WO2019228252A1 - 一种高活性csf1r抑制剂化合物 - Google Patents

一种高活性csf1r抑制剂化合物 Download PDF

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WO2019228252A1
WO2019228252A1 PCT/CN2019/088221 CN2019088221W WO2019228252A1 WO 2019228252 A1 WO2019228252 A1 WO 2019228252A1 CN 2019088221 W CN2019088221 W CN 2019088221W WO 2019228252 A1 WO2019228252 A1 WO 2019228252A1
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cancer
alkyl
compound
stereoisomer
cycloalkyl
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English (en)
French (fr)
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刘世峰
俞智勇
庞伟
王骥
陈鹏
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Adlai Nortye Biopharma Co Ltd
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Adlai Nortye Biopharma Co Ltd
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Priority to US16/977,093 priority Critical patent/US11591328B2/en
Priority to EP19810043.0A priority patent/EP3744718A4/en
Priority to CN201980005226.1A priority patent/CN111295380B/zh
Priority to JP2021510517A priority patent/JP7090958B2/ja
Publication of WO2019228252A1 publication Critical patent/WO2019228252A1/zh
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/54—Spiro-condensed
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • 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
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • 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
    • C07D401/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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
    • C07D471/02—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 system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • 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
    • C07D487/02—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 two hetero rings
    • C07D487/10—Spiro-condensed systems

Definitions

  • the invention relates to a heterocyclic compound, in particular to a highly active CSF1R inhibitor and use thereof.
  • CSF1R colony stimulation factor
  • TAM tumor-associated macrophages
  • CSF1R is considered an important therapeutic target for osteoporosis and inflammatory arthritis.
  • increased M-CSF signaling results in increased osteoclast activity, which leads to bone loss accompanied by arthritis and other inflammatory bone erosions (see Scott et al. Rheumatology 2000, 39: 122-132, Ritchlin et al. (J. Clin. Invest. 2003, 111: 821-831).
  • inhibition of CSF1R represents a promising treatment option for arthritis and other inflammatory bone erosions, and data on the efficacy of known CSF1R inhibitors such as Ki-20227 and GW2580 in animal models of arthritis further support this ( (See Conwat et al.
  • the CSF1R antibody drugs currently in clinical practice include BMS / FPRX's FPA008, Roche's emactuzumab, Eli Lilly's LY3022855, Amgen's AMG820, etc.
  • the CSF1R small molecule drugs entering the clinic include BLZ945, Plexxikon's PLX3397, and Deciphera's DC-3014.
  • the combined use of CSF1R inhibitors and immune checkpoint inhibitors is still in the early stages of clinical practice, and no compound has entered clinical application in China. There is a continuing need for the identification of small molecules that inhibit CSF1R, particularly compounds that can be used to treat CSF1R-mediated diseases.
  • the present invention provides a compound having formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, stereoisomer mixture, or stereoisomeric racemic mixture thereof.
  • the compound has activity as a CSF1R inhibitor. It should be pointed out that when referring generally to the compound of formula I in this disclosure, it is not necessary to list some or all of the following at the same time: its pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, stereoisomers A conformational mixture or a stereoisomeric racemic mixture.
  • the compound of formula I also encompasses its pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, stereoisomer mixtures, and stereoisomeric racemic mixtures.
  • X represents CR a R a ', NR a , -C (O)-, O, S, S (O) or S (O) 2 ;
  • R 1 and R 2 and the carbon atom connected to them are synthesized into a saturated or unsaturated 3-12 member
  • a cycloalkyl or heterocycloalkyl for example the 3-12 membered cycloalkyl or heterocycloalkyl may be a 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 membered ring, said Heterocycloalkyl contains at least one heteroatom selected from O, N, and S atoms, such as 1, 2, 3, or 4 heteroatoms, and the cycloalkyl or heterocycloalkyl may be optionally 0, 1 , 2, 3, or 4 are each independently substituted with a substituent selected from R 6 : halogen, hydroxy, C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 heterocycle Alkyl,
  • R 3 and R 5 each independently represent hydrogen, halogen, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, C 3 -C 8 cycloalkyl, C 3 -C 8 heterocycloalkyl, halogen C 1 -C 8 alkyl, hydroxyl, amino, nitro, cyano, -C (O) OR a , -OC (O) R a , -C (O) -NR a R a ', -NR a -C (O) -R a , -NR a -C (O) -OR a ,-(C 1 -C 8 ) alkyl-NR a -C (O) R a , -SO 2 -NR a R a 'Or -SO 2 R a ;
  • R 4 represents Cy 2 , -NHC (O) R a , -NHC (O) NR a R a ', -C (O) R a , -C (O) NR a R a ', -S (O) 2 R a , -S (O) 2 NR a R a ', -NHS (O) 2 R a or -NHS (O) 2 NR a R a ';
  • Cy 1 and Cy 2 each independently represent a 5-12 membered ring independently substituted by 0, 1 , 2 , 3, or 4 substituents, preferably a 5-12 membered aryl group or a 5-12 membered heteroaryl group; More preferably, it is a 5-6 membered aryl group or a 5-6 membered heteroaryl group, wherein the substituents are halogen, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, C 3 -C 9 ring Alkyl, C 3 -C 9 heterocycloalkyl, halogenated C 1 -C 8 alkyl, hydroxy, nitro, cyano, -C (O) OR a , -OC (O) R a , -C ( O) -NR a R a ', -NR a -C (O) -R a , -NR a -C (O) -OR a ,-(C 1 -C 8
  • R a, R a 'independently represent hydrogen, C 1 -C 8 alkyl, C 3 -C 9 cycloalkyl, hydroxy, halogen, amino, C 1 -C 8 haloalkyl, C 1 - C 8 alkylamino, di-C 1 -C 8 alkylamino, or R a, R a 'and a ring atom attached thereto synthesis of 3-9 membered cycloalkyl or a heterocyclic group, preferably hydrogen, C 1- C 8 alkyl or C 3 -C 8 cycloalkyl;
  • n is 1, 2 or 3, preferably 1; m and o each independently represent 0, 1, 2 or 3,
  • alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl group as defined above may be further substituted with a substituent selected from the group consisting of: C 1 -C 8 alkyl, C 2- C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 8 cycloalkyl, 5-12 membered aryl, 5-12 membered heteroaryl, C 1 -C 8 haloalkyl, C 1 -C 8 Alkoxy, C 1 -C 8 alkylthio, halogen, hydroxyl, cyano, sulfonic and nitro;
  • R a has independent definitions in different substituents; R a ′ has independent definitions in different substituents.
  • C x1 -C x2 is used when referring to some substituent groups, which means that the number of carbon atoms in the substituent group may be x1 to x2.
  • C 0 -C 8 means that the group contains 0, 1 , 2, 3, 4, 5, 6, 7, or 8 carbon atoms
  • C 1- C 8 means that the group contains 1, 2, 3 , 4, 5, 6, 7, or 8 carbon atoms
  • C 2 -C 8 represents that the group contains 2, 3 , 4, 5, 6, 7, or 8 carbon atoms
  • C 3 -C 8 represents the The group contains 3, 4, 5, 6, 7, or 8 carbon atoms
  • C 4 -C 8 means that the group contains 4, 5, 6, 7, or 8 carbon atoms
  • C 1 -C 6 means the The group contains 1, 2, 3, 4, 5, or 6 carbon atoms.
  • the expression "x1-x2 membered ring” is used, which means that the number of ring atoms of the group may be x1 to x2.
  • the 3-12 membered cycloalkyl or heterocycloalkyl group may be a 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 membered ring, and the number of ring atoms thereof may be 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
  • 3-6 membered rings indicate that the cyclic group can be 3, 4, 5, or 6 membered rings, and the number of ring atoms can be 3, 4, 5 or 6;
  • 3-9 membered ring means that the cyclic group can be 3, 4, 5, 6, 7, 8 or 9 membered ring, and the number of ring atoms can be 3, 4, 5, 6, 7, 8 or 9;
  • 5-12-membered ring means that the cyclic group can be 5, 6, 7, 8, 9, 10, 11 or 12-membered ring, and the number of ring ring
  • the ring atom may be a carbon atom or a heteroatom, such as a heteroatom selected from N, O, and S.
  • the heterocyclic ring may contain 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more ring heteroatoms, for example, selected from N, O, and S Heteroatoms.
  • one or more halogens may each be independently selected from fluorine, chlorine, bromine, and iodine.
  • R 1 and R 2 and the carbon atoms connected to them are cyclically synthesized into a saturated or unsaturated 3-6 membered cycloalkyl or heterocycloalkyl.
  • Group contains at least one heteroatom selected from O, N and S atoms, and the cycloalkyl or heterocycloalkyl group may be optionally selected from 0, 1, 2, 3, or 4 each independently selected from the following R 6 Is substituted by a substituent wherein R 6 is as defined above.
  • the ring formed by R 1 and R 2 together with the carbon atom to which they are attached is selected from the following structures:
  • R c is selected from hydrogen, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, -C (O) R a , -C (O) OR a , -C (O) -NR a R a ', -SO 2 -NR a R a ' and -SO 2 R a ; * represents the binding site of R 1 and R 2 and the carbon atom to which they are attached, and the above-mentioned group may be optionally 0, 1 , 2, 3, and 4 are each independently substituted with a substituent selected from R 6 , wherein R a , R a ′, and R 6 have the same meanings as defined above.
  • X is selected from CR a R a ′, NR a , O and S, preferably O; wherein R a , R a ′ is selected from hydrogen, C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, hydroxyl, halo, C 1 -C 8 haloalkyl, C 1 -C 8 alkylamino, di-C 1 -C 8 alkylamino, or R a, R a ', and with The connected atomic rings are synthesized as 3-9 membered cycloalkyl or heterocycloalkyl, preferably hydrogen, halogen or C 1 -C 8 alkyl.
  • R 4 is preferably Cy 2 , -NHC (O) R a , -C (O) NR a R a 'or -NHC (O) NR a R a ', where Cy 2 , R a, R a 'are as defined above.
  • Cy 2 is selected from the group consisting of phenyl, pyridyl, pyrazinyl, cyclopropyl, cyclopentyl, cyclohexyl, furyl, thiazolyl, piperidinyl, piperazinyl, oxa Azolyl, imidazolyl, or thienyl; wherein Cy 2 is more preferably pyrazolyl, imidazolyl, oxazolyl, thiazolyl, phenyl, or pyridyl; and said Cy 2 may be optionally C 1 -C 8 Alkyl, C 1 -C 8 alkoxy, C 3 -C 9 cycloalkyl, C 3 -C 9 heterocyclyl, C 1 -C 8 haloalkyl, halogen, cyano, sulfo, nitro or Substituted by a hydroxyl group.
  • R a and R a ' is preferably hydrogen, halogen or C 1 -C 8 alkyl.
  • said compound of formula I is preferably selected from compounds having the structure:
  • the compounds of the present invention can also be prepared in the form of pharmaceutically acceptable salts, which can be formed using, for example, the following inorganic or organic acids: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, glycolic acid Lactic acid, pyruvate, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, mandelic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, hydroxymaleic acid, benzoic acid, hydroxy acid Benzoic acid, phenylacetic acid, cinnamic acid, salicylic acid, methanesulfonic acid, benzenesulfonic acid or toluenesulfonic acid.
  • inorganic or organic acids hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, glycolic acid Lactic acid, pyruvate
  • the pharmaceutically acceptable salts of the present invention can be prepared by conventional methods, for example, by dissolving a compound of the present invention in a water-miscible organic solvent such as acetone, methanol, ethanol, and acetonitrile, and adding an excess of an organic acid or an inorganic compound thereto. Aqueous acid solution so that the salt is precipitated from the resulting mixture, the solvent and the remaining free acid are removed therefrom, and the precipitated salt is then separated.
  • a water-miscible organic solvent such as acetone, methanol, ethanol, and acetonitrile
  • the compound of the present invention or a pharmaceutically acceptable salt thereof may include hydrates and solvates thereof.
  • the invention also provides the use of a compound of the invention in the manufacture of a medicament for the prevention and / or treatment of cancer, tumors, inflammatory diseases, autoimmune diseases or immune-mediated diseases.
  • the present invention provides a pharmaceutical composition for preventing and / or treating cancer, tumor, inflammatory disease, autoimmune disease, neurodegenerative disease, attention-related disease, or immune-mediated disease, which comprises the invention Compound as active ingredient.
  • the present invention also provides a method for inhibiting CSF1R, which comprises exposing a compound of the present invention or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the compound of the present invention or a pharmaceutically acceptable salt thereof to the CSF1R.
  • the present invention also provides a method for preventing and / or treating a disease that can be prevented and / or treated by inhibiting CSF1R, which comprises administering a compound of the present invention or a pharmaceutically acceptable salt thereof or comprising a compound of the present invention to a subject in need thereof. Or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method for preventing and / or treating cancer, tumor, inflammatory disease, autoimmune disease, neurodegenerative disease, attention-related disease, or immune-mediated disease.
  • a mammal in need thereof administers a compound of the invention.
  • inflammatory diseases may include, but are not limited to, arthritis, rheumatoid arthritis, spinal arthritis, gouty arthritis, osteoarthritis, juvenile arthritis , Other arthritic conditions, lupus, systemic lupus erythematosus (SLE), skin-related diseases, psoriasis, eczema, dermatitis, allergic dermatitis, pain, lung disease, pulmonary inflammation, adult respiratory distress syndrome (ARDS) , Pulmonary sarcoidosis, chronic pulmonary inflammatory disease, chronic obstructive pulmonary disease (COPD), cardiovascular disease, atherosclerosis, myocardial infarction, congestive heart failure, myocardial ischemia-reperfusion injury, inflammatory bowel disease, Crohn's disease, ulcerative colitis, irritable bowel syndrome, asthma, Sjogren's syndrome, autoimmune thyroid disease, urticaria (rubella), multiple sclerosis, sclero
  • cancer or tumor may include, but are not limited to, skin cancer, bladder cancer, ovarian cancer, breast cancer, stomach cancer, pancreatic cancer, prostate cancer, colon cancer, lung cancer, bone cancer, brain cancer, neuroblastoma, rectal cancer , Colon cancer, familial adenomatous polyposis cancer, hereditary nonpolyposis colorectal cancer, esophageal cancer, lip cancer, laryngeal cancer, hypopharyngeal cancer, tongue cancer, salivary adenocarcinoma, gastric cancer, adenocarcinoma, medullary thyroid cancer, Papillary thyroid cancer, kidney cancer, renal parenchymal cancer, ovarian cancer, cervical cancer, uterine body cancer, endometrial cancer, chorionic cancer, pancreatic cancer, prostate cancer, testicular cancer, urinary cancer, melanoma, brain tumors such as Glioblastoma, astrocytoma, meningiomas, neuroblastoma and peripheral neuroec
  • the compound of the present invention or a pharmaceutically acceptable salt thereof when administered in combination with another anticancer agent or an immune checkpoint inhibitor for treating cancer or tumor, the compound of the present invention or a pharmaceutically acceptable salt thereof can provide an enhanced anticancer effect. .
  • anticancer agents used to treat cancer or tumors may include, but are not limited to, cell signal transduction inhibitors, chlorambucil, melphalan, cyclophosphamide, ifosfamide, busulfan, carbohydrate Mustine, lomustine, streptozotocin, cisplatin, carboplatin, oxaliplatin, dacarbazine, temozolomide, procarbazine, methotrexate, fluorouracil, cytarabine, gemcitabine, Mercaptopurine, Fludarabine, Vincristine, Vincristine, Vincristine, Paclitaxel, Docetaxel, Topotecan, Irinotecan, Etoposide, Trabetidine, Dactinomycin, Doxorubicin , Epirubicin, daunorubicin, mitoxantrone, bleomycin, mitomycin C, ixapilone, tamoxifen, flutamide,
  • the compound of the present invention or a pharmaceutically acceptable salt thereof when administered in combination with another therapeutic agent for treating an inflammatory disease, an autoimmune disease, and an immune-mediated disease, the compound of the present invention or a pharmaceutically acceptable salt thereof can provide an enhancement Therapeutic effect.
  • therapeutic agents for treating inflammatory diseases, autoimmune diseases, and immune-mediated diseases may include, but are not limited to, steroidal drugs (e.g., prednisone, hydroponic, hydroponic, methylhydroponic Cortisone, cortisone, hydroxycortisone, betamethasone, dexamethasone, etc.), methotrexate, leflunomide, anti-TNF ⁇ agents (e.g., etanercept, infliximab, adali Monoclonal antibodies, etc.), calcineurin inhibitors (e.g., tacrolimus, pimecrolimus, etc.) and antihistamines (e.g., diphenhydramine, hydroxyzine, loratadine, ebas Tintin, ketotifen, cetirizine, levocetirizine, fexofenadine, etc.), and at least one therapeutic agent selected therefrom may be included in the pharmaceutical composition of the present invention.
  • the compound of the present invention or a pharmaceutically acceptable salt thereof can be administered orally or parenterally as an active ingredient, and the effective amount thereof ranges from 0.1 to 2,000 mg / kg body weight / day in the case of mammals including humans (about 70 kg in weight), It is preferably 1 to 1,000 mg / kg body weight / day, and is administered in single or 4 divided doses per day, or with / without following a predetermined time.
  • the dosage of the active ingredient can be adjusted according to a number of related factors, such as the condition of the subject to be treated, the type and severity of the disease, the rate of administration and the opinion of the doctor. In some cases, an amount smaller than the above dose may be appropriate. An amount greater than the above dose can be used if it does not cause harmful side effects and the amount can be administered in divided doses daily.
  • the pharmaceutical composition of the present invention can be formulated into a dosage form for oral administration or parenteral administration (including intramuscular, intravenous and subcutaneous routes) according to any one of the conventional methods, such as tablets, granules, powders, capsules, syrups , Emulsion, microemulsion, solution or suspension.
  • the pharmaceutical composition of the present invention for oral administration can be prepared by mixing the active ingredient with a carrier such as: cellulose, calcium silicate, corn starch, lactose, sucrose, dextrose, calcium phosphate, stearic acid, hard Magnesium stearate, calcium stearate, gelatin, talc, surfactant, suspending agent, emulsifier and diluent.
  • a carrier such as: cellulose, calcium silicate, corn starch, lactose, sucrose, dextrose, calcium phosphate, stearic acid, hard Magnesium stearate, calcium stearate, gelatin, talc, surfactant, suspending agent, emulsifier and diluent.
  • carriers used in the injection composition of the present invention are water, saline solution, glucose solution, glucose-like solution, alcohol, glycol, ether (e.g., polyethylene glycol 400), oil, Fatty acids, fatty acid esters, glycerides
  • FIG. 1 is a graph showing a medicinal effect of Example Compound 1.
  • FIG. Fig. 2 is a graph showing the medicinal effect of Example Compound 4.
  • the present invention describes the cis- and trans- (or E- and Z-) geometric isomers of the compounds of the present invention, and they can be separated into mixtures of isomers or in separate isomer forms.
  • the compounds of the invention can be isolated in optically active or racemic forms.
  • the compounds of the present invention can exist in a variety of tautomeric forms in which hydrogen atoms are transposed to other parts of the molecule and the chemical bonds between the atoms of the molecule are rearranged. It should be understood that all tautomeric forms that may exist are included in the present invention.
  • the definitions of the substituents of the present invention are independent and not related to each other.
  • R a (or R a ) in the substituent they are independent in the definition of different substituents. .
  • R a (or R a ′) when R a (or R a ′) is selected from one kind of substituents, it does not mean that R a (or R a ′) has the same definition in other substituents.
  • R a (or R a ′) when the definition of R a (or R a ') is selected from hydrogen, it does not mean that -C (O) -NR In a R a ', R a (or R a ') must be hydrogen.
  • substituent when a substituent is labeled as "optionally substituted", the substituent is selected from, for example, an alkyl, cycloalkyl, aryl, heterocyclyl, halogen, hydroxy, Alkoxy, oxo, alkanoyl, aryloxy, alkanoyloxy, amino, alkylamino, arylamino, arylalkylamino, disubstituted amine groups (of which 2 amino substituents are selected (From alkyl, aryl, or arylalkyl), alkanoylamino, aroylamino, aralkanoylamino, substituted alkanoylamino, substituted arylamino, substituted aralkanoylamino, thio, alkyl Thio, arylthio, arylalkylthio, arylthiocarbonyl, arylalkylthiocarbonyl, alkylsulfony
  • alkyl or "alkylene” as used herein is intended to include branched and straight chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms.
  • C1-C8 alkyl means an alkyl group having 1 to 8 carbon atoms.
  • the C1-C8 alkyl group in this specification is preferably a C1-C6 alkyl group, and more preferably a C1-C4 alkyl group.
  • alkyl examples include, but are not limited to, methyl (Me), ethyl (Et), propyl (such as n-propyl and isopropyl), butyl (such as n-butyl, isobutyl, tert-butyl), and Amyl (e.g. n-pentyl, isopentyl, neopentyl).
  • alkenyl refers to a straight or branched chain hydrocarbon group containing one or more double bonds and usually 2 to 20 carbon atoms in length.
  • C2-C8 alkenyl contains two to eight carbon atoms.
  • the C2-C8 alkenyl group in this specification is preferably a C2-C6 alkenyl group, and more preferably a C2-C4 alkenyl group.
  • Alkenyl includes, but is not limited to, for example, vinyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, heptenyl, octenyl, and the like.
  • alkynyl refers to a straight or branched chain hydrocarbon group containing one or more triple bonds and typically 2 to 20 carbon atoms in length.
  • a "C2-C8 alkynyl” contains two to eight carbon atoms.
  • the C2-C8 alkynyl group in the present specification is preferably a C2-C6 alkynyl group, and more preferably a C2-C4 alkynyl group.
  • Representative alkynyl groups include, but are not limited to, for example, ethynyl, 1-propynyl, 1-butynyl, heptynyl, octynyl, and the like.
  • alkoxy refers to -O-alkyl.
  • C1-C8 alkoxy (or alkyloxy) is intended to include C1, C2, C3, C4, C5, C6, C7 and C8 alkoxy.
  • the C1-C8 alkoxy group in the present specification is preferably a C1-C6 alkoxy group, and more preferably a C1-C4 alkoxy group.
  • alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (such as n-propoxy and isopropoxy), and tert-butoxy.
  • alkylthio or “thioalkoxy” means an alkyl group, as defined above, having a specified number of carbon atoms attached via a sulfur bridge; for example, methyl-S- and ethyl-S-.
  • aryl alone or as part of a larger portion such as “aralkyl”, “aralkoxy” or “aryloxyalkyl” refers to a monocyclic ring having a total of 5 to 12 ring members , Bicyclic or tricyclic ring systems, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members.
  • aryl refers to an aromatic ring system including, but not limited to, phenyl, biphenyl, indanyl, 1-naphthyl, 2-naphthyl, and tetrahydronaphthalene base.
  • aralkyl or "arylalkyl” refers to an alkyl residue attached to an aryl ring. Non-limiting examples include benzyl, phenethyl, and the like. A fused aryl group may be attached to another group at a suitable position on a cycloalkyl ring or an aromatic ring. An example of an arrow drawn from a ring system indicates that the bond can be connected to any suitable ring atom.
  • cycloalkyl refers to a monocyclic or bicyclic cyclic alkyl.
  • Monocyclic cyclic alkyl refers to C3-C8 cyclic alkyl, preferably C3-C6 cyclic alkyl, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and norbornyl .
  • Branched cycloalkyls such as 1-methylcyclopropyl and 2-methylcyclopropyl are included in the definition of "cycloalkyl”.
  • Bicyclic cyclic alkyl includes bridged, spiro or fused cycloalkyl.
  • cycloalkenyl refers to a monocyclic or bicyclic cyclic alkenyl.
  • Monocyclic cyclic alkenyl refers to C3-C8 cyclic alkenyl, preferably C3-C6 cyclic alkenyl, including but not limited to cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl and Norbornyl.
  • Branched cycloalkenyl groups such as 1-methylcyclopropenyl and 2-methylcyclopropenyl are included in the definition of "cycloalkenyl”.
  • Bicyclic cyclic alkenyl includes cyclic alkenyl of bridged, spiro or fused rings.
  • Halo or halogen includes fluorine, chlorine, bromine and iodine.
  • Haloalkyl is intended to include branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms and substituted with one or more halogens. Examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoro Propyl and heptachloropropyl.
  • halogenated alkyl group also include "fluoroalkyl" which is intended to include branched and straight chain saturated aliphatic hydrocarbon groups having a specified number of carbon atoms and substituted with one or more fluorine atoms.
  • Haloalkoxy or "haloalkyloxy” means a haloalkyl group, as defined above, connected via an oxygen bridge with a specified number of carbon atoms.
  • C1-C8 haloalkoxy is intended to include C1, C2, C3, C4, C5, C6, C7, and C8 haloalkoxy.
  • Examples of haloalkoxy include, but are not limited to, trifluoromethoxy, 2,2,2-trifluoroethoxy, and pentafluoroethoxy.
  • haloalkylthio or “thiohaloalkoxy” refers to a haloalkyl group as defined above having a specified number of carbon atoms attached via a sulfur bridge; for example, trifluoromethyl-S- and pentafluoroethyl -S-.
  • aryl refers to a monocyclic or bicyclic (and above bicyclic) all carbon atom aromatic group.
  • a monocyclic aromatic group refers to a phenyl group
  • a bicyclic or more aromatic group refers to a naphthyl group, an anthracenyl group, etc.
  • the aryl bicyclic ring may also be a benzene ring fused to a cycloalkyl group or a ring Alkenyl, or a cycloalkynyl.
  • arylhetero means a stable 3-, 4-, 5-, 6-, or 7-membered aromatic monocyclic or Aromatic bicyclic or 7-, 8-, 9-, 10-, 11-, 12-, 13-, or 14-membered aromatic polycyclic heterocyclic rings that are fully unsaturated, partially unsaturated, and contain carbon atoms And 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S; and includes any of the following polycyclic groups, wherein any heterocyclic ring defined above is fused with a benzene ring. Nitrogen and sulfur heteroatoms can optionally be oxidized.
  • the nitrogen atom is substituted or unsubstituted (ie N or NR, where R is H or, if defined, another substituent).
  • a heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. If the resulting compound is stable, the heterocyclyl groups described herein may be substituted on a carbon or nitrogen atom.
  • the nitrogen in the heterocycle may optionally be quaternized.
  • the total number of S and O atoms in the heteroring exceeds 1, these heteroatoms are not adjacent to each other.
  • the total number of S and O atoms in the heterocyclic ring is not greater than one.
  • heterocyclic it is intended to include heteroaryl.
  • aromatic heterocycles include, but are not limited to, acridinyl, azetidinyl, azecinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothienyl, benzoxan Oxazolyl, benzoxazoline, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzoisoxazolyl, benzoisothiazolyl, benzimidazoline, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, fluorenyl, decahydroquinolyl, 2H, 6H-1,5,2-dithiazinyl, dihydrofuro [2, 3-b] tetrahydrofuryl, furyl, furoxanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, imidazopyrid
  • heterocycloalkyl refers to a monocyclic heterocycloalkyl system, or a bicyclic heterocycloalkyl system, and also includes a spiro heterocyclic or bridged heterocycloalkyl.
  • the monocyclic heterocycloalkyl group refers to a 3-8 membered cyclic alkyl system containing at least one saturated or unsaturated but not aromatic member selected from O, N, S, and P.
  • a bicyclic heterocycloalkyl system refers to a heterocycloalkyl fused to a phenyl, or a cycloalkyl, or a cycloalkenyl, or a heterocycloalkyl, or a heteroaryl.
  • bridged cycloalkyl refers to a polycyclic compound that shares two or more carbon atoms. Can be divided into bicyclic bridged cyclic hydrocarbons and polycyclic bridged cyclic hydrocarbons. The former is composed of two alicyclic rings sharing more than two carbon atoms; the latter is a bridged cyclic hydrocarbon composed of more than three rings.
  • spirocycloalkyl refers to polycyclic hydrocarbons that share a single carbon atom (called a spiro atom) between monocyclic rings.
  • bridged heterocyclic group refers to a polycyclic compound that shares two or more carbon atoms, and the ring contains at least one atom selected from O, N, and S. Can be divided into bicyclic bridged heterocyclic ring and polycyclic bridged heterocyclic ring.
  • heterospirocyclyl refers to a polycyclic hydrocarbon that shares one carbon atom (called a spiro atom) between single rings, and the ring contains at least one atom selected from O, N, and S.
  • substitution means that at least one hydrogen atom is replaced with a non-hydrogen group, provided that the normal valence is maintained and the substitution results in a stable compound.
  • nitrogen atoms such as amines
  • these nitrogen atoms can be converted to N-oxides by treatment with an oxidant (such as mCPBA and / or hydrogen peroxide) to obtain other compounds of the invention .
  • an oxidant such as mCPBA and / or hydrogen peroxide
  • the nitrogen atoms shown and claimed are considered to encompass both the nitrogen shown and its N-oxides to obtain the derivatives of the present invention.
  • any variable occurs more than one time in any composition or formula of a compound, its definition at each occurrence is independent of its definition at every other occurrence.
  • the group may be optionally substituted with up to three R groups, and R is independently selected from the definition of R at each occurrence.
  • combinations of substituents and / or variables are allowed to exist only if the above combination results in a stable compound.
  • solvate means the physical association of a compound of the invention with one or more solvent molecules, whether organic or inorganic. This physical association includes hydrogen bonding. In some cases, such as when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid, the solvate will be able to be separated.
  • the solvent molecules in the solvate may exist in a regular arrangement and / or a disorderly arrangement.
  • Solvates can include stoichiometric or non-stoichiometric solvent molecules.
  • “Solvate” encompasses both a solution phase and a separable solvate. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Solvation methods are well known in the art.
  • patient refers to an organism that is treated by the methods of the invention.
  • organisms preferably include, but are not limited to, mammals (e.g., rodents, apes / monkeys, horses, cattle, pigs, dogs, cats, etc.) and most preferably humans.
  • the term "effective amount” means the amount of a drug or agent (ie, a compound of the invention) that will elicit, for example, a biological or medical response from a tissue, system, animal or human sought by a researcher or clinician.
  • therapeutically effective amount means an amount that results in an improved treatment, cure, prevention, or alleviation of a disease, condition, or side effect, or a reduction in the disease compared to a corresponding subject who has not received the amount described above. Or the rate of progression of the condition.
  • An effective amount can be administered in one or more administrations, administrations or doses and is not intended to be limited by a particular formulation or route of administration. The term also includes within its scope an effective amount that enhances normal physiological functions.
  • treatment includes any effect that results in amelioration of a condition, disease, disorder, etc., such as reducing, reducing, modulating, improving or eliminating, or ameliorating its symptoms.
  • composition refers to the combination of an active agent and an inert or active carrier, making the composition particularly suitable for in vivo or ex vivo diagnosis or treatment.
  • the base include, but are not limited to, alkali metal (such as sodium) hydroxide, alkaline earth metal (such as magnesium) hydroxide, ammonia, and the like.
  • alkali metal such as sodium
  • alkaline earth metal such as magnesium
  • ammonia and the like.
  • salts of the compounds of the invention For therapeutic use, salts of the compounds of the invention are expected to be pharmaceutical.
  • non-pharmaceutically acceptable salts of acids and bases can also be used, for example, in the preparation or purification of pharmaceutical compounds.
  • pharmaceutical is used herein to refer to those compounds, substances, compositions and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with human and animal tissues without excessive toxicity, irritation Sexual, allergic reactions, and / or other problems or complications, commensurate with a reasonable benefit / risk ratio.
  • the phrase "pharmaceutically acceptable carrier” means a pharmaceutical substance, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, manufacturing aid (e.g., lubricant, talc, magnesium stearate, Calcium stearate or zinc stearate or stearic acid) or a solvent-encapsulating substance that involves carrying or transporting a subject compound from one organ or body part to another organ or body part.
  • manufacturing aid e.g., lubricant, talc, magnesium stearate, Calcium stearate or zinc stearate or stearic acid
  • solvent-encapsulating substance that involves carrying or transporting a subject compound from one organ or body part to another organ or body part.
  • Each carrier must be “acceptable” in the sense that it is compatible with the other ingredients of the formulation and not harmful to the patient.
  • composition means a composition comprising a compound of the invention and at least one other pharmaceutically acceptable carrier.
  • “Pharmaceutical carrier” refers to a medium commonly accepted in the art for the delivery of a biologically active agent to an animal, particularly a mammal, and includes (i.e.) an adjuvant, excipient, or vehicle such as a diluent, preservative , Fillers, flow regulators, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, fragrances, antibacterial agents, antifungal agents, lubricants and dispersants,
  • an adjuvant, excipient, or vehicle such as a diluent, preservative , Fillers, flow regulators, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, fragrances, antibacterial agents, antifungal agents, lubricants and dispersants,
  • acceptable refers to a prescription component or active ingredient that does not unduly adversely affect the health of a general therapeutic target.
  • cancer refers to the abnormal growth of a cell that cannot be controlled and is able to metastasize (spread) under certain conditions.
  • This type of cancer includes, but is not limited to, solid tumors (such as bladder, intestine, brain, chest, uterus, heart, kidney, lung, lymphoid tissue (lymphoma), ovary, pancreas or other endocrine organs (such as thyroid), prostate , Skin (melanoma) or hematoma (such as non-leukemia).
  • combined administration refers to the administration of several selected therapeutic agents to a patient in the same or different modes of administration at the same or different times.
  • enhancing means that the expected result can be increased or extended in terms of potency or duration. Therefore, in terms of enhancing the therapeutic effect of a drug, the term “enhancing” refers to the ability of a drug to increase or extend its potency or duration in the system. As used herein, “synergy value” refers to the ability to maximize the ability of another therapeutic agent in an ideal system.
  • immune disease refers to a disease or condition that has an adverse or adverse reaction to an endogenous or exogenous antigen.
  • cell dysfunction or as a result, damage and dysfunction, or damage to organs or tissues that may produce immune symptoms.
  • kit is synonymous with “product packaging”.
  • subject or “patient” includes mammals and non-mammals.
  • Mammals include, but are not limited to, mammals: humans, non-human primates such as orangutans, apes, and monkeys; agricultural animals such as cattle, horses, goats, sheep, and pigs; domestic animals such as rabbits and dogs; experimental animals including rodents, Such as rats, mice and guinea pigs.
  • Non-mammalian animals include, but are not limited to, birds, fish, and the like. In a preferred example, the mammal selected is human.
  • treatment include alleviating, inhibiting or improving the symptoms or conditions of a disease; inhibiting the occurrence of complications; improving or preventing a potential metabolic syndrome; inhibiting the production of a disease or symptom, Such as controlling the development of a disease or condition; reducing the disease or symptom; reducing the disease or symptom; reducing the complications caused by the disease or symptom, or preventing and / or treating the symptoms caused by the disease or symptom.
  • a certain compound or pharmaceutical composition after administration, can improve a certain disease, symptom, or condition, especially its severity, delay the onset, slow the progression of the disease, or reduce the duration of the disease. Whether fixed or temporary, continuous or intermittent, can be attributed to or related to the circumstances of the administration.
  • Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ocular, pulmonary, transdermal, vaginal, and ear canal , Nasal and local administration.
  • parenteral administration includes intramuscular injection, subcutaneous injection, intravenous injection, intramedullary injection, ventricular injection, intraperitoneal injection, intralymphatic injection, and intranasal injection.
  • the mode of administration of the compounds described herein is a local rather than a systemic mode of administration.
  • the depot formulation is administered by implantation (for example, subcutaneously or intramuscularly) or by intramuscular injection.
  • the drug is administered through a targeted drug delivery system.
  • liposomes are encapsulated by organ-specific antibodies. In this specific embodiment, the liposomes are selectively targeted and absorbed into specific organs.
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of one or more compounds of the invention formulated with one or more pharmaceutically acceptable carriers (additives) and / or diluents, and optionally one One or more of the other therapeutic agents described above.
  • the compounds of the present invention can be administered by any suitable means for any of the aforementioned uses, for example orally, such as tablets, pills, powders, granules, elixirs, elixirs, suspensions (including nanosuspensions, microsuspensions, spray-dried Dispersions), syrups and emulsions; sublingual; buccal; parenteral, such as by subcutaneous, intravenous, intramuscular or intrasternal injection or infusion techniques (e.g., in sterile injectable aqueous or non-aqueous solutions or suspensions Liquid form); nasal, including administration to the nasal membrane, such as by inhalation spray; topical, such as in the form of a cream or ointment; or transrectal, such as in the form of a suppository. They can be administered alone, but are typically administered using a pharmaceutical carrier selected based on the route of administration chosen and standard pharmaceutical practice.
  • Pharmaceutical carriers are formulated according to many factors within the scope of those skilled in the art. These factors include, but are not limited to: the type and nature of the active agent being formulated; the subject to which the active agent-containing composition is to be administered; the intended route of administration of the composition; and the targeted therapeutic indication. Pharmaceutical carriers include aqueous and non-aqueous liquid media and various solid and semi-solid dosage forms.
  • the above-mentioned carrier may include many different ingredients and additives besides the active agent, and the above-mentioned other ingredients are included in the formulation for various reasons known to those skilled in the art, such as stabilizing the active agent, the binder, and the like.
  • suitable pharmaceutical carriers and the factors involved in carrier selection please refer to a number of readily available sources, such as Allen LVJr. Et al. Remington: The Science and Practice of Pharmacy (2 Volumes), 22nd Edition (2012 ), Pharmaceutical Press.
  • the dosage regimen of the compounds of the present invention will vary depending on known factors, such as the pharmacodynamic properties of a particular agent and its mode and route of administration; the recipient's species, age, sex, health status, medical condition, and weight The nature and extent of symptoms; the type of concurrent treatment; the frequency of treatment; the route of administration, the patient's kidney and liver function, and the desired effect.
  • the daily oral dose of each active ingredient should be about 0.001 mg / day to about 10-5000 mg / day, preferably about 0.01 mg / day to about 1000 mg / day, and most preferably The ground is about 0.1 mg / day to about 250 mg / day.
  • the most preferred intravenous dose should be from about 0.01 mg / kg / minute to about 10 mg / kg / minute.
  • the compounds of the invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily.
  • the compounds are generally in a suitable pharmaceutical diluent, excipient, or carrier (herein, as appropriate herein) appropriately selected according to the intended form of administration (e.g., oral tablets, capsules, elixirs, and syrups) and consistent with conventional pharmaceutical practice (Collectively referred to as drug carriers).
  • a suitable pharmaceutical diluent, excipient, or carrier appropriately selected according to the intended form of administration (e.g., oral tablets, capsules, elixirs, and syrups) and consistent with conventional pharmaceutical practice (Collectively referred to as drug carriers).
  • Dosage forms suitable for administration may contain from about 1 mg to about 2000 mg of active ingredient / dosage unit.
  • the active ingredient will generally be present in an amount of about 0.1 to 95% by weight based on the total weight of the composition.
  • a typical capsule for oral administration contains at least one compound of the invention (250 mg), lactose (75 mg) and magnesium stearate (15 mg). The mixture was passed through a 60 mesh screen and packaged into gelatin capsules of size 1.
  • a typical injectable preparation can be prepared by aseptically placing at least one compound of the invention (250 mg) in a bottle, lyophilizing and sealing aseptically. For use, the contents of the bottle were mixed with 2 mL of physiological saline to produce an injectable preparation.
  • the scope of the invention includes (either alone or in combination with a pharmaceutical carrier) a pharmaceutical composition comprising a therapeutically effective amount of at least one compound of the invention as an active ingredient.
  • a pharmaceutical composition comprising a therapeutically effective amount of at least one compound of the invention as an active ingredient.
  • the compounds of the invention can be used alone, in combination with other compounds of the invention, or in combination with one or more other therapeutic agents, such as anticancer agents or other pharmaceutically active substances.
  • the compound of the invention (which can be used in a suitable hydrated form) and / or the pharmaceutical composition of the present invention is formulated into a pharmaceutical dosage form by conventional methods known to those skilled in the art.
  • the actual dosage level of the active ingredient in the pharmaceutical composition of the present invention can be altered to obtain an amount of the active ingredient that is effective for achieving the desired therapeutic response, composition, and mode of administration of a particular patient, but is not toxic to the patient.
  • the selected dosage level will depend on a number of factors, including the activity of the particular compound of the invention or its ester, salt or amide used; the route of administration; the time of administration; the excretion rate of the particular compound used; the rate and extent of absorption The duration of treatment; other drugs, compounds, and / or substances used in combination with the particular compound used; factors such as age, sex, weight, condition, general health, and previous medical history of the patient being treated; factors well known in the medical field.
  • a physician or veterinarian having ordinary skill in the art can easily determine and prescribe an effective amount of the desired pharmaceutical composition. For example, in order to achieve the desired therapeutic effect, a physician or veterinarian can start a comparison of a compound of the invention used in a pharmaceutical composition at a lower level than desired, and gradually increase the dose until the desired effect is achieved.
  • a suitable daily dose of a compound of the invention will be that amount of the compound that is the lowest dose effective to produce a therapeutic effect.
  • Such an effective dose usually depends on the factors mentioned above.
  • oral, intravenous, intraventricular, and subcutaneous doses of a compound of the invention for a patient range from about 0.01 to about 50 mg / kg body weight / day.
  • an effective daily dose of the active compound may be administered separately in two, three, four, five, six or more sub-doses at appropriate intervals throughout the day, optionally in unit dosage form.
  • the medication is administered once a day.
  • the compound of the present invention may be administered alone, the compound is preferably administered in the form of a pharmaceutical preparation (composition).
  • kits / product packaging are also described here. These kits can consist of a conveyor, a kit, or a container box.
  • the container box can be divided into multiple compartments to accommodate one or more containers, such as vials, test tubes, and the like.
  • Each container contains A single component of the method. Suitable containers include bottles, vials, syringes and test tubes.
  • the container is made of an acceptable material such as glass or plastic.
  • the container may contain one or more of the compounds described herein, which may exist as a pharmaceutical component or as a mixture with other ingredients described herein.
  • the container may have a sterile output port (for example, the container may be an IV bag or bottle, and the stopper may be punctured by a hypodermic needle).
  • a kit may carry a compound with instructions, labels, or instructions for use as described herein.
  • a typical kit may include one or more containers, each container is filled with one or more materials (such as reagents, or concentrated mother liquor, etc.) in order to meet the needs of commercial promotion and users' use of compounds. Or device). These materials include, but are not limited to, buffers, diluents, filters, needles, syringes, conveyors, bags, containers, bottles and / or test tubes, with a list of contents and / or instructions for use, and instructions for built-in packaging. The entire set of instructions should be included.
  • the label can be displayed on or closely related to the container.
  • a label appears on a container, it means that the label's letters, numbers, or other features are pasted, molded, and engraved on the container; the label can also appear in a container box or transport box containing multiple containers, such as in a product insert.
  • a label can be used to indicate a specific therapeutic use of the contents.
  • the label may also indicate instructions for use of the content, such as those described in the methods above.
  • the compound represented by the general formula I of the present invention can be prepared by the following method, but the conditions of the method, such as the reactant, the solvent, the base, the amount of the compound used, the reaction temperature, the time required for the reaction, etc. are not limited to the following explanations.
  • the compounds of the present invention can also be conveniently prepared by combining various synthetic methods described in this specification or known in the art, and such combinations can be easily performed by those skilled in the art to which the present invention belongs.
  • X, R 3 , R 4 , R 5 , R 6 , m, o have the same meanings as defined above; p is 1, 2 or 3; q is 0, 1, 2, 3 or 4;
  • the solvent in step I and step II is selected from one of water, methanol, ethanol, THF, DMF, DMSO, dichloromethane, and chloroform, or any combination thereof.
  • Scheme A1 describes another general synthetic method for compound A4:
  • X, R 3 , R 4 , R 5 , R 6 , m, o have the same meanings as defined above; p is 1, 2 or 3; q is 0, 1, 2, 3 or 4;
  • the solvent in step I ′ and step II ′ is selected from one of water, methanol, ethanol, THF, DMF, DMSO, dichloromethane, chloroform, or any combination thereof; the base in step II ′ is selected from NaOH, NaHCO 3, KOH, KHCO 3, K or any combinations thereof 2 CO 3, triethylamine.
  • step I "and step II” is selected from water, methanol, ethanol, THF, DMF, DMSO, dichloromethane, chloroform, or any combination thereof;
  • the reaction temperature of step I " is -100 ° C. To room temperature, preferably -78 ° C to room temperature;
  • the reducing agents used in the reduction reaction in step II ′ are H 2 , NaBH 4 , and LiAlH 4.
  • the catalysts used in the reduction reaction are Raney nickel, ferrous chloride, and cobalt chloride; the reaction temperature in step II ′ is 0. ° C to room temperature.
  • the organic solvent in step I "'and step II"' is selected from the group consisting of methanol, ethanol, THF, DMF, DMSO, dichloromethane, and chloroform, or any combination thereof;
  • phase transfer catalyst in step II "'is tetrabutylammonium fluoride, tetrabutylammonium bromide, tetrabutylammonium chloride; cyclic crown ethers: for example: 18 crown 6, 15 crown 5, cyclodextrin ;
  • the catalyst used in the step III "'reduction reaction is Raney nickel, ferrous chloride, and cobalt chloride; and the reducing agents are H 2 , NaBH 4 , and LiAlH 4 .
  • Preparative HPLC usually uses an acidic method (gradient of acetonitrile and water, each containing 0.1 % Formic acid) using Thermo U3000 AFC-3000; column: Globalsil C-18 12 nm, 250 x 20 mm, 10 ⁇ m, or equivalent; flow rate: 20 mL / min, for separation.
  • compound INT-1b (37.3g, 0.17mol), compound INT-1c (42.0g, 0.20mol), cesium carbonate (220.0g, 0.67mol) and tetratriphenylphosphonium palladium (9.7g, 8.4 mmol) was added to a mixed solution of N'N-dimethylformamide (500 mL) and water (200 mL). After the reaction system was repeatedly replaced with nitrogen three times, it was stirred at 90 ° C. for 24 hours.
  • Trifluoroacetic acid (0.5 mL) was added to a dichloromethane (2 mL) solution in which the compound INT-2e (60 mg, 0.18 mmol) was dissolved, and the reaction solution was stirred at room temperature for 3 hours. LC / MS showed that the raw materials had been consumed.
  • ethyl acetate (10 mL) and saturated sodium bicarbonate solution (10 mL) were added; the organic phase was washed with saturated brine (10 mL x 2), and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure to obtain INT-2f (35 mg, yield: 83.1%) as a white solid.
  • lithium diisopropylamide (2M tetrahydrofuran solution, 7.8 mL) was added dropwise to a solution of methyl cyclohexanoate (2.0 g, 14.1 mmol) in tetrahydrofuran (30 mL).
  • the reaction solution was stirred at -78 ° C for 1.5 hours, and then tetrahydrofuran (10 mL) mixed with bromoacetonitrile (2.0 g, 16.9 mmol) and N'N'-dimethylpropionyl urea (0.90 g, 7.0 mmol) was mixed. )
  • the solution is slowly dripped in.
  • reaction solution was slowly warmed to room temperature and stirred overnight at room temperature. TLC confirmed that the consumption of raw materials was complete.
  • the reaction solution was carefully quenched with a hydrochloric acid solution (1M, 20 mL), concentrated under reduced pressure to remove most of the tetrahydrofuran, and the resulting solution was extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine (50 mL x 2) and dried over anhydrous sodium sulfate.
  • Tetrabutylammonium fluoride (1M in THF, 12.3 mL) was added to a tetrahydrofuran solution in which the compound INT-2b (1.22 g, 4.1 mmol) and trimethylcyanosilane (1.22 g, 12.3 mmol) were dissolved. The reaction was stirred at room temperature overnight. TLC showed that the starting material had been consumed. Ethyl acetate (50 mL) and water (50 mL) were added to the reaction solution, and the organic layer was washed with saturated brine (50 mL x 2) and dried over anhydrous sodium sulfate.
  • P-Toluenesulfonic acid (57 mg, 0.30 mmol) was added to a toluene (100 mL) solution in which INT-13a (1.03 g, 6.06 mmol) and ethylene glycol (0.45 g, 7.27 mmol) were dissolved; the obtained reaction solution was under reflux conditions Stir overnight.
  • a 5% aqueous sodium hydrogen carbonate solution (100 mL) and ethyl acetate (100 mL) were added to the reaction solution; the aqueous phase was further extracted with ethyl acetate (100 mL).
  • diethylaminosulfur trifluoride (2.49 g, 15.5 mmol) was added to a solution of INT-13f (444 mg, 1.55 mmol) in dichloromethane (10 mL); the reaction solution was at room temperature. Stir overnight. A 5% aqueous sodium bicarbonate solution (50 mL) and ethyl acetate (50 mL) were added to the reaction solution; the aqueous phase was further extracted with ethyl acetate (50 mL).
  • the specific operation is as follows: Set the concentration gradient of the test compound, and dilute the test compound to the working concentration with DMSO. In a 384-well plate, use the Echo 550 loading device to add 10 nL of the corresponding concentration of the test compound to each well.
  • the dilution buffer of CSF1R is 1X Enzymatic buffer containing 5mM MgCl 2 , 1mM MnCl 2 , 1mM DTT, and 12.5 nM SEB. Use this buffer to adjust the CSF1R concentration to 0.02 ng / ul. Add 5 ⁇ L of buffer containing CSF1R to 1000g for 30 seconds in a 384-well plate and incubate for 10 minutes at room temperature.
  • test value is 0.1% DMSO.
  • c-Kit comes from Eurofins (cat #: 14-559M); PDGFR ⁇ comes from BPS (cat #: 40260); PDGFR ⁇ comes from Invitrogen (cat #: PR4465B); FLT-3 comes from Carna (cat #: 08 -154); peptide substrate P2 was provided by GL Biochem (cat #: 112394) as a substrate for FLT-3 kinase; peptide substrate P22 was provided by GL Biochem (cat #: 112393), as c-Kit, PDGFR ⁇ , Substrate of PDGFR ⁇ kinase.
  • the final concentrations of the kinase and its corresponding substrates (ATP and peptide substrates P2 or P22) during the experiment are as follows:
  • DMSO solution was used to set the concentration gradient of the test compound, and RPMI1640 (cat #: 01-100-1ACS, BI) containing 10% inactivated serum (cat #: 1707125, BI) was used to dilute the test compound at 1: 500.
  • THP-1 cells were harvested, and the cell density was adjusted to 2 ⁇ 10 6 cells / ml. Take 500 ⁇ L of the cell suspension and the above-mentioned diluted compound in a 1: 1 mixture and spread them into a 24-well plate (cat #: 3524, costar). The culture plate was placed in a cell incubator for 4 hours, and the incubation conditions were: a temperature of 37 ° C, 5% CO 2 , and a humidity of 95%.
  • recombinant human MCSF (cat #: 216-MC, R & D Systems) was diluted with RPMI1640 containing 10% inactivated serum to a final concentration of 100 ng / ml. 100 ⁇ L of the diluted recombinant human MCSF was added to a 24-well plate at 100 ⁇ L per well. After mixing, the cells were incubated in an incubator for 4 minutes. The incubation conditions were: temperature 37 ° C., 5% CO 2 , and humidity 95%. After incubation, protein extraction and ELISA experiments were performed according to the method recommended in the phosphorylated CSF1R detection kit (cat #: DYC3268, R & D Systems). The microplate reader reads the data to calculate the test compound inhibition rate, uses GraphPad Prism to plot and calculates the EC 50 of the test compound.
  • Example 3 Antitumor effect of compound in mouse colon cancer MC38 cell line allograft C57BL / 6 mouse animal model
  • mice C57BL / 6 mice, female, 6-8 weeks (weeks of age of mice at the time of tumor cell inoculation), weight 18-22 g. Purchased from Shanghai Lingchang Biotechnology Co., Ltd., animal certificate number: 2013001832351. Rearing environment: SPF grade.
  • MC38 cells were cultured in DMEM medium containing 10% fetal bovine serum. MC38 cells in exponential growth phase were collected, and PBS was resuspended to a suitable concentration for inoculation of subcutaneous tumors in C57BL / 6 mice.
  • mice were inoculated with 1 ⁇ 106 MC38 cells subcutaneously on the right back, and the cells were resuspended in PBS (0.1ml / head). The tumor growth was regularly observed. When tumors grew to an average volume of 101mm3, they were randomly divided into groups according to tumor size and mouse weight Dosing. Dosing frequency is twice a day; tumor size is tested every other day.
  • T / C% is the relative tumor increase rate, that is, the percentage of tumor volume in the treatment group and control group at a certain time point.
  • T and C are the relative tumor volume (RTV) of the treatment group and the control group at a specific time point, respectively.
  • mice Using mice as test animals, the compounds of Example 1, Example 2, Compound 3, Example 4, Compound 10, and Example 14 were administered orally to mice by LC / MS / MS. Compound, the drug concentration in plasma at different times after the compound of Example 26. The pharmacokinetic behavior of the compound of the present invention in mice was studied, and its pharmacokinetic characteristics were evaluated.
  • test animals were CD-1 mice and were purchased from Shanghai Slark Experimental Animal Co., Ltd.
  • CD-1 mice were fasted orally after fasting overnight.
  • the doses were all 10 mg / kg and the volume was 10 mL / kg.
  • mice were intragastrically administered 0.1 mL of blood before and after 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, and 24.0 hours of blood collection, placed in K2-EDTA anticoagulation tubes, and centrifuged at 3500 rpm for 10 minutes to separate Plasma was stored at -20 ° C.
  • Determining the content of test compounds in mouse plasma after oral administration of drugs at different concentrations Take 20 uL of mouse plasma at each time after administration, add internal standards to contain propranolol, tolbutamide (100ng / each mL) of acetonitrile solution 200uL, vortexed for 5 minutes, centrifuged for 12 minutes (4000 rpm), plasma samples were taken 5uL of the supernatant for LC / MS / MS analysis.
  • the pharmacokinetic parameters of the compounds of the invention are as follows:

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Abstract

本发明涉及CSF1R抑制剂，具体涉及一种高活性的CSF1R抑制剂化合物，所述化合物具有式(I)结构，本发明的化合物对CSF1R具有高的抑制活性。

Description

一种高活性CSF1R抑制剂化合物
本申请要求于2018年06月01日提交中国专利局、申请号为201810559228.2、发明名称为“一种高活性CSF1R抑制剂化合物”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。
技术领域
本发明涉及杂环化合物，具体地涉及一种高活性的CSF1R抑制剂及其用途。
背景技术
CSF1R(colony stimulating factor 1 receptor)是巨噬细胞分化和募集过程中重要的细胞因子，由肿瘤细胞分泌。研究结果表明CSF1R抑制剂(抗体或小分子)可以降低肿瘤组织TAM(tumor-associated macrophages)浸润，有效抑制肿瘤的进展和转移，是肿瘤免疫治疗中一个新的热点。
由于其在破骨细胞生物学中的作用，CSF1R被认为是骨质疏松症和炎性关节炎的重要治疗靶标。例如，提高的M-CSF信号导致了升高的破骨细胞活性，这导致了伴随关节炎和其它炎性骨质侵蚀的骨丢失(参见Scott等人Rheumatology 2000,39:122-132,Ritchlin等人J.Clin.Invest.2003,111:821-831)。因此，CSF1R的抑制代表了对关节炎和其它炎性骨质侵蚀的具有前景的治疗方案，已知CSF1R抑制剂如Ki-20227和GW2580在关节炎动物模型中的效力数据进一步支持 了这一点(参见Conwat等人JPET 2008,326:41-50和Ohno等人Eur.J.Immunol.2008,38:283-291)。导致骨质疏松症的破骨细胞发育的调节异常以及骨质侵蚀和骨生成之间平衡的破坏也可能通过对CSF1R的调节进行治疗。
诺华科学家在自然杂志上报道，临床前期研究表明在小鼠胶质瘤模型中，抑制CSF1R(BLZ945)可导致肿瘤体积迅速减小，生存期明显延长，这种抑制CSF1R的作用并未杀死肿瘤相关巨噬细胞，而是将它们重新转化到抗肿瘤的状态中，在宫颈癌和乳腺癌模型中也见到了类似的结果。CSF1R的小分子抑制剂亦可有效增强机体对化疗的敏感性。Five Prime(与BMS合作开发CSF1R抑制剂)在胰腺癌小鼠模型研究发现，利用CSF1R抑制剂可以与免疫检查点抑制剂联合用药有协同增效作用，明显抑制小鼠胰腺肿瘤的生长。
目前进入临床的CSF1R抗体药物有BMS/FPRX的FPA008，罗氏的emactuzumab，礼来的LY3022855，安进的AMG820等，进入临床的CSF1R小分子药物有BLZ945，Plexxikon的PLX3397，Deciphera的DC-3014等。CSF1R抑制剂与免疫检查点抑制剂的联合用药项目还处于临床早期，国内还没有化合物进入临床申报。对于抑制CSF1R的小分子，特别是可用于治疗CSF1R-介导的疾病的化合物的鉴别存在着持续的需求。
发明内容
本发明提供了一种具有式(I)的化合物或其药学可接受的盐、溶剂化物、水合物、立体异构体、立体异构体混合物或立体异构体外消旋混合物。在某些实施方式中，该化合物具有作为CSF1R抑制剂的活性。需要指出的是，本公开内容在一般性地提及式I化合物时，不必然同时列出以下的一些或全部：其药学可接受的盐、溶剂化物、水合物、立体异构体、立体异构体混合物或立体异构体外消旋混合物。在此情况下，所述式I化合物也涵盖其药学可接受的盐、溶剂化物、水合物、立体异构体、立体异构体混合物和立体异构体外消旋混合物。
Figure PCTCN2019088221-appb-000001
其中，X表示CR aR a’、
Figure PCTCN2019088221-appb-000002
NR a、-C(O)-、O、S、S(O)或S(O) 2；R 1和R 2以及与之相连的碳原子共同环合成为饱和或不饱和的3-12元环烷基或杂环烷基，例如所述3-12元环烷基或杂环烷基可以是3、4、5、6、7、8、9、10、11或12元环，所述的杂环烷基中至少含有一个选自O、N和S原子的杂原子，例如1、2、3或4个杂原子，所述环烷基或者杂环烷基可以任意地被0、1、2、3或4个各自独立地选自下述R 6的取代基所取代：卤素、羟基、C 1-C 8烷基、C 3-C 8环烷基、C 3-C 8杂环烷基、C 2-C 8烯基、C 2-C 8炔基、C 1-C 8卤代烷基、 C 1-C 8烷氧基、C 1-C 8卤代烷氧基、C 3-C 8环烷氧基、C 3-C 8杂环烷氧基、-S-(C 1-C 8)烷基、-S-C 3-C 8环烷基、-S-C 3-C 8杂环烷基、氰基、硝基、-(C 0-C 8)烷基-NR 9R a’、-C＝NR a、-O-Cy 1、-O-(C 0-C 8)烷基-Cy 1、-(C 2-C 8)链烯基-Cy 1、-(C 2-C 8)链炔基-Cy 1、-C(O)OR a、-C(O)R a、-O-C(O)R a、-C(O)-NR aR a’、-NR a-C(O)-R a、-NR a-C(O)-OR a、-(C 1-C 8)烷基-NR a-C(O)R a、-SO 2-NR aR a’和-SO 2R a；
R 3和R 5分别独立地表示氢、卤素、C 1-C 8烷基、C 1-C 8烷氧基、C 3-C 8环烷基、C 3-C 8杂环烷基、卤代C 1-C 8烷基、羟基、氨基、硝基、氰基、-C(O)OR a、-O-C(O)R a、-C(O)-NR aR a’、-NR a-C(O)-R a、-NR a-C(O)-OR a、-(C 1-C 8)烷基-NR a-C(O)R a、-SO 2-NR aR a’或-SO 2R a；
R 4表示Cy 2、-NHC(O)R a、-NHC(O)NR aR a’、-C(O)R a、-C(O)NR aR a’、-S(O) 2R a、-S(O) 2NR aR a’、-NHS(O) 2R a或-NHS(O) 2NR aR a’；
其中，Cy 1和Cy 2分别独立地表示被0、1、2、3或4个取代基独立取代的5-12元环，优选为5-12元芳基或5-12元杂芳基；更优选为5-6元芳基或5-6元杂芳基，其中所述的取代基为卤素、C 1-C 8烷基、C 1-C 8烷氧基、C 3-C 9环烷基、C 3-C 9杂环烷基、卤代C 1-C 8烷基、羟基、硝基、氰基、-C(O)OR a、-O-C(O)R a、-C(O)-NR aR a’、-NR a-C(O)-R a、-NR a-C(O)-OR a、-(C 1-C 8)烷基-NR a-C(O)R a、-SO 2-NR aR a’和-SO 2R a；
其中，所述的R a、R a’独立地表示氢、C 1-C 8烷基、C 3-C 9环烷基、羟基、卤素、氨基、C 1-C 8卤代烷基、C 1-C 8烷基氨基、二C 1-C 8烷基氨基，或者R a、R a’以及与之相连的原子环合成为3-9元环烷基或者杂环烷基，优选为氢、C 1-C 8烷基或C 3-C 8环烷基；
n为1、2或3，优选为1；m和o分别独立地表示0、1、2或3，
对于上述所定义的烷基、环烷基、杂环烷基、芳基、杂芳基，其可以进一步的被选自下述的取代基所取代：C 1-C 8烷基、C 2-C 8烯基、C 2-C 8炔基、C 3-C 8环烷基、5-12元芳基、5-12元杂芳基、C 1-C 8卤代烷基、C 1-C 8烷氧基、C 1-C 8烷基硫基、卤素、羟基、氰基、磺酸基和硝基；
对于上述所定义的取代基中，在不同的取代基中R a具有各自地独立的定义；在不同的取代基中R a’具有各自地独立的定义。
本公开内容中，当提到一些取代基团时使用C x1-C x2的表述，这表示所述取代基团中的碳原子数可以是x1至x2个。例如，C 0-C 8表示所述基团含有0、1、2、3、4、5、6、7或8个碳原子，C 1-C 8表示所述基团含有1、2、3、4、5、6、7或8个碳原子，C 2-C 8表示所述基团含有2、3、4、5、6、7或8个碳原子，C 3-C 8表示所述基团含有3、4、5、6、7或8个碳原子，C 4-C 8表示所述基团含有4、5、6、7或8个碳原子，C 1-C 6表示所述基团含有1、2、3、4、5或6个碳原子。
本公开内容中，当提到环状基团时使用“x1-x2元环”的表述，这表示该基团的环原子数可以是x1至x2个。例如，所述3-12元环烷基或杂环烷基可以是3、4、5、6、7、8、9、10、11或12元环，其环原子数可以是3、4、5、6、7、8、9、10、11或12个；3-6元环表示该环状基团可以是3、4、5或6元环，其环原子数可以是3、4、5或6个；3-9元环表示该环状基团可以是3、4、5、6、7、8或9元 环，其环原子数可以是3、4、5、6、7、8或9个；5-12元环表示该环状基团可以是5、6、7、8、9、10、11或12元环，其环原子数可以是5、6、7、8、9、10、11或12个。所述环原子可以是碳原子或杂原子，例如选自N、O和S的杂原子。当所述环是杂环时，所述杂环可以含有1、2、3、4、5、6、7、8、9、10或更多个环杂原子，例如选自N、O和S的杂原子。
本公开内容中，一个或更多个卤素可以各自独立地选自氟、氯、溴和碘。
在本发明的一个优选实施方案中，R 1和R 2以及与之相连的碳原子共同环合成为饱和或不饱和的3-6元环烷基或杂环烷基，所述的杂环烷基中至少含有一个选自O、N和S原子的杂原子，该环烷基或杂环烷基可以任意地被0、1、2、3或4个各自独立地选自下述R 6的取代基所取代，其中R 6如上述所定义。
在本发明的一个优选实施方案中，R 1和R 2以及与之相连的碳原子共同形成的环选自如下结构：
Figure PCTCN2019088221-appb-000003
Figure PCTCN2019088221-appb-000004
其中，R c选自氢、C 1-C 6烷基、C 3-C 8环烷基、-C(O)R a、-C(O)OR a、-C(O)-NR aR a’、-SO 2-NR aR a’和-SO 2R a；*表示R 1和R 2以及与之相连的碳原子的结合位点，并且上述基团可以任选地被0、1、2、3、4个各自独立地选自下述R 6的取代基所取代，其中R a、R a’以及R 6具有如上述所定义。
在本发明的一个优选实施方案中，X选自CR aR a’、NR a、O和S，优选为O；其中，R a、R a’选自氢、C 1-C 8烷基、C 3-C 8环烷基、羟基、卤素、C 1-C 8卤代烷基、C 1-C 8烷基氨基、二C 1-C 8烷基氨基，或者R a、R a’以及与之相连的原子环合成为3-9元环烷基或者杂环烷基，优选为氢、卤素或C 1-C 8烷基。
在本发明的一个优选实施方案中，R 4优选为Cy 2、-NHC(O)R a、-C(O)NR aR a’或-NHC(O)NR aR a’，其中Cy 2、R a、R a’如上述所定义。
在本发明的一个优选实施方案中，Cy 2选自苯基、吡啶基、吡嗪基、环丙基、环戊基、环己基、呋喃基、噻唑基、哌啶基、哌嗪基、噁唑基、咪唑基或噻吩基；其中Cy 2更优选为吡唑基、咪唑基、噁唑基、噻唑基、苯基或吡啶基；并且所述Cy 2可以任选地被C 1-C 8烷基、C 1-C 8烷氧基、C 3-C 9环烷基、C 3-C 9杂环基、C 1-C 8卤代烷基、卤素、 氰基、磺酸基、硝基或羟基所取代。
在本发明的一个优选实施方案中，R a和R a’优选为氢、卤素或C 1-C 8烷基。
在本发明的一个实施方案中，其中所述式I化合物优选地选自具有以下结构的化合物：
Figure PCTCN2019088221-appb-000005
Figure PCTCN2019088221-appb-000006
Figure PCTCN2019088221-appb-000007
Figure PCTCN2019088221-appb-000008
Figure PCTCN2019088221-appb-000009
本发明的化合物也可制备成可药用盐的形式，所述可药用盐可使用例如以下的无机酸或有机酸而形成：盐酸、氢溴酸、硫酸、磷酸、硝酸、乙酸、乙醇酸、乳酸、丙酮酸、丙二酸、琥珀酸、戊二酸、富马酸、苹果酸、扁桃酸、酒石酸、柠檬酸、抗坏血酸、棕榈酸、马来酸、羟基马来酸、苯甲酸、羟基苯甲酸、苯乙酸、肉桂酸、水杨酸、甲磺酸、苯磺酸或甲苯磺酸。
本发明的可药用盐可通过常规方法制备，例如通过将本发明的化合物溶解于与水可混溶的有机溶剂(例如丙酮、甲醇、乙醇和乙腈)，向其中添加过量的有机酸或无机酸水溶液，以使得盐从所得混合物中沉淀，从中除去溶剂和剩余的游离酸，然后分离所沉淀的盐。
本发明化合物或其可药用盐可包括其水合物和溶剂化物。
本发明还提供了本发明化合物在制备用于预防和/或治疗癌症、肿瘤、炎症性疾病、自身免疫性疾病或免疫介导性疾病的药物中的用途。
此外，本发明提供了用于预防和/或治疗癌症、肿瘤、炎症性疾病、自身免疫性疾病、神经退行性疾病、注意力相关疾病或免疫介导性疾病的药物组合物，其包含本发明化合物作为活性成分。
本发明还提供一种抑制CSF1R的方法，其包括使本发明的化合物或其药学可接受的盐或者包含本发明化合物或其药学可接受的盐的药物组合物暴露于所述CSF1R。
本发明还提供一种预防和/或治疗可通过抑制CSF1R预防和/或治疗之疾病的方法，其包括向有此需要的对象施用本发明的化合物或其药学可接受的盐或者包含本发明化合物或其药学可接受的盐的药物组合物。
此外，本发明提供了一种用于预防和/或治疗癌症、肿瘤、炎症性疾病、自身免疫性疾病、神经退行性疾病、注意力相关疾病或免疫介导性疾病的方法，其包括向有此需要的哺乳动物施用本发明化合物。
炎症性疾病、自身免疫性疾病和免疫介导性疾病的代表性实例可包括但不限于，关节炎、类风湿性关节炎、脊柱关节炎、痛风性关节炎、骨关节炎、幼年型关节炎、其他关节炎性病症、狼疮、系统性红斑狼疮(SLE)、皮肤相关疾病、银屑病、湿疹、皮炎、过敏性皮肤 炎、疼痛、肺病、肺部炎症、成人呼吸窘迫综合征(ARDS)、肺结节病、慢性肺部炎症性疾病、慢性阻塞性肺病(COPD)、心血管疾病、动脉粥样硬化、心肌梗塞、充血性心力衰竭、心肌缺血再灌注损伤、炎性肠病、克罗恩病、溃疡性结肠炎、肠易激综合征、哮喘、干燥综合征、自身免疫甲状腺疾病、荨麻疹(风疹)、多发性硬化、硬皮症、器官移植排斥、异种移植、特发性血小板减少性紫癜(ITP)、帕金森病、阿尔兹海默病、糖尿病相关疾病、炎症、盆腔炎性疾病、过敏性鼻炎、过敏性支气管炎、过敏性鼻窦炎、白血病、淋巴瘤、B细胞淋巴瘤、T细胞淋巴瘤、骨髓瘤、急性淋巴性白血病(ALL)、慢性淋巴性白血病(CLL)、急性髓性白血病(AML)、慢性髓性白血病(CML)、毛细胞白血病、何杰金氏病、非何杰金淋巴瘤、多发性骨髓瘤、骨髓增生异常综合征(MDS)、骨髓增生性肿瘤(MPN)、弥漫性大B细胞淋巴瘤和滤泡性淋巴瘤。
癌症或肿瘤的代表性实例可包括但不限于，皮肤癌、膀胱癌、卵巢癌、乳腺癌、胃癌、胰腺癌、前列腺癌、结肠癌、肺癌、骨癌、脑癌、神经细胞瘤、直肠癌、结肠癌、家族性腺瘤性息肉性癌、遗传性非息肉性结直肠癌、食管癌、唇癌、喉癌、下咽癌、舌癌、唾液腺癌、胃癌、腺癌、甲状腺髓样癌、乳头状甲状腺癌、肾癌、肾实质癌、卵巢癌、宫颈癌、子宫体癌、子宫内膜癌、绒毛膜癌、胰腺癌、前列腺癌、睾丸癌、泌尿癌、黑素瘤、脑肿瘤诸如成胶质细胞瘤、星形细胞瘤、脑膜瘤、成神经管细胞瘤和外周神经外胚层肿瘤、霍奇金淋巴瘤、 非霍奇金淋巴瘤、伯基特淋巴瘤、急性淋巴性白血病(ALL)、慢性淋巴性白血病(CLL)、急性骨髓性白血病(AML)、慢性粒细胞白血病(CML)、成人T细胞白血病淋巴瘤、弥漫性大B细胞淋巴瘤(DLBCL)、肝细胞癌、胆囊癌、支气管癌、小细胞肺癌、非小细胞肺癌、多发性骨髓瘤、基底细胞瘤、畸胎瘤、成视网膜细胞瘤、脉络膜黑素瘤、精原细胞瘤、横纹肌肉瘤、颅咽管瘤、骨肉瘤、软骨肉瘤、肌肉瘤、脂肪肉瘤、纤维肉瘤、尤因肉瘤或浆细胞瘤。
当将本发明化合物或其可药用盐与另外的用于治疗癌症或肿瘤的抗癌剂或免疫检查点抑制剂组合施用时，本发明化合物或其可药用盐可提供增强的抗癌作用。
用于治疗癌症或肿瘤的抗癌剂的代表性实例可包括但不限于细胞信号转导抑制剂、苯丁酸氮芥、美法仑、环磷酰胺、异环磷酰胺、白消安、卡莫司汀、洛莫司汀、链脲佐菌素、顺铂、卡铂、奥沙利铂、达卡巴嗪、替莫唑胺、丙卡巴肼、甲氨蝶呤、氟尿嘧啶、阿糖胞苷、吉西他滨、巯基嘌呤、氟达拉滨、长春碱、长春新碱、长春瑞滨、紫杉醇、多西紫杉醇、拓扑替康、伊立替康、依托泊苷、曲贝替定、更生霉素、多柔比星、表柔比星、道诺霉素、米托蒽醌、博来霉素、丝裂霉素C、伊沙匹隆、他莫昔芬、氟他胺、戈那瑞林类似物、甲地孕酮、强的松、地塞米松、甲泼尼龙、沙利度胺、干扰素α、亚叶酸钙、西罗莫司、西罗莫司脂化物、依维莫司、阿法替尼、alisertib、amuvatinib、阿帕替尼、阿西替尼、硼替佐米、波舒替尼、布立尼布、卡博替尼、 西地尼布、crenolanib、克卓替尼、达拉菲尼、达可替尼、达努塞替、达沙替尼、多维替尼、厄洛替尼、foretinib、ganetespib、吉非替尼、依鲁替尼、埃克替尼、伊马替尼、iniparib、拉帕替尼、lenvatinib、linifanib、linsitinib、马赛替尼、momelotinib、莫替沙尼、来那替尼、尼罗替尼、niraparib、oprozomib、olaparib、帕唑帕尼、pictilisib、普纳替尼、quizartinib、瑞格菲尼、rigosertib、rucaparib、鲁索利替尼、塞卡替尼、saridegib、索拉非尼、舒尼替尼、替拉替尼、tivantinib、替沃扎尼、托法替尼、曲美替尼、凡德他尼、维利帕尼、威罗菲尼、维莫德吉、volasertib、阿仑单抗、贝伐单抗、贝伦妥单抗维多汀、卡妥索单抗、西妥昔单抗、地诺单抗、吉妥珠单抗、伊匹单抗、尼妥珠单抗、奥法木单抗、帕尼单抗、利妥昔单抗、托西莫单抗、曲妥珠单抗；IDO抑制剂、抗PD-1抗体、抗PD-L1抗体、LAG3抗体、TIM-3抗体以及抗CTLA-4抗体或它们的任意组合。
当将本发明化合物或其可药用盐与另外的用于治疗炎症性疾病、自身免疫性疾病和免疫介导性疾病的治疗剂组合施用时，本发明化合物或其可药用盐可提供增强的治疗作用。
用于治疗炎症性疾病、自身免疫性疾病和免疫介导性疾病的治疗剂的代表性实例可包括但不限于，甾体药物(例如，强的松、氢化波尼松、甲基氢化波尼松、可的松、羟基可的松、倍他米松、地塞米松等)、甲氨蝶呤、来氟米特、抗TNFα剂(例如，依那西普、英夫利昔单抗、阿达利单抗等)、钙调神经磷酸酶抑制剂(例如，他克莫司、 吡美莫司等)和抗组胺药(例如，苯海拉明、羟嗪、氯雷他定、依巴斯汀、酮替芬、西替利嗪、左西替利嗪、非索非那定等)，并且选自其中的至少一种治疗剂可包含于本发明药物组合物中。
本发明的化合物或其可药用盐可作为活性成分通过口服或肠胃外施用，其有效量的范围为在哺乳动物包括人(体重约70kg)的情况下0.1至2,000mg/kg体重/天、优选1至1,000mg/kg体重/天，并且每天以单次或4次分次剂量，或者遵循/不遵循预定时间施用。活性成分的剂量可根据多个相关因素(例如待治疗对象的情况、疾病类型和严重性、施用速率和医生意见)进行调整。在某些情况下，小于以上剂量的量可能是合适的。如果不引起有害的副作用则可使用大于以上剂量的量并且该量可以每天以分次剂量施用。
可根据常规方法中的任何一种将本发明药物组合物配制成用于口服施用或肠胃外施用(包括肌内、静脉内和皮下途径)的剂型，例如片剂、颗粒、粉末、胶囊、糖浆、乳剂、微乳剂、溶液或混悬液。
用于口服施用的本发明药物组合物可通过将活性成分与例如以下的载体混合来制备：纤维素、硅酸钙、玉米淀粉、乳糖、蔗糖、右旋糖、磷酸钙、硬脂酸、硬脂酸镁、硬脂酸钙、明胶、滑石、表面活性剂、助悬剂、乳化剂和稀释剂。在本发明的注射组合物中采用的载体的实例是水、盐溶液、葡萄糖溶液、葡萄糖样溶液(glucose-like solution)、醇、二醇、醚(例如，聚乙二醇400)、油、脂肪酸、脂肪酸酯、甘油酯、表面活性剂、助悬剂和乳化剂。
本发明描述示例性实施方案的过程中，本发明的其它特征将变得显而易见，给出所述实施方案用于说明本发明而不意欲成为其限制，以下实施例使用本发明所公开的方法制备、分离和表征。
[根据细则91更正 19.11.2019]　
可以用有机合成领域的技术人员已知的多种方式来制备本发明的化合物，可使用下述方法以及有机合成化学领域中已知的合成方法或通过本领域技术人员所了解的其变化形式来合成本发明化合物。优选方法包括但不限于下文所述的这些。在适用于所使用试剂盒材料和适用于所实现转变的溶剂或溶剂混合物中实施反应。有机合成领域的技术人员将理解，分子上存在的官能性与所提出的转变一致。这有时需要加以判断改变合成步骤的顺序或原料以获得期望的本发明化合物。
附图说明
图1为实施例化合物1的药效结果图。
图2为实施例化合物4的药效结果图。
具体实施方式
术语
如果无另外说明，用于本发明申请，包括说明书和权利要求书中的术语，定义如下。必须注意，在说明书和所附的权利要求书中，如果文中无另外清楚指示，单数形式“一个”包括复数意义。如果无另外说明，使用质谱、核磁、HPLC、蛋白化学、生物化学、重组DNA技术和药理的常规方法。在本申请中，如果无另外说明，使用“或”或“和”指“和/或”。
在说明书和权利要求书中，给定化学式或名称应涵盖所有立体和 光学异构体及其中存在上述异构体的外消旋物。除非另外指明，否则所有手性(对映异构体和非对映异构体)和外消旋形式均在本发明范围内。所述化合物中还可存在C＝C双键、C＝N双键、环系统等的许多几何异构体，且所有上述稳定异构体均涵盖于本发明内。本发明描述了本发明化合物的顺式-和反式-(或E-和Z-)几何异构体，且其可分离成异构体的混合物或分开的异构体形式。本发明化合物可以光学活性或外消旋形式加以分离。用于制备本发明化合物和其中制备的中间体的所有方法均视为本发明的部分。在制备对映异构体或非对映异构体产物时，其可通过常规方法(例如通过色谱或分段结晶)进行分离。取决于方法条件，以游离(中性)或盐形式获得本发明的终产物。这些终产物的游离形式和盐均在本发明的范围内。如果需要的话，则可将化合物的一种形式转化成另一种形式。可将游离碱或酸转化成盐；可将盐转化成游离化合物或另一种盐；可将本发明异构体化合物的混合物分离成单独的异构体。本发明化合物、其游离形式和盐可以多种互变异构体形式存在，其中氢原子转置到分子的其它部分上且由此分子的原子之间的化学键发生重排。应当理解的是，可存在的所有互变异构体形式均包括在本发明内。
除非另有定义，本发明的取代基的定义是各自独立而非互相关联的，例如对于取代基中R a(或者R a’)而言，其在不同的取代基的定义中是各自独立的。具体而言，对于R a(或者R a’)在一种取代基中选择一种定义时，并不意味着该R a(或者R a’)在其他取代基中都具有该相同的定义。更具体而言，例如(仅列举非穷举)对于NR aR a’ 中，当R a(或者R a’)的定义选自氢时，其并不意味着在-C(O)-NR aR a’中，R a(或者R a’)必然为氢。
除非另有定义，否则当取代基被标注为“任选取代的”时，所述取代基选自例如以下取代基，诸如烷基、环烷基、芳基、杂环基、卤素、羟基、烷氧基、氧代、烷酰基、芳基氧基、烷酰基氧基、氨基、烷基氨基、芳基氨基、芳基烷基氨基、二取代的胺基团(其中2个氨基取代基选自烷基、芳基或芳基烷基)、烷酰基氨基、芳酰基氨基、芳烷酰基氨基、取代的烷酰基氨基、取代的芳基氨基、取代的芳烷酰基氨基、硫基、烷基硫基、芳基硫基、芳基烷基硫基、芳基硫羰基、芳基烷基硫羰基、烷基磺酰基、芳基磺酰基、芳基烷基磺酰基、磺酰氨基例如-SO 2NH 2、取代的磺酰氨基、硝基、氰基、羧基、氨基甲酰基例如-CONH 2、取代的氨基甲酰基例如-CONH烷基、-CONH芳基、-CONH芳基烷基或在氮上具有两个选自烷基、芳基或芳基烷基的取代基的情况、烷氧基羰基、芳基、取代的芳基、胍基、杂环基，例如吲哚基、咪唑基、呋喃基、噻吩基、噻唑基、吡咯烷基、吡啶基、嘧啶基、吡咯烷基、哌啶基、吗啉基、哌嗪基、高哌嗪基等和取代的杂环基。
本文使用的术语“烷基”或“亚烷基”意欲包括具有指定碳原子数的支链和直链饱和脂族烃基团。例如，“C1-C8烷基”表示具有1个至8个碳原子的烷基。本说明书中的C1-C8烷基优选为C1-C6烷基，更优选为C1-C4烷基。烷基的实例包括但不限于甲基(Me)、乙基(Et)、丙基(例如正丙基和异丙基)、丁基(例如正丁基、异丁基、叔丁基)和 戊基(例如正戊基、异戊基、新戊基)。
术语“烯基”表示含一个或多个双键且通常长度为2至20个碳原子的直链或支链的烃基。例如，“C2-C8烯基”含有两个至八个碳原子。本说明书中的C2-C8烯基优选为C2-C6烯基，更优选为C2-C4烯基。烯基包括但不限于例如乙烯基、丙烯基、丁烯基、1-甲基-2-丁烯-1-基、庚烯基、辛烯基等。
术语“炔基”表示含一个或多个三键且通常长度为2至20个碳原子的直链或支链的烃基。例如，“C2-C8炔基”含有两个至八个碳原子。本说明书中的C2-C8炔基优选为C2-C6炔基，更优选为C2-C4炔基。代表性炔基包括但不限于例如乙炔基、1-丙炔基、1-丁炔基、庚炔基、辛炔基等。
术语“烷氧基”或“烷基氧基”是指-O-烷基。“C1-C8烷氧基”(或烷基氧基)意欲包括C1、C2、C3、C4、C5、C6、C7和C8烷氧基。本说明书中的C1-C8烷氧基优选为C1-C6烷氧基，更优选为C1-C4烷氧基。烷氧基的实例包括但不限于甲氧基、乙氧基、丙氧基(例如正丙氧基和异丙氧基)和叔丁氧基。类似地，“烷基硫基”或“硫代烷氧基”表示具有指定数量碳原子的经硫桥连接的如上文所定义的烷基；例如甲基-S-和乙基-S-。
术语“羰基”是指由碳和氧两种原子通过双键连接而成的有机官能团(C＝O)。
术语“芳基”，单独或作为较大部分诸如“芳烷基”、“芳烷氧基”或“芳基氧基烷基”的部分，是指具有总计5至12个环成员的单环、二 环或三环的环系统，其中所述系统中的至少一个环为芳族的且其中所述系统中的每个环含有3至7个环成员。在本发明的某些实施方案中，“芳基”是指芳族环系统，其包括但不限于苯基、联苯基、茚满基、1-萘基、2-萘基和四氢萘基。术语“芳烷基”或“芳基烷基”是指连接至芳基环的烷基残基。非限制性实例包括苄基、苯乙基等。稠合的芳基可在环烷基环或芳族环的合适位置上连接至另一基团。例从环系统中画出的箭头线表明键可连接至任意合适的环原子。
术语“环烷基”是指单环或二环的环状烷基。单环的环状烷基指C3-C8的环状烷基，优选C3-C6的环状烷基，包括但不限于环丙基、环丁基、环戊基、环己基和降莰烷基。支化环烷基诸如1-甲基环丙基和2-甲基环丙基包括在“环烷基”的定义中。二环的环状烷基包括桥环、螺环或融合环的环烷基。
术语“环烯基”是指单环或二环的环状烯基。单环的环状烯基指C3-C8的环状烯基，优选C3-C6的环状烯基，包括但不限于环丙烯基、环丁烯基、环戊烯基、环己烯基和降莰烯基。支化环烯基诸如1-甲基环丙烯基和2-甲基环丙烯基包括在“环烯基”的定义中。二环的环状烯基包括桥环、螺环或融合环的环状烯基。
“卤代”或“卤素”包括氟、氯、溴和碘。“卤代烷基”意欲包括具有指定碳原子数且取代有1个或多个卤素的支链和直链饱和脂族烃基团。卤代烷基的实例包括但不限于氟甲基、二氟甲基、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。卤代烷基的实例还包括意欲包括具有指定碳原子数且取代有1个 或多个氟原子的支链和直链饱和脂族烃基团的“氟烷基”。
“卤代烷氧基”或“卤代烷基氧基”表示具有指定数量碳原子的经氧桥连接的如上文所定义的卤代烷基。例如，“C1-C8卤代烷氧基”意欲包括C1、C2、C3、C4、C5、C6、C7和C8卤代烷氧基。卤代烷氧基的实例包括但不限于三氟甲氧基、2,2,2-三氟乙氧基和五氟乙氧基。类似地，“卤代烷基硫基”或“硫代卤代烷氧基”表示具有指定数量碳原子的经硫桥连接的如上文所定义的卤代烷基；例如三氟甲基-S-和五氟乙基-S-。
术语“芳基”指的是单环或二环(及二环以上)的全为碳原子的芳香基。单环的芳香基指的是苯基，二环及二环以上的芳香基指萘基、蒽基等，同时此芳基二环也可为苯环融合了一个环烷基、或融合一个环烯基、或融合一个环炔基。
术语“芳杂基”、“芳杂环”、“芳杂环基”或“芳杂环基团”意指稳定的3元、4元、5元、6元、或7元芳香单环或芳香二环或7元、8元、9元、10元、11元、12元、13元或14元芳香多环杂环，其为完全不饱和的、部分不饱和的，且其含有碳原子和1个、2个、3个或4个独立地选自N、O和S的杂原子；且包括任何以下多环基团，其中上文所定义的任意杂环与苯环稠合。氮和硫杂原子可任选地被氧化。氮原子为取代的或未取代的(即N或NR，其中R为H或如果被定义，则为另一取代基)。杂环可在得到稳定结构的任何杂原子或碳原子处连接至其侧基。如果所得化合物是稳定的，则本文所述的杂环基可在碳或氮原子上被取代。杂环中的氮可任选地被季铵化。优选地，当杂 环中S和O原子的总数超过1时，则这些杂原子彼此不相邻。优选地，杂环中S和O原子的总数不大于1。当使用术语“杂环”时，其意欲包括杂芳基。芳杂环的实施例包括但不限于吖啶基、氮杂环丁基、吖辛因基、苯并咪唑基、苯并呋喃基、苯并硫代呋喃基、苯并噻吩基、苯并噁唑基、苯并噁唑啉基、苯并噻唑基、苯并三唑基、苯并四唑基、苯并异噁唑基、苯并异噻唑基、苯并咪唑啉基、咔唑基、4aH-咔唑基、咔啉基、色满基、色烯基、噌啉基、十氢喹啉基、2H,6H-1,5,2-二噻嗪基、二氢呋喃并[2,3-b]四氢呋喃基、呋喃基、呋咱基、咪唑烷基、咪唑啉基、咪唑基、1H-吲唑基、咪唑并吡啶基、假吲哚基(indolenyl)、二氢吲哚基、吲嗪基、吲哚基、3H-吲哚基、靛红酰基(isatinoyl)、异苯并呋喃基、异色满基、异吲唑基、异二氢吲哚基、异吲哚基、异喹啉基、异噻唑基、异噻唑并吡啶基、异噁唑基、异噁唑并吡啶基、亚甲基二氧基苯基、吗啉基、二氮杂萘基、八氢异喹啉基、噁二唑基、1,2,3-噁二唑基、1,2,4-噁二唑基、1,2,5-噁二唑基、1,3,4-噁二唑基、噁唑烷基、噁唑基、噁唑并吡啶基、噁唑烷基、萘嵌间二氮杂苯基、羟吲哚基、嘧啶基、菲啶基、菲咯啉基、吩嗪基、吩噻嗪基、吩噁噻基、吩噁嗪基、酞嗪基、哌嗪基、哌啶基、哌啶酮基、4-哌啶酮基、胡椒基、喋啶基、嘌呤基、吡喃基、吡嗪基、吡唑烷基、吡唑啉基、吡唑并吡啶基、吡唑基、哒嗪基、吡啶并噁唑基、吡啶并咪唑基、吡啶并噻唑基、吡啶基、嘧啶基、吡咯烷基、吡咯啉基、2-吡咯烷酮基、2H-吡咯基、吡咯基、喹唑啉基、喹啉基、4H-喹嗪基、喹喔啉基、奎宁环基、四唑基、四氢呋喃基、四氢异喹啉基、四氢喹啉基、6H-1,2,5- 噻二嗪基、1,2,3-噻二唑基、1,2,4-噻二唑基、1,2,5-噻二唑基、1,3,4-噻二唑基、噻蒽基、噻唑基、噻吩基、噻唑并吡啶基、噻吩并噻唑基、噻吩并噁唑基、噻吩并咪唑基、噻吩基、三嗪基、1,2,3-三唑基、1,2,4-三唑基、1,2,5-三唑基、1,3,4-三唑基和呫吨基、喹啉基、异喹啉基、酞嗪基、喹唑啉基、吲哚基、异吲哚基、二氢吲哚基、1H-吲唑基、苯并咪唑基、1,2,3,4-四氢喹啉基、1,2,3,4-四氢异喹啉基、5,6,7,8-四氢-喹啉基、2,3-二氢-苯并呋喃基、色满基、1,2,3,4-四氢-喹喔啉基和1,2,3,4-四氢-喹唑啉基。本发明还包括含有例如上述杂环的稠环和螺环化合物。
本文使用的术语“杂环烷基”指的是一个单环杂环烷基体系，或为一个二环杂环烷基体系，同时还包括螺杂环或桥杂环烷基。单环的杂环烷基指的是3-8元、且至少含一个选自O、N、S、P的饱和或不饱和但不为芳香性的环状烷基体系。二环杂环烷基体系指的是一个杂环烷基融合到一个苯基、或一个环烷基、或一个环烯基、或一个杂环烷基、或一个杂芳基。
本文使用的术语“桥环烷基”指的是共用两个或两个以上碳原子的多环化合物。可分为二环桥环烃及多环桥环烃。前者由两个脂环共用两个以上碳原子所构成；后者是由三个以上的环组成的桥环烃。
本文使用的术语“螺环烷基”指的是单环之间共用一个碳原子(称螺原子)的多环烃。
本文使用的术语“桥环杂基”指的是共用两个或两个以上碳原子的多环化合物，该环中至少含一个选自O、N、S原子。可分为二环 桥环杂环及多环桥杂环。
本文使用的术语“杂螺环基”指的是单环之间共用一个碳原子(称螺原子)的多环烃，该环中至少含一个选自O、N、S原子。
本文中所用的术语“取代”意指至少一个氢原子被非氢基团替代，条件是维持正常化合价且所述取代得到稳定的化合物。本文所用的环双键为在两个相邻环原子之间形成的双键(例如C＝C、C＝N或N＝N)。
在本发明化合物上存在氮原子(例如胺)的情形下，可通过使用氧化剂(例如mCPBA和/或过氧化氢)进行处理来将这些氮原子转化成N-氧化物以获得本发明的其它化合物。因此，所显示和要求保护的氮原子视为均涵盖所显示氮及其N-氧化物以获得本发明衍生物。
当任何变量在化合物的任何组成或式中出现一次以上时，其每次出现时的定义均独立于其在其它每种情况下出现时的定义。因此，例如如果显示基团取代有0-3个R，则所述基团可任选地取代有至多三个R基团，且在每次出现时R独立地选自R的定义。此外，取代基和/或变量的组合仅在上述组合可产生稳定的化合物时才容许存在。
术语“溶剂化物”意指本发明化合物与一个或多个溶剂分子(无论有机的还是无机的)的物理缔合。该物理缔合包括氢键。在某些情形中，例如当一个或多个溶剂分子纳入结晶固体的晶格中时，溶剂化物将能够被分离。溶剂化物中的溶剂分子可按规则排列和/或无序排列存在。溶剂化物可包含化学计量或非化学计量的溶剂分子。“溶剂合物”涵盖溶液相和可分离的溶剂化物。示例性溶剂化物包括但不限于 水合物、乙醇合物、甲醇合物和异丙醇合物。溶剂化方法是本领域公知的。
本文使用的术语“患者”是指通过本发明的方法进行治疗的有机体。这类有机体优选包括但不限于哺乳动物(例如鼠类、猿/猴、马、牛、猪、犬、猫等)且最优选是指人类。
本文使用的术语“有效量”意指将会引起例如研究人员或临床医师所寻求的组织、系统、动物或人的生物学或医学响应的药物或药剂(即本发明化合物)的量。此外，术语“治疗有效量”意指这样的量：与未接受上述量的相应受试者相比，所述量导致改善的治疗、治愈、预防或减轻疾病、病症或副作用，或降低在疾病或病症的进展速度。有效量可以一个或多个给药、施用或剂量给予且不意欲被特定的制剂或给药途径限制。该术语还包括在其范围内的增强正常生理机能的有效量。
本文使用的术语“治疗”包括导致改善病症、疾病、障碍等的任何效果，例如减轻、减少、调节、改善或消除，或改善其症状。
本文使用的术语“药物组合物”是指活性剂与惰性或活性的载体的组合，使得所述组合物尤其适用于体内或离体诊断或治疗。碱的实例包括但不限于碱金属(例如钠)氢氧化物、碱土金属(例如镁)氢氧化物、氨等。对于治疗用途，本发明化合物的盐对于治疗用途，本发明化合物的盐预期为是药用的。然而，非药用的酸和碱的盐也可用于例如药用化合物的制备或纯化中。
术语“药用”在本文中用于指如下那些化合物、物质、组合物和/ 或剂型：在合理医学判断的范围内，其适于与人类和动物的组织接触使用而无过高毒性、刺激性、过敏反应和/或其它问题或并发症，并与合理的益处/风险比相称。
本文使用的短语“药用载体”意指药用物质、组合物或媒介物，诸如液体或固体填充剂、稀释剂、赋形剂、制造助剂(例如润滑剂、滑石、硬脂酸镁、硬脂酸钙或硬脂酸锌或硬脂酸)或溶剂包囊物质，其涉及将主题化合物从一个器官或身体的部分携带或运送至另一个器官或身体的部分。每种载体在与制剂的其它成分相容和对患者无害的意义上必须是“可接受的”。
术语“药物组合物”意指包含本发明化合物与至少一种其它药用载体的组合物。“药用载体”是指本领域中通常接受用于将生物活性剂递送至动物(具体为哺乳动物)的介质，包括(即)佐剂、赋形剂或媒介物，诸如稀释剂、防腐剂、填充剂、流动调控剂、崩解剂、润湿剂、乳化剂、悬浮剂、增甜剂、矫味剂、芳香剂、抗细菌剂、抗真菌剂、润滑剂和分散剂，
这取决于给药模式和剂型的性质。
特定药学及医学术语
术语“可接受的”，如本文所用，指一个处方组分或活性成分对一般治疗目标的健康没有过分的有害影响。
术语“癌症”，如本文所用，指一种不能控制的细胞的异常生长，并且在某种条件下能够转移(传播)。这种类型的癌症包括但不限于， 实体肿瘤(如膀胱、肠、脑、胸、子宫、心脏、肾、肺、淋巴组织(淋巴瘤)、卵巢、胰腺或其它内分泌器官(如甲状腺)、前列腺、皮肤(黑色素瘤)或血液瘤(如非白血性白血病)。
术语“联合给药”或其类似术语，如本文所用，指将几种所选的治疗药物给一个病人用药，以相同或不同的给药方式在相同或不同的时间给药。
术语“增强”或“能增强”，如本文所用，指预期的结果能够在效价或是持续时间方面都有增加或延长。因此，在增强药物的治疗效果方面，术语“能增强”指药物在系统中有提高或延长效价或持续时间的能力。本文所用的“增效值”，指在理想的系统中，能够最大限度地的增强另外一个治疗药物的能力。
术语“免疫性疾病”指对内源性或外源性抗原产生的不良或有害反应的疾病或症状。结果通常会造成细胞的功能障碍、或因此而破坏并造成机能障碍、或破坏可能产生免疫症状的器官或组织。
术语“试剂盒”与“产品包装”是同义词。
术语“受试者”或“病人”包括哺乳动物和非哺乳动物。哺乳动物包括但不限于，哺乳类：人、非人灵长类如猩猩、猿及猴类；农业动物如牛、马、山羊、绵羊、猪；家畜如兔、狗；实验动物包括啮齿类，如大鼠、小鼠及豚鼠等。非哺乳类动物包括但不限于，鸟、鱼等。在一优选例中，所选哺乳动物是人。
术语“治疗”、“治疗过程”或“疗法”如本文所用，包括缓和、抑制或改善疾病的症状或状况；抑制并发症的产生；改善或预防潜在代谢 综合症；抑制疾病或症状的产生，如控制疾病或情况的发展；减轻疾病或症状；使疾病或症状减退；减轻由疾病或症状引起的并发症，或预防和/或治疗由疾病或症状引起的征兆。
如本文所用，某一化合物或药物组合物，给药后，可以使某一疾病、症状或情况得到改善，尤指其严重度得到改善，延迟发病，减缓病情进展，或减少病情持续时间。无论固定给药或临时给药、持续给药或断续给药，可以归因于或与给药有关的情况。
给药途径
适合的给药途径包括但不限于，口服、静脉注射、直肠、气雾剂、非肠道给药、眼部给药、肺部给药、经皮给药、阴道给药、耳道给药、鼻腔给药及局部给药。此外，仅作举例说明，肠道外给药，包括肌肉注射、皮下注射、静脉注射、髓内注射、心室注射、腹膜内注射、淋巴管内注射、及鼻内注射。
在一方面，此处描述的化合物给药方式是局部的而不是全身性的给药方式。在特定的具体实施例中，长效制剂通过植入给药(例如皮下或肌肉)或通过肌肉注射。此外，在另一具体化实施例中，药物通过靶向药物给药系统来给药。例如，由器官特异性抗体包裹的脂质体。在这种具体实施例中，所述脂质体被选择性的导向特定器官并吸收。
药物组合物和剂量
本发明还提供药用组合物，其包含治疗有效量的与一种或多种药 用载体(添加剂)和/或稀释剂一起配制的一种或多种本发明的化合物，和任选的一种或多种上述其它治疗剂。可通过任意合适方式给予本发明化合物以用于任意上述用途，例如口服，诸如片剂、丸剂、粉剂、颗粒剂、酏剂、酊剂、悬浮液(包括纳米悬浮液、微悬浮液、喷雾干燥的分散液)、糖浆和乳液；经舌下；含服；经肠胃外，诸如通过皮下、静脉内、肌内或胸骨内注射或输注技术(例如以无菌可注射水性或非水性溶液或悬浮液形式)；经鼻，包括向鼻膜给药，诸如通过吸入喷雾；局部，诸如以乳膏剂或软膏剂形式；或经直肠，诸如以栓剂形式。它们可单独给药，但通常使用基于所选给药途径和标准药学实践选择的药物载体给药。
根据本领域技术人员认识范围内的诸多因素来调配药用载体。这些因素包括，但不限于：所调配活性剂的类型和性质；含有活性剂的组合物所要给药的受试者；组合物的预期给药途径；及所靶向的治疗适应症。药用载体包括水性和非水性液体介质及各种固体和半固体剂型。
上述载体可包括除活性剂外的诸多不同成分和添加剂，上述其它成分出于本领域技术人员公知的各种原因包括于制剂中，例如稳定活性剂、粘合剂等。关于合适的药用载体和载体选择中所涉及的因素的描述可参见多个容易获得的来源，例如Allen L.V.Jr.et al.Remington:The Science and Practice of Pharmacy(2 Volumes),22nd Edition(2012),Pharmaceutical Press。
当然，本发明化合物的剂量方案取决于已知因素而有所变化，诸 如具体药剂的药效学特性及其给药模式和途径；接受者的物种、年龄、性别、健康状况、医学病状和重量；症状的性质和程度；同时治疗的种类；治疗频率；给药途径、患者的肾和肝功能及期望效应。根据一般指导，当用于指定效应时，各活性成分的日口服剂量应为约0.001mg/天至约10-5000mg/天，优选地为约0.01mg/天至约1000mg/天，且最优选地为约0.1mg/天至约250mg/天。在恒速输注期间，静脉内最优选剂量应为约0.01mg/kg/分钟至约10mg/kg/分钟。本发明化合物可以单一日剂量给药，或可以每日两次、三次或四次的分开剂量给药总日剂量。
所述化合物通常以与根据预期给药形式(例如口服片剂、胶囊剂、酏剂和糖浆剂)适当地选择且与常规药学实践相符合的合适药物稀释剂、赋形剂或载体(在本文中统称为药物载体)的混合物形式进行给药。
适于给药的剂型(药物组合物)可含有约1毫克至约2000毫克活性成分/剂量单位。在这些医药组合物中，以组合物的总重量计，活性成分通常将以约0.1-95重量％的量存在。
用于口服给药的典型胶囊剂含有至少一种本发明化合物(250mg)、乳糖(75mg)和硬脂酸镁(15mg)。使该混合物穿过60目网筛，并包装成1号明胶胶囊。
典型的可注射制剂可如下制备：以无菌方式将至少一种本发明化合物(250mg)置于瓶中、以无菌方式冻干并密封。为进行使用，将瓶内容物与2mL生理盐水混合，以产生可注射制剂。
本发明范围包括(单独或与药物载体组合)包含治疗有效量的至少 一种本发明化合物作为活性成分的药物组合物。任选地，本发明化合物可单独使用、与本发明其它化合物组合使用或与一种或多种其它治疗剂(例如抗癌剂或其它药学活性物质)组合使用。
不考虑所选择的给药路径，通过本领域技术人员已知的常规方法来将本发的化合物(其可以合适的水合形式使用)和/或本发明的药物组合物配制成药用剂量形式。
可改变活性成分在本发明的药物组合物中的实际剂量水平，从而获得对于实现特定患者的期望的治疗响应、组成和给药模式有效的而对患者无毒的活性成分量。
选定的剂量水平会取决于多种因素，包括所用的本发明的特定化合物或其酯、盐或酰胺的活性；给药路径；给药时间；所用的特定化合物的排泄速率；吸收速率和程度；治疗的持续时间；与所用的特定化合物组合使用的其它药物、化合物和/或物质；所治疗的患者的年龄、性别、重量、状况、一般健康和先前的医学史等医学领域公知的因素。
具有本领域普通技术的医生或兽医可容易地确定并开出有效量的所需药物组合物。例如，为了达到所期望的治疗效果，医师或兽医可在低于所需的水平开始药物组合物中所用的本发明化合物的较量，并逐步增加剂量直至实现所期望的效果。通常，合适日剂量的本发明化合物将是有效产生治疗效果的最低剂量的化合物的量。此种有效剂量通常取决于上述因素。通常，口服、静脉内、脑室内和皮下剂量的用于患者的本发明化合物的范围为约0.01至约50mg/kg体重/天。如 果需要的话，有效日剂量的活性化合物可以两个、三个、四个、五个、六个或更多个亚剂量在一天当中的适当的间隔分别给药，任选地呈单位剂型形式。在本发明的某些方面中，服药为每天一次给药。
虽然本发明化合物可单独给药，但优选以药物制剂(组合物)形式给予化合物。
试剂盒/产品包装
为了用于上述适应症的治疗，试剂盒/产品包装也在此进行描述。这些试剂盒可以由输送器、药包或容器盒组成，容器盒可被划分成多格，以容纳一种或多种容器，如管形瓶、试管及类似物等，每个容器中包含所述方法中的单独一种成分。合适的容器包括瓶子，管形瓶，注射器和试管等。容器由可接受的玻璃或塑料等材料制作而成。
举例来讲，容器可装有一种或多种在此所述的化合物，化合物可能以药物组分形式存在，也可能与在本文中所述的其它成分组成混合物体存在。容器可有一个无菌输出口(例如容器可为静脉输液包或瓶，瓶塞可被皮下注射器针头刺破)。这样的试剂盒可带有一种化合物，及本文中所述的使用方法的说明、标签或操作说明。
一个典型的试剂盒可包括一种或多种容器，为适应商业推广和使用者对化合物使用的需求，每个容器装有一种或多种材料(如试剂，也可以是浓缩的母液，和/或器械)。这些材料包括但不局限于缓冲液，稀释液，滤器，针头，注射器，输送器，包，容器，瓶和/或试管，附有内容清单和/或使用说明书，内置包装也附有说明书。整套的说 明都要包括在内。
标签可显示在容器上或与容器紧密相关。标签出现在容器上即指标签字母、数字或其它特征被粘贴、铸模、刻在容器上；标签也可出现在装有多种容器的容器盒或运输盒内，如在产品插页中。一个标签可用来提示内容物的某种特定治疗用途。标签也可标示内容物使用说明，诸如在上述方法中描述的。
在本说明书中被描述的所有特征(包括任何所述的权利要求、摘要和图),和/或任何方法或过程中涉及的所有步骤，均有可能以任意一种组合存在，除非某些特征或步骤在同一组合中是相互排斥的。
本发明提到的上述特征，或实施例提到的特征可以任意组合。本案说明书所揭示的所有特征可与任何组合物形式并用，说明书中所揭示的各个特征，可以任何可提供相同、均等或相似目的的替代性特征取代。因此除有特别说明，所揭示的特征仅为均等或相似特征的一般性例子。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。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。除非另外说明，否则所有的百分数、比率、比例、或份数按重量计。
本发明中的重量体积百分比中的单位是本领域技术人员所熟知的，例如是指在100毫升的溶液中溶质的重量。除非另行定义，文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。 此外，任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。文中所述的较佳实施方法与材料仅作示范之用。
在本发明的优选例中，提供但不局限于以下化合物：
Figure PCTCN2019088221-appb-000010
Figure PCTCN2019088221-appb-000011
Figure PCTCN2019088221-appb-000012
Figure PCTCN2019088221-appb-000013
Figure PCTCN2019088221-appb-000014
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。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。除非另外说明，否则百分比和份数按重量计算。
实施例
当未包括制备途径时，相关中间体是市售的(例如来自Sigma Aldrich,Alfa)。
通用过程
本发明通式I所示化合物可通过如下的方法制得，然而该方法的条件，例如反应物，溶剂，碱，所用化合物的量，反应温度，反应所需时间等不限于下面的解释。本发明化合物还可以任选将在本说明书 中描述的或本领域已知的各种合成方法组合起来而方便的制得，这样的组合可由本发明所属领域的技术人员容易地进行。
反应式A描述了化合物A4的通用合成方法：
Figure PCTCN2019088221-appb-000015
其中X、R 3、R 4、R 5、R 6、m、o具有如上述所定义；p为1、2或3；q为0、1、2、3或4；
其中步骤I和步骤II中的溶剂选自水、甲醇、乙醇、THF、DMF、DMSO、二氯甲烷、氯仿中的一种或其任意组合。
反应式A1描述了化合物A4的另外一个通用合成方法：
Figure PCTCN2019088221-appb-000016
其中X、R 3、R 4、R 5、R 6、m、o具有如上述所定义；p为1、2或3；q为0、1、2、3或4；
其中步骤I’和步骤II’中的溶剂选自水、甲醇、乙醇、THF、DMF、DMSO、二氯甲烷、氯仿中的一种或其任意组合；步骤II’中的碱选自NaOH、NaHCO 3、KOH、KHCO 3、K 2CO 3、三乙胺中的一种或其任意组合。
反应式B描述了化合物A3的通用合成方法：
Figure PCTCN2019088221-appb-000017
其中，p为1、2或3；q为0、1、2、3或4；
其中，步骤I”和步骤II”中的溶剂选自水、甲醇、乙醇、THF、DMF、DMSO、二氯甲烷、氯仿中的一种或其任意组合；步骤I”的反应温度为-100℃至室温，优选为-78℃至室温；
步骤II’中的还原反应所使用的还原剂为H 2、NaBH 4、LiAlH 4，其中还原反应使用的催化剂为雷尼镍、氯化亚铁、氯化钴；步骤II’的反应温度为0℃至室温。
反应式B1描述了化合物A3的通用合成方法：
Figure PCTCN2019088221-appb-000018
其中，p为1、2或3；q为0、1、2、3或4；
其中，步骤I”’和步骤II”’中的有机溶剂选自甲醇、乙醇、THF、DMF、DMSO、二氯甲烷、氯仿中的一种或其任意组合；
步骤II”’中的相转移催化剂为四丁基氟化铵、四丁基溴化铵、四丁基氯化铵；环状冠醚类：例如：18冠6、15冠5、环糊精；
其中，步骤III”’还原反应使用的催化剂为雷尼镍、氯化亚铁、氯化钴；还原剂为H 2、NaBH 4、LiAlH 4。
使用市售试剂而不需进一步纯化。室温是指20-27℃。1H-NMR 谱在Bruker仪器上于400MHz或500MHz记录。化学位移值以百万分率表示，即δ值。以下简写用于NMR信号的多重性：s＝单峰，brs＝宽峰，d＝二重峰，t＝三重峰，m＝多重峰。耦合常数以J值列出，以Hz测量。NMR和质谱结果根据背景峰校正。色谱是指使用100筛目硅胶进行并在氮气压力(快速色谱)条件下完成的柱色谱。用于监测反应的TLC指使用特定流动相和来自Merck的硅胶F254作为固定相进行的TLC。
LC/MS实验在以下条件下测量：
仪器：Thermo U3000,ALLtech ELSD,MSQ，UV检测器结合ELSD和MSD(流出比为4：1)。柱：Waters X-Bridge C-18,3.5μm，4.6x50mm；柱温：30℃。梯度【时间(min)/溶剂B在A中(％)】：0.00/5.0，0.70/95，1.40/95，1.41/5，1.50/5。(溶剂A＝0.01％三氟乙酸在水中；溶剂B＝0.01％三氟乙酸在乙腈中)。UV检测：214/254/280/300nm；DAD检测：200-400nm；流速：4mL/min；MS：ESI，100-1500m/z制备型HPLC通常使用酸性方法(乙腈和水的梯度，各含有0.1％甲酸)用Thermo U3000 AFC-3000；柱：Globalsil C-18 12nm,250 x 20mm,10μm,或相当；流速：20mL/min，进行分离。
中间体的合成
化合物INT-1的制备：
Figure PCTCN2019088221-appb-000019
在0℃条件下，将碳酸铯(241.0g，0.74mol)和5-溴-2-硝基吡啶(100.0g，0.49mol)依次加入到溶有2-氯-4-羟基吡啶(70.2g，0.54mol)的N,N-二甲基甲酰胺(1.5L)溶液中。反应液在80℃的条件下搅拌24小时。反应液过滤后，滤液减压浓缩除去大部分溶剂，用乙酸乙酯(2L)稀释；有机层依次用水洗(2L x 2)和饱和食盐水洗(1L x 2)后，用无水硫酸镁干燥。滤液减压浓缩后得到粗品，用硅胶柱层析(石油醚：乙酸乙酯＝100：1至1：1)纯化得到黄色油状物INT-1a(43.5g，收率：31.9％)。 1H NMR(DMSO-d 6,400MHz)δ8.64(s,1H),8.47-8.40(m,2H),8.14–8.02(m,1H),7.39(s,1H),7.25(s,1H)；MS:252.0[M+H]+。
将氯化铵(91.0g，1.7mol)和锌粉(110.5g，1.7mol)依次加入溶有INT-1a(43.5g，0.17mol)的四氢呋喃(500mL)和甲醇(500mL)的混合溶液。反应液在室温条件下搅拌过夜。滤液减压浓缩后得到红棕色固体INT-1b(37.3g，收率：97.5％)。MS:222.0[M+H]+。
在氮气保护下，将化合物INT-1b(37.3g,0.17mol)，化合物INT-1c(42.0g,0.20mol)，碳酸铯(220.0g,0.67mol)和四三苯基磷钯(9.7g，8.4mmol)加入至N’N-二甲基甲酰胺(500mL)和水(200mL) 的混合溶液中。反应体系再用氮气反复置换3次后，在90℃的条件下搅拌24小时。反应液过滤后，滤液减压浓缩除去大部分溶剂，用乙酸乙酯(1L)稀释；有机层依次用水洗(1L x 2)和饱和食盐水洗(1Lx 2)后，用无水硫酸镁干燥。滤液减压浓缩后得到粗品，用硅胶柱层析(石油醚：乙酸乙酯＝100：1至1：1)纯化得到近白色固体INT-1(23.5g，收率：52.2％)。 1H NMR(DMSO-d 6,400MHz)δ8.33(d,J＝5.7Hz,1H),8.25(s,1H),7.95(s,1H),7.82(d,J＝2.7Hz,1H),7.30(dd,J＝8.9,2.7Hz,1H),7.16(d,J＝2.4Hz,1H),6.59(dd,J＝5.7,2.4Hz,1H),6.55–6.46(m,1H),6.03(s,2H),3.86(s,3H)。MS:268.0[M+H]+。
化合物INT-2的制备：
Figure PCTCN2019088221-appb-000020
在0℃条件下，双(三甲基硅基)氨基钠(2.0M的四氢呋喃溶液，4.68mL)缓慢滴入溶有5-溴-6-甲基-吡啶-2-胺(500mg，2.67mmol)的二氯甲烷(10mL)溶液。反应液在搅拌条件下逐渐升至室温，并在室温条件下搅拌1小时。随后将溶有二碳酸二叔丁酯(700mg，3.21mmol)的四氢呋喃(5mL)溶液缓慢滴入上述反应液中，所得反应液在室温条件下再搅拌1小时。LC/MS显示原料已消耗完全，在反应液中加入水(30mL)和二氯甲烷(20mL)使其分层。有机相用 饱和食盐水(30mL x 2)洗涤，用无水硫酸钠干燥。滤液减压浓缩后得到粗品，用硅胶柱层析(石油醚：乙酸乙酯＝100：0至5：1)纯化得到白色固体INT-2a(582mg，收率：75.8％)。
在氮气保护下，将化合物INT-2a(582mg，2.03mmol)，化合物INT-2b(148mg，0.20mmol)，联硼酸频哪醇酯(669mg，2.63mmol)和醋酸钾(398mg，4.05mmol)加入至二氧六环(12mL)溶液中。反应体系再用氮气反复置换3次后，在90℃的条件下搅拌16小时。LC/MS显示原料已经消耗完毕；反应液减压浓缩后得到粗品，用硅胶柱层析(石油醚：乙酸乙酯＝100：0至3：1)纯化得到白色固体INT-2c(330mg，收率：41.9％)。 1H NMR(DMSO-d 6,500MHz)δ9.78(s,1H),7.85(d,J＝8.2Hz,1H),7.60(d,J＝8.2Hz,1H),2.50(s,3H),1.43(s,9H),1.27(s,12H)。
在0℃条件下，双氧水(30％w/w，482mg)加入至溶有化合物INT-2c(330mg，0.85mmol)的四氢呋喃(3mL)溶液中。反应液在搅拌下逐渐升至室温，并在室温条件下搅拌3小时。随后，5％亚硫酸钠溶液(5mL)加入至反应液中淬灭多余的双氧水，并加入乙酸乙酯(30mL)和水(25mL)。有机相用饱和食盐水(30mL x 2)洗涤，用无水硫酸钠干燥。滤液减压浓缩后得到粗品，用硅胶柱层析(石油醚：乙酸乙酯＝100：0至3：1)纯化得到白色固体INT-2d(100mg，收率：52.5％)。 1H NMR(DMSO-d 6,500MHz)δ9.30(s,1H),9.22(s,1H),7.36(d,J＝8.5Hz,1H),7.06(d,J＝8.5Hz,1H),2.21(s,3H),1.43(s,9H)。
将碳酸铯(290mg，0.89mmol)加入至溶有化合物INT-2d(100mg，0.45mmol)和2,4-二氯吡啶(86mg，0.58mmol)的N,N-二甲基甲酰胺(3mL)溶液中，反应液在65℃条件下搅拌小时。LC/MS显示原料已消耗完毕，随后加入乙酸乙酯(20mL)和水(20mL)，所得水相进一步用乙酸乙酯(20mL)萃取。合并有机相用饱和食盐水(40mL x 2)洗涤，用无水硫酸钠干燥。滤液减压浓缩后得到粗品，用硅胶柱层析(石油醚：乙酸乙酯＝4：1)纯化得到黄色固体INT-2e(60mg，收率：40％)。
将三氟乙酸(0.5mL)加入溶有化合物INT-2e(60mg，0.18mmol)的二氯甲烷(2mL)溶液中，反应液在室温条件下搅拌3小时。LC/MS显示原料已消耗完毕。反应液减压浓缩后，加入乙酸乙酯(10mL)和饱和碳酸氢钠溶液(10mL)；有机相用饱和食盐水(10mL x 2)洗涤，用无水硫酸钠干燥。滤液减压浓缩后得到白色固体INT-2f(35mg，收率：83.1％)。 1H NMR(DMSO-d 6,500MHz)δ8.24(d,J＝5.8Hz,1H),7.31(d,J＝8.4Hz,1H),6.93(s,1H),6.88(dd,J＝5.8,1.9Hz,1H),6.43(d,J＝8.4Hz,1H),2.06(s,3H)。
从化合物INT-2f开始，参照化合物INT-1的合成，得到白色固体化合物INT-2。 1H NMR(DMSO-d 6,500MHz)δ8.38(d,J＝6.0Hz,1H),7.87(s,1H),7.25(s,1H),7.21(d,J＝8.7Hz,1H),6.93(d,J＝2.3Hz,1H),6.64-6.57(m,1H),6.47(d,J＝8.7Hz,1H),3.94(s,3H),2.28(s,3H)。MS:282.7[M+H]+。
化合物INT-3的制备：
Figure PCTCN2019088221-appb-000021
在-78℃的条件下，将二异丙基氨基锂(2M四氢呋喃溶液，7.8mL)滴加至溶有环己甲酸甲酯(2.0g，14.1mmol)的四氢呋喃(30mL)溶液中。反应液在-78℃的条件下继续搅拌1.5小时，然后将混有溴乙腈(2.0g，16.9mmol)和N’N’-二甲基丙酰基脲(0.90g，7.0mmol)的四氢呋喃(10mL)溶液慢慢滴入。所得反应液缓慢升至室温，并在室温条件下搅拌过夜。TLC确定原料消耗完毕，反应液用盐酸溶液(1M，20mL)小心淬灭，减压条件下浓缩除去大部分四氢呋喃，所得溶液用乙酸乙酯萃取(20mL x 3)。合并有机相用饱和食盐水洗涤(50mL x 2)，无水硫酸钠干燥。滤液减压浓缩后得到粗品，用用硅胶柱层析(石油醚：乙酸乙酯＝15：1)纯化得到黄色油状物INT-3a(1.10g，收率：43％)。 1H NMR(CDCl 3，400MHz)δ3.67(s,3H),2.70(s,2H),1.96-1.92(m,2H),1.56-1.50(m,2H),1.47-1.27(m,6H)。
在氮气保护和0℃条件下，硼氢化钠(1.04g，27.6mmol)分批加入到化合物INT-3a(1.0g，5.52mmol)和无水氯化钴(0.36g，2.76mmol)的四氢呋喃(20mL)和水(10mL)的混合溶液中。反应液在室温条件下搅拌过夜；随后在反应液中再次补加无水氯化钴(0.18g，1.38mmol)和硼氢化钠(0.50g，13.8mmol)；所得反应液继续室温搅拌过夜。反应液过滤后，滤液减压浓缩，所得粗品用乙酸乙酯(100 mL)溶解，并用饱和食盐水洗涤(100mL x 2)，无水硫酸钠干燥。滤液减压浓缩后得到粗品，用硅胶柱层析(石油醚：乙酸乙酯＝3：1)纯化得到白色固体INT-3(230mg，收率：27％)。 1H NMR(CDCl 3,400MHz)δ5.95(br s,1H),3.30(t,J＝6.8Hz,2H),2.03(t,J＝7.2Hz,2H),1.74-1.62(m,5H),1.46-1.44(m,2H),1.38-1.26(m,3H)。
参照化合物INT-3的制备方法，制备得到了化合物INT-4,INT-5,INT-6,INT-7,INT-8，具体谱图信息如下表：
Figure PCTCN2019088221-appb-000022
Figure PCTCN2019088221-appb-000023
化合物INT-9的制备：
Figure PCTCN2019088221-appb-000024
从化合物INT-9a开始，参照化合物INT-3a的合成，得到黄色油状物INT-9b。MS:210.3[M+H]+。
溶有化合物INT-9b(1.60g，7.65mmol)的二乙胺基三氟化硫(3mL)溶液在室温下搅拌过夜。LC/MS显示原料已经消耗完毕后，将冰水(20mL)缓慢滴入反应液中淬灭反应，随后后饱和碳酸氢钠溶液调节pH值至8-9，再用乙酸乙酯(50mL x 3)萃取。合并有机相用饱和食盐水洗涤(100mL x 2)，无水硫酸钠干燥。滤液减压浓缩后得到粗品，用硅胶柱层析(石油醚：乙酸乙酯＝5：1)纯化得到无色油状物INT-9c(1.00g，收率：57％)。MS:232.3[M+H]+。
从化合物INT-9c开始，参照化合物INT-3的合成，得到淡黄色固体INT-9。 1HNMR(CDCl 3,400MHz)δ5.64(br s,1H),3.34-3.16(m,2H),2.65-2.55(m,1H),2.50-2.29(m,1H),1.98-1.68(m,5H),1.43-1.33 (m,1H)。
参照化合物INT-9的制备方法，制备得到了化合物INT-10,INT-11，具体谱图信息如下表：
Figure PCTCN2019088221-appb-000025
化合物INT-12的制备：
Figure PCTCN2019088221-appb-000026
对甲基苯磺酰氯(1.11g，5.83mmol)加入到溶有化合物INT-12a(700mg，4.86mmol)，4-二甲基吡啶(59mg，0.49mmol)和三乙胺(1.36mL,9.71mmol)的二氯甲烷溶液(10mL)。所得反应液在室温条件下搅拌过夜后，TLC显示原料已消耗完毕。在反应液中加入二氯甲烷(20mL)和水(40mL)，有机层用饱和食盐水洗涤(40mLx 2)，无水硫酸钠干燥。滤液减压浓缩后得到粗品，用硅胶柱层析(石 油醚：乙酸乙酯＝100：0到3：1)纯化得到无色油状物INT-12b(1.0g，收率：69％)。 1H NMR(500MHz,DMSO-d 6)δ7.78(d,J＝8.2Hz,2H),7.49(d,J＝8.2Hz,2H),4.15(s,2H),3.97(q,J＝7.0Hz,2H),2.43(s,3H),1.17(br s,2H),1.07(t,J＝7.0Hz,3H),0.99(br s,2H)；MS:299.4[M+H]+。
四丁基氟化铵(1M in THF,12.3mL)加入到溶有化合物INT-2b(1.22g,4.1mmol)和三甲基氰硅烷(1.22g,12.3mmol)的四氢呋喃溶液中。反应液在室温条件下搅拌过夜，TLC显示原料已经消耗完毕。在反应液中加入乙酸乙酯(50mL)和水(50mL)，有机层用饱和食盐水洗涤(50mL x 2)，无水硫酸钠干燥。滤液减压浓缩后得到粗品，用硅胶柱层析(石油醚：乙酸乙酯＝100：0到3：1)纯化得到淡黄色油状物INT-12c(500mg，收率：79.8％)。 1H NMR(500MHz,DMSO-d 6)δ4.10(q,J＝7.1Hz,2H),2.79(s,2H),1.19(br s,2H),1.18(t,J＝7.1Hz,3H),1.00(br s,2H)。
雷尼镍(100mg,0.65mmol)加入到溶有化合物INT-12c(100mg,0.65mmol)的氨甲醇溶液(7M,3mL)。反应液在氢气(15psi)条件下室温搅拌48小时。硅藻土过滤除去雷尼镍，滤液减压浓缩后得到粗品，用硅胶柱层析(二氯甲烷：甲醇＝100：0到10：1)纯化得到白色固体INT-12(34mg，收率：46.9％)。 1H NMR(500MHz,DMSO-d 6)δ7.54(s,1H),3.29(t,J＝7.1Hz,2H),2.08(t,J＝7.1Hz,2H),0.78(br s,2H),0.67(br s,2H)。
化合物INT-13的制备：
Figure PCTCN2019088221-appb-000027
将对甲苯磺酸(57mg，0.30mmol)加入至溶有INT-13a(1.03g，6.06mmol)和乙二醇(0.45g，7.27mmol)的甲苯(100mL)溶液中；所得反应液在回流条件下搅拌过夜。反应液中加入5％碳酸氢钠水溶液(100mL)和乙酸乙酯(100mL)；水相进一步用乙酸乙酯(100mL)萃取。合并有机相用饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩后用硅胶柱层析(石油醚:乙酸乙酯＝10:1)得到淡黄色油状物INT-13b(1.09g，收率：84％)；MS:215.4[M+H]+
参照化合物INT-3a的制备方法，通过化合物INT-13b制备得到淡黄色油状物INT-13c；MS:254.3[M+H]+
参照化合物INT-12的制备方法，通过化合物INT-13c制备得到近白色固体INT-13d； 1H NMR(400MHz,CDCl 3)δ6.23(brs,1H),3.94(s,4H),3.31-3.27(m,2H),2.40-2.25(m,1H),2.15-2.00(m,1H),1.99-1.93(m,1H),1.85-1.70(m,2H),1.69-1.64(m,1H),1.60-1.45(m,4H)；MS: 212.4[M+H]+
在0度条件下，将钠氢(60％w/w在煤油中，122mg，3.06mmol)加入至溶有化合物INT-13d(430mg，2.04mmol)的干燥四氢呋喃(10mL)溶液中；所得混合物在室温条件下搅拌半小时。随后对甲氧基苄氯(383mg，2.45mmol)和四正丁基溴化磷(69mg，0.20mmol)加入至上述体系中，所得反应液在室温条件下搅拌过夜。反应液中加入水(50mL)和乙酸乙酯(50mL)；水相进一步用乙酸乙酯(50mL)萃取。合并有机相用饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩后用硅胶柱层析(石油醚:乙酸乙酯＝1:1)得到淡黄色油状物INT-13e(555mg，收率：82％)；MS:332.2[M+H]+
在室温下，将对甲苯磺酸(32mg)加入到溶有INT-13e(555mg，1.68mmol)的丙酮(10mL)溶液中；反应液在室温条件下搅拌过夜。反应液中加入5％碳酸氢钠水溶液(50mL)和乙酸乙酯(50mL)；水相进一步用乙酸乙酯(50mL)萃取。合并有机相用饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩后用硅胶柱层析(石油醚:乙酸乙酯＝1:1)得到无色油状物INT-13f(444mg，收率：92％)；MS:288.3[M+H]+
在室温条件下，将二乙胺基三氟化硫(2.49g，15.5mmol)加入 到溶有INT-13f(444mg，1.55mmol)的二氯甲烷(10mL)溶液中；反应液在室温条件下搅拌过夜。反应液中加入5％碳酸氢钠水溶液(50mL)和乙酸乙酯(50mL)；水相进一步用乙酸乙酯(50mL)萃取。合并有机相用饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩后用硅胶柱层析(石油醚:乙酸乙酯＝2:1)得到淡黄色油状物INT-13g(410mg，收率：86％)；MS:310.3[M+H]+
在室温条件下，将预先溶有硝酸铈铵(3.64g，6.63mmol)的水(3mL)溶液加入溶有INT-13g(410mg，1.33mmol)的乙腈(15mL)溶液中；反应液在室温条件下搅拌过夜。反应液中加入5％碳酸氢钠水溶液(50mL)和乙酸乙酯(50mL)；水相进一步用乙酸乙酯(50mL)萃取。合并有机相用饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩后用硅胶柱层析(石油醚:乙酸乙酯＝2:1–0:1)得到淡黄色固体INT-13(132mg，收率：53％)；1H NMR(400MHz,CDCl 3)δ6.03(brs,1H),3.40-3.26(m,2H),2.25-2.04(m,4H),1.95-1.80(m,2H),1.80-1.60(m,4H)；MS:190.1[M+H]+
参照化合物INT-13的制备方法，制备得到了化合物INT-14和INT-15，具体谱图信息如下表：
Figure PCTCN2019088221-appb-000028
Figure PCTCN2019088221-appb-000029
实施例1：化合物1的制备
Figure PCTCN2019088221-appb-000030
在0℃条件下，将预先溶于四氢呋喃(2mL)的三光气(95mg，0.32mmol)溶液缓慢滴加至化合物INT-1(107mg，0.40mmol)和三乙胺(222μL，1.60mmol)的四氢呋喃(5mL)溶液中。反应液在搅拌条件下逐渐升至室温，并在室温条件下继续搅拌1小时。LC/MS显示原料已消耗完全，反应液减压浓缩后加入水(15mL)与二氯甲烷与甲醇的混合溶液(15mL，v/v＝10/1)。有机相用饱和食盐水(15mL x 2)洗涤，无水硫酸钠干燥。滤液减压浓缩后得到化合物1a，该化合物无需分离，直接进入下一步反应。
在0℃条件下，将钠氢(60％w/w在煤油中；80mg，2.0mmol)加入至化合物INT-5(50mg，0.4mmol)的四氢呋喃溶液中。反应液在搅拌条件下逐渐升至室温，并在室温条件下搅拌半小时；随后加入上段描述的预先溶于四氢呋喃(3mL)中的化合物1a；所得反应液 继续在室温条件下搅拌1小时。LC/MS显示化合物1a消耗完全，加入水(0.5mL)淬灭多余的钠氢。所得反应液在减压条件下浓缩除去绝大部分溶剂，随后加入二氯甲烷(15mL)和水(15mL)。有机相用饱和食盐水(15mL x 2)洗涤，无水硫酸钠干燥。滤液减压浓缩后得到粗品，用制备薄层层析(二氯甲烷：甲醇＝20：1)纯化得到白色固体1。 1H NMR(DMSO-d 6,500MHz)δ11.09(s,1H),8.37(d,J＝5.0Hz,1H),8.28(s,1H),8.26(s,1H),8.07(d,J＝9.0Hz,1H),7.96(s,1H),7.78-7.72(m,1H),7.23(s,1H),6.70(d,J＝5.0Hz,1H),3.84(s,3H),3.69(t,J＝6.5Hz,2H),2.40-2.25(m,2H),2.18(t,J＝6.5Hz,2H),2.05-1.85(m,4H)。MS:419.5[M+H]+。
参照化合物1的制备方法，制备得到了化合物2,3,4,5,6,7,8,9,10，24，25，26；具体谱图信息如下表：
Figure PCTCN2019088221-appb-000031
Figure PCTCN2019088221-appb-000032
Figure PCTCN2019088221-appb-000033
Figure PCTCN2019088221-appb-000034
Figure PCTCN2019088221-appb-000035
Figure PCTCN2019088221-appb-000036
Figure PCTCN2019088221-appb-000037
Figure PCTCN2019088221-appb-000038
实施例2：化合物11的制备
Figure PCTCN2019088221-appb-000039
从化合物INT-1开始，参照化合物1的合成，得到白色固体11a。1HNMR(DMSO-d 6,500MHz)δ11.04(s,1H),8.37(d,J＝5.7Hz,1H),8.27(d,J＝3.0Hz,1H),8.25(s,1H),8.08(d,J＝9.0Hz,1H),7.96(s,1H),7.76(dd,J＝9.0,3.0Hz,1H),7.23(d,J＝3.0Hz,1H),6.69(dd,J＝5.7,3.0Hz,1H),3.84(s,3H),3.79(t,J＝7.1Hz,4H),3.07-2.92(m,2H),2.03(t,J＝7.1Hz,2H),1.65-1.53(m,4H),1.40(s,9H)；MS:548.3[M+H]+。
在溶有化合物11a(350mg,0.64mmol)的二氯甲烷溶液中(6mL)加入盐酸(4M in二氧六环,0.8mL)。反应液在室温条件下搅拌4小时后，LC/MS显示原料已消耗完毕。反应液减压浓缩得到白色固体11。 1H NMR(500MHz,DMSO-d 6)δ11.05(s,1H),8.78(s,1H),8.56(d,J＝6.0Hz,1H),8.46(s,1H),8.41(s,1H),8.14(d,J＝9.0Hz,1H),7.91(d,J＝9.0Hz,1H),7.75(s,1H),7.21-7.16(m,1H),3.92(s,3H),3.80(t,J＝7.0Hz,2H),3.29-3.24(m,2H),3.04-3.00(m,2H),2.07(t,J＝7.0Hz, 2H),1.99-1.95(m,2H),1.83-1.77(m,2H)；MS:448.5[M+H]+。
实施例3：化合物12的制备
Figure PCTCN2019088221-appb-000040
在溶有化合物11(120mg,0.25mmol)和乙酸酐(30.4mg，0.30mmol)的二氯甲烷溶液(5mL)中加入三乙胺(50mg，0.50mmol)。反应液在室温条件下搅拌4小时，LC/MS显示原料已经消耗完毕。在反应液中加入二氯甲烷(15mL)和水(20mL)，有机层用饱和食盐水洗涤(20mL x 2)，无水硫酸钠干燥。滤液减压浓缩后得到粗品，用制备薄层层析(二氯甲烷：甲醇＝10：1)纯化得到白色固体12(65mg，收率：53％)。 1H NMR(500MHz,DMSO-d 6)δ11.04(s,1H),8.37(d,J＝6.0Hz,1H),8.27(br s,1H),8.26(s,1H),8.07(d,J＝9.0Hz,1H),7.95(s,1H),7.76(d,J＝9.0Hz,1H),7.23(s,1H),6.69(d,J＝6.0Hz,1H),4.16-4.11(m,1H),3.83(s,3H),3.82–3.71(m,3H),3.24–3.16(m,1H),2.90-2.82(m,1H),2.05(t,J＝7.0Hz,2H),2.00(s,3H),1.72-1.68(m,1H),1.65–1.54(m,3H)；MS:490.4[M+H]+。
实施例4：化合物13的制备
Figure PCTCN2019088221-appb-000041
从化合物11和甲磺酸酐开始，参照化合物12的合成，得到白色固 体13。1H NMR(500MHz,DMSO-d 6)δ11.04(s,1H),8.37(d,J＝5.5Hz,1H),8.27(d,J＝3.0Hz,1H),8.26(s,1H),8.08(d,J＝9.0Hz,1H),7.96(s,1H),7.76(dd,J＝9.0,3.0Hz,1H),7.23(d,J＝2.0Hz,1H),6.69(dd,J＝5.5,2.0Hz,1H),3.84(s,3H),3.80(t,J＝7.1Hz,2H),3.49-3.47(m,2H),2.95-2.91(m,2H),2.89(s,3H),2.02(t,J＝7.1Hz,2H),1.83-1.71(m,4H)；MS:526.3[M+H]+。
实施例5：化合物14的制备
Figure PCTCN2019088221-appb-000042
在0℃条件下，将预先溶于四氢呋喃(1mL)的三光气(23.5mg,0.79mmol)缓慢滴入溶有化合物INT-8(20mg,0.15mmol)和三乙胺(21.4mg，0.21mmol)的无水四氢呋喃(2mL)溶液中。反应液在搅拌状态下逐渐升至室温，并在室温条件下搅拌1小时；随后进一步回流2小时。反应液中加入乙酸乙酯(15mL)和水(15mL)，有机层用饱和食盐水洗涤(20mL x 2)，无水硫酸钠干燥。滤液减压浓缩后得到粗品化合物14a。
将预先溶于二氯甲烷(1mL)的上述粗品加入溶有化合物INT-2(30mg，0.106mmol)和三乙胺(21.4mg，0.211mmol)的二氯甲烷(3mL)溶液中。反应液在室温条件下搅拌16小时后，LC/MS显 示产物为主峰。反应液中加入二氯甲烷(15mL)和水(20mL)，有机层用饱和食盐水洗涤(20mL x 2)，无水硫酸钠干燥。滤液减压浓缩后得到粗品，用制备薄层层析(DCM：MeOH＝20：1)纯化得到白色固体14(19mg，收率：36.2％)。 1H NMR(500MHz,DMSO-d 6)δ10.98(s,1H),8.40(d,J＝6.0Hz,1H),8.31(s,1H),8.01(s,1H),7.93(d,J＝8.8Hz,1H),7.68(d,J＝8.8Hz,1H),7.25(br s,1H),6.68(br s,1H),3.87(s,3H),3.80(t,J＝7.0Hz,2H),2.28(s,3H),2.17-2.07(m,2H),2.05(t,J＝7.0Hz,2H),2.00-1.90(m,2H),1.85-1.75(m,4H)；MS:497.5[M+H]+。
参照化合物14和INT-2的制备方法，制备得到了化合物15，16，具体谱图信息如下表：
Figure PCTCN2019088221-appb-000043
Figure PCTCN2019088221-appb-000044
实施例6：化合物17的制备
Figure PCTCN2019088221-appb-000045
将溶有化合物17a(500mg，3.2mmol)的二氯亚砜(1mL)溶液在80度条件下搅拌3小时；浓缩后得到的酰氯加入至预先溶有甲胺(118mg，3.8mmol)和三乙胺(0.88mL，6.4mmol)的二氯甲烷(8mL)溶液中。所得反应液在室温条件下搅拌2小时后，减压浓缩后用硅胶柱层析(石油醚：乙酸乙酯＝0:100 to 50:100)得到黄色油状物17b(250mg，收率：46％)。
将碳酸铯(832mg，2.55mmol)加入至预先溶有化合物17b(218mg，1.28mmol)和化合物17c(450mg，1.28mmol)的N’N-二甲基甲酰胺溶液(15mL)；所得反应液在90度条件下搅拌16小时。反应液中加入乙酸乙酯(100mL)和水(100mL)；所得有机相用饱和食盐水(100mL)洗涤，无水硫酸钠干燥，减压浓缩后用硅胶柱层析(石油醚：乙酸乙酯＝0:100 to 50:100)得到白色固体17d(420mg，收率：68％)。
将溶有化合物17d(400mg，0.82mmol)的醋酸(2mL)和水(0.6mL)的混合溶液在75度条件下搅拌2小时。所得反应液冷却后过滤，在滤液中加入乙酸乙酯(40mL)，并用20％氢氧化钠水溶液条件pH至8；所得有机相用饱和食盐水(100mL)洗涤，无水硫酸钠干燥，减压浓缩后得到白色固体17e(150mg，收率：75％)；MS:245.4[M+H]+
参照化合物14的制备方法，由化合物17e和化合物14a得到化合物17。1H NMR(500MHz,DMSO-d6)δ11.06(s,1H),8.79(d,J＝4.8Hz,1H),8.54(d,J＝5.6Hz,1H),8.33(d,J＝2.9Hz,1H),8.12(d,J＝9.0Hz,1H),7.83(dd,J＝9.0,2.9Hz,1H),7.42(d,J＝2.6Hz,1H),7.20(dd,J＝5.6,2.6Hz,1H),3.80(t,J＝7.1Hz,2H),2.79(d,J＝4.8Hz,3H),2.15-2.07(m,2H),2.05(t,J＝7.1Hz,2H),2.00-1.88(m,2H),1.85-1.75(m,4H)；MS:460.2[M+H]+
实施例7：化合物18的制备
Figure PCTCN2019088221-appb-000046
在溶有化合物INT-1a(150mg，0.60mmol)和N,N-二甲基脲(105mg，1.20mmol)的二氧六环溶液(5mL)中加入dppf(33mg，0.06mmol)，Pd2(dba)3(27mg，0.03mmol)和碳酸铯(388mg，1.20mmol)；在氮气保护下，所得反应液在95度条件下搅拌16小时。反应液浓缩后用硅胶柱层析(石油醚：乙酸乙酯＝0:100 to 80:100)得到黄色固体18a(110mg，收率：61％)；MS:304.4[M+H]+
在氢气(1atm)气氛下，将溶有化合物18a(88mg，0.29mmol)和10％钯碳(10mg)的甲醇溶液(10mL)在室温条件下搅拌16小时。反应液过滤后，滤液减压浓缩后得到黄色固体18b(78mg，收率：98％)；MS:274.0[M+H]+
参照化合物14的制备方法，由化合物18b和化合物14a得到化合物18。1H NMR(500MHz,DMSO-d6)δ11.05(s,1H),8.93(s,1H),8.27(d,J＝2.5Hz,1H),8.14(d,J＝5.7Hz,1H),8.10(d,J＝9.0Hz,1H),7.76(dd,J＝9.0,2.8Hz,1H),7.41(d,J＝2.0Hz,1H),6.63(dd,J＝5.7,2.3Hz,1H),3.81(t,J＝7.1Hz,2H),2.90(s,6H),2.16-2.09(m,2H),2.05(t,J＝7.1Hz,2H),1.98-1.90(m,2H),1.86-1.76(m,4H)；MS:489.5[M+H]+
参照化合物18的制备方法，制备得到了化合物19，具体谱图信息如下表：
Figure PCTCN2019088221-appb-000047
Figure PCTCN2019088221-appb-000048
实施例8：化合物20的制备
Figure PCTCN2019088221-appb-000049
参照化合物14的制备方法，由化合物20a和化合物14a得到黄色固体化合物20b；MS:416.4[M+H]+
在氢气(1atm)气氛下，将溶有化合物20b(2.86g，6.9mmol)和10％钯碳(300mg)的甲醇溶液(150mL)在室温条件下搅拌16小时。反应液过滤后，滤液减压浓缩后得到黄色固体20c(2.20g，收率：98％)；MS:326.4[M+H]+
将碳酸铯(2.58g，7.9mmol)加入至溶有化合物20c(2.2g，6.1mmol)和2-氯-4-氟吡啶(841mg，6.4mmol)的N’N-二甲基甲酰胺 (15mL)中，所得反应液在室温条件下搅拌2小时。反应液中加入乙酸乙酯(150mL)和水(150mL)；所得有机相用饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩后用硅胶柱层析(石油醚：乙酸乙酯＝1:1)得到黄色固体20d(2.1g，收率：80％)；MS:436.1[M+H]+
参照化合物INT-1最后一步的制备方法，由化合物20d和化合物20e得到黄色固体20。1H NMR(500MHz,CDCl3)δ11.10(s,1H),8.60(d,J＝5.5Hz,2H),8.21(d,J＝2.0Hz,1H),8.18(d,J＝8.5Hz,1H),7.73(s,1H),7.60(s,1H),7.50(dd,J＝8.9,2.6Hz,1H),7.31(d,J＝1.9Hz,1H),6.86(dd,J＝5.4,2.1Hz,1H),3.90(t,J＝7.1Hz,2H),2.65(s,3H),2.38-2.27(s,2H),2.05-2.00(m,4H),1.94-1.84(m,2H),1.76-1.71(m,2H)；MS:494.3[M+H]+
参照化合物20的制备方法，从相应的商业化试剂，制备得到了化合物21，22和23，具体谱图信息如下表：
Figure PCTCN2019088221-appb-000050
Figure PCTCN2019088221-appb-000051
Figure PCTCN2019088221-appb-000052
生物测试实施例
实施例1：CSF1R激酶活性测试
具体操作如下:设置待测化合物浓度梯度，用DMSO将待测化合物稀释到工作浓度。在384孔板中用Echo 550加样设备在每个孔中加入10nL相应浓度的待测化合物。，CSF1R的稀释缓冲液为含有5mM MgCl 2,1mM MnCl 2,1mM DTT,12.5 nM SEB的1XEnzymatic buffer。用此缓冲液调整CSF1R的浓度为0.02ng/ul。在384孔板中加入5μL含有CSF1R的缓冲液1000g离心30s后在室温下孵育10分钟，加入5μL含有TK-substrate-biotin(2μM)和ATP(8μM)的缓冲液(配方同上),1000g离心30s后室温条件下孵育40分钟后加入10μL终止液(含有5μL浓度为250nM Sa-XL665和5μL TK-antibody-Cryptate)，孵育60分钟后用Envision 2104 plate reader检测在620nm(Cryptaet)和665nm(XL665)的荧光信号，得到比率(665/620nm)。每个点的抑制率通过下述公式得到：
Figure PCTCN2019088221-appb-000053
其中，
Figure PCTCN2019088221-appb-000054
为实验的阳性对照无；
Figure PCTCN2019088221-appb-000055
为0.1％DMSO的测试值。以化合物浓度和抑制率为横纵坐标，绘制曲线，使用Graphpad 5.0软件拟合曲线并计算IC 50。
c-Kit,PDGFRα,PDGFRβ,FLT-3激酶活性测试
采用Caliper迁移率变动检测技术(Caliper mobility shift assay)测定c-Kit,PDGFRα,PDGFRβ,FLT-3激酶活性。其中，c-Kit来源于Eurofins(cat#:14-559M)；PDGFRα来源于BPS(cat#:40260)；PDGFRβ来源于Invitrogen(cat#:PR4465B)；FLT-3来源于Carna(cat#:08-154)；多肽底物P2由GL Biochem提供(cat#:112394)，作为FLT-3激酶的底物；多肽底物P22由GL Biochem提供(cat#:112393)，作为c-Kit,PDGFRα,PDGFRβ激酶的底物。
实验过程中的激酶及其对应的底物(ATP和多肽底物P2或P22)的最终浓度如下表：
Figure PCTCN2019088221-appb-000056
在384孔板中加入5μL的5倍反应终浓度的化合物(10％DMSO)。加入10μL的2.5倍酶溶液后在室温下孵育10分钟，再加入10μL的2.5倍底物(ATP和多肽底物，P2或者P22)。28℃下孵育60分钟 后加入25μL终止液终止反应。Caliper EZ Reader II(Caliper Life Sciences)上读取转化率数据。把转化率转化成抑制率数据(％抑制率＝(max-样品转化率)/(max-min)x100)。其中max是指DMSO对照的转化率，min是指无酶活对照的转化率。以化合物浓度和抑制率为横纵坐标绘制曲线，使用XLFit excel add-in version4.3.1软件拟合曲线并计算IC 50。
实施例中所列化合物对于CSF1R,c-Kit,PDGFRα,PDGFRβ和FLT-3的活性结果：
Figure PCTCN2019088221-appb-000057
Figure PCTCN2019088221-appb-000058
实施例2：化合物对FMS磷酸化抑制性实验(ELISA实验)
用DMSO溶液设置待测化合物的浓度梯度，用含10％灭活血清(cat#:1707125，BI)的RPMI1640(cat#:01-100-1ACS,BI)按照1:500对待测化合物进行稀释。收获THP-1细胞，调整细胞密度为2x10 6 cells/ml。取500μL细胞悬液与上述稀释好的化合物按照1:1混匀后铺入24孔板(cat#:3524，costar)中。将培养板置于细胞培养箱中孵育4小时，孵育条件为：温度37℃，5％CO 2，湿度95％。孵育完成后，用含10％灭活血清的RPMI1640将重组人MCSF(cat#:216-MC，R&D Systems)进行稀释，使其终浓度为100ng/ml。将稀释好的重组人MCSF以每孔100μL加入24孔板中，迅速混匀后置于培养箱中孵育4分钟，孵育条件为：温度37℃，5％CO 2，湿度95％。孵育完成后按照磷酸化CSF1R检测试剂盒(cat#：DYC3268，R&D Systems)中建议的方法进行蛋白提取和ELISA实验。酶标仪读取数据后计算待测化合物抑制率，使用GraphPad Prism作图并计算待测化合物的EC 50。
化合物编号 FMS EC 5o(nM)
BLZ-945 182
1 3.5
4 15.5
10 4.0
14 118
26 9.0
实施例3：化合物在小鼠结肠癌MC38细胞株同种移植C57BL/6小鼠动物模型中的抗肿瘤作用
实验动物：C57BL/6小鼠，雌性，6-8周(肿瘤细胞接种时的小鼠周龄)，体重18-22g。购自上海灵畅生物科技有限公司，动物合格证编号：2013001832351。饲养环境：SPF级。
称取一定量药物，加0.5％甲基纤维素水溶液配置成0.24，0.8和2.4mg/mL无色澄清透明液体或者均匀分散的悬浊液。对应给药剂量均分别为2.4，8.0和24mg/kg，给药体积为10mL/kg。
MC38细胞培养在含10％胎牛血清的DMEM培养液中。收集指数生长期的MC38细胞，PBS重悬至适合浓度用于C57BL/6小鼠皮下肿瘤接种。
实验小鼠于右侧背部皮下接种1×106 MC38细胞，细胞重悬PBS中(0.1ml/只)，定期观察肿瘤生长情况，待肿瘤生长至平均体积101mm3时根据肿瘤大小和小鼠体重随机分组给药。给药频率为一天两次；肿瘤大小每隔一天测试一次。
T/C％为相对肿瘤增值率，即在某一时间点，治疗组和对照组相对肿瘤体积的百分比值。T和C分别为治疗组和对照组在某一特定时间点的相对肿瘤体积(RTV)。
所有实验结果以平均瘤体积±SEM(平均标准误差)表示。不同组间的统计分析选择最佳药物治疗点(通常是在最后一次给药后)。用独立样本T检验方法比较治疗组相对肿瘤体积和瘤重与对照组相比有无显著性差异。所有的数据均用SPSS 18.0进行分析。p<0.05为具有显著性差异。
[根据细则91更正 19.11.2019]　
受试化合物的药效结果如图1-2所示：
[根据细则91更正 19.11.2019]　
药代动力学评价
以小鼠为受试动物，应用LC/MS/MS法测定了小鼠灌胃给予实施例1化合物，实施例2化合物，实施例3化合物，实施例4化合物，实施例10化合物，实施例14化合物，实施例26化合物后不同时刻血浆中的药物浓度。研究本发明化合物在小鼠体内的药代动力学行为，评价其药动学特征。
试验动物为CD-1小鼠，购自上海斯莱克实验动物有限公司。
称取一定量药物，加5％体积的DMSO或者DMAc，5％体积的PEG400和90％体积的生理盐水配置成1.0mg/mL无色澄清透明液体或者均匀分散的悬浊液。
CD-1小鼠禁食过夜后灌胃给药，给药剂量均为10mg/kg，给药体积为10mL/kg。
小鼠灌胃于给药前及给药后0.25，0.5，1.0，2.0，4.0，6.0，8.0，24.0小时采血0.1mL，置于K2-EDTA抗凝管中，3500转/分钟离心10分钟分离血浆，于-20℃保存。
测定不同浓度的药物灌胃给药后小鼠血浆中的待测化合物含量：取给药后各时刻的小鼠血浆20uL，加入内标容纳也普萘洛尔，甲苯磺丁脲(各100ng/mL)的乙腈溶液200uL，涡旋混合5分钟，离心12分钟(4000转/分钟)，血浆样品取上清液5uL进行LC/MS/MS分析。
本发明化合物的药代动力学参数如下：
Figure PCTCN2019088221-appb-000060
以上所述仅是本发明的一些优选实施方式，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明技术原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也应视为在本发明的保护范围内。

Claims (15)

  1. 一种式I结构的化合物或其药学可接受的盐、溶剂化物、水合物、立体异构体、立体异构体混合物或立体异构体外消旋混合物：
    Figure PCTCN2019088221-appb-100001
    其中，X表示CR aR a’、
    Figure PCTCN2019088221-appb-100002
    NR a、-C(O)-、O、S、S(O)、S(O) 2；R 1和R 2以及与之相连的碳原子共同环合成为饱和或不饱和的3-12元环烷基或杂环烷基，所述的杂环烷基中至少含有一个选自O、N和S原子的杂原子，所述环烷基或者杂环烷基可以任意地被0、1、2、3或4个各自独立地选自下述R 6的取代基所取代：卤素、羟基、C 1-C 8烷基、C 3-C 8环烷基、C 3-C 8杂环烷基、C 2-C 8烯基、C 2-C 8炔基、C 1-C 8卤代烷基、C 1-C 8烷氧基、C 1-C 8卤代烷氧基、C 3-C 8环烷氧基、C 3-C 8杂环烷氧基、-S-(C 1-C 8)烷基、-S-C 3-C 8环烷基、-S-C 3-C 8杂环烷基、氰基、硝基、-(C 0-C 8)烷基-NR 9R a’、-C＝NR a、-O-Cy 1、-O-(C 0-C 8)烷基-Cy 1、-(C 2-C 8)链烯基-Cy 1、-(C 2-C 8)链炔基-Cy 1、-C(O)OR a、-C(O)R a、-O-C(O)R a、-C(O)-NR aR a’、-NR a-C(O)-R a、-NR a-C(O)-OR a、-(C 1-C 8)烷基-NR a-C(O)R a、-SO 2-NR aR a’和-SO 2R a；
    R 3和R 5分别独立地表示氢、卤素、C 1-C 8烷基、C 1-C 8烷氧基、 C 3-C 8环烷基、C 3-C 8杂环烷基、卤代C 1-C 8烷基、羟基、氨基、硝基、氰基、-C(O)OR a、-O-C(O)R a、-C(O)-NR aR a’、-NR a-C(O)-R a、-NR a-C(O)-OR a、-(C 1-C 8)烷基-NR a-C(O)R a、-SO 2-NR aR a’或-SO 2R a；
    R 4表示Cy 2、-NHC(O)R a、-NHC(O)NR aR a’、-C(O)R a、-C(O)NR aR a’、-S(O) 2R a、-S(O) 2NR aR a’、NHS(O) 2R a或-NHS(O) 2NR aR a’；
    其中，Cy 1和Cy 2分别独立地表示被0、1、2、3或4个取代基独立取代的5-12元环，优选为5-12元芳基或5-12元杂芳基；更优选为5-6元芳基或5-6元杂芳基，其中所述的取代基为卤素、C 1-C 8烷基、C 1-C 8烷氧基、C 3-C 9环烷基、C 3-C 9杂环烷基、卤代C 1-C 8烷基、羟基、硝基、氰基、-C(O)OR a、-O-C(O)R a、-C(O)-NR aR a’、-NR a-C(O)-R a、-NR a-C(O)-OR a、-(C 1-C 8)烷基-NR a-C(O)R a、-SO 2-NR aR a’和-SO 2R a；
    其中，所述的R a、R a’独立地表示氢、C 1-C 8烷基、C 3-C 9环烷基、羟基、卤素、氨基、C 1-C 8卤代烷基、C 1-C 8烷基氨基、二C 1-C 8烷基氨基或者R a、R a’和与之相连的原子环合成为3-9元环烷基或者杂环烷基，优选为氢、C 1-C 8烷基或C 3-C 8环烷基；
    n为1、2或3，优选为1；m和o分别独立地表示0、1、2或3，
    对于上述所定义的烷基、环烷基、杂环烷基、芳基、杂芳基，其可以进一步的被选自下述的取代基所取代：C 1-C 8烷基、C 2-C 8烯基、C 2-C 8炔基、C 3-C 8环烷基、5-12元芳基、5-12元杂芳基、C 1-C 8卤代烷基、C 1-C 8烷氧基、C 1-C 8烷基硫基、卤素、羟基、氰基、磺酸基和硝基；
    对于上述所定义的取代基中，在不同的取代基中R a或者R a’均具 有各自地独立的定义。
  2. 如权利要求1所述的化合物或其药学可接受的盐、溶剂化物、水合物、立体异构体、立体异构体混合物或立体异构体外消旋混合物，其中，R 1、R 2和与之相连的碳原子共同环合成为饱和或不饱和的3-6元环烷基或杂环烷基，所述的杂环烷基中至少含有一个选自O、N和S原子的杂原子，该环烷基或杂环烷基可以任意地被0、1、2、3或4个各自独立地选自下述R 6的取代基所取代，其中R 6如上述权利要求1所定义。
  3. 如权利要求1所述的化合物或其药学可接受的盐、溶剂化物、水合物、立体异构体、立体异构体混合物或立体异构体外消旋混合物，其中，R 1、R 2和与之相连的碳原子共同形成的环选自如下结构：
    Figure PCTCN2019088221-appb-100003
    Figure PCTCN2019088221-appb-100004
    其中，R c选自氢、C 1-C 6烷基、C 3-C 8环烷基、-C(O)R a、-C(O)OR a、-C(O)-NR aR a’、-SO 2-NR aR a’和-SO 2R a；*表示R 1和R 2以及与之相连的碳原子的结合位点，并且上述基团可以任选地被0、1、2、3、4个各自独立地选自下述R 6的取代基所取代，其中R a、R a’以及R 6具有如权利要求1或2所定义。
  4. 如权利要求1-3任一项所述的化合物或其药学可接受的盐、溶剂化物、水合物、立体异构体、立体异构体混合物或立体异构体外消旋混合物，其中X选自CR aR a’、NR a、O和S，优选为O；其中，R a、R a’选自氢、C 1-C 8烷基、C 3-C 8环烷基、羟基、卤素、C 1-C 8卤代烷基、C 1-C 8烷基氨基、二C 1-C 8烷基氨基，或者R a、R a’以及与之相连的原子环合成为3-9元环烷基或者杂环烷基，优选为氢、卤素或C 1-C 8烷基。
  5. 如权利要求1-4任一项所述的化合物或其药学可接受的盐、溶剂化物、水合物、立体异构体、立体异构体混合物或立体异构体外消旋混合物，其中，R 4优选为Cy 2、-NHC(O)R a、-C(O)NR aR a’或-NHC(O)NR aR a’，其中Cy 2、R a、R a’如上述权利要求1-4任一项所定义。
  6. 如权利要求1-5任一项所述的化合物或其药学可接受的盐、溶剂化物、水合物、立体异构体、立体异构体混合物或立体异构体外消旋混合物，其中，Cy 2选自苯基、吡啶基、吡嗪基、环丙基、环戊基、环己基、呋喃基、噻唑基、哌啶基、哌嗪基、噁唑基、咪唑基和噻吩基；其中Cy 2更优选为吡唑基、咪唑基、噁唑基、噻唑基、苯基和吡啶基；并且所述Cy 2可以任选地被C 1-C 8烷基、C 1-C 8烷氧基、C 3-C 9环烷基、C 3-C 9杂环基、C 1-C 8卤代烷基、卤素、氰基、磺酸基、硝基或羟基所取代。
  7. 如权利要求1-6任一项所述的化合物或其药学可接受的盐、溶剂化物、水合物、立体异构体、立体异构体混合物或立体异构体外消旋混合物，其中，R a和R a’优选为氢、卤素或C 1-C 8烷基。
  8. 如权利要求1-7任一项所述的化合物或其药学可接受的盐、溶剂化物、水合物、立体异构体、立体异构体混合物或立体异构体外消旋混合物，其中所述化合物具有选自以下的结构：
    Figure PCTCN2019088221-appb-100005
    Figure PCTCN2019088221-appb-100006
    Figure PCTCN2019088221-appb-100007
    Figure PCTCN2019088221-appb-100008
    Figure PCTCN2019088221-appb-100009
  9. 一种药物组合物其包含权利要求1-8任意一项所述的化合物或其药学可接受的盐、溶剂化物、水合物、立体异构体、立体异构体混合物或立体异构体外消旋混合物，以及药学上可接受的载体。
  10. 如权利要求9所述的药物组合物或者药物制剂，其进一步包含另外的治疗剂和/或免疫检查点抑制剂，所述另外的治疗剂优选地选自苯丁酸氮芥、美法仑、环磷酰胺、异环磷酰胺、白消安、卡莫司汀、洛莫司汀、链脲佐菌素、顺铂、卡铂、奥沙利铂、达卡巴嗪、替莫唑胺、丙卡巴肼、甲氨蝶呤、氟尿嘧啶、阿糖胞苷、吉西他滨、巯基嘌呤、氟达拉滨、长春碱、长春新碱、长春瑞滨、紫杉醇、多西紫杉醇、拓扑替康、伊立替康、依托泊苷、曲贝替定、更生霉素、多柔比星、表柔比星、道诺霉素、米托蒽醌、博来霉素、丝裂霉素C、伊沙匹隆、他莫昔芬、氟他胺、戈那瑞林类似物、甲地孕酮、强的松、地塞米松、甲泼尼龙、沙利度胺、干扰素α、亚叶酸钙、西罗莫司、西罗莫司脂化物、依维莫司、阿法替尼、alisertib、amuvatinib、阿帕替尼、阿西替尼、硼替佐米、波舒替尼、布立尼布、卡博替尼、西地尼布、crenolanib、克卓替尼、达拉菲尼、达可替尼、达努塞替、达沙替尼、多维替尼、厄洛替尼、foretinib、ganetespib、吉非替尼、依鲁替尼、埃克替尼、伊马替尼、iniparib、拉帕替尼、lenvatinib、linifanib、linsitinib、马赛替尼、momelotinib、莫替沙尼、来那替尼、尼罗替尼、niraparib、oprozomib、olaparib、帕唑帕尼、pictilisib、普纳替尼、quizartinib、瑞格菲尼、rigosertib、rucaparib、鲁索利替尼、塞卡替尼、saridegib、索拉非尼、舒尼替尼、替拉替尼、tivantinib、替沃扎尼、托法替尼、曲美替尼、凡德他尼、维利帕尼、威罗菲尼、维莫德吉、volasertib、阿仑单抗、贝伐单抗、贝伦妥单抗维多汀、卡妥索单抗、西妥昔单抗、地诺单抗、吉妥珠单抗、伊匹单抗、尼妥珠单抗、奥法木单抗、帕尼 单抗、利妥昔单抗、托西莫单抗、曲妥珠单抗IDO抑制剂、抗PD-1抗体、抗PD-L1抗体、LAG3抗体、TIM-3抗体及抗CTLA-4抗体。
  11. 如权利要求1-8任一项所述的化合物或其药学可接受的盐、溶剂化物、水合物、立体异构体、立体异构体混合物或立体异构体外消旋混合物或者如权利要求9-10任一项所述的药物组合物在制备用于通过抑制CSF1R来预防和/或治疗肿瘤、癌症、病毒感染、器官移植排斥、神经退行性疾病、注意力相关疾病或自身免疫性疾病的药物中的应用。
  12. 如权利要求11所述的用途，其中，所述肿瘤或癌症选自皮肤癌、膀胱癌、卵巢癌、乳腺癌、胃癌、胰腺癌、前列腺癌、结肠癌、肺癌、骨癌、脑癌、神经细胞瘤、直肠癌、结肠癌、家族性腺瘤性息肉性癌、遗传性非息肉性结直肠癌、食管癌、唇癌、喉癌、下咽癌、舌癌、唾液腺癌、胃癌、腺癌、甲状腺髓样癌、乳头状甲状腺癌、肾癌、肾实质癌、卵巢癌、宫颈癌、子宫体癌、子宫内膜癌、绒毛膜癌、胰腺癌、前列腺癌、睾丸癌、泌尿癌、黑素瘤、脑肿瘤诸如成胶质细胞瘤、星形细胞瘤、脑膜瘤、成神经管细胞瘤和外周神经外胚层肿瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、伯基特淋巴瘤、急性淋巴性白血病(ALL)、慢性淋巴性白血病(CLL)、急性骨髓性白血病(AML)、慢性粒细胞白血病(CML)、成人T细胞白血病淋巴瘤、弥漫性大B细胞淋巴瘤(DLBCL)、肝细胞癌、胆囊癌、支气管癌、小细胞肺癌、非小细胞肺癌、多发性骨髓瘤、基底细胞瘤、畸胎瘤、成视网膜细胞瘤、脉络膜黑素瘤、精原细胞瘤、横纹肌肉瘤、颅咽管瘤、骨肉瘤、软骨肉瘤、 肌肉瘤、脂肪肉瘤、纤维肉瘤、尤因肉瘤或浆细胞瘤。
  13. 一种预防和/或治疗肿瘤、癌症、病毒感染、器官移植排斥、神经退行性疾病、注意力相关疾病或自身免疫性疾病的方法，其包括向有此需要的哺乳动物施用权利要求1-8所述的化合物或其药学可接受的盐、溶剂化物、水合物、立体异构体、立体异构体混合物或立体异构体外消旋混合物或权利要求9-10所述的药物组合物。
  14. 一种抑制CSF1R的方法，其包括使权利要求1-8任一项的化合物或其药学可接受的盐、溶剂化物、水合物、立体异构体、立体异构体混合物或立体异构体外消旋混合物或者权利要求9或10所述的药物组合物或药物制剂暴露于所述CSF1R。
  15. 一种预防和/或治疗可通过抑制CSF1R预防和/或治疗之疾病的方法，其包括向有此需要的对象施用权利要求1-8任一项的化合物或其药学可接受的盐、溶剂化物、水合物、立体异构体、立体异构体混合物或立体异构体外消旋混合物或者权利要求9或10所述的药物组合物或药物制剂。
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EP3744718A1 (en) 2020-12-02
CN111548343B (zh) 2021-06-01
CN111518016A (zh) 2020-08-11
CN111548343A (zh) 2020-08-18
US20200399265A1 (en) 2020-12-24
CN111518016B (zh) 2022-02-25
CN111484442B (zh) 2021-11-09
CN111295380A (zh) 2020-06-16
JP2021520418A (ja) 2021-08-19
US11591328B2 (en) 2023-02-28
CN111295380B (zh) 2020-11-20
JP7090958B2 (ja) 2022-06-27
CN111484442A (zh) 2020-08-04

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