佳地，所述卤素为F。
在一优选实施例中，具有结构
在一优选实施例中，n为0或1；R1选自：卤素、氰基、C1-C6烷基；
较佳地，R1选自：氟、氰基、甲基。
较佳地，R1选自：氟、氯、氰基、甲基。
在一优选实施例中，p为0。
在一优选实施例中，所述式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里，所述式I所示化合物为如下任一化合物：

一种化合物，其为如下任一结构
在本发明第二方面，提供了一种药物组合物，包括如第一方面任一所述的化合物、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。
提供了一种药物组合物，包括如第一方面任一所述的化合物、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，和药学上可接受的载体和/或其他活性药物。
在本发明第三方面，提供了如第一方面任一所述的化合物、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的用途，或第二方面任一所述的药物组合物的用途，所述用途包括：
1)抑制微管蛋白聚合和/或Src激酶；
2)预防和/或治疗与微管蛋白聚合和/或Src激酶相关的疾病；
3)制备微管蛋白聚合和/或Src激酶抑制剂；
4)制备预防和/或治疗与微管蛋白聚合和/或Src激酶相关的疾病的药物、药物组合物或制剂。
较佳地，所述用途包括：抑制微管蛋白聚合；和/或，预防和/或治疗微管蛋白聚合相关的疾病；和/或，制备微管蛋白聚合抑制剂，和/或，制备预防和/或治疗与微管蛋白聚合相关的疾病的药物、药物组合物或制剂。
较佳地，所述用途包括：抑制Src激酶；和/或，预防和/或治疗Src激酶相关的疾病；和/或，制备Src激酶抑制剂；和/或，制备预防和/或治疗与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。
较佳地，所述微管蛋白聚合和/或Src激酶相关的疾病包括肿瘤、皮肤疾病。
本发明第四方面，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在制备治疗肿瘤和/或皮肤疾病的药物中的用途；或如第二方面任一所述的药物组合物在制备治疗肿瘤和/或皮肤疾病的药物中的用途。
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。
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 少一种或本发明第二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。
在一优选实施例中，所述肿瘤包括：实体瘤、肉瘤、血液系统癌症；
较佳地，所述肿瘤包括：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(例如皮肤鳞状细胞癌)、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。
在一优选实施例中，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。
在本发明第六方面，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，或如本发明第二方面所述的药物组合物。
在本发明第七方面，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，或如本发明第二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 YoRb)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。
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。
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。
如本文所用，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”表示从饱和的直链或支链烃基中去掉两个氢原子所得到的饱和的二价烃基基团。亚烷基基团的实例包括亚甲基(-CH2-)，亚乙基(包括-CH2CH2-或-CH(CH3)-)，亚异丙基(包括-CH(CH3)CH2-或-C(CH3)2-)等等。
在单独或作为其他取代基一部分时，术语“碳环”、“烯环”、“环烷基”或“碳环基”是指一种环状烷基。术语“m-n元环烷基”或者“Cm-Cn环烷基”具有相同的定义，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，“3-8元环烷基”则含有3-8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“3-6元环烷基”应理解为表示饱和的一价单环或双环烃环，其具有3～6个碳原子，包括稠合或桥接的多环系统。例如环丙基、环丁基、环戊基、环己基。未取代的环烷基的实例包括但不限于环丙烯基，环丁烯基，环戊烯基，环己烯基和环己二烯基。在一些实施方案中，3-15元环烷基优选3-10元环烷基；更优选3-8元环烷基。
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。
术语“C2-C6烯基”应理解为表示直连或支链的一价烃基，其包含一个或多个双键并且具有2、3、4、5或6个碳原子，具有2或3个碳原子(即，C2-C3烯基)。应理解，在所述烯基包含多于一个双键的情况下，所述双键可相互分离或者共轭。所述烯基是例如乙烯基、烯丙基、(E)-2-甲基乙烯基、(Z)-2-甲基乙烯基、(E)-丁-2-烯基、(Z)-丁-2-烯基、(E)-丁-1-烯基、(Z)-丁-1-烯基。
术语“C2-C6炔基”应理解为表示直连或支链的一价烃基，其包含一个或多个三键并且具有2、3、4、5或6个碳原子，具有2或3个碳原子(“C2-C3炔基”)。所述炔基是例如乙炔基、丙-1-炔基、丙-2-炔基、丁-1-炔基、丁-2-炔基、丁-3-炔基。
术语“6-10元芳基”应理解为具有6～10个碳原子的一价芳香性或部分芳香性的单环、双环或三环烃环，特别是具有6个碳原子的环(“C6芳基”)，例如苯基；或联苯基，或者是具有9个碳原子的环(“C9芳基”)，例如茚满基或茚基，或者是具有10个碳原子的环(“C10芳基”)，例如四氢化萘基、二氢萘基或萘基。当所述C6-C10芳基被取代时，其可以为单取代或者多取代。并且，对其取代位点没有限制，例如可以为邻位、对位或间位取代。
术语“5-10元杂芳基”应理解为具有5～10个环原子且包含1-5个独立选自N、O和S的杂原子的一价单环、双环或三环芳族环基团，例如“5-14元杂芳基”。术语“5-14元杂芳基”应理解为具有5、6、7、8、9、10、11、12、13或14个环原子——特别是5或6或9或10个碳原子——且其包含1-5个，优选1-3个——独立选自N、O和S的杂原子的一价单环、双环或三环芳族环基团，并且，另外在每一种情况下可为苯并稠合的。特别地，杂芳基选自噻吩基、呋喃基、吡咯基、噁唑基、噻唑基、咪唑基、吡唑基、异噁唑基、异噻唑基、噁二唑基、三唑基、噻二唑基等以及它们的苯并衍生物，例如苯并呋喃基、苯并噻吩基、苯并噁唑基、苯并异噁唑基、苯并咪唑基、苯并三唑基、吲唑基、吲哚基、异吲哚基等；或吡啶基、哒嗪基、嘧啶基、吡嗪基、三嗪基等，以及它们的苯并衍生物，例如喹啉基、喹唑啉基、异喹啉基等；或吲嗪基、嘌呤基等以及它们的苯并衍生物；或酞嗪基、喹唑啉基、喹喔啉基等。
在单独或作为其他取代基一部分时，术语“杂环”、“杂环烷基”或“杂环基”具有相同的定义。术语“4-10元杂环基”或者应理解为表示具有4至10个原子的饱和、不饱和或部分饱和的单环、二环或三环，其中1、2、3、 4或5个环原子选自N、O、S和P(优选地选自N、O、S)；应该理解的是，当杂环基中S原子和O原子的总数超过1时，这些杂原子不彼此相邻。若所述杂环基为单环，则其一定不是芳族的。杂环基的实例包括但不限于哌啶基、哌嗪基、氮杂环丁烷基、氧杂环丁烷基、吗啉基、四氢异喹啉基、四氢喹啉基、二氢吲哚基、四氢吡喃基、二氢-2H-吡喃基、四氢呋喃基、四氢噻喃基。术语“4-6元杂环基”应理解为具有4-6个原子的饱和、不饱和或部分饱和的单环，其中1、2、3或4个(较佳地为1、2或3个)环原子选自N、O和S。
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。
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“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。
本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氘(2H)，氚(3H)，碘-125(125I)或C-14(14C)。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包括在本发明的范围之内。
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。
本文所用的术语“治疗”和其它类似的同义词包括以下含义：
(i)预防疾病或病症在哺乳动物中出现，特别是当这类哺乳动物易患有该疾病或病症，但尚未被诊断为已患有该疾病或病症时；
(ii)抑制疾病或病症，即遏制其发展；
(iii)缓解疾病或病症，即，使该疾病或病症的状态消退；或者
(iv)减轻该疾病或病症所造成的症状。
在符合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。
本发明所用试剂和原料均市售可得。
本发明的积极进步效果在于：
提供了一种如第一方面所述的微管蛋白-SRC双靶点抑制剂的方法及中间体，所述方法操作简单、收率高、纯度高，可用于医药工业化生产。
本发明人经过广泛而深入地研究，意外地开发了一种微管蛋白-SRC双 靶点抑制剂，所述双靶点抑制剂具有如本发明第一方面所述的结构。其可以作为微管蛋白和Src激酶双靶点抑制剂，也可以作为单独的微管蛋白或Src激酶抑制剂使用。实验表明，本发明所述的抑制剂能明显抑制微管蛋白单体的聚合和抑制细胞增殖；对光化性角化病具有很好的治疗作用；符合皮肤局部给药的药代动力学性质；潜在全身毒性小，成药性好；具有很好的p-SRC抑制活性，能阻断SRC下游信号通路。
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
以下结合具体实施例，进一步说明本发明。需理解，以下的描述仅为本发明的最优选实施方式，而不应当被认为是对于本发明保护范围的限制。在充分理解本发明的基础上，下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件，本领域技术人员可以对本发明的技术方案作出非本质的改动，这样的改动应当被视为包括于本发明的保护范围之中的。
中间体A1的制备
室温下将N-苄基-2-(5-溴吡啶-2-基)乙酰胺(2.0g,6.55mmol)，4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯酚(1.73g,7.86mmol)、氟化钾(1.52g,26.2mmol)和1,1'-二(二苯膦基)二茂铁二氯化钯(II)(480mg,0.66mmol)加入到反应瓶中，以氮气置换三次，然后加入溶剂二氧六环(20mL)和水(2mL)，反应液在80℃下搅拌10h，TLC检测反应完成后冷却到室温，浓缩旋蒸掉 溶剂得到粗品，过柱纯化N-苄基-2-(5-(4-羟基苯基)吡啶-2-基)乙酰胺(中间体A1)(1.65g,产率79％)。
LC-MS,M/Z(ESI):319.2[M+H]+
中间体A2的制备
第一步：3-氯-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-氯苯酚(5.0g,24.10mmol)，K2CO3(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，残留物用柱层析纯化(石油醚:乙酸乙酯(V/V)＝2:3)得化合物3-氯-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯酚(2.6g,白色固体，产率42.4％)。
第二步：N-苄基-2-(5-(2-氯-4-羟基苯基)吡啶-2-基)乙酰胺的制备
将化合物3-氯-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯酚(2.1g,8.25mmol)，N-苄基-2-(5-溴吡啶-2-基)乙酰胺(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(0.065g，0.089mmol)加入到二氧六环中(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)得化合物N-苄基-2-(5-(2-氯-4-羟基苯基)吡啶-2-基)乙酰胺(中间体A2)(2.6g,白色固体，产率42.4％)。
实施例1化合物I-1的制备
合成路线如下所示
第一步：4-(4-溴苯氧基)-2-甲基丁-2-醇的制备
室温下将化合物4-溴-2-甲基丁-2-醇(0.5g,2.99mmol)和4-溴苯酚(0.59g,3.29mmol)加入到N,N-二甲基甲酰胺(10mL)中,然后加入碳酸铯(1.46g,4.49mmol)，氮气保护下加热至120℃，搅拌16h。反应液冷却至室温，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4-(4-溴苯氧基)-2-甲基丁-2-醇(400mg,产率51.6％)。
第二步：2-甲基-4-(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯氧基)丁-2-醇的制备
室温下将化合物4-(4-溴苯氧基)-2-甲基丁-2-醇(0.3g,1.2mmol)和联硼酸频那醇酯(0.88g,3.47mmol)加入到1,4-二氧六环(5mL)中,然后加入醋酸钾(0.34g,3.47mmol)，氮气保护下加入1,1'-二(二苯膦基)二茂铁二氯化钯(II)(42mg,0.058mmol)，加热至100℃，搅拌6h。反应液冷却至室温，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2-甲基-4-(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯氧基)丁-2-醇(200mg,产率56.4％)。
第三步：N-苄基-2-(5-(4-(3-羟基-3-甲基丁氧基)苯基)吡啶-2-基)乙酰胺的制备
室温下将化合物2-甲基-4-(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯氧基)丁-2-醇(151mg,0.49mmol)和N-苄基-2-(5-溴吡啶-2-基)乙酰胺(100mg,0.33mmol)加入到乙二醇二甲醚(5mL)中，然后加入碳酸钠溶液(2mol/L,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。反应液冷却至室温，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，残留物经制备液相色谱纯化得N-苄基-2-(5-(4-(3-羟基-3-甲基丁氧基)苯基)吡啶-2-基)乙酰胺(I-1)(12.3mg,产率9.3％)。
1H NMR(400MHz,CDCl3)δ8.70(d,1H),7.82(dd,1H),7.70–7.60(m,2H),7.55–7.44(m,3H),7.35–7.28(m,3H),7.24(d,1H),7.04–6.99(m,2H),4.49(d,2H),4.26–4.19(m,2H),3.82(s,2H),2.13(s,1H),2.03(t,2H),1.33(d,6H)。
LC-MS,M/Z(ESI):405.3[M+H]+。
实施例2化合物I-2的制备
合成路线如下所示
第一步：1-(2-(4-溴苯氧基)乙基)-4-甲基哌啶-4-醇的制备
室温下将化合物1-溴-4-(2-溴乙氧基)苯(0.5g,1.78mmol)，K2CO3(0.741g,5.36mmol)和4-甲基哌啶-4-醇(0.226g,1.96mmol)加入到乙腈(5mL)中，氮气保护下85℃搅拌12小时。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，残留物用薄层硅胶板分离纯化(石油醚:乙酸乙酯(V/V)＝2:3)得化合物1-(2-(4-溴苯氧基)乙基)-4-甲基哌啶-4-醇(0.53g,白色固体，产率94％)。
第二步：4-甲基-1-(2-(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼戊环-2-基)苯氧基)乙基)哌啶-4-醇的制备
将化合物1-(2-(4-溴苯氧基)乙基)-4-甲基哌啶-4-醇(0.28g,0.891mmol)，联硼酸频那醇酯(0.339g,1.337mmol)，醋酸钾(0.262g,2.67mmol)和1,1-双(二苯基膦)二茂铁二氯化钯(0.065g，0.089mmol)加入到二氧六环中(3.0mL)中，置换氮气，升温至85℃搅拌10小时。加入水(10mL)稀释，用乙酸乙酯(10mL×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，得粗品4-甲基-1-(2-(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼戊环-2-基)苯氧基)乙基)哌啶-4-醇(0.18g,产率56％)。
第三步：N-苄基-2-(5-(4-(2-(4-羟基-4-甲基哌啶-1-基)乙氧基)苯基)吡啶-2-基)乙酰胺的制备

将4-甲基-1-(2-(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼戊环-2-基)苯氧基)乙基)哌啶-4-醇(0.18g,0.498mmol)，N-苄基-2-(5-溴吡啶-2-基)乙酰胺(0.304g,0.996mmol)和四三苯基膦钯(0.058g,0.05mmol)，碳酸钠(0.158g，1.495mmol)加入到乙二醇二甲醚(3ml)和水(0.5ml)中升温至100℃搅拌12小时。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，残留物用薄层硅胶板分离纯化(石油醚:乙酸乙酯(V/V)＝1:2)，再用制备液相色谱纯化得N-苄基-2-(5-(4-(2-(4-羟基-4-甲基哌啶-1-基)乙氧基)苯基)吡啶-2-基)乙酰胺(I-2)(60mg，产率26.2％)。
LC-MS,M/Z(ESI):460.3[M+H]+。
1H NMR(400MHz,CDCl3)δ8.70(d,1H),7.81(dd,1H),7.64(s,1H),7.49(d,2H),7.31(dt,4H),7.24(d,2H),7.01(d,2H),4.49(d,2H),4.23(t,2H),3.82(s,2H),2.89(d,4H),2.66(s,2H),1.82(s,2H),1.65(d,2H),1.28(s,3H)。
实施例3化合物I-3的制备
合成路线如下所示：
室温下将N-苄基-2-(5-(4-羟基苯基)吡啶-2-基)乙酰胺(中间体A1)(0.1g,0.31mmol)，和碳酸铯(0.61g,0.89mmol)加入到微波反应瓶中，再加入溶剂二甲亚砜(2mL)，在80℃下搅拌10min，然后加入1-氯-2-甲基丙-2-醇(0.21g,0.89mmol)，微波180℃下反应2h，TLC检测反应完成后冷却到室温，制备纯化得到N-苄基-2-(5-(4-(2-羟基-2-甲基丙氧基)苯基)吡啶-2-基)乙酰胺(I-3)(19mg,产率15％)。
1H NMR(400MHz,DMSO-d6)δ8.74(d,1H),8.64–8.59(m,1H),7.96(dd,1H),7.66–7.61(m,2H),7.39(d,1H),7.34–7.21(m,5H),7.05(d,2H),4.65(s, 1H),4.30(d,2H),3.76(s,2H),3.71(s,2H),1.25–1.18(m,6H)。
LC-MS,M/Z(ESI):391.2[M+H]+
实施例4化合物I-4的制备
合成路线如下所示：
第一步：1-(2-溴乙基)环丙-1-醇的制备
室温下将3-溴丙酸乙酯(2.0g，12.0mmol)和钛酸四乙酯(3.4g，12mmol)加入无水四氢呋喃(20mL)中，冷却到0℃，缓慢滴加乙基溴化镁(19.2mL,2M in THF)。滴加完成室温搅拌12h。TLC监测反应完成后用水(20mL)淬灭反应，在加5％(v/v)硫酸(20mL)处理反应液，用乙酸乙酯(20mL*3)萃取混合物，用饱和碳酸氢钠水溶液(20mL)和饱和溴化钠水溶液(20mL)洗涤合并的萃取液，蒸发溶剂，残余物经硅胶色谱纯化(石油醚/乙酸乙酯＝8：1-4：1为洗脱液)，得到1-(2-溴乙基)环丙醇(1.1g,产率56％)。
第二步：N-苄基-2-(5-(4-(2-(1-羟基环丙基)乙氧基)苯基)吡啶-2-基)乙酰胺的制备
室温下将N-苄基-2-(5-(4-羟基苯基)吡啶-2-基)乙酰胺(0.2g,0.63mmol)和碳酸钾(0.26g,1.89mmol)加入到无水乙腈中(5mL)，加热到80℃搅拌1h，然后加入1-(2-溴乙基)环丙-1-醇(0.11g,0.94mmol)，继续加热在80℃下搅拌10h，TLC检测反应完成，反应液冷却到室温，浓缩旋蒸掉溶剂得到粗品， 经制备高效液相色谱纯化得化合物N-苄基-2-(5-(4-(2-(1-羟基环丙基)乙氧基)苯基)吡啶-2-基)乙酰胺(I-4)(126mg,产率49％).
1H NMR(400MHz,DMSO-d6)δ8.74(d,1H),8.61(t,1H),7.96(dd,1H),7.64(dd,2H),7.39(d,1H),7.35–7.18(m,5H),7.04(d,2H),5.24(s,1H),4.29(t,2H),4.24–4.17(m,2H),3.71(s,2H),1.93(t,2H),0.58(dd,2H),0.46(dd,2H).
LC-MS,M/Z(ESI):403.2[M+H]+
实施例5-15
下列化合物的制备参考本发明其他化合物的合成方法：


实施例16化合物I-16的制备
合成路线如下所示：
室温下将N-苄基-2-(5-(2-氯-4-羟基苯基)吡啶-2-基)乙酰胺(0.4g,1.13mmol)和碳酸钾(0.47g,3.4mmol)加入到无水乙腈中(15mL)，加热到85℃下搅拌1h，然后加入4-溴-2-甲基丁-2-醇(0.57g,3.40mmol)，继续加热在85℃ 下搅拌10h，点板检测反应完成后冷却到室温，浓缩旋蒸掉溶剂得到粗品，用硅胶柱分离纯化得化合物N-苄基-2-(5-(2-氯-4-(3-羟基-3-甲基丁氧基)苯基)吡啶-2-基)乙酰胺(I-16)(0.34g,产率68％).
1H NMR(400MHz,DMSO-d6)δ8.66(t,1H),8.51(d,1H),7.79(dd,1H),7.40(dd,2H),7.35–7.20(m,4H),7.17(d,1H),7.03(dd,1H),4.43(s,1H),4.31(d,2H),4.16(t,2H),3.74(s,2H),1.85(t,2H),1.17(s,6H).
LC-MS,M/Z(ESI):439.2[M+H]+
本发明测试例中的对照化合物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。对照化合物I的制备参考专利WO 2008/002676 A2，对照化合物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
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，与对照化合物I相比，抑制活性更优。
测试例2：化合物抑制细胞增殖试验
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 2104 Multilabel 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测试化合物对不同细胞增殖活性抑制结果
表3测试化合物对不同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3所示，结果表明，本发明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6800g，2-8℃离心6min，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1分钟，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WinNonlin 7.0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
小鼠药代动力学试验结果如表4和5所示，结果表明，本发明化合物体内代谢快，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 (24)

  1. 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，具有结构：
    其中，W选自：-O-、-S-、-NH-、-N(C1-C6烷基)-；
    Q为
    L1为C1-C6亚烷基；
    L2、L3各自独立地为不存在或为C1-C6亚烷基；
    且L2和L3不同时不存在；
    环A为3-6元环烷基或4-8元杂环基；
    环B不存在或选自：3-8元环烷基、4-10元杂环基、6-10元芳基、5-10元杂芳基；
    所述L1、L2、L3任选地被一个或多个RL取代；当RL为多个时，所述RL相同或不同；
    RL、Rb、R1、R2各自独立地选自：卤素、羟基、氨基、氰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、-O-C1-C6烷基、-COO-C1-C6烷基、-CO-C1-C6烷基、-C(O)NR11R12；
    其中，R11、R12各自独立地为氢、C1-C6烷基；
    所述RL、Rb、R1、R2任选地被一个或多个选自下列的取代基取代：卤素、羟基、氨基、氰基、C1-C6烷基，当取代基为多个时，所述取代基相同或 不同；
    m为0、1、2或3；当Rb为多个时，所述Rb相同或不同；
    n为0、1、2或3；当R1为多个时，所述R1相同或不同；
    p为0、1、2或3；当R2为多个时，所述R2相同或不同。
  2. 如权利要求1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，其特征在于，选自：
  3. 如权利要求1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，其特征在于，W选自：-O-、-S-、-NH-；较佳地，W为-O-。
  4. 如权利要求2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，其特征在于，为
  5. 如权利要求1或2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，其特征在于，环A为3-6元环烷基或4-6元杂环基；
    L1、L2、L3任选地被一个或多个RL取代；当RL为多个时，所述RL相同或不同；
    所述RL选自：卤素、羟基、氨基、氰基、C1-C6烷基、-O-C1-C6烷基；
    所述RL任选地被一个或多个选自下列的取代基取代：卤素、羟基、氨 基、氰基、C1-C6烷基；当取代基为多个时，所述取代基相同或不同；
    较佳地，所述RL选自：C1-C6烷基或C1-C6卤代烷基；
    较佳地，环A为3-6元环烷基；
    较佳地，所述卤素为F。
  6. 如权利要求1或2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，其特征在于，环B选自：3-8元环烷基、4-10元杂环基；
    较佳地，环B选自：3-6元环烷基、4-6元杂环基；
    较佳地，所述环B为单环、并环、桥环、螺环；
    较佳地，所述3-6元环烷基、4-6元杂环基为单环；
    较佳地，所述环B具有1、2或3选自N、O、S、P的杂原子；
    较佳地，所述环B具有S杂原子，所述环B具有结构
  7. 如权利要求1或2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，其特征在于，m为0、1或2；
    Rb选自：卤素、羟基、氨基、氰基、C1-C3烷基、C2-C4烯基、C2-C4炔基、-O-C1-C3烷基、-COO-C1-C3烷基、-CO-C1-C3烷基、-C(O)NR11R12；
    其中，R11、R12各自独立地为氢、甲基、乙基、丙基；
    所述Rb任选地被一个或多个选自下列的取代基取代：卤素、羟基、氨基、氰基、C1-C3烷基，当取代基为多个时，所述取代基相同或不同；
    或Rb选自：卤素、羟基、氨基、氰基、C1-C6烷基、-O-C1-C6烷基；
    所述Rb任选地被一个或多个选自下列的取代基取代：卤素、C1-C6烷基；当取代基为多个时，所述取代基相同或不同；
    较佳地，Rb选自：C1-C6烷基；所述Rb任选地被一个或多个卤素取代；当卤素为多个时，所述卤素相同或不同；
    较佳地，Rb选自：甲基、乙基、丙基、异丙基；所述Rb任选地被一个或 多个卤素取代；当卤素为多个时，所述卤素相同或不同；
    较佳地，所述卤素为F。
  8. 如权利要求1或2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，其特征在于，
    具有结构
  9. 如权利要求1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，其特征在于，n为0或1；
    R1选自：卤素、氰基、C1-C6烷基；
    较佳地，R1选自：氟、氰基、甲基。
  10. 如权利要求1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，其特征在于，其满足以下条件中的一个或多个：
    (1)W选自-O-；
    (2)Q为L1为C1-C6亚烷基；环B不存在或选自：3-8元环烷基、4-10元杂环基；Rb、R1各自独立地选自：卤素、C1-C6烷基；m为0或1；
    (3)n为0或1；
    (4)p为0。
  11. 如权利要求1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，其特征在于，W选自-O-；
    Q为
    L1为C1-C6亚烷基；
    环B不存在或选自：3-8元环烷基、4-10元杂环基；
    Rb、R1各自独立地选自：卤素、C1-C6烷基；
    m为0或1；
    n为0或1；
    p为0。
  12. 如权利要求1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，其特征在于，其满足以下条件中的一个或多个：
    (1)所述的环B里，所述的3-8元环烷基为3-6元环烷基；
    (2)所述的环B里，所述的3-8元环烷基为单环、并环、桥环或螺环；
    (3)所述的环B里，所述的3-8元环烷基为饱和环；
    (4)所述的环B里，所述的4-10元杂环基为4-6元杂环基；
    (5)所述的环B里，所述的4-10元杂环基为单环、并环、桥环或螺环；
    (6)所述的环B里，所述的4-10元杂环基为饱和环；
    (7)所述的环B里，所述的4-10元杂环基中的杂原子为N或O；
    (8)所述的环B里，所述的4-10元杂环基通过N原子与L1连接；
    (9)所述的Rb里，所述的卤素为氟或氯；
    (10)所述的Rb里，所述的C1-C6烷基为甲基或乙基；
    (11)所述的R1里，所述的卤素为氟或氯；
    (12)所述的R1里，所述的C1-C6烷基为甲基或乙基；
    (13)选自：
  13. 如权利要求1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，其特征在于，其满足以下条件中的一个或两 个：
    (1)所述环B里，所述的3-8元环烷基为环丙基、环丁基、环戊基、环己基；
    (2)所述环B里，所述的4-10元杂环基为
  14. 如权利要求1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，其特征在于，包括：

  15. 一种药物组合物，包括如权利要求1-14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。
  16. 一种药物组合物，包括如权利要求1-14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，和
    药学上可接受的载体和/或其他活性药物。
  17. 如权利要求1-14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的用途，或权利要求15所述的药物组合物的用途，或权利要求16所述的药物组合物的用途，所述用途包括：
    1)抑制微管蛋白聚合和/或Src激酶、
    2)预防和/或治疗微管蛋白聚合和/或Src激酶相关的疾病、
    3)制备微管蛋白聚合和/或Src激酶抑制剂、
    4)制备预防和/或治疗与微管蛋白聚合和/或Src激酶相关的疾病的药物、药物组合物或制剂；
    较佳地，所述与微管蛋白聚合和/或Src激酶相关的疾病包括肿瘤、皮肤疾病；
    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。
  18. 如权利要求1-14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在制备治疗肿瘤和/或皮肤疾病的药物中的用途；或如权利要求15所述的药物组合物在制备治疗肿瘤和/或皮肤疾病的药物中的用途；或如权利要求16所述的药物组合物在制备治疗肿瘤和/或皮肤疾病的药物中的用途；
    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。
  19. 如权利要求18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；
    较佳地包括：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。
  20. 如权利要求18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。
  21. 如权利要求1-14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15所述的药物组合物，或如权利要求16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。
  22. 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1-14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15所述的药物组合物，或如权利要求16所述的药物组合物。
  23. 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1-14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15所述的药物组合物，或如权利要求16所述的药物组合物。
  24. 一种化合物，其特征在于，所述化合物为如下任一化合物
PCT/CN2023/072144 2022-01-14 2023-01-13 微管蛋白-src双靶点抑制剂 WO2023134753A1 (zh)

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