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WO2015110092A1 - 4-取代吡咯并[2,3-d]嘧啶化合物及其用途 - Google Patents

4-取代吡咯并[2,3-d]嘧啶化合物及其用途 Download PDF

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WO2015110092A1
WO2015110092A1 PCT/CN2015/074989 CN2015074989W WO2015110092A1 WO 2015110092 A1 WO2015110092 A1 WO 2015110092A1 CN 2015074989 W CN2015074989 W CN 2015074989W WO 2015110092 A1 WO2015110092 A1 WO 2015110092A1
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compound
formula
group
acetonitrile
pyrimidin
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PCT/CN2015/074989
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English (en)
French (fr)
Inventor
秦引林
苏梅
严守升
伍贤志
陈涛
蒋建华
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江苏柯菲平医药股份有限公司
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Priority to US15/112,196 priority Critical patent/US10385056B2/en
Publication of WO2015110092A1 publication Critical patent/WO2015110092A1/zh

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    • 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
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • 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
    • A61P37/02—Immunomodulators

Definitions

  • the present invention relates to a 4-substituted pyrrolo[2,3-d]pyrimidine compound and its use in the preparation of a medicament for the treatment of diseases of the immune system, treatment of rheumatoid diseases such as rheumatoid, tumors and the like.
  • Protein kinases also known as protein phosphakinase, are a class of enzymes that catalyze the phosphorylation of proteins. It can transfer the ⁇ -phosphate on adenosine triphosphate (ATP) to the amino acid residues of protein molecules, thereby changing the conformation and activity of proteins and enzymes. Phosphorylation of proteins is an important part of many signaling pathways, and most important life processes in cells are inseparable from protein phosphorylation. These enzymes are key factors in regulating cellular signaling, including cell proliferation and cell differentiation.
  • ATP adenosine triphosphate
  • Protein kinase signaling plays a major role in transduction: one is to regulate protein activity through phosphorylation. Phosphorylation and dephosphorylation are common mechanisms for reversible activation of most signaling pathway components. Some proteins are phosphorylated. It has activity, some is active after dephosphorylation; the other is to gradually amplify the signal through the stepwise phosphorylation of the protein, causing cell reaction.
  • Janus-activated kinase Singal transducers and activators of transcriprion is a newly discovered intracellular signaling pathway closely related to cytokines, which is involved in cell proliferation and differentiation. Many important biological processes such as apoptosis and immune regulation.
  • Janus kinase is a non-receptor tyrosine protein kinase.
  • JAK is a very important drug target
  • JAK inhibitors have been proven to be useful in the treatment of blood system diseases, tumors, rheumatoid arthritis and psoriasis. Because JAK inhibitors have significant medical uses and can be used in a variety of related disease drugs, the research and discovery of such compounds is extremely beneficial.
  • JAK inhibitor of a related disease Its mother core structure is shown in the following chemical formula.
  • As an effective JAK inhibitor it can be used as a drug substance for the preparation of a medicament for treating diseases such as rheumatoid arthritis, skin diseases, cancer, and myeloproliferative diseases.
  • Pfizer's Tofacitinib which has been marketed as a typical JAK inhibitor drug, is the first drug for the treatment of rheumatoid arthritis.
  • JAK inhibitors the therapeutic field of JAK inhibitors involves a wide range of applications, and it is an effort in the field to seek new, more active, and more highly compounded compounds.
  • a first technical object of the present invention is to provide a novel JAK inhibitor compound; a second technical object of the present invention is to provide a JAK inhibitor compound of the present invention in the preparation of a medicament for treating a disease associated with a JAK inhibitor application.
  • Y is any halogen atom, that is, the corresponding structure includes a terminal of 0-3 halogen atoms (F, Cl, Any one of Br, I) an alkane, olefin or alkyne group optionally substituted with from 1 to 4 carbon atoms.
  • Y is any halogen atom, that is, the corresponding structure is an aromatic benzene ring having 0-3 halogen atoms (one of F, Cl, Br, I) Substituted group.
  • Y is any halogen atom, that is, the corresponding structure is an aromatic benzene ring having 0-3 halogen atoms (one of F, Cl, Br, I) Substituted methyl group.
  • R3 is:
  • R4 is selected from the group consisting of hydrogen, (C1-C4) alkyl, (C2-C4) alkenyl, (C2-C4) alkynyl, C3-C7 cycloalkane, or
  • R5 and R6 are selected from the group consisting of hydrogen, (C1-C4) alkyl, (C2-C4) alkenyl, (C2-C4) alkynyl, or C3-C7 cycloalkane; and R5 is the same as or different from R6.
  • R3 is
  • W is S, N or C, and n is 1-3;
  • X is CH 2 or N.
  • R3 of the formula I of the present invention can mainly refer to two types of groups, one is a sulfonic acid group having a hydrocarbon group substituent; the other is a carbonyl group substituted with a cycloheteroalkyl group;
  • the hydrocarbon group described above includes an alkane, a cycloalkane, an alkene, and an alkyne group; the cycloheteroalkyl group, an N heterocycloalkane, an O heterocycloalkane, and a thicycloalkane.
  • a method of preparing a compound of the formula I according to the present invention which comprises the steps of:
  • a secondary amine of the compound in the structure of the compound A is added with an amine protecting group to give a compound B.
  • the amine protecting reagent used in one embodiment of the invention is triisopropylchlorosilane (TIPSCl).
  • the reaction substrate used in the bromine substitution method is selected from the group consisting of N-bromosuccinimide (NBS).
  • the alkaline environment includes a solid inorganic base and an organic base.
  • an inorganic base such as sodium carbonate, sodium hydrogencarbonate or sodium hydroxide; or an organic base such as triethylamine or N,N-diisopropylethylamine is selected as the binding acid.
  • Agent such as sodium carbonate, sodium hydrogencarbonate or sodium hydroxide; or an organic base such as triethylamine or N,N-diisopropylethylamine is selected as the binding acid. Agent.
  • Compound H is deprotected in the presence of a strong acid or a strong base to remove the protective group 2-(trimethylsilyl)ethoxymethyl group to obtain the target product I protected by the present patent.
  • a strong acid or strong base used is selected from trifluoroacetic acid.
  • R 1 , R 2 , R 3 and X contained in the structural formula are identical to those specified in the first aspect.
  • the present invention also protects a pharmaceutically acceptable salt of the compound of formula I.
  • pharmaceutically acceptable salts which are useful in the compounds of the invention are those which produce a non-toxic compound with the compounds of the invention.
  • a pharmaceutically acceptable metal ion salt such as a sodium salt or a potassium salt.
  • the technical effect of the above-mentioned addition salt is to further promote the bioavailability of the drug in the human body, which has the same pharmacological activity and therapeutic effect as the raw material compound.
  • the present invention also protects optical isomers of the compounds of formula I.
  • optical isomer of the compound of the formula I can be expected to produce the same technical effect as the compound of the present invention, i.e., it has the same pharmaceutically active and therapeutic effects as the starting compound.
  • the invention also protects a pharmaceutically acceptable acid addition salt of a compound of formula I.
  • acids which are useful in the pharmaceutically acceptable acid addition salts of the compounds of the present invention are those which produce a non-toxic compound with the compounds of the present invention, i.e., are pharmaceutically acceptable for the production of the bases of the present invention. Accepted addition salts.
  • the technical effect of the above-mentioned addition salt is to further promote the bioavailability of the drug in the human body, which has the same pharmacological activity and therapeutic effect as the raw material compound.
  • the compounds of the formula I described in the present invention include, but are not limited to, the following compounds, as described in Table 1:
  • the application specifically includes: application in preparing a disease for treating itself; application in preparing a therapeutic rheumatoid arthritis; or application in preparing an antitumor drug.
  • the raw material SM1 (24 g, 0.205 mol) was dissolved in THF (240 mL), and then was then applied to hexanes, and then cooled to -78 ° C.
  • n-BuLi (106 mL, 0.265 mol, 1.3 eq) was slowly added dropwise, and the mixture was stirred for 1 h.
  • TIPSCl (52.8g, 0.274mol, 1.3eq) and keep the temperature at -78 °C.
  • the reaction was carried out for 1 h, and the reaction was followed by TLC. After completion of the reaction, water was quenched, extracted with EA, dried and dried to yield 73 g of crude oil as yellow oil.
  • the starting material CF0726C (10g, P30%, 0.0075mol ), SM3 (2.1g, 0.0074mol, 1eq), Na2CO3 (1.59g, 0.015mol, 2eq), Pd (PPh 3) 4 (0.26g, 0.000225mol, 0.03eq Soluble in ethanol/water (80mL, 1:1), about 80 °C reaction, LCMS tracking, add SM3 to the disappearance of the raw materials, after the reaction is diluted with DCM, filtered to remove insoluble matter, H 2 O / DCM extraction, organic phase Dry and spin dry to obtain 8.5 g of a crude yellow oil. The next reaction was carried out without purification (containing about 21.6% of product).
  • the raw material CF0726Y (0.4g, 0.0021mol) was dissolved in saturated hydrogen chloride in dioxane solution (10mL), first dissolved, and then white solid precipitated. After the disappearance of the raw material, the solvent was dissolved and dissolved in THF (10 mL).
  • the raw material CF0726F (0.19g, 0.00035mol) was dissolved in DCM (5mL), TFA (2mL) was added, stirred at rt, followed by LCMS. After the reaction was completed, spin dry, add DCM and then spin twice to remove excess acid, add methanol to dissolve Add saturated aqueous ammonia (10 mL), stir at rt, precipitate with solids, follow LCMS, complete the reaction, add ice to cool, filter, and dry to obtain 80 mg of pale yellow product.
  • Example 2-6 The title compound of Example 2-6 can be prepared by a similar preparation method as in Example 1:
  • the raw material SM1 (24 g, 0.205 mol) was dissolved in THF (240 mL), and then was then applied to hexanes, and then cooled to -78 ° C.
  • n-BuLi (106 mL, 0.265 mol, 1.3 eq) was slowly added dropwise, and the mixture was stirred for 1 h.
  • TIPSCl (52.8g, 0.274mol, 1.3eq) was slowly added dropwise, maintaining the temperature at -78 °C. After the addition of the incubation reaction for 1 h, the reaction was followed by TLC. After the reaction was completed, water was quenched, extracted with EA, dried and dried to yield 73 g of yellow. The oily crude product was directly subjected to the next reaction without purification.
  • the starting material CF0726C (10g, P30%, 0.0075mol ), SM3 (2.1g, 0.0074mol, 1eq), Na2CO3 (1.59g, 0.015mol, 2eq), Pd (PPh 3) 4 (0.26g, 0.000225mol, 0.03eq Soluble in ethanol/water (80mL, 1:1), about 80 °C reaction, LCMS tracking, add SM3 to the disappearance of the raw materials, after the reaction is diluted with DCM, filtered to remove insoluble matter, H 2 O / DCM extraction, organic phase Dry and spin dry to obtain 8.5 g of a crude yellow oil. The next reaction was carried out without purification (containing about 21.6% of product).
  • the raw material CF0726F (0.1 g, 0.000177 mol) was dissolved in DCM (5 mL), TFA (2 mL) was added, rt was stirred, LCMS was followed, and the reaction was followed by spin-drying, DCM was added and then dried twice to remove excess acid and dissolved in methanol. Saturated ammonia water (10 mL) was added, stirred at rt, and solid precipitated. LCMS was followed. After the reaction was completed, it was ice-cooled, filtered, and dried to give 70 mg of pale yellow product.
  • Example 8-10 The title compound of Example 8-10 can be prepared by a similar preparation method as in Example 7:
  • the raw material CF0726F (0.2 g, 0.0003 mol) was dissolved in DCM (10 mL), TFA (4 mL) was added, rt was stirred, LCMS was followed, and the mixture was followed by LCMS. After the reaction was completed, the mixture was evaporated to dryness. 10mL) was dissolved, saturated aqueous ammonia (10mL) was added, stirred at rt, a small amount of solid was precipitated, LCMS was traced, the reaction was completed, then methanol was removed, EA was extracted, dried and dried to obtain a crude product, which was purified by a preparative column to obtain 80 mg of pale yellow product.
  • Example 12-19 The title compound of Example 12-19 was prepared by a similar procedure to that of Example 11.
  • the starting material SM1 (10 g, 0.074 mol) was dissolved in THF (100 mL), and then filtered, and then cooled to -78 ° C.
  • n-BuLi 37.7 mL, 0.09 mol, 1.2 eq
  • TIPSCl (17.2 g, 0.089 mol, 1.2 eq) was slowly added dropwise, maintaining the temperature at -78 °C.
  • TLC TLC.
  • the crude oil was yellow oil and the next reaction was carried out without purification.
  • the raw material CF0726Y (0.4g, 0.0021mol) was dissolved in saturated hydrogen chloride in dioxane solution (10mL), first dissolved, and then white solid precipitated. After the disappearance of the raw material, the solvent was dissolved and dissolved in THF (10 mL).
  • the starting material CF0726F (0.2 g, 0.00052 mol) was dissolved in acetonitrile (5 mL).
  • the raw material CF0726F (0.1 g, 0.00018 mol) was dissolved in DCM (5 mL), TFA (2 mL) was added, rt was stirred, LCMS was followed, and the reaction was followed by spin-drying, DCM was added and then dried twice to remove excess acid and dissolved in methanol.
  • Add saturated aqueous ammonia (10 mL) stir at rt, precipitate with solids, follow LCMS, complete the reaction, add ice to cool, filter, and dry to obtain 50 mg of pale yellow product.
  • Example 21 The title compounds of Examples 21-61 were prepared by a similar preparation procedure as in Example 20.
  • the raw material CF0726J (0.1 g, 0.00035 mol) was dissolved in DCM (5 mL), TFA (2 mL) was added, the temperature was warmed to 45 ° C, rt was stirred for 1 h, DCM was added and then dried twice to remove excess acid, acetone: methanol: water The mixed solvent was recrystallized to give 53 mg of CF0726J trifluoroacetate.
  • the raw material CF0726K (0.1 g, 0.00023 mol) was dissolved in DCM (5 mL), phosphoric acid (1.5 mL) was added, the temperature was raised to 40 ° C, rt was stirred for 2 h, DCM was added and then dried twice to remove excess acid, and acetone: methanol was added. The mixed solvent of water was recrystallized to obtain 38 mg of a phosphate of CF0726K.
  • the Km value of the different adenosine triphosphate (ATP) concentrations was examined by the Caliper Mobility Shift Assay method to examine the effects of the following enumerated compounds of the invention on inhibitors of the Janus series of kinases.
  • the inhibitory effect of the compounds of the invention on the JAK-STAT pathway was found to be very pronounced.
  • CTLL-2 cells were cultured and added to a 6-well plate at 1 ⁇ 10 7 cells per well. Then, the compound of the present invention was added, cultured for 6 hours under starvation, and IL-2 was added thereto to a final concentration of 150 U/mL. Incubate for 10 min and collect the cells. The cell lysate is added to lyse the cells. Proteins were collected for WEST-Blot detection to detect phosphorylation of phosphorylated JAK1 and JAK2. And phosphorylate STAT5 and obtain its IC50 value.
  • the compound of the present invention is for inhibiting proliferation of human lymphocyte tumor cells.
  • Jurkat cells were cultured in vitro to plate flat-bottom 96-well plates at 1500 cells/well. In the culture system, the highest concentration of the compound was 50 ⁇ M, and the drug concentration was diluted according to a 10-fold gradient. After the compound was applied for 48 hours, 10 ⁇ l of CCk-8 was added, and after incubation for 6 hours, the 450 nM wavelength absorption value was measured by a microplate reader.
  • NCI National Cancer Institute
  • the compound of the present invention inhibits the action of rheumatoid arthritis, and DBA/1J mice were selected, and 50 ug of bovine type II collagen was completely emulsified with an equal volume of complete Freund's adjuvant (CFA) and subcutaneously injected. After 21 days, 50 ug of the same antigen and incomplete Freund's adjuvant (IFA fully emulsified, boosted once. The observation was started from the 45th day. Using 1-4 scoring method: 1 point, normal; 2 points, 1 Joint swelling; 3 points, more than 1 joint swelling, but did not accumulate all joints; 4 points, the entire paw was severely swollen or stiff. The score of each claw was added to obtain the total score of joint inflammation in mice.
  • CFA complete Freund's adjuvant
  • mice greater than 1 were successfully established in the model. After successfully establishing a mouse model of rheumatoid arthritis, the mice of the present invention were intragastrically administered with the compound of the present invention, and the joint inflammation of the mice was scored after 2 weeks of administration, and the result showed that the product was displayed. It has obvious therapeutic effects on rheumatoid arthritis in mice.

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Abstract

本发明涉及一种4-取代吡咯并[2,3-d]嘧啶化合物，及其在制备治疗类风湿、免疫系统疾病、肿瘤等JAK相关靶点疾病的药物中的用途。本发明所述的4-取代吡咯并[2,3-d]嘧啶化合物如化学结构式I所示。通过本发明的活性实验结果表明，上述新化合物，在对Janus系列激酶的抑制、对JAK-STAT的抑制、对人淋巴细胞瘤细胞增殖的抑制，以及对类风湿性关节炎的抑制上有相当明显的作用和活性。

Description

4-取代吡咯并[2,3-d]嘧啶化合物及其用途 技术领域
本发明涉及一种4-取代吡咯并[2,3-d]嘧啶化合物，及其在制备免疫系统疾病、治疗类风湿、肿瘤等JAK相关靶点疾病的药物中的用途。
背景技术
蛋白激酶(Protein kinases)又称蛋白质磷酸化酶(Protein phosphakinase)，是一类催化蛋白质磷酸化反应的酶。它能把腺苷三磷酸(ATP)上的γ-磷酸转移到蛋白质分子的氨基酸残基上，从而改变蛋白质、酶的构象和活性。蛋白质的磷酸化是多种信号传导途径的重要环节，细胞内大部分重要的生命活过程都离不开蛋白质磷酸化。这些酶在调节细胞信号包括细胞增殖和细胞分化中是关键的因素。
蛋白激酶信号在转导中主要有两个方面的作用：一是通过磷酸化调节蛋白质的活性，磷酸化和去磷酸化是大多数信号通路组分可逆激活的共同机制，有些蛋白质在磷酸化后具有活性，有些则在去磷酸化后具有活性；二是通过蛋白质的逐级磷酸化，使信号逐级放大，引起细胞反应。
Janus激酶\信号传导及转录激活因子(Janus-activated kinase Singal transducers and activators of transcriprion，JAK-STAT)是近年来新发现的一条与细胞因子密切相关的细胞内信号传导通路，参与细胞的增殖、分化、凋亡以及免疫调节等许多重要的生物学过程。Janus激酶是一种非受体型酪氨酸蛋白激酶。有4个家族成员，分别是JAK1、JAK2、TYK2和JAK3/。而JAK是一类非常重要的药物靶点，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。由于JAK抑制剂有着显著的医疗用途，可以用于各种相关疾病药物，所以对该类化合物的研究及发现是极其有益的。
中国专利申请CN 102026999A公开了一种氮杂环丁烷和环丁烷衍生物，以及它们的组合物及使用和制备方法，它们是可用于治疗包括例如炎性疾病和自身免疫疾病以及癌症的JAK相关性疾病的JAK抑制剂。其母核结构如下化学式所示。其作为一种有效的JAK抑制剂，可以作为原料药，用于制备治疗类风湿性关节炎、皮肤病、癌症、骨髓增殖性疾病等疾病的药物。
Figure PCTCN2015074989-appb-000001
目前辉瑞公司的Tofacitinib，作为典型的JAK抑制剂药物已经上市，是用于类风湿性关节炎(rheumatoid arthritis)治疗的首创药物。但是JAK抑制剂的治疗领域涉及面及其广，寻求新的，活性更强，成药性更高的化合物是本领域的一个努力方向。
发明内容
本发明的第一技术目的，在于提供一种新的JAK抑制剂化合物；本发明的第二技术目的，在于提供本发明所述JAK抑制剂化合物在制备治疗与JAK抑制剂相关疾病的药物中的应用。
为了实现本发明的技术目的，本发明的技术方案如下。
一、一种如化学结构式I所示的化合物，
Figure PCTCN2015074989-appb-000002
其中，R1、R2为苯环任一位置取代基，并独立的选自：连接芳香环上的氢、任意一个卤素原子、-(CHZ)nCN、-(CHZ)nCH3、
Figure PCTCN2015074989-appb-000003
n＝0-3，Z＝0-2；或-CYn、或-(CHZ)nCYn、或-(CHZ)n、或-O(CHZ)n CH3、或C3-C6的环烷烃。
进一步的，所述的基团-(CHZ)nCN，即氰基取代基的通式表达；其中，n＝0-3，Z＝1-2，即对应的结构为氰基、乙氰基、丙氰基以及对应的烯或炔氰基。
所述的基团-(CHZ)nCH3或-(CHZ)n，即烃基取代基的通式表达；其中，n＝0-3，Z＝0-2，即对应的结构包括1-4个碳的烷烃、烯烃以及炔烃基团。
所述基团
Figure PCTCN2015074989-appb-000004
n＝0-3，Z＝0-2；即对应异丙基、异丁基、异戊基等支链烷烃基团。
所述的基团-(CHZ)nCYn，其中，n＝0-3，Z＝1-2，Y为任意一个卤素原子，即对应结构包括末端由0-3个卤素原子(F、Cl、Br、I之一)任意取代的1-4个碳原子的烷烃，烯烃或炔烃基团。
所述的基团-nY，其中，n＝0-3，Y为任意一个卤素原子，即对应结构为芳香苯环上有0-3个卤素原子(F、Cl、Br、I之一)任意取代的基团。
所述的基团-CYn，其中，n＝0-3，Y为任意一个卤素原子，即对应结构为芳香苯环上有0-3个卤素原子(F、Cl、Br、I之一)任意取代的甲基基团。
所述的基团-O(CHZ)n CH3，即烷氧取代基的通式表达；其中，n＝0-3，Z＝0-2，即对应结构包括1-4个碳的烷烃、烯烃以及炔烃的氧代基团。
其中R3是：
Figure PCTCN2015074989-appb-000005
进一步的，R4选自氢、(C1-C4)的烷基、(C2-C4)的烯基、(C2-C4)的炔基、C3-C7的环烷烃，或
Figure PCTCN2015074989-appb-000006
R5与R6选自氢、(C1-C4)的烷基、(C2-C4)的烯基、(C2-C4)的炔基，或C3-C7的环烷烃；R5与R6相同或不同。
或者，R3是
Figure PCTCN2015074989-appb-000007
进一步的，W为S、N或C，n是1-3；
X为CH2或N。
如上述结构式的选择可知，本发明结构式I的R3主要可以述及两类基团，一类是带烃基取代基的磺酸基团；另一类是带环杂烷基取代的羰基基团；上述所述的烃基包括烷烃、环烷烃、烯烃以及炔烃基团；所述环杂烷基，N杂环烷烃，O杂环烷烃，硫杂环烷烃。
二、本发明所述化学结构式I所示的化合物的制备方法，其包括如下步骤：
(1)化合物A结构中所述化合物的仲胺添加胺基保护基团，得到化合物B。
例如，优选的，本发明某一实施例中使用的胺基保护试剂为三异丙基氯硅烷(TIPSCl)。
Figure PCTCN2015074989-appb-000008
(2)化合物B的如下述化学反应式的位置氢被溴取代，生成化合物C。
其中，本发明某一实施例中，所述溴取代方法所使用的反应底物选自N-溴代丁二酰亚胺(NBS)。
Figure PCTCN2015074989-appb-000009
(3)化合物C与双戊酰二硼(Pin2B2)反应，生成化合物D。
Figure PCTCN2015074989-appb-000010
(4)在碱性环境下，将化合物D与化合物E反应，生成化合物F。
所述的碱性环境，包括固体无机碱、有机碱。优选的，在本发明的实施例中，选用了诸如：碳酸钠，碳酸氢钠，氢氧化钠等无机碱；或三乙胺，N,N-二异丙基乙胺等有机碱作为缚酸剂。
Figure PCTCN2015074989-appb-000011
(5)化合物F与化合物G反应，其中使用1,8-二氮杂二环[5.4.0]十一碳-7-烯(DBU)作为催化剂，生成化合物H。
Figure PCTCN2015074989-appb-000012
(6)化合物H在强酸或强碱存在的条件下，脱除保护基团2-(三甲基硅基)乙氧基甲基，得到本专利保护的目标产物I。例如优选的，在本发明一实施例中，使用的强酸或强碱选择了三氟乙酸。
Figure PCTCN2015074989-appb-000013
综上，上述制备方法的总化学反应方程式如下：
Figure PCTCN2015074989-appb-000014
其中，结构式中所包含的的R1、R2、R3、X所示结构与第一技术方案所指定的一致。
三、更进一步的，本发明还保护化学结构式I所述的化合物的药学上可接受的盐。
本领域技术人员知道，可用于本发明所述化合物的药学上可接受的盐，是与本发明化合物生产无毒化合物的盐。例如钠盐、钾盐等药学上常用的金属离子盐。并且，本领域技术人员可知，上述加成盐的技术效果在于进一步促进药物在人体中的生物利用度的，其与原料化合物具有同样的药学活性和病灶治疗效果。
四、更进一步的，本发明还保护化学结构式I所述的化合物的光学异构体。
本领域技术人员知道，化学结构式I所述的化合物的光学异构体，可以预见地产生和本发明的化合物同样的技术效果，即，其与原料化合物具有同样的药学活性和病灶治疗效果。
五、另外，本发明还保护化学结构式I所述的化合物的药学上可接受的酸加成盐。
本领域技术人员知道，可用于本发明所述化合物的药学上可接受的酸加成盐的酸，是与本发明化合物生产无毒化合物的酸，也即与本发明所述碱生产药学上可接受的加成盐。例如盐酸盐、氢溴酸盐、氢碘酸盐、三氟甲酸盐、三氟甲酸盐、硫酸盐、硫酸氢盐、硝酸盐、磷酸盐、磷酸氢盐、乙酸盐、丙酸、丙烯酸、丙二酸、丁酸、草酸盐、乳酸盐、柠檬酸盐、酸式柠檬酸盐、酒石酸盐、酒石酸氢盐、琥珀酸盐、马来酸盐、富马酸盐、马来酸盐、肉桂酸盐、香草酸盐、苹果酸盐、葡糖糖酸盐、甲磺酸盐、乙磺酸盐、苯磺酸盐、苯甲酸盐、对甲苯磺酸盐等。并且，本领域技术人员可知，上述加成盐的技术效果在于进一步促进药物在人体中的生物利用度的，其与原料化合物具有同样的药学活性和病灶治疗效果。
具体到本发明的实施方式而言，本发明所述的化学结构式I所述的化合物，其包括但不限于下列化合物，如表1所述：
表1
Figure PCTCN2015074989-appb-000015
Figure PCTCN2015074989-appb-000016
Figure PCTCN2015074989-appb-000017
Figure PCTCN2015074989-appb-000018
Figure PCTCN2015074989-appb-000019
Figure PCTCN2015074989-appb-000020
Figure PCTCN2015074989-appb-000021
Figure PCTCN2015074989-appb-000022
Figure PCTCN2015074989-appb-000023
Figure PCTCN2015074989-appb-000024
Figure PCTCN2015074989-appb-000025
Figure PCTCN2015074989-appb-000026
Figure PCTCN2015074989-appb-000027
三、本发明化学结构式I所述化合物在制备治疗JAK激酶相关疾病的药物中的应用。
进一步地，所述的应用具体包括：在制备治疗自身免疾病中的应用；在制备治疗类风湿性关节炎中的应用；或者在制备抗肿瘤药物中的应用。
通过本发明的实施例67-69的活性测试例表明，本发明的化合物结构式为I的新化合物，在对Janus系列激酶的抑制以及相关疾病体内模型上有相当明显的作用和活性。
具体实施例
以下通过具体实施方式的举例来更详细地说明本发明。以上实施方式是为了说明本发明的技术目的和有益效果而提供，而绝不意在以任何方式限制本发明。本领域技术人员通过本发明权利要求书和说明书发明内容的记载，将容易认识到，可以通过改变或者改良各种非关键参数，以获得基本上相同的技术方案的结果，这些结果也将落入本发明的权利要求书的保护范围。
实施例1：
Figure PCTCN2015074989-appb-000028
制备方法：
1)第一步：CF0726A的合成
Figure PCTCN2015074989-appb-000029
原料SM1(24g,0.205mol)溶于THF(240mL)中，氮气保护，冷至-78℃左右，慢慢滴加n-BuLi(106mL,0.265mol，1.3eq)，加完保温搅拌1h。慢慢滴加TIPSCl(52.8g,0.274mol，1.3eq)，保持温度在-78℃左右，加完保 温反应1h，TLC跟踪反应，反应结束后加水淬灭，EA萃取，干燥旋干得73g黄色油状粗品，无需纯化，直接进行下一步反应。
2)第二步：CF0726B的合成
Figure PCTCN2015074989-appb-000030
CF0726A(36.5g，P＝90％，0.121mol)溶于THF(365mL)中，冷至-78℃左右，慢慢加入NBS(23g，0.129mol，1.07eq)，加完保温1h，LCMS跟踪反应。反应结束后加水淬灭，EA萃取，干燥旋干得50g淡黄色粗品，碱性Al2O3过柱得21.4g白色固体产品(PE洗脱)。
3)第三步：CF0726C的合成
Figure PCTCN2015074989-appb-000031
将原料CF0726B(12.5g，P91.7％，0.0327mol)、Pin2B2(41.5g，0.163mol，5eq)、KOAc(16g，0.163mol，5eq)、Pd(dppf)Cl2(2g，0.0026mol，0.08eq)置于250mL三口瓶中，油泵抽真空30min，加入二氧六环(140mL)，氮气保护下80～95℃反应过夜。LCMS跟踪，反应结束后加DCM稀释，过滤除去不溶物，H2O/DCM萃取，有机相干燥旋干得10g淡黄色油状物粗品(含约30％产品、Pin2B2、CF0726A)。
4)第四步：CF0726E的合成
Figure PCTCN2015074989-appb-000032
将原料CF0726C(10g，P30％，0.0075mol)、SM3(2.1g，0.0074mol，1eq)、Na2CO3(1.59g，0.015mol，2eq)、Pd(PPh3)4(0.26g，0.000225mol，0.03eq)溶于乙醇/水(80mL，1:1)，80℃左右反应，LCMS跟踪，补加SM3至原料消失，反应结束后加DCM稀释，过滤除去不溶物，H2O/DCM萃取，有机相干燥旋干得8.5g黄色油状物粗品，不纯化直接下一步反应(含约21.6％产品)。
5)第五步：CF0726F的合成
Figure PCTCN2015074989-appb-000033
将原料CF0726E(8.5g，P21.6％，0.0035mol)、TBAF(4.3g，0.0165mol，4.7eq)溶于THF(85mL)，r.t搅拌，LCMS跟踪，反应结束后旋干，加H2O/EA萃取，有机相干燥旋干，过柱得白色固体产品(PE/EA＝1:4洗脱)得1g白色固体产品。
6)第六步：SM2的合成
Figure PCTCN2015074989-appb-000034
1、氰甲基磷酸二乙酯溶于THF(75mL)，氮气保护，降至-7～-5℃，滴加叔丁醇钾/THF(3.6g溶于35mLTHF)，加完保温3h，滴加1-Boc-3-氮杂环丁酮/THF溶液(5g溶于15mLTHF)，保温1h后室温搅拌过夜，加水淬灭后EA/H2O萃取，干燥旋干得8g粗品，上柱得4.3g白色固体产品CF0726Y。
2、将原料CF0726Y(0.4g，0.0021mol)溶于饱和氯化氢的二氧六环溶液(10mL)，先溶清，然后有白色固体析出，原料消失后旋干溶剂，加THF(10mL)溶解后滴加DIPEA(0.8g，6.18mmol，3eq)，搅10min，滴加乙基磺酰氯(0.32g，0.0025mol，1.2eq)，r.t搅拌，LCMS跟踪，反应结束后旋干，EA/H2O萃取，饱和NaHCO3洗涤一次，饱和食盐水洗涤，干燥旋干得0.3g黄色油状粗品。
7)第七步：CF0726H的合成
Figure PCTCN2015074989-appb-000035
将原料CF0726F(0.1g，0.00027mol)溶于乙腈(5mL)中，加SM2(0.1g，0.00054mol，2eq)、DBU(0.1g，0.00066mol，2.4eq)，r.t搅拌过夜，反应结束后旋干，H2O/EA萃取，有机相干燥旋干过柱得0.19g产品(PE/EA＝3:1～1:1)。
8)第八步：CF0726J的合成
Figure PCTCN2015074989-appb-000036
将原料CF0726F(0.19g,0.00035mol)溶于DCM(5mL)中，加入TFA(2mL)，r.t搅拌，LCMS跟踪，反应结束后旋干，加DCM再旋干两次除去多余酸，加甲醇溶解，加饱和氨水(10mL)，r.t搅拌，有固体析出，LCMS跟踪，反应完全后加冰冷却，过滤，烘干得80mg淡黄色产品。
MS ES+：421.2
1H-NMR(400MHz，DMSO)；δ(ppm)：7.09-8.80(m，8H，aromatic-H)，4.73(d，2H，J＝4.4Hz，-N-CH2-)，4.49(d，2H，J＝4.6Hz，-N-CH2-)，3.64(s，2H，-CH2-CN)，3.22(q，J＝7.2Hz，2H，S-CH2-CH3)，1.24(t，J＝2.0Hz，3H，S-CH2-CH3)。
通过与实施例1类似的制备方法，可制备实施例2-6标题化合物：
实施例2
2-(3-(3-(7H-吡咯[2,3-d]嘧啶-4-基)-1H-吲哚-1-基)-1-(甲基磺酰基)氮杂环丁烷-3-基)乙腈。
实施例3
2-(3-(3-(7H-吡咯[2,3-d]嘧啶-4-基)-1H-吲哚-1-基)-1-(丙基磺酰基)氮杂环丁烷-3-基)乙腈。
实施例4
2-(3-(3-(7H-吡咯[2,3-d]嘧啶-4-基)-1H-吲哚-1-基)-1-(异丙基磺酰基)氮杂环丁烷-3-基)乙腈。
实施例5
2-(3-(3-(7H-吡咯[2,3-d]嘧啶-4-基)-1H-吲哚-1-基)-1-(环丙基磺酰基)氮杂环丁烷-3-基)乙腈。
实施例6
2-(3-(3-(7H-吡咯[2,3-d]嘧啶-4-基)-1H-吲哚-1-基)-1-(丁基磺酰基)氮杂环丁烷-3-基)乙腈。
实施例7：
Figure PCTCN2015074989-appb-000037
制备方法：
1)第一步：CF0726A的合成
Figure PCTCN2015074989-appb-000038
原料SM1(24g,0.205mol)溶于THF(240mL)中，氮气保护，冷至-78℃左右，慢慢滴加n-BuLi(106mL，0.265mol，1.3eq)，加完保温搅拌1h。慢慢滴加TIPSCl(52.8g,0.274mol，1.3eq)，保持温度在-78℃左右，加完保温反应1h，TLC跟踪反应，反应结束后加水淬灭，EA萃取，干燥旋干得73g黄色油状粗品，无需纯化，直接进行下一步反应。
2)第二步：CF0726B的合成
Figure PCTCN2015074989-appb-000039
CF0726A(36.5g，P＝90％，0.121mol)溶于THF(365mL)中，冷至-78℃左右，慢慢加入NBS(23g，0.129mol， 1.07eq)，加完保温1h，LCMS跟踪反应。反应结束后加水淬灭，EA萃取，干燥旋干得50g淡黄色粗品，碱性Al2O3过柱得21.4g白色固体产品(PE洗脱)。
3)第三步：CF0726C的合成
Figure PCTCN2015074989-appb-000040
将原料CF0726B(12.5g，P91.7％，0.0327mol)、Pin2B2(41.5g，0.163mol，5eq)、KOAc(16g，0.163mol，5eq)、Pd(dppf)Cl2(2g，0.0026mol，0.08eq)置于250mL三口瓶中，油泵抽真空30min，加入二氧六环(140mL)，氮气保护下80～95℃反应过夜。LCMS跟踪，反应结束后加DCM稀释，过滤除去不溶物，H2O/DCM萃取，有机相干燥旋干得10g淡黄色油状物粗品(含约30％产品、Pin2B2、CF0726A)。
4)第四步：CF0726E的合成
Figure PCTCN2015074989-appb-000041
将原料CF0726C(10g，P30％，0.0075mol)、SM3(2.1g，0.0074mol，1eq)、Na2CO3(1.59g，0.015mol，2eq)、Pd(PPh3)4(0.26g，0.000225mol，0.03eq)溶于乙醇/水(80mL，1:1)，80℃左右反应，LCMS跟踪，补加SM3至原料消失，反应结束后加DCM稀释，过滤除去不溶物，H2O/DCM萃取，有机相干燥旋干得8.5g黄色油状物粗品，不纯化直接下一步反应(含约21.6％产品)。
5)第五步：CF0726F的合成
Figure PCTCN2015074989-appb-000042
将原料CF0726E(8.5g，P21.6％，0.0035mol)、TBAF(4.3g，0.0165mol，4.7eq)溶于THF(85mL)，r.t搅拌，LCMS跟踪，反应结束后旋干，加H2O/EA萃取，有机相干燥旋干，过柱得白色固体产品(PE/EA＝1:4洗脱)得1g白色固体产品。
6)第六步：SM2的合成
Figure PCTCN2015074989-appb-000043
1、氰甲基磷酸二乙酯溶于THF(75mL)，氮气保护，降至-7～-5℃，滴加叔丁醇钾/THF(3.6g溶于35mLTHF)，加完保温3h，滴加1-Boc-3-氮杂环丁酮/THF溶液(5g溶于15mLTHF)，保温1h后室温搅拌过夜，加水淬灭后EA/H2O萃取，干燥旋干得8g粗品，上柱得4.3g白色固体产品CF0726Y。
2、将原料CF0726Y(0.5g，0.0026mol)溶于饱和氯化氢的二氧六环溶液(10mL)，先溶清，然后有白色固体析出，原料消失后旋干溶剂，加THF(10mL)溶解后滴加DIPEA(1.0g，7.75mmol，3eq)，搅10min，滴加N,N-二甲胺基磺酰氯(0.4g，0.0028mol，1.1eq)，r.t搅拌，LCMS跟踪，反应结束后旋干，EA/H2O萃取，饱和NaHCO3洗涤一次，饱和食盐水洗涤，干燥旋干得0.55g黄色油状粗品。
7)第七步：CF0726H的合成
Figure PCTCN2015074989-appb-000044
将原料CF0726F(0.1g，0.00027mol)溶于乙腈(5mL)中，加SM2(0.1g，0.0005mol，1.8eq)、DBU(0.1g，0.00066mol，2.4eq)，r.t搅拌过夜，反应结束后旋干，H2O/EA萃取，有机相干燥旋干过柱得0.1g产品(PE/EA＝3:1～1:1)。
8)第八步：CF0726I的合成
Figure PCTCN2015074989-appb-000045
将原料CF0726F(0.1g,0.000177mol)溶于DCM(5mL)中，加入TFA(2mL)，r.t搅拌，LCMS跟踪，反应结束后旋干，加DCM再旋干两次除去多余酸，加甲醇溶解，加饱和氨水(10mL)，r.t搅拌，有固体析出，LCMS跟踪，反应完全后加冰冷却，过滤，烘干得70mg淡黄色产品。
MS ES+：436.2
1H-NMR(400MHz，DMSO)；δ(ppm)：7.09-8.80(m，8H，aromatic-H)，4.60(d，2H，J＝4.4Hz，-N-CH2-)，4.47(d，2H，J＝4.4Hz，-N-CH2-)，3.63(s，2H，-CH2-CN)，2.82(s，3H，-N-CH3)。
通过与实施例7类似的制备方法，可制备实施例8-10标题化合物：
实施例8
2-(3-(3-(7H-吡咯[2,3-d]嘧啶-4-基)-1H-吲哚-1-基)-3-(乙氰基)-N,N-甲乙基氮杂环丁烷-1-磺胺。
实施例9
2-(3-(3-(7H-吡咯[2,3-d]嘧啶-4-基)-1H-吲哚-1-基)-3-(乙氰基)-N,N-二乙基氮杂环丁烷-1-磺胺。
实施例10
2-(3-(3-(7H-吡咯[2,3-d]嘧啶-4-基)-1H-吲哚-1-基)-3-(乙氰基)-吡咯烷-1-磺胺。
实施例11
Figure PCTCN2015074989-appb-000046
制备方法：
1)第一步：CF0726A的合成
Figure PCTCN2015074989-appb-000047
1(24g,0.205mol)溶于THF(240mL)中，氮气保护，冷至-78℃左右，慢慢滴加n-BuLi(106mL，.265mol，1.3eq)，加完保温搅拌1h。慢慢滴加TIPSCl(52.8g,0.274mol，1.3eq)，保持温度在-78℃左右，加完保温反应1h，TLC跟踪反应，反应结束后加水淬灭，EA萃取，干燥旋干得73g黄色油状粗品，无需纯化，直接进行下一步反应。
2)第二步：CF0726B的合成
Figure PCTCN2015074989-appb-000048
CF0726A(36.5g，P＝90％，0.121mol)溶于THF(365mL)中，冷至-78℃左右，慢慢加入NBS(23g，0.129mol，1.07eq)，加完保温1h，LCMS跟踪反应。反应结束后加水淬灭，EA萃取，干燥旋干得50g淡黄色粗品，碱性Al2O3过柱得21.4g白色固体产品(PE洗脱)。
3)第三步：CF0726C的合成
Figure PCTCN2015074989-appb-000049
将原料CF0726B(12.5g，P91.7％，0.0327mol)、Pin2B2(41.5g，0.163mol，5eq)、KOAc(16g，0.163mol，5eq)、 Pd(dppf)Cl2(2g，0.0026mol，0.08eq)置于250mL三口瓶中，油泵抽真空30min，加入二氧六环(140mL)，氮气保护下80～95℃反应过夜。LCMS跟踪，反应结束后加DCM稀释，过滤除去不溶物，H2O/DCM萃取，有机相干燥旋干得10g淡黄色油状物粗品(含约30％产品、Pin2B2、CF0726A)。
4)第四步：CF0726E的合成
Figure PCTCN2015074989-appb-000050
将原料CF0726C(10g，P30％，0.0075mol)、SM3(2.1g，0.0074mol，1eq)、Na2CO3(1.59g，0.015mol，2eq)、Pd(PPh3)4(0.26g，0.000225mol，0.03eq)溶于乙醇/水(80mL，1:1)，80℃左右反应，LCMS跟踪，补加SM3至原料消失，反应结束后加DCM稀释，过滤除去不溶物，H2O/DCM萃取，有机相干燥旋干得8.5g黄色油状物粗品，不纯化直接下一步反应(含约21.6％产品)。
5)第五步：CF0726F的合成
Figure PCTCN2015074989-appb-000051
将原料CF0726E(8.5g，P21.6％，0.0035mol)、TBAF(4.3g，0.0165mol，4.7eq)溶于THF(85mL)，r.t搅拌，LCMS跟踪，反应结束后旋干，加H2O/EA萃取，有机相干燥旋干，过柱得白色固体产品(PE/EA＝1:4洗脱)得1g白色固体产品。
6)第六步：SM2的合成
Figure PCTCN2015074989-appb-000052
1、氰甲基磷酸二乙酯溶于THF(75mL)，氮气保护，降至-7～-5℃，滴加叔丁醇钾/THF(3.6g溶于35mLTHF)，加完保温3h，滴加1-Boc-3-氮杂环丁酮/THF溶液(5g溶于15mLTHF)，保温1h后室温搅拌过夜，加水淬灭后EA/H2O萃取，干燥旋干得8g粗品，上柱得4.3g白色固体产品CF0726Y。
2、将原料CF0726Y(0.5g，0.0026mol)溶于饱和氯化氢的二氧六环溶液(10mL)，先溶清，然后有白色固体析出，原料消失后旋干溶剂，加DCM(10mL)溶解后加TEA(1.51g，14.9mmol，5.8eq)，搅拌10min，再加EDCI(0.62g，3.2mmol，1.25eq)、HOBT(0.43g，3.2mmol，1.25eq)，搅15min后加入N-Boc-L-脯氨酸(0.56g，2.6mmol，1.0eq)，r.t搅拌过夜。LCMS跟踪，反应结束后加DCM/H2O萃取，饱和NaHCO3溶液洗涤，干燥旋干的棕褐色油状物(0.7g)。
7)第七步：CF0726H的合成
Figure PCTCN2015074989-appb-000053
将原料CF0726F(0.1g，0.00027mol)溶于乙腈(5mL)中，加SM2(0.1g，0.00036mol，1.3eq)、DBU(0.1g，0.00066mol，2.4eq)，r.t搅拌过夜，反应结束后旋干，H2O/EA萃取，有机相干燥旋干过柱得0.2g产品(PE/EA＝3:1～1:1)。
8)第八步：CF0726L的合成
Figure PCTCN2015074989-appb-000054
将原料CF0726F(0.2g,0.0003mol)溶于DCM(10mL)中，加入TFA(4mL)，r.t搅拌，LCMS跟踪，反应结束后旋干，加DCM再旋干两次除去多余酸，加甲醇(10mL)溶解，加饱和氨水(10mL)，r.t搅拌，有少量固体析出，LCMS跟踪，反应完全后旋去甲醇，EA萃取，干燥旋干得粗品，送制备柱纯化得80mg淡黄色产品。
MS ES+：426.2；
1H-NMR(400MHz，DMSO)；δ(ppm)：7.28-8.80(m，8H，aromatic-H)，4.54-4.69(m，4H，-N-CH2-*2)，4.49(d，2H，J＝4.6Hz，-N-CH2-)，3.61(s，2H，-CH2-CN)，3.60(s，1H，-CH-N)，3.59(m，2H，-CH-N)，1.74-1.78(m，4H，-CH2-CH2-)。
通过与实施例11类似的制备方法，可制备实施例12-19标题化合物。
实施例12
2-(3-(3-(7H-吡咯[2,3-d]嘧啶-4-基)-1H-吲哚-1-基)-1-(哌啶烷-2-羰基)氮杂环丁烷-3-基)乙腈。
实施例13
2-(3-(3-(7H-吡咯[2,3-d]嘧啶-4-基)-1H-吲哚-1-基)-1-(氮杂环庚烷-2-羰基)氮杂环丁烷-3-基)乙腈。
实施例14
2-(3-(3-(7H-吡咯[2,3-d]嘧啶-4-基)-1H-吲哚-1-基)-1-(四氢呋喃-2-羰基)氮杂环丁烷-3-基)乙腈。
实施例15
2-(3-(3-(7H-吡咯[2,3-d]嘧啶-4-基)-1H-吲哚-1-基)-1-(四氢吡啶-2-羰基)氮杂环丁烷-3-基)乙腈。
实施例16
2-(3-(3-(7H-吡咯[2,3-d]嘧啶-4-基)-1H-吲哚-1-基)-1-(氧杂环庚烷-2-羰基)氮杂环丁烷-3-基)乙腈。
实施例17
2-(3-(3-(7H-吡咯[2,3-d]嘧啶-4-基)-1H-吲哚-1-基)-1-(四氢噻吩-2-羰基)氮杂环丁烷-3-基)乙腈。
实施例18
2-(3-(3-(7H-吡咯[2,3-d]嘧啶-4-基)-1H-吲哚-1-基)-1-(四氢噻喃-2-羰基)氮杂环丁烷-3-基)乙腈。
实施例19
2-(3-(3-(7H-吡咯[2,3-d]嘧啶-4-基)-1H-吲哚-1-基)-1-(硫杂环庚烷-2-羰基)氮杂环丁烷-3-基)乙腈。
实施例20
Figure PCTCN2015074989-appb-000055
制备方法：
1)第一步：CF0726A的合成
Figure PCTCN2015074989-appb-000056
原料SM1(10g,0.074mol)溶于THF(100mL)中，氮气保护，冷至-78℃左右，慢慢滴加n-BuLi(37.7mL,0.09mol，1.2eq)，加完保温搅拌1h。慢慢滴加TIPSCl(17.2g,0.089mol，1.2eq)，保持温度在-78℃左右，加完保温反应1h，TLC跟踪反应，反应结束后加水淬灭，EA萃取，干燥旋干得17.3g黄色油状粗品，无需纯化，直接进行下一步反应。
2)第二步：CF0726B的合成
Figure PCTCN2015074989-appb-000057
CF0726A(17g，P＝79％，0.046mol)溶于THF(170mL)中，冷至-78℃左右，慢慢加入NBS(8.2g，0.046mol，1.eq)，加完保温1h，LCMS跟踪反应，补加NBS至原料消失。反应结束后加水淬灭，EA萃取，干燥旋干得36g红色粗品，碱性Al2O3过柱得36g白色固体产品(PE洗脱，超重)。
3)第三步：CF0726C的合成
Figure PCTCN2015074989-appb-000058
将原料CF0726B(14g，P97％，0.038mol)、Pin2B2(48.2g，0.19mol，5eq)、KOAc(18.6g，0.19mol，5eq)、Pd(dppf)Cl2(3g，0.0039mol，0.1eq)置于250mL三口瓶中，油泵抽真空30min，加入二氧六环(140mL)，氮气保护下80～95℃反应过夜。LCMS跟踪，反应结束后加DCM稀释，过滤除去不溶物，H2O/DCM萃取，有机相干燥 旋干得29g淡黄色油状物粗品(含约32％产品、Pin2B2、CF0726A)。
4)第四步：CF0726E的合成
Figure PCTCN2015074989-appb-000059
将原料CF0726C(2g，P32％，0.0015mol)、SM3(0.6g，0.0021mol，1.4eq)、Na2CO3(0.44g，0.041mol，2.7eq)、Pd(PPh3)4(0.06g，0.00005mol，0.03eq)溶于乙醇/水(20mL，1:1)，80℃左右反应，LCMS跟踪，补加SM3至原料消失，反应结束后加DCM稀释，过滤除去不溶物，H2O/DCM萃取，有机相干燥旋干得1.7g黄色油状物粗品，不纯化直接下一步反应(含约11.5％产品)。
5)第五步：CF0726F的合成
Figure PCTCN2015074989-appb-000060
将原料CF0726E(1.7g，P11.5％，0.0003mol)、TBAF(0.82g，0.003mol，10eq)溶于THF(17mL)，r.t搅拌，LCMS跟踪，反应结束后旋干，加H2O/EA萃取，有机相干燥旋干，过柱得白色固体产品(PE/EA＝1:4洗脱)得0.2g白色固体产品。
6)第六步：SM2的合成
Figure PCTCN2015074989-appb-000061
1、氰甲基磷酸二乙酯溶于THF(75mL)，氮气保护，降至-7～-5℃，滴加叔丁醇钾/THF(3.6g溶于35mLTHF)，加完保温3h，滴加1-Boc-3-氮杂环丁酮/THF溶液(5g溶于15mLTHF)，保温1h后室温搅拌过夜，加水淬灭后EA/H2O萃取，干燥旋干得8g粗品，上柱得4.3g白色固体产品CF0726Y。
2、将原料CF0726Y(0.4g，0.0021mol)溶于饱和氯化氢的二氧六环溶液(10mL)，先溶清，然后有白色固体析出，原料消失后旋干溶剂，加THF(10mL)溶解后滴加DIPEA(0.8g，6.18mmol，3eq)，搅10min，滴加乙基磺酰氯(0.32g，0.0025mol，1.2eq)，r.t搅拌，LCMS跟踪，反应结束后旋干，EA/H2O萃取，饱和NaHCO3洗涤一次，饱和食盐水洗涤，干燥旋干得0.3g黄色油状粗品。
7)第七步：CF0726H的合成
Figure PCTCN2015074989-appb-000062
将原料CF0726F(0.2g，0.00052mol)溶于乙腈(5mL)中，加SM2(0.2g，0.00108mol，2.1eq)、DBU(0.2g，0.00132mol，2.5eq)，r.t搅拌过夜，反应结束后旋干，H2O/EA萃取，有机相干燥旋干过柱得0.1g产品(PE/EA＝3:1～1:1)。
8)第八步：CF0726K的合成
Figure PCTCN2015074989-appb-000063
将原料CF0726F(0.1g,0.00018mol)溶于DCM(5mL)中，加入TFA(2mL)，r.t搅拌，LCMS跟踪，反应结束后旋干，加DCM再旋干两次除去多余酸，加甲醇溶解，加饱和氨水(10mL)，r.t搅拌，有固体析出，LCMS跟踪，反应完全后加冰冷却，过滤，烘干得50mg淡黄色产品。
MS ES+：439.2
1H-NMR(400MHz，DMSO)；δ(ppm)：7.11-8.80(m，7H，aromatic-H)，4.72(d，2H，J＝4.4Hz，-N-CH2-)，4.49(d，2H，J＝4.4Hz，-N-CH2-)，3.63(s，2H，-CH2-CN)，3.24(q，J＝7.4Hz，2H，S-CH2-CH3)，1.24(t，J＝3.6Hz，3H，S-CH2-CH3)。
通过与实施例20类似的制备方法，可制备实施例21-61标题化合物。
实施例21
2-(1-(甲基磺酰基)-3-(6-氟-3-(7H-吡咯[2,3-d]嘧啶-4-基)-1H-吲哚-1-基)氮杂环丁烷-3-基)乙腈。
实施例22
2-(1-(丙基磺酰基)-3-(6-氟-3-(7H-吡咯[2,3-d]嘧啶-4-基)-1H-吲哚-1-基)氮杂环丁烷-3-基)乙腈。
实施例23
2-(1-(异丙基磺酰基)-3-(6-氟-3-(7H-吡咯[2,3-d]嘧啶-4-基)-1H-吲哚-1-基)氮杂环丁烷-3-基)乙腈。
实施例24
2-(1-(环丙基磺酰基)-3-(6-氟-3-(7H-吡咯[2,3-d]嘧啶-4-基)-1H-吲哚-1-基)氮杂环丁烷-3-基)乙腈。
实施例25
2-(1-(甲基磺酰基)-3-(6-氯-3-(7H-吡咯[2,3-d]嘧啶-4-基)-1H-吲哚-1-基)氮杂环丁烷-3-基)乙腈。
实施例26
2-(1-(乙基磺酰基)-3-(6-氯-3-(7H-吡咯[2,3-d]嘧啶-4-基)-1H-吲哚-1-基)氮杂环丁烷-3-基)乙腈。
实施例27
2-(1-(丙基磺酰基)-3-(6-氯-3-(7H-吡咯[2,3-d]嘧啶-4-基)-1H-吲哚-1-基)氮杂环丁烷-3-基)乙腈。
实施例28
2-(1-(异丙基磺酰基)-3-(6-氯-3-(7H-吡咯[2,3-d]嘧啶-4-基)-1H-吲哚-1-基)氮杂环丁烷-3-基)乙腈。
实施例29
2-(1-(环丙基磺酰基)-3-(6-氯-3-(7H-吡咯[2,3-d]嘧啶-4-基)-1H-吲哚-1-基)氮杂环丁烷-3-基)乙腈。
实施例30
2-(1-(甲基磺酰基)-3-(6-溴-3-(7H-吡咯[2,3-d]嘧啶-4-基)-1H-吲哚-1-基)氮杂环丁烷-3-基)乙腈。
实施例31
2-(1-(乙基磺酰基)-3-(6-溴-3-(7H-吡咯[2,3-d]嘧啶-4-基)-1H-吲哚-1-基)氮杂环丁烷-3-基)乙腈。
实施例32
2-(1-(甲基磺酰基)-3-(5,6-二氟-3-(7H-吡咯[2,3-d]嘧啶-4-基)-1H-吲哚-1-基)氮杂环丁烷-3-基)乙腈。
实施例33
2-(1-(乙基磺酰基)-3-(5,6-二氟-3-(7H-吡咯[2,3-d]嘧啶-4-基)-1H-吲哚-1-基)氮杂环丁烷-3-基)乙腈。
实施例34
2-(1-(丙基磺酰基)-3-(5,6-二氟-3-(7H-吡咯[2,3-d]嘧啶-4-基)-1H-吲哚-1-基)氮杂环丁烷-3-基)乙腈。
实施例35
2-(1-(环丙基磺酰基)-3-(5,6-二氟-3-(7H-吡咯[2,3-d]嘧啶-4-基)-1H-吲哚-1-基)氮杂环丁烷-3-基)乙腈。
实施例36
2-(1-(甲基磺酰基)-3-(6,7-二氟-3-(7H-吡咯[2,3-d]嘧啶-4-基)-1H-吲哚-1-基)氮杂环丁烷-3-基)乙腈。
实施例37
2-(1-(乙基磺酰基)-3-(6,7-二氟-3-(7H-吡咯[2,3-d]嘧啶-4-基)-1H-吲哚-1-基)氮杂环丁烷-3-基)乙腈。
实施例38
2-(1-(丙基磺酰基)-3-(6,7-二氟-3-(7H-吡咯[2,3-d]嘧啶-4-基)-1H-吲哚-1-基)氮杂环丁烷-3-基)乙腈。
实施例39
2-(1-(异丙基磺酰基)-3-(6,7-二氟-3-(7H-吡咯[2,3-d]嘧啶-4-基)-1H-吲哚-1-基)氮杂环丁烷-3-基)乙腈。
实施例40
2-(1-(环丙基磺酰基)-3-(6,7-二氟-3-(7H-吡咯[2,3-d]嘧啶-4-基)-1H-吲哚-1-基)氮杂环丁烷-3-基)乙腈。
实施例41
2-(1-(甲基磺酰基)-3-(6,8-二氟-3-(7H-吡咯[2,3-d]嘧啶-4-基)-1H-吲哚-1-基)氮杂环丁烷-3-基)乙腈。
实施例42
2-(1-(乙基磺酰基)-3-(6,8-二氟-3-(7H-吡咯[2,3-d]嘧啶-4-基)-1H-吲哚-1-基)氮杂环丁烷-3-基)乙腈。
实施例43
2-(1-(丙基磺酰基)-3-(6,8-二氟-3-(7H-吡咯[2,3-d]嘧啶-4-基)-1H-吲哚-1-基)氮杂环丁烷-3-基)乙腈。
实施例44
2-(1-(异丙基磺酰基)-3-(6,8-二氟-3-(7H-吡咯[2,3-d]嘧啶-4-基)-1H-吲哚-1-基)氮杂环丁烷-3-基)乙腈。
实施例45
2-(1-(环丙基磺酰基)-3-(6,8-二氟-3-(7H-吡咯[2,3-d]嘧啶-4-基)-1H-吲哚-1-基)氮杂环丁烷-3-基)乙腈。
实施例46
2-(1-(乙基磺酰基)-3-(5,7-二氟-3-(7H-吡咯[2,3-d]嘧啶-4-基)-1H-吲哚-1-基)氮杂环丁烷-3-基)乙腈。
实施例47
2-(1-(乙基磺酰基)-3-(5,7-二氟-3-(7H-吡咯[2,3-d]嘧啶-4-基)-1H-吲哚-1-基)氮杂环丁烷-3-基)乙腈。
实施例48
2-(1-(乙基磺酰基)-3-(5,8-二氟-3-(7H-吡咯[2,3-d]嘧啶-4-基)-1H-吲哚-1-基)氮杂环丁烷-3-基)乙腈。
实施例49
2-(1-(乙基磺酰基)-3-(7,8-二氟-3-(7H-吡咯[2,3-d]嘧啶-4-基)-1H-吲哚-1-基)氮杂环丁烷-3-基)乙腈。
实施例50
2-(1-(乙基磺酰基)-3-(6-氰基-3-(7H-吡咯[2,3-d]嘧啶-4-基)-1H-吲哚-1-基)氮杂环丁烷-3-基)乙腈。
实施例51
2-(1-(乙基磺酰基)-3-(6-乙氰基-3-(7H-吡咯[2,3-d]嘧啶-4-基)-1H-吲哚-1-基)氮杂环丁烷-3-基)乙腈。
实施例52
2-(1-(乙基磺酰基)-3-(6-三氟甲基-3-(7H-吡咯[2,3-d]嘧啶-4-基)-1H-吲哚-1-基)氮杂环丁烷-3-基)乙腈。
实施例53
2-(1-(乙基磺酰基)-3-(6-三氟乙基-3-(7H-吡咯[2,3-d]嘧啶-4-基)-1H-吲哚-1-基)氮杂环丁烷-3-基)乙腈。
实施例54
2-(1-(乙基磺酰基)-3-(6-甲基-3-(7H-吡咯[2,3-d]嘧啶-4-基)-1H-吲哚-1-基)氮杂环丁烷-3-基)乙腈。
实施例55
2-(1-(乙基磺酰基)-3-(6-乙基-3-(7H-吡咯[2,3-d]嘧啶-4-基)-1H-吲哚-1-基)氮杂环丁烷-3-基)乙腈。
实施例56
2-(1-(乙基磺酰基)-3-(6-丙基-3-(7H-吡咯[2,3-d]嘧啶-4-基)-1H-吲哚-1-基)氮杂环丁烷-3-基)乙腈。
实施例57
2-(1-(乙基磺酰基)-3-(6-异丙基-3-(7H-吡咯[2,3-d]嘧啶-4-基)-1H-吲哚-1-基)氮杂环丁烷-3-基)乙腈。
实施例58
2-(1-(乙基磺酰基)-3-(6-甲氧基-3-(7H-吡咯[2,3-d]嘧啶-4-基)-1H-吲哚-1-基)氮杂环丁烷-3-基)乙腈。
实施例59
2-(1-(乙基磺酰基)-3-(6-乙氧基-3-(7H-吡咯[2,3-d]嘧啶-4-基)-1H-吲哚-1-基)氮杂环丁烷-3-基)乙腈。
实施例60
2-(1-(乙基磺酰基)-3-(6-丙氧基-3-(7H-吡咯[2,3-d]嘧啶-4-基)-1H-吲哚-1-基)氮杂环丁烷-3-基)乙腈。
实施例61
2-(1-(乙基磺酰基)-3-(6-异丙氧基-3-(7H-吡咯[2,3-d]嘧啶-4-基)-1H-吲哚-1-基)氮杂环丁烷-3-基)乙腈。
实施例62
2-(1-(乙磺酰基)-3-(5-氟-3-(7H-吡咯[2,3-d]嘧啶-4-基)-1H-吲哚-1-基)氮杂环丁烷-3-基)乙腈。
实施例63
2-(1-(乙磺酰基)-3-(5-三氟甲基-3-(7H-吡咯[2,3-d]嘧啶-4-基)-1H-吲哚-1-基)氮杂环丁烷-3-基)乙腈。
实施例64
2-(1-(乙磺酰基)-3-(5-甲氧基-3-(7H-吡咯[2,3-d]嘧啶-4-基)-1H-吲哚-1-基)氮杂环丁烷-3-基)乙腈。
实施例65：CF0726J三氟乙酸盐的合成
Figure PCTCN2015074989-appb-000064
将原料CF0726J(0.1g,0.00035mol)溶于DCM(5mL)中，加入TFA(2mL)，升温至45℃，r.t搅拌1h，加DCM再旋干两次除去多余酸，加入丙酮：甲醇：水的混合溶剂重结晶，得到CF0726J三氟乙酸盐53mg。
实施例66：CF0726K磷酸盐的合成
Figure PCTCN2015074989-appb-000065
将原料CF0726K(0.1g，0.00023mol)溶于DCM(5mL)中，加入磷酸(1.5mL)，升温至40℃，r.t搅拌2h，加DCM再旋干两次除去多余酸，加入丙酮：甲醇：水的混合溶剂重结晶，得到CF0726K的磷酸盐38mg。
实施例67
采用体Caliper Mobility Shift Assay方法在不同三磷酸腺苷(ATP)浓度下Km值研究检测本发明下述列举化合物对Janus系列激酶的抑制剂的作用。发现本发明化合物对JAK-STAT途径的抑制作用非常明显。部分数据如下：
Figure PCTCN2015074989-appb-000066
Figure PCTCN2015074989-appb-000067
Figure PCTCN2015074989-appb-000068
实施例68
采用体外CTLL-2细胞检测JAK的磷酸化水平，来考察本发明下述化合物对JAK-STAT的抑制作用，CTLL-2细胞培养后按照1×107个细胞每孔，加入到6孔板中，然后加入本发明的化合物，饥饿培养6小时，加入IL-2，终浓度为150U/mL。孵育10min，收集细胞。加入细胞裂解液使细胞裂解。收集蛋白进行WEST-Blot检测，检测磷酸化JAK1、JAK2的磷酸化。以及磷酸化STAT5，并获得其IC50值。
Figure PCTCN2015074989-appb-000069
实施例69
本发明化合物，用于抑制人淋巴细胞瘤细胞的增殖。体外培养Jurkat细胞按照1500个细胞/孔铺平底96孔板。培养体系中，化合物最高浓度为50μM，按照10倍梯度做药物浓度稀释。化合物作用48小时后加入10μlCCk-8，孵育6h后，利用酶标仪测定450nM波长吸收值。化合物对肿瘤细胞生长抑制率计算方法按照美国国家癌症研究所(National Cancer Institute，NCI)标准方法进行：当Ti(药物组培养48h，CCK-8显色吸收OD值)≥Tz(不含药物 组培养起始时CCK-8显色吸收OD值)，肿瘤细胞存活率＝[(Ti-Tz)/(C-Tz)]×100，其中C为不含药物组48小时后CCK-8显色吸收OD值；当Ti<Tz时，肿瘤细胞存活率＝[(Ti-Tz)/Tz]×100。
Figure PCTCN2015074989-appb-000070
实施例70
本发明化合物抑制类风湿性关节炎的作用，选择DBA/1J小鼠，将50ug牛Ⅱ型胶原与等体积完全弗氏佐剂(CFA)完全乳化后皮下注射。21天后以50ug相同抗原与不完全弗氏佐剂(IFA充分乳化后，加强免疫1次。从第45天开始观察记录。采用1-4计分法：1分，正常；2分，1个关节肿胀；3分，超过1个关节肿胀，但并未累积全部关节；4分，整个爪的严重肿胀或强直。每只爪的评分相加即得到小鼠关节炎症的总评分。关节总评分大于1的小鼠为模型建立成功。成功建立小鼠类风湿关节炎模型后采用本发明化合物给小鼠灌胃给药，给药2周后对小鼠的关节炎症进行评分，结果显示本品对小鼠类风湿性关节炎有明显的治疗作用。
化合物组别 关节炎评分
Control 1
生理盐水对照组 4
环孢菌素对照组 2.4
实施例66化合物 1.8
实施例6化合物 2.3
实施例64化合物 2.3
实施例7化合物 2.5
实施例20化合物 1.6
JAK抑制剂Baricitinib 2.4

Claims (9)

  1. 一种如化学结构式I所示的化合物，
    Figure PCTCN2015074989-appb-100001
    其中，R1、R2为苯环任一位置取代基，并独立的选自：
    氢；任意一个卤素原子；
    或-(CHZ)nCN，n＝0-3，Z＝1-2；
    或-(CHZ)nCH3，n＝0-3，Z＝0-2；
    或-CYn，n＝0-3，Y为任意一个卤素原子；
    或-(CHZ)nCYn，n＝0-3，Z＝1-2，Y为任意一个卤素原子；
    Figure PCTCN2015074989-appb-100002
    n＝0-3，Z＝0-2；
    或-(CHZ)n，n＝0-3，Z＝0-2；
    或-O(CHZ)n CH3，n＝0-3，Z＝0-2；
    或C3-C6的环烷烃；
    R3是：
    Figure PCTCN2015074989-appb-100003
    其中，R4选自氢、(C1-C4)的烷基、(C2-C4)的烯基、(C2-C4)的炔基、C3-C7的环烷烃，或
    Figure PCTCN2015074989-appb-100004
    R5与R6选自氢、(C1-C4)的烷基、(C2-C4)的烯基、(C2-C4)的炔基，或C3-C7的环烷烃，或R5和R6成4～6元环；R5与R6相同或不同；
    或者，R3是：
    Figure PCTCN2015074989-appb-100005
    W为S、N或C，n是1-3；
    X为CH2或N。
  2. 权利要求1所述的化学结构式I所示的化合物的制备方法，其特征在于包括如下步骤：
    (1)化合物A结构中所述化合物的仲胺添加胺基保护基团，得到化合物B
    Figure PCTCN2015074989-appb-100006
    (2)化合物B的如下述化学反应式的位置氢被溴取代，生成化合物C
    Figure PCTCN2015074989-appb-100007
    (3)化合物C与双戊酰二硼(Pin2B2)反应，生成化合物D
    Figure PCTCN2015074989-appb-100008
    (4)在碱性环境下，将化合物D与化合物E反应，生成化合物F
    Figure PCTCN2015074989-appb-100009
    (5)化合物F与化合物G反应，其中使用1,8-二氮杂二环[5.4.0]十一碳-7-烯(DPU)作为催化剂，生成化合物H
    Figure PCTCN2015074989-appb-100010
    (6)化合物H在强酸或强碱存在的条件下，脱除保护基团2-(三甲基硅基)乙氧基甲基，得到化学结构式I的化合物。
  3. 权利要求1所述的化学结构式I所示的化合物的药学上可接受的盐。
  4. 权利要求1所述的化学结构式I所示的化合物的光学异构体。
  5. 权利要求1所述的化学结构式I所示的化合物的药学上可接受的酸加成盐。
  6. 权利要求1所述的化学结构式I所示的化合物在制备治疗JAK激酶相关疾病的药物中的应用。
  7. 根据权利要求6所述的应用，其特征在于是在在制备治疗自身免疾病中的应用。
  8. 根据权利要求6所述的应用，其特征在于是在制备治疗类风湿性关节炎中的应用。
  9. 根据权利要求6所述的应用，其特征在于是在制备抗肿瘤药物中的应用。
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