WO2022078305A1 - Dérivé hétérocyclique et son application médicale - Google Patents

Dérivé hétérocyclique et son application médicale Download PDF

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WO2022078305A1
WO2022078305A1 PCT/CN2021/123157 CN2021123157W WO2022078305A1 WO 2022078305 A1 WO2022078305 A1 WO 2022078305A1 CN 2021123157 W CN2021123157 W CN 2021123157W WO 2022078305 A1 WO2022078305 A1 WO 2022078305A1
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alkyl
amino
methyl
halogen
alkoxy
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PCT/CN2021/123157
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English (en)
Chinese (zh)
Inventor
张晨
赵明亮
李路
余彦
叶飞
唐平明
杨定菊
邓华
李瑶
倪佳
严庞科
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四川海思科制药有限公司
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Priority to CN202180053180.8A priority Critical patent/CN117355508A/zh
Publication of WO2022078305A1 publication Critical patent/WO2022078305A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4192—1,2,3-Triazoles
    • 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
    • A61K31/4196—1,2,4-Triazoles
    • 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
    • A61K31/4245—Oxadiazoles
    • 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
    • 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
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D247/00—Heterocyclic compounds containing rings having two nitrogen atoms as the only ring hetero atoms, according to more than one of groups C07D229/00 - C07D245/00
    • C07D247/02—Heterocyclic compounds containing rings having two nitrogen atoms as the only ring hetero atoms, according to more than one of groups C07D229/00 - C07D245/00 having the nitrogen atoms in positions 1 and 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D261/14—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to a compound of general formula (I) or a stereoisomer, tautomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, and The intermediate and preparation method thereof, as well as the application in the preparation of medicines for treating diseases related to JAK kinase activity or expression level.
  • IBD Inflammatory bowel disease
  • 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.
  • 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 JAKs that are orally administrable and achieve therapeutically relevant exposures in the gastrointestinal tract with minimal systemic exposure inhibitor.
  • novel JAK inhibitors for the treatment of atopic dermatitis that have minimal systemic exposure.
  • the object of the present invention is to provide a compound capable of inhibiting JAK kinase or its stereoisomer, tautomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, and The intermediate and preparation method thereof, as well as the application in the preparation of medicines for treating diseases related to the activity or expression of JAK.
  • the compounds of the present invention have good JAK kinase inhibitory activity, anti-inflammatory activity, good safety, intestinal targeting, skin targeting and good skin penetration.
  • the present invention provides a compound of general formula (I) or a stereoisomer, tautomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein
  • 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 substituted with a substituent selected from H, halogen, CF 3 , OH, cyano, NH 2 , C 1-6 alkyl or C 1-6 alkoxy;
  • R n2 is selected from H or C 1-6 alkyl, said alkyl is optionally further 0 to 4 selected from H, halogen, CF 3 , OH, cyano, NH 2 , Substituted by C 1-6 alkyl or C 1-6 alkoxy substituent;
  • R n2 is selected from H or C 1-4 alkyl
  • Rn2 is selected from H, methyl or ethyl
  • Rn2 is selected from H or methyl
  • Rn1 , Rn2 are selected from H;
  • Ring A is selected from a 5-8 membered heteroaromatic ring optionally further substituted with 0 to 3 R a , said heteroaromatic ring containing 1 to 5 selected from Heteroatoms of O, S, N;
  • Ring A is selected from a 5- to 6-membered heteroaromatic ring optionally further substituted with 0, 1 or 2 R a , said heteroaromatic ring containing 1 to 3 Heteroatoms selected from O, S, N;
  • Ring A is selected from substituted or unsubstituted one of the following groups: pyrimidinyl, pyrazinyl, pyridazinyl, pyridinyl, triazinyl, pyrazolyl, imidazolyl, pyrrolyl, triazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, thiadiazolyl, when substituted, optionally further substituted with 0, 1 or 2 R a ;
  • Ring A is selected from substituted or unsubstituted one of the following groups: pyrimidinyl, pyrazinyl, triazolyl or oxadiazolyl, when substituted, optionally further 0, 1 or 2 R a substituted; in certain embodiments, ring A is selected from A 1 is selected from O, S, NH, N(CH 3 ) or N(CH 2 CH 3 ), and A 2 is selected from CR a or N;
  • Ring A is selected from one of the following groups, substituted or unsubstituted: When substituted, optionally further substituted by 0, 1 or 2 R a above which is attached to L;
  • Ring A is selected from one of the following groups, substituted or unsubstituted: When substituted, optionally further substituted by 0, 1 or 2 R a above which is attached to L;
  • each R is independently selected from H, F, cyano, OH, CF3 , CHF2 , CH2F , methyl, ethyl, isopropyl, methoxy, ethoxy , propoxy, isopropoxy, pyrazolyl, triazolyl, thiazolyl, imidazolyl, oxazolyl, thienyl, furyl, pyrrolyl, isoxazolyl, isothienyl, pyridyl, pyrimidine base, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidine, oxetanyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, -P(
  • each R is independently selected from H, F, cyano, OH, CF3 , CHF2 , methyl, ethyl, isopropyl, methoxy, ethoxy, propoxy , isopropoxy, pyrazolyl, triazolyl, thiazolyl, imidazolyl, oxazolyl, thienyl, furanyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, pyrrolyl, isoxazole base, isothienyl, pyridyl, pyrimidinyl, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidine, pyrrolidinyl, piperidinyl, morpholinyl, thiomorph Linoyl, -O-cyclopropyl, -O-cyclopentyl,
  • each Ra is independently selected from H, F, -OCH3 , -OCH( CH3 ) 2 , -OCH2CH3 , -CF3 , -CH2OH , -CONH2 , - CONH-cyclopropyl, -OCH 2 CH 2 OCH 3 , -OCH 2 CH 2 OH, -OCH 2 CH 2 N(CH 3 ) 2 , -OCH(CH 3 )CH 2 N(CH 3 ) 2 ,
  • each R a3 is independently selected from -(CH 2 ) q -NR a1 R a2 , -(CH 2 ) q -C 3-10 carbocyclic or -(CH 2 ) q -3 to 12
  • each R a3 is independently selected from -(CH 2 ) q -NR a1 R a2 , -(CH 2 ) q -C 3-6 carbocyclic or -(CH 2 ) q -3 to 6
  • each R a3 is independently selected from -CH 2 N(CH 3 ) 2 , -CH 2 CH 2 N(CH 3 ) 2 , -CH(CH 3 )CH 2 N(CH 3 ) 2 , -CH 2 CH 2 N(CH 2 CH 3 ) 2 , -CH 2 CH 2 NH 2 , -CH 2 CH 2 NHCH 3 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidine base, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, oxetanyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, -CH 2 -cyclopropyl, -CH 2 - Cyclobutyl, -CH2 -cyclopentyl, -CH2 -cyclohexyl, -CH2 -aze
  • Linoyl, -CH 2 -piperazinyl, -CH 2 -oxetanyl, -CH 2 -tetrahydrofuranyl, -CH 2 -tetrahydropyranyl, -CH 2 CH 2 -piperidinyl, -CH 2 CH 2 -pyrrolidinyl, -CH 2 CH 2 -azetidinyl, -CH 2 CH 2 -morpholinyl, The cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidine, oxetanyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidine base, piperazinyl, morpholinyl, optionally further substituted by 0, 1, 2, 3 or 4 substituents selected from H, F, CF3 , OH, O, cyano, NH2 ,
  • each R a3 is independently selected from -CH 2 CH 2 N(CH 3 ) 2 , -CH(CH 3 )CH 2 N(CH 3 ) 2 , cyclopentyl, oxetanyl , tetrahydrofuranyl, tetrahydropyranyl, -CH 2 -pyrrolidinyl, -CH 2 CH 2 -piperidinyl, -CH 2 CH 2 -morpholinyl, The cyclopentyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, morpholinyl, optionally further substituted by 0, 1, 2, 3 or 4 substituents selected from H, F, OH, methyl;
  • each R a3 is independently selected from the following:
  • 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, b- , bridged, or spiro rings are optionally further substituted with 0 to 3 R substituents;
  • Ring B is selected from C 3-8 monocycloalkyl, C 4-10 cycloalkyl, C 5-12 spirocycloalkyl, C 5-12 bridged cycloalkyl, said cycloalkyl is optionally further substituted with 0 to 3 R substituents ;
  • 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 substituted or unsubstituted cyclohexyl or adamantyl, when substituted, optionally further substituted with 0, 1, or 2 R;
  • each R b is independently selected from H, halogen, cyano, OH, C 1-6 alkyl or C 1-6 alkoxy, optionally further C1-6 alkyl substituted by 0 to 4 selected from H, halogen, OH, cyano, NH 2 , C 1-6 alkyl, halogen, C 1-6 alkoxy or C 3-6 cycloalkane substituted by the substituent of the base;
  • each R b is independently selected from H, halogen, cyano, OH, C 1-6 alkyl or C 1-6 alkoxy, optionally further C1-6 alkyl substituted by 0 to 4 selected from H, halogen, OH, cyano, NH 2 , C 1-6 alkyl, halogen, C 1-6 alkoxy or C 3-6 cycloalkane and when B contains 2 R b substituents, when any one R b is OH, the other cannot be OH or -CH 2 OH;
  • each R b is independently selected from H, halogen, cyano, OH, C 1-4 alkyl or C 1-4 alkoxy, optionally further C1-4 alkyl substituted with 0 to 4 selected from H, halogen, OH, cyano, NH 2 , C 1-4 alkyl, halogen, C 1-4 alkoxy or C 3-4 cycloalkane and when B contains 2 R b substituents, when any one R b is OH, the other cannot be OH or -CH 2 OH;
  • R b is each independently selected from H, halogen, cyano, OH, C 1-4 alkyl or C 1-4 alkoxy, and when B contains 2 R b substituents, any When one R b is OH, the other cannot be OH;
  • R b is each independently selected from H, OH, or C 1-4 alkyl optionally further substituted with cyano, and when B contains 2 R b substituents, When any one R b is OH, the other cannot be OH;
  • each R b is independently selected from H or F;
  • each R b is independently selected from H;
  • R 1 is selected from 5 to 10 membered heteroaryl or phenyl optionally further substituted with 0 to 4 R 1a ;
  • each R 1 is independently selected from m is independently selected from 0, 1 or 2;
  • R 1 is selected from m is independently selected from 0, 1 or 2;
  • 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 radical, cycloalkyl or heterocyclyl optionally further substituted by 0 to 4 C 1-6 alkyl groups selected from H, halogen, OH, cyano, NH 2 , halogen, C 1-6 alkyl, C 1 -6 alkoxy or C 3-6 cycloalkyl substituent;
  • 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 is optionally further selected by 0 to 4 groups 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;
  • 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 C1-4 alkyl substituted with 0, 1 or 2 selected from H, halogen, OH, cyano, NH2 , halogen , C 1-4 alkyl, C 1-4 alkoxy or C 3-6 cycloalkyl substituent;
  • each R 1a is independently selected from H, methyl, optionally further substituted with OH;
  • R 1b is selected from C 1-6 alkyl, C 3-6 cycloalkyl, and said alkyl or cycloalkyl is optionally further 0 to 4 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 1b is selected from C 1-4 alkyl, C 3-6 cycloalkyl, and said alkyl or cycloalkyl 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, C 1-4 alkoxy or C 3-6 cycloalkyl substituent;
  • R 1b is selected from methyl, ethyl, isopropyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, said methyl, ethyl, isopropyl , propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl optionally further substituted with 0, 1 or 2 C 1-4 alkanes selected from H, halogen, OH, cyano, NH 2 , halogen substituted by substituents of base, C 1-4 alkyl, C 1-4 alkoxy or C 3-6 cycloalkyl;
  • R 2 is selected from halogen, cyano, OH, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, -NH( C 1-6 alkyl), -(CH 2 ) q -C 3-10 carbocycle or -(CH 2 ) q -3- to 12-membered heterocycle, the -CH 2 -, alkyl, alkenyl, Alkynyl, alkoxy, carbocycle or heterocycle is optionally further 0 to 4 selected from H, halogen, OH, cyano, C1-6 alkyl, halogen substituted C1-6 alkyl, cyano Substituted by the substituents of substituted C 1-6 alkyl or C 1-6 alkoxy, the heterocycle contains 1 to 3 heteroatoms selected from O, S, N;
  • R 2 is selected from halogen, cyano, OH, C 1-4 alkyl, C 1-4 alkoxy, -NH(C 1-4 alkyl), -(CH 2 ) q -C 3-10 carbocycle 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 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 are substituted, and the heterocycle contains 1 to 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 or -NH(C 1-4 alkyl), said -CH 2 -, alkyl, alkoxy, carbocycle or heterocycle 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 substituents are substituted, and the heterocycle contains 1 to 3 heteroatoms selected from O, S, N;
  • R2 is selected from F, cyano, OH, -OCH3 , methyl , ethyl , CF3 , -CH2OH , -CH2CH2OH , -CH2CH2CH2 OH , -CH2CN , -CH2CH2CN , -CH2CH2CH2CN , -CH2CH2CH2CH2CN , -NHCH2CN , -NHCH2CH2CN , -NHCH2CH 2 CH 2 CN, -NHCH 2 CH 2 CH 2 CH 2 CN,
  • R 2 is selected from OH, -OCH 3 , -CH 2 CN;
  • R 2 is selected from OH, -CH 2 CN;
  • R 2 is selected from OH
  • 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 The alkyl, carbocyclyl or heterocyclyl is optionally further selected from 0 to 4 groups 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 3-12 carbocyclyl, 3- to 12-membered heterocyclyl, hydroxy-substituted 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 selected from O, Heteroatoms of S and 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 group 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 , -NH(C 3-6 cycloalkyl), C 1-4 alkyl, C 3-8 carbocyclyl, 3- to 8-membered heterocyclyl, hydroxy-substituted 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 selected from O, Heteroatoms of S and N;
  • R a1 , R a2 , R 2a , R 2b are each independently selected from H, C 1-4 alkyl, C 3-6 carbocyclyl, or 3- to 6-membered heterocyclyl
  • the alkyl, carbocyclyl or heterocyclyl group 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 , -NH(C 3-6 cycloalkyl), C 1-4 alkyl, C 3-6 carbocyclyl, 3- to 6-membered heterocyclyl, hydroxy-substituted 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 selected from O, Heteroatoms of S and N;
  • R a1 , R a2 are each independently selected from H, C 1-4 alkyl, C 3-6 carbocyclyl;
  • each q is independently selected from 0, 1, 2, 3, or 4;
  • each q is independently selected from 0, 1 or 2;
  • the compound represented by the above general formula (I) or its stereoisomers, tautomers, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or a eutectic where,
  • 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 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;
  • Ring A is selected from a 5-8 membered heteroaromatic ring, the heteroaromatic ring is optionally further substituted by 0 to 3 R a , and the heteroaromatic ring contains 1 to 5 heteroaromatic rings selected from O, S, N atom;
  • 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 substituents ;
  • 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 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 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
  • 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 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 selected from 0 to 4 groups 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 3-12 carbocyclyl, 3 to 12 membered heterocyclyl, hydroxy substituted 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 heteroatoms selected from O, S, N;
  • q is each independently selected from 0, 1, 2, 3 or 4.
  • R n2 is selected from H, C 1-6 alkyl or C 3-6 cycloalkyl, and said alkyl or cycloalkyl is optionally further selected by 0 to 4 selected from H, halogen, CF 3 , OH, cyano substituted by substituents of radical, NH 2 , C 1-6 alkyl or C 1-6 alkoxy;
  • p is each independently selected from 0, 1 or 2;
  • Ring A is selected from a 5- to 6-membered heteroaromatic ring, and the heteroaromatic ring contains 1 to 3 heteroatoms selected from O, S, N;
  • Ring B is selected from C 3-8 monocycloalkyl, C 4-10 cycloalkyl, C 5-12 spirocycloalkyl, C 5-12 bridged cycloalkyl, and said cycloalkyl is optionally further substituted with 0 to 3 R b substituents;
  • 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 is selected from
  • 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
  • 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;
  • n is independently selected from 0, 1 or 2;
  • R 1b is selected from C 1-6 alkyl, 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 , C 1-6 alkyl, halogen-substituted C 1-6 alkyl, C 1-6 alkoxy or C 3-6 cycloalkyl substituent;
  • R 2 is selected from halogen, cyano, OH, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, -NH(C 1-6 alkyl) , -(CH 2 ) q -C 3-10 carbocyclic ring or -(CH 2 ) q -3 to 12-membered heterocycle, the -CH 2 -, alkyl, alkenyl, alkynyl, alkoxy,
  • the carbocycle or heterocycle is optionally further 0 to 4 selected from H, halogen, OH, cyano, C1-6 alkyl, halogen substituted C1-6 alkyl, cyano substituted C1-6 alkyl substituted by a substituent of C 1-6 alkoxy group or C 1-6 alkoxy group, the heterocycle contains 1 to 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 is optionally further selected from 0 to 4 groups 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 3-12 carbocyclyl, 3 to 12 membered heterocyclyl, hydroxy substituted 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 heteroatoms selected from O, S, N;
  • q is independently selected from 0, 1, 2, 3 or 4;
  • the compound represented by the aforementioned general formula (Ia) or its stereoisomers, tautomers, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or a eutectic where,
  • R n2 is selected from H or C 1-4 alkyl
  • 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 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 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 is selected from C 1-4 alkyl, 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 , C 1-4 alkyl, halogen substituted C 1-4 alkyl, C 1-4 alkoxy or C 3-6 cycloalkyl substituent;
  • R 2 is selected from halogen, cyano, OH, C 1-4 alkyl, C 1-4 alkoxy, -NH(C 1-4 alkyl), -(CH 2 ) q -C 3-10 carbocycle Or -(CH 2 ) q -3- to 10-membered heterocyclic ring, the -CH 2 -, alkyl, alkoxy, carbocyclic or heterocyclic ring 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 The heterocyclic ring contains 1 to 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, said alkyl, carbocyclyl or heterocyclyl 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 , - NH (C 3-6 cycloalkyl), C 1-4 alkyl, C 3-8 carbocyclyl, 3- to 8-membered heterocyclyl, hydroxy-substituted 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 heteroatoms selected from O, S, N;
  • q is independently selected from 0, 1 or 2
  • the compound represented by the aforementioned general formula (Ia) or its stereoisomers, tautomers, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or a eutectic where,
  • R n2 is selected from H, methyl or ethyl
  • 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, 1 or 2 C1-4 alkyl, C1-4 alkyl substituted with 0, 1 or 2 selected from H, halogen, OH, cyano, NH2 , halogen , C 1-4 alkoxy or C 3-6 cycloalkyl substituent;
  • R 1b is selected from methyl, ethyl, isopropyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, the methyl, ethyl, isopropyl, propyl, cyclopropyl , cyclobutyl, cyclopentyl, cyclohexyl optionally further substituted by 0, 1, or 2 C 1-4 alkyl groups selected from H, halogen, OH, cyano, NH 2 , halogen, C 1-4 Substituents of alkyl, C 1-4 alkoxy or C 3-6 cycloalkyl;
  • 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, cyclobuty
  • R b is each independently selected from H, halogen, cyano, OH, C 1-4 alkyl or C 1-4 alkoxy;
  • Ring A is selected from one of the following groups: pyrimidinyl, pyrazinyl, pyridazinyl, pyridyl, triazinyl, pyrazolyl, imidazolyl, pyrrolyl, triazolyl, oxazolyl, isoxazolyl , oxadiazolyl, thienyl, thiazolyl, thiadiazolyl;
  • 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 or -NH(C 1-4 alkyl), the -CH 2 -, alkyl, alkoxy, carbocycle or heterocycle is optionally further substituted by 0 to 4 one is 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 the substituent, the heterocycle contains 1 to 3 heteroatoms selected from O, S, N;
  • the compound represented by the aforementioned general formula (Ia) or its stereoisomers, tautomers, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or a eutectic where,
  • Ring B is selected from The right side is directly connected to R2;
  • R 2 is selected from F, cyano, OH, -OCH 3 , methyl, ethyl, CF 3 , -CH 2 OH, -CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH, -CH 2 CN, -CH2CH2CN , -CH2CH2CH2CN , -CH2CH2CH2CH2CN , -NHCH2CN , -NHCH2CH2CN , -NHCH2CH2CH2CN , -NHCH _ _ 2 CH 2 CH 2 CH 2 CN,
  • R 1 is selected from
  • R a is each independently selected from H, F, cyano, OH, CF3 , CHF2 , CH2F , methyl, ethyl, isopropyl, methoxy, ethoxy, propoxy, isopropyl Oxy, pyrazolyl, triazolyl, thiazolyl, imidazolyl, oxazolyl, thienyl, furyl, pyrrolyl, isoxazolyl, isothienyl, pyridyl, pyrimidinyl, phenyl, cyclopropyl base, cyclobutyl, cyclopentyl, cyclohexyl, azetidine, oxetanyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, morpholinyl , thiomorpholinyl, piperazinyl,
  • R a3 is independently selected from -CH 2 N(CH 3 ) 2 , -CH 2 CH 2 N(CH 3 ) 2 , -CH(CH 3 )CH 2 N(CH 3 ) 2 , -CH 2 CH 2 N (CH 2 CH 3 ) 2 , -CH 2 CH 2 NH 2 , -CH 2 CH 2 NHCH 3 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidine, pyrrolidinyl, piperidine Imidyl, morpholinyl, piperazinyl, oxetanyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, -CH2 -cyclopropyl, -CH2 -cyclobutyl, -CH2 -Cyclopentyl, -CH2 -cyclohexyl, -CH2 -azeti
  • Ring A is selected from pyrimidinyl, pyrazinyl, triazolyl or oxadiazolyl;
  • a 1 is selected from O, S, NH, N(CH 3 ) or N(CH 2 CH 3 );
  • a 2 is selected from CR a or N;
  • R n2 are each independently selected from H or methyl
  • R 2 is selected from OH, -OCH 3 , -CH 2 CN;
  • R 1 is selected from
  • R a is each independently selected from H, F, cyano, OH, CF3 , CHF2 , methyl, ethyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, pyridine azolyl, triazolyl, thiazolyl, imidazolyl, oxazolyl, thienyl, furyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, pyrrolyl, isoxazolyl, isothienyl, pyridine base, pyrimidinyl, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidine, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, -O-ring Propyl, -O-cyclopentyl, -O-cyclo
  • p is each independently selected from 0, 1 or 2;
  • the present invention relates to a compound shown below or a stereoisomer, tautomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein the compound is selected from the following structures one:
  • L is selected from a bond or NRn2 .
  • L is selected from NRn2 .
  • L is selected from a bond.
  • R n1 is selected from H, C 1-6 alkyl or C 3-6 cycloalkyl, said alkyl or cycloalkyl being optionally further selected from 0 to Substituted with 4 substituents selected from H, halogen, CF 3 , OH, cyano, NH 2 , C 1-6 alkyl or C 1-6 alkoxy.
  • Rn1 is selected from H.
  • each R n2 is independently selected from H, C 1-6 alkyl or C 3-6 cycloalkyl, and the alkyl or cycloalkyl is optionally further selected from 0 to 4 selected from H, halogen , CF 3 , OH, cyano, NH 2 , C 1-6 alkyl or C 1-6 alkoxy substituents.
  • R n2 is selected from H or C 1-6 alkyl, and said alkyl is optionally further 0 to 4 selected from H, halogen, CF 3 , OH, cyano, NH 2 , C 1- 6 alkyl or C 1-6 alkoxy substituent.
  • R n2 is selected from H or C 1-4 alkyl.
  • Rn2 is selected from H, methyl or ethyl.
  • Rn2 is selected from H or methyl.
  • Rn1 , Rn2 are selected from H.
  • Ring A is selected from 5-8 membered heteroaromatic rings optionally further substituted by 0 to 3 R a are substituted, and the heteroaromatic ring contains 1 to 5 heteroatoms selected from O, S, and N.
  • Ring A is selected from a 5- to 6-membered heteroaromatic ring optionally further substituted by O, 1 or 2 R a are substituted, and the heteroaromatic ring contains 1 to 3 heteroatoms selected from O, S and N.
  • Ring A is selected from one of the following substituted or unsubstituted groups: pyrimidinyl, pyrazinyl, pyridazine base, pyridyl, triazinyl, pyrazolyl, imidazolyl, pyrrolyl, triazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, thiadiazolyl, when When substituted, it is optionally further substituted with 0, 1 or 2 R a .
  • Ring A is selected from one of the following substituted or unsubstituted groups: pyrimidinyl, pyrazinyl, triazole or oxadiazolyl, when substituted, is optionally further substituted with 0, 1 or 2 R a .
  • Ring A is selected from one of the following substituted or unsubstituted groups: When substituted, it is optionally further substituted with 0, 1 or 2 R a to which L is attached.
  • Ring A is selected from one of the following substituted or unsubstituted groups: When substituted, it is optionally further substituted with 0, 1 or 2 R a to which L is attached.
  • Ring A is selected from A 1 is selected from O, S, NH, N(CH 3 ) or N(CH 2 CH 3 ), and A 2 is selected from CR a or N.
  • Ring A is selected from one of the following groups: It is connected to L above it.
  • each R is independently selected from H, F, cyano, OH, CF3 , CHF2 , CH2F , methyl, ethyl, isopropyl, methoxy, ethoxy, propoxy base, isopropoxy, pyrazolyl, triazolyl, thiazolyl, imidazolyl, oxazolyl, thienyl, furyl, pyrrolyl, isoxazolyl, isothienyl, pyridyl, pyrimidinyl, benzene radical, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidine, oxetanyl,
  • each R is independently selected from H, F, cyano, OH, CF3 , CHF2 , methyl, ethyl, isopropyl, methoxy, ethoxy, propoxy, isopropyl Oxy, pyrazolyl, triazolyl, thiazolyl, imidazolyl, oxazolyl, thienyl, furanyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, pyrrolyl, isoxazolyl, iso thienyl, pyridyl, pyrimidinyl, phenyl, cyclopropyl, cyclobutyl, cyclopent
  • each R is independently selected from H, F, CF3 , methyl, methoxy, ethoxy, isopropoxy, pyrazolyl, imidazolyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrofuranyl Hydropyranyl, pyridyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, -O-cyclopentyl, -O-oxetanyl, -O- Tetrahydrofuranyl, -O-tetrahydropyranyl, -O- CH2 -pyrrolidinyl, -OCH2CH2
  • each R a is independently selected from H, F, -OCH 3 , -OCH(CH 3 ) 2 , -OCH 2 CH 3 , -CF 3 , -CH 2 OH, -CONH 2 , -CONH-ring Propyl, -OCH 2 CH 2 OCH 3 , -OCH 2 CH 2 OH, -OCH 2 CH 2 N(CH 3 ) 2 , -OCH(CH 3 )CH 2 N(CH 3 ) 2 , -OCH(CH 3 )CH 2 N(CH 3 ) 2 ,
  • each R a3 is independently selected from -CH 2 N(CH 3 ) 2 , -CH 2 CH 2 N(CH 3 ) 2 , -CH(CH 3 )CH 2 N(CH 3 ) 2 , -CH 2CH2N ( CH2CH3 ) 2 , -CH2CH2NH2 , -CH2CH2NHCH3 , cyclopropyl , cyclobutyl , cyclopentyl , cyclohexyl, azetidine , pyrrole Alkyl, piperidinyl, morpholinyl, piperazinyl, oxetanyl, tetrahydrofuranyl, dihydrofuranyl, te
  • each R a3 is independently selected from -CH 2 CH 2 N(CH 3 ) 2 , -CH(CH 3 )CH 2 N(CH 3 ) 2 , cyclopentyl, oxetanyl, tetrahydrofuranyl , tetrahydropyranyl, -CH 2 -pyrrolidinyl, -CH 2 CH 2 -piperidinyl, -CH 2 CH 2 -morpholinyl, The cyclopentyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, morpholinyl, Optionally further substituted with 0, 1, 2, 3 or 4
  • each R a3 is independently selected from the following:
  • ring B is selected from non-aromatic C 3-12 carbocycles optionally selected from monocyclic, paracyclic, bridged or spirocyclic
  • the ring, said carbocyclic, monocyclic, paracyclic, bridged or spirocyclic, is optionally further substituted with 0 to 3 Rb substituents.
  • Ring B is selected from C 3-8 monocycloalkyl, C 4-10 cycloalkyl, C 5-12 spirocycloalkyl, C 5-12 bridged cycloalkyl optionally further substituted with 0 to 3 R b substituents.
  • 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, cyclopropylspirocyclobutyl, cyclopropylspirocyclobutyl, cyclopropylspirocyclopentyl, cyclopropylspirocyclohexyl, cyclobutylspirocyclobutane cyclopropyl,
  • Ring B is selected from substituted or unsubstituted cyclohexyl or adamantyl, when substituted, optionally further by 0, 1, or 2 R b substituted.
  • each R b is independently selected from H, halogen, cyano, OH, C 1-6 alkyl or C 1-6 alkoxy, so Said alkyl or alkoxy is optionally further 0 to 4 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.
  • each R b is independently selected from H, halogen, cyano, OH, C 1-6 alkyl or C 1-6 alkoxy, so Said alkyl or alkoxy is optionally further 0 to 4 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 substituents, and when B contains 2 R b substituents, when either R b is OH, the other cannot be OH or -CH 2 OH.
  • each R b is independently selected from H, halogen, cyano, OH, C 1-4 alkyl or C 1-4 alkoxy, so Said alkyl or alkoxy is optionally further 0 to 4 selected from 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 substituents, and when B contains 2 R b substituents, when either R b is OH, the other cannot be OH or -CH 2 OH.
  • each R b is independently selected from H, halogen, cyano, OH, C 1-4 alkyl or C 1-4 alkoxy, and When B contains 2 R b substituents, when either R b is OH, the other cannot be OH.
  • R b is each independently selected from H, OH or C 1-4 alkyl, said alkyl is optionally further substituted by cyano, And when B contains 2 R b substituents, when either R b is OH, the other cannot be OH.
  • each R b is independently selected from H or F.
  • each R b is independently selected from H.
  • R 1 is selected from 5 to 10 membered heteroaryl or phenyl optionally further substituted with 0 to 4 R 1a .
  • each R 1 is independently selected from m is independently selected from 0, 1 or 2, provided that when R 1 is , ring A is not
  • R 1 is selected from m is each independently selected from 0, 1 or 2.
  • 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, ring
  • the alkyl or heterocyclyl group is optionally further substituted by 0 to 4 C1-6 alkyl groups selected from H, halogen, OH, cyano, NH 2 , halogen, C 1-6 alkyl, C 1-6 alkane Substituents of oxy or C
  • 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 selected from 0 to 4 groups 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 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 optionally further substituted with 0, 1 or 2 C1-4 alkyl groups selected from H, halogen, OH, cyano, NH2 , halogen, C1 -4 alkyl, C 1-4 alkoxy or C 3-6 cycloalkyl substituent.
  • each R 1a is independently selected from H, methyl, optionally further substituted with OH.
  • R 1b is selected from C 1-6 alkyl, 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 , C 1-6 alkyl, halogen-substituted C 1-6 alkyl, C 1-6 alkoxy or C 3-6 cycloalkyl substituent.
  • R 1b is selected from C 1-4 alkyl, 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 , C 1-4 alkyl, halogen substituted C 1-4 alkyl, C 1-4 alkoxy or C 3-6 cycloalkyl substituent.
  • R 1b is selected from methyl, ethyl, isopropyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, said methyl, ethyl, isopropyl, propyl , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl optionally further substituted by 0, 1 or 2 C 1-4 alkyl groups selected from H, halogen, OH, cyano, NH 2 , halogen, C 1-4 alkyl, C 1-4 alkoxy or C 3-6 cycloalkyl substituent.
  • R 2 is selected from halogen, cyano, OH, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, -NH(C 1-6 6 alkyl), -(CH 2 ) q -C 3-10 carbocyclic ring or -(CH 2 ) q -3 to 12-membered heterocycle, the -CH 2 -, alkyl, alkenyl, alkynyl,
  • the alkoxy, carbocycle or heterocycle is optionally further 0 to 4 selected from H, halogen, OH, cyano, C 1-6 alkyl, halogen substituted C 1-6 alkyl, cyano substituted C 1-6 alkyl or
  • R 2 is selected from halogen, cyano, OH, C 1-4 alkyl, C 1-4 alkoxy, -NH(C 1-4 alkyl), -(CH 2 ) q -C 3 -10 carbocycle or -(CH 2 ) q -3 to 10 membered heterocycle, said -CH 2 -, alkyl, alkoxy, carbocycle or heterocycle is optionally further selected from 0 to 4 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 heterocycle contains 1 to 3 heteroatoms selected from O, S
  • 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 or -NH(C 1-4 alkyl), said -CH 2 -, alkyl, alkoxy, carbocycle or heterocycle are optionally further 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 substituents, and the heterocycle contains 1
  • R2 is selected from F, cyano , OH, -OCH3 , methyl, ethyl , CF3 , -CH2OH , -CH2CH2OH , -CH2CH2CH2OH , - CH2CN , -CH2CH2CN , -CH2CH2CH2CN , -CH2CH2CH2CH2CN , -NHCH2CN , -NHCH2CH2CN , -NHCH2CH2CH2 _ _ _ CN, -NHCH 2 CH 2 CH 2 CH 2 CN,
  • R2 is selected from OH, -OCH3 , -CH2CN .
  • R2 is selected from OH, -CH2CN .
  • R2 is selected from OH.
  • 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 optionally further selected from 0 to 4 groups 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 3-12 carbocyclyl, 3- to 12-membered heterocyclyl, hydroxy-substituted C 1-6 alkyl, halogen substitute
  • 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 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 , -NH(C 3-6 cycloalkyl), C 1-4 alkyl, C 3-8 carbocyclyl, 3- to 8-membered heterocyclyl, hydroxy-substituted C 1-4 alkyl, halogen
  • R a1 , R a2 , R 2a , R 2b are each independently selected from H, C 1-4 alkyl, C 3-6 carbocyclyl or 3- to 6-membered heterocyclyl, the alkyl , carbocyclyl or heterocyclyl 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 , -NH(C 3-6 cycloalkyl), C 1-4 alkyl, C 3-6 carbocyclyl, 3- to 6-membered heterocyclyl, hydroxy-substituted C 1-4 alkyl, halogen substitute
  • R a1 and R a2 are each independently selected from H, C 1-4 alkyl, and C 3-6 carbocyclyl.
  • each q is independently selected from 0, 1, 2, 3 or 4.
  • each q is independently selected from 0, 1 or 2.
  • each p is independently selected from 0, 1 or 2.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising any of the above compounds or their stereoisomers, tautomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals, and pharmaceutical an acceptable carrier.
  • the present invention relates to any of the foregoing compounds or stereoisomers, tautomers, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals thereof for use in the preparation of therapeutics with JAK kinase activity Or the application in the medicine of expression level related diseases, preferably, the disease is selected from inflammatory diseases.
  • 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; 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.
  • the compound of the present invention can be prepared by the following scheme:
  • R 1 , R 2 , R n2 , R a , ring A and ring B have the same definitions as the substituents in the compound represented by the general formula (Ia);
  • X is selected from a leaving group, preferably F, Cl, Br, I, -OSO 2 -methyl, -OSO 2 -phenyl, said methyl or phenyl optionally being further replaced by 0, 1, 2, 3 Or substituted by 4 substituents selected from F, Cl, Br, I, C 1-4 alkyl, C 1-4 alkoxy;
  • 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, coupling reaction or hydrogenation reaction to obtain the compound of general formula (M-2) (M-3) compound; the compound of general formula (M-3) obtains the compound of general formula (M-4) through nucleophilic substitution reaction or coupling reaction.
  • the compound of general formula (M-3) is selected from compounds of general formula (M-3a) or (M-3b):
  • R n2 is selected from H or methyl;
  • R 1 is selected from X is selected from a leaving group, preferably F, Cl, Br, I, -OSO 2 -methyl, -OSO 2 -phenyl, said methyl or phenyl optionally being further replaced by 0, 1, 2, 3 or 4 substituents selected from F, Cl, Br, I, methyl, ethyl, methoxy or ethoxy.
  • the 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, and 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 C
  • 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, amide base, 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 Substituents substituted by a membered carbocyclyloxy group, a 3- to 8-membered heterocyclyloxy group, a carb
  • Halogen-substituted refers to substitution with F, Cl, Br or I, including but not limited to 1 to 10 substituents selected from F, Cl, Br or I, 1 to 6 selected from F, Cl, Br or substituted by the substituent of I, substituted by 1 to 4 substituents selected from F, Cl, Br or I.
  • Halogen-substituted is abbreviated as "halo”.
  • Alkoxy refers to -O-alkyl. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexyloxy, cyclopropoxy 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.
  • Cycloalkyl refers to a straight or branched chain saturated cyclic aliphatic hydrocarbon group of 3 to 20 carbon atoms, preferably a cycloalkyl group of 3 to 10 carbon atoms. Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl.
  • 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 substituted or unsubstituted linear and branched unsaturated hydrocarbon groups having at least 1, usually 1, 2 or 3 carbon-carbon double bonds, and the main chain includes, but is not limited to, 2 to 10 1, 2 to 6, or 2 to 4 carbon atoms
  • 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 Alkenyl, 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
  • Alkynyl refers to substituted or unsubstituted linear and branched monovalent unsaturated hydrocarbon groups having at least 1, usually 1, 2 or 3 carbon-carbon triple bonds, including but not limited to, in the main chain Including 2 to 10 carbon atoms, 2 to 6 carbon atoms, 2 to 4 carbon atoms, and examples of alkynyl groups include, but are not limited to, ethynyl, propargyl, 1-propynyl, 2-propynyl, 1 -butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-1-butynyl base, 2-methyl-1-butynyl, 2-methyl-3-butynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl Hex
  • 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 a bridged ring or a spiro ring, non-limiting examples include oxirane, aziridopropyl, oxetanyl, azetidine Butyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxanyl, azepanyl, pyridyl, furanyl, thienyl, pyran base, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithiyl, dihydrofuranyl, Dihydropyranyl, dithiopenanyl, tetrahydrofuranyl, tetrahydropyrrolyl,
  • Heterocyclyl groups appearing herein are defined in accordance with this definition.
  • 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 a system shares an adjacent pair of atoms with other rings in the system, wherein one or more rings may contain zero or more double bonds and may be substituted
  • 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.
  • Heteromonocycle refers to a “heterocyclyl” or “heterocycle” of a monocyclic ring system, and heteromonocycles appearing herein are as defined herein.
  • Heterocyclic refers to a “heterocyclic” containing a heteroatom. Heterocycles appearing herein are defined in accordance with this definition.
  • Heterospirocycle refers to a “spirocycle” containing a heteroatom. Heterospirocycles appearing herein are defined in accordance with this definition.
  • Heterobridged ring refers to a “bridged ring” containing a heteroatom. Heterobridged 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, sulfur Morpholine, 1,3-dithiane, benzimidazole, benzimidazole, benzopyridine, pyrrolopyridine, etc.
  • the heteroaryl ring may 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 or heteroaromatic rings 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 X-Y 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 rings 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.
  • “Pharmaceutically acceptable salt” or “a pharmaceutically acceptable salt thereof” means that a compound of the present invention retains the biological effectiveness and properties of a free acid or free base that is treated with a non-toxic inorganic base or Organic bases, said free bases are salts obtained by reacting with non-toxic inorganic or organic acids.
  • “Pharmaceutical composition” refers to a mixture of one or more of the compounds of the present invention, pharmaceutically acceptable salts or prodrugs thereof and other chemical components, wherein “other chemical components” refers to pharmaceutically acceptable Accepted carriers, excipients 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.
  • Excipient refers to an inert substance added to a pharmaceutical composition to facilitate administration of a compound.
  • Non-limiting examples include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, binders and disintegrants.
  • 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.
  • Animal is meant to include mammals such as humans, companion animals, zoo animals and domestic animals, preferably humans, horses or dogs.
  • Steps refer to isomers resulting from different arrangements of atoms in a molecule in space, including cis-trans isomers, enantiomers and conformational isomers.
  • heterocyclyl optionally substituted with an alkyl group means that the alkyl group may, but need not, be present, and the description includes instances where the heterocyclyl group is substituted with an alkyl group, as well as where the heterocyclyl group is not substituted with an alkyl group Condition.
  • IC50 is the concentration of drug or inhibitor required to inhibit by half a given biological process (or some component of the process such as an enzyme, receptor, cell, etc.).
  • the compounds used in the reactions described herein are prepared according to organic synthesis techniques known to those skilled in the art, starting from commercially available chemicals and/or compounds described in the chemical literature "commercially available” Chemicals” were obtained from standard commercial sources, including Shanghai Aladdin Biochemical Technology Co., Ltd., Shanghai McLean Biochemical Technology Co., Ltd., Sigma-Aldrich, Alfa Aesar (China) Chemical Co., Ltd., Tishi Ai (Shanghai) Co., Ltd. ) Chemical Industry Development Co., Ltd., Anaiji Chemical, Shanghai Titan Technology Co., Ltd., Kelon Chemical, Bailingwei Technology Co., Ltd., etc.
  • 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;
  • N,N-diisopropylethylamine (2.00 g, 15.26 mmol) was added to 2,4,6-trichloropyrimidine (1b) (1.40 g, 7.63 mmol), 3-methyl-1H- Pyrazol-5-amine (1a) (1.11 g, 11.45 mmol) in ethanol (15 ml).
  • 20 mL of water was added to the reaction solution, and the reaction was continued for 1 hour with stirring. Filtration gave a white solid, the desired product, 2,6-dichloro-N-(3-methyl-1H-pyrazol-5-yl)pyrimidin-4-amine (1c) (1.00 g, 54%).
  • Step 2 4-[(4-Chloro-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl)amino]adamantan-1-ol (1f)
  • N,N-diisopropylethylamine (317 mg, 2.45 mmol) was added to 4-aminoadamantan-1-ol hydrochloride (1d) (100 mg, 0.49 mmol), 2,6-dichloro -N-(3-Methyl-1H-pyrazol-5-yl)pyrimidin-4-amine (1c) (251 mg, 1.03 mmol) in DMSO (2 ml). The temperature was raised to 100°C for 14 hours.
  • reaction solution was poured into water (10 mL) to quench the reaction, extracted with ethyl acetate (10 mL x 2), the organic phases were combined, backwashed with saturated brine (10 mL x 2), and dried over anhydrous sodium sulfate. , filtered, and concentrated the mother liquor to obtain the crude product.
  • Preparation method the crude product is dissolved in DMF (N,N-dimethylformamide), and filtered through a 0.45 ⁇ m filter membrane to prepare a sample solution.
  • Mobile phase system acetonitrile/water (containing 0.05% ammonia water).
  • Gradient elution method acetonitrile was eluted from 10% gradient to 55% (flow rate: 12 mL/min; elution time 17 min), lyophilized to obtain:
  • N,N-diisopropylethylamine (265 mg, 2.05 mmol) was added to 2,6-dichloro-N-(3-methyl-1H-pyrazol-5-yl)pyrimidine-4- Amine (1c) (100 mg, 0.41 mmol), 2-[(1s,4s)-4-aminocyclohexyl]acetonitrile (2a) (57 mg, 0.41 mmol) in DMSO (2 ml) solution, warmed to 100 °C for reaction 14 Hour.
  • Step 2 trans-2-[4-[(4-methoxy-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl)amino]cyclohexyl] Trifluoroacetate salt of acetonitrile (compound 2)
  • N,N-diisopropylethylamine (704 mg, 5.45 mmol) was added to 2,4,6-trichloropyrimidine (1b) (200 mg, 1.09 mmol), 1-methyl-1H-imidazole- 4-amine (159 mg, 1.64 mmol) in ethanol (5 ml).
  • 20 mL of water was added to the reaction solution, and the reaction was continued for 1 hour with stirring. Filtration gave a white solid, the target product, 2,6-dichloro-N-(1-methyl-1H-imidazol-4-yl)pyrimidin-4-amine (3c) (200 mg, 75%).
  • N,N-Diisopropylethylamine (424 mg, 3.28 mmol) was added to 2,6-dichloro-N-(1-methyl-1H-imidazol-4-yl)pyrimidin-4-amine at room temperature (3c) (200 mg, 0.82 mmol), Cis-4-aminoadamantan-1-ol hydrochloride (3d) (184 mg, 0.90 mmol) in DMSO (4 ml). The temperature was raised to 100°C for 14 hours.
  • reaction solution was poured into water (10 mL) to quench the reaction, extracted with ethyl acetate (10 mL x 2), the organic phases were combined, backwashed with saturated brine (10 mL x 2), and dried over anhydrous sodium sulfate. ,filter.
  • Preparation method the crude product is dissolved in DMF, and filtered with a 0.45 ⁇ m filter membrane to prepare a sample solution.
  • N,N-diisopropylethylamine (6.35 g, 49.10 mmol) was added to Cis-4-aminoadamantan-1-ol hydrochloride (3d) (2.00 g, 9.82 mmol), 2, 6-Dichloro-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (1c) (2.64 g, 10.80 mmol) in DMSO (20 mL). The temperature was raised to 100°C for 14 hours. Then it was lowered to room temperature, and the reaction solution was poured into water (50 mL) and stirred for half an hour.
  • the filter cake is the target product Cis-4-[(4-chloro-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl ) amino]adamantan-1-ol (4b) (1.30 g, 35%).
  • Preparation method the crude product is dissolved in DMF, and filtered with a 0.45 ⁇ m filter membrane to prepare a sample solution.
  • Mobile phase system acetonitrile/water (containing 0.05% ammonia water).
  • Gradient elution method acetonitrile was eluted from 10% gradient to 55% (flow rate: 12 mL/min; elution time 17 min), lyophilized to obtain Cis-4-[(4-[(5-methyl-1H-pyrazole- 3-yl)amino]-6-(prop-2-yloxy)pyrimidin-2-yl)amino]adamantan-1-ol (compound 4) (4 mg, 9%).
  • N,N-diisopropylethylamine (2.38 g, 18.44 mmol) was added to 2,4-dichloro-6-(trifluoromethyl)pyrimidine (5a) (1.00 g, 4.61 mmol), 3-Methyl-1H-pyrazol-5-amine (490 mg, 5.07 mmol) in DMF (10 ml).
  • N,N-diisopropylethylamine (317 mg, 2.45 mmol) was added to Cis-4-aminoadamantan-1-ol hydrochloride (3d) (100 mg, 0.49 mmol), 2-chloro- N-(3-Methyl-lH-pyrazol-5-yl)-6-(trifluoromethyl)pyrimidin-4-amine (5b) (136 mg, 0.49 mmol) in DMSO (2 ml). The temperature was raised to 100°C for 14 hours.
  • the reaction solution was poured into water (10 mL) to quench the reaction, extracted with ethyl acetate (10 mL ⁇ 2), the organic phases were combined, backwashed with saturated brine (10 mL ⁇ 2), dried over anhydrous sodium sulfate, and filtered. , the mother liquor was concentrated to obtain the crude product.
  • Preparation method the crude product is dissolved in DMF, and filtered with a 0.45 ⁇ m filter membrane to prepare a sample solution.
  • N,N-diisopropylethylamine (2.00 g, 15.26 mmol) was added to methyl 2,6-dichloropyrimidine-4-carboxylate (6a) (1.60 g, 7.63 mmol), 3- Methyl-1H-pyrazol-5-amine (890 mg, 9.16 mmol) in DMSO (15 ml). The reaction was maintained at room temperature for 12 hours.
  • N,N-Diisopropylethylamine (4.83 g, 37.35 mmol) was added to 2-chloro-6-[(3-methyl-1H-pyrazol-5-yl)amino]pyrimidine-4 at room temperature - Methyl carboxylate (6b) (2.00 g, 7.47 mmol), hydrochloride salt of Cis-4-aminoadamantan-1-ol (3d) (1.52 g, 7.47 mmol) in DMSO (15 ml). The reaction was maintained at 100°C for 12 hours. After the reaction was completed, 50 mL of water was added to the reaction solution, and the reaction was continued to stir for 1 hour.
  • Methyl acid (6c) (30 mg, 0.08 mmol) was added to a sealed tube containing a 4M solution of ammonia in methanol (5 ml), and then the temperature was raised to 100° C. to react for 12 hours.
  • Cyclopropylamine (43 mg, 0.75 mmol) was added to Cis-6-[(5-methyl-1H-pyrazol-3-yl)amino]methyl-2-[(5-hydroxyadamantane- 2-yl(amino]pyrimidine-4-carboxylate methyl ester (6c) (30 mg, 0.08 mmol) in methanol (5 ml) solution (sealed tube), then heated to 100 ° C for 12 hours. After the reaction was completed, the reaction was The liquid is concentrated to dryness to obtain the crude product.
  • Preparation method the crude product is used DMF was dissolved and filtered with a 0.45 ⁇ m filter membrane to prepare a sample solution.
  • Mobile phase system acetonitrile/water (containing 0.05% ammonia water).
  • Compound 8 was identified as Cis-4-[(4-chloro-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl)amino]adamantan-1-ol (4b) Using sodium ethoxide as starting material, referring to the synthetic method of Example 3, Cis-4-[(4-ethoxy-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidine was obtained -2-yl)amino]adamantan-1-ol (Compound 8)
  • Cis-4-[(4-chloro-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl)amino]adamantan-1-ol (4b) (50 mg , 0.13 mmol) was dissolved in a mixed solution of methanol (10 mL) and tetrahydrofuran (10 mL), replaced with hydrogen three times, and vigorously stirred for 48 h under a hydrogen atmosphere.
  • Pad diatomaceous earth and filter, rinse with tetrahydrofuran (5mL*2), concentrate the filtrate under reduced pressure to obtain the residue, and the residue is purified by Pre-HPLC (instrument and preparative column: use WATERS 2767 to prepare the liquid phase, the preparative column model is X select C18, 5 ⁇ m, inner diameter*length 19mm*150mm).
  • 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).
  • 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).
  • Compound 11 was identified as cis-4-[(4-chloro-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl)amino]adamantan-1-ol (4b) and N-methyl-D-prolinol as starting material with reference to the synthetic method of Example 10 to obtain Cis-4-[(4-[(5-methyl-1H-pyrazol-3-yl)amino] - The trifluoroacetate salt of 6- ⁇ [(2R)-1-methylpyrrolidin-2-yl]methoxy ⁇ pyrimidin-2-yl)amino]adamantan-1-ol (compound 11).
  • Compound 12 was identified as Cis-4-[(4-chloro-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl)amino]adamantan-1-ol (4b) With N,N-dimethylethanolamine as starting material, refer to the synthetic method of Example 10 to obtain Cis-4-[(4-(2-(dimethylamino)ethoxy)-6-[(5- Methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl)amino]adamantan-1-ol (compound 12) trifluoroacetate salt.
  • Compound 13 was identified as Cis-4-[(4-chloro-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl)amino]adamantan-1-ol (4b) With 1-piperidine ethanol as starting material, refer to the synthetic method of Example 10 to obtain Cis-4-[(4-[(5-methyl-1H-pyrazol-3-yl)amino]-6-(2 -(piperidin-1-yl)ethoxy)pyrimidin-2-yl)amino]adamantan-1-ol (compound 13) trifluoroacetate salt.
  • Compound 14 was identified as Cis-4-[(4-chloro-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl)amino]adamantan-1-ol (4b) With 2-morpholinoethanol as starting material, refer to the synthetic method of Example 10 to obtain cis-4-[(4-[(5-methyl-1H-pyrazol-3-yl)amino]-6-(2 -(Morpholin-4-yl)ethoxy)pyrimidin-2-yl)amino]adamantan-1-ol (compound 14) trifluoroacetate salt.
  • Compound 15 was identified with Cis-4-[(4-chloro-6-[(1-methyl-1H-imidazol-4-yl)amino]pyrimidin-2-yl)amino]adamantan-1-ol (3f) and [(2S)-4,4-Difluoro-1-methylpyrrolidin-2-yl]methanol (with N-BOC-4,4-difluoro-L-proline methyl ester as the starting material, according to The synthetic method of patent US2016/168090 is obtained) as the starting material and the synthetic method of Example 10 is used to obtain Cis-4-[(4- ⁇ [(2S)-4,4-difluoro-1-methylpyrrolidine Trifluoro of -2-yl]methoxy ⁇ -6-[(1-methyl-1H-imidazol-4-yl)amino]pyrimidin-2-yl)amino]adamantan-1-ol (compound 15) Acetate.
  • Compound 16 was identified as Cis-4-[(4-chloro-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl)amino]adamantan-1-ol (4b) With 3-hydroxytetrahydrofuran (CAS: 453-20-3) as starting material, refer to the synthetic method of Example 10 to obtain Cis-4-((4-((5-methyl-1H-pyrazol-3-yl ) amino)-6-((tetrahydrofuran-3-yloxy)pyrimidin-2-yl)amino)adamantan-1-ol (compound 16) trifluoroacetate salt.
  • Compound 17 was identified as Cis-4-[(4-chloro-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl)amino]adamantan-1-ol (4b) With 1-(dimethylamino)propan-2-ol as starting material, refer to the synthetic method of Example 10 to obtain Cis-4-((4-((1-(dimethylamino)propan-2-yl )oxy)-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)aminoadamantan-1-ol (Compound 17).
  • Cis-4-[(4-chloro-6-(oxetan-3-oxy)pyrimidin-2-yl)amino]adamantan-1-ol (18c) (120 mg, 0.34 mmol), 3- Amino-5-methyl-pyrazole-1-carboxylic acid tert-butyl ester (80 mg, 0.41 mmol), tris(dibenzylideneacetone)dipalladium (20 mg, 0.03 mmol), 2-(dicyclohexylphosphine)-3 ,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl (10mg, 0.03mmol), cesium carbonate (220mg, 0.68mmol) was added to 1,4- In dioxane (3 mL), nitrogen was replaced, and the temperature was raised to 100 °C 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).
  • Gradient elution method acetonitrile was eluted from 10% gradient to 60% (elution time 16min), and after lyophilization, Cis-4-((4-((5-methyl-1H-pyrazol-3-yl)amino was obtained )-6-(oxetan-3-yloxy)pyrimidin-2-yl)amino)adamantan-1-ol (compound 18) as trifluoroacetate salt (10 mg, 9%),
  • Compound 19 uses 2,4,6-trichloropyrimidine (1a) and Cis-4-aminoadamantan-1-ol hydrochloride (3d) as starting materials. Refer to the synthesis method of Example 18 to obtain Cis-4- ((2-Methoxy-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)amino)adamantan-1-ol (Compound 19).
  • Compound 20 was identified as Cis-4-[(4-chloro-6-[(1-methyl-1H-imidazol-4-yl)amino]pyrimidin-2-yl)amino]adamantan-1-ol (3f) and Using 2-morpholinoethanol as the starting material, referring to the synthetic method of Example 10, Cis-4-[(4-[(1-methyl-1H-imidazol-4-yl)amino]-6-(2- (Morpholin-4-yl)ethoxy)pyrimidin-2-yl)amino]adamantan-1-ol (Compound 20).
  • 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-chloro-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl)amino]adamantan-1-ol (4b ) 50 mg, 0.13 mmol
  • 1H-imidazole 156 mg, 2.3 mmol
  • N,N-diisopropylethylamine 310 mg, 2.41 mmol
  • N-methylpyrrolidone (2 mL)
  • 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).
  • Compound 24 was identified as Cis-4-[(4-chloro-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl)amino]adamantan-1-ol (4b) Using thiomorpholine-1,1-dioxide as the starting material, referring to the synthetic method of Example 23, Cis-4-(2-((5-hydroxyadamantan-2-yl)amino)-6 was obtained -((5-Methyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)thiomorpholine-1,1-dioxide (compound 24) trifluoroacetate salt.
  • Cis-4-[(4-chloro-5-fluoro-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl)amino]adamantan-1-ol ( 25c) 51 mg, 0.13 mmol was dissolved in methanol (2 mL), 20% methanol solution of sodium methoxide (63 mg, 0.39 mmol) was added, and the reaction was stopped after reacting at 80° C. for 48 h.
  • Preparation method The reaction solution was filtered with a 0.45 ⁇ m filter membrane to prepare a sample solution.
  • Mobile phase system acetonitrile/water (with 0.5% trifluoroacetic acid).
  • Compound 26 uses 2,6-dichloropyrazine, 3-methyl-1H-pyrazol-5-amine, and the hydrochloride of Cis-4-aminoadamantan-1-ol as materials, and the synthesis of reference example 5 method to afford tris of Cis-4-[(6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrazin-2-yl)amino]adamantan-1-ol (compound 26) Fluoroacetate.
  • Cis-4-[(4-chloro-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl)amino]adamantan-1-ol (4b ) (20 mg, 0.053 mmol) was dissolved in 1,4-dioxane (2 mL).
  • (1-methyl-1H-pyrazol-4-yl)boronic acid 13.41 mg, 0.11 mmol
  • [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) 7.76 mg, 0.011 mmol
  • cesium carbonate 51.81 mg, 0.16 mmol
  • water 0.2 ml
  • the mixture was reacted at 100 °C for 2 h under nitrogen protection, and the reaction was completed by LCMS. Then it was lowered to room temperature, the reaction solution was poured into water (10 mL), extracted with ethyl acetate (10 mL x 2), the organic phases were combined, backwashed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered, The mother liquor was concentrated to obtain crude product.
  • Preparation method the crude product is dissolved in DMF, and filtered with a 0.45 ⁇ m filter membrane to prepare a sample solution.
  • Mobile phase system acetonitrile/water (containing 0.05% ammonia water).
  • Gradient elution method Gradient elution of acetonitrile from 10% to 55% (flow rate: 12 mL/min; elution time 17 min) to obtain Cis-3-[(4-[(5-methyl-1H-pyrazole after lyophilization -3-yl)amino]-6-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino]adamantan-1-ol (compound 27) (10 mg, 45%).
  • Compound 28 was identified as Cis-4-[(4-chloro-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl)amino]adamantan-1-ol (4b) Using 5-methoxypyridine-3-boronic acid as the starting material, referring to the synthetic method of Example 27, Cis-3-[(4-(5-methoxypyridine-3-yl)-6-[( 5-Methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl)amino]adamantan-1-ol (compound 28).
  • Compound 29 was identified as Cis-4-[(4-chloro-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl)amino]adamantan-1-ol (4b) Using ethylene glycol monomethyl ether as starting material, referring to the synthetic method of Example 10, Cis-4-[(4-(2-methoxyethoxy)-6-[(5-methyl-1H) was obtained -Pyrazol-3-yl)amino]pyrimidin-2-yl)amino]adamantan-1-ol (Compound 29)
  • Compound 30 was identified as Cis-4-[(4-chloro-6-[(1-methyl-1H-imidazol-4-yl)amino]pyrimidin-2-yl)amino]adamantan-1-ol (3f) and Ethylene glycol was used as the starting material to refer to the synthetic method of Example 10 to obtain cis-4-[(4-(2-hydroxyethoxy)-6-[(1-methyl-1H-imidazol-4-yl) Trifluoroacetate salt of amino]pyrimidin-2-yl)amino]adamantan-1-ol (compound 30).
  • Compound 31 was identified as Cis-4-[(4-chloro-5-fluoro-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl)amino]adamantane-1- Alcohol (25c) and ethylene glycol as starting materials refer to the synthetic method of Example 10 to obtain cis-4-[(5-fluoro-4-(2-hydroxyethoxy)-6-[(5-methyl) -1H-Pyrazol-3-yl)amino]pyrimidin-2-yl)amino]adamantan-1-ol (compound 31) trifluoroacetate salt.
  • Compound 32 was identified as Cis-4-[(4-chloro-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl)amino]adamantan-1-ol (4b) With ethylene glycol as starting material, refer to the synthetic method of Example 10 to obtain Cis-4-[(4-(2-hydroxyethoxy)-6-[(5-methyl-1H-pyrazole-3- yl)amino]pyrimidin-2-yl)amino]adamantan-1-ol (compound 32) trifluoroacetate salt.
  • Compound 33 was identified as Cis-4-[(4-chloro-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl)amino]adamantan-1-ol (4b) With N-(2-hydroxyethyl)-pyrrolidine as the starting material, referring to the synthetic method of Example 10, Cis-4-[(4-[(5-methyl-1H-pyrazol-3-yl) Amino]-6-(2-(pyrrolidin-1-yl)ethoxy)pyrimidin-2-yl)amino]adamantan-1-ol (compound 33) trifluoroacetate salt.
  • Compound 34 was identified as Cis-4-[(4-chloro-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl)amino]adamantan-1-ol (4b) With [(2R)-oxopent-2-yl]methanol as the starting material, referring to the synthetic method of Example 10, Cis-4-[(4-[(5-methyl-1H-pyrazole-3- yl)amino]-6- ⁇ [(2R)-oxopent-2-yl]methoxy ⁇ pyrimidin-2-yl)amino]adamantan-1-ol (compound 34) trifluoroacetate salt.
  • Compound 35 was identified as cis-4-[(4-chloro-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl)amino]adamantan-1-ol (4b) With [(2S)-oxopent-2-yl]methanol as the starting material, referring to the synthesis method of Example 10, Cis-4-[(4-[(5-methyl-1H-pyrazole-3- yl)amino]-6- ⁇ [(2S)-oxopent-2-yl]methoxy ⁇ pyrimidin-2-yl)amino]adamantan-1-ol (compound 35) trifluoroacetate salt.
  • Preparation method the crude product is dissolved in DMSO, and filtered with a 0.45 ⁇ m filter membrane to prepare a sample solution.
  • Mobile phase system acetonitrile/water (with 0.5% trifluoroacetic acid).
  • Compound 37 was identified as cis-4-[(4-chloro-5-fluoro-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl)amino]adamantane-1- Alcohol (25c) and (S)-3-pyrrolidinol were used as starting materials to obtain (3S)-1-(5-fluoro-6-[(5-methyl-1H-pyrrolidone) with reference to the synthetic method of Example 36.
  • 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 (containing 0.5% ammonia water).
  • N,N-Diisopropylethylamine (558.32 mg, 4.32 mmol) was added to 6- ⁇ [(tert-butoxy)carbonyl]ethyl](1-[(tert-butoxy)carbonyl] at room temperature -5-Methyl-1H-pyrazol-3-yl)amino ⁇ -2-chloro-5-fluoropyrimidine-4-carboxylate ethyl ester (39b) (500 mg, 1.08 mmol), Trans-4-(methylamino) ) of the trifluoroacetate salt of adamantan-1-ol (39c) (350.82 mg, 1.19 mmol) in dimethyl sulfoxide (3 ml).
  • Trifluoroacetic acid (4 ml) was added to Trans-6- ⁇ [(tert-butoxy)carbonyl](1-[(tert-butoxy)carbonyl]-5-methyl-1H-pyrazole-3 at room temperature -yl)amino ⁇ -5-fluoro-2-(methyl[5-hydroxyadamantan-2-yl]amino)pyrimidine-4-carboxylate (39d) (250 mg, 0.39 mmol) in dichloromethane ( 4ml) solution. The reaction was carried out at room temperature for 4 hours. After the completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain a crude product.
  • the crude product was separated and purified by a C18 reverse preparative column (purification method: the crude product was dissolved in DMF, filtered, and prepared into a sample solution.
  • Mobile phase system acetonitrile/water (containing 0.5% ammonia water).
  • the mother liquor was concentrated under reduced pressure to obtain crude product.
  • Preparation method the crude product is dissolved in DMF, and filtered with a 0.45 ⁇ m filter membrane to prepare a sample solution.
  • Mobile phase system acetonitrile/water (containing 0.05% ammonia water).
  • Methyl 2-chloro-6-[((5-methyl-1H-pyrazol-3-yl)amino]pyrimidine-4-carboxylate (6b) (100 mg, 0.37 mmol), Cis-4-(methyl) Amino)adamantan-1-ol trifluoroacetate (110mg, 0.37mmol), N,N-diisopropylethylamine (240mg, 1.85mmol) was added to n-butanol (4mL), the temperature was raised to 160 °C, microwave reaction 38h, then fall to room temperature.
  • Preparation method the crude product was dissolved in methanol, and filtered with a 0.45 ⁇ m filter membrane to prepare a sample solution.
  • Mobile phase system acetonitrile/water (containing 0.5% formic acid).
  • Cis-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-(methyl[5-hydroxyadamantan-2-yl]amino)pyrimidine-4-carboxylate n-butyl The formate (45 mg, 0.09 mmol) of ester (40b) was dissolved in MeOH (10 mL), solid sodium borohydride (17 mg, 0.45 mmol) and calcium chloride (50 mg, 0.45 mmol) were added under an ice-water bath, and the reaction was heated to Raw materials disappear.
  • the first step Trans-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-(methyl[5-hydroxyadamantan-2-yl]amino)pyrimidine-4-carboxyl Formate salt of butyl acid (41b)
  • Step 2 Cis-5-fluoro-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-[(5-hydroxyadamantan-2-yl)amino]pyrimidine-4 - trifluoroacetate salt of ethyl carboxylate (42b)
  • 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% to 60% (elution time 16min), and after lyophilization, Cis-5-fluoro-6-[(5-methyl-1H-pyrazol-3-yl)amino was obtained ]-2-[(5-Hydroxyadamantan-2-yl)amino]pyrimidine-4-carboxylate ethyl ester (42b) as trifluoroacetate salt (160 mg, 75%).
  • Cis-5-fluoro-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-[(5-hydroxyadamantan-2-yl)amino]pyrimidine-4-carboxylic acid The trifluoroacetate salt of ethyl ester (42b) (50 mg, 0.09 mmol) was dissolved in MeOH (5 mL), and solid sodium borohydride (14 mg, 0.37 mmol) and calcium chloride (20 mg, 0.18 mmol) were added under ice-water bath. , room temperature reaction until the original disappears.
  • the first step Trans-6- ⁇ [(tert-butoxy)carbonyl](1-[(tert-butoxy)carbonyl]-5-methyl-1H-pyrazol-3-yl)amino ⁇ -5- Ethyl fluoro-2-[(5-hydroxyadamantan-2-yl)amino]pyrimidine-4-carboxylate (43b)
  • 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 (containing 0.5% trifluoroacetic acid).
  • Gradient elution method acetonitrile was eluted from 10% gradient to 60% (elution time 16min), and after lyophilization, Trans-5-fluoro-6-[(5-methyl-1H-pyrazol-3-yl)amino was obtained ]-2-[(5-Hydroxyadamantan-2-yl)amino]pyrimidine-4-carboxylic acid ethyl ester (43c) as trifluoroacetate salt (150 mg, 71%),
  • Methyl 2-chloro-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidine-4-carboxylate (200 mg, 0.75 mmol), Trans-4-aminoadamantane -1-ol hydrochloride (150 mg, 0.75 mmol), N,N-diisopropylethylamine (480 mg, 3.75 mmol) were added to DMSO (10 mL), the temperature was raised to 100° C. for 46 h, and then lowered to room temperature.
  • Compound 45 was identified as Cis-4-[(4-chloro-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl)amino]adamantan-1-ol (4b) With cyclopentanol as starting material, with reference to the synthetic method of Example 10, Cis-4-[(4-[(5-methyl-1H-pyrazol-3-yl)amino]-6-(propane- 2-yloxy)pyrimidin-2-yl)amino]adamantan-1-ol (compound 45) trifluoroacetate salt
  • Example 46 Cis-4-[(4- ⁇ [(3S,3aR,6aS)-3a,6a-dihydro-hexahydrofuro[2,3-b]furan-3-yl]oxy ⁇ -6 -[(5-Methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl)amino]adamantan-1-ol (compound 46) trifluoroacetate salt
  • Compound 46 was identified as Cis-4-[(4-chloro-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl)amino]adamantan-1-ol (4b) With (3S,3aR,6aS)-hexahydrofuro[2,3-b]furan-3-ol (CAS: 156928-10-8) as the starting material, referring to the synthetic method of Example 10, Cis- 4-[(4- ⁇ [(3S,3aR,6aS)-3a,6a-dihydro-hexahydrofuran[2,3-b]furan-3-yl]oxy ⁇ -6-[(5-methyl Trifluoroacetate salt of yl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl)amino]adamantan-1-ol (compound 46)
  • reaction solution was poured into 10 mL of water, extracted with ethyl acetate (10 mL x 2), the organic phases were combined, backwashed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and the mother liquor was concentrated under reduced pressure to obtain the crude product
  • Preparation method The crude product was dissolved in DMF, and 0.45 ⁇ m Filter membrane to prepare sample solution.
  • Compound 48 was identified as Cis-4-[(4-chloro-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl)amino]adamantan-1-ol (4b) With cis-tetrahydrofuran-3,4-diol as the starting material, referring to the synthetic method of Example 10, Cis-(3R,4S)-4-[(6-[(5-methyl-1H-pyrazole- 3-yl)amino]-2- ⁇ [5-hydroxyadamantan-2-yl]amino ⁇ pyrimidin-4-yl)oxy]oxa-3-ol (Compound 48)
  • Compound 50 was identified as Cis-4-[(4-chloro-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl)amino]adamantan-1-ol (4b) and 1,4:3,6-dianhydromannitol (CAS:641-74-7) as the starting material refer to the synthetic method of Example 10 to obtain Cis-(3R,6R)-6-[(6-[ (5-Methyl-1H-pyrazol-3-yl)amino]-2- ⁇ [5-hydroxyadamantan-2-yl]amino ⁇ pyrimidin-4-yl)oxy]-hexahydrofuran[3, 2-b] Furan-3-ol (Compound 50)
  • Compound 51 was identified as Cis-4-[(4-chloro-5-fluoro-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl)amino]adamantane-1- Alcohol (25c) and cis-tetrahydrofuran-3,4-diol are starting materials and refer to the synthetic method of Example 10 to obtain Cis-(3R,4S)-4-[(5-fluoro-6-[(5- Methyl-1H-pyrazol-3-yl)amino]-2- ⁇ [5-hydroxyadamantan-2-yl]amino ⁇ pyrimidin-4-yl)oxy]oxa-3-ol (Compound 51)
  • 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 0.5% trifluoroacetic acid).
  • Gradient elution method acetonitrile was eluted from 5% gradient to 50% (elution time 15 min). Lyophilized to obtain Cis-4-[(4-(4,5-dihydrofuran-2-yl)-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl ) amino]adamantan-1-ol (compound 53) trifluoroacetate salt (50 mg, 27%).
  • Cis-4-[(4-(4,5-dihydrofuran-2-yl)-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidine-2- yl)amino]adamantan-1-ol (compound 53) (30 mg, 0.073 mmol) was dissolved in 15 mL of methanol, 10% palladium on carbon was added, and the solution was stirred at room temperature for 16 hours under hydrogen. The filtrate was filtered, and the solvent was removed under reduced pressure to obtain the crude product.
  • 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).
  • Compound 55 was identified as Cis-4-[(4-chloro-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl)amino]adamantan-1-ol (4b) And 2-(2,5-dihydrofuran-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane as starting material, reference example Synthesis of 53 to give Cis-4-[(4-(2,5-dihydrofuran-3-yl)-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidine- 2-yl)amino]adamantan-1-ol (compound 55) trifluoroacetate salt
  • Compound 56 was identified as Cis-4-[(4-(2,5-dihydrofuran-3-yl)-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl ) Amino]adamantan-1-ol (Compound 55) as the starting material, referring to the synthetic method of Example 54 to obtain Cis-4-[(4-[(5-methyl-1H-pyrazol-3-yl ) amino]-6-(oxazol-3-yl)pyrimidin-2-yl)amino]adamantan-1-ol (compound 56) trifluoroacetate salt
  • Compound 58 was identified as Cis-4-[(4-chloro-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl)amino]adamantan-1-ol (4b) With azetidine-3-ol as starting material, with reference to the synthetic method of Example 21, Cis-1-(6-[(5-methyl-1H-pyrazol-3-yl)amino]- Acetate salt of 2-[(5-hydroxyadamantan-2-yl)amino]pyrimidin-4-yl)azetidin-3-ol (Compound 58)
  • Compound 60 was prepared as 2,6-dichloro-N-(3-methyl-1H-pyrazol-5-yl)pyrimidin-4-amine (1c), Trans-4-aminoadamantan-1-ol hydrochloride Using thiomorpholine-1,1-dioxide as starting material, referring to the synthetic method of Example 23, Trans-4-(2-((5-hydroxyadamantan-2-yl)amino)-6 was obtained -((5-Methyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)thiomorpholine-1,1-dioxide (compound 60) trifluoroacetate salt.
  • 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).
  • Compound 62 was identified as Trans-4-[(4-chloro-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl)(methyl)amino]adamantane-1- Alcohol (61a) and cis-tetrahydrofuran-3,4-diol are starting materials.
  • Compound 63 was identified as Cis-4-[(4-chloro-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl)amino]adamantan-1-ol (4b) Using (R)-(-)-3-hydroxytetrahydrofuran as the starting material, referring to the synthetic method of Example 3, Cis-4-[(4-[(5-methyl-1H-pyrazol-3-yl was obtained. )amino]-6-[(3R)-oxopent-3-yloxy]pyrimidin-2-yl)amino]adamantan-1-ol (Compound 63)
  • Compound 64 was identified as Cis-4-[(4-chloro-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl)amino]adamantan-1-ol (4b) With 3-hydroxytetrahydropyran as starting material, with reference to the synthetic method of Example 3, Cis-4-[((4-[(5-methyl-1H-pyrazol-3-yl)amino]- 6-(Epoxyhexane-3-yloxy)pyrimidin-2-yl)amino]adamantan-1-ol trifluoroacetate salt (Compound 64)
  • Compound 65 was identified as Cis-4-[(4-chloro-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl)amino]adamantan-1-ol (4b) Using tetrahydrofuran-3-methanol as the starting material, referring to the synthetic method of Example 3, Cis-4-[(4-[(5-methyl-1H-pyrazol-3-yl)amino]-6-[ (Tetrahydrofuran-3-yl)methoxy]pyrimidin-2-yl)amino]adamantan-1-ol trifluoroacetate salt (Compound 65)
  • Compound 66 was identified as Trans-3-[(4-chloro-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl)amino]adamantan-1-ol and (R) -(-)-3-Hydroxytetrahydrofuran was used as the starting material, and with reference to the synthetic method of Example 3, Trans-4-[(4-[(5-methyl-1H-pyrazol-3-yl)amino]- 6-[(3R)-oxopent-3-yloxy]pyrimidin-2-yl)amino]adamantan-1-ol (Compound 66)
  • Compound 67 uses 2,4-dichloro-6-(trifluoromethyl)pyrimidine and Trans-4-aminoadamantan-1-ol hydrochloride as starting materials, referring to the synthetic method of Example 5 to obtain Trans- Trifluoro of 4-[(4-[(5-Methyl-1H-pyrazol-3-yl)amino]-6-(trifluoromethyl)pyrimidin-2-yl)amino]adamantan-1-ol Acetate (Compound 67)
  • Compound 68 was identified as Cis-4-[(4-chloro-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl)amino]adamantan-1-ol (4b) and 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester (CAS: 287944-16-5) as starting material, referring to the synthetic method of Example 27, Cis-4-[(4 -(3,6-Dihydro-2H-pyran-4-yl)-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl)amino]adamantane- Trifluoroacetate salt of 1-alcohol (Compound 68)
  • Compound 69 was identified as cis-4-[(4-chloro-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl)amino]adamantan-1-ol (4b) With (S)-(+)-3-hydroxytetrahydrofuran as starting material, refer to the synthetic method of Example 10 to obtain Cis-4-[(4-[(5-methyl-1H-pyrazol-3-yl) Amino]-6-[(3S)-oxazolidine-3-acyloxy]pyrimidin-2-yl)amino]adamantan-1-ol (Compound 69).
  • Example 70 Cis-1-(5-fluoro-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2- ⁇ [5-hydroxyadamantan-2-yl]amino ⁇ Trifluoroacetate salt of pyrimidin-4-yl)piperidin-4-ol (Compound 70)
  • Compound 70 was identified as Cis-4-[(4-chloro-5-fluoro-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl)amino]adamantane-1- Alcohol (25c) and 4-hydroxypiperidine as starting materials refer to the synthetic method of Example 36 to obtain Cis-1-(5-fluoro-6-[(5-methyl-1H-pyrazol-3-yl) Amino]-2- ⁇ [5-hydroxyadamantan-2-yl]amino ⁇ pyrimidin-4-yl)piperidin-4-ol (compound 70) trifluoroacetate salt.
  • Compound 71 was synthesized with 2,6-dichloro-5-fluoro-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amino (25b), Trans-4-aminoadamantane-1 - Alcohol hydrochloride and azetidine-3-ol as starting materials refer to the synthetic method of Example 38 to obtain Trans-1-(5-fluoro-6-[(5-methyl-1H-pyridine Trifluoroethyl of azol-3-yl)amino]-2- ⁇ [cis-5-hydroxyadamantan-2-yl]amino ⁇ pyrimidin-4-yl)azetidin-3-ol (Compound 71) acid salt.
  • Compound 72 was identified with 2,6-dichloro-5-fluoro-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amino (25b), Trans-4-aminoadamantane-1- Alkyl hydrochloride and sodium methoxide are starting materials with reference to the synthetic method of Example 25 to obtain Trans-4-[(5-fluoro-4-methoxy-6-[(5-methyl-1H-pyrazole- 3-yl)amino]pyrimidin-2-yl)amino]adamantan-1-ol (compound 72) trifluoroacetate salt.
  • N,N-diisopropylethylamine (1.70 g, 13.15 mmol) was added to 2,4,6-trichloropyrimidine (1b) (0.6 g, 3.27 mmol), 5-[(benzyloxy ) methyl]-1H-pyrazol-3-amino hydrochloride (74a) (1.17 g, 4.91 mmol) in ethanol (30 ml).
  • 74a 5-[(benzyloxy ) methyl]-1H-pyrazol-3-amino hydrochloride
  • 20 mL of water was added to the reaction solution, and the reaction was continued for 1 hour with stirring.

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Abstract

L'invention concerne un composé représenté par la formule générale (I) ou un stéréoisomère, tautomère, une substance deutérér, un solvate, un promédicament, un métabolite, un sel pharmaceutiquement acceptable ou un co-cristal de celui-ci, un intermédiaire de celui-ci, et son procédé de préparation, ainsi qu'une application dans la préparation d'un médicament pour le traitement de maladies associées à l'activité ou à l'expression de la kinase JAK.
PCT/CN2021/123157 2020-10-12 2021-10-12 Dérivé hétérocyclique et son application médicale WO2022078305A1 (fr)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023279105A1 (fr) * 2021-07-01 2023-01-05 Aerie Pharmaceuticals, Inc. Azétidinyl pyrimidines et utilisations associées

Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009145856A1 (fr) * 2008-04-16 2009-12-03 Portola Pharmaceuticals, Inc. 2, 6-DIAMINO-PYRIMIDIN- B-YL-CARBOXAMIDES SERVANT D'INHIBITEURS DE Syk KINASES ET DE JANUS KINASES
US20100048567A1 (en) * 2008-04-16 2010-02-25 Portola Pharmaceuticals Inc. Inhibitors of syk and JAK protein kinases
WO2010106016A1 (fr) * 2009-03-17 2010-09-23 Glaxo Group Limited Dérivés de pyrimidine utilisés comme inhibiteurs de ltk
CN102066339A (zh) * 2008-04-16 2011-05-18 波托拉医药品公司 作为syk或jak蛋白激酶抑制剂的2,6-二氨基-嘧啶-5-基甲酰胺类化合物
CN102203086A (zh) * 2008-09-03 2011-09-28 拜尔农作物科学股份公司 作为杀真菌剂的噻吩基氨基嘧啶类化合物
CN102421761A (zh) * 2009-05-08 2012-04-18 安斯泰来制药株式会社 二氨基杂环甲酰胺化合物
US20180186783A1 (en) * 2008-04-16 2018-07-05 Portola Pharmaceuticals, Inc. Inhibitors of protein kinases
WO2019222538A1 (fr) * 2018-05-16 2019-11-21 The University Of North Carolina At Chapel Hill Aminopyrimidines et aminopyridines en tant qu'inhibiteurs de mertk et leur application dans le traitement du cancer
CN110832070A (zh) * 2017-05-10 2020-02-21 艾欧凡斯生物治疗公司 液体肿瘤来源肿瘤浸润淋巴细胞的扩增及其治疗用途
WO2020172258A1 (fr) * 2019-02-19 2020-08-27 Nalo Therapeutics Modulateurs de la protéine proto-oncogène de la famille myc

Patent Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009145856A1 (fr) * 2008-04-16 2009-12-03 Portola Pharmaceuticals, Inc. 2, 6-DIAMINO-PYRIMIDIN- B-YL-CARBOXAMIDES SERVANT D'INHIBITEURS DE Syk KINASES ET DE JANUS KINASES
US20100048567A1 (en) * 2008-04-16 2010-02-25 Portola Pharmaceuticals Inc. Inhibitors of syk and JAK protein kinases
CN102066339A (zh) * 2008-04-16 2011-05-18 波托拉医药品公司 作为syk或jak蛋白激酶抑制剂的2,6-二氨基-嘧啶-5-基甲酰胺类化合物
US20180186783A1 (en) * 2008-04-16 2018-07-05 Portola Pharmaceuticals, Inc. Inhibitors of protein kinases
CN102203086A (zh) * 2008-09-03 2011-09-28 拜尔农作物科学股份公司 作为杀真菌剂的噻吩基氨基嘧啶类化合物
WO2010106016A1 (fr) * 2009-03-17 2010-09-23 Glaxo Group Limited Dérivés de pyrimidine utilisés comme inhibiteurs de ltk
CN102421761A (zh) * 2009-05-08 2012-04-18 安斯泰来制药株式会社 二氨基杂环甲酰胺化合物
CN110832070A (zh) * 2017-05-10 2020-02-21 艾欧凡斯生物治疗公司 液体肿瘤来源肿瘤浸润淋巴细胞的扩增及其治疗用途
WO2019222538A1 (fr) * 2018-05-16 2019-11-21 The University Of North Carolina At Chapel Hill Aminopyrimidines et aminopyridines en tant qu'inhibiteurs de mertk et leur application dans le traitement du cancer
WO2020172258A1 (fr) * 2019-02-19 2020-08-27 Nalo Therapeutics Modulateurs de la protéine proto-oncogène de la famille myc

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CATHERINE M. ALDER, AMBLER MARTIN, CAMPBELL AMANDA J., CHAMPIGNY AURELIE C., DEAKIN ANGELA M., HARLING JOHN D., HARRIS CAROL A., L: "Identification of a Novel and Selective Series of Itk Inhibitors via a Template-Hopping Strategy", ACS MEDICINAL CHEMISTRY LETTERS, AMERICAN CHEMICAL SOCIETY, US, vol. 4, no. 10, 1 January 2013 (2013-01-01), US , pages 948 - 952, XP055357203, ISSN: 1948-5875, DOI: 10.1021/ml400206q *
PADILLA FERNANDO, BHAGIRATH NIALA, CHEN SHAOQING, CHIAO ERIC, GOLDSTEIN DAVID M., HERMANN JOHANNES C., HSU JONATHAN, KENNEDY-SMITH: "Pyrrolopyrazines as Selective Spleen Tyrosine Kinase Inhibitors", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 56, no. 4, 28 February 2013 (2013-02-28), US , pages 1677 - 1692, XP055922084, ISSN: 0022-2623, DOI: 10.1021/jm301720p *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023279105A1 (fr) * 2021-07-01 2023-01-05 Aerie Pharmaceuticals, Inc. Azétidinyl pyrimidines et utilisations associées

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