WO2023151069A1 - Dérivé à noyau hétéroaromatique à six chaînons de pyrrolo[2,3-d], son procédé de préparation et son utilisation pharmaceutique - Google Patents

Dérivé à noyau hétéroaromatique à six chaînons de pyrrolo[2,3-d], son procédé de préparation et son utilisation pharmaceutique 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
compound
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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 PCT/CN2022/076138 priority Critical patent/WO2023151069A1/fr
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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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • 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 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

L'invention concerne un dérivé à noyau hétéroaromatique à six chaînons de pyrrolo[2,3-d] de formule générale (I), lequel dérivé a une activité inhibitrice sur la janus kinase (JAK), en particulier, a une activité inhibitrice sélective et relativement élevée sur la kinase JAK3, et a une excellente capacité d'absorption par voie orale. La présente invention concerne également un procédé de préparation d'un tel composé, et une composition pharmaceutique le contenant et une méthode de traitement l'utilisant. Le composé peut être administré sous forme de médicament, basé sur l'effet inhibiteur de JAK3, utile pour prévenir et/ou traiter des maladies associées ayant une expression anormale de JAK3.
PCT/CN2022/076138 2022-02-14 2022-02-14 Dérivé à noyau hétéroaromatique à six chaînons de pyrrolo[2,3-d], son procédé de préparation et son utilisation pharmaceutique WO2023151069A1 (fr)

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PCT/CN2022/076138 WO2023151069A1 (fr) 2022-02-14 2022-02-14 Dérivé à noyau hétéroaromatique à six chaînons de pyrrolo[2,3-d], son procédé de préparation et son utilisation pharmaceutique
CN202310064329.3A CN116003417A (zh) 2022-02-14 2023-02-06 吡咯并[2,3-d]六员杂芳环衍生物、其制备方法和药物用途

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