WO2022242697A1 - Inhibiteur sélectif de tyk2 et son utilisation - Google Patents

Inhibiteur sélectif de tyk2 et son utilisation Download PDF

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WO2022242697A1
WO2022242697A1 PCT/CN2022/093719 CN2022093719W WO2022242697A1 WO 2022242697 A1 WO2022242697 A1 WO 2022242697A1 CN 2022093719 W CN2022093719 W CN 2022093719W WO 2022242697 A1 WO2022242697 A1 WO 2022242697A1
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alkyl
halogenated
disease
formula
alkynyl
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PCT/CN2022/093719
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English (en)
Chinese (zh)
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王利莎
陈弘道
王琳
王婕
李进
赵树海
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 CN202280021571.6A priority Critical patent/CN117043162A/zh
Publication of WO2022242697A1 publication Critical patent/WO2022242697A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the application belongs to the field of chemical medicine, and specifically relates to a TYK2 selective inhibitor and its application.
  • Autoimmune disease is a family of at least 80 diseases, such as rheumatoid arthritis, systemic lupus erythematosus, and inflammatory bowel disease, is a group of immune cell activation and excessive production of autoantibodies that mistakenly attack their own organs, 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, as chronic and debilitating diseases with high medical costs and reduced quality of life for patients, have become a huge burden for 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 development of the disease.
  • JAK Janus kinase
  • JAK3 The non-receptor tyrosine kinases of the JAK family play an important role in mediating a variety of cytokines leading to inflammation (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).
  • 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 a strong association between IL-12R and IL-23B (encoding p40 subunit) polymorphisms and inflammatory bowel disease (Stahl EA, Raychaudhuri S, Remmers EF, Xie G, Eyre S, Thomson BP 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 enhancement of the expression and release of autoantigens (Hall J C, Rosen A. Type I interferons: critical participants in disease amplification in autoimmunity[J]. Nature Reviews Rheumatology, 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.). In summary, drugs that inhibit the action of IL-12, IL-23, and type I interferon have therapeutic benefit in human autoimmune diseases.
  • TYK2 as well as other members of the JAK family, is characterized by a dual kinase domain, a tyrosine kinase domain (JH1) and a pseudokinase domain (JH2), respectively.
  • 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 TYK2 Inhibitors[J]. Journal of Medicinal Chemistry, 2013, 56(11): 4521.), Partial mutations in JH2 of JAKs have been shown to be associated with hematological and immunological diseases. Therefore, TYK2 JH2 selective inhibitors may be able to more specifically inhibit TYK2 activity.
  • the synthesis of new TYK2 JH2 selective inhibitors can benefit patients with autoimmune diseases by regulating IL-12, IL-23 and type I interferon in vivo.
  • the application discloses a compound that can be used as a selective inhibitor of TYK2 and its use in the preparation of drugs for preventing or treating related diseases mediated by TYK2.
  • the application discloses a compound of formula (I):
  • Ring A is selected from aryl, heteroaryl or partially unsaturated heterocyclic
  • X, Y 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, halogenated C 1 -C 6 alkyl, deuterated 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 , -R a OR b , -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
  • R 2 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, deuterated 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 , -R a OR b , -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
  • 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, deuterated C 1 -C 6 alkyl, Halogenated C 2 -C 6 alkenyl, halogenated C 2 -C 6 alkynyl, halogen, cyano, nitro, carbonyl, -C(O)NR a R b , -C(O)R a , -C (O)OR a , -OR a , -R a OR b , -OR a OR b , -OC(O)R a , -OR a C(O)R b , -OC(O)OR a , -OC (O)NR a R b , -NR a R b , -NC(O)R a , -RcNR a R
  • R 4 is selected from hydrogen, Or a 3-10 membered saturated or unsaturated ring containing 0-3 heteroatoms optionally substituted by 1-3 R a , Z is -NH-, -N(CH 2 )- or a direct bond;
  • R 5 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, deuterated 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 , -R a OR b , -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
  • R 6 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, deuterated 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 , -R a OR b , -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
  • Each R a , R b , R c is independently selected from hydrogen, deuterium, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogenated C 1 -C 6 Alkyl, deuterated C 1 -C 6 alkyl, halogenated C 2 -C 6 alkenyl, halogenated C 2 -C 6 alkynyl, halogen, cyano, nitro, amino, carboxyl, carbonyl, hydroxy, hydroxy Alkyl, alkoxy, haloalkoxy, deuterated alkoxy, C 3 -C 6 cycloalkyl, haloC 3 -C 6 cycloalkyl, alkoxy substituted C 3 -C 6 cycloalkyl , C 3 -C 6 heterocyclyl, halogenated C 3 -C 6 heterocyclyl, alkyl substituted C 3 -C 6 heteroaryl, -
  • n 0, 1, 2 or 3.
  • ring A is selected from phenyl, pyridyl, pyrazinyl, tetrahydropyridyl, pyrazolyl, benzothiazolyl or imidazo[1,5-a]pyridyl.
  • R is selected from Z is -NH-, -N(CH 2 )- or a direct bond.
  • R is selected from
  • Formula (I) is Formula (Ia):
  • R 2 ' is selected from hydrogen, C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, C3-C6 cycloalkyl, halogen, -NH 2 or -NHCH 3 ;
  • n, X, Y, Z, R 1 , R 3 , R 5 , and R 6 are as defined above.
  • Formula (I) is Formula (Ib):
  • R 1 , R 2 ′, R 3 , R 5 , and R 6 are as defined above.
  • Formula (I) is Formula (Ic):
  • R 2 ' is selected from hydrogen, C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, C3-C6 cycloalkyl, halogen, -NH 2 or -NHCH 3 ;
  • n, X, Y, Z, R 1 , R 3 , R 5 , and R 6 are as defined above.
  • Formula (I) is Formula (Id):
  • R 1 , R 3 , R 5 , R 6 are as defined in claim 1, and R 2 ' is as defined above.
  • R 1 is selected from hydrogen, methyl, -CD 3 , ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl,
  • R 3 is selected from hydrogen, methyl, ethyl, fluorine, chlorine, cyano, methoxy, ethoxy, hydroxymethyl, carbonyl, carboxyl, -CHF 2 , -OCHF 2 , -CF 3 , -OCF 3 , -OCD 3 ,
  • the compound represented by general formula (I) is selected from:
  • the present application also provides the use of the aforementioned compounds, their isomers or pharmaceutically acceptable salts thereof in the preparation of drugs for diseases mediated by TYK2.
  • the TYK2-mediated disease is an autoimmune disease, an inflammatory disease, a proliferative disease, an endocrine disease, a nervous system disease, or a transplant-related disease.
  • the disease is an autoimmune disease.
  • the autoimmune disease is selected from type 1 diabetes, ankylosing spondylitis, systemic lupus erythematosus, multiple sclerosis, systemic sclerosis, psoriasis, Crohn's disease, ulcer colitis or inflammatory bowel disease.
  • the disease is an inflammatory disease.
  • the inflammatory disease is selected from 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, which comprises a therapeutically effective amount of the aforementioned compound, its 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.
  • the present application includes R and S configurations, Z and E double bond isomers, Z and E conformational isomers, single stereochemical isomers and enantiomers, diastereomers for each asymmetric center. Mixtures of isomers and geometric (or conformational) isomers.
  • Suitable acid addition salts are formed with acids which form non-toxic salts, eg hydrochlorides/chlorides.
  • Suitable base salts are formed from bases which form non-toxic salts, such as calcium and sodium salts.
  • Half-salts of acids and bases, such as the hemisulfate and hemicalcium salts, may also be formed.
  • terapéuticaally effective amount refers to the amount of a compound of the present application that (i) treats a specific disease, condition or disorder; (ii) alleviates, relieves or eliminates one or more symptoms of a specific disease, condition or disorder or (iii) preventing or delaying the onset of one or more symptoms of a particular 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 formulated therewith.
  • 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 , 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl Base, 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 an aliphatic hydrocarbon 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.
  • C2-6 alkenyl includes straight or branched chain unsaturated groups (having at least one carbon-carbon double bond) of 2 to 6 carbon atoms, including but not limited to ethenyl, 1-propenyl , 2-propenyl (allyl), isopropenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, etc.
  • alkynyl refers to an aliphatic hydrocarbon having at least one carbon-carbon triple bond, including straight and branched chains having at least one carbon-carbon triple bond.
  • an alkynyl group has 2 to 20 carbon atoms, 2 to 10 carbon atoms, 2 to 6 carbon atoms, or 3 to 6 carbon atoms.
  • C 2-6 alkynyl includes straight or branched chain unsaturated groups (having at least one carbon-carbon triple bond) of 2 to 6 carbon atoms.
  • alkoxy refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl is as defined above.
  • alkoxy 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 containing 3 to 12 carbon atoms, more preferably containing 3 to 6 carbon atoms (for example 3, 4, 5 or 6 carbon atoms), most preferably contain 5 to 6 carbon atoms.
  • Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene Base, cyclooctyl, etc.; polycyclic cycloalkyl includes spiro ring, fused ring and bridged ring cycloalkyl.
  • spirocycloalkyl refers to a polycyclic group that shares one carbon atom (called a spiro atom) between a 5- to 20-membered monocyclic ring, which may contain one or more double bonds, but each ring does not have a complete Conjugated ⁇ -electron systems.
  • a spiro atom a polycyclic group that shares one carbon atom (called a spiro atom) between a 5- to 20-membered monocyclic ring, which may contain one or more double bonds, but each ring does not have a complete Conjugated ⁇ -electron systems.
  • it is 6 to 14 yuan, more preferably 7 to 10 yuan (eg 7, 8, 9 or 10 yuan).
  • the spirocycloalkyl group is divided into a single spirocycloalkyl group, a double spirocycloalkyl group or a multi-spirocycloalkyl group, preferably a single spirocycloalkyl group and a double spirocycloalkyl group, 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 monospirocycloalkyl group.
  • fused cycloalkyl refers to a 5 to 20 membered all-carbon polycyclic group in which each ring of the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more rings may contain one or Multiple double bonds, but each ring does not have a fully conjugated ⁇ -electron system.
  • it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • the number of rings it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic condensed cycloalkyl groups, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicycloalkyl groups.
  • bridged cycloalkyl refers to a 5 to 20 membered, all-carbon polycyclic group with any two rings sharing two carbon atoms not directly attached, which may contain one or more double bonds, but each ring has no It has a fully conjugated ⁇ -electron system. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic.
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising 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), but excluding ring portions of -O-O-, -O-S- or -S-S-, the remaining ring atoms being carbon.
  • ring atoms Preferably contain 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably contain 3 to 8 ring atoms, of which 1 to 3 are heteroatoms; most preferably contain 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, tetrahydrothiophenyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrazolyl, Hydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc., preferably tetrahydropyranyl, piperidinyl, pyrrolidinyl.
  • Polycyclic heterocyclyls include spiroheterocyclyls, fused heterocyclyls and bridged heterocyclyls.
  • spiroheterocyclyl refers to a polycyclic heterocyclic group that shares one atom (called a spiro atom) between 5 to 20-membered monocyclic rings, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O )m (wherein m is an integer from 0 to 2), the remaining ring atoms are carbon. It may contain one or more double bonds, but each ring does not have a fully conjugated pi-electron system. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • the spiroheterocyclyl is divided into a single spiroheterocyclyl, a double spiroheterocyclyl or a polyspiroheterocyclyl, preferably a single spiroheterocyclyl and a double 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 monospiro heterocyclic 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 rings may contain one or more double bond, but each ring does not have a fully conjugated ⁇ -electron system, 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), The remaining ring atoms are carbon. Preferably 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 heterocyclic group in which any two rings share two atoms not directly attached, which may contain one or more double bonds, but each ring has no A fully conjugated ⁇ -electron system in which 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.
  • m is an integer from 0 to 2
  • 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.
  • the heterocyclic group includes heterocyclic groups as described above (including monocyclic, spiro heterocyclic, fused heterocyclic and bridged heterocyclic) fused to an aryl, heteroaryl or cycloalkyl ring, wherein with the parent structure
  • the rings joined together are heterocyclyl, non-limiting examples of which include:
  • aryl refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic (that is, rings sharing adjacent pairs of carbon atoms) group, preferably 6 to 10 membered, having a conjugated pi-electron system, 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; preferred examples are imidazolyl, furyl, thienyl, thiazolyl, pyryl Azolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl and pyridazinyl, etc.
  • the heteroaryl group includes a heteroaryl group as described above fused to an aryl, heterocyclyl or cycloalkyl ring wherein the ring bonded to the parent structure is a heteroaryl ring, non-limiting examples of which include :
  • saturated or unsaturated ring includes the aforementioned aryl, heteroaryl, cycloalkyl or heterocycloalkyl.
  • hydroxyalkyl refers to an alkyl group substituted by a hydroxy group, 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 group is as defined above.
  • deuteroalkyl 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 group is as defined above.
  • cycloalkylalkyl refers to an alkyl group substituted by 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 by 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.
  • hydroxyl refers to a -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-(4-bromo-2-methylphenyl)-1H-1,2,4-triazole.
  • the title compound (1.140 g, 4.788 mmol) was obtained.
  • Step 2 Preparation of 3-(4-bromo-2-methylphenyl)-1-methyl-1H-1,2,4-triazole (IM-1).
  • Method 1 Dissolve 3-(4-bromo-2-methylphenyl)-1H-1,2,4-triazole (1.140g, 4.788mmol, 1eq.) in DMF (20mL), add cesium carbonate (4.680g, 14.365mmol, 3eq.), iodomethane (1.359g, 9.576mmol, 2eq.), react at room temperature for 20 hours, spin the system to dryness, add 50mL of water, the solid precipitates, filters, and the filter cake is dried to obtain The title compound (0.800 g, 3.173 mmol).
  • Step 1 Preparation of N-(3-bromo-5-(trifluoromethyl)phenyl)-N-(methylsulfonyl)methanesulfonamide.
  • 3-bromo-5-(trifluoromethyl)aniline (10.00g, 41.663mmol, 1eq.)
  • DCM 100mL
  • TEA 21.08g, 208.32mmol, 5.0eq.
  • methanesulfonic anhydride 21.77g, 125.0mmol, 3.0eq.
  • wash the DCM phase with water (200mL*2), dry over anhydrous magnesium sulfate, filter, concentrate, and perform column chromatography (PE:EA 3:1) to obtain The title compound (6.80 g, 17.163 mmol).
  • Step 2 Preparation of N-(3-bromo-5-(trifluoromethyl)phenyl)methanesulfonamide (IM-2).
  • N-(3-bromo-5-(trifluoromethyl)phenyl)-N-(methylsulfonyl)methanesulfonamide (6.80g, 17.163mmol, 1eq.)
  • Example 34 The intermediate of Example 34 was prepared according to the above method.
  • Step 2 Preparation of 3-bromo-5-(difluoromethyl)aniline.
  • Step 3 refer to the preparation method of intermediate 2 step 1.
  • Step 4 refer to the preparation method of intermediate 2 step 2 to prepare.
  • Step 1 Preparation of 3-bromo-5-(methylsulfonyl)phenol.
  • Example 66 The intermediate of Example 66 was prepared according to the above method.
  • Step 1 Preparation of (3-bromo-5-(methylsulfonyl)phenyl)methanol.
  • Step 2 Preparation of 1-bromo-3-(methoxymethyl)-5-(methylsulfonyl)benzene (IM-8).
  • Dissolve (3-bromo-5-(methylsulfonyl)phenyl)methanol (2.50g, 10.23mmol, 1.0eq.) in THF (50mL), cool down to 0°C under nitrogen protection, add NaH (304.134mg , 12.673mmol, 1.2eq.), stirred for 30 minutes, added MeI (2.249g, 15.842mmol, 1.5eq.), raised to room temperature and stirred for 12 hours, added saturated ammonium chloride to quench (100mL), EA extracted (50mL* 2), the organic phase was washed with saturated sodium chloride (100mL*2), dried over anhydrous magnesium sulfate, filtered, concentrated, and column chromatography (PE:EA 3:1) gave the title compound (2.50g, 8.95mmol, yield rate 84.8%).
  • Example 61 The intermediate of Example 61 was prepared according to the above method.
  • Step 1 Preparation of 1,3-dibromo-5-(methylsulfonyl)benzene.
  • NaHCO 3 5.024g, 59.806mmol, 2.0eq.
  • Na 2 SO 3 5.653g, 44.855mmol, 1.5eq.
  • H 2 O 75mL
  • 3,5-dibromobenzenesulfonyl chloride (10.00g, 29.903mmol, 1eq.)
  • Step 2 Preparation of 4-(3-bromo-5-(methylsulfonyl)phenyl)-1,5-dimethyl-1H-pyrazole (IM-10).
  • 1,3-dibromo-5-(methylsulfonyl)benzene (1.00g, 3.185mmol, 1eq.)
  • 1,4-dioxane (15mL)
  • Base-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolin-2-yl)-1H-pyrazole 707.3mg, 3.185mmol, 1.0eq)
  • Pd (dppf)Cl 2 116.516mg, 159.239 ⁇ mol, 0.05eq.
  • K 2 CO 3 (1.320g, 9.554mmol, 3eq.
  • H 2 O 5mL
  • Example 74, 79, 91, 94, 95, 96, 106, 107, 109, 110, 111, 112, 114, 117, 118, 128, 133, 134, 136, 142 refer to the method of the above intermediate preparation.
  • Example 78 The intermediate of Example 78 was prepared according to the method of the above intermediate.
  • Example 82 The intermediate of Example 82 was prepared according to the method of the above intermediate.
  • Example 88 The intermediate of Example 88 was prepared according to the method of the above intermediate.
  • Step 1 Preparation of 1-bromo-3-fluoro-5-(methylsulfonyl)benzene. Using 3-bromo-5-fluorobenzenesulfonyl chloride as raw material, it is prepared by referring to the preparation method of intermediate 10 step 1.
  • Step 2 Preparation of 4-(3-bromo-5-(methylsulfonyl)phenyl)morpholine (IM-15).
  • 1-bromo-3-fluoro-5-(methylsulfonyl)benzene (1.00g, 3.951mmol, 1eq.)
  • DMAc (10.000mL
  • morpholine 1.33g, 11.854mmol, 3eq.
  • heated to 100° C. for 20 hours cooled to room temperature, added ice water (50 mL), filtered, and dried to obtain the title compound (1.10 g, 3.435 mmol, yield 86.944%).
  • Step 1 Preparation of 1-((3-bromophenyl)sulfonyl)propan-2-one.
  • 1,3-Dibromo-5-(methylsulfonyl)benzene (2.00g, 6.370mmol, 1eq.) was dissolved in THF (20mL), cooled to -78°C, and n-butyllithium (2.5M, 6.370mmol, 1eq.), the addition is completed, and the reaction is incubated for 0.5 hours.
  • Add N-methoxy-N-methylacetamide (656.824mg, 6.370mmol, 1eq.), the addition is completed, and the reaction is 0.5 hours.
  • Step 2 Preparation of 1-((3-bromophenyl)sulfonyl)propan-2-ol (IM-16).
  • Example 105 The intermediate of Example 105 was prepared according to the method of the above intermediate.
  • Example 115 The intermediate of Example 115 was prepared according to the method of the above intermediate.
  • Step 1 Preparation of 3,5-dibromobenzenesulfonyl chloride. Add 3,5-dibromoaniline (5.00g, 19.927mmol, 1eq.), AcOH (57mL), concentrated hydrochloric acid (31mL) into a four-neck flask, cool down to about 0°C in an ice bath, and dropwise add NaNO 2 (1.512g , 21.919mmol, 1.1eq.)+4.5mL water, stirred for 10 minutes, reacted for 0.5 hours, set aside.
  • 3,5-dibromoaniline 5.00g, 19.927mmol, 1eq.
  • AcOH 57mL
  • concentrated hydrochloric acid 31mL
  • Step 2 Preparation of 3,5-dibromo-N,N-dimethylbenzenesulfonamide.
  • Step 3 3-bromo-N, N-dimethyl-5-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)benzenesulfonamide (IM-18) refer to the middle Body 10 is prepared by the method of step 2.
  • Step 1 Preparation of 3-bromo-5-fluorobenzenesulfonyl chloride. Refer to the preparation method of step 1 of intermediate 18.
  • Step 2 Preparation of 3-bromo-5-fluoro-N,N-dimethylbenzenesulfonamide. It can be prepared by referring to the preparation method of step 2 of intermediate 18.
  • Step 3 Preparation of 3-bromo-5-(3-methoxyazetidin-1-yl)-N,N-dimethylbenzenesulfonamide (IM-19). Refer to the preparation method of intermediate 15 step 2.
  • Example 150 was prepared according to the method of the above intermediate.
  • Example 164 The intermediate of Example 164 was prepared according to the method of the above intermediate.
  • 2,6-dichloro-4-methoxypyridine (3.75g, 21.06mmol, 1eq.) was dissolved in DMSO (30mL), and 40% aqueous sodium methylthiolate solution (7.60g, 21.06mmol, 1eq.) was added , and the resulting mixture was heated to 40° C. for 1 hour.
  • the reaction solution was diluted with water and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous magnesium sulfate, and spin-dried under reduced pressure to obtain 2-chloro-4-methoxy-6-methylthiopyridine (3.80 g, 20.03 mmol, yield 95%).
  • 2,6-Dichloro-4-iodopyridine (3.00 g, 10.95 mmol, 1 eq.) was dissolved in 1,4-dioxane (10 mL), and 3-methoxyazetidine salt was added separately salt (1.61g, 13.08mmol, 1.2eq.), cesium carbonate (10.70g, 32.84mmol, 3eq.), Pd 2 (dba) 3 (501mg, 0.54mmol, 0.05eq.) and XantPhos (633mg, 1.09mmol , 0.1eq.), the resulting mixture was protected with nitrogen and heated to 100°C for 14 hours.
  • the reaction solution was cooled, filtered, and the filter cake was washed with ethyl acetate.
  • Example 180 was synthesized with reference to the above method.
  • the intermediate obtained above (1.00g, 4.81mmol, 1.0eq.) was dissolved in DMF (10mL), cesium carbonate (2.36g, 7.24mmol, 1.5eq.) and difluoroiodoethane (1.14g, 5.32 mmol, 1.1eq.), the resulting mixture was reacted at room temperature for 2 hours.
  • the reaction solution was poured into water and extracted with ethyl acetate; the organic phases were combined, dried and spin-dried under reduced pressure.
  • the intermediate IM-28 (1.15 g, 4.23 mmol, yield 87.8%) was obtained.
  • Step 1 Preparation of 4-bromo-N,2,6-trimethylbenzamide.
  • 4-Bromo-2,6-dimethylbenzoic acid (3.000 g, 13.096 mmol, 1 eq.) was dissolved in SOCl 2 (3.895 g, 32.741 mmol, 2.5 eq.) in DMF (9.573 mg, 130.964 ⁇ mol, 0.01 eq.), heated to 50°C, reacted for 1 hour, cooled the system, spin-dried, DCM was dissolved, and added dropwise at -25°C to a solution of methylamino alcohol (733.496mg, 26.196mmol, 2eq.) in DCM (80mL), Rise to room temperature, pour into water, separate the liquids, wash the organic phase once with a saturated NaHCO3 aqueous solution, separate the liquids, wash the organic phase once with a saturated NaCl aqueous solution, separate the liquids, dry the organic phase with anhydrous magnesium sulf
  • Step 2 Preparation of N,2,6-trimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolin-2-yl)benzamide.
  • 4-Bromo-N,2,6-trimethylbenzamide (0.500 g, 2.065 mmol, 1 eq.) was dissolved in 1,4-dioxane (10.0 mL), and the pinacol-coupled boron Ester (576.865mg, 2.272mmol, 1.1eq.), Pd(dppf)Cl 2 (150.963mg, 206.516 ⁇ mol, 0.1eq.), potassium acetate (608.037mg, 6.195mmol, 3eq.), nitrogen replacement three times, nitrogen Protected, heated to 100°C, reacted for 2 hours, and directly put into the next step.
  • Step 3 Preparation of 4-(5-chloro-1-methyl-1H-pyrrolo[2,3-c]pyridin-3-yl)-N,2,6-trimethylbenzamide.
  • 3-bromo-5-chloro-1-methyl-1H-pyrrolo[2,3-c]pyridine 507.003mg, 2.065mmol, 1eq.
  • potassium carbonate 856.253mg, 6.195mmol, 3eq.
  • Pd(dppf)Cl 2 (150.963mg, 206.516 ⁇ mol, 0.1eq.
  • water (10.000mL), nitrogen replacement three times, nitrogen protection, heated to 100°C, reacted for 2 hours, and cooled the system , poured into water (100mL), extracted with EtOAC (200mL), separated, the organic phase was washed once with saturated NaCl aqueous solution, separated, the organic phase was dried with anhydrous magnesium sulfate, filtered, concentrated, column chromatography (n-heptyl Alkane: Et
  • Step 4 Preparation of 4-(5-acetamido-1-methyl-1H-pyrrolo[2,3-c]pyridin-3-yl)-N,2,6-trimethylbenzamide.
  • 4-(5-Chloro-1-methyl-1H-pyrrolo[2,3-c]pyridin-3-yl)-N,2,6-trimethylbenzamide (0.270 g, 823.65 ⁇ mol, 1 eq.) was dissolved in 1,4-dioxane (20 mL) and acetamide (145.952 mg, 2.471 mmol, 3 eq.), cesium carbonate (805.087 mg, 2.471 mmol, 3 eq.), Pd 2 (dba) were added 3 (75.364mg, 82.365 ⁇ mol, 0.1eq.), X-Phos (39.206mg, 82.365 ⁇ mol, 0.1eq.), nitrogen replacement three times, nitrogen protection, heated to 120 ° C, reacted for 2 hours,
  • Examples 8, 9, 10, 11, 12, 14, 15, 19, 20, 21, 22, 23, 24, 26, 27, 28, 31, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 56, 59, 61, 97, 101, 102, 165, 166, 167, 168, 169, 171, 172, 174, 175, 176, 177, 178, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 227 were all prepared according to the above method.
  • Step 1 Preparation of 5-chloro-1-methyl-1H-pyrrolo[2,3-c]pyridine. Take a 250mL single-necked bottle, add 5-chloro-1H-pyrrolo[2,3-c]pyridine (5.00g, 32.770mmol, 1eq.), DMF (50mL), cesium carbonate (12.812g, 39.323mmol, 1.2eq. ), methyl iodide (5.581g, 39.323mmol, 1.2eq.), heated to 100°C for 3 hours.
  • reaction solution was poured into ice water, extracted with ethyl acetate, the organic phases were combined, dried over anhydrous magnesium sulfate, filtered and spin-dried to obtain the title compound (5.05 g, 30.311 mmol, yield 92.497%).
  • Step 2 Preparation of N-(1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide.
  • 5-chloro-1-methyl-1H-pyrrolo[2,3-c]pyridine 5.00g, 30.011mmol, 1eq.
  • acetamide 5.318g, 90.032mmol, 3eq.
  • X-PHOS 2.861g, 6.002mmol, 0.2eq.
  • Pd 2 (DBA) 3 2.748g, 3.001mmol, 0.1eq.
  • Cs 2 CO 3 29.334g, 90.032mmol, 3eq.
  • Step 4 1-(6-(5-acetamido-1-methyl-1H-pyrrolo[2,3-c]pyridin-3-yl)pyridin-2-yl)cyclopropane-1-carboxylic acid Preparation of methyl esters.
  • Step 5 1-(6-(5-acetamido-1-methyl-1H-pyrrolo[2,3-c]pyridin-3-yl)pyridin-2-yl)cyclopropane-1-carboxylic acid preparation. Take a 100mL one-mouth bottle, add 1-(6-(5-acetamido-1-methyl-1H-pyrrolo[2,3-c]pyridin-3-yl)pyridin-2-yl)cyclopropane-1 -Methyl carboxylate (120mg, 329.311 ⁇ mol, 1eq.), LiOH.H 2 O (39.432mg, 1.647mmol, 5eq.), methanol (5mL) and water (5mL), nitrogen replacement 3 times, the temperature was controlled at 50°C, reacted for 3 hours, added ice water (50mL), adjusted the pH to about 5-6, extracted with EA (30mL*2), dried the organic phase with anhydrous magnesium sulfate, concentrated, and column chromat
  • Example 29 was prepared according to the above method.
  • Step 1 Preparation of N-(4-methyl-5-nitropyridin-2-yl)acetamide. Add 4-methyl-5-nitropyridin-2-amine (226.50g, 1.479mol, 1eq.) and acetic anhydride (2260mL) into a 3000mL single-necked bottle, heat to 95°C for 15 hours, concentrate to dryness, and make Carry water for distillation (500mL*2), beat with MTBE, filter, wash the filter cake with a small amount of MTBE, and dry to obtain the title compound (276.50g, 1.417mol, yield 95.783%).
  • Step 2 Preparation of N-(4-(2-(dimethylamino)vinyl)-5-nitropyridin-2-yl)acetamide. Dissolve N-(4-methyl-5-nitropyridin-2-yl)acetamide (276.50 g, 1.417 mol, 1 eq.) in DMF (2760 mL), add N,N-dimethylformamide dimethyl Acetal (371.391g, 3.117mol, 2.2eq.) was heated to 80°C for 5 hours, concentrated to dryness, distilled with toluene as a water-carrying agent (500mL*1), beaten with MTBE (1500mL), filtered, and dried to obtain The title compound (306.50 g, 1.23 mol, yield 86.5%).
  • Step 3 Preparation of N-(1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide. Dissolve N-(4-(2-(dimethylamino)vinyl)-5-nitropyridin-2-yl)acetamide (303.50 g, 1.213 mol, 1 eq.) in THF (700.000 mL) and add 5 % palladium carbon (11.50g, 1.213mol, 1eq.), reacted under hydrogen atmosphere for 3 days, replaced nitrogen three times, added MeOH (1L), filtered, a small amount of MeOH washed the filter cake, and the filtrate was concentrated to dryness to obtain the title compound (210.46g, 1.201 mol, yield 99.058%).
  • Step 4 Preparation of N-(3-bromo-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide.
  • Step 5 Preparation of N-(3-bromo-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide.
  • N-(3-Bromo-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide (223.00 g, 877.666 mmol, 1 eq.) was dissolved in MeCN (6600 mL), Cs 2 CO 3 (571.920 g, 1.755mol, 2.0eq.), dropwise added dimethyl sulfate (116.235g, 921.549mmol, 1.05eq.), stirred for 1 hour, added THF (4L), combined and filtered, the filtrate was concentrated to dryness, washed with ice water, and dried After drying, the title compound (235.06 g, 876.731 mmol, yield 99.894%) was obtained.
  • Step 6 N-(3-(3-(2-methoxyethoxy)-5-(methylsulfonyl)phenyl)-1-methyl-1H-pyrrole[2,3-c]pyridine -5-yl)acetamide preparation.
  • N-(3-bromo-5-(2-methoxyethoxy)phenyl)methanesulfonamide (0.300 g, 925.380 ⁇ mol, 1 eq.)
  • 1,4-dioxane 10 mL
  • boronic acid pinacol ester (258.488mg, 1.018mmol, 1.1eq.)
  • potassium acetate 272.456mg, 2.776mmol, 3eq.
  • Pd(dppf)Cl 2 33.855mg, 46.269 ⁇ mol, 0.05eq .
  • Step 1 Preparation of 3-bromo-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-amine.
  • Step 2 Preparation of 1-(3-bromo-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)urea.
  • Step 3 Preparation of 1-(1-methyl-3-(3-(methylsulfonyl)phenyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)urea.
  • 3-methylsulfonylphenylboronic acid (163.525 mg, 817.547 ⁇ mol, 1.1 eq.)
  • 1-(3-bromo-1-methyl-1H-pyrrolo[2,3-c]pyridine-5 -yl)urea 0.2g, 743.225 ⁇ mol, 1eq.
  • Pd(dppf)Cl2 54.382mg , 74.322 ⁇ mol, 0.1eq.
  • K2CO3 308.154mg , 2.230mmol , 3.0eq.
  • Examples 51, 52, 55, 60, 65, 66, 67, and 73 were prepared according to the above method.
  • Step 1 Preparation of (1r,3r)-3-cyanocyclobutyl methanesulfonate.
  • diisopropylethylamine 1.597g, 12.356mmol, 1.2eq.
  • Methanesulfonic anhydride (2.152g, 12.356mmol, 1.2eq.)
  • reacted for 2 hours added water to the reaction solution, extracted with DCM, separated the organic phase, combined, dried over anhydrous magnesium sulfate, filtered, and spin-dried to obtain the crude product title Compound (1.90 g, 10.844 mmol, yield 105.316%) was directly carried to the next step.
  • Step 2 Preparation of (1s,3s)-3-(3-bromo-5-chloro-1H-pyrrolo[2,3-c]pyridin-1-yl)cyclobutane-1-carbonitrile.
  • 3-bromo-5-chloro-1H-pyrrolo[2,3-c]pyridine (1.986g, 13.013mmol, 1.2eq.)
  • (1r,3r)-3-cyanocyclobutyl methanesulfonate Acetate (1.90g, 10.844mmol, 1eq.)
  • cesium carbonate (5.300g, 16.267mmol, 1.5eq.
  • DMF 20mL
  • heated to 100 ° C reacted for 2 hours, poured the reaction solution into ice water, filtered , and the filter cake was dried to obtain the title compound (2.60 g, 11.222 mmol, yield 103.485%).
  • Step 3 (1s, 3s)-3-(5-chloro-3-(6-(1-cyanochloropropyl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine- Preparation of 1-yl)cyclobutane-1-carbonitrile.
  • the method of step two three makes.
  • Step 4 N-(1-((1s,3s)-3-cyanochlorobutyl)-3-(6-(1-cyanochloropropyl)pyridin-2-yl)-1H-pyrrolo[ Preparation of 2,3-c]pyridin-5-yl)acetamide.
  • MS (m/z) [M+H] + 398.0.
  • Examples 13, 16, 17, 18, 25, 30, 32, 75, 77, 78, 83, 84, 85, 86, 87, 90, 98, 194, 195 were prepared according to the above method.
  • Step 1 Preparation of 1-(3-bromo-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)-3-methylurea.
  • 3-Bromo-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-amine (1.00g, 4.423mmol, 1eq.) was dissolved in THF (38mL) and DIPEA (1.715g, 13.270 mmol, 3eq.), under nitrogen protection, cool down to -78°C, add triphosgene (1.378g, 4.645mmol, 1.05eq.) dropwise in toluene (12mL) solution, then keep warm for 15 minutes, add 33% formazan Ammonia ethanol solution (4mL), after adding, keep it warm for 15 minutes, then rise to room temperature and react for 1 minute, add saturated saline (20mL) to the system, add EA (10mL), separate the liquid, dry the organic phase, spin dry, and make sand , column chromatography (EA
  • Step 2 N-(3-(1-methyl-5-(3-methylureido)-1H-pyrrolo[2,3-c]pyridin-3-yl)-5-morpholinephenyl) Preparation of methylsulfonamide.
  • Example 80 was prepared according to the above method.
  • Step 1 Preparation of 1-methyl-3-(3-(methylsulfonyl)phenyl)-1H-pyrrolo[2,3-c]pyridin-5-amine.
  • Step 2 N-(1-methyl-3-(3-(methylsulfonyl)phenyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide-2,2, Preparation of 2-d3.
  • Example 179 was synthesized according to the above method.
  • Step 1 Intermediate 2-4 (500mg, 1.86mmol, 1eq.) was dissolved in DMF (10mL), and coupled boric acid pinacol ester (705mg, 2.79mmol, 1.5eq.), potassium acetate (549mg , 5.59mmol, 3eq.), X-Phos (88mg, 0.18mmol, 0.1eq.) and Pd 2 (dba) 3 (170mg, 0.18mmol, 0.1eq.), the resulting mixture was protected with nitrogen and heated to 90 °C for 4 hours.
  • TYK2 JH2 (N-His-Tev, 575-869) was expressed in Sf9, the protein expression was from our laboratory, the fluorescein-labeled probe was synthesized by our company, and Anti-6xHis-terbium labeled antibody was purchased from Cisbio.
  • the assay buffer used in the experiment consisted of 20mM Hepes pH 7.5, 150mM NaCl, 10mM MgCl 2 , 2mM DTT, 50 ⁇ g/mL BSA and 0.015% Tween-20. Prepare the stock solution of the compound to be tested in DMSO, and perform a three-fold concentration gradient dilution with DMSO for 12 points according to the experimental requirements.
  • 4% DMSO compound, TYK2 JH2 enzyme, fluorescein-labeled probe, Anti-6xHis-terbium labeled antibody were prepared using assay buffer, after preparation, 5 ⁇ L 4% DMSO compound, 5 ⁇ L TYK2 JH2 enzyme, 5 ⁇ L fluorescein-labeled probe and 5 ⁇ L Anti-6xHis-terbium labled antibody were added to the OptiPlate-384 White Opaque plate, cover the membrane, rotate at 800 for 1 min, and incubate at room temperature for 1.5 hours.
  • the final concentrations of compound, TYK2 JH2 enzyme, luciferin-labeled probe and Anti-6xHis-terbium labeled antibody in 4% DMSO were 1%, 2.5nM, 50nM and 1x, respectively.
  • 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).
  • Table 1 shows the IC 50 values of the representative compounds of the present application for the TYK2 JH2 kinase activity inhibition assay.
  • Example number TYK2 JH2(nM) Example number TYK2 JH2(nM) 1 110 137 2.7 2 62 138 4 3 1.3 139 4.5 4 1.8 140 3.9 5 3.1 141 3.1 6 2.1 142 3.1 7 2 143 0.5 8 2 144 3.5 9 8.8 145 3.1 10 2 146 2.9 11 10.4 147 1.9 12 6.8 148 4.2 13 1.9 149 4.5 14 5.3 150 3.5 15 1.8 151 1.6 16 43 152 4.3 17 15 153 3.6 18 1.9 154 4.6 19 54 155 7.1 20 2.7 156 2.2
  • the purpose of this experiment is to investigate the pharmacokinetic characteristics of the test compound in CD1 mice after single intravenous injection and intragastric administration.
  • Reference compound 1 was prepared by referring to the method in International Patent Publication WO2019178079A1.
  • mice Male, 6-8 weeks old, 22-28 g, were purchased from Shanghai Jihui Experimental Animal Breeding Co., Ltd. for each test drug.
  • Intravenous injection (IV) and intragastric administration (PO) formulations are formulated with 80% PEG400+20% water. Except that the concentration of group IV in Example 99 was 0.4 mg/mL, the concentration of other group IV was 0.2 mg/mL, and the concentration of group PO was 1 mg/mL.
  • Embodiment 99, embodiment 202, embodiment 220, embodiment 222, embodiment 241 IV group animals are given 2mg/kg test drug through tail vein, other IV group animals are all given 1mg/kg test drug through tail vein, PO group Animals were given 10 mg/kg test drug by gavage.

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Abstract

L'invention concerne un composé représenté par la formule (I), ou un tautomère, un mésomère, un racémate, un énantiomère ou un diastéréomère de celui-ci ou un sel pharmaceutiquement acceptable de celui-ci, et une utilisation de celui-ci pour préparer un médicament pour le traitement de maladies dont la médiation est assurée par TYK2.
PCT/CN2022/093719 2021-05-19 2022-05-19 Inhibiteur sélectif de tyk2 et son utilisation WO2022242697A1 (fr)

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WO2023250064A1 (fr) * 2022-06-23 2023-12-28 Biogen Ma Inc. Inhibiteurs de tyrosine kinase 2 et leurs utilisations

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