WO2018019223A1 - 作为选择性jak抑制剂化合物，该化合物的盐类及其治疗用途 - Google Patents

作为选择性jak抑制剂化合物，该化合物的盐类及其治疗用途 Download PDF

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WO2018019223A1
WO2018019223A1 PCT/CN2017/094254 CN2017094254W WO2018019223A1 WO 2018019223 A1 WO2018019223 A1 WO 2018019223A1 CN 2017094254 W CN2017094254 W CN 2017094254W WO 2018019223 A1 WO2018019223 A1 WO 2018019223A1
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phenyl
methyl
pyridin
azetidin
triazolo
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PCT/CN2017/094254
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English (en)
French (fr)
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张文燕
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张文燕
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Priority to KR1020197004619A priority Critical patent/KR102492378B1/ko
Priority to CN201780044487.5A priority patent/CN109843883B/zh
Priority to US16/320,796 priority patent/US11279699B2/en
Priority to EA201990386A priority patent/EA039352B1/ru
Priority to JP2019504825A priority patent/JP6978098B2/ja
Priority to EP17833526.1A priority patent/EP3492469B1/en
Publication of WO2018019223A1 publication Critical patent/WO2018019223A1/zh

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    • 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
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to a class of selective JAK inhibitor compounds, and isomers, solvates thereof, and salts of the compounds, and drugs which are active in the compound or a salt thereof, and in the preparation of therapeutic immunity Use in drugs for JAK-related target diseases such as systemic diseases, rheumatoid arthritis, and tumors.
  • JAK-STAT signaling pathway is a cytokine-stimulated signal transduction pathway discovered in recent years. JAK plays an important role in cytokine signaling.
  • the downstream substrates of the kinase JAK family include transcriptional protein signal transducers and Activator (STAT).
  • STAT transcriptional protein signal transducers and Activator
  • JAK protein is an important member of this pathway, and its abnormal increase in activity often leads to disease, many diseases are related to abnormal cellular responses of JAK-STAT signaling pathway, including autoimmune diseases, inflammatory diseases, bone diseases, metabolic diseases , neurological and neurodegenerative diseases, cancer, cardiovascular disease, allergy and asthma, Alzheimer's disease.
  • RA Rheumatoid arthritis
  • NSAIDs non-steroidal anti-inflammatory drugs
  • DMARDs improved anti-rheumatic drugs
  • antibody drugs for a long time, the first-line drugs for the treatment of RA were DMARDs.
  • MTX methotrexate
  • RA treatment has made great progress, and the patient's condition can be effectively controlled by existing treatment methods.
  • patients with RA are still suffering from recurrence of disease, unsatisfactory treatment effectiveness, poor long-term tolerance, and some adverse reactions.
  • the quality of life of RA patients includes joints. Such organ functions have not really improved in existing treatments, so there is still a huge unmet clinical need in this area with a view to restoring the normal functioning of patients.
  • RA synovial tissue and infiltrating mononuclear/macrophage, lymphocytes, etc. in the cell produce a large number of cytokines through autocrine, and these cytokines interact through different Pathway activation of JAK/STAT signaling pathway (Januskinase/Signal transducer and activators of transcription signaling pathway) can block the cascading amplification of these cytokines by specifically inhibiting JAK/STAT signaling pathway, thereby improving the symptoms of damaged joints in RA patients. Therefore, the JAK/STAT signaling pathway is a potential target for the treatment of RA.
  • the oral JAK inhibitor Tofacitinib was first approved by the FDA for the treatment of rheumatoid arthritis (RA), making it the first successful kinase inhibitor drug in the field.
  • JAK-STAT signaling pathway is a cytokine-stimulated signal transduction pathway discovered in recent years. JAK plays an important role in cytokine signaling.
  • JAK kinase JAK kinase (JANus kinase, referred to as JAKs, includes four known members JAK1). , JAK2, JAK3, TYK2) is a small family of cytoplasmic non-receptor tyrosine protein kinase superfamilies.
  • JAK3 is distributed in the bone marrow and lymphatic system, and JAK1, TYK2, and JAK2 are widely distributed in various tissue cells.
  • JAKs When JAKs bind to cytokine receptors on the cell surface, they activate receptor-coupled JAKs, which in turn phosphorylate receptors, which are cytoplasmic signaling and activators of Transcription (STAT1-). 4, STAT5a, STAT5b, STAT6) provide a recruitment site, JAKs phosphorylate STAT protein, the latter dimerization and transfer to the nucleus to regulate gene expression, this pathway is JAK / STAT signaling pathway (0'Shea JJ, Et al., N. Engl. J. Med., 2013, 368: 161-170).
  • the JAK/STAT signaling pathway is a signaling pathway stimulated by a variety of cytokines and growth factor receptors, including interleukins, interferons (IFN- ⁇ , IFN- ⁇ , IFN- ⁇ ), and erythropoietin. (EPO), granulocyte and giant cell colony stimulating factor (GM-CSF), somatotropin (GH), prolactin (PRL), thrombopoietin (TPO), etc., which are involved in the proliferation of immune cells and hematopoietic stem cells.
  • EPO interleukins, interferons
  • GM-CSF granulocyte and giant cell colony stimulating factor
  • GH somatotropin
  • PRL prolactin
  • TPO thrombopoietin
  • JAK1 can interact with IL-10, IL-19, IL-20, IL-22, IL-26, IL-28, IFN- réelle, IFN- ⁇ , IL-6 in the gp130 family, and other receptors containing ⁇ c. Binding (Rodig SJ, et al. Cell, 1998, 93: 373-383). JAK1 knockout experiments on mouse models indicate that this enzyme plays a key role in regulating the biological effects of various cytokine receptors described above (Kisseleva T., et al., Gene, 2002, 285: 1-24) . JAK1 is an immune related disease,
  • JAK1 inhibitors can be used to treat/prevent themselves
  • Inflammation of the disease such as leukemia, lymph Tumor, melanoma, arthritis, psoriasis, Crohn's disease, lupus erythematosus, acquired immunodeficiency syndrome (Hou S., et al., Hum. Genet., 2013, 132: 1049-1058) and the like.
  • JAK2 plays an important role in the regulation of various receptor signals including IL-3, IFN- ⁇ , EPO, GH (Levy DE, et al., Nat. Rev. Mol. Cell Biol., 2002, 3: 651 -662;). Knocking out JAK2 in a mouse model can lead to death in anemia animals (Schindler C., et al., J. Biol.
  • JAK3 regulates cell signaling by binding to the gamma co-chain ( ⁇ c) in cytokine receptor complexes such as IL-2, IL-4, IL-7, IL-9, IL-15, IL-21. Both JAK3 or ⁇ c mutations can lead to severe combined immunodeficiency (SCID) (Villa A., et al., Blood, 1996, 88: 817-823). Abnormal JAK3 activity is characterized by a large decrease in T cells and NK cells, loss of B cell function, and severely affecting the normal biological functions of the immune system. Based on its functional characteristics and special tissue distribution, JAK3 has become an attractive drug target for immune system-related diseases.
  • SCID severe combined immunodeficiency
  • RA rheumatoid arthritis
  • Crohn's disease systemic lupus erythematosus
  • multiple It has important clinical application value in the treatment/prevention of diseases such as sclerosis, type I diabetes, psoriasis, allergic diseases, asthma, chronic obstructive pulmonary disease, leukemia, lymphoma, organ transplantation and others (Papageorgiou AC, et Al., 2004, Trends Pharm. Sci., 2004, 25: 558-562).
  • TYK2 is the first member of the JAK family and is activated by a variety of receptors such as interferons (IFNs), IL-10, IL-12, IL-23, IL-27.
  • IFNs interferons
  • IL-10 interferons
  • IL-12 IL-12
  • IL-23 IL-27
  • loss of TYK2 function causes defects in the signaling pathways of various cytokine receptors, leading to viral infection, decreased immune function, and increased likelihood of pulmonary infection (Kisseleva T., et al., 2002, Gene, 285: 1-24).
  • Larner A.C group showed that TYK2 can help inhibit the growth and metastasis of breast cancer (Zhang Q., et al., 2011, J. Interferon Cytokine Res., 31:671-677).
  • JAK kinase is involved in various important physiological processes in the body, extensive inhibition of different subtypes may have adverse reactions.
  • Tofacitinib is used in patients with moderate to severe RA with insufficient MTX response or intolerance. Clinical trials have been accompanied by certain adverse reactions. Including infection, tuberculosis, cancer, anemia, liver damage and increased cholesterol. Tofacitinib has significant inhibitory activity on JAK1, JAK2, and JAK3 subtypes. Since JAK2 activity is associated with red blood cell differentiation and lipid metabolism, some of the above adverse reactions are thought to be related to the non-selective inhibition characteristics of the drug. Therefore, the search for selective JAK1 and / or JAK3 inhibitors will become a new direction of RA drug research.
  • JAK inhibitors have been proven to be useful in blood system diseases, tumors, rheumatoid arthritis and Treatment drugs such as psoriasis.
  • a first object of the invention is to provide a class of selective JAK inhibitor compounds.
  • the invention provides a class of selective JAK inhibitor compounds having the structure of formula (I):
  • R is selected from:
  • R 1 is hydrogen, C 1 -C 6 alkyl, or a halogen atom
  • R 2 is hydrogen or a C 1 -C 3 alkyl group
  • R 3 is hydrogen, C 1 -C 3 alkyl, or C 1 -C 6 alkylsulfonyl
  • n is selected from 0, 1, 2;
  • R 1 is hydrogen, C 1 -C 6 alkyl, or a halogen atom
  • R 4 is hydrogen, C 1 -C 7 alkanoyl, C 3 -C 7 cycloalkanoyl, or C 1 -C 6 alkanesulfonate, and may be C 1 -C 6 alkoxy, C 1 -C 6 Any substitution with an alkylsulfonyl group or a halogen;
  • R 5 is selected from C 1 -C 5 alkyl, C 3 -C 7 cycloalkyl, and may be optionally substituted by a halogen atom;
  • n is selected from 0, 1, 2;
  • preferred compounds of the structure of formula (I) of the present invention are:
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the above compound, isomer, solvate or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the present invention also provides the use of the above compound for the preparation of a medicament for treating a disease associated with JAK kinase.
  • the use is in the preparation of a medicament for the treatment of autoimmune diseases, rheumatoid arthritis, skin disorders, multiple sclerosis, psoriatic arthritis, inflammatory bowel disease, myasthenia gravis, psoriasis.
  • alkyl refers to a straight or branched alkyl group having from 1 to 12 carbon atoms in the chain, and examples of the alkyl group include methyl (Me), ethyl (Et), n-propyl, isopropyl. , butyl, isobutyl, sec-butyl, tert-butyl (t-Bu), pentyl, isopentyl, tert-amyl, hexyl, isohexyl, and according to one of ordinary skill in the art and text The teachings provided are considered to be equivalent to any of the above examples.
  • alkoxy refers to an alkyl group as defined above which is bonded to an oxygen atom.
  • the alkoxy group is attached to the parent structure via an oxygen atom.
  • amino refers to an -NH 2 group or mono or dialkylamino.
  • cycloalkyl refers to saturated and partially saturated, monocyclic, fused polycyclic, bridged polycyclic, or polycyclic carbocyclic rings having from 3 to 12 ring atoms per carbon atom.
  • cycloalkyl groups include the following entities in the form of suitable bonding moieties:
  • aryl refers to a 5-6 membered carbon aromatic ring, such as benzene
  • Bicyclic rings wherein at least one of the rings is a carbon aromatic ring such as naphthalene, anthracene and 1,2,3,4-tetrahydroquinoline; and a tricyclic ring wherein at least one of the rings is a carbon aromatic ring, such as hydrazine.
  • an aryl group includes a 5-6 membered carbon aromatic ring and a 5-7 membered heterocyclic ring including one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, provided that the point of attachment is in the carbon aromatic ring
  • a divalent radical by a substituted benzene derivative and having a free valence state on the ring, it is named as a substituted phenylene radical.
  • a naphthyl group having two points of attachment is referred to as a naphthylene group.
  • the aryl group does not contain, nor does it overlap in any way with the heterocyclic aryl groups respectively defined below.
  • the resulting ring system is an aromatic heterocyclic group rather than an aryl group.
  • arylhetero refers to:
  • An atom is a carbon atom
  • N, O and S such as from 1 to 4 heteroatoms, and in some embodiments, from 1 to 3 heteroatoms, other atoms on the ring.
  • heterocycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising from 3 to 20 ring atoms wherein one or more ring atoms are selected from nitrogen, oxygen or S (O) a hetero atom of m (where m is an integer from 0 to 2), and the remaining ring atoms are carbon. It preferably comprises from 3 to 12 ring atoms, wherein from 1 to 4 heteroatoms, more preferably a heterocycloalkyl ring contains from 3 to 10 ring atoms, more preferably a heterocycloalkyl ring contains from 5 to 6 ring atoms.
  • Non-limiting examples of monocyclic heterocycloalkyl groups include pyrrolidinyl, piperidinyl, morpholinyltetrahydrofuranyl and the like.
  • Polycyclic heterocycloalkyl groups include spiro, fused, and bridged heterocycloalkyl groups.
  • the heterocyclic ring may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, haloalkyl, alkoxy, alkylamino, halo, hydroxy Amino, oxo, alkylamino, cycloalkyl, heterocycloalkyl, heterocycloalkoxy, hydroxyalkyl, carboxy or carboxylate.
  • halogen means chloro, fluoro, bromo or iodo.
  • halo denotes chloro, fluoro, bromo or iodo.
  • haloalkyl refers to an alkyl group as defined above which is substituted by one or more halogen atoms.
  • haloalkoxy refers to an alkoxy group as defined above which is substituted by one or more halogen atoms.
  • acyl refers to a radical RC(0)- of a straight, branched, or cyclic configuration of 1 to 10 carbon atoms, or a combination thereof, which is attached to the parent structure through a hydroxy function, such a group It is saturated or unsaturated, and ester or aromatic.
  • the compound of the present invention if it contains a basic group, can be salted with an acid, and a salt of a pyrimidine derivative can be produced by a method well known to those skilled in the art.
  • Common acid salts include organic acid salts, inorganic acid salts, and the like.
  • organic acid salts are citrate, fumarate, oxalate, malate, lactate, sulfonate (eg camphor sulfonate, p-toluenesulfonate, methanesulfonic acid) Salts, etc.
  • inorganic acid salts include hydrohalides, sulfates, phosphates, nitrates, and the like.
  • a lower alkylsulfonic acid such as methanesulfonic acid, trifluoromethanesulfonic acid or the like may form a mesylate salt, a triflate salt; and an arylsulfonic acid such as benzenesulfonic acid or p-toluenesulfonic acid.
  • p-toluenesulfonate besylate; forming an appropriate salt with an organic carboxylic acid such as acetic acid, fumaric acid, tartaric acid, oxalic acid, maleic acid, malic acid, succinic acid or citric acid;
  • glutamic acid or aspartic acid can form glutamate or aspartate.
  • Corresponding salts may also be formed with inorganic acids such as hydrohalic acids (e.g., hydrofluoric acid, hydrobromic acid, hydroiodic acid, hydrochloric acid), nitric acid, carbonic acid, sulfuric acid or phosphoric acid.
  • hydrohalic acids e.g., hydrofluoric acid, hydrobromic acid, hydroiodic acid, hydrochloric acid
  • nitric acid e.g., carbonic acid, sulfuric acid or phosphoric acid.
  • the present invention provides a medicament using the JAK inhibitor compound of the formula (I), an isomer or a pharmaceutically acceptable salt or solvent compound thereof as an active ingredient.
  • One or more pharmaceutically acceptable carriers may also be included in the above-mentioned drugs, including conventional diluents, excipients, and fillers in the pharmaceutical field.
  • a binder, a wetting agent, a disintegrant, an absorption enhancer, a surfactant, an adsorption carrier, a lubricant, etc., if necessary, a flavoring agent, a sweetener or the like may be added.
  • the medicament of the present invention can be prepared into various forms such as tablets, powders, granules, capsules, oral liquids and injectable preparations, and the medicaments of the above respective dosage forms can be prepared according to a conventional method in the pharmaceutical field.
  • the present invention provides a compound of formula (I), a pharmaceutically acceptable salt thereof, for use in the treatment of a human or animal autoimmune disease, rheumatoid arthritis, a skin condition, multiple sclerosis, rheumatoid
  • autoimmune disease rheumatoid arthritis
  • a skin condition multiple sclerosis
  • rheumatoid a pharmaceutically acceptable salt thereof
  • JAK kinase particularly JAK1 or JAK3
  • JAK1 or JAK3 has a good inhibitory effect
  • the inhibitory activity against JAK2 is low, suggesting that the product is a selective JAK inhibitor
  • the compound (I) is heterogeneous.
  • Step 4 N-(5-(4-((3-(methylsulfonyl)azetidin-1-yl)methyl)phenyl)-[1,2,4]triazolo[1,5 -a]pyridin-2-yl]cyclopropanecarboxamide
  • the effect of the study compound on the activity of purified recombinant JAK was to study the inhibitory activity of the compound against JAK at the enzymatic level.
  • the experimental principle is to use a luminescent kinase assay to detect the ADP content produced by the reaction of JAK with the substrate Poly (4:1Glu, Tyr) peptide: ADP can be used as Ultra-Glo fluorescein after ADP is converted to ATP. The enzyme catalyzes the substrate of the reaction, producing an optical signal. The luminescent signal is positively correlated with the amount of ADP and kinase activity. Therefore, the inhibitory effect on the recombinant JAK was determined by observing the luminescence signal produced by the reaction of the compound with JAK and the substrate, and it was expressed by IC 50 .

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Abstract

公开了一类作为选择性JAK抑制剂化合物，及其异构体、溶剂合物、或其药学上可接受的盐，其中：（A）、R、R1、n的定义详见说明书。此外，还公开了以该化合物、及其盐类为活性成分的药物，及其在制备治疗免疫系统疾病、类风湿关节炎、肿瘤等与JAK相关靶点疾病的药物中的用途。

Description

作为选择性JAK抑制剂化合物，该化合物的盐类及其治疗用途 技术领域
本发明涉及一类作为选择性JAK抑制剂化合物，及其异构体、溶剂合物及该化合物的盐类和以该化合物或其盐类为活性成涉分的药物，及其在制备治疗免疫系统疾病、类风湿关节炎、肿瘤等JAK相关靶点疾病的药物中的用途。
背景技术
JAK-STAT信号通路是近年来发现的一条由细胞因子刺激的信号转导通路，JAK在细胞因子信号传导中起着重要的作用，激酶JAK家族的下游底物包括转录蛋白的信号转导剂和激活剂(STAT)。JAK蛋白是该通路中重要成员，而其活性的异常提高往往导致疾病的发生，很多疾病都与JAK-STAT信号通路异常细胞反应有关，这些疾病包括自身免疫病、炎性病、骨病、代谢病、神经和神经变性病、癌症、心血管病、变态反应和哮喘、阿尔兹海默氏病。
类风湿性关节炎(rheumatoid arthritis,RA)是一种临床常见的慢性自身免疫性疾病，主要表现为关节肿胀、疼痛、僵硬、畸形和功能严重受损等，人群发病率为0.5％-1.0％。由于RA的发病机制尚未明确，因此其病理过程难以控制，致残率高，严重损害患者身心健康，降低患者生存质量。目前用于治疗RA的药物主要有非甾体抗炎药(NSAID)、改善病情抗风湿药(DMARD)、以及抗体类药物。长期以来，治疗RA的一线药物为DMARDs，1988年，第1个DMARD药物甲氨蝶呤(MTX)获FDA批准治疗RA，MTX是RA治疗史上的一个重要里程碑。该药物因其有效性、耐受性、安全性等优势而被广泛应用，但其具有包括恶心、呕吐、胃部不适、肝毒性等不良反应。相比之下，新近发展的抗体类药物对于中重度RA具有较好的疗效性和安全性指标，但是因其靶向特定的细胞因子，获益人群受到明显限制，同时治疗费用和注射方式给药也限制了这类药物的推广。
在过去20年的发展历程中，RA治疗已经取得长足进步，患者病情经现有治疗方法已经可以有效控制。尽管如此，RA患者仍经受疾病复发、治疗有效性不理想、长期耐受性差及一些不良反应等问题。更为重要的是，RA患者的生活质量包括关节 等器官功能在现有治疗手段并没有得到真正的改善，因此，着眼于恢复患者的正常机能在这一领域仍存在巨大的未满足的临床需求。
研究表明，在RA中起核心治病作用的是RA滑膜组织及细胞中浸润的单核/巨噬细胞、淋巴细胞等通过自分泌的方式产生大量细胞因子，这些细胞因子相互作用，通过不同途径激活JAK/STAT信号通路(Januskinase/Signal transducer and activators of transcription signaling pathway)，通过特异性抑制JAK/STAT信号通路，可阻断上述细胞因子的级联放大作用，从而改善RA患者受损关节症状，因此，JAK/STAT信号通路成为治疗RA的潜在靶点。2012年11月，口服JAK抑制剂Tofacitinib首获FDA批准用于治疗类风湿性关节炎(rheumatoid arthritis，RA)，成为该领域第1个成功的激酶抑制剂药物。
JAK-STAT信号通路是近年来发现的一条由细胞因子刺激的信号转导通路，JAK在细胞因子信号传导中起着重要的作用，JAK激酶(Janus kinase，简称JAKs，包括四个已知成员JAK1、JAK2、JAK3、TYK2)是胞浆内非受体酪氨酸蛋白激酶超家族中的一个小家族。JAK3分布于骨髓和淋巴系统中，JAK1、TYK2、JAK2则广泛分布于多种组织细胞中。当JAKs结合到细胞表面的细胞因子受体后，激活受体偶联的JAKs，进而使受体磷酸化，这为胞浆信号传导和转录激活因子STAT蛋白(Signal Transducers and Activators Of Transcription，STAT1-4、STAT5a、STAT5b、STAT6)提供了募集反应位点，JAKs磷酸化STAT蛋白，后者二聚化后转移到细胞核内调控基因表达，这条途径即JAK/STAT信号通路(0’Shea J.J.,et al.,N.Engl.J.Med.,2013,368:161-170)。
JAK/STAT信号通路是一条由多种细胞因子和生长因子受体刺激的信号传导通路，这些因子包括白介素类、干扰素类(IFN-а、IFN-β、IFN-γ)、促红细胞生成素(EPO)、粒细胞和巨细胞集落刺激因子(GM-CSF)、促生长素(GH)、催乳素(PRL)、促血小板生成素(TPO)等，其在参与免疫细胞和造血干细胞的增殖、免疫调节的生物学过程中起关键作用(Ghoreschi K.,et al.Immunol.Rev.,2009,228:273-287)。
JAK1可与IL-10、IL-19、IL-20、IL-22、IL-26、IL-28、IFN-а、IFN-γ、gp130家族中的IL-6以及含γc的其它受体等结合(Rodig S.J.,et al.Cell,1998,93:373-383)。小鼠模型上的JAK1基因敲除实验表明该酶在调节上述多种细胞因子受体的生物学效应中起着关键作用(Kisseleva T.,et al.,Gene,2002,285:1-24)。JAK1是免疫相关疾病、
炎症和癌症等疾病领域的新型靶点。JAK1抑制剂可用于治疗/预防自身免
疫性疾病炎症和(Hornakova T.,et al.,Blood,2010,115:3287-3295)，如白血病、淋巴 瘤、黑色素瘤、关节炎、银屑病、克罗恩病、红斑狼疮、获得性免疫缺陷综合症(Hou S.,et al.,Hum.Genet.,2013,132:1049-1058)等。
JAK2在包括IL-3、IFN-γ、EPO、GH等多种受体信号的调节过程中发挥重要作用(Levy D.E.,et al.,Nat.Rev.Mol.Cell Biol.,2002,3:651-662；)。在小鼠模型中敲除JAK2可导致贫血动物死亡(Schindler C.,et al.,J.Biol.Chem.,2007,282:20059-20063)；人体中的JAK2基因上的一个碱基突变JAK2V617F，其与骨髓增生性疾病中的真性红细胞增多症(PV)、特发性血小板增多症(ET)等的发生密切相关(Ghoreschi K.,et al.,Immunol.Rev.,2009,228:273-287)。
JAK3通过与IL-2、IL-4、IL-7、IL-9、IL-15、IL-21等细胞因子受体复合物中的γ共链(γc)相结合，调节细胞信号传导。JAK3或γc突变都可导致重症联合免疫缺陷(SCID)(Villa A.,et al.,Blood,1996,88:817-823)。JAK3活性异常表现为T细胞和NK细胞大量减少，B细胞功能丧失，严重影响免疫系统等的正常生物学功能。基于其功能特点和特殊的组织分布，JAK3成为针对免疫系统相关疾病极具吸引力的药物靶点，其抑制剂在类风湿性关节炎(RA)、克罗恩病、系统性红斑狼疮、多发性硬化症、I型糖尿病、银屑病、过敏性疾病、哮喘、慢性阻塞性肺病、白血病、淋巴瘤、器官移植和其它等疾病的治疗/预防方面具有重要的临床应用价值(Papageorgiou A.C.,et al.,2004,Trends Pharm.Sci.,2004,25:558-562)。
TYK2是JAK家族中的第一个成员，其可被干扰素(IFNs)、IL-10、IL-12、IL-23、IL-27等多种受体激活。在小鼠中，TYK2功能缺失会引起多种细胞因子受体的信号通路发生缺陷，进而导致病毒感染、抗菌免疫功能下降并增加了肺部感染的可能性等(Kisseleva T.,et al.，2002,Gene,285:1-24)。另外，LarnerA.C小组的研究表明TYK2可有助于抑制乳腺癌的生长和转移(Zhang Q.,et al.,2011,J.Interferon Cytokine Res.,31:671-677)。
由于JAK激酶参与体内各种重要的生理过程，对不同亚型的广泛抑制有可能产生不良反应，Tofacitinib用于MTX反应不足或不耐受的中重度RA患者，临床试验观察其伴随一定的不良反应，包括感染、结核、肿瘤、贫血、肝损伤及胆固醇增加等。Tofacitinib对JAK1，JAK2，JAK3亚型均有显著的抑制活性，由于JAK2活性与红细胞分化以及脂代谢过程相关，上述部分不良反应被认为与该药物的非选择性抑制特点相关。因此，寻找选择性JAK1和/或JAK3抑制剂将成为RA药物研究的新方向。
目前JAK抑制剂已经被证实可以用于血液系统疾病、肿瘤、类风湿性关节炎及 银屑病等治疗药物。
发明内容
本发明的第一个目的是提供一类选择性JAK抑制剂化合物。
具体地说，本发明提供了一类选择性JAK抑制剂化合物，其具有式(I)结构：
Figure PCTCN2017094254-appb-000001
及其异构体、溶剂合物或其药学上可接受的盐；
当
Figure PCTCN2017094254-appb-000002
选自：
Figure PCTCN2017094254-appb-000003
R选自:
Figure PCTCN2017094254-appb-000004
其中：
Figure PCTCN2017094254-appb-000005
为4-10元合氮杂环，其碳原子并可被O、S、或-SO2-替代；
R1为氢、C1-C6烷基、或卤原子；
R2为氢、或C1-C3烷基；
R3为氢、C1-C3烷基、或C1-C6烷磺酰基；
n选自0、1、2；
当
Figure PCTCN2017094254-appb-000006
选自：
Figure PCTCN2017094254-appb-000007
其中：
Figure PCTCN2017094254-appb-000008
选自：
Figure PCTCN2017094254-appb-000009
R1为氢、C1-C6烷基、或卤原子；
R4为氢、C1-C7烷酰基、C3-C7环烷酰基、或C1-C6烷磺酸基，并可被C1-C6烷氧 基、C1-C6烷磺酰基、或卤素任意取代；
R5选自C1-C5烷基、C3-C7环烷基，可被卤原子任意取代；
n选自0、1、2；
或其药学上可接受的盐或溶剂化合物
更优选地，本发明式(Ⅰ)结构的优选化合物为：
N-(5-(4-((3-(甲磺酰基)氮杂环丁-1-基)甲基)苯基)-[1,2,4]三唑并[1,5-a]吡啶-2-基]环丙甲酰胺；
N-(5-(3-氟-4-((3-(甲磺酰基)氮杂环丁-1-基)甲基)苯基)-[1,2,4]三唑并[1,5-a]吡啶-2-基]环丙甲酰胺；
N-(5-(3,5-二氟-4-((3-(甲磺酰基)氮杂环丁-1-基)甲基)苯基)-[1,2,4]三唑并[1,5-a]吡啶-2-基]环丙甲酰胺；
N-(5-(4-((3-(甲磺酰基)氮杂环丁-1-基)甲基)苯基)-[1,2,4]三唑并[1,5-a]吡啶-2-基]异丁酰胺；
N-(5-(4-((3-(环丙磺酰基)氮杂环丁-1-基)甲基)苯基)-[1,2,4]三唑并[1,5-a]吡啶-2-基]异丁酰胺；
N-(5-(4-((3-(乙磺酰基)氮杂环丁-1-基)甲基)苯基)-[1,2,4]三唑并[1,5-a]吡啶-2-基]异丁酰胺；
N-(5-(4-((3-(乙基磺酰基)氮杂环丁-1-基)甲基)苯基)-[1,2,4]三唑并[1,5-a]吡啶-2-基]环丙甲酰胺；
5-(4-((3-(甲磺酰基)氮杂环丁-1-基)甲基)苯基)-[1,2,4]三唑并[1,5-a]吡啶-2-氨基；
N-(8-(4-((3-(甲磺酰基)氮杂环丁-1-基)甲基)苯基)-[1,2,4]三唑并[1,5-a]吡啶-2-基]环丙甲酰胺；
N-(8-(4-((3-(环丙磺酰基)氮杂环丁-1-基)甲基)苯基)-[1,2,4]三唑并[1,5-a]吡啶-2-基]环丙甲酰胺；
N-(8-(4-((3-(乙磺酰基)氮杂环丁-1-基)甲基)苯基)-[1,2,4]三唑并[1,5-a]吡啶-2-基]环丙甲酰胺；
N-(8-(4-((3-(甲磺酰基)氮杂环丁-1-基)甲基)苯基)-[1,2,4]三唑并[1,5-a]吡啶-2-基]环丙甲酰胺；
N-(8-(4-((3-(环丙磺酰基)氮杂环丁-1-基)甲基)苯基)-[1,2,4]三唑并[1,5-a]吡啶-2-基]异丁酰胺；
N-(8-(4-((3-(乙磺酰基)氮杂环丁-1-基)甲基)苯基)-[1,2,4]三唑并[1,5-a]吡啶-2-基]异丁酰胺；
N-(8-(3-氟-4-((3-(甲磺酰基)氮杂环丁-1-基)甲基)苯基)-[1,2,4]三唑并[1,5-a]吡啶-2-基]环丙甲酰胺；
N-(8-(3,5-二氟-4-((3-(甲磺酰基)氮杂环丁-1-基)甲基)苯基)-[1,2,4]三唑并[1,5-a]吡啶-2-基]环丙甲酰胺；
8-(4-((3-(甲磺酰基)氮杂环丁-1-基)甲基)苯基)-[1,2,4]三唑并[1,5-a]吡啶-2-基胺；
8-(4-((3-(乙磺酰基)氮杂环丁-1-基)甲基)苯基)-[1,2,4]三唑并[1,5-a]吡啶-2-基胺；
4-(4-(7H-吡咯并[2,3-d]嘧啶-4-基)苄基)硫代吗啉1,1-二氧化物；
4-(4-(7H-吡咯并[2,3-d]嘧啶-4-基)苄基)吗啉；
4-(4-((4-甲基哌嗪-1-基)甲基)苯基)-7H-吡咯并[2,3-d]嘧啶；
1-(4-(7H-吡咯并[2,3-d]嘧啶-4-基)苄基)哌啶-4-酮；
4-(4-(吡咯-1-基甲基)苯基)-7H-吡咯并[2,3-d]嘧啶；
4-(4-(1H-吡咯并[2,3-b]吡啶-4-基)苄基)硫代吗啉1,1-二氧化物；
4-(4-(1H-吡咯并[2,3-b]吡啶-3-基)苄基)硫代吗啉1,1-二氧化物；
4-(4-(1H-吡咯并[2,3-b]吡啶-3-基)苄基)吗啉；
3-(4-((4-甲基哌嗪-1-基)甲基)苯基)-7H-吡咯并[2,3-b]吡啶；
4-(4-(1H-吡咯并[2,3-b]吡啶-3-基)苄基)哌啶-4-酮或
3-(4-(吡咯-1-基甲基)苯基)-1H-吡咯并[2,3-b]吡啶；
及其异构体、溶剂合物或其药学上可接受的盐。
本发明还提供一种药物组合物，其包括上述化合物、异构体、溶剂合物或其药学上可接受的盐，以及药学上可接受的载体。
本发明还提供一种上述化合物在制备治疗JAK激酶相关疾病的药物中的应用。
优选地，该应用是在制备治疗自身免疫疾病、类风湿性关节炎、皮肤病症、多发性硬化、银屑性关节炎、炎性肠病、重症肌无力、牛皮藓中的应用。
专业术语
术语“烷基”是指链中具有1至12个碳原子的直链或支链的烷基，烷基的实例包括甲基(Me)、乙基(Et)、正丙基、异丙基、丁基、异丁基、仲丁基、叔丁基(t-Bu)、戊基，异戊基、叔戊基、己基，异己基、以及根据本领域普通技术人员和文本所提 供的教导认为是相当于上述实例中的任何一种基团。
术语“烷氧基”是指键接氧原子的如上定义的烷基。烷氧基经由氧原子连接到母体结构。
术语“氨基”是指-NH2基团或单或二烷基氨基。
术语环烷基是指饱和和部分饱和的，单环的、稠合多环的、桥连多环的、或爆多环的碳环，每个碳原子具有3至12个环原子数。环烷基的说明性实例包括以下的适当键合部分形式的实体：
Figure PCTCN2017094254-appb-000010
术语“芳基”是指5-6元的碳芳香环，如，苯；
双环，其中至少有一个环是碳芳香环，如，萘，茚和1，2，3，4-四氢喹啉；以及三环，其中至少有一个环是碳芳香环，如，芴。
例如，芳基包括含5-6元的碳芳香环并一个5-7元杂环，这个杂环包括一个或多个选自氮﹑氧和硫的杂原子，条件是连接点在碳芳香环上.通过取代的苯的衍生物且环上原子有自由价态的形成二价自由基，其命名为取代的亚苯基自由基。由命名以“基”结尾的单价多环烃自由基通过减少一个自由价态的氢原子衍生而来的二价自由基，其命名就是在相应的单价自由基的后面加上“亚基”，例如，有两个连接点的萘基被称为亚萘基。但是，芳基不包含﹑也不通过任何方式与下面分别定义的杂环芳基重叠。因此，在此定义，如果一个或多个碳芳香环与一个杂芳香环并列，由此产生的环系统是芳杂环基，而不是芳基。
术语“芳杂基”指的是：
5-8元的单环芳烃，含一个或多个选自N，O和S的杂原子，如1-4个杂原子，在一些实施方案中，为1-3个杂原子，环上其它原子是碳原子；
8-12元的双环芳烃，含一个或多个选自N，O和S的杂原子，如1-4个杂原子，在一些实施方案中，为1-3个杂原子，环上其它原子是碳原子；其中至少有一个环是芳香环；以及
Figure PCTCN2017094254-appb-000011
Figure PCTCN2017094254-appb-000012
术语“杂环烷基”是指饱和或部分不饱和单环或多环环状烃取代基，其包括3至20个环原子，其中一个或多个环原子选自氮、氧或S(O)m(其中m是0-2的整数)的杂原子，其余环原子为碳。优选包括3至12个环原子，其中1～4个杂原子，更优选的杂环烷基环包含3至10个环原子，更优选的杂环烷基环包含5至6个环原子。单环杂环烷基的非限制性实例包含吡咯烷基、哌啶基、吗啉基四氢呋喃基等。多环杂环烷基包括螺环、稠环和桥环的杂环烷基。杂环可以是取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、卤代烷基、烷氧基、烷基氨基、卤素、羟基、氨基、氧代基、烷氨基、环烷基、杂环烷基、杂环烷氧基、羟烷基、羧基或羧酸酯基。
术语”卤素”表示氯、氟、溴或碘。术语“卤代”代表氯代，氟代，溴代或碘代。术语“卤代烷基”是指如上所定义的烷基，其被一个或多个卤原子取代。
术语“卤代烷氧基”是指如上所定义的烷氧基，其被一个或多个卤原子取代。
术语“酰基”是指1至10个碳原子的直链、支链、或环状构型或其组合的基团R-C(0)-，其通过羟基官能团连接到母体结构，这样的基团可以是饱和的或不饱和的，和酯族或芳族的。
在本发明所提供的实施方案中，本发明的化合物如含有碱性基团，则可与酸成盐，采用本领域技术人员所熟知的方法可以制备嘧啶类衍生物的盐。
常见酸盐有有机酸盐、无机酸盐等。通常，比较常用的有机酸盐有枸橼酸盐、富马酸盐、草酸盐、苹果酸盐、乳酸盐、磺酸盐(例如樟脑磺酸盐、对甲苯磺酸盐、甲磺酸盐等)等；无机酸盐有氢卤酸盐、硫酸盐、磷酸盐、硝酸盐等。
例如，与低级烷基磺酸，如甲磺酸，三氟甲磺酸等可形成甲磺酸盐、三氟甲磺酸盐；与芳基磺酸，如苯磺酸或对甲苯磺酸等可形成对甲苯磺酸盐、苯磺酸盐；与有机羧酸，如乙酸，富马酸，酒石酸，草酸，马来酸，苹果酸，琥珀酸或柠檬酸等可形成相应的盐；与氨基酸，如谷氨酸或天冬氨酸可形成谷氨酸盐或天冬氨酸盐。与无机酸，如氢卤酸(如氢氟酸、氢溴酸、氢碘酸、氢氯酸)，硝酸，碳酸，硫酸或磷酸等也可形成相应的盐。
第二方面，本发明提供利用本发明式(I)JAK抑制剂化合物、异构体或其药学上可接受的盐或溶剂化合物为活性成分的药物。在上述药物中还可以含有一种或多种药学上可接受的载体，所述载体包括药学领域的常规稀释剂，赋形剂，填充剂， 粘合剂，湿润剂，崩解剂，吸收促进剂，表面活性剂，吸附载体，润滑剂等，必要时还可以加入香味剂，甜味剂等。本发明药物可以制成片剂，粉剂，粒剂，胶囊，口服液及注射用药等多种形式，上述各剂型的药物均可以按照药学领域的常规方法制备。
第三方面，本发明提供式(I)JAK抑制剂化合物、及其药学上可接受的盐，可应用治疗人或动物自身免疫疾病、类风湿性关节炎、皮肤病症、多发性硬化，类风湿关节炎、银屑性关节炎、炎性肠病、重症肌无力、牛皮藓中的药物中，特别是JAK激酶相关疾病的药物中的应用。
本发明发明人通过实验证实，对JAK激酶特别是JAK1或JAK3具有较好的抑制作用，对JAK2抑制活性较低，提示本品为选择性JAK抑制剂，对采用式(I)化合物、异构体或其药学上可接的盐治疗自身免疫疾病、类风湿性关节炎、皮肤病症、多发性硬化，类风湿关节炎、银屑性关节炎、炎性肠病、重症肌无力、牛皮藓的药物中，具有更低的毒性。
具体实施方式
下面通过实施例来说明本发明的可实施性，本领域的技术人员应当理解，根据现有技术的教导，对相应的技术特征进行修改或替换，仍然属于本发明要求保护的范围。
实施例1、N-(5-(4-((3-(甲磺酰基)氮杂环丁-1-基)甲基)苯基)-[1,2,4]三唑并[1,5-a]吡啶-2-基]环丙甲酰胺
Figure PCTCN2017094254-appb-000013
步骤1、1-(6-溴-吡啶-2-基)-3-乙氧羰基-硫脲
10g 2-氨基-6-溴吡啶，加100ml二氯甲烷溶解，冰浴冷至5℃，加入6.8ml异硫氰酸乙氧基羰基酯，逐渐升温至室温20℃，搅拌10小时，过滤，石油醚洗涤，干燥，得固体12g。
步骤2、5-溴-[1，2，4]三唑并[1，5a]吡啶-2-基胺
Figure PCTCN2017094254-appb-000014
10.0g羟胺盐酸盐溶于100ml乙醇中，加入14.5ml N，N-二异丙基乙胺，在室温搅拌反应1小时，然后添加9g步骤1产物，将混合物加热回流，3小时后，冷却析出固体，过滤，洗涤，晾干的目的物6g。
步骤3、N-(5-溴-[1，2，4]三唑并[1，5a]吡啶-2-基)环丙甲酰胺
Figure PCTCN2017094254-appb-000015
5g步骤2产物，加100ml二氯甲烷，二异丙基乙胺9g，冰浴冷至0℃，滴加6.1g环丙甲酰氯，反应1小时后溶清，继续反应4小时后，将反应体系浓缩至干，得油状固体，然后冰盐浴冷却下，向其中加入7ml氨水与43ml甲醇的混合溶液，搅拌约3小时，体系变为棕色混浊液，抽滤，固体水洗，烘干后得目标物4g。
步骤4、N-(5-(4-((3-(甲磺酰基)氮杂环丁-1-基)甲基)苯基)-[1,2,4]三唑并[1,5-a]吡啶-2-基]环丙甲酰胺
在二氧元环/水(5:1)30ml中，加入N-(5-溴-[1,2,4]三唑并[1,5-a]吡啶-2-基)环丙甲酰胺1g,3-(甲磺酰基)-1-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苄基)氮杂环丁烷1.25g，碳酸钾1.0g,Pd(dppf)Cl20.14g，加热至100℃反应2h，过滤，滤液旋干除二氧元环加水稀释，乙酸乙酯萃取，柱层析得目标物0.86g。
1HNMR(400MHz,DMSO-D6)δ9.21(s,1H),7.94(m,2H),7.56-7.62(m,2H),7.44(m,2H),7.26(s,1H),7.07(d,1H),3.94(m,1H),3.77(s,2H),3.60-3.73(m,4H),2.93(s,3H),1.79(s,1H),1.18(m,2H),0.91(m,2H).
MS(ESI):426.16(M+1)
实施例2、N-(5-(3-氟-4-((3-(甲磺酰基)氮杂环丁-1-基)甲基)苯基)-[1,2,4]三唑并[1,5-a]吡啶-2-基]环丙甲酰胺
Figure PCTCN2017094254-appb-000016
参考实施例1方法制备。
MS(ESI):443.15(M+1)
实施例3、N-(5-(3,5-二氟-4-((3-(甲磺酰基)氮杂环丁-1-基)甲基)苯基)-[1,2,4]三唑并[1,5-a]吡啶-2-基]环丙甲酰胺
Figure PCTCN2017094254-appb-000017
参考实施例1方法制备。
MS(ESI):462.14(M+1)
实施例4、N-(5-(4-((3-(甲磺酰基)氮杂环丁-1-基)甲基)苯基)-[1,2,4]三唑并[1,5-a]吡啶-2-基]异丁酰胺
Figure PCTCN2017094254-appb-000018
参考实施例1方法制备。
MS(ESI):428.17(M+1)
实施例5、N-(5-(4-((3-(环丙磺酰基)氮杂环丁-1-基)甲基)苯基)-[1,2,4]三唑并[1,5-a]吡啶-2-基]异丁酰胺
Figure PCTCN2017094254-appb-000019
参考实施例1方法制备。
MS(ESI):454.18(M+1)
实施例6、N-(5-(4-((3-(乙磺酰基)氮杂环丁-1-基)甲基)苯基)-[1,2,4]三唑并[1,5-a]吡啶-2-基]异丁酰胺
Figure PCTCN2017094254-appb-000020
参考实施例1方法制备。
MS(ESI):442.18(M+1)
实施例7、N-(5-(4-((3-(乙基磺酰基)氮杂环丁-1-基)甲基)苯基)-[1,2,4]三唑并[1,5-a]吡啶-2-基]环丙甲酰胺
Figure PCTCN2017094254-appb-000021
参考实施例1方法制备。
MS(ESI):440.17(M+1)
实施例8、5-(4-((3-(甲磺酰基)氮杂环丁-1-基)甲基)苯基)-[1,2,4]三唑并[1,5-a]吡啶-2-氨基
Figure PCTCN2017094254-appb-000022
在二氧元环/水(5:1)30ml中，加入5-溴-[1，2，4]三唑并[1，5a]吡啶-2-基胺1g,3-(甲磺酰基)-1-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苄基)氮杂环丁烷1.5g，碳酸钾1.0g,Pd(dppf)Cl2 0.2g，加热至100℃反应2h，过滤，滤液旋干除二氧元环加水稀释，乙酸乙酯萃取，柱层析得目标物0.86g。
MS(ESI):358.13(M+1)
实施例9、N-(8-(4-((3-(甲磺酰基)氮杂环丁-1-基)甲基)苯基)-[1,2,4]三唑并[1,5-a]吡啶-2-基]环丙甲酰胺
Figure PCTCN2017094254-appb-000023
参考实施例1方法制备。
MS(ESI):426.16(M+1)
实施例10、N-(8-(4-((3-(环丙磺酰基)氮杂环丁-1-基)甲基)苯基)-[1,2,4]三唑并[1,5-a]吡啶-2-基]环丙甲酰胺
Figure PCTCN2017094254-appb-000024
参考实施例1方法制备。
MS(ESI):452.17(M+1)
实施例11、N-(8-(4-((3-(乙磺酰基)氮杂环丁-1-基)甲基)苯基)-[1,2,4]三唑并[1,5-a]吡啶-2-基]环丙甲酰胺
Figure PCTCN2017094254-appb-000025
参考实施例1方法制备。
MS(ESI):440.17(M+1)
实施例12、N-(8-(4-((3-(甲磺酰基)氮杂环丁-1-基)甲基)苯基)-[1,2,4]三唑并[1,5-a]吡啶-2-基]环丙甲酰胺
Figure PCTCN2017094254-appb-000026
参考实施例1方法制备。
MS(ESI):428.17(M+1)
实施例13、N-(8-(4-((3-(环丙磺酰基)氮杂环丁-1-基)甲基)苯基)-[1,2,4]三唑并[1,5-a]吡啶-2-基]异丁酰胺
Figure PCTCN2017094254-appb-000027
参考实施例1方法制备。
MS(ESI):454.18(M+1)
实施例14、N-(8-(4-((3-(乙磺酰基)氮杂环丁-1-基)甲基)苯基)-[1,2,4]三唑并[1,5-a]吡啶-2-基]异丁酰胺
Figure PCTCN2017094254-appb-000028
参考实施例1方法制备。
MS(ESI):442.18(M+1)
实施例15、N-(8-(3-氟-4-((3-(甲磺酰基)氮杂环丁-1-基)甲基)苯基)-[1,2,4]三唑并[1,5-a]吡啶-2-基]环丙甲酰胺
Figure PCTCN2017094254-appb-000029
参考实施例1方法制备。
MS(ESI):443.15(M+1)
实施例16、N-(8-(3,5-二氟-4-((3-(甲磺酰基)氮杂环丁-1-基)甲基)苯基)-[1,2,4]三唑并[1,5-a]吡啶-2-基]环丙甲酰胺
Figure PCTCN2017094254-appb-000030
参考实施例1方法制备。
MS(ESI):462.14(M+1)
实施例17、8-(4-((3-(甲磺酰基)氮杂环丁-1-基)甲基)苯基)-[1,2,4]三唑并[1,5-a]吡啶-2-基胺
Figure PCTCN2017094254-appb-000031
参考实施例1方法制备。
MS(ESI):358.13(M+1)
实施例18、8-(4-((3-(乙磺酰基)氮杂环丁-1-基)甲基)苯基)-[1,2,4]三唑并[1,5-a]吡啶-2-基胺
Figure PCTCN2017094254-appb-000032
参考实施例1方法制备。
MS(ESI):372.14(M+1)
实施例19、4-(4-(7H-吡咯并[2,3-d]嘧啶-4-基)苄基)硫代吗啉1,1-二氧化物
Figure PCTCN2017094254-appb-000033
步骤1、4-(4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苄基)硫代吗啉1,1-二氧化物
Figure PCTCN2017094254-appb-000034
在100ml三口圆底玻璃瓶中，加入5g 2-(4-(溴甲基)苯基)-4，4,5,5-四甲基-1,3,2-二氧硼杂环戊烷，用10ml N，N-二甲基甲酰胺溶解，然后加入5.8g碳酸钾，4g盐酸硫代吗啉1,1-二氧化物，氮气保护下，室温反应2小时，薄层层析示发反应完毕，加冰水于反应混合物中，加乙酸乙酯萃取，(25ml×3)，有机层水洗，干燥(硫酸钠)，过滤，浓缩，得目的物6g。
步骤2、4-(4-(7-((2-(三甲硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-4-基)苄基)硫代吗啉1,1-二氧化物
Figure PCTCN2017094254-appb-000035
在二氧元环/水(5:1)30ml中，加入2g 4-氯-7-((2-(三甲硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶,2.7g步骤1产物，碳酸钾1.0g,Pd(dppf)Cl20.3g，加热至100℃反应2h，过滤，滤液旋干除二氧元环加水稀释，乙酸乙酯萃取，柱层析得目标物1.8g。
步骤3、4-(4-(7H-吡咯并[2,3-d]嘧啶-4-基)苄基)硫代吗啉1,1-二氧化物
将3g步骤2产物用15ml二氯甲烷溶解，冰浴冷至0℃，加5ml三氟乙酸于反应混合物中，加毕，撤去冰浴，恢复室温反应，5小时后，薄层层析示反应完毕， 减压浓缩除溶剂，再加二氯甲烷，旋转蒸发除去残余的三氟乙酸，得黄色油状物。加入15ml甲醇溶解，冰盐浴冷至0℃，向反应混合物中，滴加无水乙二胺3ml，滴加完毕，撤去冰浴，室温反应过夜，次日，反应完毕，析出固体，过滤，硅胶柱层析纯化，得目的物1.6g。
1HNMR(400MHz,DMSO-D6)δ12.06(s,1H),8.83(s,1H),8.17(d,2H),7.66(d,1H),755(d,2H),6.90(s,1H),3.78(s,2H),3.15(m,4H),2.93(m,4H).
MS(ESI):343.12(M+1)
实施例20、4-(4-(7H-吡咯并[2,3-d]嘧啶-4-基)苄基)吗啉
Figure PCTCN2017094254-appb-000036
参考实施例19方法制备。
1HNMR(400MHz,DMSO-D6)δ12.21(s,1H),8.84(s,1H),8.15(d,2H),7.66(d,1H),753(d,2H),6.90(d,1H),3.62-3.58(m,4H),3.56(s,2H),2.41(s,4H).
MS(ESI):343.12(M+1)
实施例21、4-(4-((4-甲基哌嗪-1-基)甲基)苯基)-7H-吡咯并[2,3-d]嘧啶
Figure PCTCN2017094254-appb-000037
参考实施例19方法制备。
1HNMR(400MHz,CDCl3)δ12.31(s,1H),9.01(s,1H),8.11(d,2H),7.52(d,2H),7.43(d,1H),753(d,2H),6.85(d,1H),3.62(s,4H),2.55(m,8H),2.33(s,3H).
实施例22、1-(4-(7H-吡咯并[2,3-d]嘧啶-4-基)苄基)哌啶-4-酮
Figure PCTCN2017094254-appb-000038
参考实施例19方法制备。
1HNMR(400MHz,DMSO-D6)δ12.32(s,1H),8.19(d,2H),7.15(d,1H),7.66(d,1H),758(d,2H),6.90(d,1H),3.72(s,2H),2.74(t,4H),2.40(t,4H).
实施例23、4-(4-(吡咯-1-基甲基)苯基)-7H-吡咯并[2,3-d]嘧啶
Figure PCTCN2017094254-appb-000039
参考实施例19方法制备。
1HNMR(400MHz,DMSO-D6)δ12.27(s,1H),8.83(s,1H),8.15(d,1H),7.66(d,1H),753(d,2H),6.90(m,1H),3.69(s,2H),2.50-2.47(m,4H),1.72(s,4H).
实施例24、4-(4-(1H-吡咯并[2,3-b]吡啶-4-基)苄基)硫代吗啉1,1-二氧化物
Figure PCTCN2017094254-appb-000040
参考实施例19方法制备。
MS(ESI):342.12(M+1)
实施例25、4-(4-(1H-吡咯并[2,3-b]吡啶-3-基)苄基)硫代吗啉1,1-二氧化物
Figure PCTCN2017094254-appb-000041
参考实施例19方法制备。
MS(ESI):342.12(M+1)
实施例26、4-(4-(1H-吡咯并[2,3-b]吡啶-3-基)苄基)吗啉
Figure PCTCN2017094254-appb-000042
参考实施例19方法制备。
1HNMR(400MHz,DMSO-D6)δ11.93(s,1H),8.32-8.24(m,1H),7.85(s,1H),7.69(d,2H),7.36(d,2H),7.15(m,1H),3.64-3.52(m,4H),2.50-2.47(m,4H),3.48(s,2H),2.38(s,4H).
实施例27、3-(4-((4-甲基哌嗪-1-基)甲基)苯基)-7H-吡咯并[2,3-b]吡啶
Figure PCTCN2017094254-appb-000043
参考实施例19方法制备。
1HNMR(400MHz,DMSO-D6)δ11.93(s,1H),8.28(m,2H),7.85(s,1H),7.68(d,2H),7.35(d,2H),7.15(m,1H),3.46(s,2H),2.36(brs,8H),2.15(s,3H).
实施例28、4-(4-(1H-吡咯并[2,3-b]吡啶-3-基)苄基)哌啶-4-酮
Figure PCTCN2017094254-appb-000044
参考实施例19方法制备。
1HNMR(400MHz,DMSO-D6)δ12.05(s,1H),8.41(m,2H),7.99(d,1H),7.82(d,2H),7.53(d,2H),7.26(dd,1H),3.72(s,2H),2.81(t,4H),2.47(t,4H).
实施例29、3-(4-(吡咯-1-基甲基)苯基)-1H-吡咯并[2,3-b]吡啶
Figure PCTCN2017094254-appb-000045
参考实施例19方法制备。
1HNMR(400MHz,DMSO-D6)δ11.92(s,1H),8.27(m,2H),7.84(s,1H),7.65(m,2H),7.35(d,2H),7.15(dd,1H),3.57(s,2H),2.42(dd,4H),1.69(m,4H).
实施例30、对JAK的抑制作用
研究化合物对纯化的重组JAK活性的影响,是从酶学水平研究化合物对JAK的抑制活性。其实验原理为采用一种发光法激酶检测方法，用于检测JAK与底物Poly(4:1Glu,Tyr)肽反应产生的ADP含量：ADP转化为ATP后，ATP即可作为Ultra-Glo荧光素酶催化反应的底物，产生光信号。发光信号与ADP的量和激酶活性正相关。因此，通过观察化合物对JAK与底物反应产生的发光信号来确定其对重组的JAK的抑制效果，用IC50表示。
实验方法：10个不同浓度的化合物分别在37℃与JAK1、JAK2和JAK3孵育60分钟，然后加入底物及ATP混合，37℃反应50分钟后加入25μlADP-GloTM混合2分钟，室温反应50分钟。再加入50μl检测试剂混合2分钟，室温孵育50分钟，用化学发光仪检测。结果见表1。
表1对JAK的抑制作用实验结果
Figure PCTCN2017094254-appb-000046
Figure PCTCN2017094254-appb-000047
注：1.(a)20nM以下；
2.(b)>20nM至50nM；
3.(c)>50nM
其中，以实施例1为例，与同等实验条件下的现有JAK抑制剂的实验结果进行比较，结果见表2。
表2本发明化合物与现有JAK抑制剂对JAK的抑制作用对比
Figure PCTCN2017094254-appb-000048
结果表明：实施例1化合物对JAK1的抑制活性是JAK2的10倍，而filgotinib(CN104262337公开的化合物)对JAK1和JAK2的抑制活性在本实验中相当，提示本发明公开的化合物对JAK1具有更好的选择性，因而具有较低的毒性。

Claims (5)

  1. 式(Ⅰ)化合物：
    Figure PCTCN2017094254-appb-100001
    及其异构体、溶剂合物、或其药学上可接受的盐。
    当
    Figure PCTCN2017094254-appb-100002
    选自：
    Figure PCTCN2017094254-appb-100003
    R选自:
    Figure PCTCN2017094254-appb-100004
    其中：
    Figure PCTCN2017094254-appb-100005
    为4-10元合氮杂环，其碳原子并可被O、S、或-SO2-替代；
    R1为氢、C1-C6烷基、或卤原子；
    R2为氢、或C1-C3烷基；
    R3为氢、C1-C3烷基、或C1-C6烷磺酰基；
    n选自0、1、2；
    当
    Figure PCTCN2017094254-appb-100006
    选自：
    Figure PCTCN2017094254-appb-100007
    其中：
    Figure PCTCN2017094254-appb-100008
    选自：
    Figure PCTCN2017094254-appb-100009
    R1为氢、C1-C6烷基、或卤原子；
    R4为氢、C1-C7烷酰基、C3-C7环烷酰基、或C1-C6烷磺酸基，并可被C1-C6烷氧基、C1-C6烷磺酰基、或卤素任意取代；
    R5选自C1-C5烷基、C3-C7环烷基，可被卤原子任意取代；
    n选自0、1、2；
  2. 根据权利要求书1所述的化合物，其特征在于所述化合物共有下列结构体：
    N-(5-(4-((3-(甲磺酰基)氮杂环丁-1-基)甲基)苯基)-[1,2,4]三唑并[1,5-a]吡啶-2-基]环丙甲酰胺；
    N-(5-(3-氟-4-((3-(甲磺酰基)氮杂环丁-1-基)甲基)苯基)-[1,2,4]三唑并[1,5-a]吡啶-2-基]环丙甲酰胺；
    N-(5-(3,5-二氟-4-((3-(甲磺酰基)氮杂环丁-1-基)甲基)苯基)-[1,2,4]三唑并[1,5-a]吡啶-2-基]环丙甲酰胺；
    N-(5-(4-((3-(甲磺酰基)氮杂环丁-1-基)甲基)苯基)-[1,2,4]三唑并[1,5-a]吡啶-2-基]异丁酰胺；
    N-(5-(4-((3-(环丙磺酰基)氮杂环丁-1-基)甲基)苯基)-[1,2,4]三唑并[1,5-a]吡啶-2-基]异丁酰胺；
    N-(5-(4-((3-(乙磺酰基)氮杂环丁-1-基)甲基)苯基)-[1,2,4]三唑并[1,5-a]吡啶-2-基]异丁酰胺；
    N-(5-(4-((3-(乙基磺酰基)氮杂环丁-1-基)甲基)苯基)-[1,2,4]三唑并[1,5-a]吡啶-2-基]环丙甲酰胺；
    5-(4-((3-(甲磺酰基)氮杂环丁-1-基)甲基)苯基)-[1,2,4]三唑并[1,5-a]吡啶-2-氨基；
    N-(8-(4-((3-(甲磺酰基)氮杂环丁-1-基)甲基)苯基)-[1,2,4]三唑并[1,5-a]吡啶-2-基]环丙甲酰胺；
    N-(8-(4-((3-(环丙磺酰基)氮杂环丁-1-基)甲基)苯基)-[1,2,4]三唑并[1,5-a]吡啶-2-基]环丙甲酰胺；
    N-(8-(4-((3-(乙磺酰基)氮杂环丁-1-基)甲基)苯基)-[1,2,4]三唑并[1,5-a]吡啶-2-基]环丙甲酰胺；
    N-(8-(4-((3-(甲磺酰基)氮杂环丁-1-基)甲基)苯基)-[1,2,4]三唑并[1,5-a]吡啶-2-基]环丙甲酰胺；
    N-(8-(4-((3-(环丙磺酰基)氮杂环丁-1-基)甲基)苯基)-[1,2,4]三唑并[1,5-a]吡啶-2-基]异丁酰胺；
    N-(8-(4-((3-(乙磺酰基)氮杂环丁-1-基)甲基)苯基)-[1,2,4]三唑并[1,5-a]吡啶-2-基]异丁酰胺；
    N-(8-(3-氟-4-((3-(甲磺酰基)氮杂环丁-1-基)甲基)苯基)-[1,2,4]三唑 并[1,5-a]吡啶-2-基]环丙甲酰胺；
    N-(8-(3,5-二氟-4-((3-(甲磺酰基)氮杂环丁-1-基)甲基)苯基)-[1,2,4]三唑并[1,5-a]吡啶-2-基]环丙甲酰胺；
    8-(4-((3-(甲磺酰基)氮杂环丁-1-基)甲基)苯基)-[1,2,4]三唑并[1,5-a]吡啶-2-基胺；
    8-(4-((3-(乙磺酰基)氮杂环丁-1-基)甲基)苯基)-[1,2,4]三唑并[1,5-a]吡啶-2-基胺；
    4-(4-(7H-吡咯并[2,3-d]嘧啶-4-基)苄基)硫代吗啉1,1-二氧化物；
    4-(4-(7H-吡咯并[2,3-d]嘧啶-4-基)苄基)吗啉；
    4-(4-((4-甲基哌嗪-1-基)甲基)苯基)-7H-吡咯并[2,3-d]嘧啶；
    1-(4-(7H-吡咯并[2,3-d]嘧啶-4-基)苄基)哌啶-4-酮；
    4-(4-(吡咯-1-基甲基)苯基)-7H-吡咯并[2,3-d]嘧啶；
    4-(4-(1H-吡咯并[2,3-b]吡啶-4-基)苄基)硫代吗啉1,1-二氧化物；
    4-(4-(1H-吡咯并[2,3-b]吡啶-3-基)苄基)硫代吗啉1,1-二氧化物；
    4-(4-(1H-吡咯并[2,3-b]吡啶-3-基)苄基)吗啉；
    3-(4-((4-甲基哌嗪-1-基)甲基)苯基)-7H-吡咯并[2,3-b]吡啶；
    4-(4-(1H-吡咯并[2,3-b]吡啶-3-基)苄基)哌啶-4-酮或
    3-(4-(吡咯-1-基甲基)苯基)-1H-吡咯并[2,3-b]吡啶；
    及其异构体、溶剂合物或其药学上可接受的盐。
  3. 一种药物组合物，其特征在于，包括根据权利要求1所述的化合物、异构体、溶剂合物或其药学上可接受的盐，以及药学上可接受的载体。
  4. 根据权利要求1或2所述的化合物在制备治疗JAK激酶相关疾病的药物中的应用。
  5. 根据权利要求4所述的应用，其特征在于，所述应用是在制备治疗自身免疫疾病、类风湿性关节炎、皮肤病症、多发性硬化、银屑性关节炎、炎性肠病、重症肌无力、牛皮藓中的应用。
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WO2021164786A1 (zh) * 2020-02-21 2021-08-26 珠海联邦制药股份有限公司 Jak抑制剂的晶型及其应用
WO2022161205A1 (zh) * 2021-01-29 2022-08-04 珠海联邦制药股份有限公司 一种含有jak抑制剂或其盐或其晶型的口服制剂及其制备方法和应用

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US11414413B2 (en) 2022-08-16
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