CN110446713A - 一种吡唑嘧啶衍生物及其用途和药物组合物 - Google Patents
一种吡唑嘧啶衍生物及其用途和药物组合物 Download PDFInfo
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- CN110446713A CN110446713A CN201980001001.9A CN201980001001A CN110446713A CN 110446713 A CN110446713 A CN 110446713A CN 201980001001 A CN201980001001 A CN 201980001001A CN 110446713 A CN110446713 A CN 110446713A
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- alkyl
- hydrate
- metabolite
- metabolized
- pyrazolopyrimidine derivative
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Abstract
本发明公开了一种具有通式(I)所示结构的吡唑嘧啶衍生物,其可药用盐、水合物,或以任何形式代谢形成的代谢产物,及其在制备预防和/或治疗与JAK激酶功能有关的适应症的药物中的用途,以及用其制备的预防和/或治疗与JAK激酶功能有关的适应症的药物组合物。本发明是选择性JAK激酶抑制剂,通过作用于JAK激酶,在免疫及炎症反应等方面具有一定的药物治疗作用。
Description
技术领域
本发明涉及一种吡唑嘧啶衍生物及其在制备预防和/或治疗与JAK激酶功能有关的适应症的药物中的用途和药物组合物。
背景技术
细胞因子影响细胞分化、增殖和激活,并且可调节促炎症反应和抗炎症反应。多种细胞因子的信号传导包括蛋白酪氨酸激酶的Janus激酶家族(JAK)和信号转导和转录激活因子(STAT)。JAK激酶为细胞内非受体酪氨酸激酶,能够介导细胞因子,在牵涉免疫应答的细胞增殖和功能中具有一定的调节作用。JAK激酶家族共有四个成员,分别是JAK激酶1、JAK激酶2、JAK激酶3和酪氨酸激酶2。一般情况下,细胞因子通过与细胞因子受体结合而活化JAK激酶,JAK活化后激活STATs,活化的STATs进入细胞核中调控基因表达。JAKs-STATs家族作为细胞因子受体介导的主要信号转导途径,可能与其他信号转导通路相互影响,参与了多种免疫和造血细胞的发育、分化、成熟、凋亡和功能表达过程,在调节机体的免疫、炎症反应过程中发挥着极为重要的作用。
JAKs-STATs通路的异常活化与多种疾病密切相关。癌症中JAK/STAT的激活可通过细胞因子刺激等的减少而发生。因此JAK激酶抑制剂可以用于强直性脊柱炎等免疫性疾病、克罗恩病等炎症性疾病、真性红细胞增多症、特应性皮炎、银屑病关节炎、原发性血小板增多症、骨髓纤维化和癌症等疾病的治疗。
发明内容
本发明所要解决的技术问题是提供一种新型的吡唑嘧啶衍生物,其是理想的选择性JAK激酶抑制剂。
本发明同时还提供吡唑嘧啶衍生物,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JAK激酶功能有关的适应症的药物中的用途。
本发明同时还提供了一种预防和/或治疗与JAK激酶功能有关的适应症的药物组合物。
为解决以上技术问题,本发明采取的一种如下技术方案:
一种具有通式(I)所示结构的吡唑嘧啶衍生物,其可药用盐、水合物,或以任何形式代谢形成的代谢产物,
其中:
R1为R2为
其中,R3为SO2R6或C(O)R6;
X为C(=O)、C(=O)N(R7)、C(=O)C(R7)2、S(=O)2、C(=O)O、C(=O)OC(R7)2或C(=O)N(R7)C(R7)2,R7为H或C1-4烷基;
Y为未被取代或被选自氟、氯、溴、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基和C1-6卤代烷基中的一种或多种所取代的C1-6烷基、C3-14环烷基、C2-13杂环烷基、C6-14芳基或C3-14杂芳基;
R6为未被取代或被卤代的烃基、NHCH3、N(CH3)2、苯基、吡啶基或嘧啶基;
R4、R5独立地选自H、氟、氯或溴;
所述具有通式(I)所示结构的吡唑嘧啶衍生物,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。
根据本发明的一些优选方面,R2为
根据本发明的一些优选方面,X为S(=O)2或C(=O)。
根据本发明的一些优选方面,Y为甲基、乙基、丙基、异丙基或丁基;或者,Y为被选自氟、氯、溴、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基和C1-6卤代烷基中的一种或多种所取代的6元杂芳基。其中,C1-6烷基可以为甲基、乙基、正丙基、异丙基、环丙基、正丁基、异丁基、叔丁基等等;C2-6烯基可以为乙烯基、丙烯基、丁烯基、戊烯基、己烯基等等;C2-6炔基可以为乙炔基、丙炔基、1-丁炔基、1-戊炔基、2-戊炔基、1-己炔基、2-己炔基等等;C1-6卤代烷基可以为选自氟、氯和溴中的一个或多个所取代的甲基、乙基、正丙基、异丙基、环丙基、正丁基、异丁基、叔丁基等等;6元杂芳基可以为选自氮原子、硫原子和氧原子中的一个或多个所取代的苯基。
根据本发明的一些优选方面,所述6元杂芳基含有一个氮原子,所述6元杂芳基上与所述X相连的碳原子与所述6元杂芳基上的所述氮原子之间处于间位或对位。其中6元杂芳基可以为选自氮原子、硫原子和氧原子中的一个或多个所取代的苯基。
根据本发明的一些优选方面,R6为未被取代或卤代的直链烃基、环烷基,或具有至少一个双键的直链烃基或支链烃基,R6的碳原子数为1-20。其中,直链烃基可以包括直链的烷基、直链的烯基和直链的炔基,直链的烷基可以为甲基、乙基、正丙基、正丁基、正戊基、正己基等;直链的烯基可以为乙烯基、正丙烯基、正丁烯基、正戊烯基、正己烯基等;直链的炔基可以为乙炔基、正丙炔基、正丁炔基、正戊炔基、正己炔基等;支链的烃基可以为异丙基、异丁基、异戊基、新戊基等等;环烷基可以为环丙基、环丁基、环己基等等。
根据本发明的一些进一步优选方面,R6为未被取代或卤代的C1-6烷基。其中,C1-6烷基可以为甲基、乙基、正丙基、异丙基、环丙基、正丁基、异丁基、叔丁基等。
根据本发明的一些优选且具体的方面,R2为其中,R8不存在,或者为R9为R10为甲基、乙基、丙基或异丙基,R11为被选自氟、氯、溴和卤代的C1-6烷基中的至少一个取代基所取代的吡啶基,且吡啶基上与羰基的碳原子相连接的原子与吡啶基上的氮原子处于对位。其中,C1-6烷基可以为甲基、乙基、正丙基、异丙基、环丙基、正丁基、异丁基、叔丁基等。
根据本发明的一个具体方面,当R8不存在时,R9为根据本发明的另一具体方面,当R8为时,R9为
根据本发明的一些优选且具体的方面,所述吡唑嘧啶衍生物,其可药用盐、水合物,或以任何形式代谢形成的代谢产物为如下结构式表示的化合物中的一种:
根据本发明,所述的吡唑嘧啶衍生物的化合物,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)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)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)的至少一种化合物或其盐。
本发明吡唑嘧啶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。
本发明提供的又一技术方案:上述所述的具有通式(I)的吡唑嘧啶衍生物,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JAK激酶功能有关的适应症的药物中的用途。
根据本发明的一些具体方面,所述与JAK激酶功能有关的适应症包括强直性脊柱炎等免疫性疾病、克罗恩病等炎症性疾病、真性红细胞增多症、特应性皮炎、银屑病关节炎、原发性血小板增多症、骨髓纤维化和癌症等疾病。
本发明提供的又一技术方案:一种预防和/或治疗与JAK激酶功能有关的适应症的药物组合物,所述药物组合物含有上述所述的具有通式(I)的吡唑嘧啶衍生物,其可药用盐、水合物,或以任何形式代谢形成的代谢产物。
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吡唑嘧啶衍生物,其是理想的选择性JAK激酶抑制剂,通过作用于JAK激酶,在免疫及炎症反应等方面具有一定的药物治疗作用。
术语定义
除非另外定义,本文使用的所有技术和科学术语具有与本发明所属领域的普通技术人员通常理解的相同的含义。
术语“异构体”是指由分子中原子在空间上排列方式不同所产生的异构体。包括顺反异构体、对映异构体和构象异构体。所有立体异构体均属于本发明的范围。本发明的化合物可以为单独立体异构体或其它异构体的混合例如外消旋体,或者所有其它立体异构体的混合。
术语“盐”是指本发明所述的化合物与酸形成的药学上可接受的盐,所述的酸可以是有机酸或无机酸,具体可选自:磷酸、硫酸、盐酸、氢溴酸、柠檬酸、马来酸、丙二酸、扁桃酸、琥珀酸、富马酸、醋酸、乳酸、硝酸、磺酸、对甲苯磺酸、苹果酸、甲烷磺酸或其类似物。
术语“溶剂化物”是指通过与溶剂分子配位形成固态或液态的配合物的本发明化合物的形式。水合物是溶剂化物的特殊形式,其中与水发生配位。在本发明范围内,溶剂化物优选是水合物。
术语“结晶”是指本发明所述的化合物形成的各种固体形态,包括晶型、无定形。
术语“烃基”是指直链、支链或环状的饱和或不饱和主要由碳和氢构成的取代基。优选1-20个碳原子,更优选1-12个碳原子。术语“烷基”是指直链、支链的饱和烃基。烷基具体包括甲基、乙基、正丙基、异丙基、环丙基、正丁基、异丁基、叔丁基、环丁基、正戊基、异戊基、新戊基、环己基、正己基、异己基、2,2,-甲基丁基和2,3-二甲基丁基、16-烷基、18-烷基。术语“C1-20烷基”是指含有1-20个碳原子的直链、支链饱和烃基。取代烷基指被取代基取代的烷基。当烷基被取代时,取代基可以在任何可使用的连接点上取代,取代基可以是单取代或多取代。取代基独立的选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、氘、卤素、硫醇、羟基、硝基、羧基、酯基、氰基,环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、氧代,在命名时取代基通常置于烷基之前。
术语“环烷基”指饱和和/或部分不饱和单环或多环环烃基。单环可包括3-10个碳原子。单环环烷烃基的非限制实例包括环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基等。多环环烷基包括螺环、稠环和桥环的环烷基。环烷基包括无取代基和含有取代基。取代基选自一个或多个取代基团,包括但不仅限于以下基团,独立的选自烷基、环烷基、烷氧基、卤素、羧基、酯基、氨基、酰胺基、羟基、氰基、硝基、芳基、杂芳基。
术语“卤素”是指氟、氯、溴、碘,优选为氟、氯、溴。
术语“卤代烷基”是指至少被一个卤素原子取代的烷基。
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
本实施例提供三种具体的吡唑嘧啶衍生物,即式Ig化合物,式Ii化合物和式Ip化合物。
式Ig化合物,式Ii化合物和式Ip化合物的结构式分别如下所示。
以上三个化合物可通过如下合成路线获得:
化合物的制备方法具体包括如下步骤:
1.化合物A-1的合成:
在-20℃下,把DIPEA(63g,0.488mol,中文名称:N,N-二异丙基乙胺)的THF(50mL)溶液缓慢加入SM(50g,0.324mol)和2-(三甲基硅烷基)乙氧甲基氯(62g,0.39mol,SEMCl)的DMF(50mL)和THF(200mL)的混合溶液中,在-20℃下搅拌3个小时之后,加入水猝灭,用乙酸乙酯萃取,有机相干燥,过滤,浓缩得到粗产物,以石油醚与乙酸乙酯(v/v=1/1)为洗脱剂通过快速柱纯化得到淡黄色油状物A-1(45g,0.158mol,产率:32.6%)。
2.化合物A-2的合成:
把四三苯基膦钯加入化合物A-1(45g,0.158mol)、1-(1-乙氧基乙基)-4-吡唑硼酸频哪醇(63g,0.237mol)和碳酸钾(43.6g,0.316mol)的正丁醇(200mL)和水(200mL)的混合溶液中,用氩气置换四次,反应液在100℃下搅拌过夜.冷却到室温,过滤,萃取,干燥,浓缩,以石油醚与乙酸乙酯(v/v=2/1)为洗脱剂通过快速柱纯化得到黄色的油状物A-2(31g,0.1288mol,产率:81.5%)。
3.化合物A-3的合成:
将化合物A-2(50g,0.1288mol)的四氢呋喃(800mL)溶液和1.5N盐酸水溶液(100mL)的混合溶液在室温下搅拌过夜,浓缩,然后把浓缩液加到饱和碳酸氢钠水溶液中,搅拌过夜,过滤,滤饼干燥得到白色固体A-3(31g,0.098mol,产率:76%)。
4.化合物A-4的合成:
将化合物A-3(31g,0.098mol),3-(氰基亚甲基)氮杂环丁烷-1-甲酸叔丁酯(29g,0.147mol)和DBU(30g,0.196mol)的乙腈(500mL)混合液在70℃下搅拌四个小时,然后减压浓缩,以石油醚与乙酸乙酯(v/v=2/1)为洗脱剂通过快速柱纯化得到白色固体A-4(40g,0.0784mol,产率:80%)。
5.化合物A合成:
将化合物A-4(31g,0.0784mol)的乙酸乙酯(800mL,4N HCl)溶液在室温下搅拌过夜,浓缩,然后把浓缩液加到饱和碳酸氢钠水溶液中,搅拌过夜,过滤,滤饼干燥得到白色固体A,没有纯化,直接用于下一步。
6.化合物B-1的合成:
将化合物A(来自上一步反应),N-叔丁氧羰基-4-哌啶酮(23.4g,1.176mol)和三乙酰基硼氢化钠(42.3g,0.196mol)的1,2-二氯乙烷(500mL)溶液在室温下搅拌过夜,然后减压浓缩,以石油醚与乙酸乙酯(v/v=2/1)为洗脱剂通过快速柱纯化得到白色固体B-1(30g,0.05059mol,产率:83%)。
7.化合物B的合成:
将化合物B-1(30g,0.05059mol))的甲醇(600mL,4N HCl)溶液在室温下搅拌过夜,浓缩,然后把浓缩液加到饱和碳酸氢钠水溶液中,搅拌过夜,过滤,滤饼干燥得到白色固体B(22g,0.04462mmol,产率:88%)。
8.化合物Ii-1的合成:
将化合物B(16g,0.03245mol),DIPEA(8.37g,0.0649mmol),HATU(18.5g,0.048675mmol,中文名称为:2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸盐)和2-三氟甲基-3-氟异烟酸(8.8g,0.042185mmol)的二氯甲烷(200mL)溶液在室温下搅拌过夜,然后减压浓缩,通过硅胶柱(乙酸乙酯作为展开剂)纯化得到白色固体Ii-1(8g,0.01169mol,产率:36%)。9.化合物Ii的合成:
将化合物Ii-1(8g,0.01169mol)的二氯甲烷(50mL)和三氟乙酸(50mL)的混合溶液在室温下搅拌一个小时,然后减压浓缩后,加入甲醇(50mL)和氨水(10mL),室温搅拌两个小时,移去溶剂,把浓缩液加入水中,用二氯甲烷萃取,干燥,浓缩,通过硅胶柱纯化得到白色固体Ii(3.67g,产率:56.6%)。
10.化合物Ig-1的合成:
在0℃下,向化合物B(14g,0.0284mol)和Et3N(5.7g,0.0568mmol)的二氯甲烷(200mL)溶液缓慢滴加乙基磺酰氯,在室温下搅拌过夜,然后减压浓缩,把浓缩液加入水中,用二氯甲烷萃取,干燥,浓缩后通过硅胶柱(乙酸乙酯作为展开剂)纯化得到白色固体Ig-1(15g,0.02564mol,产率:90.3%)。
11.化合物Ig的合成:
将化合物Ig-1(15g,0.02564mol)的二氯甲烷(100mL)和三氟乙酸(100mL)的混合溶液在室温下搅拌一个小时,然后减压浓缩后,加入甲醇(100mL)和氨水(20mL),室温搅拌两个小时,移去溶剂,把浓缩液加入水中,用二氯甲烷萃取,干燥,二氯甲烷/甲醇=10/1作为展开剂纯化得到白色固体Ig(10.3g,0.022637mol,产率88.3%)。
12.化合物Ip-1的合成:
在0℃下,向化合物A(16g,0.039mol)和Et3N(7.9g,0.078mmol)的二氯甲烷(200mL)溶液中缓慢滴加乙基磺酰氯(7.5g,0.0585mmol),在室温下搅拌过夜,然后减压浓缩,把浓缩液加入水中,用二氯甲烷萃取,干燥,浓缩后通过硅胶柱(乙酸乙酯作为展开剂)纯化得到白色固体Ip-1(17g,0.03386mol,产率:86.8%)。
13.化合物Ip的合成:
将化合物Ip-1(17g,0.03386mol)的二氯甲烷(100mL)和三氟乙酸(100mL)的混合溶液在室温下搅拌一个小时,然后减压浓缩后,加入甲醇(100mL)和氨水(20mL),室温搅拌两个小时,移去溶剂,把浓缩液加入水中,用二氯甲烷萃取,干燥,浓缩后通过硅胶柱(二氯甲烷/甲醇=10/1作为展开剂)纯化得到白色固体Ip(9.2g,0.02473mol,产率:73%)。
对得到的目标产品Ii进行了氢核磁共振1H-NMR和质谱测试,结果如下:
1H-NMR(500MHz)(DMSO-d6):δppm 14.09(s,1H),8.99(s,1H),8.87-8.85(d,2H),8.68-8.66(d,1H),8.55(s,1H),7.91(s,1H),4.10-4.07(d,1H),3.78-3.86(d,2H),3.61-3.57(t,4H),3.46-3.42(d,1H),3.30-3.27(d,1H),3.08-3.04(t,1H),2.51(s,1H),1.77-1.64(d,2H),1.31-1.23(d,2H);LCMS[M+H]+=555.2.
对得到的目标产品Ig进行了氢核磁共振1H-NMR和质谱测试,结果如下:
1H NMR(400MHz,DMSO-d6)δppm 9.00(s,1H),8.88(d,J=9.2Hz,2H),8.57(s,1H),3.76(d,J=8.0Hz,2H),3.60-3.57(m,4H),3.48-3.44(m,2H),3.06-3.00(m,2H),2.42(m,1H),1.75-1.72(m,2H),1.30-1.26(m,2H),1.20(t,J=7.6Hz,3H);LC-MS(ESI,m/z):456[M+l]+.
对得到的目标产品Ip进行了氢核磁共振1H-NMR和质谱测试,结果如下:
1H NMR(400MHz,DMSO-d6)δppm 9.11(s,1H),8.89(d,J=9.2Hz,2H),8.62(s,1H),4.62(d,J=9.6Hz,2H),4.26(d,J=9.2Hz,2H),3.71(s,2H),3.28-3.22(q,2H),1.25(t,J=7.6Hz,3H);LC-MS(ESI,m/z):373[M+l]+.
实施例2药效等试验
一、化合物酶活性测试:
1、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CaliperMobility Shift Assay,所测定的激酶为JAK1、JAK2、JAK3和TYK2,所应用的标准参照化合物为星形孢菌素(staurosporine)。
2、试验结果
表1总结了化合物酶活性抑制实验结果。结果显示目标化合物(Ig、Ii和Ip)对JAK1和JAK2激酶具有较强的抑制作用,同时,结果显示目标化合物(Ig、Ii和Ip)对JAK3和TYK2的抑制活性较弱,具有很好的选择性。这一选择性的抑制作用对类风湿性关节炎、真性红细胞增多症、银屑病、原发性血小板增多症和骨髓纤维化等疾病的治疗具有重要的治疗意义。
表1化合物酶活性抑制实验结果
二、药物动力学实验
1、实验方法:
实验动物:小鼠,雄性和雌性,体重:23-25g;
供试品配制:将目标化合物(Ig、Ii和Ip)配制成0.4mg/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:5mL/kg(静脉注射)或10mL/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TripleQuad6500+。
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2中。
表2按照非房室模型法计算出的目标化合物药物动力学参数
试验结果表明本发明化合物具有良好的药物动力学特征。
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JAK激酶抑制剂,可期望用于治疗或预防类风湿性关节炎、真性红细胞增多症、银屑病、原发性血小板增多症和骨髓纤维化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 (11)
1.一种具有通式(I)所示结构的吡唑嘧啶衍生物,其可药用盐、水合物,或以任何形式代谢形成的代谢产物,
其中:
R1为R2为其中,R3为SO2R6或C(O)R6;
X为C(=O)、C(=O)N(R7)、C(=O)C(R7)2、S(=O)2、C(=O)O、C(=O)OC(R7)2或C(=O)N(R7)C(R7)2,R7为H或C1-4烷基;
Y为未被取代或被选自氟、氯、溴、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基和C1-6卤代烷基中的一种或多种所取代的C1-6烷基、C3-14环烷基、C2-13杂环烷基、C6-14芳基或C3-14杂芳基;
R6为未被取代或被卤代的烃基、NHCH3、N(CH3)2、苯基、吡啶基或嘧啶基;
R4、R5独立地选自H、氟、氯或溴;
所述具有通式(I)所示结构的吡唑嘧啶衍生物,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所述的吡唑嘧啶衍生物,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
3.根据权利要求1或2所述的吡唑嘧啶衍生物,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:X为S(=O)2或C(=O);和/或,
Y为甲基、乙基、丙基、异丙基或丁基;或者,Y为被选自氟、氯、溴、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基和C1-6卤代烷基中的一种或多种所取代的6元杂芳基。
4.根据权利要求3所述的吡唑嘧啶衍生物,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6元杂芳基含有一个氮原子,所述6元杂芳基上与所述X相连的碳原子与所述6元杂芳基上的所述氮原子之间处于间位或对位。
5.根据权利要求1所述的吡唑嘧啶衍生物,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:R6为未被取代或卤代的直链烃基、环烷基,或具有至少一个双键的直链烃基或支链烃基,R6的碳原子数为1-20。
6.根据权利要求5所述的吡唑嘧啶衍生物,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:R6为未被取代或卤代的C1-6烷基。
7.根据权利要求1所述的吡唑嘧啶衍生物,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为其中,R8不存在,或者为R9为R10为甲基、乙基、丙基或异丙基,R11为被选自氟、氯、溴和卤代的C1-6烷基中的至少一个取代基所取代的吡啶基,且吡啶基上与羰基的碳原子相连接的原子与吡啶基上的氮原子处于对位。
8.根据权利要求1所述的吡唑嘧啶衍生物,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:所述吡唑嘧啶衍生物,其可药用盐、水合物,或以任何形式代谢形成的代谢产物为如下结构式表示的化合物中的一种:
9.如权利要求1至8中任一项权利要求所述的具有通式(I)的吡唑嘧啶衍生物,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JAK激酶功能有关的适应症的药物中的用途。
10.根据权利要求9所述的用途,其特征在于:所述与JAK激酶功能相关的适应症包括强直性脊柱炎免疫性疾病、克罗恩病炎症性疾病、真性红细胞增多症、特应性皮炎、银屑病关节炎、原发性血小板增多症、骨髓纤维化和癌症。
11.一种预防和/或治疗与JAK激酶功能有关的适应症的药物组合物,其特征在于,所述药物组合物含有如权利要求1-8中任一项权利要求所述的具有通式(I)的吡唑嘧啶衍生物,其可药用盐、水合物,或以任何形式代谢形成的代谢产物。
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