WO2019144781A1 - 五氟硫烷基取代的酰胺类化合物、其制备方法及其在医药学上的应用 - Google Patents

五氟硫烷基取代的酰胺类化合物、其制备方法及其在医药学上的应用 Download PDF

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WO2019144781A1
WO2019144781A1 PCT/CN2019/000019 CN2019000019W WO2019144781A1 WO 2019144781 A1 WO2019144781 A1 WO 2019144781A1 CN 2019000019 W CN2019000019 W CN 2019000019W WO 2019144781 A1 WO2019144781 A1 WO 2019144781A1
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cancer
alkyl
compound
pharmaceutically acceptable
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PCT/CN2019/000019
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English (en)
French (fr)
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陈向阳
庞育成
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北京诺诚健华医药科技有限公司
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Priority to EP19743196.8A priority Critical patent/EP3747865A4/en
Priority to US16/965,546 priority patent/US11389445B2/en
Priority to JP2020562814A priority patent/JP2021512171A/ja
Publication of WO2019144781A1 publication Critical patent/WO2019144781A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/56—Amides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D215/14—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/18—Halogen atoms or nitro radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/38—Nitrogen atoms
    • C07D215/42—Nitrogen atoms attached in position 4
    • C07D215/46—Nitrogen atoms attached in position 4 with hydrocarbon radicals, substituted by nitrogen atoms, attached to said nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—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 directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to a novel amide compound containing a pentafluorosulfane substituent or a pharmaceutically acceptable salt thereof, which comprises or inhibits the activity of indoleamine 2,3-dioxygenase (IDO)
  • IDO indoleamine 2,3-dioxygenase
  • Pharmaceutical composition of a pharmaceutically acceptable salt thereof, a process for the preparation of the compound or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition of the compound or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable salt thereof Use of the substance in the manufacture of a medicament for the treatment and/or prevention of IDO-mediated related disorders, in particular tumors, and methods of use thereof.
  • Indoleamine 2,3-dioxygenase is a heme-containing monomeric protein widely distributed in tissues other than the liver, catalyzing the oxidative degradation of tryptophan into kynurenine, which is a canine urine.
  • the rate-limiting enzyme of the acid metabolism pathway Tryptophan is an essential amino acid for the proliferation of T cells and a precursor for the synthesis of neurotransmitters. If the concentration of tryptophan in the cell microenvironment is lowered and the level of kynurenine is increased, T cells will be arrested in the middle of G1, thereby affecting the proliferation, differentiation and activity of T cells.
  • IDO is expressed at low levels in normal cells, but is overexpressed in many tumor tissues, leading to abnormal local tryptophan metabolism and regulatory T cell formation, which in turn mediates local T cell immune tolerance in malignant tumors. It played an important role in the process of occurrence, development and transfer. If the activity of IDO is inhibited, the metabolism of tryptophan around the tumor cells is effectively prevented, which promotes the growth of T cells, thereby enhancing the function of the body's immune system against tumors. Therefore, the development of IDO inhibitors has become a hot topic in the research of tumor immunotherapy drugs.
  • IDO selective inhibitor INCB-024360 can effectively inhibit the activity of blank mouse plasma IDO in the level of IDO-deficient mice, and repeated administration hinders the expansion of CT26 tumors (Koblish et. Al, Mol. Cancer Ther. 2010, 9, 489-98).
  • IDO inhibitors can also be combined with other anti-tumor small molecule drugs and immunological checkpoint inhibitors, such as CTLA-4, PD-1 and PD-L1, to enhance the anti-tumor efficacy of the drug.
  • Combination immunotherapy with small molecule IDO inhibitors and immunological checkpoint inhibitors is in clinical trials, such as indoximod/ipilimumab, epacadostat/pembrolizumab, epacadostat/nivolumab, indoximod/MEDI-4736, and the like.
  • IDO small molecule inhibitor and PD-1 combination have additional effects, achieve good disease control rate in a variety of tumor treatments, and have less side effects than PD-1/CTLA-4, showing a broad tumor Prospects for immunotherapy (AACR, 2017; ASCO, 2017).
  • IDO In addition to cancer, IDO is associated with many other diseases, such as immunosuppression, chronic infections, viral infections, autoimmune diseases or conditions (such as rheumatoid arthritis), neurological or neuropsychiatric diseases or conditions (such as depression). Therefore, IDO inhibitors have enormous therapeutic value.
  • IDO inhibitor drugs are still in clinical trials, in addition to Incyte's INCB-024360 (epacadostat), Newlink Genetics' indoximod, Bristol-Myers Squibb's BMS-986205, and Pfizer's PF-0684003.
  • IDO inhibitors Due to the promise of IDO inhibitors in the treatment of multiple tumors and other diseases alone and in combination with immunotherapy, its development has attracted the attention of many biopharmaceutical companies, and a series of patent applications for IDO inhibitors have been published, including WO2006122150A1. WO2011056652A1, WO2013069765A1, WO2014186035A1, WO2015002918A1, WO2016073738A2, WO2016073770A1, WO2016181348A1, WO2016161960A1, WO2017079669A1, etc., but still need to develop new compounds which have better drug availability and higher response rates in immunotherapy. Through continuous efforts, the present invention has devised a compound having a structure represented by the general formula (I), and has found that a compound having such a structure exhibits an excellent effect and effect of suppressing IDO activity.
  • the present invention provides a compound of the formula (I) as an IDO inhibitor:
  • Ring A is a benzene ring or a 5-6 membered heteroaryl ring
  • B is -C(O)- or -NH-;
  • D is N or CR 3 ;
  • E is N or CR 4 ;
  • G is an optionally substituted 5-10 membered heteroaryl or 6-10 membered aryl
  • L is a bond or -O-
  • R 1 and R 2 are each independently selected from H or an optionally substituted C 1-4 alkyl group, a C 3-6 cycloalkyl group or a 4-7 membered heterocyclic group; or, R 1 and R 2 are bonded to a carbon.
  • the atoms together form a 3-7 membered ring optionally containing a hetero atom selected from the group consisting of O, N and S;
  • R 3 and R 4 are each independently selected from H, halogen, CN, OH, optionally substituted C 1-4 alkyl or -OC 1-4 alkyl;
  • R is independently selected from H or optionally substituted C 1-4 alkyl, C 3-6 cycloalkyl, 4-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl; in the same nitrogen atom
  • the two R groups above are optionally combined with the nitrogen atom to which they are attached to form a 4- to 7-membered heterocyclic ring optionally containing an additional hetero atom selected from O, N and S;
  • the optional substitution means substitution with a substituent selected from the group consisting of halogen, -CN, -NO 2 , oxo, -SF 5 , C 1-4 alkyl, C 3-7 cycloalkyl, 4-7 Aromeric heterocyclic group, phenyl group, 5-6 membered heteroaryl group, -OR', -NR'R", -C(O)R', -C(O)OR', -C(O)NR'R ", -C(O)N(R')OR", -OC(O)R', -OC(O)NR'R", -N(R')C(O)OR", -N(R ')C(O)R", -N(R"")C(O)NR'R", -N(R')S(O) 2 R", -S(O) m R', -S (O) 2 NR'R", wherein R', R" and R"" are each independently selected from H,
  • n 1 or 2.
  • One embodiment of the present invention relates to the compound of the above formula (I) or a pharmaceutically acceptable salt, prodrug, stable isotope derivative, isomer thereof and mixtures thereof, wherein:
  • Ring A is a benzene ring or a pyridine ring
  • B is -C(O)- or -NH-;
  • D is N or CR 3 ;
  • E is N or CR 4 ;
  • G is an optionally substituted 5-10 membered heteroaryl or 6-10 membered aryl
  • L is a bond or -O-
  • R 1 and R 2 are each independently selected from H or an optionally substituted C 1-4 alkyl group, a C 3-6 cycloalkyl group or a 4-7 membered heterocyclic group; or, R 1 and R 2 are bonded to a carbon.
  • the atoms together form a 3-7 membered ring optionally containing a hetero atom selected from the group consisting of O, N and S;
  • R 3 and R 4 are each independently selected from H, halogen, CN, OH, optionally substituted C 1-4 alkyl or -OC 1-4 alkyl;
  • the optional substitution means substitution with a substituent selected from the group consisting of halogen, -CN, -NO 2 , oxo, -SF 5 , C 1-4 alkyl, C 3-7 cycloalkyl, 4-7 Aromeric heterocyclic group, phenyl group, 5-6 membered heteroaryl group, -OR', -NR'R", -C(O)R', -C(O)OR', -C(O)NR'R ", -C(O)N(R')OR", -OC(O)R', -OC(O)NR'R", -N(R')C(O)OR", -N(R ')C(O)R", -N(R"")C(O)NR'R", -N(R')S(O) 2 R", -S(O) m R', -S (O) 2 NR'R", wherein R', R" and R"" are each independently selected from H,
  • n 1 or 2.
  • Another embodiment of the present invention relates to the compound of any of the above embodiments, or a pharmaceutically acceptable salt, prodrug, stable isotope derivative, isomer thereof, and mixtures thereof, wherein the compound is of the formula (II) Compounds shown:
  • B is -C(O)- or -NH-;
  • D is N or CR 3 ;
  • E is N or CR 4 ;
  • G is an optionally substituted 5-10 membered heteroaryl or 6-10 membered aryl
  • L is a bond or -O-
  • R 1 and R 2 are each independently selected from H or an optionally substituted C 1-4 alkyl group, a C 3-6 cycloalkyl group or a 4-7 membered heterocyclic group; or, R 1 and R 2 are bonded to a carbon.
  • the atoms together form a 3-7 membered ring optionally containing a hetero atom selected from the group consisting of O, N and S;
  • R 3 and R 4 are each independently selected from H, halogen, CN, OH, optionally substituted C 1-4 alkyl or -OC 1-4 alkyl;
  • the optional substitution means substitution with a substituent selected from the group consisting of halogen, -CN, -NO 2 , oxo, -SF 5 , C 1-4 alkyl, C 3-7 cycloalkyl, 4-7 Aromeric heterocyclic group, phenyl group, 5-6 membered heteroaryl group, -OR', -NR'R", -C(O)R', -C(O)OR', -C(O)NR'R ", -C(O)N(R')OR", -OC(O)R', -OC(O)NR'R", -N(R')C(O)OR", -N(R ')C(O)R", -N(R"")C(O)NR'R", -N(R')S(O) 2 R", -S(O) m R', -S (O) 2 NR'R", wherein R', R" and R"" are each independently selected from H,
  • n 1 or 2.
  • Another embodiment of the present invention relates to the compound of any one of the above embodiments, or a pharmaceutically acceptable salt, prodrug, stable isotope derivative, isomer thereof, and mixtures thereof, wherein B is -NH-, C is -C(O)-.
  • Another embodiment of the invention relates to the compound of any of the above embodiments, wherein L is a bond.
  • Another embodiment of the invention relates to the compound of any of the above embodiments, wherein both D and E are CH.
  • Another embodiment of the invention relates to the compound of any of the above embodiments, wherein G is 5-10 membered heteroaryl optionally substituted by halogen, CN, C 1-4 alkyl or -OC 1-4 alkyl A radical, especially a quinolinyl or pyridyl group, more particularly a fluoroquinolyl group.
  • a further embodiment of the invention relates to the compound according to any of the preceding embodiments, wherein R 1 and R 2 are each independently selected from H or C 1-4 alkyl, in particular R 1 is C 1-4 alkyl, R 2 is H, more particularly R 1 is a methyl group and R 2 is H.
  • Another embodiment of the invention relates to the compound of any of the above embodiments which is a compound of the following formula (IIIa)-(IIIc):
  • Another embodiment of the present invention relates to the compound of any of the above embodiments, which is a compound of the following formula (IV):
  • Another embodiment of the present invention relates to the compound of the above formula (IV), wherein R 1 is a methyl group.
  • One embodiment of the invention relates to the compound of the above formula (I), wherein the compound is selected from the group consisting of:
  • a prodrug thereof a stable isotope derivative, a pharmaceutically acceptable salt, an isomer, and mixtures thereof.
  • Compounds of the invention having the activity of Hela cells IDO significant inhibitory effect, preferably an IC 50 less than 200 nM, more preferably IC 50 of less than 50nM.
  • the compounds of the invention are therefore useful in the treatment or prevention of IDO-mediated related diseases including, but not limited to, cancer, immunosuppression, chronic infection, viral infection, autoimmune disease or condition (eg rheumatoid arthritis), neurological or neuropsychiatric A disease or condition (such as depression).
  • IDO-mediated related diseases including, but not limited to, cancer, immunosuppression, chronic infection, viral infection, autoimmune disease or condition (eg rheumatoid arthritis), neurological or neuropsychiatric A disease or condition (such as depression).
  • the compound of the present invention is used for treating or preventing IDO-related tumors, including but not limited to prostate cancer, colon cancer, rectal cancer, membrane adenocarcinoma, cervical cancer, gastric cancer, endometrial cancer, brain cancer, liver cancer, bladder cancer, Ovarian cancer, testicular cancer, head cancer, neck cancer, skin cancer (including melanoma and basal cancer), endometrial cancer, lymphoma, leukemia, esophageal cancer, breast cancer, muscle cancer, connective tissue cancer, Lung cancer (including small cell lung cancer and non-small cell carcinoma), adrenal cancer, thyroid cancer, kidney cancer, bone cancer, glioblastoma, mesothelioma, sarcoma (including Kaposi's sarcoma), choriocarcinoma, skin base Cell carcinoma or testicular seminoma.
  • IDO-related tumors including but not limited to prostate cancer, colon cancer, rectal cancer, membrane adenocarcinoma, cervical cancer, gastric cancer,
  • the present invention provides a method of treating or preventing an IDO-mediated disease, such as the tumor, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable compound thereof Salts, prodrugs, stable isotope derivatives, isomers, and mixtures thereof, or pharmaceutical compositions comprising the compounds.
  • Another aspect of the invention relates to a compound of the formula (I), or a pharmaceutically acceptable salt, prodrug, stable isotope derivative, isomer thereof and mixtures thereof, for use as a medicament or for medical use, for use in Treatment or prevention of IDO-mediated diseases such as cancer, immunosuppression, chronic infection, viral infection, autoimmune disease or condition (such as rheumatoid arthritis), neurological or neuropsychiatric diseases or conditions (such as depression), and the like.
  • IDO-mediated diseases such as cancer, immunosuppression, chronic infection, viral infection, autoimmune disease or condition (such as rheumatoid arthritis), neurological or neuropsychiatric diseases or conditions (such as depression), and the like.
  • the invention further relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the invention, or a pharmaceutically acceptable salt, prodrug, stable isotope derivative, isomer thereof, and mixtures thereof, and a pharmaceutically acceptable carrier And excipients.
  • Another aspect of the invention relates to a compound of the formula (I), or a pharmaceutically acceptable salt, prodrug, stable isotope derivative, isomer thereof and mixtures thereof, or a pharmaceutical composition thereof for use in the preparation of a medicament Uses wherein the medicament is for the treatment or prevention of IDO mediated diseases such as tumors and immunosuppression.
  • Another aspect of the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the formula (I) or a pharmaceutically acceptable salt, prodrug, stable isotope derivative, isomer thereof and mixtures thereof And at least one additional drug, wherein the at least one additional drug is a chemotherapeutic agent, an immune and/or inflammatory modulator (such as an immunological checkpoint inhibitor), a neurologically relevant disease modulator, or an anti-infective agent.
  • the medicament may be in any pharmaceutical dosage form including, but not limited to, tablets, capsules, solutions, lyophilized preparations, injections.
  • the pharmaceutical preparation of the present invention can be administered in the form of a dosage unit containing a predetermined amount of the active ingredient per dosage unit.
  • a dosage unit may comprise, for example, from 0.5 mg to 1 g, preferably from 1 mg to 700 mg, particularly preferably from 5 mg to 300 mg, of a compound of the invention, depending on the condition being treated, the method of administration and the age, weight and condition of the patient.
  • Preferred dosage unit formulations are those containing the daily or divided doses indicated above or their corresponding fractions of the active ingredient.
  • pharmaceutical preparations of this type can be prepared using methods well known in the pharmaceutical art.
  • the pharmaceutical preparations of the invention may be adapted for administration by any suitable method desired, for example by oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral. (including subcutaneous, intramuscular, intravenous or intradermal) methods of administration.
  • Such formulations can be prepared by, for example, combining the active ingredient with one or more excipients or one or more adjuvants, using all methods known in the art of pharmacy.
  • C xy denotes a range of the number of carbon atoms, wherein x and y are both integers, for example, C 3-8 cycloalkyl represents a cycloalkyl group having 3 to 8 carbon atoms, that is, having 3 a cycloalkyl group of 4, 5, 6, 7 or 8 carbon atoms. It should also be understood that “ C3-8 " also encompasses any subranges therein, such as C3-7 , C3-6 , C4-7 , C4-6 , C5-6, and the like.
  • Alkyl means a saturated straight or branched chain hydrocarbon radical containing from 1 to 20 carbon atoms, for example from 1 to 8 carbon atoms, from 1 to 6 carbon atoms or from 1 to 4 carbon atoms.
  • alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropane 1,1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl -2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-Dimethylbutyl and 2-ethylbutyl.
  • the alkyl
  • alkenyl means a straight or branched chain hydrocarbon radical containing at least one carbon to carbon double bond and usually 2 to 20 carbon atoms, for example 2 to 8 carbon atoms, 2 to 6 carbon atoms or 2 to 4 carbon atoms. Group. Non-limiting examples of alkenyl groups include ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-2-propenyl, 1 , 4-pentadienyl and 1,4-butadienyl. The alkenyl group can be optionally substituted.
  • Alkynyl means a straight or branched chain hydrocarbon radical containing at least one carbon to carbon triple bond and typically 2 to 20 carbon atoms, for example 2 to 8 carbon atoms, 2 to 6 carbon atoms or 2 to 4 carbon atoms. Group. Non-limiting examples of alkynyl groups include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl and 3-butynyl. The alkynyl group can be optionally substituted.
  • Alkylene means a divalent group of a straight or branched chain saturated hydrocarbon having from 1 to 20 carbon atoms, for example from 1 to 8 carbon atoms, from 1 to 6 carbon atoms or from 1 to 4 carbon atoms.
  • alkylene groups include -CH 2 -, -CH(CH 3 )-, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 -, and CH 2 CH(CH 3 )CH 2 -.
  • the alkylene group can be optionally substituted.
  • Cycloalkyl means a saturated cyclic hydrocarbyl substituent containing from 3 to 14 carbon ring atoms.
  • the cycloalkyl group may be a single carbon ring and usually contains 3 to 8, 3 to 7, or 3 to 6 carbon ring atoms.
  • Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • the cycloalkyl group may alternatively be a double or tricyclic ring fused together, such as decahydronaphthyl.
  • the cycloalkyl group can be optionally substituted.
  • Heterocyclyl or heterocyclic refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic group comprising from 3 to 20 ring atoms, for example from 3 to 14, from 3 to 12, from 3 to 10 , 3 to 8, 3 to 6, or 5 to 6 ring atoms, wherein one or more of the ring atoms are selected from nitrogen, oxygen or S(O) m (where m is an integer from 0 to 2), but does not include The ring portion of -OO-, -OS- or -SS-, the remaining ring atoms are carbon.
  • It preferably comprises from 3 to 12 ring atoms, more preferably from 3 to 10 ring atoms, more preferably from 4 to 7 ring atoms, most preferably 5 or 6 ring atoms, of which from 1 to 4 are heteroatoms, more preferably from 1 to 3
  • One is a hetero atom, and most preferably one or two are heteroatoms.
  • monocyclic heterocyclic groups include pyrrolidinyl, piperidinyl, piperazinyl, pyranyl, morpholinyl, thiomorpholinyl, homopiperazinyl, oxetanyl and nitrogen Heterocyclobutane.
  • Polycyclic heterocyclic groups include fused, bridged or spiro polycyclic heterocyclic groups. The heterocyclic or heterocyclic ring may be optionally substituted.
  • Aryl or aromatic ring refers to an aromatic monocyclic or fused polycyclic group containing from 6 to 14 carbon atoms, preferably from 6 to 10 members, such as phenyl and naphthyl, most preferably phenyl.
  • the aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring to which the parent structure is attached is an aryl ring, non-limiting examples include:
  • the aryl or aromatic ring may be optionally substituted.
  • Heteroaryl or heteroaryl ring refers to a heteroaromatic system containing from 5 to 14 ring atoms, wherein from 1 to 4 ring atoms are selected from heteroatoms including oxygen, sulfur and nitrogen.
  • the heteroaryl group is preferably from 5 to 10 members. More preferably, the heteroaryl group is 5- or 6-membered, such as furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyrazolyl, imidazolyl, tetrazolyl, Oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, quinolyl and the like.
  • the heteroaryl ring may be fused to an aryl, heterocyclic or cycloalkyl ring, wherein the ring to which the parent structure is attached is a heteroaryl ring, non-limiting examples include:
  • heteroaryl or heteroaryl ring can be optionally substituted.
  • Halogen means fluoro, chloro, bromo or iodo.
  • heterocyclic group optionally substituted by an alkyl group means that an alkyl group may be, but is not necessarily, present, and the expression includes a case where a heterocyclic group is substituted with an alkyl group and a case where a heterocyclic group is not substituted with an alkyl group.
  • Optionally substituted means that one or more hydrogen atoms in the group, preferably 5, more preferably 1 to 3, hydrogen atoms are independently substituted with each other by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art will be able to determine (by experiment or theory) substitutions that may or may not be possible without undue effort. For example, an amino group or a hydroxyl group having a free hydrogen may be unstable when combined with a carbon atom having an unsaturated (e.g., olefinic) bond.
  • the substituents include, but are not limited to, halogen, -CN, -NO 2 , oxo, -SF 5 , C 1-4 alkyl, C 3-7 cycloalkyl, 4-7 membered heterocyclic, phenyl, 5-6 membered heteroaryl, -OR', -NR'R", -C(O)R', -C(O)OR', -C(O)NR'R", -C(O)N (R')OR", -OC(O)R', -OC(O)NR'R", -N(R')C(O)OR", -N(R')C(O)R" , -N(R'"'C(O)S(O) 2 R", -S(O) m R' (m is 1 or 2), -S( O) 2 NR'R" and the like, wherein R', R" and R"" are each independently selected from
  • “Isomer” refers to a compound having the same molecular formula but differing in the nature or sequence of its atomic bonding or in the spatial arrangement of its atoms. Isomers whose atomic space is arranged differently are referred to as “stereoisomers”. Stereoisomers include optical isomers, geometric isomers, and conformational isomers.
  • optical isomer form The compounds of the invention may exist in optical isomer form. These optical isomers are in the "R” or “S” configuration depending on the configuration of the substituents around the chiral carbon atom. Optical isomers include enantiomers and diastereomers. Methods of preparing and isolating optical isomers are known in the art.
  • Geometric isomers may also be present in the compounds of the invention.
  • the present invention contemplates various geometric isomers and mixtures thereof resulting from the distribution of substituents around carbon-carbon double bonds, carbon-nitrogen double bonds, cycloalkyl groups or heterocyclic groups.
  • the substituents around the carbon-carbon double bond or carbon-nitrogen bond are designated as the Z or E configuration, and the substituents around the cycloalkyl or heterocycle are designated in the cis or trans configuration.
  • the compounds of the invention may also exhibit tautomerism, such as keto-enol tautomerization.
  • the invention includes any tautomeric or stereoisomeric forms and mixtures thereof, and is not limited to any one of the tautomeric or stereoisomeric forms used in the nomenclature or chemical structural formula of the compound.
  • isotope includes all isotopes of atoms occurring in the compounds of the invention. Isotopes include those atoms having the same atomic number but different mass numbers. Examples of isotopes suitable for incorporation into the compounds of the invention are hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, for example but not limited to 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F and 36 Cl.
  • Isotopically labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by methods analogous to those described in the accompanying examples, using the appropriate isotopically labeled reagents in place of the non-isotopically labeled reagents.
  • Such compounds have a variety of potential uses, for example as a standard and reagent in the determination of biological activity. In the case of stable isotopes, such compounds have the potential to advantageously alter biological, pharmacological or pharmacokinetic properties.
  • Prodrug means that the compound of the invention can be administered in the form of a prodrug.
  • Prodrugs are derivatives which are converted to the biologically active compounds of the invention under physiological conditions in vivo, for example by oxidation, reduction, hydrolysis, etc., each of which is carried out using an enzyme or without the participation of an enzyme.
  • a prodrug is a compound in which an amino group in a compound of the invention is acylated, alkylated or phosphorylated, such as eicosylamino, alanylamino, pivaloyloxymethylamino, or Wherein the hydroxy group is acylated, alkylated, phosphorylated or converted to a borate such as acetoxy, palmitoyloxy, pivaloyloxy, succinyloxy, fumaryloxy, alanyloxy
  • These compounds can be prepared from the compounds of the present invention according to known methods.
  • “Pharmaceutically acceptable salt” or “pharmaceutically acceptable salt” refers to a salt made from a pharmaceutically acceptable base or acid, including inorganic bases or acids and organic bases or acids. Where the compounds of the invention contain one or more acidic or basic groups, the invention also includes their corresponding pharmaceutically acceptable salts. Thus, the compounds of the invention containing an acidic group may be present in the form of a salt and may be used according to the invention, for example as an alkali metal salt, an alkaline earth metal salt or as an ammonium salt. More specific examples of such salts include sodium salts, potassium salts, calcium salts, magnesium salts or salts with ammonia or organic amines such as ethylamine, ethanolamine, triethanolamine or amino acids.
  • the compounds of the invention containing a basic group may be present in the form of a salt and may be used in accordance with the invention in the form of their addition salts with inorganic or organic acids.
  • suitable acids include hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acid, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, and C.
  • the compound of the invention contains both acidic and basic groups in the molecule, the invention includes, in addition to the salt forms mentioned, internal or internal ammonium salts.
  • Each salt can be obtained by conventional methods known to those skilled in the art, for example by contacting these with an organic or inorganic acid or base in a solvent or dispersant or by anion exchange or cation exchange with other salts.
  • “Pharmaceutical composition” means a compound containing one or more of the compounds described herein, or a pharmaceutically acceptable salt, prodrug, stable isotope derivative, isomer thereof, and mixtures thereof, and other components such as a pharmaceutically acceptable carrier And a combination of excipients.
  • the purpose of the pharmaceutical composition is to promote the administration of the organism, which facilitates the absorption of the active ingredient and thereby exerts biological activity.
  • tumor includes benign tumors and malignant tumors (eg, cancer).
  • terapéuticaally effective amount refers to an amount that includes a compound of the invention that is effective to inhibit the function of IDO and/or to treat or prevent the disease.
  • the invention also provides methods of making the compounds.
  • the preparation of the compounds of the general formula (I) of the present invention can be carried out by the following exemplary methods and examples, but the methods and examples should not be construed as limiting the scope of the invention in any way.
  • the compounds of the invention may also be synthesized by synthetic techniques known to those skilled in the art, or a combination of methods known in the art and methods of the invention may be employed.
  • the product obtained in each step of the reaction is obtained by separation techniques known in the art including, but not limited to, extraction, filtration, distillation, crystallization, chromatographic separation and the like.
  • the starting materials and chemical reagents required for the synthesis can be conventionally synthesized or purchased according to the literature (available from SciFinder).
  • the pentafluorosulfanyl-substituted amide compound of the formula (I) of the present invention can be synthesized according to the route described in Process A: firstly converting the intermediate acid A2 into an acid chloride or an amide condensing agent, and further containing pentafluorosulfur Coupling of the (hetero)arylamine A1 of the alkyl substituent gives the target product amide compound A3.
  • the pentafluorosulfanyl-substituted amide compound of the formula (I) of the present invention can also be synthesized according to the route described in Process B: the (hetero)arylcarboxylic acid B1 containing a pentafluorosulfane substituent becomes an acid chloride, and then Coupling with the intermediate amine B2 gives the target product amide compound B3.
  • the intermediate acid A2 can be synthesized according to the route described in Process C: ketone C1 is reacted with trifluoromethanesulfonic anhydride under basic conditions to form a hydrocarbon alkenyl triflate C2; C2 with a boronic ester or boric acid GB (OR) 2 by Suzuki coupling reaction to obtain C3, which is reduced by hydrogenation to form C4; then substituted with one equivalent of halogenated alkane, or can be further substituted with another equivalent of alkyl halide to form C5; finally hydrolyzed under base catalysis Acid A2 was obtained.
  • the intermediate lipid D7 can also be synthesized according to the route described in Process D: the ketone D1 is reacted with N-phenylbis(trifluoromethanesulfonyl)imide under basic conditions to form a hydrocarbon alkenyl triflate D2; D2 D3 is obtained by Suzuki coupling reaction with boric acid ester or boric acid GB(OR) 2 , which is hydrogenated and deprotected to form ketone D4; ketone D4 is reduced to form mainly trans-alcohol D5; alcohol D5 is formed under alkaline conditions.
  • Sulfonyl ester D6; D6 is substituted with the sodium salt of di-tert-butyl malonate to form a cis intermediate which is then deprotected and decarboxylated under acidic conditions to yield the cis intermediate ester D7.
  • the intermediate acid A2 can also be synthesized according to the route described in Process E: E1 and halide GX are coupled to each other by Buchwald coupling reaction to obtain E2; E2 is decarburized to obtain E3 under acid catalysis; E3 is subjected to substitution reaction to obtain E4; finally, hydrolysis is carried out under base catalysis. Acid A2 was obtained.
  • the intermediate acid A2 can also be synthesized according to the route described in Process F: F1 and halide GX are subjected to Buchwald coupling reaction to obtain F2; F2 is dehydrogenated with a base (such as LHMDS), and then substituted with one equivalent of a halogenated alkane, or This is followed by a second substitution reaction with another equivalent of an alkyl halide to form F3; finally, hydrolysis under base catalysis gives the acid A2.
  • a base such as LHMDS
  • the intermediate acid A2 can also be synthesized according to the route described in Method G: G1 is reduced to G2 with a boron reagent; G2 is subjected to a nucleophilic substitution reaction or a light delay reaction to obtain G3; and G3 is hydrolyzed under base catalysis to obtain an acid A2.
  • the chiral intermediate acid A2 can be synthesized according to the route described in Process H: acid H1 is first formed with an acid chloride (such as pivaloyl chloride) under base catalysis to form an anhydride, and then by (R)-chiral auxiliary (such as (R)- The lithium salt of 4-benzylmethyloxazol-2-one is substituted to form (R)-H2; (R)-H2 is dehydrogenated with a strong base, and then reacted with methyl iodide to obtain (R)-H3; Hydrolysis under catalysis gives the acid (R)-A2. If (S)-chiral auxiliary (such as (S)-4-benzylmethyloxazolidin-2-one) is used, (S)-A2 is obtained.
  • an acid chloride such as pivaloyl chloride
  • R chiral auxiliary
  • the intermediate amine B2 can be synthesized according to the route described in Method I: I2 is obtained from I1 by similar methods C and G; I2 is reduced to alcohol by LAH, followed by oxidation with an oxidant of Days-Martin to form aldehyde I3; I3 and a reagent are reacted to form I4 ; I4 undergoes a light delay reaction to form I5; finally deprotection to obtain an amine B2.
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or mass spectrometry (MS).
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • the NMR was measured by a Bruker ASCEND-400 nuclear magnetic apparatus, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), and the internal standard was four.
  • DMSO-d 6 dimethyl sulfoxide
  • CDCl 3 deuterated chloroform
  • CD 3 OD deuterated methanol
  • TMS Methylsilane
  • chemical shifts are given in units of 10 -6 (ppm).
  • the MS was measured using an Agilent SQD (ESI) mass spectrometer (manufacturer: Agilent, model: 6120).
  • ESI Agilent SQD
  • the HPLC was measured using an Agilent 1260 DAD high pressure liquid chromatograph (Poroshell 120EC-C18, 50 x 3.0 mm, 2.7 ⁇ m column) or a Waters Arc high pressure liquid chromatograph (Sunfirc C18, 150 x 4.6 mm, 5 ⁇ m column).
  • the thin-layer chromatography silica gel plate uses Qingdao Ocean GF254 silica gel plate, and the silica gel plate used for thin-layer chromatography (TLC) has a specification of 0.15 mm to 0.2 mm.
  • the specification for separation and purification of thin layer chromatography is 0.4 mm to 0.5 mm. silicone board.
  • the known starting materials of the present invention may be synthesized by or according to methods known in the art, or may be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc., Beijing. Coupling chemicals and other companies.
  • An argon atmosphere or a nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon having a volume of about 1 L.
  • the hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon of about 1 L volume.
  • the hydrogenation reaction is usually evacuated, charged with hydrogen, and operated three times.
  • the microwave reaction used a CEM Discover-SP type microwave reactor.
  • the temperature of the reaction is room temperature, and the temperature range is from 20 ° C to 30 ° C.
  • the progress of the reaction in the examples was monitored using an Agilent LC/MS (1260/6120).
  • the progress of the reaction can also be monitored by thin layer chromatography (TLC).
  • the system used for the developing agent is A: dichloromethane and methanol system; B: petroleum ether and ethyl acetate system, the volume ratio of the solvent is based on the polarity of the compound. Adjust differently.
  • the system for purifying the compound using the column chromatography eluent and the system for developing the thin layer chromatography include A: dichloromethane and methanol systems; B: petroleum ether and ethyl acetate system, the volume ratio of the solvent according to the compound The polarity is adjusted to adjust, and a small amount of triethylamine and an acidic or alkaline reagent may be added for adjustment.
  • the purified compound was also subjected to a Waters mass spectrometric automated preparation system (mass spectrometer: SQD2), using a suitable gradient of acetonitrile/water (containing 0.1% trifluoroacetic acid) or acetonitrile/water (containing 0.05% aqueous ammonia) depending on the polarity of the compound.
  • a reverse phase high pressure column (XBridge-C18, 19 x 150 mm, 5 ⁇ m) was eluted at a flow rate of 20 ml/min.
  • the suspension was cooled to -78 ° C and then a light yellow solution that had been cooled to -78 ° C was added.
  • the reaction mixture was gradually warmed to room temperature and stirring was continued for 3 hours.
  • a saturated ammonium chloride solution (10 ml) was added to the mixture and the mixture was evaporated.
  • the organic phases were combined and washed with brine (20 ml ⁇ 2).
  • Example 2 can be obtained simultaneously in the synthesis of Example 1.
  • the compound piperazine-1-carboxylic acid tert-butyl ester 6a (100 mg, 0.537 mmol), 4-bromo-6-fluoroquinoline (146 mg, 0.644 mmol), tris(dibenzylideneacetone) dipalladium (49 mg, 0.537) Ment), 4,5-bisdiphenylphosphino-9,9-dimethyloxaxan (62 mg, 0.107 mmol), cesium carbonate (350 mg, 1.074 mmol) and 1,4-dioxane (10 ml) Mix and then heat in a microwave reactor for 30 minutes under a nitrogen atmosphere.
  • the compound 2-(piperidin-4-yl)acetate 7a (500 mg, 2.92 mmol), 4-bromo-6-fluoroquinoline (791.2 mg, 3.5 mmol), tris(dibenzylideneacetone) palladium (267.5 mg, 0.292 mmol), 4,5-bisdiphenylphosphino-9,9-dimethyloxaxan (338 mg, 0.584 mmol), cesium carbonate (1.89 g, 5.89 mmol) and 1,4-di Oxycyclohexane (10 ml) was mixed and then heated in a microwave reactor for 30 minutes under a nitrogen atmosphere.
  • Methyl 4-(6-fluoroquinolin-4-yl)cyclohex-3-ene-1-carboxylate 9c (3.32 g, 11.67 mmol) was dissolved in methanol (50 mL) then 10% palladium carbon (200 mg) The mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere. Filtration and concentration of the filtrate under reduced pressure gave ethyl 4-(6-fluoroquinolin-4-yl)cyclohexane-1-carboxylate 9d (3.04 g, pale yellow solid).
  • IDO expression is low in Hela cells without any induction conditions, but a certain concentration of IFN- ⁇ can induce Hela cells to express IDO, which catalyzes the production of N-formyl kynurenine by tryptophan. It can be hydrolyzed by trichloroacetic acid to form kynurenine, and then reacted with Ehrlich reagent to detect the activity of IDO.
  • the absorbance at 490 nm (OD490) is directly proportional to the IDO activity.
  • the compound was dissolved in DMSO (Sigma, Cat. No. D5879) and diluted to 5 mM, then serially diluted 3 times with DMSO to a minimum concentration of 2.29 ⁇ M, and each concentration point was again DMEM medium without FBS (ThermoFisher, article number Diluted 50 times for 11995073). If the compound is very low IC 50 values, the concentration of the starting compound can be reduced.
  • Hela cells ATCC, Cat. No. CCL-2) were cultured in DMEM complete medium containing 10% FBS (GBICO, Cat. No. 10099-141) and 100 U/ml penicillin (ThermoFisher, Cat. No. 15140122).
  • the cells were covered in the culture vessel for 80-90%, they were digested with 0.25% trypsin (containing EDTA) (ThermoFisher, Cat. No. 25200056) and then planted in 96-well plates (Corning, Cat. No. 3599). 30000 cells (80 ⁇ l DMEM medium) were then incubated overnight (18-20 hours) in a 37 ° C, 5% CO 2 incubator.
  • trypsin containing EDTA
  • 30000 cells 80 ⁇ l DMEM medium
  • Y is the percent inhibition
  • Bottom is the bottom platform value of the S-curve
  • Top is the top platform value of the S-curve
  • X is the logarithm of the concentration of the test compound
  • slope factor is the slope coefficient of the curve.
  • Compound number IC 50 Compound number IC 50 1 A 2 C 3 A 4 B 5 A 6 7 8 C 9 A
  • Example embodiments of the present invention are the compounds having intracellular IDO activity statistically significant inhibitory effect, preferably IC 50 less than 200 nM, more preferably IC 50 of less than 50nM.

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Abstract

本发明公开了一种调控或抑制吲哚胺2,3-双加氧酶(IDO)活性的五氟硫烷基取代的酰胺类化合物，其制备方法及其在医药学上的应用。具体而言，本发明公开了一种通式(I)所示的化合物及其可药用的盐、含有所述化合物或其可药用的盐的药物组合物、应用所述化合物或其可药用的盐治疗和/或预防IDO介导的相关性病症、特别是肿瘤的方法以及所述化合物或其可药用的盐的制备方法。本发明还公开了所述化合物或其可药用的盐或含有所述化合物或其可药用的盐的药物组合物在制备用于治疗和/或预防IDO介导的相关性病症、特别是肿瘤的药物中的用途。其中通式(I)的各取代基与说明书中的定义相同。

Description

五氟硫烷基取代的酰胺类化合物、其制备方法及其在医药学上的应用 技术领域
本发明涉及一种新的调控或抑制吲哚胺2，3-双加氧酶(IDO)活性的含有五氟硫烷取代基的酰胺类化合物或其可药用的盐、含有所述化合物或其可药用的盐的药物组合物、所述化合物或其可药用的盐的制备方法以及所述化合物或其可药用的盐或含有所述化合物或其可药用的盐的药物组合物在制备用于治疗和/或预防IDO介导的相关性病症、特别是肿瘤的药物中的用途和其使用方法。
背景技术
吲哚胺2，3-双加氧酶(IDO)是一种含血红素的单体蛋白，广泛分布于除肝脏以外的组织中，催化色氨酸氧化降解成犬尿氨酸，是犬尿氨酸代谢途径的限速酶。色氨酸是T细胞增殖的必需氨基酸，同时也是合成神经递质的前体物质。如果细胞微环境中的色氨酸浓度降低，而犬尿氨酸的水平增高，会导致T细胞停滞于G1中期，从而对T细胞的增殖、分化和活性产生影响。
IDO在正常细胞内呈低水平表达，但在很多肿瘤组织中过度表达，导致肿瘤局部色氨酸代谢异常及调节性T细胞形成，进而介导肿瘤局部的T细胞免疫耐受，在恶性肿瘤的发生、发展和转移过程中发挥了重要作用。如果IDO的活性受到抑制，肿瘤细胞周围的色氨酸代谢得到有效的阻止，可促进T细胞的生长，从而增强机体免疫系统对抗肿瘤的功能。因此，IDO抑制剂的研发已成为肿瘤免疫治疗药物研究的前沿热点。临床前研究显示IDO的选择性抑制剂INCB-024360单次给药能有效地把空白小鼠血浆IDO的活性抑制在IDO缺陷小鼠的水平，重复给药阻碍了CT26肿瘤的扩大(Koblish et.al，Mol.Cancer Ther.2010，9，489-98)。
IDO抑制剂还可以与其它抗肿瘤小分子药物及免疫检查点抑制剂，比如CTLA-4、PD-1和PD-L1等抗体进行联合治疗，以加强药物的抗肿瘤疗效。小分子IDO抑制剂与免疫检查点抑制剂的联合免疫治疗处于临床试验中，比如indoximod/ipilimumab、epacadostat/pembrolizumab、epacadostat/nivolumab、indoximod/MEDI-4736等的联合治疗临床试验。初步临床结果显示IDO小分子抑制剂和PD-1联合用药，具有附加效应，在多种肿瘤治疗上取得良好的疾病控制率，且比PD-1/CTLA-4副作用小，展现出广阔的肿瘤免疫治疗前景(AACR，2017；ASCO，2017)。
除了癌症，IDO还与其他很多疾病相关，比如免疫抑制、慢性感染、病毒感染、自身免疫性疾病或病症(例如类风湿关节炎)、神经或神经 精神疾病或病症(例如抑郁症)等。因此，IDO抑制剂具有巨大的治疗价值。
目前小分子IDO抑制剂药物还处于临床试验阶段，除了Incyte的INCB-024360(epacadostat)，还有NewLink Genetics的indoximod、百时美施贵宝的BMS-986205、辉瑞的PF-0684003等。
由于IDO抑制剂在单独和联合免疫治疗多种肿瘤以及其它疾病中所展示的前景，其开发吸引了众多生物制药公司的关注，现已公开了一系列的IDO抑制剂的专利申请，其中包括WO2006122150A1、WO2011056652A1、WO2013069765A1、WO2014186035A1、WO2015002918A1、WO2016073738A2、WO2016073770A1、WO2016181348A1、WO2016161960A1、WO2017079669A1等等，但仍需开发新的化合物，其具有更好成药性和在免疫治疗中更高的应答率。经过不断努力，本发明设计了具有通式(I)所示结构的化合物，并发现具有此类结构的化合物表现出优异的抑制IDO活性的效果和作用。
发明内容
本发明提供作为IDO抑制剂的一种通式(I)所示的化合物：
Figure PCTCN2019000019-appb-000001
或其可药用的盐、前药、稳定同位素衍生物、异构体及其混合物形式，
其中：
环A为苯环或5-6元杂芳环；
B为-C(O)-或-NH-；
当B为-C(O)-，C为-NH-；当B为-NH-，C为-C(O)-；
D为N或CR 3；
E为N或CR 4；
G为任选取代的5-10元杂芳基或6-10元芳基；
L为键或-O-；
R 1和R 2各自独立地选自H或任选取代的C 1-4烷基、C 3-6环烷基或4-7元杂环基；或者，R 1和R 2与连接的碳原子共同形成一任选含有选自O、N和S的杂原子的3-7元环；
R 3和R 4各自独立地选自H、卤素、CN、OH、任选取代的C 1-4烷基或-O-C 1-4烷基；
R独立地选自H或任选取代的C 1-4烷基、C 3-6环烷基、4-7元杂环基、苯基或5-6元杂芳基；在同一个氮原子上的两个R任选与它们连接的氮原子共同形成一任选含有选自O、N和S的另外的杂原子的4- 7元杂环；
所述任选取代是指被选自以下的取代基取代：卤素、-CN、-NO 2、氧代、-SF 5、C 1-4烷基、C 3-7环烷基、4-7元杂环基、苯基、5-6元杂芳基、-OR′、-NR′R″、-C(O)R′、-C(O)OR′、-C(O)NR′R″、-C(O)N(R′)OR″、-OC(O)R′、-OC(O)NR′R″、-N(R′)C(O)OR″、-N(R′)C(O)R″、-N(R″′)C(O)NR′R″、-N(R′)S(O) 2R″、-S(O) mR′、-S(O) 2NR′R″，其中R′、R″和R″′各自独立地选自H、C 1-4烷基、C 3-7环烷基、卤代C 1-4烷基、4-7元杂环基、C 6-10芳基、5-10元杂芳基；在同一个氮原子上的R′和R″任选与它们连接的氮原子共同形成一任选含有另外的选自O、S和N的杂原子的4-7元杂环，且
m为1或2。
本发明的一个实施方案涉及上述通式(I)所示的化合物或其可药用的盐、前药、稳定同位素衍生物、异构体及其混合物形式，其中：
环A为苯环或吡啶环；
B为-C(O)-或-NH-；
当B为-C(O)-，C为-NH-；当B为-NH-，C为-C(O)-；
D为N或CR 3；
E为N或CR 4；
G为任选取代的5-10元杂芳基或6-10元芳基；
L为键或-O-；
R 1和R 2各自独立地选自H或任选取代的C 1-4烷基、C 3-6环烷基或4-7元杂环基；或者，R 1和R 2与连接的碳原子共同形成一任选含有选自O、N和S的杂原子的3-7元环；
R 3和R 4各自独立地选自H、卤素、CN、OH、任选取代的C 1-4烷基或-O-C 1-4烷基；
所述任选取代是指被选自以下的取代基取代：卤素、-CN、-NO 2、氧代、-SF 5、C 1-4烷基、C 3-7环烷基、4-7元杂环基、苯基、5-6元杂芳基、-OR′、-NR′R″、-C(O)R′、-C(O)OR′、-C(O)NR′R″、-C(O)N(R′)OR″、-OC(O)R′、-OC(O)NR′R″、-N(R′)C(O)OR″、-N(R′)C(O)R″、-N(R″′)C(O)NR′R″、-N(R′)S(O) 2R″、-S(O) mR′、-S(O) 2NR′R″，其中R′、R″和R″″各自独立地选自H、C 1-4烷基、C 3-7环烷基、卤代C 1-4烷基、4-7元杂环基、C 6-10芳基、5-10元杂芳基；在同一个氮原子上的R′和R″任选与它们连接的氮原子共同形成一任选含有另外的选自O、S和N的杂原子的4-7元杂环，且
m为1或2。
本发明的另一个实施方案涉及上述任一实施方案所述的化合物或其可药用的盐、前药、稳定同位素衍生物、异构体及其混合物形式，所述化合物为通式(II)所示的化合物：
Figure PCTCN2019000019-appb-000002
其中：
B为-C(O)-或-NH-；
当B为-C(O)-，C为-NH-；当B为-NH-，C为-C(O)-；
D为N或CR 3；
E为N或CR 4；
G为任选取代的5-10元杂芳基或6-10元芳基；
L为键或-O-；
R 1和R 2各自独立地选自H或任选取代的C 1-4烷基、C 3-6环烷基或4-7元杂环基；或者，R 1和R 2与连接的碳原子共同形成一任选含有选自O、N和S的杂原子的3-7元环；
R 3和R 4各自独立地选自H、卤素、CN、OH、任选取代的C 1-4烷基或-O-C 1-4烷基；
所述任选取代是指被选自以下的取代基取代：卤素、-CN、-NO 2、氧代、-SF 5、C 1-4烷基、C 3-7环烷基、4-7元杂环基、苯基、5-6元杂芳基、-OR′、-NR′R″、-C(O)R′、-C(O)OR′、-C(O)NR′R″、-C(O)N(R′)OR″、-OC(O)R′、-OC(O)NR′R″、-N(R′)C(O)OR″、-N(R′)C(O)R″、-N(R′″)C(O)NR′R″、-N(R′)S(O) 2R″、-S(O) mR′、-S(O) 2NR′R″，其中R′、R″和R′″各自独立地选自H、C 1-4烷基、C 3-7环烷基、卤代C 1-4烷基、4-7元杂环基、C 6-10芳基、5-10元杂芳基；在同一个氮原子上的R′和R″任选与它们连接的氮原子共同形成一任选含有另外的选自O、S和N的杂原子的4-7元杂环，且
m为1或2。
本发明的另一个实施方案涉及上述任一实施方案所述的化合物或其可药用的盐、前药、稳定同位素衍生物、异构体及其混合物形式，其中B为-NH-，C为-C(O)-。
本发明的另一个实施方案涉及上述任一实施方案所述的化合物，其中L为键。
本发明的另一个实施方案涉及上述任一实施方案所述的化合物，其中D和E均为CH。
本发明的另一个实施方案涉及上述任一实施方案所述的化合物，其中G为任选被卤素、CN、C 1-4烷基或-O-C 1-4烷基取代的5-10元杂芳基，特别是喹啉基或吡啶基，更特别是氟代喹啉基。
本发明的另一个实施方案涉及上述任一实施方案所述的化合物，其中R 1和R 2各自独立地选自H或C 1-4烷基，特别是R 1为C 1-4烷基、R 2为H，更特别是R 1为甲基、R 2为H。
本发明的另一个实施方案涉及上述任一实施方案所述的化合物，其为以下通式(IIIa)-(IIIc)的化合物：
Figure PCTCN2019000019-appb-000003
本发明的另一个实施方案涉及上述任一实施方案所述的化合物，其为以下通式(IV)的化合物：
Figure PCTCN2019000019-appb-000004
本发明的另一个实施方案涉及上述通式(IV)所示的化合物，其中R 1为甲基。
本发明的一个实施方案涉及上述通式(I)所示的化合物，其中所述化合物选自：
Figure PCTCN2019000019-appb-000005
Figure PCTCN2019000019-appb-000006
或其前药、稳定同位素衍生物、可药用的盐、异构体及其混合物形式。
本发明化合物对Hela细胞中IDO的活性具有显著抑制效应，优选其IC 50小于200nM，更优选IC 50小于50nM。
因此本发明化合物可用于治疗或者预防IDO介导的相关性疾病，包括但不限于癌症、免疫抑制、慢性感染、病毒感染、自身免疫性疾病或病症(例如类风湿关节炎)、神经或神经精神疾病或病症(例如抑郁症)等。本发明化合物用于治疗或者预防IDO相关性肿瘤，包括但不限于前列腺癌、结肠癌、直肠癌、膜腺癌、子宫颈癌、胃癌、子宫内膜癌、脑癌、肝癌、膀肮癌、卵巢癌、辜丸癌、头部癌、颈部癌、皮肤癌(包括黑素瘤及基底癌)、问皮内膜癌、淋巴瘤、白血病、食道癌、乳癌、肌肉癌、结缔组织癌、肺癌(包括小细胞肺癌及非小细胞癌)、肾上腺癌、甲状腺癌、肾癌、骨癌，胶质母细胞瘤、问皮瘤、肉瘤(包括卡波 西肉瘤)、绒膜癌、皮肤基底细胞癌或辜丸精原细胞瘤等。因此，再一方面，本发明提供一种治疗或者预防IDO介导的疾病(例如所述肿瘤)的方法，其包括给予有需要的患者治疗有效量的本发明所述化合物或其可药用的盐、前药、稳定同位素衍生物、异构体及其混合物、或包含所述化合物的药物组合物。
本发明的另一方面涉及作为药物或者用于医药用途的通式(I)所示的化合物或其可药用的盐、前药、稳定同位素衍生物、异构体及其混合物，其用于治疗或者预防IDO介导的疾病，例如癌症、免疫抑制、慢性感染、病毒感染、自身免疫性疾病或病症(例如类风湿关节炎)、神经或神经精神疾病或病症(例如抑郁症)等。
本发明进一步涉及一种药物组合物，所述药物组合物包含本发明所述化合物或其可药用的盐、前药、稳定同位素衍生物、异构体及其混合物及药学上可接受的载体和赋形剂。
本发明的另一方面涉及通式(I)所示的化合物或其可药用的盐、前药、稳定同位素衍生物、异构体及其混合物、或所述药物组合物在制备药物中的用途，其中所述药物用于治疗或者预防IDO介导的疾病，例如肿瘤和免疫抑制。
本发明的另一方面涉及一种药物组合物，所述药物组合物包含通式(I)所示的化合物或其可药用的盐、前药、稳定同位素衍生物、异构体及其混合物和至少一种额外的药物，其中所述至少一种额外的药物为化学治疗剂、免疫和/或炎症调节剂(比如免疫检查点抑制剂)、神经相关疾病调节剂或抗感染剂。
根据本发明，所述药物可以是任何药物剂型，包括但不限于片剂、胶囊剂、溶液剂、冻干制剂、注射剂。
本发明的药物制剂可以以每剂量单位包含预定量的活性成分的剂量单位形式给药。这种单位可根据治疗的病症、给药方法和患者的年龄、体重和状况包含例如0.5毫克至1克，优选1毫克至700毫克，特别优选5毫克至300毫克的本发明的化合物。优选剂量单位制剂是包含如上指示的日剂量或分剂量或其相应分数的活性成分的那些。此外，可以使用制药领域中公知的方法制备这种类型的药物制剂。
本发明药物制剂可适于通过任何所需的合适方法给药，例如通过经口(包括口腔或舌下)、直肠、经鼻、局部(包括口腔、舌下或经皮)、阴道或肠道外(包括皮下、肌内、静脉内或皮内)方法给药。可以使用制药领域中已知的所有方法通过例如将活性成分与一种或多种赋形剂或一种或多种辅助剂合并来制备这样的制剂。
具体实施方式
除非有相反陈述，否则下列用在说明书和权利要求书中的术语具有下述含义。
在本文中使用的表示方式“C x-y”表示碳原子数的范围，其中x和y均为整数，例如C 3-8环烷基表示具有3-8个碳原子的环烷基，即具有3、4、5、6、7或8个碳原子的环烷基。还应理解，“C 3-8”还包含其中的任意亚范围，例如C 3-7、C 3-6、C 4-7、C 4-6、C 5-6等。
“烷基”指含有1至20个碳原子，例如1至8个碳原子、1至6个碳原子或1至4个碳原子的饱和的直链或支链的烃基基团。烷基的非限制性实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1，1-二甲基丙基、1，2-二甲基丙基、2，2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1，1，2-三甲基丙基、1，1-二甲基丁基、1，2-二甲基丁基、2，2-二甲基丁基、1，3-二甲基丁基和2-乙基丁基。所述烷基可以是任选取代的。
“烯基”指含有至少一个碳碳双键和通常2至20个碳原子，例如2至8个碳原子、2至6个碳原子或2至4个碳原子的直链或支链的烃基基团。烯基的非限制性实例包括乙烯基、1-丙烯基、2-丙烯基、1-丁烯基、2-丁烯基、3-丁烯基、2-甲基-2-丙烯基、1，4-戊二烯基和1，4-丁二烯基。所述烯基可以是任选取代的。
“炔基”指含有至少一个碳碳三键和通常2至20个碳原子，例如2至8个碳原子、2至6个碳原子或2至4个碳原子的直链或支链的烃基基团。炔基的非限制性实例包括乙炔基、1-丙炔基、2-丙炔基、1-丁炔基、2-丁炔基和3-丁炔基。所述炔基可以是任选取代的。
“亚烷基”指含有1至20个碳原子，例如1至8个碳原子、1至6个碳原子或1至4个碳原子的直链或支链的饱和烃的二价基团。亚烷基的非限制性实例包括-CH 2-、-CH(CH 3)-、-CH 2CH 2-、-CH 2CH 2CH 2-、-CH 2CH 2CH 2CH 2-和-CH 2CH(CH 3)CH 2-。所述亚烷基可以是任选取代的。
“环烷基”指含有3至14个碳环原子的饱和环形烃基取代基。环烷基可以是单碳环，通常含有3至8个、3至7个或3至6个碳环原子。单环环烷基的非限制性实例包括环丙基、环丁基、环戊基、环己基和环庚基。环烷基可选择地可以是稠合到一起的双或三环，如十氢萘基。所述环烷基可以是任选取代的。
“杂环基或杂环”指饱和或部分不饱和的单环或多环环状基团，其包括3至20个环原子，例如可以是3至14个、3至12个、3至10个、3至8个、3至6个或5至6个环原子，其中一个或多个环原子选自氮、氧或S(O) m(其中m是整数0至2)，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。优选包括3至12个环原子，更优选3至10个环原子，更优选4至7个环原子，最优选5或6个环原子，其中1～4个是杂原子，更优选1～3个是杂原子，最优选1～2个是杂原子。单环杂环基的非限制性实例包含吡咯烷基、哌啶基、哌嗪基、吡喃基、吗啉基、硫代吗啉基、高哌嗪基、氧杂环己烷基和氮杂环丁烷基。多环杂环基包括稠合、桥接或螺多环杂环基。所述杂环基或杂环可以是任 选取代的。
“芳基或芳环”指含有6至14个碳原子的芳香族单环或稠合多环基团，优选为6至10元，例如苯基和萘基，最优选苯基。所述芳基环可以稠合于杂芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为芳基环，非限制性实例包括：
Figure PCTCN2019000019-appb-000007
所述芳基或芳环可以是任选取代的。
“杂芳基或杂芳环”指包含5至14个环原子的杂芳族体系，其中1至4个环原子选自包括氧、硫和氮的杂原子。杂芳基优选为5至10元。更优选杂芳基是5元或6元，例如呋喃基、噻吩基、吡啶基、吡咯基、N-烷基吡咯基、嘧啶基、吡嗪基、吡唑基、咪唑基、四唑基、噁唑基、异噁唑基、噻唑基、异噻唑基、喹啉基等。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环，非限制性实例包括：
Figure PCTCN2019000019-appb-000008
所述杂芳基或杂芳环可以是任选取代的。
“卤素”指氟、氯、溴或碘。
“氰基”指-CN。
“任选”或“任选地”意味着随后所描述的事件或环境可以但不必发生，该表述包括该事件或环境发生或不发生的场合。例如，“任选被烷基取代的杂环基团”意味着烷基可以但不必须存在，该表述包括杂环基团被烷基取代的情形和杂环基团不被烷基取代的情形。
“任选取代的”指基团中的一个或多个氢原子，优选为5个，更优选为1～3个氢原子彼此独立地被相应数目的取代基取代。不言而喻，取代基仅处在它们的可能的化学位置，本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如，具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。所述取代基包括但不限于卤素、-CN、-NO 2、氧代、-SF 5、C 1-4烷基、C 3-7环烷基、4-7元杂环基、苯基、5-6元杂芳基、-OR′、-NR′R″、-C(O)R′、-C(O)OR′、-C(O)NR′R″、-C(O)N(R′)OR″、-OC(O)R′、-OC(O)NR′R″、-N(R′)C(O)OR″、-N(R′)C(O)R″、-N(R′″)C(O)NR′R″、-N(R′)S(O) 2R″、-S(O) mR′(m为1或2)、-S(O) 2NR′R″等，其中R′、R″和R′″各自独立地选自H、C 1-4烷基、C 3-7环烷基、卤代C 1-4烷基、4-7元 杂环基、C 6-10芳基、5-10元杂芳基等；在同一个氮原子上的R′和R″任选与它们连接的氮原子共同形成一任选含有另外的选自O、S和N的杂原子的4-7元杂环。
“异构体”指具有相同分子式但其原子结合的性质或顺序或其原子的空间排列不同的化合物。其原子空间排列不同的异构体称为“立体异构体”。立体异构体包括光学异构体、几何异构体和构象异构体。
本发明的化合物可以以光学异构体形式存在。根据手性碳原子周围取代基的构型，这些光学异构体是“R”或“S”构型。光学异构体包括对映异构体和非对映异构体。制备和分离光学异构体的方法是本领域中已知的。
本发明的化合物也可以存在几何异构体。本发明考虑由碳-碳双键、碳-氮双键、环烷基或杂环基团周围的取代基的分布所产生的各种几何异构体和其混合物。碳-碳双键或碳-氮键周围的取代基指定为Z或E构型，环烷基或杂环周围的取代基指定为顺式或反式构型。
本发明的化合物还可能显示互变异构现象，例如酮-烯醇互变异构。
应该理解，本发明包括任何互变异构或立体异构形式和其混合物，并且不仅仅限于化合物的命名或化学结构式中所使用的任何一个互变异构或立体异构形式。
“同位素”包括在本发明化合物中出现的原子的所有同位素。同位素包括具有相同原子序数但不同质量数的那些原子。适合并入本发明化合物中的同位素的实例是氢、碳、氮、氧、磷、氟和氯，分别例如但不限于 2H、 3H、 13C、 14C、 15N、 18O、 17O、 31P、 32P、 35S、 18F和 36Cl。本发明的同位素标记化合物通常可通过本领域技术人员已知的传统技术或通过与所附实施例中描述的那些类似的方法使用适当的同位素标记的试剂代替非同位素标记的试剂来制备。这样的化合物具有各种潜在用途，例如作为测定生物活性中的标样和试剂。在稳定同位素的情况下，这样的化合物具有有利地改变生物、药理学或药代动力学性质的潜力。
“前药”是指本发明的化合物可以以前药的形式给予。前药是指在活体内的生理条件下例如通过氧化、还原、水解等(它们各自利用酶或在没有酶参与下进行)转化成本发明的生物活性化合物的衍生物。前药的实例是下述化合物：其中本发明的化合物中的氨基被酰化、烷基化或磷酸化，例如二十烷酰基氨基、丙氨酰氨基、新戊酰氧基甲基氨基，或其中羟基被酰化、烷基化、磷酸化或转化成硼酸盐，例如乙酰氧基、棕榈酰氧基、新戊酰氧基、琥珀酰氧基、富马酰氧基、丙氨酰氧基，或其中羧基被酯化或酰胺化，或其中巯基与选择性地向靶和/或向细胞的胞质溶胶递送药物的载体分子，例如肽形成二硫桥键。这些化合物可以由本发明的化合物根据公知方法制备。
“可药用的盐”或者“药学上可接受的盐”是指由可药用的碱或酸， 包括无机碱或酸和有机碱或酸制成的盐。在本发明的化合物含有一个或多个酸性或碱性基团的情况下，本发明还包含它们相应的可药用盐。因此，含有酸性基团的本发明的化合物可以以盐形式存在并可根据本发明使用，例如作为碱金属盐、碱土金属盐或作为铵盐。这样的盐的更确切实例包括钠盐、钾盐、钙盐、镁盐或与氨或有机胺，例如乙胺、乙醇胺、三乙醇胺或氨基酸的盐。含有碱性基团的本发明的化合物可以以盐形式存在并可根据本发明以它们与无机或有机酸的加成盐的形式使用。合适的酸的实例包括盐酸、氢溴酸、磷酸、硫酸、硝酸、甲磺酸、对甲苯磺酸、萘二磺酸、草酸、乙酸、酒石酸、乳酸、水杨酸、苯甲酸、甲酸、丙酸、特戊酸、丙二酸、琥珀酸、庚二酸、富马酸、马来酸、苹果酸、氨基磺酸、苯基丙酸、葡糖酸、抗坏血酸、异烟酸、柠檬酸、己二酸和本领域技术人员已知的其它酸。如果本发明的化合物在分子中同时含有酸性和碱性基团，本发明除所提到的盐形式外还包括内盐或内铵盐。各盐可通过本领域技术人员已知的常规方法获得，例如通过在溶剂或分散剂中使这些与有机或无机酸或碱接触或通过与其它盐阴离子交换或阳离子交换。
“药物组合物”指含有一种或多种本文所述的化合物或其可药用的盐、前药、稳定同位素衍生物、异构体及其混合物形式以及其他组分例如可药用的载体和赋形剂的组合物。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。
因此，在本申请中当提及“化合物”、“本发明化合物”或“本发明所述化合物”时，包括所有所述化合物形式，例如其可药用的盐、前药、稳定同位素衍生物、异构体及其混合物。
在本文中，术语“肿瘤”包括良性肿瘤和恶性肿瘤(例如癌症)。
在本文中，术语“治疗有效量”是指包括可有效抑制IDO的功能和/或治疗或防止所述疾病的本发明化合物的量。
合成方法
本发明还提供制备所述化合物的方法。本发明通式(I)所述化合物的制备，可通过以下示例性方法和实施例完成，但这些方法和实施例不应以任何方式被认为是对本发明范围的限制。也可通过本领域技术人员所知的合成技术合成本发明所述的化合物，或者综合使用本领域已知方法和本发明所述方法。每步反应所得的产物用本领域已知的分离技术得到，包括但不限于萃取、过滤、蒸馏、结晶、色谱分离等。合成所需的起始原料和化学试剂可以根据文献(可从SciFinder上查询)常规合成或购买。
本发明通式(I)所述五氟硫烷基取代的酰胺类化合物可按照方法A所述路线合成：先把中间体酸A2变成酰氯或用酰胺缩合剂活化，再与含有五氟硫烷取代基的(杂)芳胺A1偶联得到目标产物酰胺化合物A3。
方法A：
Figure PCTCN2019000019-appb-000009
本发明通式(I)所述五氟硫烷基取代的酰胺类化合物也可按照方法B所述路线合成：含有五氟硫烷取代基的(杂)芳基羧酸B1变成酰氯，再与中间体胺B2偶联得到目标产物酰胺化合物B3。
方法B：
Figure PCTCN2019000019-appb-000010
中间体酸A2可按照方法C所述路线合成：酮C1在碱性条件下与三氟甲磺酸酐反应生成烃烯基三氟甲磺酸酯C2；C2与硼酸酯或硼酸G-B(OR) 2通过Suzuki偶联反应得到C3，其经氢化还原生成C4；然后与一当量的卤代烷烃进行取代反应，也可接着与另一当量的卤代烷进行二次取代反应生成C5；最后在碱催化下水解得到酸A2。
方法C：
Figure PCTCN2019000019-appb-000011
中间体脂D7也可按照方法D所述路线合成：酮D1在碱性条件下与N-苯基双(三氟甲烷磺酰)亚胺反应生成烃烯基三氟甲磺酸酯D2；D2与硼酸酯或硼酸G-B(OR) 2通过Suzuki偶联反应得到D3，其经氢化和脱保护生成酮D4；酮D4还原生成主要是反式的醇D5；醇D5在碱性条件下生成甲磺酰酯D6；D6被丙二酸二叔丁酯的钠盐取代生成顺式的中间体，然后在酸性条件下脱保护和脱羧生成顺式的中间体脂D7。
方法D：
Figure PCTCN2019000019-appb-000012
中间体酸A2也可按照方法E所述路线合成：E1与卤化物G-X通过Buchwald偶联反应得到E2；E2在酸催化下脱Boc得到E3；E3经过取代反应得到E4；最后在碱催化下水解得到酸A2。
方法E：
Figure PCTCN2019000019-appb-000013
中间体酸A2还可按照方法F所述路线合成：F1与卤化物G-X通过Buchwald偶联反应得到F2；F2用碱(比如LHMDS)脱氢，然后与一当量的卤代烷烃进行取代反应，也可接着与另一当量的卤代烷进行二次取代反应生成F3；最后在碱催化下水解得到酸A2。
方法F：
Figure PCTCN2019000019-appb-000014
中间体酸A2还可按照方法G所述路线合成：G1用硼试剂还原为G2；G2进行亲核取代反应或光延反应得到G3；G3在碱催化下水解得到酸A2。
方法G：
Figure PCTCN2019000019-appb-000015
手性中间体酸A2可按照方法H所述路线合成：酸H1先与酰氯(比如特戊酰氯)在碱催化下生成一酸酐，然后被(R)-手性助剂(比如(R)-4-苯甲基噁唑烷-2-酮的锂盐)取代生成(R)-H2；(R)-H2用强碱脱氢，再与碘甲烷反应得到(R)-H3；最后在碱催化下水解得到酸(R)-A2。如果使用(S)-手性助剂(比如(S)-4-苯甲基噁唑烷-2-酮)，则得到(S)-A2。
方法H：
Figure PCTCN2019000019-appb-000016
中间体胺B2可按照方法I所述路线合成：通过类似方法C和G从I1得到I2；I2被LAH还原成醇，接着用戴斯-马丁氧化剂氧化生成醛I3；I3和格试剂反应生成I4；I4经过光延反应生成I5；最后脱保护得到胺B2。
方法I：
Figure PCTCN2019000019-appb-000017
实施例
化合物的结构是通过核磁共振(NMR)或质谱(MS)来确定的。 NMR的测定是用Bruker ASCEND-400核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d 6)、氘代氯仿(CDCl 3)、氘代甲醇(CD 3OD)，内标为四甲基甲硅烷(TMS)，化学位移是以10 -6(ppm)作为单位给出。
MS的测定用Agilent SQD(ESI)质谱仪(生产商：Agilent，型号：6120)。
HPLC的测定使用安捷伦1260DAD高压液相色谱仪(Poroshell120EC-C18，50×3.0mm，2.7μm色谱柱)或Waters Arc高压液相色谱仪(Sunfirc C18，150×4.6mm，5μm色谱柱)。
薄层层析硅胶板使用青岛海洋GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm～0.2mm，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm硅胶板。
柱层析一般使用青岛海洋200～300目硅胶为载体。
本发明的已知的起始原料可以采用或按照本领域已知的方法来合成，或可购买自ABCR GmbH&Co.KG、Acros Organics、Aldrich Chemical Company、韶远化学科技(Accela ChemBio Inc.)、北京耦合化学品等公司。
实施例中如无特殊说明，反应均在氩气气氛或氮气气氛下进行。
氩气气氛或氮气气氛是指反应瓶连接一个约1L容积的氩气或氮气气球。
氢气气氛是指反应瓶连接一个约1L容积的氢气气球。
氢化反应通常抽真空，充入氢气，反复操作3次。
微波反应使用CEM Discover-SP型微波反应器。
实施例中如无特殊说明，反应的温度为室温，温度范围是20℃-30℃。
实施例中的反应进程的监测使用安捷伦的液质联用仪(1260/6120)。反应进程的监测也可采用薄层色谱法(TLC)，展开剂所使用的体系有A：二氯甲烷和甲醇体系；B：石油醚和乙酸乙酯体系，溶剂的体积比根据化合物的极性不同而进行调节。
纯化化合物采用的柱层析的洗脱剂的体系和薄层色谱法的展开剂的体系包括A：二氯甲烷和甲醇体系；B：石油醚和乙酸乙酯体系，溶剂的体积比根据化合物的极性不同而进行调节，也可以加入少量的三乙胺和酸性或碱性试剂等进行调节。纯化化合物还采用Waters的质谱导向自动制备系统(质谱检测器：SQD2)，根据化合物的极性用适当的乙腈/水(含0.1％三氟乙酸)或乙腈/水(含0.05％氨水)梯度于20ml/min的流速洗脱反相高压柱(XBridge-C18，19×150mm，5μm)。
实施例1
(R)-2-((1s，4S)-4-(6-氟喹啉-4-基)环己基)-N-(4-(五氟-λ 6-硫烷基)苯基)丙酰胺
Figure PCTCN2019000019-appb-000018
第一步
2-(4-(((三氟甲基)磺酰)氧基)环己-3-烯-1-基)乙酸乙酯
将化合物2，6-二叔丁-4-甲基吡啶(4.1g，20mmol)溶于二氯甲烷(15ml)中，然后依次加入2-(4-羰基环己基)乙酸乙酯1a(1.80g，18mmol)和三氟甲磺酸酐(5.4g，19mmol)。反应混合物在氩气气氛下室温搅拌24小时后过滤。减压除去溶剂，残余物用乙酸乙酯洗涤(30ml×3)。有机相合并后，依次用冷的1N盐酸(50ml)和饱和食盐水(50ml)洗涤后用无水碳酸钠干燥。再次过滤后，滤液减压除去溶剂得到目标产物2-(4-(((三氟甲基)磺酰)氧基)环己-3-烯-1-基)乙酸乙酯1b(3.0g，无色油状物)，产率：76％。
1H NMR(400MHz，CDCl 3)δ5.72-5.62(m，1H)，4.11(q，J＝7.1Hz，2H)，2.45-2.21(m，5H)，2.19-2.01(m，1H)，1.96-1.83(m，2H)，1.49(dtd，J＝13.1，10.3，5.9Hz，1H)，1.23(t，J＝7.1Hz，3H)。
第二步
2-(4-(6-氟喹啉-4-基)环己-3-烯-1-基)乙酸乙酯
将混合物2-(4-(((三氟甲基)磺酰)氧基)环己-3-烯-1-基)乙酸乙酯1b(3.48g，11mmol)、(6-氟喹啉-4-基)硼酸(1.91g，10mmol)、[1，1′-双(二苯基膦基)二茂铁]二氯化钯二氯甲烷络合物(41mg，0.5mmol)、碳酸钾(2.76g，20mmol)、水(10ml)和1，4-二氧六环(30ml)在氮气保护下加热至100℃，并继续搅拌2小时。将反应混合物冷却至室温，减压浓缩，残余物用硅胶柱层析纯化(石油醚/乙酸乙酯＝50/1至10/1)，得到目标产物2-(4-(6-氟喹啉-4-基)环己-3-烯-1-基)乙酸乙酯1c(2.5g， 黄色油状物)，产率：80％。
MS m/z(ESI)：314[M+1]
第三步
2-(4-(6-氟喹啉-4-基)环己基)乙酸乙酯
将2-(4-(6-氟喹啉-4-基)环己-3-烯-1-基)乙酸乙酯1c(2.5g，8mmol)溶于甲醇(50ml)，然后加入10％钯碳(250mg)，在氢气气氛下室温下搅拌2小时。过滤，减压浓缩滤液，得到目标产物2-(4-(喹啉-4-基)环己基)乙酸乙酯1d(2.2g，淡黄色固体)，产率：88％。
MS m/z(ESI)：316[M+1]
第四步
2-(4-(6-氟喹啉-4-基)环己基)乙酸
将2-(4-(6-氟喹啉-4-基)环己基)乙酸乙酯1d(3.15g，10mmol)、氢氧化锂一水合物(630mg，15mmol)和四氢呋喃(20ml)混合，然后加入水(10ml)。反应混合物加热至50℃，搅拌5小时。反应完成后，在减压条件下除去溶剂，残余物用反相高效液相色谱纯化，得到目标产物2-(4-(6-氟喹啉-4-基)环己基)乙酸1e(2.53g，白色固体)，产率：88％。
MS m/z(ESI)：288[M+1]
第五步
(R)-4-苯甲基-3-(2-(4-(6-氟喹啉-4-基)环己基)乙酰基)噁唑烷-2-酮
将化合物2-(4-(6-氟喹啉-4-基)环己基)乙酸1e(287mg，1mmol)溶于无水四氢呋喃(10ml)，加入三乙胺(202mg，2mmol)并在氮气气氛下冷却到-78℃，然后逐滴加入特戊酰氯(150mg，1.25mmol)。在0℃下搅拌一小时后，得到一个混悬液待用。
将(R)-4-苯甲基噁唑烷-2-酮(230mg，1.3mmol)溶于无水四氢呋喃(10ml)，冷却到-78℃，然后在氮气气氛下逐滴加入正丁基锂的己烷溶液(2.5M，0.52ml，1.3mmol)。在-78℃下搅拌15分钟后，逐渐升温到0℃并搅拌15分钟。然后将生成的淡黄色溶液再次冷却到-78℃待用。
将上述混悬液冷却到-78℃，然后加入已经冷却到-78℃的淡黄色溶液。反应混合物逐渐升温至室温并继续搅拌3小时。向反应混合物中加入饱和氯化铵溶液(10ml)，并用乙酸乙酯萃取(50ml×3)。有机相合并后，用饱和食盐水(20ml×2)洗涤。用无水硫酸钠干燥后过滤，滤液在减压条件下除去溶剂，残余物用硅胶柱层析(石油醚/乙酸乙酯＝1/1至1/5)纯化，得到目标产物(R)-4-苯甲基-3-(2-(4-(6-氟喹啉-4-基)环己基)乙酰基)噁唑烷-2-酮1f(350mg，无色油状物)，产率：78％。
MS m/z(ESI)：447[M+1]
第六步
(R)-4-苯甲基-3-((R)-2-(4-(6-氟喹啉-4-基)环己基)丙酰)噁唑烷-2-酮
将化合物(R)-4-苯甲基-3-(2-(4-(6-氟喹啉-4-基)环己基)乙酰基)噁唑烷-2-酮1f(223mg，0.5mmol)溶于无水四氢呋喃(5ml)，冷却到-50℃， 然后加入二(三甲基硅烷基)氨基钠的四氢呋喃溶液(2M，0.3ml，0.6mmol)。搅拌10分钟后，在此温度下加入碘甲烷(99.4mg，0.7mmol)并继续搅拌2小时。用饱和氯化铵溶液(10ml)淬灭后，用乙酸乙酯萃取(20ml×3)。有机相合并后，用饱和食盐水(20ml)洗涤。用无水硫酸钠干燥后过滤，滤液在减压条件下除去溶剂，残余物用硅胶柱层析(石油醚/乙酸乙酯＝1/1至1/5)纯化，得到目标产物(R)-4-苯甲基-3-((R)-2-(4-(6-氟喹啉-4-基)环己基)丙酰)噁唑烷-2-酮1g(180mg，无色油状物)，产率：78％。
MS m/z(ESI)：461[M+1]
第七步
(R)-2-(4-(6-氟喹啉-4-基)环己基)丙酸
将化合物(R)-4-苯甲基-3-((R)-2-(4-(6-氟喹啉-4-基)环己基)丙酰)噁唑烷-2-酮1g(500mg，1.1mmol)、水(10ml)和四氢呋喃(10ml)混合，冷却到0℃，然后依次加入35％过氧化氢溶液(0.5mL)和氢氧化锂一水合物(73mg，1.74mmol)。逐渐升温到室温后，继续搅拌1小时。重新冷却到0℃，缓慢加入饱和亚硫酸钠溶液淬灭反应。用乙酸乙酯萃取(20ml×3)。有机相合并后减压条件下除去溶剂，残余物用硅胶柱层析(石油醚/乙酸乙酯＝1/1至1/4)纯化，得到目标产物(R)-2-(4-(6-氟喹啉-4-基)环己基)丙酸1h(250mg，无色油状物)，产率：76％。
MS m/z(ESI)：302[M+1]
第八步
(R)-2-((1s，4S)-4-(6-氟喹啉-4-基)环己基)-N-(4-(五氟-λ 6-硫烷基)苯基)丙酰胺
将化合物(R)-2-(4-(6-氟喹啉-4-基)环己基)丙酸1h(250mg，无色油状物)溶于二氯甲烷(10ml)，冷却到0℃后，依次加入草酰氯(254mg，2mmol)和N，N-二甲基甲酰胺(0.025ml)。逐渐升温到室温后，搅拌1小时，减压除去溶剂。残余物与4-(五氟-λ 6-硫烷基)苯胺(328mg，1.5mmol)、三乙胺(202mg，2mmol)和二氯甲烷(20ml)混合，然后加热回流3小时。冷却到室温后，减压除去溶剂，残余物用反相制备高效液相色谱纯化，得到目标产物(R)-2-((1s，4S)-4-(6-氟喹啉-4-基)环己基)-N-(4-(五氟-λ 6-硫烷基)苯基)丙酰胺1(97.1mg，白色固体)，产率：18％；以及(R)-2-((1r，4R)-4-(6-氟喹啉-4-基)环己基)-N-(4-(五氟-λ 6-硫烷基)苯基)丙酰胺2(61.6mg，白色固体)，产率：11％
MS m/z(ESI)：503[M+1]
1H NMR(400MHz，CD 3OD)δ8.81(d，J＝4.7Hz，1H)，8.11(dd，J＝9.3，5.6Hz，1H)，7.92(dd，J＝10.6，2.7Hz，1H)，7.85-7.73(m，4H)，7.67-7.56(m，2H)，3.47(d，J＝3.5Hz，1H)，2.95(dd，J＝10.9，6.8Hz，1H)，2.17-2.03(m，2H)，2.01-1.77(m，7H)，1.30(d，J＝6.8Hz，3H)。
实施例2
(R)-2-((1r，4R)-4-(6-氟喹啉-4-基)环己基)-N-(4-(五氟-λ 6-硫烷基)苯基)丙酰胺
Figure PCTCN2019000019-appb-000019
实施例2可以在实施例1的合成中同时得到。
MS m/z(ESI)：503[M+1]
1H NMR(400MHz，CD 3OD)δ9.13(s，1H)，8.35(s，2H)，8.09(d，J＝3.2Hz，2H)，7.81(t，J＝7.6Hz，4H)，3.65(t，J＝11.9Hz，1H)，2.45(dd，J＝14.4，7.1Hz，1H)，2.20(s，4H)，1.88-1.73(m，3H)，1.64-1.43(m，2H)，1.31(d，J＝6.9Hz，3H)。
实施例3
(R)-2-((1s，4S)-4-(2-甲基吡啶-4-基)环己基)-N-(4-(五氟-λ 6-硫烷基)苯基)丙酰胺
Figure PCTCN2019000019-appb-000020
第一步
1，4-二氧杂螺[4.5]癸-7-烯-8-基三氟甲磺酸酯
将化合物1，4-二氧杂螺[4.5]癸烷-8-酮3a(50g，320mmol)溶于无水四氢呋喃(500ml)，在氮气气氛下冷却到-40℃，然后加入二(三甲基硅基)氨基钠的四氢呋喃溶液(2M，192ml，384mmol)。在-40℃下搅拌1小时后，逐渐加入N-苯基双(三氟甲烷磺酰)亚胺(137g，384mmol)的四氢呋喃溶液(200ml)并继续搅拌1小时。反应完成后，用饱和硫酸氢钾溶液(50ml)淬灭，过滤后滤液在减压条件除去溶剂。残余物溶 于甲基叔丁基醚(500ml)和石油醚(500ml)的混合溶剂后过滤，滤液用30％氢氧化钠溶液(200ml×3)后，用无水硫酸钠干燥，过滤后减压除去溶剂，得到目标产物1，4-二氧杂螺[4.5]癸-7-烯-8-基三氟甲磺酸酯3b(71.5g，无色油状物)，产率：77％。
1H NMR(400MHz，CDCl 3)δ5.66(tt，J＝4.0，1.3Hz，1H)，4.05-3.93(m，4H)，2.60-2.47(m，2H)，2.41(dt，J＝4.0，2.5Hz，2H)，1.90(t，J＝6.6Hz，2H)。
第二步
2-甲基-4-(1，4-二氧杂螺[4.5]癸-7-烯-8-基)吡啶
将混合物1，4-二氧杂螺[4.5]癸-7-烯-8-基三氟甲磺酸酯3b(4.0g，13.9mmol)、2-甲基-4-吡啶硼酸(1.58g，11.6mmol)、[1，1′-双(二苯基膦基)二茂铁]二氯化钯二氯甲烷络合物(422mg，0.57mmol)、碳酸钾(2.39g，17.4mmol)、水(10ml)和1，4-二氧六环(50ml)在氮气保护下加热至100℃，并继续搅拌3小时。将反应混合物冷却至室温，减压浓缩，残余物用硅胶柱层析纯化(二氯甲烷/甲醇＝9/1)，得到目标产物2-甲基-4-(1，4-二氧杂螺[4.5]癸-7-烯-8-基)吡啶3c(2.3g，无色油状物)，产率：86％。
MS m/z(ESI)：232[M+1]
第三步
2-甲基-4-(1，4-二氧杂螺[4.5]癸烷-8-基)吡啶
将2-甲基-4-(1，4-二氧杂螺[4.5]癸-7-烯-8-基)吡啶3c(2.3g，9.95mmol)溶于甲醇(30ml)，然后加入10％钯碳(230mg)，在氢气气氛下室温下搅拌2小时。过滤，减压浓缩滤液，得到目标产物2-甲基-4-(1，4-二氧杂螺[4.5]癸烷-8-基)吡啶3d(2.3g，无色油状物)，产率：99％。
MS m/z(ESI)：234[M+1]
第四步
4-(2-甲基吡啶-4-基)环己-1-酮
将化合物2-甲基-4-(1，4-二氧杂螺[4.5]癸烷-8-基)吡啶3d(2.3g，9.87mmol)溶于四氢呋喃(30ml)，然后加入6N盐酸(5ml)。加热至50℃并搅拌18小时后，减压除去溶剂，残余物用饱和碳酸氢钠溶液(5ml)中和，然后用乙酸乙酯(50ml×3)萃取。有机相合并后，减压除去溶剂，残余物用硅胶柱层析(二氯甲烷/甲醇＝9/1)纯化，得到目标产物4-(2-甲基吡啶-4-基)环己-1-酮3e(1.8g，无色油状物)，产率：96％。
MS m/z(ESI)：190[M+1]
第五步
(1r，4r)-4-(2-甲基吡啶-4-基)环己烷-1-醇
将化合物4-(2-甲基吡啶-4-基)环己-1-酮3e(1.8g，无色油状物)溶于异丙醇(30ml)，冷却到0℃，加入硼氢化钠(361mg，9.52mmol)。 0℃下搅拌1小时后，用饱和氯化铵溶液淬灭并过滤。滤液减压除去溶剂，残余物用硅胶柱层析(二氯甲烷/甲醇＝9/1)纯化，得到目标产物(1r，4r)-4-(2-甲基吡啶-4-基)环己烷-1-醇3f(1.6g，无色油状物)，产率：88％。
MS m/z(ESI)：192[M+1]
第六步
(1r，4r)-4-(2-甲基吡啶-4-基)环己基甲磺酸酯
将化合物(1r，4r)-4-(2-甲基吡啶-4-基)环己烷-1-醇3f(1.6g，8.37mmol)溶于无水四氢呋喃(30ml)，冷却到0℃，依次加入三乙胺(1.27g，12.6mmol)和甲磺酰氯(1.06g，9.21mmol)。0℃下搅拌1小时后过滤，滤液减压除去溶剂，残余物用硅胶柱层析(二氯甲烷/甲醇＝9/1)纯化，得到目标产物(1r，4r)-4-(2-甲基吡啶-4-基)环己基甲磺酸酯3g(2.2g，无色油状物)，产率：98％。
MS m/z(ESI)：270[M+1]
第七步
2-((1s，4s)-4-(2-甲基吡啶-4-基)环己基)乙酸
将丙二酸二叔丁酯(5.54g，25.6mmol)溶于无水四氢呋喃(30ml)，冷却到0℃，然后加入60％氢化钠(1.02g，25.5mmol)。搅拌30分钟后，加入(1r，4r)-4-(2-甲基吡啶-4-基)环己基甲磺酸酯3g(2.2g，8.17mmol)，加热到90℃并搅拌18小时。冷却到室温后，用6N盐酸调节至pH＝2，然后加热到100℃并搅拌18小时。冷却到室温后，减压除去溶剂，残余物用硅胶柱层析(二氯甲烷/甲醇＝9/1)纯化，得到目标产物2-((1s，4s)-4-(2-甲基吡啶-4-基)环己基)乙酸3h(1.9g，无色油状物)，产率：99％。
MS m/z(ESI)：234[M+1]
第八步
(R)-4-苯甲基-3-(2-((1s，4S)-4-(2-甲基吡啶-4-基)环己基)乙酰基)噁唑烷-2-酮
将化合物2-((1s，4s)-4-(2-甲基吡啶-4-基)环己基)乙酸3h(1.9g，8.14mmol)溶于无水四氢呋喃(20ml)，加入三乙胺(1.73g，17.16mmol)并在氮气气氛下冷却到-78℃，然后逐滴加入特戊酰氯(1.13g，9.44mmol)。在0℃下搅拌一小时后，得到一个混悬液待用。
将(R)-4-苯甲基噁唑烷-2-酮(1.97g，11.15mmol)溶于无水四氢呋喃(10ml)，冷却到-78℃，然后在氮气气氛下逐滴加入正丁基锂的己烷溶液(2.5M，4.4ml，11mmol)。在-78℃下搅拌15分钟后，逐渐升温到0℃并搅拌15分钟。然后将生成的淡黄色溶液再次冷却到-78℃待用。
将上述混悬液冷却到-78℃，然后加入已经冷却到-78℃的淡黄色溶液。反应混合物逐渐升温至室温并继续搅拌3小时。向反应混合物中加入饱和氯化铵溶液(100ml)，并用乙酸乙酯萃取(100ml×3)。有机 相合并后，用饱和食盐水(20ml×2)洗涤。用无水硫酸钠干燥后过滤，滤液在减压条件下除去溶剂，残余物用硅胶柱层析(二氯甲烷/甲醇＝9/1)纯化，得到目标产物(R)-4-苯甲基-3-(2-((1s，4S)-4-(2-甲基吡啶-4-基)环己基)乙酰基)噁唑烷-2-酮3i(3g，无色油状物)，产率：91％。
MS m/z(ESI)：393[M+1]
第九步
(R)-4-苯甲基-3-((R)-2-((1s，4S)-4-(2-甲基吡啶-4-基)环己基)丙酰)噁唑烷-2-酮
将化合物(R)-4-苯甲基-3-(2-((1s，4S)-4-(2-甲基吡啶-4-基)环己基)乙酰基)噁唑烷-2-酮3i(3g，7.65mmol)溶于无水四氢呋喃(30ml)，冷却到-50℃，然后加入二(三甲基硅烷基)氨基钠的四氢呋喃溶液(2M，7.7ml，15.4mmol)。搅拌30分钟后，在此温度下加入碘甲烷(1.63g，11.48mmol)并继续搅拌3小时。用饱和氯化铵溶液(10ml)淬灭后，逐渐升温到室温，然后用乙酸乙酯萃取(50ml×3)。有机相合并后，用饱和食盐水(20ml)洗涤。用无水硫酸钠干燥后过滤，滤液在减压条件下除去溶剂，残余物用硅胶柱层析(二氯甲烷/甲醇＝9/1)纯化，得到目标产物(R)-4-苯甲基-3-((R)-2-((1s，4S)-4-(2-甲基吡啶-4-基)环己基)丙酰)噁唑烷-2-酮3j(3.02g，无色油状物)，产率：96％。
MS m/z(ESI)：407[M+1]
第十步
(R)-2-((1s，4S)-4-(2-甲基吡啶-4-基)环己基)丙酸
将化合物(R)-4-苯甲基-3-((R)-2-((1s，4S)-4-(2-甲基吡啶-4-基)环己基)丙酰)噁唑烷-2-酮3j(3g，7.38mmol)、水(10ml)和四氢呋喃(30ml)混合，冷却到0℃，然后依次加入35％过氧化氢溶液(2mL)和氢氧化锂一水合物(266mg，11.03mmol)。逐渐升温到室温后，继续搅拌1小时。重新冷却到0℃，缓慢加入饱和亚硫酸钠溶液淬灭反应。用乙酸乙酯萃取(50ml×3)。有机相合并后减压条件下除去溶剂，残余物用硅胶柱层析(二氯甲烷/甲醇＝9/1)纯化，然后再用反相高效液相色谱纯化，得到目标产物(R)-2-((1s，4S)-4-(2-甲基吡啶-4-基)环己基)丙酸3k(500mg，无色油状物)，产率：27％。
MS m/z(ESI)：248[M+1]
第十一步
(R)-2-((1s，4S)-4-(2-甲基吡啶-4-基)环己基)-N-(4-(五氟-λ 6-硫烷基)苯基)丙酰胺
将化合物(R)-2-((1s，4S)-4-(2-甲基吡啶-4-基)环己基)丙酸3k(50mg，0.202mmol)溶于二氯甲烷(10ml)，然后加入草酰氯(0.5ml)。室温下搅拌30分钟后，减压除去溶剂，残余物与4-(五氟-λ 6-硫烷基)苯胺(44mg，0.2mmol)和三乙胺(41mg，0.4mmol)共同溶于四氢呋喃(10ml)。室温下搅拌3小时后，减压除去溶剂，残余物用反相高效液相色谱纯化， 得到目标产物(R)-2-((1s，4S)-4-(2-甲基吡啶-4-基)环己基)-N-(4-(五氟-λ 6-硫烷基)苯基)丙酰胺3(27mg，白色固体)，产率：30％。
MS m/z(ESI)：449[M+1]
1H NMR(400MHz，CD 3OD)δ8.32(d，J＝5.1Hz，1H)，7.78(brs，4H)，7.35-7.19(m，2H)，2.75(d，J＝6.6Hz，2H)，2.54(s，3H)，2.02-1.99(m，2H)，1.87-1.61(m，7H)，1.24(d，J＝6.6Hz，3H)。
实施例4
(R)-N-(4-(五氟-λ 6-硫烷基)苯基)-2-(4-(吡唑并[1，5-a]嘧啶-7-基)环己基)丙酰胺
Figure PCTCN2019000019-appb-000021
第一步
2-(4-(吡唑并[1，5-a]嘧啶-7-基)环己-3-烯-1-基)乙酸乙酯
将化合物2-(4-(((三氟甲基)磺酰)氧基)环己-3-烯-1-基)乙酸乙酯1b(632mg，2.00mmol)、双(频哪醇合)二硼(610mg，2.40mmol)、乙酸钾(392mg，4.00mmol)、[1，1′-双(二苯基膦基)二茂铁]二氯化钯二氯甲烷络合物(146mg，0.2mmol)和1，4-二氧六环(20ml)混合，在减压条件下除氧，然后在氮气气氛下加热至100℃。搅拌15小时后，冷却至室温后，然后依次加入7-氯吡唑并[1，5-a]嘧啶(368mg，2.40mmol)、碳酸钾(331mg，2.40mmol)和[1，1′-双(二苯基膦基)二茂铁]二氯化钯二氯甲烷络合物(146mg，0.2mmol)，在减压条件下除氧后，再次在氮气气氛下加热至100℃并搅拌4小时。冷却到室温后，减压除去溶剂，残余物用硅胶柱层析(石油醚/乙酸乙酯＝100/1至5/1)纯化，得到目标产物2-(4-(吡唑并[1，5-a]嘧啶-7-基)环己-3-烯-1-基)乙酸乙酯4a (420mg，黄色油状物)，产率：74％。
MS m/z(ESI)：286[M+H]
第二步
2-(4-(吡唑并[1，5-a]嘧啶-7-基)环己基)乙酸乙酯
将化合物2-(4-(吡唑并[1，5-a]嘧啶-7-基)环己-3-烯-1-基)乙酸乙酯4a(420mg，1.47mmol)溶于乙醇(20ml)和四氢呋喃(20ml)的混合溶剂中，然后加入10％钯碳(210mg)并在氢气气氛下搅拌2小时。过滤后，滤液在减压条件下除去溶剂，得到目标产物2-(4-(吡唑并[1，5-a]嘧啶-7-基)环己基)乙酸乙酯4b(420mg，黄色油状物)，产率：99％。
MS m/z(ESI)：288[M+H]
第三步
2-(4-(吡唑并[1，5-a]嘧啶-7-基)环己基)乙酸
将化合物2-(4-(吡唑并[1，5-a]嘧啶-7-基)环己基)乙酸乙酯4b(420mg，1.46mmol)溶于四氢呋喃(20ml)，然后加入氢氧化锂水溶液(1M，3ml，3mmol)。室温下搅拌24小时后，用1N盐酸调节至pH＝6至7，然后在减压条件下除去溶剂。残余物用反相制备高效液相色谱纯化，得到目标产物2-(4-(吡唑并[1，5-a]嘧啶-7-基)环己基)乙酸4c(300mg，白色固体)，产率：79％。
MS m/z(ESI)：260[M+H]
第四步
(R)-4-苯甲基-3-(2-(4-(吡唑并[1，5-a]嘧啶-7-基)环己基)乙酰基)噁唑烷-2-酮
将化合物2-(4-(吡唑并[1，5-a]嘧啶-7-基)环己基)乙酸4c(300mg，1.16mmol)和三乙胺(236mg，2.32mmol)溶于四氢呋喃(20ml)，冷却至-10℃，然后加入特戊酰氯(174mg，1.45mmol)，然后逐渐升温到室温并搅拌30分钟，然后冷却到-78℃待用。
将化合物(R)-4-苯甲基噁唑烷-2-酮(268mg，1.51mmol)溶于无水四氢呋喃(20ml)，冷却到-78℃，然后加入正丁基锂(2.4M，0.63mL，1.51mmol)并在此温度下搅拌30分钟，得到一澄清溶液。将此溶液逐渐滴加到上述-78℃的待用混合物中，然后边搅拌边逐渐升温到室温并继续搅拌30分钟。减压除去溶剂，残余物用反相制备高效液相色谱纯化，得到目标产物(R)-4-苯甲基-3-(2-(4-(吡唑并[1，5-a]嘧啶-7-基)环己基)乙酰基)噁唑烷-2-酮4d(410mg，白色固体)，产率：84％。
MS m/z(ESI)：419[M+H]
第五步
(R)-4-苯甲基-3-((R)-2-(4-(吡唑并[1，5-a]嘧啶-7-基)环己基)丙酰)噁唑烷-2-酮
将化合物(R)-4-苯甲基-3-(2-(4-(吡唑并[1，5-a]嘧啶-7-基)环己基)乙酰基)噁唑烷-2-酮4d(410mg，0.98mmol)溶于无水四氢呋喃(20ml)， 冷却到-50℃，然后加入二(三甲基硅基)氨基钠的四氢呋喃溶液(2N，0.98ml，1.96mmol)并在此温度下搅拌1小时。逐滴加入碘甲烷(417mg，2.94mmol)，并在-50℃并继续搅拌5小时。向反应混合物中加入饱和柠檬酸溶液(2ml)并升温到室温，然后加入饱和食盐水(10ml)并用乙酸乙酯(50ml×2)萃取。有机相合并后用无水硫酸钠干燥，过滤后滤液在减压条件下除去溶剂，残余物残余物用反相制备高效液相色谱纯化，得到目标产物(R)-4-苯甲基-3-((R)-2-(4-(吡唑并[1，5-a]嘧啶-7-基)环己基)丙酰)噁唑烷-2-酮4e(300mg，白色固体)，产率：71％。
MS m/z(ESI)：433[M+H]
第六步
(R)-2-(4-(吡唑并[1，5-a]嘧啶-7-基)环己基)丙酸
将化合物(R)-4-苯甲基-3-((R)-2-(4-(吡唑并[1，5-a]嘧啶-7-基)环己基)丙酰)噁唑烷-2-酮4e(300mg，0.69mmol)、30％过氧化氢溶液(0.5ml)和四氢呋喃(15ml)混合，冷却到0℃，然后加入氢氧化锂水溶液(1N，1ml)并逐渐升温到室温。搅拌15小时后，加入甲酸(0.5ml)，然后在减压条件下除去溶剂。残余物残余物用反相制备高效液相色谱纯化，得到目标产物(R)-2-(4-(吡唑并[1，5-a]嘧啶-7-基)环己基)丙酸4f(130mg，白色固体)，产率：69％。
MS m/z(ESI)：274[M+H]
第七步
(R)-2-(4-(吡唑并[1，5-a]嘧啶-7-基)环己基)丙酸-3H-[1，2，3]三唑并[4，5-b]吡啶-3-基酯
将化合物(R)-2-(4-(吡唑并[1，5-a]嘧啶-7-基)环己基)丙酸4f(40mg，0.146mmol)和三乙胺(45mg，0.44mmol)溶于N，N-二甲基甲酰胺(2ml)，然后加入2-(7-氧化苯并三氮唑)-N，N，N′，N′-四甲基脲六氟磷酸盐(167mg，0.44mmol)并继续搅拌1小时。减压除去溶剂，残余物残余物用反相制备高效液相色谱纯化，得到目标产物(R)-2-(4-(吡唑并[1，5-a]嘧啶-7-基)环己基)丙酸-3H-[1，2，3]三唑并[4，5-b]吡啶-3-基酯4g(40mg，白色固体)，产率：70％。
MS m/z(ESI)：392[M+H]
第八步
(R)-N-(4-(五氟-λ6-硫烷基)苯基)-2-(4-(吡唑并[1，5-a]嘧啶-7-基)环己基)丙酰胺
将化合物4-(五氟-λ 6-硫烷基)苯胺(45mg，0.2mmol)溶于四氢呋喃(3ml)，冷却到0℃，然后加入氢化钠(60％，6mg，0.15mmol)。搅拌30分钟后，加入(R)-2-(4-(吡唑并[1，5-a]嘧啶-7-基)环己基)丙酸-3H-[1，2，3]三唑并[4，5-b]吡啶-3-基酯4g(40mg，0.1mmol)的四氢呋喃溶液(1ml)。室温下搅拌1小时后，用水(0.5ml)淬灭，然后减压除去溶剂。残余物用反相制备高效液相色谱纯化，得到目标产物(R)-N-(4-(五氟-λ 6-硫烷 基)苯基)-2-(4-(吡唑并[1，5-a]嘧啶-7-基)环己基)丙酰胺4(1.1mg，白色固体)，产率：2％。
MS m/z(ESI)：475[M+1]
1H NMR(400MHz，CD 3OD)δ8.36(dd，J＝11.6，4.4Hz，1H)，8.07(t，J＝2.1Hz，1H)，7.77-7.53(m，4H)，6.84(dd，J＝34.1，4.4Hz，1H)，6.62-6.54(m，1H)，3.59(s，1H)，2.72(dd，J＝10.7，6.8Hz，1H)，2.30-2.15(m，1H)，2.08(dd，J＝27.4，13.8Hz，1H)，1.97-1.89(m，2H)，1.85(s，1H)，1.77-1.58(m，3H)，1.56-1.45(m，1H)，1.15(dd，J＝6.8，2.8Hz，3H)。
实施例5
2-(4-(6-氟喹啉-4-基)-1-羟基环己基)-N-(4-(五氟-λ 6-硫烷基)苯基)乙酰胺
Figure PCTCN2019000019-appb-000022
第一步
6-氟-4-(1，4-二氧杂螺[4.5]癸-7-烯-8-基)喹啉
将化合物4-溴-6-氟喹啉5a(5g，22.12mmol)、4，4，5，5-四甲基-2-(1，4-二氧杂螺[4.5]癸-7-烯-8-基)-1，3，2-二噁硼戊环(6.5g，24.3mmol)、碳酸钾(6.1g，44.24mmol)、[1，1′-双(二苯基膦基)二茂铁]二氯化钯二氯甲烷络合物(0.9g，1.1mmol)、1，4-二氧六环(50ml)和水(10ml)在室温下混合，然后在氮气气氛下加热至100℃并继续搅拌2小时。冷却到室温后，减压除去溶剂，残余物用硅胶柱层析纯化(石油醚/乙酸乙酯＝3/1)，得到目标产物6-氟-4-(1，4-二氧杂螺[4.5]癸-7-烯-8-基)喹啉5b(5.2g，淡黄色固体)，产率：82％。
MS m/z(ESI)：286[M+1]
第二步
6-氟-4-(1，4-二氧杂螺[4.5]癸烷-8-基)喹啉
将化合物6-氟-4-(1，4-二氧杂螺[4.5]癸-7-烯-8-基)喹啉5b(5g，17.54mmol)、10％钯碳(500mg)和乙醇(50ml)混合，然后在氢气气氛下室温搅拌5小时。反应结束后过滤，滤液在减压条件下除去溶剂，得到目标产物6-氟-4-(1，4-二氧杂螺[4.5]癸烷-8-基)喹啉5c(4.5g，无色油状物)，产率：90％。
MS m/z(ESI)：288[M+1]
第三步
4-(6-氟喹啉-4-基)环己烷-1-酮
将化合物6-氟-4-(1，4-二氧杂螺[4.5]癸烷-8-基)喹啉5c(4.5g，15.68mmol)溶于丙酮(50ml)，然后加入浓盐酸(1ml)并继续在室温搅拌过夜。反应完成后，减压除去溶剂，残余物用乙酸乙酯(100ml×2)萃取。有机相合并后，用饱和食盐水洗涤，并用无水硫酸钠干燥。干燥后过滤，滤液在减压条件下除去溶剂，得到目标产物4-(6-氟喹啉-4-基)环己烷-1-酮5d(3.6g，无色油状物)，产率：94％。
MS m/z(ESI)：244[M+1]
第四步
2-(4-(6-氟喹啉-4-基)-1-羟基环己基)乙酸乙酯
将乙酸乙酯(440mg，4.92mmol)溶于无水四氢呋喃(10ml)，冷却至-78℃，然后加入双-(三甲基硅烷基)氨基锂(1M，5.7ml，5.7mmol)的四氢呋喃溶液。搅拌1小时后，逐滴加入4-(6-氟喹啉-4-基)环己烷-1-酮5d(1g，4.1mmol)的四氢呋喃(4ml)溶液。反应逐渐升到室温并继续搅拌1小时，用盐酸(1N，10ml)淬灭后加入水(100ml)并用乙酸乙酯(100ml×3)萃取。有机相合并后，用饱和食盐水(100ml)洗涤后用无水硫酸钠干燥。过滤后滤液在减压条件下除去溶剂，残余物用硅胶柱层析(石油醚/乙酸乙酯＝100/0至2/3)纯化，得到目标产物2-(4-(6-氟喹啉-4-基)-1-羟基环己基)乙酸乙酯5e(1.2g，无色油状物)，产率：83％。
MS m/z(ESI)：332[M+H]
第五步
2-(4-(6-氟喹啉-4-基)-1-羟基环己基)乙酸
向2-(4-(6-氟喹啉-4-基)-1-羟基环己基)乙酸乙酯5e(600mg，1.81mmol)、水(1ml)和四氢呋喃(6ml)的混合物中加入氢氧化锂一水合物(114mg，2.71mmol)。室温搅拌1小时后，减压除去溶剂，残余物用硅胶柱层析(石油醚/乙酸乙酯＝100/0至1/9)纯化，得到目标产物2-(4-(6-氟喹啉-4-基)-1-羟基环己基)乙酸5f(230mg，白色固体)，产率：41％。
MS m/z(ESI)：304[M+H]
第六步
2-(4-(6-氟喹啉-4-基)-1-羟基环己基)-N-(4-(五氟-λ 6-硫烷基)苯基)乙酰胺
将化合物2-(4-(6-氟喹啉-4-基)-1-羟基环己基)乙酸5f(150mg，0.5mmol)、4-(五氟-λ 6-硫烷基)苯胺(330mg，1.5mmol)、2-(7-氧化苯并三氮唑)-N，N，N′，N′-四甲基脲六氟磷酸盐(250mg，0.65mmol)、二异丙基乙基胺(260mg，2.0mmol)和N，N-二甲基甲酰胺(3ml)混合， 室温下搅拌12小时后，将该反应液直接用反相高效液相色谱纯化，得到目标产物2-(4-(6-氟喹啉-4-基)-1-羟基环己基)-N-(4-(五氟-λ 6-硫烷基)苯基)乙酰胺5(1.16mg，白色固体)，产率：0.5％。
MS m/z(ESI)：505[M+H]
1H NMR(400MHz，DMSO-d 6)δ10.32(s，1H)，8.83(d，J＝4.5Hz，2H)，8.09(dd，J＝9.2，5.8Hz，1H)，8.01(dd，J＝10.9，2.6Hz，1H)，7.85(d，J＝9.7Hz，2H)，7.71-7.62(m，1H)，7.56(d，J＝4.5Hz，1H)，6.50(s，1H)，4.88(s，2H)，2.73(s，2H)，2.05-1.65(m，8H)。
实施例6
2-(4-(6-氟喹啉-4-基)哌嗪-1-基)-N-(4-(五氟-λ 6-硫烷基)苯基)丙酰胺
Figure PCTCN2019000019-appb-000023
第一步
4-(6-氟喹啉-4-基)哌嗪-1-羧酸叔丁酯
将化合物哌嗪-1-羧酸叔丁酯6a(100mg，0.537mmol)、4-溴-6-氟喹啉(146mg，0.644mmol)、三(二亚苄基丙酮)二钯(49mg，0.537mmol)、4，5-双二苯基膦-9，9-二甲基氧杂蒽(62mg，0.107mmol)、碳酸铯(350mg，1.074mmol)和1，4-二氧六环(10ml)混合，然后在氮气气氛下用微波反应器加热30分钟。反应完成后过滤，滤液在减压条件下除去溶剂，得到目标产物4-(6-氟喹啉-4-基)哌嗪-1-羧酸叔丁酯6b(80mg，粗品)，产率：45％。该产品未经进一步纯化，直接用于下一步反应。
MS m/z(ESI)：332[M+H]
第二步
6-氟-4-(哌嗪-1-基)喹啉
将化合物4-(6-氟喹啉-4-基)哌嗪-1-羧酸叔丁酯6b(800mg，粗品)溶于氯化氢的1，4-二氧六环溶液(0.4M，20ml)，然后在室温下搅拌12小时。反应完成后，减压除去溶剂，得到目标产物6-氟-4-(哌嗪-1-基)喹啉6c(800mg，粗品)。该产品未经进一步纯化，直接用于下一步反应。
MS m/z(ESI)：232[M+H]
第三步
2-(4-(6-氟喹啉-4-基)哌嗪-1-基)丙酸乙酯
将化合物6-氟-4-(哌嗪-1-基)喹啉6c(800mg，粗品)、2-溴丙酸乙酯(751mg，4.15mmol)、三乙胺(699mg，6.92mmol)和二氯甲烷(10ml)混合，在室温下搅拌12小时。减压除去溶剂，残余物用硅胶柱层析(二氯甲烷/甲醇＝5/1)纯化，得到目标产物2-(4-(6-氟喹啉-4-基)哌嗪-1-基)丙酸乙酯6d(200mg，0.604mmol)，产率：两步25％。
MS m/z(ESI)：332[M+H]
第四步
2-(4-(6-氟喹啉-4-基)哌嗪-1-基)丙酸
将化合物2-(4-(6-氟喹啉-4-基)哌嗪-1-基)丙酸乙酯6d(200mg，0.604mmol)溶于四氢呋喃(10ml)中，然后加入氢氧化锂一水合物(1g，23mmol)的水(5ml)溶液并在室温下搅拌12小时。反应完成后过滤，滤液减压除去溶剂，残余物用反相高效液相色谱纯化，得到目标产物2-(4-(6-氟喹啉-4-基)哌嗪-1-基)丙酸6e(50mg，白色固体)，产率：27％。
MS m/z(ESI)：304[M+H]
第五步
2-(4-(6-氟喹啉-4-基)哌嗪-1-基)-N-(4-(五氟-λ 6-硫烷基)苯基)丙酰胺
将化合物2-(4-(6-氟喹啉-4-基)哌嗪-1-基)丙酸6e(50mg，0.165mmol)、4-(五氟-λ 6-硫烷基)苯胺(144mg，0.66mmol)和二氯甲烷(10ml)混合，然后加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(127mg，0.66mmol)。室温下搅拌3小时后，减压除去溶剂，残余物用反相高效液相色谱纯化，得到目标产物2-(4-(6-氟喹啉-4-基)哌嗪-1-基)-N-(4-(五氟-λ 6-硫烷基)苯基)丙酰胺盐酸盐6(15.8mg，白色固体)，产率：18％。
MS m/z(ESI)：505[M+H]
1H NMR(400MHz，CD 3OD)δ8.69(d，J＝5.8Hz，1H)，8.07(dd，J＝9.2，4.6Hz，1H)，7.91(d，J＝8.6Hz，1H)，7.81(dd，J＝17.6，8.5Hz，3H)，7.72(d，J＝9.2Hz，2H)，7.37(d，J＝5.9Hz，1H)，4.33(d，J＝6.6Hz，1H)，4.06(s，4H)，3.75(d，J＝20.8Hz，4H)，1.71(d，J＝6.4Hz，3H)。
实施例7
2-(1-(6-氟喹啉-4-基)哌啶-4-基)-N-(4-(五氟-λ 6-硫烷基)苯基)丙酰胺
Figure PCTCN2019000019-appb-000024
Figure PCTCN2019000019-appb-000025
第一步
2-(1-(6-氟喹啉-4-基)哌啶-4-基)乙酸乙酯
将化合物2-(哌啶-4-基)乙酸乙酯7a(500mg，2.92mmol)、4-溴-6-氟喹啉(791.2mg，3.5mmol)、三(二亚苄基丙酮)二钯(267.5mg，0.292mmol)、4，5-双二苯基膦-9，9-二甲基氧杂蒽(338mg，0.584mmol)、碳酸铯(1.89g，5.89mmol)和1，4-二氧六环(10ml)混合，然后在氮气气氛下用微波反应器加热30分钟。反应完成后过滤，滤液在减压条件下除去溶剂，残余物用硅胶柱层析(石油醚/乙酸乙酯＝1/9)纯化，得到目标产物2-(1-(6-氟喹啉-4-基)哌啶-4-基)乙酸乙酯7b(500mg，黄色固体)，产率：54％。
MS m/z(ESI)：317[M+H]
第二步
2-(1-(6-氟喹啉-4-基)哌啶-4-基)丙酸乙酯
将2-(1-(6-氟喹啉-4-基)哌啶-4-基)乙酸乙酯7b(500mg，1.58mmol)溶于四氢呋喃(20ml)中，冷却到-40℃，然后逐滴加入二(三甲基硅烷基)氨基钠的四氢呋喃溶液(2M，0.8ml，1.6mmol)。搅拌1小时后，加入碘甲烷(247mg，1.74mmol)并继续搅拌1小时。用水淬灭，然后用二氯甲烷萃取(50ml×2)。有机相合并后，减压除去溶剂，得到目标产物2-(1-(6-氟喹啉-4-基)哌啶-4-基)丙酸乙酯7c(500mg，粗品)。该产品未经进一步纯化直接用于下一步反应。
MS m/z(ESI)：331[M+H]
第三步
2-(1-(6-氟喹啉-4-基)哌啶-4-基)丙酸
将化合物2-(1-(6-氟喹啉-4-基)哌啶-4-基)丙酸乙酯7c(500mg，粗品)溶于四氢呋喃(10ml)中，然后加入氢氧化锂一水合物(1.2g，28.5mmol)的水(5ml)溶液并在室温下搅拌12小时。反应完成后过滤，滤液减压除去溶剂，残余物用反相高效液相色谱纯化，得到目标产物2-(1-(6-氟喹啉-4-基)哌啶-4-基)丙酸7d(137mg，白色固体)，产率：29％
MS m/z(ESI)：303[M+H]
第四步
2-(1-(6-氟喹啉-4-基)哌啶-4-基)-N-(4-(五氟-λ 6-硫烷基)苯基)丙酰胺
将化合物2-(1-(6-氟喹啉-4-基)哌啶-4-基)丙酸7d(20mg，0.066mmol)、 4-(五氟-λ 6-硫烷基)苯胺(144mg，0.66mmol)和二氯甲烷(10ml)混合，然后加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(100mg，0.5mmol)。室温下搅拌3小时后，减压除去溶剂，残余物用反相高效液相色谱纯化，得到目标产物2-(1-(6-氟喹啉-4-基)哌啶-4-基)-N-(4-(五氟-λ 6-硫烷基)苯基)丙酰胺6(7.28mg，白色固体)，产率：21％。
MS m/z(ESI)：504[M+H]
1H NMR(400MHz，DMSO-d 6)δ10.37(s，1H)，8.66(d，J＝4.9Hz，1H)，8.01(dd，J＝9.0，5.7Hz，1H)，7.89-7.78(m，3H)，7.65-7.53(m，2H)，7.02(d，J＝5.0Hz，1H)，3.60-3.44(m，2H)，2.87-2.69(m，2H)，2.47-2.38(m，1H)。
实施例8
(R)-2-((1s，4S)-4-(6-氟喹啉-4-基)环己基)-N-(3-(五氟-λ 6-硫烷基)苯基)丙酰胺
Figure PCTCN2019000019-appb-000026
第一步
(R)-2-((1s，4S)-4-(6-氟喹啉-4-基)环己基)-N-(3-(五氟-λ 6-硫烷基)苯基)丙酰胺
将化合物(R)-2-(4-(6-氟喹啉-4-基)环己基)丙酸1h(301mg，1mmol)溶于二氯甲烷(10ml)，然后加入草酰氯(254mg，2mmol)。室温下搅拌30分钟后，减压除去溶剂，残余物与4-(五氟-λ 6-硫烷基)苯胺(438mg，2mmol)和三乙胺(202mg，2mmol)共同溶于四氢呋喃(10ml)。室温下搅拌3小时后，减压除去溶剂，残余物用反相高效液相色谱纯化，得到目标产物(R)-2-((1s，4S)-4-(6-氟喹啉-4-基)环己基)-N-(3-(五氟-λ 6-硫烷基)苯基)丙酰胺3(342mg，白色固体)，产率：63％。
MS m/z(ESI)：503[M+1]
1H NMR(400MHz，CD 3OD)δ8.81(d，J＝4.7Hz，1H)，8.29(t，J＝2.0Hz，1H)，8.11(dd，J＝9.3，5.6Hz，1H)，7.92(dd，J＝10.6，2.7Hz，1H)，7.80(d，J＝7.8Hz，1H)，7.65-7.48(m，4H)，3.47(dd，J＝12.2，8.7Hz，1H)，2.92(dt，J＝13.3，6.7Hz，1H)，2.16-2.04(m，2H)，2.02-1.96(m，2H)，1.95-1.88(m，3H)，1.82(dd，J＝16.6，6.1Hz，2H)，1.30(d，J＝6.8Hz，3H)。
实施例9
N-(1-((1s，4s)-4-(6-氟喹啉-4-基)环己基)乙基)-4-(五氟-λ 6-硫烷基)苯酰胺
Figure PCTCN2019000019-appb-000027
第一步
4-(((三氟甲基)磺酰)氧代)环己-3-烯-1-羧酸甲酯
将化合物2，6-二叔丁-4-甲基吡啶(4.1g，20mmol)溶于二氯甲烷(15ml)中，然后依次加入4-氧代环己烷-1-羧酸甲酯9a(1.80g，18mmol)和三氟甲磺酸酐(5.7g，20mmol)。反应混合物在氩气气氛下室温搅拌24小时后过滤。减压除去溶剂，残余物用乙酸乙酯洗涤(30ml×3)。有机相合并后，依次用冷的1N盐酸(50ml)和饱和食盐水(50ml)洗涤后用无水碳酸钠干燥。再次过滤后，滤液减压除去溶剂得到目标产物4-(((三氟甲基)磺酰)氧代)环己-3-烯-1-羧酸甲酯9b(4.2g，无色油状物)，产率：76％。
1H NMR(400MHz，CDCl 3)δ5.82-5.68(m，1H)，3.70(s，3H)，2.60(ddd，J＝10.5，7.0，3.3Hz，1H)，2.48-2.35(m，4H)，2.13(ddd，J＝8.9，4.1，1.4Hz，1H)，1.93(ddd，J＝6.9，4.7，2.6Hz，1H)。
第二步
4-(6-氟喹啉-4-基)环己-3-烯-1-羧酸甲酯
将混合物4-(((三氟甲基)磺酰)氧代)环己-3-烯-1-羧酸甲酯9b(4.2g，14.6mmol)、(6-氟喹啉-4-基)硼酸(2.78g，14.6mmol)、[1，1′-双(二苯基膦基)二茂铁]二氯化钯二氯甲烷络合物(1.19g，1.46mmol)、碳酸钾(403mg，2.92mmol)、水(5ml)和1，4-二氧六环(20ml)在氮气保护下加热至100℃，并继续搅拌2小时。将反应混合物冷却至室温，减压浓缩，残余物用硅胶柱层析纯化(石油醚/乙酸乙酯＝20/1至1/1)，得到目标产物4-(6-氟喹啉-4-基)环己-3-烯-1-羧酸甲酯9c(3.32g，淡黄色油状物)，产率：80％。
MS m/z(ESI)：286[M+1]
第三步
4-(6-氟喹啉-4-基)环己烷-1-羧酸甲酯
将4-(6-氟喹啉-4-基)环己-3-烯-1-羧酸甲酯9c(3.32g，11.67mmol)溶于甲醇(50ml)，然后加入10％钯碳(200mg)，在氢气气氛下室温下搅拌2小时。过滤，减压浓缩滤液，得到目标产物4-(6-氟喹啉-4-基)环己烷-1-羧酸甲酯9d(3.04g，淡黄色固体)，产率：91％。
MS m/z(ESI)：288[M+1]
第四步
(4-(6-氟喹啉-4-基)环己基)甲醇
将化合物4-(6-氟喹啉-4-基)环己烷-1-羧酸甲酯9d(1.2g，4.18mmol)溶于无水四氢呋喃(20ml)中，然后加入氢化铝锂(190mg，5mmol)。室温搅拌1小时后，依次加入水(0.5ml)、15％氢氧化钠溶液(1ml)、水(0.5ml)和无水硫酸钠(1g)。搅拌15分钟后过滤，滤液在减压条件下除去溶剂，得到目标产物(4-(6-氟喹啉-4-基)环己基)甲醇9e(810mg，淡黄色固体)，产率：80％。
MS m/z(ESI)：260[M+1]
第五步
4-(6-氟喹啉-4-基)环己烷-1-甲醛
将化合物(4-(6-氟喹啉-4-基)环己基)甲醇9e(800mg，3.08mmol)溶于二氯甲烷(20ml)，冷却至0℃，然后加入戴斯-马丁氧化剂(1.5g，3.7mmol)。在0℃下搅拌2小时后过滤，滤液在减压条件下除去溶剂，残余物用硅胶柱层析(石油醚/乙酸乙酯＝10/1至1/1)纯化，得到目标产物4-(6-氟喹啉-4-基)环己烷-1-甲醛9f(596mg，无色油状物)，产率：75％。
MS m/z(ESI)：258[M+1]
第六步
1-(4-(6-氟喹啉-4-基)环己基)乙烷-1-醇
将化合物4-(6-氟喹啉-4-基)环己烷-1-甲醛9f(1.67g，6.47mmol)溶于无水四氢呋喃(20ml)，冷却至0℃，然后在氮气气氛下加入甲基氯化镁的四氢呋喃溶液(3M，2.26mml，6.80mmol)。搅拌2小时后，用饱和氯化铵溶液淬灭，然后在减压条件下除去溶剂。残余物用硅胶柱层析(石油醚/乙酸乙酯＝5/1至1/1)纯化，得到目标产物1-(4-(6-氟喹啉-4-基)环己基)乙烷-1-醇9g(1.2g，无色油状物)，产率：70％。
MS m/z(ESI)：274[M+1]
第七步
2-(1-(4-(6-氟喹啉-4-基)环己基)乙基)异二氢吲哚-1，3-二酮
将化合物1-(4-(6-氟喹啉-4-基)环己基)乙烷-1-醇9g(274mg，1.93mmol)、邻苯二甲酰亚胺(162mg，1.1mmol)和三苯基膦(314mg，1.2mmol)混合，在氮气气氛下加入偶氮二甲酸二异丙酯(243mg，1.2mmol)。室温下搅拌5小时后，减压除去溶剂。残余物用硅胶柱层 析(石油醚/乙酸乙酯＝10/1至1/1)纯化，得到目标产物2-(1-(4-(6-氟喹啉-4-基)环己基)乙基)异二氢吲哚-1，3-二酮9h(102mg，白色固体)，产率：25％。
MS m/z(ESI)：403[M+1]
第八步
1-(4-(6-氟喹啉-4-基)环己基)乙烷-1-胺
将化合物2-(1-(4-(6-氟喹啉-4-基)环己基)乙基)异二氢吲哚-1，3-二酮9h(600mg，1.5mmol)溶于乙醇(20ml)，加入水合肼(1ml)，然后加热到50℃并搅拌5小时。冷却到室温后，减压除去溶剂，残余物用反相高效液相色谱纯化，得到目标产物1-(4-(6-氟喹啉-4-基)环己基)乙烷-1-胺9i(320mg，白色固体)，产率：74％。
MS m/z(ESI)：273[M+1]
第九步
N-(1-((1s，4s)-4-(6-氟喹啉-4-基)环己基)乙基)-4-(五氟-λ 6-硫烷基)苯酰胺
将化合物1-(4-(6-氟喹啉-4-基)环己基)乙烷-1-胺9i(50mg，0.184mmol)和二异丙基乙基胺(47mg，0.367mmol)溶于无水四氢呋喃(10ml)，然后加入4-(五氟-λ 6-硫烷基)苯甲酰氯(49mg，0.184mmol)。室温搅拌2小时后，减压除去溶剂，残余物用反相高效液相色谱纯化，得到目标产物N-(1-((1s，4s)-4-(6-氟喹啉-4-基)环己基)乙基)-4-(五氟-λ 6-硫烷基)苯酰胺盐酸盐9(42.1mg，白色固体)，产率：42％。
MS m/z(ESI)：503[M+1]
1H NMR(400MHz，CD 3OD)δ9.12(d，J＝5.7Hz，1H)，8.54(dd，J＝34.3，8.9Hz，1H)，8.38-8.27(m，2H)，8.14(d，J＝5.8Hz，1H)，8.03-8.00(m，2H)，7.99-7.95(m，2H)，4.71-4.58(m，1H)，3.80-3.64(m，1H)，2.13-1.86(m，9H)，1.35(d，J＝8.0Hz，3H)。
IDO细胞内活性抑制测试
通过Ehrlich方法评估本发明的化合物对IFN-γ诱导的Hela细胞中吲哚胺2，3-双加氧酶(IDO)活性的影响。
实验原理概述如下：在没有任何诱导条件下，Hela细胞中IDO表达低，但是一定浓度的IFN-γ能够诱导Hela细胞表达IDO，使其催化色氨酸生成N-甲酰基犬尿氨酸，其可被三氯乙酸水解生成犬尿氨酸，然后和Ehrlich试剂发生显色反应，从而检测到IDO的活性，在490nm处吸光度(OD490)与IDO活性成正比。
将化合物用DMSO(Sigma，货号为D5879)溶解并稀释至5mM，然后用DMSO进行3倍的系列稀释至最低浓度为2.29μM，每个浓度点再用不含FBS的DMEM培养基(ThermoFisher，货号为11995073)稀释50倍。如果化合物IC 50值非常低，可以降低化合物的起始浓度。 Hela细胞(ATCC，货号为CCL-2)在含有10％FBS(GBICO，货号为10099-141)和100U/ml青链霉素混合液(ThermoFisher，货号为15140122)的DMEM完全培养基中培养，当细胞在培养容器中覆盖率达80-90％时，用0.25％胰酶(含EDTA)(ThermoFisher，货号为25200056)消化吹散后种植于96孔板(Corning，货号为3599)，每孔30000细胞(80μl DMEM培养基)，然后把96孔板置于37℃、5％CO 2的培养箱中培养过夜(18-20小时)。
过夜后每孔加入10μL DMEM稀释后的化合物，以及10μl 500ng/ml的INF-γ，轻轻混匀。该96孔板置于37℃、5％CO 2的培养箱中继续培养，24小时后取出于室温2000×g离心5分钟，然后将上清液转移至反应板(Sigma，货号为CLS3695)，加二十分之一的三氯乙酸(Sigma，货号为T9159)，混合均匀后在60℃孵育。30分钟后，将反应板取出于室温2000×g离心5分钟，将上清液转移至干净反应板，加入等体积的Ehrlich试剂，混匀后室温孵育，15分钟后检测各孔的OD490。
该实验不加IFN-γ，用DMEM培养基替代组的OD490作为OD490 100％抑制；加IFN-γ，并且DMSO终浓度为0.2％组的OD490作为OD490 0％抑制。化合物对Hela细胞中IDO活性抑制的百分比可以用以下公式计算：
抑制百分比＝100-100*(OD490 化合物-OD490 100％抑制)/(OD490 0％抑制-OD490 100％抑制)
化合物IC 50值由8个浓度点用XLfit(ID Business Solutions Ltd.，UK)软件通过以下公式拟合得出：
Y＝Bottom+(Top-Bottom)/(1+10^((logIC 50-X)*slope factor))
其中Y为抑制百分比，Bottom为S型曲线的底部平台值，Top为S型曲线的顶部平台值，X为待测化合物浓度的对数值，slope factor为曲线斜率系数。
部分代表性实施例化合物的活性数据如下：
化合物编号 IC 50 化合物编号 IC 50
1 A 2 C
3 A 4 B
5 A 6  
7   8 C
9 A    
A＜50nM；50nM≤B＜200nM；200nM≤C＜1000nM
本发明的实施例化合物分别对细胞内IDO的活性具有显著抑制效应，优选IC 50小于200nM，更优选IC 50小于50nM。

Claims (14)

  1. 通式(I)所示的化合物：
    Figure PCTCN2019000019-appb-100001
    或其可药用的盐、前药、稳定同位素衍生物、异构体及其混合物形式，
    其中：
    环A为苯环或5-6元杂芳环；
    B为-C(O)-或-NH-；
    当B为-C(O)-，C为-NH-；当B为-NH-，C为-C(O)-；
    D为N或CR 3；
    E为N或CR 4；
    G为任选取代的5-10元杂芳基或6-10元芳基；
    L为键或-O-；
    R 1和R 2各自独立地选自H或任选取代的C 1-4烷基、C 3-6环烷基或4-7元杂环基；或者，R 1和R 2与连接的碳原子共同形成一任选含有选自O、N和S的杂原子的3-7元环；
    R 3和R 4各自独立地选自H、卤素、CN、OH、任选取代的C 1-4烷基或-O-C 1-4烷基；
    所述任选取代是指被选自以下的取代基取代：卤素、-CN、-NO 2、氧代、-SF 5、C 1-4烷基、C 3-7环烷基、4-7元杂环基、苯基、5-6元杂芳基、-OR′、-NR′R″、-C(O)R′、-C(O)OR′、-C(O)NR′R″、-C(O)N(R′)OR″、-OC(O)R′、-OC(O)NR′R″、-N(R′)C(O)OR″、-N(R′)C(O)R″、-N(R″′)C(O)NR′R″、-N(R′)S(O) 2R″、-S(O) mR′、-S(O) 2NR′R″，其中R′、R″和R′″各自独立地选自H、C 1-4烷基、C 3-7环烷基、卤代C 1-4烷基、4-7元杂环基、C 6-10芳基、5-10元杂芳基；在同一个氮原子上的R′和R″任选与它们连接的氮原子共同形成一任选含有另外的选自O、S和N的杂原子的4-7元杂环，且
    m为1或2。
  2. 根据权利要求1所述的化合物或其可药用的盐、前药、稳定同位素衍生物、异构体及其混合物形式，其中
    环A为苯环或吡啶环；
    B为-C(O)-或-NH-；
    当B为-C(O)-，C为-NH-；当B为-NH-，C为-C(O)-；
    D为N或CR 3；
    E为N或CR 4；
    G为任选取代的5-10元杂芳基或6-10元芳基；
    L为键或-O-；
    R 1和R 2各自独立地选自H或任选取代的C 1-4烷基、C 3-6环烷基或4-7元杂环基；或者，R 1和R 2与连接的碳原子共同形成一任选含有选自O、N和S的杂原子的3-7元环；
    R 3和R 4各自独立地选自H、卤素、CN、OH、任选取代的C 1-4烷基或-O-C 1-4烷基；
    所述任选取代是指被选自以下的取代基取代：卤素、-CN、-NO 2、氧代、-SF 5、C 1-4烷基、C 3-7环烷基、4-7元杂环基、苯基、5-6元杂芳基、-OR′、-NR′R″、-C(O)R′、-C(O)OR′、-C(O)NR′R″、-C(O)N(R′)OR″、-OC(O)R′、-OC(O)NR′R″、-N(R′)C(O)OR″、-N(R′)C(O)R″、-N(R′″)C(O)NR′R″、-N(R′)S(O) 2R″、-S(O) mR′、-S(O) 2NR′R″，其中R′、R″和R′″各自独立地选自H、C 1-4烷基、C 3-7环烷基、卤代C 1-4烷基、4-7元杂环基、C 6-10芳基、5-10元杂芳基；在同一个氮原子上的R′和R″任选与它们连接的氮原子共同形成一任选含有另外的选自O、S和N的杂原子的4-7元杂环，且
    m为1或2。
  3. 根据权利要求1或2所述的化合物或其可药用的盐、前药、稳定同位素衍生物、异构体及其混合物形式，所述化合物为以下通式(II)的化合物：
    Figure PCTCN2019000019-appb-100002
    其中：
    B为-C(O)-或-NH-；
    当B为-C(O)-，C为-NH-；当B为-NH-，C为-C(O)-；
    D为N或CR 3；
    E为N或CR 4；
    G为任选取代的5-10元杂芳基或6-10元芳基；
    L为键或-O-；
    R 1和R 2各自独立地选自H或任选取代的C 1-4烷基、C 3-6环烷基或4-7元杂环基；或者，R 1和R 2与连接的碳原子共同形成一任选含有选自O、N和S的杂原子的3-7元环；
    R 3和R 4各自独立地选自H、卤素、CN、OH、任选取代的C 1-4烷基或-O-C 1-4烷基；
    所述任选取代是指被选自以下的取代基取代：卤素、-CN、-NO 2、 氧代、-SF 5、C 1-4烷基、C 3-7环烷基、4-7元杂环基、苯基、5-6元杂芳基、-OR′、-NR′R″、-C(O)R′、-C(O)OR′、-C(O)NR′R″、-C(O)N(R′)OR″、-OC(O)R′、-OC(O)NR′R″、-N(R′)C(O)OR″、-N(R′)C(O)R″、-N(R′″)C(O)NR′R″、-N(R′)S(O) 2R″、-S(O) mR′、-S(O) 2NR′R″，其中R′、R″和R′″各自独立地选自H、C 1-4烷基、C 3-7环烷基、卤代C 1-4烷基、4-7元杂环基、C 6-10芳基、5-10元杂芳基；在同一个氮原子上的R′和R″任选与它们连接的氮原子共同形成一任选含有另外的选自O、S和N的杂原子的4-7元杂环，且
    m为1或2。
  4. 根据前述权利要求任一项所述的化合物或其可药用的盐、前药、稳定同位素衍生物、异构体及其混合物形式，其中B为-NH-，C为-C(O)-。
  5. 根据前述权利要求任一项所述的化合物或其可药用的盐、前药、稳定同位素衍生物、异构体及其混合物形式，其中L为键。
  6. 根据前述权利要求任一项所述的化合物或其可药用的盐、前药、稳定同位素衍生物、异构体及其混合物形式，其中D和E均为CH。
  7. 根据前述权利要求任一项所述的化合物或其可药用的盐、前药、稳定同位素衍生物、异构体及其混合物形式，其中G为5-10元杂芳基。
  8. 根据前述权利要求任一项所述的化合物，其为以下通式(IIIa)-(IIIc)的化合物：
    Figure PCTCN2019000019-appb-100003
  9. 根据前述权利要求任一项所述的化合物，其为以下通式(IV)的化合物：
    Figure PCTCN2019000019-appb-100004
    其中：
    R 1为C 1-4烷基。
  10. 前述权利要求任一项所述的化合物或其可药用的盐、前药、稳 定同位素衍生物、异构体及其混合物形式，所述化合物选自：
    Figure PCTCN2019000019-appb-100005
  11. 药物组合物，所述药物组合物包含根据权利要求1-10任一项所述的化合物或其可药用的盐、前药、稳定同位素衍生物、异构体及其混合物形式和药学上可接受的载体和赋形剂。
  12. 药物组合物，所述药物组合物包含根据权利要求1-10任一项所述的化合物或其可药用的盐、前药、稳定同位素衍生物、异构体及其混合物形式和至少一种额外的药物，其中所述至少一种额外的药物为化学治疗剂、免疫和/或炎症调节剂、神经相关疾病调节剂或抗感染剂。
  13. 根据权利要求12所述的药物组合物，其中所述至少一种额外的药物为免疫检查点抑制剂。
  14. 根据权利要求1-10任一项所述的化合物或其可药用的盐、前药、稳定同位素衍生物、异构体及其混合物形式或根据权利要求11-13任一项所述的药物组合物在制备用于治疗和/或预防IDO介导的相关性疾病，特别是肿瘤的药物中的用途，其中所述肿瘤选自前列腺癌、结肠癌、直肠癌、膜腺癌、子宫颈癌、胃癌、子宫内膜癌、脑癌、肝癌、膀肮癌、卵巢癌、辜丸癌、头部癌、颈部癌、皮肤癌、问皮内膜癌、淋巴瘤、白血病、食道癌、乳癌、肌肉癌、结缔组织癌、肺癌、肾上腺癌、甲状腺癌、肾癌、骨癌、胶质母细胞瘤、问皮瘤、肉瘤、绒膜癌、皮肤基底细胞癌或辜丸精原细胞瘤。
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