WO2018028491A1 - 吲哚胺2，3-双加氧酶抑制剂及其在药学中的用途 - Google Patents

吲哚胺2，3-双加氧酶抑制剂及其在药学中的用途 Download PDF

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WO2018028491A1
WO2018028491A1 PCT/CN2017/095669 CN2017095669W WO2018028491A1 WO 2018028491 A1 WO2018028491 A1 WO 2018028491A1 CN 2017095669 W CN2017095669 W CN 2017095669W WO 2018028491 A1 WO2018028491 A1 WO 2018028491A1
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cancer
compound
preparation
substituted
group
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French (fr)
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梅德盛
刘爱风
汪奎
孙靖
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苏州国匡医药科技有限公司
杭州阿诺生物科技股份有限公司
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Publication of WO2018028491A1 publication Critical patent/WO2018028491A1/zh

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    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4188—1,3-Diazoles condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4155—1,2-Diazoles non condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
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    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
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    • 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
    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • 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
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
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    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings

Definitions

  • the present invention relates to a compound, a method of preparing a compound, a pharmaceutical composition and a medicament of the compound, and the use of the compound for the treatment, prevention, and diagnosis of one or more indoleamine 2,3-dioxygenase-related diseases and disorders Or symptoms.
  • Tumors are the first, most common, dead and malignant disease in humans.
  • the current trend in the field of cancer, tumor-related fields and functional disorders is the combination of tumor immunotherapy and traditional chemotherapy and radiotherapy.
  • tumor immunotherapy identifies and removes tumor cells as foreign invaders by activating the body's own immune system. Therefore, the tumor immune strategy has the characteristics of good clinical effect and small side effects. It is currently believed that tumor immunotherapy is the ultimate strategy for curing tumors.
  • IDO Indoleamine 2,3-dioxygenase
  • IDO1 is a gene targeting IFN- ⁇ , which plays an important role in the immune regulation of human body: metabolizing tryptophan to produce kynurenine (This pathway is the kynurenine metabolic pathway of tryptophan).
  • the concentration of tryptophan in the immune system is positively correlated with T cells.
  • activated or overexpressed IDO results in depletion of tryptophan, which in turn leads to T cell death, inactivation of the immune system, and ultimately to tumor immunotolerance and immune escape.
  • IDO receptors have become an important target for immunotherapy such as tumors.
  • IDO In addition to tumors, IDO is also associated with viral infections, depression, organ transplant rejection, or autoimmune diseases. Thus, drugs that target IDO are also of great value for treating the above diseases.
  • the present invention is intended to provide a class of compounds, pharmaceutical compositions, medicaments and methods having aryl(hetero)cyclo-cycloalkyl/cycloalkenyl/aryl(hetero)-based structural fragments which can be used for (a) diagnosis, prevention, treatment a disease, disorder or symptom associated with one or more indoleamine 2,3-dioxygenases; (b) amelioration of side effects or symptoms associated with indoleamine 2,3-dioxygenase; (c) Controls diseases, disorders or symptoms associated with one or more indoleamine 2,3-dioxygenases.
  • diseases, disorders or symptoms may be caused by one or more hereditary, medical, immunological, infectious, metabolic, neoplastic, toxic, surgical, and/or traumatic causes. Caused by learning.
  • the methods, compounds, pharmaceutical compositions, and medicaments set forth herein are comprised of inhibitors that inhibit one or more indoleamine 2,3-dioxygenase activities.
  • X and Y are each N, O or C, and at least one of X and Y is an N atom;
  • R 1 is H, halogen, alkoxy, substituted alkoxy, nitrile, amine, substituted amine, or substituted fluorenyl;
  • R 2 and R 3 are each independently H, halogen, nitrile, amine, substituted amine, nitro, substituted C1-C6 alkyl, substituted C1-C6 alkenyl, substituted C1-C6 alkynyl, alkane Oxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, ester, amide, substituted carbonyl, substituted sulfone, substituted sulfonamide a substituted sulfonic acid group, a substituted phosphonic acid group, or a substituted phosphoamido group;
  • R 2 and R 3 are bonded to each other to form a substituted or unsubstituted saturated cycloalkyl group, a substituted or unsubstituted saturated cycloheteroalkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted one.
  • R 4 is H, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C1-C6 alkenyl group or a substituted or unsubstituted C1-C6 alkynyl group;
  • R 5 is H, or OH
  • n is an integer from 0-2;
  • R 5 is OH
  • It is a phenyl group, a pyridyl group, an imidazolyl group, an oxazolyl group, a quinolyl group, a substituted or unsubstituted carbazolyl group.
  • the compounds provided herein are selected from, but are not limited to, the following compounds:
  • a pharmaceutical composition comprising a compound provided herein and a pharmaceutically acceptable excipient as described above.
  • the pharmaceutical composition is in the form of an aqueous dispersion, a liquid, a mash, a syrup, a medicinal agent, a syrup, a suspension, an aerosol, a fast solvent, an effervescent agent, a lyophilizate , tablets, powders, pills, dragees, capsules, multiparticulates, or immediate release agents.
  • the treatment of cancer, viral infection, organ transplant rejection or autoimmune disease is a compound provided by the present invention as described above, or a pharmaceutically acceptable salt, hydrate, solvate or isotope thereof Compound or former a drug as an active ingredient; or a compound provided by the present invention, or a pharmaceutically acceptable salt, hydrate, solvate, isotope compound or prodrug thereof, as described above, such as PD-1/PD-L1, CTLA-4 , CART and other target drugs are used in combination.
  • the cancer is selected from the group consisting of skin cancer, bladder cancer, ovarian cancer, breast cancer, gastric cancer, pancreatic cancer, prostate cancer, colon cancer, lung cancer, bone cancer, brain cancer, neurocytoma, rectal cancer, Colon cancer, familial adenomatous polyposis, hereditary nonpolyposis colorectal cancer, esophageal cancer, lip cancer, laryngeal cancer, hypopharyngeal carcinoma, tongue cancer, salivary gland cancer, gastric cancer, adenocarcinoma, medullary thyroid carcinoma, nipple Thyroid cancer, kidney cancer, renal parenchymal cancer, ovarian cancer, cervical cancer, endometrial cancer, endometrial cancer, choriocarcinoma, pancreatic cancer, prostate cancer, testicular cancer, urinary cancer, melanoma, brain tumors, etc.
  • Glioblastoma Glioblastoma, astrocytoma, meningiomas, medulloblastoma and peripheral neuroectodermal tumors, Hodgkin's lymphoma, non-Hodgkin's lymphoma, Burkitt's lymphoma, acute lymphocytic leukemia (ALL) ), chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), adult T-cell leukemia lymphoma, diffuse large B-cell lymphoma (DLBCL), hepatocellular carcinoma, gallbladder carcinoma , bronchial cancer, small fine Lung cancer, non-small cell lung cancer, multiple myeloma, basal cell tumor, teratoma, retinoblastoma, choroidal melanoma, seminoma, rhabdomyosarcoma, craniopharyngioma, osteosar
  • the starting materials i and ii are subjected to a suzuki coupling reaction with the participation of a metal palladium catalyst to obtain an intermediate iii; and then the intermediate and the methyl ketone derivative are subjected to basic conditions to form an ⁇ , ⁇ -unsaturated ketone (intermediate).
  • Iv) then the intermediate iv is deprotected under acidic conditions and further cyclized to give the intermediate v; finally the carbonyl group in the intermediate v is reduced to obtain the compound of the present invention as described above;
  • intermediate vi an ⁇ , ⁇ -unsaturated ketone
  • intermediate vi in the presence of a format reagent, CuCl, the intermediate vi is first reacted with iodide, and then Deprotection under AcOH conditions affords intermediate vi; then, intermediate vi undergoes intramolecular cyclization to yield intermediate v-ii; and finally carbonyl of intermediate v-ii Substituting a base to obtain a compound provided by the present invention as described above;
  • the metal palladium catalyst is selected from the group consisting of transition metal catalysts such as Pd(PPh 3 ) 4 , Pd(OAc) 2 , PdCl 2 , Pd(PPh 3 ) 2 Cl 2 .
  • the basic conditions include the presence of NaOEt, MeONa, Cs 2 CO 3 , and the like.
  • the acidic conditions include conditions in which HOAc, HCl, H 2 SO 4 , methanesulfonic acid, or p-toluenesulfonic acid, and the like are present.
  • kits comprising the compound of the present invention as described above, or a pharmaceutically acceptable salt, hydrate, solvate, isotope compound or prodrug thereof And one or more target drugs selected from the group consisting of PD-1/PD-L1, CTLA-4, and CART target drugs.
  • the treatment comprises administering a compound provided by the present invention, or a pharmaceutically acceptable salt, hydrate, solvate, isotopic compound or prodrug thereof, as described above; or as described above
  • the cancer is selected from the group consisting of skin cancer, bladder cancer, ovarian cancer, breast cancer, gastric cancer, pancreatic cancer, prostate cancer, colon cancer, lung cancer, bone cancer, brain cancer, neurocytoma, rectal cancer, Colon cancer, familial adenomatous polyposis, hereditary nonpolyposis colorectal cancer, esophageal cancer, lip cancer, laryngeal cancer, hypopharyngeal carcinoma, tongue cancer, salivary gland cancer, gastric cancer, adenocarcinoma, medullary thyroid carcinoma, nipple Thyroid cancer, kidney cancer, renal parenchymal cancer, ovarian cancer, cervical cancer, endometrial cancer, endometrial cancer, choriocarcinoma, pancreatic cancer, prostate cancer, testicular cancer, urinary cancer, melanoma, brain tumors, etc.
  • Glioblastoma Glioblastoma, astrocytoma, meningiomas, medulloblastoma and peripheral neuroectodermal tumors, Hodgkin's lymphoma, non-Hodgkin's lymphoma, Burkitt's lymphoma, acute lymphocytic leukemia (ALL) ), chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), adult T-cell leukemia lymphoma, diffuse large B-cell lymphoma (DLBCL), hepatocellular carcinoma, gallbladder carcinoma , bronchial cancer, small fine Lung cancer, non-small cell lung cancer, multiple myeloma, basal cell tumor, teratoma, retinoblastoma, choroidal melanoma, seminoma, rhabdomyosarcoma, craniopharyngioma, osteosar
  • the present invention provides a novel, highly toxic, low-toxic IDO inhibitor.
  • the series of compounds provided by the present invention have significantly higher enzyme activity and cell level (including Hela cells and HEK293) than NLG919.
  • enzyme 39 was 7 times higher than NLG919; Hela cell activity, compound 39 was 64 times higher than NLG919; HEK293 cell activity, compound 39 was 29 times higher than NLG919.
  • the present invention also finds a novel and important structure-activity relationship, that is, in addition to the known 2-position hydroxyl group (such as the secondary hydroxyl group in NLG919), the ortho-hydroxy group of the 2-position hydroxyl group is the 3-position hydroxyl group (uncle).
  • the simultaneous presence of a hydroxy group, as in the case of compound 39, can significantly increase the cellular level activity of such compounds with a 2-3 fold increase in activity.
  • the introduced aryl (hetero) group i.e., the compound provided by the present invention
  • the introduced aryl (hetero) group also has a very good effect on the increase in compound activity, such as a 2-3 fold increase in enzyme level activity.
  • the present invention provides a compound Part of the introduced aryl and arylhetero substituents, as well as a variety of different aromatic heterocyclic substituents, the cell-level activity of the compounds has an order of magnitude difference, such as aryl-containing compounds (compound 6- 7,10-17)
  • aryl-containing compounds compound 6- 7,10-17
  • the EC50 of the cell level is 100-200 nM
  • the EC50 of the pyridine-containing heterocyclic compound (Compound 9) is 320 nM
  • the carbazole-containing compound such as Compound 39
  • This part of the study shows that choosing the right one Part of the extreme importance.
  • the compounds provided by the present invention are the IDO/TDO dual target inhibitors currently sought.
  • the compound provided by the invention has good pharmacokinetic properties, such as the pharmacological properties of compound 39 is significantly better than INCB024360 (the pharmacokinetic parameters of compound 39 and INCB024360 are compared as follows: Cmax, 31.8.84 ng/mL Vs. 290.46 ng /mL; AUC (0-t), 31.8.84 ng / mL Vs. 1711.42 h * ng / mL; F%, 95 Vs. 44.).
  • the compounds described herein inhibit one or more indoleamine 2,3-dioxygenases, and the compounds described herein have a wide range of therapeutic effects as indoleamine 2,3-dioxygenase inhibitors.
  • the present invention provides a compound of formula I or a pharmaceutically acceptable salt, hydrate, solvate, isotope compound or prodrug thereof:
  • X and Y are each N, O or C, and at least one of X and Y is an N atom;
  • R 1 is H, halogen, alkoxy, substituted alkoxy, nitrile, amine, substituted amine, or substituted fluorenyl;
  • R 2 and R 3 are each independently H, halogen, nitrile, amine, substituted amine, nitro, substituted C1-C6 alkyl, substituted C1-C6 alkenyl, substituted C1-C6 alkynyl, alkane Oxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, ester, amide, substituted carbonyl, substituted sulfone, substituted sulfonamide a substituted sulfonic acid group, a substituted phosphonic acid group, or a substituted phosphoamido group;
  • R 2 and R 3 are bonded to each other to form a substituted or unsubstituted saturated cycloalkyl group, a substituted or unsubstituted saturated cycloheteroalkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted one.
  • R 4 is H, a substituted or unsubstituted C 1 -C 6 alkyl group, a substituted or unsubstituted C 1 -C 6 alkenyl group or a substituted or unsubstituted C 1 -C 6 alkynyl group;
  • R 5 is H, or OH
  • n is an integer from 0 to 2, such as 0, 1, or 2;
  • R 5 is OH
  • It is a phenyl group, a pyridyl group, an imidazolyl group, an oxazolyl group, a quinolyl group, a substituted or unsubstituted carbazolyl group.
  • R 4 is H, C1-C3 alkyl, C1-C3 alkenyl or C1-C3 alkynyl.
  • It is a substituted or unsubstituted C5-C7 cycloalkyl group, a bicyclo[3.1.0]hexane group, or a spiro[3.5]decylalkyl group.
  • R 1 is H, fluoro, chloro, C 1 -C 3 alkoxy, halo C 1 -C 3 alkoxy, nitrile, C 1 -C 3 alkylamino, or C 1 -C 3 alkyl ⁇ .
  • n is an integer from 0 to 3, such as 0, 1, 2, and 3.
  • R 2 and R 3 are H, fluoro, chloro, nitrile, nitro, C1-C3 alkyl, halo C1-C3 alkyl, C1-C3 alkenyl, C1-C3 alkyne, respectively.
  • Compounds of formula (I) include, but are not limited to, the descriptions in Table 1.
  • the compounds of the present invention can be prepared by methods such as those shown in the following schemes utilizing chemical transformations known to those skilled in the art. Solvents, temperatures, pressures, and other reaction conditions can be readily selected by one of ordinary skill in the art. Starting materials are either commercially available or readily prepared by one of ordinary skill in the art. These schemes are illustrative and are not intended to limit the possible techniques that one skilled in the art can use to make the compounds disclosed herein. Different methods may be apparent to those skilled in the art. Furthermore, multiple steps in the synthesis can be carried out in an alternate sequence or order to yield the desired compound or compounds.
  • the compound of formula (I) can be prepared by the exemplary methods described in the following schemes and working examples, and related published procedures used by those skilled in the art. Exemplary reagents and procedures for these reactions appear in the following and working examples. Protection and deprotection in the methods below can be carried out by procedures well known in the art (see, for example, Greene, T. W. et al., Protecting Groups in Organic Synthesis, 3rd Edition, Wiley (1999)).
  • Method 1 The starting materials i and ii are subjected to a suzuki coupling reaction with a metal palladium catalyst such as Pd(PPh 3 ) 4 , Pd(OAc) 2 or the like to obtain an intermediate iii; and then the intermediate and the methyl ketone are derived.
  • the ⁇ , ⁇ -unsaturated ketone (intermediate iv) is formed under basic conditions such as NaOEt; the intermediate iv is in acidic conditions such as HOAc, HCl, H2SO4, methanesulfonic acid, p-toluenesulfonic acid and the like.
  • the lower ring is combined to give the key intermediate v; the carbonyl group of the final intermediate is reduced under conditions of NaBH 4 /MeOH to give the desired product I-1.
  • Method 2 The intermediate v is reacted with a format reagent to obtain a tertiary alcohol derivative I-2.
  • Method 3 The starting material i and the methyl ketone derivative are formed in the presence of basic conditions such as NaOEt to form an ⁇ , ⁇ -unsaturated ketone (intermediate vi); in the presence of a format reagent and CuCl, the intermediate Vi is first reacted with iodide, and then deprotected under AcOH conditions to give intermediate vi; then, intermediate vi undergoes intramolecular cyclization to produce intermediate v-ii; finally intermediate v-ii is as NaBH4 Reduction under conditions such as /MeOH to give the objective product I-3.
  • basic conditions such as NaOEt
  • CuCl the intermediate vi is first reacted with iodide, and then deprotected under AcOH conditions to give intermediate vi; then, intermediate vi undergoes intramolecular cyclization to produce intermediate v-ii; finally intermediate v-ii is as NaBH4 Reduction under conditions such as /MeOH to give the objective product I-3.
  • the compound of formula (I) is prepared according to a pharmaceutically acceptable acid addition salt (a pharmaceutically acceptable salt) by the free base form of the compound with a pharmaceutically acceptable inorganic or Organic acid reactions, including but not limited to inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid; and salts prepared from, for example, the following organic acids: acetic acid, propionic acid, succinic acid, glycolic acid, hard Fatty acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfamic acid, 2-acetoxybenzene Formic acid, fumaric acid, methyl 20 benzene sulfonic acid, methane sulfonic acid, ethane disulfonic acid,
  • references to pharmaceutically acceptable salts include solvent added forms or crystalline forms, especially solvates or polymorphs.
  • the solvate contains a stoichiometric or non-stoichiometric amount of solvent and is selectively formed during crystallization with a pharmaceutically acceptable solvent such as water, ethanol, and the like.
  • a hydrate is formed when the solvent is water, or an alcoholate is formed when the solvent is ethanol.
  • Solvates of the compounds of formula (I) are conveniently prepared or formed according to the methods described herein.
  • the hydrate of the compound of the formula (I) is conveniently obtained by recrystallization from a mixed solvent of water/organic solvent, and the organic solvent used includes, but not limited to, dioxane, tetrahydrofuran, ethanol or methanol.
  • the compounds mentioned herein can exist in unsolvated as well as solvated forms. In summary, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.
  • the compounds of formula (I) are prepared in various forms including, but not limited to, amorphous, pulverized and nano-granular forms.
  • the compound of the formula (I) includes a crystalline form and may also serve as a polymorph.
  • Polymorphs include different lattice arrangements of the same elemental composition of the compound. Polymorphs usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal form, optical and electrical properties, stability and solubility. Different factors such as recrystallization solvent, crystallization rate and storage temperature may cause a single crystal form to dominate.
  • the IDO inhibitors provided in this patent not only inhibit the IDO receptor, but also inhibit the tryptophan 2,3-dioxygenase (TDO) receptor.
  • TDO tryptophan 2,3-dioxygenase
  • IDO inhibitor refers to an agent that is capable of inhibiting the activity of indoleamine 2,3-dioxygenase (IDO) and thereby reversing IDO-mediated immunosuppression.
  • IDO inhibitors can inhibit IDO1 and/or IDO2 (INDOL1).
  • the IDO inhibitor can be a reversible or irreversible IDO inhibitor.
  • a "reversible IDO inhibitor” is a compound that reversibly inhibits the activity of an IDO enzyme at a catalytic site or at a non-catalytic site.
  • An “irreversible IDO inhibitor” is a compound that irreversibly destroys the activity of an IDO enzyme by forming a covalent bond with an enzyme. .
  • the present invention describes cis- and trans- (or E- and Z-) geometric isomers of the compounds of the invention, and which can be separated into a mixture of isomers or as separate isomers.
  • the compounds of the invention can be isolated in optically active or racemic forms.
  • All methods for preparing the compounds of the invention and the intermediates prepared therein are considered part of the invention.
  • they can be separated by conventional methods, for example by chromatography or fractional crystallization.
  • the end products of the invention are obtained in free (neutral) or salt form depending on the process conditions. Free forms and salts of these end products are within the scope of the invention.
  • one form of the compound can be converted to another form.
  • the free base or acid can be converted to a salt; the salt can be converted to the free compound or another salt; the mixture of isomer compounds of the invention can be separated into the individual isomers.
  • the compounds of the invention may exist in a variety of tautomeric forms in which a hydrogen atom is transposed to other portions of the molecule and thereby the chemical bonds between the atoms of the molecule are rearranged. It should be understood that all tautomeric forms that may be present are included within the invention.
  • substituent when a substituent is referred to as “optionally substituted,” the substituent is selected, for example, from the following substituents such as alkyl, cycloalkyl, aryl, heterocyclyl, halogen, hydroxy, alkane.
  • -SO2NH2 substituted sulfonylamino, nitro, cyano, carb
  • alkyl or "alkylene” as used herein is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms.
  • C1-C6 alkyl means an alkyl group having from 1 to 6 carbon atoms.
  • alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (eg, n-propyl and isopropyl), butyl (eg, n-butyl, isobutyl, t-butyl), and A pentyl group (eg, n-pentyl, isopentyl, neopentyl).
  • alkenyl denotes a straight or branched chain hydrocarbon radical containing one or more double bonds and generally having from 2 to 20 carbon atoms in length.
  • C2-C8 alkenyl contains two to eight carbon atoms.
  • Alkenyl groups include, but are not limited to, for example, ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, heptenyl, octenyl, and the like.
  • alkynyl denotes a straight or branched chain hydrocarbon radical containing one or more triple bonds and generally having a length of from 2 to 20 carbon atoms.
  • C2-C8 alkynyl contains two to eight carbon atoms.
  • Representative alkynyl groups include, but are not limited to, for example, ethynyl, 1-propynyl, 1-butynyl, heptynyl, octynyl, and the like.
  • alkoxy refers to -O-alkyl.
  • C1-6 alkoxy (or alkyloxy) is intended to include C1, C2, C3, C4, C5 and C6 alkoxy groups. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (eg, n-propoxy and isopropoxy) and t-butoxy.
  • alkylthio or “thioalkoxy” denotes a thio-bridged alkyl group as defined above having the indicated number of carbon atoms; for example, methyl-S- and ethyl-S-.
  • aryl alone or as part of a larger moiety such as “aralkyl”, “aralkyloxy” or “aryloxyalkyl”, refers to a single ring having a total of from 5 to 15 ring members.
  • “aryl” refers to an aromatic ring system including, but not limited to, phenyl, biphenyl, indanyl, 1-naphthyl, 2-naphthyl, and tetrahydronaphthalene. base.
  • aralkyl or "arylalkyl” refers to an alkyl residue attached to an aryl ring. Non-limiting examples include benzyl, phenethyl and the like.
  • the fused aryl group may be attached to another group at a suitable position of the cycloalkyl ring or the aromatic ring.
  • An arrow line drawn from the ring system indicates that the bond can be attached to any suitable ring atom.
  • cycloalkyl refers to a monocyclic or bicyclic cyclic alkyl group.
  • Monocyclic cyclic alkyl refers to a C3-C8 cyclic alkyl group including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and norbornyl.
  • Branched cycloalkyl groups such as 1-methylcyclopropyl and 2-methylcyclopropyl are included in the definition of "cycloalkyl”.
  • the bicyclic cyclic alkyl group includes a bridged ring, a spiro ring or a cycloalkyl group of a fusion ring.
  • cycloalkenyl refers to a monocyclic or bicyclic cyclic alkenyl group.
  • Monocyclic cyclic alkenyl refers to C3-C8 cyclic alkenyl groups including, but not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, and norbornyl.
  • Branched cycloalkenyl groups such as 1-methylcyclopropenyl and 2-methylcyclopropenyl are included in the definition of "cycloalkenyl”.
  • Bicyclic cyclic alkenyl groups include bridged rings, spiro rings or A cyclic alkenyl group of a fusion ring.
  • cycloalkylalkyl refers to a cycloalkyl or substituted cycloalkyl group bonded to an alkyl group attached to the oxazole core of the compound.
  • Halo or halogen includes fluoro, chloro, bromo and iodo.
  • Haloalkyl is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms and substituted with one or more halogens. Examples of haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoro Propyl and heptachloropropyl.
  • haloalkyl group examples include "fluoroalkyl group" which is intended to include a branched and straight-chain saturated aliphatic hydrocarbon group having a specified number of carbon atoms and substituted with one or more fluorine atoms.
  • Haloalkoxy or "haloalkyloxy” denotes an oxo-5 alkyl group as defined above attached via an oxygen bridge having the indicated number of carbon atoms.
  • C1-6 haloalkoxy is intended to include C1, C2, C3, C4, C5 and C6 haloalkoxy groups.
  • Examples of haloalkoxy groups include, but are not limited to, trifluoromethoxy, 2,2,2-trifluoroethoxy, and pentafluoroethoxy.
  • haloalkylthio or “thiohaloalkoxy” denotes a thio bridged haloalkyl group as defined above having the indicated number of carbon atoms; for example, trifluoromethyl-S- and pentafluoroethyl -S-.
  • aryl refers to a monocyclic or bicyclic (and above bicyclic) aryl group which is all carbon atoms.
  • a monocyclic aromatic group means a phenyl group
  • a bicyclic or bicyclic or higher aromatic group means a naphthyl group, a fluorenyl group or the like
  • the aryl bicyclic ring may also be a benzene ring in which a cycloalkyl group is fused or a ring is fused.
  • Alkenyl, or a cycloalkynyl group Alkenyl, or a cycloalkynyl group.
  • arylhetero means a stable 3-, 4-, 5-, or 7-membered aromatic monocyclic or aromatic bicyclic ring. Or a 7-, 8-, 9-, 10-, 11-, 12-, 13- or 14-membered aromatic polycyclic heterocyclic ring which is completely unsaturated, partially unsaturated, and which contains a carbon atom and 1 , 2, 3 or 4 heteroatoms independently selected from N, O and S; and include any of the following polycyclic groups, wherein any of the heterocycles defined above are fused to a benzene ring.
  • the nitrogen and sulfur heteroatoms can be optionally oxidized.
  • the nitrogen atom is substituted or unsubstituted (i.e., N or NR, wherein R is H or, if defined, another substituent).
  • the heterocycle can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. If the resulting compound is stable, the heterocyclic groups described herein can be substituted on a carbon or nitrogen atom.
  • the nitrogen in the heterocycle can optionally be quaternized.
  • the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to each other.
  • the total number of S and O atoms in the heterocycle is no more than one.
  • heterocycle it is intended to include heteroaryl.
  • aromatic heterocycles include, but are not limited to, acridinyl, azetidinyl, anthracycline, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothienyl, benzoxan Azolyl, benzoxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, carbazolyl, 4aH-carbazolyl, porphyrinyl, chromanyl, chromenyl, porphyrinyl, decahydroquinolinyl, 2H, 6H-1,5,2-dithiazinyl, dihydrofuran[2, 3-b]tetrahydrofuranyl, furyl, furfuryl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-carbazo
  • cycloheteroalkyl refers to a monocyclic cycloheteroalkyl system or a bicyclic heteroalkyl system.
  • the monocyclic cycloheteroalkyl group means a 3-8 membered material and contains at least one saturated or unsaturated but not aromatic cyclic alkyl group selected from O, N, S, P.
  • a bicyclic heteroalkyl system refers to a cycloheteroalkyl group fused to a phenyl group, or a cycloalkyl group, or a cycloalkenyl group, or a cycloheteroalkyl group, or a heteroaryl group.
  • bridged cyclic hydrocarbon refers to a polycyclic compound that shares two or more carbon atoms. It can be divided into bicyclic bridge cyclic hydrocarbons and polycyclic bridge cyclic hydrocarbons. The former consists of two alicyclic rings sharing two or more carbon atoms; the latter is a bridged cyclic hydrocarbon composed of three or more rings.
  • spirocyclic hydrocarbon refers to a polycyclic hydrocarbon that shares a carbon atom (called a spiro atom) between the individual rings.
  • substituted means that at least one hydrogen atom is replaced by a non-hydrogen group, provided that the normal valence is maintained and the substitution results in a stable compound.
  • nitrogen atom for example, an amine
  • these nitrogen atoms can be converted into N-oxides by treatment with an oxidizing agent such as mCPBA and/or hydrogen peroxide to obtain other compounds of the present invention.
  • an oxidizing agent such as mCPBA and/or hydrogen peroxide
  • the nitrogen atoms shown and claimed are considered to cover both the nitrogen and its N-oxide (N ⁇ O) derivatives.
  • any variable occurs more than once in any composition or formula of a compound, its definition at each occurrence is independent of its definition in each of the other cases.
  • the group can be optionally substituted with up to three R groups, and R is independently selected from the definition of R on each occurrence.
  • combinations of substituents and/or variables are only permitted if the combination described above produces a stable compound.
  • pharmaceutically acceptable refers to those compounds, substances, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity or irritation. Sex, allergic reactions and/or other problems or complications are commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salt refers to a derivative of a compound of the invention wherein the parent compound is modified by the preparation of its acid or base salt.
  • pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic groups such as amines; and alkali metal or organic salts of acidic groups such as carboxylic acids.
  • Pharmaceutically acceptable salts include the conventional non-toxic or quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • the above conventional non-toxic salts include those derived from, for example, the following inorganic acids: hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, and nitric acid; and salts prepared from, for example, the following organic acids: acetic acid, propionic acid, succinic acid , glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfamic acid, 2 - acetoxybenzoic acid, fumaric acid, toluene 20 benzenesulfonic acid, methanesulfonic acid, ethane disulfonic acid, oxalic acid and isethionethane, and the like.
  • inorganic acids hydrochloric acid, hydrobromic acid, sulfur
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing a basic or acidic moiety by conventional chemical methods.
  • the above salts can be prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of a suitable base or acid in water or an organic solvent or a mixture of the two; usually, preferably, for example, diethyl ether, ethyl acetate, ethanol, Non-aqueous medium such as isopropyl alcohol or acetonitrile.
  • a list of suitable salts can be found in Remington: The Science and Practice of Pharmacy, 22nd Edition, 25 Allen, L. V. Jr., Ed.; Pharmaceutical Press, London, UK (2012), the disclosure of which is incorporated herein by reference.
  • the compounds of formula (I) may have the form of prodrugs.
  • Prodrugs within the scope and spirit of the invention are any compound that is converted in vivo to provide a bioactive agent (i.e., a compound of formula (I)).
  • a bioactive agent i.e., a compound of formula (I)
  • Various forms of prodrugs are well known in the art. Examples of such prodrug derivatives can be found in: a) Bundgaard, H., ed., Design of Prodrugs, Elsevier (1985), and Widder, K. et al., eds., Methods in Enzymology, 112: 309-396.
  • physiologically hydrolyzable esters of the compound of formula (I) include C1-6 alkyl, C1-6 alkylbenzyl, 4-methoxybenzyl, indanyl, phthaloyl, methoxy , C1-6 alkanoyloxy-C1-6 alkyl (eg acetoxymethyl, pivaloyloxymethyl or propionyloxymethyl), C1-6 alkoxycarbonyloxy-C1 -6 alkyl (eg methoxycarbonyl-oxymethyl or ethoxycarbonyloxymethyl, glycyloxymethyl, phenylglycyloxymethyl, (5-methyl-2-oxo-) Esters of 1,3-dioxol-4-yl)-methyl) and other well-known physiologicallyzable esters for use in, for example, penicillin and cephalosporin techniques.
  • the above esters can be prepared by conventional techniques known in the art.
  • prodrugs are well known in the art and is described, for example, in King, FD, ed., Medicinal Chemistry: Principles 15 and Practice, The Royal Society of Chemistry, Cambridge, UK (2nd edition, reproduced, 2006); Testa, B.et Al., Hydrolysis in Drug and Prodrug Metabolism. Chemistry, Biochemistry and Enzymology, VCHA and Wiley-VCH, Zurich, Switzerland (2003); Wermuth, CG, ed., The Practice, of Medicinal Chemistry, 3rd edition, Academic Press, San Diego, CA (2008).
  • the invention is intended to include all isotopes of atoms present in the compounds of the invention.
  • Isotopes include atoms having the same atomic number but different mass numbers.
  • isotopes of hydrogen include deuterium and tritium.
  • Carbon isotopes include 13C and 14C.
  • Isotopically labeled compounds of the invention can be prepared by generally replacing the unlabeled reagents used in other situations with conventional techniques known to those skilled in the art or by methods analogous to those described herein using appropriate isotopically labeled reagents.
  • solvate means a physical association of a compound of the invention with one or more solvent molecules, whether organic or inorganic. This physical association includes hydrogen bonding. In some cases, such as when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid, the solvate will be capable of being separated.
  • the solvent molecules in the solvate may be present in a regular arrangement and/or a disordered arrangement.
  • Solvates may comprise stoichiometric or non-stoichiometric solvent molecules.
  • “Solvate” encompasses both the solution phase and the separable solvate. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Solvation methods are well known in the art.
  • patient refers to an organism that is treated by the methods of the invention.
  • organisms preferably include, but are not limited to, mammals (e.g., rodents, baboons, monkeys, horses, cows, pigs, dogs, cats, etc.) and most preferably humans.
  • an effective amount means the amount of a drug or agent (ie, a compound of the invention) that will elicit, for example, a biological or medical response of a tissue, system, animal or human sought by a researcher or clinician.
  • a therapeutically effective amount means an amount which results in an improved treatment, cure, prevention or alleviation of a disease, disorder or side effect, or a reduction in disease, as compared to a corresponding subject not receiving the above amount. Or the speed of progression of the condition.
  • An effective amount can be administered in one or more administrations, administrations or dosages and is not intended to be limited by the particular formulation or route of administration. The term also includes an effective amount within its scope that enhances normal physiological function.
  • treating includes any effect that results in an amelioration of a condition, disease, disorder, etc., such as reducing, reducing, regulating, ameliorating or eliminating, or ameliorating the symptoms thereof.
  • composition refers to a combination of an active agent with an inert or active carrier, such that the composition is especially suitable for in vivo or ex vivo diagnosis or treatment.
  • bases include, but are not limited to, alkali metal (e.g., sodium) hydroxides, alkaline earth metal (e.g., magnesium) hydroxides, ammonia, and the like.
  • Salts of the Compounds of the Invention For therapeutic use, the salts of the compounds of the invention are expected to be pharmaceutically acceptable. However, non-pharmaceutically acceptable salts of acids and bases can also be used, for example, in the manufacture of pharmaceutical compounds. Prepared or purified.
  • pharmaceutically acceptable is used herein to mean those compounds, substances, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity or irritation. Sex, allergic reactions and/or other problems or complications, and commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable carrier means a pharmaceutical substance, composition or vehicle, such as a liquid or solid filler, diluent, excipient, manufacturing aid (eg, lubricant, talc, magnesium stearate, Calcium stearate or zinc stearate or stearic acid) or a solvent encapsulating material which involves carrying or transporting a subject compound from one organ or part of the body to another organ or part of the body.
  • manufacturing aid eg, lubricant, talc, magnesium stearate, Calcium stearate or zinc stearate or stearic acid
  • solvent encapsulating material which involves carrying or transporting a subject compound from one organ or part of the body to another organ or part of the body.
  • Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not deleterious to the patient.
  • composition means a composition comprising a compound of the invention and at least one other pharmaceutically acceptable carrier.
  • “Pharmaceutically acceptable carrier” refers to a medium that is generally accepted in the art for delivery of a biologically active agent to an animal, particularly a mammal, including (ie) an adjuvant, excipient or vehicle, such as a diluent, preservative , fillers, flow regulators, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, fragrances, antibacterial agents, antifungals, lubricants and dispersing agents,
  • an adjuvant, excipient or vehicle such as a diluent, preservative , fillers, flow regulators, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, fragrances, antibacterial agents, antifungals, lubricants and dispersing agents,
  • acceptable refers to a prescription component or active ingredient that does not have an unduly detrimental effect on the health of a general therapeutic target.
  • guanamine 2,3-dioxygenase mediated or "IDO related”, as used herein, refers to a disease or condition caused in the presence of a guanamine 2,3-dioxygenase.
  • cancer refers to abnormal growth of an uncontrollable cell and is capable of metastasis (propagation) under certain conditions.
  • This type of cancer includes, but is not limited to, solid tumors (eg, bladder, intestine, brain, chest, uterus, heart, kidney, lung, lymphoid tissue (lymphoma), ovary, pancreas or other endocrine organs (eg thyroid), prostate) , skin (melanoma) or hematoma (eg non-leukocytic leukemia).
  • administered in combination refers to the administration of several selected therapeutic agents to a patient, administered at the same or different times, in the same or different modes of administration.
  • the term “enhancement” or “enhancement”, as used herein, means that the desired result can be increased or prolonged in potency or duration.
  • the term “enhanced” in terms of enhancing the therapeutic effect of a drug means the ability of the drug to increase or extend the potency or duration in the system.
  • potency value refers to the ability to maximize the effectiveness of another therapeutic agent in an ideal system.
  • immune disease refers to a disease or condition that produces an adverse or deleterious response to an endogenous or exogenous antigen. The result is usually a dysfunction of the cell, or it can destroy and cause dysfunction, or destroy an organ or tissue that may produce an immune symptom.
  • kit is synonymous with “product packaging.”
  • subject or “patient” includes mammals and non-mammals.
  • Mammals include, but are not limited to, mammals: Humans, non-human primates such as orangutans, baboons and monkeys; agricultural animals such as cattle, horses, goats, sheep, pigs; livestock such as rabbits and dogs; experimental animals include rodents such as rats, mice and guinea pigs.
  • Non-mammals include, but are not limited to, birds, fish, and the like.
  • the selected mammal is a human.
  • treatment include alleviating, inhibiting, or ameliorating the symptoms or condition of a disease; inhibiting the production of complications; ameliorating or preventing a potential metabolic syndrome; inhibiting the production of a disease or condition, Such as controlling the development of a disease or condition; reducing a disease or symptom; making a disease or symptom diminished; reducing a complication caused by the disease or symptom, or preventing or treating a symptom caused by the disease or symptom.
  • a compound or pharmaceutical composition after administration, can ameliorate a disease, condition, or condition, particularly if the severity is improved, delays the onset, slows progression, or reduces the duration of the condition. Whether administered fixedly or temporarily, continuously or intermittently, it may be attributable to or related to the administration.
  • the compound of formula (I) inhibits one or more guanamine 2,3-dioxygenases.
  • the compounds of formula (I) are shown to be effective in the treatment of cancer, viral infections, organ transplant rejection or autoimmune diseases.
  • the compounds and pharmaceutical compositions of the invention are useful for treating or preventing any disease or condition that is susceptible to the enzymatic activity of IDO.
  • diseases or conditions include proliferative diseases (eg cancer), viruses and other infections (eg skin infections, gastrointestinal (GI) infections, urinary tract infections, genitourinary infections, systemic infections), autoimmune diseases (eg rheumatoid) Arthritis, lupus).
  • the compound and pharmaceutical composition can be administered to an animal, preferably a mammal (e.g., a domestic animal, a cat, a dog, a mouse, a rat), more preferably a human. Any method of administration can be used to deliver the compound or pharmaceutical composition to a patient.
  • the compound or pharmaceutical composition is administered orally.
  • the compound or pharmaceutical composition is administered parenterally.
  • the compounds of the invention modulate the activity of indoleamine-2,3-dioxygenase (IDO).
  • IDO indoleamine-2,3-dioxygenase
  • modulate means the ability to increase or decrease the activity of an enzyme or receptor.
  • the compounds of the invention are useful in methods of modulating IDO by reacting an enzyme with any one or more of the compounds described herein.
  • the compounds of the invention act as inhibitors of IDO.
  • the compounds of the invention are useful for modulating the activity of IDO in a cell or individual in need of modulation by administration of a modulatory (e.g., inhibitory) amount of a compound of the invention.
  • a modulatory e.g., inhibitory
  • the compounds of the invention inhibit the activity of indoleamine-2,3-dioxygenase (IDO).
  • IDO indoleamine-2,3-dioxygenase
  • the compounds of the invention are useful for inhibiting the activity of IDO in cells or individuals in need of modulating the enzyme by administering an inhibitory amount of a compound of the invention.
  • the invention also provides methods of inhibiting tryptophan degradation in systems comprising cells expressing IDO, such as tissues, living organisms or cell culture.
  • the invention provides methods of altering (eg, increasing) extracellular tryptophan levels in a mammal by administering an effective amount of a compound or composition provided herein. Methods for measuring tryptophan levels and tryptophan degradation are routine in the art.
  • the invention also provides methods of immunosuppressing, such as IDO-mediated immunosuppression, in a patient by administering to the patient an effective amount of a compound or composition recited herein.
  • immunosuppressing such as IDO-mediated immunosuppression
  • IDO-mediated immunosuppression has been associated with, for example, cancer, tumor growth, Transfer, viral infection and viral replication are associated.
  • the invention further provides for treatment of an IDO activity or expression (including abnormal activity and/or overexpression) in a subject (e.g., a patient) by administering to a subject in need of such treatment a therapeutically effective amount or dose of a compound of the invention or a pharmaceutical composition thereof.
  • a subject e.g., a patient
  • Example diseases can include any disease, disorder, or condition that is directly or indirectly related to the expression or activity of an IDO enzyme, such as overexpression or abnormal activity.
  • IDO related diseases can also include any disease, disorder or condition that can be prevented, ameliorated or cured by modulating enzyme activity.
  • IDO-related diseases include cancer, viral infections such as HIV infection, HCV infection, depression, neurodegenerative diseases such as Alzheimer's disease and Huntington's disease, trauma, age-related cataracts, organ transplantation (eg, organ transplant rejection), and autoimmunity Sexual diseases, including asthma, rheumatoid arthritis, multiple sclerosis, allergic inflammation, inflammatory bowel disease, psoriasis and systemic lupus erythematosus.
  • cell means a cell in vitro, ex vivo or in vivo.
  • the ex vivo cells can be part of a tissue sample that is excised from an organism, such as a mammal.
  • the in vitro cells can be cells in cell culture.
  • the cells in vivo are cells that are active in an organism, such as a mammal.
  • Types of cancer that can be treated with the compounds of the invention include, but are not limited to, brain cancer, skin cancer, bladder cancer, ovarian cancer, breast cancer, gastric cancer, pancreatic cancer, prostate cancer, colon cancer, blood cancer, lung cancer, and bone cancer.
  • Examples of the above cancer types include neuroblastoma; intestinal cancer such as rectal cancer, colon cancer, familial adenomatous polypoid cancer, and hereditary non-polyposis colorectal cancer; esophageal cancer; lip cancer; laryngeal cancer; hypopharyngeal cancer; Tongue cancer; salivary adenocarcinoma; gastric cancer; adenocarcinoma, medullary thyroid carcinoma; papillary thyroid carcinoma; renal cancer; renal parenchymal carcinoma; ovarian cancer; cervical cancer; endometrial cancer; endometrial cancer; choriocarcinoma; pancreatic cancer; Prostate cancer; testicular cancer; breast cancer; urinary cancer; melanoma; brain tumors such as glioblastoma, astrocytoma, meningiomas, medulloblastoma and peripheral neuroectodermal tumors; Hodgkin's lymphoma Non-Hodgkin's lymphoma
  • the invention provides a method of providing an autoimmune disease treated by a compound or composition of the invention to a patient in need thereof.
  • autoimmune diseases include, but are not limited to, collagen diseases such as rheumatoid arthritis, systemic lupus erythematosus, Sharp syndrome; CREST syndrome (calcium deposition, Raynaud's syndrome, esophageal dysfunction, capillaries) Expansion); dermatomyositis; vasculitis (Wegener's disease) and Sjogren's syndrome; nephropathy, such as Goodpaschi syndrome; rapid progressive glomerulonephritis and membranous proliferative glomerulonephritis type II Endocrine diseases such as type I diabetes; autoimmune polyendocrine adenosis - candidiasis - ectodermal dystrophy (APECED); autoimmune parathyroid disease; pernicious anemia; gonadal insufficiency;
  • APECED autoimmune
  • One or more other drugs or treatments such as antiviral agents, chemotherapeutic or other anticancer agents, immunopotentiators, immunosuppressive agents, radiation therapy, anti-tumor and antiviral vaccine therapies, cytokine therapies (eg IL2 and GM-CSF) and/or tyrosine kinase inhibitors, optionally in combination with a compound of the invention, are useful in the treatment of IDO related diseases, disorders or conditions.
  • the agents may be combined with the compounds of the invention in a single dosage form, or the agents may be administered simultaneously or sequentially as separate dosage forms.
  • Suitable combination anticancer drugs include antibody therapeutics such as trastuzumab (Herceptin), antibodies against costimulatory molecules such as CTLA-4, 4-1BB, PD-1/PD-L1, CART, or against cells An antibody to a factor (IL-1O or TGF- ⁇ ).
  • trastuzumab Herceptin
  • costimulatory molecules such as CTLA-4, 4-1BB, PD-1/PD-L1, CART
  • IL-1O or TGF- ⁇ an antibody to a factor
  • Suitable chemotherapeutic agents or other anticancer agents include, for example, alkylating agents (including but not limited to nitrogen mustards, ethyleneimine derivatives, alkyl sulfonates, nitrosoureas, and triazines) such as urine.
  • alkylating agents including but not limited to nitrogen mustards, ethyleneimine derivatives, alkyl sulfonates, nitrosoureas, and triazines
  • alkylating agents including but not limited to nitrogen mustards, ethyleneimine derivatives, alkyl sulfonates, nitrosoureas, and triazines
  • alkylating agents including but not limited to nitrogen mustards, ethyleneimine derivatives, alkyl sulfonates, nitrosoureas, and triazines
  • Suitable chemotherapy or other anticancer agents include, for example, antimetabolites (including but not limited to folic acid antagonists, pyrimidine analogs guanidine analogs, and adenosine deaminase inhibitors) such as methotrexate, 5-fluorouracil, fluorouridine , cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, pentastatin and gemcitabine.
  • antimetabolites including but not limited to folic acid antagonists, pyrimidine analogs guanidine analogs, and adenosine deaminase inhibitors
  • methotrexate including but not limited to folic acid antagonists, pyrimidine analogs guanidine analogs, and adenosine deaminase inhibitors
  • methotrexate including but not limited to folic acid antagonists, pyrimidine analogs guanidine analogs, and adenosine deamina
  • Suitable chemotherapeutic or other anticancer agents also include, for example, certain natural products and derivatives thereof (eg, vinca alkaloids, antitumor antibiotics, enzymes, lymphokines and epipodophyllotoxin, vinblastine, vincristine, vinca) Xin, bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, cytarabine, paclitaxel (taxol), mithramycin, deoxycorthromycin , mitomycin-C, L-asparaginase, interferon (especially IFN-a), etoposide and teniposide.
  • certain natural products and derivatives thereof eg, vinca alkaloids, antitumor antibiotics, enzymes, lymphokines and epipodophyllotoxin, vinblastine, vincristine, vinca
  • Xin eg, vinca alkaloids, antitumor antibiotics
  • cytotoxic agents include Noviben, CPT-11, anastrozole, letrozole, capecitabine, raloxifene, and droloxifene.
  • cytotoxic agents such as epipodophyllotoxin, anti-tumor enzymes, topoisomerase inhibitors, procarbazine, mitoxantrone, platinum coordination complexes such as cisplatin and carboplatin, biological reactions Modulators, growth inhibitors, anti-hormone therapeutics, folinic acid, tegafur, and hematopoietic growth factors.
  • anticancer agents also include those that block the migration of immune cells, such as chemokine receptor antagonists including CCR2 and CCR4.
  • anticancer agents also include those that enhance the immune system, such as adjuvants or adoptive T cell metastases.
  • Anticancer vaccines include dendritic cells, synthetic peptides, DNA vaccines, and recombinant viruses.
  • compositions of the invention may optionally include at least one signal transduction inhibitor (STI).
  • STI signal transduction inhibitor
  • a "signal transduction inhibitor” is an agent that selectively inhibits a signal transduction pathway in one or more important steps in the normal function of cancer cells, thereby causing apoptosis.
  • Suitable STIs include, but are not limited to, (i) bcr/abl kinase inhibitors, such as STI571; (ii) epidermis Growth factor (EGF) receptor inhibitors, such as kinase inhibitors (SSI-774) and antibodies; (iii) HER-2/neu receptor inhibitors, such as farnesyltransferase inhibitors (FTI), such as L- 744,832; (iv) an inhibitor of the Akt family kinase or Akt pathway, such as rapamycin (see, eg, Sekulic et al., Cancer Res., 60:3504-3513 (2000)); (v) a cell cycle kinase inhibitor, For example, flirapine and UCN-O1; and (vi) phosphatidylinositol kinase inhibitors, such as LY294002 (see, eg, Vlahos et al., J.
  • At least one STI and at least one IDO inhibitor can be in separate pharmaceutical compositions.
  • at least one IDO inhibitor and at least one STI can be administered to the patient simultaneously or sequentially.
  • at least one IDO inhibitor can be administered first, or at least one STI can be administered first, or at least one IDO inhibitor and at least one STI can be administered at the same time.
  • the compounds can be administered in any order.
  • the invention also provides a pharmaceutical composition for treating a chronic viral infection in a patient comprising at least one IDO inhibitor, optionally at least one chemotherapeutic agent, and optionally at least one disease resistant agent in a pharmaceutically acceptable carrier Toxic agent.
  • the pharmaceutical composition may include at least one IDO inhibitor of the invention.
  • At least one of the IDO inhibitors of the pharmaceutical composition is selected from the group consisting of compounds of formula (I).
  • the invention also provides a method for treating a chronic viral infection by administering an effective amount of the above pharmaceutical composition in a patient.
  • at least one IDO inhibitor can be administered to the patient simultaneously or sequentially and at least A chemotherapeutic agent.
  • at least one IDO inhibitor can be administered first, or at least one chemotherapeutic agent can be administered first, or at least one IDO inhibitor and at least one STI can be administered at the same time.
  • the compound can be administered in any order.
  • any antiviral agent or STI can be administered at any point as compared to administration of an IDO inhibitor.
  • Chronic viral infections that can be treated using this combination therapy include, but are not limited to, diseases caused by the following viruses: hepatitis C virus (HCV), human papillomavirus (HPV), cytomegalovirus (CMV), herpes simplex virus ( HSV), Epstein-Barr virus (EBV), varicella zoster virus, Coxsackie virus, human immunodeficiency virus (HIV).
  • HCV hepatitis C virus
  • HPV human papillomavirus
  • CMV cytomegalovirus
  • HSV herpes simplex virus
  • EBV Epstein-Barr virus
  • varicella zoster virus Coxsackie virus
  • Coxsackie virus human immunodeficiency virus
  • a pharmaceutical composition comprising at least one IDO inhibitor of the invention can be administered to a patient to prevent arterial restenosis, such as balloon restenosis or arterial restenosis after stent placement.
  • the pharmaceutical composition further comprises at least one taxane (e.g., paclitaxel (Taxel); see, e.g., Scheller et al., Circulation, 110: 810-814 (2004)).
  • Suitable antiviral agents contemplated for use in combination with the compounds of the invention may include nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors, and other antiviral drugs.
  • NRTIs nucleoside and nucleotide reverse transcriptase inhibitors
  • NRTIs non-nucleoside reverse transcriptase inhibitors
  • protease inhibitors and other antiviral drugs.
  • NRTI examples include zidovudine (AZT), didanosine (ddl), zalcitabine (ddC), stavudine (d4T), lamivudine (3TC), abacavir ( 1592U89), adefovir dipivoxil [double (POM)-PMEA], tenofovir disoproxil, lobucarbe (BMS-180194), BCH-I0652, emtricitabine [(-)-FTC], ⁇ -L-FD4 (also known as ⁇ -L-D4C and named ⁇ -L-2', 3'-dideoxy-5-fluoro-cytidine), DAPD((-)- ⁇ -D-2,6 - Diaminopurine dioxolane) Lod Adenosine (FddA).
  • ZT zidovudine
  • ddl didanosine
  • ddC zalcitabine
  • d4T stav
  • Typical fit NNRTI includes nevirapine (BI-RG-587), delavirdine (BHAP, U-90152), efavirenz (DMP-266), PNU-142721, AG-1549, MKC-442 (1-(ethoxy) -Methyl)-5-(1-methylethyl)-6-(phenylmethyl)-(2,4(1H,3H)-pyrimidinedione), and (+)-calanolide A (NSC- 675451) and B.
  • Typical suitable protease inhibitors include saquinavir (Ro 31-8959), ritonavir (ABT-538), indinavir (MK-639), nelfinavir (AG) -1343), aprenavir (141W94), rasinavir (BMS-234475), DMP-450, BMS-2322623, ABT-378, and AG-1549.
  • Other antiviral agents include hydroxyurea, ribavi Lin, IL-2, IL-12, pentafoxi.
  • kits useful for, for example, treating or preventing an IDO-associated disease or condition, obesity, diabetes, and other diseases referred to herein comprising one or more containers containing a pharmaceutical composition, the pharmaceutical composition A therapeutically effective amount of a compound of the invention is included.
  • kits also include, if desired, one or more different conventional pharmaceutical kit components, such as containers and one or more pharmaceutically acceptable carriers, other containers, as will be apparent to those skilled in the art.
  • the kit may also contain instructions, either as an insert or label, indicating the amount of components to be administered, guidelines for administration, and/or guidelines for mixing the components.
  • Combination therapy is intended to include administering the therapeutic agents in a sequential manner, i.e., wherein each therapeutic agent is administered at different times, and the therapeutic agents or at least two of the therapeutic agents are administered in a substantially simultaneous manner.
  • Substantially simultaneous administration can be achieved, for example, by administering to the subject a fixed ratio of each therapeutic agent or multiple single dosage forms in the form of each therapeutic agent.
  • the sequential or substantially simultaneous administration of each therapeutic agent can be accomplished by any suitable route including, but not limited to, the oral route, the intravenous route, the intramuscular route, and direct absorption through mucosal tissue.
  • the therapeutic agent can be administered by the same route or by different routes.
  • the first therapeutic agent of the selected combination can be administered by intravenous injection and the other therapeutic agents of the combination can be administered orally.
  • all therapeutic agents can be administered orally or all therapeutic agents can be administered by intravenous injection.
  • Combination therapies can also include the administration of the above therapeutic agents in further combination with other biologically active ingredients and non-pharmacological therapies, such as surgery or radiation therapy.
  • the combination therapy further includes non-pharmacological treatment
  • the non-pharmacological treatment can be performed at any suitable time as long as the synergistic effect from the combination of the therapeutic agent and the non-pharmacological treatment is achieved. For example, where appropriate, when non-drug treatment is temporarily removed from the administration of the therapeutic agent, it may be days or even weeks to achieve a beneficial effect.
  • Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ocular, pulmonary, transdermal, vaginal, oral canal. , nasal administration and topical administration.
  • parenteral administration includes intramuscular, subcutaneous, intravenous, intramedullary, ventricular, intraperitoneal, intralymphatic, and intranasal injections.
  • the modes of administration of the compounds described herein are topical rather than systemic.
  • the drug depot is administered by implantation (e.g., subcutaneously or intramuscularly) or by intramuscular injection.
  • the drug is administered by a targeted drug delivery system.
  • liposomes encapsulated by organ-specific antibodies In this particular embodiment, the liposomes are selectively directed to a particular organ and absorbed.
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of one or more compounds of formula (I) formulated with one or more pharmaceutically acceptable carriers (additives) and/or diluents, and optionally One or more of the other therapeutic agents described above.
  • the compounds of the invention may be administered by any suitable means for any of the above uses, for example, orally, such as tablets, pills, powders, granules, elixirs, elixirs, suspensions (including nanosuspensions, microsuspensions, spray dried Dispersion), syrup and emulsion; sublingual; buccal; parenteral, such as by subcutaneous, intravenous, intramuscular or intrasternal injection or infusion techniques (eg, in sterile injectable aqueous or nonaqueous solutions or suspensions) Nasal, including nasal administration, such as by inhalation spray; topical, such as in the form of a cream or ointment; or transrectal, such as in the form of a suppository. They can be administered alone, but are usually administered using a pharmaceutical carrier selected based on the chosen route of administration and standard pharmaceutical practice.
  • Pharmaceutical carriers are formulated according to a number of factors within the scope of those skilled in the art. These factors include, but are not limited to, the type and nature of the active agent being formulated; the subject to which the active agent-containing composition is to be administered; the intended route of administration of the composition; and the targeted therapeutic indication.
  • Pharmaceutically acceptable carriers include aqueous and non-aqueous liquid vehicles and various solid and semi-solid dosage forms.
  • the above carriers may include a number of different ingredients and additives in addition to the active ingredients, which are included in the formulation for various reasons well known to those skilled in the art, such as stabilizing active agents, binders and the like.
  • suitable pharmaceutical carriers and carriers can be found in a number of readily available sources, such as Allen, LV Jr. et. al. Remington: The Science and Practice of Pharmacy (2 Volumes), 22nd Edition ( 2012), Pharmaceutical Press.
  • the dosage regimen of the compounds of the invention will vary depending on known factors, such as the pharmacodynamic properties of the particular agent and its mode of administration and route; the species, age, sex, health, medical condition and weight of the recipient The nature and extent of the symptoms; the type of treatment at the same time; the frequency of treatment; the route of administration, the kidney and liver function of the patient, and the desired effect.
  • the daily oral dose of each active ingredient should be from about 0.001 mg/day to about 10-5000 mg/day, preferably from about 0.01 mg/day to about 1000 mg/day, and most preferably The ground is from about 0.1 mg/day to about 250 mg/day.
  • the most preferred intravenous dose during a constant rate infusion should be from about 0.01 mg/kg/min to about 10 mg/kg/min.
  • the compounds of the invention may be administered in a single daily dose, or the total daily dose may be administered in divided doses of two, three or four times daily.
  • the compounds are usually administered in a suitable pharmaceutical diluent, excipient or carrier, as appropriate in accordance with the intended mode of administration (for example, oral administration of tablets, capsules, elixirs and syrups) and in accordance with conventional pharmaceutical practice. Administration is carried out in the form of a mixture of the medium and the drug carriers.
  • Dosage forms suitable for administration may contain from about 1 mg to about 2000 mg of active ingredient per dosage unit.
  • the active ingredient will generally be present in an amount of from about 0.1% to about 95% by weight, based on the total weight of the composition.
  • a typical capsule for oral administration contains at least one compound of the invention (250 mg), lactose (75 mg) and magnesium stearate (15 mg). The mixture was passed through a 60 mesh screen and packaged into size 1 gelatin capsules.
  • a typical injectable preparation can be prepared by sterilizing at least one compound of the invention (250 mg) in a vial, lyophilizing and sealing in a sterile manner. For use, the contents of the bottle were mixed with 2 mL of physiological saline to produce an injectable preparation.
  • the scope of the invention includes (alone or in combination with a pharmaceutical carrier) comprising a therapeutically effective amount of at least one compound of the invention A pharmaceutical composition as an active ingredient.
  • the compounds of the invention may be used alone, in combination with other compounds of the invention or in combination with one or more other therapeutic agents, such as anti-cancer agents or other pharmaceutically active substances.
  • the compounds of the present invention (which may be used in a suitable hydrated form) and/or the pharmaceutical compositions of the present invention are formulated into pharmaceutical dosage forms by conventional methods known to those skilled in the art, regardless of the chosen route of administration.
  • the actual dosage level of the active ingredient in the pharmaceutical compositions of the present invention can be varied to achieve an amount of active ingredient that is effective to achieve a desired therapeutic response, composition, and mode of administration for a particular patient without toxicity to the patient.
  • the selected dosage level will depend on a variety of factors, including the activity of the particular compound of the invention or its ester, salt or amide employed; the route of administration; the time of administration; the excretion rate of the particular compound employed; the rate and extent of absorption. Duration of treatment; other drugs, compounds and/or substances used in combination with the particular compound used; factors known in the medical arts, such as age, sex, weight, condition, general health and prior medical history of the patient being treated.
  • a physician or veterinarian having ordinary skill in the art can readily determine and prescribe an effective amount of the desired pharmaceutical composition.
  • a physician or veterinarian can begin the contest of the compounds of the invention used in the pharmaceutical compositions below the desired level and gradually increase the dosage until the desired effect is achieved.
  • a suitable daily dose of a compound of the invention will be the amount of the compound which is the lowest dose effective to produce a therapeutic effect.
  • Such effective dosage will generally depend on the above factors.
  • oral, intravenous, intraventricular, and subcutaneous doses of a compound of the invention for a patient range from about 0.01 to about 50 mg/kg body weight per day.
  • an effective daily dose of the active compound may be administered separately in two, three, four, five, six or more sub-doses at appropriate intervals throughout the day, optionally in unit dosage form. In certain aspects of the invention, the administration is once a day.
  • the compound of the present invention can be administered alone, it is preferred to administer the compound in the form of a pharmaceutical preparation (composition).
  • Kits/product packages are also described herein for use in the treatment of the above indications. These kits may be comprised of a conveyor, a pack or a container, which may be divided into a plurality of compartments to accommodate one or more containers, such as vials, test tubes, and the like, each containing a container A single component of the method. Suitable containers include bottles, vials, syringes and test tubes. The container is made of materials such as glass or plastic that are acceptable.
  • the container may contain one or more of the compounds described herein, and the compound may exist as a pharmaceutical component or as a mixture with other ingredients described herein.
  • the container may have a sterile outlet (for example, the container may be an IV bag or bottle, and the stopper may be pierced by a hypodermic needle).
  • kits may carry a compound, as well as instructions, labels or instructions for use as described herein.
  • a typical kit may include one or more containers that are adapted to commercial promotion and user demand for compound use, each container containing one or more materials (eg, reagents, or concentrated mother liquor, and / Or equipment). These materials include, but are not limited to, buffers, diluents, filters, needles, syringes, conveyors, bags, containers, bottles and/or test tubes, with a list of contents and/or instructions for use, as well as instructions for the internal packaging. The entire set of instructions must be included.
  • materials eg, reagents, or concentrated mother liquor, and / Or equipment.
  • materials include, but are not limited to, buffers, diluents, filters, needles, syringes, conveyors, bags, containers, bottles and/or test tubes, with a list of contents and/or instructions for use, as well as instructions for the internal packaging. The entire set of instructions must be included.
  • the label can be displayed on or closely related to the container.
  • a label appears on a container, meaning that the label letter, number, or other feature is Pasting, molding, engraving on a container; labels can also be found in container boxes or shipping boxes containing a variety of containers, such as in product inserts.
  • a label can be used to indicate a particular therapeutic use of the contents.
  • the label may also indicate a usage statement for the content, such as described in the above method.
  • 2-formylbenzeneboronic acid (1.55 g, 6.88 mmol), 1-tritylmethyl-4-iodoimidazole (3.0 g, 4.59 mmol), potassium phosphate (4.38 g, 13.77 mmol), Pd(PPh 3 ) 4 (0.3 g, 10%, w/w%) was added to a mixed solution of DMF (30 mL) and water (6 mL), and the system was replaced with nitrogen four times, and reacted at 90 ° C overnight under nitrogen atmosphere. The reaction was completed by TLC. EtOAc was evaporated. EtOAc. The yield was 75.6%.
  • the BH 3 ⁇ THF (1M, 9.0mL , 9.0mmol) was added to (4-ethyl-cyclohexyl) benzene (1.62g, 8.7mmoL) and anhydrous THF (74.5mL) mixed solution, stirred at room temperature overnight.
  • the reaction was complete by TLC.
  • Aqueous NaOH was added under ice (3M, 12.5mL) and H 2 O 2 (30%, 12.5mL). The ice bath was removed and stirred at room temperature for 3 hours.
  • the volatile matter was evaporated under reduced pressure and extracted with ethyl acetate.
  • the organic phase was evaporated under reduced pressure and the residue was purified by flash column chromatography.
  • keto-1-one 1-(4-(1-ethyl-1H-indazol-5-yl)cyclohexyl)-2-(6-fluoro-5H-imidazo[5,1-a]isoindole-5-)
  • the preparation of keto-1-one is the same as in Example 3 (1-hydroxy-4-phenylcyclohexyl)-2-(5H-imidazo[5,1-a]isoindole-5-yl)-1- Preparation of ethyl ketone.
  • Cyclohexyl)ethan-1-one is the same as (1-hydroxy-4-phenylcyclohexyl)-2-(5H-imidazo[5,1-a]isoindole-5-yl)-1- in Example 3. Preparation of ethyl ketone. The yield was 42%.
  • Test buffer solution 400 ⁇ M L-tryptophan, 20 mM ascorbate, 20 ⁇ M methyl blue, 1000 U/mL catalase, 100 mM PBS, pH 6.5;
  • reaction mixing system 50 nM of hIDO and a certain concentration of the test compound were added to 100 ⁇ L of the buffer solution. hIDO and buffer should be preheated to 37 ° C;
  • IDO-1 enzyme level
  • the cell culture plate 3903 was allowed to equilibrate for 30 minutes at room temperature.
  • IDO cell level assays are shown in the table below. IDO-1, Hela cells.
  • IDO cell level assays are shown in the table below. IDO-1, HEK293 cells.
  • Test buffer solution 400 ⁇ M L-tryptophan, 20 mM ascorbic acid, 20 ⁇ M methyl blue, 1000 U/ml catalase, 100 mM PBS, pH 6.5;
  • reaction solution 200 ng of TDO and different concentrations of the compound to be tested were added to 100 ⁇ L of the reaction buffer solution.
  • the TDO and the buffer solution are preheated at 37 ° C first;
  • TDO enzyme level
  • test drug delivery solution was completed at CRO according to the following preparation instructions provided by the customer.
  • the test sample is prepared as a free radical concentration, and the purity does not need to be converted.
  • test substance An appropriate amount of the test substance was weighed and dissolved in 10% DMA + 90% physiological saline to obtain a colorless clear solution (pH ⁇ 7) at a concentration of 2 mg/mL for intravenous administration.
  • the intravenous administration group collected samples at 0.083h, 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h and 24h before and after administration; the oral administration group was 0.25h before and after administration.
  • 0.5h, 1h, 2h, 4h, 6h, 8h, 10h and 24h blood was collected from the jugular vein by about 0.25mL, heparin sodium was anticoagulated, blood samples were collected and placed on ice, and the plasma was separated by centrifugation (centrifugation conditions: 8000 rpm) , 6 minutes, 4C).
  • the collected plasma was stored at –80C prior to analysis.
  • the BLQ before C max (including “No peak”) is calculated as 0; the BLQ (including “No peak”) appearing after C max is not involved in the calculation.
  • the Phoenix WinNonlin 7.0 software calculates the following pharmacokinetic parameters: AUC (0-t) , AUC (0- ⁇ ) , T 1/2 , MRT (0- ⁇ ) , C max , T max, F.

Abstract

一种或多种吲哚胺2，3-双加氧酶的抑制剂化合物，包含该化合物的药物组分及制剂，及这类吲哚胺2，3-双加氧酶抑制剂的用途，可单一用药或与其它药物联合用药，用来治疗与吲哚胺2，3-双加氧酶相关的症状。

Description

吲哚胺2，3-双加氧酶抑制剂及其在药学中的用途 技术领域
本发明涉及化合物，制备化合物的方法，化合物的药物组合物和药剂，及将该化合物用于治疗、预防、诊断一种或多种吲哚胺2，3-双加氧酶相关的疾病、失调或症状。
背景技术
肿瘤是人类第一大致死、致残恶性疾病。目前在肿瘤领域、肿瘤相关领域和功能化失调领域治疗的发展趋势，在于将肿瘤免疫治疗和传统的化疗和及放疗相互结合。与传统的化疗比较，肿瘤免疫疗法通过激活人体自身的免疫***而识别和清除作为外来入侵者的肿瘤细胞，因而肿瘤免疫策略具有临床效果好、毒副作用小的显著特点。目前一般认为，肿瘤免疫疗法是治愈肿瘤的终极策略。
吲哚胺2,3-双加氧酶(IDO，也称为IDO1)是一个靶向IFN-γ的基因，它在人体的免疫调控中承担了重要功能：代谢色氨酸生成犬尿氨酸(此途径即为色氨酸的犬尿氨酸代谢途径)。免疫***中色氨酸的浓度和T细胞正性相关。在肿瘤免疫微环境中，活化或过表达的IDO导致色氨酸耗竭，而后导致T细胞死亡、免疫***失活，并最终导致发生肿瘤免疫耐受和免疫逃逸。现有研究表明，由IDO所导致的免疫平衡失调深入的参与了肿瘤的生成和进展。因而IDO受体已成为肿瘤等免疫治疗的重要靶点。
IDO除了和肿瘤相关外，也和病毒感染、抑郁、器官移植排斥或自身免疫性疾病相关。因而，靶向IDO的药物对于治疗上述疾病也具有巨大价值。
IDO抑制剂类抗肿瘤药物的研究目前在全球范围内已取得重要进展，如INCB024360和NLG919均已进入临床。但INCB024360由于存在毒副作用问题，致使现有临床研究剂量(50mg bid,或100mg bid)是最佳剂量(300mg bid,600mg bid)的30％左右，临床活性受到很大限制；同时INCB024360的毒性基团又是药效团，INCB024360及其衍生物存在毒性较大的问题。NLG919的安全性较好，但NLG919的生物活性较差。因而基于NLG919，开展具有高生物活性、高安全性的新型化合物研究，这对于发现临床治疗活性更好如可能治愈肿瘤而非仅仅抑制肿瘤的新型IDO类肿瘤免疫治疗药物，具有非常重要的现实意义。
在NLG919的化合物核心专利US2014066625A1中，同时也报道了两个具有芳杂基-环杂烷基结构的NLG919结构衍生物[Compound X和Y(自命名),US2014066625A1，P53和P9]。但此两衍生物对IDO的实测酶水平活性显著弱于NLG919。在药学研究中，环杂烷基与环烷基/环烯基/芳(杂)基的结构间细微差异有时可能会带来化合物活性的较大变化。
Figure PCTCN2017095669-appb-000001
因此，本领域迫切需要提供可能存在的高活性IDO抑制剂。
发明内容
本发明旨在提供一类具有芳(杂)环-环烷基/环烯基/芳(杂)基结构片段的化合物、药物组合物，药剂和方法，可用于(a)诊断、预防、治疗与一种或多种吲哚胺2，3-双加氧酶相关的疾病、失调或症状；(b)减轻与吲哚胺2，3-双加氧酶相关的副作用或症状；(c)控制与一种或多种吲哚胺2，3-双加氧酶相关的疾病、失调或症状。这些疾病、失调或症状可能是由一个或多个遗传性的、医疗性的、免疫性的、感染性的、代谢性的、肿瘤性的、毒性的、手术性的和/或创伤性的病因学引起的。在一方面，在此阐述的方法、化合物、药物组合物和药剂由抑制一种或多种吲哚胺2，3-双加氧酶活性的抑制剂构成。
在本发明的第一方面，提供了一种式(I)化合物或其药学上可接受的盐，水合物、溶剂化物、同位素化合物或前药：
Figure PCTCN2017095669-appb-000002
式(I)
其中：
X和Y分别是N,O或C，且X和Y中至少有一个为N原子；
R1是H,卤素，烷氧基，取代的烷氧基，腈基，胺基，取代的胺基，或取代的巯基；
R2和R3分别是H，卤素，腈基，胺基，取代的胺基，硝基，取代的C1-C6烷基，取代的C1-C6烯基，取代的C1-C6炔基，烷氧基，取代的烷氧基，环烷基，取代的环烷基，环杂烷基，取代的环杂烷基，酯基，酰胺基，取代的羰基，取代的砜基，取代的磺酰胺基，取代的磺酸基，取代的膦酸基，或取代的膦酰胺基；
或者，R2和R3相互连接，构建成取代的或未取代的饱和环烷基、取代的或未取代的饱和环杂烷基、取代的或未取代的芳基、取代的或未取代的芳杂基；
R4是H，取代或未取代的C1-C6烷基，取代或未取代的C1-C6烯基或取代或未取代的 C1-C6炔基；
R5是H，或OH；
n为0-2的整数；
Figure PCTCN2017095669-appb-000003
是C3-C8环烷基，取代的C3-C8环烷基，环烯基，取代的环烯基，取代的或未取代的桥环基，或取代的或未取代的螺环基，取代的或未取代的芳基，取代的或未取代的芳杂基；
Figure PCTCN2017095669-appb-000004
是C3-C6环烷基，C3-C6饱和环杂烷基，取代的或未取代的芳基，取代的或未取代的芳杂基。
在另一优选例中，R5是OH。
在另一优选例中，
Figure PCTCN2017095669-appb-000005
是苯基、吡啶基、咪唑基、噁唑基、喹啉基、取代或未取代的吲唑基。
在另一优选例中，
Figure PCTCN2017095669-appb-000006
是取代的或未取代的
Figure PCTCN2017095669-appb-000007
Figure PCTCN2017095669-appb-000008
在另一优选例中，本发明提供的化合物，选自但不局限于以下化合物：
Figure PCTCN2017095669-appb-000009
Figure PCTCN2017095669-appb-000010
Figure PCTCN2017095669-appb-000011
Figure PCTCN2017095669-appb-000012
Figure PCTCN2017095669-appb-000013
Figure PCTCN2017095669-appb-000014
在本发明的第二方面，提供了一种药物组合物，该组合包含如上所述的本发明提供的化合物和药学上可接受的赋形剂。
在另一优选例中，所述药物组合物的形式为水性分散剂、液体、啫哩、糖浆、西也剂、药浆、悬浮液、气雾剂、速溶剂、泡腾剂、冻干剂、片剂、粉末、药丸、糖衣丸、胶囊、多微粒剂、或立即释放剂。
在本发明的第三方面，提供了一种如上所述的本发明提供的化合物或其药学上可接受的盐、水合物、溶剂化物、同位素化合物或前药在制备治疗癌症、病毒感染、器官移植排斥或自身免疫性疾病的药物中的应用。
在另一优选例中，所述治疗癌症、病毒感染、器官移植排斥或自身免疫性疾病是将如上所述的本发明提供的化合物或其药学上可接受的盐、水合物、溶剂化物、同位素化合物或前 药作为活性成分；或是将如上所述的本发明提供的化合物或其药学上可接受的盐、水合物、溶剂化物、同位素化合物或前药与如PD-1/PD-L1、CTLA-4、CART等靶点药物联合使用。
在另一优选例中，所述癌症选自皮肤癌、膀胱癌、卵巢癌、乳腺癌、胃癌、胰腺癌、***癌、结肠癌、肺癌、骨癌、脑癌、神经细胞瘤、直肠癌、结肠癌、家族性腺瘤性息肉性癌、遗传性非息肉性结直肠癌、食管癌、唇癌、喉癌、下咽癌、舌癌、唾液腺癌、胃癌、腺癌、甲状腺髓样癌、***状甲状腺癌、肾癌、肾实质癌、卵巢癌、***、子宫体癌、子宫内膜癌、绒毛膜癌、胰腺癌、***癌、睾丸癌、泌尿癌、黑素瘤、脑肿瘤诸如成胶质细胞瘤、星形细胞瘤、脑膜瘤、成神经管细胞瘤和外周神经外胚层肿瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、伯基特淋巴瘤、急性淋巴性白血病(ALL)、慢性淋巴性白血病(CLL)、急性骨髓性白血病(AML)、慢性粒细胞白血病(CML)、成人T细胞白血病淋巴瘤、弥漫性大B细胞淋巴瘤(DLBCL)、肝细胞癌、胆囊癌、支气管癌、小细胞肺癌、非小细胞肺癌、多发性骨髓瘤、基底细胞瘤、畸胎瘤、成视网膜细胞瘤、脉络膜黑素瘤、***瘤、横纹肌肉瘤、颅咽管瘤、骨肉瘤、软骨肉瘤、肌肉瘤、脂肪肉瘤、纤维肉瘤、尤因肉瘤或浆细胞瘤。
在本发明的第四方面，提供了一种如上所述的本发明提供的化合物的制备方法，所述方法包括下述一般制备步骤：
将起始原料i和ii在金属钯催化剂参与下发生suzuki偶联反应，得到中间体iii；而后此中间体与甲基酮衍生物在碱性条件下生成α，β-不饱和酮(中间体iv)；继而中间体iv在酸性条件下脱保护基进而环合，得到中间体v；最后将中间体v中的羰基还原，制得如上所述的本发明提供的化合物；
Figure PCTCN2017095669-appb-000015
或将中间体v与格式试剂反应，得到如上所述的本发明提供的化合物；
Figure PCTCN2017095669-appb-000016
或将起始原料i与甲基酮衍生物在碱性条件下生成α，β-不饱和酮(中间体v-i)；在格式试剂、CuCl存在条件下，中间体v-i先与碘化物反应，而后在AcOH条件下脱保护基，得到中间体v-i；继而，中间体v-i发生分子内环合，制得中间体v-ii；最后将中间体v-ii的羰 基下还原，得到如上所述的本发明提供的化合物；
Figure PCTCN2017095669-appb-000017
在另一优选例中，所述金属钯催化剂选自Pd(PPh3)4、Pd(OAc)2、PdCl2、Pd(PPh3)2Cl2等过渡金属催化剂。
在另一优选例中，所述碱性条件包括NaOEt、MeONa、Cs2CO3等存在的情况。
在另一优选例中，所述酸性条件包括HOAc、HCl、H2SO4、甲磺酸、或对甲苯磺酸等存在的条件。
在本发明的第五方面，提供了一种药盒，所述药盒中含有如上所述的本发明提供的化合物或其药学上可接受的盐、水合物、溶剂化物、同位素化合物或前药，以及选自下述的一种以上的靶点药物：PD-1/PD-L1、CTLA-4、CART靶点药物。
在本发明的第六方面，提供了一种如上所述的本发明提供的化合物或其药学上可接受的盐、水合物、溶剂化物、同位素化合物或前药在治疗癌症、病毒感染、器官移植排斥或自身免疫性疾病中的应用。
在另一优选例中，所述治疗包括将如上所述的本发明提供的化合物或其药学上可接受的盐、水合物、溶剂化物、同位素化合物或前药单独给药；或将如上所述的本发明提供的化合物或其药学上可接受的盐、水合物、溶剂化物、同位素化合物或前药与选自下述的一种以上：PD-1/PD-L1、CTLA-4、CART靶点药物联合给药。
在另一优选例中，所述癌症选自皮肤癌、膀胱癌、卵巢癌、乳腺癌、胃癌、胰腺癌、***癌、结肠癌、肺癌、骨癌、脑癌、神经细胞瘤、直肠癌、结肠癌、家族性腺瘤性息肉性癌、遗传性非息肉性结直肠癌、食管癌、唇癌、喉癌、下咽癌、舌癌、唾液腺癌、胃癌、腺癌、甲状腺髓样癌、***状甲状腺癌、肾癌、肾实质癌、卵巢癌、***、子宫体癌、子宫内膜癌、绒毛膜癌、胰腺癌、***癌、睾丸癌、泌尿癌、黑素瘤、脑肿瘤诸如成胶质细胞瘤、星形细胞瘤、脑膜瘤、成神经管细胞瘤和外周神经外胚层肿瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、伯基特淋巴瘤、急性淋巴性白血病(ALL)、慢性淋巴性白血病(CLL)、急性骨髓性白血病(AML)、慢性粒细胞白血病(CML)、成人T细胞白血病淋巴瘤、弥漫性大B细胞淋巴瘤(DLBCL)、肝细胞癌、胆囊癌、支气管癌、小细胞肺癌、非小细胞肺癌、多发性骨髓瘤、基底细胞瘤、畸胎瘤、成视网膜细胞瘤、脉络膜黑素瘤、***瘤、横纹肌肉瘤、颅咽管瘤、骨肉瘤、软骨肉瘤、肌肉瘤、脂肪肉瘤、纤维肉瘤、尤因肉瘤或浆细胞瘤。
据此，本发明提供了高效、低毒的新型IDO抑制剂。
在下面的说明中将会详细阐述上述化合物、方法、药物组合物的各个具体方面、特性和优势，使本发明的内容变得十分明了。在此应理解，下述的详细说明及实例描述了具体的实施例，仅用于参考。在阅读了本发明的说明内容后，本领域的技术人员可对本发明作各种改动或修改，这些等价形势同样落于本申请所限定的范围。
具体实施方式
1.本发明提供的系列化合物，酶水平、细胞水平(包括Hela细胞和HEK293)活性均显著优于NLG919。如酶水平活性，化合物39比NLG919高7倍；Hela细胞活性，化合物39比NLG919高64倍；HEK293细胞活性，化合物39比NLG919高29倍。
2.本发明同时发现了一个新型且重要的构效关系，即除了已知的2-位羟基(如NLG919中的仲羟基)外，2-位羟基的邻位羟基即3-位羟基(叔羟基，如化合物39中情形)的同时存在，能显著增加此类化合物的细胞水平活性，活性增加2-3倍。
3.本发明中，所引入的芳(杂)基(即本发明提供的化合物的
Figure PCTCN2017095669-appb-000018
部分)对于化合物活性提高也有非常好的影响，如酶水平活性增加2-3倍。
4.此外，本发明提供化合物
Figure PCTCN2017095669-appb-000019
部分所引入的芳基和芳杂基这两类取代基，以及各种不同的芳杂环取代基之间，化合物的细胞水平活性具有数量级上的差异，如含芳基的化合物(化合物6-7,10-17)细胞水平EC50为100-200nM,含吡啶杂环化合物(化合物9)EC50为320nM，而含吲唑基化合物(如化合物39)则显示出极高细胞水平活性，其EC50为22.5nM。此部分研究表明选择合适的
Figure PCTCN2017095669-appb-000020
部分的极端重要性。
5.本发明提供的化合物，是类目前所追求的IDO/TDO双靶点抑制剂。如化合物39对TDO的酶水平抑制活性，IC50＝144.0nM，比NLG919高2倍左右。
6.本发明所提供的化合物，具有良好的药代性质，如化合物39的药代性质显著优于INCB024360(化合物39和INCB024360的药代参数依次对比如下：Cmax，3815.84ng/mL Vs.290.46ng/mL；AUC(0-t)，3815.84ng/mL Vs.1711.42h*ng/mL；F％，95Vs.44.)。
在此基础上，完成了本发明。
如本文所述化合物，可抑制一种或多种吲哚胺2，3-双加氧酶，本文所述的化合物作为吲哚胺2，3-双加氧酶抑制剂具有广泛的治疗作用。
化合物
本发明提供了一种式I化合物或其药学上可接受的盐，水合物，溶剂化物，同位素化合物或前药：
Figure PCTCN2017095669-appb-000021
其中，
X和Y分别是N,O或C，且X和Y中至少有一个为N原子；
R1是H,卤素，烷氧基，取代的烷氧基，腈基，胺基，取代的胺基，或取代的巯基；
R2和R3分别是H，卤素，腈基，胺基，取代的胺基，硝基，取代的C1-C6烷基，取代的C1-C6烯基，取代的C1-C6炔基，烷氧基，取代的烷氧基，环烷基，取代的环烷基，环杂烷基，取代的环杂烷基，酯基，酰胺基，取代的羰基，取代的砜基，取代的磺酰胺基，取代的磺酸基，取代的膦酸基，或取代的膦酰胺基；
或者，R2和R3相互连接，构建成取代的或未取代的饱和环烷基、取代的或未取代的饱和环杂烷基、取代的或未取代的芳基、取代的或未取代的芳杂基；
R4是H，取代或未取代的C1-C6烷基，取代或未取代的C1-C6烯基或取代或未取代的C1-C6炔基；
R5是H，或OH；
n为0-2的整数，例如0、1或2；
Figure PCTCN2017095669-appb-000022
是C3-C8环烷基，取代的C3-C8环烷基，环烯基，取代的环烯基，取代的或未取代的桥环烃，或取代的或未取代的螺环烃,取代的或未取代的芳基，取代的或未取代的芳杂基。
Figure PCTCN2017095669-appb-000023
是C3-C6环烷基，C3-C6饱和环杂烷基，,取代的或未取代的芳基，取代的或未取代的芳杂基。
在某些实施方式中，R5是OH。
在某些实施方式中，
Figure PCTCN2017095669-appb-000024
是苯基、吡啶基、咪唑基、噁唑基、喹啉基、取代或未取代的吲唑基。
在某些实施方式中，R4是H，C1-C3烷基，C1-C3烯基或C1-C3炔基。
在某些实施方式中，
Figure PCTCN2017095669-appb-000025
是取代的或未取代的C5-C7环烷基、二环[3.1.0]己烷基、或螺[3.5]壬烷基。
在某些实施方式中，R1是H、氟、氯、C1-C3烷氧基、卤代C1-C3烷氧基、腈基、C1-C3烷基胺基、或C1-C3烷基取代的巯基。
在某些实施方式中，n为0-3的整数，例如0、1、2和3。
在某些实施方式中，R2和R3分别是H、氟、氯、腈基、硝基、C1-C3烷基、卤代C1-C3烷基、C1-C3烯基、C1-C3炔基、C1-C3烷氧基、卤代C1-C3烷氧基、胺基、C1-C3烷基取代的胺基、C1-C3环烷基、C1-C3烷基取代的羰基、C1-C3烷氧基取代的羰基、C1-C3烷基取代的酰胺基、C1-C3烷基取代的磺酰胺基、C1-C3烷基取代的膦酸基、或C1-C3烷基取代的膦酰胺基。
在某些实施方式中，
Figure PCTCN2017095669-appb-000026
是未取代的、C1-C3烷基取代、或C1-C3环烷基取代的
Figure PCTCN2017095669-appb-000027
以上说明的对于不同变量的基团的任何组合在此都给予预期。
式(I)化合物包括但不限于表1中的说明。
表1。
Figure PCTCN2017095669-appb-000028
Figure PCTCN2017095669-appb-000029
Figure PCTCN2017095669-appb-000030
Figure PCTCN2017095669-appb-000031
Figure PCTCN2017095669-appb-000032
Figure PCTCN2017095669-appb-000033
化合物的合成
本发明化合物可通过诸如在利用本领域技术人员已知的化学转换的下列方案中所示那些方法来制备。本领域普通技术人员可容易地选择溶剂、温度、压力和其它反应条件。起始物质为市售的或容易地本领域普通技术人员制备。这些方案是说明性的而非意在限制本领域技术人员可用于制造本文所公开的化合物的可能的技术。不同的方法对本领域技术人员可能是显而易见的。此外，合成中的多个步骤可以交替顺序或次序进行，得到所期望的一种或多种化合物。此外，在这些方案中的反应描述为离散的步骤并不排除它们以串联方式进行或通过将多个步骤叠缩在同一反应容器中或通过进行多个步骤而无需纯化或表征一个或多个中20间体。此外，许多通过以下方法制备的化合物可使用本领域技术人员公知的常规化学进一步 修饰。通过引用的方式将本文引用的所有文献整体并入本文。涉及本文所用的多种所述化学转换可参见Smith,M.B.et al.,March’s Advanced OrganicChemistry Reactions,Mechanisms,and Structure,Fifth Edition,Wiley-Interscience,New York(2001)或主题为合成有机化学的其它标准文本。某些转换可能要求通过一种或多种保护基来掩蔽反应性官能团。可提供用于引入、除去的条件和对这些基团的反应条件的相对易感性的适宜文献为Greene,T.W.et al.,Protective Groups in Organic Synthesis,Third Edition,Wiley-Interscience,New York(1999)。
可通过在下列方案和工作实施例中所述的示例性方法及本领域技术人员所使用的相关公开文献程序来制备式(I)化合物。用于这些反应的示例性试剂和程序出现在下文和工作实施例中。下文方法中的保护和去保护可通过本领域中熟知的程序来进行(参见例如Greene,T.W.et al.,Protecting Groups in Organic Synthesis,3rd Edition,Wiley(1999))。有机合成和官能团转换的一般方法参见：Trost,B.M.et al.,eds.,Comprehensive Organic Synthesis:Selectivity,Strategy&Efficiency in Modern Organic Chemistry,Pergamon Press,New York,NY(1991)；March,J.,Advanced Organic Chemistry:Reactions,Mechanisms,and Structure.4th Edition,Wiley&Sons,New York,NY(1992)；Katritzky,A.R.et al.,eds.,Comprehensive Organic FunctionalGroups transformations,1st Edition,Elsevier Science Inc.,Tarrytown,NY(1995)；Larock,R.C.,Comprehensive Organic transformations,VCH Publishers,Inc.,New York,NY(1989)及其中的参考文献。
目标化合物的几种一般制备方法：
方法一：将起始原料i和ii在金属钯催化剂如Pd(PPh3)4、Pd(OAc)2等参与下发生suzuki偶联反应，得到中间体iii；而后此中间体与甲基酮衍生物在碱性条件下如NaOEt等存在条件下，生成α，β-不饱和酮(中间体iv)；中间体iv在酸性条件如HOAc、HCl、H2SO4、甲磺酸、对甲苯磺酸等条件下环合，得到关键中间体v；最后中间体的羰基在NaBH4/MeOH等条件下还原，制得目标产物I-1。
Figure PCTCN2017095669-appb-000034
方法二：将中间体v与格式试剂反应，即可得叔醇衍生物I-2。
Figure PCTCN2017095669-appb-000035
方法三：将起始原料i与甲基酮衍生物在碱性条件如NaOEt等存在条件下，生成α，β-不饱和酮(中间体v-i)；在格式试剂、CuCl存在条件下，中间体v-i先与碘化物反应，而后在AcOH条件下脱保护基，得到中间体v-i；继而，中间体v-i发生分子内环合，制得中间体v-ii；最后将中间体v-ii在如NaBH4/MeOH等条件下还原，制得目标产物I-3。
Figure PCTCN2017095669-appb-000036
式(I)化合物的合成在实施例中概述。
化合物的进一步形式
在某个具体实施例中，式(I)化合物按照药学上可接受的酸加成盐(一种药学上可接受的盐)来制备，通过化合物的自由碱形式与药学上可接受的无机或有机酸反应，包括但不限于无机酸，如盐酸、氢溴酸、硫酸、氨基磺酸、磷酸和硝酸；及由例如以下有机酸制备的盐：乙酸、丙酸、琥珀酸、乙醇酸、硬脂酸、乳酸、苹果酸、酒石酸、柠檬酸、抗坏血酸、扑酸、马来酸、羟基马来酸、苯乙酸、谷氨酸、苯甲酸、水杨酸、磺胺酸、2-乙酰氧基苯甲酸、富马酸、甲20苯磺酸、甲烷磺酸、乙烷二磺酸、草酸和羟乙磺酸等。
应理解药学上可接受的盐的参考包括溶剂添加形式或结晶形式，尤其是溶剂化物或多晶型。溶剂化物含有化学计量或非化学计量的溶剂，且是在与药学上可接受溶剂如水，乙醇等，结晶化过程中选择性形成的。当溶剂是水时形成水合物，或当溶剂是乙醇时形成醇化物。式(I)化合物的溶剂化物按照本文所述的方法，很方便的制得或形成。举例说明，式(I)化合物的水合物从水/有机溶剂的混合溶剂中重结晶而方便的制得，使用的有机溶剂包括但不限于，二氧杂环乙烷，四氢呋喃，乙醇或甲醇。此外，在此提到的化合物能够以非溶剂化和溶剂化形式存在。总之，对于在此提供的化合物和方法为目的，溶剂化形式被认为相当于非溶剂化形式。
在其他具体实施例中，式(I)化合物被制备成不同的形式，包括但不限于，无定形，粉碎形和毫微-粒度形式。此外，式(I)化合物包括结晶型，也可以作为多晶型。多晶型包括化合物的相同元素组成的不同晶格排列。多晶型通常有不同的X-射线衍射图，红外光谱，熔点，密度，硬度，晶型，光和电的性质，稳定性和溶解性。不同的因素如重结晶溶剂，结晶速率和贮存温度可能引起单一晶型为主导。
术语
如果无另外说明，用于本发明申请，包括说明书和权利要求书中的术语，定义如下。必须注意，在说明书和所附的权利要求书中，如果文中无另外清楚指示，单数形式“一个”包括复数意义。如果无另外说明，使用质谱、核磁、HPLC、蛋白化学、生物化学、重组DNA技术和药理的常规方法。在本申请中，如果无另外说明，使用“或”或“和”指“和/或”。
除非另外指明，否则本专利中所提供的IDO抑制剂不仅仅能抑制剂IDO受体，还可以抑制色氨酸2,3-双加氧酶(TDO)受体。因而，本专利中的此类抑制剂有可能通过同时抑制IDO受体和TDO受体；同时，本专利所提供的IDO抑制剂也有可能选择性的抑制IDO,或者选择性的抑制TDO。
术语“IDO抑制剂”是指能够抑制吲哚胺2,3-双加氧酶(IDO)的活性且由此逆转IDO介导的免疫抑制的药剂。IDO抑制剂可抑制IDO1和/或IDO2(INDOL1)。IDO抑制剂可为可逆的或不可逆的IDO抑制剂。“可逆的IDO抑制剂”为在催化位点或在非催化位点可逆地抑制IDO酶活性的化合物而“不可逆的IDO抑制剂”为通过与酶形成共价键不可逆地破坏IDO酶活性的化合物。
在说明书和权利要求书中，给定化学式或名称应涵盖所有立体和光学异构体及其中存在上述异构体的外消旋物。除非另外指明，否则所有手性(对映异构体和非对映异构体)和外消旋形式均在本发明范围内。所述化合物中还可存在C＝C双键、C＝N双键、环***等的许多几何异构体，且所有上述稳定异构体均涵盖于本发明内。本发明描述了本发明化合物的顺式-和反式-(或E-和Z-)几何异构体，且其可分离成异构体的混合物或分开的异构体形式。本发明化合物可以光学活性或外消旋形式加以分离。用于制备本发明化合物和其中制备的中间体的所有方法均视为本发明的部分。在制备对映异构体或非对映异构体产物时，其可通过常规方法(例如通过色谱或分段结晶)进行分离。取决于方法条件，以游离(中性)或盐形式获得本发明的终产物。这些终产物的游离形式和盐均在本发明的范围内。如果需要的话，则可将化合物的一种形式转化成另一种形式。可将游离碱或酸转化成盐；可将盐转化成游离化合物或另一种盐；可将本发明异构体化合物的混合物分离成单独的异构体。本发明化合物、其游离形式和盐可以多种互变异构体形式存在，其中氢原子转置到分子的其它部分上且由此分子的原子之间的化学键发生重排。应当理解的是，可存在的所有互变异构体形式均包括在本发明内。
除非另有定义，否则当取代基被标注为“任选取代的”时，所述取代基选自例如以下取代基诸如烷基、环烷基、芳基、杂环基、卤素、羟基、烷氧基、氧代、烷酰基、芳基氧基、烷酰基氧基、氨基、烷基氨基、芳基氨基、芳基烷基氨基、二取代的胺基团(其中2个氨基取代基选自烷基、芳基或芳基烷基)、烷酰基氨基、芳酰基氨基、芳烷酰基氨基、取代的烷酰基氨基、取代的芳基氨基、取代的芳烷酰基氨基、硫基、烷基硫基、芳基硫基、芳基烷基硫基、芳基硫羰基、芳基烷基硫羰基、烷基磺酰基、芳基磺酰基、芳基烷基磺酰基、磺酰氨基 例如-SO2NH2、取代的磺酰氨基、硝基、氰基、羧基、氨基甲酰基例如-CONH2、取代的氨基甲酰基例如-CONH烷基、-CONH芳基、-CONH芳基烷基或在氮上具有两个选自烷基、芳基或芳基烷基的取代基的情况、烷氧基羰基、芳基、取代的芳基、胍基、杂环基例如吲哚基、咪唑基、呋喃基、噻吩基、噻唑基、吡咯烷基、吡啶基、嘧啶基、吡咯烷基、哌啶基、吗啉基、哌嗪基、高哌嗪基等和取代的杂环基。
本文使用的术语“烷基”或“亚烷基”意欲包括具有指定碳原子数的支链和直链饱和脂族烃基团。例如，“C1-C6烷基”表示具有1个至6个碳原子的烷基。烷基的实例包括但不限于甲基(Me)、乙基(Et)、丙基(例如正丙基和异丙基)、丁基(例如正丁基、异丁基、叔丁基)和戊基(例如正戊基、异戊基、新戊基)。
术语“烯基”表示含一个或多个双键且通常长度为2至20个碳原子的直链或支链的烃基。例如，“C2-C8烯基”含有两个至八个碳原子。烯基包括但不限于例如乙烯基、丙烯基、丁烯基、1-甲基-2-丁烯-1-基、庚烯基、辛烯基等。
术语“炔基”表示含一个或多个三键且通常长度为2至20个碳原子的直链或支链的烃基。例如，“C2-C8炔基”含有两个至八个碳原子。代表性炔基包括但不限于例如乙炔基、1-丙炔基、1-丁炔基、庚炔基、辛炔基等。
术语“烷氧基”或“烷基氧基”是指-O-烷基。“C1-6烷氧基”(或烷基氧基)意欲包括C1、C2、C3、C4、C5和C6烷氧基。烷氧基的实例包括但不限于甲氧基、乙氧基、丙氧基(例如正丙氧基和异丙氧基)和叔丁氧基。类似地，“烷基硫基”或“硫代烷氧基”表示具有指定数量碳原子的经硫桥连接的如上文所定义的烷基；例如甲基-S-和乙基-S-。
术语“羰基”是指由碳和氧两种原子通过双键连接而成的有机官能团(C＝O)。
术语“芳基”，单独或作为较大部分诸如“芳烷基”、“芳烷氧基”或“芳基氧基烷基”的部分，是指具有总计5至15个环成员的单环、二环或三环的环***，其中所述***中的至少一个环为芳族的且其中所述***中的每个环含有3至7个环成员。在本发明的某些实施方案中，“芳基”是指芳族环***，其包括但不限于苯基、联苯基、茚满基、1-萘基、2-萘基和四氢萘基。术语“芳烷基”或“芳基烷基”是指连接至芳基环的烷基残基。非限制性实例包括苄基、苯乙基等。稠合的芳基可在环烷基环或芳族环的合适位置上连接至另一基团。例从环***中画出的箭头线表明键可连接至任意合适的环原子。
术语“环烷基”是指单环或二环的环状烷基。单环的环状烷基指C3-C8的环状烷基，包括但不限于环丙基、环丁基、环戊基、环己基和降莰烷基。支化环烷基诸如1-甲基环丙基和2-甲基环丙基包括在“环烷基”的定义中。二环的环状烷基包括桥环、螺环或融合环的环烷基。
术语“环烯基”是指单环或二环的环状烯基。单环的环状烯基指C3-C8的环状烯基，包括但不限于环丙烯基、环丁烯基、环戊烯基、环己烯基和降莰烯基。支化环烯基诸如1-甲基环丙烯基和2-甲基环丙烯基包括在“环烯基”的定义中。二环的环状烯基包括桥环、螺环或 融合环的环状烯基。
术语“环烷基烷基”是指与连接至化合物的咔唑核心的烷基键合的环烷基或取代的环烷基。
“卤代”或“卤素”包括氟、氯、溴和碘。“卤代烷基”意欲包括具有指定碳原子数且取代有1个或多个卤素的支链和直链饱和脂族烃基团。卤代烷基的实例包括但不限于氟甲基、二氟甲基、三氟甲基、三氯甲基、五氟乙基、五氯乙基、2,2,2-三氟乙基、七氟丙基和七氯丙基。卤代烷基的实例还包括意欲包括具有指定碳原子数且取代有1个或多个氟原子的支链和直链饱和脂族烃基团的“氟烷基”。
“卤代烷氧基”或“卤代烷基氧基”表示具有指定数量碳原子的经氧桥连接的如上文所定义的卤代5烷基。例如，“C1-6卤代烷氧基”意欲包括C1、C2、C3、C4、C5和C6卤代烷氧基。卤代烷氧基的实例包括但不限于三氟甲氧基、2,2,2-三氟乙氧基和五氟乙氧基。类似地，“卤代烷基硫基”或“硫代卤代烷氧基”表示具有指定数量碳原子的经硫桥连接的如上文所定义的卤代烷基；例如三氟甲基-S-和五氟乙基-S-。
术语“芳基”指的是单环或二环(及二环以上)的全为碳原子的芳香基。单环的芳香基指的是苯基，二环及二环以上的芳香基指萘基、蒽基等，同时此芳基二环也可为苯环融合了一个环烷基、或融合一个环烯基、或融合一个环炔基。
术语“芳杂基”、“芳杂环”、“芳杂环基”或“芳杂环基团”意指稳定的3元、4元、5元、或7元芳香单环或芳香二环或7元、8元、9元、10元、11元、12元、13元或14元芳香多环杂环，其为完全不饱和的、部分不饱和的，且其含有碳原子和1个、2个、3个或4个独立地选自N、O和S的杂原子；且包括任何以下多环基团，其中上文所定义的任意杂环与苯环稠合。氮和硫杂原子可任选地被氧化。氮原子为取代的或未取代的(即N或NR，其中R为H或如果被定义，则为另一取代基)。杂环可在得到稳定结构的任何杂原子或碳原子处连接至其侧基。如果所得化合物是稳定的，则本文所述的杂环基可在碳或氮原子上被取代。杂环中的氮可任选地被季铵化。优选地，当杂环中S和O原子的总数超过1时，则这些杂原子彼此不相邻。优选地，杂环中S和O原子的总数不大于1。当使用术语“杂环”时，其意欲包括杂芳基。芳杂环的实施例包括但不限于吖啶基、氮杂环丁基、吖辛因基、苯并咪唑基、苯并呋喃基、苯并硫代呋喃基、苯并噻吩基、苯并噁唑基、苯并噁唑啉基、苯并噻唑基、苯并***基、苯并四唑基、苯并异噁唑基、苯并异噻唑基、苯并咪唑啉基、咔唑基、4aH-咔唑基、咔啉基、色满基、色烯基、噌啉基、十氢喹啉基、2H,6H-1,5,2-二噻嗪基、二氢呋喃并[2,3-b]四氢呋喃基、呋喃基、呋咱基、咪唑烷基、咪唑啉基、咪唑基、1H-吲唑基、咪唑并吡啶基、假吲25哚基(indolenyl)、二氢吲哚基、吲嗪基、吲哚基、3H-吲哚基、靛红酰基(isatinoyl)、异苯并呋喃基、异色满基、异吲唑基、异二氢吲哚基、异吲哚基、异喹啉基、异噻唑基、异噻唑并吡啶基、异噁唑基、异噁唑并吡啶基、亚甲基二氧基苯基、吗啉基、二氮杂萘基、八氢异喹啉基、噁二唑基、1,2,3-噁二唑基、1,2,4-噁二唑基、1,2,5-噁二唑基、1,3,4- 噁二唑基、噁唑烷基、噁唑基、噁唑并吡啶基、噁唑烷基、萘嵌间二氮杂苯基、羟吲哚基、嘧啶基、菲啶基、菲咯啉基、吩嗪基、吩噻嗪基、吩噁噻基、吩噁嗪基、酞嗪基、哌嗪基、哌啶基、哌啶酮基、4-哌啶酮基、胡椒基、喋啶基、嘌呤基、吡喃基、吡嗪基、吡唑烷基、吡唑啉基、吡唑并吡啶基、吡唑基、哒嗪基、吡啶并噁唑基、吡啶并咪唑基、吡啶并噻唑基、吡啶基、嘧啶基、吡咯烷基、吡咯啉基、2-吡咯烷酮基、2H-吡咯基、吡咯基、喹唑啉基、喹啉基、4H-喹嗪基、喹喔啉基、奎宁环基、四唑基、四氢呋喃基、四氢异喹啉基、四氢喹啉基、6H-1,2,5-噻二嗪基、1,2,3-噻二唑基、1,2,4-噻二唑基、1,2,5-噻二唑基、1,3,4-噻二唑基、噻蒽基、噻唑基、噻吩基、噻唑并吡啶基、噻吩并噻唑基、噻吩并噁唑基、噻吩并咪唑基、噻吩基、三嗪基、1,2,3-***基、1,2,4-***基、1,2,5-***基、1,3,4-***基和呫吨基、喹啉基、异喹啉基、酞嗪基、喹唑啉基、吲哚基、异吲哚基、二氢吲哚基、1H-吲唑基、苯并咪唑基、1,2,3,4-四氢喹啉基、1,2,3,4-四氢异喹啉基、5,6,7,8-四氢-喹啉基、2,3-二氢-苯并呋喃基、色满基、1,2,3,4-四氢-喹喔啉基和1,2,3,4-四氢-喹唑啉基。本发明还包括含有例如上述杂环的稠环和螺环化合物。
本文使用的术语“环杂烷基”指的是一个单环环杂烷基体系，或为一个二环杂烷基体系。单环的环杂烷基指的是3-8元、且至少含一个选自O、N、S、P的饱和或不饱和但不为芳香性的环状烷基体系。二环杂烷基体系指的是一个环杂烷基融合到一个苯基、或一个环烷基、或一个环烯基、或一个环杂烷基、或一个杂芳基。
本文使用的术语“桥环烃”指的是共用两个或两个以上碳原子的多环化合物。可分为二环桥环烃及多环桥环烃。前者由两个脂环共用两个以上碳原子所构成；后者是由三个以上的环组成的桥环烃。
本文使用的术语“螺环烃”指的是单环之间共用一个碳原子(称螺原子)的多环烃。
本文中所用的术语“取代”意指至少一个氢原子被非氢基团替代，条件是维持正常化合价且所述取代得到稳定的化合物。本文所用的环双键为在两个相邻环原子之间形成的双键(例如C＝C、C＝N或N＝N)。
在本发明化合物上存在氮原子(例如胺)的情形下，可通过使用氧化剂(例如mCPBA和/或过氧化氢)进行处理来将这些氮原子转化成N-氧化物以获得本发明的其它化合物。因此，所显示和要求保护的氮原子视为均涵盖所显示氮及其N-氧化物(N→O)衍生物。
当任何变量在化合物的任何组成或式中出现一次以上时，其每次出现时的定义均独立于其在其它每种情况下出现时的定义。因此，例如如果显示基团取代有0-3个R，则所述基团可任选地取代有至多三个R基团，且在每次出现时R独立地选自R的定义。此外，取代基和/或变量的组合仅在上述组合可产生稳定的化合物时才容许存在。
当键合至取代基的键显示为与连接环中的两个原子的键交叉时，则上述取代基可键合至该环上的任一原子。当列举取代基但未指明该取代基中键合至具有给定式的化合物的其余部分上的原子时，则上述取代基可经由该取代基中的任一原子来键合。取代基和/或变量的组合 仅在上述组合可产生稳定的化合物时才容许存在。
术语“药用”在本文中用于是指如下那些化合物、物质、组合物和/或剂型：在合理医学判断的范围内，其适于与人类和动物的组织接触使用而无过高毒性、刺激性、过敏反应和/或其它问题或并发症并与合理的益处/风险比相称。
本文使用的“药用盐”是指本发明化合物的衍生物，其中母体化合物通过制备其酸或碱盐来修饰。药用盐的实例包括但不限于碱性基团(诸如胺)的无机或有机酸盐；及酸性基团(诸如羧酸)的碱金属盐或有机盐。药用盐包括由(例如)无毒的无机或有机酸形成的母体化合物的常规无毒盐或季铵盐。例如，上述常规无毒盐包括衍生自例如以下无机酸的那些：盐酸、氢溴酸、硫酸、氨基磺酸、磷酸和硝酸；及由例如以下有机酸制备的盐：乙酸、丙酸、琥珀酸、乙醇酸、硬脂酸、乳酸、苹果酸、酒石酸、柠檬酸、抗坏血酸、扑酸、马来酸、羟基马来酸、苯乙酸、谷氨酸、苯甲酸、水杨酸、磺胺酸、2-乙酰氧基苯甲酸、富马酸、甲20苯磺酸、甲烷磺酸、乙烷二磺酸、草酸和羟乙磺酸等。
本发明的药用盐可通过常规化学方法自含有碱性或酸性部分的母体化合物合成。通常，可通过在水或有机溶剂或二者的混合物中使这些化合物的游离酸或碱形式与化学计量的适合碱或酸反应来制备上述盐；通常，优选如***、乙酸乙酯、乙醇、异丙醇或乙腈等非水性介质。合适盐的列表可参见Remington:The Science and Practice of Pharmacy,22nd Edition,25Allen,L.V.Jr.,Ed.；Pharmaceutical Press,London,UK(2012)，通过引用的方式将其披露内容并入本文中。
此外，式(I)化合物可具有前药形式。本发明的范围和主旨内的前药为在体内转化以提供生物活性剂(即式(I)化合物)的任意化合物。前药的各种形式是本领域中公知的。上述前药衍生物的实例可参见：a)Bundgaard,H.,ed.,Design of Prodrugs,Elsevier(1985),and Widder,K.et al.,eds.,Methods in Enzymology,112:309-396,Academic Press(1985)；b)Bundgaard,H.,Chapter5,"Design and Application of Prodrugs,"A Textbook of Drug Design and Development,pp.113-191,Krosgaard-Larsen,P.et al.,eds.,Harwood Academic Publishers(1991)；c)Bundgaard,H.,Adv.Drug Deliv.Rev.,8:1-38(1992)；d)Bundgaard,H.et al.,J.Pharm.Sci.,77:285(1988)；e)Kakeya,N.et al.,Chem.Pharm.Bull.,32:692(1984)；和f)Rautio,J(Editor).Prodrugs and Targeted Delivery(Methods and Principles in Medicinal Chemistry),Vol 47,Wiley-VCH,2011。
含有羧基、羟基、胺基和膦酸基的化合物可形成生理学上可水解的酯，所述酯通过在机体中自身水解以产生式(I)化合物来用作前药。由于在许多情形下主要在消化酶的影响下发生水解，因此优选地口服给药上述前药。肠胃外给药可用于酯自身具有活性的情形或在血液中发生水解的那些情形。式(I)化合物的生理学上可水解酯的实例包括C1-6烷基、C1-6烷基苄基、4-甲氧基苄基、茚满基、邻苯二甲酰基、甲氧基甲基、C1-6烷酰基氧基-C1-6烷基(例如乙酰氧基甲基、新戊酰基氧基甲基或丙酰基氧基甲基)、C1-6烷氧基羰基氧基-C1-6烷基 (例如甲氧基羰基-氧基甲基或乙氧基羰基氧基甲基、甘氨酰基氧基甲基、苯基甘氨酰基氧基甲基、(5-甲基-2-氧代-1,3-二氧杂环戊烯-4-基)-甲基)的酯和用于例如青霉素和头孢菌素技术中的其它公知的生理学上可水解酯。上述酯可通过本领域中已知的常规技术来制备。
前药的制备是本领域中公知的且述于例如King,F.D.,ed.,Medicinal Chemistry:Principles15and Practice,The Royal Society of Chemistry,Cambridge,UK(2nd edition,reproduced,2006)；Testa,B.et al.,Hydrolysis in Drug and Prodrug Metabolism.Chemistry,Biochemistry and Enzymology,VCHA and Wiley-VCH,Zurich,Switzerland(2003)；Wermuth,C.G.,ed.,The Practice、of Medicinal Chemistry,3rd edition,Academic Press,San Diego,CA(2008)中。
本发明意欲包括存在于本发明化合物中的原子的所有同位素。同位素包括具有相同原子序数但具有不同质量数的原子。通过一般举例而非限制的方式，氢的同位素包括氘和氚。碳的同位素包括13C和14C。本发明的同位素标记的化合物可如下制备：一般通过本领域技术人员已知的常规技术或通过与本文所述类似的方法使用适当的同位素标记的试剂代替其它情况下使用的未标记的试剂。
术语“溶剂化物”意指本发明化合物与一个或多个溶剂分子(无论有机的还是无机的)的物理缔合。该物理缔合包括氢键。在某些情形中，例如当一个或多个溶剂分子纳入结晶固体的晶格中时，溶剂化物将能够被分离。溶剂化物中的溶剂分子可按规则排列和/或无序排列存在。溶剂化物可包含化学计量或非化学计量的溶剂分子。“溶剂合物”涵盖溶液相和可分离的溶剂化物。示例性溶剂化物包括但不限于水合物、乙醇合物、甲醇合物和异丙醇合物。溶剂化方法是本领域公知的。
本文使用的术语“患者”是指通过本发明的方法进行治疗的有机体。这类有机体优选包括但不限于哺乳动物(例如鼠类、猿/猴、马、牛、猪、犬、猫等)且最优选是指人类。
本文使用的术语“有效量”意指将会引起例如研究人员或临床医师所寻求的组织、***、动物或人的生物学或医学响应的药物或药剂(即本发明化合物)的量。此外，术语“治疗有效量”意指这样的量：与未接受上述量的相应受试者相比，所述量导致改善的治疗、治愈、预防或减轻疾病、病症或副作用，或降低在疾病或病症的进展速度。有效量可以一个或多个给药、施用或剂量给予且不意欲被特定的制剂或给药途径限制。该术语还包括在其范围内的增强正常生理机能的有效量。
本文使用的术语“治疗”包括导致改善病症、疾病、障碍等的任何效果，例如减轻、减少、调节、改善或消除，或改善其症状。
本文使用的术语“药物组合物”是指活性剂与惰性或活性的载体的组合，使得所述组合物尤其适用于体内或离体诊断或治疗。碱的实例包括但不限于碱金属(例如钠)氢氧化物、碱土金属(例如镁)氢氧化物、氨等。对于治疗用途，本发明化合物的盐对于治疗用途，本发明化合物的盐预期为是药用的。然而，非药用的酸和碱的盐也可用于例如药用化合物的制 备或纯化中。
术语“药用”在本文中用于指如下那些化合物、物质、组合物和/或剂型：在合理医学判断的范围内，其适于与人类和动物的组织接触使用而无过高毒性、刺激性、过敏反应和/或其它问题或并发症，并与合理的益处/风险比相称。
本文使用的短语“药用载体”意指药用物质、组合物或媒介物，诸如液体或固体填充剂、稀释剂、赋形剂、制造助剂(例如润滑剂、滑石、硬脂酸镁、硬脂酸钙或硬脂酸锌或硬脂酸)或溶剂包囊物质，其涉及将主题化合物从一个器官或身体的部分携带或运送至另一个器官或身体的部分。每种载体在与制剂的其它成分相容和对患者无害的意义上必须是“可接受的”。
术语“药物组合物”意指包含本发明化合物与至少一种其它药用载体的组合物。“药用载体”是指本领域中通常接受用于将生物活性剂递送至动物(具体为哺乳动物)的介质，包括(即)佐剂、赋形剂或媒介物，诸如稀释剂、防腐剂、填充剂、流动调控剂、崩解剂、润湿剂、乳化剂、悬浮剂、增甜剂、矫味剂、芳香剂、抗细菌剂、抗真菌剂、润滑剂和分散剂，
这取决于给药模式和剂型的性质。
特定药学及医学术语
术语“可接受的”，如本文所用，指一个处方组分或活性成分对一般治疗目标的健康没有过分的有害影响。
术语“吲哚胺2，3-双加氧酶介导”或“IDO相关”，如本文所用，指在吲哚胺2，3-双加氧酶存在时所导致的疾病或症状。
术语“癌症”，如本文所用，指一种不能控制的细胞的异常生长，并且在某种条件下能够转移(传播)。这种类型的癌症包括但不限于，固体肿瘤(如膀胱、肠、脑、胸、子宫、心脏、肾、肺、淋巴组织(淋巴瘤)、卵巢、胰腺或其它内分泌器官(如甲状腺)、***、皮肤(黑色素瘤)或血液瘤(如非白血性白血病)。
术语“联合给药”或其类似术语，如本文所用，指将几种所选的治疗药物给一个病人用药，以相同或不同的给药方式在相同或不同的时间给药。
术语“增强”或“能增强”，如本文所用，指预期的结果能够在效价或是持续时间方面都有增加或延长。因此，在增强药物的治疗效果方面，术语“能增强”指药物在***中有提高或延长效价或持续时间的能力。本文所用的“增效值”，指在理想的***中，能够最大限度地的增强另外一个治疗药物的能力。
术语“免疫性疾病”指对内源性或外源性抗原产生的不良或有害反应的疾病或症状。结果通常会造成细胞的功能障碍、或因此而破坏并造成机能障碍、或破坏可能产生免疫症状的器官或组织。
术语“试剂盒”与“产品包装”是同义词。
术语“受试者”或“病人”包括哺乳动物和非哺乳动物。哺乳动物包括但不限于，哺乳类： 人、非人灵长类如猩猩、猿及猴类；农业动物如牛、马、山羊、绵羊、猪；家畜如兔、狗；实验动物包括啮齿类，如大鼠、小鼠及豚鼠等。非哺乳类动物包括但不限于，鸟、鱼等。在一优选例中，所选哺乳动物是人。
术语“治疗”、“治疗过程”或“疗法”如本文所用，包括缓和、抑制或改善疾病的症状或状况；抑制并发症的产生；改善或预防潜在代谢综合症；抑制疾病或症状的产生，如控制疾病或情况的发展；减轻疾病或症状；使疾病或症状减退；减轻由疾病或症状引起的并发症，或预防或治疗由疾病或症状引起的征兆。
如本文所用，某一化合物或药物组合物，给药后，可以使某一疾病、症状或情况得到改善，尤指其严重度得到改善，延迟发病，减缓病情进展，或减少病情持续时间。无论固定给药或临时给药、持续给药或断续给药，可以归因于或与给药有关的情况。
治疗用途
一方面，式(I)化合物可抑制一种或几种吲哚胺2，3-双加氧酶。另一方面，式(I)化合物显示了有效地治疗癌症、病毒感染、器官移植排斥或自身免疫性疾病。
本发明的化合物和药物组合物可用于治疗或预防任何对IDO的酶活性敏感的疾病或病症。这些疾病或病症包括增殖性疾病(例如癌症)、病毒和其它感染(例如皮肤感染、胃肠道(GI)感染、***、生殖泌尿感染、全身感染)、自身免疫性疾病(例如类风湿性关节炎、狼疮)。所述化合物和药物组合物可给予给动物，优选哺乳动物(例如家畜、猫、狗、小鼠、大鼠)，更优选人类。任何给药的方法可用于向患者递送所述化合物或药物组合物。在某些实施方案中，口服给予所述化合物或药物组合物。在其它实施方案中，胃肠外给予所述化合物或药物组合物。
本发明化合物可调节吲哚胺-2,3-双加氧酶(IDO)的活性。术语“调节”意指提高或降低酶或受体的活性的能力。因此，本发明化合物可用于通过使酶与任意一种或多种本文所述的化合物调节IDO的方法。在一些实施方案中，本发明化合物可作为IDO的抑制剂起作用。
在其它实施方案中，本发明化合物可用于在需要通过给予调节(例如抑制)量的本发明化合物调节的细胞或个体中调节IDO的活性。
本发明化合物可抑制吲哚胺-2,3-双加氧酶(IDO)的活性。例如，本发明化合物可用于在需要通过给予抑制量的本发明化合物调节酶的细胞或个体中抑制IDO的活性。
本发明还提供在含有表达IDO的细胞的***诸如组织、活有机体或细胞培养物中抑制色氨酸降解的方法。在一些实施方案中，本发明提供在哺乳动物中通过给予有效量的本文提供的化合物或组合物以改变(例如增加)细胞外色氨酸水平的方法。测量色氨酸水平和色氨酸降解的方法是本领域常规的。
本发明还提供在患者中通过向患者给予有效量的本文所列举的化合物或组合物进行免疫抑制诸如IDO介导的免疫抑制的方法。IDO介导的免疫抑制已经与例如癌症、肿瘤生长、 转移、病毒感染和病毒复制相关。
本发明还提供在个体(例如患者)中通过向需要上述治疗的个体给予治疗有效量或剂量的本发明化合物或其药物组合物治疗与IDO活性或表达(包括异常活性和/或过表达)相关的疾病。实例疾病可包括直接或间接地与IDO酶的表达或活性诸如过表达或异常活性的有关的任何疾病、障碍或病症。IDO相关的疾病也可包括可通过调节酶活性预防、改善或治愈任何疾病、障碍或病症。IDO相关的疾病实例包括癌症、病毒感染诸如HIV感染、HCV感染、抑郁、神经变性疾病诸如阿尔茨海默病和亨廷顿病、创伤、年龄相关性白内障、器官移植(例如器官移植排斥)和自身免疫性疾病，包括哮喘、类风湿性关节炎、多发性硬化症、过敏性炎症、炎性肠病、银屑病和***性红斑狼疮。
本文所用的术语“细胞”意指在体外、离体或体内的细胞。在一些实施方案中，离体细胞可为从有机体诸如哺乳动物中切除的组织样品的部分。在一些实施方案中，体外细胞可为细胞培养物中的细胞。在一些实施方案中，体内细胞为活在有机体诸如哺乳动物中的细胞。
可用本发明化合物治疗的癌症的类型包括但不限于脑癌、皮肤癌、膀胱癌、卵巢癌、乳腺癌、胃癌、胰腺癌、***癌、结肠癌、血癌、肺癌和骨癌。上述癌症类型的实例包括成神经细胞瘤；肠癌诸如直肠癌、结肠癌、家族性腺瘤性息肉性癌和遗传性非息肉性结直肠癌；食管癌；唇癌；喉癌；下咽癌；舌癌；唾液腺癌；胃癌；腺癌、甲状腺髓样癌；***状甲状腺癌；肾癌；肾实质癌；卵巢癌；***；子宫体癌；子宫内膜癌；绒毛膜癌；胰腺癌；***癌；睾丸癌；乳腺癌；泌尿癌；黑素瘤；脑肿瘤诸如成胶质细胞瘤、星形细胞瘤、脑膜瘤、成神经管细胞瘤和外周神经外胚层肿瘤；霍奇金淋巴瘤；非霍奇金淋巴瘤；伯基特淋巴瘤；急性淋巴性白血病(ALL)；慢性淋巴性白血病(CLL)；急性骨髓性白血病(AML)；慢性粒细胞白血病(CML)；成人T细胞白血病淋巴瘤；弥漫性大B细胞淋巴瘤(DLBCL)；肝细胞癌；胆囊癌；支气管癌；小细胞肺癌；非小细胞肺癌；多发性骨髓瘤；基底细胞瘤；畸胎瘤；成视网膜细胞瘤；脉络膜黑素瘤；***瘤；横纹肌肉瘤；颅咽管瘤；骨肉瘤；软骨肉瘤；肌肉瘤；脂肪肉瘤；纤维肉瘤；尤因肉瘤和浆细胞瘤。
因此，根据另一个实施方案，本发明提供通过向有此需要的患者提供本发明的化合物或组合物治疗的自身免疫疾病的方法。此类自身免疫疾病的实例包括但不限于胶原病，诸如类风湿性关节炎、***性红斑狼疮、Sharp综合征；CREST综合征(钙质沉着、雷诺氏综合征、食管运动功能障碍、毛细血管扩张)；皮肌炎；血管炎(韦格纳病)和舍格伦综合征；肾病，诸如古德帕斯丘综合征；急进性肾小球肾炎和膜性增生性肾小球肾炎II型；内分泌疾病，诸如I型糖尿病；自身免疫性多内分泌腺病-念珠菌病-外胚层营养不良(APECED)；自身免疫性甲状旁腺病；恶性贫血；性腺机能不全；特发性阿狄森病；甲状腺功能亢进；桥本甲状腺炎和原发性粘液性水肿；皮肤病，诸如寻常型天疱疮、大疱性类天疱疮、妊娠疱疹、大疱性表皮松解和中兴多形性红斑；肝病，诸如原发性胆汁性肝硬化、自身免疫性胆管炎、自身免疫性1型肝炎、自身免疫性2型肝炎、原发性硬化性胆管炎；神经元疾病，诸如多发性硬化、 重症肌无力、朗伯-伊顿肌无力综合征、获得性神经性肌强直、格林-巴利综合征(穆勒-费舍尔综合征)、僵人综合征、小脑变性、共济失调、视性眼阵挛、感觉性神经病和失弛缓症；血液疾病，诸如自身免疫性溶血性贫血、特发性血小板减少性紫癜)韦尔霍夫病)；具有相关的自身免疫反应的感染性疾病，诸如AIDS、疟疾和查加斯病。
一种或多种其它药物或治疗方法，例如抗病毒剂、化疗剂或其它抗癌剂、免疫增强剂、免疫抑制剂、放射疗法、抗肿瘤和抗病毒疫苗疗法、细胞因子疗法(例如IL2和GM-CSF)和/或酪氨酸激酶抑制剂，可任选地与本发明化合物组合用于治疗IDO相关的疾病、障碍或病症。所述药剂可与本发明化合物组合在单一剂型中，或试剂可作为单独的剂型同时或依序给药。
合适的联合抗癌药物包括抗体治疗剂诸如曲妥珠单抗(赫赛汀)，针对共刺激分子诸如CTLA-4、4-1BB、PD-1/PD-L1、CART的抗体，或针对细胞因子(IL-1O或TGF-β)的抗体。
合适的化疗剂或其它抗癌剂包括例如烷化剂(包括但不限于氮芥类、乙撑亚胺衍生物类、烷基磺酸盐类、亚硝基脲类和三嗪类)诸如尿嘧啶氮芥、氮芥、环磷酰胺异环磷酰胺、美法仑、苯丁酸氮芥、哌泊溴烷、三乙撑-密胺、三乙撑硫代磷酰胺、白消安、卡莫司汀、洛莫司汀、链佐星、，达卡巴嗪和替莫唑胺。
合适的化疗或其它抗癌剂包括例如抗代谢物(包括但不限于叶酸拮抗剂、嘧啶类似物嘌呤类似物和腺苷脱氨酶抑制剂)诸如甲氨蝶呤、5-氟尿嘧啶、氟尿苷、阿糖胞苷、6-巯基嘌呤，6-硫鸟嘌呤、磷酸氟达拉滨、喷司他丁和吉西他滨。
合适的化疗或其它抗癌剂还包括例如某些天然产物及其衍生物(例如，长春花生物碱、抗肿瘤抗生素、酶、淋巴因子和表鬼臼毒素、长春碱、长春新碱、长春地辛、博来霉素、更生霉素、柔红霉素、阿霉素、表阿霉素、伊达比星、阿糖胞苷、紫杉醇(泰素)、光神霉素、脱氧柯福霉素、丝裂霉素-C、L-天冬酰胺酶、干扰素(特别是IFN-a)、依托泊苷和替尼泊苷。
其它细胞毒剂包括诺维本、CPT-11、阿那曲唑、来曲唑、卡培他滨、雷洛昔芬和屈洛昔芬。
也合适的药剂为细胞毒性剂，诸如表鬼臼毒素、抗肿瘤酶、拓扑异构酶抑制剂、丙卡巴肼、米托蒽醌、铂配位络合物诸如顺铂和卡铂、生物反应调节剂、生长抑制剂、抗激素治疗剂、亚叶酸、替加氟和造血生长因子。
其它抗癌剂还包括那些阻断免疫细胞迁移的药剂，诸如包括CCR2和CCR4的趋化因子受体拮抗剂。
其它抗癌剂还包括那些增强免疫***的药剂，诸如佐剂或过继性T细胞转移。
抗癌疫苗包括树突细胞、合成肽、DNA疫苗和重组病毒。
本发明的药物组合物可任选地包括至少一种信号转导抑制剂(STI)。“信号转导抑制剂”为在癌细胞的正常功能中选择性抑制信号传导途径的一个或多个重要的步骤，从而导致细胞凋亡的药剂。合适的STI包括但不限于：(i)bcr/abl激酶抑制剂，例如STI571；(ii)表皮 生长因子(EGF)受体抑制剂，例如激酶抑制剂(SSI-774)和抗体；(iii)HER-2/neu受体抑制剂，诸如法尼基转移酶抑制剂(FTI)，例如L-744,832；(iv)Akt家族激酶或Akt途径的抑制剂，例如雷帕霉素(参见例如Sekulic et al.,CancerRes.,60:3504-3513(2000))；(v)细胞周期激酶抑制剂，例如夫拉平度和UCN-O1；和(vi)磷脂酰肌醇激酶抑制剂，例如LY294002(参见例如Vlahos et al.,J.Biol.Chem.,269:5241-5248(1994))。可选择地，至少一种STI和至少一种IDO抑制剂可在分开的药物组合物中。在本发明的一个具体实施方案中，可向患者同时或依序给予至少一种IDO抑制剂和至少一种STI。换言之，可首先给予至少一种IDO抑制剂，或首先给予至少一种STI，或可在同一时间给予至少一种IDO抑制剂和至少一种STI。此外，当使用一种以上的IDO抑制剂和/或STI时，可以任意顺序给予所述化合物。
本发明还提供用于在患者中治疗慢性病毒感染的药物组合物，其在药用载体中包含至少一种IDO抑制剂、任选地至少一种化疗药物，及任选地至少一种抗病毒剂。除了至少一种公认的(已知的)IDO抑制剂之外，所述药物组合物可包括至少一种本发明的IDO抑制剂。
在一个具体的实施方案中，药物组合物的IDO抑制剂中的至少一种选自式(I)的化合物。
本发明还提供用于在患者中通过给予有效量的上述药物组合物治疗慢性病毒感染的方在本发明的一个具体实施方案中，可向患者同时或依序给予至少一种IDO抑制剂和至少一种化学治疗剂。换言之，可首先给予至少一种IDO抑制剂，或首先给予至少一种化疗剂，或可在同一时间给予至少一种IDO抑制剂和至少一种STI。此外，当使用一种以上的IDO抑制剂和/或化学治疗剂时，可以任意次序给予所述化合物。类似地，与给予IDO抑制剂相比，也可在任何点给予任何抗病毒剂或STI。
可使用本组合治疗来治疗的慢性病毒感染包括但不限于有以下病毒引起的疾病：丙型肝炎病毒(HCV)、人***状瘤病毒(HPV)、巨细胞病毒(CMV)、单纯疱疹病毒(HSV)、EB病毒(EBV)、水痘带状疱疹病毒、柯萨奇病毒、人免疫缺陷病毒(HIV)。值得注意的是，寄生虫感染(例如疟疾)也可通过上述方法治疗，其中任选地加入已知用于治疗寄生虫疾病的化合物代替抗病毒剂。
在又一个实施方案中，可向患者给予包含至少一种本发明的IDO抑制剂的药物组合物，以防止动脉再狭窄，诸如气囊内镜或支架置入之后的动脉再狭窄。在一个具体的实施方案中，药物组合物还包含至少一种紫杉烷(例如紫杉醇(泰素)；参见例如Scheller etal.,Circulation,110:810-814(2004))。
预期与本发明化合物组合使用的合适的抗病毒剂可包括核苷与核苷酸逆转录酶抑制剂(NRTI)、非核苷逆转录酶抑制剂(NNRTI)、蛋白酶抑制剂和其它抗病毒药物。合适的NRTI实例包括齐多夫定(AZT)、去羟肌苷(ddl)、扎西他滨(ddC)、司他夫定(d4T)、拉米夫定(3TC)、阿巴卡韦(1592U89)、阿德福韦酯[双(POM)-PMEA]、泰诺福韦酯、洛布卡韦(BMS-180194)、BCH-I0652、恩曲他滨[(-)-FTC]、β-L-FD4(也称为β-L-D4C且命名为β-L-2’,3’-二脱氧-5-氟-胞苷)、DAPD((-)-β-D-2,6-二氨基嘌呤二氧戊环)洛德腺苷(FddA)。典型的合适 的NNRTI包括奈韦拉平(BI-RG-587)、地拉夫定(BHAP，U-90152)、依法韦仑(DMP-266)、PNU-142721、AG-1549、MKC-442(1-(乙氧基-甲基)-5-(1-甲基乙基)-6-(苯基甲基)-(2,4(1H，3H)-嘧啶二酮)、和(+)-calanolide A(NSC-675451)和B。典型的合适的蛋白酶抑制剂包括沙奎那韦(Ro 31-8959)、利托那韦(ABT-538)、茚地那韦(MK-639)、那非那韦(AG-1343)、安普那韦(141W94)、拉西那韦(BMS-234475)、DMP-450、BMS-2322623、ABT-378、和AG-1549。其它抗病毒剂包括羟基脲、利巴韦林、IL-2、IL-12、喷他夫西。
本发明还包括可用于例如治疗或预防IDO相关的疾病或病症、肥胖症、糖尿病和本文涉及的其它疾病的药物试剂盒，其包括含有药物组合物的一个或多个容器，所述药物组合物包含治疗有效量的本发明化合物。上述试剂盒还包括，如果需要的话，一种或多种不同的常规药物试剂盒组分，例如容器与一种或多种药用载体、其它容器，这对于本领域技术人员显而易见的。试剂盒还可包含说明书，无论是作为插页或标签，其指示要施用的组分的量、给药的指导方针和/或用于混合组分的指导方针。组合治疗意在包括以依序的方式给予这些治疗剂，即其中每种治疗剂在不同的时间给药，及以基本上同时的方式给予这些治疗剂或至少两种所述治疗剂。例如通过向受试者给予具有固定比率的每种治疗剂或呈每种治疗剂的多个单一剂型形式可实现基本上同时给药。每种治疗剂的依序或基本上同时给药可通过任何适当途径来实现，其包括但不限于口服途径、静脉内途径、肌内途径和通过粘膜组织直接吸收。所述治疗剂可通过相同途径或通过不同途径给药。例如，所选组合的第一治疗剂可通过静脉注射给药而所述组合的其它治疗剂可口服给药。可选择地，例如所有治疗剂可口服给药或所有治疗剂可通过静脉内注射给药。组合疗法也可包括与其它生物活性成分和非药物疗法(例如手术或放射治疗)进一步组合给予上述治疗剂。当组合治疗进一步包括非药物治疗时，非药物治疗可在任何合适的时间进行，只要实现来自治疗剂与非药物治疗的组合的共同作用的有益效果。例如，在适当的情况下，当从治疗剂的给药暂时除去非药物治疗时，可能是数天或甚至数周，仍实现有益效果。
给药途径
适合的给药途径包括但不限于，口服、静脉注射、直肠、气雾剂、非肠道给药、眼部给药、肺部给药、经皮给药、***给药、耳道给药、鼻腔给药及局部给药。此外，仅作举例说明，肠道外给药，包括肌肉注射、皮下注射、静脉注射、髓内注射、心室注射、腹膜内注射、***内注射、及鼻内注射。
在一方面，此处描述的化合物给药方式是局部的而不是全身性的给药方式。在特定的具体实施例中，长效制剂通过植入给药(例如皮下或肌肉)或通过肌肉注射。此外，在另一具体化实施例中，药物通过靶向药物给药***来给药。例如，由器官特异性抗体包裹的脂质体。在这种具体实施例中，所述脂质体被选择性的导向特定器官并吸收。
药物组合物和剂量
本发明还提供药用组合物，其包含治疗有效量的与一种或多种药用载体(添加剂)和/或稀释剂一起配制的一种或多种式(I)化合物，和任选的一种或多种上述其它治疗剂。可通过任意合适方式给予本发明化合物以用于任意上述用途，例如口服，诸如片剂、丸剂、粉剂、颗粒剂、酏剂、酊剂、悬浮液(包括纳米悬浮液、微悬浮液、喷雾干燥的分散液)、糖浆和乳液；经舌下；含服；经肠胃外，诸如通过皮下、静脉内、肌内或胸骨内注射或输注技术(例如以无菌可注射水性或非水性溶液或悬浮液形式)；经鼻，包括向鼻膜给药，诸如通过吸入喷雾；局部，诸如以乳膏剂或软膏剂形式；或经直肠，诸如以栓剂形式。它们可单独给药，但通常使用基于所选给药途径和标准药学实践选择的药物载体给药。
根据本领域技术人员认识范围内的诸多因素来调配药用载体。这些因素包括，但不限于：所调配活性剂的类型和性质；含有活性剂的组合物所要给药的受试者；组合物的预期给药途径；及所靶向的治疗适应症。药用载体包括水性和非水性液体介质及各种固体和半固体剂型。
上述载体可包括除活性剂外的诸多不同成分和添加剂，上述其它成分出于本领域技术人员公知的各种原因包括于制剂中，例如稳定活性剂、粘合剂等。关于合适的药用载体和载体选择中所涉及的因素的描述可参见多个容易获得的来源，例如Allen,L.V.Jr.et.al.Remington:The Science and Practice of Pharmacy(2Volumes),22nd Edition(2012),Pharmaceutical Press。
当然，本发明化合物的剂量方案取决于已知因素而有所变化，诸如具体药剂的药效学特性及其给药模式和途径；接受者的物种、年龄、性别、健康状况、医学病状和重量；症状的性质和程度；同时治疗的种类；治疗频率；给药途径、患者的肾和肝功能及期望效应。根据一般指导，当用于指定效应时，各活性成分的日口服剂量应为约0.001mg/天至约10-5000mg/天，优选地为约0.01mg/天至约1000mg/天，且最优选地为约0.1mg/天至约250mg/天。在恒速输注期间，静脉内最优选剂量应为约0.01mg/kg/分钟至约10mg/kg/分钟。本发明化合物可以单一日剂量给药，或可以每日两次、三次或四次的分开剂量给药总日剂量。
所述化合物通常以与根据预期给药形式(例如口服片剂、胶囊剂、酏剂和糖浆剂)适当地选择且与常规药学实践相符合的合适药物稀释剂、赋形剂或载体(在本文中统称为药物载体)的混合物形式进行给药。
适于给药的剂型(药物组合物)可含有约1毫克至约2000毫克活性成分/剂量单位。在这些医药组合物中，以组合物的总重量计，活性成分通常将以约0.1-95重量％的量存在。
用于口服给药的典型胶囊剂含有至少一种本发明化合物(250mg)、乳糖(75mg)和硬脂酸镁(15mg)。使该混合物穿过60网目筛，并包装成1号明胶胶囊。
典型的可注射制剂可如下制备：以无菌方式将至少一种本发明化合物(250mg)置于瓶中、以无菌方式冻干并密封。为进行使用，将瓶内容物与2mL生理盐水混合，以产生可注射制剂。
本发明范围包括(单独或与药物载体组合)包含治疗有效量的至少一种本发明化合物 作为活性成分的药物组合物。任选地，本发明化合物可单独使用、与本发明其它化合物组合使用或与一种或多种其它治疗剂(例如抗癌剂或其它药学活性物质)组合使用。
不考虑所选择的给药路径，通过本领域技术人员已知的常规方法来将本发明的化合物(其可以合适的水合形式使用)和/或本发明的药物组合物配制成药用剂量形式。
可改变活性成分在本发明的药物组合物中的实际剂量水平，从而获得对于实现特定患者的期望的治疗响应、组成和给药模式有效的而对患者无毒的活性成分量。
选定的剂量水平会取决于多种因素，包括所用的本发明的特定化合物或其酯、盐或酰胺的活性；给药路径；给药时间；所用的特定化合物的***速率；吸收速率和程度；治疗的持续时间；与所用的特定化合物组合使用的其它药物、化合物和/或物质；所治疗的患者的年龄、性别、重量、状况、一般健康和先前的医学史等医学领域公知的因素。
具有本领域普通技术的医生或兽医可容易地确定并开出有效量的所需药物组合物。例如，为了达到所期望的治疗效果，医师或兽医可在低于所需的水平开始药物组合物中所用的本发明化合物的较量，并逐步增加剂量直至实现所期望的效果。通常，合适日剂量的本发明化合物将是有效产生治疗效果的最低剂量的化合物的量。此种有效剂量通常取决于上述因素。通常，口服、静脉内、脑室内和皮下剂量的用于患者的本发明化合物的范围为约0.01至约50mg/kg体重/天。如果需要的话，有效日剂量的活性化合物可以两个、三个、四个、五个、六个或更多个亚剂量在一天当中的适当的间隔分别给药，任选地呈单位剂型形式。在本发明的某些方面中，服药为每天一次给药。
虽然本发明化合物可单独给药，但优选以药物制剂(组合物)形式给予化合物。
试剂盒/产品包装
为了用于上述适应症的治疗，试剂盒/产品包装也在此进行描述。这些试剂盒可以由输送器、药包或容器盒组成，容器盒可被划分成多格，以容纳一种或多种容器，如管形瓶、试管及类似物等，每个容器中包含所述方法中的单独一种成分。合适的容器包括瓶子，管形瓶，注射器和试管等。容器由可接受的玻璃或塑料等材料制作而成。
举例来讲，容器可装有一种或多种在此所述的化合物，化合物可能以药物组分形式存在，也可能与在本文中所述的其它成分组成混合物体存在。容器可有一个无菌输出口(例如容器可为静脉输液包或瓶，瓶塞可被皮下注射器针头刺破)。这样的试剂盒可带有一种化合物，及本文中所述的使用方法的说明、标签或操作说明。
一个典型的试剂盒可包括一种或多种容器，为适应商业推广和使用者对化合物使用的需求，每个容器装有一种或多种材料(如试剂，也可以是浓缩的母液，和/或器械)。这些材料包括但不局限于缓冲液，稀释液，滤器，针头，注射器，输送器，包，容器，瓶和/或试管，附有内容清单和/或使用说明书，内置包装也附有说明书。整套的说明都要包括在内。
标签可显示在容器上或与容器紧密相关。标签出现在容器上即指标签字母、数字或其它特征被 粘贴、铸模、刻在容器上；标签也可出现在装有多种容器的容器盒或运输盒内，如在产品插页中。一个标签可用来提示内容物的某种特定治疗用途。标签也可标示内容物使用说明，诸如在上述方法中描述的。
在本说明书中被描述的所有特征(包括任何所述的权利要求、摘要和图),和/或任何方法或过程中涉及的所有步骤，均有可能以任意一种组合存在，除非某些特征或步骤在同一组合中是相互排斥的。
本发明提到的上述特征，或实施例提到的特征可以任意组合。本案说明书所揭示的所有特征可与任何组合物形式并用，说明书中所揭示的各个特征，可以任何可提供相同、均等或相似目的的替代性特征取代。因此除有特别说明，所揭示的特征仅为均等或相似特征的一般性例子。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件或按照制造厂商所建议的条件。除非另外说明，否则所有的百分数、比率、比例、或份数按重量计。
本发明中的重量体积百分比中的单位是本领域技术人员所熟知的，例如是指在100毫升的溶液中溶质的重量。除非另行定义，文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。此外，任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。文中所述的较佳实施方法与材料仅作示范之用。
这些实施例仅供例证说明的目的，并不限定在此提供的权利要求的范围。
概述。1H-NMR谱Bruker-400或OXFORD-AS500核磁共振仪，化学位移的单位是百万分之一，内标是四甲基硅烷。耦合常数(J)接近0.1Hz。使用的缩略语如下说明：s,单重峰；d，双重峰；t,三重峰；q,四重峰；qu，五重峰；m，多重峰；br，宽峰。质谱使用Quattro MicroTM API三重四极杆质谱仪。
实施例1 2-(1-三苯甲基-1H-咪唑-4-基)苯甲醛的制备
Figure PCTCN2017095669-appb-000037
将2-甲酰基苯硼酸(1.55g,6.88mmol)，1-三苯甲基-4-碘咪唑(3.0g,4.59mmol)，磷酸钾(4.38g,13.77mmol)，Pd(PPh3)4(0.3g,10％，w/w％)加入到DMF(30mL)和水(6mL)的混合溶液中，体系氮气置换4次，在氮气保护下于90℃反应过夜。TLC检测反应完全，冷却至室温，过滤，滤液用乙酸乙酯(300mL)稀释，用水(100mL)洗涤三次，有机相减压蒸去溶剂， 残留物用快速柱层析分离，得目标产物2.15g，收率为75.6％。1H NMR(CDCl3,400MHz)δ10.44(s,1H),7.94(dd,J1＝0.8Hz,J2＝0.8Hz,1H),7.65-7.63(m,1H),7.58-7.53(m,2H),7.40-7.36(m,10H),7.18-7.21(m,6H),7.04(d,J＝1.2Hz,1H)。
实施例2 1-(1-羟基-4-苯基环己基)乙基-1-酮的制备
Figure PCTCN2017095669-appb-000038
将4-苯基环己酮(0.26g,1.5mmol)溶于四氢呋喃(1.0mL)中，置换氮气三次，缓慢滴加二碘化杉溶液(0.1M in THF,15mL，1.5mmoL)，然后将乙酰氯(0.39g,1.0mmoL)慢慢滴加至反应瓶中，滴毕，室温搅拌反应过夜，TLC反应完全，用0.1M盐酸猝灭。减压蒸去可挥发物质，残留物用快速柱层析分离，得目标产物0.16g，收率为52％。1H NMR(DMSO-d6,400MHz)δ7.31-7.15(m,5H),5.20(s,1H),2.20(s,3H),1.82-1.77(m,2H),1.65-1.59(m,6H)。
实施例3 (1-羟基-4-苯基环己基)-2-(5H-咪唑[5,1-a]异吲哚-5-基)-1-乙基酮的制备
Figure PCTCN2017095669-appb-000039
将1-(1-羟基-4-苯基环己基)乙基-1-酮(100mg,0.46mmoL),2-(1-三苯甲基-1H-咪唑-4-基)苯甲醛(190mg,0.46mmoL)溶于四氢呋喃(4.0mL)中，搅拌溶清，滴入乙醇钠溶液(31mg,21％/wt％)室温搅拌过夜，TLC监测，反应完毕，减压蒸去溶剂，加入饱和氯化铵溶液(10mL),用二氯甲烷(20mL)萃取，有机相减压蒸去溶剂，残留物直接用于下步反应。将上述所得残留物溶于甲醇(4mL)和醋酸(1mL)的混合溶液中，于90℃反应3h,TLC检测反应完全，减压蒸去溶剂,残留物快速柱层析分离，得目标化合物110mg，收率为64％。1H NMR(CDCl3,400MHz)δ7.56-7.53(m,2H),7.39(t,J＝7.4Hz,1H),7.33-7.28(m,4H),7.24-7.18(m,3H),7.13(s,1H),5.67(dd,J1＝3.2Hz,J2＝3.6Hz,1H),3.39(dd,J1＝3.6Hz,J2＝3.6Hz,1H),3.22-3.15(m,1H),2.57-2.51(m,1H),1.96-1.55(m,8H)。
实施例4 1-(1-羟基-2-(咪唑[5,1-a]异吲哚-5-基)-4-苯基环己基-1-醇(化合物1)的制备
Figure PCTCN2017095669-appb-000040
将1-(1-羟基-4-苯基环己基)-2-(5H-咪唑[5,1-a]异吲哚-5-基)-1-乙基酮(103mg,0.28mmoL) 加入到甲醇(2mL)中，再在冰浴下加入硼氢化钠(32.0mg,0.83mmoL)。TLC检测反应完全，减压蒸去溶剂，残留物中加入2M盐酸(2mL)，搅拌10分钟，用饱和碳酸氢钠中和，二氯甲烷(3×5mL)萃取，减压蒸去溶剂,残留物用快速柱层析分离，得目标产物70mg，白色固体，收率为68％。1H NMR(CDCl3,400MHz)δ8.57(s,1H),7.56(d,J＝7.6Hz,1H),7.45(d,J＝7.2Hz,1H),7.39(t,J＝7.4Hz,1H),7.33-7.29(m,2H),7.26-7.24(m,5H),5.46(t,J＝6Hz,1H),3.84-3.81(m,1H),2.47-2.41(m,1H),2.23-2,27(m,2H),1.93-1.80(m,8H)。MS-ESI:375.5[M+H]+。
实施例5 (4-亚乙基环己基)苯的制备
Figure PCTCN2017095669-appb-000041
在冰浴下，将叔丁醇钾(1.35g,12.0mmoL)加入到乙基三苯基溴化膦(4.46g,12mmoL)和无水THF(25.0mL)的混合溶液中。再在冰浴下继续搅拌30分钟，后加入4-苯基环己酮(1.74g,10.0mmoL)。加热回流过夜。冷却，减压蒸去溶剂。残留物中加入乙酸乙酯(25.0mL)，用水(10.0mL)，分液。有机相减压蒸去溶剂，残留物用用快速柱层析分离，得目标产物1.62g，收率为87％。1H NMR(CDCl3,500MHz)δ7.38-7.17(m,5H),5.32-5.22(m,1H),2.80(d,J＝13.5Hz,1H),2.72(td,J1＝12.2Hz,J2＝2.7Hz,1H),2.35(d,J＝13.0Hz,1H),2.22(t,J＝13.2Hz,1H),2.00(t,J＝10.5Hz,2H),1.89(t,J＝13.4Hz,1H),1.72-1.62(m,3H),1.61-1.43(m,2H)。
实施例6 1-(4-苯基环己基)-1-乙醇的制备
Figure PCTCN2017095669-appb-000042
将BH3·THF(1M,9.0mL,9.0mmol)加入到(4-亚乙基环己基)苯(1.62g,8.7mmoL)和无水THF(74.5mL)的混合溶液中，室温搅拌过夜。TLC检测反应完全。在冰浴下加入NaOH水溶液(3M,12.5mL)和H2O2(30％，12.5mL)。撤去冰浴，在室温下搅拌3小时。减压蒸去可挥发物质，用乙酸乙酯提取。有机相减压蒸去溶剂，残留物用快速柱层析分离，得目标产物1.78g，收率为74％。1H NMR(CDCl3,500MHz，两异构体2:1混合物)δ7.30-7.18(m,15H),4.30(s,3H),3.77(s,2H),3.42(s,1H),2.65(s,2H),2.45(t,J＝1.0Hz,1H),2.00-0.87(m,36H)。
实施例7 (顺式)1-(4-苯基环己基)-1-乙酮和(反式)1-(4-苯基环己基)-1-乙酮的制备
Figure PCTCN2017095669-appb-000043
在冰浴下，将氯铬酸吡啶(PCC)(2.88g,13.3mmoL)和中性硅胶(2.86g)加入到1-(4-苯基环己基)-1-乙醇(1.7g,8.9mmoL)的DCM(20.0mL)溶液中。自然升至室温，搅拌过夜。TLC检测反应完全，硅藻土过滤，用DCM洗涤。减压蒸去溶剂，残留物用快速柱用快速柱层析分离，得顺式产物1.38g,收率为49％；反式产物0.50g,收率为17％。顺式产物1H NMR(CDCl3,500MHz)δ7.29-7,26(m,2H),7.19-7.17(m,3H),2.64(s,1H),2.57-2.54(m,1H),2.18-2.17(m,5H),1.78-1.66(m,2H),1.59-1.50(m,4H).反式产物1H NMR(CDCl3,500MHz)δ＝7.31-7.26(m,2H),7.21-7.18(m,3H),2.55-2.50(m,1H),2.41(m,1H),2.18(s,3H),2.03-2.00(m,4H),1.52-1.48(m,4H)。
实施例8 (顺式)(顺式)2-(5H-咪唑[5,1-a]异吲哚-5-基)-1-(4-苯基环己基)-1-乙酮的制备
Figure PCTCN2017095669-appb-000044
(顺式)2-(5H-咪唑[5,1-a]异吲哚-5-基)-1-(4-苯基环己基)-1-乙酮的制备同实施例3中(1-羟基-4-苯基环己基)-2-(5H-咪唑[5,1-a]异吲哚-5-基)-1-乙基酮的制备。收率为72％。1H NMR(CDCl3,500MHz)δ7.63(s,1H),7.55(d,J＝5.0Hz,1H),7.38(t,J＝10.0Hz,1H),7.31-7.25(m,4H),7.21-7.17(m,4H),5.66(dd,J1＝10.0Hz,J2＝5.0Hz,2H),3.24(dd,J1＝10.0Hz,J2＝5.0Hz,1H),2.95(dd,J1＝20.0Hz,J2＝10.0Hz,1H),2.55-2.44(m,2H),2.09-2.02((m,4H),1.57-1.46(m,4H)。
实施例9 (顺式)2-(5H-咪唑[5,1-a]异吲哚-5-基)-1-(4-苯基环己基)-1-乙醇(化合物2)的制备
Figure PCTCN2017095669-appb-000045
化合物2的制备同化合物1。白色固体，收率为82％。1H NMR(CDCl3,500MHz)δ7.82(s, 1H),7.56-7.54(m,1H),7.46(d,J＝5.0Hz,1H),7.38-7.35(m,1H),7.27-7.24(m,3H),7.19-7.16(m,3H),5.51-5.50(m,0.24H),5.39(t,J＝5.0Hz,0.78H),3.84-3.69(m,1H),2.46(t,J＝10.0Hz,1H),2.15-1.80(m,8H),1.48-1.43(m,3H)。
实施例10 (反式)2-(5H-咪唑[5,1-a]异吲哚-5-基)-1-(4-苯基环己基)-1-乙酮的制备
Figure PCTCN2017095669-appb-000046
(反式)2-(5H-咪唑[5,1-a]异吲哚-5-基)-1-(4-苯基环己基)-1-乙酮的制备同实施例3中(1-羟基-4-苯基环己基)-2-(5H-咪唑[5,1-a]异吲哚-5-基)-1-乙基酮的制备。收率为70％。1H NMR(CDCl3,500MHz)δ7.63(s,1H),7.55(d,J＝5.0Hz,1H),7.38(t,J＝10.0Hz,1H),7.31-7.25(m,4H),7.21-7.17(m,4H),5.66(dd,J1＝10.0Hz,J2＝5.0Hz,2H),3.24(dd,J1＝10.0Hz,J2＝5.0Hz,1H),2.95(dd,J1＝20.0Hz,J2＝10.0Hz,1H),2.55-2.44(m,2H),2.09-2.02(m,4H),1.60-1.46(m,4H)。
实施例11 (反式)2-(5H-咪唑[5,1-a]异吲哚-5-基)-1-(4-苯基环己基)-1-乙醇(化合物3)的制备
Figure PCTCN2017095669-appb-000047
化合物3的制备同化合物1。白色固体，收率为78％。1H NMR(CDCl3,500MHz)δ7.86(s,1H),7.56(d,J＝10.0Hz,1H),7.46(d,J＝5.0Hz,1H),7.38(t,J＝5.0Hz,1H),7.31-7.17(m,7H),5.43-5.38(m,1H),4.00(m,0.4H),3.78(m,0.6H),2.72-2.11(m,6H),2.18-2.43(m,6H)。
实施例12 2-氟-6-(1-三苯甲基-1H-咪唑-4-基)苯甲醛的制备
Figure PCTCN2017095669-appb-000048
2-氟-6-(1-三苯甲基-1H-咪唑-4-基)苯甲醛的制备同实施例1中2-(1-三苯甲基-1H-咪唑-4-基)苯甲醛的制备，收率为67％。1H NMR(CDCl3,500MHz)δ10.27(s,1H),7.55(s,1H),7.40-7.33(m,10H),7.19-7.15(m,7H),7.11(s,1H),7.04-7.02(m,1H)。
实施例13 (顺式)2-(6-氟-5H-咪唑[5,1-a]异吲哚-5-基)-1-(4-苯基环己基)-1-乙酮的制备
Figure PCTCN2017095669-appb-000049
(顺式)2-(6-氟-5H-咪唑[5,1-a]异吲哚-5-基)-1-(4-苯基环己基)-1-乙酮的制备同实施例3中(1-羟基-4-苯基环己基)-2-(5H-咪唑[5,1-a]异吲哚-5-基)-1-乙基酮的制备。收率为87％。1H NMR(CDCl3,500MHz)δ7.64(s,1H),7.37-7.28(m,4H),7.21-7.19(m,4H),6.95(t,J＝5.0Hz,1H),5.79(d,J＝10.0Hz,1H),3.55(d,J＝20.0Hz,1H),2.87-2.81(m,1H),2.55-2.46(m,2H),2.11-2.01(m,4H),1.59-1.44(m,4H)。
实施例14 (顺式)2-(6-氟-5H-咪唑基[5,1-a]异吲哚-5-基)-1-(4-苯基环基基)-1-乙醇(化合物4)的制备
Figure PCTCN2017095669-appb-000050
化合物4的制备同化合物1。白色固体，收率为91％。1H NMR(CDCl3,500MHz)δ7.87(s,0.7H),7.83(s,0.3H),7.38-7.33(m,2H),7.30-7.26(m,2H),7.24-7.16(m,4H),6.94(t,J＝10.0Hz,1H),5.67(m,0.3H),5.48(m,0.7H),3.69(m,1H),2.46-2.37(m,2H),2.14(m,1H),1.95(m,3H),1.77(d,1H),1.44(m,3H),1.30-1.19(m,2H)。
实施例15 (顺式)-2-(6-氟-5H-咪唑[5,1-a]异吲哚-5-基)-1-(4-(吡啶-4-基)环己基)-1-乙酮的制备
Figure PCTCN2017095669-appb-000051
(顺式)-2-(6-氟-5H-咪唑[5,1-a]异吲哚-5-基)-1-(4-(吡啶-4-基)环己基)-1-乙酮的制备同实施例3中(1-羟基-4-苯基环己基)-2-(5H-咪唑[5,1-a]异吲哚-5-基)-1-乙基酮的制备。收率为54％。1H NMR(CDCl3,500MHz)δ7.60(s,1H),7.42-7.31(m,3H),7.21-7.19(m,4H),6.98(t,J＝5.0Hz,1H),5.79(d,J＝10.0Hz,1H),3.55(d,J＝20.0Hz,1H),2.87-2.81(m,1H),2.55-2.46(m,2H),2.11-2.01(m,4H),1.59-1.44(m,4H)。
实施例16 (顺式)-2-(6-氟-5H-咪唑[5,1-a]异吲哚-5-基)-1-(4-(吡啶-4-基)环己基)-1-乙醇(化合物5)的制备
Figure PCTCN2017095669-appb-000052
化合物5的制备同化合物1。白色固体，收率为67％。1H NMR(CDCl3,500MHz)δ7.78(s,1H),7.38-7.33(m,2H),7.30-7.26(m,2H),7.24-7.16(m,3H),6.94(t,J＝10.0Hz,1H),5.67(m,0.3H),5.48(m,0.7H),3.69(m,1H),2.46-2.37(m,2H),2.14(m,1H),1.95(m,3H),1.77(d,1H),1.44(m,3H),1.30-1.19(m,2H)。
实施例17 2-(6-氟-5H-咪唑[5,1-a]异吲哚)-1-(1-羟基-4-苯基环己基)-1-乙酮的制备
Figure PCTCN2017095669-appb-000053
2-(6-氟-5H-咪唑[5,1-a]异吲哚)-1-(1-羟基-4-苯基环己基)-1-乙酮的制备同实施例3中(1-羟基-4-苯基环己基)-2-(5H-咪唑[5,1-a]异吲哚-5-基)-1-乙基酮的制备。收率为63％。1H NMR(CDCl3,500MHz)δ7.58(s,1H),7.33-7.44(m,5H),7.24-7.28(m,3H),7.10(t,J＝7.5Hz,1H),5.85(d,J＝10Hz,1H),3.73(dd,J1＝5Hz,J2＝20Hz,1H),3.08-3.14(m,1H),2.55-2.65(m,1H),1.84-1.98(m,8H)。
实施例18 1-(2-(6-氟-5H-咪唑[5,1-a]异吲哚-5-基)-1-羟乙基)-4-苯基环基-1-醇(化合物6)的制备
Figure PCTCN2017095669-appb-000054
化合物6的制备同化合物1的制备。白色固体，收率为83％。1H NMR(CDCl3,500MHz)δ7.92(s,0.61H),7.89(s,0.38H),7.28-7.39(m,4H),7.17-7.25(m,4H),6.96(t,J＝10Hz,1H),5.70(d,J＝15Hz,0.38H),5.53(t,J＝5Hz,0.65H),3.73(d,J＝10Hz,0.40H),3.60(d,J＝10Hz,0.66H),2.61-2.67(m,0.45H),2.43-2.50(m,2H),2.20-2.25(m,1H),1.83-1.92(m,8H)。
实施例19 2-(6-氟-5H-咪唑[5,1-a]异吲哚-5-基)-1-(4-(4-氟苯基)-1-羟基环己基)-1-乙酮的制备
Figure PCTCN2017095669-appb-000055
2-(6-氟-5H-咪唑[5,1-a]异吲哚-5-基)-1-(4-(4-氟苯基)-1-羟基环己基)-1-乙酮的制备同实施例3中(1-羟基-4-苯基环己基)-2-(5H-咪唑[5,1-a]异吲哚-5-基)-1-乙基酮的制备。收率为82％。1H NMR(CDCl3,500MHz)δ7.82(d,J＝5Hz,3H),7.65-7.72(m,4H)，7.52(s,1H),7.30(t,J＝10Hz,1H),5.76(d,J＝10Hz,1H),3.54-3.78(m,2H),2.27(t,J＝7.5Hz,1H),1.57-1.81(m,8H)。
实施例20 1-(2-(6-氟-5H-咪唑[5,1-a]异吲哚-5-基)-1-羟乙基)-4-(4-氟苯基)-1-环基醇(化合物7)的制备
Figure PCTCN2017095669-appb-000056
化合物7的制备同化合物1的制备。白色固体，收率为73％。1HNMR(500MHz,CDCl3):δ8.02(d,J＝5Hz,1H),7.38-7.42(m,2H),7.21-7.24(m,3H),7.01(t,J＝7.5Hz,3H),5.58-5.57(m,1H),3.64-3.78(m,1H),2.49-2.71(m,2H),2.25-2.28(m,1H),1.90-2.05(m,8H).ESI-MS:m/z 411.3[M+H]+.
实施例21 4-(1,4-二氧杂螺[4,5]癸-7-烯-8-基)喹啉的制备
Figure PCTCN2017095669-appb-000057
将4-喹啉硼酸(2.84g,16mmol)，1,4-二氧杂螺(4,5)癸-7-烯-8-基三氟甲磺酸酯(9.47g,32mmol)，碳酸钾(4.55g,32mmol)，氯化锂(2.09g,48mmol)，)和四三苯基膦钯(1.9g,1.6mmol)加入到1,4-二氧六环(60mL)和水(6.0mL)混合溶液中，体系置换N2三次，在氮气保护下升温80℃反应过夜，TLC监控反应的完全。，反应完毕，降至室温过滤，滤液旋干，残留物中加入水用乙酸乙酯(100 50mL)稀释，加水用乙酸乙酯(50 100mL)萃取，有机相旋干，用快速柱层析分离得目标产物1.5g，收率35.78％。1H NMR(CDCl3,500MHz)δ8.83(d,J＝5Hz,1H),8.10(d,J＝10Hz,1H),8.01(d,J＝5Hz,1H),7.70(t,J＝7.5Hz,1H),7.53(t,J＝7.5Hz,1H),7.22(d,J＝5Hz,1H),5.74-5.75(m,1H),4.08(d,J＝5Hz,4H), 2.63-2.66(m,2H),2.54-2.56(m,2H),2.00(t,J＝7.5Hz,2H)。
实施例22 4-(喹啉-4-基)环己-1-酮的制备
Figure PCTCN2017095669-appb-000058
将4-(1,4-二氧杂螺[4,5]癸-7-烯-8-基)喹啉(1.05g,3.9mmol)，钯炭(200mg,20％w/w)加入到甲醇(10mL)中，体系置换氢气三次，氢气还原，室温搅拌。TLC监控，反应完毕，过滤，有机相旋干得固体产物。将上述固体产物加入到丙酮(10mL)和水(10mL)中，然后加入4-甲苯磺酸吡啶盐(1.14g,4.5mmol)，体系升温65℃反应。TLC监控，反应完毕，降至室温，将体系中丙酮旋干，加入乙酸乙酯(100mL)萃取，有机相旋干，用快速柱层析分离得目标产物0.39g，收率44％。1H NMR(CDCl3,500MHz)δ8.88(d,J＝5Hz,1H),8.15(t,J＝10Hz,2H),7.74(t,J＝7.5Hz,1H),7.63(t,J＝7.5Hz,1H),7.27(d,J＝5Hz,1H),3.83-3.87(m,1H),2.60-2.70(m,4H),2.36-2.42(m,2H),2.02-2.10(m,2H)。
实施例23 1-(1-羟基-4-[喹啉-4-基]环己基)乙-1-酮的制备
Figure PCTCN2017095669-appb-000059
1-(1-羟基-4-[喹啉-4-基]环己基)乙-1-酮的制备实施例2中1-(1-羟基-4-苯基环己基)乙基-1-酮的制备。收率43.0％。1H NMR(CDCl3,500MHz)δ8.75(d,J＝5Hz,1H),8.02(t,J＝10Hz,2H),7.62(t,J＝7.5Hz,1H),7.51(t,J＝7.5Hz,1H),7.16(d,J＝5Hz,1H),2.83-2.87(m,1H),2.24(s,3H),1.97-2.11(m,8H)。
实施例24 2-(6-氟-5H-咪唑并[5,1-α]异吲哚-5-基)-1-(1-羟基-4-(喹啉-4-基)环己基)乙-1-酮的制备
Figure PCTCN2017095669-appb-000060
2-(6-氟-5H-咪唑并[5,1-α]异吲哚-5-基)-1-(1-羟基-4-(喹啉-4-基)环己基)乙-1-酮的制备同实施例3中(1-羟基-4-苯基环己基)-2-(5H-咪唑[5,1-a]异吲哚-5-基)-1-乙基酮的制备。收率31％。1H NMR(CDCl3,500MHz)δ8.84(d,J＝5Hz,1H),8.12(d,J＝5Hz,1H),8.05(d,J＝10Hz,1 H),7.70(t,J＝7.5Hz,1H),7.56(t,J＝10Hz,2H),7.32-7.40(m,3H),7.14(s,1H),6.98(t,J＝7.5Hz,1H),5.81(d,J＝10Hz,1H),3.72-3.76(m,1H),3.40(t,J＝12.5Hz,1H),3.16-3.21(dd,J1＝10Hz,J2＝20Hz,1H),1.97-2.11(m,8H)。
实施例25 1-(2-(6-氟-5H-咪唑并[5,1-α]异吲哚-5-基)-1-羟乙基)-4-(喹啉-4-基)环己-1-醇(化合物8)的制备
Figure PCTCN2017095669-appb-000061
化合物8的制备同化合物1。白色固体，收率49.0％。1H NMR(CDCl3,500MHz)δ8.84(d,J＝5Hz,1H),8.12(d,J＝10Hz,1H),8.05(d,J＝10Hz,1H),7.92(d,J＝15Hz,1H),7.70(t,J＝7.5Hz,1H),7.35-7.55(m,1H),7.33-7.38(m,3H),7.20(d,J＝5Hz,1H),6.98(t,J＝10Hz,1H),5.73(d,J＝10Hz,0.36H),5.57-5.67(m,0.58H),3.80(d,J＝15Hz,0.31H),3.63(d,J＝10Hz,0.58H),3.28(t,J＝12.5Hz,1H),1.98-2.70(m,2H),1.69-1.94(m,8H)。
实施例26 1-(1-羟基-4-(吡啶-4-基)环己基)乙-1-酮的制备
Figure PCTCN2017095669-appb-000062
1-(1-羟基-4-(吡啶-4-基)环己基)乙-1-酮的制备同实施例2中1-(1-羟基-4-苯基环己基)乙基-1-酮的制备。收率38.5％。1H NMR(CDCl3,500MHz):δ8.55(d,J＝10Hz,2H),7.22(d,J＝10Hz,2H),2.70-2.74(m,1H),2.20(s,3H),1.73-1.90(m,8H)。
实施例27 2-(6-氟-5H-咪唑并[5,1-α]异吲哚-5-基)-1-(1-羟基-4-(吡啶-4-基)环己基)乙-1-酮的制备
Figure PCTCN2017095669-appb-000063
2-(6-氟-5H-咪唑并[5,1-α]异吲哚-5-基)-1-(1-羟基-4-(吡啶-4-基)环己基)乙-1-酮的制备同实施例3中(1-羟基-4-苯基环己基)-2-(5H-咪唑[5,1-a]异吲哚-5-基)-1-乙基酮的制备。收率71％。1H NMR(CDCl3,500MHz)δ8.55(d,J＝10Hz,2H),7.96(s,1H),7.70(d,J＝10Hz,1H),7.40-7.45(m,3H),7.21(d,J＝5Hz,2H),4.64-4.83(m,1H),3.62(d,J＝15Hz,1H),3.26(s,1H), 2.51-2.55(m,1H),1.62-1.84(m,8H)。
实施例28 1-(2-(6-氟-5H-咪唑并[5,1-α]异吲哚-5-基)-1-羟乙基)-4-(吡啶-4-基)环己-1-醇(化合物9)的制备
Figure PCTCN2017095669-appb-000064
化合物9的制备同化合物1。白色固体，收率72％。1H NMR(CDCl3,500MHz)δ8.67(d,J＝5Hz,2H),7.96(s,0.70H),7.90(s,0.29H),7.36-7.41(m,2H),7.23(s,0.31H),7.22(s,0.70H),7.16(d,J＝5Hz,2H),7.05(t,J＝10Hz,1H),4.93(d,J＝5Hz,0.31H),4.77(t,J＝5Hz,0.70H),3.52-3.56(m,1H),2.76(d,J＝5Hz,0.33H),2.63(d,J＝5Hz,0.73H),2.24-2.28(m,0.28H),2.03-2.05(m,1.70H),1.61-1.89(m,8H)。
实施例29 1-(4-(3-氯-4-氟苯基)-1-羟基环己基)乙-1-酮的制备
Figure PCTCN2017095669-appb-000065
1-(4-(3-氯-4-氟苯基)-1-羟基环己基)乙-1-酮的制备同实施例2中1-(1-羟基-4-苯基环己基)乙基-1-酮的制备。收率47％。1H NMR(DMSO-d6,500MHz)δ7.41-7.43(m,1H),7.32(t,J＝7.5Hz,1H),7.23-7.26(m,1H),2.53-2.56(m,1H),2.19(s,3H),1.60-1.76(m,8H)。
实施例30 1-(4-(3-氯-4-氟苯基)-1-羟基环己基)-2-(6-氟-5H-咪唑并[5,1-α]异吲哚-5-基)乙-1-酮的制备
Figure PCTCN2017095669-appb-000066
1-(4-(3-氯-4-氟苯基)-1-羟基环己基)-2-(6-氟-5H-咪唑并[5,1-α]异吲哚-5-基)乙-1-酮的制备同实施例3中(1-羟基-4-苯基环己基)-2-(5H-咪唑[5,1-a]异吲哚-5-基)-1-乙基酮的制备。收率57％。1H NMR(CDCl3,500MHz)δ7.58(s,1H),7.37-7.42(m,1H),7.34(d,J＝5Hz,1H),7.25(s,1H),7.17(s,1H),7.05-7.08(m,2H),6.97(t,J＝10Hz,1H),5.80(d,J＝10Hz,1H),3.65-3.69(m,1H),3.04-3.10(m,1H),2.50-2.54(m,1H),1.76-1.90(m,8H)。
实施例31 4-(3-氯-4-氟苯基)-1-(2-(6-氟-5H-咪唑并[5,1-α]异吲哚-5-基)-1-羟基甲基)环己-1-醇(化合物10)的制备
Figure PCTCN2017095669-appb-000067
化合物10的制备同化合物1。白色固体，收率92％。1H NMR(CDCl3,500MHz)δ7.89(s,0.71H),7.84(s,0.28H),7.32-7.38(m,2H),7.24(s,1H),7.18(s,1H),7.02-7.07(m,2H),6,96(t,J＝10Hz,1H),5.68(d,J＝10Hz,0.28H),5.53(t,J＝5Hz,0.71H),3.71(d,J＝10Hz,0.29H),3.66(d,J＝10Hz,0.71H),2.60-2.62(m,0.28H),2.42-2.47(m,1.69H),2.22-2.27(m,1H),1.74-1.86(m,8H)。
实施例32 4-(4-乙酰基-4-羟基环己基)苄腈的制备
Figure PCTCN2017095669-appb-000068
4-(4-乙酰基-4-羟基环己基)苄腈的制备同实施例2中1-(1-羟基-4-苯基环己基)乙基-1-酮的制备。收率33％。1H NMR(500MHz,DMSO-d6):δ7.78(d,J＝10Hz,2H),7.48(d,J＝5Hz,2H),5.26(s,1H),2.66(t,J＝10Hz,1H),2.22(s,3H),1.64-1.82(m,8H)。
实施例33 4-{4-[2-(6-氟-5H-咪唑并[5,1-α]异吲哚-5-基)乙酰基]-4-羟基环己基}苄腈的制备
Figure PCTCN2017095669-appb-000069
4-{4-[2-(6-氟-5H-咪唑并[5,1-α]异吲哚-5-基)乙酰基]-4-羟基环己基}苄腈的制备同实施例3中(1-羟基-4-苯基环己基)-2-(5H-咪唑[5,1-a]异吲哚-5-基)-1-乙基酮的制备。收率47％。1H NMR(500MHz,CDCl3):δ7.54(d,J＝5Hz,3H),7.37-7.44(m,4H),7.24(s,1H),7.01(t,J＝10Hz,1H),5.85(d,J＝10Hz,1H),3.70-3.73(m,2H),2.27(t,J＝7.5Hz,1H),1.61-2.06(m,8H)。
实施例34 4-{4-[2-(6-氟-5H-咪唑并[5,1-α]异吲哚-5-基)-1-羟基-乙基]-4-羟基环己基}苄腈(化合物11)的制备
Figure PCTCN2017095669-appb-000070
化合物11的制备同化合物1。白色固体，收率70％。1H NMR(500MHz,CDCl3):δ7.95(s,0.67H),7.89(s,0.30H),7.63(d,J＝5Hz,2H),7.37-7.42(m,4H),7.22(s,1H),7.01(t,J＝10Hz,1H),5.74(d,J＝10Hz,0.30H),5.58(t,J＝5Hz,0.66H),3.62-3.69(m,1H),2.56-2.51(m,2H),2.26-2.31(m,1H),1.81-2.05(m,8H)。
实施例35 1-[4-(4-三氟甲基苯基)-1-羟基环己基]乙酮的制备
Figure PCTCN2017095669-appb-000071
1-[4-(4-三氟甲基苯基)-1-羟基环己基]乙酮的制备同实施例2中1-(1-羟基-4-苯基环己基)乙基-1-酮的制备。收率30％。1H NMR(500MHz,DMSO-d6):δ7.68(d,J＝10Hz,2H),7.50(d,J＝5Hz,2H),5.26(s,1H),2.66(t,J＝12.5Hz,1H),2.23(s,3H),1.60-1.79(m,8H)。
实施例36 2-(6-氟-5H-咪唑并[5,1-α]异吲哚-5-基)-1-[1-羟基-4-(4-三氟甲基苯基)环己基]乙酮的制备
Figure PCTCN2017095669-appb-000072
2-(6-氟-5H-咪唑并[5,1-α]异吲哚-5-基)-1-[1-羟基-4-(4-三氟甲基苯基)环己基]乙酮的制备同实施例3中(1-羟基-4-苯基环己基)-2-(5H-咪唑[5,1-a]异吲哚-5-基)-1-乙基酮的制备。收率36％。1H NMR(500MHz,CDCl3):δ7.72(d,J＝5Hz,1H),7.53(d,J＝15Hz,2H),7.36-7.38(m,4H),7.20(s,1H),6.96(t,J＝7.5Hz,1H),5.35-5.71(m,2H),3.73-3.56(m,1H),2.45-2.52(m,1H),2.22-2.25(m,1H),1.73-1.91(m,8H)。
实施例37 1-[2-(6-氟-5H-咪唑并[5,1-α]异吲哚-5-基)-1-羟基-乙基]-4-(4-三氟甲基苯基)环己醇(化合物12)的制备
Figure PCTCN2017095669-appb-000073
化合物12的制备同化合物1。白色固体，收率66％。1H NMR(500MHz,CDCl3):δ7.95(s,0.70H),7.93(s,0.31H),7.53(d,J＝15Hz,2H),7.36-7.38(m,4H),7.20(s,1H),6.96(t,J＝7.5Hz,1H),5.35-5.71(m,2H),3.56-3.73(m,1H),2.45-2.52(m,1H),2.22-2.25(m,1H).ESI-MS:m/z 461.3[M+H]+
实施例38 1-(1-羟基-4-(4-(三氟甲氧基)苯基)环己基)乙-1-酮的制备
Figure PCTCN2017095669-appb-000074
1-(1-羟基-4-(4-(三氟甲氧基)苯基)环己基)乙-1-酮的制备同实施例2中1-(1-羟基-4-苯基环己基)乙基-1-酮的制备。收率67％。1H NMR(DMSO-d6,500MHz)δ7.36(d,J＝5Hz,2H),7.27(d,J＝5Hz,2H),5.21(s,1H),2.49(t,J＝2.5Hz,1H),2.20(s,3H),1.64-1.80(m,8H)。
实施例39 2-(6-氟-5H-咪唑并[5,1-α]异吲哚-5-基)-1-(1-羟基-4-(4-(三氟甲氧基)苯基)环己基)乙-1-酮的制备
Figure PCTCN2017095669-appb-000075
2-(6-氟-5H-咪唑并[5,1-α]异吲哚-5-基)-1-(1-羟基-4-(4-(三氟甲氧基)苯基)环己基)乙-1-酮的制备同实施例3中(1-羟基-4-苯基环己基)-2-(5H-咪唑[5,1-a]异吲哚-5-基)-1-乙基酮的制备。收率68％。1H NMR(CDCl3,500MHz)δ7.59(s,1H),7.38-7.40(m,1H),7.34(d,J＝15Hz,2H),7.24(d,J＝10Hz,2H),7.18(s,1H),7.14(d,J＝10Hz,2H),6.97(t,J＝10Hz,2H),5.80(d,J＝10Hz,1H),3.68(dd,J1＝5Hz,J2＝20Hz,1H),3.06(dd,J1＝10Hz,J2＝20Hz,1H),2.56(m,1H),1.72-1.93(m,8H)。
实施例40 1-(2-(6-氟-5H-咪唑并[5,1-α]异吲哚-5-基)-1-羟乙基)-4-(4-(三氟甲氧基)苯基)环己烷-1-醇(化合物13)的制备
Figure PCTCN2017095669-appb-000076
化合物13的制备同化合物1。白色固体，收率81％。1H NMR(CDCl3,500MHz)δ7.90(s,0.71H),7.85(s,0.28H),7.32-7.38(m,2H),7.23(d,J＝10Hz,2H),7.18(s,1H),7.13(d,J＝10Hz,2H),6.96(t,J＝10Hz,1H),5.68(d,J＝10Hz,0.28H),5.54(t,J＝7.5Hz,0.76H),3.73(d,J＝10Hz,0.29H),3.58(d,J＝15Hz,0.74H),2.45-2.62(m,2H),2.21-2.27(m,1H),1.88-1.26(m,2H)。
实施例41 1-(1-羟基-4-(4-异丙基苯基)环己基)乙-1-酮的制备
Figure PCTCN2017095669-appb-000077
1-(1-羟基-4-(4-异丙基苯基)环己基)乙-1-酮的制备同实施例2中1-(1-羟基-4-苯基环己基)乙基-1-酮的制备。收率48％。1H NMR(DMSO-d6,500MHz):δ7.14(d,J＝10Hz,2H),6.84(d,J＝10Hz,2H),5.18(s,1H),4.54-4.59(m,1H),2.43-2.48(m,1H),2.22(s,3H),1.60-1.79(m,8H),1.26(d,J＝5Hz,6H)。
实施例42 2-(6-氟-5H-咪唑并[5,1-α]异吲哚-5-基)-1-(1-羟基-4-(4-异丙基苯基)环己基)乙基-1-酮
Figure PCTCN2017095669-appb-000078
2-(6-氟-5H-咪唑并[5,1-α]异吲哚-5-基)-1-(1-羟基-4-(4-异丙基苯基)环己基)乙基-1-酮的制备同实施例3中(1-羟基-4-苯基环己基)-2-(5H-咪唑[5,1-a]异吲哚-5-基)-1-乙基酮的制备。收率69％。1H NMR(CDCl3,500MHz):δ7.63(s,1H),7.37-7.43(m,2H),7.22(s,1H),7.16(d,J＝10Hz,2H),7.01(t,J＝15Hz,1H),6.86(d,J＝5Hz,2H),4.53-4.56(m,1H),3.72(d,J＝15Hz,1H),3.36(s,1H),3.08-3.14(m,1H),2.51-2.55(m,1H),1.72-1.94(m,8H),1.36(d,J＝5Hz,6H)。
实施例43 1-(2-(6-氟-5H-咪唑并[5,1-α]异吲哚-5-基)-1-羟乙基)-4-(4-异丙基苯基)环己烯-1-醇(化合物14)的制备
Figure PCTCN2017095669-appb-000079
化合物14的制备同化合物1。白色固体，收率72％。1H NMR(CDCl3,500MHz):δ7.96(s,0.70H),7.90(s,0.29H),7.36-7.41(m,2H),7.23(s,0.31H),7.22(s,0.70H),7.16(d,J＝5Hz,2H),7.00(t,J＝10Hz,1H),6.87(d,J＝5Hz,2H),5.73(d,J＝5Hz,0.31H),5.57(t,J＝5Hz,0.70H),4.52-4.56(m,1H),3.76(d,J＝5Hz,0.33H),3.63(d,J＝5Hz,0.73H),2.64-2.68(m,0.28H),2.43-2.52(m,1.70H),2.22-2.28(m,1H),1.81-1.89(m,8H),1,36(d,J＝5Hz,6H)。
实施例44 1-[4-对甲苯基-1-羟基环己基]乙酮的制备
Figure PCTCN2017095669-appb-000080
1-[4-对甲苯基-1-羟基环己基]乙酮的制备同实施例2中1-(1-羟基-4-苯基环己基)乙基-1-酮的制备。收率45％。1H NMR(500MHz,DMSO-d6):δ7.10-7.14(m,4H),5.20(s,1H),2.47(t,J＝12.5Hz,1H),2.28(s,3H),2.22(s,3H),1.60-1.79(m,8H)。
实施例45 2-(6-氟-5H-咪唑并[5,1-α]异吲哚-5-基)-1-(1-羟基-4-对甲苯基-环己基)-乙酮的制备
Figure PCTCN2017095669-appb-000081
2-(6-氟-5H-咪唑并[5,1-α]异吲哚-5-基)-1-(1-羟基-4-对甲苯基-环己基)-乙酮的制备同实施例3中(1-羟基-4-苯基环己基)-2-(5H-咪唑[5,1-a]异吲哚-5-基)-1-乙基酮的制备。收率43％。1H NMR(500MHz,CDCl3):δ7.64(s,1H),7.43-7.38(m,2H),7.23(s,1H),7.16(s,4H),7.01(t,J＝7.5Hz,1H),5.85(d,J＝10Hz,2H),3.74-3.08(m,3H),3.72(d,J＝20Hz,1H),3.32(s,1H),3.14-3.08(m,1H),2.36(s,3H),1.94-1.73(m,8H)。
实施例46 1-[2-(6-氟-5H-咪唑并[5,1-α]异吲哚-5-基)-1-羟基-乙基]-4-对甲苯基-环己醇(化合物15)的制备
Figure PCTCN2017095669-appb-000082
化合物15的制备同化合物1。白色固体，收率55％。1H NMR(500MHz,CDCl3):δ7.96(s,0.75H),7.92(s,0.23H),7.37-7.41(m,2H),7.25(d,J＝10Hz,1H),7.16(s,4H),7.01(t,J＝7.5Hz,1H),5.53-5.74(m,1H),3.75(d,J＝10Hz,0.28H),3.62(d,J＝10Hz,0.83H),2.44-2.52(m,1H),2.36(s,3H),2.25-2.27(m,1H),2.05-2.14(m,1H),1.55-1.88(m,8H)。
实施例47 1-(1-羟基-4-(苯并[d][1,3]二氧杂环)环己基)乙-1-酮的制备
Figure PCTCN2017095669-appb-000083
1-(1-羟基-4-(苯并[d][1,3]二氧杂环)环己基)乙-1-酮的制备同实施例2中1-(1-羟基-4-苯基环己基)乙基-1-酮的制备。收率57％。1H NMR(DMSO-d6,500MHz):δ6.80(d,J＝15Hz,2H),6.68(d,J＝10Hz,1H),5.95(s,2H),5.16(s,1H),2.41-2.46(m,1H),2.19(s,3H),1.56-1.76(m,8H)。
实施例48 2-(6-氟-5H-咪唑并[5,1-α]异吲哚-5-基)-1-(1-羟基-4-(苯并[d][1,3]二氧杂环)环己基)乙-1-酮
Figure PCTCN2017095669-appb-000084
2-(6-氟-5H-咪唑并[5,1-α]异吲哚-5-基)-1-(1-羟基-4-(苯并[d][1,3]二氧杂环)环己基)乙-1-酮的制备同实施例3中(1-羟基-4-苯基环己基)-2-(5H-咪唑[5,1-a]异吲哚-5-基)-1-乙基酮的制备。收率90％。1H NMR(CDCl3,500MHz):δ7.58(s,1H),7.32-7.39(m,2H),7.17(s,1H),6.96(t,J＝10Hz,1H),6.74(d,J＝10Hz,1H),5.92(s,2H),5.79(d,J＝10Hz,1H),3.67(d,J＝15Hz,1H),3.50-3.51(m,1H),3.06(dd,J1＝10HZ,J2＝20Hz,1H),2.48(t,J＝12.5Hz,1H),1.68-1.90(m,8H)δ
实施例49 4-(苯并[d][1,3]二氧杂环戊烯-5-基)-1-(2-(6-氟-5H-咪唑并[5,1-α]异吲哚-5-基)-1-羟基甲基)环己-1-醇(化合物16)的制备
Figure PCTCN2017095669-appb-000085
化合物16的制备同化合物1。白色固体，收率83％。1H NMR(CDCl3,500MHz):δ7.91(s,0.63H),7.86(s,0.32H),7.32-7.37(m,2H),7.18(d,J＝5Hz,1H),6.96(t,J＝7.5Hz,1H),6.66-6.74(m,3H),5.91(s,2H),5.69(d,J＝10Hz,0.35H),5.53(t,J＝5Hz,0.66H),3.56-3.72(m,1H),2.44-2.61(m,1H),2.38-2.36(m,1H),2.20-2,25(m,1H),1.38-1.85(m,8H)。
实施例50 1-(4-(2,2-二氟苯并[d][1,3]二氧杂环戊烯-5-基)-1-羟基环己基)乙-1-酮的制备
Figure PCTCN2017095669-appb-000086
1-(4-(2,2-二氟苯并[d][1,3]二氧杂环戊烯-5-基)-1-羟基环己基)乙-1-酮的制备同实施例2中1-(1-羟基-4-苯基环己基)乙基-1-酮的制备。收率32％。1H NMR(CDCl3,500MHz):δ6.98-7.03(m,3H),3.76(s,1H),2.62-2.66(m,1H),2.34(s,3H),1.69-2.01(m,8H)。
实施例51 1-(4-(2,2-二氟苯并[d][1,3]二氧杂环戊烯-5-基)-1-羟基环己基)-2-(6-氟-5H-咪唑并[5,1-α]异吲哚-5-基)乙-1-酮的制备
Figure PCTCN2017095669-appb-000087
1-(4-(2,2-二氟苯并[d][1,3]二氧杂环戊烯-5-基)-1-羟基环己基)-2-(6-氟-5H-咪唑并[5,1-α]异吲哚-5-基)乙-1-酮的制备同实施例3中(1-羟基-4-苯基环己基)-2-(5H-咪唑[5,1-a]异吲哚-5-基)-1-乙基酮的制备。收率46％。1H NMR(CDCl3,500MHz):δ7.62(s,1H),7.42-7.44(m,1H),7.38(d,J＝10Hz,1H),7.21(s,1H),6.95-7.03(m,4H),5.84(d,J＝10Hz,1H),3.72(d,J＝15Hz,1H),3.08-3.14(m,1H),2.59-2.61(m,1H),1.77-1.96(m,8H)。
实施例52 4-(2,2-二氟苯并[d][1,3]二氧杂环戊烯-5-基)-1-(2-(6-氟-5H-咪唑并[5,1-α]异吲哚-5-基)-1-羟乙基)环己基-1-醇(化合物17)的制备
Figure PCTCN2017095669-appb-000088
化合物17的制备同化合物1。白色固体，收率71％。1H NMR(CDCl3,500MHz)：δ7.98(s,0.69H),7.95(s,0.33H),7.37-7.41(m,2H),7.24(s,1H),6.94-7.03(m,4H),5.74(d,J＝10Hz,0.33H),5.58(t,J＝5Hz,0.70H),3.75(d,J＝10Hz,0.34H),3.61(d,J＝10Hz,0.73H),2.64-2.68(m,0.31H),2.49-2.52(m,1.73H),2.26-2.30(m,1H),1.80-1.90(m,8H)。
实施例53 4-(4-亚乙基环己基)喹啉的制备
Figure PCTCN2017095669-appb-000089
4-(4-亚乙基环己基)喹啉的制备同实施例5中(4-亚乙基环己基)苯的制备。收率70％。1H NMR(CDCl3,500MHz):δ8.83(s,1H),8.83(s,1H),8.13(t,J＝10Hz,2H),7.70(t,J＝7.5Hz,1H),7.58(t,J＝7.5Hz,1H),7.25(s,1H),6.28-6.29(m,1H),3.5-3.55(m,1H),2.86(d,J＝15Hz,1H),2.33-2.41(m,2H),1.97-2.13(m,3H),1.56-1.65(m,5H)。
实施例54 1-(4-(喹啉-4-基)环己基)乙基-1-醇的制备
Figure PCTCN2017095669-appb-000090
1-(4-(喹啉-4-基)环己基)乙基-1-醇的制备同实施例6中1-(4-苯基环己基)-1-乙醇的制备。收率为87％。1H NMR(DMSO-d6,500MHz):δ8.80(d,J＝5Hz,1H),8.28(d,J＝5Hz,1H),8.02(d,J＝5Hz,1H),7.74-7.77(m,1H),7.63-7.66(m,1H),7.37(d,J＝5Hz,1H),5.23(dd,J1＝20Hz,J2＝10Hz,1H),3.61(dd,J1＝15Hz,J2＝2.5Hz,1H),2.77(d,J＝7.5Hz,1H),2.30-2.36(m,2H),1.96-2.06(m,3H),1.60(d,J＝10Hz,3H),1.46-1.58(m,2H),1.23-1.31(m,1H)。
实施例55 1-(4-(喹啉-4-基)环己基)乙-1-酮的制备
Figure PCTCN2017095669-appb-000091
1-(4-(喹啉-4-基)环己基)乙-1-酮的制备同实施例7中(顺式)1-(4-苯基环己基)-1-乙酮和(反式)1-(4-苯基环己基)-1-乙酮的制备。收率25％。1H NMR(CDCl3,500MHz):δ8.82-8.86(m,1H),8.13(d,J＝5Hz,1H),8.06(d,J＝5Hz,1H),7.69-7.72(m,1H),7.56-7.59(m,1H),7.26-7.27(m,1H),3.33-3.43(m,1H),2.78-2.82(m,1H),2.37(d,J＝15Hz,2H),2.23(s,3H),1.66-1.93(m,5H)。
实施例56 2-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(4-(喹啉-4-基)环己基)乙基-1-酮的制备
Figure PCTCN2017095669-appb-000092
2-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(4-(喹啉-4-基)环己基)乙基-1-酮的制备同实施例3中(1-羟基-4-苯基环己基)-2-(5H-咪唑[5,1-a]异吲哚-5-基)-1-乙基酮的制备。收率40％。1H NMR(CDCl3,500MHz):δ8.84-8.85(m,1H),8.13(d,J＝7.5Hz,1H),8.06(d,J＝10Hz,1H),7.71(t,J＝7.5Hz,1H),7.66(s,1H),7.59(t,J＝7.5Hz,1H),7.33-7.41(m,2H),7.24-7.26(m,2H),7.20(s,1H),6.96(t,J＝10Hz,1H),5.82(d,J＝15Hz,1H),3.59(d,J＝20Hz,1H),3.38(t,J＝12.5Hz,1H),2.86-2.92(m,1H),2.59(t,J＝12.5Hz,1H),2.11-2.21(m,4H),1.58-1.85(m,4H)。
实施例57 2-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(4-(喹啉-4-基)环己基)乙-1-醇(化合物18)的制备
Figure PCTCN2017095669-appb-000093
化合物18的制备同化合物1。白色固体，收率79％。1H NMR(CDCl3,500MHz):δ8.83-8.84(m,1H),8.11(d,J＝5Hz,1H),8.05(d,J＝5Hz,1H),7.90(s,0.75H),7.86(s,0.25H),7.58-7.71(m,1H),7.54-7.57(m,1H),7.33-7.38(m,2H),7.25-7.26(m,1H),7.21-7.23(m,1H),6.94(t,J＝10Hz,1H),5.71(d,J＝10Hz,0.25H),5.51-5.54(m,0.75H),3.75-3.84(m, 1H),3.27-3.32(m,1H),2.41-2.59(m,1H),2.06-2.22(m,4H),1.91(d,J＝10Hz,1H),1.38-1.86(m,5H)。
实施例58 (4-亚乙基环己基)-2,3-二氢苯并[b][1,4]二恶英的制备
Figure PCTCN2017095669-appb-000094
(4-亚乙基环己基)-2,3-二氢苯并[b][1,4]二恶英的制备同实施例5中(4-亚乙基环己基)苯的制备。收率87％。1H NMR(500MHz,CDCl3):δ8.96(d,J＝5Hz,1H),8.55(d,J＝5Hz,1H),8.03(d,J＝10Hz,1H),7.71(t,J＝7.5Hz,1H),7.46-7.50(m,2H),5.32-5.35(m,1H),3.52(t,J＝10Hz,1H),2.91(d,J＝10Hz,1H),2.35-2.46(m,2H),2.02-2.15(m,3H),1.69(d,J＝5Hz,3H),1.61-1.66(m,2H)。
实施例59 1-(4-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)环己基)乙-1-醇的制备
Figure PCTCN2017095669-appb-000095
1-(4-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)环己基)乙-1-醇的制备同实施例6中1-(4-苯基环己基)-1-乙醇的制备。收率62％。1H NMR(500MHz,CDCl3):δ8.96(d,J＝5Hz,1H),8.51(d,J＝10Hz,1H),8.04(d,J＝10Hz,1H),7.72(t,J＝7.5Hz,1H),7.47-7.54(m,2H),3.44-3.48(m,1H),1.70-1.96(m,8H),1.35(d,J＝5Hz,3H)。
实施例60 1-(4-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)环己基)乙-1-酮的制备
Figure PCTCN2017095669-appb-000096
1-(4-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)环己基)乙-1-酮的制备同同实施例7中(顺式)1-(4-苯基环己基)-1-乙酮和(反式)1-(4-苯基环己基)-1-乙酮的制备。收率84％。1H NMR(500MHz,CDCl3):δ8.95-8.96(m,1H),8.48(d,J＝10Hz,1H),8.02(d,J＝10Hz,1H),7.70(t,J＝7.5Hz,1H),7.45-7.49(m,2H),3.32-3.37(m,1H),2.41-2.62(m,2H),2.28(d,J＝5Hz,3H),1.73-1.94(m,4H),1.31-1.34(m,2H)。
实施例61 1-(4-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)环己基)-2-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)乙-1-酮的制备
Figure PCTCN2017095669-appb-000097
1-(4-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)环己基)-2-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)乙-1-酮的制备同实施例3中(1-羟基-4-苯基环己基)-2-(5H-咪唑[5,1-a]异吲哚-5-基)-1-乙基酮的制备。收率88％。1H NMR(500MHz,CDCl3):δ8.96-8.98(m,1H),8.47(d,J＝10Hz,1H),8.04(d,J＝10Hz,1H),7.71-7.73(m,2H),7.38-7.51(m,4H),7.25(s,1H),7.01(t,J＝10Hz,1H),5.87(d,J＝10Hz,1H),3.66(d,J＝20Hz,1H),3.35(t,J＝10Hz,1H),2.91-2.96(m,1H),2.61-2.66(m,1H),2.14-2.25(m,3H),1.69-1.86(m,5H)。
实施例62 1-(4-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)环己基)-2-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)乙基-1-醇(化合物19)的制备
Figure PCTCN2017095669-appb-000098
化合物19的制备同化合物1。白色固体，收率85％。1H NMR(500MHz,CDCl3):δ7.86(s,0.72H),7.82(s,0.28H),7.36-7.33(s,2H),7.21-7.20(s,1H),6.94(t,J＝10Hz,1H),6.77(d,J＝5.0Hz,1H),6.69-6.65(m,2H),5.66(m,0.28H),5.48(m,0.82H),4.23(s,4H),3.75-3.67(m,1H),2.38-2.13(m,1.5H),2.13(m,0.5H),1.93-1.77(m,5H),1.38-1.16(m,5H)。
实施例63 5-(4-亚乙基环己基)-1-甲基-1H-吲唑的制备
Figure PCTCN2017095669-appb-000099
5-(4-亚乙基环己基)-1-甲基-1H-吲唑的制备同实施例5中(4-亚乙基环己基)苯的制备。收率82％。1H NMR(CDCl3,500MHz):δ7.90(s,1H),7.52(s,1H),7.32(d,J＝10Hz,1H),7.28(d,J＝10Hz,1H),5.22-5.26(m,1H),4.05(s,3H),2.77-2.82(m,2H),2.19-2.34(m,2H),1.97-2.05(m,2H),1.88(t,J＝15Hz,1H),1.62(d,J＝5Hz,3H),1.49-1.57(m,2H)。
实施例64 1-(4-(1-甲基-1H-吲唑-5-基)环己基)乙-1-醇的制备
Figure PCTCN2017095669-appb-000100
1-(4-(1-甲基-1H-吲唑-5-基)环己基)乙-1-醇的制备同实施例6中1-(4-苯基环己基)-1-乙醇的制备。收率为64％。1H NMR(CDCl3,500MHz):δ7.91(s,1H),7.56(s,1H),7.29-7.34(m,2H),4.05(s,3H),3.64-4.00(m,1H),2.56-2.82(m,1H),1.54-2.07(m,8H),1.25(d,J＝10Hz,3H)。
实施例65 1-(4-(1-甲基-1H-吲唑-5-基)环己基)乙-1-酮的制备
Figure PCTCN2017095669-appb-000101
1-(4-(1-甲基-1H-吲唑-5-基)环己基)乙-1-酮的制备同实施例7中(顺式)1-(4-苯基环己基)-1-乙酮和(反式)1-(4-苯基环己基)-1-乙酮的制备。收率54％。1H NMR(CDCl3,500MHz):δ7.91(s,0.28H),7.89(s,0.68H),7.52(s,0.28H),7.50(s,0.73H),7.24-7.34(m,2H),4.05(s,0.82H),4.04(s,2.21H),2.64-2.67(m,1H),2.26-2.28(m,2H),2.21(s,2.24H),2.20(s,0.76H),2.04-2.09(m,1H),1.66-1.81(m,5H),1.53-1.57(m,1H)。
实施例66 2-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(4-(1-甲基-1H-吲唑-5-基)环己基)乙-1-酮的制备
Figure PCTCN2017095669-appb-000102
2-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(4-(1-甲基-1H-吲唑-5-基)环己基)乙-1-酮的制备同实施例3中(1-羟基-4-苯基环己基)-2-(5H-咪唑[5,1-a]异吲哚-5-基)-1-乙基酮的制备。收率83％。1H NMR(CDCl3,500MHz):δ7.91(s,1H),7.65(s,1H),7.51(s,1H),7.32-7.40(m,3H),7.24-7.26(m,1H),7.19(s,1H),6.95(t,J＝10Hz,1H),5.79(d,J＝10Hz,1H),4.05(s,3H),3.56(d,J＝20Hz,1H),2.83-2.89(m,1H),2.64(t,J＝10Hz,1H),2.51(t,J＝10Hz,1H),2.04-2.13(m,4H),1.51-1.67(m,4H)。
实施例67 2-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(4-(1-甲基-1H-吲唑-5-基)环己基)乙-1-醇(化合物20)的制备
Figure PCTCN2017095669-appb-000103
化合物20的制备同化合物1。白色固体，收率79％。1H NMR(CDCl3,500MHz):δ7.9(s,1H),7.88(s,0.75H),7.84(s.0.23H),7.50(s,1H),7.31-7.38(m,3H),7.24-7.26(m,1H),7.20-7.22(m,1H),6.95(t,J＝10Hz,1H),5.68(d,J＝5Hz,0.25H),5.50(t,J＝5Hz,0.78H),4.04(s,3H),3.70-3.70(m,1H),2.55-2.60(m,1H),2.38-2.52(m,1H),2.15-2.22(m,1H),1.97-2.09(m,3H),1.81-1.84(m,2H),1.45-1.55(m,2H),1.22-1.33(m,2H)。
实施例68 5-(4-亚乙基环己基)-2-甲基-2H-吲唑的制备
Figure PCTCN2017095669-appb-000104
5-(4-亚乙基环己基)-2-甲基-2H-吲唑的制备同实施例5中(4-亚乙基环己基)苯的制备。收77％。1H NMR(CDCl3,500MHz):δ7.80(s,1H),7.61(d,J＝10Hz,1H),7.40(s,1H),7.18(d,J＝10Hz,1H),5.21-5.25(m,1H),4.19(s,3H),2.72-2.79(m,2H),2.17-2.33(m,2H),1.98-2.05(m,2H),1.87(t,J＝15Hz,1H),1.63(d,J＝5Hz,3H),1.47-1.50(m,2H)。
实施例69 1-(4-(2-甲基-2H-吲唑-5-基)环己基)乙-1-醇的制备
Figure PCTCN2017095669-appb-000105
1-(4-(2-甲基-2H-吲唑-5-基)环己基)乙-1-醇的制备同实施例6中1-(4-苯基环己基)-1-乙醇的制备。1H NMR(CDCl3,500MHz):δ7.80(s,1H),7.62(d,J＝5Hz,1H),7.45(s,1H),7.20(d,J＝10Hz,1H),4.20(s,3H),3.65-4.00(m,1H),2.09-2.75(m,1H),1.52-2.01(m,8H),1.25(d,J＝10Hz,3H)。
实施例70 1-(4-(2-甲基-2H-吲唑-5-基)环己基)乙-1-酮的制备
Figure PCTCN2017095669-appb-000106
1-(4-(2-甲基-2H-吲唑-5-基)环己基)乙-1-酮的制备同实施例7中(顺式)1-(4-苯基环己基)-1-乙酮和(反式)1-(4-苯基环己基)-1-乙酮的制备。收率43％。1H NMR(CDCl3,500MHz):δ7.80(s,1H),7.64(d,J＝5Hz,1H),7.43(s,1H),7.24(d,J＝10Hz,1H),4.20(s,3H),2.63-2.66(m,1H),2.25-2.27(m,2H),2.20(s,3H),2.02-2.07(m,1H),1.64-1.80(m,5H),1.51-1.56(m,1H)。
实施例71 2-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(4-(2-甲基-2H-吲唑-5-基)环己基)乙基-1-酮的制备
Figure PCTCN2017095669-appb-000107
2-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(4-(2-甲基-2H-吲唑-5-基)环己基)乙基-1-酮的制备同实施例3中(1-羟基-4-苯基环己基)-2-(5H-咪唑[5,1-a]异吲哚-5-基)-1-乙基酮的制备。收率64％。1H NMR(CDCl3,500MHz):δ7.81(s,1H),7.65(s,1H),7.62(d,J＝10Hz,1H),7.32-7.40(m,3H),7.19(s,1H),7.15(d,J＝10Hz,1H),6.95(t,J＝10Hz,1H),5.79(d,J＝10Hz,1H),4.20(s,3H),3.56(d,J＝20Hz,1H),2.82-2.88(m,1H),2.59(t,J＝10Hz,1H),2.50(t,J＝10Hz,1H),2.03-2.12(m,4H),1.50-1.66(m,4H)。
实施例72 2-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(4-(2-甲基-2H-吲唑-5-基)环己基)乙-1-醇(化合物21)的制备
Figure PCTCN2017095669-appb-000108
化合物21的制备同化合物1。白色固体，收率60％。1H NMR(CDCl3,500MHz):δ7.88(s,0.75H),7.84(s,0.25H),7.80(s.1H),7.61(d,J＝10Hz,1H),7.32-7.39(m,3H),7.14-7.22(m,2H),6.95(t,J＝10Hz,1H),5.68(d,J＝5Hz,0.25H),5.50(t,J＝5Hz,0.78H),4.19(s,3H),3.70-3.78(m,1H),2.39-2.51(m,2H),2.19-2.20(m,1H),1.96-2.02(m,3H),1.81-1.84(m,2H),1.47-1.51(m,2H),1.24-1.39(m,2H)。
实施例73 (4-亚乙基环己基)咪唑并[1,2-a]吡啶的制备
Figure PCTCN2017095669-appb-000109
(4-亚乙基环己基)咪唑并[1,2-a]吡啶的制备同实施例5中(4-亚乙基环己基)苯的制备。收率85.2％。1H NMR(500MHz,CDCl3):δ8.52(s,1H),7.53(m,2H),7.41(d,J＝5Hz,1H),7.20(d,J＝10Hz,1H),5.30-5.34(m,1H),2.89-2.91(m,1H),2.32-2.45(m,4H),2.19(d,J＝10Hz,3H),1.99-2.03(m,2H),1.75-1.80(m,2H)。
实施例74 1-(4-(咪唑并[1,2-a]吡啶-6-基)环己基)乙-1-醇的制备
Figure PCTCN2017095669-appb-000110
1-(4-(咪唑并[1,2-a]吡啶-6-基)环己基)乙-1-醇的制备同实施例6中1-(4-苯基环己基)-1-乙醇的制备。收率为48％。1H NMR(500MHz,CDCl3):δ8.56(s,1H),7.45-7.57(m,3H),7.25(d,J＝10Hz,1H),3.50-3.54(m,1H),2.70-2.80(m,1H),1.75-1.96(m,8H),1.30(d,J＝5Hz,3H).
实施例75 1-(4-(咪唑并[1,2-a]吡啶-6-基)环己基)乙-1-酮的制备
Figure PCTCN2017095669-appb-000111
1-(4-(咪唑并[1,2-a]吡啶-6-基)环己基)乙-1-酮的制备同实施例7中(顺式)1-(4-苯基环己基)-1-乙酮和(反式)1-(4-苯基环己基)-1-乙酮的制备。收率23％。1H NMR(500MHz,CDCl3):δ8.60(s,1H),7.44-7.56(m,3H),7.23(d,J＝10Hz,1H),2.80-2.85(m,1H),2.51-2.54(m,2H),2.18(s,3H),1.65-1.83(m,8H)。
实施例76 2-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(4-(咪唑并[1,2-a]吡啶-6-基)环己基)乙-1-酮的制备
Figure PCTCN2017095669-appb-000112
2-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(4-(咪唑并[1,2-a]吡啶-6-基)环己基)乙-1-酮的制备同实施例3中(1-羟基-4-苯基环己基)-2-(5H-咪唑[5,1-a]异吲哚-5-基)-1-乙基酮的制备。收率64％。1H NMR(500MHz,CDCl3):δ8.80(s,1H),8.03(s,1H),7.65(d,J＝10Hz, 1H),7.51-7.54(m,2H),7.30-7.41(m,4H),7.25(d,J＝10Hz,1H),5.67-5.72(m,1H),3.46(d,J＝10Hz,1H),3.25(t,J＝10Hz,1H),2.71-2.76(m,1H),2.41-2.45(m,1H),2.04-2.15(m,4H),1.65-1.78(m,4H)。
实施例77 2-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(4-(咪唑并[1,2-a]吡啶-6-基)环己基)乙-1-醇(化合物22)的制备
Figure PCTCN2017095669-appb-000113
化合物22的制备同化合物1。白色固体，收率83％。1H NMR(500MHz,CDCl3):δ8.65(s,1H),8.02(s,1H),7.70(d,J＝10Hz,1H),7.42-7.51(m,3H),7.32-7.48(m,3H),7.22(d,J＝5Hz,1H),5.70(s,0.34H),5.58(s,0.74H),3.51(s,0.35H),3.45(s,0.69H),3.26(t,J＝5Hz,1H),2.50-2.66(m,1H),2.03-2.38(m,4H),1.72-1.85(m,2H),1.34-1.59(m,4H)。
实施例78 4-(4-亚乙基环己基)-1-甲基-1H-吡唑的制备
Figure PCTCN2017095669-appb-000114
4-(4-亚乙基环己基)-1-甲基-1H-吡唑的制备同实施例5中(4-亚乙基环己基)苯的制备。收率70％。1H NMR(CDCl3,500MHz):δ7.32(s,1H),7.12(s,1H),5.17-5.22(m,1H),3.85(s,3H),2.62-2.69(m,2H),2.10-2.16(m,2H),1.97-2.05(m,2H),1.83(t,J＝15Hz,1H),1.59(d,J＝5Hz,3H),1.26-1.41(m,3H)。
实施例79 1-(4-(1-甲基-1H-吡唑-4-基)环己基)乙-1-醇的制备
Figure PCTCN2017095669-appb-000115
1-(4-(1-甲基-1H-吡唑-4-基)环己基)乙-1-醇的制备同同实施例6中1-(4-苯基环己基)-1-乙醇的制备。1H NMR(CDCl3,500MHz):δ7.34(s,1H),7.16(s,1H),3.85(s,3H),3.65(m,1H),2.39-2.87(m,1H),1.24-1.85(m,9H),1.16(d,J＝5Hz,3H)。
实施例80 1-(4-(1-甲基-1H-吡唑-4-基)环己基)乙-1-酮的制备
Figure PCTCN2017095669-appb-000116
1-(4-(1-甲基-1H-吡唑-4-基)环己基)乙-1-酮的制备同实施例7中(顺式)1-(4-苯基环己基)-1-乙酮和(反式)1-(4-苯基环己基)-1-乙酮的制备。收率50％。1H NMR(CDCl3,500MHz):δ7.32(s,0.29H),7.30(s,0.71H),7.13(s,1H),3.84(s,3H),2.36-2.69(m,2H),2.14(s,3H),1.93-2.08(m,2H),1.60-1.80(m,4H),1.28-1.47(m,2H)。
实施例81 2-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(4-(1-甲基-1H-吡唑-4-基)环己基)乙-1-酮的制备
Figure PCTCN2017095669-appb-000117
2-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(4-(1-甲基-1H-吡唑-4-基)环己基)乙-1-酮的制备同同实施例3中(1-羟基-4-苯基环己基)-2-(5H-咪唑[5,1-a]异吲哚-5-基)-1-乙基酮的制备。收率44％。1H NMR(CDCl3,500MHz):δ7.62(s,1H),7.31-7.38(m,3H),7.18(s,1H),7.13(s,1H),6.94(t,J＝10Hz,1H),5.77(d,J＝10Hz,1H),3.86(s,3H),3.52(d,J＝20Hz,1H),2.40-2.50(m,2H),1.95-2.10(m,4H),1.45-1.62(m,2H),1.25-1.39(m,3H)。
实施例82 2-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(4-(1-甲基-1H-吡唑-4-基)环己基)乙基-1-醇(化合物23)的制备
Figure PCTCN2017095669-appb-000118
化合物23的制备同化合物1。白色固体，收率53％。1H NMR(CDCl3,500MHz):δ7.86(s,0.73H),7.82(s,0.25H),7.31-7.38(m,3H),7.20(s,0.28H),7.19(s,0.72H),6.94(t,J＝10Hz,1H),5.66(d,J＝5Hz,0.27H),5.48(t,J＝5Hz,0.74H),3.84(s,3H),3.65-3.73(m,1H),2.34-2.51(m,2H),2.12-2.18(m,1H),1.73-2.07(m,5H),1.14-1.39(m,4H).
实施例83 (4-亚乙基环己基)呋喃的制备
Figure PCTCN2017095669-appb-000119
(4-亚乙基环己基)呋喃的制备同实施例5中(4-亚乙基环己基)苯的制备。收率74％。1H NMR(500MHz,CDCl3):δ7.33(s,1H),7.19(s,1H),6.29(s,1H),5.18-5.22(m,1H),2.68(d,J＝5Hz,1H),2.57-2.64(m,1H),2.25(d,J＝5Hz,1H),2.13(t,J＝15Hz,1H),1.99(t,J＝15Hz,2H),1.80-1.86(m,1H),1.59(d,J＝5Hz,3H),1.31-1.41(m,2H)。
实施例84 1-(4-(呋喃-3-基)环己基)乙-1-醇的制备
Figure PCTCN2017095669-appb-000120
1-(4-(呋喃-3-基)环己基)乙-1-醇的制备同实施例6中1-(4-苯基环己基)-1-乙醇的制备。收率37％。1H NMR(500MHz,CDCl3):δ7.34-7.35(m,1H),7.19-7.23(m,1H),6.29(s,1H),3.66(t,J＝5Hz,1H),3.59(t,J＝5Hz,1H),2.0(m,1H),1.69-1.79(m,4H),1.35-1.47(m,4H),1.16(d,J＝5Hz,1H)。
实施例85 1-(4-(呋喃-3-基)环己基)乙-1-酮的制备
Figure PCTCN2017095669-appb-000121
将上述产物加至8mL二氯甲烷中，冰盐浴降温10min，加入氯铬酸吡啶盐(0.288g,1.34mmol)和硅胶(0.288g，1.34mol)，升至室温搅拌过夜，TLC监控反应完毕，过滤，有机相旋干，用快速柱层析分离得5.1-(4-(呋喃-3-基)环己基)乙基-1-酮60mg，收率35％。
实施例86 1-(4-(呋喃-3-基)环己基)-2-(5H-咪唑并[5,1-a]异吲哚-5-基)乙基-1-酮的制备
Figure PCTCN2017095669-appb-000122
1-(4-(呋喃-3-基)环己基)-2-(5H-咪唑并[5,1-a]异吲哚-5-基)乙基-1-酮的制备同实 施例3中(1-羟基-4-苯基环己基)-2-(5H-咪唑[5,1-a]异吲哚-5-基)-1-乙基酮的制备。收率70％。1H NMR(500MHz,CDCl3):δ7.62(s,1H),7.26-7.34(m,4H),7.18-7.2(m,2H),6.93-6.98(m,1H),6.29(s,1H),5.78(d,J＝5Hz,1H),3.48-3.56(m,1H),3.15(s,1H),2.80-2.86(m,1H),2.42-2.47(t,J＝12.5Hz,2H),1.96-2.11(m,4H),1.26-1.39(m,2H)。
实施例87 1-(4-(呋喃-3-基)环己基)-2-(5H-咪唑并[5,1-a]异吲哚-5-基)乙基-1-醇(化合物24)的制备
Figure PCTCN2017095669-appb-000123
化合物24的制备同化合物1。白色固体，收率66％。1H NMR(500MHz,CDCl3):δ7.72-7.86(m,2H),7.32-7.37(m,3H),7.19-7.21(m,2H),6.96(t,J＝7.5Hz,1H),6.28(s,1H),5.48-5.67(m,2H),3.67-3.74(m,2H),2.34-2.39(m,2H),1.89-1.92(m,2H),1.75-1.77(m,2H),1.17-1.33(m,4H)。
实施例88 (4-亚乙基环己基)-2-甲氧基嘧啶的制备
Figure PCTCN2017095669-appb-000124
(4-亚乙基环己基)-2-甲氧基嘧啶的制备同实施例5中(4-亚乙基环己基)苯的制备。收率89％。1H NMR(500MHz,CDCl3):δ8.40(s,2H),5.29-5.30(m,1H),4.04(s,3H),2.83(d,J＝15Hz,1H),2.68-2.73(m,1H),2.38(d,J＝15Hz,1H),2.22(t,J＝12.5Hz,1H),1.99(d,J＝12.5Hz,2H),1.90(t,J＝12.5Hz,1H),1.66(d,J＝5Hz,3H),1.46-1.55(m,2H)。
实施例89 1-(4-(2-甲氧基嘧啶-5-基)环己基)乙-1-醇的制备
Figure PCTCN2017095669-appb-000125
1-(4-(2-甲氧基嘧啶-5-基)环己基)乙-1-醇的制备同实施例6中1-(4-苯基环己基)-1-乙醇的制备。1H NMR(500MHz,CDCl3):δ8.50(s,2H),4.08(s,3H),3.50-3.53(m,1H),3.05-3.08(m,1H),2.55-2.57(m,4H),2.40-2.45(m,1H),2.28-2.31(m,2H),1.87-1.92(m,2H),1.43(d,J＝5Hz,3H)。
实施例90 1-(4-(2-甲氧基嘧啶-5-基)环己基)乙-1-酮的制备
Figure PCTCN2017095669-appb-000126
1-(4-(2-甲氧基嘧啶-5-基)环己基)乙-1-酮的制备：同实施例7中(顺式)1-(4-苯基环己基)-1-乙酮和(反式)1-(4-苯基环己基)-1-乙酮的制备。收率49％。1H NMR(500MHz,CDCl3):δ8.60(s,2H),4.04(s,3H),3.40-3.45(m,1H),2.50-2.53(m,1H),2.04(s,3H),1.85-1.97(m,8H)。
实施例91 2-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(4-(2-甲氧基嘧啶-5-基)环己基)乙-1-酮的制备
Figure PCTCN2017095669-appb-000127
2-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(4-(2-甲氧基嘧啶-5-基)环己基)乙-1-酮的制备同实施例3中(1-羟基-4-苯基环己基)-2-(5H-咪唑[5,1-a]异吲哚-5-基)-1-乙基酮的制备。收率70％。1H NMR(500MHz,CDCl3):δ8.53(s,2H),7.82(s,1H),7.56-7.63(m,2H),7.42(s,1H),7.01(t,J＝10Hz,1H),5.77-5.81(m,1H),4.06(s,3H),3.56(d,J＝10Hz,1H),3.15(m,1H),2.61-2.66(m,1H),2.20-2.33(m,1H),2.04-2.08(m,4H),1.86-1.93(m,4H)。
实施例92 2-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(4-(2-甲氧基嘧啶-5-基)环己基)乙基-1-醇(化合物25)的制备
Figure PCTCN2017095669-appb-000128
化合物25的制备同化合物1。白色固体，收率83％。1H NMR(500MHz,CDCl3):δ8.43(s,2H),7.95(s,1H),7.41-7.53(m,2H),7.32(s,1H),7.04(t,J＝5Hz,1H),5.76(s,0.31H),5.60(s,0.73H),4.02(s,3H),3.60(s,0.27H),3.56(s,0.75H),3.25(m,1H),2.31-2.36(m,1H),2.10-2.13(m,1H),1.96-2.05(m,5H),1.65-1.78(m,4H)。
实施例93 4-(4-亚乙基环己-1-烯-1-基)-3,5-二甲基异恶唑的制备
Figure PCTCN2017095669-appb-000129
4-(4-亚乙基环己-1-烯-1-基)-3,5-二甲基异恶唑的制备同实施例5中(4-亚乙基环己基)苯的制备。收率99％。1H NMR(CDCl3,500MHz):δ5.26(d,J＝5Hz,1H),2.79(d,J＝15Hz,1H),2.56(t,J＝5Hz,1H),2.34(s,3H),2.29(s,3H),1.65(d,J＝5Hz,3H),1.49-2.34(m,7H)。
实施例94 1-(4-(3,5-二甲基异恶唑-4-基)环己-3-烯-1-基)乙-1-醇的制备
Figure PCTCN2017095669-appb-000130
1-(4-(3,5-二甲基异恶唑-4-基)环己-3-烯-1-基)乙-1-醇的制备同实施例6中1-(4-苯基环己基)-1-乙醇的制备。收率81％。1H NMR(CDCl3,500MHz):δ3.45(s,1H),2.46(s,3H),2.42(s,3H),1.20-1.73(m,10H),1.07(d,J＝10Hz,3H)。
实施例95 1-(4-(3,5-二甲基异恶唑-4-基)环己-3-烯-1-基)乙-1-酮的制备
Figure PCTCN2017095669-appb-000131
1-(4-(3,5-二甲基异恶唑-4-基)环己-3-烯-1-基)乙-1-酮的制备同实施例7中(顺式)1-(4-苯基环己基)-1-乙酮和(反式)1-(4-苯基环己基)-1-乙酮的制备。收率33％。1H NMR(CDCl3,500MHz):δ2.73(s,1H),2.34(s,3H),2.27(d,J＝15Hz,2H),2.23(s,3H),2.22(s,3H),1.60-1.72(m,8H)。
实施例96 1-(4-(3,5-二甲基异恶唑-4-基)环己基)-2-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)乙-1-酮的制备
Figure PCTCN2017095669-appb-000132
1-(4-(3,5-二甲基异恶唑-4-基)环己基)-2-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)乙-1-酮同实施例3中(1-羟基-4-苯基环己基)-2-(5H-咪唑[5,1-a]异吲哚-5-基)-1-乙基酮的制备。收 率65％。1H NMR(CDCl3,500MHz):δ7.68(s,1H),7.39-7.44(m,2H),7.24(s,1H),7.00(t,J＝10Hz,1H),5.83(d,J＝10Hz,1H),3.61(d,J＝15Hz,1H),2.89-2.92(m,1H),2.39(s,3H),2.29(s,3H),1.31-2.01(m,10H)。
实施例97 1-(4-(3,5-二甲基异恶唑-4-基)环己基)-2-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)乙基-1-醇(化合物26)的制备
Figure PCTCN2017095669-appb-000133
化合物26的制备同化合物。白色固体，收率47％。1H NMR(CDCl3,500MHz):δ7.91(s,0.69H),7.88(s,0.30H),7.31-7.42(m,2H),7.21(d,J＝5Hz,1H),7.00(t,J＝10Hz,1H),5.72(d,J＝10Hz,0.25H),5.54(t,J＝5Hz,0.70H),3.80(s,0.27H),3.72(s,0.71H),2.38(s,3H),2.28(s,3H),1.20-2.55(m,12H)。
实施例98 (4-亚乙基环己基)-2-甲基异喹啉-1(2H)-酮的制备
Figure PCTCN2017095669-appb-000134
(4-亚乙基环己基)-2-甲基异喹啉-1(2H)-酮的制备同实施例5中(4-亚乙基环己基)苯的制备。收率75％。1H NMR(CDCl3,500MHz):δ8.26(m,1H),7.24(m,2H),6.99(m,1H),6.37(m,1H),5.31(d,J＝5Hz,1H),3.34(s,3H),2.72(d,J＝15Hz,1H),2.25(d,J＝5Hz,3H),1.44-2.42(m,8H)。
实施例99 (4-(1-羟乙基)环己基)-2-甲基异喹啉-1(2H)-酮的制备
Figure PCTCN2017095669-appb-000135
(4-(1-羟乙基)环己基)-2-甲基异喹啉-1(2H)-酮的制备同实施例6中1-(4-苯基环己基)-1-乙醇的制备。1H NMR(CDCl3,500MHz):δ8.21(m,1H),7.18(m,2H),6.82(m,1H),6.33(m,1H),3.65(s,3H),3.52(s,1H),2.73(m,1H),1.36-1.90(m,11H),1.12(d,J＝10Hz,3H)。
实施例100 (4-乙酰基环己基)-2-甲基异喹啉-1(2H)-酮的制备
Figure PCTCN2017095669-appb-000136
(4-乙酰基环己基)-2-甲基异喹啉-1(2H)-酮的制备同实施例7中(顺式)1-(4-苯基环己基)-1-乙酮和(反式)1-(4-苯基环己基)-1-乙酮的制备。收率34％。1H NMR(CDCl3,500MHz):δ8.36(m,1H),7.34(m,2H),7.09(m,1H),6.47(m,1H),3.63(d,J＝5Hz,3H),2.25(d,J＝5Hz,3H),1.59-2.72(m,10H)。
实施例101 6-(4-(2-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)乙酰基)环己基)-2-甲基异喹啉-1(2H)的制备
Figure PCTCN2017095669-appb-000137
6-(4-(2-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)乙酰基)环己基)-2-甲基异喹啉-1(2H)的制备同实施例3中(1-羟基-4-苯基环己基)-2-(5H-咪唑[5,1-a]异吲哚-5-基)-1-乙基酮的制备。收率74％。1H NMR(CDCl3,500MHz):δ8.40(d,J＝10Hz,1H),7.70(s,1H),7.35-7.39(m,4H),7.24(s,1H),7.10(d,J＝10Hz,1H),7.00(t,J＝10Hz,1H),6.49(d,J＝10Hz,1H),5.84(d,J＝10Hz,1H),3.64(s,3H),1.61-3.60(m,12H)。
实施例102 6-(4-(2-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-1-羟乙基)环己基)-2-甲基异喹啉-1(2H)(化合物27)的制备
Figure PCTCN2017095669-appb-000138
化合物27的制备同化合物1。白色固体，收率51％。1H NMR(CDCl3,500MHz):δ8.39(d,J＝10Hz,1H),7.93(s,0.72H),7.91(s,0.26H),7.32-7.39(m,4H),7.20(s,1H),7.10(d,J＝5Hz,1H),7.01(t,J＝7.5Hz,1H),6.49(d,J＝10Hz,1H),5.73(d,J＝5Hz,0.26H),5.56(s,0.78H),3.84(s,0.22H),3.75(s,0.74H),3.64(s,3H),1.30-2.64(m,12H).
实施例103 5-(4-亚乙基环己基)喹啉的制备
Figure PCTCN2017095669-appb-000139
5-(4-亚乙基环己基)喹啉的制备同实施例5中(4-亚乙基环己基)苯的制备。收率91％。1H NMR(500MHz,CDCl3):δ8.96(d,J＝5Hz,1H),8.55(d,J＝5Hz,1H),8.03(d,J＝10Hz,1H),7.71(t,J＝7.5Hz,1H),7.46-7.50(m,2H),5.32-5.35(m,1H),3.52(t,J＝10Hz,1H),2.91(d,J＝10Hz,1H),2.35-2.46(m,2H),2.02-2.15(m,3H),1.69(d,J＝5Hz,3H),1.61-1.66(m,2H)。
实施例104 1-(4-喹啉-5-基)环己基)乙-1-醇的制备
Figure PCTCN2017095669-appb-000140
1-(4-喹啉-5-基)环己基)乙-1-醇的制备同实施例6中1-(4-苯基环己基)-1-乙醇的制备。1H NMR(500MHz,CDCl3):δ8.96(d,J＝5Hz,1H),8.51(d,J＝10Hz,1H),8.04(d,J＝10Hz,1H),7.72(t,J＝7.5Hz,1H),7.47-7.54(m,2H),3.44-3.48(m,1H),1.70-1.96(m,8H),1.35(d,J＝5Hz,3H)。
实施例105 1-(4-(喹啉-5-基)环己基)乙-1-酮的制备
Figure PCTCN2017095669-appb-000141
1-(4-(喹啉-5-基)环己基)乙-1-酮的制备同实施例7中(顺式)1-(4-苯基环己基)-1-乙酮和(反式)1-(4-苯基环己基)-1-乙酮的制备。收率48％。1H NMR(500MHz,CDCl3):δ8.95-8.96(m,1H),8.48(d,J＝10Hz,1H),8.02(d,J＝10Hz,1H),7.70(t,J＝7.5Hz,1H),7.45-7.49(m,2H),3.32-3.37(m,1H),2.41-2.62(m,2H),2.28(d,J＝5Hz,3H),1.73-1.94(m,4H),1.31-1.34(m,2H)。
实施例106 2-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(4-(喹啉-5-基)环己基)乙-1-酮的制备
Figure PCTCN2017095669-appb-000142
2-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(4-(喹啉-5-基)环己基)乙-1-酮的制备同实施例3中(1-羟基-4-苯基环己基)-2-(5H-咪唑[5,1-a]异吲哚-5-基)-1-乙基酮的制备。收率68％。1H NMR(500MHz,CDCl3):δ8.96-8.98(m,1H),8.47(d,J＝10Hz,1H),8.04(d,J＝10Hz,1H),7.71-7.73(m,2H),7.38-7.51(m,4H),7.25(s,1H),7.01(t,J＝10Hz,1H),5.87(d,J＝10Hz,1H),3.66(d,J＝20Hz,1H),3.35(t,J＝10Hz,1H),2.91-2.96(m,1H),2.61-2.66(m,1H),2.14-2.25(m,3H),1.69-1.86(m,5H)。
实施例107 2-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(4-(喹啉-5-基)环己基)乙基-1-醇(化合物28)的制备
Figure PCTCN2017095669-appb-000143
化合物28的制备同化合物1。白色固体，收率89％。1H NMR(500MHz,CDCl3):δ8.94-8.98(m,1H),8.47(d,J＝10Hz,1H),8.03(d,J＝10Hz,1H),7.95(s,0.71H),7.91(s,0.24H),7.72(t,J＝5Hz,1H),7.41-7.48(m,4H),7.25-7.28(m,1H),7.02(t,J＝5Hz,1H),5.77(s,0.27H),5.58(s,0.73H),3.88(s,0.25H),3.79(s,0.69H),3.28(t,J＝5Hz,1H),2.60(t,J＝5Hz,0.3H),2.49(d,J＝10Hz,0.69H),2.12-2.28(m,4H),1.82-1.96(m,2H),1.44-1.49(m,4H)。
实施例108 5-(4-乙缩醛-环己基)-苯基[1,3]-间二氧杂环戊烯的制备
Figure PCTCN2017095669-appb-000144
5-(4-乙缩醛-环己基)-苯基[1,3]-间二氧杂环戊烯的制备同实施例5中(4-亚乙基环己基)苯的制备。收率90％。1H NMR(CDCl3,500MHz):δ6.69-6.78(m,3H),5.96(s,2H),5.25(d,J＝5Hz,1H),2.79(d,J＝15Hz,1H),2.65(t,J＝12.5Hz,1H),2.33(d,J＝15Hz,1H),2.20(t, J＝12.5Hz,1H),1.96(t,J＝15Hz,2H),1.87(t,J＝12.5Hz,1H),1.65(d,J＝5Hz,3H),1.30-1.49(m,2H)。
实施例109 1-(4-苯基[1,3]二氧杂环戊烯-5-基-环己基)-乙基-1-醇的制备
Figure PCTCN2017095669-appb-000145
1-(4-苯基[1,3]二氧杂环戊烯-5-基-环己基)-乙基-1-醇的制备同同实施例6中1-(4-苯基环己基)-1-乙醇的制备。收率64％。1H NMR(CDCl3,500MHz):δ6.83(d,J＝10Hz,2H),6.71(d,J＝10Hz,1H),5.98(s,2H),3.40(s,1H),2.54-2.59(m,1H),1.11-1.62(m,11H),1.07(d,J＝10Hz,3H)。
实施例110 1-(4-苯基[1,3]二氧杂环戊烯-5-基-环己基)-乙基-1-酮的制备
Figure PCTCN2017095669-appb-000146
1-(4-苯基[1,3]二氧杂环戊烯-5-基-环己基)-乙基-1-酮的制备同同实施例7中(顺式)1-(4-苯基环己基)-1-乙酮和(反式)1-(4-苯基环己基)-1-乙酮的制备。收率62％。1H NMR(CDCl3,500MHz):δ6.71-6.79(m,3H),5.97(d,J＝5Hz,2H),2.46(t,J＝5Hz,2H),2.23(d,J＝5Hz,3H),2.01-2.09(m,4H),1.47-1.56(m,4H)。
实施例111 1-(4-苯基[1,3]二氧杂环戊烯-5-基-环己基)-2-(6-氟-5H-咪唑[5,1-a]异吲哚-5-基)-乙-1-酮的制备
Figure PCTCN2017095669-appb-000147
1-(4-苯基[1,3]二氧杂环戊烯-5-基-环己基)-2-(6-氟-5H-咪唑[5,1-a]异吲哚-5-基)-乙-1-酮的制备同实施例3中(1-羟基-4-苯基环己基)-2-(5H-咪唑[5,1-a]异吲哚-5-基)-1-乙基酮的制备。收率78％。1H NMR(CDCl3,500MHz):δ7.68(t,J＝20Hz,1H),7.31-7.42(m,2H),7.21(s,1H),7.00(t,J＝7.5Hz,1H),6.68-6.83(m,3H),5.97(s,2H),5.83(d,J＝5Hz,1H),3.58-3.61(d,J＝15Hz,1H),2.86-2.91(m,1H),2.50(t,J＝7.5HZ,2H),1.42-2.27(m,10H)。
实施例112 1-(4-苯并[1,3]间二氧杂环戊烯-5-基-环己基)-2-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-乙基-1-醇(化合物29)的制备
Figure PCTCN2017095669-appb-000148
化合物29的制备同化合物1。白色固体，收率54％。1H NMR(CDCl3,500MHz):δ7.93(s,0.74H),7.89(s,0.24H),7.39(m,2H),7.21(d,J＝5Hz,1H),7.00(t,J＝10Hz,1H),6.68-6.79(m,3H),5.97(s,2H),5.72(d,J＝10Hz,0.24H),5.55(s,0.73H),3.81(s,0.27H),3.73(s,0.72H),1.25-2.55(m,12H)。
实施例113 2-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)N-(4-(4-乙酰基环己基)苯基)氨磺酰基)氨基的制备
Figure PCTCN2017095669-appb-000149
2-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)N-(4-(4-乙酰基环己基)苯基)氨磺酰基)氨基的制备同实施例3中(1-羟基-4-苯基环己基)-2-(5H-咪唑[5,1-a]异吲哚-5-基)-1-乙基酮的制备。收率51％。1H NMR(500MHz,CDCl3):δ8.03(s,1H),7.83(d,J＝10Hz,1H),7.50(d,J＝10Hz,2H),7.30-7.45(m,3H),7.01(d,J＝10Hz,2H),5.76-5.83(m,1H),3.56(d,J＝10Hz,1H),3.24(t,J＝7.5Hz,1H),2.81-2.85(m,1H),2.42-2.46(m,1H),1.83-1.98(m,4H),1.65-1.74(m,2H),1.35-1.46(m,2H)。
实施例114 2-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-(N-(4-(4-(1-羟乙基)环己基)苯基)氨磺酰基)氨基(化合物30)的制备
Figure PCTCN2017095669-appb-000150
化合物30的制备同化合物1。白色固体，收率83％。1H NMR(500MHz,CDCl3):δ8.02-8.05(m,1H),7.85(d,J＝10Hz,1H),7.42-7.52(m,2H),7.25-9.38(m,3H),6.98(d,J＝10Hz,2H),5.74(s,0.29H),5.61(s,0.68H),3.73(s,0.36H),3.61(s,0.75H),3.17(t,J＝5Hz,1H),2.65(t,J＝10Hz,1H),2.07-2.15(m,4H),1.80-1.89(m,2H),1.30-1.41(m,4H)。
实施例115 6-(4-亚乙基环己基)-1-甲基-1H-吲哚的制备
Figure PCTCN2017095669-appb-000151
6-(4-亚乙基环己基)-1-甲基-1H-吲哚的制备同实施例5中(4-亚乙基环己基)苯的制备。收率76％。1H NMR(500MHz,CDCl3):δ8.04(d,J＝5Hz,1H),7.9(d,J＝10Hz,1H),6.46(d,J＝10Hz,1H),6.02(m,2H),5.2(s,1H),3.7(s,3H),2.6(m,1H),2.3(m,4H),2.04(s,3H),1.73(m,4H)。
实施例116 1-(4-(1-甲基-1H-吲哚-6-基)环己基)乙-1-醇的制备
Figure PCTCN2017095669-appb-000152
1-(4-(1-甲基-1H-吲哚-6-基)环己基)乙-1-醇的制备同实施例6中1-(4-苯基环己基)-1-乙醇的制备。收率57％。不做纯化，直接用于下一步反应。
实施例117 1-(4-(1-甲基-1H-吲哚-6-基)环己基)乙基-1-酮的制备
Figure PCTCN2017095669-appb-000153
1-(4-(1-甲基-1H-吲哚-6-基)环己基)乙基-1-酮的制备同实施例7中(顺式)1-(4-苯基环己基)-1-乙酮和(反式)1-(4-苯基环己基)-1-乙酮的制备收率33％。1H NMR(500MHz,CDCl3):δ8.05(m,1H),7.80(s,1H),7.21(d,J＝10Hz,1H),7.0(m,1H),6.5(m,1H),3.75(s,3H),2.72(t,J＝10Hz,1H),2.37(d,J＝10Hz,1H),2.06(s,3H),1.4-1.9(m,8H)。
实施例118 2-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(4-(1-甲基-1H-茚-6-基)环己基)乙基-1-酮
Figure PCTCN2017095669-appb-000154
2-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(4-(1-甲基-1H-茚-6-基)环己基)乙基-1-酮同实施例3中(1-羟基-4-苯基环己基)-2-(5H-咪唑[5,1-a]异吲哚-5-基)-1-乙基酮的制备。收率60％。1H NMR(500MHz,CDCl3):δ8.0(s,1H),7.78(m,1H),7.57(d,J＝10Hz,1H),7.41-7.50(m,4H),7.30(s,1H),6.60(d,J＝10Hz,1H),6.40(m,1H),5.2(s,1H),3.6(t,J＝12.5Hz,2H),3.1-3.3(m,2H),2.7(m,1H),2.3(m,1H),1.48-1.86(m,8H),1.25(d,J＝10Hz,1H)。
实施例119 2-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(4-(1-甲基-1H-茚-6-基)环己基)乙-1-醇(化合物31)的制备
Figure PCTCN2017095669-appb-000155
化合物31的制备同化合物1。白色固体，收率33％。1H NMR(500MHz,CDCl3):δ8.05(s,1H),7.96(s,1H),7.91(s,1H),7.70(s,1H),7.47(s,1H),7.40-7.42(m,2H),7.21(d,J＝10Hz,1H),7.0(m,1H),6.47(s,1H),4.88(t,J＝12.5Hz,1H),4.14(s,1H),3.74(s,1H),3.30(t,J＝12.5Hz,1H),2.72(t,J＝12.5Hz,1H),2.19(m,2H),1.61-1.86(m,4H),1.34-1.59(m,5H)。
实施例120 1-乙基-5-(4-亚乙基环己基)-1H-吲唑的制备
Figure PCTCN2017095669-appb-000156
1-乙基-5-(4-亚乙基环己基)-1H-吲唑的制备同实施例5中(4-亚乙基环己基)苯的制备。收率89.9％。1H NMR(500MHz,CDCl3):δ7.97(s,1H),7.58(s,1H),7.41(d,J＝10Hz,1H),7.33(d,J＝5Hz,1H),5.28-5.31(m,1H),4.47(q,J＝7.5Hz,2H),2.82-2.88(m,2H),2.24-2.39(m,2H),2.03-2.10(m,2H),1.91-1.96(m,1H),1.69(d,J＝5Hz,3H),1.56-1.62(m,2H),1.55(t,J＝5Hz,3H)。
实施例121 1-(4-(1-乙基-1H-吲唑-5-基)环己基)乙-1-醇的制备
Figure PCTCN2017095669-appb-000157
1-(4-(1-乙基-1H-吲唑-5-基)环己基)乙-1-醇的制备同实施例6中1-(4-苯基环己基)-1-乙醇的制备。收率67％。不做纯化，直接用于下步反应。
实施例122 1-(4-(1-乙基-1H-吲唑-5-基)环己基)乙-1-酮的制备
Figure PCTCN2017095669-appb-000158
1-(4-(1-乙基-1H-吲唑-5-基)环己基)乙-1-酮的制备同实施例7中(顺式)1-(4-苯基环己基)-1-乙酮和(反式)1-(4-苯基环己基)-1-乙酮的制备。收率64％。1H NMR(500MHz,CDCl3):δ7.96(s,1H),7.56(s,1H),7.39(d,J＝10Hz,1H),7.30(d,J＝10Hz,1H),4.47(q,J＝7.5Hz,2H),2.70-2.73(m,2H),2.32-2.34(m,2H),2.26(m,3H),1.85-1.87(m,2H),1.71-1.79(m,3H),1.55(t,J＝7.5Hz,3H)。
实施例123 1-(4-(1-乙基-1H-吲唑-5-基)环己基)-2-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-)乙基-1-酮的制备
Figure PCTCN2017095669-appb-000159
1-(4-(1-乙基-1H-吲唑-5-基)环己基)-2-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-)乙基-1-酮的制备同同实施例3中(1-羟基-4-苯基环己基)-2-(5H-咪唑[5,1-a]异吲哚-5-基)-1-乙基酮的制备。1H NMR(500MHz,CDCl3):δ7.97(s,1H),7.70(s,1H),7.57(s,1H),7.38-7.45(m,3H),7.28-7.30(m,1H),7.25(s,1H),7.00(t,J＝7.5Hz,1H),5.86(t,J＝10Hz,1H),4.47(q,J＝7.5Hz,2H),3.60-3.64(m,1H),2.90(q,J＝10Hz,1H),2.67-2.72(m,1H),2.54-2.59(m,1H),2.11-2.18(m,4H),1.70-1.73(m,2H),1.59-1.62(m,2H),1.55(t,J＝7.5Hz,3H)。
实施例124 1-(4-(1-乙基-1H-吲唑-5-基)环己基)-2-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)(化合物32)的制备
Figure PCTCN2017095669-appb-000160
化合物32的制备同化合物32。白色固体，收率为91％。1H NMR(500MHz,CDCl3):δ7.96(s,1H),7.93(s,0.78H),7.90(s,0.24H),7.56(s,1H),7.37-7.39(m,3H),7.26-7.28(m,2H),7.00(t,J＝5Hz,1H),5.74(d,J＝10Hz,0.25H),5.56(s,0.74H),4.47(q,J＝7.5Hz,2H),3.75-3.85(m,1H),2.43-2.62(m,2H),2.23-2.25(m,0.44H),2.02-2.08(m,2H),1.68-1.87(m,3.63H),1.48-1.58(m,5H),1.30-1.35(m,2H)。
实施例125 2-乙基-5-(4-亚乙基环己基)-2H-吲唑-2-烯的制备
Figure PCTCN2017095669-appb-000161
2-乙基-5-(4-亚乙基环己基)-2H-吲唑-2-烯的制备同实施例5中(4-亚乙基环己基)苯的制备。收率88％。1H NMR(500MHz,CDCl3):δ7.89(s,1H),7.68(d,J＝10Hz,1H),7.46(s,1H),7.23(d,J＝10Hz,1H),5.28(d,J＝10Hz,1H),4.48-4.53(q,J＝7.5Hz,2H),2.77-2.84(m,2H),2.26-2.38(m,2H),2.05(t,J＝15Hz,2H),1.72(t,J＝12.5Hz,1H),1.67(m,3H),1.65(m,3H),1.52-1.58(m,2H)。
实施例126 1-(4-(2-乙基-2H-吲唑-5-基)环己基)乙-1-醇的制备
Figure PCTCN2017095669-appb-000162
1-(4-(2-乙基-2H-吲唑-5-基)环己基)乙-1-醇的制备同实施例6中1-(4-苯基环己基)-1-乙醇的制备。不做纯化，直接用于下步反应。有机相再水洗两次，旋干直接用于下步反应。1H NMR(500MHz,CDCl3):δ7.91(s,1H),7.62(d,J＝10Hz,1H),7.48(s,1H),6.98(d,J＝10Hz,1H),4.48-4.53(q,J＝7.5Hz,2H),3.50-3.96(m,1H),2.56-2.82(m,1H),1.54-1.96(m,8H),1.29(t,J＝5Hz,3H),1.11(d,J＝10Hz,3H)。
实施例127 1-(4-(2-乙基-2H-吲唑-5-基)环己基)乙-1-酮的制备
Figure PCTCN2017095669-appb-000163
1-(4-(2-乙基-2H-吲唑-5-基)环己基)乙-1-酮的制备同实施例7中(顺式)1-(4-苯基环己基)-1-乙酮和(反式)1-(4-苯基环己基)-1-乙酮的制备。收率33％。1H NMR(500MHz,CDCl3):δ7.90(s,0.28H),7.88(s,0.68H),7.70(d,J＝10Hz,0.26H),7.67(d,J＝10Hz,0.69H),7.47(s,0.23H),7.45(s,0.69H),7.18-7.23(m,1H),4.48-4.52(q,J＝7.5Hz,2H),2.05(s,3H),1.62(s,3H),1.62-2.70(m,10H)。
实施例128 1-(4-(2-乙基-2H-吲唑-5-基)环己基)-2-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)乙-1-酮的制备
Figure PCTCN2017095669-appb-000164
1-(4-(2-乙基-2H-吲唑-5-基)环己基)-2-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)乙-1-酮的制备同实施例3中(1-羟基-4-苯基环己基)-2-(5H-咪唑[5,1-a]异吲哚-5-基)-1-乙基酮的制备。收率79％。1H NMR(500MHz,CDCl3):δ7.90(s,1H),7.69(d,J＝5Hz,2H),7.38-7.46(m,3H),7.25(s,1H),7.20(d,J＝5Hz,1H),7.00(t,J＝10Hz,1H),5.85(d,J＝10Hz,1H),4.49-4.53(q,J＝7.5Hz,2H),3.63(d,J＝15Hz,1H),2.88-2.94(m,1H),2.63(t,J＝10Hz,1H),2.55(t,J＝12.5Hz,1H),2.06-2.17(m,4H),1.67(t,J＝5Hz,3H),1.55-1.71(m,4H)。
实施例129 1-(4-(2-乙基-2H-吲唑-5-基)环己基)-2-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)乙-1-醇(化合物33)的制备
Figure PCTCN2017095669-appb-000165
化合物33的制备同化合物1。白色固体，收率86％。1H NMR(500MHz,CDCl3):δ7.94(s,0.74H),7.90(s,0.26H),7.89(s.1H),7.67-7.69(d,J＝10Hz,1H),7.39-7.45(m,3H),7.19-7.27(m,2H),7.00(t,J＝10Hz,1H),5.73(d,J＝5Hz,0.25H),5.55(t,J＝5Hz,0.74H),4.50(q,J＝7.5Hz,2H),3.83(s,0.25H),3.76(s,0.71H),1.66(t,J＝5Hz,3H),1.27-2.57(m,12H)。
实施例130 5-(4-亚乙基环己基)-1-异丙基-1H-吲唑的制备
Figure PCTCN2017095669-appb-000166
5-(4-亚乙基环己基)-1-异丙基-1H-吲唑的制备同实施例5中(4-亚乙基环己基)苯的制备。收率97％。1H NMR(500MHz,CDCl3):δ7.93(s,1H),7.52(s,1H),7.37(d,J＝10Hz,1H),7.25(d,J＝10Hz,1H),5.22-5.26(m,1H),4.79-4.85(m,1H),2.78(d,J＝10Hz,2H),2.32(d,J＝10Hz,1H),2.21(t,J＝15Hz,1H),2.00(t,J＝15Hz,2H),1.88(t,J＝15Hz,1H),1.63(d,J＝5Hz,3H),1.58(d,J＝10Hz,6H),1.41-1.56(m,2H)。
实施例131 1-(4-(1-异丙基-1H-吲唑-5-基)环己基)乙-1-醇的制备
Figure PCTCN2017095669-appb-000167
1-(4-(1-异丙基-1H-吲唑-5-基)环己基)乙-1-醇的制备同实施例6中1-(4-苯基环己基)-1-乙醇的制备。不做纯化，直接用于下步反应。
实施例132 1-(4-(1-异丙基-1H-吲唑-5-基)环己基)乙-1-酮的制备
Figure PCTCN2017095669-appb-000168
1-(4-(1-异丙基-1H-吲唑-5-基)环己基)乙-1-酮的制备同实施例7中(顺式)1-(4-苯基环己基)-1-乙酮和(反式)1-(4-苯基环己基)-1-乙酮的制备。收率60％。1H NMR(500MHz,CDCl3):δ7.92(s,1H),7.50(s,1H),7.36(d,J＝10Hz,1H),7.22(d,J＝10Hz,1H),4.79-4.84(m,1H),2.63-2.68(m,2H),2.26-2.28(m,2H),2.21(s,3H),1.81(d,J＝10Hz,2H),1.64-1.74(m,4H),1.58(d,J＝10Hz,6H).
实施例133 2-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(4-(1-异基-1H-吲唑-5-基)环己基)乙-1-酮的制备
Figure PCTCN2017095669-appb-000169
2-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(4-(1-异基-1H-吲唑-5-基)环己基)乙-1-酮的制备同实施例3中(1-羟基-4-苯基环己基)-2-(5H-咪唑[5,1-a]异吲哚-5-基)-1-乙基酮的制备。收率74％。1H NMR(500MHz,CDCl3):δ7.94(s,1H),7.65(s,1H),7.51(s,1H),7.32-7.39(m,3H),7.22(d,J＝5Hz,1H),7.19(s,1H),6.95(t,J＝10Hz,1H),5.80(d,J＝10Hz,1H),4.79-4.85(m,1H),3.56(d,J＝20Hz,1H),2.86(dd,J1＝10Hz,J2＝20Hz,1H),2.61-2.66(m,4H),2.49-2.53(m,1H),2.03-2.15(m,4H),1.51-1.67(m,10H)。
实施例134 2-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(4-(1-异丙基-1H-吲唑-5-基)环己基)乙基-1-醇(化合物34)的制备
Figure PCTCN2017095669-appb-000170
化合物34的制备同化合物1。白色固体，收率87％。1H NMR(500MHz,CDCl3):δ7.93(s,1H),7.87(d,J＝20Hz,1H),7.51(s,1H),7.33-7.38(m,3H),7.21-7.24(m,2H),6.95(t,J＝10Hz,1H),5.51-5.70(m,1H),4.79-4.85(m,1H),3.71-3.79(m,1H),2.39-2.57(m,2H),2.15-2.21(m,1H),1.48-2.21(m,12H),1.23-1.33(m,2H).
实施例135 5-(4-亚乙基环己基)-2-异丙基-2H-吲唑的制备
Figure PCTCN2017095669-appb-000171
5-(4-亚乙基环己基)-2-异丙基-2H-吲唑的制备同实施例5中(4-亚乙基环己基)苯的制备。收率80％。1H NMR(500MHz,CDCl3):δ7.87(s,1H),7.65(d,J＝10Hz,1H),7.42(s,1H),7.17(d,J＝10Hz,1H),5.21-5.25(m,1H),4.74-4.78(m,1H),2.72-2.79(m,2H),2.32(d,J＝15Hz,1H),2.20(t,J＝15Hz,1H),2.00(t,J＝15Hz,2H),1.87(t,J＝15Hz,1H),1.63(d,J＝5Hz,6H),1.62(d,J＝5Hz,3H),1.42-1.55(m,2H).
实施例136 1-(4-(2-异丙基-2H-吲唑-5-基)环己基)乙-1-醇的制备
Figure PCTCN2017095669-appb-000172
1-(4-(2-异丙基-2H-吲唑-5-基)环己基)乙-1-醇的制备同实施例6中1-(4-苯基环己基)-1-乙醇的制备。不做纯化，直接用于下步反应。
实施例137 1-(4-(2-异丙基-2H-吲唑-5-基)环己基)乙-1-酮的制备
Figure PCTCN2017095669-appb-000173
1-(4-(2-异丙基-2H-吲唑-5-基)环己基)乙-1-酮的制备同实施例7中(顺式)1-(4-苯基环己基)-1-乙酮和(反式)1-(4-苯基环己基)-1-乙酮的制备。收率49％。1H NMR(500MHz,CDCl3):δ7.87(d,J＝10Hz,1H),7.62-7.67(m,1H),7.41(d,J＝10Hz,1H),7.13-7.17(m,1H),4.71-4.79(m,1H),2.43-2.65(m,2H),2.26(d,J＝10Hz,1H),2.20(s,3H),2.04-2.08(m,1H),1.81(d,J＝10Hz,1H),1.65-1.73(m,3H),1.64(d,J＝5Hz,6H),1.51-1.57(m,2H)。
实施例138 2-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(4-(2-异基-2H-吲唑-5-基)环己基)乙-1-酮的制备
Figure PCTCN2017095669-appb-000174
2-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(4-(2-异基-2H-吲唑-5-基)环己基)乙-1-酮的制备同实施例3中(1-羟基-4-苯基环己基)-2-(5H-咪唑[5,1-a]异吲哚-5-基)-1-乙基酮的制备。收率72％。1H NMR(500MHz,CDCl3):δ7.89(d,J＝15Hz,1H),7.65-7.70(m,2H),7.32-7.43(m,3H),7.19(s,1H),7.15(d,J＝10Hz,1H),6.95(t,J＝10Hz,1H),5.79(d,J＝10Hz,1H),4.74-4.79(m,1H),3.56(d,J＝20Hz,1H),2.86(dd,J1＝20Hz,J2＝15Hz,1H),2.59(t,J＝10Hz,1H),2.50(t,J＝10Hz,1H),2.05-2.12(m,4H),1.62-1.70(m,8H),1.47-1.58(m,2H)。
实施例139 2-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(4-(2-异丙基-2H-吲唑-5-基)环己基)乙-1-醇(化合物35)的制备
Figure PCTCN2017095669-appb-000175
化合物35的制备同化合物1。白色固体，收率93％。1H NMR(500MHz,CDCl3):δ7.84-7.89(m.2H),7.65(d,J＝10Hz,1H),7.33-7.40(m,3H),7.14-7.22(m,2H),6.95(t,J＝10 Hz,1H),5.50-5.69(m,1H),4.74-4.79(m,1H),3.69-3.77(m,1H),2.39-2.52(m,2H),1.81-2.21(m,6H),1.41-1.65(m,1H)。
实施例140 1-(1-羟基-4-(2-甲基-2H-吲唑-5-基)环己基)乙-1-酮
Figure PCTCN2017095669-appb-000176
1-(1-羟基-4-(2-甲基-2H-吲唑-5-基)环己基)乙-1-酮同实施例2中1-(1-羟基-4-苯基环己基)乙基-1-酮的制备。收率69％。1H NMR(500MHz,CDCl3):δ8.24(s,1H),7.52-7.54(d,J＝10Hz,1H),7.48(s,1H),7.16-7.18(d,J＝10Hz,1H),5.23(s,1H),4.16(s,3H),2.53-2.57(m,1H),2.24(m,3H),1.84-1.85(m,1H),1.69(s,6H),1.27(s,1H)。
实施例141 2-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(1-羟基-4-(2-甲基-2H-吲唑-5-基)环己基)-1-酮的制备
Figure PCTCN2017095669-appb-000177
2-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(1-羟基-4-(2-甲基-2H-吲唑-5-基)环己基)-1-酮的制备同实施例3中(1-羟基-4-苯基环己基)-2-(5H-咪唑[5,1-a]异吲哚-5-基)-1-乙基酮的制备。收率67％。1H NMR(500MHz,CDCl3):δ7.87(s,1H),7.67-7.69(m,1H),7.65(s,1H),7.50(s,1H),7.46(m,1H),7.39(m,1H),7.22-7.24(m,2H),7.02(t,J＝7.5Hz,1H),5.87(d,J＝10Hz,1H),4.25(s,3H),3.77(m,1H),3.45(s,1H),3.11-3.17(m,1H),2.66(m,1H),1.87-2.03(m,8H)。
实施例142 1-(2-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-1-羟乙基)-4-(2-甲基-2H-吲唑-5-基)环己烷-1-醇(化合物36)
Figure PCTCN2017095669-appb-000178
化合物36的制备同化合物1。白色固体，收率78％。1H NMR(500MHz,CDCl3):δ7.95(s,0.73H),7.91(s,0.27H),7.85(s,1H),7.67(d,J＝10Hz,1H),7.48(s,1H),7.41(m,1H),7.38(m,1H), 7.22-7.25(m,1H),6.99-7.03(t,J＝5Hz,1H),5.75(m,0.28H),5.60(t,J＝5Hz,0.73H),4.24(s,3H),3.80(m,0.48H),3.65(d,J＝10.0Hz,0.73H),2.55-2.38(m,2H),1.92-1.50(m,8H)。
实施例143 1-(1-羟基-4-(2-甲基-2H-吲唑-6-基)环己基乙基酮的制备
Figure PCTCN2017095669-appb-000179
1-(1-羟基-4-(2-甲基-2H-吲唑-6-基)环己基乙基酮的制备同实施例2中1-(1-羟基-4-苯基环己基)乙基-1-酮的制备。收率为68％。1H NMR(500MHz,CDCl3):δ8.23(s,1H),7.62-7.58(m,2H),7.34(s,1H),6.95(d,J＝10Hz,1H),5.21(s,1H),4.12(s,3H),2.57(m,1H),2.11(m,3H),1.83-1.66(m,9H)。
实施例144 2-(6-氟-5H-咪唑[5,1-a]异吲哚-5-基)-1-(1-羟基-4-(2-甲基-2H-吲唑-6-基)环己基)乙酮的制备
Figure PCTCN2017095669-appb-000180
2-(6-氟-5H-咪唑[5,1-a]异吲哚-5-基)-1-(1-羟基-4-(2-甲基-2H-吲唑-6-基)环己基)乙酮的制备同实施例3中(1-羟基-4-苯基环己基)-2-(5H-咪唑[5,1-a]异吲哚-5-基)-1-乙基酮的制备。收率86％。1H NMR(500MHz,CDCl3):δ7.83(s,1H),7.60(s,1H),7.57(d,J＝10.0Hz,1H),7.48(s,1H),7.39-7.37(m,1H),7.34(d,J＝5.0Hz,1H),7.18(s,1H),7.00-6.95(m,2H),5.81(d,J＝10.0Hz,1H),3.73(d,J＝5.0Hz,1H),3.59(brs,1H),3.13-3.07(m,1H),2.67-2.62(m,1H),1.97-1.93(m,8H)。
实施例145 1-(2-(6-氟-5H-咪唑[5,1-a]异吲哚-5-基)-1-羟乙基)-4-(2-甲基-2H-吲唑-6-基)环己基-1-醇(化合物37)的制备
Figure PCTCN2017095669-appb-000181
化合物37的制备同化合物1。白色固体，收率80％。1H NMR(500MHz,CDCl3):δ7.93(s,0.7H),7.88(s,0.3H),7.82(s,1H),7.55(d,J＝5.0Hz,1H),7.49(s,1H),7.36-7.32(m,2H),7.21(m,1H),7.00-6.94(m,2H),5.70(d,J＝10.0Hz,0.3H),5.54(t,J＝5.0Hz,0.7H),3.75(s,0.7H),3.61(d,J＝5.0Hz,1H),2.64-2.47(m,2H),2.23-2.20(m,1H),1.91-1.44(m,8H).
实施例146 化合物37四个手性异构体(化合物38～41)的分离
Figure PCTCN2017095669-appb-000182
化合物37(5.0克)先用大赛璐的CHIRALCEL OJ手性柱(2.5c m I.D.×25cm L，MeOH/DEA＝100/0.1(V/V))分离，得到手性纯的化合物40(0.6g)和化合物41(1.7g)，以及化合物38和39的混合物。而后化合物38和39的混合物再用CHIRALPAK IG手性柱(5.0cm I.D.×25cm L，MeOH/DCM/DEA＝80/20/0.1(V/V/V))分离，得到手性纯的化合物38(0.5g)和化合物39(1.8g)。
化合物38 1H NMR(500MHz,DMSO)δ8.21(s,1H),7.96(s,1H),7.57(d,J＝8.6Hz,1H),7.51–7.41(m,2H),7.32(s,1H),7.22(s,1H),7.12(t,J＝8.8Hz,1H),6.94(d,J＝8.7Hz,1H),5.65(d,J＝10.3Hz,1H),5.19(d,J＝6.5Hz,1H),4.11(d,J＝5.0Hz,4H),3.66–3.49(m,1H),3.17(d,J＝5.1Hz,1H),2.42(t,J＝12.4Hz,1H),1.80(dd,J＝23.6,11.0Hz,2H),1.74–1.43(m,7H).MS-ESI:447.0[M+H]+。.
化合物39 1H NMR(500MHz,DMSO)δ8.22(s,1H),7.99(s,1H),7.57(d,J＝8.6Hz,1H),7.47–7.37(m,2H),7.32(s,1H),7.17(s,1H),7.09(t,J＝7.9Hz,1H),6.94(d,J＝8.7Hz,1H),5.63(t,1H),4.73(d,J＝6.1Hz,1H),4.16(s,1H),4.12(s,3H),3.37(s,2H),3.17(d,J＝5.0Hz,1H),2.55(d,J＝14.4Hz,1H),1.96–1.75(m,3H),1.63(t,J＝11.8Hz,4H),1.50(t,J＝11.6Hz,2H).MS-ESI:447.0[M+H]+。.
化合物40 1H NMR(500MHz,DMSO)δ8.21(s,1H),7.96(s,1H),7.57(d,J＝8.6Hz,1H),7.50–7.39(m,2H),7.32(s,1H),7.21(s,1H),7.12(t,J＝8.8Hz,1H),6.93(d,J＝8.7Hz,1H),5.65(d,J＝10.7Hz,1H),5.19(d,J＝6.4Hz,1H),4.11(d,J＝5.7Hz,4H),3.58(s,1H),2.41(t,J＝12.2Hz,1H),1.80(dd,J 1＝23.7Hz,J2＝10.7Hz,2H),1.75–1.44(m,7H).MS-ESI:447.0[M+H]+。
化合物41 1H NMR(500MHz,DMSO)δ8.22(s,1H),7.99(s,1H),7.57(d,J＝8.6Hz,1H),7.43(d,J＝8.1Hz,2H),7.32(s,1H),7.17(s,1H),7.09(t,J＝8.7Hz,1H),6.94(d,J＝8.6Hz,1H),5.63(t,1H),4.73(d,J＝5.8Hz,1H),4.16(s,1H),4.12(s,3H),2.55(d,J＝14.7Hz,1H),2.06–1.74(m,4H),1.72–1.38(m,6H).MS-ESI:447.0[M+H]+。
实施例147 2-(6-溴-7-氟-5H-咪唑[5,1-a]异吲哚-5-基)-1-(4-(3-氯-4-氟苯基)-1-羟基环己基)乙-1-酮的制备
Figure PCTCN2017095669-appb-000183
2-(6-溴-7-氟-5H-咪唑[5,1-a]异吲哚-5-基)-1-(4-(3-氯-4-氟苯基)-1-羟基环己基)乙-1-酮同实施例3中(1-羟基-4-苯基环己基)-2-(5H-咪唑[5,1-a]异吲哚-5-基)-1-乙基酮的制备。收率42％。1H NMR(500MHz,CDCl3):δ7.58(s,1H),7.45-7.40(m,1H),7.34(d,J＝5Hz,1H),7.25(s,1H),7.17(s,1H),7.08-7.06(m,1H),6.97(t,J＝10Hz,1H),5.80(d,J＝10Hz,1H),3.65-3.69(m,1H),3.04-3.10(m,1H),2.50-2.54(m,1H),1.76-1.90(m,8H)。
实施例148 4-(3-氯-4-氟苯基)-1-(2-(6-溴-7-氟-5H-咪唑[5,1-a]异吲哚-5-基)-1-羟乙基)环己-1-醇(化合物42)的制备
Figure PCTCN2017095669-appb-000184
化合物42的制备同化合物1。白色固体，收率为93％。1H NMR(500MHz,CDCl3):δ7.90(s,0.71H),7.82(s,0.28H),7.32-7.38(m,1H),7.24(s,1H),7.18(s,1H),7.06-7.03(m,2H),6,96(t,J＝10Hz,1H),5.68(d,J＝10Hz,0.28H),5.53(t,J＝5Hz,0.71H),3.71(d,J＝10Hz,0.29H),3.66(d,J＝10Hz,0.71H),2.60-2.62(m,0.28H),2.42-2.47(m,1.69H),2.22-2.27(m,1H),1.74-1.86(m,8H)。
实施例149 1-(4-(3-氯-4-氟苯基)-1-羟基环己基)-2-(7-腈基-6-氟-5H-咪唑[5,1-a]异吲哚-5-基)乙-1-酮的制备
Figure PCTCN2017095669-appb-000185
1-(4-(3-氯-4-腈基苯基)-1-羟基环己基)-2-(7-氯-6-氟-5H-咪唑[5,1-a]异吲哚-5-基)乙-1-酮的制备同实施例3中(1-羟基-4-苯基环己基)-2-(5H-咪唑[5,1-a]异吲哚-5-基)-1-乙基酮的制备。收率67％。1H NMR(500MHz,CDCl3):δ7.58(s,1H),7.40-7.37(m,1H),7.34(d,J＝5Hz,1H),7.25(s,1H),7.17(s,1H),7.08-7.04(m,1H),6.97(t,J＝10Hz,1H),5.80(d,J＝10Hz,1H),3.65-3.69(m,1H),3.04-3.10(m,1H),2.50-2.54(m,1H),1.76-1.90(m,8H)。
实施例150 4-(3-氯-4-氟苯基)-1-(2-(7-腈基-6-氟-5H-咪唑[5,1-a]异吲哚-5-基)-1-羟乙基)环己-1-醇(化合物43)的制备
Figure PCTCN2017095669-appb-000186
化合物43的制备同化合物1。白色固体，收率87％。1H NMR(500MHz,CDCl3):δ7.89(s,0.71H),7.84(s,0.28H),7.40-7.38(m,2H),7.24(s,1H),7.18(s,1H),7.08-7.05(m,2H),6,96(t,J＝10Hz,1H),5.68(d,J＝10Hz,0.28H),5.53(t,J＝5Hz,0.71H),3.71(d,J＝10Hz,0.29H),3.66(d,J＝10Hz,0.71H),2.60-2.62(m,0.28H),2.42-2.47(m,1.69H),2.22-2.27(m,1H),1.74-1.86(m,8H)。ESI-MS：470.0[M+H]+。.
实施例151 1-(4-(3-氯-4-氟苯基)-1-羟基环己基)-2-(6-氟-7-(三氟氧基)-5H-咪唑[5,1-a]异吲哚-5-基)乙基-1-酮的制备
Figure PCTCN2017095669-appb-000187
1-(4-(3-氯-4-氟苯基)-1-羟基环己基)-2-(6-氟-7-(三氟氧基)-5H-咪唑[5,1-a]异吲哚-5-基)乙基-1-酮的制备同实施例3中(1-羟基-4-苯基环己基)-2-(5H-咪唑[5,1-a]异吲哚-5-基)-1-乙基酮的制备。1H NMR(500MHz,CDCl3):δ7.58(s,1H),7.52-7.47(m,1H),7.34(d,J＝5Hz,1H),7.25(s,1H),7.17(s,1H),7.09-7.06(m,1H),6.97(t,J＝10Hz,1H),5.80(d,J＝10Hz,1H),3.65-3.69(m,1H),3.04-3.10(m,1H),2.50-2.54(m,1H),1.76-1.90(m,8H)。
实施例152 4-(3-氯-4-氟苯基)-1-(2-(7-三氟氧基-6-氟-5H-咪唑[5,1-a]异吲哚-5-基)-1-羟乙基)环己-1-醇(化合物44)的制备
Figure PCTCN2017095669-appb-000188
化合物44的制备同化合物1。白色固体，收率为84％。1H NMR(500MHz,CDCl3):δ7.89(s,0.71H),7.84(s,0.28H),7.50-7.45(m,2H),7.24(s,1H),7.18(s,1H),7.07-7.04(m,1H),6,96(t,J＝10Hz,1H),5.68(d,J＝10Hz,0.28H),5.53(t,J＝5Hz,0.71H),3.71(d,J＝10Hz,0.29H),3.66(d,J＝10Hz,0.71H),2.60-2.62(m,0.28H),2.42-2.47(m,1.69H),2.22-2.27(m,1H),1.74-1.86(m,8H)。
实施例153 1-(4-(3-氯-4-氟苯基)-1-羟基环己基)-2-(6-氟-7-甲基-5H-咪唑[5,1-a]异吲哚-5-基)乙-1-酮的制备
Figure PCTCN2017095669-appb-000189
1-(4-(3-氯-4-氟苯基)-1-羟基环己基)-2-(6-氟-7-甲基-5H-咪唑[5,1-a]异吲哚-5-基)乙-1-酮的制备同实施例3中(1-羟基-4-苯基环己基)-2-(5H-咪唑[5,1-a]异吲哚-5-基)-1-乙基酮的制备。1H NMR(500MHz,CDCl3):δ7.58(s,1H),7.47-7.42(m,1H),7.34(d,J＝5Hz,1H),7.25(s,1H),7.17(s,1H),7.10-7.06(m,1H),6.97(t,J＝10Hz,1H),5.80(d,J＝10Hz,1H),3.65-3.69(m,1H),3.04-3.10(m,1H),2.50-2.54(m,1H),2.35(s,3H),1.76-1.90(m,8H)。
实施例154 4-(3-氯-4-氟苯基)-1-(2-(6-氟-7-甲基-5H-咪唑[5,1-a]异吲哚-5-基)-1-羟乙基)环己-1-醇(化合物45)的制备
Figure PCTCN2017095669-appb-000190
化合物45的制备同化合物1。白色固体，收率92％。1H NMR(500MHz,CDCl3):δ7.89(s,0.71H),7.84(s,0.28H),7.52-7.37(m,2H),7.24(s,1H),7.18(s,1H),7.04-7.00(m,1H),6,96(t,J＝10Hz,1H),5.68(d,J＝10Hz,0.28H),5.53(t,J＝5Hz,0.71H),3.71(d,J＝10Hz,0.29H),3.66(d,J＝10Hz,0.71H),2.60-2.62(m,0.28H),2.42-2.47(m,1.69H),2.35(s,3H),2.22-2.27(m,1H),1.74-1.86(m,8H)。
实施例155 2-(6-氟-5H-咪唑[5,1-a]异吲哚-5-基)-1-(3-(4-氟苯基)环戊基)乙-1-酮的制备
Figure PCTCN2017095669-appb-000191
2-(6-氟-5H-咪唑[5,1-a]异吲哚-5-基)-1-(3-(4-氟苯基)环戊基)乙-1-酮的制备同实施例3中(1-羟基-4-苯基环己基)-2-(5H-咪唑[5,1-a]异吲哚-5-基)-1-乙基酮的制备。1H NMR(500MHz,CDCl3):δ7.90(d,J＝5Hz,3H),7.68-7.65(m,4H)，7.52(s,1H),7.30(t,J＝10Hz,1H),5.76(d,J＝10Hz,1H),3.54-3.78(m,2H),2.50(m,1H),2.27(t,J＝7.5Hz,1H),1.57-1.81(m,6H)。
实施例156 2-(6-氟-5H-咪唑[5,1-a]异吲哚-5-基)-1-(3-(4-氟苯基)环戊基)乙-1-醇(化合物46)的制备
Figure PCTCN2017095669-appb-000192
化合物46的制备同化合物1。白色固体，收率86％。1H NMR(500MHz,CDCl3):δ8.02(d,J＝5Hz,1H),7.38-7.42(m,2H),7.21-7.24(m,3H),7.01(t,J＝7.5Hz,3H),5.58-5.57(m,1H),3.64-3.78(m,1H),2.49-2.71(m,2H),2.48(m,1H),2.25-2.28(m,1H),1.90-2.05(m,6H).
实施例157 2-(6-氟-5H-咪唑[5,1-a]异吲哚-5-基)-1-(6-(4-氟苯基)二环[3.1.0]己-3-基)乙-1-酮
Figure PCTCN2017095669-appb-000193
2-(6-氟-5H-咪唑[5,1-a]异吲哚-5-基)-1-(6-(4-氟苯基)二环[3.1.0]环己-3-基)乙-1-酮的制备实施例3中(1-羟基-4-苯基环己基)-2-(5H-咪唑[5,1-a]异吲哚-5-基)-1-乙基酮的制备。1H NMR(500MHz,CDCl3):δ7.87-7.81(m,3H),7.73-7.69(m,4H)，7.52(s,1H),7.30(t,J＝10Hz,1H),5.76(d,J＝10Hz,1H),3.54-3.78(m,2H),2.50(m,1H),2.43(t,J＝7.5Hz,1H),1.92-1.57(m,6H).
实施例158 2-(6-氟-5H-咪唑[5,1-a]异吲哚-5-基)-1-(6-(4-氟苯基)二环[3.1.0]己-3-基)乙-1-醇(化合物47)的制备
Figure PCTCN2017095669-appb-000194
化合物47的制备同化合物1。白色固体，收率95％。1H NMR(500MHz,CDCl3):δ8.10(d,J＝5Hz,1H),7.42-7.36(m,2H),7.25-7.21(m,3H),7.01(t,J＝7.5Hz,3H),5.58-5.57(m,1H),3.64-3.78(m,1H),2.49-2.71(m,2H),2.25-2.28(m,1H),2.00-1.90(m,6H)。
实施例159 2-(6-氟-5H-咪唑[5,1-a]异吲哚-5-基)-1-(2-(4-氟苯基)螺[3.5]壬-7-基)乙-1-酮的制备
Figure PCTCN2017095669-appb-000195
2-(6-氟-5H-咪唑[5,1-a]异吲哚-5-基)-1-(2-(4-氟苯基)螺[3.5]壬-7-基)乙-1-酮的制备同实施例3中(1-羟基-4-苯基环己基)-2-(5H-咪唑[5,1-a]异吲哚-5-基)-1-乙基酮的制备。1H NMR(500MHz,CDCl3):δ7.92-7.85(m,3H),7.65-7.72(m,4H)，7.52(s,1H),7.30(t,J＝10Hz,1H),5.52(d,J＝10Hz,1H),3.54-3.78(m,2H),2.50(m,1H),2.27(t,J＝7.5Hz,1H),1.95-1.45(m,10H)。
实施例160 2-(6-氟-5H-咪唑[5,1-a]异吲哚-5-基)-1-(2-(4-氟苯基l)螺[3.5]壬-7-基)乙-1-醇(化合物48)的制备
Figure PCTCN2017095669-appb-000196
化合物48的制备同化合物1。白色固体，收率85％。1H NMR(500MHz,CDCl3):δ8.06(d,J＝5Hz,1H),7.42-7.35(m,2H),7.21-7.24(m,6H),5.58-5.57(m,1H),3.64-3.78(m,1H),2.49-2.71(m,3H),2.25-2.28(m,1H),2.05-1.90(m,10H)。
实施例161 2-(6-氟-5H-咪唑[5,1-a]异吲哚-5-基)-1-(4-(4-***啉苯基)环己基)乙-1-酮的制备
Figure PCTCN2017095669-appb-000197
2-(6-氟-5H-咪唑[5,1-a]异吲哚-5-基)-1-(4-(4-***啉苯基)环己基)乙-1-酮的制备同实施例3中(1-羟基-4-苯基环己基)-2-(5H-咪唑[5,1-a]异吲哚-5-基)-1-乙基酮的制备。1H NMR(500MHz,CDCl3):δ8.12(d,J＝5Hz,1H),8.05(d,J＝10Hz,1H),7.70(t,J＝7.5Hz,1H),7.56(t,J＝10Hz,2H),7.32-7.40(m,3H),7.14(s,1H),5.81(d,J＝10Hz,1H),3.72-3.76(m,5H),3.40(t,J＝12.5Hz,1H),3.16-3.21(dd,J1＝10Hz,J2＝20Hz,5H),2.55(m,1H),1.97-2.11(m,9H)。
实施例162 2-(6-氟-5H-咪唑[5,1-a]异吲哚-5-基)-1-(4-(4-***啉苯基)环己基)乙-1-醇(化合物49)的制备
Figure PCTCN2017095669-appb-000198
化合物49的制备同化合物1。白色固体，收率为92％。1H NMR(500MHz,CDCl3):δ8.84(d,J＝5Hz,1H),8.12(d,J＝5Hz,1H),8.05(d,J＝10Hz,1H),7.70(t,J＝7.5Hz,1H),7.56(t,J＝10Hz,2H),7.32-7.40(m,3H),7.14(s,1H),6.98(t,J＝7.5Hz,1H),5.81(d,J＝10Hz,1H),3.72-3.76(m,1H),3.40(t,J＝12.5Hz,m,1 5H),3.16-3.21(dd,J1＝10Hz,J2＝20Hz,1H),2.55(m,1H),1.97-2.11(m,9H)。
实施例163 2-氟-4-(4-(2-(6-氟-5H-咪唑[5,1-a]异吲哚-5-基)乙酰)环己基)-N-甲甲苯甲酰胺的制备
Figure PCTCN2017095669-appb-000199
2-氟-4-(4-(2-(6-氟-5H-咪唑[5,1-a]异吲哚-5-基)乙酰)环己基)-N-甲甲苯甲酰胺的制备同同实施例3中(1-羟基-4-苯基环己基)-2-(5H-咪唑[5,1-a]异吲哚-5-基)-1-乙基酮的制备。1H NMR(500MHz,CDCl3):δ7.58(s,1H),7.37-7.42(m,1H),7.34(d,J＝5Hz,1H),7.25(s,1H),7.17(s,1H),7.05-7.08(m,2H),6.97(t,J＝10Hz,1H),5.80(d,J＝10Hz,1H),3.65-3.69(m,1H),3.04-3.10(m,1H),2.81(s,3H),2.50-2.54(m,2H),1.76-1.90(m,8H)。
实施例164 2--4-(4-(氟2-(6-氟-5H-咪唑[5,1-a]异吲哚-5-基)-1-羟乙基)环己基)-N-甲基苯甲酰胺(化合物50)的制备
Figure PCTCN2017095669-appb-000200
化合物50的制备同化合物1。白色固体，收率为78％。1H NMR(CDCl3,500MHz)δ7.89(s,0.71H),7.84(s,0.28H),7.32-7.38(m,2H),7.24(s,1H),7.18(s,1H),7.02-7.07(m,2H),6,96 (t,J＝10Hz,1H),5.68(d,J＝10Hz,0.28H),5.53(t,J＝5Hz,0.71H),3.71(d,J＝10Hz,0.29H),3.66(d,J＝10Hz,0.71H),2.70(s,3H),2.60-2.62(m,0.28H),2.42-2.47(m,1.69H),2.22-2.27(m,2H),1.74-1.86(m,8H)。
实施例165 (4-(4-(2-(6-氟-5H-咪唑[5,1-a]异吲哚-5-基)乙酰)环已基)苯基)膦酸二甲酯的制备
Figure PCTCN2017095669-appb-000201
(4-(4-(2-(6-氟-5H-咪唑[5,1-a]异吲哚-5-基)乙酰)环已基)苯基)膦酸二甲酯的制备同实施例3中(1-羟基-4-苯基环己基)-2-(5H-咪唑[5,1-a]异吲哚-5-基)-1-乙基酮的制备。1H NMR(CDCl3,500MHz)δ7.68(t,J＝20Hz,1H),7.31-7.42(m,3H),7.21(s,1H),7.00(t,J＝7.5Hz,1H),6.68-6.83(m,3H),5.97(s,1H),3.78(s,6H),3.58-3.61(d,J＝15Hz,1H),2.86-2.91(m,1H),2.50(m,2H),1.42-2.27(m,8H)。
实施例166 (4-(4-(2-(6-氟-5H-咪唑[5,1-a]异吲哚-5-基)乙酰)环已基)苯基)膦酸二甲酯(化合物51)的制备
Figure PCTCN2017095669-appb-000202
化合物51的制备同化合物1。白色固体，收率79％。1H NMR(CDCl3,500MHz):δ7.93(s,0.74H),7.89(s,0.24H),7.39(m,2H),7.21(d,J＝5Hz,1H),7.00(t,J＝10Hz,1H),6.68-6.79(m,2H),5.72(d,J＝10Hz,0.24H),5.55(s,0.73H),3.81(s,0.27H),3.73(s,0.72H),3.50(s,6H),1.25-2.55(m,12H)。
实施例167 6-(4-(2-(6-氟-5H-咪唑[5,1-a]异吲哚-5-基)乙酰)环己基)-2H-香豆素-2-酮的制备
Figure PCTCN2017095669-appb-000203
6-(4-(2-(6-氟-5H-咪唑[5,1-a]异吲哚-5-基)乙酰)环己基)-2H-香豆素-2-酮的制备同实施例 3中(1-羟基-4-苯基环己基)-2-(5H-咪唑[5,1-a]异吲哚-5-基)-1-乙基酮的制备。1H NMR(CDCl3,500MHz):δ8.04(d,J＝10Hz,1H),7.71-7.73(m,2H),7.38-7.51(m,4H),7.25(s,1H),7.01(t,J＝10Hz,1H),6.45(d,J＝10Hz,1H),5.87(d,J＝10Hz,1H),3.66(d,J＝20Hz,1H),3.35(t,J＝10Hz,1H),2.91-2.96(m,1H),2.61-2.66(m,1H),2.14-2.25(m,3H),1.69-1.86(m,5H)。
实施例168 6-(4-(2-(6-氟-5H-咪唑[5,1-a]异吲哚l-5-基)-1-羟乙基)环己基)-2H-香豆素-2-酮(化合物52)的制备
化合物52的制备同化合物1。白色固体，收率76％。1H NMR(500MHz,CDCl3):δ8.03(d,J＝10Hz,1H),7.95(s,0.71H),7.91(s,0.24H),7.72(t,J＝5Hz,1H),7.41-7.48(m,4H),7.25-7.28(m,1H),7.02(t,J＝5Hz,1H),6.55(d,＝10Hz,1H),5.77(s,0.27H),5.58(s,0.73H),3.88(s,0.25H),3.79(s,0.69H),3.28(t,J＝5Hz,1H),2.60(t,J＝5Hz,0.3H),2.49(d,J＝10Hz,0.69H),2.12-2.28(m,4H),1.82-1.96(m,2H),1.44-1.49(m,4H)。
实施例169 3-(2-溴苯基)-1-(4-(4-氟苯基)环己基)-3-(1H-咪唑-5-基)丙-1-酮的制备
Figure PCTCN2017095669-appb-000205
于室温向4-碘三苯甲基咪唑(830mg,1.91mmol)在四氢呋喃(10mL)中的溶液中滴加EtMgBr(1.91mmol，2.1mL，在THF中的0.9M溶液)，于室温搅拌2h。溶液冷却至-15℃，将上述体系加入到(E)-3-(2-溴苯基l)-1-(4-(4-氟苯基)环己基)丙-2-烯-1-酮(738mg,1.910mmol)和CuCl(0.38mmol)的THF(8mL)冷(-15℃)溶液中。自然升温，搅拌过夜。减压去除溶剂，将残留物中加入饱和NH4Cl(8mL)溶液和二氯甲烷(100mL)。将溶液搅拌10分钟，分层，水相用二氯甲烷(20mL)萃取。合并的有机相用水洗涤(10mL).。有机相用无水Na2SO4干燥，过滤，浓缩以得到白色固体。粗产物用乙酸(1mL)稀释，并于90℃在甲醇(5mL)中加热2h。在冷却至室温后，减压去除溶剂，粗制物用饱和NaHCO3溶液中和，加入水(3mL)和CH2Cl2(25mL)稀释。分液。减压蒸去溶剂，残留物用快速柱层析分离。得白色固体676mg，收率87％。1H NMR(500MHz,CDCl3):δ7.58-7.48(m,2H),7.30-7.14(m,4H),7.04(m,3H),6.67(s,1H),5.03(dd,J1＝10.0Hz，J2＝5.0Hz,1H),3.35(m,1H),3.03(m,1H),2.52-2.22(m,2H),1.88-1.25(m,8H).
实施例170 1-(4-(4-氟苯基)环己基l)-2-(9H-咪唑[1,5-a]吲哚-9-基)乙-1-酮的制备
Figure PCTCN2017095669-appb-000206
将3-(2-溴苯基)-1-(4-(4-氟苯基)环己基)-3-(1H-咪唑-5-基)丙-1-酮(585mg,1.29mmol)、Cs2CO3(843mg,2.59mmol)、4,7-二甲氧基-1,10-邻二氮杂菲(62mg,0.26mmol)和CuI(0.129mmol)加入到1,4-二氧六环(10mL)中，用高纯氮抽置换气。于100℃搅拌过夜。冷却至室温后，减压去除溶剂，粗制物用1％NH4OH(30mL)溶液和二氯甲烷(25mL)稀释。分离有机层，水层用CH2Cl2(60mL)萃取。合并的有机相，减压蒸去溶剂，残留物用快速柱层析分离。得白色固体309mg,收率64％。1H NMR(500MHz,CDCl3):δ7.88(s,1H),7.40-7.32(m,3H),7.24(d,J＝5Hz,2H),7.18(t,J＝10Hz,2H),7.04(d,J＝5Hz,2H),6.89(s,1H),5.76(d,J＝10Hz,1H),3.54-3.78(m,2H),2.52-2.22(m,2H),1.57-1.81(m,8H)。
实施例171 1-(4-(4-氟苯基)环己基)-2-(9H-咪唑[1,5-a]吲哚l-9-基)乙-1-醇(化合物53)的制备
Figure PCTCN2017095669-appb-000207
化合物53的制备同化合物1。白色固体，收率为93％。1H NMR(500MHz,CDCl3):δ7.74(s,1H),7.40-7.32(m,3H),7.24(d,J＝5Hz,2H),7.18(t,J＝10Hz,2H),7.04(d,J＝5Hz,2H),6.95(s,1H),5.58-5.57(m,1H),3.64-3.78(m,1H),2.49-2.71(m,2H),2.51-2.28(m,2H),1.90-2.05(m,8H)。
实施例172 1-(2-(6-氟-5H-咪唑[5,1-a]异吲哚l-5-基)-1-(羟基-d)乙基)-4-(2-甲基-2H-吲唑-6-基)环己-1-醇(化合物54)的制备
Figure PCTCN2017095669-appb-000208
将中间体2-(6-氟-5H-咪唑[5,1-a]异吲哚-5-基)-1-(1-羟基-4-(2-甲基-2H-吲唑-6-基环己基)乙-1-酮(100mg,0.22mmoL)、氘代硼氢化钠(80mg,0.88mmoL)加入到氘代甲醇(3.0mL)中，室 温搅拌30分钟。减压蒸去溶剂，残留物用快速柱层析分离得化合物54。白色固体，收率83％。1H NMR(500MHz,CDCl3):δ7.92(s,0.7H),7.87(s,0.3H),7.82(s,1H),7.55(d,J＝5.0Hz,1H),7.49(s,1H),7.36-7.32(m,2H),7.21(m,1H),7.00-6.94(m,2H),5.70(d,J＝10.0Hz,0.3H),5.54(t,J＝5.0Hz,0.7H),3.75(s,0.7H),3.61(d,J＝5.0Hz,1H),2.64-2.47(m,2H),2.23-2.20(m,1H),1.91-1.44(m,8H)。ESI-MS:448.0[M+H]+。
实施例173 1-(1-胺基-2-(6-氟-5H-咪唑[5,1-a]异吲哚-5-基)乙基)-4-(2-甲基-2H-吲唑-6-基)环己-1-醇(化合物55)
Figure PCTCN2017095669-appb-000209
将中间体2-(6-氟-5H-咪唑[5,1-a]异吲哚-5-基)-1-(1-羟基-4-(2-甲基-2H-吲唑-6-基环己基)乙-1-酮(100mg,0.22mmoL)加入到乙醇(5mL)中，再加入50％的水合肼(0.66mmoL)，在50℃下反应过夜。冷却，减压蒸去溶剂，得到残留物。此残留物加入到甲醇(5mL)，加入10％Pd-C(20mg)，催化氢化过夜，TLC检测反应完全。减压蒸去溶剂，残留物用快速柱层析分离，得到化合物81mg，收率83％。1H NMR(500MHz,CDCl3):δ7.93-7.88(m,1H),7.82(s,1H),7.55(d,J＝5.0Hz,1H),7.49(s,1H),7.36-7.32(m,2H),7.21(m,1H),7.00-6.94(m,2H),5.70(d,J＝10.0Hz,0.3H),5.54(t,J＝5.0Hz,0.7H),4.52(m,1H),3.61(d,J＝5.0Hz,1H),2.64-2.47(m,2H),2.23-2.20(m,1H),1.91-1.44(m,8H)。ESI-MS:447.0[M+H]+。
实施例174 2-(6-氟-5H-咪唑[5,1-a]异吲哚-5-基)-1-(4'-氟-[1,1'-二苯]-4-基)乙-1-醇的制备
Figure PCTCN2017095669-appb-000210
2-(6-氟-5H-咪唑[5,1-a]异吲哚-5-基)-1-(4'-氟-[1,1'-二苯]-4-基)乙-1-醇的制备同：同实施例3中(1-羟基-4-苯基环己基)-2-(5H-咪唑[5,1-a]异吲哚-5-基)-1-乙基酮的制备。1H NMR(500MHz,CDCl3):δ7.82-7.78(m,6H),7.72-7.66(m,4H)，7.52(s,1H),7.30(t,J＝10Hz,2H),5.84(d,J＝10Hz,1H),2.27(d,J＝10Hz,2H)。
实施例175 2-(6-氟-5H-咪唑[5,1-a]异吲哚l-5-基)-1-(4'-氟-[1,1'-二苯基]-4-基)乙-1-醇(化合物56)的制备
Figure PCTCN2017095669-appb-000211
化合物56的制备同化合物1。白色固体，收率为96％。1H NMR(500MHz,CDCl3):δ7.80-7.74(m,6H),7.72-7.68(m,4H)，7.48(s,1H),7.32(t,J＝10Hz,2H),5.52(d,J＝10Hz,1H),4.32(m,1H),2.58(t,J＝10Hz,2H)。ESI-MS:389.0[M+H]+。
实施例176 2-(6-氟-5H-咪唑[5,1-a]异吲哚-5-基)-1-(4-(2-甲基-2H-吲唑-6-基)环己-3-烯-1-基)乙-1-酮的制备
Figure PCTCN2017095669-appb-000212
2-(6-氟-5H-咪唑[5,1-a]异吲哚-5-基)-1-(4-(2-甲基-2H-吲唑-6-基)环己-3-烯-1-基)乙-1-酮的制备同实施例3中(1-羟基-4-苯基环己基)-2-(5H-咪唑[5,1-a]异吲哚-5-基)-1-乙基酮的制备。1H NMR(500MHz,CDCl3):1H NMR(CDCl3,500MHz):δ7.79(s,1H),7.67(s,1H),7.60(d,J＝10Hz,1H),7.44-7.36(m,3H),7.19(s,1H),7.15(d,J＝10Hz,1H),6.95(t,J＝10Hz,1H),5.95(m,1H),5.52(d,J＝10Hz,1H),4.20(s,3H),3.56(d,J＝20Hz,1H),2.88-2.84(m,1H),2.56(t,J＝10Hz,1H),,2.03-1.12(m,6H)。
实施例177 2-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-1-(4-(2-甲基-2H-吲唑-5-基)环己基)乙-1-醇(化合物57)的制备
Figure PCTCN2017095669-appb-000213
化合物57的制备同化合物1。白色固体，收率83％。1H NMR(CDCl3,500MHz):δ7.90(s,0.75H),7.85(s,0.25H),7.80(s.1H),7.61(d,J＝10Hz,1H),7.32-7.39(m,3H),7.14-7.22(m,2H),6.95(t,J＝10Hz,1H),5.68(d,J＝5Hz,0.25H),5.62(m,1H),5.50(t,J＝5Hz,0.78H),4.19(s,3H),3.70-3.78(m,2H),2.39-2.51(m,1H),2.10-1.39(m,6H)。ESI-MS:429.0[M+H]+。
实施例178 (R)-2-((S)-6-氟-5H-咪唑[5,1-a]异吲哚-5-基)-1-(1-羟基-4-(2-甲基-2H-吲唑-6-基)环己基)乙基(叔丁氧羰基)-L-丙氨酸酯(化合物58)
Figure PCTCN2017095669-appb-000214
将1-((R)-2-((S)-6-氟-5H-咪唑[5,1-a]异吲哚-5-基)-1-羟乙基)-4-(2-甲基-2H-吲唑-6-基)环己-1-醇(化合物39)(100mg,0.22mmoL)、N-BOC-L-丙氨酸(41.6mg,0.22mmoL)、EDCI(50.6mg,0.26mmoL)、HOBt(36.0mg,0.26mmoL)和DIPEA(34.0mg,0.26mmoL)加入到无水DCM(10mL)中，室温搅拌过夜。减压蒸去溶剂。残留物中加入水(5mL)，用DCM(10mL)提取。有机相减压蒸去溶剂，残留物用快速柱层析分离，得白色固体91mg，收率67％。1H NMR(500MHz,DMSO)δ8.20(s,1H),7.87(s,1H),7.52(d,J＝8.6Hz,1H),7.47-7.37(m,2H),7.28(s,1H),7.17(s,1H),7.09(t,J＝7.9Hz,1H),6.94(d,J＝8.7Hz,1H),5.57(t,1H),4.89(d,J＝6.1Hz,1H),4.16(s,1H),4.12(s,3H),4.42(m,1H),3.37(s,2H),3.17(d,J＝5.0Hz,1H),2.55(d,J＝14.4Hz,1H),1.96-1.50(m,9H),1.42-1.38(m,12H)。MS-ESI:618.0[M+H]+。.
实施例179 化合物对IDO1酶水平抑制活性研究
试剂：
1.试验缓冲溶液:400μM的L-色氨酸,20mM的抗坏血酸盐,20μM的甲基蓝,1000U/mL的过氧化氢酶,100mM PBS,pH6.5；
2.hIDO:由Medicilon提供；
3.30％(w/v)三氯乙酸；
4.Ehrlich’s试剂。
试验步骤：
1.制备反应混合体系:50nM的hIDO和一定浓度的待测化合物加入到100μL的缓冲溶液中。hIDO和缓冲液需先预热至37℃；
2.在37℃下孵育30分钟；
3.用50μL的30％(w/v)三氯乙酸停止反应；
4.再在52℃下孵育30分钟；
5.在室温于12000转下离心；
6.将100μL上清液用用100μL Ehrlich’s试剂混合；
7.在OD 480nm读数；
8.计算IC50值。
IDO酶水平测定的结果示于下表中。IDO-1，酶水平。
化合物 IC50(酶水平，nM)
NLG919(阳性对照药) 170.2
化合物1 37.3
化合物2 75.4
化合物3 57.3
化合物4 47.8
化合物5 42.6
化合物6 22.5
化合物7 15.2
化合物8 33.9
化合物9 52.0
化合物10 38.9
化合物11 45.2
化合物12 54.3
化合物13 58.3
化合物14 43.1
化合物15 31.9
化合物16 40.3
化合物17 62.7
化合物18 57.0
化合物19 31.0
化合物20 79.0
化合物21 39.6
化合物22 41.2
化合物23 27.3
化合物24 47.8
化合物25 57.6
化合物26 32.3
化合物27 29.6
化合物28 51.0
化合物29 33.8
化合物30 67.5
化合物31 37.6
化合物32 67.0
化合物33 32.5
化合物33 72.3
化合物35 81.2
化合物36 47.0
化合物37 23.6
化合物38 58.0
化合物39 25.0
化合物40 325.7
化合物41 2489.0
化合物42 27.8
化合物43 33.9
化合物44 25.6
化合物45 41.3
化合物46 52.7
化合物47 37.5
化合物48 53.6
化合物49 47.2
化合物50 53.8
化合物51 42.3
化合物52 31.6
化合物53 27.5
化合物54 30.1
化合物55 35.0
化合物56 143.0
化合物57 56.8
化合物58 NA
实施例180 人干扰素-γ诱导IDO1Hela细胞实验的化合物活性研究
具体步骤：
1.细胞铺板
a.配制完全培养基,充分混匀。
b.选择生长状态良好的细胞株。
c.将细胞培养瓶从培养箱中取出,核对瓶上标记的细胞名称,培养基类型及细胞代数。
d.弃去培养基，用胰酶消化，消化完后，用含血清的培养基中和，吹打细胞，使细胞脱落。用移液管将细胞悬液移入离心管中,800-1000的转速离心3-5分钟。
e.吸弃离心管中的细胞上清液。
f.向离心管中加适当体积的培养基,轻柔吹打使细胞重悬均匀。
g.使用Vi-Cell XR细胞计数仪计数。
h.将细胞悬液调至合适浓度。
i.依照下面的示意图将细胞悬液加入底透壁白的96孔板中，80微升/孔。标记细胞名称，种板密度，日期等详细信息，将培养板放置于CO2培养箱中过夜。
2.化合物的准备和添加:
a.用DMSO将化合物配制成420uM，以DMSO将化合物3倍梯度稀释，得到10个浓度梯度的化合物。
b.将DMSO配制的200×化合物按比例用对应的细胞培养液配成10×稀释液。
c.细胞种板24小时后，每孔中加入10μL 10×相应化合物稀释液和10μL 10×IFNγ。
d.在37℃培养箱中孵育48小时。
3.检测及分析
a.在倒置显微镜下观察细胞形态。
b.取80ul上清加到3894板中，每孔加10ul 6.1N trichloroacetic acid，振荡2分钟，放入50度恒温箱中反应30分钟。
c.离心，2500转10分钟
d.取上清70ul转到3635UV板中，加入70ul反应液，振荡2分钟，使其反应均匀
e.使用EnSpire(PE)检测OD值为480nm时的数据
f.将细胞培养板3903放置室温中平衡30分钟。
g.将细胞活性检测试剂100μl/孔加入培养板中。
h.在振板机上混匀2分钟,诱导细胞溶解。
i.将96孔板在室温中放置10分钟,使其发光信号稳定。
j.粘贴白色的底膜于培养板底部,使用Flexstation3测板.(相关设置为:发光,整合时间500ms)。
k.记录分析所得的实验结果。
IDO细胞水平测定的结果示于下表中。IDO-1，Hela细胞。
Figure PCTCN2017095669-appb-000215
Figure PCTCN2017095669-appb-000216
Figure PCTCN2017095669-appb-000217
实施例181 IDO1HEK293细胞实验的化合物活性研究
试剂：
(1)30％(w/v)三氯乙酸；
(2).Ehrlich’s试剂。
试验步骤
(1)用50μl 30％(w/v)三氯乙酸停止反应；.
(2)在52℃孵育30分钟；
(3)在12000g室温下离心；
(4)取100μL上清液，用100μL Ehrlich’s t试剂混合；
(5)在OD 480nm读数；
(6)计算EC50值。
IDO细胞水平测定的结果示于下表中。IDO-1，HEK293细胞。
化合物 EC50(HEK293细胞，nM)
NLG919 1070.0
化合物39 36.5
实施例182 化合物对TDO酶水平的抑制研究
试剂
(1)试验缓冲溶液：400μM L-色氨酸，20mM抗坏血酸，20μM甲基兰，1000U/ml过氧化氢酶，100mM PBS,PH6.5；
(2)TDO:Cat#71195(BPS Bioscience公司)；
(3)30％(w/v)三氯乙酸；
(4)Ehrlich’s试剂。
试验步骤：
(1)准备反应溶液：将200ng of TDO和不同待测浓度的化合物加入到in 100μL反应缓冲溶液中。在此步中TDO和缓冲溶液需在先在37℃下预热；
(2)在37℃孵育30分钟；
(3)用50μl 30％(w/v)三氯乙酸停止反应；
(4)在52℃继续孵育30分钟；
(5)在12000g转速下离心，室温；
(6)取100μL上清液，用100μL Ehrlich’s试剂混合；
(7)在OD 480nm读数值；
(8)计算IC50。
TDO酶水平测定的结果示于下表中。TDO，酶水平。
化合物 IC50(TDO,nM)
NLG919 250.7
化合物39 144.0
实施例183 活性化合物的药代研究
供试品制备
供试品给药溶液的配制根据客户提供的下述制备说明在CRO公司完成。供试品配制为游离基浓度，纯度不需要进行折算。
IV(化合物39)：称取适量受试物，溶于10％DMA+10％solutol+80％生理盐水中，得到浓度为2mg/mL的无色澄清溶液(pH～7)，用于静脉给药。
PO(化合物39)：称取适量受试物，溶于0.5％MC中，得到浓度为1mg/mL的白色混悬液(pH～7)，用于口服给药。
IV(INCBO24360)：称取适量受试物，溶于10％DMA+90％生理盐水中，得到浓度为2mg/mL的无色澄清溶液(pH～7)，用于静脉给药。
PO(INCBO24360)：称取适量受试物，溶于0.5％MC中，得到浓度为1mg/mL的白色混悬液(pH～7)，用于口服给药。
给药剂量及给药方式
雄性SD大鼠12只，购于上海西普尔-必凯实验动物有限公司。按下表给药。口服组给药前禁食约14小时。给药后约4小时后恢复饲料。
Figure PCTCN2017095669-appb-000218
样本采集及处理
静脉给药组在给药前和给药后0.083h，0.25h，0.5h，1h，2h，4h，6h，8h和24h采集样品；口服给药组在给药前和给药后0.25h，0.5h，1h，2h，4h，6h，8h，10h和24h，经颈静脉采血约0.25mL，肝素钠抗凝，血液样本采集后置于冰上，离心分离血浆(离心条件：8000转/分钟，6分钟，4C)。收集的血浆分析前存放于–80C。
生物样品分析方法及所有样品的分析由美迪西普亚医药科技(上海)有限公司分析实验室完成，详细信息见附录A。
数据分析数据分析
进行血浆药物浓度-时间曲线绘制时，BLQ均记为0。
进行药代参数计算时，Cmax之前的BLQ(包括“No peak”)按照0计算；Cmax之后出现的BLQ(包括“No peak”)一律不参与计算。
Phoenix WinNonlin 7.0软件计算以下药代动力学参数：AUC(0-t)、AUC(0-∞)、T1/2、MRT(0-∞)、Cmax、Tmax、F。
药代研究数据如下表所示：
Figure PCTCN2017095669-appb-000219
此处描述的实施例只用于说明(作为例证)，技术人员所做的各种修改或变更也应包括在专利申请的实质和范围内以及附加权利要求范畴之内。

Claims (14)

  1. 一种式(I)化合物或其药学上可接受的盐，水合物、溶剂化物、同位素化合物或前药：
    Figure PCTCN2017095669-appb-100001
    其中：
    X和Y分别是N,O或C，且X和Y中至少有一个为N原子；
    R1是H,卤素，烷氧基，取代的烷氧基，腈基，胺基，取代的胺基，或取代的巯基；
    R2和R3分别是H，卤素，腈基，胺基，取代的胺基，硝基，取代的C1-C6烷基，取代的C1-C6烯基，取代的C1-C6炔基，烷氧基，取代的烷氧基，环烷基，取代的环烷基，环杂烷基，取代的环杂烷基，酯基，酰胺基，取代的羰基，取代的砜基，取代的磺酰胺基，取代的磺酸基，取代的膦酸基，或取代的膦酰胺基；
    或者，R2和R3相互连接，构建成取代的或未取代的饱和环烷基、取代的或未取代的饱和环杂烷基、取代的或未取代的芳基、取代的或未取代的芳杂基；
    R4是H，取代或未取代的C1-C6烷基，取代或未取代的C1-C6烯基或取代或未取代的C1-C6炔基；
    R5是H，或OH；
    n为0-2的整数；
    Figure PCTCN2017095669-appb-100002
    是C3-C8环烷基，取代的C3-C8环烷基，环烯基，取代的环烯基，取代的或未取代的桥环基，取代的或未取代的螺环基，取代的或未取代的芳基，取代的或未取代的芳杂基；
    Figure PCTCN2017095669-appb-100003
    是C3-C6环烷基，C3-C6饱和环杂烷基，取代的或未取代的芳基，取代的或未取代的芳杂基。
  2. 如权利要求1所述的化合物，其中：
    R5是OH。
  3. 如权利要求1所述的化合物，其中：
    Figure PCTCN2017095669-appb-100004
    是苯基、吡啶基、咪唑基、噁唑基、喹啉基、取代的或未取代的吲唑基。
  4. 如权利要求1所述的化合物，其中：
    Figure PCTCN2017095669-appb-100005
    是取代的或未取代的
    Figure PCTCN2017095669-appb-100006
    Figure PCTCN2017095669-appb-100007
  5. 一种化合物，其特征在于，选自但不局限于以下化合物：
    Figure PCTCN2017095669-appb-100008
    Figure PCTCN2017095669-appb-100009
    Figure PCTCN2017095669-appb-100010
    Figure PCTCN2017095669-appb-100011
    Figure PCTCN2017095669-appb-100012
    Figure PCTCN2017095669-appb-100013
  6. 一种药物组合物，该组合包含如权利要求1-5任一项所述的化合物和药学上可接受的赋形剂。
  7. 如权利要求6所述的药物组合物，其中药物组合物的形式为水性分散剂、液体、啫哩、糖浆、西也剂、药浆、悬浮液、气雾剂、速溶剂、泡腾剂、冻干剂、片剂、粉末、药丸、糖衣丸、胶囊、多微粒剂、或立即释放剂。
  8. 一种如权利要求1-5任一项所述的化合物或其药学上可接受的盐、水合物、溶剂化物、同位素化合物或前药，在制备治疗癌症、病毒感染、器官移植排斥或自身免疫性疾病的药物中的应用。
  9. 如权利要求8所述的用途，其特征在于，所述癌症选自皮肤癌、膀胱癌、卵巢癌、乳腺癌、胃癌、胰腺癌、***癌、结肠癌、肺癌、骨癌、脑癌、神经细胞瘤、直肠癌、结肠癌、家族性腺瘤性息肉性癌、遗传性非息肉性结直肠癌、食管癌、唇癌、喉癌、下咽癌、舌癌、唾液腺癌、胃癌、腺癌、甲状腺髓样癌、***状甲状腺癌、肾癌、肾实质癌、卵巢癌、***、子宫体癌、子宫内膜癌、绒毛膜癌、胰腺癌、***癌、睾丸癌、泌尿癌、黑素瘤、脑肿瘤诸如成胶质细胞瘤、星形细胞瘤、脑膜瘤、成神经管细胞瘤和外周神经外胚层肿瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、伯基特淋巴瘤、急性淋巴性白血病(ALL)、慢性淋巴性白血病(CLL)、急性骨髓性白血病(AML)、慢性粒细胞白血病(CML)、成人T细胞白血病淋巴瘤、弥漫性大B细胞淋巴瘤(DLBCL)、肝细胞癌、胆囊癌、支气管癌、小细胞肺癌、非小细胞肺癌、多发性骨髓瘤、基底细胞瘤、畸胎瘤、成视网膜细胞瘤、脉络膜黑素瘤、***瘤、横纹肌肉瘤、颅咽管瘤、骨肉瘤、软骨肉瘤、肌肉瘤、脂肪肉瘤、纤维肉瘤、尤因肉瘤或浆细胞瘤。
  10. 一种如权利要求1-5任一项所述的化合物的制备方法，其特征在于，所述方法包括下述一般制备步骤：
    将起始原料i和ii在金属钯催化剂参与下发生suzuki偶联反应，得到中间体iii；而后此中间体与甲基酮衍生物在碱性条件下生成α，β-不饱和酮(中间体iv)；继而中间体iv在酸性条件下脱保护基进而环合，得到中间体v；最后将中间体v中的羰基还原，制得如权利要求1-5任一项所述的化合物；
    Figure PCTCN2017095669-appb-100014
    或将中间体v与格式试剂反应，得到如权利要求1-5任一项所述的化合物；
    Figure PCTCN2017095669-appb-100015
    或将起始原料i与甲基酮衍生物在碱性条件下生成α，β-不饱和酮(中间体v-i)；在格式试剂、CuCl存在条件下，中间体v-i先与碘化物反应，而后在AcOH条件下脱保护基，得到中间体v-i；继而，中间体v-i发生分子内环合，制得中间体v-ii；最后将中间体v-ii的羰基下还原，得到如权利要求1-5任一项所述的化合物；
    Figure PCTCN2017095669-appb-100016
  11. 一种药盒，其特征在于，所述药盒中含有如权利要求1-5任一项所述的化合物或其药学上可接受的盐、水合物、溶剂化物、同位素化合物或前药，和选自下述的一种以上的靶点药物：PD-1/PD-L1、CTLA-4、CART靶点药物。
  12. 一种如权利要求1-5任一项所述的化合物或其药学上可接受的盐、水合物、溶剂化物、同位素化合物或前药在治疗癌症、病毒感染、器官移植排斥或自身免疫性疾病中的应用。
  13. 如权利要求12所述的应用，其特征在于，所述治疗包括将如权利要求1-5任一项所述的化合物或其药学上可接受的盐、水合物、溶剂化物、同位素化合物或前药单独给药；或将如权利要求1-5任一项所述的化合物或其药学上可接受的盐、水合物、溶剂化物、同位素 化合物或前药与选自下述的一种以上：PD-1/PD-L1、CTLA-4、CART靶点药物联合给药。
  14. 如权利要求12所述的应用，其特征在于，所述癌症选自皮肤癌、膀胱癌、卵巢癌、乳腺癌、胃癌、胰腺癌、***癌、结肠癌、肺癌、骨癌、脑癌、神经细胞瘤、直肠癌、结肠癌、家族性腺瘤性息肉性癌、遗传性非息肉性结直肠癌、食管癌、唇癌、喉癌、下咽癌、舌癌、唾液腺癌、胃癌、腺癌、甲状腺髓样癌、***状甲状腺癌、肾癌、肾实质癌、卵巢癌、***、子宫体癌、子宫内膜癌、绒毛膜癌、胰腺癌、***癌、睾丸癌、泌尿癌、黑素瘤、脑肿瘤诸如成胶质细胞瘤、星形细胞瘤、脑膜瘤、成神经管细胞瘤和外周神经外胚层肿瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、伯基特淋巴瘤、急性淋巴性白血病(ALL)、慢性淋巴性白血病(CLL)、急性骨髓性白血病(AML)、慢性粒细胞白血病(CML)、成人T细胞白血病淋巴瘤、弥漫性大B细胞淋巴瘤(DLBCL)、肝细胞癌、胆囊癌、支气管癌、小细胞肺癌、非小细胞肺癌、多发性骨髓瘤、基底细胞瘤、畸胎瘤、成视网膜细胞瘤、脉络膜黑素瘤、***瘤、横纹肌肉瘤、颅咽管瘤、骨肉瘤、软骨肉瘤、肌肉瘤、脂肪肉瘤、纤维肉瘤、尤因肉瘤或浆细胞瘤。
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