WO2016169421A1 - 咪唑并异吲哚类衍生物、其制备方法及其在医药上的应用 - Google Patents

咪唑并异吲哚类衍生物、其制备方法及其在医药上的应用 Download PDF

Info

Publication number
WO2016169421A1
WO2016169421A1 PCT/CN2016/079054 CN2016079054W WO2016169421A1 WO 2016169421 A1 WO2016169421 A1 WO 2016169421A1 CN 2016079054 W CN2016079054 W CN 2016079054W WO 2016169421 A1 WO2016169421 A1 WO 2016169421A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
compound
mmol
formula
reaction
Prior art date
Application number
PCT/CN2016/079054
Other languages
English (en)
French (fr)
Inventor
屠汪洋
徐国际
张海棠
池江涛
董庆
Original Assignee
江苏恒瑞医药股份有限公司
上海恒瑞医药有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 江苏恒瑞医药股份有限公司, 上海恒瑞医药有限公司 filed Critical 江苏恒瑞医药股份有限公司
Priority to US15/566,848 priority Critical patent/US10899764B2/en
Priority to EP16782568.6A priority patent/EP3287461B1/en
Priority to CA2981998A priority patent/CA2981998A1/en
Priority to AU2016250976A priority patent/AU2016250976B2/en
Priority to KR1020177032851A priority patent/KR20170139064A/ko
Priority to CN201680001855.3A priority patent/CN106715440B/zh
Priority to BR112017020824-5A priority patent/BR112017020824A2/zh
Priority to MX2017013310A priority patent/MX2017013310A/es
Priority to RU2017136715A priority patent/RU2717577C2/ru
Priority to JP2017552042A priority patent/JP6801159B2/ja
Publication of WO2016169421A1 publication Critical patent/WO2016169421A1/zh

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • 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
    • 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
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
    • 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
    • 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
    • A61P25/24—Antidepressants
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • 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 invention belongs to the field of medicine and relates to imidazoisoindole derivatives, a preparation method thereof and application thereof in medical research, and the invention discloses as an IDO inhibitor for treating IDO-mediated tryptophan metabolism.
  • Pathways characterized by diseases including cancer, Alzheimer's disease, autoimmune diseases, depression, anxiety, cataracts, psychological disorders, and AIDS.
  • Tumors are one of the major diseases that seriously endanger human life, and more than half of them occur in developing countries.
  • the incidence of malignant tumors in China is generally on the rise, and the incidence rate is increasing at an average annual rate of 3% to 5%.
  • Ageing, urbanization, industrialization and lifestyle changes In China's hospital drug market, the sales scale of anti-cancer drugs has been growing steadily in recent years. In 2012, it reached 66.42 billion yuan, an increase of 13.07% year-on-year. It is expected that by 2017, the market size of anti-cancer drugs will reach 105.57 billion yuan. The year-on-year growth was 7.57%.
  • Tumor biotherapy is a new treatment for cancer prevention and treatment using modern biotechnology and related products. Because of its safety, effectiveness, and low adverse reactions, it has become the fourth mode of tumor treatment after surgery, radiotherapy and chemotherapy.
  • the host's natural defense mechanisms such as inhibition of IDO-mediated tumor immune escape mechanisms) or the naturally occurring highly targeted substances to achieve anti-tumor effects.
  • Indoleamine-pyrrole-2,3-dioxygenase is a heme-containing monomeric protein consisting of 403 amino acid residues, including two folds.
  • the alpha-helical domain, the large domain contains a catalytic pocket, and the substrate can be hydrophobic with the IDO in the catalytic pocket.
  • IDO is an enzyme that catalyzes the conversion of tryptophan to formyl kynurenine. It is widely distributed in tissues other than the liver of humans and other mammals (rabbits, mice) and is the only restriction outside the liver that catalyzes the catabolism of tryptophan.
  • Fast enzyme which is an essential amino acid for cells to maintain activation and proliferation, is also an indispensable component of protein.
  • IDO interferon
  • IL interleukin
  • tumor necrosis factor tumor necrosis factor
  • IDO interferon
  • IL interleukin
  • tumor necrosis factor tumor necrosis factor
  • other cytokines they can activate IDO under certain conditions.
  • IDO In the cell cycle of T-cells, there is a regulation point that is very sensitive to tryptophan levels.
  • IDO depletes local tryptophan, causing T-cells to arrest in the middle of G1 phase, thereby inhibiting the proliferation of T cells;
  • IDO catalyzes the main product produced by the metabolism of tryptophan.
  • Canine urea is induced by oxygen free radicals to induce changes in intracellular oxidants and antioxidants to induce T-cell apoptosis, which is an intrinsic immunosuppressive mechanism present in the body.
  • IDO is highly expressed in leukemia cells, which inhibits the proliferation of local T cells, inhibits T-cell-mediated immune responses, and blocks T-cell activation signal transduction, thereby mediating tumor cell escape from the immune system. attack.
  • Most human tumors have been found to constitutively express IDO. Therefore, IDO is a potential cancer immunotherapy target.
  • Inhibitors of the disclosed selective inhibitors of IDO include WO2012142237, WO2004094409, WO2006122150, WO2007075598, WO2010005958 and WO2014066834, and the like.
  • IDO inhibitors have good application prospects in the pharmaceutical industry as a drug, but no good IDO inhibitors have been found as marketable drugs. In order to achieve better tumor treatment effects and better meet market demand, we hope to Developed a new generation of highly efficient and low toxicity selective IDO inhibitors.
  • the present invention will provide a novel structure of selective IDO inhibitors, and it has been found that compounds having such structures exhibit excellent effects and effects, particularly excellent pharmacogen absorption activities.
  • the object of the present invention is to provide a compound of the formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer thereof, or a mixture form, or a pharmaceutically acceptable salt thereof, wherein the compound of the formula (I) has the following structure:
  • M is a mineral acid or an organic acid, preferably trifluoroacetic acid
  • A is selected from the group consisting of a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group, wherein the cycloalkyl group, heterocyclic group, aryl group, and heteroaryl group are further optionally selected from the group consisting of an alkyl group, a halogen, an amino group, and a nitrate. Substituted by one or more substituents of a hydroxy group, a hydroxy group, a cyano group, an alkoxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;
  • R 1 is selected from the group consisting of a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, -OR 4 , -C(O)R 4 and -C(O)OR 4 , -S(O) m R 4 , -NR 5 R 6 , -C(O)NR 5 R 6 , -C(O)NHR 5 , -NR 5 C(O)R 6 and -NR 5 S(O) m R 6 ;
  • R 2 is the same or different and is each independently selected from the group consisting of a hydrogen atom, an alkyl group, a halogenated alkyl group, an alkoxy group, a halogenated alkoxy group, a halogen, an amino group, a nitro group, a hydroxyl group, a cyano group, a cycloalkyl group, a heterocyclic group, and an aromatic group.
  • R 3 is the same or different and is each independently selected from the group consisting of a hydrogen atom, an alkyl group, a halogenated alkyl group, an alkoxy group, a halogenated alkoxy group, a halogen, an amino group, a nitro group, a hydroxyl group, a cyano group, a cycloalkyl group, a heterocyclic group, and an aromatic group.
  • heteroaryl Base, heteroaryl, -OR 4 , -C(O)R 4 , -C(O)OR 4 , -S(O) m R 4 , -NR 5 R 6 , -C(O)NR 5 R 6 And -NR 5 C(O)R 6 and -NR 5 S(O) m R 6 ; wherein the alkyl group, haloalkyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group are optionally further Selected from alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -R a , -OR 7 , -C(O)R 7 , -C(O)OR 7 , -S(O) m R 7 , -NR 7 R 8 ,
  • R a is selected from the group consisting of an alkyl group, a halogenated alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group, wherein the alkyl group, haloalkyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group are Further selected from the group consisting of alkyl, halogen, amino, nitro, hydroxy, alkoxy, hydroxyalkyl, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR 4 , -C ( O) R 4 , -C(O)OR 4 , -S(O) m R 4 , -NR 5 R 6 , -C(O)NR 5 R 6 , -NR 5 C(O)R 6 and -NR Substituting one or more substituents in 5 S(O) m R 6 ;
  • R 4 is selected from the group consisting of a hydrogen atom, an alkyl group, a halogenated alkyl group, a hydroxyl group, an amino group, an alkoxy group, a halogenated alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group; wherein the alkyl group, a halogenated alkyl group,
  • the cycloalkyl, heterocyclic, aryl and heteroaryl groups are optionally further selected from the group consisting of alkyl, halo, amino, nitro, cyano, hydroxy, hydroxyalkyl, alkoxy, cycloalkyl, heterocyclyl , aryl, heteroaryl, -R a , -OR 7 , -C(O)R 7 , -C(O)OR 7 , -S(O) m R 7 , -NR 7 R 8 , -C( O)
  • R 5 and R 6 are the same or different and are each independently selected from a hydrogen atom, an alkyl group, a hydroxyl group, an amino group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group, wherein the alkyl group, the cycloalkyl group And a heterocyclic group, an aryl group and a heteroaryl group are further selected from the group consisting of an alkyl group, a halogen, a hydroxyl group, an amino group, a nitro group, a cyano group, an alkoxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group.
  • R 7 and R 8 are the same or different and are each independently selected from the group consisting of a hydrogen atom, an alkyl group, a hydroxyl group, an amino group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group, wherein the alkyl group, the cycloalkyl group And a heterocyclic group, an aryl group and a heteroaryl group are further selected from the group consisting of an alkyl group, a halogen, a hydroxyl group, an amino group, a nitro group, a cyano group, an alkoxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group. And substituted with one or more substituents in the heteroaryl;
  • p is an integer of 0, 1, 2, 3 or 4;
  • Y is an integer of 0, 1, 2 or 3;
  • n is an integer of 0, 1, or 2;
  • n is an integer of 0, 1, 2, 3, 4 or 5.
  • a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof A form or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein y is 0, 1 or 3, especially 0.
  • a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof a form or a mixture thereof, or a pharmaceutically acceptable salt thereof wherein A is selected from a heterocyclic group and a cycloalkyl group, wherein said cycloalkyl group and heterocyclic group are further selected from the group consisting of alkyl, halogen, amino, Substituted by one or more substituents of a nitro group, a hydroxyl group, a cyano group, an alkoxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group.
  • a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof a form or a mixture thereof, or a pharmaceutically acceptable salt thereof which is a compound of the formula (II) or a tautomer thereof, a mesogen, a racemate, an enantiomer, or a non- An enantiomer or a mixture thereof, or a pharmaceutically acceptable salt thereof,
  • X is CH or N
  • R 1 to R 3 , M, p, n and y are as defined in the formula (I);
  • a is an integer of 0, 1, 2 or 3;
  • b is an integer of 0, 1, 2 or 3.
  • a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof a form or a mixture thereof, or a pharmaceutically acceptable salt thereof which is a compound of the formula (II-A) or a tautomer, a mesogen, a racemate, an enantiomer thereof , diastereomers or mixtures thereof, or a pharmaceutically acceptable salt thereof,
  • R 1 to R 3 , M, p, n and y are as defined in the formula (I).
  • a compound of the formula (II-A) or a tautomer, a mesogen, a racemate, an enantiomer or a non-pair thereof a compound or a mixture thereof, or a pharmaceutically acceptable salt thereof which is a compound of the formula (II-B) or a tautomer, a mesogen, a racemate, an enantiomer a conformation, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof,
  • R 2 , R 5 , R 6 , M, p and y are as defined in the formula (I).
  • a compound of the formula (II) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer a form or a mixture thereof, or a pharmaceutically acceptable salt thereof which is a compound of the formula (III) or a tautomer, a mesogen, a racemate, an enantiomer, a non- An enantiomer or a mixture thereof, or a pharmaceutically acceptable salt thereof,
  • R 1 to R 3 , M, p, n and y are as defined in the formula (I).
  • a compound of the formula (III) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer a form or a mixture thereof, or a pharmaceutically acceptable salt thereof which is a compound of the formula (IV) or a tautomer, a mesogen, a racemate, an enantiomer, or a non- An enantiomer or a mixture thereof, or a pharmaceutically acceptable salt thereof,
  • R 2 , R 3 , M, p, n and y are as defined in the formula (I).
  • a compound of the formula (III) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer a conformation or a mixture thereof, or a pharmaceutically acceptable salt which is a compound of the formula (IV-1) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer thereof or In the form of a mixture, or a pharmaceutically acceptable salt thereof,
  • R 2 , R a , M, p and y are as defined in the formula (I).
  • a compound of the formula (III) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer a form or a mixture thereof, or a pharmaceutically acceptable salt thereof which is a compound of the formula (IV-2) or a tautomer, a mesogen, a racemate, an enantiomer thereof , diastereomers or mixtures thereof, or a pharmaceutically acceptable salt thereof,
  • R 2 , R 4 , M, p and y are as defined in the formula (I).
  • a compound of the formula (IV) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer a form or a mixture thereof, or a pharmaceutically acceptable salt thereof which is a compound represented by the formula (IV-A) and the formula (IV-B) or a tautomer, a mesogen thereof, a foreign form a form of a rot, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof,
  • R 2 , R 3 , M, p, n and y are as defined in the formula (I).
  • a compound of the formula (V) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer a form or a mixture thereof which is a compound of the formula (II) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer, Or an intermediate in the form of a mixture thereof,
  • Q is a mineral acid or an organic acid, preferably trifluoroacetic acid
  • X is CH or N
  • R 2 , p, a and b are as defined in the formula (II);
  • x is an integer of 0, 1, 2, or 3.
  • a compound of the formula (II-1) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer thereof is prepared.
  • the compound of the formula (V) is subjected to a coupling reaction with a halogenated substance of R 1 in the presence of a catalyst under basic conditions, and the obtained product is optionally further reacted with a boronic acid or a boronic acid ester of R 3 to obtain a formula (II- 1) a compound;
  • X is N
  • R 1 to R 3 , p, n, a and b are as defined in the formula (II);
  • a compound of the formula (II) or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof is prepared.
  • a method of salt in the form of a mixture the method comprising:
  • X is CH or N
  • R 1 to R 3 , M, p, y, n, a and b are as defined in the formula (II).
  • Another aspect of the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of the formula or a tautomer, a mesomer, a racemate, an enantiomer, Diastereomers, or mixtures thereof, or pharmaceutically acceptable salts, and one or more pharmaceutically acceptable carriers, diluents or excipients.
  • the present invention also relates to a process for the preparation of the above composition which comprises the compounds of the general formula or their tautomers, meso, racemate, enantiomers, diastereomers The isomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, is mixed with a pharmaceutically acceptable carrier, diluent or excipient.
  • the invention further relates to a compound of the formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture thereof, or Use of a pharmaceutically acceptable salt, or a pharmaceutical composition comprising the same, for the manufacture of a medicament for the prevention and/or treatment of a disease having a pathological feature of an IDO-mediated tryptophan metabolism pathway.
  • IDO inhibitors can be used for the inhibition of cardiac disorders as well as for the treatment of other pathological features of IDO-mediated tryptophan metabolism pathways, including infections of viruses such as AIDS, such as Lyme disease and streptococcal infections.
  • neurodegenerative disorders eg Alzheimer's disease, Huntington's disease and Parkson's disease
  • autoimmune diseases depression, anxiety, cataracts, psychological disorders, AIDS, cancer (including T-cell leukemia and colon cancer) , eye disease states (such as cataracts and age-related yellowing), and autoimmune diseases
  • cancer may be selected from the group consisting of breast cancer, cervical cancer, colon cancer, lung cancer, stomach cancer, rectal cancer, pancreatic cancer, and brain cancer.
  • skin cancer skin cancer, oral cancer, prostate cancer, bone cancer, kidney cancer, ovarian cancer, bladder cancer, liver cancer, fallopian tube tumor, ovarian tumor, peritoneal tumor, stage IV melanoma, glioma, glioblastoma, liver Cell carcinoma, mastoid renal tumor, head and neck tumor, leukemia, lymphoma, myeloma, and non-small cell lung cancer.
  • the present invention also relates to a compound of the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer or a mixture thereof, or A pharmaceutically acceptable salt, or a pharmaceutical composition comprising the same, for use in the prevention and/or treatment of a disease preventing the pathological features of the IDO-mediated tryptophan metabolism pathway.
  • the cancer may be selected from the group consisting of breast cancer, cervical cancer, colon cancer, lung cancer, stomach cancer, rectal cancer, pancreatic cancer, brain cancer, skin cancer, oral cancer, prostate cancer, bone cancer, kidney cancer, ovarian cancer, bladder cancer, liver cancer, Tubal neoplasms, ovarian tumors, peritoneal tumors, stage IV melanoma, glioma, glioblastoma, hepatocellular carcinoma, mastoid renal tumor, head and neck tumor, leukemia, lymphoma, myeloma and non-small Cell lung cancer
  • the present invention also relates to a method of treating a disease preventing and/or treating a pathological feature having an IDO-mediated tryptophan metabolism pathway, comprising administering to a patient a therapeutically effective amount of a compound of the formula (I) Or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.
  • diseases include infections of viruses such as AIDS, cellular infections such as Lyme disease and streptococcal infection, neurodegenerative disorders (such as Alzheimer's disease, Huntington's disease and Parkson's disease), autoimmune diseases, depression, Anxiety disorders, cataracts, psychological disorders, AIDS, cancer (including T-cell leukemia and colon cancer), eye disease states (such as cataracts and age-related yellowing), and autoimmune diseases, wherein the cancer may be selected from the breast Cancer, cervical cancer, colon cancer, lung cancer, stomach cancer, rectal cancer, pancreatic cancer, brain cancer, skin cancer, oral cancer, prostate cancer, bone cancer, kidney cancer, ovarian cancer, bladder cancer, liver cancer, fallopian tube tumor, ovarian tumor, Peritoneal tumors, stage IV melanoma, glioma, glioblastoma, hepatocellular carcinoma, papillary renal tumor, head and neck tumor, leukemia, lymphoma, myeloma, and non-small cell lung cancer.
  • viruses such as
  • Another aspect of the invention relates to a method of treating cancer comprising administering to a patient a therapeutically effective amount of a compound of the formula (I) of the invention or a tautomer, a mesogen thereof, a foreign body A form of a rot, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof.
  • the method exhibits outstanding efficacy and less side effects, wherein the cancer can be selected from the group consisting of breast cancer, cervical cancer, colon cancer, lung cancer, stomach cancer, rectal cancer, pancreatic cancer, brain cancer, skin cancer, oral cancer, prostate Cancer, bone cancer, kidney cancer, ovarian cancer, bladder cancer, liver cancer, fallopian tube tumor, ovarian tumor, peritoneal tumor, stage IV melanoma, glioma, glioblastoma, hepatocellular carcinoma, mastoid renal tumor Head and neck tumors, leukemias, lymphomas, myelomas and non-small cell lung cancers, preferably fallopian tube tumors, peritoneal tumors, stage IV melanoma, myeloma and breast cancer, more preferably breast cancer.
  • the cancer can be selected from the group consisting of breast cancer, cervical cancer, colon cancer, lung cancer, stomach cancer, rectal cancer, pancreatic cancer, brain cancer, skin cancer, oral cancer, prostate Cancer, bone cancer, kidney cancer
  • the active ingredient-containing pharmaceutical composition may be in a form suitable for oral administration, such as tablets, dragees, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or Tincture.
  • Oral compositions can be prepared according to any method known in the art for preparing pharmaceutical compositions, such compositions may contain one or more ingredients selected from the group consisting of sweeteners, flavoring agents, coloring agents, and preservatives, To provide a pleasing and tasty pharmaceutical preparation.
  • Tablet containing the active ingredient and a non-toxic pharmaceutically acceptable tablet for mixing Excipients used. These excipients can be inert excipients, granulating agents, disintegrants and lubricants. These tablets may be uncoated or may be coated by masking the taste of the drug or delaying disintegration and absorption in the gastrointestinal tract, thus providing a sustained release effect over a longer period of time.
  • Oral formulations can also be provided in soft gelatin capsules in which the active ingredient is mixed with an inert solid diluent, or an active ingredient in admixture with a water-soluble carrier or oil vehicle or olive oil.
  • the aqueous suspension contains the active substance and excipients suitable for the preparation of the aqueous suspension for mixing. Such excipients are suspending, dispersing or wetting agents.
  • the aqueous suspensions may also contain one or more preservatives such as ethylparaben or n-propylparaben, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents. Flavor.
  • An oil suspension can be formulated by suspending the active ingredient in vegetable oil or mineral oil.
  • the oil suspension may contain a thickening agent.
  • the above sweeteners and flavoring agents may be added to provide a palatable preparation. These compositions can be preserved by the addition of an antioxidant.
  • Dispersible powders and granules suitable for use in the preparation of aqueous suspensions may be employed in the preparation of the active ingredient and dispersion or dispersing or suspending agents or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or
  • the pharmaceutical compositions of the invention may also be in the form of an oil-in-water emulsion.
  • the oil phase can be a vegetable oil or a mineral oil or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids or partial ester emulsions and may also contain sweetening, flavoring, preservatives and antioxidants.
  • the pharmaceutical composition may be in the form of a sterile injectable aqueous solution. Among the acceptable vehicles or solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution.
  • the sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oily phase. The injection or microemulsion can be injected into the bloodstream of the patient by a local injection.
  • the pharmaceutical composition may be in the form of a sterile injectable aqueous or oily suspension for intramuscular and subcutaneous administration.
  • the suspension may be formulated according to known techniques using those suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension prepared in a parenterally acceptable non-toxic diluent or solvent.
  • sterile fixed oils may conveniently be employed as a solvent or suspension medium.
  • the compounds of the invention may be administered in the form of a suppository for rectal administration.
  • These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and thus dissolves in the rectum to release the drug.
  • the dosage of the drug to be administered depends on a variety of factors including, but not limited to, the following factors: the activity of the particular compound used, the age of the patient, the weight of the patient, the health of the patient, and the patient's behavior.
  • the dosage, the patient's diet, the time of administration, the mode of administration, the rate of excretion, the combination of drugs, etc.; in addition, the optimal treatment mode such as the mode of treatment, the daily dosage of the compound of formula (I) or a pharmaceutically acceptable salt The type can be verified according to traditional treatment options.
  • alkyl refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing from 1 to 20 carbon atoms, preferably an alkyl group having from 1 to 12 carbon atoms, more preferably from 1 to 6 carbons.
  • the alkyl group of the atom is a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing from 1 to 20 carbon atoms, preferably an alkyl group having from 1 to 12 carbon atoms, more preferably from 1 to 6 carbons.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 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, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2 -methylhexyl, 3-methylhexyl, 4-methylhexyl,
  • lower alkyl groups having from 1 to 6 carbon atoms, non-limiting examples including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl Base, n-pentyl, 1,1-dimethylpropyl, 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-dimethyl Butyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl Base, 2,3-dimethylbutyl and the like.
  • the alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups independently selected from the group consisting of an alkane Base, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, naphthenic An oxy group, a heterocycloalkoxy group, a cycloalkylthio group, a heterocycloalkylthio group, an oxo group, a carboxyl group or a carboxylate group.
  • an alkane Base alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, hetero
  • alkylene means that one hydrogen atom of the alkyl group is further substituted, for example, "methylene” refers to -CH 2 -, "ethylene” refers to -(CH 2 ) 2 -, "propylene” Refers to -(CH 2 ) 3 -, "butylene” means -(CH 2 ) 4 - and the like.
  • alkenyl refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, such as ethenyl, 1-propenyl, 2-propenyl, 1-, 2- or -butenyl and the like.
  • the alkenyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio group.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 carbon atoms, preferably from 3 to 12 carbon atoms, more preferably from 3 to 8 carbon atoms. One carbon atom; most preferably from 3 to 6 carbon atoms.
  • Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene
  • a polycycloalkyl group includes a spiro ring, a fused ring, and a cycloalkyl group.
  • spirocycloalkyl refers to a polycyclic ring sharing a carbon atom (called a spiro atom) between 5 to 20 members of a single ring.
  • a group which may contain one or more double bonds, but none of which has a fully conjugated pi-electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members.
  • the spirocycloalkyl group is classified into a monospirocycloalkyl group, a bispirocycloalkyl group or a polyspirocycloalkyl group, preferably a monospirocycloalkyl group and a bispirocycloalkyl group, depending on the number of common spiro atoms between the rings. More preferably, it is 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6-membered monospirocycloalkyl group.
  • Non-limiting examples of spirocycloalkyl groups include:
  • fused cycloalkyl refers to 5 to 20 members, and each ring in the system shares an all-carbon polycyclic group of an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or Multiple double bonds, but none of the rings have a fully conjugated ⁇ -electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members.
  • fused cycloalkyl groups include:
  • bridged cycloalkyl refers to an all-carbon polycyclic group of 5 to 20 members, any two rings sharing two carbon atoms which are not directly bonded, which may contain one or more double bonds, but none of the rings have complete Conjugate ⁇ -electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl group, preferably a bicyclic ring, a tricyclic ring or a tetracyclic ring, and more preferably a bicyclic ring or a tricyclic ring.
  • bridged cycloalkyl groups include:
  • the cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring to which the parent structure is attached is a cycloalkyl group, non-limiting examples include indanyl, tetrahydronaphthalene Base, benzocycloheptyl and the like.
  • the cycloalkyl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio a heterocycloalkylthio group, an oxo group, a carboxyl group or a carboxylate group.
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 ring atoms wherein one or more ring atoms are selected from nitrogen, oxygen or S(O).
  • the hetero atom of m (where m is an integer of 0 to 2), but excluding the ring moiety of -OO-, -OS- or -SS-, the remaining ring atoms are carbon. It preferably contains from 3 to 12 ring atoms, of which from 1 to 4 are heteroatoms; more preferably from 3 to 6 ring atoms.
  • Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidine.
  • the base, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl and the like are preferably piperidinyl or pyrrolidinyl.
  • Polycyclic heterocyclic groups include spiro, fused, and bridged heterocyclic groups.
  • spiroheterocyclyl refers to a polycyclic heterocyclic group in which one atom (called a spiro atom) is shared between 5 to 20 members of a single ring, wherein one or more ring atoms are selected from nitrogen, oxygen or S (O). ) m (where m is an integer 0 to 2) heteroatoms, and the remaining ring atoms are carbon. It may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members.
  • the spiroheterocyclyl group is classified into a monospiroheterocyclic group, a dispiroheterocyclic group or a polyspirocyclic group according to the number of shared spiro atoms between the ring and the ring, and is preferably a monospiroheterocyclic group and a dispiroheterocyclic group. More preferably, it is 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6-membered monospiroheterocyclic group.
  • Non-limiting examples of spiroheterocyclyl groups include:
  • fused heterocyclyl refers to 5 to 20 members, and each ring in the system shares an adjacent pair of atomic polycyclic heterocyclic groups with other rings in the system, and one or more rings may contain one or more Double bond, but none of the rings have a fully conjugated ⁇ -electron system in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) m (where m is an integer from 0 to 2), and the remaining rings
  • the atom is carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members.
  • fused heterocyclic groups include:
  • bridge heterocyclyl refers to a polycyclic heterocyclic group of 5 to 14 members, any two rings sharing two atoms which are not directly bonded, which may contain one or more double bonds, but none of the rings have a total A ⁇ -electron system of a yoke in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) m (where m is an integer from 0 to 2), the remaining ring atoms being carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members.
  • the number of the constituent rings may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic group, preferably a bicyclic ring, a tricyclic ring or a tetracyclic ring, and more preferably a bicyclic ring or a tricyclic ring.
  • bridge heterocyclic groups include:
  • the heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring to which the parent structure is attached is a heterocyclic group, non-limiting examples of which include:
  • the heterocyclic group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio a heterocycloalkylthio group, an oxo group, a carboxyl group or a carboxylate group.
  • aryl refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic ring (ie, a ring that shares a pair of adjacent carbon atoms) having a conjugated ⁇ -electron system, preferably 6 to 10 members, such as benzene. Base and naphthyl. More preferred is 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 of which include:
  • the aryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle An alkylthio group, a carboxyl group or a carboxylate group.
  • heteroaryl refers to a heteroaromatic system containing from 1 to 4 heteroatoms, from 5 to 14 ring atoms, wherein the heteroatoms are selected from the group consisting of oxygen, sulfur and nitrogen.
  • the heteroaryl group is preferably 5 to 10 members, more preferably 5 or 6 members, such as imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl,
  • a pyrimidinyl group, a thiadiazole, a pyrazinyl group or the like is preferably an imidazolyl group, a pyrazolyl group or a pyrimidinyl group, or a thiazolyl group; and a pyrazolyl group is more preferred.
  • the heteroaryl ring may be fused to an aryl, heterocyclic or cycloalkyl ring, wherein the ring to
  • the heteroaryl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio a heterocycloalkylthio group, a carboxyl group or a carboxylate group.
  • alkoxy refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl is as defined above.
  • alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy.
  • the alkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio a heterocycloalkylthio group, a carboxyl group or a carboxylate group.
  • haloalkyl refers to an alkyl group substituted by one or more halogens, wherein alkyl is as defined above.
  • haloalkoxy refers to an alkoxy group substituted by one or more halogens, wherein alkoxy is as defined above.
  • hydroxyalkyl refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.
  • hydroxy refers to an -OH group.
  • halogen means fluoro, chloro, bromo or iodo.
  • amino means -NH 2.
  • cyano refers to -CN.
  • nitro refers to -NO 2 .
  • carboxylate group refers to -C(O)O(alkyl) or -C(O)O(cycloalkyl), wherein alkyl is as defined above.
  • acyl halide refers to a compound containing a -C(O)-halogen group.
  • X is selected from A, B, or C
  • X is selected from A, B, and C
  • X is A, B, or C
  • X is A, B, and C
  • heterocyclic group optionally substituted by an alkyl group means that an alkyl group may be, but not necessarily, present, and the description includes the case where the heterocyclic group is substituted with an alkyl group and the case where the heterocyclic group is not substituted with an alkyl group.
  • Substituted refers to one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3, hydrogen atoms, independently of each other, substituted 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.
  • “Pharmaceutical composition” means a mixture comprising one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, as well as other components such as physiological/pharmaceutically acceptable carriers. And 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.
  • “Pharmaceutically acceptable salt” refers to a salt of a compound of the invention which is safe and effective for use in a mammal and which possesses the desired biological activity.
  • the reagent providing basic conditions is preferably lithium diisopropylamide
  • the compound of the formula (II-a) is subjected to an addition reaction with a bromobenzene compound to obtain the formula (II-b).
  • a compound of the formula (II-b) which is reacted with a methanesulfonyl chloride compound under basic conditions (a reagent which provides basic conditions, preferably sodium hydride or triethylamine) to give a compound of the formula (II-c);
  • the obtained compound of the formula (II-c) is reacted with an imidazole under basic conditions to give a compound of the formula (II-d);
  • the obtained compound of the formula (II-d) is heated, a base and a phosphine palladium catalyst ( The catalyst is preferably intramolecularly coupled to obtain a compound of the formula (II-e) in the presence of a catalyst of triphenylphosphine and palladium acetate;
  • the obtained compound of the formula (II-e) is deprotected under acidic conditions to give a formula ( a compound of the formula (V);
  • the compound of the formula (V) is further subjected to a coupling
  • the resulting product is optionally further compound of formula (II-a) with a R boronic acid or boronic ester coupling 3; compound of formula (II-a) in Under conditions of salt formation, to give a compound of formula (II-b).
  • the reagents providing basic conditions include organic bases including, but not limited to, triethylamine, N,N-diisopropylethylamine, n-butyllithium, lithium diisopropylamide, and inorganic bases.
  • organic bases including, but not limited to, triethylamine, N,N-diisopropylethylamine, n-butyllithium, lithium diisopropylamide, and inorganic bases.
  • potassium acetate, sodium t-butoxide or potassium t-butoxide, and the inorganic bases include, but are not limited to, sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate or cesium carbonate.
  • the phosphine palladium catalysts involved therein include, but are not limited to, 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl, ( ⁇ )-2,2'-bis-(diphenylphosphine)- 1,1'-binaphthyl, tris(dibenzylideneacetone)dipalladium, palladium acetate, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, triphenylphosphine, tetra (triphenylphosphine) palladium.
  • R 1 to R 3 , M, p, n, a, b and y are as defined in the formula (II); and Q and x are as defined in the formula (V).
  • the compound of the formula (II-f) is reacted with p-toluenesulfonylhydrazide to obtain a compound of the formula (II-g); the obtained compound of the formula (II-g) is reacted with a bromobenzaldehyde compound under basic conditions, A compound of the formula (II-h) is obtained; the obtained compound of the formula (II-h) is reduced in the presence of a reducing agent (the reducing agent is preferably sodium borohydride) to give a compound of the formula (II-b); (II-b) The compound is reacted with a sulfonyl chloride compound under basic conditions (a reagent providing basic conditions is preferably sodium hydride or triethylamine) to give a compound of the formula (II-c); The compound of the formula (II-c) is reacted with an imidazole under basic conditions to give a compound of the formula (II-d); the obtained compound of the
  • the reagents providing basic conditions include organic bases including, but not limited to, triethylamine, N,N-diisopropylethylamine, n-butyllithium, lithium diisopropylamide, and inorganic bases.
  • organic bases including, but not limited to, triethylamine, N,N-diisopropylethylamine, n-butyllithium, lithium diisopropylamide, and inorganic bases.
  • potassium acetate, sodium t-butoxide or potassium t-butoxide, and the inorganic bases include, but are not limited to, sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate or cesium carbonate.
  • the phosphine palladium catalysts involved therein include, but are not limited to, 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl, ( ⁇ )-2,2'-bis-(diphenylphosphine)- 1,1'-binaphthyl, tris(dibenzylideneacetone)dipalladium, palladium acetate, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, triphenylphosphine, tetra (triphenylphosphine) palladium.
  • the reducing agent described therein includes, but is not limited to, Fe powder, Zn powder, H 2 , sodium borohydride, sodium triacetoxyborohydride, sodium nitrile borohydride or lithium aluminum hydride.
  • R 1 to R 3 , M, p, n, a, b and y are as defined in the formula (II); and Q and x are as defined in the formula (V).
  • Method 1 under the protection of inert gas, high temperature, basic, phosphine-palladium catalyst, the compound of formula (V) and the halogen of R 1 are directly heated or coupled in a microwave reactor, and the obtained product is Further, it is further coupled with a boronic acid or a boric acid ester of R 1 to obtain a compound of the formula (II-1); the halogenated product of R 3 of the reaction is preferably an aryl halogenated compound; and the alkaline agent is preferably sodium t-butoxide.
  • Method 2 Under high temperature and basic conditions, the compound of the general formula (V) is directly coupled with the halogenated substance of R 1 , and the obtained product is optionally further coupled with a boronic acid or a boronic acid ester of R 3 to obtain a general formula ( II-1) a compound; the halogenated product of R 1 of the reaction is preferably a heteroaryl halogenated compound; and the alkaline agent is preferably triethylamine.
  • Process 3 The compound of the formula (V) is directly reacted with a halogenated product of R 3 at room temperature under basic conditions to obtain a compound of the formula (II-1); the halogenated product of the reaction is preferably an iodide and a highly active acyl group.
  • a halogen compound; the alkaline agent under this condition is preferably potassium carbonate.
  • the phosphine palladium catalysts involved therein include, but are not limited to, 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl, ( ⁇ )-2,2'-bis-(diphenylphosphine)- 1,1'-binaphthyl, tris(dibenzylideneacetone)dipalladium, palladium acetate, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, triphenylphosphine, tetra (triphenylphosphine) palladium.
  • the reagents providing basic conditions include organic bases and inorganic bases, including but not limited to Sodium tert-butoxide, triethylamine, N,N-diisopropylethylamine, n-butyllithium, lithium diisopropylamide, potassium t-butoxide or potassium t-butoxide, preferably sodium t-butoxide;
  • the inorganic bases include, but are not limited to, sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate or cesium carbonate.
  • X is N
  • R 1 to R 3 , p, n, a, and b are as defined in the formula (II); and Q and x are as defined in the formula (V).
  • 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 AVANCE-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 measurement of the MS was carried out using a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantage MAX).
  • ESI FINNIGAN LCQAd
  • the HPLC was measured using an Agilent 1200 DAD high pressure liquid chromatograph (Sunfire C18 150 x 4.6 mm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150 x 4.6 mm column).
  • the thin layer chromatography silica gel plate uses Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate.
  • the specification of silica gel plate used for thin layer chromatography (TLC) is 0.15mm ⁇ 0.2mm.
  • the specification for separation and purification of thin layer chromatography is 0.4mm. ⁇ 0.5mm silica gel plate.
  • 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 Organnics, Aldrich Chemical Company, Accela ChemBio Inc, Companies such as Dare Chemicals.
  • 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 pressurized hydrogenation reaction was carried out using a Parr Model 3916EKX hydrogenation apparatus and a clear blue QL-500 type hydrogen generator or a HC2-SS type hydrogenation apparatus.
  • the hydrogenation reaction is usually evacuated, charged with hydrogen, and operated three times.
  • the microwave reaction used a CEM Discover-S Model 908860 microwave reactor.
  • the solution in the reaction means an aqueous solution unless otherwise specified.
  • the temperature of the reaction was room temperature unless otherwise specified.
  • Room temperature is the most suitable reaction temperature, and the temperature range is from 20 ° C to 30 ° C.
  • the progress of the reaction in the examples was monitored by thin layer chromatography (TLC).
  • TLC thin layer chromatography
  • the system used for the reaction was: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: petroleum ether And the ethyl acetate system, D: acetone, the volume ratio of the solvent is adjusted depending on the polarity of the compound.
  • the system for the eluent of the column chromatography and the system for the thin layer chromatography of the developer used for the purification of the compound include: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: n-hexane, acetic acid Ethyl ester and dichloromethane system, D: petroleum ether and ethyl acetate system, E: ethyl acetate, the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of triethylamine and acid or alkali may be added. The reagents and the like are adjusted.
  • Lithium diisopropylamide (32.5 mL, 65.0 mmol) was added to 50 mL of tetrahydrofuran, and a solution of 25 mL of 1-bromo-3-fluorobenzene 1a (8.75 g, 50.0 mmol) in tetrahydrofuran was added dropwise at -78 °C. Stir at 78 ° C for 1 hour.
  • a pre-formed 25 mL solution of tert-butyl 4-formylpiperidine-1-carboxylate 1b (8.75 g, 50.0 mmol) in tetrahydrofuran was added dropwise at -78 ° C and stirred at -78 ° C for one hour.
  • the imidazole (12.5 g, 184.3 mmol) was dissolved in 50 mL of N,N-dimethylformamide, and sodium hydride (7.40 g, 184.3 mmol) was added portionwise, stirred at room temperature for 1 hour, and 20 mL of pre-formed compound 1d was added dropwise.
  • a solution of 10.0 g, 18.43 mmol) in N,N-dimethylformamide was stirred at 100 ° C for 12 hours.
  • the crude compound 2e (6.17 g, 16.0 mmol) was dissolved in 100 mL of methanol. The reaction mixture was cooled to 0 ° C, and sodium borohydride (1.21 g, 32.0 mmol) was slowly added at 0 ° C, and the reaction was stirred at 0 ° C for 1 hour. After completion of the reaction, 200 mL of ethyl acetate was added, and the mixture was washed with EtOAc EtOAc (EtOAc) The product was directly subjected to the next reaction without purification.
  • EtOAc EtOAc
  • the crude compound 9a (165 mg, 0.4 mmol) was dissolved in 5 mL of ethylene glycol dimethyl ether and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-diox was added.
  • Heteroborolan-2-yl)-1H-pyrazole (166 mg, 0.8 mmol), sodium carbonate (127 mg, 1.2 mmol) and 0.5 mL of water, stirred well, then [1,1'-bis(diphenyl) Phosphorus) ferrocene] palladium dichloride (29 mg, 0.04 mmol) was subjected to microwave reaction at 120 ° C for 40 minutes under an argon atmosphere.
  • the crude compound 17a (260 mg, 1.005 mmol) was dissolved in 2.5 mL of ethanol, and 4-(2-chloropyrimidin-4-yl)morpholine 17b (100 mg, 0.503 mmol, using a known method "Chemistry & Biology Interface, 2012" was added. , 2(5), 347-361 "prepared") and triethylamine (203 mg, 2.012 mmol) were reacted at 100 ° C for 48 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure.
  • the bis(trichloromethyl) carbonate (297 mg, 1.0 mmol) was dissolved in 2 mL of dichloromethane, and a pre-prepared 2 mL of p-aminobenzonitrile (118 mg, 1.0 mmol) in dichloromethane was added dropwise.
  • a solution of triethylamine (0.28 mL) in dichloromethane was reacted for 1 hour at room temperature. After concentration under reduced pressure, 5 mL of tetrahydrofuran, 0.28 mL of triethylamine and Compound 1 g (243 mg, 0.5 mmol) were added and reacted at room temperature for 12 hours. After completion of the reaction, the reaction mixture was evaporated to dryness crystals crystals crystals crystals
  • Lithium diisopropylamide (13 mL, 26 mmol) was added to 20 mL of tetrahydrofuran under argon atmosphere, cooled to -78 ° C, and pre-prepared 10 mL of 1-bromo-3-fluorobenzene 1a (3.5 g) was added dropwise at -78 °C. A solution of 20.0 mmol) in tetrahydrofuran was reacted at -78 ° C for 1 hour.
  • tert-butyl 3-formylpyrrolidine-1-carboxylate 25a (3.985 g, 20.0 mmol) was added dropwise at -78 ° C, and was prepared by a known method "Jpn. Tokkyo Koh, 2009, 03 Jun, 4272338". A tetrahydrofuran solution was reacted at -78 ° C for 1 hour. After the reaction was completed, the reaction was quenched with EtOAc (EtOAc) (EtOAc) (EtOAc) ), the yield was 68.8%.
  • the crude compound 25c (2.4 g, 5.3 mmol) was dissolved in 10 mL of acetonitrile, imidazole (3.6 g, 53 mmol) was added, and N,N-diisopropylethylamine (6.85 g, 53 mmol) was added. 1 hour and 40 minutes. After completion of the reaction, 100 mL of ethyl acetate was added, and the mixture was washed with water (60 mL ⁇ 2), washed with a saturated sodium chloride solution (60 mL), and the organic phase was dried over anhydrous sodium sulfate. g, brown viscous solid), the product was directly subjected to the next reaction without purification.
  • the compound 25 g (23 mg, 0.072 mmol) was dissolved in 5 mL of dichloromethane, and 0.5 mL of trifluoroacetic acid was added thereto, and the mixture was reacted at room temperature for 60 minutes. After completion of the reaction, the reaction mixture was evaporated to dryness.
  • the crude compound 26e (1.7 g, 4.76 mmol) was dissolved in 20 mL of dichloromethane, and 1 mL of trifluoroacetic acid was added dropwise and reacted at room temperature for 48 hours. After completion of the reaction, the reaction mixture was evaporated.
  • the crude product 33f (60 mg, 0.2 mmol) was dissolved in 2 mL of N,N-dimethylformamide, 3-methoxyaniline (25 mg, 0.2 mmol), 1-hydroxybenzotriazole (32 mg, 0.24 mmol) , 1-ethyl-(3-dimethylaminopropyl)carbonyldiimide hydrochloride (46 mg, 0.24 mmol) and N,N-diisopropylethylamine (129 mg, 1 mmol). hour.
  • the reaction mixture was purified by EtOAcqqqqqqqqqq
  • the crude product 34b (620 mg, 1.692 mmol) was dissolved in 40% hydrobromic acid solution, cooled to 0-5 ° C, 1 mL of pre-formed sodium nitrite (128 mg, 1.86 mmol) solution was added dropwise, after the addition was completed at 0 ° C After reacting for 40 minutes, the reaction solution was poured into a hydrobromic acid solution at 0 ° C, and the mixture was heated to 60 ° C for 2 hours.
  • the reaction solution was cooled to room temperature, and then added with 350 mL of water, and ethyl acetate (60 mL ⁇ 3), and the organic phase was combined, washed with water (120 mL ⁇ 2), washed with saturated sodium chloride solution (60 mL), dried over anhydrous sodium sulfate The filtrate was concentrated under reduced pressure to give the crude title compound 35b (170 mg, tan solid). should.
  • the reaction mixture was cooled to room temperature, and then added with 150 ml of dichloromethane, and the mixture was washed with water (100 ml ⁇ 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • the title compound 36b (260 mg, brown solid).
  • the crude product 38b (349 mg, 1 mmol) was dissolved in 5 mL of ethanol, and tetrahydrofuran-3-methanesulfonic acid 38c (333 mg, 2 mmol, prepared by the method disclosed in the patent application "WO2014049133”) and potassium carbonate (420 mg, 3 mmol), The reaction was carried out in a microwave at 125 ° C for 1 hour. The reaction mixture was cooled to room temperature, filtered, and the filtrate was evaporated.
  • 4-(4-Iodophenoxy)piperidine 39a (600 mg, 2 mmol, prepared by the method disclosed in the patent application "WO2004089373") was dissolved in 15 mL of dichloromethane, and triethylamine (404 mg, 4 mmol) was added. Methanesulfonyl chloride (273.6 mg, 2.4 mmol) was added dropwise, and the reaction was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was evaporated. Yellow solid), the product was directly subjected to the next reaction without purification.
  • Tris(dibenzylideneacetone)dipalladium (2.92 g, 3.19 mmol) was added, and the reaction mixture was heated to 110 ° C, and the reaction was stirred for 2 hours. After the completion of the reaction, the reaction mixture was filtered, and the filtrate was evaporated, evaporated, evaporated, evaporated,,,,,,,,,,,,,,,,,,,,,,,,,,,, ), yield: 29%.
  • the crude product 46a 500 mg, 1.52 mmol
  • 2,5-dichloropyridine 47a (292 mg, 1.97 mmol) were dissolved in 10 mL of dimethyl sulfoxide and N,N-diisopropylethylamine (980 mg, 7.6 mmol) was added.
  • the reaction was carried out in a microwave at 140 ° C for 3.5 hours.
  • the reaction mixture was cooled to room temperature.
  • Test Example 1 Determination of Protease Inhibitory Activity of Human IDO1 by the Compound of the Present Invention
  • the human IDO1 protease activity in vitro was tested by the following method.
  • This method is used to determine the inhibitory effect of the compounds of the invention on the activity of human IDO1 protease.
  • Microplate reader (Synergy HT, BIOTEK)
  • Catalase is derived from bovine liver (C1345-1G, Sigma-Aldrich)
  • the human IDO1 gene was transferred into the Pet30a plasmid by gene cloning technology and then transferred into competent E. coli rosseta; in liquid LB (Luria-Bertani) medium [according to the Guide to Molecular Cloning (J. Sambrook) DW Russell)) was prepared by enlarging the culture medium per liter of medium, collecting the cells, sonicating, and eluting the column to elute the purified IDO1 protease.
  • liquid LB Lia-Bertani
  • reaction plate 24 ⁇ l of the enzyme (IDO1) was diluted 100-fold to 2400 ⁇ l with a concentration of 2.6 ng/ ⁇ l of the enzyme solution with 50 mM KPB in a 96-well reaction plate (AXYGEN, PCR-96-FLT-C) (hereinafter referred to as the reaction plate). The well was added to 24 ⁇ l of the enzyme solution.
  • KPB buffer preparation 50 mM: Weigh KH 2 PO 4 6.805 g into an 1000 ml beaker with an analytical balance, add deionized water to 900 ml with a measuring cylinder, and adjust the pH to 6.5 with 1 M KOH.
  • protease inhibitory activity of the compound of the present invention against human IDO1 was measured by the above test, and the IC 50 values measured are shown in Table 1.
  • the compounds of the present invention have a significant inhibitory effect on the activity of human IDO1 protease.
  • Test Example 2 Determination of the inhibitory activity of the compound of the present invention against human TDO protease
  • This method is used to determine the inhibitory effect of the compounds of the invention on human TDO protease activity.
  • Microplate reader (Synergy HT, BIOTEK)
  • Catalase is derived from bovine liver (C1345-1G, Sigma-Aldrich)
  • mini plate centrifuge Mini-P25, ABSON life science equipment
  • the constructed plasmid containing the human TDO gene was transferred to competent E. coli Rosseta; in liquid LB (Luria-Bertani) medium [according to the Guide to Molecular Cloning (J. Sambrook DW Russell) In the preparation of each liter of medium], the culture was amplified, the cells were collected, sonicated, and the purified TDO1 protease was eluted by hanging the column.
  • LB Lia-Bertani
  • reaction plate 24 ⁇ l of the enzyme (TDO) was diluted 100-fold to 2400 ⁇ l with a concentration of 2.6 ng/ ⁇ l of the enzyme solution with 50 mM KPB in a 96-well reaction plate (AXYGEN, PCR-96-FLT-C) (hereinafter referred to as the reaction plate). The well was added to 24 ⁇ l of the enzyme solution.
  • KPB buffer preparation 50 mM: Weigh KH 2 PO 4 6.805 g into an 1000 ml beaker with an analytical balance, add deionized water to 900 ml using a measuring cylinder, and adjust the pH to 1 M KOH to 6.5, introduce it into a 1L measuring cylinder and replenish it to 1L. Store at 4 ° C]. 1 ⁇ l of the compound or DMSO was added to the reaction well to the corresponding reaction well.
  • Prepare solution A Take 200 ⁇ l of 500 mM L-ascorbate plus 1050 ⁇ l of KPB and mix at a maximum speed of the turbo mixer for 3 seconds.
  • Solution B 100 ⁇ l of 10 mM tryptophan acid plus 100 ⁇ l of 100000 unit/ml catalase, add 5 ⁇ l of 10 mM methylene blue, and finally add 1050 ⁇ l of KPB, and mix at a maximum speed of the turbo mixer for 3 seconds. Take 1200 ⁇ l of A solution and 1200 ⁇ l of B solution and mix for 3 seconds at the maximum speed on the turbo mixer. This mixture was then added to the reaction plate at 24 ⁇ l per well. The reaction plate was placed in a plate centrifuge for 15 seconds at the highest speed, and the reaction liquid was collected at the bottom. The shaker was mixed for 30 seconds, and incubated at 37 ° C for 1 h in a constant temperature incubator.
  • reaction plate 10 ⁇ l of 30% (w/v) trichloroacetic acid was added to each well, and incubated at 65 ° C for 15 minutes in an incubator. The plate was centrifuged at 4700 RPM on a centrifuge at room temperature for 5 minutes. 40 ⁇ l of the supernatant was transferred from the reaction plate with a lance to a corresponding 96-well test plate (Corning, #3599). 40 ⁇ l of 2% (w/v) 4-(dimethylamino)benzaldehyde/glacial acetic acid solution was added to each well and mixed for 1 minute at maximum speed on a shaker. After incubation for 2 minutes at room temperature, the absorbance at 480 nm was read on a Synergy HT Reader.
  • the compound of the present invention has a human TDO protease inhibitory activity as measured by the above test, and the measured IC 50 values are shown in Table 2.
  • the compounds of the present invention have a significant inhibitory effect on human TDO protease activity.
  • Test Example 3 Determination of IDO protease inhibitory activity in HeLa cells by the compound of the present invention
  • the IDO protease activity in HeLa cells was tested by the following method.
  • Microplate reader (Synergy HT, BIOTEK)
  • a HeLa cell suspension was prepared from fresh cell culture medium, and added to a 100-well culture system 96-well cell culture plate at 10,000 cells/well, and cultured at 5% carbon dioxide at 37 ° C for 24 hours. The supernatant was removed, and 90 ⁇ l of serum-free DMEM high glucose medium was added to each well; then 10 ⁇ l of each compound formulated in INF- ⁇ and tryptophan-containing medium was added to each well (the final concentration was 10000, 1000, 100).
  • the IDO protease inhibitory activity of the compound of the present invention against HeLa cells was measured by the above test, and the IC 50 values measured are shown in Table 3.
  • the compounds of this invention inhibit the protease activity IC 50 within the pair of HeLa cells IDO
  • the compounds of the present invention have a significant inhibitory effect on IDO protease activity in HeLa cells.
  • SD rats were used as test animals, and the concentration of the drug in plasma at different times after administration of the compounds of Examples 3 and 9 by intragastric administration was determined by LC/MS/MS method.
  • the pharmacokinetic behavior of the compounds of the invention in rats was investigated and their pharmacokinetic characteristics were evaluated.
  • 0.2 ml of blood was collected from the eyelids before administration and 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 11.0, 24.0 h after administration, and placed in a heparinized test tube, and the plasma was separated by centrifugation at 3500 rpm for 10 minutes. Store at 20 ° C and eat 2 h after dosing.
  • the content of the test compound in the plasma of rats after intragastric administration of different compounds was determined by LC/MS/MS method.
  • the compound of the present invention has good absorption of the drug and has obvious pharmacological absorption effect.
  • C57bl/6 mice were used as test animals, and the concentration of the drug in plasma at different times after administration of the compounds of Examples 28 and 41 by c57bl/6 mice was determined by LC/MS/MS method.
  • the pharmacokinetic behavior of the compounds of the invention in c57bl/6 mice was investigated and their pharmacokinetic characteristics were evaluated.
  • mice Eighteen c57bl/6 mice, female, were divided into two groups, 9 rats/group. After fasting overnight, they were intragastrically administered with a dose of 0.2 ml/kg.
  • 0.2 ml of blood was collected at 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 11.0, 24.0 h after administration, placed in a heparinized test tube, and the plasma was separated by centrifugation at 3500 rpm for 10 minutes, and stored at -20 ° C.
  • the content of the test compound in the plasma of rats after intragastric administration of different compounds was determined by LC/MS/MS method.
  • the compound of the present invention has good absorption of the drug and has obvious pharmacological absorption effect.

Abstract

本发明涉及咪唑并异吲哚类衍生物、其制备方法及其在医药上的应用。特别地，本发明涉及通式(I)所示的咪唑并异吲哚类衍生物、其制备方法及含有该衍生物的药物组合物，以及其治疗具有IDO介导的色氨酸代谢途径病理学特征的疾病的用途，所述的疾病包括癌症、阿尔茨海默病、自身免疫性疾病、抑郁症、焦虑症、白内障、心理障碍和艾滋病，其中通式(I)中的各取代基与说明书中的定义相同。

Description

咪唑并异吲哚类衍生物、其制备方法及其在医药上的应用 技术领域
本发明属于医药领域，涉及咪唑并异吲哚类衍生物、其制备方法及其在医药研究上的应用，本发明公开了其作为IDO抑制剂，用于治疗具有IDO介导的色氨酸代谢途径病理学特征的疾病，所述的疾病包括癌症、阿尔茨海默病、自身免疫性疾病、抑郁症、焦虑症、白内障、心理障碍和艾滋病。
背景技术
肿瘤是严重危害人类生命的重大疾病之一，一半以上发生在发展中国家。我国恶性肿瘤发病率总体呈上升趋势，发病率以年均3％～5％的速度递增，预计到2020年，我国将有400万人发生癌症，300万人死于癌症，其主要原因是：老龄化、城镇化、工业化及生活习惯改变。在中国医院用药市场，抗肿瘤药物的销售规模近几年来一直稳步增长，2012年达到了664.2亿元，同比增长了13.07％，预计到2017年，抗肿瘤药物的市场规模将达到1055.7亿元，同比增长7.57％。
由于恶性肿瘤的无限制生长与浸润、转移，现今临床采用的三大常规治疗方法(手术、放疗和化疗)无法完全切除或彻底杀灭肿瘤细胞，因此常出现肿瘤转移或复发。肿瘤生物治疗是应用现代生物技术及其相关产品进行肿瘤防治的新疗法，因其安全、有效、不良反应低等特点，成为继手术、放疗、化疗之后肿瘤治疗的第四种模式，其通过调动宿主的天然防御机制(比如抑制IDO介导的肿瘤免疫逃逸机制)或给予天然产生的靶向性很强的物质来获得抗肿瘤的效应。
吲哚胺-吡咯-2,3-双加氧酶(Indoleamine-pyrrole-2,3-dioxygenase，IDO)是一种含铁血红素单体蛋白，由403个氨基酸残基组成，包括两个折叠的α-螺旋结构域，大结构域包含催化口袋，底物可在催化口袋内与IDO发生疏水等作用。IDO是催化色氨酸转化为甲酰犬尿氨酸的酶，广泛分布在人和其他哺乳动物(兔、鼠)除肝脏以外的组织中，是肝脏以外唯一可催化色氨酸分解代谢的限速酶，而色氨酸是细胞维持活化和增殖所必需的氨基酸，也是构成蛋白质不可缺少的重要成分。IDO与干扰素(interferon，IFN)、白细胞介素(interleukin，IL)、肿瘤坏死因子等多种细胞因子关系密切，它们在一定条件下可激活IDO。而T-细胞的细胞周期中存在一个对色氨酸水平非常敏感的调节点，一方面，IDO使局部色氨酸耗竭，致使T-细胞停滞于G1期中期，从而抑制了T细胞的增殖；另一方面，IDO催化色氨酸代谢产生的主要产物犬尿素由氧自由基介导引起细胞内氧化剂和抗氧化剂改变而诱导T-细胞凋亡，这是存在于机体的固有的免疫抑制机制。目前大量研究表明IDO在白血病细胞中较高表达，使局部T细胞增殖受抑，抑制T-细胞介导的免疫反应，使T-细胞活化信号转导受阻，从而介导肿瘤细胞逃逸免疫系统的攻击。已经发现大多数人类肿瘤组成性地表达IDO。因此，IDO是一个具潜力的癌症免疫治疗的 靶标。
公开的选择性抑制IDO的抑制剂专利申请包括WO2012142237、WO2004094409、WO2006122150、WO2007075598、WO2010005958和WO2014066834等。
IDO抑制剂作为药物在医药行业具有良好的应用前景，但是目前尚未找到很好的IDO抑制剂可作为上市药物，为了达到更好的肿瘤治疗效果的目的，更好的满足市场需求，我们希望能开发出新一代的高效低毒的选择性IDO抑制剂。本发明将提供一种新型结构的选择性IDO抑制剂，并发现具有此类结构的化合物表现出优异的效果和作用，特别是优异的药代吸收活性。
发明内容
本发明的目的在于提供一种通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中通式(I)所示的化合物结构如下：
Figure PCTCN2016079054-appb-000001
其中：
M为无机酸或有机酸，优选三氟乙酸；
A选自环烷基、杂环基、芳基和杂芳基，其中所述的环烷基、杂环基、芳基和杂芳基任选进一步被选自烷基、卤素、氨基、硝基、羟基、氰基、烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
R1选自氢原子、烷基、环烷基、杂环基、芳基、杂芳基、-OR4、-C(O)R4和-C(O)OR4、-S(O)mR4、-NR5R6、-C(O)NR5R6、-C(O)NHR5、-NR5C(O)R6和-NR5S(O)mR6；
R2相同或不同，且各自独立地选自氢原子、烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、环烷基、杂环基、芳基和杂芳基；
R3相同或不同，且各自独立地选自氢原子、烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、环烷基、杂环基、芳基、杂芳基、-OR4、-C(O)R4、-C(O)OR4、-S(O)mR4、-NR5R6、-C(O)NR5R6、-NR5C(O)R6和-NR5S(O)mR6；其中所述的烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基任选进一步被选自烷基、卤代烷基、卤素、氨基、硝基、氰基、羟基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基、杂芳基、-Ra、-OR7、-C(O)R7、-C(O)OR7、-S(O)mR7、 -NR7R8、-C(O)NR7R8、-NR7C(O)R8和-NR7S(O)mR8中的一个或多个取代基所取代；
Ra选自烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基任选进一步被选自烷基、卤素、氨基、硝基、羟基、烷氧基、羟烷基、氰基、环烷基、杂环基、芳基、杂芳基、-OR4、-C(O)R4、-C(O)OR4、-S(O)mR4、-NR5R6、-C(O)NR5R6、-NR5C(O)R6和-NR5S(O)mR6中的一个或多个取代基所取代；
R4选自氢原子、烷基、卤代烷基、羟基、氨基、烷氧基、卤代烷氧基、环烷基、杂环基、芳基和杂芳基；其中所述的烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基任选进一步被选自烷基、卤素、氨基、硝基、氰基、羟基、羟烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、-Ra、-OR7、-C(O)R7、-C(O)OR7、-S(O)mR7、-NR7R8、-C(O)NR7R8、-NR7C(O)R8和-NR7S(O)mR8中的一个或多个取代基所取代；
R5和R6相同或不同，且各自独立地选自氢原子、烷基、羟基、氨基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、环烷基、杂环基、芳基和杂芳基任选进一步被选自烷基、卤素、羟基、氨基、硝基、氰基、烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基、-Ra、-OR7、-C(O)R7、-C(O)OR7、-S(O)mR7、-NR7R8、-C(O)NR7R8、-NR7C(O)R8和-NR7S(O)mR8中的一个或多个取代基所取代；
R7和R8相同或不同，且各自独立地选自氢原子、烷基、羟基、氨基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、环烷基、杂环基、芳基和杂芳基任选进一步被选自烷基、卤素、羟基、氨基、硝基、氰基、烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
p为0、1、2、3或4的整数；
y为0、1、2或3的整数；
m为0、1或2的整数；且
n为0、1、2、3、4或5的整数。
在本发明的一个优选实施例方案中，一种通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，其中y为0、1或3，特别是0。
在本发明的一个优选实施例方案中，一种通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，其中A选自杂环基和环烷基，其中所述的环烷基和杂环基任选进一步被选自烷基、卤素、氨基、硝基、羟基、氰基、烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代。
在本发明的一个优选实施例方案中，一种通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可 药用盐，其中n为0、1和2的整数。
在本发明的一个优选实施例方案中，一种通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，其为通式(II)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，
Figure PCTCN2016079054-appb-000002
其中：
X为CH或N；
R1～R3、M、p、n和y如通式(I)中所定义；
a为0、1、2或3的整数；且
b为0、1、2或3的整数。
在本发明的一个优选实施例方案中，一种通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，其为通式(II-A)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，
Figure PCTCN2016079054-appb-000003
其中：
R1～R3、M、p、n和y如通式(I)中所定义。
在本发明的一个优选实施例方案中，一种通式(II-A)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，其为通式(II-B)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，
Figure PCTCN2016079054-appb-000004
其中：
R2、R5、R6、M、p和y如通式(I)中所定义。
在本发明的一个优选实施例方案中，一种通式(II)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，其为通式(III)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，
Figure PCTCN2016079054-appb-000005
其中：
R1～R3、M、p、n和y如通式(I)中所定义。
在本发明的一个优选实施例方案中，一种通式(III)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，其为通式(IV)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，
Figure PCTCN2016079054-appb-000006
其中：
R2、R3、M、p、n和y如通式(I)中所定义。
在本发明的一个优选实施例方案中，一种通式(III)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其 可药用盐，其为通式(IV-1)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，
Figure PCTCN2016079054-appb-000007
其中：
R2、Ra、M、p和y如通式(I)中所定义。
在本发明的一个优选实施例方案中，一种通式(III)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，其为通式(IV-2)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，
Figure PCTCN2016079054-appb-000008
其中：
R2、R4、M、p和y如通式(I)中所定义。
在本发明的一个优选实施例方案中，一种通式(IV)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，其为通式(IV-A)和通式(IV-B)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，
Figure PCTCN2016079054-appb-000009
其中：
R2、R3、M、p、n和y如通式(I)中所定义。
在本发明的一个优选实施例方案中，一种通式(V)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，其为制备通式(II)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式的中间体，
Figure PCTCN2016079054-appb-000010
其中：
Q为无机酸或有机酸，优选三氟乙酸；
X为CH或N；
R2、p、a和b如通式(II)中所述定义；且
x为0、1、2、或3的整数。
在本发明的一个优选实施例方案中，一种制备通式(II-1)化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐的方法，该方法包括：
Figure PCTCN2016079054-appb-000011
通式(V)化合物在催化剂存在下在碱性条件下，与R1的卤代物发生偶联反应，得到的产物任选进一步与R3的硼酸或者硼酸酯反应，得到通式(II-1)化合物；
其中：
X为N；
R1～R3、p、n、a和b如通式(II)中所述定义；且
Q和x如通式(V)中所述定义。
在本发明的一个优选实施例方案中，一种制备通式(II)化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式的盐的方法，该方法包括：
Figure PCTCN2016079054-appb-000012
通式(II-1)化合物在酸性条件下成盐，得到通式(II)化合物；
其中：
X为CH或N；
R1～R3、M、p、y、n、a和b如通式(II)中所述定义。
本发明的另一方面涉及一种药物组合物，其含有治疗有效剂量的各通式所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或可药用的盐，以及一种或多种药学上可接受的载体、稀释剂或赋形剂。本发明还涉及一种制备上述组合物的方法，其包括将各通式所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐与药学上可接受的载体、稀释剂或赋形剂相混合。
本发明进一步涉及通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，或包含其的药物组合物在制备用于预防和/或治疗预防具有IDO介导的色氨酸代谢途径的病理学特征的疾病的药物中的用途。IDO抑制剂可以用于心脏障碍的抑制以及治疗其他具有IDO介导的色氨酸代谢途径的病理学特征的疾病，这些疾病包括诸如AIDS等病毒的感染，诸如莱姆病和链球菌感染等细胞感染、神经退行性病症(例如阿尔茨海默病、亨廷顿病和拍金森病)、自身免疫性疾病、抑郁症、焦虑症、白内障、心理障碍、艾滋病、癌症(包括T细胞白血病和结肠癌)、眼睛疾病状态(例如白内障和与年龄相关的黄化)以及自身免疫性疾病，其中所述的癌症可以选自乳腺癌、宫颈癌、结肠癌、肺癌、胃癌、直肠癌、胰腺癌、脑癌、皮肤癌、口腔癌、前列腺癌、骨癌、肾癌、卵巢癌、膀胱癌、肝癌、输卵管肿瘤、卵巢瘤、腹膜肿瘤、IV期黑色素瘤、神经胶质瘤、神经胶母细胞瘤、肝细胞癌、乳突肾性瘤、头颈部肿瘤、白血病、淋巴瘤、骨髓瘤和非小细胞肺癌。
本发明还涉及通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，或包含其的药物组合物，其用于预防和/或治疗预防具有IDO介导的色氨酸代谢途径的病理学特征的疾病。这些疾病包括诸如AIDS等病毒的感染，诸如莱姆病和链球菌感染等细胞感染、神经退行性病症(例如阿尔茨海默病、亨廷顿病和拍金森病)、自身免疫 性疾病、抑郁症、焦虑症、白内障、心理障碍、艾滋病、癌症(包括T细胞白血病和结肠癌)、眼睛疾病状态(例如白内障和与年龄相关的黄化)以及自身免疫性疾病，其中所述的癌症可以选自乳腺癌、宫颈癌、结肠癌、肺癌、胃癌、直肠癌、胰腺癌、脑癌、皮肤癌、口腔癌、前列腺癌、骨癌、肾癌、卵巢癌、膀胱癌、肝癌、输卵管肿瘤、卵巢瘤、腹膜肿瘤、IV期黑色素瘤、神经胶质瘤、神经胶母细胞瘤、肝细胞癌、乳突肾性瘤、头颈部肿瘤、白血病、淋巴瘤、骨髓瘤和非小细胞肺癌。
本发明还涉及一种治疗预防和/或治疗预防具有IDO介导的色氨酸代谢途径的病理学特征的疾病的方法，其包括向患者施用治疗有效剂量的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，或包含其的药物组合物。这些疾病包括诸如AIDS等病毒的感染，诸如莱姆病和链球菌感染等细胞感染、神经退行性病症(例如阿尔茨海默病、亨廷顿病和拍金森病)、自身免疫性疾病、抑郁症、焦虑症、白内障、心理障碍、艾滋病、癌症(包括T细胞白血病和结肠癌)、眼睛疾病状态(例如白内障和与年龄相关的黄化)以及自身免疫性疾病，其中所述的癌症可以选自乳腺癌、宫颈癌、结肠癌、肺癌、胃癌、直肠癌、胰腺癌、脑癌、皮肤癌、口腔癌、前列腺癌、骨癌、肾癌、卵巢癌、膀胱癌、肝癌、输卵管肿瘤、卵巢瘤、腹膜肿瘤、IV期黑色素瘤、神经胶质瘤、神经胶母细胞瘤、肝细胞癌、乳突肾性瘤、头颈部肿瘤、白血病、淋巴瘤、骨髓瘤和非小细胞肺癌。
本发明另一方面涉及一种治疗癌症的方法，该方法包括向患者施用治疗有效剂量的本发明的通式(I)所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐。该方法显示出突出的疗效和较少的副作用，其中所述的癌症可以选自乳腺癌、宫颈癌、结肠癌、肺癌、胃癌、直肠癌、胰腺癌、脑癌、皮肤癌、口腔癌、前列腺癌、骨癌、肾癌、卵巢癌、膀胱癌、肝癌、输卵管肿瘤、卵巢瘤、腹膜肿瘤、IV期黑色素瘤、神经胶质瘤、神经胶母细胞瘤、肝细胞癌、乳突肾性瘤、头颈部肿瘤、白血病、淋巴瘤、骨髓瘤和非小细胞肺癌，优选为输卵管肿瘤、腹膜肿瘤、IV期黑色素瘤、骨髓瘤和乳腺癌，更优选为乳腺癌。
含活性成分的药物组合物可以是适用于口服的形式，例如片剂、糖锭剂、锭剂、水或油混悬液、可分散粉末或颗粒、乳液、硬或软胶囊，或糖浆剂或酏剂。可按照本领域任何已知制备药用组合物的方法制备口服组合物，此类组合物可含有一种或多种选自以下的成分：甜味剂、矫味剂、着色剂和防腐剂，以提供悦目和可口的药用制剂。片剂含有活性成分和用于混合的适宜制备片剂的无毒的可药 用的赋形剂。这些赋形剂可以是惰性赋形剂、造粒剂、崩解剂和润滑剂。这些片剂可以不包衣或可通过掩盖药物的味道或在胃肠道中延迟崩解和吸收，因而在较长时间内提供缓释作用的已知技术将其包衣。
也可用其中活性成分与惰性固体稀释剂，或其中活性成分与水溶性载体或油溶媒或橄榄油混合的软明胶胶囊提供口服制剂。
水悬浮液含有活性物质和用于混合的适宜制备水悬浮液的赋形剂。此类赋形剂是悬浮剂，分散剂或湿润剂。水混悬液也可以含有一种或多种防腐剂例如尼泊金乙酯或尼泊金正丙酯、一种或多种着色剂、一种或多种矫味剂和一种或多种甜味剂。
油混悬液可通过使活性成分悬浮于植物油或矿物油中配制而成。油悬浮液可含有增稠剂。可加入上述的甜味剂和矫味剂，以提供可口的制剂。可通过加入抗氧化剂保存这些组合物。
通过加入水可使适用于制备水混悬液的可分散粉末和颗粒提供活性成分和用于混合的分散剂或湿润剂、悬浮剂或一种或多种防腐剂。适宜的分散剂或湿润剂和悬浮剂可说明上述的例子。也可加入其他赋形剂例如甜味剂、矫味剂和着色剂。
本发明的药物组合物也可以是水包油乳剂的形式。油相可以是植物油或矿物油或其混合物。适宜的乳化剂可以是天然产生的磷脂或偏酯乳剂也可以含有甜味剂、矫味剂、防腐剂和抗氧剂。药物组合物可以是无菌注射水溶液形式。可以使用的可接受的溶媒或溶剂有水、林格氏液和等渗氯化钠溶液。无菌注射制剂可以是其中活性成分溶于油相的无菌注射水包油微乳。可通过局部大量注射，将注射液或微乳注入患者的血流中。
药物组合物可以是用于肌内和皮下给药的无菌注射水或油混悬液的形式。可按已知技术，用上述那些适宜的分散剂或湿润剂和悬浮剂配制该混悬液。无菌注射制剂也可以是在肠胃外可接受的无毒稀释剂或溶剂中制备的无菌注射溶液或混悬液。此外，可方便地用无菌固定油作为溶剂或悬浮介质。
可按用于直肠给药的栓剂形式给予本发明化合物。可通过将药物与在普通温度下为固体但在直肠中为液体，因而在直肠中会溶化而释放药物的适宜的无刺激性赋形剂混合来制备这些药物组合物。
如本领域技术人员所熟知的，药物的给药剂量依赖于多种因素，包括但并非限定于以下因素：所用具体化合物的活性、患者的年龄、患者的体重、患者的健康状况、患者的行被、患者的饮食、给药时间、给药方式、排泄的速率、药物的组合等；另外，最佳的治疗方式如治疗的模式、通式化合物(I)的日用量或可药用的盐的种类可以根据传统的治疗方案来验证。
发明的详细说明
除非有相反陈述，在说明书和权利要求书中使用的术语具有下述含义。
术语“烷基”指饱和脂肪族烃基团，其为包含1至20个碳原子的直链或支链基团，优选含有1至12个碳原子的烷基，更优选含有1至6个碳原子的烷基。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、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,3-二甲基戊基、2,4-二甲基戊基、2,2-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、2,2-二甲基己基、3,3-二甲基己基、4,4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、正壬基、2-甲基-2-乙基己基、2-甲基-3-乙基己基、2,2-二乙基戊基、正癸基、3,3-二乙基己基、2,2-二乙基己基，及其各种支链异构体等。更优选的是含有1至6个碳原子的低级烷基，非限制性实施例包括甲基、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、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基等。烷基可以是取代的或非取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，所述取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基。
术语“亚烷基”是指烷基的一个氢原子进一步被取代，例如：“亚甲基”指-CH2-、“亚乙基”指-(CH2)2-、“亚丙基”指-(CH2)3-、“亚丁基”指-(CH2)4-等。术语“烯基”指由至少由两个碳原子和至少一个碳-碳双键组成的如上定义的烷基，例如乙烯基、1-丙烯基、2-丙烯基、1-、2-或3-丁烯基等。烯基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基。
术语“环烷基”指饱和或部分不饱和单环或多环环状烃取代基，环烷基环包含3至20个碳原子，优选包含3至12个碳原子，更优选包含3至8个碳原子；最优选包含3～6个碳原子。单环环烷基的非限制性实例包括环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等；多环环烷基包括螺环、稠环和桥环的环烷基。
术语“螺环烷基”指5至20元的单环之间共用一个碳原子(称螺原子)的多环 基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元。根据环与环之间共用螺原子的数目将螺环烷基分为单螺环烷基、双螺环烷基或多螺环烷基，优选为单螺环烷基和双螺环烷基。更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺环烷基。螺环烷基的非限制性实例包括：
Figure PCTCN2016079054-appb-000013
术语“稠环烷基”指5至20元，系统中的每个环与体系中的其他环共享毗邻的一对碳原子的全碳多环基团，其中一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠环烷基，优选为双环或三环，更优选为5元/5元或5元/6元双环烷基。稠环烷基的非限制性实例包括：
Figure PCTCN2016079054-appb-000014
术语“桥环烷基”指5至20元，任意两个环共用两个不直接连接的碳原子的全碳多环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环桥环烷基，优选为双环、三环或四环，更有选为双环或三环。桥环烷基的非限制性实例包括：
Figure PCTCN2016079054-appb-000015
所述环烷基环可以稠合于芳基、杂芳基或杂环烷基环上，其中与母体结构连接在一起的环为环烷基，非限制性实例包括茚满基、四氢萘基、苯并环庚烷基等。环烷基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基。
术语“杂环基”指饱和或部分不饱和单环或多环环状烃取代基，其包含3至20个环原子，其中一个或多个环原子为选自氮、氧或S(O)m(其中m是整数0至2) 的杂原子，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。优选包含3至12个环原子，其中1～4个是杂原子；更优选包含3至6个环原子。单环杂环基的非限制性实例包括吡咯烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、二氢咪唑基、二氢呋喃基、二氢吡唑基、二氢吡咯基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基等，优选哌啶基、吡咯烷基。多环杂环基包括螺环、稠环和桥环的杂环基。
术语“螺杂环基”指5至20元的单环之间共用一个原子(称螺原子)的多环杂环基团，其中一个或多个环原子为选自氮、氧或S(O)m(其中m是整数0至2)的杂原子，其余环原子为碳。其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元。根据环与环之间共用螺原子的数目将螺杂环基分为单螺杂环基、双螺杂环基或多螺杂环基，优选为单螺杂环基和双螺杂环基。更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺杂环基。螺杂环基的非限制性实例包括：
Figure PCTCN2016079054-appb-000016
术语“稠杂环基”指5至20元，系统中的每个环与体系中的其他环共享毗邻的一对原子的多环杂环基团，一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统，其中一个或多个环原子为选自氮、氧或S(O)m(其中m是整数0至2)的杂原子，其余环原子为碳。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠杂环基，优选为双环或三环，更优选为5元/5元或5元/6元双环稠杂环基。稠杂环基的非限制性实例包括：
Figure PCTCN2016079054-appb-000017
术语“桥杂环基”指5至14元，任意两个环共用两个不直接连接的原子的多环杂环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统，其中一个或多个环原子为选自氮、氧或S(O)m(其中m是整数0至2)的杂原子，其余环原子为碳。优选为6至14元，更优选为7至10元。根据组成环的数 目可以分为双环、三环、四环或多环桥杂环基，优选为双环、三环或四环，更有选为双环或三环。桥杂环基的非限制性实例包括：
Figure PCTCN2016079054-appb-000018
所述杂环基环可以稠合于芳基、杂芳基或环烷基环上，其中与母体结构连接在一起的环为杂环基，其非限制性实例包括：
Figure PCTCN2016079054-appb-000019
等。
杂环基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基。
术语“芳基”指具有共轭的π电子体系的6至14元全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团，优选为6至10元，例如苯基和萘基。更优选苯基。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，其非限制性实例包括：
Figure PCTCN2016079054-appb-000020
优选
Figure PCTCN2016079054-appb-000021
芳基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。
术语“杂芳基”指包含1至4个杂原子、5至14个环原子的杂芳族体系，其中杂原子选自氧、硫和氮。杂芳基优选为5至10元，更优选为5元或6元，例如咪唑基、呋喃基、噻吩基、噻唑基、吡唑基、噁唑基、吡咯基、四唑基、吡啶基、 嘧啶基、噻二唑、吡嗪基等，优选为咪唑基、吡唑基或嘧啶基、噻唑基；更有选吡唑基。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，其非限制性实例包括：
Figure PCTCN2016079054-appb-000022
Figure PCTCN2016079054-appb-000023
优选
Figure PCTCN2016079054-appb-000024
杂芳基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。
术语“烷氧基”指-O-(烷基)和-O-(非取代的环烷基)，其中烷基的定义如上所述。烷氧基的非限制性实例包括：甲氧基、乙氧基、丙氧基、丁氧基、环丙氧基、环丁氧基、环戊氧基、环己氧基。烷氧基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。
术语“卤代烷基”指被一个或多个卤素取代的烷基，其中烷基如上所定义。
术语“卤代烷氧基”指被一个或多个卤素取代的烷氧基，其中烷氧基如上所定义。
术语“羟烷基”指被羟基取代的烷基，其中烷基如上所定义。
术语“羟基”指-OH基团。
术语“卤素”指氟、氯、溴或碘。
术语“氨基”指-NH2。
术语“氰基”指-CN。
术语“硝基”指-NO2。
术语“氧代基”指＝O。
术语“羧基”指-C(O)OH。
术语“羧酸酯基”指-C(O)O(烷基)或-C(O)O(环烷基)，其中烷基如上所定义。
术语“酰卤”指含有-C(O)-卤素的基团的化合物。
“X选自A、B、或C”、“X选自A、B和C”、“X为A、B或C”、“X为A、B和C”等不同用语均表达了相同的意义，即表示X可以是A、B、C中的任意一种或几种。
“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，该说明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，该说明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。
“取代的”指基团中的一个或多个氢原子，优选为最多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。
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上/可药用的盐或前体药物与其他化学组分的混合物，以及其他组分例如生理学/可药用的载体和赋形剂。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。
“可药用盐”是指本发明化合物的盐，这类盐用于哺乳动物体内时具有安全性和有效性，且具有应有的生物活性。
本发明化合物的合成方法
为了完成本发明的目的，本发明采用如下技术方案：
本发明通式(II)和通式(II-1)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用的盐的制备方法，包括以下步骤：
Figure PCTCN2016079054-appb-000025
方案一
在低温碱性条件下(提供碱性条件的试剂优选为二异丙基氨基锂)，通式(II-a)化合物与溴代苯类化合物发生加成反应，得到通式(II-b)化合物；通式(II-b)化合物在碱性条件下(提供碱性条件的试剂优选为氢化钠或三乙胺)，与甲磺酰氯化合物进行反应，得到通式(II-c)化合物；将得到的通式(II-c)化合物在碱性条件下与咪唑反应，得到通式(II-d)化合物；得到的通式(II-d)化合物在加热、碱和膦钯类催化剂(该催化剂优选为三苯基膦和醋酸钯)存在下，分子内偶联得到通式(II-e)化合物；得到的通式(II-e)化合物在酸性条件下，脱保护得到通式(V)或其盐的化合物；通式(V)化合物在碱性(提供碱性条件的试剂优选为叔丁醇钠)，膦钯类催化剂存在下，进一步与R3的卤代物发生偶联反应，得到的产物任选进一步与R3的硼酸或者硼酸酯偶联得到通式(II-a)化合物；通式(II-a)化合物在酸性条件下成盐，得到通式(II-b)化合物。
提供碱性条件的试剂包括有机碱和无机碱类，所述的有机碱类包括但不限于三乙胺、N,N-二异丙基乙胺、正丁基锂、二异丙基氨基锂、醋酸钾、叔丁醇钠或叔丁醇钾，所述的无机碱类包括但不限于氢化钠、磷酸钾、碳酸钠、碳酸钾或碳酸铯。
其中涉及到的膦钯类催化剂包括但不限于2-二环己基膦-2,4,6-三异丙基联苯、(±)-2,2’-双-(二苯基膦)-1,1’-联萘、三(二亚苄基丙酮)二钯、醋酸钯、[1,1'-双(二苯基磷)二茂铁]二氯化钯、三苯基膦、四(三苯基膦)钯。
其中：
R1～R3、M、p、n、a、b和y如通式(II)中所定义；Q、x如通式(V)中所定义。
Figure PCTCN2016079054-appb-000026
方案二
通式(II-f)化合物与对甲苯磺酰肼反应得到通式(II-g)化合物；得到的通式(II-g)化合物与溴代苯甲醛类化合物在碱性条件下发生反应，得到通式(II-h)化合物；得到的通式(II-h)化合物在还原剂(该还原剂优选为硼氢化钠)存在下，被还原得到通式(II-b)化合物；通式(II-b)化合物在碱性条件(提供碱性条件的试剂优选为氢化钠或三乙胺)下，与磺酰氯类化合物进行反应，得到通式(II-c)化合物；将得到的通式(II-c)化合物在碱性条件下与咪唑反应，得到通式(II-d)化合物；得到的通式(II-d)化合物在加热、碱和膦钯类催化剂(该催化剂优选为三苯基膦和醋酸钯)存在下，分子内偶联得到通式(II-e)化合物；得到的通式(II-e)化合物在酸性条件下，脱保护得到通式(V)或其盐的化合物；通式(V)化合物在碱性(提供碱性条件的试剂优选为叔丁醇钠)，膦钯类催化剂存在下，进一步与R3的卤代物发生偶联反应，得到的产物任选进一步与R3的硼酸或者硼酸酯偶联得到通式(II-a)化 合物；通式(II-a)化合物在酸性条件下成盐，得到通式(II-b)化合物。
提供碱性条件的试剂包括有机碱和无机碱类，所述的有机碱类包括但不限于三乙胺、N,N-二异丙基乙胺、正丁基锂、二异丙基氨基锂、醋酸钾、叔丁醇钠或叔丁醇钾，所述的无机碱类包括但不限于氢化钠、磷酸钾、碳酸钠、碳酸钾或碳酸铯。
其中涉及到的膦钯类催化剂包括但不限于2-二环己基膦-2,4,6-三异丙基联苯、(±)-2,2’-双-(二苯基膦)-1,1’-联萘、三(二亚苄基丙酮)二钯、醋酸钯、[1,1'-双(二苯基磷)二茂铁]二氯化钯、三苯基膦、四(三苯基膦)钯。
其中所述的还原剂包括但不限于Fe粉、Zn粉、H2、硼氢化钠、三乙酰氧基硼氢化钠、腈基硼氢化钠或氢化铝锂。
其中：
R1～R3、M、p、n、a、b和y如通式(II)所定义；Q、x如通式(V)中所定义。
方案三
从通式(V)化合物合成通式(II-1)化合物根据化合物的不同有以下几种具体的合成方法，
Figure PCTCN2016079054-appb-000027
方法一：在惰性气体保护下，高温、碱性、膦钯类催化剂条件下，通式(V)化合物和R1的卤代物直接加热或在微波反应仪中发生偶联反应，得到的产物任选进一步与R1的硼酸或者硼酸酯偶联得到通式(II-1)化合物；该反应的R3的卤代物优选为芳基类卤代化合物；碱性试剂优选为叔丁醇钠。
方法二：在高温、碱性条件下，通式(V)化合物直接与R1的卤代物发生偶联反应，得到的产物任选进一步与R3的硼酸或者硼酸酯偶联得到通式(II-1)化合物；该反应的R1的卤代物优选为杂芳基类卤代化合物；碱性试剂优选为三乙胺。
方法三：在室温、碱性的条件下，通式(V)化合物直接与R3的卤代物反应得到通式(II-1)化合物；该反应的卤代物优选为碘代物和活性高的酰卤化合物；该条件下的碱性试剂优选为碳酸钾。
其中涉及到的膦钯类催化剂包括但不限于2-二环己基膦-2,4,6-三异丙基联苯、(±)-2,2’-双-(二苯基膦)-1,1’-联萘、三(二亚苄基丙酮)二钯、醋酸钯、[1,1'-双(二苯基磷)二茂铁]二氯化钯、三苯基膦、四(三苯基膦)钯。
提供碱性条件的试剂包括有机碱和无机碱类，所述的有机碱类包括但不限于 叔丁醇钠、三乙胺、N,N-二异丙基乙胺、正丁基锂、二异丙基氨基锂、叔丁醇钠醋酸钾或叔丁醇钾，优选叔丁醇钠；所述的无机碱类包括但不限于氢化钠、磷酸钾、碳酸钠、碳酸钾或碳酸铯。
其中：
X为N；
R1～R3、p、n、a、和b如通式(II)所定义；Q、x如通式(V)中所定义。
具体实施方式
以下结合实施例进一步描述本发明，但这些实施例并非限制着本发明的范围。
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 AVANCE-400核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d6)、氘代氯仿(CDCl3)、氘代甲醇(CD3OD)，内标为四甲基硅烷(TMS)，化学位移是以10-6(ppm)作为单位给出。
MS的测定用FINNIGAN LCQAd(ESI)质谱仪(生产商：Thermo,型号：Finnigan LCQ advantage MAX)。
HPLC的测定使用安捷伦1200DAD高压液相色谱仪(Sunfire C18 150×4.6mm色谱柱)和Waters 2695-2996高压液相色谱仪(Gimini C18 150×4.6mm色谱柱)。
激酶平均抑制率及IC50值的测定用NovoStar酶标仪(德国BMG公司)。
薄层层析硅胶板使用烟台黄海HSGF254或青岛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物采用的规格是0.4mm～0.5mm硅胶板。
柱层析一般使用烟台黄海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 Organnics，Aldrich Chemical Company，韶远化学科技(Accela ChemBio Inc)、达瑞化学品等公司。
实施例中如无特殊说明，反应均在氩气氛或氮气氛下进行。
氩气氛或氮气氛是指反应瓶连接一个约1L容积的氩气或氮气气球。
氢气氛是指反应瓶连接一个约1L容积的氢气气球。
加压氢化反应使用Parr 3916EKX型氢化仪和清蓝QL-500型氢气发生器或HC2-SS型氢化仪。
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-S 908860型微波反应器。
实施例中如无特殊说明，反应中的溶液是指水溶液。
实施例中如无特殊说明，反应的温度为室温。
室温为最适宜的反应温度，温度范围是20℃～30℃。
实施例中的反应进程的监测采用薄层色谱法(TLC)，反应所使用的展开剂的体系有：A：二氯甲烷和甲醇体系，B：正己烷和乙酸乙酯体系，C：石油醚和乙酸乙酯体系，D：丙酮，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：正己烷和乙酸乙酯体系，C：正己烷、乙酸乙酯和二氯甲烷体系，D：石油醚和乙酸乙酯体系，E：乙酸乙酯，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。
实施例1
6-氟-5-(1-苯基哌啶-4-基)-5H-咪唑并[5,1-a]异吲哚三氟乙酸盐
Figure PCTCN2016079054-appb-000028
第一步
4-((2-溴-6-氟苯)(羟基)甲基)哌啶-1-甲酸叔丁酯1c
将二异丙基氨基锂(32.5mL，65.0mmol)加入50mL四氢呋喃中，于-78℃滴加预制的25mL 1-溴-3-氟苯1a(8.75g，50.0mmol)的四氢呋喃溶液，于-78℃搅拌1小时。再于-78℃滴加预制的25mL 4-甲酰基哌啶-1-甲酸叔丁酯1b(8.75g，50.0mmol)的四氢呋喃溶液，于-78℃搅拌1小时。反应结束后，于-78℃滴加25mL甲醇淬灭反应，将反应液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残留物，得到化合物1c(16.3g，黄色糖浆固体)，产率84.0％。
MS m/z(LC-MS):332.0[M-56]
第二步
4-((2-溴-6-氟苯基)(对甲苯磺酰基氧基)甲基)哌啶-1-甲酸叔丁酯1d
将化合物1c(15g，38.63mmol)溶于350mL四氢呋喃中，分批加入氢化钠(3.09g，77.26mmol)，搅拌至无气体放出。滴加250mL预制的对甲苯磺酰氯(8.10g，42.49mmol)的四氢呋喃溶液，于室温下搅拌30分钟，回流搅拌4小时，于70℃搅拌48小时。反应结束后，冷却至0℃，滴加50mL水淬灭反应，加入50mL饱和氯化钠溶液，分液，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残留物，得到化合物1d(6.6g，淡黄色粘稠固体)，产率：31.80％。
MS m/z(LC-MS):314.0/316.0[M-56-TsO]
第三步
4-((2-溴-6-氟苯)(1H-咪唑-1-基)甲基)哌啶-1-甲酸叔丁酯1e
将咪唑(12.5g，184.3mmol)溶于50mL N,N-二甲基甲酰胺中，分批加入氢化钠(7.40g，184.3mmol)，于室温搅拌1小时，滴加20mL预制的化合物1d(10.0g，18.43mmol)的N,N-二甲基甲酰胺溶液，于100℃搅拌12小时。反应结束后，加入300mL乙酸乙酯，用饱和氯化钠溶液洗涤(150mL×3)，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残留物，得到化合物1e(1.90g，棕色粘稠固体)，产率：23.5％。
MS m/z(LC-MS):438.1/440.1[M+1]
第四步
4-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-甲酸叔丁酯1f
将化合物1e(1.90g，4.33mmol)，N,N-二环己基甲基胺(1.35g，6.93mmol)，三苯基磷(908mg，3.46mmol)加入10mL N,N-二甲基甲酰胺溶液中，氩气氛下，加入醋酸钯(390mg，1.74mmol)，于100℃搅拌4.5小时。反应结束后，将反应液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残留物，得到化合物1f(1.30g，黄色粘稠固体)，产率：83.8％。
MS m/z(LC-MS):358.1[M+1]
第五步
6-氟-5-(哌啶-4-基)-5H-咪唑并[5,1-a]异吲哚二三氟乙酸盐1g
将化合物1f(1.30g，3.64mmol)溶于5mL二氯甲烷中，滴加5mL三氟乙酸，于室温下搅拌1小时。反应结束后，将反应液减压浓缩，得到粗品化合物1g(1.77g，棕色粘稠固体)，产品不经纯化直接进行下一步反应。
MS m/z(LC-MS):258.3[M+1]
第六步
6-氟-5-(1-苯基哌啶-4-基)-5H-咪唑并[5,1-a]异吲哚1h
将粗品化合物1g(230mg，0.50mmol)，溴苯(314mg，2.00mmol)，(±)-2,2'- 双-(二苯膦基)-1,1'-联萘(39mg，0.0625mmol)，叔丁醇钠(192mg，2.0mmol)，溶于5mL 1,4-二氧六环中，氩气氛下，加入三(二亚苄基丙酮)二钯(46mg，0.05mmol)，于100℃搅拌4小时。反应结束后，加入20mL乙酸乙酯，用水洗涤(10mL×3)，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，用高效液相色谱法纯化所得残留物，得到化合物1h(6.3mg，棕色粘稠固体)，收率3.6％。
MS m/z(ESI):334.3[M+1]
第七步
6-氟-5-(1-苯基哌啶-4-基)-5H-咪唑并[5,1-a]异吲哚三氟乙酸盐1
将化合物1h(6.3mg，0.018mmol)溶于0.5mL二氯甲烷中，加入0.01mL三氟乙酸，于室温搅拌60分钟。反应结束后，将反应液减压浓缩得到化合物1(8.3mg，浅棕固体)，收率100％。
MS m/z(ESI):334.3[M+1]
1H NMR(400MHz,CD3OD)δ9.35(s,1H),7.93(s,1H),7.74(d,1H),7.69-7.64(m,1H),7.60-7.50(m,5H),7.38-7.34(m,1H),6.15(d,1H),3.79-3.71(m,1H),3.69-3.61(m,2H),3.61-3.51(m,1H),3.02-2.92(m,1H),2.14-2.04(m,2H),1.76-1.59(m,2H).
实施例2
7-氟-5-(1-苯基哌啶-4-基)-5H-咪唑并[5,1-a]异吲哚三氟乙酸盐
Figure PCTCN2016079054-appb-000029
Figure PCTCN2016079054-appb-000030
第一步
4-(2-对甲苯磺酰基腙基)哌啶-1-甲酸叔丁酯2c
将对甲苯磺酰肼2a(9.31g，50.0mmol)加入100mL甲醇中，加入N-叔丁氧羰基哌啶酮2b(9.96g，50.0mmol，采用公知的方法“ACS Medicinal Chemistry Letters,2014,5(5),550-555”制备而得)，反应体系于室温反应2小时。反应结束后，将反应液减压浓缩，将所得残留物干燥得粗品化合物2c(18.37g，白色固体)，产品不经纯化直接进行下一步反应。
MS m/z(LC-MS):368.0[M+1]
第二步
4-(2-溴-5-氟苯甲酰基)哌啶-1-甲酸叔丁酯2e
将粗品化合物2c(5.52g，15.0mmol)，2-溴-5-氟苯甲醛2d(3.05g，15.0mmol)，碳酸铯(7.33g，22.5mmol)加入封管中，氩气氛下，加入60mL 1,4-二氧六环，反应体系于110℃搅拌10小时。反应结束后，加入20mL乙酸乙酯，用水(100mL×1)洗涤，再用饱和氯化钠溶液(100mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗品化合物2e(6.17g，黄色粘稠固体)，产品不经纯化直接进行下一步反应。
MS m/z(LC-MS):330.0/332.0[M-56]
第三步
4-((2-溴-5-氟苯基)(羟基)甲基)哌啶-1-甲酸叔丁酯2f
将粗品化合物2e(6.17g，16.0mmol)溶于100mL甲醇中，反应体系冷却至0℃，于0℃缓慢加入硼氢化钠(1.21g，32.0mmol)，反应体系于0℃搅拌1小时。反应结束后，加入200mL乙酸乙酯，用饱和氯化钠溶液(100mL×3)洗涤，用无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗品标题产物化合物2f(6.21g，黄色糖浆)，产品不经纯化直接进行下一步反应。
MS m/z(LC-MS):332.0/334.0[M-56]
第四步
4-((2-溴-5-氟苯基)((甲基磺酰基)氧基)甲基)哌啶-1-甲酸叔丁酯2g
将粗品化合物2f(6.21g，16.0mmol)溶于100mL二氯甲烷中，冷却至0℃，加入三乙胺(3.24g，32.0mmol)，滴加甲基磺酰氯(2.75g，24.0mmol)，反应体系于0℃搅拌1小时。反应结束后，反应液用水(50mL×3)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得粗品化合物2g(7.46g，棕色粘稠固体)，产品不经纯化直接进行下一步反应。
第五步
4-((2-溴-5-氟苯基)(1H-咪唑-1-基)甲基)哌啶-1-甲酸叔丁酯2h
将粗品化合物2g(7.46g，16.0mmol)，1-H咪唑(10.89g，160.0mmol)，N,N-二异丙基乙基胺(20.68g，160.0mmol)加入封管中，加入50mL乙腈，反应体系于120℃搅拌12小时。反应结束后，冷却至室温，加入200mL乙酸乙酯，用水(100mL×3)洗涤，饱和氯化钠溶液(100mL×3)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残留物，得到化合物2h(4.68g，棕黄色泡状固体)，收率66.7％。
MS m/z(LC-MS):438.1/440.1[M+1]
第六步
4-(7-氟-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-甲酸叔丁酯2i
将化合物2h(4.68g，10.68mmol)，N,N-二环己基甲基胺(3.34g，17.08mmol)，三苯基磷(2.24g，8.54mmol)加入50mL N,N-二甲基甲酰胺溶液中，氩气氛下，加入醋酸钯(960mg，4.28mmol)，反应体系于100℃反应17小时。反应结束后，将反应液减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残留物，得到化合物2i(3.81g，黄色固体)，产率：99.0％。
MS m/z(LC-MS):358.1[M+1]
第七步
7-氟-5-(哌啶-4-基)-5H-咪唑并[5,1-a]异吲哚二三氟乙酸盐2j
将化合物2i(3.81g，10.68mmol)溶于10mL二氯甲烷中，滴加10mL三氟乙酸，于室温下反应2小时。反应结束后，将反应液减压浓缩，得到粗品化合物2j(5.18g，棕色粘稠固体)，产品不经纯化直接进行下一步反应。
MS m/z(LC-MS):258.3[M+1]
第八步
7-氟-5-(1-苯基哌啶-4-基)-5H-咪唑并[5,1-a]异吲哚2k
将粗品化合物2j(115mg，0.25mmol)，溴苯(47mg，0.30mmol)，2-二环己基磷-2,4,6-三异丙基联苯(6mg，0.025mmol)，叔丁醇钠(96mg，1.0mmol)，醋酸钯(6.0mg，0.025mmol)加入1.8mL甲苯和叔丁醇(V:V＝5:1)的混合溶剂中，反应体系于120℃微波反应1小时。反应结束后，加入50mL二氯甲烷，用饱和亚硫酸钠溶液洗涤(25mL×3)，用无水硫酸钠干燥，过滤，滤液减压浓缩，用高效液相色谱法纯化所得残留物，得到化合物2k(12.6mg，棕色糖浆)，收率15.2％。
MS m/z(ESI):334.3[M+1]
第九步
7-氟-5-(1-苯基哌啶-4-基)-5H-咪唑并[5,1-a]异吲哚三氟乙酸盐2
将化合物2k(12.6mg，0.038mmol)溶于0.5mL二氯甲烷中，加入0.01mL三氟乙酸，于室温反应60分钟。反应结束后，将反应液减压浓缩得到化合物2(16.9mg，浅棕色固体)，收率100％。
MS m/z(ESI):334.3[M+1]
实施例3
6-氟-5-(1-(3-氟苯基)哌啶-4-基)-5H-咪唑并[5,1-a]异吲哚三氟乙酸盐
Figure PCTCN2016079054-appb-000031
第一步
6-氟-5-(1-(3-氟苯基)哌啶-4-基)-5H-咪唑并[5,1-a]异吲哚3a
将粗品化合物1g(230mg，0.5mmol)，1-溴-3-氟苯(105mg，0.6mmol)，2-二环己基磷-2,4,6-三异丙基联苯(24mg，0.05mmol)，叔丁醇钠(192mg，2.0mmol)，加入3mL甲苯和叔丁醇(V:V＝5:1)的混合溶剂中，氩气氛下，加入醋酸钯(12.0mg，0.05mmol)，反应体系于120℃反应12小时。反应结束后，加入20mL乙酸乙酯，用水(10mL×3)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，用高效液相色谱法纯化所得残留物，得到化合物3a(17.3mg，黑色糖浆)，收率10％。
MS m/z(ESI):352.3[M+1]
第二步
6-氟-5-(1-(3-氟苯基)哌啶-4-基)-5H-咪唑并[5,1-a]异吲哚三氟乙酸盐3
将化合物3a(17.3mg，0.05mmol)溶于0.5mL二氯甲烷中，加入0.01mL三氟乙酸，于室温反应60分钟。反应结束后，将反应液减压浓缩得到化合物3(23mg，浅棕色固体)，收率100％。
MS m/z(ESI):352.3[M+1]
1H NMR(400MHz,DMSO-d6)δ9.51(s,1H),8.06(s,1H),7.76(d,1H),7.67-7.62(m,1H),7.47-7.32(m,1H),7.23-7.10(m,1H),6.76-6.62(m,2H),6.57-6.45(m,1H),6.12(d,1H),3.85-3.73(m,1H),3.73-3.63(m,1H),2.79-2.67(m,1H),2.67-2.50(m,2H),1.83-1.68(m,1H),1.61-1.45(m,1H),1.35-1.23(m,1H),1.10-0.94(m,1H).
实施例4
6-氟-5-(1-(4-甲氧基苯基)哌啶-4-基)-5H-咪唑并[5,1-a]异吲哚三氟乙酸盐
Figure PCTCN2016079054-appb-000032
第一步
6-氟-5-(1-(4-甲氧基苯基)哌啶-4-基)-5H-咪唑并[5,1-a]异吲哚4a
将粗品化合物1g(115mg，0.25mmol)，4-碘苯甲醚(70mg，0.3mmol)，2-二环己基磷-2,4,6-三异丙基联苯(12mg，0.025mmol)，叔丁醇钠(96mg，1.0mmol)，加入1.8mL甲苯和叔丁醇(V:V＝5:1)的混合溶剂中，氩气氛下，加入醋酸钯(6.0mg，0.025mmol)，反应体系于160℃微波反应30分钟。反应结束后，用饱和亚硫酸钠溶液洗涤(25mL×3)，用二氯甲烷萃取(20mL×3)，合并有机相，用饱和亚硫酸钠溶液(25mL×3)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，用高效液相色谱法纯化所得残留物，得到标题产物化合物4a(29mg，棕色糖浆)，收率33.6％。
MS m/z(ESI):364.3[M+1]
第二步
6-氟-5-(1-(4-甲氧基苯基)哌啶-4-基)-5H-咪唑并[5,1-a]异吲哚三氟乙酸盐4
将化合物4a(29mg，0.084mmol)溶于0.5mL二氯甲烷中，加入0.5mL三氟乙酸，于室温反应60分钟。反应结束后，将反应液减压浓缩得到化合物4(40mg，浅棕色固体)，收率100％。
MS m/z(ESI):364.3[M+1]
1H NMR(400MHz,DMSO-d6)δ9.41(s,1H),8.02(s,1H),7.75(d,1H),7.68-7.63(m,1H),7.44-7.39(m,1H),7.21-7.10(m,2H),6.97-6.87(m,2H),6.14(d,1H),3.71(s,3H), 3.59-3.50(m,1H),3.49-3.40(m,1H),3.18-2.82(m,2H),2.69-2.55(m,2H),1.95-1.83(m,1H),1.83-1.66(m,1H),1.42-1.30(m,1H),1.26-1.10(m,1H).
实施例5
4-(4-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)苯甲腈三氟乙酸盐
Figure PCTCN2016079054-appb-000033
第一步
4-(4-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)苯甲腈5a
将粗品化合物1g(230mg，0.5mmol)，对碘苯腈(137mg，0.6mmol)，2-二环己基磷-2,4,6-三异丙基联苯(24mg，0.05mmol)，叔丁醇钠(192mg，2.0mmol)，醋酸钯(12.0mg，0.05mmol)，加入3mL甲苯和叔丁醇(V:V＝5:1)的混合溶剂中，氩气氛下，反应体系于120℃微波反应1小时。反应结束后，加入20mL二氯甲烷，用饱和亚硫酸钠溶液(10mL×3)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，用高效液相色谱法纯化所得残留物，得到化合物5a(67mg，棕色糖浆)，收率29.7％。
MS m/z(ESI):359.1[M+1]
第二步
4-(4-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)苯甲腈三氟乙酸盐5
将化合物5a(67mg，0.188mmol)溶于0.5mL二氯甲烷中，加入0.1mL三氟乙酸，于室温反应60分钟。反应结束后，将反应液减压浓缩得到化合物5(70mg，浅棕固体)，收率100％。
MS m/z(ESI):359.1[M+1]
实施例6
4-(4-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)苯甲酰胺三氟乙酸盐
Figure PCTCN2016079054-appb-000034
第一步
4-(4-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)苯甲酰胺6a
将化合物5(60mg，0.127mmol)，锌粉(340mg，5.2mmol)，3mL乙酸，0.2mL浓盐酸加入反应瓶中，于125℃反应19小时。反应结束后，滤去锌粉，滤液减压浓缩，用高效液相色谱法纯化所得残留物，得到化合物6a(4.5mg，棕色糖浆)，收率9.4％。
MS m/z(ESI):377.4[M+1]
第二步
4-(4-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)苯甲酰胺三氟乙酸盐6
将化合物6a(4.5mg，0.012mmol)溶于0.5mL二氯甲烷中，加入0.1mL三氟乙酸，于室温反应60分钟。反应结束后，将反应液减压浓缩得到化合物6(5.8mg，浅棕色固体)，收率100％。
MS m/z(ESI):377.4[M+1]
实施例7
6-氟-5-(1-(4-(甲基磺酰基)苯基)哌啶-4-基)-5H-咪唑并[5,1-a]异吲哚三氟乙酸盐
Figure PCTCN2016079054-appb-000035
第一步
6-氟-5-(1-(3-(甲基磺酰基)苯基)哌啶-4-基)-5H-咪唑并[5,1-a]异吲哚7b
将粗品化合物1g(150mg，0.33mmol)，1-溴-3-(甲基磺酰基)苯7a(93mg，0.40mmol)，2-二环己基磷-2,4,6-三异丙基联苯(16mg，0.033mmol)，叔丁醇钠(158mg，1.65mmol)，醋酸钯(20.0mg，0.083mmol)，加入3mL甲苯和叔丁醇(V:V＝5:1)的混合溶剂中，反应体系于160℃微波反应30分钟。反应结束后，加硅藻土辅助过滤，滤液减压浓缩，用高效液相色谱法纯化所得残留物，得到化合物7b(14.5mg，淡橙色固体)，收率13.0％。
MS m/z(ESI):412.0[M+1]
第二步
6-氟-5-(1-(3-(甲基磺酰基)苯基)哌啶-4-基)-5H-咪唑并[5,1-a]异吲哚三氟乙酸盐7
将化合物7b(14.5mg，0.035mmol)溶于5mL二氯甲烷中，加入0.5mL三氟乙酸，于室温反应12小时。反应结束后，将反应液减压浓缩得到化合物7(18mg，浅橙色固体)，收率100％。
MS m/z(ESI):412.0[M+1]
1H NMR(400MHz,CDCl3)δ9.05(br.s,1H),7.60-7.56(m,3H),7.45-7.38(m,3H),7.26-7.22(t,1H),7.14-7.12(d,1H),5.75(s,1H),3.06(s,3H),2.91-2.75(m,2H),1.94-1.74(m,2H),1.49-1.46(m,1H),1.37-1.19(m,4H).
实施例8
6-氟-5-(1-(3-(1-甲基-1H-吡唑-4-基)苯基)哌啶-4-基)-5H-咪唑并[5,1-a]异吲哚
Figure PCTCN2016079054-appb-000036
将粗品化合物1g(229mg，0.5mmol)，4-(3-溴苯基)-1-甲基-1H-吡唑8a(236mg，1mmol，采用专利申请“WO2013043946”公开的方法制备而得)溶于10mL甲苯中，加入(±)-2,2'-双-(二苯膦基)-1,1'-联萘(31.1mg，0.05mmol)，叔丁醇钠(192mg，2mmol)，三(二亚苄基丙酮)二钯(45.78mg，0.05mmol)，反应体系于120℃微波反应1小时。反应结束后，滤液减压浓缩，用高效液相色谱法纯化所得残留物，得到化合物8(30mg，白色固体)，收率11.3％。
MS m/z(ESI):414.2[M+1]
1H NMR(400MHz,CDCl3)δ8.18-8.16(m,2H),7.99-7.93(m,1H),7.90-7.85(m,2H),7.74-7.72(m,1H),7.69-7.65(m,4H),7.36-7.32(m,1H),6.66(s,1H),3.96(s,3H),3.36(m,1H),3.15(m,1H),2.78(m,1H),2.66(m,1H),2.40(m,1H),2.03(m,1H),1.78(m,1H),1.28(m,1H),1.01(m,1H).
实施例9
6-氟-5-(1-(4-(1-甲基-1H-吡唑-4-基)苯基)哌啶-4-基)-5H-咪唑并[5,1-a]异吲哚
Figure PCTCN2016079054-appb-000037
第一步
5-(1-(4-溴苯基)哌啶-4-基)-6-氟-5H-咪唑并[5,1-a]异吲哚9a
将粗品化合物1g(1.45g，3mmol)溶于30mL甲苯中，加入对二溴苯(1.41g，6mmol)，加入(±)-2,2'-双-(二苯膦基)-1,1'-联萘(187mg，0.3mmol)，叔丁醇钠(1.15mg，12mmol)，三(二亚苄基丙酮)二钯(275mg，0.3mmol)，氩气氛下，反应体系于80℃反应12小时。反应结束后，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残留物，得到化合物9a(670mg，黄色固体)，收率50％。
MS m/z(LC-MS):412.2[M+1]
第二步
6-氟-5-(1-(4-(1-甲基-1H-吡唑-4-基)苯基)哌啶-4-基)-5H-咪唑并[5,1-a]异吲哚9
将粗品化合物9a(165mg，0.4mmol)溶于5mL乙二醇二甲醚中，加入1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)-1H-吡唑(166mg，0.8mmol)，碳酸钠(127mg，1.2mmol)和0.5mL水，搅拌均匀后，加入[1,1'-双(二苯基磷)二茂铁]二氯化钯(29mg，0.04mmol)，氩气氛下，于120℃微波反应40分钟。反应结束后，加入50mL乙酸乙酯和20mL水，分液，水相用乙酸乙酯(30mL)萃取，合并有机相。有机相用饱和氯化钠溶液(40mL)洗涤，用无水硫酸钠干燥，过滤，滤液减压浓缩，用高效液相色谱法纯化所得残留物，得到化合物9(10mg，白色固体)，产率6.06％。
MS m/z(LC-MS):414.4[M+1]
1H NMR(400MHz,DMSO-d6)δ7.99(s,1H),7.95(s,1H),7.71(s,1H),7.51-7.46(m,2H),7.35(d,2H),7.23(s,1H),7.16-7.13(m,1H),6.87(d,2H),5.70(s,1H),3.83(s,3H),3.76-3.73(m,1H),3.63-3.60(m,1H),2.70-2.64(m,1H),2.37-2.34(m,1H),1.79-1.76(m,1H),1.70-1.65(m,1H),1.34-1.30(m,1H),1.20-1.17(m,1H),0.91-0.87(m,1H).
实施例10
6-氟-5-(1-(4-(哌嗪-1-基)苯基)哌啶-4-基)-5H-咪唑并[5,1-a]异吲哚三氟乙酸盐
Figure PCTCN2016079054-appb-000038
第一步
4-(4-(4-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)苯基)哌嗪-1-甲酸叔丁酯10a
将化合物9a(82mg，2mmol)和1-叔丁氧羰基哌嗪(760mg，4mmol)溶于15mL甲苯中，加入(±)-2,2'-双-(二苯膦基)-1,1'-联萘(125mg，0.2mmol)，叔丁醇钠(576mg，6mmol)，三(二亚苄基丙酮)二钯(183mg，0.2mmol)，反应体系于120℃微波反应75分钟。反应结束后，用硅藻土助滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残留物，得到化合物10a(517mg，黄色固体)，收率50％。
MS m/z(LC-MS):518.2[M+1]
第二步
6-氟-5-(1-(4-(哌嗪-1-基)苯基)哌啶-4-基)-5H-咪唑并[5,1-a]异吲哚10b
将化合物10a(517mg，1mmol)溶于16mL二氯甲烷中，加入4mL三氟乙酸，室温下反应过夜。反应结束后，将反应液减压浓缩，用高效液相色谱法纯化所得残留物，得到化合物10b(15.4mg，淡黄色固体)，产率3.7％。
MS m/z(LC-MS):418.2[M-1]
第三步
6-氟-5-(1-(4-(哌嗪-1-基)苯基)哌啶-4-基)-5H-咪唑并[5,1-a]异吲哚三氟乙酸盐10
将化合物10b(14.5mg，0.035mmol)溶于5mL二氯甲烷中，加入0.5mL三氟乙酸，于室温反应12小时。反应结束后，将反应液减压浓缩得到化合物10(20mg，淡黄色固体)，收率100％。
MS m/z(ESI):418.2[M+1]
1H NMR(400MHz,CDCl3)δ7.77(s,1H),7.34-7.38(m,3H),7.22(s,1H),6.98-6.96(m,1H),6.85-6.84(m,3H),5.38(s,1H),3.65(m,1H),3.62(m,1H),3.34(m,1H),3.09(m,1H),2.70(m,1H),2.56(m,2H),2.38(m,2H),1.86(m,3H),1.31-1.16(m,5H).
实施例11
4-(4-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)-N-(四氢-2H-吡喃-4-基)苯甲酰胺三氟乙酸盐
Figure PCTCN2016079054-appb-000039
第一步
4-(4-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)苯甲酸11a
将化合物5a(630mg，1.76mmol)加入15mL 6N的盐酸中，反应体系于100℃反应12小时。反应结束后，将反应液减压浓缩，干燥所得残留物，得到粗品化合物11a(664mg，浅棕色固体)，产品不经纯化直接进行下一步反应。
MS m/z(LC-MS):378.1[M+1]
第二步
4-(4-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)-N-(四氢-2H-吡喃-4-基)苯甲酰胺11b
将粗品化合物11a(75mg，0.2mmol)，4-氨基四氢吡喃(40mg，0.4mmol)，三乙胺(0.14mL，1.0mmol)加入1.0mL N,N-二甲基甲酰胺中，加入2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(152mg，0.4mmol)，反应体系于50℃下反应12小时。反应结束后，将反应液减压浓缩，用高效液相色谱法纯化所得残留物，得到化合物11b(48mg，浅棕色固体)，产率52.1％。
MS m/z(LC-MS):461.4[M+1]
第三步
4-(4-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)-N-(四氢-2H-吡喃-4-基)苯甲酰胺三氟乙酸盐11
将化合物11b(48mg，0.104mmol)溶于0.5mL二氯甲烷中，加入0.1mL三氟乙酸，于室温反应60分钟。反应结束后，将反应液减压浓缩得到化合物11(60mg，浅棕色固体)，收率100％。
MS m/z(ESI):461.4[M+1]
1H NMR(400MHz,DMSO-d6)δ9.46(s,1H),8.04(s,1H),7.98(d,1H),7.76-7.63(m, 4H),7.44-7.39(m,1H),6.89(d,2H),6.11(d,1H),3.98-3.80(m,5H),3.38-3.32(m,2H),2.83-2.73(m,1H),2.73-2.63(m,1H),2.62-2.54(m,1H),1.79-1.68(m,3H),1.59-1.48(m,3H),1.34-1.25(m,1H),1.05-0.95(m,1H).
实施例12
N-(3-(4-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)苯基)乙酰胺三氟乙酸盐
Figure PCTCN2016079054-appb-000040
第一步
6-氟-5-(1-(3-硝基苯)哌啶-4-基)-5H-咪唑并[5,1-a]异吲哚12a
将粗品化合物1g(230mg，0.5mmol)，1-碘-3-硝基苯(149mg，0.6mmol)，2-二环己基磷-2,4,6-三异丙基联苯(24mg，0.05mmol)，叔丁醇钠(192mg，2.0mmol)，醋酸钯(12.0mg，0.05mmol)，加入3mL甲苯和叔丁醇(V:V＝5:1)的混合溶剂中，反应体系于160℃微波反应30分钟。反应结束后，入20mL饱和亚硫酸钠溶液，用二氯甲烷萃取(20mL×3)，合并有机相，用饱和亚硫酸钠溶液(20mL×3)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残留物，得到化合物12a(50mg，棕色粘稠物)，收率26.5％。
MS m/z(LC-MS):379.1[M+1]
第二步
3-(4-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)苯胺12b
将化合物12a(50mg，0.132mmol)，10mg 10％钯碳加入2mL甲醇和四氢呋喃(V:V＝1:1)的混合溶剂中，反应体系用氢气置换三次，室温反应3小时。反应结束后，将反应液减压浓缩，得到粗品化合物12b(46mg，红棕色粘稠固体)，产品不经纯化直接进行下一步反应。
MS m/z(LC-MS):349.0[M+1]
第三步
N-(3-(4-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)苯基)乙酰胺12c
将粗品化合物12b(46mg，0.132mmol)，乙酸(16mg，0.264mmol)，1-羟基苯并三唑(36mg，0.264mmol)，1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(51mg，0.264mmol)，N,N-二异丙基乙基胺(85mg，0.66mmol)加入1mL N,N-二甲基甲酰胺中，反应体系于室温反应2小时。反应结束后，将反应液减压浓缩，用高效液相色谱法纯化所得残留物，得到化合物12c(8.4mg，棕色糖浆)，产率16.3％。
MS m/z(LC-MS):391.4[M+1]
第四步
N-(3-(4-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)苯基)乙酰胺三氟乙酸盐12
将化合物12c(8.4mg，0.021mmol)溶于0.5mL二氯甲烷中，加入0.05mL三氟乙酸，于室温反应60分钟。反应结束后，将反应液减压浓缩得到化合物12(10.8mg，浅棕的固体)，收率100％。
MS m/z(ESI):391.4[M+1]
实施例13
2-(3-(4-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)苯基)-N-甲基乙酰胺三氟乙酸盐
Figure PCTCN2016079054-appb-000041
第一步
2-(3-(4-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)苯基)乙酸甲酯13b
将粗品化合物1g(1.21g，2.5mmol)，2-(3-溴苯)乙酸甲酯13a(1.15g，5.0mmol，采用公知的方法“Journal of Medicinal Chemistry,2008,51(3),392-395”制备而得)，碘化亚铜(95mg，0.5mmol)，L-脯氨酸(115mg，1mmol)，碳酸钾(1.38g，10.0mmol)，加入10mL二甲基亚砜，氩气氛下，反应体系于90℃反应24小时。反应结束后，加入100mL乙酸乙酯，用水(250mL×3)洗涤，无水硫酸钠干燥，过滤，滤液减 压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残留物，得到标题产物化合物13b(410mg，棕色糖浆)，收率40.5％。
MS m/z(LC-MS):406.0[M+1]
第二步
2-(3-(4-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)苯基)乙酸13c
将化合物13b(410mg，1.0mmol)溶于4mL四氢呋喃中，加入4mL 1M氢氧化钠溶液，室温下反应12小时。反应结束后，加入40mL水，用乙酸乙酯萃取(25mL×3)，水相滴加乙酸调节pH为6，用二氯甲烷萃取(20mL×3)，合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗品化合物13c(190mg，棕色固体)，产品不经纯化直接进行下一步反应。
MS m/z(LC-MS):392.0[M+1]
第三步
2-(3-(4-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)苯基)-N-甲基乙酰胺13d
将粗品化合物13c(190mg，0.485mmol)，一甲胺盐酸盐(65mg，0.97mmol)，2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(369mg，0.097mmol)，三乙胺(245mg，2.425mmol)，加入2mL N,N-二甲基甲酰胺中，反应体系于50℃反应12小时。反应结束后，将反应液减压浓缩，用高效液相色谱法纯化所得残留物，得到化合物13d(39mg，棕色固体)，产率19.9％。
MS m/z(LC-MS):405.0[M+1]
第四步
2-(3-(4-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)苯基)-N-甲基乙酰胺三氟乙酸盐13
将化合物13d(39mg，0.096mmol)溶于0.5mL二氯甲烷中，加入0.05mL三氟乙酸，于室温反应60分钟。反应结束后，将反应液减压浓缩得到化合物13(50mg，浅棕色固体)，收率100％。
MS m/z(ESI):405.0[M+1]
1H NMR(400MHz,DMSO-d6)δ9.52(s,1H),8.07(s,1H),7.97-7.89(m,1H),7.76(d,1H),7.70-7.64(m,1H),7.46-7.41(m,1H),7.22-7.14(m,1H),7.04-6.73(m,3H),6.14(d,1H),3.73-3.63(m,1H),3.63-3.53(m,1H),3.32(s,2H),3.00-2.70(m,2H),2.63-2.53(m,1H),2.55(d,3H),1.91-1.81(m,1H),1.73-1.58(m,1H),1.38-1.28(m,1H),1.10-1.00(m,1H).
实施例14
6-氟-5-(1-(1-甲基-1H-吲哚-4-基)哌啶-4-基)-5H-咪唑并[5,1-a]异吲哚三氟乙酸盐
Figure PCTCN2016079054-appb-000042
Figure PCTCN2016079054-appb-000043
第一步
6-氟-5-(1-(1-甲基-1H-吲哚-4-基)哌啶-4-基)-5H-咪唑并[5,1-a]异吲哚14a
将粗品化合物1g(367mg，0.76mmol)和4-溴-1-甲基-1H-吲哚(150mg，0.714mmol)溶于15mL甲苯和叔丁醇(V:V＝5:1)的混合溶剂中，加入2-二环己基磷-2,4,6-三异丙基联苯(34mg，0.071mmol)，叔丁醇钠(274mg，2.86mmol)，醋酸钯(16.0mg，0.071mmol)，氩气氛下，反应体系于120℃反应12小时。反应结束后，将反应液过滤，滤液减压浓缩，用高效液相色谱法纯化所得残留物，得到化合物14a(23mg，黄色固体)，收率8.4％。
MS m/z(LC-MS):387.4[M-1]
第二步
6-氟-5-(1-(1-甲基-1H-吲哚-4-基)哌啶-4-基)-5H-咪唑并[5,1-a]异吲哚三氟乙酸盐14
将化合物14a(23mg，0.06mmol)溶于2mL二氯甲烷中，加入0.1mL三氟乙酸，于室温反应60分钟。反应结束后，将反应液减压浓缩得到化合物14(30mg，黄色固体)，收率100％。
MS m/z(LC-MS):387.4[M+1]
1H NMR(400MHz,DMSO-d6)δ9.54(s,1H),8.09(s,1H),7.78(d,1H),7.65-7.71(m,1H),7.45(t,1H),7.02-7.33(m,3H),6.75(br.s,1H),6.41(br.s,1H),6.12(s,1H),3.75(s,3H),3.55-3.74(m,2H),2.52-2.80(m,2H),1.70-2.00(m,3H),1.30-1.40(m,1H),1.20-1.30(m,1H).
实施例15
6-氟-5-(1-(吡啶-2-基)哌啶-4-基)-5H-咪唑并[5,1-a]异吲哚三氟乙酸盐
Figure PCTCN2016079054-appb-000044
第一步
6-氟-5-(1-(吡啶-2-基)哌啶-4-基)-5H-咪唑并[5,1-a]异吲哚15a
将粗品化合物1g(115mg，0.25mmol)，2-溴吡啶(47mg，0.30mmol)，2- 二环己基磷-2,4,6-三异丙基联苯(12.0mg，0.025mmol)，叔丁醇钠(96mg，1.0mmol)加入1.8mL甲苯和叔丁醇(V:V＝5:1)的混合溶剂中，搅拌均匀，加入醋酸钯(6.0mg，0.025mmol)，反应体系于160℃微波反应30分钟。反应结束后，加入20mL水，用二氯甲烷萃取(20mL×3)，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，用高效液相色谱法纯化所得残留物，得到化合物15a(7.1mg，棕色糖浆)，收率6.8％。
MS m/z(LC-MS):335.0[M+1]
第二步
6-氟-5-(1-(吡啶-2-基)哌啶-4-基)-5H-咪唑并[5,1-a]异吲哚三氟乙酸盐15
将化合物15a(7.1mg，0.21mmol)溶于0.5mL二氯甲烷中，加入0.1mL三氟乙酸，于室温反应60分钟。反应结束后，将反应液减压浓缩得到化合物15(9.5mg，浅棕固体)，收率100％。
MS m/z(LC-MS):335.0[M+1]
实施例16
6-氟-5-(1-(嘧啶-2-基)哌啶-4-基)-5H-咪唑并[5,1-a]异吲哚三氟乙酸盐
Figure PCTCN2016079054-appb-000045
第一步
6-氟-5-(1-(嘧啶-2-基)哌啶-4-基)-5H-咪唑并[5,1-a]异吲哚16a
将粗品化合物1g(230mg，0.5mmol)，2-氯嘧啶(57mg，0.50mmol)，三乙胺(202mg，2.0mmol)加入封管中，加入5mL乙醇，反应体系于100℃反应12小时。反应结束后，将反应液液减压浓缩，用高效液相色谱法纯化所得残留物，得到化合物16a(127mg，浅棕色糖浆)，收率75.5％。
MS m/z(LC-MS):336.0[M+1]
第二步
6-氟-5-(1-(嘧啶-2-基)哌啶-4-基)-5H-咪唑并[5,1-a]异吲哚三氟乙酸盐16
将16a(127mg，0.38mmol)溶于2mL二氯甲烷中，加入0.5mL三氟乙酸，于室温反应60分钟。反应结束后，将反应液减压浓缩得到化合物16(170mg，浅棕色固体)，收率100％。
MS m/z(ESI):336.0[M+1]
1H NMR(400MHz,DMSO-d6)δ9.48(s,1H),8.31(d,2H),8.04(s,1H),7.75(d,1H), 7.67-7.61(m,1H),7.42-7.37(m,1H),6.58-6.56(m,1H),6.10(d,1H),4.85-4.75(m,1H),4.71-4.61(m,1H),2.93-2.81(m,1H),2.81-2.62(m,3H),1.85-1.74(m,1H),1.46-1.36(m,1H),1.32-1.22(m,1H),0.87-0.77(m,1H).
实施例17
4-(2-(4-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)嘧啶-4-基)吗啉三氟乙酸盐
Figure PCTCN2016079054-appb-000046
第一步
6-氟-5-(哌啶-4-基)-5H-咪唑并[5,1-a]异吲哚17a
将化合物1f(17.1g，47.9mmol)溶于100mL二氯甲烷中，滴加50mL三氟乙酸，室温下反应12小时。反应结束后，减压浓缩除去大部分二氯甲烷和三氟乙酸。加入100mL二氯甲烷，滴加饱和碳酸氢钠溶液至无气泡放出，调至pH为7，分液，水相用二氯甲烷萃取(200mL×3)，合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗品化合物17a(12.3g，棕色糖浆)，产物不经纯化直接进行下一步反应。
MS m/z(LC-MS):258.3[M+1]
第二步
4-(2-(4-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)嘧啶-4-基)吗啉17c
将粗品化合物17a(260mg，1.005mmol)溶于2.5mL乙醇中，加入4-(2-氯嘧啶-4-基)吗啉17b(100mg，0.503mmol，采用公知的方法“Chemistry & Biology Interface,2012,2(5),347-361”制备而得)和三乙胺(203mg，2.012mmol)，于100℃闷罐反应48小时。反应结束后，将反应液减压浓缩，用高效液相色谱法纯化所得残留物，得到化合物17c(59mg，黄色固体)，收率30％。
MS m/z(LC-MS):421.3[M+1]
第三步
4-(2-(4-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)嘧啶-4-基)吗啉三氟乙酸盐17
将化合物17c(59mg，0.14mmol)溶于3mL二氯甲烷中，加入0.1mL三氟乙酸，于室温反应30分钟。反应结束后，将反应液减压浓缩得到化合物17(75mg，黄色胶状物)，收率100％。
MS m/z(ESI):421.3[M+1]
1H NMR(400MHz,DMSO-d6)δ9.36(s,1H),8.03(s,1H),7.86(d,1H),7.75(d,1H),7.63-7.68(m,1H),7.41(t,1H),6.52(d,1H),6.10(d,1H),4.30-4.55(m,2H),3.60-3.85(m,8H),3.09(t,1H),2.99(t,1H),2.70-2.80(m,1H),1.82-1.88(m,1H),1.36-1.55(m,1H),1.30-1.36(m,1H),0.88-1.05(m,1H).
实施例18
6-氟-5-(1-(5-(1-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)嘧啶-2-基)哌啶-4-基)-5H-咪唑并[5,1-a]异吲哚
Figure PCTCN2016079054-appb-000047
第一步
5-(1-(5-溴嘧啶-2-基)哌啶-4-基)-6-氟-5H-咪唑并[5,1-a]异吲哚18a
在封管中将粗品化合物1g(1.0g，2.2mol)，5-溴-2-氯嘧啶(468mg，2.42mmol)，三乙胺(1.1g，11mmol)加入20mL乙醇中，于90℃反应12小时。反应结束后，将反应液减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得到化合物18a(730mg，橙黄色固体)，收率80.2％。
MS m/z(LC-MS):414.2[M+2]
第二步
6-氟-5-(1-(5-(1-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)嘧啶-2-基)哌啶-4-基)-5H-咪唑并[5,1-a]异吲哚18
将化合物18a(124mg，0.3mmol)溶于5mL乙二醇二甲醚与0.5mL水中，加入1-(四氢-2H-吡喃-4-基)-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑18b(125mg，0.45mmol，采用公知的方法“Bioorganic & Medicinal Chemistry,2013,21(21),6804-6820”制备而得)，四(三苯基膦)钯(69mg，0.06mmol)，碳酸钠(63.6mg，0.6mmol)，氩气氛下，于80℃反应12小时。反应结束后，加入30mL水，用二氯甲烷萃取(40mL×3)，合并有机相，有机相用饱和氯化钠溶液洗涤(40mL)，用无水硫酸钠干燥，过滤，滤液减压浓缩，用高效液相色谱法纯化所得残留物，得到化合物18(30mg，白色固体)，收率20.7％。
MS m/z(LC-MS):486.5[M+1]
1H NMR(400MHz,DMSO-d6)δ8.56(s,2H),8.18(s,1H),7.94(s,1H),7.82(s,1H),7.48-7.46(m,2H),7.20(s,1H),7.16-7.11(m,1H),5.68(s,1H),4.81-4.78(m,1H),4.64-4.61(m,1H),4.42-4.36(m,1H),3.98-3.95(m,2H),3.50-3.44(m,2H),2.92-2.86(m,1H),2.78-2.72(m,1H),2.01-1.89(m,4H),1.81-1.78(m,1H),1.53-1.45(m,1H),1.26-1.24(m,1H),1.19-1.17(m,1H),0.73-0.63(m,1H).
实施例19
6-氟-5-(1-甲基哌啶-4-基)-5H-咪唑并[5,1-a]异吲哚三氟乙酸盐
Figure PCTCN2016079054-appb-000048
第一步
6-氟-5-(1-甲基哌啶-4-基)-5H-咪唑并[5,1-a]异吲哚19a
将粗品化合物1g(121mg，0.25mmol)溶于2mL N,N-二甲基甲酰胺中，加入碳酸钾(173mg，1.25mmol)，搅拌均匀，加入碘甲烷(21mg，0.15mmol)，室温反应48小时。反应结束后，加入20mL乙酸乙酯，用水洗涤(10mL×3)，无水硫酸钠干燥，过滤，滤液减压浓缩，用高效液相色谱法纯化所得残留物，得到化合物19a(16.0mg，浅棕色粘稠物)，收率38.9％。
MS m/z(LC-MS):272.0[M+1]
第二步
6-氟-5-(1-甲基哌啶-4-基)-5H-咪唑并[5,1-a]异吲哚三氟乙酸盐19
将粗品化合物19a(16.0mg，0.59mmol)溶于0.5mL二氯甲烷中，加入0.05mL 三氟乙酸，于室温反应60分钟。反应结束后，将反应液减压浓缩得到化合物19(22.6mg，浅棕色固体)，收率100％。
MS m/z(LC-MS):272.0[M+1]
1H NMR(400MHz,CD3OD)δ9.31(s,1H),7.91(s,1H),7.73(d,1H),7.67-7.62(m,1H),7.36-7.31(m,1H),6.08(d,1H),3.61-3.52(m,1H),3.52-3.43(m,1H),3.12-2.98(m,2H),2.88-2.76(m,1H),2.83(s,3H),2.01-1.92(m,1H),1.87-1.73(m,1H),1.73-1.62(m,1H),1.54-1.39(m,1H).
实施例20
1-(4-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)乙酮三氟乙酸盐
Figure PCTCN2016079054-appb-000049
第一步
1-(4-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)乙酮20a
将粗品化合物1g(31mg，0.084mmol)溶于2mL二氯甲烷中，加入三乙胺(34mg，0.336mmol)，搅拌均匀，加入乙酰氯(13mg，0.168mmol)，室温反应48小时。反应结束后，减压浓缩反应液，用高效液相色谱法纯化所得残留物，得到化合物20a(7.2mg，棕色固体)，收率40％。
MS m/z(LC-MS):300.0[M+1]
第二步
1-(4-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)乙酮三氟乙酸盐
将粗品化合物20a(7.2mg，0.024mmol)溶于0.5mL二氯甲烷中，加入0.01mL三氟乙酸，于室温反应60分钟。反应结束后，将反应液减压浓缩得到化合物20(10mg，浅棕色固体)，收率100％。
MS m/z(LC-MS):300.0[M+1]
实施例21
4-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-N-苯基哌啶-1-甲酰胺三氟乙酸盐
Figure PCTCN2016079054-appb-000050
第一步
4-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-N-苯基哌啶-1-甲酰胺21a
将双(三氯甲基)碳酸酯(297mg，1.0mmol)溶于2mL二氯甲烷中，滴加预制的2mL苯胺(93mg，1.0mmol)的二氯甲烷溶液，滴加预制的1mL三乙胺(0.28mL)的二氯甲烷溶液，室温下反应10分钟。减压浓缩后，加入5mL四氢呋喃，0.28mL三乙胺，加入化合物1g(243mg，0.5mmol)，室温反应12小时。反应结束后，加入20mL乙酸乙酯，20mL水，分液，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，用高效液相色谱法纯化所得残留物，得到化合物21a(92mg，淡黄色固体)，收率48.9％。
MS m/z(LC-MS):377.0[M-1]
第二步
4-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-N-苯基哌啶-1-甲酰胺三氟乙酸盐21
将粗品化合物21a(92mg，0.244mmol)溶于2mL二氯甲烷中，加入0.5mL三氟乙酸，于室温反应60分钟。反应结束后，将反应液减压浓缩得到化合物21(120mg，浅棕固体)，收率100％。
MS m/z(LC-MS):377.0[M-1]
1H NMR(400MHz,DMSO-d6)δ9.47(s,1H),8.45(s,1H),8.04(s,1H),7.75(d,1H),7.68-7.63(m,1H),7.43-7.37(m,3H),7.21-7.17(m,2H),6.91-6.88(m,1H),6.08(d,1H),4.28-4.18(m,1H),4.15-4.05(m,1H),2.83-2.68(m,2H),2.64-2.54(m,1H),1.76-1.67(m,1H),1.42-1.32(m,1H),1.28-1.19(m,1H),0.91-0.81(m,1H).
实施例22
N-(4-苯腈)-4-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-甲酰胺三氟乙酸盐
Figure PCTCN2016079054-appb-000051
Figure PCTCN2016079054-appb-000052
第一步
N-(4-苯腈)-4-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-甲酰胺22a
将双(三氯甲基)碳酸酯(297mg，1.0mmol)溶于2mL二氯甲烷中，滴加预制的2mL对氨基苯腈(118mg，1.0mmol)的二氯甲烷溶液，滴加预制的1mL三乙胺(0.28mL)的二氯甲烷溶液，室温下反应1小时。减压浓缩后，加入5mL四氢呋喃，0.28mL三乙胺，化合物1g(243mg，0.5mmol)，室温反应12小时。反应结束后，减压浓缩反应液，用高效液相色谱法纯化所得残留物，得到化合物22a(101mg，浅棕色固体)，收率50.5％。
MS m/z(LC-MS):402.0[M+1]
第二步
N-(4-苯腈)-4-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-甲酰胺三氟乙酸盐22
将化合物22a(101mg，0.25mmol)溶于2mL二氯甲烷中，加入0.5mL三氟乙酸，于室温反应60分钟。反应结束后，将反应液减压浓缩得到化合物22(130mg，浅棕固体)，收率100％。
MS m/z(LC-MS):402.0[M+1]
1H NMR(400MHz,DMSO-d6)δ9.47(s,1H),8.99(s,1H),8.06(s,1H),7.76(d,1H),7.68-7.60(m,5H),7.44-7.39(m,1H),6.09(d,1H),4.30-4.20(m,1H),4.15-4.05(m,1H),2.91-2.81(m,1H),2.81-2.71(m,1H),2.68-2.58(m,1H),1.79-1.68(m,1H),1.44-1.34(m,1H),1.31-1.21(m,1H),0.93-0.83(m,1H).
实施例23
2-(4-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)-5-苯基噻唑三氟乙酸盐
Figure PCTCN2016079054-appb-000053
第一步
5-溴-2-(4-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)噻唑23a
将粗品化合物1g(2.43g，5.0mmol)，2,5-二溴噻唑(1.82g，7.5mmol)，三乙胺(2.02g，20.0mmol)加入15mL二甲基亚砜中，反应体系于120℃微波反应1.5小时。反应结束后，加入250mL乙酸乙酯，用水洗涤(150mL×3)，饱和氯化钠溶液洗涤(150mL)，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得到化合物23a(710mg，棕色固体)，收率33.9％。
MS m/z(LC-MS):420.0[M+1]
第二步
2-(4-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)-5-苯基噻唑23b
将化合物23a(105mg，0.25mmol)，苯硼酸(46mg，0.375mmol)，四(三苯基膦)钯(58mg，0.05mmol)，磷酸钾三水(133mg，0.5mmol)加入1.4mL N,N-二甲基甲酰胺和水(V:V＝6:1)的混合溶剂中，反应体系于120℃微波反应35分钟。反应结束后，将反应液减压浓缩，用高效液相色谱法纯化所得残留物，得到化合物23b(24mg，棕色糖浆)，收率22.7％。
MS m/z(LC-MS):417.0[M+1]
第三步
2-(4-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)-5-苯基噻唑三氟乙酸盐23
将化合物23b(24mg，0.057mmol)溶于0.5mL二氯甲烷中，加入0.05mL三氟乙酸，于室温反应60分钟。反应结束后，将反应液减压浓缩得到化合物23(30mg，浅棕色固体)，收率100％。
MS m/z(LC-MS):417[M+1]
1H NMR(400MHz,DMSO-d6)δ9.42(s,1H),8.02(s,1H),7.74(d,1H),7.68-7.62(m,1H),7.57(s,1H),7.44-7.38(m,3H),7.35-7.31(m,2H),7.18-7.22(m,1H),6.11(d,1H),4.06-3.99(m,1H),3.92-3.84(m,1H),3.17-3.07(m,1H),3.04-2.94(m,1H),2.70-2.60(m,1H),1.91-1.81(m,1H),1.67-1.52(m,1H),1.34-1.25(m,1H),1.04-0.93(m,1H).
实施例24
5-(1-(1H-苯并[d]咪唑-2-基)哌啶-4-基)-6-氟-5H-咪唑并[5,1-a]异吲哚
Figure PCTCN2016079054-appb-000054
将粗品化合物1g(257g，1mmol)，2-氯苯并咪唑(153mg，1mmol)溶于10mL N-甲基吡咯烷酮，加入N,N-二异丙基乙基胺(390mg，3mmol)，于90℃ 反应12小时。反应结束后，将反应液减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得到化合物24(20mg，白色固体)，收率41％。
MS m/z(LC-MS):374.2[M-1]
1H NMR(400MHz,CDCl3)δ7.74(s,1H),7.38-7.17(m,5H),7.17(s,1H),6.98(s,2H),5.32(s,1H),4.38-4.21(m,2H),3.04-2.93(m,2H),2.48(m 1H),1.82-1.71(m,2H),1.29-1.23(m,1H),0.92(m,1H).
实施例25
6-氟-5-(1-苯基吡咯烷-3-基)-5H-咪唑并[5,1-a]异吲哚三氟乙酸盐
Figure PCTCN2016079054-appb-000055
第一步
3-((2-溴-6-氟苯基)(羟基)甲基)吡咯烷-1-甲酸叔丁酯25b
将二异丙基氨基锂(13mL，26mmol)加入20mL四氢呋喃中，氩气保护下，冷却至-78℃，于-78℃滴加预制的10mL 1-溴-3-氟苯1a(3.5g，20.0mmol)的四氢呋喃溶液，于-78℃反应1小时。再于-78℃滴加预制的10mL 3-甲酰基吡咯烷-1-甲酸叔丁酯25a(3.985g，20.0mmol，采用公知的方法“Jpn.Tokkyo Koh,2009,03Jun,4272338”制备而得)的四氢呋喃溶液，于-78℃反应1小时。反应结束后，于-78℃滴加10mL甲醇淬灭反应，将反应液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残留物，得到化合物25b(5.15g，淡黄色油状物)，产率68.8％。
MS m/z(LC-MS):320.0[M-56]
第二步
3-((2-溴-6-氟苯基)((甲基磺酰基)氧基)甲基)吡咯烷-1-甲酸叔丁酯25c
将化合物25b(5.1g，13.6mmol)溶于50mL二氯甲烷中，加入三乙胺(3.8mL，27.7mmol)，冰浴下滴加甲基磺酰氯(1.639g，14.3mmol)，于室温下反应1小时。反应结束后，加入50mL二氯甲烷，用水洗涤(60mL)，饱和氯化钠溶液洗涤(60mL)，用无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗品化合物25c(5.9g，黄色粘稠固体)，产品不经纯化直接进行下一步反应。
MS m/z(LC-MS):300 0 [M-56-95]
第三步
3-((2-溴-6-氟苯基)(1H-咪唑-1-基)甲基)吡咯烷-1-甲酸叔丁酯25d
将粗品化合物25c(2.4g，5.3mmol)溶于10mL乙腈中，加入咪唑(3.6g，53mmol)，加入N,N-二异丙基乙基胺(6.85g，53mmol)，于120℃微波反应1小时40分钟。反应结束后，加入100mL乙酸乙酯，用水洗涤(60mL×2)，用饱和氯化钠溶液洗涤(60mL)，用无水硫酸钠干燥有机相，过滤，滤液减压浓缩，得到化合物25d(2.7g，棕色粘稠固体)，产品不经纯化直接进行下一步反应。
MS m/z(LC-MS):424.3[M+1]
第四步
3-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)吡咯烷-1-甲酸叔丁酯25e
将粗品化合物25d(2.4g，5.66mmol)溶于10mL N,N-二甲基甲酰胺溶液中，加入N,N-二环己基甲基胺(1.77g，9.05mmol)，三苯基磷(594mg，2.264mmol)，醋酸钯(254mg，1.132mmol)，于120℃微波反应1小时。反应结束后，减压浓缩除去N,N-二甲基甲酰胺溶液，加入100mL乙酸乙酯，用水洗涤(40mL×2)，饱和氯化钠溶液洗涤(60mL)，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残留物，得到化合物25e(1.62g，淡棕色油状物)，产率：78.3％。
MS m/z(LC-MS):344.2[M+1]
第五步
6-氟-5-(吡咯烷-3-基)-5H-咪唑并[5,1-a]异吲哚二三氟乙酸盐25f
将化合物25e(1.62g，4.71mmol)溶于20mL二氯甲烷中，滴加2.69mL三氟乙酸，于室温下反应4小时。反应结束后，将反应液减压浓缩，得到粗品化合物25f(2.76g，褐色油状物)，产品不经纯化直接进行下一步反应。
MS m/z(LC-MS):243.9[M+1]
第六步
6-氟-5-(1-苯基吡咯烷-3-基)-5H-咪唑并[5,1-a]异吲哚25g
将粗品化合物25f(292mg，0.50mmol)溶于1.5mL甲苯和乙醇(V:V＝5:1)的混合溶剂中，加入溴苯(94mg，0.6mmol)，2-二环己基磷-2',4',6'-三异丙基联萘(24mg，0.05mmol)，叔丁醇钠(240mg，2.50mmol)，醋酸钯(11mg，0.05mmol)，氩气氛 下，于120℃微波反应50分钟。反应结束后，将反应液减压浓缩，用高效液相色谱法纯化所得残留物，得到化合物25g(23mg，棕色油状物)，收率14.3％。
MS m/z(ESI):320.3[M+1]
第七步
6-氟-5-(1-苯基吡咯烷-3-基)-5H-咪唑并[5,1-a]异吲哚三氟乙酸盐25
将化合物25g(23mg，0.072mmol)溶于5mL二氯甲烷中，加入0.5mL三氟乙酸，于室温反应60分钟。反应结束后，将反应液减压浓缩得到化合物25(31mg，棕色油状物固体)，收率100％。
MS m/z(ESI):320.3[M+1]
实施例26
6-氟-5-(1-(3-氟苯基)哌啶-3-基)-5H-咪唑并[5,1-a]异吲哚三氟乙酸盐
Figure PCTCN2016079054-appb-000056
第一步
3-((2-溴-6-氟苯基)(羟基)甲基)哌啶-1-甲酸叔丁酯26b
将15mL四氢呋喃加入反应瓶中，氩气氛下，冷却至-78℃，加入二异丙基氨基锂(9.3mL，18.6mmol)，滴加1-溴-3-氟苯1a(2.5g，14.3mmol)，于-78℃反应1 小时。滴加预制的5mL 3-甲酰基哌啶-1-甲酸叔丁酯26a(3.0g，14.3mmol)的四氢呋喃溶液，于-78℃反应1小时。反应结束后，于-78℃滴加15mL甲醇淬灭反应，将反应液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残留物，得到化合物26b(3.9g，微黄色固体)，产率34％。
MS m/z(LC-MS):334.0[M-55]
第二步
3-((2-溴-6-氟苯基)((甲基磺酰基)氧基)甲基)哌啶-1-甲酸叔丁酯26c
将化合物26b(3.9g，10mmol)溶于40mL二氯甲烷中，加入三乙胺(2.02g，20mmol)，滴加甲基磺酰氯(1.2g，10.05mmol)，于室温下反应12小时。反应结束后，将反应液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残留物，得到化合物26c(1.9g，浅黄色油状物)，收率40.7％。
MS m/z(LC-MS):314.0[M-152]
第三步
3-((2-溴-6-氟苯基)(1H-咪唑-1-基)甲基)哌啶-1-甲酸叔丁酯26d
将化合物26c(2.0g，4.28mmol)溶于5mL乙腈中，加入咪唑(2.9g，42.8mmol)，加入N,N-二异丙基乙基胺(5.5g，42.8mmol)，于120℃微波反应1小时。反应结束后，将反应液减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残留物，得到标题产物化合物26d(0.85g，浅褐色油状物)，产率：47％。
MS m/z(LC-MS):440.0[M+2]
第四步
3-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-甲酸叔丁酯26e
将化合物26d(1.0g，2.28mmol)溶于5mL N,N-二甲基甲酰胺溶液中，加入N,N-二环己基甲基胺(712mg，3.65mmol)，三苯基磷(239mg，0.91mmol)，醋酸钯(100mg，0.45mmol)，于120℃微波反应1小时。反应结束后，将反应液减压浓缩，得粗品化合物26e(1.21g，橙色油状物)，产品不经纯化直接进行下一步反应。
MS m/z(LC-MS):358.2[M+1]
第五步
6-氟-5-(哌啶-3-基)-5H-咪唑并[5,1-a]异吲哚二三氟乙酸盐26f
将粗品化合物26e(1.7g，4.76mmol)溶于20mL二氯甲烷中，滴加1mL三氟乙酸，于室温下反应48小时。反应结束后，将反应液减压浓缩，得到粗品化合物26f(2.5g，褐色油状物)，产品不经纯化直接进行下一步反应。
MS m/z(LC-MS):258.0[M+1]
第六步
6-氟-5-(1-(3-氟苯基)哌啶-3-基)-5H-咪唑并[5,1-a]异吲哚26g
将粗品化合物26f(200mg，0.44mmol)，1-溴-3-氟苯(93mg，0.53mmol)，2-二环己基磷-2',4',6'-三异丙基联苯(21mg，0.044mmol)，叔丁醇钠(211mg，2.2 mmol)，醋酸钯(20mg，0.089mmol)溶于5mL甲苯和乙醇(V:V＝5:1)的混合溶剂中，于120℃微波反应1小时。反应结束后，用硅藻土助滤，滤液减压浓缩，用高效液相色谱法纯化所得残留物，得到化合物26g(3.7mg，褐色油状物)，收率3％。
MS m/z(ESI):352.0[M+1]
第七步
6-氟-5-(1-(3-氟苯基)哌啶-3-基)-5H-咪唑并[5,1-a]异吲哚三氟乙酸盐26
将化合物26g(3.7mg，0.01mmol)溶于5mL二氯甲烷中，加入0.5mL三氟乙酸，于室温反应12小时。反应结束后，将反应液减压浓缩得到化合物26(4.8mg，褐色油状物)，收率100％。
MS m/z(ESI):352.0[M+1]
实施例27，28
(R)-6-氟-5-(1-(4-(1-甲基-1H-吡唑-4-基)苯基)哌啶-4-基)-5H-咪唑并[5,1-a]异吲哚27
(S)-6-氟-5-(1-(4-(1-甲基-1H-吡唑-4-基)苯基)哌啶-4-基)-5H-咪唑并[5,1-a]异吲哚28
Figure PCTCN2016079054-appb-000057
将化合物9(1.9g,4.59mmol)进行手性制备(分离条件：手性柱CHIRALPAKIF，流动相：二氯甲烷：甲醇＝70：30，流速：30mL/分钟)，收集其相应组分，减压浓缩，得到化合物27(700mg,1.69mmol)，收率73.7％；化合物28(640mg，1.54mmol)，收率67.4％。
27：
MS m/z(ESI):414.4[M+1]
手性HPLC分析：保留时间2.466分钟，ee值＞99.0％。(色谱柱：CHIRALPAK ID；流动相：DCM/MeOH/TEA＝80/20/0.1(V/V/V)
1H NMR(400MHz,DMSO-d6)δ7.98(s,1H),7.94(s,1H),7.70(s,1H),7.44-7.51(m,2H),7.34(d,2H),7.22(s,1H),7.11-7.17(m,1H),6.86(d,2H),5.69(s,1H),3.82(s,3H),3.73(d,1H),3.60(d,1H),2.63-2.69(m,1H),2.33-2.36(m,1H),1.75-1.78(m,1H),1.64-1.69(m,1H),1.16-1.33(m,2H),0.87-0.90(m,1H).
28：
MS m/z(ESI):414.4[M+1]
手性HPLC分析：保留时间4.122分钟，ee值＞99.0％。(色谱柱：CHIRALPAK ID；流动相：DCM/MeOH/TEA＝80/20/0.1(V/V/V)
1H NMR(400MHz,DMSO-d6)δ7.98(s,1H),7.94(s,1H),7.70(s,1H),7.44-7.51(m,2H),7.34(d,2H),7.22(s,1H),7.11-7.17(m,1H),6.86(d,2H),5.69(s,1H),3.82(s,3H),3.73(d,1H),3.60(d,1H),2.63-2.69(m,1H),2.33-2.36(m,1H),1.75-1.78(m,1H),1.64-1.69(m,1H),1.16-1.33(m,2H),0.87-0.90(m,1H).
实施例29
(2S)-3-(4-(4-(4-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)苯基)-1H-吡唑-1-基)丙烷-1,2-二醇
Figure PCTCN2016079054-appb-000058
第一步
(S)-1-((2,2-二甲基-1,3-二氧戊环-4-基)甲基)-4-(4,4,5,5-四甲基l-1,3,2-二氧杂戊硼烷-2-基)-1H-吡唑29c
将4-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)-1H-吡唑29a(1g，5.15mmol)溶于6mL N,N-二甲基甲酰胺中，室温下加入250mg的钠氢(60％)，室温搅拌反应20分钟，加入(R)-4-(氯甲基)-2,2-二甲基-1,3-二氧戊环29b(1.164g，7.73mmol)，升温至100℃搅拌反应12小时。反应液冷却至室温，减压浓缩后用硅胶柱色谱法以洗脱剂体系A纯化所得残留物，得到标题化合物29c(790mg，黄色油状物)，产率：50％。
第二步
5-(1-(4-(1-(((S)-2,2-二甲基1,3-二氧戊环-4-基)甲基)-1H-吡唑-4-基)苯基)哌啶-4-基)-6-氟-5H-咪唑并[5,1-a]异吲哚29d
将9a(250mg，0.606mmol)和29c(560mg，1.82mmol)加入7mL正丁醇中，加入磷酸钾(386mg，1.82mmol)，三(二亚苄基丙酮)二钯(41.7mg，0.0455mmol)，2-双环己基膦-2',4',6'-三异丙基联苯(87mg，0.182mmol)，升温至100℃反应12小时。反应液冷却至室温，减压浓缩后用硅胶柱色谱法以洗脱剂体系A纯化所得残留物，再用薄层色谱法以展开剂体系A纯化所得残留物，得到标题化合物29d(120mg，黄色固体)，产率：38.6％。
第三步
(2S)-3-(4-(4-(4-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)苯基)-1H-吡唑-1-基)丙烷-1,2-二醇29
将29d(120mg，0.234mmol)溶于4mL甲醇中，加入2mL 2N的盐酸，室温下搅拌反应3小时。反应液减压浓缩，用高效液相色谱法纯化所得残留物，得标题化合物29(95mg，桔黄色固体)，产率：79％。
MS m/z(ESI):474.5[M+1]
1H NMR(400MHz,DMSO-d6)δ9.59(s,1H),8.17(s,1H),8.12(s,1H),7.92(s,1H),7.65-7.83(m,6H),7.46(t,1H),6.24(s,1H),4.23(dd,1H),3.95-4.05(m,1H),3.80-3.86(m,1H),3.50-3.75(m,2H),3.25-3.50(m,4H),2.78-2.95(m,1H),2.00-2.30(m,2H),1.50-1.70(m,2H).
实施例30
(2R)-3-(4-(4-(4-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)苯基)-1H-吡唑-1-基)丙烷-1,2-二醇三氟乙酸盐
Figure PCTCN2016079054-appb-000059
Figure PCTCN2016079054-appb-000060
第一步
(R)-1-((2,2-二甲基-1,3-二氧戊环-4-基)甲基)-4-(4,4,5,5-四甲基l-1,3,2-二氧杂戊硼烷-2-基)-1H-吡唑30b
将29a(500mg，2.58mmol)溶于3mL N,N-二甲基甲酰胺中，室温下加入113mg的钠氢(60％)，室温搅拌反应20分钟，加入(S)-4-(氯甲基)-2,2-二甲基-1,3-二氧戊环30a(505mg，3.35mmol)，升温至100℃搅拌反应12小时。向反应液中加入0.5mL甲醇淬灭反应，减压浓缩除去N,N-二甲基甲酰胺，所得残余物中加入50mL乙酸乙酯和5mL水，分液，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗品标题化合物30b(400mg，黄色油状物)，产品不经纯化直接进行下一步反应。
第二步
5-(1-(4-(1-(((R)-2,2-二甲基1,3-二氧戊环-4-基)甲基)-1H-吡唑-4-基)苯基)哌啶-4-基)-6-氟-5H-咪唑并[5,1-a]异吲哚30c
将9a(100mg，0.242mmol)和粗品30b(223mg，0.726mmol)溶于5mL正丁醇中，加入磷酸钾(154mg，0.726mmol)，三(二亚苄基丙酮)二钯(22mg，0.0242mmol)，2-双环己基膦-2',4',6'-三异丙基联苯(46mg，0.0968mmol)，升温至100℃搅拌反应12小时。反应液冷却至室温，得到粗品标题化合物30c(150mg，棕黄色油状物)，产品不经纯化直接进行下一步反应。
第三步
(2R)-3-(4-(4-(4-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)苯基)-1H-吡唑-1-基)丙烷-1,2-二醇三氟乙酸盐30
将30c(150mg，0.292mmol)溶于5mL甲醇中，加入5mL 2N盐酸，室温下搅拌反应12小时。反应液减压浓缩后用高效液相色谱法纯化所得残留物，得标题化合物30(8mg，白色固体)，产率5.8％。
MS m/z(ESI):474.4[M+1]
1H NMR(400MHz,DMSO-d6)δ9.51(s,1H),8.07(s,1H),8.01(s,1H),7.75-7.80(m,2H),7.65-7.70(m,1H),7.40-7.55(m,3H),7.00-7.10(m,2H),6.15(s,1H),4.20(dd,1H),3.94-4.02(m,1H),3.60-3.85(m,3H),3.25-3.40(m,2H),2.70-3.02(m,2H),2.60-2.70(m,1H),1.82-1.90(m,1H),1.65-1.80(m,1H),1.30-1.40(m,1H),1.15-1.20(m,1H).
实施例31
6-氟-5-(1-(4-(1-(1-(甲基磺酰基)哌啶-4-基)-1H-吡唑-4-基)苯基)哌啶-4-基)-5H-咪唑并[5,1-a]异吲哚三氟乙酸盐
Figure PCTCN2016079054-appb-000061
第一步
4-(4-(4-(4-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)苯基)-1H-吡唑-1-基)哌啶-1-甲酸叔丁酯31b
将9a(250mg，0.606mmol)和4-(4-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)-1H-吡唑-1-基)哌啶-1-甲酸叔丁酯31a(343mg，0.91mmol，采用公知的方法“Bioorganic & Medicinal Chemistry,2013,21(21),6804-6820”制备而得)溶于5mL正丁醇中，加入磷酸钾(260mg，1.212mmol)，三(二亚苄基丙酮)二钯(17mg，0.018mmol)和2-双环己基膦-2',4',6'-三异丙基联苯(35mg，0.073mmol)，升温至100℃搅拌反应12小时。反应液冷却至室温，减压浓缩后用硅胶柱色谱法以洗脱剂体系A纯化所得残留物，得到标题化合物31b(160mg，黄色固体)，产率：45.3％。
第二步
6-氟-5-(1-(4-(1-(哌啶-4-基)-1H-吡唑-4-基)苯基)哌啶-4-基)-5H-咪唑并[5,1-a]异吲哚 31c
将31b(160mg，0.275mmol)溶于3mL二氯甲烷中，加入0.5mL三氟乙酸，室温下搅拌反应2小时。反应液减压浓缩，得粗品标题化合物31c(250mg，黄色油状物)，产品不经纯化直接进行下一步反应。
第三步
6-氟-5-(1-(4-(1-(1-(甲基磺酰基)哌啶-4-基)-1H-吡唑-4-基)苯基)哌啶-4-基)-5H-咪唑并[5,1-a]异吲哚三氟乙酸盐31
将粗品31c(125mg，0.138mmol)溶于3mL二氯甲烷中，加入0.5mL三氟乙酸和甲基磺酰氯(47mg，0.412mmol)，室温下搅拌反应2小时。反应液中加入10mL二氯甲烷和2mL水，分液，有机相减压浓缩，用高效液相色谱法纯化所得残留物，得标题化合物31(12mg，白色固体)，产率：12.9％。
MS m/z(ESI):561.5[M+1]
1H NMR(400MHz,DMSO-d6)δ9.47(s,1H),8.16(s,1H),8.05(s,1H),7.74-7.80(m,2H),7.63-7.70(m,1H),7.38-7.50(m,3H),6.96(d,2H),6.13(s,1H),4.25-4.34(m,1H),3.60-3.80(m,4H),2.90-3.00(m,5H),2.50-2.70(m,3H),2.10-2.20(m,2H),1.92-2.05(m,2H),1.81-1.85(m,1H),1.61-.165(m,1H),1.30-1.34(m,1H),1.00-1.15(m,1H).
实施例32
6-氟-5-(1-(4-(1-((R)-四氢呋喃-3-基)-1H-吡唑-4-基)苯基)哌啶-4-基)-5H-咪唑并[5,1-a]异吲哚三氟乙酸盐
Figure PCTCN2016079054-appb-000062
将9a(103mg，0.25mmol)和(R)-1-(四氢呋喃-3-基)-4-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)-1H-吡唑32a(99mg，0.375mmol，采用专利申请“WO201493647”公开的方法制备而得)溶于3mL正丁醇中，加入磷酸钾(106mg，0.5mmol)，三(二亚苄基丙酮)二钯(17mg，0.018mmol)和2-双环己基膦-2',4',6'-三异丙基联苯(36mg，0.075mmol)，升温至100℃反应12小时。反应液冷却至室温，垫硅藻土过滤，滤液减压浓缩，用高效液相色谱法纯化所得残留物，得到标题化合物32(55mg，白色固体)，产率：37.9％。
MS m/z(ESI):470.5[M+1]；
1H NMR(400MHz,DMSO-d6)δ9.49(s,1H),8.10(s,1H),8.06(s,1H),7.8(s,1H),7.76-7.78(m,1H),7.41-7.45(m,3H),6.97(d,2H),6.14(s,1H),4.98-5.00(m,1H),3.97-4.02(m,2H),3.89-3.92(m,1H),3.80-3.86(m,1H),3.73-3.76(m,1H),3.63-3.66(m,1H),2.75-2.85(m,1H),2.62-2.75(m,1H),2.53-2.59(m,1H),2.29-2.41(m,2H),1.82-1.85(m,1H),1.62-1.64(m,1H),1.31-1.34(m,1H),1.07-1.13(m,1H),0.85-0.87(m,1H).
实施例33
(1S,4s)-4-((R)-6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-N-(3-甲氧基苯基)环己基甲酰胺
Figure PCTCN2016079054-appb-000063
第一步
(1S,4s)-4-((R)-(2-溴-6-氟代苯基)(羟基)甲基)环己烷羧酸甲酯33b
将26.8mL的二异丙基氨基锂溶于50mL四氢呋喃中，冷却至-78℃，滴加预制的20mL 1a(7.2g，41.18mmol)的四氢呋喃溶液，搅拌反应1小时，再滴加预制的50mL(1r,4r)-4-甲酰基环己烷羧酸甲酯33a(7g，41.18mmol，采用专利申请“WO2013050334”公开的方法制备而得)的四氢呋喃溶液，搅拌反应2小时。向反应液中加入10mL甲醇淬灭反应，升至室温，加入100mL乙酸乙酯，用水洗涤(100mL)，无水硫酸钠干燥，过滤，滤液减压浓缩后用硅胶柱色谱法以洗脱剂体系B纯化所得残留物，得到标题化合物33b(6.8g，棕黄色油状物)，产率：47.9％。
第二步
(1S,4s)-4-((R)-(2-溴-6-氟苯基)((甲磺酰基)氧基)甲基)环己烷羧酸甲酯33c
将33b(6.8g，19.7mmol)溶于100mL二氯甲烷中，加入三乙胺(3.99g，39.4mmol)，再滴加甲基磺酰氯(2.48g，21.67mmol)，室温搅拌反应12小时。向反应液中加入50mL二氯甲烷，用饱和氯化钠溶液洗涤(100mL)，无水硫酸钠干燥，过滤，滤液减压浓缩后得到粗品标题化合物33c(8.33g，棕色油状物)，产品不经纯化直接进行下一步反应。
第三步
(1S,4s)-4-((R)-(2-溴-6-氟代苯基)(1H-咪唑-1-基)甲基)环己烷羧酸甲酯33d
将粗品33c(1.4g，3.3mmol)溶于5mL乙腈中，加入1H-咪唑(2.25g，33mmol)和N,N-二异丙基乙胺(4.26g，33mmol)，微波130℃反应45分钟。反应液冷却至室温，减压浓缩后用硅胶柱色谱法以洗脱剂体系B纯化所得残留物，得到标题化合物33d(2.8g，棕色油状物)，产率：35.95％。
第四步
(1S,4s)-4-((R)-6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)环己烷羧酸甲酯33e
将33d(2.8g，7.08mmol)溶于12mL N,N-二甲基甲酰胺中，加入N,N-二环己基甲基胺(2.2g，11.328mmol)，三苯基磷(743mg，2.8mmol)和醋酸钯(318mg，1.4mmol)，微波120℃反应1小时。反应液冷却至室温，减压浓缩后用硅胶柱色谱法以洗脱剂体系B纯化所得残留物，得到标题化合物33e(628mg，棕色固体)，产率：28.5％。
第五步
(1S,4s)-4-((R)-6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)环己烷羧酸33f
将33e(628mg，2mmol)溶于20mL甲醇中，加入5mL水，再加入氢氧化钠(400mg，10mmol)，室温搅拌反应12小时。减压浓缩除去反应液中的甲醇，所得残余物中加入30mL水，用乙酸乙酯萃取(50mL)，向水相滴加6M盐酸至pH为5-6，用二氯甲烷和甲醇(V/V＝5:1)的混合溶剂萃取(60mL×3)，合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩，得到标题化合物33f(600mg，棕色油状物)，产品不经纯化直接进行下一步反应。
第六步
(1S,4s)-4-((R)-6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-N-(3-甲氧基苯基)环己基甲酰胺33
将粗品33f(60mg，0.2mmol)溶于2mL N,N-二甲基甲酰胺中，加入3-甲氧基苯胺(25mg，0.2mmol)，1-羟基苯并三唑(32mg，0.24mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(46mg，0.24mmol)和N,N二异丙基乙胺(129mg，1mmol)，室温搅拌反应48小时。反应液用高效液相色谱法纯化，得到标题化合物33(13mg，白色固体)，产率：16.25％。
MS m/z(ESI):406.4[M+1]
1H NMR(400MHz,DMSO-d6)δ9.72(s,1H),7.97(s,1H),7.44-7.49(m,2H),7.26-7.3(m,1H),7.21(s,1H),7.11-7.18(m,2H),7.05-7.10(m,1H),6.56-6.59(m,1H),5.60(s,1H),3.69(s,3H),2.10-2.36(m,3H),1.69-1.92(m,3H),1.44-1.58(m,1H),1.28-1.43(m,2H),0.55-0.68(m,1H).
实施例34
6-氟-5-(1-(2-氟-4-(1-甲基-1H-吡唑-4-基)苯基)哌啶-4-基)-5H-咪唑并[5,1-a]异吲哚
Figure PCTCN2016079054-appb-000064
第一步
6-氟-5-(1-(2-氟-4-硝基苯)哌啶-4-基)-5H-咪唑并[5,1-a]异吲哚34a
将粗品1g(1.7g，3.51mmol)溶于20mL二甲基亚砜中，加入1,2-二氟-4-硝基苯(0.557g，3.51mmol)和三乙胺(1.42g，14.04mmol)，室温搅拌反应2.5小时。向反应液中加入150mL乙酸乙酯，用水洗涤(100mL×2)，有机相减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残留物，得到标题化合物34a(970mg，黄色固体)，产率：53.8％。
第二步
3-氟-4-(4-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)苯胺34b
将34a(970mg，2.45mmol)溶于20mL甲醇中，加入200mg 10％钯碳，反应体系用氢气置换三次，室温搅拌反应12小时。反应液减压浓缩，得到粗品标题化合物34b(920mg，黄色固体)，产品不经纯化直接进行下一步反应。
第三步
5-(1-(4-溴-2-氟苯基)哌啶-4-基)-6-氟-5H-咪唑并[5,1-a]异吲哚34c
将粗品34b(620mg，1.692mmol)溶于40％的氢溴酸溶液中，冷却至0-5℃，滴加1mL预制的亚硝酸钠(128mg，1.86mmol)溶液，滴加完毕后于0℃反应40分钟，将反应液倒入0℃的氢溴酸溶液中，升温至60℃反应2小时。向反应液中滴加入2N氢氧化钠溶液至pH为8-9，用乙酸乙酯萃取(100mL×2)，合并有机相依次用水(100mL)和饱和氯化钠溶液(100mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残留物，得到标题化合物34c(450mg，白色固体)，产率：61.8％。
第四步
6-氟-5-(1-(2-氟-4-(1-甲基-1H-吡唑-4-基)苯基)哌啶-4-基)-5H-咪唑并[5,1-a]异吲哚 34
将34c(200mg，0.465mmol)溶于11mL乙二醇二甲醚和水(V:V＝10:1)的混合溶剂中，加入1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)-1H-吡唑(145mg，0.697mml)，四三苯基膦钯(54mg，0.0465mmol)和碳酸钠(99mg，0.93mmol)，升温至80℃搅拌反应48小时。反应液冷却至室温，减压浓缩后用高效液相色谱法纯化所得残留物，得到标题化合物34(160mg，褐色固体)，产率：35％。
MS m/z(ESI):432.4[M+1]
1HNMR(400MHz,DMSO-d6)δ8.06(s,2H),7.80(s,1H),7.45-7.55(m,2H),7.22-7.40(m,3H),7.16-7.21(m,1H),6.97(t,1H),5.71(s,1H),3.83(s,3H),3.20-3.45(m,2H),2.68(t,1H),2.56(t,1H),2.35(t,1H),1.65-1.85(m,2H),1.14-1.25(m,1H),0.85-1.00(m,1H).
实施例35
6-氟-5-(1-(3-氟-4-(1-甲基-1H-吡唑-4-基)苯基)哌啶-4-基)-5H-咪唑并[5,1-a]异吲哚三氟乙酸盐
Figure PCTCN2016079054-appb-000065
第一步
4-(4-溴-2-氟苯基)-1-甲基-1H-吡唑35b
将4-氟-2-溴-1碘苯35a(301mg，1mmol)溶于3mL二甲基亚砜中，加入1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)-1H-吡唑(139mg,0.67mmol)，[1,1'-双(二苯基膦基)二茂铁]二氯化钯(49mg，0.067mmol)，醋酸钾(66mg，0.67mmol)和碳酸铯(650mg，2.01mmol)，升温至80℃搅拌反应1小时。反应液冷却至室温，加入350mL水，用乙酸乙酯萃取(60mL×3)，合并有机相，用水洗涤(120mL×2)，饱和氯化钠溶液洗涤(60mL)，无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗品标题化合物35b(170mg，棕褐色固体)，产品不经纯化直接进行下一步反 应。
第二步
6-氟-5-(1-(3-氟-4-(1-甲基-1H-吡唑-4-基)苯基)哌啶-4-基)-5H-咪唑并[5,1-a]异吲哚三氟乙酸盐35
将粗品1g(200mg，0.41mmol)溶于10mL甲苯中，加入粗品35b(170mg，0.67mmol)，三(二亚苄基丙酮)二钯(61mg，0.067mmol)，(±)-2,2'-双-(二苯膦基)-1,1'-联萘(442mg，0.067mmol)和叔丁醇钠(257mg，2.68mmol)，升温至80℃搅拌反应12小时。反应液冷却至室温，加入30mL水，用二氯甲烷萃取(30mL×3)，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残留物，得到标题化合物35(5mg，白色固体)，产率2.8％
MS m/z(ESI):432.3[M+1]
实施例36
4-(5-(4-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)-1,3,4-噻二唑-2-基)吡啶-2-胺三氟乙酸盐
Figure PCTCN2016079054-appb-000066
第一步
2-(4-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)-1,3,4-噻二唑36a
将粗品1g(4.85g，10.0mmol)，2-溴-1,3,4-噻二唑(1.65g，10.0mmol)和三乙胺(10.1g，100.0mmol)加入20mL二甲基亚砜中，升温至120℃封管反应12小时。反应液冷却至室温，加入200mL二氯甲烷，用水(200mL×3)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残留物，得到标题化合物36a(1.09g，浅棕色固体)，产率：31.9％。
第二步
2-(4-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)-5-(2-氟吡啶-4-基)-1,3,4-噻二唑36b
将36a(800mg，2.34mmol)，4-溴-2-氟吡啶(824mg，4.68mmol)和醋酸钯(76mg，0.334mmol)，三(叔丁基)磷(1.35g，0.668mmol)，碳酸铯(1.52g，4.68mmol)加入10mL N,N-二甲基甲酰胺中，升温至150℃搅拌反应4小时。反应液冷却至室温，加入150mL二氯甲烷，用水(100mL×3)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残留物，得到标题化合物36b(260mg，棕色固体)，产率：25.5％。
第三步
4-(5-(4-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)-1,3,4-噻二唑-2-基)-N-(4-甲氧基苯基)吡啶-2-胺36c
将36b(260mg，0.60mmol)溶于3mL二甲基亚砜中，加入(4-甲氧基苯基)甲胺(823mg，6.0mmol)，升温至130℃搅拌反应4小时。反应液冷却至室温，加入100mL二氯甲烷，用水(100mL×3)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残留物，得到标题化合物36c(130mg，浅棕色固体)，产率：39.1％。
第四步
4-(5-(4-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)-1,3,4-噻二唑-2-基)吡啶-2-胺三氟乙酸盐36
将36c(130mg，0.235mmol)溶于5mL三氟乙酸中，升温至60℃搅拌反应4小时。反应液冷却至室温，减压浓缩后用高效液相色谱法纯化所得残留物，得到标题化合物36(30mg，浅棕色固体)，产率：23.4％。
MS m/z(LC-MS):434.3[M+1]
实施例37
6-氟-5-(1-(5-((1-(甲基磺酰基)哌啶-3-基)氧基)嘧啶-2-基)哌啶-4-基-5H-咪唑并[5,1-a]异吲哚三氟乙酸盐
Figure PCTCN2016079054-appb-000067
Figure PCTCN2016079054-appb-000068
第一步
5-(1-(5-(苄氧基)嘧啶-2-基)哌啶-4-基)-6-氟-5H-咪唑并[5,1-a]异吲哚37a
将粗品17a(1.5g，5.83mmol)，5-(苄氧基)-2-氯嘧啶37a(1.29g，5.83mmol)溶于10mL N,N-二甲基乙酰胺中，加入N,N-二异丙基乙胺(3.76g，29.1mmol)，于150℃微波反应1小时。反应液冷却至室温，过滤，滤液中加入100mL乙酸乙酯和50mL水，分液，有机相用水和饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残留物，得到标题化合物37a(600mg，棕色油状物)，产率：40％。
第二步
2-(4-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)嘧啶-5-醇37c
将37a(600mg，1.36mmol)溶于15mL甲醇中，加入120mg钯碳(10％)，用氢气置换三次，搅拌反应3小时。反应液过滤除去钯碳，滤液减压浓缩，得到粗品标题化合物37c(455mg，黄色固体)，产品不经纯化直接进行下一步反应。
第三步
3-((2-(4-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)嘧啶-5-基)氧基)哌啶-1-甲酸叔丁酯37d
将粗品37c(200mg，0.57mmol)，3-羟基哌啶-1-甲酸叔丁酯(114mg，0.57mmol)，偶氮二甲酸二异丙酯(162mg，0.856mmol)，三苯基膦(224mg，0.856mmol)溶于5mL四氢呋喃中，室温下搅拌反应12小时。反应液减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残留物，得到标题化合物37d(100mg，浅棕色固体)，产率：33.1％。
第四步
6-氟-5-(1-(5-((1-(甲基磺酰基)哌啶-3-基)氧基)嘧啶-2-基)哌啶-4-基-5H-咪唑并[5,1-a] 异吲哚三氟乙酸盐37
将37d(38mg，0.087mmol)溶于5mL二氯甲烷中，加入0.25mL三氟乙酸和11滴甲磺酰氯，室温搅拌反应12小时。反应液减压浓缩，用高效液相色谱法纯化所得残留物，得到标题化合物37(14mg，白色固体)，产率：20％。
MS m/z(ESI):513.3[M+1]
实施例38
6-氟-5-(1-(4-((四氢呋喃-3-基)氧基)苯基)哌啶-4-基)-5H-咪唑并[5,1-a]异吲哚
Figure PCTCN2016079054-appb-000069
第一步
4-(4-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)苯酚38b
将1g(5.82g，12mmol)和1,4-环己烷二酮38a(1.61g，14.4mmol)溶于40mL乙醇中，加入三乙胺(2.424g，24mmol)和200mg钯碳(10％)，升温至85℃搅拌反应12小时。反应液冷却至室温，加入水，用二氯甲烷萃取(50mL×3)，合并有机相，用饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得粗品标题产物38b(4.19g，棕色固体)，产品不经纯化直接进行下一步反应。
第二步
6-氟-5-(1-(4-((四氢呋喃-3-基)氧基)苯基)哌啶-4-基)-5H-咪唑并[5,1-a]异吲哚38
将粗品38b(349mg，1mmol)溶于5mL乙醇中，加入四氢呋喃-3-甲磺酸38c(333mg，2mmol，采用专利申请“WO2014049133”公开的方法制备而得)和碳酸钾(420mg，3mmol)，微波125℃反应1小时。反应液冷却至室温，过滤，滤液减压浓缩，向所得残余物中加入水，用二氯甲烷萃取(20mL×3)，合并有机相，用饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩用高效液相色谱法纯化所得残余物，得到标题化合物38(20mg，淡黄色固体)，产率：4.8％。
MS m/z(ESI):420.5[M+1]
实施例39
6-氟-5-(1-(4-((1-(甲磺酰基)哌啶-4-基)氧基)苯基)哌啶-4-基)-5H-咪唑并[5,1-a]异吲哚
Figure PCTCN2016079054-appb-000070
第一步
4-(4-碘代苯氧基)-1-(甲磺酰基)哌啶39b
将4-(4-碘代苯氧基)哌啶39a(600mg，2mmol，采用专利申“WO2004089373”公开的方法制备而得)溶于15mL二氯甲烷中，加入三乙胺(404mg，4mmol)，再滴加入甲磺酰氯(273.6mg，2.4mmol)，室温搅拌反应1小时。反应液中加入水，用乙酸乙酯萃取(20mL×3)，合并有机相，用饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得到粗品标题化合物39b(100mg，淡黄色固体)，产品不经纯化直接进行下一步反应。
第二步
6-氟-5-(1-(4-((1-(甲磺酰基)哌啶-4-基)氧基)苯基)哌啶-4-基)-5H-咪唑并[5,1-a]异吲哚39
将粗品39b(114mg，0.3mmol)和1g(122mg，0.25mmol)溶于5mL甲苯中，加入三(二亚苄基丙酮)二钯(22.9mg，0.025mmol)，2-二环己基磷-2,4,6-三异丙基联苯(12mg，0.025mmol)和叔丁醇钠(36mg，0.375mmol)，微波156℃反应40分钟。反应液冷却至室温，用高效液相色谱法纯化所得残余物，得到标题化合物39(10mg，淡黄色固体)，产率：7.8％。
MS m/z(ESI):511.6[M+1]
实施例40，41
(R)-2-(4-(4-(4-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)苯基)-1H-吡唑-1-基)乙醇40
(S)-2-(4-(4-(4-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)苯基)-1H-吡唑-1-基)乙 醇41
Figure PCTCN2016079054-appb-000071
第一步
Figure PCTCN2016079054-appb-000072
6-氟-5-(1-(4-(1-(2-((四氢-2H-吡喃-2-基)氧基)乙基)-1H-吡唑-4-基)苯基)哌啶-4-基)-5H-咪唑并[5,1-a]异吲哚40b
将4-(4-溴苯基)-1-(2-((四氢-2H-吡喃-2-基)氧基)乙基)-1H-吡唑40a(14.8g，42mmol)，6-氟-5-(哌啶-4-基)-5H-咪唑并[5,1-a]异吲哚17a(13.9g，42mmol)加入300mL N,N-二甲基甲酰胺中，加入四氟硼酸三叔丁基膦(1.863g，64.5mmol)和磷酸钾(35g，168mmol)，氩气置换三次。加入三(二亚苄基丙酮)二钯(2.92g，3.19mmol)，氩气置换一次，反应液升温至110℃，搅拌反应2小时。反应结束后，将反应液过滤，滤液减压浓缩除去N,N-二甲基甲酰胺，用硅胶柱色谱法以洗脱剂体系A纯化所得残留物，得到化合物40b(6.38g，灰色油状物)，产率：29％。
MS m/z(LC-MS):528.3[M+1]
第二步
Figure PCTCN2016079054-appb-000073
2-(4-(4-(4-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)苯基)-1H-吡唑-1-基)乙醇40c
将化合物40b(9g，17.1mmol)溶于100mL甲醇中，加入5.7mL浓盐酸(12M)，反应液升至45℃，搅拌反应1小时。反应结束后，将反应液冷却至室温，加入饱和碳酸钠调反应液pH为8，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残留物，得到化合物40c(5.2g，黄色固体)，产率：65％。
MS m/z(LC-MS):444.4[M+1]
第三步
Figure PCTCN2016079054-appb-000074
(R)-2-(4-(4-(4-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)苯基)-1H-吡唑-1-基)乙醇40
(S)-2-(4-(4-(4-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)苯基)-1H-吡唑-1-基)乙醇41
将化合物40c(1.4g,3.16mmol)进行手性制备(分离条件：手性制备柱Superchiral S-AS(Chiralway),2cm I.D.*25cm Length,5um；流动相：CO2/MeOH/DEA＝60/40/0.05(v/v)，流速：50mL/min)，收集其相应组分，减压浓缩，得到化合物40(630mg，黄色固体)和化合物41(652mg，黄色固体)。
40：
MS m/z(ESI):444.5[M+1]；
手性HPLC分析:保留时间3.064分钟，手性纯度：97.79％(色谱柱：Superchiral S-AS(Chiralway),0.46cm I.D.*25cm Length,5um；流动相：CO2/MeOH/DEA＝60/40/0.05(v/v)
1H NMR(400MHz,DMSO-d6)δ9.97(s,2H),7.73(s,1H),7.44-7.51(m,2H),7.36(d,2H),7.22(s,1H),7.10-7.19(m,1H),6.87(d,2H),5.70(d,1H),4.91(t,1H),4.12(t,2H),3.70-3.79(m,3H),3.62(d,1H),2.62-2.73(m,1H),2.52-2.58(m,1H),2.31-2.43(m,1H),1.55-1.83(m,2H),1.13-1.23(m,1H),0.82-0.96(m,1H).
41：
MS m/z(ESI):444.5[M+1]；
手性HPLC分析:保留时间4.280分钟，手性纯度：99.52％。(色谱柱：Superchiral S-AS(Chiralway),0.46cm I.D.*25cm Length,5um；流动相：CO2/MeOH/DEA＝60/40/0.05(v/v)
1H NMR(400MHz,DMSO-d6)δ9.97(s,2H),7.73(s,1H),7.44-7.51(m,2H),7.36(d,2H),7.22(s,1H),7.10-7.19(m,1H),6.87(d,2H),5.70(d,1H),4.91(t,1H),4.12(t,2H),3.70-3.79(m,3H),3.62(d,1H),2.62-2.73(m,1H),2.52-2.58(m,1H),2.31-2.43(m,1H),1.55-1.83(m,2H),1.13-1.23(m,1H),0.82-0.96(m,1H).
实施例42
6-氟-5-(1-(4-(1-(2-甲氧基乙基)-1H-吡唑4-基)苯基)哌啶-4-基)-5H-咪唑并[5,1-a]异吲哚三氟乙酸盐
Figure PCTCN2016079054-appb-000075
将9a(100mg，0.242mmol)和1-(2-甲氧基乙基)-4-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)-1H-吡唑42a(91mg，0.363mmol，采用专利申“WO2014015088”公开的方法制备而得)溶于5mL正丁醇中，加入三(二亚苄基丙酮)二钯(13mg，0.0142mmol)，2-二环己基磷-2,4,6-三异丙基联苯(28mg，0.0581mmol)和磷酸钾(154mg，0.726mmol)，升温至100℃搅拌反应2小时。反应液冷却至室温，用高效液相色谱法纯化所得残余物，得到标题化合物42(8mg，白色固体)，产率：5.8％。
MS m/z(ESI):458.4[M+1]
实施例43
N-(2-(4-(4-(4-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)苯基)-1H-吡唑-1-基)乙基)乙酰胺三氟乙酸盐
Figure PCTCN2016079054-appb-000076
Figure PCTCN2016079054-appb-000077
第一步
(2-(4-(4-(4-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)苯基)-1H-吡唑-1-基)乙基)氨基甲酸叔丁酯43b
将9a(100mg，0.243mmol)溶于3mL正丁醇中，加入(2-(4-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)-1H-吡唑-1-基)乙基)氨基甲酸叔丁酯43a(123mg，0.364mmol，采用专利申请“CN103087050”公开的方法制备而得)，三(二亚苄基丙酮)二钯(11mg，0.0122mmol)，2-双环己基膦-2',4',6'-三异丙基联苯(23mg，0.0486mmol)和磷酸钾(103mg，0.486mmol)，升温至100℃搅拌反应2小时。反应液冷却至室温，减压浓缩后用硅胶柱色谱法以洗脱剂体系A纯化所得残留物，得到标题化合物43b(50mg，黄色固体)，产率：38％。
第二步
2-(4-(4-(4-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)苯基)-1H-吡唑-1-基)乙胺43c
将43b(50mg，0.092mmol)溶于3mL二氯甲烷中，加入0.5mL三氟乙酸，室温搅拌反应2小时。反应液减压浓缩后所得残余物，得到粗品标题化合物43c(60mg，棕色油状物)，产品不经纯化直接进行下一步反应。
第三步
N-(2-(4-(4-(4-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)苯基)-1H-吡唑-1-基)乙基)乙酰胺三氟乙酸盐43
将粗品43c(60mg，0.092mmol)溶于二氯甲烷中，加入乙酰氯(14mg，0.184mmol)和三乙胺(28mg，0.276mmol)，室温搅拌反应3小时。反应液减压浓缩后用高效液相色谱法纯化所得残余物，得到标题化合物43(7mg，灰白色固体)，产率：13％。
MS m/z(ESI):485.5[M+1]；
1H NMR(400MHz,DMSO-d6)δ9.51(s,1H),8.00-8.20(m,3H),7.75-7.95(m,2H),7.64-7.73(m,1H),7.40-7.60(m,3H),7.00-7.18(m,2H),6.16(s,1H),4.14(t,2H),3.72(d,1H),3.62(d,1H),3.41-3.46(m,2H),2.70-3.00(m,2H),2.55-2.70(m,1H),1.60-1.90(m,5H),1.30-1.40(m,1H),1.10-1.20(m,1H).
实施例44
6-氟-5-(1-(4-(1-((R)-四氢呋喃-3-基)-1H-吡唑-4-基)苯基)哌啶-4-基)-5H-咪唑并[5,1-a]异吲哚三氟乙酸盐
Figure PCTCN2016079054-appb-000078
将9a(103mg，0.25mmol)溶于3mL正丁醇中，加入(S)-1-(四氢呋喃-3-基)-4-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)-1H-吡唑44a(99mg，0.375mmol，采用专利申请“US20080167287”公开的方法制备而得)，三(二亚苄基丙酮)二钯(17mg，0.01875mmol)，2-双环己基膦-2',4',6'-三异丙基联苯(36mg，0.075mmol)和磷酸钾(106mg，0.5mmol)，升温至100℃搅拌反应2小时。反应液冷却至室温，用硅藻土过滤除去不溶物，滤液减压浓缩后用高效液相色谱法纯化所得残余物，得到标题化合物44(30mg，白色固体)，产率：40.3％。
MS m/z(ESI):470.5[M+1]；
1H NMR(400MHz,DMSO-d6)δ9.49(s,1H),8.10(s,1H),8.06(s,1H),7.8(s,1H),7.76-7.78(m,1H),7.41-7.45(m,3H),6.97(d,2H),6.14(s,1H),4.98-5.00(m,1H),3.97-4.02(m,2H),3.89-3.92(m,1H),3.80-3.86(m,1H),3.73-3.76(m,1H),3.63-3.66(m,1H),2.75-2.85(m,1H),2.62-2.75(m,1H),2.53-2.59(m,1H),2.29-2.41(m,2H),1.82-1.85(m,1H),1.62-1.64(m,1H),1.31-1.34(m,1H),1.07-1.13(m,1H),0.85-0.87(m,1H).
实施例45
2-氟-4-(4-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)苯甲腈
Figure PCTCN2016079054-appb-000079
将17a(500mg，1.94mmol)，2,4-二氟苯甲腈45a(270mg，1.94mmol)和三乙 胺(216mg，2.14mmol)溶于5mL二甲亚砜中，升温至80℃搅拌反应12小时。反应液冷却至室温，用高效液相色谱法纯化所得残余物，得到标题化合物45(190mg，浅棕色固体)，产率：26％。
MS m/z(ESI):377.1[M+1]
1H NMR(400MHz,DMSO-d6)δ8.1(s,1H),7.74(dd,1H),7.46-7.49(m,2H),7.24(s,1H),7.17-7.12(m,1H),6.96(dd,1H),6.88(td,1H),5.72(s,1H),3.49-3.59(m,2H),2.88(t,1H),2.73(t,1H),2.37-3.43(m,1H),1.76-1.84(m,1H),1.61-1.71(m,1H),1.20-1.29(m,1H),0.91-1.01(m,1H).
实施例46
5-(1-(3,4-二氟苯基)哌啶-4-基)-6-氟-5H-咪唑并[5,1-a]异吲哚
Figure PCTCN2016079054-appb-000080
第一步
6-氟-5-(哌啶-4-基)-5H-咪唑并[5,1-a]异吲哚盐酸盐46a
将1f(17.7g，49.6mmol)溶于180mL二氯甲烷和1,4-二氧六环(V/V＝5:1)的混合溶剂中，冰浴冷却后，滴加41.2mL浓盐酸，室温搅拌反应2小时。反应液减压浓缩后所得残余物，得到粗品标题化合物46a(16.37g，白色固体)，产品不经纯化直接进行下一步反应。
第二步
5-(1-(3,4-二氟苯基)哌啶-4-基)-6-氟-5H-咪唑并[5,1-a]异吲哚46
将粗品46a(165mg，0.5mmol)，4-溴-1,2-二氟苯46b(116mg，0.6mmol)溶于6mL甲苯和叔丁醇(V/V＝5:1)的混合溶剂中，加入醋酸钯(11.22mg，0.05mmol)，2-二环己基磷-2,4,6-三异丙基联苯(24mg，0.05mmol)和叔丁醇钠(200mg，2mmol)，微波160℃反应0.5小时。反应液冷却至室温，减压浓缩后用高效液相色谱法纯化所得残余物，得到标题化合物46(10mg，白色固体)，产率：5.4％。
MS m/z(ESI):370.4[M+1]
1H NMR(400MHz,CDCl3)δ7.72(s,1H),7.34(dd,1H),7.22-7.26(m,2H),6.96(s,2H),6.54-6.65(m,2H),5.57(dd,1H),3.49-3.59(m,2H),2.61(t,1H),2.58(t,1H),2.54(m,1H),1.76-1.84(m,1H),1.61-1.71(m,1H),1.20-1.29(m,1H),0.91-1.01(m,1H).
实施例47
5-(1-(5-氯代吡啶-2-基)哌啶-4-基)-6-氟-5H-咪唑并[5,1-a]异吲哚
Figure PCTCN2016079054-appb-000081
将粗品46a(500mg，1.52mmol)和2,5-二氯吡啶47a(292mg，1.97mmol)溶于10mL二甲亚砜中，加入N,N-二异丙基乙胺(980mg，7.6mmol)，微波140℃反应3.5小时。反应液冷却至室温，用高效液相色谱法纯化所得残余物，得到标题化合物47(105mg，橙黄色固体)，产率：18.7％。
MS m/z(ESI):369.8[M+1]
1H NMR(400MHz,DMSO-d6):δ8.05-8.04(d,1H),7.97(s,1H),7.54-7.51(dd,1H),7.48-7.46(m,2H),7.23(s,1H),7.17-7.12(m,1H),6.81-6.79(d,1H),6.70-6.69(d,1H),4.39-4.36(d,1H),4.22-4.19(d,1H),2.85-2.79(m,1H),2.72-2.66(m,1H),1.54-1.45(m,1H),1.30-1.24(m,2H),1.97-1.14(m,2H).
生物学评价
以下结合测试例进一步描述解释本发明，但这些实施例并非意味着限制本发明的范围。
测试例1、本发明化合物对人源IDO1蛋白酶抑制活性的测定
体外人源IDO1蛋白酶活性通过以下的方法进行测试。
该方法用来测定本发明中的化合物对人源IDO1蛋白酶活性的抑制作用。
一、实验材料及仪器
1、酶标仪(Synergy HT,BIOTEK)
2、色氨酸(T0254-5G,Sigma-Aldrich)
3、过氧化氢酶来源于牛肝脏(C1345-1G,Sigma-Aldrich)
4、亚甲蓝(M9140-25G,Sigma-Aldrich)
5、L-抗坏血酸钠(A7631-25G,Sigma-Aldrich)
6、4-(二甲基氨基)苯甲醛(D2004-25G,Sigma-Aldrich)
7、三氯乙酸(T9159-100G,Sigma-Aldrich)
8、人源IDO1基因(SC126221,Origene)
二、实验步骤
IDO1蛋白酶的自制
将人源IDO1基因通过基因克隆技术转入到Pet30a质粒中，然后转入感受态的大肠杆菌rosseta；在液态LB(Luria-Bertani)培养基[根据《分子克隆实验指南》(J.萨姆布鲁克D.W.拉塞尔著)配制每升培养基]中放大培养，收集菌体，超声破碎，通过挂柱，洗脱得到纯化的IDO1蛋白酶。
化合物测试实验：
用50mM的KPB将24μl的酶(IDO1)100倍稀释至2400μl，浓度为2.6ng/μl的酶溶液，在96孔反应板(AXYGEN，PCR-96-FLT-C)(以下简称反应板)每孔加入加入24μl酶溶液。空白孔加入24μl KPB[KPB缓冲液的配制(50mM)：用分析天平称取KH2PO4 6.805g放入1000ml的烧杯，用量筒加入去离子水至900ml，用1M的KOH调整PH至6.5，将其导入1L的量筒内，补水至1L即可。4℃储存]。在反应板加入1μl的化合物或DMSO到对应的反应孔中。准备A液：取200μl 500mML-抗坏血酸钠加1050μl KPB，涡轮混合器最大速度混匀3秒。B液：100μl 10mM色氨的酸加100μl 100000unit/ml的过氧化氢酶，加5μl 10mM的亚甲蓝，最后加1050μl KPB，涡轮混合器最大速度混匀3秒。取1200μl A液与1200μl B液，在涡轮混合器上最大速度混匀3秒。然后将此混合液以每孔24μl加入反应板中。将反应板放入板式离心机最高速度离心15秒，使反应液体都汇聚到底部，振荡器混匀30秒，在恒温孵育箱内，37℃，孵育1h。在反应板中，每孔加入10μl 30％(W/V)三氯乙酸每孔，在孵育箱内65℃孵育15分钟。将反应板在离心机上4700RPM离心，室温，5分钟。用排枪从反应板中转移40μl上清液到对应96孔测试板(Corning，#3599)中。每孔加入40μl 2％(W/V)的4-(二甲基氨基)苯甲醛/冰醋酸溶液，在振荡器上最大速度，混匀1分钟。在室温孵育2分钟后，在Synergy HT(BIOTEK)上读取480nm处的吸光值。
本发明中化合物对人源IDO1蛋白酶抑制活性通过以上的试验进行测定，测得的IC50值见表1。
表1 本发明中化合物对人源IDO1蛋白酶活性抑制IC50
实施例编号 IC50(nM)
1 87.40
3 71.74
4 96.21
5 81.17
8 78.84
9 25.69
11 73.17
12 68.71
18 34.02
22 56.93
23 48.16
28 5.17
29 35.86
30 58.75
31 14.22
32 32.98
33 36.06
34 15.81
35 7.65
36 10.55
37 17.83
38 28.10
39 15.51
41 9.22
42 36.31
43 63.33
44 16.59
45 8.84
46 6.68
47 7.23
结论：本发明化合物对人源IDO1蛋白酶活性具有明显的抑制作用。
测试例2、本发明化合物对人源TDO蛋白酶抑制活性的测定
体外人源TDO蛋白酶活性通过以下的方法进行测试。
该方法用来测定本发明中的化合物对人源TDO蛋白酶活性的抑制作用。
一、实验材料及仪器
1、酶标仪(Synergy HT,BIOTEK)
2、色氨酸(T0254-5G,Sigma-Aldrich)
3、过氧化氢酶来源于牛肝脏(C1345-1G,Sigma-Aldrich)
4、亚甲蓝(M9140-25G,Sigma-Aldrich)
5、L-抗坏血酸钠(A7631-25G,Sigma-Aldrich)
6、4-(二甲基氨基)苯甲醛(D2004-25G,Sigma-Aldrich)
7、三氯乙酸(T9159-100G,Sigma-Aldrich)
8、人源TDO(U32989.1,苏州金唯智生物科技有限公司)
9、Rosseta(CW0811A,北京康为世纪生物科技有限公司)
10、涡轮混合器(6776,Corning)
11、迷你板式离心机(Mini-P25,ABSON life science equipment)
二、实验步骤
TDO蛋白酶的自制
将构建好的含人源TDO基因的质粒，转入感受态的大肠杆菌Rosseta；在液态LB(Luria-Bertani)培养基[根据《分子克隆实验指南》(J.萨姆布鲁克D.W.拉塞尔著)配制每升培养基]中放大培养，收集菌体，超声破碎，通过挂柱，洗脱得到纯化的TDO1蛋白酶。
化合物测试实验：
用50mM的KPB将24μl的酶(TDO)100倍稀释至2400μl，浓度为2.6ng/μl的酶溶液，在96孔反应板(AXYGEN，PCR-96-FLT-C)(以下简称反应板)每孔加入加入24μl酶溶液。空白孔加入24μl KPB缓冲液[KPB缓冲液的配制(50mM)：用分析天平称取KH2PO4 6.805g放入1000ml的烧杯，用量筒加入去离子水至900ml，用1M的KOH调整PH至6.5，将其导入1L的量筒内，补水至1L即可。4℃储存]。在反应板加入1μl的化合物或DMSO到对应的反应孔中。准备A液：取200μl 500mM L-抗坏血酸钠加1050μl KPB，涡轮混合器最大速度混匀3秒。B液：100μl 10mM色氨的酸加100μl 100000unit/ml的过氧化氢酶，加5μl 10mM的亚甲蓝，最后加1050μl KPB，涡轮混合器最大速度混匀3秒。取1200μl A液与1200μl B液，在涡轮混合器上最大速度混匀3秒。然后将此混合液以每孔24μl加入反应板中。将反应板放入板式离心机最高速度离心15秒，使反应液体都汇聚到底部，振荡器混匀30秒，在恒温孵育箱内，37℃，孵育1h。在反应板中，每孔加入10μl30％(W/V)三氯乙酸，在孵育箱内65℃孵育15分钟。将反应板在离心机上4700RPM离心，室温，5分钟。用排枪从反应板中转移40μl上清液到对应96孔测试板(Corning，#3599)中。每孔加入40μl 2％(W/V)的4-(二甲基氨基)苯甲醛/冰醋酸溶液，在振荡器上最大速度，混匀1分钟。在室温孵育2分钟后，在Synergy HT Reader上读取480nm处的吸光值。
本发明中化合物对人源TDO蛋白酶抑制活性通过以上的试验进行测定，测得的IC50值见表2。
表2 本发明中化合物对人源TDO蛋白酶活性抑制IC50
实施例编号 IC50(nM)
1 338.4
2 214.9
3 370.9
5 393.7
6 393.9
9 131.7
18 361.2
23 399.0
25 256.6
28 30.6
29 219.8
30 318.7
31 103.5
32 296.5
33 184.0
34 142.6
35 64.6
36 104.4
39 243.1
41 42.0
42 217.1
43 247.3
44 202.5
45 234.4
46 68.9
47 194.9
结论：本发明化合物对人源TDO蛋白酶活性具有明显的抑制作用。
测试例3、本发明化合物对HeLa细胞内IDO蛋白酶抑制活性的测定
HeLa细胞内IDO蛋白酶活性通过以下的方法进行测试。
该方法用来测定本发明中的化合物对HeLa细胞内IDO蛋白酶活性的抑制作用。(注：HeLa细胞株在干扰素伽马(INF-γ)的诱导下表达吲哚胺2,3-双加氧酶(IDO))
一、实验材料及仪器
1、酶标仪(Synergy HT,BIOTEK)
2、色氨酸(T0254-5G,Sigma-Aldrich)
3、4-(二甲基氨基)苯甲醛(D2004-25G,Sigma-Aldrich)
4、三氯乙酸(T9159-100G,Sigma-Aldrich)
5、HeLa细胞株(CCL-2,ATCC)
二、实验步骤
用新鲜细胞培养基制取HeLa细胞悬液，以10000个细胞/孔加入100μl培养体系的96孔细胞培养板中，5％二氧化碳37℃培养24小时。去除上清，先每孔加入90μl无血清DMEM高糖培养基；然后每孔分别加入10μl配制在含INF-γ和色氨酸的培养基中的化合物(其终浓度为：10000，1000，100，10，1，0.1nM)，48小时5％二氧化碳37℃培养取出96孔细胞培养板中上清80μl至96孔圆底板中，每孔加入16μl 30％(W/V)三氯乙酸每孔，在孵育箱内65℃孵育25分钟。将反应板在离心机上4700RPM离心，5分钟。用排枪从反应板中转移50μl上清液到96孔平底透明板中，然后每孔加入50μl 2％(W/V)的4-(二甲基氨基)苯甲醛/冰醋酸溶液，在振荡器上混匀1分钟。在室温孵育2分钟后，在Synergy HT Reader 上读取480nm处的吸光值。
本发明中化合物对HeLa细胞内IDO蛋白酶抑制活性通过以上的试验进行测定，测得的IC50值见表3。
表3 本发明中化合物对HeLa细胞内IDO蛋白酶活性抑制IC50
实施例编号 IC50(nM)
3 167.1
4 187.6
5 353.1
8 252.9
9 100.9
11 477.3
12 70.57
15 199.2
16 260.3
18 197.8
21 477
22 129.8
23 438.9
28 85.16
29 292.4
30 333.8
32 225
33 47.23
34 29.34
35 69.06
36 27.76
37 113.8
38 150.7
39 198.3
41 47.7
42 253.8
43 171.1
44 174.7
45 231
46 69.1
47 88.3
结论：本发明化合物对HeLa细胞内IDO蛋白酶活性具有明显的抑制作用。
药代动力学评价
测试例4、本发明实施例3和9化合物的药代动力学测试
1、摘要
以SD大鼠为受试动物，应用LC/MS/MS法测定了大鼠灌胃给予实施例3和9化合物后不同时刻血浆中的药物浓度。研究本发明化合物在大鼠体内的药代动力学行为，评价其药动学特征。
2、试验方案
2.1 试验药品
实施例3和9化合物
2.2 试验动物
健康成年SD大鼠8只，雌雄各半，购自上海西普尔-必凯实验动物有限公司，动物生产许可证号：SCXK(沪)2008-0016。
2.3 药物配制
称取适量样品，加入0.5％ CMC-Na，超声制成0.5mg/ml混悬液。
2.4 给药
SD大鼠8只，雌雄各半，平均分成2组；禁食一夜后分别灌胃给药，给药体积10ml/kg。
3、操作
灌胃给药组于给药前及给药后0.5、1.0、2.0、4.0、6.0、8.0、11.0、24.0h由眼眶采血0.2ml，置于肝素化试管中，3500rpm离心10min分离血浆，于-20℃保存，给药后2h进食。
用LC/MS/MS法测定不同化合物灌胃给药后大鼠血浆中的待测化合物含量。
4、药代动力学参数结果
本发明实施例3和9化合物的药代动力学参数如下：
Figure PCTCN2016079054-appb-000082
结论：本发明化合物的药代吸收良好，具有明显的药代吸收效果。
测试例5、本发明实施例28和41化合物的药代动力学测试
1、摘要
以c57bl/6小鼠为受试动物，应用LC/MS/MS法测定了c57bl/6小鼠灌胃给予实施例28和41化合物后不同时刻血浆中的药物浓度。研究本发明化合物在c57bl/6小鼠体内的药代动力学行为，评价其药动学特征。
2、试验方案
2.1 试验药品
实施例28和41化合物
2.2 试验动物
c57bl/6小鼠18只，雌性，购自上海西普尔-必凯实验动物有限公司。
2.3 药物配制
称取适量样品，加入0.5％CMC-Na，超声制成1mg/ml混悬液。
2.4 给药
c57bl/6小鼠18只，雌性，平均分成2组，9只/组；禁食一夜后分别灌胃给药，给药体积0.2ml/kg。
3、操作
灌胃给药组于给药后0.5,1.0,2.0,4.0,6.0,8.0,11.0,24.0h采血0.2ml，置于肝素化试管中，3500rpm离心10min分离血浆，于-20℃保存。
用LC/MS/MS法测定不同化合物灌胃给药后大鼠血浆中的待测化合物含量。
4、药代动力学参数结果
本发明实施例28和41化合物的药代动力学参数如下：
Figure PCTCN2016079054-appb-000083
结论：本发明化合物的药代吸收良好，具有明显的药代吸收效果。

Claims (18)

  1. 一种通式(I)所示的化合物：
    Figure PCTCN2016079054-appb-100001
    或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用的盐，
    其中：
    M为无机酸或有机酸，优选三氟乙酸；
    A选自环烷基、杂环基、芳基和杂芳基，其中所述的环烷基、杂环基、芳基和杂芳基任选进一步被选自烷基、卤素、氨基、硝基、羟基、氰基、烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
    R1选自氢原子、烷基、环烷基、杂环基、芳基、杂芳基、-OR4、-C(O)R4、-C(O)OR4、-S(O)mR4、-NR5R6、-C(O)NR5R6、-C(O)NHR5、-NR5C(O)R6和-NR5S(O)mR6；
    R2相同或不同，且各自独立地选自氢原子、烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、环烷基、杂环基、芳基和杂芳基；
    R3相同或不同，且各自独立地选自氢原子、烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、环烷基、杂环基、芳基、杂芳基、-OR4、-C(O)R4、-C(O)OR4、-S(O)mR4、-NR5R6、-C(O)NR5R6、-NR5C(O)R6和-NR5S(O)mR6；其中所述的烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基任选进一步被选自烷基、卤代烷基、卤素、氨基、硝基、氰基、羟基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基、杂芳基、-Ra、-OR7、-C(O)R7、-C(O)OR7、-S(O)mR7、-NR7R8、-C(O)NR7R8、-NR7C(O)R8和-NR7S(O)mR8中的一个或多个取代基所取代；
    Ra选自烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基任选进一步被选自烷基、卤素、氨基、硝基、羟基、烷氧基、羟烷基、氰基、环烷基、杂环基、芳基、杂芳基、-OR4、-C(O)R4、-C(O)OR4、-S(O)mR4、-NR5R6、-C(O)NR5R6、-NR5C(O)R6和-NR5S(O)mR6中的一个或多个取代基所取代；
    R4选自氢原子、烷基、卤代烷基、羟基、氨基、烷氧基、卤代烷氧基、环烷基、杂环基、芳基和杂芳基；其中所述的烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基任选进一步被选自烷基、卤素、氨基、硝基、氰基、羟基、羟烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、-Ra、-OR7、-C(O)R7、-C(O)OR7、-S(O)mR7、 -NR7R8、-C(O)NR7R8、-NR7C(O)R8和-NR7S(O)mR8中的一个或多个取代基所取代；
    R5和R6相同或不同，且各自独立地选自氢原子、烷基、羟基、氨基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、环烷基、杂环基、芳基和杂芳基任选进一步被选自烷基、卤素、羟基、氨基、硝基、氰基、烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基、-Ra、-OR7、-C(O)R7、-C(O)OR7、-S(O)mR7、-NR7R8、-C(O)NR7R8、-NR7C(O)R8和-NR7S(O)mR8中的一个或多个取代基所取代；
    R7和R8相同或不同，且各自独立地选自氢原子、烷基、羟基、氨基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、环烷基、杂环基、芳基和杂芳基任选进一步被选自烷基、卤素、羟基、氨基、硝基、氰基、烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
    p为0、1、2、3或4的整数；
    y为0、1、2或3的整数；
    m为0、1或2的整数；且
    n为0、1、2、3、4或5的整数。
  2. 根据权利要求1所述的通式(I)所示的化合物，其中y为0、1或3，特别是0。
  3. 根据权利要求1或2所述的通式(I)所示的化合物，其中A选自杂环基和环烷基，其中所述的杂环基和环烷基任选进一步被选自烷基、卤素、氨基、硝基、羟基、氰基、烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代。
  4. 根据权利要求1～3中任一项所述的通式(I)所示的化合物，其中n为0、1或2。
  5. 根据权利要求1所述的通式(I)所示的化合物，其为通式(II)所示的化合物：
    Figure PCTCN2016079054-appb-100002
    或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，
    其中：
    X为CH或N；
    R1～R3、M、p、n和y如权利要求1中所定义；
    a为0、1、2或3的整数；且
    b为0、1、2或3的整数。
  6. 根据权利要求1～5任一项所述的通式(I)所示的化合物，其为通式(III)所示的化合物：
    Figure PCTCN2016079054-appb-100003
    或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，
    其中：
    R1～R3、M、p、n和y如权利要求1中所定义。
  7. 根据权利要求1、5和6中任一项所述的通式(I)所示的化合物，其为通式(IV)所示的化合物：
    Figure PCTCN2016079054-appb-100004
    或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，
    其中：
    R2、R3、M、p、n和y如权利要求1中所定义。
  8. 根据权利要求1、5、6和7中任一项所述的通式(I)所示的化合物，其为通式(IV-1)所示的化合物：
    Figure PCTCN2016079054-appb-100005
    或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，
    其中：
    R2、Ra、M、p和y如权利要求1中所定义。
  9. 根据权利要求1、5、6和7中任一项所述的通式(I)所示的化合物，其为通式(IV-2)所示的化合物:
    Figure PCTCN2016079054-appb-100006
    或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，
    其中：
    R2、R4、M、p和y如权利要求1中所定义。
  10. 根据权利要求1、5、6和7中任一项所述的通式(I)所示的化合物，其为通式(IV-A)和通式(IV-B)所示的化合物:
    Figure PCTCN2016079054-appb-100007
    或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，
    其中：
    R2、R3、M、p、n和y如权利要求1中所定义。
  11. 根据权利要求1～10中任一项所述的通式(I)所示的化合物，其选自：
    Figure PCTCN2016079054-appb-100008
    Figure PCTCN2016079054-appb-100009
    Figure PCTCN2016079054-appb-100010
    Figure PCTCN2016079054-appb-100011
  12. 根据权利要求1～10中任一项所述的通式(I)所示的化合物，其选自：
    Figure PCTCN2016079054-appb-100012
    Figure PCTCN2016079054-appb-100013
  13. 一种通式(V)所示的化合物：
    Figure PCTCN2016079054-appb-100014
    或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，
    其中：
    Q为无机酸或有机酸，优选三氟乙酸；
    X为CH或N；
    R2、p、a和b如权利要求5中所述定义；且
    x为0、1、2、或3的整数。
  14. 一种制备通式(II-1)化合物的方法，该方法包括：
    Figure PCTCN2016079054-appb-100015
    通式(V)化合物在催化剂存在下在碱性条件下，与R1的卤代物发生偶联反应，得到的产物任选进一步与R3的硼酸或者硼酸酯反应，得到通式(II-1)化合物；
    其中：
    X为N；
    R1～R3、p、n、a和b如权利要求5中所述定义；且
    Q和x如权利要求13中所述定义。
  15. 一种制备根据权利要求5所述的通式(II)化合物的方法，该方法包括：
    Figure PCTCN2016079054-appb-100016
    通式(II-1)化合物在酸性条件下成盐，得到通式(II)化合物；
    其中：
    X为CH或N；
    R1～R3、M、p、y、n、a和b如权利要求5中所述定义。
  16. 一种药物组合物，其含有治疗有效量的根据权利要求1～12中任一项所述的化合物通式(I)所示的或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，以及一种或多种药学上可接受的载体、稀释剂或赋形剂。
  17. 根据权利要求1～12中任一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐或根据权利要求16所述的组合物在制备用于预防和/或治疗具有IDO介导的色氨酸代谢途径的病理学特征的疾病的药物中的用途。
  18. 根据权利要求17所述的用途，其中所述具有IDO介导的色氨酸代谢途径 病理学特征的疾病选自癌症、骨髓增生异常综合征、阿尔茨海默病、自身免疫性疾病、抑郁症、焦虑症、白内障、心理障碍和艾滋病；所述的癌症优选选自乳腺癌、宫颈癌、结肠癌、肺癌、胃癌、直肠癌、胰腺癌、脑癌、皮肤癌、口腔癌、前列腺癌、骨癌、肾癌、卵巢癌、膀胱癌、肝癌、输卵管肿瘤、卵巢瘤、腹膜肿瘤、IV期黑色素瘤、神经胶质瘤、神经胶母细胞瘤、肝细胞癌、乳突肾性瘤、头颈部肿瘤、白血病、淋巴瘤、骨髓瘤和非小细胞肺癌。
PCT/CN2016/079054 2015-04-21 2016-04-12 咪唑并异吲哚类衍生物、其制备方法及其在医药上的应用 WO2016169421A1 (zh)

Priority Applications (10)

Application Number Priority Date Filing Date Title
US15/566,848 US10899764B2 (en) 2015-04-21 2016-04-12 Imidazo isoindole derivative, preparation method therefor and medical use thereof
EP16782568.6A EP3287461B1 (en) 2015-04-21 2016-04-12 Imidazo isoindole derivative, preparation method therefor and medical use thereof
CA2981998A CA2981998A1 (en) 2015-04-21 2016-04-12 Imidazo isoindole derivative, preparation method therefor and medical use thereof
AU2016250976A AU2016250976B2 (en) 2015-04-21 2016-04-12 Imidazo isoindole derivative, preparation method therefor and medical use thereof
KR1020177032851A KR20170139064A (ko) 2015-04-21 2016-04-12 이미다조 이소인돌 유도체, 이의 제조방법 및 이의 의학적 용도
CN201680001855.3A CN106715440B (zh) 2015-04-21 2016-04-12 咪唑并异吲哚类衍生物、其制备方法及其在医药上的应用
BR112017020824-5A BR112017020824A2 (zh) 2015-04-21 2016-04-12 Imidazo isoindoline derivatives, their preparation and their application in medicine
MX2017013310A MX2017013310A (es) 2015-04-21 2016-04-12 Derivado de imidazol-isoindol, su metodo de preparacion y su uso medico.
RU2017136715A RU2717577C2 (ru) 2015-04-21 2016-04-12 Производное имидазоизоиндола, способ его получения и медицинское применение
JP2017552042A JP6801159B2 (ja) 2015-04-21 2016-04-12 イミダゾイソインドール誘導体、その製造方法及びその医薬用途

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CN201510192491.9 2015-04-21
CN201510192491 2015-04-21
CN201511019241.1 2015-12-30
CN201511019241 2015-12-30

Publications (1)

Publication Number Publication Date
WO2016169421A1 true WO2016169421A1 (zh) 2016-10-27

Family

ID=57142879

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2016/079054 WO2016169421A1 (zh) 2015-04-21 2016-04-12 咪唑并异吲哚类衍生物、其制备方法及其在医药上的应用

Country Status (11)

Country Link
US (1) US10899764B2 (zh)
EP (1) EP3287461B1 (zh)
JP (1) JP6801159B2 (zh)
KR (1) KR20170139064A (zh)
CN (1) CN106715440B (zh)
AU (1) AU2016250976B2 (zh)
BR (1) BR112017020824A2 (zh)
CA (1) CA2981998A1 (zh)
MX (1) MX2017013310A (zh)
RU (1) RU2717577C2 (zh)
WO (1) WO2016169421A1 (zh)

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017107979A1 (en) 2015-12-24 2017-06-29 Genentech, Inc. Tdo2 inhibitors
WO2018072742A1 (zh) * 2016-10-21 2018-04-26 江苏恒瑞医药股份有限公司 一种咪唑并异吲哚类衍生物的游离碱的结晶形式及其制备方法
WO2018072743A1 (zh) * 2016-10-21 2018-04-26 苏州盛迪亚生物医药有限公司 Pd-1抗体与ido抑制剂联合在制备抗肿瘤的药物中的用途
WO2019001551A1 (zh) * 2017-06-30 2019-01-03 江苏恒瑞医药股份有限公司 一种咪唑并异吲哚类衍生物游离碱的晶型及其制备方法
WO2019005559A1 (en) * 2017-06-28 2019-01-03 Genentech, Inc. INHIBITORS OF TDO2 AND IDO1
WO2019011287A1 (zh) * 2017-07-13 2019-01-17 江苏恒瑞医药股份有限公司 一种咪唑并异吲哚类衍生物的制备方法
WO2019029507A1 (zh) * 2017-08-08 2019-02-14 江苏恒瑞医药股份有限公司 一种咪唑并异吲哚类衍生物的制备方法
CN109384791A (zh) * 2017-08-09 2019-02-26 江苏恒瑞医药股份有限公司 一种咪唑并异吲哚类衍生物游离碱的晶型及其制备方法
CN109893654A (zh) * 2017-12-11 2019-06-18 江苏恒瑞医药股份有限公司 Vegfr抑制剂治疗肿瘤的方法
CN110041334A (zh) * 2018-01-15 2019-07-23 江苏恒瑞医药股份有限公司 一种氨基苯酚类化合物的制备方法
CN110664812A (zh) * 2018-07-02 2020-01-10 江苏恒瑞医药股份有限公司 一种包含咪唑并异吲哚类衍生物的药物组合物
EP4052705A1 (en) 2021-03-05 2022-09-07 Universität Basel Vizerektorat Forschung Compositions for the treatment of ebv associated diseases or conditions
WO2022184930A2 (en) 2021-03-05 2022-09-09 Universität Basel Compositions for the treatment of ebv associated diseases or conditions

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3645537A1 (en) * 2017-06-28 2020-05-06 Genentech, Inc. Tdo2 and ido1 inhibitors
WO2020063618A1 (zh) * 2018-09-27 2020-04-02 深圳微芯生物科技股份有限公司 具有吲哚胺-2,3-双加氧酶抑制活性的喹啉衍生物

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012142237A1 (en) * 2011-04-15 2012-10-18 Newlink Geneticks Corporation Fused imidazole derivatives useful as ido inhibitors

Family Cites Families (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP4272338B2 (ja) 2000-09-22 2009-06-03 バイエル アクチェンゲゼルシャフト ピリジン誘導体
US8008281B2 (en) 2003-03-27 2011-08-30 Lankenau Institute For Medical Research Methods for the treatment of cancer
GB0308333D0 (en) 2003-04-10 2003-05-14 Glaxo Group Ltd Novel compounds
US7241779B2 (en) * 2003-12-23 2007-07-10 Cephalon, Inc. Fused pyrrolocarbazoles
AU2006244068B9 (en) 2005-05-10 2012-10-25 Incyte Holdings Corporation Modulators of indoleamine 2,3-dioxygenase and methods of using the same
CA2634198C (en) 2005-12-20 2014-06-03 Incyte Corporation N-hydroxyamidinoheterocycles as modulators of indoleamine 2,3-dioxygenase
GEP20125658B (en) 2006-11-22 2012-10-10 Incyte Corp Imidazotriazines and imidazo pyrimidines as kinase inhibitors
PL2315756T3 (pl) 2008-07-08 2015-02-27 Incyte Holdings Corp 1,2,5-oksadiazole jako inhibitory 2,3-dioksygenazy indoloaminy
US20130079485A1 (en) 2011-09-22 2013-03-28 Prc-Desoto International, Inc. Sulfur-containing polyureas and methods of use
JP6062948B2 (ja) 2011-10-05 2017-01-18 エフ．ホフマン−ラ ロシュ アーゲーＦ． Ｈｏｆｆｍａｎｎ−Ｌａ Ｒｏｃｈｅ Ａｋｔｉｅｎｇｅｓｅｌｌｓｃｈａｆｔ Ｖ１ａアンタゴニストとしてのシクロヘキシル−４Ｈ，６Ｈ−５−オキサ−２，３，１０ｂ−トリアザ−ベンゾ［ｅ］アズレン
CN103087050A (zh) 2011-10-28 2013-05-08 山东轩竹医药科技有限公司 芳基激酶抑制剂
WO2014015088A1 (en) 2012-07-19 2014-01-23 Bristol-Myers Squibb Company Amide, urea or sulfone amide linked benzothiazole inhibitors of endothelial lipase
WO2014049133A1 (en) 2012-09-28 2014-04-03 H. Lundbeck A/S New positive allosteric modulators of nicotinic acetylcholine receptor
EP2911669B1 (en) 2012-10-26 2024-04-10 The University of Chicago Synergistic combination of immunologic inhibitors for the treatment of cancer
WO2014193647A2 (en) 2013-05-26 2014-12-04 Calitor Sciences, Llc Alkenyl compounds and methods of use
WO2016131380A1 (en) * 2015-02-16 2016-08-25 Shanghai De Novo Pharmatech Co.,Ltd. Fused-ring compounds, pharmaceutical composition and uses thereof
WO2016165613A1 (en) * 2015-04-12 2016-10-20 Hangzhou Innogate Pharma Co., Ltd. Heterocycles useful as ido and tdo inhibitors
US10800780B2 (en) * 2015-12-24 2020-10-13 Genentech, Inc. TDO2 Inhibitors

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012142237A1 (en) * 2011-04-15 2012-10-18 Newlink Geneticks Corporation Fused imidazole derivatives useful as ido inhibitors

Cited By (26)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017107979A1 (en) 2015-12-24 2017-06-29 Genentech, Inc. Tdo2 inhibitors
US10800780B2 (en) 2015-12-24 2020-10-13 Genentech, Inc. TDO2 Inhibitors
CN110072864A (zh) * 2015-12-24 2019-07-30 基因泰克公司 Tdo2抑制剂
EP3394068A4 (en) * 2015-12-24 2019-07-03 Genentech, Inc. TDO2 INHIBITORS
WO2018072742A1 (zh) * 2016-10-21 2018-04-26 江苏恒瑞医药股份有限公司 一种咪唑并异吲哚类衍生物的游离碱的结晶形式及其制备方法
WO2018072743A1 (zh) * 2016-10-21 2018-04-26 苏州盛迪亚生物医药有限公司 Pd-1抗体与ido抑制剂联合在制备抗肿瘤的药物中的用途
CN108884099A (zh) * 2016-10-21 2018-11-23 江苏恒瑞医药股份有限公司 一种咪唑并异吲哚类衍生物的游离碱的结晶形式及其制备方法
CN108884099B (zh) * 2016-10-21 2021-10-08 江苏恒瑞医药股份有限公司 一种咪唑并异吲哚类衍生物的游离碱的结晶形式及其制备方法
WO2019005559A1 (en) * 2017-06-28 2019-01-03 Genentech, Inc. INHIBITORS OF TDO2 AND IDO1
US11603373B2 (en) 2017-06-28 2023-03-14 Genentech, Inc. TDO2 and IDO1 inhibitors
WO2019001551A1 (zh) * 2017-06-30 2019-01-03 江苏恒瑞医药股份有限公司 一种咪唑并异吲哚类衍生物游离碱的晶型及其制备方法
CN109983018A (zh) * 2017-06-30 2019-07-05 江苏恒瑞医药股份有限公司 一种咪唑并异吲哚类衍生物游离碱的晶型及其制备方法
CN109983020A (zh) * 2017-07-13 2019-07-05 江苏恒瑞医药股份有限公司 一种咪唑并异吲哚类衍生物的制备方法
WO2019011287A1 (zh) * 2017-07-13 2019-01-17 江苏恒瑞医药股份有限公司 一种咪唑并异吲哚类衍生物的制备方法
CN109983019A (zh) * 2017-08-08 2019-07-05 江苏恒瑞医药股份有限公司 一种咪唑并异吲哚类衍生物的制备方法
WO2019029507A1 (zh) * 2017-08-08 2019-02-14 江苏恒瑞医药股份有限公司 一种咪唑并异吲哚类衍生物的制备方法
CN109983019B (zh) * 2017-08-08 2021-12-21 江苏恒瑞医药股份有限公司 一种咪唑并异吲哚类衍生物的制备方法
CN109384791A (zh) * 2017-08-09 2019-02-26 江苏恒瑞医药股份有限公司 一种咪唑并异吲哚类衍生物游离碱的晶型及其制备方法
CN109893654A (zh) * 2017-12-11 2019-06-18 江苏恒瑞医药股份有限公司 Vegfr抑制剂治疗肿瘤的方法
CN109893654B (zh) * 2017-12-11 2021-07-27 江苏恒瑞医药股份有限公司 Vegfr抑制剂治疗肿瘤的方法
CN110041334A (zh) * 2018-01-15 2019-07-23 江苏恒瑞医药股份有限公司 一种氨基苯酚类化合物的制备方法
CN110041334B (zh) * 2018-01-15 2020-10-20 江苏恒瑞医药股份有限公司 一种氨基苯酚类化合物的制备方法
CN110664812A (zh) * 2018-07-02 2020-01-10 江苏恒瑞医药股份有限公司 一种包含咪唑并异吲哚类衍生物的药物组合物
CN110664812B (zh) * 2018-07-02 2023-04-07 江苏恒瑞医药股份有限公司 一种包含咪唑并异吲哚类衍生物的药物组合物
WO2022184930A2 (en) 2021-03-05 2022-09-09 Universität Basel Compositions for the treatment of ebv associated diseases or conditions
EP4052705A1 (en) 2021-03-05 2022-09-07 Universität Basel Vizerektorat Forschung Compositions for the treatment of ebv associated diseases or conditions

Also Published As

Publication number Publication date
EP3287461B1 (en) 2020-03-18
BR112017020824A2 (zh) 2018-07-03
CA2981998A1 (en) 2016-10-27
US20180118750A1 (en) 2018-05-03
EP3287461A4 (en) 2018-11-14
CN106715440B (zh) 2019-02-22
US10899764B2 (en) 2021-01-26
CN106715440A (zh) 2017-05-24
MX2017013310A (es) 2018-02-26
RU2717577C2 (ru) 2020-03-24
JP6801159B2 (ja) 2020-12-16
AU2016250976A1 (en) 2017-10-26
EP3287461A1 (en) 2018-02-28
JP2018513145A (ja) 2018-05-24
AU2016250976B2 (en) 2020-02-27
KR20170139064A (ko) 2017-12-18
RU2017136715A3 (zh) 2019-09-30
RU2017136715A (ru) 2019-05-21

Similar Documents

Publication Publication Date Title
WO2016169421A1 (zh) 咪唑并异吲哚类衍生物、其制备方法及其在医药上的应用
CN111377917B (zh) 杂环类化合物、中间体、其制备方法及应用
KR102057877B1 (ko) 질소함유 헤테로고리 유도체 및 그의 약물에서의 용도
WO2018166493A1 (zh) 杂芳基并[4，3-c]嘧啶-5-胺类衍生物、其制备方法及其在医药上的应用
WO2017084494A1 (zh) 苯并呋喃类衍生物、其制备方法及其在医药上的应用
KR20210143803A (ko) Tead 전사인자의 신규한 소분자 저해제
WO2015127872A1 (zh) 2,4-二取代苯-1,5-二胺衍生物及其应用以及由其制备的药物组合物和药用组合物
WO2022166974A1 (zh) 吡啶并嘧啶酮类衍生物及其制备方法和用途
WO2020030107A1 (zh) 一种含有酰胺类衍生物的药物组合物及其制备方法和应用
CN102656164A (zh) 作为结核病抑制剂的嘧啶化合物
WO2016169504A1 (zh) 稠环嘧啶氨基衍生物﹑其制备方法、中间体、药物组合物及应用
JP2014511355A (ja) ヒストンデアセチラーゼ阻害薬並びにその組成物及び使用方法
WO2021185256A1 (zh) 取代的嘧啶或吡啶胺衍生物、其组合物及医药上的用途
WO2020007275A1 (zh) 吡啶并嘧啶类衍生物、其制备方法及其在医药上的应用
WO2020168927A1 (zh) 含氮并环化合物、其制备方法及用途
WO2017024996A1 (zh) 羟基脒类衍生物、其制备方法及其在医药上的应用
TW202210488A (zh) 吡嗪類衍生物及其在抑制shp2中的應用
WO2022166860A1 (zh) Pim激酶抑制剂
WO2022017494A1 (zh) 一种哒嗪类衍生物自由碱的晶型及其制备方法和应用
WO2020011220A1 (zh) 杂芳基类衍生物、其制备方法及其在医药上的应用
WO2019062657A1 (zh) 氮杂环类衍生物、其制备方法及其医药用途
TW201835079A (zh) ６－吡唑－［１，２，４］三唑並［４，３－α］吡啶－３－醯胺類衍生物、其製備方法及其在醫藥上的應用
WO2022253081A1 (zh) 氧化膦衍生物及其制备方法和应用
WO2019149205A1 (zh) 苯并杂芳基类衍生物、其制备方法及其在医药上的应用
WO2022199676A1 (zh) 稠合四环类化合物、其制备方法及其在医药上的应用

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 16782568

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 2017552042

Country of ref document: JP

Kind code of ref document: A

ENP Entry into the national phase

Ref document number: 2981998

Country of ref document: CA

REG Reference to national code

Ref country code: BR

Ref legal event code: B01A

Ref document number: 112017020824

Country of ref document: BR

WWE Wipo information: entry into national phase

Ref document number: 15566848

Country of ref document: US

Ref document number: MX/A/2017/013310

Country of ref document: MX

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2016250976

Country of ref document: AU

Date of ref document: 20160412

Kind code of ref document: A

ENP Entry into the national phase

Ref document number: 20177032851

Country of ref document: KR

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 2017136715

Country of ref document: RU

ENP Entry into the national phase

Ref document number: 112017020824

Country of ref document: BR

Kind code of ref document: A2

Effective date: 20170928