WO2019141153A1 - 吲哚胺2,3-双加氧酶抑制剂及其用途 - Google Patents

吲哚胺2,3-双加氧酶抑制剂及其用途 Download PDF

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WO2019141153A1
WO2019141153A1 PCT/CN2019/071704 CN2019071704W WO2019141153A1 WO 2019141153 A1 WO2019141153 A1 WO 2019141153A1 CN 2019071704 W CN2019071704 W CN 2019071704W WO 2019141153 A1 WO2019141153 A1 WO 2019141153A1
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compound
group
alkyl
amino
solvate
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PCT/CN2019/071704
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French (fr)
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李磐
温俏冬
王骥
甘泉
路杨
杨东晖
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杭州阿诺生物医药科技有限公司
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Priority to CN201980004340.2A priority Critical patent/CN111406050B/zh
Publication of WO2019141153A1 publication Critical patent/WO2019141153A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • 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
    • A61P37/02—Immunomodulators
    • 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
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/08—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing alicyclic 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
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/08—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing alicyclic 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
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to a novel guanamine 2,3-dioxygenase (IDO) inhibitor having inhibitory activity against tryptophan metabolism, a pharmaceutical composition comprising the IDO inhibitor, and the IDO inhibitor and The use of a pharmaceutical composition for the treatment of a disease associated with abnormal IDO activity.
  • IDO guanamine 2,3-dioxygenase
  • Tryptophan is an alpha-amino acid used in protein biosynthesis. It contains an alpha-amino group, an alpha-carboxylic acid group and a side chain oxime. It is essential for human beings. The human body cannot synthesize it, but must be obtained from the diet. Tryptophan is also a precursor to the synthetic neurotransmitter serotonin and the hormone N-acetyl-5-methoxytryptamine.
  • the heme-dependent enzyme guanamine 2,3-dioxygenase (also known as IDO, or IDO1) is a metabolic enzyme responsible for converting tryptophan to N-formyl-kynurenine, which is a color ammonia.
  • N-formyl-kynurenine is a precursor of a variety of bioactive molecules, kynurenine (or Kyn), which has immunomodulatory functions (Schwarcz et al, Nat. Rev. Neurosci. 2012; 13(7): 465).
  • IDO Indoleamine 2,3-dioxygenase
  • solid tumors Uyttenhove et al, Nat. Med. 2003; 10: 1269
  • IDO is induced by pro-inflammatory factors in tumors, including type I and type II interferons produced by infiltrating lymphocytes (Tnani and Bayard, Biochim Biophys Acta. 1999; 1451(l): 59; Mellor and Munn, Nat.
  • IDO In the tumor immune microenvironment, activated or overexpressed IDO results in depletion of tryptophan, which in turn leads to T cell death, inactivation of the immune system, and ultimately to tumor immunotolerance and immune escape.
  • IDO has become an important target for immunotherapy such as tumors.
  • IDO In addition to tumors, IDO is also associated with viral infection, depression, organ transplant rejection, or autoimmune disease (Johnson and Munn, Immunol. Invest. 2012; 41(6-7): 765).
  • drugs that target IDO are also of great value for treating the above diseases.
  • IDO inhibitors can be used to activate T cells, thereby increasing the activation of T cells when T cells are inhibited by viruses such as pregnancy, malignancy or HIV. Forcing IDO induction in cancer cells has been shown to have a survival advantage (Uyttenhove et al, Nat Med. 2003; 10:1269). In addition, in vivo studies have shown that IDO inhibitors reduce lymphocyte dependence by reducing kynurenine levels during tumor growth (Liu et al, Blood. 2010; 115(17): 3520).
  • IDO inhibitors have synergistic effects when combined with other oncology drugs, such as radiation, chemotherapy or vaccines (Koblish et al, Mol. Cancer Ther. 2010; 9(2): 489; Hou et al, Cancer Res. 2007; 67(2): 792; Sharma et al, Blood. 2009; 113(24): 6102).
  • the invention provides a compound of formula (I), a salt, solvate, prodrug, metabolite, oxynitride, stereoisomer or isotopic derivative thereof:
  • Cy 1 is selected from a 5-15 membered ring optionally substituted by a substituent selected from the group consisting of halogen, hydroxy, C 1-6 alkyl, amino, halo C 1-6 alkyl, fluorenyl, a C 1-6 alkyl fluorenyl group, a C 1-6 alkylamino group, a di(C 1-6 alkyl)amino group, and a cyano group;
  • Cy 2 is selected from C 6-10 membered cycloalkyl, C 6-10 membered heterocyclyl, C 6-10 membered aryl or C 6-10 optionally substituted with one, two or more R 2 a heteroaryl group; preferably a phenyl group, a pyridyl group, a cyclohexyl group, a piperidinyl group, a piperazinyl group, a pyrazinyl group, a pyrimidinyl group, a morpholinyl group substituted by one, two or more R 2 ;
  • R 1 and R 2 are independently selected from the group consisting of a hydrogen atom, a halogen, a hydroxyl group, a nitro group, a cyano group, a sulfonic acid group, a C 1-6 alkyl group, a C 3-6 cycloalkyl group, a C 2-6 alkenyl group, C 2-6 alkynyl, C 1-6
  • n are integers selected from 0, 1, 2, 3 and 4;
  • R a, R b are each independently selected from hydrogen, C 1 -C 6 alkyl or C 3 - 6 cycloalkyl;
  • X is selected from CR a R b , NR e or O;
  • Y is selected from CR e or N; wherein R e represents hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl, C 1-6 haloalkyl.
  • a compound, a salt, a solvate, a prodrug, a metabolite, an oxynitride, a stereoisomer or an isotopic derivative thereof which is represented by the formula (II):
  • Cy 1 is selected from the group consisting of:
  • R 3 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl;
  • the above group may be one or more selected from the group consisting of halogen, hydroxy, C 1-6 alkyl, amino, halogenated C 1-6 alkyl, decyl, C 1-6 alkyl fluorenyl, C 1-6 alkane Substituted by a substituent of a benzylamino group, a di(C 1-6 alkyl)amino group or a cyano group.
  • the invention provides a compound, salt, solvate, prodrug, metabolite, oxynitride, stereoisomer or isotopic derivative thereof, as shown in formula (III):
  • R 1 , R 2 , R a , R b , X, Y, W 1 , W 2 , W 3 , W 4 , m, n, p are as defined in formula II.
  • the invention provides a compound, salt, solvate, prodrug, metabolite, oxynitride, stereoisomer or isotopic derivative thereof, as shown in formula (IV):
  • Q 1 and Q 2 are each independently selected from CR a R b , NR e or O;
  • Q 3 is selected from CR a or N; wherein R 1 , R 2 , R a , R b , R e , X, Y , W 1 , W 2 , W 3 , W 4 , m, p are as defined in formula II;
  • the compound of formula II has the structure of formula (V):
  • R 1 , R 2 , R a , R b , X, Y, W 1 , W 2 , W 3 , W 4 , m, p are as defined in the above formula II.
  • all compound structures of the invention also include stereoisomers (including: enantiomeric, diastereomeric, geometric, conformional, and rotational) that may be present.
  • stereoisomers including: enantiomeric, diastereomeric, geometric, conformional, and rotational
  • the R and S configurations of each chiral center, the E and Z isomers of each olefinic double bond are included in this invention.
  • the position of the substituent can also be freely rotated, for example:
  • Structural formula Also represents: Also represents its tautomer:
  • the compounds of the present invention can also be prepared in the form of a pharmaceutically acceptable salt 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, pyruvic acid, 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, hydroxybenzene Formic acid, phenylacetic acid, cinnamic acid, salicylic acid, methanesulfonic acid, benzenesulfonic acid and toluenesulfonic acid.
  • these pharmaceutically acceptable salts of the compounds of the invention are also contemplated.
  • the pharmaceutically acceptable salts of the present invention can be prepared by conventional methods, for example, by dissolving the 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 inorganic thereto. An aqueous acid solution is used to precipitate a salt from the resulting mixture, from which the solvent and the remaining free acid are removed, and then the precipitated salt is separated.
  • a water-miscible organic solvent such as acetone, methanol, ethanol and acetonitrile
  • the present invention provides a method for preventing or treating a disease associated with abnormal activity of indoleamine 2,3-dioxygenase, which comprises administering a compound of the present invention as described above to a patient in need thereof, A salt, solvate, prodrug, metabolite, oxynitride, stereoisomer or isotope derivative thereof or a pharmaceutical composition comprising the same.
  • the present invention provides a method for combating immunosuppression comprising administering to a patient in need thereof a compound of the present invention, a salt, a solvate thereof, a prodrug, a metabolite, an oxynitride, a stereospecific A conformation or isotopic derivative or a pharmaceutical composition comprising the same.
  • the invention also provides the use of a compound of the invention in the manufacture of a medicament for the prevention or treatment of a cancer, a tumor, an inflammatory disease, an autoimmune disease or an immune-mediated disease.
  • the present invention provides a pharmaceutical composition for preventing or treating cancer, a tumor, an inflammatory disease, an autoimmune disease or an immune-mediated disease, which comprises the compound of the present invention as an active ingredient.
  • the present invention provides a method for preventing or treating cancer, a tumor, an inflammatory disease, an autoimmune disease or an immune-mediated disease, which comprises administering a compound of the present invention to a mammal in need thereof.
  • cancer or tumor can 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, neurocytoma, rectal cancer.
  • Colon cancer familial adenomatous polyposis, hereditary non-polyposis colorectal cancer, esophageal cancer, lip cancer, laryngeal cancer, hypopharyngeal carcinoma, tongue cancer, salivary gland cancer, gastric cancer, adenocarcinoma, medullary thyroid carcinoma, Papillary thyroid cancer, renal cancer, renal parenchymal cancer, ovarian cancer, cervical cancer, endometrial cancer, endometrial cancer, choriocarcinoma, pancreatic cancer, prostate cancer, testicular cancer, urinary cancer, melanoma, brain tumor such as Glioblastoma, astrocytoma, meningiomas, medulloblastoma and peripheral neuroectodermal
  • the compound of the present invention or a pharmaceutically acceptable salt thereof when administered in combination with another anticancer agent for treating cancer or a tumor, the compound of the present invention or a pharmaceutically acceptable salt thereof can provide an enhanced anticancer effect.
  • anticancer agents for treating cancer or tumors may include, but are not limited to, cell signaling inhibitors chlorambucil, melphalan, cyclophosphamide, ifosfamide, busulfan, camo Statin, lomustine, streptozotocin, cisplatin, carboplatin, oxaliplatin, dacarbazine, temozolomide, procarbazine, methotrexate, fluorouracil, cytarabine, gemcitabine, thiol Bismuth, fludarabine, vinblastine, vincristine, vinorelbine, paclitaxel, docetaxel, topotecan, irinotecan, etoposide, trobeidine, dactinomycin, doxorubicin, Epirubicin, daunorubicin, mitoxantrone, bleomycin, mitomycin C, ixabepilone, tamoxifen, flu
  • inflammatory diseases may include, but are not limited to, arthritis, rheumatoid arthritis, spondylarthritis, gouty arthritis, osteoarthritis, juvenile arthritis , other arthritic conditions, lupus, systemic lupus erythematosus (SLE), skin-related diseases, psoriasis, eczema, dermatitis, allergic dermatitis, pain, lung disease, lung 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,
  • a compound of the present invention or a pharmaceutically acceptable salt thereof When a compound of the present invention or a pharmaceutically acceptable salt thereof is 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 be provided Enhanced therapeutic effect.
  • therapeutic agents for treating inflammatory diseases, autoimmune diseases, and immune-mediated diseases may include, but are not limited to, steroidal drugs (eg, prednisone, hydrogenated prednisone, methylhydroponone) Pine, cortisone, hydroxycortisone, betamethasone, dexamethasone, etc.), methotrexate, leflunomide, anti-TNF ⁇ agents (eg, etanercept, infliximab, Adali Monoclonal antibodies, etc., calcineurin inhibitors (eg, tacrolimus, pimecrolimus, etc.) and antihistamines (eg, diphenhydramine, hydroxyzine, loratadine, Ibas
  • At least one therapeutic agent selected from the group consisting of statins, ketotifen, cetirizine, levocetirizine, fexofenadine, etc. 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 in an amount effective to be 0.1 to 2,000 mg/kg body weight/day in the case of a mammal including a human body (body weight: about 70 kg). It is preferably from 1 to 1,000 mg/kg body weight/day, and is administered in a single or four divided doses per day, or with/without following a predetermined time.
  • the dosage of the active ingredient can be adjusted based on a number of relevant 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 physician. In some cases, amounts less than the above dosages may be suitable. An amount greater than the above dosage can be used if it does not cause harmful side effects and the amount can be administered in divided doses per day.
  • compositions of the present invention may be formulated into tablets, granules, powders, capsules, syrups, emulsions or for oral administration or parenteral administration, including intramuscular, intravenous and subcutaneous routes, according to any of the conventional methods.
  • parenteral administration including intramuscular, intravenous and subcutaneous routes, according to any of the conventional methods.
  • the form of microemulsion may be formulated into tablets, granules, powders, capsules, syrups, emulsions or for oral administration or parenteral administration, including intramuscular, intravenous and subcutaneous routes, according to any of the conventional methods.
  • the form of microemulsion may be formulated into tablets, granules, powders, capsules, syrups, emulsions or for oral administration or parenteral administration, including intramuscular, intravenous and subcutaneous routes, according to any of the conventional methods.
  • the form of microemulsion may be formulated into tablets, granules, powders, capsules, syrup
  • the pharmaceutical composition of the present invention for oral administration can be prepared by mixing the active ingredient with, for example, a carrier such as cellulose, calcium silicate, corn starch, lactose, sucrose, dextrose, calcium phosphate, stearic acid, hard.
  • a carrier such as cellulose, calcium silicate, corn starch, lactose, sucrose, dextrose, calcium phosphate, stearic acid, hard.
  • Examples of carriers for use in the injectable compositions of the present invention are water, saline solutions, dextrose solutions, glucose-like solutions, alcohols, glycols, ethers (e.g., polyethylene glycol 400), oils, Fatty acids, fatty acid esters, glycerides, surfactants, suspending agents and emulsifiers.
  • Another aspect of the present invention also provides a method of inhibiting guanamine 2,3-dioxygenase comprising the compound of the present invention, a salt, a solvate, a prodrug, a metabolite, an oxynitride
  • the stereoisomer or isotope derivative or pharmaceutical composition is exposed to the indoleamine 2,3-dioxygenase.
  • the compounds of the present invention can be prepared in a variety of ways known to those skilled in the art of organic synthesis, and can be synthesized using the methods described below, as well as synthetic methods known in the art of organic synthetic chemistry or by variations thereof as appreciated by those skilled in the art.
  • the reaction is carried out in a solvent or solvent mixture suitable for the kit materials used and for the transitions achieved.
  • Those skilled in the art of organic synthesis will understand that the functionality present on the molecule is consistent with the proposed transition. This sometimes requires judgment to alter the order or starting materials of the synthetic steps to obtain the desired compounds of the invention.
  • the present invention describes cis- and trans- (or E- and Z-) geometric isomers of the compounds of the invention, and which can be separated into a mixture of isomers or as separate isomers.
  • the compounds of the invention can be isolated in optically active or racemic forms.
  • All methods for preparing the compounds of the invention and the intermediates prepared therein are considered part of the invention.
  • they can be separated by conventional methods, for example by chromatography or fractional crystallization.
  • the end products of the invention are obtained in free (neutral) or salt form depending on the process conditions. Free forms and salts of these end products are within the scope of the invention.
  • one form of the compound can be converted to another form.
  • the free base or acid can be converted to a salt; the salt can be converted to the free compound or another salt; the mixture of isomer compounds of the invention can be separated into the individual isomers.
  • the compounds of the invention may exist in a variety of tautomeric forms in which a hydrogen atom is transposed to other portions of the molecule and thereby the chemical bonds between the atoms of the molecule are rearranged. It should be understood that all tautomeric forms that may be present are included within the invention.
  • substituent when a substituent is referred to as “optionally substituted,” the substituent is selected, for example, from the following substituents such as alkyl, cycloalkyl, aryl, heterocyclyl, halogen, hydroxy, alkane.
  • alkyl or "alkylene” as used herein is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms.
  • C1-6 alkyl means an alkyl group having from 1 to 6 carbon atoms.
  • alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (eg, n-propyl and isopropyl), butyl (eg, n-butyl, isobutyl, t-butyl), and A pentyl group (eg, n-pentyl, isopentyl, neopentyl).
  • alkenyl denotes a straight or branched chain hydrocarbon radical containing one or more double bonds and generally having from 2 to 20 carbon atoms in length.
  • C2-8 alkenyl contains two to eight carbon atoms.
  • Alkenyl groups include, but are not limited to, for example, ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, heptenyl, octenyl, and the like.
  • alkynyl denotes a straight or branched chain hydrocarbon radical containing one or more triple bonds and generally having a length of from 2 to 20 carbon atoms.
  • C2-8 alkynyl contains two to eight carbon atoms.
  • 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.
  • C1-6 alkoxy (or alkyloxy) is intended to include C1, C2, C3, C4, C5 and C6 alkoxy groups. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (eg, n-propoxy and isopropoxy) and t-butoxy.
  • alkylthio or “thioalkoxy” denotes a thio-bridged alkyl group as defined above having the indicated number of carbon atoms; for example, methyl-S- and ethyl-S-.
  • aryl alone or as part of a larger moiety such as “aralkyl”, “aralkyloxy” or “aryloxyalkyl”, refers to a single ring having a total of from 5 to 15 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.
  • the fused aryl group may be attached to another group at a suitable position of the cycloalkyl ring or the aromatic ring.
  • An arrow line drawn from the ring system indicates that the bond can be attached to any suitable ring atom.
  • ring refers to a saturated or unsaturated monocyclic, cyclized, bridged or spiro ring which may optionally contain one or more heteroatoms.
  • a 5-15 membered ring may refer to a 5-15 membered monocyclic ring, a 5-15 membered monocyclic heterocyclic ring, a 5-15 membered ring, a 5-15 membered heterocyclic ring, a 5-15 membered bridged ring, and a 5-membered ring.
  • cycloalkyl refers to a monocyclic or bicyclic cyclic alkyl group.
  • Monocyclic cyclic alkyl refers to a C3-C8 cyclic alkyl group including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and norbornyl.
  • Branched cycloalkyl groups such as 1-methylcyclopropyl and 2-methylcyclopropyl are included in the definition of "cycloalkyl”.
  • the bicyclic cyclic alkyl group includes a bridged ring, a spiro ring or a cycloalkyl group of a fusion ring.
  • cycloalkenyl refers to a monocyclic or bicyclic cyclic alkenyl group.
  • Monocyclic cyclic alkenyl refers to C3-C8 cyclic alkenyl groups 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”.
  • the bicyclic cyclic alkenyl group includes a bridged ring, a spiro ring or a cyclic alkenyl group of a fused ring.
  • Halo or halogen includes fluoro, chloro, bromo and iodo.
  • Haloalkyl is intended to include both 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 groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoro Propyl and heptachloropropyl.
  • haloalkyl group examples include "fluoroalkyl group" which is intended to include a branched and straight-chain saturated aliphatic hydrocarbon group having a specified number of carbon atoms and substituted with one or more fluorine atoms.
  • Haloalkoxy or "haloalkyloxy” denotes an oxo-5 alkyl group as defined above attached via an oxygen bridge having the indicated number of carbon atoms.
  • C1-6 haloalkoxy is intended to include C1, C2, C3, C4, C5 and C6 haloalkoxy groups.
  • Examples of haloalkoxy groups include, but are not limited to, trifluoromethoxy, 2,2,2-trifluoroethoxy, and pentafluoroethoxy.
  • haloalkylthio or “thiohaloalkoxy” denotes a thio bridged haloalkyl group as defined above having the indicated number of carbon atoms; for example, trifluoromethyl-S- and pentafluoroethyl -S-.
  • aryl refers to a monocyclic or bicyclic (and above bicyclic) aryl group which is all carbon atoms.
  • a monocyclic aromatic group means a phenyl group
  • a bicyclic or bicyclic or higher aromatic group means a naphthyl group, a fluorenyl group or the like
  • the aryl bicyclic ring may also be a benzene ring in which a cycloalkyl group is fused or a ring is fused.
  • Alkenyl, or a cycloalkynyl group Alkenyl, or a cycloalkynyl group.
  • heteroaryl means a stable 3-, 4-, 5-, or 7-membered aromatic monocyclic or aromatic bicyclic ring. Or a 7-, 8-, 9-, 10-, 11-, 12-, 13- or 14-membered aromatic polycyclic heterocyclic ring which is completely unsaturated, partially unsaturated, and which contains a carbon atom and 1 , 2, 3 or 4 heteroatoms independently selected from N, O and S; and include any of the following polycyclic groups, wherein any of the heterocycles defined above are fused to a benzene ring.
  • the nitrogen and sulfur heteroatoms can be optionally oxidized.
  • the nitrogen atom is substituted or unsubstituted (i.e., N or NR, wherein R is H or, if defined, another substituent).
  • the heterocycle 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 heterocyclic groups described herein can be substituted on a carbon or nitrogen atom.
  • the nitrogen in the heterocycle can optionally be quaternized.
  • the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to each other.
  • the total number of S and O atoms in the heterocycle is no more than one.
  • heterocycle it is intended to include heteroaryl.
  • aromatic heterocycles include, but are not limited to, acridinyl, azetidinyl, anthracycline, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothienyl, benzoxan Azolyl, benzoxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, carbazolyl, 4aH-carbazolyl, porphyrinyl, chromanyl, chromenyl, porphyrinyl, decahydroquinolinyl, 2H, 6H-1,5,2-dithiazinyl, dihydrofuran[2, 3-b]tetrahydrofuranyl, furyl, furfuryl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-carbazo
  • heterocycloalkyl refers to a monocyclic heteroalkyl system or a bicyclic heteroalkyl system.
  • the monocyclic cycloheteroalkyl group means a 3-8 membered material and contains at least one saturated or unsaturated but not aromatic cyclic alkyl group selected from O, N, S, P.
  • a bicyclic heteroalkyl system refers to a cycloheteroalkyl group fused to a phenyl group, or a cycloalkyl group, or a cycloalkenyl group, or a cycloheteroalkyl group, or a heteroaryl group.
  • bridged ring refers to a polycyclic compound that shares two or more carbon atoms. It can be divided into bicyclic bridge cyclic hydrocarbons and polycyclic bridge cyclic hydrocarbons. The former consists of two alicyclic rings sharing two or more carbon atoms; the latter is a bridge ring composed of three or more rings.
  • spirocyclic refers to a polycyclic ring that shares a carbon atom (called a spiro atom) between the individual rings.
  • substituted means that at least one hydrogen atom is replaced by a non-hydrogen group, provided that the normal valence is maintained and the substitution results in a stable compound.
  • nitrogen atom for example, an amine
  • these nitrogen atoms can be converted into N-oxides by treatment with an oxidizing agent such as mCPBA and/or hydrogen peroxide to obtain other compounds of the present invention.
  • an oxidizing agent such as mCPBA and/or hydrogen peroxide
  • the nitrogen atoms shown and claimed are considered to cover both the nitrogen and its N-oxide (N ⁇ O) derivatives.
  • any variable occurs more than once in any composition or formula of a compound, its definition at each occurrence is independent of its definition in each of the other cases.
  • the group can be optionally substituted with up to three R groups, and R is independently selected from the definition of R on each occurrence.
  • combinations of substituents and/or variables are only permitted if the combination described above produces a stable compound.
  • integer as used herein specifically refers to 0 and a positive integer (eg, 1, 2, 3, 4, 5...n).
  • solvate means a 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 the crystalline solid, the solvate will be capable of being separated.
  • the solvent molecules in the solvate may be present in a regular arrangement and/or a disordered arrangement.
  • Solvates may comprise stoichiometric or non-stoichiometric solvent molecules.
  • “Solvate” encompasses both the solution phase and the 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, baboons, monkeys, horses, cows, pigs, dogs, cats, etc.) and most preferably humans.
  • an 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 of a tissue, system, animal or human sought by a researcher or clinician.
  • a therapeutically effective amount means an amount which results in an improved treatment, cure, prevention or alleviation of a disease, disorder or side effect, or a reduction in disease, as compared to a corresponding subject not receiving the above amount. Or the speed of progression of the condition.
  • An effective amount can be administered in one or more administrations, administrations or dosages and is not intended to be limited by the particular formulation or route of administration. The term also includes an effective amount within its scope that enhances normal physiological function.
  • treating includes any effect that results in an amelioration of a condition, disease, disorder, etc., such as reducing, reducing, regulating, ameliorating or eliminating, or ameliorating the symptoms thereof.
  • composition refers to a combination of an active agent with an inert or active carrier, such that the composition is especially suitable for in vivo or ex vivo diagnosis or treatment.
  • bases include, but are not limited to, alkali metal (e.g., sodium) hydroxides, alkaline earth metal (e.g., magnesium) hydroxides, ammonia, and the like.
  • Salts of the Compounds of the Invention For therapeutic use, the salts of the compounds of the invention are expected to be pharmaceutically acceptable. However, salts of non-pharmaceutically acceptable acids and bases can also be used, for example, in the preparation or purification of pharmaceutical compounds.
  • pharmaceutically acceptable is used herein to mean those compounds, substances, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity or irritation. Sex, allergic reactions and/or other problems or complications, and commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable carrier means a pharmaceutical substance, composition or vehicle, such as a liquid or solid filler, diluent, excipient, manufacturing aid (eg, lubricant, talc, magnesium stearate, Calcium stearate or zinc stearate or stearic acid) or a solvent encapsulating material which involves carrying or transporting a subject compound from one organ or part of the body to another organ or part of the body.
  • manufacturing aid eg, lubricant, talc, magnesium stearate, Calcium stearate or zinc stearate or stearic acid
  • solvent encapsulating material which involves carrying or transporting a subject compound from one organ or part of the body to another organ or part of the body.
  • Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not deleterious to the patient.
  • composition means a composition comprising a compound of the invention and at least one other pharmaceutically acceptable carrier.
  • “Pharmaceutically acceptable carrier” refers to a medium that is generally accepted in the art for delivery of a biologically active agent to an animal, particularly a mammal, including (ie) an adjuvant, excipient or vehicle, such as a diluent, preservative , fillers, flow regulators, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, fragrances, antibacterials, antifungals, lubricants and dispersing agents, depending on The mode of administration and the nature of the dosage form.
  • an adjuvant, excipient or vehicle such as a diluent, preservative , fillers, flow regulators, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, fragrances, antibacterials, antifungals, lubricants and dispersing agents, depending on The mode of
  • acceptable refers to a prescription component or active ingredient that does not have an unduly detrimental effect on the health of a general therapeutic target.
  • cancer refers to abnormal growth of an uncontrollable cell and is capable of metastasis (propagation) under certain conditions.
  • This type of cancer includes, but is not limited to, solid tumors (eg, bladder, intestine, brain, chest, uterus, heart, kidney, lung, lymphoid tissue (lymphoma), ovary, pancreas or other endocrine organs (eg thyroid), prostate) , skin (melanoma) or hematoma (eg non-leukocytic leukemia).
  • administered in combination refers to the administration of several selected therapeutic agents to a patient, administered at the same or different times, in the same or different modes of administration.
  • the term “enhancement” or “enhancement”, as used herein, means that the desired result can be increased or prolonged in potency or duration.
  • the term “enhanced” in terms of enhancing the therapeutic effect of a drug means the ability of the drug to increase or extend the potency or duration in the system.
  • potency value refers to the ability to maximize the effectiveness of another therapeutic agent in an ideal system.
  • immune disease refers to a disease or condition that produces an adverse or deleterious response to an endogenous or exogenous antigen. The result is usually a dysfunction of the cell, or it can destroy and cause dysfunction, or destroy an organ or tissue that may produce an immune symptom.
  • 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, baboons and monkeys; agricultural animals such as cattle, horses, goats, sheep, pigs; livestock such as rabbits, dogs; experimental animals including rodents, Such as rats, mice and guinea pigs.
  • Non-mammals include, but are not limited to, birds, fish, and the like.
  • the selected mammal is a human.
  • treatment include alleviating, inhibiting, or ameliorating the symptoms or condition of a disease; inhibiting the production of complications; ameliorating or preventing a potential metabolic syndrome; inhibiting the production of a disease or condition, Such as controlling the development of a disease or condition; reducing a disease or symptom; making a disease or symptom diminished; reducing a complication caused by the disease or symptom, or preventing or treating a symptom caused by the disease or symptom.
  • a compound or pharmaceutical composition after administration, can ameliorate a disease, condition, or condition, particularly if the severity is improved, delays the onset, slows progression, or reduces the duration of the condition. Whether administered fixedly or temporarily, continuously or intermittently, it may be attributable to or related to the administration.
  • Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ocular, pulmonary, transdermal, vaginal, oral canal. , nasal administration and topical administration.
  • parenteral administration includes intramuscular, subcutaneous, intravenous, intramedullary, ventricular, intraperitoneal, intralymphatic, and intranasal injections.
  • the modes of administration of the compounds described herein are topical rather than systemic.
  • the drug depot is administered by implantation (e.g., subcutaneously or intramuscularly) or by intramuscular injection.
  • the drug is administered by a targeted drug delivery system.
  • liposomes encapsulated by organ-specific antibodies In this particular embodiment, the liposomes are selectively directed to a particular organ and absorbed.
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of one or more compounds of the invention formulated together 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 invention may be administered by any suitable means for any of the above uses, for example, orally, such as tablets, pills, powders, granules, elixirs, elixirs, suspensions (including nanosuspensions, microsuspensions, spray dried Dispersion), syrup and emulsion; sublingual; buccal; parenteral, such as by subcutaneous, intravenous, intramuscular or intrasternal injection or infusion techniques (eg, in sterile injectable aqueous or nonaqueous solutions or suspensions) Nasal, including nasal administration, 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 usually administered using a pharmaceutical carrier selected based on the chosen route of administration and standard pharmaceutical practice.
  • Pharmaceutical carriers are formulated according to a number of 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.
  • Pharmaceutically acceptable carriers include aqueous and non-aqueous liquid vehicles and various solid and semi-solid dosage forms.
  • the above carriers may include a number of different ingredients and additives in addition to the active ingredients, which are included in the formulation for various reasons well known to those skilled in the art, such as stabilizing active agents, binders and the like.
  • suitable pharmaceutical carriers and carriers can be found in a number of readily available sources, for example, Allen, LV Jr. et. al. Remington: The Science and Practice of Pharmacy (2 Volumes), 22nd Edition. (2012), Pharmaceutical Press.
  • the dosage regimen of the compounds of the invention will vary depending on known factors, such as the pharmacodynamic properties of the particular agent and its mode of administration and route; the species, age, sex, health, medical condition and weight of the recipient The nature and extent of the symptoms; the type of treatment at the same time; the frequency of treatment; the route of administration, the kidney and liver function of the patient, and the desired effect.
  • the daily oral dose of each active ingredient should be from about 0.001 mg/day to about 10-5000 mg/day, preferably from about 0.01 mg/day to about 1000 mg/day, and most preferably The ground is from about 0.1 mg/day to about 250 mg/day.
  • the most preferred intravenous dose during a constant rate infusion should be from about 0.01 mg/kg/min to about 10 mg/kg/min.
  • the compounds of the invention may be administered in a single daily dose, or the total daily dose may be administered in divided doses of two, three or four times daily.
  • the compounds are usually administered in a suitable pharmaceutical diluent, excipient or carrier, as appropriate in accordance with the intended mode of administration (for example, oral administration of tablets, capsules, elixirs and syrups) and in accordance with conventional pharmaceutical practice. Administration is carried out in the form of a mixture of the medium and the drug carriers.
  • Dosage forms suitable for administration may contain from about 1 mg to about 2000 mg of active ingredient per dosage unit.
  • the active ingredient will generally be present in an amount of from about 0.1% to about 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 size 1 gelatin capsules.
  • a typical injectable preparation can be prepared by sterilizing at least one compound of the invention (250 mg) in a vial, lyophilizing and sealing in a sterile manner. 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 (individually 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 may be used alone, in combination with other compounds of the invention or in combination with one or more other therapeutic agents, such as anti-cancer agents or other pharmaceutically active substances.
  • the compounds of the invention (which may be used in a suitable hydrated form) and/or the pharmaceutical compositions of the invention are formulated in pharmaceutical dosage forms.
  • the actual dosage level of the active ingredient in the pharmaceutical compositions of the present invention can be varied to achieve an amount of active ingredient that is effective to achieve a desired therapeutic response, composition, and mode of administration for a particular patient without toxicity to the patient.
  • the selected dosage level will depend on a variety of factors, including the activity of the particular compound of the invention or its ester, salt or amide employed; the route of administration; the time of administration; the excretion rate of the particular compound employed; the rate and extent of absorption. Duration of treatment; other drugs, compounds and/or substances used in combination with the particular compound used; factors known in the medical arts, such as age, sex, weight, condition, general health and prior medical history of the patient being treated.
  • a physician or veterinarian having ordinary skill in the art can readily determine and prescribe an effective amount of the desired pharmaceutical composition.
  • a physician or veterinarian can begin the contest of the compounds of the invention used in the pharmaceutical compositions below the desired level and gradually increase the dosage until the desired effect is achieved.
  • a suitable daily dose of a compound of the invention will be the amount of the compound which is the lowest dose effective to produce a therapeutic effect.
  • Such effective dosage will generally depend on the above factors.
  • 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 per 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. In certain aspects of the invention, the administration is once a day.
  • the compound of the present invention can be administered alone, it is preferred to administer the compound in the form of a pharmaceutical preparation (composition).
  • Kits/product packages are also described herein for use in the treatment of the above indications. These kits may be comprised of a conveyor, a pack or a container, which may be divided into a plurality of compartments to accommodate one or more containers, such as vials, test tubes, and the like, each containing a container A single component of the method. Suitable containers include bottles, vials, syringes and test tubes. The container is made of materials such as glass or plastic that are acceptable.
  • the container may contain one or more of the compounds described herein, and the compound may exist as a pharmaceutical component or as a mixture with other ingredients described herein.
  • the container may have a sterile outlet (for example, the container may be an IV bag or bottle, and the stopper may be pierced by a hypodermic needle).
  • kits may carry a compound, as well as instructions, labels or instructions for use as described herein.
  • a typical kit may include one or more containers that are adapted to commercial promotion and user demand for compound use, each container containing one or more materials (eg, reagents, or concentrated mother liquor, and / Or equipment). 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, as well as instructions for the internal packaging. The entire set of instructions must be included.
  • materials eg, reagents, or concentrated mother liquor, and / Or equipment.
  • 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, as well as instructions for the internal packaging. The entire set of instructions must be included.
  • the label can be displayed on or closely related to the container.
  • the presence of a label on a container means that the label letter, number or other feature is pasted, molded, or engraved on the container; the label may also be present in a container or shipping box containing a plurality of containers, such as in a product insert.
  • a label can be used to indicate a particular therapeutic use of the contents.
  • the label may also indicate a usage statement for the content, such as described in the above method.
  • the compounds of the present invention can be synthesized by known procedures with reference to the following description. All purchased solvents and reagents are used without treatment. All synthetic compounds can be verified by, but not limited to, the following methods: LCMS (liquid chromatography mass spectrometry) and NMR (nuclear magnetic resonance). Nuclear magnetic resonance (NMR) was measured by a Bruker AVANCE-500 nuclear magnetic apparatus. The deuterated solvents used in the determination were deuterated dimethyl sulfoxide (d6-DMSO), deuterated chloroform (CDCl3), and tetramethylsilane (TMS). Internal standard.
  • d6-DMSO deuterated dimethyl sulfoxide
  • CDCl3 deuterated chloroform
  • TMS tetramethylsilane
  • the compounds of the present invention can be prepared by referring to the following.
  • the first step ethyl 4-oxocyclohexaneacetate (2.0 g, 10.86 mmol) was dissolved in 60 mL of ultra-dry tetrahydrofuran, and bis(trimethylsilane) was added dropwise to the solution under a nitrogen atmosphere at -78 °C. Sodium amide (2 mol/L tetrahydrofuran solution) (6.5 mL, 13.03 mmol). The reaction solution was stirred at this temperature for 1 hour. A solution of N-phenylbis(trifluoromethanesulfonyl)imide (4.65 g, 13.03 mmol) in tetrahydrofuran (20 mL) was then added.
  • reaction mixture was further stirred at room temperature overnight until the consumption of the starting material was completely detected by TLC.
  • the reaction mixture was quenched with 5 mL aqueous EtOAc. 50 mL of methyl tert-butyl ether was added to the residue, and the organic layer was washed with a 1.0 mol/L sodium hydroxide solution (3 ⁇ 20 mL), and washed with 20 mL of brine. The organic layer was dried with anhydrous sodium sulfate, filtered and evaporated.
  • Second step The crude intermediate (1.0 eq) obtained in the previous step was dissolved in acetic acid, and the mixture was stirred at 100 ° C for 19 hours, and then the mixture was concentrated. The residue was purified by reverse high performance liquid preparative chromatography to give the final compound.
  • the first step triethyl phosphonoacetate (968 mg, 4.32 mmol) was dissolved in 16 mL of dry dry tetrahydrofuran, and sodium tert-butoxide (415 mg, 4.32 mmol) was added at 0 ° C ice bath. After 10 minutes, a solution of the intermediate E' (1 g, 4.12 mmol) in tetrahydrofuran (4 mL) was added to the mixture. After 2 hours of reaction, it was quenched with water. The aqueous solution was extracted with EtOAc (EtOAc)EtOAc.
  • the second step NaH (383 mg, 9.57 mmol) was added to 15 mL of dimethyl sulfoxide, and trimethylsulfoxonium iodide (2.11 g, 9.57 mmol) was added to the suspension. The mixture was stirred at room temperature for 1.5 hours. Then a solution of the intermediate F" (1.0 g, 3.19 mmol) in dimethyl sulfoxide (5 mL) was added to the reaction mixture. The reaction was stirred at room temperature overnight. The intermediate G" (820 mg) was obtained by a column chromatography to give a colorless oily liquid, yield 78%.
  • the fourth step the intermediate H" (1.0 eq) was dissolved in N,N-dimethylformamide, and HATU (1.1 eq) and diisopropylethylamine (3.0 eq) were added. Substituted 1,2-diamine or substituted anthranilidine (1.5 eq). The reaction mixture was stirred at 30 ° C overnight. Then water and ethyl acetate were added to the reaction mixture, and the organic phase was washed with saturated brine. The sodium was dried, filtered and concentrated. The obtained crude intermediate was dissolved in acetic acid, and the mixture was stirred at 100 ° C for 19 hours, and then the reaction mixture was concentrated.
  • the third step the intermediate I"' (1.0 eq) was dissolved in N,N-dimethylformamide, and HATU (1.1 eq) and diisopropylethylamine (3.0 eq) were added. The substituted 1,2-diamine or substituted anthranilidine (1.5 eq) was added. The reaction mixture was stirred at 30 ° C overnight. Then water and ethyl acetate were added to the mixture and the organic phase was washed with brine. Drying over sodium sulfate, filtration and concentration. The obtained crude intermediate was dissolved in acetic acid, and the mixture was stirred at 100 ° C for 19 hours, then the reaction mixture was concentrated, and the residue was purified by reverse-purification preparative chromatography.
  • Compound 19 and Compound 20 were obtained by resolution of Compound 18 from Example 2 by a chiral column. Among them, the compound 19 corresponds to the former in the chiral resolution, and the compound 20 corresponds to the latter in the chiral resolution.
  • Compound 23 and Compound 24 were obtained by subjecting compound 22 of Example 3 to a chiral column. Among them, the compound 23 corresponds to the former in the chiral resolution, and the compound 24 corresponds to the latter in the chiral resolution.
  • Compound 15 and Compound 16 were obtained by subjecting Compound 14 of Example 4 to a chiral column. Among them, the compound 15 corresponds to the former in the chiral resolution, and the compound 16 corresponds to the latter in the chiral resolution.
  • Compound 31 and Compound 32 were obtained by subjecting compound 30 of Example 11 to a chiral column. Among them, the compound 31 corresponds to the former in the chiral resolution, and the compound 32 corresponds to the latter in the chiral resolution.
  • Compound 53 and Compound 54 were obtained by resolution of compound 52 from Example 21 by a chiral column. Among them, the compound 53 corresponds to the former in the chiral resolution, and the compound 54 corresponds to the latter in the chiral resolution.
  • the method for testing the activity of the compounds of the present invention in Hela cells and HEK293 cells expressing human IDO1 protein is referred to the method disclosed in the prior art ("Blood, 2010, 115(17): 3520-3530").
  • the specific test is as follows:
  • Hela cells were seeded in 96-well culture plates and cultured for 24 hours at 37 ° C in a 100% relative humidity, 5% CO 2 incubator.
  • the compound was dissolved in DMSO and diluted to the appropriate concentration, and the candidate compound was diluted 100-fold to the final concentration with DMEM medium containing interferon-gamma and 10% fetal bovine serum.
  • the old medium in the 96-well plate was discarded, and 200 ⁇ l of the medium containing the compound and interferon- ⁇ in the previous step was added to each well.
  • the tryptophan content in the medium was 16 mg/l, and the interferon- ⁇ concentration was 50 ng/ml.
  • HEK293-IDO cells highly expressing human IDO1 protein were prepared by electroporation, and the cells were seeded in a 96-well culture plate and cultured at 37 ° C, 100% relative humidity, 5% CO 2 incubator for 24 hours.
  • the compound was dissolved in DMSO and diluted to the appropriate concentration, and the candidate compound was diluted 100-fold to the final concentration with DMEM medium containing 10% fetal bovine serum.
  • the old medium in the 96-well plate was discarded, and 200 ⁇ l of the medium containing the compound in the previous step was added to each well.
  • the tryptophan content in the medium was 16 mg/l.

Abstract

涉及式(I)所示的化合物，包含所述式 (I) 化合物的药物组合物，其抑制吲哚胺2,3-双加氧酶的方法以及其在医学上的用途。

Description

吲哚胺2,3-双加氧酶抑制剂及其用途 技术领域
本发明涉及一种对色氨酸代谢具有抑制活性的新型吲哚胺2,3-双加氧酶(IDO)抑制剂，包含所述IDO抑制剂的药物组合物，以及所述IDO抑制剂和药物组合物用于治疗与IDO活性异常相关疾病的用途。
背景技术
色氨酸(TRP)是一种用于蛋白质生物合成的α-氨基酸。它含有α-氨基、α-羧酸基团和侧链吲哚。它是人类必不可少的，人的身体不能合成它，而必须从饮食中获得。色氨酸也是合成神经递质5-羟色胺(serotonin)和激素N-乙酰-5-甲氧基色胺(melatonin)的前体。血红素依赖酶吲哚胺2,3-双加氧酶(也叫IDO,或IDO1)是肝外负责将色氨酸转换为N-甲酰基-犬尿氨酸的代谢酶，这是色氨酸代谢过程中的第一步，也是整个过程的限速步骤。N-甲酰基-犬尿氨酸是多种生物活性分子犬尿氨酸(kynurenine，或Kyn)的前体，犬尿氨酸具有免疫调节功能(Schwarcz et al,Nat.Rev.Neurosci.2012；13(7):465)。
吲哚胺2,3-双加氧酶(IDO)广泛表达于实体肿瘤(Uyttenhove et al,Nat.Med.2003；10:1269)，在原发癌和转移癌细胞中也均有表达。在肿瘤中IDO由促炎因子诱导产生，包括由浸润淋巴细胞产生的I型和II型干扰素(Tnani and Bayard,Biochim Biophys Acta.1999；1451(l):59；Mellor and Munn,Nat.Rev.Immunol.2004；4(10):762；Munn,Front Biosci.2012；4:734)和转化生长因子-β(TGF-β)(Pallotta et al,Nat.Immunol.201 1；12(9):870)。近年来，越来越多的证据表明，IDO作为一种诱导型酶，在免疫细胞调节中起着重要作用。色氨酸水平的降低和犬尿氨酸的增加会抑制免疫效应细胞，并通过诱导和维持调节性T细胞促进适应性免疫抑制；免疫系统中色氨酸的浓度和T细胞正性相关。在肿瘤免疫微环境中，活化或过表达的IDO导致色氨酸耗竭，而后导致T细胞死亡、免疫系统失活，并最终导致发生肿瘤免疫耐受和免疫逃逸。现有研究表明，由IDO所导致的免疫平衡失调深入的参与了肿瘤的生成和进展。因而IDO成为肿瘤等免疫治疗的重要靶点。IDO除了和肿瘤相关外，也和病毒感染、抑郁、器官移植排斥或自身免疫性疾病相关(Johnson and Munn,Immunol.Invest.2012；41(6-7):765)。因而，靶向IDO的药物对于治疗上述疾病也具有巨大价值。总之，开发具有活性和选择性的IDO抑制剂，通过调节犬尿氨酸通道并维持身体内色氨酸水平来有效地治疗由于犬尿氨酸途径中的有害物质而产生的疾病，无论是作为 单剂或联合疗法都很有必要。
大量发表的临床前数据也进一步证实了IDO在抗肿瘤免疫反应中的作用。IDO抑制剂可用于激活T细胞，因而提高T细胞被妊娠、恶性肿瘤或HIV等病毒抑制时T细胞的激活。在癌细胞中强迫IDO诱导被证明具有生存优势(Uyttenhove et al,Nat Med.2003；10:1269)。另有体内研究表明，IDO抑制剂在肿瘤生长中通过降低犬尿氨酸水平而减少对淋巴细胞的依赖(Liu et al,Blood.2010；115(17):3520)。临床前研究还表明IDO抑制剂如果与其他肿瘤药物联用，如放疗、化疗或疫苗等等具有协同效果(Koblish et al,Mol.Cancer Ther.2010；9(2):489；Hou et al,Cancer Res.2007；67(2):792；Sharma et al,Blood.2009；113(24):6102)。
IDO抑制剂类抗肿瘤药物的研究目前在全球范围内已取得重要进展，如INCB024360，NLG919和BMS-986205均已进入临床。但INCB024360由于存在毒副作用问题，致使现有临床研究剂量(50mg bid,或100mg bid)是最佳剂量(300mg bid,600mg bid)的30％左右，临床活性受到很大限制；同时INCB024360的毒性基团又是药效团，INCB024360及其衍生物存在毒性较大的问题。NLG919的安全性较好，但NLG919的生物活性较差。BMS-986205目前也已经进入临床，但是临床数据有限。还需要用于肿瘤治疗的更好的IDO抑制剂。
发明内容
本发明一方面提供一种如式(I)所示的化合物、其盐、溶剂合物、前药、代谢产物、氮氧化物、立体异构体或同位素衍生物：
Figure PCTCN2019071704-appb-000001
其中
Figure PCTCN2019071704-appb-000002
表示：
Figure PCTCN2019071704-appb-000003
或者
Figure PCTCN2019071704-appb-000004
Cy 1选自任选地被取代基取代的5-15元环，所述的取代基选自：卤素、羟基、C 1-6烷基、氨基、卤代C 1-6烷基、巯基、C 1-6烷基巯基、C 1-6烷基氨基、二(C 1-6 烷基)氨基和氰基；
Cy 2选自任选地被一个、两个或更多个R 2取代的C 6-10元环烷基、C 6-10元杂环基、C 6-10元芳基或C 6-10元杂芳基；优选为被一个、两个或更多个R 2取代的苯基、吡啶基、环己基、哌啶基、哌嗪基、吡嗪基、嘧啶基、吗啉基；哒嗪基；R 1和R 2独立地选自氢原子、卤素、羟基、硝基、氰基、磺酸基、C 1-6烷基、C 3-6环烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、卤代C 1-C 6烷基、卤代C 1-C 6烷氧基、卤代C 3-C 6环烷基、C 1-6烷基硫基、C 1-6烷基羰基、C 1-6烷氧基羰基、二(C 1-6烷基)氨基C 2-6烷氧基羰基、氨基、C 1-6烷基氨基、二(C 1-6烷基)氨基、氨基甲酰基、C 1-6烷基氨基甲酰基、二(C 1-6烷基)氨基甲酰基、二(C 1-6烷基)氨基C 2-6烷基氨基甲酰基、氨磺酰基、C 1-6烷基氨磺酰基、二(C 1-6烷基)氨磺酰基、二(C 1-6烷基)氨基C 2-6烷基氨磺酰基、C 1-6烷基磺酰基、C 1-6烷基亚硫酰基、二(C 1-6烷基)膦酰基、羟基C 1-6烷基、羟基羰基C 1-6烷基、C 1-6烷氧基C 1-6烷基、C 1-6烷基磺酰基C 1-6烷基、C 1-6烷基亚硫酰基C 1-6烷基、二(C 1-6烷基)膦酰基C 1-6烷基、羟基C 2-6烷氧基、C 1-6烷氧基C 2-6烷氧基、氨基C 1-6烷基、C 1-6烷基氨基C 1-6烷基、二(C 1-6烷基)氨基C 1-6烷基、二(C 1-6烷基)氨基乙酰基、氨基C 2-6烷氧基、C 1-6烷基氨基C 2-6烷氧基、二(C 1-6烷基)氨基C 2-6烷氧基、羟基C 2-6烷基氨基、C 1-6烷氧基C 2-6烷基氨基、氨基C 2-6烷基氨基、C 1-6烷基氨基C 2-6烷基氨基、二(C 1-6烷基)氨基C 2-6烷基氨基；或者相邻的两个R 1或R 2相互环合形成3-8元环，该环中含有0-3个杂原子；
m、n为选自0、1、2、3和4的整数；
R a、R b各自独立地选自氢、C 1-C 6烷基或C 3- 6环烷基；
X选自CR aR b、NR e或O；
Y选自CR e或N；其中R e表示氢、C 1-6烷基或者C 3-6环烷基、C 1-6卤代烷基。
本发明另一方面提供一种如式(II)所示的化合物、其盐、溶剂合物、前药、代谢产物、氮氧化物、立体异构体或同位素衍生物：
Figure PCTCN2019071704-appb-000005
Figure PCTCN2019071704-appb-000006
其中，W 1、W 2、W 3、W 4分别独立地选自CR e、C＝O或N；p为选自0、1、2、3和4的整数；R 1、R 2、Cy 1、R a、R b、R e、X、Y、m、n如式I所定义；虚线表示单键或者双键。
在本发明的一个实施方案中，Cy 1选自以下基团：
Figure PCTCN2019071704-appb-000007
其中R 3选自氢、C 1-C 6烷基、C 3-C 6环烷基；
上述基团可以被一个或两个以上的选自卤素、羟基、C 1-6烷基、氨基、卤代C 1-6烷基、巯基、C 1-6烷基巯基、C 1-6烷基氨基、二(C 1-6烷基)氨基、氰基的取代基所取代。
本发明一方面提供一种如式(III)所示的化合物、其盐、溶剂合物、前药、代谢产物、氮氧化物、立体异构体或同位素衍生物：
Figure PCTCN2019071704-appb-000008
其中，R 1、R 2、R a、R b、X、Y、W 1、W 2、W 3、W 4、m、n、p如式II所定义。
本发明一方面提供一种如式(IV)所示的化合物、其盐、溶剂合物、前药、代谢产物、氮氧化物、立体异构体或同位素衍生物：
Figure PCTCN2019071704-appb-000009
其中Q 1和Q 2分别独立地选自CR aR b、NR e或O；Q 3选自CR a或N；其中，R 1、R 2、R a、R b、R e、X、Y、W 1、W 2、W 3、W 4、m、p如式II所定义；
在本发明的另一个实施方案中，所述式II化合物具有如式(V)结构：
Figure PCTCN2019071704-appb-000010
其中R 1、R 2、R a、R b、X、Y、W 1、W 2、W 3、W 4、m、p如上述式II所定义。
在本公开中，
Figure PCTCN2019071704-appb-000011
表示
Figure PCTCN2019071704-appb-000012
或者
Figure PCTCN2019071704-appb-000013
在本公开中，
Figure PCTCN2019071704-appb-000014
优选为
Figure PCTCN2019071704-appb-000015
除非另外说明，本发明的所有化合物结构也包括其可能存在的立体异构体(包括：enantiomeric,diastereomeric,geometric,conformational,and rotational)。例如，每个手性中心的R和S构型，每个烯烃双键的E和Z异构体都包括在此发明中。对于有些可以自由旋转的键，取代基的位置也可以跟着自由转动，例如：
结构式
Figure PCTCN2019071704-appb-000016
也同时代表：
Figure PCTCN2019071704-appb-000017
也代表其互变异构体：
Figure PCTCN2019071704-appb-000018
所以，一个单一的立体化学异构体，以及其对映体混合物，几何异构体混合物，构象异构体混合物，互变异构体都在本专利申请范畴。
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、苯磺酸和甲苯磺酸。当提到本发明化合物时，也涵盖本发明化合物的这些可药用盐。
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。
当提及本发明化合物或其可药用盐时，还涵盖其水合物和溶剂化物。
在另一个方面中，本发明还提供一种预防或治疗吲哚胺2,3-双加氧酶活性异常相关疾病的方法，其包括向有此需要的患者施用以上所述的本发明化合物、其盐、溶剂合物、前药、代谢产物、氮氧化物、立体异构体或同位素衍生物或包含其的药物组合物。
另外，本发明还提供一种对抗免疫抑制的方法，其包括向有此需要的患者施用以上所述的本发明化合物、其盐、溶剂合物、前药、代谢产物、氮氧化物、立体异构体或同位素衍生物或包含其的药物组合物。
本发明还提供了本发明化合物在制备用于预防或治疗癌症、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组合物，其包含本发明化合物作为活性成分。
此外，本发明提供了一种用于预防或治疗癌症、肿瘤、炎症性疾病、自身免疫性疾病或免疫介导性疾病的方法，其包括向有此需要的哺乳动物施用本发明化合物。
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一种用于治疗癌症或肿瘤的抗癌剂组合施用时，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、PD-1抗体、PD-L1抗体，并且选自其中的至少一种抗癌剂可包含于本发明药物组合物中。
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。
当将本发明化合物或其可药用盐与另一种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)的片剂、颗粒、粉末、胶囊、糖浆、乳剂或微乳剂的形式。
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。
本发明的另一方面还提供了一种抑制吲哚胺2,3-双加氧酶的方法，其包括使本发明的化合物、其盐、溶剂合物、前药、代谢产物、氮氧化物、立体异构体或同位素衍生物或者药物组合物暴露于吲哚胺2,3-双加氧酶。
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。
可以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。
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，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-SO2NH2、取代的磺酰氨基、硝基、氰基、羧基、氨基甲酰基例如-CONH2、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，“C1-6烷基”表示具有1个至6个碳原子的烷基。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，“C2-8烯基”含有两个至八个碳原子。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，“C2-8炔基”含有两个至八个碳原子。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。“C1-6烷氧基”(或烷基氧基)意欲包括C1、C2、C3、C4、C5和C6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15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”是指饱和或不饱和的单环、并环、桥环或螺环，其可以任选地含有一个或两个以上的杂原子。例如，5-15元环可以指5-15元单环、5-15元单 环杂环、5-15元并环、5-15元并环杂环、5-15元桥环、5-15元桥环杂环、5-15元螺环、5-15元螺环杂环。
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，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，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个或两个以上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5烷基。例如，“C1-6卤代烷氧基”意欲包括C1、C2、C3、C4、C5和C6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“杂芳基”、“杂芳环”、“杂芳环基”或“杂芳环基团”意指稳定的3元、4元、5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”指的是一个单环杂烷基体系，或为一个二环杂烷基体系。单环的环杂烷基指的是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。二环杂烷基体系指的是一个环杂烷基融合到一个苯基、或一个环烷基、或一个环烯基、或一个环杂烷基、或一个杂芳基。
本文使用的术语“桥环”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。
本文使用的术语“螺环”指的是单环之间共用一个碳原子(称螺原子)的多环。
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(N→O)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。
本文使用的术语“整数”特指的是0及正整数(例如1、2、3、4、5……n)。
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，固体肿瘤(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患者用药，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“患者”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网目筛，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
本发明的化合物(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：
具体实施例
Figure PCTCN2019071704-appb-000019
Figure PCTCN2019071704-appb-000020
Figure PCTCN2019071704-appb-000021
设计和反应实例
本发明的化合物可参照下面说明通过所知步骤合成得到。所有购买的溶剂和试剂都未经过处理而直接使用。所有合成的化合物可以通过，但不限于以下方法分析验证：LCMS(liquid chromatography mass spectrometry，液相质谱)和NMR(nuclear magnetic resonance，核磁共振)。核磁共振(NMR)由Bruker AVANCE-500核磁仪测定，测定时所用的氘代溶剂为氘代二甲基亚砜(d6-DMSO)、氘代氯仿(CDCl3)，四甲基硅烷(TMS)作为内标物。以下缩写表示各种类型的分裂峰：单峰(s)、双重峰(d)、三重峰(t)、多重峰(m)、宽峰(br)。质谱(MS)的测定采用Thermo Fisher-MSQ Plus液质联用仪，手性化合物的拆分用大赛璐的
Figure PCTCN2019071704-appb-000022
AD-H手性柱(0.46cm I.D.×15cm L,HEP:ETOH(0.1％DEA)＝60:40(V/V))分离。
本发明的化合物可参照下面来制备。
通用路线一：
中间体F的合成(顺式和反式混合物、外消旋化合物)
Figure PCTCN2019071704-appb-000023
第一步：将4-氧代环己烷乙酸乙酯(2.0g,10.86mmol)溶于60mL超干四氢呋喃中，在氮气氛和-78℃下向该溶液中滴加双(三甲基硅基)氨基钠(2mol/L四氢呋喃溶液)(6.5mL,13.03mmol)。反应液在该温度下搅拌1小时。然后加入N-苯基双(三氟甲烷磺酰)亚胺(4.65g,13.03mmol)的四氢呋喃(20mL)溶液。滴加完毕后反应混合物在室温下继续搅拌过夜直至TLC检测反应原料消耗完全。反应液用5mL硫酸氢钾水溶液淬灭，过滤除去固体，浓缩滤液。向残余液中加入50mL甲基叔丁基醚，有机层用1.0mol/L氢氧化钠溶液洗(3x20mL)，20mL饱和食盐水洗。有机层用无水硫酸钠干燥，过滤，浓缩得到中间体A(3.12g)，橘红色油状液体，收率91％。 1H NMR(500MHz,CDCl 3)δ5.74–5.70(m,1H),4.15(q,J＝7.0Hz,2H),2.48–2.40(m,1H),2.38–2.32(m,2H),2.30(d,J＝7.0Hz,2H),2.18–2.10(m,1H),1.97–1.89(m,2H),1.57–1.48(m,1H),1.27(t,J＝7.0Hz,3H).
第二步：将中间体A(3.12g,9.86mmol)溶于15mL二氧六环中，依次加入联硼酸频那醇酯(3.26g,12.82mmol)，醋酸钾(2.90g,29.59mmol)，溴化钠(406mg,3.95mmol)和Pd(dppf)Cl 2(722mg,0.98mmol)。反应混合物在氮气氛下回流反应过夜。然后蒸干反应溶剂二氧六环，加入乙酸乙酯，用硅藻土过滤，滤液浓缩之后用快速过柱机分离得到中间体B(1.66g)，无色液体，收率57％。 1H NMR(500MHz,CDCl 3)δ6.54–6.48(m,1H),4.12(q,J＝6.5Hz,2H),2.30–2.02(m,7H),1.84–1.72(m,2H),1.27–1.23(m,15H).
第三步：将中间体B(1.66g,5.64mmol)溶于12mL/3mL二氧六环/水中，依次加入4-氯-6-氟喹啉(860mg,4.74mmol)，碳酸钾(1.96g,14.21mmol)和Pd(PPh 3) 4(274mg,0.24mmol)。反应混合物在氮气氛下回流反应过夜。然后浓缩反应液，加入50mL水稀释，用乙酸乙酯萃取(3x50mL)，有机相浓缩之后用快速过柱机分离得到中间体C(1.48g)，淡黄色液体，收率100％。MS(ESI):m/z313.9(M+H) +. 1H NMR(500MHz,CDCl 3)δ8.81(d,J＝4.5Hz,1H),8.16(dd,J＝8.5,5.5Hz,1H),7.62(dd,J＝10.0,2.5Hz,1H),7.52–7.46(m,1H),7.22(d,J＝4.5 Hz,1H),5.86–5.81(m,1H),4.19(q,J＝7.0Hz,2H),2.56–2.26(m,6H),2.08–1.98(m,2H),1.64–1.55(m,1H),1.30(t,J＝7.0Hz,3H).
第四步：将中间体C(1.48g,4.72mmol)溶于30mL乙醇中，加入10％钯碳(300mg)。反应混合物在氢气氛下室温搅拌过夜。然后用硅藻土滤除钯碳，浓缩滤液。残留物用快速过柱机分离得到中间体D(1.31g)，淡黄色液体，收率88％。MS(ESI):m/z 316.0(M+H) +. 1H NMR(500MHz,CDCl 3)δ8.84–8.79(m,1H),8.13(dd,J＝9.0,5.5Hz,1H),7.66(dd,J＝10.5,2.5Hz,1H),7.51–7.44(m,1H),7.34(d,J＝4.5Hz,1H),4.20–4.14(m,2H),3.26–3.18(m,1H),2.53–2.43(m,2H),2.31(d,J＝7.0Hz,1H),2.07–1.97(m,2H),1.90–1.70(m,5H),1.68–1.58(m,1H),1.31–1.25(m,3H).
第五步：将二异丙胺(1.54g,15.22mmol)溶于18mL四氢呋喃中。在氮气氛和-78℃条件下，向该溶液中滴加2.5M正丁基锂(6.1mL,15.22mmol)的正己烷溶液。然后滴加中间体D(2.4g,7.61mmol)的四氢呋喃(6mL)溶液。反应混合液在-78℃继续搅拌1.5小时。接着滴加碘甲烷(2.16g,15.22mmol)，反应混合液升至室温搅拌过夜。用饱和氯化铵淬灭反应，乙酸乙酯萃取(3x50mL)，合并有机相，用50mL饱和食盐水洗，无水硫酸钠干燥，过滤，浓缩。残留物用快速过柱机分离得到中间体E(1.96g)，淡黄色液体，收率78％。MS(ESI):m/z 330.5(M+H) +. 1H NMR(500MHz,CDCl 3)δ8.84–8.79(m,1H),8.16–8.10(dd,1H),7.66(d,J＝10.5Hz,1H),7.51–7.44(m,1H),7.35(d,J＝4.5Hz,1H),4.22–4.14(m,2H),3.32–3.23(m,1H),2.82–2.72(m,1H),2.12–1.98(m,2H),1.96–1.55(m,7H),1.32–1.24(m,3H),1.20(d,J＝6.5Hz,3H).
第六步：将中间体E(400mg,1.21mmol)溶于4mL/4mL四氢呋喃/乙醇中，加入2mL水。然后向溶液中加入氢氧化钠(243mg,6.07mmol)。反应混合物在50℃搅拌过夜，浓缩。加入3mL水稀释，用4mol/L盐酸溶液调节pH＝3，过滤得到中间体F(330mg)，白色固体，收率90％。MS(ESI):m/z 302.6(M+H) +. 1H NMR(500MHz,d 6-DMSO)δ12.22(s,1H),8.81(d,J＝4.5Hz,1H),8.14–8.06(m,1H),8.01–7.94(m,1H),7.66(t,J＝8.5Hz,1H),7.52(s,1H),3.32–3.23(m,1H),2.76–2.66(m,1H),1.97–1.62(m,7H),1.61–1.51(m,1H),1.49–1.31(m,1H),1.09(d,J＝6.5Hz,3H).
通用路线二：非对称合成路线
Figure PCTCN2019071704-appb-000024
中间体K’的非对称合成方法采用文献报道的合成方法(WO2016073774A2)
通用路线三：
Figure PCTCN2019071704-appb-000025
第一步：将中间体F(或者K’,1.0eq)溶于N,N-二甲基甲酰胺中，加入HATU(1.1eq)和二异丙基乙胺(3.0eq)。再向反应液中加入取代的1,2-二胺或取代的邻氨基苯胺(1.5eq)。反应混合物在30℃下搅拌过夜。然后向反应液中加入水和乙酸乙酯，有机相用饱和食盐水洗，无水硫酸钠干燥，过滤，浓缩，得到粗品中间体不需要纯化直接用于下一步。
第二步：将上一步得到的粗品中间体(1.0eq)溶于醋酸中，混合物在100℃ 下搅拌反应19小时，然后浓缩反应液。残留物用反向高效液相制备色谱纯化得到最终化合物。
通用路线四：
Figure PCTCN2019071704-appb-000026
第一步：将膦酰基乙酸三乙酯(968mg,4.32mmol)溶于16mL超干四氢呋喃中，在0℃冰浴下加入叔丁醇钠(415mg,4.32mmol)。10分钟后，将中间体E’(1g,4.12mmol)的四氢呋喃(4mL)溶液加入反应液中。反应2小时后，用水淬灭。水溶液用20mL乙酸乙酯萃取三次，合并有机相，用20mL饱和食盐水洗，无水硫酸钠干燥，过滤，浓缩。残留物用快速过柱机分离得到中间体F”(1.18g)，白色固体，收率92％。MS(ESI):m/z 314.0(M+H) +. 1H NMR(500MHz,CDCl 3)δ8.81(d,J＝4.5Hz,1H),8.17(dd,J＝9.0,5.5Hz,1H),7.72(dd,J＝10.0,2.5Hz,1H),7.53–7.47(m,1H),7.28(d,J＝4.5Hz,1H),5.75(s,1H),4.19(q,J＝7.0Hz,2H),3.52–3.42(m,1H),2.54–2.48(m,2H),2.26–2.11(m,4H),1.80–1.68(m,2H),1.30(t,J＝7.0Hz,3H).
第二步：将NaH(383mg,9.57mmol)加入15mL二甲基亚砜中，向该悬浊液中加入三甲基碘化亚砜(2.11g,9.57mmol)。混合物在室温下搅拌1.5小时。然后将中间体F”(1.0g,3.19mmol)的二甲基亚砜(5mL)溶液加入到反应液中。反应在室温条件下搅拌过夜。然后用水淬灭，用乙酸乙酯萃取，用快速过柱机分离得到中间体G”(820mg)，无色油状液体，收率78％。MS(ESI):m/z 328.1(M+H) +. 1H NMR(500MHz,CDCl 3)δ8.83(d,J＝4.5Hz,1H),8.24(dd,J＝9.0,5.5Hz,1H),7.71(dd,J＝10.0,2.5Hz,1H),7.55–7.49(m,1H),7.35(d,J＝4.5Hz,1H),4.19(q,J＝7.0Hz,2H),3.32–3.24(m,1H),2.17(td,J＝13.0,3.5Hz,1H),2.07–1.90(m,4H),1.87–1.78(m,1H),1.58(dd,J＝8.0,5.5Hz,1H),1.46–1.37(m,1H),1.30(t,J＝7.0Hz,3H),1.28–1.24(m,2H),1.16–1.11(m,1H),1.00(dd,J＝ 8.0,4.5Hz,1H).
第三步：将中间体G”(200mg,0.61mmol)溶于10mL乙醇中，加入4mL 2mol/L氢氧化钠溶液。反应液加热至50℃，反应2小时。待反应液冷却至室温，用4mol/L盐酸溶液中和至pH＝1。用乙酸乙酯萃取水相。合并有机相，用无水硫酸钠干燥，过滤，浓缩。残留物用制备薄层层析分离得到中间体H”(150mg)，白色固体，产率83％。MS(ESI):m/z 300.0(M+H) +. 1H NMR(500MHz,d 6-DMSO)δ12.02(br,1H),8.83(d,J＝4.5Hz,1H),8.10(dd,J＝9.0,5.5Hz,1H),8.03(dd,J＝10.0,2.5Hz,1H),7.71–7.64(m,1H),7.38(d,J＝4.5Hz,1H),3.48–3.41(m,1H),2.21–2.13(m,1H),2.01–1.80(m,4H),1.75–1.65(m,1H),1.51(dd,J＝8.0,5.5Hz,1H),1.38–1.32(m,1H),1.11–1.05(m,1H),1.04–0.99(m,1H),0.95(dd,J＝7.5,4.0Hz,1H).
第四步：将中间体H”(1.0eq)溶于N,N-二甲基甲酰胺中，加入HATU(1.1eq)和二异丙基乙胺(3.0eq)。再向反应液中加入取代的1,2-二胺或取代的邻氨基苯胺(1.5eq)。反应混合物在30℃下搅拌过夜。然后向反应液中加入水和乙酸乙酯，有机相用饱和食盐水洗，无水硫酸钠干燥，过滤，浓缩。将得到的粗品中间体溶于醋酸中，混合物在100℃下搅拌反应19小时，然后浓缩反应液。残留物用反向高效液相制备色谱纯化得到最终化合物。
通用路线五：
Figure PCTCN2019071704-appb-000027
第一步：在-78℃条件下，将正丁基锂(0.49mL,1.22mmol)滴加到二异丙胺(123mg,1.22mmol)的四氢呋喃(15mL)溶液中。再向其中滴加中间体G”(200mg,0.61mmol)的四氢呋喃(5mL)溶液。反应在-78℃下搅拌1小时。然后向反应液中滴加碘甲烷(173mg,1.22mmol)的四氢呋喃(2mL)溶液，反应维持在-78℃半小时后升至室温，搅拌过夜。用饱和氯化铵溶液淬灭，用乙酸乙酯萃取水相。合并有机相，用无水硫酸钠干燥，过滤，浓缩。残留物用制备薄层层析分离得到化合物中间体H”’(121mg)，无色油状液体，产率58％。MS(ESI):m/z 342.4 (M+H) +.
第二步：将中间体H”’(100mg,0.29mmol)溶于10mL乙醇中，加入2mL 2mol/L氢氧化钠溶液。反应液加热至50℃，反应2小时。待反应液冷却至室温，用4mol/L盐酸溶液中和至pH＝1。用乙酸乙酯萃取水相。合并有机相，用无水硫酸钠干燥，过滤，浓缩。残留物用制备薄层层析分离得到中间体I”’(76mg)，白色固体，产率83％。MS(ESI):m/z 314.3(M+H) +.
第三步：将中间体I”’(1.0eq)溶于N,N-二甲基甲酰胺中，加入HATU(1.1eq)和二异丙基乙胺(3.0eq)。再向反应液中加入取代的1,2-二胺或取代的邻氨基苯胺(1.5eq)。反应混合物在30℃下搅拌过夜。然后向反应液中加入水和乙酸乙酯，有机相用饱和食盐水洗，无水硫酸钠干燥，过滤，浓缩。将得到的粗品中间体溶于醋酸中，混合物在100℃下搅拌反应19小时，然后浓缩反应液。残留物用反向高效液相制备色谱纯化得到最终化合物。
实施例1：化合物1
Figure PCTCN2019071704-appb-000028
化合物1从中间体F(20mg)和4-氯-1,2-苯二胺出发，经由通用路线一和通用路线三制备而来。得到化合物1(10.05mg)，白色固体，收率37％。MS(ESI):m/z 408.3(M+H) +. 1H NMR(500MHz,d 6-DMSO)δ12.40(s,1H),8.79(d,J＝4.5Hz,1H),8.11–8.04(m,1H),7.97(d,J＝10.5Hz,1H),7.65(t,J＝8.5Hz,1H),7.60–7.45(m,2H),7.42(d,J＝4.0Hz,1H),7.15(d,J＝8.5Hz,1H),3.30–3.24(m,1H),2.95–2.88(m,1H),1.95(t,J＝10.5Hz,2H),1.90–1.79(m,2H),1.61–1.47(m,3H),1.45–1.32(m,5H).
实施例2：化合物17和化合物18
Figure PCTCN2019071704-appb-000029
化合物17(反式，外消旋)和化合物18(顺式，外消旋)从中间体F(40mg)和4-氟-1,2-苯二胺出发，经由通用路线一和通用路线三制备而来。
得到化合物17(8.49mg)，第一个洗脱的异构体，白色固体，收率16％。MS(ESI):m/z 392.5(M+H) +. 1H NMR(500MHz,d 6-DMSO)δ12.28(s,1H),8.79(s,1H),8.11–8.04(m,1H),7.97(d,J＝10.5Hz,1H),7.65(t,J＝8.5Hz,1H),7.45–7.39(m,2H),7.34(d,J＝10.0Hz,1H),7.02–6.92(m,1H),3.29–3.23(m,1H),2.93–2.87(m,1H),2.00–1.91(m,2H),1.89–1.79(m,2H),1.61–1.46(m,3H),1.45–1.33(m,5H).
得到化合物18(9.24mg)，第二个洗脱的异构体，白色固体，收率18％。MS(ESI):m/z 392.5(M+H) +. 1H NMR(500MHz,d 6-DMSO)δ12.31(s,1H),8.86(s,1H),8.13–8.06(m,1H),7.97(d,J＝11.0Hz,1H),7.66(t,J＝8.5Hz,1H),7.58(s,1H),7.44–7.39(m,1H),7.23(d,J＝9.0Hz,1H),7.01–6.92(m,1H),3.45–3.35(m,2H),2.15–2.09(m,1H),2.06–1.99(m,1H),1.93–1.83(m,2H),1.82–1.71(m,2H),1.68–1.60(m,1H),1.59–1.53(m,1H),1.34(d,J＝6.5Hz,3H),1.21–1.14(m,1H).
实施例3：化合物21和化合物22
Figure PCTCN2019071704-appb-000030
化合物21(反式，外消旋)和化合物22(顺式，外消旋)从中间体F(40mg)和4-甲基-1,2-苯二胺出发，经由通用路线一和通用路线三制备而来。
得到化合物21(11.40mg)，第一个洗脱的异构体，白色固体，收率22％。MS(ESI):m/z 388.5(M+H) +. 1H NMR(500MHz,d 6-DMSO)δ11.98(s,1H),8.79(s,1H),8.11–8.04(m,1H),7.97(d,J＝10.5Hz,1H),7.65(t,J＝8.5Hz,1H),7.44–7.38(m,2H),7.20(s,1H),6.93(t,J＝9.5Hz,1H),3.30–3.23(m,1H),2.91–2.83(m,1H),2.39(s,3H),2.00–1.91(m,2H),1.89–1.78(m,2H),1.61–1.46(m,3H),1.44–1.33(m,5H).
得到化合物22(13.51mg)，第二个洗脱的异构体，白色固体，收率26％。MS(ESI):m/z 388.5(M+H) +. 1H NMR(500MHz,d 6-DMSO)δ12.02(s,1H),8.86(s,1H),8.13–8.06(m,1H),7.97(d,J＝11.0Hz,1H),7.66(t,J＝9.0Hz,1H),7.58(s,1H),7.39(d,J＝8.5Hz,1H),7.20(s,1H),6.93(t,J＝10.0Hz,1H),3.46–3.34(m,2H),2.38(s,3H),2.16–2.09(m,1H),2.06–1.99(m,1H),1.93–1.83(m,2H),1.82–1.70(m,2H),1.67–1.51(m,2H),1.33(d,J＝6.5Hz,3H),1.21–1.14(m,1H).
实施例4：化合物13和化合物14
Figure PCTCN2019071704-appb-000031
化合物13(反式，外消旋)和化合物14(顺式，外消旋)从中间体F(50mg)和4-氯-1,2-苯二胺出发，经由通用路线一和通用路线三制备而来。
得到化合物13(7.93mg)，第一个洗脱的异构体，白色固体，收率12％。MS(ESI):m/z 408.4(M+H) +. 1H NMR(500MHz,d 6-DMSO)δ12.36(s,1H),8.80(s,1H),8.11–8.04(m,1H),7.97(d,J＝11.0Hz,1H),7.65(t,J＝8.5Hz,1H),7.60(s,1H),7.46–7.40(m,2H),7.15(t,J＝10.5Hz,1H),3.30–3.23(m,1H),2.95–2.88(m,1H),2.00–1.91(m,2H),1.89–1.79(m,2H),1.61–1.46(m,3H),1.45–1.32(m,5H).
得到化合物14(10.25mg)，第二个洗脱的异构体，白色固体，收率15％。MS(ESI):m/z 408.4(M+H) +. 1H NMR(500MHz,d 6-DMSO)δ12.42(s,1H),8.86(d,J＝4.0Hz,1H),8.13–8.07(m,1H),7.98(d,J＝11.0Hz,1H),7.67(t,J＝8.5Hz,1H),7.61–7.56(m,2H),7.45(d,J＝8.5Hz,1H),7.17–7.11(m,1H),3.45–3.37(m,2H),2.16–2.09(m,1H),2.07–2.00(m,1H),1.93–1.83(m,2H),1.82–1.71(m,2H),1.68–1.60(m,1H),1.59–1.52(m,1H),1.34(d,J＝6.5Hz,3H),1.19–1.12(m,1H).
实施例5：化合物33和化合物34
Figure PCTCN2019071704-appb-000032
化合物33(反式，外消旋)和化合物34(顺式，外消旋)从中间体F(40mg)和4-三氟甲基-1,2-苯二胺出发，经由通用路线一和通用路线三制备而来。
得到化合物33(5.95mg)，第一个洗脱的异构体，白色固体，收率10％。MS(ESI):m/z 442.4(M+H) +. 1H NMR(500MHz,d 6-DMSO)δ12.63(s,1H),8.79(s,1H),8.10–8.04(m,1H),7.97(d,J＝11.0Hz,1H),7.91(s,1H),7.67–7.61(m,2H),7.49–7.40(m,2H),3.30–3.23(m,1H),3.02–2.94(m,1H),2.00–1.91(m,2H),1.91–1.82(m,2H),1.61–1.47(m,3H),1.46–1.35(m,5H).
得到化合物34(4.55mg)，第二个洗脱的异构体，白色固体，收率8％。MS(ESI):m/z 442.4(M+H) +. 1H NMR(500MHz,d 6-DMSO)δ12.66(s,1H),8.87(s,1H),8.12–8.06(m,1H),7.98(d,J＝10.5Hz,1H),7.90(s,1H),7.69–7.62(m,2H),7.59(s,1H),7.48–7.41(m,1H),3.52–3.38(m,2H),2.21–2.11(m,1H),2.09–2.01(m,1H),1.94–1.73(m,4H),1.69–1.61(m,1H),1.60–1.54(m,1H),1.37(d,J＝6.0Hz,3H),1.19–1.13(m,1H).
实施例6：化合物27和化合物28
Figure PCTCN2019071704-appb-000033
化合物27(反式，外消旋)和化合物28(顺式，外消旋)从中间体F(50mg)和4-甲氧基-1,2-苯二胺出发，经由通用路线一和通用路线三制备而来。
得到化合物27(3.67mg)，第一个洗脱的异构体，白色固体，收率5％。(ESI):m/z404.4(M+H) +. 1H NMR(500MHz,d 6-DMSO)δ11.99(s,1H),8.80(s,1H),8.10–8.07(m,1H),7.98(d,J＝10.0Hz,1H),7.69–7.62(m,1H),7.46–7.39(m,2H),6.92(s,1H),6.78–6.70(m,1H),3.77(s,3H),3.30–3.22(m,1H),2.89–2.82(m,1H),2.00–1.91(m,2H),1.90–1.76(m,2H),1.60–1.46(m,3H),1.44–1.31(m,5H).
得到化合物28(6.69mg)，第二个洗脱的异构体，白色固体，收率9％。(ESI):m/z 404.4(M+H) +. 1H NMR(500MHz,d 6-DMSO)δ12.02(s,1H),8.87(s,1H),8.13–8.06(m,1H),7.98(d,J＝11.0Hz,1H),7.67(t,J＝8.5Hz,1H),7.58(s,1H),7.39(d,J＝8.5Hz,1H),7.08(s,1H),6.74(t,J＝10.0Hz,1H),3.76(s,3H),3.46–3.36(m,2H),2.15–2.07(m,1H),2.06–1.98(m,1H),1.92–1.83(m,2H),1.82–1.69(m,2H),1.67–1.59(m,1H),1.58–1.51(m,1H),1.33(d,J＝6.5Hz,3H),1.22–1.14(m,1H).
实施例7：化合物35和化合物36
Figure PCTCN2019071704-appb-000034
化合物35(反式，外消旋)和化合物36(顺式，外消旋)从中间体F(50mg)和4-溴-1,2-苯二胺出发，经由通用路线一和通用路线三制备而来。
得到化合物35(12.85mg)，第一个洗脱的异构体，白色固体，收率17％。(ESI):m/z 452.3(M+H) +. 1H NMR(500MHz,d 6-DMSO)δ12.39(d,J＝22.9Hz,1H),8.80(s,1H),8.10–8.04(m,1H),7.98(d,J＝11.0Hz,1H),7.74(s,1H),7.65(t,J＝8.5Hz,1H),7.46–7.38(m,2H),7.26(t,J＝9.0Hz,1H),3.31–3.24(m,1H),2.95–2.87(m,1H),1.99–1.90(m,2H),1.89–1.79(m,2H),1.61–1.46(m,3H),1.46–1.30(m,5H).
得到化合物36(15.29mg)，第二个洗脱的异构体，白色固体，收率20％。(ESI):m/z 452.3(M+H) +. 1H NMR(500MHz,d 6-DMSO)δ12.42(s,1H),8.86(s,1H),8.12–8.07(m,1H),7.98(d,J＝11.0Hz,1H),7.73(s,1H),7.69–7.63(m,1H),7.60–7.56(m,1H),7.49(d,J＝9.0Hz,1H),7.28–7.22(m,1H),3.45–3.38(m,2H),2.15–2.08(m,1H),2.07–1.99(m,1H),1.92–1.83(m,2H),1.82–1.70(m,2H),1.68–1.59(m,1H),1.58–1.52(m,1H),1.34(d,J＝6.0Hz,3H),1.18–1.11(m,1H).
实施例8：化合物37和化合物38
Figure PCTCN2019071704-appb-000035
化合物37(反式，外消旋)和化合物38(顺式，外消旋)从中间体F(40mg)和6-氯-2,3-二氨基吡啶出发，经由通用路线一和通用路线三制备而来。
得到化合物37(4.03mg)，第一个洗脱的异构体，白色固体，收率7％。MS(ESI):m/z 409.4(M+H) +. 1H NMR(500MHz,d 6-DMSO)δ12.79(s,1H),8.80(s,1H),8.11–8.04(m,1H),8.02–7.87(m,2H),7.66(t,J＝8.0Hz,1H),7.44(s,1H),7.24(d,J＝8.0Hz,1H),3.30–3.23(m,1H),2.98–2.89(m,1H),2.00–1.91(m,2H),1.90–1.80(m,2H),1.61–1.47(m,3H),1.45–1.35(m,5H).
得到化合物38(7.12mg)，第二个洗脱的异构体，白色固体，收率12％。MS(ESI):m/z 409.4(M+H) +. 1H NMR(500MHz,d 6-DMSO)δ12.81(s,1H),8.87(d,J＝4.5Hz,1H),8.10(dd,J＝9.5,6.0Hz,1H),8.03–7.90(m,2H),7.67(td,J＝9.0,3.0Hz,1H),7.59(d,J＝4.5Hz,1H),7.23(d,J＝8.5Hz,1H),3.47–3.39(m,2H),2.18–2.12(m,1H),2.07–2.00(m,1H),1.92–1.83(m,2H),1.82–1.71(m,2H),1.69–1.61(m,1H),1.59–1.53(m,1H),1.35(d,J＝7.0Hz,3H),1.17–1.11(m,1H).
实施例9：化合物39和化合物40
Figure PCTCN2019071704-appb-000036
化合物39(反式，外消旋)和化合物40(顺式，外消旋)从中间体F(40mg)和5-氯-2,3-二氨基吡啶出发，经由通用路线一和通用路线三制备而来。
得到化合物39(5.08mg)，第一个洗脱的异构体，白色固体，收率9％。MS(ESI):m/z 409.4(M+H) +. 1H NMR(500MHz,d 6-DMSO)δ12.80(s,1H),8.81(s,1H),8.12–8.05(m,1H),8.04–7.88(m,2H),7.65(t,J＝8.0Hz,1H),7.43(s,1H),7.26(d,J＝8.0Hz,1H),3.31–3.23(m,1H),2.99–2.88(m,1H),2.02–1.90(m,2H),1.93–1.81(m,2H),1.60–1.46(m,3H),1.46–1.34(m,5H).
得到化合物40(8.37mg)，第二个洗脱的异构体，白色固体，收率15％。MS(ESI):m/z 409.4(M+H) +. 1H NMR(500MHz,d 6-DMSO)δ12.81(s,1H),8.81(s,1H),8.12–8.04(m,1H),8.03–7.87(m,2H),7.64(t,J＝8.0Hz,1H),7.45(s,1H),7.26(d,J＝8.0Hz,1H),3.46–3.37(m,2H),2.15–2.07(m,1H),2.05–1.98(m,1H),1.93–1.85(m,2H),1.84–1.68(m,2H),1.67–1.60(m,1H),1.57–1.50(m,1H),1.36(d,J＝6.5Hz,3H),1.25–1.14(m,1H).
实施例10：化合物41和化合物42
Figure PCTCN2019071704-appb-000037
化合物41(反式，外消旋)和化合物42(顺式，外消旋)从中间体F(40mg)和6-氯-3,4-二氨基吡啶出发，经由通用路线一和通用路线三制备而来。
得到化合物41(2.98mg)，第一个洗脱的异构体，白色固体，收率5％。MS(ESI):m/z 409.4(M+H) +. 1H NMR(500MHz,d 6-DMSO)δ12.89(s,1H),8.87(s,1H),8.63(s,1H),8.14–8.08(m,1H),7.98(d,J＝11.0Hz,1H),7.70–7.55(m,3H),3.48–3.40(m,1H),3.01–2.92(m,1H),2.05–1.94(m,2H),1.96–1.85(m,2H),1.65–1.49(m,3H),1.48–1.38(m,5H).
得到化合物42(3.17mg)，第二个洗脱的异构体，白色固体，收率6％。MS(ESI):m/z 409.4(M+H) +. 1H NMR(500MHz,d 6-DMSO)δ12.90(s,1H),8.87(s,1H),8.63(s,1H),8.14–8.07(m,1H),7.99(d,J＝11.0Hz,1H),7.71–7.56(m,3H),3.49–3.40(m,2H),2.18–2.11(m,1H),2.07–2.01(m,1H),1.93–1.83(m,2H),1.82–1.72(m,2H),1.69–1.61(m,1H),1.60–1.53(m,1H),1.36(d,J＝6.0Hz,3H),1.17–1.10(m,1H).
实施例11：化合物29和化合物30
Figure PCTCN2019071704-appb-000038
化合物29(反式，外消旋)和化合物30(顺式，外消旋)从中间体F(40mg)和4-氯-5-氟-1,2-苯二胺出发，经由通用路线一和通用路线三制备而来。
得到化合物29(3.45mg)，第一个洗脱的异构体，白色固体，收率5％。MS(ESI):m/z 426.4(M+H) +. 1H NMR(500MHz,d 6-DMSO)δ12.49(s,1H),8.79(d,J＝4.5Hz,1H),8.10–8.04(m,1H),7.97(d,J＝11.0Hz,1H),7.68–7.57(m,2H),7.48(d,J＝9.5Hz,1H),7.44-7.41(m,1H),3.29-3.23(m,1H),2.94-2.88(m,1H),1.99-1.90(m,2H),1.88-1.79(m,2H),1.61–1.46(m,3H),1.44-1.34(m,5H).
得到化合物30(4.15mg)，第二个洗脱的异构体，白色固体，收率6％。MS(ESI):m/z 426.4(M+H) +. 1H NMR(500MHz,d 6-DMSO)δ12.54(s,1H),8.87(s,1H),8.13–8.06(m,1H),7.98(d,J＝11.0Hz,1H),7.78–7.63(s,2H),7.61–7.40(m,2H),3.45–3.39(m,2H),2.16–2.08(m,1H),2.07–2.00(m,1H),1.92–1.83(m,2H),1.82–1.70(m,2H),1.68–1.60(m,1H),1.59–1.52(m,1H),1.34(d,J＝6.5Hz,3H),1.18–1.11(m,1H).
实施例12：化合物45和化合物46
Figure PCTCN2019071704-appb-000039
化合物45(反式，外消旋)和化合物46(顺式，外消旋)从中间体F(40mg)和2-氨基-4-氯苯酚出发，经由通用路线一和通用路线三制备而来。
得到化合物45(6.36mg)，第一个洗脱的异构体，白色固体，收率12％。MS(ESI):m/z 409.4(M+H) +. 1H NMR(500MHz,d 6-DMSO)δ8.87(d,J＝4.5Hz,1H),8.11(dd,J＝9.0,6.0Hz,1H),8.00(dd,J＝11.0,3.0Hz,1H),7.93(d,J＝2.0Hz,1H),7.74(d,J＝8.5Hz,1H),7.69(td,J＝8.5,3.0Hz,1H),7.65(d,J＝4.5Hz,1H),7.42(dd,J＝8.5,2.0Hz,1H),3.65–3.56(m,1H),3.48–3.44(m,1H),2.17–2.11(m,1H),2.05–1.98(m,1H),1.92–1.71(m,5H),1.67–1.61(m,1H),1.39(d,J＝7.0Hz,3H),1.30–1.25(m,1H).
得到化合物46(9.27mg)，第二个洗脱的异构体，白色固体，收率17％。MS(ESI):m/z 409.4(M+H) +. 1H NMR(500MHz,d 6-DMSO)δ8.86(d,J＝4.5Hz,1H),8.10(dd,J＝9.0,6.0Hz,1H),8.01(dd,J＝11.0,3.0Hz,1H),7.92(d,J＝2.0Hz,1H),7.72(d,J＝8.5Hz,1H),7.68(td,J＝8.5,3.0Hz,1H),7.63(d,J＝4.5Hz,1H),7.41(dd,J＝8.5,2.0Hz,1H),3.64–3.50(m,2H),2.17–2.11(m,1H),2.05–1.98(m,1H),1.92–1.71(m,5H),1.67–1.61(m,1H),1.39(d,J＝7.0Hz,3H),1.30–1.25(m,1H).
实施例13：化合物43和化合物44
Figure PCTCN2019071704-appb-000040
化合物43(反式，外消旋)和化合物44(顺式，外消旋)从中间体F(40mg)和2-氨基-5-氯苯酚出发，经由通用路线一和通用路线三制备而来。
得到化合物43(8.42mg)，第一个洗脱的异构体，白色固体，收率16％。MS(ESI):m/z 409.4(M+H) +. 1H NMR(500MHz,d 6-DMSO)δ8.86(d,J＝4.5Hz,1H),8.10(dd,J＝9.0,6.0Hz,1H),8.01(dd,J＝11.0,3.0Hz,1H),7.92(d,J＝2.0Hz,1H),7.72(d,J＝8.5Hz,1H),7.68(td,J＝8.5,3.0Hz,1H),7.63(d,J＝4.5Hz,1H),7.41(dd,J＝8.5,2.0Hz,1H),3.64–3.56(m,1H),3.48–3.43(m,1H),2.17–2.11(m,1H),2.05–1.98(m,1H),1.92–1.71(m,5H),1.67–1.61(m,1H),1.39(d,J＝7.0Hz,3H),1.30–1.25(m,1H).
得到化合物44(10.05mg)，第二个洗脱的异构体，白色固体，收率19％。MS(ESI):m/z 409.4(M+H) +. 1H NMR(500MHz,d 6-DMSO)δ8.86(d,J＝4.5Hz,1H),8.10(dd,J＝9.0,6.0Hz,1H),8.01(dd,J＝11.0,3.0Hz,1H),7.92(d,J＝2.0Hz,1H),7.72(d,J＝8.5Hz,1H),7.68(td,J＝8.5,3.0Hz,1H),7.63(d,J＝4.5Hz,1H),7.41(dd,J＝8.5,2.0Hz,1H),3.64–3.50(m,2H),2.17–2.11(m,1H),2.05–1.98(m,1H),1.92–1.71(m,5H),1.67–1.61(m,1H),1.39(d,J＝7.0Hz,3H),1.30–1.25(m,1H).
实施例14：化合物48
Figure PCTCN2019071704-appb-000041
化合物48从中间体H”(40mg)和4-甲基-1,2-苯二胺出发，经由通用路线四制备而来。得到化合物48(28.67mg)，白色固体，收率56％。(ESI):m/z 386.4(M+H) +. 1H NMR(500MHz,d 6-DMSO)δ12.32(s,1H),8.82(s,1H),8.11–8.04(m,1H),8.00(d,J＝11.0Hz,1H),7.66(t,J＝8.5Hz,1H),7.39(s,1H),7.37–7.29(m,1H),7.29–7.19(m,1H),6.91(d,J＝8.0Hz,1H),3.42–3.37(m,1H),2.37(s,3H),2.28–2.20(m,1H),2.08–2.02(m,1H),1.95–1.86(m,3H),1.59–1.46(m,2H),1.46–1.41(m,1H),1.23(d,J＝13.5Hz,1H),1.15–1.03(m,2H).
实施例15：化合物49
Figure PCTCN2019071704-appb-000042
化合物49从中间体I”’(40mg)和4-氯-1,2-苯二胺出发，经由通用路线五制备而来。得到化合物49(15.23mg)，白色固体，收率28％。(ESI):m/z 420.4(M+H) +. 1H NMR(500MHz,d 6-DMSO)δ12.32(s,1H),8.82(s,1H),8.11–8.04(m,1H),8.00(d,J＝11.0Hz,1H),7.66(t,J＝8.5Hz,1H),7.39(s,1H),7.37–7.29(m,1H),7.29–7.19(m,1H),6.91(d,J＝8.0Hz,1H),2.45(s,3H),3.42–3.37(m,1H),2.28–2.20(m,1H),2.08–2.02(m,1H),1.95–1.86(m,3H),1.59–1.46(m,2H),1.46–1.41(m,1H),1.15–1.03(m,2H).
实施例16：化合物19和化合物20
Figure PCTCN2019071704-appb-000043
化合物19和化合物20由实施例2中化合物18经过手性柱拆分得到。其中，化合物19对应手性拆分中的前者，化合物20对应手性拆分中的后者。
化合物19：MS(ESI):m/z 392.4(M+H) +. 1H NMR(500MHz,d 6-DMSO)δ12.33(s,1H),8.86(s,1H),8.13–8.07(m,1H),7.98(d,J＝10.5Hz,1H),7.67(t,J＝8.5Hz,1H),7.58(s,1H),7.44–7.39(m,1H),7.24(d,J＝8.5Hz,1H),7.01–6.92(m,1H),3.45–3.35(m,2H),2.15–2.09(m,1H),2.06–1.99(m,1H),1.93–1.83(m,2H),1.82–1.71(m,2H),1.68–1.60(m,1H),1.59–1.53(m,1H),1.33(d,J＝6.0Hz,3H),1.21–1.14(m,1H).
化合物20：MS(ESI):m/z 392.4(M+H) +. 1H NMR(500MHz,d 6-DMSO)δ12.34(s,1H),8.87(s,1H),8.13–8.07(m,1H),7.98(d,J＝10.5Hz,1H),7.67(t,J＝8.5Hz,1H),7.58(s,1H),7.44–7.39(m,1H),7.24(d,J＝8.5Hz,1H),7.01–6.92(m,1H),3.45–3.35(m,2H),2.15–2.09(m,1H),2.06–1.99(m,1H),1.93–1.83(m,2H),1.82–1.71(m,2H),1.68–1.60(m,1H),1.59–1.53(m,1H),1.34(d,J＝6.5Hz,3H),1.21–1.14(m,1H).
实施例17：化合物23和化合物24
Figure PCTCN2019071704-appb-000044
化合物23和化合物24由实施例3中化合物22经过手性柱拆分得到。其中，化合物23对应手性拆分中的前者，化合物24对应手性拆分中的后者。
化合物23：MS(ESI):m/z 388.4(M+H) +. 1H NMR(500MHz,d 6-DMSO)δ12.03(s,1H),8.86(s,1H),8.13–8.06(m,1H),7.97(d,J＝10.5Hz,1H),7.66(t,J＝9.0Hz,1H),7.58(s,1H),7.41–7.18(m,2H),6.93(s,1H),3.46–3.34(m,2H),2.38(s,3H),2.16–2.09(m,1H),2.06–1.99(m,1H),1.93–1.83(m,2H),1.82–1.70(m,2H),1.66–1.58(m,1H),1.57–1.50(m,1H),1.33(d,J＝6.5Hz,3H),1.21–1.14(m,1H).
化合物24：MS(ESI):m/z 388.4(M+H) +. 1H NMR(500MHz,d 6-DMSO)δ12.07(s,1H),8.87(s,1H),8.13–8.06(m,1H),7.97(d,J＝10.5Hz,1H),7.66(t,J＝9.0Hz,1H),7.58(s,1H),7.41–7.18(m,2H),6.93(s,1H),3.46–3.34(m,2H),2.38(s,3H),2.16–2.09(m,1H),2.06–1.99(m,1H),1.93–1.83(m,2H),1.82–1.70(m,2H),1.66–1.58(m,1H),1.57–1.50(m,1H),1.33(d,J＝6.5Hz,3H),1.21–1.14(m,1H).
实施例18：化合物15和化合物16
Figure PCTCN2019071704-appb-000045
化合物15和化合物16由实施例4中化合物14经过手性柱拆分得到。其中，化合物15对应手性拆分中的前者，化合物16对应手性拆分中的后者。
化合物15：MS(ESI):m/z 408.4(M+H) +. 1H NMR(500MHz,d 6-DMSO)δ12.41(s,1H),8.87(s,1H),8.12–8.06(m,1H),7.98(d,J＝10.5Hz,1H),7.67(t,J＝8.5Hz,1H),7.61–7.56(m,2H),7.46(d,J＝8.5Hz,1H),7.17–7.11(m,1H),3.45–3.37(m,2H),2.16–2.09(m,1H),2.07–2.00(m,1H),1.93–1.83(m,2H),1.82–1.71(m,2H),1.68–1.60(m,1H),1.59–1.52(m,1H),1.35(d,J＝6.5Hz,3H),1.19–1.12(m,1H).
化合物16：MS(ESI):m/z 408.4(M+H) +. 1H NMR(500MHz,d 6-DMSO)δ12.46(s,1H),8.87(s,1H),8.12–8.06(m,1H),7.98(d,J＝10.5Hz,1H),7.67(t,J＝8.5Hz,1H),7.62–7.40(m,3H),7.14(d,J＝8.5Hz,1H),3.45–3.37(m,2H),2.16–2.09(m,1H),2.07–2.00(m,1H),1.93–1.83(m,2H),1.82–1.71(m,2H),1.68–1.60(m,1H),1.59–1.52(m,1H),1.35(d,J＝6.5Hz,3H),1.19–1.12(m,1H).
实施例19：化合物31和化合物32
Figure PCTCN2019071704-appb-000046
化合物31和化合物32由实施例11中化合物30经过手性柱拆分得到。其中，化合物31对应手性拆分中的前者，化合物32对应手性拆分中的后者。
化合物31：MS(ESI):m/z 426.4(M+H) +. 1H NMR(500MHz,d 6-DMSO)δ12.55(s,1H),8.87(s,1H),8.13–8.06(m,1H),7.98(d,J＝11.0Hz,1H),7.78–7.63(s,2H),7.61–7.40(m,2H),3.45–3.39(m,2H),2.16–2.08(m,1H),2.07–2.00(m,1H),1.92–1.83(m,2H),1.82–1.70(m,2H),1.68–1.60(m,1H),1.59–1.52(m,1H),1.34(d,J＝6.5Hz,3H),1.18–1.11(m,1H).
化合物32：MS(ESI):m/z 426.4(M+H) +. 1H NMR(500MHz,d 6-DMSO)δ12.54(s,1H),8.86(s,1H),8.13–8.06(m,1H),7.98(d,J＝11.0Hz,1H),7.78–7.63(s,2H),7.61–7.40(m,2H),3.45–3.39(m,2H),2.16–2.08(m,1H),2.07–2.00(m,1H),1.92–1.83(m,2H),1.82–1.70(m,2H),1.68–1.60(m,1H),1.59–1.52(m,1H),1.34(d,J＝6.5Hz,3H),1.18–1.11(m,1H).
实施例20：化合物51和化合物52
Figure PCTCN2019071704-appb-000047
化合物51(反式，外消旋)和化合物52(顺式，外消旋)从中间体F(40mg)和4,5-二氟-1,2-苯二胺出发，经由通用路线一和通用路线三制备而来。
得到化合物51(3.45mg)，第一个洗脱的异构体，白色固体，收率5％。MS(ESI):m/z 410.2(M+H) +. 1H NMR(500MHz,d 6-DMSO)δ12.49(s,1H),8.79(d,J＝4.5Hz,1H),8.10–8.04(m,1H),7.97(d,J＝11.0Hz,1H),7.68–7.57(m,2H),7.48(d,J＝9.5Hz,1H),7.44-7.41(m,1H),3.29-3.23(m,1H),2.94-2.88(m,1H),1.99-1.90(m,2H),1.88-1.79(m,2H),1.61–1.46(m,3H),1.44-1.34(m,5H).
得到化合物52(4.15mg)，第二个洗脱的异构体，白色固体，收率6％。MS(ESI):m/z 410.2(M+H) +. 1H NMR(500MHz,d 6-DMSO)δ12.54(s,1H),8.87(s,1H),8.13–8.06(m,1H),7.98(d,J＝11.0Hz,1H),7.78–7.63(s,2H),7.61–7.40(m,2H),3.45–3.39(m,2H),2.16–2.08(m,1H),2.07–2.00(m,1H),1.92–1.83(m,2H),1.82–1.70(m,2H),1.68–1.60(m,1H),1.59–1.52(m,1H),1.34(d,J＝6.5Hz,3H),1.18–1.11(m,1H).
实施例21：化合物53和化合物54
Figure PCTCN2019071704-appb-000048
化合物53和化合物54由实施例21中化合物52经过手性柱拆分得到。其中，化合物53对应手性拆分中的前者，化合物54对应手性拆分中的后者。
化合物53：MS(ESI):m/z 410.2(M+H) +. 1H NMR(500MHz,d 6-DMSO)δ12.54(s,1H),8.87(s,1H),8.13–8.06(m,1H),7.98(d,J＝11.0Hz,1H),7.78–7.63(s,2H),7.61–7.40(m,2H),3.45–3.39(m,2H),2.16–2.08(m,1H),2.07–2.00(m,1H),1.92–1.83(m,2H),1.82–1.70(m,2H),1.68–1.60(m,1H),1.59–1.52(m,1H),1.34(d,J＝6.5Hz,3H),1.18–1.11(m,1H).
化合物54：MS(ESI):m/z 410.2(M+H) +. 1H NMR(500MHz,d 6-DMSO)δ12.54(s,1H),8.87(s,1H),8.13–8.06(m,1H),7.98(d,J＝11.0Hz,1H),7.78–7.63(s,2H),7.61–7.40(m,2H),3.45–3.39(m,2H),2.16–2.08(m,1H),2.07–2.00(m,1H),1.92–1.83(m,2H),1.82–1.70(m,2H),1.68–1.60(m,1H),1.59–1.52(m,1H),1.34(d,J＝6.5Hz,3H),1.18–1.11(m,1H).
本发明的化合物在Hela细胞中的活性研究
本发明的化合物在Hela细胞和高表达人IDO1蛋白的HEK293细胞活性测试方法参照已有技术中所公开的方法(“Blood，2010,115(17)：3520-3530”)。具体测试如下：
将Hela细胞接种于96孔培养板中，在37℃，100％相对湿度，5％CO 2培养箱中培养24小时。将化合物溶解于DMSO并稀释至合适浓度，再用含有干扰素-γ及10％胎牛血清的DMEM培养基将候选化合物稀释100倍至作用终浓度。吸弃96孔板中的旧培养基，每孔加200μl上一步含有化合物和干扰素-γ 的培养基。培养基中色氨酸含量为16mg/l，干扰素-γ浓度50ng/ml。细胞置于37℃，100％相对湿度，5％CO2培养箱中培养48小时后，吸取140μl细胞培养上清与15μl三氯乙酸混合，并置于52℃反应30min后，室温离心取离心上清与等体积Ehrlich’s试剂混合，测定480nm下的光吸收，计算IC50值。
化合物 IC50(HeLa细胞)
化合物1 B
化合物2 B
化合物3 A
化合物4 A
化合物5 A
化合物6 B
化合物7 B
化合物8 A
化合物9 A
化合物10 A
化合物11 A
化合物12 B
化合物13 A
化合物14 A
化合物15 B
化合物16 A
化合物17 B
化合物18 A
化合物19 B
化合物20 A
化合物21 A
化合物22 A
化合物23 B
化合物24 A
化合物25 B
化合物26 A
化合物27 B
化合物28 A
化合物29 B
化合物30 A
化合物31 B
化合物32 A
化合物33 A
化合物34 A
化合物35 A
化合物36 A
化合物37 B
化合物38 A
化合物39 B
化合物40 A
化合物41 B
化合物42 A
化合物43 C
化合物44 B
化合物45 C
化合物46 B
化合物47 C
化合物48 C
化合物49 B
注：A:IC50＝0.1nM～10nM；B:IC50＝10nM～100nM；C:IC50>100nM；
本发明的化合物化合物在高表达人IDO1蛋白的HEK293细胞中的活性研究
利用电转化制备高表达人IDO1蛋白的HEK293-IDO细胞，并将细胞接种于96孔培养板中，在37℃，100％相对湿度，5％CO2培养箱中培养24小时。将化合物溶解于DMSO并稀释至合适浓度，再用含有10％胎牛血清的DMEM培养基将候选化合物稀释100倍至作用终浓度。吸弃96孔板中的旧培养基，每孔加200μl上一步含有化合物的培养基。培养基中色氨酸含量为16mg/l。细胞置于37℃，100％相对湿度，5％CO2培养箱中培养24小时后，吸取140μl细胞培养上清与15μl三氯乙酸混合，并置于52℃反应30min后，室温离心取离心上清与等体积Ehrlich’s试剂混合，测定480nm下的光吸收，计算IC50值。
化合物 IC50(HEK293细胞)
化合物1 B
化合物13 B
化合物14 B
化合物16 B
化合物17 B
化合物18 B
化合物20 B
化合物21 B
化合物22 B
化合物24 B
化合物25 B
化合物26 B
化合物28 B
化合物29 B
化合物30 B
化合物32 B
化合物33 B
化合物34 B
化合物35 B
化合物36 B
化合物37 B
化合物38 B
化合物39 B
注：A:IC50＝0.1nM～10nM；B:IC50＝10nM～100nM；C:IC50>100nM。

Claims (15)

  1. 一种如式(I)所示的化合物、其盐、溶剂合物、前药、代谢产物、氮氧化物、立体异构体或同位素衍生物：
    Figure PCTCN2019071704-appb-100001
    式(I)
    其中
    Figure PCTCN2019071704-appb-100002
    表示：——、
    Figure PCTCN2019071704-appb-100003
    或者
    Figure PCTCN2019071704-appb-100004
    Cy 1选自任选地被取代基所取代的5-15元环，所述的取代基选自：卤素、羟基、C 1-6烷基、氨基、卤代C 1-6烷基、巯基、C 1-6烷基巯基、C 1-6烷基氨基、二(C 1-6烷基)氨基、和氰基；
    Cy 2选自任选地被一个、两个或更多个R 2取代的C 6-10元环烷基、C 6-10元杂环基、C 6-10元芳基或C 6-10元杂芳基；优选为被一个、两个或更多个R 2取代的苯基、吡啶基、环己基、哌啶基、哌嗪基、吡嗪基、嘧啶基、吗啉基；哒嗪基；R 1和R 2独立地选自氢原子、卤素、羟基、硝基、氰基、磺酸基、C 1-6烷基、C 3-6环烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、卤代C 1-C 6烷基、卤代C 1-C 6烷氧基、卤代C 3-C 6环烷基、C 1-6烷基硫基、C 1-6烷基羰基、C 1-6烷氧基羰基、二(C 1-6烷基)氨基C 2-6烷氧基羰基、氨基、C 1-6烷基氨基、二(C 1-6烷基)氨基、氨基甲酰基、C 1-6烷基氨基甲酰基、二(C 1-6烷基)氨基甲酰基、二(C 1-6烷基)氨基C 2-6烷基氨基甲酰基、氨磺酰基、C 1-6烷基氨磺酰基、二(C 1-6烷基)氨磺酰基、二(C 1-6烷基)氨基C 2-6烷基氨磺酰基、C 1-6烷基磺酰基、C 1-6烷基亚硫酰基、二(C 1-6烷基)膦酰基、羟基C 1-6烷基、羟基羰基C 1-6烷基、C 1-6烷氧基C 1-6烷基、C 1-6烷基磺酰基C 1-6烷基、C 1-6烷基亚硫酰基C 1-6烷基、二(C 1-6烷基)膦酰基C 1-6烷基、羟基C 2-6烷氧基、C 1-6烷氧基C 2-6烷氧基、氨基C 1-6烷基、C 1-6烷基氨基C 1-6烷基、二(C 1-6烷基)氨基C 1-6烷基、二(C 1-6烷基)氨基乙酰基、氨基C 2-6烷氧基、C 1-6烷基氨基C 2-6烷氧基、二(C 1-6烷基)氨基C 2-6烷氧基、羟基C 2-6烷基氨基、C 1-6烷氧基C 2-6烷基氨基、氨基C 2-6烷基氨基、C 1-6烷基氨基C 2-6烷基氨基、二(C 1-6 烷基)氨基C 2-6烷基氨基；或者相邻的两个R 1或R 2相互环合形成3-8元环，该环中含有0-3个杂原子；
    m、n各自独立地为选自0、1、2、3和4的整数；
    R a、R b各自独立地选自氢、C 1-C 6烷基或C 3-6环烷基；
    X独立地选自CR aR b、NR e或O；
    Y独立地选自CR e或N；其中R e独立地表示氢、C 1-6烷基或者C 3-6环烷基、C 1-6卤代烷基。
  2. 如权利要求1所述的化合物、其盐、溶剂合物、前药、代谢产物、氮氧化物、立体异构体或同位素衍生物，其中所述化合物具有式(II)结构：
    Figure PCTCN2019071704-appb-100005
    其中，W 1、W 2、W 3、W 4各自独立地选自CR e、C＝O或N；p为选自0、1、2、3和4的整数；R 1、R 2、Cy 1、R a、R b、R e、X、Y、m、n如权利要求1所定义；虚线表示单键或者双键。
  3. 如权利要求1或2所述的化合物、其盐、溶剂合物、前药、代谢产物、氮氧化物、立体异构体或同位素衍生物，其中Cy 1选自以下基团：
    Figure PCTCN2019071704-appb-100006
    其中R 3选自氢、C 1-6烷基、C 3-6环烷基；
    上述Cy 1基团任选地被一个、两个或更多个选自卤素、羟基、C 1-6烷基、氨基、卤代C 1-6烷基、巯基、C 1-6烷基巯基、C 1-6烷基氨基、二(C 1-6烷基)氨基和氰基的取代基所取代。
  4. 如权利要求2所述的化合物、其盐、溶剂合物、前药、代谢产物、氮氧化物、立体异构体或同位素衍生物，其具有式(III)结构：
    Figure PCTCN2019071704-appb-100007
    其中，R 1、R 2、R a、R b、X、Y、W 1、W 2、W 3、W 4、m、n、p如权利要求2所定义。
  5. 如权利要求2所述的化合物、其盐、溶剂合物、前药、代谢产物、氮氧化物、立体异构体或同位素衍生物，其具有式(IV)结构：
    Figure PCTCN2019071704-appb-100008
    其中Q 1和Q 2各自独立地选自CR aR b、NR e或O；Q 3选自CR a或N；其中，R 1、R 2、R a、R b、R e、X、Y、W 1、W 2、W 3、W 4、m、p如权利要求2所定义。
  6. 如权利要求2所述的化合物、其盐、溶剂合物、前药、代谢产物、氮氧化物、立体异构体或同位素衍生物，其具有式(V)结构：
    Figure PCTCN2019071704-appb-100009
    其中R 1、R 2、R a、R b、X、Y、W 1、W 2、W 3、W 4、m、p如权利要求2所定义。
  7. 如权利要求1所述的化合物，其选自：
    Figure PCTCN2019071704-appb-100010
    Figure PCTCN2019071704-appb-100011
    Figure PCTCN2019071704-appb-100012
  8. 如权利要求1-7任一项所述的化合物，其中
    Figure PCTCN2019071704-appb-100013
    表示——、
    Figure PCTCN2019071704-appb-100014
    或者
    Figure PCTCN2019071704-appb-100015
    优选为
    Figure PCTCN2019071704-appb-100016
  9. 一种药物组合物，其包含权利要求1至8任意一项所述的化合物、其盐、溶剂合物、前药、代谢产物、氮氧化物、立体异构体或同位素衍生物，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，其中进一步包括另一种治疗剂，所述另一种治疗剂优选为苯丁酸氮芥、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、PD-1抗体、PD-L1抗体或它们的任意组合。
  11. 一种抑制吲哚胺2,3-双加氧酶的方法，其包括使权利要求1-8所述化合物、其盐、溶剂合物、前药、代谢产物、氮氧化物、立体异构体或同位素衍生物或者权利要求9-10所述的药物组合物暴露于吲哚胺2,3-双加氧酶。
  12. 一种预防或治疗吲哚胺2,3-双加氧酶活性异常相关疾病的方法，其包括向有此需要的患者施用权利要求1-8任一项所述化合物、其盐、溶剂合物、前药、代谢产物、氮氧化物、立体异构体或同位素衍生物或权利要求9-10任一项所述的药物组合物。
  13. 一种对抗免疫抑制的方法，其包括向有此需要的患者施用权利要求1-8任一项所述化合物、其盐、溶剂合物、前药、代谢产物、氮氧化物、立体异构体或同位素衍生物或权利要求9-10任一项所述的药物组合物。
  14. 一种预防或治疗肿瘤、癌症、病毒感染、器官移植排斥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所述化合物、其盐、溶剂合物、前药、代谢产物、氮氧化物、立体异构体或同位素衍生物或权利要求9-10所述的药物组合物。
  15. 权利要求1-8任一项所述的化合物、其盐、溶剂合物、前药、代谢产物、氮氧化物、立体异构体或同位素衍生物或权利要求9-10任一项所述的药物组合物在制备用于抑制吲哚胺2,3-双加氧酶、用于预防或治疗吲哚胺2,3-双加氧酶活性异常相关疾病、用于对抗免疫抑制、或者用于预防或治疗肿瘤、癌症、病毒感染、器官移植排斥或自身免疫性疾病的药物中的用途。
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