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WO2018001331A1 - 一种咪唑吡啶胺苯基衍生物及其用途 - Google Patents

一种咪唑吡啶胺苯基衍生物及其用途 Download PDF

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WO2018001331A1
WO2018001331A1 PCT/CN2017/090908 CN2017090908W WO2018001331A1 WO 2018001331 A1 WO2018001331 A1 WO 2018001331A1 CN 2017090908 W CN2017090908 W CN 2017090908W WO 2018001331 A1 WO2018001331 A1 WO 2018001331A1
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Prior art keywords
imidazolidinium
hydrate
phenyl derivative
metabolism
pharmaceutically acceptable
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English (en)
French (fr)
Inventor
殷建明
吕裕斌
李邦良
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HANGZHOU HUADONG MEDICINE GROUP PHARMACEUTICAL RESEARCH INSTITUTE Co Ltd
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HANGZHOU HUADONG MEDICINE GROUP PHARMACEUTICAL RESEARCH INSTITUTE Co Ltd
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Priority to EP17819328.0A priority Critical patent/EP3480199B1/en
Priority to ES17819328T priority patent/ES2878973T3/es
Priority to KR1020197002682A priority patent/KR102215172B1/ko
Priority to CA3032795A priority patent/CA3032795C/en
Priority to AU2017287553A priority patent/AU2017287553B2/en
Priority to JP2018569169A priority patent/JP6715357B2/ja
Priority to US16/311,979 priority patent/US10640512B2/en
Publication of WO2018001331A1 publication Critical patent/WO2018001331A1/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
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • 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
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/04—Drugs for skeletal disorders for non-specific disorders of the connective tissue
    • 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
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • 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
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • 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
    • A61P37/08—Antiallergic agents

Definitions

  • the present invention relates to an imidazolidinium phenyl derivative and its use in the manufacture of a medicament for preventing and/or treating an indication associated with BTK function.
  • BTK Bruton's Tyrosine Kinase
  • BCR B cell receptor
  • BTK is proximal and immediately downstream of the BCR membrane, and BTK deficiency blocks BCR signaling.
  • inhibition of BTK can provide an effective therapeutic route to block B cell mediated diseases.
  • BTK inhibitors can be used in the treatment of diseases such as rheumatoid arthritis, B cell lymphoma, leukemia, multiple myeloma, allergy, asthma, multiple sclerosis, type I diabetes, and systemic lupus erythematosus.
  • the two BTK inhibitors currently being developed the fastest are Ibrutinib and ACP-196 (Acalabrutinib).
  • the former was approved by the FDA in 2013 for the treatment of mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL).
  • MCL mantle cell lymphoma
  • CLL chronic lymphocytic leukemia
  • Both BTK inhibitors have some toxic side effects: thrombocytopenia, hemoglobin reduction, diarrhea, neutropenia, anemia, fatigue, headache, musculoskeletal pain, angioedema, upper respiratory tract infection, Nausea, bruising, difficulty breathing, constipation, rash, joint pain, abdominal pain, vomiting and loss of appetite.
  • ibrutinib is much more toxic than ACP-196 (Acalabrutinib (ACP-196) in Relapsed Chronic Lymphocytic Leukemia (The New England Journal of Medicine, 374; 4, 2016)).
  • the three kinases EGFR/ITK/TEC have a clear side-reaction correlation as disclosed in the literature Acalabrutinib (ACP-196) in Relapsed Chronic Lymphocytic Leukemia (The New England Journal of Medicine, 374; 4, 2016).
  • the technical problem to be solved by the present invention is to provide a novel imidazolidinium phenyl derivative which has low toxic side effects and is an ideal non-reversible BTK inhibitor.
  • the present invention also provides the use of an imidazolidinium phenyl derivative, a pharmaceutically acceptable salt, hydrate thereof, or a metabolite formed by metabolism in any form for the preparation of a medicament for preventing and/or treating an indication associated with BTK function. .
  • the present invention adopts the following technical solutions:
  • An object of the present invention is to provide an imidazolidinium phenyl derivative having a structure represented by the general formula (I), which is a pharmaceutically acceptable salt, a hydrate, or a metabolite formed by metabolism in any form,
  • Z is selected from the group consisting of NH, CO or O;
  • R 1 is an aromatic ring, a five-membered heteroaryl ring or a six-membered heteroaryl ring, which is optionally independently substituted by 0-5 C1-C4 alkyl groups or halogen;
  • R 2 is H, C1-C4 alkyl or halogen
  • R 3 is Wherein R 4 is C(O)CCR 5 or C(O)CHCHR 5 , and R 5 is H or a C1-C4 alkyl group.
  • R 1 is a benzene ring, a six-membered heteroaryl ring containing 1 or 2 nitrogens, which is optionally substituted with 0 to 2 C1-C4 alkyl groups.
  • R 1 is
  • R 2 is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.
  • R 3 is
  • R 5 is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.
  • the imidazolidinium phenyl derivative is one of the compounds represented by the following structural formula:
  • Another object of the present invention is to provide an imidazolidinium phenyl derivative having a structure represented by the general formula (II), a pharmaceutically acceptable salt, a hydrate thereof, or a metabolite formed by metabolism in any form,
  • One of X and Y is NH and the other is CO;
  • R 1 is an aromatic ring, a five-membered heteroaryl ring or a six-membered heteroaryl ring, which is optionally independently substituted by 0-5 C1-C4 alkyl groups or halogen;
  • R 2 is H, C1-C4 alkyl or halogen
  • R 3 is wherein, R 4 is C (O) CCR 5 or C (O) CHCHR 5, R 5 is H or C1-C4 alkyl;
  • R 1 is an unsubstituted heteroaryl ring
  • R 2 is a C1-C4 alkyl group.
  • R 1 is a benzene ring, a six-membered heteroaryl ring containing 1 or 2 nitrogens, optionally substituted by 0 to 2 C1-C4 alkyl groups
  • R 1 is
  • R 2 is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.
  • R 3 is
  • R 5 is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.
  • the imidazolidinium phenyl derivative is one of the compounds represented by the following structural formula:
  • the compound of the imidazolidinium phenyl derivative includes not only a single compound form but also a mixture of a plurality of compounds satisfying the requirements of the general formula (I) or the general formula (II). And different isomeric forms of the same compound such as racemates, enantiomers, diastereomers and the like.
  • the pharmaceutically acceptable salts include, but are not limited to, hydrochloride, phosphate, sulfate, acetate, maleate, methanesulfonate, besylate, benzoate, toluenesulfonate , succinate, fumarate, fumarate, tartrate, gallate, citrate, and the like.
  • prodrug of a compound having the general formula (I) or the general formula (II) means a substance which, when administered by an appropriate method, can be converted into a structural form by metabolic or chemical reaction in a subject. (I) or at least one compound of the formula (II) or a salt thereof.
  • the preparation of the imidazolidinium phenyl derivatives of the invention can be carried out by synthetic routes to those analogous methods well known in the chemical art, especially in accordance with the description contained herein.
  • the reagents are generally obtained from commercial sources or are readily prepared using methods well known to those skilled in the art.
  • an aromatic ring refers to a planar ring system having a conjugate, and the bonds between atoms are not discontinuous single and double bond alternating, but an organic aromatic compound covered by a delocalized ⁇ electron cloud, which is carbon in the ring. element.
  • the five-membered heteroaryl ring and the six-membered heteroaryl ring mean that the ring of the aromatic ring has a non-carbon element.
  • a third object of the present invention is to provide an imidazolidinium phenyl derivative having the formula (I) as described, which is a pharmaceutically acceptable salt, a hydrate, or a metabolite formed by metabolism in any form or as described
  • the indications associated with BTK function include diseases such as rheumatoid arthritis, B cell lymphoma, leukemia, multiple myeloma, allergy, asthma, multiple sclerosis, type I diabetes, and systemic lupus erythematosus.
  • a fourth object of the present invention is to provide a metabolite of the imidazole pyridinamine phenyl derivative of the formula (I), which is pharmaceutically acceptable salt, hydrate, or metabolized in any form, or
  • R 1 is R 4 is a nitrogen protecting group or H
  • R 2 is halogen or NH 2 ;
  • R 3 is Z is selected from NH, CO or O; one of X, Y is NH and the other is CO; R 1 is an aromatic ring, a five-membered heteroaryl ring or a six-membered heteroaryl ring, which is optionally 0-5 The C1-C4 alkyl group or halogen is independently substituted; and R 2 is H, C1-C4 alkyl or halogen.
  • the nitrogen protecting group is a benzyloxycarbonyl group.
  • the halogen in R 2 is Cl.
  • the intermediate is one of the following structural formulas:
  • Z is selected from the group consisting of NH, CO or O;
  • One of X and Y is NH and the other is CO;
  • R 1 is an aromatic ring, a five-membered heteroaryl ring or a six-membered heteroaryl ring, which is optionally independently substituted by 0-5 C1-C4 alkyl groups or halogen;
  • R 2 is H, C1-C4 alkyl or halogen.
  • the present invention has the following advantages compared with the prior art:
  • the compounds provided by the present invention are novel imidazolidinium phenyl derivatives which are ideal high potency BTK inhibitors and which provide an effective therapeutic route to block B cell mediated diseases by inhibiting BTK.
  • the compound of the invention has novel structure, strong activity, good pharmacokinetic properties and high oral bioavailability.
  • the compounds of the invention have high kinase selectivity, weak or no irreversible inhibition of related kinases, and reduce the resulting adverse effects. At the same time, faster metabolic rates and a short half-life can avoid the risk of immunological side effects due to excessive inhibition of BTK.
  • the peak concentration T max of the blood concentration of the compound of the present invention after oral administration is small, and the peak of the blood concentration can be reached very quickly, so that the onset of the drug can be fast.
  • the compounds of the present invention are useful in the preparation of a medicament for the treatment or prevention of various indications associated with BTK function and have lower toxic side effects.
  • the compound of formula I a can be obtained by the following synthetic route:
  • the preparation method of the compound of formula I a specifically comprises the following steps:
  • the obtained target product I a was subjected to hydrogen nuclear magnetic resonance 1 H-NMR (400 MHz, d-DMSO) and mass spectrometry, and the results were as follows:
  • the preparation method of the compound of formula Ib specifically comprises the following steps:
  • the obtained target product I b was subjected to hydrogen nuclear magnetic resonance 1 H-NMR (400 MHz, d-DMSO) and mass spectrometry, and the results were as follows:
  • the preparation method of the compound of formula I c specifically includes the following steps:
  • the obtained target product I c was subjected to hydrogen nuclear magnetic resonance 1 H-NMR (400 MHz, d-DMSO) and mass spectrometry, and the results were as follows:
  • the preparation method of the compound of formula I d specifically includes the following steps:
  • the obtained target product I d was subjected to hydrogen nuclear magnetic resonance 1 H-NMR (400 MHz, d-DMSO) and mass spectrometry, and the results were as follows:
  • the half-inhibitory concentration IC 50 of the compound (the concentration of the compound required to inhibit the enzymatic activity to 50%) is determined by mixing a specific substrate with a fixed enzyme and different concentrations of the test compound.
  • the assay used was the Caliper Mobility Shift Assay, which was determined to be BTK, ITK, TEC, EGFR, HER2, HER4, JAK3, HCK, LYN, SRC, and SYK.
  • the standard reference compound used was Staurosporine.
  • Table 1 summarizes the results of experiments on inhibition of BTK enzyme activity by the target compounds (I a, I b, I c and I d ). The results showed that the target compounds (I b and I d ) had a very strong inhibitory effect on BTK kinase, and the compounds of formula I a and I c also had a strong inhibitory effect on BTK kinase.
  • Table 2 summarizes the results of inhibition experiments of the target compound I d against ITK, TEC, EGFR, HER2, HER4, JAK3, HCK, LYN, SRC and SYK enzyme activities, and the results show that the selective inhibitory activity of the target compound I d is good.
  • This selective inhibition has important treatments for the treatment of rheumatoid arthritis, B-cell lymphoma, leukemia, multiple myeloma, allergy, asthma, multiple sclerosis, type I diabetes, and systemic lupus erythematosus. significance.
  • Other compound tests of the invention also have similar classes of results.
  • mice CD-1 mice, males and females; body weight: 20-25 g;
  • Test preparation The target compound was formulated into 0.2 mg/mL (for intravenous administration) and 1.0 mg/mL (for oral administration), and was used. Route of administration: oral / intravenous. Dosing capacity and frequency: 2 mL/kg (intravenous) or 5 mL/kg (oral), single administration.
  • Sample collection Blood was collected at the following time points, and blood was taken at 5 min, 15 min, 30 min, 1 hr, 2 hr, 4 hr, 8 hr, and 24 hr after administration.
  • Sample analysis The collected samples were tested using the LC-MS/MS method.
  • the instrument model is API4000.
  • test results show that the compound of the present invention has good pharmacokinetic characteristics and a short half-life, which can reduce the risk of immunological side reactions which may be caused by inhibition of BTK.
  • T max is small, and the peak plasma concentration can be reached very quickly, so that the drug can be activated quickly.
  • in vitro liver microsomal metabolism of the compounds of the invention was also tested.
  • the test compound will be co-incubated with NADPH and mouse or human liver microsomes in a 37 ° C water bath, and the test compound is added to initiate the reaction. 20 ⁇ L of the incubation sample was taken at different time points (0, 10, 20, 40, 60 min) and transferred to acetonitrile containing the internal standard. After the protein was precipitated, the supernatant was centrifuged. The test compound in the supernatant was analyzed by the LC-MS/MS method. The in vitro clearance rate in vitro was calculated based on the elimination half-life of the test compound in the incubation system. Midazolam was incubated as a positive control in parallel.
  • the T 1/2 of the compound of formula I d in mouse and human liver microsomes was 8.26 and 3.13 min, respectively, and the intrinsic clearance (CL int ) was 660.83 and 555.11 mL/min/kg, respectively.
  • Acalabrutinib had T 1/2 of 23.32 and 11.88 min in mouse and human liver microsomes, respectively, and the intrinsic clearance rates were 234.03 and 146.3 mL/min/kg, respectively.
  • the results of these tests indicate that the compound of formula I d is metabolized faster than Acalabrutinib in vivo, thereby predicting that the compound of formula I d is less susceptible to immunological side effects than Acalabrutinib because of inhibition of BTK.
  • Other compound tests of the invention also have similar classes of results.
  • the compounds of the present invention are ideal highly potent and selective BTK kinase inhibitors and are expected to be useful for the treatment or prevention of rheumatoid arthritis, B cell lymphoma, leukemia, multiple myeloma, allergy, asthma, Diseases such as multiple sclerosis, type I diabetes, and systemic lupus erythematosus have achieved very good results. They can also be combined with different types of medicinal salts to form oral preparations (tablets or capsules, etc.). A tablet or capsule made with a compound of the invention can be taken one or more times a day. The compound of the present invention can also be combined with other drugs to prepare a compound preparation.

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Abstract

本发明涉及一种咪唑吡啶胺苯基衍生物，其可药用盐、水合物或以任何形式代谢形成的代谢产物，及在制备预防和/或治疗与BTK功能有关的适应症的药物中的用途。本发明的咪唑吡啶胺苯基衍生物是理想的高效BTK抑制剂，可用于治疗或预防类风湿性关节炎、B细胞淋巴瘤、白血病、多发性骨髓瘤、过敏、哮喘、多发性硬化、I型糖尿病和全身性红斑狼疮等疾病。

Description

一种咪唑吡啶胺苯基衍生物及其用途 技术领域
本发明涉及一种咪唑吡啶胺苯基衍生物及其在制备预防和/或治疗与BTK功能有关的适应症的药物中的用途。
背景技术
布鲁顿氏酪氨酸激酶(Bruton’s Tyrosine Kinase，BTK)是酪氨酸激酶TEC家族成员，在B细胞活化和细胞传导中发挥重要作用。B细胞受体(BCR)是B细胞活性的关键调节点并且异常的信号传导可以引起失调的B细胞增殖和病原性自身抗体的形成，从而导致多种自身免疫疾病和炎症疾病。
BTK在BCR的膜近端和紧接下游，BTK缺乏可以阻断BCR信号传导。因此通过抑制BTK能够提供一种阻断B细胞介导的疾病的有效治疗途径。BTK抑制剂可以用于类风湿性关节炎、B细胞淋巴瘤、白血病、多发性骨髓瘤、过敏、哮喘、多发性硬化、I型糖尿病和全身性红斑狼疮等疾病的治疗。
目前研发得最快的两个BTK抑制剂为依鲁替尼(Ibrutinib)和ACP-196(Acalabrutinib)。前者已于2013年由FDA批准上市，用于套细胞淋巴瘤(MCL)、慢性淋巴细胞白血病(CLL)等的治疗。后者目前处于III期临床中。
这两个BTK抑制剂均存在一些毒副作用，分别表现为：血小板减少症、血红蛋白减少、腹泻、中性粒细胞减少、贫血、乏力、头痛、肌肉骨骼痛、血管神经性水肿、上呼吸道感染、恶心、青紫、呼吸困难、便秘、皮疹、关节痛、腹痛、呕吐和食欲下降等。其中依鲁替尼相对ACP-196毒副作用要大许多(Acalabrutinib(ACP-196)in Relapsed Chronic Lymphocytic Leukemia(The New England Journal of Medicine，374；4，2016))。
这些毒副作用的产生的原因是药物对激酶的选择性不高，半衰期长。
在文献Acalabrutinib(ACP-196)in Relapsed Chronic Lymphocytic Leukemia(The New England Journal ofMedicine，374；4，2016)中披露了EGFR/ITK/TEC这三个激酶有明确的副反应相关性。
在会议论文Presented at the 2nd International Conference on New Concepts in B-Cell Malignancies；9-11 September 2016；Estoril，Portugal中披露了依鲁替尼的半衰期为6小时，ACP-196的半衰期为1.13小时。
发明内容
本发明所要解决的技术问题是提供一种新型的咪唑吡啶胺苯基衍生物，其具有较低的毒副作用，是理想的非可逆性BTK抑制剂。
本发明同时还提供咪唑吡啶胺苯基衍生物，其可药用盐、水合物，或以任何形式代谢形成的代谢产物在制备预防和/或治疗与BTK功能有关的适应症的药物中的用途。
为解决以上技术问题，本发明采取如下技术方案：
本发明的一个目的是提供一种具有通式(I)所示结构的咪唑吡啶胺苯基衍生物，其可药用盐、水合物，或以任何形式代谢形成的代谢产物，
Figure PCTCN2017090908-appb-000001
其中：Z选自NH、CO或O；
R1为芳环、五元杂芳环或六元杂芳环，其任选地被0-5个C1-C4烷基或卤素独立地取代；
R2为H、C1-C4烷基或卤素；
R3为
Figure PCTCN2017090908-appb-000002
其中，R4为C(O)CCR5或C(O)CHCHR5，R5为H或C1-C4烷基。
本发明中，所述具有通式(I)所示结构的咪唑吡啶胺苯基衍生物，其可药用盐、水合物，或以任何形式代谢形成的代谢产物中，非交换性的氢未被取代，或部分或全部被氘取代。
优选地，R1为苯环、含有1或2个氮的六元杂芳环，其任选地被0～2个C1-C4烷基取代。
进一步优选地，R1为
Figure PCTCN2017090908-appb-000003
Figure PCTCN2017090908-appb-000004
优选地，R2为H、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基。
优选地，R3为
Figure PCTCN2017090908-appb-000005
优选地，R5为H、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基。
具体地，所述咪唑吡啶胺苯基衍生物为如下结构式表示的化合物中的一种：
Figure PCTCN2017090908-appb-000006
Figure PCTCN2017090908-appb-000007
Figure PCTCN2017090908-appb-000008
本发明的另一个目的是提供一种具有通式(II)所示结构的咪唑吡啶胺苯基衍生物，其可药用盐、水合物，或以任何形式代谢形成的代谢产物，
Figure PCTCN2017090908-appb-000009
其中：
X、Y中的一个为NH，另一个为CO；
R1为芳环、五元杂芳环或六元杂芳环，其任选地被0-5个C1-C4烷基或卤素独立地取代；
R2为H、C1-C4烷基或卤素；
R3为
Figure PCTCN2017090908-appb-000010
其中，R4为C(O)CCR5或C(O)CHCHR5，R5为H或C1-C4烷基；
其中当X为CO，Y为NH，R3为
Figure PCTCN2017090908-appb-000011
且R1为未被取代的杂芳环时，R2为C1-C4烷基。
本发明中，所述具有通式(II)所示结构的咪唑吡啶胺苯基衍生物，其可药用盐、水合物，或以任何形式代谢形成的代谢产物中，非交换性的氢未被取代，或部分或全部被氘取代。
优选地，R1为苯环、含有1或2个氮的六元杂芳环，其任选地被0～2个C1-C4烷基取代
进一步优选地，R1为
Figure PCTCN2017090908-appb-000012
Figure PCTCN2017090908-appb-000013
优选地，R2为H、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基。
优选地，R3为
Figure PCTCN2017090908-appb-000014
优选地，R5为H、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基。
具体地，所述咪唑吡啶胺苯基衍生物为如下结构式表示的化合物中的一种：
Figure PCTCN2017090908-appb-000015
Figure PCTCN2017090908-appb-000016
Figure PCTCN2017090908-appb-000017
根据本发明，所述的咪唑吡啶胺苯基衍生物的化合物，其不仅包括单一的某种化合物形式，还包括多种结构满足通式(I)或通式(II)要求的化合物的混合物形式，以及同一化合物的不同异构体形式例如外消旋体、对映异构体、非对映异构体等。所述的可药用盐包括但不限于盐酸盐、磷酸盐、硫酸盐、醋酸盐、马来酸盐、甲磺酸盐、苯磺酸盐、苯酸盐、甲基苯磺酸盐、琥珀酸盐、延胡索酸盐、富马酸盐、酒石酸盐、没食子酸盐、柠檬酸盐等。所述的“具有通式(I)或通式(II)的化合物的前药“指一种物质，当采用适当的方法施用后，可在受试者体内进行代谢或化学反应而转变成结构式(I)或结构式(II)的至少一种化合物或其盐。
本发明咪唑吡啶胺苯基衍生物的制备可以通过化学领域众所周知的那些类似的方法的合成途径，特别是根据本文包含的描述合成本发明的化合物。试剂一般从商业来源获得或易于使用本领域技术人员众所周知的方法制备。
本发明中，芳环是指拥有共轭的平面环体系，原子间成键并不是不连续的单双键交替，而是被离域π电子云覆盖的有机芳香化合物，其环中均为碳元素。五元杂芳环和六元杂芳环是指芳环的环中有非碳元素。
本发明的第三个目的是提供如所述的具有通式(I)的咪唑吡啶胺苯基衍生物，其可药用盐、水合物，或以任何形式代谢形成的代谢产物或如所述的具有通式(II)的咪唑吡啶胺苯基衍生物，其可药用盐、水合物，或以任何形式代谢形成的代谢产物在制备预防和/或治疗与BTK功能有关的适应症的药物中的用途。
具体地，所述与BTK功能相关的适应症包括类风湿性关节炎、B细胞淋巴瘤、白血病、多发性骨髓瘤、过敏、哮喘、多发性硬化、I型糖尿病和全身性红斑狼疮等疾病。
本发明的第四个目的是提供制备所述的具有通式(I)的咪唑吡啶胺苯基衍生物，其可药用盐、水合物，或以任何形式代谢形成的代谢产物或所述的具有通式(II)的咪唑吡啶胺苯基衍生物，其可药用 盐、水合物，或以任何形式代谢形成的代谢产物的中间体，所述的中间体的结构通式为：
Figure PCTCN2017090908-appb-000018
其中，R1为
Figure PCTCN2017090908-appb-000019
R4为氮保护基或H；
R2为卤素或NH2；
R3为
Figure PCTCN2017090908-appb-000020
Z选自NH、CO或O；X、Y中的一个为NH，另一个为CO；R1为芳环、五元杂芳环或六元杂芳环，其任选地被0-5个C1-C4烷基或卤素独立地取代；R2为H、C1-C4烷基或卤素。
优选地，所述的氮保护基为苄氧羰基。
优选地，R2中的卤素为Cl。
具体地，所述的中间体为如下结构通式中的一种：
Figure PCTCN2017090908-appb-000021
其中，Z选自NH、CO或O；
X、Y中的一个为NH，另一个为CO；
R1为芳环、五元杂芳环或六元杂芳环，其任选地被0-5个C1-C4烷基或卤素独立地取代；
R2为H、C1-C4烷基或卤素。
由于以上技术方案的实施，本发明与现有技术相比具有如下优点：
本发明提供的化合物是新型的咪唑吡啶胺苯基衍生物，其是理想的高效BTK抑制剂，通过抑制BTK能够提供一种阻断B细胞介导的疾病的有效治疗途径。本发明化合物结构新颖，活性强，具有较好的药代动力学性质，口服生物利用度高。本发明化合物具有很高的激酶选择性、对相关激酶具有较弱或没有不可逆抑制，减少因此而产生的不良反应。同时，较快的代谢速度和很短的半衰期，可以避免因为过度抑制BTK产生的免疫副反应风险。另外，本发明化合物口服后的血药浓度达峰时间Tmax很小，可以很 快达到血药浓度峰值，这样药物起效可以很快。因此本发明化合物可用于制备治疗或预防各种与BTK功能有关的适应症的药物且具有更低的毒副作用。
具体实施方式
下面结合具体实施例对本发明做进一步详细的说明，但本发明并不限于以下实施例。
实施例1
Figure PCTCN2017090908-appb-000022
式I a化合物可通过如下合成路线获得：
Figure PCTCN2017090908-appb-000023
式I a化合物的制备方法具体包括如下步骤：
(1)、制备中间体2：在2L的高压釜中依次加入1(90g，645mmol)，CH3COOH(1L)，和雷尼 镍(RaneyNi)(20g)。反应液在高压釜中，氢气压力1MPa的条件下，常温搅拌反应48h。反应结束后，将反应液通过硅藻土过滤，并用HCl的MeOH溶液(200mL，6.0N)洗涤硅藻土。滤液浓缩后，倒入甲苯搅拌，然后再次浓缩。得到的混合物在MTBE(甲基叔丁基醚)中搅拌，过滤。滤饼在MTBE和MeOH中搅拌，过滤得到中间体2(40g，收率为35％)，为棕色固体。LCMS显示分子离子峰(M+1)144.0。
(2)、制备中间体3：在3L的反应瓶中，依次加入DCM(二氯甲烷)(500mL)，中间体2(39g，217mmol)，1148-11-4(N-苄氧羰基-L-脯氨酸)(54g，217mmol)和Et3N(87.7g，868mmol)。在氮气保护下，将反应液冷却到0℃，分批加入HATU(2-(7-偶氮苯并三氮唑)-四甲基脲六氟磷酸酯)(98.8g，260mmol)。将反应液自然升温到室温，搅拌反应14h。反应结束后，加入HCl(400mL，0.5N H2O)，通过硅藻土过滤、萃取，有机相用NaHCO3(5％)和饱和食盐水洗涤，Na2SO4干燥浓缩，过柱(PE(聚乙烯)∶EA(丙烯酸乙酯)＝1∶1)得到中间体3(12.7g，收率为14.7％)。为白色固体。LCMS显示分子离子峰(M+1)375.0。
(3)、制备中间体4：在250mL的三口反应瓶中，加入ACN(乙腈)(48mL)和POCl3(16mL，175mol)，并预热到80℃。将中间体3(8g，21.3mmol)溶解到ACN(32mL)中，然后快速的加到预热好的溶液中。反应液在80℃继续反应3.5h。冷却到室温后，将反应液缓慢倒入NH3.H2O和冰水溶液中。继续加入NH3.H2O调节pH＝8-9。用乙酸乙酯萃取水相三次，有机相用饱和食盐水洗涤，Na2SO4干燥浓缩得到的固体中间体4直接用于下一步反应。LCMS显示分子离子峰(M+I)357.0。
(4)、制备中间体5：在100mL反应瓶中，依次加入DMF(N，N-二甲基甲酰胺)(20mL)，中间体4(21.3mmol)，和NBS(n-溴代丁二酰亚胺)(3.791g，21.3mmol)。反应液在常温搅拌12h，反相柱纯化得到中间体5(6.67g，72％两步收率)，为白色固体。LCMS显示分子离子峰(M+1)434.9。
(5)、制备中间体6：在250mL封管中依次加入中间体5(6g，13.8mmol)，IPA(异丙醇)(90mL)和NH3.H2O(135mL)。反应液在90℃反应14h，浓缩，反相柱纯化得到中间体6(5g，收率为87％)，为白色固体。LCMS显示分子离子峰(M+1)415.9。
(6)、制备中间体8：在1L反应瓶中，依次加入SOCl2(thionyl dichloride)(100mL)和7a(36.9g，300mmol)。在氮气保护下，反应液在80℃搅拌4h，冷却后浓缩。加入DCM(二氯甲烷)(400mL)，冷却到10℃，氮气保护下缓慢加入Et3N(121.1g，1200mmol)。冷却到0℃，滴入106-40-1(对溴苯胺)(51.6g，300mmol)的DCM(100mL)溶液。自然升温到室温，继续反应14h。浓缩，快速柱层析分离得到中间体8(33.39g，收率为40％)，为灰色固体。LCMS显示分子离子峰(M+1)277.0。
(7)、制备中间体9：在1L反应瓶中，依次加入中间体8(13.8g，50mmol)，联硼酸频那醇酯(13.97g，55mmol)，KOAc(乙酸钾)(14.7g，150mmol)，Pd(dppf)Cl2([1，1′-双(二苯基瞵基)二茂铁]二氯化钯)(1.5g)和二氧六环(250mL)。反应液在氩气保护下，100℃反应14h。冷却后，浓缩，快速柱层析分离得到中间体9(10.93g，收率为68％)，为白色固体。LCMS显示分子离子峰(M+1)325.0。
(8)、制备中间体10：在30mL微波反应管中依次加入中间体9(970mg，3mmol)，中间体6(625mg，1.5mmol)，Pd(dppf)Cl2(200mg)，K2CO3(2.2mL 2.0N，4.4mmol)和二氧六环(7mL)。将反应液氮气置换，微波加热到140℃反应30分钟。冷却后，用EA(丙烯酸乙酯)萃取三次。有机相浓缩后，快速柱层析和反相柱纯化得到中间体10(500mg，收率为62％)，为棕色固体。LCMS显示分子离子峰(M+1)534.0。
(9)、制备中间体11：在50mL反应瓶中，依次加入中间体10(500mg，0.94mmol)和HBr的CH3COOH溶液(7mL，HBr的质量浓度为33％)。反应液在常温搅拌4h。加入水，用DCM(二氯甲烷)萃取三次。水相用固体Na2CO3调节pH＝8-9。DCM萃取三次，有机相用饱和食盐水洗涤，Na2SO4干燥，浓缩后反相柱纯化得到中间体11(100mg，收率为27％)，为白色固体。LCMS显示分子离子峰(M+1)400.0。
(10)、制备式I a化合物：在25mL反应瓶中，依次加入DCM(二氯甲烷)(5mL)，中间体11(90mg，0.23mmol)，590-93-2(2-丁炔酸)(19.3mg，0.23mmol)，Et3N(68mg，0.68mmol)，和HATU(2-(7-偶氮苯并三氮唑)-四甲基脲六氟磷酸酯)(87.5mg，0.23mmol)。反应液在氮气保护下，常温搅拌30分钟。浓缩，大板纯化和反相柱纯化得到式I a化合物(47mg，收率为45％)，为白色固体。
LCMS显示分子离子峰(M+1)466.3。
对得到的目标产品I a进行了氢核磁共振1H-NMR(400MHz，d-DMSO)和质谱测试，结果如下：
1H-NMR谱图中吸收峰：δ＝10.80(1H，CONH)，8.78-8.77(1H，ArH)，8.20-8.18(1H，ArH)，8.11-8.06(3H，ArH)，7.81-7.74(1H，ArH)，7.71-7.69(1H，ArH)，7.60-7.59(2H，ArH)，7.11-7.06(1H，ArH)，6.09-6.03(2H，NH2)，5.71-5.45(1H，a-H)，3.83-3.78，3.61-3.55(2H，d-H)，2.42-1.93，1.63(7H，b-H，c-H，-CH3)。
m/z[MH]+：466.3。计算得出产品具有分子式C26H23N7O2，精确分子质量(exactmass)为465.19。
实施例2
式I b化合物(即上述II-2)，其化学结构如下：
Figure PCTCN2017090908-appb-000024
式I b化合物可通过如下合成路线获得：
Figure PCTCN2017090908-appb-000025
式I b化合物的制备方法具体包括如下步骤：
(1)、制备中间体12：在500mL反应瓶中，依次加入THF(四氢呋喃)(100mL)，7a(10.75g，50mmol)，Et3N(15.15g，150mmol)和HATU(2-(7-偶氮苯并三氮唑)-四甲基脲六氟磷酸酯)(19g，50mmol)。氩气保护下，常温搅拌20min。向以上溶液中缓慢加入504-29-0(2-氨基吡啶)(4.5g，47.9mmol)的THF(100mL)溶液，常温搅拌14h。浓缩，快速柱层析和反相柱纯化得到中间体16(2g，收率为14.2％)，为白色固体。LCMS显示分子离子峰(M+1)290.9。
(2)、制备中间体13：合成中间体13的方法和合成中间体9的方法类似，得到中间体13(1.3g，收率为56％)，为黄色固体。LCMS显示分子离子峰(M+1)339.1。
(3)、制备中间体14：合成中间体14的方法和合成中间体10的方法类似，得到中间体14(513mg，收率为67％)，为黄色固体。LCMS显示分子离子峰(M+1)548.0。
(4)、制备中间体15：合成中间体15的方法和合成中间体11的方法类似，得到中间体15(210mg， 收率为69.6％)，为黄色固体。LCMS显示分子离子峰(M+1)414.0。
(5)、制备式I b化合物：合成式I b化合物的方法和合成式I a化合物的方法类似。得到式I b化合物(35mg，收率为18.2％)，为白色固体。
对得到的目标产品I b进行了氢核磁共振1H-NMR(400MHz，d-DMSO)和质谱测试，结果如下：
1H-NMR谱图中吸收峰：δ＝10.79(1H，CONH)，8.37-8.36(1H，ArH)，8.23-8.21(1H，ArH)，7.87-7.77(2H，ArH)，7.62-7.60(1H，ArH)，7.50-7.45(2H，ArH)，7.18-7.09(2H，ArH)，6.14-6.09(2H，NH2)，5.72-5.46(1H，a-H)，3.84-3.80，3.62-3.56(2H，d-H)，2.47(3H，PhCH3)，2.42-1.92，1.63(7H，b-H，c-H，-CH3)。
m/z[MH]+：480.2。计算得出产品具有分子式C27H25N7O2，精确分子质量(exactmass)为479.21。
实施例3
式I c化合物(即上述I-2)，其化学结构如下：
Figure PCTCN2017090908-appb-000026
式I c化合物可通过如下合成路线获得：
Figure PCTCN2017090908-appb-000027
式I c化合物的制备方法具体包括如下步骤：
(1)、制备中间体16：在50mL反应瓶中，依次加入DMF(N，N-二甲基甲酰胺)(20mL)，7c(1.71g，10mmol)，372-48-5(2-氟吡啶)(970mg，10mmol)，和Cs2CO3(6.52g，20mmol)。反应液在氩气保护下，加热反应12h。冷却后，加入H2O，乙酸乙酯萃取三次。有机相用饱和食盐水洗涤，Na2SO4干燥，浓缩后得到中间体16(1.8g)，直接用于下一步反应。LCMS显示分子离子峰(M+1)250.0。
(2)、制备中间体17：在50mL反应瓶中，依次加入中间体16(1.8g，7mmol)，联硼酸频那醇酯(3.556g，14mmol)，K2CO3(2.898g，21mmol)，Pd(PPh3)4(四(三苯基瞵)钯)(500mg)和二氧六环(10mL)。反应液在氩气保护下，100℃反应15h。冷却后，浓缩，快速柱层析分离得到中间体17(2g)，为棕色固体。LCMS显示分子离子峰(M+1)298.1。
(3)、制备中间体18：在30mL微波反应管中依次加入中间体17(2g，6.7mmol)，中间体6(625mg，1.5mmol)，Pd(dppf)Cl2([1，1′-双(二苯基瞵基)二茂铁]二氯化钯)(300mg)，K2CO3(2mL 2.0N，4mmol)和二氧六环(8mL)。将反应液氮气置换，微波加热到140℃反应30分钟。冷却后，浓缩，反相柱纯化 得到中间体18(220mg，收率为28.9％)，为白色固体。LCMS显示分子离子峰(M+1)507.1。
(4)、制备中间体19：在50mL反应瓶中，依次加入中间体18(220mg，0.43mmol)和HBr的CH3COOH溶液(8mL，HBr的质量浓度为33％)。反应液在常温搅拌4h。加入水，用DCM(二氯甲烷)萃取三次。水相用固体Na2CO3调节pH＝8-9。DCM萃取三次，有机相用饱和食盐水洗涤，Na2SO4干燥，浓缩后反相柱纯化得到中间体19(120mg，收率为75％)，为白色固体。LCMS显示分子离子峰(M+1)373.1。
(5)、制备式I c化合物：在25mL反应瓶中，依次加入DCM(二氯甲烷)(5mL)，中间体23(120mg，0.32mmol)，590-93-2(2-丁炔酸)(27mg，0.32mmol)，Et3N(96mg，0.96mmol)，和HATU(2-(7-偶氮苯并三氮唑)-四甲基脲六氟磷酸酯)(152mg，0.4mmol)。反应液在氮气保护下，常温搅拌4h。浓缩，反相柱纯化得到式I c化合物(59mg，收率为42％)，为白色固体。
对得到的目标产品I c进行了氢核磁共振1H-NMR(400MHz，d-DMSO)和质谱测试，结果如下：
1H-NMR谱图中吸收峰：δ＝8.20-8.19(1H，ArH)，7.90-7.87(1H，ArH)，7.83-7.75(1H，ArH)，7.64-7.60(2H，ArH)，7.26-7.24(2H，ArH)，7.18-7.15(1H，ArH)，7.11-7.17(2H，ArH)，6.13-6.07(2H，NH2)，5.71-5.45(1H，a-H)，3.82-3.79(1H，d-H)，3.61-3.54(1H，d-H)，2.43-1.92，1.63(7H，b-H，c-H，-CH3)。
m/z[MH]+：439.2。计算得出产品具有分子式C25H22N6O2，精确分子质量(exact mass)为438.18。
实施例4
式I d化合物(即上述I-1)，其化学结构如下：
Figure PCTCN2017090908-appb-000028
式I d化合物可通过如下合成路线获得：
Figure PCTCN2017090908-appb-000029
式I d化合物的制备方法具体包括如下步骤：
(1)、制备中间体21：合成中间体21的方法和合成中间体18的方法类似，得到中间体21(200mg，收率为46.4％)，为白色固体。LCMS显示分子离子峰(M+1)506.2。
(2)、制备中间体22：合成中间体22的方法和合成中间体19的方法类似，得到中间体22(116mg，收率为78％)，为白色固体。LCMS显示分子离子峰(M+1)372.1。
(3)、制备式I d化合物：合成式I d化合物的方法和合成式I c化合物的方法类似，得到式I d化合物(116mg，收率为43.6％)，为白色固体。
对得到的目标产品I d进行了氢核磁共振1H-NMR(400MHz，d-DMSO)和质谱测试，结果如下：
1H-NMR谱图中吸收峰：δ＝7.82-7.34(1H，ArH)，7.61-7.57(2H，ArH)，7.44-7.40(2H，ArH)，7.19-7.15(1H，ArH)，7.13-7.05(5H，ArH)，6.11-6.05(2H，NH2)，5.70-5.44(1H，a-H)，3.82-3.79，3.61-3.55(2H，d-H)，2.43-1.94，1.62(7H，b-H，c-H，-CH3)。
m/z[MH]+：438.2。计算得出产品具有分子式C26H23N5O2，精确分子质量(exactmass)为437.19。
药效等试验
化合物酶活性测试：
试验方法
化合物的半抑制浓度IC50(把酶活性抑制至50％时所需的化合物的浓度)是以固定的酶混合特定底物及不同浓度的待测化合物来测定的。所用的测定方法是卡尺迁移变动分析(Caliper Mobility Shift Assay)，所测定的激酶为BTK、ITK、TEC、EGFR、HER2、HER4、JAK3、HCK、LYN、SRC和SYK，所应用的标准参照化合物为星形孢菌素(staurosporine)。
试验结果
表1总结了目标化合物(I a、I b、I c和I d)对BTK酶活性抑制实验结果。结果显示目标化合物(I b和I d)对BTK激酶具有非常强的抑制作用，式I a和I c化合物对BTK激酶也具有较强的抑制作用。
表2总结了目标化合物I d对ITK、TEC、EGFR、HER2、HER4、JAK3、HCK、LYN、SRC和SYK酶活性抑制实验结果，结果显示目标化合物I d的选择性抑制活性较好。这一选择性的抑制作用对类风湿性关节炎、B细胞淋巴瘤、白血病、多发性骨髓瘤、过敏、哮喘、多发性硬化、I型糖尿病和全身性红斑狼疮等疾病的治疗具有重要的治疗意义。本发明其他化合物试验也有相似类的结果。
表1
化合物 激酶抑制活性(IC50，nM)
式I a化合物 415
式I b化合物 50
式I c化合物 577
式I d化合物 4.8
Ibrutinib 1.5
Acalabrutinib 11
表2
Figure PCTCN2017090908-appb-000030
Figure PCTCN2017090908-appb-000031
药物动力学属性评估：
1、实验方法
实验动物：CD-1小鼠、雄性和雌性；体重：20-25g；
供试品配制：将目标化合物配制成0.2mg/mL(为静脉给药用)和1.0mg/mL(为口服给药用)，待用。给药途径：口服/静脉注射。给药容量及频率：2mL/kg(静脉注射)或5mL/kg(口服)，单次给药。
样品采集：按照下列时间点采集血液，给药后5min、15min、30min、1hr、2hr、4hr、8hr和24hr取血。
2、样品分析及结果
样品分析：使用LC-MS/MS方法对采集样品进行检测。使用仪器型号为API4000。
药物动力学数据分析：使用WinNolin按照非房室模型法对所得血药浓度数据进行拟合和计算，部分结果总结在表3中。
表3
Figure PCTCN2017090908-appb-000032
表3中，CL：清除率。Vss：稳态表观分布容积。Terminal t1/2：半衰期。AUClast：曲线下面积。MRTINF：平均驻留时间。Tmax：峰时间。Cmax：峰浓度。F：生物利用度，指口服剂量实际到达血液循环的分数。
试验结果表明本发明化合物具有良好的药物动力学特征，并且半衰期短，可以降低因为抑制BTK可能产生的免疫副反应风险。同时，Tmax很小，可以很快达到血药浓度峰值，这样药物起效可以很快。
另外，还对本发明化合物的体外肝微粒体代谢进行了测试。受试化合物将与NADPH和小鼠或人肝微粒体在37℃水浴锅中进行共孵育，加入受试化合物启动反应。在不同的时间点(0、10、20、40、60min)取出20μL孵育样品转移至含有内标的乙腈中。蛋白沉淀后，离心取上清。上清液中的受试化合物由LC-MS/MS方法分析。根据受试化合物在孵育体系中的清除半衰期算出体外内在清除率。咪达唑仑 作为阳性对照平行孵育。式I d化合物在小鼠和人肝微粒体中的T1/2分别为8.26和3.13min，内在清除率(CLint)分别为660.83和555.11mL/min/kg。同一测试实验Acalabrutinib在小鼠和人肝微粒体中的T1/2分别为23.32和11.88min，内在清除率分别为234.03和146.3mL/min/kg。这些试验结果表明式I d化合物在体内的代谢比Acalabrutinib快，以此可以预测式I d化合物因为抑制BTK而产生免疫副反应的风险比Acalabrutinib小。本发明其他化合物试验也有相似类的结果。
以上实施例仅是代表性的。通过上述实施例可见，本发明的化合物是理想的高效选择性BTK激酶抑制剂，可期望用于治疗或预防类风湿性关节炎、B细胞淋巴瘤、白血病、多发性骨髓瘤、过敏、哮喘、多发性硬化、I型糖尿病和全身性红斑狼疮等疾病并取得非常好的效果，其还可以和不同类型的药用盐相结合制成口服制剂(片剂或胶囊等)。用本发明化合物制成的片剂或胶囊可被服用每日一次或多次。本发明化合物还可和其他它药物结合制成复方制剂。
上述实施例只为说明本发明的技术构思及特点，其目的在于让熟悉此项技术的人士能够了解本发明的内容并据以实施，并不能以此限制本发明的保护范围。凡根据本发明精神实质所作的等效变化或修饰，都应涵盖在本发明的保护范围之内。

Claims (15)

  1. 具有通式(I)所示结构的咪唑吡啶胺苯基衍生物，其可药用盐、水合物，或以任何形式代谢形成的代谢产物，
    Figure PCTCN2017090908-appb-100001
    其中：Z选自NH、CO或O；
    R1为芳环、五元杂芳环或六元杂芳环，其任选地被0-5个C1-C4烷基或卤素独立地取代；
    R2为H、C1-C4烷基或卤素；
    R3为
    Figure PCTCN2017090908-appb-100002
    其中，R4为C(O)CCR5或C(O)CHCHR5，R5为H或C1-C4烷基；
    所述具有通式(I)所示结构的咪唑吡啶胺苯基衍生物，其可药用盐、水合物，或以任何形式代谢形成的代谢产物中，非交换性的氢未被取代，或部分或全部被氘取代。
  2. 根据权利要求1所述的咪唑吡啶胺苯基衍生物，其可药用盐、水合物，或以任何形式代谢形成的代谢产物，其特征在于：R1为苯环、含有1或2个氮的六元杂芳环，其任选地被0～2个C1-C4烷基取代。
  3. 根据权利要求1所述的咪唑吡啶胺苯基衍生物，其可药用盐、水合物，或以任何形式代谢形成的代谢产物，其特征在于：R2为H、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基。
  4. 根据权利要求1所述的咪唑吡啶胺苯基衍生物，其可药用盐、水合物，或以任何形式代谢形成的代谢产物，其特征在于：R3为
    Figure PCTCN2017090908-appb-100003
  5. 根据权利要求1所述的咪唑吡啶胺苯基衍生物，其可药用盐、水合物，或以任何形式代谢形成的代谢产物，其特征在于：R5为H、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基。
  6. 根据权利要求1所述的咪唑吡啶胺苯基衍生物，其可药用盐、水合物，或以任何形式代谢形成的代谢产物，其特征在于：所述咪唑吡啶胺苯基衍生物为如下结构式表示的化合物中的一种：
    Figure PCTCN2017090908-appb-100004
    Figure PCTCN2017090908-appb-100005
    Figure PCTCN2017090908-appb-100006
  7. 具有通式(II)所示结构的咪唑吡啶胺苯基衍生物，其可药用盐、水合物，或以任何形式代谢形成的代谢产物，
    Figure PCTCN2017090908-appb-100007
    其中：
    X、Y中的一个为NH，另一个为CO；
    R1为芳环、五元杂芳环或六元杂芳环，其任选地被0-5个C1-C4烷基或卤素独立地取代；
    R2为H、C1-C4烷基或卤素；
    R3为
    Figure PCTCN2017090908-appb-100008
    其中，R4为C(O)CCR5或C(O)CHCHR5，R5为H或C1-C4烷基；
    其中当X为CO，Y为NH，R3为
    Figure PCTCN2017090908-appb-100009
    且R1为未被取代的杂芳环时，R2为C1-C4烷基；
    所述具有通式(II)所示结构的咪唑吡啶胺苯基衍生物，其可药用盐、水合物，或以任何形式代谢形成的代谢产物中，非交换性的氢未被取代，或部分或全部被氘取代。
  8. 根据权利要求7所述的咪唑吡啶胺苯基衍生物，其可药用盐、水合物，或以任何形式代谢形成的代谢产物，其特征在于：R1为苯环、含有1或2个氮的六元杂芳环，其任选地被0～2个C1-C4烷基取代。
  9. 根据权利要求7所述的咪唑吡啶胺苯基衍生物，其可药用盐、水合物，或以任何形式代谢形成的代谢产物，其特征在于：R2为H、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基。
  10. 根据权利要求7所述的咪唑吡啶胺苯基衍生物，其可药用盐、水合物，或以任何形式代谢形成的 代谢产物，其特征在于：R3为
    Figure PCTCN2017090908-appb-100010
  11. 根据权利要求7所述的咪唑吡啶胺苯基衍生物，其可药用盐、水合物，或以任何形式代谢形成的代谢产物，其特征在于：R5为H、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基。
  12. 根据权利要求7所述的咪唑吡啶胺苯基衍生物，其可药用盐、水合物，或以任何形式代谢形成的代谢产物，其特征在于：所述咪唑吡啶胺苯基衍生物为如下结构式表示的化合物中的一种：
    Figure PCTCN2017090908-appb-100011
    Figure PCTCN2017090908-appb-100012
    Figure PCTCN2017090908-appb-100013
  13. 如权利要求1至6中任一项权利要求所述的具有通式(I)的咪唑吡啶胺苯基衍生物，其可药用盐、水合物，或以任何形式代谢形成的代谢产物或如权利要求7至12中任一项权利要求所述的具有通式(II)的咪唑吡啶胺苯基衍生物，其可药用盐、水合物，或以任何形式代谢形成的代谢产物在制备预防和/或治疗与BTK功能有关的适应症的药物中的用途。
  14. 根据权利要求13所述的用途，其特征在于：所述与BTK功能相关的适应症包括类风湿性关节炎、B细胞淋巴瘤、白血病、多发性骨髓瘤、过敏、哮喘、多发性硬化、I型糖尿病和全身性红斑狼疮。
  15. 制备如权利要求1至6中任一项权利要求所述的具有通式(I)的咪唑吡啶胺苯基衍生物，其可药用盐、水合物，或以任何形式代谢形成的代谢产物或如权利要求7至12中任一项权利要求所述的具有通式(II)的咪唑吡啶胺苯基衍生物，其可药用盐、水合物，或以任何形式代谢形成的代谢产物的中间体，其特征在于：所述的中间体的结构通式为：
    Figure PCTCN2017090908-appb-100014
    其中，R1为
    Figure PCTCN2017090908-appb-100015
    R2为卤素或NH2；
    R3为
    Figure PCTCN2017090908-appb-100016
    Z选自NH、CO或O；X、Y中的一个为NH，另一个为CO；
    R1为芳环、五元杂芳环或六元杂芳环，其任选地被0-5个C1-C4烷基或卤素独立地取代；R2为H、C1-C4烷基或卤素；
    R4为H或氮的保护基。
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