WO2019120267A1 - 一种咪唑并[1,2-b]哒嗪大环类激酶抑制剂 - Google Patents

一种咪唑并[1,2-b]哒嗪大环类激酶抑制剂 Download PDF

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WO2019120267A1
WO2019120267A1 PCT/CN2018/122522 CN2018122522W WO2019120267A1 WO 2019120267 A1 WO2019120267 A1 WO 2019120267A1 CN 2018122522 W CN2018122522 W CN 2018122522W WO 2019120267 A1 WO2019120267 A1 WO 2019120267A1
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amino
alkyl
halogen
hydroxy
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李进
张登友
王志
潘垒昌
王强
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成都先导药物开发股份有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed systems contains four or more hetero rings
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains four or more hetero rings
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings

Definitions

  • the present invention relates to an imidazo[1,2-b]pyridazine macrocyclic compound and its use in the preparation of a medicament.
  • Trk The tropomyosin receptor kinase (Trk) family is a class of receptor tyrosine kinases whose family includes three members: TrkA, TrkB and TrkC. When Trk is activated by neurotrophic factors, it affects the survival and differentiation of neurons through various signaling pathways, which significantly affects the function of neurons.
  • Inhibitors of the Trk/neurotrophin pathway have been reported to be effective in pain models in many animals (Zahn, PK et al. J. Pain, 2004 (5): 157-163; Shelton, DL et al. Pain, 2005 ( 116): 8-16;).
  • the secretion of neurotrophic factors by tumor cells and tumor invading macrophages directly stimulates TrkA on peripheral pain fibers.
  • Activation of the TrkB pathway has been reported to regulate various types of pain, including inflammatory pain (Matayoshi, S. et al. J. Physiol, 2005 (569): 685-695), neuropathic pain (Thompson, SW et al. Proc. Natl. Acad. Sci., 1999 (96): 7714-7718) and surgical pain (Li, CQ et al. Molecular Pain, 2008 (28): 1-11).
  • Trk Overexpression, activation, amplification and/or mutation of Trk has been reported to be associated with a variety of cancers, including neuroblastoma (Brodeur, GM et al. Nat. Rev. Cancer, 2003 (3): 203-216), melanoma. (Truzzi, F. et al. Dermato-Endocrinology, 2008 (1): 32-36), breast cancer (Jin, W. et al. Carcinogenesis, 2010 (11): 1939-1947) and gastric cancer (Du, J. Et al. World J. Gastroenterology, 2003 (7): 1431-1434) and the like.
  • TrkA, TrkB and TrkC effectively inhibited tumor growth and halted tumor metastasis (Pierottia, MA et al. Cancer Letters, 2006 (232): 90-98; Eric Adriaenssens, E. et al. Cancer Res, 2008 (68): 346-351).
  • Non-selective small molecule inhibitors of TrkA, TrkB and TrkC have also been reported to be effective in preclinical models of inflammatory diseases including asthma (Freund, MV et al. Pharmacology & Therapeutics, 2008 (117): 52- 76), inflammatory bowel disease (Mola, FF et al. Gut, 2000 (46): 670-678) and specific dermatitis (Dou, YCArch. Derma. Res., 2006 (298): 31-37), etc. .
  • Trk/neurotrophin pathway is involved in neurodegenerative diseases including multiple sclerosis, Parkinson's disease and Alzheimer's disease (Sohrabji, F. et al. Neuroendocrinology, 2006 (27): 404-414 ).
  • Trk small molecule inhibitors for treatment in the fields of pain, cancer, inflammation, and neurological retirement diseases.
  • the present invention provides an imidazo[1,2-b]pyridazine macrocyclic kinase inhibitor.
  • the present invention provides a compound of Formula I, or a stereoisomer thereof, or a crystalline form thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, or a metabolite thereof :
  • R 1 , R 1 ' , R 2 and R 2 ' are each independently selected from the group consisting of hydrogen, halogen, hydroxy, amino, trifluoromethyl, carboxy, cyano, C 1 -C 10 alkyl, C 1 -C 10 Alkoxy group, C 1 -C 10 alkylamino group;
  • R 1 and R 2 are bonded to form a 3- to 8-membered cycloalkane and a 3- to 8-membered heterocycloalkane;
  • the A ring is selected from a 5- to 6-membered aromatic ring, a 5- to 6-membered aromatic heterocyclic ring substituted with m R 3 ; wherein m is 0, 1, 2, 3 or 4; and R 3 is selected from the group consisting of halogen, hydroxy, amino, and tri a fluoromethyl group, a carboxyl group, a cyano group, a C 1 -C 10 alkyl group, a C 1 -C 10 alkoxy group, or a C 1 -C 10 alkylamino group;
  • X is selected from -CR 4 R 5 -, -NR 4 -, -O-, -S-; wherein R 4 and R 5 are selected from hydrogen, C 1 -C 10 alkyl;
  • L is selected from C 1 -C 10 alkylene groups substituted by n R 6 ; wherein n is 0, 1, 2, 3 or 4; R 6 is selected from the group consisting of halogen, hydroxy, amino, trifluoromethyl, carboxyl, cyano, C 1 ⁇ C 10 alkyl group, an alkoxy group of C 1 ⁇ C 10, C 1 ⁇ C 10 alkylamino group is.
  • R 1 , R 1 ' , R 2 , R 2 ' are each independently selected from the group consisting of hydrogen, halogen, hydroxy, amino, trifluoromethyl, carboxy, cyano, C 1 -C 4 alkyl, C 1 a C 4 alkoxy group, a C 1 -C 4 alkylamino group;
  • R 1 and R 2 are bonded to form a 3- to 6-membered cycloalkane or a 3- to 6-membered heterocycloalkane;
  • the A ring is selected from a 5- to 6-membered aromatic ring, a 5- to 6-membered aromatic heterocyclic ring substituted with m R 3 ; wherein m is 0, 1, 2 or 3; and R 3 is selected from the group consisting of halogen, hydroxy, amino, trifluoromethyl a group, a carboxyl group, a cyano group, a C 1 -C 4 alkyl group, a C 1 -C 4 alkoxy group, or a C 1 -C 4 alkylamino group;
  • X is selected from -CR 4 R 5 -, -NR 4 -, -O-, -S-; wherein R 4 and R 5 are selected from hydrogen, C 1 -C 4 alkyl;
  • L is selected from C 1 -C 5 alkylene substituted by n R 6 ; wherein n is 0, 1, 2, 3 or 4; R 6 is selected from halogen, hydroxy, amino, trifluoromethyl, carboxy, cyano, C 1 ⁇ C 4 alkyl group, an alkoxy group of C 1 ⁇ C 4, C 1 ⁇ C 4 alkylamino of.
  • R 1 , R 1 ' , R 2 , R 2 ' are each independently selected from the group consisting of hydrogen, halogen, hydroxy, amino, trifluoromethyl, carboxy, cyano, C 1 -C 4 alkyl, C Alkoxy group of 1 to C 4 and alkylamino group of C 1 to C 4 ;
  • R 1 and R 2 are bonded to form a 3-membered cycloalkane or a 3-membered heterocycloalkane;
  • the A ring is selected from a 6-membered aromatic ring or a 6-membered aromatic heterocyclic ring substituted with m R 3 ; wherein m is 0, 1 or 2; and R 3 is selected from the group consisting of halogen, hydroxy, amino, trifluoromethyl, carboxyl, cyano a C 1 -C 4 alkyl group, a C 1 -C 4 alkoxy group, or a C 1 -C 4 alkylamino group;
  • X is selected from -CR 4 R 5 -, -O-, -S-; wherein R 4 and R 5 are selected from hydrogen, C 1 -C 4 alkyl;
  • L is selected from C 1 -C 5 alkylene substituted by n R 6 ; wherein n is 0, 1, 2 or 3; R 6 is selected from halogen, hydroxy, amino, trifluoromethyl, carboxyl, cyano , C 1 ⁇ C 4 alkyl, C 1 ⁇ C 4 alkoxy group is, C 1 ⁇ C 4 alkylamino of.
  • R 1 , R 1 ' , R 2 , R 2 ' are each independently selected from hydrogen and halogen;
  • R 1 and R 2 are joined to form a 3-membered cycloalkane
  • the A ring is selected from a 6-membered aromatic ring or a 6-membered aromatic heterocyclic ring substituted with m R 3 ; wherein m is 0, 1 or 2; and R 3 is selected from the group consisting of halogen, hydroxy, amino, trifluoromethyl, carboxyl, cyano a C 1 -C 4 alkyl group, a C 1 -C 4 alkoxy group, or a C 1 -C 4 alkylamino group;
  • X is selected from -CR 4 R 5 -, -O-, -S-; wherein R 4 and R 5 are selected from hydrogen, C 1 -C 4 alkyl;
  • L is selected from C 1 -C 5 alkylene substituted by n R 6 ; wherein n is 0, 1, 2 or 3; R 6 is selected from halogen, hydroxy, amino, trifluoromethyl, C 1 -C An alkyl group of 4 , a C 1 -C 4 alkoxy group, or a C 1 -C 4 alkylamino group.
  • Y is selected from CH or N;
  • R a1 and R a2 are each selected from the group consisting of hydrogen and a C 1 -C 4 alkyl group.
  • the compound of formula II above is:
  • the present invention provides the aforementioned compound, or a stereoisomer thereof, or a crystal form thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, or a metabolite thereof, in the preparation of a kinase inhibitor Use in medicine.
  • the kinase inhibitor drug is a Trk kinase inhibitor drug.
  • the Trk kinase inhibitor drug is a TrkA kinase inhibitor drug.
  • the present invention provides the aforementioned compound, or a stereoisomer thereof, or a crystal form thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, or a metabolite thereof, in the preparation of a therapeutic and kinase activity Use in drugs for abnormally related diseases.
  • the disease associated with abnormal kinase activity is a disease associated with abnormal Trk kinase activity.
  • the disease associated with abnormal Trk kinase activity is any one or more of diseases associated with neurodegenerative diseases, pain, cancer, inflammation.
  • the present invention provides the aforementioned compound, or a stereoisomer thereof, or a crystal form thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, or a metabolite thereof, in the preparation of a therapeutic neurological retirement Use in medicines for diseases, chronic pain, acute pain, cancer or inflammatory diseases.
  • the disease is multiple sclerosis, Parkinson's disease, Alzheimer's disease, inflammatory pain, neuropathic pain, surgical pain, neurocytoma, melanoma, breast cancer, stomach cancer, asthma, inflammatory Enteropathy or specific dermatitis.
  • the present invention provides a medicament which is the aforementioned compound, or a stereoisomer thereof, or a crystal form thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, or a metabolism thereof
  • a medicament which is the aforementioned compound, or a stereoisomer thereof, or a crystal form thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, or a metabolism thereof
  • the product together with a preparation prepared from a pharmaceutically acceptable adjuvant.
  • the disease associated with Trk activity as defined in the present invention is a disease in which TrkA, TrkB, and TrkC play an important role in the pathogenesis of the disease.
  • Trk activity diseases associated with Trk activity include pain, cancer or malignancy, inflammatory diseases, or neurodegenerative diseases.
  • Pain includes chronic pain and acute pain, including but not limited to bone pain, visceral pain, inflammatory pain, migraine, chronic low back pain, bladder pain syndrome, and neuropathy caused by cancer, surgery, fractures, tumor metastasis, etc. pain.
  • Cancer refers to any of a variety of diseases characterized by abnormal proliferation of uncontrolled cells, the ability of affected cells to spread locally or through the bloodstream and lymphatic system to other sites. The body (ie, metastasis) and any of a number of characteristic structures and/or molecular features.
  • Cell cancer cells refers to cells that undergo early, intermediate or late stages of multi-step tumor progression. Cancer includes sarcoma, breast cancer, lung cancer, brain cancer, bone cancer, liver cancer, kidney cancer, colon cancer, and prostate cancer.
  • the compound of Formula I is for use in treating a cancer selected from the group consisting of colon cancer, brain cancer, breast cancer, fibrosarcoma, and squamous cell carcinoma.
  • the cancer is selected from the group consisting of melanoma, breast cancer, colon cancer, lung cancer, and ovarian cancer.
  • the cancer treated is a metastatic cancer.
  • Inflammatory diseases include a variety of conditions characterized by histopathological inflammation.
  • inflammatory diseases include acne vulgaris, asthma, celiac disease, chronic prostatitis, glomerulonephritis, inflammatory bowel disease, pelvic inflammatory disease, reperfusion injury, rheumatoid arthritis, sarcoidosis, vasculitis, Airway inflammation and interstitial cystitis caused by house dust mites.
  • Some embodiments of the invention relate to the treatment of inflammatory disease asthma.
  • the immune system usually involves inflammatory diseases, which are manifested in allergic reactions and some myopathy, and many immune system diseases cause abnormal inflammation.
  • Neurological retirement diseases include multiple sclerosis, Parkinson's disease, and Alzheimer's disease.
  • the compounds and derivatives provided in the present invention may be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, Columbus, OH) nomenclature system.
  • substitution means that a hydrogen atom in a molecule is replaced by a different atom or molecule.
  • the minimum and maximum values of the carbon atom content in the hydrocarbon group are indicated by a prefix, for example, the alkyl group prefixed with C a to C b indicates any alkyl group having from "a" to "b" carbon atoms, including straight chain or Branched alkyl.
  • a C 1 -C 4 alkyl group means a straight-chain alkyl group or a branched alkyl group having 1 to 4 carbon atoms.
  • alkoxy group of C a to C b and “alkylamino group of C a to C b” mean that an alkyl group having "a” to "b” carbon atoms is bonded to a corresponding oxygen atom or an amino group, respectively. The resulting group.
  • the alkoxy group of C 1 to C 4 means a substituent formed by a linear alkyl group of 1 to 4 carbon atoms or a hydrogen atom of a branched alkyl group substituted with a hydroxyl group; for example, C 1 to C 4
  • the alkylamino group means a substituent formed by a linear alkyl group of 1 to 4 carbon atoms or a hydrogen atom of a branched alkyl group substituted amino group.
  • cycloalkane or “cycloalkyl” means a saturated ring or a non-aromatic unsaturated ring formed by linking carbon atoms.
  • heterocyclic ring means a saturated ring or a non-aromatic unsaturated ring containing at least one hetero atom, wherein the hetero atom means a nitrogen atom, an oxygen atom or a sulfur atom.
  • aromatic ring and “aryl group” mean an aromatic unsaturated ring formed by linking carbon atoms.
  • aromatic heterocyclic ring and “aromatic heterocyclic group” in the present invention means an aromatic unsaturated ring containing at least one hetero atom, wherein the hetero atom means a nitrogen atom, an oxygen atom or a sulfur atom.
  • alkylene is attached to a hydrocarbon group respectively bonded to two atoms.
  • Halogen is fluorine, chlorine, bromine or iodine.
  • pharmaceutically acceptable means that a carrier, carrier, diluent, adjuvant, and/or salt formed is generally chemically or physically compatible with the other ingredients that constitute a pharmaceutical dosage form, and is physiologically Compatible with the receptor.
  • salts and “pharmaceutically acceptable salt” refer to the above-mentioned compounds or stereoisomers thereof, acid and/or basic salts formed with inorganic and/or organic acids and bases, and also includes zwitterionic salts (within Salts) also include quaternary ammonium salts such as alkylammonium salts. These salts can be obtained directly in the final isolation and purification of the compounds. It can also be obtained by mixing the above compound, or a stereoisomer thereof, with a certain amount of an acid or a base as appropriate (for example, an equivalent amount).
  • the salt in the present invention may be a hydrochloride, a sulfate, a citrate, a besylate, a hydrobromide, a hydrofluoride, a phosphate, an acetate, a propionate or a dibutyl compound.
  • one or more compounds of the invention may be used in combination with one another.
  • the compounds of the invention may be used in combination with any other active agent for the preparation of a medicament or pharmaceutical composition that modulates cellular function or treats a disease. If a group of compounds is used, the compounds can be administered to the subject simultaneously, separately or sequentially.
  • M means mol/L
  • mM means mmol/L
  • ⁇ M means ⁇ mol/L
  • room temperature as used in the present invention means 25 ⁇ 5 °C.
  • novel compound of the formula I disclosed in the present invention exhibits a good TRK inhibitory activity and provides a new option for clinical treatment of diseases associated with abnormal TRK activity.
  • Figure 1 is a graph showing the inhibition of tumor growth in mice by the compound of Example 1 and the compound of Example 5.
  • the raw materials and equipment used in the specific embodiments of the present invention are known products and are obtained by purchasing commercially available products.
  • the raw materials used in the present invention are mainly purchased from suppliers such as Belling Chemical, Suiyuan Chemical Technology Co., Ltd., Alfa Aesar, Jiangsu Aikang Biomedical Research and Development Co., Ltd. and TCI (Shanghai) Chemical Industry Development Co., Ltd.
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or (and) mass spectrometry (MS).
  • NMR shift ( ⁇ ) is given in units of 10 -6 (ppm).
  • NMR was measured using a (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic apparatus, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (MeOD), Marked as tetramethylsilane (TMS).
  • DMSO-d 6 dimethyl sulfoxide
  • CDCl 3 deuterated chloroform
  • MeOD deuterated methanol
  • TMS Marked as tetramethylsilane
  • HPLC high performance preparative liquid chromatography
  • MPLC Medium Pressure Preparative Liquid Chromatography
  • tert-Butyl 2-(5-fluoro-2-methoxyphenyl)-tetrahydropyrrole-1-carboxylate (5.10 g, 17.3 mmol) was dissolved in dichloromethane (10.0 mL) at 0 ° C A dichloromethane solution (51.8 mL, 51.8 mmol) containing 1 mol/L of boron tribromide was added. Stir at 0 ° C for 1 hour.
  • the solvent was distilled off under reduced pressure, and purified by reverse-phase MPLC (purified with pure water and acetonitrile, eluted with pure water, gradually increased the ratio of acetonitrile, eluted at a ratio of 5% of acetonitrile, and the desired product was obtained.
  • the eluate was evaporated to remove the solvent under reduced pressure to give 2-(5-fluoro-2-hydroxyphenyl)tetrahydropyrrole (2.60 g, 14.3 mmol, yield 83%).
  • the aqueous solution (10.0 mL) was stirred at room temperature for 2 hours, then the pH was adjusted to 4-5 with 1M diluted hydrochloric acid, and then extracted with ethyl acetate and water, and the aqueous phase was extracted twice with ethyl acetate.
  • Example 3 (14R) -9- fluoro-14-methyl-13-oxa-pentyl -2,16,20,24,25- heteropentacycle [16.5.2.0 2,6 .0 7,12 .0 21 , 25 ] Preparation of dipentadecane-1 (24), 7, 9, 11 , 18, 20, 22 -hepten-17-one.
  • Example 4 9-fluoro-13-oxa-pentyl -2,16,20,24,25- heteropentacycle [16.5.2.0 2,6 .0 7,12 .0 21,25] pentacosa-1 (24) Preparation of 7(12), 8, 10, 18, 20, 22-hepten-17-one.
  • Example 5 (15R) -9-difluoro-15-methyl-13-oxa-pentyl -2,16,20,24,25- heteropentacycle [16.5.2.0 2,6 .0 7,12 .0 21 ,25 ] Preparation of dipentadecane-1(24),7(12),8,10,18,20,22-hepten-17-one
  • step 4 The (S)-tert-butyl 2-hydroxypropyl carbamate in step 4 was replaced by (R)-tert-butyl(1-hydroxypropyl-2-yl)amino group according to the method in Example 1. formate, to give the compound (15R) -9- difluoro-15-methyl-13-oxa-pentyl -2,16,20,24,25- heteropentacycle [16.5.2.0 2,6 .0 7,12 .0 21,25 ], dipentadecane-1 (24), 7 (12), 8, 10, 18, 20, 22-hepten-17-one.
  • Example 6 (15S) -9- difluoro-15-methyl-13-oxa-pentyl -2,16,20,24,25- heteropentacycle [16.5.2.0 2,6 .0 7,12 .0 21 ,25 ] Preparation of dipentadecane-1(24),7(12),8,10,18,20,22-hepten-17-one
  • step 4 The (S)-tert-butyl 2-hydroxypropyl carbamate in step 4 was replaced by (S)-tert-butyl(1-hydroxypropyl-2-yl)amino group according to the method in Example 1. formate, to give the compound (15S) -9- difluoro-15-methyl-13-oxa-pentyl -2,16,20,24,25- heteropentacycle [16.5.2.0 2,6 .0 7,12 .0 21,25 ], dipentadecane-1 (24), 7 (12), 8, 10, 18, 20, 22-hepten-17-one.
  • the 1-tert-butoxycarbonyl-pyrrolidine in the step 1 was replaced with the 3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester according to the method in Example 1 to give the compound (14S)- 10-fluoro-15-methyl-14-oxa-2,17,21,25,26-pentahexyl ring [17.5.2.0 2,7 .0 4,6 .0 8,13 .0 22,26 Dihexadecane-1 (25), 8 (13), 9, 11, 19, 21, 23-heptenene-18-one.
  • Example 8 (14S) -4,9- difluoro-14-methyl-13-oxa-pentyl -2,16,20,24,25- heteropentacycle [16.5.2.0 2,6 .0 7,12 .0 21,26 ] Preparation of dipentadecane -1(24),7(12),8,10,18,20,22-hepten-17-one
  • the 1-tert-butoxycarbonyl-pyrrolidine in the step 1 was replaced with 1-tert-butoxycarbonyl-3-fluoropyrrolidine according to the method in Example 1 to give the compound (14S)-4,9-difluoro- 14- methyl-13-oxa-pentyl -2,16,20,24,25- heteropentacycle [16.5.2.0 2,6 .0 7,12 .0 21,26] pentacosa-1 (24 ), 7(12), 8, 10, 18, 20, 22-hepten-17-one.
  • the 1-tert-butoxycarbonyl-pyrrolidine in the step 1 was replaced with 1-tert-butoxycarbonyl-3,3-difluoropyrrolidine according to the method in Example 1, to obtain the compound (14S)-4,4.
  • the present invention provides the following test examples.
  • An enzyme reaction buffer was prepared in which the MOPS concentration was 25 mM, the MgCl 2 concentration was 5 mM, the DTT concentration was 500 ⁇ M, the Triton content was 0.005%, and the pH was adjusted to 7.5.
  • the test compound was diluted with DMSO to 200 times the desired final concentration, and after mixing, 3 ⁇ L of the solution was added to 117 ⁇ L of the enzyme reaction buffer solution, and the mixture was thoroughly mixed.
  • a compound prepared by pipetting 3 ⁇ L of the enzyme reaction buffer was added to a 96-well PCR plate, and 3 ⁇ L of an enzyme reaction buffer containing 2.5% DMSO was added to the positive control well and the negative control well, respectively.
  • the TRK protein was diluted to 0.4 ng/ ⁇ L with enzyme reaction buffer, and 6 ⁇ L of diluted TRK protein was added to each well except the blank control group. 6 ⁇ L of enzyme reaction buffer was added to the blank control group, and the reaction plate was centrifuged at 1000 rpm/min for 1 minute.
  • Compounds and TRK were pre-incubated for 10 minutes at room temperature.
  • a mixture solution having an ATP concentration of 160 ⁇ M and a substrate concentration of 1 ⁇ M was prepared by using an enzyme reaction buffer, and 6 ⁇ L of each well was added to the reaction well, and the reaction plate was centrifuged at 1000 rpm/min for 1 minute, and incubated at room temperature for 35 minutes.
  • Residual viability 100 * (Lumin compound group - Lumin blank control ) / (Lumin positive control - Lumin blank control )
  • Tests have shown that the compounds of the examples of the present invention have good TRK inhibitory activity and can be effectively used for the treatment associated with abnormal TRK activity.
  • Cell line Ba/F3 ETV6-NTRK3-G623R cell line, Ba/F3 LMNA-NTRK1-G595R cell line, Ba/F3 LMNA-NTRK1-F589L cell line (RPMI1640+10% FBS medium); Reagents and consumables: Fetal Bovine serum FBS (GBICO, Cat#10099-141), Luminescent Cell Viability Assay (Promega, Cat# G7572), 96-well transparent flat black panel ( Cat#3603); Instruments: SpectraMax multi-label microplate reader, MD, 2104-0010A; CO 2 incubator, Thermo Scientific, Model 3100 Series; biosafety cabinet, Thermo Scientific, Model 1300 Series A2; inverted microscope, Olympus , CKX41SF; refrigerator, SIEMENS, KK25E76TI.
  • Cell culture and inoculation (1) Cells in logarithmic growth phase were harvested and cell counts were performed using a platelet counter. Cell viability was measured by trypan blue exclusion to ensure cell viability was above 90%. (2) Adjust the cell concentration; add 90 ⁇ L of the cell suspension to a 96-well plate. (3) The cells in the 96-well plate were cultured overnight at 37 ° C, 5% CO 2 , and 95% humidity.
  • Drug dilution and dosing (1) Prepare 10 times drug solution, the highest concentration is 10uM, 9 concentrations, 3.16 times dilution, add 10 ⁇ L drug solution per well in 96-well plate inoculated with cells, set the concentration of each drug three Multiple holes. (2) The cells in the administrated 96-well plate were further cultured at 37 ° C, 5% CO 2 , 95% humidity for 72 hours, and then subjected to CTG analysis. RXDX-101 (Entrectinib) was used as a positive control.
  • End reading plate (1) Melt the CTG reagent and equilibrate the cell plate to room temperature for 30 minutes. (2) Add an equal volume of CTG solution to each well. (3) The cells were lysed by shaking for 5 minutes on an orbital shaker. (4) The cell plate was placed at room temperature for 20 minutes to stabilize the cold light signal. (5) Read the luminescent value.
  • Test Example 3 TRKA in vivo pharmacodynamic test method
  • NIH-3T3 ⁇ TRKA G595R cells are polyclonal stable cell lines constructed in this laboratory.
  • the NIH-3T3 ⁇ TRKA G595R cells in the logarithmic growth phase were collected, counted, and the cell density was adjusted.
  • test results demonstrate that the compounds prepared by the present invention have an effect of significantly inhibiting tumor growth.
  • novel compound of the formula I disclosed in the present invention exhibits a good TRK inhibitory activity and provides a new option for clinical treatment of diseases associated with abnormal TRK activity.

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Abstract

本发明公开了一种咪唑并[1,2-b]哒嗪大环类激酶抑制剂，该化合物、或其立体异构体、或其晶型、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物如式(I)所示，实验表明，本发明公开的式(I)所示的新化合物，具有良好的TRK抑制活性，为临床制备治疗与TRK活性异常相关的疾病的药物提供了一种新的选择。

Description

一种咪唑并[1,2-b]哒嗪大环类激酶抑制剂 技术领域
本发明涉及一种咪唑并[1,2-b]哒嗪大环类化合物及其在制备药物中的用途。
背景技术
原肌球蛋白受体激酶(简称Trk)家族是一类受体酪氨酸激酶，其家族包括三个成员：TrkA、TrkB和TrkC。Trk受神经营养因子激活后，通过多种信号通路影响神经元的存活和分化，显著影响神经元的功能。
已有报道Trk/神经营养因子通路的抑制剂在很多动物的疼痛模型中有效(Zahn,P.K.et al.J.Pain,2004(5):157-163；Shelton,D.L.et al.Pain,2005(116):8-16；)。另外，肿瘤细胞和肿瘤侵入性巨噬细胞分泌神经营养因子会直接刺激末梢疼痛纤维上的TrkA。有报道TrkB通路的活化可以调节多种类型的疼痛，包括炎性疼痛(Matayoshi,S.et al.J.Physiol,2005(569):685-695)、神经性疼痛(Thompson,S.W.et al.Proc.Natl.Acad.Sci.,1999(96):7714-7718)和手术疼痛(Li,C.Q.et al.Molecular Pain,2008(28):1-11)。
有报道Trk的过表达、活化、扩增和/或突变与多种癌症相关，包括神经细胞瘤(Brodeur,G.M.et al.Nat.Rev.Cancer,2003(3):203-216)、黑色素瘤(Truzzi,F.et al.Dermato-Endocrinology,2008(1):32-36)、乳腺癌(Jin,W.et al.Carcinogenesis,2010(11):1939-1947)和胃癌(Du,J.et al.World J.Gastroenterology,2003(7):1431-1434)等。在临床前模型中，TrkA、TrkB和TrkC的非选择性小分子抑制剂有效地抑制了肿瘤的生长以及终止肿瘤的转移(Pierottia,M.A.et al.Cancer Letters,2006(232):90-98；Eric Adriaenssens,E.et al.Cancer Res,2008(68):346-351)。
有报道TrkA、TrkB和TrkC的非选择性小分子抑制剂在炎性疾病的临床前模型中也是有效的，这些炎性疾病包括哮喘(Freund,M.V.et al.Pharmacology&Therapeutics,2008(117):52-76)、炎性肠病(Mola,F.F.et al.Gut,2000(46):670-678)和特异性皮炎(Dou,Y.C.Arch.Derma.Res.,2006(298):31-37)等。
另有报道Trk/神经营养因子通路涉及神经退行性疾病，包括多发性硬化症、帕金森氏症和阿茨海默症等(Sohrabji,F.et al.Neuroendocrinology,2006(27):404-414)。
因此有需要进一步开发Trk小分子抑制剂用于疼痛、癌症、炎症、神经退休性疾病等领域的治疗。
发明内容
为了解决上述问题，本发明提供了一种咪唑并[1,2-b]哒嗪大环类激酶抑制剂。
本发明提供了一种式Ⅰ所示的化合物、或其立体异构体、或其晶型、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物：
Figure PCTCN2018122522-appb-000001
式中，
R 1、R 1’、R 2、R 2’各自独立地选自氢、卤素、羟基、氨基、三氟甲基、羧基、氰基、C 1～C 10的烷基、C 1～C 10的烷氧基、C 1～C 10的烷氨基；
或者，R 1、R 2相连形成3～8元环烷烃、3～8元杂环烷烃；
A环选自被m个R 3取代的5～6元芳环、5～6元芳杂环；其中m为0、1、2、3或4；R 3选自卤素、羟基、氨基、三氟甲基、羧基、氰基、C 1～C 10的烷基、C 1～C 10的烷氧基、C 1～C 10的烷氨基；
X选自-CR 4R 5-、-NR 4-、-O-、-S-；其中R 4、R 5选自氢、C 1～C 10的烷基；
L选自被n个R 6取代的C 1～C 10的亚烷基；其中n为0、1、2、3或4；R 6选自卤素、羟基、氨基、三氟甲基、羧基、氰基、C 1～C 10的烷基、C 1～C 10的烷氧基、C 1～C 10的烷氨基。
优选地，R 1、R 1’、R 2、R 2’各自独立地选自氢、卤素、羟基、氨基、三氟甲基、羧基、氰基、C 1～C 4的烷基、C 1～C 4的烷氧基、C 1～C 4的烷氨基；
或者，R 1、R 2相连形成3～6元环烷烃、3～6元杂环烷烃；
A环选自被m个R 3取代的5～6元芳环、5～6元芳杂环；其中m为0、1、2或3；R 3选自卤素、羟基、氨基、三氟甲基、羧基、氰基、C 1～C 4的烷基、C 1～C 4的烷氧基、C 1～C 4的烷氨基；
X选自-CR 4R 5-、-NR 4-、-O-、-S-；其中R 4、R 5选自氢、C 1～C 4的烷基；
L选自被n个R 6取代的C 1～C 5的亚烷基；其中n为0、1、2、3或4；R 6选自卤素、羟基、氨基、三氟甲基、羧基、氰基、C 1～C 4的烷基、C 1～C 4的烷氧基、C 1～C 4的烷氨基。
更优选地，R 1、R 1’、R 2、R 2’各自独立地选自氢、卤素、羟基、氨基、三氟甲基、羧基、氰基、C 1～C 4的烷基、C 1～C 4的烷氧基、C 1～C 4的烷氨基；
或者，R 1、R 2相连形成3元环烷烃、3元杂环烷烃；
A环选自被m个R 3取代的6元芳环、6元芳杂环；其中m为0、1或2；R 3选自卤素、 羟基、氨基、三氟甲基、羧基、氰基、C 1～C 4的烷基、C 1～C 4的烷氧基、C 1～C 4的烷氨基；
X选自-CR 4R 5-、-O-、-S-；其中R 4、R 5选自氢、C 1～C 4的烷基；
L选自被n个R 6取代的C 1～C 5的亚烷基；其中n为0、1、2或3；R 6选自卤素、羟基、氨基、三氟甲基、羧基、氰基、C 1～C 4的烷基、C 1～C 4的烷氧基、C 1～C 4的烷氨基。
进一步更优选地，R 1、R 1’、R 2、R 2’各自独立地选自氢、卤素；
或者，R 1、R 2相连形成3元环烷烃；
A环选自被m个R 3取代的6元芳环、6元芳杂环；其中m为0、1或2；R 3选自卤素、羟基、氨基、三氟甲基、羧基、氰基、C 1～C 4的烷基、C 1～C 4的烷氧基、C 1～C 4的烷氨基；
X选自-CR 4R 5-、-O-、-S-；其中R 4、R 5选自氢、C 1～C 4的烷基；
L选自被n个R 6取代的C 1～C 5的亚烷基；其中n为0、1、2或3；R 6选自卤素、羟基、氨基、三氟甲基、C 1～C 4的烷基、C 1～C 4的烷氧基、C 1～C 4的烷氨基。
前述式I所示的化合物如式II所示：
Figure PCTCN2018122522-appb-000002
式中，
Y选自CH或N；
R a1、R a2分别选自氢、C 1～C 4的烷基。
优选地，前述式II所示化合物为：
Figure PCTCN2018122522-appb-000003
Figure PCTCN2018122522-appb-000004
本发明提供了前述化合物、或其立体异构体、或其晶型、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物在制备激酶抑制剂类药物中的用途。
优选地，所述激酶抑制剂类药物为Trk激酶抑制剂类药物。
更优选地，所述Trk激酶抑制剂类药物为TrkA激酶抑制剂类药物。
本发明提供了前述化合物、或其立体异构体、或其晶型、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物在制备治疗与激酶活性异常相关的疾病的药物中的用途。
优选地，所述与激酶活性异常相关的疾病为与Trk激酶活性异常相关的疾病。
更优选地，所述与Trk激酶活性异常相关的疾病是与神经退行性疾病、疼痛、癌症、炎症相关的疾病中的任一种或几种。
本发明提供了前述化合物、或其立体异构体、或其晶型、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物在制备治疗神经退休性疾病、慢性疼痛、急性疼痛、癌症或炎性疾病药物中的用途。
优选地，所述疾病为多发性硬化症、帕金森氏症、阿茨海默症、炎性疼痛、神经性疼痛、手术疼痛、神经细胞瘤、黑色素瘤、乳腺癌、胃癌、哮喘、炎性肠病或特异性皮炎。
本发明提供了一种药物，它是以前述化合物、或其立体异构体、或其晶型、或其药学上 可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物，加上药学上可接受的辅料制备而成的制剂。
本发明所定义的Trk活性相关的疾病是TrkA、TrkB、TrkC在该疾病的病理发生中起重要作用的疾病。
Trk活性相关的疾病包括疼痛、癌症或恶性肿瘤、炎性疾病或神经退行性疾病等。
疼痛包括慢性疼痛和急性疼痛，包括但不限于由癌症、外科手术、骨折、肿瘤转移等引起的骨痛、内脏痛、炎性痛、偏头痛、慢性腰背痛、膀胱疼痛综合征和神经性疼痛。
“癌症”或“恶性肿瘤”是指以不受控制的细胞异常增殖为特征的多种疾病中的任何一种，受影响的细胞在局部或通过血流和淋巴系统扩散到其他部位的能力的身体(即转移)以及许多特征结构和/或分子特征中的任何一个。“癌细胞”是指经历多步骤肿瘤进展的早期，中期或晚期阶段的细胞。癌症包括肉瘤、乳腺癌、肺癌、脑癌、骨癌、肝癌、肾癌、结肠癌和前列腺癌。在一些实施方案中，式I的化合物用于治疗选自结肠癌、脑癌、乳腺癌、纤维肉瘤和鳞状细胞癌的癌症。在一些实施方案中，癌症选自黑素瘤、乳腺癌、结肠癌、肺癌和卵巢癌。在一些实施方案中，所治疗的癌症是转移性癌症。
炎性疾病包括以组织病理性炎症为特征的多种病症。炎性疾病的例子包括寻常性痤疮、哮喘、腹腔疾病、慢性前列腺炎、肾小球性肾炎、炎症性肠病、盆腔炎、再灌注损伤、类风湿性关节炎、结节病、血管炎、房尘螨引起的气道炎症和间质性膀胱炎。炎性疾病与自身免疫性疾病之间存在显著重叠。本发明的一些实施方案涉及炎性疾病哮喘的治疗。免疫系统通常涉及炎症性疾病，在过敏反应和一些肌病中都有表现，许多免疫系统疾病导致异常炎症。
神经退休性疾病包括多发性硬化症、帕金森氏症和阿尔茨海默症等。
本发明中提供的化合物和衍生物可以根据IUPAC(国际纯粹与应用化学联合会)或CAS(化学文摘服务社，Columbus，OH)命名系统命名。
关于本发明的使用术语的定义：除非另有说明，本文中基团或者术语提供的初始定义适用于整篇说明书的该基团或者术语；对于本文没有具体定义的术语，应该根据公开内容和上下文，给出本领域技术人员能够给予它们的含义。
“取代”是指分子中的氢原子被其它不同的原子或分子所替换。
碳氢基团中碳原子含量的最小值和最大值通过前缀表示，例如，前缀C a～C b的烷基表明任何含“a”至“b”个碳原子的烷基，包括直链或支链烷基。因此，例如，C 1～C 4的烷基是指包含1～4个碳原子的直链烷基或支链烷基。
本发明中“C a～C b的烷氧基”、“C a～C b的烷氨基”分别是指含有“a”至“b”个碳原子的烷基与对应的氧原子、氨基相连得到的基团。例如，C 1～C 4的烷氧基是指1～4个碳原子的直链 烷基或支链烷基取代羟基中的一个氢原子而形成的取代基；再例如，C 1～C 4的烷氨基是指1～4个碳原子的直链烷基或支链烷基取代氨基中的一个氢原子而形成的取代基。
本发明中“环烷烃”、“环烷基”指由碳原子相连形成的饱和环或非芳香性的不饱和环。
本发明中“杂环”、“杂环烷烃”、“杂环烷基”指包含至少一个杂原子的饱和环或非芳香性的不饱和环，其中杂原子指氮原子、氧原子、硫原子。
本发明中“芳环”、“芳基”指由碳原子相连形成的具有芳香性的不饱和环。
本发明中“芳杂环”、“芳杂基”指包含至少一个杂原子的芳香性不饱和环，其中杂原子指氮原子、氧原子、硫原子。
本发明中“亚烷基”至分别与两个原子相连的碳氢基团。
卤素为氟、氯、溴或碘。
术语“药学上可接受的”是指某载体、运载物、稀释剂、辅料，和/或所形成的盐通常在化学上或物理上与构成某药物剂型的其它成分相兼容，并在生理上与受体相兼容。
术语“盐”和“可药用的盐”是指上述化合物或其立体异构体，与无机和/或有机酸和碱形成的酸式和/或碱式盐，也包括两性离子盐(内盐)，还包括季铵盐，例如烷基铵盐。这些盐可以是在化合物的最后分离和纯化中直接得到。也可以是通过将上述化合物，或其立体异构体，与一定数量的酸或碱适当(例如等当量)进行混合而得到。这些盐可能在溶液中形成沉淀而以过滤方法收集，或在溶剂蒸发后回收而得到，或在水介质中反应后冷冻干燥制得。本发明中所述盐可以是化合物的盐酸盐、硫酸盐、枸橼酸盐、苯磺酸盐、氢溴酸盐、氢氟酸盐、磷酸盐、乙酸盐、丙酸盐、丁二酸盐、草酸盐、苹果酸盐、琥珀酸盐、富马酸盐、马来酸盐、酒石酸盐或三氟乙酸盐。
在某些实施方式中，本发明的一种或多种化合物可以彼此联合使用。也可选择将本发明的化合物与任何其它的活性试剂结合使用，用于制备调控细胞功能或治疗疾病的药物或药物组合物。如果使用的是一组化合物，则可将这些化合物同时、分别或有序地对受试对象进行给药。
本发明中“M”是指mol/L；“mM”是指mmol/L；“μM”是指μmol/L。
本发明中所述“室温”是指25±5℃。
本发明公开的式I所示的新化合物，表现出了良好的TRK抑制活性，为临床治疗与TRK活性异常相关的疾病提供了一种新的选择。
显然，根据本发明的上述内容，按照本领域的普通技术知识和惯用手段，在不脱离本发明上述基本技术思想前提下，还可以做出其它多种形式的修改、替换或变更。
以下通过实施例形式的具体实施方式，对本发明的上述内容再作进一步的详细说明。但 不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
附图说明
图1为实施例1化合物和实施例5化合物对小鼠肿瘤生长的抑制。
具体实施方式
本发明具体实施方式中使用的原料、设备均为已知产品，通过购买市售产品获得。
1)原料与试剂
本发明所用原料主要购买于百灵威化学、韶远化学科技有限公司、Alfa Aesar、江苏艾康生物医药研发有限公司和梯希爱(上海)化成工业发展有限公司等供应商。
2)主要仪器
化合物的结构是通过核磁共振(NMR)或(和)质谱(MS)来确定的。NMR位移(δ)以10 -6(ppm)的单位给出。NMR的测定是用(Bruker AvanceIII 400和Bruker Avance 300)核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d 6)，氘代氯仿(CDCl 3)，氘代甲醇(MeOD)，内标为四甲基硅烷(TMS)。
液相色谱质谱分析仪(LC-MS)的测定用岛津液质联用仪(Shimadzu LC-MS 2020(ESI))。
高效制备液相色谱(HPLC)的测定使用岛津高压液相色谱仪(Shimadzu LC-20A)。
中压制备液相色谱(MPLC)使用Gilson GX-281反相制备色谱仪。
柱层析一般使用烟台黄海硅胶200～300目硅胶为载体。
实施例1(14S)-9-氟-14-甲基-13-氧杂-2,16,20,24,25-戊杂戊环[16.5.2.0 2,6.0 7,12.0 21,26]二十五烷-1(24),7,9,11,18,20,20,22-七烯-17-酮及其立体异构体的制备
Figure PCTCN2018122522-appb-000005
1、叔丁基2-(5-氟-2-甲氧基苯基)-四氢吡咯-1-甲酸酯的制备
Figure PCTCN2018122522-appb-000006
氮气保护下，将1-叔丁氧羰基-吡咯烷(9.42g,55.0mmol)溶于无水THF(120mL)中。在-40℃下滴加仲丁基锂四氢呋喃溶液(55.0mL,1.0M,55.0mmol)，滴完后于-40℃下反应10分钟，然后滴加含有1mol/L氯化锌的THF溶液(33.0mL,33.0mmol)，滴完后升至室温后继续搅拌30分钟。氮气保护下加入2-氯-3-溴-5-氟吡啶(10.3g,50.0mmol)、醋酸钯(560mg,2.50mmol)和三叔丁基膦四氟硼酸盐(910mg,3.10mmol)，室温搅拌16小时后用乙酸乙酯和水萃取，再将水相用乙酸乙酯萃取两次，合并有机相，并用无水硫酸钠干燥，减压蒸馏除去溶剂。柱层析(先用纯石油醚洗脱，再用石油醚：乙酸乙酯＝10：1洗脱，将有目标产物的洗脱液减压蒸馏除去溶剂)，得到叔丁基2-(5-氟-2-甲氧基苯基)-四氢吡咯-1-甲酸酯(5.10g,17.3mmol,产率35％)。
对制得的化合物进行表征：MS(ESI)m/z＝296(M+1) +。
2、2-(5-氟-2-羟基苯基)四氢吡咯的制备
Figure PCTCN2018122522-appb-000007
将叔丁基2-(5-氟-2-甲氧基苯基)-四氢吡咯-1-甲酸酯(5.10g,17.3mmol)溶于二氯甲烷(10.0mL)，在0℃下加入含有1mol/L三溴化硼的二氯甲烷溶液(51.8mL,51.8mmol)。在0℃下搅拌1小时。减压蒸馏除去溶剂，并用反相MPLC纯化(以纯水和乙腈为洗脱液，先用纯水洗脱，逐渐提高乙腈比例，在乙腈比例为5％时洗脱出产物，将有目标产物的洗脱液减压蒸馏除去溶剂)，得到2-(5-氟-2-羟基苯基)四氢吡咯(2.60g,14.3mmol,产率83％)。
对制得的化合物进行表征：MS(ESI)m/z＝182(M+1) +。
3、乙基6-(2-(5-氟-2-羟基苯基)四氢吡咯-1-基)咪唑[1,2-b]嘧啶-3-甲酸酯的制备
Figure PCTCN2018122522-appb-000008
将2-(5-氟-2-羟基苯基)四氢吡咯(1.11g,6.13mmol)和6-氯咪唑并[1,2-B]吡嗪-3-羧酸乙酯(1.38g,6.13mmol)于正丁醇(2.0mL)和N,N-二异丙基乙胺(3.95g,30.7mmol)中，120℃下搅拌24小时。减压蒸馏除去溶剂，柱层析(先用石油醚/乙酸乙酯＝3/1进行洗脱，再用石油醚/乙酸乙酯＝1/1进行洗脱，将含有产物的洗脱液减压蒸馏除去溶剂)，得到乙基6-(2-(5-氟-2-羟基苯基)四氢吡咯-1-基)咪唑[1,2-b]嘧啶-3-甲酸酯(1.31g,3.54mmol,产率58％)。
对制得的化合物进行表征：MS(ESI)m/z＝371(M+1) +。
4、(R)-1-((叔丁氧羰基)氨基)丙基-2-甲烷磺酸酯的制备
Figure PCTCN2018122522-appb-000009
将(S)-叔丁基2-羟基丙基氨基甲酸酯(5.26g,30.0mmol)溶于二氯甲烷(50.0mL)中，冰浴下加入三乙胺(12.1g,120mmol,16.6mL)和甲磺酰氯(6.87g,60.0mmol)，冰浴下搅拌1小时后用乙酸乙酯和水萃取，再将水相用乙酸乙酯萃取两次，合并有机相并用无水硫酸钠干燥，减压蒸馏除去溶剂，得到(R)-1-((叔丁氧羰基)氨基)丙基-2-甲烷磺酸酯(5.20g,20.6mmol,产率69％)，并直接用于下一步。
对制得的化合物进行表征：MS(ESI)m/z＝254(M+1) +、198((M+1)-56) +。
5、乙基6-(2-(((S)-1-((叔丁氧羰基)氨基)丙基-2-基)氧)-5-氟-2-羟基苯基)四氢吡咯-1-基)咪唑[1,2-b]嘧啶-3-甲酸酯的制备
Figure PCTCN2018122522-appb-000010
将乙基6-(2-(5-氟-2-羟基苯基)四氢吡咯-1-基)咪唑[1,2-b]嘧啶-3-甲酸酯(1.31g,3.54mmol)溶于N,N-二甲基甲酰胺(10.0mL)，加入碳酸铯(3.52g,10.8mmol)和(R)-1-((叔丁氧羰基)氨基)丙基-2-甲烷磺酸酯(1.83g,7.20mmol)，80℃下搅拌2小时后用乙酸乙酯和水萃取，再将水相用乙酸乙酯萃取两次，合并有机相并用无水硫酸钠干燥，减压蒸馏除去溶剂。柱层析(直接用石油醚/乙酸乙酯＝2/1进行洗脱，将含有产物的洗脱液减压蒸馏除去溶剂)，得到乙基6-(2-(((S)-1-((叔丁氧羰基)氨基)丙基-2-基)氧)-5-氟-2-羟基苯基)四氢吡咯-1-基)咪唑[1,2-b]嘧啶-3-甲酸酯(1.15g,2.18mmol,产率62％)。
对制得的化合物进行表征：MS(ESI)m/z＝528(M+1) +。
6、6-(2-(((S)-1-((叔丁氧羰基)氨基)丙基-2-基)氧)-5-氟-2-羟基苯基)四氢吡咯-1-基)咪唑[1,2-b]嘧啶-3-甲酸的制备
Figure PCTCN2018122522-appb-000011
将乙基6-(2-(((S)-1-((叔丁氧羰基)氨基)丙基-2-基)氧)-5-氟-2-羟基苯基)四氢吡咯-1-基)咪唑[1,2-b]嘧啶-3-甲酸酯(1.15g,2.18mmol)溶于甲醇(10.0mL)和四氢呋喃(10.0mL)中，加入氢氧化锂(280mg,6.54mmol)的水溶液(10.0mL)中，室温搅拌2小时后用1M的稀盐酸调pH至4-5,再用乙酸乙酯和水萃取，再将水相用乙酸乙酯萃取两次，合并有机相并用无水硫酸钠干燥，减压蒸馏除去溶剂得到，6-(2-(((S)-1-((叔丁氧羰基)氨基)丙基-2-基)氧)-5-氟-2-羟基苯基)四氢吡咯-1-基)咪唑[1,2-b]嘧啶-3-甲酸(1.00g,2.01mmol,产率92％)，并直接用于下一步。
对制得的化合物进行表征：MS(ESI)m/z＝500(M+1) +。
7、6-(2-(((S)-1-氨基丙基-2-基)氧)-5-氟-2-羟基苯基)四氢吡咯-1-基)咪唑[1,2-b]嘧啶-3-甲酸的制备
Figure PCTCN2018122522-appb-000012
将6-(2-(((S)-1-((叔丁氧羰基)氨基)丙基-2-基)氧)-5-氟-2-羟基苯基)四氢吡咯-1-基)咪唑[1,2-b]嘧啶-3-甲酸(1.00g,2.01mmol)溶于二氯甲烷(10.0mL)，加入三氟乙酸(5.00mL)，室温搅拌1小时后，减压蒸馏除去溶剂得粗品6-(2-(((S)-1-氨基丙基-2-基)氧)-5-氟-2-羟基苯基)四氢吡咯-1-基)咪唑[1,2-b]嘧啶-3-甲酸(760mg,1.91mmol,产率95％)。
对制得的化合物进行表征：MS(ESI)m/z＝400(M+1)+。
8、(14S)-9-氟-14-甲基-13-氧杂-2,16,20,24,25-戊杂戊环[16.5.2.0 2,6.0 7,12.0 21,26]二十五烷-1(24),7,9,11,18,20,20,22-七烯-17-酮的制备
Figure PCTCN2018122522-appb-000013
将6-(2-(((S)-1-氨基丙基-2-基)氧)-5-氟-2-羟基苯基)四氢吡咯-1-基)咪唑[1,2-b]嘧啶-3-甲酸 (760mg,1.91mmol)溶于N,N-二甲基甲酰胺(60.0mL)，加入N,N-二异丙基乙胺(1.23g,9.55mmol)、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(730mg,3.82mmol)和N-羟基-7-氮杂苯并三氮唑(520mg,3.82mmol)。室温搅拌16小时后用乙酸乙酯和水萃取，再将水相用乙酸乙酯萃取两次，合并有机相并用无水硫酸钠干燥，减压蒸馏除去溶剂，反相MPLC纯化(以纯水和乙腈为洗脱液，先用纯水洗脱，逐渐提高乙腈比例，在乙腈比例为55％时洗脱出产物)，将有目标产物的洗脱液减压蒸馏除去溶剂，得到(14S)-9-氟-14-甲基-13-氧杂-2,16,20,24,25-戊杂戊环[16.5.2.0 2,6.0 7,12.0 21,26]二十五烷-1(24),7,9,11,18,20,20,22-七烯-17-酮(180mg,470μmol,产率25％)。然后再通过手性柱拆分，得到异构体a(6R,14S)-9-氟-14-甲基-13-氧杂-2,16,20,24,25-戊杂戊环[16.5.2.0 2,6.0 7,12.0 21,26]二十五烷-1(24),7,9,11,18,20,20,22-七烯-17-酮(66mg,172μmol,产率9.2％)和异构体b(6S,14S)-9-氟-14-甲基-13-氧杂-2,16,20,24,25-戊杂戊环[16.5.2.0 2,6.0 7,12.0 21,26]二十五烷-1(24),7,9,11,18,20,20,22-七烯-17-酮(46mg,120μmol,产率6.4％)。
对制得的化合物进行表征：MS(ESI)m/z＝382(M+1) +
实施例1化合物：
1HNMR(400MHz,MeOD):δ＝7.98-7.95(m,1H),7.86(d,J＝10.0,1H),7.17-7.14(m,1H),7..09-6.87(m,3H),5.71-5.21(m,1H),4.50-4.44(m,1H),4.12-4.00(m,2H),3.78-3.72(m,1H),3.58-3.39(m,1H),2.25-2.38(m,1H),2.21-2.14(m,1H),1.93-1.84(m,1H),1.76(d,J＝6.8,1H),1.57(d,J＝6.0,3H).
异构体a
1HNMR(400MHz,MeOD):δ＝7.94(s,1H),7.82(d,J＝10.0,1H),7.13(d,J＝10.0,1H),7.01-7.06(m,2H),6.88-6.93(m,1H),5.66-5.69(m,1H),4.67-4.74(m,1H),4.00-4.11(m,2H),3.71-3.77(m,1H),3.39-3.45(m,1H),2.47-2.56(m,1H),2.36-2.45(m,1H),2.13-2.22(m,1H),1.84-1.92(m,1H),1.56(d,J＝6.4,3H).
异构体b
1HNMR(400MHz,MeOD):δ＝7.96(s,1H),7.85(d,J＝10.0,1H),7.15(d,J＝10.0,1H),7.03-7.06(m,1H),6.89-6.99(m,2H),5.74-5.77(m,1H),4.44-4.49(m,2H),4.20-4.24(m,1H),4.09-4.15(m,1H),3.72-3.78(m,1H),2.40-2.58(m,2H),2.16-2.23(m,1H),1.88-1.95(m,1H),1.50(d,J＝6.8,3H).
实施例2(15R)-9-氟-15-甲基-2,11,16,20,24,25-六杂戊环[16.5.2.0 2,6.0 7,12.0 21,26]二十五烷-1(24),7,9,11,18,20,22-七烯-17-酮及其立体异构体的制备
Figure PCTCN2018122522-appb-000014
1、叔丁基2-(2-氯-5-氟吡啶-3-基)-四氢吡咯-1-甲酸酯的制备
Figure PCTCN2018122522-appb-000015
氮气保护下，将1-叔丁氧羰基-吡咯烷(9.42g,55.0mmol)溶于无水THF(120mL)中。在-40℃下加仲丁基锂四氢呋喃溶液(55.0mL,1.0M,55.0mmol)，滴完后于-40℃下反应10分钟，然后滴加含有1mol/L氯化锌的THF溶液(33.0mL,33.0mmol)，滴完后升至室温后继续搅拌30分钟。氮气保护下加入2-氯-3-溴-5-氟吡啶(10.5g,50.0mmol)、醋酸钯(560mg,2.50mmol)和三叔丁基膦四氟硼酸盐(910mg,3.10mmol)，室温搅拌16小时后用乙酸乙酯和水萃取，再将水相用乙酸乙酯萃取两次，合并有机相并用无水硫酸钠干燥，减压蒸馏除去溶剂。柱层析(直接用石油醚/乙酸乙酯＝10/1进行洗脱，再将含有产物是洗脱液减压蒸馏除去溶剂)，纯化得叔丁基2-(2-氯5-氟吡啶-3-基)-四氢吡咯-1-羧酸(3.80g,12.6mmol,产率25％)。
对制得的化合物进行表征：MS(ESI)m/z＝301(M+1) +
2、2-氯-5-氟-3-(四氢吡咯-2-基)吡啶的制备
Figure PCTCN2018122522-appb-000016
将叔丁基2-(2-氯5-氟吡啶-3-基)-四氢吡咯-1-羧酸(1.10g,3.66mmol)溶于二氯甲烷(10.0mL)，加入三氟乙酸(5.00mL)，室温下搅拌1小时后，减压蒸馏除去溶剂得粗品2-氯-5-氟-3-(四氢吡咯-2-基)吡啶(700mg,3.50mmol,产率96％)。
对制得的化合物进行表征：MS(ESI)m/z＝201(M+1) +
3、乙基6-(2-(2-氯-5-氟-吡啶-3-基)四氢吡咯-1-基)咪唑[1,2-b]哒嗪-3-甲酸酯的制备
Figure PCTCN2018122522-appb-000017
将2-氯-5-氟-3-(四氢吡咯-2-基)吡啶(300mg,1.50mmol)和6-氯咪唑并[1,2-B]哒嗪-3-羧酸乙酯(410mg,1.80mmol)溶于正丁醇(1.00mL)和N,N-二异丙基乙胺(970mg,7.50mmol)，120℃下搅拌24小时。减压蒸馏除去溶剂，柱层析(先用石油醚/乙酸乙酯＝2/1进行洗脱，再用石油醚/乙酸乙酯＝1/1进行洗脱，将含有产物是洗脱液减压蒸馏除去溶剂)，得到乙基6-(2-(2-氯-5-氟-吡啶-3-基)四氢吡咯-1-基)咪唑[1,2-b]哒嗪-3-甲酸酯(110mg,280μmol,产率19％)。
对制得的化合物进行表征：MS(ESI)m/z＝390(M+1) +
4、乙基6-(2-(2((R)3-((叔丁氧羰基)氨基)-1-丁炔-1)-5-氟吡啶-3-基)四氢吡咯-1-基)咪唑[1,2-b]哒嗪-3-甲酸酯的制备
Figure PCTCN2018122522-appb-000018
将乙基6-(2-(2-氯-5-氟-吡啶-3-基)四氢吡咯-1-基)咪唑[1,2-b]哒嗪-3-甲酸酯(110mg,280μmol)溶于DMF(4.00mL)，加入(R)-叔丁基3-丁炔-2甲酸酯(54.0mg,324μmol)、[1,1'-双(二苯基膦)二茂铁]二氯化钯(20.0mg,27.0μmol)、碘化亚铜(10.0mg,54.0μmol)和三乙胺(82.0mg,810μmol)。氮气保护下于100℃搅拌16小时。减压蒸馏除去溶剂并用乙酸乙酯和水萃取，再将水相用乙酸乙酯萃取两次，合并有机相并用无水硫酸钠干燥，减压蒸馏除去溶剂。柱层析(先用石油醚/乙酸乙酯＝2/1进行洗脱，再用石油醚/乙酸乙酯＝1/1进行洗脱，将含有产物是洗脱液减压蒸馏除去溶剂)，得到乙基6-(2-(2((R)3-((叔丁氧羰基)氨基)-1-丁炔-1)-5-氟吡啶-3-基)四氢吡咯-1-基)咪唑[1,2-b]哒嗪-3-甲酸酯(100mg,190μmol,产率68％)。
对制得的化合物进行表征：MS(ESI)m/z＝523(M+1) +
5、乙基6-(2-(2((R)3-((叔丁氧羰基)氨基)丁基)-5-氟吡啶-3-基)四氢吡咯-1-基)咪唑[1,2-b]哒嗪-3-甲酸酯的制备
Figure PCTCN2018122522-appb-000019
将乙基6-(2-(2((R)3-((叔丁氧羰基)氨基)-1-丁炔-1)-5-氟吡啶-3-基)四氢吡咯-1-基)咪唑[1,2-b]哒嗪-3-甲酸酯(100mg,190μmol)溶于甲醇(10.0mL)，室温下加入钯碳(10.0mg)。在氢气下室温搅拌6小时。过滤除去固体，减压蒸馏除去溶剂得到粗品乙基6-(2-(2((R)3-((叔丁氧羰基)氨基)丁基)-5-氟吡啶-3-基)四氢吡咯-1-基)咪唑[1,2-b]哒嗪-3-甲酸酯(95.0mg,180μmol,产率95％)。
对制得的化合物进行表征：MS(ESI)m/z＝527(M+1) +
6、6-(2-(2((R)3-((叔丁氧羰基)氨基)丁基)-5-氟吡啶-3-基)四氢吡咯-1-基)咪唑[1,2-b]哒嗪-3-甲酸的制备
Figure PCTCN2018122522-appb-000020
将乙基6-(2-(2((R)3-((叔丁氧羰基)氨基)丁基)-5-氟吡啶-3-基)四氢吡咯-1-基)咪唑[1,2-b]哒嗪-3-甲酸酯(95.0mg,180μmol)溶于甲醇(2.00mL)和四氢呋喃(2.00mL)，加入氢氧化锂(22.0mg,540μmol)的水溶液(2.00mL)，室温下搅拌2小时后用1M的稀盐酸调pH至5-6，再用乙酸乙酯和水萃取，再将水相用乙酸乙酯萃取两次，合并有机相并用无水硫酸钠干燥，减压蒸馏除去溶剂得到6-(2-(2((R)3-((叔丁氧羰基)氨基)丁基)-5-氟吡啶-3-基)四氢吡咯-1-基)咪唑[1,2-b]哒嗪-3-甲酸(85.0mg,170μmol,产率94％)，并直接用于下一步。
对制得的化合物进行表征：MS(ESI)m/z＝499(M+1) +
7、6-(2-(2((R)-3-氨基丁基)-5-氟吡啶-3-基)四氢吡咯-1-基)咪唑[1,2-b]哒嗪-3-甲酸的制备
Figure PCTCN2018122522-appb-000021
将6-(2-(2((R)3-((叔丁氧羰基)氨基)丁基)-5-氟吡啶-3-基)四氢吡咯-1-基)咪唑[1,2-b]哒嗪-3-甲酸(85.0mg,170μmol)溶于二氯甲烷(3.00mL)，加入三氟乙酸(1.00mL)，室温下搅拌1小时后，减压蒸馏除去溶剂得粗品6-(2-(2((R)-3-氨基丁基)-5-氟吡啶-3-基)四氢吡咯-1-基)咪唑[1,2-b]哒嗪-3-甲酸(64.0mg,160μmol,产率94％)。
对制得的化合物进行表征：MS(ESI)m/z＝399(M+1) +
8、(15R)-9-氟-15-甲基-2,11,16,20,24,25-六杂戊环[16.5.2.0 2,6.0 7,12.0 21,26]二十五烷-1(24),7,9,11,18,20,22-七烯-17-酮的制备
Figure PCTCN2018122522-appb-000022
将6-(2-(2((R)-3-氨基丁基)-5-氟吡啶-3-基)四氢吡咯-1-基)咪唑[1,2-b]哒嗪-3-甲酸(64.0mg,160μmol)溶于N,N-二甲基甲酰胺(5.00mL)，加入N,N-二异丙基乙胺(103mg,800μmol)、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(61.0mg,320μmol)和N-羟基-7-氮杂苯并三氮唑(43.0mg,320μmol)。室温下搅拌16小时后用乙酸乙酯和水萃取，再将水相用乙酸乙酯萃取两次，合并有机相并用无水硫酸钠干燥，减压蒸馏除去溶剂，MPLC纯化(以纯水和乙腈为洗脱液，先用纯水洗脱，逐渐提高乙腈比例，在乙腈比例为50％时洗脱出产物，将有目标产物的洗脱液减压蒸馏除去溶剂)，得到(15R)-9-氟-15-甲基-2,11,16,20,24,25-六杂戊环[16.5.2.0 2,6.0 7,12.0 21,26]二十五烷-1(24),7,9,11,18,20,22-七烯-17-酮的两种非对映异构体a(1.10mg,2.90μmol,产率1.8％)和b(1.30mg,3.40μmol,产率2.1％)。
对制得的化合物进行表征：MS(ESI)m/z＝381(M+1)+
异构体a:
1HNMR(400MHz,MeOD):δ＝9.334(d,J＝8.8,1H),8.31(d,J＝2.8,1H),7.95(s,1H),7.45(dd,J＝3.2,J＝9.6,1H),7.24(s,1H),5.50-5.47(m,1H),4.16-4.10(m,1H),3.88-3.83(m,1H), 3.67-3.63(m,1H),3.61-3.57(m,1H),3.54-3.48(m,2H),2.80-2.78(m,1H),2.67-2.61(m,2H),2.38-2.31(m,1H),2.25-2.19(m,1H),1.93-1.84(m,1H),1.37(d,J＝6.8,3H).
异构体b:
1HNMR(400MHz,MeOD):δ＝8.89(d,J＝6.8,1H),8.33(d,J＝2.8,1H),7.94(s,1H),7.53(dd,J＝2.8,J＝9.6,1H),7.23(s,1H),5.47-5.43(m,1H),3.84-3.80(m,1H),3.67-3.65(m,1H),3.61-3.57(m,1H),3.54-3.50(m,3H),3.16-3.12(m,2H),2.64-2.51(m,1H),2.36-2.3(m,1H),2.23-2.15(m,1H),1.87-1.79(m,1H),1.26(d,J＝6.8,3H).
实施例3(14R)-9-氟-14-甲基-13-氧杂-2,16,20,24,25-戊杂戊环[16.5.2.0 2,6.0 7,12.0 21,25]二十五烷-1(24),7,9,11,18,20,22-七烯-17-酮的制备。
Figure PCTCN2018122522-appb-000023
根据实施例1中的方法，将步骤4中的(S)-叔丁基2-羟基丙基氨基甲酸酯换成(R)-叔丁基2-羟基丙基氨基甲酸酯，得到化合物(14R)-9-氟-14-甲基-13-氧杂-2,16,20,24,25-戊杂戊环[16.5.2.0 2,6.0 7,12.0 21,25]二十五烷-1(24),7,9,11,18,20,22-七烯-17-酮。
对制得的化合物进行表征：MS(ESI)m/z＝382(M+1) +
实施例4 9-氟-13-氧杂-2,16,20,24,25-戊杂戊环[16.5.2.0 2,6.0 7,12.0 21,25]二十五烷-1(24),7(12),8,10,18,20,22-七烯-17-酮的制备。
Figure PCTCN2018122522-appb-000024
根据实施例1中的方法，将步骤4中的(S)-叔丁基2-羟基丙基氨基甲酸酯换成叔丁基2-羟基乙基氨基甲酸酯，得到化合物9-氟-13-氧杂-2,16,20,24,25-戊杂戊环[16.5.2.0 2,6.0 7,12.0 21,25]二十五烷-1(24),7(12),8,10,18,20,22-七烯-17-酮。
对制得的化合物进行表征：MS(ESI)m/z＝368(M+1) +
实施例5(15R)-9-氟-15-甲基-13-氧杂-2,16,20,24,25-戊杂戊环[16.5.2.0 2,6.0 7,12.0 21,25]二十五烷-1(24),7(12),8,10,18,20,22-七烯-17-酮的制备
Figure PCTCN2018122522-appb-000025
根据实施例1中的方法，将步骤4中的(S)-叔丁基2-羟基丙基氨基甲酸酯换成(R)-叔丁基(1-羟丙基-2-基)氨基甲酸酯，得到化合物(15R)-9-氟-15-甲基-13-氧杂-2,16,20,24,25-戊杂戊环[16.5.2.0 2,6.0 7,12.0 21,25]二十五烷-1(24),7(12),8,10,18,20,22-七烯-17-酮。
对制得的化合物进行表征：MS(ESI)m/z＝382(M+1) +
实施例6(15S)-9-氟-15-甲基-13-氧杂-2,16,20,24,25-戊杂戊环[16.5.2.0 2,6.0 7,12.0 21,25]二十五烷-1(24),7(12),8,10,18,20,22-七烯-17-酮的制备
Figure PCTCN2018122522-appb-000026
根据实施例1中的方法，将步骤4中的(S)-叔丁基2-羟基丙基氨基甲酸酯换成(S)-叔丁基(1-羟丙基-2-基)氨基甲酸酯，得到化合物(15S)-9-氟-15-甲基-13-氧杂-2,16,20,24,25-戊杂戊环[16.5.2.0 2,6.0 7,12.0 21,25]二十五烷-1(24),7(12),8,10,18,20,22-七烯-17-酮。
对制得的化合物进行表征：MS(ESI)m/z＝382(M+1) +
实施例7(14S)-10-氟-15-甲基-14-氧杂-2,17,21,25,26-戊杂己环[17.5.2.0 2,7.0 4,6.0 8,13.0 22,26]二十六烷-1(25),8(13),9,11,19,21,23-七烯-18-酮的制备
Figure PCTCN2018122522-appb-000027
根据实施例1中的方法，将步骤1中的1-叔丁氧羰基-吡咯烷换成3-氮杂双环[3.1.0]己烷-3-甲酸叔丁酯，得到化合物(14S)-10-氟-15-甲基-14-氧杂-2,17,21,25,26-戊杂己环[17.5.2.0 2,7.0 4,6.0 8,13.0 22,26]二十六烷-1(25),8(13),9,11,19,21,23-七烯-18-酮。
对制得的化合物进行表征：MS(ESI)m/z＝394(M+1) +
实施例8(14S)-4,9-二氟-14-甲基-13-氧杂-2,16,20,24,25-戊杂戊环[16.5.2.0 2,6.0 7,12.0 21,26]二十 五烷-1(24),7(12),8,10,18,20,22-七烯-17-酮的制备
Figure PCTCN2018122522-appb-000028
根据实施例1中的方法，将步骤1中的1-叔丁氧羰基-吡咯烷换成1-叔丁氧羰基-3-氟吡咯烷，得到化合物(14S)-4,9-二氟-14-甲基-13-氧杂-2,16,20,24,25-戊杂戊环[16.5.2.0 2,6.0 7,12.0 21,26]二十五烷-1(24),7(12),8,10,18,20,22-七烯-17-酮。
对制得的化合物进行表征：MS(ESI)m/z＝400(M+1) +
实施例9(14S)-4,4,9-三氟-14-甲基-13-氧杂-2,16,20,24,25-戊杂戊环[16.5.2.0 2,6.0 7,12.0 21,25]二十五烷-1(24),7(12),8,10,18,20,22-七烯-17-酮的制备
Figure PCTCN2018122522-appb-000029
根据实施例1中的方法，将步骤1中的1-叔丁氧羰基-吡咯烷换成1-叔丁氧羰基-3,3-二氟吡咯烷，得到化合物(14S)-4,4,9-三氟-14-甲基-13-氧杂-2,16,20,24,25-戊杂戊环[16.5.2.0 2,6.0 7,12.0 21,25]二十五烷-1(24),7(12),8,10,18,20,22-七烯-17-酮。
对制得的化合物进行表征：MS(ESI)m/z＝418(M+1) +
为了说明本发明的有益效果，本发明提供以下试验例。
试验例1 TRK抑制活性的检测
1、实验材料与试剂：
酶标仪 TECAN Infinite M200 PRO
DMSO MP/CAT NO.196055
MOPS Sigma Cat#RDD003 Lot#SLBJ8407V
Triton-100 Solarbio life science Cat#T8200
MgCl 2.6H 2O 成都科龙化工Lot#20120728
DTT Sigma Cat#43815-1G
384孔板 Corning Cat#3574
96well PCR板 Axygen Cat#321-63-051
ADP-Glo TM Kinase Assay kit Promega Cat#:V9102
TRKA Protein(野生型) abcam Cat#:ab60887
poly(4:1 Glu,Tyr)peptide signalchem Cat#P61-58,Lot#C1887-5
2、试验方法
配制酶反应缓冲液，其中MOPS浓度为25mM，MgCl 2浓度为5mM，DTT浓度为500μM，Triton含量为0.005％，调节pH至7.5。
用DMSO稀释受试化合物至所需终浓度的200倍，混匀后吸取3μL加入117μL酶反应缓冲液液中，充分混匀。吸取3μL酶反应缓冲液配制的化合物加入96孔PCR板中，阳性对照孔和阴性对照孔分别加入3μL含2.5％DMSO的酶反应缓冲液。用酶反应缓冲液稀释TRK蛋白至0.4ng/μL，除空白对照组外其余各孔加入6μL已稀释的TRK蛋白，空白对照组加入6μL酶反应缓冲液，反应板1000rpm/分钟离心1分钟，使化合物和TRK室温预孵育10分钟。用酶反应缓冲液配制ATP浓度为160μM，底物浓度为1μM的混合液，于反应各孔中加入6μL，反应板1000rpm/分钟离心1分钟，室温孵育35分钟。酶反应结束后于反应各孔中加入15μLADP-Glo，反应板1000rpm/分钟离心1分钟，室温孵育40分钟，之后每孔转移15μL反应液至384孔板，再于对应的384孔板孔中加入15μL检测底物，384孔板1000rpm/分钟离心1分钟，室温孵育40分钟。反应结束后，酶标仪读取384孔板中的冷发光信号值。
3、数据分析
计算各浓度剩余活力百分比，公式如下：
剩余活力(％)＝100*(Lumin 化合物组-Lumin 空白对照)/(Lumin 阳性对照-Lumin 空白对照)
之后用GraphPad 5.0拟合剂效曲线计算IC 50值。
按照上述方法对实施例制备的化合物进行去TRK抑制活性检测，试验结果见表1，其中测定各化合物的IC 50按照说明分类，表1中：
“+”表示IC 50测定值大于500nM；
“++”表示IC 50测定值小于500nM大于100nM；
“+++”表示IC 50测定值小于100nM；
NA表示未进行检测。
表1、化合物对TRKA的抑制活性
实施例 TRKA TRKA(G667C) TRKA(G595R)
1 +++ +++ NA
1a +++ +++ +++
1b +++ NA NA
2a +++ +++ NA
2b +++ +++ NA
3 +++ +++ +++
4 +++ +++ +++
5 +++ +++ NA
6 +++ +++ +++
7 +++ +++ NA
8 +++ ++ NA
9 +++ +++ NA
试验表明，本发明实施例的化合物具有良好的TRK抑制活性，可以有效用于与TRK活性异常疾病有关的治疗。
试验例2 TRK抑制剂细胞实验的检测
1、实验材料与试剂：
细胞系：Ba/F3 ETV6-NTRK3-G623R细胞系，Ba/F3 LMNA-NTRK1-G595R细胞系，Ba/F3 LMNA-NTRK1-F589L细胞系(RPMI1640+10％FBS培养基)；试剂与耗材：胎牛血清FBS(GBICO,Cat#10099-141)，
Figure PCTCN2018122522-appb-000030
Luminescent Cell Viability Assay(Promega,Cat#G7572)，96孔透明平底黑壁板(
Figure PCTCN2018122522-appb-000031
Cat#3603)；仪器：SpectraMax多标记微孔板检测仪，MD，2104-0010A；CO 2培养箱，Thermo Scientific，Model 3100 Series；生物安全柜，Thermo Scientific，Model 1300 Series A2；倒置显微镜，Olympus，CKX41SF；冰箱，SIEMENS，KK25E76TI。
2、试验方法
细胞培养和接种：(1)收获处于对数生长期的细胞并采用血小板计数器进行细胞计数。用台盼蓝排斥法检测细胞活力，确保细胞活力在90％以上。(2)调整细胞浓度；分别添加90μL细胞悬液至96孔板中。(3)将96孔板中的细胞置于37℃、5％CO 2、95％湿度条件下培养过夜。
药物稀释和加药：(1)配制10倍药物溶液，最高浓度为10uM，9个浓度，3.16倍稀释，在接种有细胞的96孔板中每孔加入10μL药物溶液，每个药物浓度设置三个复孔。(2)将已加药的96孔板中的细胞置于37℃、5％CO 2、95％湿度条件下继续培养72小时，之后进行CTG分析。以RXDX-101(Entrectinib)为阳性对照品。
终点读板：(1)融化CTG试剂并平衡细胞板至室温30分钟。(2)每孔加入等体积的CTG溶液。(3)在定轨摇床上振动5分钟使细胞裂解。(4)将细胞板放置于室温20分钟以稳定冷光信号。(5)读取冷光值。
3、数据分析
使用GraphPad Prism 7.0软件分析数据，利用非线性S曲线回归来拟合数据得出剂量-效应曲线，并由此计算IC 90和IC 50值。
细胞存活率(％)＝(Lum 待测药-Lum 培养液对照)/(Lum 细胞对照-Lum 培养液对照)×100％
表2、化合物对TRKA突变细胞系的抑制活性
Figure PCTCN2018122522-appb-000032
试验表明，本发明制备的化合物对TRKA突变细胞系具有良好的抑制活性。
试验例3 TRKA体内药效实验方法
1、实验材料
NIH-3T3 ΔTRKA G595R细胞为本实验室构建的多克隆稳转细胞系。Balb/c Nude小鼠，雌性，6-8周龄，体重18-22克，购自成都的达硕实验动物有限公司。
2、实验方法
收取对数生长期的NIH-3T3 ΔTRKA G595R细胞，计数，调整细胞密度，将0.1mL(2×10 6个细胞)皮下接种于每只小鼠的右后背，肿瘤平均体积达到约100mm 3时随机分组给药(n＝6)。
实验期间，每天进行一次动物活动观察，给药前对每只动物称量一次体重，每周三次用游 标卡尺测量肿瘤长径和短径。在实验结束后，将所有存活的实验动物处死。
3、数据分析
肿瘤体积的计算公式为：V＝0.5(a×b 2)，a和b分别表示肿瘤的长径和短径。
根据肿瘤测量的结果计算出相对肿瘤体积(relative tumor volume，RTV)，计算公式为RTV＝V t/V 0，其中V 0是分组给药时(即D 0)测量所得平均肿瘤体积，V t为某一次测量时的平均肿瘤体积，用Graph Pad Prism 6.0进行作图分析。结果如图1所示。
试验结果证明，本发明制备的化合物具有明显抑制肿瘤生长的作用。
综上所述，本发明公开的式I所示的新化合物，表现出了良好的TRK抑制活性，为临床治疗与TRK活性异常相关的疾病提供了一种新的选择。

Claims (15)

  1. 式Ⅰ所示的化合物、或其立体异构体、或其晶型、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物：
    Figure PCTCN2018122522-appb-100001
    式中，
    R 1、R 1’、R 2、R 2’各自独立地选自氢、卤素、羟基、氨基、三氟甲基、羧基、氰基、C 1～C 10的烷基、C 1～C 10的烷氧基、C 1～C 10的烷氨基；
    或者，R 1、R 2相连形成3～8元环烷烃、3～8元杂环烷烃；
    A环选自被m个R 3取代的5～6元芳环、5～6元芳杂环；其中m为0、1、2、3或4；R 3选自卤素、羟基、氨基、三氟甲基、羧基、氰基、C 1～C 10的烷基、C 1～C 10的烷氧基、C 1～C 10的烷氨基；
    X选自-CR 4R 5-、-NR 4-、-O-、-S-；其中R 4、R 5选自氢、C 1～C 10的烷基；
    L选自被n个R 6取代的C 1～C 10的亚烷基；其中n为0、1、2、3或4；R 6选自卤素、羟基、氨基、三氟甲基、羧基、氰基、C 1～C 10的烷基、C 1～C 10的烷氧基、C 1～C 10的烷氨基。
  2. 根据权利要求1所述的化合物，其特征在于：
    R 1、R 1’、R 2、R 2’各自独立地选自氢、卤素、羟基、氨基、三氟甲基、羧基、氰基、C 1～C 4的烷基、C 1～C 4的烷氧基、C 1～C 4的烷氨基；
    或者，R 1、R 2相连形成3～6元环烷烃、3～6元杂环烷烃；
    A环选自被m个R 3取代的5～6元芳环、5～6元芳杂环；其中m为0、1、2或3；R 3选自卤素、羟基、氨基、三氟甲基、羧基、氰基、C 1～C 4的烷基、C 1～C 4的烷氧基、C 1～C 4的烷氨基；
    X选自-CR 4R 5-、-NR 4-、-O-、-S-；其中R 4、R 5选自氢、C 1～C 4的烷基；
    L选自被n个R 6取代的C 1～C 5的亚烷基；其中n为0、1、2、3或4；R 6选自卤素、羟基、氨基、三氟甲基、羧基、氰基、C 1～C 4的烷基、C 1～C 4的烷氧基、C 1～C 4的烷氨基。
  3. 根据权利要求2所述的化合物，其特征在于：
    R 1、R 1’、R 2、R 2’各自独立地选自氢、卤素、羟基、氨基、三氟甲基、羧基、氰基、C 1～C 4的烷基、C 1～C 4的烷氧基、C 1～C 4的烷氨基；
    或者，R 1、R 2相连形成3元环烷烃、3元杂环烷烃；
    A环选自被m个R 3取代的6元芳环、6元芳杂环；其中m为0、1或2；R 3选自卤素、羟基、氨基、三氟甲基、羧基、氰基、C 1～C 4的烷基、C 1～C 4的烷氧基、C 1～C 4的烷氨基；
    X选自-CR 4R 5-、-O-、-S-；其中R 4、R 5选自氢、C 1～C 4的烷基；
    L选自被n个R 6取代的C 1～C 5的亚烷基；其中n为0、1、2或3；R 6选自卤素、羟基、氨基、三氟甲基、羧基、氰基、C 1～C 4的烷基、C 1～C 4的烷氧基、C 1～C 4的烷氨基。
  4. 根据权利要求3所述的化合物，其特征在于：
    R 1、R 1’、R 2、R 2’各自独立地选自氢、卤素；
    或者，R 1、R 2相连形成3元环烷烃；
    A环选自被m个R 3取代的6元芳环、6元芳杂环；其中m为0、1或2；R 3选自卤素、羟基、氨基、三氟甲基、羧基、氰基、C 1～C 4的烷基、C 1～C 4的烷氧基、C 1～C 4的烷氨基；
    X选自-CR 4R 5-、-O-、-S-；其中R 4、R 5选自氢、C 1～C 4的烷基；
    L选自被n个R 6取代的C 1～C 5的亚烷基；其中n为0、1、2或3；R 6选自卤素、羟基、氨基、三氟甲基、C 1～C 4的烷基、C 1～C 4的烷氧基、C 1～C 4的烷氨基。
  5. 根据权利要求4所述的化合物，其特征在于：所述式I所示的化合物如式II所示：
    Figure PCTCN2018122522-appb-100002
    式中，
    Y选自CH或N；
    R a1、R a2分别选自氢、C 1～C 4的烷基。
  6. 根据权利要求5所述的化合物，其特征在于：所述式II所示化合物为：
    Figure PCTCN2018122522-appb-100003
    Figure PCTCN2018122522-appb-100004
  7. 权利要求1～6任一项所述的化合物、或其立体异构体、或其晶型、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物在制备激酶抑制剂类药物中的用途。
  8. 根据权利要求7所述的用途，其特征在于：所述激酶抑制剂类药物为Trk激酶抑制剂类药物。
  9. 根据权利要求8所述的用途，其特征在于：所述Trk激酶抑制剂类药物为TrkA激酶抑制剂类药物。
  10. 权利要求1～6任一项所述的化合物、或其立体异构体、或其晶型、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物在制备治疗与激酶活性异常相关的疾病的药物中的用途。
  11. 根据权利要求10所述的用途，其特征在于：所述与激酶活性异常相关的疾病为与Trk激酶活性异常相关的疾病。
  12. 根据权利要求11所述的用途，其特征在于：所述与Trk激酶活性异常相关的疾病是与神经退行性疾病、疼痛、癌症、炎症相关的疾病中的任一种或几种。
  13. 权利要求1～6任一项所述的化合物、或其立体异构体、或其晶型、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物在制备治疗神经退休性疾病、慢性疼痛、急性疼痛、癌症或炎性疾病药物中的用途。
  14. 根据权利要求13所述的用途，其特征在于：所述疾病为多发性硬化症、帕金森氏 症、阿茨海默症、炎性疼痛、神经性疼痛、手术疼痛、神经细胞瘤、黑色素瘤、乳腺癌、胃癌、哮喘、炎性肠病或特异性皮炎。
  15. 一种药物，其特征在于：它是以权利要求1～6任一项所述的化合物、或其立体异构体、或其晶型、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物，加上药学上可接受的辅料制备而成的制剂。
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