WO2018028491A1 - Inhibiteurs indoamine2, 3-dioxygénase et leurs utilisations en pharmacie - Google Patents

Inhibiteurs indoamine2, 3-dioxygénase et leurs utilisations en pharmacie 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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Chinese (zh)
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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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    • 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
    • A61K31/4164—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
    • 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
    • A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
    • 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
    • A61K31/42—Oxazoles
    • A61K31/422—Oxazoles 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
    • A61K31/435—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
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—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
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • 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

L'invention concerne en outre un composé pour un ou plusieurs inhibiteurs indoamine2, 3-dioxygénase comprenant des composants pharmaceutiques du composé et une préparation; et des utilisations des inhibiteurs indoamine2, 3-dioxygénase. Les inhibiteurs indoamine2, 3-dioxygénase peuvent être utilisés séparément ou en combinaison avec d'autres médicaments, et sont utilisés pour traiter des symptômes liés à l'indoamine2, 3-dioxygénase.
PCT/CN2017/095669 2016-08-09 2017-08-02 Inhibiteurs indoamine2, 3-dioxygénase et leurs utilisations en pharmacie WO2018028491A1 (fr)

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CN111116614B (zh) * 2018-11-01 2022-12-13 复旦大学 免疫调节因子与紫杉烷的共价链接物及其白蛋白纳米制剂及制备方法
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CN105884828A (zh) * 2015-02-16 2016-08-24 上海迪诺医药科技有限公司 多环化合物、其药物组合物及应用
WO2016165613A1 (fr) * 2015-04-12 2016-10-20 Hangzhou Innogate Pharma Co., Ltd. Hétérocycles utiles comme inhibiteurs d'ido et de tdo

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JP6680766B2 (ja) * 2014-09-05 2020-04-15 メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツングＭｅｒｃｋ Ｐａｔｅｎｔ Ｇｅｓｅｌｌｓｃｈａｆｔ ｍｉｔ ｂｅｓｃｈｒａｅｎｋｔｅｒ Ｈａｆｔｕｎｇ 癌治療のためのインドール−アミン−２，３−ジオキシゲナーゼ（ｉｄｏ）拮抗薬としてのシクロヘキシル−エチル置換ジアザ及びトリアザ三環化合物

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CN103547579A (zh) * 2011-04-15 2014-01-29 新联基因公司 用作ido抑制剂的稠合咪唑衍生物
CN105884828A (zh) * 2015-02-16 2016-08-24 上海迪诺医药科技有限公司 多环化合物、其药物组合物及应用
WO2016165613A1 (fr) * 2015-04-12 2016-10-20 Hangzhou Innogate Pharma Co., Ltd. Hétérocycles utiles comme inhibiteurs d'ido et de tdo

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