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WO2022083560A1 - Tyk2选择性抑制剂及其用途 - Google Patents

Tyk2选择性抑制剂及其用途 Download PDF

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WO2022083560A1
WO2022083560A1 PCT/CN2021/124527 CN2021124527W WO2022083560A1 WO 2022083560 A1 WO2022083560 A1 WO 2022083560A1 CN 2021124527 W CN2021124527 W CN 2021124527W WO 2022083560 A1 WO2022083560 A1 WO 2022083560A1
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alkyl
alkynyl
alkenyl
hydrogen
halogen
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PCT/CN2021/124527
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English (en)
French (fr)
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李进
陈弘道
杨民民
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南京药石科技股份有限公司
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Priority to CN202180065577.9A priority Critical patent/CN116249526A/zh
Publication of WO2022083560A1 publication Critical patent/WO2022083560A1/zh

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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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • 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]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the application belongs to the field of chemical medicine, and specifically relates to a TYK2 selective inhibitor and use thereof.
  • Autoimmune diseases are a family of at least 80 diseases, such as rheumatoid arthritis, systemic lupus erythematosus, and inflammatory bowel disease, etc., are a group of immune cells activated and autoantibodies overproduce to mistakenly attack their own organs and tissues and cellular diseases. Autoimmune diseases affect 5%-10% of people worldwide (Shoenfeld Y, Tincani A, Gershwin ME (2012) Sex gender and autoimmunity. J Autoimmun 38:J71–J73). Autoimmune diseases are chronic and debilitating diseases with high medical costs and reduced quality of life for patients, which have become a huge burden on patients, their families and society. Although the pathogenesis of these diseases is not fully understood, studies have shown that multiple factors such as genetics, environment and immune response play an important role in the occurrence and development of the disease.
  • JAK Janus kinase
  • JAK3 JAK3
  • TYK2 non-receptor tyrosine kinases of the JAK family play an important role in mediating multiple cytokines leading to inflammation
  • O Shea J J, Schwartz D M, Villarino AV, et al.The JAK-STAT Pathway:Impact on Human Disease and Therapeutic Intervention*[J].Annual Review of Medicine,2015,66(1):311-328).
  • TYK2 acid kinase 2
  • IL-12 and IL-23 can activate antigen presenting cells and can promote the differentiation and proliferation of Th1 and Th17.
  • Human genomics studies have found that IL-12R and IL-23B (encoding p40 subunit) polymorphisms are strongly associated with inflammatory bowel disease (Stahl EA, Raychaudhuri S, Remmers EF, Xie G, Eyre S, Thomson BP , et al.
  • Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk loci. Nat Genet. 2010;42(6):508–514.R.H.Duerr,K.D;Taylor,S.R.Brant,et al..A Genome -Wide Association Study Identifies IL23R as an Inflammatory Bowel Disease Gene[J].Science,2006.).
  • Type I interferons have multiple effects on the innate and adaptive immune systems, including activation of cellular and humoral immunity and enhanced expression and release of autoantigens (Hall J C, Rosen A. Type I interferons:crucial participants in disease amplification in autoimmunity[J].Nature ReviewsRheumatology,2010,6(1):40.).
  • Elevated serum IFN levels have been observed in patients with systemic lupus erythematosus (SLE) and correlate with disease activity and severity (Bengtsson A, Sturfelt G, Truedsson L, et al. Activation of type I interferon system in systemic lupus erythematosus correlates with disease activity but not with antiretroviral antibodies[J]. Lupus, 2000, 9(9):664.).
  • drugs that inhibit the effects of IL-12, IL-23 and type I interferon have therapeutic benefits in human autoimmune diseases.
  • TYK2 and other members of the JAK family are characterized by dual kinase domains, a tyrosine kinase domain (JH1) and a pseudokinase domain (JH2).
  • JH1 tyrosine kinase domain
  • JH2 pseudokinase domain
  • JH2 plays an important role in the regulation of JAKs function (Lead Optimization of a 4-Aminopyridine Benzamide Scaffold To Identify Potent,Selective,and Orally Bioavailable TYK2Inhibitors[J].Journal of Medicinal Chemistry,2013,56(11):4521.), JAKs Mutations in part of JH2 have been shown to be associated with hematological and immunological diseases. Therefore, TYK2 JH2 selective inhibitors may be able to inhibit TYK2 activity more specifically.
  • the present application discloses a class of compounds that can be used as TYK2 selective inhibitors and their use in the preparation of medicaments for preventing or treating TYK2-mediated related diseases.
  • a 1 , A 2 , A 4 , A 5 , A 6 , A 7 , A 8 are selected from C or N, and A 3 is selected from C, N or And when A 2 is N, at least one of A 4 , A 5 , A 6 , A 7 , and A 8 is N;
  • R 1 is selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogen, cyano, nitro, -C(O)NR a R b , -C (O)R a , -C(O)OR a , -OR a , -OC(O)R a , -OC(O)OR a , -OC(O)NR a R b , -NR a R b , -SR a , -S(O)R a , -S(O) 2 R a or a 3-10 membered saturated or unsaturated ring containing 0-3 heteroatoms, the alkyl, alkenyl, alkynyl, A 3-10 membered saturated or unsaturated ring containing 0-3 heteroatoms is optionally substituted by 1-3 R a ;
  • R 2 is selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogen, cyano, nitro, -C(O)NR a R b , -C (O)R a , -C(O)OR a , -OR a , -OC(O)R a , -OC(O)OR a , -OC(O)NR a R b , -NR a R b , -SR a , -S(O)R a , -S(O) 2 R a or a 3-10 membered saturated or unsaturated ring containing 0-3 heteroatoms, the alkyl, alkenyl, alkynyl, A 3-10 membered saturated or unsaturated ring containing 0-3 heteroatoms is optionally substituted by 1-3 R a ;
  • R 4 is selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogen, cyano, nitro, -C(O)NR a R b , -C (O)R a , -C(O)OR a , -OR a , -OC(O)R a , -OC(O)OR a , -OC(O)NR a R b , -NR a R b , -SR a , -S(O)R a , -S(O) 2 R a or a 3-10 membered saturated or unsaturated ring containing 0-3 heteroatoms, the alkyl, alkenyl, alkynyl, A 3-10 membered saturated or unsaturated ring containing 0-3 heteroatoms is optionally substituted by 1-3 R a ;
  • Each R a , R b is independently selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 3 - C 6 heterocycloalkyl, halogen, hydroxy, cyano, nitro, -C(O)NR c R d , -C(O)R c , -(CH 2 ) n C(O)OR c , -OR c , -(CH 2 ) n OR c , -OC(O)R c , -OC(O)OR c , -OC(O)NR c R d , -NR c R d , -SR c , -S( O)R c or -S(O) 2 R c , the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloal
  • Each R c , R d is independently selected from hydrogen, halogen, carbonyl, -C(O)CH 3 , hydroxy, cyano, nitro, C 1 -C 6 alkyl, halogenated C 1 -C 6 alkane group, C 3 -C 6 cycloalkyl or halogenated C 3 -C 6 cycloalkyl; and
  • n is independently selected from 0, 1, 2 or 3.
  • a 1 , A 2 , A 4 , A 5 , A 6 , A 7 , A 8 are selected from C or N, and A 3 is selected from C, N or And when A 2 is N, at least one of A 4 , A 5 , A 6 , A 7 , and A 8 is N;
  • R 1 is selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogen, cyano, nitro, -C(O)NR a R b , -C (O)R a , -C(O)OR a , -OR a , -OC(O)R a , -OC(O)OR a , -OC(O)NR a R b , -NR a R b , -SR a , -S(O)R a , -S(O) 2 R a or a 3-10 membered saturated or unsaturated ring containing 0-3 heteroatoms, the alkyl, alkenyl, alkynyl, A 3-10 membered saturated or unsaturated ring containing 0-3 heteroatoms is optionally substituted by 1-3 R a ;
  • R 2 is selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogen, cyano, nitro, -C(O)NR a R b , -C (O)R a , -C(O)OR a , -OR a , -OC(O)R a , -OC(O)OR a , -OC(O)NR a R b , -NR a R b , -SR a , -S(O)R a , -S(O) 2 R a or a 3-10 membered saturated or unsaturated ring containing 0-3 heteroatoms, the alkyl, alkenyl, alkynyl, A 3-10 membered saturated or unsaturated ring containing 0-3 heteroatoms is optionally substituted by 1-3 R a ;
  • R 3 is selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogen, cyano, nitro, -C(O)NR a R b , -C (O)R a , -C(O)OR a , -OR a , -OC(O)R a , -OC(O)OR a , -OC(O)NR a R b , -NR a R b , -SR a , -S(O)R a , -S(O) 2 R a or a 3-10 membered saturated or unsaturated ring containing 0-3 heteroatoms, the alkyl, alkenyl, alkynyl, A 3-10 membered saturated or unsaturated ring containing 0-3 heteroatoms is optionally substituted by 1-3 R a ;
  • R 4 is selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogen, cyano, nitro, -C(O)NR a R b , -C (O)R a , -C(O)OR a , -OR a , -OC(O)R a , -OC(O)OR a , -OC(O)NR a R b , -NR a R b , -SR a , -S(O)R a , -S(O) 2 R a or a 3-10 membered saturated or unsaturated ring containing 0-3 heteroatoms, the alkyl, alkenyl, alkynyl, A 3-10 membered saturated or unsaturated ring containing 0-3 heteroatoms is optionally substituted by 1-3 R a ;
  • Each R a , R b is independently selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 3 - C 6 heterocycloalkyl, halogen, hydroxy, cyano, nitro, -C(O)NR c R d , -C(O)R c , -(CH 2 ) n C(O)OR c , -OR c , -(CH 2 ) n OR c , -OC(O)R c , -OC(O)OR c , -OC(O)NR c R d , -NR c R d , -SR c , -S( O)R c or -S(O) 2 R c , the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloal
  • Each R c , R d is independently selected from hydrogen, halogen, carbonyl, -C(O)CH 3 , hydroxy, cyano, nitro, C 1 -C 6 alkyl, halogenated C 1 -C 6 alkane group, C 3 -C 6 cycloalkyl or halogenated C 3 -C 6 cycloalkyl; and
  • n is independently selected from 0, 1, 2 or 3.
  • general formula (I) is a compound of general formula (Ib):
  • a 1 and A 3 are selected from C or N ;
  • R 1 is selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogen, cyano, nitro, -C(O)NR a R b , -C (O)R a , -C(O)OR a , -OR a , -OC(O)R a , -OC(O)OR a , -OC(O)NR a R b , -NR a R b , -SR a , -S(O)R a , -S(O) 2 R a or a 3-10 membered saturated or unsaturated ring containing 0-3 heteroatoms, the alkyl, alkenyl, alkynyl, A 3-10 membered saturated or unsaturated ring containing 0-3 heteroatoms is optionally substituted by 1-3 R a ;
  • R 2 is selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogen, cyano, nitro, -C(O)NR a R b , -C (O)R a , -C(O)OR a , -OR a , -OC(O)R a , -OC(O)OR a , -OC(O)NR a R b , -NR a R b , -SR a , -S(O)R a , -S(O) 2 R a or a 3-10 membered saturated or unsaturated ring containing 0-3 heteroatoms, the alkyl, alkenyl, alkynyl, A 3-10 membered saturated or unsaturated ring containing 0-3 heteroatoms is optionally substituted by 1-3 R a ;
  • R 3 is selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogenated C 1 -C 6 alkyl, halogenated C 2 -C 6 alkenyl, Halogenated C 2 -C 6 alkynyl, halogen, cyano, nitro, -C(O)NR a R b , -C(O)R a , -C(O)OR a , -OR a , -( CH 2 ) n OR a , -NR a R b or -S(O) 2 R a ;
  • R 4 ' is selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogenated C 1 -C 6 alkyl, halogenated C 2 -C 6 alkenyl , halogenated C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, halogenated C 3 -C 6 cycloalkyl, halogen, cyano, nitro or -NR a R b ;
  • Each R a , R b is independently selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 3 - C 6 heterocycloalkyl, halogen, hydroxy, cyano, nitro, -C(O)NR c R d , -C(O)R c , -(CH 2 ) n C(O)OR c , -OR c , -(CH 2 ) n OR c , -OC(O)R c , -OC(O)OR c , -OC(O)NR c R d , -NR c R d , -SR c , -S( O)R c or -S(O) 2 R c , the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloal
  • Each R c , R d is independently selected from hydrogen, halogen, carbonyl, -C(O)CH 3 , hydroxy, cyano, nitro, C 1 -C 6 alkyl, halogenated C 1 -C 6 alkane group, C 3 -C 6 cycloalkyl or halogenated C 3 -C 6 cycloalkyl; and
  • n is independently selected from 0, 1, 2 or 3.
  • general formula (I) is a compound of general formula (Ic):
  • A is selected from C or N;
  • R 1 is selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogen, cyano, nitro, -C(O)NR a R b , -C (O)R a , -C(O)OR a , -OR a , -OC(O)R a , -OC(O)OR a , -OC(O)NR a R b , -NR a R b , -SR a , -S(O)R a , -S(O) 2 R a or a 3-10 membered saturated or unsaturated ring containing 0-3 heteroatoms, the alkyl, alkenyl, alkynyl, A 3-10 membered saturated or unsaturated ring containing 0-3 heteroatoms is optionally substituted by 1-3 R a ;
  • R 2 is selected from hydrogen, C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, halogen, cyano, -C(O)OR a , -(CH 2 ) n OR a or -NH 2 ;
  • R 3 is selected from hydrogen, C 1 -C 6 alkyl or -OR a ;
  • R 4 ' is selected from hydrogen, C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, halogen or -NH 2 ;
  • Each R a , R b is independently selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 3 - C 6 heterocycloalkyl, halogen, hydroxy, cyano, nitro, -C(O)NR c R d , -C(O)R c , -(CH 2 ) n C(O)OR c , -OR c , -(CH 2 ) n OR c , -OC(O)R c , -OC(O)OR c , -OC(O)NR c R d , -NR c R d , -SR c , -S( O)R c or -S(O) 2 R c , the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloal
  • Each R c , R d is independently selected from hydrogen, halogen, carbonyl, -C(O)CH 3 , hydroxy, cyano, nitro, C 1 -C 6 alkyl, halogenated C 1 -C 6 alkane group, C 3 -C 6 cycloalkyl or halogenated C 3 -C 6 cycloalkyl; and
  • n is independently selected from 0, 1, 2 or 3.
  • R 1 is selected from hydrogen, -CH 3 ,
  • R 2 is selected from hydrogen, -CH 3 ,
  • R3 is
  • R 4 is hydrogen, -C(O)CH 3 , or -C(O) NH2 .
  • the compound represented by general formula (I) is selected from:
  • the present application also provides the use of the aforementioned compounds, isomers or pharmaceutically acceptable salts thereof for the preparation of medicaments for diseases mediated by TYK2.
  • the TYK2-mediated disease is an autoimmune disease, an inflammatory disease, a proliferative disease, an endocrine disease, a neurological disease, or a transplant-related disease.
  • the disease is an autoimmune disease.
  • the autoimmune disease is selected from the group consisting of type 1 diabetes, ankylosing spondylitis, systemic lupus erythematosus, multiple sclerosis, systemic sclerosis, psoriasis, Crohn's disease, ulcers colitis or inflammatory bowel disease.
  • the disease is an inflammatory disease.
  • the 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.
  • the present application also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of the aforementioned compound, an isomer or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier or excipient.
  • isomer includes enantiomeric, diastereomeric, and geometric (or conformational) isomeric forms of a given structure.
  • this application includes the R and S configurations, Z and E double bond isomers, Z and E conformational isomers, single stereochemical isomers as well as enantiomers, diastereomers for each asymmetric center Isomers and geometric (or conformational) isomer mixtures.
  • Suitable acid addition salts are formed from acids, which form non-toxic salts such as hydrochloride/chloride.
  • Suitable base salts are formed from bases, which form non-toxic salts such as calcium and sodium salts. Hemi-salts of acids and bases, such as hemi-sulfate and hemi-calcium salts, can also be formed.
  • terapéuticaally effective amount refers to an amount of a compound of the present application that (i) treats a particular disease, condition or disorder; (ii) alleviates, alleviates or eliminates one or more symptoms of a particular disease, condition or disorder or (iii) preventing or delaying the onset of one or more symptoms of the specified disease, condition or disorder described herein.
  • pharmaceutically acceptable carrier or excipient refers to a non-toxic carrier, adjuvant or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated.
  • alkyl refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms, more preferably 1 to 6 carbon atoms atom of the alkyl group.
  • Non-limiting examples of lower alkyl groups containing 1 to 6 carbon atoms include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl base, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methyl Butyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, etc.
  • alkenyl refers to aliphatic hydrocarbons having at least one carbon-carbon double bond, including straight and branched chains having at least one carbon-carbon double bond.
  • an alkenyl group has 2 to 20 carbon atoms, 2 to 10 carbon atoms, 2 to 6 carbon atoms, 3 to 6 carbon atoms, or 2 to 4 carbon atoms.
  • C 2-6 alkenyl includes straight or branched chain unsaturated groups of 2 to 6 carbon atoms (having at least one carbon-carbon double bond), including but not limited to vinyl, 1-propenyl , 2-propenyl (allyl), isopropenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl and the like.
  • alkynyl refers to aliphatic hydrocarbons having at least one carbon-carbon triple bond, including straight and branched chains having at least one carbon-carbon triple bond.
  • the alkynyl group has 2 to 20, 2 to 10, 2 to 6, or 3 to 6 carbon atoms.
  • C2-6alkynyl includes straight or branched chain hydrocarbon alkynyl groups as defined above having 2 to 6 carbon atoms.
  • alkoxy refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl is as defined above.
  • alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 6 carbon atoms carbon atoms (eg 3, 4, 5 or 6 carbon atoms), most preferably 5 to 6 carbon atoms.
  • Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene
  • Polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups.
  • spirocycloalkyl refers to a 5- to 20-membered monocyclic polycyclic group sharing one carbon atom (called a spiro atom), which may contain one or more double bonds, but none of the rings are fully conjugated ⁇ electron system.
  • a spiro atom may contain one or more double bonds, but none of the rings are fully conjugated ⁇ electron system.
  • it is 6 to 14 yuan, more preferably 7 to 10 yuan (eg 7, 8, 9 or 10 yuan).
  • spirocycloalkyl groups are classified into mono-spirocycloalkyl groups, double-spirocycloalkyl groups or poly-spirocycloalkyl groups, preferably mono-spirocycloalkyl groups and double-spirocycloalkyl groups. More preferably 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monospirocycloalkyl.
  • fused cycloalkyl refers to an all-carbon polycyclic group of 5 to 20 members in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or more rings. Multiple double bonds, but none of the rings have a fully conjugated pi electron system. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicycloalkyl.
  • bridged cycloalkyl refers to an all-carbon polycyclic group of 5 to 20 members, any two rings sharing two non-directly connected carbon atoms, which may contain one or more double bonds, but none of the rings have complete Conjugated pi electron system. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic.
  • heterocycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen or S(O )m (where m is an integer from 0 to 2) heteroatoms excluding ring moieties of -O-O-, -O-S- or -S-S-, the remaining ring atoms being carbon.
  • It preferably contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; most preferably contains 3 to 8 ring atoms, of which 1 to 3 are heteroatoms; and most preferably contains 5 to 6 ring atoms, of which 1 to 2 or 1 to 3 are heteroatoms.
  • Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrazolyl Hydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc., preferably tetrahydropyranyl, piperidinyl, and pyrrolidinyl.
  • Polycyclic heterocycloalkyl groups include spiro heterocyclyl, fused heterocyclyl, and bridged heterocyclyl.
  • spiroheterocyclyl refers to a 5- to 20-membered monocyclic polycyclic heterocyclic group sharing one atom (called a spiro atom), wherein one or more ring atoms are selected from nitrogen, oxygen or S(O )m (where m is an integer from 0 to 2) heteroatoms and the remaining ring atoms are carbon. It may contain one or more double bonds, but none of the rings have a fully conjugated pi electron system. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • spiroheterocyclyls are classified into mono-spiroheterocyclyl, bis-spiroheterocyclyl or poly-spiroheterocyclyl, preferably mono-spiroheterocyclyl and bis-spiroheterocyclyl. More preferably, it is a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monospiroheterocyclyl group.
  • fused heterocyclyl refers to a 5- to 20-membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, and one or more of the rings may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system, where one or more ring atoms are heteroatoms selected from nitrogen, oxygen, or S(O)m (where m is an integer from 0 to 2), the remaining rings Atom is carbon.
  • it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • the number of constituent rings it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic groups.
  • bridged heterocyclyl refers to a 5- to 14-membered, polycyclic heterocyclyl group in which any two rings share two atoms that are not directly connected, which may contain one or more double bonds, but none of the rings have a complete common
  • the pi-electron system of the yoke wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, or S(O)m (where m is an integer from 0 to 2) and the remaining ring atoms are carbon.
  • it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • the number of constituent rings it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic.
  • aryl refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (ie, rings that share adjacent pairs of carbon atoms) groups having a conjugated pi-electron system, preferably 6 to 10 membered, such as benzene base and naphthyl.
  • heteroaryl refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen.
  • Heteroaryl is preferably 5 to 10-membered, containing 1 to 3 heteroatoms; more preferably 5- or 6-membered, containing 1 to 2 heteroatoms; preferably, for example, imidazolyl, furyl, thienyl, thiazolyl, pyridine oxazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl and pyridazinyl and the like.
  • hydroxyalkyl refers to an alkyl group substituted with hydroxy, wherein alkyl is as defined above.
  • haloalkyl refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.
  • haloalkoxy refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.
  • deuterated alkyl refers to an alkyl group substituted with one or more deuterium atoms, wherein alkyl is as defined above.
  • deuterated alkoxy refers to an alkoxy group substituted with one or more deuterium atoms, wherein alkoxy is as defined above.
  • cycloalkylalkyl refers to an alkyl group substituted with one or more cycloalkyl groups, wherein cycloalkyl and alkyl are as defined above.
  • cycloalkyloxy refers to -O-cycloalkyl, wherein cycloalkyl is as defined above.
  • heterocyclylalkyl refers to an alkyl group substituted with one or more heterocyclyl groups, wherein heterocyclyl and alkyl are as defined above.
  • arylalkyl refers to an alkyl group substituted with one or more aryl groups, wherein aryl and alkyl are as defined above.
  • hydroxy refers to the -OH group.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • amino refers to -NH2 .
  • cyano refers to -CN.
  • nitro refers to -NO2 .
  • Step 1 Preparation of 3-(6-bromo-4-methylpyridin-2-yl)tetrahydrofuran-3-ol.
  • 2,6-Dibromo-4-methylpyridine (45.0g, 179mmol, 1.00eq.) was dissolved in DCM (500mL), n-BuLi (197mmol, 78.9mL, 1.10eq.) was added dropwise at -78°C, Stir for 1 h, add dihydrofuran-3(2H)-one (16.98 g, 197.28 mmol, 1.1 eq.), react at -78°C for 0.5 h, then naturally warm to room temperature for 1 h.
  • Step 2 Preparation of (R)-2-bromo-6-(3-methoxytetrahydrofuran-3-yl)-4-methylpyridine.
  • 3-(6-Bromo-4-methylpyridin-2-yl)tetrahydrofuran-3-ol (29.0 g, 112 mmol, 1.00 eq.) was dissolved in DMF (180 mL), and NaH (3.00 g, 125 mmol, 1.1 eq.) was added .
  • CH 3 I (17.5 g, 124 mmol, 1.1 eq.
  • Mobile phase A is CO2 and B is ethanol (0.1% NH3H2O ); gradient: B 15 %; flow rate: 70 mL/min; back pressure: 100 bar; column temperature: 35 °C; wavelength: 254 nm; cycle time : ⁇ 1.5min; Interval: 0.5min; Sample preparation: Compounds were dissolved in 200 mL of ethanol.
  • Step 1 Preparation of 3-bromo-6-chloro-1H-pyrrolo[3,2-c]pyridine.
  • 6-Chloro-1H-pyrrolo[3,2-c]pyridine (20g, 131mmol, 1.0eq.) was dissolved in DMF (120mL), NBS (23g, 131mmol, 1eq.) was added, and the reaction was carried out at 25°C for 12h.
  • the reaction solution was poured into 600 mL of water, a large amount of solid was precipitated, filtered and dried.
  • the title compound was obtained (30.3 g, 99%).
  • MS (m/z) 230.92 [M+H] + .
  • Step 2 Preparation of 6-chloro-3-vinyl-1H-pyrrolo[3,2-c]pyridine.
  • 3-Bromo-6-chloro-1H-pyrrolo[3,2-c]pyridine (1.00 g, 4.32 mmol, 1 eq.), 4,4,5,5-tetramethyl-2-vinyl-1, 3,2-Dioxaborane (665mg, 4.32mmol, 1eq.), Pd(dppf)Cl2 ( 3.16g , 4.32mmol, 1eq .), K2CO3 ( 597mg , 4.32mmol, 1eq.) dissolved In water (2 mL) and dioxane (10 mL), the reaction was carried out at 100 °C for 3 h under nitrogen protection.
  • Step 1 Preparation of 6-chloro-3-iodo-1H-pyrrolo[3,2-c]pyridine.
  • 6-Chloro-1H-pyrrolo[3,2-c]pyridine (2.00 g, 13.1 mmol, 1 eq.) was dissolved in DMF (12 mL), and NIS (2.95 g, 13.1 mmol, 1 eq.) was added in portions at 0 °C. ), reacted at 25°C for 12h.
  • the reaction solution was poured into 60 mL of water, a large amount of solid was precipitated, filtered, and the filter cake was dried to obtain the title compound (3.50 g, yield 96%).
  • MS (m/z) 278.91 [M+H] + .
  • Step 2 Preparation of 6-chloro-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-c]pyridine.
  • 6-Chloro-3-iodo-1H-pyrrolo[3,2-c]pyridine (3.50 g, 12.6 mmol, 1 eq.) was dissolved in DMF (20 mL), and NaH (331 mg, 13.8 mmol, 1.1 eq.) was added at 0°C. ), stirred for 15 min, then added SemCl (2.10 g, 12.6 mmol, 1 eq.), and reacted at 25° C. for 2 h.
  • Step 3 Preparation of 6-chloro-3-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-c]pyridine.
  • Cyclopropylboronic acid (84 mg, 978 ⁇ mol, 2.0 eq.), 6-chloro-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3 ,2-c]pyridine (0.20g, 489 ⁇ mol, 1eq.), tricyclohexylphosphine (27.4mg, 97.9 ⁇ mol, 0.2eq.), Pd(OAc) 2 (11mg, 48.9 ⁇ mol, 0.1eq.) dissolved in toluene (5mL) and water (0.2mL) mixed solution, react at 100°C for 12h.
  • Step 4 Preparation of 6-chloro-3-cyclopropyl-1H-pyrrolo[3,2-c]pyridine.
  • Step 1 Preparation of 3-cyano-N-methoxy-N-methylbicyclo[1.1.1]pentane-1-carboxamide.
  • HATU (6.65g, 17.5mmol, 1.20eq.
  • DIEA 3.77g, 29.2mmol, 2.00eq.
  • Step 2 Preparation of 3-(4,6-dichloronicotinoyl)bicyclo[1.1.1]pentane-1-carbonitrile.
  • 5-Bromo-2,4-dichloropyridine (2.10g, 9.25mmol, 1eq.) was dissolved in THF (20mL), isopropylmagnesium chloride (10.2mmol, 5.09mL, 1.1eq.) was added dropwise at -78°C, The reaction was carried out for 2h, and then 3-cyano-N-methoxy-N-methylbicyclo[1.1.1]pentane-1-carboxamide (2.00g, 11.10mmol, 1.20eq.) was added dropwise at -78°C, naturally Raised to room temperature and reacted for 10h.
  • Step 3 Preparation of 3-(6-chloro-1H-pyrazolo[4,3-c]pyridin-3-yl)bicyclo[1.1.1]pentane-1-carbonitrile. 3-(4,6-Dichloronicotinyl)bicyclo[1.1.1]pentane-1-carbonitrile (1.50g, 5.62mmol, 1eq.) was dissolved in THF (20mL), and hydrazine hydrate (562mg, 25°C) was added.
  • Step 2 3-(6-Chloro-1-((2-(trimethylsilyl)ethoxy)methyl)tert-butyl-1-pyrrolo[3,2-c]pyridine-3- yl)-3-hydroxyazetidine-1-carboxylate.
  • Step three 3-(6-Chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-c]pyridin-3-yl)- Preparation of tert-butyl 3-(((methylthio)carbonthio)oxy)azetidine-1-carboxylate.
  • Step 5 Preparation of tert-butyl 3-(6-chloro-1H-pyrrolo[3,2-c]pyridin-3-yl)azetidine-1-carboxylate.
  • Alkane-1-carboxylate tert-butyl ester (2.0 g, 1.0 eq.) was dissolved in a THF solution (20 mL) of tetrabutylammonium fluoride, and reacted at 80° C. for 5 h.
  • Step 1 Preparation of 3-bromo-6-chloro-1H-pyrrolo[3,2-c]pyridine.
  • 6-Chloro-1H-pyrrolo[3,2-c]pyridine (20g, 131mmol, 1.0eq.) was dissolved in DMF (120mL), NBS (23g, 131mmol, 1eq.) was added, and the reaction was carried out at 25°C for 12h.
  • the reaction solution was poured into 600 mL of water, a large amount of solid was precipitated, filtered and dried.
  • the title compound was obtained (30.3 g, 99%).
  • MS (m/z) 230.92 [M+H] + .
  • Step 2 Preparation of 6-chloro-3-vinyl-1H-pyrrolo[3,2-c]pyridine.
  • 3-Bromo-6-chloro-1H-pyrrolo[3,2-c]pyridine (1.00 g, 4.32 mmol, 1 eq.), 4,4,5,5-tetramethyl-2-vinyl-1, 3,2-Dioxaborane (665mg, 4.32mmol, 1eq.), Pd(dppf)Cl2 ( 3.16g , 4.32mmol, 1eq .), K2CO3 ( 597mg , 4.32mmol, 1eq.) dissolved In water (2 mL) and dioxane (10 mL), the reaction was carried out at 100 °C for 3 h under nitrogen protection.
  • Step 3 6-Chloro-1-(6-(3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-3-vinyl-1H-pyrrolo[3,2- c] Preparation of pyridine.
  • Step 4 N-(1-(6-(3-Methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-3-vinyl-1H-pyrrolo[3,2-c ] Preparation of pyridin-6-yl)acetamide.
  • Example 28a or Example 28b N-(3-((1s,3s)-3-cyanocyclobutyl)-1-(6-(3-methoxytetrahydrofuran-3-yl)-4-methyl pyridin-2-yl)-1H-pyrrolo[3,2-c]pyridin-6-yl)acetamide or N-(3-((1r,3r)-3-cyanocyclobutyl)-1 -(6-(3-Methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-1H-pyrrolo[3,2-c]pyridin-6-yl)acetamide
  • Step 1 Preparation of tert-butyl 3-bromo-6-chloro-1H-pyrrolo[3,2-c]pyridine-1-carboxylate.
  • 3-Bromo-6-chloro-1H-pyrrolo[3,2-c]pyridine (2.00 g, 8.64 mmol, 1 eq.), (Boc) 2 O (1.89 g, 8.64 mmol, 1.0 eq.), DMAP ( 105mg, 864 ⁇ mol, 0.1eq.), TEA (1.31g, 12.9mmol, 1.5eq.) was dissolved in THF (20mL) and reacted at 25°C for 1h.
  • MS (m/z) 330.98 [M+H] + .
  • Step 2 Preparation of 6-chloro-3-(3-cyano-1-hydroxycyclobutyl)-1H-pyrrolo[3,2-c]pyridine-1-carboxylic acid tert-butyl ester.
  • 3-Bromo-6-chloro-1H-pyrrolo[3,2-c]pyridine-1-carboxylate tert-butyl ester (2.80 g, 8.44 mmol, 1 eq.) was dissolved in THF (30 mL) at -78°C n-BuLi (8.87mmol, 3.20mL, 1.05eq.) was added dropwise, kept at -78°C for 1h, then 3-oxocyclobutanenitrile (883mg, 9.29mmol, 1.1eq.) was added dropwise, and the mixture was reacted at -78°C for 1h.
  • Step 3 Preparation of 3-(6-chloro-1H-pyrrolo[3,2-c]pyridin-3-yl)cyclobutane-1-carbonitrile.
  • Et 3 SiH (6.69 g, 57.5 mmol, 10.0 eq.)
  • TFA 6.56 g, 57.5 mmol, 10.0 eq.
  • Step 4 3-(6-Chloro-1-(6-(3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-1H-pyrrolo[3,2-c] Preparation of pyridin-3-yl)cyclobutane-1-carbonitrile.
  • Step 5 N-(3-(3-cyanocyclobutyl)-1-(6-(3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-1H-pyrrole Preparation of [3,2-c]pyridin-6-yl)acetamide.
  • 1 H NMR(400MHz, DMSO) ⁇ 10.38(s,1H), 9.07(s,1H), 8.58(s,1H), 8.02(s,1H), 7.61(s,1H), 7.30(s,1H) ), 4.21(d, J 9.7Hz, 1H), 4.09-3.94(m, 2H), 3.92(d, 1H), 3.81(dt, 1H), 3.51-3.37(m, 1H), 3.15(s, 3H), 2.87 (ddd, 2H), 2.68 (dt, 2H), 2.57 (dd, 2H), 2.47 (s, 3H), 2.10 (s, 3H).
  • Step 1 (R)-2-(4-(6-acetylamino-1-(6-(3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-1H-pyrrole Preparation of ethyl [3,2-c]pyridin-3-yl)cyclohexyl)acetate.
  • Step 2 (R)-2-(4-(6-acetylamino-1-(6-(3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-1H-pyrrole Preparation of [3,2-c]pyridin-3-yl)cyclohexyl)acetic acid.
  • Example 31 was prepared in a similar manner with reference to Example 30.
  • Step 1 (R)-4-(6-acetamido-1-(6-(3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-1H-pyrrolo[ Preparation of 3,2-c]pyridin-3-yl)piperidine-1-carboxylate tert-butyl ester.
  • Step 2 (R)-N-(1-(6-(3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-3-(piperidin-4-yl)- Preparation of 1H-pyrrolo[3,2-c]pyridin-6-yl)acetamide.
  • Example 33 was prepared in a similar manner with reference to Example 32.
  • Example 34a or 34b N-(3-((1s,4S)-4-aminocyclohexyl)-1-(6-((R)-3-methoxytetrahydrofuran-3-yl)-4-methyl pyridin-2-yl)-1H-pyrrolo[3,2-c]pyridin-6-yl)acetamide or N-(3-((1r,4R)-4-aminocyclohexyl)-1-( 6-((R)-3-Methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-1H-pyrrolo[3,2-c]pyridin-6-yl)acetamide
  • Apparatus Waters 200, preparative SFC (QC-R-LC-07); Column: ChiralPak IC, 250 x 30 mm ID, 5 ⁇ m; Mobile phase: A is CO2 and B is ethanol (0.1% NH3H2O ) ; Gradient: B 30%; Flow rate: 70 mL/min; Back pressure: 100 bar; Column temperature: 35° C.; Wavelength: 210 nm; Cycle time: ⁇ 4 min; Interval time: 0.5 min;
  • Example 36a (R)-N-(3-(azetidin-3-yl)-1-(6-(3-methoxytetrahydrofuran-3-yl)-4-methylpyridine-2 -yl)-1H-pyrrolo[3,2-c]pyridin-6-yl)acetamide and
  • Example 36b (R)-N-(1-(6-(3-methoxytetrahydrofuran-3- yl)-4-methylpyridin-2-yl)-3-(1-methylazetidin-3-yl)-1H-pyrrolo[3,2-c]pyridin-6-yl)ethyl Amide
  • Example 37a (R)-N-(1-(6-(3-Methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-3-(2-azaspiro[3.3 ]hept-6-yl)-1H-pyrrolo[3,2-c]pyridin-6-yl)acetamide and
  • Example 37b (R)-N-(1-(6-(3-methoxy) Tetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-3-(2-methyl-2-azaspiro[3.3]heptyl-6-yl)-1H-pyrrolo[3,2 -c]pyridin-6-yl)acetamide
  • Examples 39-40 were prepared analogously to Example 38.
  • Example 41a or Example 41b N-(7-((1s,3S)-3-cyanocyclobutyl)-5-(6-((R)-3-methoxytetrahydrofuran-3-yl) -4-Methylpyridin-2-yl)-7H-pyrrolo[2,3-c]pyridazin-3-yl)acetamide or N-(7-((1r,3R)-3-cyano ring Butyl)-5-(6-((R)-3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-7H-pyrrolo[2,3-c]pyridazine -3-yl)acetamide
  • Step 1 Preparation of 5-bromo-3-chloro-7H-pyrrolo[2,3-c]pyridazine.
  • 3-Chloro-7H-pyrrolo[2,3-c]pyridazine (2.00g, 13.0mmol, 1eq.) was dissolved in DMF (12mL), NBS (2.32g, 13.0mmol, 1eq.) was added, 20°C The reaction was carried out for 2h. The reaction solution was poured into 60 mL of water, a large amount of solid was precipitated, filtered, and the filter cake was dried to obtain the title compound (3 g, yield 99%).
  • MS (m/z) 231.92 [M+H] + .
  • Step 2 Preparation of 3-cyanocyclobutyl methanesulfonate.
  • 3-Hydroxycyclobutanenitrile (1.50g, 15.4mmol, 1eq.), MsCl (2.12g, 18.5mmol, 1.2eq.), TEA (2.34g, 23.1mmol, 1.5eq.) were dissolved in DCM (20mL), 20 °C reaction 2h.
  • the reaction solution was poured into 10 mL of water, separated and concentrated to obtain the title compound (2.7 g, yield 99%).
  • Step 3 Preparation of 3-(5-bromo-3-chloro-7H-pyrrolo[2,3-c]pyridazin-7-yl)cyclobutane-1-carbonitrile.
  • 5-Bromo-3-chloro-7H-pyrrolo[2,3-c]pyridazine (1.19 g, 5.14 mmol, 1 eq.)
  • 3-cyanocyclobutylmethanesulfonate (2.70 g, 15.4 mmol, 3.0 eq. .)
  • Cs 2 CO 3 (3.35 g, 10.2 mmol, 2.0 eq.) was dissolved in DMF (10 mL) and reacted at 80° C. for 12 h.
  • Step 4 (R)-3-(3-Chloro-5-(6-(3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-7H-pyrrolo[2, Preparation of 3-c]pyridazin-7-yl)cyclobutane-1-carbonitrile.
  • Step 5 (R)-N-(7-(3-cyanocyclobutyl)-5-(6-(3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl) Preparation of -7H-pyrrolo[2,3-c]pyridazin-3-ylacetamide.
  • 1 H NMR 400MHz, DMSO
  • Step 1 Preparation of 6-(3-methoxytetrahydrofuran-3-yl)-4-methylpicolinic acid.
  • 2-Bromo-6-(3-methoxytetrahydrofuran-3-yl)-4-methylpyridine (1.00 g, 3.67 mmol, 1 eq.) was dissolved in THF (10 mL), and n- BuLi (3.67mmol, 1.5mL, 1.0eq.) was reacted for 0.5h, then CO 2 was introduced, the temperature was naturally warmed to room temperature and reacted for 1h, 10mL of water was added to the reaction solution, and the solution was concentrated to obtain the title compound (0.8g, yield 91%).
  • MS (m/z) 238.10 [M+H] + .
  • Step 2 Preparation of tert-butyl ((5-chloropyrazin-2-yl)methyl)carbamate.
  • 5-Chloropyrazine-2-carbaldehyde (1.00g, 7.02mmol, 1eq.)
  • Et3SiH (8.16g, 70.1mmol, 10.0eq.)
  • NH2Boc (1.64g, 14.03mmol, 2.0eq.
  • TFA (2.40 g, 21.0 mmol, 3.0 eq.) was dissolved in ACN (10 mL), reacted at 25°C for 24 h, added 10 mL of saturated sodium carbonate, spun out ACN, extracted with 10 mL of EA, concentrated to give the title compound (1.2 g, collected rate 70%).
  • MS (m/z) 244.08 [M+H] + .
  • Step 3 Preparation of (5-chloropyrazin-2-yl)methanamine.
  • ((5-Chloropyrazin-2-yl)methyl)carbamate tert-butyl ester (1.20 g, 4.92 mmol, 1 eq.) was dissolved in HCl in EA (10 mL) solution, reacted at 25°C for 16 h, and concentrated to obtain the title Compound (0.8 g, 100% yield).
  • MS (m/z) 144.03 [M+H] + .
  • Step 4 Preparation of N-((5-chloropyrazin-2-yl)methyl)-6-(3-methoxytetrahydrofuran-3-yl)-4-methylpyridinoline amide.
  • (5-Chloropyrazin-2-yl)methanamine (181 mg, 1.26 mmol, 3.0 eq.)
  • 6-(3-methoxytetrahydrofuran-3-yl)-4-methylpicolinic acid 100 mg, 0.42 mmol , 1.0eq.
  • HATU 480mg, 1.26mmol, 3.0eq.
  • DIEA 544mg, 4.2mmol, 10.0eq.
  • Step five 6-chloro-3-(6-(3-(3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)imidazo[1,5-a]pyrazine
  • N-((5-Chloropyrazin-2-yl)methyl)-6-(3-methoxytetrahydrofuran-3-yl)-4-methylpyridinolineamide (0.10 g, 275 ⁇ mol, 1 eq.
  • Step Six N-(3-(6-(3-Methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)imidazo[1,5-a]pyrazin-6-yl) Preparation of acetamide.
  • 6-Chloro-3-(6-(3-(3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)imidazo[1,5-a]pyrazine (0.10 g, 290 ⁇ mol, 1eq.), Cesium Carbonate (283mg, 870 ⁇ mol, 3.0eq.), Acetamide (25.7mg, 435 ⁇ mol, 1.5eq.), Pd 2 (dba) 3 (26.5mg, 29.0 ⁇ mol, 0.1eq.), X -phos (5.70mg, 58.0 ⁇ mol, 0.2eq.) was dissolved in 1,4-dioxane (5mL) and reacted at 100°C for 12h under nitrogen protection.
  • Step 1 Preparation of 6-(3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-amine.
  • 2-Bromo-6-(3-methoxytetrahydrofuran-3-yl)-4-methylpyridine (0.50 g, 1.84 mmol, 1 eq.)
  • dimethylethylenediamine (16.2 mg, 183 ⁇ mol, 0.1 eq.
  • Cu 2 O (13.1mg, 91.8 ⁇ mol, 0.05eq.)
  • potassium carbonate (508mg, 3.67mmol, 2.0eq.) were dissolved in ethylene glycol (5mL) and ammonia water (4.6mL) at 80°C under nitrogen protection The reaction was carried out for 12h.
  • Step 2 Preparation of N-(2-chloro-5-nitropyridin-4-yl)-6-(3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-amine.
  • 2,4-Dichloro-5-nitropyridine (278 mg, 1.44 mmol, 1 eq.)
  • 6-(3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-amine (0.30 g, 1.44 mmol, 1 eq.)
  • DIPEA 186 mg, 1.44 mmol, 1 eq.
  • MS (m/z) 365.09 [M+H] + .
  • Step 3 Preparation of 6-chloro-N 4 -(6-(3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)pyridine-3,4-diamine.
  • Step 4 6-Chloro-1-(6-(3-(3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-1,3-dihydro-2H-imidazo Preparation of [4,5-c]pyridin-2-one.
  • Step 5 6-Chloro-1-(6-(3-(3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-3-methyl-1,3-dihydro Preparation of -2H-imidazo[4,5-c]pyridin-2-one.
  • Step 6 N-(1-(6-(3-Methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-3-methyl-2-oxo-2,3-di Preparation of Hydro-1H-imidazo[4,5-c]pyridin-6-yl)acetamide.
  • Step 1 (R)-6-Chloro-1-(6-(3-(methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-1H-pyrrolo[3,2- c] Preparation of pyridine.
  • 6-Chloro-1H-pyrrolo[3,2-c]pyridine (6.000 g, 39.324 mmol, 1.00 eq.) was dissolved in 1,4-dioxane (80 mL) and added (R)-2-Bromo-6-(3-methoxytetrahydrofuran-3-yl)-4-methylpyridine (10.702 g, 39.324 mmol, 1.00 eq.), K 2 CO 3 (16.305 g, 0.118 mol) , 3.0eq.), CuI (0.375mg, 1.966mmol, 0.05eq.), N,N-dimethylethylenediamine (0.348g, 3.933mmol, 0.1eq.), refluxed for 12h under nitrogen protection.
  • Step 2 (R)-N-(1-(6-(6-(3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-1H-pyrrolo[3,2 -c] Preparation of pyridin-6-yl)acetamide.
  • Step three (R)-N-(3-iodo-1-(6-(3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-1H-pyrrolo[3, Preparation of 2-c]pyridin-6-yl)acetamide.
  • Step 4 (R)-N-(1-(6-(3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-3-(oxetan-3-yl) Preparation of ethynyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)acetamide.
  • Step 1 (R)-3-((6-acetylamino-1-(6-(3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-1H-pyrrolo[ Preparation of 3,2-c]pyridin-3-yl)ethynyl)azetidine-1-carboxylate tert-butyl ester.
  • MS (m/z) 546 [M+H] + .
  • Step 2 (R)-N-(3-(azetidin-3-ylethynyl)-1-(6-(3-methoxytetrahydrofuran-3-yl)-4-methylpyridine- Preparation of 2-yl)-1H-pyrrolo[3,2-c]pyridin-6-yl)acetamide.
  • Step 3 (R)-N-(3-((1-acetylazetidin-3-yl)ethynyl)-1-(6-(3-methoxytetrahydrofuran-3-yl)-4 - Preparation of methylpyridin-2-yl)-1H-pyrrolo[3,2-c]pyridin-6-yl)acetamide.
  • Example 52 was prepared in a manner similar to that of Example 51.
  • Example 55 was prepared in a similar manner to that of Example 54.
  • Examples 60-62 were prepared analogously to Example 35.
  • Examples 71-72 were prepared analogously to Example 1 and Example 56.
  • Example 73a and Example 73b were prepared analogously with reference to Example 28a and Example 28b.
  • TYK2 JH2 (N-His-Tev, 575-869) was expressed in Sf9, the protein was expressed from our laboratory, the fluorescein-labeled probe was synthesized by our company, and the Anti-6xHis-terbium labled antibody was purchased from Cisbio. High purity Hepes, NaCl, MgCl2 , DTT, BSA, Tween-20 and DMSO were purchased from Sigma.
  • the assay buffer used in the experiments consisted of 20 mM Hepes pH 7.5, 150 mM NaCl, 10 mM MgCl 2 , 2 mM DTT, 50 ⁇ g/mL BSA, and 0.015% Tween-20. Prepare the test compound DMSO storage stock solution, and use DMSO for three-fold concentration gradient dilution for 12 points according to the needs of the experiment. 4% DMSO compound, TYK2 JH2 enzyme, fluorescein-labeled probe, Anti-6xHis-terbium labled antibody were prepared using assay buffer.
  • the plate was read on a SPARK multi-template reader of TECAN (Switzerland), the excitation light wavelength was 340 nm, and the emission light wavelengths were 520 nm and 485 nm, respectively.
  • IC50 values for inhibitors were obtained using Prism 8 (La Jolla, CA).
  • JAK1 N-GST-his-TEV, 850-1154
  • TK kit was purchased from Cisbio. High purity ATP, MgCl2 , MnCl2, DTT and DMSO were purchased from Sigma.
  • the assay buffer used in TYK2 JH1 experiments consisted of 5mM MgCl 2 , 1mM MnCl 2 , 1mM DTT, 12.5 ⁇ M SEB and 1x Enzymatic buffer.
  • the assay buffer used in JAK2/3 experiments consisted of 5mM MgCl 2 , 1mM DTT and 1x Enzymatic buffer.
  • Assay buffer used in JAK1 experiments consisted of 5mM MgCl 2 , 1mM MnCl 2 , 1mM DTT and 1x Enzymatic buffer.
  • test compound DMSO storage stock solution Prepares the test compound DMSO storage stock solution, and use DMSO for three-fold concentration gradient dilution for 12 points according to the needs of the experiment.
  • Compounds, enzymes, TK-Substrate, and ATP in 4% DMSO were prepared using assay buffer. After the preparation, 2.5 ⁇ L of compounds in 4% DMSO, 2.5 ⁇ L of enzyme, and 5 ⁇ L of TK-Substrate/ATP mixture were added to OptiPlate-384 White Opaque plate. medium, cover with membrane, 800 rpm for 1 min, and incubate at room temperature for 1 h.
  • TK-Antibody-Cryptate antibody and Streptavidin-XL665 diluted in HTRF detection buffer were added, and incubated at room temperature for 1 h. Final concentrations were 1x and 15.61 nM.
  • the plate was read on the SPARK multi-template reader of TECAN (Switzerland), the excitation light wavelength was 320 nm, and the emission light wavelengths were 665 nm and 620 nm, respectively.
  • IC50 values for inhibitors were obtained using Prism 8 (La Jolla, CA).
  • Table 1 shows the IC50 values of TYK2 JH2, TYK2 JH1, JAK1, JAK2, and JAK3 kinase activity inhibition assays for representative compounds of the present application.
  • Reference compound 1 and reference compound 2 were prepared with reference to the method in International Patent Publication WO2019178079A1.
  • HBSS buffer is preheated in a water bath at 37°C.
  • HBSS+ with 0.3% DMSO and 5 ⁇ M Lucifer Yellow Add 150 ⁇ L DMSO and 125 ⁇ L of a 2 mM Lucifer Yellow solution to 50 mL of HBSS+ buffer (pH 7.4).
  • HBSS+ with 0.1% DMSO and 5 ⁇ M Lucifer Yellow Add 50 ⁇ L of DMSO and 125 ⁇ L of a 2 mM Lucifer Yellow solution to 50 mL of HBSS+ buffer (pH 7.4).
  • HBSS+ with 0.3% DMSO Add 150 ⁇ L DMSO to 50 mL of HBSS+ buffer (pH 7.4).
  • HBSS+ with 0.1% DMSO Add 50 ⁇ L DMSO to 50 mL HBSS+ buffer (pH 7.4).
  • HBSS+ with 0.4% DMSO Add 200 ⁇ L DMSO to 50 mL of HBSS+ buffer (pH 7.4).
  • HBSS+ with 0.4% DMSO and 5 ⁇ M Lucifer Yellow Add 200 ⁇ L of DMSO and 50 ⁇ L of 5 mM Lucifer Yellow solution to 50 mL of HBSS+ buffer (pH 7.4).
  • B-A (dosing side) 900 ⁇ L of B-to-A dosing solution (100 ⁇ L for sample collection at the start of culture).
  • BA (receiver side): 500 ⁇ L of HBSS + with 0.4% DMSO and 5 ⁇ M Lucifer Yellow (100 ⁇ L for sample collection at the start of Lucifer Yellow incubation).
  • the dosing and receiving fluid samples were diluted with 0.4% DMSO HBSS buffer, then mixed with CAN containing internal standard and sent to LC/MS analysis.
  • Transmembrane resistance (resistance value sample - resistance value blank) ⁇ membrane area
  • Apparent permeability coefficient (P app ) (volume of receiving side/(membrane area ⁇ culture time)) ⁇ (fluorescence value of receiving side at the end of culture – fluorescence value of blank solution)/((fluorescence value of administration side at the beginning of culture – Fluorescence value of blank solution) ⁇ dilution factor)
  • Apparent permeability coefficient (P app ) (volume of recipient side/(membrane area ⁇ incubation time)) ⁇ (drug concentration of recipient side at the end of culture/(drug concentration of administration side at the beginning of culture ⁇ dilution factor)
  • % recovery 100 ⁇ (total compound on the dosing side at 90 minutes + total compound on the receiving side at 90 minutes)/(total compound on the dosing side at 0 minutes).
  • Table 2 shows the apparent permeability coefficients of the representative compounds of the present application and the reference compounds 1 and 2.

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Abstract

一种TYK2选择性抑制剂及其用途，具体涉及一种式(I)化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其可药用的盐，以及其用于制备由TYK2介导的疾病药物中的用途。

Description

TYK2选择性抑制剂及其用途 技术领域
本申请属于化学医药领域，具体涉及一种TYK2选择性抑制剂及其用途。
背景技术
自身免疫性疾病是一个至少有80种疾病的家族，如类风湿关节炎、系统性红斑狼疮和炎症性肠炎等，是一组以免疫细胞激活和自身抗体过量产生从而错误地攻击自身器官、组织和细胞的疾病。自身免疫性疾病影响着全世界范围内5％-10％的人(Shoenfeld Y,Tincani A,Gershwin ME(2012)Sex gender and autoimmunity.J Autoimmun 38:J71–J73)。自身免疫性疾病作为慢性和使人衰弱的疾病，医疗费用高昂，患者生活质量下降，已成为患者、其家庭和社会的巨大负担。虽然这些疾病的发病机制尚不完全清楚，但研究表明，遗传、环境和免疫反应等多种因素在疾病的发生发展中起着重要作用。
激酶在调节免疫细胞功能方面起着十分重要的作用(Deng,Bellanti,Zheng.Essential Kinases and Transcriptional Regulators and Their Roles in Autoimmunity[J].Biomolecules,2019,9(4))。Janus激酶(JAK)家族成员包括JAK1、JAK2、JAK3和TYK2，JAK家族的非受体酪氨酸激酶在介导多种细胞因子导致炎症中起重要作用(O"Shea J J,Schwartz D M,Villarino A V,et al.The JAK-STAT Pathway:Impact on Human Disease and Therapeutic Intervention*[J].Annual Review of Medicine,2015,66(1):311-328)。全基因组关联研究显示，酪氨酸激酶2(TYK2)的其他变体与克罗恩病、牛皮癣、系统性红斑狼疮以及类风湿性关节炎等自身免疫性疾病相关，这进一步表明TYK2在自体免疫中的重要性(Ellinghaus D,Ellinghaus E,Nair RP,Stuart PE,Esko T,Metspalu A,et al.Combined analysis of genome-wide association studies for Crohn disease and psoriasis identifies seven shared susceptibility loci.Am J Hum Genet.(2012)90:636–47.10.1016/j.ajhg.2012.02.020；Graham D S C,Akil M,Vyse T J.Association of polymorphisms across the tyrosine kinase gene,TYK2in UKSLE families[J].Rheumatology,2007(6):927-930；Eyre S,et al.High-density genetic mapping identifies new susceptibility loci for rheumatoid arthritis.Nat Genet.2012；44:1336–40.)。TYK2在IL-12、IL-23和I型干扰素受体的调控信号转导级联下游中至关 重要(Karaghiosoff M,Steinborn R,Kovarik P,et al.Central role for type I interferons and Tyk2 in lipopolysaccharide-induced endotoxin shock.[J].Nature Immunology,2003,4(5):471.)。IL-12和IL-23可以活化抗原递呈细胞并且能够促进Th1和Th17的分化和增殖。人类基因组学研究发现，IL-12R和IL-23B(编码p40亚基)多态性与炎症性肠炎有很强的相关性(Stahl EA,Raychaudhuri S,Remmers EF,Xie G,Eyre S,Thomson BP,et al.Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk loci.Nat Genet.2010；42(6):508–514.R.H.Duerr,K.D；Taylor,S.R.Brant,et al..A Genome-Wide Association Study Identifies IL23R as an Inflammatory Bowel Disease Gene[J].Science,2006.)。I型干扰素对先天性和适应性免疫系统具有多种效应，包括活化细胞免疫和体液免疫以及增强自体抗原的表达和释放(Hall J C,Rosen A.Type I interferons:crucial participants in disease amplification in autoimmunity[J].Nature Reviews Rheumatology,2010,6(1):40.)。在系统性红斑狼疮(SLE)患者中观察到血清IFN水平的升高，且该水平与疾病的活动性和严重程度相关(Bengtsson A,Sturfelt G,Truedsson L,et al.Activation of type I interferon system in systemic lupus erythematosus correlates with disease activity but not with antiretroviral antibodies[J].Lupus,2000,9(9):664.)。综上，抑制IL-12、IL-23和I型干扰素作用的药物在人类自体免疫性疾病种具有治疗益处。
研究表明，选择性的抑制TYK2的活性可以作为一种能够平衡治疗和安全之间关系的新的治疗多种自身免疫性疾病的方法(Leitner,Nicole,R,et al..Tyrosine kinase 2-Surveillant of tumours and bona fide oncogene[J].Cytokine,2017.)。TYK2以及JAK家族的其他成员的特征是有双激酶结构域，分别是酪氨酸激酶结构域(JH1)和假性激酶结构域(JH2)。在JAK家族中，JH1区域具有很高的序列同源性，这为设计TYK2选择性抑制剂提出了挑战。JH2在JAKs功能调节方面起重要作用(Lead Optimization of a 4-Aminopyridine Benzamide Scaffold To Identify Potent,Selective,and Orally Bioavailable TYK2Inhibitors[J].Journal of Medicinal Chemistry,2013,56(11):4521.)，JAKs的JH2部分突变已被证明与血液病以及免疫学疾病有关。因此，TYK2 JH2选择性抑制剂或能更加特异性地抑制TYK2活性。
综上，合成新的TYK2 JH2选择性抑制剂，通过调节体内IL-12、IL-23以及I型干扰素等，可以使自身免疫性疾病患者受益。
发明内容
本申请公开了一类可作为TYK2选择性抑制剂的化合物以及其在制备预防或治疗TYK2介导的相关疾病药物中的用途。
一方面，本申请公开一种通式(I)所示的化合物：
Figure PCTCN2021124527-appb-000001
或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其可药用的盐，
其中，A 1、A 2、A 4、A 5、A 6、A 7、A 8选自C或N，A 3选自C、N或
Figure PCTCN2021124527-appb-000002
且当A 2为N时，A 4、A 5、A 6、A 7、A 8中至少有1个为N；
Figure PCTCN2021124527-appb-000003
为饱和或不饱和环；
R 1选自氢、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、卤素、氰基、硝基、-C(O)NR aR b、-C(O)R a、-C(O)OR a、-OR a、-OC(O)R a、-OC(O)OR a、-OC(O)NR aR b、-NR aR b、-SR a、-S(O)R a、-S(O) 2R a或含有0-3个杂原子的3-10元饱和或非饱和环，所述烷基、烯基、炔基、含有0-3个杂原子的3-10元饱和或非饱和环可选的被1-3个R a取代；
R 2选自氢、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、卤素、氰基、硝基、-C(O)NR aR b、-C(O)R a、-C(O)OR a、-OR a、-OC(O)R a、-OC(O)OR a、-OC(O)NR aR b、-NR aR b、-SR a、-S(O)R a、-S(O) 2R a或含有0-3个杂原子的3-10元饱和或非饱和环，所述烷基、烯基、炔基、含有0-3个杂原子的3-10元饱和或非饱和环可选的被1-3个R a取代；
R 4选自氢、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、卤素、氰基、硝基、-C(O)NR aR b、-C(O)R a、-C(O)OR a、-OR a、-OC(O)R a、-OC(O)OR a、-OC(O)NR aR b、-NR aR b、-SR a、 -S(O)R a、-S(O) 2R a或含有0-3个杂原子的3-10元饱和或非饱和环，所述烷基、烯基、炔基、含有0-3个杂原子的3-10元饱和或非饱和环可选的被1-3个R a取代；
每个R a、R b分别独立的选自氢、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 6环烷基、C 3-C 6杂环烷基、卤素、羟基、氰基、硝基、-C(O)NR cR d、-C(O)R c、-(CH 2) nC(O)OR c、-OR c、-(CH 2) nOR c、-OC(O)R c、-OC(O)OR c、-OC(O)NR cR d、-NR cR d、-SR c、-S(O)R c或-S(O) 2R c，所述烷基、烯基、炔基、环烷基、杂环烷基可选的被1-3个R c取代；
每个R c、R d分别独立的选自氢、卤素、羰基、-C(O)CH 3、羟基、氰基、硝基、C 1-C 6烷基、卤代C 1-C 6烷基、C 3-C 6环烷基或卤代C 3-C 6环烷基；并且
每个n分别独立的选自0、1、2或3。
在一些实施方案中，通式(Ia)所示的化合物：
Figure PCTCN2021124527-appb-000004
或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其可药用的盐，
其中，A 1、A 2、A 4、A 5、A 6、A 7、A 8选自C或N，A 3选自C、N或
Figure PCTCN2021124527-appb-000005
且当A 2为N时，A 4、A 5、A 6、A 7、A 8中至少有1个为N；
Figure PCTCN2021124527-appb-000006
为饱和或不饱和环；
R 1选自氢、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、卤素、氰基、硝基、-C(O)NR aR b、-C(O)R a、-C(O)OR a、-OR a、-OC(O)R a、-OC(O)OR a、-OC(O)NR aR b、-NR aR b、-SR a、-S(O)R a、-S(O) 2R a或含有0-3个杂原子的3-10元饱和或非饱和环，所述烷基、 烯基、炔基、含有0-3个杂原子的3-10元饱和或非饱和环可选的被1-3个R a取代；
R 2选自氢、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、卤素、氰基、硝基、-C(O)NR aR b、-C(O)R a、-C(O)OR a、-OR a、-OC(O)R a、-OC(O)OR a、-OC(O)NR aR b、-NR aR b、-SR a、-S(O)R a、-S(O) 2R a或含有0-3个杂原子的3-10元饱和或非饱和环，所述烷基、烯基、炔基、含有0-3个杂原子的3-10元饱和或非饱和环可选的被1-3个R a取代；
R 3选自氢、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、卤素、氰基、硝基、-C(O)NR aR b、-C(O)R a、-C(O)OR a、-OR a、-OC(O)R a、-OC(O)OR a、-OC(O)NR aR b、-NR aR b、-SR a、-S(O)R a、-S(O) 2R a或含有0-3个杂原子的3-10元饱和或非饱和环，所述烷基、烯基、炔基、含有0-3个杂原子的3-10元饱和或非饱和环可选的被1-3个R a取代；
R 4选自氢、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、卤素、氰基、硝基、-C(O)NR aR b、-C(O)R a、-C(O)OR a、-OR a、-OC(O)R a、-OC(O)OR a、-OC(O)NR aR b、-NR aR b、-SR a、-S(O)R a、-S(O) 2R a或含有0-3个杂原子的3-10元饱和或非饱和环，所述烷基、烯基、炔基、含有0-3个杂原子的3-10元饱和或非饱和环可选的被1-3个R a取代；
每个R a、R b分别独立的选自氢、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 6环烷基、C 3-C 6杂环烷基、卤素、羟基、氰基、硝基、-C(O)NR cR d、-C(O)R c、-(CH 2) nC(O)OR c、-OR c、-(CH 2) nOR c、-OC(O)R c、-OC(O)OR c、-OC(O)NR cR d、-NR cR d、-SR c、-S(O)R c或-S(O) 2R c，所述烷基、烯基、炔基、环烷基、杂环烷基可选的被1-3个R c取代；
每个R c、R d分别独立的选自氢、卤素、羰基、-C(O)CH 3、羟基、氰基、硝基、C 1-C 6烷基、卤代C 1-C 6烷基、C 3-C 6环烷基或卤代C 3-C 6环烷基；并且
每个n分别独立的选自0、1、2或3。
在一些实施方案中，通式(I)为通式(Ib)所示的化合物：
Figure PCTCN2021124527-appb-000007
或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其可药用的盐，其中，A 1、A 3选自C或N；
R 1选自氢、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、卤素、氰基、硝基、-C(O)NR aR b、-C(O)R a、-C(O)OR a、-OR a、-OC(O)R a、-OC(O)OR a、-OC(O)NR aR b、-NR aR b、-SR a、-S(O)R a、-S(O) 2R a或含有0-3个杂原子的3-10元饱和或非饱和环，所述烷基、烯基、炔基、含有0-3个杂原子的3-10元饱和或非饱和环可选的被1-3个R a取代；
R 2选自氢、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、卤素、氰基、硝基、-C(O)NR aR b、-C(O)R a、-C(O)OR a、-OR a、-OC(O)R a、-OC(O)OR a、-OC(O)NR aR b、-NR aR b、-SR a、-S(O)R a、-S(O) 2R a或含有0-3个杂原子的3-10元饱和或非饱和环，所述烷基、烯基、炔基、含有0-3个杂原子的3-10元饱和或非饱和环可选的被1-3个R a取代；
R 3选自氢、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、卤代C 1-C 6烷基、卤代C 2-C 6烯基、卤代C 2-C 6炔基、卤素、氰基、硝基、-C(O)NR aR b、-C(O)R a、-C(O)OR a、-OR a、-(CH 2) nOR a、-NR aR b或-S(O) 2R a；
R 4’选自氢、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、卤代C 1-C 6烷基、卤代C 2-C 6烯基、卤代C 2-C 6炔基、C 3-C 6环烷基、卤代C 3-C 6环烷基、卤素、氰基、硝基或-NR aR b；
每个R a、R b分别独立的选自氢、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 6环烷基、C 3-C 6杂环烷基、卤素、羟基、氰基、硝基、-C(O)NR cR d、-C(O)R c、-(CH 2) nC(O)OR c、-OR c、-(CH 2) nOR c、-OC(O)R c、-OC(O)OR c、-OC(O)NR cR d、-NR cR d、-SR c、-S(O)R c或-S(O) 2R c，所述烷基、烯基、炔基、环烷基、杂环烷基 可选的被1-3个R c取代；
每个R c、R d分别独立的选自氢、卤素、羰基、-C(O)CH 3、羟基、氰基、硝基、C 1-C 6烷基、卤代C 1-C 6烷基、C 3-C 6环烷基或卤代C 3-C 6环烷基；并且
每个n分别独立的选自0、1、2或3。
在另一些实施方案中，通式(I)为通式(Ic)所示的化合物：
Figure PCTCN2021124527-appb-000008
或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其可药用的盐，其中，A 3选自C或N；
R 1选自氢、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、卤素、氰基、硝基、-C(O)NR aR b、-C(O)R a、-C(O)OR a、-OR a、-OC(O)R a、-OC(O)OR a、-OC(O)NR aR b、-NR aR b、-SR a、-S(O)R a、-S(O) 2R a或含有0-3个杂原子的3-10元饱和或非饱和环，所述烷基、烯基、炔基、含有0-3个杂原子的3-10元饱和或非饱和环可选的被1-3个R a取代；
R 2选自氢、C 1-C 6烷基、卤代C 1-C 6烷基、卤素、氰基、-C(O)OR a、-(CH 2) nOR a或-NH 2；
R 3选自氢、C 1-C 6烷基或-OR a；
R 4’选自氢、C 1-C 6烷基、卤代C 1-C 6烷基、C 3-C 6环烷基、卤素或-NH 2；
每个R a、R b分别独立的选自氢、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 6环烷基、C 3-C 6杂环烷基、卤素、羟基、氰基、硝基、-C(O)NR cR d、-C(O)R c、-(CH 2) nC(O)OR c、-OR c、-(CH 2) nOR c、-OC(O)R c、-OC(O)OR c、-OC(O)NR cR d、-NR cR d、-SR c、-S(O)R c或-S(O) 2R c，所述烷基、烯基、炔基、环烷基、杂环烷基可选的被1-3个R c取代；
每个R c、R d分别独立的选自氢、卤素、羰基、-C(O)CH 3、羟基、氰基、硝 基、C 1-C 6烷基、卤代C 1-C 6烷基、C 3-C 6环烷基或卤代C 3-C 6环烷基；并且
每个n分别独立的选自0、1、2或3。
在另一些实施方案中，R 1选自氢、-CH 3、
Figure PCTCN2021124527-appb-000009
Figure PCTCN2021124527-appb-000010
在另一些实施方案中，R 2选自氢、-CH 3、
Figure PCTCN2021124527-appb-000011
Figure PCTCN2021124527-appb-000012
在另一些实施方案中，R 3为
Figure PCTCN2021124527-appb-000013
在另一些实施方案中，R 4为氢、-C(O)CH 3、
Figure PCTCN2021124527-appb-000014
或-C(O)NH 2。
在另一些实施方案中，通式(I)所示的化合物选自：
Figure PCTCN2021124527-appb-000015
Figure PCTCN2021124527-appb-000016
Figure PCTCN2021124527-appb-000017
Figure PCTCN2021124527-appb-000018
Figure PCTCN2021124527-appb-000019
另一方面，本申请还提供前述化合物、其异构体或其药学上可接受的盐用于制备由TYK2介导的疾病药物中的用途。
在一些实施方案中，所述TYK2介导的疾病为自身免疫性疾病，发炎性疾病，增殖性疾病，内分泌疾病，神经系统疾病或与移植相关的疾病。
在另一些实施方案中，所述疾病为自身免疫性疾病。
在另一些实施方案中，所述自身免疫性疾病选自1型糖尿病、强直性脊椎炎、全身性红斑性狼疮症、多发性硬化症、全身性硬化症、牛皮癣、克罗恩氏病、溃疡性结肠炎或发炎性肠病。
在另一些实施方案中，所述疾病为发炎性疾病。
在另一些实施方案中，所述发炎性疾病选自风湿性关节炎、哮喘、慢性阻塞性肺病、牛皮癣、克罗恩氏病、溃疡性结肠炎及发炎性肠病。
另一方面，本申请还提供一种药物组合物，其包含治疗有效量的前述化合物、其异构体或其药学上可接受的盐；以及药学上可接受的载体或赋形剂。
术语：
除非有相反陈述，在说明书和权利要求书中使用的术语具有下述含义。
术语“异构体”包括给定结构的对映异构形式、非对映异构形式和几何(或构象)异构形式。例如，本申请包括每个不对称中心的R和S构型、Z和E双键异构体、Z和E构象异构体、单一立体化学异构体及对映异构体、非对映异构体和几何(或构象)异构体混合物。
术语“药学上可接受的盐”指，诸如其酸加成盐和/或碱盐。合适的酸加成盐由酸形成，其形成无毒盐，例如盐酸盐/氯化物。合适的碱盐由碱形成，其形成无毒盐，例如钙盐和钠盐。还可形成酸和碱的半盐，例如半硫酸盐和半钙盐。
术语“治疗有效量”是指本申请化合物的以下量，其(i)治疗具体的疾病、病症或障碍；(ii)减轻、缓解或消除具体的疾病、病症或障碍的一种或多种症状；或(iii)预防或延迟本申请所述具体的疾病、病症或障碍的一种或多种症状 的发作。
术语“药学上可接受的载体或赋形剂”是指不破坏用其配制的化合物的药理活性的无毒载体、辅料或媒介物。
术语“烷基”指饱和脂肪族烃基团，其为包含1至20个碳原子的直链或支链基团，优选含有1至12个碳原子的烷基，更优选含有1至6个碳原子的烷基。含有1至6个碳原子的低级烷基的非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基等。
术语“烯基”指具有至少一个碳-碳双键的脂族烃，包括具有至少一个碳-碳双键的直链和支链。在一些实施方案中，烯基基团具有2至20个碳原子、2至10个碳原子、2至6个碳原子、3至6个碳原子或2至4个碳原子。例如，术语“C 2-6烯基”包括2至6个碳原子的直链或支链不饱和基团(具有至少一个碳-碳双键)，包括但不限于乙烯基、1-丙烯基、2-丙烯基(烯丙基)、异丙烯基、2-甲基-1-丙烯基、1-丁烯基、2-丁烯基等。
术语“炔基”指具有至少一个碳-碳三键的脂族烃，包括具有至少一个碳-碳三键的直链和支链。在一些实施方案中，炔基基团具有2至20、2至10、2至6、或3至6个碳原子。例如，“C 2-6炔基”包括具有2至6个碳原子的如上定义的直链或支链烃链炔基基团。
术语“烷氧基”指-O-(烷基)和-O-(非取代的环烷基)，其中烷基如上所定义。烷氧基的非限制性实例包括：甲氧基、乙氧基、丙氧基、丁氧基、环丙氧基、环丁氧基、环戊氧基、环己氧基。
术语“环烷基”指饱和或部分不饱和单环或多环环状烃取代基，环烷基环包含3至20个碳原子，优选包含3至12个碳原子，更优选包含3至6个碳原子(例如3、4、5或6个碳原子)，最优选包含5至6个碳原子。单环环烷基的非限制性实例包括环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等；多环环烷基包括螺环、稠环和桥环的环烷基。
术语“螺环烷基”指5至20元的单环之间共用一个碳原子(称螺原子)的多环 基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元(例如7、8、9或10元)。根据环与环之间共用螺原子的数目将螺环烷基分为单螺环烷基、双螺环烷基或多螺环烷基，优选为单螺环烷基和双螺环烷基。更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺环烷基。
术语“稠环烷基”指5至20元，系统中的每个环与体系中的其他环共享毗邻的一对碳原子的全碳多环基团，其中一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠环烷基，优选为双环或三环，更优选为5元/5元或5元/6元双环烷基。
术语“桥环烷基”指5至20元，任意两个环共用两个不直接连接的碳原子的全碳多环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环桥环烷基，优选为双环、三环或四环，更优选为双环或三环。
术语“杂环烷基”指饱和或部分不饱和单环或多环环状烃取代基，其包含3至20个环原子，其中一个或多个环原子为选自氮、氧或S(O)m(其中m是整数0至2)的杂原子，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。优选包含3至12个环原子，其中1～4个是杂原子；最优选包含3至8个环原子，其中1～3个是杂原子；最优选包含5至6个环原子，其中1～2或1～3个是杂原子。单环杂环基的非限制性实例包括吡咯烷基、咪唑烷基、四氢呋喃基、四氢吡喃基、四氢噻吩基、二氢咪唑基、二氢呋喃基、二氢吡唑基、二氢吡咯基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基等，优选四氢吡喃基、哌啶基、吡咯烷基。多环杂环烷基包括螺杂环基、稠杂环基和桥杂环基。
术语“螺杂环基”指5至20元的单环之间共用一个原子(称螺原子)的多环杂环基团，其中一个或多个环原子为选自氮、氧或S(O)m(其中m是整数0至2)的杂原子，其余环原子为碳。其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元。根据环与环之间共用螺原子的数目将螺杂环基分为单螺杂环基、双螺杂环基或多螺杂环基，优选为单螺杂环基和双螺杂环基。更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺杂环基。
术语“稠杂环基”指5至20元，系统中的每个环与体系中的其他环共享毗邻的一对原子的多环杂环基团，一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统，其中一个或多个环原子为选自氮、氧或S(O)m(其中m是整数0至2)的杂原子，其余环原子为碳。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠杂环基，优选为双环或三环，更优选为5元/5元或5元/6元双环稠杂环基。
术语“桥杂环基”指5至14元，任意两个环共用两个不直接连接的原子的多环杂环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统，其中一个或多个环原子为选自氮、氧或S(O)m(其中m是整数0至2)的杂原子，其余环原子为碳。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环桥杂环基，优选为双环、三环或四环，更优选为双环或三环。
术语“芳基”指具有共轭的π电子体系的6至14元全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团，优选为6至10元，例如苯基和萘基。
术语“杂芳基”指包含1至4个杂原子、5至14个环原子的杂芳族体系，其中杂原子选自氧、硫和氮。杂芳基优选为5至10元，含1至3个杂原子；更优选为5元或6元，含1至2个杂原子；优选例如咪唑基、呋喃基、噻吩基、噻唑基、吡唑基、噁唑基、吡咯基、四唑基、吡啶基、嘧啶基、噻二唑、吡嗪基和哒嗪基等。
术语“羟烷基”指被羟基取代的烷基，其中烷基如上所定义。
术语“卤代烷基”指烷基被一个或多个卤素取代，其中烷基如上所定义。
术语“卤代烷氧基”指烷氧基被一个或多个卤素取代，其中烷氧基如上所定义。
术语“氘代烷基”指烷基被一个或多个氘原子取代，其中烷基如上所定义。
术语“氘代烷氧基”指烷氧基被一个或多个氘原子取代，其中烷氧基如上所定义。
术语“环烷基烷基”指烷基被一个或多个环烷基取代，其中环烷基和烷基如上所定义。
术语“环烷基氧基”指-O-环烷基，其中环烷基如上所定义。
术语“杂环基烷基”指烷基被一个或多个杂环基取代，其中杂环基和烷基如上所定义。
术语“芳基烷基”指烷基被一个或多个芳基取代，其中芳基和烷基如上所定义。
术语“羟基”指-OH基团。
术语“卤素”指氟、氯、溴或碘。
术语“氨基”指-NH 2。
术语“氰基”指-CN。
术语“硝基”指-NO 2。
术语“羧基”指-C(O)OH。
具体实施方式
中间体制备
中间体1.1的制备：(R)-2-溴-6-(3-甲氧基四氢呋喃-3-基)-4-甲基吡啶
Figure PCTCN2021124527-appb-000020
步骤一：3-(6-溴-4-甲基吡啶-2-基)四氢呋喃-3-醇的制备。2,6-二溴-4-甲基吡啶(45.0g，179mmol，1.00eq.)溶于DCM(500mL)中，-78℃下滴加n-BuLi(197mmol，78.9mL，1.10eq.)，搅拌1h，加入二氢呋喃-3(2H)-酮(16.98g，197.28mmol，1.1eq.)，-78℃反应0.5h，自然升温至室温反应1h。加入350mL饱和氯化铵溶液，分液后用50mL饱和氯化钠洗涤，浓缩。粗产品通过柱层析纯化(PE/EtOAc＝5:1-1:1)得到标题化合物(31g，收率67％)。MS(m/z)＝258.01[M+H] +。
步骤二：(R)-2-溴-6-(3-甲氧基四氢呋喃-3-基)-4-甲基吡啶的制备。3-(6-溴-4-甲基吡啶-2-基)四氢呋喃-3-醇(29.0g，112mmol，1.00eq.)溶于DMF(180mL)中，加入NaH(3.00g，125mmol，1.1eq.)，CH 3I(17.5g，124mmol，1.1eq.)，25℃反应1.5h。反应液倒入400mL冰水中，EA(100mL*3)萃取，粗产品通过柱层析纯化(PE/EtOAc＝5:1-3:1)后再进行手性拆分得到标题化合物(RT＝2.26min，12g，收率40％)。MS(m/z)＝272.02[M+H] +。
手性拆分条件：
仪器：Waters 200，制备SFC(QC-R-LC-07)；色谱柱：ChiralPak IC,250×30mm I.D.,5μm；
流动相：A为CO 2且B为乙醇(0.1％NH 3H 2O)；梯度：B 15％；流速：70mL/min；背压：100bar；柱温：35℃；波长：254nm；循环时间：～1.5min；间隔时间：0.5min；样品制备：化合物溶于200mL乙醇。
中间体1.2-1.6参考中间体1.1的方法制得。
Figure PCTCN2021124527-appb-000021
Figure PCTCN2021124527-appb-000022
中间体2.1的制备：6-氯-3-乙烯基-1H-吡咯并[3,2-c]吡啶
Figure PCTCN2021124527-appb-000023
步骤一：3-溴-6-氯-1H-吡咯并[3,2-c]吡啶的制备。6-氯-1H-吡咯并[3,2-c]吡啶(20g，131mmol，1.0eq.)溶于DMF(120mL)中，加入NBS(23g，131mmol，1eq.)，25℃反应12h。反应液倒入600mL水中，析出大量固体，过滤，烘干。得到标题化合物(30.3g，99％)。MS(m/z)＝230.92[M+H] +。
步骤二：6-氯-3-乙烯基-1H-吡咯并[3,2-c]吡啶的制备。3-溴-6-氯-1H-吡咯并[3,2-c]吡啶(1.00g，4.32mmol，1eq.)，4,4,5,5-四甲基-2-乙烯基-1,3,2-二氧杂硼 烷(665mg，4.32mmol，1eq.)，Pd(dppf)Cl 2(3.16g，4.32mmol，1eq.)，K 2CO 3(597mg，4.32mmol，1eq.)溶于水(2mL)和二氧六环(10mL)中，氮气保护下100℃反应3h。将反应液旋干，粗产品通过柱层析纯化(PE/EtOAc＝10:1-1:1)得到标题化合物(0.7g，收率90％)。MS(m/z)＝179.03[M+H] +。
中间体2.2-2.9参考中间体2.1的方法制得。
Figure PCTCN2021124527-appb-000024
Figure PCTCN2021124527-appb-000025
中间体3的制备：6-氯-3-环丙基-1H-吡咯并[3,2-c]吡啶的制备
Figure PCTCN2021124527-appb-000026
步骤一：6-氯-3-碘-1H-吡咯并[3,2-c]吡啶的制备。6-氯-1H-吡咯并[3,2-c]吡啶(2.00g，13.1mmol，1eq.)溶于DMF(12mL)中，0℃下分批加入NIS(2.95g，13.1mmol，1eq.)，25℃反应12h。将反应液倒入到60mL水中，析出大量固体，过滤，滤饼烘干得到标题化合物(3.50g，产率96％)。MS(m/z)＝278.91[M+H] +。
步骤二：6-氯-3-碘-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[3,2-c]吡啶的制备。6-氯-3-碘-1H-吡咯并[3,2-c]吡啶(3.50g，12.6mmol，1eq.)于DMF(20mL)，0℃下加入NaH(331mg，13.8mmol，1.1eq.)，搅拌15min，再加入SemCl(2.10g，12.6mmol，1eq.)，25℃反应2h。将反应液倒入到100mL 水中，用50mLEA萃取，分液，有机相干燥过滤。粗产品通过柱层析纯化(PE/EtOAc＝10:1-1:1)得到标题化合物(5g，收率97％)。MS(m/z)＝408.99[M+H] +。
步骤三：6-氯-3-环丙基-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[3,2-c]吡啶的制备。环丙基硼酸(84mg，978μmol，2.0eq.)，6-氯-3-碘-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[3,2-c]吡啶(0.20g，489μmol，1eq.)，三环己基膦(27.4mg，97.9μmol，0.2eq.)，Pd(OAc) 2(11mg，48.9μmol，0.1eq.)溶于甲苯(5mL)和水(0.2mL)的混合溶液中，100℃反应12h。粗产品通过柱层析纯(PE/EtOAc＝10:1-1:1)得到标题化合物(0.15g，收率94％)。MS(m/z)＝323.13[M+H] +。
步骤四：6-氯-3-环丙基-1H-吡咯并[3,2-c]吡啶的制备。6-氯-3-环丙基-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[3,2-c]吡啶(0.15g，464μmol，1eq.)溶于10mL四丁基氟化铵的THF(1M)溶液中，回流10h。加水并用EA萃取，粗产品通过柱层析纯化(PE/EtOAc＝10:1-1:1)得到标题化合物(0.10g，收率94％)。MS(m/z)＝193.05[M+H] +。
中间体4的制备：6-氯-3-(1-甲基-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[3,2-c]吡啶
Figure PCTCN2021124527-appb-000027
6-氯-1H-吡咯并[3,2-c]吡啶(370mg，3.28mmol，1eq.)溶于MeOH(5mL)中，加入KOH(184mg，3.28mmol，1eq.)，1-甲基哌啶-4-酮(370mg，3.28mmol，1eq.)，70℃反应12h。将反应液浓缩，加入50mL水和100mL EA，分液并浓缩有机相得到标题化合物(0.70g，收率86％)。MS(m/z)＝248.09[M+H] +。
中间体5的制备：3-(6-氯-1H-吡咯并[3,2-c]吡啶-3-基)-1-甲基氮杂环丁烷-3-醇
Figure PCTCN2021124527-appb-000028
6-氯-1H-吡咯并[3,2-c]吡啶(279mg，2.29mmol，0.7eq.)溶于MeOH(5mL)中，加入KOH(184mg，3.28mmol，1eq.)，1-甲基氮杂环丁烷-3-酮盐酸盐(370mg，3.28mmol，1eq.)，70℃反应12h。将反应液浓缩，加入50mL水和100mL EA，分液并浓缩有机相得到标题化合物(0.20g，收率26％)。MS(m/z)＝238.07[M+H] +。
中间体6的合成：3-(6-氯-1H-吡唑并[4,3-c]吡啶-3-基)双环[1.1.1]戊烷-1-腈
Figure PCTCN2021124527-appb-000029
步骤一：3-氰基-N-甲氧基-N-甲基双环[1.1.1]戊烷-1-羧酰胺的制备。3-氰基双环[1.1.1]戊烷-1-羧酸(2.00g，14.6mmol，1eq.)，N,O-二甲基羟胺盐酸盐(1.42g，14.6mmol，1eq.)，HATU(6.65g，17.5mmol，1.20eq.)，DIEA(3.77g，29.2mmol，2.00eq.)溶于DCM(20mL)中，20℃反应12h。反应液加入10mL柠檬酸，分液后用饱和碳酸钠10mL洗一次，再用10mL饱和氯化钠洗一次，浓缩得到标题化合物(2g，收率76％)。
步骤二：3-(4,6-二氯烟酰基)双环[1.1.1]戊烷-1-腈的制备。5-溴-2,4-二氯吡啶(2.10g，9.25mmol，1eq.)溶于THF(20mL)，-78℃下滴加异丙基氯化镁(10.2mmol，5.09mL，1.1eq.)，反应2h，然后-78℃滴加3-氰基-N-甲氧基-N-甲基双环[1.1.1]戊烷-1-羧酰胺(2.00g，11.10mmol，1.20eq.)，自然升至室温，反应10h。反应液中加入20mL饱和氯化铵溶液，分液后浓缩。粗产品通过柱层析纯化(PE/EtOAc＝10:1-1:1)得到标题化合物(1.5g，收率60％)。MS(m/z)＝267.00[M+H] +。
步骤三：3-(6-氯-1H-吡唑并[4,3-c]吡啶-3-基)双环[1.1.1]戊烷-1-腈的制备。3-(4,6-二氯烟酰基)双环[1.1.1]戊烷-1-腈(1.50g，5.62mmol，1eq.)溶于THF(20mL)中，25℃加入水合肼(562mg，8.42mmol，1.5eq.)，反应12h后，将反应液倒入到10mL水中，加入10mL EA萃取，粗产品通过柱层析纯化(PE/EtOAc＝10:1-2:1)得到标题化合物(1.00g，产率72.8％)。MS(m/z)＝245.05[M+H] +。
中间体7的合成：3-(6-氯-1H-吡咯并[3,2-c]吡啶-3-基)氮杂环丁烷-1-羧酸叔丁酯
Figure PCTCN2021124527-appb-000030
步骤一：参考中间体2步骤二的方法制得3-溴-6-氯-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[3,2-c]吡啶。MS(m/z)＝361.01[M+H] +。
步骤二：3-(6-氯-1-((2-(三甲基甲硅烷基)乙氧基)甲基)叔丁基-1-吡咯并[3,2-c]吡啶-3-基)-3-羟基氮杂环丁烷-1-羧酸酯的制备。3-溴-6-氯-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[3,2-c]吡啶(5.00g，13.8mmol，1eq.)溶于THF(30mL)中，-78℃下滴加n-BuLi(14.5mmol，3.20mL，1.05eq.)，-78℃保温1h，再滴加3-氧代氮杂环丁烷-1-羧酸叔丁酯(2.37g，13.8mmol，1eq.)，-78℃反应1h，反应液用饱和氯化铵淬灭，粗产品通过柱层析纯化(PE/EtOAc＝10:1-2:1)。得到标题化合物(3.50g，产率55.8％)。MS(m/z)＝454.19[M+H] +。
步骤三：3-(6-氯-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[3,2-c]吡啶-3-基)-3-(((甲硫基)碳硫基)氧)氮杂环丁烷-1-羧酸叔丁酯的制备。3-(6-氯-1-((2-(三甲基甲硅烷基)乙氧基)甲基)叔丁基-1-吡咯并[3,2-c]吡啶-3-基)-3-羟基氮杂环丁烷-1-羧酸酯(3.50g，7.71mmol，1eq.)溶于THF(50mL)中，-78℃下加入NaHMDS(2.83g，15.4mmol，2.0eq.)，CS 2(1.17g，15.4mmol，2.0eq.)，-78℃ 反应1h，加入CH 3I(2.19g，15.4mmol，2.0eq.)后，20℃反应2h。反应液用50mL饱和氯化铵溶液淬灭，再用50mL EA萃取，粗产品通过柱层析纯化(PE/EtOAc＝10:1-3:1)得到标题化合物(3.00g，产率71.51％)。MS(m/z)＝544.14[M+H] +。
步骤四：3-(6-氯-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1-吡咯并[3,2-c]吡啶-3-基)氮杂环丁烷-1-羧酸叔丁酯的制备。3-(6-氯-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[3,2-c]吡啶-3-基)-3-(((甲硫基)碳硫基)氧)氮杂环丁烷-1-羧酸叔丁酯的制备(3.00g，5.51mmol，1eq.)溶于甲苯(60mL)中，加入AIBN(90.5mg，551μmol,0.1eq.)，Bu 3SnH(2.41g，8.27mmol，1.5eq.)，氮气保护下85℃反应3h。粗产品通过柱层析纯化(PE/EtOAc＝10:1-3:1)得到无色液体(2.0g，收率82％)。MS(m/z)＝438.19[M+H] +。
步骤五：3-(6-氯-1H-吡咯并[3,2-c]吡啶-3-基)氮杂环丁烷-1-羧酸叔丁酯的制备。3-(6-氯-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1-吡咯并[3,2-c]吡啶-3-基)氮杂环丁烷-1-羧酸叔丁酯(2.0g，1.0eq.)溶于四丁基氟化铵的THF溶液(20mL)中，80℃反应5h。反应液加入50mL水，用50mL EA萃取，分液并浓缩，粗产品通过柱层析纯化(PE/EtOAc＝50:1-1:1)得到标题化合物(1.00g，产率71.16％)。MS(m/z)＝308.11[M+H] +。
中间体8的合成：6-(6-氯-1H-吡咯并[3,2-c]吡啶-3-基)-2-氮杂螺[3.3]庚烷-2-羧酸叔丁酯
Figure PCTCN2021124527-appb-000031
中间体8参考中间体7的方法制得。MS(m/z)＝348.14[M+H] +。
实施例1：N-(1-(6-(3-甲氧基四氢呋喃-3-基)-4-甲基吡啶-2-基)-3-乙烯基-1H-吡咯并[3,2-c]吡啶-6-基)乙酰胺
Figure PCTCN2021124527-appb-000032
步骤一：3-溴-6-氯-1H-吡咯并[3,2-c]吡啶的制备。6-氯-1H-吡咯并[3,2-c]吡啶(20g，131mmol，1.0eq.)溶于DMF(120mL)中，加入NBS(23g，131mmol，1eq.)，25℃反应12h。反应液倒入600mL水中，析出大量固体，过滤，烘干。得到标题化合物(30.3g，99％)。MS(m/z)＝230.92[M+H] +。
步骤二：6-氯-3-乙烯基-1H-吡咯并[3,2-c]吡啶的制备。3-溴-6-氯-1H-吡咯并[3,2-c]吡啶(1.00g，4.32mmol，1eq.)，4,4,5,5-四甲基-2-乙烯基-1,3,2-二氧杂硼烷(665mg，4.32mmol，1eq.)，Pd(dppf)Cl 2(3.16g，4.32mmol，1eq.)，K 2CO 3(597mg，4.32mmol，1eq.)溶于水(2mL)和二氧六环(10mL)中，氮气保护下100℃反应3h。将反应液旋干，粗产品通过柱层析纯化(PE/EtOAc＝10:1-1:1)得到标题化合物(0.7g，收率90％)。MS(m/z)＝179.03[M+H] +。
步骤三：6-氯-1-(6-(3-甲氧基四氢呋喃-3-基)-4-甲基吡啶-2-基)-3-乙烯基-1H-吡咯并[3,2-c]吡啶的制备。2-溴-6-(3-甲氧基四氢呋喃-3-基)-4-甲基吡啶(152mg，559μmol，1eq.)，6-氯-3-乙烯基-1H-吡咯并[3,2-c]吡啶(0.1g，559μmol，1eq.)，K 2CO 3(232mg，1.68mmol，3.0eq.)，CuI(5.33mg，27.99μmol，0.05eq.)，N,N-二甲基乙二胺(4.94mg，56μmol，0.1eq.)溶于1,4-二氧六环(30mL)中，氮气保护下回流反应12h。将反应液旋干，粗产品通过柱层析纯化(PE/EtOAc＝5:1-1:1)得到标题化合物(0.2g，收率97％)。MS(m/z)＝370.12[M+H] +。
步骤四：N-(1-(6-(3-甲氧基四氢呋喃-3-基)-4-甲基吡啶-2-基)-3-乙烯基-1H-吡咯并[3,2-c]吡啶-6-基)乙酰胺的制备。6-氯-1-(6-(3-甲氧基四氢呋喃-3-基)-4-甲基吡啶-2-基)-3-乙烯基-1H-吡咯并[3,2-c]吡啶(0.20g，540μmol，1eq.)，乙酰胺(47.9mg，811μmol，1.5eq.)，Cs 2CO 3(528mg，1.62mmol，3.0eq.)，Pd 2(dba) 3 (49.5mg，54.1μmol，0.1eq.)，X-phos(52mg，108μmol，0.2eq.)溶于1,4-二氧六环(30mL)中，氮气保护下回流反应12h。将反应液旋干，粗产品通过柱层析纯化(PE/EtOAc＝2:1-0:1)得到标题化合物(0.2g，收率94％)。MS(m/z)＝393.18[M+H] +。 1H NMR(400MHz,DMSO)δ10.45(s,1H),9.08(s,1H),8.94(s,1H),8.19(s,1H),7.56(s,1H),7.34(s,1H),6.92(dd,1H),5.92(d,1H),5.33(d,1H),4.20(d,1H),4.08–3.82(m,3H),3.15(s,3H),2.74–2.62(m,1H),2.47(s,4H),2.11(s,3H)。
实施例2-20的化合物参考实施例1的方法制得。
Figure PCTCN2021124527-appb-000033
Figure PCTCN2021124527-appb-000034
Figure PCTCN2021124527-appb-000035
Figure PCTCN2021124527-appb-000036
Figure PCTCN2021124527-appb-000037
Figure PCTCN2021124527-appb-000038
Figure PCTCN2021124527-appb-000039
Figure PCTCN2021124527-appb-000040
实施例21：N-(3-乙基-1-(6-(3-甲氧基四氢呋喃-3-基)-4-甲基吡啶-2-基)-1H-吡咯并[3,2-c]吡啶-6-基)乙酰胺
Figure PCTCN2021124527-appb-000041
N-(1-(6-(3-甲氧基四氢呋喃-3-基)-4-甲基吡啶-2-基)-3-乙烯基-1H-吡咯并[3,2-c]吡啶-6-基)乙酰胺(0.05g，127μmol，1eq.)溶于MeOH(10mL)中，氢气置换三次，20℃反应12h。反应液过滤粗产品通过柱层析纯化(PE/EtOAc＝2:1-0:1)得到标题化合物(0.05g，收率99％)。MS(m/z)＝395.20[M+H] +。 1H NMR(400MHz,DMSO)δ10.38(s,1H),9.06(s,1H),8.63(s,1H),7.80(s,1H),7.53(s,1H),7.27(s,1H),4.20(d,1H),4.05–3.88(m,3H),3.14(s,3H),2.80(q,2H),2.68(dt,1H),2.46(s,4H),2.10(s,3H),1.35(t,3H)。
实施例22-27的化合物参考实施例21的方法制得。
Figure PCTCN2021124527-appb-000042
Figure PCTCN2021124527-appb-000043
Figure PCTCN2021124527-appb-000044
实施例28a或实施例28b：N-(3-((1s，3s)-3-氰基环丁基)-1-(6-(3-甲氧基四氢呋喃-3-基)-4-甲基吡啶-2-基)-1H-吡咯并[3,2-c]吡啶-6-基)乙酰胺或N-(3-((1r，3r)-3-氰基环丁基)-1-(6-(3-甲氧基四氢呋喃-3-基)-4-甲基吡啶-2-基)-1H-吡咯并[3,2-c]吡啶-6-基)乙酰胺
Figure PCTCN2021124527-appb-000045
步骤一：3-溴-6-氯-1H-吡咯并[3,2-c]吡啶-1-羧酸叔丁酯的制备。3-溴-6-氯-1H-吡咯并[3,2-c]吡啶(2.00g，8.64mmol，1eq.)，(Boc) 2O(1.89g，8.64mmol，1.0eq.)，DMAP(105mg，864μmol，0.1eq.)，TEA(1.31g，12.9mmol，1.5eq.)溶于THF(20mL)中，25℃反应1h。粗产品通过柱层析纯化(PE/EtOAc＝10:1-3:1)得到标题化合物(2.80g，97.7％)。MS(m/z)＝330.98[M+H] +。
步骤二：6-氯-3-(3-氰基-1-羟基环丁基)-1H-吡咯并[3,2-c]吡啶-1-羧酸叔丁酯的制备。3-溴-6-氯-1H-吡咯并[3,2-c]吡啶-1-羧酸叔丁酯(2.80g，8.44mmol，1eq.)溶于THF(30mL)中，-78℃下滴加n-BuLi(8.87mmol，3.20mL，1.05eq.)，-78℃保温1h，再滴加3-氧代环丁腈(883mg，9.29mmol，1.1eq.)，-78℃反应1h。反应液用饱和氯化铵淬灭，分液后干燥，过滤浓缩。粗产品通过柱层析纯化(PE/EtOAc＝5:1-1:1)得到标题化合物(2.00g，68.10％)。MS(m/z)＝348.10[M+H] +。
步骤三：3-(6-氯-1H-吡咯并[3,2-c]吡啶-3-基)环丁烷-1-腈的制备。6-氯-3-(3-氰基-1-羟基环丁基)-1H-吡咯并[3,2-c]吡啶-1-羧酸叔丁酯(2.00g，5.75mmol，1eq.)，Et 3SiH(6.69g，57.5mmol，10.0eq.)，TFA(6.56g，57.5mmol，10.0eq.) 溶于DCM(30mL)中，25℃反应1h。反应液旋干，加入10mL饱和碳酸钠溶液和10mL乙酸乙酯，分液后有机相干燥过滤并浓缩得到标题化合物(1.00g，75.06％)。MS(m/z)＝232.06[M+H] +。
步骤四：3-(6-氯-1-(6-(3-甲氧基四氢呋喃-3-基)-4-甲基吡啶-2-基)-1H-吡咯并[3,2-c]吡啶-3-基)环丁烷-1-腈的制备。2-溴-6-(3-甲氧基四氢呋喃-3-基)-4-甲基吡啶(1.17g，4.32mmol，1eq.)，3-(6-氯-1H-吡咯并[3,2-c]吡啶-3-基)环丁烷-1-腈(1.00g，4.32mmol，1eq.)，K 2CO 3(1.79g，12.9mmol，3.0eq.)，CuI(1.10mg，216μmol，0.05eq.)，N,N-二甲基乙二胺(38.1mg，431μmol，0.1eq.)溶于1,4-二氧六环(30mL)中，氮气保护下回流反应12h。将反应液旋干，粗产品通过柱层析纯化(PE/EtOAc＝5:1-1:1)得到标题化合物(1g，收率55％)。MS(m/z)＝423.15[M+H] +。
步骤五：N-(3-(3-氰基环丁基)-1-(6-(3-甲氧基四氢呋喃-3-基)-4-甲基吡啶-2-基)-1H-吡咯并[3,2-c]吡啶-6-基)乙酰胺的制备。3-(6-氯-1-(6-(3-甲氧基四氢呋喃-3-基)-4-甲基吡啶-2-基)-1H-吡咯并[3,2-c]吡啶-3-基)环丁烷-1-腈(1.00g，2.36mmol，1eq.)，乙酰胺(209mg，3.55mmol，1.5eq.)，Cs 2CO 3(2.31g，7.09mmol，3.0eq.)，Pd 2(dba) 3(216mg，236μmol，0.1eq.)，X-phos(225mg，473μmol，0.2eq.)溶于1,4-二氧六环(50mL)中，氮气保护下回流反应12h。将反应液旋干，粗产品通过柱层析纯化(EtOAc)得到标题化合物(0.2g，收率19％)。MS(m/z)＝446.21[M+H] +。
步骤六：步骤五所得化合物经制备型TLC纯化(展开剂：EtOAc，R f 1＝0.43，R f 2＝0.36)得实施例28a和实施例28b的化合物。 1H NMR(400MHz,DMSO)δ10.38(s,1H),9.07(s,1H),8.58(s,1H),8.02(s,1H),7.61(s,1H),7.30(s,1H),4.21(d,J＝9.7Hz,1H),4.09–3.94(m,2H),3.92(d,1H),3.81(dt,1H),3.51–3.37(m,1H),3.15(s,3H),2.87(ddd,2H),2.68(dt,2H),2.57(dd,2H),2.47(s,3H),2.10(s,3H)。 1H NMR(400MHz,DMSO)δ10.40(s,1H),9.07(s,1H),8.61(s,1H),7.99(s,1H),7.58(s,1H),7.30(s,1H),4.21(d,J＝9.7Hz,1H),4.08–3.86(m,4H),3.53(ddd,1H),3.15(s,3H),2.87–2.75(m,2H),2.72–2.58(m,3H),2.47(s,4H),2.10(s,3H)。
实施例29a和实施例29b参考实施例28a和实施例28b类似方法制得(展开剂：EtOAc，R f 1＝0.43，R f 2＝0.36)。
Figure PCTCN2021124527-appb-000046
实施例30：(R)-2-(4-(6-乙酰氨基-1-(6-(3-甲氧基四氢呋喃-3-基)-4-甲基吡啶-2-基)-1H-吡咯并[3,2-c]吡啶-3-基)环己基)乙酸
Figure PCTCN2021124527-appb-000047
步骤一：(R)-2-(4-(6-乙酰氨基-1-(6-(3-甲氧基四氢呋喃-3-基)-4-甲基吡啶-2-基)-1H-吡咯并[3,2-c]吡啶-3-基)环己基)乙酸乙酯的制备。2-(4-(6-乙酰胺基-1-(6-((R)-3-甲氧基四氢呋喃-3-基)-4-甲基吡啶-2-基)-1H-吡咯并[3,2-c]吡啶-3-基)环己-3-烯-1-基)乙酸乙酯由中间体2.5和中间体1.1经实施例1类似的方法制得，再经实施例22类似的方法，制得标题化合物。MS(m/z)＝535.28[M+H] +。
步骤二：(R)-2-(4-(6-乙酰氨基-1-(6-(3-甲氧基四氢呋喃-3-基)-4-甲基吡啶-2-基)-1H-吡咯并[3,2-c]吡啶-3-基)环己基)乙酸的制备。(R)-2-(4-(6-乙酰氨基-1-(6-(3-甲氧基四氢呋喃-3-基)-4-甲基吡啶-2-基)-1H-吡咯并[3,2-c]吡啶-3-基)环己基)乙酸乙酯(0.30g，561μmol，1eq.)，LiOH·H 2O(47.1mg，1.12mmol，2.0eq.)溶于H 2O(3mL)和THF(9mL)中，20℃反应12h。反应液旋出THF，剩余液体，用1N HCl调至pH为5，析出大量固体，过滤，滤饼烘干。得到标题化合物(0.2g，收率70％)。MS(m/z)＝507.25[M+H] +。 1H NMR(400MHz,DMSO)δ10.38(d,1H),9.06(s,1H),8.66(d,1H),7.75(d,1H),7.58(d,1H),7.27(s,1H),4.21(d,1H),4.05–3.77(m,3H),3.16(s,3H),2.94(s,1H),2.79(s,1H),2.72–2.59(m,2H),2.46(s,3H),2.21–2.02(m,5H),2.00–1.92(m,2H),1.88(d,1H),1.80(d,3H),1.68–1.47(m,2H)。
实施例31参考实施例30类似方法制得。
Figure PCTCN2021124527-appb-000048
Figure PCTCN2021124527-appb-000049
实施例32：(R)-N-(1-(6-(3-甲氧基四氢呋喃-3-基)-4-甲基吡啶-2-基)-3-(哌啶-4-基)-1H-吡咯并[3,2-c]吡啶-6-基)乙酰胺
Figure PCTCN2021124527-appb-000050
步骤一：(R)-4-(6-乙酰胺基-1-(6-(3-甲氧基四氢呋喃-3-基)-4-甲基吡啶-2-基)-1H-吡咯并[3,2-c]吡啶-3-基)哌啶-1-羧酸叔丁酯的制备。(R)-4-(6-乙酰胺基-1-(6-(3-甲氧基四氢呋喃-3-基)-4-甲基吡啶-2-基)-1H-吡咯并[3,2-c]吡啶-3-基)-3,6-二氢吡啶-1(2H)-羧酸叔丁酯由中间体2.7和中间体1.1经实施例1类似的方法制得，再经实施例22类似的方法，制得标题化合物。MS(m/z)＝550.30[M+H] +。
步骤二：(R)-N-(1-(6-(3-甲氧基四氢呋喃-3-基)-4-甲基吡啶-2-基)-3-(哌啶-4-基)-1H-吡咯并[3,2-c]吡啶-6-基)乙酰胺的制备。(R)-4-(6-乙酰胺基-1-(6-(3-甲氧基四氢呋喃-3-基)-4-甲基吡啶-2-基)-1H-吡咯并[3,2-c]吡啶-3-基)哌啶-1-羧酸叔丁酯(500mg，909μmol，1eq.)溶于DCM(5mL)和TFA(1mL)中，20℃反应1h。反应液用饱和碳酸钠调至pH为10，加入20mLEA萃取，分液并旋干。得到标题化合物(0.2g，收率49％)。MS(m/z)＝450.24[M+H] +。 1H NMR(400MHz,DMSO)δ10.40(s,1H),9.05(s,1H),8.72(s,1H),7.77(s,1H),7.56(s,1H),7.29(s,1H),4.20(d,1H),4.08–3.85(m,4H),3.19–3.07(m,5H),3.00(t,1H),2.77(t,2H),2.69–2.61(m,2H),2.46(s,3H),2.10(s,3H),2.01(d,2H),1.70(dd,2H)。
实施例33参考实施例32类似方法制得。
Figure PCTCN2021124527-appb-000051
实施例34a或34b：N-(3-((1s，4S)-4-氨基环己基)-1-(6-((R)-3-甲氧基四氢呋喃-3-基)-4-甲基吡啶-2-基)-1H-吡咯并[3,2-c]吡啶-6-基)乙酰胺或N-(3-((1r，4R)-4-氨基环己基)-1-(6-((R)-3-甲氧基四氢呋喃-3-基)-4-甲基吡啶-2-基)-1H-吡咯并[3,2-c]吡啶-6-基)乙酰胺
Figure PCTCN2021124527-appb-000052
实施例34a和34b由实施例33化合物经手性拆分制得(RT 1＝3.38min，RT 2＝4.19min)。
手性拆分条件：
仪器：Waters 200，制备SFC(QC-R-LC-07)；色谱柱：ChiralPak IC,250×30mm I.D.,5μm；流动相：A为CO 2且B为乙醇(0.1％NH 3H 2O)；梯度：B 30％；流速：70mL/min；背压：100bar；柱温：35℃；波长：210nm；循环时间：～4min；间隔时间：0.5min；样品制备：化合物溶于200mL乙醇。
1H NMR(400MHz,DMSO)δ10.37(s,1H),9.05(s,1H),8.70(s,1H),7.78(s,1H),7.56(s,1H),7.29(s,1H),4.20(d,1H),4.10–3.82(m,3H),3.78–3.54(m,4H),3.16(s,3H),2.97(s,1H),2.73–2.60(m,1H),2.46(s,3H),2.10(s,3H),1.99(t,2H),1.83–1.60(m,4H),1.40(d,2H)。MS(m/z)＝464.26[M+H] +。
1H NMR(400MHz,DMSO)δ10.37(s,1H),9.04(s,1H),8.70(s,1H),7.75(s,1H),7.54(s,1H),7.28(s,1H),4.20(d,1H),4.07–3.87(m,3H),3.71(s,1H),3.64(d,1H),3.14(s,3H),2.67(dd,4H),2.45(s,3H),2.10(s,3H),2.06(s,2H),1.97–1.84(m,2H),1.60(dd,2H),1.33(d,2H)。MS(m/z)＝464.26[M+H] +。
实施例35：(R)-N-(3-(1-乙基哌啶-4-基)-1-(6-(3-甲氧基四氢呋喃-3-基)-4-甲基吡啶-2-基)-1H-吡咯并[3,2-c]吡啶-6-基)乙酰胺
Figure PCTCN2021124527-appb-000053
(R)-N-(1-(6-(3-甲氧基四氢呋喃-3-基)-4-甲基吡啶-2-基)-3-(哌啶-4-基)-1H-吡咯并[3,2-c]吡啶-6-基)乙酰胺(100mg，222μmol，1eq.)溶于37％乙醛水溶液(2.73mL)和DCM(2.27mL)中，搅拌1h，然后加入STAB(377mg，445μmol，2.0eq.)，20℃反应14h反应液用饱和碳酸钠调至pH为10，加入20mL EA萃取，分液，有机相干燥，过滤，旋干得到标题化合物(0.1g，收率94％)。MS(m/z)＝478.27[M+H] +。 1H NMR(400MHz,DMSO)δ10.41(s,1H),9.05(s,1H),8.84(s,1H),7.83(s,1H),7.57(s,1H),7.31(s,1H),4.20(d,1H),3.98(ddd,3H),3.59(s,2H),3.15(s,7H),2.66(dt,2H),2.47(s,4H),2.25(d,2H),2.11(s,5H),1.36–1.21(m,3H)。
实施例36a：(R)-N-(3-(氮杂环丁烷-3-基)-1-(6-(3-甲氧基四氢呋喃-3-基)-4-甲基吡啶-2-基)-1H-吡咯并[3,2-c]吡啶-6-基)乙酰胺和实施例36b：(R)-N-(1-(6-(3-甲氧基四氢呋喃-3-基)-4-甲基吡啶-2-基)-3-(1-甲基氮杂环丁烷-3-基)-1H-吡咯并[3,2-c]吡啶-6-基)乙酰胺
Figure PCTCN2021124527-appb-000054
参考实施例1和实施例35的方法，得到标题化合物。
36a：MS(m/z)＝422[M+H] +。 1H NMR(400MHz,DMSO)δ10.39(s,1H),9.06(s,1H),8.76(s,1H),7.93(s,1H),7.56(s,1H),7.29(s,1H),4.20(d,1H),4.13(t,1H),4.02(m,2H),3.91(m,3H),3.80(m,2H),3.33(s,1H),3.14(s,3H),2.68(m,1H),2.49(m,4H),2.11(s,3H)。
36b：MS(m/z)＝436.23[M+H] +。 1H NMR(400MHz,DMSO)δ10.42(s,1H),9.07(s,1H),8.68(s,1H),8.17(s,1H),7.56(s,1H),7.34(s,1H),4.39(s,2H),4.31–4.19(m,2H),4.12(s,2H),3.98(ddd,3H),3.15(s,3H),2.83(s,3H),2.68(dt,1H),2.49(s,4H),2.11(s,3H)。
实施例37a：(R)-N-(1-(6-(3-甲氧基四氢呋喃-3-基)-4-甲基吡啶-2-基)-3-(2-氮杂螺[3.3]庚-6-基)-1H-吡咯并[3,2-c]吡啶-6-基)乙酰胺和实施例37b：(R)-N-(1-(6-(3-甲氧基四氢呋喃-3-基)-4-甲基吡啶-2-基)-3-(2-甲基-2-氮杂螺[3.3]庚基-6-基)-1H-吡咯并[3,2-c]吡啶-6-基)乙酰胺
Figure PCTCN2021124527-appb-000055
参考实施例1和实施例35的方法，得到标题化合物。
37a：MS(m/z)＝462[M+H] +。 1H NMR(400MHz,DMSO)δ10.40(s,1H),9.04(s,1H),9.00(s,1H),8.56(s,1H),7.86(s,1H),7.56(s,1H),7.29(s,1H),4.19(d,1H),4.13(m,1H),3.98(m,5H),3.60(m,1H),3.33(s,1H),3.14(s,3H),2.76(m,2H),2.68(m,1H),2.49(m,6H),2.10(s,3H)。
37b：MS(m/z)＝476.26[M+H] +。 1H NMR(400MHz,DMSO)δ10.35(s,1H),9.04(s,1H),8.55(s,1H),7.85(s,1H),7.55(s,1H),7.29(s,1H),4.31–4.19(m,8H),3.14-3.20(m,4H),2.83(s,3H),2.52-2.68(m,5H),2.49(s,4H),2.11(s,3H)。
实施例38：(R)-N-(3-(1-乙酰基哌啶-4-基)-1-(6-(3-甲氧基四氢呋喃-3-基)-4-甲基吡啶-2-基)-1H-吡咯并[3,2-c]吡啶-6-基)乙酰胺
Figure PCTCN2021124527-appb-000056
(R)-N-(1-(6-(3-甲氧基四氢呋喃-3-基)-4-甲基吡啶-2-基)-3-(哌啶-4-基)-1H-吡咯并[3,2-c]吡啶-6-基)乙酰胺(0.30g，739μmol，1eq.)溶于DCM(10mL)，加入TEA(149mg，1.48mmol，2.0eq.)和乙酰氯(69.7mg，888μmol，1.2eq.)，20℃反应1h后反应液泼入到10mL水中，分液旋干得到标题化合物(0.3g，收率82％)。MS(m/z)＝492.25[M+H] +。 1H NMR(400MHz,CDCl 3)δ8.94(s,1H),8.59(s,1H),8.21(s,1H),7.43(s,1H),7.29(s,1H),7.21(s,1H),4.11-4.30(m,4H),3.05-3.25(m,4H),2.75-2.85(m,6H),1.80-2.50(m,13H)。
实施例39-40参考实施例38类似方法制得。
Figure PCTCN2021124527-appb-000057
Figure PCTCN2021124527-appb-000058
实施例41a或实施例41b：N-(7-((1s，3S)-3-氰基环丁基)-5-(6-((R)-3-甲氧基四氢呋喃-3-基)-4-甲基吡啶-2-基)-7H-吡咯并[2,3-c]哒嗪-3-基)乙酰胺或N-(7-((1r，3R)-3-氰基环丁基)-5-(6-((R)-3-甲氧基四氢呋喃-3-基)-4-甲基吡啶-2-基)-7H-吡咯并[2,3-c]哒嗪-3-基)乙酰胺
Figure PCTCN2021124527-appb-000059
步骤一：5-溴-3-氯-7H-吡咯并[2,3-c]哒嗪的制备。3-氯-7H-吡咯并[2,3-c]哒嗪(2.00g，13.0mmol，1eq.)溶于DMF(12mL)中，加入NBS(2.32g，13.0mmol，1eq.)，20℃反应2h。反应液倒入到60mL水中，析出大量固体，过滤，滤饼烘干得到标题化合物(3g，收率99％)。MS(m/z)＝231.92[M+H] +。
步骤二：3-氰基环丁基甲磺酸酯的制备。3-羟基环丁腈(1.50g，15.4mmol，1eq.)，MsCl(2.12g，18.5mmol，1.2eq.)，TEA(2.34g，23.1mmol，1.5eq.)溶于DCM(20mL)中，20℃反应2h。反应液倒入到10mL水中，分液并浓缩得到标题化合物(2.7g，收率99％)。
步骤三：3-(5-溴-3-氯-7H-吡咯并[2,3-c]哒嗪-7-基)环丁烷-1-腈的制备。5-溴-3-氯-7H-吡咯并[2,3-c]哒嗪(1.19g，5.14mmol，1eq.)，3-氰基环丁基甲磺酸酯(2.70g，15.4mmol，3.0eq.)，Cs 2CO 3(3.35g，10.2mmol，2.0eq.)溶于DMF(10mL)中，80℃反应12h。反应液倒入50mL水中，析出大量固体，过滤，滤饼烘干得到标题化合物(1.2g，收率75％)。MS(m/z)＝310.96[M+H] +。
步骤四：(R)-3-(3-氯-5-(6-(3-甲氧基四氢呋喃-3-基)-4-甲基吡啶-2-基)-7H-吡咯并[2,3-c]哒嗪-7-基)环丁烷-1-腈的制备。3-(5-溴-3-氯-7H-吡咯并[2,3-c]哒嗪-7-基)环丁烷-1-腈(500mg，1.60mmol，1eq.)，偶联硼酸频哪醇酯(407mg，1.60 mmol，1.0eq.)，Pd(dppf)Cl 2DCM(131mg，160μmol，0.1eq.)，乙酸钾(315mg，3.21mmol，2.0eq)溶于10mL二氧六环中，氮气保护下110℃反应2h，反应降至室温，加入磷酸钾(681mg，3.21mmol，2.0eq)，10mL二氧六环，2-溴-6-(3(R)-甲氧基-四氢呋喃-3-基)-4-甲基-吡啶(437mg，1.60mmol，1eq)和水(2mL)，继续110℃反应1h。反应液直接制砂，粗产品通过柱层析纯化(PE/EtOAc＝2:1-1:1)得到类白色固体为标题化合物(0.5g，收率74％)。MS(m/z)＝424.15[M+H] +。
步骤五：(R)-N-(7-(3-氰基环丁基)-5-(6-(3-甲氧基四氢呋喃-3-基)-4-甲基吡啶-2-基)-7H-吡咯并[2,3-c]哒嗪-3-基乙酰胺的制备。(S)-3-(3-氯-5-(6-(3-甲氧基四氢呋喃-3-基)-4-甲基吡啶-2-基)-7H-吡咯并[2,3-c]哒嗪-7-基)环丁烷-1-腈(500mg，1.18mmol，1eq.)，碳酸铯(1.15g，3.54mmol，3.0eq.)，乙酰胺(104mg，1.77mmol，1.5eq.)，Pd 2(dba) 3(108mg，118μmol，0.1eq.)，X-phos(23.0mg，236μmol，0.2eq.)溶于1,4-二氧六环(5mL)中，氮气保护下110℃反应15h。粗产品通过柱层析纯化(EtOAc)得到标题化合物(0.1g，收率19％)。MS(m/z)＝447.21[M+H] +。
步骤六：步骤五所得化合物经制备型TLC纯化(展开剂：EtOAc，R f 1＝0.45，R f 2＝0.42)得实施例41a和实施例41b的化合物。 1H NMR(400MHz,DMSO)δ10.93(s,1H),9.34(s,1H),8.95(s,1H),7.72(s,1H),7.20(s,1H),5.86–5.63(m,1H),4.27–4.15(m,1H),4.08–3.97(m,2H),3.89(d,1H),3.68–3.53(m,1H),3.21–3.06(m,5H),3.01–2.88(m,2H),2.72(dt,1H),2.42(s,4H),2.18(s,3H)。 1H NMR(400MHz,DMSO)δ10.93(s,1H),9.35(s,1H),9.11(s,1H),7.78(s,1H),7.20(s,1H),5.58–5.47(m,1H),4.21(d,1H),4.08–3.97(m,2H),3.89(d,1H),3.41–3.35(m,1H),3.11(s,3H),3.08–3.00(m,2H),2.95(dd,2H),2.81–2.65(m,2H),2.43(s,3H),2.17(s,3H)。
实施例42：N-(3-(6-(3-甲氧基四氢呋喃-3-基)-4-甲基吡啶-2-基)咪唑并[1,5-a]吡嗪-6-基)乙酰胺
Figure PCTCN2021124527-appb-000060
步骤一：6-(3-甲氧基四氢呋喃-3-基)-4-甲基吡啶甲酸的制备。2-溴-6-(3-甲氧基四氢呋喃-3-基)-4-甲基吡啶(1.00g，3.67mmol，1eq.)溶于THF(10mL)中，-78℃下滴加n-BuLi(3.67mmol，1.5mL，1.0eq.)，反应0.5h后，再通入CO 2，自然升温至室温反应1h后，反应液加入10mL水，分液浓缩得到标题化合物(0.8g，收率91％)。MS(m/z)＝238.10[M+H] +。
步骤二：((5-氯吡嗪-2-基)甲基)氨基甲酸叔丁酯的制备。5-氯吡嗪-2-甲醛(1.00g，7.02mmol，1eq.)，Et 3SiH(8.16g，70.1mmol，10.0eq.)，NH 2Boc(1.64g，14.03mmol，2.0eq.)，TFA(2.40g，21.0mmol，3.0eq.)溶于ACN(10mL)中，25℃反应24h后，加入10mL饱和碳酸钠，旋出ACN，用10mL EA萃取，浓缩得到标题化合物(1.2g，收率70％)。MS(m/z)＝244.08[M+H] +。
步骤三：(5-氯吡嗪-2-基)甲胺的制备。((5-氯吡嗪-2-基)甲基)氨基甲酸叔丁酯(1.20g，4.92mmol，1eq.)溶于HCl的EA(10mL)溶液中，25℃反应16h后，浓缩得到标题化合物(0.8g，收率100％)。MS(m/z)＝144.03[M+H] +。
步骤四：N-((5-氯吡嗪-2-基)甲基)-6-(3-甲氧基四氢呋喃-3-基)-4-甲基吡啶啉酰胺的制备。(5-氯吡嗪-2-基)甲胺(181mg，1.26mmol，3.0eq.)，6-(3-甲氧基四氢呋喃-3-基)-4-甲基吡啶甲酸(100mg，0.42mmol，1.0eq.)，HATU(480mg，1.26mmol，3.0eq.)，DIEA(544mg，4.2mmol，10.0eq.)溶于10mL DCM中，室温反应15h。加入10mL水，分液后通过柱层析纯化(PE/EtOAc＝2:1-1:1)得到标题化合物(0.1g，收率65％)。MS(m/z)＝363.11[M+H] +。
步骤五：6-氯-3-(6-(3-(3-甲氧基四氢呋喃-3-基)-4-甲基吡啶-2-基)咪唑并[1,5-a]吡嗪的制备。N-((5-氯吡嗪-2-基)甲基)-6-(3-甲氧基四氢呋喃-3-基)-4-甲基 吡啶啉酰胺(0.10g，275μmol，1eq.)溶于ACN(5mL)中，加入POCl 3(211mg，1.38mmol，5.0eq.)，90℃反应3h，加入10mL水淬灭后用二氯甲烷萃取得到标题化合物(0.1g，收率95％)。MS(m/z)＝345.10[M+H] +。
步骤六：N-(3-(6-(3-甲氧基四氢呋喃-3-基)-4-甲基吡啶-2-基)咪唑并[1,5-a]吡嗪-6-基)乙酰胺的制备。6-氯-3-(6-(3-(3-甲氧基四氢呋喃-3-基)-4-甲基吡啶-2-基)咪唑并[1,5-a]吡嗪(0.10g，290μmol，1eq.)，碳酸铯(283mg，870μmol，3.0eq.)，乙酰胺(25.7mg，435μmol，1.5eq.)，Pd 2(dba) 3(26.5mg，29.0μmol，0.1eq.)，X-phos(5.70mg，58.0μmol，0.2eq.)溶于1,4-二氧六环(5mL)中，氮气保护下100℃反应12h。反应液浓缩，通过柱层析纯化(PE/EtOAc＝2:1-0:1)得到标题化合物(0.08g，收率75％)。MS(m/z)＝368.16[M+H] +。 1H NMR(400MHz,DMSO)δ10.50(s,1H),10.27(s,1H),9.10(d,1H),8.10(s,1H),8.03(d,1H),7.40(s,1H),4.31(d,1H),4.10–3.97(m,2H),3.95(d,1H),3.14(s,3H),2.76(dt,1H),2.59–2.53(m,1H),2.47(s,3H),2.14(s,3H)。
实施例43：N-(1-(6-(3-甲氧基四氢呋喃-3-基)-4-甲基吡啶-2-基)-3-甲基-2-氧代-2,3-二氢-1H-咪唑[4,5-c]吡啶-6-基)乙酰胺
Figure PCTCN2021124527-appb-000061
步骤一：6-(3-甲氧基四氢呋喃-3-基)-4-甲基吡啶-2-胺的制备。2-溴-6-(3-甲氧基四氢呋喃-3-基)-4-甲基吡啶(0.50g，1.84mmol，1eq.)，二甲基乙二胺(16.2mg，183μmol，0.1eq.)，Cu 2O(13.1mg，91.8μmol，0.05eq.)，碳酸钾(508mg，3.67mmol，2.0eq.)溶于乙二醇(5mL)和氨水(4.6mL)中，氮气保护下80℃反应12h。反应液中加入20mL EA和20mL水，分液后浓缩并通过柱层析纯化(PE/EtOAc＝2:1-0:1)得到标题化合物(0.3g，收率78％)。MS(m/z)＝209.12[M+H] +。
步骤二：N-(2-氯-5-硝基吡啶-4-基)-6-(3-甲氧基四氢呋喃-3-基)-4-甲基吡啶 -2-胺的制备。2,4-二氯-5-硝基吡啶(278mg，1.44mmol，1eq.)，6-(3-甲氧基四氢呋喃-3-基)-4-甲基吡啶-2-胺(0.30g，1.44mmol，1eq.)，DIPEA(186mg，1.44mmol，1eq.)溶于乙醇(10mL)中，78℃反应12h后。通过柱层析纯化(PE/EtOAc＝5:1-1:1)得到标题化合物(0.5g，收率95％)。MS(m/z)＝365.09[M+H] +。
步骤三：6-氯-N 4-(6-(3-甲氧基四氢呋喃-3-基)-4-甲基吡啶-2-基)吡啶-3,4-二胺的制备。N-(2-氯-5-硝基吡啶-4-基)-6-(3-甲氧基四氢呋喃-3-基)-4-甲基吡啶-2-胺(0.50g，1.37mmol，1eq.)和Fe(383mg，6.85mmol，5eq.)溶于饱和氯化铵溶液(10mL)和乙醇(10mL)中，70℃反应3h。旋干，用EA萃取，通过柱层析纯化(PE/EtOAc＝5:1-1:1)得到标题化合物(0.4g，收率87％)。MS(m/z)＝335.12[M+H] +。
步骤四：6-氯-1-(6-(3-(3-甲氧基四氢呋喃-3-基)-4-甲基吡啶-2-基)-1,3-二氢-2H-咪唑并[4,5-c]吡啶-2-酮的制备。6-氯-N 4-(6-(3-甲氧基四氢呋喃-3-基)-4-甲基吡啶-2-基)吡啶-3,4-二胺(0.40g，1.19mmol，1eq.)，三光气(354mg，1.19mmol，1eq.)和TEA(120mg，1.19mmol，1eq.)溶于DCM(12mL)中，20℃反应1h。反应液倒入10mL水中，分液并浓缩得到标题化合物(0.3g，收率70％)。MS(m/z)＝361.10[M+H] +。
步骤五：6-氯-1-(6-(3-(3-甲氧基四氢呋喃-3-基)-4-甲基吡啶-2-基)-3-甲基-1,3-二氢-2H-咪唑并[4,5-c]吡啶-2-酮的制备。6-氯-1-(6-(3-(3-甲氧基四氢呋喃-3-基)-4-甲基吡啶-2-基)-1,3-二氢-2H-咪唑并[4,5-c]吡啶-2-酮(0.30g，831μmol，1eq.)溶于DMF(2mL)中，20℃加入NaH(20mg，831μmol，1eq.)，反应15分钟后，加入碘甲烷(118mg，831μmol，1eq.)，继续反应2h。反应液倒入10mL水中并加入10mL EA萃取，分液并浓缩得到标题化合物(0.2g，收率64％)。MS(m/z)＝375.11[M+H] +。
步骤六：N-(1-(6-(3-甲氧基四氢呋喃-3-基)-4-甲基吡啶-2-基)-3-甲基-2-氧代-2,3-二氢-1H-咪唑[4,5-c]吡啶-6-基)乙酰胺的制备。6-氯-1-(6-(3-(3-甲氧基四氢呋喃-3-基)-4-甲基吡啶-2-基)-3-甲基-1,3-二氢-2H-咪唑并[4,5-c]吡啶-2-酮(0.20g，534μmol，1eq.)，乙酰胺(37.8mg，640μmol，1.2eq.)，Pd 2(dba) 3(49mg，53μmol，0.1eq.)，X-phos(50.87mg，106μmol，0.2eq.)，碳酸铯(522mg，1.60mmol，3eq.)溶于1,4-二氧六环(5mL)中，氮气保护下100℃反应12h。 浓缩并通过柱层析纯化(PE/EtOAc＝2:1-0:1)得到标题化合物(0.2g，收率94％)。MS(m/z)＝398.18[M+H] +。 1H NMR(400MHz,DMSO)δ10.41(s,1H),8.62(s,1H),8.23(s,1H),7.78(s,1H),7.40(s,1H),4.16(d,1H),3.95(dd,2H),3.90(d,1H),3.44(s,3H),3.13(s,3H),2.59(dd,1H),2.45(d,3H),2.44(d,1H),2.07(s,3H)。
实施例44：(R)-N-(1-(6-(3-甲氧基四氢呋喃-3-基)-4-甲基吡啶-2-基)-3-(氧杂环丁-3-基乙炔基)-1H-吡咯并[3,2-c]吡啶-6-基)乙酰胺
Figure PCTCN2021124527-appb-000062
步骤一：(R)-6-氯-1-(6-(3-(甲氧基四氢呋喃-3-基)-4-甲基吡啶-2-基)-1H-吡咯并[3,2-c]吡啶的制备。将6-氯-1H-吡咯并[3,2-c]吡啶(6.000g，39.324mmol，1.00eq.)溶于1,4-二氧六环(80mL)中，加入(R)-2-溴-6-(3-甲氧基四氢呋喃-3-基)-4-甲基吡啶(10.702g，39.324mmol，1.00eq.)，K 2CO 3(16.305g，0.118mol，3.0eq.)，CuI(0.375mg，1.966mmol，0.05eq.)，N,N-二甲基乙二胺(0.348g，3.933mmol，0.1eq.)，氮气保护下回流反应12h。将反应液旋干，粗产品通过柱层析纯化(PE/EtOAc＝1:1)得到标题化合物(11.040g，收率81.65％)。MS(m/z)＝344[M+H] +。
步骤二：(R)-N-(1-(6-(6-(3-甲氧基四氢呋喃-3-基)-4-甲基吡啶-2-基)-1H-吡咯并[3,2-c]吡啶-6-基)乙酰胺的制备。将(R)-6-氯-1-(6-(3-(甲氧基四氢呋喃-3-基)-4-甲基吡啶-2-基)-1H-吡咯并[3,2-c]吡啶(9.820g，28.562mmol，1.0eq.)溶于1,4-二氧六环(100mL)中，加入乙酰胺(2.531g，42.843mmol，1.5eq.)，Pd 2(dba) 3(2.615g，2.856mmol，0.1eq.)，X-phos(2.723g，5.713mmol，0.2eq.)，Cs 2CO 3(18.612g，57.124mmol，2.0eq.)，氮气保护下，100℃反应5h。反应液冷却， 倒入水(150mL)中，用EA(200mL)萃取，分液，有机相用饱和NaCl水溶液洗一次，分液，有机相用无水硫酸镁干燥，过滤，浓缩，通过柱层析纯化(PE/EtOAc＝1:1)得到标题化合物(9.500g，收率90.70％)。MS(m/z)＝367[M+H] +。
步骤三：(R)-N-(3-碘-1-(6-(3-甲氧基四氢呋喃-3-基)-4-甲基吡啶-2-基)-1H-吡咯并[3,2-c]吡啶-6-基)乙酰胺的制备。将(R)-N-(1-(6-(6-(3-甲氧基四氢呋喃-3-基)-4-甲基吡啶-2-基)-1H-吡咯并[3,2-c]吡啶-6-基)乙酰胺(9.500g，25.927mmol，1.0eq.)溶于DMF(50mL)中，加入NIS(8.166g，36.298mmol，1.4eq.)，在60℃反应1h。反应液冷却，倒入水(150mL)中，用EA(200mL)萃取，分液，有机相用亚硫酸钠水溶液洗一次，分液，有机相用饱和NaCl水溶液洗一次，分液，有机相用无水硫酸镁干燥，过滤，浓缩，通过柱层析纯化(PE/EtOAc＝1:1)得到标题化合物(6.400g，收率35.81％)。MS(m/z)＝493[M+H] +。
步骤四：(R)-N-(1-(6-(3-甲氧基四氢呋喃-3-基)-4-甲基吡啶-2-基)-3-(氧杂环丁-3-基乙炔基)-1H-吡咯并[3,2-c]吡啶-6-基)乙酰胺的制备。将(R)-N-(3-碘-1-(6-(3-甲氧基四氢呋喃-3-基)-4-甲基吡啶-2-基)-1H-吡咯并[3,2-c]吡啶-6-基)乙酰胺(0.200g，0.408mmol，1.0eq.)溶于三乙胺(10mL)中，加入3-乙炔基氧杂环丁烷(0.0504g，0.612mmol，1.5eq.)，Pd(pph 3) 2Cl 2(0.0288g，0.0408mmol，0.1eq.)，CuI(0.0308g，0.1632mmol，0.4eq.)，氮气保护，在28℃反应15h。将反应液倒入水(20mL)中，用DCM(50mL)萃取，分液，有机相用饱和NH 4Cl水溶液洗一次，分液，有机相用饱和NaCl水溶液洗一次，分液，有机相用无水硫酸镁干燥，过滤，浓缩，通过柱层析纯化(DCM/MeOH＝30:1)得到标题化合物(0.080g，收率43.90％)。MS(m/z)＝447[M+H] +。 1H NMR(400MHz,DMSO)δ10.51(s,1H),9.07(s,1H),8.65(d,1H),8.34(s,1H),7.61(s,1H),7.36(s,1H),4.87(dd,2H),4.70(dd,2H),4.22(m,2H),3.96(m,3H),3.14(s,3H),2.67(m,1H),2.46(m,4H),2.11(s,3H)。
实施例45：(R)-N-(3-((3-羟基氧杂环丁-3-基)乙炔基)-1-(6-(3-甲氧基四氢呋喃-3-基)-4-甲基吡啶-2-基)-1H-吡咯并[3,2-c]吡啶-6-基)乙酰胺
Figure PCTCN2021124527-appb-000063
参考实施例44合成方法得标题化合物。MS(m/z)＝463[M+H] +。 1H NMR(400MHz,DMSO)δ10.54(s,1H),9.09(s,1H),8.68(d,1H),8.40(s,1H),7.63(s,1H),7.37(s,1H),6.68(s,1H),4.85(dd,2H),4.65(dd,2H),4.20(dd,1H),3.98(m,3H),3.15(s,3H),2.67(m,1H),2.46(m,4H),2.11(s,3H)。
实施例46：(R)-N-(1-(6-(3-甲氧基四氢呋喃-3-基)-4-甲基吡啶-2-基)-3-((3-甲基氧杂环丁-3-基)乙炔基)-1H-吡咯并[3,2-c]吡啶-6-基)乙酰胺
Figure PCTCN2021124527-appb-000064
参考实施例44合成方法得标题化合物。MS(m/z)＝461[M+H] +。 1H NMR(400MHz,DMSO)δ10.52(s,1H),9.09(s,1H),8.65(d,1H),8.34(s,1H),7.62(s,1H),7.35(s,1H),4.84(d,2H),4.49(d,2H),4.20(dd,1H),4.00(m,3H),3.15(s,3H),2.67(m,1H),2.46(m,4H),2.11(s,3H),1.71(s,3H)。
实施例47：(R)-N-{3-(1-乙酰基-氮杂环丁烷-3-基乙炔基)-1-[6-(3-甲氧基-四氢呋喃-3-基)-4-甲基-吡啶-2-基]-1H-吡咯并[3,2-c]吡啶-6-基}-乙酰胺
Figure PCTCN2021124527-appb-000065
步骤一：(R)-3-((6-乙酰氨基-1-(6-(3-甲氧基四氢呋喃-3-基)-4-甲基吡啶-2-基)-1H-吡咯并[3,2-c]吡啶-3-基)乙炔基)氮杂环丁烷-1-羧酸叔丁酯的制备。参考实施例44合成方法得标题化合物。MS(m/z)＝546[M+H] +。
步骤二：(R)-N-(3-(氮杂环丁烷-3-基乙炔基)-1-(6-(3-甲氧基四氢呋喃-3-基)-4-甲基吡啶-2-基)-1H-吡咯并[3,2-c]吡啶-6-基)乙酰胺的制备。将(R)-3-((6-乙酰氨基-1-(6-(3-甲氧基四氢呋喃-3-基)-4-甲基吡啶-2-基)-1H-吡咯并[3,2-c]吡啶-3-基)乙炔基)氮杂环丁烷-1-羧酸叔丁酯(0.15g，0.275mmol，1.0eq.)溶于DCM(10mL)中，室温下加入TFA(4mL)，搅拌30min。反应体系倒入30mL的水中，用碳酸钠调pH至10，用100mL的DCM萃取，分液，有机相用饱和NH 4Cl水溶液洗一次，分液，有机相用饱和NaCl水溶液洗一次，分液，有机相用无水硫酸镁干燥，过滤，浓缩，得标题化合物(0.12g，收率95％)。MS(m/z)＝446[M+H] +。
步骤三：(R)-N-(3-((1-乙酰氮杂环丁烷-3-基)乙炔基)-1-(6-(3-甲氧基四氢呋喃-3-基)-4-甲基吡啶-2-基)-1H-吡咯并[3,2-c]吡啶-6-基)乙酰胺的制备。将(R)-N-(3-(氮杂环丁烷-3-基乙炔基)-1-(6-(3-甲氧基四氢呋喃-3-基)-4-甲基吡啶-2-基)-1H-吡咯并[3,2-c]吡啶-6-基)乙酰胺(0.12g，0.269mmol，1.0eq.)溶于DCM(10mL)中，室温下加入乙酸酐(0.042g，0.405mmol，1.5eq.)搅拌反应30min。将体系倒入10mL的水中，用饱和碳酸钠水溶液调pH至10，用50mL的DCM萃取，分液，有机相用饱和NH 4Cl水溶液洗一次，分液，有机相用饱和NaCl 水溶液洗一次，分液，有机相用无水硫酸镁干燥，过滤，浓缩，通过柱层析纯化(DCM/MeOH＝30:1)得到标题化合物(0.045g，收率34.4％)。MS(m/z)＝488[M+H] +。 1H NMR(400MHz,DMSO)δ10.52(s,1H),9.07(s,1H),8.66(d,1H),8.34(s,1H),7.60(s,1H),7.36(s,1H),4.48(t,1H),4.22(m,3H),4.00(m,4H),3.80(m,1H),3.15(s,3H),2.67(m,1H),2.46(m,4H),2.11(s,3H),1.80(s,3H)。
实施例48：(R)-N-(3-((3-甲氧基氧杂环丁-3-基)乙炔基)-1-(6-(3-甲氧基四氢呋喃-3-基)-4-甲基吡啶-2-基)-1H-吡咯并[3,2-c]吡啶-6-基)乙酰胺
Figure PCTCN2021124527-appb-000066
参考实施例44合成方法得标题化合物。MS(m/z)＝477[M+H] +。 1H NMR(400MHz,DMSO)δ10.54(s,1H),9.09(s,1H),8.68(s,1H),8.47(s,1H),7.64(s,1H),7.38(s,1H),4.84(d,2H),4.70(d,2H),4.20(m,1H),3.98(m,3H),3.41(s,3H),3.15(s,3H),2.67(m,1H),2.46(m,4H),2.11(s,3H)。
实施例49：(R)-N-(3-(4-羟基丁-1-炔-1-基)-1-(6-(3-甲氧基四氢呋喃-3-基)-4-甲基吡啶-2-基)-1H-吡咯并[3,2-c]吡啶-6-基)乙酰胺
Figure PCTCN2021124527-appb-000067
参考实施例44合成方法得标题化合物。MS(m/z)＝435[M+H] +。 1H NMR(400MHz,DMSO)δ10.50(s,1H),9.07(s,1H),8.60(d,1H),8.27(s,1H),7.60(s,1H),7.34(s,1H),4.95(t,1H),4.21(d,1H),4.01(m,3H),3.65(q,2H),3.15(s,3H),2.65(m,3H),2.46(m,4H),2.11(s,3H)。
实施例50：(R)-1-(6-(3-甲氧基四氢呋喃-3-基)-4-甲基吡啶-2-基)-3-(1-甲基氮杂环丁-3-基)-1H-吡咯并[3,2-c]吡啶-6-胺
Figure PCTCN2021124527-appb-000068
将(R)-N-(1-(6-(3-甲氧基四氢呋喃-3-基)-4-甲基吡啶-2-基)-3-(1-甲基氮杂环丁烷-3-基)-1H-吡咯并[3,2-c]吡啶-6-基)乙酰胺(0.10g，0.229mmol，1.0eq.)溶于甲醇(10mL)中，加入4M的氢氧化钠水溶液(5mL),加热至60℃，反应15h。旋干体系，通过柱层析纯化(DCM/MeOH＝30:1)得到标题化合物。MS(m/z)＝394[M+H] +。 1H NMR(400MHz,DMSO)δ8.33(s,1H),7.70(s,1H),7.48(s,1H),7.28(s,1H),7.22(s,1H),5.66(s,2H),4.21(m,2H),4.01(m,2H),3.89(m,4H),3.50(s,2H),3.11(s,3H),2.48(m,4H),2.45(s,3H)。
实施例51：(R)-N-(3-(1-乙酰氮杂环丁烷-3-基)-1-(6-(3-甲氧基四氢呋喃-3-基)-4-甲基吡啶-2-基)-1H-吡咯并[3,2-c]吡啶-6-基)乙酰胺
Figure PCTCN2021124527-appb-000069
参考实施例47合成方法得标题化合物。MS(m/z)＝464[M+H] +。 1H NMR(400MHz,DMSO)δ10.42(s,1H),9.09(s,1H),8.59(s,1H),8.09(s,1H),7.59(s,1H),7.30(s,1H),4.62(t,1H),4.30(m,2H),4.21(d,1H),4.01(m,5H),3.14(s,3H),2.68(m,1H),2.44(m,4H),2.11(s,3H),1.81(s,3H)。
实施例52参考实施例51类似方法制得。
Figure PCTCN2021124527-appb-000070
Figure PCTCN2021124527-appb-000071
实施例53：(R)-N-(3-(1-异丙基氮杂环丁烷-3-基)-1-(6-(3-甲氧基四氢呋喃-3-基)-4-甲基吡啶-2-基)-1H-吡咯并[3,2-c]吡啶-6-基)乙酰胺
Figure PCTCN2021124527-appb-000072
参考实施例35合成方法得标题化合物。MS(m/z)＝464[M+H] +。 1H NMR(400MHz,DMSO)δ10.41(s,1H),9.07(s,1H),8.69(s,1H),8.09(s,1H),7.57(s,1H),7.32(s,1H),4.20(d,1H),4.00(m,5H),3.31(s,4H),3.14(s,3H),2.68(m,1H),2.44(m,4H),2.11(s,3H),1.08(m,6H)。
实施例54：(R)-N-(1-(6-(3-甲氧基四氢呋喃-3-基)-4-甲基吡啶-2-基)-3-(1-(2,2,2-三氟乙基)氮杂环丁烷-3-基)-1H-吡咯并[3,2-c]吡啶-6-基)乙酰胺
Figure PCTCN2021124527-appb-000073
将(R)-N-(3-(氮杂环丁烷-3-基)-1-(6-(3-甲氧基四氢呋喃-3-基)-4-甲基吡啶-2-基)-1H-吡咯并[3,2-c]吡啶-6-基)乙酰胺(0.125g，0.291mmol，1.0eq.)溶于THF(10mL)中，加入 2,2,2-三氟乙基三氟甲烷磺酸酯(0.081g，0.349mmol，1.2eq.),三乙胺(0.0589g，0.582mmol，2.0eq.)，室温反应15h。将体系倒入20mL的水中，用80mL的乙酸乙酯萃取，分液，有机相用饱和NH 4Cl水溶液洗一次，分液，有机相用饱和NaCl水溶液洗一次，分液，有机相用无水硫酸镁干燥，过滤，浓缩，通过柱层析纯化(DCM/MeOH＝30:1)得到标题化合物(0.04g，收率27％)。MS(m/z)＝504[M+H] +。 1H NMR(400MHz,DMSO)δ10.39(s,1H),9.06(s,1H),8.75(t,1H),7.96(s,1H),7.56(s,1H),7.29(s,1H),4.21(t,1H),4.00(m,5H),3.51(t,2H),3.30(m,3H),3.14(s,3H),2.68(m,1H),2.48(m,4H),2.11(s,3H)。
实施例55参考实施例54类似方法制得。
Figure PCTCN2021124527-appb-000074
Figure PCTCN2021124527-appb-000075
实施例56：N-(3-(2-甲基-2-氮杂螺[3.3]庚基-6-基)-1-(4-甲基吡啶-2-基)-1H-吡咯并[3,2-c]吡啶-6-基)乙酰胺
Figure PCTCN2021124527-appb-000076
参考实施例1和35合成方法得标题化合物。MS(m/z)＝376[M+H] +。 1H NMR(400MHz,DMSO)δ10.38(s,1H),8.99(d,1H),8.55(d,1H),8.40(d,1H),7.85(d,1H),7.61(s,1H),7.17(d,1H),4.16(s,2H),3.97(s,2H),3.64(t,1H),2.75(m,5H),2.48(m,5H),2.09(s,3H)。
实施例57：(R)-1-(1-(1-(6-(3-甲氧基四氢呋喃-3-基)-4-甲基吡啶-2-基)-3-(1-甲基氮杂环丁烷-3-基)-1H-吡咯并[3,2-c]吡啶-6-基)脲
Figure PCTCN2021124527-appb-000077
将(R)-1-(6-(3-甲氧基四氢呋喃-3-基)-4-甲基吡啶-2-基)-3-(1-甲基氮杂环丁-3-基)-1H-吡咯并[3,2-c]吡啶-6-胺(0.20g，0.508mmol，1.0eq.)溶于乙酸(10mL)和水(30mL)中，升温至90℃，一小时内分批加入氰酸钾(2.06g，25.41mmol，50eq.)，反应20min。将反应液冷却至室温，用碳酸钾调节pH至9左右，二氯甲烷萃取，有机相合并浓缩，通过柱层析纯化(DCM/MeOH＝30:1)得到标题化合物(0.01g，收率4.5％)。MS(m/z)＝437[M+H] +。 1H NMR(400MHz,CDCl 3)δ9.71(s,1H),8.50(s,1H),7.85(s,1H),7.73(s,1H),7.31(s,1H),7.25(s,1H),4.30(m,6H),4.05(m,2H),3.25(s,3H),2.86(s,3H),2.81(m,1H),2.51(s,3H),2.48(m,2H),1.60(m,2H)。
实施例58：(R)-1-(1-(1-(6-(3-甲氧基四氢呋喃-3-基)-4-甲基吡啶-2-基)-3-(2-甲基-2-氮杂螺[3.3]庚-6-基)-1H-吡咯并[3,2-c]吡啶-6-基)脲
Figure PCTCN2021124527-appb-000078
参考实施例50和57合成方法得标题化合物。MS(m/z)＝477[M+H] +。 1H NMR(400MHz,MeOD)δ8.48(s,1H),8.16(s,1H),7.65(d,1H),7.41(s,1H),7.33(s,1H),4.25(d,1H),4.14(m,4H),4.00(s,2H),3.79(s,2H),3.67(m,1H),3.25(s,3H),2.81(m,2H),2.70(m,4H),2.54(m,6H)。
实施例59：(R)-N-(1-(6-(3-甲氧基四氢呋喃-3-基)-4-甲基吡啶-2-基)-3-(1H-吡唑-5-基)-1H-吡咯并[3,2-c]吡啶-6-基)乙酰胺
Figure PCTCN2021124527-appb-000079
参考实施例1和44合成方法得标题化合物。MS(m/z)＝433[M+H] +。 1H NMR(400MHz,DMSO)δ12.89(s,1H),10.47(s,1H),9.23(s,1H),9.12(s,1H),8.44(s, 1H),7.84(d,1H),7.63(s,1H),7.33(s,1H),6.80(s,1H),4.22(d,1H),4.00(m,3H),3.17(s,3H),2.68(m,1H),2.48(m,4H),2.11(s,3H)。
实施例60-62参考实施例35类似方法制得。
Figure PCTCN2021124527-appb-000080
Figure PCTCN2021124527-appb-000081
实施例63-64的化合物参考实施例1的方法制得。
Figure PCTCN2021124527-appb-000082
实施例65(R)-N-(1-(6-(3-甲氧基四氢呋喃-3-基)-4-甲基吡啶-2-基)-3-(1-甲基氮杂环丁烷-3-基)-1H-吡咯并[3,2-c]吡啶-6-基)环丙烷甲酰胺
Figure PCTCN2021124527-appb-000083
参考实施例1和35合成方法得标题化合物。MS(m/z)＝462[M+H] +。 1H NMR(400MHz,DMSO)δ10.73(s,1H),9.06(s,1H),8.69(s,1H),8.19(s,1H),7.57(s,1H),7.31(s,1H),4.35(m,2H),4.24(m,1H),4.15(m,1H),4.13(m,1H),3.99(m,2H),3.88(m,2H),3.14(s,3H),2.80(s,3H),2.68(m,1H),2.49(m,4H),2.03(m,1H),1.79(m,4H)。
实施例66 4-(6-乙酰氨基-3-(2-甲基-2-氮杂螺[3.3]庚烷-6-基)-1H-吡咯并[3,2-c]吡啶-1-基)-2,6-二甲基苯甲酸甲酯
Figure PCTCN2021124527-appb-000084
参考实施例56的合成方法得标题化合物。MS(m/z)＝447[M+H] +。 1H NMR(400MHz,DMSO)δ10.44(s,1H),8.58(s,1H),8.33(s,1H),7.52(s,1H),7.32(s,2H),4.01(s,2H),3.89(s,3H),3.82(s,2H),3.60(m,1H),2.72(m,2H),2.65(s,3H),2.43(m,2H),2.33(s,6H),2.07(s,3H)。
实施例67(R)-N-(3-(6-(3-甲氧基四氢呋喃-3-基)-4-甲基吡啶-2-基)咪唑并[1,5-a]吡嗪-6-基)乙酰胺
Figure PCTCN2021124527-appb-000085
参考实施例42合成方法制得标题化合物。MS(m/z)＝368.42[M+H] +。 1H NMR(400MHz,DMSO)δ10.51(s,1H),10.26(s,1H),9.10(m,1H),8.09(s,1H),8.02(m,1H),7.39(m,1H),3.13(s,3H),2.90-2.93(m,2H),2.46(s,3H),1.70(m,2H),1.32-1.37(m,2H)。
实施例68-69的化合物参考实施例1的方法制得。
Figure PCTCN2021124527-appb-000086
实施例70(R)-N-(1-(6-(3-甲氧基四氢呋喃-3-基)-4-甲基吡啶-2-基)-3-(2-(甲基-d3)-2-氮杂螺[3.3]庚烷-6-基)-1H-吡咯并[3,2-c]吡啶-6-基)乙酰胺
Figure PCTCN2021124527-appb-000087
(R)-N-(1-(6-(3-甲氧基四氢呋喃-3-基)-4-甲基吡啶-2-基)-3-(2-氮杂螺[3.3]庚-6-基)-1H-吡咯并[3,2-c]吡啶-6-基)乙酰胺(0.100g，216.659μmol，1eq)溶于DMF(10mL)，加入NaHCO 3(36.402mg，433.318μmol，2eq.)，氘代碘甲烷(21.984mg，151.661μmol，0.7eq.)，室温反应15h。反应液倒入50mL的水中，用100mL的EtOAC萃取，分液，有机相用饱和NaCl水溶液洗一次，分液，有机相用无水硫酸镁干燥，过滤，浓缩。用DCM：MeOH＝20:1爬大板，得标题化合物(0.002g)。MS(m/z)＝479.61[M+H] +。 1H NMR(400MHz,MeOD)δ8.98(s,1H),8.53(s,1H),7.75(m,1H),7.45(s,1H),7.35(m,1H),4.26-4.33(m,3H),4.08-4.15(m,4H),3.73-3.77(m,1H),3.27(s,3H),2.86-2.91(m,2H),2.78-2.81(m,1H),2.56-2.62(m,5H),2.21(s,3H),2.05(s,1H),1.31(s,1H)。
实施例71-72实施例1和实施例56类似方法制得。
Figure PCTCN2021124527-appb-000088
Figure PCTCN2021124527-appb-000089
实施例73a和实施例73b参考实施例28a和实施例28b类似方法制得。
Figure PCTCN2021124527-appb-000090
Figure PCTCN2021124527-appb-000091
生物学评价
实验例1 TYK2 JH2、TYK2 JH1、JAK1、JAK2、JAK3激酶活性抑制测定
TYK2 JH2激酶活性抑制测定
TYK2 JH2(N-His-Tev，575-869)在Sf9中表达，来自本实验室的蛋白表达，荧光素标记探针由本公司合成，Anti-6xHis-terbium labled antibody购自Cisbio。高纯度的Hepes、NaCl、MgCl 2、DTT、BSA、Tween-20和DMSO购自Sigma。
实验所用的assay buffer由20mM Hepes pH 7.5,150mM NaCl,10mM MgCl 2,2mM DTT,50μg/mL BSA,和0.015％Tween-20组成。配置待测化合物DMSO存储母液，并根据实验所需采用DMSO进行三倍浓度梯度稀释12个点。4％DMSO的化合物、TYK2 JH2酶、荧光素标记探针、Anti-6xHis-terbium labled antibody使用assay buffer配制，配制完成后，5μL 4％DMSO的化合物、5μL TYK2 JH2酶、5μL荧光素标记探针和5μL Anti-6xHis-terbium labled antibody分别加入OptiPlate-384 White Opaque板中，盖膜，800转1min，室温孵育1.5h。4％DMSO的化合物、TYK2 JH2酶、荧光素标记探针和Anti-6xHis-terbium  labled antibody最终浓度分别是1％、2.5nM、50nM、1x。1.5h后，在TECAN(Switzerland)的SPARK多模板读数器上读取平板，激发光波长为340nm，发射光波长分别为520nm和485nm。抑制剂的IC 50值通过使用Prism 8(La Jolla,CA)获得。
TYK2 JH1、JAK1、JAK2、JAK3激酶活性抑制测定
TYK2 JH1(NP_003322.3)、JAK2(NP_004963.1)和JA3(NP_000206.2)购自carna公司，JAK1(N-GST-his-TEV，850-1154)在HI5中表达，来自本实验室的蛋白表达，TK试剂盒购Cisbio。高纯度的ATP、MgCl 2、MnCl 2、DTT和DMSO购自Sigma。
TYK2 JH1实验所用的assay buffer由5mM MgCl 2,1mM MnCl 2,1mM DTT,12.5μM SEB和1x Enzymatic buffer组成。
JAK2/3实验所用的assay buffer由5mM MgCl 2,1mM DTT和1x Enzymatic buffer组成。
JAK1实验所用的assay buffer由5mM MgCl 2,1mM MnCl 2,1mM DTT和1x Enzymatic buffer组成。
配置待测化合物DMSO存储母液，并根据实验所需采用DMSO进行三倍浓度梯度稀释12个点。4％DMSO的化合物、酶、TK-Substrate、ATP使用assay buffer配制，配制完成后，2.5μL 4％DMSO的化合物、2.5μL酶、5μL TK-Substrate/ATP混合液分别加入OptiPlate-384 White Opaque板中，盖膜，800转1min，室温孵育1h。4％DMSO的化合物的最终浓度为1％，TYK2 JH1、JAK1、JAK2和JAK3酶最终浓度为0.2ng/μL、10ng/μL、0.125ng/μL和0.3ng/μL，TK-Substrate/ATP最终浓度分别是0.25μM和3μM。1h后分别加入稀释于HTRF检测缓冲液中的TK-Antibody-Cryptate抗体和Streptavidin-XL665各5μL，室温孵育1h。最终浓度为1x和15.61nM。1h后在TECAN(Switzerland)的SPARK多模板读数器上读取平板，激发光波长为320nm，发射光波长分别为665nm和620nm。抑制剂的IC 50值通过使用Prism 8(La Jolla,CA)获得。
本申请代表性化合物的TYK2 JH2、TYK2 JH1、JAK1、JAK2、JAK3激酶活性抑制测定IC 50值见表1。
表1
实施例编 TYK2 JH2 TYK2 JH1 JAK1(nM) JAK2(nM) JAK3(nM)
号 (nM) (nM)      
1 2.2        
2 13.0        
3 18.7        
4 239.6        
5 114.7        
6 290.4        
7 31.2        
8 2.4        
9 5        
10 2.9        
11 5.1        
12 1.0 >10000   2480  
13 >1000        
14 >100        
15 0.6 >10000   >10000  
16 3.1        
17 1.9 >10000   8488  
18 5.7        
19 >1000        
20 3.9        
21 1.6        
22 1.8        
23 1.8        
24 3.3 >10000 >10000 >10000 >10000
25 0.4        
26 5.3        
27 2.1 >10000 >10000 >10000 >10000
28a 1        
28b 1.4        
29a 1.7 >10000 >10000 >10000 >10000
29b 1.6 >10000   >10000 >10000
30 3.8        
31 4.1        
32 4.6        
33 3.9        
34a 2.2        
34b 2.6        
35 2.7 >10000 >10000 >10000 398.3
36a 3.8        
36b 2.5     >10000  
37a 2        
37b 4.3     >10000  
38 2        
39 2.7     6159  
40 0.5        
41a 40.4        
41b 31.9        
42 20.2        
43 147.4        
44 6.9        
45 12.9        
46 15.3        
47 3.6        
48 27.5        
49 16.1        
50 186        
51 2.3        
52 1.5        
53 4.9        
54 3.1        
55 1.9        
56 11.2        
57 2.2        
58 1.8        
59 2.9        
60 2.6        
61 3.6        
62 9.8        
63          
64          
65 203        
66 1.3        
67 17        
68          
69 6.4        
70          
71          
72 18        
73a 3.4        
73b 2        
注：空白表示未测。
结果表明，本申请的代表性化合物能有效抑制TYK2 JH2的激酶活性，且对TYK2 JH1、JAK1、JAK2、JAK3表现出了良好的选择性。
实验例2 Caco-2细胞单层的通透性测定
材料：
Caco-2细胞及试验用试剂溶剂均以市售方式获得
对照化合物1和对照化合物2参考国际专利公开文本WO2019178079A1中的方法制得。
Caco-2细胞单层的通透性测定的一般方法：
1、预热：HBSS缓冲液37℃水浴预热。
2、从-20℃取出样品，超声处理不少于1分钟。
3、缓冲液配制
给药侧空白溶液：
A-to-B方向：
含0.3％DMSO与5μM路西法黄的HBSS+：将150μL DMSO及125μL的 2mM路西法黄溶液加入50mL的HBSS+缓冲液(pH 7.4)。
含0.1％DMSO与5μM路西法黄的HBSS+：将50μL DMSO及125μL的2mM路西法黄溶液加入50mL的HBSS+缓冲液(pH 7.4)。
B-to-A方向：
含0.3％DMSO的HBSS+：将150μL DMSO加入50mL的HBSS+缓冲液(pH 7.4)。
含0.1％DMSO的HBSS+：将50μL DMSO加入50mL的HBSS+缓冲液(pH7.4)。
接收侧溶液：
A-to-B方向：
含0.4％DMSO的HBSS+：将200μL DMSO加入50mL的HBSS+缓冲液(pH 7.4)。
B-to-A方向：
含0.4％DMSO与5μM路西法黄的HBSS+：将200μL DMSO及50μL的5mM路西法黄溶液加入50mL的HBSS+缓冲液(pH 7.4)。
4、测量跨膜电阻：
从培养箱中取出细胞培养板，用HBSS缓冲液润洗细胞两次(上层细胞板每孔加400μL，下侧支持板加25mL)，室温下用Millicell ERS电阻仪测量跨膜电阻。
5、将给药侧溶液置于离心机，4000rpm离心5分钟。收集上清作为给药侧溶液。
6、给药：
A-B(给药侧)：600μL A-to-B给药溶液(100μL用于路西法黄培养开始时样品收集，100μL用于培养开始时样品收集)。
A-B(接收侧)：800μL含0.4％DMSO的HBSS +。
B-A(给药侧)：900μL B-to-A给药溶液(100μL用于培养开始时样品收集)。
B-A(接收侧)：500μL含0.4％DMSO与5μM路西法黄的HBSS +(100μL用于路西法黄培养开始时样品收集)。
7、将已给药的上层板和下层板分别放入37℃培养箱预热5分钟。然后从给药侧取出100μL用于开始时样品收集(A-B D0，B-A D0)；从上层板每孔取出 100μL置于96孔黑色荧光测量板中用于路西法黄培养开始时样品收集(D0)。
8、把上层板和下层板合到一起开始通透性试验，37℃培养90分钟。
9、培养结束后，将上层板与下层板分开，从给药侧取出100μL样品放入96孔板黑色荧光测量板中，测量90分钟后路西法黄的量(激发波长485nm，发射波长535nm)。
10、给药液和接收液样品用0.4％的DMSO HBSS缓冲液稀释，然后与含内标的CAN混合后送至液质联用分析。
11、数据处理
跨膜电阻(TEER)＝(电阻值样品–电阻值空白)×膜面积
路法西黄通透性：
表观通透系数(P app)＝(接受侧体积/(膜面积×培养时间))×(培养结束时接受侧荧光值–空白溶液荧光值)/((培养开始时给药侧荧光值–空白溶液荧光值)×稀释倍数)
受试化合物通透性：
表观通透系数(P app)＝(接受侧体积/(膜面积×培养时间))×(培养结束时接受侧药物浓度/(培养开始时给药侧药物浓度×稀释倍数)
本实验采用Millipore细胞培养板(PSHT 010 R5)：膜面积＝0.7cm 2，接受侧体积＝0.8mL(A-to-B)或0.4mL(B-to-A)，培养时间＝90分钟。
化合物回收率：
％回收率＝100×(90分钟给药侧化合总量+90分钟接收侧化合物总量)/(0分钟给药侧化合总量)。
本申请代表性化合物与对照化合物1、对照化合物2的表观通透系数见表2。
表2
Figure PCTCN2021124527-appb-000092
Figure PCTCN2021124527-appb-000093
结果显示本申请化合物的表观通透系数B-A/A-B的比值相比于对照化合物更低，药物的吸收能力优于对照化合物，且不易发生外排，更易在细胞内产生药效。

Claims (16)

  1. 通式(I)所示的化合物：
    Figure PCTCN2021124527-appb-100001
    或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其可药用的盐，
    其中，A 1、A 2、A 4、A 5、A 6、A 7、A 8选自C或N，A 3选自C、N或
    Figure PCTCN2021124527-appb-100002
    且当A 2为N时，A 4、A 5、A 6、A 7、A 8中至少有1个为N；
    Figure PCTCN2021124527-appb-100003
    为饱和或不饱和环；
    R 1选自氢、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、卤素、氰基、硝基、-C(O)NR aR b、-C(O)R a、-C(O)OR a、-OR a、-OC(O)R a、-OC(O)OR a、-OC(O)NR aR b、-NR aR b、-SR a、-S(O)R a、-S(O) 2R a或含有0-3个杂原子的3-10元饱和或非饱和环，所述烷基、烯基、炔基、含有0-3个杂原子的3-10元饱和或非饱和环可选的被1-3个R a取代；
    R 2选自氢、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、卤素、氰基、硝基、-C(O)NR aR b、-C(O)R a、-C(O)OR a、-OR a、-OC(O)R a、-OC(O)OR a、-OC(O)NR aR b、-NR aR b、-SR a、-S(O)R a、-S(O) 2R a或含有0-3个杂原子的3-10元饱和或非饱和环，所述烷基、烯基、炔基、含有0-3个杂原子的3-10元饱和或非饱和环可选的被1-3个R a取代；
    R 4选自氢、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、卤素、氰基、硝基、-C(O)NR aR b、-C(O)R a、-C(O)OR a、-OR a、-OC(O)R a、-OC(O)OR a、-OC(O)NR aR b、-NR aR b、-SR a、-S(O)R a、-S(O) 2R a或含有0-3个杂原子的3-10元饱和或非饱和环，所述烷基、烯基、炔基、含有0-3个杂原子的3-10元饱和或非饱和环可选的被1-3个R a取代；
    每个R a、R b分别独立的选自氢、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 6环烷基、C 3-C 6杂环烷基、卤素、羟基、氰基、硝基、-C(O)NR cR d、-C(O)R c、-(CH 2) nC(O)OR c、-OR c、-OC(O)R c、-OC(O)OR c、-OC(O)NR cR d、-NR cR d、-SR c、-S(O)R c或-S(O) 2R c，所述烷基、烯基、炔基、环烷基、杂环烷基可选的被1-3个R c取代；
    每个R c、R d分别独立的选自氢、卤素、羰基、-C(O)CH 3、羟基、氰基、硝基、C 1-C 6烷基、卤代C 1-C 6烷基、C 3-C 6环烷基或卤代C 3-C 6环烷基；并且
    每个n分别独立的选自0、1、2或3。
  2. 根据权利要求1所述的通式(I)所示的化合物，其为通式(Ia)所示的化合物：
    Figure PCTCN2021124527-appb-100004
    或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其可药用的盐，
    其中，A 1、A 2、A 4、A 5、A 6、A 7、A 8选自C或N，A 3选自C、N或
    Figure PCTCN2021124527-appb-100005
    且当A 2为N时，A 4、A 5、A 6、A 7、A 8中至少有1个为N；
    Figure PCTCN2021124527-appb-100006
    为饱和或不饱和环；
    R 1选自氢、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、卤素、氰基、硝基、-C(O)NR aR b、-C(O)R a、-C(O)OR a、-OR a、-OC(O)R a、-OC(O)OR a、-OC(O)NR aR b、-NR aR b、-SR a、-S(O)R a、-S(O) 2R a或含有0-3个杂原子的3-10元饱和或非饱和环，所述烷基、烯基、炔基、含有0-3个杂原子的3-10元饱和或非饱和环可选的被1-3个R a取代；
    R 2选自氢、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、卤素、氰基、硝基、-C(O)NR aR b、-C(O)R a、-C(O)OR a、-OR a、-OC(O)R a、-OC(O)OR a、-OC(O)NR aR b、-NR aR b、-SR a、-S(O)R a、-S(O) 2R a或含有0-3个杂原子的3-10元饱和或非饱和环，所述烷基、烯基、炔基、含有0-3个杂原子的3-10元饱和或非饱和环可选的被1-3个R a取代；
    R 3选自氢、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、卤素、氰基、硝基、-C(O)NR aR b、-C(O)R a、-C(O)OR a、-OR a、-OC(O)R a、-OC(O)OR a、-OC(O)NR aR b、-NR aR b、-SR a、-S(O)R a、-S(O) 2R a或含有0-3个杂原子的3-10元饱和或非饱和环，所述烷基、烯基、炔基、含有0-3个杂原子的3-10元饱和或非饱和环可选的被1-3个R a取代；
    R 4选自氢、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、卤素、氰基、硝基、-C(O)NR aR b、-C(O)R a、-C(O)OR a、-OR a、-OC(O)R a、-OC(O)OR a、-OC(O)NR aR b、-NR aR b、-SR a、-S(O)R a、-S(O) 2R a或含有0-3个杂原子的3-10元饱和或非饱和环，所述烷基、烯基、炔基、含有0-3个杂原子的3-10元饱和或非饱和环可选的被1-3个R a取代；
    每个R a、R b分别独立的选自氢、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 6环烷基、C 3-C 6杂环烷基、卤素、羟基、氰基、硝基、-C(O)NR cR d、-C(O)R c、-(CH 2) nC(O)OR c、-OR c、-(CH 2) nOR c、-OC(O)R c、-OC(O)OR c、-OC(O)NR cR d、-NR cR d、-SR c、-S(O)R c或-S(O) 2R c，所述烷基、烯基、炔基、环烷基、杂环烷基可选的被1-3个R c取代；
    每个R c、R d分别独立的选自氢、卤素、羰基、-C(O)CH 3、羟基、氰基、硝基、C 1-C 6烷基、卤代C 1-C 6烷基、C 3-C 6环烷基或卤代C 3-C 6环烷基；并且
    每个n分别独立的选自0、1、2或3。
  3. 根据权利要求1所述的通式(I)所示的化合物，其为通式(Ib)所示的化合物：
    Figure PCTCN2021124527-appb-100007
    或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其可药用的盐，其中，A 1、A 3选自C或N；
    R 1选自氢、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、卤素、氰基、硝基、-C(O)NR aR b、-C(O)R a、-C(O)OR a、-OR a、-OC(O)R a、-OC(O)OR a、-OC(O)NR aR b、-NR aR b、-SR a、-S(O)R a、-S(O) 2R a或含有0-3个杂原子的3-10元饱和或非饱和环，所述烷基、烯基、炔基、含有0-3个杂原子的3-10元饱和或非饱和环可选的被1-3个R a取代；
    R 2选自氢、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、卤素、氰基、硝基、-C(O)NR aR b、-C(O)R a、-C(O)OR a、-OR a、-OC(O)R a、-OC(O)OR a、-OC(O)NR aR b、-NR aR b、-SR a、-S(O)R a、-S(O) 2R a或含有0-3个杂原子的3-10元饱和或非饱和环，所述烷基、烯基、炔基、含有0-3个杂原子的3-10元饱和或非饱和环可选的被1-3个R a取代；
    R 3选自氢、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、卤代C 1-C 6烷基、卤代C 2-C 6烯基、卤代C 2-C 6炔基、卤素、氰基、硝基、-C(O)NR aR b、-C(O)R a、-C(O)OR a、-OR a、-(CH 2) nOR a、-NR aR b或-S(O) 2R a；
    R 4’选自氢、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、卤代C 1-C 6烷基、卤代C 2-C 6烯基、卤代C 2-C 6炔基、C 3-C 6环烷基、卤代C 3-C 6环烷基、卤素、氰基、硝基或-NR aR b；
    每个R a、R b分别独立的选自氢、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 6环烷基、C 3-C 6杂环烷基、卤素、羟基、氰基、硝基、-C(O)NR cR d、-C(O)R c、-(CH 2) nC(O)OR c、-OR c、-(CH 2) nOR c、-OC(O)R c、-OC(O)OR c、-OC(O)NR cR d、-NR cR d、-SR c、-S(O)R c或-S(O) 2R c，所述烷基、烯基、炔基、环烷基、杂环烷基 可选的被1-3个R c取代；
    每个R c、R d分别独立的选自氢、卤素、羰基、-C(O)CH 3、羟基、氰基、硝基、C 1-C 6烷基、卤代C 1-C 6烷基、C 3-C 6环烷基或卤代C 3-C 6环烷基；并且
    每个n分别独立的选自0、1、2或3。
  4. 根据权利要求1所述的通式(I)所示的化合物，其为通式(Ic)所示的化合物：
    Figure PCTCN2021124527-appb-100008
    或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其可药用的盐，其中，A 3选自C或N；
    R 1选自氢、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、卤素、氰基、硝基、-C(O)NR aR b、-C(O)R a、-C(O)OR a、-OR a、-OC(O)R a、-OC(O)OR a、-OC(O)NR aR b、-NR aR b、-SR a、-S(O)R a、-S(O) 2R a或含有0-3个杂原子的3-10元饱和或非饱和环，所述烷基、烯基、炔基、含有0-3个杂原子的3-10元饱和或非饱和环可选的被1-3个R a取代；
    R 2选自氢、C 1-C 6烷基、卤代C 1-C 6烷基、卤素、氰基、-C(O)OR a、-(CH 2) nOR a或-NH 2；
    R 3选自氢、C 1-C 6烷基或-OR a；
    R 4’选自氢、C 1-C 6烷基、卤代C 1-C 6烷基、C 3-C 6环烷基、卤素或-NH 2；
    每个R a、R b分别独立的选自氢、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 6环烷基、C 3-C 6杂环烷基、卤素、羟基、氰基、硝基、-C(O)NR cR d、-C(O)R c、-(CH 2) nC(O)OR c、-OR c、-(CH 2) nOR c、-OC(O)R c、-OC(O)OR c、-OC(O)NR cR d、-NR cR d、-SR c、-S(O)R c或-S(O) 2R c，所述烷基、烯基、炔基、环烷基、杂环烷基可选的被1-3个R c取代；
    每个R c、R d分别独立的选自氢、卤素、羰基、-C(O)CH 3、羟基、氰基、硝基、C 1-C 6烷基、卤代C 1-C 6烷基、C 3-C 6环烷基或卤代C 3-C 6环烷基；并且
    每个n分别独立的选自0、1、2或3。
  5. 根据权利要求1-4中任一项所述的化合物，其中，R 1选自氢、-CH 3、
    Figure PCTCN2021124527-appb-100009
    Figure PCTCN2021124527-appb-100010
    Figure PCTCN2021124527-appb-100011
    -CN、
    Figure PCTCN2021124527-appb-100012
    -F、
    Figure PCTCN2021124527-appb-100013
    Figure PCTCN2021124527-appb-100014
  6. 根据权利要求1-4中任一项所述的化合物，其中，R 2选自氢、-CH 3、
    Figure PCTCN2021124527-appb-100015
    Figure PCTCN2021124527-appb-100016
  7. 根据权利要求1-4中任一项所述的化合物，其中，R 3为
    Figure PCTCN2021124527-appb-100017
  8. 根据权利要求1或2所述的化合物，其中，R 4为氢、-C(O)CH 3、
    Figure PCTCN2021124527-appb-100018
    或-C(O)NH 2。
  9. 根据权利要求1所述的通式(I)所示的化合物，其选自：
    Figure PCTCN2021124527-appb-100019
    Figure PCTCN2021124527-appb-100020
    Figure PCTCN2021124527-appb-100021
    Figure PCTCN2021124527-appb-100022
    Figure PCTCN2021124527-appb-100023
  10. 权利要求1-9中任一项化合物、其异构体或其药学上可接受的盐用于制备由TYK2介导的疾病药物中的用途。
  11. 根据权利要求10所述的用途，其中，所述TYK2介导的疾病为自身免疫性疾病，发炎性疾病，增殖性疾病，内分泌疾病，神经系统疾病或与移植相关的疾病。
  12. 根据权利要求11所述的用途，其中，所述疾病为自身免疫性疾病。
  13. 根据权利要求12所述的用途，其中，所述自身免疫性疾病选自1型糖尿病、强直性脊椎炎、全身性红斑性狼疮症、多发性硬化症、全身性硬化症、牛皮癣、克罗恩氏病、溃疡性结肠炎或发炎性肠病。
  14. 根据权利要求11所述的用途，其中，所述疾病为发炎性疾病。
  15. 根据权利要求14所述的用途，其中，所述发炎性疾病选自风湿性关节炎、哮喘、慢性阻塞性肺病、牛皮癣、克罗恩氏病、溃疡性结肠炎及发炎性肠病。
  16. 一种药物组合物，其包含治疗有效量的权利要求1-9任一项所述的化合物、其异构体或其药学上可接受的盐；以及药学上可接受的载体或赋形剂。
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