WO2023151069A1 - 吡咯并[2,3-d]六元杂芳环衍生物、其制备方法和药物用途 - Google Patents

吡咯并[2,3-d]六元杂芳环衍生物、其制备方法和药物用途 Download PDF

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WO2023151069A1
WO2023151069A1 PCT/CN2022/076138 CN2022076138W WO2023151069A1 WO 2023151069 A1 WO2023151069 A1 WO 2023151069A1 CN 2022076138 W CN2022076138 W CN 2022076138W WO 2023151069 A1 WO2023151069 A1 WO 2023151069A1
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linear
branched
alkyl
branched alkyl
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王永钢
陈海杰
廖辉
胡双华
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湖南南新制药股份有限公司
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Priority to CN202310064329.3A priority patent/CN116003417A/zh
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention provides a pyrrolo[2,3-d] six-membered heteroaryl ring derivative having pyrrolo[2,3-d]pyrimidinyl or pyrrolo[2,3-d]pyridinyl derivative and having Janus kinase (JAK) kinase inhibitory activity, especially selective and high inhibitory activity on JAK3 kinase.
  • the invention also relates to compositions comprising such compounds, methods for preparing such compounds, and methods for treating and preventing diseases mediated through JAK3 dysregulation.
  • Janus kinases belong to a family of tyrosine kinases that alter the function of proteins containing them through their ability to phosphorylate tyrosine residues. After being stimulated by specific growth factors, growth hormones, chemokines, cytokines and various cell surface receptors, it is activated to have tyrosine kinase activity and bind in pairs, and the dimeric JAK can undergo spontaneous phosphorylation It binds to STAT proteins, phosphorylates STAT transcription factors and transfers them to the nucleus, transfers extracellular signals from cell surface receptors to the intracellular nucleus, and changes the transcription of DNA and the subsequent translation of proteins.
  • JAKs Janus kinases
  • JAK-STAT pathway acts on more than 50 downstream cytokines and growth factors. Therefore, JAK kinases are considered to be the central communication nodes of the immune system.
  • Janus kinases (JAKs) have four family members: JAK1, JAK2, JAK3 and TYK2. Among them, JAK1, JAK2 and TYK2 widely exist in various tissues and cells in the body, and JAK3 mainly exists in bone marrow cells, thymocytes, NK cells and activated B lymphocytes and T lymphocytes.
  • JAK1 has become a new target in the fields of immunity, inflammation and cancer
  • JAK2 has become an exact target for the treatment and prevention of blood system-related diseases
  • JAK3 It has become a popular target for the treatment of autoimmune diseases.
  • Each cell surface receptor requires a pair of identical homodimers (such as JAK2/JAK2) or heterodimers (such as JAK1/JAK3) to signal and activate downstream STAT proteins (signal transducers and activation Objects), regulate the corresponding target gene promoters to affect the transcription of DNA and the subsequent translation of proteins.
  • Each pair of JAKs has different activating ligands and downstream effectors (Pharmacological Research, 2019, 147, 104392).
  • the JAK-STAT signaling pathway has a wide range of functions and participates in many important biological processes such as cell proliferation, differentiation, apoptosis, and immune regulation.
  • the JAK-STAT pathway acts on more than 50 downstream cytokines and growth factors, including interleukins (IL-2-7, IL-9, IL-10, IL-15, IL-21), interferons ( IFN- ⁇ , IFN- ⁇ , IFN- ⁇ ), erythropoietin (EPO), granulocyte and giant cell colony-stimulating factor (GM-CSF), growth-stimulating hormone (GH), prolactin (PRL), platelet-stimulating TPO, etc., play a key role in the biological processes involved in the proliferation and immune regulation of immune cells and hematopoietic stem cells.
  • IL-2-7, IL-9, IL-10, IL-15, IL-21 interferons
  • IFN- ⁇ , IFN- ⁇ , IFN- ⁇ erythropoietin
  • JAK1 can interact with IL-10, IL-19, IL-20, IL-22, IL-26, IL-28, IFN- ⁇ , IFN- ⁇ , IL-6 in the gp130 family and other receptors containing ⁇ c, etc. Binding (Cell, 1998, 93:373-383).
  • the JAK1 gene knockout experiment on the mouse model shows that this enzyme plays a key role in regulating the biological effects of the above-mentioned various cytokine receptors (Gene, 2002, 285: 1-24).
  • JAK1 is a novel target in disease areas such as immunity, inflammation and cancer.
  • JAK1 inhibitors can be used to treat/prevent autoimmune diseases, inflammation and tumors (Blood, 2010, 115:3287-3295), such as leukemia, lymphoma, melanoma, arthritis, psoriasis, Crohn's disease, erythema Lupus, acquired immunodeficiency syndrome, Behcet's disease (Hum. Genet., 2013, 132:1049-1058), etc.
  • JAK2 plays an important role in many receptor signal regulation processes including EPO, GH, PRL, IL-3, IFN- ⁇ (Gene, 2002, 285:1-24; Nat.Rev.Mol.CellBiol., 2002, 3:651-662).
  • JAK2 Knocking out JAK2 in the mouse model can lead to animal death caused by anemia (J.Biol.Chem., 2007,282:20059-20063); a base mutation JAK2V617F on the JAK2 gene in humans, which is related to myeloproliferative Diseases such as polycythemia vera (PV), essential thrombocythemia (ET), idiopathic myelofibrosis (IMF), and chronic myeloid leukemia (CML) are closely related to each other (Immunol.Rev., 2009 , 228:273-287). Therefore, JAK2 has become a definite target for the treatment/prevention of such diseases.
  • PV polycythemia vera
  • ET essential thrombocythemia
  • IMF idiopathic myelofibrosis
  • CML chronic myeloid leukemia
  • JAK3 regulates cell signaling by binding to the gamma co-chain ( ⁇ c) in cytokine receptor complexes such as IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. Mutations in either JAK3 or ⁇ c can cause severe combined immunodeficiency (SCID) (Blood, 1996, 88:817-823). The abnormal activity of JAK3 is manifested by a large reduction of T cells and NK cells and loss of B cell function, which seriously affects the normal biological functions of the immune system. Based on its functional characteristics and special tissue distribution, JAK3 has become an attractive drug target for immune system-related diseases.
  • SCID severe combined immunodeficiency
  • TYK2 is the first member of the JAK family, which can be activated by various receptors such as IFNs, IL-10, IL-6, IL-12, IL-23, and IL-27. In mice, the loss of TYK2 function will cause defects in the signaling pathways of various cytokine receptors, which will lead to viral infection, decreased antibacterial immune function, and increased the possibility of lung infection (Gene, 2002, 285: 1- twenty four).
  • JAK inhibitors are all non-selective JAK inhibitors.
  • Ruxolitinib the first JAK inhibitor developed by Incyte of the United States, was approved for marketing in the United States. Drugs for the treatment of myelofibrosis.
  • Tofacitinib was approved by the FDA for the treatment of rheumatoid arthritis (RA)
  • Baricitinib was first approved for marketing in Europe in 2017, but it was not approved by the FDA.
  • the marketing application of Baricitinib was rejected; after completing relevant clinical trials, Baricitinib was finally approved by the FDA in January 2018.
  • pan-JAKs inhibitors all have a black box warning: the risk of serious infection, malignant tumor, and thrombosis.
  • the pan-JAKs inhibitor Tofacitinib has side effects including a decrease in the number of red blood cells and white blood cells and an increase in cholesterol levels, which may be related to its high JAK2 inhibitory activity (J.Med.Chem., 2012,55:6176-6193).
  • JAK3 is a member of the Janus family of protein kinases comprising JAK1, JAK2, JAK3, and TYK2, and is expressed at varying levels in all tissues. Many cytokine receptors signal through the following combined JAK kinase pairs: JAK1/JAK2, JAK1/JAK3, JAK1/TYK2, JAK2/TYK2, or JAK2/JAK2. Animal studies have shown that JAK3 is involved in the development, function and homeostasis of the immune system. Modulation of immune activity through inhibition of JAK3 kinase activity may prove useful in the treatment of various immune disorders (J.
  • the present invention relates to novel compounds that are selective JAK3 modulators useful in the treatment of diseases associated with JAK3 dysregulation.
  • the present invention also provides pharmaceutical compositions comprising such JAK3 modulators and methods of treating and/or preventing such diseases. Therefore, the present invention provides the compound represented by formula (I), its optical isomer or their mixture, its pharmaceutically acceptable salt, solvate, its N-oxide or their prodrug, which has the following structure :
  • X is independently selected from N, CH or CCN;
  • R is independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, C1-C8 alkynyl, C1-C8 haloalkynyl, C3-C5 cycloalkyl substituted alkynyl, methyleneoxyalkyl substituted alkynyl, Methylene oxyhaloalkyl substituted alkynyl, 5-6 membered aromatic ring or heteroaryl ring substituted alkynyl, C1-C6 linear or branched alkyl, C1-C6 linear or branched alkoxymethylene, halogenated C1-C6 linear or branched alkoxymethylene, C1-C6 linear or branched alkoxydifluoromethylene, halogenated C1-C6 linear or branched alkoxydifluoromethylene, C1- C6 linear or branched alkoxy fluoromethylene, halogenated C1-C6 linear or branched alkoxy fluoromethylene, C
  • R is independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, C1-C8 alkynyl, C1-C8 haloalkynyl, C3-C5 cycloalkyl substituted alkynyl, methyleneoxyalkyl substituted alkynyl, Methylene oxyhaloalkyl substituted alkynyl, 5-6 membered aromatic ring or heteroaryl ring substituted alkynyl, C1-C6 linear or branched alkyl, C1-C6 linear or branched alkoxymethylene, halogenated C1-C6 linear or branched alkoxymethylene, C1-C6 linear or branched alkoxydifluoromethylene, halogenated C1-C6 linear or branched alkoxydifluoromethylene, C1- C6 linear or branched alkoxy fluoromethylene, halogenated C1-C6 linear or branched alkoxy fluoromethylene, C
  • R is independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, C1-C8 alkynyl, C1-C8 haloalkynyl, C3-C5 cycloalkyl substituted alkynyl, methyleneoxyalkyl substituted alkynyl, Methylene oxyhaloalkyl substituted alkynyl, 5-6 membered aromatic ring or heteroaryl ring substituted alkynyl, C1-C6 linear or branched alkyl, C1-C6 linear or branched alkoxymethylene, halogenated C1-C6 linear or branched alkoxymethylene, C1-C6 linear or branched alkoxydifluoromethylene, halogenated C1-C6 linear or branched alkoxydifluoromethylene, C1- C6 linear or branched alkoxy fluoromethylene, halogenated C1-C6 linear or branched alkoxy fluoromethylene, C
  • R is independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, C1-C8 alkynyl, C1-C8 haloalkynyl, C3-C5 cycloalkyl substituted alkynyl, methyleneoxyalkyl substituted alkynyl, Methylene oxyhaloalkyl substituted alkynyl, 5-6 membered aromatic ring or heteroaryl ring substituted alkynyl, C1-C6 linear or branched alkyl, C1-C6 linear or branched alkoxymethylene, halogenated C1-C6 linear or branched alkoxymethylene, C1-C6 linear or branched alkoxydifluoromethylene, halogenated C1-C6 linear or branched alkoxydifluoromethylene, C1- C6 linear or branched alkoxy fluoromethylene, halogenated C1-C6 linear or branched alkoxy fluoromethylene, C
  • the present invention provides compounds selected from the group consisting of:
  • the present invention also provides:
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of the present invention
  • the present invention relates to a class of pyrrolo[2,3-d]pyrimidinyl and pyrrolo[2,3-d]pyridine derivatives and their analogs.
  • the present invention relates to compounds useful as inhibitors of JAKs, especially JAK3, including pyrrolo[2,3-d]pyrimidinyl and pyrrolo[2,3-d]pyridine derivatives and the like things. While the invention is not so limited, an appreciation of various aspects of the invention will be gained through the following discussion and examples.
  • the compounds of the present invention may be administered alone or in combination with one or more additional agents that modulate the mammalian immune system or with anti-inflammatory agents in a pharmaceutically acceptable form.
  • agents may include, but are not limited to, cyclosporin A (such as Sandimin TM or Neostimulus TM ), rapamycin, FK-506 (tacrolimus), leflunomide, deoxyspergualin, Mycophenolate mofetil (such as Cellcet TM ), Azathioprine (such as Imuran TM ), Daclizumab (such as Zenapax TM ), OKT3 (such as Orthocolone TM ), AtGam TM , Aspirin, Acetaminophen, Ibuprofen, naproxen, piroxicam, and anti-inflammatory steroids (such as Deflazacort, prednisolone, or dexamethasone), IFN-beta, teriflunomide, laquinimod, glatiramer
  • the present invention also provides a JAK3 selective inhibitor composition, its optical isomer or their mixture, including the compound of the present invention, its pharmaceutically acceptable salt, solvate or prodrug.
  • all isomers are included unless otherwise specified.
  • double bonds, collective isomers in rings E type, Z type, cis (cis), trans (trans)
  • alkyl groups include straight chain alkyl groups and branched chain alkyl groups, depending on the presence or absence of Optical isomers (R, S type) produced by symmetrical carbon atoms, etc., and their mixtures in any proportion, racemic mixtures, and all isomers produced by tautomers are included in the present invention .
  • the compounds represented by general formula I can be converted into corresponding salts by known methods.
  • the salts are preferably water-soluble.
  • pharmaceutically acceptable non-toxic acid addition salts are amino acids with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid), or by using other methods known in the art, such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, besylate, benzoate, bisulfate, borate, butyrate, camphorate Salt, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate Salt, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl Sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, bis Moxamate, Pectate, Persulfate
  • Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1-4 alkyl) 4 salts.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Additional pharmaceutically acceptable salts include non-toxic salts formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkylsulfonates, and arylsulfonates, as appropriate. Ammonium, quaternary ammonium, and amine cations.
  • the term "JAK3 inhibitor” provided herein includes compounds having formula (I), formula (II), formula (III), formula (IV) each of which includes different stereoisomers having the same molecular formula , where stereoisomers also include enantiomers and diastereoisomers, enantiomers are optical isomers, and diastereomers are stereoisomers that do not form chiral enantiomers Isomers, and different isomers with the same molecular formula as the compound of the present invention are also within the protection scope of the present invention.
  • solvate herein may also be referred to as “solvate”, and “solvate” refers to a compound containing a solvent, wherein the solvent molecules can be formed by coordination bonds, covalent bonds, van der Waals forces, etc. , ionic bonds, hydrogen bonds and other ways to combine with compound molecules.
  • the term “pharmaceutically acceptable salt” herein refers to the compound of the present invention and/or the formed salt, which is chemically or physically compatible with other ingredients constituting a certain pharmaceutical dosage form, and physiologically Compatible with receptors.
  • “Pharmaceutically acceptable salts” may be acidic and/or basic salts with inorganic and/or organic acids and bases, and also include zwitterionic salts (inner salts), and also include quaternary ammonium salts, such as alkylammonium Salt. These salts may be obtained directly in the final isolation and purification of the compounds. It can also be obtained by appropriately mixing the compound of the present invention or its stereoisomer or solvate with a certain amount of acid or base. These salts may form precipitates in solution and be collected by filtration, or be recovered after solvent evaporation, or be obtained by cooling and drying after reaction in an aqueous medium.
  • alkyl herein refers to those having 1 to 4 carbon atoms (“C1-4 alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms ("C1-3 alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms ("C1-2 alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“C1 alkyl”). Each instance of an alkyl group is independently optionally substituted, ie, unsubstituted (“unsubstituted alkyl”) or substituted with one or two substituents (“substituted alkyl").
  • exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furyl, and thiophenyl.
  • exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolinyl, isoxazolinyl, thiazolyl, and isothiazolyl.
  • Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, thiazolyl, oxadiazolyl, and thiadiazolyl.
  • Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl.
  • heterocycloalkyl refers to a non-aromatic ring in which one or more atoms constituting the ring are heteroatoms, and the heteroatoms include but are not limited to nitrogen atoms, oxygen atoms and sulfur atoms, etc. , and the rest are stable 3-10 membered saturated heterocyclic ring system groups composed of carbon.
  • a heterocycloalkyl group may be monocyclic ("monocyclic heterocycloalkyl"), or a bicyclic, tricyclic, or multicyclic ring system, which may include and Cyclic (fused), bridged (bridged) or spiro ring systems (e.g.
  • bicyclic heterocycloalkyl bicyclic ring systems
  • Heterocycloalkyl bicyclic ring systems can be in a or both rings include one or more heteroatoms; and are saturated.
  • Exemplary 3-membered heterocyclyl groups include, but are not limited to, aziridyl, oxiranyl, and thiiridine, or stereoisomers thereof;
  • exemplary 4-membered heterocyclyl groups include, but are not limited to, azetidinyl, epoxypropylene, thietanyl, or isomers and stereoisomers thereof Conformers;
  • Exemplary 5-membered heterocyclyl groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, imidazole Alkyl, pyrazolidinyl, di
  • Exemplary 6-membered heterocyclyl groups include but Not limited to piperidinyl, tetrahydropyranyl, cyclopentylsulfide, morpholinyl, thiomorpholinyl, dithianyl, dioxanyl, piperazinyl, triazinyl, or the same isomers and stereoisomers;
  • exemplary 7-membered heterocyclyl groups include, but are not limited to, azepanyl, oxepanyl, thiepanyl, and diazepanyl group, or its isomers and stereoisomers.
  • heterocycloalkyl is a 4-6 membered heterocycloalkyl group, wherein the heteroatoms are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3.
  • heteroaryl refers to an aromatic group containing heteroatoms, which may be a single ring or a condensed ring, preferably containing 1-4 5-12 membered heteroaryl groups independently selected from N, O and S, including but Not limited to pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolinyl, isoquinolyl, Triazolyl, tetrahydropyrrolyl. In a certain aspect, typically a 5-6 membered monocyclic heteroaryl group containing 1 or more heteroatoms independently selected from N, O and S.
  • linking substituents are described.
  • the Markush variables recited for that group are to be understood as linking groups.
  • the Markush group definition for that variable recites “alkyl” or “aryl,” it is understood that “alkyl” or “aryl” respectively represents the linking group.
  • alkyl group when an alkyl group is clearly indicated as a linking group, then the alkyl group represents a linked alkylene group, for example, the group "halo-C1-C6 alkyl"
  • halo and halogen refer to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).
  • mamal refers to humans, domestic animals or cats and dogs.
  • the present invention uses traditional methods such as mass spectrometry and NMR to identify compounds, and each step and condition can refer to the conventional operating steps and conditions in the art.
  • the present invention employs standard nomenclature and standard laboratory procedures and techniques of analytical chemistry, synthetic organic chemistry and optics. In some cases, standard techniques are used for chemical synthesis, chemical analysis, and performance testing of light-emitting devices.
  • the reagents and raw materials used in the present invention are all commercially available.
  • the compound of the present invention or its stereoisomer or prodrug, or a pharmaceutically acceptable salt of the compound's stereoisomer or prodrug may be in the form of a pharmaceutical composition , which contains a pharmaceutically acceptable carrier, vehicle or diluent. They can also be used to prepare and treat diseases related to JAK3 kinase activity abnormality.
  • Pd(PPh3)4 Tetrakis(triphenylphosphine) palladium
  • TMSOTf Trimethylsilyl trifluoromethanesulfonate
  • PE petroleum ether
  • Example 1 1-((2S,4S,5S)-5-((7H-pyrrole[2,3-d]pyrimidin-4-yl)amino)-4-fluoro-2-methylpiperidine-1 -yl) propen-2-en-1-one (compound 1) and 1-((2R,4R,5R)-5-((7H-pyrrole[2,3-d]pyrimidin-4-yl)amino) Preparation of -4-fluoro-2-methylpiperidin-1-yl)propen-2-en-1-one (compound 2)
  • Step 1 Add allylamine 1-2 (13.07mL, 174mmol) dropwise to acetaldehyde 1-1 (34.8mL, 174mmol, 5mol/L) at 0°C, and stir the reaction solution at 25°C for 1 hour, Molecular sieves (15 g) and tetrahydrofuran (250 mL) were added and cooled to 0° C., then allylmagnesium bromide (1.0 mol/L in Et 2 O, 191.4 mL, 191.4 mmol) was added dropwise.
  • Step 3 Dissolve 2-methyl-3,6-dihydropyridine-1(2H)-carboxylate benzyl ester 1-4 (21g, 90.8mmol) in acetonitrile (706mL), add ethylenediaminetetraacetic acid di Sodium aqueous solution (0.0004mol/L, 454mL, 0.18mmol), the solution was cooled to 0°C, and 1,1,1-trifluoroacetone (101.74g, 908mmol) was added.
  • Step 4 Benzyl (1R,4S,6S)-4-methyl-7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate 1-5 (12.4g, 50.1mmol ) was dissolved in methanol (90 mL) and water (30 mL), and sodium azide (9.77 g, 150.3 mmol) and ammonium chloride (6.03 g, 112.73 mmol) were added. The reaction mixture was stirred at 60 °C for 16 hours. The reaction solution was concentrated, diluted with water (150 mL), and extracted with ethyl acetate (150 mL*2).
  • Step 6 Dissolve compound 1-7 (20g, 44.7mmol, purity 55%) in anhydrous dichloromethane (120mL), add triethylamine (9.05g, 89.4mmol) and a catalytic amount of 4- Dimethylaminopyridine (270mg, 2.235mmol). Under nitrogen protection, the reaction mixture was stirred at 0°C for 15 minutes, then a solution of di-tert-butyl dicarbonate (19.51 g, 89.4 mmol) in anhydrous dichloromethane (20 mL) was added dropwise. The reaction was stirred at 0 °C for 1 hour.
  • Step 7 Dissolve compound 1-8 (10g, 28.8mmol) in tetrahydrofuran (100mL), add tetrabutylammonium fluoride (1 mol/L in THF, 28.8mL, 28.8mmol), under nitrogen protection, the reaction solution Stir at 45°C for 48 hours.
  • Step 8 Dissolve 1-9 (2.5g, 6.8mmol) in dichloromethane (20mL), add hydrogen chloride in 1,4-dioxane solution (6mL, 4mol/L), and stir the mixture at 25°C 4 hours. Concentration gave crude compound 1-10 (2 g), which was used in the next step without further purification.
  • LCMS (ESI) [M+H] + m/z 267.14.
  • Step 9 Dissolve 1-10 (4.32g, 16.55mmol) in n-butanol (50mL), add 1-11 (4.67g, 24.8mmol,) and N,N-diisopropylethylamine (5.97g, 46.2 mmol), under the protection of nitrogen, the reaction solution was stirred at 140° C. for 30 hours.
  • Step 10 Dissolve compound 1-12 (700mg, 1.67mmol) in tetrahydrofuran (10mL) and water (3mL), add 10% palladium carbon (200mg), under hydrogen protection (5Mpa), stir the reaction solution at 45°C After 24 hours, the reaction was completed, and concentrated by filtration to obtain the crude product 1-13 (333 mg, yield 80%), which was used in the next step without further purification.
  • LCMS (ESI) [M+H] + m/z 250.2.
  • Step 13 Dissolve 1-13 (100mg, 0.4mmol) in tetrahydrofuran (2.5mL), add an aqueous solution (1mL) of potassium phosphate (341mg, 1.6mmol), stir the reaction mixture at 0°C, and add 3 - A solution of chloropropionyl chloride (62 mg, 0.48 mmol) in tetrahydrofuran (0.5 mL) was stirred at 0° C. for 2 hours. An aqueous solution (1 mL) of sodium hydroxide (81 mg, 2.01 mmol) was added dropwise to the above reaction mixture, and the reaction solution was stirred at room temperature for 18 hours.
  • Example 2 1-((2S,4S,5S)-5-((7H-pyrrole[2,3-d]pyridin-4-yl)amino)-4-fluoro-2-methylpiperidine-1 -yl) propen-2-en-1-one (compound 3) and 1-((2R,4R,5R)-5-((7H-pyrrole[2,3-d]pyridin-4-yl)amino) -4-fluoro-2-methylpiperidin-1-yl)propen-2-en-1-one (compound 4)
  • Step 4 Dissolve compound 3-4 (390mg, 1.12mmol) in tetrahydrofuran (15mL) and water (5mL), add 10% palladium carbon (300mg), under hydrogen protection (5Mpa), stir the reaction solution at 45°C After 24 hours, the reaction was completed, and concentrated by filtration to obtain the crude product 3-5 (237 mg, yield 85%), which was used in the next step without further purification.
  • LCMS (ESI) [M+H] + m/z 249.14.
  • Step 5 Dissolve 3-5 (99mg, 0.4mmol) in tetrahydrofuran (2.5mL), add an aqueous solution (1mL) of potassium phosphate (341mg, 1.6mmol), stir the reaction mixture at 0°C, and add 3 - A solution of chloropropionyl chloride (62 mg, 0.48 mmol) in tetrahydrofuran (0.5 mL) was stirred at 0° C. for 2 hours. An aqueous solution (1 mL) of sodium hydroxide (81 mg, 2.01 mmol) was added dropwise to the above reaction mixture, and the reaction solution was stirred at room temperature for 18 hours.
  • Example 3 1-((2S,4S,5S)-5-((5-cyano-7H-pyrrole[2,3-d]pyridin-4-yl)amino)-4-fluoro-2-methyl Basepiperidin-1-yl)propene-2-en-1-one compound 5 and 1-((2R,4R,5R)-5-((5-cyano-7H-pyrrole[2,3-d] Pyridin-4-yl)amino)-4-fluoro-2-methylpiperidin-1-yl)propene-2-en-1-one (compound 6)
  • Step 1 Dissolve 1-10 (700mg, 2.78mmol) in n-butanol (10mL), add 5-1 (602mg, 3.47mmol,) and N,N-diisopropylethylamine (896mg, 6.94mmol) , under the protection of nitrogen, the reaction solution was stirred at 100° C. for 10 hours.
  • Step 2 Dissolve compound 5-2 (678mg, 1.66mmol) in tetrahydrofuran (10mL) and water (3mL), add 10% palladium carbon (200mg), under hydrogen protection (5Mpa), stir the reaction solution at 45°C After 24 hours, the reaction was completed, and concentrated by filtration to obtain the crude product 5-3 (386 mg, yield 85%), which was used in the next step without further purification.
  • LCMS (ESI) [M+H] + m/z 274.14.
  • Step 3 Dissolve 5-3 (200mg, 0.73mmol) in tetrahydrofuran (5mL), add an aqueous solution (2mL) of potassium phosphate (680mg, 0.32mmol), stir the reaction mixture at 0°C, and add 3- A solution of chloropropionyl chloride (124 mg, 0.96 mmol) in tetrahydrofuran (0.5 mL) was stirred at 0° C. for 2 hours. An aqueous solution (1 mL) of sodium hydroxide (160 mg, 4 mmol) was added dropwise to the above reaction mixture, and the reaction solution was stirred at room temperature for 18 hours.
  • Example 4 Ethyl 4-(((3S,4S,6S)-1-acryloyl-4-fluoro-6-methylpiperidin-3-yl)amino)-7H-pyrrole[2,3-d ]pyrimidine-5-carboxylic acid compound 7 and ethyl 4-(((3R,4R,6R)-1-acryloyl-4-fluoro-6-methylpiperidin-3-yl)amino)-7H-pyrrole Preparation of [2,3-d]pyrimidine-5-carboxylic acid (Compound 8)
  • Step 1 Dissolve 1-10 (800mg, 2.64mmol) in n-butanol (10mL), add 7-1 (894mg, 3.86mmol,) and N,N-diisopropylethylamine (997mg, 7.72mmol) , under the protection of nitrogen, the reaction solution was stirred at 140° C. for 20 hours.
  • Step 2 Dissolve compound 7-2 (782mg, 1.71mmol) in tetrahydrofuran (10mL) and water (3mL), add 10% palladium carbon (200mg), under hydrogen protection (5Mpa), stir the reaction solution at 45°C After 24 hours, the reaction was completed, and concentrated by filtration to obtain the crude product 7-3 (452 mg, yield 82%), which was used in the next step without further purification.
  • LCMS (ESI) [M+H] + m/z 322.16.
  • Step 3 Dissolve 7-3 (100mg, 0.31mmol) in tetrahydrofuran (2.5mL), add an aqueous solution (1mL) of potassium phosphate (341mg, 1.6mmol), stir the reaction mixture at 0°C, and add 3 - A solution of chloropropionyl chloride (62 mg, 0.48 mmol) in tetrahydrofuran (0.5 mL) was stirred at 0° C. for 2 hours. An aqueous solution (1 mL) of sodium hydroxide (81 mg, 2.01 mmol) was added dropwise to the above reaction mixture, and the reaction solution was stirred at room temperature for 18 hours.
  • Example 5 1-((2S,4S,5S)-5-((5-((R)-2,2-difluorocyclopropyl)-7H-pyrrole[2,3-d]pyrimidine-4 -yl)amino)-4-fluoro-2-methylpiperidin-1-yl)prop-2-en-1-one (compound 9); 1-((2S,4S,5S)-5-(( 5-((S)-2,2-difluorocyclopropyl)-7H-pyrrole[2,3-d]pyrimidin-4-yl)amino)-4-fluoro-2-methylpiperidine-1- base) the preparation of prop-2-en-1-one (compound 10)
  • Step 1 Dissolve 4-chloro-7H-pyrrolo[2,3-d]pyrimidine-5-carbaldehyde 9-1 (5 g, 66.45 mmol) in N, N-dimethylformamide (50 mL), and Sodium hydride (0.80 g, 34 mmol) was added under ice-bath condition, and then 2-(trimethylsilyl)ethoxymethyl chloride (6.90 g, 41.42 mol) was added slowly. The reaction solution was reacted at 25° C. for 2 hours. LCMS detected that the reaction was complete, and water was added to the reaction solution, which was extracted with ethyl acetate.
  • Step 2 Dissolve methyltriphenylphosphine bromide (3,42mg, 9.63mmol) in toluene (45mL), then add potassium tert-butoxide (1.08g, 9.63mmol) under ice-bath conditions, and under nitrogen protection, This was followed by stirring at 0°C for 30 minutes.
  • Compound 9-2 (1.5 g, 4.8 mmol) was added to the reaction system again and stirred for 2 hours.
  • LCMS detected that the reaction was complete, the solvent was spin-dried, and then water was added to the reaction liquid, and extracted with dichloromethane. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated.
  • Step 3 Compound 9-3 (500mg, 1.6mmol) was dissolved in acetonitrile (10mL), then sodium iodide (723mg, 4.8mmol) and trifluoromethyltrimethylsilane (686mg, 4.8mmol) were added. Under nitrogen protection, stir at 110°C for 1 hour. LCMS detected that the reaction was complete, the solvent was spin-dried, and then water was added to the reaction liquid, and extracted with dichloromethane. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated.
  • Step 4 Compound (2S, 4S, 5S)-1-10 (224 mg, 0.72 mmol) was dissolved in n-butanol (5 mL), and 9-4 (400 g, 1.11 mmol,) and N, N-diisopropyl Ethylamine (0.266g, 2.06mmol), under the protection of nitrogen, the reaction solution was stirred at 140°C for 30 hours.
  • Step 6 Dissolve compound 9-6 (180mg, 0.39mmol) in tetrahydrofuran (5mL) and water (1.5mL), add 10% palladium on carbon (100mg), under hydrogen protection (5Mpa), the reaction solution was heated at 45°C After stirring for 24 hours, the reaction was completed and concentrated by filtration to obtain the crude product 9-7 (102 mg, yield 80%), which was used in the next step without further purification.
  • LCMS (ESI) [M+H] + m/z 326.15.
  • Step 7 Dissolve 9-7 (102mg, 0.31mmol) in tetrahydrofuran (2.5mL), add an aqueous solution (1mL) of potassium phosphate (264mg, 1.24mmol), stir the reaction mixture at 0°C, and add 1 dropwise -14
  • a solution of 3-chloropropionyl chloride (48mg, 0.37mmol) in tetrahydrofuran (0.5mL) was stirred at 0°C for 2 hours.
  • An aqueous solution (1 mL) of sodium hydroxide 62 mg, 1.55 mmol was added dropwise to the above reaction mixture, and the reaction solution was stirred at room temperature for 18 hours.
  • Step 1 Dissolve compound 1 (2g, 6.59mmol) in acetonitrile (60mL) under nitrogen protection, and add N-iodosuccinimide (1.63g, 7.25mmol) at 0°C.
  • LCMS (ESI) [M+Na] + m/z 430.05.
  • Step 2 Compound 11-1 (106mg, 0.25mmol,) was dissolved in anhydrous dichloromethane (3mL), and triethylamine (102mg, 1.0mmol) and a catalytic amount of 4-dimethylamino were added at 0°C Pyridine (2 mg). Under nitrogen protection, the reaction mixture was stirred at 0°C for 15 minutes, then a solution of di-tert-butyl dicarbonate (109 mg, 0.5 mmol) in anhydrous dichloromethane (2 mL) was added dropwise. The reaction was stirred at 0 °C for 1 hour.
  • Step 3 Dissolve compound 11-2 (111mg, 0.21mmol) in tetrahydrofuran (4mL) under nitrogen atmosphere, add dppf Pd G3 (120mg, 0.21mmol), cuprous iodide (13mg, 0.07mmol) successively, dppf (12mg, 0.021mmol), 2-cyclopropylacetylene (67mg, 1.05mmol) and triethylamine (0.6mL), the reaction solution was stirred at 25°C for 3 hours.
  • Step 4 Compound 11-3 (69 mg, 0.14 mmol) was dissolved in dichloromethane (1 mL), and trifluoroacetic acid (0.5 mL) was added under ice-water bath. The reaction solution was stirred at 0°C for 2 hours. The solvent was spin-dried to obtain the title product compound 11 (52 mg, yield: 68%) as a white solid.
  • Step 1 Dissolve compound 11-2 (100mg, 0.19mmol) in tetrahydrofuran (4mL) under nitrogen atmosphere, add dppf Pd G3 (110mg, 0.19mmol), cuprous iodide (13mg, 0.07mmol) successively, dppf (11mg, 0.019mmol), 3-methoxypropyne (68mg, 0.95mmol) and triethylamine (0.6mL), the reaction solution was stirred at 25°C for 3 hours.
  • dppf Pd G3 110mg, 0.19mmol
  • cuprous iodide 13mg, 0.07mmol
  • dppf 11mg, 0.019mmol
  • 3-methoxypropyne 68mg, 0.95mmol
  • triethylamine 0.6mL
  • Step 2 Compound 12-1 (58 mg, 0.12 mmol) was dissolved in dichloromethane (1 mL), and trifluoroacetic acid (0.5 mL) was added under ice-water bath. The reaction solution was stirred at 0°C for 2 hours. The solvent was spin-dried to obtain the title product 1-((2S,4S,5S)-5-((5-(3-methoxy-propyn-1-yl)-7H-pyrrole[2,3-d]pyrimidine -4-yl)amino)-4-fluoro-2-methylpiperidin-1-yl)prop-2-en-1-one compound 12 (37 mg, yield: 81%), white solid.
  • Example 8 1-((2S,4S,5S)-5-((5-(3-(fluoromethoxy)propyn-1-yl)-7H-pyrrole[2,3-d]pyrimidine Preparation of -4-yl)amino)-4-fluoro-2-methylpiperidin-1-yl)prop-2-en-1-one (compound 13)
  • Step 1 Dissolve compound 11-2 (100mg, 0.19mmol) in tetrahydrofuran (4mL) under nitrogen atmosphere, add dppf Pd G3 (110mg, 0.19mmol), cuprous iodide (13mg, 0.07mmol) successively, dppf (11mg, 0.019mmol), 3-(fluoromethoxy)propyne (71mg, 0.95mmol) and triethylamine (0.6mL), the reaction solution was stirred at 25°C for 3 hours.
  • Step 2 Compound 13-1 (58 mg, 0.11 mmol) was dissolved in dichloromethane (1 mL), and trifluoroacetic acid (0.5 mL) was added under ice-water bath. The reaction solution was stirred at 0°C for 2 hours. The solvent was spin-dried to obtain the title product compound 13 (26 mg, yield: 71%) as a white solid.
  • Step 1 Dissolve compound 11-2 (100mg, 0.19mmol) in tetrahydrofuran (4mL) under nitrogen atmosphere, add dppf Pd G3 (110mg, 0.19mmol), cuprous iodide (13mg, 0.07mmol) successively, dppf (11mg, 0.019mmol), (1H-pyrrol-4yl)acetylene (85mg, 0.95mmol) and triethylamine (0.6mL), the reaction solution was stirred at 25°C for 3 hours.
  • dppf Pd G3 110mg, 0.19mmol
  • cuprous iodide 13mg, 0.07mmol
  • dppf 11mg, 0.019mmol
  • (1H-pyrrol-4yl)acetylene 85mg, 0.95mmol
  • triethylamine 0.6mL
  • Step 2 Compound 14-1 (44 mg, 0.09 mmol) was dissolved in dichloromethane (1 mL), and trifluoroacetic acid (0.5 mL) was added under ice-water bath. The reaction solution was stirred at 0°C for 2 hours. The solvent was spin-dried to obtain the title product compound 14 (24 mg, yield: 69%) as a white solid.
  • Step 1 Dissolve compound 11-2 (100mg, 0.19mmol) in tetrahydrofuran (4mL) under nitrogen atmosphere, add dppf Pd G3 (110mg, 0.19mmol), cuprous iodide (13mg, 0.07mmol) successively, dppf (11mg, 0.019mmol), (1H-pyrrol-4yl)acetylene (101mg, 0.95mmol) and triethylamine (0.6mL), the reaction solution was stirred at 25°C for 3 hours.
  • Step 2 Compound 15-1 (43 mg, 0.085 mmol) was dissolved in dichloromethane (1 mL), and trifluoroacetic acid (0.5 mL) was added under ice-water bath. The reaction solution was stirred at 0°C for 2 hours. The solvent was spin-dried to obtain the title product Compound 15 (23 mg, yield: 65%) as a white solid.
  • the four LanthaScreen JAK biochemical assay panels (JAK1, 2, 3, and Tyk2) were loaded in common kinase reaction buffer (50 mM HEPES, pH 7.5, 0.01% Brij-35, 10 mM MgCl 2 , and 1 mM EGTA).
  • Recombinant GST-tagged JAK enzyme and GFP-tagged STAT1 peptide substrate were obtained from Life Technologies.
  • IC50 values were determined using Prism software (GraphPad Software) using a 4-parameter robust fit model. Fitting of these data yielded best fit IC50 values where test compounds titrated and resulted in inhibition of peptide product formation.
  • Example 12 Human whole blood cell (HWB) IL-15 induced STAT5 phosphorylation inhibitory activity assay
  • PBS PBS
  • the compounds selected by the present invention have inhibitory activity on HWB IL-15-induced STAT5 phosphorylation

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Abstract

一种如通式(I)的吡咯并[2,3-d]六元杂芳环衍生物，具有Janus激酶（JAK）激酶抑制活性，尤其对JAK3激酶具有选择性的、较高的抑制活性、且具有优异的口服吸收性。还涉及包含这样的化合物的制备方法、包含其的药物组合物及使用其的治疗方法。通过施用所述化合物提供一种基于JAK3抑制作用、对JAK3表达异常相关的疾病预防和/或治疗有用的医药。

Description

吡咯并[2,3-d]六员杂芳环衍生物、其制备方法和药物用途 技术领域
本发明提供了一种吡咯并[2,3-d]六员杂芳环衍生物具有吡咯并[2,3-d]嘧啶基或吡咯并[2,3-d]吡啶基衍生物且具有Janus激酶(JAK)激酶抑制活性，尤其对JAK3激酶具有选择性的、较高的抑制活性。本发明还涉及包含这样的化合物的组合物、用于制备这样的化合物的方法，以及用于治疗和预防通过JAK3失调所介导的疾病的方法。
背景技术
Janus激酶(JAKs)属于酪氨酸激酶家族，通过它们磷酸化酪氨酸残基的能力来改变含有它们的蛋白质的功能。在受到特异性生长因子、生长激素、趋化因子、细胞因子和多种细胞表面受体刺激后被激活，使其具有酪氨酸激酶活性并成对结合，二聚体JAK能发生自发性磷酸化，与STAT蛋白结合，使STAT转录因子磷酸化并转移到细胞核内，将细胞外信号从细胞表面受体转移到细胞内细胞核，改变DNA的转录和随后的翻译蛋白质。JAK-STAT通路作用于50种以上的下游细胞因子和生长因子，因此，JAK激酶被认为是为免疫***的中枢沟通节点。Janus激酶(JAKs)有四个家族成员：JAK1、JAK2、JAK3和TYK2。其中，JAK1、JAK2和TYK2广泛存在于体内各种组织和细胞中，JAK3主要存在于骨髓细胞、胸腺细胞、NK细胞及活化的B淋巴细胞、T淋巴细胞中。基于JAK激酶家族中各亚型的功能特点和特殊的组织分布，JAK1已成为免疫、炎症和癌症等疾病领域的新型靶点；JAK2已成为血液***相关疾病治疗和预防的确切作用靶点；JAK3已成为治疗自身免疫性疾病的热门靶标。每个细胞表面受体都需要通过一对相同的同型二聚体(例如JAK2/JAK2)或异二聚体(例如JAK1/JAK3)来发出信号，激活下游的STAT蛋白(信号转导器和激活物)，调控相应靶基因启动子进而影响DNA的转录和随后的翻译蛋白质。每对JAK都有不同的激活配体和作用的下游效应子(Pharmacological Research，2019，147，104392)。
JAK-STAT信号通路功能广泛，参与细胞的增殖、分化、凋亡以及免疫调节等许多重要的生物学过程。JAK-STAT通路作用于50种以上的下游细胞因子和生长因子，这些因子包括白介素类(IL-2～7、IL-9、IL-10、IL-15、IL-21)、干扰素类(IFN-α、IFN-β、IFN-γ)、***(EPO)、粒细胞和巨细胞集落刺激因子(GM-CSF)、促生长素(GH)、催乳素(PRL)、促血小板生成素(TPO)等，其在参与免疫细胞和造血干细胞的增殖、免疫调节的生物学过程 中起关键作用。不同受体可激活不同亚型的JAK激酶，从而实现差异化的生物学功能。JAK1可与IL-10、IL-19、IL-20、IL-22、IL-26、IL-28、IFN-α、IFN-γ、gp130家族中的IL-6以及含γc的其它受体等结合(Cell,1998,93:373-383)。小鼠模型上的JAK1基因敲除实验表明该酶在调节上述多种细胞因子受体的生物学效应中起着关键作用(Gene,2002,285:1-24)。JAK1是免疫、炎症和癌症等疾病领域的新型靶点。JAK1抑制剂可用于治疗/预防自身免疫性疾病、炎症和肿瘤(Blood,2010,115:3287-3295)，如白血病、淋巴瘤、黑色素瘤、关节炎、银屑病、克罗恩病、红斑狼疮、获得性免疫缺陷综合症、白塞病(Hum.Genet.,2013,132:1049-1058)等。JAK2在包括EPO、GH、PRL、IL-3、IFN-γ等多种受体信号调节过程中发挥重要作用(Gene,2002,285:1-24；Nat.Rev.Mol.CellBiol.,2002,3:651-662)。在小鼠模型中敲除JAK2可导致贫血引起的动物死亡(J.Biol.Chem.,2007,282:20059-20063)；人体中的JAK2基因上的一个碱基突变JAK2V617F，其与骨髓增生性疾病中的真性红细胞增多症(PV)、特发性血小板增多症(ET)、特发性骨髓纤维化(IMF)、慢性粒细胞白血病(CML)等的发生密切相关(Immunol.Rev.,2009,228:273-287)。因此，JAK2已成为该类疾病的治疗/预防的确切作用靶点。JAK3通过与IL-2、IL-4、IL-7、IL-9、IL-15、IL-21等细胞因子受体复合物中的γ共链(γc)相结合，调节细胞信号传导。JAK3或γc突变都可导致重症联合免疫缺陷(SCID)(Blood，1996,88:817-823)。JAK3活性异常表现为T细胞和NK细胞大量减少、B细胞功能丧失，严重影响免疫***等的正常生物学功能。基于其功能特点和特殊的组织分布，JAK3成为针对免疫***相关疾病极具吸引力的药物靶点，其抑制剂在类风湿性关节炎(RA)、克罗恩病和溃疡性结肠炎、***性红斑狼疮、多发性硬化症、Ⅰ型糖尿病、银屑病、过敏性疾病、哮喘、慢性阻塞性肺病、白血病、淋巴瘤、器官移植和其它等疾病的治疗/预防方面具有重要的临床应用价值(Trends Pharm.Sci.,2004,25:558-562)。TYK2是JAK家族中的第一个成员，其可被IFNs、IL-10、IL-6、IL-12、IL-23、IL-27等多种受体激活。在小鼠中，TYK2功能缺失会引起多种细胞因子受体的信号通路发生缺陷，进而导致病毒感染、抗菌免疫功能下降并增加了肺部感染的可能性等(Gene,2002,285:1-24)。
早期获批的JAK抑制剂都属于非选择性的JAK抑制剂，2011年，首个由美国Incyte公司开发的JAK抑制剂鲁索利替尼(Ruxolitinib)在美国批准上市，是第一款专门用于治疗骨髓纤维化的药物。2012年，随着托法替布(Tofacitinib)被FDA批准用于治疗类风湿关节炎(RA)后，2017年，由Incyte和Eli Lilly合作开发的Baricitinib首先在欧洲获得上市许可， 但其在FDA的上市申请遭到拒绝；在完善相关临床试验后，2018年1月Baricitinib最终获得了FDA的许可。但目前这几个pan-JAKs抑制剂都带有黑框警告：严重感染、恶性肿瘤、血栓形成的风险。pan-JAKs抑制剂Tofacitinib具有包括引起红细胞与白细胞数量下降、胆固醇水平上升等副作用，这或许与其具有高JAK2抑制活性相关(J.Med.Chem.,2012,55:6176-6193)。
JAK3是包含JAKl、JAK2、JAK3和TYK2的Janus家族蛋白激酶的成员，并且在所有组织中以不同水平表达。许多细胞因子受体通过下列组合的JAK激酶对传递信号：JAKl/JAK2、JAKl/JAK3、JAK1/TYK2、JAK2/TYK2或JAK2/JAK2。动物研究表明在免疫***的发育、功能和稳态中牵涉JAK3通过抑制JAK3激酶活性来调节免疫活性可证明在治疗多种免疫病症中的用途(J.lmmunol.,178,2623—2629(2007)；Gene,285,1—24(2002)；Cell,109,(suppl.)Sl21—S131(2002)),同时避免JAK2依赖性红细胞生成素(EPO)和血小板生成素(TPO)信号传导(Cell,93(3),397—409(1998)；Cell,93(3),385—95(1998))。目前，选择性JAK抑制剂(特别是JAK3)的研究与发现已成为制药公司等机构在JAK抑制剂领域的主要发展方向。
发明内容
本发明涉及新型化合物，它们是可用于治疗与JAK3调节异常相关的疾病的选择性JAK3调节剂。本发明还提供包含这样的JAK3调节剂的药物组合物以及治疗和/或预防这样的疾病的方法。因此，本发明提供式(I)所示化合物，其光学异构体或它们的混合物、其药学上可接受的盐、溶剂合物、其N-氧化物或它们的前药，其具有以下结构：
Figure PCTCN2022076138-appb-000001
其中X独立地选自N，CH或CCN；
R独立地选自氢、氘、氟、氯、氰基、C1-C8炔基、C1-C8卤代炔基、C3-C5环烷基取代炔基、亚甲基氧烷基取代炔基、亚甲基氧卤代烷基取代炔基、5-6元芳环或杂芳环取代炔基、 C1-C6线性或支链烷基、C1-C6线性或支链烷氧基亚甲基、卤代C1-C6线性或支链烷氧基亚甲基、C1-C6线性或支链烷氧基二氟亚甲基、卤代C1-C6线性或支链烷氧基二氟亚甲基、C1-C6线性或支链烷氧基氟代亚甲基、卤代C1-C6线性或支链烷氧基氟代亚甲基、C3-C6环烷基、C3-C6烷基取代环烷基、C3-C6卤素取代环烷基、C6-C10芳基、包含5-和/或6-元环的单环或双环杂芳基、(芳基)C1-C6线性或支链烷基、(杂芳基)C1-C6线性或支链烷基、(杂环基)C1-C6线性或支链烷基、(C1-C6线性或支链烷基)芳基、(C1-C6线性或支链烷基)杂芳基、(C1-C6线性或支链烷基)杂环基、C1-C6线性或支链全氟烷基、C1-C6线性或支链烷氧基、C1-C6线性或支链全氟烷氧基、异丙基羰基、叔丁基羰基、氨基、羧基、氨基羰基、(C1-C6线性或支链烷基)氨基羰基氨基、(C1-C6线性或支链烷基)氨基羰基、乙氧基羰基、异丙氧基羰基、异丁氧基羰基；其中所述烷基、芳基和杂芳基独立任选地被选自下列的一个或多个取代基取代：烷基、卤素、羟基、甲氧基、氨基、氰基、烷基氨基、二烷基氨基、CF3、氨基羰基、(C1-C6线性或支链烷基)氨基羰基和C3-C6环烷基。
当X选自N时，优选结构如式(II)：
Figure PCTCN2022076138-appb-000002
R独立地选自氢、氘、氟、氯、氰基、C1-C8炔基、C1-C8卤代炔基、C3-C5环烷基取代炔基、亚甲基氧烷基取代炔基、亚甲基氧卤代烷基取代炔基、5-6元芳环或杂芳环取代炔基、C1-C6线性或支链烷基、C1-C6线性或支链烷氧基亚甲基、卤代C1-C6线性或支链烷氧基亚甲基、C1-C6线性或支链烷氧基二氟亚甲基、卤代C1-C6线性或支链烷氧基二氟亚甲基、C1-C6线性或支链烷氧基氟代亚甲基、卤代C1-C6线性或支链烷氧基氟代亚甲基、C3-C6环烷基、C3-C6烷基取代环烷基、C3-C6卤素取代环烷基、C6-C10芳基、包含5-和/或6-元环的单环或双环杂芳基、(芳基)C1-C6线性或支链烷基、(杂芳基)C1-C6线性或支链烷基、(杂环基)C1-C6线性或支链烷基、(C1-C6线性或支链烷基)芳基、(C1-C6线性或支链烷基)杂芳基、(C1-C6线性或支链烷基)杂环基、C1-C6线性或支链全氟烷基、C1-C6线性或支链烷氧基、C1-C6线性或 支链全氟烷氧基、异丙基羰基、叔丁基羰基、氨基、羧基、氨基羰基、(C1-C6线性或支链烷基)氨基羰基氨基、(C1-C6线性或支链烷基)氨基羰基、乙氧基羰基、异丙氧基羰基、异丁氧基羰基；其中所述烷基、芳基和杂芳基独立任选地被选自下列的一个或多个取代基取代：烷基、卤素、羟基、甲氧基、氨基、氰基、烷基氨基、二烷基氨基、CF3、氨基羰基、(C1-C6线性或支链烷基)氨基羰基和C3-C6环烷基。
当X选自CH时，优选结构如式(III)：
Figure PCTCN2022076138-appb-000003
R独立地选自氢、氘、氟、氯、氰基、C1-C8炔基、C1-C8卤代炔基、C3-C5环烷基取代炔基、亚甲基氧烷基取代炔基、亚甲基氧卤代烷基取代炔基、5-6元芳环或杂芳环取代炔基、C1-C6线性或支链烷基、C1-C6线性或支链烷氧基亚甲基、卤代C1-C6线性或支链烷氧基亚甲基、C1-C6线性或支链烷氧基二氟亚甲基、卤代C1-C6线性或支链烷氧基二氟亚甲基、C1-C6线性或支链烷氧基氟代亚甲基、卤代C1-C6线性或支链烷氧基氟代亚甲基、C3-C6环烷基、C3-C6烷基取代环烷基、C3-C6卤素取代环烷基、C6-C10芳基、包含5-和/或6-元环的单环或双环杂芳基、(芳基)C1-C6线性或支链烷基、(杂芳基)C1-C6线性或支链烷基、(杂环基)C1-C6线性或支链烷基、(C1-C6线性或支链烷基)芳基、(C1-C6线性或支链烷基)杂芳基、(C1-C6线性或支链烷基)杂环基、C1-C6线性或支链全氟烷基、C1-C6线性或支链烷氧基、C1-C6线性或支链全氟烷氧基、异丙基羰基、叔丁基羰基、氨基、羧基、氨基羰基、(C1-C6线性或支链烷基)氨基羰基氨基、(C1-C6线性或支链烷基)氨基羰基、乙氧基羰基、异丙氧基羰基、异丁氧基羰基；其中所述烷基、芳基和杂芳基独立任选地被选自下列的一个或多个取代基取代：烷基、卤素、羟基、甲氧基、氨基、氰基、烷基氨基、二烷基氨基、CF3、氨基羰基、(C1-C6线性或支链烷基)氨基羰基和C3-C6环烷基。
当X选自CCN时，优选结构如式(IV),
Figure PCTCN2022076138-appb-000004
R独立地选自氢、氘、氟、氯、氰基、C1-C8炔基、C1-C8卤代炔基、C3-C5环烷基取代炔基、亚甲基氧烷基取代炔基、亚甲基氧卤代烷基取代炔基、5-6元芳环或杂芳环取代炔基、C1-C6线性或支链烷基、C1-C6线性或支链烷氧基亚甲基、卤代C1-C6线性或支链烷氧基亚甲基、C1-C6线性或支链烷氧基二氟亚甲基、卤代C1-C6线性或支链烷氧基二氟亚甲基、C1-C6线性或支链烷氧基氟代亚甲基、卤代C1-C6线性或支链烷氧基氟代亚甲基、C3-C6环烷基、C3-C6烷基取代环烷基、C3-C6卤素取代环烷基、C6-C10芳基、包含5-和/或6-元环的单环或双环杂芳基、(芳基)C1-C6线性或支链烷基、(杂芳基)C1-C6线性或支链烷基、(杂环基)C1-C6线性或支链烷基、(C1-C6线性或支链烷基)芳基、(C1-C6线性或支链烷基)杂芳基、(C1-C6线性或支链烷基)杂环基、C1-C6线性或支链全氟烷基、C1-C6线性或支链烷氧基、C1-C6线性或支链全氟烷氧基、异丙基羰基、叔丁基羰基、氨基、羧基、氨基羰基、(C1-C6线性或支链烷基)氨基羰基氨基、(C1-C6线性或支链烷基)氨基羰基、乙氧基羰基、异丙氧基羰基、异丁氧基羰基；其中所述烷基、芳基和杂芳基独立任选地被选自下列的一个或多个取代基取代：烷基、卤素、羟基、甲氧基、氨基、氰基、烷基氨基、二烷基氨基、CF3、氨基羰基、(C1-C6线性或支链烷基)氨基羰基和C3-C6环烷基。
具体地，本发明提供选自下列的化合物：
1-((2S,4S,5S)-5-((5-((2-甲基-2H-四氮唑-5基)乙炔基)-7H-吡咯[2,3-d]嘧啶-4-基)氨基)-4-氟-2-甲基哌啶-1-基)丙-2-烯-1-酮；
1-((2S,4S,5S)-5-((5-((1H-吡咯-4基)乙炔基)-7H-吡咯[2,3-d]嘧啶-4-基)氨基)-4-氟-2-甲基哌啶-1-基)丙-2-烯-1-酮；
1-((2S,4S,5S)-5-((5-(3-(氟代甲氧基)丙炔-1-基)-7H-吡咯[2,3-d]嘧啶-4-基)氨基)-4-氟-2-甲基哌啶-1-基)丙-2-烯-1-酮；
1-((2S,4S,5S)-5-((5-(3-甲氧基-丙炔-1-基)-7H-吡咯[2,3-d]嘧啶-4-基)氨基)-4-氟-2-甲基哌啶-1-基)丙-2-烯-1-酮；
1-((2S,4S,5S)-5-((5-(环丙基乙炔基)-7H-吡咯[2,3-d]嘧啶-4-基)氨基)-4-氟-2-甲基哌啶-1-基)丙-2-烯-1-酮；
1-((2S,4S,5S)-5-((5-((R)-2,2-二氟环丙基)-7H-吡咯[2,3-d]嘧啶-4-基)氨基)-4-氟-2-甲基哌啶-1-基)丙-2-烯-1-酮；
1-((2S,4S,5S)-5-((5-((S)-2,2-二氟环丙基)-7H-吡咯[2,3-d]嘧啶-4-基)氨基)-4-氟-2-甲基哌啶-1-基)丙-2-烯-1-酮；
乙基4-(((3S,4S,6S)-1-丙烯酰-4-氟-6-甲基哌啶-3-基)氨基)-7H-吡咯[2,3-d]嘧啶-5-羧酸；
乙基4-(((3R,4R,6R)-1-丙烯酰-4-氟-6-甲基哌啶-3-基)氨基)-7H-吡咯[2,3-d]嘧啶-5-羧酸；
1-((2S,4S,5S)-5-((5-氰基-7H-吡咯[2,3-d]吡啶-4-基)氨基)-4-氟-2-甲基哌啶-1-基)丙烯-2-烯-1-酮；
1-((2R,4R,5R)-5-((5-氰基-7H-吡咯[2,3-d]吡啶-4-基)氨基)-4-氟-2-甲基哌啶-1-基)丙烯-2-烯-1-酮；
1-((2S,4S,5S)-5-((7H-吡咯[2,3-d]吡啶-4-基)氨基)-4-氟-2-甲基哌啶-1-基)丙烯-2-烯-1-酮；
1-((2R,4R,5R)-5-((7H-吡咯[2,3-d]吡啶-4-基)氨基)-4-氟-2-甲基哌啶-1-基)丙烯-2-烯-1-酮；
1-((2S,4S,5S)-5-((7H-吡咯[2,3-d]嘧啶-4-基)氨基)-4-氟-2-甲基哌啶-1-基)丙烯-2-烯-1-酮；
1-((2R,4R,5R)-5-((7H-吡咯[2,3-d]嘧啶-4-基)氨基)-4-氟-2-甲基哌啶-1-基)丙烯-2-烯-1-酮；
或其药学上可接受的盐。
在其它方面中，本发明还提供：
药物组合物，其包含药学上可接受的载体和本发明的化合物；
治疗或预防病症或病况的方法，所述病症或病况选自类风湿性关节炎、克罗恩氏病和溃疡性结肠炎的炎性肠病、直肠炎、嗜酸细胞性胃肠炎或肥大细胞增多症、肌炎、血管炎、天疤疮、阿尔茨海默病、狼疮、肾炎、***性红斑狼疮、银屑病、湿疹皮炎、瘙痒症或其它瘙痒病况、白瘢风、脱发、自身免疫性甲状腺病、多发性硬化、重性抑郁症、哮喘、干燥病、***性硬化病、结节性多动脉炎、干眼综合征、自身免疫性溶血性贫血、恶性贫血的自身免疫性萎缩性胃炎、自身免疫性脑脊髓炎、自身免疫性***、自身免疫性血小板减少症、交感性眼炎、重症肌无力、原发性胆汁性肝硬变、慢性活动性肝炎、膜性肾小球病、器官移植排斥、移植物抗宿主病、诸如骨髓、软骨、角膜、心脏、椎间盘、胰岛、肾、四肢、肝、肺、肌肉、成肌细胞、神经、胰、皮肤、小肠或气管的器官和细胞移植排斥或者异种移植，包括 强直性脊柱炎、自身免疫性脱发、慢性阻塞性肺病、急性呼吸道疾病、恶病质、和自身抗体介导的脑病的神经精神性病症相关的慢性神经炎症、眼疾病、病症或病况(包括眼的自身免疫疾病、角膜结膜炎、春季结膜炎、包括与贝切特氏病相关的葡萄膜炎和晶状体诱发性葡萄膜炎的葡萄膜炎、角膜炎、疤疹性角膜炎、圆锥形角膜炎、角膜上皮营养障碍、角膜白斑、虹膜炎、干燥性角膜结膜炎(干眼症)、小疤、虹膜睫状体炎、结节病、内分泌性眼病、交感性眼炎、变应性结膜炎和眼新生血管形成)，所述方法包括向个体给药治疗有效量的包含本文中所述的化合物、其光学异构体或它们的混合物、其药学上可接受的盐、溶剂合物、其N-氧化物或它们的前药，或其组合物的步骤。所述方法通过向有需要的哺乳动物给药治疗有效量的本发明的化合物或其药学上可接受的盐。
治疗病况或病症的方法，所述病况或病症包括特应性皮炎、湿疹、银屑病、硬皮症、狼疮、瘙痒症、其它瘙痒病况、夏季湿疹、炎症性气道疾病、复发性气道梗阻、气道高反应和慢性阻塞性肺病，所述方法通过向有需要的哺乳动物给药治疗有效量的本发明的化合物、其光学异构体或它们的混合物、其药学上可接受的盐、溶剂合物、其N-氧化物或它们的前药，或其组合物进行；以及制备本发明的化合物的方法。通过以下说明(仅作为实例给出)，会进一步理解本发明。本发明涉及一类吡咯并[2,3-d]嘧啶基和吡咯并[2,3-d]吡啶衍生物及其类似物。特别地，本发明涉及可用作JAK(特别是JAK3)的抑制剂的化合物，其包括吡咯并[2,3-d]嘧啶基和吡咯并[2,3-d]吡啶衍生物及其类似物。尽管本发明并不如此受限，但通过下列讨论和实施例会获得对本发明各方面的了解。
本发明的化合物可以药学上可接受的形式单独给药或与一种或多种调节哺乳动物免疫***的额外药剂或与抗炎剂联合给药。这些药剂可包括但不限于环孢菌素A(例如山地明 TM或新体睦 TM)、雷帕霉素、FK-506(他克莫司)、来氟米特、脱氧精胍菌素、霉酚酸酯(例如骁悉 TM)、硫唑嘌呤(例如依木兰 TM)、达克珠单抗(例如赛尼哌 TM)、OKT3(例如Orthocolone TM)、AtGam TM、阿司匹林、醋氨酚、布洛芬、萘普生、吡罗昔康和抗炎甾体(例如Deflazacort、***龙或***)、IFN-β、特立氟胺、拉喹莫德、格拉默醋酸盐、富马酸二甲酯(dimethylf umerate)、利妥昔单抗、芬戈莫德、那他珠单抗、阿仑珠单抗、米托蒽醌、柳氮磺吡啶(Azulfidine)、美沙拉秦(Apriso、安萨科、Lialda等)、巴柳氮(巴柳氮二钠(Colazal))和奥沙拉秦(奥柳氮钠(Dipentum))以及巯嘌呤(巯基嘌呤(Purinethol))、抗生素(抗分支杆菌药，例如甲硝唑、环丙沙星)、乌司奴单抗和维多珠单抗。这些药剂可根据本领域技术人员已知的标准药学操作， 以相同或分开的剂型的一部分，通过相同或不同的给药途径，并且按相同或不同的给药时间表给药。
本发明还提供了一种JAK3选择性抑制剂组合物,其光学异构体或它们的混合物、包括本发明化合物、其药学上可接受的盐、溶剂合物或前药。本发明中，如果没有特殊说明，应包括所有异构体。例如，双键，环中的集合异构体(E型，Z型，顺式的(cis)，反式的(trans))，烷基包括直链烷基和支链烷基，由存在不对称碳原子等而产生的光学异构体(R，S型，)及它们任意比例的混合物，外消旋混合物，以及所有的由互变异构体产生的异构体均包括在本发明中。
通式I表示的化合物可以通过公知的方法转化为相应的盐。盐优选为水溶性的药学上可接受的无毒酸加成盐的实例为氨基与无机酸(如盐酸、氢溴酸、磷酸、硫酸以及高氯酸)或与有机酸(如乙酸、草酸、顺丁烯二酸、酒石酸、柠檬酸、琥珀酸或丙二酸)形成的盐，或通过使用本领域中已知的其他方法(例如离子交换法)形成的盐。其他药学上可接受的盐包括己二酸盐、藻酸盐、抗坏血酸盐、天冬氨酸盐、苯磺酸盐、苯甲酸盐、硫酸氢盐、硼酸盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、柠檬酸盐、环戊烷丙酸盐、二葡糖酸盐、十二烷基硫酸盐、乙烷磺酸盐、甲酸盐、富马酸盐、葡庚糖酸盐、甘油磷酸盐、葡糖酸盐、半硫酸盐、庚酸盐、己酸盐、氢碘化物、2-羟基-乙烷磺酸盐、乳糖酸盐、乳酸盐、月桂酸盐、月桂基硫酸盐、苹果酸盐、马来酸盐、丙二酸盐、甲烷磺酸盐、2-萘磺酸盐、烟酸盐、硝酸盐、油酸盐、草酸盐、棕榈酸盐、双羟萘酸盐、果胶酸盐、过硫酸盐、3-苯基丙酸盐、磷酸盐、苦味酸盐、新戊酸盐、丙酸盐、硬脂酸盐、琥珀酸盐、硫酸盐、酒石酸盐、硫氰酸盐、对-甲苯磺酸盐、十一烷酸盐、戊酸盐等。衍生自适当碱的盐包括碱金属盐、碱土金属盐、铵盐以及N +(C 1-4烷基) 4盐。代表性碱金属或碱土金属盐包括钠盐、锂盐、钾盐、钙盐、镁盐等。适当时，另外的药学上可接受的盐包括使用如卤离子、氢氧根、羧酸根、硫酸根、磷酸根、硝酸根、低级烷基磺酸根以及芳基磺酸根等平衡离子形成的无毒铵、季铵以及胺阳离子。
除非另外说明，本文中术语“JAK3抑制剂”中提供包括具有式(Ⅰ)、式(Ⅱ)、式(Ⅲ)、式(Ⅳ)分子式每种化合物均包括具有相同分子式的不同立体异构体，其中的立体异构体还包括对映异构体和非对映异构体，对映异构体即为光学异构体,非对映异构体为不成手性对映的立体异构体，与本发明化合物具有相同分子式的不同异构体也在本发明的保护范围内。
除非另外说明，本文中的术语“溶剂合物”也可以称为“溶剂化合物”、“溶剂化物”指 的是含有溶剂的化合物，其中溶剂分子可以以包括配位键、共价键、范德华力、离子键、氢键等其他方式与化合物分子相结合。
除非另外说明，本文中的术语“药学上可接受的盐”是指本发明的化合物和/或所形成的盐，在化学上或物理上与构成某药物剂型的其它成分相兼容，并在生理上与受体相兼容。“药学上可接受的盐”可以为与无机和/或有机酸和碱形成的酸式和/或碱式盐，也包括两性离子盐(内盐)，还包括季铵盐，例如烷基铵盐。这些盐可以是在化合物的最后分离和纯化中直接得到。也可以是通过将本发明的化合物或其立体异构体或溶剂合物，与一定数量的酸或碱适当混合而得到的。这些盐可能在溶液中形成沉淀而以过滤方法收集，或在溶剂蒸发后回收而得到，或在水介质中反应后冷却干燥制得。
除非另外说明，本文中的术语“烷基”是指具有具有1至4个碳原子(“C1-4烷基”)。在一些实施例中，烷基基团具有1至3个碳原子(“C1-3烷基”)。在一些实施例中，烷基基团具有1至2个碳原子(“C1-2烷基”)。在一些实施例中，烷基基团具有1个碳原子(“C1烷基”)。烷基基团的每个实例是独立地任选取代地，即，未取代的(“未取代的烷基”)或被一个或两个取代基取代的(“取代的烷基”)。
除非另外说明，本文中的术语“5-元杂芳基”除非另外说明，包含一个杂原子的示例性5-元杂芳基基团包括但不限于，吡咯基、呋喃基以及苯硫基。包含两个杂原子的示例性5-元杂芳基基团包括但不限于，咪唑基、吡唑基、噁唑啉基、异噁唑啉基、噻唑基以及异噻唑基。包含三个杂原子的示例性5-元杂芳基基团包括但不限于，噻唑基、噁二唑基以及噻二唑基。包含四个杂原子的示例性5-元杂芳基基团包括但不限于四唑基。
除非另外说明，本文中的术语“杂环烷基”指的是非芳香环的一个或多个构成环的原子是杂原子，所述的杂原子包括而不限于氮原子、氧原子和硫原子等，其余为碳组成的稳定的3-10元饱和杂环***的基团。除非本说明书中另外特别指明，否则杂环烷基基团可以是单环的(“单环的杂环烷基”)，或者是双环、三环或更多环的环体系，其可包括并环的(稠合的)、桥联的(桥环的)或螺的环***(例如二环***(“二环的杂环烷基”)。杂环烷基二环的环***可以在一个或两个环中包括一个或多个杂原子；并且是饱和的。示例性3-元杂环基基团包括但不限于氮杂环丙基、环氧乙烷基以及硫杂环丙烷基，或者其立体异构体；示例性4-元杂环基基团包括但不限于氮杂环丁烷基、环氧丙烷基、硫杂环丁烷基，或者其同分异构体和立体异构体；示例性5-元杂环基基团包括但不限于四氢呋喃基、四氢噻吩基、吡咯烷基、噻唑烷 基、异噻唑烷基、噁唑烷基、异噁唑烷基、咪唑烷基、吡唑烷基、二氧戊环基、氧杂硫呋喃基、二硫呋喃基，或者其同分异构体和立体异构体。示例性6-元杂环基基团包括但不限于哌啶基、四氢吡喃基、硫化环戊烷基、吗啉基、硫代吗啉基、二噻烷基、二噁烷基、哌嗪基、三嗪烷基，或者其同分异构体和立体异构体；示例性7-元杂环基基团包括但不限于氮杂环庚烷基、氧杂环庚烷基、硫杂环庚烷基以及二氮杂环庚基，或者其同分异构体和立体异构体。在某一方案中，典型的含1个或多个独立选自N、O和S的杂原子的5-6元单环杂环基。方案中，“杂环烷基”为4-6元杂环烷基，其中杂原子选自N、O和S中的一种或多种，杂原子数为1、2或3个。
术语“杂芳基”是指含有杂原子的芳香基团，可为单环或稠合环，优选含有1-4个独立选自N、O和S的5-12元杂芳基，包括但不限于吡咯基、呋喃基、噻吩基、咪唑基、噁唑基、异噁唑基、吡唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、喹啉基、异喹啉基、***基、四氢吡咯基。在某一方案中，典型地含1个或多个独立选自N、O和S的杂原子的5-6元单环杂芳基。
当所列举的基团中没有明确指明其具有取代基时，这种基团仅指未被取代。例如当“C1～C4烷基”前没有“取代或未取代的”的限定时，仅指“C1～C4烷基”本身或“未取代的C1～C4烷基”。
在本发明的各部分，描述了连接取代基。当该结构清楚地需要连接基团时，针对该基团所列举的马库什变量应理解为连接基团。例如，如果该结构需要连接基团并且针对该变量的马库什基团定义列举了“烷基”或“芳基”，则应该理解，该“烷基”或“芳基”分别代表连接的亚烷基基团或亚芳基基团。
在一些具体的结构中，当烷基基团清楚地表示为连接基团时，则该烷基基团代表连接的亚烷基基团，例如，基团“卤代-C1-C6烷基”中的C1-C6烷基应当理解为C1-C6亚烷基。
术语“卤素”(halo和halogen)是指氟(F)、氯(Cl)、溴(Br)或碘(I)。
术语“哺乳动物”是指人、家畜或猫和狗。
除非另有规定，本文使用的所有技术术语和科学术语具有要求保护主题所属领域的标准含义。倘若对于某术语存在多个定义，则以本文定义为准。应该理解，在本发明中使用的单数形式，如“一种”，包括复数指代，除非另有规定。
此外，术语“包括”是开放性限定并非封闭式，即包括本发明所指明的内容，但并不排 除其他方面的内容。
除非另有说明，本发明采用质谱、核磁等传统方法鉴定化合物，各步骤和条件可参照本领域常规的操作步骤和条件。
除非另有指明，本发明采用分析化学、有机合成化学和光学的标准命名及标准实验室步骤和技术。在某些情况下，标准技术被用于化学合成、化学分析、发光器件性能检测。
另外，需要说明的是，除非以其他方式明确指出，在本发明中所采用的描述方式“…独立地选自”应做广义理解，是指所描述的各个个体之间彼此独立地被选择。因此，各取代基与其它取代基可以相同或不相同。更详细地，描述方式“…独立地选自”既可以是指在不同基团中，相同符号之间所表达的具体选项之间互相不影响；也可以表示在相同的基团中，相同符号之间所表达的具体选项之间互相不影响。
本领域技术人员可以理解，根据本领域中使用的惯例，本申请描述基团的结构式中所使用的
Figure PCTCN2022076138-appb-000005
是指，相应的基团通过该位点与化合物中的其它片段、基团进行连接。在不违背本领域常识的基础上，上述各优选条件，可任意组合，即得本发明各较佳实例。
本发明所用试剂和原料均市售可得。
在本发明某些实施方式中，本发明的化合物、或其立体异构体或前药，或所述化合物的立体异构体或前药的一种可药用盐可以以药物组合物的形式，其中包含可药用载体、运载剂或稀释剂。它们也可用于制备与用于治疗与JAK3激酶活性异常相关疾病的药物。
具体实施方式
下面通过实施例的方式进一步说明本发明，提供本申请中所述的合成实施例和生物学实施例以说明本文所提供的化合物、药物组合物、以及方法。以下实施例仅用于对本发明进行示例性说明，但不用于限制本发明，在本发明保护范围内所做的修改、改变、变型等都在本发明的保护范围内。
本文所提供的化合物可以使用下文所阐述的特定合成方案的将为本领域技术人员公知的操作方案，由容易获得的起始物质来制备。下列实施例中未注明具体条件的实验方法，按照常规方法和条件，可以由本领域技术人员通过常规的优化程序来确定。
下述实施例中，缩写解释：
Boc 2O：二叔丁基二碳酸酯；
DIEA：N,N-二异丙基乙胺
Xantphos：4,5-双(二苯基膦)-9,9-二甲基氧杂蒽
dppf Pd G3：(甲磺酸(1,1'-双(二苯基膦)二茂铁)(2'-氨基-1,1'-联苯-2-基)钯(II)
Pd(PPh3)4：四(三苯基膦)钯
Pd(Pd(PPh 3) 2Cl 2：双苯基磷二氯钯
Pd(dppf)Cl 2：[1,1'-双(二苯基磷)二茂铁]二氯化钯
Pd 2(dba) 3：三(二亚苄基丙酮)二钯
CuI：碘化亚铜
Pd/C：钯碳催化剂
KOtBu：叔丁醇钾
NaOtBu：叔丁醇钠
SEMCl：2-(三甲硅烷基)乙氧甲基氯
NIS：N-碘代琥珀酰胺
TEA：三乙胺
TMSOTf：三氟甲磺酸三甲基硅烷酯
TFA：三氟乙酸
TFAA：三氟乙酸酐
TMS：三甲基硅烷基
PE：石油醚；
EA：乙酸乙酯；
DMF：N,N-二甲基甲酰胺；
DCM：二氯甲烷；
THF：四氢呋喃
MeOH：甲醇
Na 2CO 3：碳酸钠
Prep-HPLC:高压制备液相色谱
Rf：比移值；
g；克
mg：毫克
h：小时
rt：室温
mol：摩尔
mmol：毫摩尔
mL：毫升
M：摩尔/升
实施例1：1-((2S,4S,5S)-5-((7H-吡咯[2,3-d]嘧啶-4-基)氨基)-4-氟-2-甲基哌啶-1-基)丙烯-2-烯-1-酮(化合物1)和1-((2R,4R,5R)-5-((7H-吡咯[2,3-d]嘧啶-4-基)氨基)-4-氟-2-甲基哌啶-1-基)丙烯-2-烯-1-酮(化合物2)的制备
参照下面的步骤合成化合物1和化合物2:
Figure PCTCN2022076138-appb-000006
步骤1：在0℃下，将烯丙胺1-2(13.07mL,174mmol)滴加到乙醛1-1(34.8mL,174mmol,5mol/L)中，反应液在25℃下搅拌1小时，加入分子筛(15g)和四氢呋喃(250mL)，并冷却至0℃，然后滴加烯丙基溴化镁(1.0mol/L in Et 2O,191.4mL,191.4mmol)。搅拌30分钟后，缓慢加入氯甲酸苄酯(35.70g,208.8mmol)的四氢呋喃(50mL)溶液，将反应混合物升温至25℃搅拌1小时。反应结束，用饱和氯化铵溶液(900mL)淬灭反应，用乙酸乙酯(500mL X 3)萃取，用盐水洗涤有机相并用无水硫酸钠干燥，过滤浓缩滤液。通过硅胶柱色谱法(石油醚/乙酸乙酯＝10:1)纯化得到化合物1-3(23g,纯度90％,收率45％)。LCMS(ESI)[M+H] +m/z＝260.0。
步骤2：将苄基烯丙基(戊-4-烯-2-基)氨基甲酸酯1-3(23g,88.7mmol)溶于二氯甲烷(2L)， 加入苯基亚甲基双(三环己基磷)二氯化钌(3.65g,4.4mmol)。氮气保护，将反应液在25℃下搅拌5小时。将混合物浓缩并通过硅胶柱色谱法(石油醚/乙酸乙酯＝6:1)纯化得到化合物1-4(21g,纯度85％,收率87％)。LCMS(ESI)[M+H] +m/z＝232.1。
步骤3：将2-甲基-3,6-二氢吡啶-1(2H)-羧酸苄酯1-4(21g,90.8mmol)溶解在乙腈(706mL)中，加入乙二胺四乙酸二钠水溶液(0.0004mol/L,454mL,0.18mmol)，将溶液冷却至0℃，加入1,1,1-三氟丙酮(101.74g,908mmol)。在30分钟内分批加入过氧单磺酸钾(279.1g,454mmol)和碳酸氢钠(61.02g,726.4mmol)的混合物，并将反应混合物在0℃下再搅拌1小时。反应结束，加入饱和亚硫酸钠溶液(1.2L)淬灭反应并搅拌0.5小时，用乙酸乙酯(800mLX3)萃取，用盐水洗涤有机相并用无水硫酸钠干燥，过滤并浓缩滤液，粗产物通过硅胶柱色谱纯化(石油醚/乙酸乙酯＝3:1)得到化合物1-5(14g,纯度90％,收率59％)。LCMS(ESI)[M+H] +m/z＝248.1。
步骤4：将(1R,4S,6S)-4-甲基-7-氧杂-3-氮杂双环[4.1.0]庚烷-3-羧酸苄酯1-5(12.4g,50.1mmol)溶于甲醇(90mL)和水(30mL)，加入叠氮化钠(9.77g,150.3mmol)和氯化铵(6.03g,112.73mmol)。将反应混合物在60℃下搅拌16小时。浓缩反应液，加入水(150mL)稀释，用乙酸乙酯(150mL*2)萃取。用盐水洗涤有机相并用无水硫酸钠干燥，过滤并将滤液浓缩获得粗产物1-6(14g)，无需进一步纯化即可用于下一步。LCMS(ESI)[M+H] +m/z＝291.1。
步骤5：将(2S,4S,5S)-5-叠氮基-4-羟基-2-甲基哌啶-1-羧酸苄酯1-6(14g,48.2mmol)溶于(100mL)，加入三苯基磷(12.64g,48.2mmol)。氮气保护，将反应液在85℃下搅拌9小时。将反应液浓缩并通过硅胶柱色谱法(石油醚/乙酸乙酯＝1.5:1)纯化得到化合物1-7(20g,纯度55％)。LCMS(ESI)[M+H] +m/z＝247.2。
步骤6：将化合物1-7(20g,44.7mmol,纯度55％)溶于无水二氯甲烷(120mL)，在0℃下加入三乙胺(9.05g,89.4mmol)和催化量的4-二甲基氨基吡啶(270mg,2.235mmol)。氮气保护，将反应混合物在0℃下搅拌15分钟，然后滴加二碳酸二叔丁酯(19.51g,89.4mmol)的无水二氯甲烷(20mL)的溶液。反应在0℃下搅拌1小时。反应结束，加入冰水(300mL)淬灭反应，用二氯甲烷(150mL*2)萃取，用盐水(300mL*2)洗涤有机相并用无水硫酸钠干燥，过滤浓缩，通过硅胶柱色谱法(石油醚/乙酸乙酯＝3:1)纯化得到化合物1-8(12g,纯度90％,收率69％)。LCMS(ESI)[M+Na] +m/z＝369.2。
步骤7：将化合物1-8(10g,28.8mmol)溶于四氢呋喃(100mL)，加入四丁基氟化铵(1 mol/L in THF,28.8mL,28.8mmol)，氮气保护下，将反应液在45℃下搅拌48小时。反应结束，加入饱和碳酸氢钠水溶液(300mL)稀释并用乙酸乙酯(200mL*2)萃取，用饱和食盐水(250mL)洗涤有机相，无水硫酸钠干燥，过滤浓缩，通过硅胶柱色谱法(石油醚/乙酸乙酯＝3:1)纯化得到化合物1-9(2.5g,纯度90％,收率16.6％)。。LCMS(ESI)[M+Na] +m/z＝389.2。
步骤8：将1-9(2.5g,6.8mmol)溶于二氯甲烷(20mL)，加入氯化氢的1,4-二氧六环溶液(6mL,4mol/L)，将混合物在25℃下搅拌4小时。浓缩得到粗产物化合物1-10(2g)，无需进一步纯化即可用于下一步。LCMS(ESI)[M+H] +m/z＝267.14。
步骤9：将1-10(4.32g,16.55mmol)溶于正丁醇(50mL)，加入1-11(4.67g,24.8mmol,)和N,N-二异丙基乙胺(5.97g,46.2mmol)，氮气保护下，将反应液在140℃下搅拌30小时。反应结束后，用碳酸钠溶液调节至PH＝10，用乙酸乙酯(200mL X 3)萃取，用盐水洗涤有机相并用无水硫酸钠干燥，过滤并浓缩滤液，通过硅胶柱色谱法(二氯甲烷/甲醇＝20:1)纯化得到化合物1-12(2.93g,收率42％)。LCMS(ESI)[M+H] +m/z＝418.1。
步骤10：将化合物1-12(700mg,1.67mmol)溶于四氢呋喃(10mL)和水(3mL)，加入10％钯碳(200mg)，氢气保护下(5Mpa)，将反应液在45℃下搅拌24小时，反应结束，过滤浓缩，得到粗产品1-13(333mg,收率80％)，无需进一步纯化即可用于下一步。LCMS(ESI)[M+H] +m/z＝250.2.
步骤13：将1-13(100mg,0.4mmol)溶于四氢呋喃(2.5mL)，加入磷酸钾(341mg,1.6mmol)的水溶液(1mL)，将反应混合物在0℃下搅拌，并逐滴加入3-氯丙酰氯(62mg,0.48mmol)的四氢呋喃(0.5mL)溶液，在0℃下继续搅拌2小时。将氢氧化钠(81mg，2.01mmol)的水溶液(1mL)滴加到上述反应混合物中，将反应液在室温下搅拌18小时。反应结束，用饱和氯化铵溶液(20mL)稀释，用乙酸乙酯(10mL X 3)萃取，用盐水洗涤有机相并用无水硫酸钠干燥，过滤浓缩，通过Chiral-HPLC(40％ETOH/(NH 4OH0.2％))纯化，得到粗产物，再通过制备型HPLC(0.1％FA/MeCN＝90％至60％)进一步纯化粗产物，得到以下白色固体：
化合物1(21.9mg,纯度99.442％),LCMS(ESI)[M+H] +m/z＝304.2. 1H NMR(400MHz,CD 3OD)δ7.20(s,1H),6.37(d,J＝2.0Hz,1H),6.13(dd,J＝12.9,8.9Hz,1H),5.97(s,1H),5.64(d,J＝13.9Hz,1H),5.28(d,J＝8.5Hz,1H),4.77-4.68(m,1H),4.67-4.61(m,0.5H),4.58(s,0.5H),4.50(s,0.5H),4.36(s,0.5H),4.19-4.09(m,1.5H),3.27-2.98(m,1H),2.44(s,1H),2.20(d,J＝6.1Hz,1H),1.71(s,3H).
化合物2(15.6mg,纯度99.724％),LCMS(ESI)[M+H] +m/z＝304.2. 1H NMR(400MHz,CD 3OD)δ7.20(s,1H),6.37(d,J＝2.6Hz,1H),6.13(dd,J＝13.3,8.6Hz,1H),5.96(d,J＝2.3Hz,1H),5.64(dd,J＝13.5,1.5Hz,1H),5.28(dd,J＝8.4,1.4Hz,1H),4.78-4.68(m,1H),4.67-4.58(m,1H),4.56-4.43(m,0.5H),4.36(s,0.5H),4.20-4.10(m,1.5H),3.26-3.01(m,1H),2.44(d,J＝4.5Hz,1H),2.25(s,1H),1.77-1.68(m,3H)..
实施例2：1-((2S,4S,5S)-5-((7H-吡咯[2,3-d]吡啶-4-基)氨基)-4-氟-2-甲基哌啶-1-基)丙烯-2-烯-1-酮(化合物3)和1-((2R,4R,5R)-5-((7H-吡咯[2,3-d]吡啶-4-基)氨基)-4-氟-2-甲基哌啶-1-基)丙烯-2-烯-1-酮(化合物4)
参照下面的步骤合成和化合物3和化合物4:
Figure PCTCN2022076138-appb-000007
步骤1：用DMF(50mL)将化合物3-1(4.6g,30mmo)溶解到反应瓶中，冷却到0℃，往反应体系中加入60％的NaH(1.4g,36mmol)，同温度下搅拌混合物1h，然后滴加SEMCl(6.8mL,39mmol)。物料加完后，体系在0℃下搅拌4小时。LCMS监控反应结束。反应混合物中加入100mL饱和NH4Cl，用乙酸乙酯(50mLX3)萃取，萃取后的有机相用Na 2SO 4干燥过滤后减压浓缩后得到的粗产品减压浓缩后得到的粗产品通过薄层层析板制备(乙酸乙酯)纯化得到白色固体化合物3-2(7.67g,收率90％)。LCMS(ESI)m/z[M+H] +＝283.1。
步骤2：在圆底烧瓶中加入化合物3-2(1.05g,3.72mmol)和化合物1-10(5.62g,18.6mmol)的混合物中加入2-(二叔丁基膦基)联苯(222mg,0.75mmol)、Cs 2CO 3(1.2g,3.72mmol)和Pd(OAc) 2(84mg,0.36mmol)。在110℃氮气气氛下搅拌2h，冷却至室温后加入CHCl3和MeOH稀释。在室温下搅拌10分钟后，通过硅藻土过滤混合物。滤液减压浓缩，残液经柱层析(正己烷/乙酸乙酯＝9/1～4/1)纯化得到化合物3-3(889mg，50％收率)。LCMS(ESI)m/z [M+H] +＝479.2。
步骤3：将化合物化3-3(880mg,1.84mmol)溶于10毫升THF中，加入四甲基乙二胺(0.64g,5.52mmol)和5.52mL TBAF THF(1M in THF,5.52mmol)溶液。升温至60度反应过夜。加入25毫升乙酸乙酯萃取，饱和食盐水洗涤三次，无水硫酸钠干燥，过滤旋干，硅胶过柱(PE:EA＝10:1)洗脱得化合物3-4(397mg，收率：62％)产品。LCMS(ESI)m/z[M+H] +＝349.2。
步骤4：将化合物3-4(390mg,1.12mmol)溶于四氢呋喃(15mL)和水(5mL)，加入10％钯碳(300mg)，氢气保护下(5Mpa)，将反应液在45℃下搅拌24小时，反应结束，过滤浓缩，得到粗产品3-5(237mg,收率85％)，无需进一步纯化即可用于下一步。LCMS(ESI)[M+H] +m/z＝249.14。
步骤5：将3-5(99mg,0.4mmol)溶于四氢呋喃(2.5mL)，加入磷酸钾(341mg,1.6mmol)的水溶液(1mL)，将反应混合物在0℃下搅拌，并逐滴加入3-氯丙酰氯(62mg,0.48mmol)的四氢呋喃(0.5mL)溶液，在0℃下继续搅拌2小时。将氢氧化钠(81mg，2.01mmol)的水溶液(1mL)滴加到上述反应混合物中，将反应液在室温下搅拌18小时。反应结束，用饱和氯化铵溶液(20mL)稀释，用乙酸乙酯(10mL X 3)萃取，用盐水洗涤有机相并用无水硫酸钠干燥，过滤浓缩，通过Chiral-HPLC(40％ETOH/(NH 4OH 0.2％))纯化，得到粗产物,再通过制备型HPLC(0.1％FA/MeCN＝90％至60％)进一步纯化粗产物，得到以下白色固体：
化合物3(35.1mg,纯度99.2％),LCMS(ESI)[M+H] +m/z＝303.2. 1H NMR(400MHz,CD 3OD)δ8.26(d,J＝2.4Hz,1H),7.96(m,1H),7.01(d,J＝2.4Hz,1H),6.37(d,J＝2.0Hz,1H),6.13(dd,J＝12.9,8.9Hz,1H),5.97(s,1H),5.65(d,J＝13.9Hz,1H),5.27(d,J＝8.5Hz,1H),4.78-4.68(m,1H),4.67-4.61(m,0.5H),4.58(s,0.5H),4.50(s,0.5H),4.36(s,0.5H),4.20-4.10(m,1.5H),3.26-3.15(m,0.5H),2.98(s,0.5H),2.45(s,1H),2.21(d,J＝6.1Hz,1H),1.73(s,3H)..
化合物4(25.3mg,纯度99.5％),LCMS(ESI)[M+H] +m/z＝303.2. 1H NMR(400MHz,CD 3OD)δ8.27(d,J＝2.4Hz,1H),7.98(m,1H),7.02(d,J＝2.4Hz,1H),6.38(d,J＝2.0Hz,1H),6.15(dd,J＝12.9,8.9Hz,1H),5.97(s,1H),5.65(d,J＝13.9Hz,1H),5.27(d,J＝8.5Hz,1H),4.78-4.68(m,1H),4.67-4.62(m,0.5H),4.56(s,0.5H),4.52(s,0.5H),4.36(s,0.5H),4.20-4.10(m,1.5H),3.26-2.98(m,1H),2.44(s,1H),2.20(d,J＝6.1Hz,1H),1.74(s,3H).
实施例3：1-((2S,4S,5S)-5-((5-氰基-7H-吡咯[2,3-d]吡啶-4-基)氨基)-4-氟-2-甲基哌啶-1-基)丙烯-2-烯-1-酮化合物5和1-((2R,4R,5R)-5-((5-氰基-7H-吡咯[2,3-d]吡啶-4-基)氨基)-4-氟-2-甲基哌啶-1-基)丙烯-2-烯-1-酮(化合物6)
化合物5和化合物6的制备步骤如下：
Figure PCTCN2022076138-appb-000008
步骤1：将1-10(700mg,2.78mmol)溶于正丁醇(10mL)，加入5-1(602mg,3.47mmol,)和N,N-二异丙基乙胺(896mg,6.94mmol)，氮气保护下，将反应液在100℃下搅拌10小时。反应结束后，用碳酸钠溶液调节至PH＝10，用乙酸乙酯(30mL X 3)萃取，用盐水洗涤有机相并用无水硫酸钠干燥，过滤并浓缩滤液，通过硅胶柱色谱法(二氯甲烷/甲醇＝20:1)纯化得到化合物5-2(678mg,收率72％)。LCMS(ESI)[M+H] +m/z＝408.18。
步骤2：将化合物5-2(678mg,1.66mmol)溶于四氢呋喃(10mL)和水(3mL)，加入10％钯碳(200mg)，氢气保护下(5Mpa)，将反应液在45℃下搅拌24小时，反应结束，过滤浓缩，得到粗产品5-3(386mg,收率85％)，无需进一步纯化即可用于下一步。LCMS(ESI)[M+H] +m/z＝274.14.
步骤3：将5-3(200mg,0.73mmol)溶于四氢呋喃(5mL)，加入磷酸钾(680mg,0.32mmol)的水溶液(2mL)，将反应混合物在0℃下搅拌，并逐滴加入3-氯丙酰氯(124mg,0.96mmol)的四氢呋喃(0.5mL)溶液，在0℃下继续搅拌2小时。将氢氧化钠(160mg，4mmol)的水溶液(1mL)滴加到上述反应混合物中，将反应液在室温下搅拌18小时。反应结束，用饱和氯化铵溶液(20mL)稀释，用乙酸乙酯(10mL X 3)萃取，用盐水洗涤有机相并用无水硫酸钠干燥，过滤浓缩，通过Chiral-HPLC(40％ETOH/(NH 4OH 0.2％))纯化，得到粗产物,再通过制备型HPLC(0.1％FA/MeCN＝90％至60％)进一步纯化粗产物，得到以下白色固体：
化合物5(45mg,纯度99.2％),LCMS(ESI)[M+H] +m/z＝328.15. 1H NMR(400MHz,CD 3OD)δ11.12(s,1H),9.06(s,1H),7.93-7.85(m,1H),6.62(dd,J＝12.9,8.9Hz,1H),6.15-6.05(m,1H),5.58(d,J＝13.9Hz,1H),5.28(d,J＝8.5Hz,1H),4.77-4.68(m,1H),4.67-4.60(m, 0.5H),4.58(s,0.5H),4.50(s,0.5H),4.36(s,0.5H),4.19-4.09(m,1.5H),3.26-2.98(m,1H),2.42(s,1H),2.21(d,J＝6.1Hz,1H),1.70(s,3H)..
化合物6(32mg,纯度99.4％),LCMS(ESI)[M+H] +m/z＝328.15. 1H NMR(400MHz,CD 3OD)δ11.06(s,1H),9.05(s,1H),7.92-7.88(m,1H),6.64(dd,J＝12.9,8.9Hz,1H),6.16-6.08(m,1H),5.58(d,J＝13.9Hz,1H),5.28(d,J＝8.5Hz,1H),4.77-4.68(m,1H),4.67-4.60(m,0.5H),4.58(s,0.5H),4.50(s,0.5H),4.36(s,0.5H),4.20-4.06(m,1.5H),3.28-2.96(m,1H),2.44(s,1H),2.22(d,J＝6.1Hz,1H),1.73(s,3H).
实施例4：乙基4-(((3S,4S,6S)-1-丙烯酰-4-氟-6-甲基哌啶-3-基)氨基)-7H-吡咯[2,3-d]嘧啶-5-羧酸化合物7和乙基4-(((3R,4R,6R)-1-丙烯酰-4-氟-6-甲基哌啶-3-基)氨基)-7H-吡咯[2,3-d]嘧啶-5-羧酸(化合物8)的制备
参照下面的步骤合成化合物7和化合物8:
Figure PCTCN2022076138-appb-000009
步骤1：将1-10(800mg,2.64mmol)溶于正丁醇(10mL)，加入7-1(894mg,3.86mmol,)和N,N-二异丙基乙胺(997mg,7.72mmol)，氮气保护下，将反应液在140℃下搅拌20小时。反应结束后，用碳酸钠溶液调节至PH＝10，用乙酸乙酯(200mL X 3)萃取，用盐水洗涤有机相并用无水硫酸钠干燥，过滤并浓缩滤液，通过硅胶柱色谱法(二氯甲烷/甲醇＝20:1)纯化得到化合物7-2(782g,收率65％)。LCMS(ESI)[M+H] +m/z＝456.20。
步骤2：将化合物7-2(782mg,1.71mmol)溶于四氢呋喃(10mL)和水(3mL)，加入10％钯碳(200mg)，氢气保护下(5Mpa)，将反应液在45℃下搅拌24小时，反应结束，过滤浓缩，得到粗产品7-3(452mg,收率82％)，无需进一步纯化即可用于下一步。LCMS(ESI)[M+H] +m/z＝322.16.
步骤3：将7-3(100mg,0.31mmol)溶于四氢呋喃(2.5mL)，加入磷酸钾(341mg,1.6mmol)的水溶液(1mL)，将反应混合物在0℃下搅拌，并逐滴加入3-氯丙酰氯(62mg,0.48mmol)的四氢呋喃(0.5mL)溶液，在0℃下继续搅拌2小时。将氢氧化钠(81mg，2.01mmol)的水溶液 (1mL)滴加到上述反应混合物中，将反应液在室温下搅拌18小时。反应结束，用饱和氯化铵溶液(20mL)稀释，用乙酸乙酯(10mL X 3)萃取，用盐水洗涤有机相并用无水硫酸钠干燥，过滤浓缩，通过Chiral-HPLC(40％ETOH/(NH 4OH 0.2％))纯化，得到粗产物，再通过制备型HPLC(0.1％FA/MeCN＝90％至60％)进一步纯化粗产物，得到以下白色固体：
化合物7(23mg,纯度99.3％),LCMS(ESI)[M+H] +m/z＝376.17. 1H NMR(400MHz,CD 3OD)δ11.04(s,1H),8.96(s,1H),7.90-7.80(m,1H),6.66(dd,J＝12.9,8.9Hz,1H),6.16-6.08(m,1H),5.58(d,J＝12.9Hz,1H),5.26(d,J＝8.5Hz,1H),4.12(q,J＝8Hz,2H)，3.80-3.20(m,5H)1.78-1.62(m,2H)，1.30(t,J＝8Hz,3H)，1.26(d,J＝6.8Hz,3H).
化合物8(18mg,纯度99.1％),LCMS(ESI)[M+H] +m/z＝376.17. 1H NMR(400MHz,CD 3OD)δ11.01(s,1H),8.98(s,1H),7.94-7.89(m,1H),6.64(dd,J＝12.9,8.9Hz,1H),6.16-6.08(m,1H),5.58(d,J＝12.9Hz,1H),5.28(d,J＝8.5Hz,1H),4.14(q,J＝8Hz,2H)，3.80-3.20(m,5H)1.77-1.65(m,2H)，1.31(t,J＝8Hz,3H)，1.26(d,J＝6.8Hz,3H).
实施例5：1-((2S,4S,5S)-5-((5-((R)-2,2-二氟环丙基)-7H-吡咯[2,3-d]嘧啶-4-基)氨基)-4-氟-2-甲基哌啶-1-基)丙-2-烯-1-酮(化合物9)；1-((2S,4S,5S)-5-((5-((S)-2,2-二氟环丙基)-7H-吡咯[2,3-d]嘧啶-4-基)氨基)-4-氟-2-甲基哌啶-1-基)丙-2-烯-1-酮(化合物10)的制备
参照下面的步骤合成和化合物9和化合物10:
Figure PCTCN2022076138-appb-000010
步骤1：将4-氯-7H-吡咯并[2,3-d]嘧啶-5-甲醛9-1(5g,66.45mmol)溶于N，N－二甲基甲 酰胺(50mL)中，并在冰浴条件下加入氢化钠(0.80g,34mmol)，然后缓慢加入2-(三甲基硅基)乙氧基甲基氯(6.90g,41.42mol)。反应液于25℃反应2小时。LCMS检测反应完成，向反应液中加入水，用乙酸乙酯萃取。有机相合并，饱和食盐水洗涤，无水硫酸钠干燥并浓缩。将得到的残留物用硅胶柱[石油醚/乙酸乙酯＝3/1]纯化后得到4-氯-7-((2-(三甲基硅基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-5-氨基甲醛9-2(5.9g,黄色固体)，收率:63％。LCMS(ESI)[M+H] +m/z 312.10.
步骤2：将甲基三苯基溴化膦(3,42mg,9.63mmol)溶于甲苯(45mL),然后在冰浴条件下加入叔丁醇钾(1.08g,9.63mmol),氮气保护下，接着在0℃搅拌30分钟。再次将化合物9-2(1.5g,4.8mmol)加到反应体系中并搅拌2小时。LCMS检测反应完成，将溶剂旋干，再向反应液中加入水，用二氯甲烷萃取。有机相合并，饱和食盐水洗涤，无水硫酸钠干燥并浓缩。将得到的残留物用硅胶柱[石油醚/乙酸乙酯＝4/1]纯化后得到化合物9-3(505mg,白色固体)，收率：34％。LCMS(ESI)[M+H] +m/z 310.1.
步骤3：将化合物9-3(500mg,1.6mmol)溶于乙腈(10mL),然后加入碘化钠(723mg,4.8mmol)和三氟甲基三甲基硅烷(686mg,4.8mmol)。氮气保护下，110℃搅拌1小时。LCMS检测反应完成，将溶剂旋干，再向反应液中加入水，用二氯甲烷萃取。有机相合并，饱和食盐水洗涤，无水硫酸钠干燥并浓缩。将得到的残留物用硅胶柱[石油醚/乙酸乙酯＝4/1]纯化后得到化合物9-4(400mg,黄色固体)，收率：69％。LCMS(ESI)[M+H] +m/z 360.21.
步骤4：将化合物(2S,4S,5S)-1-10(224mg,0.72mmol)溶于正丁醇(5mL)，加入9-4(400g,1.11mmol,)和N,N-二异丙基乙胺(0.266g,2.06mmol)，氮气保护下，将反应液在140℃下搅拌30小时。反应结束后，用碳酸钠溶液调节至PH＝10，用乙酸乙酯(10mL X 3)萃取，用盐水洗涤有机相并用无水硫酸钠干燥，过滤并浓缩滤液，通过硅胶柱色谱法(二氯甲烷/甲醇＝20:1)纯化得到化合物9-5(294mg,收率45％)。LCMS(ESI)[M+H] +m/z＝590.27。
步骤5：将化合物化9-5(290mg,0.49mmol)溶于5毫升THF中，加入四甲基乙二胺(0.17g,1.47mmol)和5.52mL TBAF THF(1M in THF,1.47mmol)溶液。升温至60度反应过夜。加入25毫升乙酸乙酯萃取，饱和食盐水洗涤三次，无水硫酸钠干燥，过滤旋干，硅胶过柱(PE:EA＝10:1)洗脱得化合物9-6(180mg，收率：80％)产品。LCMS(ESI)m/z[M+H] +＝460.2。
步骤6：将化合物9-6(180mg,0.39mmol)溶于四氢呋喃(5mL)和水(1.5mL)，加入10％ 钯碳(100mg)，氢气保护下(5Mpa)，将反应液在45℃下搅拌24小时，反应结束，过滤浓缩，得到粗产品9-7(102mg,收率80％)，无需进一步纯化即可用于下一步。LCMS(ESI)[M+H] +m/z＝326.15。
步骤7：将9-7(102mg,0.31mmol)溶于四氢呋喃(2.5mL)，加入磷酸钾(264mg,1.24mmol)的水溶液(1mL)，将反应混合物在0℃下搅拌，并逐滴加入1-14 3-氯丙酰氯(48mg,0.37mmol)的四氢呋喃(0.5mL)溶液，在0℃下继续搅拌2小时。将氢氧化钠(62mg，1.55mmol)的水溶液(1mL)滴加到上述反应混合物中，将反应液在室温下搅拌18小时。反应结束，用饱和氯化铵溶液(20mL)稀释，用乙酸乙酯(10mL X 3)萃取，用盐水洗涤有机相并用无水硫酸钠干燥，过滤浓缩，通过Chiral-HPLC(40％ETOH/(NH 4OH 0.2％))纯化，得到粗产物,再通过制备型HPLC(0.1％FA/MeCN＝90％至60％)进一步纯化粗产物，得到以下白色固体：
化合物9(38mg,纯度99.2％),LCMS(ESI)[M+H] +m/z＝380.16； 1H NMR(400MHz,CD 3OD)δ11.01(s,1H),8.98(s,1H),7.92-7.83(m,1H),6.68(dd,J＝12.9,8.9Hz,1H),6.16-6.08(m,1H),5.58(d,J＝12.9Hz,1H),5.26(d,J＝8.5Hz,1H),3.80-3.20(m,5H)1.88-1.62(m,2H)，1.26(d,J＝6.8Hz,3H).
化合物10(45.6mg,纯度99.4％),LCMS(ESI)[M+H] +m/z＝380.16； 1H NMR(400MHz,CD 3OD)δ11.03(s,1H),8.96(s,1H),7.90-7.80(m,1H),6.68(dd,J＝12.9,8.9Hz,1H),6.18-6.08(m,1H),5.60(d,J＝12.9Hz,1H),5.28(d,J＝8.5Hz,1H),3.78-3.24(m,5H)1.86-1.60(m,2H)，1.27(d,J＝6.8Hz,3H)。
实施例6：1-((2S,4S,5S)-5-((5-(环丙基乙炔基)-7H-吡咯[2,3-d]嘧啶-4-基)氨基)-4-氟-2-甲基哌啶-1-基)丙-2-烯-1-酮(化合物11)的制备
参照下面的步骤合成和化合物11.
Figure PCTCN2022076138-appb-000011
步骤1：氮气保护下将化合物1(2g,6.59mmol,溶于乙腈(60mL)，在0℃下加入N-碘代丁二酰亚胺(1.63g,7.25mmol)。将反应混合物在0℃下搅拌8小时，反应结束，加入冰水(200mL)淬灭反应，用乙酸乙酯(100mL*2)萃取，用盐水(300mL*2)洗涤有机相并用无水硫酸钠干燥，过滤浓缩，通过硅胶柱色谱法(石油醚/乙酸乙酯＝3:1)纯化得到化合物11-1(2.12g,收率75％)。LCMS(ESI)[M+Na] +m/z＝430.05。
步骤2：将化合物11-1(106mg,0.25mmol,)溶于无水二氯甲烷(3mL)，在0℃下加入三乙胺(102mg,1.0mmol)和催化量的4-二甲基氨基吡啶(2mg)。氮气保护，将反应混合物在0℃下搅拌15分钟，然后滴加二碳酸二叔丁酯(109mg,0.5mmol)的无水二氯甲烷(2mL)的溶液。反应在0℃下搅拌1小时。反应结束，加入冰水(10mL)淬灭反应，用二氯甲烷(20mL*2)萃取，用盐水(20mL*2)洗涤有机相并用无水硫酸钠干燥，过滤浓缩，通过硅胶柱色谱法(石油醚/乙酸乙酯＝3:1)纯化得到化合物11-2(111mg,收率85％)。LCMS(ESI)[M+Na] +m/z＝530.10。
步骤3：在氮气气氛下，将化合物11-2(111mg,0.21mmol)溶于四氢呋喃(4mL)中，依次加入dppf Pd G3(120mg,0.21mmol)，碘化亚铜(13mg,0.07mmol)，dppf(12mg,0.021mmol)，2-环丙基乙炔(67mg,1.05mmol)和三乙胺(0.6mL)，反应液在25℃下搅拌3小时。将溶剂旋干，浓缩得到的残留物用硅胶柱(石油醚/乙酸乙酯＝1/1)纯化得到化合物11-3(69mg，收率：71％)，白色固体。LCMS(ESI)[M+H] +m/z＝468.23.
步骤4：将化合物11-3(69mg,0.14mmol)溶于二氯甲烷(1mL)中，在冰水浴下加入三氟乙酸(0.5mL)。反应液在0℃下搅拌2小时。将溶剂旋干得到标题产物化合物11(52mg,收率：68％)，白色固体。LCMS(ESI)[M+H] +m/z＝368.18； 1H NMR(400MHz,CD 3OD)δ11.01(s,1H),8.98(s,1H),7.95-7.82(m,1H),6.68(dd,J＝12.9,8.9Hz,1H),6.16-6.05(m,1H),5.62(d,J＝12.9Hz,1H),5.26(d,J＝8.5Hz,1H),3.80-3.22(m,5H)1.27(d,J＝6.8Hz,3H)， 0.95-0.60(m,2H)。
实施例7：1-((2S,4S,5S)-5-((5-(3-甲氧基-丙炔-1-基)-7H-吡咯[2,3-d]嘧啶-4-基)氨基)-4-氟-2-甲基哌啶-1-基)丙-2-烯-1-酮(化合物12)的制备
参照下面的步骤合成和化合物12：
Figure PCTCN2022076138-appb-000012
步骤1：在氮气气氛下，将化合物11-2(100mg,0.19mmol)溶于四氢呋喃(4mL)中，依次加入dppf Pd G3(110mg,0.19mmol)，碘化亚铜(13mg,0.07mmol)，dppf(11mg,0.019mmol)，3-甲氧基丙炔(68mg,0.95mmol)和三乙胺(0.6mL)，反应液在25℃下搅拌3小时。将溶剂旋干，浓缩得到的残留物用硅胶柱(石油醚/乙酸乙酯＝1/1)纯化得到化合物12-1(58mg，收率：65％)，白色固体。LCMS(ESI)[M+H] +m/z＝472.23.
步骤2：将化合物12-1(58mg,0.12mmol)溶于二氯甲烷(1mL)中，在冰水浴下加入三氟乙酸(0.5mL)。反应液在0℃下搅拌2小时。将溶剂旋干得到标题产物1-((2S,4S,5S)-5-((5-(3-甲氧基-丙炔-1-基)-7H-吡咯[2,3-d]嘧啶-4-基)氨基)-4-氟-2-甲基哌啶-1-基)丙-2-烯-1-酮化合物12(37mg,收率：81％)，白色固体。LCMS(ESI)[M+H] +m/z＝372.18； 1H NMR(400MHz,CD 3OD)δ11.01(s,1H),8.98(s,1H),7.95-7.82(m,1H),6.68(dd,J＝12.9,8.9Hz,1H),6.16-6.05(m,1H),5.62(d,J＝12.9Hz,1H),5.26(d,J＝8.5Hz,1H),4.15(s,3H),3.80-3.22(m,5H)，3.30(s,3H),1.27(d,J＝6.8Hz,3H)。
实施例8：1-((2S,4S,5S)-5-((5-(3-(氟代甲氧基)丙炔-1-基)-7H-吡咯[2,3-d]嘧啶-4-基)氨基)-4-氟-2-甲基哌啶-1-基)丙-2-烯-1-酮(化合物13)的制备
参照下面的步骤合成和化合物13：
Figure PCTCN2022076138-appb-000013
步骤1：在氮气气氛下，将化合物11-2(100mg,0.19mmol)溶于四氢呋喃(4mL)中， 依次加入dppf Pd G3(110mg,0.19mmol)，碘化亚铜(13mg,0.07mmol)，dppf(11mg,0.019mmol)，3-(氟代甲氧基)丙炔(71mg,0.95mmol)和三乙胺(0.6mL)，反应液在25℃下搅拌3小时。将溶剂旋干，浓缩得到的残留物用硅胶柱(石油醚/乙酸乙酯＝1/1)纯化得到化合物13-1(53mg，收率：58％)，白色固体。LCMS(ESI)[M+H] +m/z＝490.22.
步骤2：将化合物13-1(58mg,0.11mmol)溶于二氯甲烷(1mL)中，在冰水浴下加入三氟乙酸(0.5mL)。反应液在0℃下搅拌2小时。将溶剂旋干得到标题产物化合物13(26mg,收率：71％)，白色固体。LCMS(ESI)[M+H] +m/z＝390.18； 1H NMR(400MHz,CD 3OD)δ11.02(br s,1H),8.96(s,1H),7.96-7.82(m,1H),6.67(dd,J＝12.9,8.9Hz,1H),6.16(s,3H),6.15-6.05(m,1H),5.62(d,J＝12.9Hz,1H),5.26(d,J＝8.5Hz,1H),4.16(s,3H),3.80-3.22(m,5H)，1.26(d,J＝6.8Hz,3H)。
实施例9：1-((2S,4S,5S)-5-((5-((1H-吡咯-4基)乙炔基)-7H-吡咯[2,3-d]嘧啶-4-基)氨基)-4-氟-2-甲基哌啶-1-基)丙-2-烯-1-酮(化合物14)的制备
参照下面的步骤合成和化合物14：
Figure PCTCN2022076138-appb-000014
步骤1：在氮气气氛下，将化合物11-2(100mg,0.19mmol)溶于四氢呋喃(4mL)中，依次加入dppf Pd G3(110mg,0.19mmol)，碘化亚铜(13mg,0.07mmol)，dppf(11mg,0.019mmol)，(1H-吡咯-4基)乙炔(85mg,0.95mmol)和三乙胺(0.6mL)，反应液在25℃下搅拌3小时。将溶剂旋干，浓缩得到的残留物用硅胶柱(石油醚/乙酸乙酯＝1/1)纯化得到化合物14-1(44mg，收率：48％)，白色固体。LCMS(ESI)[M+H] +m/z＝494.22.
步骤2：将化合物14-1(44mg,0.09mmol)溶于二氯甲烷(1mL)中，在冰水浴下加入三氟乙酸(0.5mL)。反应液在0℃下搅拌2小时。将溶剂旋干得到标题产物化合物14(24mg,收率：69％)，白色固体。LCMS(ESI)[M+H] +m/z＝394.18； 1H NMR(400MHz,CD 3OD)δ13.85(brs,1H),11.02(br s,1H),8.96(s,1H),8.94-8.85(m,2H),7.96-7.82(m,1H),6.67(dd,J＝12.9,8.9Hz,1H),6.15-6.05(m,1H),5.62(d,J＝12.9Hz,1H),5.26(d,J＝8.5Hz,1H),3.80-3.25(m,5H)，1.26(d,J＝6.8Hz,3H)。
实施例10：1-((2S,4S,5S)-5-((5-((2-甲基-2H-四氮唑-5基)乙炔基)-7H-吡咯[2,3-d]嘧啶-4-基)氨基)-4-氟-2-甲基哌啶-1-基)丙-2-烯-1-酮(化合物15)的制备
参照下面的步骤合成和化合物15：
Figure PCTCN2022076138-appb-000015
步骤1：在氮气气氛下，将化合物11-2(100mg,0.19mmol)溶于四氢呋喃(4mL)中，依次加入dppf Pd G3(110mg,0.19mmol)，碘化亚铜(13mg,0.07mmol)，dppf(11mg,0.019mmol)，(1H-吡咯-4基)乙炔(101mg,0.95mmol)和三乙胺(0.6mL)，反应液在25℃下搅拌3小时。将溶剂旋干，浓缩得到的残留物用硅胶柱(石油醚/乙酸乙酯＝1/1)纯化得到化合物15-1(43mg，收率：45％)，白色固体。LCMS(ESI)[M+H] +m/z＝510.23.
步骤2：将化合物15-1(43mg,0.085mmol)溶于二氯甲烷(1mL)中，在冰水浴下加入三氟乙酸(0.5mL)。反应液在0℃下搅拌2小时。将溶剂旋干得到标题产物化合物15(23mg,收率：65％)，白色固体。LCMS(ESI)[M+H] +m/z＝410.18； 1H NMR(400MHz,CD 3OD)δ11.03(br s,1H),8.98(s,1H),7.98-7.82(m,1H),6.66(dd,J＝12.9,8.9Hz,1H),6.15-6.05(m,1H),5.65(d,J＝12.9Hz,1H),5.28(d,J＝8.5Hz,1H),3.80-3.25(m,5H)，3.64(s,3H),1.27(d,J＝6.8Hz,3H)。
实施例11：激酶抑制活性的测定
将四种LanthaScreen JAK生物化学分析的组(JAK1、2、3和Tyk2)载于常见激酶反应缓冲液(50mM HEPES，pH 7.5，0.01％Brij-35，10mM MgCl 2，和1mM EGTA)中。重组GST标记的JAK酶和GFP标记的STAT1肽底物获自Life Technologies。
使连续稀释的化合物与四种JAK酶中的每一者和底物在白色384孔微量培养板(Corning)中一起在环境温度下预培育1小时。随后添加总体积为10μL、具有1％DMSO的ATP以引发激酶反应。JAK1、2、3和Tyk2的最终酶浓度分别是1nM、0.1nM、0.1nM和0.25nM；所用的相应Km ATP浓度是25μM、3μM、1.6μM和10μM；而用于所有四个分析的底物浓度均是200nM。在环境温度下使激酶反应进行1小时，之后加入EDTA(10mM最终浓度)和Tb抗pSTAT1(pTyr701)抗体(Life Technologies，2nM最终浓度)于TRFRET稀释缓冲液(Life  Technologies)中的10μL制剂。在环境温度下将培养板培育1小时，之后在EnVision读取器(Perkin Elmer)上读取。记录且使用发射比信号(520nm/495nm)，以基于DMSO和背景对照计算抑制百分比值。
对于剂量反应分析，相较于化合物浓度绘制抑制百分比数据，且用Prism软件(GraphPad Software)、利用4参数稳固拟合模型测定IC 50值。在测试化合物滴定并导致肽产物形成抑制的情况下，这些数据拟合产生最佳拟合IC50值。
化合物抑制率(％inh)＝(阴性对照平均值-化合物)/(阴性对照平均值-阳性对照平均值)*100％
阴性对照：空白DMSO
阳性对照：PF06651600
b)利用以下非线性拟合公式来得到化合物的IC 50(半数抑制浓度)：
Y＝Bottom+(Top-Bottom)/(1+10^((LogIC 50-X)*HillSlope))
X:化合物浓度log值
Y:化合物抑制率(％inh)
这些测定的结果如下表1所示，其中“A”代表计算的IC50小于1nM；“B”表示计算的IC50为1nM至小于100nM；“C”表示计算的IC50为100nM至小于1μM；“D”表示计算的IC 50大于或等于1μM，“NT”表示未在指定的测定中测试指定的化合物。
[根据细则91更正 02.11.2022]
表1.本发明选择的化合物对JAK1、JAK2、JAK3和TYK2的抑制活性
Figure PCTCN2022076138-appb-000016
Figure PCTCN2022076138-appb-000017
以上的结果表明本发明的化合物对JAK3具有良好的选择性抑制作用。
实施例12：人全血细胞(HWB)IL-15诱导STAT5磷酸化抑制活性测定
用DMSO将测试化合物以1:2系列稀释至期望的浓度(最终500X)，然后将化合物在PBS中进一步稀释(通过在96μL PBS中加入4μL化合物，[DMSO]＝4％，最终20X)。相96孔聚丙烯板中加入90μl HWB(肝素处理的人全血)/孔，随后加入5μl/孔D-PBS中的4％DMSO或不同浓度的D-PBS(w/o Ca +2或Mg +2)中4％DMSO中的20X抑制剂，以得到在0.2％DMSO中1X浓度。在37℃下混合并孵育45分钟，然后加入5μl D-PBS(未刺激对照)或5μl人IL-15的20X储备液(终浓度为50ng/ml)，混合三次。在37℃下孵育1 5分钟后，将1X裂解/固定缓冲液(BDPhosflow5x裂解/固定缓冲液)以1000μl/孔加入到所有孔中，然后在37℃下孵育20分钟，并以1200rpm旋转5分钟。用1000μl FACS缓冲液洗涤并以1200rpm旋转5分钟后，向各孔中加入400μl冰冷的Perm缓冲液III。轻轻混合(1-2X)并在冰上孵育30分钟后，以1200rpm在无中断下旋转5分钟，并用冷的1000ml FACS缓冲液(含有0.1％BSA和0.1％叠氮化钠的D-PBS)洗涤1X，以250μl/孔加入期望的用FACS缓冲液以1:125稀释的AlexaFluor647缀合的抗磷酸化STAT5抗体。在4℃下孵育过夜后，将所有样品转移至96孔聚丙烯U底板中，并通过流式细胞术(门控总淋巴细胞)检查。得到的IC 50值在表中列出。

表2.本发明选择的化合物对HWB IL-15诱导STAT5磷酸化的抑制活性
化合物 HWB IL15-pSTAT5IC 50(nM)
PF06651600 136
1 60
3 55
5 198
7 87
9 351
11 1850
12 685
13 96
14 560
15 990
以上的结果表明本发明的化合物对HWB的IL-15诱导STAT5磷酸化具有明显的抑制作用。

Claims (12)

  1. 一种具有通式(I)所示结构的化合物、其对映异构体或非对映异构体或其混合物、其药学上可接受的盐、溶剂合物、阻转异构体、同位素标记的衍生物、结晶形式或前药：
    Figure PCTCN2022076138-appb-100001
    其中，X独立地选自N，CH或CCN；
    R独立地选自氢、氘、氟、氯、氰基、C1-C8炔基、C1-C8卤代炔基、C3-C5环烷基取代炔基、亚甲基氧烷基取代炔基、亚甲基氧卤代烷基取代炔基、5-6元芳环或杂芳环取代炔基、C1-C6线性或支链烷基、C1-C6线性或支链烷氧基亚甲基、卤代C1-C6线性或支链烷氧基亚甲基、C1-C6线性或支链烷氧基二氟亚甲基、卤代C1-C6线性或支链烷氧基二氟亚甲基、C1-C6线性或支链烷氧基氟代亚甲基、卤代C1-C6线性或支链烷氧基氟代亚甲基、C3-C6环烷基、C3-C6烷基取代环烷基、C3-C6卤素取代环烷基、C6-C10芳基、包含5-和/或6-元环的单环或双环杂芳基、(芳基)C1-C6线性或支链烷基、(杂芳基)C1-C6线性或支链烷基、(杂环基)C1-C6线性或支链烷基、(C1-C6线性或支链烷基)芳基、(C1-C6线性或支链烷基)杂芳基、(C1-C6线性或支链烷基)杂环基、C1-C6线性或支链全氟烷基、C1-C6线性或支链烷氧基、C1-C6线性或支链全氟烷氧基、异丙基羰基、叔丁基羰基、氨基、羧基、氨基羰基、(C1-C6线性或支链烷基)氨基羰基氨基、(C1-C6线性或支链烷基)氨基羰基、乙氧基羰基、异丙氧基羰基、异丁氧基羰基；其中所述烷基、芳基和杂芳基独立任选地被选自下列的一个或多个取代基取代：烷基、卤素、羟基、甲氧基、氨基、氰基、烷基氨基、二烷基氨基、CF3、氨基羰基、(C1-C6线性或支链烷基)氨基羰基和C3-C6环烷基。
  2. 根据权利要求1所述的化合物、其对映异构体或非对映异构体或其混合物、其药学上可接受的盐、溶剂合物、阻转异构体、同位素标记的衍生物、结晶形式或前药，当X为N时，具有如下式(II)所示结构：
    Figure PCTCN2022076138-appb-100002
    其中，R独立地选自氢、氘、氟、氯、氰基、C1-C8炔基、C1-C8卤代炔基、C3-C5环烷基取代炔基、亚甲基氧烷基取代炔基、亚甲基氧卤代烷基取代炔基、5-6元芳环或杂芳环取代炔基、C1-C6线性或支链烷基、C1-C6线性或支链烷氧基亚甲基、卤代C1-C6线性或支链烷氧基亚甲基、C1-C6线性或支链烷氧基二氟亚甲基、卤代C1-C6线性或支链烷氧基二氟亚甲基、C1-C6线性或支链烷氧基氟代亚甲基、卤代C1-C6线性或支链烷氧基氟代亚甲基、C3-C6环烷基、C3-C6烷基取代环烷基、C3-C6卤素取代环烷基、C6-C10芳基、包含5-和/或6-元环的单环或双环杂芳基、(芳基)C1-C6线性或支链烷基、(杂芳基)C1-C6线性或支链烷基、(杂环基)C1-C6线性或支链烷基、(C1-C6线性或支链烷基)芳基、(C1-C6线性或支链烷基)杂芳基、(C1-C6线性或支链烷基)杂环基、C1-C6线性或支链全氟烷基、C1-C6线性或支链烷氧基、C1-C6线性或支链全氟烷氧基、异丙基羰基、叔丁基羰基、氨基、羧基、氨基羰基、(C1-C6线性或支链烷基)氨基羰基氨基、(C1-C6线性或支链烷基)氨基羰基、乙氧基羰基、异丙氧基羰基、异丁氧基羰基；其中所述烷基、芳基和杂芳基独立任选地被选自下列的一个或多个取代基取代：烷基、卤素、羟基、甲氧基、氨基、氰基、烷基氨基、二烷基氨基、CF3、氨基羰基、(C1-C6线性或支链烷基)氨基羰基和C3-C6环烷基。
  3. 根据权利要求1所述的化合物、其对映异构体或非对映异构体或其混合物、其药学上可接受的盐、溶剂合物、阻转异构体、同位素标记的衍生物、结晶形式或前药，当X为CH时，具有如下式(III)所示结构：
    Figure PCTCN2022076138-appb-100003
    其中，R独立地选自氢、氘、氟、氯、氰基、C1-C8炔基、C1-C8卤代炔基、C3-C5环烷基取代炔基、亚甲基氧烷基取代炔基、亚甲基氧卤代烷基取代炔基、5-6元芳环或杂芳环取代炔基、C1-C6线性或支链烷基、C1-C6线性或支链烷氧基亚甲基、卤代C1-C6线性或支链烷氧基亚甲基、C1-C6线性或支链烷氧基二氟亚甲基、卤代C1-C6线性或支链烷氧基二氟亚甲基、C1-C6线性或支链烷氧基氟代亚甲基、卤代C1-C6线性或支链烷氧基氟代亚甲基、C3-C6环烷基、C3-C6烷基取代环烷基、C3-C6卤素取代环烷基、C6-C10芳基、包含5-和/或6-元环的单环或双环杂芳基、(芳基)C1-C6线性或支链烷基、(杂芳基)C1-C6线性或支链烷基、(杂环基)C1-C6线性或支链烷基、(C1-C6线性或支链烷基)芳基、(C1-C6线性或支链烷基)杂芳基、(C1-C6线性或支链烷基)杂环基、C1-C6线性或支链全氟烷基、C1-C6线性或支链烷氧基、C1-C6线性或支链全氟烷氧基、异丙基羰基、叔丁基羰基、氨基、羧基、氨基羰基、(C1-C6线性或支链烷基)氨基羰基氨基、(C1-C6线性或支链烷基)氨基羰基、乙氧基羰基、异丙氧基羰基、异丁氧基羰基；其中所述烷基、芳基和杂芳基独立任选地被选自下列的一个或多个取代基取代：烷基、卤素、羟基、甲氧基、氨基、氰基、烷基氨基、二烷基氨基、CF3、氨基羰基、(C1-C6线性或支链烷基)氨基羰基和C3-C6环烷基。
  4. 根据权利要求1所述的化合物、其对映异构体或非对映异构体或其混合物、其药学上可接受的盐、溶剂合物、阻转异构体、同位素标记的衍生物、结晶形式或前药，当X为CCN时，具有如下式(IV)所示结构：
    Figure PCTCN2022076138-appb-100004
    其中，R独立地选自氢、氘、氟、氯、氰基、C1-C8炔基、C1-C8卤代炔基、C3-C5环烷基取代炔基、亚甲基氧烷基取代炔基、亚甲基氧卤代烷基取代炔基、5-6元芳环或杂芳环取代炔基、C1-C6线性或支链烷基、C1-C6线性或支链烷氧基亚甲基、卤代C1-C6线性或支链烷氧基亚甲基、C1-C6线性或支链烷氧基二氟亚甲基、卤代C1-C6线性或支链烷氧基 二氟亚甲基、C1-C6线性或支链烷氧基氟代亚甲基、卤代C1-C6线性或支链烷氧基氟代亚甲基、C3-C6环烷基、C3-C6烷基取代环烷基、C3-C6卤素取代环烷基、C6-C10芳基、包含5-和/或6-元环的单环或双环杂芳基、(芳基)C1-C6线性或支链烷基、(杂芳基)C1-C6线性或支链烷基、(杂环基)C1-C6线性或支链烷基、(C1-C6线性或支链烷基)芳基、(C1-C6线性或支链烷基)杂芳基、(C1-C6线性或支链烷基)杂环基、C1-C6线性或支链全氟烷基、C1-C6线性或支链烷氧基、C1-C6线性或支链全氟烷氧基、异丙基羰基、叔丁基羰基、氨基、羧基、氨基羰基、(C1-C6线性或支链烷基)氨基羰基氨基、(C1-C6线性或支链烷基)氨基羰基、乙氧基羰基、异丙氧基羰基、异丁氧基羰基；其中所述烷基、芳基和杂芳基独立任选地被选自下列的一个或多个取代基取代：烷基、卤素、羟基、甲氧基、氨基、氰基、烷基氨基、二烷基氨基、CF3、氨基羰基、(C1-C6线性或支链烷基)氨基羰基和C3-C6环烷基。
  5. 根据权利要求1-4中任意一项所述的化合物,其对映异构体或非对映异构体或其混合物、其药学上可接受的盐、溶剂合物、阻转异构体、同位素标记的衍生物、结晶形式或前药，包括以下化合物：
    Figure PCTCN2022076138-appb-100005
  6. 一种药物组合物，所述药物组合物包含如权利要求1至5中任一项所述的化合物、其药学上可接受的盐、溶剂合物、阻转异构体、同位素标记的衍生物、结晶形式或前药，以及药学上可接受的辅料、稀释剂或载体。
  7. 根据权利要求1-5中任意一项所述的化合物、其药学上可接受的盐、溶剂合物、阻转异 构体、同位素标记的衍生物、结晶形式或前药或者根据权利要求6所述的药物组合物在制备用于治疗或预防病症或病况的药物中的用途，所述病症或病况选自白癜风、脱发、类风湿性关节炎、包括克罗恩氏病和溃疡性结肠炎的炎性肠病、直肠炎、嗜酸细胞性胃肠炎或肥大细胞增多症、肌炎、血管炎、天疱疮、大疱性类天疱疮、狼疮、肾炎、***性红斑狼疮、银屑病、湿疹皮炎、瘙痒症或其它瘙痒病况、自身免疫性甲状腺病、多发性硬化、哮喘、干燥病、***性硬化病、结节性多动脉炎、干眼综合征、交感性眼炎、器官移植排斥、移植物抗宿主病、自身免疫性脱发慢性阻塞性肺病、急性呼吸道疾病、包括下列的眼疾病、病症或病况：眼的自身免疫疾病、角膜结膜炎、春季结膜炎、包括与贝切特氏病相关的葡萄膜炎和晶状体诱发性葡萄膜炎的葡萄膜炎、角膜炎、疱疹性角膜炎、圆锥形角膜炎、角膜白斑、眼天疱疮、干燥性角膜结膜炎(干眼症)、虹膜睫状体炎、结节病、内分泌性眼病、交感性眼炎、变应性结膜炎。
  8. 一种治疗病症或病况的方法，包括将权利要求1-5中任意一项所述的化合物、其药学上可接受的盐、溶剂合物、阻转异构体、同位素标记的衍生物、结晶形式或前药或者根据权利要求6所述的药物组合物给予有需要的受试者，其中，所述病症或病况选自白癜风、脱发、类风湿性关节炎、包括克罗恩氏病和溃疡性结肠炎的炎性肠病、直肠炎、嗜酸细胞性胃肠炎或肥大细胞增多症、肌炎、血管炎、天疱疮、大疱性类天疱疮、狼疮、肾炎、***性红斑狼疮、银屑病、湿疹皮炎、瘙痒症或其它瘙痒病况、自身免疫性甲状腺病、多发性硬化、哮喘、干燥病、***性硬化病、结节性多动脉炎、干眼综合征、交感性眼炎、器官移植排斥、移植物抗宿主病、自身免疫性脱发慢性阻塞性肺病、急性呼吸道疾病、包括下列的眼疾病、病症或病况：眼的自身免疫疾病、角膜结膜炎、春季结膜炎、包括与贝切特氏病相关的葡萄膜炎和晶状体诱发性葡萄膜炎的葡萄膜炎、角膜炎、疱疹性角膜炎、圆锥形角膜炎、角膜白斑、眼天疱疮、干燥性角膜结膜炎(干眼症)、虹膜睫状体炎、结节病、内分泌性眼病、交感性眼炎、变应性结膜炎。
  9. 根据权利要求7所述的用途或权利要求8所述的方法，其中，所述病症或病况为炎性肠病。
  10. 根据权利要求7所述的用途或权利要求8所述的方法，其中，所述病症或病况为类风湿性关节炎。
  11. 根据权利要求7所述的用途或权利要求8所述的方法，其中，所述病症或病况为脱发。
  12. 根据权利要求7所述的用途或权利要求8所述的方法，其中，所述病症或病况为白癜风。
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