CN114644633A - 杂环类jak抑制剂 - Google Patents
杂环类jak抑制剂 Download PDFInfo
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- CN114644633A CN114644633A CN202011495497.0A CN202011495497A CN114644633A CN 114644633 A CN114644633 A CN 114644633A CN 202011495497 A CN202011495497 A CN 202011495497A CN 114644633 A CN114644633 A CN 114644633A
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- Prior art keywords
- cycloalkyl
- alkyl
- phenyl
- heterocyclyl
- heteroaryl
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- 125000000623 heterocyclic group Chemical group 0.000 title claims description 57
- 229940122245 Janus kinase inhibitor Drugs 0.000 title description 10
- 150000001875 compounds Chemical class 0.000 claims abstract description 85
- 150000003839 salts Chemical class 0.000 claims abstract description 30
- 208000023275 Autoimmune disease Diseases 0.000 claims abstract description 10
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 10
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 9
- 201000010099 disease Diseases 0.000 claims abstract description 9
- 201000011510 cancer Diseases 0.000 claims abstract description 7
- 208000027866 inflammatory disease Diseases 0.000 claims abstract description 6
- 230000001404 mediated effect Effects 0.000 claims abstract description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 31
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 30
- 125000001424 substituent group Chemical group 0.000 claims description 26
- 229910003827 NRaRb Inorganic materials 0.000 claims description 24
- 229910052736 halogen Inorganic materials 0.000 claims description 23
- 125000001072 heteroaryl group Chemical group 0.000 claims description 23
- 125000000217 alkyl group Chemical group 0.000 claims description 22
- 150000002367 halogens Chemical class 0.000 claims description 21
- 238000000034 method Methods 0.000 claims description 21
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 20
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 17
- 229910052739 hydrogen Inorganic materials 0.000 claims description 16
- 229910052757 nitrogen Inorganic materials 0.000 claims description 15
- 229910052799 carbon Inorganic materials 0.000 claims description 14
- 125000005842 heteroatom Chemical group 0.000 claims description 14
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 13
- 239000000651 prodrug Substances 0.000 claims description 12
- 229940002612 prodrug Drugs 0.000 claims description 12
- 229910052717 sulfur Inorganic materials 0.000 claims description 11
- 208000022559 Inflammatory bowel disease Diseases 0.000 claims description 9
- 125000003118 aryl group Chemical group 0.000 claims description 8
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- 239000008194 pharmaceutical composition Substances 0.000 claims description 8
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- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 2
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- 125000001153 fluoro group Chemical group F* 0.000 claims description 2
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- 101000997832 Homo sapiens Tyrosine-protein kinase JAK2 Proteins 0.000 description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 11
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- 101000844245 Homo sapiens Non-receptor tyrosine-protein kinase TYK2 Proteins 0.000 description 10
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 10
- 102100032028 Non-receptor tyrosine-protein kinase TYK2 Human genes 0.000 description 10
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 10
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 10
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- 239000000543 intermediate Substances 0.000 description 9
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- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 8
- 239000002253 acid Substances 0.000 description 8
- 208000006673 asthma Diseases 0.000 description 8
- 125000004432 carbon atom Chemical group C* 0.000 description 8
- 210000001072 colon Anatomy 0.000 description 8
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- CXNIUSPIQKWYAI-UHFFFAOYSA-N xantphos Chemical compound C=12OC3=C(P(C=4C=CC=CC=4)C=4C=CC=CC=4)C=CC=C3C(C)(C)C2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 CXNIUSPIQKWYAI-UHFFFAOYSA-N 0.000 description 8
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- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 6
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- BWEHAWAXNXZSRX-UHFFFAOYSA-N 1-[4-[1-(azetidin-1-yl)-2-methyl-1-oxopropan-2-yl]anilino]-3-(2,6-difluorophenyl)-6,7-dihydro-5H-imidazo[1,5-a]pyrazin-8-one Chemical compound CC(C)(C(N1CCC1)=O)C(C=C1)=CC=C1NC1=C(C(NCC2)=O)N2C(C(C(F)=CC=C2)=C2F)=N1 BWEHAWAXNXZSRX-UHFFFAOYSA-N 0.000 description 5
- CPYBSSQNSFQAED-UHFFFAOYSA-N 1-bromo-3-(2,6-difluorophenyl)-8-methoxyimidazo[1,5-a]pyrazine Chemical compound COC1=NC=CN2C(C(C(F)=CC=C3)=C3F)=NC(Br)=C12 CPYBSSQNSFQAED-UHFFFAOYSA-N 0.000 description 5
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- IXDBSISXQMZQSJ-UHFFFAOYSA-N 3-(1-acetylpiperidin-4-yl)-1-[4-(morpholine-4-carbonyl)anilino]-7H-imidazo[1,5-a]pyrazin-8-one Chemical compound CC(N(CC1)CCC1C1=NC(NC(C=C2)=CC=C2C(N2CCOCC2)=O)=C2N1C=CNC2=O)=O IXDBSISXQMZQSJ-UHFFFAOYSA-N 0.000 description 5
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- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical group C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
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Abstract
本发明涉及作为Janus激酶(JAK)抑制剂的杂环类化合物或其可药用的盐。具体而言,本发明涉及一种通式(I)所示的化合物或其可药用的盐。本发明还涉及所述化合物或其可药用的盐的制备方法。本发明的化合物可用于治疗和/或预防JAK介导的相关性疾病,特别是炎性疾病、自身免疫性疾病和癌症。其中通式(I)所示的各取代基与说明书中的定义相同。
Description
技术领域
本发明涉及一种调控或抑制Janus激酶(JAK)活性的杂环类化合物或其可药用的盐。本发明还涉及所述化合物或其可药用的盐的制备方法。本发明进一步涉及所述化合物或其可药用的盐在治疗和/或预防炎性疾病、自身免疫性疾病及癌症的用途和使用方法。
背景技术
Janus激酶(JAK)是一种非受体酪氨酸蛋白激酶,由四个家族成员,即JAK1、JAK2、JAK3和TYK2。JAK在结构上有7个同源结构域(JAK Homology Domain,JH),其中JH1结构域为激酶区、JH2结构域为伪激酶区(对JH1的激酶催化活性起调节作用)、JH6和JH7是受体结合区域。当细胞因子受体(Cytokine Receptor)的细胞表面区域与细胞因子(Cytokine)结合,引起与之细胞内区域相结合的JAK被磷酸化,从而为信号转导和转录激活因子(STAT)蛋白创建停泊位点,使STAT蛋白被激活的JAK磷酸化,形成二聚体,进入细胞核,调控相关基因的表达和转录,实现信号从细胞膜至细胞核的转导(Lionard et al.,Ann.Rev.Immunol.1998,16,293-322)。因此,JAK通过JAK-STAT通路转导细胞因子介导的信号,在细胞因子依赖性调节的细胞增殖、分化、凋亡以及免疫反应等许多细胞功能中起重要作用,是治疗炎性疾病、自身免疫性疾病和癌症的热门靶点之一(Alicea-Velazquez etal.,Curr.Drug Targets 2011,12,546-55)。目前已有几个JAK的抑制剂药物被批准上市,包括用于治疗骨髓纤维化的JAK1/JAK2抑制剂鲁索替尼(ruxolitinib)和JAK2抑制剂fedratinib、用于治疗类风湿性关节炎的泛JAK抑制剂托法替尼(tofacitinib)、JAK1/JAK2抑制剂baricitinib、泛JAK抑制剂peficitinib和JAK1抑制剂upadacitinib等。
JAK和STAT对不同免疫应答的控制起高度的特异作用。一种JAK激酶可以参与多种细胞因子的信号转导过程,一种细胞因子的信号通路也可以激活多个JAK激酶,但细胞因子对激活的STAT蛋白却具有一定的选择性,例如白细胞介素(IL)-4激活STAT1/3/5/6,而IL-12却特异性激活STAT4。JAK1、JAK2和TYK2广泛存在于各种组织和细胞中,JAK1与IL-6、干扰素(IFN)等炎症因子的激活密切相关。因此JAK1选择性抑制剂被认为对治疗类风湿性关节炎(RA)、银屑病等自身免疫性疾病具有潜在的治疗效果。JAK2可单独介导红细胞生成素(EPO)和血小板生成素(TPO)等细胞因子(Won et al.,BMC Bioinformatics 2009,10,S53)的信号传导,与血液细胞的增殖分化密切相关。TYK2涉及炎症细胞因子如干扰素(IFNs)、IL-12和IL-23等的信号转导,在先天免疫和适应性免疫中发挥着关键作用,因此TYK2作为自身免疫性疾病的靶点也得到了极大的关注,比如TYK2抑制剂用于治疗牛皮癣、系统性红斑狼疮(SLE)和炎性肠疾病(IBD)等。JAK3仅存在于骨髓和淋巴系统,介导IL-2、IL-4、IL-7、IL-9、IL-15和IL-21的信号传导,这些细胞因子对诱导T细胞的增殖分化、激活B细胞产生抗体、活化巨噬细胞、增强自然杀伤细胞(NK细胞)的活性和IFN等其它细胞因子的诱导具有重要作用,因此JAK3选择性抑制剂有望对器官移植、自身免疫性疾病、炎性肺炎等治疗具有重要作用。
炎症性肠病(IBD)一种常见的慢性肠道炎症性疾病,包括克罗恩病(Crohn'sdisease,CD)、溃疡性结肠炎(ulcerative colitis,UC)和未定型IBD(IBDU)。炎症性肠病影响了全世界500万人,且患病率逐年增加。临床症状为腹泻、便血、腹痛、疲惫、高烧等,常用的治疗药物,包括5-氨基水杨酸(5-ASAs)、糖皮质激素、免疫抑制剂(如硫唑嘌呤)及生物制剂(如抗TNF、IL-12/IL-23单抗)等,但许多接受治疗的患者没有得到缓解,高达80%的克罗恩病患者和30%的UC患者最终需要接受手术。这一领域还有巨大的未满足医疗需求,需要更有效和安全的药物。
在该病发生过程中,IL-13和IL-17等促炎因子的表达增加,从而通过JAK-STAT通路诱发炎症。JAK抑制剂作为一种新型的口服小分子药物,具有治疗CD和UC的潜在用途,其中托法替尼已经在多个国家被批准用于UC的治疗,但托法替尼对JAK1/2/3的非选择性抑制,引起了较为严重的副作用,比如严重感染和引发恶性肿瘤。可是由于JAK激酶家族成员的催化活性部位的高度序列相似性,设计一个具有治疗所需系统暴露量的口服选择性JAK抑制剂是相当困难的。因此开发新的JAK抑制剂,使其只在作用部位(比如结肠、皮肤等)富集治疗所需的局部暴露量,但极少的血液溶度以避免全身不良反应,从而发挥药效又提高了安全性。Theravance公司开发的TD-1473为一个具有肠道局部吸收的泛JAK抑制剂,已进入临床三期试验,表现了良好的耐受性。
发明内容
定义
除非另有相反陈述,否则下列用在说明书和权利要求书中的术语具有下述含义。
“Cx-y”表示碳原子数的范围,其中x和y均为整数,例如C3-8环烷基表示具有3-8个碳原子的环烷基,即具有3、4、5、6、7或8个碳原子的环烷基。还应理解,“C3-8”还包含其中的任意亚范围,例如C3-7、C3-6、C4-7、C4-6、C5-6等。
“烷基”指含有1至20个碳原子,例如1至8个碳原子、1至6个碳原子或1至4个碳原子的饱和的直链或支链的烃基基团。烷基的非限制性实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基等。
“环烷基”指含有3至14个碳环原子的饱和环状烃基取代基。环烷基可以是单碳环,通常含有3至8个、3至7个或3至6个碳环原子。单环环烷基的非限制性实例包括环丙基、环丁基、环戊基、环己基、环庚基等。环烷基还可以是稠合、桥接或螺合到一起的双或三环,如十氢萘基、二环[2.2.2]辛烷、螺[3.3]庚烷等。
“杂环基或杂环”指饱和或部分不饱和的单环或多环环状基团,其包括3至20个环原子,例如可以是3至14个、3至12个、3至10个、3至8个、3至6个或5至6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是整数0至2),但不包括-O-O-、-O-S-或-S-S-的环部分,其余环原子为碳。优选包括3至12个环原子,更优选3至10个环原子,更优选4至7个环原子,更优选4至6个环原子,最优选5或6个环原子,其中1~4个是杂原子,更优选1~3个是杂原子,最优选1~2个是杂原子。单环杂环基的非限制性实例包含吡咯烷基、噁丁环基、哌啶基、哌嗪基、四氢呋喃基、四氢吡喃基、四氢噻喃基、吗啉基、硫代吗啉基、高哌嗪基、吖丁啶基等。多环杂环基包括稠合、桥接或螺合多环杂环基,如八氢环戊二烯并[c]吡咯、八氢吡咯并[1,2-a]吡嗪、3,8-二氮杂二环[3.2.1]辛烷、5-氮杂螺[2.4]庚烷、2-氧杂-7-氮杂螺[3.5]壬烷等。
“芳基或芳环”指含有6至14个碳原子的芳香族单环或稠合多环基团,优选为6至10元,例如苯基和萘基,最优选苯基。所述芳基环可以稠合于杂芳基、杂环基或环烷基环上,其中与母体结构连接在一起的环为芳基环,非限制性实例包括:
“杂芳基或杂芳环”指含有5至14个环原子的杂芳香族体系,其中1至4个环原子选自包括氧、硫和氮的杂原子。杂芳基优选为5至10元,更优选杂芳基是5元或6元,例如呋喃基、噻吩基、吡啶基、吡咯基、嘧啶基、吡嗪基、吡唑基、咪唑基、四唑基、噁唑基、异噁唑基、噻唑基、异噻唑基、喹啉基、异喹啉基、吲哚基、异吲哚基等。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上,其中与母体结构连接在一起的环为杂芳基环,非限制性实例包括:
“卤素”指氟、氯、溴或碘。
“氰基”指-CN。
“任选”意味着随后所描述的事件或环境可以但不必发生,该表述包括该事件或环境发生或不发生的情形。例如,“任选被烷基取代的杂环基团”意味着烷基可以但不必须存在,该表述包括杂环基团被烷基取代的情形和杂环基团不被烷基取代的情形。
“取代”指基团中的一个或多个氢原子,优选为5个,更优选为1~3个氢原子彼此独立地被相应数目的取代基取代。不言而喻,取代基仅处在它们可能的化学位置,本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如,具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。所述取代基包括但不限于卤素、氰基、硝基、氧代、-SF5、C1-4烷基、C3-7环烷基、4-7元杂环基、苯基、5-6元杂芳基等。
“异构体”指具有相同分子式但其原子结合的性质或顺序或其原子的空间排列不同的化合物。原子空间排列不同的异构体称为“立体异构体”。立体异构体包括旋光异构体、几何异构体和构象异构体。
本发明的化合物可以以旋光异构体形式存在。旋光异构体包括对映异构体和非对映异构体。对映异构体是指两个立体异构体彼此镜像但相互不可重叠。外消旋混合物或外消旋体是指手性分子的左右手对映异构体数量相等的混合物。非对映异构体是指两个立体异构体不是彼此的镜像且不可重叠。当旋光异构体为单一异构体且其绝对构型确定,根据手性碳原子上取代基的构型,其为“R”或“S”的绝对构型;当旋光异构体的绝对构型未确定,依据所测的旋光值,其为(+)或(-)。制备和分离光学异构体的方法是本领域中已知的。
本发明的化合物也可以存在几何异构体。本发明考虑由碳-碳双键、碳-氮双键、环烷基或杂环基团周围的取代基的分布所产生的各种几何异构体和其混合物。碳-碳双键或碳-氮键周围的取代基指定为Z或E构型,环烷基或杂环周围的取代基指定为顺式或反式构型。
本发明的化合物还可能显示互变异构现象,例如酮-烯醇互变异构。
应该理解,本发明包括任何互变异构或立体异构形式和其混合物,并且不仅仅限于化合物的命名或化学结构式中所使用的任何一个互变异构或立体异构形式。
“同位素”是指在本发明化合物中出现的原子的所有同位素。同位素包括具有相同原子序数但不同质量数的那些原子。适合并入本发明化合物中的同位素的实例是氢、碳、氮、氧、磷、氟和氯,分别例如但不限于2H(D)、3H、13C、14C、15N、17O、18O、31P、32P、35S、18F和36Cl。本发明的同位素标记化合物通常可通过本领域技术人员已知的传统技术或通过与所附实施例中描述的那些类似的方法使用适当的同位素标记的试剂代替非同位素标记的试剂来制备。这样的化合物具有各种潜在用途,例如作为测定生物活性中的标样和试剂。在稳定同位素的情况下,这样的化合物具有有利地改变生物、药理学或药代动力学性质的潜力。氘(D)为本发明的优选同位素,比如甲基、亚甲基或次甲基中的氢可被氘取代。
本发明的化合物可以以前药的形式给予。“前药”是指在活体内的生理条件下例如通过氧化、还原、水解等(它们各自利用酶或在没有酶参与下进行)转化成本发明的生物活性化合物的衍生物。前药的实例有下述化合物:其中本发明的化合物中的氨基被酰化、烷基化或磷酸化,例如二十烷酰基氨基、丙氨酰氨基、新戊酰氧基甲基氨基,或其中羟基被酰化、烷基化、磷酸化或转化成硼酸盐,例如乙酰氧基、棕榈酰氧基、新戊酰氧基、琥珀酰氧基、富马酰氧基、丙氨酰氧基,或其中羧基被酯化或酰胺化,或其中巯基与选择性地向靶和/或向细胞的胞质溶胶递送药物的载体分子,例如肽形成二硫桥键。这些化合物可以由本发明的化合物根据公知方法制备。
“可药用的盐”或者“药学上可接受的盐”是指由可药用的碱或酸,包括无机碱或酸和有机碱或酸制成的盐。在本发明的化合物含有一个或多个酸性或碱性基团的情况下,本发明还包含它们相应的可药用盐。因此,含有酸性基团的本发明的化合物可以以盐形式存在并可根据本发明使用,例如作为碱金属盐、碱土金属盐或作为铵盐。这样的盐的更确切实例包括钠盐、钾盐、钙盐、镁盐或与氨或有机胺,例如乙胺、乙醇胺、三乙醇胺或氨基酸形成的盐。含有碱性基团的本发明的化合物可以以盐形式存在并可根据本发明以它们与无机或有机酸的加成盐的形式使用。合适的酸的实例包括盐酸、氢溴酸、磷酸、硫酸、硝酸、甲磺酸、对甲苯磺酸、萘二磺酸、草酸、乙酸、酒石酸、乳酸、水杨酸、苯甲酸、甲酸、丙酸、特戊酸、丙二酸、琥珀酸、庚二酸、富马酸、马来酸、苹果酸、氨基磺酸、苯基丙酸、葡糖酸、抗坏血酸、异烟酸、柠檬酸、己二酸和本领域技术人员已知的其它酸。如果本发明的化合物在分子中同时含有酸性和碱性基团,本发明除所提到的盐形式外还包括内盐或内铵盐。各盐可通过本领域技术人员从已知的常规方法获得,例如通过在溶剂或分散剂中使本发明的化合物与有机或无机酸或碱接触或通过与其它盐阴离子交换或阳离子交换。
“药物组合物”指含有一种或多种本发明所述的化合物或其可药用的盐、稳定同位素衍生物、异构体、前药及其混合物形式以及其他组分例如可药用的载体和辅料的组合物。药物组合物的目的是促进对生物体的给药,利于活性成分的吸收进而发挥生物活性。
因此,在本申请中当提及“化合物”、“本发明化合物”或“本发明所述化合物”时,包括所有所述化合物形式,例如其可药用的盐、稳定同位素衍生物、异构体、前药及其混合物。
在本文中,术语“癌症/肿瘤”包括但不限于消化道/胃肠道癌、结肠癌、肝癌、乳腺癌、卵巢癌、前列腺癌、头颈癌、皮肤癌、淋巴瘤、白血病(包括急性骨髓性白血病和慢性髓细胞性白血病)、肾癌、肺癌、肌肉癌、骨癌、膀胱癌、脑癌、黑素瘤、多发性骨髓瘤、血管增生相关病症/肿瘤。
在本文中,术语“炎性疾病或自身免疫性疾病”包括但不限于关节炎、桥本氏甲状腺炎、自身免疫性溶血性贫血、恶性贫血的自身免疫性萎缩性胃炎、自身免疫性脑脊髓炎、自身免疫性睾丸炎、古德帕斯丘病、自身免疫性血小板减少症、交感性眼炎、重症肌无力、格雷夫斯病、原发性胆汁性肝硬化、肝炎、原发性硬化性胆管炎、慢性侵袭性肝炎、非酒精性脂肪性肝病、非酒精性脂肪性肝炎、溃疡性结肠炎、膜性肾小球病、系统性红斑狼疮、类风湿性关节炎、牛皮癣性关节炎、干燥综合征、赖特综合征、多肌炎、皮肌炎、I-型干扰素病包括Aicardi-Goutières综合征和其他过度表达I-型干扰素的系统性硬化症、孟德尔疾病、结节性多动脉炎、多发性硬化症、复发缓解型多发性硬化症、原发性进行性多发性硬化症、继发性进展性多发性硬化症、大疱性类天疱疮,肠炎症如克罗恩氏病、溃疡性结肠炎、炎性肠病、乳糜泻、直肠炎、嗜酸性粒细胞胃肠炎、肥大细胞增多症,皮肤疾病如特应性皮炎、湿疹、牛皮癣、硬皮病、瘙痒症或其他瘙痒症状、白癜风、脱发,基于O-细胞(体液)或T-细胞的自身免疫性疾病包括科根综合征、强直性脊柱炎、韦格纳肉芽肿病、自身免疫性脱发、I-型或青少年型糖尿病、甲状腺炎等,过敏反应如过敏性皮炎、夏季湿疹、马蹄痒、痉挛、炎性气道疾病、气道反复阻塞、气道高反应性、慢性阻塞性肺病等,哮喘和其他阻塞性气道疾病包括但不限于慢性或过度哮喘、迟发性哮喘、支气管炎、支气管哮喘、过敏性哮喘、内源性哮喘、外源性哮喘、尘埃性哮喘。
在本文中,术语“治疗有效量”是指包括可有效治疗或防止所述疾病的本发明化合物的量。
在本文中,术语“患者”是指哺乳动物,尤其是人类。
本发明提供作为JAK抑制剂的一种通式(I)所示的化合物或其可药用的盐、稳定同位素衍生物、异构体及其前药:
其中:
键a为单键或双键;
R1和R2各自独立地选自H、D、CN、C1-6烷基或C3-6环烷基,其中所述烷基的一个或多个氢任选被D或氟所取代;
A为C3-10环烷基、4-10元杂环基、C6-10芳基或5-10元杂芳基,其中所述环烷基、杂环基、芳基和杂芳基任选被一个或多个选自D、卤素、氰基、-ORa、-NRaRb、-C(O)Ra、-C(O)NRaRb、-S(O)2Ra、-P(O)(CH3)2、C1-6烷基、C3-6环烷基、4-8元杂环基或5-6元杂芳基的取代基所取代;B为苯基或5-6元杂芳基,其中所述苯基和杂芳基任选被一个或多个选自D、卤素、氰基、-ORa、-NRaRb、-COORa、-C(O)Ra、-NRaC(O)Rb、-C(O)NRaRb、-S(O)2Ra、-S(O)2NRaRb、-S(O)(NRa)Rb、-P(O)(CH3)2、C1-6烷基、C3-6环烷基、4-8元杂环基或5-6元杂芳基的取代基所取代,所述烷基、环烷基、杂环基和杂芳基任选进一步被一个或多个选自D、卤素、CN、-OH、-NH2、C1-6烷基、-OC1-6烷基、-COORa、-C(O)Ra或-C(O)NRaRb的取代基所取代;
Ra和Rb各自独立地选自H、C1-6烷基、C3-6环烷基或4-8元杂环基,其中所述烷基、环烷基和杂环基任选被一个或多个选自D、卤素、C1-6烷基的取代基所取代。
在一个优选实施方案中,R1和R2都为H。
在一个实施方案中,A为C3-8环烷基、4-8元杂环基、C6-10芳基或5-6元杂芳基,其中所述环烷基、杂环基、芳基和杂芳基任选被一个或多个选自D、卤素、氰基、-ORa、-NRaRb、-C(O)Ra、-C(O)NRaRb、-S(O)2Ra、C1-6烷基、C3-6环烷基、4-8元杂环基或5-6元杂芳基的取代基所取代。
在一个优选实施方案中,A为C3-8环烷基、4-8元杂环基、苯基或5-6元杂芳基,其中所述环烷基、杂环基、苯基和杂芳基任选被一个或多个选自卤素、-C(O)Ra、C1-6烷基和C3-6环烷基的取代基所取代。
在一个更优选实施方案中,A为苯基,其中所述苯基的一个或多个氢任选被卤素所取代。
在一个实施方案中,B为苯基或5-6元杂芳基,其中所述苯基和杂芳基任选被一个或多个选自卤素、-COORa、-C(O)Ra、-C(O)NRaRb、-S(O)2Ra、C1-6烷基、C3-6环烷基、含N、S和/或O杂原子的4-8元杂环基的取代基所取代,所述烷基、环烷基和杂环基任选进一步被一个或多个选自C1-6烷基、-C(O)Ra和-C(O)NRaRb的取代基所取代。
在一个实施方案中,Ra和Rb各自独立地选自H、C1-6烷基、C3-6环烷基或含N、S和/或O杂原子的4-6元杂环基,其中所述烷基、环烷基和杂环基的一个或多个氢任选被C1-6烷基所取代。
在一些实施方案中,通式(I)的化合物如通式(II)所示:
其中:
A为C3-8环烷基、4-8元杂环基、苯基或5-6元杂芳基,其中所述环烷基、杂环基、苯基和杂芳基任选被一个或多个选自卤素、-C(O)Ra、C1-6烷基和C3-6环烷基的取代基所取代。
在一个优选实施方案中,A为苯基,其中所述苯基的一个或多个氢任选被卤素所取代。
B为苯基或5-6元杂芳基,其中所述苯基和杂芳基任选被一个或多个选自卤素、-COORa、-C(O)Ra、-C(O)NRaRb、-S(O)2Ra、C1-6烷基、C3-6环烷基、含N、S和/或O杂原子的4-8元杂环基的取代基所取代,所述烷基、环烷基和杂环基任选进一步被一个或多个选自C1-6烷基、-C(O)Ra和-C(O)NRaRb的取代基所取代。
Ra和Rb各自独立地选自H、C1-6烷基、C3-6环烷基或含N、S和/或O杂原子的4-6元杂环基,其中所述烷基、环烷基和杂环基的一个或多个氢任选被C1-6烷基所取代。
在另一些实施方案中,通式(I)的化合物如通式(III)所示:
其中:
A为A为苯基,其中所述苯基的一个或多个氢任选被卤素所取代。
B为苯基或5-6元杂芳基,其中所述苯基和杂芳基任选被一个或多个选自卤素、-COORa、-C(O)Ra、-C(O)NRaRb、-S(O)2Ra、C1-6烷基、C3-6环烷基、含N、S和/或O杂原子的4-8元杂环基的取代基所取代,所述烷基、环烷基和杂环基任选进一步被一个或多个选自C1-6烷基、-C(O)Ra和-C(O)NRaRb的取代基所取代。
Ra和Rb各自独立地选自H、C1-6烷基、C3-6环烷基或含N、S和/或O杂原子的4-6元杂环基,其中所述烷基、环烷基和杂环基的一个或多个氢任选被C1-6烷基所取代。
本发明还涉及以下化合物1-40,或其可药用的盐、稳定同位素衍生物、异构体、前药及其混合物。
本发明的化合物能够有效抑制JAK的活性,优选其IC50小于100nM,更优选其IC50小于10nM。
本发明也涉及一种药物组合物,所述药物组合物包含通式(I)所示的化合物或其可药用的盐、稳定同位素衍生物、异构体及其前药和一种或多种药学上可接受的载体或辅料。
本发明的另一方面提供一种治疗或者预防JAK介导的疾病的方法,所述方法包括给予有需要的患者治疗有效量的通式(I)所示的化合物或其可药用的盐、稳定同位素衍生物、异构体、前药及其混合物,或包含所述化合物的药物组合物;所述疾病包括但不限于包括肠炎症在内的炎性疾病、自身免疫性疾病、癌症等,尤其是炎症性肠病、皮炎、湿疹、类风湿性关节炎、系统性红斑狼疮、银屑病、斑秃等。
根据本发明,所述药物可以是任何药物剂型,包括但不限于片剂、胶囊剂、溶液剂、冻干制剂、注射剂。
本发明的药物制剂可以以每剂量单位包含预定量的活性成分的剂量单位形式给药。这种单位可根据治疗的病症、给药方法和患者的年龄、体重和状况包含例如0.5毫克至1克,优选1毫克至700毫克,特别优选5毫克至500毫克的本发明的化合物。此外,可以使用制药领域中所知的方法制备这种类型的药物制剂,比如把活性成分与一种或多种辅料和/或佐剂混合。
本发明药物制剂可适于通过任何所需的合适方法给药,例如通过经口(包括口腔或舌下)、直肠、经鼻、局部(包括口腔、舌下或经皮)、阴道或肠道外(包括皮下、肌内、静脉内或皮内)方法给药。
本发明还提供制备所述化合物的方法。本发明通式(I)所述化合物的制备可通过以下示例性方法和实施例完成,但这些方法和实施例不应以任何方式被认为是对本发明范围的限制。也可通过本领域技术人员所知的合成技术合成本发明所述的化合物,或者综合使用本领域已知方法和本发明所述方法。每步反应所得的产物用本领域已知的分离技术得到,包括但不限于萃取、过滤、蒸馏、结晶、色谱分离等。合成所需的起始物料和化学试剂可以根据文献(可从SciFinder上查询)常规合成或购买。
合成方法
本发明通式(I)所述杂环类化合物可按照下方所述路线合成:1)羧酸A1与胺A2缩合得到A3;2)A3在酸性条件下脱水环化得到A4;3)A4用NBS溴化得到A5;4)A5与甲醇钠反应得到A6;5)A6与胺B-NH2通过Bulkwald偶联反应得到A7;6)A7脱保护得到A8。有些A7和A8的官能团FG1和FG2可进一步被衍生化得到各种目标化合物,比如FG1中含被保护胺,脱保护得到胺,胺进一步酰胺化或还原胺化得到酰胺和取代的胺;又如FG2中的酯被碱(例如LiOH)水解生成酸,酸进一步酰胺化得到酰胺等。
本发明通式(I)所述杂环类化合物也可按照下方所述路线合成:1)A8经氢化得到B1。有些B1的官能团FG1和FG2可进一步被衍生化得到各种目标化合物,比如FG2中的酯被碱(例如LiOH)水解生成酸,酸进一步酰胺化得到酰胺等。
实施例
本发明的起始原料可以按照本领域已知的方法来合成,或可购自ABCR GmbH&Co.KG、Acros Organics、Aldrich Chemical Company、韶远化学科技(Accela ChemBioInc.)、北京偶合等化学品公司。
本发明化合物的结构是通过核磁共振(NMR)和/或质谱(MS)来确定的。NMR的测定使用Bruker ASCEND-400核磁仪,所用溶剂为氘代二甲基亚砜(DMSO-d6)、氘代氯仿(CDC13)或氘代甲醇(CD3OD)等,内标为四甲基甲硅烷(TMS),化学位移是以10-6(ppm)作为单位给出。MS的测定使用Agilent SQD(ESI)质谱仪(安捷伦6120)。
HPLC使用安捷伦1260DAD高压液相色谱仪(Poroshell 120EC-C18,50×3.0mm,2.7μm色谱柱)或Waters Arc高压液相色谱仪(Sunfirc C18,150×4.6mm,5μm色谱柱)。
实施例中如无特殊说明,反应温度为室温(20~30℃)。
实施例中如无特殊说明,反应均在氩气气氛或氮气气氛下进行。氩气气氛或氮气气氛是指反应瓶连接一个约1L容积的氩气或氮气气球。
氢气气氛是指反应瓶在抽真空再充入氢气(反复3次)后,连接一个约1L容积的氢气气球。
微波反应使用CEM Discover-SP型微波反应器。
实施例中的反应进程的监测使用安捷伦的液质联用色谱仪(1260/6120),也可采用薄层层析(TLC),所用硅胶板的厚度为0.15~0.2mm(青岛海洋GF254)。
化合物的纯化采用柱层析或薄层层析,其中柱层析使用青岛海洋的200~300目硅胶,薄层层析使用青岛海洋的厚度为0.4~0.5mm的GF254硅胶板。
柱层析或薄层层析展开溶剂体系通常有a)二氯甲烷和甲醇体系,b)石油醚和乙酸乙酯体系,或如实施例中所示。溶剂的体积比根据化合物的极性不同而进行调节,也可以加入少量的三乙胺、或其它酸性或碱性试剂进一步调节。
化合物的纯化还采用Waters的质谱导向自动制备系统(质谱检测器:SQD2),根据化合物的极性用适当的乙腈/水(含0.1%三氟乙酸或甲酸,或0.05%氨水)梯度于20mL/min的流速洗脱反相高压柱(XBridge-C18,19×150mm,5μm)。部分实施例可在使用自动制备系统纯化后加入1N稀盐酸,然后减压除去溶剂,得到盐酸盐。
缩写DMF是指N,N-二甲基甲酰胺。
缩写TFA是指三氟乙酸。
缩写DIPEA是指N,N-二异丙基乙胺。
缩写NBS是指N-溴代琥珀酰亚胺。
缩写HATU是指2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸盐。
缩写XantPhos是指4,5-双(二苯基膦)-9,9-二甲基氧杂蒽。
缩写Pd2(dba)3是指三(二亚苄基丙酮)二钯。
缩写Brettphos是指2-(二环己基膦)-3,6-二甲氧基-2',4',6'-三异丙基-1,1'-联苯。
中间体1f
1-溴-3-(2,6-二氟苯基)-8-甲氧基咪唑并[1,5-a]吡嗪
第一步
N-((3-氯吡嗪-2-基)甲基)-2,6-二氟苯甲酰胺(1c)
将2,6-二氟苯甲酸1a(5g,31.6mmol)溶解在二氯甲烷(100mL)中,加入3滴DMF并冷却至0℃,然后滴加草酰氯(8g,63.3mmol)。室温下搅拌1小时后,将混合物浓缩至干。将残余物溶于二氯甲烷(10mL),得到溶液A。在另一个250mL圆底烧瓶中放入(3-氯吡嗪-2-基)甲胺盐酸盐1b(5.7g,31.6mmol),然后加入二氯甲烷(100mL)和三乙胺(9.6g,94.8mmol)并冷却至0℃,然后逐滴加入溶液A。将混合物在室温搅拌1小时后,用水(50mL)淬灭。分出的有机相经无水硫酸钠干燥,过滤后,滤液在减压条件下浓缩至干,残余物用硅胶柱层析(乙酸乙酯/二氯甲烷=1/1)纯化,得到目标产物1c(6.8g,76%)。
MS m/z(ESI):284[M+1]
1H NMR(400MHz,CDCl3)δ8.47(d,J=2.5Hz,1H),8.39-8.30(m,1H),7.44-7.37(m,2H),7.03-6.90(m,2H),4.93(d,J=4.5Hz,2H).
第二步
8-氯-3-(2,6-二氟苯基)咪唑并[1,5-a]吡嗪(1d)
向1c(6.8g,24mmol)的乙腈(80mL)溶液中加入三氯氧膦(18.4g,120mmol)。将混合物加热至90℃并搅拌16小时。冷却到室温后,再添加三氯氧膦(18.4g,120mmol),将混合物再次加热至90℃并搅拌28小时。冷却至室温,浓缩至干,然后加入饱和碳酸氢钠溶液(50mL)并用二氯甲烷(2×100mL)萃取。合并的有机相经无水硫酸钠干燥,过滤后,滤液在减压条件下浓缩至干,残余物用硅胶柱层析(乙酸乙酯/二氯甲烷=1/2)纯化,得到目标产物1d(5.9g,92%)。
MS m/z(ESI):266[M+1]
1H NMR(400MHz,CDCl3)δ8.10(s,1H),7.60-7.50(m,2H),7.44(d,J=5.0Hz,1H),7.14(t,J=8.1Hz,2H).
第三步
1-溴-8-氯-3-(2,6-二氟苯基)咪唑并[1,5-a]吡嗪(1e)
向1d(880mg,3.31mmol)的乙腈(40mL)溶液中加入NBS(590mg,3.31mmol)。将混合物在室温搅拌18小时,然后浓缩至干。将残余物溶解在乙酸乙酯(100mL)中,用水(2×50mL)洗涤,然后用无水硫酸钠干燥。过滤后,滤液在减压条件下浓缩至干,残余物用硅胶柱层析(石油醚/乙酸乙酯=2/1),得到目标产物1e(940mg,82%)。
MS m/z(ESI):344[M+1]
1H NMR(400MHz,CDCl3)δ7.57(tt,J=8.5,6.3Hz,1H),7.49-7.46(m,1H),7.41(d,J=5.0Hz,1H),7.13(t,J=8.1Hz,2H).
第四步
1-溴-3-(2,6-二氟苯基)-8-甲氧基咪唑并[1,5-a]吡嗪(1f)
将1e(590mg,1.71mmol)溶于甲醇(40mL),冷却至0℃并逐滴加入甲醇钠溶液(463mg,2.57mmol,30%的甲醇溶液)。将所得混合物搅拌2小时,然后倒入饱和氯化铵溶液(100mL),并用乙酸乙酯(3×50mL)萃取。合并的有机相经无水硫酸钠干燥,过滤后,滤液在减压条件下浓缩至干,残余物用硅胶柱层析(石油醚/乙酸乙酯=1/1)纯化,得到目标产物1f(570mg,98%)。
MS m/z(ESI):340[M+1]
1H NMR(400MHz,CDCl3)δ7.56-7.49(m,1H),7.21(dt,J=5.0,1.9Hz,1H),7.17(d,J=5.1Hz,1H),7.13-7.08(m,2H),4.18(s,3H).
下表中的中间体均参照中间体1f的实验步骤操作,但在第一步中用不同的羧酸代替2,6-二氟苯甲酸1a。
中间体3f、19a的核磁数据如下:
中间体33c
2-(4-氨基苯基)-2-甲基丙酰胺
第一步
2-甲基-2-(4-硝基苯基)丙酰胺(33b)
0℃下向2-甲基-2-(4-硝基苯基)丙腈33a(2.00g,10.52mmol)的乙醇/水(20mL,体积比1/1)溶液中加入碳酸钾(0.58g,4.21mmol)和30%过氧化氢水溶液(35ml),并在0℃下搅拌0.5小时,然后升温至室温并搅拌16小时。反应完成后,加入饱和亚硫酸钠溶液(50mL)并在室温搅拌0.5小时,然后用乙酸乙酯(3×50mL)萃取。合并的有机相经无水硫酸钠干燥,过滤后,滤液在减压条件下浓缩至干。残余物用硅胶柱层析(二氯甲烷/甲醇=20/1)纯化,得到目标产物33b(0.76g,35%)。
MS m/z(ESI):209[M+1]
第二步
2-(4-氨基苯基)-2-甲基丙酰胺(33c)
向33b(0.76g,3.65mmol)的甲醇(10mL)溶液中加入20%钯碳(0.15g)。将混合物在氢气气氛下搅拌12小时,然后过滤。滤液在减压条件下浓缩至干,得到目标产物33c(0.65g,100%)。
MS m/z(ESI):179[M+1]
中间体36d
4-(2-(4-氨基苯基)-2-甲基丙酰基)哌嗪-1-羧酸叔丁酯
第一步
2-甲基-2-(4-硝基苯基)丙酸(36a)
0℃下向33a(5.00g,26.29mmol)和水(25mL)的混合物中加入浓硫酸(25mL),然后将加热至120℃并搅拌12小时。冷却到室温后,加入水(50mL),并用饱和碳酸氢钠溶液调节至pH=8,然后用乙酸乙酯(3×50mL)萃取。合并的有机相经无水硫酸钠干燥,过滤后,滤液在减压条件下浓缩至干,得到目标产物36a(5.00g,91%)。
MS m/z(ESI):210[M+1]
第二步
2-甲基-2-(4-硝基苯基)丙酰氯(36b)
0℃下将36a(5.00g,23.90mmol)加入到氯化亚砜中,然后加热至85℃并搅拌12小时。冷却至室温后,浓缩至干,得到目标产物36b(5.20g,96%)。
第三步
4-(2-甲基-2-(4-硝基苯基)丙酰基)哌嗪-1-羧酸叔丁酯
室温下向哌嗪-1-甲酸叔丁酯(1.84g,9.89mmol)的二氯甲烷(20mL)溶液中加入三乙胺(2.00g,19.77mmol)并搅拌10分钟。然后冷却到0℃并加入36c(1.50g,6.59mmol)的二氯甲烷(10mL)溶液。室温搅拌2小时后,加入水(20mL),并用二氯甲烷(3×30mL)萃取。合并的有机相经无水硫酸钠干燥,过滤后,滤液浓缩至干,残余物用硅胶柱层析(二氯甲烷/甲醇=100/1)纯化,得到目标产物36c(1.50g,60%)。
MS m/z(ESI):378[M+1]
第四步
4-(2-(4-氨基苯基)-2-甲基丙酰基)哌嗪-1-羧酸叔丁酯(36d)
向36c(1.50g,3.97mmol)的甲醇(250mL)溶液中添加20%钯碳(0.3g),然后在氢气气氛下搅拌12小时。过滤并将滤液浓缩至干,得到目标产物36d(1.38g,100%)。
MS m/z(ESI):348[M+1]
中间体35d参照中间体36d的实验步骤合成,但在第三步中用N-甲基哌啶代替哌嗪-1-甲酸叔丁酯。
实施例1
3-(2,6-二氟苯基)-1-((4-(吗啉-4-羰基)苯基)氨基)咪唑并[1,5-a]吡嗪-8(7H)-酮
第一步
(4-((3-(2,6-二氟苯基)-8-甲氧基咪唑并[1,5-a]吡嗪-1-基)氨基)苯基)(吗啉代)甲酮(1h)
向1f(200mg,0.59mmol)、(4-氨基苯基)(吗啉代)甲酮1g(121mg,0.59mmol)和1,4-二氧六环(2mL)的混合物中加入叔丁醇钠(144mg,1.5mmol),然后加入XantPhos(69mg,0.12mmol)和Pd2(dba)3(55mg,0.06mmol)。将混合物在微波反应器中加热至100℃并搅拌1小时。冷却到室温后,将反应混合物用水(20mL)稀释,然后用乙酸乙酯(3×20mL)萃取。合并的有机相经无水硫酸钠干燥,过滤后,滤液在减压条件下浓缩至干,残余物用硅胶柱层析(二氯甲烷/甲醇=20/1)纯化,得到目标产物1h(260mg,95%)。
MS m/z(ESI):466[M+1]
第二步
3-(2,6-二氟苯基)-1-((4-(吗啉-4-羰基)苯基)氨基)咪唑并[1,5-a]吡嗪-8(7H)-酮(1)
向1h(260mg,0.56mmol)的乙腈(10mL)溶液中,加入6N盐酸(10mL),加热到70℃并搅拌1小时。冷却到室温后,浓缩至干,残余物用水(10mL)稀释,然后用饱和碳酸氢钠溶液调节至pH=8并用乙酸乙酯(2×50mL)萃取。合并的有机相经无水硫酸钠干燥,过滤后,滤液在减压条件下浓缩至干,残余物用硅胶柱层析(二氯甲烷/甲醇=20/1)纯化,得到目标产物1(固体,150mg,59%)。
MS m/z(ESI):452[M+1]
1H NMR(400MHz,DMSO-d6)δ10.56(d,J=5.3Hz,1H),8.42(s,1H),7.78-7.63(m,3H),7.43-7.27(m,4H),6.84(d,J=5.3Hz,1H),6.59(t,J=5.7Hz,1H),3.59(d,J=4.5Hz,4H),3.50(s,4H).
下表中的实施例或中间体均参照实施例1的实验步骤操作,但在第一步中分别用不同的化合物代替1f和1g。
实施例3、4、6、7、9、11、14、22、26、27、28、29、30、31、32、33、34、35、36、37和38的核磁数据如下:
实施例2
3-(2,6-二氟苯基)-1-((4-(吗啉-4-羰基)苯基)氨基)-6,7-二氢咪唑并[1,5-a]吡嗪-8(5H)-酮(2)
将1(97mg,0.215mmol)、甲醇(30mL)和10%钯炭(97mg)混合,然后在氢气气氛下加热至30℃并搅拌16小时。过滤后,滤液浓缩至干,残余物用反相制备高效液相色谱纯化,得到目标产物2(固体,25mg,26%)。
MS m/z(ESI):490[M+1]
1H NMR(400MHz,CD3OD)δ7.73(d,J=6.3Hz,1H),7.66(td,J=6.2,2.8Hz,3H),7.58(d,J=8.3Hz,2H),7.28(ddd,J=9.1,7.6,3.3Hz,1H),7.19(dd,J=9.1,4.2Hz,1H),6.94(d,J=6.4Hz,1H),4.73(s,2H),4.52(t,J=11.5Hz,1H),3.99(s,3H),3.76-3.70(m,1H),2.21-2.03(m,6H),1.63-1.53(m,2H).
下表中的实施例均参照实施例2的实验步骤操作,但在操作中用不同的化合物代替1。
实施例5、8、10、12、16、18和23的核磁数据如下:
实施例13
1-((4-(1-(氮杂环丁烷-1-基)-2-甲基-1-氧代丙烷-2-基)苯基)氨基)-3-(2,6-二氟苯基)-6,7-二氢咪唑[1,5-a]吡嗪-8(5H)-酮
第一步
2-(4-((3-(2,6-二氟苯基)-8-甲氧基咪唑并[1,5-a]吡嗪-1-基)氨基)苯基)-2-甲基丙酸叔丁酯(13b)
在氮气气氛下向1f(200mg,0.588mmol)的1,4-二氧六环(5mL)溶液中加入2-(4-氨基苯基)-2-甲基丙酸叔丁酯13a(280mg,1.17mmol)、Brettphos(62mg,0.118mmol),Pd2(dba)3(53mg,0.058mmol)和碳酸铯(600mg,1.76mmol),然后在微波反应器中加热至90℃并搅拌1小时。冷却到室温后,减压浓缩至干,残余物用硅胶柱层析(石油醚/乙酸乙酯=100/0至7/3)纯化,得到目标产物13b(200mg,68%)。
MS m/z(ESI):495[M+1]
第二步
2-(4-((3-(2,6-二氟苯基)-8-氧代-7,8-二氢咪唑并[1,5-a]吡嗪-1-基)氨基)苯基)-2-甲基丙酸乙酯(13c)
向13b(100mg,0.1mmol)的乙醇(4mL)溶液中加入HCl的乙醇(12N,2mL)溶液。将该溶液在70℃下搅拌2小时,然后冷却到室温并浓缩至干,得到目标产物13c(90mg)。该产品未经进一步纯化,直接用于下一步反应。
MS m/z(ESI):453[M+1]
第三步
2-(4-((3-(2,6-二氟苯基)-8-氧代-5,6,7,8-四氢咪唑并[1,5-a]吡嗪-1-基)氨基)苯基)-2-甲基丙酸乙酯(13d)
将13c(90mg,0.2mmol)、乙醇(5mL)和10%钯碳(100mg)混合,在氢气气氛下搅拌3小时后过滤,滤液浓缩至干,得到目标产物13d(80mg,88%)。
MS m/z(ESI):455[M+1]
第四步
2-(4-((3-(2,6-二氟苯基)-8-氧代-5,6,7,8-四氢咪唑并[1,5-a]吡嗪-1-基)氨基)苯基)-2-甲基丙酸(13e)
向13d(90mg,0.2mmol)的四氢呋喃(5mL)溶液加入氢氧化锂一水合物(17mg,0.4mmol),加热到60℃并搅拌18小时。冷却到室温后,将反应溶液浓缩至干,残余物用反相制备高效液相色谱纯化,得到目标产物13e(60mg,含TFA)。
MS m/z(ESI):427[M+1]
第五步
1-((4-(1-(氮杂环丁烷-1-基)-2-甲基-1-氧代丙烷-2-基)苯基)氨基)-3-(2,6-二氟苯基)-6,7-二氢咪唑[1,5-a]吡嗪-8(5H)-酮(13)
向13e(17mg,0.04mmol)、DMF(2mL)、HATU(20mg,0.052mmol)和氮杂环丁烷(10mg,0.12mmol)的混合物中加入二异丙基乙胺(26mg,0.2mmol)。将所得溶液在室温搅拌1小时,然后直接用反相制备高效液相色谱纯化,得到目标产物13(固体,2.69mg,14%)。
MS m/z(ESI):466[M+1]
1H NMR(400MHz,DMSO-d6)δ8.04(s,1H),7.81(s,1H),7.75-7.65(m,1H),7.59(d,J=8.7Hz,2H),7.42-7.29(m,2H),7.10(d,J=8.7Hz,2H),4.06-3.93(m,2H),3.86-3.71(m,2H),3.53-3.47(m,2H),2.59-2.51(m,2H),2.03-1.84(m,2H),1.37(s,6H).
实施例15
3-(2-氯-6-氟苯基)-1-((4-(吗啉-4-羰基)苯基)氨基)-6,7-二氢咪唑并[1,5-a]吡嗪-8(5H)-酮(15)
向3(140mg,0.3mmol)的乙醇(10mL)溶液中加入氯苯(1mL)和二氧化铂(70mg)。将混合物在氢气气氛下搅拌70分钟,然后过滤。滤液浓缩至干,残余物用反相制备高效液相色谱纯化,得到目标产物15(固体,62.7mg,44%)。
MS m/z(ESI):312[M+1]
1H NMR(400MHz,DMSO-d6)δ8.29(s,1H),7.87(s,1H),7.72-7.63(m,3H),7.57(d,J=8.1Hz,1H),7.47(t,J=8.7Hz,1H),7.31(d,J=8.6Hz,2H),3.95-3.90(m,2H),3.61-3.55(m,4H),3.54-3.45(m,6H).
实施例17
3-(2,6-二氟苯基)-1-((4-(2-甲基-1-吗啉代-1-氧代丙烷-2-基)苯基)氨基)咪唑并[1,5-a]吡嗪-8(7H)-酮
第一步
2-(4-((3-(2,6-二氟苯基)-8-氧代-7,8-二氢咪唑并[1,5-a]吡嗪-1-基)氨基)苯基)-2-甲基丙酸(17a)
将13b(420mg,0.848mmol)的三氟乙酸(10mL)溶液加热至70℃并搅拌1小时。冷却到室温后,反应液在减压条件下浓缩至干,得到目标产物17a(360mg)。该产品未经进一步纯化,直接用于下一步。
MS m/z(ESI):425[M+1]
第二步
3-(2,6-二氟苯基)-1-((4-(2-甲基-1-吗啉代-1-氧代丙烷-2-基)苯基)氨基)咪唑并[1,5-a]吡嗪-8(7H)-酮盐酸盐(17)
将17a(360mg,0.85mmol)、DMF(5mL)、HATU(420mg,1.1mmol)、吗啉(220mg,2.55mmol)和DIPEA(442mg,3.2mmol)混合。室温搅拌1小时后,反应混合物直接用反相制备高效液相色谱纯化,得到目标产物17(固体,320mg,76%,盐酸盐)。
MS m/z(ESI):494[M+1]
1H NMR(400MHz,DMSO-d6)δ10.47(d,J=5.3Hz,1H),8.12(s,1H),7.78-7.67(m,1H),7.64(d,J=8.7Hz,2H),7.42-7.31(m,2H),7.08(d,J=8.7Hz,2H),6.81(d,J=5.5Hz,1H),6.62-6.49(m,1H),3.69-3.41(m,8H),1.40(s,6H).
实施例19
3-(1-乙酰基哌啶-4-基)-1-((4-(吗啉-4-羰基)苯基)氨基)咪唑并[1,5-a]吡嗪-8(7H)-酮
第一步
4-(8-甲氧基-1-((4-(吗啉-4-羰基)苯基)氨基)咪唑并[1,5-a]吡嗪-3-基)哌啶-1-甲酸苄酯(19b)
向19a(206mg,1mmol)、1,4-二氧六环(8mL)和碳酸铯(813mg,2.5mmol)的混合物中加入XantPhos(116mg,0.2mmol)和Pd2(dba)3(92mg,0.1mmol)。将混合物在微波反应器中加热到90℃搅拌1小时。冷却到室温后过滤,滤液浓缩至干,残余物用硅胶柱层析(二氯甲烷/甲醇=100/0至19/1)纯化,得到目标产物19b(490mg,86%)。
MS m/z(ESI):571[M+1]
第二步
(4-((8-甲氧基-3-(哌啶-4-基)咪唑并[1,5-a]吡嗪-1-基)氨基)苯基)(吗啉代)甲酮(19c)
向19b(230mg,0.403mmol)的甲醇(10mL)溶液中加入10%钯碳(115mg)。将混合物在氢气气氛下搅拌30分钟,然后过滤。滤液浓缩至干,得到目标产物19c(190mg)。该产品未经进一步纯化,直接用于下一步反应。
MS m/z(ESI):437[M+1]
第三步
1-(4-(8-甲氧基-1-((4-(吗啉-4-羰基)苯基)氨基)咪唑并[1,5-a]吡嗪-3-基)哌啶-1-基)乙烷-1-酮(19d)
向19c(122mg,0.279mmol)的二氯甲烷(5mL)溶液加入三乙胺(85mg,0837mmol)。冷却至0℃后,逐滴加入乙酰氯(22mg,0.279mmol)。室温搅拌30分钟后,将混合物浓缩至干,残余物用硅胶柱层析(二氯甲烷/甲醇=100/0至19/1)纯化,得到目标产物19d(81mg,61%)。
MS m/z(ESI):479[M+1]
第四步
3-(1-乙酰基哌啶-4-基)-1-((4-(吗啉-4-羰基)苯基)氨基)咪唑并[1,5-a]吡嗪-8(7H)-酮(19)
向19d(81mg,0.17mmol)的乙腈(2mL)溶液中加入HCl乙醇溶液(33%,1mL)然后加热至50℃并搅拌30分钟。冷却到室温后,反应混合物浓缩至干,得到黄色固体(85mg)。取出其中的45mg,用反相制备高效液相色谱纯化,得到目标产物19(固体,31.1mg,69%)。
MS m/z(ESI):465[M+1]
1H NMR(400MHz,CD3OD)δ7.50-7.42(m,3H),7.34-7.28(m,2H),6.88(d,J=6.1Hz,1H),4.72(d,J=13.5Hz,1H),4.14(d,J=13.8Hz,1H),3.85-3.57(m,9H),3.38(dd,J=19.4,7.5Hz,1H),2.88(t,J=11.9Hz,1H),2.19(s,3H),2.17-2.06(m,2H),1.97-1.75(m,2H).
实施例20
1-((4-(吗啉-4-羰基)苯基)氨基)-3-(哌啶-4-基)咪唑并[1,5-a]吡嗪-8(7H)-酮(20)
向19c(40mg,0.092mmol)的乙腈(2mL)溶液中,加入HCl溶液(30%的乙醇溶液,1mL),加热到50℃并搅拌30分钟。冷却到室温后,浓缩至干,残余物用反相制备高效液相色谱纯化,得到目标产物20(固体,10.3mg,25%)。
MS m/z(ESI):423[M+1]
1H NMR(400MHz,CD3OD)δ7.66-7.61(m,2H),7.44-7.39(m,2H),7.28(d,J=6.1Hz,1H),6.63(d,J=6.0Hz,1H),3.72(s,8H),3.62(t,J=3.5Hz,1H),3.58(t,J=3.5Hz,1H),3.56-3.49(m,1H),3.30-3.20(m,2H),2.29-2.17(m,4H).
实施例21
3-(1-环丙基哌啶-4-基)-1-((4-(吗啉-4-羰基)苯基)氨基)咪唑并[1,5-a]吡嗪-8(7H)-酮
第一步
(4-((3-(1-环丙基哌啶-4-基)-8-甲氧基咪唑并[1,5-a]吡嗪-1-基)氨基)苯基)(吗啉代)甲酮(21a)
向19c(150mg,0.344mmol)、甲醇(2mL)和四氢呋喃(2mL)的混合物中加入(1-乙氧基环丙氧基)三甲基硅烷(120mg,0.687mmol),然后加入乙酸(103mg,1.72mmol)和氰基硼氢化钠(32mg,0.86mmol)。将混合物加热至60℃并搅拌20小时。冷却至室温后,加入饱和碳酸氢钠溶液(20mL),然后用乙酸乙酯(3×20mL)萃取。合并的有机相用饱和食盐水(20mL)洗涤,经无水硫酸钠干燥。过滤后,滤液浓缩至干,残余物用硅胶柱层析(二氯甲烷/甲醇=100/0至19/1)纯化,得到目标产物21a(46mg,28%)。
MS m/z(ESI):477[M+1]
第二步
3-(1-环丙基哌啶-4-基)-1-((4-(吗啉-4-羰基)苯基)氨基)咪唑并[1,5-a]吡嗪-8(7H)-酮(21)
向21a(46mg,0.0965mmol)的乙腈(2mL)溶液加入氯化氢溶液(30%的乙醇溶液,1mL),然后加热至50℃并搅拌30分钟。冷却到室温后浓缩至干,残余物用反相制备高效液相色谱纯化,得到目标产物21(固体,16.9mg,38%)。
MS m/z(ESI):463[M+1]
1H NMR(400MHz,CD3OD)δ7.77(d,J=8.6Hz,2H),7.38(d,J=8.6Hz,2H),7.15(d,J=6.0Hz,1H),6.46(d,J=6.0Hz,1H),3.71(s,4H),3.68(s,4H),3.28(d,J=11.9Hz,2H),3.15-3.06(m,1H),2.57(t,J=10.5Hz,2H),2.13-1.94(m,4H),1.90(s,1H),0.66-0.49(m,4H).
实施例24
3-(2,6-二氟苯基)-1-((1-(2-吗啉代-2-氧代乙基)-1H-吡唑-4-基)氨基)-6,7-二氢咪唑并[1,5-a]吡嗪-8(5H)-酮
第一步
2-(4-硝基-1H-吡唑-1-基)乙酸叔丁酯(24b)
室温下向4-硝基-1H-吡唑24a(2g,17.7mmol)、碳酸钾(4.8g,35mmol)和DMF(10mmol)的混合物中加入2-溴乙酸叔丁酯(4g,17.7mmol)。所得混合物在室温下搅拌12小时后,用水(200mL)稀释,然后用乙酸乙酯(2×150mL)萃取。合并的有机相用饱和食盐水(2×150mL)洗涤,然后用无水硫酸钠干燥。过滤后,将滤液在减压条件下浓缩至干。残余物用硅胶柱层析(二氯甲烷/甲醇=100/0至99/1)纯化,得到目标产物24b(5g,110%)。
MS m/z(ESI):228[M+1]
第二步
2-(4-氨基-1H-吡唑-1-基)乙酸叔丁酯(24c)
向24b(5g,20mmol)的乙醇(20mL)溶液中加入10%钯炭(700mg),在氢气气氛下搅拌12小时,然后过滤。滤液在减压条件下浓缩至干,得到目标产物24c(3.45g,77%)。
MS m/z(ESI):198[M+1]
第三步
2-(4-((3-(2,6-二氟苯基)-8-甲氧基咪唑并[1,5-a]吡嗪-1-基)氨基)-1H-吡唑-1-基)乙酸叔丁酯(24d)
将1f(600mg,1.77mmol)、1,4-二氧六环(15mL)、24c(720mg,3.53mmol)、Brettphos(192mg,0.353mmol)、Pd2(dba)3(180mg,0.177mmol)和碳酸铯(1.7g,5.32mmol)的混合物在氮气气氛下用微波反应器加热至90℃并搅拌1小时。冷却到室温后,减压除去溶剂,残余物用硅胶柱层析(石油醚/乙酸乙酯=100/0至1/4)纯化,得到目标产物24d(450mg,47%)。
MS m/z(ESI):457[M+1]
第四步
2-(4-((3-(2,6-二氟苯基)-8-氧代-7,8-二氢咪唑并[1,5-a]吡嗪-1-基)氨基)-1H-吡唑-1-基)乙酸(24e)
将24d(450mg,0.98mmol)的三氟乙酸(10mL)溶液加热至80℃并搅拌12小时。冷却到室温后,将反应液在减压条件下浓缩至干,得到目标产物24e(815mg)。该产品未经进一步纯化,直接用于下一步反应。
MS m/z(ESI):387[M+1]
第五步
2-(4-((3-(2,6-二氟苯基)-8-氧代-5,6,7,8-四氢咪唑并[1,5-a]吡嗪-1-基)氨基)-1H-吡唑-1-基)乙酸(24f)
向24e(800mg,2.07mmol)的乙醇(30mL)溶液中加入10%钯碳(300mg),然后在氢气气氛下搅拌12小时。过滤后,滤液在减压条件下浓缩至干,得到目标产物24f(280mg,35%)。
MS m/z(ESI):389[M+1]
第六步
3-(2,6-二氟苯基)-1-((1-(2-吗啉代-2-氧代乙基)-1H-吡唑-4-基)氨基)-6,7-二氢咪唑并[1,5-a]吡嗪-8(5H)-酮(24)
向24f(10mg,0.0257mmol)、HATU(13mg,0.0335mmol)、吗啉(0.025mL)和DMF(0.5mL)中加入DIPEA(10mg,0.0771mmol)。室温搅拌1小时后,将反应溶液直接用反相制备高效液相色谱纯化,得到目标产物24(固体,2.12mg,18%)。
MS m/z(ESI):458[M+1]
1H NMR(400MHz,DMSO-d6)δ7.84-7.81(m,1H),7.80(s,1H),7.72-7.62(m,2H),7.55(s,1H),7.36-7.29(m,2H),5.03(s,2H),3.97-3.90(m,2H),3.60-3.52(m,2H),3.50-3.39(m,8H).
实施例25参照实施例24的实验步骤操作,但在第六步中用N-甲基哌嗪代替吗啉。
实施例25的核磁数据如下:
实施例39
4-((3-(2,6-二氟苯基)-8-氧代-7,8-二氢咪唑并[1,5-a]吡嗪-1-基)氨基)苯甲酸(39)
向39a(150mg,0.37mmol)在甲醇、四氢呋喃和水(3/3/1v/v/v,7mL)的混合溶液中加入氢氧化锂一水合物(155mg,3.7mmol),然后加热至50℃并搅拌12小时。冷却到室温后,在减压条件下浓缩除去有机溶剂。残余物用1N盐酸调节至pH=1并在室温下搅拌5小时,然后浓缩至干。残余物用反相制备高效液相色谱纯化,得到目标产物39(固体,25mg,18%)。
MS m/z(ESI):383[M+1]
1H NMR(400MHz,DMSO-d6)δ12.36(s,1H),10.61(d,J=5.5Hz,1H),8.62(s,1H),7.81(d,J=8.8Hz,2H),7.70(d,J=8.9Hz,3H),7.39(d,J=8.2Hz,2H),6.87(d,J=5.6Hz,1H),6.60(s,1H).
实施例40参照实施例39的实验步骤操作,但在操作中用40a代替39a。
实施例40的核磁数据如下:
生物学实验
JAK2的活性抑制测试
使用体外激酶检测实验评估本发明的化合物对JAK2活性的影响
实验方法概述如下:
使用均相时间分辨荧光(HTRF)激酶检测试剂盒(Cisbio,62TK0PEC),通过检测激酶反应中底物的磷酸化水平来测定JAK2的酶活性。反应缓冲液包含试剂盒自带酶反应缓冲液(1×)、5mM MgCl2、1mM DTT和0.01%Brij35;人源重组JAK2蛋白(Carna Biosciences,08-045)用反应缓冲液稀释成0.15ng/μL的激酶反应溶液;底物反应溶液包括用反应缓冲液稀释成0.25μM的生物素标记的酪氨酸激酶底物和2.5μM ATP;检测缓冲液包括用反应缓冲液稀释成0.1ng/μL的Eu3+标记的笼状抗体(Cisbio,61T66KLB)和12.5nM链霉亲和素标记的XL665(Cisbio,610SAXLB);化合物用DMSO溶解稀释至10μM,然后用DMSO进行4倍的系列稀释至最低浓度为0.061nM,每个浓度点再使用反应缓冲液稀释40倍。
向384孔检测板(Corning,3674)中添加4μL系列浓度的化合物溶液和2μL激酶反应溶液,混合均匀后室温孵育15分钟;随后加入4μL底物反应溶液,将反应混合物在室温孵育30分钟。随后加入10μL检测缓冲液,混合均匀并在室温条件下静置30分钟后,用Envision读板机(Perkin Elmer)在620nm和665nm波长下检测反应进程。信号值(吸光度665nm/吸光度620nm)与底物的磷酸化程度呈正相关性,从而检测出JAK2的激酶活性。该实验中,未加JAK2激酶蛋白组作为100%抑制组,加JAK2激酶蛋白但是未加化合物组作为0%抑制组,使用XLfit软件绘制化合物抑制曲线并计算其抑制的IC50,实验结果见表1。
TYK2的活性抑制测试
使用体外激酶检测实验评估本发明的化合物对TYK2活性的影响
实验方法概述如下:
使用均相时间分辨荧光(HTRF)激酶检测试剂盒(Cisbio,62TK0PEC),通过检测激酶反应中底物的磷酸化水平来测定TYK2的酶活性。反应缓冲液包含试剂盒自带酶反应缓冲液(1×)、5mM MgCl2、1mM DTT和0.01%Brij35;人源重组TYK2蛋白(Carna Biosciences,08-147)用反应缓冲液稀释成0.25ng/μL的激酶反应溶液;底物反应溶液包括用反应缓冲液稀释成0.5μM的生物素标记的酪氨酸激酶底物和11.25μM ATP;检测缓冲液包括用反应缓冲液稀释成0.1ng/μL的Eu3+标记的笼状抗体(Cisbio,61T66KLB)和25nM链霉亲和素标记的XL665(Cisbio,610SAXLB);将化合物用DMSO溶解稀释至10μM,然后用DMSO进行4倍的系列稀释至最低浓度为0.061nM,每个浓度点再使用反应缓冲液稀释40倍。
向384孔检测板(Corning,3674)中添加4μL系列浓度的化合物溶液和2μL激酶反应溶液,混合均匀后室温孵育15分钟。随后加入4μL底物反应溶液,将反应混合物在室温孵育40分钟。随后加入10μL检测缓冲液,混合均匀并在室温条件下静置30分钟后,用Envision读板机(Perkin Elmer)在620nm和665nm波长下检测反应进程。信号值(吸光度665nm/吸光度620nm)与底物的磷酸化程度呈正相关性,从而检测出TYK2的激酶活性。该实验中,未加TYK2激酶蛋白组作为100%抑制组,加TYK2激酶蛋白但是未加化合物组作为0%抑制组,使用XLfit软件绘制化合物抑制曲线并计算其抑制的IC50,实验结果见表1。
表1
本发明的实施例化合物对JAK2和TYK2的活性均具有抑制效应,优选其IC50小于100nM,更优选其IC50小于10nM。
NK92细胞中IL-12诱导的IFN-γ分泌量抑制的测定
通过酶联免疫吸附(ELISA)方法评估本发明的化合物对IL-12诱导的NK92细胞中IFN-γ分泌量的影响。
实验原理概述如下:IL-12R主要由活化的T细胞、NK细胞(NK92是一株NK细胞株)、DC细胞和B细胞表达,与IL-12结合,激活NK细胞和活化的T淋巴细胞中的JAK2/TYK2信号转导通路,从而诱导IFN-γ的产生。
实验方法概述如下:
将化合物用DMSO溶解稀释至2.5mM,然后用DMSO进行4倍的系列稀释至最低浓度为0.31μM,每个浓度点再用不含FBS的MEMα培养基(Thermofisher,12561-056)稀释50倍。
NK92细胞(南京科佰,CBP60980)在含有12.5%FBS(Ausbian,VS500T)、12.5%马血清(Thermofisher,16050-122)、0.02mM叶酸(Sigma,F8758)、0.2mM肌醇(Sigma,17850)、0.55mMβ-巯基乙醇(Thermofish,21985-023)、200U/mL IL-2(R&D Systems,202-1L)和100U/mL青链霉素混合液(Thermofisher,15140122)的MEMα完全培养基中培养,当细胞在培养容器中覆盖率达80-90%时,将细胞吹散后种植于96孔板(Thermofish,167425),每孔100,000细胞(80μL不含IL-2的MEMα完全培养基),然后将96孔板置于37℃、5%CO2的培养箱中培养过夜。
过夜后每孔加入10μL稀释后的化合物,以及10μL 50ng/mL的IL-12(R&D Systems,219-1L),轻轻混匀,然后将96孔板置于37℃、5%CO2的培养箱中继续培养。24小时后取出于室温800rpm离心10分钟,将50μL上清液转移至已包被了抗IFN-γ的抗体的96孔板(Sigma,CLS3695),按照Human IFN-γDuoSet ELISA检测试剂盒(R&D Systems,DY285B)的方法检测IFN-γ的分泌量。其中,无刺激对照组不加IL-12和测试的化合物,用MEMα培养基替代(100%抑制);刺激对照组加IL-12和0.2%DMSO(0%抑制),使用XLfit软件绘制化合物抑制曲线并计算其抑制的IC50,实验结果见表2。
表2
化合物编号 | IC<sub>50</sub>(NK92_IL12/IFN-γ)(nM) |
1 | 57 |
2 | 95 |
3 | 66 |
4 | 175 |
5 | 1308 |
6 | 198 |
10 | 122 |
11 | 242 |
12 | 110 |
13 | 1061 |
14 | 113 |
15 | 193 |
16 | 1443 |
17 | 520 |
18 | 1406 |
26 | 149 |
27 | 60 |
28 | 38 |
29 | 75 |
30 | 318 |
31 | 56 |
32 | 425 |
33 | 66 |
34 | 65 |
35 | 191 |
36 | 3477 |
37 | 268 |
38 | 2854 |
39 | 4095 |
40 | 406 |
小鼠药代动力学实验
将待测化合物在20%HP-β-CD溶媒中配制成5mg/mL的给药样品(混悬液或溶液)。
在25mg/kg剂量下以灌胃方式(PO)分别给予3只进食雌性C57小鼠5mL/kg的给药样品,在给药后4小时采集血样,然后CO2处死,取靠近直肠端的结肠,长度约4~6cm,切开,用冷的盐水冲洗,然后用吸水纸吸干,称重。
血浆和肠匀浆样品中待测化合物的浓度用API-4500质谱仪进行LC-MS/MS定量分析,血浆定量限(LOQ)为1ng/mL。用WinNonlin计算药代动力学(PK)参数,结果汇总在表3。
表3
化合物 | 血浆的暴露量(ng/mL) | 结肠的暴露量(ng/g) |
1 | 249 | 5210 |
28 | 15 | 2853 |
29 | 75 | 3925 |
30 | BLOQ | 12200 |
34 | 50 | 2705 |
36 | 18 | 5093 |
Claims (10)
1.一种通式(I)所示的化合物,或其可药用的盐、稳定同位素衍生物、异构体及其前药:
其中:
键a为单键或双键;
R1和R2各自独立地选自H、D、CN、C1-6烷基或C3-6环烷基,其中所述烷基的一个或多个氢任选被D或氟所取代;
A为C3-10环烷基、4-10元杂环基、C6-10芳基或5-10元杂芳基,其中所述环烷基、杂环基、芳基和杂芳基任选被一个或多个选自D、卤素、氰基、-ORa、-NRaRb、-C(O)Ra、-C(O)NRaRb、-S(O)2Ra、-P(O)(CH3)2、C1-6烷基、C3-6环烷基、4-8元杂环基或5-6元杂芳基的取代基所取代;
B为苯基或5-6元杂芳基,其中所述苯基和杂芳基任选被一个或多个选自D、卤素、氰基、-ORa、-NRaRb、-COORa、-C(O)Ra、-NRaC(O)Rb、-C(O)NRaRb、-S(O)2Ra、-S(O)2NRaRb、-S(O)(NRa)Rb、-P(O)(CH3)2、C1-6烷基、C3-6环烷基、4-8元杂环基或5-6元杂芳基的取代基所取代,所述烷基、环烷基、杂环基和杂芳基任选进一步被一个或多个选自D、卤素、CN、-OH、-NH2、C1-6烷基、-OC1-6烷基、-COORa、-C(O)Ra或-C(O)NRaRb的取代基所取代;
Ra和Rb各自独立地选自H、C1-6烷基、C3-6环烷基或4-8元杂环基,其中所述烷基、环烷基和杂环基任选被一个或多个选自D、卤素、C1-6烷基的取代基所取代。
2.根据权利要求1所述的化合物或其可药用的盐、稳定同位素衍生物及其异构体,R1和R2都为H。
3.根据权利要求1所述的化合物或其可药用的盐、稳定同位素衍生物及其异构体,其为通式(II)所示的化合物:
其中:
A为C3-8环烷基、4-8元杂环基、苯基或5-6元杂芳基,其中所述环烷基、杂环基、苯基和杂芳基任选被一个或多个选自卤素、-C(O)Ra、C1-6烷基和C3-6环烷基的取代基所取代;
B为苯基或5-6元杂芳基,其中所述苯基和杂芳基任选被一个或多个选自卤素、-COORa、-C(O)Ra、-C(O)NRaRb、-S(O)2Ra、C1-6烷基、C3-6环烷基、含N、S和/或O杂原子的4-8元杂环基的取代基所取代,所述烷基、环烷基和杂环基任选进一步被一个或多个选自C1-6烷基、-C(O)Ra和-C(O)NRaRb的取代基所取代;
Ra和Rb各自独立地选自H、C1-6烷基、C3-6环烷基或含N、S和/或O杂原子的4-6元杂环基,其中所述烷基、环烷基和杂环基的一个或多个氢任选被C1-6烷基所取代。
4.根据权利要求1或3所述的化合物或其可药用的盐、稳定同位素衍生物及其异构体,A为苯基,所述苯基的一个或多个氢任选被卤素所取代。
5.根据权利要求1所述的化合物或其可药用的盐、稳定同位素衍生物及其异构体,其为通式(II)所示的化合物:
其中:
A为A为苯基,所述苯基的一个或多个氢任选被卤素所取代;
B为苯基或5-6元杂芳基,其中所述苯基和杂芳基任选被一个或多个选自卤素、-COORa、-C(O)Ra、-C(O)NRaRb、-S(O)2Ra、C1-6烷基、C3-6环烷基、含N、S和/或O杂原子的4-8元杂环基的取代基所取代,所述烷基、环烷基和杂环基任选进一步被一个或多个选自C1-6烷基、-C(O)Ra和-C(O)NRaRb的取代基所取代;
Ra和Rb各自独立地选自H、C1-6烷基、C3-6环烷基或含N、S和/或O杂原子的4-6元杂环基,其中所述烷基、环烷基和杂环基的一个或多个氢任选被C1-6烷基所取代。
8.一种药物组合物,其包含权利要求1-7中任一项所述的化合物或其可药用的盐、稳定同位素衍生物、异构体及其前药和一种或多种可药用的载体或辅料。
9.一种预防或治疗由JAK介导的相关疾病的方法,该方法包括向有需要的患者施用治疗有效量的权利要求1-8中任一项所述的化合物或其可药用的盐、稳定同位素衍生物、异构体及其前药,或包含所述化合物的药物组合物,其中由JAK介导的疾病为炎性疾病、自身免疫性疾病或癌症等。
10.根据权利要求9的方法,其中所述疾病为炎症性肠病、皮炎、湿疹、类风湿性关节炎、系统性红斑狼疮、银屑病、斑秃等。
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