WO2019007382A1 - 吲哚甲酰胺类衍生物、其制备方法及其在医药上的应用 - Google Patents

吲哚甲酰胺类衍生物、其制备方法及其在医药上的应用 Download PDF

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WO2019007382A1
WO2019007382A1 PCT/CN2018/094610 CN2018094610W WO2019007382A1 WO 2019007382 A1 WO2019007382 A1 WO 2019007382A1 CN 2018094610 W CN2018094610 W CN 2018094610W WO 2019007382 A1 WO2019007382 A1 WO 2019007382A1
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group
compound
formula
alkyl
cycloalkyl
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PCT/CN2018/094610
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English (en)
French (fr)
Inventor
刘�东
陆标
钱文建
董怀德
刘苏星
张儒民
贺峰
陶维康
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江苏恒瑞医药股份有限公司
上海恒瑞医药有限公司
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Application filed by 江苏恒瑞医药股份有限公司, 上海恒瑞医药有限公司 filed Critical 江苏恒瑞医药股份有限公司
Priority to EP18828893.0A priority Critical patent/EP3650448A4/en
Priority to CN201880004378.5A priority patent/CN109952298B/zh
Priority to RU2020102353A priority patent/RU2742770C1/ru
Priority to JP2019569914A priority patent/JP2020525419A/ja
Priority to KR1020207002908A priority patent/KR20200024880A/ko
Priority to CA3068083A priority patent/CA3068083A1/en
Priority to BR112019026945-2A priority patent/BR112019026945A2/pt
Priority to AU2018298193A priority patent/AU2018298193A1/en
Priority to US16/627,590 priority patent/US20200131123A1/en
Publication of WO2019007382A1 publication Critical patent/WO2019007382A1/zh
Priority to ZA2019/08091A priority patent/ZA201908091B/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • 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
    • A61K31/403—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 carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • 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
    • A61K31/435—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
    • A61K31/535—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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
    • 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

Definitions

  • the invention belongs to the field of medicine and relates to anthraquinone derivatives, a preparation method thereof and application thereof in medicine.
  • the present invention relates to an indolecarboxamide derivative represented by the formula (I), a process for producing the same, a pharmaceutical composition containing the same, which is used as an ROR agonist and for preventing and/or treating a tumor Or use in drugs for cancer.
  • Retinoid-related orphan receptors are members of the nuclear receptor family and are a class of ligand-dependent transcription factors that regulate a variety of physiological and biochemical processes, including reproductive development. Metabolism, regulation of the immune system, etc. (Mech Dev. 1998 Jan, 70 (1-2: 147-53; EMBO J. 1998 Jul 15, 17, (14): 3867-77).
  • the ROR family includes three types of ROR ⁇ , ROR ⁇ and ROR ⁇ ( Curr Drug Targets Inflamm Allergy. 2004 Dec, 3(4): 395-412), in which ROR ⁇ can be expressed in many tissues, including thymus, liver, kidney, fat, and skeletal muscle (Immunity.1998Dec, 9(6): 797 -806.).
  • ROR ⁇ 1 ROR ⁇ 1
  • ROR ⁇ t ROR ⁇ 2
  • TH17 and Tc17 cells are a class of effector cells that promote inflammatory response and enhance acquired immunity by secreting interleukin-17 (IL-17) and other inflammatory factors (such as IL-21). Reaction and autoimmune response.
  • IL-17 interleukin-17
  • IL-21 other inflammatory factors
  • Th17 can also recruit cytotoxic CD8+ T cells and natural killer cells into the tumor microenvironment to kill tumor cells for anti-tumor purposes (Blood.2009Aug 6,114(6):1141-9; Clin Cancer Res.2008Jun1,14 (11): 3254-61). Therefore, activation of ROR ⁇ t may become a new anti-tumor therapy.
  • ROR ⁇ t a small molecule drug developed by Lycera Corp.
  • LYC-54143 activates ROR ⁇ t to regulate the differentiation of Th17 and Tc17 cells, promote the expression of other cytokines such as IL-17, and increase the activity of T cells.
  • activated ROR ⁇ t can regulate the expression of multiple genes in the immune system, inhibit the expression of PD-1 in the cell, thereby reducing immunosuppression and increasing anticancer activity (Oncoimmunology.2016Nov 4,5(12):e1254854;ACS Chem Biol.
  • the present inventors designed an indole carboxamide compound having a structure represented by the general formula (I) to exhibit a remarkable effect of stimulating ROR.
  • the change of the ortho group of the ring A changes its regulation effect when the ring A ortho group
  • the group is a hindered group (for example, H)
  • the compound represented by the formula (I) is an inverse agonist
  • the ring A ortho group is a haloalkyl group (for example, a trifluoromethyl group) or an alkyl group
  • the compound represented by the formula (I) is a ROR agonist when a group having a large hindrance such as an ethyl group and a halogenated alkoxy group (for example, a trifluoromethoxy group).
  • the invention also provides a pharmacodynamic test, which exhibits good antitumor activity when the compound of the invention is administered alone, and additionally, the compound of the invention exhibits a synergistic effect when combined with the PD-1 antibody, and opens up a new effect for improving the therapeutic effect of the immunotherapy. way.
  • G 1 , G 2 and G 3 are the same or different and are each independently selected from C, CH, CH 2 or N;
  • Ring A is selected from the group consisting of an aryl group, a heteroaryl group, a cycloalkyl group, and a heterocyclic group;
  • R 1 is the same or different and is each independently selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, a halogenated alkyl group, an alkoxy group, a halogenated alkoxy group, a cyano group, an amino group, a nitro group, a hydroxyl group, and a hydroxyalkyl group;
  • R 2 is a haloalkyl group
  • R 3 is selected from the group consisting of alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, halogen, cyano, amino, nitro, hydroxy, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein The alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are each independently optionally substituted with one or more selected from the group consisting of hydroxyl, halogen, alkyl, alkoxy and amino groups. Substituted by
  • R 4 are the same or different and are each independently selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, a halogenated alkyl group, an alkoxy group, a halogenated alkoxy group, a cyano group, an amino group, a nitro group, a hydroxyl group, a hydroxyalkyl group, a cycloalkyl group, and a hetero group. a cyclic group, an aryl group and a heteroaryl group;
  • R 5 is selected from the group consisting of a hydrogen atom, an alkyl group, a halogenated alkyl group, an amino group, a hydroxyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, NR 10 R 11 , an aryl group, and a heteroaryl group, wherein the alkyl group, naphthenic group And optionally substituted by one or more substituents selected from the group consisting of hydroxyl, halo, alkyl, amino, cycloalkyl and heterocyclyl;
  • R 6 are the same or different and are each independently selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, a halogenated alkyl group, an alkoxy group, a halogenated alkoxy group, a cyano group, an amino group, a nitro group, a hydroxyl group, a hydroxyalkyl group, a cycloalkyl group, and a heterocyclic group. a cyclic group, an aryl group and a heteroaryl group;
  • R 7 is selected from the group consisting of a hydrogen atom, an alkyl group, a halogenated alkyl group, a cycloalkyl group, and a heterocyclic group, wherein the alkyl group is optionally selected from one or more of a halogen, a nitro group, a cycloalkyl group, and a heterocyclic group. Substituted by a substituent;
  • R 8 and R 9 are the same or different and are each independently selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, a halogenated alkyl group, an alkoxy group, a cyano group, an amino group, a nitro group, a hydroxyl group, and a hydroxyalkyl group;
  • R 10 and R 11 are the same or different and are each independently selected from the group consisting of a hydrogen atom, an alkyl group, a halogenated alkyl group, an amino group, a hydroxyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;
  • n 0, 1, 2, 3 or 4;
  • s 0, 1, 2 or 3;
  • t 0, 1, 2 or 3.
  • the compound of the formula (I) is a compound of the formula (II):
  • R a is a hydrogen atom or an alkyl group
  • Ring A, G 1 to G 3 , R 1 , R 4 to R 7 , n, s and t are as defined in the formula (I).
  • the compound of the formula (I) is a compound of the formula (II):
  • Ring A, G 1 to G 3 , R 1 , R 4 to R 7 , n, s and t are as defined in the formula (I).
  • the compound of the formula (I) is a compound of the formula (I'):
  • Ring A, R 1 to R 9 , n, s and t are as defined in the formula (I).
  • the compound of the formula (II) is a compound represented by the following formula (II'):
  • Rings A, R 1 , R 4 to R 7 , n, s and t are as defined in the formula (II).
  • the compound of the formula (I) wherein ring A is selected from the group consisting of phenyl, pyridyl, imidazolyl, pyrazolyl and morpholinyl.
  • the compound of the formula (I) is a compound of the formula (III):
  • R 1 , R 5 to R 7 , n and t are as defined in the formula (I).
  • the compound of the formula (I) is a compound of the formula (IV):
  • R 1 , R 5 to R 7 , n and t are as defined in the formula (I).
  • the compound of the formula (I), wherein R 5 is selected from the group consisting of ethyl, cyclopropyl, cyclopropylmethyl or -NH-cyclopropyl.
  • the compound of the formula (I), wherein R 6 is a hydrogen atom or a halogen is a hydrogen atom or a halogen.
  • the compound of the formula (I), wherein R 7 is selected from the group consisting of alkyl, cycloalkyl and haloalkyl.
  • Typical compounds of formula (I) include, but are not limited to:
  • a tautomer a meso form, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof.
  • Another aspect of the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of the formula (I) or a tautomer thereof, a mesogen, a racemate, an enantiomer a form, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt, and one or more pharmaceutically acceptable carriers, diluents or excipients.
  • the present invention also relates to a process for the preparation of the pharmaceutical composition
  • the pharmaceutical composition comprising the compound of the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer thereof
  • the diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof is admixed with a pharmaceutically acceptable carrier, diluent or excipient.
  • the pharmaceutical composition further comprises an anti-PD-1 antibody, preferably an anti-murine PD-1 antibody.
  • the invention further relates to a compound of the formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture thereof, or Use of a pharmaceutically acceptable salt, or a pharmaceutical composition comprising the same, in the manufacture of a ROR agonist.
  • the invention further relates to a compound of the formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture thereof, or A pharmaceutically acceptable salt, or a pharmaceutical composition comprising the same, for use as a ROR agonist in the manufacture of a medicament for the prevention and/or treatment of a tumor or cancer.
  • the invention further relates to a compound of the formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture thereof, or Use of a pharmaceutically acceptable salt (as an ROR agonist), or a pharmaceutical composition comprising the same, in combination with an anti-PD-1 antibody, for the manufacture of a medicament for the prevention and/or treatment of a tumor or cancer.
  • the invention further relates to a compound of the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer or a mixture thereof, or A pharmaceutically acceptable salt, or a pharmaceutical composition comprising the same, for use as a medicament.
  • the present invention also relates to a compound of the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer or a mixture thereof, or A pharmaceutically acceptable salt, or a pharmaceutical composition comprising the same, as an ROR agonist.
  • the present invention also relates to a compound of the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer or a mixture thereof, or A pharmaceutically acceptable salt, or a pharmaceutical composition comprising the same, for use as an ROR agonist for the prevention and/or treatment of a tumor or cancer.
  • the present invention also relates to a compound of the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer or a mixture thereof, or A pharmaceutically acceptable salt, or a pharmaceutical composition comprising the same, in combination with an anti-PD-1 antibody for use in the prevention and/or treatment of a tumor or cancer.
  • the present invention also relates to a method for the treatment of preventing and/or treating a tumor or cancer comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the formula (I) or a tautomer thereof as an ROR agonist. a form, a meso form, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.
  • the present invention also relates to a method for the prophylactic and/or therapeutic treatment of preventing tumors or cancer comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the formula (I) or a tautomer thereof, internal elimination A form of a rot, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same and an anti-PD-1 antibody.
  • the active ingredient-containing pharmaceutical composition may be in a form suitable for oral administration, such as tablets, dragees, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or Tincture.
  • Oral compositions can be prepared according to any method known in the art for preparing pharmaceutical compositions, such compositions may contain one or more ingredients selected from the group consisting of sweeteners, flavoring agents, coloring agents, and preservatives, To provide a pleasing and tasty pharmaceutical preparation. Tablets contain the active ingredient and non-toxic pharmaceutically acceptable excipients suitable for the preparation of a tablet for admixture.
  • excipients can be inert excipients, granulating agents, disintegrating agents, binders, and lubricants. These tablets may be uncoated or may be coated by masking the taste of the drug or delaying disintegration and absorption in the gastrointestinal tract, thus providing a sustained release effect over a longer period of time.
  • Oral formulations can also be provided in soft gelatine capsules in which the active ingredient is mixed with an inert solid diluent or the active ingredient in admixture with a water-soluble vehicle or an oil vehicle.
  • the aqueous suspension contains the active substance and excipients suitable for the preparation of the aqueous suspension for mixing. Such excipients are suspending, dispersing or wetting agents.
  • the aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents.
  • the oil suspension can be formulated by suspending the active ingredient in vegetable oil, or mineral oil.
  • the oil suspension may contain a thickening agent.
  • the above sweeteners and flavoring agents may be added to provide a palatable preparation. These compositions can be preserved by the addition of an antioxidant.
  • compositions of the invention may also be in the form of an oil-in-water emulsion.
  • the oil phase can be a vegetable oil, or a mineral oil or a mixture thereof.
  • Suitable emulsifiers can be naturally occurring phospholipids, and emulsions can also contain sweeteners, flavoring agents, preservatives, and antioxidants.
  • Such formulations may also contain a demulcent, a preservative, a colorant, and an antioxidant.
  • the pharmaceutical compositions of the invention may be in the form of a sterile injectable aqueous solution.
  • acceptable vehicles or solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution.
  • the sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oily phase.
  • the injection or microemulsion is injected into the bloodstream of the patient by topical injection.
  • the solution and microemulsion are preferably administered in a manner that maintains a constant circulating concentration of the compound of the invention.
  • a continuous intravenous delivery device can be used.
  • An example of such a device is the Deltec CADD-PLUS.TM.5400 intravenous pump.
  • compositions of the invention may be in the form of a sterile injectable aqueous or oily suspension for intramuscular and subcutaneous administration.
  • the suspension may be formulated according to known techniques using those suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension prepared in a parenterally acceptable non-toxic diluent or solvent.
  • sterile fixed oils may conveniently be employed as a solvent or suspension medium. Any blended fixed oil can be used for this purpose.
  • fatty acids can also be prepared as injections.
  • the compounds of the invention may be administered in the form of a suppository for rectal administration.
  • These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and thus dissolves in the rectum to release the drug.
  • the dosage of the drug to be administered depends on a variety of factors including, but not limited to, the following factors: the activity of the particular compound used, the age of the patient, the weight of the patient, the health of the patient, the behavior of the patient. , the patient's diet, the time of administration, the mode of administration, the rate of excretion, the combination of drugs, etc.; in addition, the optimal treatment modality such as the mode of treatment, the daily dosage of the compound of formula (I) or the pharmaceutically acceptable salt
  • the type can be verified according to traditional treatment options.
  • alkyl refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing from 1 to 20 carbon atoms, preferably an alkyl group having from 1 to 12 carbon atoms, more preferably from 1 to 6 carbons.
  • the alkyl group of the atom is a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing from 1 to 20 carbon atoms, preferably an alkyl group having from 1 to 12 carbon atoms, more preferably from 1 to 6 carbons.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1 ,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2- Methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3 - dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2 -methylhexyl, 3-methylhexyl, 4-methylhexyl,
  • lower alkyl groups having from 1 to 6 carbon atoms, non-limiting examples including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl Base, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethyl Butyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl Base, 2,3-dimethylbutyl and the like.
  • the alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups independently selected from the group consisting of an alkane Base, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, naphthenic An oxy group, a heterocycloalkoxy group, a cycloalkylthio group, a heterocycloalkylthio group, an oxo group, a carboxyl group, and a carboxylate group.
  • an alkane Base alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl,
  • alkoxy refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl and cycloalkyl are as defined above.
  • alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy.
  • the alkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio a heterocycloalkylthio group, a carboxyl group, and a carboxylate group.
  • the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 carbon atoms, preferably from 3 to 12 carbon atoms, more preferably from 3 to 6 carbon atoms. One carbon atom.
  • Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene
  • a polycycloalkyl group includes a spiro ring, a fused ring, and a cycloalkyl group.
  • spirocycloalkyl refers to a polycyclic group that shares a carbon atom (referred to as a spiro atom) between 5 to 20 members of a single ring, which may contain one or more double bonds, but none of the rings have a fully conjugated ⁇ electronic system. It is preferably 6 to 14 members, more preferably 7 to 10 members.
  • the spirocycloalkyl group is classified into a monospirocycloalkyl group, a bispirocycloalkyl group or a polyspirocycloalkyl group, preferably a monospirocycloalkyl group and a bispirocycloalkyl group, depending on the number of common spiro atoms between the rings.
  • spirocycloalkyl groups include:
  • fused cycloalkyl refers to 5 to 20 members, and each ring in the system shares an all-carbon polycyclic group of an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or Multiple double bonds, but none of the rings have a fully conjugated ⁇ -electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members.
  • fused cycloalkyl groups include:
  • bridged cycloalkyl refers to an all-carbon polycyclic group of 5 to 20 members, any two rings sharing two carbon atoms which are not directly bonded, which may contain one or more double bonds, but none of the rings have complete Conjugate ⁇ -electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl group, preferably a bicyclic ring, a tricyclic ring or a tetracyclic ring, and more preferably a bicyclic ring or a tricyclic ring.
  • bridged cycloalkyl groups include:
  • the cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring to which the parent structure is attached is a cycloalkyl group, non-limiting examples include indanyl, tetrahydronaphthalene Base, benzocycloheptyl and the like.
  • the cycloalkyl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio a heterocycloalkylthio group, an oxo group, a carboxyl group, and a carboxylate group.
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 ring atoms wherein one or more ring atoms are selected from nitrogen, oxygen or S(O).
  • a hetero atom of m (where m is an integer of 0 to 2), but excluding the ring moiety of -OO-, -OS- or -SS-, the remaining ring atoms being carbon.
  • ring atoms Preferably comprising from 3 to 12 ring atoms, wherein from 1 to 4 are heteroatoms; most preferably from 3 to 8 ring atoms, wherein from 1 to 3 are heteroatoms; most preferably from 3 to 6 ring atoms, wherein from 1 to 2 It is a hetero atom.
  • monocyclic heterocyclic groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidine.
  • the base, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl and the like are preferably piperidinyl, piperazinyl or morpholinyl.
  • Polycyclic heterocyclic groups include spiro, fused, and bridged heterocyclic groups.
  • spiroheterocyclyl refers to a polycyclic heterocyclic group in which one atom (called a spiro atom) is shared between 5 to 20 members of a single ring, wherein one or more ring atoms are selected from nitrogen, oxygen or S (O). ) m (where m is an integer 0 to 2) heteroatoms, and the remaining ring atoms are carbon. It may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members.
  • the spiroheterocyclyl group is classified into a monospiroheterocyclic group, a dispiroheterocyclic group or a polyspirocyclic group according to the number of shared spiro atoms between the ring and the ring, and is preferably a monospiroheterocyclic group and a dispiroheterocyclic group.
  • spiroheterocyclyl groups include:
  • fused heterocyclyl refers to 5 to 20 members, and each ring in the system shares an adjacent pair of atomic polycyclic heterocyclic groups with other rings in the system, and one or more rings may contain one or more Double bond, but none of the rings have a fully conjugated ⁇ -electron system in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) m (where m is an integer from 0 to 2), and the remaining rings
  • the atom is carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members.
  • fused heterocyclic groups include:
  • bridge heterocyclyl refers to a polycyclic heterocyclic group of 5 to 14 members, any two rings sharing two atoms which are not directly bonded, which may contain one or more double bonds, but none of the rings have a total A ⁇ -electron system of a yoke in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) m (where m is an integer from 0 to 2), the remaining ring atoms being carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members.
  • bridge heterocyclic groups include:
  • the heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring to which the parent structure is attached is a heterocyclic group, non-limiting examples of which include:
  • the heterocyclic group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio a heterocycloalkylthio group, an oxo group, a carboxyl group, and a carboxylate group.
  • the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, ary
  • aryl refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic ring (ie, a ring that shares a pair of adjacent carbon atoms) having a conjugated ⁇ -electron system, preferably 6 to 10 members, such as benzene. Base and naphthyl. More preferred is phenyl.
  • the aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring to which the parent structure is attached is an aryl ring, non-limiting examples of which include:
  • the aryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle An alkylthio group, a carboxyl group or a carboxylate group.
  • heteroaryl refers to a heteroaromatic system containing from 1 to 4 heteroatoms, from 5 to 14 ring atoms, wherein the heteroatoms are selected from the group consisting of oxygen, sulfur and nitrogen.
  • the heteroaryl group is preferably 5 to 10 members, and has 1 to 3 hetero atoms; more preferably 5 or 6 members, and 1 to 2 hetero atoms; preferably, for example, imidazolyl, furyl, thienyl, thiazolyl, pyridyl Azolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, etc., preferably imidazolyl, tetrazolyl, pyridyl, thienyl, pyrazolyl or pyrimidinyl , thiazolyl; more selective pyridyl.
  • the heteroaryl ring may be fuse
  • the heteroaryl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio a heterocycloalkylthio group, a carboxyl group, and a carboxylate group.
  • the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl
  • haloalkyl refers to an alkyl group substituted by one or more halogens, wherein alkyl is as defined above.
  • haloalkoxy refers to an alkoxy group substituted by one or more halogens, wherein alkoxy is as defined above.
  • hydroxyalkyl refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.
  • hydroxy refers to an -OH group.
  • halogen means fluoro, chloro, bromo or iodo.
  • amino means -NH 2.
  • cyano refers to -CN.
  • nitro refers to -NO 2 .
  • carboxylate group refers to -C(O)O(alkyl) or -C(O)O(cycloalkyl), wherein alkyl, cycloalkyl are as defined above.
  • acyl halide refers to a compound containing a -C(O)-halogen group.
  • heterocyclic group optionally substituted by an alkyl group means that an alkyl group may be, but is not necessarily, present, and the description includes the case where the heterocyclic group is substituted with an alkyl group and the case where the heterocyclic group is not substituted with an alkyl group.
  • Substituted refers to one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3, hydrogen atoms, independently of each other, substituted by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art will be able to determine (by experiment or theory) substitutions that may or may not be possible without undue effort. For example, an amino group or a hydroxyl group having a free hydrogen may be unstable when combined with a carbon atom having an unsaturated (e.g., olefinic) bond.
  • “Pharmaceutical composition” means a mixture comprising one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, as well as other components such as physiological/pharmaceutically acceptable carriers. And excipients.
  • the purpose of the pharmaceutical composition is to promote the administration of the organism, which facilitates the absorption of the active ingredient and thereby exerts biological activity.
  • “Pharmaceutically acceptable salt” refers to a salt of a compound of the invention which is safe and effective for use in a mammal and which possesses the desired biological activity.
  • Figure 1 shows the effect of the compound of Example 4 alone or in combination with an anti-mouse-PD-1 antibody on the growth of MC38 colorectal tumors in C57BL/6 mice.
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS).
  • NMR shift ( ⁇ ) is given in units of 10 -6 (ppm).
  • NMR was measured using a Bruker AVANCE-400 nuclear magnetic apparatus, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), internal standard was four.
  • DMSO-d 6 dimethyl sulfoxide
  • CDCl 3 deuterated chloroform
  • CD 3 OD deuterated methanol
  • TMS Methyl silane
  • the measurement of the MS was carried out using a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantage MAX).
  • ESI FINNIGAN LCQAd
  • the HPLC was measured using an Agilent 1200 DAD high pressure liquid chromatograph (Sunfire C18 150 x 4.6 mm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150 x 4.6 mm column).
  • Chiral HPLC analysis assays were performed using LC-10A vp (Shimadzu) or SFC-analytical (Berger Instruments Inc.).
  • Thin layer chromatography silica gel plate uses Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate.
  • the specification of silica gel plate used for thin layer chromatography (TLC) is 0.15mm ⁇ 0.2mm.
  • the specification for thin layer chromatography separation and purification is 0.4mm. ⁇ 0.5mm.
  • the CombiFlash Rapid Preparer uses the Combiflash Rf200 (TELEDYNE ISCO).
  • the known starting materials of the present invention may be synthesized by or according to methods known in the art, or may be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Dari Chemicals, Shanghai Bi De Pharmaceutical Technology Co., Ltd. and other companies.
  • the reactions can all be carried out under an argon atmosphere or a nitrogen atmosphere.
  • An argon atmosphere or a nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon having a volume of about 1 L.
  • the hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon of about 1 L volume.
  • the pressurized hydrogenation reaction was carried out using a Parr Model 3916EKX hydrogenation apparatus and a clear blue QL-500 type hydrogen generator or a HC2-SS type hydrogenation apparatus.
  • the hydrogenation reaction is usually evacuated, charged with hydrogen, and operated three times.
  • the microwave reaction used a CEM Discover-S Model 908860 microwave reactor.
  • the solution means an aqueous solution.
  • reaction temperature is room temperature and is 20 ° C to 30 ° C.
  • the progress of the reaction in the examples was monitored by thin layer chromatography (TLC), the developing agent used for the reaction, the column chromatography eluent system used for the purification of the compound, and the thin layer chromatography developing solvent system including: A: Methylene chloride/methanol system, B: n-hexane/ethyl acetate system, the volume ratio of the solvent is adjusted according to the polarity of the compound, and may be adjusted by adding a small amount of an alkaline or acidic reagent such as triethylamine or acetic acid.
  • TLC thin layer chromatography
  • A Methylene chloride/methanol system
  • B n-hexane/ethyl acetate system
  • the volume ratio of the solvent is adjusted according to the polarity of the compound, and may be adjusted by adding a small amount of an alkaline or acidic reagent such as triethylamine or acetic acid.
  • the compound 8f (350 mg, 0.927 mmol) was dissolved in 10 mL of tetrahydrofuran, and a solution of tetrabutylammonium fluoride tetrahydrofuran (1.85 mL, 1.85 mmol) was added thereto, and the mixture was stirred at 0 ° C for 2 hours, and 10 mL of water was added to the reaction mixture. It was extracted with ethyl acetate (10 mL ⁇ 3), and the organic phase was combined, washed with saturated sodium chloride solution (10 mL ⁇ 1), dried over anhydrous sodium sulfate, filtered and evaporated. The obtained residue was purified to give the title compound 8 g (230 mg, yield: 68%).
  • 4-(cyclopropylmethyl)sulfonylbromobenzene 13d (2.48 g, 9.01 mmol) was dissolved in 80 mL of 1,4-dioxane, 10 mL of water was added, and vinyl boronic acid pinacol ester 13e (2.78) was added. g, 18.03 mmol) and tetrakistriphenylphosphine palladium (520.49 mg, 450.64 ⁇ mol), additional cesium carbonate (5.88 g, 18.03 mmol), argon-protected, heated to 80 ° C and stirred for 2 hours. The reaction mixture was concentrated under reduced vacuo.
  • Sodium hydroxide (121 mg, 3.02 mmol) was dissolved in 15 mL of water, and 5 mL of potassium citrate dihydrate (14.84 mg, 40.33 ⁇ mol) was dissolved.
  • the tert-butyl carbamate (413.3 mg, 3.53 mmol) was dissolved at room temperature.
  • the mixture was mixed with the above aqueous sodium hydroxide solution in 10 mL of n-propanol, and tert-butyl hypochlorite (328.4 mg, 3.02 mmol) was added dropwise at room temperature. After stirring for 5 minutes, hydrogenated quinidine 1,4- (2) was added.
  • Test Example 1 Determination of in vitro activity of ROR ⁇ by the compound of the present invention
  • TR-FRET ROR ⁇ co-activation system (Life Technologies)
  • Modulation of RORy activity by the compounds of the invention was screened using a LanthaScreen TR-FRET (Time Resolved Fluorescence Energy Resonance Transfer) ROR ⁇ co-activation system.
  • LanthaScreen TR-FRET Time Resolved Fluorescence Energy Resonance Transfer
  • the Complete TR-FRET Coregulator (Life Technologies) was first formulated to contain a final concentration of 5 mM DTT. The final concentration of DMSO was 2%. The test compound was serially diluted to 2 x final concentration in intact buffer D containing 2% DMSO at a maximum dose of 60 ⁇ m. 10 ⁇ l/well was added to the test well of a 384-well plate (PerkinElmer). Two parallel control wells were placed at the same concentration for each test compound. Prepare 4X ROR ⁇ LBD (AB Vector). The ROR ⁇ LBD concentration was diluted to 1 ng/ ⁇ L using intact buffer D. 5 ⁇ l/well was added to the test well of a 384-well assay plate.
  • the negative control wells were 5 [mu]L of intact buffer D without ROR[gamma]LBD.
  • Fluorescence readings were detected using a Tecan Infinite M1000, and a logarithmic curve of the ratio of the emission wavelength of 520 nm / 495 nm to the concentration of the compound was plotted by GraphPad Prism 6.0 software to calculate the EC 50 /IC 50 value of the test compound.
  • Table 1 Compound of the invention 50 activity in vitro EC ROR ⁇ values and values of Comparative Example 50 of IC.
  • a if it is an agonist, the value is indicated as EC 50 ; if it is an inverse agonist, the value is indicated as IC 50 ;
  • the compounds of the present invention have obvious agonistic effects on the in vitro activity of ROR ⁇ , and Applicants have found that the change of the ortho group of the ring A changes its regulation effect, and when the ring A ortho group is a group with less steric hindrance (for example, Example 17 at H) is an inverse agonist.
  • Test Example 2 Quantitative Analysis of Activity of IL-17A Enzyme-Linked Immunosorbent Assay
  • PBMC Human peripheral blood mononuclear cells
  • PBMC peripheral blood mononuclear cells
  • Table 2 EC 50 values of quantitative analysis of IL-17A enzyme-linked immunosorbent assay of the compounds of the present invention
  • the compounds of the present invention have a significant regulatory effect on the activity of IL-17A enzyme-linked immunoassay.
  • Test Example 3 Mouse pharmacokinetic test of the compound of the present invention
  • mice Using mice as test animals, the concentration of the drug in plasma at different times after administration of the compound of Example 4 by intragastric administration was determined by LC/MS/MS method. The pharmacokinetic behavior of the compounds of the invention in mice was investigated and their pharmacokinetic characteristics were evaluated.
  • mice were divided into 1 group, female, purchased from Shanghai Jiesijie Experimental Animal Co., Ltd., animal production license number: SCXK (Shanghai) 2013-0006.
  • a certain amount of the drug was weighed, and 5% by volume of DMSO, 5% by volume of Tween 80 and 90% of physiological saline were placed in a 0.1 mg/ml colorless clear liquid.
  • mice were intragastrically administered overnight after fasting, and the dose was 2.0 mg/kg, and the administration volume was 0.2 ml/10 g.
  • the compound of Example 4 was administered by gavage in mice, and 0.1 ml (3 animals per time point) was collected before administration and after 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 11.0, 24.0 hours after administration.
  • the cells were placed in heparinized tubes, centrifuged at 3500 rpm for 10 minutes, and stored at -20 °C.
  • the content of the test compound in the plasma of mice after different doses of the drug was measured: 25 ⁇ l of the mouse plasma at each time after administration, 80 ⁇ l of camptothecin (100 ng/mL), 200 ⁇ l of acetonitrile, vortex The mixture was spun for 5 minutes, centrifuged for 10 minutes (3600 rpm), and plasma samples were taken for 1 ⁇ l of the supernatant for LC/MS/MS analysis.
  • the pharmacokinetic parameters of the compounds of the invention are as follows:
  • the compounds of the present invention have better pharmacological absorption and have pharmacokinetic advantages.
  • the MC38 mouse model was used to evaluate the inhibitory effect of the compound of Example 4 on MC38 tumor growth.
  • mice purchased from Charles River Lab (USA), were purchased at 20-25 grams, 7-9 weeks old. 10 / cage feeding, temperature 23 ⁇ 1 ° C constant temperature, humidity 50 ⁇ 60%, free to eat water. Everything is treated and used in accordance with the Laboratory Animal Care and Use Committee (IACUC approved guidelines). After the animals were purchased, the experiment was started after 7 days of adaptive feeding.
  • IACUC approved guidelines Laboratory Animal Care and Use Committee
  • Anti-mouse PD-1 (CD279) antibody was purchased from BioXcell (clone RMP1-14; catalog number BP0146);
  • the IgG2a isotype control antibody was purchased from BioXcell (clone 2A3; catalog number BE0089).
  • mice After adaptive breeding in mice, the groups are as follows:
  • Dosing regimen IgG2a isotype control antibody loading control group 8 Intraperitoneal injection/oral Q3dx4/BIDx21 Anti-mouse PD-1 antibody 8 Intraperitoneal injection Q3dx4 Example 4 compound 8 oral BIDx21 Anti-mouse PD-1 antibody plus compound of Example 4 8 Intraperitoneal injection/oral Q3dx4/BIDx21
  • 1.Q3dx4 represents every three days of dosing, a total of four times, fixed on the 5th, 8th, 11th, 14th day;
  • BIDx21 represents 2 doses per day for 21 consecutive days
  • mice Female C57BL/6 mice (20-25 grams, 7-9 weeks old) were used in the experiment. In vivo anti-administration of the compound of Example 4 or the compound of Example 4 in combination with an anti-mouse-PD-1 antibody was assessed by detecting the growth of the isotype MC38 colorectal tumor (Synta Pharmaceuticals) in inbred C57BL/6 mice. Tumor activity. 500,000 (5 ⁇ 10 5 ) MC38 cells were implanted subcutaneously into the right abdomen of each mouse. After 5 days, after the tumors grew to 40-80 mm 3 , the mice were randomly divided into groups and the compound of Example 4 was administered daily ( 30 mg/kg) 2 times, continuous administration for 21 days.
  • isotype MC38 colorectal tumor Synta Pharmaceuticals
  • mice bearing MC38 tumors were intraperitoneally (ip) injected with anti-mouse PD-1 (CD279) antibody on days 5, 8, 11, and 14 ( BioXcell) (5 mg/kg).
  • the control group was the vehicle CMC-Na drug formulation and the IgG2a isotype control antibody.
  • the unit is mm.
  • TGI As shown in Figure 1, when 30 mg/kg of the compound of Example 4 was administered alone, the TGI was 40%. When the anti-mouse PD-1 (CD279) antibody (5 mg/kg) was injected alone, the TGI was 51%. The compound of Example 4 (30 mg/kg) exhibited a synergistic effect (TGI of 63%) when administered in combination with an anti-mouse PD-1 monoclonal antibody (5 mg/kg). These data indicate that the isogenic MC38 colorectal tumor In the model, the compound of Example 4 was administered alone to exhibit antitumor activity, while the compound of Example 4 showed synergistic effect in combination with the PD-1 antibody, which also indicated that the compound of Example 4 has the same function as ROR ⁇ activation (rather than inhibition). Biological activity opens up new avenues for improving the efficacy of immunotherapy.

Abstract

一种吲哚甲酰胺类衍生物、其制备方法及其在医药上的应用。特别地，如通式（I）所示的吲哚甲酰胺类衍生物、其制备方法、含有该衍生物的药物组合物，其作为ROR激动剂的用途以及其用于预防和/或***或癌症的用途。

Description

吲哚甲酰胺类衍生物、其制备方法及其在医药上的应用 技术领域
本发明属于医药领域，涉及吲哚甲酰胺类衍生物、其制备方法及其在医药上的应用。特别地，本发明涉及通式(I)所示的吲哚甲酰胺类衍生物、其制备方法、含有该衍生物的药物组合物，其作为ROR激动剂以及其用于预防和/或***或癌症的药物中的用途。
背景技术
维甲酸相关孤儿核受体(Retinoid-related orphan receptors,ROR)是核受体家族的成员之一，也是一类配体依赖的转录因子，它能够调控多种生理和生化过程，包括生殖发育、新陈代谢、免疫***调节等(Mech Dev.1998Jan,70(1-2:147-53；EMBO J.1998Jul 15,17(14):3867-77)。ROR家族包括三种类型RORα、RORβ和RORγ(Curr Drug Targets Inflamm Allergy.2004Dec,3(4):395-412),其中RORγ可以在许多组织中表达，包括胸腺、肝脏、肾脏、脂肪和骨骼肌等(Immunity.1998Dec,9(6):797-806.)。
RORγ有两种亚型：RORγ1和RORγt(RORγ2)，其中RORγ1在许多组织中表达，如：胸腺、肌肉、肾脏和肝脏中表达，而RORγt则只在免疫细胞内表达(Eur J Immunol.1999Dec,29(12):4072-80)。已有文献报道，RORγt能够调节在免疫细胞分化的过程中T细胞的存活，并能激活和促进CD4+、CD8+的细胞分化成辅助T细胞17(Th17)和细胞毒性T细胞(Tc17)(J Immunol.2014Mar 15,192(6):2564-75)，其中TH17和Tc17细胞是一类效应细胞，通过分泌白介素17(IL-17)和其他炎症因子(如IL-21)促进炎症反应、增强获得性免疫反应和自身免疫应答。此外，现有研究证明，通过将Th17和Tc17细胞移植到荷瘤小鼠中，可以明显抑制移植瘤的生长(J Immunol.2010Apr 15,184(8):4215-27)。Th17还可以招募细胞毒性CD8+T细胞和自然杀伤细胞进入肿瘤微环境，从而杀死肿瘤细胞，达到抗肿瘤的目的(Blood.2009Aug 6,114(6):1141-9；Clin Cancer Res.2008Jun1,14(11):3254-61)。因此，激活RORγt，有可能成为新的抗肿瘤疗法。
目前，已有医药公司开发出RORγt的激动剂，比如Lycera Corp.公司开发的小分子药物LYC-55716。临床前研究表明，其类似物LYC-54143可通过两条不同的通路抑制肿瘤生长，表现出优越的抗癌活性。首先，LYC-54143激活RORγt后可通过传统途径调节Th17和Tc17细胞的分化，促进IL-17等其他细胞因子的表达，提高T细胞活性。另外，激活的RORγt可以调节免疫***中的多种基因表达，抑制细胞检查受体PD-1的表达，从而降低免疫抑制，提高抗癌活性(Oncoimmunology.2016Nov 4,5(12):e1254854；ACS Chem Biol.2016Apr 15,11(4):1012-8)。虽然 LYC-55716目前已经进入临床II期，但是有关该靶点激动剂的药物仍然非常少，并且无上市药物出现，已公开的专利有如WO2015171558、WO2008152260、WO2007068580、WO2007068579、WO2005056516、WO2005056510、WO2005066116、WO00228810，仍需要继续开发更高效的新的RORγt激动剂，以期为患者提供新的有效的抗癌药物。
本发明人设计具有通式(I)所示结构的吲哚甲酰胺类化合物，表现出显著的激动ROR的作用。在研究ROR激动剂的过程中，发明人还发现在本发明所述的通式(I)所示的化合物中，环A邻位基团的变化会改变其调节效果，当环A邻位基团为位阻较小的基团(例如H)时通式(I)所示的化合物为反激动剂，当环A邻位基团为卤代烷基(例如三氟甲基)、烷基(例如乙基)和卤代烷氧基(例如三氟甲氧基)类位阻较大的基团时通式(I)所示的化合物为ROR激动剂。本发明还提供了药效试验，单独施用本发明化合物时表现出良好的抑瘤活性，另外，本发明化合物与PD-1抗体联合用药时表现出协同作用，为提高免疫治疗的疗效开辟了新途径。
发明内容
本发明的目的在于提供一种通式(I)所示的化合物：
Figure PCTCN2018094610-appb-000001
或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用的盐，
其中：
Figure PCTCN2018094610-appb-000002
为双键或单键；
G 1、G 2和G 3相同或不同，且各自独立地选自C、CH、CH 2或N；
环A选自芳基、杂芳基、环烷基和杂环基；
R 1相同或不同，且各自独立地选自氢原子、卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、氰基、氨基、硝基、羟基和羟烷基；
R 2为卤代烷基；
R 3选自烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、卤素、氰基、氨基、硝基、羟基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自羟基、卤素、烷基、烷氧基 和氨基中的一个或多个取代基所取代；
R 4相同或不同，且各自独立地选自氢原子、卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基；
R 5选自氢原子、烷基、卤代烷基、氨基、羟基、羟烷基、环烷基、杂环基、NR 10R 11、芳基和杂芳基，其中所述的烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自羟基、卤素、烷基、氨基、环烷基和杂环基中的一个或多个取代基所取代；
R 6相同或不同，且各自独立地选自氢原子、卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基；
R 7选自氢原子、烷基、卤代烷基、环烷基和杂环基，其中所述的烷基任选被选自卤素、硝基、环烷基和杂环基中的一个或多个取代基所取代；
R 8和R 9相同或不同，且各自独立地选自氢原子、卤素、烷基、卤代烷基、烷氧基、氰基、氨基、硝基、羟基和羟烷基；
R 10和R 11相同或不同，且各自独立地选自氢原子、烷基、卤代烷基、氨基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基；
n为0、1、2、3或4；
s为0、1、2或3；且
t为0、1、2或3。
在本发明一个优选的实施方案中，所述的通式(I)所示的化合物为通式(II)所示的化合物：
Figure PCTCN2018094610-appb-000003
其中：
R a为氢原子或烷基；
Figure PCTCN2018094610-appb-000004
环A、G 1～G 3、R 1、R 4～R 7、n、s和t如通式(I)中所定义。
在本发明一个优选的实施方案中，所述的通式(I)所示的化合物为通式(II)所示的化合物：
Figure PCTCN2018094610-appb-000005
其中：
Figure PCTCN2018094610-appb-000006
环A、G 1～G 3、R 1、R 4～R 7、n、s和t如通式(I)中所定义。
在本发明优选的实施方案中，所述的通式(I)所示化合物为如下通式(I’)所示的化合物：
Figure PCTCN2018094610-appb-000007
环A、R 1～R 9、n、s和t如通式(I)中所定义。
在本发明另一个优选的实施方案中，所述的通式(II)所示化合物为如下通式(II’)所示的化合物：
Figure PCTCN2018094610-appb-000008
环A、R 1、R 4～R 7、n、s和t如通式(II)中所定义。
在本发明一个优选的实施方案中，所述的通式(I)所示的化合物，其中环A选自苯基、吡啶基、咪唑基、吡唑基和吗啉基。
在本发明一个优选的实施方案中，所述的通式(I)所示的化合物，其中
Figure PCTCN2018094610-appb-000009
选自：
Figure PCTCN2018094610-appb-000010
Figure PCTCN2018094610-appb-000011
在本发明一个优选的实施方案中，所述的通式(I)所示的化合物为通式(III)所示的化合物：
Figure PCTCN2018094610-appb-000012
其中：
R 1、R 5～R 7、n和t如通式(I)中所定义。
在本发明一个优选的实施方案中，所述的通式(I)所示的化合物为通式(IV)所示的化合物：
Figure PCTCN2018094610-appb-000013
其中：
R 1、R 5～R 7、n和t如通式(I)中所定义。
在本发明一个优选的实施方案中，所述的通式(I)所示的化合物，其中R 1为氢原子、卤素和烷基。
在本发明一个优选的实施方案中，所述的通式(I)所示的化合物，其中R 5选自烷基、NR 10R 11或环烷基，其中所述的烷基或环烷基各自独立地任选被选自羟基、卤素、烷基、氨基、环烷基和杂环基中的一个或多个取代基所取代；R 10和R 11如通式(I)中所定义。
在本发明一个优选的实施方案中，所述的通式(I)所示的化合物，其中R 5选自乙基、环丙基、环丙基甲基或-NH-环丙基。
在本发明一个优选的实施方案中，所述的通式(I)所示的化合物，其中R 6为氢原子或卤素。
在本发明一个优选的实施方案中，所述的通式(I)所示的化合物，其中R 7选自烷基、环烷基和卤代烷基。
典型的通式(I)的化合物，包括但不限于：
Figure PCTCN2018094610-appb-000014
Figure PCTCN2018094610-appb-000015
Figure PCTCN2018094610-appb-000016
或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐。
本发明的另一方面涉及一种药物组合物，其含有治疗有效剂量的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或可药用的盐，以及一种或多种药学上可接受的载体、稀释剂或赋形剂。本发明还涉及一种制备所述药物组合物的方法，其包括将通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐与药学上可接受的载体、稀释剂或赋形剂相混合。在本发明一个实施方案中，所述药物组合物进一步含有抗PD-1抗体，优选抗鼠PD-1抗体。
本发明进一步涉及通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，或包含其的药物组合物在制备ROR激动剂中的用途。
本发明进一步涉及通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，或包含其的药物组合物在作为ROR激动剂在制备用于预防和/或***或癌症的药物中 的用途。
本发明进一步涉及通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐(作为ROR激动剂)，或包含其的药物组合物与抗PD-1抗体联合在制备用于预防和/或***或癌症的药物中的用途。
本发明进一步涉及通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式、或其可药用盐，或包含其的药物组合物，其用作药物。
本发明还涉及通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式、或其可药用盐，或包含其的药物组合物，其作为ROR激动剂。
本发明还涉及通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式、或其可药用盐，或包含其的药物组合物，其作为ROR激动剂用于预防和/或***或癌症。
本发明还涉及通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式、或其可药用盐，或包含其的药物组合物与抗PD-1抗体的组合，其用于预防和/或***或癌症。
本发明还涉及一种治疗预防和/或***或癌症的方法，其包括向需要其的患者施用治疗有效剂量的作为ROR激动剂的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，或包含其的药物组合物。
本发明还涉及一种治疗预防和/或治疗预防肿瘤或癌症的方法，其包括向需要其的患者施用治疗有效剂量的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，或包含其的药物组合物和抗PD-1抗体。
含活性成分的药物组合物可以是适用于口服的形式，例如片剂、糖锭剂、锭剂、水或油混悬液、可分散粉末或颗粒、乳液、硬或软胶囊，或糖浆剂或酏剂。可按照本领域任何已知制备药用组合物的方法制备口服组合物，此类组合物可含有一种或多种选自以下的成分：甜味剂、矫味剂、着色剂和防腐剂，以提供悦目和可口的药用制剂。片剂含有活性成分和用于混合的适宜制备片剂的无毒的可药用的赋形剂。这些赋形剂可以是惰性赋形剂，造粒剂、崩解剂，粘合剂，和润滑剂，。这些片剂可以不包衣或可通过掩盖药物的味道或在胃肠道中延迟崩解和吸收，因而在较长时间内提供缓释作用的已知技术将其包衣。
也可用其中活性成分与惰性固体稀释剂或其中活性成分与水溶性载体或油溶媒混合的软明胶胶囊提供口服制剂。
水悬浮液含有活性物质和用于混合的适宜制备水悬浮液的赋形剂。此类赋形剂是悬浮剂，分散剂或湿润剂。水混悬液也可以含有一种或多种防腐剂、一种或多种着色剂、一种或多种矫味剂和一种或多种甜味剂。
油混悬液可通过使活性成分悬浮于植物油，或矿物油配制而成。油悬浮液可含有增稠剂。可加入上述的甜味剂和矫味剂，以提供可口的制剂。可通过加入抗氧化剂保存这些组合物。
本发明的药物组合物也可以是水包油乳剂的形式。油相可以是植物油，或矿物油或其混合物。适宜的乳化剂可以是天然产生的磷脂，乳剂也可以含有甜味剂、矫味剂、防腐剂和抗氧剂。此类制剂也可含有缓和剂、防腐剂、着色剂和抗氧剂。
本发明的药物组合物可以是无菌注射水溶液形式。可以使用的可接受的溶媒或溶剂有水、林格氏液和等渗氯化钠溶液。无菌注射制剂可以是其中活性成分溶于油相的无菌注射水包油微乳可通过局部大量注射，将注射液或微乳注入患者的血流中。或者，最好按可保持本发明化合物恒定循环浓度的方式给予溶液和微乳。为保持这种恒定浓度，可使用连续静脉内递药装置。这种装置的实例是Deltec CADD-PLUS.TM.5400型静脉注射泵。
本发明的药物组合物可以是用于肌内和皮下给药的无菌注射水或油混悬液的形式。可按已知技术，用上述那些适宜的分散剂或湿润剂和悬浮剂配制该混悬液。无菌注射制剂也可以是在肠胃外可接受的无毒稀释剂或溶剂中制备的无菌注射溶液或混悬液。此外，可方便地用无菌固定油作为溶剂或悬浮介质。为此目的，可使用任何调和固定油。此外，脂肪酸也可以制备注射剂。
可按用于直肠给药的栓剂形式给予本发明化合物。可通过将药物与在普通温度下为固体但在直肠中为液体，因而在直肠中会溶化而释放药物的适宜的无刺激性赋形剂混合来制备这些药物组合物。
如本领域技术人员所熟知的，药物的给药剂量依赖于多种因素，包括但并非限定于以下因素：所用具体化合物的活性、患者的年龄、患者的体重、患者的健康状况、患者的行为、患者的饮食、给药时间、给药方式、***的速率、药物的组合等；另外，最佳的治疗方式如治疗的模式、通式化合物(I)的日用量或可药用的盐的种类可以根据传统的治疗方案来验证。
发明的详细说明
除非有相反陈述，在说明书和权利要求书中使用的术语具有下述含义。
术语“烷基”指饱和脂肪族烃基团，其为包含1至20个碳原子的直链或支链基团，优选含有1至12个碳原子的烷基，更优选含有1至6个碳原子的烷基。非限制性实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁 基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,3-二甲基戊基、2,4-二甲基戊基、2,2-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、2,2-二甲基己基、3,3-二甲基己基、4,4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、正壬基、2-甲基-2-乙基己基、2-甲基-3-乙基己基、2,2-二乙基戊基、正癸基、3,3-二乙基己基、2,2-二乙基己基，及其各种支链异构体等。更优选的是含有1至6个碳原子的低级烷基，非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基等。烷基可以是取代的或非取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，所述取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基和羧酸酯基。
术语“烷氧基”指-O-(烷基)和-O-(非取代的环烷基)，其中烷基和环烷基的定义如上所述。烷氧基的非限制性实例包括：甲氧基、乙氧基、丙氧基、丁氧基、环丙氧基、环丁氧基、环戊氧基、环己氧基。烷氧基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基和羧酸酯基。
术语“环烷基”指饱和或部分不饱和单环或多环环状烃取代基，环烷基环包含3至20个碳原子，优选包含3至12个碳原子，更优选包含3至6个碳原子。单环环烷基的非限制性实例包括环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等；多环环烷基包括螺环、稠环和桥环的环烷基。
术语“螺环烷基”指5至20元的单环之间共用一个碳原子(称螺原子)的多环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子***。优选为6至14元，更优选为7至10元。根据环与环之间共用螺原子的数目将螺环烷基分为单螺环烷基、双螺环烷基或多螺环烷基，优选为单螺环烷基和双螺环烷基。更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺环烷基。螺环烷基的非限制性实例包括：
Figure PCTCN2018094610-appb-000017
术语“稠环烷基”指5至20元，***中的每个环与体系中的其他环共享毗邻的一对碳原子的全碳多环基团，其中一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子***。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠环烷基，优选为双环或三环，更优选为5元/5元或5元/6元双环烷基。稠环烷基的非限制性实例包括：
Figure PCTCN2018094610-appb-000018
术语“桥环烷基”指5至20元，任意两个环共用两个不直接连接的碳原子的全碳多环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子***。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环桥环烷基，优选为双环、三环或四环，更有选为双环或三环。桥环烷基的非限制性实例包括：
Figure PCTCN2018094610-appb-000019
所述环烷基环可以稠合于芳基、杂芳基或杂环烷基环上，其中与母体结构连接在一起的环为环烷基，非限制性实例包括茚满基、四氢萘基、苯并环庚烷基等。环烷基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基和羧酸酯基。
术语“杂环基”指饱和或部分不饱和单环或多环环状烃取代基，其包含3至20个环原子，其中一个或多个环原子为选自氮、氧或S(O) m(其中m是整数0至2)的杂原子，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。优选包含3至12个环原子，其中1～4个是杂原子；最优选包含3至8个环原子，其中1～3是杂原子；最优选包含3至6个环原子，其中1～2是杂原子。单环杂环基的非限制性实例包括吡咯烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、二氢咪唑基、二氢呋喃基、二氢吡唑基、二氢吡咯基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、 高哌嗪基、吡喃基等，优选哌啶基、哌嗪基或吗啉基。多环杂环基包括螺环、稠环和桥环的杂环基。
术语“螺杂环基”指5至20元的单环之间共用一个原子(称螺原子)的多环杂环基团，其中一个或多个环原子为选自氮、氧或S(O) m(其中m是整数0至2)的杂原子，其余环原子为碳。其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子***。优选为6至14元，更优选为7至10元。根据环与环之间共用螺原子的数目将螺杂环基分为单螺杂环基、双螺杂环基或多螺杂环基，优选为单螺杂环基和双螺杂环基。更优选为3元/6元、4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺杂环基。螺杂环基的非限制性实例包括：
Figure PCTCN2018094610-appb-000020
术语“稠杂环基”指5至20元，***中的每个环与体系中的其他环共享毗邻的一对原子的多环杂环基团，一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子***，其中一个或多个环原子为选自氮、氧或S(O) m(其中m是整数0至2)的杂原子，其余环原子为碳。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠杂环基，优选为双环或三环，更优选为5元/5元或5元/6元双环稠杂环基。稠杂环基的非限制性实例包括：
Figure PCTCN2018094610-appb-000021
术语“桥杂环基”指5至14元，任意两个环共用两个不直接连接的原子的多环杂环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子***，其中一个或多个环原子为选自氮、氧或S(O) m(其中m是整数0至2)的杂原子，其余环原子为碳。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环桥杂环基，优选为双环、三环或四环，更有选为双环或三环。桥杂环基的非限制性实例包括：
Figure PCTCN2018094610-appb-000022
所述杂环基环可以稠合于芳基、杂芳基或环烷基环上，其中与母体结构连接在一起的环为杂环基，其非限制性实例包括：
Figure PCTCN2018094610-appb-000023
等。
杂环基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基和羧酸酯基。
术语“芳基”指具有共轭的π电子体系的6至14元全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团，优选为6至10元，例如苯基和萘基。更优选苯基。所述芳基环可以稠合于杂芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为芳基环，其非限制性实例包括：
Figure PCTCN2018094610-appb-000024
芳基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。
术语“杂芳基”指包含1至4个杂原子、5至14个环原子的杂芳族体系，其中杂原子选自氧、硫和氮。杂芳基优选为5至10元，含1至3个杂原子；更优选为5元或6元，含1至2个杂原子；优选例如咪唑基、呋喃基、噻吩基、噻唑基、吡唑基、噁唑基、吡咯基、四唑基、吡啶基、嘧啶基、噻二唑、吡嗪基等，优选为咪唑基、四唑基、吡啶基、噻吩基、吡唑基或嘧啶基、噻唑基；更有选吡啶基。 所述杂芳基环可以稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环，其非限制性实例包括：
Figure PCTCN2018094610-appb-000025
杂芳基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基和羧酸酯基。
术语“卤代烷基”指被一个或多个卤素取代的烷基，其中烷基如上所定义。
术语“卤代烷氧基”指被一个或多个卤素取代的烷氧基，其中烷氧基如上所定义。
术语“羟烷基”指被羟基取代的烷基，其中烷基如上所定义。
术语“羟基”指-OH基团。
术语“卤素”指氟、氯、溴或碘。
术语“氨基”指-NH 2。
术语“氰基”指-CN。
术语“硝基”指-NO 2。
术语“氧代基”指＝O。
术语“羰基”指C＝O。
术语“羧基”指-C(O)OH。
术语“羧酸酯基”指-C(O)O(烷基)或-C(O)O(环烷基)，其中烷基、环烷基如上所定义。
术语“酰卤”指含有-C(O)-卤素的基团的化合物。
“任选”或“任选地”意味着随后所描述的事件或环境可以但不必发生，该说明包括该事件或环境发生或不发生的场合。例如，“任选被烷基取代的杂环基团”意味着烷基可以但不必须存在，该说明包括杂环基团被烷基取代的情形和杂环基团不被烷基取代的情形。
“取代的”指基团中的一个或多个氢原子，优选为最多5个，更优选为1～3个氢原子彼此独立地被相应数目的取代基取代。不言而喻，取代基仅处在它们的可能的化学位置，本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如，具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上/可药用的盐或前体药物与其他化学组分的混合物，以及其他组分例如生理学/可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。
“可药用盐”是指本发明化合物的盐，这类盐用于哺乳动物体内时具有安全性和有效性，且具有应有的生物活性。
附图说明
图1显示实施例4化合物单独施用或者与抗鼠-PD-1抗体联合用药在C57BL/6小鼠中对MC38结肠直肠肿瘤生长的影响。
具体实施方式
以下结合实施例进一步描述本发明，但这些实施例并非限制着本发明的范围。
实施例
化合物的结构是通过核磁共振(NMR)或/和质谱(MS)来确定的。NMR位移(δ)以10 -6(ppm)的单位给出。NMR的测定是用Bruker AVANCE-400核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d 6)，氘代氯仿(CDCl 3)，氘代甲醇(CD 3OD),内标为四甲基硅烷(TMS)。
MS的测定用FINNIGAN LCQAd(ESI)质谱仪(生产商:Thermo,型号：Finnigan LCQ advantage MAX)。
HPLC的测定使用安捷伦1200DAD高压液相色谱仪(Sunfire C18 150×4.6mm色谱柱)和Waters 2695-2996高压液相色谱仪(Gimini C18 150×4.6mm色谱柱)。
手性HPLC分析测定使用LC-10A vp(Shimadzu)或者SFC-analytical(Berger Instruments Inc.)。
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm～0.2mm，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm。
柱层析一般使用烟台黄海硅胶200～300目硅胶为载体。
手性制备柱层析使用Prep Star SD-1(Varian Instruments Inc.)或SFC-multigram(Berger Instruments Inc.)。
CombiFlash快速制备仪使用Combiflash Rf200(TELEDYNE ISCO)。
激酶平均抑制率及IC 50值的测定用NovoStar酶标仪(德国BMG公司)。
本发明的已知的起始原料可以采用或按照本领域已知的方法来合成，或可购买自ABCR GmbH&Co.KG，Acros Organics，Aldrich Chemical Company，韶远化学科技(Accela ChemBio Inc)、达瑞化学品、上海毕得医药科技有限公司等公司。
实施例中无特殊说明，反应能够均在氩气氛或氮气氛下进行。
氩气氛或氮气氛是指反应瓶连接一个约1L容积的氩气或氮气气球。
氢气氛是指反应瓶连接一个约1L容积的氢气气球。
加压氢化反应使用Parr 3916EKX型氢化仪和清蓝QL-500型氢气发生器或HC2-SS型氢化仪。
氢化反应通常抽真空，充入氢气，反复操作3次。
微波反应使用CEM Discover-S 908860型微波反应器。
实施例中无特殊说明，溶液是指水溶液。
实施例中无特殊说明，反应的温度为室温，为20℃～30℃。
实施例中的反应进程的监测采用薄层色谱法(TLC)，反应所使用的展开剂，纯化化合物采用的柱层析的洗脱剂的体系和薄层色谱法的展开剂体系包括：A：二氯甲烷/甲醇体系，B：正己烷/乙酸乙酯体系，溶剂的体积比根据化合物的极性不同而进行调节，也可以加入少量的三乙胺和醋酸等碱性或酸性试剂进行调节。
实施例1
N-(1-(4-(乙磺酰基)苯基)-2-羟乙基)-1-异丙基-2-(2-(三氟甲基)苄基)-1H-吲哚-5-甲酰胺1
Figure PCTCN2018094610-appb-000026
第一步
2-(2-三氟甲基)苄基)-1H-吲哚-5-甲酸甲酯1c
将1H-吲哚-5-甲酸甲酯1b(400mg，2.29mmol)，1-(溴甲基)-2-(三氟甲基)苯1a(574mg，2.4mmol)，双(乙腈)二氯化钯(II)(118mg，0.46mmol)，双环[2.2.1]-2-庚烯(429mg，4.6mmol)和碳酸氢钠(384mg，4.6mmol)加入10mL N,N-二甲基乙酰胺中，氩气氛下，加热至70℃，搅拌16小时。反应结束后，反应液倒入水中，乙酸乙酯萃取三次，合并有机相，依次用水、饱和氯化钠溶液洗涤，无水硫酸钠干燥。过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题化合物1c(570mg，产率：74.9％)。
第二步
1-异丙基-2-(2-(三氟甲基)苄基)-1H-吲哚-5-甲酸甲酯1d
将化合物1c(500mg，1.5mmol)溶于15mL N,N-二甲基甲酰胺中，加入60％氢化钠(120mg，3.0mmol)，室温搅拌反应30分钟，再加入2-碘丙烷(1.02g，6.0mmol)，密封反应管内70℃反应16小时。反应液冷却至室温后倒入水中，乙酸乙酯萃取三次，合并有机相，水洗涤一次，无水硫酸钠干燥。过滤，滤液减压浓缩，用薄层层析色谱法以展开剂体系B纯化所得残余物，得到标题化合物1d(80mg，产率：14.2％)。
第三步
1-异丙基-2-(2-(三氟甲基)苄基)-1H-吲哚-5-甲酸1e
将化合物1d(80mg，0.21mmol)溶于5mL甲醇和2mL四氢呋喃的混合溶剂中，加入3mL 4N的氢氧化钠溶液，60℃搅拌反应1小时。浓盐酸中和反应液，加入水，乙酸乙酯萃取三次，合并有机相，用饱和氯化钠溶液洗涤，无水硫酸钠干燥。过滤，滤液减压浓缩，得到粗品标题化合物1e(70mg)，产物不经纯化直接用于下一步反应。
第四步
N-(1-(4-(乙磺酰基)苯基)-2-羟乙基)-1-异丙基-2-(2-(三氟甲基)苄基)-1H-吲哚-5-甲酰胺1
将2-氨基-2-(4-乙磺酰基苯基)乙醇1f(67mg，0.29mmol，采用专利申请“WO2016061160”公开的方法制备而得)，粗品化合物1e(70mg，0.193mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(56mg，0.29mmol)，1-羟基苯并***(40mg，0.29mmol)和三乙胺(101mg，1mmol)加入10mL二氯甲烷中，室温搅拌16小时。反应液减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得到标题化合物1(40mg，产率：36.0％)。
MS m/z(ESI):573.5[M+1]。
1H NMR(400HMz,CDCl 3)δ8.12(d,1H),7.92(d,2H),7.76(d,1H),7.69(dd,1H),7.64(d,2H),7.59(d,1H),7.47-7.38(m,2H),7.14-7.09(m,2H),6.35(s,1H),5.41-5.37(m,1H),4.49-4.42(m,1H),4.35(s,2H),4.12-4.08(m,2H),3.14(q,2H),2.37(brs,1H),1.52(d,6H),1.32(t,3H)。
实施例2
2-(4-氯-2-(三氟甲基)苄基)-N-(1-(4-(乙磺酰基)苯基)-2-羟乙基)-1-(2-氟代乙基)-1H-吲哚-5-甲酰胺2
Figure PCTCN2018094610-appb-000027
Figure PCTCN2018094610-appb-000028
第一步
2-(4-氯-2-(三氟甲基)苄基)-1H-吲哚-5-甲酸甲酯2b
将化合物1b(7g，39.96mmol)，1-(溴甲基)-4-氯-2-(三氟甲基)苯2a(13.11g，47.95mmol)溶于200mL N,N-二甲基乙酰胺中，加入双(乙腈)二氯化钯(II)(2.07g，7.99mmol)，双环[2.2.1]-2-庚烯(3.76g，39.96mmol)和碳酸钠(8.47g，79.92mmol)，氩气氛下，加热至80℃搅拌反应17小时。冷却反应液，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题化合物2b(13g，产率：88.47％)。
MS m/z(ESI):368.1[M+1]。
第二步
2-(4-氯-2-(三氟甲基)苄基)-1-(2-氟代乙基)-1H-吲哚-5-甲酸甲酯2c
将化合物2b(0.3g,815.77μmol)，1-溴-2-氟乙烷(310.7mg,2.45mmol)溶于10mL N,N-二甲基甲酰胺，加入碳酸铯(797.38mg,2.45mmol)，微波条件下100℃反应1小时。冷却反应，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题化合物2c(0.25g，产率：74.06％)。
MS m/z(ESI):414.1[M+1]。
第三步
2-(4-氯-2-(三氟甲基)苄基)-1-(2-氟代乙基)-1H-吲哚-5-甲酸2d
将化合物2c(0.25g，604.17μmol)溶于20mL甲醇中，加入1.5mL 4N的氢氧化钠溶液，回流搅拌反应1小时。反应液冷却至室温，滴加入1M盐酸调节pH为3～4，加入水和乙酸乙酯各20mL，乙酸乙酯萃取(20mL×2)，合并有机相，无水硫酸钠干燥。过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得到标题化合物2d(0.24g，产率：99.4％)。
MS m/z(ESI):400.1[M+1]。
第四步
2-(4-氯-2-(三氟甲基)苄基)-N-(1-(4-(乙磺酰基)苯基)-2-羟乙基)-1-(2-氟代乙基)-1H-吲哚-5-甲酰胺2
将化合物2d(10mg，25.01μmol)溶于2mL N,N-二甲基甲酰胺中，加入化合物1f(8.67mg，37.83μmol)和N,N-二异丙基乙胺(6.47mg，50.03μmol)，再加入2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(11.77mg，50.03μmol)，室温搅拌反应2小时。减压浓缩反应液，用高效液相色谱法纯化所得残余物，制得标题化合物2(7.9mg，51.7％)。
MS m/z(ESI):611.5[M+1]。
1H NMR(400MHz,CDCl 3)δ8.13(s,1H),7.93-7.90(m,2H),7.77-7.75(m,2H),7.64-7.62(m,2H),7.47-7.45(m,1H),7.37-7.35(m,1H),7.16-7.14(m,1H),7.13-7.11(m,1H),6.33(s,1H)，5.40-5.38(m,1H),4.70-4.68(m,1H)，4.57-4.56(m,1H)，4.37-4.35(m,1H),4.35(s,2H),4.30-4.31(m,1H),4.11-4.06(m,2H),3.16-3.11(m,2H),1.33-1.29(m,3H)。
实施例3,4
(S)-2-(4-氯-2-(三氟甲基)苄基)-N-(1-(4-(乙磺酰基)苯基)-2-羟乙基)-1-(2-氟代乙基)-1H-吲哚-5-甲酰胺3
(R)-2-(4-氯-2-(三氟甲基)苄基)-N-(1-(4-(乙磺酰基)苯基)-2-羟乙基)-1-(2-氟代乙基)-1H-吲哚-5-甲酰胺4
Figure PCTCN2018094610-appb-000029
将化合物2(120mg，0.197mmol)进行手性制备(分离条件：Superchiral S-AD(Chiralway),2cm I.D.×25cm Length,5um；流动相：二氧化碳/乙醇/二乙胺＝60/40/0.05(v/v/v)，流速：50g/min)，收集其相应组分，减压浓缩，得到标题化合物3(52mg)和标题化合物4(52mg)。
化合物3：
MS m/z(ESI):610.9[M+1]。
手性HPLC分析:保留时间7.882分钟，手性纯度：100％(色谱柱：Lux Amylose-1(AD)4.6×150mm 5um(带保护柱)；流动相：正己烷/乙醇(0.1％二乙胺)＝60/40(v/v))。 1H NMR(400MHz,CDCl 3)δ8.13(s,1H),7.93-7.90(m,2H),7.77-7.75(m,2H),7.64-7.62(m,2H),7.47-7.45(m,1H),7.37-7.35(m,1H),7.16-7.14(m,1H),7.13-7.11(m,1H),6.33(s,1H)，5.40-5.38(m,1H),4.70-4.68(m,1H)，4.57-4.56(m,1H)，4.37-4.35(m,1H),4.35(s,2H),4.31-4.30(m,1H),4.11-4.06(m,2H),3.16-3.11(m,2H),1.33-1.29(m,3H)。
化合物4：
MS m/z(ESI):611.0[M+1]。
手性HPLC分析:保留时间11.747分钟，手性纯度：100％(色谱柱：Lux Amylose-1 (AD)4.6×150mm 5um(带保护柱)；流动相：正己烷/乙醇(0.1％二乙胺)＝60/40(v/v))。 1H NMR(400MHz,CDCl 3)δ8.12(s,1H),7.93-7.91(m,2H),7.76-7.74(m,2H),7.65-7.63(m,2H),7.47-7.45(m,1H),7.37-7.35(m,1H),7.15-7.11(m,2H),6.33(s,1H)，5.39-5.38(m,1H),4.70-4.69(m,1H)，4.59-4.56(m,1H)，4.37-4.36(m,1H),4.35(s,2H),4.31-4.30(m,1H),4.11-4.06(m,2H),3.17-3.11(m,2H),2.33(brs,1H),1.34-1.30(m,3H)。
实施例5
(R)-2-(4-氯-2-(三氟甲基)苄基)-N-(1-(4-(乙磺酰基)苯基)-2-羟乙基)-6-氟-1-(2-氟代乙基)-1H-吲哚-5-甲酰胺5
Figure PCTCN2018094610-appb-000030
第一步
2-(4-氯-2-(三氟甲基)苄基)-6-氟-1H-吲哚-5-甲酸甲酯5b
将6-氟-1H-吲哚-5-甲酸甲酯5a(500mg，2.59mmol)，化合物2a(1.06g，88mmol)，双(乙腈)二氯化钯(II)(67.15mg，258.83μmol)，双环[2.2.1]-2-庚烯(487.40mg，5.18mmol)和碳酸钾(714.38mg，5.18mmol)加入20mL N,N-二甲基乙酰胺中，氩气氛下，加热至80℃，搅拌16小时。反应液冷却至室温，过滤，滤液倒入水中，乙酸乙酯萃取，合并有机相，无水硫酸钠干燥。过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题化合物5b(600mg，产率：60.1％)。
MS m/z(ESI):386.1[M+1]。
第二步
2-(4-氯-2-(三氟甲基)苄基)-6-氟-1-(2-氟代乙基)-1H-吲哚-5-甲酸甲酯5c
将化合物5b(100mg，259.24μmol)，1-氟-2-碘-乙烷(67.64mg，388.86μmol)和碳酸铯(254.32mg，777.72μmol)加入5mL乙腈中，微波条件下100℃反应1小 时。反应液倒入水中，乙酸乙酯萃取，合并有机相，无水硫酸钠干燥。过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题化合物5c(80mg，产率：71.5％)。
MS m/z(ESI):432.1[M+1]。
第三步
2-(4-氯-2-(三氟甲基)苄基)-6-氟-1-(2-氟代乙基)-1H-吲哚-5-甲酸5d
将化合物5c(80mg，185.28μmol)和氢氧化钠(37.05mg，926.39μmol)加入6mL甲醇和0.5mL水的混合溶剂中，60℃搅拌反应2小时。减压浓缩除去甲醇，所得残余物中滴加1M稀盐酸调节pH～3，乙酸乙酯萃取，有机相用无水硫酸钠干燥。过滤，滤液减压浓缩，得到粗品标题化合物5d(50mg)，产物不经纯化直接用于下一步反应。
MS m/z(ESI):418.0[M+1]。
第四步
(R)-2-(4-氯-2-(三氟甲基)苄基)-N-(1-(4-(乙磺酰基)苯基)-2-羟乙基)-6-氟-1-(2-氟代乙基)-1H-吲哚-5-甲酰胺5
将(R)-2-氨基-2-(4-(乙磺酰基)苯基)乙醇5e(16.47mg，71.81μmol，采用专利申请“WO2016061160”公开的方法制备而得)，粗品化合物5d(30mg，71.81μmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(20.57mg，107.72μmol)，1-羟基苯并***(16.39mg，107.72μmol)和N,N-二异丙基乙胺(27.84mg，215.43μmol)加入3mL N,N-二甲基甲酰胺中，室温搅拌16小时。反应液用乙酸乙酯萃取，合并有机相，无水硫酸钠干燥。过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题化合物5(19mg，产率：42.1％)。
MS m/z(ESI):629.5[M+1]。
1H NMR(400MHz,CDCl 3)δ8.26(d,1H),7.89(d,2H),7.72-7.60(m,4H),7.42(d,1H),7.11-7.03(m,2H),6.27(s,1H),5.41-5.39(m,1H),4.63-4.51(m,2H),4.27-4.19(m,4H),4.06-4.01(m,2H),3.12-3.07(m,2H),2.35(brs,1H),1.30-1.27(m,3H)。
实施例6
(R)-2-(4-氯-2-(三氟甲基)苄基)-1-环丙基-N-(1-(4-(乙磺酰基)苯基)-2-羟乙基)-6-氟-1H-吲哚-5-甲酰胺6
Figure PCTCN2018094610-appb-000031
Figure PCTCN2018094610-appb-000032
第一步
2-(4-氯-2-(三氟甲基)苄基)-1-环丙基-6-氟-1H-吲哚-5-甲酸甲酯6b
将化合物5b(100mg，259.24μmol)，环丙基硼酸6a(44.54mg，518.48μmol)，2,2’-联吡啶(48.59mg，311.09μmol)，醋酸铜(56.50mg，311.09μmol)和碳酸钠(54.95mg，518.48μmol)加入20mL四氢呋喃中，氩气氛下，60℃搅拌16小时。反应液过滤，滤液用乙酸乙酯萃取，无水硫酸钠干燥。过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题化合物6b(80mg，产率：72.47％)。
MS m/z(ESI):426.1[M+1]。
第二步
2-(4-氯-2-(三氟甲基)苄基)-1-环丙基-6-氟-1H-吲哚-5-甲酸6c
将化合物6b(90mg,211.37μmol.)和氢氧化钠(42.27mg,1.06mmol)加入6mL甲醇和0.5mL水的混合溶剂中，60℃搅拌反应2小时。减压浓缩除去甲醇，所得残余物中滴加1M盐酸调节pH～3，乙酸乙酯萃取，有机相用无水硫酸钠干燥。过滤，滤液减压浓缩，得到粗品标题化合物6c(60mg)，产物不经纯化直接用于下一步反应。
MS m/z(ESI):412.0[M+1]。
第三步
(R)-2-(4-氯-2-(三氟甲基)苄基)-1-环丙基-N-(1-(4-(乙磺酰基)苯基)-2-羟乙基)-6-氟-1H-吲哚-5-甲酰胺6
将化合物5e(16.71mg，72.86μmol)，粗品化合物6c(30mg，72.86μmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(20.87mg，109.28μmol)，1-羟基苯并***(16.63mg，109.28μmol)和N,N-二异丙基乙胺(28.25mg，218.57μmol)加入3mL N,N-二甲基甲酰胺中，室温搅拌16小时。反应液用乙酸乙酯萃取，合并有机相，无水硫酸钠干燥。过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题化合物6(15mg，产率：33.0％)。
MS m/z(ESI):623.5[M+1]。
1H NMR(400MHz,CDCl 3)δ8.23(d,1H),7.91(d,2H),7.71(d,2H),7.62(d,2H),7.42(d,1H),7.28(d,1H),7.03(d,1H),6.17(s,1H),5.40(s,1H),4.37(s,2H),4.08-4.04(m,2H),3.14-3.10(m,2H),2.98-2.90(m,1H),2.21(brs,1H),1.31-1.27(m,3H),1.14-1.12(m,2H),0.98-0.89(m,2H)。
实施例7
N-((R)-1-(4-(乙基磺酰基)苯基)-2-羟乙基)-1-(2-氟乙基)-2-((3-(三氟甲基)吗啉基)甲基)-1H-吲哚-5-甲酰胺7
Figure PCTCN2018094610-appb-000033
第一步
4-((5-溴-1H-吲哚-2-基)甲基)-3-(三氟甲基)吗啉7c
将5-溴-1H-吲哚-2-甲醛7a(120mg，0.54mmol，采用公知的的方法“Journal of Medicinal Chemistry,2014,57(2),364-377”制备而得)溶于10mL 1,2-二氯乙烷，加入3-(三氟甲基)吗啉盐酸盐7b(120mg，0.63mmol)和5滴醋酸，搅拌反应1.5小时，加入三乙酰基硼氢化钠(240mg，1.1mmol)，搅拌反应16小时。反应液中加入饱和碳酸氢钠溶液，用乙酸乙酯萃取三次，合并有机相，饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，用CombiFlash快速制备仪以洗脱剂体系B纯化，得到标题化合物7c(150mg，产率：76.5％)。
MS m/z(ESI):363[M+1]。
第二步
4-((5-溴-1-(2-氟乙基)-1H-吲哚-2-基)甲基)-3-(三氟甲基)吗啉7d
将化合物7c(80mg，0.22mmol)，1-氟-2碘乙烷(60uL),碳酸铯(200mg，0.61mmol)和10mL N,N-二甲基甲酰胺加入微波反应管。微波条件下100℃反应1小时。向反应液中加入水，用乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，用CombiFlash快速制备仪以洗脱剂体系B纯化所得残余物，得到标题化合物7d(92mg，产率：100％)。
MS m/z(ESI):409[M+1]。
第三步
1-(2-氟乙基)-2-((3-(三氟甲基)吗啉基)甲基)-1H-吲哚-5-甲酸7e
将化合物7d(28mg，68μmol)、六羰基钼(35mg，133μmol)、反式二-(m)-双[2-(二邻甲苯基膦)苄基]乙酸二钯(II)(14mg，15μmol)、三叔丁基膦四氟硼酸盐(14mg，48μmol)，1,8-二氮杂二环十一碳-7-烯(50uL)加入水(50uL)和1,4二氧六环(0.5mL)混合溶剂中，微波条件下150℃反应15分钟。反应液用CombiFlash快速制备仪以洗脱剂体系A纯化得到标题化合物7e(15mg，产率：58％)。
MS m/z(ESI):375[M+1]。
第四步
N-((R)-1-(4-(乙基磺酰基)苯基)-2-羟乙基)-1-(2-氟乙基)-2-((3-(三氟甲基)吗啉基)甲基)-1H-吲哚-5-甲酰胺7
将化合物7e(18mg，48μmol)溶于0.8mLN,N-二甲基甲酰胺中，加入化合物5e(12mg，52μmol)、N,N-二异丙基乙胺(40uL)和2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(30mg，78μmol)，搅拌反应2小时。反应液用高效液相色谱法纯化,得到标题化合物7(6mg，产率：21.4％)。
MS m/z(ESI):586[M+1]。
1H NMR(400MHz,CDCl 3)δ8.03(s,1H),7.79(d,2H),7.64(d,1H),7.51(d,2H),7.30(d,1H),7.11(d,1H),6.47(s,1H),5.24(brs,1H),4.75-4.73(m,1H),4.62-4.37(m,3H),4.12(d,1H),4.05-3.81(m,4H),3.81-3.51(m,3H),3.08-2.87(m,4H),2.38(d,1H),1.20(t,3H)。
实施例8
(R)-1-环丙基-N-(1-(4-(乙磺酰基)苯基)-2-羟乙基)-6-氟-2-((3-甲基-5-(三氟甲基)-1H-吡唑-1-基)甲基)-1H-吲哚-5-甲酰胺8
Figure PCTCN2018094610-appb-000034
Figure PCTCN2018094610-appb-000035
第一步
4-氨基-2-氟-5-碘苯甲酸甲酯8b
将4-氨基-2-氟苯甲酸甲酯(3.4g，20.2mmol，采用专利申请“WO2013068467”公开的方法制备而得)溶于30mL二氯甲烷和甲醇的混合溶剂中(V:V＝2:1)，室温下加入氯化碘(3.6g，22.2mmol)和碳酸钙(4.03g，40.4mmol)，搅拌反应2小时。反应液过滤，滤液用饱和硫代硫酸钠溶液洗涤(50mL×1)，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题化合物8b(6.5g，产率：100％)。
MS m/z(ESI):296[M+1]。
第二步
2-氟-5-碘-4-(2,2,2-三氟乙酰氨基)苯甲酸甲酯8c
将化合物8b(6.5g，20.2mmol)溶于100mL二氯甲烷中，冰浴下加入三氟乙酸酐(3.6g，22.2mmol),搅拌反应1小时。反应液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题化合物8c(5.4g，产率：69％)。
MS m/z(ESI):392[M+1]。
第三步
2-(((叔丁基二甲基硅烷基)氧基)甲基)-6-氟-1H-吲哚-5-羧酸甲酯8e
将化合物8c(2.28g，5.8mmol)和叔丁基二甲基(2-丙炔-1-基氧基)硅烷8d(1.49g，8.74mmol，采用公知的方法“Journal of the American Chemical Society,2016,138(24),7532-7535”制备而得)溶解于10mL N,N-二甲基甲酰胺中，加入二(三苯基膦)氯化钯(0.61g，0.88mmol)，碘化亚铜(0.222g，1.17mmol)和三乙胺(4.07mL，29.2mmol)，70℃搅拌反应4小时。向反应液中加入40mL水，用乙酸乙酯萃取(30mL×3)，合并有机相，饱和氯化钠溶液洗涤(30mL×1)，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题化合物8e(1.29g，产率：65％)。
MS m/z(ESI):338[M+1]。
第四步
2-(((叔丁基二甲基硅烷基)氧基)甲基)-1-环丙基-6-氟-1H-吲哚-5-羧酸甲酯8f
将化合物8e(0.633g，1.88mmol)和环丙基硼酸(1.61g，18.8mmol)溶解于5mL1,2-二氯乙烷中，加入醋酸铜(1.43g，7.88mmol)，2,2-双吡啶(1.23g，7.88mmol)和碳酸钠(0.84g，7.88mmol)，80℃搅拌反应16小时。反应液过滤，二氯甲烷洗涤滤饼，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题化合物8f(350mg，产率：50％)。
MS m/z(ESI):378[M+1]。
第五步
1-环丙基-6-氟-2-(羟甲基)-1H-吲哚-5-羧酸甲酯8g
将化合物8f(350mg，0.927mmol)溶解于10mL四氢呋喃中，冰浴下加入四丁基氟化铵四氢呋喃溶液(1.85mL，1.85mmol)，0℃搅拌反应2小时，向反应液中加入10mL水，用乙酸乙酯萃取(10mL×3)，合并有机相，饱和氯化钠溶液洗涤(10mL×1)，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题化合物8g(230mg，产率：68％)。
MS m/z(ESI):264[M+1]。
第六步
1-环丙基-6-氟-2-((3-甲基-5-(三氟甲基)-1H-吡唑-1-基)甲基)-1H-吲哚-5-羧酸甲酯8i
将化合物8g(84mg，0.32mmol)和3-甲基-5-三氟甲基吡唑8h(192mg，1.28mmol，采用公知的方法“Tetrahedron Letters,2016,57(14),1555-1559”制备而得)溶解于10mL四氢呋喃中，室温下加入三苯基膦(336mg，1.85mmol)和二乙基偶氮二羧酸酯(200uL，1.28mmol)，搅拌反应16小时。向反应液中加入30mL乙酸乙酯，依次用水(10mL)、饱和氯化钠溶液(10mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题化合物8i(49mg，产率：39％)。
MS m/z(ESI):396[M+1]。
第七步
1-环丙基-6-氟-2-((3-甲基-5-(三氟甲基)-1H-吡唑-1-基)甲基)-1H-吲哚-5-羧酸8j
将化合物8i(50mg，0.124mmol)溶解于1mL甲醇中，室温下加入2M氢氧化钾溶液(1mL，2mmol)，室温搅拌反应16小时。向反应液中加入6M盐酸调节pH至1～2，加入10mL水，用乙酸乙酯萃取(10mL×3)，合并有机相，饱和氯化钠溶液洗涤(10mL×1)，无水硫酸钠干燥，过滤，滤液减压浓缩得到粗品标题化合物8j(50mg)，产物不经纯化直接用于下步反应。
MS m/z(ESI):382[M+1]。
第八步
(R)-1-环丙基-N-(1-(4-(乙磺酰基)苯基)-2-羟乙基)-6-氟-2-((3-甲基-5-(三氟甲基)-1H-吡唑-1-基)甲基)-1H-吲哚-5-甲酰胺8
将化合物8j(3.9mg，0.01mmol)和化合物5e(4mg，0.015mmol)溶解于1mL二氯甲烷中，室温下加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(3.9mg，0.02mmol)，1-羟基苯并***(2.7mg，0.02mmol)和三乙胺(7uL,0.05mmol)，室温搅拌反应4小时，反应液减压浓缩，用高效液相色谱法纯化所得残余物，得到标题化合物8(3mg，产率：50％)。
MS m/z(ESI):593[M+1]。
实施例9
(R)-N-(1-(4-(乙磺酰基)苯基)-2-羟乙基)-6-氟-1-(2-氟乙基)-2-((3-甲基-5-(三氟甲基)-1H-吡唑-1-基)甲基)-1H-吲哚-5-甲酰胺9
Figure PCTCN2018094610-appb-000036
第一步
2-(((叔丁基二甲基硅烷基)氧基)甲基)-6-氟-1-(2-氟乙基)-1H-吲哚-5-羧酸甲酯9a
将化合物8e(0.6g，1.78mmol)溶解于5mL N,N-二甲基甲酰胺中，加入2-氟碘乙烷(0.775g，4.45mmol)和碳酸钾(0.862g，6.24mmol)，80℃搅拌反应4小时。向反应液中加入40mL水，用乙酸乙酯萃取(20mL×3)，合并有机相，饱和氯化钠溶液洗涤(30mL×1)，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题化合物9a(610mg，产率：90％)。
MS m/z(ESI):384[M+1]。
第二步
6-氟-1-(2-氟乙基)-2-(羟甲基)-1H-吲哚-5-羧酸甲酯9b
采用实施例8第五步化合物8g的合成路线，将原料化合物8f替换为化合物9a得到标题化合物9b(340mg，产率：80％)。
MS m/z(ESI):270[M+1]。
第三步
6-氟-1-(2-氟乙基)-2-((3-甲基-5-(三氟甲基)-1H-吡唑-1-基)甲基)-1H-吲哚-5-羧酸甲酯9c
采用实施例8第六步化合物8i的合成路线，将原料化合物8g替换为化合物9b得到标题化合物9c(170mg，产率：73％)。
MS m/z(ESI):402[M+1]。
第四步
6-氟-1-(2-氟乙基)-2-((3-甲基-5-(三氟甲基)-1H-吡唑-1-基)甲基)-1H-吲哚-5-羧酸9d
采用实施例8第七步化合物8j的合成路线，将原料化合物8i替换为化合物9c得到粗品标题化合物9d(150mg，产率：90％)，产物不经纯化直接用于下步反应。
MS m/z(ESI):388[M+1]。
第五步
(R)-N-(1-(4-(乙磺酰基)苯基)-2-羟乙基)-6-氟-1-(2-氟乙基)-2-((3-甲基-5-(三氟乙基)-1H-吡唑-1-基)甲基)-1H-吲哚-5-甲酰胺9
采用实施例8第八步化合物8的合成路线，将原料化合物8j替换为化合物9d得到标题化合物9(1.4mg，产率：20％)。
MS m/z(ESI):599[M+1]。
实施例10
(R)-2-(4-氯-2-(三氟甲基)苄基)-N-(1-(4-(乙磺酰基)苯基)-2-羟乙基)-1-异丙基-1H-吲哚-5-甲酰胺10
Figure PCTCN2018094610-appb-000037
Figure PCTCN2018094610-appb-000038
第一步
2-(4-氯-2-(三氟甲基)苄基)-1-异丙基-1H-吲哚-5-羧酸甲酯10a
将化合物2b(47.5mg，0.13mmol)溶于1.5mL N,N-二甲基甲酰胺中，加入60％氢化钠(32mg，0.774mmol)，加入2-碘丙烷(77.4μL，0.774mmol)，75℃反应16小时。反应液冷却至室温，加入15mL水，乙酸乙酯萃取(10mL×3)，合并有机相，饱和氯化钠溶液洗涤(10mL×3)，无水硫酸钠干燥。过滤，滤液减压浓缩，用硅胶柱色谱法以展开剂体系B纯化所得残余物，得到标题化合物10a(20mg，产率：40％)。
MS m/z(ESI):410[M+1]。
第二步
2-(4-氯-2-(三氟甲基)苄基)-1-异丙基-1H-吲哚-5-甲酸10b
采用实施例9第四步的合成路线，将原料化合物9c替换为化合物10a，制得得到粗品标题化合物10b(21mg,100％)，产物不经纯化直接用于下步反应。
MS m/z(ESI):396[M+1]。
第三步
(R)-2-(4-氯-2-(三氟甲基)苄基)-N-(1-(4-(乙磺酰基)苯基)-2-羟乙基)-1-异丙基-1H-吲哚-5-甲酰胺10
采用实施例9第五步的合成路线，将原料化合物9d替换为化合物10b，制得标题化合物10(25.2mg)。
MS m/z(ESI):607[M+1]。
1H NMR(300MHz,CDCl 3)δ8.01(s,1H),7.82(d,2H),7.68-7.43(m,4H),7.32(d,1H),7.02(s,1H),6.94(d,1H),6.24(s,1H),5.29(s,1H),4.31(q,1H),4.22(s,2H),4.00(d,2H),3.03(q,2H),1.43(d,6H),1.22(t,3H)。
实施例11
(R)-2-(4-氯-2-(三氟甲基)苄基)-1-环丙基-N-(1-(4-(乙磺酰基)苯基)-2-羟乙基)-1H-吲哚-5-甲酰胺11
Figure PCTCN2018094610-appb-000039
采用实施例6的合成路线，将原料化合物5b替换为化合物2b，制得标题化合物11(23.8mg)。
MS m/z(ESI):623[M+1]。
1H NMR(300MHz,CDCl 3)δ7.95(s,1H),7.81(d,2H),7.67-7.58(m,2H),7.53(d,3H),7.34(d,1H),7.04(bs,1H),6.95(d,1H),6.13(s,1H),5.25(m,1H),4.34(s,2H),4.12-3.93(m,3H),3.02(q,2H),2.89(b,1H),1.27-1.13(m,3H),1.09-0.88(m,4H)。
实施例12
(R)-2-(4-氯-2-(三氟甲基)苄基)-N-(1-(4-(N-环丙基胺磺酰基)苯基)-2-羟乙基)-1-(2-氟代乙基)-1H-吲哚-5-甲酰胺12
Figure PCTCN2018094610-appb-000040
第一步
N-环丙基-4-乙烯基苯磺酰胺12b
将对苯乙烯磺酸钠12a溶于40mL甲苯，室温下加入二氯亚砜(11.54g，97.00mmol)和N,N-二甲基甲酰胺(0.5mL)，加热至100℃搅拌反应2小时。冷却反应液，减压浓缩，加入二氯甲烷(100mL)，滴加环丙胺(2.22g，38.80mmol)，加完室温搅拌反应1小时。过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题化合物12b(2.0g，产率：46.2％)。
MS m/z(ESI):224[M+1]。
第二步
(R)-(1-(4-(N-环丙基胺磺酰基)苯基)-2-羟乙基)氨基甲酸叔丁酯12c
将氢氧化钠(1.07g，26.87mmol)溶于15mL水中，取5mL溶解二水合锇酸钾(132.00mg，358.28μmol)备用，室温下将叔丁基氨基甲酸酯(3.67g，31.35mmol) 溶于100mL正丙醇中，与上述氢氧化钠水溶液混合，室温滴加叔丁基次氯酸酯(2.92g，26.87mmol)，加完搅拌5分钟，加入氢化奎尼定1,4-(2,3-二氮杂萘)二醚(418.64mg，537.42μmol)，室温搅拌反应10分钟。滴加预制的20mL化合物12b(2.0g，8.96mmol)的正丙醇溶液和5mL二水合锇酸钾氢氧化钠溶液，加完室温搅拌反应5小时。用饱和硫代硫酸钠溶液淬灭反应，乙酸乙酯萃取(1000mL×2)，合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得标题化合物12c(0.3g，产率：9.4％)。
MS m/z(ESI):357[M+1]。
第三步
(R)-4-(1-氨基-2-羟乙基)-N-环丙基苯磺酰胺12d
将化合物12c(300mg，841.67μmol)溶于10mL甲醇中，加入4mL浓盐酸，室温搅拌反应2小时。减压浓缩反应液，得标题化合物12d(215mg，99.6％)。MS m/z(ESI):257.4[M+1]。
第四步
(R)-2-(4-氯-2-(三氟甲基)苄基)-N-(1-(4-(N-环丙基磺酰胺基)苯基)-2-羟乙基)-1-(2-氟代乙基)-1H-吲哚-5-甲酰胺12
将化合物2d(100mg，250.15μmol)溶于2mL N,N-二甲基甲酰胺中，加入化合物12d(87.89mg，300.2μmol)和N,N-二异丙基乙胺(64.66mg，500.3μmol)，再加入2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(190mg，500.3μmol)，室温搅拌反应2小时。减压浓缩反应液，用高效液相色谱法纯化所得残余物，制得标题化合物12(50mg，30.3％)。
MS m/z(ESI):638[M+1]。
1H NMR(400MHz,CD 3OD)δ8.69-8.67(d,1H),8.12(s,1H),7.89-7.87(m,2H),7.80(s,1H),7.76-7.73(d,1H),7.68-7.66(m,2H),7.61-7.59(m,1H),7.49-7.47(m,1H),7.28-7.26(m,1H),6.17(s,1H),5.32-5.30(m,1H),4.73(s,1H),4.61(s,1H),4.48(s,1H),4.41-4.40(m,3H),3.95-3.93(m,2H),2.15-2.14(m,1H),1.36-1.31(m,1H),0.55-0.53(m,4H)。
实施例13
(R)-2-(4-氯-2-(三氟甲基)苄基)-N-(1-(4-((环丙基甲基)磺酰基)苯基)-2-羟乙基)-1-(2-氟代乙基)-1H-吲哚-5-甲酰胺13
Figure PCTCN2018094610-appb-000041
Figure PCTCN2018094610-appb-000042
第一步
(4-溴苯基)(环丙基甲基)硫醚13c
将4-溴苯硫酚13a(2.00g，10.58mmol)溶于15mL N,N-二甲基甲酰胺中，加入碳酸钾(1.61g，11.64mmol)和溴甲基环丙烷13b(1.57g，11.64mmol)，
氩气保护，室温搅拌反应16小时。过滤，减压浓缩滤液，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，制得标题化合物13c(2.5g，97.2％)。
第二步
1-溴-4-((环丙基甲基)磺酰基)苯13d
将化合物13c(2.57g，10.58mmol)溶于50mL二氯甲烷中，放入冰水浴中冷却，加入间氯过氧苯甲酸(4.60g，26.42mmol)，室温搅拌反应16小时。过滤，减压浓缩反应液，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，制得标题化合物13c(2.9g，88.3％)。
MS m/z(ESI):292[M+18]。
第三步
1-((环丙基甲基)磺酰基)-4-乙烯基苯13f
将4-(环丙基甲基)磺酰基溴苯13d(2.48g，9.01mmol)溶于80mL 1,4-二氧六环中，加入10mL水，加入乙烯基硼酸频哪醇酯13e(2.78g，18.03mmol)和四三苯基膦钯(520.49mg，450.64μmol)，再加入碳酸铯(5.88g，18.03mmol)，氩气保护，加热至80℃搅拌反应2小时。减压浓缩反应液，用高效液相色谱法纯化所得残余物，制得标题化合物13f(1.83g，91.3％)。
MS m/z(ESI):240[M+18]。
第四步
(R)-(1-(4-(环丙基甲基磺酰基)苯基)-2-羟乙基)氨基甲酸叔丁酯13g
将氢氧化钠(1.00g，24.70mmol)溶于15mL水中，取5mL溶解二水合锇酸钾(121.18mg，329.28μmol)备用，室温下将叔丁基氨基甲酸酯(3.38g，28.81mmol)溶于100mL正丙醇中，与上述氢氧化钠水溶液混合，室温滴加叔丁基次氯酸酯(2.68 g，24.70mmol)，加完搅拌5分钟，加入氢化奎尼定1,4-(2,3-二氮杂萘)二醚(384.64mg，493.92μmol)，室温搅拌反应10分钟。滴加预制的20mL4-环丙基甲基磺酰基苯乙烯13f(1.83g，8.23mmol)的正丙醇溶液和5mL二水合锇酸钾氢氧化钠溶液，加完室温搅拌反应5小时。用饱和硫代硫酸钠溶液淬灭反应，乙酸乙酯萃取(1000mL×2)，合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得标题化合物13g(1.3g，产率：44.43％)。
MS m/z(ESI):256[M-100+1]。
第五步
(R)-2-氨基-2-(4-((环丙基甲基)磺酰基)苯基)乙醇13h
将化合物13g(1.30g，3.66mmol)溶于10mL甲醇中，加入4mL浓盐酸，室温搅拌反应2小时。减压浓缩反应液，得标题化合物13h(0.9g，96.4％)。
第六步
(R)-2-(4-氯-2-(三氟甲基)苄基)-N-(1-(4-((环丙基甲基)磺酰基)苯基)-2-羟乙基)-1-(2-氟代乙基)-1H-吲哚-5-甲酰胺13
将化合物2d(200mg，500.29μmol)溶于5mL N,N-二甲基甲酰胺中，加入化合物13h(218.97mg，750.44μmol)和N,N-二异丙基乙胺(129.32mg，1.00mmol)，再加入2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(235.41mg，1.00mmol)，室温搅拌反应2小时。减压浓缩反应液，用高效液相色谱法纯化所得残余物，制得标题化合物13(41mg，12.8％)。
MS m/z(ESI):637[M+1]。
1H NMR(400MHz,CDCl 3)δ8.13-8.12(d,1H),7.97-7.95(m,2H),7.76-7.75(m,1H),7.65-7.63(m,2H),7.47-7.45(m,1H),7.39-7.38(d,1H),7.20-7.16(m,1H),7.13-7.11(m,1H),6.30(s,1H),5.39-5.35(m,1H),4.70-4.68(t,1H),4.59-4.56(t,1H),4.38-4.35(m,3H),4.31-4.29(m,1H),4.15-4.11(dd,1H),4.08-4.04(dd,1H),3.05-3.04(d,2H),1.09-1.05(m,1H),0.64-0.59(m,2H),0.24-0.20(m,2H)。
实施例14
(R)-N-(1-(4-((环丙基甲基)磺酰基)苯基-2-羟乙基)-2-(4-氟-2-(三氟甲基)苄基)-1-(2-氟代乙基)-1H-吲哚-5-甲酰胺14
Figure PCTCN2018094610-appb-000043
Figure PCTCN2018094610-appb-000044
第一步
2-(4-氟-2-(三氟甲基)苄基)-1H-吲哚-5-甲酸甲酯14b
将4-氟-2-三氟甲基苄溴14a(2.29g，8.90mmol)，化合物1b(1.30g，7.42mmol)，双(乙腈)二氯化钯(II)(385.05mg，1.48mmol)，双环[2.2.1]-2-庚烯(698.67mg，7.42mmol)和碳酸钠(1.57g，14.84mmol)加入20mL N,N-二甲基乙酰胺中，氩气氛下，加热至80℃，搅拌16小时。反应液冷却至室温，过滤，滤液倒入水中，乙酸乙酯萃取，合并有机相，无水硫酸钠干燥。过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题化合物14b(2.0g，产率：76.7％)。MS m/z(ESI):350[M-1]。
第二步
2-(4-氟-2-(三氟甲基)苄基)-1-(2-氟代乙基)-1H-吲哚-5-甲酸甲酯14c
将化合物14b(140mg，398.53μmol)，1-氟-2-碘-乙烷(151.2mg，1.20mmol)和碳酸铯(389.54mg，1.20mmol)加入15mL乙腈中，微波条件下100℃反应1小时。反应液倒入水中，乙酸乙酯萃取，合并有机相，无水硫酸钠干燥。过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题化合物14c(135mg，产率：85.25％)。
MS m/z(ESI):396[M-1]。
第三步
2-(4-氟-2-(三氟甲基)苄基)-1-(2-氟代乙基)-1H-吲哚-5-甲酸14d
将化合物14c(135mg，339.76μmol)和氢氧化钠(37.05mg，926.39μmol)加入6mL甲醇和0.5mL水的混合溶剂中，60℃搅拌反应2小时。减压浓缩除去甲醇，所得残余物中滴加1M稀盐酸调节pH～3，乙酸乙酯萃取，有机相用无水硫酸钠干燥。过滤，滤液减压浓缩，得到粗品标题化合物14d(130mg)，产物不经纯化直接用于下一步反应。
MS m/z(ESI):382[M-1]。
第四步
(R)-N-(1-(4-((环丙基甲基)磺酰基)苯基-2-羟乙基)-2-(4-氟-2-(三氟甲基)苄 基)-1-(2-氟代乙基)-1H-吲哚-5-甲酰胺14
将化合物14d(300mg，782.65μmol)溶于5mL N,N-二甲基甲酰胺中，加入化合物13h(342.56mg，1.17mmol)和N,N-二异丙基乙胺(202.3mg，1.57mmol)，再加入2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(594.82mg，1.57mmol)，室温搅拌反应2小时。减压浓缩反应液，用高效液相色谱法纯化所得残余物，制得标题化合物14(200mg，41.2％)。
MS m/z(ESI):621[M+1]。
1H NMR(400MHz,CDCl 3)δ8.13-8.12(d,1H),7.94-7.92(m,2H),7.77-7.74(m,1H),7.63-7.61(m,2H),7.50-7.47(m,1H),7.36-7.34(d,1H),7.25-7.23(m,1H),7.20-7.14(m,1H),6.30(s,1H),5.39-5.35(m,1H),4.69-4.67(t,1H),4.58-4.55(t,1H),4.38-4.35(m,3H),4.32-4.29(m,1H),4.12-4.08(dd,1H),4.05-4.01(dd,1H),3.05-3.02(d,2H),1.05-0.98(m,1H),0.64-0.59(m,2H),0.24-0.20(m,2H)。
实施例15
(R)-2-(4-氯-2-(三氟甲基)苄基)-N-(1-(4-(环丙基磺酰基)苯基)-2-羟乙基)-1-(2-氟代乙基)-1H-吲哚-5-甲酰胺15
Figure PCTCN2018094610-appb-000045
第一步
1-((环丙基)磺酰基)-4-乙烯基苯15b
将4-环丙基磺酰基溴苯15a(315mg，1.21mmol)溶于20mL 1,4-二氧六环中，加入5mL水，加入化合物13e(223mg，1.45mmol)和四三苯基膦钯(55.8mg，48.25μmol)，再加入碳酸铯(786.5mg，2.41mmol)，氩气保护，加热至80℃搅拌反应2小时。减压浓缩反应液，用高效液相色谱法纯化所得残余物，制得标题化合物15b(210mg，83.6％)。
MS m/z(ESI):226[M+18]
第二步
(R)-(1-(4-(环丙基磺酰基)苯基)-2-羟乙基)氨基甲酸叔丁酯15c
将氢氧化钠(121mg，3.02mmol)溶于15mL水中，取5mL溶解二水合锇酸钾(14.84mg，40.33μmol)备用，室温下将叔丁基氨基甲酸酯(413.3mg，3.53mmol)溶于10mL正丙醇中，与上述氢氧化钠水溶液混合，室温滴加叔丁基次氯酸酯(328.4mg，3.02mmol)，加完搅拌5分钟，加入氢化奎尼定1,4-(2,3-二氮杂萘)二醚(47.13mg，60.5μmol)，室温搅拌反应10分钟。滴加10mL化合物15b(0.21g，1.01mmol)正丙醇溶液和5mL二水合锇酸钾氢氧化钠溶液，加完室温搅拌反应5小时。用饱和硫代硫酸钠溶液淬灭反应，乙酸乙酯萃取(50mL×2)，合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得标题化合物15c(133mg，产率：38.6％)。
MS m/z(ESI):242[M-100+1]
第三步
(R)-2-氨基-2-(4-((环丙基)磺酰基)苯基)乙醇15d
将化合物15c(133mg，389.56μmol)溶于10mL甲醇中，加入4mL浓盐酸，室温搅拌反应2小时。减压浓缩反应液，得标题化合物15d(90mg，96.4％)。
第四步
(R)-2-(4-氯-2-(三氟甲基)苄基)-N-(1-(4-(环丙基磺酰基)苯基)-2-羟乙基)-1-(2-氟代乙基)-1H-吲哚-5-甲酰胺15
将化合物2d(150mg，375.22μmol)溶于5mL N,N-二甲基甲酰胺中，加入化合物15d(90.54mg，375.22μmol)和N,N-二异丙基乙胺(97.00mg，750.44μmol)，再加入2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(285.41mg，750.44μmol)，室温搅拌反应2小时。减压浓缩反应液，用高效液相色谱法纯化所得残余物，制得标题化合物15(100mg，42.8％)。
MS m/z(ESI):621[M-1]。
1H NMR(400MHz,CDCl 3)δ8.13(s,1H),7.94-7.92(m,2H),7.77-7.75(m,2H),7.64-7.62(m,2H),7.48-7.45(m,1H),7.38-7.36(m,1H),7.15-7.12(m,2H),6.34(s,1H),5.41-5.38(m,1H),4.70-4.68(t,1H),4.60-4.56(t,1H),4.38-4.36(m,3H),4.31-4.29(m,1H),4.16-4.12(dd,1H),4.09-4.05(dd,1H),2.51-2.46(m,1H),1.41-1.37(m,2H),1.09-1.05(m,2H)。
实施例16
(R)-2-(4-氯-2-(三氟甲基)苄基)-N-(1-(4-(乙磺酰基)苯基)-2-甲氧基乙基)-1-(2-氟代乙基)-1H-吲哚-5-甲酰胺16
Figure PCTCN2018094610-appb-000046
Figure PCTCN2018094610-appb-000047
第一步
(R)-(1-(4-(乙磺酰基)苯基)-2-羟乙基)氨基甲酸叔丁酯16a
将化合物5e(50mg，218.06μmol)溶于6mL二氯甲烷中，0℃下加入三乙胺(44.63mg,436.12μmol)和二碳酸二叔丁酯(95.07mg,436.12μmol)，搅拌反应1小时，加入冰水淬灭反应，乙酸乙酯萃取，有机相用无水硫酸钠干燥。过滤，滤液减压浓缩，粗品用薄层色谱法以洗脱剂体系B纯化得化合物16b(45mg,产率:62.6％)。
MS m/z(ESI):230.2[M-100+1]。
第二步
(R)-(1-(4-(乙基磺酰基)苯基)-2-甲氧基乙基)氨基甲酸叔丁酯16b
将化合物16a(50mg，151.79μmol)溶于6mL四氢呋喃中，0℃下加入氢化钠(11.63mg,303.57μmol)搅拌反应10分钟，加入碘甲烷(23.70mg,166.96μmol)，搅拌反应2小时，加入冰水淬灭反应，乙酸乙酯萃取，有机相用无水硫酸钠干燥。过滤，滤液减压浓缩，粗品用薄层色谱法以洗脱剂体系B纯化，得化合物16b(45mg，产率:86.32％)。
第三步
(R)-1-(4-(乙基磺酰基)苯基)-2-甲氧基乙胺16c
将化合物16b(45mg，131.03μmol)溶于10mL二氯甲烷中，加入三氟乙酸(298.80mg，2.62mmol)，室温搅拌反应16小时。减压浓缩，得到粗品标题化合物16c(40mg)，产物不经纯化直接用于下一步反应。
第四步
(R)-2-(4-氯-2-(三氟甲基)苄基)-N-(1-(4-(乙磺酰基)苯基)-2-甲氧基乙基)-1-(2-氟代乙基)-1H-吲哚-5-甲酰胺16
将化合物2d(44.75mg,111.94μmol)，粗品化合物16c(40.00mg,111.94μmol)溶于20mL N,N-二甲基甲酰胺中，加入2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(31.60mg,134.32μmol)和N,N-二异丙基乙胺(43.40mg,335.81μmol)，室温搅拌16小时。反应液加水，用乙酸乙酯萃取，合并有机相，无水硫酸钠干燥。过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标 题化合物16(25mg，产率：35.73％)。
MS m/z(ESI):625.6[M+1]
1H NMR(400MHz,CDCl 3)δ8.07(s,1H),7.87-7.85(d,2H),7.73-7.71(m,2H),7.62-7.60(m,2H),7.43-7.41(m,1H),7.34-7.31(m,1H),7.15-7.08(m,2H),6.28(s,1H),5.44-5.40(m,1H),4.66-4.64(m,1H),4.55-4.52(m,1H),4.34-4.29(m,3H),4.28-4.25(m,1H),3.83-3.74(m,2H),3.39(s,3H),3.12-3.06(m,2H),1.29-1.26(m,3H)。
实施例17(对照例)
(R)-2-(4-(三氟甲基)苄基)-N-(1-(4-(乙基磺酰基)苯基)-2-羟乙基)-1-(2-氟代乙基)-1H-吲哚-5-甲酰胺17
Figure PCTCN2018094610-appb-000048
第一步
2-(4-(三氟甲基)苄基)-1H-吲哚-5-甲酸甲酯17b
将化合物1b(1.00g，5.71mmol)，4-(三氟甲基)苄溴17a(16.40g，6.86mmol)溶于15mL N,N-二甲基乙酰胺中，加入双(乙腈)二氯化钯(II)(296.17m g，1.14mmol)，双环[2.2.1]-2-庚烯(1.1g，11.68mmol)和碳酸钠(1.22g，11.51mmol)，氩气氛下，加热至80℃搅拌反应17小时。冷却反应液，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题化合物17b(1.60g，产率：84.10％)。
MS m/z(ESI):334.1[M+1]。
第二步
2-(4-(三氟甲基)苄基)-1-(2-氟代乙基)-1H-吲哚-5-甲酸甲酯17c
将化合物17b(500mg，1.50mmol)，1-氟-2-溴-乙烷(381.0mg，3.0mmol)和碳酸铯(976mg，2.0mmol)加入10mL乙腈中，微波条件下100℃反应1小时。反应液倒入水中，乙酸乙酯萃取，合并有机相，无水硫酸钠干燥。过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题化合物17c(500mg，产率：87.86％)。
MS m/z(ESI):380.1[M+1]。
第三步
2-(4-(三氟甲基)苄基)-1-(2-氟代乙基)-1H-吲哚-5-甲酸17d
将化合物17c(500mg，1.32mmol)和氢氧化钠(527.2mg，13.18mmol)加入10mL甲醇和2mL水的混合溶剂中，60℃搅拌反应2小时。减压浓缩除去甲醇，所得残余物中滴加1M稀盐酸调节pH～3，乙酸乙酯萃取，有机相用无水硫酸钠干燥。过滤，滤液减压浓缩，得到粗品标题化合物17d(500mg)，产物不经纯化直接用于下一步反应。
MS m/z(ESI):366.1[M+1]。
第四步
(R)-2-(4-(三氟甲基)苄基)-N-(1-(4-(乙基磺酰基)苯基)-2-羟乙基)-1-(2-氟代乙基)-1H-吲哚-5-甲酰胺17
将(R)-2-氨基-2-(4-(乙磺酰基)苯基)乙醇5e(76mg，0.33mmol)，粗品化合物17d(100mg，0.27mmol)，O-(7-氮杂苯并***-1-基)-N,N,N’N’-四甲基脲六氟磷酸酯(125mg，0.33mmol)，和N,N-二异丙基乙胺(54mg，0.42mmol)加入5mL N,N-二甲基甲酰胺中，室温搅拌16小时。反应液用乙酸乙酯萃取，合并有机相，无水硫酸钠干燥。过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题化合物17(46mg，产率：29.14％)。
MS m/z(ESI):577.1[M+1]。
1H NMR(400MHz,CD 3OD)δ8.65(d,1H),8.12(s,1H),7.88(d,2H),7.86(d,3H),7.63(d,2H),7.46-7.43(m 3H),6.3(s,1H),5.3(d,1H),4.64-4.62(t,1H),4.52-4.5(t,1H),4.47-4.45(t,1H),4.41-4.38(t,1H),4.10(d,2H),3.92(d,2H),3.22-3.16(m 2H),1.26-1.19(m,3H)。
生物学评价
以下结合测试例进一步描述解释本发明，但这些实施例并非意味着限制本发明的范围。
测试例1、本发明化合物对RORγ体外活性的测定
一、实验材料及仪器
1.
Figure PCTCN2018094610-appb-000049
TR-FRET RORγ共激活体系(Life Technologies)
2.RORγLBD(AB Vector)
3.DMSO(SigmaAldrich)
4.酶标仪(Tecan)
二、实验步骤
采用LanthaScreen TR-FRET(时间分辨荧光能量共振转移)RORγ共激活体系筛选本发明的化合物对RORγ活性的调节。
首先配制完整缓冲液D(complete TR-FRET Coregulator)(Life Technologies)包含终浓度5mM DTT。DMSO终浓度为2％。将待测化合物在含有2％DMSO的完整缓冲液D中连续稀释为2x终浓度，最高剂量为的60μm。10μl/孔加入384孔板的试验孔(PerkinElmer)。每个检测化合物在相同浓度下设置2个平行对照孔。准备4X RORγLBD(AB Vector)。使用完整缓冲液D稀释RORγLBD浓度为1ng/μL。5μl/孔加入384孔测定板的试验孔。阴性对照孔为5μL完整缓冲液D，无RORγLBD。使用完全缓冲液D配制含有0.6μM荧光素-D22(4X)和8nM铽(Tb)标记的抗GST抗体(4X)(Life Technologies)混合液，将5μL混合液加入到384孔板中。总反应体系为20μL。在振荡器上轻轻混匀该384孔板并在室温下避光孵育2-4小时。
使用Tecan Infinite M1000检测荧光读数,通过GraphPad Prism 6.0软件绘制发射波长520nm/495nm的比值与化合物浓度的对数曲线，计算待测化合物的EC 50/IC 50值。
本发明化合物对RORγ体外活性通过以上的试验进行测定，测得的EC 50值见表1。
表1 本发明化合物对RORγ体外活性的EC 50值和对照例的IC 50值。
Figure PCTCN2018094610-appb-000050
Figure PCTCN2018094610-appb-000051
a:如果是激动剂，数值标示为EC 50；如果是反激动剂，数值标示为IC 50；
b:如果是激动剂，数据表示为Emax(％)；如果是反激动剂，数值表示为最大抑制率。
结论：本发明化合物对RORγ体外活性具有明显的激动作用，同时申请人发现环A邻位基团的变化会改变其调节效果，当环A邻位基团为位阻较小的基团(例如H)时的实施例17为反激动剂。
测试例2、本发明化合物对IL-17A酶联免疫定量分析活性测定
一、实验材料及仪器
1.人外周血单核细胞(PBMC)(Zenbio)
2.淋巴细胞培养基(Zenbio)
3.TexMACS(Miltenyi Biotec)
4.人Cytostim(Miltenyi Biotec)
5.人IL-17酶联免疫试剂盒(R&D***)
6.CO 2培养箱(Fisher Scientific)
7.离心机(Fisher Scientific)
8.96孔细胞培养板(Fisher Scientific)
9.酶标仪(Tecan)
二、实验步骤
将冻存的人外周血单核细胞(PBMC)在预热的淋巴细胞培养基中快速复苏，离心1000rpm，10min，除去细胞培养上清，将细胞轻轻悬浮于TexMACS培养基中，计数细胞。在细胞悬液中按比例加入T细胞激活试剂cytostim(10μl/ml)，然后以1×10 5外周血单核细胞/孔的密度将细胞种植于96孔细胞培养板中。使用TexMACS培养基梯度稀释待测化合物，分别加入各实验孔中，每组2-3个平行孔。准备只含细胞不含cytostim的阴性对照孔，以得到背景读数。将细胞培养板放置于5％二氧化碳37℃培养箱孵育3天。药物处理3天后收取细胞培养上清液，离心去除悬浮物。然后使用IL-17A酶联免疫试剂盒定量上清液中IL-17A。使用GraphPad Prism 6.0计算待测化合物的EC 50值。
本发明化合物对IL-17A酶联免疫定量分析通过以上的试验进行测定，测得的EC 50值见表2。
表2 本发明化合物对IL-17A酶联免疫定量分析的EC 50值
实施例编号 EC 50(nM) Emax(％)
2 90 82％
3 169 136％
4 85 93％
11 276 72％
12 25 71％
13 27 65％
14 42 99％
16 8 99％
结论：本发明化合物对IL-17A酶联免疫定量分析活性具有明显的调节作用。
药代动力学评价
测试例3、本发明化合物的小鼠药代动力学测试
1、摘要
以小鼠为受试动物，应用LC/MS/MS法测定了小鼠灌胃给予实施例4化合物后不同时刻血浆中的药物浓度。研究本发明化合物在小鼠体内的药代动力学行为，评价其药动学特征。
2、试验方案
2.1试验药品
实施例4化合物。
2.2试验动物
C57小鼠9只为1组，雌性，购自上海杰思捷实验动物有限公司，动物生产许可证号：SCXK(沪)2013-0006。
2.3药物配制
称取一定量药物，加5％体积的DMSO、5％体积的吐温80和90％生理盐水配置成0.1mg/ml无色澄清透明液体。
2.4给药
C57小鼠禁食过夜后灌胃给药，给药剂量均为2.0mg/kg，给药体积均为0.2ml/10g。
3、操作
小鼠灌胃给药实施例4化合物，于给药前及给药后0.25，0.5，1.0，2.0，4.0，6.0，8.0，11.0，24.0小时采血0.1ml(每个时间点3只动物)，置于肝素化试管中，3500转/分钟离心10分钟分离血浆，于-20℃保存。
测定不同浓度的药物灌胃给药后小鼠血浆中的待测化合物含量：取给药后各时刻的小鼠血浆25μl，加入内标溶液喜树碱80μl(100ng/mL)，乙腈200μl，涡旋混合5分钟，离心10分钟(3600转/分钟)，血浆样品取上清液1μl进行LC/MS/MS分析。
4、药代动力学参数结果
本发明化合物的药代动力学参数如下：
Figure PCTCN2018094610-appb-000052
Figure PCTCN2018094610-appb-000053
结论：本发明化合物的药代吸收较好，具有药代动力学优势。
药效学评价
测试例4、RORγ激动剂在同种型MC38结肠直肠肿瘤小鼠模型的药效
1.实验目的
用MC38小鼠模型来评估实施例4化合物对MC38肿瘤生长的抑制作用。
2.实验方法和实验材料
2.1.实验动物和饲养条件
实验用雌性C57BL/6小鼠，购自Charles River Lab(美国)，购入时20-25克，7-9周龄。10只/笼饲养，温度23±1℃恒温，湿度50～60％，自由进食进水。一切按照实验动物护理和使用委员会(IACUC批准指南)进行护理和使用。动物购进后，进行7天适应性饲养后开始实验。
2.2.实验药品
实施例4化合物；
抗鼠PD-1(CD279)抗体购自BioXcell(克隆RMP1-14；目录编号BP0146)；
IgG2a同型对照抗体购自BioXcell(克隆2A3；目录编号BE0089)。
2.3.实验设计和实验方法
2.3.1.动物分组：
小鼠适应性饲养后，分组如下：
分组 n 给药方式 给药方案
IgG2a同型对照抗体加载体对照组 8 腹腔注射/口服 Q3dx4/BIDx21
抗鼠PD-1抗体 8 腹腔注射 Q3dx4
实施例4化合物 8 口服 BIDx21
抗鼠PD-1抗体加实施例4化合物 8 腹腔注射/口服 Q3dx4/BIDx21
注：1.Q3dx4代表每隔三天给药，总共给四次，固定在第5，8，11，14天给药；
2.BIDx21代表每天给药2次，连续给药21天；
2.3.2.实验方法：
实验使用雌性C57BL/6小鼠(20-25克，7-9周龄)。通过检测同种型MC38结肠直肠肿瘤(Synta Pharmaceuticals)在自交系C57BL/6小鼠的生长情况评估单独施用实施例4化合物或实施例4化合物与抗鼠-PD-1抗体联合施用的体内抗肿瘤活性。将五十万(5×10  5)MC38细胞植入每只小鼠的右侧腹部皮下，待5天后当肿瘤生长至40-80mm 3后，将小鼠随机分组，每天施用实施例4化合物(30mg/kg) 2次，连续给药21天。在抗体单用或与实施例4化合物联合施用治疗实验中，固定在第5、8、11、14天分别对携带MC38肿瘤的小鼠腹腔(i.p.)注射抗鼠PD-1(CD279)抗体(BioXcell)(5mg/kg)。对照组是载体CMC-Na药剂配方与IgG2a同型对照抗体。
2.4.数据表达：
用卡尺在三个维度中测量肿瘤体积，然后根据下式计算：肿瘤体积(mm 3)＝l×w×h×0.5236，其中，1表示肿瘤长度，w表示肿瘤的宽度，h表示肿瘤的高度，单位为毫米。肿瘤生长抑制率TGI％＝100x(TV 对照-TV 肿瘤)/(TV 对照-TV 初始)，其中TV 对照＝对照组的肿瘤体积；TV 肿瘤＝治疗组的肿瘤体积；TV 初始＝5天时起始肿瘤体积。
3.结果和讨论：
如图1所示，单独施用30mg/kg实施例4化合物时，TGI为40％。单独注射抗鼠PD-1(CD279)抗体(5mg/kg)时，TGI为51％。当与抗鼠PD-1单克隆抗体(5mg/kg)联合施用时，实施例4化合物(30mg/kg)表现出协同效应(TGI为63％。这些数据表明了在同基因的MC38结肠直肠肿瘤模型中，单独施用实施例4化合物表现出抑瘤活性，同时实施例4化合物与PD-1抗体联合施用表现出协同作用，这也表明实施例4化合物具有与RORγ激活(而非抑制)一致的生物活性，为提高免疫治疗的疗效开辟了新途径。

Claims (16)

  1. 一种通式(I)所示的化合物：
    Figure PCTCN2018094610-appb-100001
    或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用的盐，
    其中：
    Figure PCTCN2018094610-appb-100002
    为双键或单键；
    G 1、G 2和G 3相同或不同，且各自独立地选自C、CH、CH 2或N；
    环A选自芳基、杂芳基、环烷基和杂环基；
    R 1相同或不同，且各自独立地选自氢原子、卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、氰基、氨基、硝基、羟基和羟烷基；
    R 2为卤代烷基；
    R 3选自烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、卤素、氰基、氨基、硝基、羟基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自羟基、卤素、烷基、烷氧基和氨基中的一个或多个取代基所取代；
    R 4相同或不同，且各自独立地选自氢原子、卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基；
    R 5选自氢原子、烷基、卤代烷基、氨基、羟基、羟烷基、环烷基、杂环基、NR 10R 11、芳基和杂芳基，其中所述的烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自羟基、卤素、烷基、氨基、环烷基和杂环基中的一个或多个取代基所取代；
    R 6相同或不同，且各自独立地选自氢原子、卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基；
    R 7选自氢原子、烷基、卤代烷基、环烷基和杂环基，其中所述的烷基任选被选自卤素、硝基、环烷基和杂环基中的一个或多个取代基所取代；
    R 8和R 9相同或不同，且各自独立地选自氢原子、卤素、烷基、卤代烷基、烷氧基、氰基、氨基、硝基、羟基和羟烷基；
    R 10和R 11相同或不同，且各自独立地选自氢原子、烷基、卤代烷基、氨基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基；
    n为0、1、2、3或4；
    s为0、1、2或3；且
    t为0、1、2或3。
  2. 根据权利要求1所述的通式(I)所示的化合物，其为通式(IA)所示的化合物：
    Figure PCTCN2018094610-appb-100003
    其中：
    R a为氢原子或烷基；
    Figure PCTCN2018094610-appb-100004
    环A、G 1～G 3、R 1、R 4～R 7、n、s和t如权利要求1中所定义。
  3. 根据权利要求1或2所述的通式(I)所示的化合物，其为通式(II)所示的化合物：
    Figure PCTCN2018094610-appb-100005
    其中：
    Figure PCTCN2018094610-appb-100006
    环A、G 1～G 3、R 1、R 4～R 7、n、s和t如权利要求1中所定义。
  4. 根据权利要求1～3中任一项所述的通式(I)所示的化合物，其中环A选自 苯基、吡啶基、咪唑基、吡唑基和吗啉基。
  5. 根据权利要求1～4中任一项所述的通式(I)所示的化合物，其为通式(III)所示的化合物：
    Figure PCTCN2018094610-appb-100007
    其中：
    R 1、R 5～R 7、n和t如权利要求1中所定义。
  6. 根据权利要求1～5中任一项所述的通式(I)所示的化合物，其为通式(IV)所示的化合物：
    Figure PCTCN2018094610-appb-100008
    其中：
    R 1、R 5～R 7、n和t如权利要求1中所定义。
  7. 根据权利要求1～6中任一项所述的通式(I)所示的化合物，其中R 1选自氢原子、卤素和烷基。
  8. 根据权利要求1～7中任一项所述的通式(I)所示的化合物，其中R 5选自烷基、NR 10R 11或环烷基，其中所述的烷基或环烷基各自独立地任选被选自羟基、卤素、烷基、氨基、环烷基和杂环基中的一个或多个取代基所取代；R 10和R 11如权利要求1中所定义。
  9. 根据权利要求1～8中任一项所述的通式(I)所示的化合物，其中R 6为氢原子或卤素。
  10. 根据权利要求1～9中任一项所述的通式(I)所示的化合物，其中R 7选自烷基、环烷基和卤代烷基。
  11. 根据权利要求1～10中任一项所述的通式(I)所示的化合物，其选自：
    Figure PCTCN2018094610-appb-100009
  12. 一种药物组合物，其含有治疗有效量的根据权利要求1～11中任一项所述的通式(I)所示的化合物，以及一种或多种药学上可接受的载体、稀释剂或赋形剂。
  13. 根据权利要求12所述的药物组合物，其进一步含有抗PD-1抗体。
  14. 根据权利要求1～11中任一项所述的通式(I)所示的化合物或根据权利要求12所述的药物组合物在制备ROR激动剂中的用途。
  15. 根据权利要求1～11中任一项所述的通式(I)所示的化合物或根据权利要 求12所述的药物组合物作为ROR激动剂在制备用于预防和/或***或癌症的药物中的用途。
  16. 根据权利要求1～11中任一项所述的通式(I)所示的化合物或根据权利要求12所述的药物组合物与抗PD-1抗体联合在制备用于预防和/或***或癌症的药物中的用途。
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CN113227048A (zh) * 2019-01-04 2021-08-06 江苏恒瑞医药股份有限公司 吲哚甲酰胺类衍生物的晶型及其制备方法
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WO2020182109A1 (zh) * 2019-03-11 2020-09-17 江苏恒瑞医药股份有限公司 氘原子取代的吲哚甲酰胺类衍生物的晶型及其制备方法
CN113365980A (zh) * 2019-03-11 2021-09-07 江苏恒瑞医药股份有限公司 氘原子取代的吲哚甲酰胺类衍生物的晶型及其制备方法
CN113365980B (zh) * 2019-03-11 2022-04-12 江苏恒瑞医药股份有限公司 氘原子取代的吲哚甲酰胺类衍生物的晶型及其制备方法
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CN112745268A (zh) * 2019-10-31 2021-05-04 江苏恒瑞医药股份有限公司 苯并咪唑衍生物的晶型及制备方法
CN112745268B (zh) * 2019-10-31 2022-09-16 江苏恒瑞医药股份有限公司 苯并咪唑衍生物的晶型及制备方法

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