WO2019129114A1 - 吲哚胺2,3-双加氧酶抑制剂以及它们在医学上的应用 - Google Patents

吲哚胺2,3-双加氧酶抑制剂以及它们在医学上的应用 Download PDF

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WO2019129114A1
WO2019129114A1 PCT/CN2018/124110 CN2018124110W WO2019129114A1 WO 2019129114 A1 WO2019129114 A1 WO 2019129114A1 CN 2018124110 W CN2018124110 W CN 2018124110W WO 2019129114 A1 WO2019129114 A1 WO 2019129114A1
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alkyl
compound
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cancer
amino
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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 CN201880057640.2A priority Critical patent/CN111741946B/zh
Priority to GB2009911.5A priority patent/GB2583606C/en
Publication of WO2019129114A1 publication Critical patent/WO2019129114A1/zh
Priority to US16/914,142 priority patent/US11111230B2/en

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    • 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
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    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
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    • C07D491/04—Ortho-condensed systems
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Definitions

  • the present invention relates to a novel indoleamine 2,3-dioxygenase inhibitor having an inhibitory activity against tryptophan metabolism, and a pharmaceutical composition comprising the same as an active ingredient.
  • 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 in humans, 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 (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 Rev Immunol 2004; 4(10): 762; Munn, Front Biosci. 2012; 4: 734) and transforming growth factor-beta (TGF-beta) (Pallotta et al, Nat Immunol.
  • TGF-beta transforming growth factor-beta
  • IDO as an inducible enzyme, plays a major role in immune cell regulation.
  • Decreased tryptophan levels and increased kynurenine inhibit immune effector cells and promote adaptive immunosuppression by inducing and maintaining regulatory T cells (Tregs; Munn, Front Biosci. 2012; 4:734); immune system
  • the concentration of tryptophan is positively correlated with T cells.
  • 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 receptors have become an important target for immunotherapy such as 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.
  • active and selective IDO inhibitors effective in the treatment of diseases caused by harmful substances in the kynurenine pathway by regulating the kynurenine pathway and maintaining the level of tryptophan in the body, whether as a Single dose or combination therapy is necessary.
  • 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).
  • One aspect of the invention provides a compound of formula I,
  • A represents -C(O)-, -S(O) 2 - or -S(O)-;
  • each R 1 is 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 alkoxy, halogenated C 1 -C 6 alkyl, halogenated C 1 -C 6 alkoxy, halogenated C 1 -C 6 cycloalkyl, C 1- 6 alkylthio, C 1-6 alkylcarbonyl, C 1-6 alkoxycarbonyl, bis(C 1-6 alkyl)amino C 2-6 alkoxycarbonyl, amino, C 1-6 alkyl Amino, di(C 1-6 alkyl)amino, carbamoyl, C 1-6 alkylcarbamoyl, di(C 1-6 alkyl)
  • Cy 1 is selected from a 5-15 membered bridged ring group substituted with an arbitrary substituent, a 5-15 membered spirocyclic group, a 5-15 membered bridged heterocyclic group, or a 5-15 membered spiroheterocyclic group, said substituent Is: halogen, hydroxy, C 1-6 alkyl, amino, halogenated C 1-6 alkyl, fluorenyl, C 1-6 alkyl fluorenyl, C 1-6 alkylamino, di (C 1-6 alkyl An amino group, a cyano group;
  • R a, R b, R 2 are each independently selected from hydrogen, C 1 -C 6 alkyl or C 3 - 6 cycloalkyl;
  • Cy 2 is a C 5 -C 10 aryl group having one or two or more substituents, a C 5 -C 10 heteroaryl group, a C 5 -C 10 cycloalkyl group, a C 5 -C 10 heterocycloalkyl group;
  • the substituent may be selected from the group consisting of halogen, hydroxy, nitro, cyano, sulfonate, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkoxy, halogenated C 1 -C 6 alkyl, halogenated C 1 -C 6 alkoxy, C 1-6 alkylthio, C 1-6 alkylcarbonyl, C 1-6 Alkylcarbonyloxy, C 1-6 alkoxycarbonyl, bis(C 1-6 alkyl)amino C 2-6 alkoxycarbonyl, amino, C 1-6 alkylamino, di (C 1-6 Alky
  • Cy 1 is selected from the group consisting of an 8-12 membered spiro group or an 8-12 membered spiro group, an 8-12 membered bridged heterocyclic group, or an 8-12 membered snail substituted with a substituent.
  • the substituent is: halogen, hydroxy, C 1-6 alkyl, amino, halogenated C 1-6 alkyl, fluorenyl, C 1-6 alkyl fluorenyl, C 1-6 alkylamino , (C 1-6 alkyl)amino group, cyano group.
  • Cy 1 is selected from the group consisting of:
  • the above group may be 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 alkylamino, di (C) Substituted by a substituent of 1-6 alkyl)amino and cyano.
  • Cy 1 is selected from the group consisting of:
  • the above group may be 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 alkylamino, di (C) Substituted by a substituent of 1-6 alkyl)amino and cyano.
  • One aspect of the invention provides a compound of formula (II),
  • R 1 , R 2 , R a , R b , Cy 2 , m, n, A are as defined in formula I;
  • X is selected from (CR c R d ) o , wherein any CR c R d can be O or Substituting NR e ;
  • Y is selected from CR f or N; wherein R c , R d , R e , R f are each independently selected from hydrogen or C 1-6 alkyl; o is selected from 0, 1, 2, 3 4, 5.
  • One aspect of the invention provides a compound of formula (III),
  • W is selected from CR c R d or NR e , or O;
  • A R 1 , R 2 , R a , R b , R c , R d , R e , Cy 2 , m, n, Y, eg Defined by the above formula (II).
  • Another aspect of the invention also provides a compound of formula (IV),
  • R 1 , R 2 , R a , R b , Cy 2 , m, n, X, Y, A are as defined in the above formula (II);
  • Z is selected from (CR g ) p , wherein any CR g can be Substituted by N;
  • R g are each independently selected from hydrogen or C 1-6 alkyl;
  • p is selected from 0, 1 , 2, 3, 4, 5.
  • R 1 , R 2 , R c , R d , R f , Cy 2 , m, and A are as defined in the above formula (II).
  • R 1 , R 2 , R c , R d , Cy 2 , m, and A are as defined in the above formula (II).
  • R 1 , R 2 , R e , R f , Cy 2 , m, and A are as defined in the above formula (II).
  • R 1 , R 2 , R c , R d , R f , Cy 2 , m, and A are as defined in the above formula (II).
  • R 1 , R 2 , R c , R d , R e , R f , Cy 2 , m, and A are as defined in the above formula (II).
  • A is selected from -C(O)- or S(O) 2- .
  • the invention also provides a preparation method of a compound having the structure of formula (X):
  • the base used in the step (1) is selected from an inorganic base or an organic base, including but not limited to: sodium hydride, calcium hydride, sodium amide, sodium methoxide, sodium ethoxide, potassium hydroxide, sodium hydroxide, lithium hydroxide, hydrogenation.
  • the organic solvent used in the step (1) includes, but is not limited to, 1,4-dioxane, N,N-dimethylformamide, dichloromethane, chloroform, DMSO, DMF, THF, acetone, methanol, Ethanol or any combination thereof;
  • ylide selected for use in step (2) is selected from the group consisting of sulfur ylide or phosphorus ylide;
  • the Grignard reagent used in the step (3) is selected from the group consisting of CH 3 MgCl, CH 3 MgBr, C 2 H 5 MgCl, C 2 H 5 MgBr, i-PrMgCl, i-PrMgBr, PhCH 2 MgCl, PhCH 2 MgBr or random combination.
  • the invention also provides a preparation method of a compound having the structure of formula (XI):
  • the catalyst used in the step (1) is selected from the group consisting of methyl titanate, ethyl titanate, n-propyl titanate, isopropyl titanate, butyl titanate or any combination thereof;
  • the base used in the step (2) is selected from an inorganic base or an organic base, including but not limited to: sodium hydride, calcium hydride, sodium amide, sodium methoxide, sodium ethoxide, potassium hydroxide, sodium hydroxide, lithium hydroxide, hydrogenation.
  • the organic solvent used in the step (2) includes, but is not limited to, 1,4-dioxane, N,N-dimethylformamide, dichloromethane, chloroform, DMSO, DMF, THF, acetone, methanol, Ethanol or any combination thereof;
  • ylide selected for use in step (2) is selected from the group consisting of sulfur ylide or phosphorus ylide;
  • step (3) is carried out under acidic conditions selected from the group consisting of, but not limited to, hydrochloric acid, sulfuric acid, hydrobromic acid, oxalic acid, citric acid, formic acid, acetic acid or any combination thereof;
  • the organic solvent used in the step (4) includes, but is not limited to, 1,4-dioxane, N,N-dimethylformamide, dichloromethane, chloroform, DMSO, DMF, THF, acetone, methanol. , ethanol or any combination thereof.
  • the invention also provides a preparation method of a compound having the structure of formula (XII):
  • the catalyst used in the step (1) is selected from the group consisting of methyl titanate, ethyl titanate, n-propyl titanate, isopropyl titanate, butyl titanate or any combination thereof;
  • the non-nucleophilic strong base is selected from, but not limited to, lithium diisopropylamide, lithium diethylamide, isopropylcyclohexylamino Lithium, lithium dicyclohexylamide, lithium 2,2,6,6-tetramethylpiperidino, lithium hexamethyldisilazide;
  • the hydrolysis reaction described in the step (3) is carried out under acidic conditions, and the acid is selected from the group consisting of, but not limited to, hydrochloric acid, sulfuric acid, hydrobromic acid, oxalic acid, citric acid, formic acid, acetic acid or any combination thereof;
  • the Grignard reagent used in the step (4) is selected from the group consisting of CH 3 MgCl, CH 3 MgBr, C 2 H 5 MgCl, C 2 H 5 MgBr, i-PrMgCl, i-PrMgBr, PhCH 2 MgCl, PhCH 2 MgBr or random combination;
  • the alkylation reaction agent is selected from a halogenated alkyl group, and the reaction is carried out under the action of a Lewis acid as a catalyst, and the Lewis acid is preferably AlCl 3 , FeCl 2 , CuCl 2 .
  • the invention also provides a preparation method of a compound having the structure of formula (XIII):
  • the base used in the step (1) and the step (3) is selected from an inorganic base or an organic base, including but not limited to: sodium hydride, calcium hydride, sodium amide, sodium methoxide, sodium ethoxide, potassium hydroxide, sodium hydroxide , lithium hydroxide, lithium aluminum hydride, t-butyl lithium, t-butyl potassium, potassium t-butoxide, lithium diisopropylamide, cesium hydroxide or any combination thereof;
  • the organic solvent used in the step (1) to the step (3) includes, but is not limited to, 1,4-dioxane, N,N-dimethylformamide, dichloromethane, chloroform, DMSO, DMF, , THF, acetone, methanol, ethanol or any combination thereof;
  • the oxidizing agent used in the step (2) is selected from, but not limited to, m-chloroperoxybenzoic acid, CrO 3 , KMnO 4 , MnO 2 , NaCr 2 O 7 , HIO 4 , PbAc 4 , OsO 4 , hydrogen peroxide or any combination thereof;
  • the hydrolysis reaction described in the step (4) is carried out under acidic conditions, and the acid is selected from the group consisting of, but not limited to, hydrochloric acid, sulfuric acid, hydrobromic acid, oxalic acid, citric acid, formic acid, acetic acid or any combination thereof;
  • the Grignard reagent used in the step (5) is selected from the group consisting of CH 3 MgCl, CH 3 MgBr, C 2 H 5 MgCl, C 2 H 5 MgBr, i-PrMgCl, i-PrMgBr, PhCH 2 MgCl, PhCH 2 MgBr or random combination.
  • the invention also provides a preparation method of a compound having the structure of formula (XIV):
  • step (1) is carried out in the presence of an alkali metal fluoride or an alkaline earth metal fluoride selected from the group consisting of, but not limited to, LiF, NaF, KF, MgF 2 , CaF 2 ;
  • the reduction reaction of the step (2) may be palladium carbon catalytic hydrogenation reduction, or may be Na/liquid ammonia reduction;
  • the Grignard reagent used in the step (3) is selected from the group consisting of CH 3 MgCl, CH 3 MgBr, C 2 H 5 MgCl, C 2 H 5 MgBr, i-PrMgCl, i-PrMgBr, PhCH 2 MgCl, PhCH 2 MgBr or random combination;
  • the alkylation reaction agent is selected from a halogenated alkyl group, and the reaction is carried out under the action of a Lewis acid as a catalyst, and the Lewis acid is preferably AlCl 3 , FeCl 2 , CuCl 2 .
  • a salt, solvate or hydrate of a compound is an alternative form of the compound, which can be converted to the compound under certain conditions, and thus when a compound is referred to herein It also generally includes its pharmaceutically acceptable salts, and further includes solvates and hydrates thereof. Similarly, when referring to a compound herein, it also includes prodrugs, metabolites, and oxynitrides.
  • the salt is formed using, but not limited to, 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, hydroxybenzoic acid , phenylacetic acid, cinnamic acid, salicylic acid, methanesulfonic acid, benzenesulfonic acid and toluenesulfonic acid.
  • 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,
  • the pharmaceutically acceptable salts of the present invention can be prepared by a conventional method, 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 thereto. Or an aqueous solution of a mineral acid 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 invention 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.
  • the tumor or cancer is selected from, but 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, kidney cancer, renal parenchymal cancer, ovarian cancer, cervical cancer, endometrial cancer, endometrial cancer, choriocarcinoma, pancreatic cancer, prostate cancer, testicular cancer, urinary cancer, melanoma, brain tumors such as gelatin Cell tumor, astrocytoma, meningioma, medulloblastoma and peripheral neuroectodermal tumor, Hodgkin's lymphoma, non-Hodgkin's lymphoma, Burkitt's lymphoma, acute lymphocytic leukemia (ALL), Chronic lymphocytic leukemia (CLL), acute myeloid
  • 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 can include, but are not limited to, cell signal transduction inhibitors (eg, chlorambucil, melphalan, cyclophosphamide, ifosfamide, busulfan, Carmustine, lomustine, streptozotocin, cisplatin, carboplatin, oxaliplatin, dacarbazine, temozolomide, procarbazine, methotrexate, fluorouracil, cytarabine, gemcitabine , thiopurine, fludarabine, vinblastine, vincristine, vinorelbine, paclitaxel, docetaxel, topotecan, irinotecan, etoposide, trobeidine, dactinomycin, doxorubicin Star, epirubicin, daunorubicin, mitoxantrone, bleomycin, mitomycin C, ixabepilone, tamoxi
  • the invention further relates to a method of inhibiting guanamine 2,3-dioxygenase comprising exposing a compound or pharmaceutical composition of the invention to a guanamine 2,3-dioxygenase.
  • 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.
  • 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 assay were deuterated dimethyl sulfoxide (d 6 -DMSO), deuterated chloroform (CDCl 3 ), tetramethylsilane (TMS). ) as an internal standard.
  • reaction solution was further stirred at this temperature for 60 minutes, and then the reaction liquid was allowed to warm to room temperature, and stirred overnight until the reaction material was completely consumed by TLC.
  • the reaction solution was quenched with 3 mL of aqueous sodium hydrogen sulfate. 3 mL of methyl tert-butyl ether was added to the residual liquid, and the organic layer was washed three times with 45 mL of a sodium hydroxide (5%) solution and once with 50 mL of brine.
  • the third step Compound 1b (5.7 g, 21.48 mmol) was dissolved in 60 mL / 15 mL of dioxane / water, followed by the addition of 4-chloro-6-fluoroquinoline (3.0 g, 16.53 mmol), potassium carbonate (6.8 g) , 49.56 mmol) and Pd(PPh3) 4 (954 mg, 0.83 mmol). The reaction mixture was refluxed overnight under a nitrogen atmosphere. The reaction mixture was then concentrated, extracted with EtOAc EtOAc EtOAc EtOAc EtOAc MS (ESI):.
  • the sixth 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 compound 1e (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 residue was isolated by flash column chromatography to afford compound 1f (l.
  • the eighth step 4-chloroaniline (94 mg, 0.73 mmol) was dissolved in 5 mL of tetrahydrofuran, and a 2 mol/L solution of isopropylmagnesium chloride in tetrahydrofuran (0.4 mL, 0.73 mmol) was added. The mixture was stirred at room temperature for 5 minutes, and a solution of compound 1 g (60 mg, 0.18 mmol) in tetrahydrofuran (2 mL) was added to the mixture. The reaction was stirred at room temperature overnight then quenched with saturated aq. The combined organic layers were dried with anhydrous sodium s The residue was purified by reverse preparative chromatography to afford compound 1 (16.
  • the second step 4-chloroaniline (36 mg, 0.28 mmol) was dissolved in tetrahydrofuran (2 mL), and a solution of 2.0 mol/L isopropylmagnesium chloride in tetrahydrofuran (0.2 mL, 0.28 mmol) was added. The mixture was stirred at room temperature for 5 minutes, and a solution of compound 9a (24 mg, 0.07 mmol) in tetrahydrofuran (1 mL) was added to the mixture. The reaction was stirred at room temperature overnight then quenched with saturated aq. The combined organic layers were dried with anhydrous sodium s The residue was purified by reverse preparative chromatography to afford compound 9 (12.
  • the compound 10a and the compound 10b were obtained by subjecting the compound 1 of Example 1 to a chiral column, and the absolute configuration was not determined. Among them, the compound 10a corresponds to the former in the chiral resolution (retention time 3.027 minutes), and the compound 10b corresponds to the latter in the chiral resolution (retention time 3.842 minutes).
  • the first step ethyl methanesulfonate (2.45 g, 19.75 mmol) was dissolved in ultra dry tetrahydrofuran (30 mL), and di-trimethylsilylamine lithium (1.0 M) was added under a dry ice bath at -78 ° C under nitrogen. In THF, 19.8 mL, 19.75 mmol), the reaction was stirred at this temperature for 30 min. A solution of Compound 1e (4.0 g, 16.46 mmol) in tetrahydrofuran (20 mL) was then added to the reaction mixture and was reacted at -78 ° C for 3 hours. The reaction was quenched with water and EtOAcqqqqm It does not require purification and is used directly in the next step. MS (ESI): m/z 368.4 (M+H) +
  • the third step Compound 14b (216 mg, 0.62 mmol) was dissolved in a mixed solvent of ethylene glycol dimethyl ether/water (5/5 mL), and potassium thiocyanide (60 mg, 0.62 mmol) was added. The reaction mixture was heated to 90 ° C overnight. After cooling to room temperature, it was diluted with 10 mL, extracted three times with ethyl acetate and then evaporated and evaporated. This solid was dissolved in thionyl chloride (5 mL), and then N,N-dimethylformamide (0.5 mL) was added dropwise, and the mixture was heated to 80 ° C for 3 hours. The solvent was evaporated to dryness. The residue was dissolved in dry methylene chloride (5 mL).
  • the fourth step NaH (37 mg, 0.93 mmol) was added to dimethyl sulfoxide (15 mL), and trimethyl sulfonium iodide (205 mg, 0.93 mmol) was added to the suspension. The mixture was stirred at room temperature for 1 hour. A solution of compound 14c (124 mg, 0.31 mmol) in dimethyl sulfoxide (5 mL) was then added to the mixture. The reaction was stirred at 60 ° C for 3 hours. It was then quenched with EtOAc (EtOAc)EtOAc. The residue was isolated by preparative EtOAc EtOAc (EtOAc) MS (ESI): m/z 412.4 (M+H) +
  • the seventh step the compound 14f (30 mg, 0.08 mmol) was dissolved in pyridine (2 mL), then 4-chloroaniline (20 mg, 0.16 mmol), 4-dimethylaminopyridine (12 mg, 0.01 mmol) was added, and the reaction mixture was heated. Continue to 100 ° C overnight. The solvent was evaporated to dryness. EtOAc EtOAc m. The residue was purified by reverse preparative chromatography to afford compound 14 ( 5. ⁇ RTIgt; MS (ESI):.
  • the first step Compound 1e (500 mg, 2.06 mmol) was dissolved in 20 mL of ultra dry tetrahydrofuran, and tetraethoxytitanium (2.81 g, 12.36 mmol) was added under nitrogen, followed by t-butylsulfinamide (747 mg, 6.18mmol),.
  • the reaction mixture was reacted at 60 ° C for 4 hours.
  • the reaction was cooled to room temperature, and the mixture was poured into an equal volume of saturated brine and stirred, and the obtained suspension was filtered over Celite, and filtered.
  • the organic layer was washed with brine, dried over anhydrous sodium sulfate
  • the residue was isolated by a flash column chromatography to afford compound 20a ( 510 mg).
  • the second step trimethylsulfoxonium iodide (486 mg, 2.21 mmol) was added to 20 mL of ultra dry dimethyl sulfoxide, then NaH (88 mg, 2.21 mmol) was added and stirred at room temperature for 20 min. Then, a solution of Compound 20a (510 mg, 1.47 mmol) in 2 mL of dimethyl sulfoxide was added to the reaction mixture. The reaction mixture was stirred at room temperature for 1 hour. The reaction was quenched with EtOAc (EtOAc)EtOAc. The residue was isolated by a flash column chromatography to afford compound 20b (320mg). MS (ESI): m/z 361.4 (M+H) +
  • EtOAc EtOAc
  • the first step (cyclopropylmethyl)triphenylphosphonium bromide (2.0 eq) was added to ultra dry tetrahydrofuran, and NaH (2.0 eq) was added to the suspension, followed by stirring at room temperature for 2 hours. Further, Compound 1e (1.0 eq) and tris(3,6-dioxaheptyl)amine (0.1 eq) were added to the reaction mixture. The reaction mixture was stirred at room temperature for 10 minutes and then heated to 62 ° C for 4 hours. The reaction solvent was spin-dried, and the residue was separated using a flash column apparatus to give compound 32a. MS (ESI): m/z 268.3 (M+H) +
  • the fifth step Compound 32d (1.0 eq) was dissolved in ethyl acetate. pyridine (3.0 eq) and tripropylphosphonic acid anhydride (2.5 eq) were sequentially added and stirred at room temperature for 10 min. Then 4-chloroaniline (3.0 eq) was added and the reaction was stirred at room temperature overnight. A 2 M sodium hydroxide solution was added to the reaction mixture, and the mixture was diluted with water. The combined organic layers were dried with anhydrous sodium s The residue was purified by reverse preparative chromatography to afford compound 32 as a white solid.
  • the second step Compound 38a (1.0 eq) was dissolved in tetrahydrofuran, and cooled to 0 ° C with ice water, and triphenylphosphine (2.0 eq) and carbon tetrachloride (2.0 eq) were sequentially added to the reaction mixture. After the reaction mixture was stirred at 0 ° C for 1 hour, the reaction was allowed to proceed to room temperature for 2 hours. The reaction solution was diluted with diethyl ether, filtered, and the filtrate was evaporated. MS (ESI): m / z 348.4 (M + H) +.
  • the third step A solution of compound 38b (1.0 eq) in dry diethyl ether was added portionwise to a suspension of magnesium (1. After the reaction liquid was allowed to exotherm, it was heated to reflux for 30 minutes. The reaction suspension was cooled to 25 ° C and slowly added dropwise to a solution of sulfonyl chloride (3.0 eq) in anhydrous dichloromethane at 0 °C. The reaction mixture was warmed to 25 ° C. Compound 38c was obtained which was used in the next step without purification.
  • the fourth step the compound 38c (1.0 eq) obtained in the previous step was dissolved in anhydrous dichloromethane, cooled to 0 ° C with an ice water bath, and 4-chloroaniline (1.0 eq) and triethylamine were sequentially added to the reaction mixture. (1.1eq). The reaction mixture was stirred at 25 ° C for further 30 minutes and then concentrated. The residue was purified by reverse preparative chromatography to afford compound 38 as a white solid. MS (ESI): m/z 459.4 (M+H) +
  • the second step diisopropylamine (2.0 eq) was dissolved in ultra dry tetrahydrofuran, and 2.5 M n-butyllithium (2.0 eq) was added dropwise under a dry ice bath at -78 ° C under nitrogen. Then, a solution of the compound 50a (2.0 eq) in tetrahydrofuran was slowly added dropwise to the reaction mixture. The reaction was further stirred at -78 ° C for 1 hour, then a solution of compound 1e (1.0 eq) in tetrahydrofuran was added, and the reaction was slowly warmed to room temperature and allowed to react at room temperature for 3 hours. The reaction was quenched with EtOAc (EtOAc m. The residue was isolated using a flash column to give compound 50b, yield 54%. MS (ESI): m/z 476.4 (M+H) +
  • the third step Compound 50b (1.0 eq) was dissolved in tetrahydrofuran, and 1M tetrabutylammonium fluoride in tetrahydrofuran (10.0 eq) was added. The reaction mixture was reacted at 60 ° C for 4 hours. Water was added to the reaction mixture, and the mixture was evaporated. MS (ESI): m/z 3621. (M+H) +
  • the fifth step 4-chloroaniline (4.0 eq) was dissolved in tetrahydrofuran, and a 2 mol/L solution of isopropylmagnesium chloride in tetrahydrofuran (4.0 eq) was added under ice bath at 0 °C. The mixture was stirred at room temperature for 5 minutes, and a solution of the compound 50d (1.0 eq) in tetrahydrofuran was added to the mixture. The reaction was stirred at room temperature overnight then quenched with saturated aq. The combined organic layers were dried with anhydrous sodium s The residue was purified by reverse preparative chromatography to afford compound 50 as a white solid. .
  • the second step diisopropylamine (2.0 eq) was dissolved in ultra dry tetrahydrofuran, and 2.5 M n-butyllithium (2.0 eq) was added dropwise under a dry ice bath at -78 ° C under nitrogen. Then, a solution of the compound 62a (1.0 eq) in tetrahydrofuran was slowly added dropwise to the reaction mixture. The reaction was further stirred at -78 ° C for 1 hour, then a solution of oxalyl chloride monoethyl ester (2.0 eq) in tetrahydrofuran was added, and the reaction was slowly warmed to room temperature and allowed to react at room temperature for 3 hours. The reaction was quenched with EtOAc (EtOAc m. The residue was isolated using a flash column chromatography to afford compound 62b. MS (ESI): m/z 358.4 (M+H) +
  • the fifth step 4-chloroaniline (4.0 eq) was dissolved in tetrahydrofuran, and a solution of 2 mol/L of isopropylmagnesium chloride in tetrahydrofuran (4.0 eq) was added to an ice bath at 0 °C. The mixture was stirred at room temperature for 5 minutes, and a solution of compound 62d (1.0 eq) in tetrahydrofuran was added to the mixture. The reaction was stirred at room temperature overnight then quenched with saturated aq. The combined organic layers were dried with anhydrous sodium s The residue was purified by reverse preparative chromatography to afford compound 62 as a white solid. .
  • n-butyl lithium (2.5M in hexane, 6.0mL, 15.0mmol) was added dropwise to 2,2,6,6-tetramethylpiperidine (2.12g, 15.0mmol) at -78 °C.
  • 2,2,6,6-tetramethylpiperidine (2.12g, 15.0mmol) at -78 °C.
  • tetrahydrofuran (30 mL).
  • Compound 1d (2.87 g, 10.0 mmol) in tetrahydrofuran (20 mL) was added dropwise. The reaction was stirred at -78 °C for 2 hours.
  • the third step triethyl phosphonoacetate (1.74 g, 7.76 mmol) was dissolved in EtOAc (20 mL). After 10 minutes, a solution of compound 80b (1.9 g, 7.39 mmol) in tetrahydrofuran (10 mL) was added to the mixture. After 2 hours of reaction, it was quenched with water. The aqueous solution was extracted three times with 50 mL of EtOAc EtOAc. The residue was isolated using a flash column chromatography to afford compound ⁇ RTIgt; MS (ESI):.
  • the fifth step 4-chloroaniline (76 mg, 0.60 mmol) was dissolved in 5 mL of tetrahydrofuran, and a solution of 2.0 mol/L isopropylmagnesium chloride in tetrahydrofuran (0.3 mL, 0.60 mmol) was added. The mixture was stirred at room temperature for 5 minutes, and a solution of compound 80d (50 mg, 0.15 mmol) in tetrahydrofuran (2 mL) was added to the mixture. The reaction was stirred at room temperature overnight then quenched with saturated aq.
  • the first step Compound 1f (400 mg, 1.28 mmol) was dissolved in acetonitrile (15 mL) and N-methoxymethyl-N-(trimethylsilane)benzylamine (3.03 g, 12.8 mmol) was added. Lithium fluoride (998 mg, 38.4 mmol) was added. The reaction mixture was reacted at 60 ° C for 24 hours. The reaction was cooled to room temperature, 50 mL of water was added and the aqueous phase was extracted with ethyl acetate. The combined organic layers were dried with anhydrous sodium s The residue was isolated by preparative thin-layer chromatography to afford compound 87a (376 mg). MS (ESI): m/z 447.4 (M+H) +
  • the fifth step Compound 87d (40 mg, 0.12 mmol) was dissolved in ethyl acetate (5 mL), pyridine (28 mg, 0.36 mmol) and tripropylphosphonic acid (50% wt in EA, 114 mg, 0.18 mmol) Stir at room temperature for 10 minutes. Then 4-chloroaniline (23 mg, 0.18 mmol) was added and the reaction was stirred at room temperature overnight. A 2 mol/L sodium hydroxide (2 mL) solution was added to the reaction solution, and then diluted with 20 mL of water, and the aqueous phase was extracted with ethyl acetate.
  • Compound 92 and Compound 93 were obtained by resolution of compound 9 from Example 9 by a chiral column, and the absolute configuration was not determined. Among them, the compound 92 corresponds to the former in the chiral resolution, and the compound 93 corresponds to the latter in the chiral resolution.
  • the third step Compound 94c (1.2 g, 4.49 mmol) was dissolved in dichloromethane (3 mL), and a solution of 4.0 mol/L hydrochloric acid dioxane (6 mL) was added in an ice bath at 0 °C. The reaction was carried out for 2 hours at room temperature, and the resulting solid was filtered and dried to give compound 94d (900 mg) as a white solid. Used directly in the next step.
  • the third step triethyl phosphonoacetate (172 mg, 0.77 mmol) was dissolved in EtOAc (10 mL). After 10 minutes, a solution of compound 100b (190 mg, 0.73 mmol) in tetrahydrofuran (5 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 residue was isolated using a flash column chromatography to afford compound 100c (180 mg). MS (ESI): m / z 332.5 (M+H) + .
  • the fourth step NaH (65 mg, 1.62 mmol) was added to dimethyl sulfoxide (10 mL), and trimethylsulfoxonium iodide (356 mg, 1.62 mmol) was added to the suspension. The mixture was stirred at room temperature for 1.5 hours. A solution of compound 100c (180 mg, 0.54 mmol) in dimethyl sulfoxide (5 mL) was then added to the mixture. The reaction was stirred at 40 ° C overnight. It was then quenched with water, extracted with EtOAc EtOAc (EtOAc) MS (ESI): m/z 346.5 (M+H) +
  • the fourth step 4-chloroaniline (117 mg, 0.92 mmol) was dissolved in 5 mL of tetrahydrofuran, and a 2 mol/L solution of isopropylmagnesium chloride in tetrahydrofuran (0.5 mL, 0.92 mmol) was added. The mixture was stirred at room temperature for 5 minutes, and a solution of compound 100d (80 mg, 0.23 mmol) in tetrahydrofuran (2 mL) was added to the mixture. The reaction was stirred at room temperature overnight then quenched with saturated aq. The combined organic layers were dried with anhydrous sodium s The residue was purified by reverse preparative chromatography to afford compound 100 (j.
  • n-butyl lithium (2.5M in hexane, 2.8mL, 6.97mmol) was added dropwise to 2,2,6,6-tetramethylpiperidine (983mg, 6.97) under nitrogen at -78 °C. Methyl) in tetrahydrofuran (50 mL). Further, a solution of Compound 1d (2.0 g, 6.97 mmol) in tetrahydrofuran (20 mL) was added dropwise. The reaction was stirred at -78 °C for 2 hours.
  • the third step triethyl phosphonoacetate (430 mg, 1.92 mmol) was dissolved in EtOAc EtOAc (EtOAc) After 10 minutes, a solution of compound 102b (700 mg, 1.90 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 residue was isolated using a flash column chromatography to afford compound 102c (730 mg). MS (ESI): m/z 440.4 (M+H) +
  • the fifth step 4-chloroaniline (447 mg, 3.52 mmol) was dissolved in tetrahydrofuran (5 mL), and a solution of isopropylmagnesium chloride in tetrahydrofuran (2.0 mol/L in THF, 1.8 mL, 3.52 mmol) was added in an ice bath at 0 °C. ). The mixture was stirred at room temperature for 5 minutes, and a solution of compound 102d (400 mg, 0.88 mmol) in tetrahydrofuran (2 mL) was added to the mixture. The reaction was stirred at room temperature overnight then quenched with saturated aq. The combined organic layers were dried with anhydrous sodium s The residue was isolated using a flash column chromatography to afford compound 102e (400 mg). MS (ESI): m/z 535.4 (M+H) +
  • the first step 4-chloro-6,7-dimethoxyquinoline (1.0 g, 4.48 mmol) was dissolved in dichloromethane (30 mL), and boron tribromide (1.0 mol) was added dropwise under ice bath. /L, 12.0 mL, 12.0 mmol) in dichloromethane, stirring was continued for 2 h and then warmed to room temperature overnight. The reaction was quenched by LCMS, 50 mL water was added and the aqueous phase was extracted with dichloromethane (40 ⁇ RTIgt; The combined organics were dried with EtOAc EtOAc EtOAc EtOAc MS (ESI): m/z: 196.5 (M+H) + .
  • the second step Compound 103a (800 mg, 4.10 mmol) was dissolved in N,N-dimethylformamide (30 ml), potassium carbonate (2.12 g, 15.38 mmol) and 1,2-dibromoethane (3.84). g, 20.45 mmol). The reaction mixture was stirred at 60 ° C for 2 hours. The reaction was quenched with water and extracted with ethyl acetate.
  • the third step the compound borate (664 mg, 2.50 mmol) was dissolved in 40 mL/10 mL of dioxane/water, and compound 103b (460 mg, 2.08 mmol), potassium carbonate (861 mg, 6.24 mmol), Pd 2 (Pd 2 ( Dba) 3 (95 mg, 0.104 mmol) and PCy 3 (70 mg, 0.25 mmol). The reaction mixture was refluxed overnight under a nitrogen atmosphere.
  • the sixth step triethyl phosphonoacetate (214 mg, 0.89 mmol) was dissolved in ultra dry tetrahydrofuran (10 mL), and sodium tert-butoxide (85 mg, 0.89 mmol) was added in an ice bath at 0 °C. After 10 minutes, a solution of compound 103e (250 mg, 0.88 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 residue was isolated using a flash column chromatography to afford compound 103f (168 mg).
  • the seventh step NaH (40 mg, 0.99 mmol) was added to dimethyl sulfoxide (10 mL), and trimethylsulfoxonium iodide (249 mg, 1.13 mmol) was added to the suspension. The mixture was stirred at room temperature for 1.5 hours. A solution of compound 103f (100 mg, 0.28 mmol) in dimethyl sulfoxide (5 mL) was then added to the mixture. The reaction was stirred at 40 ° C overnight. It was then quenched with water, EtOAc (EtOAc)EtOAc.
  • the eighth step 4-chloroaniline (81 mg, 0.64 mmol) was dissolved in 5 mL of tetrahydrofuran, and a 2 mol/L solution of isopropylmagnesium chloride in tetrahydrofuran (0.3 mL, 0.64 mmol) was added. The mixture was stirred at room temperature for 5 minutes, and a solution of the compound 103 g (60 mg, 0.16 mmol) in tetrahydrofuran (2 mL) was added to the mixture. The reaction was stirred at room temperature overnight then quenched with saturated aq.
  • the first step 4-bromo-6-fluoroquinoline (500 mg, 2.21 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL), and 1.6 M n-butyllithium (2.8 mL) was added dropwise to the solution at -78 °C. 4.42 mmol), the reaction solution was stirred at -78 ° C for 5 minutes. Then, a solution of Compound 104b (345 mg, 2.21 mmol) in anhydrous tetrahydrofuran (4 mL) was added dropwise. The reaction was stirred at -78 ° C for 1 hour. The mixture was quenched with aq. EtOAc EtOAc. The residue was isolated using a flash column chromatography to afford compound 104c (83mg) MS (ESI): m / z 304.6 (M + H) +.
  • the third step triethyl phosphonoacetate (280 mg, 1.25 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL), and sodium tert-butoxide (120 mg, 1.25 mmol) was added at 0 ° C ice. After 10 minutes, a solution of compound 104d (295 mg, 1.14 mmol) in tetrahydrofuran (2 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 residue was isolated using a flash column chromatography to afford compound 104e (183 mg) MS (ESI): m/z 330.5 (M+H) +
  • the fourth step NaH (67 mg, 1.68 mmol) was added to dimethyl sulfoxide (5 mL), and trimethylsulfoxonium iodide (370 mg, 1.68 mmol) was added to the suspension. The mixture was stirred at room temperature for 1.5 hours. A solution of compound 104e (183 mg, 0.56 mmol) in dimethyl sulfoxide (2 mL) was then added to the mixture. The reaction was stirred at room temperature overnight. It was then quenched with water, EtOAc (EtOAc)EtOAc. MS (ESI): m/z 344.5 (M+H) + .
  • Step 6 Compound 104g (20mg, 0.06mmol) was dissolved in N,N-dimethylformamide (2mL), then diisopropylethylamine (24mg, 0.18mmol) and HATU (34mg, 0.09mmol) ), stirred at room temperature for 1 hour. Then 4-chloroaniline (23 mg, 0.18 mmol) was added and the reaction was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the aqueous phase was extracted with ethyl acetate. The combined organic layers were dried with anhydrous sodium s The residue was purified by reverse preparative chromatography to afford compound 104 (5. MS (ESI):.
  • the first step NaH (986 mg, 24.6 mmol) was dissolved in ultra-dry tetrahydrofuran (25 mL), and the compound triethyl 2-phosphonylpropyl ester (5.9 g, 24.6 mmol) was added dropwise in an ice bath at 0 ° C. Stir at 0 ° C for 30 minutes. A solution of Compound 1e (2.0 g, 8.2 mmol) in dry dry tetrahydrofuran (10 mL) was added dropwise. After the reaction was stirred at room temperature for 2 hrs, EtOAc EtOAc m. The residue was isolated using a flash column chromatography to afford compound 106a (2.5 g). MS (ESI):.
  • the second step NaH (734 mg, 18.36 mmol) was added to dimethyl sulfoxide (20 mL). To the suspension was added trimethylsulfoxonium iodide (4.04 g, 18.36 mmol). The mixture was stirred at room temperature for 1.5 hours. A solution of compound 106a (1.5 g, 4.59 mmol) in dimethyl sulfoxide (10 mL) was then added to the mixture. The reaction was stirred at 70 ° C overnight. It was then quenched with water, EtOAc (EtOAc)EtOAc. MS (ESI):.
  • the fourth step Compound 106c (50 mg, 0.16 mmol) was dissolved in methylene chloride (5 mL). The reaction solvent was evaporated, and the ⁇ The obtained pale-yellow solid was dissolved in anhydrous tetrahydrofuran (5 mL), 4-chloroaniline (41 mg, 0.32 mmol) was added, and triethylamine (48 mg, 0.48 mmol) was added dropwise under ice-water bath. The reaction mixture was stirred for 30 minutes in an ice water bath, and the mixture was stirred at room temperature for 2 hr. The reaction was quenched with water and extracted with ethyl acetate.
  • the third step Compound 107b (100 mg, 0.28 mmol) was dissolved in ethanol (20 mL), and 2 mol/L aqueous solution of LiOH (10 mL) was added, and the mixture was stirred at 25 ° C for 4 hours. The ethanol was spun and the pH was adjusted to 4-5 with 4 mol/L aqueous HCl (10 mL) and concentrated. The residue was isolated by preparative EtOAc EtOAc (EtOAc) MS (ESI): m/z 325.5 (M+H) + .
  • the first step Compound 103a (1.0 g, 5.13 mmol) was dissolved in N,N-dimethylformamide (20 mL), chlorobromomethane (986 mg, 7.70 mmol), cesium carbonate (2.51 g, 7.70 mmol) . The mixture was heated to 110 ° C for 2 hours. After cooling to room temperature, water was added to the reaction mixture, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried with anhydrous sodium s The residue was isolated using a flash column chromatography to afford compound 110a (480m MS (ESI): m / z 208.4 (M + H) +.
  • the second step the compound borate (741 mg, 2.78 mmol) was dissolved in dioxane / water (40 mL / 10 mL), and then compound 110a (480 mg, 2.32 mmol), potassium carbonate (960 mg, 6.96 mmol), Pd 2 (dba) 3 (106 mg, 0.116 mmol) and PCy 3 (78 mg, 0.28 mmol).
  • the reaction mixture was refluxed overnight under a nitrogen atmosphere.
  • the reaction mixture was then concentrated with ethyl acetate. EtOAc was evaporated.
  • the fifth step triethyl phosphonoacetate (235 mg, 1.05 mmol) was dissolved in EtOAc (10 mL). After 10 minutes, a solution of compound 110d (255 mg, 0.95 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 residue was isolated using a flash column chromatography to afford compound 110e (m. MS (ESI): m/z 340.5 (M+H) +
  • the sixth step NaH (35 mg, 0.87 mmol) was added to dimethyl sulfoxide (10 mL), and trimethylsulfoxonium iodide (191 mg, 0.87 mmol) was added to the suspension. The mixture was stirred at room temperature for 1.5 hours. A solution of compound 110e (100 mg, 0.29 mmol) in dimethyl sulfoxide (5 mL) was then added to the mixture. The reaction was stirred at 40 ° C overnight. It was then quenched with water, EtOAc (EtOAc)EtOAc. MS (ESI): m / z 354.5 (M + H) +.
  • the seventh step 4-chloroaniline (86 mg, 0.68 mmol) was dissolved in 5 mL of tetrahydrofuran, and a solution of 2.0 mol/L of isopropylmagnesium chloride in tetrahydrofuran (0.4 mL, 0.68 mmol) was added. The mixture was stirred at room temperature for 5 minutes, and a solution of compound 110f (60 mg, 0.17 mmol) in tetrahydrofuran (2 mL) was added to the mixture. The reaction was stirred at room temperature overnight then quenched with saturated aq. The combined organic layers were dried with anhydrous sodium s The residue was purified by reverse preparative chromatography to afford compound 110 (10. MS (ESI):.
  • the second step Compound 111a (822 mg, 2.92 mmol) was dissolved in dichloromethane (3 mL), and a 4 mol/L hydrochloric acid dioxane solution (6 mL) was added in an ice bath at 0 °C. The mixture was reacted for 2 hours at room temperature, and the precipitated solid was filtered and dried to give Compound 111b (550 mg) as white solid. Used directly in the next step.
  • the third step Compound 94a (53 mg, 0.17 mmol) was dissolved in methylene chloride (2 mL). The reaction solvent was evaporated. The solid was dissolved in anhydrous dichloromethane (3 mL). EtOAc (mjjjjjj Stir for 10 minutes in an ice water bath, and continue to stir for 2 hours at room temperature. The reaction was quenched with water and extracted with ethyl acetate. The combined organic layers were dried with anhydrous sodium s The residue was purified by reverse preparative EtOAc (EtOAc) MS (ESI): m/z 477.5 (M+H) + .
  • the third step Compound 94a (85 mg, 0.27 mmol) was dissolved in N,N-dimethylformamide (5 mL), diisopropylethylamine (138 mg, 1.07 mmol) and HATU (122 mg, 0.32 mmol) The reaction mixture was stirred at room temperature for 30 minutes. Compound 112b (60 mg, 0.39 mmol) was added to the reaction mixture, and the mixture was stirred at 40 ° C for 2 hr. The reaction was quenched with EtOAc (EtOAc)EtOAc.EtOAc. The residue was purified by reverse preparative chromatography to afford compound 112 (j. MS (ESI):.
  • n-butyl lithium (2.5 M in hexane, 4.2 mL, 10.46 mmol) was added dropwise to 2,2,6,6-tetramethylpiperidine (1.47 g, under -78 ° C under nitrogen atmosphere. 10.46 mmol) in tetrahydrofuran (50 mL). Further, a solution of Compound 1d (2.0 g, 6.97 mmol) in tetrahydrofuran (20 mL) was added dropwise. The reaction was stirred at -78 °C for 2 hours.
  • the fifth step triethyl phosphonoacetate (345 mg, 1.54 mmol) was dissolved in EtOAc (EtOAc) (EtOAc) After 10 minutes, a solution of compound 115d (423 mg, 1.47 mmol) in tetrahydrofuran (5 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 residue was isolated using a flash column chromatography to afford compound 115e (500mg) MS (ESI): m/z 358.4 (M+H) +
  • Step 7 Dissolve 4-chloroaniline (66 mg, 0.52 mmol) in tetrahydrofuran (5 mL), and add isopropylmagnesium chloride in tetrahydrofuran (2.0 mol/L in THF, 0.3 mL, 0.52 mmol). ). The mixture was stirred at room temperature for 5 minutes, and a solution of compound 115f (50 mg, 0.13 mmol) in tetrahydrofuran (2 mL) was added to the mixture. The reaction was stirred at room temperature overnight then quenched with saturated aq.
  • 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 ul 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.
  • the cells were cultured at 37 ° C, 100% relative humidity, 5% CO 2 incubator for 48 hours, then pipet 140 ul of cell culture supernatant and 15 ul of trichloroacetic acid, and placed at 52 ° C for 30 min, centrifuged at room temperature for centrifugation. The mixture was mixed with an equal volume of Ehrlich's reagent, and the light absorption at 480 nm was measured to calculate the IC 50 value.
  • Compound 84 A Compound 85 A Compound 86 A Compound 87 C Compound 88 C Compound 89 C Compound 90 C Compound 91 C Compound 92 A Compound 93 C Compound 94 A Compound 95 A Compound 96 B Compound 97 C Compound 98 A Compound 99 C Compound 100 A Compound 101 A Compound 102 A Compound 103 C Compound 104 C Compound 105 B
  • 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 ul 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.
  • the cells were cultured at 37 ° C, 100% relative humidity, 5% CO 2 incubator for 24 hours, then pipet 140 ul of cell culture supernatant and 15 ul of trichloroacetic acid, and placed at 52 ° C for 30 min, then centrifuge at room temperature to obtain a supernatant.
  • the light absorption at 480 nm was measured by mixing with an equal volume of Ehrlich's reagent, and the IC 50 value was calculated.
  • Compound IC 50 (HEK293 cells) Compound 1 B Compound 2 B Compound 3 C Compound 4 C Compound 5 B Compound 6 B Compound 7 B Compound 8 B Compound 9 A Compound 10a A Compound 10b C Compound 11 B Compound 12 B Compound 13 B Compound 92 A Compound 93 C Compound 94 B Compound 95 B

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Abstract

本发明涉及式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。(I)

Description

吲哚胺2,3-双加氧酶抑制剂以及它们在医学上的应用
本申请要求于2017年12月29日提交中国专利局、申请号为201711478307.2、发明名称为“吲哚胺2,3-双加氧酶抑制剂以及它们在医学上的应用”的中国专利申请，以及于2018年6月29日提交中国专利局、申请号为201810754253.6、发明名称为“吲哚胺2,3-双加氧酶抑制剂以及它们在医学上的应用”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。
技术领域
本发明涉及一种对色氨酸代谢具有抑制活性的新型吲哚胺2,3-双加氧酶抑制剂，以及包含其作为活性成分的药物组合物。
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。它在人类必不可少的，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主要作用。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(Tregs；Munn,Front Biosci.2012；4:734)；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受体已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；1 13(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，基于BMS-986205，开展具有高生物活性、高安全性的新型化合物研究，这对于发现临床治疗活性更好如可能治愈肿瘤而非仅仅抑制肿瘤的新型IDO类肿瘤免疫治疗药物，具有非常重要的现实意义。
发明内容
本发明一方面提供一种如式I所示的化合物，
Figure PCTCN2018124110-appb-000001
其中
Figure PCTCN2018124110-appb-000002
表示：——、
Figure PCTCN2018124110-appb-000003
或者
Figure PCTCN2018124110-appb-000004
A表示-C(O)-、-S(O) 2-或者-S(O)-；
其中，每个R 1各自独立地选自氢原子、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 1-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R 1相互环合形成3-8元环，该环中含有0、1、2、3个杂原子；
Cy 1选自被任意取代基取代的5-15元桥环基、5-15元螺环基、5-15元桥杂环基、或5-15元螺杂环基，所述的取代基为：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；
R a、R b、R 2各自独立地选自氢、C 1-C 6烷基或C 3- 6环烷基；
Cy 2为含有一个或两个以上的取代基的C 5-C 10芳基、C 5-C 10杂芳基、C 5-C 10环烷基、C 5-C 10杂环烷基；所述的取代基可以选自卤素、羟基、硝基、氰基、磺酸基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-6环烷基、C 1-6烷氧基、卤代C 1-C 6烷基、卤代C 1-C 6烷氧基、C 1-6烷基硫基、C 1-6烷基羰基、C 1-6烷基羰基氧基、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、-S(O)C 1-6烷基；或者当两个取代基相邻时，能够形成3-8元环，该3-8元环可以含有0、1、2、3个O、S、N原子；m、n为0、1、2、3、4。
在本发明的另一技术方案中，Cy 1选自被取代基取代的8-12元螺环基或8-12元螺环基、8-12元桥杂环基、或8-12元螺杂环基，所述的取代基为：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。
在本发明的另一技术方案中，Cy 1选自以下基团：
Figure PCTCN2018124110-appb-000005
上述基团可以被选自卤素、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、氰基的取代基取代。
在本发明的另一个技术方案中，Cy 1选自以下基团：
Figure PCTCN2018124110-appb-000006
Figure PCTCN2018124110-appb-000007
上述基团可以被选自卤素、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、氰基的取代基取代。
本发明一方面提供一种如式(II)所示的化合物，
Figure PCTCN2018124110-appb-000008
其中，R 1、R 2、R a、R b、Cy 2、m、n、A如式I所定义；X选自(CR cR d) o，其中任意地CR cR d可以被O或NR e所替代；Y选自CR f或N；其中R c、R d、R e、R f分别各自独立地选自氢或者C 1-6烷基；o选自0、1、2、3、4、5。
本发明一方面提供一种如式(III)所示的化合物，
Figure PCTCN2018124110-appb-000009
其中，W，Q选自CR cR d或NR e,或O；A、R 1、R 2、R a、R b、R c、R d、R e、Cy 2、m、n、Y如上述式(II)所定义。
本发明另一方面还提供了一种如式(IV)所示的化合物，
Figure PCTCN2018124110-appb-000010
其中，R 1、R 2、R a、R b、Cy 2、m、n、X、Y、A如上述式(II)所定义；Z选自(CR g) p，其中任意的CR g可以被N所替代；R g分别各自独立地选自氢或者C 1-6烷基；p选自0、1、2、3、4、5。
在本发明的优选技术方案中，具有如式(V)结构：
Figure PCTCN2018124110-appb-000011
其中R 1、R 2、R c、R d、R f、Cy 2、m、A如上述式(II)所定义。
在本发明的优选技术方案中，具有如式(VI)结构：
Figure PCTCN2018124110-appb-000012
其中R 1、R 2、R c、R d、Cy 2、m、A如上述式(II)所定义。
在本发明的优选技术方案中，具有如式(VII)结构：
Figure PCTCN2018124110-appb-000013
其中R 1、R 2、R e、R f、Cy 2、m、A如上述式(II)所定义。
在本发明的优选技术方案中，具有如式(VIII)结构：
Figure PCTCN2018124110-appb-000014
其中R 1、R 2、R c、R d、R f、Cy 2、m、A如上述式(II)所定义。
在本发明的优选技术方案中，具有如式(IX)结构：
Figure PCTCN2018124110-appb-000015
其中R 1、R 2、R c、R d、R e、R f、Cy 2、m、A如上述式(II)所定义。
在本发明的技术方案中，
Figure PCTCN2018124110-appb-000016
表示——、
Figure PCTCN2018124110-appb-000017
或者
Figure PCTCN2018124110-appb-000018
在本发明的技术方案中，
Figure PCTCN2018124110-appb-000019
优选为
Figure PCTCN2018124110-appb-000020
在本发明的技术方案中，A选自-C(O)-或S(O) 2-。
本发明还提供了一种具有式(X)结构的化合物的制备方法：
Figure PCTCN2018124110-appb-000021
在路径I反应中：
其中步骤(1)所使用的碱选自无机碱或有机碱，包括但不限于：氢化钠、氢化钙、氨基钠、甲醇钠、乙醇钠、氢氧化钾、氢氧化钠、氢氧化锂、氢化铝锂、叔丁基锂、叔丁基钾、叔丁醇钾、二异丙基氨基锂、氢氧化钡或其任意组合；
其中步骤(1)所使用的有机溶剂包括但不限于：1,4-二氧六环、N,N-二甲基甲酰胺、二氯甲烷、氯仿、DMSO、DMF、THF、丙酮、甲醇、乙醇或其任意组合；
其中步骤(2)所使用的内鎓盐选自硫叶立德或者磷叶立德；
其中步骤(3)所使用的格氏试剂选自CH 3MgCl、CH 3MgBr、C 2H 5MgCl、C 2H 5MgBr、i-PrMgCl、i-PrMgBr，PhCH 2MgCl、PhCH 2MgBr或其任意组合。
本发明还提供了一种具有式(XI)结构的化合物的制备方法：
Figure PCTCN2018124110-appb-000022
在路径II反应中：
其中步骤(1)所使用的催化剂选自钛酸甲酯、钛酸乙酯、钛酸正丙酯、钛酸异丙酯、钛酸丁酯或其任意组合；
其中步骤(2)所使用的碱选自无机碱或有机碱，包括但不限于：氢化钠、氢化钙、氨基钠、甲醇钠、乙醇钠、氢氧化钾、氢氧化钠、氢氧化锂、氢化铝锂、叔丁基锂、叔丁基钾、叔丁醇钾、二异丙基氨基锂、氢氧化钡或其任意组合；
其中步骤(2)所使用的有机溶剂包括但不限于：1,4-二氧六环、N,N-二甲基甲酰胺、二氯甲烷、氯仿、DMSO、DMF、THF、丙酮、甲醇、乙醇或其任意组合；
其中步骤(2)所使用的内鎓盐选自硫叶立德或者磷叶立德；
其中步骤(3)的水解是在酸性条件下进行的，所述的酸选自但不限于盐酸、硫酸、氢溴酸、草酸、柠檬酸、甲酸、乙酸或者其任意组合；
其中步骤(4)所使用的有机溶剂包括但不限于：1,4-二氧六环、N,N-二甲基甲酰胺、二氯甲烷、氯仿、DMSO、DMF、、THF、丙酮、甲醇、乙醇或其任意组合。
本发明还提供了一种具有式(XII)结构的化合物的制备方法：
Figure PCTCN2018124110-appb-000023
在路径III中：
其中步骤(1)所使用的催化剂选自钛酸甲酯、钛酸乙酯、钛酸正丙酯、钛酸异丙酯、钛酸丁酯或其任意组合；
其中步骤(2)所非亲核性强碱作用下进行的，所述的非亲核性强碱选自但不限于二异丙基氨基锂、二乙基氨基锂、异丙基环己基氨基锂、二环己基氨基锂、2,2,6,6-四甲基哌啶子基锂、六甲基二硅基氨基锂；
其中步骤(3)所述的水解反应是在酸性条件下进行的，所述的酸选自但不限于盐酸、硫酸、氢溴酸、草酸、柠檬酸、甲酸、乙酸或者其任意组合；
其中步骤(4)所使用的格氏试剂选自CH 3MgCl、CH 3MgBr、C 2H 5MgCl、C 2H 5MgBr、i-PrMgCl、i-PrMgBr，PhCH 2MgCl、PhCH 2MgBr或其任意组合；
其中，当进行步骤(5)中所述的烷基化反应时，所述的烷基化反应试剂选自卤代烷基，所述反应是在路易斯酸作为催化剂下进行的，所述路易斯酸优选为AlCl 3、FeCl 2、CuCl 2。
本发明还提供了一种具有式(XIII)结构的化合物的制备方法：
Figure PCTCN2018124110-appb-000024
在路径IV中
其中步骤(1)和步骤(3)中所使用的碱选自无机碱或有机碱，包括但不限于：氢化钠、氢化钙、氨基钠、甲醇钠、乙醇钠、 氢氧化钾、氢氧化钠、氢氧化锂、氢化铝锂、叔丁基锂、叔丁基钾、叔丁醇钾、二异丙基氨基锂、氢氧化钡或其任意组合；
其中步骤(1)至步骤(3)中所使用的有机溶剂包括但不限于：1,4-二氧六环、N,N-二甲基甲酰胺、二氯甲烷、氯仿、DMSO、DMF、、THF、丙酮、甲醇、乙醇或其任意组合；
其中步骤(2)所使用的氧化剂选自但不限于间氯过氧苯甲酸、CrO 3、KMnO 4、MnO 2、NaCr 2O 7、HIO 4、PbAc 4、OsO 4、双氧水或其任意组合；
其中步骤(4)所述的水解反应是在酸性条件下进行的，所述的酸选自但不限于盐酸、硫酸、氢溴酸、草酸、柠檬酸、甲酸、乙酸或者其任意组合；
其中步骤(5)所使用的格氏试剂选自CH 3MgCl、CH 3MgBr、C 2H 5MgCl、C 2H 5MgBr、i-PrMgCl、i-PrMgBr，PhCH 2MgCl、PhCH 2MgBr或其任意组合。
本发明还提供了一种具有式(XIV)结构的化合物的制备方法：
Figure PCTCN2018124110-appb-000025
在路径V中：
其中步骤(1)是在碱金属氟化物或碱土金属氟化物存在下进行的，所述的碱金属氟化物选自但不限于LiF、NaF、KF、MgF 2、CaF 2；
其中步骤(2)的还原反应可以为钯碳催化加氢还原，也可以为Na/液氨还原；
其中步骤(3)所使用的格氏试剂选自CH 3MgCl、CH 3MgBr、C 2H 5MgCl、C 2H 5MgBr、i-PrMgCl、i-PrMgBr，PhCH 2MgCl、PhCH 2MgBr或其任意组合；
其中，当进行步骤(4)中所述的烷基化反应时，所述的烷基化反应试剂选自卤代烷基，所述反应是在路易斯酸作为催化剂下进行的，所述路易斯酸优选为AlCl 3、FeCl 2、CuCl 2。
具体实施方式
在本文中，当提及具有特定结构式的“化合物”时，一般地还涵盖其立体异构体、非对映异构体、对映异构体、外消旋混合物和同位素衍生物。本领域技术人员公知，一种化合物的盐、溶剂合物、水合物是化合物的替代性存在形式，它们都可以在一定条件下转化为所述化合物，因此在本文中当提到一种化合物时，一般地还包括它的可药用盐，进而还包括其溶剂合物和水合物。相似地，在本文中当提到一种化合物时，一般地还包括其前药、代谢产物和氮氧化物。
当本发明的化合物形成药学上可接受的盐的形式，所述盐使用但不限于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。
本发明的药学上可接受的盐可通过常规方法制备，例如通过将本发明的化合物溶解于与水可混溶的有机溶剂(例如丙酮、甲醇、乙醇和乙腈)，向其中添加过量的有机酸或无机酸水溶液，以使得盐从所得混合物中沉淀，从中除去溶剂和剩余的游离酸，然后分离所沉淀的盐。
本发明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。
其中，肿瘤或癌症选自但不限于皮肤癌、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(例如苯丁酸氮芥、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、曲妥珠单抗或它们的任意组合)。
本发明还涉及一种抑制吲哚胺2,3-双加氧酶的方法，包括使本发明所述的化合物或者药物组合物暴露于吲哚胺2,3-双加氧酶。
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。
实施例
Figure PCTCN2018124110-appb-000026
Figure PCTCN2018124110-appb-000027
Figure PCTCN2018124110-appb-000028
Figure PCTCN2018124110-appb-000029
Figure PCTCN2018124110-appb-000030
Figure PCTCN2018124110-appb-000031
Figure PCTCN2018124110-appb-000032
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(d 6-DMSO)、氘代氯仿(CDCl 3)，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。通用合成分析和实例描述如下：
实施例1
N-(4-chlorophenyl)-6-(6-fluoroquinolin-4-yl)spiro[2.5]octane-1-carbo xamide
N-(4-氯苯基)-6-(6-氟喹啉-4-基)螺[2.5]辛烷-1-甲酰胺
Figure PCTCN2018124110-appb-000033
第一步：将1,4-环己二酮单乙二醇缩酮(10.0g,64.03mmol)溶于250mL甲基叔丁基醚中，加入N-苯基双(三氟甲烷磺酰)亚胺(22.9g,64.03mmol)。将反应液冷却至-78℃，在氮气氛下往反应液中滴加双(三甲基硅基)氨基钠(2mol/L四氢呋喃溶液)(32mL,64.03mmol)。滴加完毕后反应液在该温度下继续搅拌60分钟，然后将反应液升至室温，搅拌过夜直至TLC检测反应原料消耗完全。反应液用3mL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3mL甲基叔丁基醚，有机层用45mL氢氧化钠(5％)溶液洗三次，50mL饱和食盐水洗一次。有机层用无水硫酸钠干燥，过滤，浓缩得到化合物 1a(17.23g)，橘红色油状液体，收率93％。 1H NMR(500MHz,CDCl 3)δ5.66(J＝4.0Hz,1H),4.01–3.96(m,4H),2.56–2.52(m,2H),2.42–2.40(m,2H),1.90(t,J＝6.5Hz,2H).
第二步：将化合物1a(13g,45.1mmol)溶于100mL二氧六环中，依次加入联硼酸频那醇酯(14.9g,58.64mmol)，醋酸钾(13.3g,135.3mmol)和Pd(dppf)Cl 2(1.65g,2.26mmol)。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化合物1b(7.6g)，淡黄色固体，收率63％。 1H NMR(500MHz,CDCl 3)δ6.48–6.45(m,1H),3.98(s,4H),2.40–2.34(m,4H),1.73(t,J＝6.5Hz,2H),1.25(s,12H).
第三步：将化合物1b(5.7g,21.48mmol)溶于60mL/15mL二氧六环/水中，依次加入4-氯-6-氟喹啉(3.0g,16.53mmol)，碳酸钾(6.8g,49.56mmol)和Pd(PPh3)4(954mg,0.83mmol)。反应混合物在氮气氛下回流反应过夜。然后浓缩反应液，用乙酸乙酯萃取，有机相浓缩之后用快速过柱机分离得到化合物1c(2.42g)，淡黄色液体，收率51％。MS(ESI):m/z 286.1(M+H) +. 1H NMR(500MHz,CDCl 3)δ8.81(d,J＝4.5Hz,1H),8.15(dd,J＝9.0,5.5Hz,1H),7.65(dd,J＝10.0,2.5Hz,1H),7.49(td,J＝9.0,2.5Hz,1H),7.26(d,J＝4.5Hz,1H),5.77(t,J＝3.5Hz,1H),4.08–40.6(m,4H),2.65–2.60(m,2H),2.56–2.53(m,2H),2.00(t,J＝6.5Hz,2H).
第四步：将化合物1c(2.42g,8.49mmol)溶于45mL异丙醇中，加入10％钯碳(300mg)。反应混合物在氢气氛下加热至55℃反应过夜。然 后用硅藻土滤除钯碳，滤液浓缩得到粗品化合物1d(2.04g)，浆状液体，收率84％，直接用于下一步反应。MS(ESI):m/z 288.1(M+H) +.
第五步：将化合物1d(2.04g,7.11mmol)溶于36mL丙酮中，加入9mL4mol/L盐酸。反应混合物加热至45℃反应过夜。然后蒸除溶剂，水溶液用6mol/L氢氧化钠中和至pH＝9，用乙酸乙酯萃取水相。有机相合并后用饱和食盐水洗，无水硫酸钠干燥，过滤，浓缩。残留物用快速过柱机分离得到化合物1e(1.17g)，淡黄色固体，收率67％。MS(ESI):m/z 244.3(M+H) +. 1H NMR(500MHz,CDCl 3)δ8.85(d,J＝4.5Hz,1H),8.22(dd,J＝9.0,5.5Hz,1H),7.74(dd,J＝10.0,2.5Hz,1H),7.57–7.50(m,1H),7.33(d,J＝4.5Hz,1H),3.74–3.66(m,1H),2.72–2.58(m,4H),2.41–2.34(m,2H),2.11–2.00(m,2H).
第六步：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，将化合物1e(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化合物1f(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).
第七步：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。然后将化合物1f(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化合物1g(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).
第八步：将4-氯苯胺(94mg,0.73mmol)溶于5mL四氢呋喃中，在0℃冰浴下加入2mol/L异丙基氯化镁的四氢呋喃溶液(0.4mL,0.73mmol)。混合物在室温下搅拌5分钟，将化合物1g(60mg,0.18mmol)的四氢呋喃(2mL)溶液加入该混合物中。反应液在室温下搅拌过夜，然后用饱和氯化铵溶液淬灭，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。残留物用反向制备色谱提纯得到化合物1(16.04mg)，白色固体，产率21％。MS(ESI):m/z 408.9(M+H) +. 1H NMR(500MHz,d 6-DMSO)δ10.37(s,1H),8.81(s,1H),8.11–8.05(m,1H),8.02(d,J＝11.0Hz,1H),7.69–7.63(m,3H),7.38–7.31(m,3H),3.48–3.40(m,1H),2.20(t,J＝12.0Hz,1H),1.97–1.84(m,4H),1.78(d, J＝12.5Hz,1H),1.72(t,J＝6.5Hz,1H),1.35–1.26(m,1H),1.17–1.08(m,2H),0.96–0.90(m,1H).
实施例2
N-(4-fluorophenyl)-6-(6-fluoroquinolin-4-yl)spiro[2.5]octane-1-carboxamide
N-(4-氟苯基)-6-(6-氟喹啉-4-基)螺[2.5]辛烷-1-甲酰胺
Figure PCTCN2018124110-appb-000034
化合物2的合成同化合物1，将4-氟苯胺替代实施例1中的4-氯苯胺。得到化合物2(16.97mg)，白色固体，收率22％。MS(ESI):m/z 393.3(M+H) +. 1H NMR(500MHz,d 6-DMSO)δ10.28(s,1H),8.81(s,1H),8.10–8.05(m,1H),8.03(d,J＝11.0Hz,1H),7.69–7.60(m,3H),7.37(s,1H),7.13(t,J＝8.0Hz,2H),3.49–3.40(m,1H),2.20(t,J＝12.0Hz,1H),1.98–1.85(m,4H),1.78(d,J＝11.0Hz,1H),1.72(t,J＝6.5Hz,1H),1.37–1.28(m,1H),1.17–1.07(m,2H),0.94–0.89(m,1H).
实施例3
N-(4-chlorobenzyl)-6-(6-fluoroquinolin-4-yl)spiro[2.5]octane-1-carboxamide
N-(4-氯苄基)-6-(6-氟喹啉-4-基)螺[2.5]辛烷-1-甲酰胺
Figure PCTCN2018124110-appb-000035
化合物3的合成从实施例1中的中间体1g出发，经由以下步骤制备：
Figure PCTCN2018124110-appb-000036
第一步：将化合物1g(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化合物3a(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).
第二步：将化合物3a(40mg,0.13mmol)溶于5mL N,N-二甲基甲酰胺中，依次加入二异丙基乙胺(52mg,0.39mmol)和HATU(61mg,0.16mmol)，在室温下搅拌30分钟。然后加入4-氯苄胺(57mg,0.39mmol)，继续在室温下搅拌反应2小时。向反应液中加入20mL水淬灭，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。残留物用反向制备色谱提纯得到化合物3(6.34mg)，白色固体，收率11％。MS(ESI):m/z 423.4(M+H) +. 1H NMR(500MHz,d 6-DMSO)δ8.81(s,1H),8.68(s,1H),8.12–8.07(m,1H),8.00(d,J＝11.0Hz,1H),7.67(t,J＝8.5Hz,1H),7.36–7.31(m,4H),7.14(s,1H),4.44(dd,J＝15.0,6.5Hz,1H),4.18(dd,J＝15.0Hz,5.0Hz,1H),3.42–3.34(m,1H),2.13(t,J＝12.5Hz,1H),1.86–1.74(m,4H),1.63(d,J＝12.5Hz,1H),1.54–1.48(m,1H),1.25–1.15(m,1H),1.08–0.96(m,2H),0.82–0.76(m,1H).
实施例4
N-(4-chlorophenethyl)-6-(6-fluoroquinolin-4-yl)spiro[2.5]octane-1-carboxamide
N-(4-氯苯乙基)-6-(6-氟喹啉-4-基)螺[2.5]辛烷-1-甲酰胺
Figure PCTCN2018124110-appb-000037
化合物4的合成同化合物3，将4-氯苯乙胺替代实施例3中的4-氯苄胺。得到化合物4(17.15mg)，白色固体，收率29％。MS(ESI):m/z437.4(M+H) +. 1H NMR(500MHz,d 6-DMSO)δ8.84(d,J＝4.5Hz,1H),8.19(t,J＝5.5Hz,1H),8.12–8.07(m,1H),7.99(d,J＝11.0Hz,1H),7.67(t,J＝8.5Hz,1H),7.27(d,J＝4.1Hz,1H),7.25–7.21(m,4H), 3.49–3.42(m,1H),3.30–3.22(m,2H),2.74(t,J＝6.5Hz,2H),2.11(t,J＝12.5Hz,1H),1.85–1.75(m,4H),1.67(d,J＝12.5Hz,1H),1.46–1.41(m,1H),1.26–1.14(m,1H),1.03–0.95(m,2H),0.75–0.70(m,1H).
实施例5
6-(6-fluoroquinolin-4-yl)-N-(4-(trifluoromethyl)phenyl)spiro[2.5]octane-1-carboxamide
6-(6-氟喹啉-4-基)-N-(4-(三氟甲基)苯基)螺[2.5]辛烷-1-甲酰胺
Figure PCTCN2018124110-appb-000038
化合物5的合成从实施例3中的中间体3a出发，经由以下步骤制备：
Figure PCTCN2018124110-appb-000039
将化合物3a(40mg,0.13mmol)溶于5mL乙酸乙酯中，依次加入吡啶(32mg,0.39mmol)和三丙基磷酸酐(127mg,0.33mmol)，在室温下搅拌10分钟。然后加入4-三氟甲基苯胺(65mg,0.39mmol)，继续在室温下搅拌反应过夜。向反应液中加入2mL 2mol/L氢氧化钠溶液，再加入20mL水稀释，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。残留物用反向制备色谱提纯得到化合物5(2.65 mg)，白色固体，收率5％。MS(ESI):m/z 437.4(M+H) +. 1H NMR(500MHz,d 6-DMSO)δ10.63(s,1H),8.80(d,J＝4.5Hz,1H),8.10–8.05(m,1H),8.03(d,J＝11.0Hz,1H),7.84(d,J＝8.0Hz,2H),7.69–7.63(m,3H),7.36(s,1H),3.48–3.41(m,1H),2.25–2.17(m,1H),1.99–1.85(m,4H),1.80–1.74(m,2H),1.35–1.25(m,1H),1.21–1.09(m,2H),0.99–0.95(m,1H).
实施例6
N-(4-cyanophenyl)-6-(6-fluoroquinolin-4-yl)spiro[2.5]octane-1-carboxamide
N-(4-氰基苯基)-6-(6-氟喹啉-4-基)螺[2.5]辛烷-1-甲酰胺
Figure PCTCN2018124110-appb-000040
化合物6的合成同化合物5，将4-氨基苯腈替代实施例5中的4-三氟甲基苯胺。得到化合物6(28.36mg)，白色固体，收率53％。MS(ESI):m/z 400.4(M+H) +. 1H NMR(500MHz,d 6-DMSO)δ10.70(s,1H),8.80(d,J＝4.5Hz,1H),8.10–8.06(m,1H),8.03(d,J＝11.0Hz,1H),7.82(d,J＝8.5Hz,2H),7.75(d,J＝8.5Hz,2H),7.66(t,J＝9.0Hz,1H),7.35(d,J＝3.5Hz,1H),3.48–3.40(m,1H),2.25–2.17(m,1H),1.99–1.83(m,4H),1.81–1.74(m,2H),1.33–1.23(m,1H),1.21–1.10(m,2H),1.02–0.96(m,1H).
实施例7
N-(6-chloropyridin-3-yl)-6-(6-fluoroquinolin-4-yl)spiro[2.5]octane-1-carboxamide
N-(6-氯吡啶-3-基)-6-(6-氟喹啉-4-基)螺[2.5]辛烷-1-甲酰胺
Figure PCTCN2018124110-appb-000041
化合物7的合成同化合物5，将3-氨基-6-氯吡啶替代实施例5中的4-三氟甲基苯胺。得到化合物7(7.07mg)，白色固体，收率13％。MS(ESI):m/z 410.4(M+H) +. 1H NMR(500MHz,d 6-DMSO)δ10.62(s,1H),8.81(s,1H),8.63(s,1H),8.15–8.06(m,2H),8.03(d,J＝11.0Hz,1H),7.66(t,J＝8.5Hz,1H),7.45(d,J＝8.0Hz,1H),7.38(s,1H),3.48–3.41(m,1H),2.25–2.16(m,1H),1.99–1.82(m,4H),1.82–1.72(m,2H),1.35–1.26(m,1H),1.20–1.09(m,2H),1.00–0.95(m,1H).
实施例8
N-(5-chloropyridin-2-yl)-6-(6-fluoroquinolin-4-yl)spiro[2.5]octane-1-carboxamide
N-(5-氯吡啶-2-基)-6-(6-氟喹啉-4-基)螺[2.5]辛烷-1-甲酰胺
Figure PCTCN2018124110-appb-000042
化合物8的合成同化合物5，将2-氨基-5-氯吡啶替代实施例5中的4-三氟甲基苯胺。得到化合物8(19.54mg)，白色固体，收率36％。MS(ESI):m/z 410.4(M+H) +. 1H NMR(500MHz,d 6-DMSO)δ11.04(s,1H),8.80(s,1H),8.38(s,1H),8.13(d,J＝8.5Hz,1H),8.07(t,J＝8.0Hz,1H),8.02(d,J＝11.0Hz,1H),7.85(d,J＝9.0Hz,1H),7.66(t,J＝8.0Hz,1H),7.34(s,1H),3.47–3.40(m,1H),2.19(t,J＝12.5Hz,1H),2.02–1.84(m,5H),1.78(d,J＝11.0Hz,1H),1.33–1.22(m,1H),1.21–1.15(m,1H),1.08(d,J＝12.5Hz,1H),0.98–0.92(m,1H).
实施例9
N-(4-chlorophenyl)-6-(6-fluoro-7-methylquinolin-4-yl)spiro[2.5]octane-1-carboxamide
N-(4-氯苯基)-6-(6-氟-7-甲基喹啉-4-基)-螺[2.5]辛烷-1-甲酰胺
Figure PCTCN2018124110-appb-000043
化合物9的合成从实施例1中的中间体1g出发，经由以下步骤制备：
Figure PCTCN2018124110-appb-000044
第一步：在-78℃条件下，将正丁基锂(2.5M,0.5mL,1.22mmol)滴加到二异丙胺(123mg,1.22mmol)的四氢呋喃(5mL)溶液中。再向其中滴加化合物1g(200mg,0.61mmol)的四氢呋喃(2mL)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9a(24mg)，无色油状液体，收率12％。MS(ESI):m/z 342.4(M+H) +.
第二步：将4-氯苯胺(36mg,0.28mmol)溶于四氢呋喃(2mL)中，在0℃冰浴下加入2.0mol/L异丙基氯化镁的四氢呋喃溶液(0.2mL,0.28mmol)。混合物在室温下搅拌5分钟，将化合物9a(24mg,0.07mmol)的四氢呋喃(1mL)溶液加入该混合物中。反应液在室温下搅拌过夜，然后用饱和氯化铵溶液淬灭，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。残留物用反向制备色谱提纯得到化合物9(12.01mg)，白色固体，收率41％。MS(ESI):m/z 423.4(M+H) +. 1H NMR(500MHz,d 6-DMSO)δ10.37(s,1H),8.75(s,1H),7.99–7.91(m,2H),7.80–7.56(m,3H),7.34(d,J＝8.0Hz,2H),7.28(s,1H),3.44–3.37(m,1H),2.44(s,3H),2.23–2.14(m,1H),1.98–1.84(m,4H),1.78–1.69(m,2H),1.17–1.07(m,2H),0.95–0.92 (m,1H).
实施例10
(S)-N-(4-chlorophenyl)-6-(6-fluoroquinolin-4-yl)spiro[2.5]octane-1-carboxamide(10a)
(S)-N-(4-氯苯基)-6-(6-氟喹啉-4-基)螺[2.5]辛烷-1-甲酰胺(10a)
Figure PCTCN2018124110-appb-000045
(R)-N-(4-chlorophenyl)-6-(6-fluoroquinolin-4-yl)spiro[2.5]octane-1-carboxamide(10b)
(R)-N-(4-氯苯基)-6-(6-氟喹啉-4-基)螺[2.5]辛烷-1-甲酰胺(10b)
Figure PCTCN2018124110-appb-000046
化合物10a和化合物10b由实施例1中化合物1经过手性柱拆分得到，绝对构型未确定。其中，化合物10a对应手性拆分中的前者(保留时间3.027分钟)，化合物10b对应手性拆分中的后者(保留时间3.842分钟)。
化合物10a：MS(ESI):m/z 409.4(M+H) +. 1H NMR(500MHz, d 6-DMSO)δ10.37(s,1H),8.81(s,1H),8.11–8.05(m,1H),8.02(d,J＝11.0Hz,1H),7.69–7.63(m,3H),7.38–7.31(m,3H),3.48–3.40(m,1H),2.20(t,J＝12.0Hz,1H),2.00–1.85(m,4H),1.78(d,J＝12.0Hz,1H),1.72(d,J＝6.5Hz,1H),1.36–1.28(m,1H),1.17–1.08(m,2H),0.96–0.90(m,1H).
化合物10b：MS(ESI):m/z 409.4(M+H) +. 1H NMR(500MHz,d 6-DMSO)δ10.37(s,1H),8.81(s,1H),8.10–8.05(m,1H),8.02(d,J＝11.0Hz,1H),7.69–7.63(m,3H),7.38–7.31(m,3H),3.48–3.40(m,1H),2.20(t,J＝12.0Hz,1H),1.98–1.84(m,4H),1.78(d,J＝12.0Hz,1H),1.72(d,J＝6.5Hz,1H),1.37–1.28(m,1H),1.17–1.08(m,2H),0.96–0.90(m,1H).
实施例11
N-(4-bromophenyl)-6-(6-fluoroquinolin-4-yl)spiro[2.5]octane-1-carboxamide
N-(4-溴苯基)-6-(6-氟喹啉-4-基)螺[2.5]辛烷-1-甲酰胺
Figure PCTCN2018124110-appb-000047
化合物11的合成同化合物5，得到化合物11(22.4mg)，白色固体，收率45％。MS(ESI):m/z 454.1(M+H) +. 1H NMR(500MHz,d 6-DMSO)δ10.40(s,1H),8.80(d,J＝4.5Hz,1H),8.08(dd,J＝9.0,6.0Hz,1H),8.03(dd,J＝11.0,2.5Hz,1H),7.69–7.64(m,1H),7.63–7.58(m, 2H),7.50–7.44(m,2H),7.35(d,J＝4.5Hz,1H),3.44(t,J＝11.5Hz,1H),2.20(td,J＝12.5,4.0Hz,1H),2.00–1.84(m,4H),1.77(d,J＝12.5Hz,1H),1.72(dd,J＝7.5,5.5Hz,1H),1.35–1.25(m,1H),1.17–1.13(m,1H),1.10(d,J＝12.5Hz,1H),0.93(dd,J＝7.5,4.0Hz,1H).
实施例12
N-(4-chloro-3-fluorophenyl)-6-(6-fluoroquinolin-4-yl)spiro[2.5]octane-1-carboxamide
N-(4-氯-3-氟苯基)-6-(6-氟喹啉-4-基)螺[2.5]辛烷-1-甲酰胺
Figure PCTCN2018124110-appb-000048
化合物12的合成同化合物5，得到化合物12(20.8mg)，白色固体，收率48％。MS(ESI):m/z 428.1(M+H) +. 1H NMR(500MHz,d 6-DMSO) 1H NMR(500MHz,d 6-DMSO)δ10.62(s,1H),8.80(d,J＝3.5Hz,1H),8.10–8.05(m,1H),8.02(d,J＝10.5Hz,1H),7.82(d,J＝12.0Hz,1H),7.66(t,J＝8.5Hz,1H),7.49(t,J＝8.5Hz,1H),7.37(d,J＝9.5Hz,2H),3.47–3.41(m,1H),2.23–2.15(m,1H),1.97–1.82(m,4H),1.77(d,J＝12.5Hz,1H),1.71(t,J＝6.0Hz,1H),1.32–1.21(m,1H),1.18–1.14(m,1H),1.11(d,J＝12.5Hz,1H),0.98–0.94(m,1H).
实施例13
N-(5-chlorothiophen-2-yl)-6-(6-fluoroquinolin-4-yl)spiro[2.5]octane-1 -carboxamide
N-(5-氯噻吩-2-基)-6-(6-氟喹啉-4-基)螺[2.5]辛烷-1-甲酰胺
Figure PCTCN2018124110-appb-000049
化合物13的合成同化合物5，得到化合物13(17.8mg)，白色固体，收率42％。MS(ESI):m/z 415.3(M+H) +. 1H NMR(500MHz,d 6-DMSO)δ11.71(s,1H),8.81(d,J＝4.0Hz,1H),8.10–8.06(m,1H),8.03(d,J＝11.0Hz,1H),7.67(t,J＝8.5Hz,1H),7.36(d,J＝4.0Hz,1H),6.86(d,J＝3.5Hz,1H),6.50(d,J＝3.5Hz,1H),3.48–3.40(m,1H),2.23–2.16(m,1H),1.97–1.74(m,5H),1.72–1.67(m,1H),1.28–1.16(m,2H),1.11(d,J＝12.5Hz,1H),1.02–0.98(m,1H).
实施例14
N-(4-chlorophenyl)-6-(6-fluoroquinolin-4-yl)spiro[2.5]octane-1-sulfonamide
N-(4-氯苯基)-6-(6-氟喹啉-4-基)螺[2.5]辛烷-1-磺酰胺
Figure PCTCN2018124110-appb-000050
化合物14的合成从实施例1中的中间体1e出发，经由以下步骤 制备：
Figure PCTCN2018124110-appb-000051
第一步：将甲磺酸乙酯(2.45g,19.75mmol)溶于超干四氢呋喃(30mL)中，在-78℃干冰浴和氮气保护下加入双三甲基硅基胺基锂(1.0M in THF,19.8mL,19.75mmol)，在该温度下搅拌反应30分钟。然后将化合物1e(4.0g,16.46mmol)的四氢呋喃(20mL)溶液加入反应液中，并在-78℃反应3小时。用水淬灭反应，浓缩蒸干溶剂得到化合物14a(6.2g)，白色固体，收率100％。不需要纯化直接用于下一步。MS(ESI):m/z 368.4(M+H) +.
第二步：将化合物14a(2.0g,5.45mmol)溶于吡啶(10mL)中，并将溶液冷却至0℃，滴加氯化亚砜(1.30g,10.90mmol)，反应在0℃搅拌2小时后升至室温过夜。加入饱和碳酸氢钠水溶液淬灭反应，中和至碱性。水相用乙酸乙酯萃取，合并有机相，用饱和食盐水洗，无水硫酸钠干燥，过滤，浓缩。残留物用快速过柱机分离得到化合物14b(216mg)，黄色油状液体，收率11％。MS(ESI):m/z 350.4(M+H) +.
第三步：将化合物14b(216mg,0.62mmol)溶于乙二醇二甲醚/水(5/5mL)的混合溶剂中，加入硫氰化钾(60mg,0.62mmol)。反应混合物加热至90℃过夜。冷却至室温，加入10mL稀释，用乙酸乙酯萃取三次，水相浓缩蒸干得到粗品固体。将该固体溶于氯化亚砜(5mL)中，再滴加N,N-二甲基甲酰胺(0.5mL)，加热至80℃反应3小时。蒸干溶剂，用干燥二氯甲烷重蒸三次。残留物溶于干燥二氯甲烷(5mL)中，冰水浴冷却至0℃，加入苯酚(117mg,1.24mmol)，再加入三乙胺(313mg,3.10mmol)。反应在0℃搅拌1小时后升至室温过夜。加入饱和氯化铵水溶液淬灭反应。水相用乙酸乙酯萃取，合并有机相，用饱和食盐水洗，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14c(124mg)，黄色固体，收率50％。MS(ESI):m/z 398.4(M+H) +.
第四步：将NaH(37mg,0.93mmol)加入二甲基亚砜(15mL)中，向该悬浊液中加入三甲基碘化亚砜(205mg,0.93mmol)。混合物在室温下搅拌1小时。然后将化合物14c(124mg,0.31mmol)的二甲基亚砜(5mL)溶液加入到反应液中。反应在60℃搅拌反应3小时。然后用水淬灭，用乙酸乙酯萃取，合并有机相，用饱和食盐水洗，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14d(65mg)，白色固体，收率51％。MS(ESI):m/z 412.4(M+H) +.
第五步：将化合物14d(50mg,0.12mmol)溶于乙醇(5mL)中，加入40％氢氧化钾水溶液(3mL)。反应混合物在80℃下搅拌48小时。冷却至室温，加入4.0mol/L盐酸溶液调节pH至1～3，蒸干水溶液， 得到白色固体。加入甲醇，过滤，滤液浓缩得到化合物14e(35mg)，黄色固体，收率87％，不需要纯化直接用于下一步。MS(ESI):m/z336.5(M+H) +.
第六步：将化合物14e(35mg,0.10mmol)加入到氯化亚砜(5mL)中，再滴加N,N-二甲基甲酰胺(0.5mL)，加热至80℃反应3小时。蒸干溶剂，用干燥二氯甲烷重蒸三次。浓缩得到化合物14f(30mg)，白色固体，收率85％，不需要纯化直接用于下一步。MS(ESI):m/z354.5(M+H) +.
第七步：将化合物14f(30mg,0.08mmol)溶于吡啶(2mL)中，依次加入4-氯苯胺(20mg,0.16mmol)，4-二甲氨基吡啶(12mg,0.01mmol)，反应混合物加热至100℃过夜。蒸干溶剂，加入20mL水，水溶液用乙酸乙酯萃取三次，合并有机相，用饱和食盐水洗，无水硫酸钠干燥，过滤，浓缩。残留物用反向制备色谱提纯得到化合物14(5.69mg)，白色固体，收率16％。MS(ESI):m/z 445.5(M+H) +. 1H NMR(500MHz,d 6-DMSO)δ10.10(br,1H),8.82(d,J＝4.5Hz,1H),8.09(dd,J＝9.0,6.0Hz,1H),8.02(dd,J＝11.0,2.5Hz,1H),7.71–7.64(m,1H),7.40(d,J＝9.0Hz,2H),7.27(d,J＝9.0Hz,2H),7.16(d,J＝4.5Hz,1H),3.45–3.40(m,1H),2.56(dd,J＝8.0,5.5Hz,1H),2.13(d,J＝13.5Hz,1H),2.08–1.98(m,2H),1.88–1.74(m,3H),1.52–1.42(m,1H),1.20–1.12(m,2H),1.09(d,J＝13.5Hz,1H).
化合物15,16,17,18,19的合成同化合物14。
Figure PCTCN2018124110-appb-000052
Figure PCTCN2018124110-appb-000053
Figure PCTCN2018124110-appb-000054
实施例20
N-(4-chlorophenyl)-6-(6-fluoroquinolin-4-yl)-1-azaspiro[2.5]octane-1-carboxamide
N-(4-氯苯基)-6-(6-氟喹啉-4-基)-1-氮杂螺[2.5]辛烷-1-甲酰胺
Figure PCTCN2018124110-appb-000055
化合物20的合成从实施例1中的中间体1e出发，经由以下步骤制备：
第一步：将化合物1e(500mg,2.06mmol)溶于20mL超干四氢呋喃中，在氮气条件下加入四乙氧基钛(2.81g,12.36mmol)，然后加入叔丁基亚磺酰胺(747mg,6.18mmol),。反应混合物在60℃下反应4小时。将反应冷却至室温，混合物倒入等体积的饱和食盐水中并搅拌，得到的悬浊液用硅藻土过滤，滤饼用乙酸乙酯洗。有机层用饱和食盐水洗，无水硫酸钠干燥，过滤，浓缩。残留物用快速过柱机分离得到化合物20a(510mg)，收率86％。MS(ESI):m/z 347.4(M+H) +.
第二步：将三甲基碘化亚砜(486mg,2.21mmol)加入20mL超干二甲亚砜中，再加入NaH(88mg,2.21mmol)，在室温下搅拌20分钟。然后向反应液中加入化合物20a(510mg,1.47mmol)的2mL二甲亚砜溶液。反应混合物在室温下搅拌反应1小时。用水淬灭反应，水相用乙酸乙酯萃取(3x20mL)，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化合物20b(320mg)，收率60％。MS(ESI):m/z 361.4(M+H) +.
第三步：将化合物20b(320mg,0.89mmol)溶于20mL四氢呋喃中，向其中滴加57％氢碘酸水溶液(3mL)，反应混合物在室温下搅拌反应30分钟。然后反应冷却至0℃，用2M KOH中和反应液至pH＝12-14，继续在室温下搅拌45分钟。用乙酸乙酯萃取反应液(3x20mL)，合并 有机相，用20mL饱和食盐水洗，无水硫酸钠干燥，过滤，浓缩得到化合物20c(200mg)，收率88％,不需要纯化直接用于下一步。MS(ESI):m/z 257.5(M+H) +.
第四步：将化合物20c(100mg,0.39mmol)溶于10mL四氢呋喃中，冰水浴冷却至0℃，加入三乙胺(118mg,1.17mmol)，然后加入4-氯苯基异氰酸酯(60mg,0.39mmol)。反应混合物升至室温搅拌反应3小时。用10mL饱和氯化铵淬灭反应，水溶液用乙酸乙酯萃取(3x10mL)，合并有机相，用10mL饱和食盐水洗，无水硫酸钠干燥，过滤，浓缩。残留物用反向制备色谱提纯得到化合物20(70mg)，白色固体，收率44％。MS(ESI):m/z 410.4(M+H) +.
化合物21,22,23,24,25的合成同化合物20。
Figure PCTCN2018124110-appb-000056
Figure PCTCN2018124110-appb-000057
Figure PCTCN2018124110-appb-000058
Figure PCTCN2018124110-appb-000059
实施例26
N-(4-chlorophenyl)-6-(6-fluoroquinolin-4-yl)-1-azaspiro[2.5]octane-1-sulfonamide
N-(4-氯苯基)-6-(6-氟喹啉-4-基)-1-氮杂螺[2.5]辛烷-1-磺酰胺
Figure PCTCN2018124110-appb-000060
化合物26的合成从实施例20中的中间体20c出发，经由以下步骤制备：
第一步：将4-氯苯胺(3.0eq)溶于二氯甲烷中，并用冰水浴冷却至0℃。向反应液中慢慢滴加氯磺酸(1.0eq)的二氯甲烷溶液。反应在0℃下继续搅拌30分钟，然后撤去冰水浴，在室温下搅拌1小时。过滤收集反应产生的沉淀并真空干燥得到淡红色固体。将该固体加入到甲苯中，再加入五氯化磷(1.0eq)，反应混合液在75℃下加热反应2小时。反应冷却至室温，过滤掉固体，固体用甲苯洗，滤液浓缩干燥后得到化合物26a，收率72％，不需要纯化直接用于下一步。
第二步：将化合物20c(1.0eq)溶于四氢呋喃中，冰水浴冷却至0℃，加入三乙胺(2.0eq)，然后加入化合物26a(1.2eq)。反应混合物升至室温搅拌反应3小时。用饱和氯化铵淬灭反应，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。残留物用反向制备色谱提纯得到化合物26，白色固体。
化合物27,28,29,30,31的合成同化合物26。
Figure PCTCN2018124110-appb-000061
Figure PCTCN2018124110-appb-000062
Figure PCTCN2018124110-appb-000063
实施例32
N-(4-chlorophenyl)-7-(6-fluoroquinolin-4-yl)spiro[3.5]nonane-1-carboxamide
N-(4-氯苯基)-7-(6-氟喹啉-4-基)螺[3.5]壬烷-1-甲酰胺
Figure PCTCN2018124110-appb-000064
化合物32的合成从实施例1中的中间体1e出发，经由以下步骤制备：
第一步：将(环丙基甲基)三苯基溴化膦(2.0eq)加入到超干四氢呋喃中，向该悬浊液中加入NaH(2.0eq)，然后再室温下搅拌2小时。再向反应液中加入化合物1e(1.0eq)和三(3,6-二氧杂庚基)胺(0.1eq)。反应混合物在室温下搅拌10分钟，然后加热至62℃反应4小时。旋干反应溶剂，残留物用快速过柱机分离得到化合物32a，收率75％。MS(ESI):m/z 268.3(M+H) +.
第二步：将化合物32a(1.0eq)溶于二氯甲烷中，在0-5℃条件下分批加入间氯过氧苯甲酸(1.4eq)。反应混合物在0-5℃下反应40分钟，然后升至室温反应1小时。用二氯甲烷稀释反应液，有机相依次用10％氢氧化钠水溶液和饱和食盐水洗，无水硫酸钠干燥，过滤，浓缩。残留物用快速过柱机分离得到化合物32b，收率35％。MS(ESI):m/z284.3(M+H) +.
第三步：将化合物32b(1.0eq)和对甲基苯磺酰甲基异腈(2.0eq)溶于1,2-二甲氧基乙烷和甲醇(v/v:16/1)中，在0-5℃条件下加入叔丁醇钾(3.0eq)。反应混合物在室温下搅拌4小时，然后将其倒入水中，用1M盐酸溶液中和至pH＝6-7。水溶液用乙酸乙酯萃取三次，合并有机相，用饱和食盐水洗，无水硫酸钠干燥，过滤，浓缩。残留物用快速过柱机分离得到化合物32c，收率20％。MS(ESI):m/z 295.3(M+H) +.
第四步：将化合物32c(1.0eq)溶于乙醇中，加入40％氢氧化钠溶液(10.0eq)，混合物在95℃下加热反应3小时。用水稀释反应液，用4M盐酸溶液中和至pH＝1-2。用乙酸乙酯萃取水相，合并有机相，用 饱和食盐水洗，无水硫酸钠干燥，过滤，浓缩得到化合物32d，收率82％，不需要纯化直接用于下一步。MS(ESI):m/z 314.3(M+H) +.
第五步：将化合物32d(1.0eq)溶于乙酸乙酯中，依次加入吡啶(3.0eq)和三丙基磷酸酐(2.5eq)，在室温下搅拌10分钟。然后加入4-氯苯胺(3.0eq)，继续在室温下搅拌反应过夜。向反应液中加入2M氢氧化钠溶液，再加入水稀释，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。残留物用反向制备色谱提纯得到化合物32，白色固体.
化合物33,34,35,36,37的合成同化合物32。
Figure PCTCN2018124110-appb-000065
Figure PCTCN2018124110-appb-000066
Figure PCTCN2018124110-appb-000067
Figure PCTCN2018124110-appb-000068
Figure PCTCN2018124110-appb-000069
实施例38
N-(4-chlorophenyl)-7-(6-fluoroquinolin-4-yl)spiro[3.5]nonane-1-sulfonamide
N-(4-氯苯基)-7-(6-氟喹啉-4-基)螺[3.5]壬烷-1-磺酰胺
Figure PCTCN2018124110-appb-000070
化合物38的合成从实施例32中的中间体32b出发，经由以下步骤制备：
第一步：将化合物32b(1.0eq)溶于甲醇中，用冰水浴冷却至0℃，向反应液中分批加入硼氢化钠(1.2eq)。反应混合物在0-5℃下搅拌1小时。TLC检测反应结束后，蒸除反应溶剂甲醇，加入饱和食盐水，用乙酸乙酯萃取三次，合并有机相，用饱和食盐水洗，无水硫酸钠干燥，过滤，浓缩。残留物用快速过柱机分离得到化合物38a，收率86％。MS(ESI):m/z 286.3(M+H) +.
第二步：将化合物38a(1.0eq)溶于四氢呋喃中，用冰水浴冷却至0℃，向反应液中依次加入三苯基膦(2.0eq)和四氯化碳(2.0eq)。反应混合液在0℃搅拌1小时后，升至室温继续反应2小时。用乙醚稀释反应液，过滤，浓缩滤液，残留物用快速过柱机分离得到化合物38b，收率51％。MS(ESI):m/z 348.4(M+H) +.
第三步：将化合物38b(1.0eq)的无水乙醚溶液分批加入到镁屑(1.7eq)的无水乙醚悬浊液中。待反应液放热结束后，加热至回流反应30分钟。将反应悬浊液冷却至25℃，并在0℃条件下缓慢滴加至磺酰氯(3.0eq)的无水二氯甲烷溶液中。反应混合物升至25℃，浓缩，残留物用正己烷萃取并浓缩。得到化合物38c，不需要纯化直接用于下一步。
第四步：将上一步得到的化合物38c(1.0eq)溶于无水二氯甲烷中，用冰水浴冷却至0℃，向反应液中依次加入4-氯苯胺(1.0eq)和三乙胺(1.1eq)。反应混合物在25℃下继续搅拌30分钟，然后浓缩。残留物用反向制备色谱提纯得到化合物38，白色固体。MS(ESI):m/z459.4(M+H) +.
化合物39,40,41,42,43的合成同化合物38。
Figure PCTCN2018124110-appb-000071
Figure PCTCN2018124110-appb-000072
实施例50
N-(4-chlorophenyl)-7-(6-fluoroquinolin-4-yl)-1-oxaspiro[3.5]nonane-3 -carboxamide
N-(4-氯苯基)-7-(6-氟喹啉-4-基)-1-氧杂螺[3.5]壬烷-3-甲酰胺
Figure PCTCN2018124110-appb-000073
化合物50的合成从实施例1中的中间体1e出发，经由以下步骤制备：
第一步：将3-羟基丙酸乙酯(1.0eq)溶于干燥的二氯甲烷中，加入咪唑(1.5eq)。在冰浴条件下向反应液中加入叔丁基二甲基氯硅烷(1.2eq)。将反应升至室温搅拌2小时，用饱和氯化铵淬灭反应，水溶液用乙酸乙酯萃取三次，合并有机相，用饱和食盐水洗，无水硫酸钠干燥，过滤，浓缩。残留物快速过柱机分离得到化合物50a，收率88％。
第二步：将二异丙胺(2.0eq)溶于超干四氢呋喃中，在-78℃干冰浴和氮气保护下滴加2.5M正丁基锂(2.0eq)。然后向反应液中慢慢滴加化合物50a(2.0eq)的四氢呋喃溶液。反应继续在-78℃下搅拌1 小时，接着加入化合物1e(1.0eq)的四氢呋喃溶液，反应缓慢升至室温，在室温下反应3小时。用饱和氯化铵淬灭反应，水溶液用乙酸乙酯萃取三次，合并有机相，用饱和食盐水洗，无水硫酸钠干燥，过滤，浓缩。残留物用快速过柱机分离得到化合物50b，收率54％。MS(ESI):m/z 476.4(M+H) +.
第三步：将化合物50b(1.0eq)溶于四氢呋喃中，加入1M四丁基氟化铵的四氢呋喃溶液(10.0eq)。反应混合物在60℃下反应4小时。向反应液中加入水，水溶液用乙酸乙酯萃取，合并有机相，用饱和食盐水洗，无水硫酸钠干燥，过滤，浓缩得到化合物50c，收率76％，不需要纯化直接用于下一步。MS(ESI):m/z 362.3(M+H) +.
第四步：将化合物50c(1.0eq)溶于吡啶中，加入对甲基苯磺酰氯(1.5eq)，反应混合物在80℃下反应过夜。蒸除反应溶剂，残留物用快速过柱机分离得到化合物50d，收率41％。MS(ESI):m/z 344.4(M+H) +.
第五步：将4-氯苯胺(4.0eq)溶于四氢呋喃中，在0℃冰浴下加入2mol/L异丙基氯化镁的四氢呋喃溶液(4.0eq)。混合物在室温下搅拌5分钟，将化合物50d(1.0eq)的四氢呋喃溶液加入该混合物中。反应液在室温下搅拌过夜，然后用饱和氯化铵溶液淬灭，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。残留物用反向制备色谱提纯得到化合物50，白色固体。.
化合物51,52,53,54,55的合成同化合物50。
Figure PCTCN2018124110-appb-000074
Figure PCTCN2018124110-appb-000075
Figure PCTCN2018124110-appb-000076
Figure PCTCN2018124110-appb-000077
Figure PCTCN2018124110-appb-000078
Figure PCTCN2018124110-appb-000079
实施例62
N-(4-chlorophenyl)-7-(6-fluoroquinolin-4-yl)-2-oxaspiro[3.5]nonane-1-carboxamide
N-(4-氯苯基)-7-(6-氟喹啉-4-基)-2-氧杂螺[3.5]壬烷-1-甲酰胺
Figure PCTCN2018124110-appb-000080
化合物62的合成从实施例1中的中间体1e出发，经由以下步骤制备：
第一步：将甲氧基甲基三苯基氯化膦(1.1eq)加入到超干四氢呋喃中，冷却至-78℃。向反应液中滴加1M双三甲基硅基胺基锂(1.1eq)的四氢呋喃溶液。反应混合物在-78℃继续搅拌2小时，然后向其中滴加化合物1e(1.0eq)的四氢呋喃溶液。将反应温度升至室温，搅拌过 夜。向反应液中加入2N HCl溶液，搅拌反应1小时。水溶液用乙酸乙酯萃取三次，合并有机相，用饱和食盐水洗，无水硫酸钠干燥，过滤，浓缩。残留物快速过柱机分离得到化合物62a，收率90％。MS(ESI):m/z 258.4(M+H) +.
第二步：将二异丙胺(2.0eq)溶于超干四氢呋喃中，在-78℃干冰浴和氮气保护下滴加2.5M正丁基锂(2.0eq)。然后向反应液中慢慢滴加化合物62a(1.0eq)的四氢呋喃溶液。反应继续在-78℃下搅拌1小时，接着加入草酰氯单乙酯(2.0eq)的四氢呋喃溶液，反应缓慢升至室温，在室温下反应3小时。用饱和氯化铵淬灭反应，水溶液用乙酸乙酯萃取三次，合并有机相，用饱和食盐水洗，无水硫酸钠干燥，过滤，浓缩。残留物用快速过柱机分离得到化合物62b，收率51％。MS(ESI):m/z 358.4(M+H) +.
第三步：将化合物62b(1.0eq)溶于乙醇中，冷却至-18℃。向反应液中加入硼氢化钠(2.0eq)。反应混合物在-18℃下搅拌30分钟。用饱和氯化铵淬灭反应，水溶液用乙酸乙酯萃取三次，合并有机相，用饱和食盐水洗，无水硫酸钠干燥，过滤，浓缩。残留物快速过柱机分离得到化合物62c，收率83％。MS(ESI):m/z 362.4(M+H) +.
第四步：将化合物62c(1.0eq)溶于吡啶中，加入对甲基苯磺酰氯(1.5eq)，反应混合物在80℃下反应过夜。蒸除反应溶剂，残留物用快速过柱机分离得到化合物62d，收率50％。MS(ESI):m/z 344.4(M+H) +.
第五步：将4-氯苯胺(4.0eq)溶于四氢呋喃中，在0℃冰浴下加入 2mol/L异丙基氯化镁的四氢呋喃溶液(4.0eq)。混合物在室温下搅拌5分钟，将化合物62d(1.0eq)的四氢呋喃溶液加入该混合物中。反应液在室温下搅拌过夜，然后用饱和氯化铵溶液淬灭，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。残留物用反向制备色谱提纯得到化合物62，白色固体。.
化合物63,64,65,66,67的合成同化合物62。
Figure PCTCN2018124110-appb-000081
Figure PCTCN2018124110-appb-000082
Figure PCTCN2018124110-appb-000083
Figure PCTCN2018124110-appb-000084
实施例68
N-(4-chlorophenyl)-7-(6-fluoroquinolin-4-yl)-1-azaspiro[3.5]nonane-1-carboxamide
N-(4-氯苯基)-7-(6-氟喹啉-4-基)-1-氮杂螺[3.5]壬烷-1-甲酰胺
Figure PCTCN2018124110-appb-000085
化合物68的合成从实施例1中的中间体1e出发，经由以下步骤制备：
第一步：将甲基三苯基溴化膦(1.5eq)加入到超干四氢呋喃中，冰水浴冷却至0℃。向该悬浊液中滴加2.5M正丁基锂(1.3eq)溶液。混合物在室温条件下搅拌4小时，然后加入化合物1e(1.0eq)的四氢呋喃溶液，反应继续在室温下搅拌过夜。用饱和氯化铵淬灭反应，水溶液用乙酸乙酯萃取三次，合并有机相，用饱和食盐水洗，无水硫酸钠干燥，过滤，浓缩。残留物用快速过柱机分离得到化合物68a，收率90％。MS(ESI):m/z 242.3(M+H) +.
第二步：在0℃冰水浴条件下，将氯磺酰异氰酸酯(1.0eq)滴加至化合物68a(1.0eq)的乙醚溶液中。反应混合物在室温下搅拌20小时。向反应液中加入饱和亚硫酸钠溶液，再加入10％氢氧化钾溶液，继续搅拌1小时。水溶液用乙酸乙酯萃取三次，合并有机相，用饱和食盐水洗，无水硫酸钠干燥，过滤，浓缩。残留物用快速过柱机分离得到化合物68b，收率56％。MS(ESI):m/z 285.3(M+H) +.
第三步：将化合物68b(1.0eq)溶于四氢呋喃溶液中，在0℃冰水浴条件下，加入氢化铝锂(2.0eq)。反应混合物在室温条件下搅拌2小时。 向反应液中加入2当量的水，然后加入无水硫酸镁。得到的悬浊液用硅藻土过滤，滤饼用乙酸乙酯洗，浓缩。残留物用快速过柱机分离得到化合物68c，收率75％。MS(ESI):m/z 271.3(M+H) +.
第四步：将化合物68c(1.0eq)溶于四氢呋喃中，冰水浴冷却至0℃，加入三乙胺(3.0eq)，然后加入4-氯苯基异氰酸酯(1.0eq)。反应混合物升至室温搅拌反应3小时。用饱和氯化铵淬灭反应，水溶液用乙酸乙酯萃取，合并有机相，用饱和食盐水洗，无水硫酸钠干燥，过滤，浓缩。残留物用反向制备色谱提纯得到化合物68，白色固体，收率44％。MS(ESI):m/z 424.4(M+H) +.
化合物69,70,71,72,73的合成同化合物68。
Figure PCTCN2018124110-appb-000086
Figure PCTCN2018124110-appb-000087
Figure PCTCN2018124110-appb-000088
实施例74
N-(4-chlorophenyl)-7-(6-fluoroquinolin-4-yl)-1-azaspiro[3.5]nonane-1-sulfonamide
N-(4-氯苯基)-7-(6-氟喹啉-4-基)-1-氮杂螺[3.5]壬烷-1-磺酰胺
Figure PCTCN2018124110-appb-000089
化合物74的合成从实施例68中的中间体68c出发，经由以下步骤制备：
将化合物68c(1.0eq)溶于四氢呋喃中，冰水浴冷却至0℃，加入三乙胺(2.0eq)，然后加入化合物26a(1.2eq)。反应混合物升至室温搅拌反应3小时。用饱和氯化铵淬灭反应，水溶液用乙酸乙酯萃取三次，合并有机相，用饱和食盐水洗，无水硫酸钠干燥，过滤，浓缩。残留物用反向制备色谱提纯得到化合物74，白色固体。MS(ESI):m/z 460.4 (M+H) +.
化合物75,76,77,78,79的合成同化合物74。
Figure PCTCN2018124110-appb-000090
Figure PCTCN2018124110-appb-000091
实施例80
6-(6-fluoro-7-methylquinolin-4-yl)-N-(4-fluorophenyl)spiro[2.5]octane-1-carboxamide
Figure PCTCN2018124110-appb-000092
化合物80的合成从实施例1中的中间体1d出发，经由以下步骤制备：
Figure PCTCN2018124110-appb-000093
第一步：在-78℃条件下，将正丁基锂(2.5M in hexane,6.0mL,15.0mmol)滴加到2,2,6,6-四甲基哌啶(2.12g,15.0mmol)的四氢呋喃(30mL)溶液中。再向其中滴加化合物1d(2.87g,10.0mmol)的四氢呋喃(20mL)溶液。反应在-78℃下搅拌2小时。然后向反应液中滴加碘甲烷(1.3mL,20.0mmol)，反应维持在-78℃半小时后升至室温，继续搅拌2小时。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。残留物用快速过柱机分离得到化合物80a(2.27g)，白色固体，收率75％。MS(ESI):m/z 302.4(M+H) +. 1H NMR(500MHz,CDCl 3)δ8.76(d,J＝4.5Hz,1H),7.95(d,J＝7.5Hz,1H),7.62(d,J＝11.5Hz,1H),7.28(d,J＝4.5Hz,1H),4.02(s,4H),3.24–3.17(m,1H),2.49(s,3H),2.04–1.80(m,8H).
第二步：将化合物80a(2.5g,8.31mmol)溶于丙酮(40mL)中，加入4mol/L盐酸(10mL)。反应混合物加热至45℃反应过夜。然后蒸除溶剂，水溶液用6mol/L氢氧化钠中和至pH＝9，用乙酸乙酯萃取水相。有机相合并后用饱和食盐水洗，无水硫酸钠干燥，过滤，浓缩。残留物用快速过柱机分离得到化合物80b(1.9g)，淡黄色固体，收率89％。MS(ESI):m/z 258.4(M+H) +. 1H NMR(500MHz,CDCl 3)δ8.80(d,J＝4.5Hz,1H),7.99(d,J＝7.5Hz,1H),7.67(d,J＝11.0Hz,1H),7.24(d,J＝4.5Hz,1H),3.67(t,J＝12.0Hz,1H),2.72–2.59(m,4H),2.52(s,3H),2.36(d,J＝13.0Hz,2H),2.10–1.98(m,2H).
第三步：将膦酰基乙酸三乙酯(1.74g,7.76mmol)溶于超干四氢呋喃(20mL)中，在0℃冰浴下加入叔丁醇钠(745mg,7.76mmol)。10分钟后，将化合物80b(1.9g,7.39mmol)的四氢呋喃(10mL)溶液加入反应液中。反应2小时后，用水淬灭。水溶液用50mL乙酸乙酯萃取三次，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化合物80c(2.1g)，白色固体，收率87％。MS(ESI):m/z 328.4(M+H) +. 1H NMR(500MHz,CDCl 3)δ8.76(d,J＝4.5Hz,1H),7.94(d,J＝7.5Hz,1H),7.64(d,J＝11.5Hz,1H),7.18(d,J＝4.5Hz,1H),5.74(s,1H),4.18(q,J＝7.0Hz,2H),4.14–4.06(m,1H),3.48–3.39(m,1H),2.53–2.47(m,5H),2.22–2.12(m,3H),1.78–1.66(m,2H),1.30(t,J＝7.0Hz,3H).
第四步：将NaH(697mg,17.43mmol)加入二甲基亚砜(20mL)中，向该悬浊液中加入三甲基碘化亚砜(3.83g,17.43mmol)。混合物在室温下搅拌1.5小时。然后将化合物80c(1.9g,5.81mmol)的二甲基亚砜(10mL)溶液加入到反应液中。反应在40℃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化合物80d(1.1g)，白色固体，收率56％。MS(ESI):m/z 342.4(M+H) +. 1H NMR(500MHz,CDCl 3)δ8.77(d,J＝4.5Hz,1H),7.97(d,J＝8.0Hz,1H),7.64(d,J＝11.5Hz,1H),7.25(d,J＝4.5Hz,1H),4.18(q,J＝7.0Hz,2H),3.24(t,J＝12.0Hz,1H),2.50(s,3H),2.15(t,J＝12.0Hz,1H),2.03–1.90(m,4H),1.85–1.76(m,1H),1.59–1.54(m,1H),1.44–1.35(m,1H),1.30(t,J＝7.0Hz,3H),1.27–1.24(m,1H),1.12(d,J＝13.5Hz,1H),1.02–0.97(m,1H).
第五步：将4-氯苯胺(76mg,0.60mmol)溶于5mL四氢呋喃中，在0℃冰浴下加入2.0mol/L异丙基氯化镁的四氢呋喃溶液(0.3mL,0.60mmol)。混合物在室温下搅拌5分钟，将化合物80d(50mg,0.15mmol)的四氢呋喃(2mL)溶液加入该混合物中。反应液在室温下搅拌过夜，然后用饱和氯化铵溶液淬灭，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。残留物用反向制备色谱提纯得到化合物80(27.27mg)，白色固体，收率45％。MS(ESI):m/z 407.4(M+H) +. 1H NMR(500MHz,d 6-DMSO)δ10.30(s,1H),8.75(d,J＝4.5Hz,1H),7.99–7.92(m,2H),7.65–7.60(m,2H),7.29(d,J＝5.0Hz,1H),7.13(t,J＝9.0Hz,2H),3.44–3.37(m,1H),2.45(s,3H),2.22–2.15(m,1H),1.97–1.86(m,4H),1.79–1.74(m,1H),1.70(dd,J＝7.5,5.0Hz,1H),1.30(dd,J＝12.0,4.0Hz,1H),1.15–1.12(m,1H),1.11–1.07(m,1H),0.91(dd,J＝7.5,4.0Hz,1H).
化合物81,82,83,84,85,86的合成同化合物80。
Figure PCTCN2018124110-appb-000094
Figure PCTCN2018124110-appb-000095
Figure PCTCN2018124110-appb-000096
Figure PCTCN2018124110-appb-000097
实施例87
N-(4-chlorophenyl)-8-(6-fluoroquinolin-4-yl)-2-methyl-2-azaspiro[4.5]decane-4-carboxamide
N-(4-氯苯基)-8-(6-氟喹啉-4-基)-2-甲基-2-氮杂螺[4.5]癸烷-4-甲酰胺
Figure PCTCN2018124110-appb-000098
化合物87的合成从实施例1中的中间体1f出发，经由以下步骤制备：
Figure PCTCN2018124110-appb-000099
第一步：将化合物1f(400mg,1.28mmol)溶于乙腈(15mL)中，加入N-甲氧基甲基-N-(三甲基硅烷)苄基胺(3.03g,12.8mmol)，再加入氟化锂(998mg,38.4mmol)。反应混合物在60℃反应24小时。反应冷却至室温，加入50mL水，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87a(376mg)，无色油状液体，收率66％。MS(ESI):m/z 447.4(M+H) +.
第二步：将化合物87a(400mg,0.90mmol)溶于甲醇(20mL)中，加入10％钯碳催化剂(40mg)，反应在氢气氛围下反应过夜。然后用硅藻土滤除钯碳，滤液浓缩得到粗品化合物87b(300mg)，油状液体，收率94％，不需要纯化直接用于下一步。MS(ESI):m/z357.3(M+H) +.
第三步：将化合物87b(300mg,0.84mmol)溶于二氯乙烷(10mL)中，依次加入甲醛水溶液(50mg,0.84mmol)、三乙酰基硼氢化钠(178mg,0.84mmol)，向反应溶液中加入2滴醋酸，混合物在室温下搅拌过夜。加入20mL水，用二氯甲烷萃取水相。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87c(136mg)，淡黄色液体，收率44％。MS(ESI):m/z371.3(M+H) +.
第四步：将化合物87c(136mg,0.37mmol)溶于乙醇(10mL)中，加入2mol/L氢氧化钠(4.0mL,8.0mmol)溶液。反应液加热至50℃，反应24小时。待反应液冷却至室温，用4.0mol/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化合物87d(98mg)，白色固体，收率78％。MS(ESI):m/z 343.3(M+H) +.
第五步：将化合物87d(40mg,0.12mmol)溶于乙酸乙酯(5mL)中，依次加入吡啶(28mg,0.36mmol)和三丙基磷酸酐(50％wt in EA,114mg,0.18mmol)，在室温下搅拌10分钟。然后加入4-氯苯胺(23mg,0.18mmol)，继续在室温下搅拌反应过夜。向反应液中 加入2mol/L氢氧化钠(2mL)溶液，再加入20mL水稀释，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。残留物用反向制备色谱提纯得到化合物87(12.68mg)，白色固体，收率23％，顺反混合物。MS(ESI):m/z 452.4(M+H) +. 1H NMR(500MHz,d 6-DMSO)δ10.50(s,1H),8.72(d,J＝4.5Hz,1H),8.09–8.03(m,1H),7.98(dd,J＝11.0,2.5Hz,1H),7.72–7.63(m,3H),7.40–7.35(m,2H),7.31–7.27(m,1H),3.35–3.30(m,2H),3.24–3.18(m,1H),2.99–2.92(m,1H),2.64–2.58(m,1H),2.38–2.29(m,4H),2.06–1.96(m,2H),1.93–1.51(m,5H),1.50–1.41(m,1H).
化合物88,89,90,91的合成同化合物87。
实施例92
(1S)-N-(4-chlorophenyl)-6-(6-fluoro-7-methylquinolin-4-yl)spiro[2.5]octane-1-carboxamide
(1S)-N-(4--氯苯基)-6-(6-氟-7-甲基喹啉-4-基)-螺[2.5]辛烷-1-甲酰胺
Figure PCTCN2018124110-appb-000100
实施例93
(1R)-N-(4-chlorophenyl)-6-(6-fluoro-7-methylquinolin-4-yl)spiro[2.5] octane-1-carboxamide
(1R)-N-(4-氯苯基)-6-(6-氟-7-甲基喹啉-4-基)-螺[2.5]辛烷-1-甲酰胺
Figure PCTCN2018124110-appb-000101
化合物92和化合物93由实施例9中化合物9经过手性柱拆分得到，绝对构型未确定。其中，化合物92对应手性拆分中的前者，化合物93对应手性拆分中的后者。
化合物92：MS(ESI):m/z 423.4(M+H) +. 1H NMR(500MHz,d 6-DMSO)δ10.39(s,1H),8.75(d,J＝4.5Hz,1H),7.97(d,J＝12.0Hz,1H),7.94(d,J＝8.0Hz,1H),7.65(d,J＝9.0Hz,2H),7.34(d,J＝9.0Hz,2H),7.28(d,J＝4.5Hz,1H),3.44–3.38(m,1H),2.44(s,3H),2.24–2.14(m,1H),1.97–1.82(m,4H),1.80–1.74(m,1H),1.73–1.69(m,1H),1.32–1.24(m,1H),1.17–1.12(m,1H),1.10(d,J＝13.0Hz,1H),0.93(dd,J＝7.5,4.0Hz,1H).
化合物93：MS(ESI):m/z 423.4(M+H) +. 1H NMR(500MHz,d 6-DMSO)δ10.39(s,1H),8.75(d,J＝4.5Hz,1H),7.97(d,J＝12.0Hz,1H),7.94(d,J＝8.0Hz,1H),7.65(d,J＝9.0Hz,2H),7.34(d,J＝9.0Hz,2H),7.28(d,J＝4.5Hz,1H),3.45–3.38(m,1H),2.45(s,3H),2.24–2.14(m,1H),1.97–1.82(m,4H),1.80–1.74(m,1H),1.73–1.69(m,1H),1.32–1.24(m,1H),1.16–1.13(m,1H),1.10(d,J＝13.0Hz,1H),0.93(dd,J＝7.5,4.0Hz,1H).
实施例94
6-(6-fluoro-7-methylquinolin-4-yl)-N-(4-(2-methoxyethoxy)phenyl)spiro[2.5]octane-1-carboxamide
Figure PCTCN2018124110-appb-000102
化合物94的合成从实施例9中的中间体80d出发，经由以下步骤制备：
Figure PCTCN2018124110-appb-000103
第一步：将化合物80d(200mg,0.59mmol)溶于乙醇(10mL)中，加入2.0mol/L氢氧化钠溶液(4mL)。反应液加热至50℃，反应2小时。待反应液冷却至室温，用4.0mol/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化合物94a(150mg)，白色固体，产率81％。MS(ESI):m/z 314.4(M+H) +.
第二步：将化合物94b(1.0g,4.78mmol)和2-溴乙基甲基醚(1.33g,9.56mmol)溶于丙酮(20mL)中，然后向其中加入碳酸钾(1.98g,14.34mmol)，将反应液加热到60℃搅拌2小时。过滤浓缩，残留物用快速过柱机分离得到化合物94c(1.2g)，白色固体，收率94％。 1H NMR(500MHz,CDCl 3)δ7.25(d,J＝9.0Hz,2H),6.86(d,J＝9.0Hz,2H),6.36(s,1H),4.08(t,J＝4.5Hz,2H),3.73(t,J＝4.5Hz,2H),3.44(s,3H),1.50(s,9H).
第三步：将化合物94c(1.2g,4.49mmol)溶于二氯甲烷(3mL)中，在0℃冰浴下加入4.0mol/L盐酸二氧六环溶液(6mL)。室温下 反应2小时，过滤产生的固体，干燥得到化合物94d(900mg)，白色固体，收率98％。直接用于下一步反应。 1H NMR(500MHz,d 6-DMSO)δ10.26(br,3H),7.32(d,J＝9.0Hz,2H),7.04(d,J＝9.0Hz,2H),4.10(t,J＝4.0Hz,2H),3.65(t,J＝4.0Hz,2H),3.30(s,3H).
第四步：将化合物94a(53mg,0.17mmol)溶于无水二氯甲烷(2mL)中，加入二氯亚砜(5mL)，反应混合物回流搅拌2小时。蒸去反应溶剂，减压干燥残留物得到淡黄色的固体。将该固体溶于无水二氯甲烷(3mL)中，在冰水浴条件下加入化合物94d(30mg,0.17mmol)的二氯甲烷(2mL)溶液，加入三乙胺(52mg,0.51mmol)，在冰水浴下搅拌10分钟，升至室温继续搅拌2小时。加水淬灭反应，用二氯甲烷萃取水相。合并有机相，用无水硫酸钠干燥，过滤，浓缩。残留物用反向制备色谱提纯得到化合物94(43.60mg)，白色固体，收率56％。MS(ESI):m/z 463.7(M+H) +. 1H NMR(500MHz,d 6-DMSO)δ10.07(s,1H),8.75(d,J＝4.5Hz,1H),7.98–7.92(m,2H),7.49(d,J＝9.0Hz,2H),7.29(d,J＝4.5Hz,1H),6.87(d,J＝9.0Hz,2H),4.03(t,J＝4.5Hz,2H),3.63(t,J＝4.5Hz,2H),3.44–3.37(m,1H),3.29(s,3H),2.45(s,3H),2.22–2.14(m,1H),1.99–1.85(m,4H),1.76(d,J＝12.0Hz,1H),1.70–1.65(m,1H),1.37–1.28(m,1H),1.14–1.06(m,2H),0.88(dd,J＝7.5,4.0Hz,1H).
实施例95
N-(6-chloropyridin-3-yl)-6-(6-fluoro-7-methylquinolin-4-yl)spiro[2.5]octane-1-carboxamide
Figure PCTCN2018124110-appb-000104
化合物95的合成从实施例94中的中间体94a出发，经由以下步骤制备：
Figure PCTCN2018124110-appb-000105
将化合物94a(53mg,0.17mmol)溶于无水二氯甲烷(5mL)中，加入二氯亚砜(2.5mL)，反应混合物回流搅拌2小时。蒸去反应溶剂，残留物用无水二氯甲烷重蒸两次。将得到的淡黄色固体溶于无水四氢呋喃(5mL)中，加入3-氨基-6-氯吡啶(44mg,0.34mmol)，在冰水浴条件下滴加三乙胺(52mg,0.51mmol)。反应混合物在冰水浴下搅拌30分钟，升至室温继续搅拌2小时。加水淬灭反应，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。残留物用反向制备色谱提纯得到化合物95(24.07mg)，白色固体，收率33％。MS(ESI):m/z 424.6(M+H) +. 1H NMR(500MHz,d 6-DMSO)δ10.61(s,1H),8.75(d,J＝4.5Hz,1H),8.63(d,J＝3.0Hz,1H),8.11(dd,J＝8.5,2.5Hz,1H),7.99–7.91(m,2H),7.45(d,J＝8.5Hz,1H),7.30(d,J＝4.5Hz,1H),3.45–3.37(m,1H),2.44(s,3H),2.24–2.16(m,1H),1.97–1.82(m,4H),1.80–1.71(m,2H),1.34–1.25(m,1H),1.19–1.09(m,2H),0.97(dd,J＝7.5,4.0Hz,1H).
化合物96,97的合成同化合物95。
Figure PCTCN2018124110-appb-000106
Figure PCTCN2018124110-appb-000107
Figure PCTCN2018124110-appb-000108
实施例98
(S)-6-(6-fluoro-7-methylquinolin-4-yl)-N-(4-(2-methoxyethoxy)phenyl)spiro[2.5]octane-1-carboxamide
Figure PCTCN2018124110-appb-000109
实施例99
(R)-6-(6-fluoro-7-methylquinolin-4-yl)-N-(4-(2-methoxyethoxy)phenyl)spiro[2.5]octane-1-carboxamide
Figure PCTCN2018124110-appb-000110
化合物98和化合物99由实施例94中化合物94经过手性柱拆分得到，绝对构型未确定。其中，化合物98对应手性拆分中的 前者，化合物99对应手性拆分中的后者。
化合物98：MS(ESI):m/z 463.7(M+H) +. 1H NMR(500MHz,d 6-DMSO)δ10.07(s,1H),8.75(d,J＝4.5Hz,1H),7.98–7.92(m,2H),7.49(d,J＝9.0Hz,2H),7.29(d,J＝4.5Hz,1H),6.87(d,J＝9.0Hz,2H),4.03(t,J＝4.5Hz,2H),3.63(t,J＝4.5Hz,2H),3.44–3.37(m,1H),3.29(s,3H),2.45(s,3H),2.22–2.14(m,1H),1.99–1.85(m,4H),1.76(d,J＝12.0Hz,1H),1.70–1.65(m,1H),1.37–1.28(m,1H),1.14–1.06(m,2H),0.88(dd,J＝7.5,4.0Hz,1H).
化合物99：MS(ESI):m/z 463.7(M+H) +. 1H NMR(500MHz,d 6-DMSO)δ10.07(s,1H),8.75(d,J＝4.5Hz,1H),7.98–7.92(m,2H),7.49(d,J＝9.0Hz,2H),7.29(d,J＝4.5Hz,1H),6.87(d,J＝9.0Hz,2H),4.03(t,J＝4.5Hz,2H),3.63(t,J＝4.5Hz,2H),3.44–3.37(m,1H),3.29(s,3H),2.45(s,3H),2.22–2.14(m,1H),1.99–1.85(m,4H),1.76(d,J＝12.0Hz,1H),1.70–1.65(m,1H),1.37–1.28(m,1H),1.14–1.06(m,2H),0.88(dd,J＝7.5,4.0Hz,1H).
实施例100
N-(4-chlorophenyl)-6-(6,7-difluoroquinolin-4-yl)spiro[2.5]octane-1-carboxamide
Figure PCTCN2018124110-appb-000111
化合物100的合成从实施例1中的中间体1d出发，经由以下步骤制备：
Figure PCTCN2018124110-appb-000112
第一步：在-78℃条件下，将正丁基锂(2.5M,1.1mL,2.61mmol)滴加到2,2,6,6-四甲基哌啶(368mg,2.61mmol)的四氢呋喃(20mL)溶液中。再向其中滴加化合物1d(500mg,1.74mmol)的四氢呋喃(10mL)溶液。反应在-78℃下搅拌2小时。然后向反应液中滴加N-氟代双苯磺酰胺(1.1g,3.48mmol)的四氢呋喃(10mL)溶液，反应维持在-78℃半小时后升至室温，继续搅拌2小时。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。残留物用快速过柱机分离得到化合物101a(410mg)，白色固体，收率77％。MS(ESI):m/z 306.5(M+H) +.
第二步：将化合物100a(410mg,1.34mmol)溶于丙酮(10mL)中，加入4mol/L盐酸(3mL)。反应混合物加热至45℃反应4小时。然后蒸除溶剂，水溶液用6mol/L氢氧化钠中和至pH＝9，用乙酸乙酯萃取水相。有机相合并后用饱和食盐水洗，无水硫酸钠干燥，过滤，浓缩。残留物用快速过柱机分离得到化合物100b(190mg)，白色固体，收率54％。MS(ESI):m/z 262.5(M+H) +.
第三步：将膦酰基乙酸三乙酯(172mg,0.77mmol)溶于超干四氢呋喃(10mL)中，在0℃冰浴下加入叔丁醇钠(74mg,0.77mmol)。 10分钟后，将化合物100b(190mg,0.73mmol)的四氢呋喃(5mL)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化合物100c(180mg)，白色固体，收率74％。MS(ESI):m/z 332.5(M+H) +.
第四步：将NaH(65mg,1.62mmol)加入二甲基亚砜(10mL)中，向该悬浊液中加入三甲基碘化亚砜(356mg,1.62mmol)。混合物在室温下搅拌1.5小时。然后将化合物100c(180mg,0.54mmol)的二甲基亚砜(5mL)溶液加入到反应液中。反应在40℃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化合物100d(80mg)，无色油状液体，收率43％。MS(ESI):m/z 346.5(M+H) +.
第四步：将4-氯苯胺(117mg,0.92mmol)溶于5mL四氢呋喃中，在0℃冰浴下加入2mol/L异丙基氯化镁的四氢呋喃溶液(0.5mL,0.92mmol)。混合物在室温下搅拌5分钟，将化合物100d(80mg,0.23mmol)的四氢呋喃(2mL)溶液加入该混合物中。反应液在室温下搅拌过夜，然后用饱和氯化铵溶液淬灭，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。残留物用反向制备色谱提纯得到化合物100(36.20mg)，白色固体，收率37％。MS(ESI):m/z 427.4(M+H) +. 1H NMR(500MHz,d 6-DMSO)δ10.38(s,1H),8.83(d,J＝4.5Hz,1H),8.33(dd,J＝12.5,9.0Hz,1H),8.00(dd,J＝11.5,8.5Hz,1H),7.65(d,J＝8.5Hz,2H),7.39–7.30(m,3H), 3.49–3.41(m,1H),2.23–2.15(m,1H),1.98–1.83(m,4H),1.76(d,J＝13.0Hz,1H),1.73–1.69(m,1H),1.33–1.24(m,1H),1.16–1.13(m,1H),1.10(d,J＝13.0Hz,1H),0.93(dd,J＝7.5,4.0Hz,1H).
实施例101
N-(4-chlorophenyl)-1-cyano-6-(6-fluoroquinolin-4-yl)spiro[2.5]octane-1-carboxamide
Figure PCTCN2018124110-appb-000113
化合物101的合成同化合物1，将4-氯-6,7-二甲氧基喹啉替代实施例1中4-氯-6-氟喹啉。
Figure PCTCN2018124110-appb-000114
化合物101：MS(ESI):m/z 451.4(M+H) +. 1H NMR(500MHz, d 6-DMSO)δ10.41(s,1H),8.58(s,1H),7.65(d,J＝8.0Hz,2H),7.40(s,1H),7.37–7.33(m,3H),7.14(s,1H),3.94(s,3H),3.91(s,3H),3.47–3.42(m,1H),2.24–2.15(m,1H),1.96–1.86(m,4H),1.82–1.76(m,1H),1.75–1.70(m,1H),1.34–1.24(m,1H),1.16–1.09(m,2H),0.95–0.90(m,1H).
实施例102
N-(4-chlorophenyl)-6-(7-cyano-6-fluoroquinolin-4-yl)spiro[2.5]octane-1-carboxamide
Figure PCTCN2018124110-appb-000115
化合物102的合成从实施例1中的中间体1d出发，经由以下步骤制备：
Figure PCTCN2018124110-appb-000116
第一步：在-78℃氮气保护条件下，将正丁基锂(2.5M in hexane,2.8mL,6.97mmol)滴加到2,2,6,6-四甲基哌啶(983mg,6.97mmol)的四氢呋喃(50mL)溶液中。再向其中滴加化合物1d(2.0g,6.97mmol)的四氢呋喃(20mL)溶液。反应在-78℃下搅拌2小时。然后向反应液中滴加碘(3.54g,13.94mmol)的四氢呋喃(10mL)溶液，反应维持在-78℃半小时后升至室温，继续搅拌2小时。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。残留物用快速过柱机分离得到化合物102a(2.0g)，白色固体，收率69％。MS(ESI):m/z 414.4(M+H) +.
第二步：将化合物102a(1.0g,2.42mmol)溶于丙酮(30mL)中，加入4mol/L盐酸(9mL,36mmol)。反应混合物加热至45℃反应过夜。然后蒸除溶剂，水溶液用6mol/L氢氧化钠中和至pH＝9，用乙酸乙酯萃取水相。有机相合并后用饱和食盐水洗，无水硫酸钠干燥，过滤，浓缩。残留物用快速过柱机分离得到化合物102b(700mg)，白色固体，收率78％。MS(ESI):m/z 370.3(M+H) +.
第三步：将膦酰基乙酸三乙酯(430mg,1.92mmol)溶于超干四氢呋喃(16mL)中，在0℃冰浴下加入叔丁醇钠(184mg,1.92mmol)。10分钟后，将化合物102b(700mg,1.90mmol)的四氢呋喃(4mL)溶液加入反应液中。反应2小时后，用水淬灭。水溶液用乙酸乙酯萃取三次，合并有机相，用饱和食盐水洗，无水硫酸钠干燥，过滤，浓缩。残留物用快速过柱机分离得到化合物102c(730mg)，白色固体，收率88％。MS(ESI):m/z 440.4(M+H) +.
第四步：将NaH(199mg,4.98mmol)加入二甲基亚砜(15mL)中，向该悬浊液中加入三甲基碘化亚砜(1.10g,4.98mmol)。混合物在室温下搅拌1.5小时。然后将化合物102c(730mg,1.66mmol)的二甲基亚砜(5mL)溶液加入到反应液中。反应在40℃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化合物102d(400mg)，白色固体，收率53％。MS(ESI):m/z 454.3(M+H) +.
第五步：将4-氯苯胺(447mg,3.52mmol)溶于四氢呋喃(5mL)中，在0℃冰浴下加入异丙基氯化镁的四氢呋喃溶液(2.0mol/L in THF,1.8mL,3.52mmol)。混合物在室温下搅拌5分钟，将化合物 102d(400mg,0.88mmol)的四氢呋喃(2mL)溶液加入该混合物中。反应液在室温下搅拌过夜，然后用饱和氯化铵溶液淬灭，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。残留物用快速过柱机分离得到化合物102e(400mg)，白色固体，收率85％。MS(ESI):m/z 535.4(M+H) +.
第六步：将化合物102e(50mg,0.09mmol)溶于N,N-二甲基甲酰胺(5mL)中，加入氰化亚铜(20mg,0.22mmol)，混合物加热至160℃反应1小时。冷却至室温，用饱和氯化铵溶液淬灭反应，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。残留物用反向制备色谱提纯得到化合物102(17.23mg)，白色固体，收率44％。MS(ESI):m/z 434.5(M+H) +. 1H NMR(500MHz,d 6-DMSO)δ10.38(s,1H),8.96(d,J＝4.5Hz,1H),8.72(d,J＝7.0Hz,1H),8.37(d,J＝11.5Hz,1H),7.65(d,J＝9.0Hz,2H),7.51(d,J＝4.5Hz,1H),7.34(d,J＝9.0Hz,2H),3.53–3.43(m,1H),2.23–2.15(m,1H),1.96–1.83(m,4H),1.77(d,J＝12.0Hz,1H),1.74–1.69(m,1H),1.34-1.24(m,1H),1.16–1.07(m,2H),0.93(dd,J＝7.5,4.0Hz,1H).
实施例103
N-(4-chlorophenyl)-6-(2,3-dihydro-[1,4]dioxino[2,3-g]quinolin-9-yl)spiro[2.5]octane-1-carboxamide
Figure PCTCN2018124110-appb-000117
化合物103由以下步骤制备：
Figure PCTCN2018124110-appb-000118
第一步：将4-氯-6,7-二甲氧基喹啉(1.0g,4.48mmol)溶于二氯甲烷(30mL)中，在冰浴条件下滴加三溴化硼(1.0mol/L,12.0mL,12.0mmol)的二氯甲烷溶液，继续搅拌2小时，升至室温搅拌过夜。LCMS检测反应结束，加入50mL水，用二氯甲烷(40mLx2)萃取水相。合并有机相，用无水硫酸钠干燥，过滤，浓缩得到化合物103a(800mg)，黄色固体，产率92％。MS(ESI):m/z 196.5(M+H) +. 1H NMR(500MHz,d 6-DMSO)δ10.33(s,2H),8.47(d,J＝5.0Hz,1H),7.42(d,J＝5.0Hz,1H),7.36(s,1H),7.30(s,1H).
第二步：将化合物103a(800mg,4.10mmol)溶于N,N-二甲基甲酰胺(30ml)中，加入碳酸钾(2.12g,15.38mmol)和1,2-二溴乙烷(3.84g,20.45mmol)。反应混合物在60℃下搅拌2小时。加水淬灭反应，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。残留物用快速过柱机分离得到化合物103b(520mg)，白色固体，收率57％。MS(ESI):m/z 222.5(M+H) +. 1H NMR(500MHz,CDCl 3)δ8.59(d,J＝4.5Hz,1H),7.62(s,1H),7.58(s,1H),7.33(d,J＝4.5Hz,1H),4.40(s,4H).
第三步：将化合物硼酸酯(664mg,2.50mmol)溶于40mL/10mL二氧六环/水中，依次加入化合物103b(460mg,2.08mmol)，碳酸钾(861mg,6.24mmol)，Pd 2(dba) 3(95mg,0.104mmol)和PCy 3(70mg,0.25mmol)。反应混合物在氮气氛下回流反应过夜。然后浓缩 反应液，用乙酸乙酯萃取，有机相浓缩之后用快速过柱机分离得到化合物103c(550mg)，白色固体，收率81％。MS(ESI):m/z 326.6(M+H) +. 1H NMR(500MHz,CDCl 3)δ8.65(d,J＝4.5Hz,1H),7.56(s,1H),7.42(s,1H),7.06(d,J＝4.5Hz,1H),5.72(t,J＝3.5Hz,1H),4.41–4.34(m,4H),4.09–4.03(m,4H),2.64–2.57(m,2H),2.54–2.49(m,2H),1.97(t,J＝6.5Hz,2H).
第四步：将化合物103c(500mg,1.54mmol)溶于25mL异丙醇中，加入10％钯碳(70mg)。反应混合物在氢气氛下加热至55℃反应过夜。然后用硅藻土滤除钯碳，滤液浓缩得到粗品化合物103d(500mg)，白色固体，收率99％。直接用于下一步反应。MS(ESI):m/z 328.4(M+H) +.
第五步：将化合物103d(500mg,1.53mmol)溶于丙酮(36mL)中，加入4mol/L盐酸(9mL,36mmol)。反应混合物加热至45℃反应过夜。然后蒸除溶剂，水溶液用6mol/L氢氧化钠中和至pH＝9，用乙酸乙酯萃取水相。有机相合并后用饱和食盐水洗，无水硫酸钠干燥，过滤，浓缩。残留物用快速过柱机分离得到化合物103e(250mg)，棕色固体，收率58％。MS(ESI):m/z 284.5(M+H) +. 1H NMR(500MHz,CDCl 3)δ8.68(d,J＝4.5Hz,1H),7.60(s,1H),7.49(s,1H),7.10(d,J＝4.5Hz,1H),4.41(s,4H),3.68–3.61(m,1H),2.68–2.57(m,4H),2.39–2.31(m,2H),2.07–1.96(m,2H).
第六步：将膦酰基乙酸三乙酯(214mg,0.89mmol)溶于超干四氢呋喃(10mL)中，在0℃冰浴下加入叔丁醇钠(85mg,0.89mmol)。10分钟后，将化合物103e(250mg,0.88mmol)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化合物103f(168mg)，白色固体，收率54％。MS(ESI):m/z 354.5(M+H) +. 1H NMR(500MHz,CDCl 3)δ8.65(d,J＝4.5Hz,1H),7.59(s,1H),7.49(s,1H),7.07(d,J＝4.5Hz,1H),5.73(s,1H),4.40(s,4H),4.18(q,J＝7.0Hz,2H),4.10–4.05(m,1H),3.46–3.39(m,1H),2.51–2.45(m,2H),2.22–2.10(m,3H),1.77–1.65(m,2H),1.30(t,J＝7.0Hz,3H).
第七步：将NaH(40mg,0.99mmol)加入二甲基亚砜(10mL)中， 向该悬浊液中加入三甲基碘化亚砜(249mg,1.13mmol)。混合物在室温下搅拌1.5小时。然后将化合物103f(100mg,0.28mmol)的二甲基亚砜(5mL)溶液加入到反应液中。反应在40℃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化合物103g(70mg)，白色固体，收率68％。MS(ESI):m/z 368.5(M+H) +. 1H NMR(500MHz,CDCl 3)δ8.66(d,J＝4.5Hz,1H),7.63(s,1H),7.48(s,1H),7.14(d,J＝4.5Hz,1H),4.40(s,4H),4.18(q,J＝7.0Hz,2H),3.27–3.19(m,1H),2.13(td,J＝13.5,3.5Hz,1H),2.03–1.88(m,4H),1.84–1.74(m,1H),1.56(dd,J＝7.5,5.5Hz,1H),1.41–1.34(m,1H),1.29(t,J＝7.0Hz,3H),1.25–1.22(m,1H),1.14–1.07(m,1H),0.98(dd,J＝7.5,4.5Hz,1H).
第八步：将4-氯苯胺(81mg,0.64mmol)溶于5mL四氢呋喃中，在0℃冰浴下加入2mol/L异丙基氯化镁的四氢呋喃溶液(0.3mL,0.64mmol)。混合物在室温下搅拌5分钟，将化合物103g(60mg,0.16mmol)的四氢呋喃(2mL)溶液加入该混合物中。反应液在室温下搅拌过夜，然后用饱和氯化铵溶液淬灭，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。残留物用反向制备色谱提纯得到化合物103(7.59mg)，白色固体，收率11％。 1H NMR(500MHz,d 6-DMSO)δ10.37(s,1H),8.58(d,J＝4.5Hz,1H),7.64(d,J＝9.0Hz,2H),7.57(s,1H),7.36(s,1H),7.34(d,J＝9.0Hz,2H),7.10(d,J＝4.5Hz,1H),4.38(s,4H),3.36–3.33(m,1H),2.20–2.12(m,1H),1.97–1.84(m,4H),1.77–1.68(m,2H),1.33–1.24(m,1H),1.16–1.06(m,2H),0.92(dd,J＝7.5,4.0Hz,1H).
实施例104
N-(4-chlorophenyl)-6-(6-fluoroquinolin-4-yl)-6-hydroxyspiro[2.5]octane-1-carboxamide
Figure PCTCN2018124110-appb-000119
化合物104由以下步骤制备：
Figure PCTCN2018124110-appb-000120
第一步：将4-溴-6-氟喹啉(500mg,2.21mmol)溶于无水四氢呋喃(5mL)中，在-78℃下向溶液中滴加1.6M正丁基锂(2.8mL,4.42mmol)，反应液维持在-78℃下搅拌5分钟。然后向反应液中滴加化合物104b(345mg,2.21mmol)的无水四氢呋喃(4mL)溶液。反应在-78℃下搅拌1小时。用饱和氯化铵水溶液淬灭，水溶液用乙酸乙酯萃取三次，合并有机相，用饱和食盐水洗，无水硫酸钠干燥，过滤，浓缩。残留物用快速过柱机分离得到化合物104c(83mg)，黄色固体，收率12％。MS(ESI):m/z 304.6(M+H) +.
第二步：将化合物104c(370mg,1.22mmol)溶于四氢呋喃(4mL)中，加入3.0mol/L盐酸(3mL)。反应混合物加热至50℃搅拌12小时。冷却至室温，用饱和碳酸钠溶液中和至pH＝8，用乙酸乙酯萃取水相。有机相合并后用饱和食盐水洗，无水硫酸钠干燥，过滤，浓缩。残留物用快速过柱机分离得到化合物104d(230mg)，黄色液体，收率73％。MS(ESI):m/z 260.6(M+H) +.
第三步：将膦酰基乙酸三乙酯(280mg,1.25mmol)溶于无水四氢呋喃(10mL)中，在0℃冰浴下加入叔丁醇钠(120mg,1.25mmol)。10分钟后，将化合物104d(295mg,1.14mmol)的四氢呋喃(2mL)溶液加入反应液中。反应2小时后，用水淬灭。水溶液用乙酸乙酯萃取三次，合并有机相，用饱和食盐水洗，无水硫酸钠干燥，过 滤，浓缩。残留物用快速过柱机分离得到化合物104e(183mg)，白色固体，收率49％。MS(ESI):m/z 330.5(M+H) +.
第四步：将NaH(67mg,1.68mmol)加入二甲基亚砜(5mL)中，向该悬浊液中加入三甲基碘化亚砜(370mg,1.68mmol)。混合物在室温下搅拌1.5小时。然后将化合物104e(183mg,0.56mmol)的二甲基亚砜(2mL)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，用制备薄层层析分离得到化合物104f(23mg)，无色油状液体，收率12％。MS(ESI):m/z 344.5(M+H) +.
第五步：将化合物104f(23mg,0.07mmol)溶于乙醇(5mL)中，加入2mol/L氢氧化钠溶液(1mL)。反应液加热至50℃，反应2小时。待反应液冷却至室温，用2mol/L盐酸溶液中和至pH＝5～6。蒸干水溶液，残留物用甲醇溶解，抽滤固体，滤液浓缩得到化合物104g(20mg)，白色固体，收率91％。MS(ESI):m/z 316.5(M+H) +.
第六步：将化合物104g(20mg,0.06mmol)溶于N,N-二甲基甲酰胺(2mL)中，依次加入二异丙基乙胺(24mg,0.18mmol)和HATU(34mg,0.09mmol)，在室温下搅拌1小时。然后加入4-氯苯胺(23mg,0.18mmol)，继续在室温下搅拌反应2小时。向反应液中加入水淬灭，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。残留物用反向制备色谱提纯得到化合物104(5.85mg)，白色固体，收率20％。MS(ESI):m/z 425.6(M+H) +. 1H NMR(500MHz,d 6-DMSO)δ10.34(s,1H),8.80(d,J＝4.5Hz,1H),8.57(d,J＝12.0Hz,1H),8.07(dd,J＝9.0,6.0Hz,1H),7.65–7.58(m,3H),7.52(d,J＝4.5Hz,1H),7.32(d,J＝9.0Hz,2H),5.49(s,1H),2.45–2.41(m,1H),2.30–2.17(m,2H),2.07(d,J＝13.5Hz,1H),1.93(d,J＝13.5Hz,1H),1.76–1.66(m,3H),1.16–1.11(m,1H),0.95–0.88(m,2H).
实施例105
N-(4-chlorophenyl)-6-(6-fluoro-7-methoxyquinolin-4-yl)spiro[2.5] octane-1-carboxamide
Figure PCTCN2018124110-appb-000121
化合物105的合成从实施例102中的中间体102e出发，经由以下步骤制备：
Figure PCTCN2018124110-appb-000122
将化合物102e(50mg,0.09mmol)溶于甲醇(2mL)中，在氮气氛围下依次加入碘化亚铜(2mg,0.01mmol)，邻菲啰啉(4mg,0.02mmol)，碳酸铯(59mg,0.18mmol)。反应液加热至100℃搅拌过夜。向反应液中加入水淬灭，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。残留物用反向制备色谱提纯得到化合物105(15.90mg)，白色固体，收率40％。MS(ESI):m/z 439.5(M+H) +. 1H NMR(500MHz,d 6-DMSO)δ10.38(s,1H),8.72(d,J＝4.5Hz,1H),8.04(d,J＝13.0Hz,1H),7.65(d,J＝8.5Hz,2H),7.56(d,J＝9.0Hz,1H),7.34(d,J＝8.5Hz,2H),7.21(d,J＝4.5Hz,1H),3.99(s,3H),3.43–3.38(m,1H),2.22–2.14(m,1H),1.98–1.82(m,4H),1.78–1.69(m,2H),1.34–1.24(m,1H),1.16–1.06(m,2H),0.93(dd,J＝7.5,4.0Hz,1H).
实施例106
N-(4-chlorophenyl)-6-(6-fluoroquinolin-4-yl)-1-methylspiro[2.5]octane-1-carboxamide
Figure PCTCN2018124110-appb-000123
化合物106的合成从实施例1中的中间体1e出发，经由以下步骤制备：
Figure PCTCN2018124110-appb-000124
第一步：将NaH(986mg,24.6mmol)溶于超干四氢呋喃(25mL)中，在0℃冰浴下滴加化合物三乙基2-膦酰基丙酯(5.9g,24.6mmol)，混合物在0℃下搅拌30分钟。将化合物1e(2.0g,8.2mmol)的超干四氢呋喃(10mL)溶液滴加到反应液中。反应在室温下搅拌反应2小时后，用饱和氯化铵溶液淬灭，用50mL乙酸乙酯萃取三次，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化合物106a(2.5g)，白色固体，收率93％。MS(ESI):m/z 328.3(M+H) +. 1H NMR(500MHz,CDCl 3)δ8.81(d,J＝4.5Hz,1H),8.26–8.18(m,1H),7.74(dd,J＝10.5,2.5Hz,1H),7.56–7.48(m,1H),7.31(d,J＝4.5Hz,1H),4.23(q,J＝7.0Hz,2H),3.50–3.40(m,1H),3.32–3.25(m,1H),2.94–2.87(m,1H),2.24–2.10(m,4H),1.94(s,3H),1.78–1.65(m, 2H),1.33(t,J＝7.0Hz,3H).
第二步：将NaH(734mg,18.36mmol)加入二甲基亚砜(20mL)中，向该悬浊液中加入三甲基碘化亚砜(4.04g,18.36mmol)。混合物在室温下搅拌1.5小时。然后将化合物106a(1.5g,4.59mmol)的二甲基亚砜(10mL)溶液加入到反应液中。反应在70℃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化合物106b(726mg)，浅黄色固体，收率46％。MS(ESI):m/z 342.4(M+H) +. 1H NMR(500MHz,CDCl 3)δ8.82(d,J＝4.5Hz,1H),8.15(dd,J＝9.0,6.0Hz,1H),7.70(dd,J＝10.5,2.5Hz,1H),7.51–7.46(m,1H),7.31(d,J＝4.5Hz,1H),4.18(q,J＝7.0Hz,2H),3.30–3.23(m,1H),2.06–1.97(m,2H),1.96–1.87(m,2H),1.80–1.74(m,1H),1.70–1.62(m,2H),1.54–1.47(m,1H),1.46(s,3H),1.44(d,J＝5.0Hz,1H),1.28(t,J＝7.0Hz,3H),0.56(d,J＝5.0Hz,1H).
第三步：将化合物106b(250mg,0.73mmol)溶无水乙醇(10mL)中，加入40％氢氧化钠水溶液(365mg,3.65mmol)。反应混合物在90℃下搅拌5小时。待反应液冷却至室温，用6.0mol/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化合物106c(103mg)，白色固体，收率45％。MS(ESI):m/z 314.4(M+H) +. 1H NMR(500MHz,d 6-DMSO)δ12.19(s,1H),8.83(d,J＝4.5Hz,1H),8.09(dd,J＝9.0,6.0Hz,1H),8.03(dd,J＝11.0,3.0Hz,1H),7.70–7.65(m,1H),7.37(d,J＝4.5Hz,1H),3.49–3.42(m,1H),2.08–2.00(m,1H),2.00–1.88(m,2H),1.80(d,J＝13.0Hz,1H),1.75–1.68(m,1H),1.64–1.55(m,2H),1.46–1.40(m,1H),1.39(s,3H),1.20(d,J＝4.0Hz,1H),0.55(d,J＝4.0Hz,1H).
第四步：将化合物106c(50mg,0.16mmol)溶于无水二氯甲烷(5mL)中，加入二氯亚砜(2.5mL)，反应混合物回流搅拌2小时。蒸去反应溶剂，残留物用无水二氯甲烷重蒸两次。将得到的淡黄色固体溶于无水四氢呋喃(5mL)中，加入4-氯苯胺(41mg,0.32mmol)，在冰水浴条件下滴加三乙胺(48mg,0.48mmol)。反应混合物在冰水浴下搅拌30分钟，升至室温继续搅拌2小时。加水淬灭反 应，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。残留物用反向制备色谱提纯得到化合物106(40.24mg)，白色固体，收率60％。MS(ESI):m/z 423.4(M+H) +. 1H NMR(500MHz,d 6-DMSO)δ9.69(s,1H),8.87(s,1H),8.11–8.06(m,1H),8.03(d,J＝11.0Hz,1H),7.70–7.64(m,3H),7.55(s,1H),7.35(d,J＝7.5Hz,2H),3.45–3.38(m,1H),2.06–1.82(m,4H),1.72–1.67(m,1H),1.64–1.60(m,1H),1.54(s,3H),1.38–1.33(m,1H),1.32–1.28(m,1H),0.96–0.88(m,1H),0.48–0.43(m,1H).
实施例107
N-(4-chlorophenyl)-1-cyano-6-(6-fluoroquinolin-4-yl)spiro[2.5]octane-1-carboxamide
Figure PCTCN2018124110-appb-000125
化合物107的合成从实施例1中的中间体1e出发，经由以下步骤制备：
Figure PCTCN2018124110-appb-000126
第一步：将化合物1e(1.5g,6.17mmol)溶于甲苯(30mL)中，依次加入氰基乙酸乙酯(1.05g,9.25mmol)，哌啶(105mg,1.23mmol)，乙酸(74mg,1.23mmol)，混合物在120℃下搅拌1小时。 旋干甲苯，加入100mL水，用二氯甲烷萃取水相。合并有机相，用无水硫酸钠干燥，过滤，浓缩。残留物用快速过柱机分离得到化合物107a(1.8g)，黄色固体，收率86％。MS(ESI):m/z 339.4(M+H) +. 1H NMR(500MHz,CDCl 3)δ8.83(d,J＝4.5Hz,1H),8.16(dd,J＝9.0,6.0Hz,1H),7.70(dd,J＝10.5,3.0Hz,1H),7.52(ddd,J＝10.5,9.0,3.0Hz,1H),7.26(d,J＝4.5Hz,1H),4.32(q,J＝7.0Hz,2H),4.27–4.21(m,1H),3.56(tt,J＝12.0,3.0Hz,1H),3.36–3.30(m,1H),2.64(td,J＝14.0,4.5Hz,1H),2.42–2.27(m,3H),1.93–1.84(m,1H),1.84–1.75(m,1H),1.38(t,J＝7.0Hz,3H).
第二步：将化合物107a(1.8g,5.33mmol)溶于乙腈(30mL)中，依次加入硝基甲烷(486mg,7.98mmol)，DBU(972mg,6.38mmol)混合物在25℃下搅拌过夜。旋干乙腈，加入100mL水，用二氯甲烷萃取水相。合并有机相，用无水硫酸钠干燥，过滤，浓缩。残留物用快速过柱机分离得到化合物107b(1.5g)，黄色固体，收率80％。MS(ESI):m/z 353.4(M+H) +. 1H NMR(500MHz,d 6-DMSO)δ9.06(d,J＝4.5Hz,1H),8.38–8.29(m,2H),7.98–7.90(m,1H),7.71(d,J＝4.5Hz,1H),4.27(q,J＝7.0Hz,2H),3.78–3.70(m,1H),2.46–2.36(m,1H),2.22–2.13(m,1H),2.11–2.04(m,1H),1.96–1.89(m,1H),1.88–1.77(m,3H),1.76–1.66(m,1H),1.65–1.58(m,1H),1.34–1.29(m,1H),1.27(t,J＝7.0Hz,3H).
第三步：将化合物107b(100mg,0.28mmol)溶于乙醇(20mL)中，加入2mol/L的LiOH水溶液(10mL)，混合物在25℃下搅拌 4小时。旋干乙醇，用4mol/L的HCl水溶液(10mL)调节pH至4～5，浓缩。残留物用制备薄层层析分离得到化合物107c(50mg)，白色固体，收率54％。MS(ESI):m/z 325.5(M+H) +.
第四步：将化合物107c(50mg,0.15mmol)溶于四氢呋喃(5mL)中，依次加入吡啶(36mg,0.45mmol)和三丙基磷酸酐(50％wt in EA,146mg,0.23mmol)，在室温下搅拌10分钟。然后加入4-氯苯胺(57mg,0.45mmol)，继续在室温下搅拌反应过夜。向反应液中加入20mL水稀释，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。残留物用反向制备色谱提纯得到化合物107(4.34mg)，白色固体，收率7％。MS(ESI):m/z 434.3(M+H) +. 1H NMR(500MHz,d 6-DMSO)δ10.85(s,1H),8.91(d,J＝4.5Hz,1H),8.12–8.07(m,2H),7.71–7.63(m,4H),7.41(d,J＝9.0Hz,2H),3.56–3.49(m,1H),2.39–2.32(m,1H),2.18–2.06(m,2H),1.97–1.91(m,2H),1.79–1.73(m,1H),1.63–1.58(m,2H),1.57–1.51(m,1H),1.44–1.38(m,1H).
实施例108
(1S)-N-(4-chlorophenyl)-6-(6-fluoro-7-methoxyquinolin-4-yl)spiro[2.5]octane-1-carboxamide
Figure PCTCN2018124110-appb-000127
实施例109
(1R)-N-(4-chlorophenyl)-6-(6-fluoro-7-methoxyquinolin-4-yl)spiro[2.5]octane-1-carboxamide
Figure PCTCN2018124110-appb-000128
化合物108和化合物109由实施例105中化合物105经过手性柱拆分得到，绝对构型未确定。
化合物108：MS(ESI):m/z 439.5(M+H) +. 1H NMR(500MHz,d 6-DMSO)δ10.38(s,1H),8.72(d,J＝4.5Hz,1H),8.04(d,J＝13.0Hz,1H),7.65(d,J＝8.5Hz,2H),7.56(d,J＝9.0Hz,1H),7.34(d,J＝8.5Hz,2H),7.21(d,J＝4.5Hz,1H),3.99(s,3H),3.43–3.38(m,1H),2.22–2.14(m,1H),1.98–1.82(m,4H),1.78–1.69(m,2H),1.34–1.24(m,1H),1.16–1.06(m,2H),0.93(dd,J＝7.5,4.0Hz,1H).
化合物109：MS(ESI):m/z 439.5(M+H) +. 1H NMR(500MHz,d 6-DMSO)δ10.38(s,1H),8.72(d,J＝4.5Hz,1H),8.04(d,J＝13.0Hz,1H),7.65(d,J＝8.5Hz,2H),7.56(d,J＝9.0Hz,1H),7.34(d,J＝8.5Hz,2H),7.21(d,J＝4.5Hz,1H),3.99(s,3H),3.43–3.38(m,1H),2.22–2.14(m,1H),1.98–1.82(m,4H),1.78–1.69(m,2H),1.34–1.24(m,1H),1.16–1.06(m,2H),0.93(dd,J＝7.5,4.0Hz,1H).
实施例110
6-([1,3]dioxolo[4,5-g]quinolin-8-yl)-N-(4-chlorophenyl)spiro[2.5]octane-1-carboxamide
Figure PCTCN2018124110-appb-000129
化合物110的合成从实施例103中的中间体103a出发，经由以下步骤制备：
Figure PCTCN2018124110-appb-000130
第一步：将化合物103a(1.0g,5.13mmol)溶于N,N-二甲基甲酰胺(20mL)中，依次加入氯溴甲烷(986mg,7.70mmol)，碳酸铯(2.51g,7.70mmol)。混合物加热至110℃反应2小时。冷却至室温，向反应液中加入水淬灭，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。残留物用快速过柱机分离得到化合物110a(480mg)，白色固体，收率45％。MS(ESI):m/z 208.4(M+H) +.
第二步：将化合物硼酸酯(741mg,2.78mmol)溶于二氧六环/水(40mL/10mL)中，依次加入化合物110a(480mg,2.32mmol)，碳酸钾(960mg,6.96mmol)，Pd 2(dba) 3(106mg,0.116mmol)和PCy 3(78mg,0.28mmol)。反应混合物在氮气氛下回流反应过夜。然后浓缩反应液，用乙酸乙酯萃取，有机相浓缩之后用快速过柱机分离得到化合物110b(540mg)，白色固体，收率75％。MS(ESI):m/z312.5(M+H) +.
第三步：将化合物110b(500mg,1.61mmol)溶于异丙醇(25mL)中，加入10％钯碳(70mg)。反应混合物在氢气氛下加热至55℃反应过夜。然后用硅藻土滤除钯碳，滤液浓缩得到粗品化合物110c(500mg)，白色固体，收率99％。直接用于下一步反应。MS(ESI): m/z 314.4(M+H) +.
第四步：将化合物110c(500mg,1.60mmol)溶于丙酮(36mL)中，加入4mol/L盐酸(9mL,36mmol)。反应混合物加热至45℃反应过夜。然后蒸除溶剂，水溶液用6mol/L氢氧化钠中和至pH＝9，用乙酸乙酯萃取水相。有机相合并后用饱和食盐水洗，无水硫酸钠干燥，过滤，浓缩。残留物用快速过柱机分离得到化合物110d(255mg)，白色固体，收率59％。MS(ESI):m/z 270.5(M+H) +.
第五步：将膦酰基乙酸三乙酯(235mg,1.05mmol)溶于超干四氢呋喃(10mL)中，在0℃冰浴下加入叔丁醇钠(101mg,1.05mmol)。10分钟后，将化合物110d(255mg,0.95mmol)的四氢呋喃(4mL)溶液加入反应液中。反应2小时后，用水淬灭。水溶液用乙酸乙酯萃取三次，合并有机相，用饱和食盐水洗，无水硫酸钠干燥，过滤，浓缩。残留物用快速过柱机分离得到化合物110e(210mg)，白色固体，收率65％。MS(ESI):m/z 340.5(M+H) +.
第六步：将NaH(35mg,0.87mmol)加入二甲基亚砜(10mL)中，向该悬浊液中加入三甲基碘化亚砜(191mg,0.87mmol)。混合物在室温下搅拌1.5小时。然后将化合物110e(100mg,0.29mmol)的二甲基亚砜(5mL)溶液加入到反应液中。反应在40℃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化合物110f(78mg)，白色固体，收率76％。MS(ESI):m/z 354.5(M+H) +.
第七步：将4-氯苯胺(86mg,0.68mmol)溶于5mL四氢呋喃中，在0℃冰浴下加入2.0mol/L异丙基氯化镁的四氢呋喃溶液(0.4mL,0.68mmol)。混合物在室温下搅拌5分钟，将化合物110f(60mg,0.17mmol)的四氢呋喃(2mL)溶液加入该混合物中。反应液在室温下搅拌过夜，然后用饱和氯化铵溶液淬灭，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。残留物用反向制备色谱提纯得到化合物110(10.28mg)，白色固体，收率14％。MS(ESI):m/z 435.5(M+H) +. 1H NMR(500MHz,d 6-DMSO)δ10.36(s,1H),8.56(d,J＝4.5Hz,1H),7.65(d,J＝9.0Hz,2H),7.58(s,1H),7.37(s,1H),7.34(d,J＝9.0Hz,2H),7.11(d,J＝4.5Hz,1H),5.02(s,2H),3.36–3.32(m,1H),2.21–2.12(m,1H),1.97–1.85(m,4H),1.78–1.68 (m,2H),1.32–1.24(m,1H),1.17–1.06(m,2H),0.91(dd,J＝7.5,4.0Hz,1H).
实施例111
Methyl
2-(4-(6-(6-fluoro-7-methylquinolin-4-yl)spiro[2.5]octane-1-carboxamido)phenoxy)acetate
Figure PCTCN2018124110-appb-000131
化合物111的合成从实施例94中的中间体94a出发，经由以下步骤制备：
Figure PCTCN2018124110-appb-000132
第一步：将化合物94b(1.0g,4.78mmol)和溴乙酸甲酯(1.46g,9.56mmol)溶于丙酮(15mL)中，然后向其中加入碳酸钾(1.98g,14.34mmol)，将反应液加热到60℃搅拌2小时。过滤浓缩，残留物用快速过柱机分离得到化合物111a(822mg)，白色固体，收率61％。 1H NMR(500MHz,CDCl 3)δ7.27(d,J＝9.0Hz,2H),6.85(d,J＝9.0Hz,2H),6.36(s,1H),4.60(s,2H),3.80(s,3H),1.51(s,9H).
第二步：将化合物111a(822mg,2.92mmol)溶于二氯甲烷(3mL)中，在0℃冰浴下加入4mol/L盐酸二氧六环溶液(6mL)。室温 下反应2小时，过滤析出的固体，干燥得到化合物111b(550mg)，白色固体，收率86％。直接用于下一步反应。
第三步：将化合物94a(53mg,0.17mmol)溶于无水二氯甲烷(2mL)中，加入二氯亚砜(5mL)，反应混合物回流搅拌2小时。蒸去反应溶剂，减压干燥残留物得到淡黄色固体。将该固体溶于无水二氯甲烷(3mL)中，在冰水浴条件下加入化合物111b(30mg,0.17mmol)的二氯甲烷(2mL)溶液，加入三乙胺(52mg,0.51mmol)，在冰水浴下搅拌10分钟，升至室温继续搅拌2小时。加水淬灭反应，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。残留物用反向制备色谱提纯得到化合物111(32.56mg)，白色固体，收率40％。MS(ESI):m/z 477.5(M+H) +. 1H NMR(500MHz,d 6-DMSO)δ10.13(s,1H),8.75(d,J＝4.5Hz,1H),7.98–7.92(m,2H),7.50(d,J＝9.0Hz,2H),7.29(d,J＝4.5Hz,1H),6.87(d,J＝9.0Hz,2H),4.74(s,2H),3.69(s,3H),3.48–3.39(m,1H),2.45(s,3H),2.19(td,J＝13.0,3.5Hz,1H),2.00–1.84(m,4H),1.77(d,J＝12.0Hz,1H),1.69(dd,J＝7.5,5.0Hz,1H),1.39–1.28(m,1H),1.14–1.06(m,2H),0.88(dd,J＝7.5,4.0Hz,1H).
实施例112
6-(6-fluoro-7-methylquinolin-4-yl)-N-(4-(2-hydroxyethoxy)phenyl)spiro[2.5]octane-1-carboxamide
Figure PCTCN2018124110-appb-000133
化合物112的合成从实施例94中的中间体94a出发，经由以下步骤制备：
Figure PCTCN2018124110-appb-000134
第一步：将化合物94b(5.0g,23.90mmol)溶于N,N-二甲基甲酰胺(50mL)中，加入(2-溴乙氧基)-叔丁基二甲基硅烷(6.86g,28.68mmol)和碳酸钾(5.0g,23.90mmol)。反应混合物加热至80℃搅拌过夜。TLC检测反应结束，加入200mL水，水溶液用100mL乙酸乙酯萃取三次，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化合物112a(8.0g)，白色固体，收率91％。 1H NMR(500MHz,CDCl 3)δ7.24(d,J＝9.0Hz,2H),6.84(d,J＝9.0Hz,2H),6.34(s,1H),4.02–3.98(m,2H),3.96–3.93(m,2H),1.51(s,9H),0.90(s,9H),0.09(s,6H).
第二步：将化合物112a(300mg,0.82mmol)溶于二氯甲烷(2mL)中，在0℃冰浴下加入三氟乙酸/二氯甲烷(v/v＝1:1,10mL)混合溶液，在室温下搅拌过夜。浓缩反应液，得到化合物112b(70mg)，黄色油状液体，收率56％。直接用于下一步反应。 1H NMR(500MHz,CDCl 3)δ6.77(d,J＝8.5Hz,2H),6.65(d,J＝8.5Hz,2H),4.03–3.99(m,2H),3.94–3.89(m,2H).
第三步：将化合物94a(85mg,0.27mmol)溶于N,N-二甲基甲酰胺(5mL)中，加入二异丙基乙胺(138mg,1.07mmol)和HATU(122mg,0.32mmol)，反应混合物在室温下搅拌30分钟。再向反应液中加入化合物112b(60mg,0.39mmol)，反应混合物在40℃下搅拌2小时。LCMS检测反应结束，用水(20mL)淬灭反应，水溶液用乙酸乙酯(20mLx3)萃取，合并有机相，用饱和食盐水(20mL)洗，无水硫酸钠干燥，过滤，浓缩。残留物用反向制备色谱提纯得到化合物112(69.60mg)，白色固体，收率58％。MS(ESI):m/z 449.5(M+H) +. 1H NMR(500MHz,d 6-DMSO)δ10.08(s,1H),8.76(d,J＝ 4.5Hz,1H),7.99–7.91(m,2H),7.50(d,J＝9.0Hz,2H),7.29(d,J＝4.5Hz,1H),6.87(d,J＝9.0Hz,2H),4.85(br,1H),3.93(t,J＝5.0Hz,2H),3.72–3.66(m,2H),3.45–3.37(m,1H),2.45(s,3H),2.22–2.14(m,1H),1.98–1.83(m,4H),1.76(d,J＝11.5Hz,1H),1.70–1.65(m,1H),1.38–1.27(m,1H),1.14–1.05(m,2H),0.88(dd,J＝7.5,4.0Hz,1H).
实施例113
6-(6,7-dimethoxyquinolin-4-yl)-N-(4-(2-methoxyethoxy)phenyl)spiro[2.5]octane-1-carboxamide
Figure PCTCN2018124110-appb-000135
化合物113的合成从实施例101中的中间体101e出发，经由以下步骤制备：
Figure PCTCN2018124110-appb-000136
第一步：将化合物101e(200mg,0.54mmol)溶于乙醇(10mL)中，加入2.0mol/L氢氧化钠溶液(4mL)。反应液加热至50℃，反应2小时。待反应液冷却至室温，用4.0mol/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化合物113a(130mg)，白色固体，产率71％。MS(ESI):m/z 342.5(M+H) +.
第二步：将化合物113a(58mg,0.17mmol)溶于无水二氯甲烷(2mL)中，加入二氯亚砜(5mL)，反应混合物回流搅拌2小时。蒸去反应溶剂，减压干燥残留物得到淡黄色的固体。将该固体溶于无水二氯甲烷(3mL)中，在冰水浴条件下加入化合物94d(30mg, 0.17mmol)的二氯甲烷(2mL)溶液，加入三乙胺(52mg,0.51mmol)，在冰水浴下搅拌10分钟，升至室温继续搅拌2小时。加水淬灭反应，用二氯甲烷萃取水相。合并有机相，用无水硫酸钠干燥，过滤，浓缩。残留物用反向制备色谱提纯得到化合物113(40.86mg)，白色固体，收率49％。MS(ESI):m/z 491.5(M+H) +. 1H NMR(500MHz,d 6-DMSO)δ10.08(s,1H),8.58(d,J＝4.5Hz,1H),7.49(d,J＝9.0Hz,2H),7.40(s,1H),7.34(d,J＝4.5Hz,1H),7.14(s,1H),6.87(d,J＝9.0Hz,2H),3.94(s,3H),3.91(s,3H),4.03(t,J＝4.5Hz,2H),3.63(t,J＝4.5Hz,2H),3.44–3.37(m,1H),3.29(s,3H),2.22–2.14(m,1H),1.99–1.85(m,4H),1.76(d,J＝12.0Hz,1H),1.70–1.65(m,1H),1.37–1.28(m,1H),1.14–1.06(m,2H),0.88(dd,J＝7.5,4.0Hz,1H).
实施例114
N-(4-chlorophenyl)-6-(6-fluoro-7-(hydroxymethyl)quinolin-4-yl)spiro[2.5]octane-1-carboxamide
Figure PCTCN2018124110-appb-000137
化合物114的合成从实施例102中的化合物102出发，经由以下步骤制备：
Figure PCTCN2018124110-appb-000138
第一步：将化合物102(200mg,0.46mmol)溶于二甲基亚砜/水(5mL/1mL)的混合溶剂中，加入氢氧化锂(200mg,0.54mmol)。反应混合物在50℃搅拌3小时。用水稀释反应液，用乙酸乙酯萃取2次，弃去有机相。水相用2.0mol/L盐酸溶液调至pH＝5～6，再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114a(120mg)，白色固体，产率58％。MS(ESI):m/z 453.5(M+H) +. 1H NMR(500MHz,d 6-DMSO)δ10.38(s,1H),8.80(d,J＝4.5Hz,1H),8.26(d,J＝7.5Hz,1H),7.96(d,J＝12.0Hz,1H),7.65(d,J＝9.0Hz,2H),7.38–7.31(m,3H),3.48–3.39(m,1H),2.23–2.16(m,1H),1.96–1.84(m,4H),1.77(d,J＝11.0Hz,1H),1.74–1.69(m,1H),1.35–1.27(m,1H),1.17–1.07(m,2H),0.92(dd,J＝7.5,4.0Hz,1H).
第二步：将化合物114a(60mg,0.13mmol)溶于四氢呋喃(5mL)中，加入二异丙基乙胺(34mg,0.26mmol)，再加入碘甲烷(28mg,0.20mmol)。反应在室温下搅拌2小时。加水淬灭反应，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。残留物用薄层层析分离得到化合物114b(40mg)，白色固体，产率66％。MS(ESI):m/z 467.5(M+H) +.
第三步：将化合物114b(40mg,0.09mmol)溶于四氢呋喃(5mL)中，冰水浴冷却至0℃，加入氢化铝锂(7mg,0.18mmol)。反应缓慢升至室温搅拌2小时。加水淬灭反应，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。残留物用反向制备色谱提纯得到化合物114(13.74mg)，白色固体，收率35％。MS(ESI): m/z 439.5(M+H) +. 1H NMR(500MHz,d 6-DMSO)δ10.37(s,1H),8.78(d,J＝4.5Hz,1H),8.07(d,J＝7.5Hz,1H),7.97(d,J＝12.5Hz,1H),7.65(d,J＝9.0Hz,2H),7.34(d,J＝9.0Hz,2H),7.31(d,J＝4.5Hz,1H),5.51(t,J＝5.5Hz,1H),4.74(d,J＝5.0Hz,2H),3.46–3.38(m,1H),2.23–2.15(m,1H),1.98–1.83(m,4H),1.77(d,J＝11.5Hz,1H),1.74–1.69(m,1H),1.34–1.25(m,1H),1.17–1.13(m,1H),1.10(d,J＝13.0Hz,1H),0.93(dd,J＝7.5,4.0Hz,1H).
实施例115
N-(4-chlorophenyl)-6-(6-fluoro-7-(methoxymethyl)quinolin-4-yl)spiro[2.5]octane-1-carboxamide
Figure PCTCN2018124110-appb-000139
化合物115的合成从实施例1中的中间体1d出发，经由以下步骤制备：
Figure PCTCN2018124110-appb-000140
第一步：在-78℃氮气保护条件下，将正丁基锂(2.5M in hexane,4.2mL,10.46mmol)滴加到2,2,6,6-四甲基哌啶(1.47g,10.46mmol)的四氢呋喃(50mL)溶液中。再向其中滴加化合物1d(2.0g,6.97mmol)的四氢呋喃(20mL)溶液。反应在-78℃下搅拌2小时。然后向反应液中滴加超干N,N-二甲基甲酰胺(1.02g,13.94mmol)的四氢呋喃(10mL)溶液，反应维持在-78℃半小时后升至室温，继续搅拌2小时。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。残留物用快速过柱机分离得到化合物115a(1.8g)，白色固体，收率82％。MS(ESI):m/z 316.5(M+H) +.
第二步：将化合物115a(1.0g,3.17mmol)溶于乙醇(10mL)中，冰水浴冷却至0℃，加入硼氢化钠(241mg,6.35mmol)。反应缓慢升至室温搅拌1小时。加水淬灭反应，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。残留物用快速过柱机分离得到化合物115b(980mg)，白色固体，收率97％。MS(ESI):m/z318.5(M+H) +.
第三步：将化合物115b(980mg,3.09mmol)溶于超干N,N-二甲基甲酰胺(10mL)中，冰水浴冷却至0℃，加入氢化钠(247mg,6.18mmol)，在0℃下搅拌30分钟。然后再加入碘甲烷(527mg,3.71mmol)。反应升至室温下搅拌3小时。加水淬灭反应，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。残留物用快速过柱机分离得到化合物115c(760mg)，白色固体，产率74％。MS(ESI):m/z 332.5(M+H) +.
第四步：将化合物115c(760mg,2.30mmol)溶于四氢呋喃(20mL)中，加入4.0mol/L盐酸(6mL,24mmol)。反应混合物在室温下搅拌5小时。然后蒸除溶剂，水溶液用6.0mol/L氢氧化钠中和至pH＝9，用乙酸乙酯萃取水相。有机相合并后用饱和食盐水洗，无水硫酸钠干燥，过滤，浓缩。残留物用快速过柱机分离得到化合物115d(423mg)，白色固体，收率64％。MS(ESI):m/z 288.4(M+H) +.
第五步：将膦酰基乙酸三乙酯(345mg,1.54mmol)溶于超干四氢呋喃(15mL)中，在0℃冰浴下加入叔丁醇钠(148mg,1.54mmol)。10分钟后，将化合物115d(423mg,1.47mmol)的四氢呋喃(5mL) 溶液加入反应液中。反应2小时后，用水淬灭。水溶液用乙酸乙酯萃取三次，合并有机相，用饱和食盐水洗，无水硫酸钠干燥，过滤，浓缩。残留物用快速过柱机分离得到化合物115e(500mg)，白色固体，收率95％。MS(ESI):m/z 358.4(M+H) +.
第六步：将NaH(67mg,1.68mmol)加入二甲基亚砜(15mL)中，向该悬浊液中加入三甲基碘化亚砜(370mg,1.68mmol)。混合物在室温下搅拌1.5小时。然后将化合物115e(200mg,0.56mmol)的二甲基亚砜(5mL)溶液加入到反应液中。反应在40℃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化合物115f(145mg)，白色固体，收率70％。MS(ESI):m/z 372.4(M+H) +.
第七步：将4-氯苯胺(66mg,0.52mmol)溶于四氢呋喃(5mL)中，在0℃冰浴下加入异丙基氯化镁的四氢呋喃溶液(2.0mol/L in THF,0.3mL,0.52mmol)。混合物在室温下搅拌5分钟，将化合物115f(50mg,0.13mmol)的四氢呋喃(2mL)溶液加入该混合物中。反应液在室温下搅拌过夜，然后用饱和氯化铵溶液淬灭，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。残留物用反向制备色谱提纯得到化合物115(15.06mg)，白色固体，收率26％。MS(ESI):m/z 453.4(M+H) +. 1H NMR(500MHz,d 6-DMSO)δ10.38(s,1H),8.77(d,J＝4.5Hz,1H),8.07(d,J＝7.5Hz,1H),7.97(d,J＝12.5Hz,1H),7.65(d,J＝9.0Hz,2H),7.34(d,J＝9.0Hz,2H),7.31(d,J＝4.5Hz,1H),4.72(s,2H),3.46–3.38(m,1H),3.28(s,3H),2.23–2.15(m,1H),1.98–1.83(m,4H),1.77(d,J＝11.5Hz,1H),1.74–1.69(m,1H),1.34–1.25(m,1H),1.17–1.13(m,1H),1.10(d,J＝13.0Hz,1H),0.93(dd,J＝7.5,4.0Hz,1H).
本发明的化合物在Hela细胞中的活性研究
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200ul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％CO 2培养箱中培养48小时后，吸取140ul细胞培养上清与15ul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IC 50值。
化合物 IC 50
化合物1 A
化合物2 B
化合物3 C
化合物4 C
化合物5 C
化合物6 B
化合物7 B
化合物8 B
化合物9 A
化合物10a A
化合物10b C
化合物11 A
化合物12 B
化合物13 B
化合物14 A
化合物15 A
化合物16 A
化合物17 A
化合物18 A
化合物19 A
化合物24 C
化合物50 B
化合物51 B
化合物52 B
化合物53 B
化合物54 B
化合物55 B
化合物80 A
化合物81 A
化合物82 A
化合物83 A
化合物84 A
化合物85 A
化合物86 A
化合物87 C
化合物88 C
化合物89 C
化合物90 C
化合物91 C
化合物92 A
化合物93 C
化合物94 A
化合物95 A
化合物96 B
化合物97 C
化合物98 A
化合物99 C
化合物100 A
化合物101 A
化合物102 A
化合物103 C
化合物104 C
化合物105 B
化合物106 C
化合物107 C
化合物108 A
化合物109 C
化合物110 B
化合物111 C
化合物112 B
化合物113 A
化合物114 A
化合物115 A
注：A:IC 50＝0.1nM～10nM；B:IC 50＝10nM～100nM；C:IC 50>100nM。
本发明的化合物在高表达人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200ul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140ul细胞培养上清与15ul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IC 50值。
化合物 IC 50(HEK293细胞)
化合物1 B
化合物2 B
化合物3 C
化合物4 C
化合物5 B
化合物6 B
化合物7 B
化合物8 B
化合物9 A
化合物10a A
化合物10b C
化合物11 B
化合物12 B
化合物13 B
化合物92 A
化合物93 C
化合物94 B
化合物95 B
化合物96 C
化合物97 C
化合物98 A
化合物99 C
化合物100 B
化合物101 B
化合物102 B
化合物103 C
化合物104 C
化合物105 A
化合物106 C
化合物107 C
化合物108 A
化合物109 C
化合物110 C
化合物111 C
化合物112 C
化合物113 B
化合物114 B
化合物115 B
注：A:IC 50＝0.1nM～10nM；B:IC 50＝10nM～100nM；C:IC 50>100nM。

Claims (21)

  1. 一种如式(I)所示的化合物，
    Figure PCTCN2018124110-appb-100001
    其中
    Figure PCTCN2018124110-appb-100002
    表示：——、
    Figure PCTCN2018124110-appb-100003
    或者
    Figure PCTCN2018124110-appb-100004
    A表示-C(O)-、-S(O) 2-或者-S(O)-；
    其中，每个R 1各自独立地选自氢原子、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 1-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R 1相互环合形成3-8元环，该环中含有0-3个杂原子；
    Cy 1选自被任意取代基取代的5-15元桥环基、5-15元螺环基、5-15元桥杂环基、或5-15元螺杂环基，所述的取代基为：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；
    其中，每个R a、R b、R 2各自独立地选自氢、C 1-C 6烷基或C 3- 6环烷基；
    Cy 2为含有一个或两个以上的取代基的C 5-C 10芳基、C 5-C 10杂芳基、C 5-C 10环烷基、C 5-C 10杂环烷基；所述的取代基可以选自卤素、羟基、硝基、氰基、磺酸基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-6环烷基、C 1-6烷氧基、卤代C 1-C 6烷基、卤代C 1-C 6烷氧基、C 1-6烷基硫基、C 1-6烷基羰基、C 1-6烷基羰基氧基、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、-S(O)C 1-6烷基；或者当两个取代基相邻时，能够形成3-8元环，该3-8元环可以含有0-3个O、S、N原子；m、n为0-4的整数。
  2. 如权利要求1所述的式(I)结构的化合物，其中：Cy 1选自被取代基取代的8-12元螺环基或8-12元螺环基、8-12元桥杂环基、或8-12元螺杂环基，所述的取代基为：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。
  3. 如权利要求1或2所述的式(I)结构的化合物，其中：Cy 1选自
    Figure PCTCN2018124110-appb-100005
    Figure PCTCN2018124110-appb-100006
    Figure PCTCN2018124110-appb-100007
    上述基团可以被选自卤素、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取代。
  4. 如权利要求1或2所述的式(I)结构的化合物，其中：Cy 1选自
    Figure PCTCN2018124110-appb-100008
    Figure PCTCN2018124110-appb-100009
    Figure PCTCN2018124110-appb-100010
    上述基团可以被选自卤素、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取代。
  5. 一种如式(II)所示的化合物，
    Figure PCTCN2018124110-appb-100011
    其中，A、R 1、R 2、R a、R b、Cy 2、m、n如式权利要求1所定义；X选自(CR cR d) o，其中任意地CR cR d可以被O或NR e所替代；Y选自CR f或N；其中R c、R d、R e、R f分别各自独立地选自氢或者C 1-6烷基；o选自0-5的整数。
  6. 一种如式(III)所示的化合物，
    Figure PCTCN2018124110-appb-100012
    其中，W，Q选自CR cR d,NR e,或O；A、R 1、R 2、R a、R b、R c、R d、R e、Cy 2、m、n、Y如权利要求5所定义。
  7. 一种如式(IV)所示的化合物，
    Figure PCTCN2018124110-appb-100013
    其中，R 1、R 2、R a、R b、Cy 2、m、n、X、Y、A如权利要求5所定义；Z选自(CR g) p，其中任意的CR g可以被N所替代；R g分别各自独立地选自氢或者C 1-6烷基；p选自0-5的整数。
  8. 一种如式(V)所示的化合物，
    Figure PCTCN2018124110-appb-100014
    其中，R 1、R 2、R c、R d、R f、Cy 2、m、A如上述权利要求5所定义。
  9. 一种如式(VI)所示的化合物，
    Figure PCTCN2018124110-appb-100015
    其中R 1、R 2、R c、R d、Cy 2、m、A如权利要求5所定义。
  10. 一种如式(VII)所示的化合物，
    Figure PCTCN2018124110-appb-100016
    其中R 1、R 2、R e、R f、Cy 2、m、A如权利要求5所定义。
  11. 一种如式(VIII)所示的化合物，
    Figure PCTCN2018124110-appb-100017
    其中R 1、R 2、R c、R d、R f、Cy 2、m、A如权利要求5所定义。
  12. 一种如式(IX)所示的化合物，
    Figure PCTCN2018124110-appb-100018
    其中R 1、R 2、R c、R d、R e、R f、Cy 2、m、A如权利要求5所定义。
  13. 如权利要求要求1-12任一项所述的化合物，其中A为-C(O)-或 -S(O) 2-。
  14. 如权利要求1-5任一项所述的化合物，其具有如下结构：
    Figure PCTCN2018124110-appb-100019
    Figure PCTCN2018124110-appb-100020
    Figure PCTCN2018124110-appb-100021
    Figure PCTCN2018124110-appb-100022
    Figure PCTCN2018124110-appb-100023
    Figure PCTCN2018124110-appb-100024
    Figure PCTCN2018124110-appb-100025
  15. 如权利要求1-14任一项所述的化合物，其中
    Figure PCTCN2018124110-appb-100026
    表示——、
    Figure PCTCN2018124110-appb-100027
    或者
    Figure PCTCN2018124110-appb-100028
    优选为
    Figure PCTCN2018124110-appb-100029
  16. 一种药物组合物，其包含权利要求1至15任意一项所述的化合物，以及药学上可接受的载体。
  17. 如权利要求16所述的药物组合物，其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、曲妥珠单抗或它们的任意组合。
  18. 一种如权利要求1-15任一项所述的化合物或者如权利要求16-17任一项所述的药物组合物在制备治疗肿瘤、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。
  19. 如权利要求18所述的用途，其中所述肿瘤或癌症选自皮肤癌、膀胱癌、卵巢癌、乳腺癌、胃癌、胰腺癌、前列腺癌、结肠癌、肺癌、骨癌、脑癌、神经细胞瘤、直肠癌、结肠癌、家族性腺瘤性息肉性癌、遗传性非息肉性结直肠癌、食管癌、唇癌、喉癌、下咽癌、舌癌、唾液腺癌、胃癌、腺癌、甲状腺髓样癌、乳头状甲状腺癌、肾癌、肾实质癌、卵巢癌、宫颈癌、子宫体癌、子宫 内膜癌、绒毛膜癌、胰腺癌、前列腺癌、睾丸癌、泌尿癌、黑素瘤、脑肿瘤诸如成胶质细胞瘤、星形细胞瘤、脑膜瘤、成神经管细胞瘤和外周神经外胚层肿瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、伯基特淋巴瘤、急性淋巴性白血病(ALL)、慢性淋巴性白血病(CLL)、急性骨髓性白血病(AML)、慢性粒细胞白血病(CML)、成人T细胞白血病淋巴瘤、弥漫性大B细胞淋巴瘤(DLBCL)、肝细胞癌、胆囊癌、支气管癌、小细胞肺癌、非小细胞肺癌、多发性骨髓瘤、基底细胞瘤、畸胎瘤、成视网膜细胞瘤、脉络膜黑素瘤、精原细胞瘤、横纹肌肉瘤、颅咽管瘤、骨肉瘤、软骨肉瘤、肌肉瘤、脂肪肉瘤、纤维肉瘤、尤因肉瘤或浆细胞瘤。
  20. 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1-15任一项所述化合物或者权利要求16-17任一项所述的药物组合物。
  21. 一种抑制吲哚胺2,3-双加氧酶的方法，其包括使权利要求1-15任一项所述化合物或者权利要求16-17任一项所述的药物组合物暴露于吲哚胺2,3-双加氧酶。
PCT/CN2018/124110 2017-12-29 2018-12-27 吲哚胺2,3-双加氧酶抑制剂以及它们在医学上的应用 WO2019129114A1 (zh)

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