WO2022002118A1 - Fused-ring heterocycle derivative and medical use thereof - Google Patents

Fused-ring heterocycle derivative and medical use thereof 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
amino
ring
methyl
Prior art date
Application number
PCT/CN2021/103485
Other languages
French (fr)
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
Original Assignee
四川海思科制药有限公司
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 四川海思科制药有限公司 filed Critical 四川海思科制药有限公司
Priority to CN202180035181.XA priority Critical patent/CN115916747A/en
Publication of WO2022002118A1 publication Critical patent/WO2022002118A1/en

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).

Abstract

The present invention relates to a compound as represented by general formula (I) or a stereoisomer, a deuterated compound, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof, an intermediate thereof, a preparation method therefor, and the use thereof in the preparation of a drug for treating diseases related to the activity or expression level of JAK kinases.

Description

一种并环杂环衍生物及其在医药上的应用A kind of heterocyclic heterocyclic derivative and its application in medicine 技术领域technical field
本发明涉及一种通式(I)所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，及其中间体和制备方法，以及在制备治疗与JAK激酶活性或表达量相关疾病的药物中的应用。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.
背景技术Background technique
炎性肠病又称炎症性肠病(IBD)，为累及回肠、直肠、结肠的一种特发性肠道炎症性疾病。临床表现为腹泻、腹痛，甚至可有血便。炎性肠病包括溃疡性结肠炎(UC)和克罗恩病(CD)。溃疡性结肠炎是结肠黏膜层和黏膜下层连续性炎症，疾病通常先累及直肠，逐渐向全结肠蔓延,克罗恩病可累及全消化道，为非连续性全层炎症，最常累及部位为末端回肠、结肠和肛周。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.
炎性肠病全球发病率高，北美与欧洲许多国家发病率超过0.3％，自1990年后，非洲、亚洲与南美的发病率逐年攀升。The global incidence of inflammatory bowel disease is high, and the incidence in many countries in North America and Europe exceeds 0.3%. Since 1990, the incidence in Africa, Asia and South America has been increasing year by year.
Janus激酶\信号传导及转录激活因子(Janus-activated kinase Singal transducers and activators of transcriprion，JAK-STAT)是近年来新发现的一条与细胞因子密切相关的细胞内信号传导通路，参与细胞的增殖、分化、凋亡以及免疫调节等许多重要的生物学过程。Janus激酶是一种非受体型酪氨酸蛋白激酶。有4个家族成员，分别是JAK1、JAK2、TyK2和JAK3。JAK/STAT信号通路是多种细胞生长、活化、分化、凋亡及其功能发挥过程中重要的一条细胞内信号转导途径，许多细胞因子如干扰素(IFN)家族、糖蛋白130(gp130)家族、γ-C家族及单链家族均能激活该信号通路。细胞因子受体的信号转导链带有JAK酪氨酸蛋白激酶，当这些细胞因子与细胞表面特异受体结合后，信号转导链上的JAK分子发生聚合且相互磷酸化而激活，并通过释放磷酸根(P)使另一条受体链胞内段上的酪氨酸残基(Y)发生磷酸化成为PY，这些磷酸化的酪氨酸位点与周围的氨基酸序列形成“停泊位点”(docking site)，从而招募带有SH2结构域的转录因子STAT，此时STAT中的酪氨酸也从活化的JAK获得磷酸根而激活，并形成同源二聚体，与受体分离后，其核定位信号暴露而进入核内，与靶基因结合，调控基因的转录。JAK-STAT细胞内信号转导适用于干扰素、大多数白细胞介素以及多种细胞因子和内分泌因子。Janus-activated kinase Singal transducers and activators of transcriprion (JAK-STAT) 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. There are 4 family members, namely JAK1, JAK2, TyK2 and JAK3. 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. Many cytokines such as interferon (IFN) family, glycoprotein 130 (gp130) Family, γ-C family and single-chain family can activate this signaling pathway. The signal transduction chain of 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. The release of 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的确切发病机制尚不明确，但促炎性细胞激素在免疫反应中起关键作用(斯乔博等人,Gastroenterol,2011,140,1756-1767)。在UC中最常升高的许多促炎性细胞激素(如，IL-4、IL-6、IL-13、IL-15、IL-23、IL-24、IFNγ和瘦素)依赖于酪氨酸激酶的JAK家族(JAK1、 JAK2、JAK3和Tyk2)进行信号转导，对JAK酶家族的抑制可抑制多个关键促炎性细胞激素的信号传导。因此，预期对JAK酶家族的抑制对溃疡性结肠炎和其它发炎性疾病具有治疗益处。The exact pathogenesis of UC is unclear, but 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, IFNγ, and leptin) are tyrosine-dependent The JAK family of acid kinases (JAK1, JAK2, JAK3, and Tyk2) signal transduction, and 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.
对JAK酶家族的抑制可抑制多种关键促炎性细胞激素的信号传导。因此，JAK抑制剂很可能适用于治疗溃疡性结肠炎和其它发炎性疾病，如克罗恩病(Crohn's disease)、过敏性鼻炎、异位性皮肤炎(AD)和其它炎症性皮肤病。但是，由于JAK/STAT路径对免疫系统的调节作用，全身性暴露的JAK抑制剂具有不利的全身免疫抑制作用，因此，需要提供在作用位点具有作用而无显著全身作用的新颖JAK抑制剂。具体来说，为治疗胃肠炎症性疾病(例如溃疡性结肠炎、克罗恩病)，需要提供可口服给药且在胃肠道中实现治疗相关暴露量并具有最少全身暴露量的新颖JAK抑制剂。还需要提供用于治疗异位性皮肤炎的新颖JAK抑制剂，所述新颖JAK抑制剂具有最少的全身暴露量。Inhibition of the JAK family of enzymes inhibits 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. However, 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. Specifically, for the treatment of gastrointestinal inflammatory diseases (eg, ulcerative colitis, Crohn's disease), there is a need to provide novel JAK inhibition that is orally administrable and achieves therapeutically relevant exposures in the gastrointestinal tract with minimal systemic exposure agent. There is also a need to provide novel JAK inhibitors for the treatment of atopic dermatitis that have minimal systemic exposure.
发明内容SUMMARY OF THE INVENTION
本发明的目的之一在于提供一种能够抑制JAK激酶的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，及其中间体和制备方法，以及在制备治疗与JAK激酶活性或表达量相关疾病的药物中的应用。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.
本发明的化合物具有良好的JAK激酶抑制活性、抗炎活性、较好的安全性和/或肠靶向性。The compounds of the present invention have good JAK kinase inhibitory activity, anti-inflammatory activity, good safety and/or intestinal targeting.
本发明提供一种通式(I)所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，The present invention provides a compound of general formula (I) or its stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal,
Figure PCTCN2021103485-appb-000001
Figure PCTCN2021103485-appb-000001
在某些实施方案中，L选自键或者NR n2； In certain embodiments, L is selected from a bond or NRn2 ;
在某些实施方案中，L选自NR n2； In certain embodiments, L is selected from NRn2 ;
在某些实施方案中，L选自键；In certain embodiments, L is selected from a bond;
在某些实施方案中，R n1、R n2各自独立的选自H、C 1-6烷基或C 3-6环烷基，所述的烷基或环烷基任选进一步被0至4个(例如0、1、2、3或4个)选自H、卤素、CF 3、OH、氰基、NH 2、C 1-6烷基或C 1-6烷氧基的取代基所取代； In certain embodiments, 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 ;
在某些实施方案中，R n1、R n2各自独立的选自H、C 1-4烷基或C 3-6环烷基，所述的烷基或环烷基任选进一步被0至4个(例如0、1、2、3或4个)选自H、卤素、CF 3、OH、氰基、NH 2、C 1-4烷基或C 1-4烷氧基的取代基所取代； In certain embodiments, 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 ;
在某些实施方案中，R n1、R n2各自独立的选自H、甲基、乙基、丙基、异丙基、环丙基、环丁基、环戊基或环己基，所述的甲基、乙基、丙基、异丙基、环丙基、环丁基、环戊基或环己基任选进一步被0至4个(例如0、1、2、3或4个)选自H、卤素、CF 3、OH、氰基、NH 2、C 1-4烷基或C 1-4烷氧基的取代基所取代； In certain embodiments, 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;
在某些实施方案中，R n1、R n2各自独立的选自H、甲基、乙基、丙基、异丙基、环丙基、环丁基、环戊基或环己基，所述的甲基、乙基、丙基、异丙基、环丙基、环丁基、环戊基或环己基任选进一步被0至4个(例如0、1、2、3或4个)选自H、F、CF 3、OH、氰基、NH 2、甲基、乙基、甲氧基或乙氧基的取代基所取代； In certain embodiments, 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;
在某些实施方案中，R n1选自H，R n2选自H、甲基、乙基、丙基、异丙基； In certain embodiments, Rn1 is selected from H, Rn2 is selected from H, methyl, ethyl, propyl, isopropyl;
在某些实施方案中，R n1、R n2选自H； In certain embodiments, Rn1 , Rn2 are selected from H;
在某些实施方案中，环A选自5-6元单环杂芳环或8-10元并环杂芳环，所述的杂芳环任选进一步被0至3个(例如0、1、2或3个)R a取代，所述的杂芳环含有1至5个(例如1、2、3、4个或5)选自O、S、N的杂原子； In certain embodiments, 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;
在某些实施方案中，环A选自取代或者未取代的6并6元稠杂芳基，优选取代或者未取代的如下基团之一：异喹啉基、萘啶基、吡啶并吡嗪基、吡啶并嘧啶基、吡啶并哒嗪基、吡啶并哒嗪基、嘧啶并哒嗪基、嘧啶并哒嗪基、喹唑啉基、蝶啶基、喹喔啉基、二氢吡喃并嘧啶基或二氢二氧杂环己二烯并嘧啶基，当被取代时，任选进一步被0至3个(例如0、1、2或3个)R a取代； In certain embodiments, 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;
在某些实施方案中，环A选自取代或者未取代的5并6元稠杂芳基，优选取代或者未取代的如下基团之一：噻吩并嘧啶基、吡唑并嘧啶基、苯并吡咯基、吡咯并吡啶基、咪唑并吡啶基、三唑并吡啶基、咪唑并哒嗪基、吡咯并嘧啶基、吡唑并嘧啶基、咪唑并嘧啶基、三唑并嘧啶基、噻吩并嘧啶基、噻唑并嘧啶基、异噻唑并嘧啶基、异噁唑并嘧啶基、异噻唑并吡啶基、异噁唑并吡啶基、异噻唑并吡嗪基、异噁唑并吡嗪基、异噻唑并哒嗪基、异噁唑并哒嗪基、吡咯并吡嗪基、吡唑并吡嗪基、咪唑并吡嗪基、三唑并吡嗪基、噻唑并哒嗪基、吡咯并哒嗪基、吡唑并哒嗪基、咪唑并哒嗪基、三唑并哒嗪基、吡咯并三嗪基、咪唑并三嗪基或咪唑并吡嗪酮基，当被取代时，任选进一步被0至3个(例如0、1、2或3个)R a取代； In certain embodiments, 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, isoxazolopyridazinyl, pyrrolopyrazinyl, pyrazolopyrazinyl, imidazopyrazinyl, triazolopyrazinyl, thiazolopyridazinyl, pyrrolopyridazinyl , pyrazolopyridazinyl, imidazopyridazinyl, triazolopyridazinyl, pyrrolotriazinyl, imidazotriazinyl or imidazopyrazinone, when substituted, optionally further by O to 3 (e.g. 2 or 3) R a substituent;
在某些实施方案中，环A选自取代的或者未取代的如下基团之一：
Figure PCTCN2021103485-appb-000002
Figure PCTCN2021103485-appb-000003
X 1选自CH或N，X 2选自键、CH或N，Y、Z各自独立的选自C或N，环C选自5-6元杂芳环或苯环，所述的杂芳环含有1至3个(例如1、2或3)选自O、S、N的杂原子，当被取代时，任选进一步被0至3个(例如0、1、2或3个)R a取代； In certain embodiments, Ring A is selected from one of the following groups, substituted or unsubstituted:
Figure PCTCN2021103485-appb-000002
Figure PCTCN2021103485-appb-000003
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;
在某些实施方案中，环A选自取代的或者未取代的如下基团之一：
Figure PCTCN2021103485-appb-000004
Figure PCTCN2021103485-appb-000005
X 1选自CH或N，X 2选自键、CH或N，Y、Z各自独立的选自C或N，环C选自吡唑环、噻唑环、咪唑环、噁唑环、噻吩环、呋喃环、吡咯环、异噁唑环、异噻唑环、吡啶环、吡嗪环、哒嗪环、1,2,4-三氮唑环、嘧啶环或苯环，当被取代时，任选进一步被0至3个(例如0、1、2或3个)R a取代； In certain embodiments, Ring A is selected from one of the following groups, substituted or unsubstituted:
Figure PCTCN2021103485-appb-000004
Figure PCTCN2021103485-appb-000005
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 ;
在某些实施方案中，环A选自取代的或者未取代的如下基团之一：
Figure PCTCN2021103485-appb-000006
Figure PCTCN2021103485-appb-000007
Figure PCTCN2021103485-appb-000008
Figure PCTCN2021103485-appb-000009
Figure PCTCN2021103485-appb-000010
Figure PCTCN2021103485-appb-000011
当被取代时，任选进一步被0至3个(例如0、1、2或3个)R a取代； In certain embodiments, Ring A is selected from one of the following groups, substituted or unsubstituted:
Figure PCTCN2021103485-appb-000006
Figure PCTCN2021103485-appb-000007
Figure PCTCN2021103485-appb-000008
Figure PCTCN2021103485-appb-000009
Figure PCTCN2021103485-appb-000010
Figure PCTCN2021103485-appb-000011
When substituted, optionally further substituted with 0-3 (e.g. 2 or 3) R a;
在某些实施方案中，环A选自取代的或者未取代的如下基团之一：
Figure PCTCN2021103485-appb-000012
Figure PCTCN2021103485-appb-000013
Figure PCTCN2021103485-appb-000014
当被取代时，任选进一步被0至3个(例如0、1、2或3个)R a取代； In certain embodiments, Ring A is selected from one of the following groups, substituted or unsubstituted:
Figure PCTCN2021103485-appb-000012
Figure PCTCN2021103485-appb-000013
Figure PCTCN2021103485-appb-000014
When substituted, optionally further substituted with 0-3 (e.g. 2 or 3) R a;
在某些实施方案中，环A选自取代的或者未取代的如下基团之一：
Figure PCTCN2021103485-appb-000015
Figure PCTCN2021103485-appb-000016
Figure PCTCN2021103485-appb-000017
当被取代时，任选进一步被0至3个(例如0、1、2或3个)R a取代； In certain embodiments, Ring A is selected from one of the following groups, substituted or unsubstituted:
Figure PCTCN2021103485-appb-000015
Figure PCTCN2021103485-appb-000016
Figure PCTCN2021103485-appb-000017
When substituted, optionally further substituted with 0-3 (e.g. 2 or 3) R a;
在某些实施方案中，环A选自如下基团之一：
Figure PCTCN2021103485-appb-000018
Figure PCTCN2021103485-appb-000019
In certain embodiments, Ring A is selected from one of the following groups:
Figure PCTCN2021103485-appb-000018
Figure PCTCN2021103485-appb-000019
在某些实施方案中，R a各自独立的选自H、卤素、氰基、OH、C 1-6烷基、C 1-6烷氧基、-(CH 2) q-C(＝O)-NR a1R a2、-(CH 2) q-NR a1R a2、-(CH 2) qNR a1C(＝O)-R a2、-(CH 2) q-C 3-10碳环或-(CH 2) q-3至12元杂环，所述的-CH 2-、烷基、烷氧基、碳环或杂环任选进一步被0至4个(例如0、1、2、3或4个)选自H、卤素、OH、氰基、NH 2、NH(C 1-6烷基)、N(C 1-6烷基) 2、C 1-6烷基、卤素取代的C 1-6烷基、C 1-6烷氧基、C 3-6环烷基或3至10元杂环的取代基所取代，所述的杂环含有1至3个(例如1、2或3个)选自O、S、N的杂原子； In certain embodiments, each R a is independently selected from H, halogen, cyano, OH, C 1-6 alkyl, C 1-6 alkoxy, -(CH 2 ) q -C(=O) -NR a1 R a2 , -(CH 2 ) q -NR a1 R a2 , -(CH 2 ) q NR a1 C(=O)-R a2 , -(CH 2 ) q -C 3-10 carbocyclic or - (CH 2 ) q -3- to 12-membered heterocycle, the -CH 2 -, alkyl, alkoxy, carbocycle or heterocycle is optionally further substituted by 0 to 4 (eg 0, 1, 2, 3 or 4) 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 substituents of 3- to 10-membered heterocycles containing 1 to 3 (eg 1, 2 or 3) heteroatoms selected from O, S, N;
在某些实施方案中，R a各自独立的选自H、卤素、氰基、OH、C 1-4烷基、C 1-4烷氧基、-(CH 2) q-C 3-6碳环或-(CH 2) q-3至6元杂环、-(CH 2) q-C(＝O)-NR a1R a2、-(CH 2) q-NR a1R a2或-(CH 2) qNR a1C(＝O)-R a2，所述的-CH 2-、烷基、烷氧基、碳环或杂环任选进一步被0至4个(例如0、1、2、3或4个)选自H、卤素、OH、氰基、NH 2、NH(C 1-4烷基)、N(C 1-4烷基) 2、C 1-4烷基、卤素取代的C 1-4烷基、C 1-4烷氧基、C 3-6环烷基或3至10元杂环的取代基所取代，所述的杂环含有1至3个(例如1、2或3个)选自O、S、N的杂原子； In certain embodiments, R a is independently selected from H, halo, cyano, OH, C 1-4 alkyl, C 1-4 alkoxy, - (CH 2) q -C 3-6 carbon Ring or -(CH 2 ) q -3- to 6-membered heterocycle, -(CH 2 ) q -C(=O)-NR a1 R a2 , -(CH 2 ) q -NR a1 R a2 or -(CH 2 ) q NR a1 C(=O)-R a2 , the -CH 2 -, alkyl, alkoxy, carbocycle or heterocycle is optionally further substituted by 0 to 4 (eg 0, 1, 2, 3 or 4) 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 10-membered heterocyclic rings containing 1 to 3 (for example, 1, 2 or 3) heteroatoms selected from O, S, N;
在某些实施方案中，R a各自独立的选自H、卤素、氰基、OH、C 1-4烷基、C 1-4烷氧基、C 3-6碳环、3至6元杂环、-CH 2-C 3-6碳环、-CH 2CH 2-C 3-6碳环、-CH 2-3至6元杂环、-CH 2CH 2-3至6元杂环、NHR a2、-C(＝O)NHR a2、-NHC(＝O)R a2，所述的-CH 2-、烷基、烷氧基、碳环或杂环任选进一步被0至4个(例如0、1、2、3或4个)选自H、卤素、OH、氰基、NH 2、NH(C 1-4烷基)、N(C 1-4烷基) 2、C 1-4烷基、卤素取代的C 1-4烷基、C 1-4烷氧基、C 3-6环烷基或3至6元杂环的取代基所取代，所述的杂环含有1至3个(例如1、2或3个)选自O、S、N的杂原子； In certain embodiments, R a is independently selected from H, halo, cyano, OH, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 carbocyclic 3 to 6-membered heteroaryl ring, -CH 2 -C 3-6 carbocycle, -CH 2 CH 2 -C 3-6 carbocycle, -CH 2 -3- to 6-membered heterocycle, -CH 2 CH 2 -3- to 6-membered heterocycle, NHR a2 , -C(=O)NHR a2 , -NHC(=O)R a2 , the -CH 2 -, alkyl, alkoxy, carbocycle or heterocycle are optionally further replaced by 0 to 4 ( For example, 0, 1, 2, 3 or 4) are 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 heterocycles containing 1 to 6 3 (eg 1, 2 or 3) heteroatoms selected from O, S, N;
在某些实施方案中，R a各自独立的选自H、F、Cl、Br、氰基、OH、甲基、乙基、丙基、丁基、异丙基、甲氧基、乙氧基、吡唑基、噻唑基、咪唑基、噁唑基、噻吩基、呋喃基、吡咯基、异噁唑基、异噻吩基、吡啶基、嘧啶基、苯基、环丙基、环丁基、环戊基、环己基、-NH-吡唑基、-NH-噻唑基、-NH-咪唑基、-NH-噁唑基、-NH-噻吩基、-NH-呋喃基、-NH-吡咯基、-NH-异噁唑基、-NH-异噻吩基、-NH-吡啶基、-NH-嘧啶基、-NH-苯基、-NH-环丙基、-NH-环丁基、-NH-环戊基、-NH-环己基、-C(＝O)NH 2、-C(＝O)NHCH 3、-C(＝O)NHCH 2CH 3、-C(＝O)NH-环丙基、-C(＝O)NH-环丁基、-C(＝O)NH-环戊基、-C(＝O)NH-环已基、-C(＝O)NH-苯基、-NHC(＝O)H、-NHC(＝O)CH 3、-NHC(＝O)CH 2CH 3、-NHC(＝O)CH 2CH 2CH 3、-NHC(＝O)-环丙基、-NHC(＝O)-环丁基、-NHC(＝O)-环戊基、-NHC(＝O)-环已基或-NHC(＝O)-苯基，所述的甲基、乙基、异丙基、甲氧基、乙氧基、环丙基、环丁基、环戊基、环己基、吡唑基、噻唑基、咪唑基、噁唑基、噻吩基、呋喃基、吡咯基、异噁唑基、异噻吩基、吡啶基、嘧啶基或苯基任选进一步被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、CF 3、OH、氰基、NH 2、NH(CH 3)、NH(CH 2CH 3)、N(CH 3) 2、N(CH 2CH 3) 2、甲基、乙基、甲氧基、乙氧基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氮杂环戊基、氮杂环己基、氧杂环丁基、氧杂环戊基、氧杂环己基、吗啉基的取代基所取代； In certain embodiments, 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-pyridyl, -NH-pyrimidinyl, -NH-phenyl, -NH-cyclopropyl, -NH-cyclobutyl, -NH -Cyclopentyl, -NH-cyclohexyl, -C(=O)NH 2 , -C(=O)NHCH 3 , -C(=O)NHCH 2 CH 3 , -C(=O)NH-cyclopropane base, -C(=O)NH-cyclobutyl, -C(=O)NH-cyclopentyl, -C(=O)NH-cyclohexyl, -C(=O)NH-phenyl, - NHC (= O) H, -NHC (= O) CH 3, -NHC (= O) CH 2 CH 3, -NHC (= O) CH 2 CH 2 CH 3, -NHC (= O) - cyclopropyl , -NHC(=O)-cyclobutyl, -NHC(=O)-cyclopentyl, -NHC(=O)-cyclohexyl or -NHC(=O)-phenyl, the methyl, Ethyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrazolyl, thiazolyl, imidazolyl, oxazolyl, thienyl, furyl, Pyrrolyl, isoxazolyl, isothienyl, pyridyl, pyrimidinyl or phenyl is optionally further 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, 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 base, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidine, azetyl, azetidine, oxetanyl, oxetanyl, substituted by the substituents of oxanyl and morpholinyl;
在某些实施方案中，R a各自独立的选自H、F、Cl、Br、氰基、OH、甲基、乙基、丙基、丁基、异丙基、异丁基、仲丁基、叔丁基、甲氧基、乙氧基、吡唑基、噻唑基、咪唑基、噁唑基、噻吩基、呋喃基、吡咯基、异噁唑基、异噻吩基、吡啶基、嘧啶基、苯基、环丙基、环丁基、环戊基、环己基、-NH-吡唑基、-NH-噻唑基、-NH-咪唑基、-NH-噁唑基、-NH-噻吩基、-NH-呋喃基、-NH-吡咯基、-NH-异噁唑基、-NH-异噻吩基、-NH-吡啶基、-NH-嘧啶基、-NH-苯基、-NH-环丙基、-NH-环丁基、-NH-环戊基、-NH-环己基、-C(＝O)NH 2、-C(＝O)NHCH 3、-C(＝O)NHCH 2CH 3、-C(＝O)NH-环丙基、-C(＝O)NH-环丁基、-C(＝O)NH-环戊基、-C(＝O)NH-环已基、-C(＝O)NH-苯基、-NHC(＝O)H、-NHC(＝O)CH 3、-NHC(＝O)CH 2CH 3、-NHC(＝O)CH 2CH 2CH 3、-NHC(＝O)-环丙基、-NHC(＝O)-环丁基、-NHC(＝O)-环戊基、-NHC(＝O)-环已基或-NHC(＝O)-苯基，所述的甲基、乙基、异丙基、异丁基、仲丁基、叔丁基、甲氧基、乙氧基、环丙基、环丁基、环戊基、环己基、吡唑基、噻唑基、咪唑基、噁唑基、噻吩基、呋喃基、吡咯基、异噁唑基、异噻吩基、吡啶基、嘧啶基或苯基任选进一步被0至4个选自H、F、Cl、Br、CF 3、OH、氰基、NH 2、NH(CH 3)、NH(CH 2CH 3)、N(CH 3) 2、N(CH 2CH 3) 2、甲基、乙基、甲氧基、乙氧基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氮杂环戊基、氮杂环己基、氧杂环丁基、氧杂环戊基、氧杂环己基、吗啉基的取代基所取代； In certain embodiments, 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-isoxazolyl, -NH-isothienyl, -NH-pyridyl, -NH-pyrimidinyl, -NH-phenyl, -NH-ring propyl, -NH- cyclobutyl, -NH- cyclopentyl, -NH- cyclohexyl, -C (= O) NH 2 , -C (= O) NHCH 3, -C (= O) NHCH 2 CH 3 , -C(=O)NH-cyclopropyl, -C(=O)NH-cyclobutyl, -C(=O)NH-cyclopentyl, -C(=O)NH-cyclohexyl, -C (= O) NH- phenyl, -NHC (= O) H, -NHC (= O) CH 3, -NHC (= O) CH 2 CH 3, -NHC (= O) CH 2 CH 2 CH 3 , -NHC(=O)-cyclopropyl, -NHC(=O)-cyclobutyl, -NHC(=O)-cyclopentyl, -NHC(=O)-cyclohexyl or -NHC(= O)-phenyl, the methyl, ethyl, isopropyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl , cyclohexyl, pyrazolyl, thiazolyl, imidazolyl, oxazolyl, thienyl, furyl, pyrrolyl, isoxazolyl, isothienyl, pyridyl, pyrimidinyl or phenyl optionally further substituted by 0 to 4 is selected from H, 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, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidine, azacyclopentyl, azacyclohexyl, oxygen Substituted by the substituents of heterocyclobutyl, oxolane, oxanyl, and morpholinyl;
在某些实施方案中，R a各自独立的选自-CH 2-氮杂环丁基、-CH 2-氮杂环戊基、-CH 2-氮杂环己基、-CH 2-氧杂环丁基、-CH 2-氧杂环戊基、-CH 2-氧杂环己基、-CH 2-吗啉基、-CH 2-哌嗪基、-CH 2CH 2-氮杂环丁基、-CH 2CH 2-氮杂环戊基、-CH 2CH 2-氮杂环己基、-CH 2CH 2-氧杂环丁基、-CH 2CH 2-氧杂环戊基、-CH 2CH 2-氧杂环己基、-CH 2CH 2-吗啉基、-CH 2CH 2-哌嗪基，所述的氮杂环丁基、氮杂环戊基、氮杂环己基、氧杂环丁基、氧杂环戊基、氧杂环己基、吗啉基任选进一步被0至4个选自H、F、Cl、Br、CF 3、OH、氰基、NH 2、NH(CH 3)、NH(CH 2CH 3)、N(CH 3) 2、N(CH 2CH 3) 2、甲基、乙基、甲氧基、乙氧基的取代基所取代； In certain embodiments, 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 -morpholinyl, -CH 2 CH 2 -piperazinyl, said azetidinyl, azacyclopentyl, azacyclohexyl, oxa Cyclobutyl, oxolane, oxhexyl, morpholinyl are optionally further selected from 0 to 4 groups selected from H, 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, ethoxy substituents;
在某些实施方案中，R a各自独立的选自H、甲基、乙基、丙基、丁基、异丙基、环丙基、环丁基、-CH 2CH 2CN、
Figure PCTCN2021103485-appb-000020
Figure PCTCN2021103485-appb-000021
In certain embodiments, R a is independently selected from H, methyl, ethyl, propyl, butyl, isopropyl, cyclopropyl, cyclobutyl, -CH 2 CH 2 CN,
Figure PCTCN2021103485-appb-000020
Figure PCTCN2021103485-appb-000021
在某些实施方案中，R a各自独立的选自H、甲基、乙基、丙基、丁基、异丙基、异丁基、仲丁基、叔丁基、环丙基、环丁基、-CH 2CH 2CN、
Figure PCTCN2021103485-appb-000022
Figure PCTCN2021103485-appb-000023
Figure PCTCN2021103485-appb-000024
所述的甲基、乙基、丙基、丁基、异丙基、异丁基、仲丁基、叔丁基、环丙基、环丁基、-CH 2CH 2CN任选进一步被0至3个(例如0、1、2或3个)选自F、Cl、Br、CF 3、OH、氰基、NH 2、NH(CH 3)、NH(CH 2CH 3)、N(CH 3) 2、N(CH 2CH 3) 2、甲基、乙基、甲氧基、乙氧基的取代基所取代(例如被0、1、2或3个选自F、Cl、Br、CF 3、OH、氰基、NH 2的取代基所取代)； In certain embodiments, 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,
Figure PCTCN2021103485-appb-000022
Figure PCTCN2021103485-appb-000023
Figure PCTCN2021103485-appb-000024
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. 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, ethoxy substituents (for example, by 0, 1, 2 or 3 selected from F, Cl, Br, Substituents of CF 3 , OH, cyano, NH 2 );
在某些实施方案中，环B选自非芳香的C 3-12碳环，所述的碳环任选自单环、并环、桥环或者螺环，所述的碳环、单环、并环、桥环或者螺环任选进一步被0至3个(例如0、1、2或3个)R b所取代； In certain embodiments, 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;
在某些实施方案中，环B选自C 3-8单环烷基、C 4-10并环烷基、C 4-12螺环烷基、C 5-12桥环烷基，所述的环烷基任选进一步被0至3个(例如0、1、2或3个)R b所取代； In certain embodiments, 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;
在某些实施方案中，环B选自C 5-8单环烷基、C 8-10并环烷基、C 8-12螺环烷基、C 8-12桥环烷基，所述的环烷基任选进一步被0至3个(例如0、1、2或3个)R b所取代； In certain embodiments, 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;
在某些实施方案中，环B选自C 5-7单环烷基、C 9-10并环烷基、C 9-12螺环烷基、C 9-12桥环烷基，所述的环烷基任选进一步被0至3个(例如0、1、2或3个)R b所取代； In certain embodiments, 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;
在某些实施方案中，环B选自C 5-7单环烷基、C 9-10并环烷基、C 9-12螺环烷基、C 9-12桥环烷基，所述的环烷基任选进一步被0至3个(例如0、1、2或3个)R b所取代； In certain embodiments, 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;
在某些实施方案中，环B选自C 5单环烷基、C 6单环烷基、C 7单环烷基、C 6并环烷基、C 7并环烷基、C 8并环烷基、C 9并环烷基、C 10并环烷基、C 6螺环烷基、C 7螺环烷基、C 8螺环烷基、C 9螺环烷基、C 10螺环烷基、C 11螺环烷基、C 12螺环烷基、C 5桥环烷基、C 6桥环烷基、C 7桥环烷基、C 8桥环烷基、C 9桥环烷基、C 10桥环烷基、C 11桥环烷基、C 12桥环烷基，所述的环烷基任选进一步被0至3个(例如0、1、2或3个)R b所取代； In certain embodiments, 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 11 bridged cycloalkyl, C 12 bridged cycloalkyl, optionally further 0 to 3 (eg 0, 1, 2 or 3) R b replace;
在某些实施方案中，环B选自取代或者未取代的如下基团之一：环丙基、环丁基、环戊基、环己基、环丙基并环丁基、环丙基并环戊基、环丙基并环已基、环丁基并环丁基、环丁基并环戊基、环丁基并环已基、环戊基并环戊基、环戊基并环已基、环已基并环已基、环丙基螺环丁基、环丙基螺环戊基、环丙基螺环已基、环丁基螺环丁基、环丁基螺环戊基、环丁基螺环已基、环戊基螺环戊基、环戊基螺环已基、环已基螺环已基、双环[1.1.1]戊烷基、双环[2.1.1]己烷基、双环[2.2.1]庚烷基、双环[3.3.2]癸烷基、双环[2.2.2]辛烷基、双环[3.2.1]辛烷基、双环[3.3.3]十一烷基或金刚烷基，当被取代时，任选进一步被0至3个(例如0、1、2或3个)选自H、卤素、氰基、OH、C 1-4烷基或C 1-4烷氧基的取代基所取代； In certain embodiments, 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 cyclopentyl, cyclopropyl spiro cyclohexyl, cyclobutyl spiro cyclobutyl, cyclobutyl spiro cyclopentyl, cyclopentyl Butylspirohexyl, cyclopentylspirocyclopentyl, cyclopentylspirocyclohexyl, cyclohexylspirocyclohexyl, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl , bicyclo[2.2.1]heptyl, bicyclo[3.3.2]decyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.3.3]undecanyl or adamantyl, when substituted, optionally further substituted with 0 to 3 (e.g. 2 or 3) selected from H, halo, cyano, OH, C 1-4 alkyl or a C 1 -4 alkoxy substituents are substituted;
在某些实施方案中，环B选自
Figure PCTCN2021103485-appb-000025
Figure PCTCN2021103485-appb-000026
Figure PCTCN2021103485-appb-000027
右侧与R 2直接连接； In certain embodiments, Ring B is selected from
Figure PCTCN2021103485-appb-000025
Figure PCTCN2021103485-appb-000026
Figure PCTCN2021103485-appb-000027
R 2 is directly connected to the right;
在某些实施方案中，环B选自
Figure PCTCN2021103485-appb-000028
Figure PCTCN2021103485-appb-000029
右侧与R 2直接连接； In certain embodiments, Ring B is selected from
Figure PCTCN2021103485-appb-000028
Figure PCTCN2021103485-appb-000029
R 2 is directly connected to the right;
在某些实施方案中，环B选自
Figure PCTCN2021103485-appb-000030
Figure PCTCN2021103485-appb-000031
右侧与R 2直接连接； In certain embodiments, Ring B is selected from
Figure PCTCN2021103485-appb-000030
Figure PCTCN2021103485-appb-000031
R 2 is directly connected to the right;
在某些实施方案中，环B选自
Figure PCTCN2021103485-appb-000032
右侧与R 2直接连接； In certain embodiments, Ring B is selected from
Figure PCTCN2021103485-appb-000032
R 2 is directly connected to the right;
在某些实施方案中，环B选自
Figure PCTCN2021103485-appb-000033
右侧与R 2直接连接； In certain embodiments, Ring B is selected from
Figure PCTCN2021103485-appb-000033
R 2 is directly connected to the right;
在某些实施方案中，R b各自独立的选自H、卤素、氰基、OH、C 1-6烷基或C 1-6烷氧基，所述的烷基或烷氧基任选进一步被0至4个(例如0、1、2、3或4个)选自H、卤素、OH、氰基、NH 2、C 1-6烷基、卤素取代的C 1-6烷基、C 1-6烷氧基或C 3-6环烷基的取代基所取代； In certain embodiments, 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;
在某些实施方案中，R b各自独立的选自H、卤素、氰基、OH、C 1-4烷基或C 1-4烷氧基，所述的烷基或烷氧基任选进一步被0至4个(例如0、1、2、3或4个)选自H、卤素、OH、氰基、NH 2、C 1-4烷基、卤素取代的C 1-4烷基、C 1-4烷氧基或C 3-4环烷基的取代基所取代； In certain embodiments, 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;
在某些实施方案中，R b各自独立的选自H、卤素、氰基、OH、C 1-4烷基或C 1-4烷氧基； In certain embodiments, each R b is independently selected from H, halogen, cyano, OH, C 1-4 alkyl or C 1-4 alkoxy;
在某些实施方案中，R b各自独立的选自H、F、氰基、OH、甲基、乙基、甲氧基、乙氧基或羟甲基； In certain embodiments, each R b is independently selected from H, F, cyano, OH, methyl, ethyl, methoxy, ethoxy, or hydroxymethyl;
在某些实施方案中，R 1选自5至10元杂芳基或者苯基，所述的杂芳基或者苯基任选进一步被0至4个(例如0、1、2、3或4个)R 1a取代； In certain embodiments, 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;
在某些实施方案中，R 1选自取代或者未取代的如下基团之一：选自5至6元单环杂芳基、6并6元杂芳基、5并6元杂芳基或苯基，当被取代时，任选进一步被0至4个(例如0、1、2、3或4个)R 1a取代； In certain embodiments, 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 ;
在某些实施方案中，R 1选自取代或者未取代的如下基团之一：吡啶基、嘧啶基、吡嗪基、哒嗪基、吡唑基、吡咯基、咪唑基、噻吩基、呋喃基、噻唑基、噁唑基、异噻唑基、异噁唑基、苯并吡唑基、苯并吡咯基、苯并咪唑基、苯并噻吩基、苯并呋喃基、苯并噻唑基、苯并噁唑基、苯并异噻唑基或苯并异噁唑基，当被取代时，任选进一步被0至4个(例如0、1、2、3或4个)R 1a取代； In certain embodiments, 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 ;
在某些实施方案中，R 1选自
Figure PCTCN2021103485-appb-000034
Figure PCTCN2021103485-appb-000035
Figure PCTCN2021103485-appb-000036
R 1基团中的NH不能被R 1a取代，m选自0、1或2； In certain embodiments, R 1 is selected from
Figure PCTCN2021103485-appb-000034
Figure PCTCN2021103485-appb-000035
Figure PCTCN2021103485-appb-000036
The NH in the R 1 group cannot be substituted by R 1a , and m is selected from 0, 1 or 2;
在某些实施方案中，R 1选自
Figure PCTCN2021103485-appb-000037
Figure PCTCN2021103485-appb-000038
Figure PCTCN2021103485-appb-000039
Figure PCTCN2021103485-appb-000040
m选自0、1或2； In certain embodiments, R 1 is selected from
Figure PCTCN2021103485-appb-000037
Figure PCTCN2021103485-appb-000038
Figure PCTCN2021103485-appb-000039
Figure PCTCN2021103485-appb-000040
m is selected from 0, 1 or 2;
在某些实施方案中，R 1选自
Figure PCTCN2021103485-appb-000041
m选自0、1或2； In certain embodiments, R 1 is selected from
Figure PCTCN2021103485-appb-000041
m is selected from 0, 1 or 2;
在某些实施方案中，R 1b选自C 1-6烷基或C 3-6环烷基，所述的烷基或环烷基任选进一步被0至4个(例如0、1、2、3或4个)选自H、卤素、OH、氰基、NH 2、卤素取代的C 1-6烷基、C 1-6烷基、C 1-6烷氧基或C 3-6环烷基的取代基所取代； In certain embodiments, 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;
在某些实施方案中，R 1b选自C 1-4烷基或C 3-6环烷基，所述的烷基或环烷基任选进一步被0至4个(例如0、1、2、3或4个)选自H、卤素、OH、氰基、NH 2、卤素取代的C 1-6烷基、C 1-6烷基、C 1-6烷氧基或C 3-6环烷基的取代基所取代； In certain embodiments, 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;
在某些实施方案中，R 1b选自甲基、乙基、异丙基、环丙基、环丁基、环戊基或环己基，所述的甲基、乙基、异丙基、环丙基、环丁基、环戊基或环己基任选进一步被0至4个(例如0、1、2、3或4个)选自H、卤素、OH、氰基、NH 2、卤素取代的C 1-6烷基、C 1-6烷基、C 1-6烷氧基或C 3-6环烷基的取代基所取代； In certain embodiments, 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. 2, 3 or 4) selected from H, halo, OH, cyano, NH 2, halo-substituted substituted by the substituents of C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkoxy or C 3-6 cycloalkyl;
在某些实施方案中，R 1选自
Figure PCTCN2021103485-appb-000042
Figure PCTCN2021103485-appb-000043
Figure PCTCN2021103485-appb-000044
In certain embodiments, R 1 is selected from
Figure PCTCN2021103485-appb-000042
Figure PCTCN2021103485-appb-000043
Figure PCTCN2021103485-appb-000044
在某些实施方案中，R 1选自
Figure PCTCN2021103485-appb-000045
In certain embodiments, R 1 is selected from
Figure PCTCN2021103485-appb-000045
在某些实施方案中，R 1选自
Figure PCTCN2021103485-appb-000046
In certain embodiments, R 1 is selected from
Figure PCTCN2021103485-appb-000046
在某些实施方案中，R 1选自
Figure PCTCN2021103485-appb-000047
In certain embodiments, R 1 is selected from
Figure PCTCN2021103485-appb-000047
在某些实施方案中，R 1a各自独立的选自H、卤素、OH、氰基、NH 2、-NH(C 1-6烷基)、-N(C 1-6烷基) 2、-NH(C 3-6环烷基)、C 1-6烷基、C 1-6烷氧基、C 3-6环烷基或3至8元杂环基，所述的烷基、烷氧基、环烷基或杂环基任选进一步被0至4个(例如0、1、2、3或4个)选自H、卤素、OH、氰基、NH 2、卤素取代的C 1-6烷基、C 1-6烷基、C 1-6烷氧基或C 3-6环烷基的取代基所取代； In certain embodiments, 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. 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;
在某些实施方案中，R 1a各自独立的选自H、卤素、OH、氰基、NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、-NH(C 3-4环烷基)、C 1-4烷基或C 1-4烷氧基，所述的烷基或烷氧基任选进一步被0至4个(例如0、1、2、3或4个)选自H、卤素、OH、氰基、NH 2、卤素取代的C 1-4烷基、C 1-4烷基、C 1-4烷氧基或C 3-6环烷基的取代基所取代； In certain embodiments, 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;
在某些实施方案中，R 1a各自独立的选自H、F、OH、氰基、甲基、乙基、异丙基、丙基、甲氧基或乙氧基，所述的甲基、乙基、异丙基、丙基、甲氧基或乙氧基任选进一步被0至4个(例如0、1、2、3或4个)选自H、卤素、OH、氰基、NH 2、卤素取代的C 1-4烷基、C 1-4烷基、C 1-4烷氧基或C 3-6环烷基的取代基所取代； In certain embodiments, 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;
在某些实施方案中，R 2选自卤素、氰基、OH、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、-(CH 2) q-C(＝O)-R 2a、-(CH 2) q-C(＝O)O-R 2a、-(CH 2) q-S(＝O) 2-R 2a、-(CH 2) q-NR 2aS(＝O) 2-R 2b、-(CH 2) q-C(＝O)-NR 2aR 2b、-(CH 2) q-NR 2aR 2b、-(CH 2) qNR 2aC(＝O)-R 2b、- (CH 2) q-C 3-10碳环或-(CH 2) q-3至12元杂环，所述的-CH 2-、烷基、烯基、炔基、烷氧基、碳环或杂环任选进一步被0至4个(例如0、1、2、3或4个)选自H、卤素、OH、氰基、NH 2、C 1-6烷基、卤素取代的C 1-6烷基、氰基取代的C 1-6烷基或C 1-6烷氧基的取代基所取代，所述的杂环含有1至3个(例如1、2或3个)选自O、S、N的杂原子； In certain embodiments, R 2 is selected from halogen, cyano, OH, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, -(CH 2 ) q -C(=O)-R 2a , -(CH 2 ) q -C(=O)OR 2a , -(CH 2 ) q -S(=O) 2 -R 2a , -(CH 2 ) q -NR 2a S(=O) 2 -R 2b , -(CH 2 ) q -C(=O)-NR 2a R 2b , -(CH 2 ) q -NR 2a R 2b , -(CH 2 ) q NR 2a C(=O)-R 2b , -(CH 2 ) q -C 3-10 carbocycle or -(CH 2 ) q -3- to 12-membered heterocycle, the -CH 2 -, alkyl, alkenyl, alkynyl, 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, C 1-6 alkyl, halogen substituted C 1-6 alkyl, cyano substituted C 1-6 alkyl or C 1-6 alkoxy substituent, the heterocycle contains 1 to 3 (e.g. 1, 2 or 3) heteroatoms selected from O, S, N;
在某些实施方案中，R 2选自卤素、氰基、OH、C 1-4烷基、C 1-4烷氧基、-(CH 2) q-C(＝O)-R 2a、-(CH 2) q-C(＝O)O-R 2a、-(CH 2) q-S(＝O) 2-R 2a、-(CH 2) q-NR 2aS(＝O) 2-R 2b、-(CH 2) q-C(＝O)-NR 2aR 2b、-(CH 2) q-NR 2aR 2b、-(CH 2) qNR 2aC(＝O)-R 2b、-(CH 2) q-C 3-10碳环或-(CH 2) q-3至10元杂环，所述的-CH 2-、烷基、烷氧基、碳环或杂环任选进一步被0至4个(例如0、1、2、3或4个)选自H、卤素、OH、氰基、NH 2、C 1-4烷基、卤素取代的C 1-4烷基、氰基取代的C 1-4烷基或C 1-4烷氧基的取代基所取代，所述的杂环含有1至3个(例如1、2或3个)选自O、S、N的杂原子； In certain embodiments, R 2 is selected from halogen, cyano, OH, C 1-4 alkyl, C 1-4 alkoxy, -(CH 2 ) q -C(=O)-R 2a , - (CH 2 ) q -C(=O)OR 2a , -(CH 2 ) q -S(=O) 2 -R 2a , -(CH 2 ) q -NR 2a S(=O) 2 -R 2b , -(CH 2 ) q -C(=O)-NR 2a R 2b , -(CH 2 ) q -NR 2a R 2b , -(CH 2 ) q NR 2a C(=O)-R 2b , -(CH 2 ) q- C 3-10 carbocyclic ring or -(CH 2 ) q -3- to 10-membered heterocyclic ring, the -CH 2 -, alkyl, alkoxy, carbocyclic or heterocyclic ring is optionally further substituted by O 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 substituted by the C 1-4 alkyl or C 1-4 alkoxy substituent, the heterocycle contains 1 to 3 (eg 1, 2 or 3) heteroatoms selected from O, S, N ;
在某些实施方案中，R 2选自卤素、氰基、OH、C 1-4烷基、C 1-4烷氧基、C 3-6碳环、3至6元杂环、-CH 2-C 3-6碳环、-CH 2-3至6元杂环、-NH-C 3-6碳环、-NH-3至6元杂环或-NHC 1-4烷基，所述的-CH 2-、烷基、烷氧基、碳环或杂环任选进一步被0至4个(例如0、1、2、3或4个)选自H、卤素、OH、氰基、NH 2、C 1-4烷基、卤素取代的C 1-4烷基、氰基取代的C 1-4烷基或C 1-4烷氧基的取代基所取代，所述的杂环含有1至3个(例如1、2或3个)选自O、S、N的杂原子； In certain embodiments, 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. 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;
在某些实施方案中，R 2选自取代的或者未取代的如下基团之一：F、氰基、OH、甲基、乙基、甲氧基、乙氧基、环丙基、环丁基、环戊基、环己基、-CH 2-环丙基、-CH 2-环丁基、-CH 2-环戊基、-CH 2-环己基、氮杂环丁基、氮杂环戊基、氮杂环己基、-CH 2-氮杂环丁基、-CH 2-氮杂环戊基、-CH 2-氮杂环己基、氧杂环丁基、氧杂环戊基、氧杂环己基、-CH 2-氧杂环丁基、-CH 2-氧杂环戊基、-CH 2-氧杂环己基、-CH 2-吗啉、-CH 2-哌嗪、-NH-甲基、-NH-乙基、-NH-丙基、-NH-丁基、-NH-异丙基，当被取代时，任选进一步被0至4个(例如0、1、2、3或4个)选自H、卤素、OH、氰基、NH 2、C 1-4烷基、卤素取代的C 1-4烷基、氰基取代的C 1-4烷基或C 1-4烷氧基的取代基所取； In certain embodiments, 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 - oxolanyl, -CH 2 - oxetanyl hexyl, -CH 2 - morpholine, -CH 2 - piperazine, -NH- A group, -NH-ethyl, -NH-propyl, -NH-butyl, -NH-isopropyl, when substituted, optionally further 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, cyano substituted C 1-4 alkyl or C 1-4 alkane Taken from the substituent of oxy;
在某些实施方案中，R 2选自取代的或者未取代的如下基团之一：F、氰基、OH、甲基、乙基、甲氧基、乙氧基、环丙基、环丁基、环戊基、环己基、-CH 2-环丙基、-CH 2-环丁基、-CH 2-环戊基、-CH 2-环己基、氮杂环丁基、氮杂环戊基、氮杂环己基、-CH 2-氮杂环丁基、-CH 2-氮杂环戊基、-CH 2-氮杂环己基、氧杂环丁基、氧杂环戊基、氧杂环己基、-CH 2-氧杂环丁基、-CH 2-氧杂环戊基、-CH 2-氧杂环己基、-CH 2-吗啉、-CH 2-哌嗪、-NH- 甲基、-NH-乙基、-NH-丙基、-NH-丁基、-NH-异丙基，当被取代时，任选进一步被0至4个(例如0、1、2、3或4个)选自H、F、OH、氰基、NH 2、甲基、乙基、CF 3、-CH 2CN、-CH 2CH 2CN、-CH 2CH 2CH 2CN、甲氧基或乙氧基的取代基所取； In certain embodiments, 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 - oxolanyl, -CH 2 - oxetanyl hexyl, -CH 2 - morpholine, -CH 2 - piperazine, -NH- A group, -NH-ethyl, -NH-propyl, -NH-butyl, -NH-isopropyl, when substituted, optionally further 0 to 4 (eg 0, 1, 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 the substituent of ethoxy;
在某些实施方案中，R 2选自F、氰基、OH、-OCH 3、-OCHF 2、-OCH 2F、-OCF 3、甲基、乙基、CF 3、-CH 2OH、-CH 2CH 2OH、-CH 2CH 2CH 2OH、-CH 2CN、-CH 2CH 2CN、-CH 2CH 2CH 2CN、-CH 2CH 2CH 2CH 2CN、-NHCH 2CN、-NHCH 2CH 2CN、-NHCH 2CH 2CH 2CN、-NHCH 2CH 2CH 2CH 2CN、
Figure PCTCN2021103485-appb-000048
Figure PCTCN2021103485-appb-000049
In certain embodiments, 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,
Figure PCTCN2021103485-appb-000048
Figure PCTCN2021103485-appb-000049
在某些实施方案中，R 2选自F、OH、-OCH 3、-OCHF 2、-OCH 2F、-OCF 3、-CH 2OH、-CH 2CN、-CH 2CH 2CN、-NHCH 2CN、-NHCH 2CH 2CN； In certain embodiments, 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;
在某些实施方案中，R 2选自F、-OCHF 2、-OCH 2F、-OCF 3、-OCH 3、OH、-CH 2OH、-CH 2CN、-CH 2CH 2CN或-NHCH 2CH 2CN； In certain embodiments, 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;
在某些实施方案中，R 2选自F、OH、-CH 2OH、-CH 2CN、-NHCH 2CH 2CN或-NHCH 2CN； In certain embodiments, R 2 is selected from F, OH, -CH 2 OH, -CH 2 CN, -NHCH 2 CH 2 CN, or -NHCH 2 CN;
在某些实施方案中，R a1、R a2、R 2a、R 2b各自独立的选自H、C 1-6烷基、C 3-12碳环基或3至12元杂环基，所述的烷基、碳环基或杂环基任选进一步被0至4个(例如0、1、2、3或4个)选自H、卤素、OH、氰基、NH 2、C 1-6烷基、卤素取代的C 1-6烷基、氰基取代的C 1-6烷基或C 1-6烷氧基的取代基所取代，所述的杂环基含有1至3个(例如1、2或3个)选自O、S、N的杂原子； In certain embodiments, 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;
在某些实施方案中，R a1、R a2、R 2a、R 2b各自独立的选自H、C 1-4烷基、C 3-10碳环基或3至10元杂环基，所述的烷基、碳环基或杂环基任选进一步被0至4个(例如0、1、2、3或4个)选自H、卤素、OH、氰基、NH 2、C 1-4烷基、卤素取代的C 1-4烷基、氰基取代的C 1-4烷基或C 1-4烷氧基的取代基所取代，所述的杂环基含有1至3个(例如1、2或3个)选自O、S、N的杂原子； In certain embodiments, 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;
在某些实施方案中，R a2选自H、C 1-4烷基、C 3-6碳环基或3至6元杂环基，所述的烷基、碳环基或杂环基任选进一步被0至4个(例如0、1、2、3或4个)选自H、卤素、 OH、氰基、NH 2、C 1-4烷基、卤素取代的C 1-4烷基、氰基取代的C 1-4烷基或C 1-4烷氧基的取代基所取代，所述的杂环基含有1至3个(例如1、2或3个)选自O、S、N的杂原子； In certain embodiments, 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;
在某些实施方案中，
Figure PCTCN2021103485-appb-000050
选自
Figure PCTCN2021103485-appb-000051
Figure PCTCN2021103485-appb-000052
Figure PCTCN2021103485-appb-000053
In certain embodiments,
Figure PCTCN2021103485-appb-000050
selected from
Figure PCTCN2021103485-appb-000051
Figure PCTCN2021103485-appb-000052
Figure PCTCN2021103485-appb-000053
在某些实施方案中，
Figure PCTCN2021103485-appb-000054
选自
Figure PCTCN2021103485-appb-000055
Figure PCTCN2021103485-appb-000056
In certain embodiments,
Figure PCTCN2021103485-appb-000054
selected from
Figure PCTCN2021103485-appb-000055
Figure PCTCN2021103485-appb-000056
在某些实施方案中，
Figure PCTCN2021103485-appb-000057
选自
Figure PCTCN2021103485-appb-000058
Figure PCTCN2021103485-appb-000059
In certain embodiments,
Figure PCTCN2021103485-appb-000057
selected from
Figure PCTCN2021103485-appb-000058
Figure PCTCN2021103485-appb-000059
在某些实施方案中，
Figure PCTCN2021103485-appb-000060
选自
Figure PCTCN2021103485-appb-000061
Figure PCTCN2021103485-appb-000062
In certain embodiments,
Figure PCTCN2021103485-appb-000060
selected from
Figure PCTCN2021103485-appb-000061
Figure PCTCN2021103485-appb-000062
在某些实施方案中，
Figure PCTCN2021103485-appb-000063
选自
Figure PCTCN2021103485-appb-000064
Figure PCTCN2021103485-appb-000065
Figure PCTCN2021103485-appb-000066
In certain embodiments,
Figure PCTCN2021103485-appb-000063
selected from
Figure PCTCN2021103485-appb-000064
Figure PCTCN2021103485-appb-000065
Figure PCTCN2021103485-appb-000066
在某些实施方案中，
Figure PCTCN2021103485-appb-000067
选自
Figure PCTCN2021103485-appb-000068
Figure PCTCN2021103485-appb-000069
In certain embodiments,
Figure PCTCN2021103485-appb-000067
selected from
Figure PCTCN2021103485-appb-000068
Figure PCTCN2021103485-appb-000069
在某些实施方案中，
Figure PCTCN2021103485-appb-000070
选自
Figure PCTCN2021103485-appb-000071
Figure PCTCN2021103485-appb-000072
In certain embodiments,
Figure PCTCN2021103485-appb-000070
selected from
Figure PCTCN2021103485-appb-000071
Figure PCTCN2021103485-appb-000072
在某些实施方案中，
Figure PCTCN2021103485-appb-000073
选自
Figure PCTCN2021103485-appb-000074
In certain embodiments,
Figure PCTCN2021103485-appb-000073
selected from
Figure PCTCN2021103485-appb-000074
在某些实施方案中，
Figure PCTCN2021103485-appb-000075
选自
Figure PCTCN2021103485-appb-000076
Figure PCTCN2021103485-appb-000077
In certain embodiments,
Figure PCTCN2021103485-appb-000075
selected from
Figure PCTCN2021103485-appb-000076
Figure PCTCN2021103485-appb-000077
在某些实施方案中，
Figure PCTCN2021103485-appb-000078
选自
Figure PCTCN2021103485-appb-000079
Figure PCTCN2021103485-appb-000080
In certain embodiments,
Figure PCTCN2021103485-appb-000078
selected from
Figure PCTCN2021103485-appb-000079
Figure PCTCN2021103485-appb-000080
在某些实施方案中，
Figure PCTCN2021103485-appb-000081
选自
Figure PCTCN2021103485-appb-000082
Figure PCTCN2021103485-appb-000083
Figure PCTCN2021103485-appb-000084
In certain embodiments,
Figure PCTCN2021103485-appb-000081
selected from
Figure PCTCN2021103485-appb-000082
Figure PCTCN2021103485-appb-000083
Figure PCTCN2021103485-appb-000084
在某些实施方案中，
Figure PCTCN2021103485-appb-000085
选自
Figure PCTCN2021103485-appb-000086
Figure PCTCN2021103485-appb-000087
In certain embodiments,
Figure PCTCN2021103485-appb-000085
selected from
Figure PCTCN2021103485-appb-000086
Figure PCTCN2021103485-appb-000087
在某些实施方案中，
Figure PCTCN2021103485-appb-000088
选自
Figure PCTCN2021103485-appb-000089
In certain embodiments,
Figure PCTCN2021103485-appb-000088
selected from
Figure PCTCN2021103485-appb-000089
在某些实施方案中，环A选自
Figure PCTCN2021103485-appb-000090
上方与L直接连接，环B选自
Figure PCTCN2021103485-appb-000091
右侧与R 2直接连接； In certain embodiments, Ring A is selected from
Figure PCTCN2021103485-appb-000090
The top is directly connected to L, and the ring B is selected from
Figure PCTCN2021103485-appb-000091
R 2 is directly connected to the right;
q各自独立的选自0、1、2、3或4。q is each independently selected from 0, 1, 2, 3 or 4.
作为本发明的第一种实施方案，上述通式(I)所示化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，As the first embodiment of the present invention, the compound represented by the above general formula (I) or its stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal,
L选自键或者NR n2； L is selected from a bond or NR n2 ;
R n1、R n2各自独立的选自H、C 1-6烷基或C 3-6环烷基，所述的烷基或环烷基任选进一步被0至4个(例如0、1、2、3或4个)选自H、卤素、CF 3、OH、氰基、NH 2、C 1-6烷基或C 1-6烷氧基的取代基所取代； 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;
环A选自5-6元单环杂芳环或8-10元并环杂芳环，所述的杂芳环任选进一步被0至3个(例如0、1、2或3个)R a取代，所述的杂芳环含有1至5个(例如1、2、3、4个或5)选自O、S、N的杂原子； 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;
R a各自独立的选自H、卤素、氰基、OH、C 1-6烷基、C 1-6烷氧基、-(CH 2) q-C(＝O)-NR a1R a2、-(CH 2) q-NR a1R a2、-(CH 2) qNR a1C(＝O)-R a2、-(CH 2) q-C 3-10碳环或-(CH 2) q-3至12元 杂环，所述的-CH 2-、烷基、烷氧基、碳环或杂环任选进一步被0至4个(例如0、1、2、3或4个)选自H、卤素、OH、氰基、NH 2、NH(C 1-6烷基)、N(C 1-6烷基) 2、C 1-6烷基、卤素取代的C 1-6烷基、C 1-6烷氧基、C 3-6环烷基或3至10元杂环的取代基所取代，所述的杂环含有1至3个(例如1、2或3个)选自O、S、N的杂原子； R a is each independently selected from H, halogen, cyano, OH, C 1-6 alkyl, C 1-6 alkoxy, -(CH 2 ) q -C(=O)-NR a1 R a2 , - (CH 2 ) q -NR a1 R a2 , -(CH 2 ) q NR a1 C(=O)-R a2 , -(CH 2 ) q -C 3-10 carbocyclic or -(CH 2 ) q -3 to 12-membered heterocyclic ring, said -CH 2 -, alkyl, alkoxy, carbocyclic or heterocyclic ring is optionally further substituted with 0 to 4 (e.g. 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;
环B选自非芳香的C 3-12碳环，所述的碳环任选自单环、并环、桥环或者螺环，所述的碳环、单环、并环、桥环或者螺环任选进一步被0至3个(例如0、1、2或3个)R b所取代； 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各自独立的选自H、卤素、氰基、OH、C 1-6烷基或C 1-6烷氧基，所述的烷基或烷氧基任选进一步被0至4个(例如0、1、2、3或4个)选自H、卤素、OH、氰基、NH 2、C 1-6烷基、卤素取代的C 1-6烷基、C 1-6烷氧基或C 3-6环烷基的取代基所取代； 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选自5至10元杂芳基或者苯基，所述的杂芳基或者苯基任选进一步被0至4个(例如0、1、2、3或4个)R 1a取代； 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各自独立的选自H、卤素、OH、氰基、NH 2、-NH(C 1-6烷基)、-N(C 1-6烷基) 2、-NH(C 3-6环烷基)、C 1-6烷基、C 1-6烷氧基、C 3-6环烷基或3至8元杂环基，所述的烷基、烷氧基、环烷基或杂环基任选进一步被0至4个(例如0、1、2、3或4个)选自H、卤素、OH、氰基、NH 2、卤素取代的C 1-6烷基、C 1-6烷基、C 1-6烷氧基或C 3-6环烷基的取代基所取代； 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. 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;
R 2选自卤素、氰基、OH、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、-(CH 2) q-C(＝O)-R 2a、-(CH 2) q-C(＝O)O-R 2a、-(CH 2) q-S(＝O) 2-R 2a、-(CH 2) q-NR 2aS(＝O) 2-R 2b、-(CH 2) q-C(＝O)-NR 2aR 2b、-(CH 2) q-NR 2aR 2b、-(CH 2) qNR 2aC(＝O)-R 2b、-(CH 2) q-C 3-10碳环或-(CH 2) q-3至12元杂环，所述的-CH 2-、烷基、烯基、炔基、烷氧基、碳环或杂环任选进一步被0至4个(例如0、1、2、3或4个)选自H、卤素、OH、氰基、NH 2、C 1-6烷基、卤素取代的C 1-6烷基、氰基取代的C 1-6烷基或C 1-6烷氧基的取代基所取代，所述的杂环含有1至3个(例如1、2或3个)选自O、S、N的杂原子； R 2 is selected from halogen, cyano, OH, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, -(CH 2 ) q -C(= O)-R 2a , -(CH 2 ) q -C(=O)OR 2a , -(CH 2 ) q -S(=O) 2 -R 2a , -(CH 2 ) q -NR 2a S(= O) 2 -R 2b , -(CH 2 ) q -C(=O)-NR 2a R 2b , -(CH 2 ) q -NR 2a R 2b , -(CH 2 ) q NR 2a C(=O) -R 2b , -(CH 2 ) q -C 3-10 carbocycle or -(CH 2 ) q -3- to 12-membered heterocycle, said -CH 2 -, alkyl, alkenyl, alkynyl, alkane alkoxy, carbocyclic or heterocyclic ring optionally further substituted with 0 to 4 (e.g. 2, 3 or 4) selected from H, halo, OH, cyano, NH 2, C 1-6 alkyl, substituted by halogen-substituted C 1-6 alkyl, cyano-substituted C 1-6 alkyl or C 1-6 alkoxy substituent, the 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各自独立的选自H、C 1-6烷基、C 3-12碳环基或3至12元杂环基，所述的烷基、碳环基或杂环基任选进一步被0至4个(例如0、1、2、3或4个)选自H、卤素、OH、氰基、NH 2、C 1-6烷基、卤素取代的C 1-6烷基、氰基取代的C 1-6烷基或C 1-6烷氧基的取代基所取代，所述的杂环基含有1至3个(例如1、2或3个)选自O、S、N的杂原子； 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各自独立的选自0、1、2、3或4。q is each independently selected from 0, 1, 2, 3 or 4.
作为本发明的第二种实施方案，下述通式(Ia)、(Ib)、(Ic)、(Id)、(Ie)所示化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，As the second embodiment of the present invention, the compounds represented by the following general formulae (Ia), (Ib), (Ic), (Id), (Ie) or their stereoisomers, deuterated compounds, solvates, pro- drugs, metabolites, pharmaceutically acceptable salts or co-crystals,
Figure PCTCN2021103485-appb-000092
Figure PCTCN2021103485-appb-000092
通式(Ib)、(Ic)、(Ie)中环C中的N原子与L连接时，L选自键；When the N atom in the ring C in the general formula (Ib), (Ic), (Ie) is connected to L, L is selected from the bond;
通式(Ib)、(Ic)、(Ie)中环C中的C原子与L连接时，L选自NH或NR n2； When the C atom in the ring C in the general formula (Ib), (Ic), (Ie) is connected to L, L is selected from NH or NR n2 ;
X 1选自CH或N，X 2选自键、CH或N，Y、Z各自独立的选自C或N； 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;
条件是X 1、X 2、Y、Z中至少有1个选自N； The condition is that at least one of X 1 , X 2 , Y and Z is selected from N;
R n1、R n2各自独立的选自H、C 1-4烷基或C 3-6环烷基，所述的烷基或环烷基任选进一步被0至4个(例如0、1、2、3或4个)选自H、卤素、CF 3、OH、氰基、NH 2、C 1-4烷基或C 1-4烷氧基的取代基所取代； 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;
环C选自5-6元杂芳环或苯环，所述的杂芳环含有1至3个(例如1、2或3)选自O、S、N的杂原子；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;
R a各自独立的选自H、卤素、氰基、OH、C 1-6烷基、C 1-6烷氧基、-(CH 2) q-C(＝O)-NR a1R a2、-(CH 2) q-NR a1R a2、-(CH 2) qNR a1C(＝O)-R a2、-(CH 2) q-C 3-10碳环或-(CH 2) q-3至12元杂环，所述的-CH 2-、烷基、烷氧基、碳环或杂环任选进一步被0至4个(例如0、1、2、3或4个)选自H、卤素、OH、氰基、NH 2、NH(C 1-6烷基)、N(C 1-6烷基) 2、C 1-6烷基、卤素取代的C 1-6烷基、C 1-6烷氧基、C 3-6环烷基或3至10元杂环的取代基所取代，所述的杂环含有1至3个(例如1、2或3个)选自O、S、N的杂原子； R a is each independently selected from H, halogen, cyano, OH, C 1-6 alkyl, C 1-6 alkoxy, -(CH 2 ) q -C(=O)-NR a1 R a2 , - (CH 2 ) q -NR a1 R a2 , -(CH 2 ) q NR a1 C(=O)-R a2 , -(CH 2 ) q -C 3-10 carbocyclic or -(CH 2 ) q -3 to 12-membered heterocyclic ring, said -CH 2 -, alkyl, alkoxy, carbocyclic or heterocyclic ring is optionally further substituted with 0 to 4 (e.g. 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;
环B选自C 3-8单环烷基、C 4-10并环烷基、C 4-12螺环烷基、C 5-12桥环烷基，所述的环烷基任选进一步被0至3个(例如0、1、2或3个)R b所取代； 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选自
Figure PCTCN2021103485-appb-000093
Figure PCTCN2021103485-appb-000094
Figure PCTCN2021103485-appb-000095
R 1基团中的NH不能被R 1a取代； R 1 is selected from
Figure PCTCN2021103485-appb-000093
Figure PCTCN2021103485-appb-000094
Figure PCTCN2021103485-appb-000095
The NH in the R 1 group cannot be substituted by R 1a;
或者R 1选自
Figure PCTCN2021103485-appb-000096
or R 1 is selected from
Figure PCTCN2021103485-appb-000096
R 1a各自独立的选自H、卤素、OH、氰基、NH 2、-NH(C 1-6烷基)、-N(C 1-6烷基) 2、-NH(C 3-6环烷基)、C 1-6烷基、C 1-6烷氧基、C 3-6环烷基或3至8元杂环基，所述的烷基、烷氧基、环烷基或杂环基任选进一步被0至4个(例如0、1、2、3或4个)选自H、卤素、OH、氰基、NH 2、卤素取代的C 1-6烷基、C 1-6烷基、C 1-6烷氧基或C 3-6环烷基的取代基所取代； 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. 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;
R 1b选自C 1-6烷基或C 3-6环烷基，所述的烷基或环烷基任选进一步被0至4个(例如0、1、2、3或4个)选自H、卤素、OH、氰基、NH 2、卤素取代的C 1-6烷基、C 1-6烷基、C 1-6烷氧基或C 3-6环烷基的取代基所取代； 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 ;
m选自0、1或2；m is selected from 0, 1 or 2;
p选自0、1或2；p is selected from 0, 1 or 2;
任选地，通式(Ic)中的
Figure PCTCN2021103485-appb-000097
选自
Figure PCTCN2021103485-appb-000098
S 1或S 2各自独立的选自N或CR a时，环B选自C 9-10并环烷基、C 9-12螺环烷基、C 9-12桥环烷基，所述的环烷基任选进一步被0至3个(例如0、1、2或3个)R b所取代； Optionally, in general formula (Ic)
Figure PCTCN2021103485-appb-000097
selected from
Figure PCTCN2021103485-appb-000098
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 optionally further substituted with 0-3 (e.g. 2 or 3) R b;
任选地，通式(Id)中
Figure PCTCN2021103485-appb-000099
选自
Figure PCTCN2021103485-appb-000100
R a选自-C(＝O)-NH-吡啶，所述吡啶任选被取代时，R 1不为
Figure PCTCN2021103485-appb-000101
Optionally, in general formula (Id)
Figure PCTCN2021103485-appb-000099
selected from
Figure PCTCN2021103485-appb-000100
R a is selected from -C(=O)-NH-pyridine, and when the pyridine is optionally substituted, R 1 is not
Figure PCTCN2021103485-appb-000101
任选地，化合物不为如下化合物及其立体异构体：
Figure PCTCN2021103485-appb-000102
Figure PCTCN2021103485-appb-000103
Figure PCTCN2021103485-appb-000104
Optionally, the compound is not the following compounds and stereoisomers thereof:
Figure PCTCN2021103485-appb-000102
Figure PCTCN2021103485-appb-000103
Figure PCTCN2021103485-appb-000104
其余基团的定义与本发明第一种实施方案一致。The definitions of the remaining groups are in accordance with the first embodiment of the present invention.
作为本发明的第三种实施方案，前述通式(Ia)、(Ib)、(Ic)、(Id)、(Ie)所示化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，As the third embodiment of the present invention, the compounds represented by the aforementioned general formulae (Ia), (Ib), (Ic), (Id), (Ie) or their stereoisomers, deuterated compounds, solvates, and prodrugs , metabolites, pharmaceutically acceptable salts or co-crystals,
R 1a各自独立的选自H、卤素、OH、氰基、NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、-NH(C 3-4环烷基)、C 1-4烷基或C 1-4烷氧基，所述的烷基或烷氧基任选进一步被0至4个(例如0、1、2、3或4个)选自H、卤素、OH、氰基、NH 2、卤素取代的C 1-4烷基、C 1-4烷基、C 1-4烷氧基或C 3-6环烷基的取代基所取代； 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选自C 1-4烷基或C 3-6环烷基，所述的烷基或环烷基任选进一步被0至4个(例如0、1、2、3或4个)选自H、卤素、OH、氰基、NH 2、卤素取代的C 1-6烷基、C 1-6烷基、C 1-6烷氧基或C 3-6环烷基的取代基所取代； 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 ;
环C选自5-6元杂芳环或苯环，所述的杂芳环含有1至3个(例如1、2或3)选自O、S、N的杂原子；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;
R a各自独立的选自H、卤素、氰基、OH、C 1-4烷基、C 1-4烷氧基、-(CH 2) q-C 3-6碳环或-(CH 2) q-3至6元杂环、-(CH 2) q-C(＝O)-NR a1R a2、-(CH 2) q-NR a1R a2或-(CH 2) qNR a1C(＝O)-R a2，所述的-CH 2-、烷基、烷氧基、碳环或杂环任选进一步被0至4个(例如0、1、2、3或4个)选自H、卤素、OH、氰基、NH 2、NH(C 1-4烷基)、N(C 1-4烷基) 2、C 1-4烷基、卤素取代的C 1-4烷基、C 1-4烷氧基、C 3-6环烷基或3至6元杂环的取代基所取代，所述的杂环含有1至3个(例如1、2或3)选自O、S、N的杂原子； R a is each independently selected from H, halogen, cyano, OH, C 1-4 alkyl, C 1-4 alkoxy, -(CH 2 ) q -C 3-6 carbocyclic or -(CH 2 ) q -3- to 6-membered heterocycle, -(CH 2 ) q -C(=O)-NR a1 R a2 , -(CH 2 ) q -NR a1 R a2 or -(CH 2 ) q NR a1 C(= O) -R a2, said -CH 2 -, alkyl, alkoxy, carbocyclic or heterocyclic ring is optionally further substituted with 0 to 4 (e.g. 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各自独立的选自H、卤素、氰基、OH、C 1-4烷基或C 1-4烷氧基，所述的烷基或烷氧基任选进一步被0至4个(例如0、1、2、3或4个)选自H、卤素、OH、氰基、NH 2、C 1-4烷基、卤素取代的C 1-4烷基、C 1-4烷氧基或C 3-4环烷基的取代基所取代； 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 2选自卤素、氰基、OH、C 1-4烷基、C 1-4烷氧基、-(CH 2) q-C(＝O)-R 2a、-(CH 2) q-C(＝O)O-R 2a、-(CH 2) q-S(＝O) 2-R 2a、-(CH 2) q-NR 2aS(＝O) 2-R 2b、-(CH 2) q-C(＝O)-NR 2aR 2b、-(CH 2) q-NR 2aR 2b、-(CH 2) qNR 2aC(＝O)-R 2b、-(CH 2) q-C 3-10碳环或-(CH 2) q-3至10元杂环，所述的-CH 2-、烷基、烷氧基、碳环或杂环任选进一步被0至4个(例如0、1、2、3或4个)选自H、卤素、OH、氰基、NH 2、C 1-4烷基、卤素取代的C 1-4烷基、氰基取代的C 1-4烷基或C 1-4烷氧基的取代基所取代，所述的杂环含有1至3个(例如1、2或3)选自O、S、N的杂原子； R 2 is selected from halogen, cyano, OH, C 1-4 alkyl, C 1-4 alkoxy, -(CH 2 ) q -C(=O)-R 2a , -(CH 2 ) q -C (=O)OR 2a , -(CH 2 ) q -S(=O) 2 -R 2a , -(CH 2 ) q -NR 2a S(=O) 2 -R 2b , -(CH 2 ) q - C(=O)-NR 2a R 2b , -(CH 2 ) q -NR 2a R 2b , -(CH 2 ) q NR 2a C(=O)-R 2b , -(CH 2 ) q -C 3- 10 carbon ring or -(CH 2 ) q -3 to 10 membered heterocycle, said -CH 2 -, alkyl, alkoxy, carbocycle or heterocycle is 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, cyano substituted C 1-4 alkyl or C 1-4 alkoxy substituents, the heterocycle contains 1 to 3 (eg 1, 2 or 3) heteroatoms selected from O, S, N;
R a1、R a2、R 2a、R 2b各自独立的选自H、C 1-4烷基、C 3-10碳环基或3至10元杂环基，所述的烷基、碳环基或杂环基任选进一步被0至4个(例如0、1、2、3或4个)选自H、卤素、OH、氰基、NH 2、C 1-4烷基、卤素取代的C 1-4烷基、氰基取代的C 1-4烷基或C 1-4烷氧基的取代基所取代，所述的杂环基含有1至3个(例如1、2或3)选自O、S、N的杂原子； 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;
其余基团的定义与本发明第一、二任意一种实施方案一致。The definitions of other groups are consistent with any one of the first and second embodiments of the present invention.
作为本发明的第四种实施方案，前述通式(Ia)、(Ib)、(Ic)、(Id)、(Ie)所示化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，As the fourth embodiment of the present invention, the compounds represented by the aforementioned general formulae (Ia), (Ib), (Ic), (Id), (Ie) or their stereoisomers, deuterated compounds, solvates, and prodrugs , metabolites, pharmaceutically acceptable salts or co-crystals,
R n1、R n2各自独立的选自H、甲基、乙基、丙基、异丙基、环丙基、环丁基、环戊基或环己基，所述的甲基、乙基、丙基、异丙基、环丙基、环丁基、环戊基或环己基任选进一步被0至4个(例如0、1、2、3或4个)选自H、卤素、CF 3、OH、氰基、NH 2、C 1-4烷基或C 1-4烷氧基的取代基所取代； 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各自独立的选自H、F、OH、氰基、甲基、乙基、异丙基、丙基、甲氧基或乙氧基，所述的甲基、乙基、异丙基、丙基、甲氧基或乙氧基任选进一步被0至4个(例如0、1、2、3或4个)选自H、卤素、OH、氰基、NH 2、卤素取代的C 1-4烷基、C 1-4烷基、C 1- 4烷氧基或C 3-6环烷基的取代基所取代； 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选自甲基、乙基、异丙基、环丙基、环丁基、环戊基或环己基，所述的甲基、乙基、异丙基、环丙基、环丁基、环戊基或环己基任选进一步被0至4个(例如0、1、2、3或4个)选自H、卤素、OH、氰基、NH 2、卤素取代的C 1-6烷基、C 1-6烷基、C 1-6烷氧基或C 3-6环烷基的取代基所取代； 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;
环C选自吡唑环、噻唑环、咪唑环、噁唑环、噻吩环、呋喃环、吡咯环、异噁唑环、异噻唑环、吡啶环、吡嗪环、哒嗪环、1,2,4-三氮唑环、嘧啶环或苯环；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 a各自独立的选自H、卤素、氰基、OH、C 1-4烷基、C 1-4烷氧基、C 3-6碳环、3至6元杂环、-CH 2-C 3-6碳环、-CH 2CH 2-C 3-6碳环、-CH 2-3至6元杂环、-CH 2CH 2-3至6元杂环、NHR a2、-C(＝O)NHR a2、-NHC(＝O)R a2，所述的-CH 2-、烷基、烷氧基、碳环或杂环任选进一步被0至4个(例如0、1、2、3或4个)选自H、卤素、OH、氰基、NH 2、NH(C 1- 4烷基)、N(C 1-4烷基) 2、C 1-4烷基、卤素取代的C 1-4烷基、C 1-4烷氧基、C 3-6环烷基或3至6元杂环的取代基所取代，所述的杂环含有1至3个(例如1、2或3)选自O、S、N的杂原子； R a is each independently selected from H, 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 CH 2 -C 3-6 carbocycle, -CH 2 -3- to 6-membered heterocycle, -CH 2 CH 2 -3- to 6-membered heterocycle, NHR a2 , -C(= O)NHR a2 , -NHC(=O)R a2 , said -CH 2 -, alkyl, alkoxy, carbocycle or heterocycle are optionally further substituted by 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, halo, OH, cyano, NH 2, NH (C 1- 4 alkyl), N (C 1-4 alkyl) 2, C 1-4 alkyl, substituted by halogen C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl or substituents of 3- to 6-membered heterocyclic rings containing 1 to 3 (eg 1, 2 or 3) a heteroatom selected from O, S, N;
R a2选自H、C 1-4烷基、C 3-6碳环基或3至6元杂环基，所述的烷基、碳环基或杂环基任选进一步被0至4个(例如0、1、2、3或4个)选自H、卤素、OH、氰基、NH 2、C 1- 4烷基、卤素取代的C 1-4烷基、氰基取代的C 1-4烷基或C 1-4烷氧基的取代基所取代，所述的杂环基含有1至3个(例如1、2或3)选自O、S、N的杂原子； 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;
环B选自取代或者未取代的如下基团之一：环丙基、环丁基、环戊基、环己基、环丙基并环丁基、环丙基并环戊基、环丙基并环已基、环丁基并环丁基、环丁基并环戊基、环丁基并环已基、环戊基并环戊基、环戊基并环已基、环已基并环已基、环丙基螺环丁基、环丙基螺环戊基、环丙基螺环已基、环丁基螺环丁基、环丁基螺环戊基、环丁基螺环已基、环戊基螺环戊基、环戊基螺环已基、环已基螺环已基、双环[1.1.1]戊烷基、双环[2.1.1]己烷基、双环[2.2.1]庚烷基、双环[3.3.2]癸烷基、双环[2.2.2]辛烷基、双环[3.2.1]辛烷基、双环[3.3.3]十一烷基或金刚烷基，当被取代时，任选进一步被0至3个(例如0、1、2或3个)选自H、卤素、氰基、OH、C 1-4烷基或C 1-4烷氧基的取代基所取代； 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, cyclobutylspirocyclohexyl, Cyclopentylspirocyclopentyl, cyclopentylspirocyclohexyl, cyclohexylspirocyclohexyl, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1] heptyl, bicyclo[3.3.2]decyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.3.3]undecyl or adamantyl, when When substituted, optionally further substituted by 0 to 3 (eg 0, 1, 2 or 3) selected from H, halogen, cyano, OH, C1-4alkyl or C1-4alkoxy base substituted;
R 2选自卤素、氰基、OH、C 1-4烷基、C 1-4烷氧基、C 3-6碳环、3至6元杂环、-CH 2-C 3-6碳环、-CH 2-3至6元杂环、-NH-C 3-6碳环、-NH-3至6元杂环或-NHC 1-4烷基，所述的-CH 2-、烷基、烷氧基、碳环或杂环任选进一步被0至4个(例如0、1、2、3或4个)选自H、卤素、OH、氰基、NH 2、C 1-4烷基、卤素取代的C 1-4烷基、氰基取代的C 1-4烷基或C 1-4烷氧基的取代基所取代，所述的杂环含有1至3个(例如1、2或3)选自O、S、N的杂原子； 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. 2, 3 or 4) 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;
其余基团的定义与本发明第一、二、三种任意一种实施方案一致。The definitions of the remaining groups are consistent with any one of the first, second and third embodiments of the present invention.
作为本发明的第五种实施方案，前述通式(Ia)、(Ib)、(Ic)、(Id)、(Ie)所示化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，As the fifth embodiment of the present invention, the compounds represented by the aforementioned general formulae (Ia), (Ib), (Ic), (Id), (Ie) or their stereoisomers, deuterated compounds, solvates, and prodrugs , metabolites, pharmaceutically acceptable salts or co-crystals,
R n1、R n2各自独立的选自H、甲基、乙基、丙基、异丙基、环丙基、环丁基、环戊基或环己基，所述的甲基、乙基、丙基、异丙基、环丙基、环丁基、环戊基或环己基任选 进一步被0至4个(例如0、1、2、3或4个)选自H、F、CF 3、OH、氰基、NH 2、甲基、乙基、甲氧基或乙氧基的取代基所取代； 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;
环B选自
Figure PCTCN2021103485-appb-000105
Figure PCTCN2021103485-appb-000106
Figure PCTCN2021103485-appb-000107
右侧与R 2直接连接； Ring B is selected from
Figure PCTCN2021103485-appb-000105
Figure PCTCN2021103485-appb-000106
Figure PCTCN2021103485-appb-000107
R 2 is directly connected to the right;
R 2选自F、氰基、OH、-OCH 3、-OCHF 2、-OCH 2F、-OCF 3、甲基、乙基、CF 3、-CH 2OH、-CH 2CH 2OH、-CH 2CH 2CH 2OH、-CH 2CN、-CH 2CH 2CN、-CH 2CH 2CH 2CN、-CH 2CH 2CH 2CH 2CN、-NHCH 2CN、-NHCH 2CH 2CN、-NHCH 2CH 2CH 2CN、-NHCH 2CH 2CH 2CH 2CN、
Figure PCTCN2021103485-appb-000108
Figure PCTCN2021103485-appb-000109
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,
Figure PCTCN2021103485-appb-000108
Figure PCTCN2021103485-appb-000109
通式(Ia)中的
Figure PCTCN2021103485-appb-000110
选自
Figure PCTCN2021103485-appb-000111
Figure PCTCN2021103485-appb-000112
Figure PCTCN2021103485-appb-000113
Figure PCTCN2021103485-appb-000114
In general formula (Ia)
Figure PCTCN2021103485-appb-000110
selected from
Figure PCTCN2021103485-appb-000111
Figure PCTCN2021103485-appb-000112
Figure PCTCN2021103485-appb-000113
Figure PCTCN2021103485-appb-000114
通式(Ib)中的
Figure PCTCN2021103485-appb-000115
选自
Figure PCTCN2021103485-appb-000116
Figure PCTCN2021103485-appb-000117
In general formula (Ib)
Figure PCTCN2021103485-appb-000115
selected from
Figure PCTCN2021103485-appb-000116
Figure PCTCN2021103485-appb-000117
通式(Ic)中的
Figure PCTCN2021103485-appb-000118
选自
Figure PCTCN2021103485-appb-000119
Figure PCTCN2021103485-appb-000120
In general formula (Ic)
Figure PCTCN2021103485-appb-000118
selected from
Figure PCTCN2021103485-appb-000119
Figure PCTCN2021103485-appb-000120
通式(Id)中的
Figure PCTCN2021103485-appb-000121
选自
Figure PCTCN2021103485-appb-000122
Figure PCTCN2021103485-appb-000123
In general formula (Id)
Figure PCTCN2021103485-appb-000121
selected from
Figure PCTCN2021103485-appb-000122
Figure PCTCN2021103485-appb-000123
或者通式(Id)中的
Figure PCTCN2021103485-appb-000124
选自
Figure PCTCN2021103485-appb-000125
Figure PCTCN2021103485-appb-000126
Figure PCTCN2021103485-appb-000127
or in general formula (Id)
Figure PCTCN2021103485-appb-000124
selected from
Figure PCTCN2021103485-appb-000125
Figure PCTCN2021103485-appb-000126
Figure PCTCN2021103485-appb-000127
通式(Ie)中的
Figure PCTCN2021103485-appb-000128
选自
Figure PCTCN2021103485-appb-000129
Figure PCTCN2021103485-appb-000130
In general formula (Ie)
Figure PCTCN2021103485-appb-000128
selected from
Figure PCTCN2021103485-appb-000129
Figure PCTCN2021103485-appb-000130
R 1选自
Figure PCTCN2021103485-appb-000131
Figure PCTCN2021103485-appb-000132
R 1 is selected from
Figure PCTCN2021103485-appb-000131
Figure PCTCN2021103485-appb-000132
或或者R 1选自
Figure PCTCN2021103485-appb-000133
or R 1 is selected from
Figure PCTCN2021103485-appb-000133
R a各自独立的选自H、F、Cl、Br、氰基、OH、甲基、乙基、丙基、丁基、异丙基、异丁基、仲丁基、叔丁基、甲氧基、乙氧基、吡唑基、噻唑基、咪唑基、噁唑基、噻吩基、呋喃基、吡咯基、异噁唑基、异噻吩基、吡啶基、嘧啶基、苯基、环丙基、环丁基、环戊基、环己基、-NH-吡唑基、-NH-噻唑基、-NH-咪唑基、-NH-噁唑基、-NH-噻吩基、- NH-呋喃基、-NH-吡咯基、-NH-异噁唑基、-NH-异噻吩基、-NH-吡啶基、-NH-嘧啶基、-NH-苯基、-NH-环丙基、-NH-环丁基、-NH-环戊基、-NH-环己基、-C(＝O)NH 2、-C(＝O)NHCH 3、-C(＝O)NHCH 2CH 3、-C(＝O)NH-环丙基、-C(＝O)NH-环丁基、-C(＝O)NH-环戊基、-C(＝O)NH-环已基、-C(＝O)NH-苯基、-NHC(＝O)H、-NHC(＝O)CH 3、-NHC(＝O)CH 2CH 3、-NHC(＝O)CH 2CH 2CH 3、-NHC(＝O)-环丙基、-NHC(＝O)-环丁基、-NHC(＝O)-环戊基、-NHC(＝O)-环已基或-NHC(＝O)-苯基，所述的甲基、乙基、异丙基、异丁基、仲丁基、叔丁基、甲氧基、乙氧基、环丙基、环丁基、环戊基、环己基、吡唑基、噻唑基、咪唑基、噁唑基、噻吩基、呋喃基、吡咯基、异噁唑基、异噻吩基、吡啶基、嘧啶基或苯基任选进一步被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、CF 3、OH、氰基、NH 2、NH(CH 3)、NH(CH 2CH 3)、N(CH 3) 2、N(CH 2CH 3) 2、甲基、乙基、甲氧基、乙氧基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氮杂环戊基、氮杂环己基、氧杂环丁基、氧杂环戊基、氧杂环己基、吗啉基的取代基所取代； 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, -NH-isothienyl, -NH-pyridyl, -NH-pyrimidinyl, -NH-phenyl, -NH-cyclopropyl, -NH-ring butyl, -NH- cyclopentyl, -NH- cyclohexyl, -C (= O) NH 2 , -C (= O) NHCH 3, -C (= O) NHCH 2 CH 3, -C (= O )NH-cyclopropyl, -C(=O)NH-cyclobutyl, -C(=O)NH-cyclopentyl, -C(=O)NH-cyclohexyl, -C(=O)NH - phenyl, -NHC (= O) H, -NHC (= O) CH 3, -NHC (= O) CH 2 CH 3, -NHC (= O) CH 2 CH 2 CH 3, -NHC (= O )-cyclopropyl, -NHC(=O)-cyclobutyl, -NHC(=O)-cyclopentyl, -NHC(=O)-cyclohexyl or -NHC(=O)-phenyl, so The methyl, ethyl, isopropyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrazolyl , thiazolyl, imidazolyl, oxazolyl, thienyl, furanyl, pyrrolyl, isoxazolyl, isothienyl, pyridyl, pyrimidinyl or phenyl optionally further substituted by 0 to 4 (eg 0, 1 , 2, 3 or 4) is selected from H, 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, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidine, azacyclopentyl, Substituted by the substituents of azepanyl, oxetanyl, oxolane, oxanyl, and morpholinyl;
或者R a各自独立的选自-CH 2-氮杂环丁基、-CH 2-氮杂环戊基、-CH 2-氮杂环己基、-CH 2-氧杂环丁基、-CH 2-氧杂环戊基、-CH 2-氧杂环己基、-CH 2-吗啉基、-CH 2-哌嗪基、-CH 2CH 2-氮杂环丁基、-CH 2CH 2-氮杂环戊基、-CH 2CH 2-氮杂环己基、-CH 2CH 2-氧杂环丁基、-CH 2CH 2-氧杂环戊基、-CH 2CH 2-氧杂环己基、-CH 2CH 2-吗啉基、-CH 2CH 2-哌嗪基，所述的氮杂环丁基、氮杂环戊基、氮杂环己基、氧杂环丁基、氧杂环戊基、氧杂环己基、吗啉基任选进一步被0至4个选自H、F、Cl、Br、CF 3、OH、氰基、NH 2、NH(CH 3)、NH(CH 2CH 3)、N(CH 3) 2、N(CH 2CH 3) 2、甲基、乙基、甲氧基、乙氧基的取代基所取代； or 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 -piperazinyl, said azetidine, azacyclopentyl, azacyclohexyl, oxetanyl, oxa Cyclopentyl, oxanyl, morpholinyl are optionally further 0 to 4 selected from H, 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, ethoxy substituents;
其余基团的定义与本发明第一、二、三、四任意一种实施方案一致。The definitions of the remaining groups are consistent with any one of the first, second, third and fourth embodiments of the present invention.
作为本发明的第六种实施方案，前述通式(Ia)、(Ib)、(Ic)、(Id)、(Ie)所示化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，As the sixth embodiment of the present invention, the compounds represented by the aforementioned general formulae (Ia), (Ib), (Ic), (Id), (Ie) or their stereoisomers, deuterated compounds, solvates, and prodrugs , metabolites, pharmaceutically acceptable salts or co-crystals,
环B选自
Figure PCTCN2021103485-appb-000134
右侧与R 2直接连接； Ring B is selected from
Figure PCTCN2021103485-appb-000134
R 2 is directly connected to the right;
R 2选自F、OH、-O-CH 3、-OCHF 2、-OCH 2F、-OCF 3、-CH 2OH、-CH 2CN、-CH 2CH 2CN、-NHCH 2CN、-NHCH 2CH 2CN； 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;
通式(Ia)中的
Figure PCTCN2021103485-appb-000135
选自
Figure PCTCN2021103485-appb-000136
Figure PCTCN2021103485-appb-000137
In general formula (Ia)
Figure PCTCN2021103485-appb-000135
selected from
Figure PCTCN2021103485-appb-000136
Figure PCTCN2021103485-appb-000137
通式(Id)中的
Figure PCTCN2021103485-appb-000138
选自
Figure PCTCN2021103485-appb-000139
Figure PCTCN2021103485-appb-000140
In general formula (Id)
Figure PCTCN2021103485-appb-000138
selected from
Figure PCTCN2021103485-appb-000139
Figure PCTCN2021103485-appb-000140
或者通式(Id)中的
Figure PCTCN2021103485-appb-000141
选自
Figure PCTCN2021103485-appb-000142
Figure PCTCN2021103485-appb-000143
or in general formula (Id)
Figure PCTCN2021103485-appb-000141
selected from
Figure PCTCN2021103485-appb-000142
Figure PCTCN2021103485-appb-000143
或者通式(Id)中的
Figure PCTCN2021103485-appb-000144
选自
Figure PCTCN2021103485-appb-000145
or in general formula (Id)
Figure PCTCN2021103485-appb-000144
selected from
Figure PCTCN2021103485-appb-000145
R 1选自
Figure PCTCN2021103485-appb-000146
R 1 is selected from
Figure PCTCN2021103485-appb-000146
或者R 1选自
Figure PCTCN2021103485-appb-000147
or R 1 is selected from
Figure PCTCN2021103485-appb-000147
或者R 1选自
Figure PCTCN2021103485-appb-000148
or R 1 is selected from
Figure PCTCN2021103485-appb-000148
其余基团的定义与本发明第一、二、三、四、五任意一种实施方案一致。The definitions of the remaining groups are consistent with any one of the first, second, third, fourth and fifth embodiments of the present invention.
作为本发明的第七种实施方案，前述通式(Ia)、(Ib)、(Ic)、(Id)、(Ie)所示化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，As the seventh embodiment of the present invention, the compounds represented by the aforementioned general formulae (Ia), (Ib), (Ic), (Id), (Ie) or their stereoisomers, deuterated compounds, solvates, and prodrugs , metabolites, pharmaceutically acceptable salts or co-crystals,
环B选自
Figure PCTCN2021103485-appb-000149
右侧与R 2直接连接； Ring B is selected from
Figure PCTCN2021103485-appb-000149
R 2 is directly connected to the right;
或者环B选自
Figure PCTCN2021103485-appb-000150
or ring B is selected from
Figure PCTCN2021103485-appb-000150
R 2选自F、-OCHF 2、-OCH 2F、-OCF 3、-OCH 3、OH、-CH 2OH、-CH 2CN、-CH 2CH 2CN或-NHCH 2CH 2CN； 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;
通式(Ia)中的
Figure PCTCN2021103485-appb-000151
选自
Figure PCTCN2021103485-appb-000152
In general formula (Ia)
Figure PCTCN2021103485-appb-000151
selected from
Figure PCTCN2021103485-appb-000152
其余基团的定义与本发明第一、二、三、四、五、六任意一种实施方案一致。The definitions of the remaining groups are consistent with any one of the first, second, third, fourth, fifth and sixth embodiments of the present invention.
作为本发明的第八种实施方案，下述通式(Ia-1)或(Id-6)所示化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，As the eighth embodiment of the present invention, the compound represented by the following general formula (Ia-1) or (Id-6) or its stereoisomers, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable compounds accepted salts or co-crystals,
Figure PCTCN2021103485-appb-000153
Figure PCTCN2021103485-appb-000153
R n2选自H、甲基 R n2 is selected from H, methyl
Z 1选自N或C(R aa)； Z 1 is selected from N or C(R aa );
R aa选自H、甲基； R aa is selected from H, methyl;
R 1选自
Figure PCTCN2021103485-appb-000154
R 1 is selected from
Figure PCTCN2021103485-appb-000154
R a各自独立的选自H、甲基、乙基、丙基、丁基、异丙基、异丁基、仲丁基、叔丁基、环丙基、环丁基、-CH 2CH 2CN、
Figure PCTCN2021103485-appb-000155
Figure PCTCN2021103485-appb-000156
R a is independently selected from H, methyl, ethyl, propyl, butyl, isopropyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, -CH 2 CH 2 EN,
Figure PCTCN2021103485-appb-000155
Figure PCTCN2021103485-appb-000156
Figure PCTCN2021103485-appb-000157
Figure PCTCN2021103485-appb-000158
所述的甲基、乙基、丙基、丁基、异丙基、异丁基、仲丁基、叔丁基、环丙基、环丁基、-CH 2CH 2CN任选进一步被0至3个(例如0、1、2或3)选自F、Cl、Br、CF 3、OH、氰基、NH 2、NH(CH 3)、NH(CH 2CH 3)、N(CH 3) 2、N(CH 2CH 3) 2、甲基、乙基、甲氧基、乙氧基的取代基所取代。
Figure PCTCN2021103485-appb-000157
Figure PCTCN2021103485-appb-000158
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. 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.
作为本发明的第九种实施方案，下述通式(Ia-1’)或(Id-6’)所示化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，As the ninth embodiment of the present invention, the compound represented by the following general formula (Ia-1') or (Id-6') or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutical on an acceptable salt or co-crystal,
Figure PCTCN2021103485-appb-000159
Figure PCTCN2021103485-appb-000159
R 2选自OH、F或-OCHF 2； R 2 is selected from OH, F or -OCHF 2 ;
Z 1选自N或C(R aa)； Z 1 is selected from N or C(R aa );
R aa选自H、F、氰基、甲基、乙基、环丙基； R aa is selected from H, F, cyano, methyl, ethyl, cyclopropyl;
R 1选自
Figure PCTCN2021103485-appb-000160
R 1 is selected from
Figure PCTCN2021103485-appb-000160
其余基团的定义与本发明第一、二、三、四、五、六、七中任意一种实施方案一致。The definitions of the remaining groups are consistent with any one of the first, second, third, fourth, fifth, sixth and seventh embodiments of the present invention.
作为本发明的第十种实施方案，下述通式(Ia-2)、(Ib-1)、(Ic-1)、(Id-1)、(Ie-1)所示化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，As the tenth embodiment of the present invention, compounds represented by the following general formulae (Ia-2), (Ib-1), (Ic-1), (Id-1), (Ie-1) or their stereoisomers Conforms, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals,
Figure PCTCN2021103485-appb-000161
Figure PCTCN2021103485-appb-000161
各个基团的定义与本发明第一、二、三、四、五、六、七、八中任意一种实施方案一致。The definition of each group is consistent with any one of the first, second, third, fourth, fifth, sixth, seventh, and eighth embodiments of the present invention.
作为本发明的第十一种实施方案，下述通式(Ia-3)、(Ia-4)、(Ia-5)、(Ia-6)所示化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，As the eleventh embodiment of the present invention, compounds represented by the following general formulae (Ia-3), (Ia-4), (Ia-5), (Ia-6) or their stereoisomers, deuterated compounds , solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals,
Figure PCTCN2021103485-appb-000162
Figure PCTCN2021103485-appb-000162
X 1、X 2各自独立的选自N或CH； X 1 and X 2 are each independently selected from N or CH;
X 3、X 4各自独立的选自N或CH； X 3 and X 4 are each independently selected from N or CH;
X 5、X 6、X 7各自独立的选自O、S、NH、N(R a)、N或CH； X 5 , X 6 , X 7 are each independently selected from O, S, NH, N(R a ), N or CH;
X 8选自N或C； X 8 is selected from N or C;
X 9、X 10各自独立的选自O、S、N或CH； X 9 and X 10 are each independently selected from O, S, N or CH;
通式(Ia-4)和(Ia-3)中X 1、X 2至少有1个选自N； In general formula (Ia-4) and (Ia-3), at least one of X 1 and X 2 is selected from N;
通式(Ia-5)和(Ia-6)中X 1、X 2、X 8至少有1个选自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;
Figure PCTCN2021103485-appb-000163
代表所在的环具有芳香性；
Figure PCTCN2021103485-appb-000163
The ring in which the representative is located is aromatic;
其余基团的定义与本发明第一、二、三、四、五、六、七、八中任意一种实施方案一致。The definitions of the remaining groups are consistent with any one of the first, second, third, fourth, fifth, sixth, seventh, and eighth embodiments of the present invention.
作为本发明的第十二种实施方案，下述通式(Id-2)所示化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，As the twelfth embodiment of the present invention, the compound represented by the following general formula (Id-2) or its stereoisomers, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co- crystal,
Figure PCTCN2021103485-appb-000164
Figure PCTCN2021103485-appb-000164
各个基团的定义与本发明第二、三、四、五、六、七、八中任意一种实施方案一致。The definition of each group is consistent with any one of the second, third, fourth, fifth, sixth, seventh, and eighth embodiments of the present invention.
作为本发明的第十三种实施方案，下述通式(Id-3)、(Id-4)、(Id-5)所示化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，As the thirteenth embodiment of the present invention, compounds represented by the following general formulae (Id-3), (Id-4), (Id-5) or their stereoisomers, deuterated compounds, solvates, and prodrugs , metabolites, pharmaceutically acceptable salts or co-crystals,
Figure PCTCN2021103485-appb-000165
Figure PCTCN2021103485-appb-000165
X 1、X 2各自独立的选自N或CH； X 1 and X 2 are each independently selected from N or CH;
D 1、D 2各自独立的选自N或CH； D 1 and D 2 are each independently selected from N or CH;
D 3、D 4、D 5各自独立的选自O、S、NH、N(R a)、N或CH； D 3 , D 4 , D 5 are each independently selected from O, S, NH, N(R a ), N or CH;
通式(Id-3)和(Id-4)中X 1、X 2至少有1个选自N； In general formulas (Id-3) and (Id-4), at least one of X 1 and X 2 is selected from N;
通式(Id-5)中X 1、X 2至少有1个选自N； In the general formula (Id-5), at least one of X 1 and X 2 is selected from N;
Figure PCTCN2021103485-appb-000166
代表所在的环具有芳香性；
Figure PCTCN2021103485-appb-000166
The ring in which the representative is located is aromatic;
其余基团的定义与本发明第一、二、三、四、五、六、七、八中任意一种实施方案一致。The definitions of the remaining groups are consistent with any one of the first, second, third, fourth, fifth, sixth, seventh, and eighth embodiments of the present invention.
作为本发明的第十四种实施方案，下述通式(Iaa)、(Idd)所示化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，As the fourteenth embodiment of the present invention, 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,
Figure PCTCN2021103485-appb-000167
Figure PCTCN2021103485-appb-000167
各个基团的定义与本发明第一、二、三、四、五、六、七、八中任意一种实施方案一致。The definition of each group is consistent with any one of the first, second, third, fourth, fifth, sixth, seventh, and eighth embodiments of the present invention.
作为本发明的第十五种实施方案，上述通式(I)所示化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，其中，As the fifteenth embodiment of the present invention, the compound represented by the above general formula (I) or its stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein ,
R n1为H，R n2选自H、甲基；L选自NH、NCH 3； R n1 is H, R n2 is selected from H, methyl; L is selected from NH, NCH 3 ;
环A选自取代的或者未取代的如下基团之一：
Figure PCTCN2021103485-appb-000168
Figure PCTCN2021103485-appb-000169
Figure PCTCN2021103485-appb-000170
当被取代时，任选进一步被1至3个(例如1、2或3个)R a取代； Ring A is selected from one of the following groups, substituted or unsubstituted:
Figure PCTCN2021103485-appb-000168
Figure PCTCN2021103485-appb-000169
Figure PCTCN2021103485-appb-000170
When substituted, optionally further substituted with 1 to 3 (e.g. 1, 2 or 3) R a;
R a各自独立的选自C 1-4烷基(例如甲基、乙基)、卤素(例如氟、氯、溴)、氧杂环戊基、氮杂环戊基、-CH 2CH 2 -吗啉基、吡唑基、吡啶基，所述的C 1-4烷基(例如甲基、乙基)、氧杂环戊基、氮杂环戊基、吡唑基、吡啶基任选进一步被1至3个(例如1、2或3个)选自甲基、甲氧基、F、Cl、Br、CF 3、OH、氰基、NH 2的取代基所取代； 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;
环B选自
Figure PCTCN2021103485-appb-000171
右侧与R 2直接连接； Ring B is selected from
Figure PCTCN2021103485-appb-000171
R 2 is directly connected to the right;
R 2各自独立的选自F、OH、-CH 2OH、-CH 2CN、-NHCH 2CH 2CN或-NHCH 2CN； 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选自
Figure PCTCN2021103485-appb-000172
Figure PCTCN2021103485-appb-000173
R 1 is selected from
Figure PCTCN2021103485-appb-000172
Figure PCTCN2021103485-appb-000173
作为本发明的第十六种实施方案，上述通式(I)所示化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，其中，As the sixteenth embodiment of the present invention, the compound represented by the above general formula (I) or its stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein ,
R n1选自H，R n2为H，L选自NH、NCH 3； R n1 is selected from H, R n2 is H, and L is selected from NH, NCH 3 ;
环A选自取代的或者未取代的如下基团之一：
Figure PCTCN2021103485-appb-000174
Figure PCTCN2021103485-appb-000175
当被取代时，任选进一步被1至3个(例如1、2或3个)R a取代； Ring A is selected from one of the following groups, substituted or unsubstituted:
Figure PCTCN2021103485-appb-000174
Figure PCTCN2021103485-appb-000175
When substituted, optionally further substituted with 1 to 3 (e.g. 1, 2 or 3) R a;
R a各自独立的选自C 1-4烷基(例如甲基、乙基)、卤素(例如氟、氯、溴)、氧杂环戊基、氮杂环戊基，所述的C 1-4烷基(例如甲基、乙基)、氧杂环戊基、氮杂环戊基任选进一步被1至3个(例如1、2或3个)选自甲基、甲氧基、F、OH、氰基的取代基所取代； 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;
环B选自
Figure PCTCN2021103485-appb-000176
右侧与R 2直接连接；任选地，环B被1、2或3个R b取代； Ring B is selected from
Figure PCTCN2021103485-appb-000176
R 2 is directly connected to the right; Optionally, ring B is substituted with two or three R b;
R 2各自独立的选自OH、-CH 2CN； R 2 is each independently selected from OH, -CH 2 CN;
R 1选自
Figure PCTCN2021103485-appb-000177
Figure PCTCN2021103485-appb-000178
R 1 is selected from
Figure PCTCN2021103485-appb-000177
Figure PCTCN2021103485-appb-000178
本发明涉及如下所示的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，其中该化合物具有选自如下之一的结构：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:
Figure PCTCN2021103485-appb-000179
Figure PCTCN2021103485-appb-000179
Figure PCTCN2021103485-appb-000180
Figure PCTCN2021103485-appb-000180
Figure PCTCN2021103485-appb-000181
Figure PCTCN2021103485-appb-000181
Figure PCTCN2021103485-appb-000182
Figure PCTCN2021103485-appb-000182
Figure PCTCN2021103485-appb-000183
Figure PCTCN2021103485-appb-000183
Figure PCTCN2021103485-appb-000184
Figure PCTCN2021103485-appb-000184
Figure PCTCN2021103485-appb-000185
Figure PCTCN2021103485-appb-000185
Figure PCTCN2021103485-appb-000186
Figure PCTCN2021103485-appb-000186
Figure PCTCN2021103485-appb-000187
Figure PCTCN2021103485-appb-000187
Figure PCTCN2021103485-appb-000188
Figure PCTCN2021103485-appb-000188
本发明涉及通式(I)、(Ib)、(Ic)、(Ie)、(Ib-1)、(Ic-1)、(Ie-1)的一些实施方案中，L选自键或者NR n2。 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 .
本发明涉及通式(I)、(Ib)、(Ic)、(Ie)、(Ib-1)、(Ic-1)、(Ie-1)的一些实施方案中，L选自NR n2。 In some embodiments of the present invention relating to general formulae (I), (Ib), (Ic), (Ie), (Ib-1), (Ic-1), (Ie-1), L is selected from NRn2 .
本发明涉及通式(I)、(Ib)、(Ic)、(Ie)、(Ib-1)、(Ic-1)、(Ie-1)的一些实施方案中，L选自键。In some embodiments of the present invention relating to general formulae (I), (Ib), (Ic), (Ie), (Ib-1), (Ic-1), (Ie-1), L is selected from a bond.
本发明涉及通式(I)、(Ib)、(Ic)、(Ie)、(Ib-1)、(Ic-1)、(Ie-1)的一些实施方案中，L为NH或N(CH 3)。 In some embodiments of the present invention relating to formulae (I), (Ib), (Ic), (Ie), (Ib-1), (Ic-1), (Ie-1), L is NH or N( CH 3).
本发明涉及通式(I)、(Ia)、(Ib)、(Ic)、(Id)、(Ie)、(Id-5)的一些实施方案中，R n1、R n2各自独立的选自H、C 1-6烷基或C 3-6环烷基，所述的烷基或环烷基任选进一步被0至4个(例如0、1、2、3或4个)选自H、卤素、CF 3、OH、氰基、NH 2、C 1-6烷基或C 1-6烷氧基的取代基所取代。 The present invention relates to some embodiments of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (Id-5), 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.
本发明涉及通式(I)、(Ia)、(Ib)、(Ic)、(Id)、(Ie)、(Id-5)、(Id-6)的一些实施方案中，R n1、R n2各自独立的选自H、C 1-4烷基或C 3-6环烷基，所述的烷基或环烷基任选进一步被0至4个(例如0、1、2、3或4个)选自H、卤素、CF 3、OH、氰基、NH 2、C 1-4烷基或C 1-4烷氧基的取代基所取代。 The present invention relates to some embodiments of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (Id-5), (Id-6), 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.
本发明涉及通式(I)、(Ia)、(Ib)、(Ic)、(Id)、(Ie)、(Id-5)、(Id-6)的一些实施方案中，R n1、R n2各自独立的选自H、甲基、乙基、丙基、异丙基、环丙基、环丁基、环戊基或环己基，所述的甲基、乙基、丙基、异丙基、环丙基、环丁基、环戊基或环己基任选进一步被0至4个(例如0、1、2、3或4个)选自H、卤素、CF 3、OH、氰基、NH 2、C 1-4烷基或C 1-4烷氧基的取代基所取代。 The present invention relates to some embodiments of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (Id-5), (Id-6), 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.
本发明涉及通式(I)、(Ia)、(Ib)、(Ic)、(Id)、(Ie)、(Id-5)、(Id-6)的一些实施方案中，R n1、R n2各自独立的选自H、甲基、乙基、丙基、异丙基、环丙基、环丁基、环戊基或环己基，所述的甲基、乙基、丙基、异丙基、环丙基、环丁基、环戊基或环己基任选进一步被0至4个(例如0、1、2、3或4个)选自H、F、CF 3、OH、氰基、NH 2、甲基、乙基、甲氧基或乙氧基的取代基所取代。 The present invention relates to some embodiments of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (Id-5), (Id-6), 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.
本发明涉及通式(I)、(Ia)、(Ib)、(Ic)、(Id)、(Ie)、(Id-5)的一些实施方案中，R n1选自H，R n2选自H、甲基、乙基、丙基、异丙基。 In some embodiments of the present invention relating to general formulae (I), (Ia), (Ib), (Ic), (Id), (Ie), (Id-5), R n1 is selected from H, and R n2 is selected from H, methyl, ethyl, propyl, isopropyl.
本发明涉及通式(I)、(Ia)、(Ib)、(Ic)、(Id)、(Ie)、(Id-5)、(Id-6)的一些实施方案中，R n1、R n2选自H。 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.
本发明涉及通式(Id-6)的一些实施方案中，R aa选自R a。 In some embodiments of the present invention relating to general formula (Id-6), R aa is selected from R a .
本发明涉及通式(I)的一些实施方案中，环A选自5-6元单环杂芳环或8-10元并环杂芳环，所述的杂芳环任选进一步被0至3个(例如0、1、2或3个)R a取代，所述的杂芳环含有1至5个(例如1、2、3、4个或5)选自O、S、N的杂原子。 In some embodiments of the present invention relating to general formula (I), 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.
本发明涉及通式(I)的一些实施方案中，环A选自取代或者未取代的6并6元稠杂芳基，优选取代或者未取代的如下基团之一：异喹啉基、萘啶基、吡啶并吡嗪基、吡啶并嘧啶基、吡啶并哒嗪基、吡啶并哒嗪基、嘧啶并哒嗪基、嘧啶并哒嗪基、喹唑啉基、蝶啶基、喹喔啉基、二氢吡喃并嘧啶基或二氢二氧杂环己二烯并嘧啶基，当被取代时，任选进一步被0至3个(例如0、1、2或3个)R a取代。 In some embodiments of the general formula (I) of the present invention, 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 .
本发明涉及通式(I)的一些实施方案中，环A选自取代或者未取代的5并6元稠杂芳基，优选取代或者未取代的如下基团之一：噻吩并嘧啶基或吡唑并嘧啶基，苯并吡咯基、吡咯并吡啶基、咪唑并吡啶基、三唑并吡啶基、咪唑并哒嗪基、吡咯并嘧啶基、吡唑并 嘧啶基、咪唑并嘧啶基、三唑并嘧啶基、噻吩并嘧啶基、噻唑并嘧啶基、异噻唑并嘧啶基、异噁唑并嘧啶基、异噻唑并吡啶基、异噁唑并吡啶基、异噻唑并吡嗪基、异噁唑并吡嗪基、异噻唑并哒嗪基、异噁唑并哒嗪基、吡咯并吡嗪基、吡唑并吡嗪基、咪唑并吡嗪基、三唑并吡嗪基、噻唑并哒嗪基、吡咯并哒嗪基、吡唑并哒嗪基、咪唑并哒嗪基、三唑并哒嗪基、吡咯并三嗪基、咪唑并三嗪基或咪唑并吡嗪酮基，当被取代时，任选进一步被0至3个(例如0、1、2或3个)R a取代。 The present invention relates to some embodiments of general formula (I), 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 Pyrazinyl, isothiazolopyridazinyl, isoxazolopyridazinyl, pyrrolopyrazinyl, pyrazolopyrazinyl, imidazopyrazinyl, triazolopyrazinyl, thiazolopyridazine base, pyrrolopyridazinyl, pyrazolopyridazinyl, imidazopyridazinyl, triazolopyridazinyl, pyrrolotriazinyl, imidazotriazinyl or imidazopyrazinone, when substituted when, optionally further substituted with 0-3 (e.g. 2 or 3) R a.
本发明涉及通式(I)的一些实施方案中，环A选自取代的或者未取代的如下基团之一：
Figure PCTCN2021103485-appb-000189
X 1选自CH或N，X 2选自键、CH或N，Y、Z各自独立的选自C或N，环C选自5-6元杂芳环或苯环，所述的杂芳环含有1至3个(例如1、2或3)选自O、S、N的杂原子，当被取代时，任选进一步被0至3个(例如0、1、2或3个)R a取代。 In some embodiments of the present invention relating to general formula (I), Ring A is selected from one of the following substituted or unsubstituted groups:
Figure PCTCN2021103485-appb-000189
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.
本发明涉及通式(I)的一些实施方案中，环A选自取代的或者未取代的如下基团之一：
Figure PCTCN2021103485-appb-000190
X 1选自CH或N，X 2选自键、CH或N，Y、Z各自独立的选自C或N，环C选自吡唑环、噻唑环、咪唑环、噁唑环、噻吩环、呋喃环、吡咯环、异噁唑环、异噻唑环、吡啶环、吡嗪环、哒嗪环、1,2,4-三氮唑环、嘧啶环或苯环，当被取代时，任选进一步被0至3个(例如0、1、2或3个)R a取代。 In some embodiments of the present invention relating to general formula (I), Ring A is selected from one of the following substituted or unsubstituted groups:
Figure PCTCN2021103485-appb-000190
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.
本发明涉及通式(Ia)、(Ib)、(Ic)、(Id)、(Ie)、(Ib-1)、(Ic-1)、(Id-1)、(Ie-1)、(Iaa)、(Idd)的一些实施方案中，X 1选自CH或N，X 2选自键、CH或N，Y、Z各自独立的选自C或N，环C选自5-6元杂芳环或苯环，所述的杂芳环含有1至3个(例如1、2或3)选自O、S、N的杂原子，当被取代时，任选进一步被0至3个(例如0、1、2或3个)R a取代。 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 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.
本发明涉及通式(Ia)、(Ib)、(Ic)、(Id)、(Ie)、(Ib-1)、(Ic-1)、(Id-1)、(Ie-1)、(Iaa)、(Idd)的一些实施方案中，X 1选自CH或N，X 2选自键、CH或N，Y、Z各自独立的选自C或N，环C选自吡唑环、噻唑环、咪唑环、噁唑环、噻吩环、呋喃环、吡咯环、异噁唑 环、异噻唑环、吡啶环、吡嗪环、哒嗪环、1,2,4-三氮唑环、嘧啶环或苯环，当被取代时，任选进一步被0至3个(例如0、1、2或3个)R a取代。 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.
本发明涉及通式(I)的一些实施方案中，环A选自取代的或者未取代的如下基团之一：In some embodiments of the present invention relating to general formula (I), Ring A is selected from one of the following substituted or unsubstituted groups:
Figure PCTCN2021103485-appb-000191
Figure PCTCN2021103485-appb-000192
Figure PCTCN2021103485-appb-000193
Figure PCTCN2021103485-appb-000191
Figure PCTCN2021103485-appb-000192
Figure PCTCN2021103485-appb-000193
当被取代时，任选进一步被0至3个(例如0、1、2或3个)R a取代。 When substituted, optionally further substituted with 0-3 (e.g. 2 or 3) R a.
本发明涉及通式(I)的一些实施方案中，环A选自取代的或者未取代的如下基团之一：
Figure PCTCN2021103485-appb-000194
Figure PCTCN2021103485-appb-000195
当被取代时，任选进一步被0至3个R a(例如0、1、2或3个)取代。 In some embodiments of the present invention relating to general formula (I), Ring A is selected from one of the following substituted or unsubstituted groups:
Figure PCTCN2021103485-appb-000194
Figure PCTCN2021103485-appb-000195
When substituted, it is optionally further substituted with 0 to 3 Ra (eg 0, 1, 2 or 3).
本发明涉及通式(I)的一些实施方案中，环A选自取代的或者未取代的如下基团之一：
Figure PCTCN2021103485-appb-000196
当被取代时，任选进一步被0至3个(例如0、1、2或3个)R a取代。 In some embodiments of the present invention relating to general formula (I), Ring A is selected from one of the following substituted or unsubstituted groups:
Figure PCTCN2021103485-appb-000196
When substituted, optionally further substituted with 0-3 (e.g. 2 or 3) R a.
本发明涉及通式(Id-2)的一些实施方案中，Z或Y各自独立的选自C或N，环C选自取代或者未取代的5-6元杂芳环或苯环。In some embodiments of the present invention relating to general formula (Id-2), 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.
本发明涉及通式(Id-2)的一些实施方案中，Z或Y各自独立的选自C或N，环C选自取代或者未取代的吡唑环、噻唑环、咪唑环、噁唑环、噻吩环、呋喃环、吡咯环、异噁唑环、异噻唑环、吡啶环、嘧啶环或苯环，当被取代时，任选进一步被0至3个R a(例如0、1、2或3个)取代。 The present invention relates to some embodiments of the general formula (Id-2), 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.
本发明涉及通式(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)、(Id-5)、(Id-6)、(Iaa)、(Idd)的一些实施方案中，R a各自独立的选自H、卤素、氰基、OH、C 1-6烷基、C 1-6烷氧基、-(CH 2) q-C(＝O)-NR a1R a2、-(CH 2) q-NR a1R a2、-(CH 2) qNR a1C(＝O)-R a2、-(CH 2) q-C 3-10碳环或-(CH 2) q-3至12元杂环，所述的-CH 2-、烷基、烷氧基、碳环或杂环任选进一步被0至4个(例如0、1、2、3或4个)选自H、卤素、OH、氰基、NH 2、NH(C 1-6烷基)、N(C 1-6烷基) 2、C 1-6烷基、卤素取代的C 1-6烷基、C 1-6烷氧基、C 3-6环烷基或3至10元杂环的取代基所取代，所述的杂环含有1至3个(例如1、2或3)选自O、S、N的杂原子。 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) In some embodiments of , (Id-5), (Id-6), (Iaa), (Idd), R a is each independently selected from H, halogen, cyano, OH, C 1-6 alkyl, C 1-6 alkoxy, -(CH 2 ) q -C(=O)-NR a1 R a2 , -(CH 2 ) q -NR a1 R a2 , -(CH 2 ) q NR a1 C(=O) -R a2 , -(CH 2 ) q -C 3-10 carbocycle or -(CH 2 ) q -3- to 12-membered heterocycle, said -CH 2 -, alkyl, alkoxy, carbocycle or heterocyclyl optionally further substituted with 0 to 4 (e.g. 2, 3 or 4) selected from H, halo, 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 substituent of 3- to 10-membered heterocycle Instead, the heterocycle contains 1 to 3 (eg 1, 2 or 3) heteroatoms selected from O, S, N.
本发明涉及通式(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)、(Id-5)、(Id-6)、(Iaa)、(Idd)的一些实施方案中，R a各自独立的选自H、卤素、氰基、OH、C 1-4烷基、C 1-4烷氧基、-(CH 2) q-C 3-6碳环或-(CH 2) q-3至6元杂环、-(CH 2) q-C(＝O)-NR a1R a2、-(CH 2) q-NR a1R a2或-(CH 2) qNR a1C(＝O)-R a2，所述的-CH 2-、烷基、烷氧基、碳环或杂环任选进一步被0至4个(例如0、1、2、3或4个)选自H、卤素、OH、氰基、NH 2、NH(C 1-4烷基)、N(C 1-4烷基) 2、C 1-4烷基、卤素取代的C 1-4烷基、C 1-4烷氧基、C 3-6环烷基或3至10元杂环的取代基所取代，所述的杂环含有1至3个(例如1、2或3)选自O、S、N的杂原子。 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) Some (Id-5), (Id -6), (Iaa), (Idd) embodiment embodiment, R a is independently selected from H, halo, cyano, OH, C 1-4 alkyl, C 1-4 alkoxy, -(CH 2 ) q -C 3-6 carbocycle or -(CH 2 ) q -3- to 6-membered heterocycle, -(CH 2 ) q -C(=O)-NR a1 R a2 , -(CH 2 ) q -NR a1 R a2 or -(CH 2 ) q NR a1 C(=O)-R a2 , said -CH 2 -, alkyl, alkoxy, carbocyclic or heterocyclyl optionally further substituted with 0 to 4 (e.g. 2, 3 or 4) selected from H, halo, 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 10-membered heterocycles Instead, the heterocycle contains 1 to 3 (eg 1, 2 or 3) heteroatoms selected from O, S, N.
本发明涉及通式(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)、(Id-5)、(Id-6)、(Iaa)、(Idd)的一些实施方案中，R a各自独立的选自H、卤素、氰基、OH、C 1-4烷基、C 1-4烷氧基、C 3-6碳环、3至6元杂环、-CH 2-C 3-6碳环、-CH 2CH 2-C 3-6碳环、-CH 2-3至6元杂环、-CH 2CH 2- 3至6元杂环、NHR a2、-C(＝O)NHR a2、-NHC(＝O)R a2，所述的-CH 2-、烷基、烷氧基、碳环或杂环任选进一步被0至4个(例如0、1、2、3或4个)选自H、卤素、OH、氰基、NH 2、NH(C 1-4烷基)、N(C 1-4烷基) 2、C 1-4烷基、卤素取代的C 1-4烷基、C 1-4烷氧基、C 3-6环烷基或3至10元杂环的取代基所取代，所述的杂环含有1至3个(例如1、2或3)选自O、S、N的杂原子。 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) Some (Id-5), (Id -6), (Iaa), (Idd) embodiment embodiment, R a is independently selected from H, halo, 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 CH 2 -C 3-6 carbocycle, -CH 2 -3 to 6-membered heterocycle, -CH 2 CH 2 - 3 to 6-membered heterocycle, NHR a2 , -C(=O)NHR a2 , -NHC(=O)R a2 , 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, 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 3 to 10-membered heterocycle containing 1 to 3 (eg 1, 2 or 3) heteroatoms selected from O, S, N.
本发明涉及通式(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)、(Id-5)、(Id-6)、(Iaa)、(Idd)的一些实施方案中，R a各自独立的选自H、F、Cl、Br、氰基、OH、甲基、乙基、丙基、丁基、异丙基、甲氧基、乙氧基、吡唑基、噻唑基、咪唑基、噁唑基、噻吩基、呋喃基、吡咯基、异噁唑基、异噻吩基、吡啶基、嘧啶基、苯基、环丙基、环丁基、环戊基、环己基、-NH-吡唑基、-NH-噻唑基、-NH-咪唑基、-NH-噁唑基、-NH-噻吩基、-NH-呋喃基、-NH-吡咯基、-NH-异噁唑基、-NH-异噻吩基、-NH-吡啶基、-NH-嘧啶基、-NH-苯基、-NH-环丙基、-NH-环丁基、-NH-环戊基、-NH-环己基、-C(＝O)NH 2、-C(＝O)NHCH 3、-C(＝O)NHCH 2CH 3、-C(＝O)NH-环丙基、-C(＝O)NH-环丁基、-C(＝O)NH-环戊基、-C(＝O)NH-环已基、-C(＝O)NH-苯基、-NHC(＝O)H、-NHC(＝O)CH 3、-NHC(＝O)CH 2CH 3、-NHC(＝O)CH 2CH 2CH 3、-NHC(＝O)-环丙基、-NHC(＝O)-环丁基、-NHC(＝O)-环戊基、-NHC(＝O)-环已基或-NHC(＝O)-苯基，所述的甲基、乙基、异丙基、甲氧基、乙氧基、环丙基、环丁基、环戊基、环己基、吡唑基、噻唑基、咪唑基、噁唑基、噻吩基、呋喃基、吡咯基、异噁唑基、异噻吩基、吡啶基、嘧啶基或苯基任选进一步被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、CF 3、OH、氰基、NH 2、NH(CH 3)、NH(CH 2CH 3)、N(CH 3) 2、N(CH 2CH 3) 2、甲基、乙基、甲氧基、乙氧基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氮杂环戊基、氮杂环己基、氧杂环丁基、氧杂环戊基、氧杂环己基、吗啉基的取代基所取代。 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) In some embodiments of , (Id-5), (Id-6), (Iaa), (Idd), 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, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -NH-pyrazolyl, -NH-thiazolyl, -NH-imidazolyl, -NH-oxazole -NH-thienyl, -NH-furyl, -NH-pyrrolyl, -NH-isoxazolyl, -NH-isothienyl, -NH-pyridyl, -NH-pyrimidinyl, -NH- Phenyl, -NH-cyclopropyl, -NH-cyclobutyl, -NH-cyclopentyl, -NH-cyclohexyl, -C(=O)NH 2 , -C(=O)NHCH 3 , -C (=O)NHCH 2 CH 3 , -C(=O)NH-cyclopropyl, -C(=O)NH-cyclobutyl, -C(=O)NH-cyclopentyl, -C(=O )NH-cyclohexyl, -C(=O)NH-phenyl, -NHC(=O)H, -NHC(=O)CH 3 , -NHC(=O)CH 2 CH 3 , -NHC(= O)CH 2 CH 2 CH 3 , -NHC(=O)-cyclopropyl, -NHC(=O)-cyclobutyl, -NHC(=O)-cyclopentyl, -NHC(=O)-cyclo Hexyl or -NHC(=O)-phenyl, said methyl, ethyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyridine oxazolyl, thiazolyl, imidazolyl, oxazolyl, thienyl, furyl, pyrrolyl, isoxazolyl, isothienyl, pyridyl, pyrimidinyl or phenyl is optionally further substituted by 0 to 4 (eg 0 , 1, 2, 3 or 4) selected from H, 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, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidine, azacyclopentyl is substituted with the substituents of base, azepanyl, oxetanyl, oxolane, oxanyl, and morpholinyl.
本发明涉及通式(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)、(Id-5)、(Id-6)、(Iaa)、(Idd)的一些实施方案中，R a各自独立的选自H、F、Cl、Br、氰基、OH、甲基、乙基、丙基、丁基、异丙基、异丁基、仲丁基、叔丁基、甲氧基、乙氧基、吡唑基、噻唑基、咪唑基、噁唑基、噻吩基、呋喃基、吡咯基、异噁唑基、异噻吩基、吡啶基、嘧啶基、苯基、环丙基、环丁基、环戊基、环己基、-NH-吡唑基、-NH-噻唑基、-NH-咪唑基、-NH-噁唑基、-NH-噻吩基、-NH-呋喃基、-NH-吡咯基、-NH-异噁唑基、-NH-异噻吩基、-NH-吡啶基、 -NH-嘧啶基、-NH-苯基、-NH-环丙基、-NH-环丁基、-NH-环戊基、-NH-环己基、-C(＝O)NH 2、-C(＝O)NHCH 3、-C(＝O)NHCH 2CH 3、-C(＝O)NH-环丙基、-C(＝O)NH-环丁基、-C(＝O)NH-环戊基、-C(＝O)NH-环已基、-C(＝O)NH-苯基、-NHC(＝O)H、-NHC(＝O)CH 3、-NHC(＝O)CH 2CH 3、-NHC(＝O)CH 2CH 2CH 3、-NHC(＝O)-环丙基、-NHC(＝O)-环丁基、-NHC(＝O)-环戊基、-NHC(＝O)-环已基或-NHC(＝O)-苯基，所述的甲基、乙基、异丙基、异丁基、仲丁基、叔丁基、甲氧基、乙氧基、环丙基、环丁基、环戊基、环己基、吡唑基、噻唑基、咪唑基、噁唑基、噻吩基、呋喃基、吡咯基、异噁唑基、异噻吩基、吡啶基、嘧啶基或苯基任选进一步被0至4个选自H、F、Cl、Br、CF 3、OH、氰基、NH 2、NH(CH 3)、NH(CH 2CH 3)、N(CH 3) 2、N(CH 2CH 3) 2、甲基、乙基、甲氧基、乙氧基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氮杂环戊基、氮杂环己基、氧杂环丁基、氧杂环戊基、氧杂环己基、吗啉基的取代基所取代。 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) In some embodiments of , (Id-5), (Id-6), (Iaa), (Idd), 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, pyridyl, pyrimidinyl, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -NH-pyrazolyl, -NH-thiazolyl , -NH-imidazolyl, -NH-oxazolyl, -NH-thienyl, -NH-furyl, -NH-pyrrolyl, -NH-isoxazolyl, -NH-isothienyl, -NH- Pyridyl, -NH-pyrimidinyl, -NH-phenyl, -NH-cyclopropyl, -NH-cyclobutyl, -NH-cyclopentyl, -NH-cyclohexyl, -C(=O)NH 2 , -C(=O)NHCH 3 , -C(=O)NHCH 2 CH 3 , -C(=O)NH-cyclopropyl, -C(=O)NH-cyclobutyl, -C(=O )NH-cyclopentyl, -C(=O)NH-cyclohexyl, -C(=O)NH-phenyl, -NHC(=O)H, -NHC(=O)CH 3 , -NHC( = O) CH 2 CH 3, -NHC (= O) CH 2 CH 2 CH 3, -NHC (= O) - cyclopropyl, -NHC (= O) - cyclobutyl, -NHC (= O) - Cyclopentyl, -NHC(=O)-cyclohexyl or -NHC(=O)-phenyl, the methyl, ethyl, isopropyl, isobutyl, sec-butyl, tert-butyl, Methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrazolyl, thiazolyl, imidazolyl, oxazolyl, thienyl, furanyl, pyrrolyl, isoxazolyl , isothiazolyl, thienyl, pyridinyl, pyrimidinyl or phenyl optionally further substituted with 0 to 4 substituents selected from H, 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, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl , azetidine, azetidine, azetidine, oxetanyl, oxacyclopentyl, oxetanyl, morpholinyl substituents.
本发明涉及通式(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)、(Id-5)、(Id-6)、(Iaa)、(Idd)的一些实施方案中，R a各自独立的选自-CH 2-氮杂环丁基、-CH 2-氮杂环戊基、-CH 2-氮杂环己基、-CH 2-氧杂环丁基、-CH 2-氧杂环戊基、-CH 2-氧杂环己基、-CH 2-吗啉基、-CH 2-哌嗪基、-CH 2CH 2-氮杂环丁基、-CH 2CH 2-氮杂环戊基、-CH 2CH 2-氮杂环己基、-CH 2CH 2-氧杂环丁基、-CH 2CH 2-氧杂环戊基、-CH 2CH 2-氧杂环己基、-CH 2CH 2-吗啉基、-CH 2CH 2-哌嗪基，所述的氮杂环丁基、氮杂环戊基、氮杂环己基、氧杂环丁基、氧杂环戊基、氧杂环己基、吗啉基任选进一步被0至4个选自H、F、Cl、Br、CF 3、OH、氰基、NH 2、NH(CH 3)、NH(CH 2CH 3)、N(CH 3) 2、N(CH 2CH 3) 2、甲基、乙基、甲氧基、乙氧基的取代基所取代。 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) In some embodiments of , (Id-5), (Id-6), (Iaa), (Idd), 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 2 CH 2 -azepinyl, -CH 2 CH 2 -oxa Cyclobutyl, -CH 2 CH 2 -oxolane, -CH 2 CH 2 -oxane, -CH 2 CH 2 -morpholinyl, -CH 2 CH 2 -piperazinyl, said Azacyclobutyl, azacyclopentyl, azacyclohexyl, oxetanyl, oxacyclopentyl, oxanyl, morpholinyl are optionally further selected from 0 to 4 by 0 to 4 H, 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 substituted with substituents of methoxy, ethoxy and ethoxy.
本发明涉及通式(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)、(Id-5)、(Id-6)、(Iaa)、(Idd)的一些实施方案中，R a各自独立的选自H、甲基、乙基、丙基、丁基、异丙基、环丙基、环丁基、-CH 2CH 2CN、
Figure PCTCN2021103485-appb-000197
Figure PCTCN2021103485-appb-000198
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) Some (Id-5), (Id -6), (Iaa), (Idd) embodiment embodiment, R a is independently selected from H, methyl, ethyl, propyl, butyl, isopropyl, , cyclopropyl, cyclobutyl, -CH 2 CH 2 CN,
Figure PCTCN2021103485-appb-000197
Figure PCTCN2021103485-appb-000198
本发明涉及通式(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)、(Id-5)、(Id-6)、(Iaa)、(Idd)的一些 实施方案中，R a各自独立的选自H、甲基、乙基、丙基、丁基、异丙基、异丁基、仲丁基、叔丁基、环丙基、环丁基、-CH 2CH 2CN、
Figure PCTCN2021103485-appb-000199
Figure PCTCN2021103485-appb-000200
Figure PCTCN2021103485-appb-000201
所述的甲基、乙基、丙基、丁基、异丙基、异丁基、仲丁基、叔丁基、环丙基、环丁基、-CH 2CH 2CN任选进一步被0至3个选自F、Cl、Br、CF 3、OH、氰基、NH 2、NH(CH 3)、NH(CH 2CH 3)、N(CH 3) 2、N(CH 2CH 3) 2、甲基、乙基、甲氧基、乙氧基的取代基所取代。 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) Some (Id-5), (Id -6), (Iaa), (Idd) embodiment embodiment, R a is independently selected from H, methyl, ethyl, propyl, butyl, isopropyl, , isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, -CH 2 CH 2 CN,
Figure PCTCN2021103485-appb-000199
Figure PCTCN2021103485-appb-000200
Figure PCTCN2021103485-appb-000201
The methyl, ethyl, propyl, butyl, isopropyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, -CH 2 CH 2 CN are optionally further to 3 substituents 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. Substituents of methyl, ethyl, methoxy and ethoxy are substituted.
本发明涉及通式(I)、(Ia)、(Ib)、(Ic)、(Id)、(Ie)、(Ia-3)、(Ia-4)、(Ia-5)、(Ia-6)、(Id-3)、(Id-4)、(Id-5)(Iaa)、(Idd)、的一些实施方案中，环B选自非芳香的C 3-12碳环，所述的碳环任选自单环、并环、桥环或者螺环，所述的碳环、单环、并环、桥环或者螺环任选进一步被0至3个(例如0、1、2或3个)R b所取代。 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.
本发明涉及通式(I)、(Ia)、(Ib)、(Ic)、(Id)、(Ie)、(Ia-2)、(Ia-3)、(Ia-4)、(Ia-5)、(Ia-6)、(Id-3)、(Id-4)、(Id-5)、(Iaa)、(Idd)的一些实施方案中，环B选自C 3-8单环烷基、C 4- 10并环烷基、C 4-12螺环烷基、C 5-12桥环烷基，所述的环烷基任选进一步被0至3个(例如0、1、2或3个)R b所取代。 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.
本发明涉及通式(I)、(Ia)、(Ib)、(Ic)、(Id)、(Ie)、(Ia-3)、(Ia-4)、(Ia-5)、(Ia-6)、(Id-3)、(Id-4)、(Id-5)、(Iaa)、(Idd)的一些实施方案中，环B选自C 3-8单环烷基、C 8-10并环烷基、C 8-12螺环烷基、C 8-12桥环烷基，所述的环烷基任选进一步被0至3个(例如0、1、2或3个)R b所取代。 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.
本发明涉及通式(I)、(Ia)、(Ib)、(Ic)、(Id)、(Ie)(Ia-3)、(Ia-4)、(Ia-5)、(Ia-6)、(Id-3)、(Id-4)、(Id-5)、(Iaa)、(Idd)的一些实施方案中，环B选自C 3-8单环烷基、C 9-10并环烷基、C 9-12螺环烷基、C 9-12桥环烷基，所述的环烷基任选进一步被0至3个(例如0、1、2或3个)R b所取代。 The present invention relates to general formulae (I), (Ia), (Ib), (Ic), (Id), (Ie) (Ia-3), (Ia-4), (Ia-5), (Ia-6) ), (Id-3), (Id-4), (Id-5), (Iaa), (Idd) in some embodiments, 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.
本发明涉及通式(I)、(Ia)、(Ib)、(Ic)、(Id)、(Ie)、(Ia-3)、(Ia-4)、(Ia-5)、(Ia-6)、(Id-3)、(Id-4)、(Id-5)、(Iaa)、(Idd)的一些实施方案中，环B选自C 5-7单环烷基、C 9-10并环烷基、C 9-12螺环烷基、C 9-12桥环烷基，所述的环烷基任选进一步被0至3个(例如0、1、2或3个)R b所取代。 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.
本发明涉及通式(I)、(Ia)、(Ib)、(Ic)、(Id)、(Ie)、(Ia-3)、(Ia-4)、(Ia-5)、(Ia-6)、(Id-3)、(Id-4)、(Id-5)、(Iaa)、(Idd)的一些实施方案中，环B选自C 5单环烷基、C 6单环烷基、C 7单环烷基、C 6并环烷基、C 7并环烷基、C 8并环烷基、C 9并环烷基、C 10并环烷基、C 6螺环烷基、C 7螺环烷基、C 8螺环烷基、C 9螺环烷基、C 10螺环烷基、C 11螺环烷基、C 12螺环烷基、C 5桥环烷基、C 6桥环烷基、C 7桥环烷基、C 8桥环烷基、C 9桥环烷基、C 10桥环烷基、C 11桥环烷基、C 12桥环烷基，所述的环烷基任选进一步被0至3个(例如0、1、2或3个)R b所取代。 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 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 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 11 bridged cycloalkyl, C 12 bridged cycloalkyl, so Said cycloalkyl is optionally further substituted with 0 to 3 (eg 0, 1, 2 or 3) R b .
本发明涉及通式(I)、(Ia)、(Ib)、(Ic)、(Id)、(Ie)、(Ia-3)、(Ia-4)、(Ia-5)、(Ia-6)、(Id-3)、(Id-4)、(Id-5)、(Iaa)、(Idd)的一些实施方案中，环B选自取代或者未取代的如下基团之一：环丙基、环丁基、环戊基、环己基、环丙基并环丁基、环丙基并环戊基、环丙基并环已基、环丁基并环丁基、环丁基并环戊基、环丁基并环已基、环戊基并环戊基、环戊基并环已基、环已基并环已基、环丙基螺环丁基、环丙基螺环戊基、环丙基螺环已基、环丁基螺环丁基、环丁基螺环戊基、环丁基螺环已基、环戊基螺环戊基、环戊基螺环已基、环已基螺环已基、双环[1.1.1]戊烷基、双环[2.1.1]己烷基、双环[2.2.1]庚烷基、双环[3.3.2]癸烷基、双环[2.2.2]辛烷基、双环[3.2.1]辛烷基、双环[3.3.3]十一烷基或金刚烷基，当被取代时，任选进一步被0至3个(例如0、1、2或3个)选自H、卤素、氰基、OH、C 1-4烷基或C 1-4烷氧基的取代基所取代。 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 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, cyclopropylspirocyclobutyl, cyclopropylspirocyclopentyl base, cyclopropyl spirocyclohexyl, cyclobutyl spirocyclobutyl, cyclobutyl spirocyclopentyl, cyclobutyl spirocyclohexyl, cyclopentyl spirocyclopentyl, cyclopentyl spirocyclohexyl, cyclohexylspirocyclohexyl, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[3.3.2]decyl, bicyclo[ 2.2.2]Octyl, bicyclo[3.2.1]octyl, bicyclo[3.3.3]undecyl or adamantyl, when substituted, optionally further substituted by 0 to 3 (eg 0, 1, 2 or 3) substituted with a substituent selected from H, halogen, cyano, OH, C 1-4 alkyl or C 1-4 alkoxy.
本发明涉及通式(I)、(Ia)、(Ib)、(Ic)、(Id)、(Ie)、(Ia-3)、(Ia-4)、(Ia-5)、(Ia-6)、(Id-3)、(Id-4)、(Id-5)、(Iaa)、(Idd)的一些实施方案中，环B选自
Figure PCTCN2021103485-appb-000202
Figure PCTCN2021103485-appb-000203
Figure PCTCN2021103485-appb-000204
Figure PCTCN2021103485-appb-000205
右侧与R 2直接连接。 The present invention relates to general formulae (I), (Ia), (Ib), (Ic), (Id), (Ie), (Ia-3), (Ia-4), (Ia-5), (Ia- 6), (Id-3), (Id-4), (Id-5), (Iaa), (Idd) in some embodiments, Ring B is selected from
Figure PCTCN2021103485-appb-000202
Figure PCTCN2021103485-appb-000203
Figure PCTCN2021103485-appb-000204
Figure PCTCN2021103485-appb-000205
And R 2 is directly connected to the right side.
本发明涉及通式(I)、(Ia)、(Ib)、(Ic)、(Id)、(Ie)、(Ia-3)、(Ia-4)、(Ia-5)、(Ia-6)、(Id-3)、(Id-4)、(Id-5)、(Iaa)、(Idd)的一些实施方案中，环B选自
Figure PCTCN2021103485-appb-000206
Figure PCTCN2021103485-appb-000207
右侧与R 2直接连接。 The present invention relates to general formulae (I), (Ia), (Ib), (Ic), (Id), (Ie), (Ia-3), (Ia-4), (Ia-5), (Ia- 6), (Id-3), (Id-4), (Id-5), (Iaa), (Idd) in some embodiments, Ring B is selected from
Figure PCTCN2021103485-appb-000206
Figure PCTCN2021103485-appb-000207
And R 2 is directly connected to the right side.
本发明涉及通式(I)、(Ia)、(Ib)、(Ic)、(Id)、(Ie)、(Ia-3)、(Ia-4)、(Ia-5)、(Ia-6)、(Id-3)、(Id-4)、(Id-5)、(Iaa)、(Idd)的一些实施方案中，环B选自
Figure PCTCN2021103485-appb-000208
Figure PCTCN2021103485-appb-000209
右侧与R 2直接连接。 The present invention relates to general formulae (I), (Ia), (Ib), (Ic), (Id), (Ie), (Ia-3), (Ia-4), (Ia-5), (Ia- 6), (Id-3), (Id-4), (Id-5), (Iaa), (Idd) in some embodiments, Ring B is selected from
Figure PCTCN2021103485-appb-000208
Figure PCTCN2021103485-appb-000209
And R 2 is directly connected to the right side.
本发明涉及通式(I)、(Ia)、(Ib)、(Ic)、(Id)、(Ie)、(Ia-3)、(Ia-4)、(Ia-5)、(Ia-6)、(Id-3)、(Id-4)、(Id-5)、(Iaa)、(Idd)的一些实施方案中，环B选自
Figure PCTCN2021103485-appb-000210
右侧与R 2直接连接。 The present invention relates to general formulae (I), (Ia), (Ib), (Ic), (Id), (Ie), (Ia-3), (Ia-4), (Ia-5), (Ia- 6), (Id-3), (Id-4), (Id-5), (Iaa), (Idd) in some embodiments, Ring B is selected from
Figure PCTCN2021103485-appb-000210
And R 2 is directly connected to the right side.
本发明涉及通式(I)、(Ia)、(Ib)、(Ic)、(Id)、(Ie)、(Ia-3)、(Ia-4)、(Ia-5)、(Ia-6)、(Id-3)、(Id-4)、(Id-5)、(Iaa)、(Idd)的一些实施方案中，R b各自独立的选自H、卤素、氰基、OH、C 1-6烷基或C 1-6烷氧基，所述的烷基或烷氧基任选进一步被0至4个(例如0、1、2、3或4个)选自H、卤素、OH、氰基、NH 2、C 1-6烷基、卤素取代的C 1-6烷基、C 1- 6烷氧基或C 3-6环烷基的取代基所取代。 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), 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.
本发明涉及通式(I)、(Ia)、(Ib)、(Ic)、(Id)、(Ie)、(Ia-3)、(Ia-4)、(Ia-5)、(Ia-6)、(Id-3)、(Id-4)、(Id-5)、(Iaa)、(Idd)的一些实施方案中，R b各自独立的选自H、卤素、氰基、OH、C 1-4烷基或C 1-4烷氧基，所述的烷基或烷氧基任选进一步被0至4个(例如0、1、2、3或4个)选自H、卤素、OH、氰基、NH 2、C 1-4烷基、卤素取代的C 1-4烷基、C 1- 4烷氧基或C 3-4环烷基的取代基所取代。 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), 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.
本发明涉及通式(I)、(Ia)、(Ib)、(Ic)、(Id)、(Ie)、(Ia-3)、(Ia-4)、(Ia-5)、(Ia-6)、(Id-3)、(Id-4)、(Id-5)、(Iaa)、(Idd)的一些实施方案中，R b各自独立的选自H、卤素、氰基、OH、C 1-4烷基或C 1-4烷氧基。 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), each R b is independently selected from H, halogen, cyano, OH, C 1-4 alkyl or C 1-4 alkoxy.
本发明涉及通式(I)、(Ia)、(Ib)、(Ic)、(Id)、(Ie)、(Ia-3)、(Ia-4)、(Ia-5)、(Ia-6)、(Id-3)、(Id-4)、(Id-5)、(Iaa)、(Idd)的一些实施方案中，R b各自独立的选自H、F、氰基、OH、甲基、乙基、甲氧基、乙氧基或羟甲基。 The present invention relates to general formulae (I), (Ia), (Ib), (Ic), (Id), (Ie), (Ia-3), (Ia-4), (Ia-5), (Ia- 6), (Id-3), (Id-4), (Id-5), (Iaa), (Idd) in some embodiments, each R b is independently selected from H, F, cyano, OH, Methyl, ethyl, methoxy, ethoxy or hydroxymethyl.
本发明涉及通式(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)、(Id-4)、(Id-5)、(Id-6)、(Iaa)、(Idd)的一些实施方案中，R 1选自5至10元杂芳基或者苯基，所述的杂芳基或者苯基任选进一步被0至4个R 1a取代。 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) In some embodiments of , (Id-4), (Id-5), (Id-6), (Iaa), (Idd), 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 .
本发明涉及通式(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)、(Id-4)、(Id-5)、(Iaa)、(Idd)的一些实施方案中，R 1选自取代或者未取代的如下基团之一：选自5至6元单环杂芳基、6并6元杂芳基、5并6元杂芳基或苯基，当被取代时，任选进一步被0至4个R 1a取代。 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) In some embodiments of , (Id-4), (Id-5), (Iaa), (Idd), 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 .
本发明涉及通式(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)、(Id-4)、(Id-5)、(Id-6)、(Iaa)、(Idd)的一些实施方案中，R 1选自取代或者未取代的如下基团之一：吡啶基、嘧啶基、吡嗪基、哒嗪基、吡唑基、吡咯基、咪唑基、噻吩基、呋喃基、噻唑基、噁唑基、异噻唑基、异噁唑基、苯并吡唑基、苯并吡咯基、苯并咪唑基、苯并噻吩基、苯并呋喃基、苯并噻唑基、苯并噁唑基、苯并异噻唑基或苯并异噁唑基，当被取代时，任选进一步被0至4个R 1a取代。 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), In some embodiments of (Id-4), (Id-5), (Id-6), (Iaa), (Idd), 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, benzothienyl, benzofuranyl, benzothiazolyl, benzoxazolyl, benzisothiazolyl or benzisoxazolyl, when substituted, optionally further Substituted by 0 to 4 R 1a.
本发明涉及通式(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)、(Id-4)、(Id-5)、(Id-6)、(Iaa)、(Idd)的一些实施方案中，R 1选自
Figure PCTCN2021103485-appb-000211
Figure PCTCN2021103485-appb-000212
Figure PCTCN2021103485-appb-000213
Figure PCTCN2021103485-appb-000214
R 1基团中的NH不能被R 1a取代，m选自0、1或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) In some embodiments of , (Id-4), (Id-5), (Id-6), (Iaa), (Idd), R 1 is selected from
Figure PCTCN2021103485-appb-000211
Figure PCTCN2021103485-appb-000212
Figure PCTCN2021103485-appb-000213
Figure PCTCN2021103485-appb-000214
The NH in the R 1 group cannot be substituted by R 1a and m is selected from 0, 1 or 2.
本发明涉及通式(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)、(Id-4)、(Id-5)、(Id-6)、(Iaa)、(Idd)的一些实施方案中，R 1选自
Figure PCTCN2021103485-appb-000215
Figure PCTCN2021103485-appb-000216
Figure PCTCN2021103485-appb-000217
Figure PCTCN2021103485-appb-000218
m选自0、1或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) In some embodiments of , (Id-4), (Id-5), (Id-6), (Iaa), (Idd), R 1 is selected from
Figure PCTCN2021103485-appb-000215
Figure PCTCN2021103485-appb-000216
Figure PCTCN2021103485-appb-000217
Figure PCTCN2021103485-appb-000218
m is selected from 0, 1 or 2.
本发明涉及通式(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)、(Id-4)、(Id-5)、(Id-6)、(Iaa)、(Idd)的一些实施方案中，R 1选自
Figure PCTCN2021103485-appb-000219
Figure PCTCN2021103485-appb-000220
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) In some embodiments of , (Id-4), (Id-5), (Id-6), (Iaa), (Idd), R 1 is selected from
Figure PCTCN2021103485-appb-000219
Figure PCTCN2021103485-appb-000220
本发明涉及通式(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)、(Id-4)、(Id-5)、(Id-6)、(Iaa)、(Idd)的一些实施方案中，R 1选自
Figure PCTCN2021103485-appb-000221
m选自0、1或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) In some embodiments of , (Id-4), (Id-5), (Id-6), (Iaa), (Idd), R 1 is selected from
Figure PCTCN2021103485-appb-000221
m is selected from 0, 1 or 2.
本发明涉及通式(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)、(Id-4)、(Id-5)、(Id-6)、(Iaa)、(Idd)的一些实施方案中，R 1b选自C 1-6烷基或C 3-6环烷基，所述的烷基或环烷基任选进一步被0至4个(例如0、1、2、3或4个)选自H、卤素、OH、氰基、NH 2、卤素取代的C 1-6烷基、C 1-6烷基、C 1-6烷氧基或C 3-6环烷基的取代基所取代。 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) In some embodiments of , (Id-4), (Id-5), (Id-6), (Iaa), (Idd), 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.
本发明涉及通式(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)、(Id-4)、(Id-5)、(Id-6)、(Iaa)、(Idd)的一些实施方案中，R 1b选自C 1-4烷基或C 3-6环烷基，所述的烷基或环烷基任选进一步被0至4个(例如0、1、2、3或4个)选自H、卤素、OH、氰基、NH 2、卤素取代的C 1-6烷基、C 1-6烷基、C 1-6烷氧基或C 3-6环烷基的取代基所取代。 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) In some embodiments of , (Id-4), (Id-5), (Id-6), (Iaa), (Idd), 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.
本发明涉及通式(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)、(Id-4)、(Id-5)、(Id-6)、(Iaa)、(Idd)的一些实施方案中，R 1b选自甲基、乙基、异丙基、环丙基、环丁基、环戊基或环己基，所述的甲基、乙基、异丙基、环丙基、环丁基、环戊基或环己基任选进一步被0至4个(例如0、1、2、3或4个)选自H、卤素、OH、氰基、NH 2、卤素取代的C 1-6烷基、C 1-6烷基、C 1-6烷氧基或C 3-6环烷基的取代基所取代。 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) In some embodiments of , (Id-4), (Id-5), (Id-6), (Iaa), (Idd), 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 2, halo-substituted C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkoxy, or C 3 -6 Substituents of cycloalkyl.
本发明涉及通式(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)、(Id-4)、(Id-5)、(Id-6)、(Iaa)、(Idd)的一些实施方案中，R 1选自
Figure PCTCN2021103485-appb-000222
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) In some embodiments of , (Id-4), (Id-5), (Id-6), (Iaa), (Idd), R 1 is selected from
Figure PCTCN2021103485-appb-000222
本发明涉及通式(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)、(Id-4)、(Id-5)、(Id-6)、(Iaa)、(Idd)的一些实施方案中，R 1选自
Figure PCTCN2021103485-appb-000223
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) In some embodiments of , (Id-4), (Id-5), (Id-6), (Iaa), (Idd), R 1 is selected from
Figure PCTCN2021103485-appb-000223
本发明涉及通式(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)、(Id-4)、(Id-5)、(Iaa)、(Idd)的一些实施方案中，R 1选自
Figure PCTCN2021103485-appb-000224
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) In some embodiments of , (Id-4), (Id-5), (Iaa), (Idd), R 1 is selected from
Figure PCTCN2021103485-appb-000224
本发明涉及通式(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)、(Id-4)、(Id-5)、(Iaa)、(Idd)的一 些实施方案中，R 1选自
Figure PCTCN2021103485-appb-000225
Figure PCTCN2021103485-appb-000226
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) In some embodiments of , (Id-4), (Id-5), (Iaa), (Idd), R 1 is selected from
Figure PCTCN2021103485-appb-000225
Figure PCTCN2021103485-appb-000226
本发明涉及通式(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)、(Id-4)、(Id-5)、(Id-6)、(Iaa)、(Idd)的一些实施方案中，R 1a各自独立的选自H、卤素、OH、氰基、NH 2、-NH(C 1-6烷基)、-N(C 1-6烷基) 2、-NH(C 3-6环烷基)、C 1-6烷基、C 1-6烷氧基、C 3-6环烷基或3至8元杂环基，所述的烷基、烷氧基、环烷基或杂环基任选进一步被0至4个(例如0、1、2、3或4个)选自H、卤素、OH、氰基、NH 2、卤素取代的C 1-6烷基、C 1-6烷基、C 1-6烷氧基或C 3-6环烷基的取代基所取代。 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) In some embodiments of , (Id-4), (Id-5), (Id-6), (Iaa), (Idd), 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 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 cycloalkane substituted by the substituents of the base.
本发明涉及通式(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)、(Id-4)、(Id-5)、(Id-6)、(Iaa)、(Idd)的一些实施方案中，R 1a各自独立的选自H、卤素、OH、氰基、NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、-NH(C 3-4环烷基)、C 1-4烷基或C 1-4烷氧基，所述的烷基或烷氧基任选进一步被0至4个(例如0、1、2、3或4个)选自H、卤素、OH、氰基、NH 2、卤素取代的C 1-4烷基、C 1-4烷基、C 1-4烷氧基或C 3-6环烷基的取代基所取代。 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) In some embodiments of , (Id-4), (Id-5), (Id-6), (Iaa), (Idd), 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 , halogen substituted C 1 -4 alkyl, C 1-4 alkyl, C 1-4 alkoxy or C 3-6 cycloalkyl substituent.
本发明涉及通式(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)、(Id-4)、(Id-5)、(Id-6)、(Iaa)、(Idd)的一些实施方案中，R 1a各自独立的选自H、F、OH、氰基、甲基、乙基、异丙基、丙基、甲氧基或乙氧基，所述的甲基、乙基、异丙基、丙基、甲氧基或乙氧基任选进一步被0至4个(例如0、1、2、3或4个)选自H、卤素、OH、氰基、NH 2、卤素取代的C 1-4烷基、C 1-4烷基、C 1-4烷氧基或C 3-6环烷基的取代基所取代。 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) In some embodiments of , (Id-4), (Id-5), (Id-6), (Iaa), (Idd), 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, C 1-4 alkyl, C 1-4 alkoxy is substituted with a substituent of C 3-6 cycloalkyl or C 3-6 cycloalkyl.
本发明涉及通式(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)、(Id-4)、(Id-5)、(Id-6’)、(Iaa)、(Idd)的一些实施方案中，R 2选自卤素、氰基、OH、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、-(CH 2) q-C(＝O)-R 2a、-(CH 2) q-C(＝O)O-R 2a、-(CH 2) q-S(＝O) 2-R 2a、-(CH 2) q-NR 2aS(＝O) 2-R 2b、-(CH 2) q-C(＝O)-NR 2aR 2b、-(CH 2) q-NR 2aR 2b、-(CH 2) qNR 2aC(＝O)-R 2b、-(CH 2) q-C 3-10碳环或-(CH 2) q-3至12元杂环，所述的-CH 2-、烷基、烯基、炔基、烷氧基、碳 环或杂环任选进一步被0至4个(例如0、1、2、3或4个)选自H、卤素、OH、氰基、NH 2、C 1-6烷基、卤素取代的C 1-6烷基、氰基取代的C 1-6烷基或C 1-6烷氧基的取代基所取代，所述的杂环含有1至3个(例如1、2或3)选自O、S、N的杂原子。 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 ), (Id-4), (Id-5), (Id-6'), (Iaa), (Idd) in some embodiments, R 2 is selected from halogen, cyano, OH, C 1-6 alkane base, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, -(CH 2 ) q -C(=O)-R 2a , -(CH 2 ) q -C(= O)OR 2a , -(CH 2 ) q -S(=O) 2 -R 2a , -(CH 2 ) q -NR 2a S(=O) 2 -R 2b , -(CH 2 ) q -C( =O)-NR 2a R 2b , -(CH 2 ) q -NR 2a R 2b , -(CH 2 ) q NR 2a C(=O)-R 2b , -(CH 2 ) q -C 3-10 carbon Ring or -(CH 2 ) q -3- to 12-membered heterocycle, said -CH 2 -, alkyl, alkenyl, alkynyl, alkoxy, carbocycle or heterocycle 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, cyano substituted C 1 -6 alkyl or C 1-6 alkoxy substituent, the heterocycle contains 1 to 3 (eg 1, 2 or 3) heteroatoms selected from O, S, N.
本发明涉及通式(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)、(Id-4)、(Id-5)、(Id-6’)、(Iaa)、(Idd)的一些实施方案中，R 2选自卤素、氰基、OH、C 1-4烷基、C 1-4烷氧基、-(CH 2) q-C(＝O)-R 2a、-(CH 2) q-C(＝O)O-R 2a、-(CH 2) q-S(＝O) 2-R 2a、-(CH 2) q-NR 2aS(＝O) 2-R 2b、-(CH 2) q-C(＝O)-NR 2aR 2b、-(CH 2) q-NR 2aR 2b、-(CH 2) qNR 2aC(＝O)-R 2b、-(CH 2) q-C 3-10碳环或-(CH 2) q-3至10元杂环，所述的-CH 2-、烷基、烷氧基、碳环或杂环任选进一步被0至4个(例如0、1、2、3或4个)选自H、卤素、OH、氰基、NH 2、C 1-4烷基、卤素取代的C 1-4烷基、氰基取代的C 1-4烷基或C 1-4烷氧基的取代基所取代，所述的杂环含有1至3个(例如1、2或3)选自O、S、N的杂原子。 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 ), (Id-4), (Id-5), (Id-6'), (Iaa), (Idd) in some embodiments, R 2 is selected from halogen, cyano, OH, C 1-4 alkane base, C 1-4 alkoxy, -(CH 2 ) q -C(=O)-R 2a , -(CH 2 ) q -C(=O)OR 2a , -(CH 2 ) q -S( =O) 2 -R 2a , -(CH 2 ) q -NR 2a S(=O) 2 -R 2b , -(CH 2 ) q -C(=O)-NR 2a R 2b , -(CH 2 ) q -NR 2a R 2b , -(CH 2 ) q NR 2a C(=O)-R 2b , -(CH 2 ) q -C 3-10 carbocyclic or -(CH 2 ) q -3- to 10-membered heterocyclic ring, the -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, 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 The heterocyclic ring contains 1 to 3 (eg 1, 2 or 3) heteroatoms selected from O, S, N.
本发明涉及通式(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)、(Id-4)、(Id-5)、(Id-6)、(Iaa)、(Idd)的一些实施方案中，R 2选自卤素、氰基、OH、C 1-4烷基、C 1-4烷氧基、C 3-6碳环、3至6元杂环、-CH 2-C 3-6碳环、-CH 2-3至6元杂环、-NH-C 3-6碳环、-NH-3至6元杂环或-NHC 1-4烷基，所述的-CH 2-、烷基、烷氧基、碳环或杂环任选进一步被0至4个(例如0、1、2、3或4个)选自H、卤素、OH、氰基、NH 2、C 1-4烷基、卤素取代的C 1-4烷基、氰基取代的C 1-4烷基或C 1-4烷氧基的取代基所取代，所述的杂环含有1至3个(例如1、2或3)选自O、S、N的杂原子。 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) In some embodiments of , (Id-4), (Id-5), (Id-6), (Iaa), (Idd), 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 optionally further replaced 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 substituted C 1 -4 alkyl or C 1-4 alkoxy substituent, the heterocycle contains 1 to 3 (eg 1, 2 or 3) heteroatoms selected from O, S, N.
本发明涉及通式(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)、(Id-4)、(Id-5)、(Id-6’)、(Iaa)、(Idd)的一些实施方案中，R 2选自取代的或者未取代的如下基团之一：F、氰基、OH、甲基、乙基、甲氧基、乙氧基、环丙基、环丁基、环戊基、环己基、-CH 2-环丙基、-CH 2-环丁基、-CH 2-环戊基、-CH 2-环己基、氮杂环丁基、氮杂环戊基、氮杂环己基、-CH 2-氮杂环丁基、-CH 2-氮杂环戊基、-CH 2-氮杂环己基、氧杂环丁基、氧杂环戊基、氧杂环己基、-CH 2-氧杂环丁基、-CH 2-氧杂环戊基、-CH 2-氧杂环己基、-CH 2-吗啉、-CH 2-哌嗪、-NH-甲基、-NH-乙基、-NH-丙基、-NH-丁基、-NH-异丙基，当被取代时，任选进一步被0至4个(例如0、1、2、3或4个)选自H、卤素、OH、氰基、NH 2、C 1-4烷基、卤素取代的C 1-4烷基、氰基取代的C 1-4烷基或C 1-4烷氧基的取代基所取。 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 ), (Id-4), (Id-5), (Id-6'), (Iaa), (Idd) in some embodiments, 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, azetidine, azacyclopentyl, azacyclohexyl, -CH 2 -azetidine, -CH 2 -aza Cyclopentyl, -CH 2 -azepanyl, oxetanyl, oxolane, oxetyl, -CH 2 -oxetanyl, -CH 2 -oxetanyl, -CH 2 -oxanyl, -CH 2 -morpholine, -CH 2 -piperazine, -NH-methyl, -NH-ethyl, -NH-propyl, -NH-butyl, -NH- an isopropyl group, when substituted, optionally further 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.
本发明涉及通式(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)、(Id-4)、(Id-5)、(Id-6’)、(Iaa)、(Idd)的一些实施方案中，R 2选自取代的或者未取代的如下基团之一：F、氰基、OH、甲基、乙基、甲氧基、乙氧基、环丙基、环丁基、环戊基、环己基、-CH 2-环丙基、-CH 2-环丁基、-CH 2-环戊基、-CH 2-环己基、氮杂环丁基、氮杂环戊基、氮杂环己基、-CH 2-氮杂环丁基、-CH 2-氮杂环戊基、-CH 2-氮杂环己基、氧杂环丁基、氧杂环戊基、氧杂环己基、-CH 2-氧杂环丁基、-CH 2-氧杂环戊基、-CH 2-氧杂环己基、-CH 2-吗啉、-CH 2-哌嗪、-NH-甲基、-NH-乙基、-NH-丙基、-NH-丁基、-NH-异丙基，当被取代时，任选进一步被0至4个(例如0、1、2、3或4个)选自H、F、OH、氰基、NH 2、甲基、乙基、CF 3、-CH 2CN、-CH 2CH 2CN、-CH 2CH 2CH 2CN、甲氧基或乙氧基的取代基所取。 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 ), (Id-4), (Id-5), (Id-6'), (Iaa), (Idd) in some embodiments, 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, azetidine, azacyclopentyl, azacyclohexyl, -CH 2 -azetidine, -CH 2 -aza Cyclopentyl, -CH 2 -azepanyl, oxetanyl, oxolane, oxetyl, -CH 2 -oxetanyl, -CH 2 -oxetanyl, -CH 2 -oxanyl, -CH 2 -morpholine, -CH 2 -piperazine, -NH-methyl, -NH-ethyl, -NH-propyl, -NH-butyl, -NH- an isopropyl group, when substituted, optionally further substituted with 0 to 4 (e.g. 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.
本发明涉及通式(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)、(Id-4)、(Id-5)、(Id-6’)、(Iaa)、(Idd)的一些实施方案中，R 2选自F、氰基、OH、-OCHF 2、-OCH 2F、-OCF 3、-OCH 3、甲基、乙基、CF 3、-CH 2OH、-CH 2CH 2OH、-CH 2CH 2CH 2OH、-CH 2CN、-CH 2CH 2CN、-CH 2CH 2CH 2CN、-CH 2CH 2CH 2CH 2CN、-NHCH 2CN、-NHCH 2CH 2CN、-NHCH 2CH 2CH 2CN、-NHCH 2CH 2CH 2CH 2CN、
Figure PCTCN2021103485-appb-000227
Figure PCTCN2021103485-appb-000228
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 ), (Id-4), (Id-5), (Id-6'), (Iaa), (Idd) in some embodiments, 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 2 CH 2 CN, -NHCH 2 CH 2 CH 2 CN, -NHCH 2 CH 2 CH 2 CH 2 CN,
Figure PCTCN2021103485-appb-000227
Figure PCTCN2021103485-appb-000228
本发明涉及通式(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)、(Id-4)、(Id-5)、(Id-6’)、(Iaa)、(Idd)的一些实施方案中，R 2选自F、OH、-OCH 3、-OCHF 2、-OCH 2F、-OCF 3、-CH 2OH、-CH 2CN、-CH 2CH 2CN、-NHCH 2CN、-NHCH 2CH 2CN。 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 ), (Id-4), (Id-5), (Id-6'), (Iaa), (Idd) in some embodiments, 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.
本发明涉及通式(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)、(Id-4)、(Id-5)、(Id-6’)、(Iaa)、(Idd)的一些实施方案中，R a1、R a2、R 2a、R 2b各自独立的选自H、C 1-6烷基、C 3-12碳环基或3至12元杂环基，所述的烷基、碳环基或杂环基任选进一步被0至4个(例如0、1、2、3或4个)选自H、卤素、OH、氰基、NH 2、C 1-6烷基、卤素取代的C 1-6烷基、氰 基取代的C 1-6烷基或C 1-6烷氧基的取代基所取代，所述的杂环基含有1至3个(例如1、2或3)选自O、S、N的杂原子。 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 ), (Id-4), (Id-5), (Id-6'), (Iaa), (Idd) in some embodiments, 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, 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.
本发明涉及通式(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)、(Id-4)、(Id-5)、(Id-6’)、(Iaa)、(Idd)的一些实施方案中，R a1、R a2、R 2a、R 2b各自独立的选自H、C 1-4烷基、C 3-10碳环基或3至10元杂环基，所述的烷基、碳环基或杂环基任选进一步被0至4个(例如0、1、2、3或4个)选自H、卤素、OH、氰基、NH 2、C 1-4烷基、卤素取代的C 1-4烷基、氰基取代的C 1-4烷基或C 1-4烷氧基的取代基所取代，所述的杂环基含有1至3个(例如1、2或3)选自O、S、N的杂原子。 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 ), (Id-4), (Id-5), (Id-6'), (Iaa), (Idd) in some embodiments, 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, cyano substituted 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.
本发明涉及通式(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)、(Id-4)、(Id-5)、(Id-6’)、(Iaa)、(Idd)的一些实施方案中，R a2选自H、C 1-4烷基、C 3-6碳环基或3至6元杂环基，所述的烷基、碳环基或杂环基任选进一步被0至4个(例如0、1、2、3或4个)选自H、卤素、OH、氰基、NH 2、C 1-4烷基、卤素取代的C 1-4烷基、氰基取代的C 1-4烷基或C 1-4烷氧基的取代基所取代，所述的杂环基含有1至3个(例如1、2或3)选自O、S、N的杂原子。 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 ), (Id-4), (Id-5), (Id-6'), (Iaa), (Idd) in some embodiments, 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 Alternatively, the heterocyclyl group contains 1 to 3 (eg 1, 2 or 3) heteroatoms selected from O, S, N.
本发明涉及通式(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各自独立的选自0、1、2、3或4。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.
本发明涉及通式(Ia)、(Ib)、(Ic)、(Id)、(Ie)、(Ib-1)、(Ic-1)、(Id-1)、(Ie-1)、(Id-3)、(Id-4)、(Iaa)、(Idd)，m选自0、1或2，p选自0、1或2。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.
本发明涉及通式(Id)、(Idd)的一些实施方案中，当
Figure PCTCN2021103485-appb-000229
选自
Figure PCTCN2021103485-appb-000230
R a选自-C(＝O)-NH-吡啶，所述吡啶任选被取代时，R 1不为
Figure PCTCN2021103485-appb-000231
The present invention relates to some embodiments of general formula (Id), (Idd), when
Figure PCTCN2021103485-appb-000229
selected from
Figure PCTCN2021103485-appb-000230
R a is selected from -C(=O)-NH-pyridine, and when the pyridine is optionally substituted, R 1 is not
Figure PCTCN2021103485-appb-000231
本发明涉及通式(Ic)的一些实施方案中，
Figure PCTCN2021103485-appb-000232
选自
Figure PCTCN2021103485-appb-000233
S 1或S 2各自独立的选自N或CR a时，环B选自C 9-10并环烷基、C 9-12螺环烷基、C 9-12桥环烷基，所述的环烷基任选进一步被0至3个(例如0、1、2或3个)R b所取代。 The present invention relates to some embodiments of general formula (Ic),
Figure PCTCN2021103485-appb-000232
selected from
Figure PCTCN2021103485-appb-000233
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 .
本发明涉及通式(Ic)的一些实施方案中，
Figure PCTCN2021103485-appb-000234
选自
Figure PCTCN2021103485-appb-000235
S 1或S 2各自独立的选自N或CR a时，环B选自
Figure PCTCN2021103485-appb-000236
Figure PCTCN2021103485-appb-000237
Figure PCTCN2021103485-appb-000238
右侧与R 2直接连接。 The present invention relates to some embodiments of general formula (Ic),
Figure PCTCN2021103485-appb-000234
selected from
Figure PCTCN2021103485-appb-000235
When S 1 or S 2 are independently selected from N or CR a , ring B is selected from
Figure PCTCN2021103485-appb-000236
Figure PCTCN2021103485-appb-000237
Figure PCTCN2021103485-appb-000238
And R 2 is directly connected to the right side.
本发明涉及通式(Ic)的一些实施方案中，
Figure PCTCN2021103485-appb-000239
选自
Figure PCTCN2021103485-appb-000240
S 1或S 2各自独立的选自N或CR a时，环B选自取代或者未取代的如下基团之一：环丁基并环已基、环戊基并环戊基、环戊基并环已基、环已基并环已基、环戊基螺环戊基、环戊基螺环已基、环已基螺环已基、双环[2.2.2]辛烷基、双环[3.2.1]辛烷基、双环[3.3.3]十一烷基或金刚烷基，当被取代时，任选进一步被0至3个(例如0、1、2或3个)选自H、卤素、氰基、OH、C 1-4烷基或C 1-4烷氧基的取代基所取代。 本发明涉及通式(Ia)、(Iaa)、(Ia-2)的一些实施方案中，
Figure PCTCN2021103485-appb-000241
选自 The present invention relates to some embodiments of general formula (Ic),
Figure PCTCN2021103485-appb-000239
selected from
Figure PCTCN2021103485-appb-000240
When S 1 or S 2 are independently selected from N or CR a , 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 alkyl or C 1-4 alkoxy. The present invention relates to some embodiments of general formula (Ia), (Iaa), (Ia-2),
Figure PCTCN2021103485-appb-000241
selected from
Figure PCTCN2021103485-appb-000242
Figure PCTCN2021103485-appb-000243
Figure PCTCN2021103485-appb-000242
Figure PCTCN2021103485-appb-000243
本发明涉及通式(Ia)、(Iaa)、(Ia-2)的一些实施方案中，
Figure PCTCN2021103485-appb-000244
选自
Figure PCTCN2021103485-appb-000245
Figure PCTCN2021103485-appb-000246
The present invention relates to some embodiments of general formula (Ia), (Iaa), (Ia-2),
Figure PCTCN2021103485-appb-000244
selected from
Figure PCTCN2021103485-appb-000245
Figure PCTCN2021103485-appb-000246
本发明涉及通式(Ia)、(Iaa)、(Ia-2)的一些实施方案中，
Figure PCTCN2021103485-appb-000247
选自
Figure PCTCN2021103485-appb-000248
Figure PCTCN2021103485-appb-000249
The present invention relates to some embodiments of general formula (Ia), (Iaa), (Ia-2),
Figure PCTCN2021103485-appb-000247
selected from
Figure PCTCN2021103485-appb-000248
Figure PCTCN2021103485-appb-000249
本发明涉及通式(Ib)、(Ib-1)的一些实施方案中，
Figure PCTCN2021103485-appb-000250
选自
Figure PCTCN2021103485-appb-000251
Figure PCTCN2021103485-appb-000252
The present invention relates to some embodiments of general formula (Ib), (Ib-1),
Figure PCTCN2021103485-appb-000250
selected from
Figure PCTCN2021103485-appb-000251
Figure PCTCN2021103485-appb-000252
本发明涉及通式(Ic)、(Ic-1)的一些实施方案中，
Figure PCTCN2021103485-appb-000253
选自
Figure PCTCN2021103485-appb-000254
Figure PCTCN2021103485-appb-000255
The present invention relates to some embodiments of general formula (Ic), (Ic-1),
Figure PCTCN2021103485-appb-000253
selected from
Figure PCTCN2021103485-appb-000254
Figure PCTCN2021103485-appb-000255
本发明涉及通式(Id)、(Idd)、(Id-1)的一些实施方案中，
Figure PCTCN2021103485-appb-000256
选自
Figure PCTCN2021103485-appb-000257
Figure PCTCN2021103485-appb-000258
The present invention relates to some embodiments of general formula (Id), (Idd), (Id-1),
Figure PCTCN2021103485-appb-000256
selected from
Figure PCTCN2021103485-appb-000257
Figure PCTCN2021103485-appb-000258
本发明涉及通式(Id)、(Idd)、(Id-1)的一些实施方案中，
Figure PCTCN2021103485-appb-000259
选自
Figure PCTCN2021103485-appb-000260
The present invention relates to some embodiments of general formula (Id), (Idd), (Id-1),
Figure PCTCN2021103485-appb-000259
selected from
Figure PCTCN2021103485-appb-000260
本发明涉及通式(Id)、(Idd)、(Id-1)的一些实施方案中，
Figure PCTCN2021103485-appb-000261
选自
Figure PCTCN2021103485-appb-000262
The present invention relates to some embodiments of general formula (Id), (Idd), (Id-1),
Figure PCTCN2021103485-appb-000261
selected from
Figure PCTCN2021103485-appb-000262
本发明涉及通式(Id)、(Idd)、(Id-1)的一些实施方案中，
Figure PCTCN2021103485-appb-000263
选自
Figure PCTCN2021103485-appb-000264
The present invention relates to some embodiments of general formula (Id), (Idd), (Id-1),
Figure PCTCN2021103485-appb-000263
selected from
Figure PCTCN2021103485-appb-000264
本发明涉及通式(Id)、(Idd)、(Id-1)的一些实施方案中，
Figure PCTCN2021103485-appb-000265
选自
Figure PCTCN2021103485-appb-000266
The present invention relates to some embodiments of general formula (Id), (Idd), (Id-1),
Figure PCTCN2021103485-appb-000265
selected from
Figure PCTCN2021103485-appb-000266
本发明涉及通式(Id)、(Idd)、(Id-1)的一些实施方案中，
Figure PCTCN2021103485-appb-000267
选自
Figure PCTCN2021103485-appb-000268
Figure PCTCN2021103485-appb-000269
The present invention relates to some embodiments of general formula (Id), (Idd), (Id-1),
Figure PCTCN2021103485-appb-000267
selected from
Figure PCTCN2021103485-appb-000268
Figure PCTCN2021103485-appb-000269
本发明涉及通式(Ie)、(Ie-1)的一些实施方案中，
Figure PCTCN2021103485-appb-000270
选自
Figure PCTCN2021103485-appb-000271
Figure PCTCN2021103485-appb-000272
The present invention relates to some embodiments of general formula (Ie), (Ie-1),
Figure PCTCN2021103485-appb-000270
selected from
Figure PCTCN2021103485-appb-000271
Figure PCTCN2021103485-appb-000272
本发明涉及通式(Id)、(Idd)、(Id-1)、(Id-3)、(Id-4)、(Id-5)的一些实施方案中，化合物不为如下化合物及其立体异构体：
Figure PCTCN2021103485-appb-000273
Figure PCTCN2021103485-appb-000274
Figure PCTCN2021103485-appb-000275
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:
Figure PCTCN2021103485-appb-000273
Figure PCTCN2021103485-appb-000274
Figure PCTCN2021103485-appb-000275
本发明涉及通式(Ia)、(Iaa)、(Ia-3)、(Ia-4)、(Ia-5)、(Ia-6)的一些实施方案中，化合物不为如下化合物及其立体异构体：In some embodiments of the present invention relating to general formulae (Ia), (Iaa), (Ia-3), (Ia-4), (Ia-5), (Ia-6), the compounds are not the following compounds and their stereo isomer:
Figure PCTCN2021103485-appb-000276
Figure PCTCN2021103485-appb-000276
本发明中，药学上可接受的盐包括但不限于三氟乙酸盐。In the present invention, pharmaceutically acceptable salts include but are not limited to trifluoroacetic acid salts.
本发明涉及一种药物组合物，包括任意上述化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，以及药学上可接受的载体。The present invention relates to 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.
本发明涉及任意上述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶在制备治疗与JAK激酶活性或表达量相关疾病的药物中的应用。在某些实施方案中，所述疾病为炎性疾病。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. In certain embodiments, the disease is an inflammatory disease.
在另一个方面，本发明提供了一种预防或治疗与JAK激酶活性或表达量相关疾病(例如上文所述的疾病)的方法，其包括下列步骤：将预防或治疗有效量的本发明的化合物或其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，或者上述药物组合物施用于对其有需求的个体。In another aspect, 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.
术语“个体”(或称受试者)是指人类或非人动物。The term "individual" (or subject) refers to a human or non-human animal.
本领域的参考书和专著，详细介绍了可用于制备本文所述化合物的反应物的合成，或提供了描述该制备方法的文章以供参考。这些参考书和专著包括：“Synthetic Organic Chemistry”,John Wiley&Sons,Inc.,New York；S.R.Sandler et al.,“Organic Functional Group Preparations,”2nd Ed.,Academic Press,New York,1983；H.O.House,“Modern Synthetic Reactions”,2nd Ed.,W.A.Benjamin,Inc.Menlo Park,Calif.1972；T.L.Gilchrist,“Heterocyclic Chemistry”,2nd Ed.,John Wiley&Sons,New York,1992；J.March,“Advanced Organic Chemistry:Reactions,Mechanisms and Structure”,4th Ed.,Wiley-Interscience,New York,1992；Fuhrhop,J.and Penzlin G.“Organic Synthesis:Concepts,Methods,Starting Materials”,Second,Revised and Enlarged Edition(1994)John Wiley&Sons ISBN:3-527-29074-5；Hoffman,R.V.“Organic Chemistry,An Intermediate Text”(1996)Oxford University Press,ISBN 0-19-509618-5；Larock,R.C.“Comprehensive Organic Transformations:A Guide to Functional Group Preparations”2nd Edition(1999)Wiley-VCH,ISBN:0-471-19031-4；March,J.“Advanced Organic Chemistry:Reactions,Mechanisms,and Structure”4th Edition(1992)John Wiley&Sons,ISBN:0-471-60180-2；Otera,J.(editor)“Modern Carbonyl Chemistry”(2000)Wiley-VCH,ISBN:3-527-29871-1；Patai,S.“Patai’s 1992Guide to the Chemistry of Functional Groups”(1992)Interscience ISBN:0-471-93022-9；Solomons,T.W.G.“Organic Chemistry”7th Edition(2000)John Wiley&Sons,ISBN:0-471-19095-0；Stowell,J.C.,“Intermediate Organic Chemistry”2nd Edition(1993)Wiley-Interscience,ISBN:0-471-57456-2；“Industrial Organic Chemicals:Starting Materials and Intermediates:An Ullmann’s Encyclopedia”(1999)John Wiley&Sons,ISBN:3-527-29645-X,in 8volumes；“Organic Reactions”(1942-2000)John Wiley&Sons,in over 55volumes；and“Chemistry of Functional Groups”John Wiley&Sons,in 73volumes.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. March, "Advanced Organic Chemistry" : Reactions, Mechanisms and Structure", 4th Ed., Wiley-Interscience, New York, 1992; Fuhrhop, J. and Penzlin G. "Organic Synthesis: Concepts, Methods, Starting Materials", Second, Revised and Enlarged Edition (1994) John Wiley & Sons ISBN: 3-527-29074-5; Hoffman, RV "Organic Chemistry, An Intermediate Text" (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, RC "Comprehensive Organic Transformations: A Guide to Functional Group Preparations" 2nd Edition (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J. "Advanced Organic Chemistry: Reactions, Mechanisms, and Structure" 4th Edition (1992) John Wiley & Sons, ISBN: 0 -471-60180-2; Otera, J. (editor) "Modern Carbonyl Chemist ry" (2000) Wiley-VCH, ISBN: 3-527-29871-1; Patai, S. "Patai's 1992 Guide to the Chemistry of Functional Groups" (1992) Interscience ISBN: 0-471-93022-9; Solomons, TWG "Organic Chemistry" 7th Edition (2000) John Wiley & Sons, ISBN: 0-471-19095-0; Stowell, JC, "Intermediate Organic Chemistry" 2nd Edition (1993) Wiley-Interscience, ISBN: 0-471-57456-2; "Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia" (1999) John Wiley & Sons, ISBN: 3-527-29645-X, in 8 volumes; "Organic Reactions" (1942-2000) John Wiley & Sons, in over 55 volumes; and "Chemistry of Functional Groups" John Wiley & Sons, in 73 volumes.
通过美国化学会化学文摘社制备的已知化学物质的索引，可以选择性地识别特定和类似的反应物，这些索引可在大多数公共图书馆和大学图书馆以及在线获得。已知但在目录中不可商购的化学品可选地由定制化学合成工厂制备，其中许多标准化学供应工厂(例如，上面列出的那些)提供定制合成服务。制备和选择本文所述化合物的药用盐的参考文献是P.H.Stahl&C.G.Wermuth“Handbook of Pharmaceutical Salts”,Verlag Helvetica Chimica Acta,Zurich,2002.Specific and similar reactants can be selectively identified through indexes of known chemicals prepared by the Chemical Abstracts Service of the American Chemical Society, available in most public and university libraries and online. Chemicals that are known but not commercially available in the catalog are optionally prepared by custom chemical synthesis facilities, many of which standard chemical supply facilities (eg, those listed above) provide custom synthesis services. A reference for the preparation and selection of pharmaceutically acceptable salts of the compounds described herein is P.H. Stahl & C.G. Wermuth "Handbook of Pharmaceutical Salts", Verlag Helvetica Chimica Acta, Zurich, 2002.
合成方法resolve resolution
为了完成本发明的目的，本发明化合物可以由以下方案制备而得：In order to accomplish the purpose of the present invention, the compound of the present invention can be prepared by the following scheme:
方案一：Option One:
Figure PCTCN2021103485-appb-000277
Figure PCTCN2021103485-appb-000277
X选自Cl、Br、I、OTs(对甲苯磺酰基)或苯磺酸酯基；X is selected from Cl, Br, I, OTs (p-toluenesulfonyl) or besylate;
PG选自胺基保护基、羟基保护基，优选
Figure PCTCN2021103485-appb-000278
R 1、R 2、与通式(I)所示化合物中取代基的定义相同； PG is selected from amine protecting group, hydroxyl protecting group, preferably
Figure PCTCN2021103485-appb-000278
R 1 , R 2 , have the same definitions as the substituents in the compound represented by the general formula (I);
通式(M-1)化合物通过常规的亲核取代反应转化为通式(M-2)化合物；通式(M-2)化合物再通过亲核取代反应或偶联反应得到通式(M-3)化合物；通式(M-3)化合物通过脱保护基反应得到通式(Ia-1)化合物。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).
方案二：Option II:
Figure PCTCN2021103485-appb-000279
Figure PCTCN2021103485-appb-000279
R 1、R 2、Z、Y、环C与通式(I-d)所示化合物中取代基的定义相同； 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);
通式(N-1)化合物通过常规的亲核取代反应转化为通式(N-2)化合物；通式(N-2)化合物再通过亲核取代反应或偶联反应得到通式(Id-2)化合物。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.
除非有相反的陈述，在说明书和权利要求书中使用的术语具有下述含义。Unless stated to the contrary, terms used in the specification and claims have the following meanings.
本发明所述基团和化合物中所涉及的碳、氢、氧、硫、氮或F、Cl、Br、I均包括它们的同位素情况，即本发明所述基团和化合物中所涉及的碳、氢、氧、硫或氮任选进一步被一个或多个它们对应的同位素所替代，其中碳的同位素包括 12C、 13C和 14C，氢的同位素包括氕(H)、氘(D，又叫重氢)、氚(T，又叫超重氢)，氧的同位素包括 16O、 17O和 18O，硫的同位素包括 32S、 33S、 34S和 36S，氮的同位素包括 14N和 15N，氟的同位素包括 17F和 19F，氯的同位素包括 35Cl和 37Cl，溴的同位素包括 79Br和 81Br。 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.
“卤素”是指F、Cl、Br或I。"Halogen" means F, Cl, Br or I.
“烷基”是指1至20个碳原子的直链或支链饱和脂肪族烃基，优选为1至8个碳原子的烷基，更优选为1至6个碳原子的烷基，进一步优选为1至4个碳原子的烷基。非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、仲丁基、新丁基、叔丁基、正戊基、异戊基、新戊基、正己基及其各种支链异构体；所述的烷基可以任选进一步被0至6个选自F、Cl、Br、I、羟基、巯基、硝基、氰基、氨基、烷基氨基、酰胺基、烯基、炔基、C 1-6烷基、C 1-6羟基烷基、C 1-6烷氧基、3至8元碳环基、3至8元杂环基、3至8元碳环基氧基、3至8元杂环基氧基、羧基或者羧酸酯基的取代基所取代，本文中出现的烷基，其定义与本定义一致。 "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 or carboxylate groups, and alkyl groups appearing herein, have the same definition as this definition.
“亚烷基”是指直链和支链的二价饱和烃基，包括-(CH 2) v-(v为1至10的整数)，亚烷基实施例包括但不限于亚甲基、亚乙基、亚丙基和亚丁基等；所述的亚烷基可以任选进一步被0至5个选自F、Cl、Br、I、羟基、巯基、硝基、氰基、氨基、烷基氨基、烯基、炔基、烷基、羟基烷基、烷氧基、碳环基、杂环基、碳环基氧基、杂环基氧基、羧基或者羧酸酯基的取代基所取代。本文中出现的亚烷基，其定义与本定义一致。 "Alkylene" refers to linear and branched divalent saturated hydrocarbon groups, including -(CH 2 ) v - (v is an integer from 1 to 10). Examples of 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.
“环烷基”是指一价饱和的碳环烃基，通常有3至10个碳原子，非限制性实施例包括环丙基、环丁基、环戊基、环己基或环庚基等。所述的环烷基可以任选进一步被0至5个选自F、Cl、Br、I、羟基、巯基、硝基、氰基、氨基、烷基氨基、烯基、炔基、烷基、羟基烷基、烷氧基、碳环基、杂环基、碳环基氧基、杂环基氧基、羧基或者羧酸酯基的取代基所取代。本文中出现的环烷基，其定义与本定义一致。"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.
“烯基”是指直链和支链的一价不饱和烃基，其具有至少1个，通常有1、2或3个碳碳双键，主链包括2至10个碳原子，进一步优选2至6个碳原子，更优选在主链上有2至4个碳原子，烯基实施例包括但不限于乙烯基、烯丙基、1-丙烯基、2-丙烯基、1-丁烯基、2-丁烯基、3-丁烯基、1-戊烯基、2-戊烯基、3-戊烯基、4-戊烯基、1-甲基-1-丁烯基、2-甲基-1-丁烯基、2-甲基-3-丁烯基、1-己烯基、2-己烯基、3-己烯基、4-己烯基、5-己烯基、1-甲基-1-戊烯基、2-甲基-1-戊烯基、1-庚烯基、2-庚烯基、3-庚烯基、4-庚烯基、1-辛烯基、3-辛烯基、1-壬烯基、3-壬烯基、1-癸烯基、4-癸烯基、1,3-丁二烯、1,3-戊二烯、1,4-戊二烯和1,4-己二烯等；所述的烯基可以任选进一步被0至5个选自F、Cl、Br、I、羟基、巯基、硝基、氰基、氨基、烷基氨基、烯基、炔基、烷基、羟基烷基、烷氧基、碳环基、杂环基、碳环基氧基、杂环基氧基、羧基或者羧酸酯基的取代基所取代。本文中出现的烯基，其定义与本定义一致。"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, examples of 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-heptenyl, 4-heptenyl, 1-octene base, 3-octenyl, 1-nonenyl, 3-nonenyl, 1-decenyl, 4-decenyl, 1,3-butadiene, 1,3-pentadiene, 1, 4-pentadiene and 1,4-hexadiene, etc.; the alkenyl 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, hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, carbocyclyloxy, heterocyclyloxy, carboxyl or carboxylate substitution base substituted. Alkenyl groups appearing herein are defined in accordance with this definition.
“炔基”是指直链和支链的一价不饱和烃基，其具有至少1个，通常有1、2或3个碳碳三键，主链包括2至10个碳原子，进一步优选2至6个碳原子，更优选在主链上有2至4个碳原子，炔基实施例包括但不限于乙炔基、炔丙基、1-丙炔基、2-丙炔基、1-丁炔基、2-丁炔基、3-丁炔基、1-戊炔基、2-戊炔基、3-戊炔基、4-戊炔基、1-甲基-1-丁炔基、2-甲基-1-丁炔基、2-甲基-3-丁炔基、1-己炔基、2-己炔基、3-己炔基、4-己炔基、5-己炔基、1-甲基-1-戊炔基、2-甲基-1-戊炔基、1-庚炔基、2-庚炔基、3-庚炔基、4-庚炔基、1-辛炔基、3-辛炔基、1-壬炔基、3-壬炔基、1-癸炔基、4-癸炔基等；所述的炔基可以任选进一步被0至5个选自F、Cl、Br、I、羟基、巯基、硝基、氰基、氨基、烷基氨基、烯基、炔基、烷基、羟基烷基、烷氧基、碳环基、杂环基、碳环基氧基、杂环基氧基、羧基或者羧酸酯基的取代基所取代。本文中出现的炔基，其定义与本定义一致。"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, examples of 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, 1-methyl-1-pentynyl, 2-methyl-1-pentynyl, 1-heptynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 1-heptynyl Octynyl, 3-octynyl, 1-nonynyl, 3-nonynyl, 1-decynyl, 4-decynyl, etc.; the alkynyl group can be optionally further selected from 0 to 5 From F, Cl, Br, I, hydroxyl, mercapto, nitro, cyano, amino, alkylamino, alkenyl, alkynyl, alkyl, hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, Substituents of carbocyclyloxy, heterocyclyloxy, carboxyl or carboxylate. Alkynyl groups appearing herein are defined in accordance with this definition.
“烷氧基”是指-O-烷基。非限制性实施例包括甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、叔丁氧基、正戊氧基、正己氧基、环丙氧基和环丁氧基。所述的烷氧基可以任选进一步被0至5个选自F、Cl、Br、I、羟基、巯基、硝基、氰基、氨基、烷基氨基、烯基、炔基、烷基、羟基烷基、烷氧基、碳环基、杂环基、碳环基氧基、杂环基氧基、羧基或者羧酸酯基的取代基所取代。本文中出现的烷氧基，其定义与本定义一致。"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.
“碳环基”或“碳环”是指取代的或未取代的饱和或不饱和的芳香环或者非芳香环，芳香环或者非芳香环可以是3至8元的单环、4至12元双环或者10至15元三环体系，碳环基可以连接在芳香环上或者非芳香环上，芳香环或者非芳香环任选为单环、桥环或者螺环。非限制性实施例包括环丙烷、环丁烷、环戊烷、环己烷、环庚烷、1-环戊基-1-烯基、1-环戊基-2-烯基、1-环戊基-3-烯基、环己基、1-环己基-2-烯基、1-环己基-3-烯基、环己烯基、苯环、萘环、
Figure PCTCN2021103485-appb-000280
所述的碳环可以任选进一步被0至5个选自F、Cl、Br、I、＝O、羟基、巯基、硝基、氰基、氨基、烷基氨基、酰胺基、烯基、炔基、烷基、羟基烷基、烷氧基、碳环基、杂环基、碳环基氧基、杂环基氧基、羧基或者羧酸酯基的取代基所取代。本文中出现的碳环或碳环基，其定义与本定义一致。 "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. Non-limiting examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclopentyl Pentyl-3-enyl, cyclohexyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexenyl, benzene ring, naphthalene ring,
Figure PCTCN2021103485-appb-000280
Said carbocycle may optionally be further selected from 0 to 5 groups selected from F, Cl, Br, I, =O, hydroxyl, mercapto, nitro, cyano, amino, alkylamino, amido, alkenyl, alkyne is substituted with a substituent of a radical, alkyl, hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, carbocyclyloxy, heterocyclyloxy, carboxyl or carboxylate. Where carbocycle or carbocyclyl occurs herein, the definition is consistent with this definition.
“杂环基”或“杂环”是指取代的或未取代的饱和或不饱和的芳香环或者非芳香环，芳香环或者非芳香环可以是3至8元的单环、4至12元双环或者10至15元三环体系，且包含1至3个选自N、O或S的杂原子，优选3至8元杂环基，杂环基的环中选择性取代的N、 S可被氧化成各种氧化态。杂环基可以连接在杂原子或者碳原子上，杂环基可以连接在芳香环上或者非芳香环上，杂环基可以连接有桥环或者螺环，非限制性实施例包括环氧乙基、氮杂环丙基、氧杂环丁基、氮杂环丁基、1,3-二氧戊环基、1,4-二氧戊环基、1,3-二氧六环基、氮杂环庚基、吡啶基、呋喃基、噻吩基、吡喃基、N-烷基吡咯基、嘧啶基、吡嗪基、哒嗪基、咪唑基、哌啶基、吗啉基、硫代吗啉基、1,3-二噻基、二氢呋喃基、二氢吡喃基、二噻戊环基、四氢呋喃基、四氢吡咯基、四氢咪唑基、四氢噻唑基、四氢吡喃基、苯并咪唑基、苯并吡啶基、吡咯并吡啶基、苯并二氢呋喃基、吡咯基、吡唑基、噻唑基、噁唑基、吡嗪基、吲唑基、苯并噻吩基、苯并呋喃基、苯并吡咯基、苯并咪唑基、苯并噻唑基、苯并噁唑基、苯并吡啶基、苯并嘧啶基、苯并吡嗪基、哌嗪基、氮杂二环[3.2.1]辛烷基、氮杂二环[5.2.0]壬烷基、氧杂三环[5.3.1.1]十二烷基、氮杂金刚烷基、氧杂螺[3.3]庚烷基、
Figure PCTCN2021103485-appb-000281
Figure PCTCN2021103485-appb-000282
Figure PCTCN2021103485-appb-000283
所述的杂环基可以任选进一步被0至5个选自F、Cl、Br、I、＝O、羟基、巯基、硝基、氰基、氨基、烷基氨基、酰胺基、烯基、炔基、烷基、羟基烷基、烷氧基、碳环基、杂环基、碳环基氧基、杂环基氧基、羧基或者羧酸酯基的取代基所取代。本文中出现的杂环基，其定义与本定义一致。 "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, Tetrahydrofuranyl, Tetrahydropyrrolyl, Tetrahydroimidazolyl, Tetrahydrothiazolyl, Tetrahydropyran base, benzimidazolyl, benzopyridyl, pyrrolopyridyl, benzodihydrofuranyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, pyrazinyl, indazolyl, benzothienyl , benzofuranyl, benzopyrrolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzopyridyl, benzopyrimidinyl, benzopyrazinyl, piperazinyl, azadi Cyclo[3.2.1]octyl, azabicyclo[5.2.0]nonyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl, oxaspiro[3.3]heptyl alkyl,
Figure PCTCN2021103485-appb-000281
Figure PCTCN2021103485-appb-000282
Figure PCTCN2021103485-appb-000283
The heterocyclic group can be optionally further selected from 0 to 5 groups selected from F, Cl, Br, I, =O, hydroxyl, mercapto, nitro, cyano, amino, alkylamino, amide, alkenyl, Substituents of alkynyl, alkyl, hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, carbocyclyloxy, heterocyclyloxy, carboxyl or carboxylate. Heterocyclyl groups appearing herein are defined in accordance with this definition.
“螺环”是指取代的或未取代的单环之间共用一个碳原子(称螺原子)的5至20元多环基团，其可以包含0至5个双键，且可以含有0至5个选自N、O或S(＝O) n的杂原子(其中n为0、1、2)。优选为6至14元，进一步优选为6至12元，更优选6至10元，其非限定性实例包括：
Figure PCTCN2021103485-appb-000284
当被取代时，取代基可以为1至5个选自F、Cl、Br、I、烷基、环烷基、烷氧基、卤代烷基、硫醇、羟基、硝基、巯基、氨基、氰基、异氰基、芳基、杂芳基、杂环基、桥环基、螺 环基、并环基、羟基烷基、＝O、羰基、醛、羧酸、甲酸酯、-(CH 2) m-C(＝O)-R a、-O-(CH 2) m-C(＝O)-R a、-(CH 2) m-C(＝O)-NR bR c、-(CH 2) mS(＝O) nR a、-(CH 2) m-烯基-R a、OR d或-(CH 2) m-炔基-R a(其中m、n为0、1或2)、芳基硫基、硫代羰基、硅烷基或-NR bR c等的基团，其中R b与R c独立选自包括H、羟基、氨基、羰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、磺酰基、三氟甲磺酰基，作为选择，R b与R c可形成五或六元环烷基或杂环基。R a与R d各自独立选自芳基、杂芳基、烷基、烷氧基、环烷基、杂环基、羰基、酯基、桥环基、螺环基或并环基。本文中出现的螺环，其定义与本定义一致。 "Spirocycle" refers to a 5- to 20-membered polycyclic group of substituted or unsubstituted monocyclic rings sharing one carbon atom (called a spiro atom), which may contain 0 to 5 double bonds, and may contain 0 to 5 5 heteroatoms selected from N, O or S(=O) n (wherein n is 0, 1, 2). It is preferably 6 to 14 yuan, more preferably 6 to 12 yuan, more preferably 6 to 10 yuan, and non-limiting examples thereof include:
Figure PCTCN2021103485-appb-000284
When substituted, the substituents may be 1 to 5 selected from F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxy, nitro, mercapto, amino, cyano radical, isocyano, aryl, heteroaryl, heterocyclyl, bridged ring, spiro, cyclo, hydroxyalkyl, =O, carbonyl, aldehyde, carboxylic acid, formate, -(CH 2 ) m -C(=O)-R a , -O-(CH 2 ) m -C(=O)-R a , -(CH 2 ) m -C(=O)-NR b R c , - (CH 2 ) m S(=O) n R a , -(CH 2 ) m -alkenyl-R a , OR d or -(CH 2 ) m -alkynyl-R a (wherein m, n are 0, 1 or 2), an arylthio group, a thiocarbonyl group, a silyl group or a group such as -NR b R c , wherein R b and R c are independently selected from the group consisting of H, hydroxyl, amino, carbonyl, alkyl, alkoxy group, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, alternatively, Rb and Rc may form a five- or six-membered cycloalkyl or heterocyclyl. 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.
“并环”是指系统中的每个环与体系中的其他环共享毗邻的一对碳原子的多环基团，其中一个或多个环可以含有0个或多个双键，且可以是取代的或未取代，并环体系中的各个环可以含0至5个选自N、S(＝O) n或O的杂原子(其中n为0、1、2)。优选为5至20元，进一步优选为5至14元，更有选5至12元，再进一步优选5至10元。非限定性实例包括：
Figure PCTCN2021103485-appb-000285
Figure PCTCN2021103485-appb-000286
"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 Each ring in a substituted or unsubstituted ring system may contain 0 to 5 heteroatoms selected from N, S(=O) n or O (wherein n is 0, 1, 2). It is preferably 5 to 20 yuan, more preferably 5 to 14 yuan, more preferably 5 to 12 yuan, and still more preferably 5 to 10 yuan. Non-limiting examples include:
Figure PCTCN2021103485-appb-000285
Figure PCTCN2021103485-appb-000286
当被取代时，取代基可以为1至5个选自F、Cl、Br、I、烷基、环烷基、烷氧基、卤代烷基、硫醇、羟基、硝基、巯基、氨基、氰基、异氰基、芳基、杂芳基、杂环基、桥环基、螺环基、并环基、羟基烷基、＝O、羰基、醛、羧酸、甲酸酯、-(CH 2) m-C(＝O)-R a、-O-(CH 2) m-C(＝O)-R a、-(CH 2) m-C(＝O)-NR bR c、-(CH 2) mS(＝O) nR a、-(CH 2) m-烯基-R a、OR d或-(CH 2) m-炔基-R a(其中m、n为0、1或2)、芳基硫基、硫代羰基、硅烷基或-NR bR c等的基团，其中R b与R c独立选自包括H、羟基、氨基、羰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、磺酰基、三氟甲磺酰基，作为选择，R b与R c可形成五或六元环烷基或杂环基。R a与R d各自独立选自芳基、杂芳基、烷基、烷氧基、环烷基、杂环基、羰基、酯基、桥环基、螺环基或并环基。本文中出现的并环，其定义与本定义一致。 When substituted, the substituents may be 1 to 5 selected from F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxy, nitro, mercapto, amino, cyano radical, isocyano, aryl, heteroaryl, heterocyclyl, bridged ring, spiro, cyclo, hydroxyalkyl, =O, carbonyl, aldehyde, carboxylic acid, formate, -(CH 2 ) m -C(=O)-R a , -O-(CH 2 ) m -C(=O)-R a , -(CH 2 ) m -C(=O)-NR b R c , - (CH 2 ) m S(=O) n R a , -(CH 2 ) m -alkenyl-R a , OR d or -(CH 2 ) m -alkynyl-R a (wherein m, n are 0, 1 or 2), an arylthio group, a thiocarbonyl group, a silyl group or a group such as -NR b R c , wherein R b and R c are independently selected from the group consisting of H, hydroxyl, amino, carbonyl, alkyl, alkoxy group, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, alternatively, Rb and Rc may form a five- or six-membered cycloalkyl or heterocyclyl. 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.
“桥环”是指任意两个不直接连接的碳原子的多环基团，可以含有0个或多个双键，且可以是取代的或未取代的，并环体系中的任意环可以含0至5个选自N、S(＝O)n或O杂原子或基团(其中n为0、1、2)。环原子包含5至20个原子，优选为5至14个原子，进一步优选5至12个，在进一步优选5至10个。非限定性实例包括
Figure PCTCN2021103485-appb-000287
Figure PCTCN2021103485-appb-000288
和金刚烷。当被取代时，取代基可以为1至5个选自F、Cl、Br、I、烷基、环烷基、烷氧基、卤代烷基、硫醇、羟基、硝基、巯基、氨基、氰基、异氰基、芳基、杂芳基、杂环基、桥环基、螺环基、并环基、羟基烷基、＝O、羰基、醛、羧酸、甲酸酯、-(CH 2) m-C(＝O)-R a、-O-(CH 2) m-C(＝O)-R a、-(CH 2) m-C(＝O)-NR bR c、-(CH 2) mS(＝O) nR a、-(CH 2) m-烯基-R a、OR d或-(CH 2) m-炔基-R a(其中m、n为0、1或2)、芳基硫基、硫代羰基、硅烷基或-NR bR c等的基团，其中R b与R c独立选自包括H、羟基、氨基、羰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、磺酰基、三氟甲磺酰基，作为选择，R b与R c可形成五或六元环烷基或杂环基。R a与R d各自独立选自芳基、杂芳基、烷基、烷氧基、环烷基、杂环基、羰基、酯基、桥环基、螺环基或并环基。本文中出现的桥环，其定义与本定义一致。 "Bridged ring" refers to a polycyclic group of any two carbon atoms that are not directly connected, may contain 0 or more double bonds, and may be substituted or unsubstituted, and any ring in the ring system may contain 0 to 5 are selected from N, S(=O)n or O heteroatoms or groups (wherein n is 0, 1, 2). 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
Figure PCTCN2021103485-appb-000287
Figure PCTCN2021103485-appb-000288
and adamantane. When substituted, the substituents may be 1 to 5 selected from F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxy, nitro, mercapto, amino, cyano radical, isocyano, aryl, heteroaryl, heterocyclyl, bridged ring, spiro, cyclo, hydroxyalkyl, =O, carbonyl, aldehyde, carboxylic acid, formate, -(CH 2 ) m -C(=O)-R a , -O-(CH 2 ) m -C(=O)-R a , -(CH 2 ) m -C(=O)-NR b R c , - (CH 2 ) m S(=O) n R a , -(CH 2 ) m -alkenyl-R a , OR d or -(CH 2 ) m -alkynyl-R a (wherein m, n are 0, 1 or 2), an arylthio group, a thiocarbonyl group, a silyl group or a group such as -NR b R c , wherein R b and R c are independently selected from the group consisting of H, hydroxyl, amino, carbonyl, alkyl, alkoxy group, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, alternatively, Rb and Rc may form a five- or six-membered cycloalkyl or heterocyclyl. 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.
“碳螺环”、“螺环碳环基”、“螺碳环基”或者“碳螺环基”是指环体系仅有碳原子组成的“螺环”。本文中出现的“碳螺环”、“螺环碳环基”、“螺碳环基”或者“碳螺环基”，其定义与本定义一致。"Carbospiro", "spirocarbocyclyl", "spirocarbocyclyl" or "carbospirocyclyl" refers to a "spirocycle" in which the ring system consists of only carbon atoms. "Carbospiro", "spirocarbocyclyl", "spirocarbocyclyl" or "carbospirocyclyl" appearing herein are defined in accordance with this definition.
“碳并环”、“并环碳环基”、“并碳环基”或者“碳并环基”是指环体系仅有碳原子组成的“并环”。本文中出现的“碳并环”、“并环碳环基”、“并碳环基”或者“碳并环基”，其定义与本定义一致。"Carbocyclyl", "carbocyclyl", "carbocyclyl" or "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.
“碳桥环”、“桥环碳环基”、“桥碳环基”或者“碳桥环基”是指环体系仅有碳原子组成的“桥环”。本文中出现的“碳桥环”、“桥环碳环基”、“桥碳环基”或者“碳桥环基”，其定义与本定义一致。"Carbon-bridged ring", "bridged-ring carbocyclyl", "bridged carbocyclyl" or "carbo-bridged cyclyl" 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.
“杂单环”、“单环杂环基”或“杂单环基”是指单环体系的“杂环基”或“杂环”，本文中出现的杂环基、“单环杂环基”或“杂单环基”，其定义与本定义一致。"Heterocyclyl", "monocyclic heterocyclyl" or "heteromonocyclyl" refers to a "heterocyclyl" or "heterocycle" of a monocyclic ring system, heterocyclyl, "monocyclic heterocyclyl" appearing herein group" or "heteromonocyclyl", as defined herein.
“杂并环”、“杂并环基”或“并环杂环基”是指含有杂原子的“并环”。本文中出现的杂并环、“杂并环基”或“并环杂环基”，其定义与本定义一致。"Heterocyclyl", "heterocyclyl" or "heterocyclyl" refers to a "heterocyclyl" containing a heteroatom. As used herein, heterocyclyl, "heterocyclyl" or "heterocyclyl" is defined in accordance with this definition.
“杂螺环”、“杂螺环基”或“螺环杂环基是指含有杂原子的“螺环”。本文中出现的杂螺环、“杂螺环基”或“螺环杂环基”，其定义与本定义一致。"Heterospirocycle," "heterospirocyclyl," or "spiroheterocyclyl" refers to a "spirocycle" containing a heteroatom. As used herein, heterospirocycle, "heterospirocyclyl" or "spiroheterocycle" basis", which is defined in accordance with this definition.
“杂桥环”、“杂桥环基”或“桥环杂环基”是指含有杂原子的“桥环”。本文中出现的杂桥环、“杂桥环基”或“桥环杂环基”，其定义与本定义一致。"Heterobridged ring", "heterobridged cyclyl" or "bridged heterocyclyl" refers to a "bridged ring" containing a heteroatom. Heterobridged rings, "heterobridged cyclyl" or "bridged heterocyclyl" appearing herein are as defined herein.
“芳基”或“芳环”是指具有单环或稠合环的一价芳香族烃基，通常有6至12个碳原子，且可以是取代的或未取代的。当被取代时，取代基可以为1至5个选自F、Cl、Br、I、烷基、环烷基、烷氧基、卤代烷基、硫醇、羟基、硝基、巯基、氨基、氰基、异氰基、芳基、杂芳基、杂环基、桥环基、螺环基、并环基、羟基烷基、＝O、羰基、醛、羧酸、甲酸酯、-(CH 2) m-C(＝O)-R a、-O-(CH 2) m-C(＝O)-R a、-(CH 2) m-C(＝O)-NR bR c、-(CH 2) mS(＝O) nR a、-(CH 2) m-烯基-R a、OR d或-(CH 2) m-炔基-R a(其中m、n为0、1或2)、芳基硫基、硫代羰基、硅烷基或-NR bR c等的基团，其中R b与R c独立选自包括H、羟基、氨基、羰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、磺酰基、三氟甲磺酰基，作为选择，R b与R c可形成五或六元环烷基或杂环基。R a与R d各自独立选自芳基、杂芳基、烷基、烷氧基、环烷基、杂环基、羰基、酯基、桥环基、螺环基或并环基。本文中出现的芳基或芳环，其定义与本定义一致。 "Aryl" or "aromatic ring" refers to a monovalent aromatic hydrocarbon group having a single or fused ring, usually 6 to 12 carbon atoms, and may be substituted or unsubstituted. When substituted, the substituents may be 1 to 5 selected from F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxy, nitro, mercapto, amino, cyano radical, isocyano, aryl, heteroaryl, heterocyclyl, bridged ring, spiro, cyclo, hydroxyalkyl, =O, carbonyl, aldehyde, carboxylic acid, formate, -(CH 2 ) m -C(=O)-R a , -O-(CH 2 ) m -C(=O)-R a , -(CH 2 ) m -C(=O)-NR b R c , - (CH 2 ) m S(=O) n R a , -(CH 2 ) m -alkenyl-R a , OR d or -(CH 2 ) m -alkynyl-R a (wherein m, n are 0, 1 or 2), an arylthio group, a thiocarbonyl group, a silyl group or a group such as -NR b R c , wherein R b and R c are independently selected from the group consisting of H, hydroxyl, amino, carbonyl, alkyl, alkoxy group, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, alternatively, Rb and Rc may form a five- or six-membered cycloalkyl or heterocyclyl. 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.
“杂芳基”是指取代或未取代的5至15元芳香环，且含有1至5个选自N、O或S(＝O)n杂原子或基团(n选自0、1或2)，优选5至10元杂芳香环，进一步优选5至6元杂芳香环。杂芳基的非限制性实施例包括但不限于吡啶基、呋喃基、噻吩基、吡啶基、吡喃基、N-烷基吡咯基、嘧啶基、吡嗪基、哒嗪基、咪唑基、苯并吡唑、苯并咪唑、苯并吡啶、吡咯并吡啶等。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环，非限制性实施例包含
Figure PCTCN2021103485-appb-000289
Figure PCTCN2021103485-appb-000290
当被取代时，取代基可以为1至5个选自F、Cl、Br、I、烷基、环烷基、烷氧基、卤代烷基、硫醇、羟基、硝基、巯基、氨基、氰基、异氰基、芳基、杂芳基、杂环基、桥环基、螺环基、并环基、羟基烷基、＝O、羰基、醛、羧酸、甲酸酯、-(CH 2) m- C(＝O)-R a、-O-(CH 2) m-C(＝O)-R a、-(CH 2) m-C(＝O)-NR bR c、-(CH 2) mS(＝O) nR a、-(CH 2) m-烯基-R a、OR d或-(CH 2) m-炔基-R a(其中m、n为0、1或2)、芳基硫基、硫代羰基、硅烷基或-NR bR c等的基团，其中R b与R c独立选自包括H、羟基、氨基、羰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、磺酰基、三氟甲磺酰基，作为选择，R b与R c可形成五或六元环烷基或杂环基。R a与R d各自独立选自芳基、杂芳基、烷基、烷氧基、环烷基、杂环基、羰基、酯基、桥环基、螺环基或并环基。本文中出现的杂芳基，其定义与本定义一致。 "Heteroaryl" means a substituted or unsubstituted 5 to 15 membered aromatic ring containing 1 to 5 heteroatoms or groups selected from N, O or S(=O)n (n is selected from 0, 1 or 2), preferably a 5- to 10-membered heteroaromatic ring, more preferably a 5- to 6-membered heteroaromatic ring. Non-limiting examples of 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
Figure PCTCN2021103485-appb-000289
Figure PCTCN2021103485-appb-000290
When substituted, the substituents may be 1 to 5 selected from F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxy, nitro, mercapto, amino, cyano radical, isocyano, aryl, heteroaryl, heterocyclyl, bridged ring, spiro, cyclo, hydroxyalkyl, =O, carbonyl, aldehyde, carboxylic acid, formate, -(CH 2 ) m - C(=O)-R a , -O-(CH 2 ) m -C(=O)-R a , -(CH 2 ) m -C(=O)-NR b R c , - (CH 2 ) m S(=O) n R a , -(CH 2 ) m -alkenyl-R a , OR d or -(CH 2 ) m -alkynyl-R a (wherein m, n are 0, 1 or 2), an arylthio group, a thiocarbonyl group, a silyl group or a group such as -NR b R c , wherein R b and R c are independently selected from the group consisting of H, hydroxyl, amino, carbonyl, alkyl, alkoxy group, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, alternatively, Rb and Rc may form a five- or six-membered cycloalkyl or heterocyclyl. 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.
“含有1至4个选自O、S、N的杂原子”是指含有1、2、3或4个选自O、S、N的杂原子。"Containing 1 to 4 heteroatoms selected from O, S, N" means containing 1, 2, 3 or 4 heteroatoms selected from O, S, N.
“0至X个取代基所取代”是指被0、1、2、3….X个取代基所取代，X选自1至10之间的任意整数。如“0至4个取代基所取代”是指被0、1、2、3或4个取代基所取代。如“0至5个取代基所取代”是指被0、1、2、3、4或5个取代基所取代。如“杂桥环任选进一步被0至4个选自H或F的取代基所取代”是指杂桥环任选进一步被0、1、2、3或4个选自H或F的取代基所取代。"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. As in "substituted with 0 to 4 substituents" means substituted with 0, 1, 2, 3 or 4 substituents. As in "substituted with 0 to 5 substituents" means substituted with 0, 1, 2, 3, 4 or 5 substituents. Such as "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.
X-Y元的环(X选自小于Y大于等于3的整数，Y选自4至12之间的任意整数)包括了X+1、X+2、X+3、X+4….Y元的环。环包括了杂环、碳环、芳环、芳基、杂芳基、环烷基、杂单环、杂并环、杂螺环或杂桥环。如“4-7元杂单环”是指4元、5元、6元或7元的杂单环，“5-10元杂并环”是指5元、6元、7元、8元、9元或10元的杂并环。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. For example, "4-7 membered heteromonocycle" refers to a 4-membered, 5-membered, 6-membered or 7-membered heteromonocycle, and "5-10 membered heterocyclic ring" refers to 5-membered, 6-membered, 7-membered, 8-membered , 9- or 10-membered heterocyclic ring.
“任选”或“任选地”是指随后所描述的事件或环境可以但不必须发生，该说明包括该事件或环境发生或不发生的场合。如：“任选被F取代的烷基”指烷基可以但不必须被F取代，说明包括烷基被F取代的情形和烷基不被F取代的情形。"Optional" or "optionally" means that the subsequently described event or circumstance can, but need not, occur, and that the description includes instances where the event or circumstance does or does not occur. For example, "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.
“药学上可接受的盐”是指本发明化合物保持游离酸或者游离碱的生物有效性和特性，且所述的游离酸通过与无毒的无机碱或者有机碱，或所述的游离碱通过与无毒的无机酸或者有机酸反应获得的盐。"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.
“药物组合物”是指一种或多种本发明所述化合物、其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，与其它化学组分形成的混合物，其中，“其它化学组分”是指药学上可接受的载体、赋形剂和/或一种或多种其它治疗剂。"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.
“载体”是指不会对生物体产生明显刺激且不会消除所给予化合物的生物活性和特性的材料。"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.
“前药”是指可经体内代谢转化为具有生物活性的本发明化合物。本发明的前药通过修饰本发明化合物中的氨基或者羧基来制备，该修饰可以通过常规的操作或者在体内被除去，而得到母体化合物。当本发明的前药被施予哺乳动物个体时，前药被割裂形成游离的氨基或者羧基。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. When the prodrugs of the present invention are administered to a mammalian subject, the prodrugs are cleaved to form free amino or carboxyl groups.
“共晶”是指活性药物成分(API)和共晶形成物(CCF)在氢键或其他非共价键的作用下结合而成的晶体，其中API和CCF的纯态在室温下均为固体，并且各组分间存在固定的化学计量比。共晶是一种多组分晶体，既包含两种中性固体之间形成的二元共晶，也包含中性固体与盐或溶剂化物形成的多元共晶。"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.
“立体异构体”是指由分子中原子在空间上排列方式不同所产生的异构体，包括顺反异构体、对映异构体和构象异构体。"Stereoisomers" refer to isomers resulting from different arrangements of atoms in a molecule in space, including cis-trans isomers, enantiomers and conformational isomers.
“氘代物”是化合物分子中的氢被它的同位素氘取代的产物。A "deuterated compound" is a product in which hydrogen in the molecule of a compound is replaced by its isotope deuterium.
具体实施方式detailed description
以下实施例详细说明本发明的技术方案，但本发明的保护范围包括但是不限于此。The following examples illustrate the technical solutions of the present invention in detail, but the protection scope of the present invention includes but is not limited thereto.
化合物的结构是通过核磁共振(NMR)或(和)质谱(MS)来确定的。NMR位移(δ)以10 -6(ppm)的单位给出。NMR的测定是用(Bruker Avance III 400和Bruker Avance300)核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d 6)，氘代氯仿(CDCl 3)，氘代甲醇(CD 3OD)，内标为四甲基硅烷(TMS)； The structures of the compounds were determined by nuclear magnetic resonance (NMR) or (and) mass spectrometry (MS). NMR shifts ([delta]) are given in units of 10<"6> (ppm). NMR was measured using (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic instruments, and the solvents were deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD) , the internal standard is tetramethylsilane (TMS);
MS的测定用(Agilent 6120B(ESI)和Agilent 6120B(APCI))；For MS determination (Agilent 6120B (ESI) and Agilent 6120B (APCI));
HPLC的测定使用Agilent 1260DAD高压液相色谱仪(Zorbax SB-C18 100×4.6mm,3.5μM)；The determination of HPLC uses an Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18 100×4.6mm, 3.5μM);
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm-0.20mm，薄层层析分离纯化产品采用的规格是0.4mm-0.5mm；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;
柱层析一般使用烟台黄海硅胶200-300目硅胶为载体；Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier;
本发明的己知起始原料可以采用或按照本领域已知的方法来合成，或可购买于泰坦科技、安耐吉化学、上海德默、成都科龙化工、韶远化学科技、百灵威科技等公司；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;
SEM:
Figure PCTCN2021103485-appb-000291
THP:
Figure PCTCN2021103485-appb-000292
Boc：叔丁氧基羰基； SEM:
Figure PCTCN2021103485-appb-000291
THP:
Figure PCTCN2021103485-appb-000292
Boc: tert-butoxycarbonyl;
Figure PCTCN2021103485-appb-000293
即为
Figure PCTCN2021103485-appb-000294
Figure PCTCN2021103485-appb-000293
that is
Figure PCTCN2021103485-appb-000294
Figure PCTCN2021103485-appb-000295
即为
Figure PCTCN2021103485-appb-000296
Figure PCTCN2021103485-appb-000295
that is
Figure PCTCN2021103485-appb-000296
Figure PCTCN2021103485-appb-000297
即为
Figure PCTCN2021103485-appb-000298
Figure PCTCN2021103485-appb-000297
that is
Figure PCTCN2021103485-appb-000298
Figure PCTCN2021103485-appb-000299
即为
Figure PCTCN2021103485-appb-000300
Figure PCTCN2021103485-appb-000299
that is
Figure PCTCN2021103485-appb-000300
实施例1:cis-4-[[7-[(5-甲基-1H-吡唑-3-基)氨基]-1,6-萘啶-5-基]氨基]金刚烷-1-醇(化合物1)Example 1: cis-4-[[7-[(5-methyl-1H-pyrazol-3-yl)amino]-1,6-naphthyridin-5-yl]amino]adamantan-1-ol (Compound 1)
cis-4-[[7-[(5-methyl-1H-pyrazol-3-yl)amino]-1,6-naphthyridin-5-yl]amino]adamantan-1-olcis-4-[[7-[(5-methyl-1H-pyrazol-3-yl)amino]-1,6-naphthyridin-5-yl]amino]adamantan-1-ol
Figure PCTCN2021103485-appb-000301
Figure PCTCN2021103485-appb-000301
第一步：cis-4-[(7-氯-1,6-萘啶-5-基)氨基]金刚烷-1-醇(1b)The first step: cis-4-[(7-chloro-1,6-naphthyridin-5-yl)amino]adamantan-1-ol (1b)
cis-4-[(7-chloro-1,6-naphthyridin-5-yl)amino]adamantan-1-olcis-4-[(7-chloro-1,6-naphthyridin-5-yl)amino]adamantan-1-ol
Figure PCTCN2021103485-appb-000302
Figure PCTCN2021103485-appb-000302
将5,7-二氯-1,6-萘啶(1a)(250mg,1.26mmol)，4-氨基金刚烷-1-醇(231mg,1.38mmol)，N,N-二异丙基乙胺(487mg,3.77mmol)加入到N,N-二甲基甲酰胺(4mL)中，升温至100℃反应16h，然后降至室温。将反应液倒入到水(40mL)中，乙酸乙酯(30mL*2)萃取，合并有机相，饱和食盐水(30mL*2)反洗，无水硫酸钠干燥，抽滤，滤液减压旋干得残留物，残留物用硅胶柱柱色谱分离纯化(乙酸乙酯：石油醚(v/v)＝0:1-1:0)得淡黄色固体trans-4-[(7-氯-1,6-萘啶-5-基)氨基]金刚烷-1-醇(3b)(240mg,58％)和淡黄色固体cis-4-[(7-氯-1,6-萘啶-5-基)氨基]金刚烷-1-醇(1b)(166mg,40％)。5,7-Dichloro-1,6-naphthyridine (1a) (250 mg, 1.26 mmol), 4-aminoadamantan-1-ol (231 mg, 1.38 mmol), N,N-diisopropylethylamine (487 mg, 3.77 mmol) was added to N,N-dimethylformamide (4 mL), the temperature was raised to 100° C. for 16 h, and then lowered to room temperature. The 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. The residue was dried and purified by silica gel column chromatography (ethyl acetate:petroleum ether (v/v)=0:1-1:0) to obtain trans-4-[(7-chloro-1) as a light yellow solid ,6-Naphthyridin-5-yl)amino]adamantan-1-ol (3b) (240 mg, 58%) and pale yellow solid cis-4-[(7-chloro-1,6-naphthyridine-5- yl)amino]adamantan-1-ol (1b) (166 mg, 40%).
LCMS m/z＝330.1[M+1] +。 LCMS m/z=330.1[M+1] + .
第二步：3-氨基-5-甲基-吡唑-1H-甲酸叔丁酯(1b’)Step 2: tert-butyl 3-amino-5-methyl-pyrazole-1H-carboxylate (1b')
tert-butyl 3-amino-5-methyl-pyrazole-1-carboxylatetert-butyl 3-amino-5-methyl-pyrazole-1-carboxylate
Figure PCTCN2021103485-appb-000303
Figure PCTCN2021103485-appb-000303
将3-氨基-5-甲基吡唑(1a’)(20.00g,205.90mmol)溶于二氯甲烷(200mL)中，冰水浴下加入固体氢氧化钠(16.00g,400.00mmol)后，缓慢滴加入二碳酸二叔丁酯(50.00g,229.10mmol)，滴加完全后，恢复至室温反应2h。加入水(200mL)，二氯甲烷(200mL*2)萃取，合并有机相，无水硫酸钠干燥，过滤减压浓缩得到粗产物。用混合溶剂(甲基叔丁基醚：石油醚(v/v)＝1:1)打浆得到白色固体3-氨基-5-甲基-吡唑-1H-甲酸叔丁酯(化合物1b’)(25.00g,62％)。3-Amino-5-methylpyrazole (1a') (20.00 g, 205.90 mmol) was dissolved in dichloromethane (200 mL), and solid sodium hydroxide (16.00 g, 400.00 mmol) was added under an ice-water bath, and slowly Di-tert-butyl dicarbonate (50.00 g, 229.10 mmol) was added dropwise, and after the dropwise addition was complete, the reaction was returned to room temperature for 2 h. Water (200 mL) was added, extracted with dichloromethane (200 mL*2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude product. Beat with mixed solvent (methyl tert-butyl ether: petroleum ether (v/v)=1:1) to obtain white solid 3-amino-5-methyl-pyrazole-1H-carboxylic acid tert-butyl ester (compound 1b') (25.00 g, 62%).
LCMS m/z＝198.1[M+1] + LCMS m/z=198.1[M+1] +
第三步：cis-叔丁基3-[[5-[(5-羟基-2-金刚烷基)氨基]-1,6-萘啶-7-基]氨基]-5-甲基-吡唑-1-甲酸(1c)The third step: cis-tert-butyl 3-[[5-[(5-hydroxy-2-adamantyl)amino]-1,6-naphthyridin-7-yl]amino]-5-methyl-pyridine oxazole-1-carboxylic acid (1c)
cis-tert-butyl 3-[[5-[(5-hydroxy-2-adamantyl)amino]-1,6-naphthyridin-7-yl]amino]-5-methyl-pyrazole-1-carboxylatecis-tert-butyl 3-[[5-[(5-hydroxy-2-adamantyl)amino]-1,6-naphthyridin-7-yl]amino]-5-methyl-pyrazole-1-carboxylate
Figure PCTCN2021103485-appb-000304
Figure PCTCN2021103485-appb-000304
将cis-4-[(7-氯-1,6-萘啶-5-基)氨基]金刚烷-1-醇(1b)(50mg,0.15mmol)，3-氨基-5-甲基-吡唑-1-甲酸叔丁酯(1b’)(33mg,0.17mmol)，三(二亚苄基丙酮)二钯(7mg,0.01mmol)，2-(二环己基膦)-3,6-二甲氧基-2',4',6'-三异丙基-1,1'-联苯(8mg,0.02mmol)，碳酸铯(64mg,0.20mmol)加入到1，4-二氧六环(3mL)中，氮气置换，升温至100℃反应24h。降至室温，垫硅藻土过滤，再用乙酸乙酯(2mL*2)淋洗，然后将滤液减压旋干，得粗品cis-叔丁基3-[[5-[(5-羟基-2-金刚烷基)氨基]-1,6-萘啶-7-基]氨基]-5-甲基-吡唑-1-甲酸(1c)(80mg,108％),直接用于下一步。cis-4-[(7-Chloro-1,6-naphthyridin-5-yl)amino]adamantan-1-ol (1b) (50 mg, 0.15 mmol), 3-amino-5-methyl-pyridine tert-Butyl oxazole-1-carboxylate (1b') (33 mg, 0.17 mmol), tris(dibenzylideneacetone)dipalladium (7 mg, 0.01 mmol), 2-(dicyclohexylphosphine)-3,6-di Methoxy-2',4',6'-triisopropyl-1,1'-biphenyl (8mg, 0.02mmol), cesium carbonate (64mg, 0.20mmol) was added to 1,4-dioxane (3 mL), nitrogen was replaced, and the temperature was raised to 100 °C for 24 h. It was cooled to room temperature, filtered through celite, rinsed with ethyl acetate (2mL*2), and then the filtrate was spin-dried under reduced pressure to obtain the crude product cis-tert-butyl 3-[[5-[(5-hydroxy- 2-Adamantyl)amino]-1,6-naphthyridin-7-yl]amino]-5-methyl-pyrazole-1-carboxylic acid (1c) (80 mg, 108%) was used directly in the next step.
LCMS m/z＝491.4[M+1] +。 LCMS m/z=491.4[M+1] + .
第四步：cis-4-[[7-[(5-甲基-1H-吡唑-3-基)氨基]-1,6-萘啶-5-基]氨基]金刚烷-1-醇(化合物1)The fourth step: cis-4-[[7-[(5-methyl-1H-pyrazol-3-yl)amino]-1,6-naphthyridin-5-yl]amino]adamantan-1-ol (Compound 1)
cis-4-[[7-[(5-methyl-1H-pyrazol-3-yl)amino]-1,6-naphthyridin-5-yl]amino]adamantan-1-olcis-4-[[7-[(5-methyl-1H-pyrazol-3-yl)amino]-1,6-naphthyridin-5-yl]amino]adamantan-1-ol
Figure PCTCN2021103485-appb-000305
Figure PCTCN2021103485-appb-000305
将cis-叔丁基3-[[5-[(5-羟基-2-金刚烷基)氨基]-1,6-萘啶-7-基]氨基]-5-甲基-吡唑-1-甲酸(1c)(80mg,0.16mmol)溶于二氯甲烷(6mL)中，然后加入三氟乙酸(3mL)，20℃反应1h后，减压旋干得残留物，残留物经Pre-HPLC纯化(仪器及制备柱：采用Gilson Gx-281制备液相，制备柱型号是Sunfire，5μm，内径*长度＝30mm*150mm)。制备方法：粗品用甲醇溶解，并用0.45μm滤膜过滤，制备成样品液。流动相体系：乙腈/水(含0.5％的三氟乙酸)。梯度洗脱方法：乙腈由10％梯度洗脱60％(洗脱时间16min)，冻干后得到cis-4-[[7-[(5-甲基-1H-吡唑-3-基)氨基]-1,6-萘啶-5-基]氨基]金刚烷-1-醇；2,2,2-三氟乙酸盐(化合物1-1)(60mg,74％)，cis-tert-butyl 3-[[5-[(5-hydroxy-2-adamantyl)amino]-1,6-naphthyridin-7-yl]amino]-5-methyl-pyrazole-1 -Formic acid (1c) (80 mg, 0.16 mmol) was dissolved in dichloromethane (6 mL), then trifluoroacetic acid (3 mL) was added, reacted at 20°C for 1 h, and then spin-dried under reduced pressure to obtain a residue, which was subjected to Pre-HPLC Purification (instrument and preparative column: Gilson Gx-281 was used for preparative liquid phase, the preparative column model was Sunfire, 5 μm, inner diameter*length=30mm*150mm). Preparation method: the crude product is dissolved in methanol, and filtered with a 0.45 μm 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%),
LCMS m/z＝391.3[M+1] +。 LCMS m/z=391.3[M+1] + .
将化合物1-1(55mg)加水(10mL)溶解后，用碳酸氢钠溶液调pH＝7～8，抽滤，滤饼用水淋洗2次，加水冻干得到cis-4-[[7-[(5-甲基-1H-吡唑-3-基)氨基]-1,6-萘啶-5-基]氨基]金刚烷-1-醇(化合物1)(35mg)。After compound 1-1 (55 mg) was dissolved in water (10 mL), the pH was adjusted to 7-8 with sodium bicarbonate solution, filtered with suction, the filter cake was rinsed twice with water, and lyophilized by adding water to obtain cis-4-[[7- [(5-Methyl-1H-pyrazol-3-yl)amino]-1,6-naphthyridin-5-yl]amino]adamantan-1-ol (Compound 1) (35 mg).
LCMS m/z＝391.3[M+1] +。 LCMS m/z=391.3[M+1] + .
1H NMR(400MHz,CD 3OD)δ8.57(d,1H),8.44(d,1H),7.08(dd,1H),6.57(s,1H),6.19(s,1H),4.23-4.13(m,1H),2.56-2.46(m,2H),2.27(s,3H),2.22-2.16(m,1H),2.12-2.04(m,2H),1.95-1.73(m,6H),1.66-1.57(m,2H). 1 H NMR (400MHz, CD 3 OD) δ 8.57(d,1H), 8.44(d,1H), 7.08(dd,1H), 6.57(s,1H), 6.19(s,1H), 4.23-4.13 (m,1H),2.56-2.46(m,2H),2.27(s,3H),2.22-2.16(m,1H),2.12-2.04(m,2H),1.95-1.73(m,6H),1.66 -1.57(m,2H).
实施例2:cis-4-[[7-[[5-(羟甲基)-1H-吡唑-3-基]氨基]-1,6-萘啶-5-基]氨基]金刚烷-1-醇；2,2,2-三氟乙酸盐(化合物2)Example 2: 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)
cis-4-[[7-[[5-(hydroxymethyl)-1H-pyrazol-3-yl]amino]-1,6-naphthyridin-5-yl]amino]adamantan-1-ol；2,2,2-trifluoroacetic acidcis-4-[[7-[[5-(hydroxymethyl)-1H-pyrazol-3-yl]amino]-1,6-naphthyridin-5-yl]amino]adamantan-1-ol;2,2,2 -trifluoroacetic acid
Figure PCTCN2021103485-appb-000306
Figure PCTCN2021103485-appb-000306
第一步：5-(苄氧甲基)-1H-吡唑-3-胺(2b)The first step: 5-(benzyloxymethyl)-1H-pyrazol-3-amine (2b)
5-(benzyloxymethyl)-1H-pyrazol-3-amine5-(benzyloxymethyl)-1H-pyrazol-3-amine
Figure PCTCN2021103485-appb-000307
Figure PCTCN2021103485-appb-000307
-78℃下，将乙腈(232mg,5.66mmol)溶于干燥四氢呋喃(10mL)中，氮气保护下，向其中滴加正丁基锂(2.2mL，5.66mmol，2.5mmol/mL in Hexanes)，-78℃下搅拌0.5h。向其中加入2-苄氧基乙酸乙酯(2a)(1.00g,5.15mmol)后，缓慢回到室温，室温反应2h。将反应液倾倒入水中(40mL)，稀盐酸(1N)调pH到约5，乙酸乙酯(50mL*3)萃取；合并有机层，无水硫酸钠干燥，过滤，减压浓缩。残留物用硅胶柱色谱分离提纯(石油醚：乙酸乙酯(v/v)＝1：0-3:1)得白色固体5-(苄氧甲基)-1H-吡唑-3-胺(2b)(0.71g，68％)。At -78°C, acetonitrile (232 mg, 5.66 mmol) was dissolved in dry tetrahydrofuran (10 mL), and under nitrogen protection, n-butyllithium (2.2 mL, 5.66 mmol, 2.5 mmol/mL in Hexanes) was added dropwise, - Stir at 78°C for 0.5h. After adding 2-benzyloxyethyl acetate (2a) (1.00 g, 5.15 mmol), the mixture was slowly returned to room temperature and reacted at room temperature for 2 h. The 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. The residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (v/v)=1:0-3:1) to obtain a white solid 5-(benzyloxymethyl)-1H-pyrazol-3-amine ( 2b) (0.71 g, 68%).
LCMS m/z＝204.1[M+1] +。 LCMS m/z=204.1[M+1] + .
第二步：3-氨基-5-(苄氧基甲基)吡唑-1-羧酸叔丁酯(2c)Step 2: tert-butyl 3-amino-5-(benzyloxymethyl)pyrazole-1-carboxylate (2c)
tert-butyl 3-amino-5-(benzyloxymethyl)pyrazole-1-carboxylatetert-butyl 3-amino-5-(benzyloxymethyl)pyrazole-1-carboxylate
Figure PCTCN2021103485-appb-000308
Figure PCTCN2021103485-appb-000308
室温下，将5-(苄氧甲基)-1H-吡唑-3-胺(2b)(100mg,0.50mmol)溶于二氯甲烷(10mL)中，向其中加入氢氧化钾(40mg，1.00mmol)和二碳酸二叔丁酯(120.00mg，0.55mmol)，室温反应16h。将反应液倾倒入水中(20mL)，二氯甲烷(20mL*3)萃取；合并有机层，无水硫酸钠干燥，过滤，减压浓缩。残留物用硅胶柱色谱分离提纯(石油醚：乙酸乙酯(v/v)＝1：0-5:1)得白色固体3-氨基-5-(苄氧基甲基)吡唑-1-羧酸叔丁酯(2c)(0.11g，74％)。At room temperature, 5-(benzyloxymethyl)-1H-pyrazol-3-amine (2b) (100 mg, 0.50 mmol) was dissolved in dichloromethane (10 mL), to which was added potassium hydroxide (40 mg, 1.00 mmol) and di-tert-butyl dicarbonate (120.00 mg, 0.55 mmol), react at room temperature for 16 h. The reaction solution was poured into water (20 mL) and extracted with dichloromethane (20 mL*3); the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (v/v)=1:0-5:1) to obtain 3-amino-5-(benzyloxymethyl)pyrazole-1- as a white solid tert-Butyl carboxylate (2c) (0.11 g, 74%).
LCMS m/z＝304.2[M+1] + LCMS m/z=304.2[M+1] +
第三步：cis-5-(苄氧基甲基)-3-[[5-[(5-羟基-2-金刚烷基)氨基]-1,6-萘啶-7-基]氨基]吡唑-1-羧酸叔丁酯(2d)The third step: cis-5-(benzyloxymethyl)-3-[[5-[(5-hydroxy-2-adamantyl)amino]-1,6-naphthyridin-7-yl]amino] Pyrazole-1-carboxylate tert-butyl ester (2d)
cis-tert-butyl 5-(benzyloxymethyl)-3-[[5-[(5-hydroxy-2-adamantyl)amino]-1,6-naphthyridin-7-yl]amino]pyrazole-1-carboxylatecis-tert-butyl 5-(benzyloxymethyl)-3-[[5-[(5-hydroxy-2-adamantyl)amino]-1,6-naphthyridin-7-yl]amino]pyrazole-1-carboxylate
Figure PCTCN2021103485-appb-000309
Figure PCTCN2021103485-appb-000309
将cis-4-[(7-氯-1,6-萘啶-5-基)氨基]金刚烷-1-醇(1b)(50mg,0.15mmol)，3-氨基-5-(苄氧基甲基)-吡唑-1-羧酸叔丁酯(2c)(50mg,0.17mmol)，三(二亚苄基丙酮)二钯(7mg,0.01mmol)，2-(二环己基膦)-3,6-二甲氧基-2',4',6'-三异丙基-1,1'-联苯(8mg,0.02mmol)，碳酸铯(64mg,0.20mmol)加入到1，4-二氧六环(3mL)中，氮气置换，升温至100℃反应24h。降至室温，垫硅藻土过滤，再用乙酸乙酯(2mL*2)淋洗，然后将滤液减压旋干得残留物，残留物制备板纯化(甲醇：二氯甲烷(v/v)＝1：10)得cis-5-(苄氧基甲基)-3-[[5-[(5-羟基-2-金刚烷基)氨基]-1,6-萘啶-7-基]氨基]吡唑-1-羧酸叔丁酯(2d)(80mg,88％)。cis-4-[(7-Chloro-1,6-naphthyridin-5-yl)amino]adamantan-1-ol (1b) (50 mg, 0.15 mmol), 3-amino-5-(benzyloxy Methyl)-pyrazole-1-carboxylate tert-butyl ester (2c) (50 mg, 0.17 mmol), tris(dibenzylideneacetone)dipalladium (7 mg, 0.01 mmol), 2-(dicyclohexylphosphine)- 3,6-Dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl (8mg, 0.02mmol), cesium carbonate (64mg, 0.20mmol) was added to 1,4 - in dioxane (3 mL), nitrogen was replaced, and the temperature was raised to 100° C. to react for 24 h. It was cooled to room temperature, filtered through celite, rinsed with ethyl acetate (2mL*2), and then the filtrate was spin-dried under reduced pressure to obtain a residue. The residue was purified by plate preparation (methanol: dichloromethane (v/v) =1:10) to get cis-5-(benzyloxymethyl)-3-[[5-[(5-hydroxy-2-adamantyl)amino]-1,6-naphthyridin-7-yl] Amino]pyrazole-1-carboxylate tert-butyl ester (2d) (80 mg, 88%).
LCMS m/z＝597.3[M+1] +。 LCMS m/z=597.3[M+1] + .
第四步：cis-4-[[7-[[5-(羟甲基)-1H-吡唑-3-基]氨基]-1,6-萘啶-5-基]氨基]金刚烷-1-醇；2,2,2-三氟乙酸盐(化合物2)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)
cis-4-[[7-[[5-(hydroxymethyl)-1H-pyrazol-3-yl]amino]-1,6-naphthyridin-5-yl]amino]adamantan-1-ol；2,2,2-trifluoroacetic acidcis-4-[[7-[[5-(hydroxymethyl)-1H-pyrazol-3-yl]amino]-1,6-naphthyridin-5-yl]amino]adamantan-1-ol;2,2,2 -trifluoroacetic acid
Figure PCTCN2021103485-appb-000310
Figure PCTCN2021103485-appb-000310
将cis-5-(苄氧基甲基)-3-[[5-[(5-羟基-2-金刚烷基)氨基]-1,6-萘啶-7-基]氨基]吡唑-1-羧酸叔丁酯(2d)(50mg,0.08mmol)溶于二氯甲烷(5mL)中，氮气置换，冰浴下缓慢滴加三溴化硼(63mg,0.25mmol)的二氯甲烷(1mL)溶液，滴完后，室温反应5min。然后冰浴下用甲醇(1mL)淬灭反应，再用三乙胺调pH＝7～8，减压浓缩得残留物，残留物经Pre-HPLC纯化(仪器及制备柱：采用Gilson Gx-281制备液相，制备柱型号是Sunfire，5μm，内径*长度＝30mm*150mm)。制备方法：粗品用甲醇溶解，并用0.45μm滤膜过滤，制备成样品液。流动相体系：乙腈/水(含0.5％的三氟乙酸)。梯度洗脱方法：乙腈由10％梯度洗脱60％(洗脱时间16min)，冻干后得到cis-4-[[7-[[5-(羟甲基)-1H-吡唑-3-基]氨基]-1,6-萘啶-5-基]氨基]金刚烷-1-醇；2,2,2-三氟乙酸盐(化合物2)(15mg,34％)。cis-5-(benzyloxymethyl)-3-[[5-[(5-hydroxy-2-adamantyl)amino]-1,6-naphthyridin-7-yl]amino]pyrazole- 1-Carboxylic acid tert-butyl ester (2d) (50 mg, 0.08 mmol) was dissolved in dichloromethane (5 mL), nitrogen was replaced, and boron tribromide (63 mg, 0.25 mmol) in dichloromethane ( 1mL) solution, after dropping, react at room temperature for 5min. Then, the reaction was quenched with methanol (1 mL) under ice bath, adjusted to pH=7-8 with triethylamine, and concentrated under reduced pressure to obtain a residue, which was purified by Pre-HPLC (instrument and preparative column: Gilson Gx-281 Preparative liquid phase, the preparative column model is Sunfire, 5 μm, inner diameter*length=30mm*150mm). Preparation method: the crude product is dissolved in methanol, and filtered with a 0.45 μm 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), lyophilized to obtain cis-4-[[7-[[5-(hydroxymethyl)-1H-pyrazole-3- yl]amino]-1,6-naphthyridin-5-yl]amino]adamantan-1-ol; 2,2,2-trifluoroacetate (compound 2) (15 mg, 34%).
LCMS m/z＝407.2[M+1] +。 LCMS m/z=407.2[M+1] + .
1H NMR(400MHz,DMSO-d 6+D 2O):δ9.15(d,1H),8.56(d,1H),7.26–7.23(m,1H),6.72(s,1H),6.34(s,1H),4.48(s,2H),4.15-4.10(m,1H),2.45-2.37(m,2H),2.14-2.08(m,1H),2.07-1.97(m,2H),1.84-1.75(m,2H),1.74–1.62(m,4H),1.52-1.43(m,2H). 1 H NMR (400MHz, DMSO-d 6 +D 2 O): δ 9.15 (d, 1H), 8.56 (d, 1H), 7.26–7.23 (m, 1H), 6.72 (s, 1H), 6.34 ( s,1H),4.48(s,2H),4.15-4.10(m,1H),2.45-2.37(m,2H),2.14-2.08(m,1H),2.07-1.97(m,2H),1.84- 1.75(m, 2H), 1.74-1.62(m, 4H), 1.52-1.43(m, 2H).
实施例3:Trans-4-[[7-[(5-甲基-1H-吡唑-3-基)氨基]-1,6-萘啶-5-基]氨基]金刚烷-1-醇；2,2,2- 三氟乙酸盐(化合物3)Example 3: 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)
Trans-4-[[7-[(5-methyl-1H-pyrazol-3-yl)amino]-1,6-naphthyridin-5-yl]amino]adamantan-1-ol；2,2,2-trifluoroacetic acidTrans-4-[[7-[(5-methyl-1H-pyrazol-3-yl)amino]-1,6-naphthyridin-5-yl]amino]adamantan-1-ol; 2,2,2-trifluoroacetic acid
Figure PCTCN2021103485-appb-000311
Figure PCTCN2021103485-appb-000311
第一步：trans-4-[((7-氯-1,6-萘啶-5-基)氨基]金刚烷-1-醇(3b)The first step: trans-4-[((7-chloro-1,6-naphthyridin-5-yl)amino]adamantan-1-ol (3b)
trans-4-[(7-chloro-1,6-naphthyridin-5-yl)amino]adamantan-1-oltrans-4-[(7-chloro-1,6-naphthyridin-5-yl)amino]adamantan-1-ol
Figure PCTCN2021103485-appb-000312
Figure PCTCN2021103485-appb-000312
将trans-4-氨基-1-羟基金刚烷盐酸盐(224.08mg,1.10mmol)溶于DMF(1mL)中，加入DIPEA(0.5mL,)和5,7-二氯-1,6-萘啶(1a)(200.00mg,1.01mmol)，混合物在100℃下反应过夜,直到LCMS显示反应完成。加入10ml水，用乙酸乙酯20ml*3萃取，合并有机相无水硫酸钠干燥，过滤，减压浓缩。混合物加入水，乙酸乙酯(10mL*3)萃取，合并有机相，无水硫酸钠干燥，过滤，减压浓缩。残留物经硅胶柱层析纯化(二氯甲烷：甲醇＝100:1-30:1)得到trans-4-[((7-氯-1,6-萘啶-5-基)氨基]金刚烷-1-醇(3b)(0.30g,91％)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. The mixture was added with water, extracted with ethyl acetate (10 mL*3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol=100:1-30:1) to give trans-4-[((7-chloro-1,6-naphthyridin-5-yl)amino]adamantane -1-ol (3b) (0.30 g, 91%)
LCMS m/z＝330.2[M+1] +。 LCMS m/z=330.2[M+1] + .
第二步：trans-3-[[5-[(5-羟基-2-金刚烷基)氨基]-1,6-萘啶-7-氨基]-5-甲基-吡唑-1-甲酸叔丁酯(3c)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)
trans-tert-butyl 3-[[5-[(5-hydroxy-2-adamantyl)amino]-1,6-naphthyridin-7-yl]amino]-5-methyl-pyrazole-1-carboxylatetrans-tert-butyl 3-[[5-[(5-hydroxy-2-adamantyl)amino]-1,6-naphthyridin-7-yl]amino]-5-methyl-pyrazole-1-carboxylate
Figure PCTCN2021103485-appb-000313
Figure PCTCN2021103485-appb-000313
将4-[((7-氯-1,6-萘啶-5-基)氨基]金刚烷-1-醇(3b)(50.00mg,0.15mmol)和3-氨基-5-甲基-吡唑-1-甲酸叔丁酯(1b’)(32.86mg,0.17mmol)溶于1,4-dioxane(2mL)中，加入Pd2(dba)3(6.86mg,0.0075mmol),Brettphos(8.05mg,0.015mmol),Cs2CO3(63.4mg,0.19mmol),混合物在N2保护80℃下反应过夜,TLC表明反应完成。混合物加入水，乙酸乙酯(10mL*3)萃取，合并有机相，无水硫酸钠干燥，过滤，减压浓缩。残留物经硅胶柱层析纯化(二氯甲烷：甲醇＝100:1-30:1)得到trans-3-[[5-[(5-羟基-2-金刚烷基)氨基]-1,6-萘啶-7-氨基]-5-甲基-吡唑-1-甲酸叔丁酯(3c)(0.47g,63％)4-[((7-Chloro-1,6-naphthyridin-5-yl)amino]adamantan-1-ol (3b) (50.00 mg, 0.15 mmol) and 3-amino-5-methyl-pyridine Tert-butyl oxazole-1-carboxylate (1b') (32.86mg, 0.17mmol) was dissolved in 1,4-dioxane (2mL), Pd2(dba)3 (6.86mg, 0.0075mmol), Brettphos (8.05mg, 0.015mmol), Cs2CO3 (63.4mg, 0.19mmol), the mixture was reacted under N2 protection at 80 ° C overnight, TLC showed that the reaction was completed. The mixture was added with water, extracted with ethyl acetate (10mL*3), the organic phases were combined, anhydrous sodium sulfate It was dried, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol=100:1-30:1) to obtain trans-3-[[5-[(5-hydroxy-2-adamantane (3c) (0.47g, 63%)
LCMS m/z＝491.3[M+1] +。 LCMS m/z=491.3[M+1] + .
第三步：trans-4-[[7-[(5-甲基-1H-吡唑-3-基)氨基]-1,6-萘啶-5-基]氨基]金刚烷-1-醇；2,2,2-三氟乙酸盐(化合物3)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)
trans-4-[[7-[(5-methyl-1H-pyrazol-3-yl)amino]-1,6-naphthyridin-5-yl]amino]adamantan-1-ol；2,2,2-trifluoroacetic acidtrans-4-[[7-[(5-methyl-1H-pyrazol-3-yl)amino]-1,6-naphthyridin-5-yl]amino]adamantan-1-ol; 2,2,2-trifluoroacetic acid
Figure PCTCN2021103485-appb-000314
Figure PCTCN2021103485-appb-000314
将trans-3-[[5-[(5-羟基-2-金刚烷基)氨基]-1,6-萘啶-7-氨基]-5-甲基-吡唑-1-甲酸叔丁酯(3c)(47.00mg,0.096mmol)溶于二氯甲烷(1mL)中，加入TFA(1mL),室温反应1h后,将反应液减压浓缩得油状物，油状物用氢氧化钠溶液(1M)调pH至9左右用乙酸乙酯(10mL*3)萃取，合并有机相，无水硫酸钠干燥，过滤，减压浓缩。残留物经Pre-HPLC纯化(仪器及制备柱：采用Waters2767制备液相，制备柱型号是XBridge，5μm，内径*长度＝19mm*250mm)。制备方法：粗品用二甲亚砜溶解，并用0.45μm滤膜过滤，制备成样品 液。流动相体系：乙腈/水(含0.1％的三氟乙酸)。梯度洗脱方法：乙腈由10％梯度到50％(洗脱时间16min)，冻干后得到trans-4-[[7-[(5-甲基-1H-吡唑-3-基)氨基]-1,6-萘啶-5-基]氨基]金刚烷-1-醇；2,2,2-三氟乙酸盐(化合物3)(25.00mg,52％)。Trans-3-[[5-[(5-hydroxy-2-adamantyl)amino]-1,6-naphthyridine-7-amino]-5-methyl-pyrazole-1-carboxylic acid tert-butyl ester (3c) (47.00 mg, 0.096 mmol) was dissolved in dichloromethane (1 mL), TFA (1 mL) was added, and after reacting at room temperature for 1 h, the reaction solution was concentrated under reduced pressure to obtain an oil, which was treated with sodium hydroxide solution (1 M ) adjusted the pH to about 9, extracted with ethyl acetate (10 mL*3), combined the organic phases, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by Pre-HPLC (instrument and preparative column: Waters2767 preparative liquid phase, preparative column type XBridge, 5 μm, inner diameter*length=19mm*250mm). Preparation method: the crude product is dissolved in dimethyl sulfoxide, and filtered with a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: acetonitrile/water (with 0.1% trifluoroacetic acid). Gradient elution method: acetonitrile gradient from 10% to 50% (elution time 16min), lyophilized to obtain 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) (25.00 mg, 52%).
LCMS m/z＝391.3[M+1] +。 LCMS m/z=391.3[M+1] + .
1H NMR(400MHz,CD 3OD)δ9.00(d,1H),8.46(dd,1H),7.22(dd,1H),6.64(s,1H),6.18(s,1H),4.40-4.26(m 1H),2.48-2.40(m,2H),2.33(s,3H),2.20-2.14(m,1H),2.12-2.04(m,2H),2.00-1.91(m,2H),1.89-1.77(m,4H),1.61-1.50(m,2H)。 1 H NMR (400MHz, CD 3 OD) δ9.00(d,1H), 8.46(dd,1H), 7.22(dd,1H), 6.64(s,1H), 6.18(s,1H), 4.40-4.26 (m 1H), 2.48-2.40(m, 2H), 2.33(s, 3H), 2.20-2.14(m, 1H), 2.12-2.04(m, 2H), 2.00-1.91(m, 2H), 1.89- 1.77 (m, 4H), 1.61-1.50 (m, 2H).
实施例4:trans-4-[[7-[[5-(羟甲基)-1H-吡唑-3-基]氨基]-1,6-萘啶-5-基]氨基]金刚烷-1-醇；2,2,2-三氟乙酸盐(化合物4)Example 4: 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)
trans-4-[[7-[[5-(hydroxymethyl)-1H-pyrazol-3-yl]amino]-1,6-naphthyridin-5-yl]amino]adamantan-1-ol；2,2,2-trifluoroacetic acidtrans-4-[[7-[[5-(hydroxymethyl)-1H-pyrazol-3-yl]amino]-1,6-naphthyridin-5-yl]amino]adamantan-1-ol;2,2,2 -trifluoroacetic acid
Figure PCTCN2021103485-appb-000315
Figure PCTCN2021103485-appb-000315
第一步：trans-5-(苄氧基甲基)-3-[[5-[[5-羟基-2-金刚烷基]氨基]-1,6-萘吡啶-7-基]氨基]吡唑-1-甲酸叔丁酯(4a)The first step: trans-5-(benzyloxymethyl)-3-[[5-[[5-hydroxy-2-adamantyl]amino]-1,6-naphthypyridin-7-yl]amino] tert-Butyl pyrazole-1-carboxylate (4a)
trans-tert-butyl 5-(benzyloxymethyl)-3-[[5-[[5-hydroxy-2-adamantyl]amino]-1,6-naphthyridin-7-yl]amino]pyrazole-1-carboxylatetrans-tert-butyl 5-(benzyloxymethyl)-3-[[5-[[5-hydroxy-2-adamantyl]amino]-1,6-naphthyridin-7-yl]amino]pyrazole-1-carboxylate
Figure PCTCN2021103485-appb-000316
Figure PCTCN2021103485-appb-000316
将trans-4-[((7-氯-1,6-萘啶-5-基)氨基]金刚烷-1-醇(3b)(50.00mg,0.15mmol)和3-氨基-5-(苄氧基甲基)吡唑-1-羧酸叔丁酯(2c)(50.06mg,0.17mmol)溶于1,4-dioxane(2mL)中， 加入Pd2(dba)3(6.86mg,0.0075mmol),Brettphos(8.05mg,0.015mmol),Cs2CO3(63.4mg,0.19mmol),混合物在N2保护80℃下反应过夜,TLC表明反应完成。混合物加入水，乙酸乙酯(10mL*3)萃取，合并有机相，无水硫酸钠干燥，过滤，减压浓缩。残留物经硅胶柱层析纯化(二氯甲烷：甲醇＝100:1-30:1)得到trans-5-(苄氧基甲基)-3-[[5-[[5-羟基-2-金刚烷基]氨基]-1,6-萘吡啶-7-基]氨基]吡唑-1-甲酸叔丁酯(4a)(0.80g,93％)Trans-4-[((7-Chloro-1,6-naphthyridin-5-yl)amino]adamantan-1-ol (3b) (50.00 mg, 0.15 mmol) and 3-amino-5-(benzyl) Oxymethyl)pyrazole-1-carboxylate tert-butyl ester (2c) (50.06 mg, 0.17 mmol) was dissolved in 1,4-dioxane (2 mL) and Pd2(dba)3 (6.86 mg, 0.0075 mmol) was added , Brettphos (8.05mg, 0.015mmol), Cs2CO3 (63.4mg, 0.19mmol), the mixture was reacted under N2 protection at 80 ° C overnight, TLC showed that the reaction was completed. The mixture was added with water, extracted with ethyl acetate (10mL*3), and the organic The phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol=100:1-30:1) to obtain trans-5-(benzyloxymethyl)- 3-[[5-[[5-Hydroxy-2-adamantyl]amino]-1,6-naphthyridine-7-yl]amino]pyrazole-1-carboxylic acid tert-butyl ester (4a) (0.80g, 93%)
LCMS m/z＝597.4[M+1] +。 LCMS m/z=597.4[M+1] + .
第二步：trans-4-[[7-[[5-(羟甲基)-1H-吡唑-3-基]氨基]-1,6-萘啶-5-基]氨基]金刚烷-1-醇；2,2,2-三氟乙酸盐(化合物4)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)
trans-4-[[7-[[5-(hydroxymethyl)-1H-pyrazol-3-yl]amino]-1,6-naphthyridin-5-yl]amino]adamantan-1-ol；2,2,2-trifluoroacetic acidtrans-4-[[7-[[5-(hydroxymethyl)-1H-pyrazol-3-yl]amino]-1,6-naphthyridin-5-yl]amino]adamantan-1-ol;2,2,2 -trifluoroacetic acid
Figure PCTCN2021103485-appb-000317
Figure PCTCN2021103485-appb-000317
将trans-5-(苄氧基甲基)-3-[[5-[[5-羟基-2-金刚烷基]氨基]-1,6-萘吡啶-7-基]氨基]吡唑-1-甲酸叔丁酯(4a)(40.00mg,0.067mmol)溶于DCM(2mL)中，加入BBr3(0.2mL),混合物在室温下反应,LCMS表明反应完成。将反应液减压浓缩得油状物，油状物用氢氧化钠溶液(1M)调pH至9左右用乙酸乙酯(10mL*3)萃取，合并有机相，无水硫酸钠干燥，过滤，减压浓缩。残留物经Pre-HPLC纯化(仪器及制备柱：采用Waters2767制备液相，制备柱型号是XBridge，5μm，内径*长度＝19mm*250mm)。制备方法：粗品用二甲亚砜溶解，并用0.45μm滤膜过滤，制备成样品液。流动相体系：乙腈/水(含0.1％的三氟乙酸)。梯度洗脱方法：乙腈由10％梯度到50％(洗脱时间16min)，冻干后得到trans-4-[[7-[[5-(羟甲基)-1H-吡唑-3-基]氨基]-1,6-萘啶-5-基]氨基]金刚烷-1-醇；2,2,2-三氟乙酸(化合物4)(6.00mg,17％)。Trans-5-(benzyloxymethyl)-3-[[5-[[5-hydroxy-2-adamantyl]amino]-1,6-naphthpyridin-7-yl]amino]pyrazole- tert-Butyl 1-carboxylate (4a) (40.00 mg, 0.067 mmol) was dissolved in DCM (2 mL), BBr3 (0.2 mL) was added, the mixture was reacted at room temperature, and LCMS indicated that the reaction was complete. The reaction solution was concentrated under reduced pressure to obtain an oil. The oil was adjusted to pH 9 with sodium hydroxide solution (1M) and extracted with ethyl acetate (10 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and subjected to reduced pressure. concentrate. The residue was purified by Pre-HPLC (instrument and preparative column: Waters2767 preparative liquid phase, preparative column type XBridge, 5 μm, inner diameter*length=19mm*250mm). Preparation method: the crude product is dissolved in dimethyl sulfoxide, and filtered with a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: acetonitrile/water (with 0.1% trifluoroacetic acid). Gradient elution method: acetonitrile gradient from 10% to 50% (elution time 16min), lyophilized to obtain trans-4-[[7-[[5-(hydroxymethyl)-1H-pyrazol-3-yl ]amino]-1,6-naphthyridin-5-yl]amino]adamantan-1-ol; 2,2,2-trifluoroacetic acid (compound 4) (6.00 mg, 17%).
LCMS m/z＝407.2[M+1] +。 LCMS m/z=407.2[M+1] + .
1H NMR(400MHz,CD 3OD)δ9.00(d,1H),8.46(dd,1H),7.22(dd,1H),6.67(s,1H),6.34(s,1H),4.65(s,2H),4.40-4.25(m,1H),2.54-2.36(m,2H),2.22-2.13(m,1H),2.12-2.03(m,2H),2.01-1.92(m,2H),1.88-1.77(m,4H),1.62-1.49(m,2H)。 1 H NMR (400MHz, CD 3 OD) δ 9.00(d, 1H), 8.46(dd, 1H), 7.22(dd, 1H), 6.67(s, 1H), 6.34(s, 1H), 4.65(s ,2H),4.40-4.25(m,1H),2.54-2.36(m,2H),2.22-2.13(m,1H),2.12-2.03(m,2H),2.01-1.92(m,2H),1.88 -1.77(m, 4H), 1.62-1.49(m, 2H).
实施例5：Trans-4-[[4-[(5-甲基-1H-吡唑-3-基)氨基]-1H-吡唑啉[3,4-d]嘧啶-6-基]氨基]金刚-1-醇；2,2,2-三氟乙酸盐(化合物5)Example 5: Trans-4-[[4-[(5-Methyl-1H-pyrazol-3-yl)amino]-1H-pyrazolin[3,4-d]pyrimidin-6-yl]amino ] Adamant-1-ol; 2,2,2-trifluoroacetate (Compound 5)
Trans-4-[[4-[(5-methyl-1H-pyrazol-3-yl)amino]-1H-pyrazolo[3,4-d]pyrimidin-6- yl]amino]adamantan-1-ol；2,2,2-trifluoroacetic acidTrans-4-[[4-[(5-methyl-1H-pyrazol-3-yl)amino]-1H-pyrazolo[3,4-d]pyrimidin-6-yl]amino]adamantan-1-ol;2 ,2,2-trifluoroacetic acid
Figure PCTCN2021103485-appb-000318
Figure PCTCN2021103485-appb-000318
第一步：4,6-二氯-1-四氢吡喃-2-基-吡唑[3,4-d]嘧啶(5b)Step 1: 4,6-Dichloro-1-tetrahydropyran-2-yl-pyrazolo[3,4-d]pyrimidine (5b)
4,6-dichloro-1-tetrahydropyran-2-yl-pyrazolo[3,4-d]pyrimidine4,6-dichloro-1-tetrahydropyran-2-yl-pyrazolo[3,4-d]pyrimidine
Figure PCTCN2021103485-appb-000319
Figure PCTCN2021103485-appb-000319
室温下，将4,6-二氯-1H-吡唑并[3,4-d]嘧啶(5a)(1.00g，5.29mmol)溶于干燥二氯甲烷(15mL)和干燥二四氢呋喃(15mL)的混合溶剂中，在氮气保护下，向其中依次加入3,4-二氢-2H-吡喃(670mg，7.97mmol)和对甲苯磺酸(100mg，0.53mmol)后，室温反应4h。反应结束后，将反应液减压浓缩，加入饱和食盐水溶液(20mL)，乙酸乙酯(20mL*2)萃取；合并有机层，无水硫酸钠干燥，过滤，减压浓缩。残留物用硅胶柱色谱分离提纯(石油醚：乙酸乙酯(v/v)＝20:1-10:1)得白色固体4,6-二氯-1-四氢吡喃-2-基-吡唑[3,4-d]嘧啶(5b)(1.40g，97％)。4,6-Dichloro-1H-pyrazolo[3,4-d]pyrimidine (5a) (1.00 g, 5.29 mmol) was dissolved in dry dichloromethane (15 mL) and dry ditetrahydrofuran (15 mL) at room temperature 3,4-dihydro-2H-pyran (670 mg, 7.97 mmol) and p-toluenesulfonic acid (100 mg, 0.53 mmol) were successively added to the mixed solvent under nitrogen protection, and reacted at room temperature for 4 h. After the reaction was completed, the 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. The residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (v/v)=20:1-10:1) to obtain a white solid 4,6-dichloro-1-tetrahydropyran-2-yl- Pyrazolo[3,4-d]pyrimidine (5b) (1.40 g, 97%).
LCMS m/z＝273.1，275.1[M+1] +。 LCMS m/z=273.1, 275.1 [M+1] + .
第二步：6-氯-N-(5-甲基-1H-吡唑-3-基)-1-四氢吡喃-2-基-吡唑[3,4-d]嘧啶-4-胺(5c)Step 2: 6-Chloro-N-(5-methyl-1H-pyrazol-3-yl)-1-tetrahydropyran-2-yl-pyrazolo[3,4-d]pyrimidine-4- Amine (5c)
6-chloro-N-(5-methyl-1H-pyrazol-3-yl)-1-tetrahydropyran-2-yl-pyrazolo[3,4-d]pyrimidin-4-amine6-chloro-N-(5-methyl-1H-pyrazol-3-yl)-1-tetrahydropyran-2-yl-pyrazolo[3,4-d]pyrimidin-4-amine
Figure PCTCN2021103485-appb-000320
Figure PCTCN2021103485-appb-000320
室温下，将4,6-二氯-1-四氢吡喃-2-基-吡唑[3,4-d]嘧啶(5b)(500mg,1.83mmol)溶于无水乙醇(20mL)中，在氮气保护下，向其中依次加入3-氨基-5-甲基吡唑(220mg，2.27mmol)和N,N-二异丙基乙胺(480mg，3.72mmol)，然后60℃加热搅拌4小时。反应结束后，将反应液减压浓缩，加入饱和食盐水溶液(20mL)，乙酸乙酯(20mL*2)萃取；合并有机层，无水硫酸钠干燥，过滤，减压浓缩得黄色固体6-氯-N-(5-甲基-1H-吡唑-3-基)-1-四氢吡喃-2-基-吡唑[3,4-d]嘧啶-4-胺(5c)(600mg，98％)。4,6-Dichloro-1-tetrahydropyran-2-yl-pyrazolo[3,4-d]pyrimidine (5b) (500 mg, 1.83 mmol) was dissolved in absolute ethanol (20 mL) at room temperature , under nitrogen protection, 3-amino-5-methylpyrazole (220 mg, 2.27 mmol) and N,N-diisopropylethylamine (480 mg, 3.72 mmol) were sequentially added thereto, and then heated and stirred at 60 °C for 4 Hour. After the reaction, the 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%).
LCMS m/z＝334.2[M+1] +。 LCMS m/z=334.2[M+1] + .
第三步：Trans-4-[[4-[(5-甲基-1H-吡唑-3-基)氨基]-1H-吡唑啉[3,4-d]嘧啶-6-基]氨基]金刚-1-醇；2,2,2-三氟乙酸盐(化合物5)The third step: Trans-4-[[4-[(5-methyl-1H-pyrazol-3-yl)amino]-1H-pyrazoline[3,4-d]pyrimidin-6-yl]amino ] Adamant-1-ol; 2,2,2-trifluoroacetate (Compound 5)
Trans-4-[[4-[(5-methyl-1H-pyrazol-3-yl)amino]-1H-pyrazolo[3,4-d]pyrimidin-6-yl]amino]adamantan-1-ol；2,2,2-trifluoroacetic acidTrans-4-[[4-[(5-methyl-1H-pyrazol-3-yl)amino]-1H-pyrazolo[3,4-d]pyrimidin-6-yl]amino]adamantan-1-ol;2 ,2,2-trifluoroacetic acid
Figure PCTCN2021103485-appb-000321
Figure PCTCN2021103485-appb-000321
室温下，6-氯-N-(5-甲基-1H-吡唑-3-基)-1-四氢吡喃-2-基-吡唑[3,4-d]嘧啶-4-胺(5c)(200mg,0.60mmol)和正丁醇(10mL)加入微波管中，再依次加入反式-4-氨基-1-羟基金刚烷盐酸盐(184mg,0.90mmol)和N,N-二异丙基乙胺(331mg，2.57mmol)，然后160℃微波条件下搅拌10小时。反应结束后，将反应液减压浓缩，粗品经Pre-HPLC纯化(仪器及制备柱：采用WATERS 2767制备液相，制备柱型号是Xselect C18，5μm，内径*长度＝19mm*150mm)。制备方法：粗品用二甲亚砜溶解，并用0.45μm滤膜过滤，制备成样品液。流动相体系：乙腈/水(含0.1％TFA)。梯度洗脱方法：乙腈由5％梯度洗脱50％(洗脱时间15min)，冻干后得到Trans-4-[[4-[(5-甲基-1H-吡唑-3-基)氨基]-1H-吡唑啉[3,4-d]嘧啶-6-基]氨基]金刚-1-醇；2,2,2-三氟乙酸盐(化合物5)(40mg，14％)。6-Chloro-N-(5-methyl-1H-pyrazol-3-yl)-1-tetrahydropyran-2-yl-pyrazolo[3,4-d]pyrimidin-4-amine at room temperature (5c) (200 mg, 0.60 mmol) and n-butanol (10 mL) were added to a microwave tube, followed by trans-4-amino-1-hydroxyadamantane hydrochloride (184 mg, 0.90 mmol) and N,N-dihydrochloride isopropylethylamine (331 mg, 2.57 mmol), then stirred under microwave conditions at 160°C for 10 hours. After the reaction, the reaction solution was concentrated under reduced pressure, and the crude product was purified by Pre-HPLC (instrument and preparative column: WATERS 2767 was used to prepare the liquid phase, and the preparative column model was Xselect C18, 5 μm, inner diameter*length=19mm*150mm). Preparation method: the crude product is dissolved in dimethyl sulfoxide, and filtered with a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: acetonitrile/water (with 0.1% TFA). Gradient elution method: acetonitrile was eluted from 5% to 50% (elution time 15min), and after lyophilization, Trans-4-[[4-[(5-methyl-1H-pyrazol-3-yl)amino was obtained ]-1H-Pyrazolin[3,4-d]pyrimidin-6-yl]amino]adamant-1-ol; 2,2,2-trifluoroacetate (compound 5) (40 mg, 14%).
LCMS m/z＝381.2[M+1] +。 LCMS m/z=381.2[M+1] + .
1H NMR(400MHz,CD 3OD)δ8.39(s,1H),6.49(s,1H),4.30-4.10(m,1H),2.37(s,3H),2.34-2.28(m,2H),2.20-2.14(m,1H),2.00-1.88(m,4H),1.87-1.80(m,4H),1.65-1.54(m,2H)。 1 H NMR (400MHz, CD 3 OD) δ 8.39(s, 1H), 6.49(s, 1H), 4.30-4.10(m, 1H), 2.37(s, 3H), 2.34-2.28(m, 2H) , 2.20-2.14(m, 1H), 2.00-1.88(m, 4H), 1.87-1.80(m, 4H), 1.65-1.54(m, 2H).
实施例6：Trans-4-[[4-[(5-甲基-1H-吡唑-3-基)氨基]噻吩[3,2-d]嘧啶-2-基]氨基]金刚-1-醇；2,2,2-三氟乙酸盐(化合物6)Example 6: 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)
Trans-4-[[4-[(5-methyl-1H-pyrazol-3-yl)amino]thieno[3,2-d]pyrimidin-2-yl]amino]adamantan-1-ol；2,2,2-trifluoroacetic acidTrans-4-[[4-[(5-methyl-1H-pyrazol-3-yl)amino]thieno[3,2-d]pyrimidin-2-yl]amino]adamantan-1-ol;2,2, 2-trifluoroacetic acid
Figure PCTCN2021103485-appb-000322
Figure PCTCN2021103485-appb-000322
第一步：2-氯-N-(5-甲基-1H-吡唑-3-基)噻吩[3,2-d]嘧啶-4-胺(6b)The first step: 2-chloro-N-(5-methyl-1H-pyrazol-3-yl)thiophene[3,2-d]pyrimidin-4-amine (6b)
2-chloro-N-(5-methyl-1H-pyrazol-3-yl)thieno[3,2-d]pyrimidin-4-amine2-chloro-N-(5-methyl-1H-pyrazol-3-yl)thieno[3,2-d]pyrimidin-4-amine
Figure PCTCN2021103485-appb-000323
Figure PCTCN2021103485-appb-000323
室温下，将2,4-二氯噻吩并[3,2-d]嘧啶(6a)(1.0g,4.88mmol)溶于DMF(20mL)中，在氮气保护下，向其中依次加入3-氨基-5-甲基吡唑(550mg，5.67mmol)和N,N-二异丙基乙胺(782mg，6.06mmol)，然后室温搅拌4小时。反应结束后，加入乙酸乙酯(20mL)萃取，饱和食盐水溶液(20mL*3)洗涤，收集有机层，无水硫酸钠干燥，过滤，减压浓缩。残留物用硅胶柱色谱分离提纯(石油醚：乙酸乙酯(v/v)＝10:1-1:1)减压浓缩得白色固体2-氯-N-(5-甲基-1H-吡唑-3-基)噻吩[3,2-d]嘧啶-4-胺(6b)(650mg，50％)。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. The residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (v/v)=10:1-1:1) and concentrated under reduced pressure to obtain a white solid 2-chloro-N-(5-methyl-1H-pyridine) azol-3-yl)thiophene[3,2-d]pyrimidin-4-amine (6b) (650 mg, 50%).
LCMS m/z＝266.0[M+1] +。 LCMS m/z=266.0[M+1] + .
第二步：trans-4-[[4-[(5-甲基-1H-吡唑-3-基)氨基]噻吩[3,2-d]嘧啶-2-基]氨基]金刚-1-醇；2,2,2-三氟乙酸盐(化合物6)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)
Trans-4-[[4-[(5-methyl-1H-pyrazol-3-yl)amino]thieno[3,2-d]pyrimidin-2-yl]amino]adamantan-1-ol；2,2,2-trifluoroacetic acidTrans-4-[[4-[(5-methyl-1H-pyrazol-3-yl)amino]thieno[3,2-d]pyrimidin-2-yl]amino]adamantan-1-ol;2,2, 2-trifluoroacetic acid
Figure PCTCN2021103485-appb-000324
Figure PCTCN2021103485-appb-000324
室温下，2-氯-N-(5-甲基-1H-吡唑-3-基)噻吩[3,2-d]嘧啶-4-胺(6b)(100mg,0.38mmol)和正丁醇(10mL)加入微波管中，再依次加入trans-4-氨基-1-羟基金刚烷盐酸盐(154mg,0.76mmol)和N,N-二异丙基乙胺(292mg，2.26mmol)，然后110℃微波条件下搅拌14小时。反应结束后，将反应液减压浓缩，粗品经Pre-HPLC纯化(仪器及制备柱：采用WATERS 2767制备液相，制备柱型号是Xselect C18，5μm，内径*长度＝19mm*150mm)。制备方法：粗品用二甲亚砜溶解，并用0.45μm滤膜过滤，制备成样品液。流动相体系：乙腈/水(含0.1％TFA)。梯度洗脱方法：乙腈由5％梯度洗脱50％(洗脱时间15min)，冻干后得到trans-4-[[4-[(5-甲基-1H-吡唑-3-基)氨基]噻吩[3,2-d]嘧啶-2-基]氨基]金刚-1-醇；2,2,2-三氟乙酸盐(化合物6)(25mg，13％)。At room temperature, 2-chloro-N-(5-methyl-1H-pyrazol-3-yl)thiophene[3,2-d]pyrimidin-4-amine (6b) (100 mg, 0.38 mmol) and n-butanol ( 10mL) was added to a microwave tube, followed by trans-4-amino-1-hydroxyadamantane hydrochloride (154mg, 0.76mmol) and N,N-diisopropylethylamine (292mg, 2.26mmol), then 110 Stir under microwave conditions for 14 hours. After the reaction, the reaction solution was concentrated under reduced pressure, and the crude product was purified by Pre-HPLC (instrument and preparative column: WATERS 2767 was used to prepare the liquid phase, and the preparative column model was Xselect C18, 5 μm, inner diameter*length=19mm*150mm). Preparation method: the crude product is dissolved in dimethyl sulfoxide, and filtered with a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: acetonitrile/water (with 0.1% TFA). Gradient elution method: acetonitrile was eluted from 5% to 50% (elution time 15min), and after lyophilization, trans-4-[[4-[(5-methyl-1H-pyrazol-3-yl)amino was obtained ]thiophene[3,2-d]pyrimidin-2-yl]amino]adamant-1-ol; 2,2,2-trifluoroacetate (compound 6) (25 mg, 13%).
LCMS m/z＝397.1[M+1] +。 LCMS m/z=397.1[M+1] + .
1H NMR(400MHz,CD 3OD)δ8.30-8.04(m,1H),δ7.36-7.13(m,1H),6.46(s,1H),4.32-3.95(m,1H),2.37(s,3H),2.33-2.26(m,2H),2.20-2.13(m,1H),2.03-1.88(m,4H),1.87-1.80(m,4H),1.63-1.55(m,2H)。 1 H NMR (400MHz, CD 3 OD) δ8.30-8.04(m, 1H), δ7.36-7.13(m, 1H), 6.46(s, 1H), 4.32-3.95(m, 1H), 2.37( s,3H), 2.33-2.26(m,2H), 2.20-2.13(m,1H), 2.03-1.88(m,4H), 1.87-1.80(m,4H), 1.63-1.55(m,2H).
实施例7：Trans-4-[[4-[(5-甲基-1H-吡唑-3-基)氨基]噻吩[2,3-d]嘧啶-2-基]氨基]金刚-1-醇；2,2,2-三氟乙酸盐(化合物7)Example 7: 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)
Trans-4-[[4-[(5-methyl-1H-pyrazol-3-yl)amino]thieno[2,3-d]pyrimidin-2-yl]amino]adamantan-1-ol；2,2,2-trifluoroacetic acidTrans-4-[[4-[(5-methyl-1H-pyrazol-3-yl)amino]thieno[2,3-d]pyrimidin-2-yl]amino]adamantan-1-ol;2,2, 2-trifluoroacetic acid
Figure PCTCN2021103485-appb-000325
Figure PCTCN2021103485-appb-000325
第一步：2-氯-N-(5-甲基-1H-吡唑-3-基)噻吩[2,3-d]嘧啶-4-胺(7b)The first step: 2-chloro-N-(5-methyl-1H-pyrazol-3-yl)thiophene[2,3-d]pyrimidin-4-amine (7b)
2-chloro-N-(5-methyl-1H-pyrazol-3-yl)thieno[2,3-d]pyrimidin-4-amine2-chloro-N-(5-methyl-1H-pyrazol-3-yl)thieno[2,3-d]pyrimidin-4-amine
Figure PCTCN2021103485-appb-000326
Figure PCTCN2021103485-appb-000326
室温下，将2,4-二氯噻吩[2,3-d]嘧啶(7a)(1.00g,4.88mmol)溶于无水乙醇(25mL)中，在氮气保护下，向其中依次加入3-氨基-5-甲基吡唑(487mg，5.02mmol)和N,N-二异丙基乙胺(1.23g，9.54mmol)，然后60℃加热搅拌20小时。反应结束后，将反应液减压浓缩，加入0.5mL无水乙醇和30mL甲基叔丁基醚后，有固体析出；过滤得黄色固体2-氯-N-(5-甲基-1H-吡唑-3-基)噻吩[2,3-d]嘧啶-4-胺(7b)(600mg，46％)。At room temperature, 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. After the reaction, the 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%).
LCMS m/z＝266.1[M+1] +。 LCMS m/z=266.1[M+1] + .
第二步：Trans-4-[[4-[(5-甲基-1H-吡唑-3-基)氨基]噻吩[2,3-d]嘧啶-2-基]氨基]金刚-1-醇；2,2,2-三氟乙酸盐(化合物7)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)
Trans-4-[[4-[(5-methyl-1H-pyrazol-3-yl)amino]thieno[2,3-d]pyrimidin-2-yl]amino]adamantan-1-ol；2,2,2-trifluoroacetic acidTrans-4-[[4-[(5-methyl-1H-pyrazol-3-yl)amino]thieno[2,3-d]pyrimidin-2-yl]amino]adamantan-1-ol;2,2, 2-trifluoroacetic acid
Figure PCTCN2021103485-appb-000327
Figure PCTCN2021103485-appb-000327
室温下，将2-氯-N-(5-甲基-1H-吡唑-3-基)噻吩[2,3-d]嘧啶-4-胺(7b)(100mg,0.38mmol)和N-甲基吡咯烷酮(10mL)加入微波管中，再依次加入反式-4-氨基-1-羟基金刚烷盐酸盐(154mg,0.76mmol)和三乙胺(228mg，2.26mmol)，然后180℃微波条件下反应1小时。反应结束后，将反应液减压浓缩，粗品经Pre-HPLC纯化(仪器及制备柱：采用WATERS 2767制备液相，制备柱型号是Xselect C18，5μm，内径*长度＝19mm*150mm)。制备方法：粗品用二甲亚砜溶解，并用0.45μm滤膜过滤，制备成样品液。流动相体系：乙腈/水(含0.1％TFA)。梯度洗脱方法：乙腈由5％梯度洗脱50％(洗脱时间15min)，冻干后得到Trans-4-[[4-[(5-甲基-1H-吡唑-3-基)氨基]噻吩[2,3-d]嘧啶-2-基]氨基]金刚-1-醇；2,2,2-三氟乙酸盐(化合物7)(40mg，21％)。2-Chloro-N-(5-methyl-1H-pyrazol-3-yl)thiophene[2,3-d]pyrimidin-4-amine (7b) (100 mg, 0.38 mmol) and N- Methylpyrrolidone (10 mL) was added to a microwave tube, followed by trans-4-amino-1-hydroxyadamantane hydrochloride (154 mg, 0.76 mmol) and triethylamine (228 mg, 2.26 mmol), and then microwaved at 180°C The reaction was carried out under the conditions for 1 hour. After the reaction, the reaction solution was concentrated under reduced pressure, and the crude product was purified by Pre-HPLC (instrument and preparative column: WATERS 2767 was used to prepare the liquid phase, and the preparative column model was Xselect C18, 5 μm, inner diameter*length=19mm*150mm). Preparation method: the crude product is dissolved in dimethyl sulfoxide, and filtered with a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: acetonitrile/water (with 0.1% TFA). Gradient elution method: acetonitrile was eluted from 5% to 50% (elution time 15min), and after lyophilization, Trans-4-[[4-[(5-methyl-1H-pyrazol-3-yl)amino was obtained ]thiophene[2,3-d]pyrimidin-2-yl]amino]adamant-1-ol; 2,2,2-trifluoroacetate (compound 7) (40 mg, 21%).
LCMS m/z＝397.1[M+1] +。 LCMS m/z=397.1[M+1] + .
1H NMR(400MHz,CD 3OD)δ7.59(d,1H),7.32(d,1H),6.32(s,1H),4.14-4.08(m,1H),2.38(s,3H),2.33-2.27(m,2H),2.19-2.14(m,1H),2.04-1.90(m,4H),1.87-1.80(m,4H),1.62-1.1.52(m,2H)。 1 H NMR (400MHz, CD 3 OD) δ 7.59(d,1H), 7.32(d,1H), 6.32(s,1H), 4.14-4.08(m,1H), 2.38(s,3H), 2.33 -2.27(m, 2H), 2.19-2.14(m, 1H), 2.04-1.90(m, 4H), 1.87-1.80(m, 4H), 1.62-1.1.52(m, 2H).
实施例8：Cis-[[4-[(5-甲基-1H-吡唑-3-基)氨基]-1H-吡唑啉[3,4-d]嘧啶-6-基]氨基]金刚-1-醇；2,2,2-三氟乙酸盐(化合物8)Example 8: Cis-[[4-[(5-Methyl-1H-pyrazol-3-yl)amino]-1H-pyrazolin[3,4-d]pyrimidin-6-yl]amino]adamant -1-ol; 2,2,2-trifluoroacetate (compound 8)
Cis-4-[(5-methyl-1H-pyrazol-3-yl)amino]-1H-pyrazolo[3,4-d]pyrimidin-6-yl]amino]adamantan-1-ol；2,2,2-trifluoroacetic acidCis-4-[(5-methyl-1H-pyrazol-3-yl)amino]-1H-pyrazolo[3,4-d]pyrimidin-6-yl]amino]adamantan-1-ol;2,2,2 -trifluoroacetic acid
Figure PCTCN2021103485-appb-000328
Figure PCTCN2021103485-appb-000328
Figure PCTCN2021103485-appb-000329
Figure PCTCN2021103485-appb-000329
室温下，将6-氯-N-(5-甲基-1H-吡唑-3-基)-1-四氢吡喃-2-基-吡唑[3,4-d]嘧啶-4-胺(5c)(100mg,0.30mmol)和N-甲基吡咯烷酮(10mL)加入微波管中，再依次加入4-氨基-1-羟基金刚烷(154mg,0.75mmol)和三乙胺(364mg，3.60mmol)，然后180℃微波条件下反应1小时。反应结束后，将反应液减压浓缩，粗品经Pre-HPLC纯化(仪器及制备柱：采用WATERS 2767制备液相，制备柱型号是Xselect C18，5μm，内径*长度＝19mm*150mm)。制备方法：粗品用二甲亚砜溶解，并用0.45μm滤膜过滤，制备成样品液。流动相体系：乙腈/水(含0.1％TFA)。梯度洗脱方法：乙腈由5％梯度洗脱50％(洗脱时间15min)，冻干后得到白色固体Cis-[[4-[(5-甲基-1H-吡唑-3-基)氨基]-1H-吡唑啉[3,4-d]嘧啶-6-基]氨基]金刚-1-醇；2,2,2-三氟乙酸盐(化合物8)(20mg,14％)At room temperature, 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) and N-methylpyrrolidone (10 mL) were added to a microwave tube, followed by 4-amino-1-hydroxyadamantane (154 mg, 0.75 mmol) and triethylamine (364 mg, 3.60 mmol), and then reacted under microwave conditions at 180 °C for 1 hour. After the reaction, the reaction solution was concentrated under reduced pressure, and the crude product was purified by Pre-HPLC (instrument and preparative column: WATERS 2767 was used to prepare the liquid phase, and the preparative column model was Xselect C18, 5 μm, inner diameter*length=19mm*150mm). Preparation method: the crude product is dissolved in dimethyl sulfoxide, and filtered with a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: acetonitrile/water (with 0.1% TFA). Gradient elution method: acetonitrile was eluted from 5% to 50% (elution time 15min), and after lyophilization, white solid Cis-[[4-[(5-methyl-1H-pyrazol-3-yl)amino was obtained ]-1H-Pyrazolin[3,4-d]pyrimidin-6-yl]amino]adamant-1-ol; 2,2,2-trifluoroacetate (Compound 8) (20 mg, 14%)
LCMS m/z＝381.1[M+1] +。 LCMS m/z=381.1[M+1] + .
1H NMR(400MHz,CD 3OD)δ8.38(s,1H),6.75-6.15(m,1H),4.25-3.90(m,1H),2.42-2.37(m,2H),2.35(s,3H),2.22-2.14(m,1H),2.00-1.90(m,2H),1.86-1.80(m,4H),1.80-1.76(m,2H),1.71-1.62(m,2H)。 1 H NMR (400MHz, CD 3 OD) δ8.38(s, 1H), 6.75-6.15(m, 1H), 4.25-3.90(m, 1H), 2.42-2.37(m, 2H), 2.35(s, 3H), 2.22-2.14(m, 1H), 2.00-1.90(m, 2H), 1.86-1.80(m, 4H), 1.80-1.76(m, 2H), 1.71-1.62(m, 2H).
实施例9：cis-4-[[[4-[(5-甲基-1H-吡唑-3-基)氨基]噻吩并[3，2-d]嘧啶-2-基]氨基]金刚烷-1-醇的三氟乙酸盐(化合物9)Example 9: cis-4-[[[4-[(5-methyl-1H-pyrazol-3-yl)amino]thieno[3,2-d]pyrimidin-2-yl]amino]adamantane -1-ol trifluoroacetate salt (compound 9)
Cis-4-[[4-[(5-methyl-1H-pyrazol-3-yl)amino]thieno[3,2-d]pyrimidin-2-yl]amino]adamantan-1-ol，trifluoroacetateCis-4-[[4-[(5-methyl-1H-pyrazol-3-yl)amino]thieno[3,2-d]pyrimidin-2-yl]amino]adamantan-1-ol, trifluoroacetate
Figure PCTCN2021103485-appb-000330
Figure PCTCN2021103485-appb-000330
Figure PCTCN2021103485-appb-000331
Figure PCTCN2021103485-appb-000331
室温下，将N,N-二异丙基乙胺(0.75mmol，6.93mg)加入到2-氯-N-(5-甲基-1H-吡唑-3-基)噻吩并[3，2-d]嘧啶-4-胺(6b)(0.19mmol，50.00mg)，4-氨基金刚烷-1-醇(0.28mmol，46.82mg)的正丁醇(2.00mL)溶液中，然后在130℃下反应24小时。反应完毕后，通过旋转蒸发仪浓缩干反应液，粗品经Pre-HPLC纯化(仪器及制备柱：采用WATERS 2767制备液相，制备柱型号是Xselect C18，5μm，内径*长度＝19mm*150mm)。制备方法：粗品用二甲亚枫溶解，并用0.45μm滤膜过滤，制备成样品液。流动相体系：乙腈/水(含0.1％TFA)。梯度洗脱方法：乙腈由5％梯度洗脱50％(洗脱时间15min)，冻干后得到反式-4-[[[4-[(5-甲基-1H-吡唑-3-基)氨基]噻吩并[3，2-d]嘧啶-2-基]氨基]金刚烷-1-醇的三氟乙酸盐(化合物6)(15mg，16％)。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. After the completion of the reaction, the dry reaction solution was concentrated by a rotary evaporator, and the crude product was purified by Pre-HPLC (instrument and preparative column: WATERS 2767 was used to prepare the liquid phase, and the preparative column model was Xselect C18, 5 μm, inner diameter*length=19mm*150mm). Preparation method: the crude product is dissolved with dimethyl sulfoxide, and filtered with a 0.45 μm filter membrane to prepare a sample liquid. Mobile phase system: acetonitrile/water (with 0.1% TFA). Gradient elution method: acetonitrile was eluted from 5% gradient to 50% (elution time 15min), and after lyophilization, trans-4-[[[4-[(5-methyl-1H-pyrazol-3-yl was obtained ) amino]thieno[3,2-d]pyrimidin-2-yl]amino]adamantan-1-ol trifluoroacetate salt (Compound 6) (15 mg, 16%).
LCMS m/z＝397.2[M+1] + LCMS m/z=397.2[M+1] +
cis-4-[[[4-[(5-甲基-1H-吡唑-3-基)氨基]噻吩并[3，2-d]嘧啶-2-基]氨基]金刚烷-1-醇的三氟乙酸盐(化合物9)(10mg，10％)cis-4-[[[4-[(5-Methyl-1H-pyrazol-3-yl)amino]thieno[3,2-d]pyrimidin-2-yl]amino]adamantan-1-ol Trifluoroacetate (Compound 9) (10 mg, 10%)
LCMS m/z＝397.2[M+1]LCMS m/z=397.2[M+1]
1H NMR(400MHz,CD 3OD)δ8.25-8.09(m,1H),7.35-7.15(m,1H),6.47(s,1H),4.14-3.95(m,1H),2.43-2.30(m,5H),2.20-2.12(m,1H),2.00-1.90(m,,2H),1.86-1.75(m,,6H),1.70-1.60(m,,2H). 1H NMR (400MHz, CD 3 OD) δ8.25-8.09(m, 1H), 7.35-7.15(m, 1H), 6.47(s, 1H), 4.14-3.95(m, 1H), 2.43-2.30(m ,5H),2.20-2.12(m,1H),2.00-1.90(m,,2H),1.86-1.75(m,,6H),1.70-1.60(m,,2H).
实施例10:cis-4-[[4-[(5-甲基-1H-吡唑-3-基)氨基]噻吩并[2,3-d]嘧啶-2-基]氨基]金刚烷-1-醇；2,2,2-三氟乙酸盐(化合物10)Example 10: cis-4-[[4-[(5-methyl-1H-pyrazol-3-yl)amino]thieno[2,3-d]pyrimidin-2-yl]amino]adamantane- 1-Alcohol; 2,2,2-Trifluoroacetate (Compound 10)
cis-4-[[4-[(5-methyl-1H-pyrazol-3-yl)amino]thieno[2,3-d]pyrimidin-2-yl]amino]adamantan-1-ol；2,2,2-trifluoroacetic acidcis-4-[[4-[(5-methyl-1H-pyrazol-3-yl)amino]thieno[2,3-d]pyrimidin-2-yl]amino]adamantan-1-ol;2,2, 2-trifluoroacetic acid
Figure PCTCN2021103485-appb-000332
Figure PCTCN2021103485-appb-000332
Figure PCTCN2021103485-appb-000333
Figure PCTCN2021103485-appb-000333
将2-氯-N-(5-甲基-1H-吡唑-3-基)噻吩并[2,3-d]嘧啶-4-胺(7b)(100mg,0.38mmol)溶于NMP(1mL)中，加入Et 3N(115.14mg，1.14mmol)和4-氨基金刚烷-1-醇(63.56mg,0.38mmol)，混合物在180℃微波反应1h，然后降至室温。混合物经Pre-HPLC纯化(仪器及制备柱：采用Gilson Gx-281制备液相，制备柱型号是Sunfire，5μm，内径*长度＝30mm*150mm)。制备方法：粗品用甲醇溶解，并用0.45μm滤膜过滤，制备成样品液。流动相体系：乙腈/水(含0.5％的三氟乙酸)。梯度洗脱方法：乙腈由10％梯度洗脱60％(洗脱时间16min)，冻干后得到cis-4-[[4-[(5-甲基-1H-吡唑-3-基)氨基]噻吩并[2,3-d]嘧啶-2-基]氨基]金刚烷-1-醇；2,2,2-三氟乙酸盐(化合物10)(20mg,10％)。 2-Chloro-N-(5-methyl-1H-pyrazol-3-yl)thieno[2,3-d]pyrimidin-4-amine (7b) (100 mg, 0.38 mmol) was dissolved in NMP (1 mL) ), Et 3 N (115.14 mg, 1.14 mmol) and 4-aminoadamantan-1-ol (63.56 mg, 0.38 mmol) were added, and the mixture was microwaved at 180° C. for 1 h, and then cooled to room temperature. The mixture was purified by Pre-HPLC (instrument and preparative column: Gilson Gx-281 preparative liquid phase was used, the preparative column type was Sunfire, 5 μm, inner diameter*length=30mm*150mm). Preparation method: the crude product is dissolved in methanol, and filtered with a 0.45 μm 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%).
LCMS m/z＝397.1[M+1] +。 LCMS m/z=397.1[M+1] + .
1H NMR(400MHz,CD 3OD)δ7.61-7.55(m,1H),7.32(d,1H),6.31(s,1H),4.15-4.07(m,1H),2.38(s,3H),2.33-2.26(m,2H),2.20–2.13(m,1H),2.00–1.89(m,4H),1.87–1.78(m,4H),1.63–1.50(m,2H). 1 H NMR (400MHz, CD 3 OD) δ 7.61-7.55(m, 1H), 7.32(d, 1H), 6.31(s, 1H), 4.15-4.07(m, 1H), 2.38(s, 3H) ,2.33-2.26(m,2H),2.20-2.13(m,1H),2.00-1.89(m,4H),1.87-1.78(m,4H),1.63-1.50(m,2H).
实施例11：4-[[7-[(5-甲基-1H-吡唑-3-基)氨基]噻唑[5,4-d]嘧啶-5-基]氨基]金刚烷-1-醇；2,2,2-三氟乙酸盐-P1(化合物11-1)Example 11: 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)
4-[[7-[(5-methyl-1H-pyrazol-3-yl)amino]thiazolo[5,4-d]pyrimidin-5-yl]amino]adamantan-1-ol；2,2,2-trifluoroacetic acid4-[[7-[(5-methyl-1H-pyrazol-3-yl)amino]thiazolo[5,4-d]pyrimidin-5-yl]amino]adamantan-1-ol; 2,2,2- trifluoroacetic acid
4-[[7-[(5-甲基-1H-吡唑-3-基)氨基]噻唑[5,4-d]嘧啶-5-基]氨基]金刚烷-1-醇；2,2,2-三氟乙酸盐-P2(化合物11-2)4-[[7-[(5-Methyl-1H-pyrazol-3-yl)amino]thiazol[5,4-d]pyrimidin-5-yl]amino]adamantan-1-ol; 2,2 ,2-Trifluoroacetate-P2 (Compound 11-2)
4-[[7-[(5-methyl-1H-pyrazol-3-yl)amino]thiazolo[5,4-d]pyrimidin-5-yl]amino]adamantan-1-ol；2,2,2-trifluoroacetic acid4-[[7-[(5-methyl-1H-pyrazol-3-yl)amino]thiazolo[5,4-d]pyrimidin-5-yl]amino]adamantan-1-ol; 2,2,2- trifluoroacetic acid
Figure PCTCN2021103485-appb-000334
Figure PCTCN2021103485-appb-000334
第一步：5-氯-N-(5-甲基-1H-吡唑-3-基)噻唑[5,4-d]嘧啶-7-胺(11b)The first step: 5-chloro-N-(5-methyl-1H-pyrazol-3-yl)thiazo[5,4-d]pyrimidin-7-amine (11b)
5-chloro-N-(5-methyl-1H-pyrazol-3-yl)thiazolo[5,4-d]pyrimidin-7-amine5-chloro-N-(5-methyl-1H-pyrazol-3-yl)thiazolo[5,4-d]pyrimidin-7-amine
Figure PCTCN2021103485-appb-000335
Figure PCTCN2021103485-appb-000335
室温下，将5,7-二氯噻唑[5,4-d]嘧啶(11a)(400mg，1.94mmol)溶于二甲亚砜(15mL)后，在氮气保护下，向其中依次加入3-氨基-5-甲基吡唑(291mg，3.00mmol)和N,N-二异丙基乙胺(1.0g，7.75mmol)，然后80℃加热搅拌16小时。反应结束后，将反应温度回到室温，加入水(20mL)，有固体析出，过滤。将滤饼用乙酸乙酯冲洗，石油醚再次冲洗后得到黄色固体5-氯-N-(5-甲基-1H-吡唑-3-基)噻唑[5,4-d]嘧啶-7-胺(11b)(300mg，58％)At room temperature, 5,7-dichlorothiazol[5,4-d]pyrimidine (11a) (400 mg, 1.94 mmol) was dissolved in dimethyl sulfoxide (15 mL), and 3- Amino-5-methylpyrazole (291 mg, 3.00 mmol) and N,N-diisopropylethylamine (1.0 g, 7.75 mmol) were then heated and stirred at 80° C. for 16 hours. After the reaction was completed, the reaction temperature was returned to room temperature, water (20 mL) was added, and a solid was precipitated, which was filtered. The filter cake was washed with ethyl acetate, and then washed with petroleum ether to obtain 5-chloro-N-(5-methyl-1H-pyrazol-3-yl)thiazo[5,4-d]pyrimidine-7- as a yellow solid. Amine (11b) (300 mg, 58%)
LCMS m/z＝267.0[M+1] +。 LCMS m/z=267.0[M+1] + .
第二步：4-[[7-[(5-甲基-1H-吡唑-3-基)氨基]噻唑[5,4-d]嘧啶-5-基]氨基]金刚烷-1-醇；2,2,2-三氟乙酸盐-P1(化合物11-1)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)
4-[[7-[(5-methyl-1H-pyrazol-3-yl)amino]thiazolo[5,4-d]pyrimidin-5-yl]amino]adamantan-1-ol；2,2,2-trifluoroacetic acid4-[[7-[(5-methyl-1H-pyrazol-3-yl)amino]thiazolo[5,4-d]pyrimidin-5-yl]amino]adamantan-1-ol; 2,2,2- trifluoroacetic acid
4-[[7-[(5-甲基-1H-吡唑-3-基)氨基]噻唑[5,4-d]嘧啶-5-基]氨基]金刚烷-1-醇；2,2,2-三氟乙酸盐-P1(化合物11-2)4-[[7-[(5-Methyl-1H-pyrazol-3-yl)amino]thiazol[5,4-d]pyrimidin-5-yl]amino]adamantan-1-ol; 2,2 ,2-Trifluoroacetate-P1 (Compound 11-2)
4-[[7-[(5-methyl-1H-pyrazol-3-yl)amino]thiazolo[5,4-d]pyrimidin-5-yl]amino]adamantan-1-ol；2,2,2-trifluoroacetic acid4-[[7-[(5-methyl-1H-pyrazol-3-yl)amino]thiazolo[5,4-d]pyrimidin-5-yl]amino]adamantan-1-ol; 2,2,2- trifluoroacetic acid
Figure PCTCN2021103485-appb-000336
Figure PCTCN2021103485-appb-000336
室温下，5-氯-N-(5-甲基-1H-吡唑-3-基)噻唑[5,4-d]嘧啶-7-胺(11b)(50mg,0.19mmol)和正丁醇(5mL)加入微波管中，再依次加入4-氨基-1-羟基金刚烷(58mg，0.28mmol)和N,N-二异丙基乙胺(148mg，1.14mmol)，然后100℃微波条件下搅拌14小时。反应结束后，将反应液减压浓缩，粗品经Pre-HPLC纯化(仪器及制备柱：采用WATERS 2767制备液相，制备柱型号是Xselect C18，5μm，内径*长度＝19mm*150mm)。制备方法：粗品用二甲亚砜溶解，并用0.45μm滤膜过滤，制备成样品液。流动相体系：乙腈/水(含0.1％TFA)。梯度洗脱方法：乙腈由5％梯度洗脱50％(洗脱时间15min)，冻干后得到白色固体4-[[7-[(5-甲基-1H-吡唑-3-基)氨基]噻唑[5,4-d]嘧啶-5-基]氨基]金刚烷-1-醇；2,2,2-三氟乙酸盐-P1(化合物11-1)(15mg，29％)和白色固体4-[[7-[(5-甲基-1H-吡唑-3-基)氨基]噻唑[5,4-d]嘧啶-5-基]氨基]金刚烷-1-醇；2,2,2-三氟乙酸盐-P2(化合物11-2)(10mg，19％)At room temperature, 5-chloro-N-(5-methyl-1H-pyrazol-3-yl)thiazol[5,4-d]pyrimidin-7-amine (11b) (50 mg, 0.19 mmol) and n-butanol ( 5mL) was added to a microwave tube, followed by 4-amino-1-hydroxyadamantane (58mg, 0.28mmol) and N,N-diisopropylethylamine (148mg, 1.14mmol), and then stirred at 100°C under microwave conditions 14 hours. After the reaction, the reaction solution was concentrated under reduced pressure, and the crude product was purified by Pre-HPLC (instrument and preparative column: WATERS 2767 was used to prepare the liquid phase, and the preparative column model was Xselect C18, 5 μm, inner diameter*length=19mm*150mm). Preparation method: the crude product is dissolved in dimethyl sulfoxide, and filtered with a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: acetonitrile/water (with 0.1% TFA). Gradient elution method: acetonitrile was eluted from 5% gradient to 50% (elution time 15min), and lyophilized to obtain white solid 4-[[7-[(5-methyl-1H-pyrazol-3-yl)amino ]thiazol[5,4-d]pyrimidin-5-yl]amino]adamantan-1-ol; 2,2,2-trifluoroacetate-P1 (Compound 11-1) (15 mg, 29%) and 4-[[7-[(5-Methyl-1H-pyrazol-3-yl)amino]thiazo[5,4-d]pyrimidin-5-yl]amino]adamantan-1-ol; 2 ,2,2-Trifluoroacetate-P2 (Compound 11-2) (10 mg, 19%)
LCMS m/z＝398.2[M+1] +。 LCMS m/z=398.2[M+1] + .
1H NMR(400MHz,CD 3OD)δ8.77(s,1H),6.30(s,1H),4.14-4.08(m,1H),2.38(s,3H),2.34-2.23(m,2H),2.19-2.13(m,1H),2.05-1.97(m,2H),1.97-1.90(m,2H),1.88-1.76(m,4H),1.60-1.52(m,2H).(化合物11-1)；绝对构型没有确定，其结构为上面式11-a和11-b之一； 1 H NMR (400MHz, CD 3 OD) δ 8.77(s, 1H), 6.30(s, 1H), 4.14-4.08(m, 1H), 2.38(s, 3H), 2.34-2.23(m, 2H) ,2.19-2.13(m,1H),2.05-1.97(m,2H),1.97-1.90(m,2H),1.88-1.76(m,4H),1.60-1.52(m,2H).(Compound 11- 1); the absolute configuration is not determined, and its structure is one of the above formulas 11-a and 11-b;
LCMS m/z＝398.3[M+1] +。 LCMS m/z=398.3[M+1] + .
1H NMR(400MHz,CD 3OD)δ8.77(s,1H),6.31(s,1H),4.04-3.99(m,1H),2.41-2.32(m,5H),2.21-2.13(m,1H),2.05-1.96(m,2H),188-1.80(m,4H),1.79-1.74(m,2H),1.67-1.58(m,2H).(化合物11-2)。绝对构型没有确定，其结构为上面式11-a和11-b之一；且与化合物11-a为异构体，即，当化合物11-1结构为式11-a的结构时，化合物11-2结构为式11-b的结构；当化合物11-1结构为式11-b的结构时，化合物11-2结构为式11-a的结构。 1 H NMR (400MHz, CD 3 OD) δ8.77(s, 1H), 6.31(s, 1H), 4.04-3.99(m, 1H), 2.41-2.32(m, 5H), 2.21-2.13(m, 1H), 2.05-1.96 (m, 2H), 188-1.80 (m, 4H), 1.79-1.74 (m, 2H), 1.67-1.58 (m, 2H). (Compound 11-2). 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.
实施例12:3-[[[7-[(5-甲基-1H-吡唑-3-基)氨基]-1,6-萘啶-5-基]氨基]金刚烷-1-醇；2,2,2-三氟乙酸盐(化合物12)Example 12: 3-[[[7-[(5-Methyl-1H-pyrazol-3-yl)amino]-1,6-naphthyridin-5-yl]amino]adamantan-1-ol; 2,2,2-Trifluoroacetate (Compound 12)
3-[[7-[(5-methyl-1H-pyrazol-3-yl)amino]-1,6-naphthyridin-5-yl]amino]adamantan-1-ol；2,2,2-trifluoroacetic acid3-[[7-[(5-methyl-1H-pyrazol-3-yl)amino]-1,6-naphthyridin-5-yl]amino]adamantan-1-ol; 2,2,2-trifluoroacetic acid
Figure PCTCN2021103485-appb-000337
Figure PCTCN2021103485-appb-000337
化合物12以5,7-二氯-1,6-萘啶(1a)和3-氨基-1-羟基金刚烷盐酸盐为起始物料参考实施例1的合成方法，得到3-[[[7-[(5-甲基-1H-吡唑-3-基)氨基]-1,6-萘啶-5-基]氨基]金刚烷-1-醇；2,2,2-三氟乙酸盐(化合物12)。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).
LCMS m/z＝391.2[M+1] +。 LCMS m/z=391.2[M+1] + .
1H NMR(400MHz,CD 3OD)δ8.63(d,1H),8.46(dd,1H),7.13-7.08(m,1H),6.70-6.66(m,1H),6.01(s,1H),2.33-2.15(m,12H),1.84-1.77(m,2H),1.74-1.67(m,3H)。 1 H NMR (400MHz, CD 3 OD) δ 8.63 (d, 1H), 8.46 (dd, 1H), 7.13-7.08 (m, 1H), 6.70-6.66 (m, 1H), 6.01 (s, 1H) , 2.33-2.15 (m, 12H), 1.84-1.77 (m, 2H), 1.74-1.67 (m, 3H).
实施例13:trans-2-[4-[[7-[(5-甲基-1H-吡唑-3-基)氨基]-1,6-萘啶-5-基]氨基]环己基]乙腈(化合物13’)Example 13: trans-2-[4-[[7-[(5-methyl-1H-pyrazol-3-yl)amino]-1,6-naphthyridin-5-yl]amino]cyclohexyl] Acetonitrile (Compound 13')
Trans-2-[4-[[7-[(5-methyl-1H-pyrazol-3-yl)amino]-1,6-naphthyridin-5-yl]amino]cyclohexyl]acetonitrileTrans-2-[4-[[7-[(5-methyl-1H-pyrazol-3-yl)amino]-1,6-naphthyridin-5-yl]amino]cyclohexyl]acetonitrile
Figure PCTCN2021103485-appb-000338
Figure PCTCN2021103485-appb-000338
第一步：trans-2-[4-[(7-氯-1,6-萘啶-5-基)氨基]环己基]乙腈(13b)The first step: trans-2-[4-[(7-chloro-1,6-naphthyridin-5-yl)amino]cyclohexyl]acetonitrile (13b)
Trans-2-[4-[(7-chloro-1,6-naphthyridin-5-yl)amino]cyclohexyl]acetonitrileTrans-2-[4-[(7-chloro-1,6-naphthyridin-5-yl)amino]cyclohexyl]acetonitrile
Figure PCTCN2021103485-appb-000339
Figure PCTCN2021103485-appb-000339
将5,7-二氯-1,6-萘啶(1a)(250mg,1.26mmol)，trans-2-(4-氨基环己基)乙腈；盐酸盐(214mg,1.38mmol)(以trans-4-(叔丁氧羰氨基)环己甲酸为起始物料,按照专利WO2019/239387合成方法制备得到)，N,N-二异丙基乙胺(649mg,5.02mmol)加入到N,N-二甲基甲酰胺(4mL)中，升温至100℃反应16h，然后降至室温。将反应液倒入到水(40mL)中，乙酸乙酯(30mL*2)萃取，合并有机相，饱和食盐水(30mL*2)反洗，无水硫酸钠干燥，抽滤，滤液减压旋干得残留物，残留物用硅胶柱柱色谱分离纯化(乙酸乙酯：石油醚(v/v)＝0:1～1:0)得淡黄色固体产物trans-2-[4-[(7-氯-1,6-萘啶-5-基)氨基]环己基]乙腈(13b)(340mg，90％)。5,7-Dichloro-1,6-naphthyridine (1a) (250 mg, 1.26 mmol), trans-2-(4-aminocyclohexyl)acetonitrile; hydrochloride (214 mg, 1.38 mmol) (as trans- 4-(tert-butoxycarbonylamino)cyclohexanecarboxylic acid is the starting material, prepared according to the synthetic method of patent WO2019/239387), N,N-diisopropylethylamine (649mg, 5.02mmol) was added to N,N- In dimethylformamide (4 mL), the temperature was raised to 100° C. for 16 h, and then lowered to room temperature. The 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. The residue was dried and purified by silica gel column chromatography (ethyl acetate:petroleum ether (v/v)=0:1～1:0) to obtain trans-2-[4-[(7 -Chloro-1,6-naphthyridin-5-yl)amino]cyclohexyl]acetonitrile (13b) (340 mg, 90%).
LCMS m/z＝301.2[M+1] +。 LCMS m/z=301.2[M+1] + .
第二步：trans-3-[[5-[[4-(氰甲基)环己基]氨基]-1,6-萘啶-7-基]氨基]-5-甲基-吡唑-1-甲酸叔丁基酯(13c)Step 2: trans-3-[[5-[[4-(cyanomethyl)cyclohexyl]amino]-1,6-naphthyridin-7-yl]amino]-5-methyl-pyrazole-1 - tert-butyl formate (13c)
Trans-tert-butyl 3-[[5-[[4-(cyanomethyl)cyclohexyl]amino]-1,6-naphthyridin-7-yl]amino]-5-methyl-pyrazole-1-carboxylateTrans-tert-butyl 3-[[5-[[4-(cyanomethyl)cyclohexyl]amino]-1,6-naphthyridin-7-yl]amino]-5-methyl-pyrazole-1-carboxylate
Figure PCTCN2021103485-appb-000340
Figure PCTCN2021103485-appb-000340
将trans-2-[4-[(7-氯-1,6-萘啶-5-基)氨基]环己基]乙腈(13b)(100mg,0.33mmol)，3-氨基-5-甲基-吡唑-1-甲酸叔丁酯(1b’)(71mg,0.36mmol)，三(二亚苄基丙酮)二钯(15mg,0.02mmol)，2-(二环己基膦)-3,6-二甲氧基-2',4',6'-三异丙基-1,1'-联苯(18mg,0.03mmol)，碳酸铯(140mg,0.43mmol)加入到1，4-二氧六环(3mL)中，氮气置换，升温至100℃反应24h。降至室温，垫硅藻土过滤，再用乙酸乙酯(2mL*2)淋洗，然后将滤液 减压旋干，得粗品trans-3-[[5-[[4-(氰甲基)环己基]氨基]-1,6-萘啶-7-基]氨基]-5-甲基-吡唑-1-甲酸叔丁基酯(13c)(150mg,98％),直接用于下一步。Trans-2-[4-[(7-Chloro-1,6-naphthyridin-5-yl)amino]cyclohexyl]acetonitrile (13b) (100 mg, 0.33 mmol), 3-amino-5-methyl- Pyrazole-1-carboxylate tert-butyl ester (1b') (71 mg, 0.36 mmol), tris(dibenzylideneacetone)dipalladium (15 mg, 0.02 mmol), 2-(dicyclohexylphosphine)-3,6- Dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl (18 mg, 0.03 mmol), cesium carbonate (140 mg, 0.43 mmol) was added to 1,4-dioxane In the ring (3 mL), nitrogen was replaced, and the temperature was raised to 100 °C for 24 h. Cooled to room temperature, filtered through celite, rinsed with ethyl acetate (2mL*2), and then spin-dried the filtrate under reduced pressure to obtain the crude product trans-3-[[5-[[[4-(cyanomethyl) Cyclohexyl]amino]-1,6-naphthyridin-7-yl]amino]-5-methyl-pyrazole-1-carboxylic acid tert-butyl ester (13c) (150 mg, 98%), used directly in the next step .
LCMS m/z＝462.2[M+1] +。 LCMS m/z=462.2[M+1] + .
第三步：trans-2-[4-[[7-[(5-甲基-1H-吡唑-3-基)氨基]-1,6-萘啶-5-基]氨基]环己基]乙腈；2,2,2-三氟乙酸盐(化合物13)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-trifluoroacetic acidTrans-2-[4-[[7-[(5-methyl-1H-pyrazol-3-yl)amino]-1,6-naphthyridin-5-yl]amino]cyclohexyl]acetonitrile; 2,2,2- trifluoroacetic acid
Figure PCTCN2021103485-appb-000341
Figure PCTCN2021103485-appb-000341
将trans-3-[[5-[[4-(氰甲基)环己基]氨基]-1,6-萘啶-7-基]氨基]-5-甲基-吡唑-1-甲酸叔丁基酯(13c)(150mg,0.33mmol)溶于二氯甲烷(6mL)中，然后加入三氟乙酸(3mL)，20℃反应1h后，减压旋干得残留物，残留物经Pre-HPLC纯化(仪器及制备柱：采用Gilson Gx-281制备液相，制备柱型号是Sunfire，5μm，内径*长度＝30mm*150mm)。制备方法：粗品用甲醇溶解，并用0.45μm滤膜过滤，制备成样品液。流动相体系：乙腈/水(含0.5％的三氟乙酸)。梯度洗脱方法：乙腈由10％梯度洗脱60％(洗脱时间16min)，冻干后得到trans-2-[4-[[7-[(5-甲基-1H-吡唑-3-基)氨基]-1,6-萘啶-5-基]氨基]环己基]乙腈；2,2,2-三氟乙酸盐(化合物13)(107mg,69％)。Trans-3-[[5-[[4-(cyanomethyl)cyclohexyl]amino]-1,6-naphthyridin-7-yl]amino]-5-methyl-pyrazole-1-carboxylic acid tertiary Butyl ester (13c) (150 mg, 0.33 mmol) was dissolved in dichloromethane (6 mL), then trifluoroacetic acid (3 mL) was added, reacted at 20° C. for 1 h, and then spin-dried under reduced pressure to obtain a residue. HPLC purification (instrument and preparative column: Gilson Gx-281 was used to prepare the liquid phase, the preparative column model was Sunfire, 5 μm, inner diameter*length=30mm*150mm). Preparation method: the crude product is dissolved in methanol, and filtered with a 0.45 μm 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% to 60% (elution time 16min), and after lyophilization, trans-2-[4-[[7-[(5-methyl-1H-pyrazole-3- yl)amino]-1,6-naphthyridin-5-yl]amino]cyclohexyl]acetonitrile; 2,2,2-trifluoroacetate (Compound 13) (107 mg, 69%).
LCMS m/z＝362.2[M+1] +。 LCMS m/z=362.2[M+1] + .
1H NMR(400MHz,CD 3OD)δ8.86(dd,1H),8.42(dd,1H),7.18(dd,1H),6.65(s,1H),6.15(s,1H),4.24-4.14(m,1H),2.48(d,2H),2.32(s,3H),2.26-2.18(m,2H),2.02-1.94(m,2H),1.86–1.70(m,1H),1.60–1.30(m,4H). 1 H NMR (400MHz, CD 3 OD) δ 8.86(dd, 1H), 8.42(dd, 1H), 7.18(dd, 1H), 6.65(s, 1H), 6.15(s, 1H), 4.24-4.14 (m, 1H), 2.48 (d, 2H), 2.32 (s, 3H), 2.26-2.18 (m, 2H), 2.02-1.94 (m, 2H), 1.86–1.70 (m, 1H), 1.60–1.30 (m,4H).
第四步：trans-2-[4-[[7-[(5-甲基-1H-吡唑-3-基)氨基]-1,6-萘啶-5-基]氨基]环己基]乙腈(化合物13’)The fourth step: trans-2-[4-[[7-[(5-methyl-1H-pyrazol-3-yl)amino]-1,6-naphthyridin-5-yl]amino]cyclohexyl] Acetonitrile (Compound 13')
Trans-2-[4-[[7-[(5-methyl-1H-pyrazol-3-yl)amino]-1,6-naphthyridin-5-yl]amino]cyclohexyl]acetonitrileTrans-2-[4-[[7-[(5-methyl-1H-pyrazol-3-yl)amino]-1,6-naphthyridin-5-yl]amino]cyclohexyl]acetonitrile
Figure PCTCN2021103485-appb-000342
Figure PCTCN2021103485-appb-000342
将trans-2-[4-[[7-[(5-甲基-1H-吡唑-3-基)氨基]-1,6-萘啶-5-基]氨基]环己基]乙腈；2,2,2-三氟乙酸盐(化合物13)(93mg,0.20mmol)溶于纯化水(6mL)中，滴加饱和碳酸氢钠溶液至pH＝7～8，过滤，滤饼用纯化水(2mL*3)淋洗，然后滤饼加水冻干得trans-2-[4-[[7-[(5-甲基-1H-吡唑-3-基)氨基]-1,6-萘啶-5-基]氨基]环己基]乙腈(化合物13’)(68mg,96％)。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%).
LCMS m/z＝362.2[M+1] +。 LCMS m/z=362.2[M+1] + .
1H NMR(400MHz,CD 3OD)δ8.83(dd,1H),8.41(dd,1H),7.16(dd,1H),6.64(s,1H),6.13(s,1H),4.24-4.14(m,1H),2.48(d,2H),2.31(s,3H),2.26-2.16(m,2H),2.04-1.94(m,2H),1.84–1.70(m,1H),1.60–1.30(m,4H). 1 H NMR (400MHz, CD 3 OD) δ 8.83 (dd, 1H), 8.41 (dd, 1H), 7.16 (dd, 1H), 6.64 (s, 1H), 6.13 (s, 1H), 4.24-4.14 (m, 1H), 2.48 (d, 2H), 2.31 (s, 3H), 2.26-2.16 (m, 2H), 2.04-1.94 (m, 2H), 1.84–1.70 (m, 1H), 1.60–1.30 (m,4H).
实施例14:trans-4-[[7-[(5-甲基-1H-咪唑-3-基)氨基]-1,6-萘啶-5-基]氨基]环己醇；2,2,2-三氟乙酸(化合物14)Example 14: trans-4-[[7-[(5-methyl-1H-imidazol-3-yl)amino]-1,6-naphthyridin-5-yl]amino]cyclohexanol; 2,2 ,2-Trifluoroacetic acid (Compound 14)
Trans-4-[[7-[(5-methyl-1H-pyrazol-3-yl)amino]-1,6-naphthyridin-5-yl]amino]cyclohexanol；2,2,2-trifluoroacetic acidTrans-4-[[7-[(5-methyl-1H-pyrazol-3-yl)amino]-1,6-naphthyridin-5-yl]amino]cyclohexanol; 2,2,2-trifluoroacetic acid
Figure PCTCN2021103485-appb-000343
Figure PCTCN2021103485-appb-000343
化合物14以5,7-二氯-1,6-萘啶(1a)和trans-4-氨基环己醇为起始物料，参考实施例1的合成方法，得到反式-4-[[7-[(5-甲基-1H-咪唑-3-基)氨基]-1,6-萘啶-5-基]氨基]环己醇；2,2,2-三氟乙酸盐(化合物14)。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 ).
LCMS m/z＝339.1[M+1] +。 LCMS m/z=339.1[M+1] + .
1H NMR(400MHz,CD 3OD)δ8.86(dd,1H),8.43(dd,1H),7.19(dd,1H),6.63(s,1H),6.16(s,1H),4.24–4.10(m,1H),3.72-3.56m,1H),2.33(s,3H),2.20-2.12(m,2H),2.10-2.00(m,2H),1.59–1.37(m,4H). 1 H NMR (400MHz, CD 3 OD) δ 8.86(dd,1H), 8.43(dd,1H), 7.19(dd,1H), 6.63(s,1H), 6.16(s,1H), 4.24–4.10 (m,1H),3.72-3.56m,1H),2.33(s,3H),2.20-2.12(m,2H),2.10-2.00(m,2H),1.59-1.37(m,4H).
实施例15:3-[[7-[(5-甲基-1H-咪唑-3-基)氨基]-1,6-萘啶-5-基]氨基]环戊醇；2,2,2-三氟乙酸盐(化合物15)Example 15: 3-[[7-[(5-Methyl-1H-imidazol-3-yl)amino]-1,6-naphthyridin-5-yl]amino]cyclopentanol; 2,2,2 - Trifluoroacetate (compound 15)
3-[[7-[(5-methyl-1H-pyrazol-3-yl)amino]-1,6-naphthyridin-5-yl]amino]cyclopentanol；2,2,2-trifluoroacetic acid3-[[7-[(5-methyl-1H-pyrazol-3-yl)amino]-1,6-naphthyridin-5-yl]amino]cyclopentanol; 2,2,2-trifluoroacetic acid
Figure PCTCN2021103485-appb-000344
Figure PCTCN2021103485-appb-000344
化合物15以5,7-二氯-1,6-萘啶(1a)和3-氨基环戊醇盐酸盐为起始物料，参考实施例1的合成方法，得到3-[[7-[(5-甲基-1H-咪唑-3-基)氨基]-1,6-萘啶-5-基]氨基]环戊醇；2,2,2-三氟乙酸盐(化合物15)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)
LCMS m/z＝325.1[M+1] +。 LCMS m/z=325.1[M+1] + .
1H NMR(400MHz,CD 3OD)δ8.83(dd,1H),8.44(dd,1H),7.20(dd,1H),6.73(s,1H),6.06(s,1H),4.68-4.58(m,1H),4.40–4.32(m,1H),2.50-2.40(m,1H),2.30(s,3H),2.26–2.14(m,1H),1.98–1.76(m,3H),1.75-1.65(m,1H). 1 H NMR (400MHz, CD 3 OD) δ 8.83 (dd, 1H), 8.44 (dd, 1H), 7.20 (dd, 1H), 6.73 (s, 1H), 6.06 (s, 1H), 4.68-4.58 (m, 1H), 4.40–4.32 (m, 1H), 2.50–2.40 (m, 1H), 2.30 (s, 3H), 2.26–2.14 (m, 1H), 1.98–1.76 (m, 3H), 1.75 -1.65(m,1H).
实施例16：2-[(1S,R)-3-[[7-[(5-甲基-1H-吡唑-3-基)氨基]-1,6-萘啶-5-基]氨基]环戊基]乙腈；2,2,2-三氟乙酸盐(化合物16)Example 16: 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)
2-[(1S,3R)-3-[[7-[(5-methyl-1H-pyrazol-3-yl)amino]-1,6-naphthyridin-5-yl]amino]cyclopentyl]acetonitrile；2,2,2-trifluoroacetic acid2-[(1S,3R)-3-[[7-[(5-methyl-1H-pyrazol-3-yl)amino]-1,6-naphthyridin-5-yl]amino]cyclopentyl]acetonitrile;2, 2,2-trifluoroacetic acid
Figure PCTCN2021103485-appb-000345
Figure PCTCN2021103485-appb-000345
化合物16以5,7-二氯-1,6-萘啶(1a)和N-[(1R,3S)-3-(氰基甲基)环戊基]氨基甲酸叔丁酯(参照WO2019/239387合成方法制备得到)为起始物料，参考实施例13的合成方法，得到2-[(1S,R)-3-[[7-[(5-甲基-1H-吡唑-3-基)氨基]-1,6-萘啶-5-基]氨基]环戊基]乙腈；2,2,2-三氟乙酸盐(化合物16)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)
LCMS m/z＝348.1[M+1] +。 LCMS m/z=348.1[M+1] + .
1H NMR(400MHz,CD 3OD)δ8.89(dd,1H),8.44(dd,1H),7.21(dd,1H)，6.76(s,1H),6.06(s,1H),4.68-4.61(m,1H),2.61-2.51(m,3H),2.40-2.34(m,1H),2.31(s,3H),2.29-2.21(m,1H),2.10-1.95(m,1H),1.90-1.75(m,1H),1.69-1.60(m,1H),1.54-1.41(m,1H). 1 H NMR (400MHz, CD 3 OD) δ 8.89 (dd, 1H), 8.44 (dd, 1H), 7.21 (dd, 1H), 6.76 (s, 1H), 6.06 (s, 1H), 4.68-4.61 (m,1H),2.61-2.51(m,3H),2.40-2.34(m,1H),2.31(s,3H),2.29-2.21(m,1H),2.10-1.95(m,1H),1.90 -1.75(m,1H),1.69-1.60(m,1H),1.54-1.41(m,1H).
实施例17：Trans-[4-[[7-[(5-甲基-1H-吡唑-3-基)氨基]-1,6-萘啶-5-基]氨基]环己基]甲醇(化合物17)Example 17: Trans-[4-[[7-[(5-methyl-1H-pyrazol-3-yl)amino]-1,6-naphthyridin-5-yl]amino]cyclohexyl]methanol ( Compound 17)
Trans-[4-[[7-[(5-methyl-1H-pyrazol-3-yl)amino]-1,6-naphthyridin-5-yl]amino]cyclohexyl]methanolTrans-[4-[[7-[(5-methyl-1H-pyrazol-3-yl)amino]-1,6-naphthyridin-5-yl]amino]cyclohexyl]methanol
Figure PCTCN2021103485-appb-000346
Figure PCTCN2021103485-appb-000346
第一步：Trans-4-[(7-氯-1,6-萘啶-5-基)氨基]环己烷甲酸甲酯(17b)The first step: Trans-methyl 4-[(7-chloro-1,6-naphthyridin-5-yl)amino]cyclohexanecarboxylate (17b)
Trans-methyl 4-[(7-chloro-1,6-naphthyridin-5-yl)amino]cyclohexanecarboxylateTrans-methyl 4-[(7-chloro-1,6-naphthyridin-5-yl)amino]cyclohexanecarboxylate
Figure PCTCN2021103485-appb-000347
Figure PCTCN2021103485-appb-000347
室温下，将5,7-二氯-1,6-萘啶(1a)(300mg，1.51mmol)溶于二甲亚砜(15mL)后，向其中加入trans-4-氨基环己基甲酸甲酯盐酸盐(439mg，2.27mmol)和N,N-二异丙基乙胺(1.17g，9.06mmol)。升温至100℃，反应16h。将反应温度回到室温，加入乙酸乙酯 (20mL)，饱和食盐水(20mL*3)萃取；收集有机层，无水硫酸钠干燥，过滤。残留物用硅胶柱色谱分离提纯((石油醚：乙酸乙酯(v/v)＝10:1-1:1)得到黄色固体Trans-4-[(7-氯-1,6-萘啶-5-基)氨基]环己烷甲酸甲酯(17b)(450mg，93％)。At room temperature, 5,7-dichloro-1,6-naphthyridine (1a) (300 mg, 1.51 mmol) was dissolved in dimethyl sulfoxide (15 mL), to which was added methyl trans-4-aminocyclohexylcarboxylate The hydrochloride salt (439 mg, 2.27 mmol) and N,N-diisopropylethylamine (1.17 g, 9.06 mmol). The temperature was raised to 100°C, and the reaction was carried out for 16h. The reaction temperature was returned to room temperature, ethyl acetate (20 mL) was added, and saturated brine (20 mL*3) was added for extraction; the organic layer was collected, dried over anhydrous sodium sulfate, and filtered. The residue was separated and purified by silica gel column chromatography ((petroleum ether:ethyl acetate (v/v)=10:1-1:1) to obtain a yellow solid Trans-4-[(7-chloro-1,6-naphthyridine- Methyl 5-yl)amino]cyclohexanecarboxylate (17b) (450 mg, 93%).
LCMS m/z＝320.1[M+1] +. LCMS m/z=320.1[M+1] + .
第二步：Trans-叔丁基-3-[[5-[(4-甲氧基羰基环己基)氨基]-1,6-萘啶-7-基]氨基]-5-甲基吡唑-1-羧酸盐(17c)The second step: Trans-tert-butyl-3-[[5-[(4-methoxycarbonylcyclohexyl)amino]-1,6-naphthyridin-7-yl]amino]-5-methylpyrazole -1-Carboxylate (17c)
Trans-tert-butyl-3-[[5-[(4-methoxycarbonylcyclohexyl)amino]-1,6-naphthyridin-7-yl]amino]-5-methyl-pyrazole-1-carboxylateTrans-tert-butyl-3-[[5-[(4-methoxycarbonylcyclohexyl)amino]-1,6-naphthyridin-7-yl]amino]-5-methyl-pyrazole-1-carboxylate
Figure PCTCN2021103485-appb-000348
Figure PCTCN2021103485-appb-000348
室温下，将Trans-4-[(7-氯-1,6-萘啶-5-基)氨基]环己烷甲酸甲酯(17b)(300mg，0.94mmol)、3-氨基-5-甲基-1H-吡唑-1-甲酸叔丁酯(280mg，1.41mmol)、BrettPhos(101mg，0.2mmol)、碳酸铯(814mg，2.5mmol)和无水干燥1,4-二氧六环(15mL)加入玻璃封管中，氢气置换3次后，向反应液中加入Pd 2(dba) 3(86mg，0.1mmol)。升温至100℃，反应16h。将反应液垫硅藻土过滤，滤液减压浓缩至干得到黄色粗品Trans-叔丁基-3-[[5-[(4-甲氧基羰基环己基)氨基]-1,6-萘啶-7-基]氨基]-5-甲基吡唑-1-羧酸盐(17c)(452mg，100％)，未纯化，直接用于下一步。 At room temperature, Trans-methyl 4-[(7-chloro-1,6-naphthyridin-5-yl)amino]cyclohexanecarboxylate (17b) (300 mg, 0.94 mmol), 3-amino-5-methane tert-butyl-1H-pyrazole-1-carboxylate (280 mg, 1.41 mmol), BrettPhos (101 mg, 0.2 mmol), cesium carbonate (814 mg, 2.5 mmol) and dry 1,4-dioxane (15 mL) ) was added to a glass-sealed tube, and after 3 times of hydrogen replacement, Pd 2 (dba) 3 (86 mg, 0.1 mmol) was added to the reaction solution. The temperature was raised to 100°C, and the reaction was carried out for 16h. The reaction solution was filtered through a pad of celite, and the filtrate was concentrated to dryness under reduced pressure to obtain a yellow crude product, Trans-tert-butyl-3-[[5-[(4-methoxycarbonylcyclohexyl)amino]-1,6-naphthyridine -7-yl]amino]-5-methylpyrazole-1-carboxylate (17c) (452 mg, 100%), which was used directly in the next step without purification.
LCMS m/z＝481.3[M+1] +。 LCMS m/z=481.3[M+1] + .
第三步：Trans-甲基-4-[[7-[(5-甲基-1H-吡唑-3-基)氨基]-1,6-萘啶-5-基]氨基]环己烷羧酸盐(17d)The third step: Trans-methyl-4-[[7-[(5-methyl-1H-pyrazol-3-yl)amino]-1,6-naphthyridin-5-yl]amino]cyclohexane Carboxylate (17d)
Trans-methyl-4-[[7-[(5-methyl-1H-pyrazol-3-yl)amino]-1,6-naphthyridin-5-yl]amino]cyclohexanecarboxylateTrans-methyl-4-[[7-[(5-methyl-1H-pyrazol-3-yl)amino]-1,6-naphthyridin-5-yl]amino]cyclohexanecarboxylate
Figure PCTCN2021103485-appb-000349
Figure PCTCN2021103485-appb-000349
室温下，将Trans-叔丁基-3-[[5-[(4-甲氧基羰基环己基)氨基]-1,6-萘啶-7-基]氨基]-5-甲基吡唑-1-羧酸盐(17c)(452mg，0.94mmol)和二氯甲烷(10mL)加入反应瓶中，降温至0℃，向反应瓶中加入三氟乙酸(5mL)，缓慢升温至室温，反应2h。反应液减压浓缩，粗品经Pre-HPLC纯化(仪器及制备柱：采用WATERS 2767制备液相，制备柱型号是Xselect C18，5μm，内径*长度＝19mm*150mm)。制备方法：粗品用二甲亚砜溶解，并用0.45μm滤膜过滤，制备成样品液。流动相体系：乙腈/水。梯度洗脱方法：乙腈由5％梯度洗脱50％(洗脱时间15min)，冻干后得到黄色固体Trans-甲基-4-[[7-[(5-甲基-1H-吡唑-3-基)氨基]-1,6-萘啶-5-基]氨基]环己烷羧酸盐(17d)(215mg，60％)。Trans-tert-butyl-3-[[5-[(4-methoxycarbonylcyclohexyl)amino]-1,6-naphthyridin-7-yl]amino]-5-methylpyrazole at room temperature -1-carboxylate (17c) (452mg, 0.94mmol) and dichloromethane (10mL) were added to the reaction flask, the temperature was lowered to 0°C, trifluoroacetic acid (5mL) was added to the reaction flask, the temperature was slowly raised to room temperature, and the reaction was carried out. 2h. The reaction solution was concentrated under reduced pressure, and the crude product was purified by Pre-HPLC (instrument and preparative column: WATERS 2767 was used to prepare the liquid phase, and the preparative column model was Xselect C18, 5 μm, inner diameter*length=19mm*150mm). Preparation method: the crude product is dissolved in dimethyl sulfoxide, and filtered with a 0.45 μm 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 15min), and after lyophilization, yellow solid Trans-methyl-4-[[7-[(5-methyl-1H-pyrazole- 3-yl)amino]-1,6-naphthyridin-5-yl]amino]cyclohexanecarboxylate (17d) (215 mg, 60%).
LCMS m/z＝381.2[M+1] +。 LCMS m/z=381.2[M+1] + .
第四步：Trans-[4-[[7-[(5-甲基-1H-吡唑-3-基)氨基]-1,6-萘啶-5-基]氨基]环己基]甲醇(化合物17)The fourth step: Trans-[4-[[7-[(5-methyl-1H-pyrazol-3-yl)amino]-1,6-naphthyridin-5-yl]amino]cyclohexyl]methanol ( Compound 17)
Trans-[4-[[7-[(5-methyl-1H-pyrazol-3-yl)amino]-1,6-naphthyridin-5-yl]amino]cyclohexyl]methanolTrans-[4-[[7-[(5-methyl-1H-pyrazol-3-yl)amino]-1,6-naphthyridin-5-yl]amino]cyclohexyl]methanol
Figure PCTCN2021103485-appb-000350
Figure PCTCN2021103485-appb-000350
室温下，将Trans-甲基-4-[[7-[(5-甲基-1H-吡唑-3-基)氨基]-1,6-萘啶-5-基]氨基]环己烷羧酸盐(17d)(70mg，0.18mmol)溶于无水干燥四氢呋喃(15mL)后，将体系温度降至0℃。在氮气保护下，向反应液中缓慢加入四氢铝锂(68mg，1.8mmol)。回到室温后升温至50℃，反应1h。反应体系回到室温后，饱和氯化铵水溶液猝灭反应，将反应液垫硅藻土过滤，滤液减压浓缩。粗品经Pre-HPLC纯化(仪器及制备柱：采用WATERS 2767制备液相，制备柱型号是Xselect C18，5μm，内径*长度＝19mm*150mm)。制备方法：粗品用二甲亚砜溶解，并用0.45μm滤膜过滤，制备成样品液。流动相体系：乙腈/水。梯度洗脱方法：乙腈由5％梯度洗脱50％(洗脱时间15min)，冻干后得到黄色固体Trans-[4-[[7-[(5-甲基-1H-吡唑-3-基)氨基]-1,6-萘啶-5-基]氨基]环己基]甲醇(化合物17)(10mg，16％)。Trans-methyl-4-[[7-[(5-methyl-1H-pyrazol-3-yl)amino]-1,6-naphthyridin-5-yl]amino]cyclohexane at room temperature The carboxylate (17d) (70 mg, 0.18 mmol) was dissolved in dry tetrahydrofuran (15 mL), and the temperature of the system was lowered to 0°C. Under nitrogen protection, lithium tetrahydroaluminum (68 mg, 1.8 mmol) was slowly added to the reaction solution. After returning to room temperature, the temperature was raised to 50 °C, and the reaction was carried out for 1 h. After the 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. The crude product was purified by Pre-HPLC (instrument and preparative column: using WATERS 2767 preparative liquid phase, preparative column model is Xselect C18, 5 μm, inner diameter*length=19mm*150mm). Preparation method: the crude product is dissolved in dimethyl sulfoxide, and filtered with a 0.45 μm 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 15min), and after lyophilization, yellow solid Trans-[4-[[7-[(5-methyl-1H-pyrazole-3- yl)amino]-1,6-naphthyridin-5-yl]amino]cyclohexyl]methanol (Compound 17) (10 mg, 16%).
LCMS m/z＝353.2[M+1] +。 LCMS m/z=353.2[M+1] + .
1H NMR(400MHz,CD 3OD)δ8.54(dd,1H),8.39(d,1H),7.04(dd,1H),6.50(s,1H),6.07(s,1H),4.20-4.00(m,1H),3.44(d,2H),2.30-2.18(m,5H),1.99-1.89(m,2H),1.60-1.35(m,3H),1.28-1.13(m,2H). 1 H NMR (400MHz, CD 3 OD) δ 8.54(dd, 1H), 8.39(d, 1H), 7.04(dd, 1H), 6.50(s, 1H), 6.07(s, 1H), 4.20-4.00 (m,1H), 3.44(d,2H), 2.30-2.18(m,5H), 1.99-1.89(m,2H), 1.60-1.35(m,3H), 1.28-1.13(m,2H).
实施例：18：Trans-4-[[4-[(5-甲基-1H-吡唑-3-基)氨基]-7H-吡咯并[2,3-d]嘧啶-2-基]氨基]金刚烷-1-醇(化合物18-1)Example: 18: Trans-4-[[4-[(5-Methyl-1H-pyrazol-3-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-2-yl]amino ]adamantan-1-ol (Compound 18-1)
Trans-4-[[4-[(5-methyl-1H-pyrazol-3-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-2-yl]amino]adamantan-1-olTrans-4-[[4-[(5-methyl-1H-pyrazol-3-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-2-yl]amino]adamantan-1-ol
Cis-4-[[4-[(5-甲基-1H-吡唑-3-基)氨基]-7H-吡咯并[2,3-d]嘧啶-2-基]氨基]金刚烷-1-醇(化合物18-2)Cis-4-[[4-[(5-Methyl-1H-pyrazol-3-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-2-yl]amino]adamantane-1 - Alcohol (compound 18-2)
Cis-4-[[4-[(5-methyl-1H-pyrazol-3-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-2-yl]amino]adamantan-1-olCis-4-[[4-[(5-methyl-1H-pyrazol-3-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-2-yl]amino]adamantan-1-ol
Figure PCTCN2021103485-appb-000351
Figure PCTCN2021103485-appb-000351
第一步：2,4-二氯-7-(对甲苯磺酰基)吡咯并[2,3-d]嘧啶(18b)Step 1: 2,4-Dichloro-7-(p-toluenesulfonyl)pyrrolo[2,3-d]pyrimidine (18b)
2,4-dichloro-7-(p-tolylsulfonyl)pyrrolo[2,3-d]pyrimidine2,4-dichloro-7-(p-tolylsulfonyl)pyrrolo[2,3-d]pyrimidine
Figure PCTCN2021103485-appb-000352
Figure PCTCN2021103485-appb-000352
向盛有2,4-二氯-7H-吡咯并[2,3-d]嘧啶(18a)(2.00g,10.64mmol)的反应瓶中，加入溶剂二氯甲烷(50mL)，N,N-二异丙基乙胺(3.00g,23.25mmol)和对甲基苯磺酰氯(2.40g,13.00mmol)。室温反应16h。加入水(50ml)，二氯甲烷50ml*2萃取。合并有机相，无水硫酸钠干燥，过滤，减压浓缩。残留物用硅胶柱色谱分离提纯(石油醚：二氯甲烷(V/V)＝40:60)得到白色固体产物2,4-二氯-7-(对甲苯磺酰基)吡咯并[2,3-d]嘧啶(18b)(3.5g，96％)To a reaction flask containing 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (18a) (2.00 g, 10.64 mmol) was added the solvent dichloromethane (50 mL), N,N- Diisopropylethylamine (3.00 g, 23.25 mmol) and p-toluenesulfonyl chloride (2.40 g, 13.00 mmol). The reaction was carried out at room temperature for 16h. Add water (50ml) and extract with dichloromethane 50ml*2. The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether:dichloromethane (V/V)=40:60) to obtain 2,4-dichloro-7-(p-toluenesulfonyl)pyrrolo[2,3 as a white solid product -d]pyrimidine (18b) (3.5g, 96%)
LCMS m/z＝342.0[M+1] + LCMS m/z=342.0[M+1] +
1H NMR(400MHz,DMSO-d 6)δ8.13(d,1H),8.05(d,2H),7.52(d,2H),6.99(d,1H),2.40(s,3H). 1 H NMR (400MHz, DMSO-d 6 )δ8.13(d,1H), 8.05(d,2H), 7.52(d,2H), 6.99(d,1H), 2.40(s,3H).
第二步：2-氯-N-(3-甲基-1H-吡唑-5-基)-7-(对甲苯磺酰基)吡咯并[2,3-d]嘧啶-4-胺(18c)Step 2: 2-Chloro-N-(3-methyl-1H-pyrazol-5-yl)-7-(p-toluenesulfonyl)pyrrolo[2,3-d]pyrimidin-4-amine (18c )
2-chloro-N-(3-methyl-1H-pyrazol-5-yl)-7-(p-tolylsulfonyl)pyrrolo[2,3-d]pyrimidin-4-amine2-chloro-N-(3-methyl-1H-pyrazol-5-yl)-7-(p-tolylsulfonyl)pyrrolo[2,3-d]pyrimidin-4-amine
Figure PCTCN2021103485-appb-000353
Figure PCTCN2021103485-appb-000353
将2,4-二氯-7-(对甲苯磺酰基)吡咯并[2,3-d]嘧啶(18b)(700mg,2.04mmol)，5-甲基-1H-吡唑-3-胺(340mg,3.50mmol),N,N-二异丙基乙胺(1.30g,10.08mmol)和乙醇(10mL)加入微波反应管中，升温至80℃，反应2h。冷却至室温，加入水(10ml)，乙酸乙酯20ml*2萃取。合并有机相，无水硫酸钠干燥，过滤，减压浓缩。残留物用硅胶柱色谱分离提纯(石油醚：乙酸乙酯(V/V)＝1:4)得到白色固体产物2-氯-N-(3-甲基-1H-吡唑-5-基)-7-(对甲苯磺酰基)吡咯并[2,3-d]嘧啶-4-胺(18c)(400mg，50％)2,4-Dichloro-7-(p-toluenesulfonyl)pyrrolo[2,3-d]pyrimidine (18b) (700 mg, 2.04 mmol), 5-methyl-1H-pyrazol-3-amine ( 340mg, 3.50mmol), N,N-diisopropylethylamine (1.30g, 10.08mmol) and ethanol (10mL) were added to a microwave reaction tube, the temperature was raised to 80°C, and the reaction was carried out for 2h. Cool to room temperature, add water (10ml), and extract with ethyl acetate 20ml*2. The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V/V)=1:4) to obtain 2-chloro-N-(3-methyl-1H-pyrazol-5-yl) as a white solid product -7-(p-Tosyl)pyrrolo[2,3-d]pyrimidin-4-amine (18c) (400 mg, 50%)
LCMS m/z＝403.1[M+1] + LCMS m/z=403.1[M+1] +
1H NMR(400MHz,DMSO-d 6)δ12.21(s,1H),10.63(s,1H),7.97(d,2H),7.63(d,1H),7.47(d,2H),7.30-6.98(m,1H),6.44(s,1H),2.37(s,3H),2.25(s,3H). 1 H NMR (400MHz, DMSO-d 6 ) δ 12.21(s, 1H), 10.63(s, 1H), 7.97(d, 2H), 7.63(d, 1H), 7.47(d, 2H), 7.30- 6.98(m, 1H), 6.44(s, 1H), 2.37(s, 3H), 2.25(s, 3H).
第三步：Trans-4-[[4-[(3-甲基-1H-吡唑-5-基)氨基]-7-(对甲苯磺酰基)吡咯并[2,3-d]嘧啶-2-基]氨基]金刚烷-1-醇(18d)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)
Trans-4-[[4-[(3-methyl-1H-pyrazol-5-yl)amino]-7-(p-tolylsulfonyl)pyrrolo[2,3-d]pyrimidin-2-yl]amino]adamantan-1-olTrans-4-[[4-[(3-methyl-1H-pyrazol-5-yl)amino]-7-(p-tolylsulfonyl)pyrrolo[2,3-d]pyrimidin-2-yl]amino]adamantan- 1-ol
Cis-4-[[4-[(3-甲基-1H-吡唑-5-基)氨基]-7-(对甲苯磺酰基)吡咯并[2,3-d]嘧啶-2-基]氨基]金刚烷-1-醇(18d’)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')
Cis-4-[[4-[(3-methyl-1H-pyrazol-5-yl)amino]-7-(p-tolylsulfonyl)pyrrolo[2,3-d]pyrimidin-2-yl]amino]adamantan-1-olCis-4-[[4-[(3-methyl-1H-pyrazol-5-yl)amino]-7-(p-tolylsulfonyl)pyrrolo[2,3-d]pyrimidin-2-yl]amino]adamantan- 1-ol
将2-氯-N-(3-甲基-1H-吡唑-5-基)-7-(对甲苯磺酰基)吡咯并[2,3-d]嘧啶-4-胺(18c)(300mg,0.74mmol)，4-氨基金刚烷-1-醇(300mg,1.79mmol),N,N-二异丙基乙胺(400mg,3.10mmol)和正丁醇(8mL)加入微波反应管中，升温至100℃，反应24h。减压除去溶剂后，加入二氯甲烷：甲醇(V/V)＝10:1(10ml)，抽滤除去固体杂质后浓缩，残留物用硅胶柱色谱分离提纯(二氯甲烷：甲醇(V/V)＝15:1)得到白色固体产物Trans-4-[[4-[(3-甲基-1H-吡唑-5-基)氨基]-7-(对甲苯磺酰基)吡咯并[2,3-d]嘧啶-2-基]氨基]金刚烷-1-醇(18d)(160mg，40％)和Cis-4-[[4-[(3-甲基-1H-吡唑-5-基)氨基]-7-(对甲苯磺酰基)吡咯并[2,3-d]嘧啶-2-基]氨基]金刚烷-1-醇(18d’)(100mg，30％)。2-Chloro-N-(3-methyl-1H-pyrazol-5-yl)-7-(p-toluenesulfonyl)pyrrolo[2,3-d]pyrimidin-4-amine (18c) (300 mg , 0.74mmol), 4-aminoadamantan-1-ol (300mg, 1.79mmol), N,N-diisopropylethylamine (400mg, 3.10mmol) and n-butanol (8mL) were added to the microwave reaction tube, and the temperature was increased. To 100 ℃, the reaction was 24h. After the solvent was removed under reduced pressure, dichloromethane:methanol (V/V)=10:1 (10ml) was added, the solid impurities were removed by suction filtration and then concentrated, and the residue was separated and purified by silica gel column chromatography (dichloromethane:methanol (V/V) V)=15:1) to give the product Trans-4-[[4-[(3-methyl-1H-pyrazol-5-yl)amino]-7-(p-toluenesulfonyl)pyrrolo[2 as a white solid ,3-d]pyrimidin-2-yl]amino]adamantan-1-ol (18d) (160 mg, 40%) and Cis-4-[[4-[(3-methyl-1H-pyrazole-5 -yl)amino]-7-(p-toluenesulfonyl)pyrrolo[2,3-d]pyrimidin-2-yl]amino]adamantan-1-ol (18d') (100 mg, 30%).
Figure PCTCN2021103485-appb-000354
Figure PCTCN2021103485-appb-000354
18d和18d’的构型通过化合物18-1与化合物18-2得到确证，即18d结构为式18d-a的结构，18d’结构为式18d-b的结构。The configurations of 18d and 18d' were confirmed by compound 18-1 and compound 18-2, that is, the structure of 18d is the structure of formula 18d-a, and the structure of 18d' is the structure of formula 18d-b.
LCMS m/z＝534.3[M+1] + LCMS m/z=534.3[M+1] +
化合物18d核磁如下：The NMR of compound 18d is as follows:
1H NMR(400MHz,CD 3OD)δ7.99(d,2H),7.49(d,1H),7.45(d,2H),6.83(d,1H),6.02(s,1H),4.10-4.06(m,1H),2.44(s,3H),2.36(s,3H),2.33-2.26(m,2H),2.20-2.13(m,1H),2.07-1.88(m,6H),1.86-1.80(m,2H),1.61-1.52(m,2H). 1 H NMR (400MHz, CD 3 OD) δ 7.99(d, 2H), 7.49(d, 1H), 7.45(d, 2H), 6.83(d, 1H), 6.02(s, 1H), 4.10-4.06 (m,1H),2.44(s,3H),2.36(s,3H),2.33-2.26(m,2H),2.20-2.13(m,1H),2.07-1.88(m,6H),1.86-1.80 (m,2H),1.61-1.52(m,2H).
化合物18d’核磁如下：The NMR of compound 18d' is as follows:
1H NMR(400MHz,CD 3OD)δ7.95(d,2H),7.36(d,2H),7.19(d,1H),6.63(d,1H),6.26-5.74(m,1H),3.99-3.91(m,1H),2.39(s,3H),2.34-2.29(m,2H),2.25(s,3H),2.21-2.15(m,1H),2.05-1.95(m,2H),1.94-1.79(m,4H),1.79-1.74(m,2H),1.63-1.54(m,2H). 1 H NMR (400MHz, CD 3 OD) δ 7.95(d, 2H), 7.36(d, 2H), 7.19(d, 1H), 6.63(d, 1H), 6.26-5.74(m, 1H), 3.99 -3.91(m,1H),2.39(s,3H),2.34-2.29(m,2H),2.25(s,3H),2.21-2.15(m,1H),2.05-1.95(m,2H),1.94 -1.79(m,4H),1.79-1.74(m,2H),1.63-1.54(m,2H).
第四步：Trans-4-[[4-[(5-甲基-1H-吡唑-3-基)氨基]-7H-吡咯并[2,3-d]嘧啶-2-基]氨基]金刚烷-1-醇(化合物18-1)Step 4: Trans-4-[[4-[(5-Methyl-1H-pyrazol-3-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-2-yl]amino] Adamantane-1-ol (Compound 18-1)
Trans-4-[[4-[(5-methyl-1H-pyrazol-3-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-2-yl]amino]adamantan-1-olTrans-4-[[4-[(5-methyl-1H-pyrazol-3-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-2-yl]amino]adamantan-1-ol
将Trans-4-[[4-[(3-甲基-1H-吡唑-5-基)氨基]-7-(对甲苯磺酰基)吡咯并[2,3-d]嘧啶-2-基]氨基]金刚烷-1-醇(18d)(80mg，0.15mmol)溶于甲醇(5mL)中，加入2N氢氧化钠溶液(2.5mL)，室温反应24h。减压除去溶剂后，残留物经Pre-HPLC纯化,粗品经Pre-HPLC纯化(仪器及制备柱：采用WATERS 2767制备液相，制备柱型号是X select C18，5μm，内径*长度＝19mm*150mm)。制备方法：粗品用二甲亚砜溶解，并用0.45μm滤膜过滤，制备成样品液。流动相体系：乙腈/水。梯度洗脱方法：乙腈由5％梯度洗脱50％(洗脱时间15min)。冻干得到Trans-4-[[4-[(5-甲基-1H-吡唑-3-基)氨基]-7H-吡咯并[2,3-d]嘧啶-2-基]氨基]金刚烷-1-醇(化合物18-1)(20mg，26％)。Trans-4-[[4-[(3-methyl-1H-pyrazol-5-yl)amino]-7-(p-toluenesulfonyl)pyrrolo[2,3-d]pyrimidin-2-yl ]Amino]adamantan-1-ol (18d) (80 mg, 0.15 mmol) was dissolved in methanol (5 mL), 2N sodium hydroxide solution (2.5 mL) was added, and the reaction was carried out at room temperature for 24 h. After removing the solvent under reduced pressure, the residue was purified by Pre-HPLC, and the crude product was purified by Pre-HPLC (instrument and preparative column: WATERS 2767 was used to prepare the liquid phase, the preparative column model was X select C18, 5 μm, inner diameter*length=19mm*150mm ). Preparation method: the crude product is dissolved in dimethyl sulfoxide, and filtered with a 0.45 μm 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). Lyophilization to give Trans-4-[[4-[(5-methyl-1H-pyrazol-3-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-2-yl]amino]adamant Alkan-1-ol (Compound 18-1) (20 mg, 26%).
LCMS m/z＝380.2[M+1] + LCMS m/z=380.2[M+1] +
1H NMR(400MHz,CD 3OD)δ6.76(d,1H),6.42(d,1H),6.10(s,1H),4.07-4.03(m,1H),2.30-2.22(m,5H),2.15-2.09(m,1H),2.07-1.90(m,4H),1.85-1.79(m,4H),1.55-1.45(m,2H)。 1 H NMR (400MHz, CD 3 OD) δ 6.76(d,1H), 6.42(d,1H), 6.10(s,1H), 4.07-4.03(m,1H), 2.30-2.22(m,5H) , 2.15-2.09(m, 1H), 2.07-1.90(m, 4H), 1.85-1.79(m, 4H), 1.55-1.45(m, 2H).
第五步：Cis-4-[[4-[(5-甲基-1H-吡唑-3-基)氨基]-7H-吡咯并[2,3-d]嘧啶-2-基]氨基]金刚烷-1-醇(化合物18-2)Step 5: Cis-4-[[4-[(5-methyl-1H-pyrazol-3-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-2-yl]amino] Adamantane-1-ol (Compound 18-2)
Cis-4-[[4-[(5-methyl-1H-pyrazol-3-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-2-yl]amino]adamantan-1-olCis-4-[[4-[(5-methyl-1H-pyrazol-3-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-2-yl]amino]adamantan-1-ol
将Cis-4-[[4-[(3-甲基-1H-吡唑-5-基)氨基]-7-(对甲苯磺酰基)吡咯并[2,3-d]嘧啶-2-基]氨基]金刚烷-1-醇(18d’)(50mg，0.094mmol)溶于甲醇(3mL)中，加入2N氢氧化钠溶液(1.5mL)，室温反应24h。减压除去溶剂后，残留物经Pre-HPLC纯化,粗品经Pre-HPLC纯化(仪器及制备柱：采用WATERS 2767制备液相，制备柱型号是X select C18，5μm，内径*长度＝19mm*150mm)。制备方法：粗品用二甲亚砜溶解，并用0.45μm滤膜过滤，制备成样品液。流动相体系：乙腈/水。梯度洗脱方法：乙腈由5％梯度洗脱50％(洗脱时间15min)。冻干得到Cis-4-[[4-[(5-甲基-1H-吡唑-3-基)氨基]-7H-吡咯并[2,3-d]嘧啶-2-基]氨基]金刚烷-1-醇(化合物18-2)(8mg，22％)。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. After removing the solvent under reduced pressure, the residue was purified by Pre-HPLC, and the crude product was purified by Pre-HPLC (instrument and preparative column: WATERS 2767 was used to prepare the liquid phase, the preparative column model was X select C18, 5 μm, inner diameter*length=19mm*150mm ). Preparation method: the crude product is dissolved in dimethyl sulfoxide, and filtered with a 0.45 μm 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). Lyophilization to give Cis-4-[[4-[(5-methyl-1H-pyrazol-3-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-2-yl]amino]adamant Alkan-1-ol (Compound 18-2) (8 mg, 22%).
LCMS m/z＝380.2[M+1] + LCMS m/z=380.2[M+1] +
1H NMR(400MHz,CD 3OD)δ6.76(d,1H),6.42(d,1H),6.08(s,1H),3.97-3.92(m,1H),2.36-2.30(m,2H),2.27(s,3H),2.17-2.10(m,1H),2.06-1.98(m,2H),1.87–1.72(m,6H),1.62-1.54(m,2H). 1 H NMR (400MHz, CD 3 OD) δ6.76(d,1H), 6.42(d,1H), 6.08(s,1H), 3.97-3.92(m,1H), 2.36-2.30(m,2H) ,2.27(s,3H),2.17-2.10(m,1H),2.06-1.98(m,2H),1.87-1.72(m,6H),1.62-1.54(m,2H).
Figure PCTCN2021103485-appb-000355
Figure PCTCN2021103485-appb-000355
化合物18-1和18-2构型通过实施例57和58得到确证，即化合物18-1结构为式18-a的结构，化合物18-2结构为式18-b的结构。The configurations of compounds 18-1 and 18-2 were confirmed by Examples 57 and 58, that is, the structure of compound 18-1 was the structure of formula 18-a, and the structure of compound 18-2 was the structure of formula 18-b.
实施例19：cis-4-[[7-[(5-甲基噻唑-2-基)氨基]-1,6-萘啶-5-基]氨基]金刚烷-1-醇；2,2,2-三氟乙酸盐(化合物19)Example 19: cis-4-[[7-[(5-methylthiazol-2-yl)amino]-1,6-naphthyridin-5-yl]amino]adamantan-1-ol; 2,2 ,2-Trifluoroacetate (Compound 19)
cis-4-[[7-[(5-methylthiazol-2-yl)amino]-1,6-naphthyridin-5-yl]amino]adamantan-1-ol；2,2,2-trifluoroacetic acidcis-4-[[7-[(5-methylthiazol-2-yl)amino]-1,6-naphthyridin-5-yl]amino]adamantan-1-ol; 2,2,2-trifluoroacetic acid
Figure PCTCN2021103485-appb-000356
Figure PCTCN2021103485-appb-000356
化合物19以cis-4-[(7-氯-1,6-萘啶-5-基)氨基]金刚烷-1-醇(1b)和5-甲基-2-氨基噻唑为起始原料，参考实施例1的合成方法，得到cis-4-[[7-[(5-甲基噻唑-2-基)氨基]-1,6-萘啶-5-基]氨基]金刚烷-1-醇；2,2,2-三氟乙酸盐(化合物19)。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).
LCMS m/z＝408.2[M+1] + LCMS m/z=408.2[M+1] +
1H NMR(400MHz,CD 3OD)δ9.11(d,1H),8.66(dd,1H),7.41(dd,1H),7.12(d,1H),6.57(s,1H),4.58-4.50(m,1H),2.64-2.57(m,2H),2.44(s,3H),2.30-2.23(m,1H),2.17-2.08(m,2H),2.03-1.87(m,4H),1.86-1.80(m,2H),1.75-1.64(m 2H). 1 H NMR (400MHz, CD 3 OD) δ 9.11(d,1H), 8.66(dd,1H), 7.41(dd,1H), 7.12(d,1H), 6.57(s,1H), 4.58-4.50 (m,1H),2.64-2.57(m,2H),2.44(s,3H),2.30-2.23(m,1H),2.17-2.08(m,2H),2.03-1.87(m,4H),1.86 -1.80(m,2H),1.75-1.64(m 2H).
实施例20：cis-7-[[5-(羟甲基)噻唑-2-基]氨基]-1,6-萘吡啶-5-基]氨基]金刚烷-1-醇(化合物20)Example 20: cis-7-[[5-(hydroxymethyl)thiazol-2-yl]amino]-1,6-naphthyridine-5-yl]amino]adamantan-1-ol (Compound 20)
Cis-7-[[5-(hydroxymethyl)thiazol-2-yl]amino]-1,6-naphthyridin-5-yl]amino]adamantan-1-olCis-7-[[5-(hydroxymethyl)thiazol-2-yl]amino]-1,6-naphthyridin-5-yl]amino]adamantan-1-ol
Figure PCTCN2021103485-appb-000357
Figure PCTCN2021103485-appb-000357
化合物20以cis-4-[(7-氯-1,6-萘啶-5-基)氨基]金刚烷-1-醇(1b)和2-氨基-5-噻唑甲醇为起始原料，参考实施例1的合成方法，得到cis-7-[[5-(羟甲基)噻唑-2-基]氨基]-1,6-萘吡啶-5-基]氨基]金刚烷-1-醇(化合物20)。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).
LCMS m/z＝424.1[M+1] + LCMS m/z=424.1[M+1] +
1H NMR(400MHz,DMSO-d 6)δ10.80(s,1H),8.73-8.67(m,2H),7.17-7.11(m,2H),6.95(d,1H),6.57(s,1H),5.18(t,1H),4.56(d,2H),4.45–4.39(m,1H),4.37-4.33(m,1H),2.44-2.38(m,2H),2.14–2.06(m,3H),1.95-1.83(m,2H),1.73–1.60(m,4H),1.49-1.38(m,2H). 1 H NMR (400MHz, DMSO-d 6 ) δ 10.80(s, 1H), 8.73-8.67(m, 2H), 7.17-7.11(m, 2H), 6.95(d, 1H), 6.57(s, 1H) ), 5.18(t, 1H), 4.56(d, 2H), 4.45-4.39(m, 1H), 4.37-4.33(m, 1H), 2.44-2.38(m, 2H), 2.14-2.06(m, 3H ),1.95-1.83(m,2H),1.73-1.60(m,4H),1.49-1.38(m,2H).
实施例21：Cis-4-[[7-[(5-环丙基-1H-吡唑-3-基)氨基]-1,6-萘啶-5-基]氨基]金刚烷-1-醇；2,2,2-三氟乙酸盐(化合物21)Example 21: Cis-4-[[7-[(5-Cyclopropyl-1H-pyrazol-3-yl)amino]-1,6-naphthyridin-5-yl]amino]adamantane-1- Alcohol; 2,2,2-Trifluoroacetate (Compound 21)
Cis-4-[[7-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]-1,6-naphthyridin-5-yl]amino]adamantan-1-ol；2,2,2-trifluoroacetic acidCis-4-[[7-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]-1,6-naphthyridin-5-yl]amino]adamantan-1-ol; 2,2,2-trifluoroacetic acid
Figure PCTCN2021103485-appb-000358
Figure PCTCN2021103485-appb-000358
化合物21以cis-4-[(7-氯-1,6-萘啶-5-基)氨基]金刚烷-1-醇(1b)和5-环丙基-1H-吡唑-3-氨基为起始原料，参考实施例1的合成方法，得cis-4-[[7-[(5-环丙基-1H-吡唑-3-基)氨基]-1,6-萘啶-5-基]氨基]金刚烷-1-醇；2,2,2-三氟乙酸盐(化合物21)。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 As 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).
LCMS m/z＝417.3[M+1] + LCMS m/z=417.3[M+1] +
1H NMR(400MHz,CD 3OD)δ8.98(dd,1H),8.46(dd,1H),7.22(dd,1H),6.65(s,1H),6.02(s,1H),4.26-4.20(m,1H),2.55-2.45(m,2H),2.23-2.14(m,1H),2.09-2.02(m,2H),1.99–1.73(m,7H),1.67-1.56(m,2H),1.05–0.98(m,2H),0.81-0.72(m,2H)。 1 H NMR (400MHz, CD 3 OD) δ 8.98(dd, 1H), 8.46(dd, 1H), 7.22(dd, 1H), 6.65(s, 1H), 6.02(s, 1H), 4.26-4.20 (m,1H), 2.55-2.45(m,2H), 2.23-2.14(m,1H), 2.09-2.02(m,2H), 1.99-1.73(m,7H), 1.67-1.56(m,2H) , 1.05–0.98 (m, 2H), 0.81–0.72 (m, 2H).
实施例22：Cis-4-[[7-(1H-吡唑-3-基氨基)-1,6-萘啶-5-基]氨基]金刚烷-1-醇；2,2,2-三氟乙酸盐(化合物22)Example 22: Cis-4-[[7-(1H-pyrazol-3-ylamino)-1,6-naphthyridin-5-yl]amino]adamantan-1-ol; 2,2,2- Trifluoroacetate (Compound 22)
Cis-4-[[7-(1H-pyrazol-3-ylamino)-1,6-naphthyridin-5-yl]amino]adamantan-1-ol；2,2,2-trifluoroacetic acidCis-4-[[7-(1H-pyrazol-3-ylamino)-1,6-naphthyridin-5-yl]amino]adamantan-1-ol; 2,2,2-trifluoroacetic acid
Figure PCTCN2021103485-appb-000359
Figure PCTCN2021103485-appb-000359
化合物22以cis-4-[(7-氯-1,6-萘啶-5-基)氨基]金刚烷-1-醇(1b)和3-氨基吡唑为起始原料，参考实施例1的合成方法，得到cis-4-[[7-(1H-吡唑-3-基氨基)-1,6-萘啶-5-基]氨基]金刚烷-1-醇；2,2,2-三氟乙酸盐(化合物22)。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).
LCMS m/z＝377.2[M+1] + LCMS m/z=377.2[M+1] +
1H NMR(400MHz,CD 3OD)δ8.99(d,1H),8.46(dd,1H),7.62(d,1H),7.22(dd,1H),6.73(s,1H),6.36(s,1H),4.27-4.22(m,1H),2.58-2.48(m,2H),2.21-2.15(m,1H),2.10-2.01(m,2H),1.91-1.74(m,6H),1.67-1.53(m,2H). 1 H NMR (400MHz, CD 3 OD) δ 8.99(d,1H), 8.46(dd,1H), 7.62(d,1H), 7.22(dd,1H), 6.73(s,1H), 6.36(s ,1H),4.27-4.22(m,1H),2.58-2.48(m,2H),2.21-2.15(m,1H),2.10-2.01(m,2H),1.91-1.74(m,6H),1.67 -1.53(m,2H).
实施例23：Cis-4-[[7-[[5-(三氟甲基)-1H-吡唑-3-基]氨基]-1,6-萘啶-5-基]氨基]金刚烷-1-醇(化合物23)的三氟乙酸盐Example 23: Cis-4-[[7-[[5-(trifluoromethyl)-1H-pyrazol-3-yl]amino]-1,6-naphthyridin-5-yl]amino]adamantane -1-ol (compound 23) trifluoroacetate salt
Cis-4-[[7-[[5-(trifluoromethyl)-1H-pyrazol-3-yl]amino]-1,6-naphthyridin-5-yl]amino]adamantan-1-ol trifluoroacetateCis-4-[[7-[[5-(trifluoromethyl)-1H-pyrazol-3-yl]amino]-1,6-naphthyridin-5-yl]amino]adamantan-1-ol trifluoroacetate
Figure PCTCN2021103485-appb-000360
Figure PCTCN2021103485-appb-000360
化合物23以cis-4-[(7-氯-1,6-萘啶-5-基)氨基]金刚烷-1-醇(1b)和3-氨基-5-三氟甲基吡唑为起始物料参考实施例1的合成方法，得到cis-4-[[7-[[5-(三氟甲基)-1H-吡唑-3-基]氨基]-1,6-萘啶-5-基]氨基]金刚烷-1-醇(化合物23)的三氟乙酸盐。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).
LCMS m/z＝445.2[M+1] +。 LCMS m/z=445.2[M+1] + .
1H NMR(400MHz,CD 3OD)δ9.06(d,1H),8.57(dd,1H),7.32(dd,1H),6.55(s,1H),6.40(s,1H),4.24-4.15(m,1H),2.55-2.45(m,2H),2.21-2.14(m,1H),2.10-2.02(m,2H),1.90-1.72(m,6H),1.67-1.59(m,2H). 1 H NMR (400MHz, CD 3 OD) δ 9.06(d,1H), 8.57(dd,1H), 7.32(dd,1H), 6.55(s,1H), 6.40(s,1H), 4.24-4.15 (m,1H), 2.55-2.45(m,2H), 2.21-2.14(m,1H), 2.10-2.02(m,2H), 1.90-1.72(m,6H), 1.67-1.59(m,2H) .
实施例24：5-[[7-[(5-甲基-1H-吡唑-3-基)氨基]-1,6-萘啶-5-基]氨基]降冰片烷-2-醇(化合物24)的三氟乙酸盐Example 24: 5-[[7-[(5-Methyl-1H-pyrazol-3-yl)amino]-1,6-naphthyridin-5-yl]amino]norbornan-2-ol ( Compound 24) trifluoroacetate salt
5-[[7-[(5-methyl-1H-pyrazol-3-yl)amino]-1,6-naphthyridin-5-yl]amino]norbornan-2-ol trifluoroacetate5-[[7-[(5-methyl-1H-pyrazol-3-yl)amino]-1,6-naphthyridin-5-yl]amino]norbornan-2-ol trifluoroacetate
Figure PCTCN2021103485-appb-000361
Figure PCTCN2021103485-appb-000361
化合物24以5,7-二氯-1,6-萘啶(1a)和5-氨基双环[2.2.1]庚-2-醇盐酸盐为起始物料参考实施例1的合成方法，得到5-[[7-[(5-甲基-1H-吡唑-3-基)氨基]-1,6-萘啶-5-基]氨基]降冰片烷-2-醇(化合物24)的三氟乙酸盐。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.
LCMS m/z＝351.2[M+1] +。 LCMS m/z=351.2[M+1] + .
1H NMR(400MHz,CD 3OD)δ8.97(d,1H),8.45(dd,1H),7.21(dd,1H),6.73(s,1H),6.09(s,1H),4.37-4.30(m,1H),3.88(d,1H),2.82-2.75(m,1H),2.31(s,3H),2.23-2.02(m,3H),1.83-1.77(m,1H),1.48-1.42(m,1H),1.27-1.20(m,1H),1.12-1.04(m,1H). 1 H NMR (400MHz, CD 3 OD) δ 8.97(d,1H), 8.45(dd,1H), 7.21(dd,1H), 6.73(s,1H), 6.09(s,1H), 4.37-4.30 (m,1H),3.88(d,1H),2.82-2.75(m,1H),2.31(s,3H),2.23-2.02(m,3H),1.83-1.77(m,1H),1.48-1.42 (m,1H),1.27-1.20(m,1H),1.12-1.04(m,1H).
实施例25：Trans-4-[(4-[(1-甲基-1H-咪唑-4-基)氨基]-1H-吡唑啉[3,4-d]嘧啶-6-基)氨基]金刚烷-1-醇(化合物25)的三氟乙酸盐Example 25: Trans-4-[(4-[(1-Methyl-1H-imidazol-4-yl)amino]-1H-pyrazolin[3,4-d]pyrimidin-6-yl)amino] Trifluoroacetate salt of adamantan-1-ol (compound 25)
Trans-4-[(4-[(1-methyl-1H-imidazol-4-yl)amino]-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino]adamantan-1-ol trifluoroacetateTrans-4-[(4-[(1-methyl-1H-imidazol-4-yl)amino]-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino]adamantan-1-ol trifluoroacetate
Figure PCTCN2021103485-appb-000362
Figure PCTCN2021103485-appb-000362
化合物25以4,6-二氯-1H-吡唑并[3,4-d]嘧啶(5a)和1-甲基-4-氨基咪唑盐酸盐为起始物料参考实施例5的合成方法，得到Trans-4-[(4-[(1-甲基-1H-咪唑-4-基)氨基]-1H-吡唑啉[3,4-d]嘧啶-6-基)氨基]金刚烷-1-醇(化合物25)的三氟乙酸盐。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).
LCMS m/z＝381.2[M+1] +。 LCMS m/z=381.2[M+1] + .
1H NMR(400MHz,CD 3OD)δ8.53-8.18(m,1H),7.94(s,1H),7.72-7.44(m,1H),4.32-4.08(m,1H),3.88(s,3H),2.42-2.26(m,2H),2.20-2.15(m,1H),2.03-1.76(m,8H),1.65-1.55(m,2H). 1 H NMR (400MHz, CD 3 OD) δ 8.53-8.18(m, 1H), 7.94(s, 1H), 7.72-7.44(m, 1H), 4.32-4.08(m, 1H), 3.88(s, 3H), 2.42-2.26(m, 2H), 2.20-2.15(m, 1H), 2.03-1.76(m, 8H), 1.65-1.55(m, 2H).
实施例26：Cis-4-[(4-[(1-甲基-1H-咪唑-4-基)氨基]-1H-吡唑啉[3,4-d]嘧啶-6-基)氨基]金刚烷-1-醇(化合物26)的三氟乙酸盐Example 26: Cis-4-[(4-[(1-methyl-1H-imidazol-4-yl)amino]-1H-pyrazolin[3,4-d]pyrimidin-6-yl)amino] Trifluoroacetate salt of adamantan-1-ol (compound 26)
Cis-4-[(4-[(1-methyl-1H-imidazol-4-yl)amino]-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino]adamantan-1-ol trifluoroacetateCis-4-[(4-[(1-methyl-1H-imidazol-4-yl)amino]-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino]adamantan-1-ol trifluoroacetate
Figure PCTCN2021103485-appb-000363
Figure PCTCN2021103485-appb-000363
化合物以4,6-二氯-1H-吡唑并[3,4-d]嘧啶(5a)和1-甲基-4-氨基咪唑盐酸盐为起始物料参考实施例5的合成方法，得到cis-4-[(4-[(1-甲基-1H-咪唑-4-基)氨基]-1H-吡唑啉[3,4-d]嘧啶-6-基)氨基]金刚烷-1-醇(化合物26)的三氟乙酸盐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)
LCMS m/z＝381.3[M+1] +。 LCMS m/z=381.3[M+1] + .
1H NMR(400MHz,CD 3OD)δ8.60-8.07(m,1H),7.86(s,1H),7.56(s,1H),4.20-4.00(m,1H),3.86(s,3H),2.48-2.31(m,2H),2.24-2.11(m,1H),2.05-1.73(m,8H),1.72-1.60(m,2H). 1 H NMR (400MHz, CD 3 OD) δ 8.60-8.07(m, 1H), 7.86(s, 1H), 7.56(s, 1H), 4.20-4.00(m, 1H), 3.86(s, 3H) ,2.48-2.31(m,2H),2.24-2.11(m,1H),2.05-1.73(m,8H),1.72-1.60(m,2H).
实施例27：3-[[4-[[7-[(5-甲基-1H-吡唑-3-基)氨基]-1,6-萘啶-5-基]氨基]环己基]氨基]丙腈(化合物27)的三氟乙酸盐Example 27: 3-[[4-[[7-[(5-Methyl-1H-pyrazol-3-yl)amino]-1,6-naphthyridin-5-yl]amino]cyclohexyl]amino ] propionitrile (compound 27) trifluoroacetate salt
3-[[4-[[7-[(5-methyl-1H-pyrazol-3-yl)amino]-1,6-naphthyridin-5-yl]amino]cyclohexyl]amino]propanenitrile trifluoroacetate3-[[4-[[7-[(5-methyl-1H-pyrazol-3-yl)amino]-1,6-naphthyridin-5-yl]amino]cyclohexyl]amino]propanenitrile trifluoroacetate
Figure PCTCN2021103485-appb-000364
Figure PCTCN2021103485-appb-000364
第一步：N-[4-[(7-氯-1,6-萘啶-5-基)氨基]环己基]氨基甲酸叔丁酯(27b)The first step: tert-butyl N-[4-[(7-chloro-1,6-naphthyridin-5-yl)amino]cyclohexyl]carbamate (27b)
tert-butyl N-[4-[(7-chloro-1,6-naphthyridin-5-yl)amino]cyclohexyl]carbamatetert-butyl N-[4-[(7-chloro-1,6-naphthyridin-5-yl)amino]cyclohexyl]carbamate
Figure PCTCN2021103485-appb-000365
Figure PCTCN2021103485-appb-000365
将5,7-二氯-1,6-萘啶(1a)(0.30g,1.5mmol),N-(4-氨基环己基)氨基甲酸叔丁酯(0.45g,2.1mmol)和N,N-二异丙基乙胺(0.40g，3mmol)加入反应瓶中，加入溶剂N,N-二甲基甲酰胺(5mL)。升温至100℃反应16h。加入水(10ml)，乙酸乙酯(10mL*2)萃取。合并有机相，无水硫酸钠干燥，过滤，减压浓缩。残留物用硅胶柱色谱分离提纯(石油醚：乙酸乙酯(V/V)＝1:100)得到固体产物N-[4-[(7-氯-1,6-萘啶-5-基)氨基]环己基]氨基甲酸叔丁酯(27b)(0.50g,90％)。5,7-Dichloro-1,6-naphthyridine (1a) (0.30 g, 1.5 mmol), tert-butyl N-(4-aminocyclohexyl)carbamate (0.45 g, 2.1 mmol) and N,N - Diisopropylethylamine (0.40 g, 3 mmol) was added to the reaction flask, and the solvent N,N-dimethylformamide (5 mL) was added. The temperature was raised to 100°C for 16h. Water (10 ml) was added and extracted with ethyl acetate (10 mL*2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V/V)=1:100) to obtain a solid product N-[4-[(7-chloro-1,6-naphthyridin-5-yl) Amino]cyclohexyl]carbamate tert-butyl ester (27b) (0.50 g, 90%).
LCMS m/z＝377.1[M+1] + LCMS m/z=377.1[M+1] +
第二步：3-[[5-[[4-(叔丁氧羰基氨基)环己基]氨基]-1,6-萘啶-7-基]氨基]-5-甲基-吡唑-1-甲酸叔丁基酯(27c)The second step: 3-[[5-[[4-(tert-butoxycarbonylamino)cyclohexyl]amino]-1,6-naphthyridin-7-yl]amino]-5-methyl-pyrazole-1 - tert-butyl formate (27c)
tert-butyl-3-[[5-[[4-(tert-butoxycarbonylamino)cyclohexyl]amino]-1,6-naphthyridin-7-yl]amino]-5-methyl-pyrazole-1-carboxylatetert-butyl-3-[[5-[[4-(tert-butoxycarbonylamino)cyclohexyl]amino]-1,6-naphthyridin-7-yl]amino]-5-methyl-pyrazole-1-carboxylate
Figure PCTCN2021103485-appb-000366
Figure PCTCN2021103485-appb-000366
将N-[4-[(7-氯-1,6-萘啶-5-基)氨基]环己基]氨基甲酸叔丁酯(27b)(0.20g，0.53mmol)，3-氨基-5-甲基-吡唑-1-甲酸叔丁酯(0.12g，0.61mmol)，三(二亚苄基丙酮)二钯(23mg,0.025mmol)，二环己基(2”,4”,6”-三异丙基-3,6-二甲氧基-[1,1”-联苯]-2-基)膦(29mg,0.054mmol),碳酸铯(0.22g，0.69mmol)加入封管中，加入溶剂二氧六环(2mL)，氮气置换三次后升温至100℃反应24h。抽滤出去固体杂质后，得到粗产物3-[[5-[[4-(叔丁氧羰基氨基)环己基]氨基]-1,6-萘啶-7-基]氨基]-5-甲基-吡唑-1-甲酸叔丁基酯(27c)(0.20g,70％)。N-[4-[(7-Chloro-1,6-naphthyridin-5-yl)amino]cyclohexyl]carbamate tert-butyl ester (27b) (0.20 g, 0.53 mmol), 3-amino-5- Methyl-pyrazole-1-carboxylate tert-butyl ester (0.12g, 0.61mmol), tris(dibenzylideneacetone)dipalladium (23mg, 0.025mmol), dicyclohexyl (2", 4", 6"- Triisopropyl-3,6-dimethoxy-[1,1"-biphenyl]-2-yl)phosphine (29mg, 0.054mmol), cesium carbonate (0.22g, 0.69mmol) were added to the sealed tube, The solvent dioxane (2 mL) was added, nitrogen was replaced three times, and the temperature was raised to 100° C. for reaction for 24 h. After the solid impurities were removed by suction filtration, the crude product 3-[[5-[[4-(tert-butoxycarbonylamino)cyclohexyl]amino]-1,6-naphthyridin-7-yl]amino]-5-methyl was obtained yl-pyrazole-1-carboxylic acid tert-butyl ester (27c) (0.20 g, 70%).
LCMS m/z＝538.3[M+1] + LCMS m/z=538.3[M+1] +
第三步：N 5-(4-氨基环己基)-N 7-(5-甲基-1H-吡唑-3-基)-1,6-萘啶-5,7-二胺(27d) The third step: N 5 -(4-aminocyclohexyl)-N 7 -(5-methyl-1H-pyrazol-3-yl)-1,6-naphthyridine-5,7-diamine (27d)
N 5-(4-aminocyclohexyl)-N 7-(5-methyl-1H-pyrazol-3-yl)-1,6-naphthyridine-5,7-diamine N 5 -(4-aminocyclohexyl)-N 7 -(5-methyl-1H-pyrazol-3-yl)-1,6-naphthyridine-5,7-diamine
Figure PCTCN2021103485-appb-000367
Figure PCTCN2021103485-appb-000367
将3-[[5-[[4-(叔丁氧羰基氨基)环己基]氨基]-1,6-萘啶-7-基]氨基]-5-甲基-吡唑-1-甲酸叔丁基酯(27c)(0.20g，0.037mmol)溶于二氯甲烷(2mL)中,加入三氟乙酸(2mL)，室温反应1h。减压除去溶剂后，残留物用反向C18色谱柱分离提纯(水(0.5％碳 酸氢铵)：乙腈(V/V)＝30:70)，冻干后得到N 5-(4-氨基环己基)-N 7-(5-甲基-1H-吡唑-3-基)-1,6-萘啶-5,7-二胺(27d)(0.11g，90％)。 3-[[5-[[4-(tert-butoxycarbonylamino)cyclohexyl]amino]-1,6-naphthyridin-7-yl]amino]-5-methyl-pyrazole-1-carboxylic acid tertiary Butyl ester (27c) (0.20 g, 0.037 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (2 mL) was added, and the reaction was carried out at room temperature for 1 h. After removing the solvent under reduced pressure, the residue was separated and purified by reverse-phase C18 column chromatography (water (0.5% ammonium bicarbonate):acetonitrile (V/V)=30:70), and lyophilized to obtain N 5 -(4-amino ring) hexyl) -N 7 - (5- methyl -1H- pyrazol-3-yl) -1,6-naphthyridine-5,7-diamine (27d) (0.11g, 90% ).
LCMS m/z＝338.2[M+1] + LCMS m/z=338.2[M+1] +
第四步：3-[[4-[[7-[(5-甲基-1H-吡唑-3-基)氨基]-1,6-萘啶-5-基]氨基]环己基]氨基]丙腈(化合物27)的三氟乙酸盐The fourth step: 3-[[4-[[7-[(5-methyl-1H-pyrazol-3-yl)amino]-1,6-naphthyridin-5-yl]amino]cyclohexyl]amino ] propionitrile (compound 27) trifluoroacetate salt
3-[[4-[[7-[(5-methyl-1H-pyrazol-3-yl)amino]-1,6-naphthyridin-5-yl]amino]cyclohexyl]amino]propanenitrile trifluoroacetate3-[[4-[[7-[(5-methyl-1H-pyrazol-3-yl)amino]-1,6-naphthyridin-5-yl]amino]cyclohexyl]amino]propanenitrile trifluoroacetate
Figure PCTCN2021103485-appb-000368
Figure PCTCN2021103485-appb-000368
将N 5-(4-氨基环己基)-N 7-(5-甲基-1H-吡唑-3-基)-1,6-萘啶-5,7-二胺(27d)(50mg,0.15mmol)溶于甲醇(5mL)后，加入N,N-二异丙基乙胺(54mg，0.42mmol)和丙烯腈(13mg，0.25mmol),室温反应24h。减压除去溶剂得到残留物，残留物经Pre-HPLC纯化(仪器及制备柱：采用Gilson Gx-281制备液相，制备柱型号是Sunfire，5μm，内径*长度＝30mm*150mm)。制备方法：粗品用甲醇溶解，并用0.45μm滤膜过滤，制备成样品液。流动相体系：乙腈/水(含0.5％的三氟乙酸)。梯度洗脱方法：乙腈由10％梯度洗脱60％(洗脱时间16min)，冻干后得到3-[[4-[[7-[(5-甲基-1H-吡唑-3-基)氨基]-1,6-萘啶-5-基]氨基]环己基]氨基]丙腈(化合物27)的三氟乙酸盐(30mg,40％)。 The 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. The solvent was removed under reduced pressure to obtain a residue, which was purified by Pre-HPLC (instrument and preparative column: Gilson Gx-281 was used for preparative liquid phase, the preparative column model was Sunfire, 5 μm, inner diameter*length=30mm*150mm). Preparation method: the crude product is dissolved in methanol, and filtered with a 0.45 μm 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 3-[[4-[[7-[(5-methyl-1H-pyrazol-3-yl ) amino]-1,6-naphthyridin-5-yl]amino]cyclohexyl]amino]propionitrile (compound 27) trifluoroacetate salt (30 mg, 40%).
LCMS m/z＝391.3[M+1] + LCMS m/z=391.3[M+1] +
1H NMR(400MHz,CD 3OD)δ8.88(dd,1H),8.46(dd,1H),7.21(dd,1H),6.75(s,1H),6.08(s,1H),4.30-4.18(m,1H),3.45(t,2H),3.29-3.22(m,1H),2.97(t,2H),2.37-2.26(m,7H),1.73-1.51(m,4H). 1 H NMR (400MHz, CD 3 OD) δ 8.88 (dd, 1H), 8.46 (dd, 1H), 7.21 (dd, 1H), 6.75 (s, 1H), 6.08 (s, 1H), 4.30-4.18 (m,1H),3.45(t,2H),3.29-3.22(m,1H),2.97(t,2H),2.37-2.26(m,7H),1.73-1.51(m,4H).
实施例28：Cis-4-(甲基(4-[(5-甲基-1H-吡唑-3-基)氨基]-7H-吡咯并[2,3-d]嘧啶-2-基)氨基)金刚烷-1-醇(化合物28)的三氟乙酸盐Example 28: Cis-4-(methyl(4-[(5-methyl-1H-pyrazol-3-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-2-yl) Amino)adamantan-1-ol (compound 28) trifluoroacetate salt
Cis-4-(methyl(4-[(5-methyl-1H-pyrazol-3-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)adamantan-1-ol trifluoroacetateCis-4-(methyl(4-[(5-methyl-1H-pyrazol-3-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)adamantan-1-ol trifluoroacetate
Figure PCTCN2021103485-appb-000369
Figure PCTCN2021103485-appb-000369
第一步：4-{[(1s)-1-苯乙基]亚氨基}金刚烷-1-醇(28b)The first step: 4-{[(1s)-1-phenethyl]imino}adamantan-1-ol (28b)
4-{[(1s)-1-phenylethyl]imino}adamantan-1-ol4-{[(1s)-1-phenylethyl]imino}adamantan-1-ol
Figure PCTCN2021103485-appb-000370
Figure PCTCN2021103485-appb-000370
室温下，将5-羟基金刚烷-2-酮(28a)(5.00g，30.08mmol)和(1s)-1-苯基乙烷-1-胺(3.65g，30.08mmol)溶于50mL无水乙醇中，然后升温至90℃，反应72小时。旋干反应液后，得到粗品4-{[(1s)-1-苯乙基]亚氨基}金刚烷-1-醇(28b)(8.0g，98％)。5-Hydroxyadamantan-2-one (28a) (5.00 g, 30.08 mmol) and (1s)-1-phenylethan-1-amine (3.65 g, 30.08 mmol) were dissolved in 50 mL of dry water at room temperature In ethanol, the temperature was raised to 90°C, and the reaction was carried out for 72 hours. After the reaction solution was spin-dried, crude 4-{[(1s)-1-phenethyl]imino}adamantan-1-ol (28b) (8.0 g, 98%) was obtained.
LCMS m/z＝270.2[M+1] + LCMS m/z=270.2[M+1] +
第二步：4-{[(1s)-1-苯乙基]氨基}金刚烷-1-醇(28c)Step 2: 4-{[(1s)-1-phenethyl]amino}adamantan-1-ol (28c)
4-{[(1s)-1-phenylethyl]amino}adamantan-1-ol4-{[(1s)-1-phenylethyl]amino}adamantan-1-ol
Figure PCTCN2021103485-appb-000371
Figure PCTCN2021103485-appb-000371
室温下，将4-{[(1s)-1-苯乙基]亚氨基}金刚烷-1-醇(28b)(2.0g，7.42mmol)溶于15mL超干四氢呋喃溶液中。在0℃下，向反应液中缓慢滴加硼烷-四氢呋喃溶液(2.0 M，11.13mL,22.26mmol)，缓慢升至室温后，室温反应16小时。冷却至0℃下后，缓慢滴加饱和氯化铵水溶液猝灭反应，加入水(10ml)，二氯甲烷20ml*2萃取。合并有机相，无水硫酸钠干燥，过滤，减压浓缩得到粗品体4-{[(1s)-1-苯乙基]氨基}金刚烷-1-醇(28c)(1.8g，89％)。4-{[(1s)-1-phenethyl]imino}adamantan-1-ol (28b) (2.0 g, 7.42 mmol) was dissolved in 15 mL of ultra-dry tetrahydrofuran solution at room temperature. At 0°C, a borane-tetrahydrofuran solution (2.0 M, 11.13 mL, 22.26 mmol) was slowly added dropwise to the reaction solution, and after slowly warming to room temperature, the reaction was carried out at room temperature for 16 hours. After cooling to 0°C, the reaction was quenched by slowly adding a saturated aqueous ammonium chloride solution dropwise, adding water (10 ml), and extracting with dichloromethane 20 ml*2. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude 4-{[(1s)-1-phenethyl]amino}adamantan-1-ol (28c) (1.8 g, 89%) .
LCMS m/z＝272.2[M+1] + LCMS m/z=272.2[M+1] +
第三步：Cis-4-(甲基[(1s)-1-苯乙基]氨基)金刚烷-1-醇(28d)的三氟乙酸盐Step 3: Trifluoroacetate salt of Cis-4-(methyl[(1s)-1-phenethyl]amino)adamantan-1-ol (28d)
Cis-4-(methyl[(1s)-1-phenylethyl]amino)adamantan-1-ol trifluoroacetateCis-4-(methyl[(1s)-1-phenylethyl]amino)adamantan-1-ol trifluoroacetate
Figure PCTCN2021103485-appb-000372
Figure PCTCN2021103485-appb-000372
室温下，将4-{[(1s)-1-苯乙基]氨基}金刚烷-1-醇(28c)(1.8g，6.63mmol)溶于15mL乙腈中，再分别加入37％甲醛溶液(1.97mL，19.89mmol)和三乙酰氧基硼氢化钠(2.11g，9.95mmol),室温反应4h。减压除去溶剂后，残留物经Pre-HPLC纯化,(仪器及制备柱：采用WATERS 2767制备液相，制备柱型号是X select C18，5μm，内径*长度＝19mm*150mm)。制备方法：粗品用二甲亚砜溶解，并用0.45μm滤膜过滤，制备成样品液。流动相体系：乙腈/水(含0.1％的三氟乙酸)。梯度洗脱方法：乙腈由5％梯度洗脱50％(洗脱时间15min)。冻干得到无色油状Cis-4-(甲基[(1s)-1-苯乙基]氨基)金刚烷-1-醇(28d)的三氟乙酸盐(800mg，30％)。At room temperature, 4-{[(1s)-1-phenethyl]amino}adamantan-1-ol (28c) (1.8 g, 6.63 mmol) was dissolved in 15 mL of acetonitrile, and 37% formaldehyde solution ( 1.97 mL, 19.89 mmol) and sodium triacetoxyborohydride (2.11 g, 9.95 mmol), react at room temperature for 4 h. After removing the solvent under reduced pressure, the residue was purified by Pre-HPLC (instrument and preparative column: WATERS 2767 was used to prepare the liquid phase, the preparative column model was X select C18, 5 μm, inner diameter*length=19mm*150mm). Preparation method: the crude product is dissolved in dimethyl sulfoxide, and filtered with a 0.45 μm 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%).
LCMS m/z＝286.3[M+1] + LCMS m/z=286.3[M+1] +
第四步：Cis-4-(甲胺基)金刚烷-1-醇(28e)的三氟乙酸盐Step 4: Trifluoroacetate salt of Cis-4-(methylamino)adamantan-1-ol (28e)
Cis-4-(methylamino)adamantan-1-ol trifluoroacetateCis-4-(methylamino)adamantan-1-ol trifluoroacetate
Figure PCTCN2021103485-appb-000373
Figure PCTCN2021103485-appb-000373
将cis-4-(甲基[(1s)-1-苯乙基]氨基)金刚烷-1-醇(28d)的三氟乙酸盐(800mg，2.0mmol)溶于无水乙醇(15mL)中，加入200mg氢氧化钯-碳，在氢气下，室温反应24 h。减压除去溶剂后，得到Cis-4-(甲胺基)金刚烷-1-醇(28e)的三氟乙酸盐(550mg，93％)。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%).
LCMS m/z＝182.2[M+1] + LCMS m/z=182.2[M+1] +
第五步：Cis-4-(甲基(4-[(5-甲基-1H-吡唑-3-基)氨基]-7-(4-甲基苯磺酰基)-7H-吡咯并[2,3-d]嘧啶-2-基)氨基)金刚烷-1-醇(28f)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)
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-olCis-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
Figure PCTCN2021103485-appb-000374
Figure PCTCN2021103485-appb-000374
室温下，将N-(2-氯-7-(4-甲基苯磺酰基)-7H-吡咯并[2,3-d]嘧啶-4-基)-5-甲基-1H-吡唑-3-胺(18c)(150mg，0.37mmol)、cis-4-(甲胺基)金刚烷-1-醇(28e)的三氟乙酸(140mg，0.48mmol)、N,N-二异丙基乙胺(500mg，3.87mmol)和正丁醇(10mL)加入到微波反应管中，升温至140℃，反应24h。减压除去溶剂后，残留物用硅胶柱色谱分离提纯(二氯甲烷:甲醇(V/V)＝10:1)得到黄色固体cis-4-(甲基(4-[(5-甲基-1H-吡唑-3-基)氨基]-7-(4-甲基苯磺酰基)-7H-吡咯并[2,3-d]嘧啶-2-基)氨基)金刚烷-1-醇(28f)(80mg，39％)。At room temperature, 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. After the solvent was removed under reduced pressure, the residue was separated and purified by silica gel column chromatography (dichloromethane:methanol (V/V)=10:1) to obtain a yellow solid 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) (80 mg, 39%).
LCMS m/z＝548.2[M+1] + LCMS m/z=548.2[M+1] +
第六步：Cis-4-(甲基(4-[(5-甲基-1H-吡唑-3-基)氨基]-7H-吡咯并[2,3-d]嘧啶-2-基)氨基)金刚烷-1-醇(化合物28)的三氟乙酸盐Step 6: Cis-4-(methyl(4-[(5-methyl-1H-pyrazol-3-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-2-yl) Amino)adamantan-1-ol (compound 28) trifluoroacetate salt
Cis-4-(methyl(4-[(5-methyl-1H-pyrazol-3-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)adamantan-1-ol trifluoroacetateCis-4-(methyl(4-[(5-methyl-1H-pyrazol-3-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)adamantan-1-ol trifluoroacetate
Figure PCTCN2021103485-appb-000375
Figure PCTCN2021103485-appb-000375
将Cis-4-(甲基(4-[(5-甲基-1H-吡唑-3-基)氨基]-7-(4-甲基苯磺酰基)-7H-吡咯并[2,3-d]嘧啶-2-基)氨基)金刚烷-1-醇(28f)(80mg，0.15mmol)溶于甲醇(15mL)中，加入2N 氢氧化钠溶液(2.5mL)，升温至50℃，反应6h。减压除去溶剂后，残留物经Pre-HPLC纯化,(仪器及制备柱：采用WATERS 2767制备液相，制备柱型号是X select C18，5μm，内径*长度＝19mm*150mm)。制备方法：粗品用二甲亚砜溶解，并用0.45μm滤膜过滤，制备成样品液。流动相体系：乙腈/水(含0.1％的三氟乙酸)。梯度洗脱方法：乙腈由5％梯度洗脱50％(洗脱时间15min)。冻干得到白色固体cis-4-(甲基(4-[(5-甲基-1H-吡唑-3-基)氨基]-7H-吡咯并[2,3-d]嘧啶-2-基)氨基)金刚烷-1-醇(化合物28)的三氟乙酸盐(15mg，20％)。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. After removing the solvent under reduced pressure, the residue was purified by Pre-HPLC (instrument and preparative column: WATERS 2767 was used to prepare the liquid phase, the preparative column model was X select C18, 5 μm, inner diameter*length=19mm*150mm). Preparation method: the crude product is dissolved in dimethyl sulfoxide, and filtered with a 0.45 μm 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(4-[(5-methyl-1H-pyrazol-3-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-2-yl as a white solid ) amino)adamantan-1-ol (compound 28) trifluoroacetate salt (15 mg, 20%).
LCMS m/z＝394.2[M+1] + LCMS m/z=394.2[M+1] +
1H NMR(400MHz,CD 3OD)δ7.08(d,1H),6.69(d,1H),6.01(s,1H),4.21-4.12(m,1H),3.44(s,3H),2.67-2.58(m,2H),2.35(s,3H),2.26-2.18(m,1H),2.04-1.94(m,4H),1.88-1.75(m,4H),1.74-1.62(m,2H). 1 H NMR (400MHz, CD 3 OD) δ 7.08(d,1H), 6.69(d,1H), 6.01(s,1H), 4.21-4.12(m,1H), 3.44(s,3H), 2.67 -2.58(m, 2H), 2.35(s, 3H), 2.26-2.18(m, 1H), 2.04-1.94(m, 4H), 1.88-1.75(m, 4H), 1.74-1.62(m, 2H) .
实施例29：Trans-4-[(7-[(1-甲基-1H-咪唑-4-基)氨基]-1,6-萘啶-5-基)氨基]金刚烷-1-醇(化合物29)的三氟乙酸盐Example 29: Trans-4-[(7-[(1-methyl-1H-imidazol-4-yl)amino]-1,6-naphthyridin-5-yl)amino]adamantan-1-ol ( Compound 29) trifluoroacetate salt
Trans-4-[(7-[(1-methyl-1H-imidazol-4-yl)amino]-1,6-naphthyridin-5-yl)amino]adamantan-1-ol trifluoroacetateTrans-4-[(7-[(1-methyl-1H-imidazol-4-yl)amino]-1,6-naphthyridin-5-yl)amino]adamantan-1-ol trifluoroacetate
Figure PCTCN2021103485-appb-000376
Figure PCTCN2021103485-appb-000376
化合物以Trans-4-[(7-氯-1,6-萘啶-5-基)氨基]金刚烷-1-醇(3b)和1-甲基-4-氨基咪唑盐酸盐为起始物料参考实施例3的合成方法，得到Trans-4-[(7-[(1-甲基-1H-咪唑-4-基)氨基]-1,6-萘啶-5-基)氨基]金刚烷-1-醇(化合物29)的三氟乙酸盐。Compounds started with Trans-4-[(7-Chloro-1,6-naphthyridin-5-yl)amino]adamantan-1-ol (3b) and 1-methyl-4-aminoimidazole hydrochloride Materials refer to the synthetic method of Example 3 to obtain Trans-4-[(7-[(1-methyl-1H-imidazol-4-yl)amino]-1,6-naphthyridin-5-yl)amino]adamant The trifluoroacetate salt of alk-1-ol (compound 29).
LCMS m/z＝391.2[M+1] +。 LCMS m/z=391.2[M+1] + .
1H NMR(400MHz,CD 3OD)δ9.12(d,1H),8.60(dd,1H),8.52(s,1H),7.43(d,1H),7.35(dd,1H),6.36(d,1H),4.26-4.20(m,1H),3.94(s,3H),2.45-2.36(m,2H),2.20-2.14(m,1H),2.12-2.01(m,2H),1.89-1.78(m,6H),1.61-1.51(m,2H). 1 H NMR (400MHz, CD 3 OD) δ 9.12(d, 1H), 8.60(dd, 1H), 8.52(s, 1H), 7.43(d, 1H), 7.35(dd, 1H), 6.36(d ,1H),4.26-4.20(m,1H),3.94(s,3H),2.45-2.36(m,2H),2.20-2.14(m,1H),2.12-2.01(m,2H),1.89-1.78 (m,6H),1.61-1.51(m,2H).
实施例30：Cis-4-[(7-[(1-甲基-1H-咪唑-4-基)氨基]-1,6-萘啶-5-基)氨基]金刚烷-1-醇；(化合物30)Example 30: Cis-4-[(7-[(1-methyl-1H-imidazol-4-yl)amino]-1,6-naphthyridin-5-yl)amino]adamantan-1-ol; (compound 30)
Cis-4-[(7-[(1-methyl-1H-imidazol-4-yl)amino]-1,6-naphthyridin-5-yl)amino]adamantan-1-ol；Cis-4-[(7-[(1-methyl-1H-imidazol-4-yl)amino]-1,6-naphthyridin-5-yl)amino]adamantan-1-ol;
Figure PCTCN2021103485-appb-000377
Figure PCTCN2021103485-appb-000377
化合物以Cis-4-[(7-氯-1,6-萘啶-5-基)氨基]金刚烷-1-醇(1b)和1-甲基-4-氨基咪唑盐酸盐为起始物料参考实施例1的合成方法，得到Cis-4-[(7-[(1-甲基-1H-咪唑-4-基)氨基]-1,6-萘啶-5-基)氨基]金刚烷-1-醇(化合物30)。Compounds started with Cis-4-[(7-Chloro-1,6-naphthyridin-5-yl)amino]adamantan-1-ol (1b) and 1-methyl-4-aminoimidazole hydrochloride Materials refer to the synthetic method of Example 1 to obtain Cis-4-[(7-[(1-methyl-1H-imidazol-4-yl)amino]-1,6-naphthyridin-5-yl)amino]adamantine Alkan-1-ol (Compound 30).
LCMS m/z＝391.1[M+1] +。 LCMS m/z=391.1[M+1] + .
1H NMR(400MHz,CD 3OD)δ8.54(dd,1H),8.42(d,1H),7.38(s,1H),7.14(d,1H),7.05(dd,1H),6.32(s,1H),4.22-4.19(m,1H),3.73(s,3H),2.56-2.51(m,2H),2.22-2.16(m,1H),2.12-2.04(m,2H),1.92-1.76(m,6H),1.65-1.58(m,2H). 1 H NMR (400MHz, CD 3 OD) δ 8.54(dd, 1H), 8.42(d, 1H), 7.38(s, 1H), 7.14(d, 1H), 7.05(dd, 1H), 6.32(s ,1H),4.22-4.19(m,1H),3.73(s,3H),2.56-2.51(m,2H),2.22-2.16(m,1H),2.12-2.04(m,2H),1.92-1.76 (m,6H),1.65-1.58(m,2H).
实施例31:Cis-3-(2-((5-羟基金刚烷-2-基)氨基)-4-((5-甲基-1H-吡唑-3-基)氨基)-7H-吡咯并[2,3-d]嘧啶-7–基)丙腈(化合物31)Example 31: Cis-3-(2-((5-hydroxyadamantan-2-yl)amino)-4-((5-methyl-1H-pyrazol-3-yl)amino)-7H-pyrrole [2,3-d]pyrimidin-7-yl)propionitrile (Compound 31)
Cis-3-(2-((5-hydroxyadamantan-2-yl)amino)-4-((5-methyl-1H-pyrazol-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)propanenitrileCis-3-(2-((5-hydroxyadamantan-2-yl)amino)-4-((5-methyl-1H-pyrazol-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin -7-yl)propanenitrile
Figure PCTCN2021103485-appb-000378
Figure PCTCN2021103485-appb-000378
第一步：3-(2,4-二氯-7H-吡咯并[2,3-d]嘧啶-7-基)丙腈(31b)The first step: 3-(2,4-Dichloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)propionitrile (31b)
3-(2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)propanenitrile3-(2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)propanenitrile
Figure PCTCN2021103485-appb-000379
Figure PCTCN2021103485-appb-000379
将2,4-二氯-7H-吡咯并[2,3-d]嘧啶(18a)(2.00g,10.64mmol)溶于四氢呋喃(10mL)和乙腈(10mL)中，室温下加入碳酸钾(2.94g,21.28mmol)后，缓慢滴加入烯丙基腈(0.78g,11.70mmol)，室温反应16h。将反应液倒入到水(60mL)中，乙酸乙酯(40mL*2)萃取，合并有机相，饱和食盐水(20mL*2)反洗，无水硫酸钠干燥，抽滤，滤液减压旋干得残留物，残留物用硅胶柱柱色谱分离纯化(乙酸乙酯：石油醚(v/v)＝0:1-1:0)得淡黄色固体3-(2,4-二氯-7H-吡咯并[2,3-d]嘧啶-7-基)丙腈(31b)(2.30g,89％)。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. The 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. The residue was dried and purified by silica gel column chromatography (ethyl acetate:petroleum ether (v/v)=0:1-1:0) to obtain 3-(2,4-dichloro-7H) as a pale yellow solid -pyrrolo[2,3-d]pyrimidin-7-yl)propionitrile (31b) (2.30 g, 89%).
LCMS m/z＝241.0[M+1] +。 LCMS m/z=241.0[M+1] + .
第二步：3-(2-氯-4-[(5-甲基-1H-吡唑-3-基)氨基]-7H-吡咯并[2,3-d]嘧啶-7-基)丙腈(1c)Step 2: 3-(2-Chloro-4-[(5-methyl-1H-pyrazol-3-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl)propane Nitrile (1c)
3-(2-chloro-4-[(5-methyl-1H-pyrazol-3-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl)propanenitrile3-(2-chloro-4-[(5-methyl-1H-pyrazol-3-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl)propanenitrile
Figure PCTCN2021103485-appb-000380
Figure PCTCN2021103485-appb-000380
室温下，将3-(2,4-二氯-7H-吡咯并[2,3-d]嘧啶-7-基)丙腈(31b)(1.30g,5.39mmol)溶于无水乙醇(30mL)中，在氮气保护下，向其中依次加入3-氨基-5-甲基吡唑(784mg，8.09mmol)和N,N-二异丙基乙胺(2.09g，16.18mmol)，然后100℃加热搅拌16小时。反应结束后，将反应液减压浓缩，加入饱和食盐水溶液(20mL)，乙酸乙酯(20mL*2)萃取；合并有机层，无水硫酸钠干燥，过滤，滤液减压旋干得残留物，残留物用硅胶柱柱色谱分离纯化(乙酸乙酯：石油醚(v/v)＝0:1-1:0)得淡黄色固体3-(2-氯-4-[(5-甲基-1H-吡唑-3-基)氨基]-7H-吡咯并[2,3-d]嘧啶-7-基)丙腈(31c)(350mg,21％)。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. After the reaction was completed, the 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 the filtrate was spin-dried under reduced pressure to obtain a residue, The residue was separated and purified by silica gel column chromatography (ethyl acetate:petroleum ether (v/v)=0:1-1:0) to obtain a pale yellow solid 3-(2-chloro-4-[(5-methyl- 1H-pyrazol-3-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl)propionitrile (31c) (350 mg, 21%).
LCMS m/z＝302.1[M+1] +。 LCMS m/z=302.1[M+1] + .
第三步：Cis-3-(2-((5-羟基金刚烷-2-基)氨基)-4-((5-甲基-1H-吡唑-3-基)氨基)-7H-吡咯并[2,3-d]嘧啶-7–yl)丙腈(化合物31)The third step: Cis-3-(2-((5-hydroxyadamantan-2-yl)amino)-4-((5-methyl-1H-pyrazol-3-yl)amino)-7H-pyrrole Py[2,3-d]pyrimidine-7-yl)propionitrile (Compound 31)
Cis-3-(2-((5-hydroxyadamantan-2-yl)amino)-4-((5-methyl-1H-pyrazol-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)propanenitrileCis-3-(2-((5-hydroxyadamantan-2-yl)amino)-4-((5-methyl-1H-pyrazol-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin -7-yl)propanenitrile
Figure PCTCN2021103485-appb-000381
Figure PCTCN2021103485-appb-000381
室温下，3-(2-氯-4-[(5-甲基-1H-吡唑-3-基)氨基]-7H-吡咯并[2,3-d]嘧啶-7-基)丙腈(31c)(150mg,0.50mmol)和正丁醇(10mL)加入微波管中，再依次加入cis-4-氨基-1-羟基金刚烷盐酸盐(154mg,0.76mmol)和N,N-二异丙基乙胺(292mg，2.26mmol)，然后150℃微波条件下搅拌21小时。反应结束后，将反应液减压浓缩，粗品经Pre-HPLC纯化(仪器及制备柱：采用WATERS 2767制备液相，制备柱型号是Xselect C18，5μm，内径*长度＝19mm*150mm)。制备方法：粗品用二甲亚砜溶解，并用0.45μm滤膜过滤，制备成样品液。流动相体系：乙腈/水(含0.1％氨水)。梯度洗脱方法：乙腈由5％梯度洗脱50％(洗脱时间15min)。冻干后得到Cis-3-(2-((5-羟基金刚烷-2-基)氨基)-4-((5-甲基-1H-吡唑-3-基)氨基)-7H-吡咯并[2,3-d]嘧啶-7–yl)丙腈(化合物31)(5mg，3％)。3-(2-Chloro-4-[(5-methyl-1H-pyrazol-3-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl)propionitrile at room temperature (31c) (150 mg, 0.50 mmol) and n-butanol (10 mL) were added to a microwave tube, followed by cis-4-amino-1-hydroxyadamantane hydrochloride (154 mg, 0.76 mmol) and N,N-diiso propylethylamine (292 mg, 2.26 mmol), then stirred under microwave conditions at 150°C for 21 hours. After the reaction, the reaction solution was concentrated under reduced pressure, and the crude product was purified by Pre-HPLC (instrument and preparative column: WATERS 2767 was used to prepare the liquid phase, and the preparative column model was Xselect C18, 5 μm, inner diameter*length=19mm*150mm). Preparation method: the crude product is dissolved in dimethyl sulfoxide, and filtered with a 0.45 μm 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%).
LCMS m/z＝433.2[M+1] +。 LCMS m/z=433.2[M+1] + .
1H NMR(400MHz,DMSO-d 6)δ11.35(s,1H),8.02(s,1H),7.26-6.97(m,2H),6.76(s,1H),6.07(s,1H),4.31(t,2H),3.93-3.89(m,1H),3.09(t,2H),2.35-2.20(m,5H),2.11-2.03(m,1H),1.95-1.85(m,2H),1.75-1.58(m,6H),1.49-1.40(m,2H). 1 H NMR(400MHz, DMSO-d 6 )δ11.35(s,1H),8.02(s,1H),7.26-6.97(m,2H),6.76(s,1H),6.07(s,1H), 4.31(t,2H),3.93-3.89(m,1H),3.09(t,2H),2.35-2.20(m,5H),2.11-2.03(m,1H),1.95-1.85(m,2H), 1.75-1.58(m,6H),1.49-1.40(m,2H).
实施例32:Cis-N 5-(5-氟-2-金刚烷)-N 7-(5-甲基-1H-吡唑-3-基)-1,6-萘啶-5,7-二胺(化合物32)的三氟乙酸盐 Example 32: Cis-N 5 - ( 5- fluoro-2-adamantyl) -N 7 - (5- methyl -1H- pyrazol-3-yl) -1,6-naphthyridine-5,7 Trifluoroacetate salt of diamine (compound 32)
Cis-N 5-(5-fluoro-2-adamantyl)-N 7-(5-methyl-1H-pyrazol-3-yl)-1,6-naphthyridine-5,7-diamine trifluoroacetate Cis-N 5 -(5-fluoro-2-adamantyl)-N 7 -(5-methyl-1H-pyrazol-3-yl)-1,6-naphthyridine-5,7-diamine trifluoroacetate
Figure PCTCN2021103485-appb-000382
Figure PCTCN2021103485-appb-000382
化合物32以5,7-二氯-1,6-萘啶(1a)和5-氟金刚烷-2-胺(参照文献doi.org/10.1016/j.bmc.2018.08.005合成方法制备得到)为起始物料,参考实施例1的合成方 法，得到Cis-N 5-(5-氟-2-金刚烷)-N 7-(5-甲基-1H-吡唑-3-基)-1,6-萘啶-5,7-二胺(化合物32)的三氟乙酸盐。 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.
LCMS m/z＝393.2[M+1] +。 LCMS m/z=393.2[M+1] + .
1H NMR(400MHz,CD 3OD)δ9.02(d,1H),8.46(dd,1H),7.22(dd,1H),6.69(s,1H),6.13(s,1H),4.29-4.22(m,1H),2.66-2.56(m,2H),2.34-2.20(m,6H),1.98-1.74(m,8H). 1 H NMR (400MHz, CD 3 OD) δ 9.02(d,1H), 8.46(dd,1H), 7.22(dd,1H), 6.69(s,1H), 6.13(s,1H), 4.29-4.22 (m,1H),2.66-2.56(m,2H),2.34-2.20(m,6H),1.98-1.74(m,8H).
实施例33:2-[3-[[7-[(5-甲基1H-吡唑-3-基)氨基]-1,6-萘啶-5-基]氨基]-1-双环[1.1.1]戊基]乙腈(化合物33)的三氟乙酸盐Example 33: 2-[3-[[7-[(5-Methyl 1H-pyrazol-3-yl)amino]-1,6-naphthyridin-5-yl]amino]-1-bicyclo[1.1 .1]Amyl]acetonitrile (compound 33) trifluoroacetate salt
2-[3-[[7-[(5-methyl-1H-pyrazol-3-yl)amino]-1,6-naphthyridin-5-yl]amino]-1-bicyclo[1.1.1]pentanyl]acetonitrile trifluoroacetate2-[3-[[7-[(5-methyl-1H-pyrazol-3-yl)amino]-1,6-naphthyridin-5-yl]amino]-1-bicyclo[1.1.1]pentanyl]acetonitrile trifluoroacetate
Figure PCTCN2021103485-appb-000383
Figure PCTCN2021103485-appb-000383
化合物33以5,7-二氯-1,6-萘啶(1a)和2-(3-氨基-1-双环[1.1.1]戊基)乙腈盐酸盐(参照专利WO2018/195123合成方法制备得到)为起始物料,参考实施例1的合成方法，得到2-[3-[[7-[(5-甲基1H-吡唑-3-基)氨基]-1,6-萘啶-5-基]氨基]-1-双环[1.1.1]戊基]乙腈(化合物33)的三氟乙酸盐。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).
LCMS m/z＝346.2[M+1] +。 LCMS m/z=346.2[M+1] + .
1H NMR(400MHz,CD 3OD)δ8.80(dd,1H),8.46(dd,1H),7.22(dd,1H),6.88(s,1H),5.98(s,1H),2.85(s,2H),2.32(s,3H),2.31-2.28(m,6H). 1 H NMR (400MHz, CD 3 OD) δ 8.80(dd, 1H), 8.46(dd, 1H), 7.22(dd, 1H), 6.88(s, 1H), 5.98(s, 1H), 2.85(s ,2H),2.32(s,3H),2.31-2.28(m,6H).
实施例34：2-[[4-[[7-[(5-甲基-1H-吡唑-3-基)氨基]-1,6-萘啶-5-基]氨基]环己基]氨基]乙腈(化合物34)的三氟乙酸盐Example 34: 2-[[4-[[7-[(5-Methyl-1H-pyrazol-3-yl)amino]-1,6-naphthyridin-5-yl]amino]cyclohexyl]amino ] acetonitrile (compound 34) trifluoroacetate salt
2-[[4-[[7-[(5-methyl-1H-pyrazol-3-yl)amino]-1,6-naphthyridin-5-yl]amino]cyclohexyl]amino]acetonitrile trifluoroacetate2-[[4-[[7-[(5-methyl-1H-pyrazol-3-yl)amino]-1,6-naphthyridin-5-yl]amino]cyclohexyl]amino]acetonitrile trifluoroacetate
Figure PCTCN2021103485-appb-000384
Figure PCTCN2021103485-appb-000384
Figure PCTCN2021103485-appb-000385
Figure PCTCN2021103485-appb-000385
将N 5-(4-氨基环己基)-N 7-(5-甲基-1H-吡唑-3-基)-1,6-萘啶-5,7-二胺(27d)(40mg,0.12mmol)，2-溴乙腈(15mg,0.13mmol)，N,N-二异丙基乙胺(31mg,0.24mmol,)加入到乙腈(2mL)和N,N-二甲基甲酰胺(1mL)中，80℃反应16h，然后减压浓缩，残留物经Pre-HPLC纯化(仪器及制备柱：采用Gilson Gx-281制备液相，制备柱型号是Sunfire，5μm，内径*长度＝30mm*150mm)。制备方法：粗品用甲醇溶解，并用0.45μm滤膜过滤，制备成样品液。流动相体系：乙腈/水(含0.5％的三氟乙酸)。梯度洗脱方法：乙腈由10％梯度洗脱60％(洗脱时间16min)，冻干后得到2-[[4-[[7-[(5-甲基-1H-吡唑-3-基)氨基]-1,6-萘啶-5-基]氨基]环己基]氨基]乙腈(化合物34)的三氟乙酸盐(3mg,5％)。 The N 5 - (4- aminocyclohexyl) -N 7 - (5- methyl -1H- pyrazol-3-yl) -1,6-naphthyridine-5,7-diamine (27d) (40mg, 0.12 mmol), 2-bromoacetonitrile (15 mg, 0.13 mmol), N,N-diisopropylethylamine (31 mg, 0.24 mmol, ) was added to acetonitrile (2 mL) and N,N-dimethylformamide (1 mL) ), reacted at 80°C for 16h, then concentrated under reduced pressure, and the residue was purified by Pre-HPLC (instrument and preparative column: Gilson Gx-281 was used to prepare the liquid phase, the preparative column model was Sunfire, 5μm, inner diameter*length=30mm*150mm ). Preparation method: the crude product is dissolved in methanol, and filtered with a 0.45 μm 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%).
LCMS m/z＝377.2[M+1] +。 LCMS m/z=377.2[M+1] + .
1H NMR(400MHz,CD 3OD)δ8.87(d,1H),8.45(dd,1H),7.21(dd,1H),6.74(s,1H),6.08(s,1H),4.31(s,2H),4.28-4.18(m,1H),3.30-3.20(m,1H),2.39-2.19(m,7H),1.69-1.47(m,4H). 1 H NMR (400MHz, CD 3 OD) δ 8.87(d, 1H), 8.45(dd, 1H), 7.21(dd, 1H), 6.74(s, 1H), 6.08(s, 1H), 4.31(s ,2H),4.28-4.18(m,1H),3.30-3.20(m,1H),2.39-2.19(m,7H),1.69-1.47(m,4H).
实施例35：Trans-N 4-(3-甲基-1H-吡唑-5-基)-N 2-(4-乙基环己基)噻吩[3,2-d]嘧啶-2,4-二胺(化合物35)的三氟乙酸盐 Example 35: Trans-N 4 - ( 3- methyl -1H- pyrazol-5-yl) -N 2 - (4- ethyl-cyclohexyl) thieno [3,2-d] pyrimidine-2,4 Trifluoroacetate salt of diamine (compound 35)
Trans-N 4-(3-methyl-1H-pyrazol-5-yl)-N 2-(4-ethylcyclohexyl)thieno[3,2-d]pyrimidine-2,4-diamine trifluoroacetate Trans-N 4 -(3-methyl-1H-pyrazol-5-yl)-N 2 -(4-ethylcyclohexyl)thieno[3,2-d]pyrimidine-2,4-diamine trifluoroacetate
Figure PCTCN2021103485-appb-000386
Figure PCTCN2021103485-appb-000386
化合物35以2-氯-N-(5-甲基-1H-吡唑-3-基)噻吩[3,2-d]嘧啶-4-胺(6b)和Trans-2-(4-氨基环己基)乙腈盐酸盐(以Trans-4-(叔丁氧羰氨基)环己甲酸为起始物料,按照专利WO2019/239387合成方法制备得到)为起始物料,参考实施例6的合成方法，得到Trans-N 4- (3-甲基-1H-吡唑-5-基)-N 2-(4-乙基环己基)噻吩[3,2-d]嘧啶-2,4-二胺(化合物35)的三氟乙酸盐。 Compound 35 was identified with 2-chloro-N-(5-methyl-1H-pyrazol-3-yl)thiophene[3,2-d]pyrimidin-4-amine (6b) and Trans-2-(4-amino ring Hexyl) acetonitrile hydrochloride (with Trans-4-(tert-butoxycarbonylamino) cyclohexanecarboxylic acid as starting material, prepared according to the synthetic method of patent WO2019/239387) as starting material, with reference to the synthetic method of Example 6, to give Trans-N 4 - (3- methyl -1H- pyrazol-5-yl) -N 2 - (4- ethyl-cyclohexyl) thieno [3,2-d] pyrimidine-2,4-diamine ( The trifluoroacetate salt of compound 35).
LCMS m/z＝368.1[M+1] +。 LCMS m/z=368.1[M+1] + .
1H NMR(400MHz,CD 3OD)δ8.15(d,1H),7.23(d,1H),6.51(s,1H),4.20-3.60(m,1H),2.48(d,2H),2.36(s,3H),2.20-2.10(m,2H),2.00-1.90(m,2H),1.86–1.68(m,1H),1.56-1.41(m,2H),1.40-1.27(m,2H). 1 H NMR (400MHz, CD 3 OD) δ 8.15(d, 1H), 7.23(d, 1H), 6.51(s, 1H), 4.20-3.60(m, 1H), 2.48(d, 2H), 2.36 (s,3H), 2.20-2.10(m,2H), 2.00-1.90(m,2H), 1.86-1.68(m,1H), 1.56-1.41(m,2H), 1.40-1.27(m,2H) .
实施例36：Cis-2-[4-[(4-[(5-甲基-1H-吡唑-3-基)氨基]-7H-吡咯并[2,3-d]嘧啶-2-基)氨基]环己基]乙腈(化合物36)Example 36: Cis-2-[4-[(4-[(5-methyl-1H-pyrazol-3-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-2-yl ) amino]cyclohexyl]acetonitrile (compound 36)
Cis-2-[4-[4-[(5-methyl-1H-pyrazol-3-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino]cyclohexyl]acetonitrileCis-2-[4-[4-[(5-methyl-1H-pyrazol-3-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino]cyclohexyl]acetonitrile
Figure PCTCN2021103485-appb-000387
Figure PCTCN2021103485-appb-000387
化合物36以2-氯-N-(3-甲基-1H-吡唑-5-基)-7-(对甲苯磺酰基)吡咯并[2,3-d]嘧啶-4-胺(18c)和Cis-2-(4-氨基环己基)乙腈盐酸盐(以cis-4-(叔丁氧羰氨基)环己甲酸为起始物料,按照专利WO2019/239387合成方法制备得到)为起始物料参考实施例18的合成方法得到Cis-2-[4-[(4-[(5-甲基-1H-吡唑-3-基)氨基]-7H-吡咯并[2,3-d]嘧啶-2-基)氨基]环己基]乙腈(化合物36)。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).
LCMS m/z＝351.2[M+1] +。 LCMS m/z=351.2[M+1] + .
1H NMR(400MHz,CD 3OD)δ6.76(d,1H),6.41(d,1H),6.03(s,1H),4.10-4.00(m,1H),2.46(d,2H),2.26(s,3H),1.95-1.80(m,3H),1.80-1.69(m,4H),1.62-1.44(m,2H). 1 H NMR (400MHz, CD 3 OD) δ 6.76(d,1H), 6.41(d,1H), 6.03(s,1H), 4.10-4.00(m,1H), 2.46(d,2H), 2.26 (s,3H),1.95-1.80(m,3H),1.80-1.69(m,4H),1.62-1.44(m,2H).
实施例37：Trans-2-[4-[(7-[(5-甲基-1H-吡唑-3-基)氨基]-2-[(吗啉-4-基)甲基-1,6-萘啶-5-基)氨基]环己基]乙腈(化合物37)的三氟乙酸盐Example 37: 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) trifluoroacetate salt
Trans-2-[4-[(7-[(5-methyl-1H-pyrazol-3-yl)amino]-2-[(morpholin-4-yl)methyl]-1,6-naphthyridin-5-yl)amino]cyclohexyl]acetonitrile trifluoroacetateTrans-2-[4-[(7-[(5-methyl-1H-pyrazol-3-yl)amino]-2-[(morpholin-4-yl)methyl]-1,6-naphthyridin-5-yl )amino]cyclohexyl]acetonitrile trifluoroacetate
Figure PCTCN2021103485-appb-000388
Figure PCTCN2021103485-appb-000388
化合物37以5,7-二氯-2-[(吗啉-4-基)甲基]-1,6-萘啶(按照专利WO2016/191524合成方法制备得到)和Trans-2-(4-氨基环己基)乙腈；盐酸盐(以Trans-4-(叔丁氧羰氨基)环己甲酸为起始物料,按照专利WO2019/239387合成方法制备得到)为起始物料参考实施例1的合成方法得到Trans-2-[4-[(7-[(5-甲基-1H-吡唑-3-基)氨基]-2-[(吗啉-4-基)甲基-1,6-萘啶-5-基)氨基]环己基]乙腈(化合物37)的三氟乙酸盐。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 Synthesis of 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.
LCMS m/z＝461.3[M+1] +。 LCMS m/z=461.3[M+1] + .
实施例38：Trans-N 4-(3-甲基-1H-吡唑-5-基)-N 6-[4-乙基环己基]-1H-吡唑啉[3,4-d]嘧啶-4,6-二胺(化合物38) Example 38: Trans-N 4 - ( 3- methyl-lH-pyrazol-5-yl) -N 6 - [4- cyclohexyl-ethyl] -1H- pyrazoline [3,4-d] pyrimidine -4,6-Diamine (Compound 38)
Trans-N 4-(3-methyl-1H-pyrazol-5-yl)-N 6-[4-ethylcyclohexyl]-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine Trans-N 4 -(3-methyl-1H-pyrazol-5-yl)-N 6 -[4-ethylcyclohexyl]-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine
Figure PCTCN2021103485-appb-000389
Figure PCTCN2021103485-appb-000389
化合物38以6-氯-N-(5-甲基-1H-吡唑-3-基)-1-四氢吡喃-2-基-吡唑[3,4-d]嘧啶-4-胺(5c)和Trans-2-(4-氨基环己基)乙腈；盐酸盐(以Trans-4-(叔丁氧羰氨基)环己甲酸为起始物料,按照专利WO2019/239387合成方法制备得到)为起始物料参考实施例8的合成方法，得到N 4-(3-甲基-1H-吡唑-5-基)-N 6-[(1S,4s)-4-乙基环己基]-1H-吡唑啉[3,4-d]嘧啶-4,6-二胺(化合物38)。 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).
LCMS m/z＝352.2[M+1] +。 LCMS m/z=352.2[M+1] + .
1H NMR(400MHz,CD 3OD)δ7.85(s,1H),6.60-5.60(m,1H),3.89-3.69(m,1H),2.43(d,2H),2.38-2.00(m,5H),2.00-1.82(m,2H),1.80-1.64(m,1H),1.45-1.16(m,4H). 1 H NMR (400MHz, CD 3 OD) δ7.85(s, 1H), 6.60-5.60(m, 1H), 3.89-3.69(m, 1H), 2.43(d, 2H), 2.38-2.00(m, 5H), 2.00-1.82(m, 2H), 1.80-1.64(m, 1H), 1.45-1.16(m, 4H).
实施例39：Trans-4-[(4-[(1-甲基-1H-咪唑-4-基)氨基]-7H-吡咯并[2,3-d]嘧啶-2-基)氨基]金刚烷-1-醇(化合物39)Example 39: Trans-4-[(4-[(1-methyl-1H-imidazol-4-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino]adamant Alkan-1-ol (Compound 39)
Trans-4-[(4-[(1-methyl-1H-imidazol-4-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino]adamantan-1-olTrans-4-[(4-[(1-methyl-1H-imidazol-4-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino]adamantan-1-ol
Figure PCTCN2021103485-appb-000390
Figure PCTCN2021103485-appb-000390
化合物39以2,4-二氯-7-(对甲苯磺酰基)吡咯并[2,3-d]嘧啶(18b)和1-甲基-4-氨基咪唑盐酸盐、Trans-4-氨基金刚烷-1-醇盐酸盐为原料，参考实施例18的合成方法，得到Trans-4-[(4-[(1-甲基-1H-咪唑-4-基)氨基]-7H-吡咯并[2,3-d]嘧啶-2-基)氨基]金刚烷-1-醇(化合物39)。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).
LCMS m/z＝380.2[M+1] +。 LCMS m/z=380.2[M+1] + .
1H NMR(400MHz,DMSO-d 6)δ10.74(s,1H),9.36(s,1H),7.59(s,1H),7.36(d,1H),6.70-6.60(m,2H),5.79(d,1H),4.39(s,1H),4.01-3.89(m,1H),3.67(s,3H),2.22-2.14(m,2H),2.06-1.94(m,3H),1.82-1.74(m,2H),1.71-1.59(m,4H),1.38-1.28(m,2H). 1 H NMR (400MHz, DMSO-d 6 )δ10.74(s,1H), 9.36(s,1H), 7.59(s,1H), 7.36(d,1H), 6.70-6.60(m,2H), 5.79(d, 1H), 4.39(s, 1H), 4.01-3.89(m, 1H), 3.67(s, 3H), 2.22-2.14(m, 2H), 2.06-1.94(m, 3H), 1.82- 1.74(m,2H),1.71-1.59(m,4H),1.38-1.28(m,2H).
实施例40：Cis-4-[(4-[(1-甲基-1H-咪唑-4-基)氨基]-7H-吡咯并[2,3-d]嘧啶-2-基)氨基]金刚烷-1-醇(化合物40)Example 40: Cis-4-[(4-[(1-methyl-1H-imidazol-4-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino]adamant Alkan-1-ol (Compound 40)
Cis-4-[(4-[(1-methyl-1H-imidazol-4-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino]adamantan-1-olCis-4-[(4-[(1-methyl-1H-imidazol-4-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino]adamantan-1-ol
Figure PCTCN2021103485-appb-000391
Figure PCTCN2021103485-appb-000391
化合物40以2,4-二氯-7-(对甲苯磺酰基)吡咯并[2,3-d]嘧啶(18b)、1-甲基-4-氨基咪唑盐酸盐、Cis-4-氨基金刚烷-1-醇盐酸盐为原料，参考实施例18的合成方法，得到Cis-4-[(4-[(1-甲基-1H-咪唑-4-基)氨基]-7H-吡咯并[2,3-d]嘧啶-2-基)氨基]金刚烷-1-醇(化合物40)。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).
LCMS m/z＝380.2[M+1] +。 LCMS m/z=380.2[M+1] + .
1H NMR(400MHz,CD 3OD)δ7.48-7.38(m,2H),6.73(d,1H),6.38(d,1H),4.00-3.94(m,1H),3.74(s,3H),2.40-2.30(m,2H),2.20-2.10(m,1H),2.00-1.94(m,2H),1.88-1.71(m,6H),1.62-1.54(m,2H). 1 H NMR (400MHz, CD 3 OD) δ7.48-7.38(m, 2H), 6.73(d, 1H), 6.38(d, 1H), 4.00-3.94(m, 1H), 3.74(s, 3H) ,2.40-2.30(m,2H),2.20-2.10(m,1H),2.00-1.94(m,2H),1.88-1.71(m,6H),1.62-1.54(m,2H).
实施例41：Trans-4-[(7-溴-4-[(3-甲基-1H-吡唑-5-基)氨基]喹唑啉-2-基)氨基]金刚烷-1-醇(化合物41)Example 41: Trans-4-[(7-Bromo-4-[(3-methyl-1H-pyrazol-5-yl)amino]quinazolin-2-yl)amino]adamantan-1-ol (Compound 41)
Trans-4-[(7-bromo-4-[(3-methyl-1H-pyrazol-5-yl)amino]quinazolin-2-yl)amino]adamantan-1-olTrans-4-[(7-bromo-4-[(3-methyl-1H-pyrazol-5-yl)amino]quinazolin-2-yl)amino]adamantan-1-ol
Figure PCTCN2021103485-appb-000392
Figure PCTCN2021103485-appb-000392
第一步：7-溴-2-氯-N-(3-甲基-1H-吡唑-5-基)喹唑啉-4-氨基(41b)The first step: 7-bromo-2-chloro-N-(3-methyl-1H-pyrazol-5-yl)quinazoline-4-amino (41b)
7-bromo-2-chloro-N-(3-methyl-1H-pyrazol-5-yl)quinazolin-4-amine7-bromo-2-chloro-N-(3-methyl-1H-pyrazol-5-yl)quinazolin-4-amine
Figure PCTCN2021103485-appb-000393
Figure PCTCN2021103485-appb-000393
将7-溴-2,4-二氯喹唑啉(200mg，0.72mmol)(41a)，3-甲基-1H-吡唑-5-氨基(77mg，0.79mmol)，三乙胺(150mg，1.44mmol)依次加入到乙醇(4mL)中，25℃反应16h。反应终止后，过滤，滤饼用乙醇(1mLx2)淋洗，滤饼干燥得白色固体7-溴-2-氯-N-(3-甲基-1H-吡唑-5-基)喹唑啉-4-氨基(41b)(240mg,98％)。7-Bromo-2,4-dichloroquinazoline (200 mg, 0.72 mmol) (41a), 3-methyl-1H-pyrazol-5-amino (77 mg, 0.79 mmol), triethylamine (150 mg, 1.44 mmol) was successively added to ethanol (4 mL), and reacted at 25° C. for 16 h. After the reaction was terminated, filtered, the filter cake was rinsed with ethanol (1mL×2), and the filter cake was dried to obtain a white solid 7-bromo-2-chloro-N-(3-methyl-1H-pyrazol-5-yl)quinazoline -4-Amino (41b) (240 mg, 98%).
LCMS m/z＝340.0[M+1] +。 LCMS m/z=340.0[M+1] + .
第二步：Trans-4-[(7-溴-4-[(3-甲基-1H-吡唑5-基)氨基]喹唑啉-2-基)氨基]金刚烷-1-醇(化合物41)The second step: Trans-4-[(7-bromo-4-[(3-methyl-1H-pyrazol-5-yl)amino]quinazolin-2-yl)amino]adamantan-1-ol ( Compound 41)
Trans-4-[(7-bromo-4-[(3-methyl-1H-pyrazol-5-yl)amino]quinazolin-2-yl)amino]adamantan-1-olTrans-4-[(7-bromo-4-[(3-methyl-1H-pyrazol-5-yl)amino]quinazolin-2-yl)amino]adamantan-1-ol
Figure PCTCN2021103485-appb-000394
Figure PCTCN2021103485-appb-000394
将7-溴-2-氯-N-(3-甲基-1H-吡唑-5-基)喹唑啉-4-氨基(41b)(50mg,0.15mmol)，trans-4-氨基金刚烷-1-醇；盐酸盐(33mg,0.17mmol)，N,N-二异丙基乙胺(58mg,0.45mmol)依次加入到N-甲基吡咯烷酮(1mL)中，130℃微波反应4h。反应液经Pre-HPLC纯化(仪器及制备柱：采用WATERS 2767制备液相，制备柱型号是Xselect C18，5μm，内径*长度＝19mm*150mm)。制备方法：反应液用0.45μm滤膜过滤，制备成样品液。流动相体系：乙腈/水。梯度洗脱方法：乙腈由5％梯度洗脱70％(洗脱时间15min)，冻干后得到Trans-4-[(7-溴-4-[(3-甲基-1H-吡唑5-基)氨基]喹唑啉-2-基)氨基]金刚烷-1-醇(化合物41)(20mg,28％)。7-Bromo-2-chloro-N-(3-methyl-1H-pyrazol-5-yl)quinazoline-4-amino (41b) (50 mg, 0.15 mmol), trans-4-aminoadamantane -1-ol; hydrochloride (33 mg, 0.17 mmol), N,N-diisopropylethylamine (58 mg, 0.45 mmol) were added to N-methylpyrrolidone (1 mL) successively, and the reaction was microwaved at 130° C. for 4 h. The reaction solution was purified by Pre-HPLC (instrument and preparative column: WATERS 2767 was used to prepare the liquid phase, the preparative column model was Xselect C18, 5 μm, inner diameter*length=19mm*150mm). Preparation method: The reaction solution was filtered with a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: acetonitrile/water. Gradient elution method: acetonitrile was eluted from 5% to 70% (elution time 15min), and after lyophilization, Trans-4-[(7-bromo-4-[(3-methyl-1H-pyrazole 5- yl)amino]quinazolin-2-yl)amino]adamantan-1-ol (Compound 41) (20 mg, 28%).
LCMS m/z＝469.1,471.1[M+1] +。 LCMS m/z = 469.1, 471.1 [M+1] + .
1H NMR(400MHz,DMSO-d 6,70℃升温核磁)δ8.16(s,1H),7.46(d,1H),7.20(d,1H),6.61(s,1H),4.05(s,1H),3.38-3.35(m,1H),2.34-2.12(m,5H),2.13-1.88(m,3H),1.85-1.74(m,2H),1.74-1.61(m,4H),1.44-1.33(m,2H). 1 H NMR (400MHz, DMSO-d 6 , NMR at 70℃ temperature rise) δ8.16(s, 1H), 7.46(d, 1H), 7.20(d, 1H), 6.61(s, 1H), 4.05(s, 1H), 3.38-3.35(m, 1H), 2.34-2.12(m, 5H), 2.13-1.88(m, 3H), 1.85-1.74(m, 2H), 1.74-1.61(m, 4H), 1.44- 1.33(m,2H).
实施例42：Cis-4-[(7-溴-4-[(3-甲基-1H-吡唑5-基)氨基]喹唑啉-2-基)氨基]金刚烷-1-醇(化合物42)Example 42: Cis-4-[(7-bromo-4-[(3-methyl-1H-pyrazol-5-yl)amino]quinazolin-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-olCis-4-[(7-bromo-4-[(3-methyl-1H-pyrazol-5-yl)amino]quinazolin-2-yl)amino]adamantan-1-ol
Figure PCTCN2021103485-appb-000395
Figure PCTCN2021103485-appb-000395
化合物42以7-溴-2-氯-N-(3-甲基-1H-吡唑-5-基)喹唑啉-4-氨基(41b)和Cis-4-氨基金刚烷-1-醇盐酸盐为起始原料，参考实施例41的合成方法，得到Cis-4-[(7-溴-4-[(3-甲基-1H-吡唑5-基)氨基]喹唑啉-2-基)氨基]金刚烷-1-醇(化合物42)。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).
LCMS m/z＝469.1,471.1[M+1] +。 LCMS m/z = 469.1, 471.1 [M+1] + .
1H NMR(400MHz,DMSO-d 6,70℃升温核磁)δ12.26(s,1H),9.97(s,1H),8.19(d,1H),7.43(d,1H),7.18(dd,1H),6.67(s,1H),6.33(s,1H),4.06(s,1H),3.98-3.88(m,1H),2.30-2.18(m,5H),2.09-2.02(m,1H),2.00-1.92(m,2H),1.77-1.57(m,6H),1.48-1.36(m,2H). 1 H NMR (400MHz, DMSO-d 6 , NMR at 70℃ heating) δ12.26(s, 1H), 9.97(s, 1H), 8.19(d, 1H), 7.43(d, 1H), 7.18(dd, 1H), 6.67(s, 1H), 6.33(s, 1H), 4.06(s, 1H), 3.98-3.88(m, 1H), 2.30-2.18(m, 5H), 2.09-2.02(m, 1H) ,2.00-1.92(m,2H),1.77-1.57(m,6H),1.48-1.36(m,2H).
实施例43：Cis-4-[(4-[(5-甲基-1H-吡唑-3-基)氨基]-7-(1-甲基-1H-吡唑-4-基)喹唑啉-2-基)氨基]金刚烷-1-醇(化合物43)的三氟乙酸盐Example 43: Cis-4-[(4-[(5-Methyl-1H-pyrazol-3-yl)amino]-7-(1-methyl-1H-pyrazol-4-yl)quinazole Lin-2-yl)amino]adamantan-1-ol (compound 43) trifluoroacetate salt
Cis-4-[(4-[(5-methyl-1H-pyrazol-3-yl)amino]-7-(1-methyl-1H-pyrazol-4-yl)quinazolin-2-yl)amino]adamantan-1-ol trifluoroacetateCis-4-[(4-[(5-methyl-1H-pyrazol-3-yl)amino]-7-(1-methyl-1H-pyrazol-4-yl)quinazolin-2-yl)amino]adamantan- 1-ol trifluoroacetate
Figure PCTCN2021103485-appb-000396
Figure PCTCN2021103485-appb-000396
将Cis-4-[(7-溴-4-[(3-甲基-1H-吡唑5-基)氨基]喹唑啉-2-基)氨基]金刚烷-1-醇(化合物42)(50mg,0.11mmol)，(1-甲基-1H-吡唑-4-基)硼酸(28mg,0.22mmol)，[1,1'-双(二苯基膦)二茂铁]二氯化钯(II)(16mg,0.02mmol)，碳酸铯(110mg,0.33mmol)依次加入到1,4-二氧六环(2mL)和水(0.5mL)中，氮气置换后，100℃反应4h，反应结束后，垫硅藻土过滤，旋干滤液得残留物，残留物经Pre-HPLC纯化(仪器及制备柱：采用Waters2767制备液相，制备柱型号是XBridge，5μm，内径*长度＝19mm*250mm)。制备方法：粗品用甲醇溶解，并用0.45μm滤膜过滤，制备成样品液。流动相体系：乙腈/水(含0.1％的三氟乙酸)。梯度洗脱方法：乙腈由10％梯度到50％(洗脱时间16min)，冻干后得到Cis-4-[(4-[(5-甲基-1H-吡唑-3-基)氨基]-7-(1-甲基-1H-吡唑-4-基)喹唑啉-2-基)氨基]金刚烷-1-醇(化合物43)的三氟乙酸盐(10mg，16％)。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. The residue was purified by Pre-HPLC (instrument and preparative column: Waters2767 was used to prepare the liquid phase, and the preparative column model was XBridge, 5 μm, inner diameter*length=19mm* 250mm). Preparation method: the crude product is dissolved in methanol, and filtered with a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: acetonitrile/water (with 0.1% trifluoroacetic acid). Gradient elution method: acetonitrile gradient from 10% to 50% (elution time 16 min), lyophilized to obtain Cis-4-[(4-[(5-methyl-1H-pyrazol-3-yl)amino] - 7-(1-Methyl-1H-pyrazol-4-yl)quinazolin-2-yl)amino]adamantan-1-ol (compound 43) as trifluoroacetate salt (10 mg, 16%) .
LCMS m/z＝471.2[M+1] +。 LCMS m/z=471.2[M+1] + .
1H NMR(400MHz,CD 3OD)δ8.26(d,1H),8.20(s,1H),8.00(s,1H),7.66(d,1H),7.52(s,1H),6.53(s,1H),4.14-4.02(m,1H),3.96(s,3H),2.43-2.30(m,5H),2.22-2.12(m,1H),2.01-1.90(m,2H),1.88-1.71(m,6H),1.70-1.60(m,2H). 1 H NMR (400MHz, CD 3 OD) δ 8.26(d, 1H), 8.20(s, 1H), 8.00(s, 1H), 7.66(d, 1H), 7.52(s, 1H), 6.53(s ,1H),4.14-4.02(m,1H),3.96(s,3H),2.43-2.30(m,5H),2.22-2.12(m,1H),2.01-1.90(m,2H),1.88-1.71 (m,6H),1.70-1.60(m,2H).
实施例44：Cis--4-[(7-(5-甲氧基吡啶-3-基)-4-[(5-甲基-1H-吡唑-3-基)氨基]喹唑啉-2-基)氨基]金刚烷-1-醇(化合物44)的三氟乙酸盐Example 44: Cis--4-[(7-(5-Methoxypyridin-3-yl)-4-[(5-methyl-1H-pyrazol-3-yl)amino]quinazoline- 2-yl)amino]adamantan-1-ol (compound 44) trifluoroacetate salt
Cis-4-[(7-(5-methoxypyridin-3-yl)-4-[(5-methyl-1H-pyrazol-3-yl)amino]quinazolin-2-yl)amino]adamantan-1-ol trifluoroacetateCis-4-[(7-(5-methoxypyridin-3-yl)-4-[(5-methyl-1H-pyrazol-3-yl)amino]quinazolin-2-yl)amino]adamantan-1-ol trifluoroacetate
Figure PCTCN2021103485-appb-000397
Figure PCTCN2021103485-appb-000397
化合物44以Cis-4-[(7-溴-4-[(3-甲基-1H-吡唑5-基)氨基]喹唑啉-2-基)氨基]金刚烷-1-醇(化合物42)和(5-甲氧基吡啶-3-基)硼酸为起始原料，参考实施例43的合成方法，得到Cis--4-[(7-(5-甲氧基吡啶-3-基)-4-[(5-甲基-1H-吡唑-3-基)氨基]喹唑啉-2-基)氨基]金刚烷-1-醇(化合物44)的三氟乙酸盐。Compound 44 was identified as Cis-4-[(7-bromo-4-[(3-methyl-1H-pyrazol-5-yl)amino]quinazolin-2-yl)amino]adamantan-1-ol (compound 42) and (5-methoxypyridin-3-yl)boronic acid as starting materials, referring to the synthetic method of Example 43 to obtain Cis--4-[(7-(5-methoxypyridin-3-yl) )-4-[(5-methyl-1H-pyrazol-3-yl)amino]quinazolin-2-yl)amino]adamantan-1-ol (compound 44) as the trifluoroacetate salt.
LCMS m/z＝498.1[M+1] +。 LCMS m/z=498.1[M+1] + .
1H NMR(400MHz,DMSO-d 6,70℃升温核磁)δ11.38(s,1H),8.72(d,1H),8.59(d,1H),8.40(d,1H),8.26-8.16(m,1H),7.89-7.68(m,3H),7.32-6.85(m,3H),6.54(s,1H),4.07-4.01(m, 1H),3.95(s,3H),2.34-2.22(m,5H),2.15-2.05(m,1H),1.94-1.81(m,2H),1.80-1.61(m,6H),1.60-1.45(m,2H). 1 H NMR (400MHz, DMSO-d 6 , NMR at 70℃ heating)δ11.38(s,1H), 8.72(d,1H), 8.59(d,1H), 8.40(d,1H), 8.26-8.16( m, 1H), 7.89-7.68(m, 3H), 7.32-6.85(m, 3H), 6.54(s, 1H), 4.07-4.01(m, 1H), 3.95(s, 3H), 2.34-2.22( m,5H),2.15-2.05(m,1H),1.94-1.81(m,2H),1.80-1.61(m,6H),1.60-1.45(m,2H).
实施例45：Cis-4-[(7-甲基-4-[(5-甲基-1H-吡唑-3-基)氨基]-7H-吡咯并[2,3-d]嘧啶-2-基]氨基]金刚烷-1-醇(化合物45)的三氟乙酸盐Example 45: Cis-4-[(7-methyl-4-[(5-methyl-1H-pyrazol-3-yl)amino]-7H-pyrrolo[2,3-d]pyrimidine-2 Trifluoroacetate salt of -yl]amino]adamantan-1-ol (compound 45)
Cis-4-[(7-methyl-4-[(5-methyl-1H-pyrazol-3-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino]adamantan-1-ol trifluoroacetateCis-4-[(7-methyl-4-[(5-methyl-1H-pyrazol-3-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino]adamantan-1 -ol trifluoroacetate
Figure PCTCN2021103485-appb-000398
Figure PCTCN2021103485-appb-000398
第一步：2,4-二氯-7-甲基-7H-吡咯并[2,3-d]嘧啶(45b)Step 1: 2,4-Dichloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidine (45b)
2,4-dichloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidine2,4-dichloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidine
Figure PCTCN2021103485-appb-000399
Figure PCTCN2021103485-appb-000399
冰水浴下，将2,4-二氯-7H-吡咯并[2,3-d]嘧啶(18a)(2.00g，10.64mmol)的四氢呋喃(10ml)溶液滴加到氢化钠(0.51g，12.77mmol，含量60％)的四氢呋喃(10ml)溶液中。保持在冰水浴中继续反应0.5小时，然后将碘甲烷(1.80g，12.77mmol)的四氢呋喃(10ml)溶液滴加入反应液中。升温至25摄氏度反应4小时。反应完毕后，将反应液倒入到水(50mL)中，乙酸乙酯(50mL*2)萃取，合并有机相，饱和食盐水(10mL*2)反洗，无水硫酸钠干燥、过滤，母液浓缩至有固体析出，然后过滤即得2,4-二氯-7-甲基-7H-吡咯并[2,3-d]嘧啶(45b)(1.0g，47％)。Under an ice-water bath, a solution of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (18a) (2.00 g, 10.64 mmol) in tetrahydrofuran (10 ml) was added dropwise to sodium hydride (0.51 g, 12.77 g mmol, 60%) in tetrahydrofuran (10 ml). The reaction was continued for 0.5 hours by keeping in an ice-water bath, and then a solution of methyl iodide (1.80 g, 12.77 mmol) in tetrahydrofuran (10 ml) was added dropwise to the reaction solution. The temperature was raised to 25 degrees Celsius for 4 hours. After the reaction was completed, the reaction solution was poured into water (50 mL), extracted with ethyl acetate (50 mL*2), the organic phases were combined, backwashed with saturated brine (10 mL*2), dried over anhydrous sodium sulfate, filtered, and the mother liquor Concentrate until a solid precipitates out, then filter to give 2,4-dichloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidine (45b) (1.0 g, 47%).
LCMS m/z＝202.1,204.1[M+1] + LCMS m/z=202.1,204.1[M+1] +
第二步：N-(2-氯-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-基)-5-甲基-1H-吡唑-3-胺(45c)Step 2: N-(2-Chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-methyl-1H-pyrazol-3-amine (45c)
N-(2-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-methyl-1H-pyrazol-3-amineN-(2-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-methyl-1H-pyrazol-3-amine
Figure PCTCN2021103485-appb-000400
Figure PCTCN2021103485-appb-000400
室温下，将N,N-二异丙基乙胺(1.28g，10.00mmol)加入到5-甲基-1H-吡唑-3-胺(240mg，2.47mmol)、2,4-二氯-7-甲基-7H-吡咯并[2,3-d]嘧啶(45b)(500g，2.47mmol)的乙醇(5ml)溶液中(封管中)。然后升温至110℃反应24小时。然后降至室温，浓缩后加水(10mL)，乙酸乙酯(10mL*2)萃取，合并有机相，饱和食盐水(10mL*2)反洗，无水硫酸钠干燥、过滤、母液浓缩得粗品。粗品经柱层析分离纯化(二氯甲烷：甲醇(v/v)＝10～1)得N-(2-氯-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-基)-5-甲基-1H-吡唑-3-胺(45c)(120mg，18％)。At room temperature, N,N-diisopropylethylamine (1.28 g, 10.00 mmol) was added to 5-methyl-1H-pyrazol-3-amine (240 mg, 2.47 mmol), 2,4-dichloro- 7-Methyl-7H-pyrrolo[2,3-d]pyrimidine (45b) (500 g, 2.47 mmol) in ethanol (5 ml) (in a sealed tube). Then the temperature was raised to 110°C for 24 hours. Then it was cooled to room temperature, concentrated and added with water (10 mL), extracted with ethyl acetate (10 mL*2), the organic phases were combined, backwashed with saturated brine (10 mL*2), dried over anhydrous sodium sulfate, filtered, and the mother liquor was concentrated to obtain the crude product. The crude product was separated and purified by column chromatography (dichloromethane: methanol (v/v)=10～1) to obtain N-(2-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-4) -yl)-5-methyl-1H-pyrazol-3-amine (45c) (120 mg, 18%).
LCMS m/z＝263.1，265.1[M+1] + LCMS m/z=263.1, 265.1[M+1] +
第三步：Cis-4-[(7-甲基-4-[(5-甲基-1H-吡唑-3-基)氨基]-7H-吡咯并[2,3-d]嘧啶-2-基]氨基]金刚烷-1-醇(化合物45)的三氟乙酸盐The third step: Cis-4-[(7-methyl-4-[(5-methyl-1H-pyrazol-3-yl)amino]-7H-pyrrolo[2,3-d]pyrimidine-2 Trifluoroacetate salt of -yl]amino]adamantan-1-ol (compound 45)
Cis-4-[(7-methyl-4-[(5-methyl-1H-pyrazol-3-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino]adamantan-1-ol trifluoroacetateCis-4-[(7-methyl-4-[(5-methyl-1H-pyrazol-3-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino]adamantan-1 -ol trifluoroacetate
Figure PCTCN2021103485-appb-000401
Figure PCTCN2021103485-appb-000401
室温下，将N,N-二异丙基乙胺(200mg，1.52mmol)、N-(2-氯-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-基)-5-甲基-1H-吡唑-3-胺(45c)(100mg，0.38mmol)、Cis-4-氨基金刚烷-1-醇的盐酸盐(63mg，0.38mmol)加入到装有二甲基亚砜(2ml)的微波管中，然后在微波反应器中升温至170℃反应2小时。然后降至室温，将反应液倒入到10mL水中，乙酸乙酯(10mL*2)萃取，合并有机相，饱和食盐水(10mL*2)反洗，无水硫酸钠干燥、过滤、母液浓缩得粗品。粗品经Pre-HPLC纯化(仪器及制备柱：采用Waters 2767制备液相，制备柱型号是Sunfire@Prep C18，5μm，内径*长度＝19mm*250mm)。制备方 法：粗品用DMF溶解，并用0.45μm滤膜过滤，制备成样品液。流动相体系：乙腈/水(含0.1％的三氟乙酸)。梯度洗脱方法：乙腈由5％梯度洗脱50％(流速：15mL/min；洗脱时间15min)，冻干得Cis-4-[(7-甲基-4-[(5-甲基-1H-吡唑-3-基)氨基]-7H-吡咯并[2,3-d]嘧啶-2-基]氨基]金刚烷-1-醇(化合物45)的三氟乙酸盐(5mg，3％)。At room temperature, N,N-diisopropylethylamine (200 mg, 1.52 mmol), N-(2-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl) -5-Methyl-1H-pyrazol-3-amine (45c) (100 mg, 0.38 mmol), hydrochloride salt of Cis-4-aminoadamantan-1-ol (63 mg, 0.38 mmol) were added Methyl sulfoxide (2 ml) in a microwave tube, and then heated to 170°C in a microwave reactor for 2 hours. Then cooled to room temperature, poured the reaction solution into 10 mL of water, extracted with ethyl acetate (10 mL*2), combined the organic phases, backwashed with saturated brine (10 mL*2), dried over anhydrous sodium sulfate, filtered, and the mother liquor was concentrated to obtain Crude. The crude product was purified by Pre-HPLC (instrument and preparative column: Waters 2767 preparative liquid phase was used, the preparative column model was Sunfire@Prep C18, 5 μm, inner diameter*length=19mm*250mm). Preparation method: The crude product is dissolved in DMF, and filtered with a 0.45 μm 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% (flow rate: 15 mL/min; elution time 15 min), lyophilized to obtain Cis-4-[(7-methyl-4-[(5-methyl- 1H-Pyrazol-3-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-2-yl]amino]adamantan-1-ol (compound 45) as trifluoroacetate salt (5 mg, 3%).
LCMS m/z＝394.2[M+1] +。 LCMS m/z=394.2[M+1] + .
1H NMR(400MHz,CD 3OD)δ7.02(d,1H),6.68(d,1H),5.99(s,1H),4.07-3.99(m,1H),3.68(s,3H),2.44-2.39(m,2H),2.36(s,3H),2.20-2.15(m,1H),2.05-1.95(m,2H),1.90-1.75(m,6H),1.65-1.58(m,2H)。 1 H NMR (400MHz, CD 3 OD) δ 7.02(d, 1H), 6.68(d, 1H), 5.99(s, 1H), 4.07-3.99(m, 1H), 3.68(s, 3H), 2.44 -2.39(m, 2H), 2.36(s, 3H), 2.20-2.15(m, 1H), 2.05-1.95(m, 2H), 1.90-1.75(m, 6H), 1.65-1.58(m, 2H) .
实施例46：Trans-4-[(7-甲基-4-[(5-甲基-1H-吡唑-3-基)氨基]-7H-吡咯并[2,3-d]嘧啶-2-基]氨基]金刚烷-1-醇(化合物46)的三氟乙酸盐Example 46: Trans-4-[(7-Methyl-4-[(5-methyl-1H-pyrazol-3-yl)amino]-7H-pyrrolo[2,3-d]pyrimidine-2 -yl]amino]adamantan-1-ol (compound 46) trifluoroacetate salt
Trans-4-[(7-methyl-4-[(5-methyl-1H-pyrazol-3-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino]adamantan-1-ol trifluoroacetateTrans-4-[(7-methyl-4-[(5-methyl-1H-pyrazol-3-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino]adamantan-1 -ol trifluoroacetate
Figure PCTCN2021103485-appb-000402
Figure PCTCN2021103485-appb-000402
化合物2以N-(2-氯-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-基)-5-甲基-1H-吡唑-3-胺(45c)和Trans-4-氨基金刚烷-1-醇的盐酸盐为起始原料，参考实施例45的合成方法，得到Trans-4-[(7-甲基-4-[(5-甲基-1H-吡唑-3-基)氨基]-7H-吡咯并[2,3-d]嘧啶-2-基]氨基]金刚烷-1-醇(化合物46)的三氟乙酸盐。Compound 2 was identified as N-(2-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-methyl-1H-pyrazol-3-amine (45c) and The hydrochloride of Trans-4-aminoadamantan-1-ol was used as the starting material, and with reference to the synthetic method of Example 45, Trans-4-[(7-methyl-4-[(5-methyl-1H was obtained. - Pyrazol-3-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-2-yl]amino]adamantan-1-ol (compound 46) as the trifluoroacetate salt.
LCMS m/z＝394.2[M+1] +。 LCMS m/z=394.2[M+1] + .
1H NMR(400MHz,CD 3OD)δ7.2(d,1H),6.68(d,1H),5.99(s,1H),4.17-4.11(m,1H),3.68(s,3H),2.41-2.30(m,5H),2.20-2.13(m,1H),2.05-1.90(m,4H),1.88-1.79(m,4H),1.59-1.52(m,2H). 1 H NMR (400MHz, CD 3 OD) δ 7.2(d,1H), 6.68(d,1H), 5.99(s,1H), 4.17-4.11(m,1H), 3.68(s,3H), 2.41 -2.30(m,5H),2.20-2.13(m,1H),2.05-1.90(m,4H),1.88-1.79(m,4H),1.59-1.52(m,2H).
实施例47：Trans-2-[4-[(7-[(5-甲基-1H-吡唑-3-基)氨基]咪唑并[1,2-c]嘧啶-5-基)氨基]环己基]乙腈(化合物47)的三氟乙酸盐Example 47: Trans-2-[4-[(7-[(5-Methyl-1H-pyrazol-3-yl)amino]imidazo[1,2-c]pyrimidin-5-yl)amino] Cyclohexyl]acetonitrile (compound 47) trifluoroacetate salt
Trans-2-[4-[(7-[(5-methyl-1H-pyrazol-3-yl)amino]imidazo[1,2-c]pyrimidin-5-yl)amino]cyclohexyl]acetonitrile trifluoroacetateTrans-2-[4-[(7-[(5-methyl-1H-pyrazol-3-yl)amino]imidazo[1,2-c]pyrimidin-5-yl)amino]cyclohexyl]acetonitrile trifluoroacetate
Figure PCTCN2021103485-appb-000403
Figure PCTCN2021103485-appb-000403
化合物3以5,7-二氯咪唑并[1,2-c]嘧啶和Trans-2-(4-氨基环己基)乙腈盐酸盐(以Trans-4-(叔丁氧羰氨基)环己甲酸为起始物料,按照专利WO2019/239387合成方法制备得到)为起始原料，参考实施例13的合成方法，得Trans-2-[4-[(7-[(5-甲基-1H-吡唑-3-基)氨基]咪唑并[1,2-c]嘧啶-5-基)氨基]环己基]乙腈(化合物47)的三氟乙酸盐.Compound 3 was synthesized with 5,7-dichloroimidazo[1,2-c]pyrimidine and Trans-2-(4-aminocyclohexyl)acetonitrile hydrochloride (as Trans-4-(tert-butoxycarbonylamino)cyclohexyl) Formic acid is the starting material, prepared according to the synthetic method of patent WO2019/239387) as the starting material, with reference to the synthetic method of Example 13, Trans-2-[4-[(7-[(5-methyl-1H- Pyrazol-3-yl)amino]imidazo[1,2-c]pyrimidin-5-yl)amino]cyclohexyl]acetonitrile (compound 47) as the trifluoroacetate salt.
LCMS m/z＝351.3[M+1] +。 LCMS m/z=351.3[M+1] + .
1H NMR(400MHz,CD 3OD)δ7.84(dd,1H),7.50(d,1H),6.72(s,1H),6.05(s,1H),4.16-4.04(m,1H),2.48(d,2H),2.30(s,3H),2.27-2.19(m,2H),2.03-1.95(m,2H),1.81-1.71(m,1H),1.60-1.47(m,2H),1.42-1.28(m,2H). 1 H NMR (400MHz, CD 3 OD) δ 7.84(dd, 1H), 7.50(d, 1H), 6.72(s, 1H), 6.05(s, 1H), 4.16-4.04(m, 1H), 2.48 (d, 2H), 2.30(s, 3H), 2.27-2.19(m, 2H), 2.03-1.95(m, 2H), 1.81-1.71(m, 1H), 1.60-1.47(m, 2H), 1.42 -1.28(m,2H).
实施例48：Trans-N 4-(4-甲基-1H-吡唑-3-基)-N 2-[4-(丙-2-炔-1-基)环己基]-7H-吡咯并[2,3-d]嘧啶-2,4-二胺(化合物48) Example 48: Trans-N 4 - ( 4- methyl -1H- pyrazol-3-yl) -N 2 - [4- (prop-2-yn-1-yl) cyclohexyl] -7H- pyrrolo [2,3-d]pyrimidine-2,4-diamine (compound 48)
Trans-N 4-(4-methyl-1H-pyrazol-3-yl)-N 2-[4-(prop-2-yn-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine Trans-N 4 -(4-methyl-1H-pyrazol-3-yl)-N 2 -[4-(prop-2-yn-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidine -2,4-diamine
Figure PCTCN2021103485-appb-000404
Figure PCTCN2021103485-appb-000404
化合物48以2-氯-N-(3-甲基-1H-吡唑-5-基)-7-(对甲苯磺酰基)吡咯并[2,3-d]嘧啶-4-胺(18c)和trans-2-(4-氨基环己基)乙腈；盐酸盐(以trans-4-(叔丁氧羰氨基)环己甲酸为起始物料,按照专利WO2019/239387合成方法制备得到)为起始原料，参考实施例18的合成方法，得到Trans-N 4-(4-甲基-1H-吡唑-3-基)-N 2-[4-(丙-2-炔-1-基)环己基]-7H-吡咯并[2,3-d]嘧啶-2,4-二胺(化合物48)。 Compound 48 was prepared as 2-chloro-N-(3-methyl-1H-pyrazol-5-yl)-7-(p-toluenesulfonyl)pyrrolo[2,3-d]pyrimidin-4-amine (18c) and trans-2-(4-aminocyclohexyl)acetonitrile; hydrochloride (from trans-4-(tert-butoxycarbonylamino)cyclohexanecarboxylic acid as starting material, prepared according to the synthetic method of patent WO2019/239387) Starting material, refer to the synthetic method of Example 18 to obtain Trans-N 4 -(4-methyl-1H-pyrazol-3-yl)-N 2 -[4-(prop-2-yn-1-yl) Cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine (compound 48).
LCMS m/z＝351.3[M+1] + LCMS m/z=351.3[M+1] +
1H NMR(400MHz,CD 3OD)δ6.76(d,1H),6.42(d,1H),6.06(s,1H),3.84-3.64(m,1H),2.43(d,2H),2.26(s,3H),2.23-2.15(m,2H),2.02-1.84(m,2H),1.81-1.63(m,1H),1.44-1.22(m,4H). 1 H NMR (400MHz, CD 3 OD) δ 6.76(d,1H), 6.42(d,1H), 6.06(s,1H), 3.84-3.64(m,1H), 2.43(d,2H), 2.26 (s,3H), 2.23-2.15(m,2H), 2.02-1.84(m,2H), 1.81-1.63(m,1H), 1.44-1.22(m,4H).
实施例49：Cis-4-[[7-[(5-乙基-1H-吡唑-3-基)氨基]-1,6-萘啶-5-基]氨基]金刚烷-1-醇(化 合物49)的三氟乙酸盐Example 49: Cis-4-[[7-[(5-ethyl-1H-pyrazol-3-yl)amino]-1,6-naphthyridin-5-yl]amino]adamantan-1-ol (Compound 49) Trifluoroacetate salt
Cis-4-[[7-[(5-ethyl-1H-pyrazol-3-yl)amino]-1,6-naphthyridin-5-yl]amino]adamantan-1-ol trifluoroacetateCis-4-[[7-[(5-ethyl-1H-pyrazol-3-yl)amino]-1,6-naphthyridin-5-yl]amino]adamantan-1-ol trifluoroacetate
Figure PCTCN2021103485-appb-000405
Figure PCTCN2021103485-appb-000405
化合物49以Cis-4-[(7-氯-1,6-萘啶-5-基)氨基]金刚烷-1-醇(1b)和3-氨基-5-乙基吡唑为起始原料，参考实施例1的合成方法，得到Cis-4-[[7-[(5-乙基-1H-吡唑-3-基)氨基]-1,6-萘啶-5-基]氨基]金刚烷-1-醇(化合物49)的三氟乙酸盐Compound 49 started from Cis-4-[(7-chloro-1,6-naphthyridin-5-yl)amino]adamantan-1-ol (1b) and 3-amino-5-ethylpyrazole , with reference to the synthetic method of Example 1, to obtain Cis-4-[[7-[(5-ethyl-1H-pyrazol-3-yl)amino]-1,6-naphthyridin-5-yl]amino] Trifluoroacetate salt of adamantan-1-ol (compound 49)
LCMS m/z＝405.3[M+1] + LCMS m/z=405.3[M+1] +
1H NMR(400MHz,CD 3OD)δ8.98(d,1H),8.46(dd,1H),7.22(dd,1H),6.67(s,1H),6.16(s,1H),4.26-4.22(m,1H),2.76-2.64(q,2H),2.58-2.48(m,2H),2.20-2.15(m,1H),2.09-2.00(m,2H),1.91-1.75(m,5H),1.67-1.60(m,2H),1.33-1.27(m,4H). 1 H NMR (400MHz, CD 3 OD) δ 8.98(d, 1H), 8.46(dd, 1H), 7.22(dd, 1H), 6.67(s, 1H), 6.16(s, 1H), 4.26-4.22 (m,1H), 2.76-2.64(q,2H), 2.58-2.48(m,2H), 2.20-2.15(m,1H), 2.09-2.00(m,2H), 1.91-1.75(m,5H) ,1.67-1.60(m,2H),1.33-1.27(m,4H).
实施例50：Trans-2-[4-[(4-[(5-甲基-1H-吡唑-3-基)氨基]噻吩并[2,3-d]嘧啶-2-基)氨基]环己基]乙腈(化合物50)的三氟乙酸盐Example 50: Trans-2-[4-[(4-[(5-Methyl-1H-pyrazol-3-yl)amino]thieno[2,3-d]pyrimidin-2-yl)amino] Cyclohexyl]acetonitrile (compound 50) trifluoroacetate salt
Trans-2-[4-[(4-[(5-methyl-1H-pyrazol-3-yl)amino]thieno[2,3-d]pyrimidin-2-yl)amino]cyclohexyl]acetonitrile trifluoroacetateTrans-2-[4-[(4-[(5-methyl-1H-pyrazol-3-yl)amino]thieno[2,3-d]pyrimidin-2-yl)amino]cyclohexyl]acetonitrile trifluoroacetate
Figure PCTCN2021103485-appb-000406
Figure PCTCN2021103485-appb-000406
化合物50以2-氯-N-(5-甲基-1H-吡唑-3-基)噻吩并[2,3-d]嘧啶-4-胺(7b)和Trans-2-(4-氨基环己基)乙腈；盐酸盐(以trans-4-(叔丁氧羰氨基)环己甲酸为起始物料,按照专利WO2019/239387合成方法制备得到)为起始原料，参考实施例10的合成方法，得到Trans-2-[4-[(4-[(5-甲基-1H-吡唑-3-基)氨基]噻吩并[2,3-d]嘧啶-2-基)氨基]环己基]乙腈(化合物50)的三氟乙酸盐Compound 50 was identified as 2-chloro-N-(5-methyl-1H-pyrazol-3-yl)thieno[2,3-d]pyrimidin-4-amine (7b) and Trans-2-(4-amino Cyclohexyl)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, the synthesis of reference example 10 method to give Trans-2-[4-[(4-[(5-methyl-1H-pyrazol-3-yl)amino]thieno[2,3-d]pyrimidin-2-yl)amino] ring Hexyl]acetonitrile (compound 50) trifluoroacetate salt
LCMS m/z＝368.2[M+1] + LCMS m/z=368.2[M+1] +
1H NMR(400MHz,CD 3OD)δ7.57(d,1H),7.31(d,1H),6.35(s,1H),3.90-3.75(m,1H),2.47(d,2H),2.37(s,3H),2.23-2.14(m,2H),2.04-1.94(m,2H),1.85-1.70(m,1H),1.52-1.32(m,4H). 1 H NMR (400MHz, CD 3 OD) δ 7.57(d, 1H), 7.31(d, 1H), 6.35(s, 1H), 3.90-3.75(m, 1H), 2.47(d, 2H), 2.37 (s,3H), 2.23-2.14(m,2H), 2.04-1.94(m,2H), 1.85-1.70(m,1H), 1.52-1.32(m,4H).
实施例51：Trans-2-[4-[(4-[(5-甲基-1H-吡唑-3-基)氨基]-5H-吡咯[3,2-d]嘧啶-2-基)氨基]环己基]乙腈(化合物51)的三氟乙酸盐Example 51: Trans-2-[4-[(4-[(5-methyl-1H-pyrazol-3-yl)amino]-5H-pyrro[3,2-d]pyrimidin-2-yl) Amino]cyclohexyl]acetonitrile (compound 51) trifluoroacetate salt
Trans-2-[4-[(4-[(5-methyl-1H-pyrazol-3-yl)amino]-5H-pyrrolo[3,2-d]pyrimidin-2-yl)amino]cyclohexyl]acetonitrile trifluoroacetateTrans-2-[4-[(4-[(5-methyl-1H-pyrazol-3-yl)amino]-5H-pyrrolo[3,2-d]pyrimidin-2-yl)amino]cyclohexyl]acetonitrile trifluoroacetate
Figure PCTCN2021103485-appb-000407
Figure PCTCN2021103485-appb-000407
第一步：2,4-二氯-5-(4-甲苯磺酰基)-5H-吡咯并[3,2-d]嘧啶(51b)First step: 2,4-Dichloro-5-(4-toluenesulfonyl)-5H-pyrrolo[3,2-d]pyrimidine (51b)
2,4-dichloro-5-(4-methylbenzenesulfonyl)-5H-pyrrolo[3,2-d]pyrimidine2,4-dichloro-5-(4-methylbenzenesulfonyl)-5H-pyrrolo[3,2-d]pyrimidine
Figure PCTCN2021103485-appb-000408
Figure PCTCN2021103485-appb-000408
室温下，将2,4-二氯-5H-吡咯并[3,2-d]嘧啶(51a)(1.00g，5.32mmol)溶于20mL丙酮中，然后再加入对甲苯磺酰氯(1.22g，6.40mmol)、氢氧化钠溶液(2.00M,6.00mmol,3.00mL)，有固体析出，室温反应16小时后，过滤，滤饼用丙酮洗涤得白色固体2,4-二氯-5-(4-甲苯磺酰基)-5H-吡咯并[3,2-d]嘧啶(51b)(1.22g，66％)。2,4-Dichloro-5H-pyrrolo[3,2-d]pyrimidine (51a) (1.00 g, 5.32 mmol) was dissolved in 20 mL of acetone at room temperature, followed by the addition of p-toluenesulfonyl chloride (1.22 g, 6.40mmol), sodium hydroxide solution (2.00M, 6.00mmol, 3.00mL), there is solid precipitation, after 16 hours of reaction at room temperature, filter, filter cake is washed with acetone to obtain white solid 2,4-dichloro-5-(4 -Tosyl)-5H-pyrrolo[3,2-d]pyrimidine (51b) (1.22 g, 66%).
LCMS m/z＝342.0,343.9[M+1] + LCMS m/z=342.0,343.9[M+1] +
第二步：N-(2-氯-5-(4-甲基苯磺酰基)-5H-吡咯并[3,2-d]嘧啶-4-基)-5-甲基-1H-吡唑-3-胺(51c)Step 2: N-(2-Chloro-5-(4-methylbenzenesulfonyl)-5H-pyrrolo[3,2-d]pyrimidin-4-yl)-5-methyl-1H-pyrazole -3-amine (51c)
N-(2-chloro-5-(4-methylbenzenesulfonyl)-5H-pyrrolo[3,2-d]pyrimidin-4-yl)-5-methyl-1H-pyrazol-3-amineN-(2-chloro-5-(4-methylbenzenesulfonyl)-5H-pyrrolo[3,2-d]pyrimidin-4-yl)-5-methyl-1H-pyrazol-3-amine
Figure PCTCN2021103485-appb-000409
Figure PCTCN2021103485-appb-000409
室温下，将2,4-二氯-5-(4-甲苯磺酰基)-5H-吡咯并[3,2-d]嘧啶(51b)(400mg，1.17mmol)和5-甲基-1H-吡唑-3-胺(230mg，2.37mmol)溶于15mL乙醇中，再加入N,N-二异丙基乙胺(610mg，4.72mmol)，升温至100℃，反应14小时。冷却至室温后，过滤，滤饼用乙醇洗涤得到得白色固体N-(2-氯-5-(4-甲基苯磺酰基)-5H-吡咯并[3,2-d]嘧啶-4-基)-5-甲基-1H-吡唑-3-胺(51c)(400mg，85％)。2,4-Dichloro-5-(4-toluenesulfonyl)-5H-pyrrolo[3,2-d]pyrimidine (51b) (400 mg, 1.17 mmol) and 5-methyl-1H- Pyrazol-3-amine (230 mg, 2.37 mmol) was dissolved in 15 mL of ethanol, N,N-diisopropylethylamine (610 mg, 4.72 mmol) was added, the temperature was raised to 100° C., and the reaction was performed for 14 hours. After cooling to room temperature, it was filtered, and the filter cake was washed with ethanol to obtain a white solid N-(2-chloro-5-(4-methylbenzenesulfonyl)-5H-pyrrolo[3,2-d]pyrimidine-4- yl)-5-methyl-1H-pyrazol-3-amine (51c) (400 mg, 85%).
LCMS m/z＝403.1[M+1] + LCMS m/z=403.1[M+1] +
第三步：Trans-2-[4-[(4-[(5-甲基-1H-吡唑-3-基)氨基]-5-(4-甲基苯磺酰基)-5H-吡咯并[3,2-d]嘧啶-2-基)氨基]环己基]乙腈(51d)The third step: Trans-2-[4-[(4-[(5-methyl-1H-pyrazol-3-yl)amino]-5-(4-methylbenzenesulfonyl)-5H-pyrrolo [3,2-d]pyrimidin-2-yl)amino]cyclohexyl]acetonitrile (51d)
Trans-2-[4-[(4-[(5-methyl-1H-pyrazol-3-yl)amino]-5-(4-methylbenzenesulfonyl)-5H-pyrrolo[3,2-d]pyrimidin-2-yl)amino]cyclohexyl]acetonitrileTrans-2-[4-[(4-[(5-methyl-1H-pyrazol-3-yl)amino]-5-(4-methylbenzenesulfonyl)-5H-pyrrolo[3,2-d]pyrimidin-2- yl)amino]cyclohexyl]acetonitrile
Figure PCTCN2021103485-appb-000410
Figure PCTCN2021103485-appb-000410
室温下，将N-(2-氯-5-(4-甲基苯磺酰基)-5H-吡咯并[3,2-d]嘧啶-4-基)-5-甲基-1H-吡唑-3-胺(51c)(257mg，0.64mmol)、Trans-2-(4-氨基环己基)乙腈盐酸盐(以Trans-4-(叔丁氧羰氨基)环己甲酸为起始物料,按照专利WO2019/239387合成方法制备得到)(160mg，0.92mmol)、N,N-二异丙基乙胺(1.0g，7.74mmol)和正丁醇(10mL)加入到微波反应管中，升温至110℃，反应24h。减压除去溶剂后，残留物经Pre-HPLC纯化(仪器及制备柱：采用WATERS 2767制备液相，制备柱型号是X select C18，5μm，内径*长度＝19 mm*150mm)。制备方法：粗品用二甲亚砜溶解，并用0.45μm滤膜过滤，制备成样品液。流动相体系：乙腈/水。梯度洗脱方法：乙腈由5％梯度洗脱50％(洗脱时间15min)。冻干得黄色固体Trans-2-[4-[(4-[(5-甲基-1H-吡唑-3-基)氨基]-5-(4-甲基苯磺酰基)-5H-吡咯并[3,2-d]嘧啶-2-基)氨基]环己基]乙腈(51d)(20mg，6％)。At room temperature, N-(2-chloro-5-(4-methylbenzenesulfonyl)-5H-pyrrolo[3,2-d]pyrimidin-4-yl)-5-methyl-1H-pyrazole -3-amine (51c) (257 mg, 0.64 mmol), 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) (160 mg, 0.92 mmol), N,N-diisopropylethylamine (1.0 g, 7.74 mmol) and n-butanol (10 mL) were added to a microwave reaction tube, and the temperature was raised to 110 ℃, the reaction is 24h. After removing the solvent under reduced pressure, the residue was purified by Pre-HPLC (instrument and preparative column: using WATERS 2767 preparative liquid phase, preparative column model is X select C18, 5 μm, inner diameter * length = 19 mm * 150 mm). Preparation method: the crude product is dissolved in dimethyl sulfoxide, and filtered with a 0.45 μm 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). Lyophilized to obtain yellow solid Trans-2-[4-[(4-[(5-methyl-1H-pyrazol-3-yl)amino]-5-(4-methylbenzenesulfonyl)-5H-pyrrole and [3,2-d]pyrimidin-2-yl)amino]cyclohexyl]acetonitrile (51d) (20 mg, 6%).
LCMS m/z＝505.2[M+1] + LCMS m/z=505.2[M+1] +
第四步：Trans-2-[4-[(4-[(5-甲基-1H-吡唑-3-基)氨基]-5H-吡咯并[3,2-d]嘧啶-2-基)氨基]环己基]乙腈(化合物51)的三氟乙酸盐The fourth step: Trans-2-[4-[(4-[(5-methyl-1H-pyrazol-3-yl)amino]-5H-pyrrolo[3,2-d]pyrimidin-2-yl ) amino]cyclohexyl]acetonitrile (compound 51) trifluoroacetate salt
Trans-2-[4-[(4-[(5-methyl-1H-pyrazol-3-yl)amino]-5H-pyrrolo[3,2-d]pyrimidin-2-yl)amino]cyclohexyl]acetonitrile trifluoroacetateTrans-2-[4-[(4-[(5-methyl-1H-pyrazol-3-yl)amino]-5H-pyrrolo[3,2-d]pyrimidin-2-yl)amino]cyclohexyl]acetonitrile trifluoroacetate
Figure PCTCN2021103485-appb-000411
Figure PCTCN2021103485-appb-000411
将Trans-2-[4-[(4-[(5-甲基-1H-吡唑-3-基)氨基]-5-(4-甲基苯磺酰基)-5H-吡咯并[3,2-d]嘧啶-2-基)氨基]环己基]乙腈(51d)(20mg，0.04mmol)溶于甲醇(5mL)中，加入2N氢氧化钠溶液(2.5mL)，室温反应24h。减压除去溶剂后，残留物经Pre-HPLC纯化(仪器及制备柱：采用WATERS 2767制备液相，制备柱型号是X select C18，5μm，内径*长度＝19mm*150mm)。制备方法：粗品用二甲亚砜溶解，并用0.45μm滤膜过滤，制备成样品液。流动相体系：乙腈/水(含0.1％TFA)。梯度洗脱方法：乙腈由5％梯度洗脱50％(洗脱时间15min)。冻干得Trans-2-[4-[(4-[(5-甲基-1H-吡唑-3-基)氨基]-5H-吡咯并[3,2-d]嘧啶-2-基)氨基]环己基]乙腈(化合物51)的三氟乙酸盐(5mg，27％)。Trans-2-[4-[(4-[(5-methyl-1H-pyrazol-3-yl)amino]-5-(4-methylbenzenesulfonyl)-5H-pyrrolo[3, 2-d]pyrimidin-2-yl)amino]cyclohexyl]acetonitrile (51d) (20mg, 0.04mmol) was dissolved in methanol (5mL), 2N sodium hydroxide solution (2.5mL) was added, and the reaction was carried out at room temperature for 24h. After removing the solvent under reduced pressure, the residue was purified by Pre-HPLC (instrument and preparative column: using WATERS 2767 preparative liquid phase, preparative column model is X select C18, 5 μm, inner diameter*length=19mm*150mm). Preparation method: the crude product is dissolved in dimethyl sulfoxide, and filtered with a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: acetonitrile/water (with 0.1% TFA). Gradient elution method: acetonitrile was eluted from 5% gradient to 50% (elution time 15 min). Lyophilized to obtain Trans-2-[4-[(4-[(5-methyl-1H-pyrazol-3-yl)amino]-5H-pyrrolo[3,2-d]pyrimidin-2-yl) Amino]cyclohexyl]acetonitrile (compound 51) as trifluoroacetate salt (5 mg, 27%).
LCMS m/z＝351.2[M+1] + LCMS m/z=351.2[M+1] +
1H NMR(400MHz,CD 3OD)δ7.48(d,1H),6.55(s,1H),6.30(d,1H),3.93-3.73(m,1H),2.48(d,2H),2.34(s,3H),2.23-2.14(m,2H),2.00-1.93(m,2H),1.84-1.69(m,1H),1.50-1.25(m,4H). 1 H NMR (400MHz, CD 3 OD) δ 7.48(d, 1H), 6.55(s, 1H), 6.30(d, 1H), 3.93-3.73(m, 1H), 2.48(d, 2H), 2.34 (s,3H),2.23-2.14(m,2H),2.00-1.93(m,2H),1.84-1.69(m,1H),1.50-1.25(m,4H).
实施例52：Trans-2-[4-[(4-[(1-甲基-1H-咪唑-4-基)氨基]-7H-吡咯并[2,3-d]嘧啶-2-基)氨基]环己基]乙腈(化合物52)的三氟乙酸盐Example 52: Trans-2-[4-[(4-[(1-methyl-1H-imidazol-4-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-2-yl) Amino]cyclohexyl]acetonitrile (compound 52) trifluoroacetate salt
Trans-2-[4-[(4-[(1-methyl-1H-imidazol-4-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino]cyclohexyl]acetonitrile trifluoroacetateTrans-2-[4-[(4-[(1-methyl-1H-imidazol-4-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino]cyclohexyl]acetonitrile trifluoroacetate
Figure PCTCN2021103485-appb-000412
Figure PCTCN2021103485-appb-000412
化合物52以2,4-二氯-7-(对甲苯磺酰基)吡咯并[2,3-d]嘧啶(18b)、1-甲基-4-氨基咪唑盐酸盐、Trans-2-(4-氨基环己基)乙腈盐酸盐(以trans-4-(叔丁氧羰氨基)环己甲酸为起物料,按照专利WO2019/239387合成方法制备得到)为原料，参考实施例18的合成方法，得到Trans-2-[4-[(4-[(1-甲基-1H-咪唑-4-基)氨基]-7H-吡咯并[2,3-d]嘧啶-2-基)氨基]环己基]乙腈(化合物52)的三氟乙酸盐(15mg，20％)。Compound 52 was prepared with 2,4-dichloro-7-(p-toluenesulfonyl)pyrrolo[2,3-d]pyrimidine (18b), 1-methyl-4-aminoimidazole hydrochloride, 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 raw material, refer to the synthetic method of Example 18 , to give Trans-2-[4-[(4-[(1-methyl-1H-imidazol-4-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino] Cyclohexyl]acetonitrile (compound 52) as trifluoroacetate (15 mg, 20%).
LCMS m/z＝351.2[M+1] + LCMS m/z=351.2[M+1] +
1H NMR(400MHz,CD 3OD)δ7.91(s,1H),7.22(s,1H),6.97(d,1H),6.67-6.55(m,1H),3.83(s,1H),3.81-3.72(m,1H),2.46(d,2H),2.24-2.14(m,2H),2.01-1.91(m,2H),1.83-1.66(m,1H),1.48-1.26(m,4H). 1 H NMR (400MHz, CD 3 OD) δ 7.91(s, 1H), 7.22(s, 1H), 6.97(d, 1H), 6.67-6.55(m, 1H), 3.83(s, 1H), 3.81 -3.72(m, 1H), 2.46(d, 2H), 2.24-2.14(m, 2H), 2.01-1.91(m, 2H), 1.83-1.66(m, 1H), 1.48-1.26(m, 4H) .
实施例53：Trans-4-[(4-[(5-甲基-1H-吡唑-3-基)氨基]-5H-吡咯并[3,2-d]嘧啶-2-基)氨基]金刚烷-1-醇(化合物53)Example 53: Trans-4-[(4-[(5-Methyl-1H-pyrazol-3-yl)amino]-5H-pyrrolo[3,2-d]pyrimidin-2-yl)amino] Adamantane-1-ol (Compound 53)
Trans-4-[(4-[(5-methyl-1H-pyrazol-3-yl)amino]-5H-pyrrolo[3,2-d]pyrimidin-2-yl)amino]adamantan-1-olTrans-4-[(4-[(5-methyl-1H-pyrazol-3-yl)amino]-5H-pyrrolo[3,2-d]pyrimidin-2-yl)amino]adamantan-1-ol
Figure PCTCN2021103485-appb-000413
Figure PCTCN2021103485-appb-000413
化合物53以N-(2-氯-5-(4-甲基苯磺酰基)-5H-吡咯并[3,2-d]嘧啶-4-基)-5-甲基-1H-吡唑-3-胺(51c)Ttrans-4-氨基金刚烷-1-醇盐酸盐为起始原料，参考实施例51的合成方法，得到Trans-4-[(4-[(5-甲基-1H-吡唑-3-基)氨基]-5H-吡咯并[3,2-d]嘧啶-2-基)氨基]金刚烷-1-醇(化合物53)。Compound 53 was identified as N-(2-chloro-5-(4-methylbenzenesulfonyl)-5H-pyrrolo[3,2-d]pyrimidin-4-yl)-5-methyl-1H-pyrazole- 3-Amine (51c)Ttrans-4-aminoadamantan-1-ol hydrochloride was used as the starting material, and with reference to the synthetic method of Example 51, Trans-4-[(4-[(5-methyl-1H was obtained. -Pyrazol-3-yl)amino]-5H-pyrrolo[3,2-d]pyrimidin-2-yl)amino]adamantan-1-ol (Compound 53).
LCMS m/z＝380.2[M+1] + LCMS m/z=380.2[M+1] +
1H NMR(400MHz,CD 3OD)δ7.28(d,1H),6.43(s,1H),6.17(d,1H),4.09-4.02(m,1H),2.31(s,3H),2.27-2.20(m,2H),2.16-2.08(m,1H),2.05-1.91(m,4H),1.84-1.75(m,4H),1.56-1.46(m,2H). 1 H NMR (400MHz, CD 3 OD) δ 7.28(d, 1H), 6.43(s, 1H), 6.17(d, 1H), 4.09-4.02(m, 1H), 2.31(s, 3H), 2.27 -2.20(m, 2H), 2.16-2.08(m, 1H), 2.05-1.91(m, 4H), 1.84-1.75(m, 4H), 1.56-1.46(m, 2H).
实施例54：Cis-4-[(4-[(5-甲基-1H-吡唑-3-基)氨基]-5H-吡咯并[3,2-d]嘧啶-2-基)氨基]金刚烷-1-醇(化合物54)Example 54: Cis-4-[(4-[(5-Methyl-1H-pyrazol-3-yl)amino]-5H-pyrrolo[3,2-d]pyrimidin-2-yl)amino] Adamantane-1-ol (Compound 54)
Cis-4-[(4-[(5-methyl-1H-pyrazol-3-yl)amino]-5H-pyrrolo[3,2-d]pyrimidin-2-yl)amino]adamantan-1-olCis-4-[(4-[(5-methyl-1H-pyrazol-3-yl)amino]-5H-pyrrolo[3,2-d]pyrimidin-2-yl)amino]adamantan-1-ol
Figure PCTCN2021103485-appb-000414
Figure PCTCN2021103485-appb-000414
化合物54以N-(2-氯-5-(4-甲基苯磺酰基)-5H-吡咯并[3,2-d]嘧啶-4-基)-5-甲基-1H-吡唑-3-胺(51c)和顺式-4-氨基金刚烷-1-醇盐酸盐为起始原料，参考实施例51的合成方法，得到Cis-4-[(4-[(5-甲基-1H-吡唑-3-基)氨基]-5H-吡咯并[3,2-d]嘧啶-2-基)氨基]金刚烷-1-醇(化合物54)。Compound 54 was identified as N-(2-chloro-5-(4-methylbenzenesulfonyl)-5H-pyrrolo[3,2-d]pyrimidin-4-yl)-5-methyl-1H-pyrazole- Using 3-amine (51c) and cis-4-aminoadamantan-1-ol hydrochloride as starting materials, with reference to the synthetic method of Example 51, Cis-4-[(4-[(5-methyl- 1H-pyrazol-3-yl)amino]-5H-pyrrolo[3,2-d]pyrimidin-2-yl)amino]adamantan-1-ol (compound 54).
LCMS m/z＝380.2[M+1] + LCMS m/z=380.2[M+1] +
1H NMR(400MHz,CD 3OD)δ7.31(d,1H),6.47(s,1H),6.19(d,1H),4.02-3.90(m,1H),2.35-2.27(m,5H),2.18-2.11(m,1H),2.05-1.95(m,2H),1.90-1.77(m,4H),1.76-1.71(m,2H),1.64-1.55(m,2H). 1 H NMR (400MHz, CD 3 OD) δ 7.31(d, 1H), 6.47(s, 1H), 6.19(d, 1H), 4.02-3.90(m, 1H), 2.35-2.27(m, 5H) ,2.18-2.11(m,1H),2.05-1.95(m,2H),1.90-1.77(m,4H),1.76-1.71(m,2H),1.64-1.55(m,2H).
实施例55：Cis-4-[(1-甲基-4-[(5-甲基-1H-吡唑-3-基)氨基]-1H-吡唑啉[3,4-d]嘧啶-6-基)氨基]金刚烷-1-醇(化合物55)Example 55: Cis-4-[(1-methyl-4-[(5-methyl-1H-pyrazol-3-yl)amino]-1H-pyrazolino[3,4-d]pyrimidine- 6-yl)amino]adamantan-1-ol (Compound 55)
Cis-4-[(1-methyl-4-[(5-methyl-1H-pyrazol-3-yl)amino]-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino]adamantan-1-olCis-4-[(1-methyl-4-[(5-methyl-1H-pyrazol-3-yl)amino]-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino]adamantan-1 -ol
Figure PCTCN2021103485-appb-000415
Figure PCTCN2021103485-appb-000415
Figure PCTCN2021103485-appb-000416
Figure PCTCN2021103485-appb-000416
第一步：N-(6-氯-1-甲基-1H-吡唑并[3,4-d]嘧啶-4-基)-5-甲基-1H-吡唑-3-胺(55b)The first step: N-(6-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-5-methyl-1H-pyrazol-3-amine (55b )
N-(6-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-5-methyl-1H-pyrazol-3-amineN-(6-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-5-methyl-1H-pyrazol-3-amine
Figure PCTCN2021103485-appb-000417
Figure PCTCN2021103485-appb-000417
室温下，将4,6-二氯-1-甲基-1H-吡唑[3,4-d]嘧啶(5a)(150mg，0.74mmol)和5-甲基-1H-吡唑-3-胺(230mg，2.37mmol)溶于10mL无水乙醇中，再加入N,N-二异丙基乙胺(480mg,3.7mmol)，然后升温至85℃，反应16小时。反应结束后，降至室温，将反应液缓慢加入水(200mL)中，有固体析出，过滤后，滤饼经旋干得到N-(6-氯-1-甲基-1H-吡唑并[3,4-d]嘧啶-4-基)-5-甲基-1H-吡唑-3-胺(55b)(150mg,77％)。4,6-Dichloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine (5a) (150 mg, 0.74 mmol) and 5-methyl-1H-pyrazole-3- The amine (230 mg, 2.37 mmol) was dissolved in 10 mL of absolute ethanol, N,N-diisopropylethylamine (480 mg, 3.7 mmol) was added, and the temperature was raised to 85° C. for 16 hours. After the reaction was completed, it was lowered to room temperature, and the reaction solution was slowly added to water (200 mL), and a solid was precipitated. After filtration, the filter cake was spin-dried to obtain N-(6-chloro-1-methyl-1H-pyrazolo[ 3,4-d]pyrimidin-4-yl)-5-methyl-1H-pyrazol-3-amine (55b) (150 mg, 77%).
LCMS m/z＝264.1[M+1] + LCMS m/z=264.1[M+1] +
第二步：Cis-4-[(1-甲基-4-[(5-甲基-1H-吡唑-3-基)氨基]-1H-吡唑并[3,4-d]嘧啶-6-基)氨基]金刚烷-1-醇(化合物55)Step 2: Cis-4-[(1-methyl-4-[(5-methyl-1H-pyrazol-3-yl)amino]-1H-pyrazolo[3,4-d]pyrimidine- 6-yl)amino]adamantan-1-ol (Compound 55)
Cis-4-[(1-methyl-4-[(5-methyl-1H-pyrazol-3-yl)amino]-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino]adamantan-1-olCis-4-[(1-methyl-4-[(5-methyl-1H-pyrazol-3-yl)amino]-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino]adamantan-1 -ol
Figure PCTCN2021103485-appb-000418
Figure PCTCN2021103485-appb-000418
室温下，将N-(6-氯-1-甲基-1H-吡唑并[3,4-d]嘧啶-4-基)-5-甲基-1H-吡唑-3-胺(55b)(60mg，0.23mmol)、Cis-4-氨基-1-羟基金刚烷盐酸盐(70.3mg，0.35mmol)和正丁醇(5mL)加入微波管中。再加入N,N-二异丙基乙胺(150mg,1.15mmol)，然后160℃微波反应4小时。反应结束后，将反应液减压浓缩，粗品经Pre-HPLC纯化(仪器及制备柱：采用WATERS 2767制备液相，制备柱型号是Xselect C18，5μm，内径*长度 ＝19mm*150mm)。制备方法：粗品用二甲亚砜溶解，并用0.45μm滤膜过滤，制备成样品液。流动相体系：乙腈/水(含0.1％碳酸氢铵)。梯度洗脱方法：乙腈由5％梯度洗脱50％(洗脱时间15min)。冻干后得到Cis-4-[(1-甲基-4-[(5-甲基-1H-吡唑-3-基)氨基]-1H-吡唑并[3,4-d]嘧啶-6-基)氨基]金刚烷-1-醇(化合物55)(10mg，11％)。。At room temperature, N-(6-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-5-methyl-1H-pyrazol-3-amine (55b ) (60 mg, 0.23 mmol), Cis-4-amino-1-hydroxyadamantane hydrochloride (70.3 mg, 0.35 mmol) and n-butanol (5 mL) were added to a microwave tube. Then N,N-diisopropylethylamine (150 mg, 1.15 mmol) was added, and then the reaction was microwaved at 160° C. for 4 hours. After the reaction, the reaction solution was concentrated under reduced pressure, and the crude product was purified by Pre-HPLC (instrument and preparative column: WATERS 2767 was used to prepare the liquid phase, and the preparative column model was Xselect C18, 5 μm, inner diameter*length=19mm*150mm). Preparation method: the crude product is dissolved in dimethyl sulfoxide, and filtered with a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: acetonitrile/water (with 0.1% ammonium bicarbonate). Gradient elution method: acetonitrile was eluted from 5% gradient to 50% (elution time 15 min). After lyophilization, Cis-4-[(1-methyl-4-[(5-methyl-1H-pyrazol-3-yl)amino]-1H-pyrazolo[3,4-d]pyrimidine- 6-yl)amino]adamantan-1-ol (Compound 55) (10 mg, 11%). .
LCMS m/z＝395.3[M+1] + LCMS m/z=395.3[M+1] +
1H NMR(400MHz,CD 3OD)δ7.79(s,1H),6.18(s,1H),4.08-4.03(m,1H),3.80(s,3H),2.39-2.33(m,2H),2.29(s,3H),2.18-2.11(m,1H),2.05-1.95(m,2H),1.87-1.78(m,4H),1.76-1.71(m,2H),1.63-1.55(m,2H). 1 H NMR (400MHz, CD 3 OD) δ 7.79(s, 1H), 6.18(s, 1H), 4.08-4.03(m, 1H), 3.80(s, 3H), 2.39-2.33(m, 2H) ,2.29(s,3H),2.18-2.11(m,1H),2.05-1.95(m,2H),1.87-1.78(m,4H),1.76-1.71(m,2H),1.63-1.55(m, 2H).
实施例56:Cis-4-[(6-甲基-4-[(5-甲基-1H-吡唑-3-基)氨基]-7H-吡咯并[2,3-d]嘧啶-2-基)氨基]金刚烷-1-醇(化合物56)Example 56: Cis-4-[(6-methyl-4-[(5-methyl-1H-pyrazol-3-yl)amino]-7H-pyrrolo[2,3-d]pyrimidine-2 -yl)amino]adamantan-1-ol (Compound 56)
Cis-4-[(6-methyl-4-[(5-methyl-1H-pyrazol-3-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino]adamantan-1-olCis-4-[(6-methyl-4-[(5-methyl-1H-pyrazol-3-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino]adamantan-1 -ol
Figure PCTCN2021103485-appb-000419
Figure PCTCN2021103485-appb-000419
化合物56以2,4-二氯-6-甲基-7H-吡咯并[2,3-d]嘧啶为起始物料参考实施例18的合成方法，得到Cis-4-[(6-甲基-4-[(5-甲基-1H-吡唑-3-基)氨基]-7H-吡咯并[2,3-d]嘧啶-2-基)氨基]金刚烷-1-醇(化合物56)。Compound 56 uses 2,4-dichloro-6-methyl-7H-pyrrolo[2,3-d]pyrimidine as the starting material and refers to the synthesis method of Example 18 to obtain Cis-4-[(6-methyl -4-[(5-Methyl-1H-pyrazol-3-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino]adamantan-1-ol (Compound 56 ).
LCMS m/z＝394.3[M+1] +。 LCMS m/z=394.3[M+1] + .
1H NMR(400MHz,DMSO-d 6)δ10.57(s,1H),9.16(s,1H),6.13(s,1H),6.10-5.80(m,2H),4.05(s,1H),3.85-3.79(m,1H),2.28-2.13(m,8H),2.07-2.03(m,1H),2.00-1.91(m,2H),1.70-1.64(m,4H),1.62-1.58(m,2H),1.44-1.38(m,2H). 1 H NMR (400MHz, DMSO-d 6 )δ10.57(s,1H), 9.16(s,1H), 6.13(s,1H), 6.10-5.80(m,2H), 4.05(s,1H), 3.85-3.79(m, 1H), 2.28-2.13(m, 8H), 2.07-2.03(m, 1H), 2.00-1.91(m, 2H), 1.70-1.64(m, 4H), 1.62-1.58(m ,2H),1.44-1.38(m,2H).
实施例57：Trans-4-[[4-[(5-甲基-1H-吡唑-3-基)氨基]-7H-吡咯并[2,3-d]嘧啶-2-基]氨基]金刚烷-1-醇(化合物18-a)Example 57: Trans-4-[[4-[(5-Methyl-1H-pyrazol-3-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-2-yl]amino] Adamantane-1-ol (Compound 18-a)
Trans-4-[[4-[(5-methyl-1H-pyrazol-3-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-2-yl]amino]adamantan-1-olTrans-4-[[4-[(5-methyl-1H-pyrazol-3-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-2-yl]amino]adamantan-1-ol
Figure PCTCN2021103485-appb-000420
Figure PCTCN2021103485-appb-000420
第一步：Trans-4-[[4-[(3-甲基-1H-吡唑-5-基)氨基]-7-(对甲苯磺酰基)吡咯并[2,3-d]嘧啶-2-基]氨基]金刚烷-1-醇(18d-a)Step 1: 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-a)
Trans-4-[[4-[(3-methyl-1H-pyrazol-5-yl)amino]-7-(p-tolylsulfonyl)pyrrolo[2,3-d]pyrimidin-2-yl]amino]adamantan-1-olTrans-4-[[4-[(3-methyl-1H-pyrazol-5-yl)amino]-7-(p-tolylsulfonyl)pyrrolo[2,3-d]pyrimidin-2-yl]amino]adamantan- 1-ol
Figure PCTCN2021103485-appb-000421
Figure PCTCN2021103485-appb-000421
将2-氯-N-(3-甲基-1H-吡唑-5-基)-7-(对甲苯磺酰基)吡咯并[2,3-d]嘧啶-4-胺(18c)(500mg,1.24mmol)，Trans-4-氨基金刚烷-1-醇盐酸盐(380mg,1.86mmol),N,N-二异丙基乙胺(961mg,7.44mmol)和正丁醇(12mL)加入微波反应管中，升温至100℃，反应24h。减压除去溶剂后，加入二氯甲烷：甲醇(V/V)＝10:1(10ml)，抽滤除去固体杂质后浓缩，残留物用硅胶柱色谱分离提纯(二氯甲烷：甲醇(V/V)＝15:1)得到白色固体产物Trans-4-[[4-[(3-甲基-1H-吡唑-5-基)氨基]-7-(对甲苯磺酰基)吡咯并[2,3-d]嘧啶-2-基]氨基]金刚烷-1-醇(18d-a)(400mg，60％)。2-Chloro-N-(3-methyl-1H-pyrazol-5-yl)-7-(p-toluenesulfonyl)pyrrolo[2,3-d]pyrimidin-4-amine (18c) (500 mg , 1.24mmol), Trans-4-aminoadamantan-1-ol hydrochloride (380mg, 1.86mmol), N,N-diisopropylethylamine (961mg, 7.44mmol) and n-butanol (12mL) were added to microwave In the reaction tube, the temperature was raised to 100 °C, and the reaction was carried out for 24 h. After the solvent was removed under reduced pressure, dichloromethane:methanol (V/V)=10:1 (10ml) was added, the solid impurities were removed by suction filtration and then concentrated, and the residue was separated and purified by silica gel column chromatography (dichloromethane:methanol (V/V) V)=15:1) to give the product Trans-4-[[4-[(3-methyl-1H-pyrazol-5-yl)amino]-7-(p-toluenesulfonyl)pyrrolo[2 as a white solid ,3-d]pyrimidin-2-yl]amino]adamantan-1-ol (18d-a) (400 mg, 60%).
LCMS m/z＝534.3[M+1] + LCMS m/z=534.3[M+1] +
第二步：Trans-4-[[4-[(5-甲基-1H-吡唑-3-基)氨基]-7H-吡咯并[2,3-d]嘧啶-2-基]氨基]金刚烷-1-醇(化合物18-a)Step 2: Trans-4-[[4-[(5-Methyl-1H-pyrazol-3-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-2-yl]amino] Adamantane-1-ol (Compound 18-a)
Trans-4-[[4-[(5-methyl-1H-pyrazol-3-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-2-yl]amino]adamantan-1-olTrans-4-[[4-[(5-methyl-1H-pyrazol-3-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-2-yl]amino]adamantan-1-ol
Figure PCTCN2021103485-appb-000422
Figure PCTCN2021103485-appb-000422
将Trans-4-[[4-[(3-甲基-1H-吡唑-5-基)氨基]-7-(对甲苯磺酰基)吡咯并[2,3-d]嘧啶-2-基]氨基]金刚烷-1-醇(18d-a)(400mg，0.75mmol)溶于甲醇(5mL)中，加入2N氢氧化钠溶液(5mL)，升温至50℃反应8h。减压除去溶剂后，残留物经Pre-HPLC纯化，粗品经Pre-HPLC纯化(仪器及制备柱：采用WATERS 2767制备液相，制备柱型号是X select C18，5μm，内径*长度＝19mm*150mm)。制备方法：粗品用二甲亚砜溶解，并用0.45μm滤膜过滤，制备成样品液。流动相体系：乙腈/水。梯度洗脱方法：乙腈由5％梯度洗脱50％(洗脱时间15min)。冻干得到Trans-4-[[4-[(5-甲基-1H-吡唑-3-基)氨基]-7H-吡咯并[2,3-d]嘧啶-2-基]氨基]金刚烷-1-醇(化合物18-a)(150mg，53％)。Trans-4-[[4-[(3-methyl-1H-pyrazol-5-yl)amino]-7-(p-toluenesulfonyl)pyrrolo[2,3-d]pyrimidin-2-yl ]Amino]adamantan-1-ol (18d-a) (400 mg, 0.75 mmol) was dissolved in methanol (5 mL), 2N sodium hydroxide solution (5 mL) was added, and the temperature was raised to 50 °C for 8 h. After removing the solvent under reduced pressure, the residue was purified by Pre-HPLC, and the crude product was purified by Pre-HPLC (instrument and preparative column: using WATERS 2767 preparative liquid phase, preparative column model is X select C18, 5μm, inner diameter*length=19mm*150mm ). Preparation method: the crude product is dissolved in dimethyl sulfoxide, and filtered with a 0.45 μm 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). Lyophilization to give Trans-4-[[4-[(5-methyl-1H-pyrazol-3-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-2-yl]amino]adamant Alkan-1-ol (Compound 18-a) (150 mg, 53%).
LCMS m/z＝380.3[M+1] + LCMS m/z=380.3[M+1] +
1H NMR(400MHz,CD 3OD)δ6.76(d,1H),6.42(d,1H),6.10(s,1H),4.07-4.03(m,1H),2.30-2.22(m,5H),2.15-2.09(m,1H),2.07-1.90(m,4H),1.85-1.79(m,4H),1.55-1.45(m,2H)。 1 H NMR (400MHz, CD 3 OD) δ 6.76(d,1H), 6.42(d,1H), 6.10(s,1H), 4.07-4.03(m,1H), 2.30-2.22(m,5H) , 2.15-2.09(m, 1H), 2.07-1.90(m, 4H), 1.85-1.79(m, 4H), 1.55-1.45(m, 2H).
通过核磁对比，化合物18-1为Trans-4-[[4-[(5-甲基-1H-吡唑-3-基)氨基]-7H-吡咯并[2,3-d]嘧啶-2-基]氨基]金刚烷-1-醇(化合物18-a)。By NMR comparison, compound 18-1 is Trans-4-[[4-[(5-methyl-1H-pyrazol-3-yl)amino]-7H-pyrrolo[2,3-d]pyrimidine-2 -yl]amino]adamantan-1-ol (compound 18-a).
实施例58：Cis-4-[[4-[(5-甲基-1H-吡唑-3-基)氨基]-7H-吡咯并[2,3-d]嘧啶-2-基]氨基]金刚烷-1-醇(化合物18-b)Example 58: Cis-4-[[4-[(5-Methyl-1H-pyrazol-3-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-2-yl]amino] Adamantane-1-ol (Compound 18-b)
Cis-4-[[4-[(5-methyl-1H-pyrazol-3-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-2-yl]amino]adamantan-1-olCis-4-[[4-[(5-methyl-1H-pyrazol-3-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-2-yl]amino]adamantan-1-ol
Figure PCTCN2021103485-appb-000423
Figure PCTCN2021103485-appb-000423
Figure PCTCN2021103485-appb-000424
Figure PCTCN2021103485-appb-000424
第一步Cis-4-[[4-[(3-甲基-1H-吡唑-5-基)氨基]-7-(对甲苯磺酰基)吡咯并[2,3-d]嘧啶-2-基]氨基]金刚烷-1-醇(18d-b)The first step Cis-4-[[4-[(3-methyl-1H-pyrazol-5-yl)amino]-7-(p-toluenesulfonyl)pyrrolo[2,3-d]pyrimidine-2 -yl]amino]adamantan-1-ol (18d-b)
Cis-4-[[4-[(3-methyl-1H-pyrazol-5-yl)amino]-7-(p-tolylsulfonyl)pyrrolo[2,3-d]pyrimidin-2-yl]amino]adamantan-1-olCis-4-[[4-[(3-methyl-1H-pyrazol-5-yl)amino]-7-(p-tolylsulfonyl)pyrrolo[2,3-d]pyrimidin-2-yl]amino]adamantan- 1-ol
Figure PCTCN2021103485-appb-000425
Figure PCTCN2021103485-appb-000425
室温下，2-氯-N-(3-甲基-1H-吡唑-5-基)-7-(对甲苯磺酰基)吡咯并[2,3-d]嘧啶-4-胺(18c)(1.0g,2.48mmol)和正丁醇(15mL)加入微波管中，再依次加入顺式-4-氨基-1-羟基金刚烷盐酸盐(1.2g,5.89mmol)和N,N-二异丙基乙胺(2.5g,19.34mmol)，然后100℃微波条件下搅拌24小时。反应结束后，将反应液减压浓缩，粗品用硅胶柱色谱分离提纯(二氯甲烷：甲醇(v/v)＝96:4)得白色固体Cis-4-[[4-[(3-甲基-1H-吡唑-5-基)氨基]-7-(对甲苯磺酰基)吡咯并[2,3-d]嘧啶-2-基]氨基]金刚烷-1-醇(18d-b)(1.2g，91％)。2-Chloro-N-(3-methyl-1H-pyrazol-5-yl)-7-(p-toluenesulfonyl)pyrrolo[2,3-d]pyrimidin-4-amine (18c) at room temperature (1.0g, 2.48mmol) and n-butanol (15mL) were added to a microwave tube, followed by cis-4-amino-1-hydroxyadamantane hydrochloride (1.2g, 5.89mmol) and N,N-diiso propylethylamine (2.5 g, 19.34 mmol), then stirred under microwave conditions at 100°C for 24 hours. After the reaction, the reaction solution was concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol (v/v)=96:4) to obtain a white solid Cis-4-[[4-[(3-methylmethane yl-1H-pyrazol-5-yl)amino]-7-(p-tosyl)pyrrolo[2,3-d]pyrimidin-2-yl]amino]adamantan-1-ol (18d-b) (1.2 g, 91%).
LCMS m/z＝534.2[M+1] + LCMS m/z=534.2[M+1] +
第二步：Cis-4-[[4-[(5-甲基-1H-吡唑-3-基)氨基]-7H-吡咯并[2,3-d]嘧啶-2-基]氨基]金刚烷-1-醇(化合物18-b)Step 2: Cis-4-[[4-[(5-methyl-1H-pyrazol-3-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-2-yl]amino] Adamantane-1-ol (Compound 18-b)
Cis-4-[[4-[(5-methyl-1H-pyrazol-3-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-2-yl]amino]adamantan-1-olCis-4-[[4-[(5-methyl-1H-pyrazol-3-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-2-yl]amino]adamantan-1-ol
Figure PCTCN2021103485-appb-000426
Figure PCTCN2021103485-appb-000426
室温下，将Cis-4-[[4-[(3-甲基-1H-吡唑-5-基)氨基]-7-(对甲苯磺酰基)吡咯并[2,3-d]嘧啶-2-基]氨基]金刚烷-1-醇(18d-b)(1.2g，2.25mmol)溶于甲醇(50mL)中，加入2N氢氧化钠溶液(25mL)，升温至50℃反应8h。减压除去溶剂后，残留物经Pre-HPLC纯化(仪器及制备柱：采用WATERS 2767制备液相，制备柱型号是X select C18，5μm，内径*长度＝19mm*150mm)。制备方法：粗品用二甲亚砜溶解，并用0.45μm滤膜过滤，制备成样品液。流动相体系：乙腈/水。梯度洗脱方法：乙腈由5％梯度洗脱50％(洗脱时间15min)。冻干得Cis-4-[[4-[(5-甲基-1H-吡唑-3-基)氨基]-7H-吡咯并[2,3-d]嘧啶-2-基]氨基]金刚烷-1-醇(化合物18-b)(500mg，59％)。Cis-4-[[4-[(3-methyl-1H-pyrazol-5-yl)amino]-7-(p-toluenesulfonyl)pyrrolo[2,3-d]pyrimidine- 2-yl]amino]adamantan-1-ol (18d-b) (1.2 g, 2.25 mmol) was dissolved in methanol (50 mL), 2N sodium hydroxide solution (25 mL) was added, and the temperature was raised to 50 °C for 8 h. After removing the solvent under reduced pressure, the residue was purified by Pre-HPLC (instrument and preparative column: using WATERS 2767 preparative liquid phase, preparative column model is X select C18, 5 μm, inner diameter*length=19mm*150mm). Preparation method: the crude product is dissolved in dimethyl sulfoxide, and filtered with a 0.45 μm 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). Lyophilized to obtain Cis-4-[[4-[(5-methyl-1H-pyrazol-3-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-2-yl]amino]adamant Alkan-1-ol (compound 18-b) (500 mg, 59%).
LCMS m/z＝380.3[M+1] + LCMS m/z=380.3[M+1] +
1H NMR(400MHz,CD 3OD)δ6.76(d,1H),6.42(d,1H),6.08(s,1H),3.97-3.92(m,1H),2.36-2.30(m,2H),2.27(s,3H),2.17-2.10(m,1H),2.06-1.98(m,2H),1.87-1.72(m,6H),1.62-1.54(m,2H). 1 H NMR (400MHz, CD 3 OD) δ6.76(d,1H), 6.42(d,1H), 6.08(s,1H), 3.97-3.92(m,1H), 2.36-2.30(m,2H) ,2.27(s,3H),2.17-2.10(m,1H),2.06-1.98(m,2H),1.87-1.72(m,6H),1.62-1.54(m,2H).
通过核磁对比，确定化合物18-2为Cis-4-[[4-[(5-甲基-1H-吡唑-3-基)氨基]-7H-吡咯并[2,3-d]嘧啶-2-基]氨基]金刚烷-1-醇(化合物18-b)Through NMR comparison, it was determined that compound 18-2 was Cis-4-[[4-[(5-methyl-1H-pyrazol-3-yl)amino]-7H-pyrrolo[2,3-d]pyrimidine- 2-yl]amino]adamantan-1-ol (compound 18-b)
实施例59：Cis-4-[(4-[(5-甲基-1H-吡唑-3-基)氨基]-7-[(3S)-氧杂戊-3-基]-7H-吡咯并[2,3-d]嘧啶-2-基)氨基]金刚烷-1-醇(化合物59)的三氟乙酸盐Example 59: Cis-4-[(4-[(5-methyl-1H-pyrazol-3-yl)amino]-7-[(3S)-oxopen-3-yl]-7H-pyrrole Trifluoroacetate salt of [2,3-d]pyrimidin-2-yl)amino]adamantan-1-ol (Compound 59)
Cis-4-[(4-[(5-methyl-1H-pyrazol-3-yl)amino]-7-[(3S)-oxolan-3-yl]-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino]adamantan-1-ol trifluoroacetateCis-4-[(4-[(5-methyl-1H-pyrazol-3-yl)amino]-7-[(3S)-oxolan-3-yl]-7H-pyrrolo[2,3-d]pyrimidin -2-yl)amino]adamantan-1-ol trifluoroacetate
Figure PCTCN2021103485-appb-000427
Figure PCTCN2021103485-appb-000427
第一步：4-氯-2-氟-7-[((2S)-氧杂戊-2-基]-7H-吡咯并[2,3-d]嘧啶(59b)First step: 4-Chloro-2-fluoro-7-[((2S)-oxopent-2-yl]-7H-pyrrolo[2,3-d]pyrimidine (59b)
4-chloro-2-fluoro-7-[(2S)-oxolan-2-yl]-7H-pyrrolo[2,3-d]pyrimidine4-chloro-2-fluoro-7-[(2S)-oxolan-2-yl]-7H-pyrrolo[2,3-d]pyrimidine
Figure PCTCN2021103485-appb-000428
Figure PCTCN2021103485-appb-000428
室温下，将4-氯-2-氟-7H-吡咯并[2,3-d]嘧啶(59a)(1.25g,7.29mmol)加入到四氢呋喃(20mL)中,加入(R)-(-)-3-羟基四氢呋喃(0.64g,7.29mmol)和三苯基膦(1.91g,7.29mmol)。混合物冷却到0℃后,慢慢滴加偶氮二甲酸二异丙酯(1.47g,7.29mmol)，滴毕，混合物在室温下搅拌过夜。加水(20mL)淬灭反应，乙酸乙酯(20mL*2)萃取，合并有机相，饱和食盐水(10mL*2)反洗，无水硫酸钠干燥、过滤、母液浓缩得粗品。粗品经制备柱分离纯化(石油醚：乙酸乙酯(v/v)＝10:1)得4-氯-2-氟-7-[((2S)-氧杂戊-2-基]-7H-吡咯并[2,3-d]嘧啶(59b)(1.76g，100％)。4-Chloro-2-fluoro-7H-pyrrolo[2,3-d]pyrimidine (59a) (1.25 g, 7.29 mmol) was added to tetrahydrofuran (20 mL) at room temperature, (R)-(-) -3-Hydroxytetrahydrofuran (0.64 g, 7.29 mmol) and triphenylphosphine (1.91 g, 7.29 mmol). After the mixture was cooled to 0° C., diisopropyl azodicarboxylate (1.47 g, 7.29 mmol) was slowly added dropwise. After the drop was completed, the mixture was stirred at room temperature overnight. Add water (20 mL) to quench the reaction, extract with ethyl acetate (20 mL*2), combine the organic phases, backwash with saturated brine (10 mL*2), dry over anhydrous sodium sulfate, filter, and concentrate the mother liquor to obtain the crude product. The crude product was separated and purified by preparative column (petroleum ether:ethyl acetate (v/v)=10:1) to obtain 4-chloro-2-fluoro-7-[((2S)-oxopen-2-yl]-7H -pyrrolo[2,3-d]pyrimidine (59b) (1.76 g, 100%).
LCMS m/z＝242.1[M+1] +。 LCMS m/z=242.1[M+1] + .
第二步：Cis-4-[(4-氯-7-[(3S)-氧杂戊-3-基]-7H-吡咯并[2,3-d]嘧啶-2-基)氨基]金刚烷-1-醇(59c)Step 2: Cis-4-[(4-Chloro-7-[(3S)-oxopent-3-yl]-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino]adamant Alkan-1-ol (59c)
Cis-4-[(4-chloro-7-[(3S)-oxolan-3-yl]-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino]adamantan-1-olCis-4-[(4-chloro-7-[(3S)-oxolan-3-yl]-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino]adamantan-1-ol
Figure PCTCN2021103485-appb-000429
Figure PCTCN2021103485-appb-000429
将4-氯-2-氟-7-[((2S)-氧杂戊-2-基]-7H-吡咯并[2,3-d]嘧啶(59b)(0.7g,2.90mmol)加入到DMSO(10ml)溶液中、加入Cis-4-氨基金刚烷-1-醇的盐酸盐(0.59g,2.9mmol)和DIPEA(1.12g,8.7mmol)。混合物60℃反应16小时。冷却，加水(10mL)淬灭反应，乙酸乙酯(10mL*2)萃取，合并有机相，饱和食盐水(10mL*2)反洗，无水硫酸钠干燥、过滤、母液浓缩得粗品。粗品经制备柱分离纯化(石油醚：乙酸乙酯(v/v)＝5:1)得到Cis-4-[(4-氯-7-[(3S)-氧杂戊-3-基]-7H-吡咯并[2,3-d]嘧啶-2-基)氨基]金刚烷-1-醇(59c)(0.23g，20％)。4-Chloro-2-fluoro-7-[((2S)-oxopent-2-yl]-7H-pyrrolo[2,3-d]pyrimidine (59b) (0.7 g, 2.90 mmol) was added to In DMSO (10ml) solution, add Cis-4-aminoadamantan-1-ol hydrochloride (0.59g, 2.9mmol) and DIPEA (1.12g, 8.7mmol). The mixture was reacted at 60°C for 16 hours. Cool, add water (10mL) quenched the reaction, extracted with ethyl acetate (10mL*2), combined the organic phases, backwashed with saturated brine (10mL*2), dried over anhydrous sodium sulfate, filtered, and concentrated the mother liquor to obtain the crude product. The crude product was separated by a preparative column. Purification (petroleum ether:ethyl acetate (v/v) = 5:1) gave Cis-4-[(4-chloro-7-[(3S)-oxopen-3-yl]-7H-pyrrolo[ 2,3-d]pyrimidin-2-yl)amino]adamantan-1-ol (59c) (0.23 g, 20%).
LCMS m/z＝389.2[M+1] +。 LCMS m/z=389.2[M+1] + .
第三步：Cis-5-甲基-3-[(7-[(3S)-氧代戊-3-基]-2-{[5-羟基金刚烷-2-基]氨基}-7H-吡咯并[2,3-d]嘧啶-4-基)氨基]-1H-吡唑-1-甲酸叔丁酯(59d)The third step: Cis-5-methyl-3-[(7-[(3S)-oxopent-3-yl]-2-{[5-hydroxyadamantan-2-yl]amino}-7H- Pyrrolo[2,3-d]pyrimidin-4-yl)amino]-1H-pyrazole-1-carboxylic acid tert-butyl ester (59d)
tert-butyl Cis-5-methyl-3-[(7-[(3S)-oxolan-3-yl]-2-{[5-hydroxyadamantan-2-yl]amino}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-1H-pyrazole-1-carboxylatetert-butyl Cis-5-methyl-3-[(7-[(3S)-oxolan-3-yl]-2-{[5-hydroxyadamantan-2-yl]amino}-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino]-1H-pyrazole-1-carboxylate
Figure PCTCN2021103485-appb-000430
Figure PCTCN2021103485-appb-000430
将Cis-4-[(4-氯-7-[(3S)-氧杂戊-3-基]-7H-吡咯并[2,3-d]嘧啶-2-基)氨基]金刚烷-1-醇(59c)(82mg,0.21mmol)，3-氨基-5-甲基-吡唑-1-甲酸叔丁酯(41mg,0.21mmol)，三(二亚苄基丙酮)二钯(9.6mg,0.011mmol)，2-(二环己基膦)-3,6-二甲氧基-2',4',6'-三异丙基-1,1'-联苯(12mg,0.021mmol)，碳酸铯(204mg,0.63mmol)加入到1，4-二氧六环(3mL)中，氮气置换，升温至100℃反应16h。降至室温，垫硅藻土过滤，再用乙酸乙酯(2mL*2)淋洗，然后将滤液减压旋干，得粗品Cis-5-甲基-3-[(7-[(3S)-氧代戊-3-基]-2-{[5-羟基金刚烷-2-基]氨基}-7H-吡咯并[2,3-d]嘧啶-4-基)氨基]-1H-吡唑-1-甲酸叔丁酯(59d)(50mg,43％),直接用于下一步。Cis-4-[(4-Chloro-7-[(3S)-oxopent-3-yl]-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino]adamantane-1 - Alcohol (59c) (82 mg, 0.21 mmol), tert-butyl 3-amino-5-methyl-pyrazole-1-carboxylate (41 mg, 0.21 mmol), tris(dibenzylideneacetone)dipalladium (9.6 mg , 0.011mmol), 2-(dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl (12mg, 0.021mmol) , cesium carbonate (204 mg, 0.63 mmol) was added to 1,4-dioxane (3 mL), nitrogen was replaced, and the temperature was raised to 100 °C for 16 h. It was cooled to room temperature, filtered through celite, rinsed with ethyl acetate (2mL*2), and then the filtrate was spin-dried under reduced pressure to obtain the crude product Cis-5-methyl-3-[(7-[(3S) -oxopent-3-yl]-2-{[5-hydroxyadamantan-2-yl]amino}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-1H-pyridine tert-Butyl oxazole-1-carboxylate (59d) (50 mg, 43%) was used directly in the next step.
LCMS m/z＝550.3[M+1] +。 LCMS m/z=550.3[M+1] + .
第四步：Cis-4-[(4-[(5-甲基-1H-吡唑-3-基)氨基]-7-[(3S)-氧杂戊-3-基]-7H-吡咯并[2,3-d]嘧啶-2-基)氨基]金刚烷-1-醇(化合物59)的三氟乙酸盐Cis-4-[(4-[(5-methyl-1H-pyrazol-3-yl)amino]-7-[(3S)-oxolan-3-yl]-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino]adamantan-1-ol trifluoroacetateThe fourth step: Cis-4-[(4-[(5-methyl-1H-pyrazol-3-yl)amino]-7-[(3S)-oxopent-3-yl]-7H-pyrrole [2,3-d]pyrimidin-2-yl)amino]adamantan-1-ol (Compound 59) trifluoroacetate salt Cis-4-[(4-[(5-methyl-1H-pyrazol- 3-yl)amino]-7-[(3S)-oxolan-3-yl]-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino]adamantan-1-ol trifluoroacetate
Figure PCTCN2021103485-appb-000431
Figure PCTCN2021103485-appb-000431
将Cis-5-甲基-3-[(7-[(3S)-氧代戊-3-基]-2-{[5-羟基金刚烷-2-基]氨基}-7H-吡咯并[2,3-d]嘧啶-4-基)氨基]-1H-吡唑-1-甲酸叔丁酯(1d)(50mg,0.091mmol)溶于二氯甲烷 (4mL)中，然后加入三氟乙酸(2mL)，20℃反应1h后，减压旋干得残留物，残留物经Pre-HPLC纯化(仪器及制备柱：采用Gilson Gx-281制备液相，制备柱型号是Sunfire，5μm，内径*长度＝30mm*150mm)。制备方法：粗品用甲醇溶解，并用0.45μm滤膜过滤，制备成样品液。流动相体系：乙腈/水(含0.5％的三氟乙酸)。梯度洗脱方法：乙腈由10％梯度洗脱60％(洗脱时间16min)，冻干后得到Cis-4-[(4-[(5-甲基-1H-吡唑-3-基)氨基]-7-[(3S)-氧杂戊-3-基]-7H-吡咯并[2,3-d]嘧啶-2-基)氨基]金刚烷-1-醇(化合物59)的三氟乙酸盐(2mg,3.9％)。Cis-5-methyl-3-[(7-[(3S)-oxopent-3-yl]-2-{[5-hydroxyadamantan-2-yl]amino}-7H-pyrrolo[ 2,3-d]pyrimidin-4-yl)amino]-1H-pyrazole-1-carboxylic acid tert-butyl ester (1d) (50 mg, 0.091 mmol) was dissolved in dichloromethane (4 mL) followed by the addition of trifluoroacetic acid (2 mL), reacted at 20°C for 1 h, and spin-dried under reduced pressure to obtain the residue, which was purified by Pre-HPLC (instrument and preparative column: Gilson Gx-281 was used to prepare the liquid phase, the preparative column model was Sunfire, 5 μm, inner diameter * length=30mm*150mm). Preparation method: the crude product is dissolved in methanol, and filtered with a 0.45 μm 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% to 60% (elution time 16min), and after lyophilization, Cis-4-[(4-[(5-methyl-1H-pyrazol-3-yl)amino was obtained ]-7-[(3S)-oxopent-3-yl]-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino]adamantan-1-ol (compound 59) trifluoro Acetate salt (2 mg, 3.9%).
LCMS m/z＝450.2[M+1] + LCMS m/z=450.2[M+1] +
1H NMR(400MHz,CD 3OD)δ7.13(d,1H),6.72(d,1H),5.99(s,1H),5.31-5.23(m,1H),4.22-4.13(m,1H),4.06-3.97(m,3H),3.95-3.87(m,1H),2.62-2.47(m,1H),2.46-2.30(m,5H),2.27-2.14(m,2H),2.07-1.95(m,2H),1.91-1.71(m,6H),1.66-1.57(m,2H). 1 H NMR (400MHz, CD 3 OD) δ 7.13(d,1H), 6.72(d,1H), 5.99(s,1H), 5.31-5.23(m,1H), 4.22-4.13(m,1H) ,4.06-3.97(m,3H),3.95-3.87(m,1H),2.62-2.47(m,1H),2.46-2.30(m,5H),2.27-2.14(m,2H),2.07-1.95( m,2H),1.91-1.71(m,6H),1.66-1.57(m,2H).
实施例60：Cis-4-[[4-[(5-甲基-1H-吡唑-3-基)氨基]-7-[(3R)-草酰-3-基]-7H-吡咯[2,3-d]嘧啶-2-基)氨基]金刚烷-1-醇(化合物60)Example 60: Cis-4-[[4-[(5-Methyl-1H-pyrazol-3-yl)amino]-7-[(3R)-oxalyl-3-yl]-7H-pyrrole[ 2,3-d]pyrimidin-2-yl)amino]adamantan-1-ol (Compound 60)
Cis-4-[(4-[(5-methyl-1H-pyrazol-3-yl)amino]-7-[(3R)-oxolan-3-yl]-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino]adamantan-1-olCis-4-[(4-[(5-methyl-1H-pyrazol-3-yl)amino]-7-[(3R)-oxolan-3-yl]-7H-pyrrolo[2,3-d]pyrimidin -2-yl)amino]adamantan-1-ol
Figure PCTCN2021103485-appb-000432
Figure PCTCN2021103485-appb-000432
化合物60以4-氯-2-氟-7H-吡咯并[2,3-d]嘧啶(59a)、(S)-(-)-3-羟基四氢呋喃为起始物料，参考实施例59的合成方法，得到Cis-4-[[4-[(5-甲基-1H-吡唑-3-基)氨基]-7-[(3R)-草酰-3-基]-7H-吡咯[2,3-d]嘧啶-2-基)氨基]金刚烷-1-醇(化合物60)Compound 60 uses 4-chloro-2-fluoro-7H-pyrrolo[2,3-d]pyrimidine (59a) and (S)-(-)-3-hydroxytetrahydrofuran as starting materials, and the synthesis of reference example 59 method to obtain Cis-4-[[4-[(5-methyl-1H-pyrazol-3-yl)amino]-7-[(3R)-oxalyl-3-yl]-7H-pyrrole[2 ,3-d]pyrimidin-2-yl)amino]adamantan-1-ol (Compound 60)
LCMS m/z＝450.3[M+1] + LCMS m/z=450.3[M+1] +
1H NMR(400MHz,CD 3OD)δ6.85(d,1H),6.45(d,1H),6.07(s,1H),5.25-5.18(m,1H),4.20-4.10(m,1H),4.05-3.89(m,4H),2.53-2.43(m,1H),2.40-2.33(m,2H),2.30-2.12(m,5H),2.07-1.98(m,2H),1.89-1.70(m,6H),1.63-1.54(m,2H). 1 H NMR (400MHz, CD 3 OD) δ6.85(d,1H), 6.45(d,1H), 6.07(s,1H), 5.25-5.18(m,1H), 4.20-4.10(m,1H) ,4.05-3.89(m,4H),2.53-2.43(m,1H),2.40-2.33(m,2H),2.30-2.12(m,5H),2.07-1.98(m,2H),1.89-1.70( m,6H),1.63-1.54(m,2H).
实施例61：Trans-4-[(7-[(2R)-1-羟基丙烷-2-基]-4-[(5-甲基-1H-吡唑-3-基)氨基]-7H-吡咯并[2，3-d]嘧啶-2-基)氨基]金刚烷-1-醇(化合物61)Example 61: Trans-4-[(7-[(2R)-1-hydroxypropan-2-yl]-4-[(5-methyl-1H-pyrazol-3-yl)amino]-7H- Pyrrolo[2,3-d]pyrimidin-2-yl)amino]adamantan-1-ol (Compound 61)
Trans-4-[(7-[(2R)-1-hydroxypropan-2-yl]-4-[(5-methyl-1H-pyrazol-3-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino]adamantan-1-olTrans-4-[(7-[(2R)-1-hydroxypropan-2-yl]-4-[(5-methyl-1H-pyrazol-3-yl)amino]-7H-pyrrolo[2,3-d ]pyrimidin-2-yl)amino]adamantan-1-ol
Figure PCTCN2021103485-appb-000433
Figure PCTCN2021103485-appb-000433
化合物61以4-氯-2-氟-7H-吡咯并[2,3-d]嘧啶(59a)、(S)-1,2-丙二醇为起始物料，参考实施例59的合成方法，得到(Trans)-4-[(7-[(2R)-1-羟基丙烷-2-基]-4-[(5-甲基-1H-吡唑-3-基)氨基]-7H-吡咯并[2，3-d]嘧啶-2-基)氨基]金刚烷-1-醇(化合物61)Compound 61 was obtained by using 4-chloro-2-fluoro-7H-pyrrolo[2,3-d]pyrimidine (59a) and (S)-1,2-propanediol as starting materials, referring to the synthetic method of Example 59, to obtain (Trans)-4-[(7-[(2R)-1-hydroxypropan-2-yl]-4-[(5-methyl-1H-pyrazol-3-yl)amino]-7H-pyrrolo [2,3-d]pyrimidin-2-yl)amino]adamantan-1-ol (Compound 61)
LCMS m/z＝438.2[M+1] + LCMS m/z=438.2[M+1] +
1H NMR(400MHz,DMSO-d 6+D 2O)δ6.86-6.80(m,1H),6.57-6.43(m,1H),5.68(s,1H),4.60-4.46(m,1H),3.96-3.86(m,1H),3.72-3.60(m,2H),2.28-2.10(m,5H),2.04-1.99(m,1H),1.98-1.88(m,2H),1.82-1.72(m,2H),1.70-1.58(m,4H),1.40-1.27(m,5H). 1 H NMR (400MHz, DMSO-d 6 +D 2 O)δ6.86-6.80(m,1H),6.57-6.43(m,1H),5.68(s,1H),4.60-4.46(m,1H) ,3.96-3.86(m,1H),3.72-3.60(m,2H),2.28-2.10(m,5H),2.04-1.99(m,1H),1.98-1.88(m,2H),1.82-1.72( m,2H),1.70-1.58(m,4H),1.40-1.27(m,5H).
实施例62：Trans-4-[(1-[(2S)-1-羟基丁烷-2-基]-4-[(5-甲基-1H-吡唑-3-基)氨基]-1H-吡唑[3,4-d]嘧啶-6-基)氨基]金刚烷-1-醇(化合物62)Example 62: Trans-4-[(1-[(2S)-1-hydroxybutan-2-yl]-4-[(5-methyl-1H-pyrazol-3-yl)amino]-1H - Pyrazol[3,4-d]pyrimidin-6-yl)amino]adamantan-1-ol (Compound 62)
Trans-4-[(1-[(2S)-1-hydroxybutan-2-yl]-4-[(5-methyl-1H-pyrazol-3-yl)amino]-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino]adamantan-1-olTrans-4-[(1-[(2S)-1-hydroxybutan-2-yl]-4-[(5-methyl-1H-pyrazol-3-yl)amino]-1H-pyrazolo[3,4-d ]pyrimidin-6-yl)amino]adamantan-1-ol
Figure PCTCN2021103485-appb-000434
Figure PCTCN2021103485-appb-000434
第一步：(2R)-1-[(叔丁基二甲基硅基)氧]丁基-2-醇(62b)The first step: (2R)-1-[(tert-butyldimethylsilyl)oxy]butyl-2-ol (62b)
(2R)-1-[(tert-butyldimethylsilyl)oxy]butan-2-ol(2R)-1-[(tert-butyldimethylsilyl)oxy]butan-2-ol
Figure PCTCN2021103485-appb-000435
Figure PCTCN2021103485-appb-000435
冰浴下，将(2R)-丁基-1,2-二醇(62a)(5.00g,55.48mmol)、咪唑(3.78g,55.48mmol)溶于二氯甲烷(100mL)中，然后分批加入叔丁基二甲基氯硅烷(8.36g,55.48mmol)，加完后室温反应4h，反应结束后，将反应液用饱和食盐水(100mL)洗1次，无水硫酸钠干燥，过滤，滤液减压浓缩得残留物，残留物用硅胶柱色谱分离提纯(石油醚：乙酸乙酯(V/V)＝10:1)得到(2R)-1-[(叔丁基二甲基硅基)氧]丁基-2-醇(62b)(11.00g,97％)。Under ice bath, (2R)-butyl-1,2-diol (62a) (5.00 g, 55.48 mmol), imidazole (3.78 g, 55.48 mmol) were dissolved in dichloromethane (100 mL), then batchwise Tert-butyldimethylsilyl chloride (8.36 g, 55.48 mmol) was added, and the reaction was carried out at room temperature for 4 h. After the reaction, the reaction solution was washed once with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and The filtrate was concentrated under reduced pressure to obtain a residue, which was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V/V)=10:1) to obtain (2R)-1-[(tert-butyldimethylsilyl) ) oxy]butyl-2-ol (62b) (11.00 g, 97%).
第二步：(2S)-2-肼基丁烷-1-醇盐酸盐(62c)The second step: (2S)-2-hydrazinobutan-1-ol hydrochloride (62c)
(2S)-2-hydrazinylbutan-1-ol chlorohydrogen(2S)-2-hydrazinylbutan-1-ol chlorohydrogen
Figure PCTCN2021103485-appb-000436
Figure PCTCN2021103485-appb-000436
室温下，将(2R)-1-[(叔丁基二甲基硅基)氧]丁基-2-醇(62b)(2.0g,9.79mmol)、三苯基膦(3.85g,14.68mmol)溶于甲苯(20mL)，再缓慢加入偶氮二甲酸二叔丁酯(2.70g,11.74mmol)，氮气置换三次后，室温搅拌16小时，旋干溶剂，向反应粗品中分别加入甲醇(20mL)和氯化氢-1,4二氧六环溶液(4.0M,30mL,120mmol),室温下搅拌反应48小时。反应结束后，旋干反应溶剂，加入水(30mL)中，分别用乙酸乙酯(30mL*3)和二氯甲烷(30mL*3)萃取，水相冻干得到(2S)-2-肼基丁烷-1-醇盐酸盐(62c)(0.91g,66％)。At room temperature, (2R)-1-[(tert-butyldimethylsilyl)oxy]butyl-2-ol (62b) (2.0 g, 9.79 mmol), triphenylphosphine (3.85 g, 14.68 mmol) were mixed together ) was dissolved in toluene (20 mL), then slowly added di-tert-butyl azodicarboxylate (2.70 g, 11.74 mmol), after nitrogen replacement three times, stirred at room temperature for 16 hours, spin-dried the solvent, and added methanol (20 mL to the crude reaction product) ) and hydrogen chloride-1,4 dioxane solution (4.0 M, 30 mL, 120 mmol), and the reaction was stirred at room temperature for 48 hours. After the reaction, the reaction solvent was spin-dried, added to water (30mL), extracted with ethyl acetate (30mL*3) and dichloromethane (30mL*3), and the aqueous phase was lyophilized to obtain (2S)-2-hydrazino. Butan-1-ol hydrochloride (62c) (0.91 g, 66%).
LCMS m/z＝105.2[M+1] + LCMS m/z=105.2[M+1] +
第三步：(2S)-2-(4,6-二氯-1H-吡唑[3,4-d]嘧啶-1-基)丁烷-1-醇(62d)Step 3: (2S)-2-(4,6-Dichloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)butan-1-ol (62d)
(2S)-2-(4,6-dichloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)butan-1-ol(2S)-2-(4,6-dichloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)butan-1-ol
Figure PCTCN2021103485-appb-000437
Figure PCTCN2021103485-appb-000437
室温下，将2,4,6-三氯嘧啶-5-甲醛(1.29g，6.08mmol)溶于异丙醇(25mL)，然后在冰盐浴下，将反应体系温度降至-10℃，再依次分别缓慢加入(2S)-2-肼基丁烷-1-醇盐酸盐(62c)(900mg，6.40mmol)和三乙胺(1.94g，19.20mmol)。冰盐浴下，搅拌 2小时。反应回到室温后，减压除去溶剂后，残留物用硅胶柱色谱分离提纯(石油醚：乙酸乙酯(V/V)＝4:1)得到(2S)-2-(4,6-二氯-1H-吡唑[3,4-d]嘧啶-1-基)丁烷-1-醇(62d)(547mg，33％)。At room temperature, 2,4,6-trichloropyrimidine-5-carbaldehyde (1.29 g, 6.08 mmol) was dissolved in isopropanol (25 mL), and then the temperature of the reaction system was lowered to -10 °C under an ice-salt bath, Then (2S)-2-hydrazinobutan-1-ol hydrochloride (62c) (900 mg, 6.40 mmol) and triethylamine (1.94 g, 19.20 mmol) were added slowly successively. Under an ice-salt bath, stir for 2 hours. After the reaction was returned to room temperature, the solvent was removed under reduced pressure, and the residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V/V)=4:1) to obtain (2S)-2-(4,6-dicarbonate) Chloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)butan-1-ol (62d) (547 mg, 33%).
LCMS m/z＝261.1[M+1] + LCMS m/z=261.1[M+1] +
第四步：(2S)-2-(6-氯-4-[(5-甲基-1H-吡唑-3-基)氨基]-1H-吡唑[3,4-d]嘧啶-1-基)丁基-1-醇(62e)The fourth step: (2S)-2-(6-chloro-4-[(5-methyl-1H-pyrazol-3-yl)amino]-1H-pyrazol[3,4-d]pyrimidine-1 -yl)butyl-1-ol (62e)
(2S)-2-(6-chloro-4-[(5-methyl-1H-pyrazol-3-yl)amino]-1H-pyrazolo[3,4-d]pyrimidin-1-yl)butan-1-ol(2S)-2-(6-chloro-4-[(5-methyl-1H-pyrazol-3-yl)amino]-1H-pyrazolo[3,4-d]pyrimidin-1-yl)butan-1- ol
Figure PCTCN2021103485-appb-000438
Figure PCTCN2021103485-appb-000438
室温下，将(2S)-2-(4,6-二氯-1H-吡唑[3,4-d]嘧啶-1-基)丁烷-1-醇(62d)(261mg，1.00mmol)溶于无水乙醇(5mL)，向其中依次加入3-氨基-5-甲基吡唑(146mg，1.50mmol)和N,N-二异丙基乙胺(259mg,2.00mmol)，然后室温至100℃，加热搅16小时。反应结束后，减压除去溶剂后，残留物用硅胶柱色谱分离提纯(二氯甲烷:甲醇(V/V)＝95:5)得到(2S)-2-(6-氯-4-[(5-甲基-1H-吡唑-3-基)氨基]-1H-吡唑[3,4-d]嘧啶-1-基)丁基-1-醇(62e)(299mg，93％)。(2S)-2-(4,6-Dichloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)butan-1-ol (62d) (261 mg, 1.00 mmol) at room temperature Dissolved in absolute ethanol (5 mL), 3-amino-5-methylpyrazole (146 mg, 1.50 mmol) and N,N-diisopropylethylamine (259 mg, 2.00 mmol) were sequentially added thereto, and then the room temperature to 100 ° C, heating and stirring for 16 hours. After the reaction, the solvent was removed under reduced pressure, and the residue was separated and purified by silica gel column chromatography (dichloromethane:methanol (V/V)=95:5) to obtain (2S)-2-(6-chloro-4-[( 5-Methyl-1H-pyrazol-3-yl)amino]-1H-pyrazolo[3,4-d]pyrimidin-1-yl)butyl-1-ol (62e) (299 mg, 93%).
LCMS m/z＝322.2[M+1] + LCMS m/z=322.2[M+1] +
第五步：Trans-4-[(1-[(2S)-1-羟基丁烷-2-基]-4-[(5-甲基-1H-吡唑-3-基)氨基]-1H-吡唑[3,4-d]嘧啶-6-基)氨基]金刚烷-1-醇(化合物62)The fifth step: Trans-4-[(1-[(2S)-1-hydroxybutan-2-yl]-4-[(5-methyl-1H-pyrazol-3-yl)amino]-1H - Pyrazol[3,4-d]pyrimidin-6-yl)amino]adamantan-1-ol (Compound 62)
Trans-4-[(1-[(2S)-1-hydroxybutan-2-yl]-4-[(5-methyl-1H-pyrazol-3-yl)amino]-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino]adamantan-1-olTrans-4-[(1-[(2S)-1-hydroxybutan-2-yl]-4-[(5-methyl-1H-pyrazol-3-yl)amino]-1H-pyrazolo[3,4-d ]pyrimidin-6-yl)amino]adamantan-1-ol
Figure PCTCN2021103485-appb-000439
Figure PCTCN2021103485-appb-000439
室温下，将(2S)-2-(6-氯-4-[(5-甲基-1H-吡唑-3-基)氨基]-1H-吡唑[3,4-d]嘧啶-1-基)丁基-1-醇(62e)(50mg,0.16mmol)和正丁醇(2mL)加入微波管中，再依次加入trans-4-氨基-1- 羟基金刚烷盐酸盐(65mg,0.32mmol)和N,N-二异丙基乙胺(103mg,0.80mmol)，然后160℃微波条件下搅拌反应4小时。反应结束后，回到室温，减压除去溶剂。粗品经Pre-HPLC纯化(仪器及制备柱：采用WATERS 2767制备液相，制备柱型号是Xselect C18，5μm，内径*长度＝19mm*150mm)。制备方法：粗品用二甲亚砜溶解，并用0.45μm滤膜过滤，制备成样品液。流动相体系：乙腈/水。梯度洗脱方法：乙腈由5％梯度洗脱50％(洗脱时间15min)。冻干后得到Trans-4-[(1-[(2S)-1-羟基丁烷-2-基]-4-[(5-甲基-1H-吡唑-3-基)氨基]-1H-吡唑[3,4-d]嘧啶-6-基)氨基]金刚烷-1-醇(化合物62)(20mg，27％)。At room temperature, (2S)-2-(6-chloro-4-[(5-methyl-1H-pyrazol-3-yl)amino]-1H-pyrazolo[3,4-d]pyrimidine-1 -yl)butyl-1-ol (62e) (50 mg, 0.16 mmol) and n-butanol (2 mL) were added to a microwave tube, followed by trans-4-amino-1-hydroxyadamantane hydrochloride (65 mg, 0.32 mmol) and N,N-diisopropylethylamine (103 mg, 0.80 mmol), then the reaction was stirred under microwave conditions at 160°C for 4 hours. After the reaction was completed, the temperature was returned to room temperature, and the solvent was removed under reduced pressure. The crude product was purified by Pre-HPLC (instrument and preparative column: using WATERS 2767 preparative liquid phase, preparative column model is Xselect C18, 5 μm, inner diameter*length=19mm*150mm). Preparation method: the crude product is dissolved in dimethyl sulfoxide, and filtered with a 0.45 μm 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). Lyophilized to give Trans-4-[(1-[(2S)-1-hydroxybutan-2-yl]-4-[(5-methyl-1H-pyrazol-3-yl)amino]-1H - Pyrazol[3,4-d]pyrimidin-6-yl)amino]adamantan-1-ol (Compound 62) (20 mg, 27%).
LCMS m/z＝453.2[M+1] + LCMS m/z=453.2[M+1] +
1H NMR(400MHz,CD 3OD)δ7.88(s,1H),6.70-5.60(m,1H),4.62-4.41(m,1H),4.20-3.79(m,3H),2.40-2.17(m,5H),2.17-1.86(m,7H),1.85-1.75(m,4H),1.58-1.46(m,2H),0.77(t,3H). 1 H NMR (400MHz, CD 3 OD) δ7.88(s, 1H), 6.70-5.60(m, 1H), 4.62-4.41(m, 1H), 4.20-3.79(m, 3H), 2.40-2.17( m, 5H), 2.17-1.86(m, 7H), 1.85-1.75(m, 4H), 1.58-1.46(m, 2H), 0.77(t, 3H).
实施例63：Cis-4-[(1-(2-羟基-2-甲基丙基)-4-[(5-甲基-1H-吡唑-3-基)氨基]-1H-吡唑[3,4-d]嘧啶-6-基)氨基]金刚烷-1-醇(化合物63)Example 63: Cis-4-[(1-(2-hydroxy-2-methylpropyl)-4-[(5-methyl-1H-pyrazol-3-yl)amino]-1H-pyrazole [3,4-d]pyrimidin-6-yl)amino]adamantan-1-ol (Compound 63)
Cis-4-[(1-(2-hydroxy-2-methylpropyl)-4-[(5-methyl-1H-pyrazol-3-yl)amino]-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino]adamantan-1-olCis-4-[(1-(2-hydroxy-2-methylpropyl)-4-[(5-methyl-1H-pyrazol-3-yl)amino]-1H-pyrazolo[3,4-d]pyrimidin-6 -yl)amino]adamantan-1-ol
Figure PCTCN2021103485-appb-000440
Figure PCTCN2021103485-appb-000440
化合物63以2,4,6-三氯嘧啶-5-甲醛和1-肼基-2-甲基丙烷-2-醇(参考专利WO201056320A2合成)为起始原料，参考实施例62的合成方法，得到Cis-4-[(1-(2-羟基-2-甲基丙基)-4-[(5-甲基-1H-吡唑-3-基)氨基]-1H-吡唑[3,4-d]嘧啶-6-基)氨基]金刚烷-1-醇(化合物63)。Compound 63 uses 2,4,6-trichloropyrimidine-5-carbaldehyde and 1-hydrazino-2-methylpropan-2-ol (synthesized with reference to patent WO201056320A2) as starting materials, referring to the synthetic method of Example 62, Cis-4-[(1-(2-hydroxy-2-methylpropyl)-4-[(5-methyl-1H-pyrazol-3-yl)amino]-1H-pyrazol[3, 4-d]pyrimidin-6-yl)amino]adamantan-1-ol (compound 63).
LCMS m/z＝453.3[M+1] + LCMS m/z=453.3[M+1] +
1H NMR(400MHz,CD 3OD)δ7.87(s,1H),6.71-5.53(m,1H),4.21(s,2H),4.03-3.91(m,1H),2.39-2.21(m,5H),2.17-2.11(m,1H),2.07-1.91(m,2H),1.87-1.69(m,6H),1.64-1.53(m,2H),1.20(s,6H). 1 H NMR (400MHz, CD 3 OD) δ 7.87(s, 1H), 6.71-5.53(m, 1H), 4.21(s, 2H), 4.03-3.91(m, 1H), 2.39-2.21(m, 5H), 2.17-2.11(m, 1H), 2.07-1.91(m, 2H), 1.87-1.69(m, 6H), 1.64-1.53(m, 2H), 1.20(s, 6H).
实施例64:Cis-4-[(7-(2-羟乙基)-4-[(5-甲基-1H-吡唑-3-基)氨基]-7H-吡咯[2,3-d]嘧啶-2-基)氨基]金刚烷-1-醇(化合物64)的三氟乙酸盐Example 64: Cis-4-[(7-(2-hydroxyethyl)-4-[(5-methyl-1H-pyrazol-3-yl)amino]-7H-pyrrole[2,3-d ]pyrimidin-2-yl)amino]adamantan-1-ol (compound 64) trifluoroacetate salt
Cis-4-[(7-(2-hydroxyethyl)-4-[(5-methyl-1H-pyrazol-3-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino]adamantan-1-ol trifluoroacetateCis-4-[(7-(2-hydroxyethyl)-4-[(5-methyl-1H-pyrazol-3-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino ]adamantan-1-ol trifluoroacetate
Figure PCTCN2021103485-appb-000441
Figure PCTCN2021103485-appb-000441
化合物64以4-氯-2-氟-7H-吡咯并[2,3-d]嘧啶(59a)和2-[(叔丁基二甲基硅基)氧]乙烷-1-醇为起始物料参考实施例59的合成方法，得到Cis-4-[(7-(2-羟乙基)-4-[(5-甲基-1H-吡唑-3-基)氨基]-7H-吡咯[2,3-d]嘧啶-2-基)氨基]金刚烷-1-醇(化合物64)的三氟乙酸盐。Compound 64 starts with 4-chloro-2-fluoro-7H-pyrrolo[2,3-d]pyrimidine (59a) and 2-[(tert-butyldimethylsilyl)oxy]ethane-1-ol The starting material was referred to the synthetic method of Example 59 to obtain Cis-4-[(7-(2-hydroxyethyl)-4-[(5-methyl-1H-pyrazol-3-yl)amino]-7H- The trifluoroacetate salt of pyrrole[2,3-d]pyrimidin-2-yl)amino]adamantan-1-ol (compound 64).
LCMS m/z＝424.3[M+1] +。 LCMS m/z=424.3[M+1] + .
1H NMR(400MHz,CD 3OD)δ7.10(d,1H),6.69(d,1H),6.00(s,1H),4.19(t,2H),4.02-3.99(m,1H),3.88(t,2H),2.42-2.37(m,2H),2.36(s,3H),2.21-2.13(m,1H),2.05-1.97(m,2H),1.88-1.76(m,6H),1.65-1.58(m,2H). 1 H NMR (400MHz, CD 3 OD) δ 7.10(d, 1H), 6.69(d, 1H), 6.00(s, 1H), 4.19(t, 2H), 4.02-3.99(m, 1H), 3.88 (t,2H),2.42-2.37(m,2H),2.36(s,3H),2.21-2.13(m,1H),2.05-1.97(m,2H),1.88-1.76(m,6H),1.65 -1.58(m,2H).
实施例65:Cis-4-((7-(((S)-4,4-二氟-1-甲基吡咯烷-2-基)甲基)-4-((5-甲基-1H-吡唑-3-基)氨基)-7H-吡咯并[2,3-d]嘧啶-2-基)氨基)金刚烷-1-醇(化合物65)的三氟乙酸盐Example 65: Cis-4-((7-(((S)-4,4-difluoro-1-methylpyrrolidin-2-yl)methyl)-4-((5-methyl-1H - Pyrazol-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)adamantan-1-ol (compound 65) trifluoroacetate salt
Cis-4-((7-(((S)-4,4-difluoro-1-methylpyrrolidin-2-yl)methyl)-4-((5-methyl-1H-pyrazol-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)adamantan-1-ol trifluoroacetateCis-4-((7-(((S)-4,4-difluoro-1-methylpyrrolidin-2-yl)methyl)-4-((5-methyl-1H-pyrazol-3-yl)amino)- 7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)adamantan-1-ol trifluoroacetate
Figure PCTCN2021103485-appb-000442
Figure PCTCN2021103485-appb-000442
化合物65以4-氯-2-氟-7H-吡咯并[2,3-d]嘧啶(59a)和[(2S)-4,4-二氟-1-甲基吡咯烷-2-基]甲醇(以1-(叔丁基)2-甲基(S)-4,4-二氟吡咯烷-1,2-二羧酸酯为起始物料参考专利US2016/168090的合成方法得到)为起始物料参考实施例59的合成方法，得到:Cis-4-((7-(((S)-4,4-二氟-1-甲基吡咯烷-2-基)甲基)-4-((5-甲基-1H-吡唑-3-基)氨基)-7H-吡咯并[2,3-d]嘧啶-2-基)氨基)金刚烷-1-醇(化合物65)的三氟乙酸盐Compound 65 was identified as 4-chloro-2-fluoro-7H-pyrrolo[2,3-d]pyrimidine (59a) and [(2S)-4,4-difluoro-1-methylpyrrolidin-2-yl] Methanol (obtained with 1-(tert-butyl) 2-methyl (S)-4,4-difluoropyrrolidine-1,2-dicarboxylate as starting material with reference to the synthesis method of patent US2016/168090) is Starting materials refer to the synthetic method of Example 59 to obtain: Cis-4-((7-(((S)-4,4-difluoro-1-methylpyrrolidin-2-yl)methyl)-4 of -((5-methyl-1H-pyrazol-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)adamantan-1-ol (Compound 65) Trifluoroacetate
LCMS m/z＝513.3[M+1] +。 LCMS m/z=513.3[M+1] + .
1H NMR(400MHz,CD 3OD)δ7.22(d,1H),6.75(d,1H),6.00(d,1H),5.00-4.89(m,1H),4.04-3.98(m,1H),3.44-3.34(m,1H),3.28-3.23(m,1H),3.01-2.92(m,1H),2.89-2.75(m,1H),2.70- 2.53(m,5H),2.45-2.33(m,5H),2.22-2.14(m,1H),2.06-1.96(m,2H),1.91-1.74(m,6H),1.67-1.59(m,2H). 1 H NMR (400MHz, CD 3 OD) δ7.22(d,1H), 6.75(d,1H), 6.00(d,1H), 5.00-4.89(m,1H), 4.04-3.98(m,1H) ,3.44-3.34(m,1H),3.28-3.23(m,1H),3.01-2.92(m,1H),2.89-2.75(m,1H),2.70- 2.53(m,5H),2.45-2.33( m,5H), 2.22-2.14(m,1H), 2.06-1.96(m,2H), 1.91-1.74(m,6H), 1.67-1.59(m,2H).
生物测试例Biological test case
测试例1：对JAK1、JAK2、JAK3与Tyk2激酶的抑制活性Test Example 1: Inhibitory activity against JAK1, JAK2, JAK3 and Tyk2 kinases
采用Cisbio公司的HTRF KinEASE-TK kit(货号：62TK0PEC)进行检测，具体方法如下所示：The HTRF KinEASE-TK kit (Item No.: 62TK0PEC) from Cisbio was used for detection. The specific method is as follows:
用1x kinase buffer稀释化合物，使其为终浓度的2.5倍；分别将酶JAK1、JAK2、JAK3与Tyk2(Carna；08-144、08-045、08-046与08-147)稀释成15μg/mL、0.185μg/mL、1.665μg/mL与5μg/mL；将ATP分别稀释成19.6μM(JAK1)、19.8μM(JAK2)、7.15μM(JAK3)与25.3μM(Tyk2)；将TK Substrate-biotin储存液稀释成10μM。Compounds were diluted in 1x kinase buffer to 2.5 times the final concentration; enzymes JAK1, JAK2, JAK3 and Tyk2 (Carna; 08-144, 08-045, 08-046 and 08-147) were diluted to 15 μg/mL , 0.185 μg/mL, 1.665 μg/mL and 5 μg/mL; ATP was diluted to 19.6 μM (JAK1), 19.8 μM (JAK2), 7.15 μM (JAK3) and 25.3 μM (Tyk2), respectively; TK Substrate-biotin was stored The solution was diluted to 10 μM.
用1x kinase buffer进行10μL激酶反应：实施例化合物或1x kinase buffer 4μL+TK Substrate-biotin 2μL+酶2μL+ATP 2μL，混匀并室温孵育2小时(JAK1)、30分钟(JAK2与JAK3)或50分钟(Tyk2)后，加入5μL Streptavidin-XL665(500nM)和5μL TK Antibody-cryptate(1x)，继续室温孵育1小时。酶标仪(PHERAstar FSX)测定665nm与620nm荧光值。根据式(1)计算信号比值Ratio，使用Origin 9.2计算和分析IC 50。 10μL kinase reaction with 1x kinase buffer: Example compound or 1x kinase buffer 4μL+TK Substrate-biotin 2μL+Enzyme 2μL+ATP 2μL, mix well and incubate at room temperature for 2 hours (JAK1), 30 minutes (JAK2 and JAK3) or 50 minutes (Tyk2), 5 μL of Streptavidin-XL665 (500 nM) and 5 μL of TK Antibody-cryptate (1x) were added and the incubation was continued for 1 hour at room temperature. Fluorescence values at 665 nm and 620 nm were measured by a microplate reader (PHERAstar FSX). Signal ratio Ratio calculated according to formula (1), calculated using the Origin 9.2 analysis and IC 50.
Ratio＝[Signal 665]/[Signal 620]*10 4式(1) Ratio=[Signal 665]/[Signal 620]*10 4 Formula (1)
本发明化合物JAK1、JAK2、JAK3与Tyk2激酶的抑制活性通过以上的实验进行测定。The inhibitory activities of the compounds of the present invention JAK1, JAK2, JAK3 and Tyk2 kinases were determined by the above experiments.
表1.化合物对JAK1、JAK2、JAK3与Tyk2激酶的抑制活性Table 1. Inhibitory activity of compounds against JAK1, JAK2, JAK3 and Tyk2 kinases
Figure PCTCN2021103485-appb-000443
Figure PCTCN2021103485-appb-000443
Figure PCTCN2021103485-appb-000444
Figure PCTCN2021103485-appb-000444
结论：本发明实施例化合物对JAK1、JAK2、JAK3和Tyk2激酶具有抑制作用，对JAK1激酶的抑制活性IC 50＝0.01～10nM，对JAK2激酶的抑制活性IC 50＝0.1～10nM，对JAK3激酶的抑制活性IC 50＝0.1～10nM，对Tyk2激酶的抑制活性IC 50＝0.01～10nM。 Conclusion: The compounds of the examples of the present invention have inhibitory effects on JAK1, JAK2, JAK3 and Tyk2 kinases, the inhibitory activity of JAK1 kinase IC 50 =0.01-10nM, the inhibitory activity of JAK2 kinase IC 50 =0.1-10nM, and the inhibitory activity of JAK3 kinase. The inhibitory activity IC 50 = 0.1-10 nM, the inhibitory activity IC 50 for Tyk2 kinase = 0.01-10 nM.
测试例2：IL-2与anti-CD3刺激hPBMC(人外周血单个核细胞)分泌IFNγ实验Test Example 2: IL-2 and anti-CD3 stimulated hPBMC (human peripheral blood mononuclear cells) to secrete IFNγ
取健康志愿者外周血至抗凝管(肝素钠)中，加入等体积无菌PBS充分混匀，以降低血液粘稠度并减少红细胞聚集。向50mL离心管加入密度为1.077的Ficoll(GE Healthcare；17-1440-02)，然后用移液枪吸取稀释后的血液，在离分层液面上1厘米处，沿管壁缓慢加入分层液面上(外周血、PBS与Ficoll最终体积比为1:1:1)。400g、室温下离 心30min，离心时升降速率均调整为1。用移液枪沿管壁周缘插入到单个核细胞层，吸取单个核细胞于另一离心管中，加入5倍以上体积的PBS，300g、室温下离心10min(升降速率均调整为9)，洗涤细胞两次。弃上清，加入1mL完全培养基(RPMI 1640+10％胎牛血清+1x青霉素-链霉素溶液)重悬细胞并计数，调整细胞密度至细胞密度至4×10 6/mL。 The peripheral blood of healthy volunteers was taken into an anticoagulant tube (heparin sodium), and an equal volume of sterile PBS was added to mix well to reduce blood viscosity and red blood cell aggregation. Ficoll (GE Healthcare; 17-1440-02) with a density of 1.077 was added to a 50mL centrifuge tube, and then the diluted blood was drawn with a pipette, and the layer was slowly added along the tube wall at a distance of 1 cm from the surface of the separation layer. Liquid surface (final volume ratio of peripheral blood, PBS and Ficoll is 1:1:1). Centrifuge at 400 g for 30 min at room temperature, and adjust the lift rate to 1 during centrifugation. Insert a pipette into the mononuclear cell layer along the periphery of the tube wall, suck the mononuclear cells into another centrifuge tube, add more than 5 times the volume of PBS, centrifuge at 300 g for 10 min at room temperature (the lift rate is adjusted to 9), wash cells twice. The supernatant was discarded, and 1 mL of complete medium (RPMI 1640+10% fetal bovine serum+1x penicillin-streptomycin solution) was added to resuspend the cells and counted, and the cell density was adjusted to 4×10 6 /mL.
以每孔2×10 5个细胞(50μL)铺板于96孔板中，在37℃、5％CO 2条件下孵育1h，然后加入化合物100μL/孔，继续在37℃、5％CO 2条件下孵育1h。每孔加入50μL终浓度为100ng/mL的IL-2(R&D Systems；202-IL-050)与终浓度为1μg/mL的anti-CD3(BD Pharmingen；555329)，在37℃、5％CO 2条件下孵育24h。在4℃、500g条件下离心5min，取上清150μL。使用人IFNγQuantikine ELISA试剂盒(R&D Systems；SIF50C)检测上清中IFNγ浓度，并使用Origin 2019b拟合并计算化合物的IC 50值。 Plate 2×10 5 cells (50 μL) per well in a 96-well plate, incubate at 37°C, 5% CO 2 for 1 h, then add compound 100 μL/well, continue at 37° C, 5% CO 2 condition Incubate for 1h. 50 μL of IL-2 (R&D Systems; 202-IL-050) at a final concentration of 100 ng/mL and anti-CD3 (BD Pharmingen; 555329) at a final concentration of 1 μg/mL were added to each well at 37°C, 5% CO 2 . Incubate for 24h under conditions. Centrifuge at 4 °C and 500 g for 5 min, and take 150 μL of the supernatant. Using a human IFNγQuantikine ELISA kit (R & D Systems; SIF50C) detecting the concentration of IFNγ in the supernatant, were fitted using Origin 2019b compound IC 50 value was calculated.
表2.化合物对IL-2与anti-CD3诱导人PBMC分泌IFNγ的抑制活性IC 50值 Table 2. IC 50 values of the compounds' inhibitory activity against IL-2 and anti-CD3-induced human PBMC secretion of IFNγ
序号serial number 化合物compound IC 50(nM) IC 50 (nM)
11 化合物18-2Compound 18-2 2.862.86
22 化合物55Compound 55 6.486.48
33 化合物18-1Compound 18-1 4.824.82
结论:本发明的实施例化合物对IL-2与anti-CD3诱导人PBMC分泌IFNγ具有抑制活性，例如化合物18-1、化合物18-2、化合物55对IL-2与anti-CD3诱导人PBMC分泌IFNγ抑制活性具体数值见表2。Conclusion: The compounds of the examples of the present invention have inhibitory activity on IL-2 and anti-CD3-induced human PBMC to secrete IFNγ, for example, compound 18-1, compound 18-2, and compound 55 have inhibitory activity on IL-2 and anti-CD3-induced human PBMC secretion The specific values of IFNγ inhibitory activity are shown in Table 2.
测试例3：IL-13诱导BEAS-2B细胞(人正常肺上皮细胞)STAT6磷酸化实验Test Example 3: IL-13-induced STAT6 phosphorylation experiment in BEAS-2B cells (human normal lung epithelial cells)
BEAS-2B细胞(ATCC)培养于含10％胎牛血清(Hyclone,Cat#SH30406.05)与1X青霉素-链霉素溶液(Gibco,Cat#15140122)的DMEM培养基(ATCC,Cat#30-2002)中。以每孔7500个细胞(20μL)接种于384孔板(Perkin Elmer,Catalog#6007680)中，于37℃、5％CO2条件下过夜培养。待测化合物溶于DMSO中，并梯度稀释至终浓度的3000倍，再用培养基稀释1000倍。吸弃培养基10μL后加入待测化合物5μL，并于37℃、5％CO2条件下孵育1小时。每孔再加入5μL的IL-13(终浓度为40ng/mL)，于37℃、5％CO2条件下孵育30分钟。使用AlphaLISA试剂盒(Perkin Elmer,Catalog#ALSU-PST6-A500)检测p-STAT6水平。具体操作如下：去除培养液(含待测化合物与IL-13)后，每孔加入10μL 1×Lysis Buffer，封板，震荡10分钟。每孔加入2.5μL Acceptor Mix，封板，避光震荡2分钟后室温孵育2小时。此后，每孔再加入2.5μL Donor Mix，封板，避光震荡2分钟后室温孵育2小时。使用Envision酶标仪的AlphaScreen方法(Ex 680/Em 570)检测。所得数据使用Origin 9.2软件(DoseResp函数)拟合待测化合物的IC 50值。 BEAS-2B cells (ATCC) were cultured in DMEM medium (ATCC, Cat#30- 10% fetal bovine serum (Hyclone, Cat#SH30406.05) and 1X penicillin-streptomycin solution (Gibco, Cat#15140122) 2002). 7500 cells (20 μL) per well were seeded in 384-well plates (Perkin Elmer, Catalog #6007680) and cultured overnight at 37° C., 5% CO 2 . The compounds to be tested were dissolved in DMSO and serially diluted to 3000 times the final concentration, and then diluted 1000 times with the medium. Aspirate 10 μL of the medium, add 5 μL of the compound to be tested, and incubate at 37° C. and 5% CO2 for 1 hour. 5 μL of IL-13 (final concentration of 40 ng/mL) was added to each well, and the cells were incubated at 37° C. and 5% CO 2 for 30 minutes. p-STAT6 levels were detected using the AlphaLISA kit (Perkin Elmer, Catalog #ALSU-PST6-A500). The specific operation is as follows: after removing the culture medium (containing the compound to be tested and IL-13), add 10 μL of 1×Lysis Buffer to each well, seal the plate, and shake for 10 minutes. Add 2.5 μL of Acceptor Mix to each well, seal the plate, shake for 2 minutes in the dark, and incubate at room temperature for 2 hours. After that, 2.5 μL of Donor Mix was added to each well, the plate was sealed, shaken in the dark for 2 minutes, and incubated at room temperature for 2 hours. Detection was performed using the AlphaScreen method of the Envision microplate reader (Ex 680/Em 570). The data obtained using the Origin 9.2 software (DoseResp function) fit IC 50 values of test compounds.
表3.化合物对IL-13诱导BEAS-2B细胞STAT6磷酸化的抑制活性IC 50值 Table 3. Compound Activity IC 50 values for inhibition of IL-13-induced STAT6 phosphorylation BEAS-2B cells of
序号serial number 化合物compound IC 50(nM) IC 50 (nM)
11 化合物10Compound 10 8.628.62
22 化合物18-2Compound 18-2 18.4818.48
33 化合物36Compound 36 5.045.04
44 化合物45的三氟乙酸盐Trifluoroacetate salt of compound 45 16.6516.65
结论：本发明的实施例化合物对IL-13诱导BEAS-2B细胞STAT6磷酸化具有抑制活性，例如化合物10、18-2、36、45的三氟乙酸盐对IL-13诱导BEAS-2B细胞STAT6磷酸化抑制活性具体数值见表3。Conclusion: The example compounds of the present invention have inhibitory activity on IL-13-induced STAT6 phosphorylation in BEAS-2B cells. For example, the trifluoroacetate salts of compounds 10, 18-2, 36, and 45 can inhibit IL-13-induced BEAS-2B cells. The specific values of STAT6 phosphorylation inhibitory activity are shown in Table 3.
测试例4：IL-2/anti-CD3诱导人PBMC细胞中STAT5磷酸化实验Test Example 4: IL-2/anti-CD3-induced STAT5 phosphorylation experiment in human PBMC cells
取健康志愿者外周血至抗凝管中，将其与PBS按照1:1充分混匀稀释。在10mL离心分离管(Greiner bioone，Cat#163290)底部加入适量Ficoll，将稀释后的血液沿管壁缓慢加入，在室温、400×g条件下离心30分钟，离心后吸取单个核细胞置入另一离心管中，加入5倍体积PBS。在室温、300×g条件下离心10分钟后，洗涤细胞两次。末次离心后，弃上清，加入1mL HBSS重悬细胞并计数。化合物用DMSO溶解配成10mM母液，用HBSS稀释至3倍终浓度备用；384孔板每孔加入4μL细胞液与2μL化合物在37℃、5％CO 2条件下培养1小时(空白孔和阴性对照孔加2μL含3‰DMSO的HBSS)。加入2μL含400ng/mL IL-2(R&D，Cat#202-IL-050)与4μg/mL anti-CD3(BD，Cat#555329)的混合液后，在37℃、5％CO 2条件下孵育0.5小时。后续使用p-STAT5AlphaLisa试剂盒(PE，Cat#ALSU-PST5-B500)按如下步骤检测：每孔加入2μL的5X裂解液，封板，低速震荡10分钟；配制受体混合液(包含反应缓冲液1、反应缓冲液2、激活缓冲液与受体微珠)，每孔加入2.5μL受体混合液，封板，避光低速震荡2分钟后室温孵育1.5小时；配制供体混合液(包含稀释缓冲液与受体微珠)，并每孔加入2.5μL供体混合液，封板，避光低速震荡2分钟后室温孵育1.5小时。用BMG酶标仪(PHERAstar FSX)读板检测后，使用Origin 9.2软件中DoseResp函数拟合得出IC 50值。 The peripheral blood of healthy volunteers was taken into anticoagulation tubes, and it was thoroughly diluted with PBS at 1:1. Add an appropriate amount of Ficoll to the bottom of a 10 mL centrifuge tube (Greiner bioone, Cat#163290), slowly add the diluted blood along the tube wall, and centrifuge at room temperature and 400 × g for 30 minutes. After centrifugation, aspirate mononuclear cells and place them in another In a centrifuge tube, add 5 volumes of PBS. After centrifugation at 300 x g for 10 min at room temperature, cells were washed twice. After the final centrifugation, the supernatant was discarded, and 1 mL of HBSS was added to resuspend the cells and counted. Compounds were dissolved in DMSO to prepare a 10 mM stock solution, diluted with HBSS to 3 times the final concentration for use; 4 μL of cell fluid and 2 μL of compound were added to each well of a 384-well plate and incubated for 1 hour at 37°C, 5% CO 2 (blank wells and negative controls). Add 2 μL of HBSS containing 3‰ DMSO to the wells). After adding 2 μL of a mixture containing 400 ng/mL IL-2 (R&D, Cat#202-IL-050) and 4 μg/mL anti-CD3 (BD, Cat#555329), incubate at 37°C under 5% CO 2 conditions 0.5 hours. Subsequently, the p-STAT5AlphaLisa kit (PE, Cat#ALSU-PST5-B500) was used for detection as follows: add 2 μL of 5X lysis buffer to each well, seal the plate, and shake at low speed for 10 minutes; prepare a receptor mixture (including the reaction buffer) 1. Reaction buffer 2. Activation buffer and acceptor microbeads), add 2.5 μL of acceptor mixture to each well, seal the plate, shake at low speed in the dark for 2 minutes, and incubate at room temperature for 1.5 hours; prepare donor mixture (including dilution Buffer and acceptor microbeads), add 2.5 μL of donor mixture to each well, seal the plate, shake at low speed in the dark for 2 minutes, and incubate at room temperature for 1.5 hours. After plate reading and detection with BMG microplate reader (PHERAstar FSX), the IC 50 value was obtained by fitting the DoseResp function in Origin 9.2 software.
表4.化合物对IL-2/anti-CD3诱导人PBMC细胞中STAT5磷酸化的抑制活性IC 50值 Table 4. IC 50 values of compound inhibitory activity on IL-2/anti-CD3-induced STAT5 phosphorylation in human PBMC cells
序号serial number 化合物compound IC 50(nM) IC 50 (nM)
11 化合物18-1Compound 18-1 43.7443.74
22 化合物18-2Compound 18-2 75.9675.96
33 化合物55Compound 55 93.593.5
44 化合物46的三氟乙酸盐Trifluoroacetate salt of compound 46 85.8285.82
55 化合物56Compound 56 82.582.5
66 化合物61Compound 61 88.488.4
结论：本发明的实施例化合物对IL-2/anti-CD3诱导人PBMC细胞中STAT5磷酸化具有抑制活性，例如化合物18-1、化合物18-2、化合物55、化合物46的三氟乙酸盐、化合物56、化合物61对IL-2/anti-CD3诱导人PBMC细胞中STAT5磷酸化具有抑制活性，具体数值见表4。Conclusion: The example compounds of the present invention have inhibitory activity on IL-2/anti-CD3-induced STAT5 phosphorylation in human PBMC cells, such as compound 18-1, compound 18-2, compound 55, compound 46 trifluoroacetate salt , Compound 56 and Compound 61 have inhibitory activity on IL-2/anti-CD3-induced STAT5 phosphorylation in human PBMC cells, and the specific values are shown in Table 4.
测试例5：IL-4诱导THP-1细胞(人单核细胞白血病细胞)中STAT6磷酸化实验Test Example 5: IL-4-induced STAT6 phosphorylation assay in THP-1 cells (human monocytic leukemia cells)
THP-1细胞用RPMI-1640培养基(含10％胎牛血清，0.05mMβ-巯基乙醇)在37℃、5％CO 2条件下培养。细胞转移至离心管中，1000rpm室温离心3分钟，弃上清；离心管加入培养基重悬细胞并计数。化合物用DMSO溶解配成10mM母液，用HBSS稀释至3倍终浓度备用。384孔板每孔加入4μL细胞液与2μL化合物在37℃、5％CO 2条件下培养1小时(空白孔和阴性对照孔加2μL含3‰DMSO的HBSS)。加入2μL 120ng/mL的IL-4(R&D，Cat#204-IL-010)在37℃、5％CO 2条件下孵育0.5小时。后续使用p-STAT6AlphaLisa试剂盒(PE，Cat#ALSU-PST5-B500)按如下步骤检测：每孔加入2μL的5X裂解液，封板，低速震荡10分钟；配制受体混合液(包含反应缓冲液1、反应缓冲液2、激活缓冲液与受体微珠)，每孔加入2.5μL受体混合液，封板，避光低速震荡2分钟后室温孵育1.5小时；配制供体混合液(包含稀释缓冲液与受体微珠)，并每孔加入2.5μL供体混合液，封板，避光低速震荡2分钟后室温孵育1.5小时。用BMG酶标仪(PHERAstar FSX)读板检测后，使用Origin 9.2软件中DoseResp函数拟合得出IC 50值。 THP-1 cells were cultured in RPMI-1640 medium (containing 10% fetal bovine serum, 0.05 mM β-mercaptoethanol) at 37°C, 5% CO 2 . The cells were transferred to a centrifuge tube, centrifuged at 1000 rpm for 3 minutes at room temperature, and the supernatant was discarded; the medium was added to the centrifuge tube to resuspend the cells and counted. Compounds were dissolved in DMSO to prepare 10 mM stock solutions, which were diluted to 3-fold final concentration with HBSS for use. 4 μL of cell fluid and 2 μL of compound were added to each well of 384-well plate and incubated for 1 hour at 37°C and 5% CO 2 (blank wells and negative control wells were added with 2 μL of HBSS containing 3‰ DMSO). 2 μL of 120 ng/mL IL-4 (R&D, Cat#204-IL-010) was added and incubated for 0.5 h at 37°C, 5% CO 2 . Subsequently, the p-STAT6AlphaLisa kit (PE, Cat#ALSU-PST5-B500) was used for detection as follows: add 2 μL of 5X lysis solution to each well, seal the plate, and shake at low speed for 10 minutes; prepare a receptor mixture (including reaction buffer) 1. Reaction buffer 2. Activation buffer and acceptor microbeads), add 2.5 μL of acceptor mixture to each well, seal the plate, shake at low speed in the dark for 2 minutes, and incubate at room temperature for 1.5 hours; prepare donor mixture (including dilution Buffer and acceptor microbeads), add 2.5 μL of donor mixture to each well, seal the plate, shake at low speed in the dark for 2 minutes, and incubate at room temperature for 1.5 hours. After plate reading and detection with BMG microplate reader (PHERAstar FSX), the IC 50 value was obtained by fitting the DoseResp function in Origin 9.2 software.
表5.化合物对IL-4诱导THP-1细胞中STAT6磷酸化的抑制活性IC 50值 Table 5. Compound of IL-4-induced THP-1 cells STAT6 phosphorylation inhibitory activity IC 50 value
序号serial number 化合物compound IC 50(nM) IC 50 (nM)
11 化合物18-1Compound 18-1 14.4614.46
22 化合物18-2Compound 18-2 9.799.79
结论：本发明的实施例化合物对IL-4诱导THP-1细胞中STAT6磷酸化具有抑制活性，例如化合物18-1、化合物18-2对IL-4诱导THP-1细胞中STAT6磷酸化具有抑制活性，具体数值见表5。Conclusion: The example compounds of the present invention have inhibitory activity on IL-4-induced STAT6 phosphorylation in THP-1 cells, for example, compound 18-1 and compound 18-2 have inhibitory activity on IL-4-induced STAT6 phosphorylation in THP-1 cells activity, the specific values are shown in Table 5.
测试例6：小鼠肠血比实验Test Example 6: Mouse Intestinal Blood Ratio Experiment
6.1.试验动物：BALB/c小鼠，～25g，雄性，6～8周龄，30只，购于成都达硕实验动物有限公司，生产许可证号：SCXK(川)2020-030。6.1. Experimental animals: BALB/c mice, ~25 g, male, 6-8 weeks old, 30 mice, purchased from Chengdu Dashuo Laboratory Animal Co., Ltd., production license number: SCXK (Chuan) 2020-030.
6.2.实验设计：6.2. Experimental design:
Figure PCTCN2021103485-appb-000445
Figure PCTCN2021103485-appb-000445
Figure PCTCN2021103485-appb-000446
Figure PCTCN2021103485-appb-000446
灌胃给药溶媒：0.5％MCOral administration vehicle: 0.5% MC
于给药前及给药后异氟烷麻醉经眼眶取血0.1mL，置于EDTAK2离心管中，6000rpm，4℃离心5min，收集血浆。采血时间点：0.5h,2h,6h,8h以及24h。分析检测前，所有血浆样品存于-80℃。Before and after administration of isoflurane anesthesia, 0.1 mL of blood was collected from the orbit, placed in an EDTAK2 centrifuge tube, centrifuged at 6000 rpm at 4°C for 5 min, and plasma was collected. Blood collection time points: 0.5h, 2h, 6h, 8h and 24h. All plasma samples were stored at -80°C prior to analytical testing.
给药组结肠组织样本采集时间点：0.5h,2h,6h,8h以及24h。动物放血干净安乐死后取结肠组织，生理盐水清洗干净后用50％甲醇按m/v＝1:9比例匀浆后-80°冰箱保存待分析。The collection time points of colon tissue samples in the administration group: 0.5h, 2h, 6h, 8h and 24h. After the animals were bled and euthanized, colon tissue was collected, washed with normal saline, homogenized with 50% methanol at a ratio of m/v=1:9, and stored in a -80° refrigerator for analysis.
表6.测试化合物在小鼠血浆中药代动力学参数Table 6. Pharmacokinetic parameters of test compounds in mouse plasma
Figure PCTCN2021103485-appb-000447
Figure PCTCN2021103485-appb-000447
表7.测试化合物小鼠肠血比的结果Table 7. Results of test compound mouse intestinal blood ratio
Figure PCTCN2021103485-appb-000448
Figure PCTCN2021103485-appb-000448
结论：本发明的实施例化合物在结肠中表现出良好的暴露量，结肠/血浆药物浓度(暴露)比值高，例如化合物18-1、化合物18-2具有超过约1000倍的结肠与血浆比。Conclusion: Example compounds of the present invention showed good exposure in the colon with high colon/plasma drug concentration (exposure) ratio, eg compound 18-1, compound 18-2 had colon to plasma ratio over about 1000 times.

Claims (12)

  1. 一种化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，所述化合物选自通式(I)所示的化合物，其中A compound or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, the compound is selected from the compounds represented by the general formula (I), wherein
    Figure PCTCN2021103485-appb-100001
    Figure PCTCN2021103485-appb-100001
    L选自键或者NR n2； L is selected from a bond or NR n2 ;
    R n1、R n2各自独立的选自H、C 1-6烷基或C 3-6环烷基，所述的烷基或环烷基任选进一步被0至4个选自H、卤素、CF 3、OH、氰基、NH 2、C 1-6烷基或C 1-6烷氧基的取代基所取代； 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 0 to 4 selected from H, halogen, Substituted by substituents of CF 3 , OH, cyano, NH 2 , C 1-6 alkyl or C 1-6 alkoxy;
    环A选自5-6元单环杂芳环或8-10元并环杂芳环，所述的杂芳环任选进一步被0至3个R a取代，所述的杂芳环含有1至5个选自O、S、N的杂原子； 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 substituted by 0 to 3 R a , and the heteroaromatic ring contains 1 to 5 heteroatoms selected from O, S, N;
    R a各自独立的选自H、卤素、氰基、OH、C 1-6烷基、C 1-6烷氧基、-(CH 2) q-C(＝O)-NR a1R a2、-(CH 2) q-NR a1R a2、-(CH 2) qNR a1C(＝O)-R a2、-(CH 2) q-C 3-10碳环或-(CH 2) q-3至12元杂环，所述的-CH 2-、烷基、烷氧基、碳环或杂环任选进一步被0至4个选自H、卤素、OH、氰基、NH 2、NH(C 1-6烷基)、N(C 1-6烷基) 2、C 1-6烷基、卤素取代的C 1-6烷基、C 1-6烷氧基、C 3-6环烷基或3至10元杂环的取代基所取代，所述的杂环含有1至3个选自O、S、N的杂原子； R a is each independently selected from H, halogen, cyano, OH, C 1-6 alkyl, C 1-6 alkoxy, -(CH 2 ) q -C(=O)-NR a1 R a2 , - (CH 2 ) q -NR a1 R a2 , -(CH 2 ) q NR a1 C(=O)-R a2 , -(CH 2 ) q -C 3-10 carbocyclic or -(CH 2 ) q -3 to 12-membered heterocyclic ring, said -CH 2 -, alkyl, alkoxy, carbocyclic or heterocyclic ring optionally further substituted by 0-4 selected from H, halo, 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 cycloalkane substituted by a 3- to 10-membered heterocyclic ring containing 1 to 3 heteroatoms selected from O, S, N;
    环B选自非芳香的C 3-12碳环，所述的碳环任选自单环、并环、桥环或者螺环，所述的碳环、单环、并环、桥环或者螺环任选进一步被0至3个R b所取代； 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 The ring is optionally further substituted with 0 to 3 R b ;
    R b各自独立的选自H、卤素、氰基、OH、C 1-6烷基或C 1-6烷氧基，所述的烷基或烷氧基任选进一步被0至4个选自H、卤素、OH、氰基、NH 2、C 1-6烷基、卤素取代的C 1-6烷基、C 1-6烷氧基或C 3-6环烷基的取代基所取代； R b is each independently selected from H, halogen, cyano, OH, C 1-6 alkyl or C 1-6 alkoxy, and said alkyl or alkoxy is optionally further selected from 0 to 4 groups selected from H, halogen, OH, cyano, NH 2 , C 1-6 alkyl, halogen-substituted C 1-6 alkyl, C 1-6 alkoxy or C 3-6 cycloalkyl substituent;
    R 1选自5至10元杂芳基或者苯基，所述的杂芳基或者苯基任选进一步被0至4个R 1a取代； R 1 is selected from 5- to 10-membered heteroaryl or phenyl, and said heteroaryl or phenyl is optionally further substituted by 0 to 4 R 1a ;
    R 1a各自独立的选自H、卤素、OH、氰基、NH 2、-NH(C 1-6烷基)、-N(C 1-6烷基) 2、-NH(C 3- 6环烷基)、C 1-6烷基、C 1-6烷氧基、C 3-6环烷基或3至8元杂环基，所述的烷基、烷氧基、环烷基或杂环基任选进一步被0至4个选自H、卤素、OH、氰基、NH 2、卤素取代的C 1-6烷基、C 1-6烷基、C 1-6烷氧基或C 3-6环烷基的取代基所取代； R 1a is independently selected from H, halo, OH, cyano, NH 2, -NH (C 1-6 alkyl), - N (C 1-6 alkyl) 2, -NH (C 3- 6 cycloalkyl 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 The cyclic group is optionally further substituted with 0 to 4 C1-6 alkyl groups selected from H, halogen, OH, cyano, NH 2 , halogen , C 1-6 alkyl, C 1-6 alkoxy, or C 3-6 cycloalkyl substituents are substituted;
    R 2选自卤素、氰基、OH、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、-(CH 2) q-C(＝O)-R 2a、-(CH 2) q-C(＝O)O-R 2a、-(CH 2) q-S(＝O) 2-R 2a、-(CH 2) q-NR 2aS(＝O) 2-R 2b、-(CH 2) q-C(＝O)- NR 2aR 2b、-(CH 2) q-NR 2aR 2b、-(CH 2) qNR 2aC(＝O)-R 2b、-(CH 2) q-C 3-10碳环或-(CH 2) q-3至12元杂环，所述的-CH 2-、烷基、烯基、炔基、烷氧基、碳环或杂环任选进一步被0至4个选自H、卤素、OH、氰基、NH 2、C 1-6烷基、卤素取代的C 1-6烷基、氰基取代的C 1-6烷基或C 1-6烷氧基的取代基所取代，所述的杂环含有1至3个选自O、S、N的杂原子； R 2 is selected from halogen, cyano, OH, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, -(CH 2 ) q -C(= O)-R 2a , -(CH 2 ) q -C(=O)OR 2a , -(CH 2 ) q -S(=O) 2 -R 2a , -(CH 2 ) q -NR 2a S(= O) 2 -R 2b , -(CH 2 ) q -C(=O)-NR 2a R 2b , -(CH 2 ) q -NR 2a R 2b , -(CH 2 ) q NR 2a C(=O) -R 2b , -(CH 2 ) q -C 3-10 carbocycle or -(CH 2 ) q -3- to 12-membered heterocycle, said -CH 2 -, alkyl, alkenyl, alkynyl, alkane alkoxy, carbocyclic or heterocyclic ring optionally further substituted by 0-4 selected from H, halo, OH, cyano, NH 2, C 1-6 alkyl, halo-substituted C 1-6 alkyl, cyano-substituted substituted by the C 1-6 alkyl or C 1-6 alkoxy substituent, the heterocycle contains 1 to 3 heteroatoms selected from O, S, N;
    R a1、R a2、R 2a、R 2b各自独立的选自H、C 1-6烷基、C 3-12碳环基或3至12元杂环基，所述的烷基、碳环基或杂环基任选进一步被0至4个选自H、卤素、OH、氰基、NH 2、C 1-6烷基、卤素取代的C 1-6烷基、氰基取代的C 1-6烷基或C 1-6烷氧基的取代基所取代，所述的杂环基含有1至3个选自O、S、N的杂原子； 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 is optionally further 0 to 4 selected from H, halogen, 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 substituents, the heterocyclic group contains 1 to 3 heteroatoms selected from O, S, N;
    q各自独立的选自0、1、2、3或4。q is each independently selected from 0, 1, 2, 3 or 4.
  2. 根据权利要求1所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，其中所述化合物选自通式(Ia)、(Ib)、(Ic)、(Id)或(Ie)所代表的化合物，The compound of claim 1 or a stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein the compound is selected from the group consisting of general formula (Ia), ( A compound represented by Ib), (Ic), (Id) or (Ie),
    Figure PCTCN2021103485-appb-100002
    Figure PCTCN2021103485-appb-100002
    通式(Ib)、(Ic)、(Ie)中环C中的N原子与L连接时，L选自键；When the N atom in the ring C in the general formula (Ib), (Ic), (Ie) is connected to L, L is selected from the bond;
    通式(Ib)、(Ic)、(Ie)中环C中的C原子与L连接时，L选自NH或NR n2； When the C atom in the ring C in the general formula (Ib), (Ic), (Ie) is connected to L, L is selected from NH or NR n2 ;
    X 1选自CH或N，X 2选自键、CH或N，Y、Z各自独立的选自C或N； 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;
    条件是X 1、X 2、Y、Z中至少有1个选自N； The condition is that at least one of X 1 , X 2 , Y and Z is selected from N;
    R n1、R n2各自独立的选自H、C 1-4烷基或C 3-6环烷基，所述的烷基或环烷基任选进一步被0至4个选自H、卤素、CF 3、OH、氰基、NH 2、C 1-4烷基或C 1-4烷氧基的取代基所取代； 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 0 to 4 selected from H, halogen, Substituted by substituents of CF 3 , OH, cyano, NH 2 , C 1-4 alkyl or C 1-4 alkoxy;
    环C选自5-6元杂芳环或苯环，所述的杂芳环含有1至3个选自O、S、N的杂原子；Ring C is selected from 5-6 membered heteroaromatic ring or benzene ring, and described heteroaromatic ring contains 1 to 3 heteroatoms selected from O, S, N;
    R a各自独立的选自H、卤素、氰基、OH、C 1-6烷基、C 1-6烷氧基、-(CH 2) q-C(＝O)-NR a1R a2、-(CH 2) q-NR a1R a2、-(CH 2) qNR a1C(＝O)-R a2、-(CH 2) q-C 3-10碳环或-(CH 2) q-3至12元杂环，所述的-CH 2-、烷基、烷氧基、碳环或杂环任选进一步被0至4个选自H、卤素、OH、氰基、NH 2、NH(C 1-6烷基)、N(C 1-6烷基) 2、C 1-6烷基、卤素取代的C 1-6烷基、C 1-6烷氧基、C 3-6环烷基或3至10元杂环的取代基所取代，所述的杂环含有1至3个选自O、S、N的杂原子； R a is each independently selected from H, halogen, cyano, OH, C 1-6 alkyl, C 1-6 alkoxy, -(CH 2 ) q -C(=O)-NR a1 R a2 , - (CH 2 ) q -NR a1 R a2 , -(CH 2 ) q NR a1 C(=O)-R a2 , -(CH 2 ) q -C 3-10 carbocyclic or -(CH 2 ) q -3 to 12-membered heterocyclic ring, said -CH 2 -, alkyl, alkoxy, carbocyclic or heterocyclic ring optionally further substituted by 0-4 selected from H, halo, 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 cycloalkane substituted by a 3- to 10-membered heterocyclic ring containing 1 to 3 heteroatoms selected from O, S, N;
    环B选自C 3-8单环烷基、C 4-10并环烷基、C 4-12螺环烷基、C 5-12桥环烷基，所述的环烷基任选进一步被0至3个R b所取代； 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 R b substituted;
    R 1选自
    Figure PCTCN2021103485-appb-100003
    Figure PCTCN2021103485-appb-100004
    Figure PCTCN2021103485-appb-100005
    R 1基团中的NH不能被R 1a取代；     R 1 is selected from
    Figure PCTCN2021103485-appb-100003
    Figure PCTCN2021103485-appb-100004
    Figure PCTCN2021103485-appb-100005
    The NH in the R 1 group cannot be substituted by R 1a;
    或者R 1选自
    Figure PCTCN2021103485-appb-100006
    or R 1 is selected from
    Figure PCTCN2021103485-appb-100006
    R 1a各自独立的选自H、卤素、OH、氰基、NH 2、-NH(C 1-6烷基)、-N(C 1-6烷基) 2、-NH(C 3- 6环烷基)、C 1-6烷基、C 1-6烷氧基、C 3-6环烷基或3至8元杂环基，所述的烷基、烷氧基、环烷基或杂环基任选进一步被0至4个选自H、卤素、OH、氰基、NH 2、卤素取代的C 1-6烷基、C 1-6烷基、C 1-6烷氧基或C 3-6环烷基的取代基所取代； R 1a is independently selected from H, halo, OH, cyano, NH 2, -NH (C 1-6 alkyl), - N (C 1-6 alkyl) 2, -NH (C 3- 6 cycloalkyl 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 The cyclic group is optionally further substituted with 0 to 4 C1-6 alkyl groups selected from H, halogen, OH, cyano, NH 2 , halogen , C 1-6 alkyl, C 1-6 alkoxy, or C 3-6 cycloalkyl substituents are substituted;
    R 1b选自C 1-6烷基或C 3-6环烷基，所述的烷基或环烷基任选进一步被0至4个选自H、卤素、OH、氰基、NH 2、卤素取代的C 1-6烷基、C 1-6烷基、C 1-6烷氧基或C 3-6环烷基的取代基所取代； R 1b is selected from C 1-6 alkyl or C 3-6 cycloalkyl, and said alkyl or cycloalkyl is optionally further selected from 0 to 4 groups selected from H, halogen, OH, cyano, NH 2 , Substituents of halogen-substituted C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkoxy or C 3-6 cycloalkyl;
    m选自0、1或2；m is selected from 0, 1 or 2;
    p选自0、1或2；p is selected from 0, 1 or 2;
    通式(Ic)中的
    Figure PCTCN2021103485-appb-100007
    选自
    Figure PCTCN2021103485-appb-100008
    S 1或S 2各自独立的选自N或CR a时，环B选自C 9-10并环烷基、C 9-12螺环烷基、C 9-12桥环烷基，所述的环烷基任选进一步被0至3个R b所取代；     In general formula (Ic)
    Figure PCTCN2021103485-appb-100007
    selected from
    Figure PCTCN2021103485-appb-100008
    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 optionally further substituted with 0-3 R b;
    条件是化合物不为如下化合物及其立体异构体：
    Figure PCTCN2021103485-appb-100009
    Figure PCTCN2021103485-appb-100010
    Provided that the compound is not the following compounds and their stereoisomers:
    Figure PCTCN2021103485-appb-100009
    Figure PCTCN2021103485-appb-100010
    Figure PCTCN2021103485-appb-100011
    Figure PCTCN2021103485-appb-100011
    其余基团的定义与权1一致。The definitions of the remaining groups are the same as those of Weight 1.
  3. 根据权利要求2所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，The compound of claim 2, or a stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof,
    R 1a各自独立的选自H、卤素、OH、氰基、NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、-NH(C 3- 4环烷基)、C 1-4烷基或C 1-4烷氧基，所述的烷基或烷氧基任选进一步被0至4个选自H、卤素、OH、氰基、NH 2、卤素取代的C 1-4烷基、C 1-4烷基、C 1-4烷氧基或C 3-6环烷基的取代基所取代； R 1a is independently selected from H, halo, 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 groups 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;
    R 1b选自C 1-4烷基或C 3-6环烷基，所述的烷基或环烷基任选进一步被0至4个选自H、卤素、OH、氰基、NH 2、卤素取代的C 1-6烷基、C 1-6烷基、C 1-6烷氧基或C 3-6环烷基的取代基所取代； R 1b is selected from C 1-4 alkyl or C 3-6 cycloalkyl, and said alkyl or cycloalkyl is optionally further selected from 0 to 4 groups selected from H, halogen, OH, cyano, NH 2 , Substituents of halogen-substituted C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkoxy or C 3-6 cycloalkyl;
    环C选自5-6元杂芳环或苯环，所述的杂芳环含有1至3个选自O、S、N的杂原子；Ring C is selected from 5-6 membered heteroaromatic ring or benzene ring, and described heteroaromatic ring contains 1 to 3 heteroatoms selected from O, S, N;
    R a各自独立的选自H、卤素、氰基、OH、C 1-4烷基、C 1-4烷氧基、-(CH 2) q-C 3-6碳环或-(CH 2) q-3至6元杂环、-(CH 2) q-C(＝O)-NR a1R a2、-(CH 2) q-NR a1R a2或-(CH 2) qNR a1C(＝O)-R a2，所述的-CH 2-、烷基、烷氧基、碳环或杂环任选进一步被0至4个选自H、卤素、OH、氰基、NH 2、NH(C 1-4烷基)、N(C 1-4烷基) 2、C 1-4烷基、卤素取代的C 1-4烷基、C 1-4烷氧基、C 3-6环烷基或3至6元杂环的取代基所取代，所述的杂环含有1至3个选自O、S、N的杂原子； R a is each independently selected from H, halogen, cyano, OH, C 1-4 alkyl, C 1-4 alkoxy, -(CH 2 ) q -C 3-6 carbocyclic or -(CH 2 ) q -3- to 6-membered heterocycle, -(CH 2 ) q -C(=O)-NR a1 R a2 , -(CH 2 ) q -NR a1 R a2 or -(CH 2 ) q NR a1 C(= O)-R a2 , the -CH 2 -, alkyl, alkoxy, carbocycle or heterocycle is optionally further selected from 0 to 4 groups 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 cycloalkane substituted by a 3- to 6-membered heterocyclic ring containing 1 to 3 heteroatoms selected from O, S, N;
    R b各自独立的选自H、卤素、氰基、OH、C 1-4烷基或C 1-4烷氧基，所述的烷基或烷氧基任选进一步被0至4个选自H、卤素、OH、氰基、NH 2、C 1-4烷基、卤素取代的C 1-4烷基、C 1-4烷氧基或C 3-4环烷基的取代基所取代； R b is each independently selected from H, halogen, cyano, OH, C 1-4 alkyl or C 1-4 alkoxy, and said alkyl or alkoxy is optionally further selected from 0 to 4 H, halogen, OH, cyano, NH 2 , C 1-4 alkyl, halogen-substituted C 1-4 alkyl, C 1-4 alkoxy or C 3-4 cycloalkyl substituent;
    R 2选自卤素、氰基、OH、C 1-4烷基、C 1-4烷氧基、-(CH 2) q-C(＝O)-R 2a、-(CH 2) q-C(＝O)O-R 2a、-(CH 2) q-S(＝O) 2-R 2a、-(CH 2) q-NR 2aS(＝O) 2-R 2b、-(CH 2) q-C(＝O)-NR 2aR 2b、-(CH 2) q-NR 2aR 2b、 -(CH 2) qNR 2aC(＝O)-R 2b、-(CH 2) q-C 3-10碳环或-(CH 2) q-3至10元杂环，所述的-CH 2-、烷基、烷氧基、碳环或杂环任选进一步被0至4个选自H、卤素、OH、氰基、NH 2、C 1-4烷基、卤素取代的C 1-4烷基、氰基取代的C 1-4烷基或C 1-4烷氧基的取代基所取代，所述的杂环含有1至3个选自O、S、N的杂原子； R 2 is selected from halogen, cyano, OH, C 1-4 alkyl, C 1-4 alkoxy, -(CH 2 ) q -C(=O)-R 2a , -(CH 2 ) q -C (=O)OR 2a , -(CH 2 ) q -S(=O) 2 -R 2a , -(CH 2 ) q -NR 2a S(=O) 2 -R 2b , -(CH 2 ) q - C(=O)-NR 2a R 2b , -(CH 2 ) q -NR 2a R 2b , -(CH 2 ) q NR 2a C(=O)-R 2b , -(CH 2 ) q -C 3- 10 carbon ring or -(CH 2 ) q -3 to 10 membered heterocycle, said -CH 2 -, alkyl, alkoxy, carbocycle or heterocycle is optionally further 0 to 4 selected from H, Substituted by 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 heterocycle contains 1 to 3 heteroatoms selected from O, S, N;
    R a1、R a2、R 2a、R 2b各自独立的选自H、C 1-4烷基、C 3-10碳环基或3至10元杂环基，所述的烷基、碳环基或杂环基任选进一步被0至4个选自H、卤素、OH、氰基、NH 2、C 1-4烷基、卤素取代的C 1-4烷基、氰基取代的C 1-4烷基或C 1-4烷氧基的取代基所取代，所述的杂环基含有1至3个选自O、S、N的杂原子。 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 is optionally further 0 to 4 selected from H, 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 heterocyclic group contains 1 to 3 hetero atoms selected from O, S, N.
  4. 根据权利要求3所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，其中The compound of claim 3, or a stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein
    R n1、R n2各自独立的选自H、甲基、乙基、丙基、异丙基、环丙基、环丁基、环戊基或环己基，所述的甲基、乙基、丙基、异丙基、环丙基、环丁基、环戊基或环己基任选进一步被0至4个选自H、卤素、CF 3、OH、氰基、NH 2、C 1-4烷基或C 1-4烷氧基的取代基所取代； 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 from 0 to 4 substituents selected from H, halogen, CF 3, OH, cyano, NH 2, C 1-4 alkyl substituted by substituents of C 1-4 alkoxy groups;
    R 1a各自独立的选自H、F、OH、氰基、甲基、乙基、异丙基、丙基、甲氧基或乙氧基，所述的甲基、乙基、异丙基、丙基、甲氧基或乙氧基任选进一步被0至4个选自H、卤素、OH、氰基、NH 2、卤素取代的C 1-4烷基、C 1-4烷基、C 1-4烷氧基或C 3-6环烷基的取代基所取代； 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 0-4 further 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 substituent;
    R 1b选自甲基、乙基、异丙基、环丙基、环丁基、环戊基或环己基，所述的甲基、乙基、异丙基、环丙基、环丁基、环戊基或环己基任选进一步被0至4个选自H、卤素、OH、氰基、NH 2、卤素取代的C 1-6烷基、C 1-6烷基、C 1-6烷氧基或C 3-6环烷基的取代基所取代； R 1b is selected from methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, the methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, Cyclopentyl or cyclohexyl is optionally further substituted with 0 to 4 C1-6 alkyl groups selected from H, halogen, OH, cyano, NH 2 , halogen , C 1-6 alkyl, C 1-6 alkane substituted by oxy or C 3-6 cycloalkyl substituent;
    环C选自吡唑环、噻唑环、咪唑环、噁唑环、噻吩环、呋喃环、吡咯环、异噁唑环、异噻唑环、吡啶环、吡嗪环、哒嗪环、1,2,4-三氮唑环、嘧啶环或苯环；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 a各自独立的选自H、卤素、氰基、OH、C 1-4烷基、C 1-4烷氧基、C 3-6碳环、3至6元杂环、-CH 2-C 3-6碳环、-CH 2CH 2-C 3-6碳环、-CH 2-3至6元杂环、-CH 2CH 2-3至6元杂环、NHR a2、-C(＝O)NHR a2、-NHC(＝O)R a2，所述的-CH 2-、烷基、烷氧基、碳环或杂环任选进一步被0至4个选自H、卤素、OH、氰基、NH 2、NH(C 1-4烷基)、N(C 1-4烷基) 2、C 1-4烷基、卤素取代的C 1- 4烷基、C 1-4烷氧基、C 3-6环烷基或3至6元杂环的取代基所取代，所述的杂环含有1至3个选自O、S、N的杂原子； R a is each independently selected from H, 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 CH 2 -C 3-6 carbocycle, -CH 2 -3- to 6-membered heterocycle, -CH 2 CH 2 -3- to 6-membered heterocycle, NHR a2 , -C(= O)NHR a2 , -NHC(=O)R a2 , the -CH 2 -, alkyl, alkoxy, carbocycle or heterocycle is optionally further substituted by 0 to 4 selected from H, halogen, OH, cyano, NH 2, NH (C 1-4 alkyl), N (C 1-4 alkyl) 2, C 1-4 alkyl, halo-substituted C 1- 4 alkyl, C 1-4 alkoxy group, C 3-6 cycloalkyl or 3 to 6-membered heterocyclic substituents of the heterocyclic ring containing 1 to 3 heteroatoms selected from O, S, N heteroatoms;
    R a2选自H、C 1-4烷基、C 3-6碳环基或3至6元杂环基，所述的烷基、碳环基或杂环基任选进一步被0至4个选自H、卤素、OH、氰基、NH 2、C 1-4烷基、卤素取代的C 1-4烷基、氰基取 代的C 1-4烷基或C 1-4烷氧基的取代基所取代，所述的杂环基含有1至3个选自O、S、N的杂原子； 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 selected from H, 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 Substituted by a substituent, the heterocyclic group contains 1 to 3 heteroatoms selected from O, S, N;
    环B选自取代或者未取代的如下基团之一：环丙基、环丁基、环戊基、环己基、环丙基并环丁基、环丙基并环戊基、环丙基并环已基、环丁基并环丁基、环丁基并环戊基、环丁基并环已基、环戊基并环戊基、环戊基并环已基、环已基并环已基、环丙基螺环丁基、环丙基螺环戊基、环丙基螺环已基、环丁基螺环丁基、环丁基螺环戊基、环丁基螺环已基、环戊基螺环戊基、环戊基螺环已基、环已基螺环已基、双环[1.1.1]戊烷基、双环[2.1.1]己烷基、双环[2.2.1]庚烷基、双环[3.3.2]癸烷基、双环[2.2.2]辛烷基、双环[3.2.1]辛烷基、双环[3.3.3]十一烷基或金刚烷基，当被取代时，任选进一步被0至3个选自H、卤素、氰基、OH、C 1-4烷基或C 1-4烷氧基的取代基所取代； Ring B is selected from one of the following substituted or unsubstituted 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, cyclobutylspirocyclohexyl, Cyclopentylspirocyclopentyl, cyclopentylspirocyclohexyl, cyclohexylspirocyclohexyl, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1] Heptyl, bicyclo[3.3.2]decyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.3.3]undecyl or adamantyl, when When substituted, optionally further substituted by 0 to 3 substituents selected from H, halogen, cyano, OH, C 1-4 alkyl or C 1-4 alkoxy;
    R 2选自卤素、氰基、OH、C 1-4烷基、C 1-4烷氧基、C 3-6碳环、3至6元杂环、-CH 2-C 3-6碳环、-CH 2-3至6元杂环、-NH-C 3-6碳环、-NH-3至6元杂环或-NHC 1-4烷基，所述的-CH 2-、烷基、烷氧基、碳环或杂环任选进一步被0至4个选自H、卤素、OH、氰基、NH 2、C 1-4烷基、卤素取代的C 1-4烷基、氰基取代的C 1-4烷基或C 1-4烷氧基的取代基所取代，所述的杂环含有1至3个选自O、S、N的杂原子。 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 optionally further 0 to 4 selected from H, halogen, OH, cyano, NH 2 , C 1-4 alkyl, halogen substituted C 1-4 alkyl, cyano substituted by C 1-4 alkyl group or C 1-4 alkoxy group, the heterocyclic ring contains 1 to 3 heteroatoms selected from O, S, N.
  5. 根据权利要求4所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，其中The compound of claim 4, or a stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein
    R n1、R n2各自独立的选自H、甲基、乙基、丙基、异丙基、环丙基、环丁基、环戊基或环己基，所述的甲基、乙基、丙基、异丙基、环丙基、环丁基、环戊基或环己基任选进一步被0至4个选自H、F、CF 3、OH、氰基、NH 2、甲基、乙基、甲氧基或乙氧基的取代基所取代； 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 from 0 to 4 substituents selected H, F, CF 3, OH , cyano, NH 2, methyl, ethyl, , methoxy or ethoxy substituents;
    环B选自
    Figure PCTCN2021103485-appb-100012
    Figure PCTCN2021103485-appb-100013
    Figure PCTCN2021103485-appb-100014
    Figure PCTCN2021103485-appb-100015
    右侧与R 2直接连接；     Ring B is selected from
    Figure PCTCN2021103485-appb-100012
    Figure PCTCN2021103485-appb-100013
    Figure PCTCN2021103485-appb-100014
    Figure PCTCN2021103485-appb-100015
    R 2 is directly connected to the right;
    R 2选自F、氰基、OH、-OCH 3、-OCHF 2、-OCH 2F、-OCF 3、甲基、乙基、CF 3、-CH 2OH、-CH 2CH 2OH、-CH 2CH 2CH 2OH、-CH 2CN、-CH 2CH 2CN、-CH 2CH 2CH 2CN、-CH 2CH 2CH 2CH 2CN、-NHCH 2CN、-NHCH 2CH 2CN、-NHCH 2CH 2CH 2CN、-NHCH 2CH 2CH 2CH 2CN、
    Figure PCTCN2021103485-appb-100016
    Figure PCTCN2021103485-appb-100017
    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,
    Figure PCTCN2021103485-appb-100016
    Figure PCTCN2021103485-appb-100017
    通式(Ia)中的
    Figure PCTCN2021103485-appb-100018
    选自
    Figure PCTCN2021103485-appb-100019
    Figure PCTCN2021103485-appb-100020
    In general formula (Ia)
    Figure PCTCN2021103485-appb-100018
    selected from
    Figure PCTCN2021103485-appb-100019
    Figure PCTCN2021103485-appb-100020
    Figure PCTCN2021103485-appb-100021
    Figure PCTCN2021103485-appb-100021
    Figure PCTCN2021103485-appb-100022
    Figure PCTCN2021103485-appb-100022
    通式(Ib)中的
    Figure PCTCN2021103485-appb-100023
    选自
    Figure PCTCN2021103485-appb-100024
    Figure PCTCN2021103485-appb-100025
    In general formula (Ib)
    Figure PCTCN2021103485-appb-100023
    selected from
    Figure PCTCN2021103485-appb-100024
    Figure PCTCN2021103485-appb-100025
    通式(Ic)中的
    Figure PCTCN2021103485-appb-100026
    选自
    Figure PCTCN2021103485-appb-100027
    Figure PCTCN2021103485-appb-100028
    In general formula (Ic)
    Figure PCTCN2021103485-appb-100026
    selected from
    Figure PCTCN2021103485-appb-100027
    Figure PCTCN2021103485-appb-100028
    通式(Id)中的
    Figure PCTCN2021103485-appb-100029
    选自
    Figure PCTCN2021103485-appb-100030
    Figure PCTCN2021103485-appb-100031
    In general formula (Id)
    Figure PCTCN2021103485-appb-100029
    selected from
    Figure PCTCN2021103485-appb-100030
    Figure PCTCN2021103485-appb-100031
    Figure PCTCN2021103485-appb-100032
    Figure PCTCN2021103485-appb-100032
    或者通式(Id)中的
    Figure PCTCN2021103485-appb-100033
    选自
    Figure PCTCN2021103485-appb-100034
    Figure PCTCN2021103485-appb-100035
    or in general formula (Id)
    Figure PCTCN2021103485-appb-100033
    selected from
    Figure PCTCN2021103485-appb-100034
    Figure PCTCN2021103485-appb-100035
    通式(Ie)中的
    Figure PCTCN2021103485-appb-100036
    选自
    Figure PCTCN2021103485-appb-100037
    Figure PCTCN2021103485-appb-100038
    In general formula (Ie)
    Figure PCTCN2021103485-appb-100036
    selected from
    Figure PCTCN2021103485-appb-100037
    Figure PCTCN2021103485-appb-100038
    R 1选自
    Figure PCTCN2021103485-appb-100039
    Figure PCTCN2021103485-appb-100040
    R 1 is selected from
    Figure PCTCN2021103485-appb-100039
    Figure PCTCN2021103485-appb-100040
    或者R 1选自
    Figure PCTCN2021103485-appb-100041
    or R 1 is selected from
    Figure PCTCN2021103485-appb-100041
    R a各自独立的选自H、F、Cl、Br、氰基、OH、甲基、乙基、丙基、丁基、异丙基、异丁基、仲丁基、叔丁基、甲氧基、乙氧基、吡唑基、噻唑基、咪唑基、噁唑基、噻吩基、呋喃基、吡咯基、异噁唑基、异噻吩基、吡啶基、嘧啶基、苯基、环丙基、环丁基、环戊基、环己基、-NH-吡唑基、-NH-噻唑基、-NH-咪唑基、-NH-噁唑基、-NH-噻吩基、-NH-呋喃基、-NH-吡咯基、-NH-异噁唑基、-NH-异噻吩基、-NH-吡啶基、-NH-嘧啶基、-NH-苯基、-NH-环丙基、-NH-环丁基、-NH-环戊基、-NH-环己基、-C(＝O)NH 2、-C(＝O)NHCH 3、-C(＝O)NHCH 2CH 3、-C(＝O)NH-环丙基、-C(＝O)NH-环丁基、-C(＝O)NH-环戊基、-C(＝O)NH-环已基、-C(＝O)NH-苯基、-NHC(＝O)H、-NHC(＝O)CH 3、-NHC(＝O)CH 2CH 3、-NHC(＝O)CH 2CH 2CH 3、-NHC(＝O)-环丙基、-NHC(＝O)-环丁基、-NHC(＝O)-环戊基、-NHC(＝O)-环已基或-NHC(＝O)-苯基，所述的甲基、乙基、异丙基、异丁基、仲丁基、叔丁基、甲氧基、乙氧基、环丙基、环丁基、环戊基、环己基、吡唑基、噻唑基、咪唑基、噁唑基、 噻吩基、呋喃基、吡咯基、异噁唑基、异噻吩基、吡啶基、嘧啶基或苯基任选进一步被0至4个选自H、F、Cl、Br、CF 3、OH、氰基、NH 2、NH(CH 3)、NH(CH 2CH 3)、N(CH 3) 2、N(CH 2CH 3) 2、甲基、乙基、甲氧基、乙氧基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氮杂环戊基、氮杂环己基、氧杂环丁基、氧杂环戊基、氧杂环己基、吗啉基的取代基所取代； 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, -NH-isothienyl, -NH-pyridyl, -NH-pyrimidinyl, -NH-phenyl, -NH-cyclopropyl, -NH-ring butyl, -NH- cyclopentyl, -NH- cyclohexyl, -C (= O) NH 2 , -C (= O) NHCH 3, -C (= O) NHCH 2 CH 3, -C (= O )NH-cyclopropyl, -C(=O)NH-cyclobutyl, -C(=O)NH-cyclopentyl, -C(=O)NH-cyclohexyl, -C(=O)NH - phenyl, -NHC (= O) H, -NHC (= O) CH 3, -NHC (= O) CH 2 CH 3, -NHC (= O) CH 2 CH 2 CH 3, -NHC (= O )-cyclopropyl, -NHC(=O)-cyclobutyl, -NHC(=O)-cyclopentyl, -NHC(=O)-cyclohexyl or -NHC(=O)-phenyl, so The methyl, ethyl, isopropyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrazolyl , thiazolyl, imidazolyl, oxazolyl, thienyl, furanyl, pyrrolyl, isoxazolyl, isothienyl, pyridyl, pyrimidinyl or phenyl is optionally further selected from 0 to 4 of H, 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, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azacyclopentyl, azacyclohexyl, oxetanyl, oxa substituted by the substituents of cyclopentyl, oxanyl, and morpholinyl;
    或者R a各自独立的选自-CH 2-氮杂环丁基、-CH 2-氮杂环戊基、-CH 2-氮杂环己基、-CH 2-氧杂环丁基、-CH 2-氧杂环戊基、-CH 2-氧杂环己基、-CH 2-吗啉基、-CH 2-哌嗪基、-CH 2CH 2-氮杂环丁基、-CH 2CH 2-氮杂环戊基、-CH 2CH 2-氮杂环己基、-CH 2CH 2-氧杂环丁基、-CH 2CH 2-氧杂环戊基、-CH 2CH 2-氧杂环己基、-CH 2CH 2-吗啉基、-CH 2CH 2-哌嗪基，所述的氮杂环丁基、氮杂环戊基、氮杂环己基、氧杂环丁基、氧杂环戊基、氧杂环己基、吗啉基任选进一步被0至4个选自H、F、Cl、Br、CF 3、OH、氰基、NH 2、NH(CH 3)、NH(CH 2CH 3)、N(CH 3) 2、N(CH 2CH 3) 2、甲基、乙基、甲氧基、乙氧基的取代基所取代。 or 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 -piperazinyl, said azetidine, azacyclopentyl, azacyclohexyl, oxetanyl, oxa Cyclopentyl, oxanyl, morpholinyl are optionally further 0 to 4 selected from H, 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.
  6. 根据权利要求5所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，化合物选自(Ia)或(Id)所代表的化合物，其中The compound according to claim 5 or its stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, the compound is selected from (Ia) or (Id) represented by compounds, of which
    环B选自
    Figure PCTCN2021103485-appb-100042
    右侧与R 2直接连接；     Ring B is selected from
    Figure PCTCN2021103485-appb-100042
    R 2 is directly connected to the right;
    R 2选自F、OH、-OCH 3、-OCHF 2、-OCH 2F、-OCF 3、-CH 2OH、-CH 2CN、-CH 2CH 2CN、-NHCH 2CN、-NHCH 2CH 2CN； 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;
    通式(Ia)中的
    Figure PCTCN2021103485-appb-100043
    选自
    Figure PCTCN2021103485-appb-100044
    Figure PCTCN2021103485-appb-100045
    In general formula (Ia)
    Figure PCTCN2021103485-appb-100043
    selected from
    Figure PCTCN2021103485-appb-100044
    Figure PCTCN2021103485-appb-100045
    通式(Id)中的
    Figure PCTCN2021103485-appb-100046
    选自
    Figure PCTCN2021103485-appb-100047
    Figure PCTCN2021103485-appb-100048
    In general formula (Id)
    Figure PCTCN2021103485-appb-100046
    selected from
    Figure PCTCN2021103485-appb-100047
    Figure PCTCN2021103485-appb-100048
    或者通式(Id)中的
    Figure PCTCN2021103485-appb-100049
    选自
    Figure PCTCN2021103485-appb-100050
    Figure PCTCN2021103485-appb-100051
    or in general formula (Id)
    Figure PCTCN2021103485-appb-100049
    selected from
    Figure PCTCN2021103485-appb-100050
    Figure PCTCN2021103485-appb-100051
    或者通式(Id)中的
    Figure PCTCN2021103485-appb-100052
    选自
    Figure PCTCN2021103485-appb-100053
    or in general formula (Id)
    Figure PCTCN2021103485-appb-100052
    selected from
    Figure PCTCN2021103485-appb-100053
    R 1选自
    Figure PCTCN2021103485-appb-100054
    R 1 is selected from
    Figure PCTCN2021103485-appb-100054
    或者R 1选自
    Figure PCTCN2021103485-appb-100055
    or R 1 is selected from
    Figure PCTCN2021103485-appb-100055
    或者R 1选自
    Figure PCTCN2021103485-appb-100056
    or R 1 is selected from
    Figure PCTCN2021103485-appb-100056
  7. 根据权利要求6所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，所述化合物选自(Ia)所代表的化合物，其中The compound according to claim 6 or a stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, the compound is selected from the compounds represented by (Ia), in
    环B选自
    Figure PCTCN2021103485-appb-100057
    右侧与R 2直接连接；     Ring B is selected from
    Figure PCTCN2021103485-appb-100057
    R 2 is directly connected to the right;
    或者环B选自
    Figure PCTCN2021103485-appb-100058
    or ring B is selected from
    Figure PCTCN2021103485-appb-100058
    R 2选自F、-OCHF 2、-OCH 2F、-OCF 3、-OCH 3、OH、-CH 2OH、-CH 2CN、-CH 2CH 2CN或-NHCH 2CH 2CN； 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;
    通式(Ia)中的
    Figure PCTCN2021103485-appb-100059
    选自
    Figure PCTCN2021103485-appb-100060
    In general formula (Ia)
    Figure PCTCN2021103485-appb-100059
    selected from
    Figure PCTCN2021103485-appb-100060
  8. 根据权利要求6所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，化合物选自(Ia-1)或(Id-6)所代表的化合物The compound according to claim 6 or its stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, the compound is selected from (Ia-1) or (Id-6 ) represented by the compound
    Figure PCTCN2021103485-appb-100061
    Figure PCTCN2021103485-appb-100061
    R n2选自H、甲基 R n2 is selected from H, methyl
    Z 1选自N或C(R aa)； Z 1 is selected from N or C(R aa );
    R aa选自H、甲基； R aa is selected from H, methyl;
    R 1选自
    Figure PCTCN2021103485-appb-100062
    R 1 is selected from
    Figure PCTCN2021103485-appb-100062
    R a各自独立的选自H、甲基、乙基、丙基、丁基、异丙基、异丁基、仲丁基、叔丁基、环丙基、环丁基、-CH 2CH 2CN、
    Figure PCTCN2021103485-appb-100063
    Figure PCTCN2021103485-appb-100064
    R a is independently selected from H, methyl, ethyl, propyl, butyl, isopropyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, -CH 2 CH 2 EN,
    Figure PCTCN2021103485-appb-100063
    Figure PCTCN2021103485-appb-100064
    所述的甲基、乙基、丙基、丁基、异丙基、异丁基、仲丁基、叔丁基、环丙基、环丁基、- CH 2CH 2CN任选进一步被0至3个选自F、Cl、Br、CF 3、OH、氰基、NH 2、NH(CH 3)、NH(CH 2CH 3)、N(CH 3) 2、N(CH 2CH 3) 2、甲基、乙基、甲氧基、乙氧基的取代基所取代。 The methyl, ethyl, propyl, butyl, isopropyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, -CH 2 CH 2 CN are optionally further to 3 substituents 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. Substituents of methyl, ethyl, methoxy and ethoxy are substituted.
  9. 根据权利要求1所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，其中，所述化合物选自：The compound of claim 1, or a stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein the compound is selected from the group consisting of:
    Figure PCTCN2021103485-appb-100065
    Figure PCTCN2021103485-appb-100065
    Figure PCTCN2021103485-appb-100066
    Figure PCTCN2021103485-appb-100066
    Figure PCTCN2021103485-appb-100067
    Figure PCTCN2021103485-appb-100067
    Figure PCTCN2021103485-appb-100068
    Figure PCTCN2021103485-appb-100068
    Figure PCTCN2021103485-appb-100069
    Figure PCTCN2021103485-appb-100069
    Figure PCTCN2021103485-appb-100070
    Figure PCTCN2021103485-appb-100070
    Figure PCTCN2021103485-appb-100071
    Figure PCTCN2021103485-appb-100071
    Figure PCTCN2021103485-appb-100072
    Figure PCTCN2021103485-appb-100072
    Figure PCTCN2021103485-appb-100073
    Figure PCTCN2021103485-appb-100073
    Figure PCTCN2021103485-appb-100074
    Figure PCTCN2021103485-appb-100074
  10. 一种药物组合物，包括权利要求1-9任意一项所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，以及药学上可接受的载体。A pharmaceutical composition comprising the compound of any one of claims 1-9 or a stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, and a pharmacy an acceptable carrier.
  11. 根据权利要求1-9任意一项所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶在制备治疗与JAK激酶活性或表达量相关疾病的药物中的应用。A compound according to any one of claims 1-9, or a stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, in the manufacture of therapeutics with JAK kinase activity or expression Drug application in dose-related diseases.
  12. 根据权利要求11所述的应用，其特征在于，所述的疾病选自炎性疾病。The use according to claim 11, wherein the disease is selected from inflammatory diseases.
PCT/CN2021/103485 2020-07-01 2021-06-30 Fused-ring heterocycle derivative and medical use thereof WO2022002118A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202180035181.XA CN115916747A (en) 2020-07-01 2021-06-30 Fused heterocyclic derivative and application thereof in medicine

Applications Claiming Priority (8)

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

Publications (1)

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

Family

ID=79317518

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2021/103485 WO2022002118A1 (en) 2020-07-01 2021-06-30 Fused-ring heterocycle derivative and medical use thereof

Country Status (3)

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

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023246777A1 (en) * 2022-06-20 2023-12-28 Jacobio Pharmaceuticals Co., Ltd. K-ras mutant protein inhibitors

Citations (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103068828A (en) * 2010-08-27 2013-04-24 默克专利股份公司 Triazolopyrazine derivatives
CN103476776A (en) * 2011-01-07 2013-12-25 北京赛林泰医药技术有限公司 2,4-diamino-6,7-dihydro-5H-pyrrolo[2,3]pyrimidine derivatives as FAK/Pyk2 inhibitors
WO2014044025A1 (en) * 2012-09-20 2014-03-27 山东亨利医药科技有限责任公司 Pyrimidineamide derivative and preparation method and use thereof
WO2014051653A1 (en) * 2012-09-27 2014-04-03 Portola Pharmaceuticals, Inc. Bicyclic dihydropyridone kinase inhibitors
CN103974955A (en) * 2011-08-23 2014-08-06 远藤制药公司 Pyrimido- pyridazinone compounds and use thereof
CN104098563A (en) * 2013-04-02 2014-10-15 山东亨利医药科技有限责任公司 JNK (stress-activated kinases,SAPK) inhibitor compound
CN104837829A (en) * 2012-09-07 2015-08-12 癌症研究科技有限公司 Inhibitor compounds
WO2017024589A1 (en) * 2015-08-13 2017-02-16 北京韩美药品有限公司 Irak4 inhibitor and use thereof
CN107001372A (en) * 2014-10-06 2017-08-01 西格诺药品有限公司 Substituted adenine phosphate compound, its composition and its treatment method
CN109069512A (en) * 2016-04-01 2018-12-21 西格诺药品有限公司 Substituted adenine phosphate compound, its composition and related methods for the treatment of
CN109311896A (en) * 2016-06-30 2019-02-05 株式会社大熊制药 Pyrazolopyrimidine derivative is as kinase inhibitor
CN109476696A (en) * 2016-06-02 2019-03-15 细胞基因公司 Animal and the anti-trypanosome of people and anti-Leishmania agent
CN109563095A (en) * 2016-06-02 2019-04-02 细胞基因公司 Animal and people's anti-malarial agents
CN109937039A (en) * 2016-09-30 2019-06-25 斯坦福国际研究院 Dual CLK/CDK1 inhibitor use for cancer treatment

Patent Citations (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103068828A (en) * 2010-08-27 2013-04-24 默克专利股份公司 Triazolopyrazine derivatives
CN103476776A (en) * 2011-01-07 2013-12-25 北京赛林泰医药技术有限公司 2,4-diamino-6,7-dihydro-5H-pyrrolo[2,3]pyrimidine derivatives as FAK/Pyk2 inhibitors
CN103974955A (en) * 2011-08-23 2014-08-06 远藤制药公司 Pyrimido- pyridazinone compounds and use thereof
CN104837829A (en) * 2012-09-07 2015-08-12 癌症研究科技有限公司 Inhibitor compounds
WO2014044025A1 (en) * 2012-09-20 2014-03-27 山东亨利医药科技有限责任公司 Pyrimidineamide derivative and preparation method and use thereof
WO2014051653A1 (en) * 2012-09-27 2014-04-03 Portola Pharmaceuticals, Inc. Bicyclic dihydropyridone kinase inhibitors
CN104098563A (en) * 2013-04-02 2014-10-15 山东亨利医药科技有限责任公司 JNK (stress-activated kinases,SAPK) inhibitor compound
CN107001372A (en) * 2014-10-06 2017-08-01 西格诺药品有限公司 Substituted adenine phosphate compound, its composition and its treatment method
WO2017024589A1 (en) * 2015-08-13 2017-02-16 北京韩美药品有限公司 Irak4 inhibitor and use thereof
CN109069512A (en) * 2016-04-01 2018-12-21 西格诺药品有限公司 Substituted adenine phosphate compound, its composition and related methods for the treatment of
CN109476696A (en) * 2016-06-02 2019-03-15 细胞基因公司 Animal and the anti-trypanosome of people and anti-Leishmania agent
CN109563095A (en) * 2016-06-02 2019-04-02 细胞基因公司 Animal and people's anti-malarial agents
CN109311896A (en) * 2016-06-30 2019-02-05 株式会社大熊制药 Pyrazolopyrimidine derivative is as kinase inhibitor
CN109937039A (en) * 2016-09-30 2019-06-25 斯坦福国际研究院 Dual CLK/CDK1 inhibitor use for cancer treatment

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 (en) * 2022-06-20 2023-12-28 Jacobio Pharmaceuticals Co., Ltd. K-ras mutant protein inhibitors

Also Published As

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

Similar Documents

Publication Publication Date Title
CA3013618C (en) Substituted pyrazolo[1,5-a]pyrimidine compounds as trk kinase inhibitors
KR102132405B1 (en) Macrocyclic compounds as trk kinase inhibitors
ES2857251T3 (en) Polyfluoro compounds that act as bruton tyrosine kinase inhibitors
IL274938B2 (en) Novel compounds and pharmaceutical compositions thereof for the treatment of diseases
JP6248948B2 (en) Tricyclic pyrrolopyridine compound and JAK inhibitor
KR20140076619A (en) 5,7-SUBSTITUTED-IMIDAZO[1,2-c]PYRIMIDINES
JP2021501738A (en) Aminopyrazolopyrimidine-containing macrocycles and their pharmaceutical compositions, as well as their use
WO2022002118A1 (en) Fused-ring heterocycle derivative and medical use thereof
TW202233622A (en) Bicyclic compounds and uses thereof for the treatment of diseases
EP2445909B1 (en) DERIVATIVES OF 6,7-DIHYDRO-5H-IMIDAZO[1,2-a]IMIDAZOLE-3-CARBOXYLIC ACID AMIDES
WO2022078305A1 (en) Heterocyclic derivative and medical application thereof
JP7121033B2 (en) Fused pentacyclic imidazole derivatives as modulators of TNF activity
JP7384669B2 (en) Pharmaceutical compositions in which a substituted dihydropyrrolopyrazole compound and an immunotherapeutic agent are administered in combination
TW202348227A (en) Substituded pyridazin-3-formamide compounds as tyk2 inhibitors
WO2023155866A1 (en) Pyrazolopyridine derivative and application thereof in medicine
AU2015201984A1 (en) SUBSTITUTED PYRAZOLO[1,5-a]PYRIMIDINE 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