WO2020200161A1 - Sel de dérivé tricyclique contenant de l'indazolyle et forme cristalline de celui-ci - Google Patents

Sel de dérivé tricyclique contenant de l'indazolyle et forme cristalline de celui-ci Download PDF

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WO2020200161A1
WO2020200161A1 PCT/CN2020/082042 CN2020082042W WO2020200161A1 WO 2020200161 A1 WO2020200161 A1 WO 2020200161A1 CN 2020082042 W CN2020082042 W CN 2020082042W WO 2020200161 A1 WO2020200161 A1 WO 2020200161A1
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acid
crystal form
pyridin
characteristic peaks
compound
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PCT/CN2020/082042
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Chinese (zh)
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詹小兰
呙临松
李宗斌
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上海翰森生物医药科技有限公司
江苏豪森药业集团有限公司
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Priority to CN202080002252.1A priority Critical patent/CN112020357B/zh
Publication of WO2020200161A1 publication Critical patent/WO2020200161A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • 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
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4162—1,2-Diazoles condensed with heterocyclic ring systems
    • 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
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention belongs to the field of drug synthesis, and specifically relates to a salt of an indazole group-containing triacyl derivative and a preparation method and application of its crystal form.
  • ERK signaling pathway Members of the ERK signaling pathway, such as RAS and BRAF, often mutate in tumors. About 1/3 of human tumors express continuously activated mutant RAS, and 8% of tumors express activated BRAF.
  • the mutations and probability statistics related to the ERK signaling pathway in malignant tumors are shown in Table 1. According to statistics, 90% of pancreatic cancers, 50% of colorectal cancers, and 30% of lung cancers have RAS mutations; 50% of melanomas, 50% of thyroid cancers, and 15% of colorectal cancers have BRAF mutations.
  • Vemurafenib is the first BRAF inhibitor approved by the FDA to be marketed. It is mainly used for the treatment of advanced melanoma, but the efficacy can only be maintained for 8-9 months, which is prone to drug resistance. Studies have confirmed that reactivation of the ERK signaling pathway mediates the resistance of melanoma to verofenil. And another BRAF inhibitor Dabrafenib (Dabrafenib) is also very easy to develop resistance. In addition, verofenib has failed to show significant clinical activity in colorectal cancer patients with BRAF mutations, and the overall response rate is only 5%. In addition to BRAF inhibitors, MEK inhibitors currently on the market have also appeared to varying degrees of resistance in clinical applications.
  • MEK inhibitors have a low response rate to RAS mutation tumors, and the response rate to BRAF mutation melanoma is only 22%.
  • BRAF inhibitors and EGFR inhibitors are used clinically to reverse drug resistance, and the patient develops multidrug resistance several months later.
  • PCT patent application number: PCT/CN2018/110795 discloses the structure of a series of pyrazolyl-containing triacyl derivative inhibitors.
  • PCT/CN2018/110795 discloses the structure of a series of pyrazolyl-containing triacyl derivative inhibitors.
  • the present invention has conducted a comprehensive study on the salts of the above substances, and is dedicated to obtaining the most suitable salt and crystal form for medicine.
  • the purpose of the present invention is to provide a crystal form of the compound represented by general formula (I), the structure of which is as shown in formula (I):
  • W is selected from N or CH
  • R 1 is selected from hydrogen atom, halogen, amino, nitro, hydroxyl, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, -(CH 2 ) n R 3 , -(CH 2 ) n OR 3 , -(CH 2 ) n C(O)R 3 , -(CH 2 ) n NR 3 R 4 or -(CH 2 ) n C(O)NR 3 R 4 ;
  • R 2 is selected from hydrogen atom, halogen, amino, nitro, hydroxyl, cyano, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl or 3-8 membered heterocyclic group;
  • R 3 and R 4 are the same or different, and are each independently selected from hydrogen atom, deuterium atom, halogen, cyano, hydroxyl, amino, nitro, C 1-6 alkyl, C 1-6 haloalkyl, C 3- 8 cycloalkyl or 3-8 membered heterocyclic group, wherein the C 1-6 alkyl, C 1-6 haloalkyl, amino, C 3-8 cycloalkyl and 3-8 membered heterocyclic group are optional Further selected from deuterium atom, C 1-6 alkyl, C 1-6 haloalkyl, halogen, hydroxyl, amino, nitro, cyano, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl and 3-6 membered heterocyclic group substituted by one or more substituents;
  • M is an inorganic acid or an organic acid, wherein the inorganic acid is selected from hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, or phosphoric acid; the organic acid is selected from 2,5-dihydroxybenzoic acid, 1- Hydroxy-2-naphthoic acid, acetic acid, dichloroacetic acid, trichloroacetic acid, acetohydroxamic acid, adipic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, 4-amino Benzoic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclohexane sulfamic acid, camphor sulfonic acid, aspartic acid, camphor acid, gluconic acid, glucuronic acid, glutamic acid,
  • x is selected from an integer of 0, 1, 2 or 3;
  • n is an integer of 0, 1, 2 or 3;
  • t is an integer of 0, 1, 2, 3, 4, 5, or 6.
  • the crystal form of the compound represented by general formula (I) has a structure as shown in general formula (II):
  • W, R 1 , R 2 , M, x and t are as defined in general formula (I).
  • the crystal form of the compound represented by general formula (I) has the following compound structure:
  • x and M are as defined in general formula (I).
  • it is the free base crystal form of the compound of formula (III).
  • it is an anhydrate, and further contains water, and the water is pipeline water or crystal water, preferably containing 0.5-8 water molecules; more preferably, the hydrate contains 0.5-4 water molecules; further It preferably contains 0.5-2.5 water molecules; more preferably, it contains 1 water molecule. For example, it contains 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5 or 8 water.
  • the crystal form of the compound of formula (III) is a hydrate or an anhydrate.
  • the crystal form of the compound of formula (III) contains 0.5-8 water molecules; preferably, the hydrate contains 0.5-4 water molecules; further preferably, it contains 0.5-2.5 water molecules. Molecule; More preferably, it contains 1 water molecule. For example, it contains 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5 or 8 water.
  • M is selected from maleic acid, p-toluenesulfonic acid, hydrochloric acid, nitric acid, sulfuric acid, salicylic acid, methanesulfonic acid, benzenesulfonic acid or 1,5-naphthalenedisulfonic acid
  • x is selected from 0.5, 1, 1.5 or 2, preferably 1.
  • x and M are as defined in general formula (I).
  • Another object of the present invention is to provide a compound represented by general formula (Ia), the structure of which is as shown in formula (Ia):
  • W is selected from N or CH
  • R 1 is selected from hydrogen atom, halogen, amino, nitro, hydroxyl, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, -(CH 2 ) n R 3 , -(CH 2 ) n OR 3 , -(CH 2 ) n C(O)R 3 , -(CH 2 ) n NR 3 R 4 or -(CH 2 ) n C(O)NR 3 R 4 ;
  • R 2 is selected from hydrogen atom, halogen, amino, nitro, hydroxyl, cyano, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl or 3-8 membered heterocyclic group;
  • R 3 and R 4 are the same or different, and are each independently selected from hydrogen atom, deuterium atom, halogen, cyano, hydroxyl, amino, nitro, C 1-6 alkyl, C 1-6 haloalkyl, C 3- 8 cycloalkyl or 3-8 membered heterocyclic group, wherein the C 1-6 alkyl, C 1-6 haloalkyl, amino, C 3-8 cycloalkyl and 3-8 membered heterocyclic group are optional Further selected from deuterium atom, C 1-6 alkyl, C 1-6 haloalkyl, halogen, hydroxyl, amino, nitro, cyano, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl and 3-6 membered heterocyclic group substituted by one or more substituents;
  • M is an inorganic acid or an organic acid, wherein the inorganic acid is selected from hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, or phosphoric acid; the organic acid is selected from 2,5-dihydroxybenzoic acid, 1- Hydroxy-2-naphthoic acid, acetic acid, dichloroacetic acid, trichloroacetic acid, acetohydroxamic acid, adipic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, benzoic acid, 4-acetylaminobenzoic acid, 4-amino Benzoic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclohexane sulfamic acid, camphor sulfonic acid, aspartic acid, camphor acid, gluconic acid, glucuronic acid, glutamic acid
  • y is an integer of 1, 2 or 3;
  • n is an integer of 0, 1, 2 or 3;
  • t is an integer of 0, 1, 2, 3, 4, 5, or 6.
  • the compound represented by general formula (Ia) has a structure as shown in formula (IIa):
  • R 1 , R 2 , W, M, t, and x are as defined in general formula (I).
  • the compound represented by the general formula (Ia) has a compound structure as shown in the formula (IIIa):
  • M and y are as defined in general formula (Ia).
  • the compound represented by the general formula (IIIa) is a water anhydride, further comprising water, and the water is pipeline water or crystal water.
  • the compound represented by the general formula (IIIa) contains 0.5-8 water molecules; preferably 0.5-4 water molecules; further preferably 0.5-2.5 water molecules; Preferably 1 water molecule; for example, it contains 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5 or 8 water.
  • the compound represented by the general formula (Ia) has a compound structure as shown in formula (IVa):
  • M and y are as defined in general formula (Ia), preferably, M is selected from maleic acid, and y is 1.
  • the object of the present invention is also to provide a method for preparing the crystal form of the compound represented by general formula (I) or the compound represented by general formula (Ia), which specifically includes the following steps:
  • the benign solvent is selected from methanol, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide or N-methylpyrrolidone; preferably N,N-dimethylformamide and N- Methylpyrrolidone;
  • the organic solvent is selected from methanol, ethanol, ethyl acetate, dichloromethane, acetone, n-hexane, petroleum ether, benzene, toluene, chloroform, acetonitrile, carbon tetrachloride, dichloroethane, tetrahydrofuran, 2-butane Ketone, 3-pentanone, heptane, methyl tert-butyl ether, isopropyl ether, 1,4-dioxane, tert-butanol or N,N-dimethylformamide; preferably methanol and ethanol; the above
  • the benign solvent and organic solution must be miscible when used;
  • the poor solvent is selected from heptane, water, methyl tert-butyl ether, toluene, isopropyl ether, ethyl acetate, acetone or acetonitrile; preferably ethyl acetate, methyl tert-butyl ether, isopropyl ether and acetonitrile ;
  • the counter ion acid is selected from hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, phosphoric acid, 2,5-dihydroxybenzoic acid, 1-hydroxy-2-naphthoic acid, acetic acid, dichloro Acetic acid, trichloroacetic acid, acetohydroxamic acid, adipic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, benzoic acid, 4-acetylaminobenzoic acid, 4-aminobenzoic acid, capric acid, caproic acid, caprylic acid, Cinnamic acid, citric acid, cyclohexane sulfamic acid, camphor sulfonic acid, aspartic acid, camphor acid, gluconic acid, glucuronic acid, glutamic acid, erythorbic acid, lactic acid, malic acid, mandelic acid, py
  • the object of the present invention is also to provide a crystal form of the compound represented by general formula (I) or a method for preparing the compound represented by general formula (Ia), which specifically includes the following steps:
  • the poor solvent is selected from acetone, ethyl acetate, acetonitrile, ethanol, 88% acetone, tetrahydrofuran, 1,4-dioxane, benzene, toluene, isopropanol, n-butanol, isobutanol, N , N-dimethylformamide, N,N-dimethylacetamide, n-propanol, tert-butanol or 2-butanone; preferably methanol, ethanol, tetrahydrofuran, ethyl acetate, acetonitrile or acetone; preferably methanol, Ethanol, tetrahydrofuran, ethyl acetate, acetonitrile and acetone;
  • the organic solvent is selected from methanol, ethanol, ethyl acetate, dichloromethane, acetone, n-hexane, petroleum ether, benzene, toluene, chloroform, acetonitrile, carbon tetrachloride, dichloroethane, tetrahydrofuran, 2-butane Ketone, 3-pentanone, heptane, methyl tert-butyl ether, isopropyl ether, 1,4-dioxane, tert-butanol or N,N-dimethylformamide; preferably methanol or ethanol; the above
  • the benign solvent and organic solution must be miscible when used;
  • the counter ion acid is selected from hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, phosphoric acid, 2,5-dihydroxybenzoic acid, 1-hydroxy-2-naphthoic acid, acetic acid, dichloro Acetic acid, trichloroacetic acid, acetohydroxamic acid, adipic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, benzoic acid, 4-acetylaminobenzoic acid, 4-aminobenzoic acid, capric acid, caproic acid, caprylic acid, Cinnamic acid, citric acid, cyclohexane sulfamic acid, camphor sulfonic acid, aspartic acid, camphor acid, gluconic acid, glucuronic acid, glutamic acid, erythorbic acid, lactic acid, malic acid, mandelic acid, py
  • the object of the present invention is also to provide a crystal form of the compound represented by general formula (I) or a method for preparing the compound represented by general formula (Ia), which specifically includes the following steps:
  • the benign solvent is selected from methanol, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide or N-methylpyrrolidone; preferably N,N-dimethylformamide and N- Methylpyrrolidone;
  • the organic solvent is selected from methanol, ethanol, ethyl acetate, dichloromethane, acetone, n-hexane, petroleum ether, benzene, toluene, chloroform, acetonitrile, carbon tetrachloride, dichloroethane, tetrahydrofuran, 2-butane Ketone, 3-pentanone, heptane, methyl tert-butyl ether, isopropyl ether, 1,4-dioxane, tert-butanol or N,N-dimethylformamide; preferably methanol and ethanol; the above
  • the benign solvent and organic solution must be miscible when used;
  • the counter ion acid is selected from hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, phosphoric acid, 2,5-dihydroxybenzoic acid, 1-hydroxy-2-naphthoic acid, acetic acid, dichloro Acetic acid, trichloroacetic acid, acetohydroxamic acid, adipic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, benzoic acid, 4-acetylaminobenzoic acid, 4-aminobenzoic acid, capric acid, caproic acid, caprylic acid, Cinnamic acid, citric acid, cyclohexane sulfamic acid, camphor sulfonic acid, aspartic acid, camphor acid, gluconic acid, glucuronic acid, glutamic acid, erythorbic acid, lactic acid, malic acid, mandelic acid, pyroga
  • the crystalline form of the compound represented by the general formula (IV), the free base crystalline form I, the X-ray powder diffraction pattern is at 2 ⁇ of 6.4 and 26.7 (2 ⁇ 0.2 °) has characteristic peaks, preferably, it further includes characteristic peaks at 2 ⁇ of 7.2, 13.1, 16.8, 17.7, 18.9, 20.2, 21.2, and 28.2 (2 ⁇ 0.2°).
  • the crystal form of the compound represented by the general formula (IV) of the present invention which is a free base compound crystal form, uses Cu-K ⁇ radiation, and the X-ray characteristic diffraction peaks expressed in 2 ⁇ angles and interplanar spacing d are shown in the table 1 shown.
  • the crystalline form of the compound represented by the general formula (IV) of the present invention is the crystalline form I of the free base compound, and its X-ray powder diffraction pattern is basically shown in FIG. 1.
  • the crystal form of the compound represented by the general formula (IV) of the present invention is the crystal form I of the free base compound, and its TGA pattern is basically shown in FIG. 2.
  • the crystalline form of the compound represented by the general formula (IV) of the present invention is the crystalline form I of the free base compound, and its DSC spectrum is basically shown in FIG. 3.
  • the crystalline form of the compound represented by the general formula (IV), its free base crystalline form II, the X-ray powder diffraction pattern is at 2 ⁇ of 8.5, 13.4 and 17.0 (2 ⁇ ⁇ 0.2°) has characteristic peaks, and also includes characteristic peaks at 2 ⁇ of 10.2, 10.9, 12.8, 13.1, 16.1, 17.8, 18.8, 19.5, 23.0, 23.9, 24.4, 25.5, 26.1 and 27.6 (2 ⁇ 0.2°) .
  • the crystal form of the compound represented by the general formula (IV) of the present invention which is a free base compound crystal form, uses Cu-K ⁇ radiation, and the X-ray characteristic diffraction peaks expressed in 2 ⁇ angles and interplanar spacing d are shown in the table 2 shown.
  • the crystal form of the compound represented by the general formula (IV) of the present invention is the crystal form II of the free base compound, and its X-ray powder diffraction pattern is basically as shown in FIG. 4.
  • the crystal form of the compound represented by the general formula (IV) of the present invention is the crystal form II of the free base compound, and its TGA pattern is basically shown in FIG. 5.
  • the crystal form of the compound represented by the general formula (IV) of the present invention is the crystal form II of the free base compound, and its DSC spectrum is basically as shown in FIG. 6.
  • the powder diffraction pattern has characteristic peaks at 2 ⁇ of 5.5 and 16.3 (2 ⁇ 0.2°); it further includes characteristic peaks at 2 ⁇ of 10.8, 15.3, 17.7, 26.1, 26.4 and 27.0 (2 ⁇ 0.2°); further There are characteristic peaks at 2 ⁇ of 13.0, 14.9, 20.0 and 20.8 (2 ⁇ 0.2°);
  • the crystal form of the compound represented by the general formula (IV) of the present invention wherein M is maleic acid, and x is 1, and the maleate salt crystal form I, using Cu-K ⁇ radiation, is set at a 2 ⁇ angle and a crystal plane
  • the X-ray characteristic diffraction peaks represented by the spacing d are shown in Table 3.
  • the X-ray powder diffraction pattern is basically shown in Figure 7.
  • the DSC spectrum is basically shown in Figure 9.
  • the X-ray powder diffraction pattern has characteristic peaks at 2 ⁇ of 5.5, 10.8, 16.3 and 17.6 (2 ⁇ 0.2°); it further contains characteristic peaks at 2 ⁇ of 14.0, 26.4, 26.6 and 27.2; There are characteristic peaks at 8.8, 12.9, 18.4, 18.9, 20.6, 21.5, 22.4 and 22.8 (2 ⁇ 0.2°).
  • the X-ray characteristic diffraction peaks represented by the spacing d are shown in Table 4.
  • the X-ray powder diffraction pattern is basically shown in Figure 10.
  • the powder diffraction pattern has characteristic peaks at 2 ⁇ of 4.9, 15.1, 17.2, 17.5, 26.5 and 26.9 (2 ⁇ 0.2°); it further contains characteristic peaks at 2 ⁇ of 9.8, 14.7, 18.4 and 19.8 (2 ⁇ 0.2°) Peak; further includes characteristic peaks at 2 ⁇ of 12.3, 13.0, 14.0, and 27.5 (2 ⁇ 0.2°).
  • the powder diffraction pattern is basically shown in Figure 12.
  • the crystal form of the compound represented by formula (IV), wherein M is maleic acid, and x is 1, its maleate salt crystal form III, and its DSC spectrum is basically As shown in Figure 13.
  • the spectrum has characteristic peaks of 4.8 and 16.7 in 2 ⁇ ; it further includes characteristic peaks at 2 ⁇ of 9.6, 11.9 and 14.9 (2 ⁇ 0.2°); it is further included in 2 ⁇ of 7.2, 12.9, 14.3, 19.1, 19.3, There are characteristic peaks at 21.5 and 23.9 (2 ⁇ 0.2°).
  • the powder diffraction pattern is basically shown in Figure 14.
  • the crystal form of the compound represented by formula (IV), wherein M is maleic acid, and x is 1, its maleate crystal form IV, and its DSC spectrum is basically as shown in Figure 15.
  • the crystal form of the compound represented by formula (IV), wherein M is hydrochloric acid, the hydrochloride crystal form, and the X-ray powder diffraction pattern is at 2 ⁇ of 5.8 and 17.2 (2 ⁇ 0.2°) has characteristic peaks; further includes characteristic peaks at 2 ⁇ of 12.0, 13.6, 16.4, 21.7, 23.0, 26.1, 26.3, and 27.1 (2 ⁇ 0.2°); it is further included in 2 ⁇ of 8.9, There are characteristic peaks at 28.8 and 30.1 (2 ⁇ 0.2°).
  • the crystal form of the compound represented by formula (IV), wherein M is hydrochloric acid, its hydrochloride crystal form, and its X-ray powder diffraction pattern is basically as shown in Figure 16. .
  • M is p-toluenesulfonic acid
  • its p-toluenesulfonic acid salt crystal form I X-ray powder diffraction
  • the spectrum has characteristic peaks at 2 ⁇ of 6.1, 11.3, 17.0, 17.5 and 18.3 (2 ⁇ 0.2°); it further contains characteristic peaks at 2 ⁇ of 12.7, 19.1, 19.9, 20.6 and 22.2 (2 ⁇ 0.2°).
  • the crystal form of the compound represented by formula (IV), wherein M is p-toluenesulfonic acid, its p-toluenesulfonic acid salt crystal form I, and its X-ray powder is basically shown in Figure 17.
  • M is p-toluenesulfonic acid
  • its p-toluenesulfonic acid salt crystal form II X-ray powder diffraction
  • the spectrum has characteristic peaks at 2 ⁇ of 5.4, 8.6, 11.4, 16.8, 18.2, 19.7, 20.4, and 21.9 (2 ⁇ 0.2°); it is further included at 2 ⁇ of 13.5, 13.7, 15.7, 17.2, 23.7, 25.5 and 27.6 (2 ⁇ 0.2°) has characteristic peaks; and further includes characteristic peaks at 2 ⁇ of 16.0, 21.4, 25.9, and 28.7 (2 ⁇ 0.2°).
  • the crystal form of the compound represented by formula (IV), wherein M is p-toluenesulfonic acid, its p-toluenesulfonic acid salt crystal form II, and its X-ray powder is basically shown in Figure 18.
  • the spectrum has characteristic peaks at 2 ⁇ of 4.9, 8.6, 13.2, 18.9, 20.6, and 25.2 (2 ⁇ 0.2°); it is further included at 2 ⁇ of 9.6, 10.9, 12.6, 15.0, 15.6, 17.0, 22.6, 25.8, and 27.5. (2 ⁇ 0.2°) has characteristic peaks; and further includes characteristic peaks at 2 ⁇ of 10.5, 13.9, 16.5, 17.7, 21.7, 26.1, 26.6, 26.9, 27.8, 29.8, and 32.2 (2 ⁇ 0.2°).
  • the crystal form of the compound represented by formula (IV), wherein M is p-toluenesulfonic acid, its p-toluenesulfonic acid salt crystal form III, and its X-ray powder is basically shown in Figure 19.
  • M is p-toluenesulfonic acid
  • its p-toluenesulfonic acid salt crystal form IV X-ray powder diffraction
  • the spectrum has characteristic peaks at 2 ⁇ of 5.5, 11.9, 16.3, 19.4, and 25.5 (2 ⁇ 0.2°); it further includes 2 ⁇ at 13.8, 18.1, 18.6, 20.1, 21.3, 22.9, and 26.5 (2 ⁇ 0.2°) It has characteristic peaks; it further includes characteristic peaks at 8.7, 9.1, 10.2, 10.8, 12.9 and 20.4 (2 ⁇ 0.2°).
  • the crystal form of the compound represented by formula (IV), wherein M is p-toluenesulfonic acid, its p-toluenesulfonic acid salt crystal form IV, and its X-ray powder is basically shown in Figure 20.
  • the crystal form of the compound represented by formula (IV), wherein M is nitric acid, its nitrate crystal form, and the X-ray powder diffraction pattern at 2 ⁇ is 5.0, 16.3, 16.7 And 28.0 (2 ⁇ 0.2°) with characteristic peaks; further include characteristic peaks at 2 ⁇ of 8.2, 8.5, 11.8, 13.2, and 29.1 (2 ⁇ 0.2°); further including 2 ⁇ at 19.7, 20.4, 21.0 And 24.5 (2 ⁇ 0.2°) have characteristic peaks.
  • the crystal form of the compound represented by formula (IV), wherein M is nitric acid, its nitrate crystal form, and its X-ray powder diffraction pattern is basically as shown in FIG. 21.
  • the object of the present invention is also to provide a pharmaceutical composition, which contains a therapeutically effective amount of the crystal form of the compound of formula (I) or the compound of formula (Ia), and one or more A pharmaceutically acceptable carrier.
  • the purpose of the present invention is also to provide the crystal form of the general formula compound represented by formula (I) or the general formula compound represented by formula (Ia) and the pharmaceutical composition in the preparation for the treatment and/or prevention of ERK-mediated The use of drugs for leading cancer or tumor-related diseases.
  • the object of the present invention is also to provide the crystal form of the compound represented by formula (I) or the compound represented by formula (Ia) and its pharmaceutical composition for preparing and treating cancer, inflammation, chronic liver disease, diabetes, heart disease Application in medicine for vascular disease or AIDS.
  • the object of the present invention is also to provide a method for the treatment, prevention and/or treatment and prevention of ERK-mediated pathological characteristics of diseases, which comprises administering to a patient a therapeutically effective dose of a crystal of a compound of formula (I) or Compounds of general formula represented by formula (Ia) and pharmaceutical compositions thereof.
  • Diseases with ERK-mediated pathological characteristics include cancer, inflammation, chronic liver disease, diabetes, cardiovascular disease or AIDS.
  • the disease is selected from cancer, bone disease, inflammatory disease, immune disease, neurological disease, metabolic disease, respiratory disease, or medical application in heart disease; wherein the cancer is selected from Breast cancer, pancreatic cancer, non-small cell lung cancer, thyroid cancer, seminoma, melanoma, bladder cancer, liver cancer, kidney cancer, myelodysplastic syndrome, acute myeloid leukemia, or colorectal cancer.
  • alkyl refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms
  • the alkyl group is most preferably an alkyl group of 1 to 3 carbon atoms.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1 ,2-Dimethylpropyl, 2,2-Dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2- Methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3 -Dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2 -Methylhexyl, 3-methylhexyl, 4-methylhe
  • Alkyl groups may be substituted or unsubstituted. When substituted, the substituents may be substituted at any available attachment point.
  • the substituents are preferably one or more of the following groups, which are independently selected from alkanes Group, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkane Oxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxy or carboxylate group, the present invention preferably methyl, ethyl, isopropyl, tert-butyl, haloalkyl , Deuterated alkyl, alkoxy-substituted alkyl and hydroxy-substituted alkyl.
  • alkylene means that one hydrogen atom of the alkyl group is further substituted, for example: "methylene” means -CH 2 -, "ethylene” means -(CH 2 ) 2 -, “propylene” It refers to -(CH 2 ) 3 -, “butylene” refers to -(CH 2 ) 4 -, etc.
  • the above-mentioned substituents can be connected to different carbon atoms to form a carbon chain, or they can be connected to a carbon atom to form a cycloalkyl group.
  • alkenyl refers to an alkyl group as defined above composed of at least two carbon atoms and at least one carbon-carbon double bond, such as vinyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3 -Butenyl etc. Alkenyl groups may be substituted or unsubstituted.
  • the substituents are preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent.
  • the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 8 carbon atoms, more preferably 3 to 6 Carbon atoms.
  • Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene
  • Polycyclic cycloalkyl groups include spiro, condensed and bridged cycloalkyl groups, preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl and cycloheptyl.
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent which contains 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen or S(O) m (where m is an integer of 0 to 2) heteroatoms, but does not include the ring part of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. It preferably contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably contains 3 to 8 ring atoms; most preferably contains 3 to 8 ring atoms.
  • Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidine Group, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, etc., preferably tetrahydrofuryl, pyrazolidinyl, morpholinyl, piperazinyl and pyranyl.
  • Polycyclic heterocyclic groups include spiro, condensed and bridged heterocyclic groups; the spiro, condensed and bridged heterocyclic groups are optionally connected to other groups through a single bond, or through a ring Any two or more of the above atoms are further connected to other cycloalkyl groups, heterocyclic groups, aryl groups and heteroaryl groups; heterocyclic groups may be optionally substituted or unsubstituted, when substituted ,
  • the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano , Cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxy,
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent which contains 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen or S(O) m (where m is an integer of 0 to 2) heteroatoms, but does not include the ring part of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. It preferably contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably contains 3 to 8 ring atoms; most preferably contains 3 to 8 ring atoms.
  • Non-limiting examples of monocyclic heterocyclic groups include oxetanyl, pyrrolidinyl, pyrrolidone, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrrolidinyl Azolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, etc., preferably oxetanyl, pyrrolidonyl, tetrahydrofuranyl, Pyrazolidinyl, morpholinyl, piperazinyl and pyranyl.
  • Polycyclic heterocyclic groups include spiro, condensed and bridged heterocyclic groups; the spiro, condensed and bridged heterocyclic groups are optionally connected to other groups through a single bond, or through a ring Any two or more of the above atoms are further connected to other cycloalkyl groups, heterocyclic groups, aryl groups and heteroaryl groups.
  • alkoxy refers to -O- (alkyl) and -O- (unsubstituted cycloalkyl), where alkyl is defined as described above. It is preferably an alkoxy group having 1 to 8 carbon atoms, more preferably an alkoxy group having 1 to 6 carbon atoms, and most preferably an alkoxy group having 1 to 3 carbon atoms.
  • alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy.
  • the alkoxy group may be optionally substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthio, carboxyl or carboxylate.
  • Haloalkyl refers to an alkyl group substituted with one or more halogens, where alkyl is as defined above.
  • Haloalkoxy refers to an alkoxy group substituted with one or more halogens, where alkoxy is as defined above.
  • Hydroalkyl refers to an alkyl group substituted with a hydroxy group, where the alkyl group is as defined above.
  • Alkenyl refers to an alkenyl group, also known as an alkene group, preferably an alkenyl group containing 2 to 8 carbon atoms, more preferably an alkenyl group having 2 to 6 carbon atoms, and most preferably an alkenyl group having 2 to 3 carbon atoms ;
  • the alkenyl group can be further substituted by other related groups, such as: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano , Cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.
  • Alkynyl refers to (CH ⁇ C-), preferably an alkynyl group containing 2 to 8 carbon atoms, more preferably an alkynyl group having 2 to 6 carbon atoms, and most preferably an alkynyl group having 2 to 3 carbon atoms.
  • alkynyl group described therein may be further substituted by other related groups, such as: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, Cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxy, or carboxylate.
  • other related groups such as: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, Cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxy, or carboxylate.
  • Halogen refers to fluorine, chlorine, bromine or iodine.
  • Amino refers to -NH 2 .
  • Cyano refers to -CN.
  • Niro refers to -NO 2 .
  • Carboxy refers to -C(O)OH.
  • X is selected from A, B, or C
  • X is selected from A, B and C
  • X is A, B or C
  • X is A, B and C
  • other terms all express the same Meaning, which means that X can be any one or more of A, B, and C.
  • Substituted refers to one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, independently of each other, substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without too much effort. For example, an amino group or a hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (eg, olefinic) bond.
  • Stepoisomerism includes geometric isomerism (cis-trans isomerism), optical isomerism, and conformational isomerism.
  • the hydrogen atoms described in the present invention can be replaced by its isotope deuterium, and any hydrogen atom in the example compounds of the present invention can also be replaced by a deuterium atom.
  • “Pharmaceutical composition” means a mixture containing one or more of the compounds described herein or their physiologically/pharmaceutically acceptable salts or prodrugs and other chemical components, and other components such as physiological/pharmaceutically acceptable carriers And excipients.
  • the purpose of the pharmaceutical composition is to promote the administration to the organism, which is beneficial to the absorption of the active ingredients and thus the biological activity.
  • “Pharmaceutically acceptable salt” refers to the salt of the compound of the present invention. Such salt is safe and effective when used in mammals, and has due biological activity.
  • TGA thermogravimetric analysis
  • DSC differential scanning calorimetry
  • DVD refers to dynamic moisture adsorption (DVS) experiments.
  • XRPD refers to X-ray powder diffraction (XRPD) experiments.
  • HPLC refers to high performance liquid chromatography (HPLC) experiments.
  • PK refers to pharmacokinetic (PK) experiments.
  • Figure 1 is an XRPD diagram of the free base crystal form I.
  • Figure 2 is a TGA diagram of the free base crystal form I.
  • Figure 3 is a DSC diagram of the free base crystal form I.
  • Figure 4 is an XRPD diagram of the free base crystal form II.
  • Figure 5 is a TGA diagram of the free base crystal form II.
  • Figure 6 is a DSC chart of the free base crystal form II.
  • Figure 7 is an XRPD diagram of maleate salt form I.
  • Figure 8 is a TGA diagram of maleate salt form I.
  • Figure 9 is a DSC diagram of maleate salt form I.
  • Figure 10 is an XRPD diagram of maleate salt form II.
  • Figure 11 is a DSC chart of maleate salt form II.
  • Figure 12 is an XRPD diagram of maleate salt form III.
  • Figure 13 is a DSC chart of maleate salt form III.
  • Figure 14 is an XRPD diagram of maleate salt form IV.
  • Figure 15 is a DSC chart of maleate salt form IV.
  • Figure 16 is an XRPD diagram of the hydrochloride salt.
  • Figure 17 is an XRPD diagram of p-toluenesulfonate form I.
  • Figure 18 is an XRPD diagram of p-toluenesulfonate Form II.
  • Figure 19 is an XRPD diagram of p-toluenesulfonate Form III.
  • Figure 20 is an XRPD diagram of p-toluenesulfonate salt form IV.
  • Figure 21 is an XRPD diagram of nitrate.
  • Figure 22 is a schematic diagram of a rat PK experiment.
  • Mobile phase A: water (0.05% trifluoroacetic acid); B: acetonitrile (0.05% trifluoroacetic acid)
  • the first step preparation of methyl 3-(6-nitro-3-(pyridin-4-yl)-1-tritylmethyl-1H-indazol-5-yl)acryloyl acid
  • reaction solution is concentrated and purified by column chromatography [eluent: petroleum ether ⁇ petroleum ether/ethyl acetate (60:40)] to obtain a pale blue solid product 3-(6-nitro-3-(pyridine-4) -Yl)-1-tritylmethyl-1H-indazol-5-yl)acrylic acid methyl ester (200 mg, yield 51%).
  • reaction solution was concentrated and purified by column chromatography [eluent: petroleum ether ⁇ petroleum ether/ethyl acetate (40:60)] to obtain the product (R)-N-(1-phenylethyl)-3- (Pyridin-4-yl)-1-tritylmethyl-1,7-dihydropyrrolo[3,2-f]indazole-6-carboxamide (50 mg, yield 40%).
  • the third step Preparation of 3-(pyridin-4-yl)-1-trityl-1H-indazole-5,6-diamine
  • Step 4 Preparation of 3-(pyridin-4-yl)-6-(trichloromethyl)-1-trityl-1,7-dihydroimidazo[4,5-f]indazole
  • Step 5 Preparation of 3-(pyridin-4-yl)-1-trityl-1,7-dihydroimidazo[4,5-f]indazole-6-carboxylic acid methyl ester
  • Methyl 3-(pyridin-4-yl)-1-tritylmethyl-1,7-dihydroimidazo[4,5-f]indazole-6-carboxylate Place in a microwave reaction tube, add (R)-1-(p-benzyl)ethane-1-amine (1.0 mL), and heat to 150° C. to react for 60 min. After cooling to room temperature, 20 mL of ethyl acetate was added to the reaction solution.
  • Step 2 Preparation of N-(1-phenylethyl)-3-(pyridin-4-yl)-1,7-dihydroimidazo[4,5-f]indazole-6-carboxamide
  • N-(1-phenylethyl)-3-(pyridin-4-yl)-1-tritylmethyl-1,7-dihydroimidazo[4,5-f]indazole-6- The crude formamide (27mg) was dissolved in dichloromethane (2mL), added with trifluoroacetic acid (2mL), stirred at room temperature for 2h, concentrated to dryness, purified by column chromatography to obtain a yellow solid N-(1-phenylethyl)-3 -(Pyridin-4-yl)-1,7-dihydroimidazo[4,5-f]indazole-6-carboxamide (5 mg, yield 7% in two steps).
  • Methyl 3-(pyridin-4-yl)-1-tritylmethyl-1,7-dihydroimidazo[4,5-f]indazole-6-carboxylate Place in a microwave reaction tube, add (R)-1-(4-(trifluoromethyl)phenyl)ethane-1-amine (1.0 mL), and heat to 150° C. to react for 60 min. After cooling to room temperature, 20 mL of ethyl acetate was added to the reaction solution.
  • the obtained crude product was dissolved in a mixed solution of ethyl acetate and tetrahydrofuran, washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, and then dried over anhydrous sodium sulfate.
  • the obtained organic solvent was spin-dried and purified by preparative chromatography to obtain the yellow solid product (R)-3-(pyridin-4-yl)-N-(1-(3-(trifluoromethyl)phenyl)ethyl)- 1,7-Dihydroimidazo[4,5-f]indazole-6-carboxamide (10 mg, yield 19%).
  • Methyl 3-(pyridin-4-yl)-1-tritylmethyl-1,7-dihydroimidazo[4,5-f]indazole-6-carboxylate Place in a microwave reaction tube, add (R)-1-(3-fluorophenyl)ethane-1-amine (1.0 mL), and heat to 150° C. to react for 60 min. After cooling to room temperature, 20 mL of ethyl acetate was added to the reaction solution.
  • the third step Preparation of 6-fluoro-3-(pyridin-4-yl)-1H-pyrazolo[3,4-b]pyridine
  • Step 7 Preparation of methyl 3-(pyridin-4-yl)-1,7-dihydroimidazo[4,5-b]pyrazolo[4,3-e]pyridine-6-carboxylate
  • the first step preparation of (R)-(1-(3-bromophenyl)ethyl) t-butyl carbamate
  • Step 2 Preparation of tert-butyl (R)-(1-(3-cyclopropylphenyl)ethyl)carbamate
  • reaction solution is concentrated and purified by column chromatography [eluent: petroleum ether ⁇ petroleum ether/ethyl acetate (95/5)] to obtain a colorless oily product (R)-(1-(3-cyclopropylbenzene) (Yl)ethyl) tert-butyl carbamate (430 mg, yield 69%).
  • Step 2 (R)-N-(1-(3-(Pro-1-en-2-yl)phenyl)ethyl)-3-(pyridin-4-yl)-1-trityl Of phenyl-1,7-dihydroimidazo[4,5-f]indazole-6-carboxamide
  • reaction solution was concentrated and purified by column chromatography [eluent: petroleum ether ⁇ petroleum ether/ethyl acetate (30:70)] to obtain a brown oily product (R)-N-(1-(3-(prop-1-ene) -2-yl)phenyl)ethyl)-3-(pyridin-4-yl)-1-tritylmethyl-1,7-dihydroimidazo[4,5-f]indazole-6- Formamide (100 mg, 53%).
  • test case is to measure the inhibitory ability of the compound on ERK-1 kinase activity.
  • In vitro ERK-1 kinase analysis was performed using the LANCE Ultra (Perkin Elmer) method.
  • ERK1 enzyme Invitrogen, #PV3311, final concentration: 0.4nM
  • kinase buffer 50mM Hepes pH 7.4, 10mM MgC12, 1mM EGTA, 0.01% Triton X-100, 2mM DTT
  • substrate Ulight-MBP peptide Perkin
  • test case The purpose of this test case is to measure the compound's ability to inhibit ERK-2 kinase activity.
  • In vitro ERK-2 kinase analysis was performed using LANCE Ultra (Perkin Elmer) method. By adding 2.5 ⁇ L of test compound/DMSO (final 4%, V/V, diluted to 10 concentrations (400nM to 0.02nM) using a 1:3 dilution scheme) in a 384-well plate (Perkin Elmer OPTIPLATE TM ), adding ERK-2 enzyme (Invitrogen, #PV3313, final concentration: 0.08nM) prepared in kinase buffer (50mM Hepes pH 7.4, 10mM MgCl 2 , 1mM EGTA, 0.01% Triton X-100, 2mM DTT) and substrate Ulight-MBP Peptide (Perkin Elmer, #TRF0109-M, final concentration: 0.5 ⁇ M) mixed solution 5 ⁇ L, then add 2.5 ⁇ L of ATP (
  • the compound shown in the present invention shows a biological activity of about 0.01 nM to 100 nM (IC 50 ) in the ERK inhibition test.
  • compounds of the invention and for the IC ERK-1 / ERK-2 is 50 or less than about 10OnM, preferably less than about 10 nM compound, more preferably less than about of 5 nM, more preferably less than about 1 nM, the present invention is presented The most preferred compound is less than 0.1 nM.
  • compounds of the invention for the ERK IC 50 less than about 10OnM, preferably less than about 10 nM, more preferably less than about of 5 nM, more preferably less than about 1 nM, most preferably less than compounds listed 0.1nM.
  • the present invention is preferably a compound listed compounds show dual binding specificity, and can be less than about 10OnM, less than about 10 nM, less than about of 5 nM, less than about 1 nM, less than the IC 50 values of 0.1nM of ERK Kinases (eg, ERK-1 kinase, ERK-2 kinase, etc.) and protein kinases (eg, Ras, Raf, Her-2, MEK1, etc.).
  • ERK Kinases eg, ERK-1 kinase, ERK-2 kinase, etc.
  • protein kinases eg, Ras, Raf, Her-2, MEK1, etc.
  • test data of the embodiment is shown in Table 13:
  • the purpose of this test example is to determine the inhibitory effect of the compound of the present invention on tumor cell proliferation activity.
  • the compound's anti-tumor cell proliferation inhibitory activity was measured by the CellTiter-Glo method, and the half inhibitory concentration IC 50 of the compound's inhibitory cell proliferation activity was obtained.
  • the test compound solutions of different concentrations in gradient dilutions are added to the cells of the culture plate, and the culture plate is incubated in an incubator for 3-7 days (37° C., 5% CO 2 ).
  • the compounds of the present invention were tested for the proliferation activity of pancreatic cancer tumor cells Mia Paca 2, and the measured IC 50 values are shown in Table 14.
  • Table 14 Relative IC 50 value of compound inhibiting proliferation activity of pancreatic cancer tumor cell Mia Paca 2
  • the compound of the present invention has obvious inhibitory effect on tumor cell proliferation activity.
  • Balb/c Mouse male, purchased from Shanghai Jiesjie Laboratory Animal Co., Ltd., animal production license number (SCXK (Shanghai) 2013-0006N0.311620400001794) was used as the test animal to study the compound
  • Example 1 The pharmacokinetic behavior of Example 1, Example 2, and Example 6 in Mouse (plasma).
  • Example 1 Weigh 11.2mg of Example 1, 10.8mg of Example 2, and 9.8mg of Example 6, respectively into 4mL glass bottles, add 1.940mL, 2.160mL and 1.525mL of this solution, sonicate for 10 minutes to obtain a colorless clear solution with a concentration of 5mg/mL. After fasting overnight, PO respectively, the dose was 50 mg/kg, and the administration volume was 10 mL/kg.
  • mice BALB/c nude mice were used as test animals, and the human pancreatic cancer cell MiaPaca 2 xenograft (CDX) model was used for in vivo pharmacodynamic experiments to evaluate the anti-tumor effects of the test compounds.
  • CDX human pancreatic cancer cell MiaPaca 2 xenograft
  • Vernier caliper (CD-6"AX, Mitutoyo, Japan)
  • FBS Fetal Bovine Serum
  • Penicillin double antibody (SV30010, GE)
  • PBS Phosphate buffered saline
  • MiaPaca 2 cells Take out MiaPaca 2 cells from the cell bank, add DMEM medium (containing 10% FBS, 1% Glu, 1% P/S) after resuscitation and place them in a CO 2 incubator (the temperature of the incubator is 37°C, and the CO 2 concentration Is 5%). After the cells are 80-90% of the bottom of the culture flask, the cells are passaged. After passage, the cells are continued to be cultured in a CO 2 incubator. Repeat the process until the number of cells meets the requirement of inoculation in vivo, start to collect the cells in the logarithmic growth phase, count them with an automatic cell counter, and resuspend the cells with PBS and Matrigel (volume ratio 1:1) according to the counting results. Prepare cell suspension (density 8 suspended cells 7 /ml) and place in an ice box for later use.
  • DMEM medium containing 10% FBS, 1% Glu, 1% P/S
  • mice Female, 6-8 weeks old, weighing about 18-22 grams.
  • the mice were kept in an environment free of special pathogens and in a single ventilated cage with 5 mice per cage. All cages, litter and water are disinfected before use, and all animals can freely access standard certified commercial laboratory food.
  • the nude mice were labeled with disposable universal ear tags for rats and mice, and the skin of the inoculation site was disinfected with 75% medical alcohol before inoculation.
  • Each mouse was inoculated with 0.1ml (containing 8*10 6 cells) MiaPaca 2 subcutaneously on the right back of each mouse. Tumor cells. When the average tumor volume reaches 100-200mm 3 , group administration is started.
  • the test compound was administered by oral gavage every day, and the dosage, frequency of administration and the efficacy of each group at the end of the experiment are shown in Table 16 and Table 17.
  • the antitumor efficacy is determined by dividing the average tumor increase volume of animals treated with the compound by the average tumor increase volume of untreated animals.
  • Example 2 can significantly inhibit the growth of transplanted tumors in nude mice of MiaPaca 2 under the conditions of 100mg/kg QD and 50mg/kg BID, and the drug effect is good;
  • Example 6 100mg/kg QD can also significantly inhibit tumor growth.
  • Example 1 can significantly inhibit the growth of transplanted tumors in MiaPaca 2 nude mice under the conditions of 50 mg/kg QD administration, and the drug effect is good.
  • CHO-hERG cells are cultured in a 175cm2 culture flask. After the cell density grows to 60-80%, remove the culture solution, wash it with 7mL PBS, and then add 3mL Detachin for digestion.
  • the single-cell high-impedance sealing and the whole-cell mode formation process are all automatically completed by the Qpatch instrument.
  • the cell is clamped at -80 mV, before giving a 5 second +40 mV depolarization stimulus .
  • This voltage stimulus was applied every 15 seconds, recorded for 2 minutes, and then administered extracellular fluid for 5 minutes, and then the administration process was started.
  • the compound concentration started from the lowest test concentration, and each test concentration was given for 2.5 minutes. At least 3 cells are tested at each concentration.
  • the highest test concentration is 40uM, which are respectively 40, 13.33, 4.44, 1.48, 0.49, 0.16uM and 6 concentrations.
  • the experimental data is analyzed by XLFit software.
  • the experimental reagents used were purchased from Sigma, with a purity of >98%
  • Example 2 has no inhibitory effect on the cardiac hERG potassium ion channel, and can avoid cardiac toxic side effects at high doses.
  • the present invention provides a series of highly active and selective ERK1/2 kinase inhibitors with novel structures. It has shown good pharmacokinetic properties in both rat and mouse models, and has also shown good pharmacodynamics in the Miapaca tumor-bearing mouse model. It has great potential to be developed for tumor diseases. drug.
  • Example 2 Weigh 500 mg of the free base of Example 2 and add 5 mL of N,N-dimethylformamide ultrasonically undissolved. The system is heated at 50°C until it is completely dissolved. Separately weigh 183 mg of maleic acid and 1 mL of methanol to completely dissolve at room temperature. clear. The methanol solution of maleic acid was added to the alkali solution at 50°C, and the precipitate precipitated out quickly. After stirring for 0.5h, 10mL methyl tert-butyl ether was added to the system. After stirring for 1.5h, the heating was turned off and the temperature was cooled to room temperature.
  • the filter cake is rinsed with 20 mL of methyl tert-butyl ether, and the solid is placed in a vacuum drying oven at 40° C. and dried to a constant weight to obtain maleate crystal form I. After detection and analysis, it has an XRPD chart as shown in FIG. 7, a TGA chart as shown in FIG. 8 and a DSC chart as shown in FIG. 9.
  • Maleate crystal form I absorbs moisture and increases weight by 1.36% under the condition of RH80%, which is slightly hygroscopic; after a cycle of moisture absorption and desorption under the condition of 0-95% relative humidity, maleate crystal form I
  • the XRPD spectrum has not changed, that is, there is no crystal transformation.
  • thermodynamic solubility of the compound at room temperature was determined by HPLC and external standard method.
  • maleate crystal form I weigh 50.23mg maleate crystal form I, add 0.75mL N-methylpyrrolidone to completely dissolve it at 50°C, add 1mL isopropyl ether to the system, and quickly precipitate a yellow solid. After reacting at 50°C for 2h Continue to add 2 mL of isopropyl ether and turn off the heating to bring to room temperature. Finally, the solid is centrifuged, and the supernatant is removed, and the solid is placed in a vacuum drying oven at 40° C. and dried to a constant weight to obtain maleate crystal form IV.
  • Maleate salt crystal form I is relatively stable in acetone, acetonitrile, ethanol, ethyl acetate, isopropanol and water.
  • Comparative compound example 2 has a free base crystal form II T max , and maleate salt crystal form I has a reduced T max .

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Abstract

La présente invention concerne un sel d'un dérivé tricyclique contenant de l'indazolyle et une forme cristalline de celui-ci. En particulier, la présente invention concerne une forme cristalline d'un composé de formule générale (I), un procédé de préparation et une composition pharmaceutique contenant une quantité thérapeutiquement efficace de la forme cristalline, et l'utilisation de celle-ci dans la préparation d'un médicament pour le traitement de maladies associées médiées par ERK.
PCT/CN2020/082042 2019-04-02 2020-03-30 Sel de dérivé tricyclique contenant de l'indazolyle et forme cristalline de celui-ci WO2020200161A1 (fr)

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Citations (6)

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US5476851A (en) * 1994-09-08 1995-12-19 Rhone-Poulenc Rorer Pharmaceuticals, Inc. Pyrazolo[3,4-g]quinoxaline compounds which inhibit PDGF receptor protein tyrosine kinase
JP2004203804A (ja) * 2002-12-26 2004-07-22 Taiho Yakuhin Kogyo Kk 新規なインダゾール誘導体又はその塩及びそれらを有効成分とする医薬
WO2014179154A2 (fr) * 2013-04-30 2014-11-06 Merck Sharp & Dohme Corp. Nouveaux composés qui sont des inhibiteurs d'erk
CN104447765A (zh) * 2014-12-31 2015-03-25 深圳铂立健医药有限公司 三环化合物及其药物组合物和应用
WO2015051341A1 (fr) * 2013-10-03 2015-04-09 Araxes Pharma Llc Inhibiteurs d'erk et méthodes d'utilisation
WO2019076336A1 (fr) * 2017-10-19 2019-04-25 江苏豪森药业集团有限公司 Dérivé tricyclique contenant du pyrazolyle, son procédé de préparation et son utilisation

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104829613B (zh) * 2015-04-13 2020-06-09 赤峰蒙广生物科技有限公司 二芳基取代的吡唑并环类衍生物、其制备方法及其在医药领域的应用
TW201805000A (zh) * 2016-06-20 2018-02-16 庫拉腫瘤技術股份有限公司 利用erk抑制劑之鱗狀細胞癌之治療

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5476851A (en) * 1994-09-08 1995-12-19 Rhone-Poulenc Rorer Pharmaceuticals, Inc. Pyrazolo[3,4-g]quinoxaline compounds which inhibit PDGF receptor protein tyrosine kinase
JP2004203804A (ja) * 2002-12-26 2004-07-22 Taiho Yakuhin Kogyo Kk 新規なインダゾール誘導体又はその塩及びそれらを有効成分とする医薬
WO2014179154A2 (fr) * 2013-04-30 2014-11-06 Merck Sharp & Dohme Corp. Nouveaux composés qui sont des inhibiteurs d'erk
WO2015051341A1 (fr) * 2013-10-03 2015-04-09 Araxes Pharma Llc Inhibiteurs d'erk et méthodes d'utilisation
CN104447765A (zh) * 2014-12-31 2015-03-25 深圳铂立健医药有限公司 三环化合物及其药物组合物和应用
WO2019076336A1 (fr) * 2017-10-19 2019-04-25 江苏豪森药业集团有限公司 Dérivé tricyclique contenant du pyrazolyle, son procédé de préparation et son utilisation

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