WO2020057669A1 - 一类具有激酶抑制活性的芳香杂环类化合物 - Google Patents

一类具有激酶抑制活性的芳香杂环类化合物 Download PDF

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WO2020057669A1
WO2020057669A1 PCT/CN2019/107381 CN2019107381W WO2020057669A1 WO 2020057669 A1 WO2020057669 A1 WO 2020057669A1 CN 2019107381 W CN2019107381 W CN 2019107381W WO 2020057669 A1 WO2020057669 A1 WO 2020057669A1
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group
substituted
unsubstituted
mmol
compound
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PCT/CN2019/107381
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English (en)
French (fr)
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江磊
邓建稳
冯志勇
刘胜洋
毛旭东
尚珂
寿建勇
吴淡宜
谢小平
徐圆
赵海霞
张建华
郑明伟
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上海轶诺药业有限公司
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Priority claimed from CN201811110497.7A external-priority patent/CN110938071A/zh
Priority claimed from CN201811109355.9A external-priority patent/CN110938070A/zh
Application filed by 上海轶诺药业有限公司 filed Critical 上海轶诺药业有限公司
Priority to EA202190725A priority Critical patent/EA202190725A1/ru
Priority to KR1020217011954A priority patent/KR20210095621A/ko
Priority to JP2021540358A priority patent/JP7349750B2/ja
Priority to EP19862324.1A priority patent/EP3854793A4/en
Priority to AU2019344878A priority patent/AU2019344878B2/en
Priority to CN201980062159.7A priority patent/CN112823159B/zh
Priority to US17/278,405 priority patent/US20210371415A1/en
Priority to CA3113732A priority patent/CA3113732C/en
Publication of WO2020057669A1 publication Critical patent/WO2020057669A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present invention relates to the field of small molecule drugs, and in particular, the present invention relates to a kinase inhibitor and its preparation and use.
  • Janus kinase is a cytoplasmic tyrosine protein kinase responsible for transducing many inflammation-related cytokine signals from cytokine membrane receptors to STAT transcription factors. It is generally considered to include four main family members: JAK1, JAK2, JAK3, and TYK2. When a specific cytokine binds to its receptor, members of the JAK family coupled to the receptor undergo autophosphorylation and / or transphosphorylation with each other, and subsequently phosphorylate the substrate protein STATs, and the phosphorylated STAT migrates to the nuclear regulation Transcription, thereby transmitting extracellular signals into the cell.
  • JAK1, JAK2, JAK3, and TYK2 members of the JAK family coupled to the receptor undergo autophosphorylation and / or transphosphorylation with each other, and subsequently phosphorylate the substrate protein STATs, and the phosphorylated STAT migrates to the nuclear regulation Transcription, thereby transmitting extracellular signals into the cell.
  • JAK-STAT intracellular signal transduction pathway is the core signal transduction pathway related to immune and inflammatory response in the body. JAK-STAT is an important signal that mediates interferon IFN, most interleukin IL, and a variety of cytokines and endocrine factors such as EPO, TPO, GH, and GM-CSF.
  • Abnormal JAK / STAT signal transduction is related to many diseases. It is involved in immune inflammation-related diseases such as organ transplant rejection, multiple sclerosis, rheumatoid arthritis, type I diabetes, lupus, psoriasis, asthma, food allergies, special diseases. Atopic dermatitis, rhinitis, rash, etc .; there are also reports and development of solid and hematological malignancies and myeloproliferative disorders (including lung cancer, breast cancer, chronic spontaneous myelofibrosis, erythrocytosis, idiopathic thrombocytosis, etc.) closely related.
  • JAK kinase inhibitors provide a new way to treat JAK-related diseases such as inflammatory diseases, autoimmune diseases, myeloproliferative diseases, and cancer by blocking JAK-related signal transduction.
  • JAK kinase inhibitors have been approved by the FDA for the treatment of rheumatoid arthritis and other diseases.
  • patients taking these drugs can have some adverse reactions, such as anemia, possible severe infections, and risk of heart failure. Therefore, it is desirable to develop inhibitors with better JAK selectivity or pharmacokinetic properties or safer inhibitors to effectively treat JAK-STAT-related diseases.
  • the object of the present invention is to provide a JAK kinase inhibitor and its preparation and use.
  • X 1 , X 2 , X 3 and X 4 are each independently CH or N; and at least one of X 1 , X 2 , X 3 and X 4 is N;
  • the ring is selected from the group consisting of a 6-10 membered aromatic ring, or a 5-10 membered heteroaromatic ring;
  • R 4 and R 5 are each independently selected from the group consisting of H, halogen, CN, substituted or unsubstituted C1-C6 alkyl;
  • R 7 , R 8 , R 9 , R 10 , R 11 , R 12 are each independently selected from the group consisting of: H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, Substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 5-12 membered heterocyclic group having 1-3 heteroatoms selected from the group N, S and O;
  • each chiral center is in an R configuration or an S configuration.
  • the 5-12 membered heteroaromatic ring is selected from the group consisting of pyridine ring, pyrimidine ring, pyridazine ring, tetrazine ring, triazine ring, pyrrole ring, thiophene ring, furan ring, Azazole ring, triazole ring, imidazole ring, thiazole ring, oxazole ring, pyrazole ring, isothiazole ring, isoxazole ring, oxadiazole ring, thiadiazole ring.
  • the compound of formula I has a structure represented by the following formula Ia or Ib:
  • R 7 is selected from the group consisting of H, a substituted or unsubstituted C1-C6 alkyl group, and a substituted or unsubstituted C3-C8 cycloalkyl group.
  • the compound of formula I has a structure selected from the group consisting of:
  • the compound has a structure represented by the following formula II:
  • R 6a is selected from the group consisting of: H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy;
  • R 7a , R 8a , R 9a , R 10a is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C1-C6 alkyl;
  • R 11a is selected from the group consisting of hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 amine;
  • R 7a , R 8a , R 9a , R 10a and R 11a are connected to form-(CH 2 ) n- :
  • substitution means that one or more hydrogen atoms on the group are substituted with a substituent selected from the group consisting of halogen, hydroxyl, substituted or unsubstituted C1-C6 alkoxy.
  • R 7a , R 8a , R 9a , and R 10a are selected from the group consisting of hydrogen and methyl;
  • the R 11a is selected from the group consisting of methyl, ethyl, hydroxyethyl, methoxyethyl, and halogenated C1-C6 alkyl.
  • R 4 is H
  • R 5 is methyl
  • R 1 is selected from the group consisting of methyl and ethyl.
  • R 2 is selected from the group consisting of methyl, ethyl, methoxy, and ethoxy.
  • R 3 and R 4 are each independently hydrogen.
  • R 5 is selected from the group consisting of hydrogen, methyl, chlorine, fluorine, bromine, and trifluoromethyl.
  • R 6 is selected from the group consisting of 3,3,3-trifluoro-2-hydroxypropyl and 2- (4-methylpiperazin-1-yl) butyryl.
  • the compound of formula I is selected from the following group:
  • a pharmaceutical composition comprising (1) the compound according to the first aspect of the present invention or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof , Hydrate or solvate; (2) a pharmaceutically acceptable carrier.
  • the pharmaceutical composition is an injection, a capsule, a tablet, a pill, a powder, or a granule.
  • the pharmaceutical composition further contains another therapeutic drug, and the additional therapeutic drug is cancer, cardiovascular disease, inflammation, immune disease, bone marrow proliferative disease, viral disease, metabolism Drugs for sexually transmitted diseases or organ transplants.
  • the additional therapeutic agents include (but are not limited to): 5-fluorouracil, Avastin TM (avastin, bevacizumab), bexarotene (for bexarotene), bortezomib (bortezomib), ossification Calcitriol, canertinib, capecitabine, carboplatin, celecoxib, cetuximab, cisplatin , Dasatinib, digoxin, enzastaurin, Erlotinib, etoposide, everolimus, fulvestrant, agile Gefitinib, 2,2-difluorodeoxycytosine nucleoside (gemcitabine), genistein, imatinib, irinotecan, lapatinib (lapatinib), lenalidomide, letrozole, leucovorin, matuzumab, oxaliplatin, paclitaxel, paclitaxel
  • a compound according to the first aspect of the present invention or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or
  • the use of the pharmaceutical composition according to the second aspect of the present invention is for preparing a pharmaceutical composition for preventing and / or treating a disease related to the activity or expression level of JAK kinase.
  • the disease is selected from the group consisting of cancer, cardiovascular disease, inflammation, immune or inflammatory disease, bone marrow proliferative disease, viral disease, metabolic disease, or organ transplant.
  • the cancer includes (but is not limited to): non-small cell lung cancer, uterine cancer, rectal cancer, colon cancer, brain cancer, head cancer, neck cancer, bladder cancer, prostate cancer, breast cancer , Kidney, blood, liver, stomach, thyroid, nasopharyngeal, or pancreatic cancer.
  • the myeloproliferative diseases include (but are not limited to): spontaneous thrombocytosis (ET), idiopathic myelofibrosis (IMF), chronic myelogenous leukemia (CML), primary Bone marrow fibrosis, chronic neutrophil leukemia (CNL), or true erythrocytosis (PV).
  • EGF spontaneous thrombocytosis
  • IMF idiopathic myelofibrosis
  • CML chronic myelogenous leukemia
  • CML chronic myelogenous leukemia
  • CML chronic neutrophil leukemia
  • PV true erythrocytosis
  • the immune or inflammatory diseases include (but are not limited to): rheumatoid arthritis, osteoarthritis, rheumatoid spondylitis, gout, asthma, bronchitis, rhinitis, chronic obstruction Pulmonary disease, pulmonary fibrosis, cystic fibrosis, enteritis.
  • the metabolic diseases include (but are not limited to): type 2 diabetes, type 1 diabetes, diabetic complications (such as diabetic nephropathy, diabetic retinopathy, non-alcoholic steatohepatitis, liver fibers , Insulin resistance, obesity).
  • type 2 diabetes type 1 diabetes
  • diabetic complications such as diabetic nephropathy, diabetic retinopathy, non-alcoholic steatohepatitis, liver fibers , Insulin resistance, obesity.
  • a JAK inhibitor comprising the compound described in the first aspect of the present invention, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable Salt, hydrate or solvate.
  • the JAK inhibitor selectively inhibits one or more JAK kinases selected from the group consisting of JAK1, JAK2, JAK3, or Tyk2.
  • the JAK inhibitor is a JAK1 highly selective inhibitor.
  • the term “about” means that the value can vary from the recited value by no more than 1%.
  • the expression “about 100” includes all values between 99 and 101 and (eg, 99.1, 99.2, 99.3, 99.4, etc.).
  • the terms "containing” or “including (comprising)” may be open, semi-closed, and closed. In other words, the term also includes “consisting essentially of” or “consisting of”.
  • alkyl includes linear or branched alkyl groups.
  • C 1 -C 8 alkyl means a straight or branched chain alkyl group having 1 to 8 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl Wait.
  • alkenyl includes linear or branched alkenyl.
  • C 2 -C 6 alkenyl refers to a straight or branched chain alkenyl group having 2 to 6 carbon atoms, such as vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2 -Butenyl, or a similar group.
  • alkynyl includes straight or branched chain alkynyl.
  • C 2 -C 6 alkynyl refers to a straight or branched chain alkynyl group having 2 to 6 carbon atoms, such as ethynyl, propynyl, butynyl, or similar groups.
  • C 3 -C 8 cycloalkyl refers to a cycloalkyl group having 3 to 8 carbon atoms. It may be a monocyclic ring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or similar groups. It can also be in the form of a bicyclic ring, such as a bridge ring or a spiro ring.
  • C 1 -C 8 alkoxy refers to a straight or branched chain alkoxy group having 1 to 8 carbon atoms; for example, methoxy, ethoxy, propoxy, iso Propoxy, butoxy, isobutoxy, tert-butoxy and the like.
  • a 3-10 membered heterocycloalkyl group having 1-3 heteroatoms selected from the group N, S and O refers to a group having 3-10 atoms and wherein 1-3 atoms are A saturated or partially saturated cyclic group of a heteroatom selected from the group N, S and O. It can be monocyclic or bicyclic, such as bridge or spiro. Specific examples may be oxetane, azetidine, tetrahydro-2H-pyranyl, piperidinyl, tetrahydrofuranyl, morpholinyl, pyrrolidinyl, and the like.
  • C 6 -C 10 aryl refers to an aryl group having 6 to 10 carbon atoms, such as a phenyl or naphthyl group and the like.
  • the term "5- to 10-membered heteroaryl having 1-3 heteroatoms selected from the group N, S, and O" refers to having 5-10 atoms and wherein 1-3 atoms are selected from A heterocyclic ring aromatic group of the lower groups N, S and O. It can be monocyclic or fused ring.
  • pyridyl pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3) -triazolyl, and (1,2,3) 4) -Triazolyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, and the like.
  • the groups of the present invention may be substituted with a substituent selected from the group consisting of halogen, nitrile, nitro, hydroxyl, amino, C 1 -C 6 alkyl-amine, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, halo C 1 -C 6 alkyl, halo C 2 -C 6 alkenyl, halo C 2 -C 6 alkynyl, halo C 1 -C 6 alkoxy, allyl, benzyl, C 6 -C 12 aryl, C 1 -C 6 alkoxy-C 1 -C 6 alkyl , C 1 -C 6 alkoxy-carbonyl, phenoxycarbonyl, C 2 -C 6 alkynyl-carbonyl, C 2 -C 6 alkenyl-carbonyl, C 3 -C 6 cycl
  • halogen or halogen atom refers to F, Cl, Br, and I. More preferably, the halogen or halogen atom is selected from F, Cl and Br. "Halogenated” means substituted with an atom selected from F, Cl, Br, and I.
  • the structural formulae described herein are intended to include all isomeric forms (such as enantiomers, diastereomers, and geometric isomers (or conformers)): for example, containing asymmetry R, S configuration of the center, (Z), (E) isomers of double bonds, etc. Therefore, a single stereochemical isomer of a compound of the present invention or a mixture of enantiomers, diastereomers or geometric isomers (or conformers) thereof is within the scope of the present invention.
  • tautomers means that structural isomers with different energies can exceed low energy barriers, thereby converting each other.
  • proton tautomers ie, proton shifts
  • Valence tautomers include interconversions through the reorganization of some bonding electrons.
  • solvate refers to a complex of a compound of the present invention coordinated with a solvent molecule to form a specific ratio.
  • the present invention provides a compound represented by the following formula I:
  • X 1 , X 2 , X 3 and X 4 are each independently CH or N; and at least one of X 1 , X 2 , X 3 and X 4 is N;
  • R 1 and R 3 are each independently selected from the group consisting of H, substituted or unsubstituted C1-C6 alkyl;
  • R 2 is selected from the group consisting of: H, halogen, CN, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy;
  • R 4 and R 5 are each independently selected from the group consisting of H, halogen, CN, substituted or unsubstituted C1-C6 alkyl;
  • R 7 , R 8 , R 9 , R 10 , R 11 , R 12 are each independently selected from the group consisting of: H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, Substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 5-12 membered heterocyclic group having 1-3 heteroatoms selected from the group N, S and O;
  • each chiral center is in an R configuration or an S configuration.
  • X 1 , X 2 , X 3 , X 4 , R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are each independently the corresponding group of the compound in the embodiment.
  • the compound of formula I of the present invention is selected from the following table:
  • the compound of the present invention can be used as a JAK kinase inhibitor, and in a preferred embodiment, it is a JAK kinase selective inhibitor, for example, selectively inhibits one or more of JAK1, JAK2, JAK3, or Tyk2. In a preferred embodiment of the present invention, the JAK inhibitor inhibits JAK1 with high selectivity.
  • the compounds of formula I of the present invention can be prepared by the following methods:
  • the pharmaceutical composition can be used to prevent and / or treat a disease (eg, cancer) related to JAK kinase activity or expression.
  • a disease eg, cancer
  • the pharmaceutical composition of the present invention comprises the compound of the present invention in a safe and effective amount and a pharmaceutically acceptable excipient or carrier.
  • safe and effective amount is meant that the amount of the compound is sufficient to significantly improve the condition without causing serious side effects.
  • a pharmaceutical composition contains 1-2000 mg of a compound / agent of the invention, and more preferably 10-200 mg of a compound / agent of the invention.
  • the "one dose” is a capsule or tablet.
  • “Pharmaceutically acceptable carrier” refers to one or more compatible solid or liquid fillers or gel substances that are suitable for human use and must be of sufficient purity and low enough toxicity. "Compatibility” here means that the components of the composition can be blended with the compound of the invention and with each other without significantly reducing the pharmacological effect of the compound.
  • pharmaceutically acceptable carriers are cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, and solid lubricants (such as stearic acid).
  • Magnesium stearate calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as Tween ), Wetting agents (such as sodium lauryl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
  • vegetable oils such as soybean oil, sesame oil, peanut oil, olive oil, etc.
  • polyols such as propylene glycol, glycerin, mannitol, sorbitol, etc.
  • emulsifiers such as Tween
  • Wetting agents such as sodium lauryl sulfate
  • the method of administration of the compound or pharmaceutical composition of the present invention is not particularly limited, and representative methods of administration include (but are not limited to): oral, parenteral (intravenous, intramuscular, or subcutaneous).
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) a filler or compatibilizer, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, such as hydroxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; For example, glycerol; (d) disintegrating agents, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) Absorption accelerators, such as quaternary amine compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (
  • Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared using coatings and shell materials, such as casings and other materials known in the art. They may contain opaque agents and the release of the active compound or compounds in such a composition may be released in a certain part of the digestive tract in a delayed manner. Examples of embedding components that can be used are polymeric substances and waxes. If necessary, the active compound may also be microencapsulated with one or more of the aforementioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs.
  • liquid dosage forms may include inert diluents conventionally used in the art, such as water or other solvents, solubilizers, and emulsifiers.
  • inert diluents conventionally used in the art, such as water or other solvents, solubilizers, and emulsifiers.
  • ethanol isopropanol
  • ethyl carbonate ethyl acetate
  • propylene glycol 1
  • 3-butanediol dimethylformamide
  • oils especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures thereof.
  • composition may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweeteners, flavoring agents, and perfumes.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweeteners, flavoring agents, and perfumes.
  • the suspension may contain suspending agents, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these, and the like.
  • suspending agents for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these, and the like.
  • compositions for parenteral injection may include physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • Suitable aqueous and non-aqueous vehicles, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
  • the compounds of the invention may be administered alone or in combination with other pharmaceutically acceptable compounds.
  • the pharmaceutical composition When administered in combination, the pharmaceutical composition also includes one or more other pharmaceutically acceptable compounds.
  • One or more of the other pharmaceutically acceptable compounds may be administered simultaneously, separately or sequentially with a compound of the invention.
  • a safe and effective amount of a compound of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dose when administered is a pharmaceutically considered effective dose.
  • a mammal such as a human
  • the dosage is usually 1 to 2000 mg, preferably 20 to 500 mg.
  • the specific dosage should also consider factors such as the route of administration, the patient's health, etc., which are all within the skill of a skilled physician.
  • Example 1-2 7-chloro-1-toluenesulfonyl-1H-pyrrolo [2,3-c] pyridine
  • Example 1-3 7-chloro-3- (4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl) -1-toluenesulfonyl-1H- Pyrrolo [2,3-c] pyridine
  • Example 1-5 4- (7-chloro-1-toluenesulfonyl-1H-pyrrolo [2,3-c] pyridin-3-yl) -N- (3-methoxy-1-methyl -1H- Pyrazol-4-yl) pyrimidin-2-amine
  • Example 1-5 25 mg, 0.070 mmol
  • (R) -2- (4-methylpiperazin-1-yl) propanamide 36 mg, 0.21 mmol
  • cesium carbonate 69 mg, 0.21 mmol
  • dioxane 1 ml
  • bis (dibenzylideneacetone) palladium 13 mg, 0.014 mmol
  • 4,5-bisdiphenylphosphine-9,9-dimethyl Oxanthracene 16 mg, 0.028 mmol
  • Example 2-1 7-chloro-3- (2-chloro-5-methylpyrimidin-4-yl) -1-tosyl-1H-pyrrolo [2,3-c] pyridine
  • Example 1-3 350 mg, 0.81 mmol
  • 2,4-dichloro-5-methylpyrimidine 264 mg, 1.62 mmol
  • Pd (dppf) Cl2 60 mg, 0.08 mmol
  • sodium carbonate 168 mg, 1.22 mmol
  • Example 2-2 4- (7-Chloro-1H-pyrrolo [2,3-c] pyridin-3-yl) -N- (3-methoxy-1-methyl-1H-pyrazole- 4- ) -5-methylpyrimidin-2-amine
  • Example 2-1 A method similar to Example 1 was obtained from Example 2-1 (365 mg, 0.843 mmol) as a pale yellow solid compound Example 2-2 (25 mg, yield 8%).
  • MS (ESI): m / z 370 [M + H] + .
  • 1H NMR (400MHz, MeOD-d4): ⁇ (ppm) 8.25 (s, 1H), 8.17 (s, 1H), 8.13 (s, 1H), 7.95 (d, J 5.6, 1H), 7.63 (s, 1H), 3.89 (s, 3H), 3.73 (s, 3H), 2.39 (s, 3H).
  • Example 2-2 A white solid (7.8 mg, yield 22%) was obtained from Example 2-2 (25 mg, 0.068 mmol) in a similar manner to Example 1.
  • the target compound was obtained according to the method of Example 2 by replacing the corresponding raw materials.
  • the target compound was obtained according to the method of Example 2 by replacing the corresponding raw materials.
  • the target compound was obtained according to the method of Example 2 by replacing the corresponding raw materials.
  • Tetrahydrofuran (50 mL) was slowly dropped into a three-necked flask containing NaH (3.7 g, 89.9 mmol) at 0 ° C under a nitrogen atmosphere. After completion of the dropwise addition, PMBOH (9.9 g, 71.9 mmol) of tetrahydrofuran (50 mL) was slowly added dropwise to the reaction solution at 0 ° C. After the dropping was completed, the reaction solution was maintained at 0 ° C for 30 minutes. This mixture was slowly dropped into a solution of 17-4 (10.0 g, 59.9 mmol) in tetrahydrofuran (50 mL) at -20 ° C.
  • reaction solution was maintained at -20 ° C to 0 ° C for 1 hour and the reaction was monitored by LC-MS.
  • Example 17-6 5-fluoro-N- (3-methoxy-1-methyl-1H-pyrazol-4-yl) -4-((4-methoxybenzyl) oxo) pyrimidine- 2-amine
  • Example 17-7 5-fluoro-2-((3-methoxy-1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-phenol
  • 17-6 (2.0 g, 5.6 mmol) was added to 4N hydrochloric acid in 1,4 dioxane (20 mL) and stirred at room temperature for 30 minutes, and the reaction was monitored by LC-MS. After the reaction, the solvent was distilled off under reduced pressure. The crude product was added to ethyl acetate (20 mL) and recrystallized to obtain 17-7 (1.0 g, 75.0% yield) as a yellow solid.
  • Example 17-8 4-chloro-5-fluoro-N- (3-methoxy-1-methyl-1H-pyrazol-4-yl) pyrimidin-2-amine
  • Example 17-9 4- (7-chloro-1-toluenesulfonyl-1H-pyrrolo [2,3-c] pyridin-3-yl) -5-fluoro-N- (3-methoxy- 1-methyl-1H-pyrazol-4-yl) pyrimidin-2-amine
  • Example 18 N- (3- (2-((3-methoxy-1-methyl-1H-pyrazol-4-yl) amino) -5-methylpyrimidin-4-yl) -1H- Pyridine Pyrro [2,3-c] pyridin-7-yl) -2- (4- (oxbutan-3-yl) piperazin-1-yl) butyramide
  • the target compound was obtained by a method similar to that in Example 2 and replacing the corresponding raw materials.
  • Example 18 N- (3- (2-((3-methoxy-1-methyl-1H-pyrazol-4-yl) amino) -5-methylpyrimidin-4-yl) -1H- Pyridine Pyrro [2,3-c] pyridin-7-yl) -2- (4- (oxbutan-3-yl) piperazin-1-yl) butyramide
  • Example 19-2 7-chloro-3-iodo-1H-pyrrolo [2,3-c] pyridine
  • Example 1-3 7-chloro-3- (4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl) -1-toluenesulfonyl-1H- Pyrrolo [2,3-c] pyridine
  • Tetrahydrofuran (100 mL) was slowly dropped into a three-necked flask containing NaH (11.1 g, 277.5 mmol) under a nitrogen atmosphere at 0 ° C.
  • PMBOH (30.0 g, 217.4 mmol) of tetrahydrofuran (100 mL) was slowly added dropwise to the reaction solution at 0 ° C.
  • the reaction solution was maintained at 0 ° C for 30 minutes.
  • This mixture was slowly dropped into a solution of 2,4-dichloro-5-methylpyrimidine 19-5 (30.0 g, 84.0 mmol) in tetrahydrofuran (100 mL) at -20 ° C.
  • reaction solution was maintained at -20 ° C to 0 ° C for 1 hour and the reaction was monitored by LC-MS.
  • the reaction solution was slowly poured into a saturated aqueous ammonium chloride solution (200 mL), extracted with ethyl acetate (200 mL x 2), dried over anhydrous sodium sulfate, and dried.
  • the concentrate was slurried with petroleum ether (300 mL). The white solid was collected, washed with petroleum ether (50ml), and dried to give a white solid 19-6 (27.0g, 55.6% yield).
  • Example 19-7 N- (2-fluoro-3- (methanesulfonyl) phenyl) -4-((4-methoxybenzyl) oxo) -5-methylpyrimidin-2-amine
  • Example 19-8 4-Chloro-N- (2-fluoro-3- (methanesulfonyl) phenyl) -5-methylpyrimidin-2-amine
  • a 19-7 (25.0 g, 60.0 mmol) solution of phosphorus oxychloride (125 ml) was heated to 80 ° C and maintained at this temperature for 3 hours, and the reaction was monitored by LC-MS. After the reaction was completed, the phosphorous oxychloride was dried, and the concentrate was dissolved in dichloromethane (200 ml), and the pH was adjusted to 8 with a saturated sodium bicarbonate solution.
  • Example 19-9 4- (7-chloro-1-toluenesulfonyl-1H-pyrrolo [2,3-c] pyridin-3-yl) -N- (2-fluoro-3- (methanesulfonyl) ) Phenyl) -5-methylpyrimidin-2-amine
  • Example 19-10 4- (7-Chloro-1H-pyrrolo [2,3-c] pyridin-3-yl) -N- (2-fluoro-3- (methanesulfonyl) phenyl) -5 -Methylpyrimidine Pyridin-2-amine
  • Example 20 (5.1 mg, 28%) was obtained as a white solid and Example 21 (4.8 mg, 26%) was obtained as a yellow solid.
  • the target compound was obtained according to the method of Example 19, replacing the corresponding raw materials.
  • Example 23 After the chiral separation, Example 25 and Example 26 were obtained.
  • Example 24 N- (3- (2-((2-fluoro-3- (methanesulfonyl) phenyl) amino) -5-methylpyrimidin-4-yl) -1H-pyrrolo [2,3 -c] Pyridine-7-yl) -2- (7-methyl-2,7-diazaspiro [3.5] nonane-2-yl) butanamide
  • the target compound was obtained in a similar manner to that in Example 19, replacing the corresponding raw materials.
  • Example 27 N- (3- (5-fluoro-2-((2-fluoro-3- (methanesulfonyl) phenyl) amino) pyrimidin-4-yl) -1H-pyrrolo [2,3- c) pyridine Pyridin-7-yl) -2- (4-methylpiperazin-1-yl) butyramide
  • Example 27-1 2-chloro-5-fluoro-4-((4-methoxybenzyl) oxo) pyrimidine
  • Tetrahydrofuran (50 mL) was slowly dropped into a three-necked flask containing NaH (3.7 g, 89.9 mmol) under a nitrogen atmosphere at 0 ° C. After completion of the dropwise addition, PMBOH (9.9 g, 71.9 mmol) of tetrahydrofuran (50 mL) was slowly added dropwise to the reaction solution at 0 ° C. After the dropping was completed, the reaction solution was maintained at 0 ° C for 30 minutes. This mixture was slowly dropped into a solution of 2,4-dichloro-5-fluoropyrimidine (10.0 g, 59.9 mmol) in tetrahydrofuran (50 mL) at -20 ° C.
  • reaction solution was maintained at -20 ° C to 0 ° C for 1 hour and the reaction was monitored by LC-MS.
  • the reaction solution was slowly poured into a saturated aqueous ammonium chloride solution (100 mL), extracted with ethyl acetate (100 mL x 2), dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
  • Example 27-2 5-Fluoro-N- (2-fluoro-3- (methanesulfonyl) phenyl) -4-((4-methoxybenzyl) oxo) pyrimidin-2-amine
  • Example 27-4 4-chloro-5-fluoro-N- (2-fluoro-3- (methanesulfonyl) phenyl) pyrimidin-2-amine
  • Example 27-5 4- (7-chloro-1-toluenesulfonyl-1H-pyrrolo [2,3-c] pyridin-3-yl) -5-fluoro-N- (2-fluoro-3- (Methanesulfonyl) phenyl) pyrimidin-2-amine
  • Example 27-6 4- (7-chloro-1-toluenesulfonyl-1H-pyrrolo [2,3-c] pyridin-3-yl) -5-fluoro-N- (2-fluoro-3- (Methanesulfonyl) phenyl) pyrimidin-2-amine
  • the target compound was obtained by a method similar to that in Example 19-10, replacing the corresponding raw materials.
  • the target compound was obtained in a similar manner to that described in Example 17, replacing the corresponding raw materials.
  • the following target compound was obtained by a method similar to that in Example 27, replacing the corresponding raw materials.
  • Example 29-2 7-bromo-4-chloro-5-((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [3,2-d] pyrimidine
  • reaction solution was stirred at -78 ° C for 30 minutes.
  • a solution of triisopropyl borate (1.41 g, 7.52 mmol) in tetrahydrofuran (2.0 ml).
  • the reaction was stirred at -78 ° C for 1 hour.
  • the reaction was detected by LCMS.
  • the reaction was quenched by the addition of a saturated ammonium chloride (15 ml) solution, and then extracted with ethyl acetate (15 ml x 3). The combined organic phases were successively washed with saturated brine (20 ml) and dried over anhydrous sodium sulfate.
  • Example 29-5 7- (2-((2-fluoro-3- (methanesulfonyl) phenyl) amino) -5-methylpyrimidin-4-yl) -5-((2- (trimethyl Simethicone Alkyl) ethoxy) methyl) -5H-pyrrolo [3,2-d] pyrimidin-4-amine
  • reaction solution was heated to 90 ° C and stirred for 6 hours. The reaction was detected by LCMS. After the reaction solution was cooled to room temperature, ethyl acetate (10 ml ⁇ 2) was added for extraction. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product.
  • Example 29 N- (7- (2-((2-fluoro-3- (methanesulfonyl) phenyl) amino) -5-methylpyrimidin-4-yl) -5-((2- (tri Methylsilyl Alkyl) ethoxy) methyl) -5H-pyrrolo [3,2-d] pyrimidin-4-yl) -2- (4-methylpiperazin-1-yl) butyramide
  • reaction solution was cooled to room temperature, and 7- (2-((2-fluoro-3- (methanesulfonyl) phenyl) amino) -5-methylpyrimidin-4-yl) -5- ( (2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [3,2-d] pyrimidin-4-amine (50 mg, 0.214 mmol).
  • the reaction solution was then heated and stirred in a 90 ° C. oil bath for 8 hours. The reaction was detected by LCMS.
  • Example 30 1- (3- (2-((2-fluoro-3- (methanesulfonyl) phenyl) amino) -5-methylpyrimidin-4-yl) -1H-pyrrolo [2,3 -c] Pyridine-7-yl) -3-isopropylurea
  • Example 30-2 7-chloro-3-iodo-1-(((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-c] pyridine
  • Example 30-3 7-azido-3-iodo-1-(((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-c] pyridine
  • Example 30-4 7-azido-3- (4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl) -1-((2- ( Trimethylsilyl) ethoxy) (Methyl) -1H-pyrrolo [2,3-c] pyridine
  • Example 30-5 4- (7-azido-1-((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-c] pyridine-3 - ) -N- (2-fluoro-3- (methanesulfonyl) phenyl) -5-methylpyrimidin-2-amine
  • reaction solution was heated to 90 ° C and stirred for 6 hours.
  • the reaction was detected by LCMS.
  • Example 30-6 4- (7-azido-1H-pyrrolo [2,3-c] pyridin-3-yl) -N- (2-fluoro-3- (methanesulfonyl) phenyl)- 5-methylpyrimidine-2- amine
  • Example 30-7 3- (2-((2-fluoro-3- (methanesulfonyl) phenyl) amino) -5-methylpyrimidin-4-yl) -1H-pyrrolo [2,3- c] pyridine-7-amine
  • Example 30-8 1- (3- (2-((2-fluoro-3- (methanesulfonyl) phenyl) amino) -5-methylpyrimidin-4-yl) -1H-pyrrolo [2 , 3-c] pyridine-7- Propyl) -3-isopropylurea
  • Example 35-1 1- (2- (benzyloxy) ethyl) piperazine
  • Example 35-4 N- (3-methoxy-1-methyl-1H-pyrazol-4-yl) -4-((4-methoxybenzyl) oxo) -5-methylpyrimidine -2-amine
  • 35-4 (2.0 g, 5.6 mmol) was added to 4N hydrochloric acid in 1,4 dioxane (20 mL) and stirred at room temperature for thirty minutes, and the reaction was monitored by LC-MS. After the reaction was completed, the solvent was distilled off under reduced pressure. The crude product was added to ethyl acetate (20 mL) and recrystallized to obtain 35-5 (1.2 g, 90.6% yield) as a yellow solid.
  • Example 35-6 4-Chloro-N- (3-methoxy-1-methyl-1H-pyrazol-4-yl) -5-methylpyrimidin-2-amine
  • Example 35-7 4- (7-chloro-1-toluenesulfonyl-1H-pyrrolo [2,3-c] pyridin-3-yl) -N- (3-methoxy-1-methyl -1H-pyrazol-4-yl) -5-methylpyrimidin-2-amine
  • Example 35-8 2- (4- (2- (benzyloxy) ethyl) piperazin-1-yl) -N- (3- (2-((3-methoxy-1-methyl -1H-pyrazole -4-yl) amino) -5-methylpyrimidin-4-yl) -1H-pyrrolo [2,3-c] pyridin-7-yl) butyramide
  • Example 36 N- (3- (5-fluoro-2-((3-methoxy-1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) -1H-pyrrole Benzo [2,3-c] pyridin-7-yl) -2- (4- (oxbutan-3-yl) piperazin-1-yl) butanamide
  • the target compound was obtained according to the method of Example 17 by replacing the corresponding raw materials.
  • JAK1 protein was purchased from Thermo Fisher.
  • JAK2 and JAK3 proteins were purchased from Carna Biosciences.
  • HTRFkinEASE and TK kits were purchased from Cisbio and Bioassays.
  • BioTek microplate reader Synergy Neo 2 was used to read the plate.
  • test compound was diluted 4 times in concentration, and the final concentration was 10 ⁇ M to 0.04 nM, 10 concentrations, and two duplicate wells were used for each concentration; the content of DMSO in the detection reaction was 1%.
  • JAK 1 protein kinase 1 ⁇ M TK Substrate-biotin peptide substrate, 1.1 ⁇ M ATP, 1 ⁇ enzymatic buffer, 5 mM MgCl 2 , 1 mM MnCl 2 , 1 mM DTT, 2.5 nM SEB.
  • the detection plate was White Proxiplate 384-Plus plate (PerkinElmer). The reaction was performed at room temperature for 60 minutes, and the reaction system was 10 ⁇ l.
  • Reaction detection Add 10 ⁇ l of detection reagent to the reaction plate, containing a final concentration of 0.125 ⁇ M SA-XL665 and 5 ⁇ l 1 ⁇ TK-Antibody, incubate overnight at room temperature, and read the plate with Synergy Neo 2
  • Biological test example 2 cytology JAK1 / 2 activity test
  • IL-6 stimulation causes phosphorylation of STAT3 primarily through JAK1, while EPO stimulation phosphorylates STAT5 in a JAK2-dependent manner.
  • TF-1 cells were obtained from the American Type Culture Collection (ATCC). TF-1 cells were starved overnight in OptiMEM medium containing 0.5% bovine serum (FBS), 0.1 mM non-essential amino acids (NEAA), 1 mM sodium pyruvate, and 37 ° C non-phenol red (cell density was 100,000 cells / well ). Compounds were serially diluted in DMSO, TF-1 cells were added and incubated at 37 ° C for 20 minutes with a final DMSO concentration of 0.2%. Human recombinant cytokine IL-6 (30 ng / mL) or EPO (10 U / mL) was then added to the wells containing TF-1 cells.
  • FBS bovine serum
  • NEAA non-essential amino acids
  • EPO 10 U / mL
  • IC 50 value is determined as the 50% DMSO control with respect to the measured concentration of compound required to inhibit the phosphorylation of STAT.
  • Detection of compounds for inhibition of JAK1 and JAK2 activity in human whole blood Inhibition analysis of IL-6-induced pSTAT1 levels (CD4 + T cells) and GM-CSF-induced pSTAT5 levels (CD33 + cells) in human whole blood, respectively.
  • the specific experimental steps are as follows:
  • CD-1 mice were administered test compounds intravenously (IV) and orally (PO) separately, blood samples were collected at different time points, and LC-MS / MS was used to determine the concentration of the test substance in mouse plasma and calculate relevant parameters.
  • IV intravenously
  • PO orally
  • LC-MS / MS was used to determine the concentration of the test substance in mouse plasma and calculate relevant parameters.
  • the details are as follows: Take the required amount of the test product and formulate a solution with the required concentration for intravenous injection or oral administration. The animals were about 6-8 weeks old at the start of the dosing experiment. Blood collection time points: 0.083h, 0.25h, 0.5h, 1h, 2h, 4h, 8h and 24h after administration. Establish biological sample analysis methods and sample detection methods. Pharmacokinetic parameters were calculated from the blood drug concentration data at different time points using Phoenix WinNonlin 7.0 software.
  • mice Pharmacokinetics of mice (5mg / kg, P.O.)
  • Example 21 Example 25
  • Example 4 C max ng / mL 264 155 1065 AUC 0-24hr hr * ng / mL 1682 946 10249 T 1/2 hr 2.61 3.57 3.79 F % 97.1 66.1 106

Abstract

本发明提供了一种JAK激酶抑制剂及其制备和用途。具体地，本发明提供了一种如式(I)所示的化合物，其中，各基团的定义如说明书中所述。所述的化合物具有优异的JAK抑制活性，因此可用于制备治疗癌症和其他JAK活性相关疾病的药物组合物。

Description

一类具有激酶抑制活性的芳香杂环类化合物 技术领域
本发明涉及小分子药物领域，具体地，本发明涉及一种激酶抑制剂及其制备和用途。
背景技术
Janus激酶(JAK)是负责转导许多炎症相关细胞因子信号从细胞因子膜受体到STAT转录因子的细胞质酪氨酸蛋白激酶。一般认为主要包括四种家族成员：JAK1、JAK2、JAK3和TYK2。当特定细胞因子与其受体结合时，与该受体偶联的JAK家族成员发生自磷酸化和/或彼此转磷酸化，随后将底物蛋白STATs磷酸化，磷酸化的STAT迁移至细胞核内调节转录，从而将胞外信号传递至胞内。JAK-STAT细胞内信号转导通路是机体内核心的与免疫，炎症反应相关的信号转导通路。JAK-STAT是介导了干扰素IFN、大多数白细胞介素IL以及多种细胞因子和内分泌因子，如EPO、TP0、GH和GM-CSF等的重要信号传递。
JAK/STAT信号转导异常与许多疾病有关，参与免疫炎症相关的疾病如器官移植排斥反应、多发性硬化、类风湿性关节炎、I型糖尿病、狼疮、银屑病、哮喘、食物过敏、特应性皮炎和鼻炎、皮疹等；也有报道和实体和血液恶性肿瘤以及骨髓增生障碍(包括肺癌、乳腺癌、慢性自发性骨髓纤维变性、红细胞增多症、特发性血小板增多症等)的发生发展密切相关。
JAK激酶抑制剂通过阻断JAK相关信号转导为炎性疾病、自身免疫病、骨髓增殖性疾病和癌症等JAK相关性疾病的治疗提供新的途径。譬如目前已有JAK激酶抑制剂被FDA批准用于治疗类风湿性关节炎等疾病。然而，患者服用这些药物后会产生一些不良反应，例如贫血、可能的严重感染及和心脏衰竭风险。因此，期望开发具有更好的JAK选择性或药物代谢动力学性质的抑制剂或安全性更好的抑制剂，有效地治疗JAK-STAT相关疾病。
综上所述，本领域迫切需要开发新型的JAK选择性抑制剂。
发明内容
本发明的目的是提供一种JAK激酶抑制剂及其制备和用途。
本发明的第一方面，提供了一种如下式I所示的化合物：
Figure PCTCN2019107381-appb-000001
其中，
X 1、X 2、X 3和X 4各自独立地为CH或N；且X 1、X 2、X 3和X 4中至少有一个为N；
Figure PCTCN2019107381-appb-000002
环选自下组：6-10元芳香环，或5-10元的杂芳环；
R 1独立地选自下组：H、取代或未取代的C1-C6烷基、取代或未取代的3-6元杂环基(其包括1-3个选自N、O或S的杂原子)、-S(＝O) 2R 7；
R 2、R 3各自独立地选自下组：H、卤素、CN、取代或未取代的C1-C6烷基、取代或未取代的C1-C6烷氧基、取代或未取代的3-6元杂环基(其包括1-3个选自N、O或S的杂原子)、-S(＝O) 2R 7、-NHS(＝O) 2R 7；
R 4、R 5各自独立地选自下组：H、卤素、CN、取代或未取代的C1-C6烷基；
R 6选自下组：H、取代或未取代的C1-C6烷基、R 7-C(＝O)-、R 8-S(＝O) 2-、R 9R 10N-C(＝O)-、R 11R 12N-S(＝O) 2-、取代或未取代的具有1-3个选自下组N、S和O的杂原子的5-12元杂环基(包括单环、螺环、桥环或并环)、取代或未取代的C6-C10芳基、取代或未取代的具有1-3个选自下组N、S和O的杂原子的5-10元杂芳基；
R 7、R 8、R 9、R 10、R 11、R 12各自独立地选自下组：H、取代或未取代的C1-C6烷基、取代或未取代的C1-C6烷氧基、取代或未取代的C3-C8环烷基、取代或未取代的具有1-3个选自下组N、S和O的杂原子的5-12元杂环基；
除非特别说明，所述的“取代”是指被选自下组的一个或多个(例如2个、3个、4个等)取代基所取代：卤素、C1-C6烷氧基、卤代的C1-C6烷氧基、C3-C8环烷基、卤代的C3-C8环烷基、甲基砜基、氧代(＝O)、-CN、羟基、-NH 2、C1-C6胺基、羧基、C1-C6酰胺基(-C(＝O)-N(Rc) 2或-NH-C(＝O)(Rc)，Rc为H或C1-C5的烷基)、或取代或未取代的选自下组的基团：C1-C6烷基、C6-C10芳基、具有1-3个选自N、S和O的杂原子的5-10元杂芳基、-(CH 2)-C6-C10芳基、-(CH 2)-(具有1-3个选自N、S和O的杂原子的5-10元杂芳基)、-(具有1-3个选自N、S和O的杂原子的5-10元亚杂芳基)-(C1-C6烷基)、具有1-3个选自下组N、S和O的杂原子的5-12元杂环基(包括单环、螺环、桥环或并环)，且所述的取代基选自下组：卤素、C1-C6烷基、C1-C6亚烷基-OH、C1-C6烷氧基、氧代、-S(O) 2CH 3、-CN、-OH、C6-C10芳基、具有1-3个选自N、S和O的杂原子的3-10元杂芳基、-C(O)CHNH 2、-C(O)CHOH；
且所述的式I化合物中，各个手性中心为R构型或S构型。
在另一优选例中，所述的5-12元杂芳环选自下组：吡啶环、嘧啶环、哒嗪环、四嗪环、三嗪环、吡咯环、噻吩环、呋喃环、四氮唑环、三氮唑环、咪唑环、噻唑环、恶唑环、吡唑环、异噻唑环、异恶唑环、恶二唑环、噻二唑环。
在另一优选例中，所述的式I化合物具有如下式Ia或式Ib所示的结构：
Figure PCTCN2019107381-appb-000003
其中，R 7选自下组：H、取代或未取代的C1-C6烷基、取代或未取代的C3-C8环烷基。
在另一优选例中，所述的式I化合物具有选自下组的结构：
Figure PCTCN2019107381-appb-000004
在另一优选例中，所述的化合物具有如下式II所示的结构：
Figure PCTCN2019107381-appb-000005
其中，
R 6a选自下组：H、取代或未取代的C1-C6烷基、取代或未取代的C1-C6烷氧基；
R 7a、R 8a、R 9a、R 10a选自下组：氢、卤素、取代或未取代的C1-C6烷基；
R 11a选自下组：氢、取代或未取代的C1-C6烷基、取代或未取代的C1-C6烷氧基、取代或未取代的C1-C6胺基；
或所述的R 7a、R 8a、R 9a、R 10a和R 11a中的任意两个基团相连从而形成-(CH 2) n-：
其中，所述的取代指基团上的一个或多个氢原子被选自下组的取代基取代：卤素、羟基、取代或未取代的C1-C6烷氧基。
在另一优选例中，所述的R 7a、R 8a、R 9a、R 10a选自下组：氢、甲基；
所述的R 11a选自下组：甲基、乙基、羟乙基、甲氧基乙基、卤代的C1-C6烷基。
在另一优选例中，所述的R 4为H，且所述的R 5为甲基。
在另一优选例中，R 1选自下组：甲基、乙基。
在另一优选例中，R 2选自下组：甲基、乙基、甲氧基、乙氧基。
在另一优选例中，R 3、R 4各自独立地为氢。
在另一优选例中，R 5选自下组：氢，甲基，氯，氟，溴，三氟甲基。
在另一优选例中，R 6选自下组：3,3,3-三氟-2-羟基丙基、2-(4-甲基哌嗪-1-基)丁酰基。
在另一优选例中，所述的式I化合物选自下组：
Figure PCTCN2019107381-appb-000006
Figure PCTCN2019107381-appb-000007
Figure PCTCN2019107381-appb-000008
Figure PCTCN2019107381-appb-000009
Figure PCTCN2019107381-appb-000010
Figure PCTCN2019107381-appb-000011
本发明的第二方面，提供了一种药物组合物，包含(1)如本发明第一方面所述的化合物或其立体异构体或互变异构体，或其药学上可接受的盐、水合物或溶剂化物；(2)药学上可接受的载体。
在另一优选例中，所述的药物组合物为注射剂、囊剂、片剂、丸剂、散剂或颗粒剂。
在另一优选例中，所述的药物组合物还含有另外的治疗药物，所述的另外的治疗药物为癌症、心血管疾病、炎症、免疫性疾病、骨髓增殖性疾病、病毒性疾病、代谢性疾病、或器官移植的药物。
更佳地，所述的另外的治疗药物包括(但并不限于)：5-氟尿嘧啶、阿瓦斯丁 TM(avastin，bevacizumab)、贝沙罗汀(bexarotene)、硼替佐米(bortezomib)、骨化三醇(calcitriol)、卡奈替尼(canertinib)、卡培他滨(capecitabine)、碳铂(carboplatin)、塞来考昔(celecoxib)、西妥昔单抗(cetuximab)、顺铂(cisplatin)、达沙替尼(dasatinib)、地高辛(digoxin)、enzastaurin、埃罗替尼(Erlotinib)、依托泊甙(etoposide)、依维莫司(everolimus)、氟维司群(fulvestrant)、吉非替尼(gefitinib)、2,2-二氟脱氧胞嘧啶核苷(gemcitabine)、金雀异黄素(genistein)、伊马替尼(imatinib)、依立替康(irinotecan)、拉帕替尼(lapatinib)、来那度胺(lenalidomide)、来曲唑(letrozole)、亚叶酸(leucovorin)、马妥珠单抗(matuzumab)、奥沙利铂(oxaliplatin)、紫杉醇(paclitaxel)、帕尼单抗(panitumumab)、PEG化的粒细胞集落刺激因子(pegfilgrastin)、PEG化的α-干扰素(peglated alfa-interferon)、培美曲塞(pemetrexed)、
Figure PCTCN2019107381-appb-000012
E、沙铂(satraplatin)、西罗莫司(sirolimus)、舒尼替尼(sutent，sunitinib)、舒林酸(sulindac)、泰索帝(taxotere)、替莫唑胺(temodar、temozomolomide)、驮瑞塞尔(Torisel)、替西罗莫司(temsirolimus)、替吡法尼(tipifarnib)、曲妥单抗(trastuzumab)、丙戊酸(valproic acid)、长春氟宁(vinflunine)、Volociximab、Vorinostat、索拉非尼(Sorafenib)、安贝生坦(ambrisentan)、CD40和/或CD154特异性抗体、融合蛋白、NF-kB抑制剂、非甾体抗炎药、β-激动剂如沙美特罗等、凝血因子FXa 抑制剂(如利伐沙班等)、抗-TNF抗体、前列腺素药物或孟鲁司特(montelukast)。
本发明的第三方面，提供了一种如本发明第一方面所述的化合物或其立体异构体或互变异构体，或其药学上可接受的盐、水合物或溶剂化物，或如本发明第二方面所述的药物组合物的用途，其用于制备预防和/或治疗与JAK激酶的活性或表达量相关的疾病的药物组合物。
在另一优选例中，所述的疾病选自下组：癌症、心血管疾病、炎症、免疫性或炎性疾病、骨髓增殖性疾病、病毒性疾病、代谢性疾病、或器官移植。
在另一优选例中，所述的癌症包括(但并不限于)：非小型细胞肺癌、子宫癌、直肠癌、结肠癌、脑癌、头癌、颈癌、膀胱癌、前列腺癌、乳腺癌、肾癌、血癌、肝癌、胃癌、甲状腺癌、鼻咽癌或胰腺癌。
在另一优选例中，所述的骨髓增殖性疾病包括(但并不限于)：自发性血小板增多(ET)、特发性骨髓纤维化(IMF)、慢性髓性白血病(CML)、原发性骨髓纤维化、慢性嗜中性粒细胞白血病(CNL)或真心红细胞增多症(PV)。
在另一优选例中，所述的免疫性或炎性疾病包括(但并不限于)：类风湿关节炎、骨关节炎、类风湿性脊柱炎、痛风、哮喘、支气管炎、鼻炎、慢性阻塞性肺病、肺纤维化、囊性纤维化病、肠炎。
在另一优选例中，所述的代谢性疾病包括(但并不限于)：2型糖尿病、1型糖尿病、糖尿病并发症(如糖尿病肾病、糖尿病视网膜病变、非酒精性脂肪性肝炎、肝纤维化、胰岛素抵抗、肥胖)。
本发明的第四方面，提供了一种JAK抑制剂，所述抑制剂包含本发明第一方面所述的化合物、或其立体异构体或互变异构体、或其药学上可接受的盐、水合物或溶剂化物。
在另一优选例中，所述的JAK抑制剂选择性抑制选自下组的一种或多种JAK激酶：JAK1、JAK2、JAK3或Tyk2。
在另一优选例中，所述的JAK抑制剂是JAK1高选择性抑制剂。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
具体实施方式
本发明人经过长期而深入的研究，设计并合成了一类新型JAK激酶抑制剂。在此基础上，发明人完成了本发明。
术语
除非另外定义，否则本文中所用的全部技术与科学术语均具有如本发明所属领域的普通技术人员通常理解的相同含义。
如本文所用，在提到具体列举的数值中使用时，术语“约”意指该值可以从列举的值变动不多于1％。例如，如本文所用，表述“约100”包括99和101和之间的全部值(例如，99.1、99.2、99.3、99.4等)。
如本文所用，术语“含有”或“包括(包含)”可以是开放式、半封闭式和封闭式的。换言之，所述术语也包括“基本上由…构成”、或“由…构成”。
定义
如本文所用，术语“烷基”包括直链或支链的烷基。例如C 1-C 8烷基表示具有1-8个碳原子的直链或支链的烷基，例如甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基等。
如本文所用，术语“烯基”包括直链或支链的烯基。例如C 2-C 6烯基指具有2-6个碳原子的直链或支链的烯基，例如乙烯基、烯丙基、1-丙烯基、异丙烯基、1-丁烯基、2-丁烯基、或类似基团。
如本文所用，术语“炔基”包括直链或支链的炔基。例如C 2-C 6炔基是指具有2-6个碳原子的直链或支链的炔基，例如乙炔基、丙炔基、丁炔基、或类似基团。
如本文所用，术语“C 3-C 8环烷基”指具有3-8个碳原子的环烷基。其可以是单环，例如环丙基、环丁基、环戊基、环己基、或类似基团。也可以是双环形式，例如桥环或螺环形式。
如本文所用，术语“C 1-C 8烷氧基”是指具有1-8个碳原子的直链或支链的烷氧基；例如，甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、叔丁氧基等。
如本文所用，术语“具有1-3个选自下组N、S和O的杂原子的3-10元杂环烷基”是指具有3-10个原子的且其中1-3个原子为选自下组N、S和O的杂原子的饱和或部分饱和的环状基团。其可以是单环，也可以是双环形式，例如桥环或螺环形式。具体的实例可以为氧杂环丁烷、氮杂环丁烷、四氢-2H-吡喃基、哌啶基、四氢呋喃基、吗啉基和吡咯烷基等。
如本文所用，术语“C 6-C 10芳基”是指具有6-10个碳原子的芳基，例如，苯基或萘基等类似基团。
如本文所用，术语“具有1-3个选自下组N、S和O的杂原子的5-10元杂芳基”指具有5-10个原子的且其中1-3个原子为选自下组N、S和O的杂原子的环状芳香基团。其可以是单环，也可以是稠环形式。具体的实例可以为吡啶基、哒嗪基、嘧啶基、吡嗪基、三嗪基、吡咯基、吡唑基、咪唑基、(1,2,3)-三唑基以及(1,2,4)-三唑基、四唑基、呋喃基、噻吩基、异恶唑基、噻唑基、恶唑基等。
除非特别说明，否则本发明的基团均可被选自下组的取代基所取代：卤素、腈基、硝基、羟基、氨基、C 1-C 6烷基-胺基、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基、卤代C 1-C 6烷基、卤代C 2-C 6烯基、卤代C 2-C 6炔基、卤代C 1-C 6烷氧基、烯丙基、苄基、C 6-C 12芳基、C 1-C 6烷氧基-C 1-C 6烷基、C 1-C 6烷氧基-羰基、苯氧羰基、C 2-C 6炔基-羰基、C 2-C 6烯基-羰基、C 3-C 6环烷基-羰基、C 1-C 6烷基-磺酰基等。
如本文所用，“卤素”或“卤原子”指F、Cl、Br、和I。更佳地，卤素或卤原子选自F、Cl和Br。“卤代的”是指被选自F、Cl、Br、和I的原子所取代。
除非特别说明，本发明所描述的结构式意在包括所有的同分异构形式(如对映异构，非对映异构和几何异构体(或构象异构体))：例如含有不对称中心的R、S构型，双键的(Z)、(E)异构体等。因此，本发明化合物的单个立体化学异构体或其对映异构体、非对映异构体或几何异构体(或构象异构体)的混合物都属于本发明的范围。
如本文所用，术语“互变异构体”表示具有不同能量的结构同分异构体可以超过低能垒，从而互相转化。比如，质子互变异构体(即质子移变)包括通过质子迁移进行互变，如1H-吲唑与2H-吲唑。化合价互变异构体包括通过一些成键电子重组而进行互变。
如本文所用，术语“溶剂合物”是指本发明化合物与溶剂分子配位形成特定比例的配合物。
式I化合物
本发明提供了一种如下式I所示的化合物：
Figure PCTCN2019107381-appb-000013
其中，
X 1、X 2、X 3和X 4各自独立地为CH或N；且X 1、X 2、X 3和X 4中至少有一个为N；
R 1、R 3各自独立地选自下组：H、取代或未取代的C1-C6烷基；
R 2选自下组：H、卤素、CN、取代或未取代的C1-C6烷基、取代或未取代的C1-C6烷氧基；
R 4、R 5各自独立地选自下组：H、卤素、CN、取代或未取代的C1-C6烷基；
R 6选自下组：H、取代或未取代的C1-C6烷基、R 7-C(＝O)-、R 8-S(＝O) 2-、R 9R 10N-C(＝O)-、R 11R 12N-S(＝O) 2-、取代或未取代的具有1-3个选自下组N、S和O的杂原子的5-12元杂环基(包括单环、螺环、桥环或并环)；
R 7、R 8、R 9、R 10、R 11、R 12各自独立地选自下组：H、取代或未取代的C1-C6烷基、取代或未取代的C1-C6烷氧基、取代或未取代的C3-C8环烷基、取代或未取代的具有1-3个选自下组N、S和O的杂原子的5-12元杂环基；
除非特别说明，所述的“取代”是指被选自下组的一个或多个(例如2个、3个、4个等)取代基所取代：卤素、C1-C6烷氧基、卤代的C1-C6烷氧基、C3-C8环烷基、卤代的C3-C8环烷基、甲基砜基、氧代(＝O)、-CN、羟基、-NH 2、C1-C6胺基、羧基、C1-C6酰胺基(-C(＝O)-N(Rc) 2或-NH-C(＝O)(Rc)，Rc为H或C1-C5的烷基)、或取代或未取代的选自下组的基团：C1-C6烷基、C6-C10芳基、具有1-3个选自N、S和O的杂原子的5-10元杂芳基、-(CH 2)-C6-C10芳基、-(CH 2)-(具有1-3个选自N、S和O的杂原子的5-10元杂芳基)、-(具有1-3个选自N、S和O的杂原子的5-10元亚杂芳基)-(C1-C6烷基)、取代或未取代的具有1-3个选自下组N、S和O的杂原子的5-12元杂环基(包括单环、螺环、桥环或并环)，且所述的取代基选自下组：卤素、C1-C6烷基、C1-C6亚烷基-OH、C1-C6烷氧基、氧代、-CN、-OH、C6-C10芳基、具有1-3个选自N、S和O的杂原子的5-10元杂芳基；
且所述的式I化合物中，各个手性中心为R构型或S构型。
在另一优选例中，X 1、X 2、X 3、X 4、R 1、R 2、R 3、R 4、R 5和R 6各自独立地为实施例中化合物的对应基团。
在另一优选例中，本发明的式I化合物选自下表：
Figure PCTCN2019107381-appb-000014
Figure PCTCN2019107381-appb-000015
Figure PCTCN2019107381-appb-000016
Figure PCTCN2019107381-appb-000017
Figure PCTCN2019107381-appb-000018
本发明的化合物可以作为JAK激酶抑制剂，在优选的实施例中，为JAK激酶选择性抑制剂，例如，选择性抑制JAK1、JAK2、JAK3或Tyk2中的一种或多种。在本发明的优选实施例中，所述的JAK抑制剂高选择性抑制JAK1。
式I化合物的制备
本发明的式I化合物可以通过以下方法制备：
Figure PCTCN2019107381-appb-000019
药物组合物和施用方法
由于本发明化合物具有优异的JAK激酶的抑制活性，因此本发明化合物及其各种晶型，药学上可接受的无机或有机盐，水合物或溶剂合物，以及含有本发明化合物为主要活性成分的药物组合物可用于预防和/或治疗与JAK激酶活性或表达量相关的疾病(例如，癌症)。
本发明的药物组合物包含安全有效量范围内的本发明化合物及药学上可以接受的赋形剂或载体。其中“安全有效量”指的是：化合物的量足以明显改善病情，而不至于产生严重的副作用。通常，药物组合物含有1-2000mg本发明化合物/剂，更佳地，含有10-200mg本发明化合物/剂。较佳地，所述的“一剂”为一个胶囊或药片。
“药学上可接受的载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明化合物以及它们之间相互掺和，而不明显降低化合物的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如吐温
Figure PCTCN2019107381-appb-000020
)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
本发明化合物或药物组合物的施用方式没有特别限制，代表性的施用方式包括(但并不限于)：口服、肠胃外(静脉内、肌肉内或皮下)。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，活性化合物与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性化合物外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
本发明化合物可以单独给药，或者与其他药学上可接受的化合物联合给药。
联合给药时，所述药物组合物还包括与一种或多种其他药学上可接受的化合物。该其他药学上可接受的化合物中的一种或多种可与本发明的化合物同时、分开或顺序地给药。
使用药物组合物时，是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人)，其中施用时剂量为药学上认为的有效给药剂量，对于60kg体重的人而言，日给药剂量通常为1～2000mg，优选20～500mg。当然，具体剂量还应考虑给药途径、病人健康状况等因素，这些都是熟练医师技能范围之内的。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。
实施例1：(R)-N-(3-(2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1H- 吡咯并[2,3-c]吡啶-7-基)-2-(4-甲基哌嗪-1-基)丙酰胺
Figure PCTCN2019107381-appb-000021
实施例1-2:7-氯-1-甲苯磺酰-1H-吡咯并[2,3-c]吡啶
Figure PCTCN2019107381-appb-000022
冰水浴条件下，将钠氢(375毫克,9.37毫摩尔)分批加入到化合物1-1(950毫克,6.25毫摩尔)的DMF(15毫升)溶液中，搅拌20分钟。然后将对甲苯磺酰氯(1.42克，9.37毫摩尔)分批加入到此溶液中，室温条件下，搅拌4小时。TLC和LCMS监控反应，1-1消失后，用100毫升水淬灭反应，乙酸乙酯萃取三次(50毫升*3)，合并有机相，无水硫酸钠干燥，浓缩得产物(1.45克,收率76％)。MS(ESI):m/z＝307[M+H] +.
实施例1-3:7-氯-3-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)-1-甲苯磺酰-1H-吡咯并 [2,3-c]吡啶
Figure PCTCN2019107381-appb-000023
氮气保护下，将化合物1-2(1.01克，3.6毫摩尔)，嚬那醇硼烷(1克，7.2毫摩尔)，[Ir(COD)Cl]2(120毫克，0.18毫摩尔)，4,4’-二叔丁基-2,2’-二吡啶(96毫克，0.38毫摩尔)和三乙胺(727毫克，7.2毫摩尔)的四氢呋喃(50毫升)溶液80度条件下，搅拌3小时。LCMS监控反应，反应结束后，将此溶液直接浓缩，经柱层析提纯(石油醚：乙酸乙酯/10:1-8:1)得到产物980毫克黄色固体，收率63％。MS(ESI):m/z＝433[M+H] +.
实施例1-4:7-氯-3-(2-氯嘧啶-4-基)-1-甲苯磺酰-1H-吡咯并[2,3-c]吡啶
Figure PCTCN2019107381-appb-000024
氮气保护下，将化合物1-3(880毫克，2毫摩尔)，2,4-二氯嘧啶(301毫克，2毫摩尔)，Pd(dppf)Cl2(146毫克，0.2毫摩尔)和碳酸钾(552毫克，4毫摩尔)的1,4-二氧六环(50毫升)溶液在100度条件下，搅拌过夜。反应结束后，将此溶液浓缩干，经柱层析(石油醚：乙酸乙酯/5:1)得产物260毫克，收率30％。MS(ESI):m/z＝419[M+H] +.
实施例1-5:4-(7-氯-1-甲苯磺酰-1H-吡咯并[2,3-c]吡啶-3-基)-N-(3-甲氧基-1-甲基-1H- 吡唑-4-基)嘧啶-2-胺
Figure PCTCN2019107381-appb-000025
将化合物1-4(230毫克，0.55毫摩尔)，3-甲氧基-1-甲基-1H-吡唑-4-胺(84毫克，0.66毫摩尔)和对甲基甲苯磺酸(10毫克)的二氧六环溶液(15毫升)在100度条件下，搅拌过夜。反应结束后，用饱和碳酸氢钠溶液中和，乙酸乙酯(30毫升)萃取，无水硫酸钠干燥，浓缩，经TLC板纯化得产物(20毫克，收率10％)。1H NMR(400MHz,CD3OD-d4):δ(ppm)8.41(s,2H),8.20(d,J＝5.6Hz,1H),8.00(d,J＝4.8Hz,1H),7.67(s,1H),7.20(d,J＝5.2Hz,1H),4.03(s,3H),3.78(s,3H).MS-ESI:m/z 356[M+H]+.
实施例1-7:甲基(R)-2-(4-甲基哌嗪-1-基)丙酸酯
Figure PCTCN2019107381-appb-000026
在三口瓶(250毫升)中加二氯甲烷(50毫升)和(S)-2-羟基丙酸甲酯(3克，28.8毫摩)，2，6-二甲基吡啶(3.7毫升，31.7毫摩)，氮气保护，降温至-78℃。然后在此温度下缓慢加入三氟甲磺酸酐(5.36毫升g,31.7毫摩)。在此温度下反应30分钟，然后升至室 温反应一小时。有机相用1N盐酸水溶液洗涤两次，硫酸钠干燥，浓缩干。得到的油状物用二氯甲烷(50毫升)溶解，冷却至0℃，然后1-甲基哌嗪(6.5克，64.6毫摩)缓慢加入体系，碳酸钾(21.2克，153.7毫摩)在0℃加入体系，然后在常温下反应过夜。反应完用盐水洗涤，干燥，浓缩干得到黄色油状物5.7克。MS(ESI):m/z＝187[M+H] +.
实施例1-8:(R)-2-(4-甲基哌嗪-1-基)丙酰胺
Figure PCTCN2019107381-appb-000027
在高压釜(100毫升)中加氨甲醇溶液(7N,46毫升)，化合物1-7(3.0克，16.1毫摩)，加热至150℃搅拌48小时。将反应液直接浓缩干，制备纯化，得到白色固体(480毫克，收率17％)。 11HNMR(400MHz,MeOD):δ(ppm)3.022-2.970(m,1H),2.607-2.442(m,8H),2.276(s,3H),1.231(d,J＝3.6Hz,3H)。MS(ESI):m/z＝172[M+H] +.
实施例1：(R)-N-(3-(2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1H-吡咯并[2,3-c]吡啶-7-基)-2-(4-甲基哌嗪-1-基)丙酰胺
Figure PCTCN2019107381-appb-000028
向实施例1-5(25毫克,0.070毫摩尔),(R)-2-(4-甲基哌嗪-1-基)丙酰胺(36毫克,0.21毫摩尔),碳酸铯(69毫克,0.21毫摩尔)的二氧六环(1毫升)溶液中加入双(二亚苄基丙酮)钯(13毫克,0.014毫摩尔)，4,5-双二苯基膦-9,9-二甲基氧杂蒽(16毫克,0.028毫摩尔)，反应液加热到100℃，并搅拌过夜。液质监控，通过制备型高效液相色谱纯化获得目标产物(R)-N-(3-(2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1H-吡咯并[2,3-c]吡啶-7-基)-2-(4-甲基哌嗪-1-基)丙酰胺(1.3毫克,3.8％)，为白色固体。MS(ESI):m/z＝491.7[M+H]+
1H NMR(400MHz,DMSO-D6)δ11.53(s,1H),10.16(s,1H),8.33-8.23(m,2H),8.21(d,J＝5.3Hz,1H),7.90(s,1H),7.67(s,1H),7.11(d,J＝5.3Hz,1H),3.77(s,3H),3.68(s,3H),3.49(d,J＝7.0Hz,1H),2.64-2.50(m,4H),2.44-2.25(m,4H),2.15(s,3H),1.24(d,J＝7.0Hz,3H).
实施例2：N-(3-(2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)-5-甲基嘧啶-4- 基)-1H-吡咯并[2,3-c]吡啶-7-基)-2-(4-甲基哌嗪-1-基)丁酰胺
Figure PCTCN2019107381-appb-000029
实施例2-1:7-氯-3-(2-氯-5-甲基嘧啶-4-基)-1-甲苯磺酰-1H-吡咯并[2,3-c]吡啶
Figure PCTCN2019107381-appb-000030
依次向四氢呋喃/水(15毫升/5毫升)的混合溶液中加入实施例1-3(350毫克，0.81毫摩尔)，2,4-二氯-5-甲基嘧啶(264毫克，1.62毫摩尔)，Pd(dppf)Cl2(60毫克，0.08毫摩尔)和碳酸钠(168毫克，1.22毫摩尔)，80度下搅拌2小时。LCMS显示反应完全。将反应液用乙酸乙酯稀释后用水洗涤。有机相用无水硫酸钠干燥，浓缩得粗品。将所得粗品硅胶过柱(石油醚：乙酸乙酯＝5：1)得黄色固体(200毫克，收率57％。MS(ESI):m/z＝432[M+H] +.
实施例2-2：4-(7-氯-1H-吡咯并[2,3-c]吡啶-3-基)-N-(3-甲氧基-1-甲基-1H-吡唑-4- 基)-5-甲基嘧啶-2-胺
Figure PCTCN2019107381-appb-000031
用与实施例1类似的方法从实施例2-1(365毫克，0.843毫摩尔)得淡黄色固体化合物实施例2-2(25毫克，收率8％).MS(ESI):m/z＝370[M+H] +。1H NMR(400MHz,MeOD-d4):δ(ppm)8.25(s,1H),8.17(s,1H),8.13(s,1H),7.95(d,J＝5.6,1H),7.63(s,1H),3.89(s,3H),3.73(s,3H),2.39(s,3H).
实施例2：N-(3-(2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)-5-甲基嘧啶-4-基)-1H-吡咯并[2,3-c]吡啶-7-基)-2-(4-甲基哌嗪-1-基)丁酰胺
Figure PCTCN2019107381-appb-000032
用与实施例1类似的方法从实施例2-2(25毫克，0.068毫摩尔)得到白色固体(7.8毫克，收率22％)。MS(ESI):m/z＝519[M+H] +.1H NMR(400MHz,CD3OD)δ8.16–8.10(m,2H),8.07(s,1H),7.89(d,J＝5.6Hz,1H),7.64(s,1H),3.88(s,3H),3.71(s,3H),3.25–3.20(m,1H),2.85–2.52(m,8H),2.37(s,3H),2.32(s,3H),1.96–1.79(m,2H),1.06(t,J＝7.4Hz,3H)._
实施例3：(S)-N-(3-(2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)-5-甲基嘧啶-4- 基)-1H-吡咯并[2,3-c]吡啶-7-基)-2-(4-甲基哌嗪-1-基)丁酰胺
Figure PCTCN2019107381-appb-000033
目标化合物根据实施例2方法，替换相应原料获得。
MS(ESI):m/z＝519[M+H] +.1H NMR(400MHz,CD3OD)δ8.17–8.09(m,2H),8.07(s,1H),7.89(d,J＝5.6Hz,1H),7.64(s,1H),3.88(s,3H),3.71(s,3H),3.24–3.20(m,1H),2.85–2.52(m,8H),2.37(s,3H),2.30(s,3H),1.96–1.78(m,2H),1.06(t,J＝7.4Hz,3H).
实施例4：(R)-N-(3-(2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)-5-甲基嘧啶-4- 基)-1H-吡咯并[2,3-c]吡啶-7-基)-2-(4-甲基哌嗪-1-基)丁酰胺
Figure PCTCN2019107381-appb-000034
目标化合物根据实施例2方法，替换相应原料获得。
MS(ESI):m/z＝519[M+H] +.1H NMR(400MHz,CD3OD)δ8.14–8.09(m,2H),8.06(s,1H),7.88(d,J＝5.7Hz,1H),7.63(s,1H),3.88(s,3H),3.70(s,3H),3.21(dd,J＝7.7,5.6Hz,1H),2.85–2.49(m,8H),2.36(s,3H),2.30(s,3H),1.95–1.80(m,2H),1.06(t,J＝ 7.4Hz,3H).
实施例5：N-(3-甲氧基-1-甲基-1H-吡唑-4-基)-3-(2-((3-甲氧基-1-甲基-1H-吡唑 -4-基)氨基)-5-甲基嘧啶-4-基)-1H-吡咯并[2,3-c]吡啶-7-胺
Figure PCTCN2019107381-appb-000035
目标化合物根据实施例2方法，替换相应原料获得。
MS(ESI):m/z＝461[M+H] +. 1H NMR(400MHz,DMSO-D6-d6):δ(ppm)11.9(s,1H),8.14(s,1H),8.11(s,1H),8.06(d,J＝3.2,1H),8.02(s,1H),7.98(s,1H),7.68(m,2H),3.90(s,3H),3.79(s,3H),3.70(s,3H),3.68(s,3H),2.33(s,3H).
以下各个化合物采用与实施例2类似的方法，替换相应原料获得。
Figure PCTCN2019107381-appb-000036
Figure PCTCN2019107381-appb-000037
实施例17:N-(3-(5-氟-2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1H-吡咯 并[2,3-c]吡啶-7-基)-2-(4-甲基哌嗪-1-基)丁酰胺
Figure PCTCN2019107381-appb-000038
Figure PCTCN2019107381-appb-000039
实施例17-2:3-甲氧基-1-甲基-4-硝基-1H-吡唑
Figure PCTCN2019107381-appb-000040
将化合物17-1(10g,70mmol)溶于DMF(50mL)中,加入碘甲烷(4mL,77mmol)，碳酸钾(14.8g,105mmol)，氮气置换后，反应液于25℃下搅拌2小时。TLC检测反应结束后，反应混合液降至室温,反应液倒入水(50mL)中，用乙酸乙酯(50mL x2)萃取，合并有机层，依次用水(100mL)，饱和食盐水(100mL)洗涤，无水硫酸钠干燥，过滤，滤液减压下蒸除溶剂，粗品用柱纯化(石油醚/乙酸乙酯＝1/1)得到淡黄色固体17-2(8.9g,产率81％).
1H NMR(400MHz,CDCl3)δ7.92(s,1H),3.96(s,3H),3.73(s,3H).
实施例17-3:3-甲氧基-1-甲基-1H-吡唑-4-胺
Figure PCTCN2019107381-appb-000041
将化合物17-2(8.9g,57mmol)溶于甲醇(50mL)中,加入Pd/C(0.9g)氢气置换后，反应液于25℃下搅拌4小时。LCMS检测反应结束后，过滤，将得到的滤液减压下蒸除溶剂，得到深红色液体17-3(6.6g,91％).ESI-MS m/z＝128[M+H] +.
1H NMR(400MHz,DMSO)δ6.90(s,1H),3.74(s,3H),3.52(s,3H),3.31(s,2H).
实施例17-5:2-氯-5-氟-4-((4-甲氧苄基)氧代)嘧啶
Figure PCTCN2019107381-appb-000042
0℃下，氮气保护下向盛有NaH(3.7g,89.9mmol)的三口瓶中缓慢滴入四氢呋喃(50 mL)。滴完后，0℃下，向反应液中缓慢滴入PMBOH(9.9g,71.9mmol)的四氢呋喃(50mL)。滴完后反应液在0℃下维持30分钟。在-20℃下，将此混合物缓慢滴入17-4(10.0g,59.9mmol)的四氢呋喃(50mL)溶液中。滴完后，反应液在-20℃-0℃下维持1小时并用LC-MS监控反应。反应结束后,将反应液缓慢倒入饱和氯化铵水溶液(100mL)中,用乙酸乙酯(100mL x2)萃取,无水硫酸钠干燥,滤液减压下蒸除溶剂，粗品用柱纯化(石油醚/乙酸乙酯＝1/1)得到淡黄色固体17-5(14.0g,87.1％yield).
LC-MS:LC-MS(ESI):m/z(M+H) +269.0.
实施例17-6:5-氟-N-(3-甲氧基-1-甲基-1H-吡唑-4-基)-4-((4-甲氧苄基)氧代)嘧啶-2-胺
Figure PCTCN2019107381-appb-000043
将17-5(2.0g,7.5mmol),17-3(0.95g,7.5mmol)，Pd 2(dba) 3(0.13g,0.15mmol),BINAP(0.18g,0.30mmol),碳酸铯(4.8g,15.0mmol)的甲苯(10mL)溶液在氮气保护下升温至100℃，并在此温度下维持3小时。反应液用LC-MS监控。反应结束后,向反应液中加入水(200mL)并用乙酸乙酯(200mL x2)萃取。合并有机层，用食盐水洗，无水硫酸钠干燥,滤液减压下蒸除溶剂，粗品用柱纯化(石油醚/乙酸乙酯＝1/1)得到黄色固体17-6(2.0g,74.7％yield).
LC-MS:LC-MS(ESI):m/z(M+H) +360.0.
实施例17-7:5-氟-2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-酚
Figure PCTCN2019107381-appb-000044
将17-6(2.0g,5.6mmol)加入到4N盐酸的1,4二氧六环(20mL)中在室温下搅拌三十分钟，并用LC-MS监控反应。反应结束后,减压下蒸除溶剂，粗产品中加入乙酸乙酯(20mL)中进行重结晶，得到黄色固体17-7(1.0g,75.0％yield).LC-MS(ESI):m/z(M+H) +240.1.
实施例17-8:4-氯-5-氟-N-(3-甲氧基-1-甲基-1H-吡唑-4-基)嘧啶-2-胺
Figure PCTCN2019107381-appb-000045
向17-7(1.0g,4.2mmol)的三氯氧磷(10ml)溶液中加热至80℃，并在此温度下维持3个小时，并用LC-MS监控反应。反应结束后,将三氯氧磷旋干，粗品用碳酸氢钠饱和溶液(50mL)和二氯甲烷(50mL*2)萃取，合并有机层，用食盐水洗，无水硫 酸钠干燥,滤液减压下蒸除溶剂，粗品用柱纯化(石油醚/乙酸乙酯＝1/1)得到黄色固体17-8(1.0g,92.9％yield)
LC-MS:LC-MS(ESI):m/z(M+H)+258.2.
实施例17-9:4-(7-氯-1-甲苯磺酰-1H-吡咯并[2,3-c]吡啶-3-基)-5-氟-N-(3-甲氧基-1-甲基-1H-吡唑-4-基)嘧啶-2-胺
Figure PCTCN2019107381-appb-000046
将17-8(0.4g,1.6mmol),7A(0.88g,2.1mmol)，Pd(dppf)Cl 2(0.11g,0.16mmol),碳酸钠(0.5g,4.8mmol)的二氧六环(10mL)和水(2mL)溶液在氮气保护下升温至90℃，并在此温度下维持30分钟。反应液用LC-MS监控。反应结束后,向反应液中加入水(50mL)并用二氯甲烷(50mL*2)萃取，合并有机层，用食盐水洗，无水硫酸钠干燥,滤液减压下蒸除溶剂，粗品用柱纯化(二氯甲烷/甲醇＝10/1)得到白色固体17-9(0.56g,62.5％yield).
LC-MS(ESI):m/z(M+H) +528.1.
实施例17:N-(3-(5-氟-2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1H-吡咯并[2,3-c]吡啶-7-基)-2-(4-甲基哌嗪-1-基)丁酰胺
Figure PCTCN2019107381-appb-000047
MS(ESI):m/z＝523.50[M+H] +.
1HNMR(400MHz,DMSO-d 6)δ11.57(s,1H),10.53(s,1H),8.43(s,2H),8.30(d,J＝3.8Hz,1H),8.21(s,1H),7.92(s,1H),7.64(s,1H),3.76(s,3H),3.68(s,3H),3.39(s,1H),2.62(d,J＝18.9Hz,4H),2.32(s,4H),2.12(s,3H),1.83–1.72(m,1H),1.70-1.60(m,1H),0.91(t,J＝7.4Hz,3H).
实施例18:N-(3-(2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)-5-甲基嘧啶-4-基)-1H-吡 咯并[2,3-c]吡啶-7-基)-2-(4-(噁丁环-3-基)哌嗪-1-基)丁酰胺
目标化合物采用与实施例2类似的方法，替换相应原料获得。
Figure PCTCN2019107381-appb-000048
实施例18-1:2-(4-(噁丁环-3-基)哌嗪-1-基)丁酰胺
Figure PCTCN2019107381-appb-000049
向化合物CAS:1254115-23-5(300mg,2.11mmol)，2-溴丁酰胺(350mg,2.11mmol)的乙腈(5mL)溶液中加入碳酸钾(583mg,4.22mmol)，加热60℃反应16小时。反应液冷却后，滤除无机盐，母液浓缩，残渣用反相C-18柱分离纯化(乙腈/碳酸氢铵水溶液)，得标题化合物18-1(400mg,83％)，为白色固体。MS(ESI):m/z＝228.1[M+H] +.
实施例18:N-(3-(2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)-5-甲基嘧啶-4-基)-1H-吡 咯并[2,3-c]吡啶-7-基)-2-(4-(噁丁环-3-基)哌嗪-1-基)丁酰胺
Figure PCTCN2019107381-appb-000050
向化合物2-2(60mg,0.16mmol)，17-10(90mg，0.4mmol)，碳酸铯(168mg,52mmol)的无水二氧六环(3mL)溶液中加入三(二苯亚甲基丙酮)二钯(0)(30mg,0.032mmol)和4,5-双二苯基膦-9,9-二甲基氧杂蒽(30mg,0.052mmol)，氮气保护110℃加热密封反应2小时。冷却后，过滤，用甲醇洗涤。滤液浓缩，高效液相色谱制备得得标题化合物18(20mg,22％)，为淡黄色固体。MS(ESI):m/z＝561.2[M+H] +.
1H NMR(400MHz,CD3OD):δ8.15-8.13(m,2H),8.10(s,1H),7.88(d,J＝6.4Hz,1H),7.63(s,1H),4.68(t,J＝6.4Hz,2H),4.58(t,J＝6.4Hz,2H),3.88(s,3H),3.71(s,3H),3.56-3.51(m,1H),3.25-3.22(m,1H),2.83-2.72(m,4H),2.51-2.45(m,4H),2.37(s,3H),1.93-1.84(m,2H),1.06(t,J＝7.2Hz,3H).
实施例19:N-(3-(2-((2-氟-3-(甲磺酰)苯基)氨基)-5-甲基嘧啶-4-基)-1H-吡咯并[2,3-c] 吡啶-7-基)-2-(4-甲基哌嗪-1-基)丁酰胺
Figure PCTCN2019107381-appb-000051
实施例19-2:7-氯-3-碘-1H-吡咯并[2,3-c]吡啶
Figure PCTCN2019107381-appb-000052
在0-25℃下，向1-1(57g,375mmol)的乙腈(400mL)溶液中缓慢加入NIS(100g,450mmol)，加完后，在25℃下保持1h,并用LC-MS监控反应。反应结束后,收集固体,并用乙腈(50ml)洗，干燥得到白色固19-2(85g,81.6％yield)。LC-MS(ESI):m/z(M+H) +279.1.
实施例19-3:7-氯-3-碘-1-甲苯磺酰-1H-吡咯并[2,3-c]吡啶
Figure PCTCN2019107381-appb-000053
在0℃下，将19-2(85g,305.8mmol),氢氧化钠(122.3g,3058mmol)和四丁基硫氢化铵(10.3g,30.5mmol)的二氯甲烷(850mL)和水(366mL)溶液中缓慢加入TsCl(87.2g,458.7mmol)。反应在25℃下保持2小时并用LC-MS监控反应。反应结束后,分出水层,用二氯甲烷(200mL x 2)萃取。合并有机层，用饱和食盐水洗,无水硫酸钠干燥、旋干。浓缩液用乙酸乙酯(200mL)打浆。收集固体用乙酸乙酯洗,干燥后得到白色固体19-3(85.0g,64.4％yield).LC-MS(ESI):m/z(M+H) +433.1.
实施例1-3:7-氯-3-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)-1-甲苯磺酰-1H-吡咯并 [2,3-c]吡啶
Figure PCTCN2019107381-appb-000054
0℃下，向19-3(28.0g,64.8mmol)的四氢呋喃(560mL)溶液中30分钟内缓慢滴入异丙基溴化镁(1M,77.7mL,77.7mmol)。滴完后,反应液在0℃下维持30分钟。0℃下，向反应液中缓慢滴入异丙基硼酸频哪醇酯(14.4g,77.8mmol)，滴完后,反应液在0℃下维持1小时。反应结束后，将反应液缓慢倒入饱和氯化铵水溶液(560mL)中,用乙酸乙酯(200mL x2)萃取,合并有机层，用饱和食盐水洗,无水硫酸钠干燥、旋干。浓缩物用乙腈(100mL)重结晶得到白色固体(12.0g,42.9％yield)。LC-MS(ESI):m/z(M+H) +433.1.
实施例19-4:2-氟-3-(甲磺酰)苯胺
Figure PCTCN2019107381-appb-000055
将化合物3-溴-2-氟苯胺(16g,84.2mmol)溶于二甲基亚砜(80mL)中,加入甲基亚磺酸钠(12.42g,109.5mmol)，N,N’-二甲基乙二胺(3.62mL,33.68mmol)，碘化亚铜(8g,42.1mmol)和磷酸钾(22.3g,84.2mmol)。反应液于110℃下搅拌16小时。TLC检测反应结束后，反应混合液降至室温,倒入水(300mL)中，用乙酸乙酯(200mL x2)萃取，合并有机层，用饱和食盐水(300mL)洗涤，无水硫酸钠干燥，过滤，滤液减压下蒸除溶剂，粗品用柱纯化(石油醚/乙酸乙酯＝1/1)得到黄色固体化合物19-4(7.36g,产率46.2％).ESI-MS m/z＝190[M+H] +
实施例19-6:2-氯-4-((4-甲氧苄基)氧代)-5-甲基嘧啶
Figure PCTCN2019107381-appb-000056
0℃下，氮气保护下向盛有NaH(11.1g,277.5mmol)的三口瓶中缓慢滴入四氢呋喃(100mL)。滴完后，0℃下，向反应液中缓慢滴入PMBOH(30.0g,217.4mmol)的四氢呋喃(100mL)。滴完后反应液在0℃下维持30分钟。在-20℃下，将此混合物缓慢滴入2,4-二氯-5-甲基嘧啶19-5(30.0g,84.0mmol)的四氢呋喃(100mL)溶液中。滴完后， 反应液在-20℃-0℃下维持1小时并用LC-MS监控反应。反应结束后,将反应液缓慢倒入饱和氯化铵水溶液(200mL)中,用乙酸乙酯(200mL x2)萃取,无水硫酸钠干燥、旋干。浓缩物用石油醚(300mL)打浆。收集白色固体，用石油醚(50ml)洗，干燥后得到白色固体19-6(27.0g,55.6％yield).LC-MS(ESI):m/z(M+H) +265.1.
实施例19-7:N-(2-氟-3-(甲磺酰)苯基)-4-((4-甲氧苄基)氧代)-5-甲基嘧啶-2-胺
Figure PCTCN2019107381-appb-000057
将19-6(27.0g,102.7mmol),YN-HDB-107(19.0g,102.7mmol)，Pd 2(dba) 3(2.7g,3.0mmol),BINAP(3.7g,6.0mmol,碳酸铯(66.3g,204.0mmol)的甲苯(100mL)溶液在氮气保护下升温至120℃，并在此温度下维持30分钟。反应液用LC-MS监控。反应结束后,向反应液中加入水(200mL)并用乙酸乙酯(200mL*2)萃取.。合并有机层，用食盐水洗，无水硫酸钠干燥、旋干。浓缩物用甲基叔丁基醚(500mL)重结晶得到白色固体19-7(25.0g,58.8％yield).LC-MS(ESI):m/z(M+H) +418.7.
实施例19-8:4-氯-N-(2-氟-3-(甲磺酰)苯基)-5-甲基嘧啶-2-胺
Figure PCTCN2019107381-appb-000058
向19-7(25.0g,60.0mmol)的三氯氧磷(125ml)溶液中加热至80℃，并在此温度下维持3个小时，用LC-MS监控反应。反应结束后,将三氯氧磷旋干，浓缩物溶解于二氯甲烷(200ml)中，并用饱和碳酸氢钠溶液将pH调至8，分出有机层，水层用二氯甲烷(50ml)萃取一遍，合并有机层，无水硫酸钠干燥、旋干，浓缩物用甲基叔丁基醚打浆，得到白色固体19-8(16.0g,84.7％yield)。LC-MS(ESI):m/z(M+H) +316.2.
实施例19-9:4-(7-氯-1-甲苯磺酰-1H-吡咯并[2,3-c]吡啶-3-基)-N-(2-氟-3-(甲磺酰)苯基)-5-甲基嘧啶-2-胺
Figure PCTCN2019107381-appb-000059
将1-3(7.4g,17.0mmol),19-8(2.7g,8.5mmol)，Pd(dppf)Cl 2(0.62g,0.85mmol)和碳酸钠(3.6g,64.0mmol)的二氧六环(74mL)和水(7.4mL)在氮气保护下加热至90℃，并在90℃下维持1小时，反应用LC-MS监控。反应结束后，将二氧六环浓缩干。将浓缩物溶于二氯甲烷(50ml)和水(10ml)中，分出有机层，水层用二氯甲烷(20ml*2)萃取，合并有机层，无水硫酸钠干燥、旋干。浓缩物用柱层析纯化(洗脱溶剂：0-5％甲醇的二氯甲烷溶剂)得到白色固体19-9(4.5g,45.3％yield)。LC-MS(ESI):m/z(M+H) +586.1.
实施例19-10:4-(7-氯-1H-吡咯并[2,3-c]吡啶-3-基)-N-(2-氟-3-(甲磺酰)苯基)-5-甲基嘧 啶-2-胺
Figure PCTCN2019107381-appb-000060
向19-9(1500mg,2.56mmol)的四氢呋喃(15mL)溶液中加入四丁基溴化铵的四氢呋喃溶液(1M)(5.12mL,5.12mmol)，70℃ 加热反应1小时。反应结束后，反应液浓缩后用硅胶柱(流动相二氯甲烷：甲醇＝10:1)纯化得标题化合物(850mg,77％)，为黄色固体。
MS(ESI):m/z＝431.8[M+H]+.
实施例19-11:2-(4-甲基哌嗪-1-基)丁酰胺
Figure PCTCN2019107381-appb-000061
将化合物1-甲基哌嗪(3.8g,38mmol)溶于N,N-二甲基甲酰胺(50mL)中,加入化合物2-溴丁酰胺(15.8g,95mmol)和碳酸钾(10.5g,76mmol)，反应液于70℃下搅拌16小时。LCMS检测反应结束后，反应液冷却至室温,倒入水(200mL)中，用乙酸乙酯(100mL*2)萃取，合并有机层，用饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤，滤液减压下蒸除溶剂，粗品用柱纯化(二氯甲烷/甲醇＝0-50％)得到白色固体化合物(2)(7.4g,产率100％).
ESI-MS m/z＝186[M+H] +
实施例19:N-(3-(2-((2-氟-3-(甲磺酰)苯基)氨基)-5-甲基嘧啶-4-基)-1H-吡咯并[2,3-c] 吡啶-7-基)-2-(4-甲基哌嗪-1-基)丁酰胺
Figure PCTCN2019107381-appb-000062
向19-10(52毫克,0.12毫摩尔)，2-(4-甲基哌嗪-1-基)丁酰胺(33毫克,0.18毫摩尔)和碳酸铯(78毫克,0.24毫摩尔)的1,4-二氧六环(1.5毫升)溶液中加入三(二苯亚甲基丙酮)二钯(22毫克,0.024毫摩尔)和4,5-双二苯基膦-9,9-二甲基氧杂蒽(28毫克,0.048毫摩尔)，氮气保护下110℃加热反应过夜。反应结束后，反应液用硅藻土过滤。滤液浓缩后用反相柱(流动相：乙腈/碳酸氢铵水溶液)纯化得标题化合物19(24.4毫克,34％)，为黄色固体。
MS(ESI):m/z＝291.0[M/2+H] +.
1HNMR(400MHz,DMSO-d 6)δ11.46(s,1H),10.49(s,1H),9.24(s,1H),8.29(s,1H),8.23(t,J＝7.2Hz,1H),8.13(s,1H),8.10(d,J＝5.5Hz,1H),7.84(d,J＝5.6Hz,1H),7.52(t,J＝6.5Hz,1H),7.38(t,J＝7.9Hz,1H),3.38(s,1H),3.25(s,3H),2.62(d,J＝16.1Hz,4H),2.35(s,3H),2.30(s,3H),2.11(s,3H),1.82–1.73(m,1H),1.68–1.60(m,1H),0.91(t,J＝7.4Hz,3H).
参照实施例19的合成方法合成下列化合物：
Figure PCTCN2019107381-appb-000063
实施例20:(S)-N-(3-(2-((2-氟-3-(甲磺酰)苯基)氨基)-5-甲基嘧啶-4-基)-1H-吡咯并 [2,3-c]吡啶-7-基)-2-(4-甲基哌嗪-1-基)丁酰胺
Figure PCTCN2019107381-appb-000064
实施例19(18毫克,0.03毫摩尔)经手性拆分后得实施例20(5.1毫克,28％)，为白色固体和实施例21(4.8毫克,26％)，为黄色固体。
MS(ESI):m/z＝291.0[M/2+H] +.
1HNMR(400MHz,DMSO-d 6)δ11.46(s,1H),10.49(s,1H),9.24(s,1H),8.29(s,1H),8.23(t,J＝7.2Hz,1H),8.14(d,J＝2.3Hz,1H),8.10(d,J＝5.5Hz,1H),7.84(d,J＝5.6Hz,1H),7.52(t,J＝6.5Hz,1H),7.38(t,J＝7.9Hz,1H),3.38(s,1H),3.25(s,3H),2.62(d,J＝16.1Hz,4H),2.35(s,3H),2.30(s,3H),2.11(s,3H),1.82–1.73(m,1H),1.68–1.60(m,1H),0.91(t,J＝7.4Hz,3H).
实施例21:(R)-N-(3-(2-((2-氟-3-(甲磺酰)苯基)氨基)-5-甲基嘧啶-4-基)-1H-吡咯并 [2,3-c]吡啶-7-基)-2-(4-甲基哌嗪-1-基)丁酰胺
(ESI):m/z＝291.0[M/2+H] +.
1HNMR(400MHz,DMSO-d 6)δ11.49(s,1H),10.50(s,1H),9.24(s,1H),8.30(s,1H),8.23(t,J＝7.1Hz,1H),8.14(s,1H),8.10(d,J＝5.5Hz,1H),7.85(d,J＝5.6Hz,1H),7.54-7.51(m,1H),7.38(t,J＝8.0Hz,1H),3.38(s,1H),3.26(s,3H),2.62(d,J＝15.6Hz,4H),2.36(s,3H),2.29(s,3H),2.11(s,3H),1.83–1.72(m,1H),1.71–1.58(m,1H),0.91(t,J＝7.4Hz,3H).
实施例22:N-(3-(2-((2-氟-3-(甲基磺酰氨基)苯基)氨基)-5-甲基嘧啶-4-基)-1H-吡咯并 [2,3-c]吡啶-7-基)-2-(4-甲基哌嗪-1-基)丁酰胺
Figure PCTCN2019107381-appb-000065
实施例22-1:N-(2-氟-3-硝基苯基)甲磺酰胺
Figure PCTCN2019107381-appb-000066
将化合物1-溴-2-氟-3-硝基苯(1g,4.54mmol)溶于二氧六环(15mL)中,加入甲基 磺酰胺(519mg,5.45mmol),三(二亚苄基丙酮)二钯(412mg,0.45mmol),2-二叔丁基膦-2',4',6'-三异丙基联苯(287mg,0.675mmol)和碳酸钾(1.24g,9mmol)，反应液于80℃下搅拌2小时。TLC检测反应结束后，反应液旋干，粗品溶于乙酸乙酯(20mL)中，加入水(30mL)，分液，水层加2N盐酸(10mL)调节pH～4，用乙酸乙酯(20mL)萃取，分液，有机相用无水硫酸钠干燥，过滤，滤液减压下蒸除溶剂，得到黄色固体化合物22-1(810mg,产率76.2％).
ESI-MS m/z＝235[M+H] +
实施例22-2:N-(3-氨基-2-氟苯基)甲磺酰胺
Figure PCTCN2019107381-appb-000067
将化合物(2)(810mg,1.65mmol)溶于四氢呋喃(8mL)，甲醇(4mL)和水(2mL)中,加入铁粉(970mg,17.3mmol)和氯化铵(1.85g,34.6mmol)，反应液于65℃下搅拌16小时。LCMS检测反应结束后，反应液加硅藻土过滤，滤液减压旋干，粗品溶于乙酸乙酯(20mL)中，加入水(20mL)，分液，有机相用无水硫酸钠干燥，过滤，滤液减压下蒸除溶剂，粗品用柱纯化(石油醚/乙酸乙酯＝1/1)得到黄色固体化合物(3)(650mg,产率92％).
ESI-MS m/z＝205[M+H] +
实施例22:N-(3-(2-((2-氟-3-(甲基磺酰氨基)苯基)氨基)-5-甲基嘧啶-4-基)-1H-吡咯并[2,3-c]吡啶-7-基)-2-(4-甲基哌嗪-1-基)丁酰胺
Figure PCTCN2019107381-appb-000068
目标化合物根据实施例19的方法，替换相应原料获得。
MS(ESI):m/z＝298.5[M/2+H] +.
1HNMR(400MHz,DMSO-d 6)δ11.43(s,1H),10.58(s,1H),9.60(s,1H),8.91(s,1H),8.25(s,1H),8.11(d,J＝5.4Hz,2H),7.85(d,J＝5.6Hz,1H),7.70–7.62(m,1H),7.11(d,J＝5.4Hz,2H),3.44(s,1H),2.97(s,3H),2.70(s,8H),2.36(s,3H),2.34(s,3H),1.85–1.74(m,1H),1.71–1.57(m,1H),0.92(t,J＝7.4Hz,3H).
实施例23:N-(3-(2-((2-氟-3-(甲磺酰)苯基)氨基)-5-甲基嘧啶-4-基)-1H-吡咯并[2,3-c] 吡啶-7-基)-2-(8-甲基-3,8-二氮杂二环[3.2.1]辛烷-3-基)丁酰胺
Figure PCTCN2019107381-appb-000069
目标化合物根据实施例19的方法，替换相应原料获得。实施例23经手性拆分后得实施例25和实施例26。
MS(ESI):m/z＝304.0[M/2+H] +.
1HNMR(400MHz,DMSO-d 6)δ11.44(s,1H),10.68(s,1H),9.25(s,1H),8.30(s,1H),8.22(t,J＝7.7Hz,1H),8.11(d,J＝5.1Hz,2H),7.86(d,J＝5.5Hz,1H),7.53(t,J＝6.1Hz,1H),7.39(t,J＝8.0Hz,1H),3.83(s,2H),3.25(s,3H),2.79(s,2H),2.59(s,3H),2.36(s,3H),2.04(s,2H),1.95(s,2H),1.78-1.71(m,1H),1.68-.160(m,1H),1.30(s,1H),1.20(s,1H),1.19(s,1H),0.93(t,J＝7.3Hz,3H).
实施例25:(R)-N-(3-(2-((2-氟-3-(甲磺酰)苯基)氨基)-5-甲基嘧啶-4-基)-1H-吡咯并 [2,3-c]吡啶-7-基)-2-(8-甲基-3,8-二氮杂二环[3.2.1]辛烷-3-基)丁酰胺
MS(ESI):m/z＝304.0[M/2+H] +.
1HNMR(400MHz,DMSO-d 6)δ11.50(s,1H),10.43(s,1H),9.26(s,1H),8.29(s,1H),8.22(t,J＝7.7Hz,1H),8.14(s,1H),8.11(d,J＝5.4Hz,1H),7.85(d,J＝5.6Hz,1H),7.53(t,J＝6.4Hz,1H),7.38(t,J＝8.0Hz,1H),3.26(s,3H),3.16(s,2H),2.71(s,1H),2.63(s,3H),2.35(s,3H),2.20(s,3H),1.87(s,2H),1.77-1.70(m,3H),1.69–1.58(m,1H),0.92(t,J＝7.3Hz,3H).
实施例26:(S)-N-(3-(2-((2-氟-3-(甲磺酰)苯基)氨基)-5-甲基嘧啶-4-基)-1H-吡咯并 [2,3-c]吡啶-7-基)-2-(8-甲基-3,8-二氮杂二环[3.2.1]辛烷-3-基)丁酰胺
MS(ESI):m/z＝304.0[M/2+H] +.
1HNMR(400MHz,DMSO-d 6)δ11.51(s,1H),10.40(s,1H),9.26(s,1H),8.29(s,1H),8.23(t,J＝7.0Hz,1H),8.14(s,1H),8.11(d,J＝5.5Hz,1H),7.85(d,J＝5.5Hz,1H),7.53(t,J＝6.3Hz,1H),7.38(t,J＝8.0Hz,1H),3.26(s,3H),3.08(s,2H),2.68(s,1H),2.59(s,3H),2.35(s,3H),2.15(s,3H),1.85(s,2H),1.77-1.70(m,3H),1.64(dd,J＝14.0,6.9Hz,1H),0.92(t,J＝7.3Hz,3H).
实施例24:N-(3-(2-((2-氟-3-(甲磺酰)苯基)氨基)-5-甲基嘧啶-4-基)-1H-吡咯并[2,3-c] 吡啶-7-基)-2-(7-甲基-2,7-二氮杂螺[3.5]壬烷-2-基)丁酰胺
Figure PCTCN2019107381-appb-000070
目标化合物采用与实施例19类似的方法，替换相应原料获得
MS(ESI):m/z＝311.0[M/2+H] +.
1HNMR(400MHz,DMSO-d 6)δ11.52(s,1H),10.08(s,1H),9.25(s,1H),8.30(s,1H),8.22(t,J＝7.5Hz,1H),8.13(s,2H),7.85(s,1H),7.53(t,J＝6.3Hz,1H),7.38(t,J＝8.0Hz,1H),3.26(s,3H),3.14(s,6H),2.87(s,4H),2.52(s,2H),2.36(s,3H),1.87(s,4H),1.62(s,2H),0.88(t,J＝7.2Hz,3H).
实施例27:N-(3-(5-氟-2-((2-氟-3-(甲磺酰)苯基)氨基)嘧啶-4-基)-1H-吡咯并[2,3-c]吡 啶-7-基)-2-(4-甲基哌嗪-1-基)丁酰胺
Figure PCTCN2019107381-appb-000071
实施例27-1:2-氯-5-氟-4-((4-甲氧苄基)氧代)嘧啶
Figure PCTCN2019107381-appb-000072
0℃下，氮气保护下向盛有NaH(3.7g,89.9mmol)的三口瓶中缓慢滴入四氢呋喃(50mL)。滴完后，0℃下，向反应液中缓慢滴入PMBOH(9.9g,71.9mmol)的四氢呋喃(50mL)。滴完后反应液在0℃下维持30分钟。在-20℃下，将此混合物缓慢滴入2,4-二氯-5-氟嘧啶(10.0g,59.9mmol)的四氢呋喃(50mL)溶液中。滴完后，反应液在-20℃-0℃下维持1小时并用LC-MS监控反应。反应结束后,将反应液缓慢倒入饱和氯化铵水溶液(100mL)中,用乙酸乙酯(100mL x2)萃取,无水硫酸钠干燥,滤液减压下蒸除溶剂，粗品用柱纯化(石油醚/乙酸乙酯＝1/1)得到淡黄色固体27-1(14.0g,87.1％yield).LC-MS(ESI):m/z(M+H) +269.0.
实施例27-2:5-氟-N-(2-氟-3-(甲磺酰)苯基)-4-((4-甲氧苄基)氧代)嘧啶-2-胺
Figure PCTCN2019107381-appb-000073
将27-1(8.0g,29.8mmol),19-4(5.6g,29.8mmol)，Pd 2(dba) 3(0.54g,0.59mmol),BINAP(0.74g,1.2mmol,碳酸铯(19.4g,59.6mmol)的甲苯(80mL)溶液在氮气保护下升温至120℃，并在此温度下维持30分钟。反应液用LC-MS监控。反应结束后,向反应液中加入水(200mL)并用乙酸乙酯(200mL x2)萃取。合并有机层，用食盐水洗，无水硫酸钠干燥,滤液减压下蒸除溶剂，粗品用柱纯化(石油醚/乙酸乙酯＝1/1)得到红色油状物27-2(10.0g,79.9％yield).LC-MS(ESI):m/z(M+H) +421.1.
实施例27-3:5-氟-2-((2-氟-3-(甲磺酰)苯基)氨基)嘧啶-4-酚
Figure PCTCN2019107381-appb-000074
将27-2(2.0g,4.8mmol)加入到4N盐酸的1,4二氧六环(15mL)中在室温下搅拌三十分钟，并用LC-MS监控反应。反应结束后,减压下蒸除溶剂，粗产品中加入乙醇(2mL),乙酸乙酯(20mL),甲基叔丁基醚(20mL)中进行重结晶，得到白色固体27-3(1.0g,68.8％yield).LC-MS(ESI):m/z(M+H) +302.1.
实施例27-4:4-氯-5-氟-N-(2-氟-3-(甲磺酰)苯基)嘧啶-2-胺
Figure PCTCN2019107381-appb-000075
向27-3(1.0g,3.3mmol)的三氯氧磷(20ml)溶液中加热至80℃，并在此温度下维持3个小时，并用LC-MS监控反应。反应结束后,将三氯氧磷旋干，粗品用柱纯化(石油醚/乙酸乙酯＝1/1)得到白色固体27-4(1.0g,97.8％yield).LC-MS(ESI):m/z(M+H) +319.2.
实施例27-5:4-(7-氯-1-甲苯磺酰-1H-吡咯并[2,3-c]吡啶-3-基)-5-氟-N-(2-氟-3-(甲磺酰)苯基)嘧啶-2-胺
Figure PCTCN2019107381-appb-000076
将27-4(1.0g,3.1mmol),1-3(1.3g,3.1mmol)，Pd(dppf)Cl 2(0.21g,0.3mmol),碳酸钠(0.95g,9.0mmol)的二氧六环(10mL)和水(2mL)溶液在氮气保护下升温至90℃，并在此温度下维持30分钟。反应液用LC-MS监控。反应结束后,向反应液中加入水(50mL)并用二氯甲烷(50mL*2)萃取，合并有机层，用食盐水洗，无水硫酸钠干燥,滤液减压下蒸除溶剂，粗品用柱纯化(二氯甲烷/甲醇＝10/1)得到白色固体10(0.6g,33.3％yield).LC-MS(ESI):m/z(M+H) +589.0.
实施例27-6:4-(7-氯-1-甲苯磺酰-1H-吡咯并[2,3-c]吡啶-3-基)-5-氟-N-(2-氟-3-(甲磺酰)苯基)嘧啶-2-胺
Figure PCTCN2019107381-appb-000077
目标化合物采用与实施例19-10类似的方法，替换相应原料获得。
MS(ESI):m/z＝436.1[M+H] +.
实施例27:N-(3-(5-氟-2-((2-氟-3-(甲磺酰)苯基)氨基)嘧啶-4-基)-1H-吡咯并[2,3-c]吡啶-7-基)-2-(4-甲基哌嗪-1-基)丁酰胺
Figure PCTCN2019107381-appb-000078
目标化合物采用与实施例17类似的方法，替换相应原料获得。
MS(ESI):m/z＝585.51[M+H] +.
11HNMR(400MHz,DMSO-d 6)δ11.66(s,1H),10.56(s,1H),9.53(s,1H),8.46(d,J＝3.7Hz,1H),8.27(s,1H),8.22(d,J＝5.4Hz,1H),8.18–8.11(m,2H),7.91(d,J＝5.5Hz,1H),7.60(t,J＝6.2Hz,1H),7.44(t,J＝8.1Hz,1H),3.40(s,1H),3.29(s,3H),2.64(d,J＝19.1Hz,4H),2.36(s,4H),2.15(s,3H),1.84–1.73(m,1H),1.69-1.64(mz,1H),0.91(t,J＝7.4Hz,3H).
以下目标化合物采用与实施例27类似的方法，替换相应原料获得。
Figure PCTCN2019107381-appb-000079
实施例29:N-(7-(2-((2-氟-3-(甲磺酰)苯基)氨基)-5-甲基嘧啶-4-基)-5H-吡咯并[3,2-d] 嘧啶-4-基)-2-(4-甲基哌嗪-1-基)丁酰胺
Figure PCTCN2019107381-appb-000080
实施例29-1：7-溴-4-氯-5H-吡咯并[3,2-d]嘧啶
Figure PCTCN2019107381-appb-000081
在室温下，向4-氯-5H-吡咯并[3,2-d]嘧啶(2.00克,13.02毫摩尔)的乙腈(30毫升)混合物中分批加入N-溴代丁二酰亚胺(2.55克,14.33毫摩尔)，然后向反应液中加入三氟乙酸(2.35克,20.6毫摩尔)。该反应液于室温，搅拌2小时。反应经LCMS检测。过滤，收集固体，用二氯甲烷洗涤，干燥得7-溴-4-氯-5H-吡咯并[3,2-d]嘧啶29-1(2.60克,收率：85.9％)。MS(ESI):m/z＝231.7,233.7[M+H] +.
实施例29-2：7-溴-4-氯-5-((2-(三甲基甲硅烷基)乙氧基)甲基)-5H-吡咯并[3,2-d]嘧啶
Figure PCTCN2019107381-appb-000082
在冰浴冷却下，向7-溴-4-氯-5H-吡咯并[3,2-d]嘧啶(2.00克，8.60毫摩尔)的无水四氢呋喃(25毫升)溶液中加入分批氢化钠(60％，413毫克，10.32毫摩尔)。待该反应液于0℃搅拌20分钟，然后将2-(氯甲氧基)乙基)三甲基硅烷(1.72克，10.32毫摩尔)的四氢呋喃(5毫升)溶液滴加到反应液中。待反应在0℃搅拌0.5小时后，撤去冰浴将反应液于室温继续搅拌1小时。反应经TLC检测。将反应液冷却至0℃，加饱和氯化铵(15毫升)溶液淬灭反应，然后用乙酸乙酯(15毫升×3)萃取。合并的有机相依次用饱和食盐水洗涤(20毫升)，无水硫酸钠干燥。过滤，滤液经减压浓缩得油状物。该油状物经快速硅胶柱分离(石油醚:乙酸乙酯＝10:1)分离得白色固体7-溴-4-氯-5-((2-(三甲基甲硅烷基)乙氧基)甲基)-5H-吡咯并[3,2-d]嘧啶29-2(2.40克，收率：76.9％)。MS(ESI):m/z＝361.7,363.7.7[M+H] +.
1H NMR(400MHz,CDCl 3)δ:8.83(s,1H),7.67(s,1H),5.78(s,2H),3.67(t,J＝12.0Hz,2H),0.92(t,J＝12.0Hz,2H),-0.03(s,8H).
实施例29-3：7-溴-5-((2-(三甲基甲硅烷基)乙氧基)甲基)-5H-吡咯并[3,2-d]嘧啶-4-胺
Figure PCTCN2019107381-appb-000083
在配有磁力搅拌器的密封管中，将7-溴-4-氯-5-((2-(三甲基甲硅烷基)乙氧基)甲基)-5H-吡咯并[3,2-d]嘧啶(1.00克，2.76毫摩尔)加到氨的甲醇(20毫升，7.0摩尔 /升)溶液中。将该反应液置于80℃油浴中搅拌16小时。反应经(TLC)检测。待反应液冷却至室温后，减压浓缩得粗品。该粗品经快速硅胶柱分离(石油醚:乙酸乙酯＝10:1)分离得白色固体7-溴-5-((2-(三甲基甲硅烷基)乙氧基)甲基)-5H-吡咯并[3,2-d]嘧啶-4-胺29-3(816毫克，收率：86.2％)。MS(ESI):m/z＝342.8,344.8[M+H] +.
1H NMR(400MHz,CDCl 3)δ:8.45(s,1H),5.97(s,2H),5.46(s,2H),3.62(t,J＝8.4Hz,2H),0.97(t,J＝8.4Hz,2H),0.00(s,9H).
实施例29-4：(4-氨基-5-((2-(三甲基甲硅烷基)乙氧基)甲基)-5H-吡咯并[3,2-d]嘧啶-7- 基)硼酸
Figure PCTCN2019107381-appb-000084
室温下，向配有磁力搅拌器的50毫升三口烧瓶中加入7-溴-5-((2-(三甲基甲硅烷基)乙氧基)甲基)-5H-吡咯并[3,2-d]嘧啶-4-胺(645毫克，1.88毫摩尔)的无水四氢呋喃(10毫升)溶液。氩气置换三次后，将反应液冷却至-78℃。然后向反应液中滴加正丁基锂的正己烷溶液(3.0毫升，7.5毫摩尔，2.5摩尔/升)。滴加完毕后，该反应液于-78℃搅拌30分钟。然后向反应中滴加硼酸三异丙酯(1.41克，7.52毫摩尔)的四氢呋喃(2.0毫升)溶液。反应于-78℃继续搅拌1小时。经LCMS检测反应。加饱和氯化铵(15毫升)溶液淬灭反应，然后用乙酸乙酯(15毫升×3)萃取。合并的有机相依次用饱和食盐水洗涤(20毫升)，无水硫酸钠干燥。过滤，滤液经减压浓缩得粗品。该油状物经反向C-18硅胶柱(HCOOH)分离得白色固体4-氨基-5-((2-(三甲基甲硅烷基)乙氧基)甲基)-5H-吡咯并[3,2-d]嘧啶-7-基)硼酸29-4(140毫克，收率24％)。MS(ESI):m/z＝308.9[M+H] +.
实施例29-5：7-(2-((2-氟-3-(甲磺酰)苯基)氨基)-5-甲基嘧啶-4-基)-5-((2-(三甲基甲硅 烷基)乙氧基)甲基)-5H-吡咯并[3,2-d]嘧啶-4-胺
Figure PCTCN2019107381-appb-000085
在氩气保护下，向4-氯-N-(2-氟-3-(甲磺酰)苯基)-5-甲基嘧啶-2-胺(125毫克，0.405毫摩尔)，4-氨基-5-((2-(三甲基甲硅烷基)乙氧基)甲基)-5H-吡咯并[3,2-d]嘧啶-7-基)硼酸(125毫克,0.405毫摩尔)，磷酸钾(172毫克,0.81毫摩尔)和1,4-二氧六环(3.0毫升)/水(1.0毫升)的混合物中加入Pd(dppf)Cl 2·DCM(33毫克,0.04毫摩尔)。将该反应液加热至90℃搅拌6小时。反应经LCMS检测。待反应液冷却至室温后，加乙酸乙酯(10毫升×2)萃取。合并的有机相经无水硫酸钠干燥，过滤，滤液经减压浓缩溶剂得粗品，该粗品经C-18硅胶柱(NH 4HCO 3)分离得浅黄色固体7-(2-((2-氟-3-(甲磺酰)苯基)氨基)-5-甲基嘧啶-4-基)-5-((2-(三甲基甲硅烷基)乙氧基)甲基)-5H-吡咯并[3,2-d]嘧啶-4-胺(96毫克，收率：43.5％)。MS(ESI):m/z＝544.0[M+H] +.
实施例29：N-(7-(2-((2-氟-3-(甲磺酰)苯基)氨基)-5-甲基嘧啶-4-基)-5-((2-(三甲基甲硅 烷基)乙氧基)甲基)-5H-吡咯并[3,2-d]嘧啶-4-基)-2-(4-甲基哌嗪-1-基)丁酰胺
Figure PCTCN2019107381-appb-000086
室温下，向配有磁力搅拌器的10毫升圆底烧瓶中加入2-(4-甲基哌嗪-1-基)丁酸(143毫克,0.551毫摩尔)，N-乙基-N-异丙基丙烷-2-胺(119毫克,0.92毫摩尔)和DMF(1.5毫升)，开动搅拌器，氮气置换三次后，向反应液中加入二羰基咪唑(60毫克,0.368毫摩尔)。将反应置于80℃油浴中加热0.5小时(至无气体放出)。将反应液冷却至室温，向反应液中加入7-(2-((2-氟-3-(甲磺酰)苯基)氨基)-5-甲基嘧啶-4-基)-5-((2-(三甲基甲硅烷基)乙氧基)甲基)-5H-吡咯并[3,2-d]嘧啶-4-胺(50毫克，0.214毫摩尔)。然后将该反应液于90℃油浴加热搅拌8小时。反应经LCMS检测。该溶液经制备高效液相色谱(NH4HCO3)分离得白色固体N-(7-(2-((2-氟-3-(甲磺酰)苯基)氨基)-5-甲基嘧啶-4-基)-5-((2-(三甲基甲硅烷基)乙氧基)甲基)-5H-吡咯并[3,2-d]嘧啶-4-基)-2-(4-甲基哌嗪-1-基)丁酰胺(22毫克，收率：33.6％)。MS(ESI):m/z＝712.2[M+H] +.
实施例29：N-(7-(2-((2-氟-3-(甲磺酰)苯基)氨基)-5-甲基嘧啶-4-基)-5H-吡咯并[3,2-d] 嘧啶-4-基)-2-(4-甲基哌嗪-1-基)丁酰胺
Figure PCTCN2019107381-appb-000087
向配有磁力搅拌器的10毫升密封管中加入N-(7-(2-((2-氟-3-(甲磺酰)苯基)氨基)-5-甲基嘧啶-4-基)-5-((2-(三甲基甲硅烷基)乙氧基)甲基)-5H-吡咯并[3,2-d]嘧啶-4-基)-2-(4-甲基哌嗪-1-基)丁酰胺(17毫克，0.024毫摩尔)的三氟乙酸(1.0毫升)溶液。将反应液加热至50℃搅拌2小时。经LCMS检测反应。待反应液冷却至室温后，减压浓缩得粗品。该溶液经制备高效液相色谱(NH 4HCO 3)分离得白色固体N-(7-(2-((2-氟-3-(甲磺酰)苯基)氨基)-5-甲基嘧啶-4-基)-5H-吡咯并[3,2-d]嘧啶-4-基)-2-(4-甲基哌嗪-1-基)丁酰胺(17毫克,收率：72.2％)。MS(ESI):m/z＝582.0.[M+H] +.
1H NMR(400MHz,DMSO-d 6)δ11.55(s,1H),10.96(s,1H),9.28(s,1H),8.66(s,2H),8.39(s,1H),8.11(s,1H),7.49–7.44(m,1H),7.39(t,J＝8.0Hz,1H),3.51(s,1H),2.65(d,J＝18.4Hz,4H),2.34(s,5H),2.14(s,3H),1.80(dd,J＝14.4,7.0Hz,1H),1.69(dd,J＝13.6,6.9Hz,1H),0.94(t,J＝7.2Hz,3H)
实施例30:1-(3-(2-((2-氟-3-(甲磺酰)苯基)氨基)-5-甲基嘧啶-4-基)-1H-吡咯并[2,3-c] 吡啶-7-基)-3-异丙基脲
Figure PCTCN2019107381-appb-000088
实施例30-2：7-氯-3-碘-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-c]吡啶
Figure PCTCN2019107381-appb-000089
在冰浴冷却下，向7-氯-3-碘-1H-吡咯并[2,3-c]吡啶(5.33克，19.14毫摩尔)的无水四氢呋喃(55毫升)溶液中加入分批氢化钠(60％，919毫克，22.97毫摩尔)。待该反应液于0℃搅拌20分钟，然后将(2-(氯甲氧基)乙基)三甲基硅烷(3.83克，22.97毫摩尔)的四氢呋喃(10毫升)溶液滴加到反应液中。待反应在0℃搅拌0.5小时后，撤去冰浴将反应液于室温继续搅拌16小时。反应经TLC检测。将反应液冷却至0℃，加饱和氯化铵(30毫升)溶液淬灭反应，然后用乙酸乙酯(30毫升×3)萃取。合并的有机相依次用饱和食盐水洗涤(30毫升)，无水硫酸钠干燥。过滤，滤液经减压浓缩得油状物。该油状物经快速硅胶柱分离(石油醚:乙酸乙酯＝10:1)分离得白色固体7-氯-3-碘-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-c]吡啶(6.02克，收率：77％)。MS(ESI):m/z＝408.7,410.7[M+H] +.
实施例30-3：7-叠氮-3-碘-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-c]吡啶
Figure PCTCN2019107381-appb-000090
在配有磁力搅拌器的密封管中，将7-氯-3-碘-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-c]吡啶(3.40克，8.32毫摩尔)，叠氮钠(1.62克，24.95毫摩尔)和N-甲基吡咯烷酮(30毫升)。将该反应液置于180℃油浴中搅拌1小时。反应经(TLC)检测。待反应液冷却至室温后，将反应液倒入100毫升水中，然后用乙酸乙酯(30毫升×3)萃取。合并的有机相依次用水(30毫升*3)、饱和食盐水洗涤(30毫升)，无水硫酸钠干燥。过滤，滤液经减压浓缩得油状物。分离得白色固体7-叠氮-3-碘-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-c]吡啶(1.97克，收率：57％)。MS(ESI):m/z＝415.8[M+H] +.
实施例30-4：7-叠氮-3-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)-1-((2-(三甲基甲硅烷基)乙氧基) 甲基)-1H-吡咯并[2,3-c]吡啶
Figure PCTCN2019107381-appb-000091
在氩气保护下，向7-叠氮-3-碘-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-c]吡啶(500毫克，1.2毫摩尔)，4,4,4',4',5,5,5',5'-八甲基-2,2'-联(1,3,2-二噁硼戊环)(1.53克，6.00毫摩尔)，无水乙酸钾(590毫克,6.00毫摩尔)和1,4-二氧六环(7.0毫升)的混合物中加入Pd(dppf)Cl 2·DCM(95毫克，1.20毫摩尔)。将该反应液加热至90℃搅拌18小时。反应经LCMS检测。待反应液冷却至室温后，加乙酸乙酯(20毫升)稀释，过滤，滤液经减压浓缩得粗品。该粗品经快速硅胶柱分离得浅棕色固体7-叠氮-3-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-c]吡啶(97毫克，收率：17.4％)。MS(ESI):m/z＝416.0[M+H] +.
实施例30-5：4-(7-叠氮-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-c]吡啶-3- 基)-N-(2-氟-3-(甲磺酰)苯基)-5-甲基嘧啶-2-胺
Figure PCTCN2019107381-appb-000092
在氩气保护下，向7-叠氮-3-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-c]吡啶(200毫克，0.48毫摩尔)，4-氯-N-(2-氟-3-(甲磺酰)苯基)-5-甲基嘧啶-2-胺(198毫克，0.63毫摩尔)，磷酸钾(133毫克，0.96毫摩尔)和1,4-二氧六环(3.0毫升)/水(1.0毫升)的混合物中加入Pd(dppf)Cl 2·DCM(33毫克,0.04毫摩尔)。将该反应液加热至90℃搅拌6小时。反应经LCMS检测。待反应液冷却至室，温后，加乙酸乙酯(5毫升×3)萃取。合并的有机相经无水硫酸钠干燥，过滤，滤液经减压浓缩溶剂得粗品，该粗品经快速硅胶柱(石油醚：乙酸乙酯＝1:1)分离得浅黄色固体4-(7-叠氮-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-c]吡啶-3-基)-N-(2-氟-3-(甲磺酰)苯基)-5-甲基嘧啶-2-胺(148毫克，收率：54％)。MS(ESI):m/z＝569.0[M+H] +.
实施例30-6：4-(7-叠氮-1H-吡咯并[2,3-c]吡啶-3-基)-N-(2-氟-3-(甲磺酰)苯基)-5-甲基嘧啶-2- 胺
Figure PCTCN2019107381-appb-000093
向配有磁力搅拌器的10毫升密封管中加入4-(7-叠氮-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-c]吡啶-3-基)-N-(2-氟-3-(甲磺酰)苯基)-5-甲基嘧啶-2-胺(148毫克，0.26毫摩尔)的三氟乙酸(3.0毫升)溶液。将反应液加热至50℃搅拌2小时。经LCMS检测反应。待反应液冷却至室温后，减压浓缩得粗品。该溶液经制备高效液相色谱(NH 4HCO 3)分离得 粗品4-(7-叠氮-1H-吡咯并[2,3-c]吡啶-3-基)-N-(2-氟-3-(甲磺酰)苯基)-5-甲基嘧啶-2-胺(160毫克)，该粗品不经纯化直接用于下一步。MS(ESI):m/z＝438.9[M+H] +.
实施例30-7：3-(2-((2-氟-3-(甲磺酰)苯基)氨基)-5-甲基嘧啶-4-基)-1H-吡咯并[2,3-c]吡啶-7-胺
Figure PCTCN2019107381-appb-000094
向配有磁力搅拌器的50毫升圆底烧瓶中，依次加入4-(7-叠氮-1H-吡咯并[2,3-c]吡啶-3-基)-N-(2-氟-3-(甲磺酰)苯基)-5-甲基嘧啶-2-胺(160毫克)(160毫克)，二水合氯化锡(304毫克，1.36毫摩尔)和乙醇(90％,12毫升)溶液。将该反应液加热至回流并搅拌16小时。反应完成后，待反应液冷却至室温后，减压浓缩得粗品。该粗品经反向硅胶柱分离得3-(2-((2-氟-3-(甲磺酰)苯基)氨基)-5-甲基嘧啶-4-基)-1H-吡咯并[2,3-c]吡啶-7-胺(80毫克，总收率：71.4％)。MS(ESI):m/z＝412.8[M+H] +.
实施例30-8：1-(3-(2-((2-氟-3-(甲磺酰)苯基)氨基)-5-甲基嘧啶-4-基)-1H-吡咯并[2,3-c]吡啶-7- 基)-3-异丙基脲
Figure PCTCN2019107381-appb-000095
在室温下，向3-(2-((2-氟-3-(甲磺酰)苯基)氨基)-5-甲基嘧啶-4-基)-1H-吡咯并[2,3-c]吡啶-7-胺(45毫克，0.11毫摩尔)的四氢呋喃(2.0毫升)的混合液中加入2-异氰酸基丙烷(29毫克，0.33毫摩尔)。将该反应液于60℃搅拌3小时。反应经LCMS检测。减压浓缩溶剂得粗品，该粗品经制备高效液相色谱(HCOOH)分离得白色固体1-(3-(2-((2-氟-3-(甲磺酰)苯基)氨基)-5-甲基嘧啶-4-基)-1H-吡咯并[2,3-c]吡啶-7-基)-3-异丙基脲(18毫克，收率：33.2％)。MS(ESI):m/z＝498.2.[M+H] +.
1H NMR(400MHz,DMSO-d 6)δ12.06–11.97(m,2H),9.55(d,J＝6.8Hz,1H),9.24(s,2H),8.31(s,1H),8.24(d,J＝5.2Hz,4H),7.85(d,J＝5.6Hz,1H),7.72(d,J＝5.6Hz,1H),7.57(d,J＝6.3Hz,1H),7.42(t,J＝8.0Hz,1H),3.92(d,J＝6.8Hz,1H),3.28(s,3H),2.39(s,3H),1.21(d,J＝6.4Hz,6H).
参照实施例30的合成方法合成下列化合物：
Figure PCTCN2019107381-appb-000096
Figure PCTCN2019107381-appb-000097
实施例35:2-(4-(2-羟基乙基)哌嗪-1-基)-N-(3-(2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨 基)-5-甲基嘧啶-4-基)-1H-吡咯并[2,3-c]吡啶-7-基)丁酰胺
Figure PCTCN2019107381-appb-000098
实施例35-1:1-(2-(苄氧基)乙基)哌嗪
Figure PCTCN2019107381-appb-000099
向哌嗪(3克，35毫摩尔)的甲苯(10mL)溶液中加入((2-溴乙氧基)甲基)苯(1.5克，7毫摩尔)，加热搅拌90℃反应2小时。反应液冷却后，滤除固体，母液浓缩至干，残渣用反相C-18柱分离纯化(乙腈/氨水溶液)，得标题化合物35-1(1克，65％)，为黄色油状物。MS(ESI):m/z＝221.1[M+H] +.
实施例35-2:2-(4-(2-(苄氧基)乙基)哌嗪-1-基)丁酰胺
Figure PCTCN2019107381-appb-000100
向化合物35-2(500毫克，2.3毫摩尔)，2-溴丁酰胺(377毫克，2.3毫摩尔)的乙腈(5mL)溶液中加入碳酸钾(627毫克，4.5毫摩尔)，加热搅拌70℃反应16小时。反应液冷却后，滤除无机盐，母液浓缩至干，残渣用反相C-18柱分离纯化(乙腈/氨水溶液)，得标题化合物(400mg,58％)，为白色固体。MS(ESI):m/z＝306.2[M+H] +.
实施例35-4:N-(3-甲氧基-1-甲基-1H-吡唑-4-基)-4-((4-甲氧苄基)氧代)-5-甲基嘧啶 -2-胺
Figure PCTCN2019107381-appb-000101
将4(2.0g,7.5mmol),YN-HDB-232(0.95g,7.5mmol)，Pd 2(dba) 3(0.13g,0.15mmol),BINAP(0.18g,0.30mmol,碳酸铯(4.8g,15.0mmol)的甲苯(10mL)溶液在氮气保护下升温至100℃，并在此温度下维持3小时。反应液用LC-MS监控。反应结束后,向反应液中加入水(200mL)并用乙酸乙酯(200mL x2)萃取。合并有机层，用食盐水洗，无水硫酸钠干燥,滤液减压下蒸除溶剂，粗品用柱纯化(石油醚/乙酸乙酯＝1/1)得到黄色固体35-4(2.2g,81.9％yield).
LC-MS:LC-MS(ESI):m/z(M+H) +356.1.
实施例35-5:2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)-5-甲基嘧啶-4-酚
Figure PCTCN2019107381-appb-000102
将35-4(2.0g,5.6mmol)加入到4N盐酸的1,4二氧六环(20mL)中在室温下搅拌三十分钟，并用LC-MS监控反应。反应结束后,减压下蒸除溶剂，粗产品中加入乙酸乙酯(20mL)中进行重结晶，得到黄色固体35-5(1.2g,90.6％yield).
LC-MS:LC-MS(ESI):m/z(M+H) +236.1
实施例35-6:4-氯-N-(3-甲氧基-1-甲基-1H-吡唑-4-基)-5-甲基嘧啶-2-胺
Figure PCTCN2019107381-appb-000103
向35-5(1.0g,4.2mmol)的三氯氧磷(10ml)溶液中加热至80℃，并在此温度下维持3个小时，并用LC-MS监控反应。反应结束后,将三氯氧磷旋干，粗品用碳酸氢钠饱和溶液(50mL)和二氯甲烷(50mL x 2)萃取，合并有机层，用食盐水洗，无水硫酸钠干燥,滤液减压下蒸除溶剂，粗品用柱纯化(石油醚/乙酸乙酯＝1/1)得到黄色固体35-6(1.0g,92.7％yield)
LC-MS:LC-MS(ESI):m/z(M+H) +254.
实施例35-7:4-(7-氯-1-甲苯磺酰-1H-吡咯并[2,3-c]吡啶-3-基)-N-(3-甲氧基-1-甲基 -1H-吡唑-4-基)-5-甲基嘧啶-2-胺
Figure PCTCN2019107381-appb-000104
将35-6(0.4g,1.6mmol),1-3(0.88g,2.1mmol)，Pd(dppf)Cl 2(0.11g,0.16mmol),碳酸钠(0.5g,4.8mmol)的二氧六环(10mL)和水(2mL)溶液在氮气保护下升温至90℃，并在此温度下维持30分钟。反应液用LC-MS监控。反应结束后,向反应液中加入水(50mL)并用二氯甲烷(50mL x2)萃取，合并有机层，用食盐水洗，无水硫酸钠干燥,滤液减压下蒸除溶剂，粗品用柱纯化(二氯甲烷/甲醇＝10/1)得到白色固体35-7(0.52g,62.9％yield).
LC-MS:LC-MS(ESI):m/z(M+H) +524.1.
实施例35-8:2-(4-(2-(苄氧基)乙基)哌嗪-1-基)-N-(3-(2-((3-甲氧基-1-甲基-1H-吡唑 -4-基)氨基)-5-甲基嘧啶-4-基)-1H-吡咯并[2,3-c]吡啶-7-基)丁酰胺
Figure PCTCN2019107381-appb-000105
向化合物35-7(114毫克，0.22毫摩尔)，35-2(113毫克，0.37毫摩尔)，碳酸铯(200毫克，0.62毫摩尔)的无水二氧六环(2mL)溶液中加入三(二苯亚甲基丙酮)二钯(0)(27毫克，0.03毫摩尔)和4,5-双二苯基膦-9,9-二甲基氧杂蒽(35毫克，0.06毫摩尔)，氩气保护110℃加热密封反应16小时。冷却后，过滤，用甲醇洗涤。滤液浓缩，残渣用反相C-18柱分离纯化(乙腈/甲酸水溶液)，得标题化合物(80mg,41％)，为黄色固体。MS(ESI):m/z＝639.3[M+H] +.
实施例35:2-(4-(2-羟基乙基)哌嗪-1-基)-N-(3-(2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨 基)-5-甲基嘧啶-4-基)-1H-吡咯并[2,3-c]吡啶-7-基)丁酰胺
Figure PCTCN2019107381-appb-000106
向化合物35-8(48毫克，0.075毫摩尔)，甲酸铵(94毫克，1.5毫摩尔)的甲醇(5mL)溶液中加入10％钯碳(40毫克，含水率50％)，氩气保护下加热搅拌75℃反应3小时。反应液冷却后，滤除催化剂，母液浓缩至干，残渣用高效液相色谱制备得得标题化合物(9mg,22％)，为白色固体。MS(ESI):m/z＝549.2[M+H] +.
1H NMR(400MHz,CD3OD):δ8.16-8.13(m,2H),8.09(s,1H),7.91(d,J＝6.4Hz,1H),7.66(s,1H),3.90(s,3H),3.73(s,3H),3.70(t,J＝6.0Hz,2H),3.25-3.22(m,1H),2.86-2.66(m,8H),2.60(t,J＝6.0Hz,2H),2.39(s,3H),1.97-1.86(m,2H),1.08(t,J＝7.2Hz,3H).
实施例36:N-(3-(5-氟-2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1H-吡咯并[2,3-c]吡啶-7-基)-2-(4-(噁丁环-3-基)哌嗪-1-基)丁酰胺
Figure PCTCN2019107381-appb-000107
目标化合物根据实施例17方法，替换相应原料获得。
MS(ESI):m/z＝565.53[M+H]+
1HNMR(400MHz,DMSO-d6)δ11.59(s,1H),10.56(s,1H),8.43(s,2H),8.30(d,J＝3.7Hz,1H),8.21(s,1H),7.92(s,1H),7.65(s,1H),4.49-4.46(m,2H),4.36(t,J＝6.0Hz,2H),3.76(s,3H),3.68(s,3H),3.43(s,1H),3.38–3.32(m,1H),2.66(d,J＝18.6Hz,4H),2.25(s,4H),1.85–1.72(m,1H),1.69-1.62(m,1H),0.91(t,J＝7.3Hz,3H).
生物测试例1:JAK1/2/3激酶体外活性测试
重组人源JAK1蛋白购自Thermo Fisher。JAK2、JAK3蛋白购自Carna Biosciences。HTRF kinEASE TK kit购自Cisbio Bioassays。使用BioTek酶标仪Synergy Neo 2读板。
将测试化合物进行4倍浓度梯度稀释，终浓度为10μM到0.04nM 10个浓度，每个浓度两个复孔；DMSO在检测反应中的含量为1％。
JAK1酶反应：
0.5ng/μl JAK 1蛋白激酶，1μM TK Substrate-biotin多肽底物，1.1μM ATP，1×enzymatic buffer，5mM MgCl 2，1mM MnCl 2，1mM DTT，2.5nM SEB。检测板为White Proxiplate 384-Plus plate(PerkinElmer)，室温反应60分钟，反应体系为10μl。
JAK2酶反应：
0.001ng/μl JAK 2蛋白激酶，1μM TK Substrate-biotin多肽底物，2.7μM ATP，1×enzymatic buffer，5mM MgCl 2，1mM DTT。检测板为White Proxiplate 384-Plus plate(PerkinElmer)，室温反应25分钟，反应体系为10μl。
JAK3酶反应：
0.004ng/μl JAK 3蛋白激酶，1μM TK Substrate-biotin多肽底物，0.75μM ATP，1×enzymatic buffer，5mM MgCl 2，1mM DTT。检测板为White Proxiplate 384-Plus plate(PerkinElmer)，室温反应25分钟，反应体系为10μl。
反应检测：加入10μl的检测试剂至反应板中，含终浓度0.125μM SA-XL665和5μl1×TK-Antibody，室温孵育过夜，Synergy Neo 2读板。
数据分析：将665/620Ratio数值通过下列公式将读数转化成抑制率(％)＝(Ratio max-Ratio test)/(Ratio max-Ratio min)×100％。Ratio max为不含检测化合物的阳性对照，Ratio min为不含检测化合物和激酶的阴性对照，Ratio test为不同化合物各浓度的检测值。4参数曲线拟合测得IC50(nM)数据，具体见表1。
表1本发明部分化合物酶活实验的IC 50值
实施例 JAK1 JAK2 JAK3
1 C E H
2 B D G
3 B D G
4 A D G
5 B D G
6 B D G
7 B D G
8 B D G
9 B D G
10 B E H
11 B E H
12 A D G
17 A E G
18 A E G
19 A E H
20 B E H
21 A E H
22 B D H
23 B E H
24 B E H
25 A D H
26 C E H
27 A E H
28 A D H
29 C E H
30 B E G
32 A D G
33 B E G
各字母定义如下表所示：
Figure PCTCN2019107381-appb-000108
生物测试例2：细胞学JAK1/2活性测试
在TF-1细胞中，IL-6刺激主要通过JAK1导致STAT3磷酸化，而EPO刺激则以JAK2 依赖性地磷酸化STAT5。
TF-1细胞获自American Type Culture Collection(ATCC)。将TF-1细胞在含有0.5％牛血清(FBS)，0.1mM非必需氨基酸(NEAA)，1mM丙酮酸钠和37℃无酚红的OptiMEM培养基中饥饿过夜(细胞密度为100,000个细胞/孔)。将化合物在DMSO中连续梯度稀释，加入TF-1细胞并在37℃下与孵育20分钟，DMSO终浓度为0.2％。然后将人重组细胞因子IL-6(30ng/mL)或EPO(10U/mL)加入到含有TF-1细胞的孔中。继续将细胞板孵育30分钟后裂解细胞，在细胞裂解物中测量STAT3(IL-6)或STAT5(EPO)的磷酸化(pSTAT3/总STAT3 Elisa Kit：CST#7300C/CST#7305C；pSTAT5和总STAT5 Elisa Kit：Abcam#ab205715)。将IC 50值确定为相对于DMSO对照测量的50％抑制STAT磷酸化所需的化合物浓度。
表2本发明部分化合物细胞实验的IC 50值
实施例 Cell JAK1 Cell JAK2
2 J M
3 J M
4 J M
5 K O
6 K M
7 K N
8 K O
9 K M
10 L O
12 J M
19 K O
21 J O
22 K M
23 K N
24 K O
25 K O
27 K O
28 K N
30 J N
32 L O
33 L O
各字母定义如下表所示：
Figure PCTCN2019107381-appb-000109
生物测试例3：人全血(human whole blood)JAK活性检测
检测化合物对人全血中JAK1和JAK2活性的抑制：分别在人全血中进行IL-6诱导的pSTAT1水平(CD4+T细胞)和GM-CSF诱导的pSTAT5水平(CD33+细胞)的抑制分析。具体实验步骤如下：
1)人全血收集到肝素抗凝管中，100μL/孔接种到96孔板，放入细胞培养箱中15分钟。
2)将不同浓度的化合物(25μL/孔)加入相应的孔中，并在37℃，5％CO2下孵育30分钟。DMSO的最终浓度为0.2％。
3)用重组人IL-6(100ng/mL)或重组人GM-CSF(20ng/mL)或PBS在37℃，5％CO 2下刺激血液细胞20分钟。
4)用预热的1×裂解/固定缓冲液(BD Phosflow)在37℃处理血液10分钟以裂解红细胞并固定白细胞。
5)细胞用预冷的缓冲液(Perm buffer III)在冰上通透60分钟后，用抗pSTAT1和抗CD4抗体(IL-6刺激样本)或抗pSTAT5和抗CD33抗体(GM-CSF刺激样本)在4℃染色60分钟。
7)将细胞洗涤两次并用缓冲液重悬后进行FACS分析(Thermo Attune NxT)。
本发明部分化合物结果如下表所示：
Figure PCTCN2019107381-appb-000110
生物测试例4：小鼠药代动力学实验
分别单次静脉(IV)和口服(PO)给予CD-1小鼠测试化合物，于不同时间点采集血样，LC-MS/MS测定小鼠血浆中受试物的浓度并计算相关参数。具体如下：取所需量供试品，配成所需浓度的溶液用于静脉注射或口服。给药实验开始时动物年龄约6-8周。采血时间点：给药后0.083h，0.25h，0.5h，1h，2h，4h，8h和24h。建立生物样品分析方法及样品检测方法。通过不同时间点的血药浓度数据，运用Phoenix WinNonlin 7.0软件计算药代动力学参数。
本发明部分化合物结果如下表所示：
小鼠药代动力学(5mg/kg，P.O.)
参数 单位 实施例21 实施例25 实施例4
C max ng/mL 264 155 1065
AUC 0-24hr hr*ng/mL 1682 946 10249
T 1/2 hr 2.61 3.57 3.79
F ％ 97.1 66.1 106

Claims (10)

  1. 一种如下式I所示的化合物：
    Figure PCTCN2019107381-appb-100001
    其中，
    X 1、X 2、X 3、X 4各自独立地为CH或N；且
    X 1、X 2、X 3、X 4中至少有一个为N；
    Figure PCTCN2019107381-appb-100002
    环选自下组：6-10元芳香环，或5-10元的杂芳环；
    R 1独立地选自下组：H、取代或未取代的C1-C6烷基、取代或未取代的3-6元杂环基(其包括1-3个选自N、O或S的杂原子)、-S(＝O) 2R 7；
    R 2、R 3各自独立地选自下组：H、卤素、CN、取代或未取代的C1-C6烷基、取代或未取代的C1-C6烷氧基、取代或未取代的3-6元杂环基(其包括1-3个选自N、O或S的杂原子)、-S(＝O) 2R 7、-NHS(＝O) 2R 7；
    R 4、R 5各自独立地选自下组：H、卤素、CN、取代或未取代的C1-C6烷基；
    R 6选自下组：H、取代或未取代的C1-C6烷基、R 7-C(＝O)-、R 8-S(＝O) 2-、R 9R 10N-C(＝O)-、R 11R 12N-S(＝O) 2-、取代或未取代的具有1-3个选自下组N、S和O的杂原子的5-12元杂环基(包括单环、螺环、桥环或并环)、取代或未取代的C6-C10芳基、取代或未取代的具有1-3个选自下组N、S和O的杂原子的5-10元杂芳基；
    R 7、R 8、R 9、R 10、R 11、R 12各自独立地选自下组：H、取代或未取代的C1-C6烷基、取代或未取代的C1-C6烷氧基、取代或未取代的C3-C8环烷基、取代或未取代的具有1-3个选自下组N、S和O的杂原子的5-12元杂环基；
    除非特别说明，所述的“取代”是指被选自下组的一个或多个(例如2个、3个、4个等)取代基所取代：卤素、C1-C6烷氧基、卤代的C1-C6烷氧基、C3-C8环烷基、卤代的C3-C8环烷基、甲基砜基、氧代(＝O)、-CN、羟基、-NH 2、C1-C6胺基、羧基、C1-C6酰胺基(-C(＝O)-N(Rc) 2或-NH-C(＝O)(Rc)，Rc为H或C1-C5的烷基)、或取代或未取代的选自下组的基团：C1-C6烷基、C6-C10芳基、具有1-3个选自N、S和O的杂原子的5-10元杂芳基、-(CH 2)-C6-C10芳基、-(CH 2)-(具有1-3个选自N、S和O的杂原子的5-10元杂芳基)、-(具有1-3个选自N、S和O的杂原子的5-10元亚杂芳基)-(C1-C6烷基)、具有1-3个选自下组N、S和O的杂原子的5-12元杂环基(包括单环、螺环、桥环或并环)，且所述的取代基选自下组：卤素、C1-C6烷基、C1-C6亚烷基-OH、C1-C6烷氧基、氧代、-S(O) 2CH 3、-CN、-OH、C6-C10芳基、具有1-3个选自N、S和O的杂原子的3-10元杂芳基、-C(O)CHNH 2、-C(O)CHOH；
    且所述的式I化合物中，各个手性中心为R构型或S构型。
  2. 如权利要求1所述的化合物，其特征在于，所述的式I化合物具有如下式Ia或式Ib所示的结构：
    Figure PCTCN2019107381-appb-100003
    其中，R 7选自下组：H、取代或未取代的C1-C6烷基、取代或未取代的C3-C8环烷基。
  3. 如权利要求1所述的化合物，其特征在于，所述的式I化合物具有选自下组的结构：
    Figure PCTCN2019107381-appb-100004
    Figure PCTCN2019107381-appb-100005
  4. 如权利要求1所述的化合物，其特征在于，所述的化合物具有如下式II所示的结构：
    Figure PCTCN2019107381-appb-100006
    其中，
    R 6a选自下组：H、取代或未取代的C1-C6烷基、取代或未取代的C1-C6烷氧基；
    R 7a、R 8a、R 9a、R 10a选自下组：氢、卤素、取代或未取代的C1-C6烷基；
    R 11a选自下组：氢、取代或未取代的C1-C6烷基、取代或未取代的C1-C6烷氧基、取代或未取代的C1-C6胺基；
    或所述的R 7a、R 8a、R 9a、R 10a和R 11a中的任意两个基团相连从而形成-(CH 2) n-：
    其中，所述的取代指基团上的一个或多个氢原子被选自下组的取代基取代：卤素、羟基、取代或未取代的C1-C6烷氧基。
  5. 如权利要求1所述的化合物，其特征在于，所述的R 7a、R 8a、R 9a、R 10a选自下组：氢、甲基；
    所述的R 11a选自下组：甲基、乙基、羟乙基、甲氧基乙基、卤代的C1-C6烷基。
  6. 如权利要求1所述的化合物，其特征在于，所述的式I化合物选自下组：
    Figure PCTCN2019107381-appb-100007
    Figure PCTCN2019107381-appb-100008
    Figure PCTCN2019107381-appb-100009
    Figure PCTCN2019107381-appb-100010
    Figure PCTCN2019107381-appb-100011
  7. 一种药物组合物，其特征在于，包含(1)如权利要求1所述的化合物或其立体异构体或互变异构体，或其药学上可接受的盐、水合物或溶剂化物；(2)药学上可接受的载体。
  8. 如权利要求1所述的化合物或其立体异构体或互变异构体，或其药学上可接受的盐、水合物或溶剂化物，或如权利要求7所述的药物组合物的用途，其特征在于，用于制备预防和/或治疗与JAK激酶的活性或表达量相关的疾病的药物组合物。
  9. 如权利要求8所述的用途，其特征在于，所述的疾病选自下组：癌症、心血管疾病、炎症、免疫性或炎性疾病、骨髓增殖性疾病、病毒性疾病、代谢性疾病、或器官移植。
  10. 一种JAK抑制剂，其特征在于，所述抑制剂包含权利要求1所述的化合物、或其立体异构体或互变异构体、或其药学上可接受的盐、水合物或溶剂化物。
PCT/CN2019/107381 2018-09-21 2019-09-23 一类具有激酶抑制活性的芳香杂环类化合物 WO2020057669A1 (zh)

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