WO2020182109A1 - 氘原子取代的吲哚甲酰胺类衍生物的晶型及其制备方法 - Google Patents

氘原子取代的吲哚甲酰胺类衍生物的晶型及其制备方法 Download PDF

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WO2020182109A1
WO2020182109A1 PCT/CN2020/078506 CN2020078506W WO2020182109A1 WO 2020182109 A1 WO2020182109 A1 WO 2020182109A1 CN 2020078506 W CN2020078506 W CN 2020078506W WO 2020182109 A1 WO2020182109 A1 WO 2020182109A1
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crystal form
formula
compound represented
solvent
represented
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PCT/CN2020/078506
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English (en)
French (fr)
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陈杰
尤凌峰
冯君
贺峰
刘明明
杜振兴
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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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Priority to CN202080011641.0A priority Critical patent/CN113365980B/zh
Publication of WO2020182109A1 publication Critical patent/WO2020182109A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • C07D209/12—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the crystal form of indolecarboxamide derivatives substituted by deuterium atoms and a preparation method thereof belong to the field of pharmaceuticals.
  • Retinoid-related orphan nuclear receptors (Retinoid-related orphan receptors, ROR) is a member of the nuclear receptor family and a type of ligand-dependent transcription factor. It can regulate a variety of physiological and biochemical processes, including reproductive development, Metabolism, immune system regulation, 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. 2004Dec, 3(4): 395-412), in which ROR ⁇ can be expressed in many tissues, including thymus, liver, kidney, fat and skeletal muscle (Immunity. 1998 Dec, 9(6 ):797-806.).
  • ROR ⁇ 1 is expressed in many tissues, such as thymus, muscle, kidney and liver, while ROR ⁇ t is only expressed in immune cells (Eur J Immunol. 1999 Dec , 29(12):4072-80).
  • ROR ⁇ t can regulate the survival of T cells in the process of immune cell differentiation, and can activate and promote the differentiation of CD4+ and CD8+ cells into helper T cells 17 (Th17) and cytotoxic T cells (Tc17) (J Immunol .2014 Mar 15,192(6):2564-75), among which TH17 and Tc17 cells are a type of effector cells, which promote inflammation and enhance acquisition by secreting interleukin 17 (IL-17) and other inflammatory factors (such as IL-21) Immune response and autoimmune response.
  • IL-17 interleukin 17
  • IL-21 interleukin-21
  • Th17 can also recruit cytotoxic CD8+ T cells and natural killer cells into the tumor microenvironment, thereby killing tumor cells and achieving the purpose of anti-tumor (Blood.2009 Aug 6,114(6):1141-9; Clin Cancer Res.2008 Jun 1,14(11):3254-61). Therefore, activation of ROR ⁇ t may become a new anti-tumor therapy.
  • ROR ⁇ t agonists such as the small molecule drug LYC-54143 developed by Lycera Corp.
  • Preclinical studies have shown that LYC-54143 can inhibit tumor growth through two different pathways, showing superior anti-cancer activity.
  • LYC-54143 activates ROR ⁇ t to regulate the differentiation of Th17 and Tc17 cells through traditional methods, promote the expression of IL-17 and other cytokines, and improve T cell activity.
  • activated ROR ⁇ t can regulate the expression of a variety of genes in the immune system, inhibit the expression of cell check receptor PD-1, thereby reducing immunosuppression and improving anti-cancer activity (Oncoimmunology.2016 Nov 4,5(12):e1254854; ACS Chem Biol. 2016 Apr 15,11(4):1012-8).
  • the small molecule agonist has now entered clinical phase II, there are still very few drugs related to the target agonist, and no marketed drugs have appeared.
  • the published patents include WO2015171558, WO2008152260, WO2007068580, WO2007068579, WO2005056516, WO2005056510, WO2005066116, WO00228810 still needs to continue to develop more efficient new ROR ⁇ t agonists in order to provide patients with new and effective anticancer drugs.
  • ROR agonist represented by formula (I) is described in PCT/CN2018/105008 (application date 2018.09.11), and its crystal structure is not described in the text.
  • the crystal structure of the pharmaceutical active ingredient often affects the chemical stability of the drug. Different crystallization conditions and storage conditions may lead to changes in the crystal structure of the compound, sometimes accompanied by the production of other crystalline forms. Therefore, it is necessary to in-depth study of the crystal form of the compound of formula (I) and related preparation methods to improve various properties of the compound of formula (I).
  • the disclosure provides a crystal form A of the compound represented by formula (I).
  • the X-ray powder diffraction pattern represented by the diffraction angle 2 ⁇ is at 6.315, 9.039, 9.703, 12.536, 15.165, 16.235, 17.098 and There is a characteristic peak at 21.706,
  • the crystal form A of the compound represented by formula (I) has an X-ray powder diffraction pattern expressed in diffraction angle 2 ⁇ angles at 6.315, 9.039, 9.703, 12.536, 13.573, 15.165, 16.235, 17.098 There are characteristic peaks at, 17.876, 21.406, 21.706, 23.248, 24.669 and 25.136.
  • the present disclosure provides a crystal form A of the compound represented by formula (I), and the X-ray powder diffraction pattern represented by the diffraction angle 2 ⁇ is shown in FIG. 2.
  • the step of mixing the crystal form of compound A represented by formula (I) or the compound represented by formula (I) containing crystal form A in a solvent for beating (such as beating at 5-25° C., or heating beating).
  • the solvent is selected from ethanol, isopropyl acetate, isopropanol, isopropyl ether, water, ethyl acetate, methyl tert-butyl ether, toluene, butyl acetate, n-butanol, cyclohexane, ethanol-water mixed solvent .
  • the present disclosure provides a crystal form B of the compound represented by formula (I).
  • the X-ray powder diffraction pattern expressed by diffraction angle 2 ⁇ has characteristic peaks at 9.874, 14.893, 15.387, 19.202, 20.918, 24.179 and 25.566 .
  • the crystal form B of the compound represented by formula (I) has an X-ray powder diffraction pattern expressed in diffraction angle 2 ⁇ angles at 9.874, 14.893, 15.387, 19.202, 20.918, 22.195, 24.179, 24.689 There are characteristic peaks at, 25.566, 26.502 and 28.963.
  • the crystal form B of the compound represented by formula (I) has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ as shown in FIG. 6.
  • the invention provides a crystal form C of a compound represented by formula (I).
  • the X-ray powder diffraction pattern expressed by diffraction angle 2 ⁇ has characteristic peaks at 8.302, 11.241, 14.018, 15.861, 17.921, 19.186 and 22.874.
  • the crystal form C of the compound has an X-ray powder diffraction pattern expressed in diffraction angle 2 ⁇ angles at 7.440, 8.302, 11.241, 13.811, 14.018, 15.861, 17.921, 19.186, 22.874, 24.652, and 26.275 There are characteristic peaks everywhere.
  • the crystal form C of the compound represented by formula (I) has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ as shown in FIG. 8.
  • the present disclosure provides a crystal form D of the compound represented by formula (I).
  • the X-ray powder diffraction pattern expressed by the diffraction angle 2 ⁇ has characteristic peaks at 6.625, 8.384, 14.959, 16.453, 17.816 and 19.915.
  • the crystal form D of the compound represented by formula (I) has an X-ray powder diffraction pattern expressed by a diffraction angle of 2 ⁇ angles at 6.625, 8.384, 10.441, 11.516, 14.959, 16.453, 17.816, 19.915 There are characteristic peaks at 23.554 and 25.095.
  • the crystal form D of the compound represented by formula (I) has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ as shown in FIG. 9.
  • the present disclosure provides a crystal form E of the compound represented by formula (I), which is characterized in that: the X-ray powder diffraction pattern represented by the diffraction angle 2 ⁇ angle is at 13.824, 14.967, 15.980, 16.730, 21.684 and 25.212. Characteristic peaks.
  • the present disclosure provides a crystal form E of the compound represented by formula (I).
  • the X-ray powder diffraction pattern expressed by diffraction angle 2 ⁇ is at 12.061, 13.824, 14.967, 15.980, 16.730, 18.216 There are characteristic peaks at, 21.684, 23.256, 25.212 and 28.150.
  • the present disclosure provides a crystal form F of the compound represented by formula (I).
  • the X-ray powder diffraction pattern expressed by the diffraction angle 2 ⁇ is at 7.680, 11.319, 14.200, 15.460, 16.480, 23.000, 23.861 and 26.220. Characteristic peaks.
  • the crystal form F of the compound represented by formula (I) has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ as shown in FIG. 11.
  • the present disclosure provides a method for preparing the crystal form of compound F represented by formula (I), which comprises mixing and dissolving the compound represented by formula (I) in a first solvent (such as heating and dissolving), and adding dropwise a second solvent to crystallize Step;
  • the first solvent is tetrahydrofuran;
  • the second solvent is water;
  • the volume ratio of the first solvent to the second solvent is selected from 20:1-2:1, including 20:1, 18:1, 16 :1, 14:1, 12:1, 10:1, 8:1, 6:1, 4:1, 2:1 or any ratio between any two values.
  • the present disclosure provides a crystal form G of the compound represented by formula (I).
  • the X-ray powder diffraction pattern expressed by diffraction angle 2 ⁇ is at 7.480, 9.400, 12.201, 13.238, 15.259, 16.300, 17.859, 18.900, 22.500 And there are characteristic peaks at 25.320.
  • the crystal form G of the compound represented by formula (I) has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ as shown in FIG. 12.
  • the method for preparing the crystal form of compound G represented by formula (I) provided in the present disclosure further includes a step of cooling down.
  • the present disclosure provides a crystal form H of the compound represented by formula (I).
  • the X-ray powder diffraction pattern expressed by the diffraction angle 2 ⁇ has characteristic peaks at 8.265, 10.453, 12.476, 14.633, 16.774 and 17.933.
  • the crystal form H of the compound represented by formula (I) has an X-ray powder diffraction pattern expressed by a diffraction angle of 2 ⁇ angles at 8.265, 8.978, 10.453, 11.722, 12.476, 14.633, 16.774, 17.368 There are characteristic peaks at, 17.933 and 19.211.
  • the crystal form H of the compound represented by formula (I) has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ as shown in FIG. 13.
  • the present disclosure provides a method for preparing the H crystal form of the compound represented by formula (I), which comprises mixing a mixture of compound A crystal form and F crystal form represented by formula (I) in 2-methyltetrahydrofuran, and beating (such as The step of beating at 5 ⁇ 25°C).
  • the present disclosure provides a crystal form I of the compound represented by formula (I), which is characterized in that the X-ray powder diffraction pattern expressed by diffraction angle 2 ⁇ is at 7.098, 10.159, 12.487, 13.797, 17.119, 17.797, 18.261 And there are characteristic peaks at 24.074.
  • the crystal form I of the compound represented by formula (I) has an X-ray powder diffraction pattern expressed by diffraction angle 2 ⁇ angles at 7.098, 10.159, 12.487, 13.797, 14.489, 15.081, 17.119, 17.797 , 18.261, 21.723, 24.074 and 25.319 have characteristic peaks.
  • the X-ray powder diffraction pattern of the crystal form I of the compound represented by formula (I) is shown in FIG. 14 in terms of diffraction angle 2 ⁇ .
  • the present disclosure provides a method for preparing the crystal form I of the compound represented by formula (I), which comprises mixing the crystal form A and crystal form F of the compound represented by formula (I) in an acetone-water mixed solvent, and beating (such as 5 ⁇ Beating at 25°C).
  • the present disclosure provides a crystal form J of the compound represented by formula (I).
  • the X-ray powder diffraction pattern represented by the diffraction angle 2 ⁇ has characteristic peaks at 7.268, 9.203, 14.668, 15.024, 18.060 and 21.815.
  • the crystal form J of the compound has an X-ray powder diffraction pattern expressed in diffraction angle 2 ⁇ angles at 7.268, 9.203, 11.542, 13.884, 14.668, 15.024, 17.240, 18.060, 21.815 and 23.981. Characteristic peaks.
  • the crystal form J of the compound represented by formula (I) has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ as shown in FIG. 15.
  • the present disclosure provides a method for preparing the J crystal form of the compound represented by formula (I), comprising
  • the present disclosure provides a crystal form K of the compound represented by formula (I).
  • the X-ray powder diffraction pattern represented by the diffraction angle 2 ⁇ has characteristic peaks at 6.937, 12.267, 13.747, 16.079, 18.671 and 20.205.
  • the crystal form K of the compound represented by formula (I) has an X-ray powder diffraction pattern expressed in diffraction angle 2 ⁇ angles at 6.156, 6.937, 9.134, 12.267, 13.747, 15.319, 16.079, 18.671 There are characteristic peaks at, 20.205 and 23.141.
  • the crystal form K of the compound represented by formula (I) has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ as shown in FIG. 16.
  • the present disclosure provides a method for preparing the K crystal form of the compound represented by formula (I), comprising
  • dissolved refers to a state where the compound is fully dissolved
  • the “beating” refers to a state where the compound is not fully dissolved
  • the preparation method of the crystal form described in the present disclosure also includes steps such as filtration, washing or drying.
  • the present disclosure also relates to the compound represented by formula (I), A crystal form, B crystal form, C crystal form, D crystal form, E crystal form, F crystal form, G crystal form, H crystal form, I crystal form, J crystal Form, K crystal form, and optionally one or more pharmaceutical carriers and/or diluents.
  • the pharmaceutical composition further contains an anti-PD-1 antibody, preferably an anti-mouse PD-1 antibody.
  • the pharmaceutical composition can be made into any pharmaceutically acceptable dosage form.
  • the pharmaceutical preparations of crystal form J and crystal K can be formulated as tablets, capsules, pills, granules, solutions, suspensions, syrups, injections (including injections, sterile powders for injections and concentrated solutions for injections) ), suppositories, inhalants or sprays.
  • the pharmaceutical composition of the present disclosure can also be administered to patients or subjects in need of such treatment in any suitable administration mode, such as oral, parenteral, rectal, pulmonary or topical administration.
  • oral administration the pharmaceutical composition can be made into oral preparations, such as oral solid preparations, such as tablets, capsules, pills, granules, etc.; or, oral liquid preparations, such as oral solutions, oral mixtures, etc. Suspension, syrup, etc.
  • the pharmaceutical preparations may also contain suitable fillers, binders, disintegrants, lubricants and the like.
  • parenteral administration the pharmaceutical preparations can be made into injections, including injections, sterile powders for injections, and concentrated solutions for injections.
  • the pharmaceutical composition When made into an injection, the pharmaceutical composition can be produced using conventional methods in the existing pharmaceutical field.
  • the pharmaceutical preparations may not be added with additives, or appropriate additives may be added according to the nature of the drug.
  • the pharmaceutical preparation When used for rectal administration, the pharmaceutical preparation can be made into suppositories and the like.
  • the pharmaceutical preparations When used for pulmonary administration, can be made into inhalants or sprays.
  • the present disclosure further relates to crystal form A, crystal form B, crystal form C, crystal form D, crystal form E, crystal form F, crystal form G, crystal form H, crystal form I, crystal form J of the compound represented by formula (I) Type, K crystal form, or containing the compound represented by formula (I), A crystal form, B crystal form, C crystal form, D crystal form, E crystal form, F crystal form, G crystal form, H crystal form, I crystal form, Application of the composition of crystal form J and crystal form K in the preparation of ROR agonists.
  • the present disclosure further relates to crystal form A, crystal form B, crystal form C, crystal form D, crystal form E, crystal form F, crystal form G, crystal form H, crystal form I, crystal form J of the compound represented by formula (I) Form, K crystal form as ROR agonist or containing the compound represented by formula (I) represented by the compound of formula A crystal form, B crystal form, C crystal form, D crystal form, E crystal form, F crystal form, G crystal form, H crystal form, Use of the composition of crystal form I, crystal form J, and crystal form K in the preparation of drugs for preventing and/or treating tumors or cancers.
  • the present disclosure further relates to crystal form A, crystal form B, crystal form C, crystal form D, crystal form E, crystal form F, crystal form G, crystal form H, crystal form I, crystal form J of the compound represented by formula (I)
  • the present disclosure further relates to the compound represented by the formula (I), A crystal form, B crystal form, C crystal form, D crystal form, E crystal form, F crystal form, G crystal form, H crystal form, I crystal form, J crystal
  • the tumors or cancers described in the present disclosure are solid tumors and hematomas, preferably selected from non-Hodgkin’s lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, synovial sarcoma, breast cancer, cervical cancer, colon Cancer, lung cancer, stomach cancer, rectal cancer, pancreatic cancer, brain cancer, skin cancer, oral cancer, prostate cancer, bone cancer, kidney cancer, ovarian cancer, bladder cancer, liver cancer, fallopian tube tumor, ovarian tumor, peritoneal tumor, melanoma, One or more of glioma, glioblastoma, hepatocellular carcinoma, mastoid nephroma, head and neck tumor, leukemia, lymphoma, myeloma, and non-small cell lung cancer.
  • the present disclosure also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the aforementioned crystal form A, B crystal form, C crystal form, D crystal form, E crystal form, F crystal form, G crystal form, and H of the compound represented by formula (I).
  • the compound represented by formula (I) of the present disclosure has crystal form A, crystal form B, crystal form C, crystal form D, crystal form E, crystal form F, crystal form G, crystal form H, Crystal Form I, Crystal Form J, and Crystal Form K are present in the pharmaceutical composition or medicine in a therapeutically and/or preventively effective amount.
  • the crystal form of the compound represented by formula (I) of the present disclosure is present in a pharmaceutical composition or medicine in the form of a unit dose.
  • the present disclosure also provides a composition, which is selected from the aforementioned crystal form of the compound represented by formula (I) or a mixture thereof mixed with at least one pharmaceutically acceptable carrier, diluent or excipient be made of.
  • the present disclosure further relates to a method for preparing a pharmaceutical composition, which comprises making a crystal form of a compound represented by formula (I) or a mixture thereof selected from the present disclosure and at least one pharmaceutically acceptable carrier, diluent or excipient mixing.
  • the operation of mixing any crystalline or amorphous compound represented by formula (I) in a solvent is performed by heating and then lowering the temperature or Cool and crystallize.
  • the "heating” in the preparation method provided in the present disclosure means that the heating temperature does not exceed the boiling point temperature corresponding to the solvent used; the “cooling” and “cooling” in the preparation method provided in the present disclosure refer to the internal temperature of the system
  • the temperature is lowered to any temperature lower than the heating temperature.
  • the temperature can be a point value or an interval value.
  • the "cooling” and “cooling” processes can be programmed or non-programmed.
  • the process of cooling or cooling is as in the art The skilled person is well known to the operation of optional stirring.
  • the crystal form of the compound represented by formula (I) was determined by X-ray powder diffraction pattern (XRPD) and differential scanning calorimetry (DSC).
  • the "2 ⁇ or 2 ⁇ angle" mentioned in the present disclosure refers to the diffraction angle, ⁇ is the Bragg angle, and the unit is ° or degree; the error range of each characteristic peak 2 ⁇ is ⁇ 0.20, which can be -0.20, -0.19, -0.18 , -0.17, -0.16, -0.15, -0.14, -0.13, -0.12, -0.11, -0.10, -0.09, -0.08, -0.07, -0.06, -0.05, -0.04, -0.03, -0.02,- 0.01, 0.00, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20.
  • Figure 1 is an amorphous XRPD diagram of the compound represented by formula (I);
  • Figure 2 is an XRPD diagram of the crystal form A of the compound represented by formula (I);
  • Figure 3 is a DSC and TGA chart of the crystal form A of the compound represented by formula (I);
  • Figure 4 is a DVS diagram of the crystal form A of the compound represented by formula (I);
  • Figure 5 is the XRPD diagram of the compound represented by formula (I) before and after the crystal form A DVS;
  • Fig. 6 is an XRPD diagram of the crystal form B of the compound represented by formula (I);
  • Figure 7 is a DSC and TGA chart of the crystal form B of the compound represented by formula (I);
  • Figure 8 is an XRPD diagram of the crystal form C of the compound represented by formula (I);
  • Figure 9 is an XRPD diagram of the crystal form D of the compound represented by formula (I);
  • Figure 10 is an XRPD diagram of the crystal form E of the compound represented by formula (I);
  • Figure 11 is an XRPD diagram of the crystal form F of the compound represented by formula (I);
  • Fig. 12 is an XRPD diagram of the crystal form G of the compound represented by formula (I);
  • Figure 13 is an XRPD diagram of the crystal form H of the compound represented by formula (I);
  • Fig. 14 is an XRPD diagram of the crystal form I of the compound represented by formula (I);
  • Figure 15 is an XRPD diagram of the crystal form J of the compound represented by formula (I);
  • Figure 16 is an XRPD diagram of the crystal form K of the compound represented by formula (I);
  • Figure 17 is a DSC and TGA chart of the crystal form K of the compound represented by formula (I).
  • 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).
  • the NMR was measured with Bruker AVANCE-400 nuclear magnetic instrument, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), and the internal standard was four Methylsilane (TMS).
  • DMSO-d 6 dimethyl sulfoxide
  • CDCl 3 deuterated chloroform
  • CD 3 OD deuterated methanol
  • TMS Methylsilane
  • HPLC determination uses Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18 150 ⁇ 4.6mm chromatographic column) and Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150 ⁇ 4.6mm chromatographic column).
  • XRPD is an X-ray powder diffraction test: the measurement is carried out with a BRUKER D8 X-ray diffractometer.
  • the specific information collected Cu anode (40kV, 40mA), Cu-K ⁇ 1 ray K ⁇ 2 rays K ⁇ rays Scanning range (2q range): 3 ⁇ 64°, scanning step length 0.02, slit width (collimator) 1.0mm.
  • the number of scanning steps is 3 steps, the scanning range of each step is 19°, the starting degree is 10°, the ending degree is 48°, and the length of each step is 75s.
  • DSC is differential scanning calorimetry: METTLER TOLEDO DSC 3+ differential scanning calorimeter is used for the measurement, the heating rate is 10°C/min, the specific temperature range refers to the corresponding graph (mostly 25-300 or 25-350°C), nitrogen purge Speed 50mL/min. Or: the measurement uses TA 2500 differential scanning calorimeter, scanning rate: 10°C/min, protective gas: nitrogen, temperature range: RT-340°C, aluminum plate gland.
  • TGA thermogravimetric analysis: the detection adopts METTLER TOLEDO TGA 2 thermogravimetric analyzer, the heating rate is 10°C/min, the specific temperature range refers to the corresponding graph (mostly 25-300°C), and the nitrogen purge rate is 20mL/min. Or: use TA 5500 thermogravimetric analyzer for measurement, scan rate: 10°C/min, protective gas: nitrogen, temperature range: RT-350°C, open the aluminum plate.
  • DVS dynamic moisture adsorption: the detection adopts SMS DVS Advantage, at 25°C, the humidity change is 50%-95%-0%-95%-50%, and the step is 10% (the last step is 5%) (specific humidity range) Subject to the corresponding map, here are most of the methods used), the judgment standard is dm/dt not more than 0.02%.
  • reaction temperature is room temperature, which is 20°C to 30°C.
  • the monitoring of the reaction progress in the examples adopts thin-layer chromatography (TLC).
  • the developing reagent used in the reaction, the eluent system of column chromatography used in the purification of the compound and the developing reagent system of thin-layer chromatography include: A: Dichloromethane/methanol system, B: n-hexane/ethyl acetate system.
  • the volume ratio of the solvent is adjusted according to the polarity of the compound.
  • a small amount of basic or acidic reagents such as triethylamine and acetic acid can also be added for adjustment.
  • reaction solution was cooled to room temperature, 200 mL of water was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue obtained was purified with eluent system B to obtain the title compound 1e (8.1 g, yield: 87%).
  • the reaction solution was cooled to room temperature, extracted with ethyl acetate (30 mL ⁇ 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue obtained was purified by silica gel column chromatography with eluent system D , The title compound 11 (0.6 g, yield 86.09%) was obtained.
  • reaction solution was concentrated under reduced pressure, 20 mL of water was added, and the mixture was extracted with ethyl acetate (30 mL ⁇ 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • the reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (Waters 2767-SQ high pressure liquid chromatograph, sunfire OBD, 150*19mm 5nfi column, elution system: ammonium bicarbonate, water, acetonitrile).
  • Test Example 1 Determination of the in vitro activity of the compound represented by formula (I) on ROR ⁇
  • ROR ⁇ co-activation system was used to screen the regulation of ROR ⁇ activity by the compounds of the present disclosure.
  • the negative control well is 5 ⁇ L of complete buffer D without ROR ⁇ LBD.
  • Use complete buffer D to prepare a mixture containing 0.6 ⁇ M fluorescein-D22 (4X) and 8 nM terbium (Tb) labeled anti-GST antibody (4X) (Life Technologies), and add 5 ⁇ L of the mixture to a 384-well plate.
  • the total reaction system is 20 ⁇ L. Gently mix the 384-well plate on a shaker and incubate at room temperature in the dark for 2-4 hours.
  • Tecan Infinite M1000 was used to detect the fluorescence reading, and the logarithmic curve of the ratio of emission wavelength 520nm/495nm and the compound concentration was drawn by GraphPad Prism 6.0 software, and the EC 50 value of the test compound was calculated.
  • the in vitro activity of the compound represented by formula (I) on ROR ⁇ was determined by the above test, and the measured EC 50 (nM) was 33 and Emax (%) was 102%.
  • the compound represented by formula (I) has a significant agonistic effect on ROR ⁇ in vitro activity.
  • Test Example 2 Determination of the activity of the compound represented by formula (I) on IL-17A enzyme-linked immunoassay
  • PBMC Human peripheral blood mononuclear cells
  • the frozen human peripheral blood mononuclear cells were quickly recovered in pre-warmed lymphocyte culture medium, centrifuged at 1000 rpm for 10 min, the cell culture supernatant was removed, the cells were gently suspended in TexMACS medium, and the cells were counted.
  • the T cell activation reagent cytostim (10 ⁇ l/ml) was added to the cell suspension in proportion, and then the cells were planted in a 96-well cell culture plate at a density of 1 ⁇ 10 5 peripheral blood mononuclear cells/well.
  • Use TexMACS medium to gradually dilute the test compound and add them to each experimental well, with 2-3 parallel wells in each group. Prepare negative control wells containing only cells and no cytostim to obtain background readings.
  • the cell culture plate was placed in a 5% carbon dioxide 37°C incubator and incubated for 3 days. After 3 days of drug treatment, the cell culture supernatant was collected and centrifuged to remove suspended matter. The IL-17A enzyme-linked immunoassay kit was then used to quantify IL-17A in the supernatant. GraphPad Prism 6.0 was used to calculate the EC 50 value of the test compound.
  • the quantitative analysis of IL-17A by the compound represented by formula (I) was determined by the above test, and the measured EC 50 (nM) was 37 and Emax (%) was 100%.
  • the compound represented by formula (I) has a significant regulatory effect on IL-17A enzyme-linked immunoassay activity.
  • mice Using mice as test animals, the LC/MS/MS method was used to determine the drug concentration in plasma at different times after the mice were given the compound of formula (I) by intragastric administration. To study the pharmacokinetic behavior of the compound of the present disclosure in mice and evaluate its pharmacokinetic characteristics.
  • mice were fasted overnight and then administered by gavage.
  • the dosage was 2.0 mg/kg, and the dosage was 0.2 mL/10 g.
  • mice were intragastrically administered the compound of formula (I), and 0.1 mL of blood was collected at 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 11.0, 24.0 hours before and after administration (3 mice at each time point) Animal), placed in a heparinized test tube, centrifuged at 3500 rpm for 10 minutes to separate plasma, and stored at -20°C.
  • the DSC and TGA spectra of the crystal form of compound A represented by formula (I) are shown in Fig. 3.
  • the DSC endothermic peak is 136.1°C
  • the TGA: 24°C-120°C has a weight loss of 0.24%.
  • DVS test shows that between 10%RH-80%RH, with the increase of humidity, the mass increase is about 2.987%, less than 15% but not less than 2%.
  • the sample has hygroscopicity. Under normal storage conditions (ie 25°C and 60% humidity), the water absorption is about 1.505%; under accelerated test conditions (ie, humidity 70%), the water absorption is about 2.328%; under extreme conditions (ie, humidity 90%), the water absorption is about 3.274 %.
  • the desorption process of the sample basically coincides with the adsorption process (see Figure 4).
  • the crystal form was re-tested after DVS detection, and the crystal form was not transformed (see Figure 5).
  • the DSC and TGA spectra of the crystal form of compound B represented by formula (I) are shown in Fig. 7.
  • the DSC endothermic peak is 120.6°C
  • the TGA: 28°C-120°C has a weight loss of 3.31%.
  • the DSC spectrum of the crystal form showed that the endothermic peaks were 93.24°C and 112.88°C; the TGA spectrum showed a weight loss of 9.4% at 35°C-110°C; and the residual 4-methyl-2-pentanone solvent was 8.9wt%.
  • the DSC spectrum of the crystal form shows that the endothermic peak is 105.86°C; the TGA spectrum shows a weight loss of 8.9% at 45°C to 110°C and a weight loss of 5.38% at 120°C to 225°C.
  • the solvent dioxane remains 2.54wt%.
  • the DSC spectrum of this crystal form shows that the endothermic peak is 123.62°C.
  • the DSC spectrum of the crystal form shows the endothermic peaks at 118.51 and 138.75°C; the TGA spectrum shows a weight loss of 1.90% at 40°C to 120°C.
  • the DSC spectrum of this crystal form shows that the endothermic peak is 123.53°C; the TGA spectrum shows a weight loss of 3.71% at 40°C to 135°C.
  • the DSC spectrum of this crystal form shows that the endothermic peak is 123.21°C; the TGA spectrum shows a weight loss of 3.69% at 40°C to 135°C.
  • the solvent remains 4.4 wt% of 2-methyltetrahydrofuran.
  • the DSC spectrum of this crystal form shows that the endothermic peak is 127.4°C; the TGA spectrum shows a weight loss of 3.69% at 40°C to 135°C.
  • the DSC spectrum of this crystal form shows that the endothermic peak is 146.34°C; the TGA spectrum shows a weight loss of 0.98% at 110°C to 165°C.
  • the crystal form A (150 mg, 243 ⁇ mol) of the compound represented by formula (I) was added to 1 mL of acetonitrile, suspended, stirred at room temperature for 120 hours, filtered, and the filter cake was collected and dried in vacuo to obtain the title product (77 mg, yield: 51.33%) ).
  • the product was defined as crystal form K.
  • the XRPD spectrum is shown in Figure 16; the characteristic peak positions are shown in Table 12:
  • crystal form A (7 mg, 11 ⁇ mol), crystal form C (7 mg, 11 ⁇ mol), crystal form D (7 mg, 11 ⁇ mol), crystal form E (7 mg, 11 ⁇ mol), crystal form G (7 mg, 11 ⁇ mol) was added to 0.5 mL of isopropanol, suspended, stirred at room temperature for 72 hours, filtered, the filter cake was collected, and dried under vacuum to obtain the title product (21.2 mg, yield: 60.57%).
  • the product is crystal form A.
  • the product is crystal form A.
  • the product is crystal form A.
  • Example 2 Place the sample of the compound of formula (I) crystal form A (Example 2) open and flat, and investigate under heating (40°C, 60°C), light (4500 Lux), high humidity (RH 75%, RH 90%) conditions The stability of the sample, the sampling period is 30 days.
  • Embodiment 18 Experiments on influencing factors of crystal form B of the present disclosure
  • Example 2 The crystalline form A (Example 2) and crystalline form B (Example 4) of the compound of formula (I) were investigated for long-term (25°C, 60%RH) and accelerated (40°C, 75%RH) stability for 6 months. It has been in progress for two months and is continuing.

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Abstract

一种具有式I所示结构的氘原子取代的吲哚甲酰胺类衍生物的晶型及其制备方法。式(I)所示化合物的晶型具备良好的稳定性，可更好地用于临床治疗。

Description

氘原子取代的吲哚甲酰胺类衍生物的晶型及其制备方法
本申请要求申请日为2019年3月11日的中国专利申请201910179875.5的优先权。本申请引用上述中国专利申请的全文。
技术领域
氘原子取代的吲哚甲酰胺类衍生物的晶型及其制备方法，属于制药领域。
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、免疫系统调节等(Mech Dev.1998 Jan,70(1-2:147-53；EMBO J.1998 Jul 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.1998 Dec,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.1999 Dec,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.2014 Mar 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.2010 Apr 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.2009 Aug 6,114(6):1141-9；Clin Cancer Res.2008 Jun 1,14(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-54143。临床前研究表明，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可以调节免疫系统中的多种基因表达，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.2016 Nov 4,5(12):e1254854；ACS Chem Biol.2016 Apr 15,11(4):1012-8)。虽然该小分子激动目前已经进入临床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。
PCT/CN2018/105008(申请日2018.09.11)中描述一种式(I)所示的ROR激动剂，文本中对于其晶型结构未做描述，
Figure PCTCN2020078506-appb-000001
作为药用活性成分的晶型结构往往影响到该药物的化学稳定性，结晶条件及储存条件的不同有可能导致化合物的晶型结构的变化，有时还会伴随着产生其他形态的晶型。因此，深入研究式(I)化合物的晶型及相关制备方法，改善式(I)所示化合物的各方面性质是很有必要的。
发明内容
本公开(The disclosure)提供一种式(I)所示化合物的A晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在6.315、9.039、9.703、12.536、15.165、16.235、17.098和21.706处有特征峰，
Figure PCTCN2020078506-appb-000002
在一个实施方案中，所述式(I)所示化合物的A晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在6.315、9.039、9.703、12.536、13.573、15.165、16.235、17.098、17.876、21.406、21.706、23.248、24.669和25.136处有特征峰。
在一个实施方案中，本公开提供一种式(I)所示化合物的A晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱如图2所示。
一种制备式(I)所示化合物A晶型的方法，包括
1)将式(I)所示化合物混于溶剂中溶解(如加热溶解)，析晶(如降温析晶)的步骤， 所述溶剂选自异丙醇、乙醇、乙醇-水混合物；或
2)将式(I)所示化合物混于第一溶剂中溶解(如加热溶解)，滴加第二溶剂析晶(如降温析晶)的步骤；所述第一溶剂选自乙酸乙酯；所述第二溶剂选自正庚烷；或
3)将式(I)所示化合物B晶型混于第一溶剂中溶解，滴加第二溶剂析晶(如降温析晶)的步骤；所述第一溶剂选自乙醇；所述第二溶剂选自水；或
4)将式(I)所示化合物A晶型或含有A晶型的式(I)所示化合物混于溶剂中打浆(如5～25℃条件下打浆，或加热打浆)的步骤，所述溶剂选自乙醇、乙酸异丙酯、异丙醇、异丙醚、水、乙酸乙酯、甲基叔丁基醚、甲苯、乙酸丁酯、正丁醇、环己烷、乙醇-水混合溶剂。
本公开提供了一种式(I)所示化合物的B晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在9.874、14.893、15.387、19.202、20.918、24.179和25.566处有特征峰。
在一个实施方案中，所述式(I)所示化合物的B晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在9.874、14.893、15.387、19.202、20.918、22.195、24.179、24.689、25.566、26.502和28.963处有特征峰。
在一个优选的实施方案中，所述式(I)所示化合物的B晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱如图6所示。
一种制备式(I)所示化合物B晶型的方法，包括
1)将式(I)所示化合物混于甲醇中，溶解(如加热溶解)，析晶(如降温析晶)的步骤；或
2)将式(I)所示化合物混于第一溶剂中溶解(如加热溶解)，滴加第二溶剂析晶(如降温析晶)的步骤；所述第一溶剂为甲醇；所述第二溶剂为水；或
3)将式(I)所示化合物混于甲醇中，打浆(如5～25℃条件下打浆)的步骤；或
4)将式(I)所示化合物混合物混于甲醇中，溶解、挥发析晶的步骤。
发明提供了一种式(I)所示化合物的C晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在8.302、11.241、14.018、15.861、17.921、19.186和22.874处有特征峰。
在一个实施方案中，所述化合物的C晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在7.440、8.302、11.241、13.811、14.018、15.861、17.921、19.186、22.874、24.652和26.275处有特征峰。
在一个实施方案中，所述式(I)所示化合物的C晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱如图8所示。
一种制备式(I)所示化合物C晶型的方法，包括：
1)将式(I)所示化合物混于溶剂中，打浆(如5～25℃条件下打浆)步骤，所述溶剂为4-甲基-2-戊酮。
本公开提供了一种式(I)所示化合物的D晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在6.625、8.384、14.959、16.453、17.816和19.915处有特征峰。
在一个实施方案中，所述式(I)所示化合物的D晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在6.625、8.384、10.441、11.516、14.959、16.453、17.816、19.915、23.554和25.095处有特征峰。
在一个实施方案中，所述式(I)所示化合物的D晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱如图9所示。
一种制备式(I)所示化合物D晶型的方法，包括
1)将式(I)所示化合物A晶型混于溶剂中，打浆(如5～25℃条件下打浆)步骤，所述溶剂为二氧六环；或
2)将式(I)所示化合物A晶型混于溶剂中，挥发析晶的步骤，所述溶剂为2-甲基四氢呋喃。
本公开提供了一种式(I)所示化合物的E晶型，其特征在于：以衍射角2θ角度表示的X-射线粉末衍射图谱，在13.824、14.967、15.980、16.730、21.684和25.212处有特征峰。
在一个实施方案中，本公开提供了一种式(I)所示化合物的E晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在12.061、13.824、14.967、15.980、16.730、18.216、21.684、23.256、25.212和28.150处有特征峰。
一种制备式(I)所示化合物E晶型的方法，包括
1)将式(I)所示化合物混于第一溶剂中溶解(如加热溶解)，滴加第二溶剂析晶的步骤；所述第一溶剂为丙酮；所述第二溶剂为水；或
2)将式(I)所示化合物A晶型或者式(I)所示化合物A晶型、J晶型的混合物混于溶剂中，打浆(如5～25℃条件下打浆)的步骤，所述溶剂为丙酮、丙酮-水混合溶剂。
本公开提供了一种式(I)所示化合物的F晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在7.680、11.319、14.200、15.460、16.480、23.000、23.861和26.220处有特征峰。
在一个实施方案中，所述式(I)所示化合物的F晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱如图11所示。
本公开提供了一种制备式(I)所示化合物F晶型的方法，包括将式(I)所示化合物混于第一溶剂中溶解(如加热溶解)，滴加第二溶剂析晶的步骤；所述第一溶剂为四氢呋喃； 所述第二溶剂为水；所述第一溶剂与第二溶剂的体积比例选自20:1-2:1，包括20:1、18:1、16:1、14:1、12:1、10:1、8:1、6:1、4:1、2:1或任意两个数值之间的任意比值。
本公开提供了一种式(I)所示化合物的G晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在7.480、9.400、12.201、13.238、15.259、16.300、17.859、18.900、22.500和25.320处有特征峰。
在一个实施方案中，所述式(I)所示化合物的G晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱如图12所示。
一种制备式(I)所示化合物G晶型的方法，包括
1)将式(I)所示化合物混于第一溶剂中溶解(如加热溶解)，滴加第二溶剂析晶的步骤；所述第一溶剂为四氢呋喃；所述第二溶剂为水；所述第一溶剂与第二溶剂的体积比例小于1.5:1；或
2)将式(I)所示化合物A晶型混于溶剂中，打浆(如5～25℃条件下打浆)的步骤，所述溶剂为2-甲基四氢呋喃。
在一个实施方案中，本公开提供的制备式(I)所示化合物G晶型的方法进一步包括降温的步骤。
本公开提供了一种式(I)所示化合物的H晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在8.265、10.453、12.476、14.633、16.774和17.933处有特征峰。
在一个实施方案中，所述式(I)所示化合物的H晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在8.265、8.978、10.453、11.722、12.476、14.633、16.774、17.368、17.933和19.211处有特征峰。
在一个实施方案中，所述式(I)所示化合物的H晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱如图13所示。
本公开提供一种制备式(I)所示化合物的H晶型的方法，包括将式(I)所示化合物A晶型、F晶型的混合物混于2-甲基四氢呋喃中，打浆(如5～25℃条件下打浆)的步骤。
本公开提供了一种式(I)所示化合物的I晶型，其特征在于：以衍射角2θ角度表示的X-射线粉末衍射图谱，在7.098、10.159、12.487、13.797、17.119、17.797、18.261和24.074处有特征峰。
在一个实施方案中，所述式(I)所示化合物的I晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在7.098、10.159、12.487、13.797、14.489、15.081、17.119、17.797、18.261、21.723、24.074和25.319处有特征峰。
在一个实施方案中，所述式(I)所示化合物的I晶型，以衍射角2θ角度表示的X-射线 粉末衍射图谱如图14所示。
本公开提供一种制备式(I)所示化合物的I晶型的方法，包括将式(I)所示化合物A晶型、F晶型混于丙酮-水混合溶剂中，打浆(如5～25℃条件下打浆)的步骤。
本公开提供了一种式(I)所示化合物的J晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在7.268、9.203、14.668、15.024、18.060和21.815处有特征峰。
在一个实施方案中，所述化合物的J晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在7.268、9.203、11.542、13.884、14.668、15.024、17.240、18.060、21.815和23.981处有特征峰。
在一个实施方案中，所述式(I)所示化合物的J晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱如图15所示。
本公开提供一种制备式(I)所示化合物的J晶型的方法，包括
1)将式(I)所示化合物B晶型混于乙腈中，打浆(如5～25℃条件下打浆)的步骤；或
2)将式(I)所示化合物A晶型混于硝基甲烷中，打浆(如5～25℃条件下打浆)的步骤；或
3)将式(I)所示化合物A晶型、C晶型、D晶型、E晶型、G晶型混合物混于乙腈中，打浆(如5～25℃条件下打浆)的步骤。
本公开提供了一种式(I)所示化合物的K晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在6.937、12.267、13.747、16.079、18.671和20.205处有特征峰。
在一个实施方案中，所述式(I)所示化合物的K晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在6.156、6.937、9.134、12.267、13.747、15.319、16.079、18.671、20.205和23.141处有特征峰。
在一个实施方案中，所述式(I)所示化合物的K晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱如图16所示。
本公开提供一种制备式(I)所示化合物的K晶型的方法，包括
1)将式(I)所示化合物A晶型混于乙腈中，打浆(如5～25℃条件下打浆)步骤；或
2)将式(I)所示化合物B晶型混于硝基甲烷中，打浆(如5～25℃条件下打浆)步骤。
本公开中所述的“溶解”指化合物全溶的状态，所述“打浆”指化合物非全溶状态。
本公开中所述晶型的制备方法中还包括过滤、洗涤或干燥等的步骤。
本公开还涉及包括式(I)所示化合物A晶型、B晶型、C晶型、D晶型、E晶型、F晶型、G晶型、H晶型、I晶型、J晶型、K晶型，以及任选的一种或多种药用载体和/或稀 释剂的药物组合物。在本公开一个实施方案中，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。所述药物组合物可以制成药学上可接受的任一剂型。例如，含本公开的式(I)所示化合物的A晶型、B晶型、C晶型、D晶型、E晶型、F晶型、G晶型、H晶型、I晶型、J晶型、K晶型的药物制剂可以配制为片剂、胶囊剂、丸剂、颗粒剂、溶液剂、混悬剂、糖浆剂、注射剂(包括注射液、注射用无菌粉末与注射用浓溶液)、栓剂、吸入剂或喷雾剂。
此外，本公开所述药物组合物还可以以任何合适的给药方式，例如口服、肠胃外、直肠、经肺或局部给药等方式施用于需要这种治疗的患者或受试者。当用于口服给药时，所述药物组合物可制成口服制剂，例如口服固体制剂，如片剂、胶囊剂、丸剂、颗粒剂等；或，口服液体制剂，如口服溶液剂、口服混悬剂、糖浆剂等。当制成口服制剂时，所述药物制剂还可包含适宜的填充剂、粘合剂、崩解剂、润滑剂等。当用于肠胃外给药时，所述药物制剂可制成注射剂，包括注射液、注射用无菌粉末与注射用浓溶液。当制成注射剂时，所述药物组合物可采用现有制药领域中的常规方法来进行生产。当配制注射剂时，所述药物制剂中可以不加入附加剂，也可根据药物的性质加入适宜的附加剂。当用于直肠给药时，所述药物制剂可制成栓剂等。用于经肺给药时，所述药物制剂可制成吸入剂或喷雾剂等。
本公开进一步涉及式(I)所示化合物的A晶型、B晶型、C晶型、D晶型、E晶型、F晶型、G晶型、H晶型、I晶型、J晶型、K晶型或含有式(I)所示化合物A晶型、B晶型、C晶型、D晶型、E晶型、F晶型、G晶型、H晶型、I晶型、J晶型、K晶型的组合物在制备ROR激动剂中的用途。
本公开进一步涉及式(I)所示化合物的A晶型、B晶型、C晶型、D晶型、E晶型、F晶型、G晶型、H晶型、I晶型、J晶型、K晶型作为ROR激动剂或含有式(I)所示化合物A晶型、B晶型、C晶型、D晶型、E晶型、F晶型、G晶型、H晶型、I晶型、J晶型、K晶型的组合物在制备用于预防和/或治疗肿瘤或癌症的药物中的用途。
本公开进一步涉及式(I)所示化合物的A晶型、B晶型、C晶型、D晶型、E晶型、F晶型、G晶型、H晶型、I晶型、J晶型、K晶型联合抗PD-1抗体在制备用于预防和/或治疗肿瘤或癌症的药物中的用途。
本公开进一步涉及包含式(I)所示化合物A晶型、B晶型、C晶型、D晶型、E晶型、F晶型、G晶型、H晶型、I晶型、J晶型、K晶型与抗PD-1抗体的组合物在制备用于预防和/或治疗肿瘤或癌症的药物中的用途。
本公开中所述的肿瘤或癌症为实体瘤和血液瘤，优选选自非霍奇金淋巴瘤、弥漫大 B细胞淋巴瘤、滤泡性淋巴瘤、滑膜肉瘤、乳腺癌、宫颈癌、结肠癌、肺癌、胃癌、直肠癌、胰腺癌、脑癌、皮肤癌、口腔癌、前列腺癌、骨癌、肾癌、卵巢癌、膀胱癌、肝癌、输卵管肿瘤、卵巢瘤、腹膜肿瘤、黑色素瘤、神经胶质瘤、神经胶母细胞瘤、肝细胞癌、乳突肾性瘤、头颈部肿瘤、白血病、淋巴瘤、骨髓瘤和非小细胞肺癌中的一种或多种。
本公开还提供一种药物组合物，包含前述的式(I)所示化合物的A晶型、B晶型、C晶型、D晶型、E晶型、F晶型、G晶型、H晶型、I晶型、J晶型、K晶型中的一种或多种，以及一种或多种药学上可接受的载体、稀释剂或赋形剂。
在某些实施方案中，本公开的式(I)所示化合物的A晶型、B晶型、C晶型、D晶型、E晶型、F晶型、G晶型、H晶型、I晶型、J晶型、K晶型以治疗和/或预防有效量存在于药物组合物或药物中。在某些实施方案中，本公开的式(I)所示化合物的晶型以单位剂量的形式存在于药物组合物或药物中。
另一方面，本公开还提供一种组合物，其由选自前述的式(I)所示化合物的晶型或其混合物与至少一种药学上可接受的载体、稀释剂或赋形剂混合制得。本公开进一步涉及一种制备药物组合物的方法，包括使选自本公开的式(I)所示化合物的晶型或其混合物与至少一种药学上可接受的载体、稀释剂或赋形剂混合。
在一种实施方案中，本公开提供的式(I)所示化合物的晶型的制备方法中，任意晶形或无定型的式(I)所示化合物混合于溶剂的操作，先加热后降温或者冷却析晶。
本公开提供的制备方法中所述的“加热”是指加热温度不超过使用溶剂对应的沸点温度；本公开中提供的制备方法中所述的“降温”、“冷却”是指体系的内部温度降至低于加热温度的任意温度，该温度可以是点值或者区间值，所述的“降温”、“冷却”过程可以是程序式或非程序式，另外降温或冷却的过程中如本领域技术人员公知任选有搅拌的操作。
通过X-射线粉末衍射图谱(XRPD)、差示扫描量热分析(DSC)对所得到式(I)所示化合物的晶型进行结构测定、晶型研究。
本公开中所述的“2θ或2θ角度”是指衍射角，θ为布拉格角，单位为°或度；每个特征峰2θ的误差范围为±0.20，可以为-0.20、-0.19、-0.18、-0.17、-0.16、-0.15、-0.14、-0.13、-0.12、-0.11、-0.10、-0.09、-0.08、-0.07、-0.06、-0.05、-0.04、-0.03、-0.02、-0.01、0.00、0.01、0.02、0.03、0.04、0.05、0.06、0.07、0.08、0.09、0.10、0.11、0.12、0.13、0.14、0.15、0.16、0.17、0.18、0.19、0.20。
附图说明
图1为式(I)所示化合物无定型XRPD图；
图2为式(I)所示化合物晶型A的XRPD图；
图3为式(I)所示化合物晶型A的DSC、TGA图；
图4为式(I)所示化合物晶型A的DVS图；
图5为式(I)所示化合物晶型A DVS前后的XRPD图；
图6为式(I)所示化合物晶型B的XRPD图；
图7为式(I)所示化合物晶型B的DSC、TGA图；
图8为式(I)所示化合物晶型C的XRPD图；
图9为式(I)所示化合物晶型D的XRPD图；
图10为式(I)所示化合物晶型E的XRPD图；
图11为式(I)所示化合物晶型F的XRPD图；
图12为式(I)所示化合物晶型G的XRPD图；
图13为式(I)所示化合物晶型H的XRPD图；
图14为式(I)所示化合物晶型I的XRPD图；
图15为式(I)所示化合物晶型J的XRPD图；
图16为式(I)所示化合物晶型K的XRPD图；
图17为式(I)所示化合物晶型K的DSC、TGA图。
具体实施方式
以下将结合实施例更详细地解释本公开，本公开的实施例仅用于说明本公开的技术方案，并非限定本公开的实质和范围。
实验所用仪器的测试条件：
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)。
XRPD为X射线粉末衍射检测：测定使用BRUKER D8型X射线衍射仪进行，具体采集信息：Cu阳极(40kV，40mA)，Cu-Kα1射线
Figure PCTCN2020078506-appb-000003
Kα2射线
Figure PCTCN2020078506-appb-000004
Kβ射线
Figure PCTCN2020078506-appb-000005
扫描范围(2q范围)：3～64°、扫描步长0.02、狭缝宽度(准直器)1.0mm。采用分步扫描法，扫描步数为3步，每步扫描范围19°，起始度数10°，终止度数48°，每步时长75s。
DSC为差示扫描量热：测定采用METTLER TOLEDO DSC 3+示差扫描量热仪，升温速率10℃/min，温度具体范围参照相应图谱(多为25-300或25-350℃)，氮气吹扫速度50mL/min。或者：测定采用TA 2500差示扫描量热仪，扫描速率：10℃/min，保护气体：氮气，温度范围：RT-340℃，铝盘压盖。
TGA为热重分析：检测采用METTLER TOLEDO TGA 2型热重分析仪，升温速率10℃/min，温度具体范围参照相应图谱(多为25-300℃)，氮气吹扫速度20mL/min。或者：测定采用TA 5500热重分析仪，扫描速率：10℃/min，保护气体：氮气，温度范围：RT-350℃，铝盘开盖。
DVS为动态水分吸附：检测采用SMS DVS Advantage，在25℃，湿度变化为50％-95％-0％-95％-50％，步进为10％(最后一步为5％)(湿度具体范围以相应图谱为准，此处所列为大多使用方法)，判断标准为dm/dt不大于0.02％。
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、式(I)所示化合物的制备及活性测试
2-[[4-氯-2-(三氟甲基)苯基]甲基]-1-(2-氟乙基)-N-[(1R)-2-羟乙基-1-[4-(1,1,2,2,2-五氘代乙基磺酰基)苯基]乙基]吲哚-5-甲酰胺(I)
Figure PCTCN2020078506-appb-000006
Figure PCTCN2020078506-appb-000007
第一步
(4-氯-2-(三氟甲基)苯基)甲醇1b
将4-氯-2-(三氟甲基)苯甲醛1a(10g，48mmol，采用专利申请“WO2011021492”公开的方法制备而得)溶于100mL乙醇中，分批加入硼氢化钠(1.83g，48mmol)，搅拌反应2小时。反应液减压浓缩，所得残余物中加入水，用乙酸乙酯萃取，有机相用饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，用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1b(9.5g，产率：95％)。
第二步
1-(溴甲基)-4-氯-2-(三氟甲基)苯1c
将化合物1b(9.5g，45.2mmol)溶于100mL二氯甲烷中，滴加入三溴化磷(24.5g，90.5mmol)，搅拌反应2小时。反应液中加入水，分离有机相，水相用二氯甲烷萃取，合并有机相，依次用水、饱和碳酸氢钠溶液和饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，得粗品标题化合物1c(10.5g)，产品不经纯化直接进行下一步反应。
第三步
2-(4-氯-2-(三氟甲基)苄基)-1H-吲哚-5-甲酸甲酯1e
将1H-吲哚-5-甲酸甲酯1d(4.4g，25.8mmol，采用公知的方法“Huaxue Shiji,2015,37(7),585-589,594”制备而得)溶于40mL N,N-二甲基乙酰胺中，加入二(乙腈)二氯化钯 (1.34g，5.16mmol)、双环[2.2.1]-2-庚烯(4.85g，51.6mmol)和碳酸氢钠(4.25g，51mmol)，再加入粗品化合物1c(7.4g，27mmol)，升温至70℃搅拌反应12小时。反应液冷却至室温，加入200mL水，用乙酸乙酯萃取三次，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，得标题化合物1e(8.1g，产率：87％)。
MS m/z(ESI):368.1[M+1]。
第四步
2-(4-氯-2-(三氟甲基)苄基)-1-(2-氟代乙基)-1H-吲哚-5-甲酸甲酯1f
将化合物1e(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100℃搅拌1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1f(0.25g，产率：74.06％)。
MS m/z(ESI):414.1[M+1]。
第五步
2-(4-氯-2-(三氟甲基)苄基)-1-(2-氟代乙基)-1H-吲哚-5-甲酸1g
将化合物1f(0.25g，604.17μmol)溶于20mL甲醇中，加入1.5mL 4M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，再用乙酸乙酯萃取(20mL酸乙酯，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1g(0.24g，产率：99.4％)。
MS m/z(ESI):400.1[M+1]。
第六步
1-溴-4-(1,1,2,2,2-五氘代乙基硫基)苯1j
将4-溴苯硫酚1h(1g，5.29mmol，Adamas)、1,1,1,2,2-五氘代-2-碘-乙烷1i(1.1g，6.35mmol，Sigma)和碳酸铯(5.25g，15.87mmol)加入50mL N,N-二甲基甲酰胺中，搅拌16小时。反应液过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系D纯化所得残余物，得标题化合物1j(1.1g，产率93.62％)。
第七步
1-溴-4-(1,1,2,2,2-五氘代乙基磺酰基)苯1k
将化合物1j(1.17g，4.95mmol)溶于20mL甲醇中，加入5mL预制的过氧硫酸氢钾复合盐(6.1g，9.90mmol)溶液，搅拌反应2小时。反应液过滤，滤液减压浓缩，用硅胶柱色 谱法以洗脱剂体系D纯化所得残余物，得标题化合物1k(0.9g，产率71.52％)。
MS m/z(ESI):271[M+18]。
第八步
1-(1,1,2,2,2-五氘代乙基磺酰基)-4-乙烯基-苯1l
将化合物1k(0.8g，3.46mmol)、4,4,5,5-四甲基-2-乙烯基-1,3,2-二氧杂戊硼烷(1g，6.92mmol，韶远化学科技(上海)有限公司)溶于12mL 1,4-二氧六环和水(V:V＝5:1)的混合溶剂中，加入四三苯基膦钯(400mg，346.24μmol)和碳酸铯(2.3g，6.92mmol)，氩气氛下，反应体系于95℃搅拌18小时。反应液冷却至室温，用乙酸乙酯萃取(30mL×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D纯化所得残余物，得标题化合物1l(0.6g，产率86.09％)。
MS m/z(ESI):219[M+18]。
第九步
N-[2-羟基1-[4-(1,1,2,2,2-五氘代乙基磺酰基)苯基]乙基]氨基甲酸叔丁酯1m
将氢氧化钠(410mg，10.28mmol)溶于水(20mL)中，取其中5mL溶解二水锇酸钾(60mg，137.11μmol)备用，将15mL预制的氨基甲酸叔丁酯(98％，1.5g，12.00mmol)的正丙醇溶液加入上述氢氧化钠溶液，冰水浴冷却，滴加次氯酸叔丁酯(1.2g，10.28mmol)，搅拌5分钟，加入5mL预制的氢化奎尼定1,4-(2,3-二氮杂萘)二醚(0.17g，205.67μmol)的正丙醇溶液，加入化合物1l(0.6g，3.43mmol)和上述二水锇酸钾溶液，反应体系于25℃搅拌1小时。反应液减压浓缩，加入20mL水，用乙酸乙酯萃取(30mL×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D纯化所得残余物，得标题化合物1m(R/S＝14/1)(0.5g，产率43.62％)。
MS m/z(ESI):235[M+1-100]，279[M+1-56]。
第十步
2-氨基-2-[4-(1,1,2,2,2-五氘代乙基磺酰基)苯基]乙醇盐酸盐1n
将化合物1m(0.5g，1.5mmol)溶于15mL甲醇，加入3mL浓盐酸，搅拌反应1小时。反应液减压浓缩，得粗品标题化合物1n(350mg，产率：86.46％)。
MS m/z(ESI):235[M+1]
第十一步
2-[[4-氯-2-(三氟甲基)苯基]甲基]-1-(2-氟乙基)-N-[(1R)-2-羟乙基-1-[4-(1,1,2,2,2-五氘代乙基磺酰基)苯基]乙基]吲哚-5-甲酰胺1
将化合物1g(0.15g，500.29μmol)和粗品化合物1n(150mg，650.38μmol)溶于5mL  N,N-二甲基甲酰胺中，加入2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(0.4g，1mmol)和N,N-二异丙基乙胺(0.2g，1mmol)，搅拌反应1小时。反应液减压浓缩，用高效液相色谱法纯化(Waters 2767-SQ高压液相色谱仪，sunfire OBD,150*19mm 5nfi色谱柱，洗脱体系：碳酸氢铵，水，乙腈)所得残余物，得粗品标题化合物6(70mg)，将粗品进行手性制备(分离条件：手性制备柱Amylose-1 20*250mm,5um；流动相：乙醇/正己烷＝40/60(v/v)，流速：20mL/分钟)，收集其相应组分，减压浓缩，得到标题化合物(I)(55.8mg，产率：18.10％)。
MS m/z(ESI):616[M+1]。产物经X-射线粉末衍射检测为无定型，其XRPD图见图1。
手性HPLC：保留时间13.798分钟，(色谱柱：Lux Amylose-1(AD)4.6*150mm 5um；流动相：乙醇(含0.1％二乙胺)/正己烷＝40/60(v/v))。
1HNMR(400MHz,CDCl 3)δ8.11(s,1H),7.88-7.86(d,2H),7.75-7.72(m,2H),7.61-7.59(d,2H),7.47-7.44(d,1H),7.34-7.32(m,1H),7.29-7.27(m,1H),7.13-7.11(d,1H),6.30(s,1H),5.33-5.32(m,1H),4.69-4.66(m,1H),4.57-4.55(m,1H),4.34(s,3H),4.30-4.27(m,1H),4.08-4.05(dd,1H),4.01-3.97(dd,1H)。
生物学评价
以下结合测试例进一步描述解释本公开，但这些实施例并非意味着限制本公开的范围。
测试例1、式(I)所示化合物对RORγ体外活性的测定
一、实验材料及仪器
1.
Figure PCTCN2020078506-appb-000008
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共激活体系筛选本公开的化合物对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值。
式(I)所示化合物对RORγ体外活性通过以上的试验进行测定，测得的EC 50(nM)为33，Emax(％)为102％。式(I)所示化合物对RORγ体外活性具有明显的激动作用。
测试例2、式(I)所示化合物对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 Systems)
6.CO 2培养箱(Fisher Scientific)
7.离心机(Fisher Scientific)
8..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。
式(I)所示化合物对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(nM)为37，Emax(％)为100％。式(I)所示化合物对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、式(I)所示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式(I)所示化合物后不同时刻血浆中的药物浓度。研究本公开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
式(I)所示化合物。
2.2试验动物
C57小鼠18只，雌性，平均分为2组，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
小鼠灌胃给药式(I)所示化合物，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
式(I)所示化合物的药代动力学参数如下表1：
表1.式(I)所示化合物的药代动力学参数
Figure PCTCN2020078506-appb-000009
Figure PCTCN2020078506-appb-000010
结论：式(I)所示化合物的药代吸收较好，具有药代动力学优势。
实施例2、晶型A的制备
将式(I)所示化合物(1.57g，2.55mmol)加入到乙醇(18mL)中，加热至回流溶清，缓慢降温至室温，室温搅拌2小时，过滤，收集滤饼真空干燥，得到标题产物(1.43g，收率：91％)。
经X-射线粉末衍射检测，将该产物定义为晶型A，XRPD谱图如图2；其特征峰位置如下表2所示：
表2.A晶型特征峰
Figure PCTCN2020078506-appb-000011
Figure PCTCN2020078506-appb-000012
式(I)所示化合物A晶型的DSC、TGA谱图如图3，DSC吸热峰峰值136.1℃，TGA：24℃-120℃失重0.24％。
DVS检测显示在10％RH-80％RH之间，随着湿度增加，质量增加约为2.987％，小于15％但不小于2％，根据《中华人民共和国药典》2015年版药物引湿性试验指导原则，该样品有引湿性。在正常储存条件(即25℃湿度60％)，吸水约为1.505％；在加速试验条件(即湿度70％)，吸水约为2.328％；在极端条件(即湿度90％)，吸水约为3.274％。在0％-95％的湿度变化过程中，该样品的解吸附过程与吸附过程基本重合(见图4)。DVS检测后复测晶型，晶型未转变(见图5)。
实施例3、晶型A的制备
将式(I)所示化合物(200mg，324.6μmol)，加入乙酸乙酯(2.4mL)，加热至回流溶解，滴加正庚烷只溶液稍浑浊，缓慢降温至室温，室温搅拌16小时，过滤，收集滤饼，真空干燥，得到标题产物(124mg，产率：62.0％)，经X-射线粉末衍射检测，该产物为晶型A。
实施例4、晶型B的制备
将式(I)所示化合物(13.5g，21.9mmol)，加入到甲醇(202mL)中，加热至70℃溶清，缓慢降温至室温，室温搅拌3小时，过滤，滤饼用20mL甲醇淋洗，收集滤饼，真空干燥，得到标题产物(11.7g，产率：86.7％)。经X-射线粉末衍射检测，将该产物定义为晶型B，XRPD谱图如图6；其特征峰位置如下表3所示：
表3.B晶型特征峰
Figure PCTCN2020078506-appb-000013
Figure PCTCN2020078506-appb-000014
式(I)所示化合物B晶型的DSC、TGA谱图如图7，DSC吸热峰峰值120.6℃，TGA：28℃-120℃失重3.31％。
1HNMR(400MHz,DMSO)δ8.64(d,1H),8.09(s,1H),7.92-7.81(m,3H),7.79-7.62(m,4H),7.55(d,1H),7.33(d,1H),6.02(s,1H),5.17(q,1H),5.04(t,1H),4.74(br.s.1H),4.66-4.59(m,1H),4.53(br.s.1H)，4.46(br.s.1H)，4.35(s,2H),3.82-3.65(m,2H)。
实施例5、晶型C的制备
将式(I)所示化合物(200mg，1.17mmol)，加入到4-甲基-2-戊酮中(2.0mL)，加热至回流溶清，缓慢降至室温，室温搅拌16小时，过滤，收集滤饼，真空干燥，得到标题产物(106mg，产率：53.0％)。经X-射线粉末衍射检测，将该产物定义为晶型C，XRPD谱图如图8；其特征峰位置如下表4所示：
表4.C晶型特征峰
Figure PCTCN2020078506-appb-000015
Figure PCTCN2020078506-appb-000016
该晶型DSC谱图显示吸热峰峰值为93.24℃、112.88℃；TGA谱图显示35℃-110℃失重9.4％；4-甲基-2-戊酮溶剂残留8.9wt％。
1HNMR(400MHz,DMSO)δ8.62(d,1H),8.05(s,1H),7.91-7.82(m,3H),7.80-7.62(m,4H),7.53(d,1H),7.31(d,1H),6.01(s,1H),5.19(q,1H),5.06(t,1H),4.72(br.s.1H),4.67-4.58(m,1H),4.52(br.s.1H)，4.45(br.s.1H)，4.32(s,2H),3.81-3.68(m,2H),0.793-0.778(d,3.6H)。
实施例6、晶型D的制备
将式(I)所示化合物晶型A(200mg，81.2umol)，加入到二氧六环中(3.0mL)，室温打浆搅拌3小时，过滤，收集滤饼，真空干燥，得到标题产物(92mg，产率：46.0％)。经X-射线粉末衍射检测，将该产物定义为晶型D，XRPD谱图如图9；其特征峰位置如下表5所示：
表5.D晶型特征峰
Figure PCTCN2020078506-appb-000017
Figure PCTCN2020078506-appb-000018
该晶型DSC谱图显示吸热峰峰值为105.86℃；TGA谱图显示45℃-110℃失重8.9％，120℃-225℃失重5.38％。
1H NMR(400MHz,DMSO-d 6)ppm 8.56(d,1H),8.01(s,1H),7.73-7.85(m,3H),7.56-7.72(m,4H),7.47(d,1H),7.25(d,1H),5.94(s,1H),5.09(d,1H),4.96(t,1H),4.66(t,1H),4.55(t,1H),4.46(d,1H),4.39(d,1H),4.27(s,2H),
3.58-3.73(m,2H),3.50(s,1.46H)
溶剂二氧六环残留2.54wt％。
实施例7、晶型E的制备
将式(I)所示化合物(300mg，486.95μmol)加入2.0mL丙酮中，加热至回流溶清，滴加水至稍微浑浊，缓慢降至室温，室温搅拌2小时，过滤，收集滤饼，真空干燥，得到标题产物(215mg，产率：71.67％)。经X-射线粉末衍射检测，将该产物定义为晶型E，XRPD谱图如图10；其特征峰位置如下表6所示：
表6.E晶型特征峰
Figure PCTCN2020078506-appb-000019
Figure PCTCN2020078506-appb-000020
该晶型DSC谱图显示吸热峰峰值为123.62℃。
实施例8、晶型F的制备
将式(I)所示化合物(187mg，303.5μmol)加入1.0mL四氢呋喃中，加热至回流，搅拌溶清，滴加水(约0.2mL)至稍微浑浊，缓慢降至室温，室温搅拌2小时，过滤，收集滤饼，真空干燥，得到标题产物(80.2mg，产率：42.89％)。经X-射线粉末衍射检测，将该产物定义为晶型F，XRPD谱图如图11；其特征峰位置如表7所示：
表7.F晶型特征峰
Figure PCTCN2020078506-appb-000021
该晶型DSC谱图DSC谱图显示吸热峰峰值为118.51、138.75℃；TGA谱图显示40℃-120℃失重1.90％。
1HNMR(400MHz,DMSO)δ8.59(d,1H),8.09(s,1H),7.92-7.81(m,3H),7.79-7.63(m,4H),7.54(d,1H),7.32(d,1H),6.02(s,1H),5.20(q,1H),5.07(t,1H),4.73(br.s.1H),4.68-4.59(m,1H),4.53(br.s.1H)，4.45(br.s.1H)，4.31(s,2H),3.82-3.68(m,2H)。
实施例9、晶型G的制备
将式(I)所示化合物(300mg，486.95μmol)加入到1.8mL四氢呋喃中，加热至回流溶清，滴加水(约1.6mL)至稍微浑浊，降至室温，室温搅拌1小时，过滤，收集滤饼，真空干燥，得到标题产物(196mg，产率：65.3％)。经X-射线粉末衍射检测，该产物定义为晶型G，XRPD谱图如图12；其特征峰位置如表8所示：
表8.G晶型特征峰
Figure PCTCN2020078506-appb-000022
该晶型DSC谱图显示吸热峰峰值为123.53℃；TGA谱图显示40℃-135℃失重3.71％。
1HNMR(400MHz,DMSO)δ8.58(d,1H),8.02(s,1H),7.85-7.73(m,3H),7.73-7.57(m,4H),7.49(d,1H),7.27(d,1H),5.96(s,1H),5.10(q,1H),4.97(t,1H),4.68(s.1H),4.56(d,1H),4.47(br.s.1H)，4.40(br.s.1H)，4.29(s,2H),3.67(m,2H)。
实施例10、晶型H的制备
将式(I)所示化合物晶型A(7mg，11μmol)、晶型F(7mg，11μmol)加入0.5mL 2-甲基四氢呋喃中，为混悬液，室温打浆搅拌72小时，过滤，收集滤饼，真空干燥，得到标题产物(5.2mg，产率：37.14％)。经X-射线粉末衍射检测，该产物定义为晶型H，XRPD谱图如图13；其特征峰位置如表9所示：
表9.H晶型特征峰
Figure PCTCN2020078506-appb-000023
该晶型DSC谱图显示吸热峰峰值为123.21℃；TGA谱图显示40℃-135℃失重3.69％。
1HNMR(400MHz,DMSO)δ8.63(d,1H),8.08(s,1H),7.92-7.78(m,3H),7.78-7.61(m,4H),7.54(d,1H),7.32(d,1H),6.01(s,1H),5.16(q,1H),5.03(t,1H),4.73(br.s.1H),4.61(m,1H),4.52(br.s.1H)，4.45(br.s.1H)，4.34(s,2H),3.80-3.65(m,2H),1.111-1.104(m,0.98H)。
溶剂残留2-甲基四氢呋喃4.4wt％。
实施例11、晶型I的制备
将式(I)所示化合物晶型A(7mg，11μmol)、晶型F(7mg，11μmol)加入0.5mL丙酮和水(V:V＝1:1)混合溶剂中，为混悬液，室温打浆搅拌72小时，过滤，收集滤饼，真空干燥，得到标题产物(8.2mg，产率：58.6％)。经X-射线粉末衍射检测，该产物定义为晶型I，XRPD谱图如图14；其特征峰位置如表10所示：
表10.I晶型特征峰
Figure PCTCN2020078506-appb-000024
该晶型的DSC谱图显示吸热峰峰值为127.4℃；TGA谱图显示40℃-135℃失重3.69％。
实施例12、晶型J的制备
将式(I)所示化合物晶型A(50mg，81μmol)加入到1mL硝基甲烷中，混悬，室温搅拌72小时，过滤，收集滤饼，真空干燥，得到标题产物(29.5mg，产率：59.0％)。经X-射线粉末衍射检测，该产物为晶型J，XRPD谱图如图15；其特征峰位置如表11所示：
表11.J晶型特征峰
Figure PCTCN2020078506-appb-000025
Figure PCTCN2020078506-appb-000026
该晶型DSC谱图显示吸热峰峰值为146.34℃；TGA谱图显示110℃-165℃失重0.98％。
实施例13、晶型K的制备
将式(I)所示化合物晶型A(150mg，243μmol)加入到1mL乙腈中，混悬，室温搅拌120小时，过滤，收集滤饼，真空干燥，得到标题产物(77mg，产率：51.33％)。经X-射线粉末衍射检测，该产物定义为晶型K，XRPD谱图如图16；其特征峰位置如表12所示：
表12.K晶型特征峰
Figure PCTCN2020078506-appb-000027
式(I)所示化合物K晶型的DSC、TGA谱图如图17，吸热峰峰值为120.9℃、164.6℃；TGA：27.8℃-100℃失重1.58％。
实施例14、晶型A的制备
将式(I)所示化合物晶型A(7mg，11μmol)、晶型C(7mg，11μmol)、晶型D(7mg，11μmol)、晶型E(7mg，11μmol)、晶型G(7mg，11μmol)加入到0.5mL异丙醇中，混悬，室温搅拌72小时，过滤，收集滤饼，真空干燥，得到标题产物(21.2mg，产率：60.57％)。
经X-射线粉末衍射检测，该产物为晶型A。
实施例15、晶型A的制备
将式(I)所示化合物晶型A(7mg，11μmol)、晶型C(7mg，11μmol)、晶型D(7mg，11μmol)、晶型E(7mg，11μmol)、晶型G(7mg，11μmol)加入到0.5mL乙醇和水(V:V＝1:1)混合溶剂中，混悬，室温搅拌72小时，过滤，收集滤饼，真空干燥，得到标题产物(22.7mg，产率：64.86％)。
经X-射线粉末衍射检测，该产物为晶型A。
实施例16、晶型A的制备
将式(I)所示化合物晶型A(10mg，16μmol)、晶型J(10mg，16μmol)加入到0.5mL异丙醚中，混悬，室温搅拌72小时，过滤，收集滤饼，真空干燥，得到标题产物(12.5mg，产率：62.5％)。
经X-射线粉末衍射检测，该产物为晶型A。
实施例17、晶型A影响因素实验
将式(I)化合物晶型A(实施例2)样品敞口平摊放置，考察在加热(40℃、60℃)、光照(4500Lux)、高湿(RH 75％、RH 90％)条件下样品的稳定性，取样考察期为30天。
实验结果：
表13、式(I)化合物晶型A影响因素实验结果
Figure PCTCN2020078506-appb-000028
Figure PCTCN2020078506-appb-000029
实验结论：
由表13的影响因素实验结果表明：在光照、高温40℃、高温60℃、高湿75％、高湿90％条件下，放置30天，晶型A的物理化学稳定性较好。
实施例18、本公开晶型B影响因素实验
将式(I)化合物晶型B(实施例4)样品敞口平摊放置，考察在加热(40℃、60℃)、光照(4500Lux)、高湿(RH 75％、RH 90％)条件下样品的稳定性，取样考察期为30天。
实验结果：
表14、式(I)化合物晶型B影响因素实验结果
Figure PCTCN2020078506-appb-000030
实验结论：
由表14的影响因素实验结果表明：在光照、高温40℃、高温60℃、高湿75％、高湿90％条件下，放置30天，晶型B的物理化学稳定性较好。
实施例19、本公开晶型A、晶型B长期加速稳定性实验
式(I)化合物晶型A(实施例2)和晶型B(实施例4)进行6个月的长期(25℃、60％RH)、加速(40℃、75％RH)稳定性考察，已进行两个月，继续进行中。
实验结果
表15、式(I)化合物晶型A和晶型B长期加速稳定性实验结果：
Figure PCTCN2020078506-appb-000031
由表15的长期加速稳定性实验结果显示：晶型A和晶型B长期(25℃、60％RH)、加速(40℃、75％RH)稳定性条件下放置6个月的物理化学稳定性好。

Claims (24)

  1. 一种式(I)所示化合物的A晶型，其特征在于：以衍射角2θ角度表示的X-射线粉末衍射图谱，在6.315、9.039、9.703、12.536、15.165、16.235、17.098和21.706处有特征峰
    Figure PCTCN2020078506-appb-100001
  2. 根据权利要求1所述的式(I)所示化合物的A晶型，其特征在于：以衍射角2θ角度表示的X-射线粉末衍射图谱,在6.315、9.039、9.703、12.536、13.573、15.165、16.235、17.098、17.876、21.406、21.706、23.248、24.669和25.136处有特征峰。
  3. 根据权利要求2所述的式(I)所示化合物的A晶型，其特征在于：以衍射角2θ角度表示的X-射线粉末衍射图谱如图2所示。
  4. 一种式(I)所示化合物的B晶型，其特征在于：以衍射角2θ角度表示的X-射线粉末衍射图谱，在9.874、14.893、15.387、19.202、20.918、24.179和25.566处有特征峰
    Figure PCTCN2020078506-appb-100002
  5. 根据权利要求4所述的式(I)所示化合物的B晶型，其特征在于：以衍射角2θ角度表示的X-射线粉末衍射图谱，在9.874、14.893、15.387、19.202、20.918、22.195、24.179、24.689、25.566、26.502和28.963处有特征峰。
  6. 根据权利要求5所述的式(I)所示化合物的B晶型，其特征在于：以衍射角2θ角度表示的X-射线粉末衍射图谱如图6所示。
  7. 一种式(I)所示化合物的C晶型，其特征在于：以衍射角2θ角度表示的X-射线粉末衍射图谱，在8.302、11.241、14.018、15.861、17.921、19.186和22.874处有特征峰
    Figure PCTCN2020078506-appb-100003
  8. 一种式(I)所示化合物的D晶型，其特征在于：以衍射角2θ角度表示的X-射线粉末衍射图谱，在6.625、8.384、14.959、16.453、17.816和19.915处有特征峰
    Figure PCTCN2020078506-appb-100004
  9. 一种式(I)所示化合物的E晶型，其特征在于：以衍射角2θ角度表示的X-射线粉末衍射图谱，在13.824、14.967、15.980、16.730、21.684和25.212处有特征峰
    Figure PCTCN2020078506-appb-100005
  10. 一种式(I)所示化合物的F晶型，其特征在于：以衍射角2θ角度表示的X-射线粉末衍射图谱，在7.680、11.319、14.200、15.460、16.480、23.000、23.861和26.220处有特征峰
    Figure PCTCN2020078506-appb-100006
  11. 一种式(I)所示化合物的G晶型，其特征在于：以衍射角2θ角度表示的X-射线粉末衍射图谱，在7.480、9.400、12.201、13.238、15.259、16.300、17.859、18.900、22.500和25.320处有特征峰
    Figure PCTCN2020078506-appb-100007
  12. 一种式(I)所示化合物的H晶型，其特征在于：以衍射角2θ角度表示的X-射线粉末衍射图谱，在8.265、10.453、12.476、14.633、16.774和17.933处有特征峰
    Figure PCTCN2020078506-appb-100008
  13. 一种式(I)所示化合物的I晶型，其特征在于：以衍射角2θ角度表示的X-射线粉末衍射图谱，在7.098、10.159、12.487、13.797、17.119、17.797、18.261和24.074处有特征峰
    Figure PCTCN2020078506-appb-100009
  14. 一种式(I)所示化合物的J晶型，其特征在于：以衍射角2θ角度表示的X-射线粉末衍射图谱，在7.268、9.203、14.668、15.024、18.060和21.815处有特征峰
    Figure PCTCN2020078506-appb-100010
  15. 一种式(I)所示化合物的K晶型，其特征在于：以衍射角2θ角度表示的X-射线粉末衍射图谱，在6.937、12.267、13.747、16.079、18.671和20.205处有特征峰
    Figure PCTCN2020078506-appb-100011
  16. 根据权利要求1-15任一项所述的式(I)所示化合物的晶型，其特征在于所述2θ角度的误差范围为±0.2。
  17. 一种式(I)所示化合物的A晶型的制备方法：包括
    1)将式(I)所示化合物混于溶剂中溶解，析晶的步骤，所述溶剂选自异丙醇、乙醇、乙醇-水混合物；或
    2)将式(I)所示化合物混于第一溶剂中溶解，滴加第二溶剂析晶的步骤；所述第一溶剂选自乙酸乙酯；所述第二溶剂选自正庚烷；或
    3)将式(I)所示化合物B晶型混于第一溶剂中溶解，滴加第二溶剂析晶的步骤；所述第一溶剂选自乙醇；所述第二溶剂选自水；或
    4)将式(I)所示化合物A晶型或含有A晶型的式(I)所示化合物混于溶剂中打浆的步骤，所述溶剂选自乙醇、乙酸异丙酯、异丙醇、异丙醚、水、乙酸乙酯、甲基叔丁基醚、甲苯、乙酸丁酯、正丁醇、环己烷、乙醇-水混合溶剂。
  18. 一种式(I)所示化合物的B晶型的制备方法：包括
    1)将式(I)所示化合物混于甲醇中，溶解，析晶的步骤；或
    2)将式(I)所示化合物混于第一溶剂中溶解，滴加第二溶剂析晶的步骤；所述第一溶剂为甲醇；所述第二溶剂为水；或
    3)将式(I)所示化合物混于甲醇中打浆的步骤；或
    4)将式(I)所示化合物混合物混于甲醇中，溶解、挥发析晶的步骤。
  19. 一种药物组合物，包含权利要求1-16任一项所述的式(I)所示化合物的A晶型、B晶型、C晶型、D晶型、E晶型、F晶型、G晶型、H晶型、I晶型、J晶型、K晶型中的一种或多种，以及一种或多种药学上可接受的载体、稀释剂或赋形剂。
  20. 一种药物组合物，由选自权利要求1-16任一项所述的式(I)所示化合物的晶型或其混合物与至少一种药学上可接受的载体、稀释剂或赋形剂混合制得。
  21. 根据权利要求19或20所述的药物组合物，其特征在于所述的组合物进一步含有抗PD-1抗体。
  22. 权利要求1-16任一项所述的式(I)所示化合物的晶型或权利要求19或20所述的药物组合物在制备ROR激动剂中的用途。
  23. 权利要求1-16任一项所述的式(I)所示化合物的晶型，或者权利要求19或20所述的药物组合物在制备用于预防和/或治疗肿瘤或癌症的药物中的用途。
  24. 权利要求1-16任一项所述的式(I)所示化合物的晶型，或者权利要求19或20所述的药物组合物与抗PD-1抗体联合在制备用于预防和/或治疗肿瘤或癌症的药物中的用途。
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WO2017157332A1 (zh) * 2016-03-18 2017-09-21 江苏恒瑞医药股份有限公司 芳香酰胺类衍生物、其制备方法及其在医药上的应用
WO2019007382A1 (zh) * 2017-07-06 2019-01-10 江苏恒瑞医药股份有限公司 吲哚甲酰胺类衍生物、其制备方法及其在医药上的应用
WO2019052440A1 (zh) * 2017-09-12 2019-03-21 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、其制备方法及其在医药上的应用

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WO2017157332A1 (zh) * 2016-03-18 2017-09-21 江苏恒瑞医药股份有限公司 芳香酰胺类衍生物、其制备方法及其在医药上的应用
WO2019007382A1 (zh) * 2017-07-06 2019-01-10 江苏恒瑞医药股份有限公司 吲哚甲酰胺类衍生物、其制备方法及其在医药上的应用
WO2019052440A1 (zh) * 2017-09-12 2019-03-21 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、其制备方法及其在医药上的应用

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