CN114573586B - 一种抑制布鲁顿酪氨酸激酶活性的多环化合物、药物组合物及其应用 - Google Patents
一种抑制布鲁顿酪氨酸激酶活性的多环化合物、药物组合物及其应用 Download PDFInfo
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D231/38—Nitrogen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
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- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
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- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
本发明公开了一系列克服BTK C481S突变耐药的新型小分子抑制剂,具体而言公开式I化合物及其立体异构体或其药学上可接受的盐、其制备方法以及该化合物的药物组合物,还公开了该化合物以及包含该化合物的的药物组合物在治疗BTK功能异常相关疾病如B细胞增殖性疾病和自身免疫性疾病中的应用。本发明发明人通过实验证实,本发明化合物可同时抑制野生型和481位半胱氨酸突变的BTK激酶。本发明发明人通过实验证实,本发明化合物对MINO、OCI‑LY10等肿瘤细胞株具有抗增殖抑制作用。
Description
技术领域
本发明涉及一类可抑制野生型BTK和突变型BTK的新型多环化合物、药物组合物,以及在制备单独或与其他药物联合应用治疗从布鲁顿酪氨酸激酶活性的抑制中获益的疾病、障碍或病症药物中的应用,如B细胞增殖性疾病和自身免疫性疾病。
背景技术
布鲁顿酪氨酸激酶(Bruton's tyrosine kinase,Btk),作为一种非受体酪氨酸激酶Tec家族的成员,是在除了T淋巴细胞和自然杀伤细胞之外的所有造血细胞类型中表达的关键信号酶。Btk在连接细胞表面B细胞受体(B-cell receptor,BCR)刺激至下游细胞内应答的B细胞信号传导途径中扮演至关重要的角色。Btk是B细胞发育、激活、信号传导和存活的关键调节物。另外,Bkt在众多其他造血细胞信号传导途径中起作用,例如在巨噬细胞中的Toll样受体(Toll like receptor,TLR)和细胞因子受体介导的TNF-α产生、在肥大细胞中的免疫球蛋白E受体(FcεR1)信号传导、在B-谱系淋巴样细胞中抑制Fas/APO-1细胞凋亡的信号传导以及胶原刺激的血小板聚集。参见例如C.A.Jeffries等,J.Bio.Chem.(2003)278:26258-26264、N.J.Horwood等,J.Exp.Med.(2003)197:1603-1611。近年来研究显示,Btk信号通路是目前非霍奇金淋巴瘤(NHL),特别是慢性淋巴细胞白血病(CLL)、B细胞淋巴瘤及自身免疫疾病临床治疗研究中的新热点。小分子Btk抑制剂通过作用于BCR信号通路,与Btk结合而抑制Btk自身磷酸化,阻止Btk的激活,从而阻断细胞传导并诱导细胞凋亡。
Btk抑制剂伊布替尼的上市,被FDA定为“突破性”新药,其研究开发前景广阔。以伊布替尼为代表的第一代共价BTK抑制剂在使用中,患者已经出现耐药性突变,如481位半胱氨酸突变(C481S)。因此迫切需要开发可克服耐药性突变的新型BTK抑制剂。
此外,由于BTK在包括B细胞在内多种免疫细胞的功能调控中发挥着重要的作用。通过抑制BTK激酶的活性可以有效抑制B细胞的活化,降低自身抗体的产生。因此除B细胞恶性肿瘤外,BTK抑制剂也被应用于自身免疫***疾病的治疗。目前多个BTK抑制剂用于天胞疮、免疫性血小板减少性紫癜(ITP)、慢性移植物抗宿主病(cGvHD)、类风湿性关节炎、***性红斑狼疮的二期、三期临床研究阶段。因此开发低毒副作用的新型BTK抑制剂可用于自身免疫***疾病的治疗。
发明内容
本发明的目的是提供新颖的、未见文献报道的具有高效野生型和突变型BTK抑制活性、特异性高(激酶选择性佳)以及PK性质优良的BTK抑制化合物及其光学异构体或其药学上可接受的盐。
本发明还提供了一种包括上述化合物及其立体异构体或立体异构体混合物或其药学上可接受的盐或溶剂合物的药物组合物。
本发明同时提供了一种上述化合物及其立体异构体或立体异构体混合物或其药学上可接受的盐或溶剂合物用于制备治疗从布鲁顿老安苏安激酶活性的抑制中获益的疾病、障碍或病症药物中的应用。
本发明采用如下的技术方案:
本发明的第一方面,提供了如I式所示的化合物,或其立体异构体,或其立体异构体混合物,或其药学上可接受的盐:
环A为:
X1选自:N,CR11;
X2选自:N,CO,CR12;
X3选自:N,CR13;
X4选自:O,N,NR15,CR15;
X5选自:不存在,N,CO,NR16,CR16;
X6选自:N,NR17,NHR17,CO,CR17;
X7选自:不存在或CHR18;R18选自:C1-C5烷基;当X6选自NR17,NHR17,CO,CR17时,R17可与R18链接成环;
环A中,虚线表示化学键可存在,也可以是不存;进一步讲,其中的单虚线表示化学键可存在(表现为单键),也可以是不存在;双虚线表示化学键为双键、单键或者不存在;
Y1、Y2、Y3独自选自CR7、N;
m选自0、1、2、3、4;
n选自0、1、2;
L1选自化学键、O、NR8、(CH2)p、NHC(O)、NHS(O)2、C(O)NH、S(O)2NH;
L2选自化学键、O、NR8、(CH2)p、NHC(O)、NHS(O)2、C(O)NH、S(O)2NH;
且L1和L2至少一个为O、NR8、NHC(O)、NHS(O)2、C(O)NH或者S(O)2NH;
p选自1、2、3;
R1选自:H,D,卤素,羟基,氨基,氰基,羧基,取代或未取代的C1-C6烷基,取代或未取代的C1-C6烷氧基,取代或未取代的卤代C1-C6烷基,取代或未取代的卤代C1-C6烷氧基,取代或未取代的C3-C5环烷基;
R2选自:取代或者未取代的C1-C10烷基,取代或者未取代的C3-C7环烷基(不包含降莰烷基),取代或者未取代的四元至七元杂环基,取代或者未取代的C3-C7环烯基,取代或者未取代的C6-C10芳基,取代或者未取代的五元至十元杂芳基;
上述R2可进一步地被1-5个RX取代,RX独立选自:D,C1-C3烷基,卤素,氨基,硝基,羟基,氧代,C1-C3烷氧基,卤代C1-C3烷基,C1-C3羟烷基,-氨基C1-C3烷基,-C(O)C1-C3烷基,-C(O)O-C1-C3烷基,-C1-C3烷氨基,卤代C1-C3羟烷基,卤代C1-C3烷氨基,C3-C5环烷基,四元至六元杂环烷基;
R3选自:H,D,卤素,羟基,氨基,氰基,羧基,取代或未取代的C1-C6烷基,取代或未取代的C1-C6烷氧基,取代或未取代的卤代C1-C6烷基,取代或未取代的卤代C1-C6烷氧基,取代或未取代的C3-C5环烷基;
R11,R12,R13,R14,R15,R16,R17各自独立地选自:不存在,H,D,C1-C6烷基,C2-C6烯基,C2-C6炔基,C3~C5环烷基,C3-C7环烯基,四元至七元杂环基,C6-C10芳基,五元至十元杂芳基,卤素,硝基,氰基,ORa,SRa,,NH(CH2)Ra,C(O)Ra,S(O)Ra,SO2Ra,C(O)ORa,OC(O)Ra,NRbRc,,C(O)N(Rb)Rc,N(Rb)C(O)Rc,-P(O)RbRc;所述的烷基,烯基,炔基,环烷基,环烯基,杂环基,芳基或者杂芳基可进一步被1或者多个Rd取代;
Ra,Rb,Rc选自:H,D,烷基,烯基,炔基,卤素,氰基,氨基,硝基,羟基,氧代,羧基,酰胺,烷氧基,卤素烷基,羟烷基,氨基烷基,烷基羰基,烷氧羰基,烷氨基,卤代羟烷基,卤代烷氨基,环烷基,环烯基,杂环基,芳基或者杂芳基
Rd选自:H,D,烷基,卤素,氰基,氨基,,硝基,羟基,氧代,烷氧基,卤代烷基,羟烷基,氨基烷基,C1-C3酰基,烷氧羰基,烷氨基,卤代羟烷基,卤代烷氨基,环烷基,杂环基;
R7选自:H,D,卤素,氰基,取代或未取代的C1-C3烷基,取代或未取代的卤代C1-C3烷基,取代或未取代的C3-C5环烷基;
R8选自:H,D,取代或未取代的C1-C3烷基,取代或未取代的卤代C1-C3烷基,取代或未取代的C3-C5环烷基。
进一步的,作为限制性条件:
X1为C,X2为N或CH,X4为N,X5为CH,X6为N或CR16,-L1-L2-为-CONH-时,R2不为取代或者未取代的C1-C10烷基,取代或者未取代的C3-C7环烷基,取代或者未取代的四元至七元杂环基,取代或者未取代的C3-C7环烯基
X2为N,X3为N,X5为不存在时,-L1-L2-不为-CH2NHCO;
X2为N,X4为N,X5为CH,X6为N时;-L1-L2-不为-CH2NHCO-;
X1为C,X2为N,X3为N时,-L1-L2-的组合为-C(O)NH-或-NHC(O)-;
R2为取代或无取代环烷基、取代或无取代杂环烷基、取代或者未取代的C3-C7环烯基时,满足如下一个条件:-L1-L2-不为化学键、O、NR8、C(O)NH、-CONH-或X5不存在;进一步的:
X1选自:N,C;
X2选自:N,CO,CR12;
X3选自:N,C;
X4选自:O,N,CR15;
X5选自:不存在,N,NR16,CR16;
X6选自:N,CO,NHR17,CR17;
当X2选自CO时,X1,X3同时为N;
当X4选自O时,X5为不存在,X6为NHR17此时R17与R2可相连成环;
当X6选自CO时,X5为NR16,X4为N;
更进一步的:
环A选自以下杂环结构:
当环A选自(A)(B)(C)(D)(E)(F)(G)(H)(K)(M)之一,且-L1-L2-的组合不为-CH2NHC(O)-时,R2不为取代或者未取代的C3-C7环烷基,取代或者未取代的三元至七元杂环基,取代或者未取代的C3-C7环烯基;
当环A选自(I)时,-L1-L2-的组合为-CO(NH)-,且R2选自取代或者未取
代的C6-C10芳基,取代或者未取代的五元至十元杂芳基;
当环A选自(Q)时,-L1-L2-的组合不为-(CH2)p-NHC(O)-;
当环A选自(J),且-L1-L2-的组合为-C(O)NH-时,R2选自取代或者未取代的C6-C10芳基,取代或者未取代的五元至十元杂芳基;
当环A选自(J),且-L1-L2-的组合不为-C(O)NH-与-(CH2)p-NHC(O)时,R2不为取代或者未取代的C3-C7环烷基,取代或者未取代的三元至七元杂环基,取代或者未取代的C3-C7环烯基。
更进一步的本发明优选的化合物具有通式IIa或IIb或IIc所示的结构:
或其立体异构体,或其立体异构体混合物,或其药学上可接受的盐。
更进一步的本发明优选的化合物具有通式IIIa或IIIb或IIIc所示的结构:
或其立体异构体,或其立体异构体混合物,或其药学上可接受的盐;其中:
IIIa的环A选自环(A)(C)(D)(E)(F)(G)(I)(J)(M)(P)(Q)之一;
IIIb的环A选自环(A)(C)(D)(E)(F)(G)(J)(M)(P)之一;
IIIc的环A选自环(A)(C)(D)(E)(F)(G)(J)(M)(P)(Q)之一;
当结构通式选自IIIa,且环A选自(A)(C)(D)(E)(F)(G)(M)之一时,R2不为取代或者未取代的C3-C7环烷基,取代或者未取代的三元至七元杂环基,取代或者未取代的C3-C7环烯基;
当结构通式选自IIIa,且环A选自(I)(J)之一时,R2选自取代或者未取代的C6-C10芳基,取代或者未取代的五元至十元杂芳基;
当结构通式选自IIIc,且环A选自(A)(C)(D)(E)(F)(G)(J)(M)之一时,R2不为取代或者未取代的C3-C7环烷基,取代或者未取代的三元至七元杂环基,取代或者未取代的C3-C7环烯基。
更进一步的本发明优选的化合物具有通式IVa或IVb所示的结构:
或其立体异构体,或其立体异构体混合物,或其药学上可接受的盐;其中:
IVa的环A选自环(A)(Q)(I)(J)之一;
IVb的环A选自环(A)(F)(G)(J)之一。
当结构通式选自IVa且环A选自(A)时,R2不为取代或者未取代的C3-C7环烷基,取代或者未取代的三元至七元杂环基,取代或者未取代的C3-C7环烯基。当结构通式选自IVa且环A选自(I)(J)时,R2选自取代或者未取代的C6-C10芳基,取代或者未取代的五元至十元杂芳基。
更进一步的本发明优选的化合物具有通式Va~Vh所示的结构:
或其立体异构体,或其立体异构体混合物或其药学上可接受的盐;其中:R1选自:H,D,卤素(氟、氯),羟基,氨基,氰基,羧基,-OMe,-OEt,-OiPr,取代或者未取代C1-C3烷基,取代或者未取代卤代C1-C3烷基,OCF3,取代或者未取代3元到5元环烷基,取代或者未取代3元到5元环烷氧基。
R2选自:H,D,取代或者未取代C1-C3烷基,取代或者未取代苯基,取代或者未取代的五元至七元杂芳基,其中烷基、苯基、杂芳基可被一个或多个取代基进一步取代,取代基选自:D,C1-C3烷基,卤素,氰基,氨基,硝基,羟基,氧代,C1-C3烷氧基,卤代C1-C3烷基,C1-C3羟烷基,V-氨基C1-C3烷基,-C(O)C1-C3烷基,-C(O)O-C1-C3烷基,-C1-C3烷氨基,卤代C1-C3羟烷基,卤代C1-C3烷氨基,C3-C5环烷基,四元至六元杂环烷基;
当结构选自Vb或Vc时,R2选自取代或者未取代苯基,取代或者未取代的五元至七元杂芳基;
更进一步的本发明优选的化合物具有通式VIa~VIe所示的结构:
或其立体异构体,或其立体异构体混合物,或其药学上可接受的盐;
其中,R1选自:H,D,卤素(氟、氯),羟基,氨基,氰基,羧基,-OMe,-OEt,-OiPr,取代或者未取代C1-C3烷基,取代或者未取代卤代C1-C3烷基,OCF3,取代或者未取代3元到5元环烷基,3元到5元环烷氧基
R2选自:
其中R2可以进一步被0~5个取代基取代,取代基选自:D、F、Cl、CN、OMe、OEt、OiPr、NH2、NHMe,NHAc、CH2OH、CH2CH2OH、CO2H、CH2CO2H、Me、Et、iPr、CF3、CH2CF3、COOMe、COOiPr、CONH2、CH2CONH2。
作为优选,所述的化合物选自下列化合物:
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或其立体异构体,或其立体异构体混合物,或其药学上可接受的盐,
N-(4-(6-氨基-9-异丙基-8-氧代-8,9-二氢-7H-嘌呤-7-基)苄基)-2-甲氧基苯甲酰胺 001
N-(4-(4-氨基-7-异丙基-7H-吡咯[2,3-d]嘧啶-5-基)苄基)-5-氟-2-甲氧基苯甲酰胺 002
5-氨基-1-异丙基-3-(4-((4-(三氟甲基)吡啶-2-基)氨甲酰基)苯基)-1H-吡唑-4-甲酰胺 003
5-氨基-1-异丙基-3-(4-(吡啶-2-基氨基甲酰基)苯基)-1H-吡唑-4-甲酰胺004
3-氨基-4-环戊基-1-(4-((2-甲氧基苯甲酰胺基)甲基)苯基)-1H-吡咯-2-羧酰胺005
5-氟-N-(4-(9异丙基-6-(甲氨基)-8-氧代-8,9-二氢-7H-嘌呤-7-基)苯基)-2-甲氧基苯甲酰胺 006
N-(4-(6-氨基-9-异丙基-8-氧代-8,9-二氢-7H-嘌呤-7-基)-3-氟苄基)-2-甲氧基苯甲酰胺 007
N-(4-(6-氨基-9-异丙基-8-氧代-8,9-二氢-7H-嘌呤-7-基)-2,3-二氟苄基)-2-甲氧基苯甲酰胺 008
N-(4-(6-氨基-9-异丙基-8-氧代-8,9-二氢-7H-嘌呤-7-基)苄基)-5-氟-2-甲氧基苯甲酰胺 009
N-(4-(6-氨基-9-(1-羟基丙烷-2-基)-8-氧代-8,9-二氢-7H-嘌呤-7-基)苄基)-5-氟-2-甲氧基苯甲酰胺 010
N-(4-(6-氨基-9-(4-羟基环己基)-8-氧代-8,9-二氢-7H-嘌呤-7-基)苄基)-5-氟-2-甲氧基苯甲酰胺 011
4-(6-氨基-7-(4-((5-氟-2-甲氧基苯甲酰胺基)甲基)苯基)-8-氧代-7H-嘌呤-9(8H)-基)环己烯羧酸 012
N-(4-(6-氨基-9-(3-羟基环己基)-8-氧代-8,9-二氢-7H-嘌呤-7-基)苄基)-5-氟-2-甲氧基苯甲酰胺 013
N-(4-(6-氨基-9-(1-(2-羟基乙酰基)哌啶-3-基)-8-氧代-8,9-二氢-7H-嘌呤-7-基)苄基)-5-氟-2-甲氧基苯甲酰胺 014
N-(4-(6-氨基-9-(1-(2-吗啉乙酰基)哌啶-3-基)-8-氧代-8,9-二氢-7H-嘌呤-7-基)苄基)-5-氟-2-甲氧基苯甲酰胺 015
N-(4-(6-氨基-8-氧代-9-(1,1,1-三氟丙烷-2-基)-8,9-二氢-7H-嘌呤-7-基)苄基)-5-氟-2-甲氧基苯甲酰胺 016
N-(4-(6-氨基-8-氧代-9-苯基-8,9-二氢-7H-嘌呤-7-基)苄基)-5-氟-2-甲氧基苯甲酰胺 017
N-(4-(4-氨基-7-异丙基-7H-吡咯[2,3-d]嘧啶-5-基)苄基)-2-甲氧基苯甲酰胺018
N-(4-(4-氨基-7-异丙基-7H-吡咯[2,3-d]嘧啶-5-基)苄基)-2-乙氧基苯甲酰胺019
N-(4-(4-氨基-7-异丙基-7H-吡咯[2,3-d]嘧啶-5-基)苄基)-2-氟苯甲酰胺 020
N-(4-(4-氨基-7-(1-羟丙基-2-基)-7H-吡咯[2,3-d]嘧啶-5-基)苄基)-5-氟-2-甲氧基苯甲酰胺 021
N-(4-(4-氨基-7-(1,1,1-三氟丙烷-2-基)-7H-吡咯[2,3-d]嘧啶-5-基)苄基)-5-氟-2-甲氧基苯甲酰胺 022
N-(4-(4-氨基-7-苯基-7H-吡咯[2,3-d]嘧啶-5-基)苄基)-5-氟-2-甲氧基苯甲酰胺 023
N-(4-(4-氨基-7-(1-羟丙基-2-基)-7H-吡咯[2,3-d]嘧啶-5-基)-3-氟苄基)-5-氟-2-甲氧基苯甲酰胺 024
N-((5-(4-氨基-7-(1-羟丙基-2-基)-7H-吡咯[2,3-d]嘧啶-5-基)吡啶-2-基)甲基)-5-氟-2-甲氧基苯甲酰胺 025
N-(4-(4-氨基-7-(4-羟基环己基)-7H-吡咯[2,3-d]嘧啶-5-基)苄基)-5-氟-2-甲氧基苯甲酰胺 026
N-(4-(4-氨基-7-(3-羟基环己基)-7H-吡咯[2,3-d]嘧啶-5-基)苄基)-5-氟-2-甲氧基苯甲酰胺 027
N-(4-(4-氨基-7-(1-(2-羟基乙酰基)哌啶-3-基)-7H-吡咯[2,3-d]嘧啶-5-基)苄基)-5-氟-2-甲氧基苯甲酰胺 028
N-(4-(4-氨基-7-异丙基-6-甲基-7H-吡咯[2,3-d]嘧啶-5-基)苄基)-5-氟-2-甲氧基苯甲酰胺 029
N-(4-(4-氨基-7-(1-(2-羟基乙酰基)哌啶-3-基)-6-甲基-7H-吡咯[2,3-d]嘧啶-5-基)苄基)-5-氟-2-甲氧基苯甲酰胺 030
N-(4-(4-氨基-1-异丙基-7-氧代-6,7-二氢-1H-吡唑[3,4-d]哒嗪-3-基)苄基)-5-氟-2-甲氧基苯甲酰胺 031
N-(4-(4-氨基-7-氧代-1-苯基-6,7-二氢-1H-吡唑啉[3,4-d]哒嗪-3-基)苄基)-5-氟-2-甲氧基苯甲酰胺 032
N-(4-(4-氨基-1-(1-(2-羟基乙酰基)哌啶-3-基)-7-氧代-6,7-二氢-1H-吡唑[3,4-d]哒嗪-3-基)苄基)-5-氟-2-甲氧基苯甲酰胺 033
N-(4-(4-氨基-1-异丙基-7-氧代-6,7-二氢-1H-吡咯[2,3-d]哒嗪-3-基)苄基)-5-氟-2-甲氧基苯甲酰胺 034
N-(4-(4-氨基-1-(1-(2-羟基乙酰基)哌啶-3-基)-7-氧代-6,7-二氢-1H-吡咯[2,3-d]哒嗪-3-基)苄基)-5-氟-2-甲氧基苯甲酰胺 035
4-(4-氨基-1-苯基-1H-吡唑啉[3,4-d]嘧啶-3-基)-N-(4-(三氟甲基)吡啶-2-基)苯甲酰胺 036
4-(4-氨基-1-(3-羟基苯基)-1H-吡唑啉[3,4-d]嘧啶-3-基)-N-(4-(三氟甲基)吡啶-2-基)苯甲酰胺 037
4-(4-氨基-1-(吡啶-3-基)-1H-吡唑啉[3,4-d]嘧啶-3-基)-N-(4-(三氟甲基)吡啶-2-基)苯甲酰胺 038
N-(4-(4-氨基-1-异丙基-1H-吡唑啉[3,4-d]嘧啶-3-基)苯基)吡啶酰胺 039
4-(6-氨基-9-异丙基-8-氧代-8,9-二氢-7H-嘌呤-7-基)-N-(4-(三氟甲基)吡啶-2-基)苯甲酰胺 040
4-(6-氨基-8-氧代-9-(1,1,1-三氟丙烷-2-基)-8,9-二氢-7H-嘌呤-7-基)-N-(4-(三氟甲基)吡啶-2-基)苯甲酰胺 041
4-(6-氨基-9-(1-羟基丙烷-2-基)-8-氧代-8,9-二氢-7H-嘌呤-7-基)-N-(4-(三氟甲基)吡啶-2-基)苯甲酰胺 042
4-(4-氨基-1-异丙基-7-氧代-6,7-二氢-1H-吡唑[3,4-d]哒嗪-3-基)-N-(4-(三氟甲基)吡啶-2-基)苯甲酰胺 043
4-(4-氨基-1-(1-羟基丙烷-2-基)-7-氧代-6,7-二氢-1H-吡唑啉[3,4-d]哒嗪-3-基)-N-(4-(三氟甲基)吡啶-2-基)苯甲酰胺 044
4-(4-氨基-1-(1-吗啉丙烷-2-基)-7-氧代-6,7-二氢-1H-吡唑[3,4-d]哒嗪-3-基)-N-(4-(三氟甲基)吡啶-2-基)苯甲酰胺 045
4-(4-氨基-1-(1-羟基丙烷-2-基)-7-氧代-6,7-二氢-1H-吡咯[2,3-d]哒嗪-3-基)-N-(4-(三氟甲基)吡啶-2-基)苯甲酰胺 046
5-氨基-3-(2-氟-4-((4-(三氟甲基)吡啶-2-基)氨甲酰基)苯基)-1-异丙基-1H-吡唑-4-甲酰胺 047
5-氨基-3-(2,3-二氟-4-((4-(三氟甲基)吡啶-2-基)氨甲酰基)苯基)-1-异丙基-1H-吡唑-4-甲酰胺 048
5-氨基-3-(2,6-二氟-4-((4-(三氟甲基)吡啶-2-基)氨甲酰基)苯基)-1-异丙基-1H-吡唑-4-甲酰胺 049
5-(5-氨基-4-氨甲酰-1-异丙基-1H-吡唑-3-基)-N-(4-(三氟甲基)吡啶-2-基)吡啶酰胺 050
5-氨基-1-(1-羟基丙烷-2-基)-3-(4-((4-(三氟甲基)吡啶-2-基)氨甲酰基)苯基)-1H-吡唑-4-甲酰胺 051
5-氨基-1-(四氢-2H-吡喃-4-基)-3-(4-((4-(三氟甲基)吡啶-2-基)氨甲酰基)苯基)-1H-吡唑-4-甲酰胺 052
5-氨基-1-(3,3-二氟环丁基)-3-(4-((4-(三氟甲基)吡啶-2-基)氨甲酰基)苯基)-1H-吡唑-4-甲酰胺 053
5-氨基-1-(1-(2-羟基乙酰基)哌啶-3-基)-3-(4-((4-(三氟甲基)吡啶-2-基)氨甲酰基)苯基)-1H-吡唑-4-甲酰胺 054
N-(4-(5-氨基-4-氨甲酰-1-异丙基-1H-吡唑-3-基)苯基)吡啶酰胺 055
5-氨基-1-异丙基-3-(4-苯氧基苯基)-1H-吡唑-4-甲酰胺 056
5-氨基-3-(2,3-二氟-4-苯氧基苯基)-1-异丙基-1H-吡唑-4-甲酰胺 057
5-氨基-3-(4-(2-氟-3-甲氧基苯氧基)苯基)-1-异丙基-1H-吡唑-4-甲酰胺 058
5-氨基-3-(4-(苄氧基)苯基)-1-异丙基-1H-吡唑-4-甲酰胺 059
5-氨基-1-异丙基-3-(4-(苯氧甲基)苯基)-1H-吡唑-4-甲酰胺 060
5-氨基-1-异丙基-3-(4-(苯氨基)苯基)-1H-吡唑-4-甲酰胺 061
5-氨基-1-异丙基-3-(4-(N-(3-(三氟甲基)苯基)氨磺酰)苯基)-1H-吡唑-4-甲酰胺 062
5-氨基-1-异丙基-3-(4-(N-(4-(三氟甲基)吡啶-2-基)氨磺酰)苯基)-1H-吡唑-4-甲酰胺 063
5-氨基-1-异丙基-3-(4-(苯基磺胺甲基)苯基)-1H-吡唑-4-甲酰胺 064
3-氨基-4-环戊基-1-(4-((5-氟-2-甲氧基苯甲酰胺基)甲基)苯基)-1H-吡咯-2-甲酰胺 065
3-氨基-4-(1-(2-羟基乙酰基)哌啶-3-基)-1-(4-((2-甲氧基苯甲酰胺基)甲基)苯基)-1H-吡咯-2-甲酰胺 066
4-氨基-3-环戊基-1-(4-((2-甲氧基苯甲酰胺基)甲基)苯基)-1H-吡唑-5-甲酰胺067
4-氨基-3-异丙基-1-(4-((2-甲氧基苯甲酰胺基)甲基)苯基)-1H-吡唑-5-甲酰胺068
4-氨基-3-(1-(2-羟基乙酰基)哌啶-3-基)-1-(4-((2-甲氧基苯甲酰胺基)甲基)苯基)-1H-吡唑-5-甲酰胺 069
3-氨基-4-异丙基-1-(4-((4-(三氟甲基)吡啶-2-基)氨甲酰基)苯基)-1H-吡咯-2-甲酰胺 070
4-氨基-3-异丙基-1-(4-((4-(三氟甲基)吡啶-2-基)氨甲酰基)苯基)-1H-吡唑-5-甲酰胺 071
5-氨基-3-(4-((4-(三氟甲基)吡啶-2-基)甲酰胺基)苯基)-1-(1,1,1-三氟丙-2-基)-1H-吡唑-4-甲酰胺 072
5-氨基-3-(2-氟-4-((4-(三氟甲基)吡啶-2-基)甲酰胺基)苯基)-1-(1,1,1-三氟丙-2-基)-1H-吡唑-4-甲酰胺 073
5-氨基-3-(2-氟-4-((4-(三氟甲基)吡啶-2-基)甲酰胺基)苯基)-1-(1,1,1-三氟丁-2-基)-1H-吡唑-4-甲酰胺 074
术语说明
本发明所用术语“芳基”是指6到12个碳原子的全碳单环或稠合多环基团(其中一个稠合环可以部分饱和)。芳环的非限制性实例有:苯环、萘环、蒽环、茚环、二氢茚基(茚满基)。芳环可以是无取代或取代的。芳环的取代基选自D、卤素(优选为氟、氯、溴、碘)、氰基、硝基、氨基、羟基、羧基、羧酸甲酯、羧酸乙酯、甲酰胺、C1-C6烷基(优选为甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、异戊基、新戊基等)、C1-C6羟烷基(优选为羟甲基、羟乙基、羟丙基、羟异丙基等)、C1-C6烷氧基(优选为甲氧基、乙氧基、丙氧基、异丙基氧基、丁氧基、异丁基氧基、仲丁基氧基、叔丁基氧基等)、卤代C1-C6烷基(优选为卤代甲基、卤代乙基、卤代丙基、卤代异丙基、卤代丁基、卤代异丁基、卤代仲丁基、卤代叔丁基等)、卤代C1-C6羟烷基(优选为卤代羟甲基、卤代羟乙基、卤代羟丙基、卤代羟异丙基等)、卤代C1-C6烷氧(优选为卤代甲氧基、卤代乙氧基、卤代丙氧基、卤代异丙基氧基、卤代丁氧基、卤代异丁基氧基、卤代仲丁基氧基、卤代叔丁基氧基等)基、C3-C6环烷基(优选为环丙基、环戊基、环己基等)、卤代C3-C6环烷基(优选为卤代环丙基、卤代环戊基、卤代环己基等)、3至10元杂环基(优选为四氢呋喃基、吡咯烷基、哌啶基、哌嗪基、吗啉基等)、C6-C12芳基、C5-C14杂芳基;芳环的取代,可以是单取代(比如邻位、间位、对位取代),也可以是双取代或者三取代等。
本发明所用术语“杂芳基”指5到14个环原子的单环或稠合多环基团(其中一个稠合环可以部分饱和),相当于上述“芳基”中一个或多个碳被杂原子例如氧、氮、硫等置换。杂芳环可以是单环,也可以是双环,即通过两个环稠合而成。具体的杂芳基(杂环芳基)可以是:D、吡啶基、嘧啶基、吡嗪基、异恶唑基、异噻唑基、吡唑基、噻唑基、恶唑基、咪唑基、吲哚、二氢吲哚、苯并咪唑等。杂环芳基可以是无取代或取代的。杂环芳基的取代基选自卤素、氰基、硝基、氨基、羟基、C1-C6烷基、C1-C6羟烷基、C1-C6烷氧基、卤代C1-C6烷基、卤代C1-C6羟烷基、卤代C1-C6烷氧基、C3-C6环烷基、卤代C3-C6环烷基、3至10元杂环基、C6-C12芳基、C5-C14杂芳基。
本发明所用术语“烷基”是指一个具有一至六个碳原子的直链饱和单价烃基或一个具有三至六个碳原子的支链饱和的单价烃基,优选为甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、异戊基、新戊基等。烷基可以是无取代或单取代或多取代,多取代时取代基可以相同也可以不同;烷基的取代基选自D、卤素、硝基、羟基、羧基、羧酸甲酯、羧酸乙酯、异丙酯、胺甲酰基、C1-C6烷基、C1-C6烷氧基、C3-C10环烷基、烷氧基羰基、烷硫基、烷基磺酰基、烷基酰胺基、羟烷基酰胺基、磺酰胺基、3至10元杂环基,或者氨基或单取代或多取代氨基,其中氨基的取代基可以相同也可以不同,选自氢、C1-C6烷基、C1-C6羟烷基、C1-C6烷氧基、C3-C10环烷基、3至10元杂环基、C6-C12芳基、C5-C14杂芳基。
本发明所用术语“羟烷基”是指-烷基-OH,其中烷基如上所定义。本发明所用“羟烷基”的实例包括但不限于羟甲基、羟乙基、羟丙基、羟异丙基等。“羟烷基”还包括取代羟烷基,其取代基可为D、卤素、氨基、羟基、C1-C6烷基、C1-C6羟烷基、C1-C6烷氧基、C1-C6环烷基、3至10元杂环基、C6-C12芳基、C5-C14杂芳基。
本发明所用术语“氨基烷基”是指-烷基-NH2,其中烷基如上所定义。本发明所用“氨基烷基”的实例包括但不限于氨甲基、氨乙基、氨丙基、氨异丙基等。“氨基烷基”还包括取代氨基烷基,其取代基可为D、卤素、氨基、羟基、C1-C6烷基、C1-C6羟烷基、C1-C6烷氧基、C1-C6环烷基、3至10元杂环基、C6-C12芳基、C5-C14杂芳基,其取代基可以取代在烷基上也可以取代在NH2上。
本发明所用术语“烷胺基”是指烷基-NH-,其中烷基如上所定义。本发明所用“烷胺基”的实例包括但不限于甲胺基、乙胺基、丙胺基、异丙胺基等。“烷胺基”还包括取代烷胺基,其取代基可为D、卤素、氨基、羟基、C1-C6烷基、C1-C6羟烷基、C1-C6烷氧基、C1-C6环烷基、3至10元杂环基、C6-C12芳基、C5-C14杂芳基,其取代基可以取代在烷基上也可以取代在NH上。
本发明所用术语“烷氧基”是指-O-烷基基团,其中烷基如上所定义。本发明所用“烷氧基”的实例包括但不限于甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基和叔丁氧基。“烷氧基”还包括取代烷氧基,其取代基可为D、卤素、氨基、羟基、C1-C6烷基、C1-C6羟烷基、C1-C6烷氧基、C1-C6环烷基、3至10元杂环基、C6-C12芳基、C5-C14杂芳基。
本发明所用术语“环烷基”是指具有三个至十个碳原子的单环或多环(两个单环之间用化学键连接或桥环或螺环或稠合)的非芳香性单价烃基,优选为环丙基、环丁基、环戊基、环己基等,其中一个或两个碳原子可以由一个氧代基团替代。该环烷基可以是无取代或取代的,其取代基选自D、卤素、硝基、羟基、羧基、羧酸甲酯、羧酸乙酯、甲酰胺、C1-C6烷基、C1-C6羟烷基、C1-C6烷氧基、卤代C1-C6烷基、卤代C1-C6羟烷基、卤代C1-C6烷氧基、C3-C6环烷基、卤代C3-C6环烷基、烷氧基羰基、烷硫基、烷基磺酰基、烷基酰胺基、羟烷基酰胺基、磺酰胺基、3至10元杂环基,或者氨基或单取代或多取代氨基,其中氨基的取代基可以相同也可以不同,选自氢、C1-C6烷基、C1-C6羟烷基、C1-C6烷氧基、C3-C10环烷基、3至10元杂环基、C6-C12芳基、C5-C14杂芳基。
本发明所用术语“环烯基”是指具有三个至十个碳原子的单环或多环(两个单环之间用化学键连接或桥环或螺环或稠合)的非芳香性烃基且至少还有一个双键,优选为环丁烯基、环戊烯基、环己烯基等,其中一个或两个碳原子可以由一个氧代基团替代。该环烯基可以是无取代或取代的,其取代基选自D、卤素、硝基、羟基、羧基、羧酸甲酯、羧酸乙酯、甲酰胺、C1-C6烷基、C1-C6羟烷基、C1-C6烷氧基、卤代C1-C6烷基、卤代C1-C6羟烷基、卤代C1-C6烷氧基、C3-C6环烷基、卤代C3-C6环烷基、烷氧基羰基、烷硫基、烷基磺酰基、烷基酰胺基、羟烷基酰胺基、磺酰胺基、3至10元杂环基,或者氨基或单取代或多取代氨基,其中氨基的取代基可以相同也可以不同,选自氢、C1-C6烷基、C1-C6羟烷基、C1-C6烷氧基、C3-C10环烷基、3至10元杂环基、C6-C12芳基、C5-C14杂芳基。
本发明所用术语“杂环基”是指具有三个至十个环原子的单环或多环(两个单环之间用化学键连接或桥环或螺环或稠合)的非芳香性环基,其中部分化学键可以是不饱和的双键或三键,具有一个及以上的选自N、O、S的杂原子。该杂环基可以是无取代或取代的,其取代基选自D、卤素、硝基、羟基、羧基、羧酸甲酯、羧酸乙酯、甲酰胺、氧代、硫代、C1-C6烷基、C1-C6羟烷基、C1-C6烷氧基、卤代C1-C6烷基、卤代C1-C6羟烷基、卤代C1-C6烷氧基、C3-C6环烷基、卤代C3-C6环烷基、烷氧基羰基、烷硫基、烷基磺酰基、烷基酰胺基、羟烷基酰胺基、磺酰胺基、3至10元杂环基,或者氨基或单取代或多取代氨基,其中氨基的取代基可以相同也可以不同,选自氢、C1-C6烷基、C1-C6羟烷基、C1-C6烷氧基、C3-C10环烷基、3至10元杂环基、C6-C12芳基、C5-C14杂芳基。
本发明所用术语“烯基”指由碳和氢原子组成,含至少一个双键且具有2至10个碳原子的直链或支链的烃链基团(即C2-C10烯基),包括但不限于乙烯基、烯丙基、丁-1-烯基、戊-1-烯基、戊-1,4-二-烯基等。烯基可被一个或者多个取代基取代,所述取代基独立为D、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、卤代羟烷基、环烷基、卤代环烷基、杂环烷基、芳基、杂芳基、羟基、卤素、氰基、硝基。
本发明所用术语“炔基”指由碳和氢原子组成,含至少一个叁键且具有2至10个碳原子的直链或支链的烃链基团(即C2-C10炔基),包括但不限于乙炔基、丙炔基、丁炔基、戊炔基和己炔基等。炔基可被一个或者多个取代基取代,所述取代基独立为D、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、卤代羟烷基、环烷基、卤代环烷基、杂环烷基、芳基、杂芳基、羟基、卤素、氰基、硝基。
本发明所用术语“卤素”指氟、氯、溴、碘,优选氟、氯或溴。
本发明所用术语“卤代”指被同一个原子或不同原子被卤素取代,可以取代一次也可以取代多次,如二取代或三取代。
本发明所用术语“卤代烷基”是指被卤素(优选为氟、氯、溴、碘)取代的烷基基团,其中烷基如上所定义。“卤代烷基”可被卤素取代一次或多次。
本发明所用术语“卤代羟烷基”是指被卤素(优选为氟、氯、溴、碘)取代的羟烷基基团,其中羟烷基如上所定义。“卤代羟烷基”可被卤素取代一次或多次。
本发明采用本领域技术人员所熟知的方法可以制备本发明所述化合物的盐。所述的盐可以是有机酸盐、无机酸盐等,所述的有机酸盐包括枸橼酸盐、富马酸盐、草酸盐、苹果酸盐、乳酸盐、樟脑磺酸盐、对甲苯磺酸盐、甲磺酸盐等;所述的无机酸盐包括氢卤酸盐、硫酸盐、磷酸盐、硝酸盐等。例如,与低级烷基磺酸,如甲磺酸,三氟甲磺酸等可形成甲磺酸盐、三氟甲磺酸盐;与芳基磺酸,如苯磺酸或对甲苯磺酸等可形成对甲苯磺酸盐、苯磺酸盐;与有机羧酸,如乙酸,富马酸,酒石酸,草酸,马来酸,苹果酸,琥珀酸或柠檬酸等可形成相应的盐;与氨基酸,如谷氨酸或天冬氨酸可形成谷氨酸盐或天冬氨酸盐。与无机酸,如氢卤酸(如氢氟酸、氢溴酸、氢碘酸、氢氯酸),硝酸,碳酸,硫酸或磷酸等也可形成相应的盐。
本发明的第二个目的是提供一种药物组合物,包括上述任意一项技术方案所述的化合物中的一种或多种。本发明所述的药物组合物可以是上述任意一项技术方案所述的化合物中的一种或多种与其他化合物组成,或者上述任意一项技术方案所述的化合物中的一种或多种组成。
本发明提供了一种药物制剂,包含至少一种活性组分,所述活性组分是如上述任意一项技术方案所述的化合物中的一种或多种。所述药物制剂包含至少一种活性组分以及一种或多种药学上可接受的载体或赋形剂,所述的活性组分可以是本发明的BTK抑制剂化合物、所述化合物的光学异构体、所述化合物或其光学异构体在药学上可接受的盐、所述化合物或其光学异构体的溶剂合物中的任意一种或任意多种。
所述载体包括药学领域的常规稀释剂,赋形剂,填充剂,粘合剂,湿润剂,崩解剂,吸收促进剂,表面活性剂,吸附载体,润滑剂等,必要时还可以加入香味剂,甜味剂等。
本发明药物可以制成片剂,粉剂,粒剂,胶囊,口服液及注射用药等多种形式,上述各剂型的药物均可以按照药学领域的常规方法制备。
另一方面,本发明提供的是使用本文公开的通式I~通式V所述的化合物及其光学异构体或其药学上可接受的盐或溶剂合物来抑制布鲁顿酪氨酸激酶(Btk)活性或者治疗从布鲁顿酪氨酸激酶(Btk)活性的抑制中获益的疾病、障碍或病症。
在进一步优选的方案中,本发明提供的是通过给予有需要的治疗者一种含有治疗有效量的至少一种化合物或含有上述化合物的组合物、从而抑制所述受治疗者的布鲁顿酪氨酸激酶活性的方法,其中所述化合物的结构式为通式I~通式V所示的结构。在一些实施方式中,有需要的受治疗者罹患自身免疫性疾病,例如炎性肠病、关节炎、狼疮、类风湿性关节炎、银屑病性关节炎、骨关节炎、斯蒂尔病(Still’s disease)、青少年关节炎、糖尿病、重症肌无力症、桥本甲状腺炎(Hashimoto’s thyroiditis)、奥德甲状腺炎(Ord’sthyroiditis)、格雷夫斯氏病(Graves’disease)、类风湿性关节炎综合征(syndrome)、多发性硬化症、传染性神经元炎(Guillain-Barrésyndrome)、急性播散性脑脊髓炎、阿狄森病(Addison’s disease)、视性眼阵挛-肌阵挛综合征、强制性脊椎炎、抗磷脂抗体综合征、再生障碍性贫血、自身免疫性肝炎、乳糜泻(coeliac disease)、古德帕斯彻综合征(Goodpasture’s syndrome)、免疫性血小板减少性紫癜(ITP)、视神经炎、硬皮病、原发性胆汁性肝硬化、莱特尔综合征(Reiter’s syndrome)、高安动脉炎(Takayasu’sarteritis)、颞动脉炎、温型自身免疫性溶血性贫血、韦格纳肉芽肿病(Wegener’sgranulomatosis)、银屑病、全身脱毛、贝赫切特病(/>disease)、慢性疲劳、家族性自主神经功能异常、子宫内膜异位、间质性膀胱炎、神经肌强直、硬皮病或外阴痛和慢性移植物抗宿主病(cGvHD)。
在进一步的实施方式中,有需要的受治疗者罹患癌症。在一个实施方式中,所述癌症是B细胞增生性疾病,例如弥漫性大B细胞淋巴瘤、滤泡性淋巴瘤、慢性淋巴细胞淋巴瘤、慢性淋巴细胞白血病、B细胞前淋巴细胞性白血病、淋巴浆细胞淋巴瘤/瓦尔登斯特伦巨球蛋白血症(macroglobulinemia)、脾边缘区淋巴瘤、浆细胞性骨髓瘤、浆细胞瘤、结外边缘区B细胞淋巴瘤、***边缘区B细胞淋巴瘤、外套细胞淋巴瘤、纵膈(胸腺)大B细胞淋巴瘤、血管内大B细胞淋巴瘤、原发性渗出性淋巴瘤、伯基特淋巴瘤(Burkittlymphoma)/白血病或淋巴瘤样肉芽肿病。
本发明还提供本发明所述的化合物或其可药用盐在制备BTK抑制剂中的应用,特别是在制备治疗细胞增生疾病中的应用。所述的细胞增生疾病包括癌症。换言之,本发明还提供通式通式I~通式V所述的化合物、及其光学异构体或其药学上可接受的盐或溶剂合物单独或和其他药物联合使用在治疗增生类疾病(如癌症)中的应用。能和本发明所提供的化合物或其可药用盐联合使用的抗肿瘤药包括但并非限定至少一种以下种类:有丝***抑制剂(如长春碱、长春地辛和长春瑞宾);微管蛋白分解抑制剂(如泰素);烷基化试剂(如顺铂、卡铂和环磷酰胺);抗代谢物(如5-氟尿嘧啶、替加氟、甲氨蝶呤、阿糖胞苷和羟基脲);可***抗生素(如阿雷素、丝裂霉素和争光霉素);酶(如天门冬氨酶);拓朴异构酶抑制剂(如依托伯苷和喜树碱);生物反应调节剂(如干扰素);免疫检查点抑制剂(如PD-1抑制剂、PD-L1抑制剂、CTLA-4抑制剂);CD20单抗;BCL2抑制剂。
本发明发明人通过实验证实,本发明化合物可同时抑制野生型和481位半胱氨酸突变的BTK激酶。
本发明发明人通过实验证实,本发明化合物对MINO、OCI-LY10等肿瘤细胞株具有抗增殖抑制作用。
具体实施方式
下面通过实施例来说明本发明的可实施性,本领域的技术人员应当理解,根据现有技术的教导,对相应的技术特征进行修改或替换,仍然属于本发明要求保护的范围。
实施例1:N-(4-(6-氨基-9-异丙基-8-氧代-8,9-二氢-7H-嘌呤-7-基)苄基)-2-甲氧基苯甲酰胺(001)的制备
步骤1,将4,6-二氯-5-氨基嘧啶(2.5g)溶解于25mL正丁醇中,加入异丙基胺(3.91mL),加热至回流反应约24小时,TLC检测反应完毕后,降至室温,减压浓缩除去溶剂,所得剩余物经硅胶柱层析纯化得到淡黄色固体产物6-氯-N4-异丙基嘧啶-4,5-二胺(2.3g),收率82%。
步骤2,将6-氯-N4-异丙基嘧啶-4,5-二胺(1.9g)溶解于50mL四氢呋喃溶液中,加入CDI(5.1g),加热至回流反应20小时,TLC检测反应完毕,减压旋蒸除去四氢呋喃,然后加入乙酸乙酯和水萃取,分离得到的有机相饱和食盐水洗涤,无水硫酸钠干燥之后,过滤,减压浓缩得到的残留物经硅胶柱层析纯化得到固体产物6-氯-9-异丙基-7H-嘌呤-8(9H)-酮(1.1g),收率51%。
步骤3,将6-氯-9-异丙基-7H-嘌呤-8(9H)-酮(0.85g)溶解于10mL正丁醇中,加入4-甲氧基苄胺(1.37g),加热至回流反应约18小时,TLC检测反应完毕,降至室温,减压浓缩除去溶剂,所得残留物经硅胶柱层析纯化得到固体产物9-异丙基-6-((4-甲氧基苄基)氨基)-7H-嘌呤-8(9H)-酮(1.11g),收率89%。
步骤4,将9-异丙基-6-((4-甲氧基苄基)氨基)-7H-嘌呤-8(9H)-酮(0.23g)和(4-((2-甲氧基苯甲酰胺基)甲基)苯基)硼酸(0.64g)溶解于5mL无水DMF溶液中,加入0.2g分子筛和无水醋酸铜(0.15g),最后加入0.4mL三乙胺,在室温下搅拌反应约36小时,TLC监测反应完毕;反应液通过硅藻土过滤,所得滤液加入乙酸乙酯和水萃取,有不溶物析出,通过硅藻土过滤,滤液静止分层,所得有机相分别水洗和饱和食盐水洗涤,分离有机相用无水硫酸钠干燥,过滤,减压浓缩得到的残留物经硅胶柱层析纯化得到固体产物N-(4-(9-异丙基-6-((4-甲氧基苄基)氨基)-8-氧代-8,9-二氢-7H-嘌呤-7-基)苄基)-2-甲氧基苯甲酰胺(0.23g),收率56%。
步骤5,将N-(4-(9-异丙基-6-((4-甲氧基苄基)氨基)-8-氧代-8,9-二氢-7H-嘌呤-7-基)苄基)-2-甲氧基苯甲酰胺(0.21g)溶解于1.5mL二氯甲烷中,加入3mL三氟乙酸,加热至回流反应约20小时,TLC检测反应完毕,减压浓缩除去溶剂;加入二氯甲烷重新溶解,用饱和碳酸氢钠水溶液洗涤,分离有机相减压浓缩,所得残留物经硅胶柱层析纯化得到白色固体产物N-(4-(6-氨基-9-异丙基-8-氧代-8,9-二氢-7H-嘌呤-7-基)苄基)-2-甲氧基苯甲酰胺(0.11g),收率71%,LC-MS(ESI-MS):433[M+H]+。
实施例2:N-(4-(4-氨基-7-异丙基-7H-吡咯[2,3-d]嘧啶-5-基)苄基)-5-氟-2-甲氧基苯甲酰胺(002)的制备
步骤1,4-氨基-5-碘吡咯并[2,3-D]嘧啶(2.6g)和异丙醇(1.6mL)溶解于20mL无水四氢呋喃中,加入三苯基膦(5.24g)之后,缓慢滴加入DIAD(4.1mL),滴加完毕后在室温搅拌反应约2小时;TLC检测反应完毕,减压浓缩除去溶剂,加入10mL乙腈搅拌打浆约1小时,过滤,滤饼再次加入10mL乙腈搅拌打浆1小时,过滤,滤饼鼓风干燥得到固体产物5-碘-7-异丙基-7H-吡咯[2,3-d]嘧啶-4-胺(1.45g),收率48%。
步骤2,将5-碘-7-异丙基-7H-吡咯[2,3-d]嘧啶-4-胺(0.3g)和(4-((5-氟-2-甲氧基苯甲酰胺基)甲基)苯基)硼酸(0.48g)溶解于10mL四氢呋喃中,然后加入水(2mL),碳酸钠(0.21g)和四三苯基膦钯(106mg),加热至回流反应约12小时,TLC监测反应完毕,降至室温;加入乙酸乙酯和水萃取,再依次用水和饱和食盐水洗涤,分离有机相无水硫酸钠干燥,过滤,减压浓缩,所得残留物经硅胶柱层析纯化得到固体产物N-(4-(4-氨基-7-异丙基-7H-吡咯[2,3-d]嘧啶-5-基)苄基)-5-氟-2-甲氧基苯甲酰胺(0.28g),收率66%,1H NMR(500MHz,CD3OD)δ8.13(s,1H),7.63(dd,J=9.2,3.3 Hz,1H),7.48(s,4H),7.30(s,1H),7.27–7.23(m,1H),7.17(dd,J=9.1,4.2 Hz,1H),5.03(dd,J=13.6,6.9 Hz,1H),4.67(s,2H),3.96(s,3H),1.53(d,J=6.8 Hz,6H).LC-MS(ESI-MS):434[M+H]+。
实施例3:5-氨基-1-异丙基-3-(4-((4-(三氟甲基)吡啶-2-基)氨甲酰基)苯基)-1H-吡唑-4-甲酰胺(003)的制备
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步骤1,将5-氨基-3-溴-1H-吡唑-4-碳腈(1.1g)溶解于20mL无水DMF中,加入异丙基碘(2.1g)和碳酸铯(1.5g),在室温下搅拌反应过夜,TLC监测反应完毕;加入水和乙酸乙酯萃取,分离乙酸乙酯层用饱和食盐水洗涤,然后无水硫酸钠干燥,过滤,减压浓缩所得残留物经硅胶柱层析纯化得到固体产物5-氨基-3-溴-1-异丙基-1H-吡唑-4-碳腈(0.85g),收率62%。
步骤2,称取5-氨基-3-溴-1-异丙基-1H-吡唑-4-碳腈(0.69g),加入三氟乙酸(5mL),搅拌下滴加浓硫酸(0.3mL),加热至60℃搅拌反应过夜,TLC检测反应完毕,降温并置于冰浴中,加入水并小心加入碳酸钠固体搅拌中和至溶液呈弱碱性,用乙酸乙酯萃取,分离乙酸乙酯层用饱和食盐水洗涤,然后无水硫酸钠干燥,过滤,减压浓缩所得残留物经硅胶柱层析纯化得到固体产物5-氨基-3-溴-1-异丙基-1H-吡唑-4-甲酰胺(0.64g),收率86%。
步骤3,将5-氨基-3-溴-1-异丙基-1H-吡唑-4-甲酰胺(0.25g)和4-(4,4,5,5-四甲基-1,3,2-二氧硼杂烷-2-基)-N-(4-(三氟甲基)吡啶-2-基)苯甲酰胺(0.78g)溶解于10mL1,4-环氧六环中,加入水(2mL),碳酸钾(0.28g)和[1,1'-双(二苯基膦)二茂铁]二氯化钯(109mg),在氮气保护下加热至回流反应过夜,TLC检测反应完毕,降至室温,加入乙酸乙酯和水萃取,分离乙酸乙酯层分别用水和饱和食盐水洗涤,然后无水硫酸钠干燥,过滤,减压浓缩所得残留物经硅胶柱层析纯化得到固体产物5-氨基-1-异丙基-3-(4-((4-(三氟甲基)吡啶-2-基)氨甲酰基)苯基)-1H-吡唑-4-甲酰胺(186mg),收率43%,1H NMR(500 MHz,CDCl3)δ9.15(s,1H),8.72(s,1H),8.48(d,J=5.1 Hz,1H),8.05(d,J=8.3 Hz,2H),7.76(d,J=8.2 Hz,2H),6.61(d,J=8.4 Hz,1H),5.51(s,2H),5.40–5.20(brs,2H),4.30(dd,J=13.3,6.6 Hz,1H),1.52(d,J=6.6 Hz,6H).LC-MS(ESI-MS):433[M+H]+。
实施例4:5-氨基-1-异丙基-3-(4-(吡啶-2-基氨基甲酰基)苯基)-1H-吡唑-4-甲酰胺(004)的制备
参考实施例3的合成路线和方法,把4-(4,4,5,5-四甲基-1,3,2-二氧硼杂烷-2-基)-N-(4-(三氟甲基)吡啶-2-基)苯甲酰胺替换为N-(吡啶-2-基)-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂烷-2-基)苯甲酰胺,合成得到目标化合物5-氨基-1-异丙基-3-(4-(吡啶-2-基氨基甲酰基)苯基)-1H-吡唑-4-甲酰胺(110mg),1H NMR(500MHz,CDCl3)δ8.70(s,1H),8.40(d,J=8.5 Hz,1H),8.32(d,J=4.1 Hz,1H),8.03(d,J=8.4 Hz,2H),7.82–7.76(m,1H),7.74(d,J=8.2 Hz,2H),7.13–7.08(m,1H),5.43(s,2H),5.30(brs,2H),4.29(dd,J=13.2,6.6 Hz,1H),1.52(d,J=6.6 Hz,6H).LC-MS(ESI-MS):365[M+H]+。
实施例5:3-氨基-4-环戊基-1-(4-((2-甲氧基苯甲酰胺基)甲基)苯基)-1H-吡咯-2-羧酰胺(005)的制备
步骤1,将2-环戊基乙腈(1.1g)溶解于50mL无水四氢呋喃中,在氮气保护下降温至-78℃,滴加LDA溶液(5mL,2M in THF),滴完之后继续反应15分钟,然后缓慢滴加甲酸乙酯(0.81g)的四氢呋喃(5mL)溶液;滴加完毕之后保温反应1小时,然后自然升温至室温并反应过夜。加水淬灭反应,然后用2N盐酸水溶液调溶液pH约为3,用乙酸乙酯萃取,分离有机相用饱和食盐水洗涤,无水硫酸钠干燥,过滤,减压浓缩所得残留物经硅胶柱层析纯化得到油状产物2-环戊基-3-氧代丙烷腈(0.8g),收率58%。
步骤2,将2-(4-氨基苄基)异吲哚啉-1,3-二酮(1.26g)溶解于20mL无水四氢呋喃中,加入溴乙氰(0.78g)和三乙胺(1.5mL),加热至回流反应约12小时。TLC检测反应完成后降温至室温,加入乙酸乙酯和水萃取,分离有机相用饱和食盐水洗涤,无水硫酸钠干燥,过滤,减压浓缩所得残留物经硅胶柱层析纯化得到固体产物2-((4-((1,3-二氧代异吲哚-2-基)甲基)苯基)氨基)乙腈(1.18g),收率81%。
步骤3,将2-环戊基-3-氧代丙烷腈(0.5g)和2-((4-((1,3-二氧代异吲哚-2-基)甲基)苯基)氨基)乙腈(0.87g)溶解于15mL甲苯中,加入对甲苯磺酸(100mg),加热至回流反应过夜,TLC监测反应完全后降至室温,减压浓缩除去大部分溶剂,加入乙酸乙酯和水萃取,分离有机层用饱和食盐水洗涤,无水硫酸钠干燥,过滤,减压浓缩所得残留物经硅胶柱层析纯化得到固体产物(Z)-3-((氰甲基)(4-((1,3-二氧代异吲哚-2-基)甲基)苯基)氨基)-2-环戊基丙烯腈(0.77g),收率63%。
步骤4,将(Z)-3-((氰甲基)(4-((1,3-二氧代异吲哚-2-基)甲基)苯基)氨基)-2-环戊基丙烯腈(0.62g)溶解于10mL叔丁醇中,加入叔丁醇钾(0.35g),加热至回流反应约2小时,TLC检测反应完成,降温至室温,然后加入10mL 2N盐酸并搅拌10分钟,然后用乙酸乙酯萃取,分离有机层用饱和食盐水洗涤,无水硫酸钠干燥,过滤,减压浓缩所得残留物经硅胶柱层析纯化得到固体产物3-氨基-4-环戊基-1-(4-(((1,3-二氧异吲哚-2-基)甲基)苯基)-1H-吡咯-2-碳腈(0.37g),收率60%。
步骤5,称取3-氨基-4-环戊基-1-(4-(((1,3-二氧异吲哚-2-基)甲基)苯基)-1H-吡咯-2-碳腈(0.35g),加入三氟乙酸(3mL),搅拌下滴加浓硫酸(0.2mL),加热至60℃搅拌反应过夜,TLC检测反应完毕,降温并置于冰浴中,加入水并小心加入碳酸钠固体搅拌中和至溶液呈弱碱性,用乙酸乙酯萃取,分离乙酸乙酯层用饱和食盐水洗涤,然后无水硫酸钠干燥,过滤,减压浓缩所得残留物经硅胶柱层析纯化得到固体产物3-氨基-4-环戊基-1-(4-(((1,3-二氧代异吲哚-2-基)甲基)苯基)-1H-吡咯-2-羧酰胺(0.28g),收率78%。
步骤6,将3-氨基-4-环戊基-1-(4-(((1,3-二氧代异吲哚-2-基)甲基)苯基)-1H-吡咯-2-羧酰胺(0.27g)溶解于5mL乙醇中,加入水合肼(0.15mL),加热至回流反应2小时,TLC监测反应完毕,降至室温,用乙酸乙酯和水萃取,分离有机层用饱和食盐水洗涤,无水硫酸钠干燥,过滤,减压浓缩所得残留物经硅胶柱层析纯化得到固体产物3-氨基-1-(4-(氨基甲基)苯基)-4-环戊基-1H-吡咯-2-羧酰胺(0.16g),收率85%。
步骤7,将3-氨基-1-(4-(氨基甲基)苯基)-4-环戊基-1H-吡咯-2-羧酰胺(0.12g)和2-甲氧基苯甲酸(80mg)溶解于3mL无水DMF中,加入HATU(0.3g)和DMAP(5mg),在室温下搅拌反应约6小时,TLC监测反应完成,用乙酸乙酯和水萃取,分离有机层用饱和食盐水洗涤,无水硫酸钠干燥,过滤,减压浓缩所得残留物经硅胶柱层析纯化得到固体产物3-氨基-4-环戊基-1-(4-((2-甲氧基苯甲酰胺基)甲基)苯基)-1H-吡咯-2-羧酰胺(0.13g),收率75%,LC-MS(ESI-MS):433[M+H]+。
参考上面实施例的合成方法,可以用相似的合成路线和方法合成得到如下化合物:
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实施例75:BTK WT&BTK C481S激酶活性测试
1.化合物配制
将表1所示受试化合物溶解在100%DMSO中,配制成10mM储存液,于氮气柜避光保存。
2.激酶反应过程
(1)配制1×Kinase buffer。
(2)化合物浓度梯度的配制:受试化合物测试起始浓度为1000nM,在384source板中稀释成100倍终浓度的100%DMSO溶液,5倍稀释,7个浓度,单孔检测。使用分液器Echo550向目的板384-well-plate转移250nl 100倍终浓度的化合物。阳性和阴性对照孔加入250nl DMSO。
(3)用1×Kinase buffer配制2.5倍终浓度的激酶溶液。
(4)在化合物孔和阳性对照孔分别加10μl的2.5倍终浓度的激酶溶液;在阴性对照孔中加10μl的1×Kinase buffer。
(5)1000rpm离心30秒,反应板振荡混匀后室温孵育10分钟。
(6)用1×Kinase buffer配制5/3倍终浓度的ATP和Kinase substrate 2的混合溶液。
(7)加入15μl的5/3倍终浓度的ATP和底物的混合溶液,起始反应。
(8)将384孔板1000rpm离心30秒,振荡混匀后室温孵育30min。
(9)加入30μl终止检测液停止激酶反应,1000rpm离心30秒,振荡混匀。
(10)用Caliper EZ Reader读取转化率。
(11)拟合曲线计算IC50。结果见表1。
实施例76:肿瘤细胞增殖抑制活性测试
通过测定化合物对OCI-LY10和Mino细胞增殖的抑制作用,检测化合物对抗肿瘤药效。OCI-LY10和Mino细胞培养于含10%胎牛血清的RPMI-1640培养基中。消化细胞,将细胞按OCI-LY10和Mino 10000/孔的细胞浓度接种于96孔板,37℃,5%CO2孵育过夜。96孔板中加入不同浓度(1000nM,4倍稀释,8个浓度)的化合物于37℃,5%CO2孵育72小时后每孔加入20uL MTS。孵育2h后,每孔加入25μl10%SDS终止反应。用酶标仪测量490nm和650nm处的吸收。用GraphPad Prism 5.0计算IC50。结果见表1。
表1化合物的激酶和肿瘤细胞增殖抑制活性数据
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+:IC50<3nM;++:3nM<IC50<30nM;+++:30nM<IC50<300nM;++++:300nM<IC50
表1的结果表明,本发明的化合物对BTK WT(野生型)和BTK C481S(突变型)均有较强的抑制作用;同时,本发明的化合物还能抑制OCI-LY10和Mino肿瘤细胞的增殖,具有抗肿瘤活性。
实施例77:化合物12、14、21、25抑制B细胞活化
实验步骤:
1.采用肝素钠真空采血管采集人全血;
2.每孔90微升加入到96孔板中,37℃,5%CO2培养箱中孵育30min;
3.每孔加入不同浓度化合物,37℃,5%CO2培养箱中孵育60min;
4.对照组外每孔加入10uL anti-IgM,37℃,5%CO2培养箱中孵育16h;
5.每孔加入anti-CD19和anti-CD69流式抗体各5微升,常温染色30min;
6.每孔加入红细胞裂解液,破除红细胞;
7.流式上机检测CD19&CD69双阳性细胞比例,并计算IC50。
表2化合物B细胞活化活性
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+:IC50<3nM;++:3nM<IC50<30nM;+++:30nM<IC50<300nM;++++:300nM<IC50
表2的结果表明,本发明的化合物可有效抑制B细胞活化,可用于B细胞异常相关的自身免疫***疾病和B细胞增殖性异常疾病的治疗。
实施例78:使用化合物治疗类风湿性关节炎
在Balb/c小鼠中,通过给予抗胶原蛋白抗体和脂多糖诱导关节炎(Nandakumar等,Am.J.Pathol.2003,163:1827-1837)。
具体方法如下:在第0天,在雌性Balb/c小鼠静脉内注射100mg/kg抗II型胶原蛋白的Chemico mAb合剂,在第1天,腹膜内注射1.25mg/kg脂多糖。在第2天至12天,按10mg/kg的化合物给药,每天口服给药1次。第13天腹腔麻醉后,股动脉取血4ml左右,3000r/min离心20min,取血清使用试剂盒检测IL-1β,同时观测相关组织样本。
Claims (12)
1.一种化合物,其特征在于,具有通式IIIa所示的结构:
或其药学上可接受的盐;其中:
环A选自以下杂环结构:
Y1、Y2独自选自CR7、N;
m选自0、1、2、3、4;
n选自0、1、2;
R1选自:H,D,卤素,羟基,氨基,氰基,羧基,C1-C6烷基,C1-C6烷氧基,卤代C1-C6烷基,卤代C1-C6烷氧基,C3-C5环烷基;
R2选自:C1-C10烷基,C3-C7环烷基,四元至七元杂环基,C3-C7环烯基,C6-C10芳基,五元至十元杂芳基;
上述R2可进一步被1-5个RX取代,每个RX独立的选自:D,C1-C3烷基,卤素,氨基,硝基,羟基,氧代,C1-C3烷氧基,卤代C1-C3烷基,C1-C3羟烷基,-C(O)C1-C3烷基,-C(O)O-C1-C3烷基,-C1-C3烷氨基,卤代C1-C3羟烷基,卤代C1-C3烷氨基,C3-C5环烷基,四元至六元杂环烷基;
R3选自:H,D,卤素,羟基,氨基,氰基,羧基,C1-C6烷基,C1-C6烷氧基,卤代C1-C6烷基,卤代C1-C6烷氧基,C3-C5环烷基;
R12,R14,R15,R16,R17各自独立地选自:H,D,C1-C6烷基,C2-C6烯基,C2-C6炔基,C3~C5环烷基,C3-C7环烯基,四元至七元杂环基,C6-C10芳基,五元至十元杂芳基,卤素,硝基,氰基,ORa,SRa,NH(CH2)Ra,C(O)Ra,S(O)Ra,SO2Ra,C(O)ORa,OC(O)Ra,NRbRc,C(O)N(Rb)Rc,N(Rb)C(O)Rc,-P(O)RbRc;所述的烷基,烯基,炔基,环烷基,环烯基,杂环基,芳基或者杂芳基可进一步被1或者多个Rd取代;
Ra,Rb,Rc各自独立地选自:H,D;
Rd选自:H,D;
R7选自:H,D,卤素,氰基,C1-C3烷基,卤代C1-C3烷基,C3-C5环烷基;
当环A选自(I)时,R2选自C6-C10芳基,五元至十元杂芳基;
当环A选自(J)时,R2选自C6-C10芳基,五元至十元杂芳基;
当环A选自(A)时,R2不为取代或者未取代的C3-C7环烷基,取代或者未取代的三元至七元杂环基,取代或者未取代的C3-C7环烯基。
2.根据权利要求1所述的化合物,其特征在于,具有通式IIIa所示的结构:
或其药学上可接受的盐;其中:
IIIa的环A选自环(A)(C)(D)(F)(G)(I)(J)(P)(Q)之一;
当结构通式选自IIIa,且环A选自(A)(C)(D)(F)(G)之一时,R2不为取代或者未取代的C3-C7环烷基,取代或者未取代的三元至七元杂环基,取代或者未取代的C3-C7环烯基;
当结构通式选自IIIa,且环A选自(I)(J)之一时,R2选自C6-C10芳基,五元至十元杂芳基。
3.根据权利要求1述的化合物,其特征在于,具有通式IVa所示的结构:
或其药学上可接受的盐;其中:
IVa的环A选自环(A)(Q)(I)(J)之一;
当结构通式选自IVa且环A选自(A)时,R2不为取代或者未取代的C3-C7环烷基,取代或者未取代的三元至七元杂环基,取代或者未取代的C3-C7环烯基;
当结构通式选自IVa且环A选自(I)(J)时,R2选自C6-C10芳基,五元至十元杂芳基。
4.根据权利要求1述的化合物,其特征在于,具有通式Va~Vd所示的结构:
或其药学上可接受的盐;
其中:
R1选自:H,D,卤素,羟基,氨基,氰基,羧基,-OMe,-OEt,-OiPr,C1-C3烷基,卤代C1-C3烷基,-OCF3,3元到5元环烷基;
R2选自:C1-C3烷基,苯基,五元至七元杂芳基,其中烷基、苯基、杂芳基可被一个或多个取代基进一步取代,取代基选自:D,C1-C3烷基,卤素,氨基,硝基,羟基,氧代,C1-C3烷氧基,卤代C1-C3烷基,C1-C3羟烷基,-C(O)C1-C3烷基,-C(O)O-C1-C3烷基,-C1-C3烷氨基,卤代C1-C3羟烷基,卤代C1-C3烷氨基,C3-C5环烷基,四元至六元杂环烷基;
当结构选自Vb或Vc时,R2选自苯基,五元至七元杂芳基。
5.根据权利要求1述的化合物,其特征在于,具有通式VIe所示的结构:
或其药学上可接受的盐;
其中,
R1选自:H,D,卤素,羟基,氨基,氰基,羧基,-OMe,-OEt,-OiPr,C1-C3烷基,卤代C1-C3烷基,OCF3,3元到5元环烷基;
R2选自:
6.一种化合物,其特征在于,选自下列化合物:
或其药学上可接受的盐。
7.一种药物组合物,其特征在于,包括如权利要求1至6中任意一项所述的化合物中的一种或多种。
8.一种如权利要求1至6中任意一项所述的化合物在制备单独治疗从布鲁顿酪氨酸激酶活性的抑制中获益的疾病、障碍或病症药物中的应用。
9.如权利要求8所述的应用,其特征在于,所述的疾病、障碍或病症为从抑制布鲁顿酪氨酸激酶突变中获益的疾病、障碍或病症。
10.如权利要求8所述的应用,其特征在于,所述疾病选自B细胞增殖性疾病和自身免疫性疾病。
11.如权利要求10所述的应用,其特征在于,所述B细胞增殖性疾病选自弥漫性大B细胞淋巴瘤、滤泡性淋巴瘤、慢性淋巴细胞淋巴瘤、慢性淋巴细胞白血病、B细胞前淋巴细胞性白血病、淋巴浆细胞淋巴瘤/瓦尔登斯特伦巨球蛋白血症、脾边缘区淋巴瘤、浆细胞瘤、结外边缘区B细胞淋巴瘤、***边缘区B细胞淋巴瘤、外套细胞淋巴瘤、纵膈大B细胞淋巴瘤、血管内大B细胞淋巴瘤、原发性渗出性淋巴瘤、伯基特淋巴瘤/白血病或淋巴瘤样肉芽肿病。
12.如权利要求10所述的应用,其特征在于,所述自身免疫性疾病选自炎性肠病、关节炎、狼疮、斯蒂尔病、糖尿病、重症肌无力症、桥本甲状腺炎奥德甲状腺炎、格雷夫斯氏病、类风湿性关节炎综合征、多发性硬化症、传染性神经元炎、急性播散性脑脊髓炎、阿狄森病、视性眼阵挛-肌阵挛综合征、强制性脊椎炎、抗磷脂抗体综合征、再生障碍性贫血、自身免疫性肝炎、乳糜泻、古德帕斯彻综合征、免疫性血小板减少性紫癜、视神经炎、原发性胆汁性肝硬化、莱特尔综合征、高安动脉炎、颞动脉炎、温型自身免疫性溶血性贫血、韦格纳肉芽肿病、银屑病、全身脱毛、贝赫切特病、慢性疲劳、家族性自主神经功能异常、子宫内膜异位、间质性膀胱炎、神经肌强直、硬皮病或外阴痛和慢性移植物抗宿主病。
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Citations (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2014173289A1 (en) * | 2013-04-25 | 2014-10-30 | Beigene, Ltd. | Fused heterocyclic compounds as protein kinase inhibitors |
CN104603124A (zh) * | 2012-08-10 | 2015-05-06 | 勃林格殷格翰国际有限公司 | 用作布鲁顿酪氨酸激酶(btk)抑制剂的杂芳族化合物 |
WO2016019237A2 (en) * | 2014-07-31 | 2016-02-04 | Pharmacyclics Llc | Inhibitors of bruton's tyrosine kinase |
CN105451741A (zh) * | 2013-08-06 | 2016-03-30 | 福建海西新药创制有限公司 | 布鲁顿酪氨酸激酶的抑制剂 |
CN108431007A (zh) * | 2015-09-16 | 2018-08-21 | 洛克索肿瘤学股份有限公司 | 用于治疗癌症的作为btk抑制剂的吡唑并嘧啶衍生物 |
CN110483521A (zh) * | 2018-05-14 | 2019-11-22 | 杭州和正医药有限公司 | 一种可逆共价布鲁顿酪氨酸激酶抑制剂、药物组合物及其应用 |
CN111018865A (zh) * | 2019-10-17 | 2020-04-17 | 山东大学 | 1-取代苄基吡唑并嘧啶衍生物及其制备方法与应用 |
WO2020150681A1 (en) * | 2019-01-18 | 2020-07-23 | Xibin Liao | Bruton's tyrosine kinase inhibitors |
CN111454268A (zh) * | 2019-01-18 | 2020-07-28 | 明慧医药(上海)有限公司 | 作为布鲁顿酪氨酸激酶抑制剂的环状分子 |
CN114075190A (zh) * | 2020-08-20 | 2022-02-22 | 北京诺诚健华医药科技有限公司 | 杂环类btk抑制剂 |
CN115443277A (zh) * | 2020-03-12 | 2022-12-06 | 重庆复尚源创医药技术有限公司 | 作为激酶抑制剂的化合物 |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP6458018B2 (ja) * | 2013-07-02 | 2019-01-23 | ファーマサイクリックス エルエルシー | キナーゼ阻害剤としてのプリノン化合物 |
EP3585789A1 (en) * | 2017-02-24 | 2020-01-01 | Gilead Sciences, Inc. | Inhibitors of bruton's tyrosine kinase |
-
2020
- 2020-11-28 CN CN202011365603.3A patent/CN114573586B/zh active Active
Patent Citations (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104603124A (zh) * | 2012-08-10 | 2015-05-06 | 勃林格殷格翰国际有限公司 | 用作布鲁顿酪氨酸激酶(btk)抑制剂的杂芳族化合物 |
WO2014173289A1 (en) * | 2013-04-25 | 2014-10-30 | Beigene, Ltd. | Fused heterocyclic compounds as protein kinase inhibitors |
CN105451741A (zh) * | 2013-08-06 | 2016-03-30 | 福建海西新药创制有限公司 | 布鲁顿酪氨酸激酶的抑制剂 |
WO2016019237A2 (en) * | 2014-07-31 | 2016-02-04 | Pharmacyclics Llc | Inhibitors of bruton's tyrosine kinase |
CN108431007A (zh) * | 2015-09-16 | 2018-08-21 | 洛克索肿瘤学股份有限公司 | 用于治疗癌症的作为btk抑制剂的吡唑并嘧啶衍生物 |
CN110483521A (zh) * | 2018-05-14 | 2019-11-22 | 杭州和正医药有限公司 | 一种可逆共价布鲁顿酪氨酸激酶抑制剂、药物组合物及其应用 |
WO2020150681A1 (en) * | 2019-01-18 | 2020-07-23 | Xibin Liao | Bruton's tyrosine kinase inhibitors |
CN111454268A (zh) * | 2019-01-18 | 2020-07-28 | 明慧医药(上海)有限公司 | 作为布鲁顿酪氨酸激酶抑制剂的环状分子 |
CN111018865A (zh) * | 2019-10-17 | 2020-04-17 | 山东大学 | 1-取代苄基吡唑并嘧啶衍生物及其制备方法与应用 |
CN115443277A (zh) * | 2020-03-12 | 2022-12-06 | 重庆复尚源创医药技术有限公司 | 作为激酶抑制剂的化合物 |
CN114075190A (zh) * | 2020-08-20 | 2022-02-22 | 北京诺诚健华医药科技有限公司 | 杂环类btk抑制剂 |
Non-Patent Citations (1)
Title |
---|
布鲁顿酪氨酸激酶及其抑制剂研究进展;张鹏应等;《上海医药》;20200831;第41卷(第15期);第8-12、70页 * |
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