WO2022213980A1 - Inhibiteur de tyk2 et son utilisation - Google Patents

Inhibiteur de tyk2 et son utilisation Download PDF

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Publication number
WO2022213980A1
WO2022213980A1 PCT/CN2022/085308 CN2022085308W WO2022213980A1 WO 2022213980 A1 WO2022213980 A1 WO 2022213980A1 CN 2022085308 W CN2022085308 W CN 2022085308W WO 2022213980 A1 WO2022213980 A1 WO 2022213980A1
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alkyl
methyl
hydrogen
methoxy
mmol
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PCT/CN2022/085308
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English (en)
Chinese (zh)
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陈晓菁
陈波
廉兵
萨卡苏博斯•曼
余辰
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上海齐鲁制药研究中心有限公司
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Priority to CN202280014108.9A priority Critical patent/CN116888125B/zh
Publication of WO2022213980A1 publication Critical patent/WO2022213980A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/18—Bridged systems

Definitions

  • the invention belongs to the field of medicine, in particular to a macrocyclic TYK2 inhibitor compound, its pharmaceutically acceptable salt, its ester, its isomer, its isotopic label, its composition, use and treatment method.
  • Janus kinase is a non-receptor tyrosine protein kinase that plays a pivotal role in many cytokine receptor-mediated signal transduction, and is involved in the proliferation, differentiation, Important physiological processes such as apoptosis, angiogenesis and immune regulation.
  • JAKs family has 4 different subtypes in mammals, namely JAK1, JAK2, JAK3 and TYK2 (tyrosine kinase2).
  • JAK1, JAK2 and TYK2 are expressed in various tissues and cells of the human body.
  • JAK-3 is mainly expressed in various tissues and cells. in hematopoietic cells.
  • the JAK-STAT (Janus kinase-signal transducer and activator of tanscription) signaling pathway is the most important pathway mediated by JAKs in vivo. This pathway consists of ligands (such as cytokines), transmembrane receptors, JAK kinases and transcription factors. STAT consists of four parts.
  • JAK is a non-receptor tyrosine kinase that activates receptor-coupled JAKs when extracellular ligands including specific growth factors, growth hormones, chemokines, and cytokines bind to cytokine receptors on the surface , make it have tyrosine kinase activity and bind in pairs, the dimeric JAK can undergo spontaneous phosphorylation, bind to STAT protein, the activated STAT protein is detached from the receptor and forms a phosphorylated dimer, which is transferred to the nucleus It binds to specific DNA sequences to exert physiological functions and regulate the transcription of target genes.
  • Type I and II cytokines bind their receptors to subsequent intracellular signaling through the JAK kinase and signal transducer and activator of transcription (JAK–STAT) pathway.
  • TYK2 mainly mediates the functions of cytokines such as IFN- ⁇ , IL-6, IL-10, IL-12 and IL-23.
  • cytokines such as IFN- ⁇ , IL-6, IL-10, IL-12 and IL-23.
  • TYK2-deficient mice are resistant to collagen-induced arthritis, colitis, psoriasis, and experimental allergic encephalomyelitis, suggesting that TYK2-mediated signaling plays a role in autoimmune and inflammation-related diseases. important role.
  • Genome-wide association studies show that TYK2 variants are associated with autoimmune disorders such as Crohn's disease, psoriasis, systemic lupus erythematosus and rheumatoid arthritis, further demonstrating the importance of TYK2 in autoimmune and inflammation-related diseases .
  • TYK2 selective inhibitors can inhibit the signal transduction cascade of IL-12, IL-23 and type I interferon receptors, including systemic lupus erythematosus, inflammatory bowel disease, psoriasis, A variety of autoimmune and inflammation-related animal models, including rheumatoid arthritis, play a therapeutic role, and a TYK2 selective inhibitor is currently undergoing II or III for systemic lupus erythematosus, Crohn's disease and psoriasis indications Phase clinical research, no TYK2 selective inhibitor has been listed.
  • the problem to be solved by the present invention is to provide a macrocyclic compound with a good inhibitory effect on the TYK2 signaling pathway and a novel structure.
  • the compound specifically targets the TYK2 regulatory protein domain (pseudokinase) and has an inhibitory effect on the TYK2 pathway.
  • TYK2 regulatory protein domain pseudokinase
  • JAK1, JAK2 and/or JAK3 signaling pathway it has stronger selectivity; further, the present invention provides a TYK2 inhibitor with high selectivity, good bioavailability, good efficacy and low toxicity class compounds.
  • the present invention provides a compound represented by the following general formula (II'),
  • X is selected from CH, N;
  • R 1 is selected from hydrogen, C 1-6 alkyl, deuterated C 1-6 alkyl, cycloalkyl;
  • R 8 is selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy
  • R 1 is connected to R 8 , and forms a heterocycle together with the nitrogen atom to which it is connected;
  • X 1 and X 2 are independently selected from CH 2 , NH, and O;
  • Ring C is selected from aryl, heteroaryl, cycloalkyl, heterocyclyl;
  • R is independently selected from R 2 or R 3 ;
  • n is selected from 0, 1, 2, 3;
  • R 2 is selected from hydrogen, -OH, C 1-6 alkyl, deuterated C 1-6 alkyl, C 1-6 alkoxy, deuterated C 1-6 alkoxy, C 1-6 alkyl- C(O)-, C 1-6 alkyl-S-, C 1-6 alkyl-S(O)-, C 1-6 alkyl-S(O) 2- ;
  • R 3 is selected from hydrogen, C 1-6 alkoxy-C(O)-, (R 5 )(R 6 )NC(O)-, or the following groups optionally substituted with one or more Ra : Phenyl, heteroaryl, heterocyclyl, cycloalkyl;
  • R a is selected from hydrogen, halogen, -CN, carboxyl, (R 5 )(R 6 )NC(O)-, C 1-6 alkyl, C 1-6 alkyl-C(O)-, C 1- 6 alkyl-C(O)-NH-, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, hydroxy C 1-6 alkyl, C 1-6 alkoxy, cycloalkyl , cycloalkyl-(CH 2 )pO-, NC-cycloalkyl, or any two adjacent R a are connected to form a heterocycle together with the atoms to which they are connected; p is selected from 0, 1, 2, 3;
  • L 1 is selected from C 1-8 alkylene optionally substituted by one or more R b , and one or more CH 2 in said C 1-8 alkylene is optionally substituted by -C(O)-, -NR 7 -, -S, -S(O)-, -S(O) 2- and/or -O-substituted;
  • R b is selected from C 1-6 alkyl, or two R b located on the same carbon atom and the carbon atom to which it is attached together form cycloalkyl, heterocyclyl;
  • L 1 is selected from Wherein the ring A end is connected with the X of formula ( II '), and the L end is connected with the ring C;
  • Ring A is selected from aryl, heteroaryl
  • L 2 is selected from C 1-6 alkylene optionally substituted by one or more R c , and one or more CH 2 in said C 1-6 alkylene is optionally substituted by -C(O)-, -NR 7 -, -S-, -S(O)-, -S(O) 2 - and/or -O-substituted;
  • R c is selected from C 1-6 alkyl, or both are located on the same carbon atom R c and its attached carbon atoms together form cycloalkyl, heterocyclyl;
  • R 4 is selected from hydrogen, halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, phenyl, cycloalkyl, and the phenyl is optionally composed of one or more selected from halogen, C 1-6 6 alkyl, C 1-6 alkoxy or halogenated C 1-6 alkyl group substituted;
  • n 0, 1, 2, 3;
  • R 5 and R 6 are independently selected from hydrogen, -OH, C 1-6 alkyl, cycloalkyl, or R 5 and R 6 are connected together, and together with the nitrogen atom to which they are connected, form a heterocycle;
  • R 7 is selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkyl-C(O)-, -C(O)OCH 2 Ph.
  • X is selected from CH, N;
  • R 1 is selected from hydrogen, C 1-6 alkyl, deuterated C 1-6 alkyl, cycloalkyl;
  • R 8 is selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy
  • R 1 is connected with R 8 to form a 3-8 membered heterocycle together with the nitrogen atom to which it is connected;
  • R 2 is selected from hydrogen, -OH, C 1-6 alkyl, deuterated C 1-6 alkyl, C 1-6 alkoxy, deuterated C 1-6 alkoxy, C 1-6 alkyl- C(O)-, C 1-6 alkyl-S-, C 1-6 alkyl-S(O)-, C 1-6 alkyl-S(O) 2- ;
  • R 3 is selected from hydrogen, C 1-6 alkoxy-C(O)-, (R 5 )(R 6 )NC(O)-, or the following groups optionally substituted with one or more Ra : Phenyl, heteroaryl, heterocyclyl, cycloalkyl;
  • R a is selected from hydrogen, halogen, -CN, carboxyl, (R 5 )(R 6 )NC(O)-, C 1-6 alkyl, C 1-6 alkyl-C(O)-, C 1- 6 alkyl-C(O)-NH-, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, hydroxy C 1-6 alkyl, C 1-6 alkoxy, 3-8 membered cycloalkyl, 3-8 membered cycloalkyl-O-, 3-8 membered cycloalkyl-C 1-6 alkoxy, NC-3-8 membered cycloalkyl, or any two adjacent R a Connected to and together form a 3-8 membered heterocycle with the atoms to which it is connected;
  • p is selected from 0, 1, 2, 3;
  • L 1 is selected from C 1-8 alkylene optionally substituted by one or more R b , and one or more CH 2 in said C 1-8 alkylene is optionally substituted by -C(O)-, -NR 7 -, -S, -S(O)-, -S(O) 2- and/or -O-substituted;
  • R b is selected from C 1-4 alkyl, or two carbon atoms located on the same carbon atom. R b together with the carbon atom to which it is attached forms a 3-5 membered cycloalkyl;
  • L 1 is selected from Wherein the ring A end is connected with the NH of formula (I'), and the L 2 end is connected with the benzene ring;
  • Ring A is selected from phenyl, heteroaryl
  • L 2 is selected from C 1-6 alkylene optionally substituted by one or more R c , and one or more CH 2 in said C 1-6 alkylene is optionally substituted by -C(O)-, -NR 7 -, -S-, -S(O)-, -S(O) 2 - and/or -O-substituted;
  • R c is selected from C 1-6 alkyl, or both are located on the same carbon atom The R c and the carbon atom to which it is attached together form a 3-8 membered cycloalkyl;
  • R 4 is selected from hydrogen, halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, phenyl, 3-8 membered cycloalkyl, and the phenyl is optionally selected from one or more halogens , C 1-6 alkyl, C 1-6 alkoxy or halogenated C 1-6 alkyl group substitution;
  • n 0, 1, 2, 3;
  • R 5 , R 6 are independently selected from hydrogen, -OH, C 1-6 alkyl, 3-8 membered cycloalkyl, or R 5 and R 6 are connected together, and together with the nitrogen atom to which they are connected, form a 3-8 membered Heterocycle;
  • R 7 is selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkyl-C(O)-, -C(O)OCH 2 Ph.
  • X is selected from CH, N;
  • R 1 is selected from hydrogen, C 1-6 alkyl, deuterated C 1-6 alkyl, cycloalkyl;
  • R 2 is selected from hydrogen, -OH, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkyl-C(O)-, C 1-6 alkyl-S-, C 1- 6 alkyl-S(O)-, C 1-6 alkyl-S(O) 2 -;
  • R 3 is selected from hydrogen, C 1-6 alkoxy-C(O)-, (R 5 )(R 6 )NC(O)-, or the following groups optionally substituted with one or more Ra : Phenyl, heteroaryl;
  • R a is selected from hydrogen, halogen, (R 5 )(R 6 )NC(O)-, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy;
  • L 1 is selected from C 1-8 alkylene optionally substituted by one or more R b , and one or more CH 2 in said C 1-8 alkylene is optionally substituted by -C(O)-, -NR 7 -, -S, -S(O)-, -S(O) 2- and/or -O-substituted;
  • R b is selected from C 1-4 alkyl, or two R b located on the same carbon atom together with the carbon atom to which it is attached form a 3-5 membered cycloalkyl;
  • L 1 is selected from Wherein the ring A end is connected with the NH of formula (I'), and the L 2 end is connected with the benzene ring;
  • Ring A is selected from phenyl, heteroaryl
  • L 2 is selected from C 1-6 alkylene optionally substituted by one or more R c , and one or more CH 2 in said C 1-6 alkylene is optionally substituted by -C(O)-, -NR 7 -, -S-, -S(O)-, -S(O) 2 - and/or -O- substituted;
  • R c is selected from C 1-6 alkyl, or two R c located on the same carbon atom together with the carbon atom to which it is attached form a 3-8 membered cycloalkyl;
  • R 4 is selected from hydrogen, halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, phenyl, 3-8 membered cycloalkyl, and the phenyl is optionally selected from one or more halogens , C 1-6 alkyl, C 1-6 alkoxy or halogenated C 1-6 alkyl group;
  • n 0, 1, 2, 3;
  • R 5 and R 6 are independently selected from hydrogen and C 1-6 alkyl
  • R 7 is selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkyl-C(O)-, -C(O)OCH 2 Ph;
  • R 8 is selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy.
  • X is selected from CH, N;
  • R 1 is selected from hydrogen, C 1-4 alkyl, deuterated C 1-4 alkyl, 3-6 membered cycloalkyl;
  • R 2 is selected from hydrogen, -OH, C 1-4 alkyl, deuterated C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkyl-C(O)-, C 1-4 alkyl-S-, C 1-4 alkyl-S(O)-, C 1-4 alkyl-S(O) 2- ;
  • R 3 is selected from hydrogen, C 1-4 alkoxy-C(O)-, (R 5 )(R 6 )NC(O)-, or the following groups optionally substituted with one or more Ra : Phenyl, 5-6 membered heteroaryl, 5-6 membered heterocyclyl;
  • R a is selected from hydrogen, halogen, -CN, carboxyl, (R 5 )(R 6 )NC(O)-, C 1-4 alkyl, C 1-4 alkyl-C(O)-, C 1- 4 alkyl-C(O)-NH-, C 1-4 alkoxy, halogenated C 1-4 alkyl, halogenated C 1-4 alkoxy, hydroxy C 1-4 alkyl, 3-6 membered cycloalkyl, 3-6 membered cycloalkyl-O-, 3-6 membered cycloalkyl-C 1-4 alkoxy, NC-3-6 membered cycloalkyl, or any two adjacent R a Connected to and together form a 3-6 membered heterocycle with the atoms to which it is connected;
  • L 1 is selected from C 1-8 alkylene optionally substituted by one or more R b , and one or more CH 2 in said C 1-8 alkylene is optionally substituted by -C(O)-, -NR 7 -, -S, -S(O)-, -S(O) 2- and/or -O-substituted;
  • R b is selected from C 1-4 alkyl, or two R b located on the same carbon atom together with the carbon atom to which it is attached form a 3-5 membered cycloalkyl;
  • L 1 is selected from Wherein the ring A end is connected with the NH end of formula (I), and the L 2 end is connected with the benzene ring;
  • Ring A is selected from phenyl, 5-6 heteroaryl, or 8-10 membered fused ring heteroaryl;
  • L 2 is selected from C 1-6 alkylene, and one or more CH 2 in said C 1-6 alkylene is optionally replaced by -C(O)-, -NR 7 -, -S-, -S (O)-, -S(O) 2 - and/or -O- substitution;
  • R 4 is selected from hydrogen, halogen, C 1-4 alkyl, halogenated C 1-4 alkyl, phenyl, 3-6 membered cycloalkyl, the phenyl is optionally by one or more selected from halogen , C 1-4 alkyl, or halogenated C 1-4 alkyl group substitution;
  • n 0, 1, 2, 3;
  • R 5 and R 6 are independently selected from hydrogen, C 1-4 alkyl, 3-6-membered cycloalkyl, or R 5 and R 6 are connected together, and together with the nitrogen atom to which they are connected, form a 3-6-membered heterocycle;
  • R 7 is selected from hydrogen, C 1-4 alkyl, C 1-4 alkyl-C(O)-, -C(O)OCH 2 Ph.
  • X is selected from CH, N;
  • R 1 is selected from hydrogen, C 1-4 alkyl, deuterated C 1-4 alkyl, 3-6 membered cycloalkyl;
  • R 2 is selected from hydrogen, -OH, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkyl-C(O)-, C 1-4 alkyl-S-, C 1- 4 alkyl-S(O)-, C 1-4 alkyl-S(O) 2 -;
  • R 3 is selected from hydrogen, C 1-4 alkoxy-C(O)-, (R 5 )(R 6 )NC(O)-, or the following groups optionally substituted with one or more Ra : Phenyl, 5-6 membered heteroaryl;
  • R a is selected from hydrogen, halogen, (R 5 )(R 6 )NC(O)-, C 1-4 alkyl, C 1-4 alkoxy, halogenated C 1-4 alkyl;
  • L 1 is selected from C 1-8 alkylene optionally substituted by one or more R b , and one or more CH 2 in said C 1-8 alkylene is optionally substituted by -C(O)-, -NR 7- , -S, -S(O)-, -S(O) 2 - and/or -O- substituted;
  • R b is selected from C 1-4 alkyl, or two R b located on the same carbon atom together with the carbon atom to which it is attached form a 3-5 membered cycloalkyl;
  • L 1 is selected from Wherein the ring A end is connected with the NH end of formula (I), and the L 2 end is connected with the benzene ring;
  • Ring A is selected from phenyl, 5-6 heteroaryl, or 8-10 membered fused ring heteroaryl;
  • L 2 is selected from C 1-6 alkylene, one or more CH 2 in said C 1-6 alkylene is optionally replaced by -C(O)-, -NR 7- , -S-, -S (O)-, -S(O) 2 - and/or -O- substitution;
  • R 4 is selected from hydrogen, halogen, C 1-4 alkyl, halogenated C 1-4 alkyl, phenyl, 3-6 membered cycloalkyl, the phenyl is optionally by one or more selected from halogen , C 1-4 alkyl, or halogenated C 1-4 alkyl group;
  • n 0, 1, 2, 3;
  • R 5 and R 6 are independently selected from hydrogen and C 1-4 alkyl
  • R 7 is selected from hydrogen, C 1-4 alkyl, C 1-4 alkyl-C(O)-, -C(O)OCH 2 Ph.
  • R 1 is selected from H, -CH 3 , -CH 2 CH 3 , -CD 3 ,
  • R 1 is selected from H, -CH 3 , -CH 2 CH 3 , -CD 3 ,
  • R is selected from H
  • R 1 is attached to R 8 to form together with the nitrogen atom to which it is attached
  • R 3 is selected from hydrogen, -C(O)-OCH 3 , -C(O)-NH 2 , -C(O)-N(CH 3 ) 2 , or the following groups optionally substituted with 1-2 R a : pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, 1,2, 4-triazolyl, tetrazolyl, phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl,
  • Ra is selected from H, F, -CN, -COOH , -CH3 , -CH2CH3 , -CH2F , -CHF2 , -CF3 , -OCH3 , -OCH2CH3 , -O- CH(CH 3 ) 2 , -CF 2 CH 3 , -C(O)CH 3 , -OCHF 2 , -C(O)-N(CH 3 ) 2 , -C(O)-NHCH 3 , -NHC( O)CH 3 , -C(O)-NH 2 , Or two adjacent R a are connected and the atoms to which they are connected together form tetrahydrofuran and tetrahydropyrrole.
  • R 3 is selected from hydrogen, -C(O)-OCH 3 , -C(O)-NH 2 , -C(O)-N( CH3 ) 2 , or selected from the following groups optionally substituted with 1-2 R a : pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, 1, 2,4-triazolyl, tetrazolyl, phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl; R a is selected from hydrogen, F, -CH 3 , -CH 2 CH 3 , - CH 2 F, -CHF 2 , -CF 3 , -OCH 3 , -C(O)-N(CH 3 ) 2 .
  • R 3 is selected from hydrogen, -C(O)-OCH 3 , -C(O)-NH 2 , Or selected from the following groups optionally substituted by 1-2 R a : pyrazolyl, imidazolyl, 1,2,4-triazolyl, phenyl, pyridyl, pyrimidinyl; R a is selected from hydrogen, F, -CH 3 , -CH 2 CH 3 , -OCH 3 .
  • Ra is selected from hydrogen, F, -CH3 , -OCH3 , -O-CH( CH3 ) 2 .
  • R 3 is selected from the following groups:
  • R 3 is selected from the following groups:
  • R is selected from
  • L 1 is selected from “a” indicates that it is attached to X2 or NH through this end.
  • R 4 is selected from hydrogen, fluorine, -CH 3 , -CF 3 ,
  • n is selected from 0, 1 or 2.
  • Ring A is selected from phenyl, pyridyl, pyrazolyl, imidazolyl, thiazolyl,
  • ring A is selected from “a” indicates that it is attached to X2 or NH through this end.
  • R7 is selected from hydrogen, -CH3 , -CH2CH3, -C(O) CH3 , -C (O ) OCH2Ph .
  • L 2 is q 1 and q 2 are independently 0, 1, 2, 3, and 4;
  • Y is -O-, -S-, -NR 7 -, -NR 7 -C(O)-, -C(R 7 ) 2 -, -OC(O)-, -S(O)-, -S(O) 2 -;
  • R 7 is selected from hydrogen, C 1-4 alkyl, C 1-4 alkyl-C(O)- , -C(O)OCH 2 Ph, preferably, R 7 is selected from hydrogen, C 1-4 alkyl.
  • L 2 is q 1 and q 2 are independently 0, 1, 2, 3, and 4;
  • Y is -O-, -S-, -NR 7 -, -NR 7 -C(O)-, -C(R 7 ) 2 -, -OC(O)-, -S(O)-, -S(O) 2 -;
  • R 7 is selected from hydrogen, -CH 3 , -CH 2 CH 3 , -C(O)CH 3 , - C(O) OCH2Ph .
  • L 2 is q 1 and q 2 are independently 0, 1, 2, 3, and 4;
  • Y is -O-, -S-, -NR 7 -, -NR 7 -C(O)-, -C(R 7 ) 2 -, -OC(O)-, -S(O)-, -S(O) 2 -;
  • R 7 is selected from hydrogen, -CH 3 , -C(O)OCH 2 Ph.
  • formula (II'), formula (I') or formula (I) the sum of q 1 and q 2 is 2-5; preferably 3 or 4.
  • formula (II'), formula (I') or formula (I) the present invention further provides the compound represented by the following general formula, its pharmaceutically acceptable salt, its ester, its isomer , its isotopic label:
  • R 1 , R 2 , R 3 , R a , R 4 , L 2 , ring A, m can be selected from the definitions of any scheme of the present invention.
  • the compound of the present invention or its pharmaceutically acceptable salt, its ester, its isomer, its isotopic label, selected from the following compounds:
  • a pharmaceutical preparation composition comprising the compound described in any one of the first aspect of the present invention, a pharmaceutically acceptable salt thereof, an ester thereof, an isomer thereof, an isotope thereof marker, and one or more pharmaceutically acceptable excipients.
  • the pharmaceutical formulation can be any pharmaceutically acceptable dosage form.
  • a pharmaceutically acceptable excipient is a substance that is non-toxic, compatible with the active ingredient and otherwise biologically suitable for the organism.
  • the choice of a particular excipient will depend on the mode of administration or disease type and state used to treat the particular patient.
  • pharmaceutically acceptable excipients include, but are not limited to, solvents, diluents, dispersants, suspending agents, surfactants, isotonic agents, thickeners, emulsifiers, binders, Lubricants, stabilizers, hydrating agents, emulsification accelerators, buffers, absorbents, colorants, ion exchangers, mold release agents, coating agents, flavoring agents, antioxidants, etc.
  • flavoring agents, preservatives, sweetening agents, etc. can also be added to the pharmaceutical preparation composition.
  • the above-described pharmaceutical formulation compositions may be administered orally, parenterally, rectally, or via pulmonary administration to a patient or subject in need of such treatment.
  • the pharmaceutical composition can be made into oral preparations, for example, can be made into conventional oral solid preparations, such as tablets, capsules, pills, granules, etc.; can also be made into oral liquid preparations, such as Oral solution, oral suspension, syrup, etc.
  • suitable fillers, binders, disintegrants, lubricants and the like can be added.
  • parenteral administration the above-mentioned pharmaceutical preparations can also be prepared into injections, including injection solutions, sterile powders for injection and concentrated solutions for injection.
  • the pharmaceutical composition When preparing the injection, it can be produced by the conventional methods in the existing pharmaceutical field. When preparing the injection, no additives can be added, or suitable additives can be added according to the properties of the drug.
  • the pharmaceutical composition For rectal administration, the pharmaceutical composition can be formulated into suppositories and the like.
  • the pharmaceutical composition For pulmonary administration, can be formulated into inhalation formulations, aerosol formulations, powder aerosol formulations or spray formulations, and the like.
  • a pharmaceutical composition comprising the compound described in any one of the first aspect of the present invention, a pharmaceutically acceptable salt thereof, an ester thereof, an isomer thereof, an isotopic label thereof and one or more second therapeutically active agents
  • the second therapeutically active agents can be selected from immunosuppressants, such as hormonal drugs, such as corticosteroids; from cytokine inhibitors; from kinase inhibitors ; selected from nuclear translocation inhibitors; selected from non-steroidal anti-inflammatory drugs, such as ibuprofen; selected from antiviral agents, such as abacavir; selected from anti-proliferative agents; selected from antimalarial drugs; selected from TNF - alpha inhibitors, etc.
  • immunosuppressants such as hormonal drugs, such as corticosteroids
  • cytokine inhibitors such as corticosteroids
  • kinase inhibitors selected from nuclear translocation inhibitors
  • non-steroidal anti-inflammatory drugs such as ibuprofen
  • selected from antiviral agents
  • the medicine is used to prevent and/or treat the related diseases mediated by TYK2 in patients or subjects; preferably, the related diseases mediated by TYK2 include autoimmune diseases, transplant-related diseases, inflammation Sexual or inflammatory disease.
  • the TYK2-mediated related disease is mediated by the IL-12, IL-23 and/or IFN ⁇ signaling pathway.
  • the autoimmune disease is selected from the group consisting of type 1 diabetes, Gray's disease, rheumatoid arthritis, ankylosing spondylitis, cutaneous lupus erythematosus, systemic lupus erythematosus, discoid lupus erythematosus, lupus Nephritis, multiple sclerosis, systemic sclerosis, Sjögren's syndrome, psoriasis, Crohn's disease, ulcerative colitis, and inflammatory bowel disease.
  • the inflammatory or inflammatory disease is selected from the group consisting of rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, psoriasis, Crohn's disease, ulcerative colitis and inflammatory bowel disease, Cold porphyrin-associated periodic syndrome (CAPS), tumor necrosis factor receptor-associated periodic fever syndrome (TRAPS), familial Mediterranean fever (FMF), adult Still's disease, systemic juvenile idiopathic arthritis, gout , gouty arthritis, osteoarthritis.
  • CCAPS Cold porphyrin-associated periodic syndrome
  • TRAPS tumor necrosis factor receptor-associated periodic fever syndrome
  • FMF familial Mediterranean fever
  • adult Still's disease systemic juvenile idiopathic arthritis, gout , gouty arthritis, osteoarthritis.
  • the present invention also provides a method for treating related diseases mediated by TYK2, comprising administering to a patient or subject an effective amount of the compound described in any one of the first aspects of the present invention, Its pharmaceutically acceptable salts, its esters, its isomers, its isotopic labels.
  • the present invention also provides a method of treating a related disease mediated by IL-12, IL-23 and/or IFN ⁇ , comprising administering to a patient or subject an effective amount of the first of the present invention
  • a pharmaceutically acceptable salt thereof, an ester thereof, an isomer thereof, an isotopic label thereof comprising administering to a patient or subject an effective amount of the first of the present invention
  • the present invention also provides a method of treating an autoimmune disease, comprising administering to a patient or subject an effective amount of the compound described in any one of the first aspects of the present invention, or a pharmaceutically acceptable compound thereof. Accepted salts, esters thereof, isomers thereof, isotopic labels thereof.
  • the present invention provides a compound according to any one of the first aspects, a pharmaceutically acceptable salt thereof, an ester thereof, an isomer thereof, an isotopic label thereof, which can be used for the treatment of TYK2-mediated related diseases.
  • pharmaceutically acceptable means, within the scope of sound medical judgment, suitable for use in contact with human and animal tissues without undue toxicity, irritation, allergic reaction or other problems or complications, with a reasonable benefit/risk ratio equivalent to those compounds, materials, compositions and/or dosage forms.
  • the "pharmaceutically acceptable salt” in the present invention refers to a salt formed by an acidic functional group (such as -COOH, -OH, -SO 3 H, etc.) existing in a compound and an appropriate inorganic or organic cation (base), including Salts formed with alkali metals or alkaline earth metals, ammonium salts, and salts with nitrogen-containing organic bases; and salts with appropriate inorganic or organic anions (acids) of basic functional groups (such as -NH 2 , etc.) present in the compounds , including salts formed with inorganic or organic acids (eg, carboxylic acids, etc.).
  • an acidic functional group such as -COOH, -OH, -SO 3 H, etc.
  • base an appropriate inorganic or organic cation
  • ester in the present invention refers to the product formed by the dehydration of acid and alcohol; when there is a -COOH group in the structure of the compound of the present invention, it can be dehydrated with a pharmaceutically acceptable alcohol compound to form an ester; when the present invention There is -OH in the compound structure, which can be dehydrated with pharmaceutically acceptable organic or inorganic acid compounds to form esters.
  • the ester compound can produce the active compound of the present invention by means of metabolism or hydrolysis in vivo, and the ester can have biological activity similar to the free body or no or weak biological activity in vitro.
  • the “isomers” in the present invention include geometric isomers as well as stereoisomers, such as cis-trans isomers, enantiomers, diastereomers, tautomers, and external isomers thereof. Racemic and other mixtures, all of which are within the scope of this invention.
  • the term “enantiomers” refers to stereoisomers that are mirror images of each other.
  • the term “tautomer” refers to a type of functional group isomer that has a different point of attachment of the hydrogen by displacement of one or more double bonds, for example, ketone and its enol form are keto-enol Tautomers.
  • diastereomer refers to a stereoisomer in which a molecule has two or more chiral centers and the molecules are in a non-mirror-image relationship.
  • cis-trans isomers refers to different spatial configurations in which double bonds or single bonds of ring carbon atoms cannot rotate freely in the molecule.
  • terapéuticaally effective amount refers to an amount sufficient to produce a beneficial or desired effect when administered to a subject of a compound or composition or dosage form of the present invention; the effect may be the prevention of autoimmune symptoms Produce, and/or inhibit, reduce the development, spread of autoimmune symptoms, and/or improve clinical symptoms or indicators associated with autoimmune disease. It will be recognized, however, that the total daily dosage of the compounds of the present invention will be decided by the attending physician within the scope of sound medical judgment.
  • the particular therapeutically effective dosage level will depend upon a variety of factors, including the disorder being treated and the severity of the disorder; the activity of the particular compound employed; the particular composition employed; age, weight, general health, sex, and diet of the patient; time of administration, route of administration, and excretion rate of the particular compound employed; duration of treatment; drugs used in combination or concomitantly with the particular compound employed; and Similar factors well known in the medical field. For example, it is the practice in the art to start with a dose of the compound below that required to obtain the desired therapeutic effect and gradually increase the dose until the desired effect is obtained.
  • substituted refers to two situations in which one or more hydrogen atoms of the substituted group may be "substituted” or “unsubstituted” by one or more substituents.
  • variable R when any variable (substituent R) appears more than once in the composition or structure of the compound, its definition in each case is independent, and the substituent may be the same or different; in general, the Variables can be selected from the same or different substituent groups in the same technical scheme; for example, when m is 2 in general formula (I), ring A is substituted with two R groups, wherein each R is defined independently of each other ; for example, the R 3 is substituted with one or more R a , wherein each R a is also independent of each other. Furthermore, combinations of substituents and/or variables are preferably only present if such combinations result in stable compounds.
  • substituent R 4 can be substituted at any position on the benzene ring.
  • any adjacent two R a are connected and the atoms to which they are connected together form a heterocycle
  • “any adjacent” means that the two R a are connected at the vicinal positions of the substituted group, respectively on the atom.
  • the structure types such as When two R a are substituents of heterocyclyl or cycloalkyl, the structure type is as
  • nitrogen atoms are present on the compounds of the present invention, these nitrogen atoms can be converted to N-oxides by treatment with an oxidizing agent to obtain other compounds of the present invention. Accordingly, unless otherwise specified, all shown and claimed nitrogen atom-containing groups are understood to encompass both non-nitroxide groups and their nitroxide groups (N ⁇ O).
  • halogen in the present invention refers to a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
  • Alkyl refers to a branched or straight-chain saturated aliphatic alkane having a specified number of carbon atoms with one hydrogen-derived group removed.
  • C 1-10 alkyl is meant to include C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 alkyl, including “C 1-6 "Alkyl", “C 1-4 alkyl", “C 1-3 alkyl”; specific examples include but are not limited to: methyl, ethyl, n-propyl, isopropyl, sec-butyl, 2-methyl butyl, 1,1-dimethylbutyl, etc.
  • alkylene refers to a branched or straight-chain saturated aliphatic alkane having a specified number of carbon atoms, a group derived by removing two hydrogens.
  • C 1-10 alkylene includes C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 alkylene, including “C 1-8 "Alkylene”, “C 1-6 alkylene”, “C 1-4 alkylene”, “C 3-4 alkylene”, “C 6-8 alkylene", “C 6-7 alkylene”"Alkylene”,"C 1-6 alkylene”; preferably, the "alkylene” in the present invention is a "straight-chain alkylene"; specific examples include but are not limited to: -CH 2 -, - CH2CH2-,- CH2CH2CH2 -,- CH ( CH3 ) CH2 - , - CH2CH2CH2CH2
  • haloalkyl in the present invention refers to a group obtained by replacing the hydrogen in the alkyl group with one or more halogens, such as "fluoromethyl” including monofluoromethyl, difluoromethyl, trifluoromethyl ;
  • the "halogenated alkyl group” in the present invention is “halogenated C 1-6 alkyl group” and “halogenated C 1-4 alkyl group”.
  • Alkyl is as defined above.
  • the “deuterated alkyl group” in the present invention refers to a group obtained by replacing the hydrogen in the alkyl group with one or more deuterium (D), such as DCH 2 -, D 2 CH-, D 3 C-; preferably Typically, the “deuterated alkyl group” in the present invention is “deuterated C 1-6 alkyl group” and “deuterated C 1-4 alkyl group”. Alkyl is as defined above.
  • hydroxy C 1-6 alkyl group in the present invention refers to a group obtained by replacing the hydrogen in the alkyl group with one or more hydroxyl groups, such as HOCH 2 -, HOCH 2 -CH(OH)-, etc.; preferably Typically, the "hydroxy C 1-6 alkyl group” in the present invention is a hydroxy C 1-4 alkyl group.
  • Alkyl is as defined above.
  • NC-cycloalkyl in the present invention refers to a group obtained by substituting any hydrogen atom on a cycloalkyl with a cyano group, such as Wait. Cycloalkyl is as defined in this specification.
  • cycloalkyl-(CH 2 )pO- when p is 0, the cycloalkyl group is connected to O through a chemical bond, that is, a cycloalkyl group-O- is formed.
  • alkoxy in the present invention refers to an alkyl group as defined herein connected to other groups through an oxygen atom, ie "alkyl-O-".
  • alkyl-O- Including "C 1-6 alkoxy” (structure is C 1-6 alkyl-O-), "C 1-4 alkoxy”, specific examples include but are not limited to methoxy, ethoxy, propoxy , 1-methylethoxy, butoxy, 2-methylbutoxy, 3-methylbutoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy
  • the "alkoxy” in the present invention is a C 1-4 alkoxy group, more preferably a C 1-3 alkoxy group.
  • L 1 and L 2 are specific "C 1-8 alkylene" and "C 1-6 alkylene", unless otherwise specified, the writing mode of the specific group does not limit its relationship with the two sides.
  • L1 is The compounds include the following two:
  • L2 is , the compounds include the following two:
  • cycloalkyl group in the present invention refers to a saturated cyclic alkyl group derived from a cycloalkane by removing one hydrogen atom, including a monocyclic or polycyclic saturated hydrocarbon group;
  • the polycyclic saturated hydrocarbon group refers to a group consisting of two or more Cyclic alkyl structures are polycyclic groups formed by spiro, bridge, condensed, etc. connections.
  • the carbon atoms in the cycloalkyl group may be further oxo, ie to form C(O).
  • a certain membered cycloalkyl group described herein can be understood as a monocyclic cycloalkyl group, and when it is a polycyclic ring, it will be specifically indicated as a spiro, fused or bridged ring group.
  • the cycloalkyl group includes "3-8 membered cycloalkyl", “3-6 membered cycloalkyl” and "3-5 membered cycloalkyl".
  • the cycloalkyl group is a monocyclic, saturated structure; specific examples include but are not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl.
  • heterocyclic group in the present invention refers to a saturated cyclic group derived from the substitution of a ring carbon atom in a cycloalkyl by one or more heteroatoms, including a monocyclic or polycyclic heterocyclic group;
  • Cyclic heterocyclic group refers to a polycyclic group formed by connecting a monocyclic heterocyclic group with other heterocyclic groups or cycloalkyl groups through spiro, bridge, condensed, etc.;
  • the heteroatom is generally selected from N, O, S;
  • the carbon atom or heteroatom in the heterocyclic group can be further oxo, that is to form C(O), N(O), SO, SO 2 ; preferably, the heteroatom is independently selected from 1 - 3 Ns and/or Os.
  • a certain membered heterocyclic group described herein can be understood as a monocyclic heterocyclic group, and if it is a multi-heterocyclic group, it will be specifically indicated as a spiro, fused or bridged ring group; the heterocyclic group includes "3-8 membered heterocyclyl", “3-6 membered heterocyclyl", “3-5 membered heterocyclyl", “5-6 membered heterocyclyl”.
  • the heterocyclic group is a monocyclic, saturated structure; specific examples include but are not limited to azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, morpholinyl and the like.
  • the "heterocycle" reference applies this definition.
  • aryl group in the present invention refers to a cyclic unsaturated and aromatic group formed by carbon atoms as ring atoms, which can be a single ring or a plurality of rings fused together.
  • C6-10 membered aryl groups include, but are not limited to, phenyl, naphthyl.
  • heteroaryl in the present invention refers to an aromatic monocyclic or polycyclic group containing one or more heteroatoms in the ring, and the heteroatoms are generally selected from N, O, and S; preferably, the The heteroatoms of are independently selected from 1-3 N and/or O, in addition, the N and S atoms may be optionally oxidized and the N atom may be optionally quaternized.
  • the "heteroaryl group” includes "monocyclic heteroaryl group” and "fused ring heteroaryl group", and the said fused ring heteroaryl group means that two or more cyclic structures share two adjacent adjacent to each other. A group formed by atoms containing one or more heteroatoms and having overall aromaticity.
  • heteroaryl described herein can generally be understood as a “monocyclic heteroaryl", such as the "5-6 membered heteroaryl” described herein, which also does not have the ability to form a fused ring heteroaryl. possibility; when it is “fused ring heteroaryl”, it will be specifically indicated as “fused” heteroaryl structure, such as "8-10-membered fused ring heteroaryl”.
  • the heteroaryl group of the present invention is preferably a "nitrogen-containing heteroaryl group", preferably a "5- to 6-membered nitrogen-containing aryl group", and the heteroatom in the "nitrogen-containing heteroaryl group” contains at least one nitrogen atom, For example, only 1, 2, or 3 nitrogen atoms, or, 1 nitrogen atom and 1 or 2 other heteroatoms (eg, S and/or O atoms), or 2 nitrogen atoms and other 1 or 2 heteroatoms.
  • heteroaryl group examples include, but are not limited to: furyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl , pyrazolyl, etc.
  • the present invention includes all isotopes of atoms occurring in the compounds of the present invention.
  • Isotopes include atoms with the same atomic number but different mass numbers.
  • isotopes of hydrogen include protium (often represented by H), deuterium (often represented by D), and tritium (often represented by T); isotopes of carbon include12C , 13C , and14C .
  • Isotopically labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art, or by methods analogous to those described herein, using an appropriate isotopically labeled reagent in place of the otherwise employed unlabeled reagent.
  • a stable compound or stable structure refers to a compound that is stable enough to undergo chemical reaction, isolated in useful purity, and can be formulated as an effective therapeutic drug.
  • a preparation method of some compounds of the present invention is further provided, which comprises the following steps:
  • X, R 1 , R 2 , R 3 , L 2 , R 4 , m, and ring A are as defined in the technical solution of the first aspect of the present invention.
  • Hal is independently halogen, preferably Cl, Br;
  • P is an amino protecting group, which can be derived from acid anhydride compounds, acid chloride compounds, halides, etc.
  • Common protecting groups include but are not limited to: tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), 2-biphenyl -2-Propoxycarbonyl (BPoc), Phthalimido (pht), p-toluenesulfonyl (Tosyl), Trityl (Trityl), formyl (formyl) Fmoc, Alloc, Teoc, etc.; Preferred are Boc and Cbz.
  • step 1
  • the polar organic solvent includes but is not limited to one or more of the following: tetrahydrofuran, ether, N,N-dimethylformamide, dimethyl ether, N-methylpyrrolidone, dimethyl sulfoxide, acetonitrile .
  • Described basic condition can be to add basic catalyst, described basic catalyst includes but not limited to following one or more: bis (trimethylsilyl) sodium amide, NaH, bis (trimethylsilyl) ) lithium amide, bis(trimethylsilyl) potassium amide, lithium diisopropylamide, n-butyl lithium, sec-butyl lithium, tert-butyl lithium, potassium tert-butoxide, sodium tert-butoxide, sodium methoxide, Inorganic bases such as sodium ethoxide, magnesium methyl bromide (chloride), magnesium ethyl bromide (chloride), magnesium sec-butyl bromide (chloride), and triethylamine, N,N-diisopropylethylamine, 4-dimethylaminopyridine, DBU (1,8-diazabicycloundec-7-ene) and other organic bases.
  • the acidic conditions refer to the presence of organic acids and/or inorganic acids.
  • inorganic acids can be used, preferably hydrochloric acid; organic acids can also be used, preferably trifluoroacetic acid.
  • the intermediate 4 is added with a coupling catalyst and a metal chelate ligand under alkaline conditions, and the product is obtained by the reaction.
  • Described basic condition can be to add basic catalyst, described basic catalyst includes but not limited to following one or more: cesium carbonate, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium phosphate, potassium tert-butoxide , Sodium tert-butoxide, bis(trimethylsilyl) lithium amide, bis(trimethylsilyl) potassium amide, triethylamine, N,N-diisopropylethylamine, DBU.
  • Described coupling catalyst is selected from palladium catalyst, and described palladium catalyst is selected from tridibenzylideneacetone dipalladium, methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2', 4',6'-Triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (BrettPhos Pd G3), palladium acetate, Methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tri-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl- 2-yl)palladium(II) (XPhos Pd G3), methanesulfonic acid (2-dicyclohexylphosphino-2',6'
  • the metal chelating ligand is selected from 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (xantphos), 2-(dicyclohexylphosphine)-3,6-dimethyl Oxy-2'-4'-6'-tri-1-propyl-11'-biphenyl (BrettPhos), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (BINAP), 2 -(Di-tert-butylphosphino)biphenyl (JohnPhos), 2-dicyclohexylphosphino-2'-(N,N-dimethylamine)-biphenyl (DavePhos), 2-dicyclohexylphosphino-2', 6'-Dimethoxybiphenyl (SPhos), 2-(di-tert-butylphosphine)-3,6-dimethoxy-2'-4'-6'tri-1-propy
  • X is selected from CH;
  • R 1 is selected from C 1-4 alkyl
  • R 2 is selected from C 1-4 alkoxy
  • R 3 is selected from 5-6 membered heteroaryl optionally substituted by 1-2 R a ;
  • R a is selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 alkoxy;
  • Ring A is selected from phenyl, pyridyl, pyrimidinyl;
  • R 4 is selected from hydrogen, halogen, C 1-4 alkyl
  • n is selected from 0 and 1.
  • R 2 is selected from -OCH 3 ;
  • R 3 is selected from pyrazolyl, pyrimidinyl, pyridyl optionally substituted by 1-2 R a ;
  • Ra is selected from hydrogen, F, -CH3 , -OCH3 , -O-CH( CH3 ) 2 .
  • Y is -O-, -S-, -NH-;
  • Ring A is selected from phenyl, pyridyl, pyrimidinyl;
  • R 4 is selected from hydrogen, fluorine, -CH 3 ;
  • n is selected from 0 and 1.
  • the structure of intermediate 1 is: Wherein Y is -O-, -S-, -NR 7 -, -C(R 7 ) 2 -, -NR 7 -C(O)-, -OC(O)-, -S(O)-, - S(O) 2 -; R 7 is selected from hydrogen, C 1-4 alkyl, C 1-4 alkyl-C(O)-, -C(O)OCH 2 Ph, preferably, R 7 is selected from hydrogen , C 1-4 alkyl; q 1 , q 2 are each independently 0, 1, 2, 3, 4, preferably, the sum of q 1 and q 2 is 2-5, preferably 3 or 4.
  • R 2 is selected from C 1-4 alkoxy
  • R 3 is selected from 5-6 membered heteroaryl optionally substituted by 1-2 R a ;
  • R a is selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 alkoxy;
  • Y is -O-, -S-, -NH-;
  • Ring A is selected from phenyl, pyridyl, pyrimidinyl;
  • R 4 is selected from hydrogen, halogen, C 1-4 alkyl
  • n is selected from 0 and 1.
  • R 2 is selected from -OCH 3 ;
  • R 3 is selected from pyrazolyl, pyrimidinyl, pyridyl optionally substituted by 1-2 R a ;
  • Ra is selected from hydrogen, F, -CH3 , -OCH3 , -O-CH( CH3 ) 2 .
  • Y is -O-, -S-, -NH-;
  • Ring A is selected from phenyl, pyridyl, pyrimidinyl;
  • R 4 is selected from hydrogen, fluorine, -CH 3 ;
  • n is selected from 0 and 1.
  • the intermediate 1a is selected from the structures shown below:
  • R 2 , R 3 , R 4 , m, Ra , q 1 , q 2 , Y, P are as defined in any of the preceding schemes; preferably, Ra is selected from H, F, -CH 3 , -OCH 3 .
  • G 1 and G 2 independently represent halogen, -C(O)R', NH 2 , OH, SH; R' represents OH or halogen;
  • R 2 , R 3 , R 4 , m, ring A, q 1 , q 2 , Y, P are as defined in any of the preceding schemes.
  • Intermediate A and intermediate B are subjected to condensation reaction under suitable conditions to obtain intermediate C, which is then reduced to obtain intermediate 1a.
  • Described suitable conditions include but are not limited to: 1 Add basic catalyst, such as NaH, sodium hydroxide, potassium hydroxide, lithium hydroxide, bis (trimethylsilyl) sodium amide, bis (trimethylsilyl) Lithium amide, potassium bis(trimethylsilyl)amide, lithium diisopropylamide, n-butyllithium, sec-butyllithium, tert-butyllithium, potassium tert-butoxide, sodium tert-butoxide, sodium methoxide, ethanol Inorganic bases such as sodium, methyl bromide (chloride) magnesium, ethyl bromide (chloride) magnesium, sec-butyl bromide (chloride) magnesium and/or triethylamine, N,N-diisopropylethylamine, Organic bases such as 4-dimethylaminopyridine, DBU; 2 add dehydrating agent or condensing agent or coupling agent, specifically can be selected from: T3P
  • the reduction includes: Pd/C reduction, ferric acid reduction, catalytic hydrogenation, sodium sulfide and thiosulfuric acid reduction, hydrazine Raney nickel hydrate reduction, and the like.
  • R 2 is selected from C 1-4 alkoxy
  • R 3 is selected from 5-6 membered heteroaryl optionally substituted by 1-2 R a ;
  • R a is selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 alkoxy;
  • Y is -O-, -S-, -NH-;
  • Ring A is selected from phenyl, pyridyl, pyrimidinyl;
  • R 4 is selected from hydrogen, halogen, C 1-4 alkyl
  • n is selected from 0 and 1.
  • R 2 is selected from -OCH 3 ;
  • R 3 is selected from pyrazolyl, pyrimidinyl, pyridyl optionally substituted by 1-2 R a ;
  • Ra is selected from hydrogen, F, -CH3 , -OCH3 , -O-CH( CH3 ) 2 .
  • Y is -O-, -S-, -NH-;
  • Ring A is selected from phenyl, pyridyl, pyrimidinyl;
  • R 4 is selected from hydrogen, fluorine, -CH 3 ;
  • n is selected from 0 and 1.
  • intermediate 1a and intermediate 2 are further reacted to form the following structural compounds (for the preparation process, refer to formula (II) preparation method steps 1-3):
  • R 1 , R 4 , m, Ra , q 1 , q 2 , P, Y, Hal, G1, G2, ring A are as defined in the previous scheme;
  • the nomenclature of the title compound was converted from the compound structure by means of Chemdraw. If there is any inconsistency between the compound name and the compound structure, it can be determined by synthesizing relevant information and reaction routes; if it cannot be confirmed by other methods, the given compound structural formula shall prevail.
  • the preparation methods of some compounds in the present invention refer to the preparation methods of the aforementioned similar compounds. Those skilled in the art should know that when using or referring to the preparation methods cited therein, the charging ratio of the reactants, the reaction solvent, and the reaction temperature can be appropriately adjusted according to the different reactants.
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments enumerated below, embodiments formed in combination with other chemical synthesis methods, and those well known to those skilled in the art Equivalent to alternatives, preferred embodiments include, but are not limited to, the embodiments of the present invention.
  • the structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) or/and liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts ([delta]) are given in parts per million (ppm). NMR was measured by Varian 400M or Bruker Ascend 400 nuclear magnetic instrument, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated methanol (CD 3 OD), deuterated chloroform (CDCl 3 ) or heavy water ( D 2 O), the internal standard is tetramethylsilane (TMS).
  • DMSO-d 6 deuterated dimethyl sulfoxide
  • CD 3 OD deuterated methanol
  • CDCl 3 deuterated chloroform
  • D 2 O heavy water
  • TMS tetramethylsilane
  • LC-MS The determination of LC-MS was performed with Agilent 1260-6120B/6125B single quadrupole mass spectrometer mass spectrometer (ion source was electrospray ionization), and the column was Waters CORTECS column (C18, 2.7um, 4.6*30mm).
  • HPLC assay used Waters H-class UPLC and Agilent 1260 infinity II high performance liquid chromatography.
  • the thin-layer chromatography silica gel plate is made of GF254 silica gel plate of Yantai Jiangyou Silica Gel Development Co., Ltd. or GF254 silica gel plate of Rushan Shangbang New Materials Co., Ltd. Generally used in the chemical industry 200 ⁇ 300 mesh silica gel as the carrier.
  • the starting materials in the examples of the present invention are known and commercially available, or can be synthesized using or according to methods known in the art.
  • the component ratios of the mixed solvent or column chromatography eluent used in the examples of the present invention are all volume ratios.
  • the unit “M” represents "mol/L", which is the concentration of the reagent.
  • the first step the preparation of 4-(2-hydroxyethyl)-2-nitrophenol
  • the second step the preparation of 2-(4-methoxy-3-nitrophenyl) ethanol
  • the third step the preparation of tert-butyl (6-((4-methoxy-3-nitrophenethoxy) methyl) pyridin-2-yl carbamate
  • the fourth step the preparation of tert-butyl-(6-((3-amino-4-methoxyphenethoxy)methyl)-pyridin-2-yl carbamate
  • the fifth step tert-butyl-(6-((3-chloro-3-(methylcarbamoyl)pyridazin-4-yl)amino)-4-methoxyphenethoxy)methyl)pyridine- Preparation of 2-yl)carbamate
  • Step 6 4-((5-(2-((6-aminopyridin-2-yl)methoxy)ethyl)-2-methoxyphenyl)amino)-6-chloro-N-methyl Preparation of pyridazine-3-carboxamide
  • the seventh step 5 6 -methoxy-N-methyl-8-oxo-2,4-diaza-3(3,5)-pyridazine-1(2,6)-pyridine-5( Preparation of 1,3)-benzocyclononane-3 6 -carboxamide
  • the first step the preparation of 2-(4-fluoro-3-nitro-phenyl)ethanol
  • the third step preparation of tert-butyl (6-((4-(methylthio)-3-nitrophenethoxy)methyl)pyridin-2-yl carbamate
  • the fourth step the preparation of tert-butyl (6-((3-amino-4-(methylthio) phenethoxy) methyl) pyridin-2-yl) carbamate
  • the fifth step tert-butyl (6-((3-((6-chloro-3-(methylcarbamoyl)pyridazin-4-yl)amino)-4-(methylthio)phenethoxy ) methyl) pyridin-2-2-yl) carbamate preparation
  • Step 6 4-((5-(2-(((6-aminopyridin-2-yl)methoxy)ethyl)-2-(methylthio)phenyl)amino)-6-chloro- Preparation of N-methylpyridazine-3-carboxamide
  • the seventh step N-methyl-56-(methylthio)-8 - oxa-2,4-diaza-3(3,5)-pyridazine-1(2,6)-pyridine- Preparation of 5(1,3)-benzocyclononane-3 6 -carboxamide
  • Example 6-1 and Example 6-2 are identical to Example 6-1 and Example 6-2:
  • the first step the preparation of 2-bromo-4-(2-hydroxyethyl) phenol
  • the third step the preparation of methyl 5-(2-acetoxyethyl)-2-hydroxybenzoate
  • the fourth step the preparation of methyl 5-(2-acetoxyethyl)-2-hydroxy-3-nitrobenzoate
  • the fifth step the preparation of methyl 5-(2-acetoxyethyl)-2-methoxy-3-nitrobenzoate
  • Methyl 5-(2-acetoxyethyl)-2-hydroxy-3-nitrobenzoate (1.7 g, 6.0021 mmol) was dissolved in N,N-dimethylformamide (20 mL), followed by adding carbonic acid Potassium (1.66 g, 12 mmol) and methyl iodide (1022.33 mg, 7.20 mmol), the reaction solution was reacted at 70° C. for 8 hours.
  • the sixth step the preparation of methyl 5-(2-hydroxyethyl)-2-methoxy-3-nitrobenzoate
  • the seventh step the preparation of 5-(2-hydroxyethyl)-2-methoxy-3-nitrobenzamide
  • Step 8 Preparation of 2-(4-methoxy-3-nitro-5-(1H-1,2,4-triazol-3-yl)phenyl)ethane-1-ol
  • Step 10 2-Bromo-6-((4-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)-5-nitrophenethoxy ) methyl) pyridine preparation
  • the thirteenth step tert-butyl (6-((3-((6-chloro-3-(methylcarbamoyl)pyridazin-4-yl)amino)-4-methoxy-5-(1 - Preparation of methyl-1H-1,2,4-triazol-3-yl)phenethoxy)methyl)pyridin-2-yl)carbamate
  • tert-Butyl (6-((3-amino-4-methoxy-5-(1-methyl-1H-1,2,4-triazol-3-yl)phenethoxy)methyl) Pyridin-2-yl)carbamate (100 mg, 0.22 mmol) was dissolved in tetrahydrofuran (3 mL), followed by the addition of 4,6-dichloro-N-methylpyridazine-3-carboxamide (68 mg, 0.33 mmol) and Sodium bis(trimethylsilyl)amide (0.3 mL), the reaction solution was reacted at room temperature for 10 minutes. After the reaction was completed, water (5 mL) was added to quench, and dichloromethane was extracted (3 ⁇ 30 mL).
  • the fifteenth step 56 -methoxy-N-methyl-55-(1-methyl-1H-1,2,4-triazol- 3 -yl)-8-oxo-2,4 - Preparation of Diaza-3(3,5)-pyridazine-1(2,6)-pyridine-5(1,3)-benzocyclononane - 36-carboxamide (Compound 6-1)
  • the first step tert-butyl (6-((3-((6-chloro-3-((methyl-d3)carbamoyl)pyridazin-4-yl)amino)-4-methoxy-5 Preparation of -(1-methyl-1H-1,2,4-triazol-3-yl)phenethoxy)methyl)pyridin-2-yl)carbamate
  • tert-Butyl (6-((3-amino-4-methoxy-5-(1-methyl-1H-1,2,4-triazol-3-yl)phenethoxy)methyl) Pyridin-2-yl)carbamate (180 mg, 0.395 mmol) was dissolved in tetrahydrofuran (3 mL), followed by the addition of 4,6-dichloro-N-methylpyridazine-3-carboxamide (162 mg, 0.79 mmol) and Sodium bis(trimethylsilyl)amide (0.3 mL), the reaction solution was reacted at room temperature for 10 minutes. After the reaction was completed, water (5 mL) was added to quench, and dichloromethane was extracted (3 ⁇ 30 mL).
  • the second step 4-((5-(2-((6-aminopyridin-2-yl)methoxy)ethyl)-2-methoxy-3-(1-methyl-1H-1, Preparation of 2,4-triazol-3-yl)phenyl)amino)-6-chloro-N-(methyl-d3)pyridazine-3-carboxamide
  • the third step 56 -methoxy-N-methyl-55-(1-methyl-1H-1,2,4-triazol- 3 -yl)-8-oxo-2,4- Preparation of Diaza-3(3,5)-pyridazine-1(2,6)-pyridine-5(1,3)-benzocyclononane - 36-carboxamide
  • the first step preparation of ethyl 4-methoxy-3-(1-methyl-1H-pyrazol-3-yl)-5-nitrophenylacetate
  • the second step preparation of 2-(4-methoxy-3-(1-methyl-1H-pyrazol-3-yl)-5-nitrophenyl)ethyl-1-ol
  • the fourth step tert-butyl (6-((3-amino-4-methoxy-5-(1-methyl-1H-pyrazol-3-yl) phenethoxy) methyl) pyridine-2 - group) preparation of carbamates
  • the fifth step tert-butyl (6-((3-((6-chloro-3-(formamido)pyridazin-4-yl)amino)-4-methoxy-5-(1-methyl) Preparation of -1H-pyrazol-3-yl)phenethoxy)methyl)pyridin-2-yl)carbamate
  • Step 6 4-((5-(2-((6-aminopyridin-2-yl)methoxy)ethyl)-2-methoxy-3-(1-methyl-1H-pyrazole Preparation of -3-yl)phenyl)amino)-6-chloro-N-methylpyridazine-3-carbamate
  • the seventh step 56 -methoxy-N-methyl-55-(1-methyl-1H-pyrazol- 3 -yl)-8-oxa-2,4-diaza-3( Preparation of 3,5)-pyridazine 1(2,6)-pyridine-5(1,3)-benzocyclononane-3 6 -carboxamide
  • the first step tert-butyl (6-((3-((6-chloro-3-((methyl-d 3 )carboxamido)pyridazin-4-yl)amino)-4-methoxy- Preparation of 5-(1-methyl-1H-pyrazol-3-yl)phenethoxy)methyl)pyridin-2-yl)carbamate
  • Step 2 4-((5-(2-((6-aminopyridin-2-yl)methoxy)ethyl)-2-methoxy-3-(1-methyl-1H-pyrazole Preparation of -3-yl)phenyl)amino)-6-chloro-N-(methyl- d3 )pyridazine-3-carbamate
  • the third step 56 -methoxy-N-(methyl- d3 )-55-( 1 -methyl-1H-pyrazol-3-yl)-8-oxa-2,4-di
  • the first step the preparation of tert-butyl (tert-butoxycarbonyl) (5-fluoro-6-methylpyridin-2-yl) carbamate
  • the second step the preparation of tert-butyl (6-(bromomethyl)-5-fluoropyridin-2-yl) (tert-butoxycarbonyl) carbamate
  • the fifth step tert-butyl (6-((3-((6-chloro-3-(methylcarbamoyl)pyridazin-4-yl)amino)-4-methoxy-5-(1- Preparation of methyl-1H-pyrazol-3-yl)phenylethoxy)methyl)-5-fluoropyridin-2-yl)carbamate
  • Step 6 4-((5-(2-((6-amino-3-fluoropyridin-2-yl)methoxy)ethyl)-2-methoxy-3-(1-methyl- Preparation of 1H-pyrazol-3-yl)phenyl)amino)-6-chloro-N-methylpyridazine-3-carbamate
  • Step 7 15 -Fluoro-56-methoxy-N-methyl-55-(1-methyl-1H-pyrazol- 3 -yl)-8 - oxa-2,4-di Preparation of aza-3(3,5)-pyridazine-1(2,6)-pyridine-5(1,3)-benzocyclononane - 36-carboxamide
  • the first step preparation of (4-methoxy-3-(1-methyl-1H-pyrazol-3-yl)-5-nitrophenethyl) tert-butyl carbamate
  • the second step the preparation of (4-methoxy-3-(1-methyl-1H-pyrazol-3-yl)-5-nitrophenethyl) (methyl) carbamate tert-butyl ester
  • the third step 2-(4-methoxy-3-(1-methyl-1H-pyrazol-3-yl)-5-nitrophenyl)-N-methylethane-1-amine preparation
  • tert-butyl (6-(((4-methoxy-3-(1-methyl-1H-pyrazol-3-yl)-5-nitrophenethyl ) (methyl) amino) methyl) pyridin-2-yl carbamate preparation
  • the fifth step tert-butyl (6-((((3-amino-4-methoxy-5-(1-methyl-1H-pyrazol-3-yl) phenethyl) (methyl) amino ) methyl)pyridin-2-yl)(tert-butoxycarbonyl)carbamate preparation
  • the sixth step tert-butyl (6-((((3-((6-chloro-3-(methylcarbamoyl)pyridazin-4-yl)amino)-4-methoxy-5-( Preparation of 1-Methyl-1H-pyrazol-3-yl)phenethyl)(methyl)amino)methyl)pyridin-2-ylcarbamate
  • Step 7 4-((5-(2-((((((6-aminopyridin-2-yl)methyl)(methyl)amino)ethyl)-2-methoxy-3-(1 Preparation of -methyl-1H-pyrazol-3-yl)phenyl)amino)-6-chloro-N-methylpyridazine-3-carboxamide
  • the eighth step 56 - methoxy-N,8-dimethyl-55-( 1 -methyl-1H-pyrazol-3-yl)-2,4,8-triaza-3( Preparation of 3,5)-pyridazine-1(2,6)-pyridine-5(1,3)-benzocyclononane-3 6 -carboxamide
  • the first step the preparation of 2-[4-methoxy-3-(1-methylpyrazol-3-yl)-5-nitrophenyl]ethyl 4-toluenesulfonate
  • the second step the preparation of 2-[4-methoxy-3-(1-methylpyrazol-3-yl)-5-nitrophenyl]ethanethiol
  • the third step tert-butyl ⁇ 6-[( ⁇ 2-[4-methoxy-3-(1-methylpyrazolyl-3-yl)-5-nitrophenyl]ethyl ⁇ sulfonyl ) methyl]pyridin-2-yl ⁇ carbamate preparation
  • the fifth step tert-butyl (6-((3-((6-chloro-3-(methylcarbamoyl)pyridazin-4-yl)amino)-4-methoxy-5-(1- Preparation of methyl-1H-pyrazol-3-yl)phenethyl)thio)methyl)pyridin-2-yl)carbamate
  • the fifth step 4-((5-(2-((6-aminopyridin-2-yl)methyl)thio)ethyl)-2-methoxy-3-(1-methyl-1H- Preparation of pyrazol-3-yl)phenyl)amino)-6-chloro-N-methylpyridazine-3-carboxamide
  • the sixth step 56-methoxy-N-methyl-55-(1-methyl-1H-pyrazol- 3 -yl)-8-thi-2,4-diaza-3(3 Preparation of ,5)-pyridazine-1(2,6)-pyridine-5(1,3)-benzocyclononane-3 6 -carboxamide
  • the first step preparation of methyl 6-(bis(tert-butoxycarbonyl)amino)picolinate
  • the second step the preparation of 6-((tert-butoxycarbonyl)amino)picolinic acid
  • the third step 2-(4-methoxy-3-(1-methyl-1H-pyrazol-3-yl)-5-nitrophenethyl)isoindoline-1,3-dione preparation
  • the fourth step the preparation of 2-(4-methoxy-3-(1-methyl-1H-pyrazol-3-yl)-5-nitrophenyl)ethan-1-amine
  • the seventh step tert-butyl (6-((3-((6-chloro-3-(methylcarbamoyl)pyridazin-4-yl)amino)-4-methoxy-5-(1- Preparation of methyl-1H-pyrazol-3-yl)phenethylcarbamoyl)pyridin-2-ylcarbamate
  • tert-Butyl (6-((3-amino-4-methoxy-5-(1-methyl-1H-pyrazol-3-yl)phenethyl)carbamoyl)pyridin-2-yl) Carbamate 7 (350 mg, 0.75 mmol), 4,6-dichloro-N-methylpyridazine-3-carboxamide (230 mg, 1.12 mmol) were dissolved in tetrahydrofuran (10 mL), and bisulfite was added dropwise at room temperature Sodium (trimethylsilyl)amide (1.9 mL, 3.75 mmol, 2M in tetrahydrofuran). The mixture was stirred at 25°C for 1 hour.
  • the eighth step 4-((5-(2-(6-aminopyridinecarboxamido)ethyl)-2-methoxy-3-(1-methyl-1H-pyrazol-3-yl)benzene Preparation of yl)amino)-6-chloro-N-methylpyridazine-3-carboxamide
  • Step 9 56 - methoxy-N-methyl-55-( 1 -methyl-1H-pyrazol-3-yl)-9-oxo-2,4,8-triaza- Preparation of 3(3,5)-pyridazine-1(2,6)-pyridine-5(1,3)-benzocyclononyl-3 6 -carboxamide
  • reaction mixture was heated to 130°C in a closed tube and stirred for 2 hours. After the reaction was completed, it was filtered and concentrated to obtain the crude product. The crude product was purified by preparative liquid chromatography to give the title compound (26 mg, 14% yield).
  • the first step tert-butyl (6-((3-((6-chloro-3-(methylcarbamoyl)pyridazin-4-yl)amino)-4-methoxy-5-(1- Preparation of methyl-1H-pyrazol-4-yl)phenethoxy)methyl)pyridin-2-yl)carbamate
  • Step 2 4-((5-(2-(((6-aminopyridin-2-yl)methoxy)ethyl)-2-methoxy-3-(1-methyl-1H-pyridine Preparation of oxazol-4-yl)phenyl)amino)-6-chloro-N-methylpyridazine-3-carboxamide
  • the third step 56 -methoxy-N-methyl-55-(1-methyl-1H-pyrazol- 4 -yl)-8-oxa-2,4-diaza-3( Preparation of 3,5)-pyridazine-1(2,6)-pyridine-5(1,3)-benzocyclononyl - 36-carboxamide
  • the first step the preparation of (tert-butoxycarbonyl) (8-hydroxyquinoline-2-hydroxy) tert-butyl carbamate
  • the fifth step 4-((5-(2-(((2-aminoquinolin-8-yl)oxy)ethyl)-2-methoxy-3-(1-methyl-1H-pyridine Preparation of oxazol-3-yl)phenyl)amino)-6-chloro-N-methylpyridazine-3-carboxamide
  • the sixth step 56-methoxy-N-methyl-55-(1-methyl-1H-pyrazol- 3 -yl)-8-oxa-2,4-diaza-1( Preparation of 2,8)-quinoline-3(3,5)-pyridazine 5(1,3)-benzocyclooctane-3 6 -carboxamide
  • the first step the preparation of methyl 6-amino-3-methylpicolinate
  • the second step the preparation of 6-(bis(tert-butoxycarbonyl)amino)-3-methylpicolinate methyl ester
  • the third step the preparation of (6-(hydroxymethyl)-5-methylpyridin-2-yl) tert-butyl carbamate
  • the fourth step the preparation of (6-(bromomethyl)-5-methylpyridin-2-yl) tert-butyl carbamate
  • the seventh step tert-butyl (6-((3-((6-chloro-3-(methylcarbamoyl)pyridazin-4-yl)amino)-4-methoxy-5-(1- Preparation of methyl-1H-pyrazol-3-yl)phenethoxy)methyl)-5-methylpyridin-2-yl)carbamate
  • Step 8 4-((5-(2-(((6-amino-3-methylpyridin-2-yl)methoxy)ethyl)-2-methoxy-3-(1-methyl) Preparation of yl-1H-pyrazol-3-yl)phenyl)amino)-6-chloro-N-methylpyridazine-3-carboxamide
  • the ninth step 56 -methoxy-N, 15 -dimethyl-55-(1-methyl-1H-pyrazol- 3 -yl)-8-oxa-2,4-diaza Preparation of Hetero-3(3,5)-pyridazine-1(2,6)-pyridine-5(1,3)-benzocyclononane - 36-carboxamide
  • the first step the preparation of 4,6-dichloro-N-methylpyridine-3-carboxamide
  • the second step tert-butyl (6-((3-((2-chloro-5-(methylcarbamoyl)pyridin-4-yl)amino)-4-methoxy-5-(1-methyl) Preparation of yl-1H-pyrazol-3-yl)phenylethoxy)methyl)pyridin-2-yl)carbamate
  • the third step 4-((5-(2-((6-aminopyridin-2-yl)methoxy)ethyl)-2-methoxy-3-(1-methyl-1H-pyrazole Preparation of -3-yl)phenyl)amino)-6-chloro-N-methylnicotinamide
  • the fourth step 56 -methoxy-N-methyl-55-(1-methyl-1H-pyrazol- 3 -ethyl)-8-oxa-2,4-diaza-1 Preparation of (2,6),3(2,4)-bipyridine- 5 (1,3)-benzocyclononane-35-carboxamide
  • the first step preparation of ethyl 2-(4-methoxy-3-nitro-5-(pyrimidin-2-yl)phenyl)acetate
  • the second step preparation of 2-(4-methoxy-3-nitro-5-(pyrimidin-2-yl)phenyl)ethanol
  • the fifth step tert-butyl (6-((2-(3-((6-chloro-3-(methylcarbamoyl)pyridazin 4-yl)amino)-4-methoxy-5-( Preparation of pyrimidin-2-yl)phenyl)ethoxy]methyl)pyridin-2-yl)carbamate
  • Step 6 4-((5-(2-(((6-aminopyridin-2-yl)methoxy)ethyl)-2-methoxy-3-(pyrimidin-2-yl)phenyl ) Amino)-6-chloro-N-methylpyridazine-3-carboxamide preparation
  • Step 7 56 -methoxy-N-methyl-55-(pyrimidin- 2 -yl)-8-oxa-2,4-diaza-3(3,5)-pyridazine-1 Preparation of (2,6)-pyridine- 55 (1,3)-benzocyclononane - 36-carboxamide
  • N-(3-Amino-4-methoxy-5-(1-methyl-1H-pyrazol-3-yl)phenethyl)cyclopropane-1,1-dicarboxamide 110 mg, 0.30 mmol
  • 4,6-Dichloro-N-methylpyridazine-3-carboxamide 126 mg, 0.61 mmol
  • tetrahydrofuran 10 mL
  • sodium bis(trimethylsilyl)amide 0.62 mmol
  • the second step 6'-methoxy-N-methyl-5'-(1-methyl-1H-pyrazol-3-yl)-7', 9'-dioxospiro[cyclopropane-1, Preparation of 8'-2,6,10-triaza-1(4,2)-pyridine-3(1,3)-benzocyclodecane]-5'-carboxamide
  • N-(3-((2-Chloro-5-(methylcarbamoyl)pyridin-4-yl)amino)-4-methoxy-5-(1-methyl-1H-pyrazole-3- yl)phenethyl)cyclopropane-1,1-dicarboxamide (30 mg, 0.05 mmol), cesium carbonate (111 mg, 0.34 mmol), tris(dibenzylideneacetone)dipalladium (5 mg, 0.001 mmol), 4 ,5-Bisdiphenylphosphine-9,9-dimethylxanthene (6 mg, 0.01 mmol) was mixed in 1,4-dioxane (10 mL).
  • reaction mixture was heated to 130°C in a closed tube and stirred for 12 hours. After the reaction was completed, it was filtered and concentrated to obtain the crude product. The crude product was purified by preparative liquid chromatography to give the title compound (1.0 mg, 2% yield).
  • the first step tert-butyl (6-((3-((6-chloro-3-(methylcarbamoyl)pyridin-4-yl)amino)-4-methoxy-5-(1-methyl) Preparation of -1H-1,2,4-triazol-3-yl)phenethoxy)methyl)pyridin-2-yl)carbamate
  • tert-Butyl (6-((3-amino-4-methoxy-5-(1-methyl-1H-1,2,4-triazol-3-yl)phenethoxy)methyl) Pyridin-2-yl)carbamate (100 mg, 0.22 mmol) was dissolved in tetrahydrofuran (3 mL), followed by the addition of 4,6-dichloro-N-methylpyridazine-3-carboxamide (90 mg, 0.44 mmol) and Sodium bis(trimethylsilyl)amide (0.3 mL), the reaction solution was reacted at room temperature for 10 minutes.
  • the second step 4-((5-(2-((6-aminopyridin-2-yl)methoxy)ethyl)-2-methoxy-3-(1-methyl-1H-1, Preparation of 2,4-triazol-3-yl)phenyl)amino)-6-chloro-N-methylnicotinamide
  • the third step 56 -methoxy-N-methyl-55-(1-methyl-1H-1,2,4-triazol- 3 -yl)-8-oxo-2,4- Preparation of Diaza-1(2,6),3(2,4)-bipyridine- 5 (1,3)-benzocyclononane-35-carboxamide
  • the first step tert-butyl (6-((3-((2-chloro-5-((methyl-d3)carbamoyl)pyridin-4-yl)amino)-4-methoxy-5- Preparation of (1-methyl-1H-1,2,4-triazol-3-yl)phenethoxy)methyl)pyridin-2-yl)carbamate
  • tert-Butyl (6-((3-amino-4-methoxy-5-(1-methyl-1H-1,2,4-triazol-3-yl)phenethoxy)methyl) Pyridin-2-yl)carbamate (100 mg, 0.22 mmol) was dissolved in tetrahydrofuran (3 mL), followed by the addition of 4,6-dichloro-N-methylpyridazine-3-carboxamide (91 mg, 0.43 mmol) and Sodium bis(trimethylsilyl)amide (0.3 mL), the reaction solution was reacted at room temperature for 10 minutes.
  • the second step 4-((5-(2-((6-aminopyridin-2-yl)methoxy)ethyl)-2-methoxy-3-(1-methyl-1H-1, Preparation of 2,4-triazol-3-yl)phenyl)amino)-6-chloro-N-(methyl-d3)nicotinamide
  • the third step 5 6 -methoxy-N-(methyl-d3)-5 5- (1-methyl-1H-1,2,4-triazol-3-yl)-8-oxo- Preparation of 2,4-diaza-1(2,6),3(2,4)-bipyridine-5(1,3)-benzocyclononane-3 5 -carboxamide
  • the first step preparation of ethyl 4-methoxy-3-(1-methyl-1H-pyrazol-4-yl)-5-nitrophenylacetate
  • the second step preparation of 2-(4-methoxy-3-(1-methyl-1H-pyrazol-4-yl)-5-nitrophenyl)-1-ethanol
  • the fourth step tert-butyl (6-((3-amino-4-methoxy-5-(1-methyl-1H-pyrazol-4-yl) phenethoxy) methyl) pyridine-2 - group) preparation of carbamates
  • the fifth step tert-butyl (6-((3-((2-chloro-5-(methylcarbamoyl)pyridin-4-yl)amino)-4-methoxy-5-(1-methyl) Preparation of yl-1H-pyrazol-4-yl)phenethoxy)methyl)pyridin-2-yl)carbamate
  • Step 6 4-((5-(2-(((6-aminopyridin-2-yl)methoxy)ethyl)-2-methoxy-3-(1-methyl-1H-pyridine Preparation of azol-4-yl)phenyl)amino)-6-chloro-N-methylnicotinamide
  • the seventh step 56 -methoxy-N-methyl-55-(1-methyl-1H-pyrazol- 4 -yl)-8-oxa-2,4-diaza-1( Preparation of 2,6),3(2,4)-bipyridine-5(1,3)-phenylcyclononyl-3 5 -carboxamide
  • the first step tert-butyl (6-((3-((6-chloro-3-((methyl-d 3 )carbamoyl)pyridazin-4-yl)amino)-4-methoxy- Preparation of 5-(pyrimidin-2-yl)phenethoxy)methylpyridin-2-ylcarbamate
  • tert-Butyl (6-((3-amino-4-methoxy-5-(pyrimidin-2-yl)phenethoxy)methyl)pyridin-2-yl)carbamate (200 mg, 0.44 mmol) and 4,6-dichloro-N-(methyl-d 3 )pyridazine-3-carboxamide (273 mg, 1.32 mmol) were dissolved in tetrahydrofuran (10 mL), and bis(trimethylsilyl) was slowly added dropwise ) sodium amide (2M, 1.3 mL, 2.65 mmol), and the mixture was stirred at 25°C for 10 minutes.
  • Step 2 4-((5-(2-(((6-aminopyridin-2-yl)methoxy)ethyl)-2-methoxy-3-(pyrimidin-2-yl)phenyl ) amino)-6-chloro-N-(methyl-d 3 ) pyridazine-3-carboxamide preparation
  • the third step 56 -methoxy-N-(methyl- d3 )-55-(pyrimidin- 2 -yl)-8-oxa-2,4-diaza-3(3,5 Preparation of )-pyridazine-1(2,6)-pyridine-5(1,3)-benzocyclononane-3 6 -carboxamide
  • the first step the preparation of 2-(3-bromo-4-methoxy-5-nitrophenyl) ethan-1-ol
  • the second step the preparation of (6-((3-bromo-4-methoxy-5-nitrophenethoxy)methyl)pyridin-2-yl)carbamic acid tert-butyl ester
  • reaction was stirred at 90°C for 2 hours. After the reaction was completed, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, water was added and extracted with ethyl acetate (20 mL ⁇ 3), the combined organic layers were washed with brine (20 mL ⁇ 2), dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • Step 7 4-((5-(2-((6-aminopyridin-2-yl)methoxy)ethyl)-2-methoxy-3-(5-methylpyrimidin-2-yl )Phenyl)amino)-6-chloro-N-methylnicotinamide preparation
  • Step 8 56 -methoxy-N-methyl-55-( 5 -methylpyrimidin-2-yl)-8-oxa-2,4-diaza-1(2,6) Preparation of ,3(2,4)-bipyridine-5(1,3)-benzocyclononane-3 5 -carboxamide
  • the first step preparation of ethyl 4-methoxy-3-(5-methoxypyrimidin-2-yl)-5-nitrophenylacetate
  • the second step preparation of 2-(4-methoxy-3-(5-methoxypyrimidin-2-yl)-5-nitrophenyl)ethanol
  • the fourth step tert-butyl (6-((4-methoxy-3-(5-methoxypyrimidin-2-yl)-5-nitrophenylethoxy)methyl)pyridine-2- base) preparation of carbamates
  • the sixth step tert-butyl (6-((3-((2-chloro-5-(methylcarbamoyl)pyridin-4-yl)amino)-4-methoxy-5-(5-methyl) Preparation of oxypyrimidin-2-yl)phenylethoxy)methyl)pyridin-2-yl)carbamate
  • Step 7 4-((5-(2-((6-aminopyridin-2-yl)methoxy)ethyl)-2-methoxy-3-(5-methoxypyrimidine-2- Preparation of yl)phenyl)amino)-6-chloro-N-methylnicotinamide
  • the eighth step 56-methoxy- 55- ( 5 -methoxypyrimidin-2-yl)-N-methyl-8-oxa-2,4-diaza-1(2,6 Preparation of ),3(2,4)-bipyridine-5(1,3)-benzocyclononane-3 5 -carboxamide
  • the following specific embodiments will further describe the inhibitory effect of the compounds of the present invention on TYK2 kinase or TYK2 signaling pathway and other in vitro and in vivo effects, so as to show that the compounds of the present invention can be effectively used for the treatment of TYK2 target-related diseases.
  • the beneficial effects of the compounds of the present invention include but are not limited to the following specific implementation contents.
  • TR-FRET fluorescence resonance energy transfer
  • the compound dilution plate was equipped with a compound concentration of 200 times the final concentration. According to the 27-fold ratio dilution method, diluted from the highest concentration point, a total of 4 concentration points, and transferred to the Echo plate.
  • the compound dilution plate is equipped with a compound concentration of 100 times the final concentration. According to the 27-fold ratio dilution method, the compound is diluted from the highest concentration point, a total of 4 concentration points, and transferred to the Echo plate.
  • the compounds of the examples of the present invention have good binding activity to TYK2 JH2 pseudokinase, and their binding activity does not exceed 30nM; when the binding activity is less than 1nM, it is represented by letter A; when 1nM ⁇ binding activity ⁇ 5nM, it is represented by letter B ; When the binding activity is >5nM, it is represented by the letter C; the specific results are shown in Table 1.
  • the compounds of the examples of the present invention have no inhibitory activity on TYK2 JH1 kinase domain (IC 50 is preferably greater than 10 ⁇ M); no inhibitory activity or weak inhibitory activity on JAK1/2/3 (IC 50 is greater than 3 ⁇ M, preferably greater than 10 ⁇ M).
  • Human PBMCs were purchased from Miaoshun (Shanghai) Biotechnology Co., Ltd.
  • Fix buffer I Perm buffer III were purchased from BD Biosciences.
  • FITC CD3 antibody was purchased from Biolegend Company.
  • Alexa647pSTAT5 (pY694) antibody was purchased from BD Biosciences.
  • Generic type I IFN ⁇ protein was purchased from R&D Systems.
  • the 96-well U-shaped cell culture plate was purchased from Coring Company.
  • the pipette was purchased from RAMIN Company,
  • Fortessa (LSRFortessa) analytical flow cytometer was purchased from BD.
  • PBMC cells for analysis were thawed and suspended in 1640 medium containing 10% serum, and incubated in a carbon dioxide incubator for 1 hour.
  • Fixation Add 110 ⁇ L of preheated Fix buffer I, and incubate in a carbon dioxide incubator for 10 minutes.
  • Membrane rupture add 150mL Perm buffer III and incubate on ice for 30 minutes.
  • Antibody incubation add diluted FITC-CD3 and Alexa647pSTAT5 (pY694) antibodies (100 ⁇ L/well) to each well, and incubate at room temperature for 1 hour.
  • MFI mean fluorescence intensity
  • the IC 50 of the compounds shown in the examples of the present invention in the inhibition of cellular TYK2 signaling pathway is no more than 10 ⁇ M; when IC 50 ⁇ 50 nM, it is represented by letter A; when 50 nM ⁇ IC 50 ⁇ 100 nM , represented by letter B; when IC 50 >100nM, represented by letter C; see Table 2 for specific results.
  • Human PBMCs were purchased from Miaoshun (Shanghai) Biotechnology Co., Ltd.
  • Fix buffer I Perm buffer III were purchased from BD Biosciences.
  • FITC CD3 antibody was purchased from Biolegend Company.
  • Alexa647 pSTAT5 (pY694) antibody was purchased from BD Biosciences.
  • IL-2 protein was purchased from Nearshore Protein Technology Co., Ltd.
  • the 96-well U-shaped cell culture plate was purchased from Coring Company.
  • a centrifuge (5810R) was purchased from Eppendorf.
  • Fortessa (LSRFortessa) analytical flow cytometer was purchased from BD.
  • PBMC cells for analysis were thawed and suspended in 1640 medium containing 10% serum, and incubated in a carbon dioxide incubator for 1 hour.
  • Fixation Add 110 ⁇ L of preheated Fix buffer I, and incubate in a carbon dioxide incubator for 10 minutes.
  • Membrane rupture add 150 ⁇ L Perm buffer III and incubate on ice for 30 minutes.

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Abstract

L'invention concerne un composé de formule (II') en tant qu'inhibiteur de TYK2 macrocyclique, un sel pharmaceutiquement acceptable de celui-ci, un ester de celui-ci, un isomère de celui-ci, un marqueur isotopique de celui-ci, et l'utilisation de celui-ci dans le traitement de maladies associées à médiation par TYK2.
PCT/CN2022/085308 2021-04-07 2022-04-06 Inhibiteur de tyk2 et son utilisation WO2022213980A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023076161A1 (fr) 2021-10-25 2023-05-04 Kymera Therapeutics, Inc. Agents de dégradation de tyk2 et leurs utilisations
WO2023109954A1 (fr) * 2021-12-16 2023-06-22 Lynk Pharmaceuticals Co. Ltd. Inhibiteurs de tyk2 et compositions et procédés associés

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020086616A1 (fr) * 2018-10-22 2020-04-30 Fronthera U.S. Pharmaceuticals Llc Inhibiteurs de tyk2 et leurs utilisations
CN111909140A (zh) * 2019-04-12 2020-11-10 明慧医药（杭州）有限公司 作为tyk2抑制剂的杂环化合物及合成和使用方法
CN111936486A (zh) * 2018-03-22 2020-11-13 百时美施贵宝公司 用作IL-12、IL-23和/或IFNα响应的调节剂的包含吡啶的杂环化合物
CN112321604A (zh) * 2019-08-05 2021-02-05 华东理工大学 大环类jak2抑制剂及其应用

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011146336A1 (fr) * 2010-05-20 2011-11-24 Array Biopharma Inc. Composés macrocycliques en tant qu'inhibiteurs de kinase trk

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111936486A (zh) * 2018-03-22 2020-11-13 百时美施贵宝公司 用作IL-12、IL-23和/或IFNα响应的调节剂的包含吡啶的杂环化合物
WO2020086616A1 (fr) * 2018-10-22 2020-04-30 Fronthera U.S. Pharmaceuticals Llc Inhibiteurs de tyk2 et leurs utilisations
CN111909140A (zh) * 2019-04-12 2020-11-10 明慧医药（杭州）有限公司 作为tyk2抑制剂的杂环化合物及合成和使用方法
CN112321604A (zh) * 2019-08-05 2021-02-05 华东理工大学 大环类jak2抑制剂及其应用

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023076161A1 (fr) 2021-10-25 2023-05-04 Kymera Therapeutics, Inc. Agents de dégradation de tyk2 et leurs utilisations
WO2023109954A1 (fr) * 2021-12-16 2023-06-22 Lynk Pharmaceuticals Co. Ltd. Inhibiteurs de tyk2 et compositions et procédés associés

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