WO2022121868A1 - 含酰胺基和杂环烷基的tyk2抑制剂化合物 - Google Patents

含酰胺基和杂环烷基的tyk2抑制剂化合物 Download PDF

Info

Publication number
WO2022121868A1
WO2022121868A1 PCT/CN2021/135912 CN2021135912W WO2022121868A1 WO 2022121868 A1 WO2022121868 A1 WO 2022121868A1 CN 2021135912 W CN2021135912 W CN 2021135912W WO 2022121868 A1 WO2022121868 A1 WO 2022121868A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
cycloalkyl
alternatively
compound
membered heterocycloalkyl
Prior art date
Application number
PCT/CN2021/135912
Other languages
English (en)
French (fr)
Inventor
刘飞
张健青
施伟
王宇冰
杨列超
Original Assignee
正大天晴药业集团股份有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 正大天晴药业集团股份有限公司 filed Critical 正大天晴药业集团股份有限公司
Priority to CN202180081052.4A priority Critical patent/CN116547276A/zh
Publication of WO2022121868A1 publication Critical patent/WO2022121868A1/zh

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present application belongs to the field of medicinal chemistry, provides a TYK2 inhibitor compound containing an amide group and a heterocycloalkyl group and a preparation method thereof, and relates to its use in the preparation of a medicine for treating or preventing TYK2-related diseases.
  • Tyrosine kinase 2 is a member of the Janus kinase (JAK) family of non-receptor tyrosine kinases and has been shown in both mice and humans to be involved in IL-12, IL-23 and type I interferon Essential in the regulatory signal transduction cascade downstream of the receptor.
  • TYK2 mediates receptor-induced phosphorylation of members of the STAT transcription factor family, an essential signal leading to dimerization of STAT proteins and transcription of STAT-dependent proinflammatory genes.
  • TYK2-deficient mice are resistant to experimental models of colitis, psoriasis, and multiple sclerosis, thereby demonstrating the importance of TYK2-mediated signaling in autoimmunity and related disorders. In humans, individuals expressing inactive variants of TYK2 are protected from multiple sclerosis and possibly other autoimmune disorders.
  • TYK2 inhibitor compounds capable of modulating cytokines and/or interferons such as IL-12, IL-23 and/or IFN ⁇ and the use of these compounds in view of conditions that may benefit from treatment involving modulation of cytokines and/or interferons
  • the method can provide substantial therapeutic benefit to a large number of patients in need.
  • the application provides a compound of formula I or a pharmaceutically acceptable salt thereof:
  • Cy is selected from C 6-10 aryl or 5-10 membered heteroaryl
  • X is selected from -N(R)-, O or S;
  • R is selected from hydrogen or C 1-6 alkyl
  • L 1 is selected from -(CH 2 ) n -;
  • n is selected from 1, 2, 3 or 4;
  • R 2 is selected from C 3-10 cycloalkyl or 3-10 membered heterocycloalkyl optionally substituted with one or more R a ;
  • Each R a is independently selected from halogen, cyano, hydroxy, amino, C 1-8 alkyl, C 1-8 alkoxy, C 1-8 alkyl NH-, (C 1-8 alkyl) 2 N- or C 3-8 cycloalkyl;
  • Each R 1 is independently selected from amino, halogen, cyano, hydroxy, C 1-8 alkyl, C 1-8 alkoxy, C 3-10 cycloalkyl, C 3-10 cycloalkoxy, C 1-8 alkyl NH-, (C 1-8 alkyl) 2 N-, C 3-10 cycloalkyl NH-, 3-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 1 -8 alkyl C(O)-, C 1-8 alkyl C(O)NH-, NH 2 C(O)-, C 1-8 alkyl NHC(O)-, (C 1-8 alkyl ) 2 NC(O)-, C 1-8 alkyl OC(O)- or C 1-8 alkyl C(O)O-, the C 1-8 alkyl, C 1-8 alkoxy, C 3-10 cycloalkyl, C 3-10 cycloalkoxy, C 1-8 alkyl NH-, (C 1-8 alkyl) 2
  • n is selected from 0, 1, 2, 3 or 4;
  • L is selected from -C(O)- or a bond
  • R 4 is selected from 5-10 membered heteroaryl, C 3-10 cycloalkyl, C 6-10 aryl or 3-10 membered heterocycloalkyl, wherein the 5-10 membered heteroaryl, C 3- 10 cycloalkyl, C 6-10 aryl or 3-10 membered heterocycloalkyl optionally substituted with one or more R b ;
  • R b is selected from halogen, cyano, C 1-8 alkyl, C 1-8 alkoxy, C 3-10 cycloalkyloxy, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 3-10 membered heterocycloalkyl, amino, C 1-8 alkyl NH-, (C 1-8 alkyl) 2 N-, C 3-10 cycloalkyl NH-, -C(O)NHC 1- 8 alkyl, -C(O)N(C 1-8 alkyl) 2 , -C(O)OC 1-8 alkyl, -OC(O)C 1-8 alkyl, C 1-8 alkyl C(O)NH-, C3-10cycloalkylC (O)NH-, C1-8alkylSO2NH- or ( C1-8alkyl ) 2NSO2- .
  • the Cy is selected from phenyl or 5-6 membered heteroaryl.
  • the Cy is selected from phenyl or 6-membered heteroaryl.
  • the Cy is selected from phenyl or pyridyl. In some embodiments, Cy is selected from phenyl.
  • the R is selected from hydrogen or C 1-3 alkyl; in some embodiments, the R is selected from hydrogen.
  • the X is selected from NH or O. In some embodiments, the X is selected from NH. In some embodiments, the X is selected from O.
  • the n is selected from 1 or 2.
  • the L 1 is selected from -(CH 2 )-.
  • the R 2 is selected from C 3-10 monocyclic cycloalkyl or 3-10 membered monocyclic heterocycloalkyl, the C 3-10 monocyclic cycloalkyl or 3-10 membered unit Cycloheterocycloalkyl is optionally substituted with one or more Ra .
  • the R 2 is selected from C 3-6 monocyclic cycloalkyl or 3-6 membered monocyclic heterocycloalkyl, the C 3-6 monocyclic cycloalkyl or 3-6 membered monocyclic Cycloheterocycloalkyl is optionally substituted with one or more Ra .
  • the R 2 is selected from C 3-10 cycloalkyl or a 3-10 membered heterocycloalkyl group containing 1, 2 or 3 atoms selected from N, O or S, the C 3- 10 cycloalkyl or 3-10 membered heterocycloalkyl is optionally substituted with one or more Ra .
  • the R 2 is selected from C 3-6 cycloalkyl or a 3-6 membered heterocycloalkyl group containing 1, 2 or 3 atoms selected from N, O or S atoms, the C 3-
  • the 6 -cycloalkyl or 3-6 membered heterocycloalkyl is optionally substituted with one or more Ra .
  • the R 2 is selected from C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl, and the C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl is optionally is substituted with one or more Ra .
  • the R 2 is selected from 3-6 membered heterocycloalkyl optionally substituted with one or more R a .
  • the R 2 is selected from 3-6 membered heterocycloalkyl containing 1, 2 or 3 atoms selected from N, O or S, the 3-6 membered heterocycloalkyl optionally is substituted with one or more Ra .
  • the R 2 is selected from 5-6 membered heterocycloalkyl containing 1, 2 or 3 atoms selected from N, O or S, the 5-6 membered heterocycloalkyl optionally is substituted with one or more Ra .
  • the R 2 is selected from 5-6 membered heterocycloalkyl containing 1 or 2 atoms selected from N or O, the 5-6 membered heterocycloalkyl optionally being surrounded by one or more substituted with Ra .
  • the R 2 is selected from 1,4-dioxanyl, tetrahydropyranyl, piperidinyl, morpholinyl, pyrrolidinyl, or furanyl, the 1,4-dioxane Oxane, tetrahydropyranyl, piperidinyl, morpholinyl, pyrrolidinyl or furanyl is optionally substituted with one or more Ra .
  • the R is selected from 5-6 membered heterocycloalkyl containing 1 or 2 O atoms, the 5-6 membered heterocycloalkyl optionally substituted with one or more Ra .
  • the R 2 is selected from 1,4-dioxanyl, tetrahydropyranyl, or furanyl, the 1,4-dioxanyl, tetrahydropyranyl, or furanyl group is optionally substituted with one or more Ra .
  • the R 2 is selected from in optionally substituted with one or more Ra .
  • the R 2 is selected from in optionally substituted with one or more Ra .
  • each of the R a is independently selected from halogen, cyano, hydroxy, amino, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkyl NH-, (C 1-6 alkyl) 2 N- or C 3-6 cycloalkyl. In some embodiments, each of said R is independently selected from halogen, cyano, hydroxy, amino, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkyl NH- or (C 1-3 alkyl) 2 N-. In some embodiments, each of the R a is independently selected from C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkyl NH-, or (C 1-3 alkyl) 2 N-. In some embodiments, each of the R a is independently selected from C 1-3 alkyl. In some embodiments, each of the R a is independently selected from methyl.
  • the R2 optionally contains one or more chiral carbon atoms. In some embodiments, the R2 optionally contains only one chiral carbon atom.
  • the R 2 optionally contains one or more chiral carbon atoms, the configuration of which is optionally an R configuration or an S configuration.
  • the R 2 is selected from
  • the building blocks selected from In some embodiments, the building blocks selected from
  • the building blocks selected from In some embodiments, the building blocks selected from
  • each R 1 is independently selected from amino, halogen, cyano, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, C 1-6 alkyl NH-, (C 1-6 alkyl) 2 N-, C 3-6 cycloalkyl NH-, 3-6 membered heterocycloalkyl, 5- 6-membered heteroaryl, C 1-6 alkyl C(O)-, C 1-6 alkyl C(O)NH-, NH 2 C(O)-, C 1-6 alkyl NHC(O)- , (C 1-6 alkyl) 2 NC(O)-, C 1-6 alkyl OC(O)- or C 1-6 alkyl C(O)O-, the C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, C 1-6 alkyl NH-, (C 1-6 alkyl) NH
  • each R 1 is independently selected from halogen, cyano, C 1-3 alkyl, C 1-3 alkoxy, C 3-6 cycloalkoxy, C 1-3 Alkyl C(O)-, NH 2 C(O)-, C 1-6 alkyl NHC(O)- or (C 1-6 alkyl) 2 NC(O)-, the C 1-3 alkane base, C 1-3 alkoxy, C 3-6 cycloalkoxy, C 1-3 alkyl C(O)-, C 1-6 alkyl NHC(O)- or (C 1-6 alkyl ) 2 NC(O)- optionally substituted with one or more halogens.
  • the m is selected from 0, 1, 2, or 3. In some embodiments, the m is selected from 0, 1 or 2.
  • the m is selected from zero.
  • the L is selected from -CO-.
  • the L is selected from a bond.
  • the R 4 is selected from 6-10 membered heteroaryl, C 3-6 cycloalkyl, phenyl or 3-6 membered heterocycloalkyl, wherein the 6-10 membered heteroaryl , C 3-6 cycloalkyl, phenyl or 3-6 membered heterocycloalkyl optionally substituted with one or more R b .
  • the R 4 is selected from C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl, wherein the C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl is optionally is substituted with one or more R b .
  • the R 4 is selected from C 3-6 cycloalkyl, optionally substituted with one or more R b .
  • the R4 is selected from cyclopropyl optionally substituted with one or more Rb . In some embodiments, the R4 is selected from cyclopropyl.
  • the R b is selected from halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyloxy, C 3-6 cycloalkyl, 5-6 membered heteroaryl, 3-6 membered heterocycloalkyl, -C(O)NHC 1-6 alkyl, -C(O)N(C 1-6 alkyl) 2 , -C(O) OC 1-6 alkyl, -OC(O)C 1-6 alkyl, C 1-6 alkyl C(O)NH-, C 3-6 cycloalkyl C(O)NH-, C 1-6 Alkyl SO 2 NH- or (C 1-6 alkyl) 2 NSO 2 -.
  • the R b is selected from halogen, cyano, C 1-3 alkyl or C 1-3 alkoxy.
  • the heteroatoms in the heteroaryl or heterocycloalkyl are selected from N, O, or S.
  • the heteroatoms in the heteroaryl or heterocycloalkyl are selected from N or O. In some embodiments, the heteroatoms in the heterocyclyl, heteroaryl, or heterocycloalkyl are selected from N or S.
  • the heteroatoms in the heteroaryl or heterocycloalkyl are selected from O. In some embodiments, the heteroatoms in the heteroaryl or heterocycloalkyl are selected from N.
  • the compound of formula I, or a pharmaceutically acceptable salt thereof is selected from a compound of formula II, formula III, or formula IV, or a pharmaceutically acceptable salt thereof:
  • R 1 , R 2 , m, X or Cy are as described above.
  • the present application encompasses the above-defined variables and embodiments thereof, as well as any combination thereof.
  • the application provides the following compounds or pharmaceutically acceptable salts thereof:
  • the application provides the following compounds or pharmaceutically acceptable salts thereof:
  • the present application also provides a pharmaceutical composition comprising the above-mentioned compound of the present application or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical compositions of the present application further include pharmaceutically acceptable excipients.
  • the present application also provides a method for treating or preventing various diseases related to TYK2, comprising administering a therapeutically effective amount of the above-mentioned compound of the present application or a pharmaceutically acceptable salt thereof to a mammal in need of the treatment, preferably a human being or its pharmaceutical composition.
  • the present application also provides the use of the above-mentioned compound of the present application or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a medicament for the treatment or prevention of various diseases related to TYK2.
  • the present application also provides the use of the above-mentioned compound of the present application or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the treatment or prevention of various diseases related to TYK2.
  • the present application also provides the above-mentioned compound of the present application, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for treating or preventing various diseases related to TYK2.
  • the various diseases associated with TYK2 are selected from inflammatory or autoimmune diseases.
  • the compounds of the present application have good cellular activity (such as thermal stability against TYK2 JH2; Jurkat STAT3 phosphorylation activity), liver microsomal metabolic stability, in vivo efficacy (anti-inflammatory) and in vivo drug metabolism properties.
  • the compounds of the present application exhibit significant efficacy in a pharmacodynamic assay in a mouse colitis model (eg, in an Anti-CD40mAb-induced combined immunodeficiency mouse model).
  • a dashed line (----) in a structural unit or group in the present application represents a covalent bond.
  • the covalent bond in some structural units or groups in this application is not connected to a specific atom, it means that the covalent bond can be connected to any atom in the structural unit or group, as long as the valence bond connection rules are not violated .
  • substituted means that any one or more hydrogen atoms on a specified atom are replaced by a substituent, so long as the valence of the specified atom is normal and the compound after substitution is stable.
  • an ethyl group “optionally” substituted with halogen means that the ethyl group can be unsubstituted ( CH2CH3 ) , monosubstituted (eg CH2CH2F ) , polysubstituted (eg CHFCH2F , CH 2 CHF 2 etc.) or fully substituted (CF 2 CF 3 ). It will be understood by those skilled in the art that for any group containing one or more substituents, no substitution or substitution pattern is introduced that is sterically impossible and/or cannot be synthesized.
  • Cmn in this context is that the moiety has an integer number of carbon atoms in the given range.
  • C 1-6 means that the group may have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms.
  • C 1-3 means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms.
  • any variable eg, R
  • its definition in each case is independent. So, for example, if a group is substituted with 2 Rs, each R has independent options.
  • linking group When the number of a linking group is 0, such as -(CH 2 ) 0 -, it means that the linking group is a covalent bond.
  • substituents When a substituent's bond is cross-linked to two atoms on a ring, the substituent can bond to any atom on the ring.
  • structural unit Indicates that it can be substituted at any position on cyclohexyl or cyclohexadiene.
  • halo or halogen refers to fluorine, chlorine, bromine and iodine.
  • alkyl refers to a hydrocarbon group of the general formula CnH2n+1 .
  • the alkyl group can be straight or branched.
  • C1-6 alkyl refers to an alkyl group containing 1 to 6 carbon atoms (eg, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc.).
  • alkyl portion of alkoxy, alkylamino, dialkylamino, alkylsulfonyl, and alkylthio have the same definitions above.
  • C1-3 alkyl refers to an alkyl group containing 1 to 3 carbon atoms (eg, methyl, ethyl, propyl, and isopropyl).
  • alkoxy refers to -O-alkyl
  • cycloalkyloxy refers to -O-cycloalkyl
  • cycloalkyl refers to a carbocyclic ring that is fully saturated and may exist as a monocyclic, bridged or spirocyclic ring. Unless otherwise indicated, the carbocycle is typically a 3- to 10-membered ring.
  • Non-limiting examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, diamond Alkyl, bicyclo[1.1.1]pent-1-yl, etc.
  • C3-4cycloalkyl includes cyclopropyl and cyclobutyl.
  • heterocycloalkyl refers to a cyclic group that is fully saturated and may exist as a monocyclic, bridged (including paracyclic) or spirocyclic ring. Unless otherwise indicated, the heterocycle is typically a 3- to 7-membered ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen and/or nitrogen.
  • 3-membered heterocycloalkyl examples include, but are not limited to, oxiranyl, oxiranyl, azithryl, and non-limiting examples of 4-membered heterocycloalkyl include, but are not limited to, azetidinyl, oxetane
  • Examples of cyclyl, thibutanyl, 5-membered heterocycloalkyl include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidine
  • Examples of yl, imidazolidinyl, tetrahydropyrazolyl, 6-membered heterocycloalkyl include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl,
  • aryl refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated pi electron system.
  • an aryl group can have 6-20 carbon atoms, 6-14 carbon atoms, or 6-12 carbon atoms.
  • Non-limiting examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, and 1,2,3,4-tetralin, and the like.
  • heteroaryl refers to a monocyclic or fused polycyclic ring system containing at least one ring atom selected from N, O, S, the remaining ring atoms being C, and having at least one aromatic ring.
  • Preferred heteroaryl groups have a single 5 to 8 membered ring, or multiple fused rings containing 6 to 14, especially 6 to 10, ring atoms.
  • heteroaryl groups include, but are not limited to, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl , tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothienyl, indolyl, isoindolyl, etc.
  • the compounds of the present application may exist in specific geometric or stereoisomeric forms.
  • This application contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers isomers, (D)-isomers, (L)-isomers, and racemic mixtures thereof and other mixtures, such as enantiomerically or diastereomerically enriched mixtures, all of which belong to this within the scope of the application.
  • Additional asymmetric carbon atoms may be present in substituents such as alkyl. All such isomers, as well as mixtures thereof, are included within the scope of this application.
  • treating means administering a compound or formulation described herein to ameliorate or eliminate a disease or one or more symptoms associated with the disease, and includes:
  • prevention means administering a compound or formulation described herein to prevent a disease or one or more symptoms associated with the disease, and includes preventing the occurrence of a disease or disease state in a mammal, particularly when Such mammals are susceptible to the disease state, but have not been diagnosed with the disease state.
  • terapéuticaally effective amount means (i) treating or preventing a particular disease, condition or disorder, (ii) alleviating, ameliorating or eliminating one or more symptoms of a particular disease, condition or disorder, or (iii) preventing or delaying The amount of a compound of the present application for the onset of one or more symptoms of a particular disease, condition or disorder described herein.
  • the amount of a compound of the present application that constitutes a “therapeutically effective amount” will vary depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by those skilled in the art according to its own knowledge and the present disclosure.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissue without more toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • salts for example, metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids and the like can be mentioned .
  • composition refers to a mixture of one or more compounds of the present application or salts thereof and pharmaceutically acceptable excipients.
  • the purpose of a pharmaceutical composition is to facilitate administration of a compound of the present application to an organism.
  • pharmaceutically acceptable excipients refers to those excipients which are not significantly irritating to the organism and which do not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like.
  • tautomer or "tautomeric form” refers to structural isomers of different energies that are interconvertible via a low energy barrier.
  • proton tautomers also known as proton tautomers
  • proton tautomers include interconversions via migration of protons, such as keto-enol and imine-enamine isomerizations.
  • a specific example of a proton tautomer is an imidazole moiety in which a proton can move between two ring nitrogens.
  • Valence tautomers include interconversions through recombination of some of the bonding electrons.
  • the present application also includes isotopically-labeled compounds of the present application which are the same as those described herein, but wherein one or more atoms have been replaced by an atom having an atomic weight or mass number different from that normally found in nature.
  • isotopes that may be incorporated into the compounds of the present application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2H, 3H , 11C , 13C , 14C , 13 , respectively N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 123 I, 125 I and 36 Cl and the like.
  • isotopically-labeled compounds of the present application are useful in compound and/or substrate tissue distribution assays. Tritiated (ie 3 H) and carbon-14 (ie 14 C) isotopes are especially preferred for their ease of preparation and detectability.
  • Positron emitting isotopes such as15O , 13N , 11C and18F can be used in positron emission tomography (PET) studies to determine substrate occupancy.
  • Isotopically labeled compounds of the present application can generally be prepared by the following procedures analogous to those disclosed in the Schemes and/or Examples below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
  • substitution with heavier isotopes such as deuterium (ie 2H ) may provide certain therapeutic advantages resulting from greater metabolic stability (eg increased in vivo half-life or reduced dosage requirements), and thus in some cases
  • deuterium substitution may be partial or complete, and partial deuterium substitution means that at least one hydrogen is replaced by at least one deuterium, and all such forms of compounds are included within the scope of this application.
  • the compounds of the present application may be asymmetric, eg, have one or more stereoisomers. Unless otherwise specified, all stereoisomers include, such as enantiomers and diastereomers.
  • the compounds of the present application containing asymmetric carbon atoms can be isolated in optically pure or racemic forms. Optically pure forms can be resolved from racemic mixtures or synthesized by using chiral starting materials or chiral reagents.
  • the pharmaceutical composition of the present application can be prepared by combining the compound of the present application with suitable pharmaceutically acceptable excipients, for example, it can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders , granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols, etc.
  • Typical routes of administration of a compound of the present application, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, Intramuscular, subcutaneous, intravenous administration.
  • the pharmaceutical composition of the present application can be manufactured by methods well known in the art, such as conventional mixing method, dissolving method, granulation method, sugar-coated pill method, grinding method, emulsification method, freeze-drying method and the like.
  • the pharmaceutical composition is in oral form.
  • the pharmaceutical compositions can be formulated by admixing the active compound with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of the present application to be formulated into tablets, pills, lozenges, dragees, capsules, liquids, gels, slurries, suspensions, etc., for oral administration to patients.
  • Solid oral compositions can be prepared by conventional mixing, filling or tabletting methods. It can be obtained, for example, by mixing the active compound with solid excipients, optionally grinding the resulting mixture, adding other suitable excipients if desired, and processing the mixture into granules to give tablets or icing core.
  • Suitable adjuvants include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, and the like.
  • compositions may also be suitable for parenteral administration as sterile solutions, suspensions or lyophilized products in suitable unit dosage forms.
  • Therapeutic dosages of the compounds of the present application may depend, for example, on the particular use of the treatment, the mode of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician.
  • the ratio or concentration of a compound of the present application in a pharmaceutical composition may not be fixed and depends on a variety of factors including dosage, chemical properties (eg, hydrophobicity) and route of administration.
  • the compounds of the present application can be provided for parenteral administration in physiologically buffered aqueous solutions containing about 0.1-10% w/v of the compounds. Some typical doses range from about 1 ⁇ g/kg to about 1 g/kg body weight/day.
  • the dose ranges from about 0.01 mg/kg to about 100 mg/kg body weight/day.
  • the dosage is likely to depend on such variables as the type and extent of progression of the disease or disorder, the general state of health of the particular patient, the relative biological potency of the compound selected, the excipient formulation and its route of administration. Effective doses can be obtained by extrapolation from dose-response curves derived from in vitro or animal model test systems.
  • the compounds of the present application can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by their combination with other chemical synthesis methods, and those well known to those skilled in the art Equivalent to alternatives, preferred embodiments include but are not limited to the examples of the present application.
  • the compounds of the present application can be prepared by those skilled in the art of organic synthesis with reference to the following routes:
  • DIPEA diisopropylethylamine
  • Xantphos stands for 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene
  • DMF stands for N,N-dimethylformamide.
  • Example 3-27 Referring to the preparation process of step 4 of Example 1, the raw material compounds in the following table were substituted for compound 1-d, and the compounds of the examples in table 1 below were prepared:
  • the melting temperature (Tm) is greater than 40°C; preferably greater than 45°C; more preferably greater than 55°C; under the condition that the final concentration is 1 ⁇ M, the melting temperature (Tm) is greater than 40°C; preferably greater than 45°C; more preferably greater than 50°C.
  • STAT3 phosphorylation detection kit (Y705), manufacturer Cisbio, product number 62AT3PEG. Take Jurakt cells grown in log phase, count 20 ⁇ L, take the required number of cells (mL), centrifuge at 1300 rpm for 3 min, add phenol red-free 1640 basal medium (manufacturer Gibco, product number 11835-030) to adjust the cell density, adjust the cell density The density is about 1.7*10E7/mL. The cells were seeded according to the above cell density (384-well small volume white plate), 8 ⁇ L/well; the nanoliter sampler was added, and the compound was incubated for 1.5 h; , Cat. No.
  • the 300 ⁇ L final incubation system contains 30 ⁇ L liver microsomes (protein concentration: 5 mg/mL), 30 ⁇ L NADPH+MgCl 2 , 3 ⁇ L test compound (prepared in acetonitrile), and 237 ⁇ L PBS buffer (pH 7.4).
  • the proportion of organic solvent (acetonitrile) is 1%.
  • the reaction was stopped with 300 ⁇ L of ice acetonitrile containing internal standard.
  • ICR mice weighing 20-24 g, were randomly divided into groups of 9 mice after acclimation for 3-5 days, and the compounds to be tested were administered orally respectively.
  • test animals ICR mice were fasted for 12 hours before administration, given food for 4 hours after administration, and had free access to water before and after the experiment and during the experiment.

Abstract

一种含酰胺基和杂环烷基的TYK2抑制剂化合物及其制备方法，并涉及其在制备治疗或预防TYK2相关疾病的药物中的用途。

Description

含酰胺基和杂环烷基的TYK2抑制剂化合物
相关申请的引用
本申请要求于2020年12月08日向中华人民共和国知识产权局提交的申请号为202011446489.7的中国发明专利申请的权益，在此将它们的全部内容以援引的方式整体并入本文中。
技术领域
本申请属于药物化学领域，提供了含酰胺基和杂环烷基的TYK2抑制剂化合物及其制备方法，并涉及其在制备治疗或预防TYK2相关疾病的药物中的用途。
发明背景
酪氨酸激酶2(TYK2)为非受体酪氨酸激酶的Janus激酶(JAK)家族的成员且已在小鼠和人类两者中显示，在IL-12、IL-23和I型干扰素受体下游的调控信号转导级联中至关重要。TYK2介导受体诱导的STAT转录因子家族成员的磷酸化，其为导致STAT蛋白质的二聚化和STAT依赖性促炎性基因的转录的必需信号。TYK2缺乏小鼠抵抗结肠炎、牛皮癣和多发性硬化的实验模型，从而证明TYK2介导的信号传导在自身免疫和相关病症中的重要性。在人类中，保护表达TYK2的无活性变体的个体免受多发性硬化和可能的其它自身免疫性病症。
鉴于可通过涉及调节细胞因子和/或干扰素的治疗而获益的病症，能够调节细胞因子和/或干扰素诸如IL-12、IL-23和/或IFNα的TYK2抑制剂化合物以及使用这些化合物的方法可向众多有此需要的患者提供实质性治疗益处。
发明内容
一方面，本申请提供了一种式I化合物或其药学上可接受的盐：
Figure PCTCN2021135912-appb-000001
其中，
Cy选自C 6-10芳基或5-10元杂芳基；
X选自-N(R)-、O或S；
R选自氢或C 1-6烷基；
L 1选自-(CH 2) n-；
n选自1、2、3或4；
R 2选自C 3-10环烷基或3-10元杂环烷基，所述C 3-10环烷基或3-10元杂环烷基任选地被一个或多个R a取代；
每一个R a分别独立地选自卤素、氰基、羟基、氨基、C 1-8烷基、C 1-8烷氧基、C 1-8烷基NH-、(C 1-8烷基) 2N-或C 3-8环烷基；
每一个R 1分别独立地选自氨基、卤素、氰基、羟基、C 1-8烷基、C 1-8烷氧基、C 3-10环烷基、C 3-10环烷氧基、C 1-8烷基NH-、(C 1-8烷基) 2N-、C 3-10环烷基NH-、3-10元杂环烷基、5-10元杂芳基、C 1-8烷基C(O)-、C 1-8烷基C(O)NH-、NH 2C(O)-、C 1-8烷基NHC(O)-、(C 1-8烷基) 2NC(O)-、C 1-8烷基OC(O)-或C 1-8烷基C(O)O-， 所述C 1-8烷基、C 1-8烷氧基、C 3-10环烷基、C 3-10环烷氧基、C 1-8烷基NH-、(C 1-8烷基) 2N-、C 3-10环烷基NH-、3-10元杂环烷基、5-10元杂芳基、C 1-8烷基C(O)-、C 1-8烷基C(O)NH-、NH 2C(O)-、C 1-8烷基NHC(O)-、(C 1-8烷基) 2NC(O)-、C 1-8烷基OC(O)-或C 1-8烷基C(O)O-任选地被一个或多个卤素、羟基、氰基或氨基取代；
m选自0、1、2、3或4；
L选自-C(O)-或键；
R 4选自5-10元杂芳基、C 3-10环烷基、C 6-10芳基或3-10元杂环烷基，其中所述5-10元杂芳基、C 3-10环烷基、C 6-10芳基或3-10元杂环烷基任选地被一个或多个R b取代；
R b选自卤素、氰基、C 1-8烷基、C 1-8烷氧基、C 3-10环烷基氧基、C 3-10环烷基、5-10元杂芳基、3-10元杂环烷基、氨基、C 1-8烷基NH-、(C 1-8烷基) 2N-、C 3-10环烷基NH-、-C(O)NHC 1-8烷基、-C(O)N(C 1-8烷基) 2、-C(O)OC 1-8烷基、-OC(O)C 1-8烷基、C 1-8烷基C(O)NH-、C 3-10环烷基C(O)NH-、C 1-8烷基SO 2NH-或(C 1-8烷基) 2NSO 2-。
在一些实施方案中，所述Cy选自苯基或5-6元杂芳基。
在一些实施方案中，所述Cy选自苯基或6元杂芳基。
在一些实施方案中，所述Cy选自苯基或吡啶基。在一些实施方案中，Cy选自苯基。
在一些实施方案中，所述R选自氢或C 1-3烷基；在一些实施方案中，所述R选自氢。
在一些实施方案中，所述X选自NH或O。在一些实施方案中，所述X选自NH。在一些实施方案中，所述X选自O。
在一些实施方案中，所述n选自1或2。
在一些实施方案中，所述L 1选自-(CH 2)-。
在一些实施方案中，所述R 2选自C 3-10单环环烷基或3-10元单环杂环烷基，所述C 3-10单环环烷基或3-10元单环杂环烷基任选地被一个或多个R a取代。
在一些实施方案中，所述R 2选自C 3-6单环环烷基或3-6元单环杂环烷基，所述C 3-6单环环烷基或3-6元单环杂环烷基任选地被一个或多个R a取代。
在一些实施方案中，所述R 2选自C 3-10环烷基或含有1、2或3个选自N、O或S原子的3-10元杂环烷基，所述C 3-10环烷基或3-10元杂环烷基任选地被一个或多个R a取代。
在一些实施方案中，所述R 2选自C 3-6环烷基或含有1、2或3个选自N、O或S原子的3-6元杂环烷基，所述C 3-6环烷基或3-6元杂环烷基任选地被一个或多个R a取代。
在一些实施方案中，所述R 2选自C 3-6环烷基或3-6元杂环烷基，所述C 3-6环烷基或3-6元杂环烷基任选地被一个或多个R a取代。
在一些实施方案中，所述R 2选自3-6元杂环烷基，所述3-6元杂环烷基任选地被一个或多个R a取代。
在一些实施方案中，所述R 2选自含有1、2或3个选自N、O或S原子的3-6元杂环烷基，所述3-6元杂环烷基任选地被一个或多个R a取代。
在一些实施方案中，所述R 2选自含有1、2或3个选自N、O或S原子的5-6元杂环烷基，所述5-6元杂环烷基任选地被一个或多个R a取代。
在一些实施方案中，所述R 2选自含有1或2个选自N或O原子的5-6元杂环烷基，所述5-6元杂环烷基任选地被一个或多个R a取代。
在一些实施方案中，所述R 2选自1,4-二氧六环基、四氢吡喃基、哌啶基、吗啉基、吡咯烷基或呋喃基，所述1,4-二氧六环基、四氢吡喃基、哌啶基、吗啉基、吡咯烷基或呋喃基任选地被一个或多个R a取代。
在一些实施方案中，所述R 2选自含有1或2个O原子的5-6元杂环烷基，所述5-6元杂环烷基任选地 被一个或多个R a取代。
在一些实施方案中，所述R 2选自1,4-二氧六环基、四氢吡喃基或呋喃基，所述1,4-二氧六环基、四氢吡喃基或呋喃基任选地被一个或多个R a取代。
在一些实施方案中，所述R 2选自
Figure PCTCN2021135912-appb-000002
Figure PCTCN2021135912-appb-000003
其中
Figure PCTCN2021135912-appb-000004
Figure PCTCN2021135912-appb-000005
任选地被一个或多个R a取代。
在一些实施方案中，所述R 2选自
Figure PCTCN2021135912-appb-000006
其中
Figure PCTCN2021135912-appb-000007
Figure PCTCN2021135912-appb-000008
任选地被一个或多个R a取代。
在一些实施方案中，所述每一个R a分别独立地选自卤素、氰基、羟基、氨基、C 1-6烷基、C 1-6烷氧基、C 1-6烷基NH-、(C 1-6烷基) 2N-或C 3-6环烷基。在一些实施方案中，所述每一个R a分别独立地选自卤素、氰基、羟基、氨基、C 1-3烷基、C 1-3烷氧基、C 1-3烷基NH-或(C 1-3烷基) 2N-。在一些实施方案中，所述每一个R a分别独立地选自C 1-3烷基、C 1-3烷氧基、C 1-3烷基NH-或(C 1-3烷基) 2N-。在一些实施方案中，所述每一个R a分别独立地选自C 1-3烷基。在一些实施方案中，所述每一个R a分别独立地选自甲基。
在一些实施方案中，所述R 2任选地含有一个或多个手性碳原子。在一些实施方案中，所述R 2任选地仅含有一个手性碳原子。
在一些实施方案中，所述R 2任选地含有一个或多个手性碳原子，所述手性碳原子的构型任选地为R构型或S构型。
在一些实施方案中，所述R 2选自
Figure PCTCN2021135912-appb-000009
Figure PCTCN2021135912-appb-000010
在一些实施方案中，结构单元
Figure PCTCN2021135912-appb-000011
选自
Figure PCTCN2021135912-appb-000012
Figure PCTCN2021135912-appb-000013
在一些实施方案中，结构单元
Figure PCTCN2021135912-appb-000014
选自
Figure PCTCN2021135912-appb-000015
Figure PCTCN2021135912-appb-000016
在一些实施方案中，结构单元
Figure PCTCN2021135912-appb-000017
选自
Figure PCTCN2021135912-appb-000018
在一些实施方案中，结构单元
Figure PCTCN2021135912-appb-000019
选自
Figure PCTCN2021135912-appb-000020
Figure PCTCN2021135912-appb-000021
Figure PCTCN2021135912-appb-000022
在一些实施方案中，结构单元
Figure PCTCN2021135912-appb-000023
选自
Figure PCTCN2021135912-appb-000024
Figure PCTCN2021135912-appb-000025
在一些实施方案中，结构单元
Figure PCTCN2021135912-appb-000026
选自
Figure PCTCN2021135912-appb-000027
在一些实施方案中，结构单元
Figure PCTCN2021135912-appb-000028
选自
Figure PCTCN2021135912-appb-000029
在一些实施方案中，结构单元
Figure PCTCN2021135912-appb-000030
选自
Figure PCTCN2021135912-appb-000031
在一些实施方案中，结构单元
Figure PCTCN2021135912-appb-000032
选自
Figure PCTCN2021135912-appb-000033
在一些实施方案中，结构单元
Figure PCTCN2021135912-appb-000034
选自
Figure PCTCN2021135912-appb-000035
在一些实施方案中，结构单元
Figure PCTCN2021135912-appb-000036
选自
Figure PCTCN2021135912-appb-000037
Figure PCTCN2021135912-appb-000038
在一些实施方案中，结构单元
Figure PCTCN2021135912-appb-000039
选自
Figure PCTCN2021135912-appb-000040
Figure PCTCN2021135912-appb-000041
在一些实施方案中，结构单元
Figure PCTCN2021135912-appb-000042
选自
Figure PCTCN2021135912-appb-000043
在一些实施方案中，结构单元
Figure PCTCN2021135912-appb-000044
选自
Figure PCTCN2021135912-appb-000045
在一些实施方案中，结构单元
Figure PCTCN2021135912-appb-000046
选自
Figure PCTCN2021135912-appb-000047
在一些实施方案中，所述每一个R 1分别独立地选自氨基、卤素、氰基、羟基、C 1-6烷基、C 1-6烷氧基、C 3-6环烷基、C 3-6环烷氧基、C 1-6烷基NH-、(C 1-6烷基) 2N-、C 3-6环烷基NH-、3-6元杂环烷基、5-6元杂芳基、C 1-6烷基C(O)-、C 1-6烷基C(O)NH-、NH 2C(O)-、C 1-6烷基NHC(O)-、(C 1-6烷基) 2NC(O)-、C 1-6烷基OC(O)-或C 1-6烷基C(O)O-，所述C 1-6烷基、C 1-6烷氧基、C 3-6环烷基、C 3-6环烷氧基、C 1-6烷基NH-、(C 1-6烷基) 2N-、C 3-6环烷基NH-、3-6元杂环烷基、5-6元杂芳基、C 1-6烷基C(O)-、C 1-6烷基C(O)NH-、NH 2C(O)-、C 1-6烷基NHC(O)-、(C 1-6烷基) 2NC(O)-、C 1-6烷基OC(O)-或C 1-6烷基C(O)O-任选地被一个或多个卤素、羟基、氰基或氨基取代。
在一些实施方案中，所述每一个R 1分别独立地选自卤素、氰基、C 1-3烷基、C 1-3烷氧基、C 3-6环烷氧基、 C 1-3烷基C(O)-、NH 2C(O)-、C 1-6烷基NHC(O)-或(C 1-6烷基) 2NC(O)-，所述C 1-3烷基、C 1-3烷氧基、C 3-6环烷氧基、C 1-3烷基C(O)-、C 1-6烷基NHC(O)-或(C 1-6烷基) 2NC(O)-任选地被一个或多个卤素取代。
在一些实施方案中，所述m选自0、1、2或3。在一些实施方案中，所述m选自0、1或2。
在一些实施方案中，所述m选自0。
在一些实施方案中，所述L选自-CO-。
在一些实施方案中，所述L选自键。
在一些实施方案中，所述R 4选自6-10元杂芳基、C 3-6环烷基、苯基或3-6元杂环烷基，其中所述6-10元杂芳基、C 3-6环烷基、苯基或3-6元杂环烷基任选地被一个或多个R b取代。
在一些实施方案中，所述R 4选自C 3-6环烷基或3-6元杂环烷基，其中所述C 3-6环烷基或3-6元杂环烷基任选地被一个或多个R b取代。
在一些实施方案中，所述R 4选自C 3-6环烷基，所述C 3-6环烷基任选地被一个或多个R b取代。
在一些实施方案中，所述R 4选自任选地被一个或多个R b取代的环丙基。在一些实施方案中，所述R 4选自环丙基。
在一些实施方案中，所述R b选自卤素、氰基、C 1-6烷基、C 1-6烷氧基、C 3-6环烷基氧基、C 3-6环烷基、5-6元杂芳基、3-6元杂环烷基、-C(O)NHC 1-6烷基、-C(O)N(C 1-6烷基) 2、-C(O)OC 1-6烷基、-OC(O)C 1-6烷基、C 1-6烷基C(O)NH-、C 3-6环烷基C(O)NH-、C 1-6烷基SO 2NH-或(C 1-6烷基) 2NSO 2-。
在一些实施方案中，所述R b选自卤素、氰基、C 1-3烷基或C 1-3烷氧基。
在一些实施方案中，结构单元
Figure PCTCN2021135912-appb-000048
选自
Figure PCTCN2021135912-appb-000049
在一些实施方案中，所述杂芳基或杂环烷基中的杂原子选自N、O或S。
在一些实施方案中，所述杂芳基或杂环烷基中的杂原子选自N或O。在一些实施方案中，所述杂环基、杂芳基或杂环烷基中的杂原子选自N或S。
在一些实施方案中，所述杂芳基或杂环烷基中的杂原子选自O。在一些实施方案中，所述杂芳基或杂环烷基中的杂原子选自N。
在一些实施方案中，所述式I化合物或其药学上可接受的盐选自式II、式III或式IV化合物或其药学上可接受的盐：
Figure PCTCN2021135912-appb-000050
其中，R 1、R 2、m、X或Cy的定义如前所述。
在一些实施方案中，本申请包含上述定义的变量及其实施方案，以及它们的任意组合。
另一方面，本申请提供以下化合物或其药学上可接受的盐：
Figure PCTCN2021135912-appb-000051
Figure PCTCN2021135912-appb-000052
另一方面，本申请提供以下化合物或其药学上可接受的盐：
Figure PCTCN2021135912-appb-000053
Figure PCTCN2021135912-appb-000054
Figure PCTCN2021135912-appb-000055
另一方面，本申请还提供药物组合物，其包含本申请的上述化合物或其药学上可接受的盐。在一些实施方案中，本申请的药物组合物还包括药学上可接受的辅料。
另一方面，本申请还提供一种治疗或预防TYK2相关各种疾病的方法，包括对需要该治疗的哺乳动物，优选人类，给予治疗有效量的本申请的上述化合物其药学上可接受的盐或其药物组合物。
另一方面，本申请还提供了本申请的上述化合物或其药学上可接受的盐、或其药物组合物在制备治疗或预防TYK2相关各种疾病的药物中的用途。
另一方面，本申请还提供了本申请的上述化合物或其药学上可接受的盐、或其药物组合物在治疗或预防TYK2相关各种疾病中的用途。
另一方面，本申请还提供了一种治疗或预防TYK2相关各种疾病的本申请的上述化合物、其药学上可接受的盐、或其药物组合物。
在一些实施方案中，所述TYK2相关各种疾病选自炎性或自身免疫性疾病。
技术效果
本申请的化合物具有良好的细胞活性(如针对TYK2 JH2的热稳定性；Jurkat STAT3磷酸化活性)、肝微粒体代谢稳定性、体内药效(抗炎)及体内药物代谢性质。在一些实施方案中，本申请的化合物在小鼠结肠炎模型(例如在Anti-CD40mAb诱导的联合免疫缺陷小鼠模型)的药效实验中，表现出明显的药效。
定义
除非另有说明，本申请中所用的下列术语具有下列含义。一个特定的术语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照本领域普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。
本申请中的结构单元或者基团中的虚线(----)表示共价键。
本申请中的某些结构单元或者基团中的共价键未与具体的原子连接时，表示该共价键可以与该结构单元或者基团中的任意原子连接，只要不违背价键连接规则。
术语“被取代”是指特定原子上的任意一个或多个氢原子被取代基取代，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为氧代(即＝O)时，意味着两个氢原子被取代，氧代不会发生在芳香基上。
术语“任选”或“任选地”是指随后描述的事件或情况可以发生或不发生，该描述包括发生所述事件或情况和不发生所述事件或情况。例如，乙基“任选”被卤素取代，指乙基可以是未被取代的(CH 2CH 3)、单取代的(如CH 2CH 2F)、多取代的(如CHFCH 2F、CH 2CHF 2等)或完全被取代的(CF 2CF 3)。本领域技术人员可理解，对于包含一个或多个取代基的任何基团，不会引入任何在空间上不可能存在和/或不能合成的取代或取代模式。
本文中的C m-n，是该部分具有给定范围中的整数个碳原子。例如“C 1-6”是指该基团可具有1个碳原子、 2个碳原子、3个碳原子、4个碳原子、5个碳原子或6个碳原子。例如C 1-3是指该基团可具有1个碳原子、2个碳原子、3个碳原子。
当任何变量(例如R)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。因此，例如，如果一个基团被2个R所取代，则每个R都有独立的选项。
当一个连接基团的数量为0时，比如-(CH 2) 0-，表示该连接基团为共价键。
当其中一个变量选自共价键时，表示其连接的两个基团直接相连，比如A-L’-Z中L’代表共价键时表示该结构实际上是A-Z。
当一个取代基的键交叉连接到一个环上的两个原子时，这种取代基可以与这个环上的任意原子相键合。例如，结构单元
Figure PCTCN2021135912-appb-000056
表示其可在环己基或者环己二烯上的任意一个位置发生取代。
术语“卤”或“卤素”是指氟、氯、溴和碘。
术语“烷基”是指通式为C nH 2n+1的烃基。该烷基可以是直链或支链的。例如，术语“C 1- 6烷基”指含有1至6个碳原子的烷基(例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、1-甲基丁基、2-甲基丁基、3-甲基丁基、新戊基、己基、2-甲基戊基等)。类似地，烷氧基、烷基氨基、二烷基氨基、烷基磺酰基和烷硫基的烷基部分(即烷基)具有上述相同定义。又例如，术语“C 1- 3烷基”指含有1至3个碳原子的烷基(例如甲基、乙基、丙基和异丙基)。
术语“烷氧基”指-O-烷基。
术语“环烷基氧基”指-O-环烷基。
术语“环烷基”指完全饱和的并且可以以呈单环、桥环或螺环存在的碳环。除非另有指示，该碳环通常为3至10元环。环烷基非限制性实例包括但不限于环丙基、环丁基、环戊基、环己基、降冰片基(双环[2.2.1]庚基)、双环[2.2.2]辛基、金刚烷基、二环[1.1.1]戊-1-基等。例如，C 3-4环烷基包括环丙基和环丁基。
术语“杂环烷基”是指完全饱和的并且可以以单环、桥环(包括并环)或螺环存在的环状基团。除非另有指示，该杂环通常为含有1至3个独立地选自硫、氧和/或氮的杂原子(优选1或2个杂原子)的3至7元环。3元杂环烷基的实例包括但不限于环氧乙烷基、环硫乙烷基、环氮乙烷基，4元杂环烷基的非限制性实例包括但不限于吖丁啶基、噁丁环基、噻丁环基，5元杂环烷基的实例包括但不限于四氢呋喃基、四氢噻吩基、吡咯烷基、异噁唑烷基、噁唑烷基、异噻唑烷基、噻唑烷基、咪唑烷基、四氢吡唑基，6元杂环烷基的实例包括但不限于哌啶基、四氢吡喃基、四氢噻喃基、吗啉基、哌嗪基、1,4-噻噁烷基、1,4-二氧六环基、硫代吗啉基、1,3-二噻烷基、1,4-二噻烷基，7元杂环烷基的实例包括但不限于氮杂环庚烷基、氧杂环庚烷基、硫杂环庚烷基。优选为具有5或6个环原子的单环杂环烷基。
术语“芳基”是指具有共轭的π电子体系的全碳单环或稠合多环的芳香环基团。例如，芳基可以具有6-20个碳原子，6-14个碳原子或6-12个碳原子。芳基的非限制性实例包括但不限于苯基、萘基、蒽基和1,2,3,4-四氢化萘等。
术语“杂芳基”是指单环或稠合多环体系，其中含有至少一个选自N、O、S的环原子，其余环原子为C，并且具有至少一个芳香环。优选的杂芳基具有单个5至8元环，或包含6至14个，尤其是6至10个环原子的多个稠合环。杂芳基的非限制性实例包括但不限于吡咯基、呋喃基、噻吩基、咪唑基、噁唑基、吡唑基、吡啶基、嘧啶基、吡嗪基、喹啉基、异喹啉基、四唑基、三唑基、三嗪基、苯并呋喃基、苯并噻吩基、吲哚基、异吲哚基等。
本申请的化合物可以存在特定的几何或立体异构体形式。本申请设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本申请的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本申请的范围之内。
除非另有说明，用楔形实线键
Figure PCTCN2021135912-appb-000057
和楔形虚线键
Figure PCTCN2021135912-appb-000058
表示一个立体中心的绝对构型，用直形实线键
Figure PCTCN2021135912-appb-000059
和直形虚线键
Figure PCTCN2021135912-appb-000060
表示立体中心的相对构型，用波浪线
Figure PCTCN2021135912-appb-000061
表示楔形实线键
Figure PCTCN2021135912-appb-000062
或楔形虚线键
Figure PCTCN2021135912-appb-000063
或用波浪线
Figure PCTCN2021135912-appb-000064
表示直形实线键
Figure PCTCN2021135912-appb-000065
和直形虚线键
Figure PCTCN2021135912-appb-000066
除非另有说明，当化合物中存在双键结构，如碳碳双键、碳氮双键和氮氮双键，且双键上的各个原子均连接有两个不同的取代基时(包含氮原子的双键中，氮原子上的一对孤对电子视为其连接的一个取代基)，如果该化合物中双键上的原子与其取代基之间用波浪线
Figure PCTCN2021135912-appb-000067
连接，则表示该化合物的(Z)型异构体、(E)型异构体或两种异构体的混合物。
术语“治疗”意为将本申请所述化合物或制剂进行给药以改善或消除疾病或与所述疾病相关的一个或多个症状，且包括：
(i)抑制疾病或疾病状态，即遏制其发展；
(ii)缓解疾病或疾病状态，即使该疾病或疾病状态消退。
术语“预防”意为将本申请所述化合物或制剂进行给药以预防疾病或与所述疾病相关的一个或多个症状，且包括：预防疾病或疾病状态在哺乳动物中出现，特别是当这类哺乳动物易患有该疾病状态，但尚未被诊断为已患有该疾病状态时。
术语“治疗有效量”意指(i)治疗或预防特定疾病、病况或障碍，(ii)减轻、改善或消除特定疾病、病况或障碍的一种或多种症状，或(iii)预防或延迟本文中所述的特定疾病、病况或障碍的一种或多种症状发作的本申请化合物的用量。构成“治疗有效量”的本申请化合物的量取决于该化合物、疾病状态及其严重性、给药方式以及待被治疗的哺乳动物的年龄而改变，但可例行性地由本领域技术人员根据其自身的知识及本公开内容而确定。
术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。
作为药学上可接受的盐，例如，可以提及金属盐、铵盐、与有机碱形成的盐、与无机酸形成的盐、与有机酸形成的盐、与碱性或者酸性氨基酸形成的盐等。
术语“药物组合物”是指一种或多种本申请的化合物或其盐与药学上可接受的辅料组成的混合物。药物组合物的目的是有利于对有机体给予本申请的化合物。
术语“药学上可接受的辅料”是指对有机体无明显刺激作用，而且不会损害该活性化合物的生物活性及性能的那些辅料。合适的辅料是本领域技术人员熟知的，例如碳水化合物、蜡、水溶性和/或水可膨胀的聚合物、亲水性或疏水性材料、明胶、油、溶剂、水等。
词语“包括(comprise)”或“包含(comprise)”及其英文变体例如comprises或comprising应理解为开放的、非排他性的意义，即“包括但不限于”。
本申请的化合物和中间体还可以以不同的互变异构体形式存在，并且所有这样的形式包含于本申请的范围内。术语“互变异构体”或“互变异构体形式”是指可经由低能垒互变的不同能量的结构异构体。例如，质子互变异构体(也称为质子转移互变异构体)包括经由质子迁移的互变，如酮-烯醇及亚胺-烯胺异构化。质 子互变异构体的具体实例是咪唑部分，其中质子可在两个环氮间迁移。价互变异构体包括通过一些成键电子的重组的互变。
本申请还包括与本文中记载的那些相同的，但一个或多个原子被原子量或质量数不同于自然中通常发现的原子量或质量数的原子置换的同位素标记的本申请化合物。可结合到本申请化合物的同位素的实例包括氢、碳、氮、氧、磷、硫、氟、碘和氯的同位素，诸如分别为 2H、 3H、 11C、 13C、 14C、 13N、 15N、 15O、 17O、 18O、 31P、 32P、 35S、 18F、 123I、 125I和 36Cl等。
某些同位素标记的本申请化合物(例如用 3H及 14C标记的那些)可用于化合物和/或底物组织分布分析中。氚化(即 3H)和碳-14(即 14C)同位素对于由于它们易于制备和可检测性是尤其优选的。正电子发射同位素，诸如 15O、 13N、 11C和 18F可用于正电子发射断层扫描(PET)研究以测定底物占有率。通常可以通过与公开于下文的方案和/或实施例中的那些类似的下列程序，通过同位素标记试剂取代未经同位素标记的试剂来制备同位素标记的本申请化合物。
此外，用较重同位素(诸如氘(即 2H))取代可以提供某些由更高的代谢稳定性产生的治疗优点(例如增加的体内半衰期或降低的剂量需求)，并且因此在某些情形下可能是优选的，其中氘取代可以是部分或完全的，部分氘取代是指至少一个氢被至少一个氘取代，所有这样的形式的化合物包含于本申请的范围内。
本申请化合物可以是不对称的，例如，具有一个或多个立体异构体。除非另有说明，所有立体异构体都包括，如对映异构体和非对映异构体。本申请的含有不对称碳原子的化合物可以以光学活性纯的形式或外消旋形式被分离出来。光学活性纯的形式可以从外消旋混合物拆分，或通过使用手性原料或手性试剂合成。
本申请的药物组合物可通过将本申请的化合物与适宜的药学上可接受的辅料组合而制备，例如可配制成固态、半固态、液态或气态制剂，如片剂、丸剂、胶囊剂、粉剂、颗粒剂、膏剂、乳剂、悬浮剂、栓剂、注射剂、吸入剂、凝胶剂、微球及气溶胶等。
给予本申请化合物或其药学上可接受的盐或其药物组合物的典型途径包括但不限于口服、直肠、局部、吸入、肠胃外、舌下、阴道内、鼻内、眼内、腹膜内、肌内、皮下、静脉内给药。
本申请的药物组合物可以采用本领域众所周知的方法制造，如常规的混合法、溶解法、制粒法、制糖衣药丸法、磨细法、乳化法、冷冻干燥法等。
在一些实施方案中，药物组合物是口服形式。对于口服给药，可以通过将活性化合物与本领域熟知的药学上可接受的辅料混合，来配制该药物组合物。这些辅料能使本申请的化合物被配制成片剂、丸剂、锭剂、糖衣剂、胶囊剂、液体、凝胶剂、浆剂、悬浮剂等，用于对患者的口服给药。
可以通过常规的混合、填充或压片方法来制备固体口服组合物。例如，可通过下述方法获得：将所述的活性化合物与固体辅料混合，任选地碾磨所得的混合物，如果需要则加入其它合适的辅料，然后将该混合物加工成颗粒，得到了片剂或糖衣剂的核心。适合的辅料包括但不限于：粘合剂、稀释剂、崩解剂、润滑剂、助流剂、甜味剂或矫味剂等。
药物组合物还可适用于肠胃外给药，如合适的单位剂型的无菌溶液剂、混悬剂或冻干产品。
本申请化合物的治疗剂量可根据例如以下而定：治疗的具体用途、给予化合物的方式、患者的健康和状态，以及签处方医师的判断。本申请化合物在药用组合物中的比例或浓度可不固定，取决于多种因素，它们包括剂量、化学特性(例如疏水性)和给药途径。例如可通过含约0.1～10％w/v该化合物的生理缓冲水溶液提供本申请化合物，用于肠胃外给药。某些典型剂量范围为约1μg/kg～约1g/kg体重/日。在某些实施方案中，剂量范围为约0.01mg/kg～约100mg/kg体重/日。剂量很可能取决于此类变量，如疾病或病症的种类和发展程度、具体患者的一般健康状态、所选择的化合物的相对生物学效力、赋形剂制剂及其给药途径。 可通过由体外或动物模型试验系统导出的剂量-反应曲线外推，得到有效剂量。
本申请的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本申请的实施例。
本申请具体实施方式的化学反应是在合适的溶剂中完成的，所述的溶剂须适合于本申请的化学变化及其所需的试剂和物料。为了获得本申请的化合物，有时需要本领域技术人员在已有实施方式的基础上对合成步骤或者反应流程进行修改或选择。
本领域合成路线规划中的一个重要考量因素是为反应性官能团选择合适的保护基，例如，可参考Greene's Protective Groups in Organic Synthesis(4th Ed).Hoboken,New Jersey:John Wiley&Sons,Inc.
在一些实施方案中，本申请的化合物可以由有机合成领域技术人员参考以下路线来制备：
Figure PCTCN2021135912-appb-000068
其中，X、Cy、R 1、R 2、R 4、m、L、L 1的定义如前所述。
本申请采用下述缩略词：
DIPEA代表二异丙基乙胺；Xantphos代表4,5-双(二苯基膦)-9,9-二甲基氧杂蒽；DMF代表N,N-二甲基甲酰胺。
具体实施方式
为清楚起见，进一步用实施例来阐述本申请，但是实施例并非限制本申请的范围。本申请所使用的所有试剂是市售的，无需进一步纯化即可使用。
实施例1:化合物1-e
Figure PCTCN2021135912-appb-000069
1)化合物1-a的制备方法:
将4,6-二氯哒嗪-3-羧酸锂盐(50g)溶于500mL二氯甲烷中，在0℃条件下，加入催化量DMF后，将草酰氯(96g)缓慢滴加至上述溶液中，滴加完毕后，在室温条件下，继续搅拌反应2h，反应完全。浓缩反应液。将氘代甲胺(18.6g)、DIPEA(162g)溶于200mL二氯甲烷中，在-25℃条件下，搅拌溶清，将上述浓缩物溶于300mL二氯甲烷中，并缓慢滴加至上述溶液中，滴加完毕后继续搅拌2h。加入750mL水猝灭反应，二氯甲烷(2×500mL)萃取两次，合并有机相，饱和氯化钠水溶液洗涤，无水Na 2SO 4干燥，过滤，浓缩滤液，得到化合物1-a(52g)。ESI-MS:m/z＝209.2[M+H] +。
2)化合物1-b的制备方法:
将化合物1-a(12g)、2-甲氧基-3-氨基苯甲酸盐酸盐(11.7g)和醋酸锌(31.6g)溶于200mL异丙醇，在50℃条件下搅拌8h。反应液浓缩，加入纯化水，室温搅拌过夜，过滤，50℃真空烘干得化合物1-b(10.7g)。ESI-MS:m/z＝340.09[M+H] +。
3)化合物1-c的制备：
将化合物1-b(2.0g)、环丙甲酰胺(0.5g)、醋酸钯(0.2g)、Xantphos(0.6g)和碳酸铯(3.8g)依次溶于3mL二氧六环，氮气保护条件下，加热至130℃反应5h。反应液浓缩，柱层析纯化得化合物1-c(1.3g)。ESI-MS:m/z＝389.16[M+H] +。
4)化合物1-e的制备：
将化合物1-c(0.17g)、化合物1-d(0.1g)、EDCI(0.16g)、HOBT(0.1g)和三乙胺(0.17g)溶于DMF中，室温反应5h。浓缩，浓缩物经制备液相纯化得化合物1-e。ESI-MS:m/z＝579.18[M+H] +
1H NMR(500MHz,DMSO-d6)δ11.35(s,1H),10.98(s,1H),9.96(s,1H),9.15(s,1H),8.17(s,1H),7.56(dd,J＝7.9,1.7Hz,1H),7.50–7.39(m,2H),7.37–7.30(m,1H),7.27(t,J＝7.8Hz,1H),6.63–6.52(m,2H),5.47(t,J＝6.0Hz,1H),3.85–3.70(m,5H),3.70–3.61(m,2H),3.58(td,J＝11.3,2.6Hz,1H),3.47(td,J＝11.1,2.7Hz,1H),3.27(dd,J＝11.4,9.8Hz,1H),3.10–2.95(m,2H),2.15–2.03(m,1H),0.90–0.74(m,4H)。
实施例2：化合物2-e
Figure PCTCN2021135912-appb-000070
化合物2-e的制备方法
参考实施例1中化合物1-e的制备方法，在步骤4)中，将化合物1-d换成化合物2-d，得到化合物2-e。ESI-MS:m/z＝579.19[M+H] +
1H NMR(500MHz,DMSO-d6)δ11.35(s,1H),10.98(s,1H),9.96(s,1H),9.15(s,1H),8.17(s,1H),7.64–7.19(m,5H),6.58(d,J＝8.4Hz,2H),5.47(t,J＝5.8Hz,1H),3.88–3.53(m,8H),3.47(t,J＝11.3Hz,1H),3.27 (t,J＝10.7Hz,1H),3.12–2.95(m,2H),2.20–1.99(m,1H),0.89–0.74(m,4H)。
实施例3-27：参考实施例1步骤4的制备过程，以下表中的原料化合物替代化合物1-d，制备得到下表1实施例化合物：
表1
Figure PCTCN2021135912-appb-000071
Figure PCTCN2021135912-appb-000072
Figure PCTCN2021135912-appb-000073
实验例1 TYK2 JH2热稳定性测定
用磷酸盐缓冲液(PBS)将0.52mg/mL的TYK2 JH2蛋白母液稀释成50ng/μL，同时用DMSO将5000x的蛋白染料(Orange dye)(厂家Sigma；货号S5692)稀释成20x，先每孔加入16μL的TYK2 JH2蛋白稀释液，然后用纳升加样仪将DMSO溶解的实施例化合物加入到孔中，使化合物终浓度分别为10μM和1μM，共2个浓度，同时设空白对照孔(不含酶)与阴性对照孔(含酶，加溶媒DMSO)，设2个复孔，最后再每孔加入4μL的Orange dye蛋白染料，离心混匀。Roche LightCycler480荧光定量PCR仪检测，运行体系为：20℃15s；30℃～90℃0.02℃/s；20℃15s。使用LightCycler Thermal Shift Analysis软件分析得到熔解温度(Tm)。
本申请化合物，终浓度为10μM条件下，熔解温度(Tm)大于40℃；优选大于45℃；更优选大于55℃；在终浓度为1μM条件下，熔解温度(Tm)大于40℃；优选大于45℃；更优选大于50℃。
实验例2 Jurkat检测STAT3磷酸化方法
STAT3磷酸化检测试剂盒(Y705)，厂商Cisbio，货号62AT3PEG。取对数期生长的Jurakt细胞，取20μL计数，取需要的细胞数量(mL)，1300rpm离心3min，加入无酚红1640基础培养基(厂商Gibco，货号11835-030)进行细胞密度调整，调整细胞密度约为1.7*10E7个/mL。细胞按照上述细胞密度进行种板(384孔小体积白板)，8μL/孔；纳升加样仪加样，化合物孵育1.5h；用无酚红1640完全培养基将IFN-α(厂商义翘神州，货号13833-HNAY)稀释至75ng/mL(终浓度25ng/mL)；随后根据板分布每孔加入4μL IFN-α(3X)，空白组接种细胞，不加化合物，不加IFN-α；对照组，接种细胞，不加化合物，加IFN-α；37℃孵育20min。立即加入4μL添加封闭液的裂解液(4X)，并在室温下摇动孵育40min。加入4μL检测缓冲液配制的预先混合的抗体(vol/vol)，盖板，离心使混合均匀，室温孵育过夜。PE Envision多功能读板仪进行检测665nm/620nm信号值，四参数拟合计算IC 50。实验结果见表2。
表2
Figure PCTCN2021135912-appb-000074
实验例3体外肝微位体稳定性评价
300μL最终的温孵体系中，含30μL肝微粒体(蛋白浓度：5mg/mL)，30μL NADPH+MgCl 2，3μL受试化合物(乙腈配制)，237μL PBS缓冲液(pH7.4)。其中有机溶剂(乙腈)的比例为1％。每个种属做2份，每份0.30mL。每管先配好总体积为270μL的底物及酶的混匀液，和NADPH分别在37℃预温孵5min后，加入30μL NADPH+MgCl 2混合，分别于0、10、30、60min取出50μL用含内标的冰乙腈300μL终止反应。
50μL温孵样品，加入300μL含内标(20ng/ml)的冰乙腈沉淀，涡旋震荡10min后，离心(13000rpm，20℃)10min。吸取上清液70μL，加入70μL超纯水稀释混匀，0.5μL用于LC/MS/MS进样分析。实验结果见表3。
表3
Figure PCTCN2021135912-appb-000075
实验例4小鼠体内药代动力学评价
1.小鼠体内药代动力学评价
ICR小鼠，体重20～24g，适应3～5天后，随机分组，每组9只，分别灌胃待测化合物。
受试动物(ICR小鼠)给药前禁食12h，给药后4h给食物，实验前后和实验过程中均自由饮水。
灌胃给药后，0.25(15min)、0.5(30min)、1、2、4、6、8、10h，每只小鼠采集3～4个时间点，每个时间点3只小鼠，于眼眶取血0.1mL左右，EDTA-K2抗凝后，30min内转移到4℃，4000rpm，10min条件下离心分离血浆。收集全部血浆后立即于-20℃保存待测。
吸取20μL收集的待测血浆样品，加入400μL含内标(20ng/mL)的乙腈溶液，振荡混匀10min，13000rpm离心10min，取上清50μL，加入100μL超纯水稀释，混匀，吸取0.5μL用于LC/MS/MS测定，记录色谱图。
通过小鼠体内药物动力学实验评估本发明化合物的口服暴露量。结果下表4所示。
表4
Figure PCTCN2021135912-appb-000076

Claims (20)

  1. 式I化合物或其药学上可接受的盐：
    Figure PCTCN2021135912-appb-100001
    其中，
    Cy选自C 6-10芳基或5-10元杂芳基；
    X选自-N(R)-、O或S；
    R选自氢或C 1-6烷基；
    L 1选自-(CH 2) n-；
    n选自1、2、3或4；
    R 2选自C 3-10环烷基或3-10元杂环烷基，所述C 3-10环烷基或3-10元杂环烷基任选地被一个或多个R a取代；
    每一个R a分别独立地选自卤素、氰基、羟基、氨基、C 1-8烷基、C 1-8烷氧基、C 1-8烷基NH-、(C 1-8烷基) 2N-或C 3-8环烷基；
    每一个R 1分别独立地选自氨基、卤素、氰基、羟基、C 1-8烷基、C 1-8烷氧基、C 3-10环烷基、C 3-10环烷氧基、C 1-8烷基NH-、(C 1-8烷基) 2N-、C 3-10环烷基NH-、3-10元杂环烷基、5-10元杂芳基、C 1-8烷基C(O)-、C 1-8烷基C(O)NH-、NH 2C(O)-、C 1-8烷基NHC(O)-、(C 1-8烷基) 2NC(O)-、C 1-8烷基OC(O)-或C 1-8烷基C(O)O-，所述C 1-8烷基、C 1-8烷氧基、C 3-10环烷基、C 3-10环烷氧基、C 1-8烷基NH-、(C 1-8烷基) 2N-、C 3-10环烷基NH-、3-10元杂环烷基、5-10元杂芳基、C 1-8烷基C(O)-、C 1-8烷基C(O)NH-、NH 2C(O)-、C 1-8烷基NHC(O)-、(C 1-8烷基) 2NC(O)-、C 1-8烷基OC(O)-或C 1-8烷基C(O)O-任选地被一个或多个卤素、羟基、氰基或氨基取代；
    m选自0、1、2、3或4；
    L选自-C(O)-或键；
    R 4选自5-10元杂芳基、C 3-10环烷基、C 6-10芳基或3-10元杂环烷基，其中所述5-10元杂芳基、C 3-10环烷基、C 6-10芳基或3-10元杂环烷基任选地被一个或多个R b取代；
    R b选自卤素、氰基、C 1-8烷基、C 1-8烷氧基、C 3-10环烷基氧基、C 3-10环烷基、5-10元杂芳基、3-10元杂环烷基、氨基、C 1-8烷基NH-、(C 1-8烷基) 2N-、C 3-10环烷基NH-、-C(O)NHC 1-8烷基、-C(O)N(C 1-8烷基) 2、-C(O)OC 1-8烷基、-OC(O)C 1-8烷基、C 1-8烷基C(O)NH-、C 3-10环烷基C(O)NH-、C 1-8烷基SO 2NH-或(C 1-8烷基) 2NSO 2。
  2. 如权利要求1所述的化合物或其药学上可接受的盐，所述Cy选自苯基或5-6元杂芳基；
    或者，所述Cy选自苯基或6元杂芳基；
    或者，所述Cy选自苯基或吡啶基；
    或者，所述Cy选自苯基。
  3. 如权利要求1或2所述的化合物或其药学上可接受的盐，所述R选自氢或C 1-3烷基；
    或者，所述R选自氢。
  4. 如权利要求1-3任一项所述的化合物或其药学上可接受的盐，所述X选自NH或O；
    或者，所述X选自NH；
    或者，所述X选自O。
  5. 如权利要求1-4任一项所述的化合物或其药学上可接受的盐，所述n选自1或2；
    任选地，所述L 1选自-(CH 2)-。
  6. 如权利要求1-5任一项所述的化合物或其药学上可接受的盐，所述R 2选自C 3-10单环环烷基或3-10元单环杂环烷基，所述C 3-10单环环烷基或3-10元单环杂环烷基任选地被一个或多个R a取代；
    或者，所述R 2选自C 3-6单环环烷基或3-6元单环杂环烷基，所述C 3-6单环环烷基或3-6元单环杂环烷基任选地被一个或多个R a取代；
    或者，所述R 2选自C 3-10环烷基或含有1、2或3个选自N、O或S原子的3-10元杂环烷基，所述C 3-10环烷基或3-10元杂环烷基任选地被一个或多个R a取代；
    或者，所述R 2选自C 3-6环烷基或含有1、2或3个选自N、O或S原子的3-6元杂环烷基，所述C 3-6环烷基或3-6元杂环烷基任选地被一个或多个R a取代；
    或者，所述R 2选自C 3-6环烷基或3-6元杂环烷基，所述C 3-6环烷基或3-6元杂环烷基任选地被一个或多个R a取代；
    或者，所述R 2选自3-6元杂环烷基，所述3-6元杂环烷基任选地被一个或多个R a取代；
    或者，所述R 2选自含有1、2或3个选自N、O或S原子的3-6元杂环烷基，所述3-6元杂环烷基任选地被一个或多个R a取代；
    或者，所述R 2选自含有1、2或3个选自N、O或S原子的5-6元杂环烷基，所述5-6元杂环烷基任选地被一个或多个R a取代；
    或者，所述R 2选自含有1或2个选自N或O原子的5-6元杂环烷基，所述5-6元杂环烷基任选地被一个或多个R a取代；
    或者，所述R 2选自1,4-二氧六环基、四氢吡喃基、哌啶基、吗啉基、吡咯烷基或呋喃基，所述1,4-二氧六环基、四氢吡喃环基、哌啶环基、吗啉环基、吡咯烷基或呋喃基任选地被一个或多个R a取代；
    或者，所述R 2选自
    Figure PCTCN2021135912-appb-100002
    Figure PCTCN2021135912-appb-100003
    其中
    Figure PCTCN2021135912-appb-100004
    Figure PCTCN2021135912-appb-100005
    任选地被一个或多个R a取代；
    或者，所述R 2选自
    Figure PCTCN2021135912-appb-100006
    Figure PCTCN2021135912-appb-100007
  7. 如权利要求1-6中任一项所述的化合物或其药学上可接受的盐，所述每一个R a分别独立地选自卤素、氰基、羟基、氨基、C 1-6烷基、C 1-6烷氧基、C 1-6烷基NH-、(C 1-6烷基) 2N-或C 3-6环烷基；
    或者，所述每一个R a分别独立地选自卤素、氰基、羟基、氨基、C 1-3烷基、C 1-3烷氧基、C 1-3烷基NH-或(C 1-3烷基) 2N-；
    或者，所述每一个R a分别独立地选自C 1-3烷基、C 1-3烷氧基、C 1-3烷基NH-或(C 1-3烷基) 2N-；
    或者，所述每一个R a分别独立地选自C 1-3烷基；
    或者，所述每一个R a分别独立地选自甲基。
  8. 如权利要求1-7中任一项所述的化合物或其药学上可接受的盐，结构单元
    Figure PCTCN2021135912-appb-100008
    选自
    Figure PCTCN2021135912-appb-100009
    Figure PCTCN2021135912-appb-100010
    或者，结构单元
    Figure PCTCN2021135912-appb-100011
    选自
    Figure PCTCN2021135912-appb-100012
    Figure PCTCN2021135912-appb-100013
    Figure PCTCN2021135912-appb-100014
  9. 如权利要求1-8中任一项所述的化合物或其药学上可接受的盐，结构单元
    Figure PCTCN2021135912-appb-100015
    选自
    Figure PCTCN2021135912-appb-100016
    或者，结构单元
    Figure PCTCN2021135912-appb-100017
    选自
    Figure PCTCN2021135912-appb-100018
    Figure PCTCN2021135912-appb-100019
    或者，结构单元
    Figure PCTCN2021135912-appb-100020
    选自
    Figure PCTCN2021135912-appb-100021
    Figure PCTCN2021135912-appb-100022
    Figure PCTCN2021135912-appb-100023
    或者，结构单元
    Figure PCTCN2021135912-appb-100024
    选自
    Figure PCTCN2021135912-appb-100025
    或者，结构单元
    Figure PCTCN2021135912-appb-100026
    选自
    Figure PCTCN2021135912-appb-100027
    或者，结构单元
    Figure PCTCN2021135912-appb-100028
    选自
    Figure PCTCN2021135912-appb-100029
    或者，结构单元
    Figure PCTCN2021135912-appb-100030
    选自
    Figure PCTCN2021135912-appb-100031
    或者，结构单元
    Figure PCTCN2021135912-appb-100032
    选自
    Figure PCTCN2021135912-appb-100033
    或者，结构单元
    Figure PCTCN2021135912-appb-100034
    选自
    Figure PCTCN2021135912-appb-100035
    或者，结构单元
    Figure PCTCN2021135912-appb-100036
    选自
    Figure PCTCN2021135912-appb-100037
    或者，结构单元
    Figure PCTCN2021135912-appb-100038
    选自
    Figure PCTCN2021135912-appb-100039
    或者，结构单元
    Figure PCTCN2021135912-appb-100040
    选自
    Figure PCTCN2021135912-appb-100041
    或者，结构单元
    Figure PCTCN2021135912-appb-100042
    选自
    Figure PCTCN2021135912-appb-100043
  10. 如权利要求1-9中任一项所述的化合物或其药学上可接受的盐，每一个R 1分别独立地选自氨基、卤素、氰基、羟基、C 1-6烷基、C 1-6烷氧基、C 3-6环烷基、C 3-6环烷氧基、C 1-6烷基NH-、(C 1-6烷基) 2N-、C 3-6环烷基NH-、3-6元杂环烷基、5-6元杂芳基、C 1-6烷基C(O)-、C 1-6烷基C(O)NH-、NH 2C(O)-、C 1-6烷基NHC(O)-、(C 1-6烷基) 2NC(O)-、C 1-6烷基OC(O)-或C 1-6烷基C(O)O-，所述C 1-6烷基、C 1-6烷氧基、C 3-6环烷基、C 3-6环烷氧基、C 1-6烷基NH-、(C 1-6烷基) 2N-、C 3-6环烷基NH-、3-6元杂环烷基、5-6元杂芳基、C 1-6烷基C(O)-、C 1-6烷基C(O)NH-、NH 2C(O)-、C 1-6烷基NHC(O)-、(C 1-6烷基) 2NC(O)-、C 1-6烷基OC(O)-或C 1-6烷基C(O)O-任选地被一个或多个卤素、羟基、氰基或氨基取代；
    或者，每一个R 1分别独立地选自卤素、氰基、C 1-3烷基、C 1-3烷氧基、C 3-6环烷氧基、C 1-3烷基C(O)-、NH 2C(O)-、C 1-6烷基NHC(O)-或(C 1-6烷基) 2NC(O)-，所述C 1-3烷基、C 1-3烷氧基、C 3-6环烷氧基、C 1-3烷基C(O)-、C 1-6烷基NHC(O)-或(C 1-6烷基) 2NC(O)-任选地被一个或多个卤素取代。
  11. 如权利要求1-10中任一项所述的化合物或其药学上可接受的盐，所述m选自0、1、2或3；或者，所述m选自0、1或2；或者，所述m选自0。
  12. 如权利要求1-11中任一项所述的化合物或其药学上可接受的盐，所述L选自-CO-；
    或者，所述L选自键。
  13. 如权利要求1-12中任一项所述的化合物或其药学上可接受的盐，所述R 4选自6-10元杂芳基、C 3-6环烷基、苯基或3-6元杂环烷基，其中所述6-10元杂芳基、C 3-6环烷基、苯基或3-6元杂环烷基任选地被一个或多个R b取代；
    或者，所述R 4选自C 3-6环烷基或3-6元杂环烷基，其中所述C 3-6环烷基或3-6元杂环烷基任选地被一个或多个R b取代；
    或者，所述R 4选自C 3-6环烷基，所述C 3-6环烷基任选地被一个或多个R b取代；
    或者，所述R 4选自任选地被一个或多个R b取代的环丙基；
    或者，所述R 4选自环丙基。
  14. 如权利要求1-13中任一项所述的化合物或其药学上可接受的盐，所述R b选自卤素、氰基、C 1-6烷基、C 1-6烷氧基、C 3-6环烷基氧基、C 3-6环烷基、5-6元杂芳基、3-6元杂环烷基、-C(O)NHC 1-6烷基、-C(O)N(C 1-6烷基) 2、-C(O)OC 1-6烷基、-OC(O)C 1-6烷基、C 1-6烷基C(O)NH-、C 3-6环烷基C(O)NH-、C 1-6烷基SO 2NH-或(C 1-6烷基) 2NSO 2-；
    或者，所述R b选自卤素、氰基、C 1-3烷基或C 1-3烷氧基。
  15. 如权利要求1-14中任一项所述的化合物或其药学上可接受的盐，结构单元
    Figure PCTCN2021135912-appb-100044
    选自
    Figure PCTCN2021135912-appb-100045
  16. 如权利要求1所述的化合物或其药学上可接受的盐，其选自式II、式III或式IV化合物或其药学上可接受的盐：
    Figure PCTCN2021135912-appb-100046
  17. 以下化合物或其药学上可接受的盐：
    Figure PCTCN2021135912-appb-100047
    Figure PCTCN2021135912-appb-100048
  18. 如权利要求17所述的化合物或其药学上可接受的盐，其选自以下化合物或其药学上可接受的盐：
    Figure PCTCN2021135912-appb-100049
    Figure PCTCN2021135912-appb-100050
    Figure PCTCN2021135912-appb-100051
  19. 药物组合物，其包含权利要求1-18中任一项所述化合物或其药学上可接受的盐。
  20. 权利要求1-18中任一项所述化合物或其药学上可接受的盐、或权利要求19所述药物组合物在制备治疗或预防TYK2相关疾病的药物中的用途；
    任选地，所述TYK2相关疾病选自炎性或自身免疫性疾病。
PCT/CN2021/135912 2020-12-08 2021-12-07 含酰胺基和杂环烷基的tyk2抑制剂化合物 WO2022121868A1 (zh)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202180081052.4A CN116547276A (zh) 2020-12-08 2021-12-07 含酰胺基和杂环烷基的tyk2抑制剂化合物

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202011446489 2020-12-08
CN202011446489.7 2020-12-08

Publications (1)

Publication Number Publication Date
WO2022121868A1 true WO2022121868A1 (zh) 2022-06-16

Family

ID=81974214

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2021/135912 WO2022121868A1 (zh) 2020-12-08 2021-12-07 含酰胺基和杂环烷基的tyk2抑制剂化合物

Country Status (2)

Country Link
CN (1) CN116547276A (zh)
WO (1) WO2022121868A1 (zh)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023076161A1 (en) 2021-10-25 2023-05-04 Kymera Therapeutics, Inc. Tyk2 degraders and uses thereof

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104884454A (zh) * 2012-11-08 2015-09-02 百时美施贵宝公司 用作IL-12、IL-23和/或IFNα应答调节剂的酰胺取代的杂环化合物
WO2020086616A1 (en) * 2018-10-22 2020-04-30 Fronthera U.S. Pharmaceuticals Llc Tyk2 inhibitors and uses thereof
WO2020092196A1 (en) * 2018-10-30 2020-05-07 Bristol-Myers Squibb Company Amide-substituted heterocyclic compounds for the treatment of conditions related to the modulation of il-12, il-23 and/or ifn-alpha
CN111484480A (zh) * 2019-01-29 2020-08-04 上海翰森生物医药科技有限公司 一种多环类衍生物抑制剂、其制备方法和应用
WO2020156311A1 (zh) * 2019-01-28 2020-08-06 江苏豪森药业集团有限公司 一种哒嗪类衍生物抑制剂、其制备方法和应用
CN111909140A (zh) * 2019-04-12 2020-11-10 明慧医药（杭州）有限公司 作为tyk2抑制剂的杂环化合物及合成和使用方法

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104884454A (zh) * 2012-11-08 2015-09-02 百时美施贵宝公司 用作IL-12、IL-23和/或IFNα应答调节剂的酰胺取代的杂环化合物
WO2020086616A1 (en) * 2018-10-22 2020-04-30 Fronthera U.S. Pharmaceuticals Llc Tyk2 inhibitors and uses thereof
WO2020092196A1 (en) * 2018-10-30 2020-05-07 Bristol-Myers Squibb Company Amide-substituted heterocyclic compounds for the treatment of conditions related to the modulation of il-12, il-23 and/or ifn-alpha
WO2020156311A1 (zh) * 2019-01-28 2020-08-06 江苏豪森药业集团有限公司 一种哒嗪类衍生物抑制剂、其制备方法和应用
CN111484480A (zh) * 2019-01-29 2020-08-04 上海翰森生物医药科技有限公司 一种多环类衍生物抑制剂、其制备方法和应用
CN111909140A (zh) * 2019-04-12 2020-11-10 明慧医药（杭州）有限公司 作为tyk2抑制剂的杂环化合物及合成和使用方法

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023076161A1 (en) 2021-10-25 2023-05-04 Kymera Therapeutics, Inc. Tyk2 degraders and uses thereof

Also Published As

Publication number Publication date
CN116547276A (zh) 2023-08-04

Similar Documents

Publication Publication Date Title
TWI791511B (zh) 細胞凋亡誘導劑
CN115461342A (zh) 含磷的sos1抑制剂
JP7473545B2 (ja) トリフルオロメチル置換スルファミド系選択的ｂｃｌ－２阻害剤
CN113825754B (zh) 包括甲基和三氟甲基的双取代磺酰胺类选择性bcl-2抑制剂
WO2021202652A1 (en) Tyrosine kinase 2 inhibitors, preparation methods and medicinal uses thereof
WO2022166741A1 (zh) 含有苯并杂环的作为egfr激酶抑制剂的大环化合物、其药物组合物和用途
WO2022121868A1 (zh) 含酰胺基和杂环烷基的tyk2抑制剂化合物
CN113735836A (zh) 哒嗪类化合物及其应用
CN113773262A (zh) 哒嗪类化合物
WO2022166917A1 (zh) 含联环的tyk2抑制剂化合物
CN114907326A (zh) 含酰胺基和联环的tyk2抑制剂化合物
WO2023125707A1 (zh) 一种p38 MAPK/MK2通路调节剂及其组合物、制备方法和用途
WO2023125708A1 (zh) 一种p38 MAPK/MK2通路调节剂及其组合物、制备方法和用途
CN114057651A (zh) 含酰胺基的tyk2抑制剂化合物
TW202227444A (zh) 四環類化合物及其醫藥用途
WO2023051586A1 (zh) Kras g12d抑制剂化合物及其制备方法和应用
TW202311252A (zh) 作為tyk2/jak1假激酶結構域抑制劑的化合物及合成和使用方法
CN114685532A (zh) 大环类化合物及其医药用途
CN110776511B (zh) 含喹啉环的btk抑制剂
CN113666877A (zh) 含烷氧基及酰胺基的tyk2抑制剂化合物
CN114805438A (zh) 含磷酰基的tyk2抑制剂化合物
WO2021143927A1 (zh) 作为bcr-abl抑制剂的化合物
TWI836822B (zh) p38 MAPK/MK2通路調節劑及其組合物、製備方法和用途
CN117510477A (zh) 含吡唑或吡啶的tyk2抑制剂化合物
RU2815486C2 (ru) Трифторметилзамещенный сульфонамид в качестве селективного ингибитора bcl-2

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 21902573

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 202180081052.4

Country of ref document: CN

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 21902573

Country of ref document: EP

Kind code of ref document: A1