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WO2023138647A1 - 一种含硫异吲哚啉类衍生物的晶型 - Google Patents

一种含硫异吲哚啉类衍生物的晶型 Download PDF

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Publication number
WO2023138647A1
WO2023138647A1 PCT/CN2023/073077 CN2023073077W WO2023138647A1 WO 2023138647 A1 WO2023138647 A1 WO 2023138647A1 CN 2023073077 W CN2023073077 W CN 2023073077W WO 2023138647 A1 WO2023138647 A1 WO 2023138647A1
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Prior art keywords
formula
angle
crystal form
ray powder
characteristic peaks
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PCT/CN2023/073077
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English (en)
French (fr)
Inventor
张宝磊
奚倬勋
冯君
贺峰
杨俊然
杜振兴
Original Assignee
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 MX2024008959A priority Critical patent/MX2024008959A/es
Priority to AU2023210002A priority patent/AU2023210002A1/en
Priority to CN202380016119.5A priority patent/CN118510766A/zh
Priority to KR1020247027045A priority patent/KR20240136385A/ko
Publication of WO2023138647A1 publication Critical patent/WO2023138647A1/zh

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    • 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
    • C07D401/14—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 three or more hetero 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • 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
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present disclosure relates to a crystal form of a sulfur-containing isoindoline derivative and a preparation method thereof, specifically, a crystal form of a compound represented by formula I and a preparation method thereof are provided.
  • MM Multiple myeloma
  • MM is a malignant tumor with main symptoms including hypercalcemia, kidney damage, anemia and bone disease.
  • MM is the second most common hematological malignancy after non-Hodgkin's lymphoma, and the current treatment methods are mainly drug therapy and autologous stem cell transplantation.
  • drugs widely used clinically, which are immunomodulators of the iridamine class, proteasome inhibitors, hormones, and monoclonal antibodies.
  • Drugs in the clinical research stage include double antibodies, ADC, CAR-T, etc. The mechanism of action of these drugs is different, and combined use can often achieve better curative effect.
  • Clinically dual, triple, or even quadruple drugs are generally used, usually in combination with immunomodulators, proteasome inhibitors and hormones, and sometimes antibodies are added.
  • lenalidomide is the most commonly used immunomodulator. It is used in first-line treatment, maintenance treatment after stem cell transplantation, and second- and third-line treatment after relapse. Sales of the drug reached $9.7 billion in 2018/2019.
  • the entire MM market is also considerable and growing rapidly. This is due to the continuous improvement and perfection of the diagnosis and treatment of MM, the longer survival period of patients, and the corresponding extension of medication time. It is estimated that the MM market will reach a scale of 33 billion US dollars in 2022, of which the largest proportion is still the immunomodulator represented by lenalidomide.
  • IKZF1 immunomodulators
  • IKZF3 can also inhibit the transcription of IL2 and TNF cytokines in T/NK cells.
  • the currently approved IMiD drugs include thalidomide, lenalidomide and pomalidomide, all of which are from Celgene (currently merged by BMS).
  • the binding force of the three compounds to CRBN is sequentially enhanced, so the clinical dosage is decreased sequentially.
  • the main indication of the three compounds is MM, and thalidomide and lenalidomide have other indications, especially lenalidomide, which can be used to treat myelodysplastic syndrome (MDS).
  • MDS myelodysplastic syndrome
  • lenalidomide and pomalidomide have similar performance and have obvious bone marrow suppression, which is a toxicity related to the target; thalidomide has some other side effects, such as sedation, constipation, and neurological side effects.
  • IMiD adipimide moiety of all IMiDs binds to a hydrophobic pocket defined by three tryptophan residues in the CRBN (termed the "thalidomide-binding pocket").
  • the phthalimide/isoindolinone ring is exposed to solvent and alters the molecular surface of CRBN, thereby modulating substrate recognition.
  • Different IMiDs lead to obvious modifications on the molecular surface of CRBN and different substrate recognition preferences. Therefore, the modification of IMiDs may lead to the degradation of other transcription factors, causing unnecessary toxic side effects.
  • This mode of action of IMiD is also called molecular glue, which vividly expresses the binding effect of this small molecule on two protein substrates.
  • the applicant's patent application WO2022017365 provides a compound as shown in formula I, its chemical name is (S)-4-(4-((5-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4-yl)oxy)methyl)pyridin-2-yl)thio)piperidin-1-yl)-3-fluorobenzonitrile, which has better Cereblon regulating effect.
  • the crystal structure of the active ingredient of a drug and its salt not only affects the physical and chemical stability of the drug itself, but also affects the ease of drug preparation and production cost in the later stage.
  • Different crystallization conditions and storage conditions may lead to changes in the crystal structure of the compound and its salt, sometimes accompanied by other crystal forms. Therefore, it is necessary to study the crystal form of the compound represented by formula (I) comprehensively from the perspectives of stability, ease of drug preparation process, and production cost.
  • the present disclosure provides a crystal form of a compound represented by formula (I) and a preparation method thereof, wherein the chemical name of the compound represented by formula I is (S)-4-(4-((5-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindol-4-yl)oxy)methyl)pyridin-2-yl)thio)piperidin-1-yl)-3-fluorobenzonitrile,
  • the present disclosure provides an amorphous form of the compound represented by formula (I), and the diffraction angle 2 ⁇ of its X-ray powder diffraction pattern has no obvious characteristic peaks in the range of 2-48°.
  • the disclosure further provides a method for preparing an amorphous compound represented by formula (I), including method 1: a) mixing the compound represented by formula (I) with propylene glycol methyl ether, n-heptane or petroleum ether, b) beating and crystallizing;
  • the volume ( ⁇ l) of the solvent used in the present disclosure can be 1-200 times the mass (mg) of the compound of formula (I), and in non-limiting embodiments, it can be 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120 , 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 200.
  • the method for preparing the amorphous compound represented by (I) described in the present disclosure further includes the steps of filtering, washing or drying.
  • the present disclosure provides the crystal form A of the compound represented by formula (I), the X-ray powder diffraction pattern represented by the diffraction angle 2 ⁇ , and there are characteristic peaks at 5.765, 8.061, 9.925, 16.632, 17.900, 19.469 and 21.115.
  • the crystal form A of the compound represented by formula (I) has characteristic peaks at 5.765, 7.465, 8.061, 9.925, 12.890, 15.085, 16.632, 17.900, 19.469 and 21.115.
  • the crystal form A of the compound represented by formula (I) has characteristic peaks at 5.765, 7.465, 8.061, 9.925, 11.674, 12.890, 14.270, 15.085, 16.632, 17.900, 18.715, 19.469 and 21.115.
  • the X-ray powder diffraction pattern of the crystal form A of the compound represented by the formula (I) represented by the diffraction angle 2 ⁇ is shown in FIG. 2 .
  • the present disclosure further provides a method for preparing crystal form A of the compound represented by formula (I), including method 1: a) mixing the compound represented by formula (I) with tetrahydrofuran, dissolving, and b) adding n-heptane for crystallization;
  • Or method 2 a) the compound represented by formula (I) is mixed with dichloromethane, dissolved, and b) ethyl acetate is added for crystallization;
  • Or method 3 a) mixing the compound represented by formula (I) with water, isopropyl acetate, acetone, ethyl acetate/ethanol or ethyl acetate/n-heptane, b) beating and crystallizing;
  • the volume ( ⁇ l) of the solvent used in the present disclosure can be 1-200 times the mass (mg) of the compound of formula (I), and in non-limiting embodiments, it can be 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120 , 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 200.
  • the method for preparing crystal form A of the compound represented by formula (I) described in the present disclosure further includes steps such as filtering, washing or drying.
  • the present disclosure provides the crystal form B of the compound represented by formula (I), the X-ray powder diffraction pattern represented by the diffraction angle 2 ⁇ , and there are characteristic peaks at 4.977, 6.788, 10.047, 14.143, 15.684, 18.547 and 20.840.
  • the crystal form B of the compound represented by formula (I) has characteristic peaks at 4.977, 6.788, 10.047, 14.143, 15.684, 18.547, 20.840, 24.096 and 25.505.
  • the X-ray powder diffraction pattern of crystal form B of the compound represented by formula (I) represented by the diffraction angle 2 ⁇ is shown in FIG. 3 .
  • the present disclosure further provides a method for preparing crystal form B of compound represented by formula (I), comprising: a) mixing compound represented by formula (I) with ethyl acetate or acetonitrile/methanol, b) beating and crystallizing, and drying at 30°C;
  • the volume ( ⁇ l) of the solvent used in the present disclosure can be 1-200 times the mass (mg) of the compound of formula (I), and in non-limiting embodiments, it can be 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120 , 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 200.
  • the method for preparing crystal form B of the compound represented by formula (I) described in the present disclosure further includes steps such as filtering, washing or drying.
  • the present disclosure provides the crystal form C of the compound represented by formula (I), the X-ray powder diffraction pattern represented by the diffraction angle 2 ⁇ , and there are characteristic peaks at 5.653, 7.974, 9.989, 16.143, 17.860, 18.992 and 20.972.
  • the crystal form C of the compound represented by formula (I) has characteristic peaks at 5.653, 7.974, 9.989, 11.505, 12.798, 14.265, 16.143, 17.860, 18.992 and 20.972.
  • the crystal form C of the compound represented by formula (I) has characteristic peaks at 3.533, 5.653, 7.974, 8.790, 9.989, 11.505, 12.798, 14.265, 15.277, 16.143, 17.860, 18.992 and 20.972.
  • the X-ray powder diffraction pattern of crystal form C of the compound represented by formula (I) represented by diffraction angle 2 ⁇ is shown in FIG. 4 .
  • the present disclosure further provides a method for preparing crystal form C of the compound represented by formula (I), including method 1: a) mixing the compound represented by formula I with ethanol, isopropanol, methyl tert-butyl ether, methyl isobutyl ketone, water/ethanol, water/isopropanol, water/methanol (1:1), cyclohexane, and isopropyl ether; b) beating and crystallizing;
  • Or method 2 a) mix the compound represented by formula (I) with dichloromethane, water/acetone, tetrahydrofuran/ethanol, dissolve and clear, b) volatilize and crystallize;
  • the volume ( ⁇ l) of the solvent used in the present disclosure can be 1-200 times the mass (mg) of the compound of formula (I), and in non-limiting embodiments, it can be 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120 , 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 200.
  • the method for preparing crystal form C of the compound represented by formula (I) described in the present disclosure further includes steps such as filtering, washing or drying.
  • the present disclosure provides the crystal form D of the compound represented by formula (I), the X-ray powder diffraction pattern represented by the diffraction angle 2 ⁇ , and there are characteristic peaks at 6.831, 9.845, 13.453, 18.225, 20.117, 20.891 and 23.006.
  • the crystal form D of the compound represented by formula (I) has characteristic peaks at 6.831, 9.845, 10.927, 13.453, 16.096, 18.225, 20.117, 20.891, 23.006 and 26.132.
  • the X-ray powder diffraction pattern of crystal form D of the compound represented by formula (I) represented by the diffraction angle 2 ⁇ is shown in FIG. 5 .
  • the present disclosure further provides a method for preparing crystal form D of compound represented by formula (I), comprising:
  • Method 1 a) mixing the compound represented by formula (I) with acetonitrile, b) beating and crystallizing.
  • the volume ( ⁇ l) of the solvent used in the present disclosure can be 1-200 times the mass (mg) of the compound of formula (I), and in non-limiting embodiments, it can be 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120 , 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 200.
  • the method for preparing the crystal form D of the compound represented by formula (I) described in the present disclosure further includes steps such as filtering, washing or drying.
  • the present disclosure provides the crystal form E of the compound represented by formula (I), the X-ray powder diffraction pattern represented by the diffraction angle 2 ⁇ , and there are characteristic peaks at 5.864, 7.573, 8.087, 10.003, 16.444, 19.349 and 20.553.
  • the crystal form E of the compound represented by formula (I) has characteristic peaks at 5.864, 7.573, 8.087, 10.003, 12.471, 15.165, 16.444, 17.432, 19.349 and 20.553.
  • the crystal form E of the compound represented by formula (I) has characteristic peaks at 5.864, 7.573, 8.087, 10.003, 11.701, 12.471, 15.165, 16.444, 17.432, 19.349, 20.553, 21.067 and 21.709.
  • the X-ray powder diffraction pattern of crystal form E of the compound represented by formula (I) represented by diffraction angle 2 ⁇ is shown in FIG. 6 .
  • the present disclosure further provides a method for preparing crystal form E of compound represented by formula (I), including method 1: a) mixing compound represented by formula I with 2-butanone or 10% water/methanol, b) beating and crystallizing;
  • the volume ( ⁇ l) of the solvent used in the present disclosure can be 1-200 times the mass (mg) of the compound of formula (I), and in non-limiting embodiments, it can be 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120 , 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 200.
  • the method for preparing crystal form E of the compound represented by formula (I) described in the present disclosure further includes steps such as filtering, washing or drying.
  • the present disclosure provides the F crystal form of the compound represented by formula (I), the X-ray powder diffraction pattern represented by the diffraction angle 2 ⁇ , and there are characteristic peaks at 5.062, 7.820, 10.077, 14.231, 16.672, 18.586 and 20.435.
  • the crystal form F of the compound represented by formula (I) has characteristic peaks at 5.062, 7.820, 10.077, 14.231, 15.192, 16.672, 18.586, 20.435, 21.868 and 25.442.
  • the crystal form F of the compound represented by formula (I) has characteristic peaks at 5.062, 7.820, 10.077, 14.231, 15.192, 16.672, 18.586, 20.435, 21.868, 24.193, 25.442, 26.303 and 28.629.
  • the X-ray powder diffraction pattern of the crystal form F of the compound represented by formula (I) represented by the diffraction angle 2 ⁇ is shown in FIG. 7 .
  • the present disclosure further provides a method for preparing the F crystal form of compound represented by formula (I), comprising:
  • Method 1 a) mixing the compound represented by formula (I) with solvent II, wherein solvent II is selected from p-xylene, methanol, 2-methyltetrahydrofuran, o-xylene or toluene; b) beating and crystallizing;
  • Or method 2 a) mix the compound represented by formula (I) with dichloromethane or tetrahydrofuran, dissolve, and b) add isopropyl acetate, methyl tert-butyl ether or methyl isobutyl ketone for crystallization.
  • Or method 3 a) mix the compound represented by formula (I) with 1,4-dioxane, dissolve and clear, and b) volatilize and crystallize.
  • the volume ( ⁇ l) of the solvent used in the present disclosure can be 1-200 times the mass (mg) of the compound of formula (I), and in non-limiting embodiments, it can be 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120 , 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 200.
  • the method for preparing the crystal form F of the compound represented by formula (I) described in the present disclosure further includes steps such as filtering, washing or drying.
  • the present disclosure provides the crystal form G of the compound represented by formula (I), the X-ray powder diffraction pattern represented by the diffraction angle 2 ⁇ , and there are characteristic peaks at 5.999, 7.972, 9.951, 11.388, 17.812, 20.975 and 25.819.
  • the crystal form G of the compound represented by formula (I) is at 5.999, 7.396, 7.972, 8.637, 9.951, 11.388, There are characteristic peaks at 15.291, 17.812, 20.975 and 25.819.
  • the crystal form G of the compound represented by formula (I) has characteristic peaks at 5.999, 7.396, 7.972, 8.637, 9.951, 11.388, 12.763, 15.291, 17.812, 20.975, 23.408, 25.819 and 27.400.
  • the X-ray powder diffraction pattern of the crystal form G of the compound represented by formula (I) represented by the diffraction angle 2 ⁇ is shown in FIG. 8 .
  • the present disclosure further provides a method for preparing the crystal form of compound G shown in formula (I), comprising:
  • Method 1 a) mix the compound represented by formula (I) with chloroform, dissolve and clear, b) volatilize and crystallize.
  • Or method 2 a) mixing the compound represented by formula (I) with 1,2-dichloroethane, b) beating and crystallizing.
  • the volume ( ⁇ l) of the solvent used in the present disclosure can be 1-200 times the mass (mg) of the compound of formula (I), and in non-limiting embodiments, it can be 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120 , 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 200.
  • the method for preparing the crystal form G of the compound represented by formula (I) described in the present disclosure further includes steps such as filtering, washing or drying.
  • the present disclosure provides the H crystal form of the compound represented by formula (I), the X-ray powder diffraction pattern represented by the diffraction angle 2 ⁇ angle, with characteristic peaks at 5.758, 7.533, 9.901, 14.267, 16.420, 18.103 and 26.356. There are characteristic peaks at 67, 16.420, 18.103, 18.917, 20.489, 24.049 and 26.356.
  • the crystal form H of the compound represented by formula (I) has characteristic peaks at 5.758, 7.533, 9.901, 14.267, 16.420, 18.103, 18.917, 20.489, 24.049 and 26.356.
  • the X-ray powder diffraction pattern of the crystal form H of the compound represented by formula (I) represented by the diffraction angle 2 ⁇ is shown in FIG. 9 .
  • the present disclosure further provides a method for preparing the H crystal form of compound represented by formula (I), comprising:
  • Method 1 a) mixing the compound represented by formula (I) with n-octane or n-hexane, b) beating and crystallizing;
  • the volume ( ⁇ l) of the solvent used in the present disclosure can be 1-200 times the mass (mg) of the compound of formula (I), and in non-limiting embodiments, it can be 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120 , 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 200.
  • the method for preparing the H crystal form of the compound represented by formula (I) described in the present disclosure further includes steps such as filtering, washing or drying.
  • the present disclosure provides the crystal form I of the compound represented by formula (I), the X-ray powder diffraction pattern represented by the diffraction angle 2 ⁇ , and there are characteristic peaks at 5.294, 6.826, 7.564, 10.739, 13.699, 16.812 and 20.709.
  • the X-ray powder diffraction pattern of the crystal form I of the compound represented by the formula (I) represented by the diffraction angle 2 ⁇ is as follows: Figure 10 shows.
  • the present disclosure further provides a method for preparing the crystal form of compound I shown in formula (I), comprising:
  • Method 1 a) mixing the compound represented by formula (I) with tetrahydrofuran, dissolving it, and b) volatilizing and crystallizing.
  • Or method 2 a) mix the compound represented by formula (I) with tetrahydrofuran, dissolve it, and b) add water for crystallization.
  • the volume ( ⁇ l) of the solvent used in the present disclosure can be 1-200 times the mass (mg) of the compound of formula (I), and in non-limiting embodiments, it can be 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120 , 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 200.
  • the method for preparing the crystal form I of the compound represented by formula (I) described in the present disclosure further includes steps such as filtering, washing or drying.
  • the present disclosure provides the J crystal form of the compound represented by formula (I), the X-ray powder diffraction pattern represented by the diffraction angle 2 ⁇ , and there are characteristic peaks at 5.041, 10.068, 16.424, 20.544, 21.190, 24.077 and 25.433.
  • the crystal form J of the compound represented by formula (I) has characteristic peaks at 5.041, 8.212, 10.068, 14.101, 15.167, 16.424, 20.544, 21.190, 24.077 and 25.433.
  • the crystal form J of the compound represented by formula (I) has characteristic peaks at 5.041, 8.212, 10.068, 14.101, 15.167, 16.424, 20.544, 21.190, 22.036, 22.679, 24.077, 25.433 and 26.454.
  • the X-ray powder diffraction pattern of crystal form J of the compound represented by formula (I) represented by the diffraction angle 2 ⁇ is shown in FIG. 11 .
  • the present disclosure further provides a method for preparing crystal form J of compound represented by formula (I), comprising: a) mixing compound represented by formula (I) with dimethyl sulfoxide, dissolving, b) adding water, isopropyl acetate or methyl tert-butyl ether, and crystallizing.
  • the volume ( ⁇ l) of the solvent used in the present disclosure can be 1-200 times the mass (mg) of the compound of formula (I), and in non-limiting embodiments, it can be 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120 , 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 200.
  • the method for preparing crystal form J of the compound represented by formula (I) described in the present disclosure further includes steps such as filtering, washing or drying.
  • the present disclosure provides the K crystal form of the compound represented by formula (I), the X-ray powder diffraction pattern represented by the diffraction angle 2 ⁇ , and there are characteristic peaks at 5.156, 7.699, 10.339, 14.334, 16.203, 18.327 and 23.418.
  • the crystal form K of the compound represented by formula (I) has characteristic peaks at 5.156, 7.699, 10.339, 14.334, 16.203, 18.327, 23.418, 25.348, 25.919 and 26.446.
  • the X-ray powder diffraction pattern of crystal form K of the compound represented by formula (I) represented by the diffraction angle 2 ⁇ is shown in FIG. 12 .
  • the present disclosure further provides a method for preparing crystal form K of compound represented by formula (I), including: a) represented by formula (I) The compound is mixed with N-methylpyrrolidone, dissolved, and b) volatilized and crystallized.
  • the volume ( ⁇ l) of the solvent used in the present disclosure can be 1-200 times the mass (mg) of the compound of formula (I), and in non-limiting embodiments, it can be 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120 , 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 200.
  • the method for preparing the crystal form K of the compound represented by formula (I) described in the present disclosure further includes steps such as filtering, washing or drying.
  • the present disclosure provides the L crystal form of the compound represented by formula (I), the X-ray powder diffraction pattern represented by the diffraction angle 2 ⁇ , and there are characteristic peaks at 4.932, 5.360, 9.831, 14.844, 18.244, 20.104 and 24.914.
  • the crystal form L of the compound represented by formula (I) has characteristic peaks at 4.932, 5.360, 9.831, 10.753, 14.844, 16.369, 18.244, 20.104, 23.129, and 24.914.
  • the X-ray powder diffraction pattern of the crystal form L of the compound represented by formula (I) represented by the diffraction angle 2 ⁇ is shown in FIG. 13 .
  • the present disclosure further provides a method for preparing crystal form L of the compound represented by formula (I), comprising: a) mixing the compound represented by formula (I) with N,N dimethylacetamide, dissolving, and b) volatilizing and crystallizing.
  • the volume ( ⁇ l) of the solvent used in the present disclosure can be 1-200 times the mass (mg) of the compound of formula (I), and in non-limiting embodiments, it can be 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120 , 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 200.
  • the method for preparing the L crystal form of the compound represented by formula (I) described in the present disclosure further includes steps such as filtering, washing or drying.
  • the present disclosure provides the M crystal form of the compound represented by formula (I), the X-ray powder diffraction pattern represented by the diffraction angle 2 ⁇ , and there are characteristic peaks at 14.959, 16.322, 18.410, 20.748, 22.067, 23.670 and 26.863.
  • the crystal form M of the compound represented by formula (I) has characteristic peaks at 14.959, 16.322, 18.410, 20.748, 22.067, 23.670, 24.839, 25.873, 26.863 and 27.811.
  • the crystal form M of the compound represented by formula (I) has characteristic peaks at 14.959, 16.322, 18.410, 20.748, 22.067, 23.670, 24.322, 24.839, 25.873, 26.863 and 27.811.
  • the X-ray powder diffraction pattern of crystal form M of the compound represented by formula (I) represented by diffraction angle 2 ⁇ is shown in FIG. 14 .
  • the present disclosure further provides a method for preparing crystal form M of compound represented by formula (I), comprising: a) heating crystal form A, crystal form B, crystal form C, crystal form E, crystal form H or crystal form I of the compound represented by formula I to 225°C.
  • the volume ( ⁇ l) of the solvent used in the present disclosure can be 1-200 times the mass (mg) of the compound of formula (I), and in non-limiting embodiments, it can be 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 200.
  • the method for preparing the crystal form M of the compound represented by formula (I) described in the present disclosure further includes steps such as filtering, washing or drying.
  • the present disclosure provides the N crystal form of the compound represented by formula (I), the X-ray powder diffraction pattern represented by the diffraction angle 2 ⁇ , and there are characteristic peaks at 5.028, 9.942, 10.900, 15.428, 18.410, 20.274 and 25.252.
  • the crystal form N of the compound represented by formula (I) has characteristic peaks at 5.028, 7.671, 9.942, 10.900, 15.428, 16.560, 18.410, 20.274, 24.036 and 25.252.
  • the crystal form N of the compound represented by formula (I) has characteristic peaks at 5.028, 7.671, 9.942, 10.900, 12.677, 15.428, 16.560, 18.410, 20.274, 24.036, 25.252 and 26.385.
  • the X-ray powder diffraction pattern of the crystal form N of the compound represented by formula (I) represented by the diffraction angle 2 ⁇ is shown in FIG. 15 .
  • the present disclosure further provides a method for preparing the N crystal form of the compound represented by formula (I), comprising: a) mixing the compound represented by formula I with ethyl acetate/tetrahydrofuran (1:1), heating to dissolve, and b) cooling and crystallizing.
  • the volume ( ⁇ l) of the solvent used in the present disclosure can be 1-200 times the mass (mg) of the compound of formula (I), and in non-limiting embodiments, it can be 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120 , 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 200.
  • the method for preparing the N crystal form of the compound represented by formula (I) described in the present disclosure further includes steps such as filtering, washing or drying.
  • the present disclosure provides the O crystal form of the compound represented by formula (I), the X-ray powder diffraction pattern represented by the diffraction angle 2 ⁇ , and there are characteristic peaks at 11.796, 17.423, 18.081, 19.136, 21.707, 22.165 and 25.719.
  • the crystal form O of the compound represented by formula (I) has characteristic peaks at 7.843, 11.796, 17.423, 18.081, 19.136, 21.707, 22.165, 24.412, 25.719 and 28.521.
  • the crystal form O of the compound represented by formula (I) has characteristic peaks at 7.843, 11.796, 15.455, 17.423, 18.081, 19.136, 21.055, 21.707, 22.165, 24.412, 25.719, 27.538 and 28.521.
  • the X-ray powder diffraction pattern of the crystal form O of the compound represented by formula (I) represented by the diffraction angle 2 ⁇ is shown in FIG. 16 .
  • the disclosure further provides a method for preparing crystal form O of compound represented by formula (I), comprising: a) mixing compound represented by formula I with acetonitrile and benzenesulfonic acid, heating, and b) cooling and crystallizing.
  • the volume ( ⁇ l) of the solvent used in the present disclosure can be 1-200 times the mass (mg) of the compound of formula (I), and in non-limiting embodiments, it can be 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120 , 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 200.
  • the method for preparing the crystal form O of the compound represented by formula (I) described in the present disclosure further includes steps such as filtering, washing or drying.
  • the present disclosure provides the P crystal form of the compound represented by formula (I), the X-ray powder diffraction pattern represented by the diffraction angle 2 ⁇ , and there are characteristic peaks at 5.359, 7.491, 10.786, 14.249, 16.527, 17.729 and 20.798.
  • the crystal form P of the compound represented by formula (I) has characteristic peaks at 5.359, 7.491, 9.905, 10.786, 13.192, 14.249, 16.527, 17.729, 18.862 and 20.798.
  • the crystal form P of the compound represented by formula (I) has characteristic peaks at 5.359, 7.491, 9.905, 10.786, 13.192, 14.249, 16.527, 17.729, 18.862, 20.798, 23.799 and 26.555.
  • the X-ray powder diffraction pattern of crystal form P of the compound represented by formula (I) represented by diffraction angle 2 ⁇ is shown in FIG. 17 .
  • the present disclosure further provides a method for preparing crystal form P of the compound represented by formula (I), comprising: a) mixing crystal form C of the compound represented by formula (I) with 1,4-dioxane, and b) beating and crystallizing.
  • the volume ( ⁇ l) of the solvent used in the present disclosure can be 1-200 times the mass (mg) of the compound of formula (I), and in non-limiting embodiments, it can be 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120 , 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 200.
  • the method for preparing the P crystal form of the compound represented by formula (I) described in the present disclosure further includes steps such as filtering, washing or drying.
  • the disclosure provides the Q crystal form of the compound represented by formula (I), the X-ray powder diffraction pattern represented by the diffraction angle 2 ⁇ , and there are characteristic peaks at 5.038, 10.152, 15.850, 16.574, 18.892, 20.760 and 21.835.
  • the crystal form Q of the compound represented by formula (I) has characteristic peaks at 5.038, 10.152, 11.175, 15.850, 16.574, 18.892, 20.760, 21.835, 23.905 and 25.784.
  • the crystal form Q of the compound represented by formula (I) has characteristic peaks at 5.038, 7.682, 10.152, 11.175, 14.218, 15.850, 16.574, 18.892, 20.760, 21.835, 23.905, 25.784 and 26.418.
  • the X-ray powder diffraction pattern of crystal form Q of the compound represented by formula (I) represented by diffraction angle 2 ⁇ is shown in FIG. 18 .
  • the present disclosure further provides a method for preparing crystal form Q of the compound represented by formula (I), including method 1: a) mixing the compound represented by formula (I) with ethyl acetate, b) beating and crystallizing, and drying the solid at 70°C or 130°C;
  • the volume ( ⁇ l) of the solvent used in the present disclosure can be 1-200 times the mass (mg) of the compound of formula (I), and in non-limiting embodiments, it can be 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120 , 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 200.
  • the method for preparing the Q crystal form of the compound represented by formula (I) described in the present disclosure also includes steps such as filtering, washing or drying.
  • the present disclosure provides the U crystal form of the compound represented by formula (I), the X-ray powder diffraction pattern represented by the diffraction angle 2 ⁇ , and there are characteristic peaks at 14.155, 15.745, 17.314, 17.997, 18.838, 20.512 and 21.415.
  • the crystal form U of the compound represented by formula (I) has characteristic peaks at 14.155, 15.745, 16.564, 17.314, 17.997, 18.838, 20.512, 21.415, 23.557 and 26.313.
  • the crystal form U of the compound represented by formula (I) has characteristic peaks at 7.657, 14.155, 15.745, 16.564, 17.314, 17.997, 18.838, 20.512, 21.415, 23.557, 25.711, 26.313 and 28.029.
  • the X-ray powder diffraction pattern of the crystal form U of the compound represented by formula (I) represented by the diffraction angle 2 ⁇ is shown in FIG. 19 .
  • the present disclosure further provides a method for preparing crystal form U of the compound represented by formula (I), including method 1: a) mixing crystal form Q of the compound represented by formula (I) with water, b) beating and crystallizing;
  • Or method 2 a) mix the compound represented by formula I with DMSO, heat to dissolve, and b) add water for crystallization.
  • the volume ( ⁇ l) of the solvent used in the present disclosure can be 1-200 times the mass (mg) of the compound of formula (I), and in non-limiting embodiments, it can be 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120 , 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 200.
  • the method for preparing the U crystal form of the compound represented by formula (I) described in the present disclosure further includes steps such as filtering, washing or drying.
  • the disclosure provides the X crystal form of the compound represented by formula (I), the X-ray powder diffraction pattern represented by the diffraction angle 2 ⁇ , and there are characteristic peaks at 6.864, 9.873, 10.963, 13.801, 16.089, 18.006 and 20.929.
  • the crystal form X of the compound represented by formula (I) has characteristic peaks at 6.864, 9.873, 10.963, 13.801, 16.089, 18.006, 20.929 and 26.203.
  • the X-ray powder diffraction pattern of the crystal form X of the compound represented by formula (I) represented by the diffraction angle 2 ⁇ is shown in FIG. 20 .
  • the present disclosure further provides a method for preparing crystal form X of compound represented by formula (I), comprising: method 1: a) mixing crystal form D of compound represented by formula (I) with isopropyl ether or n-heptane, and b) beating and crystallizing.
  • the volume ( ⁇ l) of the solvent used in the present disclosure can be 1-200 times the mass (mg) of the compound of formula (I), and in non-limiting embodiments, it can be 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120 , 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 200.
  • the method for preparing crystal form X of the compound represented by formula (I) described in the present disclosure further includes steps such as filtering, washing or drying.
  • the present disclosure provides the Y crystal form of the compound represented by the formula (I), the X-ray powder diffraction represented by the diffraction angle 2 ⁇ angle There are characteristic peaks at 5.676, 7.666, 14.260, 16.562, 18.020, 21.802 and 26.425.
  • the crystal form Y of the compound represented by formula (I) has characteristic peaks at 5.676, 7.666, 9.985, 12.634, 14.260, 16.562, 18.020, 21.802, 26.425 and 26.974.
  • the crystal form Y of the compound represented by formula (I) has characteristic peaks at 5.676, 7.666, 9.985, 12.634, 14.260, 16.562, 18.020, 21.802, 24.051, 25.846, 26.425 and 26.974.
  • the X-ray powder diffraction pattern of the crystal form Y of the compound represented by formula (I) represented by the diffraction angle 2 ⁇ is shown in Figure 21 .
  • the present disclosure further provides a method for preparing crystal form Y of the compound represented by formula (I), comprising: a) mixing crystal form Q of the compound represented by formula (I) with isopropyl ether or n-heptane, and b) beating and crystallizing.
  • the volume ( ⁇ l) of the solvent used in the present disclosure can be 1-200 times the mass (mg) of the compound of formula (I), and in non-limiting embodiments, it can be 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120 , 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 200.
  • the method for preparing the Y crystal form of the compound represented by formula (I) described in the present disclosure further includes steps such as filtering, washing or drying.
  • the disclosure provides the V crystal form of the compound represented by formula (I), the X-ray powder diffraction pattern represented by the diffraction angle 2 ⁇ , and there are characteristic peaks at 5.649, 6.154, 6.720, 11.651, 18.757, 19.813 and 23.948.
  • the crystal form V of the compound represented by formula (I) has characteristic peaks at 5.649, 6.154, 6.720, 9.778, 11.651, 17.570, 18.757, 19.813, 23.948 and 26.995.
  • the crystal form V of the compound represented by formula (I) has characteristic peaks at 5.649, 6.154, 6.720, 9.778, 11.651, 13.576, 17.570, 18.757, 19.813, 21.905, 23.948, 25.825 and 26.995.
  • the X-ray powder diffraction pattern of crystal form V of the compound represented by formula (I) represented by diffraction angle 2 ⁇ is as shown in Figure 22 .
  • the present disclosure further provides a method for preparing crystal form V of the compound represented by formula (I), including method 1: a) mixing the compound represented by formula (I) with N,N-dimethylformamide, dissolving, and b) adding acetone or acetonitrile for crystallization;
  • the volume ( ⁇ l) of the solvent used in the present disclosure can be 1-200 times the mass (mg) of the compound of formula (I), and in non-limiting embodiments, it can be 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120 , 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 200.
  • the method for preparing the V crystal form of the compound represented by formula (I) described in the present disclosure further includes steps such as filtering, washing or drying.
  • the present disclosure provides the R crystal form of the compound represented by formula (I), the X-ray powder diffraction pattern represented by the diffraction angle 2 ⁇ , and there are characteristic peaks at 5.534, 7.611, 10.033, 15.782, 17.101, 19.017 and 20.567.
  • the crystal form R of the compound represented by formula (I) has characteristic peaks at 5.534, 7.611, 10.033, 11.857, 12.737, 15.782, 17.101, 19.017, 20.567 and 23.692.
  • the crystal form R of the compound represented by formula (I) has characteristic peaks at 5.534, 7.611, 10.033, 11.148, 11.857, 12.737, 14.179, 15.782, 17.101, 19.017, 20.567, 21.871 and 23.692.
  • the X-ray powder diffraction pattern of the crystal form R of the compound represented by formula (I) represented by the diffraction angle 2 ⁇ is shown in Figure 23 .
  • the disclosure further provides a method for preparing crystal form R of the compound represented by formula (I), comprising: a) mixing the compound represented by formula (I) with tetrahydrofuran, dissolving, and b) concentrating and crystallizing.
  • the volume ( ⁇ l) of the solvent used in the present disclosure can be 1-200 times the mass (mg) of the compound of formula (I), and in non-limiting embodiments, it can be 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120 , 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 200.
  • the method for preparing the R crystal form of the compound represented by formula (I) described in the present disclosure further includes steps such as filtering, washing or drying.
  • the present disclosure provides the S crystal form of the compound represented by formula (I), the X-ray powder diffraction pattern represented by the diffraction angle 2 ⁇ , and there are characteristic peaks at 6.576, 9.082, 10.921, 13.592, 19.965, 21.403 and 24.207.
  • the crystal form S of the compound represented by formula (I) has characteristic peaks at 6.576, 9.082, 10.921, 13.592, 16.805, 19.965, 21.403, 24.207, 25.662 and 27.457.
  • the crystal form S of the compound represented by formula (I) has characteristic peaks at 6.576, 7.890, 9.082, 10.921, 13.592, 15.043, 16.805, 19.965, 21.403, 24.207, 25.662, 26.537 and 27.457.
  • the X-ray powder diffraction pattern of the crystal form S of the compound represented by formula (I) represented by the diffraction angle 2 ⁇ is shown in FIG. 24 .
  • the present disclosure further provides a method for preparing the crystal form S of the compound represented by formula (I), including, method 1: a): the compound represented by formula (I) is mixed with DMF, heated to dissolve, cooled to precipitate, b) filtered, the filter cake is mixed with acetonitrile, beating, c) filtered, the filter cake is mixed with water, beated, d) filtered, dried, and then crystallized by acetonitrile beating and drying.
  • method 1 a): the compound represented by formula (I) is mixed with DMF, heated to dissolve, cooled to precipitate, b) filtered, the filter cake is mixed with acetonitrile, beating, c) filtered, the filter cake is mixed with water, beated, d) filtered, dried, and then crystallized by acetonitrile beating and drying.
  • the volume ( ⁇ l) of the solvent used in the present disclosure can be 1-200 times the mass (mg) of the compound of formula (I), and in non-limiting embodiments, it can be 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120 , 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 200.
  • the method for preparing the S crystal form of the compound represented by formula (I) described in the present disclosure further includes steps such as filtering, washing or drying.
  • the disclosure provides the T crystal form of the compound represented by formula (I), the X-ray powder diffraction pattern represented by the diffraction angle 2 ⁇ , and there are characteristic peaks at 6.915, 9.177, 9.984, 11.012, 13.595, 16.156 and 20.138.
  • the crystal form T of the compound represented by formula (I) has characteristic peaks at 6.915, 9.177, 9.984, 11.012, 13.595, 15.174, 16.156, 20.138, 24.261 and 26.391.
  • the crystal form T of the compound represented by formula (I) has characteristic peaks at 6.915, 9.177, 9.984, 11.012, 13.595, 15.174, 16.156, 18.509, 20.138, 22.954, 24.261, 26.391 and 27.514.
  • the X-ray powder diffraction pattern of the crystal form T of the compound represented by formula (I) represented by the diffraction angle 2 ⁇ is shown in Figure 25.
  • the present disclosure further provides a method for preparing the crystal form T of the compound represented by formula (I), including method 1: a) mixing the compound represented by formula (I) with DMF, heating and dissolving, cooling and crystallizing, b) filtering, mixing and stirring the filter cake with water, c) filtering, mixing and stirring the filter cake with water again, d) filtering, drying, mixing with acetonitrile, stirring and crystallizing, and drying.
  • the volume ( ⁇ l) of the solvent used in the present disclosure can be 1-200 times the mass (mg) of the compound of formula (I), and in non-limiting embodiments, it can be 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120 , 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 200.
  • the method for preparing the T crystal form of the compound represented by formula (I) described in the present disclosure further includes steps such as filtering, washing or drying.
  • the present disclosure also provides a pharmaceutical composition prepared from the crystal form of the compound represented by the aforementioned formula (I).
  • the present disclosure also provides a pharmaceutical composition, comprising the aforementioned crystal form and optionally a pharmaceutically acceptable carrier, diluent or excipient.
  • the present disclosure also provides a preparation method of a pharmaceutical composition, comprising the step of mixing the aforementioned crystal form with a pharmaceutically acceptable carrier, diluent or excipient.
  • the present disclosure also provides the use of the aforementioned crystal form, or the aforementioned composition, or the composition prepared by the aforementioned method in the preparation of a medicament for treating and/or preventing diseases related to CRBN protein.
  • the present disclosure also provides the aforementioned crystal form, or the aforementioned composition, or the use of the composition prepared by the aforementioned method in the preparation of a medicine for treating and/or preventing cancer, angiogenesis-related disorders, pain, macular degeneration or related syndromes, skin diseases, lung diseases, asbestos-related diseases, parasitic diseases, immunodeficiency diseases, CNS diseases, CNS injuries, atherosclerosis or related diseases, sleep disorders or related diseases, infectious diseases, hemoglobinopathy or related diseases, or TNF ⁇ -related diseases; Use in a medicament for the treatment and/or prevention of cancer or CNS damage.
  • the cancer is selected from the group consisting of leukemia, myeloma, lymphoma, melanoma, skin cancer, liver cancer, kidney cancer, lung cancer, nasopharyngeal cancer, gastric cancer, esophageal cancer, colorectal cancer, gallbladder cancer, bile duct cancer, choriocarcinoma, pancreatic cancer, polycythemia vera, pediatric tumors, cervical cancer, ovarian cancer, breast cancer, bladder cancer, urothelial cancer, ureteral cancer, prostate cancer, seminoma, testicular tumor, head and neck tumor, Squamous cell carcinoma of the head and neck, uterus Endometrial cancer, thyroid cancer, sarcoma, osteoma, neuroblastoma, neuroendocrine cancer, brain tumor, CNS cancer, astrocytoma, and glioma; preferably, the liver cancer is hepatocellular carcinoma; the colorectal cancer is colon cancer or rectal cancer
  • the myeloma is multiple myeloma (MM) and myelodysplastic syndrome (MDS); preferably, the multiple myeloma is relapsed, refractory or resistant.
  • the multiple myeloma is refractory or resistant to lenalidomide or pomalidomide.
  • the "2 ⁇ or 2 ⁇ angle" described in this 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 (including the situation after rounding the numbers with more than 1 decimal place), which can be -0.20, -0.19, -0.18, -0.17, -0.16, -0.15, -0.14, -0.13, -0.12, -0.1 1, -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.
  • Deliquescence absorption of sufficient water to form a liquid
  • Moisture-absorbing the weight gain of moisture-absorbing is less than 15% but not less than 2%;
  • the “differential scanning calorimetry or DSC” mentioned in this disclosure refers to measuring the temperature difference and heat flow difference between the sample and the reference object during the heating or constant temperature process of the sample, so as to characterize all the physical and chemical changes related to the thermal effect, and obtain the phase change information of the sample.
  • the drying temperature described in the present disclosure is generally 25° C. to 150° C., preferably 40° C. to 80° C., and can be dried under normal pressure or reduced pressure.
  • “Pharmaceutical composition” means a mixture containing one or more compounds of formula (I) described herein or a pharmaceutically acceptable salt thereof and other chemical components, as well as other components such as pharmaceutically acceptable carriers and excipients.
  • the purpose of the pharmaceutical composition is to promote the administration to the organism, facilitate the absorption of the active ingredient and thus exert biological activity.
  • the crystal forms described in the present disclosure include but are not limited to solvates of compounds represented by formula (I), and the solvents include but are not limited to water, methanol, ethanol, isopropanol, acetone, ethyl acetate, acetonitrile, isopropyl acetate, methyl tert-butyl ether, 2-butanone, tetrahydrofuran, dimethyl sulfoxide, N-methylpyrrolidone, methyl isobutyl ketone, dichloromethane, n-heptane, 1,4-dioxane, nitromethane, propylene glycol methyl ether, chloroform, N,N-dimethylformamide, N,N-dimethylacetamide, p-xylene, cyclohexane, dichloroethane, n-hexane, petroleum ether, n-octane, o-xylene, toluene
  • solvate in the present disclosure includes, but is not limited to, a complex formed by combining the compound of formula (I) with a solvent.
  • Figure 1 XRPD spectrum of the amorphous compound of formula (I).
  • Figure 8 XRPD pattern of the crystal form of compound G represented by formula (I).
  • Figure 16 XRPD pattern of the crystalline form of compound O represented by formula (I).
  • Fig. 17 XRPD pattern of crystal form P of compound represented by formula (I).
  • Fig. 19 XRPD pattern of crystal form U of compound represented by formula (I).
  • Figure 20 XRPD pattern of the X crystal form of compound represented by formula (I).
  • Figure 21 XRPD pattern of compound Y crystal form represented by formula (I).
  • Figure 26 The curative effect data of the compound of Example 1 and the control example CC-92480 on NCI-H929 transplanted tumor in CB-17SCID mice.
  • Figure 27 Effects of the compound of Example 1 and control example CC-92480 on body weight of CB-17SCID mice.
  • NMR nuclear magnetic resonance
  • MS mass spectroscopy
  • MS uses Agilent 1200/1290DAD-6110/6120 Quadrupole MS liquid mass spectrometer (manufacturer: Agilent, MS model: 6110/6120 Quadrupole MS), waters ACQuity UPLC-QD/SQD (manufacturer: waters, MS model: waters ACQuity Qda Detector/waters S Q Detector), THERMO Ultimate 3000-Q Exactive (manufacturer: THERMO, MS model: THERMO Q Exactive).
  • HPLC High performance liquid chromatography
  • Chiral HPLC analysis was performed using an Agilent 1260 DAD high performance liquid chromatograph.
  • the CombiFlash rapid preparation instrument uses Combiflash Rf200 (TELEDYNE ISCO).
  • Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates are used for thin-layer chromatography silica gel plates.
  • the specifications of silica gel plates used in thin-layer chromatography (TLC) are 0.15mm-0.2mm, and the specifications of thin-layer chromatography separation and purification products are 0.4mm-0.5mm.
  • Silica gel column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.
  • the known starting materials of the present disclosure can be used or synthesized according to methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Shaoyuan Chemical Technology (Accela ChemBio Inc), Darui Chemicals and other companies.
  • the reactions can all be carried out under an argon atmosphere or a nitrogen atmosphere.
  • Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a volume of about 1 L.
  • the hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1L.
  • the pressurized hydrogenation reaction uses Parr 3916EKX hydrogenation instrument and Qinglan QL-500 hydrogen generator or HC2-SS hydrogenation instrument.
  • the hydrogenation reaction is usually vacuumized and filled with hydrogen, and the operation is repeated 3 times.
  • the solution refers to an aqueous solution.
  • reaction temperature is room temperature, which is 20°C to 30°C.
  • the monitoring of the reaction process in the embodiment adopts thin-layer chromatography (TLC), the developing agent used in the reaction, the eluent system of the column chromatography adopted by the purified compound and the developing agent system of the thin-layer chromatography include: A: n-hexane/ethyl acetate system, B: methylene chloride/methanol system, the volume ratio of the solvent is adjusted according to the polarity of the compound, and can also be adjusted by adding a small amount of basic or acidic reagents such as triethylamine and acetic acid.
  • TLC thin-layer chromatography
  • Embodiment 1 the preparation of compound shown in formula (I)
  • reaction solution was diluted with water (30 mL), then extracted with ethyl acetate (40 mL ⁇ 3), the organic phases were combined, washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography with eluent system B to obtain the title compound 1b (1.0 g, yield: 96%).
  • reaction solution was poured into ice water (10 mL), then extracted with ethyl acetate (30 mL ⁇ 3), the organic phases were combined, washed with saturated sodium chloride solution (20 mL ⁇ 2), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography with eluent system B to obtain the title compound 1 g (145 mg, yield: 94%).
  • the title compound 1 is amorphous as detected by X-ray powder diffractometer.
  • the following method was used to determine the inhibitory activity of the disclosed compounds on the proliferation of NCI-H929 cells.
  • the experimental method is briefly described as follows.
  • NCI-H929 cells (ATCC, CRL-9068) were cultured with complete medium, namely RPMI1640 medium (Hyclone, SH30809.01) containing 10% fetal bovine serum (Corning, 35-076-CV) and 0.05 mM 2-mercaptoethanol (Sigma, M3148).
  • RPMI1640 medium Hyclone, SH30809.01
  • 10% fetal bovine serum Corning, 35-076-CV
  • 0.05 mM 2-mercaptoethanol Sigma, M3148.
  • NCI-H929 cells were seeded in a 96-well plate at a density of 6,000 cells/well using complete medium, and 100 ⁇ L of cell suspension was added to each well.
  • 10 ⁇ L of a gradient dilution of the compound to be tested prepared in complete medium was added to each well.
  • the compound was first dissolved in DMSO, with an initial concentration of 10 mM, and serially diluted by 5-fold concentration, with a total of 9 concentration points.
  • the blank control was 100% DMSO.
  • 5 ⁇ L of the compound dissolved in DMSO was added to 95 ⁇ L of complete medium, that is, the compound was diluted 20 times with the complete medium.
  • 10 ⁇ L of each well of the compound diluted in complete medium was added to the cell suspension, that is, the final concentration of the compound was 9 concentration points of 5-fold serial dilution starting from 50 ⁇ M, and a blank control containing 0.5% DMSO was set, and placed in a 37°C, 5% CO2 cell culture box for incubation for 5 days.
  • Compound 1 of the present disclosure has a good activity of inhibiting the proliferation of NCI-H929 cells.
  • Example 1 The compound of Example 1 and the control example CC-92480 were prepared with 5% DMSO+20% PEG400+70% (10% TPGS)+5% (1% HPMC K100LV).
  • mice 30 CB-17SCID female mice were purchased from Beijing Weitong Lihua Experimental Animal Co., Ltd. (Certificate No.: 20170011006049, SCXK (Shanghai) 2017-0011), weighing about 19 g at the time of purchase, 5 mice/cage, 12/12 hours of light/dark cycle adjustment, constant temperature of 23 ⁇ 1°C, humidity of 50-60%, free access to food and water.
  • CB-17SCID mice were grouped as follows:
  • qd means administration once a day; i.g means intragastric administration.
  • NCI-H929 cells in the logarithmic growth phase were inoculated at 5 ⁇ 10 6 cells/mouse/100 ⁇ L (including 50 ⁇ L Matrigel) subcutaneously in the right flank of 30 female CB-17SCID mice.
  • vehicle control group CC-92480-1mpk
  • Example 1-1mpk 7 only.
  • the day of grouping was set as Day0 (D0), and intragastric administration was started once a day for a total of 11 days (Table 2).
  • the tumor volume of the tumor-bearing mice was measured twice a week with a caliper and the body weight was measured with a balance and the data were recorded. When the tumor volume reached 2000mm 3 or most of the tumors ruptured or the body weight decreased by 20%, the tumor-bearing animals were euthanized as the end point of the experiment.
  • V tumor volume
  • T/C (%) (TT 0 )/(CC 0 ) ⁇ 100 (%), wherein: T, C are the treatment group and Tumor volume of the control group; T 0 , C 0 are the tumor volumes at the beginning of the experiment.
  • Tumor inhibition rate TGI(%) 1-T/C(%), when TGI(%) exceeds 100%, the specific value will not be displayed, only expressed as >100%.
  • Tumor regression (%) [(T 0 -T)/T 0 ] ⁇ 100(%).
  • the compound of the present disclosure is to the curative effect of NCI-H929 xenograft tumor in CB-17SCID mouse body
  • qd means administration once a day
  • po means oral administration.
  • the compound of Example 1 was started to be administered 10 days after tumor cell transplantation, once a day, and the tumor volume regressed significantly after 11 days of administration.
  • the calculated tumor inhibition rate was >100%, and the tumor regression rate was 88%.
  • p ⁇ 0.05 Compared with the same dose of CC-92480 at the end of the experiment, there was a statistical difference (p ⁇ 0.05), and the administration had no effect on the body weight of the mice. Under the same conditions, the tumor regression rate of the control CC-92480 was 34%.
  • mice Using mice as test animals, the drug concentration in plasma at different times after intragastric administration of the compound of Example 1 and CC-92480 of the control example to mice was determined by LC/MS/MS method. The pharmacokinetic behavior of the disclosed compound in mice was studied, and its pharmacokinetic characteristics were evaluated.
  • mice Female, were purchased from Weitong Lihua Experimental Animal Co., Ltd., animal production license number: SCXK (Shanghai) 2017-0005.
  • Example 1 Weigh the compound of Example 1, add 5% volume of DMSO and 5% Tween 80 (Shanghai Titan Technology Co., Ltd.) to dissolve it, and then add 90% physiological saline to prepare a 0.1 mg/mL clear solution.
  • mice Nine mice were intragastrically administered the compound of Example 1, the dosage was 2 mg/kg, and the dosage volume was 0.2 mL/10 g.
  • mice Nine mice were intragastrically administered the compound control example CC-92480, the dosage was 2 mg/kg, and the dosage was 0.2 mL/10 g.
  • mice were intragastrically administered the compound of Example 1 and CC-92480 of the control example, and 0.2 mL of blood was collected at 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 11.0, and 24.0 hours before administration and after administration (3 animals at each time point), placed in EDTA-K2 anticoagulant test tubes, centrifuged at 10,000 rpm for 1 minute (4°C), separated plasma within 1 hour, and stored at -20°C for testing. The process from blood collection to centrifugation was operated under ice bath conditions.
  • Determination of the content of the compound to be tested in mouse plasma after administration of different concentrations of drugs Take 25 ⁇ L of mouse plasma at various times after administration, add 50 ⁇ L (100 ng/mL) of internal standard solution camptothecin (China Institute for the Control of Biological Products) and 175 ⁇ L of acetonitrile, vortex and mix for 5 minutes, centrifuge for 10 minutes (3700 rpm), and take 1 ⁇ L of the supernatant of the plasma sample for LC/MS/MS (API4000 triple quadrupole tandem mass spectrometer, Applied USA Biosystems company; Shimadzu LC-30AD ultra-high performance liquid chromatography system, Japan Shimadzu company) analysis.
  • LC/MS/MS API4000 triple quadrupole tandem mass spectrometer
  • Monkey plasma was purchased from Shanghai Medicilon Biopharmaceutical Co., Ltd.
  • the disclosed compound has the advantage of stability in monkey plasma.
  • Embodiment 2 the preparation of amorphous compound shown in formula (I)
  • Embodiment 3 Preparation of compound A crystal form shown in formula (I)
  • the XRPD spectrum is shown in Figure 2, and the positions of its characteristic peaks are shown in Table 1.
  • the DSC spectrum shows that the endothermic peaks are 155.26°C, 183.19°C and 244.74°C.
  • the TGA spectrum shows that the weight loss is 9.48% at 25°C-220°C.
  • Embodiment 4 Preparation of compound A crystal form shown in formula (I)
  • Embodiment 5 Preparation of compound A crystal form shown in formula (I)
  • Embodiment 6 Preparation of compound A crystal form shown in formula (I)
  • Embodiment 7 Preparation of compound B crystal form shown in formula (I)
  • Embodiment 8 Preparation of compound C crystal form shown in formula (I)
  • Embodiment 9 Preparation of compound C crystal form shown in formula (I)
  • Embodiment 10 Preparation of crystal form D of compound shown in formula (I)
  • Embodiment 11 Preparation of the compound E crystal form shown in formula (I)
  • Embodiment 12 Preparation of the compound E crystal form shown in formula (I)
  • Embodiment 13 Preparation of compound F crystal form shown in formula (I)
  • the product was defined as crystal form F by X-ray powder diffraction detection.
  • the XRPD spectrum is shown in FIG.
  • the DSC spectrum shows that the peak endothermic peaks are 181.22°C and 245.03°C.
  • the TGA spectrum shows that the weight loss is 8.63% at 25°C-210°C.
  • Embodiment 14 Preparation of the compound F crystal form shown in formula (I)
  • Embodiment 15 Preparation of compound F crystal form shown in formula (I)
  • Embodiment 16 Preparation of compound G crystal form shown in formula (I)
  • Embodiment 17 Preparation of compound G crystal form shown in formula (I)
  • the product is crystal form G.
  • Embodiment 18 Preparation of crystal form H of compound shown in formula (I)
  • Embodiment 19 Preparation of compound I crystal form shown in formula (I)
  • Embodiment 20 Preparation of compound I crystal form shown in formula (I)
  • the product was defined as crystal form J by X-ray powder diffraction detection.
  • the XRPD spectrum is shown in FIG. 11 , and the positions of its characteristic peaks are shown in Table 10.
  • the DSC spectrum shows that the endothermic peaks are 154.09°C, 165.41°C and 247.39°C.
  • the TGA spectrum shows that the weight loss is 10.48% at 30°C-220°C.
  • Embodiment 23 Preparation of crystal form K of compound shown in formula (I)
  • Embodiment 25 Preparation of crystal form M of compound shown in formula (I)
  • Embodiment 26 Preparation of N crystal form of compound shown in formula (I)
  • Embodiment 27 Preparation of crystal form O of compound shown in formula (I)
  • Embodiment 28 Preparation of crystal form P of compound represented by formula (I)
  • Embodiment 29 Preparation of crystal form U of compound represented by formula (I)
  • Embodiment 30 Preparation of crystal form U of compound represented by formula (I)
  • Example 38 Research on hygroscopicity of crystal forms D, E, Q and U of compounds represented by formula (I) (2021.10.15 Nanjing)
  • the humidity starts from 50%, and the humidity range is 0%-95%, with a step of 10%.
  • the judgment standard is that the quality change dM/dT of each gradient is less than 0.002%, TMAX360min, and cycle twice.
  • Example 39 Compound D, E, Q and U Crystal Forms of Formula (I) Influencing Factors Stability
  • the sampling inspection period is 30 days.
  • Example 40 Long-term/accelerated stability of crystal forms D, E, Q and U of compounds represented by formula (I)
  • the crystal forms D, E, Q and U of the compounds represented by the formula (I) were placed at 25° C., 60% RH and 40° C., 75% RH respectively to examine their stability.

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Abstract

本公开涉及一种含硫异吲哚啉类衍生物的晶型。具体而言，本公开涉及如式（I）所示化合物的晶型及其制备方法。

Description

一种含硫异吲哚啉类衍生物的晶型
本申请要求申请日为2022/1/19的中国专利申请202210060175.6的优先权。本申请引用上述中国专利申请的全文。
技术领域
本公开涉及一种含硫异吲哚啉类衍生物的晶型及其制备方法，具体的，提供了如式I所示化合物的晶型及其制备方法。
背景技术
多发性骨髓瘤(multiple myeloma，MM)是一种恶性肿瘤，主要症状包括高钙血症、肾脏损害、贫血和骨骼疾病。MM是仅次于非霍奇金淋巴瘤的第二大最常见的血液系统恶性肿瘤，目前的治疗方法主要是药物治疗和自体干细胞移植治疗。
目前临床上广泛使用的药物主要有四大类，分别为度胺类的免疫调节剂、蛋白酶体抑制剂、激素类和单克隆抗体。处于临床研究阶段的药物有双抗、ADC，CAR-T等。这些药物的作用机理不同，联用常常能达到更好的疗效，临床上一般采用二联、三联、甚至是四联用药，一般是免疫调节剂、蛋白酶体抑制剂和激素类联用，有时会加入抗体。其中来那度胺是最常用的免疫调节剂，一线治疗，干细胞移植后的维持治疗，复发后的二三线治疗都会用到来那度胺。该药物在2018/2019的销售额达到97亿美元。另外整个MM市场也相当可观，并且增长很快，这是由于对MM的诊断和治疗的不断改进和完善，患者的生存期更长，用药时间也相应延长。预计在2022年MM市场将会达到330亿美元的规模，其中占比最大的仍是以来那度胺为代表的免疫调节剂。
免疫调节剂(immunomodulators，IMiD)治疗MM的作用机理主要是IMiD药物结合Cereblon(CRBN)蛋白之后，会激活CRBN的E3连接酶活性，进而选择性地与转录因子Ikaros(IKZF1)和Aiolos(IKZF3)结合；从而导致Ikaros和Aiolos快速泛素化并降解。Ikaros/Aiolos的下调导致c-Myc的下调，随后IRF4下调，最后导致骨髓瘤细胞生长受到抑制和凋亡。另外，IKZF3还可以抑制T/NK细胞中的IL2和TNF细胞因子的转录，IKZF3降解之后就可以解除这种抑制从而促进这些细胞因子的释放，起到免疫调节的作用。临床试验也表明IMiD药物的临床获益也与CRBN表达量的高低具有相关性。 在对来那度胺敏感的细胞系(OPM2和KMS18)中敲低CRBN后发现来那度胺抑制细胞生长的活性消失，产生耐药，CRBN敲低的水平和耐药程度相关；在细胞增殖实验中，降低细胞中CRBN的表达水平(U266-CRBN60和U266-CRBN75)，来那度胺和泊马度胺抑制细胞生长的活性均降低。
目前已经批准上市的IMiD药物有沙利度胺、来那度胺和泊马度胺，他们均来自Celgene公司(目前已被BMS公司合并)。三个化合物与CRBN的结合力依次增强，故临床用药剂量依次降低。三个化合物的主要适应症是MM，沙利度胺和来那度胺还有其它的适应症，尤其是来那度胺，可以用来治疗骨髓增生异常综合症(MDS)。副作用方面，来那度胺和泊马度胺表现相似，有明显的骨髓抑制作用，该副作用是与靶点相关的毒性；沙利度胺有一些其它的副作用，比如镇静，便秘，神经方面的副作用等。
所有IMiD的己二酰亚胺部分均与CRBN中三个色氨酸残基(称为“沙利度胺结合袋”)所定义的疏水袋结合。相反，邻苯二甲酰亚胺/异吲哚酮环暴露在溶剂中并改变CRBN的分子表面，从而调节底物识别。不同的IMiD导致CRBN分子表面发生明显的修饰，底物识别的偏好也不同。因此，对于IMiDs的修饰可能会导致其它转录因子的降解，引起不必要的毒副作用。IMiD的这种作用模式也被称为分子胶水(molecular glue)，形象地表述了这种小分子对两种蛋白底物的粘结作用。
由于目前多发性骨髓瘤的中位生存期在五年以上，生存期的延长使得多数病人对目前已经上市的药物如来那度胺和泊马度胺有较高比例的耐药性，使得该类药物的治疗效果严重下降。因此，我们设想发展活性更好的药物分子来克服耐药性的问题，同时尽量降低该类化合物的毒副作用。
公开的Cereblon调节剂专利申请包括WO2008115516A2、WO2011100380A1、WO2019226770A1、WO2019014100A1和WO2020064002A1等。
本申请人的专利申请WO2022017365提供了一种如式I所示的化合物，其化学名为(S)-4-(4-((5-(((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氧基)甲基)吡啶-2-基)硫基)哌啶-1-基)-3-氟苯甲腈，该化合物具有较好的Cereblon调节作用。
通常来说，药物的活性成分及其盐的晶型结构不仅影响到该药物本身的物理和化学稳定性，而且还影响到后期药物制备的难易程度以及生产成本，结晶条件及储存条件的不同有可能导致化合物及其盐的晶型结构的变化，有时还会伴随着产生其他形态的晶型。因此，从稳定性、药物制备工艺的难易程度以及生产成本等角度综合考虑，深入研究式(I)所示化合物的晶型是必须的。
发明内容
本公开提供了式(I)所示化合物的晶型及其制备方法，其中式I所示化合物的化学名为(S)-4-(4-((5-(((2-(2,6-二氧哌啶-3-基)-1-氧代异吲哚-4-基)氧基)甲基)吡啶-2-基)硫代)哌啶-1-基)-3-氟苯腈，
本公开提供了式(I)所示化合物的无定形，其X-射线粉末衍射图谱的衍射角2θ在2-48°范围内没有明显特征峰。
本公开进一步提供了制备式(I)所示化合物无定形的方法，包括，方法1：a)式(I)所示化合物与丙二醇甲醚、正庚烷或石油醚混合，b)打浆析晶；
在某些实施方案中，本公开所述溶剂所用体积(μl)可以为式(I)化合物质量(mg)的1-200倍，在非限制性实施方案中可以为1、5、10、15、20、25、30、35、40、45、50、55、60、65、70、75、80、85、90、95、100、105、110、115、120、125、130、135、140、145、150、155、160、165、170、175、180、185、190、200。在某些实施方案中，本公开所述的制备(I)所示化合物无定形的方法还包括过滤、洗涤或干燥步骤。
本公开提供了式(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，在5.765、8.061、9.925、16.632、17.900、19.469和21.115处有特征峰。在某些实施方案中，式(I)所示化合物的A晶型在5.765、7.465、8.061、9.925、12.890、15.085、16.632、17.900、19.469和21.115处有特征峰。在某些实施方案中，式(I)所示化合物的A晶型在5.765、7.465、8.061、9.925、11.674、12.890、14.270、15.085、16.632、17.900、18.715、19.469和21.115处有特征峰。在某些实施方案中，式(I)所示化合物化合物的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。
本公开进一步提供了制备式(I)所示化合物的A晶型的方法，包括，方法1：a)式(I)所示化合物与四氢呋喃混合，溶清，b)加入正庚烷析晶；
或者方法2：a)式(I)所示化合物与二氯甲烷混合，溶清，b)加入乙酸乙酯析晶；
或者方法3：a)式(I)所示化合物与水、醋酸异丙酯、丙酮、乙酸乙酯/乙醇或乙酸乙酯/正庚烷混合，b)打浆析晶；
在某些实施方案中，本公开所述溶剂所用体积(μl)可以为式(I)化合物质量(mg)的1-200倍，在非限制性实施方案中可以为1、5、10、15、20、25、30、35、40、45、50、55、60、65、70、75、80、85、90、95、100、105、110、115、120、125、130、135、140、145、150、155、160、165、170、175、180、185、190、200。在某些实施方案中，本公开所述的制备式(I)所示化合物的A晶型的方法还包括过滤、洗涤或干燥等步骤。
本公开提供了式(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，在4.977、6.788、10.047、14.143、15.684、18.547和20.840处有特征峰。在某些实施方案中，式(I)所示化合物的B晶型在4.977、6.788、10.047、14.143、15.684、18.547、20.840、24.096和25.505处有特征峰。在某些实施方案中，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3所示。
本公开进一步提供了制备式(I)所示化合物B晶型的方法，包括：a)式(I)所示化合物与乙酸乙酯或乙腈/甲醇混合，b)打浆析晶，30℃干燥；
在某些实施方案中，本公开所述溶剂所用体积(μl)可以为式(I)化合物质量(mg)的1-200倍，在非限制性实施方案中可以为1、5、10、15、20、25、30、35、40、45、50、55、60、65、70、75、80、85、90、95、100、105、110、115、120、125、130、135、140、145、150、155、160、165、170、175、180、185、190、200。在某些实施方案中，本公开所述的制备式(I)所示化合物的B晶型的方法还包括过滤、洗涤或干燥等步骤。
本公开提供了式(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，在5.653、7.974、9.989、16.143、17.860、18.992和20.972处有特征峰。在某些实施方案中，式(I)所示化合物的C晶型在5.653、7.974、9.989、11.505、12.798、14.265、16.143、17.860、18.992和20.972处有特征峰。在某些实施方案中，式(I)所示化合物的C晶型在3.533、5.653、7.974、8.790、9.989、11.505、12.798、14.265、15.277、16.143、17.860、18.992和20.972处有特征峰。在某些实施方案中，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4所示。
本公开进一步提供了制备式(I)所示化合物C晶型的方法，包括，方法1：a)式I所示化合物与乙醇、异丙醇、甲基叔丁基醚、甲基异丁基酮、水/乙醇、水/异丙醇、水/甲醇(1:1)、环己烷、异丙醚混合，b)打浆析晶；
或者方法2：a)式(I)所示化合物与二氯甲烷、水/丙酮、四氢呋喃/乙醇混合，溶清，b)挥发析晶；
在某些实施方案中，本公开所述溶剂所用体积(μl)可以为式(I)化合物质量(mg)的1-200倍，在非限制性实施方案中可以为1、5、10、15、20、25、30、35、40、45、50、55、60、65、70、75、80、85、90、95、100、105、110、115、120、125、130、135、140、145、150、155、160、165、170、175、180、185、190、200。在某些实施方案中，本公开所述的制备式(I)所示化合物的C晶型的方法还包括过滤、洗涤或干燥等步骤。
本公开提供了式(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，在6.831、9.845、13.453、18.225、20.117、20.891和23.006处有特征峰。在某些实施方案中，式(I)所示化合物的D晶型在6.831、9.845、10.927、13.453、16.096、18.225、20.117、20.891、23.006和26.132处有特征峰。在某些实施方案中，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5所示。
本公开进一步提供了制备式(I)所示化合物D晶型的方法，包括：
方法1：a)式(I)所示化合物与乙腈混合，b)打浆析晶。
在某些实施方案中，本公开所述溶剂所用体积(μl)可以为式(I)化合物质量(mg)的1-200倍，在非限制性实施方案中可以为1、5、10、15、20、25、30、35、40、45、50、55、60、65、70、75、80、85、90、95、100、105、110、115、120、125、130、135、140、145、150、155、160、165、170、175、180、185、190、200。在某些实施方案中，本公开所述的制备式(I)所示化合物的D晶型的方法还包括过滤、洗涤或干燥等步骤。
本公开提供了式(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，在5.864、7.573、8.087、10.003、16.444、19.349和20.553处有特征峰。在某些实施方案中，式(I)所示化合物的E晶型在5.864、7.573、8.087、10.003、12.471、15.165、16.444、17.432、19.349和20.553处有特征峰。在某些实施方案中，式(I)所示化合物的E晶型在5.864、7.573、8.087、10.003、11.701、12.471、15.165、16.444、17.432、19.349、20.553、21.067和21.709处有特征峰。在某些实施方案中，式(I)所示化合物的E晶型以衍射角2θ角度表示的X-射线粉末衍射图谱如图6所示。
本公开进一步提供了制备式(I)所示化合物E晶型的方法，包括，方法1：a)式I所示化合物与2-丁酮或10％水/甲醇混合，b)打浆析晶；
或者方法2：a)式I所示化合物与DCM混合，溶清，b)加入正庚烷析晶
在某些实施方案中，本公开所述溶剂所用体积(μl)可以为式(I)化合物质量(mg)的1-200倍，在非限制性实施方案中可以为1、5、10、15、20、25、30、35、40、45、50、55、60、65、70、75、80、85、90、95、100、105、110、115、120、125、130、135、140、145、150、155、160、165、170、175、180、185、190、200。在某些实施方案中，本公开所述的制备式(I)所示化合物的E晶型的方法还包括过滤、洗涤或干燥等步骤。
本公开提供了式(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，在5.062、7.820、10.077、14.231、16.672、18.586和20.435处有特征峰。在某些实施方案中，式(I)所示化合物的F晶型在5.062、7.820、10.077、14.231、15.192、16.672、18.586、20.435、21.868和25.442处有特征峰。在某些实施方案中，式(I)所示化合物的F晶型在5.062、7.820、10.077、14.231、15.192、16.672、18.586、20.435、21.868、24.193、25.442、26.303和28.629处有特征峰。在某些实施方案中，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7所示。
本公开进一步提供了制备式(I)所示化合物F晶型的方法，包括：
方法1：a)式(I)所示化合物与溶剂II混合，其中溶剂II选自对二甲苯、甲醇、2-甲基四氢呋喃、邻二甲苯或甲苯，b)打浆析晶；
或者方法2：a)式(I)所示化合物与二氯甲烷或四氢呋喃混合，溶清，b)加入乙酸异丙酯、甲基叔丁基醚或甲基异丁基酮析晶。
或者方法3：a)式(I)所示化合物与1，4-二氧六环混合，溶清，b)挥发析晶。
在某些实施方案中，本公开所述溶剂所用体积(μl)可以为式(I)化合物质量(mg)的1-200倍，在非限制性实施方案中可以为1、5、10、15、20、25、30、35、40、45、50、55、60、65、70、75、80、85、90、95、100、105、110、115、120、125、130、135、140、145、150、155、160、165、170、175、180、185、190、200。在某些实施方案中，本公开所述的制备式(I)所示化合物的F晶型的方法还包括过滤、洗涤或干燥等步骤。
本公开提供了式(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，在5.999、7.972、9.951、11.388、17.812、20.975和25.819处有特征峰。在某些实施方案中，式(I)所示化合物的G晶型在5.999、7.396、7.972、8.637、9.951、11.388、 15.291、17.812、20.975和25.819处有特征峰。在某些实施方案中，式(I)所示化合物的G晶型在5.999、7.396、7.972、8.637、9.951、11.388、12.763、15.291、17.812、20.975、23.408、25.819和27.400处有特征峰。在某些实施方案中，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8所示。
本公开进一步提供了制备式(I)所示化合物G晶型的方法，包括：
方法1：a)式(I)所示化合物与三氯甲烷混合，溶清，b)挥发析晶。
或者方法2：a)式(I)所示化合物与1，2-二氯乙烷混合，b)打浆析晶。
在某些实施方案中，本公开所述溶剂所用体积(μl)可以为式(I)化合物质量(mg)的1-200倍，在非限制性实施方案中可以为1、5、10、15、20、25、30、35、40、45、50、55、60、65、70、75、80、85、90、95、100、105、110、115、120、125、130、135、140、145、150、155、160、165、170、175、180、185、190、200。在某些实施方案中，本公开所述的制备式(I)所示化合物的G晶型的方法还包括过滤、洗涤或干燥等步骤。
本公开提供了式(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，在5.758、7.533、9.901、14.267、16.420、18.103和26.356处有特征峰，在某些实施方案中，式(I)所示化合物的H晶型在5.758、7.533、9.901、14.267、16.420、18.103、18.917、20.489、24.049和26.356处有特征峰。在某些实施方案中，式(I)所示化合物的H晶型在5.758、7.533、9.901、14.267、16.420、18.103、18.917、20.489、24.049和26.356处有特征峰。在某些实施方案中，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9所示。
本公开进一步提供了制备式(I)所示化合物H晶型的方法，包括：
方法1：a)式(I)所示化合物与正辛烷或正已烷混合，b)打浆析晶；
在某些实施方案中，本公开所述溶剂所用体积(μl)可以为式(I)化合物质量(mg)的1-200倍，在非限制性实施方案中可以为1、5、10、15、20、25、30、35、40、45、50、55、60、65、70、75、80、85、90、95、100、105、110、115、120、125、130、135、140、145、150、155、160、165、170、175、180、185、190、200。在某些实施方案中，本公开所述的制备式(I)所示化合物的H晶型的方法还包括过滤、洗涤或干燥等步骤。
本公开提供了式(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，在5.294、6.826、7.564、10.739、13.699、16.812和20.709处有特征峰。在某些实施方案中，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10所示。
本公开进一步提供了制备式(I)所示化合物I晶型的方法，包括：
方法1：a)式(I)所示化合物与四氢呋喃混合，溶清，b)挥发析晶。
或者方法2：a)式(I)所示化合物与四氢呋喃混合，溶清，b)加水析晶。
在某些实施方案中，本公开所述溶剂所用体积(μl)可以为式(I)化合物质量(mg)的1-200倍，在非限制性实施方案中可以为1、5、10、15、20、25、30、35、40、45、50、55、60、65、70、75、80、85、90、95、100、105、110、115、120、125、130、135、140、145、150、155、160、165、170、175、180、185、190、200。在某些实施方案中，本公开所述的制备式(I)所示化合物的I晶型的方法还包括过滤、洗涤或干燥等步骤。
本公开提供了式(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，在5.041、10.068、16.424、20.544、21.190、24.077和25.433处有特征峰。在某些实施方案中，式(I)所示化合物的J晶型在5.041、8.212、10.068、14.101、15.167、16.424、20.544、21.190、24.077和25.433处有特征峰。在某些实施方案中，式(I)所示化合物的J晶型在5.041、8.212、10.068、14.101、15.167、16.424、20.544、21.190、22.036、22.679、24.077、25.433和26.454处有特征峰。在某些实施方案中，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11所示。
本公开进一步提供了制备式(I)所示化合物J晶型的方法，包括：a)式(I)所示化合物与二甲基亚砜混合，溶清，b)加入水、乙酸异丙酯或甲基叔丁基醚，析晶。
在某些实施方案中，本公开所述溶剂所用体积(μl)可以为式(I)化合物质量(mg)的1-200倍，在非限制性实施方案中可以为1、5、10、15、20、25、30、35、40、45、50、55、60、65、70、75、80、85、90、95、100、105、110、115、120、125、130、135、140、145、150、155、160、165、170、175、180、185、190、200。在某些实施方案中，本公开所述的制备式(I)所示化合物的J晶型的方法还包括过滤、洗涤或干燥等步骤。
本公开提供了式(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，在5.156、7.699、10.339、14.334、16.203、18.327和23.418处有特征峰。在某些实施方案中，式(I)所示化合物的K晶型在5.156、7.699、10.339、14.334、16.203、18.327、23.418、25.348、25.919和26.446处有特征峰。在某些实施方案中，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12所示。
本公开进一步提供了制备式(I)所示化合物K晶型的方法，包括：a)式(I)所示 化合物与N-甲基吡咯烷酮混合，溶清，b)挥发析晶。
在某些实施方案中，本公开所述溶剂所用体积(μl)可以为式(I)化合物质量(mg)的1-200倍，在非限制性实施方案中可以为1、5、10、15、20、25、30、35、40、45、50、55、60、65、70、75、80、85、90、95、100、105、110、115、120、125、130、135、140、145、150、155、160、165、170、175、180、185、190、200。在某些实施方案中，本公开所述的制备式(I)所示化合物的K晶型的方法还包括过滤、洗涤或干燥等步骤。
本公开提供了式(I)所示化合物的L晶型，以衍射角2θ角度表示的X-射线粉末衍射图，在4.932、5.360、9.831、14.844、18.244、20.104和24.914处有特征峰。在某些实施方案中，式(I)所示化合物的L晶型在4.932、5.360、9.831、10.753、14.844、16.369、18.244、20.104、23.129、24.914处有特征峰。在某些实施方案中，式(I)所示化合物的L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。
本公开进一步提供了制备式(I)所示化合物L晶型的方法，包括：a)式(I)所示化合物与N,N二甲基乙酰胺混合，溶清，b)挥发析晶。
在某些实施方案中，本公开所述溶剂所用体积(μl)可以为式(I)化合物质量(mg)的1-200倍，在非限制性实施方案中可以为1、5、10、15、20、25、30、35、40、45、50、55、60、65、70、75、80、85、90、95、100、105、110、115、120、125、130、135、140、145、150、155、160、165、170、175、180、185、190、200。在某些实施方案中，本公开所述的制备式(I)所示化合物的L晶型的方法还包括过滤、洗涤或干燥等步骤。
本公开提供了式(I)所示化合物的M晶型，以衍射角2θ角度表示的X-射线粉末衍射图，在14.959、16.322、18.410、20.748、22.067、23.670和26.863处有特征峰。在某些实施方案中，式(I)所示化合物的M晶型在14.959、16.322、18.410、20.748、22.067、23.670、24.839、25.873、26.863和27.811处有特征峰。在某些实施方案中，式(I)所示化合物的M晶型在14.959、16.322、18.410、20.748、22.067、23.670、24.322、24.839、25.873、26.863和27.811处有特征峰。在某些实施方案中，式(I)所示化合物的M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。
本公开进一步提供了制备式(I)所示化合物M晶型的方法，包括：a)式I所示化合物的晶型A、晶型B、晶型C、晶型E、晶型H或晶型I加热至225℃。
在某些实施方案中，本公开所述溶剂所用体积(μl)可以为式(I)化合物质量(mg)的1-200倍，在非限制性实施方案中可以为1、5、10、15、20、25、30、35、40、45、 50、55、60、65、70、75、80、85、90、95、100、105、110、115、120、125、130、135、140、145、150、155、160、165、170、175、180、185、190、200。在某些实施方案中，本公开所述的制备式(I)所示化合物的M晶型的方法还包括过滤、洗涤或干燥等步骤。
本公开提供了式(I)所示化合物的N晶型，以衍射角2θ角度表示的X-射线粉末衍射图，在5.028、9.942、10.900、15.428、18.410、20.274和25.252处有特征峰。在某些实施方案中，式(I)所示化合物的N晶型在5.028、7.671、9.942、10.900、15.428、16.560、18.410、20.274、24.036和25.252处有特征峰。在某些实施方案中，式(I)所示化合物的N晶型在5.028、7.671、9.942、10.900、12.677、15.428、16.560、18.410、20.274、24.036、25.252和26.385处有特征峰。在某些实施方案中，式(I)所示化合物的N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。
本公开进一步提供了制备式(I)所示化合物N晶型的方法，包括：a)式I所示化合物与乙酸乙酯/四氢呋喃(1:1)混合，加热溶清，b)降温析晶。
在某些实施方案中，本公开所述溶剂所用体积(μl)可以为式(I)化合物质量(mg)的1-200倍，在非限制性实施方案中可以为1、5、10、15、20、25、30、35、40、45、50、55、60、65、70、75、80、85、90、95、100、105、110、115、120、125、130、135、140、145、150、155、160、165、170、175、180、185、190、200。在某些实施方案中，本公开所述的制备式(I)所示化合物的N晶型的方法还包括过滤、洗涤或干燥等步骤。
本公开提供了式(I)所示化合物的O晶型，以衍射角2θ角度表示的X-射线粉末衍射图，在11.796、17.423、18.081、19.136、21.707、22.165和25.719处有特征峰。在某些实施方案中，式(I)所示化合物的O晶型在7.843、11.796、17.423、18.081、19.136、21.707、22.165、24.412、25.719和28.521处有特征峰。在某些实施方案中，式(I)所示化合物的O晶型在7.843、11.796、15.455、17.423、18.081、19.136、21.055、21.707、22.165、24.412、25.719、27.538和28.521处有特征峰。在某些实施方案中，式(I)所示化合物的O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。
本公开进一步提供了制备式(I)所示化合物O晶型的方法，包括：a)式I所示化合物与乙腈、苯磺酸混合，加热，b)降温析晶。
在某些实施方案中，本公开所述溶剂所用体积(μl)可以为式(I)化合物质量(mg)的1-200倍，在非限制性实施方案中可以为1、5、10、15、20、25、30、35、40、45、50、55、60、65、70、75、80、85、90、95、100、105、110、115、120、125、130、135、 140、145、150、155、160、165、170、175、180、185、190、200。在某些实施方案中，本公开所述的制备式(I)所示化合物的O晶型的方法还包括过滤、洗涤或干燥等步骤。
本公开提供了式(I)所示化合物的P晶型，以衍射角2θ角度表示的X-射线粉末衍射图，在5.359、7.491、10.786、14.249、16.527、17.729和20.798处有特征峰。在某些实施方案中，式(I)所示化合物的P晶型在5.359、7.491、9.905、10.786、13.192、14.249、16.527、17.729、18.862和20.798处有特征峰。在某些实施方案中，式(I)所示化合物的P晶型在5.359、7.491、9.905、10.786、13.192、14.249、16.527、17.729、18.862、20.798、23.799和26.555处有特征峰。在某些实施方案中，式(I)所示化合物的P晶型以衍射角2θ角度表示的X-射线粉末衍射图谱如图17所示。
本公开进一步提供了制备式(I)所示化合物P晶型的方法，包括：a)式(I)所示化合物的晶型C与1,4-二氧六环混合，b)打浆析晶。
在某些实施方案中，本公开所述溶剂所用体积(μl)可以为式(I)化合物质量(mg)的1-200倍，在非限制性实施方案中可以为1、5、10、15、20、25、30、35、40、45、50、55、60、65、70、75、80、85、90、95、100、105、110、115、120、125、130、135、140、145、150、155、160、165、170、175、180、185、190、200。在某些实施方案中，本公开所述的制备式(I)所示化合物的P晶型的方法还包括过滤、洗涤或干燥等步骤。
本公开提供了式(I)所示化合物的Q晶型，以衍射角2θ角度表示的X-射线粉末衍射图，在5.038、10.152、15.850、16.574、18.892、20.760和21.835处有特征峰。在某些实施方案中，式(I)所示化合物的Q晶型在5.038、10.152、11.175、15.850、16.574、18.892、20.760、21.835、23.905和25.784处有特征峰。在某些实施方案中，式(I)所示化合物的Q晶型在5.038、7.682、10.152、11.175、14.218、15.850、16.574、18.892、20.760、21.835、23.905、25.784和26.418处有特征峰。在某些实施方案中，式(I)所示化合物的Q晶型以衍射角2θ角度表示的X-射线粉末衍射图谱如图18所示。
本公开进一步提供了制备式(I)所示化合物Q晶型的方法，包括，方法1：a)式(I)所示化合物与乙酸乙酯混合，b)打浆析晶，固体70℃或130℃干燥；
在某些实施方案中，本公开所述溶剂所用体积(μl)可以为式(I)化合物质量(mg)的1-200倍，在非限制性实施方案中可以为1、5、10、15、20、25、30、35、40、45、50、55、60、65、70、75、80、85、90、95、100、105、110、115、120、125、130、135、140、145、150、155、160、165、170、175、180、185、190、200。在某些实施方案中， 本公开所述的制备式(I)所示化合物的Q晶型的方法还包括过滤、洗涤或干燥等步骤。
本公开提供了式(I)所示化合物的U晶型，以衍射角2θ角度表示的X-射线粉末衍射图，在14.155、15.745、17.314、17.997、18.838、20.512和21.415处有特征峰。在某些实施方案中，式(I)所示化合物的U晶型在14.155、15.745、16.564、17.314、17.997、18.838、20.512、21.415、23.557和26.313处有特征峰。在某些实施方案中，式(I)所示化合物的U晶型在7.657、14.155、15.745、16.564、17.314、17.997、18.838、20.512、21.415、23.557、25.711、26.313和28.029处有特征峰。在某些实施方案中，式(I)所示化合物的U晶型以衍射角2θ角度表示的X-射线粉末衍射图谱如图19所示。
本公开进一步提供了制备式(I)所示化合物U晶型的方法，包括，方法1：a)式(I)所示化合物的Q晶型与水混合，b)打浆析晶；
或者方法2：a)式I所示化合物与DMSO混合，加热溶清，b)加水析晶。
在某些实施方案中，本公开所述溶剂所用体积(μl)可以为式(I)化合物质量(mg)的1-200倍，在非限制性实施方案中可以为1、5、10、15、20、25、30、35、40、45、50、55、60、65、70、75、80、85、90、95、100、105、110、115、120、125、130、135、140、145、150、155、160、165、170、175、180、185、190、200。在某些实施方案中，本公开所述的制备式(I)所示化合物的U晶型的方法还包括过滤、洗涤或干燥等步骤。
本公开提供了式(I)所示化合物的X晶型，以衍射角2θ角度表示的X-射线粉末衍射图，在6.864、9.873、10.963、13.801、16.089、18.006和20.929处有特征峰。在某些实施方案中，式(I)所示化合物的X晶型在6.864、9.873、10.963、13.801、16.089、18.006、20.929和26.203处有特征峰。在某些实施方案中，式(I)所示化合物的X晶型以衍射角2θ角度表示的X-射线粉末衍射图谱如图20所示。
本公开进一步提供了制备式(I)所示化合物X晶型的方法，包括:方法1：a)式(I)所示化合物的D晶型与异丙醚或正庚烷混合，b)打浆析晶。
在某些实施方案中，本公开所述溶剂所用体积(μl)可以为式(I)化合物质量(mg)的1-200倍，在非限制性实施方案中可以为1、5、10、15、20、25、30、35、40、45、50、55、60、65、70、75、80、85、90、95、100、105、110、115、120、125、130、135、140、145、150、155、160、165、170、175、180、185、190、200。在某些实施方案中，本公开所述的制备式(I)所示化合物的X晶型的方法还包括过滤、洗涤或干燥等步骤。
本公开提供了式(I)所示化合物的Y晶型，以衍射角2θ角度表示的X-射线粉末衍 射图，在5.676、7.666、14.260、16.562、18.020、21.802和26.425处有特征峰。在某些实施方案中，式(I)所示化合物的Y晶型在5.676、7.666、9.985、12.634、14.260、16.562、18.020、21.802、26.425和26.974处有特征峰。在某些实施方案中，式(I)所示化合物的Y晶型在5.676、7.666、9.985、12.634、14.260、16.562、18.020、21.802、24.051、25.846、26.425和26.974处有特征峰。在某些实施方案中，式(I)所示化合物的Y晶型以衍射角2θ角度表示的X-射线粉末衍射图谱如图21所示。
本公开进一步提供了制备式(I)所示化合物Y晶型的方法，包括：a)式(I)所示化合物的Q晶型与异丙醚或正庚烷混合，b)打浆析晶。
在某些实施方案中，本公开所述溶剂所用体积(μl)可以为式(I)化合物质量(mg)的1-200倍，在非限制性实施方案中可以为1、5、10、15、20、25、30、35、40、45、50、55、60、65、70、75、80、85、90、95、100、105、110、115、120、125、130、135、140、145、150、155、160、165、170、175、180、185、190、200。在某些实施方案中，本公开所述的制备式(I)所示化合物的Y晶型的方法还包括过滤、洗涤或干燥等步骤。
本公开提供了式(I)所示化合物的V晶型，以衍射角2θ角度表示的X-射线粉末衍射图，在5.649、6.154、6.720、11.651、18.757、19.813和23.948处有特征峰。在某些实施方案中，式(I)所示化合物的V晶型在5.649、6.154、6.720、9.778、11.651、17.570、18.757、19.813、23.948和26.995处有特征峰。在某些实施方案中，式(I)所示化合物的V晶型在5.649、6.154、6.720、9.778、11.651、13.576、17.570、18.757、19.813、21.905、23.948、25.825和26.995处有特征峰。在某些实施方案中，式(I)所示化合物的V晶型以衍射角2θ角度表示的X-射线粉末衍射图谱如图22所示。
本公开进一步提供了制备式(I)所示化合物V晶型的方法，包括，方法1：a)式(I)所示化合物与N,N-二甲基甲酰胺混合，溶清，b)加丙酮或乙腈析晶；
或者方法2)a)式I所示化合物与N,N-二甲基甲酰胺混合，b)降温析晶或搅拌析晶。
在某些实施方案中，本公开所述溶剂所用体积(μl)可以为式(I)化合物质量(mg)的1-200倍，在非限制性实施方案中可以为1、5、10、15、20、25、30、35、40、45、50、55、60、65、70、75、80、85、90、95、100、105、110、115、120、125、130、135、140、145、150、155、160、165、170、175、180、185、190、200。在某些实施方案中，本公开所述的制备式(I)所示化合物的V晶型的方法还包括过滤、洗涤或干燥等步骤。
本公开提供了式(I)所示化合物的R晶型，以衍射角2θ角度表示的X-射线粉末衍射图，在5.534、7.611、10.033、15.782、17.101、19.017和20.567处有特征峰。在某些实施方案中，式(I)所示化合物的R晶型在5.534、7.611、10.033、11.857、12.737、15.782、17.101、19.017、20.567和23.692处有特征峰。在某些实施方案中，式(I)所示化合物的R晶型在5.534、7.611、10.033、11.148、11.857、12.737、14.179、15.782、17.101、19.017、20.567、21.871和23.692处有特征峰。在某些实施方案中，式(I)所示化合物的R晶型以衍射角2θ角度表示的X-射线粉末衍射图谱如图23所示。
本公开进一步提供了制备式(I)所示化合物R晶型的方法，包括：a)式(I)所示化合物与四氢呋喃混合，溶解，b)浓缩析晶。
在某些实施方案中，本公开所述溶剂所用体积(μl)可以为式(I)化合物质量(mg)的1-200倍，在非限制性实施方案中可以为1、5、10、15、20、25、30、35、40、45、50、55、60、65、70、75、80、85、90、95、100、105、110、115、120、125、130、135、140、145、150、155、160、165、170、175、180、185、190、200。在某些实施方案中，本公开所述的制备式(I)所示化合物的R晶型的方法还包括过滤、洗涤或干燥等步骤。
本公开提供了式(I)所示化合物的S晶型，以衍射角2θ角度表示的X-射线粉末衍射图，在6.576、9.082、10.921、13.592、19.965、21.403和24.207处有特征峰。在某些实施方案中，式(I)所示化合物的S晶型在6.576、9.082、10.921、13.592、16.805、19.965、21.403、24.207、25.662和27.457处有特征峰。在某些实施方案中，式(I)所示化合物的S晶型在6.576、7.890、9.082、10.921、13.592、15.043、16.805、19.965、21.403、24.207、25.662、26.537和27.457处有特征峰。在某些实施方案中，式(I)所示化合物的S晶型以衍射角2θ角度表示的X-射线粉末衍射图谱如图24所示。
本公开进一步提供了制备式(I)所示化合物S晶型的方法，包括，方法1：a):式(I)所示化合物与DMF混合，加热溶解，降温析出，b)过滤，滤饼与乙腈混合，打浆，c)过滤，滤饼与水混合，打浆，d)过滤，干燥，然后用乙腈打浆析晶，干燥。
在某些实施方案中，本公开所述溶剂所用体积(μl)可以为式(I)化合物质量(mg)的1-200倍，在非限制性实施方案中可以为1、5、10、15、20、25、30、35、40、45、50、55、60、65、70、75、80、85、90、95、100、105、110、115、120、125、130、135、140、145、150、155、160、165、170、175、180、185、190、200。在某些实施方案中，本公开所述的制备式(I)所示化合物的S晶型的方法还包括过滤、洗涤或干燥等步骤。
本公开提供了式(I)所示化合物的T晶型，以衍射角2θ角度表示的X-射线粉末衍射图，在6.915、9.177、9.984、11.012、13.595、16.156和20.138处有特征峰。在某些实施方案中，式(I)所示化合物的T晶型在6.915、9.177、9.984、11.012、13.595、15.174、16.156、20.138、24.261和26.391处有特征峰。在某些实施方案中，式(I)所示化合物的T晶型在6.915、9.177、9.984、11.012、13.595、15.174、16.156、18.509、20.138、22.954、24.261、26.391和27.514处有特征峰。在某些实施方案中，式(I)所示化合物的T晶型以衍射角2θ角度表示的X-射线粉末衍射图谱如图25所示。
本公开进一步提供了制备式(I)所示化合物T晶型的方法，包括，方法1：a)将式(I)所示化合物与DMF混合，加热溶解，降温析晶，b)过滤，滤饼与水混合搅拌，c)过滤，滤饼再次与水混合搅拌，d)过滤，干燥，再与用乙腈混合，搅拌析晶，干燥。
在某些实施方案中，本公开所述溶剂所用体积(μl)可以为式(I)化合物质量(mg)的1-200倍，在非限制性实施方案中可以为1、5、10、15、20、25、30、35、40、45、50、55、60、65、70、75、80、85、90、95、100、105、110、115、120、125、130、135、140、145、150、155、160、165、170、175、180、185、190、200。在某些实施方案中，本公开所述的制备式(I)所示化合物的T晶型的方法还包括过滤、洗涤或干燥等步骤。
本公开还提供了由前述式(I)所示化合物的晶型制备得到的药物组合物。
本公开还提供了一种药物组合物，含前述晶型和任选自药学上可接受的载体、稀释剂或赋形剂。
本公开还提供了一种药物组合物的制备方法，包括将前述晶型与药学上可接受的载体、稀释剂或赋形剂混合的步骤。
本公开还提供了前述晶型，或前述组合物，或由前述方法制备得到的组合物在制备用于治疗和/或预防与CRBN蛋白相关疾病的药物中的用途。
本公开还提供了前述晶型，或前述组合物，或由前述方法制备得到的组合物在制备用于治疗和/或预防癌症、与血管生成相关的病症、疼痛、黄斑变性或相关综合征、皮肤病、肺部疾病、石棉相关疾病、寄生虫病、免疫缺陷病、CNS疾病、CNS损伤、动脉粥样硬化或相关病症、睡眠障碍或相关病症、感染性疾病、血红蛋白病或相关病症、或TNFα相关病症的药物中的用途；优选地，在制备用于治疗和/或预防癌症或CNS损伤的药物中的用途。
在某些实施方案中，所述的癌症选自白血病、骨髓瘤、淋巴瘤、黑色素瘤、皮肤癌、肝癌、肾癌、肺癌、鼻咽癌、胃癌、食道癌、结肠直肠癌、胆囊癌、胆管癌、绒毛膜上皮癌、胰腺癌、真性红细胞增多症、儿科肿瘤、宫颈癌、卵巢癌、乳腺癌、膀胱癌、尿路上皮癌、输尿管肿瘤、前列腺癌、精原细胞瘤、睾丸肿瘤、头颈瘤、头颈鳞状细胞癌、子宫 内膜癌、甲状腺癌、肉瘤、骨瘤、成神经细胞瘤、神经内分泌癌、脑瘤、CNS癌、星形细胞瘤和胶质瘤；优选地，所述肝癌为肝细胞癌；所述结肠直肠癌为结肠癌或直肠癌；所述肉瘤为骨肉瘤或软组织肉瘤；所述胶质瘤为胶质母细胞瘤。
在某些实施方案中，所述的骨髓瘤为多发性骨髓瘤(MM)和骨髓增生异常综合症(MDS)；优选地，所述的多发性骨髓瘤是复发性的、难治性的或抗性的。
在某些实施方案中，所述的多发性骨髓瘤是来那度胺或泊马度胺难治性的或抗性的。
本公开所述的“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(包括超过1位小数的数字经过四舍五入后的情况)，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。
依据《中国药典》2015年版四部中“9103药物引湿性指导原则”中引湿性特征描述与引湿性增重的界定，
潮解：吸收足量水分形成液体；
极具引湿性：引湿增重不小于15％；
有引湿性：引湿增重小于15％但不小于2％；
略有引湿性：引湿增重小于2％但不小于0.2％；
无或几乎无引湿性：引湿增重小于0.2％。
本公开中所述的“差示扫描量热分析或DSC”是指在样品升温或恒温过程中，测量样品与参考物之间的温度差、热流差，以表征所有与热效应有关的物理变化和化学变化，得到样品的相变信息。
本公开中所述干燥温度一般为25℃～150℃，优选40℃～80℃，可以常压干燥，也可以减压干燥。
“药物组合物”表示含有一种或多种本文所述式(I)化合物或其可药用盐与其他化学组分的混合物，以及其他组分例如药学上接受的载体和赋形剂。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。
本公开所述的晶型包括但不限于式(I)所示化合物的溶剂合物，所述的溶剂包括但不限于水、甲醇、乙醇、异丙醇、丙酮、乙酸乙酯、乙腈、乙酸异丙酯、甲基叔丁基醚、2-丁酮、四氢呋喃、二甲基亚砜、N-甲基吡咯烷酮、甲基异丁酮、二氯甲烷、正庚烷、1,4-二氧六环、硝基甲烷、丙二醇甲醚、三氯甲烷、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、对二甲苯、环己烷、二氯乙烷、正己烷、石油醚、正辛烷、邻二甲苯、甲苯、异丙醚。
本公开所述的“溶剂合物”包括但不限于式(I)化合物与溶剂结合形成的络合物。
附图说明
图1：式(I)所示化合物无定形的XRPD图谱。
图2：式(I)所示化合物A晶型的XRPD图谱。
图3：式(I)所示化合物B晶型的XRPD图谱。
图4：式(I)所示化合物C晶型的XRPD图谱。
图5：式(I)所示化合物D晶型的XRPD图谱。
图6：式(I)所示化合物E晶型的XRPD图谱。
图7：式(I)所示化合物F晶型的XRPD图谱。
图8：式(I)所示化合物G晶型的XRPD图谱。
图9：式(I)所示化合物H晶型的XRPD图谱。
图10：式(I)所示化合物I晶型的XRPD图谱。
图11：式(I)所示化合物J晶型的XRPD图谱。
图12：式(I)所示化合物K晶型的XRPD图谱。
图13：式(I)所示化合物L晶型的XRPD图谱。
图14：式(I)所示化合物M晶型的XRPD图谱。
图15：式(I)所示化合物N晶型的XRPD图谱。
图16：式(I)所示化合物O晶型的XRPD图谱。
图17：式(I)所示化合物P晶型的XRPD图谱。
图18：式(I)所示化合物Q晶型的XRPD图谱。
图19：式(I)所示化合物U晶型的XRPD图谱。
图20：式(I)所示化合物X晶型的XRPD图谱。
图21：式(I)所示化合物Y晶型的XRPD图谱。
图22：式(I)所示化合物V晶型的XRPD图谱。
图23：式(I)所示化合物R晶型的XRPD图谱。
图24：式(I)所示化合物S晶型的XRPD图谱。
图25：式(I)所示化合物T晶型的XRPD图谱。
图26：实施例1化合物和对照例CC-92480对NCI-H929移植瘤在CB-17SCID小鼠体内的疗效数据。
图27：实施例1化合物和对照例CC-92480对CB-17SCID小鼠体重的影响。
具体实施方案
以下将结合实施例或实验例更详细地解释本公开，本公开中的实施例或实验例仅用于说明本公开中的技术方案，并非限定本公开中的实质和范围。
本公开中实施例中未注明具体条件的实验方法，通常按照常规条件，或按照原料或商品制造厂商所建议的条件。未注明具体来源的试剂，为市场购买的常规试剂。
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-d6)、氘代氯仿(CDCl3)、氘代甲醇(CD3OD)，内标为四甲基硅烷(TMS)。
MS的测定用Agilent 1200/1290DAD-6110/6120 Quadrupole MS液质联用仪(生产商：Agilent，MS型号：6110/6120 Quadrupole MS)、waters ACQuity UPLC-QD/SQD(生产商：waters，MS型号：waters ACQuity Qda Detector/waters SQ Detector)、THERMO Ultimate 3000-Q Exactive(生产商：THERMO，MS型号：THERMO Q Exactive)。
高效液相色谱法(HPLC)分析使用Agilent HPLC 1200DAD、Agilent HPLC 1200VWD和Waters HPLC e2695-2489高压液相色谱仪。
手性HPLC分析测定使用Agilent 1260 DAD高效液相色谱仪。
高效液相制备使用Waters 2767、Waters 2767-SQ Detecor2、Shimadzu LC-20AP和Gilson-281制备型色谱仪。
手性制备使用Shimadzu LC-20AP制备型色谱仪。
CombiFlash快速制备仪使用Combiflash Rf200(TELEDYNE ISCO)。
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。
硅胶柱色谱法一般使用烟台黄海硅胶200～300目硅胶为载体。
激酶平均抑制率及IC50值的测定用NovoStar酶标仪(德国BMG公司)。
本公开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：正己烷/乙酸乙酯体系，B：二氯甲烷/甲醇体系，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。
本公开中实验所用仪器的测试条件：
1、差示扫描量热仪(Differential Scanning Calorimeter,DSC)
仪器型号：Mettler Toledo DSC 3+STARe System
吹扫气：氮气；氮气吹扫速度：50mL/min
升温速率：10.0℃/min
温度范围：25-350℃
2、X-射线粉末衍射谱(X-ray Powder Diffraction,XRPD)
仪器型号：BRUKER D8DiscoverX-射线粉末衍射仪
射线：单色Cu-Kα射线
扫描方式：θ/2θ，扫描范围(2θ范围)：3～50°
电压：40kV，电流：40mA
3、热重分析仪(Thermogravimetric Analysis，TGA)
仪器型号：Mettler Toledo TGA2
吹扫气：氮气；氮气吹扫速度：50mL/min
升温速率：10.0℃/min
温度范围：25-350℃
实施例1：式(I)所示化合物的制备
(S)-4-(4-((5-(((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氧基)甲基)吡啶-2-基)硫基)哌啶-1-基)-3-氟苯甲腈(化合物1)

第一步
4-((5-甲酰基吡啶-2-基)硫基)哌啶-1-羧酸叔丁酯1b
将化合物1-1a(700mg，3.22mmol)、6-氟吡啶-3-甲醛1a(443mg，3.54mmol)和碳酸钾(1.11g，8.05mmol)加入到N,N-二甲基甲酰胺(10mL)中。将反应液加热升温至80℃反应1小时。反应液用水(30mL)稀释，然后用乙酸乙酯(40mL×3)萃取，合并有机相，用饱和氯化钠溶液(100mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用柱层析色谱法以洗脱剂体系B纯化得到标题化合物1b(1.0g，产率：96％)。
MS m/z(ESI)：267.1[M-55]。
第二步
6-(哌啶-4-基硫基)烟醛三氟乙酸盐1c
将化合物1b(950mg，2.95mmol)溶于二氯甲烷(10mL)，在冰浴下，缓慢加入三氟乙酸(2mL)，反应1小时。反应液浓缩，干燥，得到标题化合物1c，粗产品不经纯化直接用于下一步反应。
MS m/z(ESI)：223.1[M+1]。
第三步
3-氟-4-(4-(((5-甲酰基吡啶-2-基)硫基)哌啶-1-基)苯甲腈1d
将化合物1c(760mg,2.94mmol)、3,4-二氟苯甲腈(817mg,5.87mmol)和碳酸钾(1.22g,8.81mmol)加入到N,N-二甲基甲酰胺(15mL)中，将反应液加热至80℃反应过夜。反应液加水(50mL)，用乙酸乙酯萃取(50mL×3)，合并有机相，用饱和氯化钠溶液(50mL×3)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，得到的残余物用柱层析色谱法以洗脱剂体系B纯化得到标题化合物1d(850mg，产率：84％)。
MS m/z(ESI)：342.1[M+1]。
第四步
3-氟-4-(4-((5-(羟甲基)吡啶-2-基)硫基)哌啶-1-基)苯甲腈1e
冰浴下，将化合物1d(600mg,1.76mmol)加入到甲醇(10mL)中，缓慢加入硼氢化钠(133mg,3.51mmol)，反应1小时。反应液用水(10mL)淬灭，然后用乙酸乙酯(30mL×3)萃取，合并有机相，用饱和氯化钠溶液洗涤(30mL)，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用柱层析色谱法以洗脱剂体系B纯化得到标题化合物1e(580mg，产率：96％)。
MS m/z(ESI)：344.1[M+1]。
第五步
4-(4-((5-(溴甲基)吡啶-2-基)硫基)哌啶-1-基)-3-氟苯甲腈1f
将化合物1e(200mg,0.582mmol)加入到二氯甲烷(6mL)中，依次加入三苯基膦(199mg,0.757mmol)和四溴化碳(251mg,0.757mmol)，反应2小时。反应液浓缩，残余物用柱层析色谱法以洗脱剂体系B纯化得到标题化合物1f(190mg，产率：80％)。
MS m/z(ESI)：406.0[M+1]；408.0[M+3]。
第六步
(S)-5-氨基-4-(4-((6-((1-(4-氰基-2-氟苯基)哌啶-4-基)硫基)吡啶-3-基)甲氧基)-1-氧代异吲哚啉-2-基)-5-氧代戊酸叔丁酯1g
将(S)-5-氨基-4-(4-羟基-1-氧代异吲哚啉-2-基)-5-氧代戊酸叔丁酯1-3a(82mg，0.246mmol，采用公知的方法“Journal of Medicinal Chemistry,2020,63(13),6648-6676”制备而得)、无水碳酸钾(65mg，0.468mmol)加入到N,N-二甲基甲酰胺(3mL)中，加入化合物1f(95mg，0.244mmol)，反应2小时。将反应液倒入冰水(10mL)中，然后用乙酸乙酯(30mL×3)萃取，合并有机相，用饱和氯化钠溶液(20mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用柱层析色谱法用洗脱剂体系B纯化，得到标题化合物1g(145mg，产率：94％)。
MS m/z(ESI)：660.2[M+1]。
第七步
(S)-4-(4-((5-(((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氧基)甲基)吡啶-2-基)硫基)哌啶-1-基)-3-氟苯甲腈1
将化合物1g(60mg，0.091mmol)加入到乙腈(5mL)中，室温加入苯磺酸(16mg，0.091mmol)，80℃反应8小时。反应液减压除去溶剂，所得残余物经高效液相制备(Gilson GX-281，洗脱体系：10mmol/L的碳酸氢铵的水溶液和乙腈，乙腈的梯度：60％-80％，流速：30mL/min)得到标题化合物1(42mg，产率：78％)。
经X-射线粉末衍射仪检测，标题化合物1为无定形。
MS m/z(ESI)：586.4[M+1]。
1H NMR(500MHz,DMSO-d6):δ10.98(s,1H),8.60(s,1H),7.78(dd,1H),7.69(dd,1H), 7.59-7.48(m,2H),7.38-7.33(m,3H),7.16(t,1H),5.24(s,2H),5.12(dd,1H),4.42(d,1H),4.26(d,1H),4.07-3.99(m,1H),3.56-3.48(m,2H),3.13-3.03(m,2H),2.96-2.87(m,1H),2.63-2.55(m,1H),2.46-2.38(m,1H),2.21-2.12(m,2H),2.02-1.94(m,1H),1.82-1.70(m,2H)。
生物学评价
测试例1NCI-H929增殖实验生物学评价
以下方法用来测定本公开化合物对NCI-H929细胞增殖的抑制活性。实验方法简述如下。
NCI-H929细胞(ATCC，CRL-9068)用完全培养基即含有10％胎牛血清(Corning，35-076-CV)和0.05mM的2-巯基乙醇(Sigma，M3148)的RPMI1640培养基(Hyclone，SH30809.01)进行培养。实验第一天，使用完全培养基将NCI-H929细胞以6000个细胞/孔的密度种于96孔板，每孔100μL细胞悬液，同时每孔加入10μL用完全培养基配制的梯度稀释的待测化合物，化合物首先溶解于DMSO中，起始浓度为10mM，进行5倍浓度梯度连续稀释，共9个浓度点，空白对照为100％DMSO。再取5μL溶于DMSO的化合物加入到95μL的完全培养基中，即化合物用完全培养基稀释20倍。最终取10μL每孔的稀释于完全培养基中的化合物加入到细胞悬液中，即化合物终浓度为从50μM开始的进行5倍梯度稀释的9个浓度点，设置含有0.5％DMSO的空白对照，放置37℃，5％CO2细胞培养箱孵育5天。第六天，取出96孔细胞培养板，每孔加入50μL CellTiter-发光细胞活性检测试剂(Promega，G7573)，室温放置10分钟后，使用多功能微孔板酶标仪(PerkinElmer，EnVision2015)读取发光信号值，用Graphpad Prism软件计算化合物抑制活性的IC50值见表I。
表I本公开化合物抑制NCI-H929细胞增殖的IC50值
结论：本公开化合物1具有很好的抑制NCI-H929细胞增殖的活性。
测试例2药效试验
1、实验目的
评价实施例1化合物和对照例CC-92480抑制人多发性骨髓瘤细胞NCI-H929移植瘤在CB-17SCID小鼠上生长的作用。
2、实验药品
实施例1化合物；
对照例CC-92480(见WO2019014100A1中化合物2，根据其中公开的方法合成)
实施例1化合物和对照例CC-92480用5％DMSO+20％PEG400+70％(10％TPGS)+5％(1％HPMC K100LV)配制。
3、实验方法和实验材料
3.1、实验动物和饲养条件
CB-17SCID雌性小鼠30只，购自北京维通利华实验动物有限公司(合格证编号：20170011006049，SCXK(沪)2017-0011)，购入时体重约19g，5只/笼饲养，12/12小时光/暗周期调节，温度23±1℃恒温，湿度50～60％，自由进食进水。
3.2、动物分组：
CB-17SCID鼠适应性饲养后，分组如下：
注：qd为一天给药1次；i.g为灌胃给药。
3.3、实验方法：
将处于对数生长期的NCI-H929细胞5×106细胞/小鼠/100μL(含50μL Matrigel)接种于30只雌性CB-17SCID小鼠右肋部皮下，经过10天，荷瘤小鼠肿瘤体积达到200mm3左右时，将小鼠按照肿瘤体积和体重随机分为3组：溶媒对照组、CC-92480-1mpk、实施例1化合物-1mpk，每组7只。分组当天设为Day0(D0),并开始每天一次灌胃给药，共给药11天(表2)。每周两次用游标卡尺测量荷瘤小鼠肿瘤体积和用天平测量体重并记录数据。当肿瘤体积达到2000mm3或多数肿瘤出现破溃或体重下降20％时，将荷瘤动物进行安乐死作为实验终点。
3.4、数据统计
所有数据使用Excel和GraphPad Prism 5软件进行作图及统计分析。
肿瘤体积(V)计算公式为：V＝1/2×a×b2，其中：a、b分别表示长、宽。
相对肿瘤增殖率T/C(％)＝(T-T0)/(C-C0)×100(％)，其中：T、C为实验结束时治疗组和 对照组的肿瘤体积；T0、C0为实验开始时的肿瘤体积。
抑瘤率TGI(％)＝1-T/C(％)，当TGI(％)超过100％后，将不显示具体数值，只用＞100％表示。
肿瘤消退(％)＝[(T0-T)/T0]×100(％)。
4、结果
实施例1化合物和对照例CC-92480对NCI-H929移植瘤在CB-17SCID小鼠体内的疗效数据见下表II和图26。
实施例1化合物和对照例CC-92480对CB-17SCID小鼠体重的影响见图27。
表II本公开化合物对NCI-H929移植瘤在CB-17SCID小鼠体内的疗效
注：qd为一天给药1次；po为口服。
5、结论
实施例1化合物在肿瘤细胞移植10天后开始给药，每天一次，给药11天后肿瘤体积发生明显消退。经计算抑瘤率>100％，肿瘤消退率为88％，实验终点时与同剂量CC-92480相比具有统计学差异(p＜0.05)，且给药对小鼠体重没有影响。相同条件下，对照例CC-92480的肿瘤消退率为34％。
测试例3药代动力学评价
1、概述
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1化合物和对照例CC-92480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
实施例1化合物和对照例CC-92480。
2.2试验动物
小鼠18只，雌性，购自维通利华实验动物有限公司，动物生产许可证号：SCXK(沪)2017-0005。
2.3药物配制
称取实施例1化合物，加5％体积的DMSO和5％吐温80(上海泰坦科技有限公司)使其溶解，然后加入90％生理盐水配制成0.1mg/mL澄明溶液。
称取对照例CC-92480，加5％体积的DMSO和5％吐温80(上海泰坦科技有限公司)使其溶解，然后加入90％生理盐水配制成0.1mg/mL澄明溶液。
2.4给药
小鼠9只灌胃给予实施例1化合物，给药剂量为2mg/kg，给药体积均为0.2mL/10g。
小鼠9只灌胃给予化合物对照例CC-92480，给药剂量为2mg/kg，给药体积均为0.2mL/10g。
3、操作
小鼠灌胃给药实施例1化合物和对照例CC-92480，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0.2mL(每个时间点3只动物)，置EDTA-K2抗凝试管中，10000rpm离心1分钟(4℃)，1小时内分离血浆，-20℃保存待测。采血至离心过程在冰浴条件下操作。
测定不同浓度的药物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(中国生物制品检定所)50μL(100ng/mL)和乙腈175μL，涡旋混合5分钟，离心10分钟(3700转/分钟)，血浆样品取上清液1μL进行LC/MS/MS(API4000三重四极杆串联质谱仪，美国Applied Biosystems公司；Shimadzu LC-30AD超高效液相色谱系统，日本Shimadzu公司)分析。
4、药代动力学参数结果
本公开化合物的药代动力学参数如下表III所示。
表III本公开化合物的药代动力学参数

结论：本公开化合物的药代吸收较好，具有药代动力学优势。
测试例4本公开化合物的血浆稳定性评价
1、摘要
应用LC-MS/MS定量测定了实施例1化合物和对照例CC-92480于猴冻存血浆中在37℃分别孵育0、15、30、60、120、180、240分钟后，实施例1化合物和CC-92480的稳定性。
2.试验方案
2.1试验药品
实施例1化合物和对照例CC-92480。
2.2试验血浆
猴血浆购自上海美迪西生物医药股份有限公司。
2.3化合物溶液配制
称取一定量实施例1化合物，加入DMSO配制成30mM储备液，取一定体积储备液，用DMSO稀释成浓度为1600μM的溶液I；再取一定体积的1600μM的溶液I用50％的甲醇稀释成浓度为16μM的工作溶液II。用上述方法配制CC-92480的30mM储备液、1600μM的溶液I’和16μM的工作溶液II’。
2.4样本孵育
取16μM实施例1化合物和对照例CC-92480的工作溶液5μL，分别加入到75μL的血浆中，使化合物的终浓度为1μM。样本于37℃水浴中孵育0、15、30、60、90、120、180分钟。孵育结束后加入240μL含内标的乙腈，然后摇床800rpm摇10分钟，离心机3700rpm，4℃离心20分钟，上清采用LC-MS分析，进样体积为2μL。
3、结果
本公开化合物在猴血浆中转化情况见下表IV。
表IV本公开化合物在猴血浆中的稳定性数据

结论：本公开化合物在猴血浆中有稳定性优势。
实施例2：式(I)所示化合物无定形的制备
式(I)化合物10mg，加入丙二醇甲醚1.0ml，室温打浆，离心，固体干燥，得到产物。经X-射线粉末衍射仪检测，该产物为无定形，XRPD谱图如图1所示。
实施例3：式(I)所示化合物A晶型的制备
将式(I)所示化合物7.3g加入到二氯甲烷中(300mL)，加入甲醇30mL溶解，加入水300mL，旋蒸除去大部分二氯甲烷，析出大量固体，过滤，得到固体后过夜晾干。向固体中加入二氯甲烷(500mL)，溶解，抽滤，得到滤液(500mL)，加入无水硫酸钠干燥，过滤，加入乙酸乙酯(200mL)，旋干，得到产物。经X-射线粉末衍射仪检测，将该产物定义为晶型A，XRPD谱图如图2所示，其特征峰位置如表1所示。DSC谱图显示，吸热峰峰值155.26℃、183.19℃和244.74℃。TGA谱图显示，25℃-220℃失重9.48％。
表1
实施例4：式(I)所示化合物A晶型的制备
式(I)化合物10mg，加入1ml水，室温打浆，离心，固体真空干燥得到产物。经X-射线粉末衍射仪检测，该产物为晶型A。
实施例5：式(I)所示化合物A晶型的制备
式(I)化合物10mg，加入1ml丙酮，打浆，离心，固体真空干燥得到产物。经X-射线粉末衍射仪检测，该产物为晶型A。
实施例6：式(I)所示化合物A晶型的制备
式(I)化合物10mg，加入THF 300ul，溶清后加入450ul正庚烷，析出固体，室温打浆，离心，固体真空干燥得到产物。经X-射线粉末衍射仪检测，该产物为晶型A。
实施例7：式(I)所示化合物B晶型的制备
式(I)化合物150mg，加入1.0ml乙腈/甲醇(V/V＝1:1)，打浆，离心，固体真空干燥得到产物。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3所示，其特征峰位置如表2所示。DSC谱图显示，吸热峰峰值182.74℃和245.37℃。TGA谱图显示，25℃-225℃失重4.57％。
表2
实施例8：式(I)所示化合物C晶型的制备
式(I)化合物10mg，加入乙醇1.0ml，室温打浆，离心，固体真空干燥，得到产物。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4所示，其特征峰位置如表3所示。DSC谱图显示，吸热峰峰值153.48℃、182.76℃和244.05℃。TGA谱图显示，25℃-215℃失重3.00％。
表3

实施例9：式(I)所示化合物C晶型的制备
式(I)化合物10mg，加入10％水/丙酮0.9ml，挥发析晶，得到产物。经X-射线粉末衍射检测，将该产物为晶型C。
实施例10：式(I)所示化合物D晶型的制备
式(I)化合物10mg，加入乙腈1.0ml，打浆，离心，固体30℃真空干燥，得到产物。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5所示，其特征峰位置如表4所示。DSC谱图显示，吸热峰峰值156.12℃和245.38℃。TGA谱图显示，25℃-205℃失重1.17％。
表4

实施例11：式(I)所示化合物E晶型的制备
式(I)化合物10mg，加入10％水/甲醇1.0ml，打浆，离心，固体真空干燥，得到产物。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6所示，其特征峰位置如表5所示。DSC谱图显示，吸热峰峰值182.71℃和245.00℃。TGA谱图显示，25℃-235℃失重0.68％。
表5
实施例12：式(I)所示化合物E晶型的制备
式(I)化合物10mg，加入DCM 300ul，溶清，加入300ul正庚烷，析出固体，室温打浆，离心，固体真空干燥，得到产物。经X-射线粉末衍射检测，将该产物为晶型E。
实施例13：式(I)所示化合物F晶型的制备
式(I)化合物10mg，加入甲醇1.0ml，室温打浆，离心，固体真空干燥，得到产物。 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7所示，其特征峰位置如表6所示。DSC谱图显示，吸热峰峰值181.22℃和245.03℃。TGA谱图显示，25℃-210℃失重8.63％。
表6
实施例14：式(I)所示化合物F晶型的制备
式(I)化合物10mg，加入二氯甲烷0.3ml溶清，再加入乙酸异丙酯0.9ml，析出固体，室温打浆，离心，固体真空干燥，得到产物。经X-射线粉末衍射检测，将该产物为晶型F。
实施例15：式(I)所示化合物F晶型的制备
式(I)化合物10mg，加入1,4二氧六环900ul，溶清，挥发，得到产物。经X-射线粉末衍射检测，将该产物为晶型F。
实施例16：式(I)所示化合物G晶型的制备
式(I)化合物10mg，加入1.0ml 1,2-二氯乙烷，室温打浆，离心，固体真空干燥，得到产物。经X-射线粉末衍射检测，将该产物定义为晶型G，XRPD谱图如图8所示，其特征峰位置如表7所示。DSC谱图显示，吸热峰峰值160.43℃、182.11℃和244.42℃。TGA谱图显示，25℃-235℃失重9.97％。
表7
实施例17：式(I)所示化合物G晶型的制备
式(I)化合物10mg，加入三氯甲烷500ul，溶清，挥发，得到产物。经X-射线粉末衍射检测，该产物为晶型G。
实施例18：式(I)所示化合物H晶型的制备
式(I)化合物约10mg，加入1.0ml正己烷，室温打浆，离心，真空干燥得到产物。经X-射线粉末衍射检测，将该产物定义为晶型H，XRPD谱图如图9所示，其特征峰位置如表8所示。DSC谱图显示，吸热峰峰值184.53℃和247.90℃。TGA谱图显示，25℃-215℃失重4.13％。
表8
实施例19：式(I)所示化合物I晶型的制备
式(I)化合物10mg，加入四氢呋喃0.4ml溶清，室温慢挥发，得到产物。经X-射线粉末衍射检测，将该产物定义为晶型I，XRPD谱图如图10所示，其特征峰位置如表9所示。DSC谱图显示，吸热峰峰值182.58℃和245.04℃。TGA谱图显示，25℃-225℃失重5.44％。
表9
实施例20：式(I)所示化合物I晶型的制备
式(I)化合物10mg，加入四氢呋喃0.3ml溶清，加入0.6ml水，固体析出，离心，真空干燥，得到产物。经X-射线粉末衍射检测，该产物为晶型I。
实施例21：式(I)所示化合物J晶型的制备
式(I)化合物10mg，加入DMSO 0.2ml溶清，再加入0.2ml水，固体析出，离心，真空干燥，得到产物。经X-射线粉末衍射检测，将该产物定义为晶型J，XRPD谱图如图11所示，其特征峰位置如表10所示。DSC谱图显示，吸热峰峰值154.09℃、165.41℃和247.39℃。TGA谱图显示，30℃-220℃失重10.48％。
表10

实施例22：式(I)所示化合物J晶型的制备
式(I)化合物10mg，加入DMSO 0.2ml溶清，加入0.4ml甲基叔丁基醚，固体析出，离心，真空干燥，得到产物。经X-射线粉末衍射检测，该产物为晶型J。
实施例23：式(I)所示化合物K晶型的制备
式(I)化合物10mg，加入N-甲基吡咯烷酮50ul溶清，室温慢挥发，得到产物。经X-射线粉末衍射检测，将该产物定义为晶型K，XRPD谱图如图12所示，其特征峰位置如表11所示。
表11
实施例24：式(I)所示化合物L晶型的制备
式(I)化合物10mg，加入N,N-二甲基乙酰胺200ul溶清，室温慢挥发，得到产物。经X-射线粉末衍射检测，将该产物定义为晶型L，XRPD谱图如图13所示，其特征峰位 置如表12所示。
表12
实施例25：式(I)所示化合物M晶型的制备
式(I)化合物的A晶型10mg加热至225℃，得到产物。经X-射线粉末衍射检测，将该产物定义为晶型M，XRPD谱图如图14所示，其特征峰位置如表13所示。
表13
实施例26：式(I)所示化合物N晶型的制备
将式(I)所示化合物80mg，加入到4.0mL乙酸乙酯和四氢呋喃(V/V＝1:1)的混合溶剂中，加热溶清，重结晶，过滤，将所得固体干燥，得到产物。经X-射线粉末衍射检测，将该产物定义为晶型N，XRPD谱图如图15所示，其特征峰位置如表14所示。DSC谱图显示，吸热峰峰值185.49℃和188.82℃。TGA谱图显示，30℃-225℃失重4.86％。
表14
实施例27：式(I)所示化合物O晶型的制备
将式(I)所示化合物60mg，加入到乙腈(5mL)中，室温加入苯磺酸16mg，80℃反应8h。反应液中有固体析出，过滤，固体45℃真空干燥得到产物。经X-射线粉末衍射检测，将该产物定义为晶型O，XRPD谱图如图16所示，其特征峰位置如表15所示。
表15

实施例28：式(I)所示化合物P晶型的制备
将式(I)所示化合物晶型C 40mg，加入到二氧六环(2.0mL)中，室温打浆，过滤，固体真空干燥，得到产物。经X-射线粉末衍射检测，将该产物定义为晶型P，XRPD如图17所示。DSC谱图显示，吸热峰峰值127.49℃，180.10℃，249.23℃；TGA谱图显示，40℃-230℃失重8.79％。
表16
实施例27：式(I)所示化合物Q晶型的制备
将式(I)所示化合物150mg加入到乙酸乙酯3mL中，室温打浆，过滤，固体在130℃真空干燥，得到产物。经X-射线粉末衍射检测，将该产物定义为晶型Q，XRPD谱图如图18所示，其特征峰位置如表17所示。DSC谱图显示，吸热峰峰值188.58℃和249.61℃。TGA谱图显示，25℃-225℃失重0.54％。
表17

实施例29：式(I)所示化合物U晶型的制备
式(I)化合物50mg，加入DMSO 0.6ml，50℃加热溶清，加入1.2ml水，析晶，离心，固体再加入2ml水搅洗，离心，固体真空干燥得到产物。经X-射线粉末衍射检测，将该产物定义为晶型U，XRPD谱图如图19所示，其特征峰位置如表18所示。DSC谱图显示，吸热峰峰值183.28℃和248.22℃。TGA谱图显示，40℃-215℃失重0.62％。
表18
实施例30：式(I)所示化合物U晶型的制备
式(I)化合物的Q晶型10mg，加入水1.0ml，室温打浆1天，得到产物。经X-射线粉末衍射检测，该产物为晶型U。
实施例31：式(I)所示化合物X晶型的制备
式(I)化合物的D晶型10mg，加入正庚烷1.0ml，室温打浆，离心，固体真空干燥，得到产物。经X-射线粉末衍射检测，将该产物定义为晶型X，XRPD谱图如图20所示，其特征峰位置如表19所示。DSC谱图显示，吸热峰峰值158.81℃、184.14℃和249.04℃。
表19
实施例32：式(I)所示化合物Y晶型的制备
式(I)化合物的Q晶型10mg，加入正庚烷1.0ml，室温打浆，离心，固体真空干燥，得到产物。经X-射线粉末衍射检测，将该产物定义为晶型Y，XRPD谱图如图21所示，其特征峰位置如表20所示。DSC谱图显示，吸热峰峰值184.97℃和248.72℃。
表20

实施例33：式(I)所示化合物V晶型的制备
将式(I)所示化合物200mg，加入0.4mL N,N-二甲基甲酰胺，然后向体系中加入2ml乙腈，在20～30℃下搅拌，抽滤，滤饼干燥后得到产物。经X-射线粉末衍射检测，将该产物定义为晶型V，XRPD谱图如图22所示，其特征峰位置如表21所示。DSC谱图显示，吸热峰峰值147.78℃。TGA谱图显示，30℃-210℃失重10.73％。
表21
实施例34：式(I)所示化合物V晶型的制备
将式(I)所示化合物200mg，加入1mL N,N-二甲基甲酰胺，升温至60℃溶解，自然降温至20～30℃，在20～30℃下搅拌，抽滤，使用0.2mL N,N-二甲基甲酰胺淋洗滤饼，滤饼在45℃减压干燥26h，得到产物。经X-射线粉末衍射检测，该产物为晶型V。
实施例35：式(I)所示化合物R晶型的制备
将式(I)所示化合物8g，加入150mL的四氢呋喃，搅拌溶解，减压浓缩至无馏分出现，得到产物。经X-射线粉末衍射检测，将该产物定义为晶型R，XRPD谱图如图23所示，其特征峰位置如表22所示。
表22
实施例36：式(I)所示化合物S晶型的制备
将式(I)所示化合物在N,N-二甲基甲酰胺中，升温溶解，然后降温析出，将其用乙腈打浆后过滤，滤饼用水打浆一次，过滤，60℃干燥样品，加入1L的乙腈，在20～30℃下搅拌，过滤，干燥后得到产物。经X-射线粉末衍射检测，将该产物定义为晶型S，XRPD谱图如图24所示，其特征峰位置如表23所示。
表23

实施例37：式(I)所示化合物T晶型的制备
将式(I)所示化合物70.9g加入200mL的N,N-二甲基甲酰胺中，升温至70-80℃溶解，然后降温至20-30℃析出并搅拌，过滤，滤饼加入1200mL水中搅拌，过滤，滤饼再次加入1200mL水中搅拌，过滤，滤饼40-45℃下干燥。将干燥后的物料45.0g加入450mL的乙腈，在20～30℃下磁力搅拌29h，抽滤，减压干燥17h后得到产物。经X-射线粉末衍射检测，将该产物定义为晶型T，XRPD谱图如图25所示，其特征峰位置如表24所示。DSC谱图显示，吸热峰峰值164.78℃和247.66℃。
表24
实施例38：式(I)所示化合物D、E、Q和U晶型引湿性研究(2021.10.15南京)
采用Surface Measurement Systems advantage 2，在25℃，湿度从50％起，考察湿度范围为0％-95％，步进为10％，判断标准为每个梯度质量变化dM/dT小于0.002％，TMAX360min，循环两圈。
表25
实施例39：式(I)所示化合物D、E、Q和U晶型影响因素稳定性
将各晶型敞口平摊放置，分别考察在光照(4500Lux)、高温(40℃、60℃)、高湿(RH 75％、RH 92.5％)条件下样品的稳定性，取样考察期为30天。
表26


结论：影响因素实验表明，式(I)化合物晶型D、E、Q和U在高湿75％和92.5％条件下，物理化学稳定性良好，在60℃、光照条件下纯度略有下降，晶型未转变。
实施例40：式(I)所示化合物D、E、Q和U晶型长期/加速稳定性
将式(I)所示化合物D、E、Q和U晶型，分别放置25℃，60％RH和40℃，75％RH条件考察其稳定性。
表27
表28
表29
表30
结论：游离态D、E、Q和U晶型在长期加速稳定性条件下放置6个月的物理、化学稳定性好。

Claims (33)

  1. 式(I)所示化合物的A晶型，
    其中，以衍射角2θ角度表示的X-射线粉末衍射图，在5.765、8.061、9.925、16.632、17.900、19.469和21.115有特征峰，优选在5.765、7.465、8.061、9.925、12.890、15.085、16.632、17.900、19.469和21.115处有特征峰，更优选在5.765、7.465、8.061、9.925、11.674、12.890、14.270、15.085、16.632、17.900、18.715、19.469和21.115处有特征峰，最优选以衍射角2θ角度表示的X-射线粉末衍射图谱如图2所示。
  2. 式(I)所示化合物的B晶型，
    其中，以衍射角2θ角度表示的X-射线粉末衍射图，在4.977、6.788、10.047、14.143、15.684、18.547和20.840处有特征峰，优选在4.977、6.788、10.047、14.143、15.684、18.547、20.840、24.096和25.505处有特征峰，更优选以衍射角2θ角度表示的X-射线粉末衍射图谱如图3所示。
  3. 式(I)所示化合物的C晶型，
    其中，以衍射角2θ角度表示的X-射线粉末衍射图，在5.653、7.974、9.989、16.143、17.860、18.992和20.972处有特征峰，优选在5.653、7.974、9.989、11.505、12.798、14.265、16.143、17.860、18.992和20.972处有特征峰，更优选在3.533、5.653、7.974、8.790、9.989、11.505、12.798、14.265、15.277、16.143、17.860、18.992和20.972处有特征峰，最优选以衍射角2θ角度表示的X-射线粉末衍射图谱如图4所示。
  4. 式(I)所示化合物的D晶型，
    其中，以衍射角2θ角度表示的X-射线粉末衍射图，在6.831、9.845、13.453、18.225、20.117、20.891和23.006处有特征峰，优选在6.831、9.845、10.927、13.453、16.096、18.225、20.117、20.891、23.006和26.132处有特征峰，更优选以衍射角2θ角度表示的X-射线粉末衍射图谱如图5所示。
  5. 式(I)所示化合物的E晶型，
    其中，以衍射角2θ角度表示的X-射线粉末衍射图，在5.864、7.573、8.087、10.003、16.444、19.349和20.553处有特征峰，优选在5.864、7.573、8.087、10.003、12.471、15.165、16.444、17.432、19.349和20.553处有特征峰，更优选在5.864、7.573、8.087、10.003、11.701、12.471、15.165、16.444、17.432、19.349、20.553、21.067和21.709处有特征峰，最优选以衍射角2θ角度表示的X-射线粉末衍射图谱如图6所示。
  6. 式(I)所示化合物的F晶型，
    其中，以衍射角2θ角度表示的X-射线粉末衍射图，在5.062、7.820、10.077、14.231、16.672、18.586和20.435处有特征峰，优选在5.062、7.820、10.077、14.231、15.192、16.672、18.586、20.435、21.868和25.442处有特征峰，更优选在5.062、7.820、10.077、14.231、15.192、16.672、18.586、20.435、21.868、24.193、25.442、26.303和28.629处有特征峰，最优选以衍射角2θ角度表示的X-射线粉末衍射图谱如图7所示。
  7. 式(I)所示化合物的G晶型，
    其中，以衍射角2θ角度表示的X-射线粉末衍射图，在5.999、7.972、9.951、11.388、17.812、20.975和25.819处有特征峰，优选在5.999、7.396、7.972、8.637、9.951、11.388、15.291、17.812、20.975和25.819处有特征峰，更优选在5.999、7.396、7.972、8.637、9.951、11.388、12.763、15.291、17.812、20.975、23.408、25.819和27.400处有特征峰，最优选以衍射角2θ角度表示的X-射线粉末衍射图谱如图8所示。
  8. 式(I)所示化合物的H晶型，
    其中，以衍射角2θ角度表示的X-射线粉末衍射图，在5.758、7.533、9.901、14.267、16.420、18.103和26.356处有特征峰，优选在5.758、7.533、9.901、14.267、16.420、 18.103、18.917、20.489、24.049和26.356处有特征峰，更优选在5.758、7.533、9.901、14.267、16.420、18.103、18.917、20.489、21.563、24.049和26.356处有特征峰，最选以衍射角2θ角度表示的X-射线粉末衍射图谱如图9所示。
  9. 式(I)所示化合物的I晶型，
    其中，以衍射角2θ角度表示的X-射线粉末衍射图，在5.294、6.826、7.564、10.739、13.699、16.812和20.709处有特征峰，优选以衍射角2θ角度表示的X-射线粉末衍射图谱如图10所示。
  10. 式(I)所示化合物的J晶型，
    其中，以衍射角2θ角度表示的X-射线粉末衍射图，在5.041、10.068、16.424、20.544、21.190、24.077和25.433处有特征峰，优选在5.041、8.212、10.068、14.101、15.167、16.424、20.544、21.190、24.077和25.433处有特征峰，更优选在5.041、8.212、10.068、14.101、15.167、16.424、20.544、21.190、22.036、22.679、24.077、25.433和26.454处有特征峰，最优选以衍射角2θ角度表示的X-射线粉末衍射图谱如图11所示。
  11. 式(I)所示化合物的K晶型，

    其中，以衍射角2θ角度表示的X-射线粉末衍射图，在5.156、7.699、10.339、14.334、16.203、18.327和23.418处有特征峰，优选在5.156、7.699、10.339、14.334、16.203、18.327、23.418、25.348、25.919和26.446处有特征峰，更优选以衍射角2θ角度表示的X-射线粉末衍射图谱如图12所示。
  12. 式(I)所示化合物的L晶型，
    其中，以衍射角2θ角度表示的X-射线粉末衍射图，在4.932、5.360、9.831、14.844、18.244、20.104和24.914处有特征峰，优选在4.932、5.360、9.831、10.753、14.844、16.369、18.244、20.104、23.129、24.914处有特征峰，更优选以衍射角2θ角度表示的X-射线粉末衍射图谱如图13所示。
  13. 式(I)所示化合物的M晶型，
    其中，以衍射角2θ角度表示的X-射线粉末衍射图，在14.959、16.322、18.410、20.748、22.067、23.670和26.863处有特征峰，优选在14.959、16.322、18.410、20.748、22.067、23.670、24.839、25.873、26.863和27.811处有特征峰，更优选在14.959、16.322、18.410、20.748、22.067、23.670、24.322、24.839、25.873、26.863和27.811处有特征峰，最优选以衍射角2θ角度表示的X-射线粉末衍射图谱如图14所示。
  14. 式(I)所示化合物的N晶型，
    其中，以衍射角2θ角度表示的X-射线粉末衍射图，在5.028、9.942、10.900、15.428、18.410、20.274和25.252处有特征峰，优选在5.028、7.671、9.942、10.900、15.428、16.560、18.410、20.274、24.036和25.252处有特征峰，更优选在5.028、7.671、9.942、10.900、12.677、15.428、16.560、18.410、20.274、24.036、25.252和26.385处有特征峰，最优选以衍射角2θ角度表示的X-射线粉末衍射图谱如图15所示。
  15. 式(I)所示化合物的O晶型，
    其中，以衍射角2θ角度表示的X-射线粉末衍射图，在11.796、17.423、18.081、19.136、21.707、22.165和25.719处有特征峰，优选在7.843、11.796、17.423、18.081、19.136、21.707、22.165、24.412、25.719和28.521处有特征峰，更优选在7.843、11.796、15.455、17.423、18.081、19.136、21.055、21.707、22.165、24.412、25.719、27.538和28.521处有特征峰，最优选以衍射角2θ角度表示的X-射线粉末衍射图谱如图16所示。
  16. 式(I)所示化合物的P晶型，
    其中，以衍射角2θ角度表示的X-射线粉末衍射图，在5.359、7.491、10.786、14.249、16.527、17.729和20.798处有特征峰，优选在5.359、7.491、9.905、10.786、13.192、 14.249、16.527、17.729、18.862和20.798处有特征峰，更优选在5.359、7.491、9.905、10.786、13.192、14.249、16.527、17.729、18.862、20.798、23.799和26.555，最优选以衍射角2θ角度表示的X-射线粉末衍射图谱如图17所示。
  17. 式(I)所示化合物的Q晶型，
    其中，以衍射角2θ角度表示的X-射线粉末衍射图，在5.038、10.152、15.850、16.574、18.892、20.760和21.835处有特征峰，优选在5.038、10.152、11.175、15.850、16.574、18.892、20.760、21.835、23.905和25.784处有特征峰，更优选在5.038、7.682、10.152、11.175、14.218、15.850、16.574、18.892、20.760、21.835、23.905、25.784和26.418处有特征峰，最优选以衍射角2θ角度表示的X-射线粉末衍射图谱如图18所示。
  18. 式(I)所示化合物的U晶型，
    其中，以衍射角2θ角度表示的X-射线粉末衍射图，在14.155、15.745、17.314、17.997、18.838、20.512和21.415处有特征峰，优选在14.155、15.745、16.564、17.314、17.997、18.838、20.512、21.415、23.557和26.313处有特征峰，更优选在7.657、14.155、15.745、16.564、17.314、17.997、18.838、20.512、21.415、23.557、25.711、26.313和28.029处有特征峰，最优选以衍射角2θ角度表示的X-射线粉末衍射图谱如图19所示。
  19. 式(I)所示化合物的X晶型，
    其中，以衍射角2θ角度表示的X-射线粉末衍射图，在6.864、9.873、10.963、13.801、16.089、18.006和20.929处有特征峰，优选在6.864、9.873、10.963、13.801、16.089、18.006、20.929和26.203处有特征峰，更优选以衍射角2θ角度表示的X-射线粉末衍射图谱如图20所示。
  20. 式(I)所示化合物的Y晶型，
    其中，以衍射角2θ角度表示的X-射线粉末衍射图，在5.676、7.666、14.260、16.562、18.020、21.802和26.425处有特征峰，优选在5.676、7.666、9.985、12.634、14.260、16.562、18.020、21.802、26.425和26.974处有特征峰，更优选在5.676、7.666、9.985、12.634、14.260、16.562、18.020、21.802、24.051、25.846、26.425和26.974处有特征峰，最优选以衍射角2θ角度表示的X-射线粉末衍射图谱如图21所示。
  21. 式(I)所示化合物的V晶型，
    其中，以衍射角2θ角度表示的X-射线粉末衍射图，在5.649、6.154、6.720、11.651、18.757、19.813和23.948处有特征峰，优选在5.649、6.154、6.720、9.778、11.651、17.570、18.757、19.813、23.948和26.995处有特征峰，更优选在5.649、6.154、6.720、9.778、 11.651、13.576、17.570、18.757、19.813、21.905、23.948、25.825和26.995处有特征峰，最优选以衍射角2θ角度表示的X-射线粉末衍射图谱如图22所示。
  22. 式(I)所示化合物的R晶型，
    其中，以衍射角2θ角度表示的X-射线粉末衍射图，在5.534、7.611、10.033、15.782、17.101、19.017和20.567处有特征峰，优选在5.534、7.611、10.033、11.857、12.737、15.782、17.101、19.017、20.567和23.692处有特征峰，更优选在5.534、7.611、10.033、11.148、11.857、12.737、14.179、15.782、17.101、19.017、20.567、21.871和23.692处有特征峰，最优选以衍射角2θ角度表示的X-射线粉末衍射图谱如图23所示。
  23. 式(I)所示化合物的S晶型，
    其中，以衍射角2θ角度表示的X-射线粉末衍射图，在6.576、9.082、10.921、13.592、19.965、21.403和24.207处有特征峰，优选在6.576、9.082、10.921、13.592、16.805、19.965、21.403、24.207、25.662和27.457处有特征峰，更优选在6.576、7.890、9.082、10.921、13.592、15.043、16.805、19.965、21.403、24.207、25.662、26.537和27.457处有特征峰，最优选以衍射角2θ角度表示的X-射线粉末衍射图谱如图24所示。
  24. 式(I)所示化合物的T晶型，
    其中，以衍射角2θ角度表示的X-射线粉末衍射图，在6.915、9.177、9.984、11.012、13.595、16.156和20.138处有特征峰，优选在6.915、9.177、9.984、11.012、13.595、15.174、16.156、20.138、24.261和26.391处有特征峰，更优选在6.915、9.177、9.984、11.012、13.595、15.174、16.156、18.509、20.138、22.954、24.261、26.391和27.514处有特征峰，最优选以衍射角2θ角度表示的X-射线粉末衍射图谱如图25所示。
  25. 根据权利要求1-24中任意一项所述的晶型，其中，所述2θ角误差范围为±0.20。
  26. 一种由权利要求1-25中任意一项所述的晶型制备得到的药物组合物。
  27. 一种药物组合物，含有权利要求1-25中任意一项所述的晶型和任选自药学上可接受的载体、稀释剂或赋形剂。
  28. 一种药物组合物的制备方法，包括将1-25中任意一项所述的晶型与药学上可接受的载体、稀释剂或赋形剂混合的步骤。
  29. 权利要求1-25中任意一项所述的晶型，或权利要求26或27所述的组合物，或由权利要求28所述方法制备得到的组合物在制备用于治疗和/或预防与CRBN蛋白相关疾病的药物中的用途。
  30. 权利要求1-25中任意一项所述的晶型，或权利要求26或27所述的组合物，或由权利要求28所述方法制备得到的组合物在制备用于治疗和/或预防癌症、与血管生成相关的病症、疼痛、黄斑变性或相关综合征、皮肤病、肺部疾病、石棉相关疾病、寄生虫病、免疫缺陷病、CNS疾病、CNS损伤、动脉粥样硬化或相关病症、睡眠障碍或相关病症、感染性疾病、血红蛋白病或相关病症、或TNFα相关病症的药物中的用途；优选地， 在制备用于治疗和/或预防癌症或CNS损伤的药物中的用途。
  31. 权利要求30所述的用途，其中所述的癌症选自白血病、骨髓瘤、淋巴瘤、黑色素瘤、皮肤癌、肝癌、肾癌、肺癌、鼻咽癌、胃癌、食道癌、结肠直肠癌、胆囊癌、胆管癌、绒毛膜上皮癌、胰腺癌、真性红细胞增多症、儿科肿瘤、宫颈癌、卵巢癌、乳腺癌、膀胱癌、尿路上皮癌、输尿管肿瘤、前列腺癌、精原细胞瘤、睾丸肿瘤、头颈瘤、头颈鳞状细胞癌、子宫内膜癌、甲状腺癌、肉瘤、骨瘤、成神经细胞瘤、神经内分泌癌、脑瘤、CNS癌、星形细胞瘤和胶质瘤；优选地，所述肝癌为肝细胞癌；所述结肠直肠癌为结肠癌或直肠癌；所述肉瘤为骨肉瘤或软组织肉瘤；所述胶质瘤为胶质母细胞瘤。
  32. 权利要求30所述的用途，其中所述的骨髓瘤为多发性骨髓瘤(MM)和骨髓增生异常综合症(MDS)；优选地，所述的多发性骨髓瘤是复发性的、难治性的或抗性的。
  33. 权利要求32所述的用途，其中所述的多发性骨髓瘤是来那度胺或泊马度胺难治性的或抗性的。
PCT/CN2023/073077 2022-01-19 2023-01-19 一种含硫异吲哚啉类衍生物的晶型 WO2023138647A1 (zh)

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