TW201712017A - Inhibitors of the TEC kinase enzyme family - Google Patents
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本發明係關於一種新穎蛋白激酶抑制劑家族、含有其之藥物組合物及該等抑制劑治療或預防與激酶功能相關之疾病、病症及病狀的用途。 The present invention relates to a novel family of protein kinase inhibitors, pharmaceutical compositions containing the same, and the use of such inhibitors to treat or prevent diseases, disorders and conditions associated with kinase function.
蛋白質激酶為真核細胞中之一大群細胞內及跨膜信號傳導蛋白質(Manning G.等人，(2002)Science,298：1912-1934)。此等酶負責將末端(γ)磷酸自ATP轉移至標靶蛋白質之特定胺基酸殘基。標靶蛋白質中之特定胺基酸殘基之磷酸化可調節其活性，導致細胞信號傳導及代謝之深遠變化。蛋白質激酶可見於細胞膜、胞液及細胞器(諸如細胞核)中且負責介導多種細胞功能，包括代謝、細胞生長及分化、細胞信號傳導、免疫反應調節及細胞死亡。絲胺酸激酶特異性使標靶蛋白質中之絲胺酸或酥胺酸殘基磷酸化。類似地，酪胺酸激酶(包括酪胺酸受體激酶)使標靶蛋白質中之酪胺酸殘基磷酸化。酪胺酸激酶家族包括：TEC、Src、Abl、Jak、Csk、Fak、Syk、Fer、Ack，且受體酪胺酸激酶亞家族包括ErbB、FGFR、VEGFR、RET及Eph。受體酪胺酸激酶超家族之子類I由ErbB受體組成且包括四個成員：ErbB1(亦稱為表皮生長因數受體(EGFR))、ErbB2、ErbB3及ErbB4。 Protein kinases are a large group of intracellular and transmembrane signaling proteins in eukaryotic cells (Manning G. et al. (2002) Science, 298: 1912-1934). These enzymes are responsible for the transfer of terminal (gamma) phosphate from ATP to a particular amino acid residue of the target protein. Phosphorylation of specific amino acid residues in the target protein modulates its activity, resulting in profound changes in cellular signaling and metabolism. Protein kinases are found in cell membranes, cytosols, and organelles (such as the nucleus) and are responsible for mediating a variety of cellular functions, including metabolism, cell growth and differentiation, cell signaling, immune response regulation, and cell death. Serine kinase specificity phosphorylates serine or leucine residues in the target protein. Similarly, tyrosine kinases, including tyrosine receptor kinases, phosphorylate tyrosine residues in target proteins. The tyrosine kinase family includes: TEC, Src, Abl, Jak, Csk, Fak, Syk, Fer, Ack, and the receptor tyrosine kinase subfamily includes ErbB, FGFR, VEGFR, RET, and Eph. Subclass I of the receptor tyrosine kinase superfamily consists of the ErbB receptor and includes four members: ErbB1 (also known as epidermal growth factor receptor (EGFR)), ErbB2, ErbB3 and ErbB4.
激酶對與健康及疾病相關之關鍵生物過程加以控制。此外，各種蛋白質激酶之异常激活或過量表現與特徵為异常細胞反應、良性及惡性增殖之多種疾病及病症以及由免疫系統之不適當激活引起之疾病的機制有關(Kyttaris VC,Drug Des Devel Ther,2012,6：245-50及Fabbro D.等人Methods Mol Biol,2012,795：1-34)。因此，選擇激酶或激酶家族之抑制劑預期可用於治療癌症、血管疾病、疼痛、神經疾病、自身免疫疾病及發炎性病狀，包括(但不限於)：實體腫瘤、血液惡性腫瘤、血栓、中風、阿爾茨海 默氏病(Alzheimer's disease)、關節炎、休格蘭氏症候群(Sjogren's syndrome)、移植物抗宿主病、紅斑狼瘡、牛皮癬、結腸炎、迴腸炎、多發性硬化、葡萄膜炎、冠狀動脉血管病變、全身性硬化、動脉粥樣硬化、哮喘、移植排斥、過敏、皮肌炎、天疱瘡及其類似疾病。 Kinases control key biological processes associated with health and disease. In addition, abnormal activation or overexpression of various protein kinases is associated with a variety of diseases and conditions characterized by abnormal cellular responses, benign and malignant proliferation, and mechanisms of disease caused by inappropriate activation of the immune system (Kyttaris VC, Drug Des Devel Ther, 2012, 6: 245-50 and Fabbro D. et al. Methods Mol Biol, 2012, 795: 1-34). Thus, inhibitors of selected kinases or kinase families are expected to be useful in the treatment of cancer, vascular disease, pain, neurological diseases, autoimmune diseases, and inflammatory conditions including, but not limited to, solid tumors, hematological malignancies, thrombosis, stroke, Alzhai Alzheimer's disease, arthritis, Sjogren's syndrome, graft versus host disease, lupus erythematosus, psoriasis, colitis, ileitis, multiple sclerosis, uveitis, coronary vascular disease , systemic sclerosis, atherosclerosis, asthma, transplant rejection, allergies, dermatomyositis, pemphigus and similar diseases.
Tec激酶為主要、但不僅僅表現於造血來源之細胞中的非受體酪胺酸激酶之家族(Bradshaw JM.Cell Signal.2010,22：1175-84)。Tec家族包括TEC、布魯頓氏酪胺酸激酶(Bruton's tyrosine kinase，BTK)、誘導型T細胞激酶(ITK)、靜止淋巴細胞激酶(RLK/TXK)及骨髓表現之激酶(BMX/ETK)。 Tec kinase is a family of non-receptor tyrosine kinases that are predominant, but not exclusively, in cells of hematopoietic origin (Bradshaw JM. Cell Signal. 2010, 22: 1175-84). The Tec family includes TEC, Bruton's tyrosine kinase (BTK), inducible T cell kinase (ITK), resting lymphocyte kinase (RLK/TXK), and bone marrow-expressing kinase (BMX/ETK).
BTK在B細胞發育及激活之B細胞受體信號傳導及調節中為重要的(Khan,W.N.等人Immunity,1995,3：283-299及Satterthwaite AB等人Immunol.Rev.2000,175：120-127)。另外，BTK歸因於免疫複合物沈積而在Fc受體信號傳導中為重要的(Ellmeier W..等人FEBS J.2011,278：1990-2000)。人類中編碼BTK之基因之突變導致X連鎖無γ球蛋白血症，其特徵為减弱之免疫功能，包括削弱之B細胞成熟、降低之免疫球蛋白及周邊B細胞水準、减弱之T細胞獨立性免疫反應(Rosen FS等人，N Engl.J.Med.,1995,333：431-440；及Lindvall JM等人Immunol.Rev.2005,203：200-215)。BTK藉由Src家族激酶激活且使PLC γ磷酸化，對B細胞功能及存活產生影響。另外，BTK對肥大細胞、巨噬細胞及中性粒細胞之細胞功能為重要的，表明BTK抑制將有效治療由此等及相關細胞介導之疾病，包括發炎、骨病症及過敏性疾病(Kawakami Y.等人，J Leukoc Biol.1999；65(3)：286-90)。 BTK is important in B cell receptor signaling and regulation in B cell development and activation (Khan, WN et al. Immunity, 1995, 3: 283-299 and Satterthwaite AB et al. Immunol. Rev. 2000, 175: 120- 127). In addition, BTK is important in Fc receptor signaling due to deposition of immune complexes (Ellmeier W.. et al. FEBS J. 2011, 278: 1990-2000). Mutations in the human gene encoding BTK lead to X-linked gamma globulinemia, characterized by attenuated immune function, including impaired B cell maturation, reduced immunoglobulin and peripheral B cell levels, and weakened T cell independence. Immune response (Rosen FS et al, N Engl. J. Med., 1995, 333: 431-440; and Lindvall JM et al. Immunol. Rev. 2005, 203: 200-215). BTK is activated by Src family kinases and phosphorylates PLC γ, which has an effect on B cell function and survival. In addition, BTK is important for the cellular functions of mast cells, macrophages, and neutrophils, suggesting that BTK inhibition will effectively treat diseases such as inflammation, bone disorders, and allergic diseases, including inflammatory, bone, and allergic diseases (Kawakami). Y. et al., J Leukoc Biol. 1999; 65(3): 286-90).
BTK抑制在淋巴瘤細胞之存活中亦為重要的(Herman SEM.Blood,2011,117：6287-6289)，表明BTK抑制可適用於治療淋巴瘤及其他癌症(Uckun FM,Int Rev Immunol.2008；27(1-2)：43-69)。實體腫瘤內之基質細胞包括腫瘤相關之淋巴細胞及骨髓細胞表現TEC家族激酶、尤其BTK(Stiff A.等人Cancer Res.76；2125-2136)。調節性B及T淋巴細胞、骨髓衍生之抑制細胞及組織駐留巨噬細胞、樹突狀細胞及肥大細胞可提供基質支撑且减少針對經轉化細胞之先天性及適應性免疫監督。因此，TEC家族激酶、尤其 BTK之抑制預期有益於治療實體腫瘤。因此，BTK及相關激酶之抑制劑作為抗炎劑及抗癌劑受到極大關注。BTK對於血小板功能及血栓形成亦為重要的，表明BTK選擇性抑制劑可證實為適用之抗血栓劑(Liu J.Blood,2006,108：2596-603)。 BTK inhibition is also important in the survival of lymphoma cells (Herman SEM. Blood, 2011, 117: 6287-6289), indicating that BTK inhibition may be useful in the treatment of lymphoma and other cancers (Uckun FM, Int Rev Immunol. 2008; 27(1-2): 43-69). Stromal cells within solid tumors, including tumor-associated lymphocytes and bone marrow cells, exhibit TEC family kinases, particularly BTK (Stiff A. et al. Cancer Res. 76; 2125-2136). Regulatory B and T lymphocytes, bone marrow-derived suppressor cells and tissue-resident macrophages, dendritic cells, and mast cells provide matrix support and reduce innate and adaptive immune surveillance against transformed cells. Therefore, TEC family kinases, especially Inhibition of BTK is expected to be beneficial for the treatment of solid tumors. Therefore, inhibitors of BTK and related kinases have received great attention as anti-inflammatory agents and anti-cancer agents. BTK is also important for platelet function and thrombosis, suggesting that BTK selective inhibitors can be demonstrated to be useful antithrombotic agents (Liu J. Blood, 2006, 108: 2596-603).
另外，BTK表現於HIV感染之T細胞中，且用BTK抑制劑治療使受感染細胞對細胞雕亡死亡敏感且導致病毒產生减少(Guendel I等人J Neurovirol.2015；21：257-75)。因此，BTK抑制劑可適用於治療HIV-AIDS及其他病毒感染。 In addition, BTK is expressed in HIV-infected T cells, and treatment with BTK inhibitors sensitizes infected cells to cell death and death and results in reduced virus production (Guendel I et al. J Neurovirol. 2015; 21: 257-75). Therefore, BTK inhibitors are useful for the treatment of HIV-AIDS and other viral infections.
BMX，對發炎、心血管疾病及癌症有一定作用之另一Tec家族成員(Cenni B.等人Int Rev Immunol.2012,31：166-173)對於膠質母細胞瘤幹細胞之自我更新及潜力亦為重要的(Guryanova OA等人Cancer Cell Cancer Cell 2011,19：498-511)。因此，BMX抑制劑可適用於治療各種疾病，包括癌症、心血管疾病及發炎。 BMX, another member of the Tec family that contributes to inflammation, cardiovascular disease, and cancer (Cenni B. et al. Int Rev Immunol. 2012, 31: 166-173) also has self-renewal and potential for glioblastoma stem cells. Important (Guryanova OA et al. Cancer Cell Cancer Cell 2011, 19: 498-511). Therefore, BMX inhibitors are useful in the treatment of a variety of diseases including cancer, cardiovascular disease and inflammation.
本發明係關於一種新穎激酶抑制劑家族。已發現此類別之化合物針對TEC激酶家族之成員、尤其BTK具有抑制活性。 This invention relates to a family of novel kinase inhibitors. Compounds of this class have been found to have inhibitory activity against members of the TEC kinase family, particularly BTK.
本發明之一個態樣係針對一種式I化合物：
或其醫藥學上可接受之鹽、溶劑合物、鹽之溶劑合物、立體异構體、互變异構體、同位素、前藥、複合物或生物活性代謝物，其中X1及X2獨立地選自氫及鹵素；m為整數0至4；
m’為整數0至4；R係選自氫及甲基；A係選自：1)
虛線獨立地為視情况存在之鍵；R'及R"獨立地選自氫、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環基、經取代或未經取代之芳基、經取代或未經取代之雜芳基、經取代或未經取代之芳烷基、或經取代或未經取代之雜芳烷基；Z1及Z3獨立地選自C或N；Z2係選自N或CR1；其中R1係選自氫、鹵素、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環基、經取代或未經取代之芳基、經取代或未經取代之雜芳基、經取代或未經取代之芳烷基、或經取代或未經取代之雜芳烷基；且其限制條件為Z1、Z2及Z3中之至少一者且不超過兩者同時為N；或2)
其中虛線獨立地為視情况存在之鍵；Z4、Z5及Z7獨立地選自C或N；Z6係選自N、C(O)或CR1；X係選自N或CH；其限制條件為Z4、Z5、Z6及Z7中之至少一者且不超過兩者同時為N；
且R1係選自由以下組成之群：氫、鹵素、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環基、經取代或未經取代之芳基、經取代或未經取代之雜芳基、經取代或未經取代之芳烷基、及經取代或未經取代之雜芳烷基；L獨立地選自經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環基、經取代或未經取代之芳基、經取代或未經取代之雜芳基、經取代或未經取代之芳烷基、經取代或未經取代之雜芳烷基，
其中B為經取代或未經取代之3至8員含氮雜環；B’為經取代或未經取代之3至8員環烷基環；n為整數0至1；且R2係選自氫及C1-6烷基；E係選自由以下組成之群：
其中Ra、Rb及Rc獨立地選自氫、鹵素、-CN、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、或經取代或未經取代之雜環基；或Ra及Rb與其所連接之碳原子結合在一起形成3至8員經取代或未經取代之環烷基環或形成3至8員經取代或未經取代之雜環，且Rc如上選擇；
或Rb及Rc與其所連接之碳原子結合在一起形成3至8員經取代或未經取代之環烷基環或形成3至8員雜環，且Ra如上選擇；或Ra及Rb與其所連接之碳原子結合在一起形成參鍵，且Rc如上選擇；其中A-L-E為
在一個實施例中，式I化合物可僅僅為簡單式I化合物。 In one embodiment, the compound of formula I may be simply a compound of formula I.
本發明亦涵蓋為由式I表示之化合物的鹽之溶劑合物、立體异構體、互變异構體、同位素取代之變體、前藥、複合物或生物活性代謝物之式I化合物。因此，本發明之一個態樣係針對一種式I化合物：
或其醫藥學上可接受之鹽、溶劑合物、鹽之溶劑合物、立體异構體、互變异構體、同位素、前藥、複合物或生物活性代謝物，其中取代基A、L、E、R、X1、X2及m及m’全部如上定義。 Or a pharmaceutically acceptable salt, solvate, salt solvate, stereoisomer, tautomer, isotope, prodrug, complex or biologically active metabolite thereof, wherein the substituents A, L , E, R, X 1 , X 2 and m and m' are all as defined above.
一實施例包括式I化合物，其中A為
其中虛線獨立地為視情况存在之鍵；R'及R"獨立地選自氫、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環基、經 取代或未經取代之芳基、經取代或未經取代之雜芳基、經取代或未經取代之芳烷基、或經取代或未經取代之雜芳烷基；Z1及Z3獨立地選自C或N；Z2係選自N或CR1；其中R1係選自氫、鹵素、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環基、經取代或未經取代之芳基、經取代或未經取代之雜芳基、經取代或未經取代之芳烷基、或經取代或未經取代之雜芳烷基；且其限制條件為Z1、Z2及Z3中之至少一者且不超過兩者同時為N。 Wherein the dotted line is independently a bond which is optionally present; R' and R" are independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted Cycloalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group, substituted or unsubstituted aralkyl group, or substituted Or unsubstituted heteroarylalkyl; Z 1 and Z 3 are independently selected from C or N; Z 2 is selected from N or CR 1 ; wherein R 1 is selected from hydrogen, halogen, substituted or unsubstituted Alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or not a substituted heteroaryl group, a substituted or unsubstituted aralkyl group, or a substituted or unsubstituted heteroarylalkyl group; and the limitation is at least one of Z 1 , Z 2 and Z 3 and Not more than both are N.
本發明包括式I化合物，其中A係選自由以下組成之群：
其中R1係選自氫、鹵素、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環基、經取代或未經取代之芳基、經取代或未經取代之雜芳基、經取代或未經取代之芳烷基、或經取代或未經取代之雜芳烷基。 Wherein R 1 is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted A cyclyl, substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted aralkyl group, or a substituted or unsubstituted heteroaralkyl group.
在一替代性實施例中，本發明包括式I化合物，其中A為
在一替代性實施例中，本發明包括式I化合物，其中A為
在一替代性實施例中，本發明包括式I化合物，其中A為 且R1為氫。 In an alternative embodiment, the invention includes a compound of formula I, wherein A is And R 1 is hydrogen.
在一替代性實施例中，本發明包括式I化合物，其中A為且R1為氫。 In an alternative embodiment, the invention includes a compound of formula I, wherein A is And R 1 is hydrogen.
一實施例包括式I化合物，其中A為
其中虛線獨立地為視情况存在之鍵；Z4、Z5及Z7獨立地選自C或N；Z6係選自N、C(O)或CR1；X係選自N或CH；且R1係選自由以下組成之群：氫、鹵素、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環基、經取代或未經取代之芳基、經取代或未經取代之雜芳基、經取代或未經取代之芳烷基、及經取代或未經取代之雜芳烷基；其限制條件為Z4、Z5、Z6及Z7中之至少一者且不超過兩者同時為N。 Wherein the dotted line is independently a bond which is optionally present; Z 4 , Z 5 and Z 7 are independently selected from C or N; Z 6 is selected from N, C(O) or CR 1 ; X is selected from N or CH; And R 1 is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or Unsubstituted heterocyclic group, substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group, substituted or unsubstituted aralkyl group, and substituted or unsubstituted heteroaryl group An alkyl group; the limiting condition is at least one of Z 4 , Z 5 , Z 6 and Z 7 and not more than both.
本發明包括式I化合物，其中A係選自由以下組成之群：
其中R1係選自氫、鹵素、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環基、經取代或未經取代之芳基、經取代或未經取代之雜芳基、經取代或未經取代之芳烷基、或經取代或未經取代之雜芳烷基；X係選自N或CH。 Wherein R 1 is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted a cyclyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted aralkyl group, or a substituted or unsubstituted heteroaralkyl group; Selected from N or CH.
在一替代性實施例中，本發明包括式I化合物，其中A為
在一替代性實施例中，本發明包括式I化合物，其中A為
在一替代性實施例中，本發明包括式I化合物，其中A為且R1為氫。 In an alternative embodiment, the invention includes a compound of formula I, wherein A is And R 1 is hydrogen.
在一替代性實施例中，本發明包括式I化合物，其中A為 且R1為氫。 In an alternative embodiment, the invention includes a compound of formula I, wherein A is And R 1 is hydrogen.
在一替代性實施例中，本發明包括式I化合物，其中A為且X為N。 In an alternative embodiment, the invention includes a compound of formula I, wherein A is And X is N.
在一替代性實施例中，本發明包括式I化合物，其中A為 且X為CH。 In an alternative embodiment, the invention includes a compound of formula I, wherein A is And X is CH.
在一替代性實施例中，本發明包括式I化合物，其中A為
在一替代性實施例中，本發明包括式I化合物，其中R為甲基。 In an alternative embodiment, the invention includes a compound of formula I, wherein R is methyl.
在一替代性實施例中，本發明包括式I化合物，其中X1為F。 In an alternative embodiment, the present invention includes compounds of formula I, wherein X 1 is F.
在一替代性實施例中，本發明包括式I化合物，其中X1為F且m’=1。 In an alternative embodiment, the invention includes a compound of formula I, wherein X 1 is F and m'=1.
在一替代性實施例中，本發明包括式I化合物，其中X2為氫。 In an alternative embodiment, the invention includes a compound of formula I wherein X 2 is hydrogen.
在一實施例中，本發明包括式I化合物，其中R為甲基，X1為F，m’=1，且X2為氫。 In one embodiment, the invention includes a compound of formula I, wherein R is methyl, X 1 is F, m' = 1, and X 2 is hydrogen.
本發明包括式I化合物，其中L係選自： a) The invention includes a compound of formula I wherein L is selected from the group consisting of: a)
其中B為經取代或未經取代之3至8員含氮雜環；n為整數0至1；及 b) Wherein B is a substituted or unsubstituted 3 to 8 membered nitrogen-containing heterocyclic ring; n is an integer from 0 to 1; and b)
其中B’為經取代或未經取代之3至8員環烷基環；n為整數0至1；且R2係選自氫及C1-6烷基。 Wherein B' is a substituted or unsubstituted 3 to 8 membered cycloalkyl ring; n is an integer from 0 to 1; and R 2 is selected from hydrogen and C 1-6 alkyl.
在一實施例中，本發明包括式1化合物，其中L獨立地選自經取代或未經取代之C1-6烷基鏈、經取代或未經取代之2至6個原子之雜烷基鏈、經取代或未經取代之3至8員環烷基環、經取代或未經取代之3至8員雜環基環、經取代或未經取代之5、6及7員芳基環、經取代或未經取代之5、6及7員雜芳基環、經取代或未經取代之芳烷基、經取代或未經取代之雜芳烷基。 In one embodiment, the invention includes a compound of formula 1, wherein L is independently selected from substituted or unsubstituted C1-6 alkyl chain, substituted or unsubstituted heteroalkyl group of 2 to 6 atoms Chain, substituted or unsubstituted 3 to 8 membered cycloalkyl ring, substituted or unsubstituted 3 to 8 membered heterocyclyl ring, substituted or unsubstituted 5, 6 and 7 membered aryl ring , substituted or unsubstituted 5, 6 and 7 membered heteroaryl rings, substituted or unsubstituted aralkyl groups, substituted or unsubstituted heteroarylalkyl groups.
本發明包括式I化合物，其中L係選自經取代或未經取代之3至8員環烷基環、經取代或未經取代之3至8員雜環基環、C1-6烷基-(3至8員)雜環基環、C1-6烷基-(3至8員)環烷基環-N(R2)-或(3至8員)環烷基環-N(R2)-。 The invention includes a compound of formula I, wherein L is selected from substituted or unsubstituted 3 to 8 membered cycloalkyl rings, substituted or unsubstituted 3 to 8 membered heterocyclyl rings, C 1-6 alkyl - (3 to 8 membered) heterocyclyl ring, C 1-6 alkyl-(3 to 8 membered) cycloalkyl ring-N(R 2 )- or (3 to 8 membered) cycloalkyl ring-N ( R 2 )-.
本發明之一實施例包括式I化合物，其中L為：
其中B為經取代或未經取代之3至8員含氮雜環，且n為整數0至1。 Wherein B is a substituted or unsubstituted 3 to 8 membered nitrogen-containing heterocyclic ring, and n is an integer from 0 to 1.
本發明之另一實施例包括式I化合物，其中L為：
其中B’為經取代或未經取代之3至8員環烷基環；n為整數0至1，且R2係選自氫及C1-6烷基。 Wherein B' is a substituted or unsubstituted 3 to 8 membered cycloalkyl ring; n is an integer from 0 to 1, and R 2 is selected from hydrogen and C 1-6 alkyl.
本發明之一實施例包括式I化合物，其中L-E係選自由以下組成之群：
本發明之一實施例包括式I化合物，其中L-E係選自由以下組成之群：
本發明之一實施例包括式I化合物，其中L-E係選自由以下組成之群：
本發明之一實施例包括式I化合物，其中L-E係選自由以下組成之群：
一實施例包括式I化合物，其中E為-CN。 An embodiment comprises a compound of formula I, wherein E is -CN.
一實施例包括式I化合物，其中E係選自由以下組成之群：
一實施例包括式I化合物，其中E為。 An embodiment comprises a compound of formula I, wherein E is .
在本發明之一實施例中，L-E為
在一實施例中，本發明包括式I化合物，其中式I為式l-1：
其中A、L及E如上定義。 Wherein A, L and E are as defined above.
本發明之另一實施例包括式I-1化合物，
其中A係選自由以下組成之群：
其限制條件為R1為氫且X為N或CH；且L-E係選自由以下組成之群：
本發明之一實施例包括具有式II之化學結構之化合物，其中式II係選自包括以下之群：
或其醫藥學上可接受之鹽、溶劑合物、鹽之溶劑合物、立體异構體、互變异構體、同位素、前藥、複合物或生物活性代謝物，其中：X1及X2獨立地選自氫及鹵素；m為整數0至4；m’為整數0至4；R係選自氫及甲基；L係選自： a) Or a pharmaceutically acceptable salt, solvate, salt solvate, stereoisomer, tautomer, isotope, prodrug, complex or biologically active metabolite thereof, wherein: X 1 and X 2 is independently selected from the group consisting of hydrogen and halogen; m is an integer from 0 to 4; m' is an integer from 0 to 4; R is selected from hydrogen and methyl; and L is selected from: a)
其中B為經取代或未經取代之3至8員含氮雜環；n為整數0至1；及 b) Wherein B is a substituted or unsubstituted 3 to 8 membered nitrogen-containing heterocyclic ring; n is an integer from 0 to 1; and b)
其中B’為經取代或未經取代之3至8員環烷基環；n為整數0至1；且R2係選自氫及甲基。 Wherein B' is a substituted or unsubstituted 3 to 8 membered cycloalkyl ring; n is an integer from 0 to 1; and R 2 is selected from hydrogen and methyl.
E係選自由以下組成之群：
其中Ra、Rb及Rc獨立地選自氫、鹵素、-CN、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、或經取代或未經取代之雜環基；或Ra及Rb與其所連接之碳原子結合在一起形成3至8員經取代或未經取代之環烷基環或形成3至8員經取代或未經取代之雜環，且Rc如上選擇；或Rb及Rc與其所連接之碳原子結合在一起形成3至8員經取代或未經取代之環烷基環或形成3至8員雜環，且Ra如上選擇；或Ra及Rb與其所連接之碳原子結合在一起形成參鍵，且Rc如上選擇。 Wherein Ra, Rb and Rc are independently selected from hydrogen, halogen, -CN, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, or a substituted or unsubstituted heterocyclic group; or Ra and Rb bonded to a carbon atom to which they are bonded to form a 3 to 8 membered substituted or unsubstituted cycloalkyl ring or formed into a 3 to 8 member substituted or unsubstituted a substituted heterocyclic ring, and Rc is selected as above; or Rb and Rc are bonded to the carbon atom to which they are attached to form a 3 to 8 membered substituted or unsubstituted cycloalkyl ring or a 3 to 8 membered heterocyclic ring, and Ra is selected as above; or Ra and Rb are bonded to the carbon atom to which they are attached to form a bond, and Rc is selected as above.
式II化合物較佳為由式II表示之化合物或其醫藥學上可接受之鹽或溶劑合物。在一個實施例中，其可僅僅為簡單式II化合物。 The compound of the formula II is preferably a compound represented by the formula II or a pharmaceutically acceptable salt or solvate thereof. In one embodiment, it may be simply a compound of formula II.
本發明之一實施例包括式II(較佳式II-5)之化合物，或其醫藥學上可接受之鹽、溶劑合物、鹽之溶劑合物、立體异構體、互變异構體、同位素、前藥、複合物或生物活性代謝物，其中L-E係選自由以下組成之群：
本發明之一實施例包括式II(較佳式II-5)之化合物，或其醫藥學上可接受之鹽、溶劑合物、鹽之溶劑合物、立體异構體、互變异構體、同位素、前藥、複合物或生物活性代謝物，其中L-E係選自由以下組成之群：
一較佳實施例包括式II(較佳式II-5)之化合物，或其醫藥學上可接受之鹽、溶劑合物、鹽之溶劑合物、立體异構體、互變异構體、同位素、前藥、複合物或生物活性代謝物，其中L-E係選自由以下組成之群：
另一較佳實施例包括式II(較佳式II-5)之化合物，或其醫藥學上可接受之鹽、溶劑合物、鹽之溶劑合物、立體异構體、互變异構體、同位素、前藥、複合物或生物活性代謝物， Another preferred embodiment comprises a compound of formula II (prepared formula II-5), or a pharmaceutically acceptable salt, solvate, salt solvate, stereoisomer, tautomer thereof , isotope, prodrug, complex or biologically active metabolite,
其中L-E係選自：
在本發明之一實施例中，L-E為
一較佳實施例包括式II(較佳式II-5)之化合物，或其醫藥學上可接受之鹽、溶劑合物、鹽之溶劑合物、立體异構體、互變异構體、同位素、前藥、複合物或生物活性代謝物，其中E為-CN。 A preferred embodiment comprises a compound of formula II (preferable formula II-5), or a pharmaceutically acceptable salt, solvate, salt solvate, stereoisomer, tautomer thereof, An isotope, prodrug, complex or biologically active metabolite, wherein E is -CN.
一實施例包括式II(較佳式II-5)之化合物，或其醫藥學上可接受之鹽、溶劑合物、鹽之溶劑合物、立體异構體、互變异構體、同位素、前藥、複合物或生物活性代謝物，其中E係選自由以下組成之群：
本發明之一實施例包括式II(較佳式II-5)之化合物，或其醫藥學上可接受之鹽、溶劑合物、鹽之溶劑合物、立體异構體、互變异構體、同位素、前藥、複合物或生物活性代謝物，其中E為。 An embodiment of the invention comprises a compound of formula II (prepared formula II-5), or a pharmaceutically acceptable salt, solvate, solvate thereof, stereoisomer, tautomer thereof , isotope, prodrug, complex or biologically active metabolite, where E is .
本發明之一較佳實施例包括具有式II-5之化學結構之化合物
或其醫藥學上可接受之鹽、溶劑合物、鹽之溶劑合物、立體异構體、互變异構體、同位素、前藥、複合物或生物活性代謝物，其中：X1及X2獨立地選自氫及鹵素；m為整數0至4；
m’為整數0至4；R係選自氫及甲基；L為：
其中B為經取代或未經取代之3至8員含氮雜環；且n為整數0至1；或
其中B’為經取代或未經取代之3至8員環烷基環；n為整數0至1；且R2係選自氫及甲基。 Wherein B' is a substituted or unsubstituted 3 to 8 membered cycloalkyl ring; n is an integer from 0 to 1; and R 2 is selected from hydrogen and methyl.
E係選自由以下組成之群：
其中Ra、Rb及Rc獨立地選自氫、鹵素、-CN、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、或經取代或未經取代之雜環基；或Ra及Rb與其所連接之碳原子結合在一起形成3至8員經取代或未經取代之環烷基環或形成3至8員經取代或未經取代之雜環，且Rc如上選擇；或Rb及Rc與其所連接之碳原子結合在一起形成3至8員經取代或未經取代之環烷基環或形成3至8員雜環，且Ra如上選擇；或Ra及Rb與其所連接之碳原子結合在一起形成參鍵，且Rc如上選擇。 Wherein Ra, Rb and Rc are independently selected from hydrogen, halogen, -CN, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, or a substituted or unsubstituted heterocyclic group; or Ra and Rb bonded to a carbon atom to which they are bonded to form a 3 to 8 membered substituted or unsubstituted cycloalkyl ring or formed into a 3 to 8 member substituted or unsubstituted a substituted heterocyclic ring, and Rc is selected as above; or Rb and Rc are bonded to the carbon atom to which they are attached to form a 3 to 8 membered substituted or unsubstituted cycloalkyl ring or a 3 to 8 membered heterocyclic ring, and Ra is selected as above; or Ra and Rb are bonded to the carbon atom to which they are attached to form a bond, and Rc is selected as above.
本發明之一實施例包括式ll-5化合物，或其醫藥學上可接受之鹽、溶劑合物、鹽之溶劑合物、立體异構體、互變异構體、同位素、前
藥、複合物或生物活性代謝物，其中L-E係選自由以下組成之群：
本發明之一實施例包括式ll-5化合物，或其醫藥學上可接受之鹽、溶劑合物、鹽之溶劑合物、立體异構體、互變异構體、同位素、前藥、複合物或生物活性代謝物，其中L-E係選自由以下組成之群：
本發明之另一實施例包括式II-5化合物，或其醫藥學上可接受之鹽、溶劑合物、鹽之溶劑合物、立體异構體、互變异構體、同位素、前藥、複合物或生物活性代謝物，其中L-E係選自由以下組成之群：
另一較佳實施例包括式II-5化合物，或其醫藥學上可接受之鹽、溶劑合物、鹽之溶劑合物、立體异構體、互變异構體、同位素、前藥、複合物或生物活性代謝物，其中L-E為：
一較佳實施例包括式II-5化合物，或其醫藥學上可接受之鹽、溶劑合物、鹽之溶劑合物、立體异構體、互變异構體、同位素、前藥、複合物或生物活性代謝物，其中E為-CN。 A preferred embodiment comprises a compound of formula II-5, or a pharmaceutically acceptable salt, solvate, solvate thereof, stereoisomer, tautomer, isotope, prodrug, complex thereof Or a biologically active metabolite, wherein E is -CN.
一較佳實施例包括式II-5化合物，或其醫藥學上可接受之鹽、溶劑合物、鹽之溶劑合物、立體异構體、互變异構體、同位素、前藥、
複合物或生物活性代謝物，其中E係選自由以下組成之群：
一較佳實施例包括式II-5化合物，或其醫藥學上可接受之鹽、溶劑合物、鹽之溶劑合物、立體异構體、互變异構體、同位素、前藥、複合物或生物活性代謝物，其中E為。 A preferred embodiment comprises a compound of formula II-5, or a pharmaceutically acceptable salt, solvate, solvate thereof, stereoisomer, tautomer, isotope, prodrug, complex thereof Or a biologically active metabolite, wherein E is .
一較佳實施例包括式II-5化合物，或其醫藥學上可接受之鹽、溶劑合物、鹽之溶劑合物、立體异構體、互變异構體、同位素、前藥、複合物或生物活性代謝物，其中L-E為
在本發明之一實施例中，式I化合物(包括式l-1)或式II化合物(包括式ll-1至ll-10之化合物)、或其醫藥學上可接受之鹽、溶劑合物、鹽之溶劑合物、立體异構體、互變异構體、同位素、前藥、複合物或生物活性代謝物共價結合至BTK，抑制酪胺酸激酶。在一替代性實施例中，本發明之化合物與BTK形成共價鍵。 In one embodiment of the invention, a compound of formula I (including formula 1-1) or a compound of formula II (including compounds of formula ll-1 to ll-10), or a pharmaceutically acceptable salt or solvate thereof The solvate, stereoisomer, tautomer, isotope, prodrug, complex or biologically active metabolite of the salt is covalently bound to BTK to inhibit tyrosine kinase. In an alternative embodiment, the compounds of the invention form a covalent bond with BTK.
在其他實施例中，本發明之化合物不可逆地抑制其共價結合之BTK。 In other embodiments, the compounds of the invention irreversibly inhibit their covalently bound BTK.
在一替代性實施例中，本發明之化合物與BTK上之半胱胺酸殘基形成共價鍵。 In an alternative embodiment, the compounds of the invention form a covalent bond with a cysteine residue on BTK.
本發明之另一態樣提供一種醫藥組合物，其包含式I化合物(包括式l-1)或式II化合物(包括式ll-1至ll-10之化合物)，或其醫藥學上可 接受之鹽、溶劑合物、鹽之溶劑合物、立體异構體、互變异構體、同位素、前藥、複合物或生物活性代謝物，及至少一種醫藥學上可接受之載劑、稀釋劑或賦形劑。 Another aspect of the present invention provides a pharmaceutical composition comprising a compound of Formula I (including Formula 1-1) or a compound of Formula II (including a compound of Formulas ll-1 to ll-10), or a pharmaceutically acceptable Accepted salts, solvates, solvates of the salts, stereoisomers, tautomers, isotopes, prodrugs, complexes or biologically active metabolites, and at least one pharmaceutically acceptable carrier, Diluent or excipient.
本發明之醫藥組合物用於預防或治療癌症、自身免疫疾病、過敏性疾病、發炎性疾病、移植物抗宿主病、血栓栓塞性疾病、神經障礙、病毒感染、骨相關疾病或其組合。 The pharmaceutical composition of the present invention is useful for preventing or treating cancer, autoimmune diseases, allergic diseases, inflammatory diseases, graft-versus-host diseases, thromboembolic diseases, neurological disorders, viral infections, bone-related diseases, or a combination thereof.
在本發明之一實施例中，式I化合物(包括式l-1)或式II化合物(包括式ll-1至ll-10)、或其醫藥學上可接受之鹽、溶劑合物、鹽之溶劑合物、立體异構體、互變异構體、同位素、前藥、複合物或生物活性代謝物適用於治療，其中個體罹患一或多種TEC激酶家族成員或BTK激酶活性所牽涉之疾病、病症或病狀。 In one embodiment of the invention, a compound of Formula I (including Formula 1-1) or a compound of Formula II (including Formulas 1-1 to ll-10), or a pharmaceutically acceptable salt, solvate, or salt thereof Solvates, stereoisomers, tautomers, isotopes, prodrugs, complexes or biologically active metabolites suitable for use in the treatment of diseases in which an individual is afflicted with one or more members of the TEC kinase family or BTK kinase activity , illness or condition.
在本發明之一實施例中，式I化合物(包括式l-1)或式II化合物(包括式ll-1至ll-10)、或其醫藥學上可接受之鹽、溶劑合物、鹽之溶劑合物、立體异構體、互變异構體、同位素、前藥、複合物或生物活性代謝物用於在組合療法中治療或預防癌症、自身免疫疾病、過敏性疾病、發炎性疾病、神經障礙或病毒感染。 In one embodiment of the invention, a compound of Formula I (including Formula 1-1) or a compound of Formula II (including Formulas 1-1 to ll-10), or a pharmaceutically acceptable salt, solvate, or salt thereof Solvates, stereoisomers, tautomers, isotopes, prodrugs, complexes or biologically active metabolites for the treatment or prevention of cancer, autoimmune diseases, allergic diseases, inflammatory diseases in combination therapy , neurological disorders or viral infections.
在本發明之一實施例中，式I化合物(包括式l-1)或式II化合物(包括式ll-1至ll-10)、或其醫藥學上可接受之鹽、溶劑合物、鹽之溶劑合物、立體异構體、互變异構體、同位素、前藥、複合物或生物活性代謝物用於治療，其進一步包含至少一種用於在組合療法中治療或預防癌症、自身免疫疾病、過敏性疾病、發炎性疾病、神經障礙或病毒感染之額外活性醫藥成分。額外活性醫藥成分係選自由以下組成之群：類固醇、白三烯拮抗劑、抗組胺劑、抗癌劑、抗病毒劑、抗生物素劑、蛋白激酶抑制劑、免疫調節劑、關卡抑制劑及其組合，且其中額外活性醫藥成分係與式I化合物(包括式l-1)或式II化合物(包括式ll-1至ll-10)、或其醫藥學上可接受之鹽、溶劑合物、鹽之溶劑合物、立體异構體、互變异構體、同位素、前藥、複合物或生物活性代謝物一起以單一劑型形式或單獨以多個劑型之一部分形式投與。 In one embodiment of the invention, a compound of Formula I (including Formula 1-1) or a compound of Formula II (including Formulas 1-1 to ll-10), or a pharmaceutically acceptable salt, solvate, or salt thereof a solvate, stereoisomer, tautomer, isotope, prodrug, complex or biologically active metabolite for use in therapy, further comprising at least one for treating or preventing cancer, autoimmune in combination therapy Additional active pharmaceutical ingredients for diseases, allergic diseases, inflammatory diseases, neurological disorders or viral infections. The additional active pharmaceutical ingredient is selected from the group consisting of steroids, leukotriene antagonists, antihistamines, anticancer agents, antiviral agents, antibiotic agents, protein kinase inhibitors, immunomodulators, checkpoint inhibitors And combinations thereof, and wherein the additional active pharmaceutical ingredient is combined with a compound of formula I (including formula 1-1) or a compound of formula II (including formulas ll-1 to ll-10), or a pharmaceutically acceptable salt thereof, or a solvent thereof The solvates, stereoisomers, tautomers, isotopes, prodrugs, complexes or biologically active metabolites are administered together in a single dosage form or separately as part of a plurality of dosage forms.
在另一態樣中，本發明係關於如本文定義之本發明化合物或 其醫藥學上可接受之鹽或溶劑合物，或如本文定義之醫藥組合物，其用於治療或預防疾病。 In another aspect, the invention relates to a compound of the invention as defined herein or A pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein for use in the treatment or prevention of a disease.
本發明之化合物在任何態樣或實施例中可用於在組合療法中治療或預防癌症、自身免疫疾病、過敏性疾病、發炎性疾病、神經障礙或病毒感染，該等自身免疫疾病選自：類風濕性關節炎、幼年型類風濕性關節炎、骨關節炎、僵直性脊椎炎、牛皮癬性關節炎、尋常性牛皮癬、尋常性天疱瘡、大疱性類天疱瘡、休格蘭氏症候群、全身性紅斑狼瘡、盤狀SLE、狼瘡性腎炎、抗磷脂沈積、惠普爾病(whipple)、皮肌炎、多肌炎、自身免疫性血小板减少症、特發性血小板减少性紫癜、血栓性血小板减少性紫癜、自身免疫性(冷)凝集素病、自身免疫性溶血性貧血、冷沈球蛋白血症、自身免疫性血管炎、ANCA相關血管炎、硬皮病、全身性硬化、多發性硬化、慢性局灶性腦炎、格林-巴利症候群(Guillian-Barre syndrome)、慢性疲勞症候群、單核細胞增多症、視神經脊髓炎、自身免疫性葡萄膜炎、格雷夫氏病(Grave's disease)、甲狀腺相關眼病、肉芽腫病伴顯微型多血管炎、韋格納肉芽腫病(Wegeners granulomatosis)、特發性肺纖維化、類肉瘤病、特發性膜性腎病、IgA腎病、腎小球硬化、胰腺炎、I型糖尿病或II型糖尿病。 The compounds of the invention may be used in any aspect or embodiment for the treatment or prevention of cancer, autoimmune diseases, allergic diseases, inflammatory diseases, neurological disorders or viral infections in combination therapies selected from: Rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, psoriatic arthritis, psoriasis vulgaris, pemphigus vulgaris, bullous pemphigoid, Hugh's syndrome, whole body Lupus erythematosus, discoid SLE, lupus nephritis, antiphospholipid deposition, Whipple, dermatomyositis, polymyositis, autoimmune thrombocytopenia, idiopathic thrombocytopenic purpura, thrombotic thrombocytopenia Purpura, autoimmune (cold) agglutinin disease, autoimmune hemolytic anemia, cryoglobulinemia, autoimmune vasculitis, ANCA-associated vasculitis, scleroderma, systemic sclerosis, multiple sclerosis, Chronic Focal Encephalitis, Gullian-Barre Syndrome, Chronic Fatigue Syndrome, Mononucleosis, Optic Neuromyelitis, Self-Exemption Uveitis, Grave's disease, thyroid-associated eye disease, granulomatosis with micro-polyangiitis, Wegeners granulomatosis, idiopathic pulmonary fibrosis, sarcoma-like disease, Idiopathic membranous nephropathy, IgA nephropathy, glomerular sclerosis, pancreatitis, type 1 diabetes, or type 2 diabetes.
在另一態樣中，本發明係關於如本文定義之本發明化合物或其醫藥學上可接受之鹽或溶劑合物，或如本文定義之醫藥組合物，其用於治療罹患蛋白激酶介導之疾病或病狀之個體。 In another aspect, the invention relates to a compound of the invention, or a pharmaceutically acceptable salt or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein, for use in the treatment of a protein kinase-mediated An individual with a disease or condition.
本發明之另一態樣提供一種式I化合物(包括式l-1)或式II化合物(包括式ll-1至ll-10)或其醫藥學上可接受之鹽或溶劑合物之用途，其用作蛋白激酶之抑制劑，更特定言之，用作BTK之抑制劑。在一實施例中，用途為離體的，例如活體外的，諸如活體外分析。 Another aspect of the invention provides the use of a compound of formula I (including formula 1-1) or a compound of formula II (including formulas ll-1 to ll-10) or a pharmaceutically acceptable salt or solvate thereof, It is used as an inhibitor of protein kinases, more specifically as an inhibitor of BTK. In one embodiment, the use is ex vivo, such as in vitro, such as in vitro analysis.
在另一態樣中，本發明係關於如定義本文之本發明化合物或其醫藥學上可接受之鹽或溶劑合物的用途，其用於製造用於個體中用於治療或預防蛋白激酶介導之疾病或病狀、用於治療癌症、自身免疫疾病、過敏性疾病、發炎性疾病、移植物抗宿主病、血栓栓塞性疾病、神經障礙、病毒感染、骨相關疾病或其組合的藥劑。 In another aspect, the invention relates to the use of a compound of the invention, or a pharmaceutically acceptable salt or solvate thereof, as defined herein, for use in the manufacture of a medicament for the treatment or prevention of protein kinases in an individual. A medicament or condition, a medicament for treating cancer, an autoimmune disease, an allergic disease, an inflammatory disease, a graft-versus-host disease, a thromboembolic disease, a neurological disorder, a viral infection, a bone-related disease, or a combination thereof.
在另一態樣中，本發明係關於一種治療或預防與蛋白激酶活 性相關之疾病或病狀之方法，該方法包括向個體投與治療有效量之如本文定義之本發明化合物或其醫藥學上可接受之鹽或溶劑合物、或如本文定義之醫藥組合物。 In another aspect, the invention relates to a therapeutic or prophylactic and protein kinase activity A method of sexually related diseases or conditions, the method comprising administering to a subject a therapeutically effective amount of a compound of the invention as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein .
本發明之另一態樣提供如本文定義之化合物或其醫藥學上可接受之鹽或溶劑合物、或醫藥組合物，其用於治療或預防涉及BTK及\或其他TEC激酶之疾病，亦即涉及B細胞、T細胞及/或肥大細胞之疾病，例如癌症、自身免疫疾病、過敏性疾病、發炎性疾病、移植物抗宿主病、血栓栓塞性疾病、骨相關疾病及其類似疾病。 Another aspect of the invention provides a compound as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition for use in the treatment or prevention of a disease involving BTK and/or other TEC kinases, That is, diseases involving B cells, T cells, and/or mast cells, such as cancer, autoimmune diseases, allergic diseases, inflammatory diseases, graft-versus-host diseases, thromboembolic diseases, bone-related diseases, and the like.
本發明之另一態樣提供化合物或其醫藥學上可接受之鹽或溶劑合物之用途，其用於製造用於治療或預防涉及BTK及\或其他TEC激酶之疾病的藥劑，該等疾病亦即涉及B細胞、T細胞及/或肥大細胞之疾病，例如癌症、自身免疫疾病、過敏性疾病、發炎性疾病、移植物抗宿主病、血栓栓塞性疾病、骨相關疾病及其類似疾病。 Another aspect of the invention provides the use of a compound, or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment or prevention of a disease involving BTK and/or other TEC kinases, such diseases That is, diseases involving B cells, T cells, and/or mast cells, such as cancer, autoimmune diseases, allergic diseases, inflammatory diseases, graft-versus-host diseases, thromboembolic diseases, bone-related diseases, and the like.
在另一態樣中，本發明提供一種治療或預防疾病或病狀之方法，該方法包括向個體投與治療有效量之如本文定義的式I化合物(包括式l-1)或式II化合物(包括式ll-1至ll-10)或其醫藥學上可接受之鹽或溶劑合物、或醫藥組合物。在一特定實施例中，該等疾病或病狀包括過敏性疾病、自身免疫疾病、發炎性疾病、血栓栓塞性疾病、骨相關疾病、癌症、移植物抗宿主病及其類似疾病。 In another aspect, the invention provides a method of treating or preventing a disease or condition, the method comprising administering to a subject a therapeutically effective amount of a compound of Formula I (including Formula 1-1) or Formula II as defined herein (Including Formulas 11-1 to 11-10) or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition. In a particular embodiment, the diseases or conditions include allergic diseases, autoimmune diseases, inflammatory diseases, thromboembolic diseases, bone related diseases, cancer, graft versus host diseases, and the like.
本發明之另一態樣提供一種調節激酶功能之方法，該方法包括使細胞與足以調節BTK之酶活性、因此調節激酶功能之量的本發明之式I化合物(包括式l-1)或式II化合物(包括式ll-1至ll-10)接觸。該方法可為離體的，例如活體外的。 Another aspect of the invention provides a method of modulating kinase function, the method comprising formulating a compound of formula I (including formula 1-1) or a formula of the invention in an amount sufficient to modulate BTK enzymatic activity, thereby modulating kinase function The II compound (including Formulas 11-1 to 11-10) is contacted. The method can be ex vivo, such as in vitro.
本發明之另一態樣提供一種活體外或活體內抑制細胞增殖或存活之方法，該方法包括使細胞與有效量之如本文定義之化合物或其醫藥學上可接受之鹽或溶劑合物接觸。 Another aspect of the invention provides a method of inhibiting cell proliferation or survival in vitro or in vivo, the method comprising contacting a cell with an effective amount of a compound as defined herein, or a pharmaceutically acceptable salt or solvate thereof .
在一個實施例中，本發明提供一種在細胞或組織中產生蛋白激酶抑制作用之方法，該方法包括使細胞或組織與有效量之式I化合物(包括式l-1)或式II化合物(包括式ll-1至ll-10)或其醫藥學上可接受之鹽或溶劑 合物接觸。 In one embodiment, the invention provides a method of producing a protein kinase inhibition in a cell or tissue, the method comprising reacting a cell or tissue with an effective amount of a compound of formula I (including formula 1-1) or a compound of formula II (including Formula ll-1 to ll-10) or a pharmaceutically acceptable salt or solvent thereof Contact with the compound.
在其他實施例中，本發明提供一種活體內產生蛋白激酶抑制作用之方法，該方法包括向個體投與有效量之化合物或其醫藥學上可接受之鹽或溶劑合物。 In other embodiments, the invention provides a method of producing a protein kinase inhibition in vivo comprising administering to an individual an effective amount of a compound or a pharmaceutically acceptable salt or solvate thereof.
本發明之另一態樣提供一種調節標靶激酶功能之方法，其包括：a)使細胞或蛋白激酶與足以藉此調節標靶激酶功能之量的本發明之化合物接觸；b)調節標靶激酶活性及信號傳導。 Another aspect of the invention provides a method of modulating the function of a target kinase comprising: a) contacting a cell or protein kinase with a compound of the invention sufficient to thereby modulate the function of the target kinase; b) modulating the target Kinase activity and signaling.
在又一態樣中，本文提供治療患者的可藉由抑制蛋白激酶治療之疾病之方法，其包括向患者投與包含治療有效量的本文揭示之化合物及或其醫藥學上可接受之鹽及一或多種醫藥學上可接受之賦形劑之醫藥組合物。在此態樣之一個實施例中，患者罹患可藉由激酶抑制治療之疾病或病症。本文揭示之式I化合物(包括式l-1)或式II化合物(包括式ll-1至ll-10)及/或其醫藥學上可接受之鹽可抑制非受體蛋白質激酶之TEC家族之一或多種激酶成員，包括(但不限於)ITK、BLK、BMX、BTK、JAK3及/或TEC。 In a further aspect, provided herein is a method of treating a disease in a patient that is inhibited by a protein kinase, comprising administering to the patient a therapeutically effective amount of a compound disclosed herein and or a pharmaceutically acceptable salt thereof, and A pharmaceutical composition of one or more pharmaceutically acceptable excipients. In one embodiment of this aspect, the patient is afflicted with a disease or condition that can be treated by kinase inhibition. The compounds of formula I (including formula 1-1) or formula II (including formulas ll-1 to ll-10) and/or pharmaceutically acceptable salts thereof disclosed herein inhibit the TEC family of non-receptor protein kinases. One or more kinase members including, but not limited to, ITK, BLK, BMX, BTK, JAK3, and/or TEC.
在另一態樣中，本發明提供一種醫藥組合，其包含本發明之化合物及至少一種用於在組合療法中治療或預防癌症、自身免疫疾病、過敏性疾病、發炎性疾病或病毒感染之額外活性醫藥成分。 In another aspect, the invention provides a pharmaceutical combination comprising a compound of the invention and at least one additional for treating or preventing cancer, autoimmune disease, allergic disease, inflammatory disease or viral infection in combination therapy Active pharmaceutical ingredients.
在一個實施例中，本發明提供一種治療方法，其進一步包括投與治療有效量之至少一種用於在組合療法中治療癌症、自身免疫疾病、過敏性疾病、發炎性疾病、神經障礙或病毒感染之額外活性醫藥成分。額外活性醫藥成分係與式I或II之化合物一起以單一劑型形式或單獨以多個劑型之一部分形式投與。額外活性醫藥成分係選自包括以下之群：類固醇、白三烯拮抗劑、抗組胺劑、抗癌劑、抗病毒劑、抗生物素劑、蛋白激酶抑制劑或其組合。 In one embodiment, the invention provides a method of treatment, further comprising administering a therapeutically effective amount of at least one of for treating cancer, an autoimmune disease, an allergic disease, an inflammatory disease, a neurological disorder, or a viral infection in combination therapy. Additional active pharmaceutical ingredients. The additional active pharmaceutical ingredient is administered together with the compound of formula I or II in a single dosage form or separately as part of a plurality of dosage forms. The additional active pharmaceutical ingredient is selected from the group consisting of steroids, leukotriene antagonists, antihistamines, anticancer agents, antiviral agents, antibiotics, protein kinase inhibitors, or combinations thereof.
本發明之化合物之投與可藉由領域中已知之任何適當手段，包括全身及局部投與。在投與之前，化合物可調配為適用於醫藥或臨床用途之組合物。該等組合物可包含適當載劑或賦形劑，諸如用於局部、 吸入或全身投與之載劑或賦形劑。本發明之化合物可單獨或與一或多種醫藥學上可接受之活性劑組合投與用於治療或預防蛋白激酶介導之病狀。 Administration of the compounds of the invention can be by systemic and topical administration by any suitable means known in the art. The compound can be formulated into a composition suitable for pharmaceutical or clinical use prior to administration. The compositions may contain suitable carriers or excipients, such as for topical, A carrier or excipient that is inhaled or administered systemically. The compounds of the invention may be administered alone or in combination with one or more pharmaceutically acceptable active agents for the treatment or prevention of a protein kinase mediated condition.
本發明進一步提供一種合成如本文定義之化合物或其醫藥學上可接受之鹽或溶劑合物之方法。 The invention further provides a method of synthesizing a compound as defined herein, or a pharmaceutically acceptable salt or solvate thereof.
本發明之另一態樣提供一種探針，該探針包含經可偵測標記或親和標簽標記之式I化合物。換言之，探針包含式I化合物(包括式l-1)或式II化合物(包括式ll-1至ll-10)之殘基或其醫藥學上可接受之鹽或溶劑合物共價結合至可偵測標記。該等可偵測標記包括(但不限於)螢光部分、化學發光部分、順磁性造影劑、金屬螯合劑、含放射性同位素之部分及生物素。 Another aspect of the invention provides a probe comprising a compound of formula I labeled with a detectable label or an affinity tag. In other words, the probe comprises a residue comprising a compound of formula I (including formula 1-1) or a compound of formula II (including formulas ll-1 to ll-10) or a pharmaceutically acceptable salt or solvate thereof, Detectable markers. Such detectable labels include, but are not limited to, fluorescent moieties, chemiluminescent moieties, paramagnetic contrast agents, metal chelators, radioisotope-containing moieties, and biotin.
本文提及之所有公開案、專利申請案、專利及其他參考文獻以全文引用的方式併入。 All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety.
本文揭示之本發明之其他特徵、目標及優勢自說明書及圖及申請專利範圍將顯而易見。 Other features, objects, and advantages of the invention are apparent from the description and drawings and claims.
圖1為用於動力學稀釋及阿瑟斯(Arthus)分析的參考化合物之結構，其揭示於WO 2013/177668中。 Figure 1 is a structure of a reference compound for kinetic dilution and Arthus analysis, which is disclosed in WO 2013/177668.
圖2為用本發明之化合物獲得的實例BTK抑制曲線。 Figure 2 is an example BTK inhibition curve obtained with a compound of the invention.
圖3為實例稀釋動力學BTK結果，與BTK藉由本發明之化合物之共價抑制一致。 Figure 3 is a graph of example dilution kinetics BTK consistent with the covalent inhibition of BTK by the compounds of the invention.
圖4為IgM介導之脾細胞增殖結果之實例抑制，與免疫細胞中之BTK之抑制一致。 Figure 4 is an example inhibition of IgM-mediated splenocyte proliferation results consistent with inhibition of BTK in immune cells.
圖5為TMD-8淋巴瘤細胞之存活之實例抑制，與淋巴瘤細胞中之BTK之抑制一致。 Figure 5 is an example inhibition of survival of TMD-8 lymphoma cells, consistent with inhibition of BTK in lymphoma cells.
圖6為展現阿瑟斯分析結果之圖。本發明之化合物在嚙齒動物中之阿瑟斯逆轉被動過敏反應中對免疫複合物急性血管炎之Fc受體激活之活體內活性。 Figure 6 is a graph showing the results of the Arthurs analysis. The in vivo activity of the compounds of the invention on Fc receptor activation of immune complex acute vasculitis in Arthurs reversal of passive allergic reactions in rodents.
本發明係關於新穎激酶抑制劑。發現此等化合物具有作為蛋白質激酶之抑制劑之活性，該等蛋白質激酶包括TEC激酶家族之成員，包 括BTK、TEC、ITK/EMT/TSK、BMX及TXK/RLK。最尤其，本發明之化合物抑制BTK酶及BTK依賴性細胞功能。 This invention relates to novel kinase inhibitors. These compounds were found to have activity as inhibitors of protein kinases, including members of the TEC kinase family, Including BTK, TEC, ITK/EMT/TSK, BMX and TXK/RLK. Most particularly, the compounds of the invention inhibit BTK enzyme and BTK-dependent cellular functions.
術語「化合物」亦指其醫藥學上可接受之鹽、溶劑合物、鹽之溶劑合物、立體异構體、互變异構體、同位素、前藥、複合物或生物活性代謝物。 The term "compound" also refers to pharmaceutically acceptable salts, solvates, solvates, stereoisomers, tautomers, isotopes, prodrugs, complexes or biologically active metabolites thereof.
在本發明之一實施例中，式I或式II之化合物(包括式l-1及式II-1至II-10之化合物)或其醫藥學上可接受之鹽或溶劑合物共價結合至BTK，抑制酪胺酸激酶。在一替代性實施例中，本發明之化合物與BTK之激活形式形成共價鍵。在其他實施例中，本發明之化合物不可逆地抑制其共價結合之BTK。在一替代性實施例中，本發明之化合物與BTK上之半胱胺酸殘基形成共價鍵。 In one embodiment of the invention, a compound of Formula I or Formula II (including a compound of Formula 1-1 and Formula II-1 to II-10) or a pharmaceutically acceptable salt or solvate thereof is covalently bonded To BTK, inhibit tyrosine kinase. In an alternative embodiment, the compounds of the invention form a covalent bond with the activated form of BTK. In other embodiments, the compounds of the invention irreversibly inhibit their covalently bound BTK. In an alternative embodiment, the compounds of the invention form a covalent bond with a cysteine residue on BTK.
本發明之化合物可調配為包含有效量之本發明之化合物與醫藥學上可接受之稀釋劑或載劑的醫藥組合物。 The compounds of the present invention may be formulated as a pharmaceutical composition comprising an effective amount of a compound of the present invention and a pharmaceutically acceptable diluent or carrier.
術語「醫藥學上有效量」係指用於人類或動物之組合物有效治療或預防與蛋白激酶活性相關之疾病或病狀的任何量。 The term "pharmaceutically effective amount" refers to any amount of a composition or a condition for the treatment or prevention of a protein kinase activity in a human or animal composition.
根據本發明，提供一種醫藥組合物，其包含式I化合物(包括式l-1)或式II化合物(包括式ll-1至ll-10)或其醫藥學上可接受之鹽或溶劑合物，結合至少一種醫藥學上可接受之賦形劑、稀釋劑或載劑。 According to the present invention there is provided a pharmaceutical composition comprising a compound of formula I (including formula 1-1) or a compound of formula II (including formula ll-1 to ll-10) or a pharmaceutically acceptable salt or solvate thereof In combination with at least one pharmaceutically acceptable excipient, diluent or carrier.
醫藥組合物可呈適用於經口投藥(例如，錠劑、膠囊、顆粒、散劑及糖漿)、非經腸投藥(例如，注射(靜脉內、肌肉內或皮下))、滴注製劑、吸入、眼睛洗劑、局部投藥(例如，軟膏、乳膏)或栓劑之習知醫藥形式。無關於所選投藥途徑，化合物可藉由為熟習此項技術者所知之習知方法調配為醫藥學上可接受之劑型。 The pharmaceutical composition may be suitable for oral administration (for example, tablets, capsules, granules, powders and syrups), parenteral administration (for example, injection (intravenous, intramuscular or subcutaneous)), instillation, inhalation, A conventional pharmaceutical form for eye lotion, topical administration (eg, ointment, cream) or suppository. Regardless of the route of administration selected, the compound can be formulated into a pharmaceutically acceptable dosage form by conventional methods known to those skilled in the art.
片語「醫藥學上可接受」在本文中用以指彼等配位體、物質、組合物及/或劑型在合理醫學判斷範疇內適用於與人類及動物之組織接觸而無過度毒性、刺激、過敏反應或其他問題或併發症，符合合理效益/風險比。 The phrase "pharmaceutically acceptable" is used herein to mean that their ligands, substances, compositions and/or dosage forms are suitable for use in contact with human and animal tissues without reasonable toxicity and irritation in the context of sound medical judgment. , allergic reactions or other problems or complications, in line with reasonable benefits / risk ratio.
如本文所用，片語「醫藥學上可接受之載劑」意謂醫藥學上可接受之物質、組合物或媒劑，諸如液體或固體填充劑、稀釋劑、賦形劑、 溶劑或囊封物質。每種載劑在與調配物之其他成分(包括活性成分)相容意義上必須為可接受的，且對患者不致傷或有害。可充當醫藥學上可接受之載劑的物質之一些實例包括：(1)糖，諸如乳糖、葡萄糖及蔗糖；(2)澱粉，諸如玉米澱粉、馬鈴薯澱粉及經取代或未經取代之β-環糊精；(3)纖維素及其衍生物，諸如羧甲基纖維素鈉、乙基纖維素及乙酸纖維素；(4)粉末狀黃蓍膠；(5)麥芽；(6)明膠；(7)滑石；(8)賦形劑，諸如可可脂及栓劑蠟；(9)油，諸如花生油、棉籽油、紅花油、芝麻油、橄欖油、玉米油及大豆油；(10)二醇，諸如丙二醇；(11)多元醇，諸如甘油、山梨糖醇、甘露糖醇及聚乙二醇；(12)酯，諸如油酸乙酯及月桂酸乙酯；(13)瓊脂；(14)緩衝劑，諸如氫氧化鎂及氫氧化鋁；(15)褐藻酸；(16)無熱原質水；(17)等張生理食鹽水；(18)林格氏溶液(Ringer's solution)；(19)乙醇；(20)磷酸鹽緩衝溶液；及(21)醫藥調配物中所用之其他無毒相容物質。對於經口調配物，可使用「醫藥學上可接受之載劑」，諸如纖維素、矽酸鈣、玉米澱粉、乳糖、蔗糖、右旋糖、磷酸鈣、硬脂酸、硬脂酸鎂、硬脂酸鈣、明膠、滑石、界面活性劑、懸浮劑、乳化劑、稀釋劑及其他。對於可注射調配物，可使用「醫藥學上可接受之載劑」，諸如水、生理食鹽水、葡萄糖溶液、葡萄糖溶液類似物、醇、二醇、醚(例如，聚乙二醇400)、油、脂肪酸、脂肪酸酯、甘油酯、界面活性劑、懸浮劑、乳化劑及其他。 As used herein, the phrase "pharmaceutically acceptable carrier" means a pharmaceutically acceptable substance, composition or vehicle, such as a liquid or solid filler, diluent, excipient, Solvent or encapsulating material. Each carrier must be acceptable in the sense of being compatible with the other ingredients of the formulation, including the active ingredient, and not deleterious or deleterious to the patient. Some examples of materials that can serve as pharmaceutically acceptable carriers include: (1) sugars such as lactose, glucose, and sucrose; (2) starches such as corn starch, potato starch, and substituted or unsubstituted beta- Cyclodextrin; (3) cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin (7) talc; (8) excipients such as cocoa butter and suppository wax; (9) oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) diol , such as propylene glycol; (11) polyols such as glycerol, sorbitol, mannitol and polyethylene glycol; (12) esters such as ethyl oleate and ethyl laurate; (13) agar; (14) Buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; Ethanol; (20) phosphate buffer solution; and (21) other non-toxic compatible materials used in pharmaceutical formulations. For oral preparations, "pharmaceutically acceptable carriers" such as cellulose, calcium citrate, corn starch, lactose, sucrose, dextrose, calcium phosphate, stearic acid, magnesium stearate, Calcium stearate, gelatin, talc, surfactants, suspending agents, emulsifiers, diluents and others. For injectable formulations, "pharmaceutically acceptable carriers" such as water, physiological saline, dextrose solutions, glucose solution analogs, alcohols, glycols, ethers (eg, polyethylene glycol 400), Oils, fatty acids, fatty acid esters, glycerides, surfactants, suspending agents, emulsifiers and others.
術語「醫藥學上可接受之鹽」係指化合物之相對無毒的無機及有機酸加成鹽。此等鹽可在最終分離及純化化合物期間原位製備，或藉由使呈其游離碱形式之經純化化合物與適合有機或無機酸單獨地反應、及分離因此形成之鹽來製備。代表性鹽包括氫溴酸鹽、鹽酸鹽、硫酸鹽、硫酸氫鹽、磷酸鹽、硝酸鹽、乙酸鹽、戊酸鹽、油酸鹽、棕櫚酸鹽、硬脂酸鹽、月桂酸鹽、苯甲酸鹽、乳酸鹽、磷酸鹽、甲苯磺酸鹽、檸檬酸鹽、順丁烯二酸鹽、反丁烯二酸鹽、丁二酸鹽、酒石酸鹽、萘酸鹽、甲磺酸鹽、葡庚糖酸鹽、乳糖酸鹽、月桂基磺酸鹽及胺基酸鹽及其類似鹽(參見例如Berge等人(1977)「Pharmaceutical Salts」,J.Pharm.Sci.66：1-19)。 The term "pharmaceutically acceptable salts" refers to relatively non-toxic, inorganic and organic acid addition salts of the compounds. Such salts can be prepared in situ during the final isolation and purification of the compound, or by separately reacting the purified compound in its free base form with a suitable organic or inorganic acid, and isolating the salt thus formed. Representative salts include hydrobromide, hydrochloride, sulfate, hydrogen sulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, Benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthate, methanesulfonate , glucoheptonate, lactoblate, lauryl sulfonate and aminic acid salt and the like (see, for example, Berge et al. (1977) "Pharmaceutical Salts", J. Pharm. Sci. 66: 1-19 ).
術語「個體」或「患者」意謂用於治療之人類或動物個體。 The term "individual" or "patient" means a human or animal individual for treatment.
本發明之含義內之術語「組合」包括同時、依序或單獨使用 組分或成分。 The term "combination" within the meaning of the present invention includes simultaneous, sequential or separate use. Component or ingredient.
本發明之醫藥組合物可藉由習知程序使用此項技術中熟知的習知醫藥賦形劑獲得。 The pharmaceutical compositions of the present invention can be obtained by conventional procedures using conventional pharmaceutical excipients well known in the art.
在其他情况下，本發明之化合物可含有一或多種酸性官能基，且因此能够與醫藥學上可接受之碱形成醫藥學上可接受之鹽。術語「醫藥學上可接受之鹽」在此等情况下係指化合物之相對無毒的無機及有機碱加成鹽。此等鹽同樣可在最終分離及純化化合物期間原位製備，或藉由使呈其游離酸形式之經純化化合物與適合碱(諸如醫藥學上可接受之金屬陽離子之氫氧化物、碳酸鹽或碳酸氫鹽)、氨或醫藥學上可接受之有機一級、二次或三級胺單獨地反應來製備。代表性鹼金屬或鹼土金屬鹽包括鋰、鈉、鉀、鈣、鎂及鋁鹽及其類似鹽。適用於形成碱加成鹽之代表性有機胺包括乙胺、二乙胺、乙二胺、乙醇胺、二乙醇胺、呱嗪及其類似物(參見例如Berge等人，如前文獻)。 In other instances, the compounds of the invention may contain one or more acidic functional groups and are therefore capable of forming a pharmaceutically acceptable salt with a pharmaceutically acceptable base. The term "pharmaceutically acceptable salts" in this context refers to relatively non-toxic, inorganic and organic base addition salts of the compounds. Such salts may likewise be prepared in situ during the final isolation and purification of the compound, or by subjecting the purified compound in its free acid form to a suitable base such as a hydroxide or carbonate of a pharmaceutically acceptable metal cation. Bicarbonate), ammonia or a pharmaceutically acceptable organic primary, secondary or tertiary amine is prepared separately by reaction. Representative alkali or alkaline earth metal salts include lithium, sodium, potassium, calcium, magnesium and aluminum salts and the like. Representative organic amines suitable for use in forming base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, oxazine, and the like (see, for example, Berge et al., supra).
如本文所用，術語「親和標簽」意謂使得結合物可自溶液提取的鍵聯至本發明之化合物或蛋白激酶域之配位體或基團。 As used herein, the term "affinity tag" means a linker or group that allows a bond to be extracted from a solution to a compound or protein kinase domain of the invention.
如本文所用，術語「螺環」係指經由僅一個原子連接之雙環系統。環可為不同或相同的。亦稱為螺原子之連接原子較佳為四級碳。螺環可視情况經一或多個如本文定義之取代基取代。 As used herein, the term "spirocyclic" refers to a bicyclic system that is attached via only one atom. The rings can be different or identical. The connecting atom, also referred to as a spiro atom, is preferably a quaternary carbon. The spiro can be optionally substituted with one or more substituents as defined herein.
如本文所用，術語「烷基」係指飽和烴鏈。烷基鏈可為直鏈或分支鏈的。烷基鏈可視情况經一或多個如本文定義之取代基取代。代表性烷基包括甲基、乙基、丙基(正丙基及异丙基)、丁基(正丁基、第三丁基及异丁基)、戊基(正戊基及异戊基)、己基及其類似基團。在某些較佳實施例中，烷基取代基為例如具有1至6個碳原子之低碳烷基。 As used herein, the term "alkyl" refers to a saturated hydrocarbon chain. The alkyl chain can be straight or branched. The alkyl chain may optionally be substituted with one or more substituents as defined herein. Representative alkyl groups include methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, tert-butyl and isobutyl), pentyl (n-pentyl and isopentyl) ), hexyl groups and the like. In certain preferred embodiments, the alkyl substituent is, for example, a lower alkyl group having from 1 to 6 carbon atoms.
如本文所用，術語「烯基」係指長度及可能的取代與上述「烷基」相似、但含有至少一個雙鍵之不飽和烴鏈。代表性烯基包括乙烯基、丙烯-2-基、巴豆基、异戊烯-2-基、1,3-丁二烯-2-基、2,4-戊二烯基及1,4-戊二烯-3-基。在某些較佳實施例中，烯基取代基為例如具有2至6個碳原子之低碳烯基。 As used herein, the term "alkenyl" refers to an unsaturated hydrocarbon chain of a length and possibly a substitution similar to the above "alkyl" but containing at least one double bond. Representative alkenyl groups include ethenyl, propen-2-yl, crotyl, pren-2-yl, 1,3-butadien-2-yl, 2,4-pentadienyl and 1,4- Pentadien-3-yl. In certain preferred embodiments, the alkenyl substituent is, for example, a lower alkenyl group having from 2 to 6 carbon atoms.
如本文所用，術語「炔基」係指長度及可能的取代與上述「烷 基」相似、但含有至少一個參鍵之不飽和烴鏈。代表性炔基包括乙炔基、1-及3-丙炔基及3-丁炔基。在某些較佳實施例中，炔基取代基為例如具有2至6個碳原子之低碳烷基。 As used herein, the term "alkynyl" refers to the length and possible substitutions with the above "alkanes". An unsaturated hydrocarbon chain which is similar but contains at least one reference. Representative alkynyl groups include ethynyl, 1- and 3-propynyl and 3-butynyl. In certain preferred embodiments, the alkynyl substituent is, for example, a lower alkyl group having from 2 to 6 carbon atoms.
如本文所用，術語「伸烷基」係指具有兩個開放原子價之烷基。 As used herein, the term "alkylene" refers to an alkyl group having two open valences.
如本文所用，術語「雜烷基」係指含有一至四個選自由O、N及S組成之群的雜原子之飽和或部分飽和鏈，且其中氮及硫原子可視情况氧化且氮原子可視情况四級銨化。雜烷基鏈可為直鏈或分支鏈的。雜烷基鏈可視情况經一或多個如本文定義之取代基取代。雜原子O、N及S可位於雜烷基之任何內部位置。至多兩個雜原子可為連續的。 As used herein, the term "heteroalkyl" refers to a saturated or partially saturated chain containing one to four heteroatoms selected from the group consisting of O, N, and S, and wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen atom may be used as appropriate. Four-grade ammonium. The heteroalkyl chain can be straight or branched. A heteroalkyl chain may optionally be substituted with one or more substituents as defined herein. The heteroatoms O, N and S can be located at any internal position of the heteroalkyl group. Up to two heteroatoms can be continuous.
如本文所用，術語「環烷基」、或者「碳環」及「碳環基」係指飽和或部分飽和非芳族環、更佳3至8員環，其中環之每個原子為碳；或係指螺環，其中每個環為飽和或部分飽和烴環且螺原子為碳。環烷基環可視情况經一或多個如本文定義之取代基取代。術語「環烷基」、「碳環」或「碳環基」亦包括具有兩個或兩個以上環狀環之多環系統，其中兩個或兩個以上碳為兩個鄰接環所共有，其中至少一個環為環烷基，例如，其他環狀環可為芳基、雜芳基及/或雜環基。代表性環烷基環包括環丙基、環丁基、環戊基、環己基、1-環己烯基、3-環己烯-1-基、環庚基、四氫萘基、二氫茚基、金剛烷基及其類似基團。 As used herein, the terms "cycloalkyl", or "carbocyclic" and "carbocyclyl" mean a saturated or partially saturated non-aromatic ring, more preferably a 3 to 8 membered ring, wherein each atom of the ring is carbon; Or refers to a spiro ring in which each ring is a saturated or partially saturated hydrocarbon ring and the spiro atom is carbon. The cycloalkyl ring may be optionally substituted with one or more substituents as defined herein. The term "cycloalkyl", "carbocyclic" or "carbocyclic" also includes polycyclic systems having two or more cyclic rings, wherein two or more carbons are shared by two adjacent rings. At least one of the rings is a cycloalkyl group, for example, the other cyclic ring may be an aryl group, a heteroaryl group, and/or a heterocyclic group. Representative cycloalkyl rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexen-1-yl, cycloheptyl, tetrahydronaphthyl, dihydrogen Mercapto, adamantyl and the like.
如本文所用，術語「雜環基」、或者「雜環」及「雜環烷基」係指非芳族環結構、更佳3至8員環，其環結構包括一至四個雜原子；或係指螺環，其中雙環系統含有1至4個雜原子。雜環基環可視情况經一或多個如本文定義之取代基取代。術語「雜環基」或「雜環」亦包括具有兩個或兩個以上環狀環之多環系統，其中兩個或兩個以上碳為兩個鄰接環所共有，其中至少一個環為雜環，例如，其他環狀環可為環烷基、芳基及/或雜芳基。雜環基包括例如四氫呋喃、呱啶、呱嗪、吡咯啶、嗎啉、內酯、內醯胺及其類似雜環基。 As used herein, the term "heterocyclyl" or "heterocycle" and "heterocycloalkyl" refers to a non-aromatic ring structure, more preferably a 3 to 8 membered ring, the ring structure of which includes one to four heteroatoms; Refers to a spiro ring in which the bicyclic system contains from 1 to 4 heteroatoms. The heterocyclyl ring may be optionally substituted with one or more substituents as defined herein. The term "heterocyclyl" or "heterocycle" also includes polycyclic systems having two or more cyclic rings wherein two or more carbons are common to two adjacent rings, at least one of which is hetero Rings, for example, other cyclic rings may be cycloalkyl, aryl and/or heteroaryl. The heterocyclic group includes, for example, tetrahydrofuran, acridine, pyridazine, pyrrolidine, morpholine, lactone, indoleamine and the like.
如本文所用，術語「芳基」係指5、6及7員芳族環，其中環之每個原子為碳。芳基環可視情况經一或多個如本文定義之取代基取 代。術語「芳基」亦包括具有兩個或兩個以上環狀環之多環系統，其中兩個或兩個以上碳為兩個鄰接環所共有，其中至少一個環為芳基，例如，其他環狀環可為環烷基、雜芳基及/或雜環基。芳基包括例如苯、萘、菲、蒽及其類似芳基。 As used herein, the term "aryl" refers to a 5, 6 and 7 membered aromatic ring wherein each atom of the ring is carbon. An aryl ring may optionally be taken via one or more substituents as defined herein generation. The term "aryl" also includes polycyclic systems having two or more cyclic rings wherein two or more carbons are shared by two adjacent rings, at least one of which is aryl, for example, other rings The ring may be a cycloalkyl group, a heteroaryl group and/or a heterocyclic group. The aryl group includes, for example, benzene, naphthalene, phenanthrene, anthracene and the like.
如本文所用，術語「雜芳基」係指5、6及7員芳族環，其環結構包括一至四個雜原子。雜芳基環可視情况經一或多個如本文定義之取代基取代。術語「雜芳基」亦包括具有兩個或兩個以上環狀環之多環系統，其中兩個或兩個以上碳為兩個鄰接環所共有，其中至少一個環為雜芳基，例如，其他環狀環可為環烷基、芳基及/或雜環基。雜芳基包括例如吡咯、呋喃、噻吩、咪唑、异噁唑、噁唑、噻唑、***、吡唑、吡啶、吡嗪、噠嗪及嘧啶。 As used herein, the term "heteroaryl" refers to a 5, 6 and 7 membered aromatic ring having a ring structure comprising from one to four heteroatoms. The heteroaryl ring may be optionally substituted with one or more substituents as defined herein. The term "heteroaryl" also includes polycyclic systems having two or more cyclic rings wherein two or more carbons are shared by two adjacent rings, at least one of which is heteroaryl, for example, Other cyclic rings may be cycloalkyl, aryl and/or heterocyclic groups. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, isoxazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine.
如本文所用，術語「多環基」或者「多環」係指兩個或兩個以上環(例如，環烷基、芳基、雜芳基及/或雜環基)，其中兩個或兩個以上碳為兩個鄰接環所共有，例如，環為「稠環」。多環基環可視情况經一或多個如本文定義之取代基取代。 As used herein, the term "polycyclic" or "polycyclic" refers to two or more rings (eg, cycloalkyl, aryl, heteroaryl, and/or heterocyclic), two or two of which More than one carbon is shared by two adjacent rings, for example, the ring is a "fused ring". The polycyclic ring can optionally be substituted with one or more substituents as defined herein.
如本文所用，術語「芳烷基」係指經芳基取代之烷基，例如-(CH2)p-Ar，且p為整數1至8，且Ar可選自任何適合芳基環系統，例如苯基或萘基。舉例而言，「芳烷基」可為苯甲基。 As used herein, the term "aralkyl" refers to an alkyl group substituted with an aryl group, such as -(CH 2 ) p -Ar, and p is an integer from 1 to 8, and Ar may be selected from any suitable aryl ring system, For example phenyl or naphthyl. For example, "aralkyl" can be benzyl.
如本文所用，術語「雜芳烷基」係指經雜芳基取代之烷基，例如-(CH2)p-Het，其中p為整數1至8，且Het為任何適合雜芳基環系統，諸如以上段落中論述之雜芳基環。 As used herein, the term "heteroaralkyl" refers to an alkyl group substituted with a heteroaryl group, such as -(CH 2 ) p -Het, wherein p is an integer from 1 to 8, and Het is any suitable heteroaryl ring system. , such as the heteroaryl ring discussed in the paragraph above.
如本文所用，術語「烷氧基」係指烷基醚取代基，其中術語烷基如上文所定義。代表性烷氧基包括甲氧基、乙氧基、丙氧基、第三丁氧基及其類似基團。 The term "alkoxy" as used herein refers to an alkyl ether substituent, wherein the term alkyl is as defined above. Representative alkoxy groups include methoxy, ethoxy, propoxy, tert-butoxy and the like.
如本文所用，術語「醚」係指橋接兩個在碳原子處鍵聯之部分之氧基。 As used herein, the term "ether" refers to an oxy group that bridges two moieties at a carbon atom.
如本文所用，術語「烷氧基烷基」係指經烷氧基取代、藉此形成醚之烷基。 As used herein, the term "alkoxyalkyl" refers to an alkyl group substituted with an alkoxy group, thereby forming an ether.
如本文所用，術語「鹵基」或「鹵素」係指氟、氯、溴及碘。 As used herein, the term "halo" or "halogen" refers to fluoro, chloro, bromo and iodo.
如本文所用，術語「雜原子」係指除碳或氫以外的任何元素之原子。較佳之雜原子為氮、氧及硫。 As used herein, the term "heteroatom" refers to an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen and sulfur.
如本文所用，術語「烴」係指完全由碳及氫組成之基團。 As used herein, the term "hydrocarbon" refers to a group consisting entirely of carbon and hydrogen.
如本文所用，術語「鹵烷基」係指烷基取代基，其中一或多個氫經鹵素置換。 As used herein, the term "haloalkyl" refers to an alkyl substituent wherein one or more hydrogens are replaced by a halogen.
如本文所用，術語「羰基」當單獨時包括甲醯基-CH(O)且在組合中為-C(O)基團。 As used herein, the term "carbonyl", when taken alone, includes indolyl-CH(O) and in combination is a -C(O) group.
如本文所用，術語「羧基(carboxyl)」或者「羧基(carboxy)」係指諸如羧酸鹽中之-C(O)OH或對應「羧酸根」陰離子。 As used herein, the term "carboxyl" or "carboxy" refers to, for example, -C(O)OH or a corresponding "carboxylate" anion in a carboxylate.
如本文所用，術語「醯基」係指-C(O)R，其中R為如上文所定義之烷基、雜烷基、鹵烷基、環烷基、雜環基、芳基或雜芳基。代表性醯基包括乙醯基、三氟乙醯基、苯甲醯基及其類似基團。 As used herein, the term "mercapto" refers to -C(O)R, wherein R is alkyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl as defined above. base. Representative sulfhydryl groups include ethenyl, trifluoroethenyl, benzamidine and the like.
如本文所用，術語「烷氧基羰基」係指-C(O)OR，其中R為如上文所定義之烷基。代表性烷氧基羰基包括甲氧基羰基、乙氧基羰基及其類似基團。 The term "alkoxycarbonyl," as used herein, refers to -C(O)OR, wherein R is alkyl as defined above. Representative alkoxycarbonyl groups include methoxycarbonyl, ethoxycarbonyl and the like.
如本文所用，術語「烷基硫基」係指硫醚-SR，其中R為如上文所定義之烷基。代表性烷基硫基包括甲基硫基、乙基硫基及其類似基團。 As used herein, the term "alkylthio" refers to thioether-SR, wherein R is alkyl as defined above. Representative alkylthio groups include methylthio, ethylthio and the like.
如本文所用，術語「磺酸酯」係指磺酸之鹽或酯-OSO2R，其中R為如上文所定義之烷基、雜烷基、鹵烷基、環烷基、雜環基、芳基或雜芳基。代表性磺酸酯基包括甲磺酸酯、苯磺酸酯、甲苯磺酸酯及其類似物。 As used herein, the term "sulfonate" refers to a salt or ester of sulfonic acid - OSO 2 R, wherein R is alkyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, as defined above, Aryl or heteroaryl. Representative sulfonate groups include mesylate, besylate, tosylate, and the like.
如本文所用，術語「磺醯基」係指-SO2R，其中R為如上文所定義之烷基、雜烷基、鹵烷基、環烷基、雜環基、芳基或雜芳基。代表性磺酸酯基包括甲磺醯基、乙磺醯基及其類似基團。 As used herein, the term "sulfonyl" refers to -SO 2 R, wherein R is alkyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl as defined above. . Representative sulfonate groups include methylsulfonyl, ethylsulfonyl and the like.
如本文所用，術語「胺磺醯基」係指-SO2NH2。 As used herein, the term "amine sulfonyl" refers to -SO 2 NH 2 .
如本文所用，術語「磺醯胺基」係指-S(O)2NRR'，其中R及R'獨立地選自如上文所定義之烷基、雜烷基、鹵烷基、環烷基、雜環基、芳基或雜芳基。R及R'可組合形成雜環。 As used herein, the term "sulfonamide" refers to -S(O) 2 NRR', wherein R and R' are, independently, selected from alkyl, heteroalkyl, haloalkyl, cycloalkyl as defined above. , heterocyclic, aryl or heteroaryl. R and R' may be combined to form a heterocyclic ring.
如本文所用，術語「胺基」係指-NRR'，其中R及R'獨立地選自氫、如上文所定義之烷基、雜烷基、鹵烷基、環烷基、雜環基、芳基或雜芳基。R及R'可組合形成雜環。 As used herein, the term "amino" refers to -NRR', wherein R and R' are independently selected from hydrogen, alkyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, as defined above, Aryl or heteroaryl. R and R' may be combined to form a heterocyclic ring.
如本文所用，術語「醯胺基」或者「醯胺」係指-C(O)NRR'，其中R及R'獨立地選自氫、如上文所定義之烷基、雜烷基、鹵烷基、環烷基、雜環基、芳基或雜芳基。R及R'可組合形成雜環基環。 As used herein, the term "ammonium" or "guanamine" refers to -C(O)NRR', wherein R and R' are independently selected from hydrogen, alkyl, heteroalkyl, haloalkyl as defined above. A group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group. R and R' may be combined to form a heterocyclic ring.
術語「經取代」係指有取代基置換主鏈之一或多個原子上的氫之部分。應理解，「取代」或「經取代」包括如下隱含限制條件：該取代根據經取代之原子及取代基之允許原子價進行，且取代產生穩定化合物，例如其不會自發諸如藉由重組、環化、消去等進行轉化。如本文所用，術語「經取代」預期包括有機化合物之所有允許取代基。對於適當有機化合物，允許取代基可為一或多個且相同或不同。出於本發明之目的，雜原子(諸如氮)可具有氫取代基及/或滿足雜原子原子價之本文所述有機化合物的任何允許取代基。 The term "substituted" refers to a moiety in which a substituent replaces hydrogen on one or more of the backbones. It should be understood that "substitution" or "substitution" includes the following implicit restrictions: the substitution proceeds according to the permissible atomic valence of the substituted atom and the substituent, and the substitution results in a stable compound, eg, it does not spontaneously, such as by recombination, Conversion, cyclization, elimination, etc. As used herein, the term "substituted" is intended to include all permissible substituents of an organic compound. For suitable organic compounds, the substituents may be one or more and the same or different. For the purposes of the present invention, a hetero atom such as nitrogen may have a hydrogen substituent and/or any permissible substituent of an organic compound described herein that satisfies the valence of a hetero atom.
取代基可包括例如烷基、烯基、炔基、鹵烷基、雜烷基、環烷基、雜環基、芳基、雜芳基、鹵素、羥基、羰基、羧基、烷氧基羰基、甲醯基或醯基、硫基羰基(諸如硫酯、硫乙酸酯或硫甲酸酯)、烷氧基、磷醯基、磷酸酯、膦酸酯、亞膦酸酯、胺基、醯胺基、脒、亞胺、氰基、硝基、疊氮基、巰基、烷基硫基、硫酸酯、磺酸酯、胺磺醯基、磺醯胺基、磺醯基。熟習此項技術者應理解，適當時，取代基可自身經取代。 Substituents may include, for example, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halogen, hydroxy, carbonyl, carboxy, alkoxycarbonyl, Mercapto or fluorenyl, thiocarbonyl (such as thioester, thioacetate or thioformate), alkoxy, phosphonium, phosphate, phosphonate, phosphonite, amine, hydrazine Amine, hydrazine, imine, cyano, nitro, azide, decyl, alkylthio, sulfate, sulfonate, amidoxime, sulfonamide, sulfonyl. Those skilled in the art will appreciate that the substituents may themselves be substituted as appropriate.
如本文所用，術語「探針」意謂經可偵測標記或親和標簽標記且能够共價或非共價結合至蛋白激酶域之本發明化合物。舉例而言，當探針非共價結合時，其可由測試化合物置換。舉例而言，當探針共價結合時，其可用以形成交聯加合物，其可藉由測試化合物定量及抑制。 As used herein, the term "probe" means a compound of the invention that is labeled with a detectable or affinity tag and that is capable of covalently or non-covalently binding to a protein kinase domain. For example, when the probe is non-covalently bound, it can be replaced by a test compound. For example, when the probe is covalently bound, it can be used to form a crosslinked adduct that can be quantified and inhibited by the test compound.
術語「前藥」指示為藥物前驅體之化合物，其在向個體投與時，在體內轉化為式I化合物(包括式I-1)或式II化合物(包括式II-1至II-10之化合物)或其醫藥學上可接受之鹽或溶劑合物。式I化合物(包括式I-1)、式II化合物(包括式II-1至II-10之化合物)或其醫藥學上可接受之鹽或溶劑合物的前藥屬在本發明之範疇內。 The term "prodrug" is intended to mean a compound of a prodrug which, when administered to an individual, is converted in vivo to a compound of formula I (including Formula I-1) or a compound of Formula II (including Formulas II-1 to II-10). a compound) or a pharmaceutically acceptable salt or solvate thereof. Prodrugs of a compound of formula I (including formula I-1), a compound of formula II (including a compound of formula II-1 to II-10), or a pharmaceutically acceptable salt or solvate thereof, are within the scope of the invention .
本發明之化合物亦包括中間物及/或最終化合物中所存在之原子的所有同位素。同位素包括具有相同原子數但不同質量數之彼等原子。舉例而言，氫之同位素包括氘及氚。 The compounds of the invention also include all isotopes of the atoms present in the intermediate and/or final compound. Isotopes include those atoms having the same number of atoms but different mass numbers. For example, isotopes of hydrogen include deuterium and tritium.
本發明之化合物可與另一藥物一起投與作為伴隨藥物，以：(1)補充及/或增强任一藥劑之預防性及/或治療性作用；(2)改良動力學/吸收，或减少任一藥劑之劑量；及/或(3)緩和任一藥劑之副作用。 The compounds of the invention may be administered as a concomitant drug with another drug to: (1) supplement and/or enhance the prophylactic and/or therapeutic effects of either agent; (2) improve kinetics/absorption, or reduce The dose of any of the agents; and/or (3) to alleviate the side effects of either agent.
含有其他藥物及本發明之化合物的伴隨藥物可以將兩種組分組合於其中之調配物形式或以單獨藥物產品形式投與。其以單獨藥物產品形式之投與包括同時投與或不同時投與兩者。 A concomitant drug containing other drugs and a compound of the present invention may be administered in a form in which the two components are combined or administered as a separate drug product. Its administration in the form of a separate pharmaceutical product includes simultaneous administration or administration of both at the same time.
在下文描述之合成方法之描述中及在用以製備起始物質之參考合成方法中，應理解，所有建議之反應條件(包括溶劑、反應氛圍、反應溫度、實驗持續時間及處理程序之選擇)可由熟習此項技術者選擇。 In the description of the synthetic methods described below and in the reference synthesis methods used to prepare the starting materials, it is understood that all of the suggested reaction conditions (including solvent, reaction atmosphere, reaction temperature, duration of the experiment, and choice of processing procedures). Can be selected by those skilled in the art.
以下部分描述可適用於製備本發明之化合物的通用合成方 法。 The following sections describe general synthetic formulas that are applicable to the preparation of the compounds of the invention. law.
如流程A、B、C、D、E、F、G及H中所示，自市售起始物質製備式II-5化合物。 The compound of formula II-5 is prepared from commercially available starting materials as shown in Schemes A, B, C, D, E, F, G and H.
如流程A及B中所示，自市售起始物質製備中間物A3及B6。 Intermediates A3 and B6 were prepared from commercially available starting materials as shown in Schemes A and B.
如流程1至16中所示，製備中間物1-c及1-c'、2-f、3-b至16-b，且如流程26至29中所示，製備中間物26-c、27-a、28-b及29-b。 Intermediates 1-c and 1-c', 2-f, 3-b to 16-b are prepared as shown in Schemes 1 through 16, and intermediates 26-c are prepared as shown in Schemes 26 through 29, 27-a, 28-b and 29-b.
中間物A3自市售起始物質A1開始，在2個步驟順序中獲得。A1鹵化提供中間物A2，中間物A2胺化提供中間物A3。在一替代性方法中，中間物A1胺化提供中間物A2'，中間物A2'鹵化提供中間物A3。 The intermediate A3 was obtained from the commercially available starting material A1 in the order of two steps. A1 halogenation provides intermediate A2 and intermediate A2 amination provides intermediate A3. In an alternative method, the amination of the intermediate A1 provides the intermediate A2' and the halogenation of the intermediate A2' provides the intermediate A3.
在市售起始物質芳基鹵化物B1與醇B2之間的金屬催化之親核性芳族取代提供醚中間物B3。中間物B3與市售起始物質苯酚衍生物B4之間的第二烏爾曼反應(Ullmann reaction)提供中間物B5。鹵素中間物B5與四烷氧基二硼或二烷氧基氫硼烷之金屬催化之交叉偶合反應提供式B6之芳基硼酸酯中間物(Ra'及Rb'為C1-C6烷基或Ra'及Rb'組合形成環硼酸酯)，可藉由水解進一步獲得對應芳基硼酸(Ra'及Rb'為氫)。 The metal-catalyzed nucleophilic aromatic substitution between the commercially available starting material aryl halide B1 and alcohol B2 provides ether intermediate B3. A second Ullmann reaction between intermediate B3 and the commercially available starting material phenol derivative B4 provides intermediate B5. Intermediate B5 halo cross coupling reaction with boron tetraalkoxide of a metal catalyst, or hydrogen dialkoxy borane provides the formula B6 aryl boronate intermediate (Ra 'and Rb' is a C 1 -C 6 alkyl The base or Ra' and Rb' are combined to form a cyclic boronic ester), and the corresponding arylboronic acid (Ra' and Rb' are hydrogen) can be further obtained by hydrolysis.
式II化合物，其中L為
係如流程C、D及E中所示，自市售起始物質製備。 Prepared from commercially available starting materials as shown in Schemes C, D and E.
中間物A3經由光延反應(Mitsunobu reaction)與中間物C1偶合，得到中間物C2。P為適當胺保護基。 The intermediate A3 is coupled to the intermediate C1 via a Mitsunobu reaction to obtain an intermediate C2. P is a suitable amine protecting group.
式C2之中間物與式B6之硼酸或硼酸酯之間在鈴木偶合反應(Suzuki coupling reaction)條件下的金屬催化劑交叉偶合反應提供中間物 D1。對中間物D1脫除保護基提供中間物D2。 Metal catalyst cross-coupling reaction between an intermediate of formula C2 and a boronic acid or borate of formula B6 under Suzuki coupling reaction provides an intermediate D1. Removal of the protecting group from the intermediate D1 provides the intermediate D2.
式II化合物係藉由醯化、磺醯化或藉由使中間物D2與溴化氰反應自中間物D2獲得。 The compound of formula II is obtained by deuteration, sulfonation or by reacting intermediate D2 with cyanogen bromide from intermediate D2.
式II化合物，其中L為
係如流程F、G及H中所示，自市售起始物質製備。 Prepared from commercially available starting materials as indicated in Schemes F, G and H.
中間物F1經由光延反應與中間物A3偶合，得到中間物F2。P為適當胺保護基。 The intermediate F1 is coupled to the intermediate A3 via a smoothing reaction to obtain an intermediate F2. P is a suitable amine protecting group.
式F2之中間物與式B6之硼酸或硼酸酯之間在鈴木偶合反應條件下的金屬催化劑交叉偶合反應提供中間物G1。對中間物G1脫除保護基提供中間物G2。 The cross-coupling reaction of the metal catalyst between the intermediate of formula F2 and the boronic acid or borate of formula B6 under Suzuki coupling reaction conditions provides intermediate G1. Removal of the protecting group from the intermediate G1 provides the intermediate G2.
式II化合物係藉由醯化、磺醯化或藉由使中間物D2與溴化氰反應自中間物G2獲得。 The compound of formula II is obtained by deuteration, sulfonation or by reacting intermediate D2 with cyanogen bromide from intermediate G2.
以下合成方法意欲代表用以製備本發明之式II化合物之化學過程且不意欲具限制性。 The following synthetic methods are intended to represent the chemical processes used to prepare the compounds of formula II of the present invention and are not intended to be limiting.
中間物1-c及1-c'、2-f、3-b至16-b如流程1至16中所示而製備。 Intermediates 1-c and 1-c', 2-f, 3-b to 16-b were prepared as shown in Schemes 1 to 16.
合成中間物1-c及1-c’：Synthetic intermediates 1-c and 1-c':
步驟1：step 1:
中間物1-bIntermediate 1-b
向中間物1-a(20.0g，129.0mmol)於2-丙醇(90ml)中之溶液中添加氫氧化銨(126ml)。將反應物在壓力容器中在95℃下加熱隔夜，隨後冷却至室溫。在减壓下移除揮發物。將殘餘物在水中濕磨；沈澱物形成，且藉由過濾收集其以提供呈白色固體狀之中間物1-b。 Ammonium hydroxide (126 ml) was added to a solution of the intermediate 1-a (20.0 g, 129.0 mmol) in 2-propanol (90 ml). The reaction was heated in a pressure vessel at 95 ° C overnight and then cooled to room temperature. The volatiles were removed under reduced pressure. The residue was wet-milled in water; a precipitate formed and collected by filtration to afford intermediate 1-b as a white solid.
中間物1-b’Intermediate 1-b’
向中間物1-a(10.0g，64.7mmol)於DMF(162ml)中之溶液中緩慢添加NBS(12.7g，71.2mmol)。將反應物在0℃下攪拌15分鐘且在室溫下攪拌隔夜。添加水；沈澱物形成，且將其藉由過濾收集、隨後在真空下乾燥以提供呈白色固體狀之中間物1-b'。 NBS (12.7 g, 71.2 mmol) was slowly added to a solution of the intermediate 1-a (10.0 g, 64.7 mmol) in DMF (162 ml). The reaction was stirred at 0 °C for 15 min and at rt overnight. Water was added; the precipitate formed and it was collected by filtration and then dried under vacuum to give intermediate 1-b' as a white solid.
步驟2：Step 2:
中間物1-cIntermediate 1-c
向中間物1-b(14.2g，105.0mmol)於DMF(120ml)中之溶液中添加N-碘丁二醯亞胺(35.5g，158.0mmol)，且將反應物在55℃下加熱隔夜，且隨後冷却至室溫。添加Na2SO3飽和水溶液，沈澱物形成，且將其藉由過濾收集、用Na2SO3飽和水溶液洗滌且隨後在真空下乾燥以提供呈白色固體狀之中間物1-c。 N-Iodobutaneimine (35.5 g, 158.0 mmol) was added to a solution of the intermediate 1-b (14.2 g, 105.0 mmol) in DMF (120 ml), and the reaction was heated overnight at 55 ° C. And then cooled to room temperature. A saturated aqueous solution of Na 2 SO 3 was added, and a precipitate was formed, which was collected by filtration, washed with saturated aqueous Na 2 SO 3 and then dried under vacuum to afford Intermediate 1-c as a white solid.
中間物1-c’Intermediate 1-c’
向中間物1-b’(6.0g，25.7mmol)於2-丙醇(36.0ml)中之溶液中添加氫氧化銨(50.0ml)。將反應物在壓力容器中在95℃下加熱隔夜，且隨後冷却至室溫。在减壓下移除揮發物。將殘餘物在水中濕磨；沈澱物形成，且將其藉由過濾收集、在真空下乾燥以提供呈白色固體狀之中間物1-c'。 Ammonium hydroxide (50.0 ml) was added to a solution of the intermediate 1-b' (6.0 g, 25.7 mmol) in 2-propanol (36.0 ml). The reaction was heated in a pressure vessel at 95 ° C overnight and then cooled to room temperature. The volatiles were removed under reduced pressure. The residue was wet-milled in water; a precipitate formed which was collected by filtration and dried under vacuum to afford intermediate 1-c' as a white solid.
合成中間物2-f：Synthetic intermediate 2-f:
步驟1：step 1:
中間物2-cIntermediate 2-c
向1-溴-3-氟-5-碘苯2-a(5.0g，16.62mmol)於甲苯(8.3ml)中之溶液中添加(2-甲基嘧啶-5-基)甲醇2-b(2.3g，18.3mmol)、1,10-菲咯啉(599mg，3.3mmol)、碘化銅(I)(316mg，1.6mmol)及碳酸銫(7.6g，23.3mmol)。將反應物在110℃下攪拌2天且隨後冷却至室溫，用乙酸乙酯稀釋且經矽藻土過濾。添加氯化銨飽和水溶液至濾液中，分離有機層，且將水相用乙酸乙酯萃取兩次。將經合併之有機萃取物用鹽水洗滌，經MgSO4乾燥，過濾且在减壓下濃縮。藉由矽膠層析純化提供呈米色固體狀之中間物2-c。 Add (2-methylpyrimidin-5-yl)methanol 2-b to a solution of 1-bromo-3-fluoro-5-iodobenzene 2-a (5.0 g, 16.62 mmol) in toluene (8.3 mL) 2.3 g, 18.3 mmol), 1,10-phenanthroline (599 mg, 3.3 mmol), copper (I) iodide (316 mg, 1.6 mmol) and cesium carbonate (7.6 g, 23.3 mmol). The reaction was stirred at 110 <0>C for 2 days and then cooled to rt. A saturated aqueous solution of ammonium chloride was added to the filtrate, the organic layer was separated, and the aqueous phase was extracted twice with ethyl acetate. The combined the organic extracts were washed with brine, dried over MgSO 4, filtered and concentrated under reduced pressure. Purification by gelatin chromatography afforded the intermediate 2-c as a beige solid.
步驟2：Step 2:
中間物2-eIntermediate 2-e
將中間物2-c(1.5g，5.0mmol)、4-氯苯酚2-d(681mg，5.3mmol)、N,N-二甲基甘胺酸(1.5g，15.1mmol)、碳酸銫(8.2g，25.2mmol)及碘化銅(I)(961mg，5.0mmol)於1,4-二噁烷(14.4ml)中之溶液在110℃下加熱2天，且隨後冷却至室溫。添加乙酸乙酯且反應物吸附在矽膠上。藉由矽膠層析純化提供呈無色油狀之中間物2-e。 Intermediate 2-c (1.5 g, 5.0 mmol), 4-chlorophenol 2-d (681 mg, 5.3 mmol), N,N-dimethylglycine (1.5 g, 15.1 mmol), cesium carbonate (8.2) A solution of g, 25.2 mmol) and copper (I) iodide (961 mg, 5.0 mmol) in 1,4-dioxane (14.4 ml) was heated at 110 ° C for 2 days and then cooled to room temperature. Ethyl acetate was added and the reaction was adsorbed onto silica gel. Purification by gelatin chromatography afforded the intermediate 2-e as a colorless oil.
步驟3：Step 3:
中間物2-fIntermediate 2-f
將中間物2-e(800mg，3.3mmol)、乙酸鈀(II)(37mg，0.17mmol)、乙酸鉀(979mg，0.17mmol)及X-Phos(158mg，0.33mmol)之脫氣溶液在壓力容器中在110℃下加熱隔夜，且隨後冷却至室溫。添加氯化銨飽和水溶液及乙酸乙酯，將有機層分離、用鹽水洗滌、經MgSO4乾燥、過濾且在减壓下濃縮。藉由矽膠層析純化提供呈黃色固體狀之中間物2-f。 a degassed solution of the intermediate 2-e (800 mg, 3.3 mmol), palladium (II) acetate (37 mg, 0.17 mmol), potassium acetate (979 mg, 0.17 mmol) and X-Phos (158 mg, 0.33 mmol) in a pressure vessel It was heated overnight at 110 ° C and then cooled to room temperature. Add saturated aqueous ammonium chloride and ethyl acetate, the organic layer was separated, washed with brine, dried over MgSO 4, filtered and concentrated under reduced pressure. Purification by gelatin chromatography afforded the intermediate 2-f as a yellow solid.
合成中間物3-b：Synthetic intermediate 3-b:
向冷却至0℃的中間物1-c(2.0g，7.7mmol)、中間物3-a(3.1g，15.3mmol)及聚合物-結合之三苯基膦(7.7g，約3mmol/g三苯基膦負載)於THF中之溶液中逐滴添加DIAD(4.5ml，23.0mmol)。在完成添加之後，將反應物在60℃下加熱2小時，且隨後冷却至室溫。過濾反應物且濾液吸附在矽膠上。藉由矽膠層析純化提供呈白色固體狀之中間物3-b。 Intermediate 1-c (2.0 g, 7.7 mmol) cooled to 0 ° C, intermediate 3-a (3.1 g, 15.3 mmol) and polymer-bound triphenylphosphine (7.7 g, about 3 mmol/g three DIAD (4.5 ml, 23.0 mmol) was added dropwise to a solution of phenylphosphine loaded in THF. After the addition was completed, the reaction was heated at 60 °C for 2 hours and then cooled to room temperature. The reaction was filtered and the filtrate was adsorbed onto silica gel. Purification by gelatin chromatography afforded the intermediate 3-b as a white solid.
合成中間物4-b：Synthetic intermediate 4-b:
向冷却至0℃的中間物1-c(1.4g，5.3mmol)、中間物4-a(1.5g，8.0mmol)及聚合物-結合之三苯基膦(3.6g，約3mmol/g三苯基膦負載)於THF中之溶液中逐滴添加DIAD(2.1ml，10.7mmol)。在完成添加之後，將反應物在60℃下加熱2小時，且隨後冷却至室溫。過濾反應物且濾液吸 附在矽膠上。藉由矽膠層析純化提供呈白色固體狀之中間物4-b。 Intermediate 1-c (1.4 g, 5.3 mmol) cooled to 0 ° C, intermediate 4-a (1.5 g, 8.0 mmol) and polymer-bound triphenylphosphine (3.6 g, about 3 mmol/g three DIAphosphine (supported with phenylphosphine) was added dropwise to DIAD (2.1 ml, 10.7 mmol) in THF. After the addition was completed, the reaction was heated at 60 °C for 2 hours and then cooled to room temperature. Filter the reaction and the filtrate is sucked Attached to silicone. Purification by gelatin chromatography afforded intermediate 4-b as a white solid.
合成中間物5-b：Synthetic intermediate 5-b:
向冷却至0℃的中間物1-c(1.0g，3.8mmol)、中間物5-a(850mg，4.2mmol)及聚合物-結合之三苯基膦(1.7g，約3mmol/g三苯基膦負載)於THF中之溶液中逐滴添加DIAD(968μl，4.2mmol)。在完成添加之後，將反應物在室溫下攪拌隔夜。過濾反應物且濾液吸附在矽膠上。藉由矽膠層析純化提供呈白色固體狀之中間物5-b。 Intermediate 1-c (1.0 g, 3.8 mmol) cooled to 0 ° C, intermediate 5-a (850 mg, 4.2 mmol) and polymer-bound triphenylphosphine (1.7 g, about 3 mmol/g triphenyl) DIAD (968 μl, 4.2 mmol) was added dropwise to the solution in THF. After the addition was completed, the reaction was stirred at room temperature overnight. The reaction was filtered and the filtrate was adsorbed onto silica gel. Purification by gelatin chromatography afforded intermediate 5-b as a white solid.
合成中間物6-b：Synthetic intermediate 6-b:
向冷却至0℃的中間物1-c(750mg，2.9mmol)、中間物6-a(538mg，2.9mmol)及聚合物-結合之三苯基膦(2.8g，約3mmol/g三苯基膦負載)於THF中之溶液中逐滴添加DIAD(1.7ml，8.6mmol)。在完成添加之後，將反應物在室溫下攪拌隔夜。過濾反應物且濾液吸附在矽膠上。藉由矽膠層析純化提供呈白色固體狀之中間物6-b。 Intermediate 1-c (750 mg, 2.9 mmol), intermediate 6-a (538 mg, 2.9 mmol) and polymer-bound triphenylphosphine (2.8 g, about 3 mmol/g triphenyl) cooled to 0 °C DIAD (1.7 ml, 8.6 mmol) was added dropwise to a solution of phosphine in THF. After the addition was completed, the reaction was stirred at room temperature overnight. The reaction was filtered and the filtrate was adsorbed onto silica gel. Purification by gelatin chromatography afforded intermediate 6-b as a white solid.
合成中間物7-b：Synthetic intermediate 7-b:
向冷却至0℃的中間物1-c(750mg，2.9mmol)、中間物7-a(578mg，2.9mmol)及聚合物-結合之三苯基膦(2.8g，約3mmol/g三苯基膦負載)於THF中之溶液中逐滴添加DIAD(1.7ml，8.6mmol)。在完成添加之後，將反應物在室溫下攪拌隔夜。過濾反應物且濾液吸附在矽膠上。藉由矽膠層析純化提供呈白色固體狀之中間物7-b。 Intermediate 1-c (750 mg, 2.9 mmol), intermediate 7-a (578 mg, 2.9 mmol) and polymer-bound triphenylphosphine (2.8 g, about 3 mmol/g triphenyl) cooled to 0 °C DIAD (1.7 ml, 8.6 mmol) was added dropwise to a solution of phosphine in THF. After the addition was completed, the reaction was stirred at room temperature overnight. The reaction was filtered and the filtrate was adsorbed onto silica gel. Purification by gelatin chromatography afforded intermediate 7-b as a white solid.
合成中間物8-b：Synthetic intermediate 8-b:
向中間物26-a．HCl(10.0g，70.6mmol)於乙醇(35ml)中之溶液中依序添加TEA(35.0ml)及Boc2O(20.0g，31.3mmol)，且將反應物在室溫下攪拌隔夜。在减壓下移除揮發物，添加乙酸乙酯及水至殘餘物中，將有機層分離，用NaHCO3飽和水溶液及鹽水洗滌，經MgSO4乾燥，過濾且在减壓下濃縮以提供呈白色固體狀之中間物8-b。 To the intermediate 26-a. TEA (35.0 ml) and Boc 2 O (20.0 g, 31.3 mmol) were added sequentially to a solution of EtOAc (10.0 g, <RTIgt; The volatiles were removed under reduced pressure, ethyl acetate and water was added to the residue, and the organic layer was separated, washed with saturated aqueous NaHCO 3 and brine, dried over MgSO 4, filtered and concentrated under reduced pressure to provide a white Solid intermediate 8-b.
合成中間物9-b：Synthetic intermediate 9-b:
向冷却至0℃的中間物1-c’(750mg，2.9mmol)、中間物8-b(1.75g，9.3mmol)及聚合物-結合之三苯基膦(3.1g，約3mmol/g三苯基膦負載)於THF中之溶液中逐滴添加DIAD(1.8ml,9.3mmol)。在完成添加之後，將反應物在室溫下攪拌隔夜。過濾反應物且濾液吸附在矽膠上。藉由矽膠層析純化提供呈白色固體狀之中間物9-b。 Intermediate 1-c' (750 mg, 2.9 mmol) cooled to 0 ° C, intermediate 8-b (1.75 g, 9.3 mmol) and polymer-bound triphenylphosphine (3.1 g, approx. 3 mmol/g DIAD (1.8 ml, 9.3 mmol) was added dropwise to a solution of phenylphosphine loaded in THF. After the addition was completed, the reaction was stirred at room temperature overnight. The reaction was filtered and the filtrate was adsorbed onto silica gel. Purification by gelatin chromatography afforded the intermediate 9-b as a white solid.
合成中間物10-b：Synthetic intermediate 10-b:
步驟1：中間物10-aStep 1: Intermediate 10-a
向中間物3-b(1.1g，2.8mmol)、中間物2-f(1.3g，2.9mmol)及碳酸鉀(1.1g，8.3mmol)於DME(14.8ml)及水(3.7ml)中之脫氣溶液中添加PdCl2(dppf)(203mg，0.3mmol)，且將反應物在壓力容器中在105℃下加熱2小時，且隨後冷却至室溫。添加乙酸乙酯，且經矽藻土過濾反應物。添加氯化銨飽和水溶液至濾液中，將有機層分離、用鹽水洗滌、經MgSO4乾燥、過濾且在减壓下濃縮。藉由矽膠層析純化提供呈白色固體狀之中間物10-a。 Intermediate 3-b (1.1 g, 2.8 mmol), intermediate 2-f (1.3 g, 2.9 mmol) and potassium carbonate (1.1 g, 8.3 mmol) in DME (14.8 ml) and water (3.7 ml) PdCl 2 (dppf) (203 mg, 0.3 mmol) was added to the degassed solution, and the reaction was heated in a pressure vessel at 105 ° C for 2 hours, and then cooled to room temperature. Ethyl acetate was added and the reaction was filtered through celite. Saturated aqueous ammonium chloride was added to the filtrate, and the organic layer was separated, washed with brine, dried over MgSO 4, filtered and concentrated under reduced pressure. Purification by gelatin chromatography afforded the intermediate 10-a as a white solid.
步驟2：中間物10-bStep 2: Intermediate 10-b
向冷却至0℃的中間物10-a(1.5g，2.4mmol)於1,4-二噁烷(10ml)及甲醇(1ml)中之溶液中添加4N HCl於1,4-二噁烷(2.9ml，96mmol)中之溶液。在完成添加之後，將反應物在室溫下攪拌1小時。添加***，沈澱物形成，且藉由過濾收集其以提供呈黃色固體狀之中間物10-b．3HCl。 To a solution of the intermediate 10-a (1.5 g, 2.4 mmol) in 1,4-dioxane (10 ml) and methanol (1 ml) was added 4N HCl in 1,4-dioxane ( A solution of 2.9 ml, 96 mmol). After the addition was completed, the reaction was stirred at room temperature for 1 hour. Ethyl ether was added and the precipitate formed and was collected by filtration to afford intermediates 10-b as a yellow solid. 3HCl.
合成中間物11-b：Synthetic intermediate 11-b:
步驟1：中間物11-aStep 1: Intermediate 11-a
向中間物4-b(1.1g，2.5mmol)、中間物2-f(1.1g，2.6mmol) 及碳酸鉀(1.0g，7.5mmol)於DME(13.4ml)及水(3.3ml)中之脫氣溶液中添加PdCl2(dppf)(184mg，0.2mmol)，且將反應物在壓力容器中在105℃下加熱隔夜，且隨後冷却至室溫。添加乙酸乙酯，且經矽藻土過濾反應物。添加氯化銨飽和水溶液至濾液中，將有機層分離、用鹽水洗滌、經MgSO4乾燥、過濾且在减壓下濃縮。藉由矽膠層析純化提供呈白色泡沫狀之中間物11-a。 Intermediate 4-b (1.1 g, 2.5 mmol), intermediate 2-f (1.1 g, 2.6 mmol) and potassium carbonate (1.0 g, 7.5 mmol) in DME (13.4 ml) and water (3.3 ml) PdCl 2 (dppf) (184 mg, 0.2 mmol) was added to the degassed solution, and the reaction was heated in a pressure vessel at 105 ° C overnight and then cooled to room temperature. Ethyl acetate was added and the reaction was filtered through celite. Saturated aqueous ammonium chloride was added to the filtrate, and the organic layer was separated, washed with brine, dried over MgSO 4, filtered and concentrated under reduced pressure. Purification by gelatin chromatography afforded the intermediate 11-a as a white foam.
步驟2：中間物11-bStep 2: Intermediate 11-b
向冷却至0℃的中間物11-a(1.5g，2.4mmol)於1,4-二噁烷(10ml)及甲醇(1ml)中之溶液中添加4N HCl於1,4-二噁烷(2.9ml，96mmol)中之溶液。在完成添加之後，將反應物在室溫下攪拌1小時。添加***，沈澱物形成，且藉由過濾收集其以提供呈黃色固體狀之中間物11-b．3HCl。將中間物11-b．3HCl懸浮於二氯甲烷中，且緩慢添加NaHCO3飽和水溶液。在攪拌15分鐘之後，將有機層分離，用NaHCO3飽和水溶液及鹽水洗滌，經MgSO4乾燥，過濾且在减壓下濃縮以提供呈黃色固體狀之中間物11-b。 To a solution of the intermediate 11-a (1.5 g, 2.4 mmol) in 1,4-dioxane (10 ml) and methanol (1 ml) was added 4N HCl in 1,4-dioxane ( A solution of 2.9 ml, 96 mmol). After the addition was completed, the reaction was stirred at room temperature for 1 hour. Ethyl ether was added and the precipitate formed and was collected by filtration to afford intermediate 11-b as a yellow solid. 3HCl. Intermediate 11-b. 3HCl suspended in dichloromethane, and saturated aqueous NaHCO 3 was added slowly. After stirring for 15 minutes, the organic layer was separated, washed with saturated aqueous NaHCO 3 and brine, dried over MgSO 4, filtered and concentrated to provide a yellow solid of intermediate 11-b thereof under reduced pressure.
合成中間物12-b：Synthetic intermediate 12-b:
步驟1：step 1:
中間物12-aIntermediate 12-a
向中間物5-b(1.7g，3.8mmol)、中間物2-f(1.7g，4.0mmol)及碳酸鉀(1.6g，11.5mmol)於DME(20.4ml)及水(5.1ml)中之脫氣溶液中添加PdCl2(dppf)(280mg，0.4mmol)，且將反應物在壓力容器中在105℃下加熱2小時，且隨後冷却至室溫。添加乙酸乙酯，且經矽藻土過濾反應物。添加氯化銨飽和水溶液至濾液中，將有機層分離、用鹽水洗滌、經MgSO4 乾燥、過濾且在减壓下濃縮。藉由矽膠層析純化提供呈白色泡沫狀之中間物12-a。 To intermediates 5-b (1.7 g, 3.8 mmol), intermediate 2-f (1.7 g, 4.0 mmol) and potassium carbonate (1.6 g, 11.5 mmol) in DME (20.4 ml) and water (5.1 ml) PdCl 2 (dppf) (280 mg, 0.4 mmol) was added to the degassed solution, and the reaction was heated in a pressure vessel at 105 ° C for 2 hours, and then cooled to room temperature. Ethyl acetate was added and the reaction was filtered through celite. Saturated aqueous ammonium chloride was added to the filtrate, and the organic layer was separated, washed with brine, dried over MgSO 4, filtered and concentrated under reduced pressure. Purification by gelatin chromatography afforded the intermediate 12-a as a white foam.
步驟2：Step 2:
中間物12-bIntermediate 12-b
向冷却至0℃的中間物12-a(2.0g，3.2mmol)於1,4-二噁烷(10ml)及甲醇(1ml)中之溶液中添加4N HCl於1,4-二噁烷(3.4ml，128mmol)中之溶液。在完成添加之後，將反應物在0℃下攪拌1小時。添加***，沈澱物形成，且藉由過濾收集其以提供呈黃色固體狀之中間物12-b．3HCl。 To a solution of the intermediate 12-a (2.0 g, 3.2 mmol) in 1,4-dioxane (10 ml) and methanol (1 ml) was added 4N HCl in 1,4-dioxane ( A solution of 3.4 ml, 128 mmol). After the addition was completed, the reaction was stirred at 0 ° C for 1 hour. Diethyl ether was added and the precipitate formed and was collected by filtration to afford intermediate 12-b as a yellow solid. 3HCl.
合成中間物13-b：Synthetic intermediate 13-b:
步驟1：step 1:
中間物13-aIntermediate 13-a
向中間物6-b(360mg，0.8mmol)、中間物2-f(402mg，0.9mmol)及碳酸鉀(347mg，2.5mmol)於DME(4.5ml)及水(1.1ml)中之脫氣溶液中添加PdCl2(dppf)(61mg，0.08mmol)，且將反應物在壓力容器中在105℃下加熱隔夜，且隨後冷却至室溫。添加乙酸乙酯，且經矽藻土過濾反應物。添加氯化銨飽和水溶液至濾液中，將有機層分離、用鹽水洗滌、經MgSO4乾燥、過濾且在减壓下濃縮。藉由矽膠層析純化提供呈白色泡沫狀之中間物13-a。 Degassed solution of intermediate 6-b (360 mg, 0.8 mmol), intermediate 2-f (402 mg, 0.9 mmol) and potassium carbonate (347 mg, 2.5 mmol) in DME (4.5 ml) and water (1.1 ml) PdCl 2 (dppf) (61 mg, 0.08 mmol) was added and the reaction was heated in a pressure vessel at 105 ° C overnight and then cooled to room temperature. Ethyl acetate was added and the reaction was filtered through celite. Saturated aqueous ammonium chloride was added to the filtrate, and the organic layer was separated, washed with brine, dried over MgSO 4, filtered and concentrated under reduced pressure. Purification by gelatin chromatography afforded the intermediate 13-a as a white foam.
步驟2：Step 2:
中間物13-bIntermediate 13-b
向冷却至0℃的中間物13-a(513mg，0.8mmol)於1,4-二噁烷(5ml)及甲醇(1ml)中之溶液中添加4N HCl於1,4-二噁烷(4.2ml，16.7 mmol)中之溶液。在完成添加之後，將反應物在0℃下攪拌1小時。在减壓下移除揮發物。添加***，沈澱物形成，且藉由過濾收集其以提供呈白色固體狀之中間物13-b．3HCl。 Add 4N HCl to 1,4-dioxane (4.2) to a solution of intermediate 13-a (513 mg, 0.8 mmol) in 1,4-dioxane (5 ml) and methanol (1 ml). Ml, 16.7 A solution in mmol). After the addition was completed, the reaction was stirred at 0 ° C for 1 hour. The volatiles were removed under reduced pressure. Ethyl ether was added and the precipitate formed and was collected by filtration to afford intermediate 13-b as a white solid. 3HCl.
合成中間物14-b：Synthetic intermediate 14-b:
步驟1：step 1:
中間物14-aIntermediate 14-a
向中間物7-b(370mg，0.8mmol)、中間物2-f(400mg，0.9mmol)及碳酸鉀(345mg，2.5mmol)於DME(4.5ml)及水(1.1ml)中之脫氣溶液中添加PdCl2(dppf)(61mg，0.08mmol)，且將反應物在壓力容器中在105℃下加熱隔夜，且隨後冷却至室溫。添加乙酸乙酯，且經矽藻土過濾反應物。添加氯化銨飽和水溶液至濾液中，將有機層分離、用鹽水洗滌、經MgSO4乾燥、過濾且在减壓下濃縮。藉由矽膠層析純化提供呈白色泡沫狀之中間物14-a。 Degassed solution of intermediate 7-b (370 mg, 0.8 mmol), intermediate 2-f (400 mg, 0.9 mmol) and potassium carbonate (345 mg, 2.5 mmol) in DME (4.5 ml) and water (1.1 ml) PdCl 2 (dppf) (61 mg, 0.08 mmol) was added and the reaction was heated in a pressure vessel at 105 ° C overnight and then cooled to room temperature. Ethyl acetate was added and the reaction was filtered through celite. Saturated aqueous ammonium chloride was added to the filtrate, and the organic layer was separated, washed with brine, dried over MgSO 4, filtered and concentrated under reduced pressure. Purification by gelatin chromatography afforded the intermediate 14-a as a white foam.
步驟2：Step 2:
中間物14-bIntermediate 14-b
向冷却至0℃的中間物14-a(522mg，0.8mmol)於1,4-二噁烷(5ml)及甲醇(1ml)中之溶液中添加4N HCl於1,4-二噁烷(4.2ml，16.7mmol)中之溶液。在完成添加之後，將反應物在0℃下攪拌1小時。在减壓下移除揮發物。添加***，沈澱物形成，且藉由過濾收集其以提供呈白色固體狀之中間物14-b．3HCl。 Add 4N HCl to 1,4-dioxane (4.2) to a solution of intermediate 14-a (522 mg, 0.8 mmol) in 1,4-dioxane (5 ml) and methanol (1 ml). A solution of ml, 16.7 mmol). After the addition was completed, the reaction was stirred at 0 ° C for 1 hour. The volatiles were removed under reduced pressure. Diethyl ether was added and the precipitate formed and was collected by filtration to afford intermediate 14-b as a white solid. 3HCl.
合成中間物15-b：Synthetic intermediate 15-b:
向冷却至0℃的中間物1-c’(300mg，1.4mmol)、中間物29-a(344mg，1.6mmol)及三苯基膦(404mg，1.5mmol)於THF中之溶液中逐滴添加DIAD(300μl，1.5mmol)。在完成添加之後，將反應物在室溫下攪拌隔夜。添加氯化銨飽和水溶液及乙酸乙酯，將有機層分離、用鹽水洗滌、經MgSO4乾燥、過濾且在减壓下濃縮。藉由矽膠層析純化提供呈黃色固體狀之中間物15-b。 Add dropwise to a solution of intermediate 1-c' (300 mg, 1.4 mmol), intermediate 29-a (344 mg, 1.6 mmol) and triphenylphosphine (404 mg, 1.5 mmol) in THF cooled to 0 °C. DIAD (300 μl, 1.5 mmol). After the addition was completed, the reaction was stirred at room temperature overnight. Add saturated aqueous ammonium chloride and ethyl acetate, the organic layer was separated, washed with brine, dried over MgSO 4, filtered and concentrated under reduced pressure. Purification by gelatin chromatography afforded intermediate 15-b as a yellow solid.
合成中間物16-b：Synthetic intermediate 16-b:
步驟1：step 1:
中間物16-aIntermediate 16-a
向中間物9-b(1.0g，2.6mmol)、中間物2-f(1.25g，2.9mmol)及碳酸鉀(1.1mg，7.8mmol)於DME(13.9ml)及水(3.5ml)中之脫氣溶液中添加PdCl2(dppf)(191mg，0.26mmol)，且將反應物在壓力容器中在105℃下加熱隔夜，且隨後冷却至室溫。添加乙酸乙酯，且經矽藻土過濾反應物。添加氯化銨飽和水溶液至濾液中，將有機層分離、用鹽水洗滌、經MgSO4乾燥、過濾且在减壓下濃縮。藉由矽膠層析純化提供呈白色泡沫狀之中間 物16-a。 Intermediate 9-b (1.0 g, 2.6 mmol), intermediate 2-f (1.25 g, 2.9 mmol) and potassium carbonate (1.1 mg, 7.8 mmol) in DME (13.9 ml) and water (3.5 ml) PdCl 2 (dppf) (191 mg, 0.26 mmol) was added to the degassed solution, and the reaction was heated overnight at 105 ° C in a pressure vessel, and then cooled to room temperature. Ethyl acetate was added and the reaction was filtered through celite. Saturated aqueous ammonium chloride was added to the filtrate, and the organic layer was separated, washed with brine, dried over MgSO 4, filtered and concentrated under reduced pressure. Purification by gelatin chromatography afforded the intermediate 16-a as a white foam.
步驟2：Step 2:
中間物16-bIntermediate 16-b
向冷却至0℃的中間物16-a(1.1g，1.8mmol)於1,4-二噁烷(10ml)及甲醇(1ml)中之溶液中添加4N HCl於1,4-二噁烷(2.2ml，71.8mmol)中之溶液。在完成添加之後，將反應物在室溫下攪拌1小時。添加***，沈澱物形成，且藉由過濾收集其以提供呈黃色固體狀之中間物16-b．3HCl。 To a solution of the intermediate 16-a (1.1 g, 1.8 mmol) in 1,4-dioxane (10 ml) and methanol (1 ml) was added 4N HCl in 1,4-dioxane ( A solution of 2.2 ml, 71.8 mmol). After the addition was completed, the reaction was stirred at room temperature for 1 hour. Ethyl ether was added and the precipitate formed and was collected by filtration to afford intermediate 16-b as a yellow solid. 3HCl.
化合物1、7、10、14、15、16、17、19、20係如流程17至25中所示製備。 Compounds 1, 7, 10, 14, 15, 16, 17, 19, 20 were prepared as shown in Schemes 17 to 25.
合成化合物1：Synthetic Compound 1:
向中間物12-b(100mg，0.16mmol)於二氯甲烷(1.6ml)中之溶液中依序添加TEA(219μl，1.6mmol)及溴化氰(20mg，0.19mmol)，且將反應物在室溫下攪拌2小時。在减壓下移除揮發物。藉由矽膠層析純化提供呈米色固體狀之化合物1。 TEA (219 μl, 1.6 mmol) and cyanogen bromide (20 mg, 0.19 mmol) were added sequentially to a solution of intermediate 12-b (100 mg, 0.16 mmol) in dichloromethane (1.6 mL). Stir at room temperature for 2 hours. The volatiles were removed under reduced pressure. Purification by gelatin chromatography gave Compound 1 as a beige solid.
化合物8及化合物33係以與化合物1類似之方式分別自中間物10-b及14-b開始製備。 Compound 8 and Compound 33 were prepared in the same manner as Compound 1, starting from Intermediates 10-b and 14-b, respectively.
合成化合物14：Synthesis of Compound 14:
向中間物12-b(100mg，0.16mmol)於NMP(1.6ml)中之溶液中依序添加DIPEA(137μl，0.78mmol)及丙烯醯氯(17mg，0.19mmol)，且將反應物在室溫下攪拌2小時。添加氯化銨飽和水溶液及二氯甲烷，將有機層分離、用鹽水洗滌、經MgSO4乾燥、過濾且在减壓下濃縮。藉由矽膠層析純化提供呈白色固體狀之化合物14。 DIPEA (137 μl, 0.78 mmol) and propylene hydrazine chloride (17 mg, 0.19 mmol) were added sequentially to a solution of intermediate 12-b (100 mg, 0.16 mmol) in NMP (1.6 mL). Stir under 2 hours. Add saturated aqueous ammonium chloride and dichloromethane, the organic layer was separated, washed with brine, dried over MgSO 4, filtered and concentrated under reduced pressure. Purification by silica gel chromatography gave Compound 14 as a white solid.
化合物12、22、23、25、27、31及34係以與化合物14類似之方式分別自中間物10-b、11-b、13-b、14-b、16-b、28-b．3HCl及29b·3TFA開始製備。 Compounds 12, 22, 23, 25, 27, 31 and 34 are in a similar manner to compound 14 from intermediates 10-b, 11-b, 13-b, 14-b, 16-b, 28-b, respectively. 3HCl and 29b · 3TFA were prepared.
合成化合物16：Synthesis of Compound 16:
向冷却至0℃的中間物10-b·3HCl(43mg，0.26mmol)於NMP(2.0ml)中之溶液中依序添加DIPEA(206μl，0.78mmol)及(E)-4-溴丁-2-烯醯 氯於二氯甲烷中之溶液，且將反應物攪拌1小時。添加1.0M二甲胺溶液(2.3ml，2.3mmol)，且隨後將混合物在室溫下攪拌隔夜。在减壓下移除揮發物，且殘餘物吸附在矽膠上。藉由矽膠層析純化提供呈白色固體狀之化合物16。 DIPEA (206 μl, 0.78 mmol) and (E)-4-bromobutane-2 were added sequentially to a solution of the intermediate 10-b · 3HCl (43 mg, 0.26 mmol) in NMP (2.0 mL). a solution of ene chloride in dichloromethane and the reaction was stirred for 1 hour. 1.0 M dimethylamine solution (2.3 ml, 2.3 mmol) was added, and the mixture was stirred at room temperature overnight. The volatiles were removed under reduced pressure and the residue was adsorbed on silica gel. Purification by gelatin chromatography afforded compound 16 as a white solid.
製備(E)-4-溴丁-2-烯醯氯： Preparation of (E)-4-bromobut-2-enyl chloride:
向(E)-4-溴丁-2-烯酸(43mg，0.26mmol)於二氯甲烷中之溶液中添加乙二醯氯(41μl，0.47mmol)及DMF(183μl，2.4mmol)，且將溶液在室溫下攪拌1小時。在减壓下移除揮發物，且殘餘物溶解於二氯甲烷中。 To a solution of (E)-4-bromobut-2-enoic acid (43 mg, 0.26 mmol) in dichloromethane, EtOAc (EtOAc, EtOAc, m. The solution was stirred at room temperature for 1 hour. The volatiles were removed under reduced pressure and the residue was dissolved in dichloromethane.
化合物9係以與化合物16類似之方式自中間物12-b開始製備。 Compound 9 was prepared starting from intermediate 12-b in a similar manner to compound 16.
合成化合物20：Synthesis of Compound 20:
向中間物10-b(100mg，0.19mmol)於DMF(2ml)中之溶液中依序添加DIPEA(165μl，0.95mmol)、EDC(55mg，0.28mmol)、HOBt(44mg，0.28mmol)及2-氟丙烯酸(21mg，0.23mmol)，且將反應物在室溫下攪拌隔夜。添加氯化銨飽和水溶液及乙酸乙酯，將有機層分離、用鹽水洗滌、經MgSO4乾燥、過濾且在减壓下濃縮。藉由矽膠層析純化提供呈白色固體狀之化合物20。 DIPEA (165 μl, 0.95 mmol), EDC (55 mg, 0.28 mmol), HOBt (44 mg, 0.28 mmol) and 2- were added sequentially to a solution of the intermediate 10-b (100 mg, 0.19 mmol) in DMF (2 mL) Fluoroacrylic acid (21 mg, 0.23 mmol), and the mixture was stirred at room temperature overnight. Add saturated aqueous ammonium chloride and ethyl acetate, the organic layer was separated, washed with brine, dried over MgSO 4, filtered and concentrated under reduced pressure. Purification by gelatin chromatography afforded compound 20 as a white solid.
化合物6及18係以與化合物類似之方式20分別自中間物12-b及11-b開始製備。 Compounds 6 and 18 were prepared in a similar manner to the compound 20 starting from intermediates 12-b and 11-b, respectively.
合成化合物19：Synthesis of Compound 19:
在0℃下向中間物11-b(100mg，0.19mmol)於二氯甲烷(2ml)中之溶液中依序添加DIPEA(170μl，0.97mmol)及2-氯乙磺醯氯(23μl，0.21mmol)，且隨後將反應物在室溫下攪拌隔夜。添加氯化銨飽和水溶液及二氯甲烷，將有機層分離、用鹽水洗滌、經MgSO4乾燥、過濾且在减壓下濃縮。藉由矽膠層析純化提供呈白色固體狀之化合物19。 DIPEA (170 μl, 0.97 mmol) and 2-chloroethanesulfonium chloride (23 μl, 0.21 mmol) were added sequentially to a solution of the intermediate 11-b (100 mg, 0.19 mmol) in dichloromethane (2 mL). The reaction was then stirred overnight at room temperature. Add saturated aqueous ammonium chloride and dichloromethane, the organic layer was separated, washed with brine, dried over MgSO 4, filtered and concentrated under reduced pressure. Purification by gelatin chromatography afforded compound 19 as a white solid.
化合物21係以與化合物19類似之方式自中間物10-b開始製備。 Compound 21 was prepared starting from intermediate 10-b in a similar manner to compound 19.
合成化合物17：Synthesis of Compound 17:
向中間物11-b·3HCl(500mg，0.8mmol)於DMF(10ml)中之溶液中依序添加丁-2-炔酸(86mg，1.0mmol)、EDC(246mg，1.3mmol)、 HOBt(196mg，1.3mmol)及DIPEA(744μl，4.3mmol)，且隨後將反應物在室溫下攪拌2小時。添加氯化銨飽和水溶液及乙酸乙酯，將有機層分離、用鹽水洗滌、經MgSO4乾燥、過濾且在减壓下濃縮。藉由矽膠層析純化提供呈白色固體狀之化合物17。 Add 4-butynoic acid (86 mg, 1.0 mmol), EDC (246 mg, 1.3 mmol), HOBt (196 mg) to a solution of the intermediate 11-b · 3 HCl (500 mg, 0.8 mmol) in DMF (10 mL) , 1.3 mmol) and DIPEA (744 μl, 4.3 mmol), and then the mixture was stirred at room temperature for 2 hr. Add saturated aqueous ammonium chloride and ethyl acetate, the organic layer was separated, washed with brine, dried over MgSO 4, filtered and concentrated under reduced pressure. Purification by gelatin chromatography afforded compound 17 as a white solid.
化合物5、11、24、26、28及32係以與化合物17類似之方式分別自中間物12-b、10-b、13-b、14-b、16-b及28-b．3HCl開始製備。 Compounds 5, 11, 24, 26, 28 and 32 are in a similar manner to compound 17 from intermediates 12-b, 10-b, 13-b, 14-b, 16-b and 28-b, respectively. 3HCl was started to prepare.
合成化合物10：Synthesis of Compound 10:
向中間物10-b(65mg，0.1mmol)於二氯甲烷(1.0ml)中之溶液中依序添加TEA(142μl，1.0mmol)、EDC(29mg，0.15mmol)及丙炔酸(10.7mg，0.15mmol)，且隨後將反應物在室溫下攪拌隔夜。在减壓下移除揮發物，且殘餘物吸附在矽膠上。藉由矽膠層析純化提供呈白色固體狀之化合物10。 TEA (142 μl, 1.0 mmol), EDC (29 mg, 0.15 mmol) and propiolic acid (10.7 mg, were added sequentially to a solution of the intermediate 10-b (65 mg, 0.1 mmol) in dichloromethane (1.0 ml). 0.15 mmol), and the reaction was stirred at rt overnight. The volatiles were removed under reduced pressure and the residue was adsorbed on silica gel. Purification by gelatin chromatography afforded compound 10 as a white solid.
化合物13係以與化合物10類似之方式自中間物12-b開始製備。 Compound 13 was prepared starting from intermediate 12-b in a similar manner to compound 10.
合成化合物15：Synthesis of Compound 15:
向中間物12-b(80mg，0.12mmol)於二氯甲烷(1.3ml)中之溶液中依序添加DIPEA(109μl，0.6mmol)、EDC(24mg，0.12mmol)及環丁-1-烯甲酸(19mg，0.18mmol)，且隨後將反應物在室溫下攪拌隔夜。添加鹽水及二氯甲烷；將有機層分離，經MgSO4乾燥，過濾且在减壓下濃縮。藉由矽膠層析純化提供呈白色固體狀之化合物15。 DIPEA (109 μl, 0.6 mmol), EDC (24 mg, 0.12 mmol) and cyclobut-1-enecarboxylic acid were added sequentially to a solution of intermediate 12-b (80 mg, 0.12 mmol) in dichloromethane (1.3 mL). (19 mg, 0.18 mmol), and then the reaction was stirred at room temperature overnight. Brine and methylene chloride; the organic layer was separated, dried over MgSO 4, filtered and concentrated under reduced pressure. Purification by gelatin chromatography afforded compound 15 as a white solid.
化合物2及3係以與化合物類似之方式15分別自中間物12-b及環戊-1-烯甲酸、環戊-1-烯甲酸酸開始製備。 Compounds 2 and 3 were prepared in a similar manner to the compound 15 starting from intermediate 12-b and cyclopent-1-enecarboxylic acid, cyclopent-1-enecarboxylic acid, respectively.
合成化合物7：Synthesis of Compound 7:
向中間物10-b(80mg，0.12mmol)於DMF(1.3ml)中之溶液中依序添加TEA(219μl，1.6mmol)及甲基丙烯酸2,5-二側氧基吡咯啶-1-酯(35mg，0.18mmol)，且隨後將反應物在室溫下攪拌隔夜。添加鹽水及乙酸 乙酯；將有機層分離，經MgSO4乾燥，過濾且在减壓下濃縮。藉由矽膠層析純化提供呈米色固體狀之化合物7。 TEA (219 μl, 1.6 mmol) and 2,5-di- oxypyrrolidin-1-carboxylate were added sequentially to a solution of the intermediate 10-b (80 mg, 0.12 mmol) in DMF (1.3 mL). (35 mg, 0.18 mmol), and then the mixture was stirred at room temperature overnight. Brine and ethyl acetate; the organic layer was separated, dried over MgSO 4, filtered and concentrated under reduced pressure. Purification by gelatin chromatography afforded compound 7 as a beige solid.
化合物4係以與化合物7類似之方式自中間物12-b開始製備。 Compound 4 was prepared starting from intermediate 12-b in a similar manner to compound 7.
中間物26-c、27-a、28-b及29-b係如流程26至29中所示製備。 Intermediates 26-c, 27-a, 28-b, and 29-b were prepared as shown in Schemes 26-29.
合成中間物26-cSynthetic intermediate 26-c
步驟2：Step 2:
中間物26-bIntermediate 26-b
向冷却至0℃的中間物8-b(2.0g，10.7mmol)於無水THF(53ml)中之溶液中緩慢添加1.0M LiAlH4於THF中之溶液(32.0ml，31.0mmol)。在完成添加之後，將反應物升溫至室溫，在65℃下攪拌2小時且隨後冷却至0℃。隨後添加15% NaOH水溶液，且在攪拌15分鐘之後，過濾反應物。在减壓下濃縮濾液。藉由矽膠層析純化提供呈白色固體狀之中間物26-b。 Intermediate was cooled to 0 ℃ the 8-b (2.0g, 10.7mmol) in dry THF (53ml) was slowly added in the solution of 1.0M LiAlH 4 in THF solution of (32.0ml, 31.0mmol). After the addition was completed, the reaction was warmed to room temperature, stirred at 65 °C for 2 hours and then cooled to 0 °C. A 15% aqueous NaOH solution was then added, and after stirring for 15 minutes, the reaction was filtered. The filtrate was concentrated under reduced pressure. Purification by gelatin chromatography afforded intermediate 26-b as a white solid.
步驟3：Step 3:
中間物26-cIntermediate 26-c
向中間物26-b(800mg，7.9mmol)於乙醇(5.0ml)中之溶液中依序添加TEA(4.9ml)及Boc2O(1.7g，7.9mmol)，且將反應物在室溫下攪拌4天。在减壓下移除揮發物，添加二氯甲烷及水至殘餘物中，分離有機層，將水層用二氯甲烷萃取兩次，將經合併之有機萃取物用NaHCO3飽 和水溶液及鹽水洗滌，經MgSO4乾燥，過濾且在减壓下濃縮以提供呈無色油狀之中間物26-c。 TEA (4.9 ml) and Boc 2 O (1.7 g, 7.9 mmol) were added sequentially to a solution of the intermediate 26-b (800 mg, 7.9 mmol) in ethanol (5.0 mL). Stir for 4 days. The volatiles were removed under reduced pressure, dichloromethane and water was added to the residue, and the organic layer was separated, washed the aqueous layer was extracted twice with dichloromethane, the combined organic extracts were washed with saturated aqueous NaHCO 3 and brine , dried over MgSO 4, filtered and concentrated to provide a colorless oil of intermediate 26-c thereof under reduced pressure.
合成中間物27-a：Synthetic intermediate 27-a:
向冷却至0℃的中間物1-c(259mg，1.0mmol)、中間物26-c(200mg，1.0mmol)及聚合物-結合之三苯基膦(1.0g，約3mmol/g三苯基膦負載)於THF中之溶液中逐滴添加DIAD(580μl，3.0mmol)。在完成添加之後，將反應物在室溫下攪拌5分鐘、在60℃下攪拌2小時，且隨後冷却至室溫。過濾反應物且濾液吸附在矽膠上。藉由矽膠層析純化提供呈白色固體狀之中間物27-a。 Intermediate 1-c (259 mg, 1.0 mmol) cooled to 0 ° C, intermediate 26-c (200 mg, 1.0 mmol) and polymer-bound triphenylphosphine (1.0 g, about 3 mmol/g triphenyl) DIAD (580 μl, 3.0 mmol) was added dropwise to a solution of phosphine in THF. After the addition was completed, the reaction was stirred at room temperature for 5 minutes, at 60 ° C for 2 hours, and then cooled to room temperature. The reaction was filtered and the filtrate was adsorbed onto silica gel. Purification by gelatin chromatography afforded intermediate 27-a as a white solid.
合成中間物28-b：Synthetic intermediate 28-b:
步驟1：step 1:
中間物28-aIntermediate 28-a
向中間物27-a(150mg，0.4mmol)、中間物2-f(162mg，0.4mmol)及碳酸鉀(140mg，1.0mmol)於DME(1.8ml)及水(450μl)中之脫氣溶液中添加PdCl2(dppf)(25mg，0.03mmol)，且將反應物在壓力容器中在105℃下加熱2小時，且隨後冷却至室溫。添加乙酸乙酯，且經矽藻土過濾反 應物。添加氯化銨飽和水溶液至濾液中，將有機層分離、用鹽水洗滌、經MgSO4乾燥、過濾且在减壓下濃縮。藉由矽膠層析純化提供呈白色泡沫狀之中間物28-a。 To a degassed solution of intermediate 27-a (150 mg, 0.4 mmol), intermediate 2-f (162 mg, 0.4 mmol) and potassium carbonate (140 mg, 1.0 mmol) in DME (1.8 ml) and water (450 μl) PdCl 2 (dppf) (25 mg, 0.03 mmol) was added and the reaction was heated in a pressure vessel at 105 °C for 2 h and then cooled to room temperature. Ethyl acetate was added and the reaction was filtered through celite. Saturated aqueous ammonium chloride was added to the filtrate, and the organic layer was separated, washed with brine, dried over MgSO 4, filtered and concentrated under reduced pressure. Purification by gelatin chromatography afforded the intermediate 28-a as a white foam.
步驟2：Step 2:
中間物28-bIntermediate 28-b
向冷却至0℃的中間物28-a(150mg，0.2mmol)於1,4-二噁烷(5ml)及甲醇(1ml)中之溶液中添加4N HCl於1,4-二噁烷(1.2ml，4.8mmol)中之溶液。在完成添加之後，將反應物在0℃下攪拌1小時。在减壓下移除揮發物。添加***，沈澱物形成，且藉由過濾收集其以提供呈白色固體狀之中間物28-b．3HCl。 Add 4N HCl to 1,4-dioxane (1.2) to a solution of the intermediate 28-a (150 mg, 0.2 mmol) in 1,4-dioxane (5 ml) and methanol (1 ml). A solution of ml, 4.8 mmol). After the addition was completed, the reaction was stirred at 0 ° C for 1 hour. The volatiles were removed under reduced pressure. Ethyl ether was added and the precipitate formed and was collected by filtration to afford intermediate 28-b as a white solid. 3HCl.
合成中間物29-b：Synthetic intermediate 29-b:
步驟1：step 1:
中間物29-aIntermediate 29-a
向中間物15-b(281mg，0.6mmol)、中間物2-f(281mg，0.6mmol)及碳酸鉀(243mg，1.7mmol)於DME(3.2ml)及水(780μl)中之脫氣溶液中添加PdCl2(dppf)(43mg，0.06mmol)，且將反應物在壓力容器中在105℃下加熱2小時，且隨後冷却至室溫。添加乙酸乙酯，且經矽藻土過濾反應物。添加氯化銨飽和水溶液至濾液中，將有機層分離、用鹽水洗滌、經MgSO4乾燥、過濾且在减壓下濃縮。藉由矽膠層析純化提供呈白色固體狀之中間物29-a。 To a degassed solution of intermediate 15-b (281 mg, 0.6 mmol), intermediate 2-f (281 mg, 0.6 mmol) and potassium carbonate (243 mg, 1.7 mmol) in DME (3.2 ml) and water (780 μl) PdCl 2 (dppf) (43 mg, 0.06 mmol) was added and the reaction was heated in a pressure vessel at 105 °C for 2 h and then cooled to room temperature. Ethyl acetate was added and the reaction was filtered through celite. Saturated aqueous ammonium chloride was added to the filtrate, and the organic layer was separated, washed with brine, dried over MgSO 4, filtered and concentrated under reduced pressure. Purification by gelatin chromatography afforded intermediate 29-a as a white solid.
步驟2：Step 2:
中間物29-bIntermediate 29-b
向中間物30-a(350mg，0.5mmol)於二氯甲烷(5ml)中之溶液中添加TFA(42μl，0.5mmol)，且將反應物在室溫下攪拌1小時。在减壓下移除揮發物。添加***至殘餘物中；沈澱物形成，且藉由過濾收集其以提供呈米色固體狀之中間物29-b·3TFA。 TFA (42 μl, 0.5 mmol) was added to aq. The volatiles were removed under reduced pressure. Diethyl ether was added to the residue; a precipitate formed which was collected by filtration to afford intermediate 29-b · 3TFA as a beige solid.
以下部分描述可適用於製備本發明之化合物且不意欲具限制性的通用合成方法。 The following sections describe general synthetic methods that are applicable to the preparation of the compounds of the invention and are not intended to be limiting.
本發明之化合物，其中A為
係根據以下程序製備：
本發明之化合物，其中A為且L-E為
係以類似上述之方式藉由將取代為製備 By way of the above Replaced by preparation
其中環B及B’、n、R、R2及E如上定義。 Wherein Rings B and B', n, R, R 2 and E are as defined above.
代表性實例列於以下：
其中：X1及X2獨立地選自氫及氟；R2係選自氫及甲基；E係選自、、、及-CN，且R係選自氫及甲基。 Wherein: X 1 and X 2 are independently selected from hydrogen and fluorine; R 2 is selected from hydrogen and methyl; and E is selected from , , , And -CN, and R is selected from the group consisting of hydrogen and methyl.
本發明之化合物，其中A為
係根據以下程序製備：
本發明之化合物，其中A為且L-E為
係以類似方式藉由將 取代為製備 In a similar manner Replaced by preparation
其中環B及B'、n、R、R2及E如上定義。 Wherein Rings B and B', n, R, R 2 and E are as defined above.
代表性實例列於以下：
其中：X1及X2獨立地選自氫及氟；R2係選自氫及甲基；E係選自、、、及-CN，且R係選自氫及甲基。 Wherein: X 1 and X 2 are independently selected from hydrogen and fluorine; R 2 is selected from hydrogen and methyl; and E is selected from , , , And -CN, and R is selected from the group consisting of hydrogen and methyl.
本發明之化合物，其中A為
可根據以下程序製備：
本發明之化合物，其中A為
且L-E為
係以類似方式藉由將取代為製備 In a similar manner Replaced by preparation
其中環B及B'、n、R、R2及E如上定義。 Wherein Rings B and B', n, R, R 2 and E are as defined above.
代表性實例列於以下：
其中：X1及X2獨立地選自氫及氟；R2係選自氫及甲基； E係選自、、、及-CN，且R係選自氫及甲基。 Wherein: X 1 and X 2 are independently selected from hydrogen and fluorine; R 2 is selected from hydrogen and methyl; , , , And -CN, and R is selected from the group consisting of hydrogen and methyl.
本發明之化合物，其中A為
係根據以下程序製備：
本發明之化合物，其中A為
且L-E為
係以類似方式藉由將 取代為製備 In a similar manner Replaced by preparation
其中環B及B'、n、R、R2及E如上定義。 Wherein Rings B and B', n, R, R 2 and E are as defined above.
代表性實例列於以下：
其中：X1及X2獨立地選自氫及氟；R2係選自氫及甲基；E係選自、、、及-CN，且R係選自氫及甲基。 Wherein: X 1 and X 2 are independently selected from hydrogen and fluorine; R 2 is selected from hydrogen and methyl; and E is selected from , , , And -CN, and R is selected from the group consisting of hydrogen and methyl.
本發明之化合物，其中A為
係根據以下程序製備：
本發明之化合物，其中A為
且L-E為
係以類似方式藉由將 取代為製備 In a similar manner Replaced by preparation
其中環B及B'、n、R、R2及E如上定義。 Wherein Rings B and B', n, R, R 2 and E are as defined above.
代表性實例列於以下：
其中：X1及X2獨立地選自氫及氟；R2係選自氫及甲基；E係選自、、、及-CN，且R係選自氫及甲基。 Wherein: X 1 and X 2 are independently selected from hydrogen and fluorine; R 2 is selected from hydrogen and methyl; and E is selected from , , , And -CN, and R is selected from the group consisting of hydrogen and methyl.
本發明之化合物，其中A為
可根據以下程序製備： It can be prepared according to the following procedure:
方法A：Method A:
方法B：Method B:
本發明之化合物，其中A為
且L-E為
係以類似方式藉由將 取代為製備 In a similar manner Replaced by preparation
其中環B及B'、n、R、R2及E如上定義。 Wherein Rings B and B', n, R, R 2 and E are as defined above.
代表性實例列於以下：
其中：X1及X2獨立地選自氫及氟；R2係選自氫及甲基；E係選自、、、及-CN，且R係選自氫及甲基。 Wherein: X 1 and X 2 are independently selected from hydrogen and fluorine; R 2 is selected from hydrogen and methyl; and E is selected from , , , And -CN, and R is selected from the group consisting of hydrogen and methyl.
本發明之化合物，其中A為
係根據以下程序製備：
本發明之化合物，其中A為
且L-E為
係以類似方式藉由將 取代為製備 In a similar manner Replaced by preparation
其中環B及B'、n、R、R2及E如上定義。 Wherein Rings B and B', n, R, R 2 and E are as defined above.
代表性實例列於以下：
其中：X1及X2獨立地選自氫及氟；R2係選自氫及甲基；E係選自、、、及-CN，且R係選自氫及甲基。 Wherein: X 1 and X 2 are independently selected from hydrogen and fluorine; R 2 is selected from hydrogen and methyl; and E is selected from , , , And -CN, and R is selected from the group consisting of hydrogen and methyl.
本發明之化合物，其中A為
且X=CH，係根據以下程序製備： And X=CH, prepared according to the following procedure:
方法A：Method A:
方法B：Method B:
本發明之化合物，其中A為
且L-E為
係以類似方式藉由將取代為製備 In a similar manner Replaced by preparation
其中環B及B'、n、R、R2及E如上定義。 Wherein Rings B and B', n, R, R 2 and E are as defined above.
本發明之化合物，其中A為
且X=N，係以類似方式藉由將取代為製備。 And X=N, in a similar manner Replaced by preparation.
代表性實例列於以下：
其中：X1及X2獨立地選自氫及氟；R2係選自氫及甲基；X係選自CH及N；E係選自 、、、及-CN，且R係選自氫及甲基。 Wherein: X 1 and X 2 are independently selected from hydrogen and fluorine; R 2 is selected from hydrogen and methyl; X is selected from CH and N; and E is selected from , , , And -CN, and R is selected from the group consisting of hydrogen and methyl.
本發明之化合物，其中A為
係根據以下程序製備：
本發明之化合物，其中A為
且L-E為
係以類似方式藉由將取代為製備 In a similar manner Replaced by preparation
其中環B及B'、n、R、R2及E如上定義。 Wherein Rings B and B', n, R, R 2 and E are as defined above.
代表性實例列於以下：
其中：X1及X2獨立地選自氫及氟；R2係選自氫及甲基；E係選自、、、及-CN，且R係選自氫及甲基。 Wherein: X 1 and X 2 are independently selected from hydrogen and fluorine; R 2 is selected from hydrogen and methyl; and E is selected from , , , And -CN, and R is selected from the group consisting of hydrogen and methyl.
用於測定激酶抑制劑之活體外活性之分析更詳細描述於隨附實例中。 The assay used to determine the in vitro activity of a kinase inhibitor is described in more detail in the accompanying examples.
所選化合物之活體外效力係針對人類BTK激酶(hBTK)使用在Eurofins Pharma Discovery Services UK Limited進行之Kinase Profiler輻射量測蛋白激酶分析定義。 The in vitro potency of the selected compounds was defined for the human BTK kinase (hBTK) using the Kinase Profiler radiation assay protein kinase assay performed at Eurofins Pharma Discovery Services UK Limited.
將hBTK激酶稀釋於緩衝液中，且將所有化合物均於100% DMSO中製備為50倍最終分析濃度。將化合物之此工作儲備液添加至分析孔中作為反應中之第一組分，隨後添加如上列的分析方案中詳述之剩餘組分。藉由添加MgATP混合起始反應。使激酶反應在室溫下在250μM受質、10mM乙酸鎂、[γ-33P-ATP](特定活性約500cpm/pmol，濃度視需要)及可變測試物濃度存在下進行40分鐘。分析中之ATP濃度為15μM之表觀。藉由添加3%磷酸溶液終止反應。隨後將10μL反應物點至P30過濾墊上，且於75mM磷酸中洗滌三次持續5分鐘且於甲醇中洗滌一次，隨後乾燥及閃爍計數。另外，陽性對照孔含有除所關注化合物以外之所有反應組分；然而，DMSO(最終濃度為2%)包括於此等孔中以針對溶劑作用進行對照，以及空白孔含有所有反應組分、參考抑制劑置換所關注之化合物。此消除激酶活性且確定基線(0%激酶活性保持)。實例結果呈現於圖2中。每種化合物之效力藉由估算IC50報導且展示於表2中。 hBTK kinase was diluted in buffer and all compounds were prepared in 100% DMSO to a 50-fold final assay concentration. This working stock of the compound is added to the assay wells as the first component in the reaction, followed by the addition of the remaining components detailed in the analytical schemes listed above. The reaction was initiated by the addition of MgATP. The kinase reaction was allowed to proceed for 40 minutes at room temperature in the presence of 250 [mu]M substrate, 10 mM magnesium acetate, [[gamma]-33P-ATP] (specific activity about 500 cpm/pmol, concentration as needed) and variable test substance concentration. The ATP concentration in the analysis was 15 μM. The reaction was stopped by the addition of a 3% phosphoric acid solution. 10 [mu]L of the reaction was then spotted onto a P30 filter pad and washed three times in 75 mM phosphoric acid for 5 minutes and once in methanol, followed by drying and scintillation counting. In addition, positive control wells contain all reaction components except the compound of interest; however, DMSO (final concentration of 2%) is included in these wells for control against solvent action, and blank wells contain all reaction components, reference The inhibitor replaces the compound of interest. This abolished kinase activity and determined baseline (0% kinase activity retention). The example results are presented in Figure 2. Potency of each compound by estimating the IC 50 reported and shown in Table 2 below.
將10-30nM化合物與7nM酶在1000uM ATP存在下預培育1小時。將[l]-[E]複合物250倍稀釋至具有1000uM ATP及2uM受質肽 之分析緩衝液中。經8小時時間在即時分析中監測稀釋樣品中之酶活性。將進展曲線用時間依賴性方程擬合以測定化合物之表觀Kobs及滯留時間。參考化合物(圖1)在BTK上之滯留半衰期為74分鐘。與BTK之共價抑制一致。資料顯示，化合物27之滯留半衰期大於10小時(圖3)。此等資料與BTK藉由化合物27之共價抑制一致。 10-30 nM of compound was pre-incubated with 7 nM enzyme for 1 hour in the presence of 1000 uM ATP. The [l]-[E] complex was diluted 250-fold to have 1000 μM ATP and 2 uM receptor peptide In the assay buffer. The enzyme activity in the diluted samples was monitored in an immediate analysis over 8 hours. The progression curve was fitted with a time dependent equation to determine the apparent Kobs and residence time of the compounds. The retention half-life of the reference compound (Figure 1) on BTK was 74 minutes. Consistent with the covalent inhibition of BTK. The data shows that the retention half-life of Compound 27 is greater than 10 hours (Figure 3). These data are consistent with the covalent inhibition of BTK by Compound 27.
脾細胞響應於抗IgM之增殖可藉由Btk之抑制阻斷。自6周大之雄性CD1小鼠(Charles River Laboratories Inc.)獲得脾細胞。將小鼠脾臟手工破裂於PBS中且使用70um細胞過濾器過濾，隨後進行氯化銨紅細胞溶解。將細胞洗滌，再懸浮於脾細胞培養基(HyClone RPMI，補充有10%熱失活FBS、0.5倍非必需胺基酸、10mM HEPES、50uM β巰基乙醇)中，且在37℃，5% CO2下培育2小時以移除黏附細胞。將懸浮細胞以50,000個細胞/孔接種於96孔盤中，且在37℃，5% CO2下培育1小時。將脾細胞一式三份地用10,000nM曲線之式1化合物預處理1小時，隨後用2.5ug/ml抗IgM F(ab')2(Jackson ImmunoResearch)刺激細胞增殖72小時。藉由Cell Titer-Glo Luminescent Assay(Promega)量測細胞增殖。實例結果呈現於圖4中。使用GraphPad Prism軟體由劑量反應化合物曲線計算EC50值(在化合物存在下與媒劑處理之對照相比50%增殖)。EC50值報導於表3中：
a=EC50>100nM且未測定 a=EC50>100nM and not determined
BTK抑制劑影響B細胞淋巴瘤之存活。將TMD-8人類激活B細胞彌漫性大B細胞淋巴瘤細胞以20,000個細胞/孔之密度接種於96孔盤中於補充有10% FBS(Fisher)/1%青黴素/鏈黴素(HyClone)之HyClone RPMI中，且在37℃，5% CO2下培育。將細胞一式三份用1,000nM或100nM曲線之化合物處理72小時。藉由Cell Titer-Glo Luminescent Assay(Promega)量測細胞存活。實例結果呈現於圖5中。使用GraphPad Prism軟體由劑量反應化合物曲線計算EC50值(在化合物存在下與媒劑處理之對照相比50%增殖)。 BTK inhibitors affect the survival of B cell lymphoma. DMD-8 human activated B cell diffuse large B-cell lymphoma cells were seeded at a density of 20,000 cells/well in 96-well plates supplemented with 10% FBS (Fisher) / 1% penicillin / streptomycin (HyClone) In HyClone RPMI, and incubated at 37 ° C, 5% CO 2 . Cells were treated in triplicate with compounds of either 1,000 nM or 100 nM curves for 72 hours. Cell survival was measured by Cell Titer-Glo Luminescent Assay (Promega). The example results are presented in Figure 5. Calculated using GraphPad Prism software EC 50 value (50% growth as compared to control vehicle-treated in the presence of the compound) from the compound dose response curve.
a=EC50>100nM且未測定 a=EC50>100nM and not determined
BTK在阿瑟斯逆轉被動過敏反應分析中為在免疫複合物急性血管炎之Fc受體激活下游激活的信號傳導路徑之重要組分。 BTK is an important component of the signaling pathway that is activated downstream of Fc receptor activation in immune complex acute vasculitis in the Arthurs reversal of passive allergic reactions.
使雌性Balb/c小鼠(到達時6-7周)習慣於動物設施至少4天。實驗當天，將動物藉由管飼(PO)用測試物(30mg/kg)或單獨媒劑預處理(t=-1h)。在t=0，向動物靜脉內注入(IV；0.1mL/小鼠)含有鶏卵白蛋白及伊文思藍(Evan's blue)(10mg/mL每一者)之生理食鹽水。十分鐘後(t=10min)，用异氟烷使動物麻醉，對背側面剃毛，且隨後在動物右側之一個部位皮內注入兔抗鶏卵白蛋白抗體(25μg於30μL中)。隨後在左側注入相同量之同型對照抗體。 Female Balb/c mice (6-7 weeks upon arrival) were accustomed to animal facilities for at least 4 days. On the day of the experiment, the animals were pretreated with tube (PO) by test (30 mg/kg) or vehicle alone (t = -1 h). At t=0, the animals were intravenously injected (IV; 0.1 mL/mouse) with physiological saline containing sputum ovalbumin and Evan's blue (10 mg/mL each). Ten minutes later (t = 10 min), the animals were anesthetized with isoflurane, the dorsal side was shaved, and then rabbit anti-sputum ovalbumin antibody (25 μg in 30 μL) was injected intradermally into a part of the animal's right side. The same amount of isotype control antibody was then injected on the left side.
隨後使動物返回其居住籠，且四小時後自每個注射部位收集皮膚切片(8mm)。將樣品置於1mL甲醯胺中在80℃下隔夜(1個皮膚活檢組織/1mL甲醯胺，於玻璃管中)。隨後藉由分光光譜法(630nm)評估甲醯胺溶液中伊文思藍之量作為血清向皮膚中之外滲之量度。將化合物活性與參考化合物圖1比較。阿瑟斯反應相對於媒劑處理之對照的抑制呈現於圖6中。 The animals were then returned to their home cage and skin sections (8 mm) were collected from each injection site four hours later. The sample was placed in 1 mL of methotrex overnight at 80 ° C (1 skin biopsy tissue / 1 mL of methotrexate in a glass tube). The amount of Evans blue in the methotrexate solution was then assessed by spectroscopic spectroscopy (630 nm) as a measure of the extravasation of serum into the skin. Compound activity was compared to the reference compound Figure 1. The inhibition of the Arthurs reaction relative to the vehicle treated control is presented in Figure 6.
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