[go: up one dir, main page]

WO2022002118A1 - Dérivé hétérocyclique à cycles fusionnés et son utilisation médicale - Google Patents

Dérivé hétérocyclique à cycles fusionnés et son utilisation médicale Download PDF

Info

Publication number
WO2022002118A1
WO2022002118A1 PCT/CN2021/103485 CN2021103485W WO2022002118A1 WO 2022002118 A1 WO2022002118 A1 WO 2022002118A1 CN 2021103485 W CN2021103485 W CN 2021103485W WO 2022002118 A1 WO2022002118 A1 WO 2022002118A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
substituted
ring
amino
cyano
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CN2021/103485
Other languages
English (en)
Chinese (zh)
Inventor
张晨
赵明亮
叶飞
谷禾
邓华
杨定菊
唐平明
李瑶
倪佳
严庞科
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sichuan Haisco Pharmaceutical Co Ltd
Original Assignee
Sichuan Haisco Pharmaceutical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Sichuan Haisco Pharmaceutical Co Ltd filed Critical Sichuan Haisco Pharmaceutical Co Ltd
Priority to CN202180035181.XA priority Critical patent/CN115916747A/zh
Publication of WO2022002118A1 publication Critical patent/WO2022002118A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4162—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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • A61K31/4965—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
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • 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
    • C07D471/02—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
    • 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

Definitions

  • the present invention relates to a compound of general formula (I) or its stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, and intermediate and preparation method thereof , and the application in the preparation of medicines for treating diseases related to JAK kinase activity or expression.
  • Inflammatory bowel disease also known as inflammatory bowel disease (IBD) is an idiopathic intestinal inflammatory disease involving the ileum, rectum, and colon. Clinical manifestations include diarrhea, abdominal pain, and even bloody stools. Inflammatory bowel diseases include ulcerative colitis (UC) and Crohn's disease (CD). Ulcerative colitis is a continuous inflammation of the colonic mucosa and submucosa. The disease usually first involves the rectum and gradually spreads to the entire colon. Crohn's disease can involve the entire digestive tract and is a discontinuous full-thickness inflammation. Terminal ileum, colon and perianal.
  • IBD inflammatory bowel disease
  • Janus-activated kinase Singal transducers and activators of transcriprion is a newly discovered intracellular signaling pathway closely related to cytokines in recent years, which is involved in cell proliferation and differentiation. , apoptosis and immune regulation and many other important biological processes.
  • Janus kinase is a non-receptor tyrosine protein kinase.
  • the JAK/STAT signaling pathway is an important intracellular signal transduction pathway in the process of various cell growth, activation, differentiation, apoptosis and its function.
  • cytokine receptors carries JAK tyrosine protein kinases. When these cytokines bind to specific receptors on the cell surface, the JAK molecules on the signal transduction chain aggregate and phosphorylate each other to activate them.
  • phosphate (P) causes phosphorylation of tyrosine residues (Y) on the intracellular segment of another receptor chain to form PY, and these phosphorylated tyrosine sites form "docking sites" with the surrounding amino acid sequence "(docking site), thereby recruiting the transcription factor STAT with SH2 domain, at this time, the tyrosine in STAT also obtains phosphate from the activated JAK and activates, and forms a homodimer, which is separated from the receptor. , its nuclear localization signal is exposed and enters the nucleus, binds to the target gene, and regulates the transcription of the gene. JAK-STAT intracellular signaling is applicable to interferons, most interleukins, and a variety of cytokines and endocrine factors.
  • UC ulcerative colitis
  • pro-inflammatory cytokines play a key role in the immune response (Schobo et al., Gastroenterol, 2011, 140, 1756-1767).
  • Many of the proinflammatory cytokines most commonly elevated in UC eg, IL-4, IL-6, IL-13, IL-15, IL-23, IL-24, IFN ⁇ , and leptin
  • JAK family of acid kinases JAK1, JAK2, JAK3, and Tyk2
  • inhibition of the JAK family of enzymes inhibits signaling of multiple key pro-inflammatory cytokines. Therefore, inhibition of the JAK family of enzymes is expected to have therapeutic benefits in ulcerative colitis and other inflammatory diseases.
  • JAK inhibitors inhibit the signaling of multiple key pro-inflammatory cytokines. Therefore, JAK inhibitors are likely to be useful in the treatment of ulcerative colitis and other inflammatory diseases such as Crohn's disease, allergic rhinitis, atopic dermatitis (AD) and other inflammatory skin diseases.
  • systemically exposed JAK inhibitors have detrimental systemic immunosuppressive effects due to the modulation of the immune system by the JAK/STAT pathway, and therefore, there is a need to provide novel JAK inhibitors that act at the site of action without significant systemic effects.
  • gastrointestinal inflammatory diseases eg, ulcerative colitis, Crohn's disease
  • novel JAK inhibition that is orally administrable and achieves therapeutically relevant exposures in the gastrointestinal tract with minimal systemic exposure agent.
  • novel JAK inhibitors for the treatment of atopic dermatitis that have minimal systemic exposure.
  • One of the objects of the present invention is to provide a compound capable of inhibiting JAK kinase, or its stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, and its intermediate and The preparation method and the application in the preparation of medicines for treating diseases related to JAK kinase activity or expression level.
  • the compounds of the present invention have good JAK kinase inhibitory activity, anti-inflammatory activity, good safety and/or intestinal targeting.
  • the present invention provides a compound of general formula (I) or its stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal,
  • L is selected from a bond or NRn2 ;
  • L is selected from NRn2 ;
  • L is selected from a bond
  • R n1 , R n2 are each independently selected from H, C 1-6 alkyl or C 3-6 cycloalkyl, and said alkyl or cycloalkyl is optionally further selected from 0 to 4 (eg 0, 1, 2, 3 or 4) substituents selected from H, halogen, CF 3 , OH, cyano, NH 2 , C 1-6 alkyl or C 1-6 alkoxy ;
  • R n1 and R n2 are each independently selected from H, C 1-4 alkyl or C 3-6 cycloalkyl, and said alkyl or cycloalkyl is optionally further selected from 0 to 4 (eg 0, 1, 2, 3 or 4) substituents selected from H, halogen, CF 3 , OH, cyano, NH 2 , C 1-4 alkyl or C 1-4 alkoxy ;
  • R n1 , R n2 are each independently selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, said Methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl are optionally further selected from 0 to 4 (eg 0, 1, 2, 3 or 4) H, halogen, CF 3 , OH, cyano, NH 2 , C 1-4 alkyl or C 1-4 alkoxy substituent;
  • R n1 , R n2 are each independently selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, said Methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl are optionally further selected from 0 to 4 (eg 0, 1, 2, 3 or 4) H, F, CF 3 , OH, cyano, NH 2 , methyl, ethyl, methoxy or ethoxy substituents;
  • Rn1 is selected from H
  • Rn2 is selected from H, methyl, ethyl, propyl, isopropyl
  • Rn1 , Rn2 are selected from H;
  • Ring A is selected from a 5-6 membered monocyclic heteroaromatic ring or an 8-10 membered heterocyclic heteroaromatic ring optionally further separated by 0 to 3 (eg, 0, 1 , 2 or 3) R a substituted, and the heteroaromatic ring contains 1 to 5 (eg 1, 2, 3, 4 or 5) heteroatoms selected from O, S, N;
  • Ring A is selected from substituted or unsubstituted 6 and 6-membered fused heteroaryl groups, preferably substituted or unsubstituted one of the following groups: isoquinolinyl, naphthyridinyl, pyridopyrazine base, pyridopyrimidinyl, pyridopyridazinyl, pyridopyridazinyl, pyrimidopyridazinyl, pyrimidopyridazinyl, quinazolinyl, pteridyl, quinoxalinyl, dihydropyrano pyrimidinyl or dioxino dihydro-pyrimidine group, when substituted, optionally further substituted with 0-3 (e.g. 2 or 3) R a;
  • Ring A is selected from substituted or unsubstituted 5 and 6-membered fused heteroaryl groups, preferably substituted or unsubstituted one of the following groups: thienopyrimidinyl, pyrazolopyrimidinyl, benzo pyrrolyl, pyrrolopyridyl, imidazopyridyl, triazolopyridyl, imidazopyridazinyl, pyrrolopyrimidyl, pyrazolopyrimidinyl, imidazopyrimidinyl, triazolopyrimidyl, thienopyrimidine base, thiazolopyrimidyl, isothiazolopyrimidyl, isoxazolopyrimidyl, isothiazolopyridyl, isoxazolopyridyl, isothiazolopyrazinyl, isoxazolopyrazinyl, isothiazole Pyridazinyl, is
  • Ring A is selected from one of the following groups, substituted or unsubstituted: X 1 is selected from CH or N, X 2 is selected from bond, CH or N, Y and Z are each independently selected from C or N, and ring C is selected from 5-6 membered heteroaromatic ring or benzene ring, the heteroaromatic
  • the ring contains 1 to 3 (eg 1, 2 or 3) heteroatoms selected from O, S, N, optionally further 0 to 3 (eg 0, 1, 2 or 3) R when substituted a replace;
  • Ring A is selected from one of the following groups, substituted or unsubstituted: X 1 is selected from CH or N, X 2 is selected from bond, CH or N, Y and Z are independently selected from C or N, and ring C is selected from pyrazole ring, thiazole ring, imidazole ring, oxazole ring, thiophene ring , furan ring, pyrrole ring, isoxazole ring, isothiazole ring, pyridine ring, pyrazine ring, pyridazine ring, 1,2,4-triazole ring, pyrimidine ring or benzene ring, when substituted, any is further substituted with 0 to 3 (e.g. 0, 1, 2 or 3) R a ;
  • Ring A is selected from one of the following groups, substituted or unsubstituted: When substituted, optionally further substituted with 0-3 (e.g. 2 or 3) R a;
  • Ring A is selected from one of the following groups, substituted or unsubstituted: When substituted, optionally further substituted with 0-3 (e.g. 2 or 3) R a;
  • Ring A is selected from one of the following groups, substituted or unsubstituted: When substituted, optionally further substituted with 0-3 (e.g. 2 or 3) R a;
  • Ring A is selected from one of the following groups:
  • R a is independently selected from H, F, Cl, Br, cyano, OH, methyl, ethyl, propyl, butyl, isopropyl, methoxy, ethoxy , pyrazolyl, thiazolyl, imidazolyl, oxazolyl, thienyl, furyl, pyrrolyl, isoxazolyl, isothienyl, pyridyl, pyrimidinyl, phenyl, cyclopropyl, cyclobutyl, Cyclopentyl, cyclohexyl, -NH-pyrazolyl, -NH-thiazolyl, -NH-imidazolyl, -NH-oxazolyl, -NH-thienyl, -NH-furanyl, -NH-pyrrolyl , -NH-isoxazolyl, -NH-isothienyl, -NH-pyri
  • R a is independently selected from H, F, Cl, Br, cyano, OH, methyl, ethyl, propyl, butyl, isopropyl, isobutyl, sec-butyl , tert-butyl, methoxy, ethoxy, pyrazolyl, thiazolyl, imidazolyl, oxazolyl, thienyl, furyl, pyrrolyl, isoxazolyl, isothienyl, pyridyl, pyrimidinyl , phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -NH-pyrazolyl, -NH-thiazolyl, -NH-imidazolyl, -NH-oxazolyl, -NH-thienyl , -NH-furyl, -NH-pyrrolyl, -NH-isox
  • R a is independently selected from -CH 2 - azetidinyl, -CH 2 - aza-cyclopentyl, -CH 2 - azetidin cyclohexyl, -CH 2 - oxetanyl Butyl, -CH 2 -oxolane, -CH 2 -oxane, -CH 2 -morpholinyl, -CH 2 -piperazinyl, -CH 2 CH 2 -azetidinyl, -CH 2 CH 2 - aza-cyclopentyl, -CH 2 CH 2 - azetidin cyclohexyl, -CH 2 CH 2 - oxetanyl, -CH 2 CH 2 - oxolanyl, -CH 2 CH 2 -oxanyl, -CH 2 CH 2 -oxanyl, -CH 2 CH 2 -morpholinyl, -CH 2 CH 2 -pipe
  • R a is independently selected from H, methyl, ethyl, propyl, butyl, isopropyl, cyclopropyl, cyclobutyl, -CH 2 CH 2 CN,
  • R a is independently selected from H, methyl, ethyl, propyl, butyl, isopropyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyloxy base, -CH 2 CH 2 CN,
  • the methyl, ethyl, propyl, butyl, isopropyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, -CH 2 CH 2 CN are optionally further to 3 (e.g.
  • Ring B is selected from non-aromatic C 3-12 carbocycles, said carbocycles are optionally selected from monocyclic, paracyclic, bridged or spirocyclic rings, said carbocyclic, monocyclic, and ring, a bridged ring or spiro ring is optionally further substituted with 0-3 (e.g. 2 or 3) R b;
  • Ring B is selected from C 3-8 monocycloalkyl, C 4-10 cycloalkyl, C 4-12 spirocycloalkyl, C 5-12 bridged cycloalkyl, said cycloalkyl optionally further substituted with 0-3 (e.g. 2 or 3) R b;
  • Ring B is selected from C 5-8 monocycloalkyl, C 8-10 cycloalkyl, C 8-12 spirocycloalkyl, C 8-12 bridged cycloalkyl, said cycloalkyl optionally further substituted with 0-3 (e.g. 2 or 3) R b;
  • Ring B is selected from C 5-7 monocycloalkyl, C 9-10 cycloalkyl, C 9-12 spirocycloalkyl, C 9-12 bridged cycloalkyl, said cycloalkyl optionally further substituted with 0-3 (e.g. 2 or 3) R b;
  • Ring B is selected from C 5-7 monocycloalkyl, C 9-10 cycloalkyl, C 9-12 spirocycloalkyl, C 9-12 bridged cycloalkyl, said cycloalkyl optionally further substituted with 0-3 (e.g. 2 or 3) R b;
  • Ring B is selected from monocyclic C 5 alkyl, C 6 monocyclic group, C 7 monocyclic group, C 6 and cycloalkyl, C 7 alkyl and cycloalkyl, C 8 cycloalkyl and alkyl, C 9 alkyl and cycloalkyl, C 10 alkyl and cycloalkyl, C 6 spiro cycloalkyl, C 7 spiro cycloalkyl, C 8 spiro cycloalkyl, C 9 spiro cycloalkyl, C 10 spiro cycloalkyl group, C 11 spiro cycloalkyl group, C 12 spiro cycloalkyl group, C 5 bridged cycloalkyl, C 6 bridged cycloalkyl, C 7 bridged cycloalkyl, C 8 bridged cycloalkyl, C 9 bridged cycloalkyl , C 10 bridged cycloalkyl , C 10
  • Ring B is selected from one of the following groups, substituted or unsubstituted: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylcyclobutyl, cyclopropylcyclobutyl Pentyl, cyclopropyl-cyclohexyl, cyclobutyl-cyclobutyl, cyclobutyl-cyclopentyl, cyclobutyl-cyclohexyl, cyclopentyl-cyclopentyl, cyclopentyl-cyclohexyl , cyclohexyl and cyclohexyl, cyclopropyl spiro cyclobutyl, cyclopropyl spiro cyclobutyl, cyclopropyl spiro cyclopentyl, cyclopropyl spiro cyclohexyl, cyclobutyl spir
  • Ring B is selected from R 2 is directly connected to the right;
  • Ring B is selected from R 2 is directly connected to the right;
  • Ring B is selected from R 2 is directly connected to the right;
  • Ring B is selected from R 2 is directly connected to the right;
  • Ring B is selected from R 2 is directly connected to the right;
  • each R b is independently selected from H, halogen, cyano, OH, C 1-6 alkyl or C 1-6 alkoxy, optionally further is 0-4 (e.g., 2, 3 or 4) selected from H, halo, OH, cyano, NH 2, C 1-6 alkyl, halo-substituted C 1-6 alkyl, C 1-6 alkoxy or C 3-6 cycloalkyl substituent;
  • each R b is independently selected from H, halogen, cyano, OH, C 1-4 alkyl or C 1-4 alkoxy, optionally further is 0-4 (e.g., 2, 3 or 4) selected from H, halo, OH, cyano, NH 2, C 1-4 alkyl, halo-substituted C 1-4 alkyl, C 1-4 alkoxy or C 3-4 cycloalkyl substituent;
  • each R b is independently selected from H, halogen, cyano, OH, C 1-4 alkyl or C 1-4 alkoxy;
  • each R b is independently selected from H, F, cyano, OH, methyl, ethyl, methoxy, ethoxy, or hydroxymethyl;
  • R 1 is selected from a 5- to 10-membered heteroaryl or phenyl optionally further substituted by 0 to 4 (eg, 0, 1, 2, 3, or 4 a) R 1a substitutions;
  • R 1 is selected from substituted or unsubstituted one of the following groups: selected from 5- to 6-membered monocyclic heteroaryl, 6- and 6-membered heteroaryl, 5- and 6-membered heteroaryl, or phenyl, when substituted, is optionally further substituted with 0 to 4 (eg 0, 1, 2, 3 or 4) R 1a ;
  • R 1 is selected from substituted or unsubstituted one of the following groups: pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, pyrrolyl, imidazolyl, thienyl, furan base, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, benzopyrazolyl, benzopyrrolyl, benzimidazolyl, benzothienyl, benzofuranyl, benzothiazolyl, benzene oxazolyl, benzisothiazolyl or benzisoxazolyl, when substituted, optionally further substituted with 0 to 4 (eg 0, 1, 2, 3 or 4) R 1a ;
  • R 1 is selected from The NH in the R 1 group cannot be substituted by R 1a , and m is selected from 0, 1 or 2;
  • R 1 is selected from m is selected from 0, 1 or 2;
  • R 1 is selected from m is selected from 0, 1 or 2;
  • R 1b is selected from C 1-6 alkyl or C 3-6 cycloalkyl optionally further substituted by 0 to 4 (eg 0, 1, 2 , 3 or 4) is selected from H, halogen, OH, cyano, NH 2 , halogen substituted C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkoxy or C 3-6 ring Substituted by alkyl substituents;
  • R 1b is selected from C 1-4 alkyl or C 3-6 cycloalkyl optionally further substituted by 0 to 4 (eg 0, 1, 2 , 3 or 4) is selected from H, halogen, OH, cyano, NH 2 , halogen substituted C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkoxy or C 3-6 ring Substituted by alkyl substituents;
  • R 1b is selected from methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, the methyl, ethyl, isopropyl, cyclohexyl cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group optionally further substituted with 0 to 4 (e.g.
  • R 1 is selected from
  • R 1 is selected from
  • R 1 is selected from
  • R 1 is selected from
  • each R 1a is independently selected from H, halogen, OH, cyano, NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , - NH (C 3-6 cycloalkyl), C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl or 3- to 8-membered heterocyclic group, the alkyl, alkoxy group, cycloalkyl or heterocyclyl is further optionally substituted with 0 to 4 (e.g.
  • each R 1a is independently selected from H, halogen, OH, cyano, NH 2 , -NH(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , - NH (C 3-4 cycloalkyl), C 1-4 alkyl or C 1-4 alkoxy, said alkyl or alkoxy optionally further replaced by 0 to 4 (eg 0, 1, 2 , 3 or 4) is selected from H, halogen, OH, cyano, NH 2 , halogen substituted C 1-4 alkyl, C 1-4 alkyl, C 1-4 alkoxy or C 3-6 ring Substituted by alkyl substituents;
  • each R 1a is independently selected from H, F, OH, cyano, methyl, ethyl, isopropyl, propyl, methoxy or ethoxy, the methyl, Ethyl, isopropyl, propyl, methoxy or ethoxy is optionally further 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, halogen, OH, cyano, NH 2. Substituents of halogen-substituted C 1-4 alkyl, C 1-4 alkyl, C 1-4 alkoxy or C 3-6 cycloalkyl;
  • heterocycle contains 1 to 3 (e.g. 1, 2 or 3) heteroatoms selected from O, S, N;
  • heterocycle contains 1 to 3 (eg 1, 2 or 3) heteroatoms selected from O, S, N ;
  • R 2 is selected from halogen, cyano, OH, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 carbocycle, 3 to 6 membered heterocycle, -CH 2 -C 3-6 carbocycle, -CH 2 -3- to 6-membered heterocycle, -NH-C 3-6 carbocycle, -NH-3 to 6-membered heterocycle or -NHC 1-4 alkyl, said -CH 2 -, alkyl, alkoxy, carbocyclic or heterocyclic ring is optionally further substituted with 0 to 4 (e.g. 2, 3 or 4) selected from H, halo, OH, cyano, NH 2.
  • 0 to 4 e.g. 2, 3 or 4
  • Substituted by C 1-4 alkyl, halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl or C 1-4 alkoxy substituent, and the heterocycle contains 1 to 3 (eg 1, 2 or 3) heteroatoms selected from O, S, N;
  • R 2 is selected from substituted or unsubstituted one of the following: F, cyano, OH, methyl, ethyl, methoxy, ethoxy, cyclopropyl, cyclobutyl cyclopentyl, cyclopentyl, cyclohexyl, -CH 2 -cyclopropyl, -CH 2 -cyclobutyl, -CH 2 -cyclopentyl, -CH 2 -cyclohexyl, azetidine, azetidine yl, azetidin cyclohexyl, -CH 2 - azetidinyl, -CH 2 - aza-cyclopentyl, -CH 2 - azacyclohexyl, oxetanyl, oxolanyl, oxa cyclohexyl, -CH 2 - oxetanyl, -CH 2
  • R 2 is selected from substituted or unsubstituted one of the following: F, cyano, OH, methyl, ethyl, methoxy, ethoxy, cyclopropyl, cyclobutyl cyclopentyl, cyclopentyl, cyclohexyl, -CH 2 -cyclopropyl, -CH 2 -cyclobutyl, -CH 2 -cyclopentyl, -CH 2 -cyclohexyl, azetidine, azetidine yl, azetidin cyclohexyl, -CH 2 - azetidinyl, -CH 2 - aza-cyclopentyl, -CH 2 - azacyclohexyl, oxetanyl, oxolanyl, oxa cyclohexyl, -CH 2 - oxetanyl, -CH 2
  • R 2 is selected from F, cyano, OH, -OCH 3, -OCHF 2 , -OCH 2 F, -OCF 3, methyl, ethyl, CF 3, -CH 2 OH, - CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH, -CH 2 CN, -CH 2 CH 2 CN, -CH 2 CH 2 CH 2 CN, -CH 2 CH 2 CH 2 CH 2 CN, -NHCH 2 CN, -NHCH 2 CH 2 CN, -NHCH 2 CH 2 CH 2 CN, -NHCH 2 CH 2 CH 2 CH 2 CN, -NHCH 2 CH 2 CH 2 CH 2 CN,
  • R 2 is selected from F, OH, -OCH 3, -OCHF 2, -OCH 2 F, -OCF 3, -CH 2 OH, -CH 2 CN, -CH 2 CH 2 CN, - NHCH 2 CN, -NHCH 2 CH 2 CN;
  • R 2 is selected from F, -OCHF 2, -OCH 2 F , -OCF 3, -OCH 3, OH, -CH 2 OH, -CH 2 CN, -CH 2 CH 2 CN or - NHCH 2 CH 2 CN;
  • R 2 is selected from F, OH, -CH 2 OH, -CH 2 CN, -NHCH 2 CH 2 CN, or -NHCH 2 CN;
  • R a1 , R a2 , R 2a , R 2b are each independently selected from H, C 1-6 alkyl, C 3-12 carbocyclyl, or 3 to 12 membered heterocyclyl, the alkyl, carbocyclyl or heterocyclyl is further optionally substituted with 0 to 4 (e.g. 2, 3 or 4) selected from H, halo, OH, cyano, NH 2, C 1-6 Alkyl, halogen-substituted C 1-6 alkyl, cyano-substituted C 1-6 alkyl or C 1-6 alkoxy substituent, the heterocyclic group contains 1 to 3 (for example 1, 2 or 3) heteroatoms selected from O, S, N;
  • R a1 , R a2 , R 2a , R 2b are each independently selected from H, C 1-4 alkyl, C 3-10 carbocyclyl, or 3 to 10 membered heterocyclyl, the alkyl, carbocyclyl or heterocyclyl is further optionally substituted with 0 to 4 (e.g. 2, 3 or 4) selected from H, halo, OH, cyano, NH 2, C 1-4 Alkyl, halogen substituted C 1-4 alkyl, cyano substituted C 1-4 alkyl or C 1-4 alkoxy substituent, the heterocyclic group contains 1 to 3 (for example 1, 2 or 3) heteroatoms selected from O, S, N;
  • R a2 is selected from H, C 1-4 alkyl, C 3-6 carbocyclyl or 3- to 6-membered heterocyclyl, said alkyl, carbocyclyl or heterocyclyl being any is further selected from 0 to 4 (e.g. 2, 3 or 4) selected from H, halo, OH, cyano, NH 2, C 1-4 alkyl, halo-substituted C 1-4 alkyl , cyano-substituted C 1-4 alkyl or C 1-4 alkoxy substituent, the heterocyclic group contains 1 to 3 (eg 1, 2 or 3) selected from O, S , N heteroatoms;
  • Ring A is selected from The top is directly connected to L, and the ring B is selected from R 2 is directly connected to the right;
  • q is each independently selected from 0, 1, 2, 3 or 4.
  • L is selected from a bond or NR n2 ;
  • R n1 and R n2 are each independently selected from H, C 1-6 alkyl or C 3-6 cycloalkyl, and the alkyl or cycloalkyl is optionally further substituted by 0 to 4 (eg 0, 1, 2, 3 or 4) are substituted with substituents selected from H, halogen, CF 3 , OH, cyano, NH 2 , C 1-6 alkyl or C 1-6 alkoxy;
  • Ring A is selected from 5-6 membered monocyclic heteroaromatic ring or 8-10 membered heterocyclic heteroaromatic ring, said heteroaromatic ring is optionally further surrounded by 0 to 3 (eg 0, 1, 2 or 3) R a is substituted, and the heteroaromatic ring contains 1 to 5 (eg 1, 2, 3, 4 or 5) heteroatoms selected from O, S, N;
  • 2, 3 or 4 is selected from H , halogen, OH, cyano, NH 2 , NH(C 1-6 alkyl), N(C 1-6 alkyl) 2 , C 1-6 alkyl, halogen-substituted C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl or 3- to 10-membered heterocycle substituents, and the heterocycle contains 1 to 3 (eg 1, 2 or 3) selected from O, Heteroatoms of S and N;
  • Ring B is selected from non-aromatic C 3-12 carbocyclic rings, said carbocyclic rings are optionally selected from monocyclic, paracyclic, bridged or spirocyclic rings, said carbocyclic, monocyclic, paracyclic, bridged or spirocyclic rings ring is optionally further substituted with 0-3 (e.g. 2 or 3) R b;
  • R b is each independently selected from H, halogen, cyano, OH, C 1-6 alkyl or C 1-6 alkoxy, said alkyl or alkoxy optionally further substituted by 0 to 4 (eg 2, 3, or 4) selected from H, halo, OH, cyano, NH 2, C 1-6 alkyl, halo-substituted C 1-6 alkyl, C 1-6 alkoxy, or C 3-6 cycloalkyl substituents are substituted;
  • R 1 is selected from 5- to 10-membered heteroaryl or phenyl, said heteroaryl or phenyl is optionally further substituted by 0 to 4 (eg 0, 1, 2, 3 or 4) R 1a ;
  • R 1a is each independently selected from H, halogen, OH, cyano, NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -NH(C 3-6 ring alkyl), C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl or 3- to 8-membered heterocyclic group, said alkyl, alkoxy, cycloalkyl or heterocyclic group cycloalkyl group optionally further substituted with 0 to 4 (e.g.
  • heterocycle contains 1 to 3 (for example, 1, 2 or 3) heteroatoms selected from O, S, N;
  • R a1 , R a2 , R 2a , R 2b are each independently selected from H, C 1-6 alkyl, C 3-12 carbocyclyl or 3- to 12-membered heterocyclyl, said alkyl, carbocyclyl or heterocyclyl optionally further C substituted with 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, halogen, OH, cyano, NH 2 , C 1-6 alkyl, halogen 1-6 alkyl, cyano-substituted C 1-6 alkyl or C 1-6 alkoxy substituent, the heterocyclic group contains 1 to 3 (eg 1, 2 or 3) Heteroatoms selected from O, S, N;
  • q is each independently selected from 0, 1, 2, 3 or 4.
  • L is selected from NH or NR n2 ;
  • X 1 is selected from CH or N
  • X 2 is selected from bond
  • CH or N is selected from bond
  • CH or N is selected from bond
  • Y and Z are each independently selected from C or N;
  • the condition is that at least one of X 1 , X 2 , Y and Z is selected from N;
  • R n1 and R n2 are each independently selected from H, C 1-4 alkyl or C 3-6 cycloalkyl, and the alkyl or cycloalkyl is optionally further substituted by 0 to 4 (eg 0, 1, 2, 3 or 4) are substituted with substituents selected from H, halogen, CF 3 , OH, cyano, NH 2 , C 1-4 alkyl or C 1-4 alkoxy;
  • Ring C is selected from a 5-6 membered heteroaromatic ring or a benzene ring, and the heteroaromatic ring contains 1 to 3 (eg 1, 2 or 3) heteroatoms selected from O, S, N;
  • 2, 3 or 4 is selected from H , halogen, OH, cyano, NH 2 , NH(C 1-6 alkyl), N(C 1-6 alkyl) 2 , C 1-6 alkyl, halogen-substituted C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl or 3- to 10-membered heterocycle substituents, and the heterocycle contains 1 to 3 (eg 1, 2 or 3) selected from O, Heteroatoms of S and N;
  • Ring B is selected from C 3-8 monocycloalkyl, C 4-10 cycloalkyl, C 4-12 spirocycloalkyl, C 5-12 bridged cycloalkyl, and the cycloalkyl is optionally further 0 to 3 (e.g. 0, 1, 2 or 3) R b substituted;
  • R 1 is selected from The NH in the R 1 group cannot be substituted by R 1a;
  • R 1 is selected from
  • R 1a is each independently selected from H, halogen, OH, cyano, NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -NH(C 3-6 ring alkyl), C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl or 3- to 8-membered heterocyclic group, said alkyl, alkoxy, cycloalkyl or heterocyclic group cycloalkyl group optionally further substituted with 0 to 4 (e.g.
  • R 1b is selected from C 1-6 alkyl or C 3-6 cycloalkyl optionally further selected from 0 to 4 (eg 0, 1, 2, 3 or 4) Substituted from substituents of H, halogen, OH, cyano, NH 2 , halogen substituted C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkoxy or C 3-6 cycloalkyl ;
  • n is selected from 0, 1 or 2;
  • p is selected from 0, 1 or 2;
  • ring B is selected from C 9-10 cycloalkyl, C 9-12 spirocycloalkyl, and C 9-12 bridged cycloalkyl, the said cycloalkyl optionally further substituted with 0-3 (e.g. 2 or 3) R b;
  • the compound is not the following compounds and stereoisomers thereof:
  • R 1a is each independently selected from H, halogen, OH, cyano, NH 2 , -NH(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , -NH(C 3-4 ring alkyl), C 1-4 alkyl or C 1-4 alkoxy, said alkyl or alkoxy optionally further selected from 0 to 4 (eg 0, 1, 2, 3 or 4) Substituted from substituents of H, halogen, OH, cyano, NH 2 , halogen substituted C 1-4 alkyl, C 1-4 alkyl, C 1-4 alkoxy or C 3-6 cycloalkyl ;
  • R 1b is selected from C 1-4 alkyl or C 3-6 cycloalkyl optionally further selected from 0 to 4 (eg 0, 1, 2, 3 or 4) Substituted from substituents of H, halogen, OH, cyano, NH 2 , halogen substituted C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkoxy or C 3-6 cycloalkyl ;
  • Ring C is selected from a 5-6 membered heteroaromatic ring or a benzene ring, and the heteroaromatic ring contains 1 to 3 (eg 1, 2 or 3) heteroatoms selected from O, S, N;
  • 2, 3 or 4 is selected from H , halogen, OH, cyano, NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , C 1-4 alkyl, halogen substituted C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl or substituents of 3 to 6-membered heterocycle, the heterocycle contains 1 to 3 (eg 1, 2 or 3) selected from O, S , N heteroatoms;
  • R b is each independently selected from H, halogen, cyano, OH, C 1-4 alkyl or C 1-4 alkoxy, said alkyl or alkoxy optionally further substituted by 0 to 4 (eg 2, 3, or 4) selected from H, halo, OH, cyano, NH 2, C 1-4 alkyl, halo-substituted C 1-4 alkyl, C 1-4 alkoxy, or C 3-4 cycloalkyl substituents are substituted;
  • R a1 , R a2 , R 2a , R 2b are each independently selected from H, C 1-4 alkyl, C 3-10 carbocyclyl or 3- to 10-membered heterocyclyl, said alkyl, carbocyclyl or heterocyclyl optionally further C substituted with 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, halogen, OH, cyano, NH 2 , C 1-4 alkyl, halogen 1-4 alkyl, cyano-substituted C 1-4 alkyl or C 1-4 alkoxy substituent, the heterocyclic group contains 1 to 3 (for example, 1, 2 or 3) heteroatoms from O, S, N;
  • R n1 and R n2 are each independently selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, the methyl, ethyl, propyl , isopropyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group optionally further substituted with 0 to 4 (e.g. 2, 3 or 4) selected from H, halo, CF 3, substituted by substituents of OH, cyano, NH 2 , C 1-4 alkyl or C 1-4 alkoxy;
  • R 1a is independently selected from H, F, OH, cyano, methyl, ethyl, isopropyl, propyl, methoxy or ethoxy, the methyl, ethyl, isopropyl, propyl, methoxy or ethoxy optionally further substituted with 0 to 4 (e.g. 2, 3 or 4) selected from H, halo, OH, cyano, NH 2, halo-substituted C 1 -4 alkyl, C 1-4 alkyl, C 1- 4 alkoxy or C 3-6 cycloalkyl substituted with a substituent;
  • R 1b is selected from methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, the methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group optionally further substituted with 0 to 4 (e.g. 2, 3 or 4) selected from H, halo, OH, cyano, NH 2, halo-substituted C 1-6 alkyl , C 1-6 alkyl, C 1-6 alkoxy or C 3-6 cycloalkyl substituent;
  • Ring C is selected from pyrazole ring, thiazole ring, imidazole ring, oxazole ring, thiophene ring, furan ring, pyrrole ring, isoxazole ring, isothiazole ring, pyridine ring, pyrazine ring, pyridazine ring, 1,2 ,4-triazole ring, pyrimidine ring or benzene ring;
  • R a2 is selected from H, C 1-4 alkyl, C 3-6 carbocyclyl or 3- to 6-membered heterocyclyl, and the alkyl, carbocyclyl or heterocyclyl is optionally further substituted by 0 to 4 (e.g., 2, 3 or 4) selected from H, halo, OH, cyano, NH 2, C 1- 4 alkyl, halo-substituted C 1-4 alkyl, cyano a C 1 -4 alkyl or C 1-4 alkoxy substituent, the heterocyclic group contains 1 to 3 (eg 1, 2 or 3) heteroatoms selected from O, S, N;
  • Ring B is selected from substituted or unsubstituted one of the following groups: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyl-cyclobutyl, cyclopropyl-cyclopentyl, cyclopropyl- cyclohexyl, cyclobutyl-cyclobutyl, cyclobutyl-cyclopentyl, cyclobutyl-cyclohexyl, cyclopentyl-cyclopentyl, cyclopentyl-cyclohexyl, cyclohexyl-cyclohexyl base, cyclopropylspirocyclobutyl, cyclopropylspirocyclopentyl, cyclopropylspirocyclohexyl, cyclobutylspirocyclobutyl, cyclobutylspirocyclopentyl, cyclobuty
  • R 2 is selected from halogen, cyano, OH, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 carbocycle, 3- to 6-membered heterocycle, -CH 2 -C 3-6 carbocycle , -CH 2 -3 to 6-membered heterocycle, -NH-C 3-6 carbocycle, -NH-3 to 6-membered heterocycle or -NHC 1-4 alkyl, the -CH 2 -, alkyl , alkoxy, carbocyclic or heterocyclic ring is optionally further substituted with 0 to 4 (e.g.
  • heterocycle selected from H, halo, OH, cyano, NH 2, C 1-4 alkyl substituted by substituents of C 1-4 alkyl, halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl or C 1-4 alkoxy, and the heterocycle contains 1 to 3 (for example, 1, 2 or 3) heteroatoms selected from O, S, N;
  • R n1 and R n2 are each independently selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, the methyl, ethyl, propyl , isopropyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group optionally further substituted with 0 to 4 (e.g. 2, 3 or 4) is selected from H, F, CF 3, OH, cyano, NH 2 , methyl, ethyl, methoxy or ethoxy substituents;
  • Ring B is selected from R 2 is directly connected to the right;
  • R 2 is selected from F, cyano, OH, -OCH 3 , -OCHF 2 , -OCH 2 F, -OCF 3 , methyl, ethyl, CF 3 , -CH 2 OH, -CH 2 CH 2 OH, - CH 2 CH 2 CH 2 OH, -CH 2 CN, -CH 2 CH 2 CN, -CH 2 CH 2 CH 2 CN, -CH 2 CH 2 CH 2 CH 2 CN, -NHCH 2 CN, -NHCH 2 CH 2 CN, -NHCH 2 CH 2 CH 2 CN, -NHCH 2 CH 2 CH 2 CH 2 CN, -NHCH 2 CH 2 CH 2 CH 2 CN, -NHCH 2 CH 2 CH 2 CH 2 CN,
  • R 1 is selected from
  • R 1 is selected from
  • R a is each independently selected from H, F, Cl, Br, cyano, OH, methyl, ethyl, propyl, butyl, isopropyl, isobutyl, sec-butyl, tert-butyl, methoxy base, ethoxy, pyrazolyl, thiazolyl, imidazolyl, oxazolyl, thienyl, furyl, pyrrolyl, isoxazolyl, isothienyl, pyridyl, pyrimidinyl, phenyl, cyclopropyl , cyclobutyl, cyclopentyl, cyclohexyl, -NH-pyrazolyl, -NH-thiazolyl, -NH-imidazolyl, -NH-oxazolyl, -NH-thienyl, -NH-furanyl, -NH-pyrrolyl, -NH-isoxazolyl,
  • R a are each independently selected from -CH 2 -azetidinyl, -CH 2 -azepanyl, -CH 2 -azepanyl, -CH 2 -oxetanyl, -CH 2 - oxolanyl, -CH 2 - oxetanyl hexyl, -CH 2 - morpholinyl, -CH 2 - piperazinyl, -CH 2 CH 2 - azetidinyl, -CH 2 CH 2 - azepin-cyclopentyl, -CH 2 CH 2 - azetidin cyclohexyl, -CH 2 CH 2 - oxetanyl, -CH 2 CH 2 - oxetanyl pentyl, -CH 2 CH 2 - oxetanyl Hexyl, -CH 2 CH 2 -morpholinyl, -CH 2 CH 2 -piperazin
  • Ring B is selected from R 2 is directly connected to the right;
  • R 2 is selected from F, OH, -O-CH 3 , -OCHF 2, -OCH 2 F, -OCF 3, -CH 2 OH, -CH 2 CN, -CH 2 CH 2 CN, -NHCH 2 CN, - NHCH 2 CH 2 CN;
  • R 1 is selected from
  • R 1 is selected from
  • R 1 is selected from
  • Ring B is selected from R 2 is directly connected to the right;
  • ring B is selected from
  • R 2 is selected from F, -OCHF 2 , -OCH 2 F, -OCF 3 , -OCH 3 , OH, -CH 2 OH, -CH 2 CN, -CH 2 CH 2 CN or -NHCH 2 CH 2 CN;
  • R n2 is selected from H, methyl
  • Z 1 is selected from N or C(R aa );
  • R aa is selected from H, methyl
  • R 1 is selected from
  • R a is independently selected from H, methyl, ethyl, propyl, butyl, isopropyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, -CH 2 CH 2 EN,
  • methyl, ethyl, propyl, butyl, isopropyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, -CH 2 CH 2 CN are optionally further to 3 (e.g. 1, 2 or 3) selected from F, Cl, Br, CF 3 , OH, cyano, NH 2, NH (CH 3 ), NH (CH 2 CH 3), N (CH 3 ) 2 , N(CH 2 CH 3 ) 2 , methyl, ethyl, methoxy and ethoxy substituents.
  • R 2 is selected from OH, F or -OCHF 2 ;
  • Z 1 is selected from N or C(R aa );
  • R aa is selected from H, F, cyano, methyl, ethyl, cyclopropyl;
  • R 1 is selected from
  • each group is consistent with any one of the first, second, third, fourth, fifth, sixth, seventh, and eighth embodiments of the present invention.
  • X 1 and X 2 are each independently selected from N or CH;
  • X 3 and X 4 are each independently selected from N or CH;
  • X 5 , X 6 , X 7 are each independently selected from O, S, NH, N(R a ), N or CH;
  • X 8 is selected from N or C
  • X 9 and X 10 are each independently selected from O, S, N or CH;
  • At least one of X 1 and X 2 is selected from N;
  • At least one of X 1 , X 2 and X 8 in the general formulae (Ia-5) and (Ia-6) is selected from N;
  • the ring in which the representative is located is aromatic
  • each group is consistent with any one of the second, third, fourth, fifth, sixth, seventh, and eighth embodiments of the present invention.
  • X 1 and X 2 are each independently selected from N or CH;
  • D 1 and D 2 are each independently selected from N or CH;
  • D 3 , D 4 , D 5 are each independently selected from O, S, NH, N(R a ), N or CH;
  • At least one of X 1 and X 2 is selected from N;
  • At least one of X 1 and X 2 is selected from N;
  • the ring in which the representative is located is aromatic
  • the compounds represented by the following general formulae (Iaa) and (Idd) or their stereoisomers, deuterated compounds, solvates, prodrugs, metabolites, and pharmaceutically acceptable salts or eutectic are represented by the following general formulae (Iaa) and (Idd) or their stereoisomers, deuterated compounds, solvates, prodrugs, metabolites, and pharmaceutically acceptable salts or eutectic,
  • each group is consistent with any one of the first, second, third, fourth, fifth, sixth, seventh, and eighth embodiments of the present invention.
  • R n1 is H, R n2 is selected from H, methyl; L is selected from NH, NCH 3 ;
  • Ring A is selected from one of the following groups, substituted or unsubstituted: When substituted, optionally further substituted with 1 to 3 (e.g. 1, 2 or 3) R a;
  • R a is independently selected from C 1-4 alkyl (e.g. methyl, ethyl), halogen (e.g. fluorine, chlorine, bromine), oxolanyl, aza-cyclopentyl, -CH 2 CH 2 - Morpholinyl, pyrazolyl, pyridyl, said C 1-4 alkyl (eg methyl, ethyl), oxolane, azacyclopentyl, pyrazolyl, pyridyl optionally further is 1 to 3 (e.g. 1, 2 or 3) selected from methyl, methoxy, F, Cl, Br, CF 3, OH, cyano, NH 2 substituted with a substituent;
  • C 1-4 alkyl e.g. methyl, ethyl
  • halogen e.g. fluorine, chlorine, bromine
  • oxolanyl aza-cyclopentyl
  • aza-cyclopentyl
  • Ring B is selected from R 2 is directly connected to the right;
  • R 2 is each independently selected from F, OH, -CH 2 OH, -CH 2 CN, -NHCH 2 CH 2 CN or -NHCH 2 CN;
  • R 1 is selected from
  • R n1 is selected from H, R n2 is H, and L is selected from NH, NCH 3 ;
  • Ring A is selected from one of the following groups, substituted or unsubstituted: When substituted, optionally further substituted with 1 to 3 (e.g. 1, 2 or 3) R a;
  • Each R a is independently selected from C 1-4 alkyl (eg methyl, ethyl), halogen (eg fluorine, chlorine, bromine), oxolane, azacyclopentyl, the C 1- 4 alkyl (eg methyl, ethyl), oxolane, azacyclopentyl optionally further selected from methyl, methoxy, F , OH, cyano substituents;
  • Ring B is selected from R 2 is directly connected to the right; Optionally, ring B is substituted with two or three R b;
  • R 2 is each independently selected from OH, -CH 2 CN;
  • R 1 is selected from
  • the present invention relates to a compound shown below, or a stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein the compound has a structure selected from one of the following:
  • the present invention relates to some embodiments of general formula (I), (Ib), (Ic), (Ie), (Ib-1), (Ic-1), (Ie-1), L is selected from bond or NR n2 .
  • L is selected from NRn2 .
  • L is selected from a bond.
  • L is NH or N( CH 3).
  • R n1 , R n2 are each independently selected from the group consisting of H, C 1-6 alkyl or C 3-6 cycloalkyl optionally further selected from H by 0 to 4 (eg 0, 1, 2, 3 or 4) , halogen, CF 3 , OH, cyano, NH 2 , C 1-6 alkyl or C 1-6 alkoxy substituents.
  • R n1 , R n2 is each independently selected from H, C 1-4 alkyl or C 3-6 cycloalkyl, said alkyl or cycloalkyl is optionally further 0 to 4 (eg 0, 1, 2, 3 or 4) substituted with substituents selected from H, halogen, CF 3 , OH, cyano, NH 2 , C 1-4 alkyl or C 1-4 alkoxy.
  • R n1 , R n2 is independently selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, the methyl, ethyl, propyl, isopropyl , cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group optionally further substituted with 0 to 4 (e.g. 2, 3 or 4) selected from H, halo, CF 3, OH, cyano , NH 2 , C 1-4 alkyl or C 1-4 alkoxy substituents.
  • R n1 , R n2 is independently selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, the methyl, ethyl, propyl
  • R n1 , R n2 is independently selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, the methyl, ethyl, propyl, isopropyl , cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group optionally further substituted with 0 to 4 (e.g. 2, 3 or 4) is selected from H, F, CF 3, OH , cyano , NH 2 , methyl, ethyl, methoxy or ethoxy substituents.
  • R n1 is selected from H
  • R n2 is selected from H, methyl, ethyl, propyl, isopropyl.
  • the present invention relates to some embodiments of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (Id-5), (Id-6), R n1 , R n2 is selected from H.
  • R aa is selected from R a .
  • Ring A is selected from a 5-6 membered monocyclic heteroaromatic ring or an 8-10 membered heterocyclic heteroaromatic ring, the heteroaromatic ring is optionally further 3 (eg 0, 1, 2 or 3) R a substitutions, and the heteroaromatic ring contains 1 to 5 (eg 1, 2, 3, 4 or 5) heteroaromatics selected from O, S, N atom.
  • ring A is selected from substituted or unsubstituted 6- and 6-membered fused heteroaryl groups, preferably substituted or unsubstituted one of the following groups: isoquinolinyl, naphthalene Imidyl, pyridopyrazinyl, pyridopyrimidinyl, pyridopyridazinyl, pyridopyridazinyl, pyrimidopyridazinyl, pyrimidopyridazinyl, quinazolinyl, pteridyl, quinoxaline group, pyrimidinyl group, or a dihydro-dihydro-pyrano dioxino pyrimidine group, when substituted, optionally further substituted with 0-3 (e.g. 2 or 3) R a .
  • 0-3 e.g. 2 or 3
  • ring A is selected from substituted or unsubstituted 5 and 6-membered fused heteroaryl groups, preferably substituted or unsubstituted one of the following groups: thienopyrimidinyl or pyridine azolopyrimidyl, benzopyrrolyl, pyrrolopyridyl, imidazopyridyl, triazolopyridyl, imidazopyridazinyl, pyrrolopyrimidyl, pyrazolopyrimidinyl, imidazolopyrimidyl, triazole pyrimidinyl, thienopyrimidinyl, thiazolopyrimidyl, isothiazolopyrimidyl, isoxazolopyrimidyl, isothiazolopyridyl, isoxazolopyridyl, isothiazolopyrazinyl, isoxazole Pyraziny
  • Ring A is selected from one of the following substituted or unsubstituted groups: X 1 is selected from CH or N, X 2 is selected from bond, CH or N, Y and Z are each independently selected from C or N, and ring C is selected from 5-6 membered heteroaromatic ring or benzene ring, the heteroaromatic
  • the ring contains 1 to 3 (eg 1, 2 or 3) heteroatoms selected from O, S, N, optionally further 0 to 3 (eg 0, 1, 2 or 3) R when substituted a replace.
  • Ring A is selected from one of the following substituted or unsubstituted groups: X 1 is selected from CH or N, X 2 is selected from bond, CH or N, Y and Z are independently selected from C or N, and ring C is selected from pyrazole ring, thiazole ring, imidazole ring, oxazole ring, thiophene ring , furan ring, pyrrole ring, isoxazole ring, isothiazole ring, pyridine ring, pyrazine ring, pyridazine ring, 1,2,4-triazole ring, pyrimidine ring or benzene ring, when substituted, any is further selected from substituted with 0-3 (e.g. 2 or 3) R a.
  • the present invention relates to general formulae (Ia), (Ib), (Ic), (Id), (Ie), (Ib-1), (Ic-1), (Id-1), (Ie-1), (
  • X 1 is selected from CH or N
  • X 2 is selected from bond
  • Y and Z are each independently selected from C or N
  • ring C is selected from 5-6 members Heteroaromatic ring or benzene ring
  • the heteroaromatic ring contains 1 to 3 (eg 1, 2 or 3) heteroatoms selected from O, S, N, when substituted, optionally further 0 to 3 (e.g. 2 or 3) R a substituent.
  • the present invention relates to general formulae (Ia), (Ib), (Ic), (Id), (Ie), (Ib-1), (Ic-1), (Id-1), (Ie-1), (In some embodiments of Iaa) and (Idd), X 1 is selected from CH or N, X 2 is selected from bond, CH or N, Y and Z are each independently selected from C or N, and ring C is selected from pyrazole ring, Thiazole ring, imidazole ring, oxazole ring, thiophene ring, furan ring, pyrrole ring, isoxazole ring, isothiazole ring, pyridine ring, pyrazine ring, pyridazine ring, 1,2,4-triazole ring, pyrimidine ring or a benzene ring, when substituted, optionally further substituted with 0-3 (e.g. 2 or 3) R a.
  • 0-3 e
  • Ring A is selected from one of the following substituted or unsubstituted groups:
  • R a When substituted, optionally further substituted with 0-3 (e.g. 2 or 3) R a.
  • Ring A is selected from one of the following substituted or unsubstituted groups: When substituted, it is optionally further substituted with 0 to 3 Ra (eg 0, 1, 2 or 3).
  • Ring A is selected from one of the following substituted or unsubstituted groups: When substituted, optionally further substituted with 0-3 (e.g. 2 or 3) R a.
  • Z or Y are each independently selected from C or N, and ring C is selected from substituted or unsubstituted 5-6 membered heteroaromatic rings or benzene rings.
  • Z or Y are each independently selected from C or N, and ring C is selected from substituted or unsubstituted pyrazole ring, thiazole ring, imidazole ring, oxazole ring , thiophene ring, furan ring, pyrrole ring, isoxazole ring, isothiazole ring, pyridine ring, pyrimidine ring or benzene ring, when substituted, optionally further by 0 to 3 R a (eg 0, 1, 2 or 3) to replace.
  • R a eg 0, 1, 2 or 3
  • the present invention relates to general formulae (I), (Ia), (Ib), (Ic), (Id), (Ie), (Ib-1), (Ic-1), (Id-1), (Ie- 1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Id-2), (Id-3), (Id-4)
  • heterocycle contains 1 to 3 (eg 1, 2 or 3) heteroatoms selected from O, S, N.
  • heterocycle contains 1 to 3 (eg 1, 2 or 3) heteroatoms selected from O, S, N.
  • the present invention relates to general formulae (I), (Ia), (Ib), (Ic), (Id), (Ie), (Ib-1), (Ic-1), (Id-1), (Ie- 1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Id-2), (Id-3), (Id-4)
  • R a is each independently selected from H, F, Cl, Br, cyano, OH, methyl, ethyl propyl, propyl, butyl, isopropyl, methoxy, ethoxy, pyrazolyl, thiazolyl, imidazolyl, oxazolyl, thienyl, furyl, pyrrolyl, isoxazolyl, isothiophene base, pyridyl, pyrimidinyl, phenyl, cyclo
  • the present invention relates to general formulae (I), (Ia), (Ib), (Ic), (Id), (Ie), (Ib-1), (Ic-1), (Id-1), (Ie- 1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Id-2), (Id-3), (Id-4)
  • R a is each independently selected from H, F, Cl, Br, cyano, OH, methyl, ethyl base, propyl, butyl, isopropyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, pyrazolyl, thiazolyl, imidazolyl, oxazolyl, thienyl, furan base, pyrrolyl, isoxazolyl, isothienyl, pyrid
  • the present invention relates to general formulae (I), (Ia), (Ib), (Ic), (Id), (Ie), (Ib-1), (Ic-1), (Id-1), (Ie- 1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Id-2), (Id-3), (Id-4)
  • R a is each independently selected from -CH 2 -azetidinyl, -CH 2 -azetidine Amyl, -CH 2 -azepinyl, -CH 2 -oxetanyl, -CH 2 -oxolane, -CH 2 -oxane, -CH 2 -morpholinyl, - CH 2 -piperazinyl, -CH 2 CH 2 -azetidine, -CH 2 CH 2 -azepanyl, -CH
  • the present invention relates to general formulae (I), (Ia), (Ib), (Ic), (Id), (Ie), (Ib-1), (Ic-1), (Id-1), (Ie- 1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Id-2), (Id-3), (Id-4)
  • R a is independently selected from H, methyl, ethyl, propyl, butyl, isopropyl, , cyclopropyl, cyclobutyl, -CH 2 CH 2 CN,
  • R a is independently selected from H, methyl, ethyl, propyl, butyl, isopropyl, , isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, -CH 2 CH 2 CN, The methyl, ethyl, propyl, butyl, isopropyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, -CH 2 CH 2 CN, The methyl, ethyl, propyl, butyl, isopropyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, -
  • the present invention relates to general formulae (I), (Ia), (Ib), (Ic), (Id), (Ie), (Ia-3), (Ia-4), (Ia-5), (Ia- In some embodiments of 6), (Id-3), (Id-4), (Id-5) (Iaa), (Idd), Ring B is selected from non-aromatic C 3-12 carbocycles, said The carbocyclic ring is optionally selected from monocyclic, paracyclic, bridged or spirocyclic rings, and the carbocyclic, monocyclic, paracyclic, bridged or spirocyclic rings are optionally further substituted by 0 to 3 (eg 0, 1, 2 or 3) R b substituted.
  • the present invention relates to general formulae (I), (Ia), (Ib), (Ic), (Id), (Ie), (Ia-2), (Ia-3), (Ia-4), (Ia- In some embodiments of 5), (Ia-6), (Id-3), (Id-4), (Id-5), (Iaa), (Idd), Ring B is selected from C 3-8 monocyclic alkyl, C 4- 10 alkyl and cycloalkyl, C 4-12 spiro cycloalkyl, C 5-12 bridged cycloalkyl, said cycloalkyl being optionally further 0-3 (e.g., 0, 1, 2 or 3) R b substituted.
  • the present invention relates to general formulae (I), (Ia), (Ib), (Ic), (Id), (Ie), (Ia-3), (Ia-4), (Ia-5), (Ia- In some embodiments of 6), (Id-3), (Id-4), (Id-5), (Iaa), (Idd), Ring B is selected from C 3-8 monocycloalkyl, C 8- 10 -cycloalkyl, C 8-12 spirocycloalkyl, C 8-12 bridged cycloalkyl, optionally further 0 to 3 (eg 0, 1, 2 or 3) R replaced by b.
  • Ring B is selected from C 3-8 monocycloalkyl, C 9-10 p-cycloalkyl, C 9-12 spirocycloalkyl, C 9-12 bridged cycloalkyl, optionally further 0 to 3 (eg 0, 1, 2 or 3) R b replaced.
  • the present invention relates to general formulae (I), (Ia), (Ib), (Ic), (Id), (Ie), (Ia-3), (Ia-4), (Ia-5), (Ia- In some embodiments of 6), (Id-3), (Id-4), (Id-5), (Iaa), (Idd), Ring B is selected from C 5-7 monocycloalkyl, C 9- 10 -cycloalkyl, C 9-12 spirocycloalkyl, C 9-12 bridged cycloalkyl, optionally further 0 to 3 (eg 0, 1, 2 or 3) R replaced by b.
  • Ring B is selected from C 5 monocycloalkyl, C 6 monocycloalkane group, C 7 monocycloalkyl, C 6 no cycloalkyl, C 7 no cycloalkyl, C 8 no cycloalkyl, C 9 no cycloalkyl, C 10 no cycloalkyl, C 6 spirocycloalkyl , C 7 spiro cycloalkyl, C 8 spiro cycloalkyl, C 9 spiro cycloalkyl, C 10 spiro cycloalkyl group, C 11 spiro cycloalkyl group, C 12 spiro cyclo
  • Ring B is selected from one of the following substituted or unsubstituted groups: Ring propyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyl-cyclobutyl, cyclopropyl-cyclopentyl, cyclopropyl-cyclohexyl, cyclobutyl-cyclobutyl, cyclobutyl- Cyclopentyl, cyclobutyl-cyclohexyl, cyclopentyl-cyclopentyl, cyclopentyl-cyclohexyl, cyclohexyl-cyclohexyl, cyclohexyl-cyclohexyl, cyclohexyl-cyclohexyl, cyclocyclohexyl, cyclohexyl, cyclohexyl, cyclohexyl, cyclohexyl, cyclohexyl, cyclohe
  • Ring B is selected from And R 2 is directly connected to the right side.
  • Ring B is selected from And R 2 is directly connected to the right side.
  • Ring B is selected from And R 2 is directly connected to the right side.
  • Ring B is selected from And R 2 is directly connected to the right side.
  • each R b is independently selected from H, halogen, cyano, OH, C 1-6 alkyl or C 1-6 alkoxy, said alkyl or alkoxy optionally further selected from 0 to 4 (eg 0, 1, 2, 3 or 4) H, halogen , OH, cyano, NH 2, C 1-6 alkyl, halo-substituted C 1-6 alkyl, C 1- 6 alkoxy group or C 3-6 cycloalkyl substituted with a substituent group.
  • each R b is independently selected from H, halogen, cyano, OH, C 1-4 alkyl or C 1-4 alkoxy, said alkyl or alkoxy optionally further selected by 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, halogen , OH, cyano, NH 2, C 1-4 alkyl, halo-substituted C 1-4 alkyl, C 1- 4 alkoxy or C 3-4 cycloalkyl substituted with a substituent group.
  • each R b is independently selected from H, halogen, cyano, OH, C 1-4 alkyl or C 1-4 alkoxy.
  • each R b is independently selected from H, F, cyano, OH, Methyl, ethyl, methoxy, ethoxy or hydroxymethyl.
  • the present invention relates to general formulae (I), (Ia), (Ib), (Ic), (Id), (Ie), (Ia-1), (Ib-1), (Ic-1), (Id- 1), (Ie-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Id-2), (Id-3)
  • R 1 is selected from 5- to 10-membered heteroaryl or phenyl, said Heteroaryl or phenyl is optionally further substituted with 0 to 4 R 1a .
  • the present invention relates to general formulae (I), (Ia), (Ib), (Ic), (Id), (Ie), (Ia-1), (Ib-1), (Ic-1), (Id- 1), (Ie-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Id-2), (Id-3)
  • R 1 is selected from substituted or unsubstituted one of the following groups: selected from 5- to 6-membered monocyclic heterocyclic Aryl, 6- and 6-membered heteroaryl, 5- and 6-membered heteroaryl, or phenyl, when substituted, are optionally further substituted with 0 to 4 R 1a .
  • R 1 is selected from substituted or unsubstituted one of the following groups: pyridyl, pyrimidine base, pyrazinyl, pyridazinyl, pyrazolyl, pyrrolyl, imidazolyl, thienyl, furyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, benzopyrazolyl, benzoyl Pyrrolyl, benzimidazolyl, benzothien
  • the present invention relates to general formulae (I), (Ia), (Ib), (Ic), (Id), (Ie), (Ia-1), (Ib-1), (Ic-1), (Id- 1), (Ie-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Id-2), (Id-3)
  • R 1 is selected from The NH in the R 1 group cannot be substituted by R 1a and m is selected from 0, 1 or 2.
  • the present invention relates to general formulae (I), (Ia), (Ib), (Ic), (Id), (Ie), (Ia-1), (Ib-1), (Ic-1), (Id- 1), (Ie-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Id-2), (Id-3)
  • R 1 is selected from m is selected from 0, 1 or 2.
  • the present invention relates to general formulae (I), (Ia), (Ib), (Ic), (Id), (Ie), (Ia-1), (Ib-1), (Ic-1), (Id- 1), (Ie-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Id-2), (Id-3)
  • R 1 is selected from
  • the present invention relates to general formulae (I), (Ia), (Ib), (Ic), (Id), (Ie), (Ia-1), (Ib-1), (Ic-1), (Id- 1), (Ie-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Id-2), (Id-3)
  • R 1 is selected from m is selected from 0, 1 or 2.
  • the present invention relates to general formulae (I), (Ia), (Ib), (Ic), (Id), (Ie), (Ia-1), (Ib-1), (Ic-1), (Id- 1), (Ie-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Id-2), (Id-3)
  • R 1b is selected from C 1-6 alkyl or C 3-6 cycloalkyl , the alkyl or cycloalkyl is optionally further substituted by 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, halogen, OH, cyano, NH 2 , halogen substituted C 1 -6 alkyl, C 1-6 alkyl, C 1-6 alkoxy or C 3-6 cycloalkyl substituent.
  • the present invention relates to general formulae (I), (Ia), (Ib), (Ic), (Id), (Ie), (Ia-1), (Ib-1), (Ic-1), (Id- 1), (Ie-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Id-2), (Id-3)
  • R 1b is selected from C 1-4 alkyl or C 3-6 cycloalkyl , the alkyl or cycloalkyl is optionally further substituted by 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, halogen, OH, cyano, NH 2 , halogen substituted C 1 -6 alkyl, C 1-6 alkyl, C 1-6 alkoxy or C 3-6 cycloalkyl substituent.
  • the present invention relates to general formulae (I), (Ia), (Ib), (Ic), (Id), (Ie), (Ia-1), (Ib-1), (Ic-1), (Id- 1), (Ie-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Id-2), (Id-3)
  • R 1b is selected from methyl, ethyl, isopropyl, cyclopropyl, Cyclobutyl, cyclopentyl or cyclohexyl, said methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl are optionally further substituted by 0 to 4 (eg 0, 2, 3 or 4) selected from H, halo, OH, cyano, NH
  • the present invention relates to general formulae (I), (Ia), (Ib), (Ic), (Id), (Ie), (Ia-1), (Ib-1), (Ic-1), (Id- 1), (Ie-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Id-2), (Id-3)
  • R 1 is selected from
  • the present invention relates to general formulae (I), (Ia), (Ib), (Ic), (Id), (Ie), (Ia-1), (Ib-1), (Ic-1), (Id- 1), (Ie-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Id-2), (Id-3)
  • R 1 is selected from
  • the present invention relates to general formulae (I), (Ia), (Ib), (Ic), (Id), (Ie), (Ia-1), (Ib-1), (Ic-1), (Id- 1), (Ie-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Id-2), (Id-3)
  • R 1 is selected from
  • the present invention relates to general formulae (I), (Ia), (Ib), (Ic), (Id), (Ie), (Ia-1), (Ib-1), (Ic-1), (Id- 1), (Ie-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Id-2), (Id-3)
  • R 1 is selected from
  • each R 1a is independently selected from H, halogen, OH, cyano, NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -NH(C 3-6 cycloalkyl), C 1-6 alkyl, C 1-6 alkoxy , C 3-6 cycloalkyl or 3- to 8-membered heterocyclic group, the alkyl, alkoxy, cycloalkyl or heterocyclic group is optionally further replaced by 0
  • each R 1a is independently selected from H, halogen, OH, cyano, NH 2 , -NH(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , -NH(C 3-4 cycloalkyl), C 1-4 alkyl or C 1-4 alkoxy , the alkyl or alkoxy group is optionally further substituted by 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, halogen, OH, cyano, NH 2 ,
  • each R 1a is independently selected from H, F, OH, cyano, methyl , ethyl, isopropyl, propyl, methoxy or ethoxy, the methyl, ethyl, isopropyl, propyl, methoxy or ethoxy optionally further replaced by 0 to 4 (e.g., 2, 3 or 4) selected from H, halo, OH, cyano, NH 2, halo-substituted C 1-4 alkyl,
  • heterocyclic ring contains 1 to 3 (eg 1, 2 or 3) heteroatoms selected from O, S, N.
  • the present invention relates to general formulae (I), (Ia), (Ib), (Ic), (Id), (Ie), (Ia-1), (Ib-1), (Ic-1), (Id- 1), (Ie-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Id-2), (Id-3)
  • R 2 is selected from halogen, cyano, OH, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 carbocycle, 3- to 6-membered heterocycle, -CH 2 -C 3-6 carbocycle, -CH 2 -3- to 6-membered heterocycle, -NH-C 3- 6- carbocycle, -NH-3 to 6-membered heterocycle or -NHC 1-4 alkyl, said -CH 2 -, alkyl, alkoxy, carbocycle or heterocycle is
  • R 2 is selected from one of the following groups, substituted or unsubstituted: F., cyano, OH, methyl, ethyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH 2 - cyclopropyl, -CH 2 - cyclobutoxy , -CH 2 -cyclopentyl, -CH 2 -cyclohexyl,
  • R 2 is selected from one of the following groups, substituted or unsubstituted: F., cyano, OH, methyl, ethyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH 2 - cyclopropyl, -CH 2 - cyclobutoxy , -CH 2 -cyclopentyl, -CH 2 -cyclohexyl,
  • 2, 3 or 4 is selected from H, F, OH, cyano, NH 2, methyl, ethyl, CF 3 , -CH 2 CN, -CH 2 CH 2 CN, -CH 2 CH 2 CH 2 CN, methoxy or ethoxy substituent.
  • R 2 is selected from F, cyano, OH, -OCHF 2 , - OCH 2 F, -OCF 3, -OCH 3, methyl, ethyl, CF 3, -CH 2 OH, -CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH, -CH 2 CN, -CH 2 CH 2 CN, -CH 2 CH 2 CH 2 CN, -CH 2 CH 2 CH 2 CH 2 CN, -NHCH 2 CN, -NHCH
  • R 2 is selected from F, OH, -OCH 3 , -OCHF 2 , -OCH 2 F, -OCF 3, -CH 2 OH, -CH 2 CN, -CH 2 CH 2 CN, -NHCH 2 CN, -NHCH 2 CH 2 CN.
  • R a1 , R a2 , R 2a , R 2b are each independently selected from H, C 1-6 alkyl, C 3-12 carbocyclyl or 3- to 12-membered heterocyclyl, said alkyl, carbocyclyl or heterocyclyl optionally further replaced by 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, halogen, OH, cyano, NH 2 , C 1-6 alkyl, halogen substituted C 1-6 alkyl, cyan
  • R a1 , R a2 , R 2a , R 2b are each independently selected from H, C 1-4 alkyl, C 3-10 carbocyclyl or 3- to 10-membered heterocyclyl, said alkyl, carbocyclyl or heterocyclyl optionally further replaced by 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, halogen, OH, cyano, NH 2 , C 1-4 alkyl, halogen substituted C 1-4 alkyl, cyan
  • R a2 is selected from H, C 1-4 alkyl, C 3- 6 carbocyclyl or 3 to 6 membered heterocyclyl, said alkyl, carbocyclyl or heterocyclyl optionally further selected from H by 0 to 4 (eg 0, 1, 2, 3 or 4) , halogen, OH, cyano, NH 2 , C 1-4 alkyl, halogen substituted C 1-4 alkyl, cyano substituted C 1-4 alkyl or C 1-4 alkoxy substituent
  • the present invention relates to general formulae (I), (Ia), (Ib), (Ic), (Id), (Ie), (Ib-1), (Ic-1), (Id-1), (Ie- 1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Id-3), (Id-4), (Id-5) , (Id-6), (Iaa), (Idd), q are each independently selected from 0, 1, 2, 3 or 4.
  • the present invention relates to general formulae (Ia), (Ib), (Ic), (Id), (Ie), (Ib-1), (Ic-1), (Id-1), (Ie-1), ( Id-3), (Id-4), (Iaa), (Idd), m is selected from 0, 1 or 2, and p is selected from 0, 1 or 2.
  • the present invention relates to some embodiments of general formula (Ic), selected from When S 1 or S 2 are each independently selected from N or CR a , ring B is selected from C 9-10 cycloalkyl, C 9-12 spirocycloalkyl, and C 9-12 bridged cycloalkyl, the said Cycloalkyl is optionally further substituted with 0 to 3 (eg, 0, 1, 2 or 3) R b .
  • the present invention relates to some embodiments of general formula (Ic), selected from When S 1 or S 2 are independently selected from N or CR a , ring B is selected from And R 2 is directly connected to the right side.
  • ring B is selected from one of the following substituted or unsubstituted groups: cyclobutyl-cyclohexyl, cyclopentyl-cyclopentyl, cyclopentyl cyclohexyl, cyclohexyl cyclohexyl, cyclopentylspirocyclopentyl, cyclopentylspirocyclohexyl, cyclohexylspirocyclohexyl, bicyclo[2.2.2]octyl, bicyclo[3.2 .1]octyl, bicyclo[3.3.3]undecyl or adamantyl, when substituted, optionally further 0 to 3 (eg 0, 1, 2 or 3) selected from H, Substituents of halogen, cyano, OH, C 1-4 al
  • the present invention relates to some embodiments of general formula (Ia), (Iaa), (Ia-2), selected from
  • the present invention relates to some embodiments of general formula (Ia), (Iaa), (Ia-2), selected from
  • the present invention relates to some embodiments of general formula (Ib), (Ib-1), selected from
  • the present invention relates to some embodiments of general formula (Ic), (Ic-1), selected from
  • the present invention relates to some embodiments of general formula (Id), (Idd), (Id-1), selected from
  • the present invention relates to some embodiments of general formula (Id), (Idd), (Id-1), selected from
  • the present invention relates to some embodiments of general formula (Id), (Idd), (Id-1), selected from
  • the present invention relates to some embodiments of general formula (Id), (Idd), (Id-1), selected from
  • the present invention relates to some embodiments of general formula (Id), (Idd), (Id-1), selected from
  • the present invention relates to some embodiments of general formula (Id), (Idd), (Id-1), selected from
  • the present invention relates to some embodiments of general formula (Ie), (Ie-1), selected from
  • the present invention relates to some embodiments of the general formula (Id), (Idd), (Id-1), (Id-3), (Id-4), (Id-5), the compound is not the following compound and its stereo isomer:
  • the compounds are not the following compounds and their stereo isomer:
  • pharmaceutically acceptable salts include but are not limited to trifluoroacetic acid salts.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising any of the above compounds or their stereoisomers, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals, and a pharmaceutically acceptable carrier.
  • the present invention relates to any of the above-mentioned compounds or their stereoisomers, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals in the preparation of medicaments for the treatment of diseases related to JAK kinase activity or expression Applications.
  • the disease is an inflammatory disease.
  • the present invention provides a method of preventing or treating a disease associated with JAK kinase activity or expression level, such as those described above, comprising the steps of: adding a preventive or therapeutically effective amount of the The compound, or a stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, or a pharmaceutical composition thereof, is administered to an individual in need thereof.
  • the term "individual” refers to a human or non-human animal.
  • references and monographs in the field detail the synthesis of reactants useful in the preparation of the compounds described herein, or provide references for articles describing such preparations. These references and monographs include: “Synthetic Organic Chemistry,” John Wiley & Sons, Inc., New York; SRSandler et al., “Organic Functional Group Preparations,” 2nd Ed., Academic Press, New York, 1983; HOHouse, “Modern Synthetic Reactions", 2nd Ed., WA Benjamin, Inc. Menlo Park, Calif. 1972; TLGilchrist, “Heterocyclic Chemistry", 2nd Ed., John Wiley & Sons, New York, 1992; J.
  • the compound of the present invention can be prepared by the following scheme:
  • X is selected from Cl, Br, I, OTs (p-toluenesulfonyl) or besylate;
  • PG is selected from amine protecting group, hydroxyl protecting group, preferably R 1 , R 2 , have the same definitions as the substituents in the compound represented by the general formula (I);
  • the compound of general formula (M-1) is converted into the compound of general formula (M-2) by conventional nucleophilic substitution reaction; the compound of general formula (M-2) is then obtained by nucleophilic substitution reaction or coupling reaction to obtain the compound of general formula (M- 3) Compound; the compound of general formula (M-3) is obtained by deprotection reaction to obtain the compound of general formula (Ia-1).
  • R 1 , R 2 , Z, Y and ring C have the same definitions as the substituents in the compound represented by the general formula (Id);
  • the compound of general formula (N-1) is converted into the compound of general formula (N-2) through conventional nucleophilic substitution reaction; the compound of general formula (N-2) is obtained by nucleophilic substitution reaction or coupling reaction to obtain the compound of general formula (Id- 2) Compounds.
  • Carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, I involved in the groups and compounds of the present invention all include their isotopic conditions, that is, the carbons involved in the groups and compounds of the present invention , hydrogen, oxygen, sulfur or nitrogen are optionally further replaced by one or more of their corresponding isotopes, wherein isotopes of carbon include 12 C, 13 C and 14 C, and isotopes of hydrogen include protium (H), deuterium (D, Also known as heavy hydrogen), tritium (T, also known as super-heavy hydrogen), the isotopes of oxygen include 16 O, 17 O and 18 O, the isotopes of sulfur include 32 S, 33 S, 34 S and 36 S, and the isotopes of nitrogen include 14 N and 15 N, fluorine isotopes include 17 F and 19 F, chlorine isotopes include 35 Cl and 37 Cl, and bromine isotopes include 79 Br and 81 Br.
  • isotopes of carbon include 12 C, 13
  • Halogen means F, Cl, Br or I.
  • Alkyl refers to a straight or branched chain saturated aliphatic hydrocarbon group of 1 to 20 carbon atoms, preferably an alkyl group of 1 to 8 carbon atoms, more preferably an alkyl group of 1 to 6 carbon atoms, even more preferably is an alkyl group of 1 to 4 carbon atoms.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl and its various branched chain isomers; the alkyl group can be optionally further selected from 0 to 6 groups selected from F, Cl, Br, I, hydroxyl, mercapto, nitro, cyano, amino, alkylamino, Amido, alkenyl, alkynyl, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, 3- to 8-membered carbocyclyl, 3- to 8-membered heterocyclyl, 3 to 8-membered Substituents substituted by 8-membered carbocyclyloxy, 3- to 8-membered heterocyclyloxy, carboxyl
  • Alkylene refers to linear and branched divalent saturated hydrocarbon groups, including -(CH 2 ) v - (v is an integer from 1 to 10).
  • alkylene include but are not limited to methylene, methylene Ethyl, propylene and butylene, etc.; the alkylene group can be optionally further selected from 0 to 5 groups selected from F, Cl, Br, I, hydroxyl, mercapto, nitro, cyano, amino, alkyl Substituted by amino, alkenyl, alkynyl, alkyl, hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, carbocyclyloxy, heterocyclyloxy, carboxyl or carboxylate substituents . Alkylene groups appearing herein are defined in accordance with this definition.
  • Cycloalkyl refers to a monovalent saturated carbocyclic hydrocarbon group, usually having 3 to 10 carbon atoms, non-limiting examples including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, and the like.
  • the cycloalkyl group can be optionally further selected from 0 to 5 groups selected from F, Cl, Br, I, hydroxyl, mercapto, nitro, cyano, amino, alkylamino, alkenyl, alkynyl, alkyl, Substituents of hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, carbocyclyloxy, heterocyclyloxy, carboxyl or carboxylate. Cycloalkyl groups appearing herein are defined in accordance with this definition.
  • alkenyl refers to linear and branched monovalent unsaturated hydrocarbon groups, which have at least 1, usually 1, 2 or 3 carbon-carbon double bonds, and the main chain includes 2 to 10 carbon atoms, more preferably 2 to 6 carbon atoms, more preferably 2 to 4 carbon atoms in the backbone
  • alkenyl groups include but are not limited to vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl , 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2- Methyl-1-butenyl, 2-methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-Methyl-1-pentenyl, 2-methyl-1-pentenyl, 1-heptenyl, 2-heptenyl, 3-he
  • Alkynyl refers to linear and branched monovalent unsaturated hydrocarbon groups, which have at least 1, usually 1, 2 or 3 carbon-carbon triple bonds, and the main chain includes 2 to 10 carbon atoms, more preferably 2 to 6 carbon atoms, more preferably 2 to 4 carbon atoms in the backbone
  • alkynyl groups include, but are not limited to, ethynyl, propargyl, 1-propynyl, 2-propynyl, 1-butynyl Alkynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-1-butynyl, 2-Methyl-1-butynyl, 2-methyl-3-butynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl base,
  • Alkoxy refers to -O-alkyl. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexyloxy, cyclopropyl oxy and cyclobutoxy.
  • the alkoxy group can be optionally further selected from 0 to 5 groups selected from F, Cl, Br, I, hydroxyl, mercapto, nitro, cyano, amino, alkylamino, alkenyl, alkynyl, alkyl, Substituents of hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, carbocyclyloxy, heterocyclyloxy, carboxyl or carboxylate. Alkoxy groups appearing herein are defined in accordance with this definition.
  • Carbocyclyl or “carbocycle” refers to a substituted or unsubstituted saturated or unsaturated aromatic or non-aromatic ring, which may be a 3- to 8-membered monocyclic, 4- to 12-membered A bicyclic or 10- to 15-membered tricyclic ring system, the carbocyclic group can be attached to an aromatic ring or a non-aromatic ring, and the aromatic or non-aromatic ring is optionally monocyclic, bridged or spirocyclic.
  • Heterocyclyl or “heterocycle” refers to a substituted or unsubstituted saturated or unsaturated aromatic or non-aromatic ring
  • the aromatic or non-aromatic ring may be a 3- to 8-membered monocyclic, 4- to 12-membered Bicyclic or 10- to 15-membered tricyclic ring system, and contains 1 to 3 heteroatoms selected from N, O or S, preferably a 3- to 8-membered heterocyclic group, the N, S optionally substituted in the ring of the heterocyclic group can be oxidized into various oxidation states.
  • the heterocyclyl group can be attached to a heteroatom or a carbon atom, the heterocyclyl group can be attached to an aromatic ring or a non-aromatic ring, the heterocyclyl group can be attached to a bridged ring or a spiro ring, non-limiting examples include oxirane , azetidine, oxetanyl, azetidine, 1,3-dioxolane, 1,4-dioxolane, 1,3-dioxanyl, nitrogen Heterocycloheptyl, pyridyl, furanyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpho Linyl, 1,3-Dithiyl, Dihydrofuranyl, Dihydropyranyl, Dithiopenyl
  • R a and R d are each independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclyl, carbonyl, ester, bridged, spiro, or bicyclyl.
  • the spiro rings appearing herein are defined in accordance with this definition.
  • Paracyclic refers to a polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain zero or more double bonds, and may be
  • Non-limiting examples include:
  • R a and R d are each independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclyl, carbonyl, ester, bridged, spiro, or bicyclyl. Conjunctions appearing in this document are defined in accordance with this definition.
  • the ring atoms contain 5 to 20 atoms, preferably 5 to 14 atoms, more preferably 5 to 12 atoms, still more preferably 5 to 10 atoms.
  • Non-limiting examples include and adamantane.
  • R a and R d are each independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclyl, carbonyl, ester, bridged, spiro, or bicyclyl. Bridged rings appearing herein are defined in accordance with this definition.
  • Carbospiro refers to a “spirocycle” in which the ring system consists of only carbon atoms.
  • Carbospiro refers to a "spirocycle” in which the ring system consists of only carbon atoms.
  • Carbocyclyl refers to a “carbocyclyl” in which the ring system consists of only carbon atoms.
  • the occurrences of “carbocyclyl”, “carbocyclyl”, “carbocyclyl” or “carbocyclyl” herein are defined in accordance with the present definitions.
  • Carbon-bridged ring refers to a “bridged ring” in which the ring system consists only of carbon atoms.
  • “Carbon-bridged ring”, “bridged-ring carbocyclyl”, “bridged carbocyclyl” or “carbon-bridged cyclyl” appearing herein are defined in accordance with this definition.
  • Heterocyclyl refers to a “heterocyclyl” or “heterocycle” of a monocyclic ring system, heterocyclyl, “monocyclic heterocyclyl” appearing herein group” or “heteromonocyclyl”, as defined herein.
  • Heterocyclyl refers to a “heterocyclyl” containing a heteroatom.
  • heterocyclyl refers to a “heterocyclyl” containing a heteroatom.
  • Heterospirocycle refers to a “spirocycle” containing a heteroatom.
  • heterospirocycle refers to a “spirocycle” containing a heteroatom.
  • Heterobridged ring refers to a “bridged ring” containing a heteroatom. Heterobridged rings, “heterobridged cyclyl” or “bridged heterocyclyl” appearing herein are as defined herein.
  • R a and R d are each independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclyl, carbonyl, ester, bridged, spiro, or bicyclyl.
  • Aryl groups or aromatic rings appearing herein are defined in accordance with this definition.
  • heteroaryl groups include, but are not limited to, pyridyl, furyl, thienyl, pyridyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, Benzopyrazole, benzimidazole, benzopyridine, pyrrolopyridine, etc.
  • the heteroaryl ring can be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring linked to the parent structure is a heteroaryl ring, non-limiting examples include
  • R a and R d are each independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclyl, carbonyl, ester, bridged, spiro, or bicyclyl.
  • Heteroaryl groups appearing herein are defined in accordance with this definition.
  • Constant 1 to 4 heteroatoms selected from O, S, N means containing 1, 2, 3 or 4 heteroatoms selected from O, S, N.
  • Substituted with 0 to X substituents means substituted with 0, 1, 2, 3 . . . X substituents, and X is selected from any integer between 1 and 10.
  • substituted with 0 to 4 substituents means substituted with 0, 1, 2, 3 or 4 substituents.
  • substituted with 0 to 5 substituents means substituted with 0, 1, 2, 3, 4 or 5 substituents.
  • heterobridged ring is optionally further substituted with 0 to 4 substituents selected from H or F” means that the heterobridged ring is optionally further substituted with 0, 1, 2, 3 or 4 substituents selected from H or F base substituted.
  • the ring of XY members (X is selected from an integer less than Y and greater than or equal to 3, and Y is selected from any integer between 4 and 12) includes X+1, X+2, X+3, X+4....Y-membered ring ring.
  • Rings include heterocycles, carbocycles, aromatic rings, aryl, heteroaryl, cycloalkyl, heteromonocycles, heterocycles, heterospirocycles, or heterobridged rings.
  • 4--7 membered heteromonocycle refers to a 4-membered, 5-membered, 6-membered or 7-membered heteromonocycle
  • 5--10 membered heterocyclic ring refers to 5-membered, 6-membered, 7-membered, 8-membered , 9- or 10-membered heterocyclic ring.
  • alkyl optionally substituted by F means that the alkyl group may but not necessarily be substituted by F, and the description includes the case where the alkyl group is substituted by F and the case where the alkyl group is not substituted by F.
  • “Pharmaceutically acceptable salt” means that a compound of the present invention retains the biological availability and properties of a free acid or free base, and said free acid is passed through with a non-toxic inorganic or organic base, or said free base Salts obtained by reaction with non-toxic inorganic or organic acids.
  • “Pharmaceutical composition” refers to one or more of the compounds of the present invention, their stereoisomers, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals, in combination with other chemical groups A mixture of components, wherein “other chemical components” refers to a pharmaceutically acceptable carrier, excipient, and/or one or more other therapeutic agents.
  • Carrier refers to a material that is not appreciably irritating to the organism and that does not abrogate the biological activity and properties of the administered compound.
  • a “prodrug” refers to a compound of the present invention that can be metabolized in vivo into a biologically active compound.
  • the prodrugs of the present invention are prepared by modifying the amino or carboxyl groups in the compounds of the present invention, and the modification can be removed by conventional operations or in vivo to obtain the parent compound.
  • the prodrugs of the present invention are administered to a mammalian subject, the prodrugs are cleaved to form free amino or carboxyl groups.
  • Co-crystal refers to a crystal formed by the combination of an active pharmaceutical ingredient (API) and a co-crystal former (CCF) under the action of hydrogen bonds or other non-covalent bonds, wherein the pure states of API and CCF are both at room temperature solid, and there is a fixed stoichiometric ratio between the components.
  • a co-crystal is a multicomponent crystal that includes both binary co-crystals formed between two neutral solids and multi-component co-crystals formed between neutral solids and salts or solvates.
  • Steps refer to isomers resulting from different arrangements of atoms in a molecule in space, including cis-trans isomers, enantiomers and conformational isomers.
  • a “deuterated compound” is a product in which hydrogen in the molecule of a compound is replaced by its isotope deuterium.
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • HPLC HPLC-based high pressure liquid chromatograph
  • the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the size of the silica gel plate used for thin layer chromatography (TLC) is 0.15mm-0.20mm, and the specification used for TLC separation and purification products is 0.4mm -0.5mm;
  • the known starting materials of the present invention can be synthesized by using or according to methods known in the art, or can be purchased from Titan Technology, Annagy Chemical, Shanghai Demer, Chengdu Kelong Chemical, Shaoyuan Chemical Technology, Bailingwei Technology, etc. company;
  • reaction solution was poured into water (40 mL), extracted with ethyl acetate (30 mL*2), the organic phases were combined, backwashed with saturated brine (30 mL*2), dried over anhydrous sodium sulfate, filtered with suction, and the filtrate was spun under reduced pressure.
  • Preparation method the crude product is dissolved in methanol, and filtered with a 0.45 ⁇ m filter membrane to prepare a sample solution.
  • Mobile phase system acetonitrile/water (with 0.5% trifluoroacetic acid).
  • Gradient elution method acetonitrile was eluted from 10% gradient to 60% (elution time 16min), cis-4-[[7-[(5-methyl-1H-pyrazol-3-yl)amino group was obtained after lyophilization ]-1,6-Naphthyridin-5-yl]amino]adamantan-1-ol; 2,2,2-trifluoroacetate (Compound 1-1) (60 mg, 74%),
  • reaction solution was poured into water (40 mL), the pH was adjusted to about 5 with dilute hydrochloric acid (1N), and extracted with ethyl acetate (50 mL*3); the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • Step 4 cis-4-[[7-[[5-(hydroxymethyl)-1H-pyrazol-3-yl]amino]-1,6-naphthyridin-5-yl]amino]adamantane- 1-Alcohol; 2,2,2-Trifluoroacetate (Compound 2)
  • the first step trans-4-[((7-chloro-1,6-naphthyridin-5-yl)amino]adamantan-1-ol (3b)
  • Trans-4-amino-1-hydroxyadamantane hydrochloride (224.08 mg, 1.10 mmol) was dissolved in DMF (1 mL), DIPEA (0.5 mL, ) and 5,7-dichloro-1,6-naphthalene were added pyridine (1a) (200.00 mg, 1.01 mmol), the mixture was reacted at 100 °C overnight until LCMS showed the reaction was complete.
  • Add 10 ml of water, extract with 20 ml of ethyl acetate*3 combine the organic phases, dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure.
  • Step 2 trans-3-[[5-[(5-hydroxy-2-adamantyl)amino]-1,6-naphthyridine-7-amino]-5-methyl-pyrazole-1-carboxylic acid tert-Butyl ester (3c)
  • the third step trans-4-[[7-[(5-methyl-1H-pyrazol-3-yl)amino]-1,6-naphthyridin-5-yl]amino]adamantan-1-ol ; 2,2,2-trifluoroacetate (compound 3)
  • Step 2 trans-4-[[7-[[5-(hydroxymethyl)-1H-pyrazol-3-yl]amino]-1,6-naphthyridin-5-yl]amino]adamantane- 1-Alcohol; 2,2,2-Trifluoroacetate (Compound 4)
  • reaction solution was concentrated under reduced pressure, saturated brine solution (20 mL) was added, and extracted with ethyl acetate (20 mL*2); the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain yellow solid 6-chloro -N-(5-Methyl-1H-pyrazol-3-yl)-1-tetrahydropyran-2-yl-pyrazol[3,4-d]pyrimidin-4-amine (5c) (600 mg, 98%).
  • Preparation method the crude product is dissolved in dimethyl sulfoxide, and filtered with a 0.45 ⁇ m filter membrane to prepare a sample solution.
  • Mobile phase system acetonitrile/water (with 0.1% TFA).
  • 2,4-Dichlorothieno[3,2-d]pyrimidine (6a) (1.0 g, 4.88 mmol) was dissolved in DMF (20 mL) at room temperature, to which 3-amino was added successively under nitrogen protection -5-Methylpyrazole (550 mg, 5.67 mmol) and N,N-diisopropylethylamine (782 mg, 6.06 mmol), then stirred at room temperature for 4 hours. After the reaction, ethyl acetate (20 mL) was added for extraction, washed with saturated brine solution (20 mL*3), the organic layer was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • Step 2 trans-4-[[4-[(5-methyl-1H-pyrazol-3-yl)amino]thiophene[3,2-d]pyrimidin-2-yl]amino]adamant-1- Alcohol; 2,2,2-Trifluoroacetate (Compound 6)
  • Preparation method the crude product is dissolved in dimethyl sulfoxide, and filtered with a 0.45 ⁇ m filter membrane to prepare a sample solution.
  • Mobile phase system acetonitrile/water (with 0.1% TFA).
  • 2,4-dichlorothiophene[2,3-d]pyrimidine (7a) (1.00 g, 4.88 mmol) was dissolved in absolute ethanol (25 mL), and under nitrogen protection, 3- Amino-5-methylpyrazole (487 mg, 5.02 mmol) and N,N-diisopropylethylamine (1.23 g, 9.54 mmol) were then heated and stirred at 60° C. for 20 hours.
  • reaction solution was concentrated under reduced pressure, and after adding 0.5 mL of absolute ethanol and 30 mL of methyl tert-butyl ether, a solid was precipitated; the yellow solid 2-chloro-N-(5-methyl-1H-pyridine was obtained by filtration.
  • Azol-3-yl)thiophene[2,3-d]pyrimidin-4-amine (7b) (600 mg, 46%).
  • Step 2 Trans-4-[[4-[(5-methyl-1H-pyrazol-3-yl)amino]thiophene[2,3-d]pyrimidin-2-yl]amino]adamant-1- Alcohol; 2,2,2-Trifluoroacetate (Compound 7)
  • Preparation method the crude product is dissolved in dimethyl sulfoxide, and filtered with a 0.45 ⁇ m filter membrane to prepare a sample solution.
  • Mobile phase system acetonitrile/water (with 0.1% TFA).
  • 6-chloro-N-(5-methyl-1H-pyrazol-3-yl)-1-tetrahydropyran-2-yl-pyrazolo[3,4-d]pyrimidine-4- Amine (5c) 100 mg, 0.30 mmol
  • N-methylpyrrolidone 10 mL
  • 4-amino-1-hydroxyadamantane 154 mg, 0.75 mmol
  • triethylamine 364 mg, 3.60 mmol
  • Preparation method the crude product is dissolved in dimethyl sulfoxide, and filtered with a 0.45 ⁇ m filter membrane to prepare a sample solution.
  • Mobile phase system acetonitrile/water (with 0.1% TFA).
  • N,N-Diisopropylethylamine (0.75 mmol, 6.93 mg) was added to 2-chloro-N-(5-methyl-1H-pyrazol-3-yl)thieno[3,2 at room temperature -d] Pyrimidine-4-amine (6b) (0.19 mmol, 50.00 mg), 4-aminoadamantan-1-ol (0.28 mmol, 46.82 mg) in n-butanol (2.00 mL), then at 130 °C The reaction was continued for 24 hours.
  • Preparation method the crude product is dissolved with dimethyl sulfoxide, and filtered with a 0.45 ⁇ m filter membrane to prepare a sample liquid.
  • Mobile phase system acetonitrile/water (with 0.1% TFA).
  • Preparation method the crude product is dissolved in methanol, and filtered with a 0.45 ⁇ m filter membrane to prepare a sample solution.
  • Mobile phase system acetonitrile/water (with 0.5% trifluoroacetic acid).
  • Gradient elution method acetonitrile was eluted from 10% gradient to 60% (elution time 16min), cis-4-[[4-[(5-methyl-1H-pyrazol-3-yl)amino group was obtained after lyophilization ] Thieno[2,3-d]pyrimidin-2-yl]amino]adamantan-1-ol; 2,2,2-trifluoroacetate (Compound 10) (20 mg, 10%).
  • Step 2 4-[[7-[(5-Methyl-1H-pyrazol-3-yl)amino]thiazo[5,4-d]pyrimidin-5-yl]amino]adamantan-1-ol ; 2,2,2-Trifluoroacetate-P1 (Compound 11-1)
  • Preparation method the crude product is dissolved in dimethyl sulfoxide, and filtered with a 0.45 ⁇ m filter membrane to prepare a sample solution.
  • Mobile phase system acetonitrile/water (with 0.1% TFA).
  • the absolute configuration is not determined, its structure is one of the above formulas 11-a and 11-b; and it is an isomer with compound 11-a, that is, when the structure of compound 11-1 is the structure of formula 11-a, the compound The structure of compound 11-2 is the structure of formula 11-b; when the structure of compound 11-1 is the structure of formula 11-b, the structure of compound 11-2 is the structure of formula 11-a.
  • Compound 12 uses 5,7-dichloro-1,6-naphthyridine (1a) and 3-amino-1-hydroxyadamantane hydrochloride as starting materials. Refer to the synthesis method of Example 1 to obtain 3-[[[ 7-[(5-Methyl-1H-pyrazol-3-yl)amino]-1,6-naphthyridin-5-yl]amino]adamantan-1-ol; 2,2,2-trifluoroethane acid salt (compound 12).
  • reaction solution was poured into water (40 mL), extracted with ethyl acetate (30 mL*2), the organic phases were combined, backwashed with saturated brine (30 mL*2), dried over anhydrous sodium sulfate, filtered with suction, and the filtrate was spun under reduced pressure.
  • Step 2 trans-3-[[5-[[4-(cyanomethyl)cyclohexyl]amino]-1,6-naphthyridin-7-yl]amino]-5-methyl-pyrazole-1 - tert-butyl formate (13c)
  • the third step trans-2-[4-[[7-[(5-methyl-1H-pyrazol-3-yl)amino]-1,6-naphthyridin-5-yl]amino]cyclohexyl] Acetonitrile; 2,2,2-Trifluoroacetate (Compound 13)
  • trans-2-[4-[[7-[(5-methyl-1H-pyrazol-3-yl)amino]-1,6-naphthyridin-5-yl]amino]cyclohexyl]acetonitrile; 2 , 2,2-trifluoroacetate (compound 13) (93 mg, 0.20 mmol) was dissolved in purified water (6 mL), saturated sodium bicarbonate solution was added dropwise to pH 7 ⁇ 8, filtered, and the filter cake was washed with purified water (2mL*3) rinsed, then the filter cake was lyophilized with water to obtain trans-2-[4-[[7-[(5-methyl-1H-pyrazol-3-yl)amino]-1,6-naphthalene Perid-5-yl]amino]cyclohexyl]acetonitrile (Compound 13') (68 mg, 96%).
  • Compound 14 uses 5,7-dichloro-1,6-naphthyridine (1a) and trans-4-aminocyclohexanol as starting materials, referring to the synthetic method of Example 1, to obtain trans-4-[[7 -[(5-Methyl-1H-imidazol-3-yl)amino]-1,6-naphthyridin-5-yl]amino]cyclohexanol; 2,2,2-trifluoroacetate (Compound 14 ).
  • Compound 15 uses 5,7-dichloro-1,6-naphthyridine (1a) and 3-aminocyclopentanol hydrochloride as starting materials, referring to the synthetic method of Example 1, to obtain 3-[[7-[ (5-Methyl-1H-imidazol-3-yl)amino]-1,6-naphthyridin-5-yl]amino]cyclopentanol; 2,2,2-trifluoroacetate (Compound 15)
  • Compound 16 was synthesized with 5,7-dichloro-1,6-naphthyridine (1a) and tert-butyl N-[(1R,3S)-3-(cyanomethyl)cyclopentyl]carbamate (refer to WO2019/ 239387 prepared by the synthetic method) as the starting material, refer to the synthetic method of Example 13 to obtain 2-[(1S,R)-3-[[7-[(5-methyl-1H-pyrazol-3-yl ) amino]-1,6-naphthyridin-5-yl]amino]cyclopentyl]acetonitrile; 2,2,2-trifluoroacetate (Compound 16)
  • Preparation method the crude product is dissolved in dimethyl sulfoxide, and filtered with a 0.45 ⁇ m filter membrane to prepare a sample solution.
  • Mobile phase system acetonitrile/water.
  • reaction system was returned to room temperature, the reaction was quenched with saturated aqueous ammonium chloride solution, the reaction solution was filtered through a pad of celite, and the filtrate was concentrated under reduced pressure.
  • Preparation method the crude product is dissolved in dimethyl sulfoxide, and filtered with a 0.45 ⁇ m filter membrane to prepare a sample solution.
  • Mobile phase system acetonitrile/water.
  • Step 2 2-Chloro-N-(3-methyl-1H-pyrazol-5-yl)-7-(p-toluenesulfonyl)pyrrolo[2,3-d]pyrimidin-4-amine (18c )
  • Step 3 Trans-4-[[4-[(3-Methyl-1H-pyrazol-5-yl)amino]-7-(p-toluenesulfonyl)pyrrolo[2,3-d]pyrimidine- 2-yl]amino]adamantan-1-ol (18d)
  • Preparation method the crude product is dissolved in dimethyl sulfoxide, and filtered with a 0.45 ⁇ m filter membrane to prepare a sample solution.
  • Mobile phase system acetonitrile/water.
  • Gradient elution method acetonitrile was eluted from 5% gradient to 50% (elution time 15 min).
  • Cis-4-[[4-[(3-methyl-1H-pyrazol-5-yl)amino]-7-(p-toluenesulfonyl)pyrrolo[2,3-d]pyrimidin-2-yl ]Amino]adamantan-1-ol (18d') 50 mg, 0.094 mmol was dissolved in methanol (3 mL), 2N sodium hydroxide solution (1.5 mL) was added, and the reaction was carried out at room temperature for 24 h.
  • Preparation method the crude product is dissolved in dimethyl sulfoxide, and filtered with a 0.45 ⁇ m filter membrane to prepare a sample solution.
  • Mobile phase system acetonitrile/water.
  • Gradient elution method acetonitrile was eluted from 5% gradient to 50% (elution time 15 min).
  • Compound 19 started from cis-4-[(7-chloro-1,6-naphthyridin-5-yl)amino]adamantan-1-ol (1b) and 5-methyl-2-aminothiazole, Referring to the synthetic method of Example 1, cis-4-[[7-[(5-methylthiazol-2-yl)amino]-1,6-naphthyridin-5-yl]amino]adamantane-1- alcohol; 2,2,2-trifluoroacetate (compound 19).
  • Compound 20 started with cis-4-[(7-chloro-1,6-naphthyridin-5-yl)amino]adamantan-1-ol (1b) and 2-amino-5-thiazolemethanol, reference The synthetic method of embodiment 1 obtains cis-7-[[5-(hydroxymethyl)thiazol-2-yl]amino]-1,6-naphthyridine-5-yl]amino]adamantan-1-ol ( compound 20).
  • Compound 21 was identified as cis-4-[(7-chloro-1,6-naphthyridin-5-yl)amino]adamantan-1-ol (1b) and 5-cyclopropyl-1H-pyrazol-3-amino
  • the starting material referring to the synthetic method of Example 1, cis-4-[[7-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]-1,6-naphthyridine-5 -yl]amino]adamantan-1-ol; 2,2,2-trifluoroacetate (compound 21).
  • Compound 22 uses cis-4-[(7-chloro-1,6-naphthyridin-5-yl)amino]adamantan-1-ol (1b) and 3-aminopyrazole as starting materials, Reference Example 1 , to obtain cis-4-[[7-(1H-pyrazol-3-ylamino)-1,6-naphthyridin-5-yl]amino]adamantan-1-ol; 2,2,2 - Trifluoroacetate (compound 22).
  • Compound 23 starts with cis-4-[(7-chloro-1,6-naphthyridin-5-yl)amino]adamantan-1-ol (1b) and 3-amino-5-trifluoromethylpyrazole Starting materials refer to the synthetic method of Example 1 to obtain cis-4-[[7-[[5-(trifluoromethyl)-1H-pyrazol-3-yl]amino]-1,6-naphthyridine-5 The trifluoroacetate salt of -yl]amino]adamantan-1-ol (compound 23).
  • Compound 24 is obtained by using 5,7-dichloro-1,6-naphthyridine (1a) and 5-aminobicyclo[2.2.1]heptan-2-ol hydrochloride as starting materials, referring to the synthetic method of Example 1, to obtain of 5-[[7-[(5-methyl-1H-pyrazol-3-yl)amino]-1,6-naphthyridin-5-yl]amino]norbornan-2-ol (Compound 24) Trifluoroacetate.
  • Compound 25 uses 4,6-dichloro-1H-pyrazolo[3,4-d]pyrimidine (5a) and 1-methyl-4-aminoimidazole hydrochloride as starting materials Reference Example 5 Synthesis method , to give Trans-4-[(4-[(1-methyl-1H-imidazol-4-yl)amino]-1H-pyrazolin[3,4-d]pyrimidin-6-yl)amino]adamantane - Trifluoroacetate salt of 1-ol (compound 25).
  • the compound uses 4,6-dichloro-1H-pyrazolo[3,4-d]pyrimidine (5a) and 1-methyl-4-aminoimidazole hydrochloride as starting materials, referring to the synthesis method of Example 5, to give cis-4-[(4-[(1-methyl-1H-imidazol-4-yl)amino]-1H-pyrazolin[3,4-d]pyrimidin-6-yl)amino]adamantane- Trifluoroacetate salt of 1-ol (compound 26)
  • N 5 - (4- aminocyclohexyl) -N 7 - (5- methyl -1H- pyrazol-3-yl) -1,6-naphthyridine-5,7-diamine (27d) (50mg, 0.15 mmol) was dissolved in methanol (5 mL), N,N-diisopropylethylamine (54 mg, 0.42 mmol) and acrylonitrile (13 mg, 0.25 mmol) were added, and the reaction was carried out at room temperature for 24 h.
  • Preparation method the crude product is dissolved in methanol, and filtered with a 0.45 ⁇ m filter membrane to prepare a sample solution.
  • Mobile phase system acetonitrile/water (with 0.5% trifluoroacetic acid).
  • the first step 4- ⁇ [(1s)-1-phenethyl]imino ⁇ adamantan-1-ol (28b)
  • Preparation method the crude product is dissolved in dimethyl sulfoxide, and filtered with a 0.45 ⁇ m filter membrane to prepare a sample solution.
  • Mobile phase system acetonitrile/water (with 0.1% trifluoroacetic acid).
  • Gradient elution method acetonitrile was eluted from 5% gradient to 50% (elution time 15 min). Lyophilization gave Cis-4-(methyl[(1s)-1-phenethyl]amino)adamantan-1-ol (28d) as a colorless oil as trifluoroacetate salt (800 mg, 30%).
  • the trifluoroacetate salt of cis-4-(methyl[(1s)-1-phenethyl]amino)adamantan-1-ol (28d) (800 mg, 2.0 mmol) was dissolved in absolute ethanol (15 mL) 200 mg of palladium hydroxide-carbon was added, and the reaction was carried out at room temperature for 24 h under hydrogen. After removal of the solvent under reduced pressure, the trifluoroacetate salt of Cis-4-(methylamino)adamantan-1-ol (28e) was obtained (550 mg, 93%).
  • the fifth step Cis-4-(methyl(4-[(5-methyl-1H-pyrazol-3-yl)amino]-7-(4-methylbenzenesulfonyl)-7H-pyrrolo[ 2,3-d]pyrimidin-2-yl)amino)adamantan-1-ol (28f)
  • N-(2-chloro-7-(4-methylbenzenesulfonyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-methyl-1H-pyrazole -3-amine (18c) (150 mg, 0.37 mmol), cis-4-(methylamino)adamantan-1-ol (28e) in trifluoroacetic acid (140 mg, 0.48 mmol), N,N-diisopropyl Ethylamine (500 mg, 3.87 mmol) and n-butanol (10 mL) were added to a microwave reaction tube, the temperature was raised to 140° C., and the reaction was carried out for 24 h.
  • Cis-4-(methyl(4-[(5-methyl-1H-pyrazol-3-yl)amino]-7-(4-methylbenzenesulfonyl)-7H-pyrrolo[2,3 -d]pyrimidin-2-yl)amino)adamantan-1-ol (28f) 80mg, 0.15mmol was dissolved in methanol (15mL), 2N sodium hydroxide solution (2.5mL) was added, the temperature was raised to 50°C, Reaction 6h.
  • Preparation method the crude product is dissolved in dimethyl sulfoxide, and filtered with a 0.45 ⁇ m filter membrane to prepare a sample solution.
  • Mobile phase system acetonitrile/water (with 0.1% trifluoroacetic acid).
  • Gradient elution method acetonitrile was eluted from 5% gradient to 50% (elution time 15 min).
  • 2,4-Dichloro-7H-pyrrolo[2,3-d]pyrimidine (18a) (2.00 g, 10.64 mmol) was dissolved in tetrahydrofuran (10 mL) and acetonitrile (10 mL), potassium carbonate (2.94 g) was added at room temperature g, 21.28 mmol), allyl nitrile (0.78 g, 11.70 mmol) was slowly added dropwise, and the reaction was carried out at room temperature for 16 h.
  • reaction solution was poured into water (60 mL), extracted with ethyl acetate (40 mL*2), the organic phases were combined, backwashed with saturated brine (20 mL*2), dried over anhydrous sodium sulfate, filtered with suction, and the filtrate was spun under reduced pressure.
  • 3-(2,4-Dichloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)propionitrile (31b) (1.30 g, 5.39 mmol) was dissolved in absolute ethanol (30 mL) at room temperature ), under nitrogen protection, 3-amino-5-methylpyrazole (784 mg, 8.09 mmol) and N,N-diisopropylethylamine (2.09 g, 16.18 mmol) were sequentially added thereto, and then 100° C. Heat and stir for 16 hours.
  • Preparation method the crude product is dissolved in dimethyl sulfoxide, and filtered with a 0.45 ⁇ m filter membrane to prepare a sample solution.
  • Mobile phase system acetonitrile/water (containing 0.1% ammonia).
  • Gradient elution method acetonitrile was eluted from 5% gradient to 50% (elution time 15 min).
  • Cis-3-(2-((5-hydroxyadamantan-2-yl)amino)-4-((5-methyl-1H-pyrazol-3-yl)amino)-7H-pyrrole was obtained after lyophilization and [2,3-d]pyrimidine-7-yl)propionitrile (compound 31) (5 mg, 3%).
  • Compound 32 was prepared from 5,7-dichloro-1,6-naphthyridine (1a) and 5-fluoroadamantan-2-amine (refer to the synthesis method of doi.org/10.1016/j.bmc.2018.08.005) As starting material, referring to the synthetic method of Example 1, Cis-N 5 -(5-fluoro-2-adamantane)-N 7 -(5-methyl-1H-pyrazol-3-yl)-1 was obtained , 6-Naphthyridine-5,7-diamine (compound 32) trifluoroacetate salt.
  • Compound 33 was synthesized with 5,7-dichloro-1,6-naphthyridine (1a) and 2-(3-amino-1-bicyclo[1.1.1]pentyl)acetonitrile hydrochloride (refer to the synthetic method of patent WO2018/195123 prepared) as the starting material, refer to the synthetic method of Example 1 to obtain 2-[3-[[7-[(5-methyl 1H-pyrazol-3-yl)amino]-1,6-naphthyridine The trifluoroacetate salt of -5-yl]amino]-1-bicyclo[1.1.1]pentyl]acetonitrile (compound 33).
  • Preparation method the crude product is dissolved in methanol, and filtered with a 0.45 ⁇ m filter membrane to prepare a sample solution.
  • Mobile phase system acetonitrile/water (with 0.5% trifluoroacetic acid).
  • Gradient elution method acetonitrile was eluted from 10% gradient to 60% (elution time 16 min), lyophilized to obtain 2-[[4-[[7-[(5-methyl-1H-pyrazol-3-yl ) amino]-1,6-naphthyridin-5-yl]amino]cyclohexyl]amino]acetonitrile (compound 34) as trifluoroacetate salt (3 mg, 5%).
  • Compound 36 was identified as 2-chloro-N-(3-methyl-1H-pyrazol-5-yl)-7-(p-toluenesulfonyl)pyrrolo[2,3-d]pyrimidin-4-amine (18c) and Cis-2-(4-aminocyclohexyl)acetonitrile hydrochloride (with cis-4-(tert-butoxycarbonylamino)cyclohexanecarboxylic acid as starting material, prepared according to the synthetic method of patent WO2019/239387) as starting material Materials refer to the synthetic method of Example 18 to obtain Cis-2-[4-[(4-[(5-methyl-1H-pyrazol-3-yl)amino]-7H-pyrrolo[2,3-d] Pyrimidin-2-yl)amino]cyclohexyl]acetonitrile (compound 36).
  • Compound 37 was prepared with 5,7-dichloro-2-[(morpholin-4-yl)methyl]-1,6-naphthyridine (prepared according to the synthetic method of patent WO2016/191524) and Trans-2-(4- Aminocyclohexyl)acetonitrile; hydrochloride (using Trans-4-(tert-butoxycarbonylamino)cyclohexanecarboxylic acid as starting material, prepared according to the synthetic method of patent WO2019/239387) as starting material
  • Reference Example 1 Method to obtain Trans-2-[4-[(7-[(5-methyl-1H-pyrazol-3-yl)amino]-2-[(morpholin-4-yl)methyl-1,6- Naphthyridin-5-yl)amino]cyclohexyl]acetonitrile (compound 37) as the trifluoroacetate salt.
  • Compound 38 was identified as 6-chloro-N-(5-methyl-1H-pyrazol-3-yl)-1-tetrahydropyran-2-yl-pyrazol[3,4-d]pyrimidin-4-amine (5c) and Trans-2-(4-aminocyclohexyl)acetonitrile; hydrochloride (with Trans-4-(tert-butoxycarbonylamino)cyclohexanecarboxylic acid as starting material, prepared according to patent WO2019/239387 synthesis method ) as the starting material, refer to the synthetic method of Example 8 to obtain N 4 -(3-methyl-1H-pyrazol-5-yl)-N 6 -[(1S,4s)-4-ethylcyclohexyl] -1H-Pyrazoline[3,4-d]pyrimidine-4,6-diamine (compound 38).
  • Compound 39 was synthesized with 2,4-dichloro-7-(p-toluenesulfonyl)pyrrolo[2,3-d]pyrimidine (18b) and 1-methyl-4-aminoimidazole hydrochloride, Trans-4-amino Adamantane-1-ol hydrochloride as raw material, with reference to the synthetic method of Example 18, to obtain Trans-4-[(4-[(1-methyl-1H-imidazol-4-yl)amino]-7H-pyrrole [2,3-d]pyrimidin-2-yl)amino]adamantan-1-ol (compound 39).
  • Compound 40 was prepared with 2,4-dichloro-7-(p-toluenesulfonyl)pyrrolo[2,3-d]pyrimidine (18b), 1-methyl-4-aminoimidazole hydrochloride, Cis-4-amino Adamantane-1-ol hydrochloride was used as raw material, and Cis-4-[(4-[(1-methyl-1H-imidazol-4-yl)amino]-7H-pyrrole was obtained with reference to the synthetic method of Example 18 [2,3-d]pyrimidin-2-yl)amino]adamantan-1-ol (compound 40).
  • the first step 7-bromo-2-chloro-N-(3-methyl-1H-pyrazol-5-yl)quinazoline-4-amino (41b)
  • Preparation method The reaction solution was filtered with a 0.45 ⁇ m filter membrane to prepare a sample solution.
  • Mobile phase system acetonitrile/water.
  • Compound 42 was identified as 7-bromo-2-chloro-N-(3-methyl-1H-pyrazol-5-yl)quinazoline-4-amino (41b) and Cis-4-aminoadamantan-1-ol Using hydrochloride as starting material, referring to the synthetic method of Example 41, Cis-4-[(7-bromo-4-[(3-methyl-1H-pyrazol 5-yl)amino]quinazoline- 2-yl)amino]adamantan-1-ol (compound 42).
  • Cis-4-[(7-bromo-4-[(3-methyl-1H-pyrazol-5-yl)amino]quinazolin-2-yl)amino]adamantan-1-ol (Compound 42) (50 mg, 0.11 mmol), (1-methyl-1H-pyrazol-4-yl)boronic acid (28 mg, 0.22 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloride Palladium (II) (16 mg, 0.02 mmol), cesium carbonate (110 mg, 0.33 mmol) were added to 1,4-dioxane (2 mL) and water (0.5 mL) successively, and after nitrogen replacement, the reaction was carried out at 100 °C for 4 h, After the reaction, the pad was filtered with diatomaceous earth, and the filtrate was spin-dried to obtain the residue.
  • Preparation method the crude product is dissolved in methanol, and filtered with a 0.45 ⁇ m filter membrane to prepare a sample solution.
  • Mobile phase system acetonitrile/water (with 0.1% trifluoroacetic acid).

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Rheumatology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pain & Pain Management (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un composé représenté par la formule générale (I) ou un stéréoisomère, un composé deutéré, un solvate, un promédicament, un métabolite, un sel pharmaceutiquement acceptable ou un co-cristal de celui-ci, un intermédiaire de celui-ci, un procédé de préparation s'y rapportant et l'utilisation de celui-ci dans la préparation d'un médicament pour le traitement de maladies liées au niveau d'activité ou d'expression de kinases JAK.
PCT/CN2021/103485 2020-07-01 2021-06-30 Dérivé hétérocyclique à cycles fusionnés et son utilisation médicale Ceased WO2022002118A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202180035181.XA CN115916747A (zh) 2020-07-01 2021-06-30 一种并环杂环衍生物及其在医药上的应用

Applications Claiming Priority (8)

Application Number Priority Date Filing Date Title
CN202010616123 2020-07-01
CN202010616123.3 2020-07-01
CN202010786985 2020-08-10
CN202010786985.0 2020-08-10
CN202011392522 2020-12-03
CN202011392522.2 2020-12-03
CN202110487067.2 2021-05-08
CN202110487067 2021-05-08

Publications (1)

Publication Number Publication Date
WO2022002118A1 true WO2022002118A1 (fr) 2022-01-06

Family

ID=79317518

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2021/103485 Ceased WO2022002118A1 (fr) 2020-07-01 2021-06-30 Dérivé hétérocyclique à cycles fusionnés et son utilisation médicale

Country Status (3)

Country Link
CN (1) CN115916747A (fr)
TW (1) TW202202498A (fr)
WO (1) WO2022002118A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023246777A1 (fr) * 2022-06-20 2023-12-28 Jacobio Pharmaceuticals Co., Ltd. Inhibiteurs de protéine mutante k-ras

Citations (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103068828A (zh) * 2010-08-27 2013-04-24 默克专利股份公司 三唑并吡嗪衍生物
CN103476776A (zh) * 2011-01-07 2013-12-25 北京赛林泰医药技术有限公司 作为FAK/Pyk2抑制剂的2,4-二氨基-6,7-二氢-5H-吡咯并[2,3]嘧啶衍生物
WO2014044025A1 (fr) * 2012-09-20 2014-03-27 山东亨利医药科技有限责任公司 Dérivé de pyrimidinamide et son procédé de préparation et son utilisation
WO2014051653A1 (fr) * 2012-09-27 2014-04-03 Portola Pharmaceuticals, Inc. Inhibiteurs de kinase à base de dihydropyridone bicyclique
CN103974955A (zh) * 2011-08-23 2014-08-06 远藤制药公司 嘧啶并-哒嗪酮化合物及其用途
CN104098563A (zh) * 2013-04-02 2014-10-15 山东亨利医药科技有限责任公司 Jnk抑制剂化合物
CN104837829A (zh) * 2012-09-07 2015-08-12 癌症研究科技有限公司 抑制剂化合物
WO2017024589A1 (fr) * 2015-08-13 2017-02-16 北京韩美药品有限公司 Inhibiteur d'irak4 et son utilisation
CN107001372A (zh) * 2014-10-06 2017-08-01 西格诺药品有限公司 取代的氨基嘌呤化合物、其组合物及其治疗方法
CN109069512A (zh) * 2016-04-01 2018-12-21 西格诺药品有限公司 取代的氨基嘌呤化合物、其组合物以及相关治疗方法
CN109311896A (zh) * 2016-06-30 2019-02-05 株式会社大熊制药 吡唑并嘧啶衍生物作为激酶抑制剂
CN109476696A (zh) * 2016-06-02 2019-03-15 细胞基因公司 动物及人抗锥虫和抗利什曼原虫剂
CN109563095A (zh) * 2016-06-02 2019-04-02 细胞基因公司 动物和人抗疟剂
CN109937039A (zh) * 2016-09-30 2019-06-25 斯坦福国际研究院 用于癌症治疗的双重clk/cdk1抑制剂

Patent Citations (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103068828A (zh) * 2010-08-27 2013-04-24 默克专利股份公司 三唑并吡嗪衍生物
CN103476776A (zh) * 2011-01-07 2013-12-25 北京赛林泰医药技术有限公司 作为FAK/Pyk2抑制剂的2,4-二氨基-6,7-二氢-5H-吡咯并[2,3]嘧啶衍生物
CN103974955A (zh) * 2011-08-23 2014-08-06 远藤制药公司 嘧啶并-哒嗪酮化合物及其用途
CN104837829A (zh) * 2012-09-07 2015-08-12 癌症研究科技有限公司 抑制剂化合物
WO2014044025A1 (fr) * 2012-09-20 2014-03-27 山东亨利医药科技有限责任公司 Dérivé de pyrimidinamide et son procédé de préparation et son utilisation
WO2014051653A1 (fr) * 2012-09-27 2014-04-03 Portola Pharmaceuticals, Inc. Inhibiteurs de kinase à base de dihydropyridone bicyclique
CN104098563A (zh) * 2013-04-02 2014-10-15 山东亨利医药科技有限责任公司 Jnk抑制剂化合物
CN107001372A (zh) * 2014-10-06 2017-08-01 西格诺药品有限公司 取代的氨基嘌呤化合物、其组合物及其治疗方法
WO2017024589A1 (fr) * 2015-08-13 2017-02-16 北京韩美药品有限公司 Inhibiteur d'irak4 et son utilisation
CN109069512A (zh) * 2016-04-01 2018-12-21 西格诺药品有限公司 取代的氨基嘌呤化合物、其组合物以及相关治疗方法
CN109476696A (zh) * 2016-06-02 2019-03-15 细胞基因公司 动物及人抗锥虫和抗利什曼原虫剂
CN109563095A (zh) * 2016-06-02 2019-04-02 细胞基因公司 动物和人抗疟剂
CN109311896A (zh) * 2016-06-30 2019-02-05 株式会社大熊制药 吡唑并嘧啶衍生物作为激酶抑制剂
CN109937039A (zh) * 2016-09-30 2019-06-25 斯坦福国际研究院 用于癌症治疗的双重clk/cdk1抑制剂

Non-Patent Citations (10)

* Cited by examiner, † Cited by third party
Title
GUCKÝ TOMÁŠ, ŘEZNÍČKOVÁ EVA, RADOŠOVÁ MUCHOVÁ TEREZA, JORDA RADEK, KLEJOVÁ ZUZANA, MALÍNKOVÁ VERONIKA, BERKA KAREL, BAZGIER VÁCLAV: "Discovery of N2‑(4-Amino-cyclohexyl)-9-cyclopentyl‑N6‑(4-morpholin-4-ylmethyl-phenyl)-9H-purine-2, 6-diamine as a Potent FLT3 Kinase Inhibitor for Acute Myeloid Leukemia with FLT3 Mutations", JOURNAL OF MEDICINAL CHEMISTRY, vol. 61, no. 9, 10 May 2018 (2018-05-10), US, pages 3855 - 3869, XP055883934, ISSN: 0022-2623, DOI: 10.1021/acs.jmedchem.7b01529 *
MALÍNKOVA VERONIKA; REZNICKOVA EVA; JORDA RADEK; GUCKY TOMAS; KRYSTOF VLADIMIR: "Trisubstituted purine inhibitors of PDGFRa and their antileukemic activity in the human eosinophilic cell line EOL-1", BIOORGANIC & MEDICINAL CHEMISTRY, vol. 25, no. 24, 21 October 2017 (2017-10-21), pages 6523 - 6535, XP085254677, ISSN: 0968-0896, DOI: 10.1016/j.bmc.2017.10.032 *
PLANTEVIN KRENITSKY VÉRONIQUE; NADOLNY LISA; DELGADO MERCEDES; AYALA LETICIA; CLAREEN STEVEN S; HILGRAF ROBERT; ALBERS RONALD; HEG: "Discovery ofCC-930, an orally active anti-fibrotic JNK inhibitor", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 22, no. 3, 10 December 2011 (2011-12-10), XP028886996, ISSN: 0960-894X, DOI: 10.1016/j.bmcl.2011.12.027 *
RAJINDER SINGH; ESTEBAN S MASUDA; DONALD G PAYAN: "Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors", JOURNAL OF MEDICINAL CHEMISTRY, vol. 55, no. 8, 26 April 2012 (2012-04-26), pages 3614 - 3643, XP055051582, ISSN: 0022-2623, DOI: 10.1021/jm201271b *
RAND SHAHIN; MUTASEM O TAHA: "Elaborate ligand-based modeling and subsequent synthetic exploration unveil new nanomolar Ca2+/calmodulin-dependent protein kinase II inhibitory leads", BIOORGANIC & MEDICINAL CHEMISTRY, vol. 20, no. 1, 25 October 2011 (2011-10-25), pages 377 - 400, XP028354069, ISSN: 0968-0896, DOI: 10.1016/j.bmc.2011.10.071 *
ŘEZNÍČKOVÁ EVA; GUCKÝ TOMÁŠ; KOVÁČOVÁ VERONIKA; AJANI HARESH; JORDA RADEK; KRYŠTOF VLADIMÍR: "Activity of 2, 6, 9-trisubstituted purines as potent PDGFRa kinase inhibitors with antileukaemic activity", EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, vol. 182, 31 August 2019 (2019-08-31), pages 1 - 17, XP085874386, ISSN: 0223-5234, DOI: 10.1016/j.ejmech.2019.111663 *
SHI YIHUI; PARK JAEHYEON; LAGISETTI CHANDRAIAH; ZHOU WEI; SAMBUCETTI LIDIA C; WEBB THOMAS R: "A triple exon-skipping luciferase reporter assay identifies a new CLK inhibitor pharmacophore", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 27, no. 3, 24 December 2016 (2016-12-24), pages 406 - 412, XP029883843, ISSN: 0960-894X, DOI: 10.1016/j.bmcl.2016.12.056 *
TOMOMI KOSUGI; DALE R MITCHELL; AIKO FUJINO; MINORU IMAI; MIKA KAMBE; SHINJI KOBAYASHI; HIROAKI MAKINO; YOHEI MATSUEDA; YASUHIRO O: "Mitogen-Activated Protein Kinase-Activated Protein Kinase 2 (MAPKAP-K2) as an Antiinflammatory Target: Discovery and in Vivo Activity of Selective Pyrazolo[1, 5-a]pyrimidine Inhibitors Using a Focused Library and Structure-Based Optimization Approach", JOURNAL OF MEDICINAL CHEMISTRY, vol. 55, no. 15, 9 August 2012 (2012-08-09), pages 6700 - 6715, XP055481892, ISSN: 0022-2623, DOI: 10.1021/jm300411k *
TORRIE LEAH S., ROBINSON DAVID A., THOMAS MICHAEL G., HOBRATH JUDITH V., SHEPHERD SHARON M., POST JOHN M., KO EUN-JUNG, FERREIRA R: "Discovery of an Allosteric Binding Site in Kinetoplastid Methionyl-tRNA Synthetase", ACS INFECTIOUS DISEASES, vol. 6, no. 5, 8 May 2020 (2020-05-08), pages 1044 - 1057, XP055883938, ISSN: 2373-8227, DOI: 10.1021/acsinfecdis.9b00453 *
VIJAY KUMAR D; CHRISTOPHE HOARAU; MATTHEW BURSAVICH; PAUL SLATTUM; DAVID GERRISH; KRAIG YAGER; MICHAEL SAUNDERS; MARK SHENDEROVICH: "Lead optimization of purine based orally bioavailable Mps1 (TTK) inhibitors", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 22, no. 13, 30 April 2012 (2012-04-30), pages 4377 - 4385, XP028491013, ISSN: 0960-894X, DOI: 10.1016/j.bmcl.2012.04.131 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023246777A1 (fr) * 2022-06-20 2023-12-28 Jacobio Pharmaceuticals Co., Ltd. Inhibiteurs de protéine mutante k-ras

Also Published As

Publication number Publication date
TW202202498A (zh) 2022-01-16
CN115916747A (zh) 2023-04-04

Similar Documents

Publication Publication Date Title
CA3013618C (fr) Composes pyrazolo[1,5-a]pyrimidines substituees en tant qu'inhibiteurs des trk kinases
KR102132405B1 (ko) Trk 키나제 저해제로서의 매크로시클릭 화합물
ES2857251T3 (es) Compuestos polifluorados que actúan como inhibidores de la tirosina cinasa de bruton
CN104918945B (zh) 作为jak抑制剂的三环稠合噻吩衍生物
IL274938B1 (en) New compounds and their pharmaceutical preparations for the treatment of diseases
RS51556B (sr) 5,7-diaminopirazolo(4,3-d)pirimidin sa inhibitornim dejstvom na pde-5
CN103987713A (zh) 5,7-取代的咪唑并[1,2-c]嘧啶
JP7121033B2 (ja) Ｔｎｆ活性のモジュレーターとしての縮合五環式イミダゾール誘導体
WO2014123167A1 (fr) Composé pyrrolopyridine tricyclique et inhibiteur de jak
CN101501035B (zh) 作为pi3k抑制剂的嘧啶衍生物及其用途
WO2022002118A1 (fr) Dérivé hétérocyclique à cycles fusionnés et son utilisation médicale
EP2445909B1 (fr) DÉRIVÉS AMIDES DE L'ACIDE 6,7-DIHYDRO-5H-IMIDAZO[1,2-a]IMIDAZOLE-3-CARBOXYLIQUE
JP2025530793A (ja) Ｅｇｆｒ阻害剤及びその使用
WO2022078305A1 (fr) Dérivé hétérocyclique et son application médicale
JP7384669B2 (ja) 置換ジヒドロピロロピラゾール化合物および免疫療法剤が組み合わせて投与される医薬組成物
TW202348227A (zh) 取代的噠嗪-3-甲醯胺化合物作為tyk2抑制劑
HK1243058A1 (en) Macrocyclic compounds as trk kinase inhibitors
HK1181756B (en) Macrocyclic compounds as trk kinase inhibitors
HK1215245B (en) Macrocyclic compounds as trk kinase inhibitors

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 21833958

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 21833958

Country of ref document: EP

Kind code of ref document: A1