WO2022062601A1 - 嘧啶并吡咯类化合物 - Google Patents

嘧啶并吡咯类化合物 Download PDF

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WO2022062601A1
WO2022062601A1 PCT/CN2021/106877 CN2021106877W WO2022062601A1 WO 2022062601 A1 WO2022062601 A1 WO 2022062601A1 CN 2021106877 W CN2021106877 W CN 2021106877W WO 2022062601 A1 WO2022062601 A1 WO 2022062601A1
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compound
alkyl
pharmaceutically acceptable
acceptable salt
membered
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PCT/CN2021/106877
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English (en)
French (fr)
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唐锋
刘力锋
蒋蕾
严玉玺
张国宝
陈家隽
周峰
唐任宏
任晋生
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江苏先声药业有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • 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 present invention relates to a novel pyrimidopyrrole compound or a pharmaceutically acceptable salt thereof, a pharmaceutical composition containing them and their use in the prevention or treatment of kinase-related diseases such as Janus kinase (Janus kinase, JAK, especially JAK3) and / or Bruton's tyrosine kinase (Bruton's tyrosine kinase, BTK) related diseases.
  • kinase-related diseases such as Janus kinase (Janus kinase, JAK, especially JAK3) and / or Bruton's tyrosine kinase (Bruton's tyrosine kinase, BTK) related diseases.
  • Autoimmune diseases are a class of diseases in which abnormal immune function causes an attack on one's own cells or tissues, leading to inflammation and tissue damage, including rheumatoid arthritis (RA), inflammatory bowel disease (IBD) and systemic lupus erythematosus (SLE) Wait.
  • RA rheumatoid arthritis
  • IBD inflammatory bowel disease
  • SLE systemic lupus erythematosus Wait.
  • BTK and JAK3 are two important targets for autoimmune diseases.
  • BTK is a member of the non-receptor tyrosine kinase TEC family, and its structure includes PH domain, TH domain, SH3 domain, SH2 domain and SH1 domain.
  • BTK plays a key role in the activation of the BCR signaling pathway, regulates the development and activation of B cells, and plays an important role in the proliferation of B cells, the expression of pro-inflammatory cytokines and the secretion of antibodies (Targeting Bruton's tyrosine kinase in B cell malignancies.Nat Rev Cancer.2014Apr;14(4):219-32), so BTK has become one of the important targets for the treatment of diseases related to abnormal activation of B cells, including autoimmune diseases and B cell lymphomas.
  • Ibrutinib, Acalabrutinib and Zanubrutinib are three BTK inhibitors that have been approved, mainly for the treatment of B-cell lymphoma, and have obvious curative effect in some patients, but serious side effects and drug resistance mutations have also been observed in clinical practice.
  • ibrutinib was approved by the US FDA for the treatment of GVHD, while other BTK inhibitors are currently being actively explored clinically for the treatment of autoimmune diseases, including RA, SLE and multiple sclerosis (MS).
  • JAK3 is a member of the JAK family of non-receptor tyrosine kinases.
  • the JAK kinase family has four members: JAK-1, JAK-2, JAK-3 and TYK-2.
  • STAT is the downstream substrate of JAK3.
  • JAK3 activates STAT to make it a dimer and enter the nucleus to regulate the transcriptional expression of specific genes.
  • the JAK-STAT signaling pathway plays an important role in lymphocyte proliferation, differentiation and the expression of pro-inflammatory cytokines (JAK inhibition as a therapeutic strategy for immune and inflammatory diseases. Nat Rev Drug Discov.
  • JAK3 has become one of the targets of autoimmune diseases and malignant tumors.
  • JAK2 plays an important role in erythropoiesis and platelet production, and the deletion of JAK2 in mice leads to embryonic lethality, which suggests the importance of the physiological function of JAK2 (The JAK-STAT pathway: impact on human disease and therapeutic intervention. Annu Rev Med. 2015, 66:311-28). Due to the lack of selectivity of JAK2, some JAK inhibitors have significantly inhibited JAK2, resulting in clinical side effects such as anemia and thrombosis.
  • Tofacitinib is an FDA-approved JAK inhibitor, and its adverse reactions, including severe infection, liver damage, etc., are also considered to be related to the insufficient selectivity of tofacitinib for JAK2. It can be seen that improving the selectivity of members of the same family has become one of the directions for the development of a new generation of small molecule drugs targeting JAK.
  • the present invention provides a compound of formula (Ia) or a pharmaceutically acceptable salt thereof:
  • X is NH
  • R 1 is selected from the following groups optionally substituted by Ra : C 1 -C 10 alkyl or 3-10 membered heterocyclyl;
  • R 2 is selected from C 3 -C 6 cycloalkyl or phenyl, said C 3 -C 6 cycloalkyl or phenyl is optionally substituted by R d ;
  • R d is selected from F, Cl, Br, I, OH, CN or C1 - C4 alkyl optionally substituted with a group selected from F, Cl, Br, I, OH;
  • R 3 is selected from H, F, Cl, Br, I or C 1 -C 10 alkyl optionally substituted with a group selected from F, Cl, Br, I, OH;
  • R 4 is C 1 -C 6 alkyl
  • n is selected from 0 or 1.
  • the H in the acryloyl group of formula (Ia) is substituted with 1 or more deuterium atoms.
  • R2 is selected from cyclopropyl or phenyl optionally substituted with Rd .
  • R 2 is selected from C 3 -C 6 cycloalkyl or phenyl.
  • R 2 is selected from cyclopropyl or phenyl.
  • R 2 is cyclopropyl
  • R 3 is selected from H, F, Cl, Br, I or C 1 -C 6 alkyl optionally substituted with a group selected from F, Cl, Br, I, OH.
  • R 3 is selected from H, F, Cl, Br, I or C 1 -C 4 alkyl optionally substituted with a group selected from F, Cl, Br, I, OH.
  • R3 is selected from H, F, Cl, Br, or I.
  • R3 is selected from H or F.
  • R3 is H.
  • R 1 is selected from C 1 -C 6 alkyl or 4-6 membered heterocyclyl optionally substituted with Ra .
  • R 1 is selected from C 1 -C 6 alkyl or 4-6 membered heterocyclyl containing O atoms and/or N atoms, the C 1 -C The 6 -alkyl or 4-6 membered heterocyclyl is optionally substituted with Ra .
  • R 1 is selected from C 1 -C 6 alkyl or 4-6 membered heterocyclyl containing O and/or N as ring atoms, the C 1 - C6 alkyl or 4-6 membered heterocyclyl is optionally substituted with Ra .
  • R 1 is selected from C 1 -C 6 alkyl or 4-6 membered heterocyclyl containing one O atom or one N atom, the C 1 -C The 6 -alkyl or 4-6 membered heterocyclyl is optionally substituted with Ra .
  • R 1 is selected from C 1 -C 6 alkyl or a 4-6 membered heterocyclyl group containing one O or one N as a ring atom, the C 1 -C 6 membered heterocyclyl group C6 alkyl or 4-6 membered heterocyclyl is optionally substituted with Ra .
  • R a is selected from deuterium, F, Cl, Br, I, OH, CN, C 1 -C 10 alkyl or C 3 -C 10 cycloalkyl.
  • R a is selected from F, Cl, Br, I, OH, CN, C 1 -C 10 alkyl, or C 3 -C 10 cycloalkyl.
  • R a is C 1 -C 6 alkyl.
  • Ra is methyl
  • R 1 is selected from deuterated methyl, ethyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, or N-methylpiperidinyl.
  • R 1 is selected from methyl, ethyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, or N-methylpiperidinyl.
  • R 1 is selected from methyl, deuterated methyl, ethyl,
  • R 1 is selected from methyl, ethyl,
  • R 1 is selected from methyl or deuterated methyl.
  • R1 is selected from methyl or CD3 .
  • R 1 is methyl
  • R 4 is methyl
  • the n is 1.
  • the compound of formula (Ia) or a pharmaceutically acceptable salt thereof is selected from a compound of formula (IIa) or a pharmaceutically acceptable salt thereof:
  • the present invention relates to the following compounds or pharmaceutically acceptable salts thereof:
  • the present invention also provides a pharmaceutical composition, which comprises a compound represented by formula (Ia) or a pharmaceutically acceptable salt thereof or the above specific compound or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier and/or excipient agent.
  • the present invention relates to a compound represented by formula (Ia) or a pharmaceutically acceptable salt thereof, or the specific compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of preventing or treating Janus kinase ( Use in the medicament of JAK, especially JAK3) and/or Bruton's tyrosine kinase (BTK) related diseases.
  • Janus kinase Use in the medicament of JAK, especially JAK3
  • BTK Bruton's tyrosine kinase
  • the present invention relates to a compound represented by formula (Ia) or a pharmaceutically acceptable salt thereof, or the specific compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the prevention or treatment of Janus kinase (JAK) , in particular JAK3) and/or Bruton's tyrosine kinase (BTK) related diseases.
  • JAK Janus kinase
  • BTK Bruton's tyrosine kinase
  • the present invention relates to a compound of formula (Ia) or a pharmaceutically acceptable salt thereof for the prevention or treatment of Janus kinase (JAK, in particular JAK3) and/or Bruton's tyrosine kinase (BTK) related diseases, or The specific compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • JAK3 Janus kinase
  • BTK Bruton's tyrosine kinase
  • the present invention also relates to a method for the treatment of Janus kinase (JAK, in particular JAK3) and/or Bruton's tyrosine kinase (BTK) related diseases, the method comprising administering to a patient a therapeutically effective dose of A compound of formula (Ia) or a pharmaceutically acceptable salt thereof or a pharmaceutical formulation of said particular compound or a pharmaceutically acceptable salt thereof.
  • JAK3 Janus kinase
  • BTK Bruton's tyrosine kinase
  • the Janus kinase (JAK, especially JAK3) and/or Bruton's tyrosine kinase (BTK)-related diseases described in the present invention include but are not limited to tumors (such as B-cell lymphoma) and autoimmune diseases (such as rheumatism) arthritis, inflammatory bowel disease, and systemic lupus erythematosus).
  • JAK3 Janus kinase
  • BTK Bruton's tyrosine kinase
  • 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.
  • pharmaceutically acceptable salts refers to pharmaceutically acceptable salts of non-toxic acids or bases, including salts of inorganic acids and bases, organic acids and bases.
  • stereoisomers refers to isomers resulting from different arrangements of atoms in a molecule in space, including cis-trans isomers, enantiomers, diastereomers and conformers .
  • the compounds of the present invention may have asymmetric carbon atoms (optical centers) or double bonds. Racemates, enantiomers, diastereomers, geometric isomers and individual isomers are included within the scope of the present invention.
  • the compounds of the present invention may exist in specific geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers isomers, (D)-isomers, (L)-isomers, and racemic and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which belong to within the scope of the present invention.
  • 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 the present invention.
  • tautomer refers to an isomer of a functional group resulting from the rapid movement of an atom in two positions in a molecule.
  • the compounds of the present invention may exhibit tautomerism.
  • Tautomeric compounds can exist as two or more interconvertible species.
  • Proton tautomers arise from the migration of covalently bonded hydrogen atoms between two atoms.
  • Tautomers generally exist in equilibrium, and attempts to separate individual tautomers usually result in a mixture whose physicochemical properties are consistent with a mixture of compounds. The position of equilibrium depends on the chemical properties within the molecule.
  • the ketone form predominates; in phenols, the enol form predominates.
  • the present invention encompasses all tautomeric forms of the compounds.
  • composition refers to a mixture of one or more compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, with other chemical components, such as a physiologically/pharmaceutically acceptable carrier and excipients.
  • a pharmaceutical composition is to facilitate the administration of a compound to an organism.
  • 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.
  • any variable eg, Ra , Rb
  • its definition in each case is independent. For example, if a group is substituted with 2 R bs , each R b has independent options.
  • Cm - Cn herein means having an integer number of carbon atoms in the range mn.
  • C 1 -C 10 alkyl means that the group may have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms atom, 8 carbon atoms, 9 carbon atoms, or 10 carbon atoms.
  • halo or halogen refers to fluorine, chlorine, bromine and iodine.
  • C 1 -C 10 alkyl is understood to mean a linear or branched saturated monovalent hydrocarbon radical having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms.
  • the alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl , 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-di
  • alkoxy can be understood as “alkyloxy” or “alkyl-O-", and refers to a monovalent group resulting from the loss of a hydrogen atom on a hydroxyl group of a linear or branched alcohol.
  • C 1 -C 10 alkoxy can be understood as “C 1 -C 10 alkyloxy” or “C 1 -C 10 alkyl-O-”.
  • C 2 -C 10 alkenyl is to be understood as preferably denoting a linear or branched monovalent hydrocarbon radical comprising one or more double bonds and having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms.
  • the alkenyl groups can be classified into “cis” and “trans” orientations (or “E” and “Z” orientations).
  • C 2 -C 6 alkenyl is to be understood as a linear or branched monovalent hydrocarbon radical comprising one or more double bonds and having 2, 3, 4, 5 or 6 carbon atoms.
  • C 2 -C 10 alkynyl is to be understood as preferably denoting a linear or branched monovalent hydrocarbon group comprising one or more triple bonds and having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms.
  • Examples of “C 2 -C 10 alkynyl” include, but are not limited to, ethynyl (-C ⁇ CH), prop-1-ynyl (1-propynyl, -C ⁇ CCH 3 ), prop-2-ynyl (propargyl), but-1-ynyl, but-2-ynyl or but-3-ynyl.
  • C2 - C3alkynyl examples include ethynyl (-C ⁇ CH), prop- 1 -ynyl (1-propynyl, -C ⁇ CCH3 ), prop-2-ynyl (propargyl ).
  • cycloalkyl refers to a carbocyclic ring that is fully saturated and exists in the form of a monocyclic, paracyclic, bridged or spirocyclic ring, and the like. Unless otherwise indicated, the carbocycle is typically a 3- to 14-membered ring.
  • C 3 -C 14 cycloalkyl may be understood to mean a saturated monovalent monocyclic, paracyclic, spiro or bridged ring having 3, 4, 5, 6, 7, 8, 9, 10 , 11, 12, 13 or 14 carbon atoms.
  • C 3 -C 10 cycloalkyl is understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms.
  • C3 - C6cycloalkyl is understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3, 4, 5, 6 carbon atoms.
  • cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, or bicyclic or tricyclic hydrocarbon groups such as norbornyl base (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, adamantyl, spiro[4.5]decyl, decalin ring and the like.
  • the bicyclic or tricyclic hydrocarbon group includes a bridged ring, a spirocyclic ring or a paracyclic structure.
  • the term "C 3 -C 14 cycloalkyl” may include “C 3 -C 10 cycloalkyl", and “C 3 -C 10 cycloalkyl” may include “C 3 -C 6 cycloalkyl”.
  • cycloalkyloxy is to be understood as “cycloalkyl-O-".
  • C 3 -C 14 cycloalkyloxy may include “C 3 -C 10 cycloalkyloxy”
  • C 3 -C 10 cycloalkyloxy may include “C 3 -C 6 cycloalkyloxy”Oxygen”.
  • 3-14 membered heterocyclyl is to be understood as a saturated or partially saturated monovalent monovalent monovalent having 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms Cyclic or bicyclic hydrocarbon rings containing 1, 2, 3, 4 or 5, preferably 1, 2 or 3 heteroatoms selected from N, O and S.
  • 3-10 membered heterocyclyl refers to a saturated or partially saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3, 4, 5, 6, 7, 8, 9 or 10 ring atoms comprising 1, 2, 3, 4 or 5, preferably 1, 2 or 3 heteroatoms selected from N, O and S.
  • 4-6 membered heterocyclyl is to be understood as a saturated or partially saturated monovalent monocyclic or bicyclic hydrocarbon ring having 4, 5, 6 ring atoms comprising 1, 2, 3, 4 or 5 , preferably 1, 2 or 3 heteroatoms selected from N, O and S.
  • the heterocyclic group may include, but is not limited to: 4-membered ring, such as azetidinyl, oxetanyl; 5-membered ring, such as tetrahydrofuranyl, dioxolyl, pyrrole Alkyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl; or 6-membered ring, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl or trithianyl; or a partially saturated 6-membered ring such as tetrahydropyridyl; or a 7-membered ring such as diazepanyl.
  • 4-membered ring such as azetidinyl, oxetanyl
  • 5-membered ring such as tetrahydrofuranyl, dioxolyl, pyrrole
  • the heterocyclyl group can be benzo-fused.
  • the heterocyclyl group may be bicyclic, such as, but not limited to, a 5,5 membered ring, such as a hexahydrocyclopento[c]pyrrole-2(1H)-yl ring, or a 5,6 membered bicyclic ring, such as a hexahydropyrrole
  • the [1,2-a]pyrazin-2(1H)-yl ring may be partially unsaturated, i.e.
  • the heterocyclic group is non-aromatic.
  • the bicyclic hydrocarbon ring includes a bridged ring, spiro ring or paracyclic structure.
  • heterocyclyloxy is to be understood as “heterocyclyl-O-”.
  • 3--14-membered heterocyclyloxy may contain “3-10-membered heterocyclyloxy”
  • 3--10-membered heterocyclyloxy may contain "4-6-membered heterocyclyloxy”.
  • C 6 -C 10 aryl is to be understood as a monovalent aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring having 6, 7, 8, 9, 10 carbon atoms, in particular having 6 A ring of 1 carbon atoms (“C 6 aryl”), such as phenyl; or a ring of 9 carbon atoms (“C 9 aryl”), such as indanyl or indenyl, or a ring of 10 carbon atoms Ring (“ Cio aryl”) such as tetrahydronaphthyl, dihydronaphthyl or naphthyl.
  • aryloxy is to be understood as “aryl-O-”.
  • 5-10 membered heteroaryl is to be understood as having 5, 6, 7, 8, 9, 10 ring atoms, especially 5 or 6 or 9 or 10 ring atoms, and it contains 1-5, Especially monovalent monocyclic, bicyclic or tricyclic aromatic ring systems of 1-3 heteroatoms independently selected from N, O and S.
  • heteroaryl is selected from the group consisting of thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiazolyl Diazolyl and the like and their benzo derivatives such as benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazole base, indazolyl, indolyl, isoindolyl, etc.; or pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, triazinyl, etc., and their benzo derivatives, such as quinolinyl, quinoline oxazolinyl, isoquinolinyl, etc;
  • heteroaryloxy is to be understood as “heteroaryl-O-”.
  • terapéuticaally effective amount refers to (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 invention 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.
  • excipient refers to a pharmaceutically acceptable inert ingredient.
  • excipient examples include, without limitation, binders, disintegrants, lubricants, glidants, stabilizers, fillers, diluents, and the like. Excipients can enhance the handling characteristics of a pharmaceutical formulation, ie make the formulation more suitable for direct compression by increasing flowability and/or stickiness.
  • typical "pharmaceutically acceptable carriers” suitable for the above-mentioned preparations are: carbohydrates, starches, cellulose and their derivatives and other commonly used adjuvants in pharmaceutical preparations.
  • the pharmaceutical composition of the present invention can be prepared by combining the compound of the present invention 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 invention, 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.
  • compositions of the present invention can be manufactured by methods well known in the art, such as conventional mixing methods, dissolution methods, granulation methods, emulsification methods, freeze drying methods, 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 invention 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 milling the resulting mixture, adding other suitable excipients if desired, and processing the mixture into granules to obtain tablets or icing core.
  • Suitable adjuvants include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants or flavoring agents.
  • compositions may also be suitable for parenteral administration as sterile solutions, suspensions or lyophilized products in suitable unit dosage forms.
  • the dose administered per day is 0.01 mg/kg to 50 mg/kg body weight, preferably 0.03 mg/kg to 30 mg/kg body weight, more preferably 0.05 mg/kg to 20 mg/kg/day kg of body weight, in single or divided doses.
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments enumerated below, embodiments formed in combination with other chemical synthesis methods, and those well known to those skilled in the art Equivalent to alternatives, preferred embodiments include, but are not limited to, the embodiments of the present invention.
  • Figure 1 is the curve of the clinical arthritis score of each group of rats in the rat CIA model with time.
  • Figure 2 is the curve of the hindlimb volume of each group of rats in the rat CIA model with time.
  • the structures of the compounds were determined by nuclear magnetic resonance (NMR) and/or mass spectrometry (MS).
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • the units of NMR shifts are 10-6 (ppm).
  • the solvents for NMR measurement are deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and the internal standard is tetramethylsilane (TMS).
  • IC50 refers to the half-inhibitory concentration, which refers to the concentration at which half of the maximum inhibitory effect is achieved; EA: ethyl acetate; PE: petroleum ether; SEM: trimethylsilylethoxymethyl; Cbz: benzyloxycarbonyl; Boc : tert-butoxycarbonyl; MeCN: acetonitrile; MeOH: methanol; Pd/C: palladium carbon; DIEA: diisopropylethylamine; DIPEA: diisopropylethylamine; DMSO: dimethyl sulfoxide; Pd 2 ( dba) 3 : tris(dibenzylideneacetone)dipalladium; BINAP: 1,1'-binaphthyl-2,2'-bisdiphenylphosphine; Xantphos: 4,5-bis(diphenylphosphonium)-9 ,9-dimethylxanthene; TFA: tri
  • the ratio indicated by the mixed solvent is the volume mixing ratio.
  • % refers to mass percent wt %.
  • the third step 5-cyclopropyl-N 2 -(1-methyl-1H-pyrazol-4-yl)-N 4 -((3R,6S)-6-methylpiperidin-3-yl) - Synthesis of 7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine (9f)
  • the fifth step 1-((2S,5R)-5-((5-cyclopropyl-2-((1-methyl-1H-pyrazol-4-yl)amino)-7H-pyrrolo[2 Synthesis of ,3-d]pyrimidin-4-yl)amino)-2-methylpiperidin-1-yl)prop-2-en-1-one (009)
  • Phenylphosphonium)-9,9-dimethylxanthene (406 mg, 702 ⁇ mol) and cesium carbonate (3.43 g, 10.5 mmol) were stirred at 100° C. for 16 hours under nitrogen atmosphere.
  • the reaction was completed by LCMS detection. Water (30 mL) was added to dilute, and ethyl acetate (100 mL x 2) was used for extraction. The organic phase was washed with saturated aqueous sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • the seventh step 1-[(2S,5R)-5-[(5-cyclopropyl- 2 -([1-(2H3)methyl-1H - pyrazol-4-yl]amino)-7H - Synthesis of pyrrolo[2,3-d]pyrimidin-4-yl)amino]-2-methylpiperidin-1-yl]prop-2-en-1-one (011)
  • Example 1 Referring to the preparation method of Example 1, the difference is that the acryloyl chloride in the fifth step is replaced with 2-acryloyl-2,3,3-( 2 H 3 )-chloride, and compound 012 is prepared in the same way.
  • Example 3 Referring to the preparation method of Example 3, the difference is that the acryloyl chloride in the seventh step is replaced with 2-acryloyl-2,3,3-( 2 H 3 )-chloride, and compound 013 is prepared in the same way.
  • the crude product obtained by concentrating the reaction solution under reduced pressure was dissolved in anhydrous methanol (30 mL), potassium carbonate (2.5 g, 18.1 mmol) was added, and the mixture was stirred at 25° C. for 16 hours.
  • the reaction was completed by LCMS detection.
  • the reaction solution was filtered and concentrated, the residue was dissolved in ethyl acetate (100 mL), the organic phase was washed with saturated aqueous sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • BTK kinase reacts with the substrate under the action of ATP after co-incubating with the compound.
  • the ADP produced in the reaction was quantified using the ADP-GLO assay kit from Promega, which reflects the enzymatic activity.
  • the compounds to be tested were diluted to different concentrations in dimethyl sulfoxide (DMSO) using the Echo pipetting system, transferred to a 384-well plate, and 2 ⁇ L/well of BTK was added, and incubated for 30 minutes. Then, 3 ⁇ L/well of a mixed solution of the substrate Poly (4:1Glu,Tyr) and ATP was added to initiate the enzymatic reaction. Final compound concentrations started at 300 nM and were diluted 3-fold. The final concentration of enzyme in the reaction was 1.7 ng/well, the final concentration of ATP was 36 ⁇ M, and the final concentration of substrate was 0.1 mg/mL.
  • DMSO dimethyl sulfoxide
  • JAK3 kinase reacts with the substrate under the action of ATP after co-incubating with the compound.
  • the ADP produced in the reaction was quantified using the ADP-GLO assay kit from Promega, which reflects the enzymatic activity.
  • the HTRF KinEASE-TK kit from Cisbio was used in this experiment. After the JAK2 kinase is incubated with the compound, it catalyzes the phosphorylation of a specific substrate under the action of ATP, and the change of the fluorescence value generated by the detection antibody reflects the inhibitory ability of the compound on the JAK2 enzyme activity. Meanwhile, referring to the method of Test Example 2, the inhibitory ability of the compound to JAK3 enzymatic activity was determined. The compound's fold JAK3/JAK2 kinase selectivity (ie, the ratio of IC50 for JAK2 to IC50 for JAK3) was obtained by comparing the ability of compounds to inhibit the enzymatic activities of JAK2 and JAK3.
  • the compound's fold JAK3/JAK2 kinase selectivity ie, the ratio of IC50 for JAK2 to IC50 for JAK3
  • the compounds to be tested were transferred to a 384-well plate using an Echo pipetting system, and 5 ⁇ L/well of JAK2 was added and incubated for 5 minutes. Then, 5 ⁇ L/well of a mixed solution of substrate and ATP was added to initiate the enzymatic reaction. The final compound concentration was started from 3 ⁇ M (the solvent was DMSO) and diluted 3-fold, respectively. The final concentration of enzyme in the reaction was 0.05 nM, the final concentration of ATP was 0.6 ⁇ M, and the final concentration of substrate was 2 ⁇ M.
  • the ratio of IC 50 of the compound in the two kinase activity assays of JAK2 and JAK3 was calculated, and the ratio of the IC 50 of JAK2 to the IC 50 of JAK3 was the fold of selectivity of the compound to JAK3/JAK2 kinase.
  • IC 50, JAK2 refers to the IC 50 value of the compound to JAK2
  • IC 50, JAK3 refers to the IC 50 value of the compound to JAK3.
  • Test Example 4 Inhibitory effect on BTK phosphorylation in Ramos cells
  • the degree of phosphorylation of BTK was detected using the BTK phospho-Y223 kit from Cisbio, and the fluorescence signals at 665nm and 615nm were finally read on the Envision microplate reader to calculate the inhibition rate and the half inhibitory concentration (IC 50 ).
  • Test Example 5 Inhibitory effect on STAT5 phosphorylation in CTLL-2 cells
  • This experiment is to evaluate the effect of compounds on the phosphorylation of STAT5, a downstream substrate of JAK3.
  • the fluorescence between donor beads and acceptor beads was detected by a time-resolved fluorescence method using the p-STAT5 (Tyr694/699) detection kit from Perkin Elmer. energy transfer, thus reflecting inhibition of phosphorylation.
  • CTLL-2 cells were seeded in 384-well plates at 1.5X104 cells/15 ⁇ l/well, compounds were transferred to 384-well plates with Echo and incubated for 30 min at 37°C, 5% CO2 incubator. Then, 5 ⁇ L/well of the stimulator IL-2 was added to a final concentration of 1 ng/mL and incubated for 30 minutes. Final compound concentrations started at 3 [mu]M and were diluted 3-fold in dimethyl sulfoxide (DMSO). Add 5 ⁇ L/well of cell lysate and incubate at room temperature for 10 minutes.
  • DMSO dimethyl sulfoxide
  • the phosphorylation degree of STAT5 was detected by the AlphaLISA p-STAT5 (Tyr694/699) detection kit of Perkin Elmer Company, and the AlphaLISA signal was finally read on the Envision microplate reader, and the inhibition rate and the half inhibitory concentration (IC 50 ) were calculated.
  • Test Example 6 Occupation of BTK targets in mouse spleen
  • This experiment is to evaluate compound occupancy of BTK target in mouse spleen.
  • the frozen spleen sample is homogenized and then incubated with the biotin-labeled probe compound.
  • the BTK protein that is not occupied by the compound binds to the probe, and the BTK protein that has been occupied by the compound cannot bind to the probe, and is detected by ELISA. Reflects the occupancy of the BTK target by the compound.
  • the compounds to be tested were formulated in 2% Tween 80/0.5% methylcellulose solution for intragastric administration at a dose of 10mg/kg, and the spleen was taken 0.5h or 24 hours after administration Store in dry ice. Frozen spleen samples were homogenized and assayed for protein concentration using the BCA kit. The spleen homogenate adjusted to the same protein concentration was incubated with the probe compound CNX-500 for 1 hour, and the final concentration of CNX-500 was 1 ⁇ M. Then transfer 100 ⁇ L/well to streptavidin-coated plates and incubate overnight.
  • the supernatant was discarded and washed, and anti-BTK antibody was added to incubate for 2 hours. Discard the supernatant and wash, add HRP-labeled Anti-rabbit IgG antibody, and incubate for 1 hour. The supernatant was discarded and washed, and the color was developed with a chromogenic solution for 10-15 minutes. After the reaction was terminated, the absorbance value was read at a wavelength of 450 nm using Envision. To calculate the occupation ratio, the calculation formula of the occupation ratio is:
  • the signal max represents: the signal generated after adding the probe compound to the control sample
  • Signal min represents: the signal generated by the control sample without probe compound
  • the signal test compound represents: the signal generated after adding the probe compound to a sample of the test compound.
  • Test Example 7 Inhibitory effect on IL-2-induced STAT5 phosphorylation in mouse whole blood
  • This experiment is to evaluate the effect of compounds on the phosphorylation of STAT5, the downstream substrate of JAK3.
  • Whole blood was taken from mice after oral administration, and the stimulator IL-2 was added to incubate for 15 minutes.
  • the phosphorylation level of STAT5 in lymphocytes was detected by flow cytometry, which reflected the inhibitory effect of the compound on the JAK3 target.
  • the compounds to be tested were prepared in 2% Tween80/0.5% methylcellulose solution, administered by gavage at a dose of 10 mg/kg, and whole blood was taken 0.5 hours after administration and placed in heparin sodium in the anticoagulant tube. 80 ⁇ L/well of whole blood was seeded in a 96-well plate, mouse Fc blocking antibody was added, and then 5 ⁇ L/well of detection antibody was added. In different batches of experiments, the detection antibody was CD8 antibody or CD3 antibody/CD4 antibody mixture. Add 10 ⁇ L/well of stimulator IL-2 and incubate for 15 minutes, the final concentration of stimulator is 200ng/mL.
  • the signal max represents: the signal generated by adding the stimulator IL-2 to the control sample
  • Signal min represents: the signal generated by the control sample without stimulator IL-2;
  • the signal test compound represents the signal generated after adding the stimulator IL-2 to a sample of the test compound.
  • the preparation method of the emulsion is as follows: the immune grade bovine type II collagen (Chondrex) with a concentration of 2 mg/ml is mixed with an equal volume of IFA (Incomplete Freund's adjuvant, Chondrex) connected with a syringe, and the IFA is initially injected into the collagen solution by bolus, The final concentration of bovine type II collagen was 1 mg/ml and the emulsion was kept cool during mixing. Seven days after the initial induction, re-induction, the same dose of emulsion was injected at the same site (avoiding the initial injection point).
  • IFA Incomplete Freund's adjuvant
  • the clinical onset generally begins in the second week, and the arthritis score can be carried out from 14 days after the initial induction, and the rats are grouped according to the disease score (main) and the swollen toe volume of each rat to ensure that the disease indicators of each group of rats are as far as possible. uniform, and after the grouping was completed, the drug treatment was started.
  • Clinical score 0, normal; 1, mild, but definite redness and swelling of the ankle or wrist, or marked redness and swelling limited to individual fingers, regardless of the number of fingers affected; 2, ankle or wrist Moderate redness and swelling of the upper part; 3, severe redness and swelling of the entire paw, including the fingers; 4, severe inflammation of the extremities, with multiple joints involved.
  • Compound 009 10mg/kg, 5mg/kg and 2.5mg/kg therapeutic administration can dose-dependently reduce the clinical score of arthritis in rats, and significantly reduce the degree of toe swelling. At the same dose, the efficacy of compound 009 was better than that of the positive reference drug JAK inhibitor tofacitinib.

Abstract

提供式(Ia)所示的嘧啶并吡咯类化合物或其药学可接受的盐、药物组合物及其制备方法，以及作为JAK3和/或BTK抑制剂的用途。

Description

嘧啶并吡咯类化合物
本发明要求2020年9月22日向国家知识产权局提交的专利申请号为202011003941.2，发明名称为“嘧啶并吡咯类化合物”以及2021年6月29日向国家知识产权局提交的专利申请号为202110730368.3，发明名称为“嘧啶并吡咯类化合物”的两件在先申请的优先权。上述申请的全文通过引用的方式结合于本发明中。
技术领域
本发明涉及一种新型的嘧啶并吡咯类化合物或其药学可接受的盐，含有它们的药物组合物以及其在预防或者治疗激酶相关性疾病如Janus激酶(Janus kinase,JAK，特别是JAK3)和/或布鲁顿酪氨酸激酶(Bruton's tyrosine kinase,BTK)相关性疾病中的用途。
背景技术
自身免疫病是由免疫功能异常引起对自身细胞或组织的攻击，导致炎症和组织损伤的一类疾病，包括风湿性关节炎(RA)，炎症性肠炎(IBD)和***性红斑狼疮(SLE)等。BTK和JAK3是针对自身免疫病的两个重要靶点。
BTK是非受体型酪氨酸激酶TEC家族的一员，其结构上包括了PH结构域、TH结构域、SH3结构域、SH2结构域和SH1结构域。BTK在BCR信号通路的活化过程中起着关键的作用，调控着B细胞的发育和活化，对B细胞的增殖、促炎细胞因子的表达和抗体的分泌发挥着重要的作用(Targeting Bruton's tyrosine kinase in B cell malignancies.Nat Rev Cancer.2014Apr；14(4):219-32)，因此BTK成为治疗B细胞异常活化相关疾病的重要靶点之一，包括自身免疫病和B细胞淋巴瘤。Ibrutinib、Acalabrutinib和Zanubrutinib是已经获批的三个BTK抑制剂，主要治疗B细胞淋巴瘤，在部分病人中有明显疗效，但是临床上也观察到存在严重的副作用和耐药突变。2017年ibrutinib被美国FDA批准用于治疗GVHD，而其它的BTK抑制剂目前正在临床上积极探索治疗自身免疫疾病，包括RA、SLE和多发性硬化症(MS)。
JAK3是非受体酪氨酸激酶JAK家族的一员。JAK激酶家族有4个成员:JAK-1、JAK-2、JAK-3和TYK-2。STAT是JAK3的下游底物，JAK3活化STAT使其成为二聚体进入细胞核内，对特定基因的转录表达进行调节。JAK-STAT信号通路对淋巴细胞增殖、分化以及促炎细胞因子的表达具有重要作用(JAK inhibition as a therapeutic strategy for immune and inflammatory diseases.Nat Rev Drug Discov.2017 December 28；17(1):78；The JAK-STAT Pathway:Impact on Human Disease and Therapeutic Intervention.Annual Review of Medicine.Vol.66:311-328)，因此JAK3成为自身免疫病及恶性肿瘤的靶点之一。JAK2在红细胞和血小板生成中发挥着重要作用，小鼠缺失JAK2直接胚胎致死，这提示了JAK2生理功能的重要性(The JAK-STAT pathway:impact on human disease and therapeutic intervention.Annu Rev Med.2015,66:311-28)。部分JAK抑制剂由于缺乏JAK2的选择性，对JAK2产生了明显抑制，造成临床上出现了贫血及血栓等副作用，这些副作用影响了药物剂量的爬升，也间接限制了临床疗效(Jak2:normal function and role in hematopoietic disorders.Curr Opin Genet Dev.2007,17(1):8-14；Clinical efficacy of new JAK inhibitors under development.Just more of the same？,Rheumatology,58(S1):i27–i33；Optimizing management of ruxolitinib in patients with myelofibrosis:the need for individualized dosing.Journal of Hematology & Oncology 2013,6(1),79；Benefit-risk profile of tofacitinib in patients with moderate-to-severe chronic plaque psoriasis:pooled analysis across six clinical trials.Br J Dermatol.2019,180(1):67-75.)。托法替尼(tofacitinib)是FDA批准的JAK抑制剂，其所表现出的不良反应，包括严重的感染、肝损伤等，也被认为与托法替尼对JAK2选择性不足有关。由此可见，提高同家族成员的选择性成为开发新一代靶向JAK的小分子药物开发的方向之一。
除了BTK和JAK3抑制剂各自单独的临床作用，同时抑制BTK/JAK3信号通路则会表现出协同的疗效。数个研究表明，在胶原蛋白诱导的大鼠关节炎(CIA)模型中同时抑制BTK和JAK，观察到关节肿胀有明显缓解，破骨细胞数量减少，病理评分也显著改善，疗效优于单药作用(2016 ACR/ARHP Annual Meeting.Abstract 484；2013 ACR/ARHP Annual Meeting.Abstract 2353)。Abbvie公司于2018年9月和2019年6月分别启动了ABBV599(BTK抑制剂和JAK抑制剂联用)针对RA和SLE的临床二期实验。另一针对BTK/JAK3双靶点抑制剂DWP212525也在小鼠CIA模型中展现出了对疾病的缓解和对关节的保护作用(2019 ACR/ARHP Annual Meeting.Abstract 965)。
鉴于庞大的自身免疫病市场以及未被满足的市场需求，基于BTK和JAK3在自身免疫病上的功能以及已有的临床效果，有必要开发针对BTK和JAK3具有良好活性，且选择性好、毒副作用低的双靶点小分子抑制剂。
发明内容
本发明提供一种式(Ia)所示化合物或其药学上可接受的盐：
Figure PCTCN2021106877-appb-000001
其中：
X为NH；
R 1选自任选被R a取代的以下基团：C 1-C 10烷基或3-10元杂环基；
R a选自氘、F、Cl、Br、I、OH、CN、＝O、NO 2或任选被R b取代的下列基团：NH 2、SH、S(O)NH 2、S(O)(C 1-C 10烷基)、S(O) 2(C 1-C 10烷基)、P(O)(C 1-C 10烷基)、C 1-C 10烷基、C 3-C 14环烷基、3-14元杂环基、C 1-C 10烷氧基、C 3-C 14环烷基氧基、3-14元杂环基氧基、C 2-C 10烯基、C 2-C 10炔基、C 6-C 10芳基、5-10元杂芳基、C 6-C 10芳基氧基或5-10元杂芳基氧基；
R b选自F、Cl、Br、I、OH、CN、＝O、NO 2、NH 2、SH、C 1-C 10烷基、C 3-C 14环烷基、3-14元杂环基、C 1-C 10烷氧基、C 3-C 14环烷基氧基、3-14元杂环基氧基、C 2-C 10烯基、C 2-C 10炔基、C 6-C 10芳基、5-10元杂芳基、C 6-C 10芳基氧基或5-10元杂芳基氧基；
R 2选自C 3-C 6环烷基或苯基，所述C 3-C 6环烷基或苯基任选被R d取代；
R d选自F、Cl、Br、I、OH、CN或任选被选自F、Cl、Br、I、OH的基团取代的C 1-C 4烷基；
R 3选自H、F、Cl、Br、I或任选被选自F、Cl、Br、I、OH的基团取代的C 1-C 10烷基；
R 4为C 1-C 6烷基；
n选自0或1。
在一些实施方案中，式(Ia)的丙烯酰基中的H被1个或多个氘原子取代。
在一些实施方案中，R 2选自环丙基或苯基，所述环丙基或苯基任选被R d取代。
在一些实施方案中，R 2选自C 3-C 6环烷基或苯基。
在一些实施方案中，R 2选自环丙基或苯基。
在一些实施方案中，R 2为环丙基。
在一些实施方案中，R 3选自H、F、Cl、Br、I或任选被选自F、Cl、Br、I、OH的基团取代的C 1-C 6烷基。
在一些实施方案中，R 3选自H、F、Cl、Br、I或任选被选自F、Cl、Br、I、OH的基团取代的C 1-C 4烷基。
在一些实施方案中，R 3选自H、F、Cl、Br或I。
在一些实施方案中，R 3选自H或F。
在一些实施方案中，R 3为H。
在一些实施方案中，R 1选自C 1-C 6烷基或4-6元杂环基，所述C 1-C 6烷基或4-6元杂环基任选被R a取代。
在一些实施方案中，R 1选自C 1-C 6烷基或4-6元杂环基，所述4-6元杂环基含有O原子和/或N原子，所述C 1-C 6烷基或4-6元杂环基任选被R a取代。
在一些实施方案中，R 1选自C 1-C 6烷基或4-6元杂环基，所述4-6元杂环基含有O和/或N作为环原子， 所述C 1-C 6烷基或4-6元杂环基任选被R a取代。
在一些实施方案中，R 1选自C 1-C 6烷基或4-6元杂环基，所述4-6元杂环基含有一个O原子或一个N原子，所述C 1-C 6烷基或4-6元杂环基任选被R a取代。
在一些实施方案中，R 1选自C 1-C 6烷基或4-6元杂环基，所述4-6元杂环基含有一个O或一个N作为环原子，所述C 1-C 6烷基或4-6元杂环基任选被R a取代。
在一些实施方案中，R a选自F、Cl、Br、I、OH、CN、＝O、NO 2或任选被R b取代的下列基团：NH 2、SH、S(O)NH 2、S(O)(C 1-C 10烷基)、S(O) 2(C 1-C 10烷基)、P(O)(C 1-C 10烷基)、C 1-C 10烷基、C 3-C 14环烷基、3-14元杂环基、C 1-C 10烷氧基、C 3-C 14环烷基氧基、3-14元杂环基氧基、C 2-C 10烯基、C 2-C 10炔基、C 6-C 10芳基、5-10元杂芳基、C 6-C 10芳基氧基或5-10元杂芳基氧基。
在一些实施方案中，R a选自F、Cl、Br、I、OH、CN、＝O、NO 2或任选被R b取代的下列基团：NH 2、SH、C 1-C 10烷基、C 3-C 10环烷基、3-10元杂环基、C 1-C 10烷氧基、C 3-C 10环烷基氧基、3-10元杂环基氧基、C 2-C 10烯基、C 2-C 10炔基、C 6-C 10芳基、5-10元杂芳基、C 6-C 10芳基氧基或5-10元杂芳基氧基。
在一些实施方案中，R b选自F、Cl、Br、I、OH、CN、＝O、NO 2、NH 2、SH、C 1-C 10烷基、C 3-C 10环烷基、3-10元杂环基、C 1-C 10烷氧基、C 3-C 10环烷基氧基、3-10元杂环基氧基、C 2-C 10烯基、C 2-C 10炔基、C 6-C 10芳基、5-10元杂芳基、C 6-C 10芳基氧基或5-10元杂芳基氧基。
在一些实施方案中，R a选自氘、F、Cl、Br、I、OH、CN、C 1-C 10烷基或C 3-C 10环烷基。
在一些实施方案中，R a选自F、Cl、Br、I、OH、CN、C 1-C 10烷基或C 3-C 10环烷基。
在一些实施方案中，R a为C 1-C 6烷基。
在一些实施方案中，R a为甲基。
在一些实施方案中，R 1选自氘代甲基、乙基、氧杂环丁基、四氢呋喃基、四氢吡喃基或N-甲基哌啶基。
在一些实施方案中，R 1选自甲基、乙基、氧杂环丁基、四氢呋喃基、四氢吡喃基或N-甲基哌啶基。
在一些实施方案中，R 1选自甲基、氘代甲基、乙基、
Figure PCTCN2021106877-appb-000002
在一些实施方案中，R 1选自甲基、乙基、
Figure PCTCN2021106877-appb-000003
在一些实施方案中，R 1选自甲基或氘代甲基。
在一些实施方案中，R 1选自甲基或CD 3。
在一些实施方案中，R 1为甲基。
在一些实施方案中，R 4为甲基。
在一些实施方案中，所述n为1。
在一些实施方案中，所述式(Ia)化合物或其药学上可接受的盐选自式(IIa)化合物或其药学上可接受的盐：
Figure PCTCN2021106877-appb-000004
其中，X、R 1、R 2、R 3、R 4和n如上文所定义。
在一些实施方案中，本发明涉及以下化合物或其药学上可接受的盐：
Figure PCTCN2021106877-appb-000005
本发明还提供药物组合物，其包含式(Ia)所示化合物或其药学上可接受的盐或者上述具体化合物或其药学上可接受的盐、以及药学上可接受的载体和/或赋形剂。
进一步地，本发明涉及式(Ia)所示的化合物或其药学上可接受的盐，或所述具体化合物或其药学上可接受的盐，或其药物组合物在制备预防或者治疗Janus激酶(JAK，特别是JAK3)和/或布鲁顿酪氨酸激酶(BTK)相关性疾病的药物中的用途。
进一步地，本发明涉及式(Ia)所示的化合物或其药学上可接受的盐，或所述具体化合物或其药学上可接受的盐，或其药物组合物在预防或者治疗Janus激酶(JAK，特别是JAK3)和/或布鲁顿酪氨酸激酶(BTK)相关性疾病中的用途。
进一步地，本发明涉及预防或者治疗Janus激酶(JAK，特别是JAK3)和/或布鲁顿酪氨酸激酶(BTK)相关性疾病的式(Ia)化合物或其药学上可接受的盐，或所述具体化合物或其药学上可接受的盐，或其药物组合物。
本发明还涉及治疗Janus激酶(JAK，特别是JAK3)和/或布鲁顿酪氨酸激酶(BTK)相关性疾病的方法，该方法包括给以患者治疗上有效剂量的包含本发明所述的式(Ia)化合物或其药学上可接受的盐或所述具体化合物或其药学上可接受的盐的药物制剂。
本发明所述的Janus激酶(JAK，特别是JAK3)和/或布鲁顿酪氨酸激酶(BTK)相关性疾病包括但不限于肿瘤(如B细胞淋巴瘤)和自身免疫性疾病(如风湿性关节炎、炎症性肠炎和***性红斑狼疮)等。
术语定义和说明
除非另有说明，本发明中所用的术语具有下列含义，本发明中记载的基团和术语定义，包括其作为实例的定义、示例性的定义、优选的定义、表格中记载的定义、实施例中具体化合物的定义等，可以彼此之间任意组合和结合。这样的组合和结合后的基团定义及化合物结构，应当属于本发明说明书记载的范围内。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，是指代其对应的商品或其活性成分。
本文中
Figure PCTCN2021106877-appb-000006
表示连接位点。
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。
术语“药学上可接受的盐”是指药学上可接受的无毒酸或碱的盐，包括无机酸和碱、有机酸和碱的盐。
术语“立体异构体”是指由分子中原子在空间上排列方式不同所产生的异构体，包括顺反异构体、对映异构体、非对映异构体和构象异构体。
本发明的化合物可以具有不对称碳原子(光学中心)或双键。外消旋体、对映异构体、非对映异构体、几何异构体和单个的异构体都包括在本发明的范围之内。
本文中消旋体或者对映体纯的化合物的图示法来自Maehr，J.Chem.Ed.1985，62:114-120。除非另有说明，用楔形键和虚线键
Figure PCTCN2021106877-appb-000007
表示一个立体中心的绝对构型。当本文所述化合物含有烯属双键或其它几何不对称中心，除非另有规定，它们包括E、Z几何异构体。同样地，所有的互变异构形式均包括在本发明的范围之内。
本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对对映体、(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发明的范围之内。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，均包括在本发明的范围之内。
术语“互变异构体”是指因分子中某一原子在两个位置迅速移动而产生的官能团异构体。本发明化合物可表现出互变异构现象。互变异构的化合物可以存在两种或多种可相互转化的种类。质子移变互变异构体来自两个原子之间共价键合的氢原子的迁移。互变异构体一般以平衡形式存在，尝试分离单一互变异构体时通常产生一种混合物，其理化性质与化合物的混合物是一致的。平衡的位置取决于分子内的化学特性。例如，在很多脂族醛和酮如乙醛中，酮型占优势；而在酚中，烯醇型占优势。本发明包含化合物的所有互变异构形式。
术语“药物组合物”表示一种或多种本文所述化合物或其生理学/药学上可接受的盐或前体药物与其它化学组分的混合物，其它组分例如生理学/药学上可接受的载体和赋形剂。药物组合物的目的是促进化合物对生物体的给药。
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。
当任何变量(例如R a、R b)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。例如，如果一个基团被2个R b所取代，则每个R b都有独立的选项。
本文中的C m-C n，是指具有m-n范围中的整数个碳原子。例如“C 1-C 10烷基”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、6个碳原子、7个碳原子、8个碳原子、9个碳原子或10个碳原子。
术语“卤”或“卤素”是指氟、氯、溴和碘。
术语“C 1-C 10烷基”可理解为表示具有1、2、3、4、5、6、7、8、9或10个碳原子的直链或支链饱和一价烃基。所述烷基是例如甲基、乙基、丙基、丁基、戊基、己基、异丙基、异丁基、仲丁基、叔丁基、异戊基、2-甲基丁基、1-甲基丁基、1-乙基丙基、1，2-二甲基丙基、新戊基、1，1-二甲基丙基、4-甲基戊基、3-甲基戊基、2-甲基戊基、1-甲基戊基、2-乙基丁基、1-乙基丁基、3，3-二甲基丁基、2，2-二甲基丁基、1，1-二甲基丁基、2，3-二甲基丁基、1，3-二甲基丁基或1，2-二甲基丁基等；“C 1-C 6烷基”可理解为表示具有1、2、3、4、5或6个碳原子的直链或支链饱和一价烃基；“C 1-C 4烷基”可理解为表示具有1、2、3或4个碳原子的直链或支链饱和一价烃基。
术语“烷氧基”可理解为“烷基氧基”或“烷基-O-”，指直链状或支链状醇类失去羟基上的氢原子产生的一价基团。例如术语“C 1-C 10烷氧基”可理解为“C 1-C 10烷基氧基”或“C 1-C 10烷基-O-”。
术语“C 2-C 10烯基”应理解为优选表示直链或支链的一价烃基，其包含一个或多个双键并且具有2、3、4、5、6、7、8、9或10个碳原子。所述烯基可分为“顺式”和“反式”取向(或者″E″和″Z″取向)。“C 2-C 6烯基” 应理解为直链或支链的一价烃基，其包含一个或多个双键并且具有2、3、4、5或6个碳原子。“C 2-C 10烯基”的实例包括但不限于乙烯基(-CH＝CH 2)、丙-1-烯基(-CH＝CHCH 3)、丙-2-烯基(-CH 2CH＝CH 2)、2-甲基丙-1-烯基、丁-1-烯基、丁-2-烯基、丁-3-烯基、丁-1，3-二烯基、2-甲基-1，3-丁二烯基、己-1-烯基、己-2-烯基、己-3-烯基或己-4-烯基。
术语“C 2-C 10炔基”应理解为优选表示直链或支链的一价烃基，其包含一个或多个三键并且具有2、3、4、5、6、7、8、9或10个碳原子。“C 2-C 10炔基”的实例包括但不限于乙炔基(-C≡CH)、丙-1-炔基(1-丙炔基、-C≡CCH 3)、丙-2-炔基(炔丙基)、丁-1-炔基、丁-2-炔基或丁-3-炔基。“C 2-C 3炔基”实例包括乙炔基(-C≡CH)、丙-1-炔基(1-丙炔基、-C≡CCH 3)、丙-2-炔基(炔丙基)。
术语“环烷基”指完全饱和的且以单环、并环、桥环或螺环等形式存在的碳环。除非另有指示，该碳环通常为3至14元环。例如，术语“C 3-C 14环烷基”可理解为表示饱和的一价单环、并环、螺环或桥环，其具有3、4、5、6、7、8、9、10、11、12、13或14个碳原子。术语“C 3-C 10环烷基”可理解为表示饱和的一价单环或双环烃环，其具有3、4、5、6、7、8、9或10个碳原子。术语“C 3-C 6环烷基”可理解为表示饱和的一价单环或双环烃环，其具有3、4、5、6个碳原子。环烷基具体实例包括但不限于环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环壬基、环癸基，或者是双环或三环烃基如降冰片基(双环[2.2.1]庚基)、双环[2.2.2]辛基、金刚烷基、螺[4.5]癸烷基、十氢化萘环等。根据本发明，所述双环或三环烃基包括桥环、螺环或并环结构。术语“C 3-C 14环烷基”可以包含“C 3-C 10环烷基”，“C 3-C 10环烷基”可以包含“C 3-C 6环烷基”。
术语“环烷基氧基”可理解为“环烷基-O-”。“C 3-C 14环烷基氧基”可以包含“C 3-C 10环烷基氧基”，“C 3-C 10环烷基氧基”可以包含“C 3-C 6环烷基氧基”。
术语“3-14元杂环基”可理解为具有3、4、5、6、7、8、9、10、11、12、13或14个环原子的饱和的或部分饱和的一价单环或双环烃环，其包含1、2、3、4或5个，优选1、2或3个选自N、O和S的杂原子。术语“3-10元杂环基”指具有3、4、5、6、7、8、9或10个环原子的饱和的或部分饱和的一价单环或双环烃环，其包含1、2、3、4或5个，优选1、2或3个选自N、O和S的杂原子。术语“4-6元杂环基”可理解为具有4、5、6个环原子的饱和的或部分饱和的一价单环或双环烃环，其包含1、2、3、4或5个，优选1、2或3个选自N、O和S的杂原子。特别地，所述杂环基可以包括但不限于：4元环，如氮杂环丁烷基、氧杂环丁烷基；5元环，如四氢呋喃基、二氧杂环戊烯基、吡咯烷基、咪唑烷基、吡唑烷基、吡咯啉基；或6元环，如四氢吡喃基、哌啶基、吗啉基、二噻烷基、硫代吗啉基、哌嗪基或三噻烷基；或部分饱和的6元环如四氢吡啶基；或7元环，如二氮杂环庚烷基。任选地，所述杂环基可以是苯并稠合的。所述杂环基可以是双环的，例如但不限于5,5元环，如六氢环戊并[c]吡咯-2(1H)-基环，或者5,6元双环，如六氢吡咯并[1,2-a]吡嗪-2(1H)-基环。含氮原子的环可以是部分不饱和的，即它可以包含一个或多个双键，例如但不限于2,5-二氢-1H-吡咯基、4H-[1,3,4]噻二嗪基、4,5-二氢噁唑基或4H-[1,4]噻嗪基，或者，它可以是苯并稠合的，例如但不限于二氢异喹啉基。根据本发明，所述杂环基是无芳香性的。所述双环烃环包括桥环、螺环或并环结构。
术语“杂环基氧基”可理解为“杂环基-O-”。“3-14元杂环基氧基”可以包含“3-10元杂环基氧基”，“3-10元杂环基氧基”可以包含“4-6元杂环基氧基”。
术语“C 6-C 10芳基”可理解为具有6、7、8、9、10个碳原子的一价芳香性或部分芳香性的单环、双环或三环烃环，特别是具有6个碳原子的环(“C 6芳基”)，例如苯基；或者具有9个碳原子的环(“C 9芳基”)，例如茚满基或茚基，或者具有10个碳原子的环(“C 10芳基”)，例如四氢化萘基、二氢萘基或萘基。
术语“芳基氧基”可理解为“芳基-O-”。
术语“5-10元杂芳基”可理解为具有5、6、7、8、9、10个环原子，特别是5或6或9或10个环原子，且其包含1-5个，特别是1-3个独立选自N、O和S的杂原子的一价单环、双环或三环芳族环系。特别地，杂芳基选自噻吩基、呋喃基、吡咯基、噁唑基、噻唑基、咪唑基、吡唑基、异噁唑基、异噻唑基、噁二唑基、***基、噻二唑基等以及它们的苯并衍生物，例如苯并呋喃基、苯并噻吩基、苯并噻唑基、苯并噁唑基、苯并异噁唑基、苯并咪唑基、苯并***基、吲唑基、吲哚基、异吲哚基等；或吡啶基、哒嗪基、嘧啶基、吡嗪基、三嗪基等，以及它们的苯并衍生物，例如喹啉基、喹唑啉基、异喹啉基等；或吖辛因基、吲嗪基、嘌呤基等以及它们的苯并衍生物等。
术语“杂芳基氧基”可理解为“杂芳基-O-”。
术语“治疗有效量”是指(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发明化合物的用量。构成“治疗有效量”的本发明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“辅料”是指可药用惰性成分。
术语“赋形剂”的种类实例非限制性地包括粘合剂、崩解剂、润滑剂、助流剂、稳定剂、填充剂和稀释剂等。赋形剂能增强药物制剂的操作特性，即通过增加流动性和/或粘着性使制剂更适于直接压缩。适用于上述制剂的典型的“药学上可接受的载体”的实例为：糖类，淀粉类，纤维素及其衍生物等在药物制剂中常用到的辅料。
词语“包括(comprise)”、“含有(comprise)”或“包含(comprise)”及其英文变体例如comprises或comprising可理解为开放的、非排他性的意义，即“包括但不限于”。
本发明的药物组合物可通过将本发明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。
给予本发明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、***内、鼻内、眼内、腹膜内、肌内、皮下、静脉内给药。
本发明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、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。这些辅料能使本发明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。
本文所述的通式化合物的所有施用方法中，每天给药的剂量为0.01mg/kg到50mg/kg体重，优选为0.03mg/kg到30mg/kg体重，更优选0.05mg/kg到20mg/kg体重，以单独或分开剂量的形式。
本发明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发明的实施例。
本发明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发明的化学变化及其所需的试剂和物料。为了获得本发明的化合物，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。
附图说明
图1为大鼠CIA模型中各组大鼠的临床关节炎评分随时间变化的曲线。
图2为大鼠CIA模型中各组大鼠的后肢体积随时间变化的曲线。
具体实施方式
以下实施例详细说明发明的技术方案，但本发明的保护范围包括但不限于此。
化合物的结构是通过核磁共振(NMR)和/或质谱(MS)来确定的。NMR位移的单位为10 -6(ppm)。NMR测定的溶剂为氘代二甲基亚砜、氘代氯仿、氘代甲醇等，内标为四甲基硅烷(TMS)。“IC 50”指半数抑制浓度，指达到最大抑制效果一半时的浓度；EA:乙酸乙酯；PE：石油醚；SEM：三甲基硅基乙氧基甲基；Cbz：苄氧羰基；Boc：叔丁氧羰基；MeCN：乙腈；MeOH：甲醇；Pd/C：钯碳；DIEA：二异丙基乙胺；DIPEA：二异丙基乙胺；DMSO：二甲基亚砜；Pd 2(dba) 3：三(二亚苄基丙酮)二钯；BINAP：1,1’-联萘 -2,2’-双二苯膦；Xantphos：4,5-双(二苯基磷)-9,9-二甲基氧杂蒽；TFA：三氟醋酸；THF：四氢呋喃；TfOH：三氟甲磺酸；TLC：薄层层析色谱；LCMS：液相色谱质谱联用；HPLC：高效液相色谱；Prep-HPLC：制备高效液相色谱。
除非另作说明，混合溶剂表示的比例是体积混合比例。
除非另作说明，否则％是指质量百分比wt％。
化合物经手工或
Figure PCTCN2021106877-appb-000008
软件命名，市售化合物采用供应商目录名称。
实施例1 化合物009的制备
1-((2S,5R)-5-((5-环丙基-2-((1-甲基-1H-吡唑-4-基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-2-甲基哌啶-1-基)丙-2-烯-1-酮
Figure PCTCN2021106877-appb-000009
合成路线及具体合成步骤：
Figure PCTCN2021106877-appb-000010
第一步：(2S,5R)-5-((2-氯-5-环丙基-7-((2-(三甲基硅基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-2-甲基哌啶-1-羧酸苄酯(9c)的合成
室温下分别将2,4-二氯-5-环丙基-7-((2-(三甲基硅基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶(9a,500mg,1.39mmol),(2S,5R)-5-氨基-2-甲基哌啶-1-羧酸苄酯(9b,346mg,1.39mmol)和DIEA(448mg,3.48mmol)加入到异丙醇(10.0mL)溶液中，将反应体系加热到110℃,并在此温度下搅拌反应16小时。将反应液在减压下浓缩得到粗产品，后经过硅胶柱层析(乙酸乙酯/石油醚＝1/1)纯化得到9c(385mg,收率：48.6％)。
LCMS:Rt:2.157min；MS m/z(ESI):570.2[M+H]；
1H NMR(400M Hz,DMSO-d 6)δ7.45-7.39(m,4H),7.35-7.32(m,1H),6.77(s,1H),5.72(d,J＝8.0Hz,1H),5.46(s,2H),5.20(dd,J＝17.6,12.4Hz,2H),4.60-4.55(m,2H),4.26-4.20(m,1H),3.54(t,J＝8.0Hz,2H),2.73(t,J＝11.6Hz,1H),2.21(s,1H),2.12-2.08(m,1H),1.93-1.88(m,1H),1.70-1.65(m,2H),1.31-1.28(m,1H),1.25(d,J＝6.8Hz,3H),0.93(t,J＝8.0Hz,3H),0.72-0.71(m,2H),0.03(s,9H).
第二步：(2S,5R)-5-((5-环丙基-2-((1-甲基-1H-吡唑-4-基)氨基)-7-((2-(三甲基硅基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-2-甲基哌啶-1-羧酸苄酯(9e)的合成
室温氮气保护下，将Pd 2(dba) 3(32.0mg,0.035mmol)和BINAP(21.8mg,0.035mmol)加入到9c(200mg，0.351mmol)，1-甲基-1H-吡唑-4-氨基(9d,40.8mg，0.421mmol)和Cs 2CO 3(285.9mg,0.878mmol)的1,4-二氧六环(10.0mL)溶液中，反应体系升温至100℃搅拌反应16小时，冷却至室温。过滤，滤饼用 乙酸乙酯(30.0mL)洗涤，将此溶液在减压下浓缩后，过Chem-flash纯化(乙腈/0.1％(v/v)三氟乙酸体系)，得到9e(195mg,收率：88.0％)。
LCMS:Rt:2.148min；MS m/z(ESI):631.3[M+H]。
第三步：5-环丙基-N 2-(1-甲基-1H-吡唑-4-基)-N 4-((3R,6S)-6-甲基哌啶-3-基)-7-((2-(三甲基硅基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-2,4-二胺(9f)的合成
室温氮气保护下，将Pd/C(5mg)加入到9e(195mg,0.309mmol)的甲醇(5.0mL)中，反应体系在氢气下室温搅拌16小时。反应混合物减压过滤，用甲醇(20.0mL)洗涤滤饼，合并滤液，减压蒸干，残留物过Chem-flash纯化(乙腈/0.1％(v/v)三氟乙酸体系)，得到9f(136mg,收率：88.3％)。
LCMS:Rt:1.212min；MS m/z(ESI):497.3[M+H]。
第四步：5-环丙基-N 2-(1-甲基-1H-吡唑-4-基)-N 4-((3R,6S)-6-甲基哌啶-3-基)-7H-吡咯并[2,3-d]嘧啶-2,4-二胺(9g)的合成
在0℃下，将三氟乙酸(1mL)加入到9f(136mg,0.273mmol)的二氯甲烷溶液(5.0mL)中，反应液室温搅拌2小时，减压下将反应液浓缩,得到的黄色油状物加入到DIEA(1.0mL)的甲醇溶液(5.0mL)中，反应液50℃搅拌6小时。减压下将反应液浓缩，残留物过Chem-flash纯化(乙腈/0.1％(v/v)三氟乙酸体系)，得到9g(95mg，收率：94.8％)。
LCMS:Rt:1.124min；MS m/z(ESI):367.2[M+H]。
第五步：1-((2S,5R)-5-((5-环丙基-2-((1-甲基-1H-吡唑-4-基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-2-甲基哌啶-1-基)丙-2-烯-1-酮(009)的合成
将9g(95mg,0.259mmol)溶解在四氢呋喃(2.0mL)和H 2O(3.0mL)的混合液中，加入磷酸钾固体(137.5mg,0.648mmol)，在0℃搅拌下，将丙烯酰氯(9h,28.2mg,0.311mmol)滴加到反应液中,室温搅拌2小时。反应液过滤，滤液用Prep-HPLC(甲酸体系)制备纯化得到009(18.35mg，收率：16.8％，de值：100％，ee值：100％)。
LCMS:Rt:4.416min；MS m/z(ESI):421.5[M+H]；
1H NMR(400M Hz,DMSO-d 6)δ10.59(s,1H),8.40(s,1H),7.81(s,1H),7.38(s,1H),6.92(brs,1H),6.43(s,1H),6.11-6.07(m,1H),5.87(d,J＝8.4Hz,1H),5.64(brs,1H),4.79-4.28(m,2H),4.13(brs,1H),3.71(s,3H),2.76-2.70(m,1H),2.03-1.99(m,1H),1.87-1.85(m,2H),1.72-1.67(m,2H),1.23(s,3H),0.83(d,J＝8.0Hz,2H),0.61-0.57(m,1H),0.47-0.43(m,1H).
实施例2 化合物010的制备
(R)-1-(3-((5-环丙基-2-((1-甲基-1H-吡唑-4-基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)吡咯烷-1-基)丙-2-烯-1-酮
Figure PCTCN2021106877-appb-000011
合成路线及具体合成步骤：
Figure PCTCN2021106877-appb-000012
第一步：(R)-3-((2-氯-5-环丙基-7-((2-(三甲基甲硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)吡咯烷-1-羧酸叔丁酯(10c)的合成
室温下分别将10a(500mg,1.4mmol),(R)-3-氨基吡咯烷-1-羧酸叔丁酯(10b,313mg,1.68mmol)和DIPEA(543mL,4.2mmol)加入到异丙醇(10.0mL)溶液内。将反应体系密封并加热到110℃,在此温度下搅拌16小时。将反应液在减压下浓缩得到粗产品，后经过硅胶柱层析(石油醚/乙酸乙酯＝4/1)纯化得到10c(450mg,收率：63.5％)。
LCMS:Rt:1.320min；MS m/z(ESI):508.3[M+H]。
第二步：((R)-3-((5-环丙基-2-((1-甲基-1H-吡唑-4-基)氨基)-7-((2-(三甲基甲硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)吡咯烷-1-羧酸叔丁酯(10e)的合成
室温在氮气保护下，将Pd 2(dba) 3(72.3mg,0.079mmol),BINAP(49.1mg,0.079mmol)加入到10c(400mg,0.79mmol),1-甲基-1H-吡唑-4-胺(10d,92mg,0.94mmol)和碳酸铯(772mg,2.37mmol)的1,4-二氧六环(30mL)溶液中，反应体系升温至100℃搅拌16小时,冷却至室温。加水(30ml)淬灭，用乙酸乙酯(50.0ml*2)萃取，将有机相浓缩后经过硅胶柱层析(石油醚/乙酸乙酯＝2/1)纯化得到10e(361mg,收率：80.4％)。
LCMS:Rt:1.474min；MS m/z(ESI):569.3[M+H]；
1H NMR(400MHz,DMSO-d 6)δ8.82(s,1H),8.00(s,1H),7.60(s,1H),6.74(d,J＝0.8Hz,1H),6.07(s,1H),5.45(s,2H),4.82-4.75(m,1H),3.90(s,3H),3.79-3.76(m,1H),3.59(t,J＝8.0Hz,3H),3.48(s,1H),3.43(s,1H),2.34(s,1H),2.14(s,2H),1.51(d,J＝8.8Hz,9H),0.94-0.91(m,4H),0.62(s,2H),0.00(s,9H).
第三步：(R)-5-环丙基-N 2-(1-甲基-1H-吡唑-4-基)-N 4-(吡咯烷-3-基)-7H-吡咯并[2,3-d]嘧啶-2,4-二胺(10f)的合成
室温下将10e(361mg,0.63mmol)加入到三氟乙酸(1.0mL)的二氯甲烷溶液(3.0mL)中，反应液室温搅拌2小时，得到单一产物。减压下将反应液浓缩，加入到四氢呋喃/水(4.0mL/2mL)的氢氧化锂溶液(100mg,2.3mmol)中，反应液室温搅拌4小时。减压下将反应液浓缩，得到10f(190mg，收率：88.8％)。
LCMS:Rt:1.245min；MS m/z(ESI):339.5[M+H]。
第四步：(R)-1-(3-((5-环丙基-2-((1-甲基-1H-吡唑-4-基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)吡咯烷-1-基)丙-2-烯-1-酮(010)的合成
将10f(190mg,0.56mmol)溶解在四氢呋喃(4.0mL)和H 2O(2.0mL)的混合液中，加入磷酸钾固体(297mg,1.4mmol)室温搅拌,将丙烯酰氯10g(71mg,0.78mmol)滴加进去,0℃下搅拌2小时,过滤，制备纯化得到010(25.59mg，收率：11.2％)。
LCMS:Rt:6.005min；MS m/z(ESI):393.2[M+H]。
1H NMR(400M Hz,DMSO-d 6)δ10.83(brs,1H),8.88(brs,1H),7.84(d,J＝2.4Hz,1H),7.49(d,J＝3.6Hz,1H),6.67-6.54(m,1H),6.51(s,1H),6.18-6.12(m,1H),5.68(t,J＝12.8Hz,1H),4.81-4.69(m,1H),4.03-3.99(m,1H),3.79(s,3H),3.74-3.59(m,2H),3.54-3.44(m,2H),2.34-2.17(m,1H),2.07-1.99(m,2H),0.79(t,J＝2.8Hz,2H),0.50(d,J＝2.4Hz,2H).
实施例3 化合物011的制备
1-[(2S,5R)-5-[(5-环丙基-2-([1-( 2H 3)甲基-1H-吡唑-4-基]氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基]-2-甲基哌啶-1-基]丙-2-烯-1-酮
Figure PCTCN2021106877-appb-000013
合成路线和具体合成步骤：
Figure PCTCN2021106877-appb-000014
第一步：1-( 2H 3)甲基-4-硝基-1H-吡唑(11b)的合成
将4-硝基-1H-吡唑11a(2.5g,22.1mmol)溶于乙腈(20mL)中，加入氘代碘甲烷(3.92g,27.6mmol)和碳酸钾(4.58g,33.1mmol)，80℃搅拌12小时，TLC检测反应完毕。将反应液冷却至室温过滤，滤液使用乙酸乙酯(200mL)稀释，有机相用饱和氯化钠水溶液(50mL x 2)洗涤，有机相减压浓缩后残留物经柱层析(四氢呋喃/石油醚＝1/2)纯化，得到白色固体11b(2.5g)。
1H NMR(400MHz,DMSO-d 6)δ8.85(s,1H),8.24(s,1H).
第二步：1-( 2H 3)甲基-1H-吡唑-4-胺(11c)的合成
将11b(2.5g,19.2mmol)溶于无水甲醇(60mL)中，加入10％Pd/C(500mg)，25℃搅拌16小时，TLC检测反应完毕。将反应液过滤浓缩，得到油状物1-( 2H 3)甲基-1H-吡唑-4-胺11c(1.89g)。
第三步：(2S,5R)-苯甲基-5-((2-氯-5-环丙基-7-((2-(三甲基甲硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-2-甲基哌啶-1-甲酸基酯(11e)的合成
将2,4-二氯-5-环丙基-7-((2-(三甲基甲硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶9a(3.0g,8.37mmol)溶于二甲亚砜(20mL)中，加入二异丙基乙胺(3.25g,25.1mmol)和(2S,5R)-5-氨基-2-甲基哌啶-1-羧酸苄基酯盐酸盐11d(2.5g,8.78mmol)，100℃搅拌2小时。LCMS检测反应完毕。将反应液冷却至室温，加入饱和氯化铵水溶液(30mL)，使用乙酸乙酯(100mL x 2)进行萃取，有机相用饱和氯化钠水溶液(50mL)洗涤，干燥过滤后有机相减压浓缩，残留物经柱层析(四氢呋喃/二氯甲烷＝1/4)纯化，得到无色油状物(2S,5R)-苯甲基5-((2-氯-5-环丙基-7-((2-(三甲基甲硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-2-甲基哌啶-1-甲酸基酯11e(3.58g)。
LC-MS:Rt:1.080min；MS m/z(ESI):570.5[M+H].
第四步：苯甲基-(2S,5R)-5-[(5-环丙基-2-([1-( 2H 3)甲基-1H-吡唑-4-基]氨基)-7-([2-(三甲基甲硅烷基)乙氧基]甲基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基]-2-甲基哌啶-1-甲酸基酯(11f)的合成
将(2S,5R)-苯甲基-5-((2-氯-5-环丙基-7-((2-(三甲基甲硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-2-甲基哌啶-1-甲酸基酯11e(2.0g,3.51mmol)和1-( 2H 3)甲基-1H-吡唑-4-胺11c(400mg,3.99mmol)溶于无水二氧六环(20mL)中，加入三(二亚苄基丙酮)二钯(322mg,351μmol)，4,5-双(二苯基磷)-9,9-二甲基氧杂蒽(406mg,702μmol)和碳酸铯(3.43g,10.5mmol)，在氮气氛围下100℃搅拌16小时。LCMS检测反应完毕。加入水(30mL)稀释，使用乙酸乙酯(100mL x 2)进行萃取，有机相用饱和氯化钠水溶液(50mL)洗涤，无水硫酸钠干燥后过滤，减压浓缩，残留物经柱层析(四氢呋喃/二氯甲烷＝1/2)纯化，得到白色固体苯甲基-(2S,5R)-5-[(5-环丙基-2-([1-( 2H 3)甲基-1H-吡唑-4-基]氨基)-7-([2-(三甲基甲硅烷基)乙氧基]甲基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基]-2-甲基哌啶-1-甲酸基酯11f(2.57g)。
LC-MS:Rt:4.356min；MS m/z(ESI):635.2[M+H].
第五步：苯甲基(2S,5R)-5-[(5-环丙基-2-([1-( 2H 3)甲基-1H-吡唑-4-基]氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基]-2-甲基哌啶-1-甲酸基酯(11g)的合成
将苯甲基-(2S,5R)-5-[(5-环丙基-2-([1-( 2H 3)甲基-1H-吡唑-4-基]氨基)-7-([2-(三甲基甲硅烷基)乙氧基]甲基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基]-2-甲基哌啶-1-甲酸基酯11f(850mg,1.34mmol)溶于无水二氯甲烷(8mL)中，加入三氟乙酸(8mL)，25℃搅拌2小时。LCMS检测反应完毕。将反应液减压浓缩得到的粗产品溶于无水四氢呋喃(12mL)和水(4mL)中，加入一水合氢氧化锂(169mg,4.02mmol)，25℃搅拌16小时。LCMS检测反应完毕。反应液过滤，将滤液用1M稀盐酸调节pH＝6，使用乙酸乙酯(100mL)萃取，有机相用饱和氯化钠水溶液(30mL)洗涤，无水硫酸钠干燥后过滤，减压浓缩，残留物经柱层析(四氢呋喃/二氯甲烷＝1/3)纯化，得到白色固体苯甲基-(2S,5R)-5-[(5-环丙基-2-([1-( 2H 3)甲基-1H-吡唑-4-基]氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基]-2-甲基哌啶-1-甲酸基酯11g(670mg)。
LC-MS:Rt:0.887min；MS m/z(ESI):526.1[M+Na].
第六步：5-环丙基-N 2-[1-( 2H 3)甲基-1H-吡唑-4-基]-N 4-[(3R,6S)-6-甲基哌啶-3-基]-7H-吡咯并[2,3-d]嘧啶-2,4-二胺(11h)的合成
将甲基-(2S,5R)-5-[(5-环丙基-2-([1-( 2H 3)甲基-1H-吡唑-4-基]氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基]-2-甲基哌啶-1-甲酸基酯11g(300mg,596μmol)溶于三氟乙酸(5mL)中，加入三氟甲磺酸(268mg,1.79mmol)，25℃搅拌30分钟。TLC检测反应完毕。反应液过滤浓缩，得到固体粗产品5-环丙基-N 2-[1-( 2H 3)甲基-1H-吡唑-4-基]-N 4-[(3R,6S)-6-甲基哌啶-3-基]-7H-吡咯并[2,3-d]嘧啶-2,4-二胺11h(200mg)。
LC-MS:Rt:0.729min；MS m/z(ESI):370.2[M+H].
第七步：1-[(2S,5R)-5-[(5-环丙基-2-([1-( 2H 3)甲基-1H-吡唑-4-基]氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基]-2-甲基哌啶-1-基]丙-2-烯-1-酮(011)的合成
将5-环丙基-N 2-[1-( 2H 3)甲基-1H-吡唑-4-基]-N 4-[(3R,6S)-6-甲基哌啶-3-基]-7H-吡咯并[2,3-d]嘧啶-2,4-二胺(200mg,541μmol)溶于四氢呋喃(4mL)和水(2mL)中，在0℃下加入磷酸钾(345mg,1.62mmol)和丙烯酰氯(73.5mg,812μmol)，25℃搅拌2小时。LCMS检测反应完毕。加水(15mL)稀释，用乙酸乙酯(50mL x 2)萃取，有机相用饱和氯化钠水溶液(30mL)洗涤，无水硫酸钠干燥后过滤，减压浓缩，残留物经柱层析(四氢呋喃/二氯甲烷＝1/1)纯化，得到的粗产品经Prep-HPLC[色谱柱Phenomenex C18 80*40mm*3μm；流动相：A：水(含0.05％氢氧化铵v/v)；B:乙腈,B％:27％-67％,9min]分离纯化，得到白色固体1-[(2S,5R)-5-[(5-环丙基-2-([1-( 2H 3)甲基-1H-吡唑-4-基]氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基]-2-甲基哌啶-1-基]丙-2-烯-1-酮011(17.3mg)。
LC-MS:Rt:0.816min；MS m/z(ESI):446.1[M+Na].
1H NMR(400MHz,DMSO-d 6)δ10.59(s,1H),8.40(s,1H),7.81(s,1H),7.39(s,1H),6.84(s,1H),6.44(s,1H),6.09(d,J＝15.4Hz,1H),5.88(d,J＝7.5Hz,1H),5.66(s,1H),4.95-4.20(m,2H),4.14(s,1H),3.09(s,1H),2.03-1.69(m,5H),1.24(s,3H),0.85(d,J＝7.8Hz,2H),0.63-0.44(m,2H).
实施例4 化合物012的制备
1-((2S,5R)-5-((5-环丙基-2-((1-甲基-1H-吡唑-4-基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-2-甲基哌啶 -1-基)-2,3,3-( 2H 3)-丙-2-烯-1-酮的合成
Figure PCTCN2021106877-appb-000015
参照实施例1的制备方法，不同的是将第五步的丙烯酰氯替换为2-丙烯酰-2,3,3-( 2H 3)-氯，同法制得化合物012。
MS m/z(ESI):424.1[M+H].
实施例5 化合物013的制备
1-((2S,5R)-5-((5-环丙基-2-((1-( 2H 3)甲基-1H-吡唑-4-基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-2-甲基哌啶-1-基)-2,3,3-( 2H 3)-丙-2-烯-1-酮的合成
Figure PCTCN2021106877-appb-000016
参照实施例3的制备方法，不同的是将第七步的丙烯酰氯替换为2-丙烯酰-2,3,3-( 2H 3)-氯，同法制得化合物013。
MS m/z(ESI):427.3[M+H].
对比例1 对比例1化合物的合成
1-((2S,5R)-5-((5-氯-2-((1-甲基-1H-吡唑-4-基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-2-甲基哌啶-1-基)丙-2-烯-1-酮
Figure PCTCN2021106877-appb-000017
合成路线和具体合成步骤：
Figure PCTCN2021106877-appb-000018
第一步：(2S,5R)-苯甲基-5-((2,5-二氯-7-((2-(三甲基甲硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-2-甲基哌啶-1-甲酸基酯(中间体2)的合成
将2,4,5-三氯-7-((2-(三甲基甲硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶(3.72g,10.5mmol)溶于二甲基亚砜(20mL)中，加入二异丙基乙胺(4.08g,31.6mmol)和(2S,5R)-5-氨基-2-甲基哌啶-1-羧酸苄基酯盐酸盐(3.0g,10.5mmol)，100℃搅拌2小时。LCMS检测反应完毕。将反应液冷却至室温，加入饱和氯化铵水溶液(30mL)，使用乙酸乙酯(100mL x 2)进行萃取，有机相用饱和氯化钠水溶液(50mL)洗涤，无水硫酸钠干燥后过滤，减压浓缩，残留物经柱层析(四氢呋喃/二氯甲烷＝1/8)纯化，得到白色固体(2S,5R)-苯甲基-5-((2,5-二氯-7-((2-(三甲基甲硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-2-甲基哌啶-1-甲酸基酯(4.65g)。
LC-MS:Rt:1.006min；MS m/z(ESI):564.1[M+H].
第二步：(2S,5R)-苯甲基5-((5-氯-2-((1-甲基-1H-吡唑-4-基)氨基)-7-((2-(三甲基甲硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-2-甲基哌啶-1-甲酸基酯(中间体3)的合成
将(2S,5R)-苯甲基-5-((2,5-二氯-7-((2-(三甲基甲硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-2-甲基哌啶-1-甲酸基酯(3.2g,5.67mmol)和1-甲基-1H-吡唑-4-胺(720mg,7.41mmol)溶于无水二氧六环(30mL)中，加入三(二亚苄基丙酮)二钯(519mg,567μmol)，4,5-双(二苯基磷)-9,9-二甲基氧杂蒽(656mg,1.13mmol)和碳酸铯(5.54g,17.0mmol)，在氮气氛围下100℃搅拌16小时。LCMS检测反应完毕。加入水(30mL)稀释，使用乙酸乙酯(100mL x 2)进行萃取，有机相用饱和氯化钠水溶液(50mL)洗涤，无水硫酸钠干燥后过滤，减压浓缩，残留物经柱层析(四氢呋喃/二氯甲烷＝1/4)纯化，得到白色固体(2S,5R)-苯甲基5-((5-氯-2-((1-甲基-1H-吡唑-4-基)氨基)-7-((2-(三甲基甲硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-2-甲基哌啶-1-甲酸基酯(2.82g)。
LC-MS:Rt:1.112min；MS m/z(ESI):625.3[M+H].
第三步：(2S,5R)-苯甲基-5-((5-氯-2-((1-甲基-1H-吡唑-4-基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-2-甲基哌啶-1-甲酸基酯(中间体4)的合成
将(2S,5R)-苯甲基-5-((5-氯-2-((1-甲基-1H-吡唑-4-基)氨基)-7-((2-(三甲基甲硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-2-甲基哌啶-1-甲酸基酯(2.0g,3.20mmol)溶于无水二氯甲烷(20mL)中，加入三氟乙酸(10mL)，25℃搅拌2小时。LCMS检测反应完毕。将反应液减压浓缩得到的粗产品溶于无水甲醇(30mL)中，加入碳酸钾(2.5g,18.1mmol)，25℃搅拌16小时。LCMS检测反应完毕。将反应液过滤浓缩，残留物用乙酸乙酯(100mL)溶解，有机相用饱和氯化钠水溶液(30mL)洗涤，无水硫酸钠干燥后过滤，减压浓缩，残留物经柱层析(四氢呋喃/二氯甲烷＝1/3)纯化，得到白色固体(2S,5R)-苯甲基-5-((5-氯-2-((1-甲基-1H-吡唑-4-基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-2-甲基哌啶-1-甲酸基酯(730mg)。
LC-MS:Rt:2.627min；MS m/z(ESI):495.3[M+H].
第四步：5-氯-N 2-(1-甲基-1H-吡唑-4-基)-N 4-((3R,6S)-6-甲基哌啶-3-基)-7H-吡咯并[2,3-d]嘧啶-2,4-二胺(中间体5)的合成
将(2S,5R)-苯甲基-5-((5-氯-2-((1-甲基-1H-吡唑-4-基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-2-甲基哌啶-1-甲酸基酯(730mg,1.47mmol)溶于三氟乙酸(5mL)中，加入三氟甲磺酸(664mg,4.42mmol)，25℃搅拌30分钟。TLC检测反应完毕。反应液过滤浓缩，得到固体粗产品5-氯-N 2-(1-甲基-1H-吡唑-4-基)-N 4-((3R,6S)-6-甲基哌啶-3-基)-7H-吡咯并[2,3-d]嘧啶-2,4-二胺(532mg)。
LC-MS:Rt:0.660min；MS m/z(ESI):361.1[M+H].
第五步：1-((2S,5R)-5-((5-氯-2-((1-甲基-1H-吡唑-4-基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-2-甲基哌啶-1-基)丙-2-烯-1-酮的合成
将5-氯-N 2-(1-甲基-1H-吡唑-4-基)-N 4-((3R,6S)-6-甲基哌啶-3-基)-7H-吡咯并[2,3-d]嘧啶-2,4-二胺(532mg,1.47mmol)溶于四氢呋喃(10mL)和水(5mL)中，在0℃下加入磷酸钾(936mg,4.41mmol)和丙烯酰氯(199mg,2.21mmol)，25℃搅拌30分钟。LCMS检测反应完毕。加水(20mL)稀释，用乙酸乙酯(50mL x 2)萃取，有机相用饱和氯化钠水溶液(30mL)洗涤，无水硫酸钠干燥后过滤，减压浓缩，残留物经柱层析(四氢呋喃/二氯甲烷＝1/3)纯化，得到的粗产品经Prep-HPLC[色谱柱：YMC Triart 30*150mm*7μm；流动相：A:水(含0.05％氢氧化铵v/v)；B:乙腈,B％:28％-68％,9min]分离纯化，得到白色固体1-((2S,5R)-5-((5-氯-2-((1-甲基-1H-吡唑-4-基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-2-甲基哌啶-1-基)丙-2-烯-1-酮(160mg)。
LC-MS:Rt:1.979min；MS m/z(ESI):415.1[M+H].
1H NMR(400MHz,DMSO-d 6)δ11.19(br s,1H),8.62(s,1H),7.80(br s,1H),7.41(br s,1H),6.91(d,J＝2.3Hz,1H),6.81(br s,1H),6.14-6.05(m,2H),5.64(br s,1H),4.92-4.09(m,1H),3.72(s,3H),3.11-2.73(m,1H),1.99-1.89(m,1H),1.83(br d,J＝9.6Hz,1H),1.70(br s,2H),1.23(br s,3H).
生物学活性及相关性质测试例
测试实施例1：BTK激酶活性抑制实验
实验原理：BTK激酶与化合物共同孵育后，在ATP的作用下与底物反应。使用Promega公司的ADP-GLO检测试剂盒对反应产生的ADP进行定量，从而反映酶活性。
实验仪器：Labcyte公司Echo650移液***；Perkin Elmer公司Envision酶标仪；Eppendorf公司5810离心机。
实验材料：
试剂 品牌 货号
Tris hydrochloride溶液 Sigma T2663
BRIJ 35 detergent(10％) Merck 203728
MgCl2溶液 Sigma M1028
ADP-Glo激酶检测试剂盒 Promega V9102
BTK Carna bioscience 08-180
Poly(4:1Glu,Tyr) Sigma P0275
384孔板 Perkin Elmer 6007290
实验方法：用Echo移液***将待测化合物在二甲基亚砜(DMSO)中稀释到不同浓度，转移至384孔板中，并且加入2μL/孔的BTK，孵育30分钟。然后加入3μL/孔的底物Poly(4:1Glu,Tyr)和ATP的混合溶液，启动酶反应。化合物终浓度从300nM起始，3倍稀释。反应中酶的终浓度为1.7ng/孔，ATP终浓度为36μM，底物的终浓度为0.1mg/mL。反应1小时后，加入5μL/孔ADP-GLO试剂，孵育40分钟。然后加入10μL/孔激酶反应检测试剂，孵育30分钟。用Envision酶标仪读取荧光信号，并计算抑制率、半数抑制浓度(IC 50)。
本发明化合物的生物活性通过以上的试验进行测定，测得的IC 50值见下表1。
表1 实施例化合物对BTK激酶活性抑制的IC 50
实施例化合物编号 IC 50(nM)
009 3.43
010 3.92
011 4.98
测试实施例2：JAK3激酶活性抑制实验
实验原理：JAK3激酶与化合物共同孵育后，在ATP的作用下与底物反应。使用Promega公司的ADP-GLO检测试剂盒对反应产生的ADP进行定量，从而反映酶活性。
实验仪器：
Labcyte公司Echo650移液***；Perkin Elmer公司Envision酶标仪；Eppendorf公司5810离心机。
实验材料：
试剂 品牌 货号
Tris hydrochloride溶液 Sigma T2663
BRIJ 35 detergent(10％) Merck 203728
MgCl 2溶液 Sigma M1028
ADP-Glo激酶检测试剂盒 Promega V9102
JAK3 Carna bioscience 08-046
Poly(4:1Glu,Tyr) Sigma P0275
384孔板 Perkin Elmer 6007290
实验方法：
用Echo移液***将待测化合物在二甲基亚砜(DMSO)中稀释到不同浓度，转移至384孔板中，并且加入2μL/孔的JAK3，孵育30分钟。然后加入3μL/孔的底物Poly(4:1Glu,Tyr)和ATP的混合溶液，启动酶反应。化合物终浓度分别从300nM起始，3倍稀释。反应中酶的终浓度为1.9ng/孔，ATP终浓度为36μM，底物的终浓度为0.1mg/mL。反应1小时后，加入5μL/孔ADP-GLO试剂，孵育40分钟。然后加入10μL/孔激酶反应检测试剂，孵育30分钟。用Envision酶标仪读取荧光信号，并计算抑制率、半数抑制浓度(IC 50)。
本发明化合物的生物活性通过以上的试验进行测定，测得的IC 50值见下表2。
表2 本发明化合物对JAK3激酶活性抑制的IC 50
实施例化合物编号 IC 50(nM)
009 1.81
010 1.27
011 1.08
测试实施例3：JAK3/JAK2激酶选择性实验
实验原理：本实验使用Cisbio公司的HTRF KinEASE-TK试剂盒。JAK2激酶与化合物共同孵育后，在ATP的作用下催化特定底物磷酸化，通过检测抗体产生的荧光值的变化，反映化合物对JAK2酶活性的抑制能力。同时，参照测试实施例2的方法，测定化合物对JAK3酶活性的抑制能力。通过比较化合物对JAK2和JAK3酶活性的抑制能力，得到化合物的JAK3/JAK2激酶选择性倍数(即对JAK2的IC 50与对JAK3的IC 50的比值)。
实验仪器：
Labcyte公司Echo650移液***；Perkin Elmer公司Envision酶标仪；Eppendorf公司5810离心机。
实验材料：
试剂 品牌 货号
JAK2酶 Carna bioscience 08-045
HTRF KinEASE-TK试剂盒 Cisbio 62TK0PEB
384孔板 Perkin Elmer 6007290
实验方法：
用Echo移液***将待测化合物转移至384孔板中，并且加入5μL/孔的JAK2，孵育5分钟。然后加入5μL/孔的底物和ATP的混合溶液，启动酶反应。化合物终浓度分别从3μM(溶剂为DMSO)起始，3倍稀释。反应中酶的终浓度为0.05nM，ATP终浓度为0.6μM，底物的终浓度为2μM。反应1小时后，加入5μL/孔Streptavidin-XL665终浓度为0.125μM,再加入5μL/孔TK Antibody-Cryptate，孵育30分钟。用Envision酶标仪读取荧光信号，并计算抑制率、半数抑制浓度(IC 50)。参照测试实施例2的方法，测定化合物对JAK3激酶活性的抑制率和IC 50。计算化合物在JAK2和JAK3两个激酶活性测试中IC 50的比值，对JAK2的IC 50与对JAK3的IC 50的比值即为化合物对JAK3/JAK2激酶的选择性倍数。
通过以上试验进行测定本发明化合物对JAK3/JAK2激酶的选择性倍数，结果见下表3。
表3 受试化合物对JAK3/JAK2激酶的选择性
受试化合物编号 IC 50,JAK2/IC 50,JAK3倍数
009 75.3
011 62.8
对比例1 4.4
注：IC 50,JAK2是指化合物对JAK2的IC 50值，IC 50,JAK3是指化合物对JAK3的IC 50值。IC 50,JAK2/IC 50,JAK3倍数越大，表明化合物对JAK3/JAK2激酶的选择性越高。
实验结论：本测试实施例表明，与对比例相比，本发明实施例化合物在JAK家族中对JAK3的抑制作用明显强于对JAK2的抑制作用，且具有良好的JAK3/JAK2激酶选择性。
测试实施例4：对Ramos细胞中BTK磷酸化的抑制作用
实验原理：将Ramos细胞与化合物和刺激剂孵育后，使用Cisbio公司的BTK磷酸化检测试剂盒，通过均相时间分辨荧光(HTRF)的方法检测荧光能量的转移，从而反映对磷酸化的抑制作用。
实验仪器：
仪器 品牌 型号
生物安全柜 ESCO CLASSⅡBSC
离心机 Eppendorf 5810
CO 2培养箱 ESCO CCL-170B-8
细胞计数仪 CountStar IC1000
Envision Perkin Elmer /
实验材料：
试剂 提供商 货号
RPMI-1640培养基 GIBCO A10491-01
灭活胎牛血清(HI-FBS) GIBCO 10100147
HBSS溶液 GIBCO 14025-092
anti-human IgM抗体 Jackson Immuno 109-006-129
BTK phospho-Y223 HTRF检测试剂盒 Cisbio 63ADK017PEH
384孔板 Perkin Elmer 6007680
Ramos ATCC CRL-1596
实验方法：
用Echo移液***将待测化合物转移至384孔板中,将Ramos细胞密度调整为1X10 7细胞/mL，加入10μL/孔细胞悬液，在37℃，5％CO 2的培养箱中孵育1小时。然后加入5μL/孔的刺激剂anti-human IgM抗体，刺激剂终浓度为10μg/mL，孵育10分钟。化合物终浓度为1μM起始，在二甲基亚砜(DMSO)中4倍稀释。加入5μL/孔的细胞裂解液，室温孵育30分钟。使用Cisbio公司的BTK phospho-Y223试剂盒对BTK的磷酸化程度进行检测，最终在Envision酶标仪上读取发射光665nm和615nm下的荧光信号，计算抑制率和半数抑制浓度(IC 50)。
本发明化合物的生物活性通过以上的试验进行测定，测得的IC 50值见下表4。
表4 本发明化合物对Ramos细胞中BTK磷酸化抑制活性
实施例化合物编号 IC 50(nM)
009 5.73
010 53.49
011 6.06
测试实施例5：对CTLL-2细胞中STAT5磷酸化的抑制作用
实验原理：此实验是评价化合物对JAK3下游底物STAT5磷酸化的影响。将CTLL-2细胞与化合物和刺激剂孵育后，使用Perkin Elmer公司的p-STAT5(Tyr694/699)检测试剂盒，通过时间分辨荧光的方法检测供体微珠和受体微珠之间的荧光能量转移，从而反映对磷酸化的抑制作用。
实验仪器：
仪器 品牌 型号
生物安全柜 Thermo Scientific 1300Series A2
离心机 Eppendorf 5702
CO 2培养箱 Thermo Scientific 371
细胞计数仪 Invitrogen C10281
Envision Perkin Elmer /
Echo Labcyte 655
实验材料：
Figure PCTCN2021106877-appb-000019
Figure PCTCN2021106877-appb-000020
实验方法：
将CTLL-2细胞种在384孔板中，1.5X10 4细胞/15μl/孔，用Echo将化合物转移至384孔板中，在37℃，5％CO 2的培养箱中孵育30分钟。然后加入5μL/孔的刺激剂IL-2，终浓度为1ng/mL，孵育30分钟。化合物终浓度从3μM起始，在二甲基亚砜(DMSO)中3倍稀释。加入5μL/孔细胞裂解液，室温孵育10分钟。用Perkin Elmer公司的AlphaLISA p-STAT5(Tyr694/699)检测试剂盒对STAT5的磷酸化程度进行检测，最终在Envision酶标仪上读取AlphaLISA信号，计算抑制率和半数抑制浓度(IC 50)。
本发明化合物的生物活性通过以上的试验进行测定，测得的IC 50值见下表5。
表5 本发明化合物对CTLL-2细胞中STAT5磷酸化的抑制活性
实施例化合物编号 IC 50(nM)
009 46.85
010 143.82
测试实施例6：对小鼠脾脏中BTK靶点的占据
实验原理：此实验是评价化合物在小鼠脾脏中对BTK靶点的占据。将冷冻的脾脏样品匀浆，然后与带生物素标记的探针化合物孵育，化合物未占据的BTK蛋白与探针结合，化合物已经占据的BTK蛋白则不能与探针结合，通过ELISA方法检测，从而反映化合物对BTK靶点的占据。
实验仪器：
仪器 品牌 型号
离心机 Eppendorf 5810
离心机 Eppendorf 5430R
组织研磨仪 美壁 LD48
Envision Perkin Elmer /
实验材料：
仪器 品牌 型号
Anti-BTK抗体 Cell signal 8547S
链霉亲和素包被板 R&D Systems CP004
CNX-500 MCE HY-100338
ELISA显色液 R&D Systems DY999
ELISA终止液 R&D Systems DY994
RIPA裂解液 Sigma R0278
Anti-rabbit IgG抗体 Cell signal 7074S
BCA Protein Assay试剂盒 Pierce 23225
实验方法：
使用C57BL/6N雌性小鼠，将待测化合物配制在2％吐温80/0.5％甲基纤维素溶液中灌胃给药，剂量为10mg/kg，给药后0.5h或者24小时后取脾脏保存于干冰中。将冷冻的脾脏样品匀浆并用BCA试剂盒检测蛋白浓度。将蛋白浓度调整一致后的脾脏匀浆液与探针化合物CNX-500孵育1小时，CNX-500终浓度为1μM。然后转移100μL/孔至链霉亲和素包被板中孵育过夜。弃上清并清洗，加入anti-BTK抗体孵育2 小时。弃上清并清洗，加入HRP标记的Anti-rabbit IgG抗体，孵育1小时。弃上清并清洗，用显色液显色10-15分钟，终止反应后，使用Envision在波长450nm下读取吸光度值。计算占据比率，占据比率计算公式为：
Figure PCTCN2021106877-appb-000021
其中：
信号 max表示：对照组样品加入探针化合物后产生的信号；
信号 min表示：对照组样品不加探针化合物后产生的信号；
信号 待测化合物表示：给待测化合物的样品加入探针化合物后产生的信号。
实验结果如表6所示。
表6 本发明化合物对小鼠脾脏中BTK靶点的占据
Figure PCTCN2021106877-appb-000022
测试实施例7：对小鼠全血中IL-2诱导的STAT5磷酸化的抑制作用
实验原理：此实验是评价化合物对JAK3下游底物STAT5磷酸化的影响。小鼠口服给药后取全血，加入刺激剂IL-2孵育15分钟，通过流式细胞技术检测淋巴细胞中STAT5磷酸化水平，从而反映化合物对JAK3靶点的抑制作用。
实验仪器：
仪器 品牌 型号
生物安全柜 ESCO CLASSⅡ BSC
离心机 Eppendorf 5810
CO 2培养箱 ESCO CCL-170B-8
Flow cytometer BD Biosciences Canto II
-4℃冷藏箱 海尔 HYC-650
实验材料：
试剂 品牌 货号
AF647 Mouse Anti-pStat5抗体 BD Biosciences 562076
BV 421 anti-mouse CD8抗体 Biolegend 100738
BV421 Anti-Mouse CD3抗体 BD Biosciences 740014
FITC Anti-Mouse CD4抗体 BD Biosciences 553047
IL-2 R&D 402-ML-020
小鼠Fc封闭抗体 Biolegend 156603
裂解固定液 BD Biosciences 558049
细胞染色液 Biolegend 420201
96孔板 Corning 3799
Perm Buffer III BD Biosciences 558050
96孔深孔板 Axygen P-96-450V-C
实验方法：
使用C57BL/6N雌性小鼠，将待测化合物配制在2％Tween80/0.5％甲基纤维素溶液中，灌胃给药，剂量为10mg/kg，给药0.5小时后取全血置于肝素钠抗凝管中。将全血80μL/孔种于96孔板中，加入小鼠Fc封闭抗体，然后再加入检测抗体5μL/孔，不同批次实验中检测抗体为CD8抗体或者CD3抗体/CD4抗体混合液。加入10μL/孔刺激剂IL-2，孵育15分钟，刺激剂终浓度为200ng/mL。将全血转移60μL/孔至96孔深孔板中，并加入裂解固定液350μL/孔，孵育10分钟。离心弃上清后，将细胞重悬于100μL/孔Perm Buffer III，孵育30分钟。离心弃上清，加入pSTAT5抗体50μL/孔，孵育30分钟。离心弃上清后，将细胞重悬于染色液中，用流式细胞仪检测pSTAT5的信号，并计算抑制率。抑制率计算公式为：
Figure PCTCN2021106877-appb-000023
其中：
信号 max表示：对照组样品加入刺激剂IL-2后产生的信号；
信号 min表示：对照组样品不加刺激剂IL-2后产生的信号；
信号 待测化合物表示：给待测化合物的样品加入刺激剂IL-2后产生的信号。
实验结果如表7所示。
表7 本发明化合物对小鼠全血中IL-2诱导的STAT5磷酸化的抑制作用
Figure PCTCN2021106877-appb-000024
测试实施例8：大鼠CIA模型药效实验
选择7-8周龄Lewis雌性大鼠，每只大鼠使用三点注射法，异氟烷麻醉大鼠，前两个点在背部两侧大腿根部剃毛后皮内注射各100μl乳剂，第三个点在离尾底2cm处，将针头斜朝上并与尾平行***，直到针头尖端离尾底0.5cm处，在尾基部皮下注射50μl乳剂。乳剂制备方法如下：将浓度为2mg/ml的免疫级牛II型胶原(Chondrex)与IFA(弗氏不完全佐剂,Chondrex)联通注射器等体积混合，起始由IFA推注到胶原溶液中，牛II型胶原终浓度为1mg/ml，在混合过程中保持乳剂的冷却。初次诱导7天后，再次诱导，在相同部位(避开初次注射点)注射同等剂量乳剂。
临床发病一般在第2周开始，可从初次诱导后14天进行关节炎评分，根据每只大鼠的疾病评分(主要)和足趾肿胀体积进行分组，保证每组大鼠的疾病指标尽可能均一，并在分组完，开始给药治疗。
疾病发病评价：
(1)临床评分：0，正常；1，轻微，但明确的发红和肿胀的脚踝或手腕，或明显的发红和肿胀仅限于个别手指，无论受影响的手指数量；2，脚踝或腕部中度发红和肿胀；3，整个爪子严重发红和肿胀，包括手指；4，肢体严重发炎，多关节受累。
(2)足趾肿胀体积测量：在选定的时间点，异氟烷麻醉大鼠，用不可磨灭的记号笔标记大鼠后爪，用肢体肿胀测量仪(ugo basile Italy)测定大鼠后爪肿胀情况，以体积变化表示。大鼠CIA模型治疗方案：将试验动物分组为空白组、阴性对照组、阳性对照组及实验组，其中实验组化合物009设置给药剂量为10mg/kg、5mg/kg和2.5mg/kg，阳性对照组为10mg/kg的JAK抑制剂托法替尼，阴性对照组为空白溶媒(2％吐温80/0.5％甲基纤维素)，自分组当天开始灌胃给药，连续治疗12天。期间监测大鼠后肢体积及临床评分，评分时由独立第二人盲法评价。
根据图1和图2所示：化合物009 10mg/kg、5mg/kg和2.5mg/kg治疗性给药，可剂量依赖性减轻大鼠关节炎临床评分，显著缓解足趾肿胀程度。同等剂量下，化合物009的药效优于阳性参照药物JAK抑制剂托法替尼。
以上，对本发明的实施方式进行了说明。但是，本发明不限定于上述实施方式。凡在本发明的精神和原则之内，所做的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。

Claims (12)

  1. 式(Ia)所示化合物或其药学上可接受的盐：
    Figure PCTCN2021106877-appb-100001
    其中，
    X为NH；
    R 1选自任选被R a取代的以下基团：C 1-C 10烷基或3-10元杂环基；
    R a选自氘、F、Cl、Br、I、OH、CN、＝O、NO 2或任选被R b取代的下列基团：NH 2、SH、S(O)NH 2、S(O)(C 1-C 10烷基)、S(O) 2(C 1-C 10烷基)、P(O)(C 1-C 10烷基)、C 1-C 10烷基、C 3-C 14环烷基、3-14元杂环基、C 1-C 10烷氧基、C 3-C 14环烷基氧基、3-14元杂环基氧基、C 2-C 10烯基、C 2-C 10炔基、C 6-C 10芳基、5-10元杂芳基、C 6-C 10芳基氧基或5-10元杂芳基氧基；
    R b选自F、Cl、Br、I、OH、CN、＝O、NO 2、NH 2、SH、C 1-C 10烷基、C 3-C 14环烷基、3-14元杂环基、C 1-C 10烷氧基、C 3-C 14环烷基氧基、3-14元杂环基氧基、C 2-C 10烯基、C 2-C 10炔基、C 6-C 10芳基、5-10元杂芳基、C 6-C 10芳基氧基或5-10元杂芳基氧基；
    R 2选自C 3-C 6环烷基或苯基，所述C 3-C 6环烷基或苯基任选被R d取代；
    R d选自F、Cl、Br、I、OH、CN或任选被选自F、Cl、Br、I、OH的基团取代的C 1-C 4烷基；
    R 3选自H、F、Cl、Br、I或任选被选自F、Cl、Br、I、OH的基团取代的C 1-C 10烷基；
    R 4为C 1-C 6烷基；
    n选自0或1。
  2. 根据权利要求1所述的式(Ia)所示化合物或其药学上可接受的盐，其中R a选自F、Cl、Br、I、OH、CN、＝O、NO 2或任选被R b取代的下列基团：NH 2、SH、S(O)NH 2、S(O)(C 1-C 10烷基)、S(O) 2(C 1-C 10烷基)、P(O)(C 1-C 10烷基)、C 1-C 10烷基、C 3-C 14环烷基、3-14元杂环基、C 1-C 10烷氧基、C 3-C 14环烷基氧基、3-14元杂环基氧基、C 2-C 10烯基、C 2-C 10炔基、C 6-C 10芳基、5-10元杂芳基、C 6-C 10芳基氧基或5-10元杂芳基氧基。
  3. 根据权利要求1所述的式(Ia)所示化合物或其药学上可接受的盐，其中R 4为甲基。
  4. 根据权利要求1-3任一项所述的式(Ia)所示化合物或其药学上可接受的盐，其中R 2选自C 3-C 6环烷基或苯基，优选为环丙基。
  5. 根据权利要求1-3任一项所述的式(Ia)所示化合物或其药学上可接受的盐，其中R 1选自C 1-C 6烷基或4-6元杂环基，所述C 1-C 6烷基或4-6元杂环基任选被R a取代。
  6. 根据权利要求5所述的式(Ia)所示化合物或其药学上可接受的盐，其中R 1选自甲基或氘代甲基。
  7. 根据权利要求1-6任一项所述的式(Ia)所示化合物或其药学上可接受的盐，其中所述式(Ia)的丙烯酰基中的H被1个或多个氘原子取代。
  8. 根据权利要求1-7任一项所述的式(Ia)所示化合物或其药学上可接受的盐，其中所述式(Ia)化合物或其药学上可接受的盐选自式(IIa)化合物或其药学上可接受的盐：
    Figure PCTCN2021106877-appb-100002
    其中，X、R 1、R 2、R 3、R 4和n如权利要求1-7任一项中所定义。
  9. 根据权利要求1-8任一项所述的化合物或其药学上可接受的盐，其中所述n为1。
  10. 如下化合物或其药学上可接受的盐：
    Figure PCTCN2021106877-appb-100003
  11. 一种药物组合物，所述组合物包含权利要求1至10任一项的化合物或其药学上可接受的盐，以及药学上可接受的载体或赋形剂。
  12. 权利要求1至10任一项的化合物或其药学上可接受的盐或者权利要求11的药物组合物在预防或者治疗Janus激酶和/或布鲁顿酪氨酸激酶相关性疾病中的用途，所述Janus激酶和/或布鲁顿酪氨酸激酶相关性疾病优选为肿瘤或自身免疫性疾病。
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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103814030A (zh) * 2011-09-22 2014-05-21 辉瑞大药厂 吡咯并嘧啶及嘌呤衍生物
CN109311896A (zh) * 2016-06-30 2019-02-05 株式会社大熊制药 吡唑并嘧啶衍生物作为激酶抑制剂
WO2019132562A1 (ko) * 2017-12-28 2019-07-04 주식회사 대웅제약 카이네이즈 저해제로서의 옥시-플루오로피페리딘 유도체
WO2019132560A1 (ko) * 2017-12-28 2019-07-04 주식회사 대웅제약 카이네이즈 저해제로서의 아미노-플루오로피페리딘 유도체
CN111527088A (zh) * 2017-12-28 2020-08-11 株式会社大熊制药 作为激酶抑制剂的氨基-甲基哌啶衍生物
WO2021147952A1 (zh) * 2020-01-21 2021-07-29 江苏先声药业有限公司 嘧啶并吡咯类化合物

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103814030A (zh) * 2011-09-22 2014-05-21 辉瑞大药厂 吡咯并嘧啶及嘌呤衍生物
CN109311896A (zh) * 2016-06-30 2019-02-05 株式会社大熊制药 吡唑并嘧啶衍生物作为激酶抑制剂
WO2019132562A1 (ko) * 2017-12-28 2019-07-04 주식회사 대웅제약 카이네이즈 저해제로서의 옥시-플루오로피페리딘 유도체
WO2019132560A1 (ko) * 2017-12-28 2019-07-04 주식회사 대웅제약 카이네이즈 저해제로서의 아미노-플루오로피페리딘 유도체
CN111527088A (zh) * 2017-12-28 2020-08-11 株式会社大熊制药 作为激酶抑制剂的氨基-甲基哌啶衍生物
WO2021147952A1 (zh) * 2020-01-21 2021-07-29 江苏先声药业有限公司 嘧啶并吡咯类化合物

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