WO2022017494A1 - Forme cristalline d'un dérivé pyridazinique sous forme de base libre, son procédé de préparation et son utilisation - Google Patents

Forme cristalline d'un dérivé pyridazinique sous forme de base libre, son procédé de préparation et son utilisation Download PDF

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WO2022017494A1
WO2022017494A1 PCT/CN2021/108103 CN2021108103W WO2022017494A1 WO 2022017494 A1 WO2022017494 A1 WO 2022017494A1 CN 2021108103 W CN2021108103 W CN 2021108103W WO 2022017494 A1 WO2022017494 A1 WO 2022017494A1
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crystal form
diffraction
diffraction peaks
places
ray powder
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PCT/CN2021/108103
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Chinese (zh)
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杜俊锋
呙临松
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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 CN202180035717.8A priority Critical patent/CN115667246A/zh
Priority to JP2023503000A priority patent/JP2023534492A/ja
Priority to CA3186000A priority patent/CA3186000A1/fr
Priority to KR1020237005311A priority patent/KR20230043887A/ko
Publication of WO2022017494A1 publication Critical patent/WO2022017494A1/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
    • A61K31/495—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
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • 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
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/501—Pyridazines; Hydrogenated pyridazines 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
    • A61K31/495—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
    • A61K31/495—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
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D237/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the invention belongs to the field of pharmaceutical synthesis, and in particular relates to a crystal form of a pyridazine derivative free base and a preparation method and application thereof.
  • Janus kinase is an intracellular non-receptor tyrosine kinase that mediates the signaling and activation of various cytokines.
  • the JAK kinase family is divided into four subtypes: JAK1, JAK2, JAK3 and TYK2. Each subtype mediates different types of cytokine signaling pathways.
  • JAK-1, JAK-2 and TYK-2 are present in various tissues and cells of the human body.
  • Expression, JAK-3 is mainly expressed in various hematopoietic cells.
  • the common feature of cytokine receptors is that the receptor itself does not have kinase activity, but the intracellular segment of the receptor has a binding site for the tyrosine kinase JAK.
  • the receptor-coupled JAKs When the cytokine receptor binds to its ligand, the receptor-coupled JAKs are activated, and the receptor is phosphorylated, and the phosphorylated tyrosine site can bind to the STAT protein containing the SH2 domain, so that the STAT is It is recruited to receptors and phosphorylated by JAKs, followed by phosphotyrosine-mediated STAT dimerization, and the activated STAT dimers are transferred to the nucleus and activate the transcription of their target genes, thereby regulating the growth, activation, differentiation and other functions.
  • TYK2 is the first subtype discovered in the JAK family, which mediates the functions of cytokines such as IFN- ⁇ , IL-6, IL-10, IL-12 and IL-23. Studies have shown that TYK2 deletion mutations can effectively inhibit allergy and autoimmunity. and immune diseases such as inflammation. IL-23 plays a crucial role in the occurrence and development of psoriasis.
  • TYK2 and JAK2 jointly mediate the downstream signaling pathway of IL-23, and inhibition of JAK2 can lead to anemia and other blood-related side effects, so targeting TYK2 is a good strategy for the treatment of psoriasis by inhibiting the IL-23 signaling pathway.
  • TYK2 inhibitors such as Tofacitinib are non-selective JAK inhibitors and are the first oral JAK inhibitors with significant inhibitory activity on JAK1, 2, and 3 subtypes.
  • the activity inhibition of other isoforms such as JAK1, JAK2 and JAK3 increases the efficacy of tofacitinib, but also brings more serious side effects, including infection, tuberculosis, tumor, anemia, liver damage and cholesterol increase.
  • JAK2 activity is related to erythroid cell differentiation and lipid metabolism, some of the above-mentioned adverse reactions such as anemia are thought to be related to the insufficient selectivity of Tofacitinib for JAK-2, which is caused by the non-selective inhibition of the drug.
  • Early JAK inhibitors mainly compete for the binding of the kinase domain to ATP, so there is a general problem of low selectivity.
  • Patent PCT/CN2020/073152 discloses the structure of a series of pyridazine derivative inhibitors.
  • this The invention has carried out comprehensive research on the free bases of the above substances, and is devoted to obtaining the most suitable crystal form.
  • the object of the present invention is to provide a crystal form of the compound represented by the general formula (I),
  • R 1 is selected from hydrogen, deuterium, halogen, amino, mercapto, nitro, hydroxyl, cyano, alkyl, deuterated alkyl, haloalkyl, alkoxy or haloalkoxy;
  • R 2 is selected from hydrogen, deuterium, halogen, amino, sulfhydryl, nitro, hydroxy, cyano, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl group, alkynyl group, cycloalkyl group or membered heterocyclyl, the amino, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl and membered heterocyclyl, optionally can be further Substituted with one or more substituents of halogen, nitro, cyano, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl or membered heterocyclyl ;and
  • x is selected from an integer of 0-3.
  • R 2 is selected from hydrogen, deuterium, halogen, cyano, C 1-3 alkyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1- 3 haloalkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl or 3-6 membered heterocyclic group, the amino, C 1-3 alkyl, C 1- 3- deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl and a 3-6 membered heterocyclic group, which can optionally be further replaced by halogen, nitro, cyano, C 1-3 alkyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 Substituted by one or more substituents in alkoxy
  • R 2 is selected from methyl, ethyl, propyl, cyclopropyl, said methyl, ethyl, propyl and cyclopropyl, which may optionally be further replaced by halogen, nitro, cyano or One or more substituents in the ethynyl group are substituted.
  • R 1 is not hydrogen.
  • the compound 6-(cyclopropanecarboxamido)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2 is provided - methoxyphenyl) amino) -N- (meth -d 3) pyridazine-3-carboxamide in crystalline form.
  • the compound 6-(cyclopropanecarboxamido)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-5 is provided -A crystalline form of fluoro-2-methoxyphenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide.
  • the compound 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-(prop-2-yn-1-yl)-1H-1 is provided , 2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3) pyridazine-3-carboxamide crystal form.
  • the compound 6-(cyclopropanecarboxamido)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl) is provided 2-methoxy-phenyl) amino) -N- (meth -d 3) pyridazine-3-carboxamide (Example 1) crystalline form AC.
  • the X-ray powder diffraction pattern of Form A has a diffraction peak at 2 ⁇ of 23.7 ⁇ 0.2°; or has a diffraction peak at 6.4 ⁇ 0.2°; or has a diffraction peak at 19.4 ⁇ 0.2°; or has a diffraction peak at 21.2 ⁇ 0.2° or a diffraction peak at 23.0 ⁇ 0.2°; or a diffraction peak at 14.8 ⁇ 0.2°; or a diffraction peak at 11.3 ⁇ 0.2°; or a diffraction peak at 28.5 ⁇ 0.2°; or Has a diffraction peak at 13.0 ⁇ 0.2°; or has a diffraction peak at 11.8 ⁇ 0.2°; preferably contains any 2-5, or 3-5, or 3-6, or 3- 8 places, or 5-8 places, or 6-8 places; more preferably including any 6 places, 7 places or 8 places;
  • the X-ray powder diffraction pattern of Form B has a diffraction peak at 2 ⁇ of 21.5 ⁇ 0.2°; or a diffraction peak at 15.0 ⁇ 0.2°; or a diffraction peak at 19.6 ⁇ 0.2°; or a diffraction peak at 23.0 ⁇ 0.2° or a diffraction peak at 23.2 ⁇ 0.2°; or a diffraction peak at 14.5 ⁇ 0.2°; or a diffraction peak at 20.8 ⁇ 0.2°; or a diffraction peak at 13.3 ⁇ 0.2°; or Has a diffraction peak at 10.5 ⁇ 0.2°; or has a diffraction peak at 11.8 ⁇ 0.2°; preferably includes any 2-5, or 3-5, or 3-6, or 3- 8, or 5-8, or 6-8, more preferably including any 6, 7 or 8 of them.
  • the X-ray powder diffraction pattern of Form C has a diffraction peak at 26.1 ⁇ 0.2°; or a diffraction peak at 24.7 ⁇ 0.2°; or a diffraction peak at 8.3 ⁇ 0.2°; or a diffraction peak at 9.9 ⁇ 0.2° or a diffraction peak at 12.8 ⁇ 0.2°; or a diffraction peak at 18.9 ⁇ 0.2°; or a diffraction peak at 26.7 ⁇ 0.2°; or a diffraction peak at 17.3 ⁇ 0.2°; or Has a diffraction peak at 10.4 ⁇ 0.2°; or has a diffraction peak at 11.0 ⁇ 0.2°; preferably includes any 2-5, or 3-5, or 3-6, or 3- 8, or 5-8, or 6-8; more preferably including any 6, 7 or 8 of them.
  • the compound 6-(cyclopropanecarboxamido)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl) is provided 2-methoxy-phenyl) amino) -N- (meth -d 3) pyridazine-3-carboxamide (Example 1) crystalline form AC.
  • the X-ray powder diffraction pattern of the crystal form A at least comprises one or more diffraction peaks located in 2 ⁇ of 23.7 ⁇ 0.2°, 6.4 ⁇ 0.2°, 19.4 ⁇ 0.2°, preferably 2 of them, more preferably 2 of them 3 places; optionally, it may further include at least one of 2 ⁇ of 21.2 ⁇ 0.2°, 23.0 ⁇ 0.2°, 14.8 ⁇ 0.2°, 11.3 ⁇ 0.2° or 28.5 ⁇ 0.2, preferably 2 and 3 of them , 4 or 5;
  • the X-ray powder diffraction pattern of the crystal form B at least contains one or more diffraction peaks located in 2 ⁇ of 21.5 ⁇ 0.2°, 15.0 ⁇ 0.2°, 19.6 ⁇ 0.2°, preferably contains two of them, more preferably contains three; optionally, it may further include at least one of 23.0 ⁇ 0.2°, 23.2 ⁇ 0.2°, 14.5 ⁇ 0.2°, 20.8 ⁇ 0.2°, and 13.3 ⁇ 0.2°; 4 or 5;
  • the X-ray powder diffraction pattern of the crystal form C at least contains one or more diffraction peaks located at 2 ⁇ of 26.1 ⁇ 0.2°, 24.7 ⁇ 0.2°, 8.3 ⁇ 0.2°, preferably contains 2 of them, more preferably contains 3 places; optionally, it may further include at least one of 2 ⁇ of 9.9 ⁇ 0.2°, 12.8 ⁇ 0.2°, 18.9 ⁇ 0.2°, 26.7 ⁇ 0.2° or 17.3 ⁇ 0.2, preferably 2 and 3 of them , 4 or 5; for example:
  • the X-ray powder diffraction pattern of the crystal form A optionally further comprises 2 ⁇ at 13.0 ⁇ 0.2°, 11.8 ⁇ 0.2°, 22.7 ⁇ 0.2°, 16.3 ⁇ 0.2°, 29.4 ⁇ 0.2°, 14.2 ⁇
  • the X-ray powder diffraction pattern of the crystal form B optionally further comprises positions at 2 ⁇ of 10.5 ⁇ 0.2°, 11.8 ⁇ 0.2°, 18.3 ⁇ 0.2°, 16.7 ⁇ 0.2°, 16.3 ⁇ 0.2°, 24.2 ⁇ 0.2°, 29.1
  • the X-ray powder diffraction pattern of the crystal form B optionally further comprises positions at 5.2 ⁇ 0.2°, 10.5 ⁇ 0.2°, 11.8 ⁇ 0.2°, 12.6 ⁇ 0.2°, 16.7 ⁇ 0.2°, 17.5 ⁇ 0.2°, 18.3 ⁇ 0.2°
  • the X-ray powder diffraction pattern of the crystal form B comprises positions at 21.5 ⁇ 0.2°, 15.0 ⁇ 0.2°, 19.6 ⁇ 0.2°, 23.0 ⁇ 0.2°, 23.2 ⁇ 0.2°, 14.5.0 ⁇ 0.2°, 20.8 ⁇ 0.2° , 13.3 ⁇ 0.2°, 10.5 ⁇ 0.2°, 11.8 ⁇ 0.2°, 18.3 ⁇ 0.2°, 16.7 ⁇ 0.2°, 16.3 ⁇ 0.2°, 24.2 ⁇ 0.2°, 29.1 ⁇ 0.2°, 5.2 ⁇ 0.2°, 12.6 ⁇ 0.2° , one or more diffraction peaks in 17.5 ⁇ 0.2°; preferably at least any of 2-3, or 4-5, or 7-8, or 10-12, or 15-18; further Preferably, any of 2, 3, 4, 5, 6, 8, 10, 12, 16, and 18 are included.
  • the X-ray powder diffraction pattern of the crystal form B comprises 2 ⁇ at 15.0 ⁇ 0.2°, 23.2 ⁇ 0.2°, 14.5 ⁇ 0.2°, 20.8 ⁇ 0.2°, 10.5 ⁇ 0.2°, 11.8 ⁇ 0.2°, 18.3 ⁇ 0.2° , 16.7 ⁇ 0.2°, 24.2 ⁇ 0.2°, 29.1 ⁇ 0.2° have diffraction peaks at one or more places; preferably, including optional 3 places, 4 places, 5 places, 6 places, 7 places, 8 places among them There are diffraction peaks at 10 and 10;
  • the X-ray powder diffraction pattern of the crystal form B has diffraction peaks at the following positions at 2 ⁇ :
  • the X-ray powder diffraction pattern of the crystal form C optionally further comprises positions at 2 ⁇ of 10.4 ⁇ 0.2°, 11.0 ⁇ 0.2°, 19.2 ⁇ 0.2°, 12.1 ⁇ 0.2°, 20.0 ⁇ 0.2°, 25.5 ⁇ 0.2° or 13.7
  • One or more diffraction peaks in ⁇ 0.2° preferably at least any 2-3, or 4-5, or 6-7 of them; more preferably, any 2, 3, 4, 5, 6, 7; e.g. 26.1 ⁇ 0.2°, 24.7 ⁇ 0.2°, 8.3 ⁇ 0.2°, 9.9 ⁇ 0.2°, 12.8 ⁇ 0.2°, 18.9 ⁇ 0.2°, 26.7 ⁇ 0.2°, 17.3 ⁇ 0.2, 10.4 ⁇ 0.2°, 11.0 ⁇ 0.2°;
  • the compound 6-(cyclopropanecarboxamido)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl) is provided 2-methoxy-phenyl) amino) -N- (meth -d 3) pyridazine-3-carboxamide
  • Example 1 crystalline form of AC, Form a of the X- ray powder diffraction pattern comprising Located at 2 ⁇ at 23.7 ⁇ 0.2°, 6.4 ⁇ 0.2°, 19.4 ⁇ 0.2°, 21.2 ⁇ 0.2°, 23.0 ⁇ 0.2°, 14.8 ⁇ 0.2°, 11.3 ⁇ 0.2°, 28.5 ⁇ 0.2, 13.0 ⁇ 0.2°, 11.8 ⁇ 0.2
  • the X-ray powder diffraction pattern of the crystal form B comprises 2 ⁇ at 21.5 ⁇ 0.2°, 15.0 ⁇ 0.2°, 19.6 ⁇ 0.2°, 23.0 ⁇ 0.2°, 23.2 ⁇ 0.2°, 14.5 ⁇ 0.2°, 20.8 ⁇ 0.2° , 13.3 ⁇ 0.2°, 10.5 ⁇ 0.2°, 11.8 ⁇ 0.2°, 18.3 ⁇ 0.2°, 16.7 ⁇ 0.2°, 16.3 ⁇ 0.2°, 24.2 ⁇ 0.2°, 29.1 ⁇ 0.2° one or more diffraction peaks,
  • the X-ray powder diffraction pattern of the crystal form B has diffraction peaks at the following positions at 2 ⁇ :
  • the X-ray powder diffraction pattern of the crystal form C comprises 2 ⁇ at 26.1 ⁇ 0.2°, 24.7 ⁇ 0.2°, 8.3 ⁇ 0.2°, 9.9 ⁇ 0.2°, 12.8 ⁇ 0.2°, 18.9 ⁇ 0.2°, 26.7 ⁇ 0.2° , 17.3 ⁇ 0.2, 10.4 ⁇ 0.2°, 11.0 ⁇ 0.2°, 19.2 ⁇ 0.2° or 12.1 ⁇ 0.2° one or more diffraction peaks; preferably, including optional 4, 5 and 6 of them , 8 or 10 diffraction peaks;
  • the XRPD pattern of Form B contains one or more peaks located at the following diffraction angles (2 ⁇ ): 21.5 ⁇ 0.2°, 15.0 ⁇ 0.2°, 19.6 ⁇ 0.2°, 23.0 ⁇ 0.2°, 23.2 ⁇ 0.2°, 14.5 ⁇ 0.2°, 20.8 ⁇ 0.2°, 13.3 ⁇ 0.2°, 10.5 ⁇ 0.2°, 11.8 ⁇ 0.2°, 18.3 ⁇ 0.2°, 16.7 ⁇ 0.2°, 16.3 ⁇ 0.2°, 24.2 ⁇ 0.2°, 29.1 ⁇ 0.2°, 26.1 ⁇ 0.2°, 16.0 ⁇ 0.2°, 23.8 ⁇ 0.2°, 27.7 ⁇ 0.2°, 15.7 ⁇ 0.2°, 17.5 ⁇ 0.2°, 24.8 ⁇ 0.2°, 5.2 ⁇ 0.2°; preferably, Form B
  • the XRPD pattern of the XRPD contains at least the above four peaks, or six peaks, or eight peaks.
  • the compound shown in Example 1 is 6-(cyclopropylcarboxamido)-4-((3-(1-cyclopropyl-1H-1,2 ,4-Triazol-3-yl)-2-methoxyphenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, Form A using Cu-K ⁇ radiation at 2 ⁇
  • the characteristic X-ray diffraction peaks represented by the interplanar spacing d are shown in Table 1.
  • the compound shown in Example 1 is 6-(cyclopropylcarboxamido)-4-((3-(1-cyclopropyl-1H-1,2,4-tri Form B of azol-3-yl)-2-methoxyphenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, most preferably, using Cu-K ⁇ radiation at 2 ⁇
  • the characteristic X-ray diffraction peaks represented by the interplanar spacing d are shown in Table 2.
  • the compound shown in Example 1 is 6-(cyclopropylcarboxamido)-4-((3-(1-cyclopropyl-1H-1,2,4-tri oxadiazol-3-yl) -2-methoxy-phenyl) amino) -N- (meth -d 3) pyridazine-3-carboxamide Form C, and most preferably, using Cu-K ⁇ radiation, 2 ⁇ to The characteristic X-ray diffraction peaks represented by the angle and the interplanar spacing d are shown in Table 3.
  • Example 1 of the present invention 6-(cyclopropanecarboxamido)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-
  • the X-ray powder diffraction pattern of Form A has a diffraction peak at 2 ⁇ of 24.5 ⁇ 0.2°; or a diffraction peak at 19.0 ⁇ 0.2°; or a diffraction peak at 13.1 ⁇ 0.2°; or a diffraction peak at 15.8 ⁇ 0.2° or a diffraction peak at 13.4 ⁇ 0.2°; or a diffraction peak at 23.8 ⁇ 0.2°; or a diffraction peak at 7.9 ⁇ 0.2°; or a diffraction peak at 14.7 ⁇ 0.2°; or Has a diffraction peak at 15.0 ⁇ 0.2°; or has a diffraction peak at 27.1 ⁇ 0.2°; preferably includes any 2-5, or 3-5, or 3-6, or 3- 8 places, or 5-8 places, or 6-8 places; more preferably including any 6 places, 7 places or 8 places;
  • the X-ray powder diffraction pattern of Form B has a diffraction peak at 2 ⁇ of 7.1 ⁇ 0.2°; or has a diffraction peak at 23.5 ⁇ 0.2°; or has a diffraction peak at 22.6 ⁇ 0.2°; or has a diffraction peak at 25.7 ⁇ 0.2° or a diffraction peak at 17.3 ⁇ 0.2°; or a diffraction peak at 23.2 ⁇ 0.2°; or a diffraction peak at 21.9 ⁇ 0.2°; or a diffraction peak at 8.2 ⁇ 0.2°; or Has a diffraction peak at 13.9 ⁇ 0.2°; or has a diffraction peak at 17.9 ⁇ 0.2°; preferably includes any 2-5, or 3-5, or 3-6, or 3- 8 places, or 5-8 places, or 6-8 places; more preferably including any 6 places, 7 places or 8 places;
  • the X-ray powder diffraction pattern of Form C has a diffraction peak at 2 ⁇ of 24.5 ⁇ 0.2°; or a diffraction peak at 13.3 ⁇ 0.2°; or a diffraction peak at 15.9 ⁇ 0.2°; or a diffraction peak at 14.6 ⁇ 0.2 or a diffraction peak at 19.0 ⁇ 0.2°; or a diffraction peak at 7.9 ⁇ 0.2°; or a diffraction peak at 15.0 ⁇ 0.2°; or a diffraction peak at 20.1 ⁇ 0.2°; Or have a diffraction peak at 13.9 ⁇ 0.2°; or have a diffraction peak at 13.1 ⁇ 0.2°; preferably include any 2-5, or 3-5, or 3-6, or 3 of the above-mentioned diffraction peaks -8 places, or 5-8 places, or 6-8 places; more preferably including any 6, 7 or 8 of them.
  • the X-ray powder diffraction pattern of the crystal form A comprises at least one or more diffraction peaks located at 2 ⁇ of 24.5 ⁇ 0.2°, 19.0 ⁇ 0.2°, 13.1 ⁇ 0.2°, preferably two of them, More preferably, it contains 3 locations; optionally, it can further comprise at least one of 2 ⁇ of 15.8 ⁇ 0.2°, 13.4 ⁇ 0.2°, 23.8 ⁇ 0.2°, 7.9 ⁇ 0.2° or 14.7 ⁇ 0.2, preferably two of them , 3, 4 or 5;
  • the X-ray powder diffraction pattern of the crystal form B at least comprises one or more diffraction peaks located at 2 ⁇ of 7.1 ⁇ 0.2°, 23.5 ⁇ 0.2°, and 22.6 ⁇ 0.2°, preferably 2 of them, more preferably 2 of them 3 places; optionally, it may further include at least one of 2 ⁇ of 25.7 ⁇ 0.2°, 17.3 ⁇ 0.2°, 23.2 ⁇ 0.2°, 21.9 ⁇ 0.2° or 8.2 ⁇ 0.2, preferably 2 and 3 of them , 4 or 5;
  • the X-ray powder diffraction pattern of the crystal form C at least comprises one or more diffraction peaks located at 24.5 ⁇ 0.2°, 13.3 ⁇ 0.2°, 15.9 ⁇ 0.2° in 2 ⁇ , preferably 2 of them, more preferably 2 of them 3 places; optionally, it may further comprise at least one of 2 ⁇ of 14.6 ⁇ 0.2°, 19.0 ⁇ 0.2°, 7.9 ⁇ 0.2°, 15.0 ⁇ 0.2° or 20.1 ⁇ 0.2, preferably 2 and 3 of them , 4 or 5;
  • the X-ray powder diffraction pattern of the crystal form A optionally further comprises positions at 2 ⁇ of 15.0 ⁇ 0.2°, 27.1 ⁇ 0.2°, 14.0 ⁇ 0.2°, 20.1 ⁇ 0.2°, 22.3°
  • the X-ray powder diffraction pattern of the crystal form B optionally further comprises positions at 2 ⁇ of 13.9 ⁇ 0.2°, 17.9 ⁇ 0.2°, 25.3 ⁇ 0.2°, 5.4 ⁇ 0.2°, 8.6 ⁇ 0.2°, 14.3 ⁇ 0.2° or 27.5°
  • One or more diffraction peaks in ⁇ 0.2° preferably at least any 2-3, or 4-5, or 6-7 of them; more preferably, any 2, 3, 4, 5, 6, 7;
  • the X-ray powder diffraction pattern of the crystal form C optionally further comprises positions at 2 ⁇ of 13.9 ⁇ 0.2°, 13.1 ⁇ 0.2°, 23.8 ⁇ 0.2°, 27.0 ⁇ 0.2°, 22.3 ⁇ 0.2°, 18.4 ⁇ 0.2° or 29.9
  • One or more diffraction peaks in ⁇ 0.2° preferably at least any 2-3, or 4-5, or 6-7 of them; more preferably, any 2, 3, 4, 5, 6, 7;
  • the X-ray powder diffraction pattern of the crystal form A includes 2 ⁇ at 24.5 ⁇ 0.2°, 19.0 ⁇ 0.2°, 13.1 ⁇ 0.2°, 15.8 ⁇ 0.2°, 13.4 ⁇ 0.2°, 23.8 ⁇ 0.2°, 7.9 ⁇
  • the X-ray powder diffraction pattern of the crystal form A has diffraction peaks at the following positions at 2 ⁇ :
  • the X-ray powder diffraction pattern of the crystal form B comprises 2 ⁇ at 7.1 ⁇ 0.2°, 23.5 ⁇ 0.2°, 22.6 ⁇ 0.2°, 25.7 ⁇ 0.2°, 17.3 ⁇ 0.2°, 23.2 ⁇ 0.2°, 21.9 ⁇ 0.2 °, 8.2 ⁇ 0.2, 13.9 ⁇ 0.2°, 17.9 ⁇ 0.2°, 25.3 ⁇ 0.2° or 5.4 ⁇ 0.2° one or more diffraction peaks; preferably, including optional 4, 5, 6 There are diffraction peaks at 8, 10 or 10;
  • the X-ray powder diffraction pattern of the crystal form B has diffraction peaks at the following positions at 2 ⁇ :
  • the X-ray powder diffraction pattern of the crystal form C comprises 2 ⁇ at 24.5 ⁇ 0.2°, 13.3 ⁇ 0.2°, 15.9 ⁇ 0.2°, 14.6 ⁇ 0.2°, 19.0 ⁇ 0.2°, 7.9 ⁇ 0.2°, 15.0 ⁇ 0.2 , 20.1 ⁇ 0.2°, 13.9 ⁇ 0.2°, 13.1 ⁇ 0.2°, 23.8 ⁇ 0.2° or 27.0 ⁇ 0.2° one or more diffraction peaks; preferably, including optional 4, 5, 6 There are diffraction peaks at 2 ⁇ , 8 or 10; for example, the X-ray powder diffraction pattern of the crystal form C has diffraction peaks at the following positions:
  • the compound 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-(prop-2-yne- Form A of 1-yl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide more preferably, Using Cu-K ⁇ radiation, characteristic X-ray diffraction peaks expressed in terms of 2 ⁇ angle and interplanar spacing d are shown in Table 4.
  • Example 6 of the present invention 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-(prop-2-yn-1-yl)-1H-
  • the crystal form A of 1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, its X-ray powder diffraction pattern is basically as shown in Figure 10
  • Its DSC spectrum is basically shown in Figure 11; its TGA spectrum is basically shown in Figure 12.
  • the compound 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-(prop-2-yne- Form B of 1-yl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide more preferably, Using Cu-K ⁇ radiation, the characteristic X-ray diffraction peaks expressed in terms of 2 ⁇ angle and interplanar spacing d are shown in Table 5.
  • Example 6 of the present invention 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-(prop-2-yn-1-yl)-1H-
  • the crystal form B of 1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, its X-ray powder diffraction pattern is basically shown in Figure 13
  • Its DSC spectrum is basically shown in Figure 14
  • TGA spectrum is basically shown in Figure 15.
  • the compound 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-(prop-2-yne- Form C of 1-yl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide most preferably, Using Cu-K ⁇ radiation, the characteristic X-ray diffraction peaks expressed in 2 ⁇ angles and interplanar spacing d values are shown in Table 6.
  • Example 6 of the present invention 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-(prop-2-yn-1-yl)-1H-
  • the crystal form C of 1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, its X-ray powder diffraction pattern is basically as shown in Figure 16 shown; its DSC spectrum is basically shown in Figure 17.
  • the relative peak intensity in the X-ray powder diffraction pattern of the top ten diffraction peak positions and the 2 ⁇ error of the diffraction peak at the corresponding position in the corresponding drawing is ⁇ 0.2° ⁇ 0.5°, preferably ⁇ 0.2 ° to ⁇ 0.3°, most preferably ⁇ 0.2°.
  • “basically” in the X-ray powder diffraction pattern as shown in FIG. 4 means that there may be certain errors, for example, the 2 ⁇ error of the diffraction peak can be ⁇ 0.2° ⁇ 0.5°, etc.
  • the basic also has the same or similar meaning.
  • the crystal form of any compound described in the general formula (I) is a solvent-containing or solvent-free crystal form, wherein the solvent is selected from water, methanol, acetone , ethyl acetate, acetonitrile, ethanol, 88% acetone, tetrahydrofuran, 2-methyl-tetrahydrofuran, dichloromethane, 1,4-dioxane, benzene, toluene, isopropanol, n-butanol, isobutanol , N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, n-propanol, tert-butanol, 2-butanone, 3-pentanone , one or more of n-heptane, heptane, ethyl formate, isopropyl acetate, wherein the solvent is selected from water, methanol,
  • the number of the solvent is 0.2-3, preferably 0.2, 0.5, 1, 1.5, 2, 2.5 or 3, More preferably 0.5, 1, 2 or 3.
  • the crystalline form of the compound of formula (I) is a non-solvent crystalline form, preferably an anhydrous crystalline form.
  • the crystal form of the compound of general formula (I) is a hydrate crystal form, and the number of water is 0.2-3, preferably 0.2, 0.5, 1, 1.5, 2, 2.5 or 3, More preferably 0.5, 1, 2 or 3.
  • the crystal form of 2-methoxyphenyl)amino)-N-(methyl-d 3 )pyridazine-3-carboxamide is a nonsolvent compound, preferably an anhydrate or a hydrate.
  • the compound 6-(cyclopropanecarboxamido)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)- The number of water in the hydrate crystal form of 2-methoxyphenyl)amino)-N-(methyl-d 3 )pyridazine-3-carboxamide is 0.2-3, preferably 0.2, 0.5, 1, 1.5, 2, 2.5 or 3, more preferably 0.5, 1, 2 or 3.
  • the compound 6-(cyclopropanecarboxamido)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)- is a nonsolvent compound, preferably an anhydrate or a hydrate.
  • the compound 6-(cyclopropanecarboxamido)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)- The number of water in the hydrate crystal form of 5-fluoro-2-methoxyphenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide is 0.2-3, preferably 0.2, 0.5, 1 , 1.5, 2, 2.5 or 3, more preferably 0.5, 1, 2 or 3.
  • the crystal form of 1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide is a non-solvent compound, preferably anhydrous or hydrate .
  • the number of water in the hydrate crystal form of 1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide is 0.2-3, preferably 0.2, 0.5, 1, 1.5, 2, 2.5 or 3, more preferably 0.5, 1, 2 or 3.
  • XRPD may have certain displacement and intensity deviations due to detection methods, conditions and instrumentation.
  • its XRPD is shown in the spectrum X, but the ordinary skilled person understands that when the key characteristic peak shift 2 ⁇ deviation is ⁇ 0.5, especially when it is about ⁇ 0.2, it can be identified as the same Crystal form; for example, the 2 ⁇ error ⁇ 0.2° of the diffraction peak in the present invention can be replaced by other reasonable errors such as ⁇ 0.3°, ⁇ 0.5°, etc.
  • the present invention also relates to a method for preparing the crystal form of the compound of general formula (I), which specifically comprises the following steps:
  • the suspension density is preferably 50-200 mg/mL
  • the suspension obtained above is shaken or beaten at a certain temperature for a certain period of time; the temperature is preferably 0-50°C; the time is 1-10 days; preferably 1-5 days;
  • the poor solvent is selected from 88% acetone, isopropanol, toluene, tetrahydrofuran, 2-methyltetrahydrofuran, acetone, ethyl acetate, n-hexane, n-heptane, acetonitrile, ethanol, dichloromethane, 1,4-dichloromethane Oxane, benzene, toluene, n-butanol, isobutanol, N,N-dimethylformamide, N,N-dimethylacetamide, n-propanol, tert-butanol, 2-butanone, or 3 - one or more of pentanone; preferably one or more of 3-pentanone, acetonitrile, dichloromethane or 1,4-dioxane.
  • the present invention also relates to a method for preparing the crystal form of the compound of general formula (I), which specifically comprises the following steps:
  • step b) adding anti-solvent dropwise to the solution obtained in step a), naturally cooling or stirring until the solid is precipitated to obtain a suspension;
  • step c) optionally further centrifuge the suspension obtained in step b), remove the supernatant, and dry to obtain the target product; drying is preferably placed in a 40°C-50°C vacuum drying oven to dry to constant weight;
  • the good solvent is selected from methanol, acetone, ethyl acetate, acetonitrile, ethanol, 88% acetone, tetrahydrofuran, 2-methyl-tetrahydrofuran, dichloromethane, 1,4-dioxane, benzene, toluene, isopropyl Alcohol, n-butanol, isobutanol, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, n-propanol, tert-butanol, 2-butanone, 3 -one or more in pentanone or dimethyl sulfoxide; preferably one or more in N-methylpyrrolidone, N,N-dimethylformamide or acetonitrile;
  • the anti-solvent is selected from one or more of heptane, isopropyl ether, ethyl acetate, acetonitrile, ethanol, toluene, isopropanol, isopropyl acetate, water, methyl tert-butyl ether or cyclohexane. species; preferably one or more of isopropyl ether, n-heptane or water.
  • the present invention also relates to a preparation compound 6-(cyclopropanecarboxamido)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methane
  • the method for the crystal form A of oxyphenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide specifically comprising the following steps:
  • the milliliter value of the N-methylpyrrolidone usage amount is preferably the value of the free base weight in grams. 3 times, that is, 3V;
  • the milliliter value of the amount of isopropanol used is preferably the same as the free base weight gram value.
  • the poor solvent is selected from 88% acetone, isopropanol, toluene, tetrahydrofuran, 2-methyltetrahydrofuran, acetone, ethyl acetate, acetonitrile, ethanol, dichloromethane, 1,4-dioxane, benzene, toluene , one of n-butanol, isobutanol, N,N-dimethylformamide, N,N-dimethylacetamide, n-propanol, tert-butanol, 2-butanone or 3-pentanone or more; preferably one or more of 3-pentanone, acetonitrile, dichloromethane or 1,4-dioxane.
  • the present invention also relates to a method for preparing the compound 6-(cyclopropanecarboxamido)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2
  • the method for the crystal form B of -methoxyphenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide specifically comprising the steps:
  • the milliliter value of the ethyl acetate usage amount is preferably 1.25 times of the free base weight gram value, that is, 1.25V ;
  • the milliliter value of the amount of n-heptane used is preferably 12.5 times the value in grams of free base weight, that is, 12.5V;
  • the milliliter value of the amount of n-heptane used is preferably half of the free base weight gram value; or
  • the present invention also relates to a method for preparing the compound 6-(cyclopropanecarboxamido)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2
  • the method for the crystal form C of -methoxyphenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide specifically comprising the steps:
  • the present invention also relates to a method for preparing the compound 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-(prop-2-yn-1-yl)-1H-1 ,
  • the method for the crystal form A of 2,4-triazol-3-yl) phenyl) amino)-N-(methyl-d3) pyridazine-3-carboxamide specifically comprising the steps:
  • the present invention also relates to a method for preparing the compound 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-(prop-2-yn-1-yl)-1H-1 ,
  • the method for the crystal form B of 2,4-triazol-3-yl) phenyl) amino)-N-(methyl-d3) pyridazine-3-carboxamide specifically comprising the steps:
  • the present invention also relates to a method for preparing the compound 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-(prop-2-yn-1-yl)-1H-1 , the method for the crystal form C of 2,4-triazol-3-yl) phenyl) amino)-N-(methyl-d3) pyridazine-3-carboxamide, specifically comprises the steps:
  • Another object of the present invention is to provide a pharmaceutical composition, which contains a therapeutically effective amount of the crystalline form of the compound represented by the formula (I), and one or more pharmaceutically acceptable carriers and diluents or excipients.
  • the purpose of the present invention is also to provide the crystal form of the compound of the general formula represented by the formula (I) and the application of the pharmaceutical composition in the preparation of a TYK2 inhibitor medicine.
  • Another object of the present invention is to provide the compound represented by the general formula (I) 6-(cyclopropanecarboxamido)-4-((3-(1-cyclopropyl-1H-1,2,4- The crystal form of triazol-3-yl)-2-methoxyphenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, and the application of the pharmaceutical composition in the preparation of TYK2 inhibitor drugs .
  • Another object of the present invention is to provide the compound represented by the general formula (I) 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-(prop-2-yne) Crystalline form of -1-yl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, and pharmaceutical composition Application in the preparation of TYK2 inhibitor drugs.
  • the object of the present invention is to provide the crystalline form of the compound represented by the general formula (I) and the application of the pharmaceutical composition in the treatment of inflammatory diseases and autoimmune diseases; wherein the inflammatory diseases and autoimmunity
  • the disease is selected from rheumatoid arthritis, dermatitis, psoriasis or inflammatory bowel disease.
  • 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 , 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
  • lower alkyl groups containing 1 to 6 carbon atoms include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl base, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-Methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylpropyl butyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl base, 2,3-dimethylbutyl, etc.
  • Alkyl groups may be substituted or unsubstituted, and when substituted, substituents may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from alkanes group, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkane Oxy group, heterocycloalkoxy group, cycloalkylthio group, heterocycloalkylthio group, oxo group, carboxyl group or carboxylate group, the present invention is preferably methyl, ethyl, isopropyl, tert-butyl, haloalkyl , deuterated alkyl, alkoxy substituted alkyl and hydroxy substituted alkyl.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 8 carbon atoms carbon atoms, and most preferably contains 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, fused 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 containing from 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen or S(O) m (where m is an integer from 0 to 2) heteroatoms, excluding ring moieties of -OO-, -OS- or -SS-, the remaining ring atoms being carbon.
  • ring atoms excluding ring moieties of -OO-, -OS- or -SS-, the remaining ring atoms being carbon.
  • it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably 3 to 8 ring atoms; most preferably 3 to 6 ring atoms.
  • Non-limiting examples of monocyclic heterocyclyl groups include oxetanyl, thietanyl, pyrrolidinyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydroimidazolyl Hydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, etc., preferably oxetanyl , pyrrolidone, tetrahydrofuranyl, pyrazolidine, morpholinyl, piperazinyl and pyranyl.
  • Polycyclic heterocyclic groups include spiro, condensed and bridged heterocyclic groups; the spiro, condensed and bridged heterocyclic groups are optionally connected with other groups through a single bond, or through a ring Any two or more atoms above are further cyclo-linked to other cycloalkyl, heterocyclyl, aryl and heteroaryl groups.
  • Heterocyclyl may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, oxo, carboxyl or carboxylate.
  • the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl,
  • Haloalkyl refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.
  • Haloalkoxy refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.
  • Hydroalkyl refers to an alkyl group substituted with hydroxy, wherein alkyl is as defined above.
  • Alkenyl refers to an alkenyl group, also known as an alkenyl group, wherein the alkenyl group may be further substituted with other related groups, such as: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkyl Amino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkanethio group, carboxyl group or carboxylate group.
  • Alkynyl refers to (CH ⁇ C-), wherein the alkynyl group may be further substituted with 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.
  • Halogen refers to fluorine, chlorine, bromine or iodine.
  • Amino means -NH 2.
  • Cyano refers to -CN.
  • Niro refers to -NO 2.
  • Carboxyl refers to -C(O)OH.
  • THF tetrahydrofuran
  • EtOAc refers to ethyl acetate
  • MeOH refers to methanol
  • DMF N,N-dimethylformamide
  • DIPEA diisopropylethylamine
  • TFA trifluoroacetic acid
  • MeCN means acetonitrile
  • DMA refers to N,N-dimethylacetamide.
  • Et 2 O refers to diethyl ether
  • DCE 1,2 dichloroethane
  • DIPEA N,N-diisopropylethylamine
  • NBS N-bromosuccinimide
  • NIS N-iodosuccinimide
  • Cbz-Cl refers to benzyl chloroformate
  • Pd 2 (dba) 3 means tris (dibenzylideneacetone) dipalladium.
  • Dppf refers to 1,1'-bisdiphenylphosphinoferrocene.
  • HATU refers to 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea hexafluorophosphate.
  • KHMDS refers to potassium hexamethyldisilazide
  • LiHMDS refers to lithium bistrimethylsilylamide.
  • MeLi refers to methyl lithium
  • n-BuLi refers to n-butyllithium
  • NaBH(OAc) 3 refers to sodium triacetoxyborohydride.
  • DMAP refers to 4-dimethylaminopyridine.
  • SEM-Cl refers to chloromethyltrimethylsilyl ethyl ether.
  • Xantphos refers to 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene.
  • DCM dichloromethane
  • 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
  • X is A, B and C
  • the hydrogen atom in the present invention can be replaced by its isotope deuterium, and any hydrogen atom in the example compounds involved in the present invention can also be replaced by deuterium atom.
  • Optional or “optionally” means that the subsequently described event or circumstance can, but need not, occur, and that the description includes instances where the event or circumstance occurs or instances where it does not.
  • a heterocyclic group optionally substituted with an alkyl group means that an alkyl group may, but need not, be present, and the description includes the case where the heterocyclic group is substituted with an alkyl group and the case where the heterocyclic group is not substituted with an alkyl group .
  • Substituted means that one or more hydrogen atoms in a group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, independently of one another, are substituted by the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and the person skilled in the art can determine (either experimentally or theoretically) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups with free hydrogens may be unstable when bound to carbon atoms with unsaturated (eg, olefinic) bonds.
  • “Pharmaceutical composition” means a mixture containing one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, with other chemical components, and other components such as a physiological/pharmaceutically acceptable carrier and excipients.
  • the purpose of the pharmaceutical composition is to facilitate the administration to the organism, facilitate the absorption of the active ingredient and then exert the biological activity.
  • “Pharmaceutically acceptable salts” refer to salts of the compounds of the present invention, which are safe and effective when used in mammals, and possess the desired biological activity.
  • Figure 1 is 6-(cyclopropanecarboxamido)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino ) -N- (meth -d 3) pyridazin-3-carboxamide illustrates XRPD Form a.
  • Figure 2 is 6-(cyclopropanecarboxamido)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino ) -N- (meth -d 3) pyridazine-3-carboxamide Form a DSC chart of.
  • Figure 3 is 6-(cyclopropylcarboxamido)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino ) -N- (meth -d 3) TGA pyridazine-3-carboxamide Form a is shown.
  • Figure 4 is 6-(cyclopropylcarboxamido)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino ) -N- (meth -d 3) pyridazin-3-carboxamide illustrates XRPD Form B is.
  • Figure 5 is 6-(cyclopropylcarboxamido)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino )-N-(methyl-d 3 )pyridazine-3-carboxamide Form B DSC diagram.
  • Figure 6 is 6-(cyclopropylcarboxamido)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino ) -N- (meth -d 3) pyridazin-3-carboxamide TGA illustrated Form B, respectively.
  • Figure 7 is 6-(cyclopropylcarboxamido)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino ) -N- (meth -d 3) pyridazin-3-carboxamide illustrates XRPD Form C.
  • Figure 8 is 6-(cyclopropylcarboxamido)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino )-N-(methyl-d 3 )pyridazine-3-carboxamide Form C DSC diagram.
  • Figure 9 is 6-(cyclopropylcarboxamido)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino ) -N- (meth -d 3) pyridazin-3-carboxamide illustrates TGA of Form C.
  • Figure 10 is 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-(prop-2-yn-1-yl)-1H-1,2,4-triazole XRPD representation of crystalline Form A of -3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide.
  • Figure 11 is 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-(prop-2-yn-1-yl)-1H-1,2,4-triazole DSC representation of crystalline Form A of -3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide.
  • Figure 12 is 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-(prop-2-yn-1-yl)-1H-1,2,4-triazole -3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide Form A TGA representation.
  • Figure 13 is 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-(prop-2-yn-1-yl)-1H-1,2,4-triazole XRPD representation of crystalline Form B of -3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide.
  • Figure 14 is 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-(prop-2-yn-1-yl)-1H-1,2,4-triazole DSC representation of crystalline Form B of -3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide.
  • Figure 15 is 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-(prop-2-yn-1-yl)-1H-1,2,4-triazole TGA representation of -3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide Form B.
  • Figure 16 is 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-(prop-2-yn-1-yl)-1H-1,2,4-triazole XRPD representation of crystalline Form C of -3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide.
  • Figure 17 is 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-(prop-2-yn-1-yl)-1H-1,2,4-triazole DSC representation of crystalline Form C of -3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide.
  • Figure 18 shows the results of PASI score in imiquimod-induced mouse psoriasis model at different doses of compounds.
  • the structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) or/and liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts ([delta]) are given in parts per million (ppm). NMR was measured by Bruker AVANCE-400 nuclear magnetic instrument, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated methanol (CD 3 OD) and deuterated chloroform (CDCl 3 ), and the internal standard was four Methylsilane (TMS).
  • DMSO-d 6 dimethyl sulfoxide
  • CD 3 OD deuterated methanol
  • CDCl 3 deuterated chloroform
  • TMS Methylsilane
  • the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the specifications used for TLC are 0.15mm ⁇ 0.20mm, and the specifications used for TLC separation and purification products are 0.4mm ⁇ 0.5mm.
  • Column chromatography generally uses 200-300 mesh Yantai Huanghai silica gel as the carrier.
  • the starting materials in the examples of the present invention are known and commercially available, or can be synthesized using methods known in the art.
  • methyl 2-methoxy-3-nitrobenzoate (5g, 23.7mmol) was dissolved in ammonia methanol solution (100mL, 7M), ammonia water (28wt%, 50mL) was added, and the mixture was It was stirred at room temperature overnight, diluted with ethyl acetate (300 mL), and the organic phase was washed with saturated aqueous NaHCO 3 (300 mL ⁇ 2) and saturated brine in this order. The organic phase was separated and dried over anhydrous sodium sulfate, the organic solvent was concentrated under reduced pressure, and the title compound 2-methoxy-3-nitrobenzamide (4.3 g, 92%) was isolated by column chromatography.
  • Methyl 4,6-dichloropyridazine-3-carboxylate (2.07 g, 10 mmol), lithium bromide (2.6 g, 30 mmol) were dissolved in acetonitrile (20 mL) and water (2 mL), cooled to 0 °C, and added dropwise DIPEA (5.2 mL, 30 mmol), naturally warmed to room temperature and reacted for 1 hour, the reaction solution was filtered, the filter cake was washed with acetonitrile (2 mL ⁇ 4), the filter cake was collected and dried to obtain the title compound 4,6-dichloropyridazine-3- Lithium carboxylate (1.73 g, 87%).
  • 6-(Cyclopropylcarboxamido)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)pyridazine -3-Zinc carboxylate (90 mg, 0.19 mmol), deuterated methylamine hydrochloride (71 mg, 1.0 mmol), DIPEA (258 mg, 2.0 mmol), mixed in DMF (1 mL), HATU (380 mg, 1.0 mmol) was added ) and reacted at 50°C overnight.
  • the first step the preparation of 3-(5-fluoro-2-methoxyphenyl)-1H-1,2,4-triazole
  • reaction solution was poured into ice water, ammonia water was slowly added dropwise, the pH value was adjusted to about 9, extracted with ethyl acetate, the organic phase was separated and dried, and the organic solvent was concentrated under reduced pressure to obtain the title compound 3-(5-fluoro-2-methyl)
  • the crude oxy-3-nitrophenyl)-1H-1,2,4-triazole (1.26 g) was used directly in the next reaction.
  • the reaction solution was diluted with dichloromethane, the organic phase was washed several times with saturated brine, then the organic phase was separated and dried with anhydrous sodium sulfate, the organic solvent was concentrated under reduced pressure, and the title compound was separated by column chromatography to obtain the title compound 6-(cyclopropanecarboxamido) )-4-((3-(1-Cyclopropyl-1H-1,2,4-triazol-3-yl)-5-fluoro-2-methoxyphenyl)amino)-N-(methyl -d3) Pyridazine-3-carboxamide (116 mg, 67%).
  • the first step 3-(2-methoxy-3-nitrophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4- Preparation of triazoles
  • the second step 2-methoxy-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)aniline preparation
  • the above crude product was dissolved in a mixed solution of ethanol (30 mL) and water (5 mL), followed by adding ammonium chloride solid (1.60 g, 30.0 mmol) and reduced iron powder (1.67 g, 30.0 mmol), and stirring at 50° C. After 2 hours, the reaction system was cooled, and the insolubles were filtered off with celite. After the filtrate was concentrated, the residue was dissolved in dichloromethane and washed with saturated brine. The organic phase was separated, dried with a desiccant, filtered, and concentrated under reduced pressure.
  • 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-((2-(trimethylsilyl)ethoxy)methyl)- 1H-1,2,4-Triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide 630 mg, 1.16 mmol
  • TFA 6.0 mL
  • the sixth step 4-((3-(1-allyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-6-(cyclopropanecarboxamido Preparation of )-N-(methyl-d3)pyridazine-3-carboxamide
  • reaction solution was concentrated under reduced pressure and separated by column chromatography to obtain the title compound 4-((3-(1-allyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino )-6-(cyclopropanecarboxamido)-N-(methyl-d3)pyridazine-3-carboxamide (12 mg, 39%).
  • the first step 3-(2-methoxy-3-nitrophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4- Preparation of triazoles
  • the second step 2-methoxy-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)aniline preparation
  • the above crude product was dissolved in a mixed solution of ethanol (30 mL) and water (5 mL), followed by adding ammonium chloride solid (1.60 g, 30.0 mmol) and reduced iron powder (1.67 g, 30.0 mmol), and stirring at 50° C. After 2 hours, the reaction system was cooled, and the insolubles were filtered off with celite. After the filtrate was concentrated, the residue was dissolved in dichloromethane and washed with saturated brine. The organic phase was separated, dried with a desiccant, filtered, and concentrated under reduced pressure.
  • 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-((2-(trimethylsilyl)ethoxy)methyl)- 1H-1,2,4-Triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide 630 mg, 1.16 mmol
  • DCM 20 mL
  • TFA 6.0 mL
  • the first step 3-(2-methoxy-3-nitrophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4- Preparation of triazoles
  • the second step 2-methoxy-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)aniline preparation
  • the above crude product was dissolved in a mixed solution of ethanol (30 mL) and water (5 mL), followed by adding ammonium chloride solid (1.60 g, 30.0 mmol) and reduced iron powder (1.67 g, 30.0 mmol), and stirring at 50° C. After 2 hours, the reaction system was cooled, and the insolubles were filtered off with celite. After the filtrate was concentrated, the residue was dissolved in dichloromethane and washed with saturated brine. The organic phase was separated, dried with a desiccant, filtered, and concentrated under reduced pressure.
  • 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-((2-(trimethylsilyl)ethoxy)methyl)- 1H-1,2,4-Triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide 630 mg, 1.16 mmol
  • TFA 6.0 mL
  • Test Example 1 Determination of the inhibitory effect of the compounds of the examples of the present invention on the cellular TYK2 signaling pathway
  • the purpose of this test example is to test the inhibitory activity of the compounds of the examples on the cellular TYK2 signaling pathway.
  • microplate reader was purchased from BioTek, USA, and the model was SynergyH1 full-function microplate reader.
  • Example 1 Compound number Cellular activity U266 pSTAT3(nM) Example 1 1.41 Example 2 2.43 Example 3 0.83 Example 4 4.95 Example 5 0.34 Example 6 0.13 Example 7 0.90 Example 8 1.88 Example 9 4.60 Example 10 2.10 Example 11 3.43
  • Test Example 2 Determination of the inhibitory effect of the compounds of the examples of the present invention on the cellular JAK2 signaling pathway
  • the purpose of this test example is to test the inhibitory activity of the compounds of the examples of the present invention on the cellular JAK2 signaling pathway.
  • microplate reader was purchased from BioTek, USA, and the model was SynergyH1 full-function microplate reader.
  • TF-1 cell line was used to activate the JAK2 signaling pathway through IL6 stimulation, and the inhibitory activity of the compound on its downstream STAT3 phosphorylation was detected, and the median inhibitory concentration IC 50 of the compound on the activity of the JAK2 signaling pathway was obtained.
  • the purpose of this experiment was to evaluate the protein binding rate of the example compounds (5 ⁇ M) in mouse plasma by equilibrium dialysis.
  • test compounds were prepared as 10 mM stock solutions with DMSO, and stored in a refrigerator at -20°C for later use;
  • the frozen plasma was thawed at room temperature or in a 37°C water bath, centrifuged at 3500 rpm for 5 min, and the supernatant was taken.
  • Working solution formulation of compounds stock solutions were diluted in DMSO to a final concentration of 1 mM.
  • Balb/C mice were used as test animals to study the pharmacokinetic behavior of the compounds of Example compounds in the plasma of mice administered orally at a dose of 5 mg/kg.
  • Balb/C Mouse (6 animals/example), male, Shanghai Jiesijie Laboratory Animal Co., Ltd., animal production license number (SCXK (Shanghai) 2013-0006N0.311620400001794).
  • mice Before and after administration of mice, at 0, 0.5, 1, 2 , 4, 6, 8 and 24 hours, 0.1 mL of blood was collected from the orbit, placed in an EDTA-K 2 test tube, and centrifuged at 6000 rpm at 4°C for 6 min to separate plasma. , and stored at -80°C.
  • Mass spectrometry conditions AB Sciex API 4000 mass spectrometer
  • a solution is 0.1% formic acid aqueous solution
  • B solution is acetonitrile
  • mice Taking Balb/C mice as the test animals, the pharmacokinetic behavior of the compound Example 1 and the reference compound BMS-986165 in different doses of oral administration in the plasma of mice was studied.
  • mice (3 mice in each group), male; after fasting overnight, po, respectively, the doses of drug prescription 0.5% CMC-Na (1% Tween80) were 1 mg/kg, 3 mg/kg, 10 mg/kg, respectively, administered Volume 10mL/kg.
  • mice Before and after administration of mice, at 0, 0.5, 1, 2 , 4, 6, 8 and 24 hours, 0.1 mL of blood was collected from the orbit, placed in an EDTA-K 2 test tube, and centrifuged at 6000 rpm at 4°C for 6 min to separate plasma. , and stored at -80°C.
  • Mass spectrometry conditions AB Sciex API 4000 mass spectrometer
  • a solution is 0.1% formic acid aqueous solution
  • B solution is acetonitrile
  • Example 1 The mouse pharmacokinetic test results of Example 1 with different doses and the reference compound BMS-986165 are shown in the following table:
  • Test Example 6 Determination of the efficacy of the compounds of the examples of the present invention at different doses on imiquimod-induced mouse psoriasis-like models
  • PASI score AUC (total score curve) change ratio % (administration group AUC-model group AUC)/model group AUC*100%.
  • Example 1 of the present invention can effectively improve the symptoms of psoriasis in the imiquimod-induced mouse psoriasis-like model, and there is a very significant difference compared with the Vehicle group, P ⁇ 0.001, Example 1, at a dose of 1 mg/kg, achieved comparable improvement in psoriasis symptoms with the reference compound BMS-986165 at a dose of 3 mg/kg.
  • 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-( Prop-2-yn-1-yl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide Form A has the XRPD pattern shown in Figure 10, the DSC pattern shown in Figure 11, and the TGA pattern shown in Figure 12.
  • 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-( Prop-2-yn-1-yl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide free base crystal Form B has the XRPD pattern shown in FIG. 13 , the DSC pattern shown in FIG. 14 , and the TGA pattern shown in FIG. 15 .
  • Mobile phase A: water (0.05% trifluoroacetic acid); B: acetonitrile (0.05% trifluoroacetic acid)
  • Crystal form A is relatively stable at 60°C, 95% RH, 50°C 75% RH, slightly degraded under light (5000lx ⁇ 500lx) conditions, and can be solved by coating and packaging in the later stage.
  • the stability of crystal form A meets the later stage. development requirements.

Abstract

La présente invention concerne une forme cristalline d'un dérivé pyridazinique sous forme de base libre et son procédé de préparation et son utilisation. Plus précisément, la présente invention concerne un composé représenté par la formule générale (I), une forme cristalline de celui-ci, un procédé de préparation associé, une composition pharmaceutique contenant une quantité thérapeutiquement efficace du composé ou d'une forme cristalline de celui-ci, et son utilisation dans la préparation de médicaments inhibiteurs de TYK2.
PCT/CN2021/108103 2020-07-24 2021-07-23 Forme cristalline d'un dérivé pyridazinique sous forme de base libre, son procédé de préparation et son utilisation WO2022017494A1 (fr)

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JP2023503000A JP2023534492A (ja) 2020-07-24 2021-07-23 ピリダジン誘導体遊離塩基の結晶形態、並びにその調製方法及びその使用
CA3186000A CA3186000A1 (fr) 2020-07-24 2021-07-23 Forme cristalline d'un derive pyridazinique sous forme de base libre, son procede de preparation et son utilisation
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US11613548B2 (en) 2021-02-19 2023-03-28 Sudo Biosciences Limited Substituted pyridines, pyridazines, pyrimidines, and 1,2,4-triazines as TYK2 inhibitors
WO2023076161A1 (fr) 2021-10-25 2023-05-04 Kymera Therapeutics, Inc. Agents de dégradation de tyk2 et leurs utilisations

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CN110475774A (zh) * 2017-03-30 2019-11-19 百时美施贵宝公司 用于制备6-(环丙烷酰氨基)-4-((2-甲氧基-3-(1-甲基-1h-1,2,4-***-3-基)苯基)氨基)-n-(甲基-d3)哒嗪-3-甲酰胺的方法
WO2020156311A1 (fr) * 2019-01-28 2020-08-06 江苏豪森药业集团有限公司 Inhibiteur de dérivé de pyridazine, son procédé de préparation et son utilisation
CN111909140A (zh) * 2019-04-12 2020-11-10 明慧医药（杭州）有限公司 作为tyk2抑制剂的杂环化合物及合成和使用方法

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CN104884454A (zh) * 2012-11-08 2015-09-02 百时美施贵宝公司 用作IL-12、IL-23和/或IFNα应答调节剂的酰胺取代的杂环化合物
CN110475774A (zh) * 2017-03-30 2019-11-19 百时美施贵宝公司 用于制备6-(环丙烷酰氨基)-4-((2-甲氧基-3-(1-甲基-1h-1,2,4-***-3-基)苯基)氨基)-n-(甲基-d3)哒嗪-3-甲酰胺的方法
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11613548B2 (en) 2021-02-19 2023-03-28 Sudo Biosciences Limited Substituted pyridines, pyridazines, pyrimidines, and 1,2,4-triazines as TYK2 inhibitors
WO2023076161A1 (fr) 2021-10-25 2023-05-04 Kymera Therapeutics, Inc. Agents de dégradation de tyk2 et leurs utilisations

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