WO2019223548A1 - 3-吲唑啉酮类化合物、其制备方法及其在医药学上的应用 - Google Patents

3-吲唑啉酮类化合物、其制备方法及其在医药学上的应用 Download PDF

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WO2019223548A1
WO2019223548A1 PCT/CN2019/086258 CN2019086258W WO2019223548A1 WO 2019223548 A1 WO2019223548 A1 WO 2019223548A1 CN 2019086258 W CN2019086258 W CN 2019086258W WO 2019223548 A1 WO2019223548 A1 WO 2019223548A1
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alkyl
cancer
compound
independently selected
mmol
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PCT/CN2019/086258
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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 EP19807362.9A priority Critical patent/EP3805212A4/en
Priority to CN201980035221.3A priority patent/CN112334458B/zh
Priority to US17/059,097 priority patent/US20210221808A1/en
Priority to JP2020565853A priority patent/JP2021525264A/ja
Publication of WO2019223548A1 publication Critical patent/WO2019223548A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/08—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing alicyclic rings

Definitions

  • the present invention relates to a novel 3-indazolinone compound or a pharmaceutically acceptable salt thereof which regulates or inhibits the activity of indoleamine 2,3-dioxygenase (IDO), or contains the compound or a pharmaceutically acceptable salt thereof.
  • a pharmaceutical composition of a pharmaceutically acceptable salt, a method for preparing the compound or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition containing the compound or a pharmaceutically acceptable salt thereof Use of a medicament for the treatment and / or prevention of IDO-mediated related disorders, especially tumors, and methods of using the same.
  • Indoleamine 2,3-dioxygenase is a heme-containing monomeric protein that is widely distributed in tissues other than the liver. It catalyzes the oxidative degradation of tryptophan to kynurenine, which is canine urine. The rate-limiting enzyme of the amino acid metabolic pathway. Tryptophan is an essential amino acid for T cell proliferation and is also a precursor substance for the synthesis of neurotransmitters. If the tryptophan concentration in the cell microenvironment is reduced and the kynurenine level is increased, T cells will stagnate in the middle stage of G1, which will affect the proliferation, differentiation and activity of T cells.
  • IDO is expressed at a low level in normal cells, but it is overexpressed in many tumor tissues, leading to abnormal tryptophan metabolism in the tumor and the formation of regulatory T cells, which in turn mediates the local T cell immune tolerance in tumors. Played an important role in the process of occurrence, development and transfer. If IDO activity is inhibited, tryptophan metabolism around tumor cells is effectively prevented, which can promote the growth of T cells, thereby enhancing the body's immune system's ability to fight tumors. Therefore, the research and development of IDO inhibitors has become the forefront of research on tumor immunotherapy drugs.
  • IDO inhibitors can also be combined with other anti-tumor small molecule drugs and immune checkpoint inhibitors, such as CTLA-4, PD-1 and PD-L1 antibodies, to enhance the anti-tumor efficacy of the drug.
  • immune checkpoint inhibitors such as CTLA-4, PD-1 and PD-L1 antibodies.
  • the combined immunotherapy of small molecule IDO inhibitors and immune checkpoint inhibitors is in clinical trials, such as indoximod / ipilimumab, epacadostat / pembrolizumab, epacadostat / nivolumab, indoximod / MEDI-4736, etc.
  • IDO In addition to cancer, IDO is also 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), and the like. Therefore, IDO inhibitors have great therapeutic value.
  • IDO inhibitor drugs are still in clinical trials.
  • INCY-024360 epacadostat
  • Incyte Indoximod of NewLink Genetics
  • BMS-986205 BMS-986205 of Bristol-Myers Squibb.
  • IDO inhibitors have attracted the attention of many biopharmaceutical companies due to the prospects shown by them in the treatment of various tumors and other diseases individually and in combination with immunotherapy.
  • a series of patent applications for IDO inhibitors have been published, including WO2006122150A1 , WO2011056652A1, WO2013069765A1, WO2014186035A1, WO2015002918A1, WO2016073738A2, WO2016073770A1, WO2016181348A1, WO2016161960A1, WO2017079669A1, etc., but new compounds need to be developed, which have better drugability and higher response rate in immunotherapy.
  • the present invention has designed compounds having a structure represented by the general formula (I), and found that compounds having such a structure exhibit excellent effects and effects of inhibiting IDO activity.
  • the present invention provides a compound represented by the general formula (I) as an IDO inhibitor:
  • Z 1 , Z 2 , Z 3 and Z 4 are each independently selected from N or CR 3 , but Z 1 , Z 2 , Z 3 and Z 4 are not N at the same time;
  • R 1 and R 2 are each independently selected from H or optionally substituted C 1-4 alkyl, C 3-6 cycloalkyl, or 4-7 membered heterocyclyl; or, R 1 and R 2 and the attached carbon The atoms together form a 3-7 membered ring optionally containing heteroatoms selected from O, N and S;
  • A is N or CR 4 ;
  • B is N or CR 5 ;
  • L is a bond, -O- or -CR 6 R 7- ;
  • C is optionally substituted 4-7 membered heterocyclic group, 6-10 membered aryl group or 5-10 membered heteroaryl group;
  • R 3 is independently selected from H, halogen, cyano, -SF 5 , -OR, -SR, -NR 2 , -S (O) m R, -S (O) 2 NR 2 , -N (R) S (O) 2 R, -C (O) NR 2 , -N (R) C (O) R, or optionally substituted C 1-4 alkyl, C 3-6 cycloalkyl, 4-7 membered hetero Cyclic, phenyl or 5-6 membered heteroaryl;
  • R 4 and R 5 are each independently selected from H, halogen, OH, or optionally substituted C 1-4 alkyl or -OC 1-4 alkyl;
  • R 6 and R 7 are each independently selected from H or optionally substituted C 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; on the same nitrogen atom Two R on it optionally together with the nitrogen atom to which they are attached form a 4-7 membered heterocyclic ring optionally containing another heteroatom selected from O, N and S;
  • n 1 or 2.
  • An embodiment of the present invention relates to a compound represented by the above-mentioned general formula (I) or a pharmaceutically acceptable salt, prodrug, stable isotope derivative, isomer thereof, and a mixture thereof, wherein:
  • Z 1 , Z 2 , Z 3 and Z 4 are each independently selected from N or CR 3 , but at most one of Z 1 , Z 2 , Z 3 and Z 4 is N;
  • R 1 and R 2 are each independently selected from H or optionally substituted C 1-4 alkyl
  • A is N or CR 4 ;
  • B is N or CR 5 ;
  • L is a bond or -O-
  • C is a 4-7 membered heterocyclic group, a 6-10 membered aryl group, or a 5-10 membered heteroaryl group optionally substituted with halogen, cyano, C 1-4 alkyl, or halogenated C 1-4 alkyl;
  • R 3 is independently selected from H, halogen, cyano, -SF 5 , -OR, -SR, -NR 2 , -S (O) m R, -S (O) 2 NR 2 , -N (R) S (O) 2 R, -C (O) NR 2 , -N (R) C (O) R, or optionally substituted C 1-4 alkyl, C 3-6 cycloalkyl, 4-7 membered hetero Cyclic, phenyl or 5-6 membered heteroaryl;
  • R 4 and R 5 are each independently selected from H, halogen, OH, 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; on the same nitrogen atom Two R on it optionally together with the nitrogen atom to which they are attached form a 4-7 membered heterocyclic ring optionally containing another heteroatom selected from O, N and S;
  • n 1 or 2.
  • Another embodiment of the present invention relates to a compound or a pharmaceutically acceptable salt, prodrug, stable isotope derivative, isomer thereof, and a mixture thereof according to any one of the above embodiments, wherein:
  • Z 1 , Z 2 , Z 3 and Z 4 are each independently selected from N or CR 3 , but at most one of Z 1 , Z 2 , Z 3 and Z 4 is N;
  • R 1 and R 2 are each independently selected from H or C 1-4 alkyl
  • A is N or CH
  • B is N or CH
  • C is a 5-10 membered heteroaryl group optionally substituted with halogen, cyano, C 1-4 alkyl, or halo C 1-4 alkyl;
  • R 3 is independently selected from H, halogen, cyano, or optionally substituted C 1-4 alkyl, -OC 1-4 alkyl, C 3-6 cycloalkyl, or 4-7 membered heterocyclyl;
  • the optional substitution refers to substitution with a substituent selected from the group consisting of halogen, -CN, -OR ', -NR'R ", wherein R' and R" are each independently selected from H, C 1-4 alkyl Or C 3-7 cycloalkyl.
  • Another embodiment of the present invention relates to a compound according to any one of the above embodiments or a pharmaceutically acceptable salt, prodrug, stable isotope derivative, isomer thereof, and a mixture thereof, wherein:
  • Z 1 and Z 4 are each independently selected from N or CH, and Z 2 and Z 3 are each independently selected from N or CR 3 , but at most one of Z 1 , Z 2 , Z 3 and Z 4 is N;
  • R 1 and R 2 are each independently selected from H or C 1-4 alkyl
  • A is CH
  • B is CH
  • C is a 5-10 membered heteroaryl group optionally substituted with halogen or C 1-4 alkyl;
  • R 3 is H, halogen or cyano.
  • Another embodiment of this invention is directed to a compound according to any one of the preceding embodiments, wherein C is quinolinyl or pyridyl, especially fluoroquinolinyl, optionally substituted with halogen or C 1-4 alkyl.
  • Another embodiment of this invention is directed to a compound according to any one of the above embodiments, wherein R 1 is C 1-4 alkyl and R 2 is H, especially R 1 is methyl and R 2 is H.
  • Another embodiment of this invention is directed to a compound according to any one of the above embodiments, which is a compound of the following general formulae (IIa)-(IIc):
  • Another embodiment of this invention is directed to a compound according to any one of the above embodiments, which is a compound of the following general formula (III):
  • Another embodiment of the present invention relates to a compound represented by the above-mentioned general formula (III), wherein R 1 is a methyl group.
  • One embodiment of the present invention relates to a compound represented by the above general formula (I), wherein the compound is selected from:
  • the compound of the present invention has a significant inhibitory effect on the activity of IDO in Hela cells, and preferably has an IC 50 of less than 200 nM, and more preferably an IC 50 of less than 50 nM.
  • 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 disorder (e.g. rheumatoid arthritis), neurological or neuropsychiatric Diseases or conditions (e.g. depression) and the like.
  • IDO-mediated related diseases including but not limited to cancer, immunosuppression, chronic infection, viral infection, autoimmune disease or disorder (e.g. rheumatoid arthritis), neurological or neuropsychiatric Diseases or conditions (e.g. depression) and the like.
  • the compounds of the present invention are used to treat or prevent IDO-related tumors, including but not limited to prostate cancer, colon cancer, rectal cancer, glandular cancer, 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), mesothelioma, lymphoma, leukemia, esophageal cancer, breast cancer, muscle cancer, connective tissue cancer, lung cancer ( (Including small cell lung cancer and non-small cell cancer), adrenal cancer, thyroid cancer, renal cancer, bone cancer, glioblastoma, mesothelioma, sarcoma (including Kaposi's sarcoma), choriocarcinoma, and skin basal cell carcinoma Or testicular seminoma.
  • IDO-related tumors including but not limited to prostate cancer, colon cancer, rectal cancer, glandular cancer, cervical cancer, gastric cancer, endometrial cancer, brain cancer
  • the present invention provides a method for treating or preventing an IDO-mediated disease (such as the tumor), which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable Salts, prodrugs, stable isotope derivatives, isomers and mixtures thereof, or pharmaceutical compositions comprising said compounds.
  • Another aspect of the present invention relates to a compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, a prodrug, a stable isotope derivative, an isomer, and a mixture thereof, which is used as a medicine or for medical use.
  • Treat or prevent IDO-mediated diseases such as cancer, immunosuppression, chronic infections, viral infections, autoimmune diseases or conditions (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 the compound of the invention or a pharmaceutically acceptable salt thereof, a prodrug, a stable isotope derivative, an isomer and a mixture thereof, and a pharmaceutically acceptable carrier And excipients.
  • Another aspect of the present invention relates to a compound represented by the general formula (I) or a pharmaceutically acceptable salt, prodrug, stable isotope derivative, isomer and mixture thereof, or a pharmaceutical composition in the preparation of a medicament.
  • the medicament is used to treat or prevent IDO-mediated diseases such as tumors and immunosuppression.
  • Another aspect of the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, a prodrug, a stable isotope derivative, an isomer, and a mixture thereof And at least one additional drug, wherein the at least one additional drug is a chemotherapeutic agent, an immune and / or inflammation modulator (such as an immune checkpoint inhibitor), a neuro-related disease modulator, or an anti-infective agent.
  • the medicament may be any pharmaceutical dosage form, including but not limited to tablets, capsules, solutions, lyophilized preparations, injections.
  • the pharmaceutical preparation of the present invention may be administered in the form of a dosage unit containing a predetermined amount of an active ingredient per dosage unit.
  • a dosage unit may contain, for example, 0.5 mg to 1 g, preferably 1 mg to 700 mg, and particularly preferably 5 mg to 300 mg of a compound of the present invention depending on the condition to be 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 dose or active fraction thereof as indicated above.
  • this type of pharmaceutical preparation can be prepared using methods known in the pharmaceutical art.
  • the pharmaceutical formulations of the present invention may be suitable for administration by any desired suitable method, such as by oral (including oral or sublingual), rectal, nasal, topical (including oral, sublingual or transdermal), vaginal or parenteral (Including subcutaneous, intramuscular, intravenous or intradermal) methods.
  • suitable methods such as by oral (including oral or sublingual), rectal, nasal, topical (including oral, sublingual or transdermal), vaginal or parenteral (Including subcutaneous, intramuscular, intravenous or intradermal) methods.
  • Such formulations can be prepared using all methods known in the pharmaceutical art, for example, by combining the active ingredient with one or more excipients or one or more adjuvants.
  • C xy means the range of the number of carbon atoms, where x and y are integers, for example, C 3-8 cycloalkyl represents a cycloalkyl group having 3-8 carbon atoms, that is, having 3 , 4, 5, 6, 7, or 8 carbon atom cycloalkyl. It should also be understood that “ C3-8 " also includes any sub-ranges thereof, such as C3-7 , C3-6 , C4-7 , C4-6 , C5-6, and the like.
  • Alkyl refers to a saturated straight or branched chain hydrocarbon group containing 1 to 20 carbon atoms, such as 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms.
  • alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl Methyl, 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.
  • Cycloalkyl refers to a saturated cyclic hydrocarbon substituent having 3 to 14 carbon ring atoms.
  • a cycloalkyl group can be a single carbocyclic ring and typically contains 3 to 8, 3 to 7, or 3 to 6 carbon ring atoms.
  • Non-limiting examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Cycloalkyl can optionally be bi or tricyclic fused together, such as decahydronaphthyl. The cycloalkyl group may be optionally substituted.
  • Heterocyclyl or heterocyclic refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic group, which includes 3 to 20 ring atoms, and may be 3 to 14, 3 to 12, 3 to 10, for example Three, eight, three to six, or five to six ring atoms, one or more of which are selected from nitrogen, oxygen, or S (O) m (where m is an integer from 0 to 2), but does not include The ring part of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon.
  • Non-limiting examples of monocyclic heterocyclyls include pyrrolidinyl, piperidinyl, piperazinyl, pyranyl, morpholinyl, thiomorpholinyl, homopiperazinyl, oxetanyl, and nitrogen Heterocycloalkyl.
  • Polycyclic heterocyclyls include fused, bridged, or spiro polycyclic heterocyclyls, such as octahydrocyclopentadieno [c] pyrrole, octahydropyrrolo [1,2-a] pyrazine, Azabicyclo [3.2.1] octane, 5-azaspiro [2.4] heptane, 2-oxa-7-azaspiro [3.5] nonane, etc.
  • the heterocyclyl or heterocyclic ring may be optionally substituted.
  • Aryl or aromatic ring refers to an aromatic monocyclic or fused polycyclic group containing 6 to 14 carbon atoms, preferably 6 to 10 members, such as phenyl and naphthyl, and most preferably phenyl.
  • the aryl ring may be fused to a heteroaryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, and non-limiting examples include:
  • the aryl or aromatic ring may be optionally substituted.
  • Heteroaryl or heteroaryl ring refers to a heteroaromatic system containing 5 to 14 ring atoms, wherein 1 to 4 ring atoms are selected from heteroatoms including oxygen, sulfur, and nitrogen. Heteroaryl is preferably 5 to 10 members. More preferably heteroaryl is 5- or 6-membered, such as furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyrazolyl, imidazolyl, tetrazolyl, Oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, quinolinyl and the like.
  • the heteroaryl ring may be fused to an aryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, and non-limiting examples include:
  • heteroaryl or heteroaryl ring may be optionally substituted.
  • Halogen means fluorine, chlorine, bromine or iodine.
  • Cyano refers to -CN.
  • an heterocyclic group optionally substituted with an alkyl group means that an alkyl group may but need not exist, and the expression includes a case where the heterocyclic group is substituted with an alkyl group and a case where the heterocyclic group is not substituted with an alkyl group .
  • Optionally substituted refers to one or more hydrogen atoms in a group, preferably 5 and more preferably 1 to 3 hydrogen atoms, independently of one another, with a corresponding number of substituents. It goes without saying that the substituents are only at their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without undue effort.
  • an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom having an unsaturated (eg, olefinic) bond.
  • the substituents include, but are not limited to, halogen, cyano, nitro, oxo, -SF 5 , C 1-4 alkyl, C 3-7 cycloalkyl, 4-7 membered heterocyclyl, 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) OR ′′, -N (R ′) C (O) R ′′, -N (R ′ ′′) C (O) NR′R ′′, -N (R ′) S
  • R ′, R ′′, and R ′ ′′ are each independently selected from H, C 1-4 alkyl, C 3-7 cycloalkyl, optionally containing heteroatoms selected from N, O, and S, 4- 7-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl, wherein the alkane , Cycloalkyl, heterocyclyl, phenyl or heteroaryl is optionally substituted with one or more groups selected from halo, cyano, C 1-4 alkyl, halo C 1-4 alkyl, -OC 1-4 Substituted by alkyl and other substituents; R ′ and R ′′ on the same nitrogen atom are optionally combined with the nitrogen atom to which they are attached to form a 4-7 optionally containing another heteroatom selected from O, S and N Membered heterocyclic ring.
  • “Isomer” refers to a compound that has the same molecular formula but differs in the form or order in which its atoms are bound or the arrangement of their atoms in space. Isomers whose atomic arrangement is different are called “stereoisomers”. Stereoisomers include optical isomers, geometric isomers, and conformers.
  • the compounds of the invention may exist as optical isomers. Depending on the configuration of the substituents around the chiral carbon atom, these optical isomers are in the "R" or "S” configuration. Optical isomers include enantiomers and diastereomers. Methods for preparing and separating optical isomers are known in the art.
  • the compounds of the invention may also exist as geometric isomers.
  • 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 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 heterocyclic ring are designated as the cis or trans configuration.
  • the compounds of the invention may also exhibit tautomerism, such as keto-enol tautomerism.
  • the present invention includes any tautomeric or stereoisomeric form 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.
  • isotopes include all isotopes of the atoms present in the compounds of the invention. Isotopes include those atoms that have the same atomic number but different mass numbers. Examples of isotopes suitable for incorporation in the compounds of the invention are hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as, 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 similar to those described in the appended examples, using appropriate isotopically-labeled reagents instead of non-isotopically-labeled reagents. Such compounds have a variety of potential uses, such as standards and reagents in determining biological activity. In the case of stable isotopes, such compounds have the potential to beneficially alter biological, pharmacological or pharmacokinetic properties.
  • Prodrug means that a compound of the invention can be administered in the form of a prodrug.
  • Prodrugs refer to derivatives of biologically active compounds of the invention that are transformed under physiological conditions in vivo, such as by oxidation, reduction, hydrolysis, etc. (they are each performed with or without the participation of an enzyme).
  • prodrugs are compounds in which an amino group in a compound of the invention is acylated, alkylated, or phosphorylated, such as eicosanoylamino, alanylamino, pivaloyloxymethylamino, or Where the hydroxyl group is acylated, alkylated, phosphorylated, or converted to a borate such as acetoxy, palmitoyloxy, pivaloyloxy, succinyloxy, fumaroyloxy, alanyloxy Group, or where the carboxyl group is esterified or amidated, or where the thiol group forms a disulfide bridge with a carrier molecule, such as a peptide, that selectively delivers the drug to the target and / or to the cytosol of the cell.
  • a carrier molecule such as a peptide
  • “Pharmaceutically acceptable salt” or “pharmaceutically acceptable salt” refers to a salt made from a pharmaceutically acceptable base or acid, including an inorganic base or acid and an organic base or acid. Where the compounds of the invention contain one or more acidic or basic groups, the invention also includes their corresponding pharmaceutically acceptable salts.
  • the compounds of the invention containing acidic groups can exist in the form of salts and can be used according to the invention, for example as alkali metal salts, alkaline earth metal salts or as ammonium salts. More specific examples of such salts include sodium, potassium, calcium, magnesium, or salts with ammonia or organic amines, such as ethylamine, ethanolamine, triethanolamine, or amino acids.
  • the compounds of the invention containing basic groups may exist in the form of salts and may be used according to 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, propylene Acid, pivalic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, sulfamic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, Adipic acid and other acids known to those skilled in the art.
  • the invention includes, in addition to the salt forms mentioned, internal salts or internal ammonium salts.
  • Each salt can be obtained by conventional methods known to those skilled in the art, such as by contacting these with organic or inorganic acids or bases in a solvent or dispersant or by anion exchange or cation exchange with other salts.
  • “Pharmaceutical composition” refers to a compound containing one or more of the compounds described herein, or a pharmaceutically acceptable salt, prodrug, stable isotope derivative, isomer and mixture thereof, and other components such as a pharmaceutically acceptable carrier And excipient composition.
  • the purpose of the pharmaceutical composition is to promote the administration to the organism, which is beneficial to the absorption of the active ingredient and then exerts the biological activity.
  • tumor includes benign and malignant tumors (eg, cancer).
  • terapéuticaally effective amount means an amount that includes a compound of the invention that is effective to inhibit the function of IDO and / or treat or prevent the disease.
  • the present invention also provides a method for preparing the compound.
  • the preparation of the compound of the general formula (I) of the present invention can be accomplished by the following exemplary methods and examples, but these methods and examples should not be considered as limiting the scope of the present invention in any way.
  • the compounds of the present invention can also be synthesized by synthetic techniques known to those skilled in the art, or a method known in the art and a method of the present invention can be used in combination.
  • the products obtained in each step are obtained using 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 routinely synthesized or purchased according to the literature (available from SciFinder).
  • the 3-indazolinone compounds of the general formula (I) of the present invention can be synthesized according to the route described in Method A: the intermediate amine A1 is reductively aminated with o-nitrobenzaldehyde or with o-bromomethylnitrobenzene After substitution reaction, A2 is generated; the alcohol solution of A2 is subjected to David-Beruit reaction under base catalysis to obtain 2-substituted indazole A3; A3 is then hydrolyzed in an acid solution to produce the target product 3-indazolinone compound A4.
  • Intermediate amine A1 can be synthesized by referring to the relevant steps in patent application WO2017192844, or can be synthesized according to the route described in Method B: the starting material ketone B1 is reacted with trifluoromethanesulfonic anhydride under alkaline conditions to form an alkenyl trifluoromethanesulfonic acid Esters B2; B2 and borate or CB (OR) 2 are obtained by Suzuki coupling reaction to obtain B3, which is reduced to hydrogen to form B4; B4 is reduced to alcohol by LAH, and then oxidized to form aldehyde B5 with Dess-Martin periodinane; The Bage reagent reacts to form B6; B6 undergoes a photo-extension reaction to form B7; and finally deprotects to obtain amine A1.
  • 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 measurement was performed using a Bruker ASCEND-400 nuclear magnetic analyzer.
  • the measurement solvents were deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDC1 3 ), and deuterated methanol (CD 3 OD).
  • the internal standard was four.
  • TMS methylsilyl
  • the chemical shift is 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 thin-layer chromatography silica gel plate uses Qingdao Ocean GF254 silica gel plate.
  • the thin-layer chromatography (TLC) silica gel plate uses a size of 0.15 to 0.2mm.
  • the thin-layer chromatography separation and purification product uses a size of 0.4 to 0.5mm silica gel plate. .
  • the known starting materials of the present invention can be synthesized by or in accordance with methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc., Beijing Coupling chemicals and other companies.
  • reaction is performed in an argon atmosphere or a nitrogen atmosphere.
  • An argon or nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon with a volume of about 1 L.
  • the hydrogen atmosphere means that a reaction balloon is connected to a hydrogen balloon with a volume of about 1 L.
  • the hydrogenation reaction is usually evacuated and charged with hydrogen, and the operation is repeated 3 times.
  • reaction temperature is room temperature, and the temperature range is 20 ° C-30 ° C.
  • the reaction progress in the examples was monitored using an Agilent LC / MS instrument (1260/6120).
  • the reaction progress can also be monitored by thin-layer chromatography (TLC).
  • the systems used as the eluent are A: dichloromethane and methanol; B: petroleum ether and ethyl acetate.
  • the volume ratio of the solvent depends on the polarity of the compound. Adjust differently.
  • the eluent system for column chromatography and the eluent system for thin-layer chromatography used to purify compounds include A: dichloromethane and methanol systems; B: petroleum ether and ethyl acetate systems. It can be adjusted by different polarities. It can also be adjusted by adding a small amount of triethylamine and acidic or alkaline reagents, or using other solvent systems.
  • the purified compounds also used Waters' mass spectrometry-oriented automatic preparation system (mass detector: SQD2), and appropriate acetonitrile / water (containing 0.1% trifluoroacetic acid or formic acid) or acetonitrile / water (containing 0.05% ammonia water) according to the polarity of the compound
  • a reverse phase high pressure column (XBridge-C18, 19 ⁇ 150 mm, 5 ⁇ m) was eluted with a gradient at a flow rate of 20 mL / min.
  • the compound 2- (1- (4- (6-fluoroquinolin-4-yl) cyclohexyl) ethyl) isodihydroindole-1,3-dione 3f (600 mg, 1.5 mmol) was dissolved in ethanol ( 20 mL), hydrazine hydrate (1 mL) was added, and then heated to 50 ° C. and stirred for 5 hours. After cooling to room temperature, the solvent was removed under reduced pressure, and the residue was purified by reverse-phase preparative high-performance liquid chromatography to obtain the target product 1- (4- (6-fluoroquinolin-4-yl) cyclohexyl) ethane-1-amine 3 g (320 mg, white solid), yield: 74%.
  • the compound 5-chloro-3-methylpyridin-2-amine 9a (5.88 g, 41.4 mmol) was dissolved in concentrated sulfuric acid (50 mL) and cooled to -10 ° C, and then an aqueous hydrogen peroxide solution (30%, 40 mL) was added dropwise. ). After gradually warming to room temperature, stirring was continued for 16 hours. After the reaction, the mixture was poured into an ice-water mixture, and a white solid precipitated. This solid was filtered and dried to obtain the target product 5-chloro-3-methyl-2-nitropyridine 9b (5.7 g, white (Solid), yield: 80%.
  • Example 10 was synthesized with reference to the synthetic procedure of Example 7, but in the first step, 1,2-dichloro-4-methyl-5-nitrobenzene 10a was used instead of 2-methyl-1-nitro-4- Chlorobenzene 7a.
  • Example 11 was synthesized with reference to the synthetic procedure of Example 7, but in the first step, 2-methyl-1-nitro-4-bromobenzene 11a was used instead of 2-methyl-1-nitro-4-chlorobenzene 7a .
  • the experimental principle is summarized as follows: without any induction conditions, the expression of IDO in Hela cells is low, but a certain concentration of IFN- ⁇ can induce Hela cells to express IDO and catalyze tryptophan to produce N-formyl kynurenine, which It can be hydrolyzed by trichloroacetic acid to generate kynurenine, and then develop a color reaction with Ehrlich reagent to detect the activity of IDO.
  • the absorbance (OD490) at 490nm is directly proportional to the activity of IDO.
  • the compound was dissolved in DMSO (Sigma, Cat. No. D5879) and diluted to 5 mM, and then serially diluted 3 times with DMSO to a minimum concentration of 2.29 ⁇ M, and each concentration point was treated with FBS-free DMEM medium (ThermoFisher, Cat. 11995073) diluted 50-fold. If the compound is very low IC 50 values, the concentration of the starting compound can be reduced.
  • Hela cells ATCC, article number CCL-2
  • DMEM complete medium containing 10% FBS GBICO, article number 10099-141
  • penicillin mixed solution ThermoFisher, article number 15140122.
  • the cells were digested with 0.25% trypsin (containing EDTA) (ThermoFisher, Cat. No. 25200056) and blown and planted in 96-well plates (Corning, Cat. No. 3599). 30,000 cells (80 ⁇ L DMEM medium), and then cultured in a 96-well plate in a 37 ° C, 5% CO 2 incubator overnight (18-20 hours).
  • trypsin containing EDTA
  • 30,000 cells 80 ⁇ L DMEM medium
  • Y is the inhibition percentage
  • Bottom is the bottom plateau value of the S-shaped curve
  • Top is the top plateau value of the S-shaped curve
  • X is the logarithmic value 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 B 2 A 3 B 4 A 5 A 6 A 7 A 8 A 9 A 10 A 11 A Zh Zh
  • the compound of the embodiment of the present invention has a significant inhibitory effect on the activity of IDO in the cells, respectively, preferably the IC 50 is less than 200 nM, and more preferably the IC 50 is less than 50 nM.

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Abstract

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3-吲唑啉酮类化合物，其制备方法及其在医药学上的应用。具体而言，本发明涉及一种通式(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。本发明还涉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。其中通式(I)的各取代基与说明书中的定义相同。

Description

3-吲唑啉酮类化合物、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3-吲唑啉酮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和百时美施贵宝的BMS-986205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 PCTCN2019086258-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：
Z 1、Z 2、Z 3和Z 4各自独立地选自N或CR 3，但Z 1、Z 2、Z 3和Z 4不同时为N；
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；
A为N或CR 4；
B为N或CR 5；
L为键、-O-或-CR 6R 7-；
C为任选取代的4-7元杂环基、6-10元芳基或5-10元杂芳基；
R 3独立地选自H、卤素、氰基、-SF 5、-OR、-SR、-NR 2、-S(O) mR、-S(O) 2NR 2、-N(R)S(O) 2R、-C(O)NR 2、-N(R)C(O)R，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；
R 4和R 5各自独立地选自H、卤素、OH，或任选取代的C 1-4烷基或-O-C 1-4烷基；
R 6和R 7各自独立地选自H或任选取代的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；
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：
Z 1、Z 2、Z 3和Z 4各自独立地选自N或CR 3，但Z 1、Z 2、Z 3和Z 4中至多一个为N；
R 1和R 2各自独立地选自H或任选取代的C 1-4烷基；
A为N或CR 4；
B为N或CR 5；
L为键或-O-；
C为任选被卤素、氰基、C 1-4烷基或卤代C 1-4烷基取代的4-7元杂环基、6-10元芳基或5-10元杂芳基；
R 3独立地选自H、卤素、氰基、-SF 5、-OR、-SR、-NR 2、-S(O) mR、-S(O) 2NR 2、-N(R)S(O) 2R、-C(O)NR 2、-N(R)C(O)R，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；
R 4和R 5各自独立地选自H、卤素、OH、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；
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：
Z 1、Z 2、Z 3和Z 4各自独立地选自N或CR 3，但Z 1、Z 2、Z 3和Z 4中至多一个为N；
R 1和R 2各自独立地选自H或C 1-4烷基；
A为N或CH；
B为N或CH；
L为键；
C为任选被卤素、氰基、C 1-4烷基或卤代C 1-4烷基取代的5-10元杂芳基；
R 3独立地选自H、卤素、氰基，或任选取代的C 1-4烷基、-O-C 1-4烷基、C 3-6环烷基或4-7元杂环基；
所述任选取代是指被选自以下的取代基取代：卤素、-CN、-OR′、-NR′R″，其中R′和R″各自独立地选自H、C 1-4烷基或C 3-7环烷基。
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：
Z 1和Z 4各自独立地选自N或CH，Z 2和Z 3各自独立地选自N或CR 3，但Z 1、Z 2、Z 3和Z 4中至多一个为N；
R 1和R 2各自独立地选自H或C 1-4烷基；
A为CH；
B为CH；
L为键；
C为任选被卤素或C 1-4烷基取代的5-10元杂芳基；
R 3为H、卤素或氰基。
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C为任选被卤素或C 1-4烷基取代的喹啉基或吡啶基，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为C 1-4烷基、R 2为H，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(IIa)-(IIc)的化合物：
Figure PCTCN2019086258-appb-000002
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(III)的化合物：
Figure PCTCN2019086258-appb-000003
本发明的另一个实施方案涉及上述通式(III)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 PCTCN2019086258-appb-000004
Figure PCTCN2019086258-appb-000005
Figure PCTCN2019086258-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、睾丸癌、头部癌、颈部癌、皮肤癌(包括黑色素瘤及基底癌)、间皮内膜癌、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、间皮瘤、肉瘤(包括卡波西肉瘤)、绒膜癌、皮肤基底细胞癌或睾丸精原细胞瘤等。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。
“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，如八氢环戊二烯并[c]吡咯、八氢吡咯并[1,2-a]吡嗪、3,8-二氮杂二环[3.2.1]辛烷、5-氮杂螺[2.4]庚烷、2-氧杂-7-氮杂螺[3.5]壬烷等等。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 PCTCN2019086258-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、恶唑 基、异恶唑基、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 PCTCN2019086258-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”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”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、氰基、硝基、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，其中所述烷基、环烷基、杂环基、苯基或杂芳基任选被一个或多个选自卤素、氰基、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″、-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) 2R′、-S(O) 2NR′R″等取代基所取代。R′、R″和R′″各自独立地选自H、任选含有选自N、O和S的杂原子的C 1-4烷基、C 3-7环烷基、4-7元杂环基、苯基或5-6元杂芳基，其中所述烷基、环烷基、杂环基、苯基或杂芳基任选被一个或多个选自卤素、氰基、C 1-4烷基、卤代C 1-4烷基、-O-C 1-4烷基等取代基所取代；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形式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)所述的3-吲唑啉酮类化合物可按照方法A所述路线合成：中间体胺A1与邻硝基苯甲醛经过还原胺化或与邻溴甲基硝基苯经过取代反应生成A2；A2的醇溶液在碱催化下进行David-Beruit反应得到2-取代的吲唑A3；A3再在酸溶液中水解生成目标产物3-吲唑啉酮化合物A4。
方法A：
Figure PCTCN2019086258-appb-000009
中间体胺A1可参照专利申请WO2017192844中相关步骤合成，也可按照方法B所述路线合成：起始物料酮B1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B2；B2与硼酸酯或硼酸C-B(OR) 2通过Suzuki偶联反应得到B3，其经氢化还原生成B4；B4被LAH还原成醇，接着用戴斯-马丁氧化剂氧化生成醛B5；B5和格试剂反应生成B6；B6经过光延反应生成B7；最后脱保护得到胺A1。
方法B：
Figure PCTCN2019086258-appb-000010
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(CDC1 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0.15～0.2mm，薄层层析分离纯化产品采用的规格是0.4～0.5mm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.)、北京偶合化学品等公司。
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，或者采用其它的溶剂体系。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％三氟乙酸或甲酸)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和2
6-氯-2-(((1r,4r)-4-(6-氟喹啉-4-基)环己基)甲基)-1,2-二氢-3H-吲唑-3-酮1和6-氯-2-(((1s,4s)-4-(6-氟喹啉-4-基)环己基)甲基)-1,2-二氢-3H-吲唑-3-酮2
Figure PCTCN2019086258-appb-000011
Figure PCTCN2019086258-appb-000012
第一步
4-(((三氟甲基)磺酰)氧基)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1a(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，滤饼用乙酸乙酯(30mL×3)洗涤。。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)氧基)环己-3-烯-1-羧酸甲酯1b(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)氧基)环己-3-烯-1-羧酸甲酯1b(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(石油醚/乙酸乙酯＝20/1至1/1)纯化，得到目标产物4-(6-氟喹啉-4-基)环己-3-烯-1-羧酸甲酯1c(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1c(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1d(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1d(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1e(810mg，淡黄色固体)，产率：80％。
MS m/z(ESI):260[M+1]
第五步
2-((4-(6-氟喹啉-4-基)环己基)甲基)异二氢吲哚-1,3-二酮
将化合物(4-(6-氟喹啉-4-基)环己基)甲醇1e(500mg，1.93mmol)、邻苯二甲酰亚胺(312mg，2.12mmol)、三苯基膦(757mg，2.89mmol)和四氢呋喃(20mL)在氮气气氛下混合，然后加入偶氮二甲酸二异丙酯(584mg，2.89mmol)。室温下搅拌5小时后，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＝1/1)纯化，得到目标产物2-((4-(6-氟喹啉-4-基)环己基)甲基)异二氢吲哚-1,3-二酮1f(400mg，白色固体)，产率：53％。
MS m/z(ESI):389[M+1]
第六步
(4-(6-氟喹啉-4-基)环己基)甲胺
将化合物2-((4-(6-氟喹啉-4-基)环己基)甲基)异二氢吲哚-1,3-二酮1f(510mg，1.31mmol)溶于乙醇(20mL)，加入水合肼(1mL)后加热至50℃并搅拌5小时。冷却到室温后，减压除去溶剂，残余物用反相制备高效液相色谱纯化，得到目标产物(4-(6-氟喹啉-4-基)环己基)甲胺1g(300mg，白色固体)，产率：80％。
MS m/z(ESI):259[M+1]
第七步
N-(4-氯-2-硝基苯甲基)-1-(4-(6-氟喹啉-4-基)环己基)甲胺
将化合物(4-(6-氟喹啉-4-基)环己基)甲胺1g(260mg，1.0mmol)和2-硝基-4-氯苯甲醛(190mg，1mmol)共同溶于甲醇(10mL)，然后加入硼氢化钠(94mg，1.5mmol)。将该反应混合物加热至70℃并搅拌1.5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＝25/1至2/1)纯化，得到目标产物N-(4-氯-2-硝基苯甲基)-1-(4-(6-氟喹啉-4-基)环己基)甲胺1h(404mg，白色固体)，产率：94％。
MS m/z(ESI):428[M+1]
第八步
4-(4-((6-氯-3-甲氧基-2H-吲唑-2-基)甲基)环己基)-6-氟喹啉
将化合物N-(4-氯-2-硝基苯甲基)-1-(4-(6-氟喹啉-4-基)环己基)甲胺1h(0.6g，1.4mmol)、甲醇(15mL)和水(15mL)混合，加入氢氧化钾(393mg，7mmol)，然后加热至60℃并搅拌24小时。加入水(50mL)，然后减压条件下除去甲醇，残余物用二氯甲烷萃取(50mL×2)。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，得到目标产物4-(4-((6-氯-3-甲氧基-2H-吲唑-2-基)甲基)环己基)-6-氟喹啉1i(550mg，白色固体)，产率：92％。
MS m/z(ESI):424[M+1]
第九步
6-氯-2-(((1r,4r)-4-(6-氟喹啉-4-基)环己基)甲基)-1,2-二氢-3H-吲唑-3-酮1和6-氯-2-(((1s,4s)-4-(6-氟喹啉-4-基)环己基)甲基)-1,2-二氢-3H-吲唑-3-酮2
将化合物4-(4-((6-氯-3-甲氧基-2H-吲唑-2-基)甲基)环己基)-6-氟喹啉1i(350mg，0.83mmol)溶于甲醇(4mL)后，加入浓硫酸(0.25mL)，然后在微波反应器中加热至100℃并搅拌过夜。冷却到室温后，用饱和碳酸氢钠溶液调节至pH＝7，然后用乙酸乙酯萃取(25mL×3)。有机相合并后，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6-氯-2-(((1r,4r)-4-(6-氟喹啉-4-基)环己基)甲基)-1,2-二氢-3H-吲唑-3-酮1(194mg，白色固体)，产率：51％；以及6-氯-2-(((1s,4s)-4-(6-氟喹啉-4-基)环己基)甲基)-1,2-二氢-3H-吲唑-3-酮2(95mg，白色固体)，产率：25％。
6-氯-2-(((1r,4r)-4-(6-氟喹啉-4-基)环己基)甲基)-1,2-二氢-3H-吲唑-3-酮1
MS m/z(ESI):410[M+1]
1H NMR(400MHz,CD 3OD)δ9.07(d,J＝5.9Hz,1H),8.32(ddd,J＝14.2,9.6,3.7Hz,2H),8.07–7.88(m,2H),7.73(d,J＝8.4Hz,1H),7.33(d,J＝1.2Hz,1H),7.14(dd,J＝8.4,1.7Hz,1H),3.92(d,J＝7.3Hz,2H),3.63(ddd,J＝11.9,9.0,3.0Hz,1H),2.16–2.07(m,J＝21.9,3H),1.96–1.80(m,2H),1.73(qd,J＝12.7,2.9Hz,2H),1.52(qd,J＝12.8,3.1Hz,2H)。
6-氯-2-(((1s,4s)-4-(6-氟喹啉-4-基)环己基)甲基)-1,2-二氢-3H-吲唑-3-酮2
MS m/z(ESI):410[M+1]
1H NMR(400MHz,CD 3OD)δ9.16(d,J＝5.9Hz,1H),8.43–8.30(m, 2H),8.23(d,J＝5.9Hz,1H),8.04(ddd,J＝9.4,7.9,2.6Hz,1H),7.77(d,J＝8.5Hz,1H),7.40(d,J＝1.4Hz,1H),7.20(dd,J＝8.5,1.7Hz,1H),4.27(d,J＝8.3Hz,2H),3.71(dd,J＝12.6,9.4Hz,1H),2.56(s,1H),2.11–1.85(m,3H),1.77(d,J＝12.3Hz,1H)。
实施例3和4
6-氯-2-(1-((1r,4r)-4-(6-氟喹啉-4-基)环己基)乙基)-1,2-二氢-3H-吲唑-3-酮3和6-氯-2-(1-((1s,4s)-4-(6-氟喹啉-4-基)环己基)乙基)-1,2-二氢-3H-吲唑-3-酮4
Figure PCTCN2019086258-appb-000013
第一步
2-硝基-4-氯苯甲醇
将化合物2-硝基-4-氯苯甲醛3a(1.66g，8.95mmol)溶于甲醇(20mL)，然后加入硼氢化钠(509mg，13.4mmol)。室温下搅拌1小时后，用水(1mL)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＝10/1至1/1)纯化，得到目标产物2-硝基-4-氯苯甲醇3b(1.26g，无色油状物)，产率：75％。
1H NMR(400MHz,CDCl 3)δ8.10(d,J＝2.1Hz,1H),7.74(d,J＝8.3Hz,1H),7.64(dd,J＝8.3,2.1Hz,1H),4.97(s,2H),2.39(s,1H)。
第二步
1-溴甲基-2-硝基-4-氯苯
将化合物2-硝基-4-氯苯甲醇3b(1.26g，6.72mmol)溶于二氯甲烷 (20mL)，然后依次加入四溴化碳(4.05g，12.1mmol)和三苯基膦(3.17g，12.1mmol)。室温下搅拌16小时后，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＝100/0至4/1)纯化，得到目标产物1-溴甲基-2-硝基-4-氯苯3c(1.18g，无色油状物)，产率：70％。
1H NMR(400MHz,CDCl 3)δ8.05(d,J＝2.1Hz,1H),7.59(dd,J＝8.3,2.1Hz,1H),7.53(d,J＝8.3Hz,1H),4.79(s,2H)。
第三步
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1e(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3d(596mg，无色油状物)，产率：75％。
MS m/z(ESI):258[M+1]
第四步
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3d(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，2.26mL，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3e(1.2g，无色油状物)，产率：70％。
MS m/z(ESI):274[M+1]
第五步
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3e(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3f(102mg，白色固体)，产率：25％。
MS m/z(ESI):403[M+1]
第六步
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3f(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，残余物用反相制备高效液相色谱纯化，得到目标产物1-(4-(6-氟喹啉-4-基)环己基)乙烷-1-胺3g(320mg，白色固体)，产率：74％。
MS m/z(ESI):273[M+1]
第七步
N-(4-氯-2-硝基苯甲基)-1-(4-(6-氟喹啉-4-基)环己基)乙烷-1-胺
将化合物1-(4-(6-氟喹啉-4-基)环己基)乙烷-1-胺3g(272mg，1.0mmol)、1-溴甲基-2-硝基-4-氯苯3c(250mg，1.0mmol)和乙腈(20mL)混合，然后加入碳酸钾(276mg，2mmol)并加热至70℃。在此温度搅拌2小时后，冷却至室温，然后过滤。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N-(4-氯-2-硝基苯甲基)-1-(4-(6-氟喹啉-4-基)环己基)乙烷-1-胺3h(265mg，白色固体)，产率：60％。
MS m/z(ESI):442[M+1]
第八步
4-(4-(1-(6-氯-3-甲氧基-2H-吲唑-2-基)乙基)环己基)-6-氟喹啉
将化合物N-(4-氯-2-硝基苯甲基)-1-(4-(6-氟喹啉-4-基)环己基)乙烷-1-胺3h(265mg，0.6mmol)、甲醇(15mL)和水(15mL)混合，加入氢氧化钾(336mg，6mmol)，然后加热至60℃并搅拌24小时。加入水(20mL)，然后减压条件下除去甲醇，残余物用二氯甲烷萃取(30mL×2)。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-(4-(1-(6-氯-3-甲氧基-2H-吲唑-2-基)乙基)环己基)-6-氟喹啉3i(136mg，白色固体)，产率：52％。
MS m/z(ESI):438[M+1]
第九步
6-氯-2-(1-((1r,4r)-4-(6-氟喹啉-4-基)环己基)乙基)-1,2-二氢-3H-吲唑-3-酮3和6-氯-2-(1-((1s,4s)-4-(6-氟喹啉-4-基)环己基)乙基)-1,2-二氢-3H-吲唑-3-酮4
将化合物4-(4-(1-(6-氯-3-甲氧基-2H-吲唑-2-基)乙基)环己基)-6-氟喹啉3i(50mg，0.11mmol)溶于甲醇(2mL)后，加入浓硫酸(0.1mL)，然后在微波反应器中加热至100℃并搅拌过夜。冷却到室温后，用饱和碳酸氢钠溶液调节至pH＝7，然后用乙酸乙酯萃取(25mL×3)。有机相合并后，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6-氯-2-(1-((1r,4r)-4-(6-氟喹啉-4-基)环己基)乙基)-1,2-二氢-3H-吲唑-3-酮盐酸盐3(5mg，白色固体)，产率：10％；以及6-氯-2-(1-((1s,4s)-4-(6-氟喹啉-4-基)环己基)乙基)-1,2-二氢-3H-吲唑-3-酮盐酸盐4(12mg，白色固体)，产率：24％。
6-氯-2-(1-((1r,4r)-4-(6-氟喹啉-4-基)环己基)乙基)-1,2-二氢-3H-吲唑- 3-酮盐酸盐3
MS m/z(ESI):424[M+1]
1H NMR(400MHz,CD 3OD)δ9.19(s,1H),8.60–7.98(m,5H),7.57(s,1H),7.18(s,1H),5.36(s,1H),3.79(s,1H),2.59(d,J＝64.8Hz,1H),2.21(d,J＝20.4Hz,2H),2.09–1.89(m,3H),1.75(d,J＝41.0Hz,3H),1.31(s,3H)。
6-氯-2-(1-((1s,4s)-4-(6-氟喹啉-4-基)环己基)乙基)-1,2-二氢-3H-吲唑-3-酮盐酸盐4
MS m/z(ESI):424[M+1]
1H NMR(400MHz,CD 3OD)δ9.19(d,J＝5.9Hz,1H),8.42–8.19(m,3H),8.07(ddd,J＝9.4,7.9,2.6Hz,1H),7.77(d,J＝8.5Hz,1H),7.38(d,J＝1.4Hz,1H),7.20(dd,J＝8.5,1.7Hz,1H),5.14(dd,J＝11.4,6.7Hz,1H),3.76(s,1H),2.34(d,J＝11.3Hz,1H),2.22–1.92(m,5H),1.88–1.72(m,2H),1.55(d,J＝6.7Hz,3H),1.43(d,J＝13.4Hz,1H)。
实施例5
6-氯-2-((R)-1-((1s,4S)-4-(2-甲基吡啶-4-基)环己基)乙基)-1,2-二氢-3H-吲唑-3-酮
Figure PCTCN2019086258-appb-000014
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5a(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)洗涤后，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5b(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5b(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5c(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5c(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5d(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5d(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5e(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5e(1.8g，9.52mmol)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5f(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5f(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5g(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5g(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5h(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)恶唑烷-2-酮
将化合物2-((1s,4s)-4-(2-甲基吡啶-4-基)环己基)乙酸5h(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-苯甲基恶唑烷-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)恶唑烷-2-酮5i(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)恶唑烷-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)恶唑烷-2-酮5i(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)恶唑烷-2-酮5j(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)恶唑烷-2-酮5j(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5k(500mg，无色油状物)，产率：27％。
MS m/z(ESI):248[M+1]
第十一步
(R)-1-((1s,4S)-4-(2-甲基吡啶-4-基)环己基)乙烷-1-胺
将化合物(R)-2-((1s,4S)-4-(2-甲基吡啶-4-基)环己基)丙酸5k(200mg，0.8mmol)、叠氮磷酸二苯酯(241mg，0.87mmol)、三乙胺(98mg，0.97mmol)和甲苯(10mL)混合后，加热至70℃并搅拌3小时。冷却到室温后，在减压条件下除去溶剂，残余物溶于四氢呋喃(5mL)，然后加入氢氧化锂水溶液(1N，5mL，5mmol)。室温下搅拌1小时后，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)-1-((1s,4S)-4-(2-甲基吡啶-4-基)环己基)乙烷-1-胺5l(150mg，黄色固体)，产率：86％。
MS m/z(ESI):219[M+1]
第十二步
(R)-N-(4-氯-2-硝基苯甲基)-1-((1s,4S)-4-(2-甲基吡啶-4-基)环己基)乙烷-1-胺
将化合物(R)-1-((1s,4S)-4-(2-甲基吡啶-4-基)环己基)乙烷-1-胺5l(150mg，0.68mmol)、1-溴甲基-2-硝基-4-氯苯3c(172mg，0.68mmol)和乙腈(10mL)混合，然后加入碳酸钾(190mg，1.37mmol)并加热至80℃。在此温度搅拌4小时后，冷却至室温，然后过滤。滤液在减压条件下除去溶剂，得到目标产物(R)-N-(4-氯-2-硝基苯甲基)-1-((1s,4S)-4-(2-甲基吡啶-4-基)环己基)乙烷-1-胺5m(120mg，黄色油状物)，产率：46％。
MS m/z(ESI):388[M+1]
第十三步
6-氯-3-甲氧基-2-((R)-1-((1s,4S)-4-(2-甲基吡啶-4-基)环己基)乙基)-2H-吲唑
将化合物(R)-N-(4-氯-2-硝基苯甲基)-1-((1s,4S)-4-(2-甲基吡啶-4-基)环己基)乙烷-1-胺5m(120mg，0.31mmol)、甲醇(10mL)和氢氧化钾水溶液(0.5N，3.3mL，1.65mmol)混合，然后加热回流18小时。冷却到室温后，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＝50/1至3/1)纯化，得到目标产物6-氯-3-甲氧基-2-((R)-1-((1s,4S)-4-(2-甲基吡啶-4-基)环己基)乙基)-2H-吲唑5n(100mg，黄色固体)，产率：84％。
MS m/z(ESI):384[M+1]
第十四步
6-氯-2-((R)-1-((1s,4S)-4-(2-甲基吡啶-4-基)环己基)乙基)-1,2-二氢-3H-吲唑-3-酮
将化合物6-氯-3-甲氧基-2-((R)-1-((1s,4S)-4-(2-甲基吡啶-4-基)环己基)乙基)-2H-吲唑5n(100mg，0.26mmol)溶于甲醇(10mL)后，加入浓硫酸(0.12mL)，然后在微波反应器中加热至100℃并搅拌5小时。冷却到室温后，用饱和碳酸氢钠溶液调节至pH＝7，然后用乙酸 乙酯萃取(25mL×3)。有机相合并后，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6-氯-2-((R)-1-((1s,4S)-4-(2-甲基吡啶-4-基)环己基)乙基)-1,2-二氢-3H-吲唑-3-酮盐酸盐5(32mg，白色固体)，产率：30％.
MS m/z(ESI):370[M+1]
1H NMR(400MHz,CD 3OD)δ8.59(d,J＝6.3Hz,1H),7.93(s,1H),7.88(dd,J＝6.2,1.4Hz,1H),7.75(d,J＝8.5Hz,1H),7.38-7.32(m,1H),7.18(dd,J＝8.5,1.7Hz,1H),5.01-4.95(m,1H),3.02-2.93(m,1H),2.80(s,3H),2.26-2.18(m,1H),2.04-1.84(m,5H),1.72-1.64(m,1H),1.62-1.55(m,1H),1.50(d,J＝8.0Hz,3H),1.35-1.28(m,1H)。
实施例6
6-氯-2-((R)-1-((1s,4S)-4-(6-氟喹啉-4-基)环己基)乙基)-1,2-二氢-3H-吲唑-3-酮
Figure PCTCN2019086258-appb-000015
第一步
(R)-N-(4-氯-2-硝基苯甲基)-1-((1s,4S)-4-(6-氟喹啉-4-基)环己基)乙烷-1-胺
将化合物1-溴甲基-2-硝基-4-氯苯3c(175mg，0.7mmol)、碳酸钾(193mg，1.4mmol)、(R)-1-((1s,4S)-4-(6-氟喹啉-4-基)环己基)乙烷-1-胺6a(190mg，0.7mmol，该化合物参照专利申请WO2017192844A1中相关步骤合成)和乙腈(20mL)混合，然后加热至80℃。在此温度搅拌4小时后，冷却至室温，用乙酸乙酯(50mL)稀释后过滤。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＝100/1至2/1)纯化，得到目标产物(R)-N-(4-氯-2-硝基苯甲基)-1-((1s,4S)-4-(6-氟喹啉-4-基)环己基)乙烷-1-胺6b(180mg，黄色油状物)，产率：58％。
MS m/z(ESI):442[M+1]
第二步
4-((1S,4s)-4-((R)-1-(6-氯-3-甲氧基-2H-吲唑-2-基)乙基)环己基)-6-氟喹啉
将化合物(R)-N-(4-氯-2-硝基苯甲基)-1-((1s,4S)-4-(6-氟喹啉-4-基)环己基)乙烷-1-胺6b(180mg，0.4mmol)、甲醇(20mL)和氢氧化钾水溶液(0.5N，4mL，2mmol)混合，然后加热回流72小时。冷却到室温后，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＝50/1至3/1)纯化，得到目标产物4-((1S,4s)-4-((R)-1-(6-氯-3-甲氧基-2H-吲唑-2-基)乙基)环己基)-6-氟喹啉6c(150mg，黄色固体)，产率：86％。
MS m/z(ESI):438[M+1]
第三步
6-氯-2-((R)-1-((1s,4S)-4-(6-氟喹啉-4-基)环己基)乙基)-1,2-二氢-3H-吲唑-3-酮
将化合物4-((1S,4s)-4-((R)-1-(6-氯-3-甲氧基-2H-吲唑-2-基)乙基)环己基)-6-氟喹啉6c(150mg，0.34mmol)溶于甲醇(10mL)后，加入浓硫酸(0.12mL)，然后加热至100℃并搅拌5小时。冷却到室温后，残余物用反相制备高效液相色谱纯化，得到目标产物6-氯-2-((R)-1-((1s,4S)-4-(6-氟喹啉-4-基)环己基)乙基)-1,2-二氢-3H-吲唑-3-酮6(80mg，绿色固体)，产率：56％.
MS m/z(ESI):424[M+1]
1H NMR(400MHz,CD 3OD)δ8.80(d,J＝4.7Hz,1H),8.09(dd,J＝9.3,5.6Hz,1H),7.89(dd,J＝10.7,2.7Hz,1H),7.74(d,J＝8.4Hz,1H),7.65(d,J＝4.7Hz,1H),7.59(ddd,J＝9.2,8.1,2.8Hz,1H),7.33(d,J＝1.4Hz,1H),7.15(dd,J＝8.4,1.7Hz,1H),5.08(dq,J＝13.5,6.8Hz,1H),3.50–3.37(m,1H),2.29(dd,J＝7.8,3.4Hz,1H),2.16–1.96(m,3H),1.94–1.84(m,2H),1.72(ddd,J＝10.1,7.0,3.6Hz,2H),1.51(d,J＝6.8Hz,3H),1.40(d,J＝13.5Hz,1H)。
实施例7
5-氯-2-((R)-1-((1s,4S)-4-(6-氟喹啉-4-基)环己基)乙基)-1,2-二氢-3H-吲唑-3-酮
Figure PCTCN2019086258-appb-000016
Figure PCTCN2019086258-appb-000017
第一步
2-溴甲基-1-硝基-4-氯苯
将化合物2-甲基-1-硝基-4-氯苯7a(2.5g，14.5mmol)、N-溴代丁二酰亚胺(3.1g，17.5mmol)、偶氮二异丁腈(237mg，1.45mmol)和四氯化碳(60mL)混合，加热回流15小时。冷却到室温后，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＝100/1至15/1)纯化，得到目标产物2-溴甲基-1-硝基-4-氯苯7b(170mg，淡黄色油状物)，产率：5％。
1H NMR(400MHz,CDCl 3)δ8.03(d,J＝8.7Hz,1H),7.58(d,J＝2.3Hz,1H),7.46(dd,J＝8.7,2.3Hz,1H),4.80(s,2H)。
第二步
(R)-N-(5-氯-2-硝基苯甲基)-1-((1s,4S)-4-(6-氟喹啉-4-基)环己基)乙烷-1-胺
将化合物2-溴甲基-1-硝基-4-氯苯7b(170mg，0.68mmol)、碳酸钾(187mg，1.36mmol)、(R)-1-((1s,4S)-4-(6-氟喹啉-4-基)环己基)乙烷-1-胺6a(185mg，0.68mmol)和乙腈(20mL)混合，然后加热至80℃。在此温度搅拌4小时后，冷却至室温，用乙酸乙酯(50mL)稀释后过滤。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＝100/1至2/1)纯化，得到目标产物(R)-N-(5-氯-2-硝基苯甲基)-1-((1s,4S)-4-(6-氟喹啉-4-基)环己基)乙烷-1-胺7c(140mg，黄色油状物)，产率：46％。
MS m/z(ESI):442[M+1]
第三步
4-((1S,4s)-4-((R)-1-(5-氯-3-甲氧基-2H-吲唑-2-基)乙基)环己基)-6-氟喹啉
将化合物(R)-N-(5-氯-2-硝基苯甲基)-1-((1s,4S)-4-(6-氟喹啉-4-基)环己基)乙烷-1-胺7c(140mg，0.31mmol)、甲醇(20mL)和氢氧化钾水溶液(0.5N，3.2mL，1.6mmol)混合，然后加热回流72小时。冷却到室温后，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＝50/1至3/1)纯化，得到目标产物4-((1S,4s)-4-((R)-1-(5-氯-3-甲氧基-2H-吲唑-2-基)乙基)环己基)-6-氟喹啉7d(120mg，黄色固体)，产率：88％。
MS m/z(ESI):438[M+1]
第四步
5-氯-2-((R)-1-((1s,4S)-4-(6-氟喹啉-4-基)环己基)乙基)-1,2-二氢-3H-吲唑-3-酮
将化合物4-((1S,4s)-4-((R)-1-(5-氯-3-甲氧基-2H-吲唑-2-基)乙基)环己基)-6-氟喹啉7d(120mg，0.27mmol)溶于甲醇(10mL)后，加入浓硫酸(0.12mL)，然后加热至100℃并搅拌5小时。冷却到室温后，残余物用反相高效液相色谱纯化，得到目标产物5-氯-2-((R)-1-((1s,4S)-4-(6-氟喹啉-4-基)环己基)乙基)-1,2-二氢-3H-吲唑-3-酮7(47mg，白色固体)，产率：40％.
MS m/z(ESI):424[M+1]
1H NMR(400MHz,CD 3OD)δ8.81(d,J＝4.7Hz,1H),8.09(dd,J＝9.3,5.6Hz,1H),7.89(dd,J＝10.7,2.7Hz,1H),7.75(d,J＝2.0Hz,1H),7.65(d,J＝4.7Hz,1H),7.60(ddd,J＝9.3,8.2,2.8Hz,1H),7.54(dd,J＝8.8,2.1Hz,1H),7.32(d,J＝8.8Hz,1H),5.09(dt,J＝13.6,6.8Hz,1H),3.50–3.38(m,1H),2.29(dd,J＝7.9,3.4Hz,1H),2.16–1.99(m,3H),1.91(dd,J＝10.2,6.1Hz,2H),1.79–1.65(m,2H),1.52(d,J＝6.8Hz,3H),1.39(d,J＝15.7Hz,1H)。
实施例8
6-氯-2-((R)-1-((1s,4S)-4-(6-氟喹啉-4-基)环己基)乙基)-1,2-二氢-3H-吡唑并[4,3-b]吡啶-3-酮
Figure PCTCN2019086258-appb-000018
第一步
2-(5-氯-3-硝基吡啶-2-基)丙二酸二乙酯
将化合物丙二酸二乙酯(4g，25mmol)、氢化钠(60％，1g，25mmol)和N,N-二甲基甲酰胺(15mL)混合，搅拌10分钟后，加入3-硝基-2，5-二氯苯8a(2.5g，13mmol)的N,N-二甲基甲酰胺(5mL)溶液并加热至40℃。在此温度下搅拌2小时后，加入水(40mL)，然后用1N盐酸调节至pH＝7-8并用乙酸乙酯萃取(100mL×2)。有机相合并后，用饱和食盐水(20mL)洗涤，然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＝100/1至2/1)纯化，得到目标产物2-(5-氯-3-硝基吡啶-2-基)丙二酸二乙酯8b(3.2g，淡黄色油状物)，产率：78％。
MS m/z(ESI):318[M+1]
第二步
2-甲基-3-硝基-5-氯吡啶
将化合物2-(5-氯-3-硝基吡啶-2-基)丙二酸二乙酯8b(3.2g，10.1mmol)和盐酸(5N，25mL)混合后，加热回流20小时。冷却到室温后，减压除去溶剂，残余物用溶于甲醇(50mL)后用饱和碳酸氢钠溶液调节至pH＝7-8，然后再次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＝100/1至1/1)纯化，得到目标产物2-甲基-3-硝基-5-氯吡啶8c(1.5g，黄色油状物)，产率：86％。
MS m/z(ESI):173[M+1]
第三步
2-(溴甲基)-3-硝基-5-氯吡啶
将化合物2-甲基-3-硝基-5-氯吡啶8c(600mg，3.48mmol)、N-溴代丁二酰亚胺(743mg，4.18mmol)、偶氮二异丁腈(57mg，0.35mmol)和氯苯(30mL)混合，加热回流15小时。冷却到室温后，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＝100/1至5/1)纯化，得到目标产物2-(溴甲基)-3-硝基-5-氯吡啶8d(300mg，淡黄色油状物)，产率：34％。
MS m/z(ESI):251[M+1]
第四步
(R)-N-((5-氯-3-硝基吡啶-2-基)甲基)-1-((1s,4S)-4-(6-氟喹啉-4-基)环己基)乙烷-1-胺
将化合物2-(溴甲基)-3-硝基-5-氯吡啶8d(250mg，1mmol)、碳酸钾(276mg，2mmol)、(R)-1-((1s,4S)-4-(6-氟喹啉-4-基)环己基)乙烷-1-胺6a(272mg，1mmol)和乙腈(20mL)混合，然后加热至80℃。在此温度搅拌4小时后，冷却至室温，用乙酸乙酯(50mL)稀释后过滤。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＝100/1至2/1)纯化，得到目标产物(R)-N-((5-氯-3-硝基吡啶-2-基)甲基)-1-((1s,4S)-4-(6-氟喹啉-4-基)环己基)乙烷-1-胺8e(120mg，黄色油状物)，产率：27％。
MS m/z(ESI):443[M+1]
第五步
4-((1S,4s)-4-((R)-1-(6-氯-3-甲氧基-2H-吡唑并[4,3-b]吡啶-2-基)乙基)环己基)-6-氟喹啉
将化合物(R)-N-((5-氯-3-硝基吡啶-2-基)甲基)-1-((1s,4S)-4-(6-氟喹啉-4-基)环己基)乙烷-1-胺8e(120mg，0.27mmol)、甲醇(20mL)和氢氧化钾水溶液(0.5N，2.7mL，1.35mmol)混合，然后加热回流72小时。冷却到室温后，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＝50/1至3/1)纯化，得到目标产物4-((1S,4s)-4-((R)-1-(6-氯-3-甲氧基-2H-吡唑并[4,3-b]吡啶-2-基)乙基)环己基)-6-氟喹啉8f(100mg，黄色固体)，产率：84％。
MS m/z(ESI):439[M+1]
第六步
6-氯-2-((R)-1-((1s,4S)-4-(6-氟喹啉-4-基)环己基)乙基)-1,2-二氢-3H-吡唑并[4,3-b]吡啶-3-酮
将化合物4-((1S,4s)-4-((R)-1-(6-氯-3-甲氧基-2H-吡唑并[4,3-b]吡啶-2-基)乙基)环己基)-6-氟喹啉8f(100mg，0.22mmol)溶于甲醇(10mL)后，加入浓硫酸(0.12mL)，然后加热至100℃并搅拌5小时。冷却到室温后，残余物用反相制备高效液相色谱纯化，得到目标产物6-氯-2-((R)-1-((1s,4S)-4-(6-氟喹啉-4-基)环己基)乙基)-1,2-二氢-3H-吡唑并[4,3-b]吡啶-3-酮8(13mg，白色固体)，产率：18％.
MS m/z(ESI):425[M+1]
1H NMR(400MHz,CD 3OD)δ8.86(d,J＝4.6Hz,1H),8.45(s,1H),8.13(dd,J＝9.2,5.5Hz,1H),7.96(dd,J＝10.5,2.2Hz,1H),7.85(d,J＝1.6Hz,1H),7.74(d,J＝4.8Hz,1H),7.67(dd,J＝11.9,5.2Hz,1H),5.17(td,J＝13.4,6.7Hz,1H),3.49(d,J＝7.1Hz,1H),2.31(d,J＝11.4Hz,1H),2.07(dd,J＝14.6,10.6Hz,3H),1.93(d,J＝4.1Hz,2H),1.81–1.67(m,2H),1.54(d,J＝6.7Hz,3H),1.41(d,J＝13.4Hz,1H)。
实施例9
5-氯-2-((R)-1-((1s,4S)-4-(6-氟喹啉-4-基)环己基)乙基)-1,2-二氢-3H-吡唑并[3,4-b]吡啶-3-酮
Figure PCTCN2019086258-appb-000019
Figure PCTCN2019086258-appb-000020
第一步
5-氯-3-甲基-2-硝基吡啶
将化合物5-氯-3-甲基吡啶-2-胺9a(5.88g，41.4mmol)溶于浓硫酸(50mL)并冷却到-10℃，然后逐滴加入过氧化氢水溶液(30％，40mL)。逐渐升温到室温后，继续搅拌16小时。反应结束后，将该混合物倒入冰水混合物中，有白色固体析出，将此固体滤出后干燥，得到目标产物5-氯-3-甲基-2-硝基吡啶9b(5.7g，白色固体)，产率：80％。
MS m/z(ESI):173[M+1]
第二步
(E)-2-(5-氯-2-硝基吡啶-3-基)-N,N-二甲基乙烯-1-胺
将化合物5-氯-3-甲基-2-硝基吡啶9b(5.16g，30mmol)和N,N-二甲基甲酰胺二甲基缩醛(4.28g，36mmol)溶于N,N-二甲基甲酰胺(100mL)，加热至110℃并搅拌过夜。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＝10/1至1/1)纯化，得到目标产物(E)-2-(5-氯-2-硝基吡啶-3-基)-N,N-二甲基乙烯-1-胺9c(5.1g，红色固体)，产率：75％。
1H NMR(400MHz,CD 3OD)δ8.18(d,J＝2.2Hz,1H),7.87(d,J＝2.2Hz,1H),7.44(d,J＝13.3Hz,1H),5.35(d,J＝13.3Hz,1H),2.99(s,6H)。
第三步
2-硝基-5-氯尼古丁醛
将化合物(E)-2-(5-氯-2-硝基吡啶-3-基)-N,N-二甲基乙烯-1-胺9c(2.28g，10mmol)溶于四氢呋喃(10mL)，然后加入高碘酸钠(3.21g，15mmol)的水溶液(15mL)。室温下搅拌过夜后过滤，滤液在减压条件下除去溶剂。残余物分散在四氢呋喃(100mL)中搅拌1小时，然后过滤。滤液在减压条件下除去溶剂，得到目标产物2-硝基-5-氯尼古丁醛9d(954mg，淡黄色固体)，产率：51％。
1H NMR(400MHz,CDCl 3)δ10.28(s,1H),8.65(d,J＝2.4Hz,1H),8.31(d,J＝2.4Hz,1H)。
第四步
(5-氯-2-硝基吡啶-3-基)甲醇
将化合物2-硝基-5-氯尼古丁醛9d(144mg，0.77mmol)溶于甲醇(20mL)，然后在0°下加入硼氢化钠(58mg，1.54mmol)。0℃下搅拌2小时后，用水(1mL)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＝10/1至1/1)纯化，得到目标产物(5-氯-2-硝基吡啶-3-基)甲醇9e(131mg，无色油状物)，产率：75％。
MS m/z(ESI):189[M+1]
第五步
3-(溴甲基)-5-氯-2-硝基吡啶
将化合物(5-氯-2-硝基吡啶-3-基)甲醇9e(131mg，0.696mmol)溶于二氯甲烷(10mL)，然后依次加入四溴化碳(415mg，1.25mmol)和三苯基膦(328mg，1.25mmol)。室温下搅拌16小时后，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＝100/0至4/1)纯化，得到目标产物1-溴甲基-2-硝基-4-氯苯9f(81mg，白色固体)，产率：46％。
MS m/z(ESI):251[M+1]
第六步
(R)-N-((5-氯-2-硝基吡啶-3-基)甲基)-1-((1s,4S)-4-(6-氟喹啉-4-基)环己基)乙烷-1-胺
将化合物1-溴甲基-2-硝基-4-氯苯9f(81mg，0.32mmol)、碳酸钾(90mg，0.65mmol)、(R)-1-((1s,4S)-4-(6-氟喹啉-4-基)环己基)乙烷-1-胺6a(88mg，0.32mmol)和乙腈(5mL)混合，然后加热至70℃。在此温度搅拌18小时后，冷却至室温，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＝100/1至2/1)纯化，得到目标产物(R)-N-((5-氯-2-硝基吡啶-3-基)甲基)-1-((1s,4S)-4-(6-氟喹啉-4-基)环己基)乙烷-1-胺9g(75mg，白色固体)，产率：52％。
MS m/z(ESI):443[M+1]
第七步
4-((1S,4s)-4-((R)-1-(5-氯-3-甲氧基-2H-吡唑并[3,4-b]吡啶-2-基)乙基)环己基)-6-氟喹啉
将化合物(R)-N-((5-氯-2-硝基吡啶-3-基)甲基)-1-((1s,4S)-4-(6-氟喹啉-4-基)环己基)乙烷-1-胺9g(75mg，0.17mmol)、甲醇(2mL)和氢氧化钾水溶液(0.5N，1.6mL，0.8mmol)混合，然后加热至60℃并搅拌24小时。冷却到室温后，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＝50/1至3/1)纯化，得到目标产物4-((1S,4s)-4-((R)-1-(5-氯-3-甲氧基-2H-吡唑并[3,4-b]吡啶-2-基)乙基)环己基)-6-氟喹啉9h(40mg，白色固体)，产率：55％。
MS m/z(ESI):439[M+1]
第八步
5-氯-2-((R)-1-((1s,4S)-4-(6-氟喹啉-4-基)环己基)乙基)-1,2-二氢-3H-吡唑并[3,4-b]吡啶-3-酮
将化合物4-((1S,4s)-4-((R)-1-(5-氯-3-甲氧基-2H-吡唑并[3,4-b]吡啶-2-基)乙基)环己基)-6-氟喹啉9h(40mg，0.1mmol)溶于甲醇(2mL)后，加入浓硫酸(0.12mL)，然后加热至100℃并搅拌5小时。冷却到室温后，残余物用反相高效液相色谱纯化，得到目标产物5-氯-2-((R)-1-((1s,4S)-4-(6-氟喹啉-4-基)环己基)乙基)-1,2-二氢-3H-吡唑并[3,4-b]吡啶-3-酮盐酸盐9(10mg，白色固体)，产率：23％。
MS m/z(ESI):425[M+1]
1H NMR(400MHz,CD 3OD)δ9.17(d,J＝5.7Hz,1H),8.56(d,J＝2.2Hz,1H),8.36(dt,J＝9.7,3.7Hz,2H),8.20(dd,J＝12.6,4.0Hz,2H),8.10–8.00(m,1H),5.23–5.10(m,1H),3.73(d,J＝10.7Hz,1H),2.35(d,J＝10.9Hz,1H),2.22–1.90(m,5H),1.86–1.68(m,2H),1.55(d,J＝6.7Hz,3H),1.44–1.30(m,1H)。
实施例10
5,6-二氯-2-((R)-1-((1s,4S)-4-(6-氟喹啉-4-基)环己基)乙基)-1,2-二氢-3H-吲唑-3-酮
Figure PCTCN2019086258-appb-000021
参照实施例7的合成步骤合成实施例10，但在第一步中用1,2-二氯-4-甲基-5-硝基苯10a代替2-甲基-1-硝基-4-氯苯7a。
MS m/z(ESI):458[M+1]
1H NMR(400MHz,CD 3OD)δ9.18(d,J＝5.9Hz,1H),8.40–8.31(m,2H),8.24(d,J＝5.9Hz,1H),8.09–8.02(m,1H),7.90(s,1H),7.54(s,1H),5.11(dq,J＝13.5,6.7Hz,1H),3.75(t,J＝11.0Hz,1H),2.37–2.28(m,1H),2.16–1.94(m,5H),1.86–1.73(m,2H),1.54(d,J＝6.7Hz,3H),1.42(d,J＝12.3Hz,1H)。
实施例11
5-溴-2-((R)-1-((1s,4S)-4-(6-氟喹啉-4-基)环己基)乙基)-1,2-二氢-3H-吲唑-3-酮
Figure PCTCN2019086258-appb-000022
参照实施例7的合成步骤合成实施例11，但在第一步中用2-甲基-1-硝基-4-溴苯11a代替2-甲基-1-硝基-4-氯苯7a。
MS m/z(ESI):468[M+1]
1H NMR(400MHz,CD 3OD)δ8.81(d,J＝4.7Hz,1H),8.10(dd,J＝9.3,5.6Hz,1H),7.90(dd,J＝11.6,2.1Hz,2H),7.70–7.56(m,3H),7.27(d,J＝8.8Hz,1H),5.10(dd,J＝11.4,6.7Hz,1H),3.44(d,J＝7.5Hz,1H),2.30(d,J＝11.1Hz,1H),2.07(dd,J＝26.4,13.9Hz,3H),1.91(d,J＝4.1Hz,2H),1.73(dd,J＝18.0,10.1Hz,2H),1.52(d,J＝6.8Hz,3H),1.39(d,J＝14.8Hz,1H)。
实施例12
2-((R)-1-((1s,4S)-4-(6-氟喹啉-4-基)环己基)乙基)-3-羰基-2,3-二氢-1H-吲唑-5-甲腈
Figure PCTCN2019086258-appb-000023
将化合物5-溴-2-((R)-1-((1s,4S)-4-(6-氟喹啉-4-基)环己基)乙基)-1,2-二氢-3H-吲唑-3-酮11(22mg，0.048mmol)、氰化锌(17mg，0.144mmol)、[1,1'-双(二苯基膦基)二茂铁]二氯化钯(7mg，0.0096mmol)和N,N-二甲基乙酰胺(3mL)混合，除氧，然后在氮气气氛下用微波反应器加热至130℃并搅拌1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2-((R)-1-((1s,4S)- 4-(6-氟喹啉-4-基)环己基)乙基)-3-羰基-2,3-二氢-1H-吲唑-5-甲腈盐酸盐12(16mg，淡黄色固体)，产率：76％。
MS m/z(ESI):415[M+1]
1H NMR(400MHz,CD 3OD)δ9.19(d,J＝5.8Hz,1H),8.43–8.33(m,2H),8.25(d,J＝5.9Hz,1H),8.19(d,J＝0.6Hz,1H),8.10–8.01(m,1H),7.82(dd,J＝8.7,1.5Hz,1H),7.49(d,J＝8.7Hz,1H),5.19(dq,J＝13.4,6.7Hz,1H),3.77(t,J＝10.8Hz,1H),2.37(d,J＝11.2Hz,1H),2.19–1.94(m,5H),1.88–1.74(m,2H),1.58(d,J＝6.7Hz,3H),1.40(d,J＝12.6Hz,1H)。
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 B 2 A
3 B 4 A
5 A 6 A
7 A 8 A
9 A 10 A
11 A    
A<50nM；50nM≤B<200nM
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 (11)

  1. 通式(I)所示的化合物：
    Figure PCTCN2019086258-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：
    Z 1、Z 2、Z 3和Z 4各自独立地选自N或CR 3，但Z 1、Z 2、Z 3和Z 4不同时为N；
    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；
    A为N或CR 4；
    B为N或CR 5；
    L为键、-O-或-CR 6R 7-；
    C为任选取代的4-7元杂环基、6-10元芳基或5-10元杂芳基；
    R 3独立地选自H、卤素、氰基、-SF 5、-OR、-SR、-NR 2、-S(O) mR、-S(O) 2NR 2、-N(R)S(O) 2R、-C(O)NR 2、-N(R)C(O)R，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；
    R 4和R 5各自独立地选自H、卤素、OH，或任选取代的C 1-4烷基或-O-C 1-4烷基；
    R 6和R 7各自独立地选自H或任选取代的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；
    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：
    Z 1、Z 2、Z 3和Z 4各自独立地选自N或CR 3，但Z 1、Z 2、Z 3和Z 4中至多一个为N；
    R 1和R 2各自独立地选自H或任选取代的C 1-4烷基；
    A为N或CR 4；
    B为N或CR 5；
    L为键或-O-；
    C为任选被卤素、氰基、C 1-4烷基或卤代C 1-4烷基取代的4-7元杂 环基、6-10元芳基或5-10元杂芳基；
    R 3独立地选自H、卤素、氰基、-SF 5、-OR、-SR、-NR 2、-S(O) mR、-S(O) 2NR 2、-N(R)S(O) 2R、-C(O)NR 2、-N(R)C(O)R，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；
    R 4和R 5各自独立地选自H、卤素、OH、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；
    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，其中：
    Z 1、Z 2、Z 3和Z 4各自独立地选自N或CR 3，但Z 1、Z 2、Z 3和Z 4中至多一个为N；
    R 1和R 2各自独立地选自H或C 1-4烷基；
    A为N或CH；
    B为N或CH；
    L为键；
    C为任选被卤素、氰基、C 1-4烷基或卤代C 1-4烷基取代的5-10元杂芳基；
    R 3独立地选自H、卤素、氰基，或任选取代的C 1-4烷基、-O-C 1-4烷基、C 3-6环烷基或4-7元杂环基；
    所述任选取代是指被选自以下的取代基取代：卤素、-CN、-OR′、-NR′R″，其中R′和R″各自独立地选自H、C 1-4烷基或C 3-7环烷基。
  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：
    Z 1和Z 4各自独立地选自N或CH，Z 2和Z 3各自独立地选自N或CR 3，但Z 1、Z 2、Z 3和Z 4中至多一个为N；
    R 1和R 2各自独立地选自H或C 1-4烷基；
    A为CH；
    B为CH；
    L为键；
    C为任选被卤素或C 1-4烷基取代的5-10元杂芳基；
    R 3为H、卤素或氰基。
  5. 根据前述权利要求任一项所述的化合物，其为以下通式(IIa)-(IIc)的化合物：
    Figure PCTCN2019086258-appb-100002
    其中：
    R 1为C 1-4烷基；
    Z 1、Z 2、Z 3和Z 4的定义如权利要求1-4中所述。
  6. 根据前述权利要求任一项所述的化合物，其为以下通式(III)的化合物：
    Figure PCTCN2019086258-appb-100003
    其中：
    R 1为C 1-4烷基；
    Z 1、Z 2、Z 3和Z 4的定义如权利要求1-4中所述。
  7. 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 PCTCN2019086258-appb-100004
  8. 药物组合物，所述药物组合物包含根据权利要求1-7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。
  9. 药物组合物，所述药物组合物包含根据权利要求1-7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。
  10. 根据权利要求9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。
  11. 根据权利要求1-7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8-10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、睾丸癌、头部癌、颈部癌、皮肤癌、间皮内膜癌、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、间皮瘤、肉瘤、绒膜癌、皮肤基底细胞癌或睾丸精原细胞瘤。
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