CN101558046A

CN101558046A - Morpholino pyrimidine derivatives for the treatment of proliferative disorders

Info

Publication number: CN101558046A
Application number: CNA2007800392665A
Authority: CN
Inventors: M·R·V·芬利
Original assignee: AstraZeneca AB
Current assignee: AstraZeneca AB
Priority date: 2006-08-24
Filing date: 2007-08-22
Publication date: 2009-10-14
Also published as: GB0616747D0; CN101541781B; RU2440349C2; TW200817384A; ES2393215T3; ZA200901015B; BRPI0715609A2; RU2009110255A; CN101541781A

Abstract

A compound of formula (I) or a pharmaceutically acceptable salt thereof, processes for their preparation, pharmaceutical compositions containing them and their use in therapy, for example in the treatment of proliferative disease such as cancer, particularly in disease mediated by an mTOR kinase and/or one or more PI3K enzyme.

Description

Morpholinopyrimidine derivatives for use in the treatment of proliferative disorders

本发明涉及吗啉代嘧啶衍生物，它们的制备方法，包含它们的药物组合物和它们在治疗中的用途，例如治疗增殖疾病，例如癌，尤其是治疗mTOR激酶和/或一或多种PI3K酶介导的疾病。The present invention relates to morpholinopyrimidine derivatives, processes for their preparation, pharmaceutical compositions comprising them and their use in therapy, for example in the treatment of proliferative diseases, such as cancer, in particular in the treatment of mTOR kinase and/or one or more PI3Ks Enzyme-mediated diseases.

目前，人们充分了解到肿瘤基因和肿瘤抑制基因的失调促使恶性肿瘤的形成，例如，通过提高细胞增殖或提高细胞存活的途径。同样，已知PI3K/mTOR家族介导的信号路径在许多细胞过程(包括增殖和存活)中具有核心作用，路径的失调是广谱人类癌症及其它疾病的成因。It is now well understood that dysregulation of oncogenes and tumor suppressor genes contributes to the formation of malignancies, for example, by increasing cell proliferation or increasing cell survival. Likewise, the PI3K/mTOR family of mediated signaling pathways is known to have a central role in many cellular processes, including proliferation and survival, and dysregulation of the pathways is responsible for a broad spectrum of human cancers and other diseases.

大环内脂类抗菌素雷帕霉素(西罗莫司(Sirolimus))的哺乳动物靶标是酶mTOR。这种酶属于蛋白激酶的磷脂酰肌醇(PI)激酶相关的激酶(PIKK)家族，其还包括ATM、ATR、DNA-PK和hSMG-1。与其它PIKK家族成员类似，mTOR不具有可检测的脂质激酶活性，但反而起到丝氨酸-苏氨酸激酶的作用。对mTOR信号的许多认识是基于使用雷帕霉素。雷帕霉素首先与12 kDa亲免素FK506-结合蛋白(FKBP 12)结合，并且这种复合物抑制mTOR信号(Tee和Blenis，Seminars in Cell andDevelopmental Biology，2005，16，29-37)。mTOR蛋白由催化激酶区域(FKBP12(雷帕霉素)-连接(FRB)区域)、假定的阻遏子区域(接近C-末端，并且在N-末端具有至多20个连续重复HEAT基元)以及FRAP-ATM-TRRAP(FAT)和FAT C-末端区域组成(Huang和Houghton，Current Opinion in Pharmacology，2003，3，371-377)。The mammalian target of the macrolide antibiotic rapamycin (Sirolimus) is the enzyme mTOR. This enzyme belongs to the phosphatidylinositol (PI) kinase-related kinase (PIKK) family of protein kinases, which also includes ATM, ATR, DNA-PK and hSMG-1. Like other PIKK family members, mTOR has no detectable lipid kinase activity, but instead functions as a serine-threonine kinase. Much of what is known about mTOR signaling is based on the use of rapamycin. Rapamycin first binds to the 12 kDa immunophilin FK506-binding protein (FKBP 12), and this complex inhibits mTOR signaling (Tee and Blenis, Seminars in Cell and Developmental Biology, 2005, 16, 29-37). The mTOR protein consists of a catalytic kinase domain (FKBP12 (rapamycin)-linked (FRB) domain), a putative repressor domain (near the C-terminus, and with up to 20 consecutive repeats of HEAT motifs at the N-terminus), and the FRAP - ATM-TRRAP (FAT) and FAT C-terminal region composition (Huang and Houghton, Current Opinion in Pharmacology, 2003, 3, 371-377).

mTOR激酶是细胞生长的关键调节剂，并且显示具有调节许多细胞功能的作用，包括转译、转录、mRNA循环、蛋白质稳定性、肌动蛋白细胞骨架重组和自噬(Jacinto和Hall，Nature Reviews Molecular andCell Biology，2005，4，117-126)。mTOR激酶将源于生长因子(例如胰岛素或胰岛素样生长因子)和营养素(例如氨基酸和葡糖)的信号进行整合，以调节细胞生长。mTOR激酶是通过PI3K-Akt路径、由生长因子活化的。mTOR激酶在哺乳动物细胞中最充分表征的功能是调节转译，其通过两个路径，即核醣体S6K1的活化(以提高携带5′-端部寡嘧啶区域(TOP)的mRNAs转译)和4E-BP1的抑制(以允许CAP-依赖性的mRNA转译)来进行。The mTOR kinase is a key regulator of cell growth and has been shown to regulate many cellular functions, including translation, transcription, mRNA recycling, protein stability, actin cytoskeletal reorganization, and autophagy (Jacinto and Hall, Nature Reviews Molecular and Cell Biology, 2005, 4, 117-126). The mTOR kinase integrates signals from growth factors (such as insulin or insulin-like growth factors) and nutrients (such as amino acids and glucose) to regulate cell growth. The mTOR kinase is activated by growth factors through the PI3K-Akt pathway. The best-characterized function of mTOR kinase in mammalian cells is to regulate translation through two pathways, activation of ribosomal S6K1 (to increase translation of mRNAs carrying 5′-terminal oligopyrimidine regions (TOP)) and 4E- Inhibition of BP1 (to allow CAP-dependent mRNA translation) was performed.

通常，研究者使用雷帕霉素和相关的雷帕霉素类似物(基于它们针对mTOR作为胞内靶向的特异性)进行抑制，探究了mTOR的生理学和病理作用。然而，最新数据提出，雷帕霉素对mTOR信号功能显示出可变的抑制作用，并且认为，直接抑制mTOR激酶区域可以显示比雷帕霉素所获得的抗癌症活性显著更广泛的抗癌症活性(Edinger等人，Cancer Research，2003，63，8451-8460)。为此，可以使用mTOR激酶活性的有效和选择性的抑制剂，以便更彻底的了解mTOR激酶功能，并提供有用的治疗剂。Typically, investigators explore the physiological and pathological roles of mTOR using inhibition by rapamycin and related rapamycin analogs based on their specificity for mTOR as an intracellular target. However, recent data suggest that rapamycin exhibits variable inhibition of mTOR signaling function, and it is argued that direct inhibition of the mTOR kinase domain may exhibit significantly broader anticancer activity than that achieved with rapamycin (Edinger et al., Cancer Research, 2003, 63, 8451-8460). To this end, potent and selective inhibitors of mTOR kinase activity could be used to gain a more complete understanding of mTOR kinase function and provide useful therapeutics.

现在有相当多的证据表明，mTOR的路径上游例如PI3K路径，在癌症中频繁地被活化(Vivanco和Sawyers，Nature Reviews Cancer，2002，2，489-501；Bjornsti和Houghton，Nature Reviews Cancer，2004，4，335-348；Inoki等人，Nature Genetics，2005，37，19-24)。例如，在不同的人类肿瘤中突变的PI3K路径的组分包括生长因子受体的活化突变和PI3K和Akt的扩增和/或超表达。There is now considerable evidence that upstream pathways of mTOR, such as the PI3K pathway, are frequently activated in cancer (Vivanco and Sawyers, Nature Reviews Cancer, 2002, 2, 489-501; Bjornsti and Houghton, Nature Reviews Cancer, 2004, 4, 335-348; Inoki et al., Nature Genetics, 2005, 37, 19-24). For example, components of the PI3K pathway that are mutated in different human tumors include activating mutations of growth factor receptors and amplification and/or overexpression of PI3K and Akt.

此外有证据说明，内皮细胞增殖可能也取决于mTOR信号。内皮细胞增殖是由PI3K-Akt-mTOR信号路径的血管内皮细胞生长因子(VEGF)活化所刺激的(Dancey，Expert Opinion on Investigational Drugs，2005，14，313-328)。此外，通过对缺氧诱导的因子-1α(HIF-1α)的表达的影响，认为mTOR激酶信号可部分地控制VEGF合成(Hudson等人，Molecular and Cellular Biology，2002，22，7004-7014)。因此，肿瘤血管生成可能以两种方式取决于mTOR激酶信号：通过肿瘤和基质细胞的VEGF的缺氧诱导的合成，和通过内皮增殖和存活(通过PI3K-Akt-mTOR信号)的VEGF激励。In addition, there is evidence that endothelial cell proliferation may also depend on mTOR signaling. Endothelial cell proliferation is stimulated by vascular endothelial growth factor (VEGF) activation of the PI3K-Akt-mTOR signaling pathway (Dancey, Expert Opinion on Investigational Drugs, 2005, 14, 313-328). Furthermore, mTOR kinase signaling is thought to control VEGF synthesis in part through effects on the expression of hypoxia-inducible factor-1α (HIF-1α) (Hudson et al., Molecular and Cellular Biology, 2002, 22, 7004-7014). Thus, tumor angiogenesis may depend on mTOR kinase signaling in two ways: through hypoxia-induced synthesis of VEGF by tumor and stromal cells, and through VEGF stimulation of endothelial proliferation and survival (via PI3K-Akt-mTOR signaling).

这些发现表示，mTOR激酶的药理学抑制剂应该具有治疗价值，可用于治疗各种形式的癌症，包括实体肿瘤例如癌和肉瘤，和血癌和淋巴的恶性肿瘤。尤其是，mTOR激酶抑制剂应该具有治疗学价值，可用于治疗例如乳癌，结肠直肠癌，肺癌(包括小细胞肺癌、非小细胞肺癌和细支气管肺泡癌症)和前列腺癌，和胆管癌，骨骼癌，膀胱癌，头和颈癌，肾癌，肝癌，胃肠组织癌，食道癌，卵巢癌，胰腺癌，皮肤癌，睾丸癌，甲状腺癌，子宫癌，宫颈和外阴癌，和血癌(包括ALL和CML)，多重骨髓癌和淋巴瘤。These findings suggest that pharmacological inhibitors of mTOR kinase should be of therapeutic value for the treatment of various forms of cancer, including solid tumors such as carcinomas and sarcomas, and hematological and lymphoid malignancies. In particular, mTOR kinase inhibitors should be of therapeutic value for the treatment of, for example, breast cancer, colorectal cancer, lung cancer (including small cell lung cancer, non-small cell lung cancer, and bronchioloalveolar cancer) and prostate cancer, and cholangiocarcinoma, bone cancer , bladder, head and neck, kidney, liver, gastrointestinal tissue, esophagus, ovary, pancreas, skin, testis, thyroid, uterus, cervix and vulva, and blood cancers (including ALL and CML), multiple myeloid carcinomas and lymphomas.

除了致肿瘤性之外，有证据说明，mTOR激酶在一系列错构瘤综合症中起一定作用。近期研究表明，肿瘤抑制蛋白例如TSC1、TSC2、PTEN和LKB1可强烈地控制mTOR激酶信号。这些肿瘤抑制蛋白的丧失可导致大量错构瘤病症，这是由于mTOR激酶信号增加的结果(Tee和Blenis，Seminars in Cell and Developmental Biology，2005，16，29-37)。与mTOR激酶的调节异常建立分子联系的综合症包括：黑斑息肉综合征(PJS)，Cowden疾病，Bannayan-Riley-Ruvalcaba综合症(BRRS)，Proteus综合症，Lhermitte-Duclos疾病和结节性硬化症(TSC)(Inoki等人，Nature Genetics，2005，37，19-24)。具有这些综合症的患者在许多器官中特异性地形成良性错构肿瘤。In addition to tumorigenicity, there is evidence that the mTOR kinase plays a role in a range of hamartoma syndromes. Recent studies have shown that tumor suppressor proteins such as TSC1, TSC2, PTEN and LKB1 strongly control mTOR kinase signaling. Loss of these tumor suppressor proteins can lead to a number of hamartoma disorders as a result of increased mTOR kinase signaling (Tee and Blenis, Seminars in Cell and Developmental Biology, 2005, 16, 29-37). Syndromes that have been molecularly linked to dysregulation of the mTOR kinase include: polyposis jersey syndrome (PJS), Cowden disease, Bannayan-Riley-Ruvalcaba syndrome (BRRS), Proteus syndrome, Lhermitte-Duclos disease, and tuberous sclerosis TSC (TSC) (Inoki et al., Nature Genetics, 2005, 37, 19-24). Patients with these syndromes develop benign hamartomas specifically in many organs.

最新的研究已经显示了mTOR激酶在其它疾病中的作用(Easton&Houghton，Expert Opinion on Therapeutic Targets，2004，8，551-564)。已经表明，通过抑制T细胞、B细胞的抗原诱导的增殖和抗体产生，雷帕霉素是有效的免疫抑制剂(Sehgal，Transplantation Proceedings，2003，35，7S-14S)并由此mTOR激酶抑制剂也是有用的免疫抑制剂。抑制mTOR的激酶活性也可有效用于预防再狭窄，在血管系统疾病的治疗中，这种再狭窄受血管系统中的正常细胞在对引入支架的响应过程中产生不希望有的增殖的控制(Morice等人，New England Journal ofMedicine，2002，346，1773-1780)。此外，雷帕霉素类似物(依维莫司)可以降低心脏异源移植血管病变的严重程度和发生率(Eisen等人，New England Journal of Medicine，2003，349，847-858)。mTOR激酶活性的提高与心脏肥大有关，这作为心力衰竭的主要危险因素在临床上是重要的，并且是心肌细胞的细胞尺寸增加的结果(Tee&Blenis，Seminars in Cell and Developmental Biology，2005，16，29-37)。由此，除了癌之外，期望mTOR激酶抑制剂具有预防和治疗多种疾病的价值。Recent studies have shown the role of mTOR kinase in other diseases (Easton & Houghton, Expert Opinion on Therapeutic Targets, 2004, 8, 551-564). It has been shown that rapamycin is a potent immunosuppressant by inhibiting antigen-induced proliferation and antibody production of T cells, B cells (Sehgal, Transplantation Proceedings, 2003, 35, 7S-14S) and thus mTOR kinase inhibitor Also a useful immunosuppressant. Inhibition of the kinase activity of mTOR may also be effective in the prevention of restenosis, which is controlled by unwanted proliferation of normal cells in the vasculature in response to the introduction of a stent in the treatment of vasculature diseases ( Morice et al., New England Journal of Medicine, 2002, 346, 1773-1780). Furthermore, a rapamycin analog (everolimus) can reduce the severity and incidence of vascular lesions in cardiac allografts (Eisen et al., New England Journal of Medicine, 2003, 349, 847-858). Elevated mTOR kinase activity is associated with cardiac hypertrophy, which is clinically important as a major risk factor for heart failure, and is a consequence of increased cell size of cardiomyocytes (Tee & Blenis, Seminars in Cell and Developmental Biology, 2005, 16, 29 -37). Thus, mTOR kinase inhibitors are expected to have value in the prevention and treatment of various diseases in addition to cancer.

同样相信，许多这些吗啉代嘧啶衍生物针对激酶的磷脂酰肌醇(PI)3-激酶家族具有抑制活性。It is also believed that many of these morpholinopyrimidine derivatives have inhibitory activity against the phosphatidylinositol (PI) 3-kinase family of kinases.

磷脂酰肌醇(PI)3-激酶(PI3Ks)是普遍存在的脂质激酶，其可在细胞表面受体的下游和在构成的胞内膜中作为信号转换器和蛋白质运输路径。所有的PI3Ks是具有脂质激酶活性的双重特异性酶，其可在3-羟基位置将磷酸肌醇磷酸化，并且具有较少充分特征化的蛋白激酶活性。PI3K-催化反应的脂质产物(包括磷脂酰肌醇3，4，5-三磷酸酯[PI(3，4，5)P₃]，磷脂酰肌醇3，4-二磷酸酯[PI(3，4)P₂]和磷脂酰肌醇3-一磷酸酯[PI(3)P])在各种信号转导途径中构成第二信使，包括对细胞增殖、粘附、存活、细胞骨架重排和囊泡通行不可少的那些途径。在所有细胞中，结构性地存在PI(3)P，并且它的水平不会随着激动剂的激励而显著地变化。相反，在大部分细胞中，名义上不存在PI(3，4)P₂和PI(3，4，5)P₃，但它们可在激动剂的激励下快速地聚集。Phosphatidylinositol (PI) 3-kinases (PI3Ks) are ubiquitous lipid kinases that serve as signal transducers and protein trafficking pathways downstream of cell surface receptors and in constitutive intracellular membranes. All PI3Ks are dual-specificity enzymes with lipid kinase activity that phosphorylates phosphoinositides at the 3-hydroxyl position and, to a lesser extent, well-characterized protein kinase activity. Lipid products of PI3K-catalyzed reactions (including phosphatidylinositol 3,4,5-triphosphate [PI(3,4,5)P ₃ ], phosphatidylinositol 3,4-bisphosphate [PI( 3,4)P ₂ ] and phosphatidylinositol 3-monophosphate [PI(3)P]) constitute second messengers in various signal transduction pathways, including cell proliferation, adhesion, survival, cytoskeleton Those pathways that are essential for rearrangement and vesicle trafficking. In all cells, PI(3)P is constitutively present and its levels do not change significantly upon agonist stimulation. In contrast, in most cells, PI(3,4)P ₂ and PI(3,4,5)P ₃ are nominally absent, but they can rapidly accumulate upon stimulation by agonists.

PI3K-产生的3-磷酸肌醇第二信使的下游效应是通过包含3-磷酸肌醇连接区域(例如普列克底物蛋白同源(PH)区域和最近确定的FYVE和phox区域)的靶分子所介导的。PI3K的较好表征的蛋白靶标包括PDK1和蛋白激酶B(PKB)。此外，酪氨酸激酶例如Btk和Itk依赖PI3K活性。Downstream effects of PI3K-generated 3-phosphoinositide second messengers are through targets containing 3-phosphoinositide linking regions such as the pleckstrin homology (PH) region and the recently identified FYVE and phox regions Molecularly mediated. Well-characterized protein targets of PI3K include PDK1 and protein kinase B (PKB). Furthermore, tyrosine kinases such as Btk and Itk are dependent on PI3K activity.

依照其生理学底物特异性，可以将PI3K脂质激酶家族分为三类(Vanhaesebroeck等人，Trends in Biol.Sci.，1997，22，267)。III类PI3K酶单独将PI磷酸化。相反，II类PI3K酶将PI和PI4-磷酸酯[PI(4)P]磷酸化。尽管认为只有PI(4，5)P₂是生理学的细胞基质，I类PI3K酶将PI、PI(4)P和PI 4，5-二磷酸酯[PI(4，5)P₂]磷酸化。PI(4，5)P₂的磷酸化产生脂质第二信使PI(3，4，5)P₃。脂质激酶超级家族的更远的相关成员是IV类激酶，例如mTOR(上面讨论到的)，和DNA-依赖性激酶(其将蛋白基质内的丝氨酸/苏氨酸残基磷酸化)。大部分研究和了解的PI3K脂质激酶是I类PI3K酶。According to their physiological substrate specificity, the PI3K lipid kinase family can be divided into three classes (Vanhaesebroeck et al., Trends in Biol. Sci., 1997, 22, 267). Class III PI3K enzymes phosphorylate PI alone. In contrast, class II PI3K enzymes phosphorylate PI and PI 4-phosphate [PI(4)P]. Although only PI(4,5)P ₂ is considered a physiological cellular substrate, class I PI3K enzymes phosphorylate PI, PI(4)P, and PI 4,5-bisphosphate [PI(4,5)P ₂ ] . Phosphorylation of PI(4,5) _P2 generates the lipid second messenger PI(3,4,5) _P3 . More distantly related members of the lipid kinase superfamily are class IV kinases, such as mTOR (discussed above), and DNA-dependent kinases (which phosphorylate serine/threonine residues within protein substrates). Most of the studied and understood PI3K lipid kinases are class I PI3K enzymes.

I类PI3Ks是由p110催化亚单位和调节亚单位组成的杂二聚体。基于调节方和调节机理，将该家族进一步分为Ia类和Ib类酶。Ia类酶包含与五个独特的调节亚单位(p85α，p55α，p50α，p85β和p55γ)二聚的三个独特的催化亚单位(p110α，p110β和p110δ)，所有的催化亚单位能够与所有的调节亚单位相互作用，形成各种杂二聚体。在对受体酪氨酸激酶的生长因子激励的响应中，通过其调节亚单位SH2区域与活化受体或接头蛋白例如IRS-1的具体磷酸基酪氨酸残基的相互作用，通常将Ia类PI3Ks活化。在所有的细胞类型中结构性地表达p110α和p110β，而p110δ表达更局限于白细胞种群和一些上皮细胞。相反，单纯的类别Ib酶包含与p101调节亚单位相互作用的p110γ催化亚单位。此外，在对G蛋白偶联受体系统(GPCRs)的响应中，类别Ib酶被活化，并且它的表达似乎限于白细胞和心肌细胞。Class I PI3Ks are heterodimers composed of a p110 catalytic subunit and a regulatory subunit. This family is further divided into class Ia and class Ib enzymes based on the regulation party and mechanism of regulation. Class Ia enzymes contain three unique catalytic subunits (p110α, p110β and p110δ) dimerized with five unique regulatory subunits (p85α, p55α, p50α, p85β and p55γ), all of which are capable of interacting with all Regulates subunit interactions to form various heterodimers. In response to growth factor stimulation of receptor tyrosine kinases, through the interaction of the SH2 domain of its regulatory subunit with specific phosphotyrosine residues of activating receptors or adapter proteins such as IRS-1, Ia is normally Activation of PI3Ks. p110α and p110β are constitutively expressed in all cell types, whereas p110δ expression is more restricted to leukocyte populations and some epithelial cells. In contrast, pure class Ib enzymes contain the p110γ catalytic subunit interacting with the p101 regulatory subunit. Furthermore, class Ib enzymes are activated in response to G protein-coupled receptor systems (GPCRs), and its expression appears to be restricted to leukocytes and cardiomyocytes.

现在有相当多的证据表明，在多种人类癌症中，Ia类PI3K酶可直接或间接地有助于致肿瘤(Vivanco和Sawyers，Nature Reviews Cancer，2002，2，489-501)。例如，在一些肿瘤中，p110α亚单位得到扩增，例如卵巢肿瘤(Shayesteh等人，Nature Genetics，1999，21，99-102)和宫颈肿瘤(Ma等人，Oncogene，2000，19，2739-2744)。近年来，在p110α催化亚单位的催化部位内的活化突变与各种其它肿瘤有关，例如结肠直肠区域和乳房和肺的那些肿瘤(Samuels等人，Science，2004，304，554)。在癌症例如卵巢和结肠癌中，也确定了p85α调节亚单位中的肿瘤相关的突变(Philp等人，Cancer Research，2001，61，7426-7429)。除了直接影响之外，人们相信，Ia类PI3Ks的活化有助于在信号路径上游出现的肿瘤发生的状况，例如，经由受体酪氨酸激酶、GPCR系统或整联蛋白的配体依赖性或配体非依赖性活化(Vara等人，CancerTreatment Reviews，2004，30，193-204)。这种上游信号路径的例子包括受体酪氨酸激酶erbB2在导致PI3K所介导路径的活化的各种肿瘤中的过度表达(Harari等人，，Oncogene，2000，19，6102-6114)和ras肿瘤基因的过度表达(Kauffmann-Zeh等人，，Nature，1997，385，544-548)。此外，Ia类PI3Ks可以间接地有助于致肿瘤性(由各种下游信号活动所引起)。例如，通过PI3K所介导的PI(3，4，5)P₃生成的失调，PTEN肿瘤抑制磷酸酶(其催化PI(3，4，5)P₃转化回到PI(4，5)P₂)的效果的丧失与很大范围的肿瘤有关(Simpson and Parsons，Exp.Cell Res.，2001，264，29-41)。此外，人们认为，其它PI3K所介导信号活动的效果的增加，将有助于促进各种癌症，例如通过Akt的活化(Nicholson和Anderson，Cellular Signalling，2002，14，381-395)。There is now considerable evidence that class Ia PI3K enzymes contribute directly or indirectly to tumorigenesis in a variety of human cancers (Vivanco and Sawyers, Nature Reviews Cancer, 2002, 2, 489-501). For example, the p110α subunit is amplified in some tumors, such as ovarian tumors (Shayesteh et al., Nature Genetics, 1999, 21, 99-102) and cervical tumors (Ma et al., Oncogene, 2000, 19, 2739-2744 ). In recent years, activating mutations within the catalytic site of the pl 10α catalytic subunit have been associated with various other tumors, such as those of the colorectal region and of the breast and lung (Samuels et al., Science, 2004, 304, 554). Tumor-associated mutations in the p85α regulatory subunit have also been identified in cancers such as ovarian and colon cancers (Philp et al., Cancer Research, 2001, 61, 7426-7429). In addition to direct effects, it is believed that activation of class Ia PI3Ks contributes to conditions that arise oncogenesis upstream of signaling pathways, for example, via receptor tyrosine kinases, GPCR systems, or integrin-dependent or ligand-dependent Ligand-independent activation (Vara et al., Cancer Treatment Reviews, 2004, 30, 193-204). Examples of such upstream signaling pathways include overexpression of the receptor tyrosine kinase erbB2 in various tumors leading to activation of PI3K-mediated pathways (Harari et al., Oncogene, 2000, 19, 6102-6114) and ras Overexpression of tumor genes (Kauffmann-Zeh et al., Nature, 1997, 385, 544-548). Furthermore, class Ia PI3Ks may contribute indirectly to tumorigenicity (due to various downstream signaling events). For example, through dysregulation of PI(3,4,5)P ₃ production mediated by PI3K, the PTEN tumor suppressor phosphatase (which catalyzes the conversion of PI(3,4,5)P ₃ back to PI(4,5)P Loss of the effect of ₂ ) is associated with a wide range of tumors (Simpson and Parsons, Exp. Cell Res., 2001, 264, 29-41). Furthermore, it is believed that the increased effect of other PI3K-mediated signaling activities will contribute to the promotion of various cancers, for example through the activation of Akt (Nicholson and Anderson, Cellular Signaling, 2002, 14, 381-395).

除了在肿瘤细胞中介导增殖和存活信号中的作用之外，有证据说明，Ia类PI3K酶在肿瘤相关的基质细胞中有助于致肿瘤性。例如，已经知道，在对前生成血管因子例如VEGF的响应中，PI3K信号在介导内皮细胞的生成血管活动中起重要作用(Abid等人，Arterioscler.Thromb.Vasc.Biol.，2004，24，294-300)。因为I类PI3K酶还涉及活动性和迁移(Sawyer，Expert Opinion Investig.Drugs，2004，13，1-19)，通过抑制肿瘤细胞侵入和转移病变，PI3K酶抑制剂应该提供治疗益处。此外，I类PI3K酶在有助于炎性细胞的前肿瘤发生效果的免疫细胞调节中起重要作用(Coussens和Werb，Nature，2002，420，860-867)。In addition to a role in mediating proliferation and survival signals in tumor cells, there is evidence that class Ia PI3K enzymes contribute to tumorigenicity in tumor-associated stromal cells. For example, it is known that PI3K signaling plays an important role in mediating angiogenic activity of endothelial cells in response to proangiogenic factors such as VEGF (Abid et al., Arterioscler. Thromb. Vasc. Biol., 2004, 24, 294-300). Because class I PI3K enzymes are also involved in motility and migration (Sawyer, Expert Opinion Investig. Drugs, 2004, 13, 1-19), PI3K enzyme inhibitors should provide therapeutic benefit by inhibiting tumor cell invasion and metastatic lesions. Furthermore, class I PI3K enzymes play an important role in the regulation of immune cells contributing to the pro-tumorigenic effects of inflammatory cells (Coussens and Werb, Nature, 2002, 420, 860-867).

这些发现表示，I类PI3K酶的药理学抑制剂具有治疗价值，可用于治疗各种疾病，包括各种形式癌症疾病，包括实体肿瘤例如癌和肉瘤，和血癌和淋巴的恶性肿瘤。尤其是，I类PI3K酶的抑制剂应该具有治疗学价值，可用于治疗例如乳癌，结肠直肠癌，肺癌(包括小细胞肺癌、非小细胞肺癌和细支气管肺泡癌症)和前列腺癌，和胆管癌，骨骼癌，膀胱癌，头和颈癌，肾癌，肝癌，胃肠组织癌，食道癌，卵巢癌，胰腺癌，皮肤癌，睾丸癌，甲状腺癌，子宫癌，宫颈和外阴癌，和血癌(包括ALL和CML)，多重骨髓癌和淋巴瘤。These findings indicate that pharmacological inhibitors of class I PI3K enzymes have therapeutic value for the treatment of various diseases, including various forms of cancer disease, including solid tumors such as carcinomas and sarcomas, and hematological and lymphoid malignancies. In particular, inhibitors of class I PI3K enzymes should be of therapeutic value for the treatment of, for example, breast cancer, colorectal cancer, lung cancer (including small cell lung cancer, non-small cell lung cancer, and bronchioloalveolar cancer) and prostate cancer, and cholangiocarcinoma , bone cancer, bladder cancer, head and neck cancer, kidney cancer, liver cancer, gastrointestinal tissue cancer, esophageal cancer, ovarian cancer, pancreatic cancer, skin cancer, testicular cancer, thyroid cancer, uterine cancer, cervical and vulvar cancer, and blood cancer (including ALL and CML), multiple myeloma and lymphoma.

PI3Kγ(Ib类PI3K)是被GPCRs活化的，这在缺乏酶的小鼠中最后得到了证明。由此，在对各种趋化性物质(例如IL-8，C5a，fMLP和MIP-1a)激励的响应中，衍生自缺乏PI3Kγ-的动物的嗜中性白细胞和巨噬细胞不能产生PI(3，4，5)P₃，而通过蛋白质酪氨酸激酶偶合受体至Ia类PI3Ks的信号是完好的(Hirsch等人，Science，2000，287(5455)，1049-1053；Li等人，Science，2002，287(5455)，1046-1049；Sasaki等人，Science，2002，287(5455)，1040-1046)。此外，在无PI3Kγ的细胞中，PI(3，4，5)P₃介导的PKB的磷酸化不是起源于这些GPCR配体。结合在一起，结果表明，至少在休息的造血细胞中，PI3Kγ是被GPCRs体内活化的唯一的PI3K异构型。当对得自鼠骨髓的嗜中性白细胞和得自野生型和PI3Kγ^-/-小鼠的腹膜巨噬细胞进行体外试验时，在趋化作用和粘附试验中观察到降低的(但不是完全消除的)性能。然而，这转化为IL-8驱动的嗜中性白细胞渗透到组织中的急剧损伤(Hirsch等人，Science，2000，287(5455)，1049-1053).最新的数据提出，PI3Kγ与路径寻找过程有关，而与机械力的产生(用于活动性)无关，因为在缺乏PI3Kγ的细胞中的无规迁移没有削弱(Hannigan等人，Proc.Nat.Acad.of Sciences of U.S.A.，2002，99(6)，3603-8)。联系PI3Kγ与呼吸系统疾病病理的数据表明，PI3Kγ在调节内毒素诱导的肺渗透和导致急性肺损伤的嗜中性白细胞活化方面具有核心作用(Yum等人，J.Immunology，2001，167(11)，6601-8)。尽管PI3Kγ在白血球中高度表达，但它的丧失似乎不妨碍造血，并且无PI3Kγ的小鼠能生长发育和能繁殖的这些事实暗示这种PI3K异构型可作为潜在的药物靶标。对于击昏小鼠的研究也证实，PI3Kγ是柱状细胞活化的必要的增强剂(Laffargue等人，Immunity，2002，16(3)，441-451)。PI3Kγ (class Ib PI3K) is activated by GPCRs, as was last demonstrated in enzyme-deficient mice. Thus, neutrophils and macrophages derived from PI3Kγ-deficient animals were unable to produce PI in response to stimulation with various chemotactic substances such as IL-8, C5a, fMLP and MIP-1a ( 3, 4, 5) P ₃ , while signaling through protein tyrosine kinase-coupled receptors to class Ia PI3Ks is intact (Hirsch et al., Science, 2000, 287(5455), 1049-1053; Li et al., Science, 2002, 287(5455), 1046-1049; Sasaki et al., Science, 2002, 287(5455), 1040-1046). Furthermore, in PI3Kγ-null cells, PI(3,4,5) _P3- mediated phosphorylation of PKB is not derived from these GPCR ligands. Taken together, the results show that, at least in resting hematopoietic cells, PI3Kγ is the only PI3K isoform activated by GPCRs in vivo. When neutrophils from murine bone marrow and peritoneal macrophages from wild-type and PI3Kγ ^-/- mice were tested in vitro, reduced (but not complete) eliminated) performance. However, this translates into a drastic impairment of IL-8-driven neutrophil infiltration into tissues (Hirsch et al., Science, 2000, 287(5455), 1049-1053). Recent data suggest that PI3Kγ is involved in the pathway-finding process related, rather than mechanical force generation (for mobility), because random migration was not impaired in cells lacking PI3Kγ (Hannigan et al., Proc. Nat. Acad. of Sciences of USA, 2002, 99(6 ), 3603-8). Data linking PI3Kγ to respiratory disease pathology suggest that PI3Kγ has a central role in regulating endotoxin-induced lung infiltration and neutrophil activation leading to acute lung injury (Yum et al., J. Immunology, 2001, 167(11) , 6601-8). Although PI3Kγ is highly expressed in white blood cells, its loss does not appear to impede hematopoiesis, and the fact that PI3Kγ-null mice grow and reproduce suggests this PI3K isoform as a potential drug target. Studies on stunned mice also demonstrated that PI3Kγ is an essential enhancer of mast cell activation (Laffargue et al., Immunity, 2002, 16(3), 441-451).

由此，除了致肿瘤性之外，有证据说明，I类PI3K酶在其它疾病中起一定作用(Wymann等人，Trends in Pharmacological Science，2003，24，366-376)。在免疫系统的细胞中，Ia类PI3K酶和单纯的Ib类酶都具有重要的作用(Koyasu，Nature Immunology，2003，4，313-319)，并由此它们是炎性和过敏适应症的治疗靶标。最新的报道表明，缺乏PI3Kγ和PI3Kδ的小鼠是能生长发育的，但具有减弱的炎性和过敏应答(Ali等人，Nature，2004，431(7011)，1007-11)。通过抗炎症效果或直接影响心肌细胞，PI3K的抑制作用也可用于治疗心血管疾病(Prasad等人，Trends in Cardiovascular Medicine，2003，13，206-212)。由此，除了癌症之外，期望I类PI3K酶的抑制剂具有预防和治疗多种疾病的价值。Thus, in addition to tumorigenicity, there is evidence that class I PI3K enzymes play a role in other diseases (Wymann et al., Trends in Pharmacological Science, 2003, 24, 366-376). Both class Ia PI3K enzymes and pure class Ib enzymes have important roles in cells of the immune system (Koyasu, Nature Immunology, 2003, 4, 313-319), and thus they are therapeutic agents for inflammatory and allergic indications target. Recent reports have shown that mice lacking PI3Kγ and PI3Kδ are viable but have attenuated inflammatory and allergic responses (Ali et al., Nature, 2004, 431(7011), 1007-11). Inhibition of PI3K may also be useful in the treatment of cardiovascular diseases through anti-inflammatory effects or directly affecting cardiomyocytes (Prasad et al., Trends in Cardiovascular Medicine, 2003, 13, 206-212). Thus, inhibitors of class I PI3K enzymes are expected to have value in the prevention and treatment of various diseases in addition to cancer.

已经鉴别了抑制PI3Ks和磷脂酰肌醇(PI)激酶相关的激酶(PI3KKs)的一些化合物，包括渥曼青霉素和栎精衍生物LY294002。这些化合物是PI3Ks和PI3KKs的合理具体抑制剂(超过其它激酶)，但它们缺乏效能，并且在PI3K家族内显示较少的选择性。A number of compounds have been identified that inhibit PI3Ks and phosphatidylinositol (PI) kinase-related kinases (PI3KKs), including wortmannin and the quercetin derivative LY294002. These compounds are reasonably specific inhibitors of PI3Ks and PI3KKs (more than other kinases), but they lack potency and show less selectivity within the PI3K family.

相应地，合乎需要的是，提供进一步有效的mTOR和/或PI3K抑制剂，用于治疗癌症、炎性或梗阻性呼吸道疾病、免疫或心血管疾病。Accordingly, it would be desirable to provide further potent mTOR and/or PI3K inhibitors for the treatment of cancer, inflammatory or obstructive airway diseases, immune or cardiovascular diseases.

吗啉代嘧啶衍生物和PI3K抑制剂是本领域已知的。Morpholinopyrimidine derivatives and PI3K inhibitors are known in the art.

国际专利申请WO 2004/048365公开了具有PI3K酶抑制活性且可用于治疗癌症的化合物。这些化合物是芳氨基和杂芳基氨基取代的嘧啶，就它们的芳氨基和杂芳基氨基取代基而论，其不同于本发明的化合物。这些取代基不相当于本发明的-XR¹取代基。在欧洲专利申请1277738中也公开了用于治疗癌症的PI3K活性的抑制剂，其提及4-吗啉代取代的双环杂芳基化合物，例如喹唑啉和吡啶并[3，2-d]嘧啶衍生物，和4-吗啉代取代的三环杂芳基化合物，而不是单环的嘧啶衍生物。International Patent Application WO 2004/048365 discloses compounds that have PI3K enzyme inhibitory activity and are useful in the treatment of cancer. These compounds are arylamino and heteroarylamino substituted pyrimidines which differ from the compounds of the invention with respect to their arylamino and heteroarylamino substituents. These substituents do not correspond to the -XR ¹ substituents of the present invention. Inhibitors of PI3K activity for the treatment of cancer are also disclosed in European Patent Application 1277738, which mentions 4-morpholino substituted bicyclic heteroaryl compounds such as quinazoline and pyrido[3,2-d] pyrimidine derivatives, and 4-morpholino substituted tricyclic heteroaryl compounds, rather than monocyclic pyrimidine derivatives.

在化学文摘数据库上已经登记了许多化合物，例如4-吗啉-4-基-6-(苯基磺酰基甲基)-2-吡啶-4-基-嘧啶和4-{6-[(苯磺酰)甲基]-2-吡啶-2-基嘧啶-4-基}吗啉，但没有表明应用性，并且没有提出这些化合物具有mTOR和/或PI3K抑制活性或有用的治疗性能。Many compounds have been registered on the Chemical Abstracts Database, such as 4-morpholin-4-yl-6-(phenylsulfonylmethyl)-2-pyridin-4-yl-pyrimidine and 4-{6-[(phenyl sulfonyl)methyl]-2-pyridin-2-ylpyrimidin-4-yl}morpholine, but no applicability has been indicated, and no mTOR and/or PI3K inhibitory activity or useful therapeutic properties have been suggested for these compounds.

意外地，我们发现某些吗啉代嘧啶衍生物具有有用的治疗性能。不希望被理论束缚，人们相信，该衍生物的治疗用途源自于它们针对mTOR激酶和/或一种或多种PI3K酶(例如Ia类酶和/或Ib类酶)的抑制活性。因为PI3K/mTOR家族介导的信号路径在许多细胞过程(包括增殖和存活)中具有核心作用，和因为这些路径的失调是广谱人类癌症及其它疾病的成因，因此人们预期该衍生物具有治疗用途。尤其是，人们预期该衍生物具有抗增殖和/或凋亡性能，这是指它们可用于治疗增殖疾病，例如癌症。本发明的化合物也可以有效用于抑制无控的细胞增殖，这种无控的细胞增殖源于各种非恶性病，例如炎性疾病、梗阻性的呼吸道疾病、免疫疾病或心血管疾病。Unexpectedly, we have found that certain morpholinopyrimidine derivatives have useful therapeutic properties. Without wishing to be bound by theory, it is believed that the therapeutic utility of the derivatives arises from their inhibitory activity against mTOR kinase and/or one or more PI3K enzymes (eg, class Ia and/or class Ib enzymes). Because PI3K/mTOR family-mediated signaling pathways are central to many cellular processes, including proliferation and survival, and because dysregulation of these pathways is responsible for a broad spectrum of human cancers and other diseases, this derivative is expected to have therapeutic use. In particular, the derivatives are expected to have antiproliferative and/or apoptotic properties, which means that they are useful in the treatment of proliferative diseases, such as cancer. The compounds of the present invention are also useful for inhibiting uncontrolled cell proliferation resulting from various non-malignant diseases such as inflammatory diseases, obstructive respiratory diseases, immune diseases or cardiovascular diseases.

通常，本发明的化合物针对mTOR激酶具有有效的抑制活性，但该化合物针对一种或多种PI3K酶(例如Ia类酶和/或Ib类酶)也可以具有有效的抑制活性。Typically, the compounds of the invention have potent inhibitory activity against mTOR kinase, but the compounds may also have potent inhibitory activity against one or more PI3K enzymes (eg, class Ia and/or class Ib enzymes).

按照本发明的一个方面，提供了式(I)的化合物According to one aspect of the present invention, there is provided a compound of formula (I)

式(I)Formula (I)

或其可药用盐；其中or its pharmaceutically acceptable salt; where

m是0、1、2、3或4；m is 0, 1, 2, 3 or 4;

¹Y和Y²独立地是N或CR⁸，条件是，¹Y和Y²之一是N，另一个是CR⁸； ¹ Y and Y ² are independently N or CR ⁸ , provided that one of ¹ Y and Y ² is N and the other is CR ⁸ ;

X是选自下列的连接基：-CR⁴＝CR⁵-，-CR⁴＝CR⁵CR⁶R⁷-，-CR⁶R⁷CR⁵＝CR⁴-，-C≡C-，-C≡CCR⁶R⁷-，-CR⁶R⁷C≡C-，-NR⁴CR⁶R⁷-，-OCR⁶R⁷-，-SCR⁶R⁷-，-S(O)CR⁶R⁷-，-S(O)₂CR⁶R⁷-，-C(O)NR⁴CR⁶R⁷-，-NR⁴C(O)CR⁶R⁷-，-NR4C(O)NR⁵CR⁶R⁷-，-NR⁴S(O)₂CR⁶R⁷-，-S(O)₂NR⁴CR⁶R⁷-，-C(O)NR⁴-，-NR⁴C(O)-，-NR⁴C(O)NR⁵-，-S(O)₂NR⁴-和-NR⁴S(O)₂-；X is a linker selected from the group consisting of: -CR ⁴ =CR ⁵ -, -CR ⁴ =CR ⁵ CR ⁶ R ⁷ -, -CR ⁶ R ⁷ CR ⁵ =CR ⁴ -, -C≡C-, -C≡C- CCR ⁶ R ⁷ -, -CR ⁶ R ⁷ C≡C-, -NR ⁴ CR ⁶ R ⁷ -, -OCR ⁶ R ⁷ -, -SCR ⁶ R ⁷ -, -S(O)CR ⁶ R ⁷ -, -S(O) ₂ CR ⁶ R ⁷ -, -C(O)NR ⁴ CR ⁶ R ⁷ -, -NR ⁴ C(O)CR ⁶ R ⁷ -, -NR4C(O)NR ⁵ CR ⁶ R ⁷ - , -NR ⁴ S(O) ₂ CR ⁶ R ⁷ -, -S(O) ₂ NR ⁴ CR ⁶ R ⁷ -, -C(O)NR ⁴ -, -NR ⁴ C(O)-, -NR ⁴ C(O)NR ⁵ -, -S(O) ₂ NR ⁴ - and -NR ⁴ S(O) ₂ -;

R¹是选自下列的基团：氢，C_1-6烷基，C_2-6烯基，C_2-6炔基，碳环，碳环C_1-6烷基，杂环基和杂环基C_1-6烷基，该基团任选被一个或多个选自下列的取代基团取代：卤素，氰基，硝基，R⁹，-OR⁹，-SR⁹，-SOR⁹，-SO₂R⁹，-COR⁹，-CO₂R⁹，-CONR⁹R¹⁰，-NR⁹R¹⁰，-NR⁹COR¹⁰，-NR⁹CO₂R¹⁰，-NR⁹CONR¹⁰R¹⁵，-NR⁹COCONR¹⁰R¹⁵和-NR⁹SO₂R¹⁰；R ¹ is a group selected from the group consisting of hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, carbocycle, carbocyclic C _1-6 alkyl, heterocyclyl and heterocyclyl Cyclic C _1-6 alkyl, which is optionally substituted by one or more substituents selected from the following groups: halogen, cyano, nitro, R ⁹ , -OR ⁹ , -SR ⁹ , -SOR ⁹ ,-SO ₂ R ⁹ ,-COR ⁹ ,-CO ₂ R ⁹ ,-CONR ⁹ R ¹⁰ ,-NR ⁹ R ¹⁰ ,-NR ⁹ COR ¹⁰ ,-NR ⁹ CO ₂ R ¹⁰ ,-NR ⁹ CONR ¹⁰ R ¹⁵ , -NR ⁹ COCONR ¹⁰ R ¹⁵ and -NR ⁹ SO ₂ R ¹⁰ ;

R²是选自下列的基团：C_1-6烷基，碳环和杂环基，该基团被-NR¹⁷SO₂R¹⁸取代，并任选被一个或多个独立地选自下列的取代基团取代：卤素，氰基，硝基，-R¹¹，-OR¹¹，-SR¹¹，-SOR¹¹，-SO₂R¹¹，-COR¹¹，-CO₂R¹¹，-CONR¹¹R¹²，-NR¹¹R¹²，-NR¹¹COR¹²和-NR¹¹COCONR¹²R¹⁶；R ² is a group selected from the following groups: C _1-6 alkyl, carbocyclic and heterocyclic groups, the group is substituted by -NR ¹⁷ SO ₂ R ¹⁸ , and optionally one or more groups independently selected from the following Substituent group substitution: halogen, cyano, nitro, -R ¹¹ , -OR ¹¹ , -SR ¹¹ , -SOR ¹¹ , -SO ₂ R ¹¹ , -COR ¹¹ , -CO ₂ R ¹¹ , -CONR ¹¹ R ¹² , -NR ¹¹ R ¹² , -NR ¹¹ COR ¹² and -NR ¹¹ COCONR ¹² R ¹⁶ ;

当存在时，每个R³独立地选自卤素，氰基，硝基，-R¹³，-OR¹³，-SR¹³，-SOR¹³，-SO₂R¹³，-COR¹³，-CO₂R¹³，-CONR¹³R¹⁴，-NR¹³R¹⁴，-NR¹³COR¹⁴，-NR¹³CO₂R¹⁴和-NR¹³SO₂R¹⁴；When present, each R ³ is independently selected from halogen, cyano, nitro, -R ¹³ , -OR ¹³ , -SR ¹³ , -SOR ¹³ , -SO ₂ R ¹³ , -COR ¹³ , -CO ₂ R ¹³ , -CONR ¹³ R ¹⁴ , -NR ¹³ R ¹⁴ , -NR ¹³ COR ¹⁴ , -NR ¹³ CO ₂ R ¹⁴ and -NR ¹³ SO ₂ R ¹⁴ ;

R⁴和R⁵独立地是氢或C_1-6烷基；R ⁴ and R ⁵ are independently hydrogen or C _1-6 alkyl;

或R¹和R⁴与它们相连接的原子一起形成5-至10-元碳环或杂环，其中1、2或3个环碳原子任选被N、O或S代替，并且该环任选被一个或多个选自下列的取代基团取代：卤素，氰基，硝基，羟基，C_1-6烷基，C_1-6烷氧基，卤素C_1-6烷基，卤素C_1-6烷氧基，羟基C_1-6烷基，羟基C_1-6烷氧基，C_1-6烷氧基C_1-6烷基，C_1-6烷氧基C_1-6烷氧基，氨基，C_1-6烷基氨基，二(C_1-6烷基)氨基，氨基C_1-6烷基，(C_1-6烷基)氨基C_1-6烷基，二(C_1-6烷基)氨基C_1-6烷基，氰基C_1-6烷基，C_1-6烷基磺酰基，C_1-6烷基磺酰氨基，C_1-6烷基磺酰基(C_1-6烷基)氨基，氨磺酰基，C_1-6烷基氨磺酰基，二(C_1-6烷基)氨磺酰基，C_1-6烷酰基氨基，C_1-6烷酰基(C_1-6烷基)氨基，氨基甲酰基，C_1-6烷基氨基甲酰基和二(C_1-6烷基)氨基甲酰基；Or R ¹ and R ⁴ form a 5- to 10-membered carbocyclic or heterocyclic ring together with the atoms to which they are attached, wherein 1, 2 or 3 ring carbon atoms are optionally replaced by N, O or S, and the ring is optionally Optionally substituted by one or more substituent groups selected from the group consisting of: halogen, cyano, nitro, hydroxyl, C _1-6 alkyl, C _1-6 alkoxy, halogen C _1-6 alkyl, halogen C _1-6 alkoxy, hydroxy C _1-6 alkyl, hydroxy C 1-6 alkoxy, C _1-6 alkoxy C _1-6 _alkyl , C _1-6 alkoxy C _1-6 alkane Oxygen, amino, C _1-6 alkylamino, two (C _1-6 alkyl) amino, amino C _1-6 alkyl, (C _1-6 alkyl) amino C _1-6 alkyl, two ( C _1-6 alkyl) amino C _1-6 alkyl, cyano C _{1-6 alkyl, C 1-6} _{alkylsulfonyl} , C _1-6 alkylsulfonylamino, C _1-6 alkylsulfonyl Acyl (C _1-6 alkyl) amino, sulfamoyl, C _1-6 alkyl sulfamoyl, di(C _1-6 alkyl) sulfamoyl, C _1-6 alkanoylamino, C _1-6 Alkanoyl (C _1-6 alkyl) amino, carbamoyl, C _1-6 alkyl carbamoyl and two (C _1-6 alkyl) carbamoyl;

R⁶和R⁷独立地选自氢，卤素，氰基，硝基和C_1-6烷基；R ⁶ and R ⁷ are independently selected from hydrogen, halogen, cyano, nitro and C _1-6 alkyl;

R⁸选自氢，卤素，氰基和C_1-6烷基； ^R is selected from hydrogen, halogen, cyano and C _1-6 alkyl;

R⁹和R¹⁰独立地是氢或选自下列的基团：C_1-6烷基，碳环，碳环C_1-6烷基，杂环基和杂环基C_1-6烷基，该基团任选被一个或多个选自下列的取代基团取代：卤素，氰基，硝基，羟基，C_1-6烷基，C_1-6烷氧基，卤素C_1-6烷基，卤素C_1-6烷氧基，羟基C_1-6烷基，羟基C_1-6烷氧基，C_1-6烷氧基C_1-6烷基，C_1-6烷氧基C_1-6烷氧基，氨基，C_1-6烷基氨基，二(C_1-6烷基)氨基，氨基C_1-6烷基，(C_1-6烷基)氨基C_1-6烷基，二(C_1-6烷基)氨基C_1-6烷基，氰基C_1-6烷基，C_1-6烷基磺酰基，C_1-6烷基磺酰氨基，C_1-6烷基磺酰基(C_1-6烷基)氨基，氨磺酰基，C_1-6烷基氨磺酰基，二(C_1-6烷基)氨磺酰基，C_1-6烷酰基氨基，C_1-6烷酰基(C_1-6烷基)氨基，氨基甲酰基，C_1-6烷基氨基甲酰基和二(C_1-6烷基)氨基甲酰基；R ⁹ and R ¹⁰ are independently hydrogen or a group selected from the group consisting of C _1-6 alkyl, carbocycle, carbocyclic C _1-6 alkyl, heterocyclyl and heterocyclyl C _1-6 alkyl, The group is optionally substituted by one or more substituents selected from the group consisting of halogen, cyano, nitro, hydroxyl, C _1-6 alkyl, C _1-6 alkoxy, halogen C _1-6 alkane Base, halogen C _1-6 alkoxy, hydroxy C 1-6 alkyl _, hydroxy C _1-6 alkoxy, C _1-6 alkoxy C _1-6 alkyl, C _1-6 alkoxy C _1-6 alkoxy, amino, C _{1-6 alkylamino, di(C 1-6} _alkyl ) amino, amino C _1-6 alkyl, (C _1-6 alkyl) amino C _1-6 alkane Base, di(C _1-6 alkyl)amino C _1-6 alkyl, cyano C _1-6 alkyl, C _1-6 alkylsulfonyl, C _1-6 alkylsulfonylamino, C _{1- 6} alkyl sulfonyl (C _1-6 alkyl) amino, sulfamoyl, C _1-6 alkyl sulfamoyl, two (C _1-6 alkyl) sulfamoyl, C _1-6 alkanoylamino, C _1-6 alkanoyl (C _1-6 alkyl) amino, carbamoyl, C _1-6 alkylcarbamoyl and two (C _1-6 alkyl) carbamoyl;

R¹¹、R¹²和R¹⁷独立地是氢或选自下列的基团：C_1-6烷基，碳环，碳环C_1-6烷基，杂环基和杂环基C_1-6烷基，该基团任选被一个或多个选自下列的取代基团取代：卤素，氰基，硝基，羟基，C_1-6烷基，C_1-6烷氧基，卤素C_1-6烷基，卤素C_1-6烷氧基，羟基C_1-6烷基，羟基C_1-6烷氧基，C_1-6烷氧基C_1-6烷基，C_1-6烷氧基C_1-6烷氧基，氨基，C_1-6烷基氨基，二(C_1-6烷基)氨基，氨基C_1-6烷基，(C_1-6烷基)氨基C_1-6烷基，二(C_1-6烷基)氨基C_1-6烷基，氰基C_1-6烷基，C_1-6烷基磺酰基，C_1-6烷酰基氨基，C_1-6烷酰基(C_1-6烷基)氨基，氨基甲酰基，C_1-6烷基氨基甲酰基和二(C_1-6烷基)氨基甲酰基；R ¹¹ , R ¹² and R ¹⁷ are independently hydrogen or a group selected from the group consisting of C _1-6 alkyl, carbocycle, carbocyclic C _1-6 alkyl, heterocyclyl and heterocyclyl C _1-6 Alkyl, which is optionally substituted by one or more substituents selected from the group consisting of halogen, cyano, nitro, hydroxyl, C _1-6 alkyl, C _1-6 alkoxy, halogen C _{1 -6} alkyl, halogen C _1-6 alkoxy, hydroxy C 1-6 alkyl _, hydroxy C _1-6 alkoxy, C _1-6 alkoxy C _1-6 alkyl, C _1-6 alkane Oxygen C _1-6 alkoxy, amino, C _1-6 alkylamino, two (C _1-6 alkyl) amino, amino C _1-6 alkyl, (C _1-6 alkyl) amino C _{1 -6} alkyl, di(C _1-6 alkyl) amino C _1-6 alkyl, cyano C _1-6 alkyl, C _1-6 alkylsulfonyl, C _1-6 alkanoylamino, C _{1 -6} alkanoyl (C _1-6 alkyl) amino, carbamoyl, C _1-6 alkylcarbamoyl and two (C _1-6 alkyl) carbamoyl;

R¹³、R¹⁴、R¹⁵、R¹⁶和R¹⁸独立地是氢或选自下列的基团：C_1-6烷基，碳环，碳环C_1-6烷基，杂环基和杂环基C_1-6烷基，该基团任选被一个或多个选自下列的取代基团取代：卤素，氰基，硝基，羟基，C_1-6烷基，C_1-6烷氧基，卤素C_1-6烷基，卤素C_1-6烷氧基，羟基C_1-6烷基，羟基C_1-6烷氧基，C_1-6烷氧基C_1-6烷基，C_1-6烷氧基C_1-6烷氧基，氨基，C_1-6烷基氨基，二(C_1-6烷基)氨基，氨基C_1-6烷基，(C_1-6烷基)氨基C_1-6烷基，二(C_1-6烷基)氨基C_1-6烷基，氰基C_1-6烷基，C_1-6烷基磺酰基，C_1-6烷基磺酰氨基，C_1-6烷基磺酰基(C_1-6烷基)氨基，氨磺酰基，C_1-6烷基氨磺酰基，二(C_1-6烷基)氨磺酰基，C_1-6烷酰基氨基，C_1-6烷酰基(C_1-6烷基)氨基，氨基甲酰基，C_1-6烷基氨基甲酰基和二(C_1-6烷基)氨基甲酰基，R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ and R ¹⁸ are independently hydrogen or a group selected from the group consisting of C _1-6 alkyl, carbocycle, carbocyclic C _1-6 alkyl, heterocyclyl and heterocyclyl Cyclic C _1-6 alkyl, which is optionally substituted by one or more substituents selected from the following groups: halogen, cyano, nitro, hydroxyl, C _1-6 alkyl, C _1-6 alkane Oxygen, halogen C _1-6 alkyl, halogen C _1-6 alkoxy, hydroxy C _1-6 alkyl, hydroxy C _1-6 alkoxy, C _1-6 alkoxy C _1-6 alkyl , C _1-6 alkoxy C _1-6 alkoxy, amino, C _1-6 alkylamino, two (C _1-6 alkyl) amino, amino C _1-6 alkyl, (C _1-6 Alkyl) amino C _1-6 alkyl, di(C _1-6 alkyl) amino C _1-6 alkyl, cyano C _1-6 alkyl, C _1-6 alkylsulfonyl, C _1-6 Alkylsulfonylamino, C _1-6 alkylsulfonyl (C _1-6 alkyl)amino, sulfamoyl, C _1-6 alkylsulfamoyl, di(C _1-6 alkyl)sulfamoyl , C _1-6 alkanoylamino, C _1-6 alkanoyl (C _1-6 alkyl) amino, carbamoyl, C _1-6 alkylcarbamoyl and di(C _1-6 alkyl) aminomethyl Acyl,

用作治疗增殖疾病的药物。Used as a drug for the treatment of proliferative diseases.

按照本发明的另一个方面，提供了式(I)的化合物According to another aspect of the present invention, there is provided a compound of formula (I)

式(I)Formula (I)

或其可药用盐；其中or its pharmaceutically acceptable salt; where

m是0、1、2、3或4；m is 0, 1, 2, 3 or 4;

¹Y和Y²独立地是N或CR⁸，条件是，¹Y和Y²之一是N，另一个是CR8； ¹ Y and Y ² are independently N or CR ⁸ , provided that one of ¹ Y and Y ² is N and the other is CR 8 ;

X是选自下列的连接基：-CR⁴＝CR⁵-，-CR⁴＝CR⁵CR⁶R⁷-，-CR⁶R⁷CR⁵＝CR⁴-，-C≡C-，-C≡CCR⁶R⁷-，-CR⁶R⁷C≡C-，-NR⁴CR⁶R⁷-，-OCR⁶R⁷-，-SCR⁶R⁷-，-S(O)CR⁶R⁷-，-S(O)₂CR⁶R⁷-，-C(O)NR⁴CR⁶R⁷-，-NR⁴C(O)CR⁶R⁷-，-NR⁴C(O)NR⁵CR⁶R⁷-，-NR⁴S(O)₂CR⁶R⁷-，-S(O)₂NR⁴CR⁶R⁷-，-C(O)NR⁴-，-NR⁴C(O)-，-NR⁴C(O)NR⁵-，-S(O)₂NR⁴-和-NR⁴S(O)₂-；X is a linker selected from the group consisting of: -CR ⁴ =CR ⁵ -, -CR ⁴ =CR ⁵ CR ⁶ R ⁷ -, -CR ⁶ R ⁷ CR ⁵ =CR ⁴ -, -C≡C-, -C≡C- CCR ⁶ R ⁷ -, -CR ⁶ R ⁷ C≡C-, -NR ⁴ CR ⁶ R ⁷ -, -OCR ⁶ R ⁷ -, -SCR ⁶ R ⁷ -, -S(O)CR ⁶ R ⁷ -, -S(O) ₂ CR ⁶ R ⁷ -, -C(O)NR ⁴ CR ⁶ R ⁷ -, -NR ⁴ C(O)CR ⁶ R ⁷ -, -NR ⁴ C(O)NR ⁵ CR ⁶ R ⁷ -, -NR ⁴ S(O) ₂ CR ⁶ R ⁷ -, -S(O) ₂ NR ⁴ CR ⁶ R ⁷ -, -C(O)NR ⁴ -, -NR ⁴ C(O)-, - NR ⁴ C(O)NR ⁵ -, -S(O) ₂ NR ⁴ - and -NR ⁴ S(O) ₂ -;

R¹是选自下列的基团：C_1-6烷基，C_2-6烯基，C_2-6炔基，碳环，碳环C_1-6烷基，杂环基和杂环基C_1-6烷基，该基团任选被一个或多个选自下列的取代基团取代：卤素，氰基，硝基，R⁹，-OR⁹，-SR⁹，-SOR⁹，-SO₂R⁹，-COR⁹，-CO₂R⁹，-CONR⁹R¹⁰，-NR⁹R¹⁰，-NR⁹COR¹⁰，-NR⁹CO₂R¹⁰，-NR⁹CONR¹⁰R¹⁵，-NR⁹COCONR¹⁰R¹⁵和-NR⁹SO₂R¹⁰； ^R is a group selected from the group consisting of C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, carbocycle, carbocyclic C _1-6 alkyl, heterocyclyl and heterocyclyl C _1-6 alkyl, which is optionally substituted by one or more substituents selected from the following groups: halogen, cyano, nitro, R ⁹ , -OR ⁹ , -SR ⁹ , -SOR ⁹ , - SO ₂ R ⁹ , -COR ⁹ , -CO ₂ R ⁹ , -CONR ⁹ R ¹⁰ , -NR ⁹ R ¹⁰ , -NR ⁹ COR ¹⁰ , -NR ⁹ CO ₂ R ¹⁰ , -NR ⁹ CONR ¹⁰ R ¹⁵ , - NR ⁹ COCONR ¹⁰ R ¹⁵ and -NR ⁹ SO ₂ R ¹⁰ ;

或X-R¹是-CR⁶R⁷OH；or XR ¹ is -CR ⁶ R ⁷ OH;

式(I)Formula (I)

或其可药用盐；其中or its pharmaceutically acceptable salt; where

m是0、1、2、3或4；m is 0, 1, 2, 3 or 4;

X是选自下列的连接基：-CR⁴＝CR⁵-，-CR⁴＝CR⁵CR⁶R⁷-，-CR⁶R⁷CR⁵＝CR⁴-，-C≡C-，-C≡CCR⁶R⁷-，-CR⁶R⁷C≡C-，-NR⁴CR⁶R⁷-，-OCR⁶R⁷-，-SCR⁶R⁷-，-S(O)CR⁶R⁷-，-S(O)₂CR⁶R⁷-，-C(O)NR⁴CR⁶R⁷-，-NR⁴C(O)NR⁵CR⁶R⁷-，-S(O)₂NR⁴CR⁶R⁷-，-C(O)NR⁴-，-NR⁴C(O)-，-NR⁴C(O)NR⁵-，-S(O)₂NR⁴-和-NR⁴S(O)₂-；X is a linker selected from the group consisting of: -CR ⁴ =CR ⁵ -, -CR ⁴ =CR ⁵ CR ⁶ R ⁷ -, -CR ⁶ R ⁷ CR ⁵ =CR ⁴ -, -C≡C-, -C≡C- CCR ⁶ R ⁷ -, -CR ⁶ R ⁷ C≡C-, -NR ⁴ CR ⁶ R ⁷ -, -OCR ⁶ R ⁷ -, -SCR ⁶ R ⁷ -, -S(O)CR ⁶ R ⁷ -, -S(O) ₂ CR ⁶ R ⁷ -, -C(O)NR ⁴ CR ⁶ R ⁷ -, -NR ⁴ C(O)NR ⁵ CR ⁶ R ⁷ -, -S(O) ₂ NR ⁴ CR ⁶ R ⁷ -, -C(O)NR ⁴ -, -NR ⁴ C(O)-, -NR ⁴ C(O)NR ⁵ -, -S(O) ₂ NR ⁴ - and -NR ⁴ S(O) _2- ;

或X-R¹是-CR⁶R⁷OH；or XR ¹ is -CR ⁶ R ⁷ OH;

或R¹和R⁴与它们相连接的原子一起形成5-至10-元碳环或杂环，其中1、2或3个环碳原子任选被N、O或S代替，并且该环任选被一个或多个选自下列的取代基团取代：卤素，氰基，硝基，羟基，C_1-6烷基，C_1-6烷氧基，卤素C_1-6烷基，卤素C_1-6烷氧基，羟基C_1-6烷基，羟基C_1-6烷氧基，C_1-6烷氧基C_1-6烷基，C_1-6烷氧基C_1-6烷氧基，氨基，C_1-6烷基氨基，二(C_1-6烷基)氨基，氨基C_1-6烷基，(C_1-6烷基)氨基C_1-6烷基，二(C_1-6烷基)氨基C_1-6烷基，氰基C_1-6烷基，C_1-6烷基磺酰基，C_1-6烷基磺酰氨基，C_1-6烷基磺酰基(C_1-6烷基)氨基，氨磺酰基，C_1-6烷基氨磺酰基，二(C_1-6烷基)氨磺酰基，C_1-6烷酰基氨基，C_1-6烷酰基(C_1-6烷基)氨基，氨基甲酰基，C_1-6烷基氨基甲酰基和二(C_1-6烷基)氨基甲酰基；Or R ¹ and R ⁴ form a 5- to 10-membered carbocyclic or heterocyclic ring together with the atoms to which they are attached, wherein 1, 2 or 3 ring carbon atoms are optionally replaced by N, O or S, and the ring is optionally Optionally substituted by one or more substituent groups selected from the group consisting of: halogen, cyano, nitro, hydroxyl, C _1-6 alkyl, C _1-6 alkoxy, halogen C _1-6 alkyl, halogen C _1-6 alkoxy, hydroxy C _1-6 alkyl, hydroxy C 1-6 alkoxy, C _1-6 alkoxy C _1-6 _alkyl , C _1-6 alkoxy C _1-6 alkane Oxygen, amino, C _1-6 alkylamino, two (C _1-6 alkyl) amino, amino C _1-6 alkyl, (C _1-6 alkyl) amino C _1-6 alkyl, two ( C _1-6 alkyl) amino C _1-6 alkyl, cyano C 1-6 alkyl, C _1-6 alkylsulfonyl, _{C 1-6} _{alkylsulfonylamino} , C _1-6 alkylsulfonyl Acyl (C _1-6 alkyl) amino, sulfamoyl, C _1-6 alkyl sulfamoyl, di(C _1-6 alkyl) sulfamoyl, C _1-6 alkanoylamino, C _1-6 Alkanoyl (C _1-6 alkyl) amino, carbamoyl, C _1-6 alkyl carbamoyl and two (C _1-6 alkyl) carbamoyl;

R¹³、R¹⁴、R¹⁵、R¹⁶和R¹⁸独立地是氢或选自下列的基团：C_1-6烷基，碳环，碳环C_1-6烷基，杂环基和杂环基C_1-6烷基，该基团任选被一个或多个选自下列的取代基团取代：卤素，氰基，硝基，羟基，C_1-6烷基，C_1-6烷氧基，卤素C_1-6烷基，卤素C_1-6烷氧基，羟基C_1-6烷基，羟基C_1-6烷氧基，C_1-6烷氧基C_1-6烷基，C_1-6烷氧基C_1-6烷氧基，氨基，C_1-6烷基氨基，二(C_1-6烷基)氨基，氨基C_1-6烷基，(C_1-6烷基)氨基C_1-6烷基，二(C_1-6烷基)氨基C_1-6烷基，氰基C_1-6烷基，C_1-6烷基磺酰基，C_1-6烷基磺酰氨基，C_1-6烷基磺酰基(C_1-6烷基)氨基，氨磺酰基，C_1-6烷基氨磺酰基，二(C_1-6烷基)氨磺酰基，C_1-6烷酰基氨基，C_1-6烷酰基(C_1-6烷基)氨基，氨基甲酰基，C_1-6烷基氨基甲酰基和二(C_1-6烷基)氨基甲酰基R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ and R ¹⁸ are independently hydrogen or a group selected from the group consisting of C _1-6 alkyl, carbocycle, carbocyclic C _1-6 alkyl, heterocyclyl and heterocyclyl Cyclic C _1-6 alkyl, which is optionally substituted by one or more substituents selected from the following groups: halogen, cyano, nitro, hydroxyl, C _1-6 alkyl, C _1-6 alkane Oxygen, halogen C _1-6 alkyl, halogen C _1-6 alkoxy, hydroxy C _1-6 alkyl, hydroxy C _1-6 alkoxy, C _1-6 alkoxy C _1-6 alkyl , C _1-6 alkoxy C _1-6 alkoxy, amino, C _1-6 alkylamino, two (C _1-6 alkyl) amino, amino C _1-6 alkyl, (C _1-6 Alkyl) amino C _1-6 alkyl, di(C _1-6 alkyl) amino C _1-6 alkyl, cyano C _1-6 alkyl, C _1-6 alkylsulfonyl, C _1-6 Alkylsulfonylamino, C _1-6 alkylsulfonyl (C _1-6 alkyl)amino, sulfamoyl, C _1-6 alkylsulfamoyl, di(C _1-6 alkyl)sulfamoyl , C _1-6 alkanoylamino, C _1-6 alkanoyl (C _1-6 alkyl) amino, carbamoyl, C _1-6 alkylcarbamoyl and di(C _1-6 alkyl) aminomethyl Acyl

式(I)Formula (I)

或其可药用盐在制备药物中的用途，该药物用于治疗增殖疾病；其中m是0、1、2、3或4；or the use of a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of proliferative diseases; wherein m is 0, 1, 2, 3 or 4;

R¹是选自下列的基团：氢，C_1-6烷基，C_2-6烯基，C_2-6炔基，碳环，碳环C_1-6烷基，杂环基和杂环基C_1-6烷基，该基团任选被一个或多个选自下列的取代基团取代：卤素，氰基，硝基，-R⁹，-OR⁹，-SR⁹，-SOR⁹，-SO₂R⁹，-COR⁹，-CO₂R⁹，-CONR⁹R¹⁰，-NR⁹R¹⁰，-NR⁹COR¹⁰，-NR⁹CO₂R¹⁰，-NR⁹CONR¹⁰R¹⁵，-NR⁹COCONR¹⁰R¹⁵和-NR⁹SO₂R¹⁰；R ¹ is a group selected from the group consisting of hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, carbocycle, carbocyclic C _1-6 alkyl, heterocyclyl and heterocyclyl Cyclic C _1-6 alkyl, which is optionally substituted by one or more substituents selected from the following groups: halogen, cyano, nitro, -R ⁹ , -OR ⁹ , -SR ⁹ , -SOR ⁹ , -SO ₂ R ⁹ , -COR ⁹ , -CO ₂ R ⁹ , -CONR ⁹ R ¹⁰ , -NR ⁹ R ¹⁰ , -NR ⁹ COR ¹⁰ , -NR ⁹ CO ₂ R ¹⁰ , -NR ⁹ CONR ¹⁰ R ¹⁵ , -NR ⁹ COCONR ¹⁰ R ¹⁵ and -NR ⁹ SO ₂ R ¹⁰ ;

R¹³、R¹⁴、R¹⁵、R¹⁶和R¹⁸独立地是氢或选自下列的基团：C_1-6烷基，碳环，碳环C_1-6烷基，杂环基和杂环基C_1-6烷基，该基团任选被一个或多个选自下列的取代基团取代：卤素，氰基，硝基，羟基，C_1-6烷基，C_1-6烷氧基，卤素C_1-6烷基，卤素C_1-6烷氧基，羟基C_1-6烷基，羟基C_1-6烷氧基，C_1-6烷氧基C_1-6烷基，C_1-6烷氧基C_1-6烷氧基，氨基，C_1-6烷基氨基，二(C_1-6烷基)氨基，氨基C_1-6烷基，(C_1-6烷基)氨基C_1-6烷基，二(C_1-6烷基)氨基C_1-6烷基，氰基C_1-6烷基，C_1-6烷基磺酰基，C_1-6烷基磺酰氨基，C_1-6烷基磺酰基(C_1-6烷基)氨基，氨磺酰基，C_1-6烷基氨磺酰基，二(C_1-6烷基)氨磺酰基，C_1-6烷酰基氨基，C_1-6烷酰基(C_1-6烷基)氨基，氨基甲酰基，C_1-6烷基氨基甲酰基和二(C_1-6烷基)氨基甲酰基。R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ and R ¹⁸ are independently hydrogen or a group selected from the group consisting of C _1-6 alkyl, carbocycle, carbocyclic C _1-6 alkyl, heterocyclyl and heterocyclyl Cyclic C _1-6 alkyl, which is optionally substituted by one or more substituents selected from the following groups: halogen, cyano, nitro, hydroxyl, C _1-6 alkyl, C _1-6 alkane Oxygen, halogen C _1-6 alkyl, halogen C _1-6 alkoxy, hydroxy C _1-6 alkyl, hydroxy C _1-6 alkoxy, C _1-6 alkoxy C _1-6 alkyl , C _1-6 alkoxy C _1-6 alkoxy, amino, C _1-6 alkylamino, two (C _1-6 alkyl) amino, amino C _1-6 alkyl, (C _1-6 Alkyl) amino C _1-6 alkyl, di(C _1-6 alkyl) amino C _1-6 alkyl, cyano C _1-6 alkyl, C _1-6 alkylsulfonyl, C _1-6 Alkylsulfonylamino, C _1-6 alkylsulfonyl (C _1-6 alkyl)amino, sulfamoyl, C _1-6 alkylsulfamoyl, di(C _1-6 alkyl)sulfamoyl , C _1-6 alkanoylamino, C _1-6 alkanoyl (C _1-6 alkyl) amino, carbamoyl, C _1-6 alkylcarbamoyl and di(C _1-6 alkyl) aminomethyl Acyl.

式(I)Formula (I)

R¹是选自下列的基团：C_1-6烷基，C_2-6烯基，C_2-6炔基，碳环，碳环C_1-6烷基，杂环基和杂环基C_1-6烷基，该基团任选被一个或多个选自下列的取代基团取代：卤素，氰基，硝基，-R⁹，-OR⁹，-SR⁹，-SOR⁹，-SO₂R⁹，-COR⁹，-CO₂R⁹，-CONR⁹R¹⁰，-NR⁹R¹⁰，-NR⁹COR¹⁰，-NR⁹CO₂R¹⁰，-NR⁹CONR¹⁰R¹⁵，-NR⁹COCONR¹⁰R¹⁵和-NR⁹SO₂R¹⁰； ^R is a group selected from the group consisting of C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, carbocycle, carbocyclic C _1-6 alkyl, heterocyclyl and heterocyclyl C _1-6 alkyl, the group is optionally substituted by one or more substituents selected from the following groups: halogen, cyano, nitro, -R ⁹ , -OR ⁹ , -SR ⁹ , -SOR ⁹ , -SO ₂ R ⁹ , -COR ⁹ , -CO ₂ R ⁹ , -CONR ⁹ R ¹⁰ , -NR ⁹ R ¹⁰ , -NR ⁹ COR ¹⁰ , -NR ⁹ CO ₂ R ¹⁰ , -NR ⁹ CONR ¹⁰ R ¹⁵ , -NR ⁹ COCONR ¹⁰ R ¹⁵ and -NR ⁹ SO ₂ R ¹⁰ ;

或X-R¹是-CR⁶R⁷OH；or XR ¹ is -CR ⁶ R ⁷ OH;

式(I)Formula (I)

或X-R¹是-CR⁶R⁷OHor XR ¹ is -CR ⁶ R ⁷ OH

当存在时，每个R³独立地选自卤素，氰基，硝基，-R¹³，-OR¹³，-SR¹³，-SOR¹³，-SO₂R¹³，-COR¹³，-CO₂R¹³，-CONR¹³R¹⁴，-NR¹³R¹⁴，-NR¹³COR¹⁴，-R¹³CO₂R¹⁴和-NR¹³SO₂R¹⁴；When present, each R ³ is independently selected from halogen, cyano, nitro, -R ¹³ , -OR ¹³ , -SR ¹³ , -SOR ¹³ , -SO ₂ R ¹³ , -COR ¹³ , -CO ₂ R ¹³ , -CONR ¹³ R ¹⁴ , -NR ¹³ R ¹⁴ , -NR ¹³ COR ¹⁴ , -R ¹³ CO ₂ R ¹⁴ and -NR ¹³ SO ₂ R ¹⁴ ;

按照本发明的进一步的方面，还提供了式(I)的化合物According to a further aspect of the present invention, there is also provided a compound of formula (I)

式(I)Formula (I)

或其可药用盐；其中or its pharmaceutically acceptable salt; where

m是O、1、2、3或4；m is 0, 1, 2, 3 or 4;

X是选自下列的连接基：-CR⁴＝CR⁵-，-CR⁴＝CR⁵CR⁶R⁷-，-CR⁶R⁷CR⁵＝CR⁴-，-C≡C-，-C≡CCR⁶R⁷-，-CR⁶R⁷C≡C-，-NR⁴CR⁶R⁷-，-OCR⁶R⁷-，-SCR⁶R⁷-，-S(O)CR⁶R⁷-，-S(O)₂CR⁶R⁷-，-C(O)NR⁴CR⁶R⁷-，-NR⁴C(O)CR⁶R⁷-，-NR⁴C(O)NR⁵CR⁶R⁷-，-NR⁴S(O)₂CR⁶R⁷-，-S(O)₂NR⁴CR⁶R⁷-，-C(O)NR⁴-，-NR⁴C(O)-，-NR⁴C(O)NR⁵-，-(O)₂NR⁴-和-NR⁴S(O)₂-；X is a linker selected from the group consisting of: -CR ⁴ =CR ⁵ -, -CR ⁴ =CR ⁵ CR ⁶ R ⁷ -, -CR ⁶ R ⁷ CR ⁵ =CR ⁴ -, -C≡C-, -C≡C- CCR ⁶ R ⁷ -, -CR ⁶ R ⁷ C≡C-, -NR ⁴ CR ⁶ R ⁷ -, -OCR ⁶ R ⁷ -, -SCR ⁶ R ⁷ -, -S(O)CR ⁶ R ⁷ -, -S(O) ₂ CR ⁶ R ⁷ -, -C(O)NR ⁴ CR ⁶ R ⁷ -, -NR ⁴ C(O)CR ⁶ R ⁷ -, -NR ⁴ C(O)NR ⁵ CR ⁶ R ⁷ -, -NR ⁴ S(O) ₂ CR ⁶ R ⁷ -, -S(O) ₂ NR ⁴ CR ⁶ R ⁷ -, -C(O)NR ⁴ -, -NR ⁴ C(O)-, - NR ⁴ C(O)NR ⁵ -, -(O) ₂ NR ⁴ - and -NR ⁴ S(O) ₂ -;

R¹是选自下列的基团：氢，C_1-6烷基，C_2-6烯基，C_2-6炔基，碳环，碳环C_1-6烷基，杂环基和杂环基C_1-6烷基，该基团任选被一个或多个选自下列的取代基团取代：卤素，氰基，硝基，-R⁹，-OR⁹，-SR⁹，-SOR⁹，-O₂R⁹，-COR⁹，-CO₂R⁹，-CONR⁹R¹⁰，-NR⁹R¹⁰，-NR⁹COR¹⁰，-NR⁹CO₂R¹⁰，-NR⁹CONR¹⁰R¹⁵，-NR⁹COCONR¹⁰R¹⁵和NR⁹SO₂R¹⁰；R ¹ is a group selected from the group consisting of hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, carbocycle, carbocyclic C _1-6 alkyl, heterocyclyl and heterocyclyl Cyclic C _1-6 alkyl, which is optionally substituted by one or more substituents selected from the following groups: halogen, cyano, nitro, -R ⁹ , -OR ⁹ , -SR ⁹ , -SOR ⁹ , -O ₂ R ⁹ , -COR ⁹ , -CO ₂ R ⁹ , -CONR ⁹ R ¹⁰ , -NR ⁹ R ¹⁰ , -NR ⁹ COR ¹⁰ , -NR ⁹ CO ₂ R ¹⁰ , -NR ⁹ CONR ¹⁰ R ¹⁵ , -NR ⁹ COCONR ¹⁰ R ¹⁵ and NR ⁹ SO ₂ R ¹⁰ ;

当存在时，每个R³独立地选自卤素，氰基，硝基，-R¹³，-OR¹³，-R¹³，-SOR¹³，-SO₂R¹³，-COR¹³，-CO₂R¹³，-CONR¹³R¹⁴，-NR¹³R¹⁴，-NR¹³COR¹⁴，-NR¹³CO₂R¹⁴和-NR¹³SO₂R¹⁴；When present, each R ³ is independently selected from halogen, cyano, nitro, -R ¹³ , -OR ¹³ , -R ¹³ , -SOR ¹³ , -SO ₂ R ¹³ , -COR ¹³ , -CO ₂ R ¹³ , -CONR ¹³ R ¹⁴ , -NR ¹³ R ¹⁴ , -NR ¹³ COR ¹⁴ , -NR ¹³ CO ₂ R ¹⁴ and -NR ¹³ SO ₂ R ¹⁴ ;

式(I)Formula (I)

或其可药用盐；其中or its pharmaceutically acceptable salt; where

m是0、1、2、3或4；m is 0, 1, 2, 3 or 4;

R¹是选自下列的基团：C_1-6烷基，C_2-6烯基，C_2-6炔基，碳环，碳环C_1-6烷基，杂环基和杂环基C_1-6烷基，该基团任选被一个或多个选自下列的取代基团取代：卤素，氰基，硝基，-R⁹，-OR⁹，-SR⁹，-SOR⁹，-O₂R⁹，-COR⁹，-CO₂R⁹，-CONR⁹R¹⁰，-NR⁹R¹⁰，-NR⁹COR¹⁰，-NR⁹CO₂R¹⁰，-NR⁹CONR¹⁰R¹⁵，-NR⁹COCONR¹⁰R¹⁵和NR⁹SO₂R¹⁰； ^R is a group selected from the group consisting of C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, carbocycle, carbocyclic C _1-6 alkyl, heterocyclyl and heterocyclyl C _1-6 alkyl, the group is optionally substituted by one or more substituents selected from the following groups: halogen, cyano, nitro, -R ⁹ , -OR ⁹ , -SR ⁹ , -SOR ⁹ , -O ₂ R ⁹ , -COR ⁹ , -CO ₂ R ⁹ , -CONR ⁹ R ¹⁰ , -NR ⁹ R ¹⁰ , -NR ⁹ COR ¹⁰ , -NR ⁹ CO ₂ R ¹⁰ , -NR ⁹ CONR ¹⁰ R ¹⁵ , - NR ⁹ COCONR ¹⁰ R ¹⁵ and NR ⁹ SO ₂ R ¹⁰ ;

或X-R¹是-CR⁶R⁷OH；or XR ¹ is -CR ⁶ R ⁷ OH;

式(I)Formula (I)

或其可药用盐；其中or its pharmaceutically acceptable salt; where

m是0、1、2、3或4；m is 0, 1, 2, 3 or 4;

或X-R¹是-CR⁶R⁷OH；or XR ¹ is -CR ⁶ R ⁷ OH;

某些式(I)的化合物能够存在立体异构形式。可以理解，本发明包括式(I)化合物的所有几何和旋光异构体和其混合物，包括消旋体。互变异构体和其混合物也形成本发明的一个方面。溶剂化物和其混合物也形成本发明的一个方面。例如，式(I)化合物的合适溶剂化物是例如水合物，例如半水合物、单水合物、二-水合物或三-水合物或其其它数目的水合物。Certain compounds of formula (I) are capable of existing in stereoisomeric forms. It will be understood that the present invention includes all geometric and optical isomers of the compounds of formula (I) and mixtures thereof, including racemates. Tautomers and mixtures thereof also form an aspect of the invention. Solvates and mixtures thereof also form an aspect of the invention. Suitable solvates of compounds of formula (I) are, for example, hydrates, such as hemihydrates, monohydrates, di- or tri-hydrates, or other numbers of hydrates thereof.

本发明涉及本文所定义的式(I)的化合物以及其盐。用于药物组合物的盐是可药用盐，但其它盐可以用于制备式(I)的化合物和它们的可药用盐。本发明的可药用盐可以例如包括本文所定义的式(I)化合物的酸加成盐，式(I)化合物是充分碱性的，以便形成这种盐。这种酸加成盐包括但不局限于富马酸盐，甲磺酸盐，盐酸盐，氢溴酸盐，柠檬酸盐和马来酸盐，和与磷酸和硫酸形成的盐。此外，如果式(I)化合物是充分酸性的，盐是碱盐，实例包括但不局限于：碱金属盐例如钠或钾盐，碱土金属盐例如钙或镁盐，或有机胺盐例如三乙胺、乙醇胺、二乙醇胺、三乙醇胺、吗啉、N-甲基哌啶、N-乙基哌啶、二苄胺或氨基酸例如赖氨酸盐。The present invention relates to compounds of formula (I) as defined herein and salts thereof. The salts used in the pharmaceutical compositions are pharmaceutically acceptable salts, but other salts may be used in the preparation of compounds of formula (I) and their pharmaceutically acceptable salts. Pharmaceutically acceptable salts of the invention may, for example, include acid addition salts of compounds of formula (I) as defined herein, which compounds are sufficiently basic to form such salts. Such acid addition salts include, but are not limited to, fumarate, methanesulfonate, hydrochloride, hydrobromide, citrate and maleate salts, and salts formed with phosphoric and sulfuric acid. Furthermore, if the compound of formula (I) is sufficiently acidic, the salt is a base salt, examples include but are not limited to: alkali metal salts such as sodium or potassium salts, alkaline earth metal salts such as calcium or magnesium salts, or organic amine salts such as triethylamine salts. Amines, ethanolamine, diethanolamine, triethanolamine, morpholine, N-methylpiperidine, N-ethylpiperidine, dibenzylamine or amino acids such as lysine salts.

也可以以体内可水解的酯的形式提供式(I)的化合物。包含羧基或羟基的式(I)化合物的体内可裂解的酯是例如：在人或动物体内可裂解产生母体酸或醇的可药用酯。这种酯可以通过例如静脉内给予试验动物试验化合物并随后检验试验动物的体液来加以鉴定。Compounds of formula (I) may also be provided in the form of in vivo hydrolyzable esters. In vivo cleavable esters of compounds of formula (I) containing carboxyl or hydroxyl groups are, for example, pharmaceutically acceptable esters which are cleaved in humans or animals to yield the parent acid or alcohol. Such esters can be identified, for example, by administering the test compound intravenously to a test animal and subsequently examining the body fluids of the test animal.

羧基的合适可药用酯包括C_1-6烷氧基甲基酯例如甲氧基甲基酯，C_1-6烷酰氧基甲基酯例如新戊酰氧基甲基酯，酞基酯，C_3-8环烷氧基羰基氧基C_1-6烷基酯例如1-环己基羰基氧基乙基酯，1，3-二氧杂环戊烯-2-酮基甲基酯例如5-甲基-1，3-二氧杂环戊烯-2-酮基甲基酯，和C_1-6烷氧基羰基氧基乙酯例如1-甲氧基羰基氧基乙酯；和可以在本发明化合物的任何羧基上形成酯。Suitable pharmaceutically acceptable esters of the carboxyl group include C _1-6 alkoxymethyl esters such as methoxymethyl esters, C _1-6 alkanoyloxymethyl esters such as pivaloyloxymethyl esters, phthaloyl esters , C _3-8 cycloalkoxycarbonyloxy C _1-6 alkyl ester such as 1-cyclohexylcarbonyloxyethyl ester, 1,3-dioxol-2-one methyl ester such as 5-methyl-1,3-dioxol-2-one methyl ester, and C _1-6 alkoxycarbonyloxyethyl ester such as 1-methoxycarbonyloxyethyl ester; and Esters may be formed at any carboxyl group of the compounds of the invention.

羟基的合适可药用酯包括无机酯例如磷酸酯(包括氨基磷酸环酯)和α-酰氧烷基醚，和由于酯的体内水解而分解得到母体羟基的相关化合物。α-酰氧烷基醚的例子包括乙酰氧基甲氧基醚和2，2-二甲基丙酰氧基甲氧基醚。形成羟基的体内可水解酯的选项包括C_1-10烷酰基，例如甲酰基，乙酰基，苯甲酰基，苯乙酰，取代的苯甲酰基和苯乙酰；C_1-10烷氧羰基(得到烷基碳酸酯)，例如乙氧羰基；二-C_1-4烷基氨基甲酰基和N-(二-C_1-4烷基氨基乙基)-N-C_1-4烷基氨基甲酰基(得到氨基甲酸酯)；二-C_1-4烷基氨基乙酰基和羧基乙酰基。苯乙酰和苯甲酰基上的环取代基的例子包括氨甲基、C_1-4烷基氨基甲基和二-(C_1-4烷基)氨甲基，和通过亚甲基连接基连接环氮原子与苯甲酰基环的3-或4-位的吗啉代或哌嗪基。其它有益的体内可水解的酯包括例如R^AC(O)OC_1-6烷基-CO-，其中R^A是例如苄氧基-C_1-4烷基或苯基。在这种酯中，苯基上的合适取代基包括例如4-C_1-4哌嗪基-C_1-4烷基，哌嗪基-C_1-4烷基和吗啉代-C_1-4烷基。Suitable pharmaceutically acceptable esters of hydroxy groups include inorganic esters such as phosphate esters (including phosphoramidate cyclic esters) and a-acyloxyalkyl ethers, and related compounds that decompose to yield the parent hydroxy group as a result of in vivo hydrolysis of the ester. Examples of α-acyloxyalkyl ethers include acetoxymethoxy ether and 2,2-dimethylpropionyloxymethoxy ether. Options for forming in vivo hydrolyzable esters of hydroxyl groups include C _1-10 alkanoyl groups such as formyl, acetyl, benzoyl, phenylacetyl, substituted benzoyl and phenylacetyl; C _1-10 alkoxycarbonyl (to give alkane ethoxycarbonyl), such as ethoxycarbonyl; di-C _1-4 alkylcarbamoyl and N-(di-C _1-4 alkylaminoethyl)-NC _1-4 alkylcarbamoyl (to give amino formate); di-C _1-4 alkylaminoacetyl and carboxyacetyl. Examples of ring substituents on phenylacetyl and benzoyl include aminomethyl, C _1-4 alkylaminomethyl and bis-(C _1-4 alkyl)aminomethyl, and via methylene linkers Ring nitrogen atom and morpholino or piperazinyl at the 3- or 4-position of the benzoyl ring. Other beneficial in vivo hydrolyzable esters include, for example, ^RA C(O) _OC1-6alkyl -CO-, where ^RA is, for example, benzyloxy- _C1-4alkyl or phenyl. In such esters, suitable substituents on phenyl include, for example, 4-C _1-4 piperazinyl-C _1-4 alkyl, piperazinyl-C _1-4 alkyl and morpholino-C _{1-4 4} alkyl.

也可以以前体药物形式给予式(I)的化合物，其在人或动物体内分解，得到式(I)的化合物。前体药物的各种形式在本领域是已知的。例如，这种前体药物衍生物参见：Compounds of formula (I) can also be administered in the form of prodrugs, which break down in the human or animal body to give compounds of formula (I). Various forms of prodrugs are known in the art. For example, such prodrug derivatives see:

a)Design of Prodrugs，edited by H.Bundgaard，(Elsevier，1985)andMethods in Enzymology，Vol.42，p.309-396，edited by K.Widder等人，(Academic Press，1985)；a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methods in Enzymology, Vol.42, p.309-396, edited by K. Widder et al., (Academic Press, 1985);

b)A Textbook of Drug Design and Development，edited byKrogsgaard-Larsen and H.Bundgaard，Chapter 5“Design and Applicationof Prodrugs”，by H.Bundgaard p.113-191(1991)；b) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H.Bundgaard, Chapter 5 "Design and Application of Prodrugs", by H.Bundgaard p.113-191(1991);

c)H.Bundgaard，Advanced Drug Delivery Reviews，8，1-38(1992)；c) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992);

d)H.Bundgaard等人，Journal of Pharmaceutical Sciences，77，285(1988)；andd) H. Bundgaard et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); and

e)N.Kakeya等人，Chem Pharm Bull，32，692(1984)。e) N. Kakeya et al., Chem Pharm Bull, 32, 692 (1984).

本说明书中的一般术语“C_p-q烷基”包括直链和支链烷基。然而，谈到单一烷基例如“丙基”仅仅具体用于直链型式(即正丙基和异丙基)，谈到单一支链烷基例如“叔丁基”仅仅具体用于支链型式。The general term "C _pq alkyl" in this specification includes linear and branched chain alkyl groups. However, references to single alkyl groups such as "propyl" are specific only to the straight chain versions (i.e., n-propyl and isopropyl), and references to single branched chain alkyl groups such as "tert-butyl" are specific only to the branched chain versions .

C_p-q烷基及其它术语(其中p和q是整数)中的前缀C_p-q表明基团中存在的碳原子范围，例如C_1-4烷基包括C₁烷基(甲基)、C₂烷基(乙基)、C₃烷基(正丙基和异丙基形式的丙基)和C₄烷基(正丁基、仲丁基、异丁基和叔丁基)。The prefix C _pq in C _pq alkyl and other terms (where p and q are integers) indicates the range of carbon atoms present in the group, for example C _1-4 alkyl includes C ₁ alkyl (methyl), C ₂ alkane (ethyl), _C3 alkyl (propyl in the form of n-propyl and isopropyl) and _C4 alkyl (n-butyl, sec-butyl, isobutyl and tert-butyl).

术语C_p-q烷氧基包括-O-C_p-q烷基。The term C _pq alkoxy includes -OC _pq alkyl.

术语C_p-q烷酰基包括-C(O)烷基。The term C _alkanoyl includes -C(O)alkyl.

术语卤素包括氟、氯、溴和碘。The term halogen includes fluorine, chlorine, bromine and iodine.

“碳环”是包含3至14个环原子的饱和、不饱和或部分饱和的单环、双环或三环系统，其中环CH₂基团可以被C＝O基团代替。“碳环”包括“芳基”、“C_p-q环烷基”和“C_p-q环烯基”。A "carbocycle" is a saturated, unsaturated or partially saturated monocyclic, bicyclic or tricyclic ring system containing from 3 to 14 ring atoms, wherein the ring _CH2 groups may be replaced by C=O groups. "Carbocycle" includes "aryl", "C _pq cycloalkyl" and "C _pq cycloalkenyl".

“芳基”是芳香族单环、双环或三环的碳环系。"Aryl" is an aromatic monocyclic, bicyclic or tricyclic carbocyclic ring system.

“C_p-q环烯基”是包含至少1个C＝C键的不饱和或部分饱和的单环、双环或三环碳环环系，其中环CH₂基团可以被C＝O基团代替。" _Cpq cycloalkenyl" is an unsaturated or partially saturated monocyclic, bicyclic or tricyclic carbocyclic ring system comprising at least 1 C=C bond, wherein a ring _CH2 group may be replaced by a C=O group.

“C_p-q环烷基”是饱和的单环、双环或三环碳环环系，其中环CH₂基团可以被C＝O基团代替。" _{Cpqcycloalkyl} " is a saturated monocyclic, bicyclic or tricyclic carbocyclic ring system in which a ring _CH2 group may be replaced by a C=O group.

“杂环基”是包含3至14个环原子的饱和、不饱和或部分饱和的单环、双环或三环系统，其中1、2、3或4个环原子选自氮、硫或氧，该环可以是碳或氮连接的，其中环中的氮或硫原子可以被氧化，其中环CH₂基团可以被C＝O基团代替。“杂环基”包括“杂芳基”、“环杂烷基”和“环杂烯基”。"Heterocyclyl" is a saturated, unsaturated or partially saturated monocyclic, bicyclic or tricyclic ring system comprising 3 to 14 ring atoms, of which 1, 2, 3 or 4 ring atoms are selected from nitrogen, sulfur or oxygen, The ring can be carbon or nitrogen linked, wherein the nitrogen or sulfur atom in the ring can be oxidized, and wherein the ring _CH2 group can be replaced by a C=O group. "Heterocyclyl" includes "heteroaryl", "cycloheteroalkyl" and "cycloheteroalkenyl".

“杂芳基”是芳香族单环、双环或三环的杂环基，尤其具有5至1O个环原子，其中1、2、3或4个环原子选自氮、硫或氧，其中环中的氮或硫可以被氧化。"Heteroaryl" is an aromatic monocyclic, bicyclic or tricyclic heterocyclic group, especially having 5 to 10 ring atoms, of which 1, 2, 3 or 4 ring atoms are selected from nitrogen, sulfur or oxygen, wherein the ring Nitrogen or sulfur in can be oxidized.

“环杂烯基”是具有5至10个环原子的不饱和或部分饱和的单环、双环或三环杂环基环系，其中1、2、3或4个环原子选自氮、硫或氧，该环可以是碳或氮连接的，其中环中的氮或硫原子可以被氧化，其中环CH₂基团可以被C＝O基团代替。"Cycloheteroalkenyl" is an unsaturated or partially saturated monocyclic, bicyclic or tricyclic heterocyclyl ring system having 5 to 10 ring atoms, wherein 1, 2, 3 or 4 ring atoms are selected from nitrogen, sulfur or oxygen, the ring may be carbon or nitrogen linked, wherein a nitrogen or sulfur atom in the ring may be oxidized, wherein a ring _CH2 group may be replaced by a C=O group.

“环杂烷基”是具有5至10个环原子的饱和单环、双环或三环杂环系统，其中1、2、3或4个环原子选自氮、硫或氧，该环可以是碳或氮连接的，其中环中的氮或硫原子可以被氧化，其中环CH₂基团可以被C＝O基团代替。"Cycloheteroalkyl" is a saturated monocyclic, bicyclic or tricyclic heterocyclic ring system having 5 to 10 ring atoms, wherein 1, 2, 3 or 4 ring atoms are selected from nitrogen, sulfur or oxygen, the ring may be Carbon or nitrogen linked, where the nitrogen or sulfur atom in the ring can be oxidized, where the ring _CH2 group can be replaced by a C=O group.

本说明书可以使用组合术语，以描述包含一个以上官能团的基团。除非本文另外描述，否则可以按照本领域所理解的来解释这种术语。例如，碳环C_p-q烷基包括被碳环取代的C_p-q烷基，杂环基C_p-q烷基包括被杂环基取代的C_p-q烷基，二(C_p-q烷基)氨基包括被2个C_p-q烷基(可以相同或不同)取代的氨基。Combination terms may be used in this specification to describe groups that contain more than one functional group. Unless otherwise described herein, such terms are to be interpreted as understood in the art. For example, carbocyclic C _pq alkyl includes C _pq alkyl substituted by carbocycle, heterocyclyl C _pq alkyl includes C _pq alkyl substituted by heterocyclyl, di(C _pq alkyl)amino includes 2 C _pq alkyl (can be the same or different) substituted amino.

卤代C_p-q烷基是被1个或1个以上卤素取代基(尤其是1、2或3个卤素取代基)取代的C_p-q烷基。同样，包含卤素的其它一般术语例如卤代C_p-q烷氧基可以包含1个或1个以上卤素取代基(尤其是1、2或3个卤素取代基)。 _HaloCpqalkyl is _Cpqalkyl substituted by 1 or more halogen substituents, especially 1, 2 or 3 halogen substituents. Likewise, other general terms containing halogen such as _{haloCpqalkoxy} may contain 1 or more halogen substituents (especially 1 , 2 or 3 halogen substituents).

羟基C_p-q烷基是被1个或1个以上羟基取代基(尤其是1、2或3个羟基取代基)取代的C_p-q烷基。同样，包含羟基的其它一般术语例如羟基C_p-q烷氧基可以包含1个或1个以上羟基取代基(尤其是1、2或3个羟基取代基)。 _{HydroxyCpqalkyl} is _Cpqalkyl substituted by 1 or more hydroxy substituents, especially 1, 2 or 3 hydroxy substituents. Likewise, other general terms comprising hydroxy such as _hydroxyC alkoxy may contain 1 or more hydroxy substituents (especially 1 , 2 or 3 hydroxy substituents).

C_p-q烷氧基C_p-q烷基是被1个或1个以上C_p-q烷氧基取代基(尤其是1、2或3个C_p-q烷氧基取代基)取代的C_p-q烷基。同样，包含C_p-q烷氧基的其它一般术语例如C_p-q烷氧基C_p-q烷氧基可以包含1个或1个以上C_p-q烷氧基取代基(尤其是1、2或3个C_p-q烷氧基取代基)。C _pq alkoxy C _pq alkyl is a C _pq alkyl substituted by 1 or more C pq alkoxy substituents, especially ₁ , 2 or 3 C _pq alkoxy substituents. Likewise, other general terms that include C _pq alkoxy such as C _pq alkoxy C _pq alkoxy may contain 1 or more C _pq alkoxy substituents (especially 1, 2 or 3 C _pq alkoxy Oxygen substituent).

如果任选的取代基选自“1或2”、“1、2或3”或“1、2、3或4”个基团或取代基，应该理解，该定义包括选自一个具体说明基团的所有取代基，即所有的取代基是相同的，或取代基选自两个或多个具体说明的基团，即取代基是不相同的。If optional substituents are selected from "1 or 2", "1, 2 or 3" or "1, 2, 3 or 4" groups or substituents, it is understood that the definition includes All substituents of the group, ie all substituents are the same, or the substituents are selected from two or more specified groups, ie the substituents are different.

借助于计算机软件(ACD/Name version 8.0)命名本发明的化合物。The compounds of the invention were named with the aid of computer software (ACD/Name version 8.0).

“增殖疾病”包括恶性病例如癌症以及非恶性病例如炎性疾病、梗阻性的呼吸道疾病、免疫疾病或心血管疾病。"Proliferative diseases" include malignant diseases such as cancer as well as non-malignant diseases such as inflammatory diseases, obstructive respiratory diseases, immune diseases or cardiovascular diseases.

任何R基团或这种基团的任何部分或取代基的合适意义包括：Suitable values for any R group or any moiety or substituent of such a group include:

C_1-4烷基：甲基，乙基，丙基，丁基，2-甲基丙基和叔丁C _1-4 Alkyl: methyl, ethyl, propyl, butyl, 2-methylpropyl and tert-butyl

基；base;

C_1-6烷基： C_1-4烷基，戊基，2，2-二甲丙基，3-甲基丁基和C _1-6 alkyl: C _1-4 alkyl, pentyl, 2,2-dimethylpropyl, 3-methylbutyl and

己基；Hexyl;

C_3-6环烷基：环丙基，环丁基，环戊基和环己基；C _3-6 cycloalkyl: cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl;

C_3-6环烷基C_1-4烷基：环丙基甲基，环丙基乙基，环丁基甲基，环戊C _3-6 cycloalkyl C _1-4 alkyl: cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentyl

基甲基和环己基甲基；hydroxymethyl and cyclohexylmethyl;

芳基：苯基和萘基；Aryl: phenyl and naphthyl;

芳基C_1-4烷基：苄基，苯乙基，萘基甲基和萘基乙基；Aryl C _1-4 alkyl: benzyl, phenethyl, naphthylmethyl and naphthylethyl;

碳环：芳基，环己烯基和C_3-6环烷基；Carbocycle: aryl, cyclohexenyl and C _3-6 cycloalkyl;

卤素：氟，氯，溴和碘；Halogen: Fluorine, Chlorine, Bromine and Iodine;

C_1-4烷氧基：甲氧基，乙氧基，丙氧基和异丙氧基；C _1-4 alkoxy: methoxy, ethoxy, propoxy and isopropoxy;

C_1-6烷氧基： C_1-4烷氧基，戊氧基，1-乙基丙氧基和己氧基；C _1-6 alkoxy: C _1-4 alkoxy, pentyloxy, 1-ethylpropoxy and hexyloxy;

C_1-6烷酰基：乙酰基，丙酰基和2-甲基丙酰基；C _1-6 alkanoyl: acetyl, propionyl and 2-methylpropionyl;

杂芳基：吡啶基，咪唑基，喹啉基，噌啉基，嘧啶基，Heteroaryl: pyridyl, imidazolyl, quinolinyl, cinnolinyl, pyrimidinyl,

噻吩基，吡咯基，吡唑基，噻唑基，噻唑基，Thienyl, pyrrolyl, pyrazolyl, thiazolyl, thiazolyl,

三唑基，噁唑基，异噁唑基，呋喃基，哒嗪基， Triazolyl, Oxazolyl, Isoxazolyl, Furanyl, Pyridazinyl,

吡嗪基，吲哚基，苯并呋喃基，二苯并呋喃基Pyrazinyl, Indolyl, Benzofuryl, Dibenzofuryl

和苯并噻吩基；and benzothienyl;

杂芳基C_1-4烷基：吡咯基甲基，吡咯基乙基，咪唑基甲基，咪唑Heteroaryl C _1-4 alkyl: pyrrolylmethyl, pyrrolylethyl, imidazolylmethyl, imidazole

基乙基，吡唑基甲基，吡唑基乙基，呋喃基甲

基，呋喃基乙基，噻吩基甲基，噻吩基乙基， ,

吡啶基甲基，吡啶基乙基，吡嗪基甲基，吡嗪Pyridylmethyl, Pyridylethyl, Pyrazinylmethyl, Pyrazine

基乙基，嘧啶基甲基，嘧啶基乙基，嘧啶基丙

基，嘧啶基丁基，咪唑基丙基，咪唑基丁基， , Pyrimidinyl Butyl, Imidazolyl Propyl, Imidazolyl Butyl,

喹啉基丙基，1，3，4-三唑基丙基和噁唑基甲基； ,

杂环基：杂芳基，吡咯烷基，异喹啉基，喹喔啉基，苯Heterocyclyl: Heteroaryl, pyrrolidinyl, isoquinolinyl, quinoxalinyl, benzene

并噻唑基，苯并噁唑基，哌啶基，哌嗪基，氮

杂环丁烷基，吗啉基，四氢异喹啉基，四氢喹

啉基，二氢吲哚基，二氢-2H-吡喃基和四氢呋

喃基。Alkyl group.

应注意，对于说明书中使用的术语所给出的实例不是限制性的。It should be noted that the examples given for the terms used in the specification are not limiting.

m、X、¹Y和Y²、R¹、R²和R³的具体意义如下。如果合适的话，这种意义可以与本发明的任何方面或其部分、以及本文所定义的任何定义、权利要求或实施方案结合使用。The specific meanings of m, X, ¹ Y and Y ² , R ¹ , R ² and R ³ are as follows. This meaning may be used in conjunction with any aspect of the invention, or part thereof, and with any definition, claim or embodiment defined herein, as appropriate.

mm

在本发明的一方面，m是0、1、2或3。In one aspect of the invention, m is 0, 1, 2 or 3.

在另一个方面，m是0、1或2。In another aspect, m is 0, 1 or 2.

在进一步的方面，m是0或1。In a further aspect, m is 0 or 1.

在又一个方面，m是0，这样R³不存在。In yet another aspect, m is 0 such that ^R3 is absent.

在又一个方面，m是1，R³是甲基。In yet another aspect, m is 1 and ^R is methyl.

¹¹ Y和YY and Y ²²

在本发明的一方面，¹Y是N，Y²是CR⁸。In one aspect of the invention, ¹ Y is N and Y ² is CR ⁸ .

在本发明的另一个方面，¹Y是N，Y²是CH。In another aspect of the invention, ¹ Y is N and Y ² is CH.

在本发明的又一个方面，¹Y是CR⁸，Y²是N。In yet another aspect of the invention, ¹ Y is CR ⁸ and Y ² is N.

在进一步的方面，¹Y是CH或CF，Y²是N。In a further aspect, ¹ Y is CH or CF and Y ² is N.

在进一步的方面，¹Y是CH，Y²是N。In a further aspect, ¹ Y is CH and Y ² is N.

Xx

在本发明的一方面，X是选自下列的连接基：-NR⁴CR⁶R⁷-，-OCR⁶R⁷-，-SCR⁶R⁷-，-S(O)CR⁶R⁷-，-S(O)₂CR⁶R⁷-，-C(O)NR⁴CR⁶R⁷-，-NR⁴C(O)NR⁵CR⁶R⁷-，-S(O)₂NR⁴CR⁶R⁷-，-NR⁴C(O)-，-C(O)NR⁴-，-S(O)₂NR⁴-和-NR⁴S(O)₂-。In one aspect of the invention, X is a linker selected from the group consisting of: -NR ⁴ CR ⁶ R ⁷ -, -OCR ⁶ R ⁷ -, -SCR ⁶ R ⁷ -, -S(O)CR ⁶ R ⁷ -, -S(O) ₂ CR ⁶ R ⁷ -, -C(O)NR ⁴ CR ⁶ R ⁷ -, -NR ⁴ C(O)NR ⁵ CR ⁶ R ⁷ -, -S(O) ₂ NR ⁴ CR ⁶ R ⁷ -, -NR ⁴ C(O)-, -C(O)NR ⁴ -, -S(O) ₂ NR ⁴ - and -NR ⁴ S(O) ₂ -.

在另一个方面，X是选自下列的连接基：-NR⁴CR⁶R⁷-，-OCR⁶R⁷-，-SCR⁶R⁷-，-S(O)CR⁶R⁷-，-S(O)₂CR⁶R⁷-，-C(O)NR⁴CR⁶R⁷-，-NR⁴C(O)NR⁵CR⁶R⁷-，-S(O)₂NR⁴CR⁶R⁷，-C(O)NR⁴-和-NR⁴C(O)-。In another aspect, X is a linker selected from the group consisting of: -NR ⁴ CR ⁶ R ⁷ -, -OCR ⁶ R ⁷ -, -SCR ⁶ R ⁷ -, -S(O)CR ⁶ R ⁷ -, -S (O) ₂ CR ⁶ R ⁷ -, -C(O)NR ⁴ CR ⁶ R ⁷ -, -NR ⁴ C(O)NR ⁵ CR ⁶ R ⁷ -, -S(O) ₂ NR ⁴ CR ⁶ R ⁷ , -C(O)NR ⁴ - and -NR ⁴ C(O)-.

在进一步的方面，X是选自下列的连接基：-NR⁴CR⁶R⁷-，-OCR⁶R⁷-，-SCR⁶R⁷-，-S(O)CR⁶R⁷-，-S(O)₂CR⁶R⁷-，-C(O)NR⁴-和-NR⁴C(O)-。In a further aspect, X is a linker selected from the group consisting of: -NR ⁴ CR ⁶ R ⁷ -, -OCR ⁶ R ⁷ -, -SCR ⁶ R ⁷ -, -S(O)CR ⁶ R ⁷ -, -S (O) ₂ CR ⁶ R ⁷ -, -C(O)NR ⁴ - and -NR ⁴ C(O)-.

在进一步的方面，X是选自下列的连接基：-NR⁴CR⁶R⁷-，-OCR⁶R⁷-，-SCR⁶R⁷-，-S(O)CR⁶R⁷-和-S(O)₂CR⁶R⁷-。In a further aspect, X is a linker selected from the group consisting of: -NR ⁴ CR ⁶ R ⁷ -, -OCR ⁶ R ⁷ -, -SCR ⁶ R ⁷ -, -S(O)CR ⁶ R ⁷ - and -S (O) ₂ CR ⁶ R ⁷ -.

在又一个方面，X是选自下列的连接基：-SCR⁶R⁷-，-S(O)CR⁶R⁷-和-S(O)₂CR⁶R⁷-。In yet another ^aspect , X is ^a linker selected from the group consisting ^of ^-SCR6R7- , ^-S (O) ^CR6R7- and -S(O) _2CR6R7- .

在另一个方面，X是选自下列的连接基：-NR⁴CH₂-，-OCH₂-，-OCH(CH₃)-，-OC(CH₃)₂-，-SCH₂-，-SCH(CH₃)-，-C(CH₃)₂-，-S(O)CH₂-，-S(O)CH(CH₃)-，-S(O)C(CH₃)₂-，-S(O)₂CH₂-，-S(O)₂CH(CH₃)-，-S(O)₂C(CH₃)₂-，-C(O)NR⁴-和-NR⁴C(O)-。In another aspect, X is a linker selected from ^-NR4CH2- , _-OCH2- , -OCH( _CH3 )- _, -OC( _CH3 ) _2- , _-SCH2- , -SCH (CH ₃ )-, -C(CH ₃ ) ₂ -, -S(O)CH ₂ -, -S(O)CH(CH ₃ )-, -S(O)C(CH ₃ ) ₂ -, - S(O) ₂ CH ₂ -, -S(O) ₂ CH(CH ₃ )-, -S(O) ₂ C(CH ₃ ) ₂ -, -C(O)NR ⁴ - and -NR ⁴ C( O)-.

在另一个方面，X是选自下列的连接基：-NR⁴CH₂-，-OCH₂-，-SCH₂-，-S(O)CH₂-，-S(O)₂CH₂-，-C(O)NR⁴-和-NR⁴C(O)-。In another aspect, X is a linker selected _from ^-NR4CH2- , _-OCH2- , _-SCH2- , -S ₍ O) _CH2- , -S(O) _2CH2- , -C(O)NR ⁴ - and -NR ⁴ C(O)-.

在另一个方面，X是选自下列的连接基：-NR⁴CH₂-，-OCH₂-，-OCH(CH₃)-，-OC(CH₃)₂-，-SCH₂-，-SCH(CH₃)-，-SC(CH₃)₂-，-S(O)CH₂-，-S(O)CH(CH₃)-，-S(O)C(CH₃)₂-，-S(O)₂CH₂-，-S(O)₂CH(CH₃)-和-S(O)₂C(CH₃)₂-。In another aspect, X is a linker selected from ^-NR4CH2- , _-OCH2- , -OCH( _CH3 )- _, -OC( _CH3 ) _2- , _-SCH2- , -SCH (CH ₃ )-, -SC(CH ₃ ) ₂ -, -S(O)CH ₂ -, -S(O)CH(CH ₃ )-, -S(O)C(CH ₃ ) ₂ -, - S(O) ₂ CH ₂ -, -S(O) ₂ CH(CH ₃ )- and -S(O) ₂ C(CH ₃ ) ₂ -.

在另一个方面，X是选自下列的连接基：-NR⁴CH₂-，-OCH₂-，-SCH₂-，-S(O)CH₂-和-S(O)₂CH₂-。In another aspect, X is a linker selected _from ^-NR4CH2- , _-OCH2- , _-SCH2- _, -S(O) _CH2- , and -S(O) _2CH2- .

在进一步的方面，X是选自下列的连接基：-NHCH₂-，-N(CH₃)CH₂-，-OCH₂-，-OCH(CH₃)-，-OC(CH₃)₂-，-SCH₂-，-SCH(CH₃)-，-SC(CH₃)₂-，-S(O)CH₂-，-S(O)CH(CH₃)-，-S(O)C(CH₃)₂-，-S(O)₂CH₂-，-S(O)₂CH(CH₃)-，-S(O)₂C(CH₃)₂-，-C(O)NH-，-C(O)N(CH₃)-，-NHC(O)-和-N(CH₃)C(O)-。In a further aspect, X is a linker selected from -NHCH ₂ -, -N(CH ₃ )CH ₂ -, -OCH ₂ -, -OCH(CH ₃ )-, -OC(CH ₃ ) ₂ - , -SCH ₂ -, -SCH(CH ₃ )-, -SC(CH ₃ ) ₂ -, -S(O)CH ₂ -, -S(O)CH(CH ₃ )-, -S(O)C (CH ₃ ) ₂ -, -S(O) ₂ CH ₂ -, -S(O) ₂ CH(CH ₃ )-, -S(O) ₂ C(CH ₃ ) ₂ -, -C(O)NH -, -C(O)N( _CH3 )-, -NHC(O)- and -N( _CH3 )C(O)-.

在进一步的方面，X是选自下列的连接基：-NHCH₂-，-N(CH₃)CH₂-，-OCH₂-，-SCH₂-，-S(O)CH₂-，-S(O)₂CH₂-，-C(O)NH-，-C(O)N(CH₃)-，-NHC(O)-和-N(CH₃)C(O)-。In a further aspect, X is a linker selected from -NHCH ₂ -, -N(CH ₃ )CH ₂ -, -OCH ₂ -, -SCH ₂ -, -S(O)CH ₂ -, -S (O) ₂ CH ₂ -, -C(O)NH-, -C(O)N(CH ₃ )-, -NHC(O)- and -N(CH ₃ )C(O)-.

在进一步的方面，X是选自下列的连接基：-NHCH₂-，-N(CH₃)CH₂-，-OCH₂-，-OCH(CH₃)-，-OC(CH₃)₂-，-SCH₂-，-SCH(CH₃)-，-SC(CH₃)₂-，-S(O)CH₂-，-S(O)CH(CH₃)-，-S(O)C(CH₃)₂-，-S(O)₂CH₂-，-S(O)₂CH(CH₃)-和-S(O)₂C(CH₃)₂-。In a further aspect, X is a linker selected from -NHCH ₂ -, -N(CH ₃ )CH ₂ -, -OCH ₂ -, -OCH(CH ₃ )-, -OC(CH ₃ ) ₂ - , -SCH ₂ -, -SCH(CH ₃ )-, -SC(CH ₃ ) ₂ -, -S(O)CH ₂ -, -S(O)CH(CH ₃ )-, -S(O)C (CH ₃ ) ₂ -, -S(O) ₂ CH ₂ -, -S(O) ₂ CH(CH ₃ )- and -S(O) ₂ C(CH ₃ ) ₂ -.

在进一步的方面，X是选自下列的连接基：-NHCH₂-，-N(CH₃)CH₂-，-OCH₂-，-SCH₂-和-S(O)₂CH₂-。In a further aspect, X is a linker selected from _-NHCH2- , -N( _CH3 )CH2-, _-OCH2- _, _-SCH2- and _-S (O) _2CH2- .

在另一个方面，X是-SCH₂-或-S(O)₂CH₂-。 _In another aspect, X is _-SCH2- or -S(O) _2CH2- .

在另一个方面，X是-SCH₂-，-SCH(CH₃)-或-SC(CH₃)₂-。In another aspect, X is _-SCH2- , -SCH( _CH3 )- or -SC( _CH3 ) _2- .

在另一个方面，X是-S(O)CH₂-，-S(O)CH(CH₃)-或-S(O)C(CH₃)₂-。In another aspect, X is -S(O) _CH2- , -S(O)CH( _CH3 )- or -S(O)C( _CH3 ) _2- .

在另一个方面，X是-S(O)₂CH₂-，-S(O)₂CH(CH₃)-或-S(O)₂C(CH₃)₂-。In another aspect, X _{is -S(O)2CH2-} _, -S(O) _2CH ( _CH3 )- or -S(O) _2C ( _CH3 ) _2- .

在另一个方面，X是-S(O)₂CH₂-。 _In another aspect, X is -S(O) _2CH2- .

在另一个方面，X是-S(O)₂C(CH₃)₂-。In another aspect, X is -S(O) _2C ( _CH3 ) _2- .

RR ¹¹

在本发明的一方面，R¹是选自下列的基团：C_1-4烷基，C_3-10环烷基，芳基，C_3-10环烷基C_1-4烷基，芳基C_1-4烷基，环杂烷基，杂芳基，环杂烷基C_1-4烷基，杂芳基C_1-4烷基，该基团任选被一个或多个选自下列的取代基团取代：卤素，氰基，硝基，R⁹，-OR⁹，-COR⁹，-CONR⁹R¹⁰，-NR⁹R¹⁰和-NR⁹COR¹⁰。In one aspect of the invention, ^R is a group selected from the group consisting of: C _1-4 alkyl, C _3-10 cycloalkyl, aryl, C _3-10 cycloalkyl, C _1-4 alkyl, aryl C _1-4 alkyl, cycloheteroalkyl, heteroaryl, cycloheteroalkyl C _1-4 alkyl, heteroaryl C _1-4 alkyl, the group is optionally selected from one or more The following substituent groups are substituted: halogen, cyano, nitro, R ⁹ , -OR ⁹ , -COR ⁹ , -CONR ⁹ R ¹⁰ , -NR ⁹ R ¹⁰ and -NR ⁹ COR ¹⁰ .

在另一个方面，R¹是选自下列的基团：金刚烷基，甲基，乙基，丙基，丁基，异丁基，叔丁基，环戊基，环己基，苯基，苄基，苯乙基，吡咯烷基，吡咯基，咪唑基，吡唑基，呋喃基，噻吩基，吡啶基，嘧啶基，吡嗪基，吡咯烷基甲基，吡咯烷基乙基，吡咯基甲基，吡咯基乙基，咪唑基甲基，咪唑基乙基，吡唑基甲基，吡唑基乙基，呋喃基甲基，呋喃基乙基，噻吩基甲基，噻吩基乙基，吡啶基甲基，吡啶基乙基，嘧啶基甲基，嘧啶基乙基，吡嗪基甲基和吡嗪基乙基，该基团任选被1、2或3个选自下列的取代基团取代：卤素，氰基，硝基，R⁹，-OR⁹，-COR⁹，-CONR⁹R¹⁰，-NR⁹R¹⁰和-NR⁹COR¹⁰。In another aspect, ^R is a group selected from the group consisting of adamantyl, methyl, ethyl, propyl, butyl, isobutyl, t-butyl, cyclopentyl, cyclohexyl, phenyl, benzyl Base, phenethyl, pyrrolidinyl, pyrrolyl, imidazolyl, pyrazolyl, furyl, thienyl, pyridyl, pyrimidinyl, pyrazinyl, pyrrolidinylmethyl, pyrrolidinylethyl, pyrrolyl Methyl, pyrrolylethyl, imidazolylmethyl, imidazolylethyl, pyrazolylmethyl, pyrazolylethyl, furylmethyl, furylethyl, thienylmethyl, thienylethyl, Pyridylmethyl, pyridylethyl, pyrimidinylmethyl, pyrimidinylethyl, pyrazinylmethyl and pyrazinylethyl, this group is optionally replaced by 1, 2 or 3 substituents selected from the following Group substitution: halogen, cyano, nitro, R ⁹ , -OR ⁹ , -COR ⁹ , -CONR ⁹ R ¹⁰ , -NR ⁹ R ¹⁰ and -NR ⁹ COR ¹⁰ .

在进一步的方面，R¹是选自下列的基团：甲基，乙基，丙基，丁基，异丁基，叔丁基，环丙基，环戊基环己基，苯基，苄基，苯乙基，吡啶基，吡唑基乙基，呋喃基甲基，噻吩基甲基，噻唑基甲基，噻二唑基甲基和吡嗪基乙基，该基团任选被1或2个选自下列的取代基团取代：氨基，卤素，氰基，甲基，甲氧基，三氟甲基，三氟甲氧基，-NHCOCH₃，-CONH₂和-CONHCH₃。In a further aspect, ^R is a group selected from the group consisting of methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, cyclopropyl, cyclopentylcyclohexyl, phenyl, benzyl , phenethyl, pyridyl, pyrazolylethyl, furylmethyl, thienylmethyl, thiazolylmethyl, thiadiazolylmethyl and pyrazinylethyl, the group is optionally replaced by 1 or Substitution with 2 substituent groups selected from amino, halogen, cyano, methyl, methoxy, trifluoromethyl, trifluoromethoxy, -NHCOCH ₃ , -CONH ₂ and -CONHCH ₃ .

在又一个方面，R¹是选自下列的基团：甲基，异丙基，环丙基，环己基，-CH₂CH₂OH，-，-CH₂CH₂NC(O)CH₃，苯基，4-氟苯基，2-氯苯基，2-三氟甲基苯基，2-甲氧基苯基，2-甲基苯基，4-乙酰胺基苯基，4-氨基苯基，，吡啶-4-基，吡啶-2-基，2-氧代吡咯烷-3-基，噻唑-2-基，4-甲基噻唑-2-基和3-甲基-1，3，4-噻二唑-2-基。In yet another aspect, R ¹ is a group selected from the group consisting of methyl, isopropyl, cyclopropyl, cyclohexyl, -CH ₂ CH ₂ OH, -, -CH ₂ CH ₂ NC(O)CH ₃ , Phenyl, 4-fluorophenyl, 2-chlorophenyl, 2-trifluoromethylphenyl, 2-methoxyphenyl, 2-methylphenyl, 4-acetamidophenyl, 4-amino Phenyl,, pyridin-4-yl, pyridin-2-yl, 2-oxopyrrolidin-3-yl, thiazol-2-yl, 4-methylthiazol-2-yl and 3-methyl-1, 3,4-Thiadiazol-2-yl.

在又一个方面，R¹是甲基。In yet another aspect, R ¹ is methyl.

X-RX-R ¹¹

在一个实施方案中，X-R¹是-C(CH₃)₂OH或-CH₂OH。In one embodiment, ^XR1 is -C( _CH3 ) _2OH or _-CH2OH .

在一个实施方案中，X-R¹是-CH₂OH。In one embodiment, ^XR1 is _-CH2OH .

RR ²²

在本发明的一方面，R²选自碳环或杂环基，该基团被-NR¹⁷SO₂R¹⁸取代，并任选被一个或多个独立地选自下列的取代基团取代：卤素，氰基，硝基，-R¹¹，-OR¹¹，-COR¹¹，-CONR¹¹R¹²，-NR¹¹R¹²和-NR¹¹COR¹²。In one aspect of the present invention, R ² is selected from carbocyclic or heterocyclic groups substituted by -NR ¹⁷ SO ₂ R ¹⁸ , and optionally substituted by one or more substituent groups independently selected from the following: Halogen, cyano, nitro, -R ¹¹ , -OR ¹¹ , -COR ¹¹ , -CONR ¹¹ R ¹² , -NR ¹¹ R ¹² and -NR ¹¹ COR ¹² .

在本发明的一方面，R²选自碳环或杂环基，该基团被-NHSO₂R¹⁸取代，并任选被一个或多个独立地选自下列的取代基团取代：卤素，氰基，硝基，-R¹¹，-OR¹¹，-COR¹¹，-CONR¹¹R¹²，-NR¹¹R¹²和-NR¹¹COR¹²。In one aspect of the invention, R ² is selected from carbocyclic or heterocyclic groups substituted by -NHSO ₂ R ¹⁸ and optionally substituted by one or more substituents independently selected from the group consisting of halogen, Cyano, Nitro, -R ¹¹ , -OR ¹¹ , -COR ¹¹ , -CONR ¹¹ R ¹² , -NR ¹¹ R ¹² and -NR ¹¹ COR ¹² .

在本发明的一方面，R²选自5或6元碳环或杂环基，该基团被-NR¹⁷SO₂R¹⁸取代，并任选被一个或多个独立地选自下列的取代基团取代：卤素，氰基，硝基，-R¹¹，-OR¹¹，-COR¹¹，-CONR¹¹R¹²，-NR¹¹R¹²和-NR¹¹COR¹²。In one aspect of the invention, R ² is selected from 5- or 6-membered carbocyclic or heterocyclic groups substituted by -NR ¹⁷ SO ₂ R ¹⁸ , and optionally substituted by one or more independently selected from Group substitution: halogen, cyano, nitro, -R ¹¹ , -OR ¹¹ , -COR ¹¹ , -CONR ¹¹ R ¹² , -NR ¹¹ R ¹² and -NR ¹¹ COR ¹² .

在本发明的一方面，R²选自5或6元碳环或杂环基，该基团被-NHSO₂R¹⁸取代，并任选被一个或多个独立地选自下列的取代基团取代：卤素，氰基，硝基，-R¹¹，-OR¹¹，-COR¹¹，-CONR¹¹R¹²，-NR¹¹R¹²和-NR¹¹COR¹²。In one aspect of the invention, R ² is selected from 5 or 6 membered carbocyclic or heterocyclic groups substituted by -NHSO ₂ R ¹⁸ , and optionally substituted by one or more substituents independently selected from Substitution: halogen, cyano, nitro, -R ¹¹ , -OR ¹¹ , -COR ¹¹ , -CONR ¹¹ R ¹² , -NR ¹¹ R ¹² and -NR ¹¹ COR ¹² .

在本发明的一方面，R²选自6元芳基和5或6元杂芳基，该基团被-NR¹⁷SO₂R¹⁸取代，并任选被一个或多个独立地选自下列的取代基团取代：卤素，氰基，硝基，-R¹¹，-OR¹¹，-COR¹¹，-CONR¹¹R¹²，-NR¹¹R¹²和-NR¹¹COR¹²。In one aspect of the present invention, R ² is selected from 6-membered aryl and 5 or 6-membered heteroaryl, which group is substituted by -NR ¹⁷ SO ₂ R ¹⁸ , and is optionally replaced by one or more independently selected from the following The substituent group substitution: halogen, cyano, nitro, -R ¹¹ , -OR ¹¹ , -COR ¹¹ , -CONR ¹¹ R ¹² , -NR ¹¹ R ¹² and -NR ¹¹ COR ¹² .

在本发明的一方面，R²选自6元芳基和5或6元杂芳基，该基团被-NHSO₂R¹⁸取代，并任选被一个或多个独立地选自下列的取代基团取代：卤素，氰基，硝基，-R¹¹，-OR¹¹，-COR¹¹，-CONR¹¹R¹²，-NR¹¹R¹²和-NR¹¹COR¹²。In one aspect of the invention, R ² is selected from 6-membered aryl and 5 or 6-membered heteroaryl substituted by -NHSO ₂ R ¹⁸ and optionally substituted by one or more independently selected from Group substitution: halogen, cyano, nitro, -R ¹¹ , -OR ¹¹ , -COR ¹¹ , -CONR ¹¹ R ¹² , -NR ¹¹ R ¹² and -NR ¹¹ COR ¹² .

在另一个方面，R²选自苯基，吡咯基，咪唑基，吡唑基，呋喃基，噻吩基，吡啶基，嘧啶基，哒嗪基，噻唑基，该基团被-NR¹⁷SO₂R¹⁸取代，并任选被一个或多个独立地选自下列的取代基团取代：卤素，氰基，硝基，-R¹¹，-OR¹¹，-COR¹¹，-CONR¹¹R¹²，-NR¹¹R¹²和-NR¹¹COR¹²。In another aspect, R ² is selected from phenyl, pyrrolyl, imidazolyl, pyrazolyl, furyl, thienyl, pyridyl, pyrimidinyl, pyridazinyl, thiazolyl, which group is represented by -NR ¹⁷ SO ₂ R ¹⁸ is substituted, and is optionally substituted by one or more substituents independently selected from the following substituent groups: halogen, cyano, nitro, -R ¹¹ , -OR ¹¹ , -COR ¹¹ , -CONR ¹¹ R ¹² , - NR ¹¹ R ¹² and -NR ¹¹ COR ¹² .

在另一个方面，R²选自苯基，吡咯基，咪唑基，吡唑基，呋喃基，噻吩基，吡啶基，嘧啶基，哒嗪基，噻唑基，该基团被-NHSO₂R¹⁸取代，并任选被一个或多个独立地选自下列的取代基团取代：卤素，氰基，硝基，-R¹¹，-OR¹¹，-COR¹¹，-CONR¹¹R¹²，-NR¹¹R¹²和-NR¹¹COR¹²。In another aspect, R ^is selected from phenyl, pyrrolyl, imidazolyl, pyrazolyl ^, furyl, thienyl, pyridyl, pyrimidinyl, pyridazinyl, thiazolyl, which is represented by _-NHSO2R18 Substituted, and optionally substituted by one or more substituent groups independently selected from the group consisting of halogen, cyano, nitro, -R ¹¹ , -OR ¹¹ , -COR ¹¹ , -CONR ¹¹ R ¹² , -NR ¹¹ R ¹² and -NR ¹¹ COR ¹² .

在另一个方面，R²选自苯基，吡咯基，咪唑基，吡唑基，呋喃基，噻吩基，吡啶基，嘧啶基，哒嗪基，噻唑基，该基团被-NR¹⁷SO₂R¹⁸取代，并任选被一个或多个独立地选自下列的取代基团取代：氟，甲基，甲氧基，羟甲基，氰基甲基，-CONH₂，-CONHCH₃和-CON(CH₃)₂。In another aspect, R ² is selected from phenyl, pyrrolyl, imidazolyl, pyrazolyl, furyl, thienyl, pyridyl, pyrimidinyl, pyridazinyl, thiazolyl, which group is represented by -NR ¹⁷ SO ₂ R ¹⁸ is substituted and optionally substituted by one or more substituents independently selected from the group consisting of fluoro, methyl, methoxy, hydroxymethyl, cyanomethyl, -CONH ₂ , -CONHCH ₃ and - CON(CH ₃ ) ₂ .

在另一个方面，R²选自苯基，吡咯基，咪唑基，吡唑基，呋喃基，噻吩基，吡啶基，嘧啶基，哒嗪基，噻唑基，该基团被-NHSO₂R¹⁸取代，并任选被一个或多个独立地选自下列的取代基团取代：氟，甲基，甲氧基，羟甲基，氰基甲基，-CONH₂，-CONHCH₃和-CON(CH₃)₂。In another aspect, R ^is selected from phenyl, pyrrolyl, imidazolyl, pyrazolyl ^, furyl, thienyl, pyridyl, pyrimidinyl, pyridazinyl, thiazolyl, which is represented by _-NHSO2R18 substituted, and optionally substituted by one or more substituents independently selected from the group consisting of fluoro, methyl, methoxy, hydroxymethyl, cyanomethyl, -CONH ₂ , -CONHCH ₃ and -CON( CH ₃ ) ₂ .

在另一个方面，R²是被-NR¹⁷SO₂R¹⁸取代、并任选被一个或多个独立地选自下列的取代基团取代的苯基或吡啶基：氟，甲基，甲氧基，羟甲基，氰基甲基，-CONH₂，-CONHCH₃和-CON(CH₃)₂。In another aspect, R ² is phenyl or pyridyl substituted with -NR ¹⁷ SO ₂ R ¹⁸ and optionally substituted with one or more substituent groups independently selected from: fluoro, methyl, methoxy radical, hydroxymethyl, cyanomethyl, -CONH ₂ , -CONHCH ₃ and -CON(CH ₃ ) ₂ .

在另一个方面，R²是被-NHSO₂R¹⁸取代、并任选被一个或多个独立地选自下列的取代基团取代的苯基或吡啶基：氟，甲基，甲氧基，羟甲基，氰基甲基，-CONH₂，-CONHCH₃和-CON(CH₃)₂。In another aspect, R ² is phenyl or pyridyl substituted with -NHSO ₂ R ¹⁸ and optionally substituted with one or more substituents independently selected from the group consisting of fluoro, methyl, methoxy, Hydroxymethyl, cyanomethyl, -CONH ₂ , -CONHCH ₃ and -CON(CH ₃ ) ₂ .

在另一个方面，R²是被-NHSO₂R¹⁸取代、并任选被一个或多个独立地选自下列的取代基团取代的苯基：氟，甲基，甲氧基，羟甲基，氰基甲基，-CONH₂，-CONHCH₃和-CON(CH₃)₂。In another aspect, ^R2 is phenyl substituted with _-NHSO2R18 and optionally substituted with one or more substituents independently selected from the group consisting ^of fluoro, methyl, methoxy, hydroxymethyl , cyanomethyl, -CONH ₂ , -CONHCH ₃ and -CON(CH ₃ ) ₂ .

在另一个方面，R²是任选被-NR¹⁷SO₂R¹⁸取代的苯基或吡啶基。In another aspect, R ² is phenyl or pyridyl optionally substituted with —NR ¹⁷ SO ₂ R ¹⁸ .

在另一个方面，R²是任选被-NHSO₂R¹⁸取代的苯基或吡啶基。In another aspect, R ² is phenyl or pyridyl optionally substituted with -NHSO ₂ R ¹⁸ .

在另一个方面，R²是In another aspect, ^R2 is

其中A¹和A²选自CH或N，条件是，至少一个A¹或A²是CH。wherein ^A1 and ^A2 are selected from CH or N, with the proviso that at least one ^A1 or ^A2 is CH.

在另一个方面，R²是In another aspect, ^R2 is

RR ⁴⁴

在本发明的一方面，R⁴是氢或甲基。In one aspect of the invention, ^R4 is hydrogen or methyl.

在另一个方面，R⁴是氢。In another aspect, ^R4 is hydrogen.

R ⁴和R ¹ R4 ^and R1 ^_

在本发明的另一个方面，当X是下列时：-NR⁴CR⁶R⁷-，-NR⁴C(O)CR⁶R⁷-，-NR⁴C(O)NR⁵CR⁶R⁷-，-NR⁴S(O)₂CR⁶R⁷-，-NR⁴C(O)-，-NR⁴C(O)NR⁵-或-NR⁴S(O)₂-，R¹和R⁴与它们相连接的原子一起形成5-至10-元杂环，其中1、2或3个环碳原子任选被N、O或S代替，并且该环任选被一个或多个选自下列的取代基团取代：卤素，氰基，硝基，羟基，C_1-6烷基，C_1-6烷氧基，卤素C_1-6烷基，卤素C_1-6烷氧基，羟基C_1-6烷基，羟基C_1-6烷氧基，C_1-6烷氧基C_1-6烷基，C_1-6烷氧基C_1-6烷氧基，氨基，C_1-6烷基氨基，二(C_1-6烷基)氨基，氨基C_1-6烷基，(C_1-6烷基)氨基C_1-6烷基，二(C_1-6烷基)氨基C_1-6烷基，氰基C_1-6烷基，C_1-6烷基磺酰基，C_1-6烷基磺酰氨基，C_1-6烷基磺酰基(C_1-6烷基)氨基，氨磺酰基，C_1-6烷基氨磺酰基，二(C_1-6烷基)氨磺酰基，C_1-6烷酰基氨基，C_1-6烷酰基(C_1-6烷基)氨基，氨基甲酰基，C_1-6烷基氨基甲酰基和二(C_1-6烷基)氨基甲酰基。In another aspect of the invention, when X is the following: -NR ⁴ CR ⁶ R ⁷ -, -NR ⁴ C(O)CR ⁶ R ⁷ -, -NR ⁴ C(O)NR ⁵ CR ⁶ R ⁷ - , -NR ⁴ S(O) ₂ CR ⁶ R ⁷ -, -NR ⁴ C(O)-, -NR ⁴ C(O)NR ⁵ - or -NR ⁴ S(O) ₂ -, R ¹ and R ⁴ Together with the atoms they are attached to form a 5- to 10-membered heterocyclic ring, wherein 1, 2 or 3 ring carbon atoms are optionally replaced by N, O or S, and the ring is optionally replaced by one or more members selected from the following Substituent group substitution: halogen, cyano, nitro, hydroxyl, C _1-6 alkyl, C _1-6 alkoxy, halogen C _1-6 alkyl, halogen C _1-6 alkoxy, hydroxyl C _1-6 alkyl, hydroxy C _1-6 alkoxy, C _1-6 alkoxy C _1-6 alkyl, C _1-6 alkoxy C _1-6 alkoxy, amino, C _1-6 Alkylamino, two (C _1-6 alkyl) amino, amino C _1-6 alkyl, (C _1-6 alkyl) amino C _1-6 alkyl, two (C _1-6 alkyl) amino C _1-6 alkyl, cyano C _1-6 alkyl, C _1-6 alkylsulfonyl, C _1-6 alkylsulfonylamino, C _1-6 alkylsulfonyl (C _1-6 alkyl) Amino, sulfamoyl, C _1-6 alkyl sulfamoyl, two (C _1-6 alkyl) sulfamoyl, C _1-6 alkanoylamino, C _1-6 alkanoyl (C _1-6 alkyl ) amino, carbamoyl, C _1-6 alkylcarbamoyl and di(C _1-6 alkyl)carbamoyl.

在本发明的另一个方面，当X是下列时：-NR⁴CR⁶R⁷-，-NR⁴C(O)CR⁶R⁷-，-NR⁴C(O)NR⁵CR⁶R⁷-，-NR⁴S(O)₂CR⁶R⁷-，-NR⁴C(O)-，-NR⁴C(O)NR⁵-或-NR⁴S(O)₂-，R¹和R⁴与它们相连接的原子一起形成5-或6-元杂环，其中1个环碳原子任选被N或O代替，并且该环任选被一个或多个选自下列的取代基团取代：卤素，氰基，硝基，羟基，C_1-6烷基，C_1-6烷氧基，卤素C_1-6烷基，卤素C_1-6烷氧基，羟基C_1-6烷基，羟基C_1-6烷氧基，C_1-6烷氧基C_1-6烷基，C_1-6烷氧基C_1-6烷氧基，氨基，C_1-6烷基氨基，二(C_1-6烷基)氨基，氨基C_1-6烷基，(C_1-6烷基)氨基C_1-6烷基，二(C_1-6烷基)氨基C_1-6烷基，氰基C_1-6烷基，C_1-6烷基磺酰基，C_1-6烷基磺酰氨基，C_1-6烷基磺酰基(C_1-6烷基)氨基，氨磺酰基，C_1-6烷基氨磺酰基，二(C_1-6烷基)氨磺酰基，C_1-6烷酰基氨基，C_1-6烷酰基(C_1-6烷基)氨基，氨基甲酰基，C_1-6烷基氨基甲酰基和二(C_1-6烷基)氨基甲酰基。In another aspect of the invention, when X is the following: -NR ⁴ CR ⁶ R ⁷ -, -NR ⁴ C(O)CR ⁶ R ⁷ -, -NR ⁴ C(O)NR ⁵ CR ⁶ R ⁷ - , -NR ⁴ S(O) ₂ CR ⁶ R ⁷ -, -NR ⁴ C(O)-, -NR ⁴ C(O)NR ⁵ - or -NR ⁴ S(O) ₂ -, R ¹ and R ⁴ Together with the atoms they are attached to form a 5- or 6-membered heterocyclic ring, wherein one ring carbon atom is optionally replaced by N or O, and the ring is optionally substituted by one or more substituent groups selected from the following: Halogen, cyano, nitro, hydroxyl, C _1-6 alkyl, C 1-6 alkoxy, halogen C _1-6 alkyl, halogen _{C 1-6} _alkoxy , hydroxy C _1-6 alkyl, Hydroxy C _1-6 alkoxy, C _1-6 alkoxy C _1-6 alkyl, C _1-6 alkoxy C _1-6 alkoxy, amino, C _1-6 alkylamino, two ( C _1-6 alkyl) amino, amino C _1-6 alkyl, (C _1-6 alkyl) amino C _1-6 alkyl, di(C _1-6 alkyl) amino C _1-6 alkyl, Cyano C _1-6 alkyl, C _1-6 alkylsulfonyl, C _1-6 alkylsulfonylamino, C _1-6 alkylsulfonyl (C _1-6 alkyl) amino, sulfamoyl, C _1-6 alkylsulfamoyl, di(C _1-6 alkyl)sulfamoyl, C _1-6 alkanoylamino, C _1-6 alkanoyl(C _1-6 alkyl)amino, carbamoyl , C _1-6 alkylcarbamoyl and di(C _1-6 alkyl)carbamoyl.

RR ⁵⁵

在本发明的一方面，R⁵是氢或甲基。In one aspect of the invention, R ⁵ is hydrogen or methyl.

在另一个方面，R⁵是氢。In another aspect, ^R5 is hydrogen.

在另一个方面，R⁵是甲基。In another aspect, R ⁵ is methyl.

RR ⁶⁶

在本发明的一方面，R⁶是氢或甲基。In one aspect of the invention, ^R6 is hydrogen or methyl.

在另一个方面，R⁶是氢。In another aspect, ^R6 is hydrogen.

在另一个方面，R⁶是甲基。In another aspect, ^R6 is methyl.

RR ⁷⁷

在本发明的一方面，R⁷是氢或甲基。In one aspect of the invention, ^R7 is hydrogen or methyl.

在另一个方面，R⁷是氢。In another aspect, ^R7 is hydrogen.

在另一个方面，R⁷是甲基。In another aspect, ^R7 is methyl.

RR ⁸⁸

在本发明的一方面，R⁸是氢或卤素。In one aspect of the invention, ^R8 is hydrogen or halogen.

在另一个方面，R⁸是氢或氟。In another aspect, ^R8 is hydrogen or fluoro.

在进一步的方面，R⁸是氢。In a further aspect, ^R8 is hydrogen.

RR ⁹⁹

在本发明的一方面，R⁹是氢或任选被1、2或3个选自下列的取代基团取代的C_1-4烷基：卤素，氰基，硝基，羟基，C_1-4烷氧基，氨基，C_1-4烷基氨基和二(C_1-4烷基)氨基。In one aspect of the invention, R ⁹ is hydrogen or C _1-4 alkyl optionally substituted by 1, 2 or 3 substituent groups selected from the group consisting of halogen, cyano, nitro, hydroxyl, C _{1- 4} alkoxy, amino, C _1-4 alkylamino and di(C _1-4 alkyl)amino.

在另一个方面，R⁹是氢或任选被1、2或3个卤素取代基取代的C_1-4烷基。In another aspect, R ⁹ is hydrogen or C _1-4 alkyl optionally substituted with 1, 2 or 3 halo substituents.

在进一步的方面，R⁹是氢、甲基或三氟甲基。In a further aspect, ^R9 is hydrogen, methyl or trifluoromethyl.

RR ¹⁰¹⁰

在本发明的一方面，R¹⁰是氢。In one aspect of the invention, R ¹⁰ is hydrogen.

RR ¹¹¹¹

在本发明的一方面，R¹¹是氢或选自C_1-4烷基、芳基和环杂烷基的基团，该基团任选被1、2或3个选自卤素、羟基和氰基的基团取代。In one aspect of the invention, R ¹¹ is hydrogen or a group selected from C _1-4 alkyl, aryl and cycloheteroalkyl optionally replaced by 1, 2 or 3 members selected from halogen, hydroxy and Cyano group substitution.

在另一个方面，R¹¹是氢、任选被羟基或氰基取代的甲基、苯基或吡咯烷基。In another aspect, R ¹¹ is hydrogen, methyl optionally substituted with hydroxy or cyano, phenyl or pyrrolidinyl.

在另一个方面，R¹¹是氢或甲基。In another aspect, R ¹¹ is hydrogen or methyl.

RR ¹²¹²

在本发明的一方面，R¹²是氢或甲基。In one aspect of the invention, ^R12 is hydrogen or methyl.

RR ¹⁷¹⁷

在本发明的一方面，R¹⁷是氢或选自下列的基团：C_1-4烷基，芳基和环杂烷基，该基团任选被1、2或3个选自下列的基团取代：卤素、羟基和氰基。In one aspect of the invention, R ¹⁷ is hydrogen or a group selected from the group consisting of C _1-4 alkyl, aryl and cycloheteroalkyl optionally replaced by 1, 2 or 3 groups selected from Group Substitution: Halo, Hydroxy and Cyano.

在另一个方面，R¹⁷是氢、任选被羟基或氰基取代的甲基、苯基或吡咯烷基。In another aspect, ^R17 is hydrogen, methyl optionally substituted with hydroxy or cyano, phenyl or pyrrolidinyl.

在另一个方面，R¹⁷是氢或甲基。In another aspect, ^R17 is hydrogen or methyl.

在另一个方面，R¹⁷是氢。In another aspect, ^R17 is hydrogen.

RR ¹⁸¹⁸

在本发明的一方面，R¹⁸是氢或选自下列的基团：C_1-6烷基，C_3-6环烷基，芳基，杂芳基，芳基C_1-6烷基和杂芳基C_1-6烷基，该基团任选被一个或多个选自下列的取代基团取代：卤素，氰基，硝基，羟基，C_1-6烷基，C_1-6烷氧基，卤素C_1-6烷基，卤素C_1-6烷氧基，羟基C_1-6烷基，羟基C_1-6烷氧基，C_1-6烷氧基C_1-6烷基，C_1-6烷氧基C_1-6烷氧基，氨基，C_1-6烷基氨基，二(C_1-6烷基)氨基，氨基C_1-6烷基，(C_1-6烷基)氨基C_1-6烷基，二(C_1-6烷基)氨基C_1-6烷基，氰基C_1-6烷基，C_1-6烷基磺酰基，C_1-6烷基磺酰氨基，C_1-6烷基磺酰基(C_1-6烷基)氨基，氨磺酰基，C_1-6烷基氨磺酰基，二(C_1-6烷基)氨磺酰基，C_1-6烷酰基氨基，C_1-6烷酰基(C_1-6烷基)氨基，氨基甲酰基，C_1-6烷基氨基甲酰基和二(C_1-6烷基)氨基甲酰基。In one aspect of the invention, R ¹⁸ is hydrogen or a group selected from the group consisting of C _1-6 alkyl, C _3-6 cycloalkyl, aryl, heteroaryl, aryl C _1-6 alkyl and Heteroaryl C _1-6 alkyl, which is optionally substituted by one or more substituents selected from the group consisting of halogen, cyano, nitro, hydroxyl, C _1-6 alkyl, C _1-6 Alkoxy, halogen C _1-6 alkyl, halogen C 1-6 alkoxy _, hydroxy C _1-6 alkyl, hydroxy C _1-6 alkoxy, C _1-6 alkoxy C _1-6 alk Base, C _1-6 alkoxy C _1-6 alkoxy, amino, C _1-6 alkylamino, two (C _1-6 alkyl) amino, amino C _1-6 alkyl, (C _{1-6 6} alkyl) amino C _1-6 alkyl, di(C _1-6 alkyl) amino C _1-6 alkyl, cyano C _1-6 alkyl, C _1-6 alkylsulfonyl, C _{1- 6} alkyl sulfonylamino, C _1-6 alkyl sulfonyl (C _1-6 alkyl) amino, sulfamoyl, C _1-6 alkyl sulfamoyl, di(C _1-6 alkyl) sulfamoyl Acyl, C _1-6 alkanoylamino, C _1-6 alkanoyl(C _1-6 alkyl)amino, carbamoyl, C _1-6 alkylcarbamoyl and di(C _1-6 alkyl)amino formyl.

在本发明的一方面，R¹⁸是氢或选自下列的基团：C_1-6烷基，C_3-6环烷基，苯基，萘基，吡咯基，咪唑基，异噁唑基，吡唑基，呋喃基，噻吩基，吡啶基，嘧啶基，哒嗪基，氮杂(aza)吲哚基，吲哚基，喹啉基，苯并咪唑基，苯并呋喃基，二苯并呋喃基，苯并噻吩基，苯基C_1-6烷基，萘基C_1-6烷基，吡咯基C_1-6烷基，咪唑基C_1-6烷基，异噁唑基C_1-6烷基，吡唑基C_1-6烷基，呋喃基C_1-6烷基，噻吩基C_1-6烷基，吡啶基C_1-6烷基，嘧啶基C_1-6烷基，哒嗪基C_1-6烷基，氮杂吲哚基C_1-6烷基，吲哚基C_1-6烷基，喹啉基C_1-6烷基，苯并咪唑基C_1-6烷基，苯并呋喃基C_1-6烷基，二苯并呋喃基C_1-6烷基，苯并噻吩基C_1-6烷基，该基团任选被一个或多个选自下列的取代基团取代：卤素，氰基，硝基，羟基，C_1-6烷基，C_1-6烷氧基，卤素C_1-6烷基，卤素C_1-6烷氧基，羟基C_1-6烷基，羟基C_1-6烷氧基，C_1-6烷氧基C_1-6烷基，C_1-6烷氧基C_1-6烷氧基，氨基，C_1-6烷基氨基，二(C_1-6烷基)氨基，氨基C_1-6烷基，(C_1-6烷基)氨基C_1-6烷基，二(C_1-6烷基)氨基C_1-6烷基，氰基C_1-6烷基，C_1-6烷基磺酰基，C_1-6烷基磺酰氨基，C_1-6烷基磺酰基(C_1-6烷基)氨基，氨磺酰基，C_1-6烷基氨磺酰基，二(C_1-6烷基)氨磺酰基，C_1-6烷酰基氨基，C_1-6烷酰基(C_1-6烷基)氨基，氨基甲酰基，C_1-6烷基氨基甲酰基和二(C_1-6烷基)氨基甲酰基。In one aspect of the invention, R is ^hydrogen or a group selected from the group consisting of C _1-6 alkyl, C _3-6 cycloalkyl, phenyl, naphthyl, pyrrolyl, imidazolyl, isoxazolyl , pyrazolyl, furyl, thienyl, pyridyl, pyrimidyl, pyridazinyl, aza (aza) indolyl, indolyl, quinolinyl, benzimidazolyl, benzofuryl, diphenyl And furyl, benzothienyl, phenyl C 1-6 alkyl, naphthyl _C _1-6 alkyl, pyrrolyl C _1-6 alkyl, imidazolyl C _1-6 alkyl, isoxazolyl C _1-6 alkyl, pyrazolyl C _1-6 alkyl, furyl C _1-6 alkyl, thienyl C _1-6 alkyl, pyridyl C _1-6 alkyl, pyrimidyl C _1-6 alkane Base, pyridazinyl C _1-6 alkyl, azaindolyl C _1-6 alkyl, indolyl C _1-6 alkyl, quinolinyl C _1-6 alkyl, benzimidazolyl C _{1 -6} alkyl, benzofuryl C _1-6 alkyl, dibenzofuryl C _1-6 alkyl, benzothienyl C _1-6 alkyl, the group is optionally selected by one or more Substitution from the following substituent groups: halogen, cyano, nitro, hydroxyl, C _1-6 alkyl, C _1-6 alkoxy, halogen C _1-6 alkyl, halogen C _1-6 alkoxy, Hydroxy C _1-6 Alkyl, Hydroxy C 1-6 Alkoxy, C _1-6 _{Alkoxy C 1-6 Alkyl, C 1-6 Alkoxy C 1-6} _Alkoxy _, _Amino , C _{1 -6} alkylamino, two (C _1-6 alkyl) amino, amino C _1-6 alkyl, (C _1-6 alkyl) amino C _1-6 alkyl, two (C _1-6 alkyl) Amino C _1-6 alkyl, cyano C _1-6 alkyl, C _1-6 alkylsulfonyl, C _1-6 alkylsulfonylamino, C _1-6 alkylsulfonyl (C _1-6 alkane base) amino, sulfamoyl, C _1-6 alkylsulfamoyl, di(C _1-6 alkyl)sulfamoyl, C _1-6 alkanoylamino, C _1-6 alkanoyl (C _1-6 Alkyl)amino, carbamoyl, C _1-6 alkylcarbamoyl and di(C _1-6 alkyl)carbamoyl.

在本发明的一方面，R¹⁸是氢或选自下列的基团：甲基，乙基，丙基，异丙基，丁基，异丁基，叔丁基，戊基，环丙基，环丁基，环戊基，环己基，苯基，噻吩基，咪唑甲基，异噁唑基，吡唑基，吡啶基和嘧啶基，该基团任选被一个或多个选自下列的取代基团取代：卤素，氰基，硝基，羟基，C_1-6烷基，C_1-6烷氧基，卤素C_1-6烷基，卤素C_1-6烷氧基，羟基C_1-6烷基，羟基C_1-6烷氧基，C_1-6烷氧基C_1-6烷基，C_1-6烷氧基C_1-6烷氧基，氨基，C_1-6烷基氨基，二(C_1-6烷基)氨基，氨基C_1-6烷基，(C_1-6烷基)氨基C_1-6烷基，二(C_1-6烷基)氨基C_1-6烷基，氰基C_1-6烷基，C_1-6烷基磺酰基，C_1-6烷基磺酰氨基，C_1-6烷基磺酰基(C_1-6烷基)氨基，氨磺酰基，C_1-6烷基氨磺酰基，二(C_1-6烷基)氨磺酰基，C_1-6烷酰基氨基，C_1-6烷酰基(C_1-6烷基)氨基，氨基甲酰基，C_1-6烷基氨基甲酰基和二(C_1-6烷基)氨基甲酰基。In one aspect of the invention, R is ^hydrogen or a group selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, cyclopropyl, Cyclobutyl, cyclopentyl, cyclohexyl, phenyl, thienyl, imidazolylmethyl, isoxazolyl, pyrazolyl, pyridyl and pyrimidinyl, the group is optionally selected from one or more of the following Substituent group substitution: halogen, cyano, nitro, hydroxyl, C _1-6 alkyl, C _1-6 alkoxy, halogen C _1-6 alkyl, halogen C _1-6 alkoxy, hydroxyl C _{1 -6} alkyl, hydroxy C _1-6 alkoxy, _C _1-6 alkoxy C 1-6 alkyl, C _1-6 alkoxy C _1-6 alkoxy, amino, C _1-6 alk Amino, two (C _1-6 alkyl) amino, amino C _1-6 alkyl, (C _1-6 alkyl) amino C _1-6 alkyl, two (C _1-6 alkyl) amino C _{1 -6} alkyl, cyano C _1-6 alkyl, C _1-6 alkylsulfonyl, C _1-6 alkylsulfonylamino, C _1-6 alkylsulfonyl (C _1-6 alkyl) amino , sulfamoyl, C _1-6 alkyl sulfamoyl, di(C _1-6 alkyl) sulfamoyl, C _1-6 alkanoylamino, C _1-6 alkanoyl (C _1-6 alkyl) Amino, carbamoyl, C _1-6 alkylcarbamoyl and di(C _1-6 alkyl)carbamoyl.

在本发明的一方面，R¹⁸是氢或选自下列的基团：甲基，乙基，丙基，异丙基，丁基，异丁基，叔丁基，戊基，环丙基，环丁基，环戊基，环己基，-CH₂(环丙基)，-CH₂CH₂NMe₂，-CH(CH₃)CH₂OH，-C(CH₃)₂CH₂OH，-CH₂CH₂OH，-CH₂CH₂CH₂OH，4-甲基苯基，4-氯苯基，4-三氟甲基苯基，4-氟苯基，4-甲氧基苯基，3，4-二氟苯基，噻吩-2-基，-CH₂(咪唑-2-基)，-CH₂(咪唑-3-基)，异噁唑基-3-基，6-氧代-1H-吡啶(pryrdin)-2-基，5-甲基异噁唑-3-基，1-甲基吡唑-4-基，6-甲氧基吡啶-3-基，5-氟吡啶-2-基，嘧啶-2-基和1H-吡唑-3-基。In one aspect of the invention, R is ^hydrogen or a group selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, cyclopropyl, Cyclobutyl, cyclopentyl, cyclohexyl, -CH ₂ (cyclopropyl), -CH ₂ CH ₂ NMe ₂ , -CH(CH ₃ )CH ₂ OH, -C(CH ₃ ) ₂ CH ₂ OH, - _CH2CH2OH _, _-CH2CH2CH2OH , 4-methylphenyl, 4 _- chlorophenyl _, 4-trifluoromethylphenyl, 4-fluorophenyl, 4-methoxyphenyl , 3,4-difluorophenyl, thiophen-2-yl, -CH ₂ (imidazol-2-yl), -CH ₂ (imidazol-3-yl), isoxazolyl-3-yl, 6-oxo Substitute-1H-pyridin (pryrdin)-2-yl, 5-methylisoxazol-3-yl, 1-methylpyrazol-4-yl, 6-methoxypyridin-3-yl, 5-fluoro Pyridin-2-yl, pyrimidin-2-yl and 1H-pyrazol-3-yl.

在本发明的一方面，R¹⁸是氢或选自下列的基团：甲基，乙基，丙基，丁基，环丙基和4-氟苯基。In one aspect of the invention, ^R18 is hydrogen or a group selected from the group consisting of methyl, ethyl, propyl, butyl, cyclopropyl and 4-fluorophenyl.

在本发明的一方面，提供了式(I)化合物的亚型或其可药用盐；m是0、1或2；In one aspect of the present invention, there is provided a subtype of a compound of formula (I) or a pharmaceutically acceptable salt thereof; m is 0, 1 or 2;

X是选自下列的连接基：-NR⁴CR⁶R⁷-，-OCR⁶R⁷-，-SCR⁶R⁷-，-S(O)CR⁶R⁷-，-S(O)₂CR⁶R⁷-，-C(O)NR⁴CR⁶R⁷-，-NR⁴C(O)NR⁵CR⁶R⁷-，-S(O)₂NR⁴CR⁶R⁷-，-NR⁴C(O)-，-S(O)₂NR⁴-和-NR⁴S(O)₂-；X is a linker selected from the group consisting of: -NR ⁴ CR ⁶ R ⁷ -, -OCR ⁶ R ⁷ -, -SCR ⁶ R ⁷ -, -S(O)CR ⁶ R ⁷ -, -S(O) ₂ CR ⁶ R ⁷ -, -C(O)NR ⁴ CR ⁶ R ⁷ -, -NR ⁴ C(O)NR ⁵ CR ⁶ R ⁷ -, -S(O) ₂ NR ⁴ CR ⁶ R ⁷ -, -NR ⁴ C(O)-, -S(O) ₂ NR ⁴ - and -NR ⁴ S(O) ₂ -;

R¹是选自下列的基团：C_1-6烷基，碳环，碳环C_1-6烷基，杂环基和杂环基C_1-6烷基，该基团任选被一个或多个选自下列的取代基团取代：卤素，氰基，硝基，R⁹，-OR⁹，-COR⁹，-CONR⁹R¹⁰，-NR⁹R¹⁰和-NR⁹COR¹⁰；或X-R¹是-C(CH₃)₂OH或-CH₂OH； ^R is a group selected from the group consisting of C _1-6 alkyl, carbocycle, carbocyclic C _1-6 alkyl, heterocyclyl and heterocyclyl C _1-6 alkyl, which group is optionally replaced by one or a plurality of substituents selected from the following substituent groups: halogen, cyano, nitro, R ⁹ , -OR ⁹ , -COR ⁹ , -CONR ⁹ R ¹⁰ , -NR ⁹ R ¹⁰ and -NR ⁹ COR ¹⁰ ; or XR ¹ is -C(CH ₃ ) ₂ OH or -CH ₂ OH;

R²选自芳基和杂芳基，该基团被-NR¹⁷SO₂R¹⁸取代，并任选被一个或多个独立地选自下列的取代基团取代：卤素，氰基，硝基，-R¹¹，-OR¹¹，-COR¹¹，-CONR¹¹R¹²，-NR¹¹R¹²和-NR¹¹COR¹²；R ² is selected from aryl and heteroaryl substituted by -NR ¹⁷ SO ₂ R ¹⁸ and optionally substituted by one or more substituents independently selected from: halogen, cyano, nitro , -R ¹¹ , -OR ¹¹ , -COR ¹¹ , -CONR ¹¹ R ¹² , -NR ¹¹ R ¹² and -NR ¹¹ COR ¹² ;

当存在时，每个R³是甲基；When present, each ^R is methyl;

或，当X是下列时：-NR⁴CR⁶R⁷-，-NR⁴C(O)NR⁵CR⁶R⁷-，-NR⁴C(O)-或-NR⁴S(O)₂-，R¹和R⁴与它们相连接的原子一起形成5-或6-元杂环，其中1个环碳原子任选被N或O代替，并且该环任选被一个或多个选自下列的取代基团取代：卤素，氰基，硝基，羟基，C_1-6烷基，C_1-6烷氧基，卤素C_1-6烷基，卤素C_1-6烷氧基，羟基C_1-6烷基，羟基C_1-6烷氧基，C_1-6烷氧基C_1-6烷基，C_1-6烷氧基C_1-6烷氧基，氨基，C_1-6烷基氨基，二(C_1-6烷基)氨基，氨基C_1-6烷基，(C_1-6烷基)氨基C_1-6烷基，二(C_1-6烷基)氨基C_1-6烷基，氰基C_1-6烷基，C_1-6烷基磺酰基，C_1-6烷基磺酰氨基，C_1-6烷基磺酰基(C_1-6烷基)氨基，氨磺酰基，C_1-6烷基氨磺酰基，二(C_1-6烷基)氨磺酰基，C_1-6烷酰基氨基，C_1-6烷酰基(C_1-6烷基)氨基，氨基甲酰基，C_1-6烷基氨基甲酰基和二(C_1-6烷基)氨基甲酰基；Or, when X is the following: -NR ⁴ CR ⁶ R ⁷ -, -NR ⁴ C(O)NR ⁵ CR ⁶ R ⁷ -, -NR ⁴ C(O)- or -NR ⁴ S(O) ₂ - , R ¹ and R ⁴ form a 5- or 6-membered heterocyclic ring together with the atoms they are attached to, wherein one ring carbon atom is optionally replaced by N or O, and the ring is optionally replaced by one or more members selected from the following Substituent group substitution: halogen, cyano, nitro, hydroxyl, C _1-6 alkyl, C _1-6 alkoxy, halogen C _1-6 alkyl, halogen C _1-6 alkoxy, hydroxyl C _1-6 alkyl, hydroxy C _1-6 alkoxy, C _1-6 alkoxy C _1-6 alkyl, C _1-6 alkoxy C _1-6 alkoxy, amino, C _1-6 Alkylamino, two (C _1-6 alkyl) amino, amino C _1-6 alkyl, (C _1-6 alkyl) amino C _1-6 alkyl, two (C _1-6 alkyl) amino C _1-6 alkyl, cyano C _1-6 alkyl, C _1-6 alkylsulfonyl, C _1-6 alkylsulfonylamino, C _1-6 alkylsulfonyl (C _1-6 alkyl) Amino, sulfamoyl, C _1-6 alkyl sulfamoyl, two (C _1-6 alkyl) sulfamoyl, C _1-6 alkanoylamino, C _1-6 alkanoyl (C _1-6 alkyl ) amino, carbamoyl, C _1-6 alkylcarbamoyl and di(C _1-6 alkyl)carbamoyl;

R⁹和R¹⁰独立地是氢或选自下列的基团：C_1-6烷基，碳环和杂环基，该基团任选被一个或多个选自下列的取代基团取代：卤素，氰基，硝基，羟基，C_1-6烷基，C_1-6烷氧基，卤素C_1-6烷基，卤素C_1-6烷氧基，羟基C_1-6烷基，羟基C_1-6烷氧基，C_1-6烷氧基C_1-6烷基，C_1-6烷氧基C_1-6烷氧基，氨基，C_1-6烷基氨基和二(C_1-6烷基)氨基；R ⁹ and R ¹⁰ are independently hydrogen or a group selected from the following: C _1-6 alkyl, carbocycle and heterocyclyl, which group is optionally substituted by one or more substituent groups selected from the following: Halogen, cyano, nitro, hydroxyl, C _1-6 alkyl, C 1-6 alkoxy, halogen C _1-6 alkyl, halogen _{C 1-6} _alkoxy , hydroxy C _1-6 alkyl, Hydroxy C _1-6 alkoxy, C _1-6 alkoxy C _1-6 alkyl, C _1-6 alkoxy C _1-6 alkoxy, amino, C _1-6 alkylamino and two ( C _1-6 alkyl) amino;

R¹¹、R¹²和R¹⁷独立地是氢或选自下列的基团：C_1-6烷基，碳环和杂环基，该基团任选被一个或多个选自下列的取代基团取代：卤素，氰基，硝基，羟基，C_1-6烷基，C_1-6烷氧基，卤素C_1-6烷基，卤素C_1-6烷氧基，羟基C_1-6烷基，羟基C_1-6烷氧基，C_1-6烷氧基C_1-6烷基，C_1-6烷氧基C_1-6烷氧基，氨基，C_1-6烷基氨基和二(C_1-6烷基)氨基；R ¹¹ , R ¹² and R ¹⁷ are independently hydrogen or a group selected from the following: C _1-6 alkyl, carbocyclic and heterocyclic groups, which are optionally replaced by one or more substituents selected from the following _Group substitution: halogen, cyano, nitro, hydroxyl, C _1-6 alkyl, C 1-6 alkoxy, halogen C _1-6 alkyl, halogen C _1-6 alkoxy, hydroxyl C _1-6 Alkyl, hydroxy C _1-6 alkoxy, C _1-6 alkoxy C _1-6 alkyl, C _1-6 alkoxy C _1-6 alkoxy, amino, C _1-6 alkylamino And two (C _1-6 alkyl) amino;

和and

R¹⁸是氢或选自下列的基团：C_1-6烷基，C_3-6环烷基，芳基，杂芳基，芳基C_1-6烷基和杂芳基C_1-6烷基，该基团任选被一个或多个选自下列的取代基团取代：卤素，氰基，硝基，羟基，C_1-6烷基，C_1-6烷氧基，卤素C_1-6烷基，卤素C_1-6烷氧基，羟基C_1-6烷基，羟基C_1-6烷氧基，C_1-6烷氧基C_1-6烷基，C_1-6烷氧基C_1-6烷氧基，氨基，C_1-6烷基氨基，二(C_1-6烷基)氨基，氨基C_1-6烷基，(C_1-6烷基)氨基C_1-6烷基，二(C_1-6烷基)氨基C_1-6烷基，氰基C_1-6烷基，C_1-6烷基磺酰基，C_1-6烷基磺酰氨基，C_1-6烷基磺酰基(C_1-6烷基)氨基，氨磺酰基，C_1-6烷基氨磺酰基，二(C_1-6烷基)氨磺酰基，C_1-6烷酰基氨基，C_1-6烷酰基(C_1-6烷基)氨基，氨基甲酰基，C_1-6烷基氨基甲酰基和二(C_1-6烷基)氨基甲酰基。R ¹⁸ is hydrogen or a group selected from the group consisting of C _1-6 alkyl, C _3-6 cycloalkyl, aryl, heteroaryl, aryl C _1-6 alkyl and heteroaryl C _1-6 Alkyl, which is optionally substituted by one or more substituents selected from the group consisting of halogen, cyano, nitro, hydroxyl, C _1-6 alkyl, C _1-6 alkoxy, halogen C _{1 -6} alkyl, halogen C _1-6 alkoxy, hydroxy C 1-6 alkyl _, hydroxy C _1-6 alkoxy, C _1-6 alkoxy C _1-6 alkyl, C _1-6 alkane Oxygen C _1-6 alkoxy, amino, C _1-6 alkylamino, two (C _1-6 alkyl) amino, amino C _1-6 alkyl, (C _1-6 alkyl) amino C _{1 -6} alkyl, di(C _1-6 alkyl) amino C _1-6 alkyl, cyano C _1-6 alkyl, C _1-6 alkylsulfonyl, C _1-6 alkylsulfonylamino, C _1-6 alkyl sulfonyl (C _1-6 alkyl) amino, sulfamoyl, C _1-6 alkyl sulfamoyl, di(C _1-6 alkyl) sulfamoyl, C _1-6 alkane Acylamino, C _1-6 alkanoyl(C _1-6 alkyl)amino, carbamoyl, C _1-6 alkylcarbamoyl and di(C _1-6 alkyl)carbamoyl.

在本发明的另一个方面，提供了式(I)化合物的亚型或其可药用盐；m是0、1或2；In another aspect of the present invention, there is provided a subtype of a compound of formula (I) or a pharmaceutically acceptable salt thereof; m is 0, 1 or 2;

X是选自下列的连接基：-NR⁴CH₂-，-OCH₂-，-OCH(CH₃)-，-OC(CH₃)₂-，-SCH₂-，-SCH(CH₃)-，-SC(CH₃)₂-，-S(O)CH₂-，-S(O)CH(CH₃)-，-S(O)C(CH₃)₂-，-S(O)₂CH₂-，-S(O)₂CH(CH₃)-，-S(O)₂C(CH₃)₂-，-C(O)NR⁴-和-NR⁴C(O)-；X is a linker selected from the group consisting of: -NR ⁴ CH ₂ -, -OCH ₂ -, -OCH(CH ₃ )-, -OC(CH ₃ ) ₂ -, -SCH ₂ -, -SCH(CH ₃ )- , -SC(CH ₃ ) ₂ -, -S(O)CH ₂ -, -S(O)CH(CH ₃ )-, -S(O)C(CH ₃ ) ₂ -, -S(O) ₂ CH ₂ -, -S(O) ₂ CH(CH ₃ )-, -S(O) ₂ C(CH ₃ ) ₂ -, -C(O)NR ⁴ - and -NR ⁴ C(O)-;

R¹是选自下列的基团：金刚烷基，甲基，乙基，丙基，丁基，异丁基，叔丁基，环戊基，环己基，苯基，苄基，苯乙基，吡咯烷基，吡咯基，咪唑基，吡唑基，呋喃基，噻吩基，吡啶基，嘧啶基，吡嗪基，吡咯烷基甲基，吡咯烷基乙基，吡咯基甲基，吡咯基乙基，咪唑基甲基，咪唑基乙基，吡唑基甲基，吡唑基乙基，呋喃基甲基，呋喃基乙基，噻吩基甲基，噻吩基乙基，吡啶基甲基，吡啶基乙基，嘧啶基甲基，嘧啶基乙基，吡嗪基甲基和吡嗪基乙基，该基团任选被1、2或3个选自下列的取代基团取代：卤素，氰基，硝基，R⁹，-OR⁹，-COR⁹，-CONR⁹R¹⁰，-NR⁹R¹⁰和-NR⁹COR¹⁰； ^R is a group selected from the group consisting of adamantyl, methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, cyclopentyl, cyclohexyl, phenyl, benzyl, phenethyl , pyrrolidinyl, pyrrolyl, imidazolyl, pyrazolyl, furyl, thienyl, pyridyl, pyrimidinyl, pyrazinyl, pyrrolidinylmethyl, pyrrolidinylethyl, pyrrolylmethyl, pyrrolyl Ethyl, imidazolylmethyl, imidazolylethyl, pyrazolylmethyl, pyrazolylethyl, furylmethyl, furylethyl, thienylmethyl, thienylethyl, pyridylmethyl, Pyridylethyl, pyrimidinylmethyl, pyrimidinylethyl, pyrazinylmethyl and pyrazinylethyl, this group is optionally substituted by 1, 2 or 3 substituents selected from the group consisting of halogen, Cyano, Nitro, R ⁹ , -OR ⁹ , -COR ⁹ , -CONR ⁹ R ¹⁰ , -NR ⁹ R ¹⁰ and -NR ⁹ COR ¹⁰ ;

或X-R¹是-C(CH₃)₂OH或-CH₂OH；or XR ¹ is -C(CH ₃ ) ₂ OH or -CH ₂ OH;

R²选自5或6元芳基和杂芳基，该基团被-NHSO₂R¹⁸取代，并任选被一个或多个独立地选自下列的取代基团取代：卤素，氰基，硝基，-R¹¹，-OR¹¹，-COR¹¹，-CONR¹¹R¹²，-NR¹¹R¹²和-NR¹¹COR¹²；R ² is selected from 5 or 6 membered aryl and heteroaryl groups substituted by -NHSO ₂ R ¹⁸ and optionally substituted by one or more substituent groups independently selected from the group consisting of halogen, cyano, Nitro, -R ¹¹ , -OR ¹¹ , -COR ¹¹ , -CONR ¹¹ R ¹² , -NR ¹¹ R ¹² and -NR ¹¹ COR ¹² ;

当存在时，每个R³是甲基；When present, each ^R is methyl;

R⁴是氢或C_1-6烷基；R ⁴ is hydrogen or C _1-6 alkyl;

或当X是-NR⁴CH₂-或-NR⁴C(O)-时，R¹和R⁴与它们相连接的原子一起形成5-或6-元杂环，其中1个环碳原子任选被N或O代替，并且该环任选被一个或多个选自下列的取代基团取代：卤素，氰基，硝基，羟基，C_1-6烷基，C_1-6烷氧基，卤素C_1-6烷基，卤素C_1-6烷氧基，羟基C_1-6烷基，羟基C_1-6烷氧基，C_1-6烷氧基C_1-6烷基，C_1-6烷氧基C_1-6烷氧基，氨基，C_1-6烷基氨基，二(C_1-6烷基)氨基，氨基C_1-6烷基，(C_1-6烷基)氨基C_1-6烷基，二(C_1-6烷基)氨基C_1-6烷基，氰基C_1-6烷基，C_1-6烷基磺酰基，C_1-6烷基磺酰氨基，C_1-6烷基磺酰基(C_1-6烷基)氨基，氨磺酰基，C_1-6烷基氨磺酰基，二(C_1-6烷基)氨磺酰基，C_1-6烷酰基氨基，C_1-6烷酰基(C_1-6烷基)氨基，氨基甲酰基，C_1-6烷基氨基甲酰基和二(C_1-6烷基)氨基甲酰基；Or when X is -NR ⁴ CH ₂ - or -NR ⁴ C(O)-, R ¹ and R ⁴ form a 5- or 6-membered heterocyclic ring together with the atoms they are connected to, wherein any ring carbon atom is is optionally replaced by N or O, and the ring is optionally substituted by one or more substituents selected from the group consisting of: halogen, cyano, nitro, hydroxyl, C _1-6 alkyl, C _1-6 alkoxy , halogen C _1-6 alkyl, halogen C _{1-6 alkoxy, hydroxy C 1-6} _alkyl , hydroxy C _1-6 alkoxy, C _1-6 alkoxy C _1-6 alkyl, C _1-6 alkoxy C _1-6 alkoxy, amino, C _1-6 alkylamino, two (C _1-6 alkyl) amino, amino C _1-6 alkyl, (C _1-6 alkyl ) amino C _1-6 alkyl, di(C _1-6 alkyl) amino C _1-6 alkyl, cyano C _1-6 alkyl, C _1-6 alkylsulfonyl, C _1-6 alkyl Sulfonylamino, C _1-6 alkylsulfonyl (C _1-6 alkyl) amino, sulfamoyl, C _1-6 alkylsulfamoyl, two (C _1-6 alkyl) sulfamoyl, C _1-6 alkanoylamino, C _1-6 alkanoyl (C _1-6 alkyl) amino, carbamoyl, C _1-6 alkylcarbamoyl and two (C _1-6 alkyl) carbamoyl;

R¹¹和R¹²独立地是氢或选自下列的基团：C_1-6烷基，碳环和杂环基，该基团任选被一个或多个选自下列的取代基团取代：卤素，氰基，硝基，羟基，C_1-6烷基，C_1-6烷氧基，卤素C_1-6烷基，卤素C_1-6烷氧基，羟基C_1-6烷基，羟基C_1-6烷氧基，C_1-6烷氧基C_1-6烷基，C_1-6烷氧基C_1-6烷氧基，氨基，C_1-6烷基氨基和二(C_1-6烷基)氨基；和R ¹¹ and R ¹² are independently hydrogen or a group selected from the group consisting of C _1-6 alkyl, carbocycle and heterocyclyl, which group is optionally substituted by one or more substituent groups selected from: Halogen, cyano, nitro, hydroxyl, C _1-6 alkyl, C 1-6 alkoxy, halogen C _1-6 alkyl, halogen _{C 1-6} _alkoxy , hydroxy C _1-6 alkyl, Hydroxy C _1-6 alkoxy, C _1-6 alkoxy C _1-6 alkyl, C _1-6 alkoxy C _1-6 alkoxy, amino, C _1-6 alkylamino and two ( C _1-6 alkyl) amino; and

在式(I)化合物或其可药用盐的另一个具体类别中；In another specific class of compounds of formula (I) or pharmaceutically acceptable salts thereof;

m是O或1；m is 0 or 1;

¹Y是CH，Y²是N； ¹ Y is CH, Y ² is N;

X是选自下列的连接基：-S(O)₂CH₂-，-S(O)₂CH(CH₃)-和-S(O)₂C(CH₃)₂-；X is a linker selected from the group consisting of -S(O) _2CH2- , -S(O) _2CH ( _CH3 )- and -S( _O ) _2C ( _CH3 ) _2- ;

R¹是选自下列的基团：甲基，乙基，丙基，丁基，异丁基，叔丁基，环丙基，环戊基环己基，苯基，苄基，苯乙基，吡啶基，吡唑基乙基，呋喃基甲基，噻吩基甲基，噻唑基甲基，噻二唑基甲基和吡嗪基乙基，该基团任选被1或2个选自下列的取代基团取代：氨基，卤素，氰基，甲基，甲氧基，三氟甲基，三氟甲氧基，-NHCOCH₃，-CONH₂和-CONHCH₃； ^R is a group selected from the group consisting of methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, cyclopropyl, cyclopentylcyclohexyl, phenyl, benzyl, phenethyl, Pyridyl, pyrazolylethyl, furylmethyl, thienylmethyl, thiazolylmethyl, thiadiazolylmethyl and pyrazinylethyl, the group is optionally selected from the following by 1 or 2 Substituent group substitution: amino, halogen, cyano, methyl, methoxy, trifluoromethyl, trifluoromethoxy, -NHCOCH ₃ , -CONH ₂ and -CONHCH ₃ ;

或-XR¹是-C(CH₃)₂OH或-CH₂OH；or -XR ¹ is -C(CH ₃ ) ₂ OH or -CH ₂ OH;

R²选自苯基，吡咯基，咪唑基，吡唑基，呋喃基，噻吩基，吡啶基，嘧啶基，哒嗪基和噻唑基，该基团被-NHSO₂R¹⁸取代，并任选被一个或多个独立地选自下列的取代基团取代：卤素，氰基，硝基，-R¹¹，-OR¹¹，-COR¹¹，-CONR¹¹R¹²，-NR¹¹R¹²和-NR¹¹COR¹²；R ² is selected from phenyl, pyrrolyl, imidazolyl, pyrazolyl, furyl, thienyl, pyridyl, pyrimidinyl, pyridazinyl and thiazolyl, this group is substituted by -NHSO ₂ R ¹⁸ , and optionally Substituted by one or more substituent groups independently selected from the group consisting of halogen, cyano, nitro, -R ¹¹ , -OR ¹¹ , -COR ¹¹ , -CONR ¹¹ R ¹² , -NR ¹¹ R ¹² and -NR ¹¹ COR ¹² ;

当存在时，R³是甲基；When present, R ³ is methyl;

在式(I)化合物或其可药用盐的进一步的具体类别中；In a further specific class of compounds of formula (I) or pharmaceutically acceptable salts thereof;

m是1；m is 1;

X是选自下列的连接基：-S(O)₂CH₂-，-S(O)₂CH(CH₃)-和-S(O)₂C(CH₃)₂-；X is a linker selected from the group consisting of -S(O) _2CH2- , -S(O) _2CH ( _CH3 )- and -S ₍ O) _2C ( _CH3 ) _2- ;

¹Y是CH，Y²是N。 ¹ Y is CH, Y ² is N.

R²是被-NHSO₂R¹⁸取代、并任选被一个或多个独立地选自下列的取代基团取代的苯基或吡啶基：氟，甲基，甲氧基，羟甲基，氰基甲基，-CONH₂，-CONHCH₃和-CON(CH₃)₂；R ² is phenyl or pyridyl substituted by -NHSO ₂ R ¹⁸ and optionally substituted by one or more substituent groups independently selected from the following: fluoro, methyl, methoxy, hydroxymethyl, cyano methyl, -CONH ₂ , -CONHCH ₃ and -CON(CH ₃ ) ₂ ;

R³是甲基；和 ^R3 is methyl; and

R¹⁸是氢或选自下列的基团：甲基，乙基，丙基，异丙基，丁基，异丁基，叔丁基，戊基，环丙基，环丁基，环戊基，环己基，苯基，噻吩基，咪唑甲基，异噁唑基，吡唑基，吡啶基和嘧啶基，该基团任选被一个或多个选自下列的取代基团取代：卤素，氰基，硝基，羟基，C_1-6烷基，C_1-6烷氧基，卤素C_1-6烷基，卤素C_1-6烷氧基，羟基C_1-6烷基，羟基C_1-6烷氧基，C_1-6烷氧基C_1-6烷基，C_1-6烷氧基C_1-6烷氧基，氨基，C_1-6烷基氨基，二(C_1-6烷基)氨基，氨基C_1-6烷基，(C_1-6烷基)氨基C_1-6烷基，二(C_1-6烷基)氨基C_1-6烷基，氰基C_1-6烷基，C_1-6烷基磺酰基，C_1-6烷基磺酰氨基，C_1-6烷基磺酰基(C_1-6烷基)氨基，氨磺酰基，C_1-6烷基氨磺酰基，二(C_1-6烷基)氨磺酰基，C_1-6烷酰基氨基，C_1-6烷酰基(C_1-6烷基)氨基，氨基甲酰基，C_1-6烷基氨基甲酰基和二(C_1-6烷基)氨基甲酰基。 ^R is hydrogen or a group selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl , cyclohexyl, phenyl, thienyl, imidazolylmethyl, isoxazolyl, pyrazolyl, pyridyl and pyrimidinyl, the group is optionally substituted by one or more substituents selected from the group consisting of halogen, Cyano _, nitro, hydroxyl, C _1-6 alkyl, C 1-6 alkoxy, halogen C _1-6 alkyl, halogen C _1-6 alkoxy, hydroxy C _1-6 alkyl, hydroxy C _1-6 alkoxy, C _1-6 alkoxy C 1-6 _alkyl , C _1-6 alkoxy C _1-6 alkoxy, amino, C _1-6 alkylamino, two (C _{1 -6} alkyl) amino, amino C _1-6 alkyl, (C _1-6 alkyl) amino C _1-6 alkyl, di(C _1-6 alkyl) amino C _1-6 alkyl, cyano C _1-6 alkyl, C _1-6 alkylsulfonyl, C _1-6 alkylsulfonylamino, C _1-6 alkylsulfonyl (C _1-6 alkyl) amino, sulfamoyl, C _{1 -6} alkyl sulfamoyl, two (C _1-6 alkyl) sulfamoyl, C _1-6 alkanoylamino, C _1-6 alkanoyl (C _1-6 alkyl) amino, carbamoyl, C _1-6 alkylcarbamoyl and di(C _1-6 alkyl)carbamoyl.

m是1；m is 1;

¹Y是CH，Y²是N。 ¹ Y is CH, Y ² is N.

R¹是选自下列的基团：甲基，异丙基，环丙基，环己基，-CH₂CH₂OH，-CH₂CH₂NC(O)CH₃，苯基，4-氟苯基，2-氯苯基，2-三氟甲基苯基，2-甲氧基苯基，2-甲基苯基，4-乙酰胺基苯基，4-氨基苯基，吡啶-4-基，吡啶-2-基，2-氧代吡咯烷-3-基，噻唑-2-基，4-甲基噻唑-2-基和3-甲基-1，3，4-噻二唑-2-基；R ¹ is a group selected from the group consisting of methyl, isopropyl, cyclopropyl, cyclohexyl, -CH ₂ CH ₂ OH, -CH ₂ CH ₂ NC(O)CH ₃ , phenyl, 4-fluorobenzene Base, 2-chlorophenyl, 2-trifluoromethylphenyl, 2-methoxyphenyl, 2-methylphenyl, 4-acetamidophenyl, 4-aminophenyl, pyridine-4- Base, pyridin-2-yl, 2-oxopyrrolidin-3-yl, thiazol-2-yl, 4-methylthiazol-2-yl and 3-methyl-1,3,4-thiadiazole- 2-base;

R²是 ^R2 is

其中：A¹和A²选自CH或N，条件是，至少一个A¹或A²是CH；Wherein: A ¹ and A ² are selected from CH or N, with the proviso that at least one A ¹ or A ² is CH;

R¹⁷是氢；R ¹⁷ is hydrogen;

R¹⁸是氢或选自下列的基团：甲基，乙基，丙基，异丙基，丁基，异丁基，叔丁基，戊基，环丙基，环丁基，环戊基，环己基，-CH₂(环丙基)，-CH₂CH₂NMe₂，-CH(CH₃)CH₂OH，-C(CH₃)₂CH₂OH，-CH₂CH₂OH，-CH₂CH₂CH₂OH，4-甲基苯基，4-氯苯基，4-三氟甲基苯基，4-氟苯基，4-甲氧基苯基，3，4-二氟苯基，噻吩-2-基，-CH₂(咪唑-2-基)，-CH₂(咪唑-3-基)，异噁唑基-3-基，6-氧代-1H-吡啶(pryrdin)-2-基，5-甲基异噁唑-3-基，1-甲基吡唑-4-基，6-甲氧基吡啶-3-基，5-氟吡啶-2-基，嘧啶-2-基和1H-吡唑-3-基； ^R is hydrogen or a group selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl , cyclohexyl, -CH ₂ (cyclopropyl), -CH ₂ CH ₂ NMe ₂ , -CH(CH ₃ )CH ₂ OH, -C(CH ₃ ) ₂ CH ₂ OH, -CH ₂ CH ₂ OH, - CH ₂ CH ₂ CH ₂ OH, 4-methylphenyl, 4-chlorophenyl, 4-trifluoromethylphenyl, 4-fluorophenyl, 4-methoxyphenyl, 3,4-difluoro Phenyl, thiophen-2-yl, -CH ₂ (imidazol-2-yl), -CH ₂ (imidazol-3-yl), isoxazolyl-3-yl, 6-oxo-1H-pyridine (pryrdin )-2-yl, 5-methylisoxazol-3-yl, 1-methylpyrazol-4-yl, 6-methoxypyridin-3-yl, 5-fluoropyridin-2-yl, pyrimidine -2-yl and 1H-pyrazol-3-yl;

和，R³是甲基。and, ^R3 is methyl.

在本发明的一方面，提供了式(Ia)或(Ib)化合物的亚型In one aspect of the invention there is provided a subtype of a compound of formula (Ia) or (Ib)

或其可药用盐；or a pharmaceutically acceptable salt thereof;

R¹是选自下列的基团：C_1-6烷基，碳环，碳环C_1-6烷基，杂环基和杂环基C_1-6烷基，该基团任选被一个或多个选自下列的取代基团取代：卤素，氰基，硝基，R⁹，-OR⁹，-COR⁹，-CONR⁹R¹⁰，-NR⁹R¹⁰ and-NR⁹COR¹⁰；或X-R¹是-C(CH₃)₂OH或-CH₂OH； ^R is a group selected from the group consisting of C _1-6 alkyl, carbocycle, carbocyclic C _1-6 alkyl, heterocyclyl and heterocyclyl C _1-6 alkyl, which group is optionally replaced by one or a plurality of substituents selected from the group consisting of: halogen, cyano, nitro, R ⁹ , -OR ⁹ , -COR ⁹ , -CONR ⁹ R ¹⁰ , -NR ⁹ R ¹⁰ and -NR ⁹ COR ¹⁰ ; or XR ¹ is -C(CH ₃ ) ₂ OH or -CH ₂ OH;

R³是甲基；R ³ is methyl;

和and

在本发明的另一个方面，提供了式(Ia)或(Ib)化合物的亚型In another aspect of the invention there is provided a subtype of a compound of formula (Ia) or (Ib)

或其可药用盐；or a pharmaceutically acceptable salt thereof;

R³是甲基；R ³ is methyl;

R⁴是氢或C_1-6烷基；R ⁴ is hydrogen or C _1-6 alkyl;

在式(Ia)或(Ib)化合物或其可药用盐的另一个具体类别中；In another specific class of compounds of formula (Ia) or (Ib) or pharmaceutically acceptable salts thereof;

¹Y是CH，Y²是N； ¹ Y is CH, Y ² is N;

R³是甲基；R ³ is methyl;

在式(Ia)或(Ib)化合物或其可药用盐的进一步的具体类别中；In a further specific class of compounds of formula (Ia) or (Ib) or pharmaceutically acceptable salts thereof;

¹Y是CH，且Y²是N。 ¹ Y is CH, and Y ² is N.

R³是甲基；和 ^R3 is methyl; and

R¹⁸是氢或选自下列的基团：甲基，乙基，丙基，异丙基，丁基，异丁基，叔丁基，戊基，环丙基，环丁基，环戊基，环己基，苯基，噻吩基，咪唑甲基，异噁唑基，吡唑基，吡啶基和嘧啶基，该基团任选被一个或多个选自下列的取代基团取代：卤素，氰基，硝基，羟基，C_1-6烷基，C_1-6烷氧基，卤素C_1-6烷基，卤素C_1-6烷氧基，羟基C_1-6烷基，羟基C_1-6烷氧基，C_1-6烷氧基C_1-6烷基，C_1-6烷氧基C_1-6烷氧基，氨基，C_1-6烷基氨基，二(C_1-6烷基)氨基，氨基C_1-6烷基，(C_1-6烷基)氨基C_1-6烷基，二(C_1-6烷基)氨基C_1-6烷基，氰基C_1-6烷基，C_1-6烷基磺酰基，C_1-6烷基磺酰氨基，C_1-6烷基磺酰基(C_1-6烷基)氨基，氨磺酰基，C_1-6烷基氨磺酰基，二(C_1-6烷基)氨磺酰基，C_1-6烷酰基氨基，C_1-6烷酰基(C_1-6烷基)氨基，氨基甲酰基，C_1-6烷基氨基甲酰基和二(C_1-6烷基)氨基甲酰基。 ^R is hydrogen or a group selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl , cyclohexyl, phenyl, thienyl, imidazolylmethyl, isoxazolyl, pyrazolyl, pyridyl and pyrimidinyl, the group is optionally substituted by one or more substituents selected from the group consisting of halogen, Cyano _, nitro, hydroxyl, C _1-6 alkyl, C 1-6 alkoxy, halogen C _1-6 alkyl, halogen C _1-6 alkoxy, hydroxy C _1-6 alkyl, hydroxy C _1-6 alkoxy, C _1-6 alkoxy C 1-6 alkyl, _C _1-6 alkoxy C _1-6 alkoxy, amino, C _1-6 alkylamino, two (C _{1 -6} alkyl) amino, amino C _1-6 alkyl, (C _1-6 alkyl) amino C _1-6 alkyl, di(C _1-6 alkyl) amino C _1-6 alkyl, cyano C _1-6 alkyl, C _1-6 alkylsulfonyl, C _1-6 alkylsulfonylamino, C _1-6 alkylsulfonyl (C _1-6 alkyl) amino, sulfamoyl, C _{1 -6} alkyl sulfamoyl, two (C _1-6 alkyl) sulfamoyl, C _1-6 alkanoylamino, C _1-6 alkanoyl (C _1-6 alkyl) amino, carbamoyl, C _1-6 alkylcarbamoyl and di(C _1-6 alkyl)carbamoyl.

m是1；m is 1;

¹Y是CH，Y²是N。 ¹ Y is CH, Y ² is N.

R¹是选自下列的基团：甲基，异丙基，环丙基，环己基，-CH₂CH₂OH，-CH₂CH₂NC(O)CH₃，苯基，4-氟苯基，2-氯苯基，2-三氟甲基苯基，2-甲氧基苯基，2-甲基苯基，4-乙酰胺基苯基，4-氨基苯基，吡啶-4-基，吡啶-2-基，2-氧代吡咯烷-3-基，，噻唑-2-基，4-甲基噻唑-2-基和3-甲基-1，3，4-噻二唑-2-基；R ¹ is a group selected from the group consisting of methyl, isopropyl, cyclopropyl, cyclohexyl, -CH ₂ CH ₂ OH, -CH ₂ CH ₂ NC(O)CH ₃ , phenyl, 4-fluorobenzene Base, 2-chlorophenyl, 2-trifluoromethylphenyl, 2-methoxyphenyl, 2-methylphenyl, 4-acetamidophenyl, 4-aminophenyl, pyridine-4- Base, pyridin-2-yl, 2-oxopyrrolidin-3-yl, thiazol-2-yl, 4-methylthiazol-2-yl and 3-methyl-1,3,4-thiadiazole -2-base;

R²是 ^R2 is

其中A¹和A²选自CH或N，条件是，至少一个A¹或A²是CH；wherein ^A1 and ^A2 are selected from CH or N, with the proviso that at least one ^A1 or ^A2 is CH;

R¹⁷是氢；和R ¹⁷ is hydrogen; and

和，R³是甲基。and, ^R3 is methyl.

本发明的另一个方面提供了选自实施例的任一项的一种化合物、或化合物的组合或其可药用盐。Another aspect of the present invention provides a compound selected from any one of the embodiments, or a combination of compounds, or a pharmaceutically acceptable salt thereof.

本发明也提供了制备式(I)化合物或其可药用盐的方法。The present invention also provides a process for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof.

式(I)的化合物，其中X＝-S(O)₂CR⁶R⁷-，可以如下制备：在室温下，在水和乙醇的混合溶剂系统中，(例如)使用

将式(I)的化合物氧化，其中X＝SCR⁶R⁷-。Compounds of formula (I), wherein X = -S(O) ₂ CR ⁶ R ⁷ -, can be prepared at room temperature in a mixed solvent system of water and ethanol, for example using

^Oxidation of compounds of formula (I) wherein X= ^SCR6R7- .

式(I)的化合物，其中R¹X＝R¹OCR⁶R⁷-，可以如下制备：任选在合适碱例如三乙胺和溶剂例如四氢呋喃或N，N-二甲基甲酰胺的存在下，式(I)的化合物(其中R¹X＝HOCR⁶R⁷-)与式(II)的化合物(其中L¹是离去基团(例如卤素、甲苯磺酰、甲磺酰基等等))进行反应。Compounds of formula (I), wherein R ¹ X = R ¹ OCR ⁶ R ⁷ -, can be prepared optionally in the presence of a suitable base such as triethylamine and a solvent such as tetrahydrofuran or N,N-dimethylformamide , a compound of formula (I) (wherein R ¹ X = HOCR ⁶ R ⁷ -) and a compound of formula (II) (wherein L ¹ is a leaving group (such as halogen, tosyl, methylsulfonyl, etc.)) react.

式(I)的化合物，其中R¹X＝R¹R⁴NCR⁶R⁷-，可以如下制备：任选在合适碱例如三乙胺和溶剂例如四氢呋喃或N，N-二甲基甲酰胺的存在下，式(I)的化合物(其中R¹X＝HR⁴NCR⁶R⁷-)与式(II)的化合物(其中L¹是离去基团(例如卤素、甲苯磺酰、甲磺酰基等等))进行反应；或，在合适还原剂例如NaCNBH₃的存在下，式(I)的化合物(其中R¹X＝HR⁴NCR⁶R⁷-)与式(III)的化合物进行反应。Compounds of formula (I), wherein R ¹ X = R ¹ R ⁴ NCR ⁶ R ⁷ -, can be prepared as follows: optionally in the presence of a suitable base such as triethylamine and a solvent such as tetrahydrofuran or N,N-dimethylformamide In the presence, a compound of formula (I) (wherein R ¹ X=HR ⁴ NCR ⁶ R ⁷ -) and a compound of formula (II) (wherein L ¹ is a leaving group (such as halogen, toluenesulfonyl, mesyl etc.)); or, a compound of formula (I) wherein R ¹ X =HR ⁴ NCR ⁶ R ⁷ -) is reacted with a compound of formula (III) in the presence of a suitable reducing agent such as NaCNBH ₃ .

式(I)的化合物，其中X¹-S(O)₂CR⁶R⁷-、-SCR⁶R⁷-、-OCR⁶R⁷-、-R⁴NCR⁶R⁷-、-S(O)CR⁶R⁷-，可以如下制备：任选在合适碱例如三乙胺和溶剂例如四氢呋喃或N，N-二甲基甲酰胺的存在下，式(IV)的化合物(其中L¹是离去基团(例如卤素、甲苯磺酰、甲磺酰基等等))与式(V)的化合物进行反应。Compounds of formula (I), wherein X ¹ -S(O) ₂ CR ⁶ R ⁷ -, -SCR ⁶ R ⁷ -, -OCR ⁶ R ⁷ -, -R ⁴ NCR ⁶ R ⁷ -, -S(O) CR ⁶ R ⁷ -, can be prepared as follows: optionally in the presence of a suitable base such as triethylamine and a solvent such as tetrahydrofuran or N,N-dimethylformamide, a compound of formula (IV) (wherein ^L A group (eg halo, tosyl, mesyl, etc.)) is reacted with a compound of formula (V).

式(I)的化合物，其中X¹＝-SCR⁶R⁷-，可以如下制备：在合适溶剂例如乙醇中，式(IV)的化合物(其中L¹是离去基团(例如卤素、甲苯磺酰、甲磺酰基等等))与硫脲进行反应，产生式(VI)的化合物，然后，在合适碱例如氢氧化钠和溶剂例如N，N-二甲基甲酰胺的存在下，使式(VI)的化合物与式(II)的化合物进行反应。Compounds of formula (I), wherein X ¹ =-SCR ⁶ R ⁷ -, can be prepared as follows: In a suitable solvent such as ethanol, a compound of formula (IV) (wherein L ¹ is a leaving group (eg halogen, tosyl Acyl, methanesulfonyl, etc.)) react with thiourea to produce a compound of formula (VI), which is then reacted with the formula (VI) in the presence of a suitable base such as sodium hydroxide and a solvent such as N,N-dimethylformamide A compound of (VI) is reacted with a compound of formula (II).

式(I)的化合物，其中X＝-R⁴NC(O)-，可以如下制备：式(VII)的化合物与式R¹R⁴NH的胺进行反应，该反应之前用文献中已知的方法，例如使用偶合剂例如HATU，或转化为酰基氯，将羧酸适当活化。Compounds of formula (I), wherein X=-R ⁴ NC(O)-, can be prepared by reacting compounds of formula (VII) with amines of formula R ¹ R ⁴ NH using methods known in the literature The carboxylic acid is suitably activated, eg, using a coupling reagent such as HATU, or conversion to an acid chloride.

式(I)的化合物，其中X＝-S(O)₂CR⁶R⁷-，可以如下制备：在合适碱例如氢化钠或叔丁醇钾的存在下，在合适溶剂例如四氢呋喃或N，N-二甲基甲酰胺中，式(I)的化合物(其中X＝-S(O)₂CH₂-)连续地与式(VIII)的化合物进行反应，而后与式(IX)的化合物(其中L¹是离去基团(例如卤素、甲苯磺酰、甲磺酰基等等))反应。Compounds of formula (I), wherein X = -S(O) ₂ CR ⁶ R ⁷ -, can be prepared in the presence of a suitable base such as sodium hydride or potassium tert-butoxide in a suitable solvent such as tetrahydrofuran or N,N - In dimethylformamide, the compound of formula (I) (wherein X=-S(O) ₂ CH ₂ -) is continuously reacted with the compound of formula (VIII), and then reacted with the compound of formula (IX) (wherein L ¹ is a leaving group (eg, halogen, tosyl, methylsulfonyl, etc.)) reaction.

式(I)的化合物，其中R¹X＝HOCR⁶R⁷-，可以如下制备：在合适溶剂中，式(X)的化合物与式(XI)和式(XII)的合适有机金属化合物例如格氏试剂进行反应。如果R⁶和R⁷是不同的，那么在随后的步骤中，可以使用文献中已知的技术，例如式(X)的化合物转化为Weinreb酰胺，并且与式(XI)的有机金属试剂反应，而后与式(XII)的有机金属试剂反应。Compounds of formula (I), wherein R ¹ X = HOCR ⁶ R ⁷ -, can be prepared by combining, in a suitable solvent, a compound of formula (X) with a suitable organometallic compound of formula (XI) and (XII), e.g. Reagent reacts. If R ^and ^R are different, then in a subsequent step, techniques known in the literature can be used, such as conversion of the compound of formula (X) into a Weinreb amide and reaction with an organometallic reagent of formula (XI), This is followed by reaction with an organometallic reagent of formula (XII).

式(I)的化合物可以如下制备：在合适金属催化剂(例如钯或铜)的存在下，在合适溶剂例如1，4-二噁烷中，用式(XIII)的化合物(其中L²是离去基团(例如卤素、甲苯磺酰、甲磺酰基、-SMe、-S(O)₂Me等等))与合适有机金属试剂(例如硼酸R²B(OH)₂或硼酸酯R²B(OR)₂等等)来制备。或者，如果R²通过氮、氧或硫原子与嘧啶环连接，式(I)化合物可以如下制备：在合适碱例如碳酸钾的存在下，在合适溶剂例如N，N-二甲基甲酰胺中，由式(XIII)的化合物(其中L²是离去基团(例如卤素、甲苯磺酰、甲磺酰基、-SMe、-S(O)₂Me等等))，通过与所需胺、醇或硫醇进行反应。Compounds of formula (I) can be prepared by using a compound of formula (XIII) (wherein ^L is the ^Degrouping ₍ such as halogen, tosyl ^, methanesulfonyl, -SMe, -S(O) ₂ Me, etc.) B(OR) ₂ , etc.) to prepare. Alternatively, if ^R2 is attached to the pyrimidine ring via a nitrogen, oxygen or sulfur atom, compounds of formula (I) can be prepared in a suitable solvent such as N,N-dimethylformamide in the presence of a suitable base such as potassium carbonate , from a compound of formula (XIII) (wherein L ² is a leaving group (such as halogen, tosyl, methylsulfonyl, -SMe, -S(O) ₂ Me, etc.)), by reacting with the desired amine, Alcohols or thiols react.

应理解，利用上列或文献中已知的技术例如氧化、烷基化、还原胺化等等，式(XIII)的化合物可以转变成另一个式(XIII)的化合物。It will be appreciated that a compound of formula (XIII) may be transformed into another compound of formula (XIII) using techniques such as oxidation, alkylation, reductive amination and the like listed above or known in the literature.

式(XIII)的化合物，其中X¹＝-S(O)₂CR⁶R⁷-、-SCR⁶R⁷-、-OCR⁶R⁷-、-R⁴NCR⁶R⁷-、-S(O)CR⁶R⁷-，可以如下制备：任选在合适碱例如三乙胺和溶剂例如四氢呋喃或N，N-二甲基甲酰胺的存在下，式(XIV)的化合物(其中L¹是离去基团(例如卤素、甲苯磺酰、甲磺酰基等等))与式(V)的化合物进行反应。Compounds of formula (XIII), wherein X ¹ =-S(O) ₂ CR ⁶ R ⁷ -, -SCR ⁶ R ⁷ -, -OCR ⁶ R ⁷ -, -R ⁴ NCR ⁶ R ⁷ -, -S(O ) CR ⁶ R ⁷ -, can be prepared as follows: optionally in the presence of a suitable base such as triethylamine and a solvent such as tetrahydrofuran or N,N-dimethylformamide, a compound of formula (XIV) (wherein L ¹ is ion Degrouping (eg halo, tosyl, mesyl, etc.)) is reacted with a compound of formula (V).

式(XIII)的化合物，其中X¹＝-SCR⁶R⁷-，可以如下制备：在合适溶剂例如乙醇中，式(XIV)的化合物(其中L¹是离去基团(例如卤素、甲苯磺酰、甲磺酰基等等))与硫脲进行反应，产生式(XV)的化合物，然后，在合适碱例如氢氧化钠和溶剂例如N，N-二甲基甲酰胺的存在下，使式(XV)的化合物与式(II)的化合物进行反应。Compounds of formula (XIII), wherein X ¹ =-SCR ⁶ R ⁷ -, can be prepared as follows: Compounds of formula (XIV), wherein L ¹ is a leaving group (eg halogen, tosyl Acyl, methylsulfonyl, etc.)) with thiourea to produce compounds of formula (XV), which are then reacted in the presence of a suitable base such as sodium hydroxide and a solvent such as N,N-dimethylformamide A compound of (XV) is reacted with a compound of formula (II).

式(XIII)的化合物，其中X-R⁴NC(O)-，可以如下制备：式(XVI)的化合物与式R¹R⁴NH的胺进行反应，该反应之前用文献中已知的方法，例如使用偶合剂例如HATU，或转化为酰基氯，将羧酸适当活化。Compounds of formula (XIII), wherein XR ⁴ NC(O)-, can be prepared by reacting compounds of formula (XVI) with amines of formula R ¹ R ⁴ NH previously by methods known in the literature, for example Carboxylic acids are suitably activated using coupling reagents such as HATU, or conversion to acid chlorides.

式(XIII)的化合物，其中X＝-S(O)₂CR⁶R⁷-，可以如下制备：在合适碱例如氢化钠或叔丁醇钾的存在下，在合适溶剂例如四氢呋喃或N，N-二甲基甲酰胺中，式(XIII)的化合物(其中X＝-S(O)₂CH₂-)连续与式(VIII)的化合物进行反应，而后与式(IX)的化合物(其中L¹是离去基团(例如卤素、甲苯磺酰、甲磺酰基等等))反应。Compounds of formula (XIII), wherein X = -S(O) ₂ CR ⁶ R ⁷ -, can be prepared in the presence of a suitable base such as sodium hydride or potassium tert-butoxide in a suitable solvent such as tetrahydrofuran or N,N - In dimethylformamide, the compound of formula (XIII) (wherein X=-S(O) ₂ CH ₂ -) is continuously reacted with the compound of formula (VIII), and then reacted with the compound of formula (IX) (wherein L ¹ is a leaving group (eg halogen, tosyl, mesyl, etc.) reaction.

式(XIII)的化合物，其中R¹X＝HOCR⁶R⁷-，可以如下制备：在合适溶剂中，式(XVII)的化合物与式(XI)和式(XII)的合适有机金属化合物例如格氏试剂进行反应。如果R⁶和R⁷是不同的，那么在随后的步骤中，可以使用文献中已知的技术，例如式(XVII)的化合物转化为Weinreb酰胺，并且与式(XI)的有机金属试剂反应，而后与式(XII)的有机金属试剂反应。Compounds of formula (XIII), wherein R ¹ X = HOCR ⁶ R ⁷ -, can be prepared by combining a compound of formula (XVII) with a suitable organometallic compound of formula (XI) and (XII) such as G Reagent reacts. If R ^and ^R are different, then in a subsequent step, techniques known in the literature can be used, for example conversion of the compound of formula (XVII) into a Weinreb amide and reaction with an organometallic reagent of formula (XI), This is followed by reaction with an organometallic reagent of formula (XII).

式(IV)的化合物可以如下制备：在合适金属催化剂(例如钯或铜)的存在下，在合适溶剂例如1，4-二噁烷中，用式(XIV)的化合物(其中L²是离去基团(例如卤素、甲苯磺酰、甲磺酰基、-SMe、-S(O)₂Me等等)，L¹是离去基团(例如卤素、甲苯磺酰、甲磺酰基等等))与合适有机金属试剂(例如硼酸R²B(OH)₂或硼酯R²B(OR)₂等等)来制备。或者，如果R²通过氮、氧或硫原子与嘧啶环连接，式(IV)化合物可以如下制备：在合适碱例如碳酸钾的存在下，在合适溶剂例如N，N-二甲基甲酰胺中，由式(XIV)的化合物(其中L²是离去基团(例如卤素、甲苯磺酰、甲磺酰基、-SMe、-S(O)₂Me等等))，通过与所需胺、醇或硫醇进行反应。Compounds of formula (IV) can be prepared by using a compound of formula (XIV) (wherein ^L is the Leaving group (such as halogen, tosyl, mesyl, -SMe, -S(O) ₂ Me, etc.), ^L is a leaving group (such as halogen, tosyl, mesyl, etc.) ) with a suitable organometallic reagent (eg boronic acid R ² B(OH) ₂ or boronic ester R ² B(OR) ₂ etc.). Alternatively, if ^R2 is attached to the pyrimidine ring via a nitrogen, oxygen or sulfur atom, compounds of formula (IV) can be prepared as follows: in a suitable solvent such as N,N-dimethylformamide in the presence of a suitable base such as potassium carbonate , from a compound of formula (XIV) (wherein L ² is a leaving group (such as halogen, tosyl, methylsulfonyl, -SMe, -S(O) ₂ Me, etc.)), by reacting with the desired amine, Alcohols or thiols react.

式(X)的化合物可以如下制备：在合适金属催化剂(例如钯或铜)的存在下，在合适溶剂例如1，4-二噁烷中，用式(XVII)的化合物(其中L²是离去基团(例如卤素、甲苯磺酰、甲磺酰基、-SMe、-S(O)₂Me等等)，R是氢或C_1-4烷基)与合适有机金属试剂(例如硼酸R²B(OH)₂或硼酯R²B(OR)₂等等)来制备。或者，如果R²通过氮、氧或硫原子与嘧啶环连接，式(X)化合物可以如下制备：在合适碱例如碳酸钾的存在下，在合适溶剂例如N，N-二甲基甲酰胺中，由式(XVII)的化合物(其中L²是离去基团(例如卤素、甲苯磺酰、甲磺酰基、-SMe、-S(O)₂Me等等))，通过与所需胺、醇或硫醇进行反应。Compounds of formula (X) can be prepared by using a compound of formula (XVII) (wherein ^L is the Degrouping (such as halogen, tosyl, methanesulfonyl, -SMe, -S(O) ₂ Me, etc.), R is hydrogen or C _1-4 alkyl) with a suitable organometallic reagent (such as boronic acid R ² B(OH) ₂ or boron ester R ² B(OR) ₂ , etc.) to prepare. Alternatively, if R ^is attached to the pyrimidine ring via a nitrogen, oxygen or sulfur atom, compounds of formula (X) can be prepared by: in the presence of a suitable base such as potassium carbonate in a suitable solvent such as N,N-dimethylformamide , from a compound of formula (XVII) (wherein L ² is a leaving group (such as halogen, tosyl, mesyl, -SMe, -S(O) ₂ Me, etc.)), by reacting with the desired amine, Alcohols or thiols react.

式(XVIII)的化合物可以如下制备：在合适金属催化剂(例如钯或铜)的存在下，在合适溶剂例如1，4-二噁烷中，用式(XIX)的化合物(其中L²是离去基团(例如卤素、甲苯磺酰、甲磺酰基、-SMe、-S(O)₂Me等等))与合适有机金属试剂(例如硼酸R²B(OH)₂或硼酯R²B(OR)₂等等)来制备。或者，如果R²通过氮、氧或硫原子与嘧啶环连接，式(XVIII)化合物可以如下制备：在合适碱例如碳酸钾的存在下，在合适溶剂例如N，N-二甲基甲酰胺中，由式(XIX)的化合物(其中L²是离去基团(例如卤素、甲苯磺酰、甲磺酰基、-SMe、-S(O)₂Me等等))，通过与所需胺、醇或硫醇进行反应。Compounds of formula (XVIII) can be prepared from compounds of formula (XIX) (wherein ^L ^Degrouping (such as halogen, tosyl _, methanesulfonyl, ^-SMe , -S(O) ₂ Me, etc.) (OR) ₂ , etc.) to prepare. Alternatively, if ^R2 is attached to the pyrimidine ring via a nitrogen, oxygen or sulfur atom, compounds of formula (XVIII) can be prepared as follows: in the presence of a suitable base such as potassium carbonate in a suitable solvent such as N,N-dimethylformamide , from a compound of formula (XIX) (wherein L ² is a leaving group (such as halogen, tosyl, mesyl, -SMe, -S(O) ₂ Me, etc.)), by reacting with the desired amine, Alcohols or thiols react.

式(XX)的化合物可以如下制备：在合适金属催化剂(例如钯或铜)的存在下，在合适溶剂例如1，4-二噁烷中，用式(XXI)的化合物(其中L²是离去基团(例如卤素、甲苯磺酰、甲磺酰基、-SMe、-S(O)₂Me等等))与合适有机金属试剂(例如硼酸R²B(OH)₂或硼酯R²B(OR)₂等等)来制备。或者，如果R²通过氮、氧或硫原子与嘧啶环连接，式(XX)化合物可以如下制备：在合适碱例如碳酸钾的存在下，在合适溶剂例如N，N-二甲基甲酰胺中，由式(XXI)的化合物(其中L²是离去基团(例如卤素、甲苯磺酰、甲磺酰基、-SMe、-S(O)₂Me等等))，通过与所需胺、醇或硫醇进行反应。Compounds of formula (XX) can be prepared by using a compound of formula (XXI) (wherein L ² is the ion ^Degrouping ₍ such as halogen, tosyl ^, methanesulfonyl, -SMe, -S(O) ₂ Me, etc.) (OR) ₂ , etc.) to prepare. Alternatively, if ^R2 is attached to the pyrimidine ring via a nitrogen, oxygen or sulfur atom, compounds of formula (XX) can be prepared as follows: in the presence of a suitable base such as potassium carbonate in a suitable solvent such as N,N-dimethylformamide , from a compound of formula (XXI) (wherein L ² is a leaving group (such as halogen, tosyl, methylsulfonyl, -SMe, -S(O) ₂ Me, etc.)), by reacting with the desired amine, Alcohols or thiols react.

式(I)的化合物，其中L¹是离去基团(例如卤素、甲苯磺酰、甲磺酰基等等)，可以如下制备：任选在合适碱例如三乙胺的存在下，在合适溶剂例如N，N-二甲基甲酰胺中，式(XXII)的化合物与式(XXIII)的化合物进行反应。Compounds of formula (I), wherein ^L is a leaving group (e.g. halogen, tosyl, mesyl, etc.), can be prepared as follows: optionally in the presence of a suitable base such as triethylamine, in a suitable solvent For example, in N,N-dimethylformamide, the compound of formula (XXII) is reacted with the compound of formula (XXIII).

应理解，利用上列或文献中已知的技术例如氧化、烷基化、还原胺化等等，式(XXII)的化合物可以被变成另一个式(XXII)的化合物。It will be appreciated that a compound of formula (XXII) may be transformed into another compound of formula (XXII) using techniques such as oxidation, alkylation, reductive amination and the like listed above or known in the literature.

式(IV)的化合物，其中L¹是离去基团(例如卤素、甲苯磺酰、甲磺酰基等等)，可以如下制备：任选在合适碱例如三乙胺的存在下，在合适溶剂例如N，N-二甲基甲酰胺中，式(XXIV)的化合物与式(XXIII)的化合物进行反应。Compounds of formula (IV), wherein ^L is a leaving group (e.g. halogen, tosyl, mesyl, etc.), can be prepared as follows: optionally in the presence of a suitable base such as triethylamine, in a suitable solvent For example, in N,N-dimethylformamide, the compound of formula (XXIV) is reacted with the compound of formula (XXIII).

式(X)的化合物，其中L¹是离去基团(例如卤素、甲苯磺酰、甲磺酰基等等)，和R是氢或C_1-4烷基，可以如下制备：任选在合适碱例如三乙胺的存在下，在合适溶剂例如N，N-二甲基甲酰胺中，式(XXV)的化合物与式(XXIII)的化合物进行反应。Compounds of formula (X), wherein ^L is a leaving group (e.g. halogen, tosyl, mesyl, etc.), and R is hydrogen or C _1-4 alkyl, can be prepared as follows: optionally in a suitable Compounds of formula (XXV) are reacted with compounds of formula (XXIII) in the presence of a base such as triethylamine in a suitable solvent such as N,N-dimethylformamide.

式(XVIII)的化合物，其中L¹是离去基团(例如卤素、甲苯磺酰、甲磺酰基等等)，可以如下制备：任选在合适碱例如三乙胺的存在下，在合适溶剂例如N，N-二甲基甲酰胺中，式(XXVI)的化合物与式(XXIII)的化合物进行反应。Compounds of formula (XVIII), wherein ^L is a leaving group (e.g. halogen, tosyl, mesyl, etc.), can be prepared as follows: optionally in the presence of a suitable base such as triethylamine, in a suitable solvent For example, in N,N-dimethylformamide, the compound of formula (XXVI) is reacted with the compound of formula (XXIII).

式(XX)的化合物，其中L¹是离去基团(例如卤素、甲苯磺酰、甲磺酰基等等)，和L²是离去基团(例如卤素、甲苯磺酰、甲磺酰基、-SMe、-S(O)₂Me等等)，可以如下制备：任选在合适碱例如三乙胺的存在下，在合适溶剂例如N，N-二甲基甲酰胺中，式(XXVII)的化合物与式(XXIII)的化合物进行反应。A compound of formula (XX), wherein L is a leaving group (such as halogen, tosyl, mesyl, etc.), and ^L is a leaving group (such as halogen, tosyl, mesyl ^, -SMe, -S(O) ₂ Me, etc.), can be prepared as follows: Formula (XXVII) in a suitable solvent such as N,N-dimethylformamide, optionally in the presence of a suitable base such as triethylamine The compound of is reacted with the compound of formula (XXIII).

式(XIII)的化合物，其中L¹是离去基团(例如卤素、甲苯磺酰、甲磺酰基等等)，和L²是离去基团(例如卤素、甲苯磺酰、甲磺酰基、-SMe、-S(O)₂Me等等)，可以如下制备：任选在合适碱例如三乙胺的存在下，在合适溶剂例如N，N-二甲基甲酰胺中，式(XXVIII)的化合物与式(XXIII)的化合物进行反应。A compound of formula (XIII), wherein ^L is a leaving group (such as halogen, tosyl, mesyl, etc.), and ^L is a leaving group (such as halogen, tosyl, mesyl, -SMe, -S(O) ₂ Me, etc.), can be prepared as follows: Formula (XXVIII) in a suitable solvent such as N,N-dimethylformamide, optionally in the presence of a suitable base such as triethylamine The compound of is reacted with the compound of formula (XXIII).

式(XIV)的化合物，其中L¹是离去基团(例如卤素、甲苯磺酰、甲磺酰基等等)，和L²是离去基团(例如卤素、甲苯磺酰、甲磺酰基、-SMe、-S(O)₂Me等等)，可以如下制备：任选在合适碱例如三乙胺的存在下，在合适溶剂例如N，N-二甲基甲酰胺中，式(XXIX)的化合物与式(XXIII)的化合物进行反应。A compound of formula (XIV), wherein ^L is a leaving group (such as halogen, tosyl, mesyl, etc.), and ^L is a leaving group (such as halogen, tosyl, mesyl, -SMe, -S(O) ₂ Me, etc.), can be prepared as follows: Formula (XXIX) in a suitable solvent such as N,N-dimethylformamide, optionally in the presence of a suitable base such as triethylamine The compound of is reacted with the compound of formula (XXIII).

式(XVII)的化合物，其中L¹是离去基团(例如卤素、甲苯磺酰、甲磺酰基等等)，和L²是离去基团(例如卤素、甲苯磺酰、甲磺酰基、-SMe、-S(O)₂Me等等)，和R是氢或C_1-4烷基，可以如下制备：任选在合适碱例如三乙胺的存在下，在合适溶剂例如N，N-二甲基甲酰胺中，式(XXX)的化合物与式(XXIII)的化合物进行反应。A compound of formula (XVII), wherein ^L is a leaving group (such as halogen, tosyl, mesyl, etc.), and ^L is a leaving group (such as halogen, tosyl, mesyl, -SMe, -S(O) ₂ Me, etc.), and R is hydrogen or C _1-4 alkyl, can be prepared as follows: optionally in the presence of a suitable base such as triethylamine in a suitable solvent such as N,N - Reaction of a compound of formula (XXX) with a compound of formula (XXIII) in dimethylformamide.

式(XIX)的化合物，其中L¹是离去基团(例如卤素、甲苯磺酰、甲磺酰基等等)，和L²是离去基团(例如卤素、甲苯磺酰、甲磺酰基、-SMe、-S(O)₂Me等等)，可以如下制备：任选在合适碱例如三乙胺的存在下，在合适溶剂例如N，N-二甲基甲酰胺中，式(XXXI)的化合物与式(XXIII)的化合物进行反应。A compound of formula (XIX), wherein L is a leaving group (such as halogen, tosyl, mesyl, etc.), and ^L is a leaving group (such as halogen, tosyl, mesyl ^, -SMe, -S(O) ₂ Me, etc.), can be prepared as follows: Formula (XXXI) in a suitable solvent such as N,N-dimethylformamide, optionally in the presence of a suitable base such as triethylamine The compound of is reacted with the compound of formula (XXIII).

式(XXI)的化合物，其中L¹是离去基团(例如卤素、甲苯磺酰、甲磺酰基等等)，和L²是离去基团(例如卤素、甲苯磺酰、甲磺酰基、-SMe、-S(O)₂Me等等)，可以如下制备：任选在合适碱例如三乙胺的存在下，在合适溶剂例如N，N-二甲基甲酰胺中，式(XXXII)的化合物与式(XXIII)的化合物进行反应。A compound of formula (XXI), wherein ^L is a leaving group (such as halogen, tosyl, mesyl, etc.), and ^L is a leaving group (such as halogen, tosyl, mesyl, -SMe, -S(O) ₂ Me, etc.), can be prepared as follows: Formula (XXXII) in a suitable solvent such as N,N-dimethylformamide, optionally in the presence of a suitable base such as triethylamine The compound of is reacted with the compound of formula (XXIII).

式(I)的化合物，其中R¹X＝H₂NCH₂-，可以如下制备：在合适溶剂例如乙醇中，用氢气和合适催化剂例如钯/碳将式(XVIII)的化合物还原，例如氢化。Compounds of formula (I), wherein ^R1X = _H2NCH2- , can be prepared by reduction, eg hydrogenation, of compounds _of formula (XVIII) with hydrogen and a suitable catalyst, eg palladium on carbon, in a suitable solvent eg ethanol.

式(I)的化合物，其中R¹X＝H₂NC(O)-，可以如下制备：在合适溶剂例如水-乙醇混合物中，用例如氢氧化钠将式(XVIII)的化合物水解。Compounds of formula (I), wherein ^R1X = _H2NC (O)-, can be prepared by hydrolysis of compounds of formula (XVIII) with, for example, sodium hydroxide in a suitable solvent, such as a water-ethanol mixture.

式(I)的化合物，其中R¹X＝H₂NCR⁶R⁷-，可以如下制备：由式(XVIII)的化合物与有机金属化合物(XI)和(XII)进行反应。Compounds of formula (I), wherein R ¹ X = H ₂ NCR ⁶ R ⁷ —, can be prepared by reacting compounds of formula (XVIII) with organometallic compounds (XI) and (XII).

式(XIII)的化合物，其中R¹X＝H₂NCH₂-，可以如下制备：在合适溶剂例如乙醇中，用氢气和合适催化剂例如钯/碳将式(XIX)的化合物还原，例如氢化。Compounds of formula (XIII), wherein ^R1X = _H2NCH2- , can be prepared by reduction, eg hydrogenation, of compounds _of formula (XIX) with hydrogen and a suitable catalyst, eg palladium on carbon, in a suitable solvent eg ethanol.

式(XIII)的化合物，其中R¹X＝H₂NC(O)-，可以如下制备：在合适溶剂例如水-乙醇混合物中，用例如氢氧化钠将式(XIX)的化合物水解。Compounds of formula (XIII), wherein ^R1X = _H2NC (O)-, can be prepared by hydrolysis of compounds of formula (XIX) with, for example, sodium hydroxide in a suitable solvent, such as a water-ethanol mixture.

式(XIII)的化合物，其中R¹X＝H₂NCR⁶R⁷-，可以如下制备：式(XIX)的化合物与有机金属化合物(XI)和(XII)进行反应。Compounds of formula (XIII), wherein R ¹ X = H ₂ NCR ⁶ R ⁷ —, can be prepared by reacting compounds of formula (XIX) with organometallic compounds (XI) and (XII).

应理解，R²基团可以最初以碳环或杂环胺的形式(任选用氮保护，这种保护基包括但不局限于硝基、叔丁氧基氨基甲酸酯等等)在任何阶段引入，在合适碱的存在下，通过与磺酰氯(或其它合适的活化物种)反应，或利用文献中已知的其它形成磺酰胺的方法，其可以在合成的后续阶段(合适的脱保护之后)转化为磺酰胺。It is to be understood that the ^R group can be initially in the form of a carbocyclic or heterocyclic amine (optionally protected with nitrogen, such protecting groups include but are not limited to nitro, tert-butoxycarbamate, etc.) in any stage introduction, by reaction with sulfonyl chloride (or other suitable activating species) in the presence of a suitable base, or using other methods known in the literature to form sulfonamides, which can be introduced at subsequent stages of the synthesis (suitable deprotection after) into the sulfonamide.

应理解，在本发明化合物中的某些各种环取代基，可以通过标准芳族取代反应引入、或通过常规官能团修饰产生，在上述过程之前或之后立即，这包括在本发明的方法方面中。例如，利用标准芳族取代反应或通过常规官能团修饰，式(I)的化合物可以转变为其它的式(I)化合物。这种反应和修饰包括：例如，借助于芳族取代反应、取代基的还原、取代基的烷基化和取代基的氧化来引入取代基。这种方法的试剂和反应条件在化学领域是众所周知的。芳族取代反应的具体例子包括：使用浓硝酸引入硝基，在Friedel工艺条件下，使用例如酰基卤和路易斯酸(例如三氯化铝)引入酰基；在Friedel工艺条件下，使用卤代烷和路易斯酸(例如三氯化铝)引入烷基；和引入卤素基团。修饰的具体例子包括：通过例如催化氢化(用镍催化剂)或用铁处理(在盐酸的存在下，加热)，将硝基还原为氨基；烷硫基氧化为烷基亚磺酰基或烷基磺酰基。It is to be understood that certain of the various ring substituents in the compounds of the present invention may be introduced by standard aromatic substitution reactions, or produced by conventional functional group modifications, either before or immediately after the above procedures, and are encompassed within the method aspects of the present invention . For example, compounds of formula (I) can be transformed into other compounds of formula (I) using standard aromatic substitution reactions or by conventional functional group modification. Such reactions and modifications include, for example, introduction of substituents by means of aromatic substitution reactions, reduction of substituents, alkylation of substituents, and oxidation of substituents. The reagents and reaction conditions for this method are well known in the chemical arts. Specific examples of aromatic substitution reactions include the introduction of nitro groups using concentrated nitric acid, the introduction of acyl groups using, for example, acyl halides and Lewis acids (e.g., aluminum trichloride) under Friedel process conditions, and the use of alkyl halides and Lewis acids under Friedel process conditions. (such as aluminum trichloride) introducing an alkyl group; and introducing a halogen group. Specific examples of modifications include: reduction of nitro groups to amino groups by, for example, catalytic hydrogenation (with nickel catalyst) or treatment with iron (in the presence of hydrochloric acid, with heating); oxidation of alkylthio groups to alkylsulfinyl or alkylsulfonyl groups Acyl.

还应理解，在本文提及的一些反应中，可能需要/希望保护化合物中的任何敏感基团。需要或希望保护的情况和保护的合适方法，对于本领域技术人员来说是已知的。可以按照标准实践使用常规保护基(为了举例说明，参见T.W.Green，Protective Groups in Organic Synthesis，John Wiley and Sons，1991)。由此，如果反应物包括基团例如氨基、羧基或羟基，可能需要在本文提及的一些反应中保护该基团。It is also understood that in some of the reactions mentioned herein it may be necessary/desirable to protect any sensitive groups in the compounds. The circumstances in which protection is needed or desired, and suitable methods of protection, are known to those skilled in the art. Conventional protecting groups can be used in accordance with standard practice (see, for an illustration, T.W. Green, Protective Groups in Organic Synthesis, John Wiley and Sons, 1991). Thus, if reactants include groups such as amino, carboxy, or hydroxy, it may be desirable to protect that group in some of the reactions mentioned herein.

氨基或烷基氨基的合适保护基是例如酰基，例如烷酰基例如乙酰基，烷氧羰基，例如甲氧羰基、乙氧羰基或叔丁氧羰基，芳基甲氧羰基，例如苄氧羰基，或芳酰基，例如苯甲酰基。上述保护基的脱保护条件必须随保护基的选择而变化。由此，例如，酰基例如烷酰基或烷氧羰基或芳酰基，可以例如通过用合适碱例如碱金属氢氧化物例如氢氧化锂或氢氧化钠水解来除去。或者，酰基例如叔丁氧羰基，可以例如通过用合适酸(例如盐酸、硫酸或磷酸或三氟乙酸)处理来除去，对于芳基甲氧羰基例如苄氧羰基，可以例如通过用催化剂例如碳载钯氢化或通过用路易斯酸例如三(三氟乙酸)硼处理来除去。对于伯氨基的合适的可能的保护基是例如邻苯二甲酰基，其可以通过用烷基胺例如二甲基氨基丙胺或用肼处理来除去。Suitable protecting groups for amino or alkylamino groups are for example acyl, for example alkanoyl, for example acetyl, alkoxycarbonyl, for example methoxycarbonyl, ethoxycarbonyl or tert-butoxycarbonyl, arylmethoxycarbonyl, for example benzyloxycarbonyl, or Aroyl groups such as benzoyl. The deprotection conditions for the above protecting groups must vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively, an acyl group such as tert-butoxycarbonyl can be removed, for example, by treatment with a suitable acid such as hydrochloric acid, sulfuric acid or phosphoric acid or trifluoroacetic acid, and an arylmethoxycarbonyl group such as benzyloxycarbonyl can be removed, for example, by treatment with a catalyst such as carbon-supported Palladium is hydrogenated or removed by treatment with a Lewis acid such as boron tris(trifluoroacetate). Suitable possible protecting groups for primary amino groups are, for example, phthaloyl groups, which can be removed by treatment with alkylamines such as dimethylaminopropylamine or with hydrazine.

羟基的合适保护基是例如酰基，例如烷酰基例如乙酰基，芳酰基例如苯甲酰基，或芳甲基例如苄基。上述保护基的脱保护条件必须随保护基的选择而变化。由此，例如，酰基例如烷酰基或芳酰基，可以例如通过用合适碱例如碱金属氢氧化物例如氢氧化锂或氢氧化钠水解来除去。或者，对于芳甲基例如苄基，可以例如通过用催化剂例如碳载钯氢化来除去。Suitable protecting groups for hydroxy are, for example, acyl groups such as alkanoyl groups such as acetyl, aroyl groups such as benzoyl, or arylmethyl groups such as benzyl. The deprotection conditions for the above protecting groups must vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively, arylmethyl groups such as benzyl groups may be removed, for example, by hydrogenation with a catalyst such as palladium on carbon.

羧基的合适保护基是例如酯化基团，例如甲基或乙基，其可以例如通过用碱例如氢氧化钠水解来除去，或例如叔丁基，其可以例如通过用酸例如有机酸例如三氟乙酸处理来除去，或例如苄基，其可以例如通过用催化剂例如碳载钯氢化来除去。Suitable protecting groups for carboxyl groups are, for example, esterification groups, such as methyl or ethyl, which can be removed, for example, by hydrolysis with a base, such as sodium hydroxide, or, for example, tert-butyl groups, which can be removed, for example, by using an acid such as an organic acid such as tris Fluoroacetic acid treatment to remove, or, for example, benzyl groups, which can be removed, for example, by hydrogenation with a catalyst such as palladium on carbon.

在使用化学领域熟知的传统方法的合成中，可以在任何方便的步骤除去保护基。Protecting groups may be removed at any convenient step in the synthesis using conventional methods well known in the chemical arts.

本文所定义的许多中间体是新的，并且作为本发明的其它特征提供这些中间体。Many of the intermediates defined herein are novel and are provided as other features of the present invention.

生物学试验biological test

下列试验可用于测定本发明化合物作为mTOR激酶抑制剂、作为PI3激酶抑制剂、作为PI3激酶信号路径活化的体外抑制剂、和作为MDA-MB-468人乳房腺癌细胞增殖的体外抑制剂的效果。The following assays can be used to determine the effect of compounds of the invention as mTOR kinase inhibitors, as PI3 kinase inhibitors, as in vitro inhibitors of PI3 kinase signaling pathway activation, and as in vitro inhibitors of MDA-MB-468 human breast adenocarcinoma cell proliferation .

(a)体外mTOR激酶试验 (a) In vitro mTOR kinase assay

该试验使用AlphaScreen技术(Gray等人，Analytical Biochemistry，2003，313：234-245)，测定试验化合物抑制由重组体mTOR磷酸化的能力。This assay measures the ability of test compounds to inhibit phosphorylation by recombinant mTOR using AlphaScreen technology (Gray et al., Analytical Biochemistry, 2003, 313:234-245).

在HEK293细胞中，将包含mTOR氨基酸残基1362至2549的mTOR的C端缺失(EMBL登记编号L34075)稳定地表达为FLAG标记的融合物，如Vilella-Bach等人，在Journal of Biochemistry，1999，274，4266-4272中描述的那样。将HEK293 FLAG标记的mTOR(1362-2549)稳定细胞系在Dulbecco改性Eagle′s生长培养基(DMEM；InvitrogenLimited，Paisley，UK Catalogue No.41966-029)中用5％CO₂在37℃下常规保持，直至达到70-90％融合，生长培养基包含10％热失活的胎儿小牛血清(FCS；Sigma，Poole，Dorset，UK，Catalogue No.F0392)、1％L-谷酰胺(Gibco，Catalogue No.25030-024)和2mg/mlGeneticin(G418硫酸盐；Invitrogen Limited，UK Catalogue No.10131-027)。在温血动物HEK293细胞系中表达之后，使用FLAG表位标记来纯化表达的蛋白(使用标准纯化技术)。In HEK293 cells, a C-terminal deletion of mTOR (EMBL Accession No. L34075) comprising mTOR amino acid residues 1362 to 2549 was stably expressed as a FLAG-tagged fusion as described by Vilella-Bach et al., in Journal of Biochemistry, 1999, 274, 4266-4272 as described. The HEK293 FLAG-tagged mTOR (1362-2549) stable cell line was routinely grown in Dulbecco's modified Eagle's growth medium (DMEM; Invitrogen Limited, Paisley, UK Catalog _No. 41966-029) with 5% CO at 37°C. Maintained until reaching 70-90% confluency, the growth medium contained 10% heat-inactivated fetal calf serum (FCS; Sigma, Poole, Dorset, UK, Catalog No. F0392), 1% L-glutamine (Gibco, Catalog No. 25030-024) and 2 mg/ml Geneticin (G418 sulfate; Invitrogen Limited, UK Catalog No. 10131-027). Following expression in the warm-blooded HEK293 cell line, the expressed protein was purified using the FLAG epitope tag (using standard purification techniques).

在DMSO中，将试验化合物制备为10mM储备溶液，并根据需要稀释到水中，得到一系列最终试验浓度。将等份(2μl)的各个化合物稀释物放入Greiner 384孔低容量(LV)白色聚苯乙烯平皿(Greiner Bio-one)的孔中。将重组体纯化的mTOR酶、1μM生物素化的肽基质(Biotin-Ahx-Lys-Lys-Ala-Asn-Gln-Val-Phe-Leu-Gly-Phe-Thr-Tyr-Val-Ala-Pro-Ser-Val-Leu-Glu-Ser-Val-Lys-Glu-NH₂；Bachem UK Ltd)、ATP(20μM)和缓冲溶液[包含Tris-HCl pH7.4缓冲液(50mM)，EGTA(0.1mM)，牛血清白蛋白(0.5mg/mL)，DTT(1.25mM)和氯化锰(10mM)]的30μl混合物在室温下搅拌90分钟。Test compounds were prepared as 10 mM stock solutions in DMSO and diluted as needed into water to give a range of final test concentrations. Aliquots (2 μl) of each compound dilution were placed into the wells of Greiner 384-well low volume (LV) white polystyrene dishes (Greiner Bio-one). The recombinant purified mTOR enzyme, 1 μM biotinylated peptide matrix (Biotin-Ahx-Lys-Lys-Ala-Asn-Gln-Val-Phe-Leu-Gly-Phe-Thr-Tyr-Val-Ala-Pro- Ser-Val-Leu-Glu-Ser-Val-Lys-Glu-NH ₂ ; Bachem UK Ltd), ATP (20 μM) and buffer solution [containing Tris-HCl pH7.4 buffer (50 mM), EGTA (0.1 mM) , bovine serum albumin (0.5 mg/mL), DTT (1.25 mM) and manganese chloride (10 mM)] was stirred at room temperature for 90 minutes.

使用5％DMSO来代替试验化合物，创建产生最大信号(相当于最大酶活性)的对照孔。通过加入EDTA(83mM)来代替试验化合物，创建产生最小信号(相当于完全抑制的酶)的对照孔。在室温下，将这些试验溶液培养2小时。Control wells producing maximal signal (equivalent to maximal enzyme activity) were created using 5% DMSO instead of test compound. Control wells producing a minimal signal (equivalent to a fully inhibited enzyme) were created by adding EDTA (83 mM) in place of the test compound. These test solutions were incubated for 2 hours at room temperature.

通过加入10μl EDTA(50mM)、牛血清白蛋白(BSA；0.5mg/mL)和Tris-HCl pH7.4缓冲液(50mM)(包含p70 S6激酶(T389)1A5单克隆抗体(Cell Signalling Technology，Catalogue No.9206B)和AlphaScreenStreptavidin供体)的混合物来终止各反应，加入A蛋白受体珠粒(200ng；Perkin Elmer，Catalogue No.分别为6760002B和6760137R)，在室温下，在暗处将试验平皿放置大约20小时。使用Packard Envision仪器，读出得到的信号(在680nm由激光激发产生)。By adding 10 μl EDTA (50mM), bovine serum albumin (BSA; 0.5mg/mL) and Tris-HCl pH7.4 buffer (50mM) (containing p70 S6 kinase (T389) 1A5 monoclonal antibody (Cell Signaling Technology, Catalog No.9206B) and AlphaScreenStreptavidin donor) to terminate each reaction, add protein A acceptor beads (200ng; Perkin Elmer, Catalog No. are 6760002B and 6760137R respectively), at room temperature, place the test plate in the dark About 20 hours. The resulting signal (generated by laser excitation at 680 nm) was read using a Packard Envision instrument.

由于mTOR介导的磷酸化，原位形成了磷酸化的生物素化肽。与AlphaScreen Streptavidin供体珠粒有关的磷酸化的生物素化肽，与p70S6激酶(T389)1A5单克隆抗体(其与Alphascreen蛋白A受体珠粒有关)形成复合物。一旦在680nm用激光激发，供体珠粒：受体珠粒复合物就产生可以测定的信号。相应地，mTOR激酶活性的存在可产生试验信号。在mTOR激酶抑制剂的存在下，信号强度降低。Phosphorylated biotinylated peptides are formed in situ as a result of mTOR-mediated phosphorylation. Phosphorylated biotinylated peptide associated with AlphaScreen Streptavidin Donor Beads, complexed with p70S6 Kinase (T389) 1A5 mAb associated with Alphascreen Protein A Acceptor Beads. Upon excitation with a laser at 680 nm, the donor bead:acceptor bead complex produces a signal that can be measured. Accordingly, the presence of mTOR kinase activity can generate an assay signal. In the presence of mTOR kinase inhibitors, the signal intensity is reduced.

对于所给予的试验化合物，mTOR酶抑制可以以IC₅₀值表示。Inhibition of mTOR enzyme can be expressed as an _IC50 value for the administered test compound.

(b)体外PI3K酶试验 (b) In vitro PI3K enzyme assay

该试验使用AlphaScreen技术(Gray等人，Analytical Biochemistry，2003，313：234-245)，以测定试验化合物抑制脂质PI(4，5)P2的重组型I PI3K酶磷酸化的能力。The assay uses AlphaScreen technology (Gray et al., Analytical Biochemistry, 2003, 313:234-245) to determine the ability of test compounds to inhibit the phosphorylation of the recombinant I PI3K enzyme of the lipid PI(4,5)P2.

使用标准分子生物学和PCR克隆技术，从cDNA库分离编码人PI3K催化和调节亚单位的DNA片段。将所选择的DNA片段用于产生杆状病毒表达载体。尤其是，将每个p110α、p110β和p110δ型Ia人类PI3K p110异构型(对于p110α、p110β和p110δ的EMBLAccession Nos.分别为HSU79143、S67334、Y10055)的全长DNA亚克隆到pDEST10载体(Invitrogen Limited，Fountain Drive，Paisley，UK)中。载体是包含6-His表位标记的Fastbac1的入口适应型式。将Ib类人类PI3K p110γ异构型的截取形式(相当于氨基酸残基144-1102(EMBL Accession No.X8336A))和全长人类p85α调节亚单位(EMBL Accession No.HSP13KIN)也亚克隆到包含6-His表位标记的pFastBac1载体中。用p85α调节亚单位共同表达类型Ia p110结构。使用标准杆状病毒表达技术在杆状病毒系统中表达之后，使用标准纯化技术，使用His表位标记，将表达的蛋白纯化。DNA fragments encoding the catalytic and regulatory subunits of human PI3K were isolated from cDNA libraries using standard molecular biology and PCR cloning techniques. The selected DNA fragments were used to generate baculovirus expression vectors. In particular, the full-length DNA of each p110α, p110β and p110δ type Ia human PI3K p110 isoform (EMBL Accession Nos. HSU79143, S67334, Y10055 for p110α, p110β and p110δ, respectively) was subcloned into the pDEST10 vector (Invitrogen Limited , Fountain Drive, Paisley, UK). The vector is an entry-adapted version of Fastbac1 containing a 6-His epitope tag. A truncated form of the class Ib human PI3K p110γ isoform (equivalent to amino acid residues 144-1102 (EMBL Accession No. X8336A)) and the full-length human p85α regulatory subunit (EMBL Accession No. HSP13KIN) were also subcloned into a DNA containing 6 -His epitope tagged pFastBac1 vector. Coexpression of the type Ia p110 construct with the p85α regulatory subunit. Following expression in the baculovirus system using standard baculovirus expression techniques, the expressed protein was purified using a His epitope tag using standard purification techniques.

使用标准分子生物学和PCR克隆技术，从cDNA库分离DNA(其相当于人类磷酸肌醇(Grp1)PH区域的一般受体的氨基酸263至380)。将得到的DNA片段亚克隆到pGEX 4T1大肠杆菌表达载体(包含GST表位标记(Amersham Pharmacia Biotech，Rainham，Essex，UK))中，如Gray等人，在Analytical Biochemistry，2003，313：234-245中所描述。表达GST标记的Grp1 PH区域，并使用标准技术纯化。Using standard molecular biology and PCR cloning techniques, DNA (which corresponds to amino acids 263 to 380 of the general receptor of the human phosphoinositide (Grp1 ) PH region) was isolated from a cDNA library. The resulting DNA fragment was subcloned into the pGEX 4T1 E. coli expression vector (containing the GST epitope tag (Amersham Pharmacia Biotech, Rainham, Essex, UK)) as described by Gray et al., in Analytical Biochemistry, 2003, 313:234-245 described in. The GST-tagged Grp1 PH region was expressed and purified using standard techniques.

在DMSO中，将试验化合物制备为10mM储备溶液，并根据需要稀释到水中，得到一系列最终试验浓度。将等份(2μl)的每个化合物稀释物放入Greiner 384孔低容量(LV)白色聚苯乙烯平皿(Greiner Bio-one，Brunel Way，Stonehouse，Gloucestershire，UK Catalogue No.784075)的孔中。将每个所选择的重组体纯化的PI3K酶(15ng)、DiC8-PI(4，5)P2基质(40μM；Cell Signals Inc.，Kinnear Road，Columbus，USA，CatalogueNo.901)、三磷腺苷(ATP；4μM)和缓冲溶液[包含Tris-HCl pH7.6缓冲液(40mM，10μl)，3-[(3-胆酰胺丙基)二甲氨基]-1-丙磺酸内盐(CHAPS；0.04％)，二硫苏糖醇(DTT；2mM)和氯化镁(10mM)]的混合物在室温下搅拌20分钟。Test compounds were prepared as 10 mM stock solutions in DMSO and diluted as needed into water to give a range of final test concentrations. Aliquots (2 μl) of each compound dilution were placed into wells of Greiner 384-well low volume (LV) white polystyrene dishes (Greiner Bio-one, Brunel Way, Stonehouse, Gloucestershire, UK Catalog No. 784075). Each selected recombinant purified PI3K enzyme (15ng), DiC8-PI(4,5)P2 matrix (40μM; Cell Signals Inc., Kinnear Road, Columbus, USA, CatalogNo.901), adenosine triphosphate (ATP; 4 μM) and buffer solution [containing Tris-HCl pH7.6 buffer solution (40 mM, 10 μ l), 3-[(3-cholamidopropyl) dimethylamino]-1-propanesulfonic acid inner salt (CHAPS; 0.04%), a mixture of dithiothreitol (DTT; 2 mM) and magnesium chloride (10 mM)] was stirred at room temperature for 20 minutes.

使用5％DMSO代替试验化合物，创建产生最小信号(相当于最大酶活性)的对照孔。加入渥曼青霉素(6uM；Calbiochem/MerckBioscience，Padge Road，Beeston，Nottingham，UK，Catalogue No.681675)代替试验化合物，创建可产生最大信号(相当于完全抑制的酶)的对照孔。在室温下，也将这些试验溶液搅伴20分钟。Control wells producing minimal signal (equivalent to maximal enzyme activity) were created using 5% DMSO instead of test compound. Control wells giving maximal signal (corresponding to complete inhibition of the enzyme) were created by adding wortmannin (6 uM; Calbiochem/Merck Bioscience, Padge Road, Beeston, Nottingham, UK, Catalog No. 681675) in place of the test compound. These test solutions were also stirred for 20 minutes at room temperature.

通过加入10μl EDTA(100mM)、牛血清白蛋白(BSA，0.045％)和Tris-HCl pH7.6缓冲液(40mM)的混合物来终止每个反应。Each reaction was stopped by adding 10 μl of a mixture of EDTA (100 mM), bovine serum albumin (BSA, 0.045%) and Tris-HCl pH 7.6 buffer (40 mM).

加入生物素化的-DiC8-PI(3，4，5)P3(50nM；Cell Signals Inc.，Catalogue No.107)、重组体纯化的GST-Grp1 PH蛋白(2.5nM)和AlphaScreen抗GST供体和受体珠粒(100ng；Packard BioscienceLimited，Station Road，Pangbourne，Berkshire，UK，Catalogue No.6760603M)，在室温下，在暗处将试验平皿放置大约5至20小时。使用Packard AlphaQuest仪器，读出得到的信号(在680nm由激光激发引起)。Add biotinylated-DiC8-PI(3,4,5)P3 (50nM; Cell Signals Inc., Catalog No.107), recombinant purified GST-Grp1 PH protein (2.5nM) and AlphaScreen anti-GST donor and acceptor beads (100ng; Packard Bioscience Limited, Station Road, Pangbourne, Berkshire, UK, Catalog No. 6760603M), at room temperature, place the test plate in the dark for about 5 to 20 hours. The resulting signal (induced by laser excitation at 680 nm) was read using a Packard AlphaQuest instrument.

由于PI(4，5)P2的PI3K介导的磷酸化，原位形成PI(3，4，5)P3。GST-Grp1 PH区域蛋白(其与AlphaScreen抗GST供体珠粒相关)与生物素化的PI(3，4，5)P3(其与Alphascreen Streptavidn受体珠粒相关)形成复合物。酶催产生的PI(3，4，5)P3与生物素化的PI(3，4，5)P3竞争与PH区域蛋白结合。一旦在680nm用激光激发，供体珠粒：受体珠粒复合物产生可以测定的信号。相应地，PI3K酶活性形成PI(3，4，5)P3和随后与生物素化的PI(3，4，5)P3竞争，导致信号降低。在PI3K酶抑制剂的存在下，信号强度得以恢复。PI(3,4,5)P3 is formed in situ due to PI3K-mediated phosphorylation of PI(4,5)P2. GST-Grp1 PH domain protein (associated with AlphaScreen anti-GST donor beads) forms a complex with biotinylated PI(3,4,5)P3 (associated with Alphascreen Streptavidn acceptor beads). Enzymatically produced PI(3,4,5)P3 competes with biotinylated PI(3,4,5)P3 for binding to PH domain proteins. Upon excitation with a laser at 680 nm, the donor bead:acceptor bead complex produces a signal that can be measured. Accordingly, PI3K enzymatic activity forms PI(3,4,5)P3 and subsequently competes with biotinylated PI(3,4,5)P3, resulting in decreased signal. In the presence of PI3K enzyme inhibitors, signal strength was restored.

对于所给予的试验化合物，PI3K酶抑制以IC₅₀值表示。PI3K enzyme inhibition is expressed as _IC50 values for the administered test compounds.

(c)体外磷酸基-Ser473 Akt试验 (c) In vitro phosphate-Ser473 Akt assay

该试验测定试验化合物抑制丝氨酸473在Akt中抑制磷酸化的能力，使用Acumen Explorer技术(Acumen Bioscience Limited)、平板读数器(可用于快速测定激光扫描所产生图像的特征)进行评价。This assay measures the ability of a test compound to inhibit the phosphorylation of serine 473 in Akt and is evaluated using Acumen Explorer technology (Acumen Bioscience Limited), a plate reader (which can be used to rapidly characterize images generated by laser scanning).

在DMEM(包含10％热失活的FCS和1％L-谷酰胺)中，将MDA-MB-468人类乳房腺癌细胞系(LGC Promochem，Teddington，Middlesex，UK，Catalogue No.HTB-132)用5％CO₂常规保持在37℃，直至达到70-90％的融合。In DMEM (containing 10% heat-inactivated FCS and 1% L-glutamine), the MDA-MB-468 human breast adenocarcinoma cell line (LGC Promochem, Teddington, Middlesex, UK, Catalog No.HTB-132) _Routinely maintain at 37 °C with 5% CO until 70-90% confluency is achieved.

对于该试验，使用‘Accutase’(Innovative Cell Technologies Inc.，San Diego，CA，USA；Catalogue No.AT104)，使用标准组织培养法，将细胞从培养瓶中移出，并再悬浮在介质中，得到每mL 1.7x10⁵个细胞。将等分样品(90μl)播种到黑色Packard 96孔平皿(PerkinElmer，Boston，MA，USA；Catalogue No.6005182)的每个内部60个孔中，得到每孔～15000个细胞的密度。将等份(90μl)培养基介质放在外部孔中，以防止边缘效应。将细胞用5％CO₂在37℃下培养过夜，使它们粘合。For this assay, using 'Accutase' (Innovative Cell Technologies Inc., San Diego, CA, USA; Catalog No. AT104), using standard tissue culture methods, cells were removed from the culture flask and resuspended in medium to give ^1.7x105 cells per mL. Aliquots (90 μl) were seeded into each inner 60 wells of black Packard 96-well plates (PerkinElmer, Boston, MA, USA; Catalog No. 6005182) to give a density of ~15000 cells per well. Aliquots (90 μl) of culture medium were placed in the outer wells to prevent edge effects. Cells were incubated overnight at 37 °C with 5% _CO2 to allow them to adhere.

在第2天，用试验化合物处理细胞，并用5％ CO₂在37℃下培养2小时。在DMSO中，将试验化合物制备为10mM储备溶液，并根据需要用生长培养基连续稀释，得到一系列浓度(其是所需最终试验浓度的10倍)。将等份(10μl)的每个化合物稀释物放在孔中(一式三份)，得到最终需要的浓度。作为最小响应对照，每个平皿包括具有100μMLY294002(Calbiochem，Beeston，UK，Catalogue No.440202)的最后浓度的孔。作为最大响应对照，孔包含1％ DMSO来代替试验化合物。培养之后，通过在室温下用1.6％甲醛水溶液(Sigma，Poole，Dorset，UK，Catalogue No.F1635)处理1小时，将平皿的内含物固定。On day 2, cells were treated with test compounds and incubated with 5% _CO2 at 37°C for 2 hours. Test compounds were prepared as 10 mM stock solutions in DMSO and serially diluted as needed in growth medium to give a series of concentrations (which were 10 times the desired final test concentration). Aliquots (10 [mu]l) of each compound dilution were placed in the wells (in triplicate) to give the final desired concentration. As a minimal response control, each plate included wells with a final concentration of 100 μM LY294002 (Calbiochem, Beeston, UK, Catalog No. 440202). As a control for maximal response, wells contained 1% DMSO instead of test compound. After incubation, the contents of the plates were fixed by treatment with 1.6% aqueous formaldehyde (Sigma, Poole, Dorset, UK, Catalog No. F1635) for 1 hour at room temperature.

使用Tecan 96孔洗碟器(抽吸速度10mm/sec)，进行所有随后的抽吸和洗涤步骤。除去固定液，用磷酸缓冲盐水(PBS；50μl；Gibco，Catalogue No.10010015)洗涤平皿的内含物。在室温下，用等份(50μl)的细胞透化缓冲液(包含PBS和0.5％Tween-20的混合物)将平皿的内含物处理10分钟。除去‘透化’缓冲液，在室温下，在PBS和0.05％Tween-20的混合物中，用包含5％脱脂奶粉[‘Marvel’(注册商标)；Premier Beverages，Stafford，GB]的等份(50μl)封闭缓冲液处理1小时，将非特异性的结合位点封闭。除去‘封闭’缓冲液，并在室温下用兔子抗磷酸基-Akt(Ser473)抗体溶液(每孔50μl；Cell Signalling，Hitchin，Herts，U.K.，Catalogue No 9277)(已经在‘封闭’缓冲液中稀释1∶500)将细胞培养1小时。在PBS和0.05％Tween-20的混合物中洗涤细胞三次。随后，在室温下，用Alexafluor488标记的山羊抗兔IgG(每孔50μl；Molecular Probes Invitrogen Limited，Paisley，UK，Catalogue No.A11008)(已经在‘封闭’缓冲液中稀释至1∶500)将细胞培养l小时。用PBS和0.05％Tween-20的混合物洗涤细胞3次。将等份的PBS(50μl)加入到每个孔中，用黑色平皿密封器来密封平皿，并检测和分析荧光信号。All subsequent aspiration and washing steps were performed using a Tecan 96-well dish washer (suction speed 10 mm/sec). The fixative was removed and the contents of the plate were washed with phosphate buffered saline (PBS; 50 μl; Gibco, Catalog No. 10010015). The contents of the plate were treated with an aliquot (50 [mu]l) of cell permeabilization buffer (comprising a mixture of PBS and 0.5% Tween-20) for 10 minutes at room temperature. The 'permeabilization' buffer was removed and, at room temperature, in a mixture of PBS and 0.05% Tween-20, with an aliquot containing 5% skim milk powder ['Marvel' (registered trademark); Premier Beverages, Stafford, GB] ( 50 μl) of blocking buffer for 1 hour to block non-specific binding sites. Remove the 'blocking' buffer, and at room temperature with rabbit anti-phospho-Akt (Ser473) antibody solution (50 μl per well; Cell Signaling, Hitchin, Herts, U.K., Catalog No 9277) (already in the 'blocking' buffer dilution 1:500) and the cells were incubated for 1 hour. Cells were washed three times in a mixture of PBS and 0.05% Tween-20. Subsequently, cells were incubated with Alexafluor488-labeled goat anti-rabbit IgG (50 μl per well; Molecular Probes Invitrogen Limited, Paisley, UK, Catalog No. A11008) (already diluted to 1:500 in 'blocking' buffer) at room temperature. Cultivate for 1 hour. Cells were washed 3 times with a mixture of PBS and 0.05% Tween-20. Aliquots of PBS (50 μl) were added to each well, the plates were sealed with black plate sealers, and fluorescent signals were detected and analyzed.

将每个化合物获得的荧光剂量反应数据进行分析，并将在Akt中的丝氨酸473的抑制度表示为IC₅₀值。Fluorescent dose-response data obtained for each compound were analyzed, and the degree of inhibition of serine 473 in Akt was expressed as an _IC50 value.

(d)体外MDA-MB-468人类乳房腺癌增殖试验 (d) In vitro MDA-MB-468 human breast adenocarcinoma proliferation assay

该试验测定试验化合物抑制细胞增殖的能力，使用CellomicsArrayscan技术进行评价。按照本文生物学测定(b)中所描述的来常规保持MDA-MB-468人类乳房腺癌细胞系(LGC Promochem，Catalogue No.HTB-132)。This assay measures the ability of test compounds to inhibit cell proliferation and is evaluated using Cellomics Arrayscan technology. The MDA-MB-468 human breast adenocarcinoma cell line (LGC Promochem, Catalog No. HTB-132) was routinely maintained as described in Biological Assay (b) herein.

对于该增殖试验，使用Accutase将细胞从培养瓶中移除，并播种到黑色Packard 96孔平皿的内部60个孔中，密度为每孔8000个细胞，在100μl完全生长培养基中。外部孔包含100μl无菌PBS。将细胞用5％CO₂在37℃下培养过夜，使它们粘合。For this proliferation assay, cells were removed from the culture flasks using Accutase and seeded into the inner 60 wells of a black Packard 96-well dish at a density of 8000 cells per well in 100 μl of complete growth medium. The outer wells contained 100 μl sterile PBS. Cells were incubated overnight at 37 °C with 5% _CO2 to allow them to adhere.

在第2天，用试验化合物处理细胞，并用5％CO₂在37℃下培养48小时。在DMSO中，将试验化合物制备为10mM储备溶液，并根据需要用生长培养基连续稀释，得到一系列试验浓度。将等份(50μl)的每个化合物稀释物放在孔中，用5％CO₂在37℃下培养2天。每个平皿包括无试验化合物的对照孔。On day 2, cells were treated with test compounds and incubated at 37°C with 5% _CO for 48 hours. Test compounds were prepared as 10 mM stock solutions in DMSO and serially diluted as needed in growth medium to give a range of test concentrations. Aliquots (50 μl) of each compound dilution were placed in wells and incubated at 37° C. with 5% CO ₂ for 2 days. Each plate included control wells without test compound.

在第4天，加入BrdU标记的试剂(Sigma，Catalogue No.B9285)(最终稀释1∶1000)，在37℃培养细胞2小时。除去介质，通过在室温下，用100μl乙醇和冰醋酸的混合物(90％乙醇，5％冰醋酸和5％水)处理30分钟，将每个孔中的细胞固定。用PBS(100μl)洗涤每个孔中的细胞两次。将盐酸水溶液(2M，100μl)加入到每个孔中。在室温下20分钟之后，用PBS洗涤细胞两次。将过氧化氢(3％，50μl；Sigma，CatalogueNo.H1009)加入到每个孔中。在室温下10分钟之后，用PBS再次洗涤孔。On day 4, BrdU-labeled reagent (Sigma, Catalog No. B9285) (final dilution 1:1000) was added and the cells were incubated at 37°C for 2 hours. The medium was removed and the cells in each well were fixed by treatment with 100 [mu]l of a mixture of ethanol and glacial acetic acid (90% ethanol, 5% glacial acetic acid and 5% water) for 30 minutes at room temperature. Cells in each well were washed twice with PBS (100 μl). Aqueous hydrochloric acid (2M, 100 μl) was added to each well. After 20 minutes at room temperature, cells were washed twice with PBS. Hydrogen peroxide (3%, 50 μl; Sigma, Catalog No. H1009) was added to each well. After 10 minutes at room temperature, the wells were washed again with PBS.

通过在室温下用小鼠抗BrdU抗体(50μl；Caltag，Burlingame，CA，US；Catalogue No.MD5200)(在包含1％BSA和0.05％Tween-20的PBS中稀释至1∶40)培养1小时来检测BrdU的结合。用PBS洗涤两次来除去未结合的抗体。为了所引入BrdU的可视化，在室温下，用PBS(50μl)和0.05％ Tween-20缓冲液(包含Alexa fluor 488标记的山羊抗小鼠IgG的1∶1000稀释物)将细胞处理1小时。为了细胞核的可视化，加入Hoechst颜料(stain)的1∶1000稀释物(Molecular Probes，CatalogueNo.H3570)。将每个平皿依次用PBS洗涤。随后，将PBS(100μl)加入到每个孔中，使用Cellomics矩阵扫描来分析平皿，从而估计总细胞数目和BrdU阳性细胞的数目。By incubating with mouse anti-BrdU antibody (50 μl; Caltag, Burlingame, CA, US; Catalog No. MD5200) (diluted to 1:40 in PBS containing 1% BSA and 0.05% Tween-20) for 1 hour at room temperature to detect BrdU binding. Unbound antibody was removed by washing twice with PBS. For visualization of introduced BrdU, cells were treated with PBS (50 μl) and 0.05% Tween-20 buffer containing a 1:1000 dilution of Alexa fluor 488-labeled goat anti-mouse IgG for 1 hour at room temperature. For visualization of nuclei, a 1:1000 dilution of Hoechst stain (Molecular Probes, Catalog No. H3570) was added. Each plate was washed sequentially with PBS. Subsequently, PBS (100 μl) was added to each well and the plate was analyzed using Cellomics matrix scanning to estimate the total cell number and the number of BrdU positive cells.

将每个化合物获得的荧光剂量反应数据进行分析，并将MDA-MB-468细胞生长的抑制度以IC₅₀值表示。The fluorescence dose-response data obtained for each compound were analyzed, and the inhibition degree of MDA-MB-468 cell growth was expressed as IC ₅₀ value.

尽管式(I)化合物的药理学性能象期望的那样随结构改变而变化，但人们通常相信式(I)化合物所具有的活性可以在一个或多个上述试验(a)至(d)中、在下列浓度或剂量下得到证明：-Although the pharmacological properties of compounds of formula (I) vary as expected with structural changes, it is generally believed that compounds of formula (I) possess activity that can be demonstrated in one or more of the above tests (a) to (d), Demonstrated at the following concentrations or doses:-

试验(a)：-对于许多化合物，对于mTOR激酶的IC₅₀值小于10μM，尤其是小于5μM，对于实施例4，在三个情况下测定IC₅₀值，值是3.32、2.49和2.25μM；Test (a): - for many compounds, the _IC50 value for mTOR kinase is less than 10 μM, especially less than 5 μM, for example 4, the _IC50 value was determined in three cases, the value is 3.32, 2.49 and 2.25 μM;

试验(b)：-对于p110γIb类人类PI3K的IC₅₀值小于10μM；对于p110α类型Ia人类PI3K的IC₅₀值小于10μM；对于实施例4，在三个情况下测定IC₅₀值，值＞134、54、＞698μM，表明该化合物可能是选择性的mTOR抑制剂；Test (b): - _IC50 values for p110γIb class human PI3Ks are less than 10 μM; _IC50 values for p110α type Ia human PI3Ks are less than 10 μM; for Example 4, _IC50 values were determined in three cases with values >134, 54. >698μM, indicating that the compound may be a selective mTOR inhibitor;

试验(c)：-对于许多化合物，对于Akt中的丝氨酸473的IC₅₀值小于100μM，尤其是小于35μM，对于实施例4，在三个情况下测定IC₅₀值，值是11.29、24.05和＞31.88μM；Test (c): - for many compounds the _IC50 values for serine 473 in Akt are less than 100 μM, especially less than 35 μM, for example 4 _IC50 values were determined in three cases and the values were 11.29, 24.05 and > 31.88 μM;

试验(d)：-IC₅₀值小于20μM；Test (d): -IC ₅₀ value is less than 20 μM;

本发明的化合物是有利的，因为它们具有药理学活性。尤其是，本发明化合物调节(尤其是抑制)mTOR激酶和/或磷脂酰肌醇-3-激酶(PI3K)酶，例如Ia类PI3K酶(例如PI3Kα、PI3Kβ和PI3Kδ)和Ib类PI3K酶(PI3Kγ)。更尤其是，本发明的化合物调节(尤其是抑制)mTOR激酶。更尤其是，本发明的化合物调节(尤其是抑制)一或多种PI3K酶。可以使用本文列出的试验方法和实验部分中的试验方法来证明式(I)化合物的抑制性能。相应地，式(I)化合物可以用于处理(治疗或预防)人和非人的动物中的病症/疾病，该病症/疾病是由mTOR激酶和/或一种或多种PI3K酶介导的，尤其是由mTOR激酶介导的。The compounds of the present invention are advantageous because they possess pharmacological activity. In particular, compounds of the invention modulate (especially inhibit) mTOR kinase and/or phosphatidylinositol-3-kinase (PI3K) enzymes, such as class Ia PI3K enzymes (such as PI3Kα, PI3Kβ and PI3Kδ) and class Ib PI3K enzymes (PI3Kγ ). More particularly, compounds of the invention modulate, especially inhibit, mTOR kinase. More particularly, the compounds of the invention modulate, especially inhibit, one or more PI3K enzymes. The inhibitory properties of compounds of formula (I) can be demonstrated using the test methods outlined herein and in the experimental section. Accordingly, compounds of formula (I) can be used for the treatment (treatment or prevention) of disorders/diseases in humans and non-human animals which are mediated by mTOR kinase and/or one or more PI3K enzymes , especially mediated by the mTOR kinase.

本发明也提供了药物组合物，其包含本文所定义的式(I)化合物或其可药用盐与可药用稀释剂或载体的结合。The present invention also provides pharmaceutical compositions comprising a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable diluent or carrier.

本发明的组合物还可以是适于口服使用的形式(例如片剂、锭剂、硬或软胶囊、含水或油性悬浮液、乳液、可分散性粉剂或颗粒、浆液或酏剂)，局部使用形式(例如乳膏、油膏、凝胶剂或含水或油性溶液或悬浮液)，吸入给药形式(例如细分散的粉末或液体气雾剂)，吹入给药形式(例如细分散的粉末)或肠胃外给药形式(例如静脉内、皮下、腹腔内或肌内注射的无菌水溶液或油性溶液，或用于直肠给药的栓剂)。The compositions of the present invention may also be in a form suitable for oral use (e.g. tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, slurries or elixirs), topical form (e.g. cream, ointment, gel or aqueous or oily solution or suspension), inhalation administration form (e.g. finely divided powder or liquid aerosol), insufflation administration form (e.g. finely divided powder ) or parenteral administration forms (eg sterile aqueous or oily solutions for intravenous, subcutaneous, intraperitoneal or intramuscular injection, or suppositories for rectal administration).

可以利用本领域熟知的常规药学赋形剂、由常规方法获得本发明的组合物。由此，为口服设计的组合物可以包含例如一种或多种着色剂、甜味剂、调味剂和/或防腐剂。The compositions of the present invention can be obtained by conventional methods using conventional pharmaceutical excipients well known in the art. Thus, compositions intended for oral administration may contain, for example, one or more colouring, sweetening, flavoring and/or preservative agents.

可以与一种或多种赋形剂混合以产生单一剂型的活性组分量需要变化，这取决于所治疗的宿主和具体给药模式。例如，为人口服设计的制剂通常包含例如1mg至1g的活性剂(更合适地是1至250mg，例如1至100mg)，活性剂与合适和方便数量的赋形剂混配，赋形剂可以是总组合物重量的大约5至大约98％之间变化。The amount of active ingredient which may be combined with one or more excipients to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. For example, formulations designed for human oral administration typically contain, for example, 1 mg to 1 g (more suitably 1 to 250 mg, such as 1 to 100 mg) of active agent in admixture with suitable and convenient amounts of excipients which may be The weight of the total composition can vary from about 5 to about 98%.

按照疾病状态的性质和严重程度、动物或患者的年龄和性别和给药途径，按照众所周知的医药原则，用于治疗或预防目的的式I化合物的量自然不同。The amount of a compound of formula I to be used for therapeutic or prophylactic purposes will naturally vary according to the nature and severity of the disease state, the age and sex of the animal or patient and the route of administration, according to well-known principles of medicine.

在使用治疗或预防目的的式(I)化合物的过程中，通常给予日剂量，范围是例如接受1mg/kg至100mg/kg体重，如果需要的话，以分开的剂量形式给药。通常，当使用肠胃外途径时，给予低剂量。由此，例如，对于静脉内给药，通常使用的剂量范围是例如1mg/kg至25mg/kg体重。同样，对于吸入给药，使用的剂量范围是例如1mg/kg至25mg/kg体重。典型地，单位剂型包含大约10mg至0.5g本发明的化合物。During the use of the compounds of formula (I) for therapeutic or prophylactic purposes, a daily dose, for example in the range of receiving 1 mg/kg to 100 mg/kg body weight, is usually administered, in divided doses, if desired. Generally, when using the parenteral route, low dosages are administered. Thus, for example, for intravenous administration, dosages in the range of, for example, 1 mg/kg to 25 mg/kg body weight are commonly used. Likewise, for administration by inhalation, the dosage range used is, for example, 1 mg/kg to 25 mg/kg body weight. Typically, unit dosage forms will contain from about 10 mg to 0.5 g of a compound of the invention.

正如本文所陈述的那样，已知mTOR激酶和PI3K酶在致肿瘤性以及许多其它疾病中具有作用。我们已经发现，式(I)的化合物具有有效的抗肿瘤活性，认为这种抗肿瘤活性是通过抑制mTOR激酶和/或一种或多种PI3K酶获得的。As stated herein, the mTOR kinase and PI3K enzymes are known to play a role in tumorigenesis as well as many other diseases. We have found that compounds of formula (I) possess potent antitumor activity which is believed to be obtained by inhibiting mTOR kinase and/or one or more PI3K enzymes.

相应地，本发明的化合物是有价值的抗肿瘤药剂。尤其是，本发明的化合物在抑制和/或治疗实体和/或液态肿瘤疾病中作为抗增殖、凋亡和/或抗侵入药剂是有价值的。尤其是，期望本发明的化合物可有效用于预防或治疗对抑制mTOR和/或一种或多种PI3K酶例如Ia类PI3K酶和Ib类PI3K酶敏感的那些肿瘤。进一步的，期望本发明的化合物可有效用于预防或治疗单独或部分由mTOR和/或一种或多种PI3K酶例如Ia类PI3K酶和Ib类PI3K酶介导的那些肿瘤。由此，该化合物可以在需要这种治疗的温血动物中产生mTOR酶抑制效果。某些化合物可以在需要这种治疗的温血动物中产生PI3K酶抑制效果。Accordingly, the compounds of the present invention are valuable antineoplastic agents. In particular, the compounds of the present invention are valuable as anti-proliferative, apoptotic and/or anti-invasive agents in the inhibition and/or treatment of solid and/or liquid neoplastic diseases. In particular, the compounds of the present invention are expected to be effective in the prevention or treatment of those tumors that are sensitive to inhibition of mTOR and/or one or more PI3K enzymes, such as class Ia PI3K enzymes and class Ib PI3K enzymes. Further, it is expected that the compounds of the present invention are effective for the prevention or treatment of those tumors mediated solely or in part by mTOR and/or one or more PI3K enzymes such as class Ia PI3K enzymes and class Ib PI3K enzymes. Thus, the compounds can produce mTOR enzyme inhibitory effects in warm-blooded animals in need of such treatment. Certain compounds can produce PI3K enzyme inhibitory effects in warm-blooded animals in need of such treatment.

正如本文陈述的那样，mTOR激酶和/或一种或多种PI3K酶的抑制剂具有治疗价值，用于治疗增殖疾病，例如癌症，尤其是实体肿瘤例如癌和肉瘤和血癌和淋巴恶性肿瘤，尤其是用于治疗例如乳癌，结肠直肠癌，肺癌(包括小细胞肺癌，非小细胞肺癌和细支气管肺泡癌症)和前列腺癌，胆管癌，骨骼癌，膀胱癌，脑和颈癌，肾癌，肝癌，胃肠组织癌，食道癌，卵巢癌，胰腺癌，皮肤癌，睾丸癌，甲状腺癌，子宫癌，宫颈和外阴癌，和血癌[包括急性的淋巴血癌(ALL)和慢性骨髓性的血癌(CML)]，多重骨髓癌和淋巴瘤。As stated herein, inhibitors of mTOR kinase and/or one or more PI3K enzymes are of therapeutic value for the treatment of proliferative diseases, such as cancer, especially solid tumors such as carcinomas and sarcomas and hematological and lymphoid malignancies, especially It is used to treat such as breast cancer, colorectal cancer, lung cancer (including small cell lung cancer, non-small cell lung cancer and bronchioloalveolar cancer) and prostate cancer, bile duct cancer, bone cancer, bladder cancer, brain and neck cancer, kidney cancer, liver cancer , gastrointestinal tissue cancer, esophageal cancer, ovarian cancer, pancreatic cancer, skin cancer, testicular cancer, thyroid cancer, uterine cancer, cervical and vulvar cancer, and blood cancer [including acute lymphovascular cancer (ALL) and chronic myeloid blood cancer ( CML)], multiple myeloid carcinomas and lymphomas.

按照本发明的进一步的方面，提供了本文所定义的式(I)化合物或其可药用盐在温血动物例如人中用作药物。According to a further aspect of the present invention there is provided a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, for use as a medicament in a warm-blooded animal such as a human.

按照本发明的进一步的方面，提供了本文所定义的式(I)化合物或其可药用盐在温血动物例如人中用于产生抗增殖效果。According to a further aspect of the present invention there is provided a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, for use in producing an antiproliferative effect in a warm-blooded animal, such as a human.

按照本发明的进一步的方面，提供了本文所定义的式(I)化合物或其可药用盐在温血动物例如人中用于产生凋亡效果。According to a further aspect of the present invention there is provided a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof for use in producing an apoptotic effect in a warm-blooded animal such as a human.

按照本发明的进一步的特征，提供了本文所定义的式(I)化合物或其可药用盐在温血动物例如人中作为抗侵入药剂、用于抑制和/或治疗增殖疾病例如癌症的用途。According to a further feature of the present invention, there is provided the use of a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof as an anti-invasion agent for inhibiting and/or treating proliferative diseases such as cancer in warm-blooded animals such as humans .

按照本发明的进一步的方面，提供了本文所定义的式(I)化合物或其可药用盐在温血动物例如人中用于产生抗增殖效果的用途。According to a further aspect of the present invention there is provided the use of a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, for producing an antiproliferative effect in a warm-blooded animal, such as a human.

按照本发明该方面的进一步的特征，提供了本文所定义的式(I)化合物或其可药用盐在制备药物中的用途，该药物用于在温血动物例如人中产生抗增殖效果。According to a further feature of this aspect of the invention, there is provided the use of a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for producing an antiproliferative effect in a warm-blooded animal such as a human.

按照本发明的进一步的方面，提供了本文所定义的式(I)化合物或其可药用盐在温血动物例如人中用于产生凋亡效果的用途。According to a further aspect of the present invention there is provided the use of a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, for producing an apoptotic effect in a warm-blooded animal such as a human.

按照本发明该方面的进一步的特征，提供了本文所定义的式(I)化合物或其可药用盐在制备药物中的用途，该药物用于在温血动物例如人中产生凋亡效果。According to a further feature of this aspect of the invention, there is provided the use of a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for producing an apoptotic effect in a warm-blooded animal such as a human.

按照本发明的进一步的特征，提供了本文所定义的式(I)化合物或其可药用盐在制备药物中的用途，该药物在温血动物例如人中作为抗侵入药剂，用于抑制和/或治疗增殖疾病例如癌症。According to a further feature of the present invention, there is provided the use of a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof in the preparation of a medicament for inhibiting and /or to treat proliferative diseases such as cancer.

按照本发明该方面的进一步的特征，提供了在需要这种治疗的温血动物例如人中产生抗增殖效果的方法，该方法包括给予所述动物有效量的本文所定义的式(I)化合物或其可药用盐。According to a further feature of this aspect of the invention, there is provided a method of producing an antiproliferative effect in a warm-blooded animal, such as a human, in need of such treatment, the method comprising administering to said animal an effective amount of a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof.

按照本发明该方面的进一步的特征，提供了在需要这种治疗的温血动物例如人中通过抑制和/或治疗实体肿瘤疾病来产生抗侵入效果的方法，该方法包括给予所述动物有效量的本文所定义的式(I)化合物或其可药用盐。According to a further feature of this aspect of the invention, there is provided a method of producing an anti-invasive effect by inhibiting and/or treating solid tumor disease in a warm-blooded animal in need of such treatment, the method comprising administering to said animal an effective amount of A compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof.

按照本发明的进一步的方面，提供了本文所定义的式(I)化合物或其可药用盐在制备药物中的用途，该药物在温血动物例如人中用于预防或治疗增殖疾病例如癌症。According to a further aspect of the present invention there is provided the use of a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the prevention or treatment of proliferative diseases such as cancer in a warm-blooded animal such as a human .

按照本发明该方面的进一步的特征，提供了在需要这种治疗的温血动物例如人中预防或治疗增殖疾病例如癌症的方法，该方法包括给予所述动物有效量的本文所定义的式(I)化合物或其可药用盐。According to a further feature of this aspect of the invention, there is provided a method of preventing or treating a proliferative disease, such as cancer, in a warm-blooded animal, such as a human, in need of such treatment, the method comprising administering to said animal an effective amount of the formula ( I) A compound or a pharmaceutically acceptable salt thereof.

按照本发明的进一步的方面，提供了本文所定义的式(I)化合物或其可药用盐，用于预防或治疗对抑制mTOR激酶和/或一种或多种PI3K酶(例如Ia类酶和/或Ib类PI3K酶)敏感的肿瘤，mTOR激酶和/或一种或多种PI3K酶参与导致肿瘤细胞增殖、存活、侵入和迁移能力的信号转导步骤。According to a further aspect of the present invention there is provided a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, for use in the prevention or treatment of inhibition of mTOR kinase and/or one or more PI3K enzymes (eg class Ia enzymes) and/or class Ib PI3K enzymes) sensitive tumors, mTOR kinase and/or one or more PI3K enzymes are involved in signal transduction steps leading to tumor cell proliferation, survival, invasion and migration ability.

按照本发明该方面的进一步的特征，提供了本文所定义的式(I)化合物或其可药用盐在制备药物中的用途，该药物用于预防或治疗对抑制mTOR激酶和/或一或多种PI3K酶(例如Ia类酶和/或Ib类PI3K酶)敏感的肿瘤，mTOR激酶和/或一种或多种PI3K酶参与导致肿瘤细胞增殖、存活、侵入和迁移能力的信号转导步骤。According to a further feature of this aspect of the present invention, there is provided the use of a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the prevention or treatment of the effect of inhibiting mTOR kinase and/or one or Tumors sensitive to multiple PI3K enzymes (e.g., class Ia enzymes and/or class Ib PI3K enzymes), mTOR kinase and/or one or more PI3K enzymes are involved in signal transduction steps leading to tumor cell proliferation, survival, invasion and migration ability .

按照本发明该方面的进一步的特征，提供了预防或治疗对抑制mTOR激酶和/或一种或多种PI3K酶(例如Ia类酶和/或Ib类PI3K酶)敏感的肿瘤的方法，mTOR激酶和/或一种或多种PI3K酶参与导致肿瘤细胞增殖、存活、侵入和迁移能力的信号转导步骤，该方法包括给予所述动物有效量的本文所定义的式(I)化合物或其可药用盐。According to a further feature of this aspect of the invention there is provided a method of preventing or treating a tumor sensitive to inhibition of mTOR kinase and/or one or more PI3K enzymes (e.g. class Ia enzyme and/or class Ib PI3K enzyme), mTOR kinase And/or one or more PI3K enzymes are involved in signal transduction steps leading to tumor cell proliferation, survival, invasion and migration capabilities, the method includes giving the animal an effective amount of a compound of formula (I) as defined herein or its alternative Medicinal salt.

按照本发明的进一步的方面，提供了本文所定义的式(I)化合物或其可药用盐，用于提供mTOR激酶抑制效果和/或PI3K酶抑制效果(例如Ia类PI3K酶或Ib类PI3K酶抑制效果)。According to a further aspect of the present invention, there is provided a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, for providing an mTOR kinase inhibitory effect and/or a PI3K enzyme inhibitory effect (such as a class Ia PI3K enzyme or a class Ib PI3K enzyme) enzyme inhibitory effect).

按照本发明该方面的进一步的特征，提供了本文所定义的式(I)化合物或其可药用盐在制备药物中的用途，该药物用于提供mTOR激酶抑制效果和/或PI3K酶抑制效果(例如Ia类PI3K酶或Ib类PI3K酶抑制效果)。According to a further feature of this aspect of the present invention, there is provided a use of a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof in the preparation of a medicament for providing mTOR kinase inhibitory effect and/or PI3K enzyme inhibitory effect (eg class Ia PI3K enzyme or class Ib PI3K enzyme inhibitory effect).

按照本发明的进一步的方面，提供了一种方法，用于提供mTOR激酶抑制效果和/或PI3K酶抑制效果(例如Ia类PI3K酶或Ib类PI3K酶抑制效果)，该方法包括给予有效量的本文所定义的式I化合物或其可药用盐。According to a further aspect of the present invention, there is provided a method for providing an mTOR kinase inhibitory effect and/or a PI3K enzyme inhibitory effect (such as a class Ia PI3K enzyme or a class Ib PI3K enzyme inhibitory effect), the method comprising administering an effective amount of A compound of formula I as defined herein, or a pharmaceutically acceptable salt thereof.

按照本发明的进一步的特征，提供了本文所定义的式(I)化合物或其可药用盐在治疗癌症、炎性疾病、梗阻性的呼吸道疾病、免疫疾病或心血管疾病中的用途。According to a further feature of the present invention, there is provided a use of a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof in the treatment of cancer, inflammatory disease, obstructive respiratory disease, immune disease or cardiovascular disease.

按照本发明的进一步的特征，提供了本文所定义的式(I)化合物或其可药用盐在治疗实体肿瘤例如癌和肉瘤和血癌和淋巴恶性肿瘤中的用途。According to a further feature of the present invention there is provided the use of a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, in the treatment of solid tumors such as carcinomas and sarcomas and hematological and lymphoid malignancies.

按照本发明的进一步的特征，提供了本文所定义的式(I)化合物或其可药用盐在治疗乳癌、结肠直肠癌、肺癌(包括小细胞肺癌、非小细胞肺癌和细支气管肺泡癌)和前列腺癌中的用途。According to a further feature of the present invention, there is provided a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof in the treatment of breast cancer, colorectal cancer, lung cancer (comprising small cell lung cancer, non-small cell lung cancer and bronchioloalveolar carcinoma) and use in prostate cancer.

按照本发明的进一步特征，提供了本文所定义的式(I)化合物或其可药用盐，用于治疗胆管癌、骨骼癌、膀胱癌、脑和颈癌、肾癌、肝癌、胃肠组织癌、食道癌、卵巢癌、胰腺癌、皮肤癌、睾丸癌、甲状腺癌、子宫癌、宫颈和外阴癌、和血癌(包括ALL和CML)、多重骨髓癌和淋巴瘤。According to a further feature of the present invention, there is provided a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, for the treatment of cholangiocarcinoma, bone cancer, bladder cancer, brain and neck cancer, kidney cancer, liver cancer, gastrointestinal tissue Cancer of the esophagus, ovary, pancreas, skin, testis, thyroid, uterus, cervix and vulva, and blood cancers (including ALL and CML), multiple myeloma and lymphoma.

按照本发明的进一步的特征，提供了本文所定义的式(I)化合物或其可药用盐在制备药物中的用途，该药物用于治疗癌、炎性疾病、梗阻性的呼吸道疾病、免疫疾病或心血管疾病。According to a further feature of the present invention, there is provided the use of a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of cancer, inflammatory diseases, obstructive respiratory diseases, immune disease or cardiovascular disease.

按照本发明的进一步的特征，提供了本文所定义的式(I)化合物或其可药用盐在制备药物中的用途，该药物用于治疗实体肿瘤例如癌和肉瘤和血癌和淋巴恶性肿瘤。According to a further feature of the present invention, there is provided the use of a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of solid tumors such as carcinomas and sarcomas and hematological and lymphoid malignancies.

按照本发明的进一步的特征，提供了本文所定义的式(I)化合物或其可药用盐在制备药物中的用途，该药物用于治疗乳癌、结肠直肠癌、肺癌(包括小细胞肺癌、非小细胞肺癌和细支气管肺泡癌)和前列腺癌。According to a further feature of the present invention, there is provided the use of a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of breast cancer, colorectal cancer, lung cancer (including small cell lung cancer, non-small cell lung cancer and bronchioloalveolar carcinoma) and prostate cancer.

按照本发明的进一步特征，提供了本文所定义的式(I)化合物或其可药用盐在制备药物中的用途，该药物用于治疗胆管癌、骨骼癌、膀胱癌、脑和颈癌、肾癌、肝癌、胃肠组织癌、食道癌、卵巢癌、胰腺癌、皮肤癌、睾丸癌、甲状腺癌、子宫癌、宫颈和外阴癌、和血癌(包括ALL和CML)、多重骨髓癌和淋巴瘤。According to a further feature of the present invention, there is provided the use of a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of cholangiocarcinoma, bone cancer, bladder cancer, brain and neck cancer, Kidney, liver, gastrointestinal tissue, esophagus, ovary, pancreas, skin, testis, thyroid, uterus, cervix and vulva, and blood cancers (including ALL and CML), multiple myeloid and lymphatic tumor.

按照本发明的进一步的特征，提供了在需要该种治疗的温血动物例如人中治疗癌、炎性疾病、梗阻性的呼吸道疾病、免疫疾病或心血管疾病的方法，该方法包括给予有效量的本文所定义的式(I)化合物或其可药用盐。According to a further feature of the present invention, there is provided a method of treating cancer, inflammatory disease, obstructive respiratory disease, immune disease or cardiovascular disease in a warm-blooded animal in need of such treatment, the method comprising administering an effective amount of A compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof.

按照本发明的进一步的特征，提供了在需要该种治疗的温血动物例如人中治疗实体肿瘤例如癌和肉瘤和血癌和淋巴恶性肿瘤的方法，该方法包括给予有效量的本文所定义的式(I)化合物或其可药用盐。According to a further feature of the present invention there is provided a method of treating solid tumors such as carcinomas and sarcomas and hematologic and lymphoid malignancies in a warm-blooded animal in need of such treatment, the method comprising administering an effective amount of the formula defined herein (I) A compound or a pharmaceutically acceptable salt thereof.

按照本发明的进一步的特征，提供了在需要该种治疗的温血动物例如人中治疗乳癌、结肠直肠癌、肺癌(包括小细胞肺癌、非小细胞肺癌和细支气管肺泡癌)和前列腺癌的方法，该方法包括给予有效量的本文所定义的式(I)化合物或其可药用盐。According to a further feature of the invention, there is provided methods for treating breast cancer, colorectal cancer, lung cancer (including small cell lung cancer, non-small cell lung cancer and bronchioloalveolar carcinoma) and prostate cancer in a warm-blooded animal in need of such treatment, such as a human. A method comprising administering an effective amount of a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof.

按照本发明的进一步特征，提供了在需要该种治疗的温血动物例如人中治疗胆管癌、骨骼癌、膀胱癌、脑和颈癌、肾癌、肝癌、胃肠组织癌、食道癌、卵巢癌、胰腺癌、皮肤癌、睾丸癌、甲状腺癌、子宫癌、宫颈和外阴癌、和血癌(包括ALL和CML)、多重骨髓癌和淋巴瘤的方法，该方法包括给予有效量的本文所定义的式(I)化合物或其可药用盐。According to a further feature of the present invention there is provided the treatment of cholangiocarcinoma, bone cancer, bladder cancer, brain and neck cancer, kidney cancer, liver cancer, gastrointestinal tissue cancer, esophagus cancer, ovarian cancer in a warm-blooded animal in need of such treatment, e.g. Cancer, pancreatic cancer, skin cancer, testicular cancer, thyroid cancer, uterine cancer, cervical and vulvar cancer, and blood cancer (including ALL and CML), multiple myeloid cancer and lymphoma, the method comprising administering an effective amount of A compound of formula (I) or a pharmaceutically acceptable salt thereof.

正如本文所陈述的那样，在给予式(I)的化合物之后，通过在人或动物体之内形成的一或多种代谢物，可以部分地发挥式(I)化合物的体内效果。As stated herein, the in vivo effects of compounds of formula (I) may be exerted in part through one or more metabolites formed in the human or animal body following administration of compounds of formula (I).

本发明进一步涉及组合治疗，其中同时或顺序给予式(I)的化合物或其可药用盐或、包含式(I)化合物的药物组合物或制剂，或以与控制肿瘤疾病所使用的其它治疗的组合制剂形式给予。The present invention further relates to combination therapy, wherein a compound of formula (I) or a pharmaceutically acceptable salt thereof or, a pharmaceutical composition or preparation comprising a compound of formula (I) is administered simultaneously or sequentially, or in combination with other treatments used to control tumor diseases given in combination formulations.

尤其是，本文所定义的治疗可以用作单一疗法，或除了本发明的化合物之外，还可以包含常规手术或放射治疗或化学治疗。相应地，本发明的化合物还可以与治疗癌的现有治疗剂组合使用。In particular, the treatment as defined herein may be used as monotherapy or may comprise, in addition to the compounds of the invention, conventional surgery or radiotherapy or chemotherapy. Accordingly, the compounds of the present invention can also be used in combination with existing therapeutic agents for the treatment of cancer.

组合中使用的合适药剂包括：Suitable agents for use in combination include:

(i)抗增殖/抗肿瘤药和其组合，例如医学肿瘤学使用的例如烷基化剂(例如顺铂，卡铂，环磷酰胺，氮芥，苯丙氨酸氮芥，苯丁酸氮芥，白消安和亚硝基脲)；代谢拮抗剂(例如抗叶酸物，例如氟嘧啶例如5-氟尿嘧啶和替加氟，雷替曲塞，氨甲喋呤，阿糖胞苷，羟基脲和吉西他滨)；抗肿瘤抗生素(例如蒽环类抗生素，例如多柔比星，博来霉素，多柔比星，柔毛霉素，表柔比星，伊达比星，丝裂霉素-C，放线菌素和光神霉素)；抗有丝分裂剂(例如长春花生物碱，例如长春花新碱，长春花碱，去乙酰长春酰胺和长春瑞宾，和紫杉类药物，例如太平洋紫杉醇和泰索帝(taxotere))；和局部异构酶抑制剂(例如表鬼臼脂素，例如依托泊苷和表鬼臼毒噻吩糖苷，安吖啶，托泊替康和喜树碱)；(i) Antiproliferative/antineoplastic agents and combinations thereof, such as those used in medical oncology such as alkylating agents (e.g. cisplatin, carboplatin, cyclophosphamide, mechlorethamine, melphalan, chlorambucil, mustard, busulfan, and nitrosourea); metabolic antagonists (eg, antifolates, such as fluoropyrimidines such as 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytarabine, hydroxyurea, and gemcitabine) ; antineoplastic antibiotics (such as anthracyclines, such as doxorubicin, bleomycin, doxorubicin, daunorubicin, epirubicin, idarubicin, mitomycin-C, put Mithramycin and mithramycin); antimitotic agents (such as vinca alkaloids, such as vincristine, vinblastine, deacetylvinbsamide, and vinorelbine, and taxanes, such as paclitaxel and taxol taxotere); and topoisomerase inhibitors (such as epipodophyllotoxins, such as etoposide and epipodophyllotoxin, amsacrine, topotecan, and camptothecin);

(ii)细胞生长抑制剂，例如抗雌激素(例如它莫西芬，枸橼酸托瑞米芬，雷诺昔酚，屈洛昔芬和iodoxyfene)，雌激素受体负调节剂(例如氟维司群)，抗雄激素(例如比卡鲁胺，氟他胺，尼鲁米特和乙酸赛普龙)，LHRH拮抗剂或LHRH激动剂(例如戈舍瑞林，亮丙瑞林和布舍瑞林)，孕激素(例如甲地孕酮)，芳香酶抑制剂(例如作为阿那曲唑，来曲唑，伏氯唑和依西美坦)和5α-还原酶的抑制剂例如非那雄胺；(ii) Cytostatic agents such as antiestrogens (such as tamoxifen, toremifene citrate, raloxifene, droloxifene, and iodoxyfene), negative estrogen receptor modulators (such as fluvirine strenoid), antiandrogens (such as bicalutamide, flutamide, nilutamide, and cyproron acetate), LHRH antagonists or LHRH agonists (such as goserelin, leuprolide, and buserel Lin), progestogens (such as megestrol), aromatase inhibitors (such as anastrozole, letrozole, vorozole, and exemestane) and inhibitors of 5α-reductase such as finasteride ;

(iii)抗侵入药剂(例如c-Src激酶家族抑制剂，例如4-(6-氯-2，3-亚甲二氧基苯胺基)-7-[2-(4-甲基哌嗪-1-基)乙氧基]-5-四氢吡喃-4-基氧基喹唑啉(AZD0530；国际专利申请WO 01/94341)和N-(2-氯-6-甲基苯基)-2-{6-[4-(2-羟乙基)哌嗪-1-基]-2-甲基嘧啶-4-基氨基}噻唑-5-羧酰胺(达沙替尼，BMS-354825；J.Med.Chem.，2004，47，6658-6661)，和金属蛋白酶抑制剂例如马立马司他(marimastat)和尿激酶纤溶酶原激活物受体功能的抑制剂)；(iii) Anti-invasive agents (such as c-Src kinase family inhibitors, such as 4-(6-chloro-2,3-methylenedioxyanilino)-7-[2-(4-methylpiperazine- 1-yl)ethoxy]-5-tetrahydropyran-4-yloxyquinazoline (AZD0530; International Patent Application WO 01/94341) and N-(2-chloro-6-methylphenyl) -2-{6-[4-(2-Hydroxyethyl)piperazin-1-yl]-2-methylpyrimidin-4-ylamino}thiazole-5-carboxamide (Dasatinib, BMS-354825 ; J.Med.Chem., 2004, 47, 6658-6661), and metalloproteinase inhibitors such as marimastat (marimastat) and inhibitors of urokinase plasminogen activator receptor function);

(iv)生长因子功能的抑制剂：例如，这种抑制剂包括生长因子抗体和生长因子受体抗体(例如，抗erbB2抗体曲妥珠单抗[Herceptin]和抗erbB1抗体西妥昔单抗[C225])；这种抑制剂也包括例如酪氨酸激酶抑制剂，例如表皮生长因子家族的抑制剂(例如EGFR家族酪氨酸激酶抑制剂例如N-(3-氯-4-氟苯基)-7-甲氧基-6-(3-吗啉代丙氧基)喹唑啉-4-胺(吉非替尼，ZD1839)，N-(3-乙炔基苯基)-6，7-二(2-甲氧基乙氧基)喹唑啉-4-胺(埃洛替尼，OSI-774)和6-丙烯酰胺基-N-(3-氯-4-氟苯基)-7-(3-吗啉代丙氧基)喹唑啉-4-胺(CI 1033)和erbB2酪氨酸激酶抑制剂，例如拉帕替尼)，肝细胞生长因子家族的抑制剂，血小板生长因子家族的抑制剂，例如伊马替尼，丝氨酸/苏氨酸激酶的抑制剂(例如Ras/Raf信号抑制剂，例如法尼基转移酶抑制剂，例如索拉非尼(BAY 43-9006))和通过MEK和/或Akt激酶的细胞信号的抑制剂；(iv) Inhibitors of growth factor function: Examples of such inhibitors include growth factor antibodies and growth factor receptor antibodies (eg, the anti-erbB2 antibody trastuzumab [Herceptin] and the anti-erbB1 antibody cetuximab [ C225]); such inhibitors also include, for example, tyrosine kinase inhibitors, such as inhibitors of the epidermal growth factor family (eg EGFR family tyrosine kinase inhibitors such as N-(3-chloro-4-fluorophenyl) -7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine (gefitinib, ZD1839), N-(3-ethynylphenyl)-6,7- Bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI-774) and 6-acrylamido-N-(3-chloro-4-fluorophenyl)-7 -(3-morpholinopropoxy)quinazolin-4-amine (CI 1033) and erbB2 tyrosine kinase inhibitors such as lapatinib), inhibitors of the hepatocyte growth factor family, platelet growth factor Family of inhibitors, eg imatinib, inhibitors of serine/threonine kinases (eg Ras/Raf signaling inhibitors eg farnesyltransferase inhibitors eg sorafenib (BAY 43-9006)) and inhibitors of cellular signaling through MEK and/or Akt kinases;

(v)抗血管形成药剂，例如抑制血管内皮生长因子效果的那些药剂，[例如抗血管内皮细胞生长因子抗体贝伐单抗(Avastin)和VEGF受体酪氨酸激酶抑制剂，例如4-(4-溴-2-氟苯胺基)-6-甲氧基-7-(1-甲基哌啶-4-基甲氧基)喹唑啉(ZD6474；WO 01/32651中的实施例2)，4-(4-氟-2-甲基吲哚-5-基氧基)-6-甲氧基-7-(3-吡咯烷-1-基丙氧基)喹唑啉(AZD2171；WO 00/47212中的实施例240)，瓦他拉尼(vatalanib)(PTK787；WO 98/35985)和SU11248(舒尼替尼(Sunitinib)；WO 01/60814)，和通过其它机理工作的化合物(例如三羧氨基喹啉，整联蛋白αvβ3功能的抑制剂和血管抑素)]；(v) Anti-angiogenic agents, such as those that inhibit the effects of vascular endothelial growth factor, [such as the anti-vascular endothelial growth factor antibody bevacizumab (Avastin) and VEGF receptor tyrosine kinase inhibitors, such as 4-( 4-bromo-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline (ZD6474; Example 2 in WO 01/32651) , 4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline (AZD2171; WO 00/47212, Example 240), vatalanib (PTK787; WO 98/35985) and SU11248 (Sunitinib; WO 01/60814), and compounds that work by other mechanisms ( such as tricarboxyaminoquinoline, an inhibitor of integrin αvβ3 function and angiostatin)];

(vi)血管损伤剂，例如康普瑞汀A4和公开在国际专利申请WO99/02166、WO 00/40529、WO 00/41669、WO 01/92224、WO 02/04434和WO 02/08213中的化合物；(vi) Vascular injury agents, such as Comprestatin A4 and compounds disclosed in International Patent Applications WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 and WO 02/08213 ;

(vii)反义疗法，例如针对上列靶标的那些，例如ISIS 2503，一种抗ras反义药剂；(vii) antisense therapies, such as those directed against the above-listed targets, such as ISIS 2503, an anti-ras antisense agent;

(viii)基因治疗方法，包括替换异常基因例如异常p53或异常BRCA1或BRCA2的方法，GDEPT(基因直接酶前体药物疗法)方法，例如使用胞嘧啶脱氨酶、胸苷激酶或细菌硝基还原酶的那些方法，和增加患者对于化学治疗或放射治疗的耐受性的方法，例如多重耐药性基因治疗；和(viii) Gene therapy methods, including methods to replace abnormal genes such as abnormal p53 or abnormal BRCA1 or BRCA2, GDEPT (Gene Direct Enzyme Prodrug Therapy) methods, such as using cytosine deaminase, thymidine kinase or bacterial nitroreduction enzymes, and methods of increasing a patient's resistance to chemotherapy or radiation therapy, such as multidrug resistance gene therapy; and

(ix)免疫治疗方法，包括提高患者肿瘤细胞的免疫原性的体外和体内方法，例如用细胞因子例如白细胞间介素2、白细胞间介素4或粒细胞巨噬细胞集落刺激因子进行转染，降低T细胞无反应性的方法，使用转染的免疫细胞例如细胞因子转染的树状细胞的方法，使用细胞因子转染的肿瘤细胞系的方法，和使用抗特应抗体的方法。(ix) Immunotherapy methods, including in vitro and in vivo methods of increasing the immunogenicity of tumor cells in patients, such as transfection with cytokines such as interleukin 2, interleukin 4, or granulocyte macrophage colony-stimulating factor , a method of reducing T cell anergy, a method of using transfected immune cells such as cytokine-transfected dendritic cells, a method of using cytokine-transfected tumor cell lines, and a method of using anti-atopic antibodies.

现在参考下列说明性实施例来进一步解释本发明。The invention will now be further explained with reference to the following illustrative examples.

除非另有说明，起始原料是可商购的。所有的溶剂和商品化的试剂是实验室等级的，并且可以原样使用。Starting materials are commercially available unless otherwise stated. All solvents and commercial reagents were laboratory grade and used as received.

在实施例中，在Bruker DPX 300(300MHz)、Bruker DRX 400(400MHz)仪器或Bruker DRX 500(500MHz)仪器上记录¹H NMR谱。氯仿-d(δ_H 7.27ppm)、二甲亚砜-d₆(δ_H 2.50ppm)或丙酮-d₆(δ_H 2.05ppm)的中央峰用作内标。使用下列缩写：s，单峰；d，双峰；t，三重峰；q，四重峰；m多重峰；br，宽峰。In the examples, ¹ H NMR spectra were recorded on a Bruker DPX 300 (300 MHz), Bruker DRX 400 (400 MHz) instrument or a Bruker DRX 500 (500 MHz) instrument. The central peaks of chloroform-d (δ _H 7.27 ppm), dimethylsulfoxide-d ₆ (δ _H 2.50 ppm) or acetone-d ₆ (δ _H 2.05 ppm) were used as internal standards. The following abbreviations are used: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad.

使用硅胶(0.04-0.063mm，Merck)进行柱色谱。通常，KromasilKR-100-5-C18反相柱(250x20mm，Akzo Nobel)用于制备HPLC，用乙腈和水[包含0.1％三氟乙酸(TFA)]的混合物用作洗脱液，流速10mL/min。Column chromatography was performed using silica gel (0.04-0.063 mm, Merck). Typically, a Kromasil KR-100-5-C18 reverse-phase column (250x20mm, Akzo Nobel) was used for preparative HPLC with a mixture of acetonitrile and water [containing 0.1% trifluoroacetic acid (TFA)] as eluent at a flow rate of 10 mL/min .

下列方法用于液相色谱(LC)/质谱(MS)分析：The following methods were used for liquid chromatography (LC)/mass spectrometry (MS) analysis:

HPLC： Agilent 1100或Waters Alliance HT(2790&2795)HPLC: Agilent 1100 or Waters Alliance HT (2790&2795)

质谱仪： Waters ZQ ESCiMass spectrometer: Waters ZQ ESCi

HPLC柱HPLC column

使用的标准HPLC柱是Phemonenex Gemini C185μm，50x2mm。The standard HPLC column used was Phemonenex Gemini C18 5 μm, 50x2mm.

酸式HPLC方法Acidic HPLC method

使用的移动相是：流动相A：水The mobile phase used was: Mobile Phase A: Water

流动相B：乙腈Mobile Phase B: Acetonitrile

流动相C：1％甲酸，在50∶50 水∶MeCN(v/v)中每个方法后面是快速平衡，使用5mL流速，0.45min。Mobile phase C: 1% formic acid in 50:50 water:MeCN (v/v) Each method was followed by a rapid equilibration using a 5 mL flow rate for 0.45 min.

四种通用HPLC方法是合适的：Four general HPLC methods are suitable:

5分钟监控酸式方法5 Minute Monitoring Acid Method

时间/分钟 time/minute 流动相A： Mobile phase A: 流动相B： Mobile Phase B: 流动相C： Mobile phase C: 特性曲线 Characteristic curve 流速/毫升/分钟 Flow rate/ml/min 0.00 0.00 95 95 0 0 5 5 1 1 1.1 1.1 4 4 0 0 95 95 5 5 6 6 1.1 1.1 4.5 4.5 0 0 95 95 5 5 6 6 1.1 1.1

前期洗脱化合物的前期酸式方法Pre-acid method for pre-eluting compounds

时间/分钟 time/minute 流动相A： Mobile phase A: 流动相B： Mobile phase B: 流动相C： Mobile phase C: 特性曲线 Characteristic curve 流速/毫升/分钟 Flow rate/ml/min 0.00 0.00 95 95 0 0 5 5 1 1 1.1 1.1 4 4 57.5 57.5 37.5 37.5 5 5 6 6 1.1 1.1 4.5 4.5 57.5 57.5 37.5 37.5 5 5 6 6 1.1 1.1

中期洗脱化合物的中期酸式方法Mid-term acid method for mid-eluting compounds

时间/分钟 time/minute 流动相A： Mobile phase A: 流动相B： Mobile phase B: 流动相C： Mobile phase C: 特性曲线 Characteristic curve 流速/毫升/分钟 Flow rate/ml/min 0.00 0.00 95 95 0 0 5 5 1 1 1.1 1.1 0.01 0.01 67.5 67.5 27.5 27.5 5 5 6 6 1.1 1.1 4.5 4.5 27.5 27.5 67.5 67.5 5 5 6 6 1.1 1.1

后期洗脱化合物的后期酸式方法Post acid method for late eluting compounds

时间/分钟 time/minute 流动相A： Mobile phase A: 流动相B： Mobile phase B: 流动相C： Mobile phase C: 特性曲线 Characteristic curve 流速/毫升/分钟 Flow rate/ml/min 0.00 0.00 95 95 0 0 5 5 1 1 1.1 1.1 0.01 0.01 27.5 27.5 67.5 67.5 5 5 6 6 1.1 1.1 4.5 4.5 5 5 95 95 5 5 6 6 1.1 1.1

碱式HPLC方法Basic HPLC method

在有些情况下，对于化合物离子化或色谱分离需要，标准酸式方法可能不适合。在此情况下，四种相应的碱式HPLC方法是合适的。In some cases, standard acidic methods may not be suitable for compound ionization or chromatographic separation needs. In this case, four corresponding basic HPLC methods are suitable.

使用的移动相是：流动相A：水The mobile phase used is: Mobile phase A: water

流动相B：乙腈 Mobile phase B: Acetonitrile

流动相D：0.1％ 880氨/乙腈 Mobile phase D: 0.1% 880 ammonia/acetonitrile

每个方法后面是快速平衡，使用5mL流速，0.45min。Each method was followed by a rapid equilibration using a flow rate of 5 mL for 0.45 min.

分钟(minute)监控碱式方法minute monitoring alkaline method

时间/分钟 time/minute 流动相A： Mobile phase A: 流动相B： Mobile Phase B: 流动相D： Mobile phase D: 特性曲线 Characteristic curve 流速/毫升/分钟 Flow rate/ml/min 0.00 0.00 95 95 0 0 5 5 1 1 1.1 1.1 4 4 0 0 95 95 5 5 6 6 1.1 1.1 4.5 4.5 0 0 95 95 5 5 6 6 1.1 1.1

前期洗脱化合物的前期碱式方法Pre-basic method for pre-eluting compounds

时间/分钟 time/minute 流动相A： Mobile phase A: 流动相B： Mobile phase B: 流动相D： Mobile phase D: 特性曲线 Characteristic curve 流速/毫升/分钟 Flow rate/ml/min 0.00 0.00 95 95 0 0 5 5 1 1 1.1 1.1 4 4 57.5 57.5 37.5 37.5 5 5 6 6 1.1 1.1 4.5 4.5 57.5 57.5 37.5 37.5 5 5 6 6 1.1 1.1

中期洗脱化合物的中期碱式方法Mid-phase basic method for mid-eluting compounds

时间/分钟 time/minute 流动相A： Mobile phase A: 流动相B： Mobile Phase B: 流动相D： Mobile phase D: 特性曲线 Characteristic curve 流速/毫升/分钟 Flow rate/ml/min 0.00 0.00 95 95 0 0 5 5 1 1 1.1 1.1 0.01 0.01 67.5 67.5 27.5 27.5 5 5 6 6 1.1 1.1 4.5 4.5 27.5 27.5 67.5 67.5 5 5 6 6 1.1 1.1

后期洗脱化合物的后期碱式方法Late base method for late eluting compounds

仪器：Agilent 1100；柱：Waters‘Symmetry’2.1x 30mm；使用化学离子化的质谱分析(APCI)；流速：0.7毫升/分钟；吸收波长：254nm；溶剂A：水+0.1％ TFA；溶剂B：乙腈+0.1％ TFA；溶剂梯度：15-95％溶剂B，2.7分钟，而后95％溶剂B，0.3分钟。Instrument: Agilent 1100; Column: Waters'Symmetry' 2.1x 30mm; Mass spectrometry using chemical ionization (APCI); Flow rate: 0.7 ml/min; Absorption wavelength: 254nm; Solvent A: water+0.1% TFA; Solvent B: Acetonitrile + 0.1% TFA; solvent gradient: 15-95% solvent B in 2.7 minutes, then 95% solvent B in 0.3 minutes.

下列方法用于LC分析：The following methods were used for LC analysis:

方法A：仪器：Agilent 1100；柱：Kromasil C18反相硅胶，100x3mm，5μm粒径；溶剂A：0.1％TFA/水，溶剂B：0.08％TFA/乙腈；流速：1毫升/分钟；溶剂梯度：10-100％溶剂B，20分钟，而后100％溶剂B，1分钟；吸收波长：220、254和280nm。通常，记录产物的保留时间。Method A: Instrument: Agilent 1100; Column: Kromasil C18 reverse phase silica gel, 100x3mm, 5μm particle size; Solvent A: 0.1% TFA/water, Solvent B: 0.08% TFA/acetonitrile; Flow rate: 1 ml/min; Solvent gradient: 10-100% solvent B for 20 minutes, then 100% solvent B for 1 minute; absorption wavelengths: 220, 254 and 280 nm. Typically, the retention time of the product is recorded.

方法B：仪器：Agilent 1100；柱：Waters‘Xterra’C8反相硅胶，100x3mm，5μm粒径；溶剂A：0.015M氨/水，溶剂B：乙腈；流速：1毫升/分钟；溶剂梯度：10-100％溶剂B，20分钟，而后100％溶剂B，1分钟；吸收波长：220、254和280rm。通常，记录产物的保留时间。Method B: Instrument: Agilent 1100; Column: Waters'Xterra'C8 reverse phase silica gel, 100x3mm, 5μm particle size; Solvent A: 0.015M ammonia/water, Solvent B: Acetonitrile; Flow rate: 1ml/min; Solvent gradient: 10 - 100% solvent B for 20 minutes, then 100% solvent B for 1 minute; absorption wavelengths: 220, 254 and 280 rm. Typically, the retention time of the product is recorded.

本文或在下列说明性实施例内使用下列缩写：The following abbreviations are used herein or within the following illustrative examples:

HPLC 高效液相色谱HPLC High performance liquid chromatography

HBTU O-(苯并三唑-1-基)-N，N，N′，N′-四甲基脲六氟磷酸盐；HBTU O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate;

HATU O-(7-氮杂苯并三唑-1-基)-N，N，N′，N′-四甲基脲六氟磷酸盐；HATU O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate;

HOBT 1-羟基苯并三唑；HOBT 1-Hydroxybenzotriazole;

HOAT 1-羟基-7-氮杂苯并三唑；HOAT 1-Hydroxy-7-azabenzotriazole;

NMP N-甲基吡咯烷-2-酮；NMP N-methylpyrrolidin-2-one;

DMSO 二甲亚砜；DMSO Dimethyl sulfoxide;

DMF N，N-二甲基甲酰胺；DMF N, N-dimethylformamide;

DMA N，N-二甲基乙酰胺；DMA N, N-dimethylacetamide;

THF 四氢呋喃；THF Tetrahydrofuran;

DME 1，2-二甲氧基乙烷；DME 1,2-dimethoxyethane;

DCCI 二环己基碳二亚胺；DCCI Dicyclohexylcarbodiimide;

MeOH 甲醇；MeOH Methanol;

MeCN 乙腈；MeCN acetonitrile;

DCM 二氯甲烷；DCM dichloromethane;

DIPEA N，N-二异丙基乙胺；DIPEA N, N-diisopropylethylamine;

DBU 1，8-二氮杂双环[5.4.0]十一-7-烯；DBU 1,8-diazabicyclo[5.4.0]undec-7-ene;

RT 室温(大约17至25℃)；RT room temperature (approximately 17 to 25°C);

tR 保留时间；tR retention time;

m/z 质量/电荷比。m/z Mass/charge ratio.

化学名称是利用软件产生的，该软件使用Lexichem Toolkit(v.1.40)(得自于OpenEye Scientific Software(www.eyesopen.com))，以产生符合IUPAC的命名。Chemical names were generated using software using the Lexichem Toolkit (v.1.40) from OpenEye Scientific Software (www.eyesopen.com) to generate IUPAC compliant nomenclature.

实施例1：Example 1:

N-[2-(羟甲基)-4-[4-(甲基磺酰基甲基)-6-吗啉-4-基-嘧啶-2-基]苯基]甲N-[2-(hydroxymethyl)-4-[4-(methylsulfonylmethyl)-6-morpholin-4-yl-pyrimidin-2-yl]phenyl]methanol 磺酰胺Sulfonamide

将N-[4-溴-2-(羟甲基)苯基]甲磺酰胺(250mg)、乙酸钾(263mg)和二(戊酰)二硼(273mg)的混合物在1，4-二噁烷(10mL)中脱气5分钟。加入1，1′-二(二苯基膦基)二茂铁二氯钯(II)二氯甲烷加合物(44mg)，将反应加热至80℃，保持3小时。加入2-氯-4-(甲基磺酰基甲基)-6-吗啉-4-基-嘧啶(261mg)、乙醇(0.75mL)、2M碳酸钠溶液(2.7mL)和额外的1，1′-二(二苯基膦基)二茂铁二氯钯(II)二氯甲烷加合物(54mg)，继续加热另外3小时。将冷却的反应混合物真空浓缩，溶于甲醇中，并装填到SCX-2柱上。用甲醇洗涤柱，用7N氨/甲醇除去化合物。真空浓缩溶液，对残余物利用硅胶色谱，用0-5％甲醇/DCM洗脱。将得到的固体用二乙醚研磨，得到所需要的物质，白色固体(62mg)。A mixture of N-[4-bromo-2-(hydroxymethyl)phenyl]methanesulfonamide (250mg), potassium acetate (263mg) and bis(pentanoyl)diboron (273mg) degassed with alkanes (10 mL) for 5 minutes. 1,1'-Bis(diphenylphosphino)ferrocenedichloropalladium(II) dichloromethane adduct (44mg) was added and the reaction was heated to 80°C for 3 hours. 2-Chloro-4-(methylsulfonylmethyl)-6-morpholin-4-yl-pyrimidine (261 mg), ethanol (0.75 mL), 2M sodium carbonate solution (2.7 mL) and additional 1,1 '-Bis(diphenylphosphino)ferrocenedichloropalladium(II) dichloromethane adduct (54 mg) and heating was continued for a further 3 hours. The cooled reaction mixture was concentrated in vacuo, dissolved in methanol, and loaded onto an SCX-2 column. The column was washed with methanol and compounds were removed with 7N ammonia/methanol. The solution was concentrated in vacuo and the residue was chromatographed on silica gel eluting with 0-5% methanol/DCM. The resulting solid was triturated with diethyl ether to give the desired material as a white solid (62mg).

NMR谱： ¹H NMR(DMSO-d₆)δ307(3H，s)，3.22(3H，s)，3.74(8H，s)，4.53(2H，s)，4.69(2H，s)，5.44(1H，s)，6.89(1H，s)，7.45(1H，d)，8.23-8.26(1H，m)，8.43(1H，s)，9.10(1H，s) NMR spectrum: ¹ H NMR (DMSO-d ₆ ) δ307 (3H, s), 3.22 (3H, s), 3.74 (8H, s), 4.53 (2H, s), 4.69 (2H, s), 5.44 (1H , s), 6.89(1H, s), 7.45(1H, d), 8.23-8.26(1H, m), 8.43(1H, s), 9.10(1H, s)

质谱：M+H⁺457。 Mass spectrum: M+H ⁺ 457.

试验(a)平均IC₅₀值5μM。Assay (a) had an average _IC50 value of 5 μM.

N-[4-溴-2-(羟甲基)苯基]甲磺酰胺的制备描述如下：The preparation of N-[4-bromo-2-(hydroxymethyl)phenyl]methanesulfonamide is described as follows:

N-[4-溴-2-(羟甲基)苯基]甲磺酰胺N-[4-Bromo-2-(hydroxymethyl)phenyl]methanesulfonamide

将5-溴-2-甲磺酰氨基-苯甲酸甲酯(1.34g)溶于THF(30mL)中，并冷却至0℃。用15分钟将氢化铝锂(8.7mL，1M THF溶液)慢慢地加入到溶液中。使反应升温至室温，搅拌2小时，而后用水淬灭，过滤。真空浓缩溶液，对残余物利用硅胶色谱，用2.5％甲醇/DCM洗脱，得到所需要的物质，白色固体(333mg)。5-Bromo-2-methanesulfonylamino-benzoic acid methyl ester (1.34 g) was dissolved in THF (30 mL) and cooled to 0 °C. Lithium aluminum hydride (8.7 mL, 1M in THF) was slowly added to the solution over 15 minutes. The reaction was allowed to warm to room temperature, stirred for 2 hours, then quenched with water and filtered. The solution was concentrated in vacuo and the residue was chromatographed on silica gel eluting with 2.5% methanol/DCM to give the desired material as a white solid (333 mg).

NMR谱： ¹H NMR(DMSO-d₆)δ3.01(3H，s)，4.61(2H，s)，5.40(1H，s)，7.26(1H，d)，7.45-7.48(1H，m)，7.62(1H，d)，9.05-9.05(1H，m) NMR spectrum: ¹ H NMR (DMSO-d ₆ ) δ 3.01 (3H, s), 4.61 (2H, s), 5.40 (1H, s), 7.26 (1H, d), 7.45-7.48 (1H, m) , 7.62(1H, d), 9.05-9.05(1H, m)

质谱：M-H⁺ 280。 Mass Spectrum: MH ⁺ 280.

5-溴-2-甲磺酰氨基-苯甲酸甲酯5-Bromo-2-methanesulfonylamino-benzoic acid methyl ester

在0℃，以份额方式将硼氢化钠(659mg)加入到2-(二(甲基磺酰基)氨基)-5-溴-苯甲酸甲酯(168g)的甲醇(40mL)和水(4mL)搅拌溶液中。使反应升温至室温，搅拌2小时。在0℃加入其它份额的硼氢化钠，搅拌18小时。加入水(10mL)和碳酸钠(2M)(5mL)，以猝灭反应。真空干燥反应，在乙酸乙酯(50mL)和水(50mL)之间分配。用硫酸镁干燥有机物，真空过滤至干，得到所需要的物质，白色固体(1.34g)。Sodium borohydride (659 mg) was added portionwise to methyl 2-(bis(methylsulfonyl)amino)-5-bromo-benzoate (168 g) in methanol (40 mL) and water (4 mL) at 0°C Stir the solution. The reaction was allowed to warm to room temperature and stirred for 2 hours. The other portion of sodium borohydride was added at 0°C and stirred for 18 hours. Water (10 mL) and sodium carbonate (2M) (5 mL) were added to quench the reaction. The reaction was dried in vacuo, partitioned between ethyl acetate (50 mL) and water (50 mL). The organics were dried over magnesium sulfate and vacuum filtered to dryness to give the desired material as a white solid (1.34g).

NMR谱： ¹H NMR(DMSO-d₆)δ3.14(3H，d)，3.89(3H，s)，7.52-7.57(1H，m)，7.78-7.81(1H，m)，7.99(1H，d) NMR spectrum: ¹ H NMR (DMSO-d ₆ ) δ 3.14 (3H, d), 3.89 (3H, s), 7.52-7.57 (1H, m), 7.78-7.81 (1H, m), 7.99 (1H, d)

质谱：M-H⁺306。 Mass Spectrum: MH ⁺ 306.

2-(二(甲基磺酰基)氨基)-5-溴-苯甲酸甲酯2-(Di(methylsulfonyl)amino)-5-bromo-benzoic acid methyl ester

将甲基-2-氨基-5-溴苯甲酸酯(1g)溶于THF(20mL)和三乙胺(3.6mL)中。在冰浴中将混合物冷却至0℃，慢慢地加入甲磺酰氯(1mL)。在0℃搅拌反应15分钟，然后在室温下搅拌19小时。用水(10mL)淬灭反应，真空浓缩。在乙酸乙酯(50mL)和水(50mL)之间分配反应物，干燥(MgSO₄)有机物，过滤，真空浓缩，得到所需要的物质(1.68g)白色固体。Methyl-2-amino-5-bromobenzoate (1 g) was dissolved in THF (20 mL) and triethylamine (3.6 mL). The mixture was cooled to 0°C in an ice bath, and methanesulfonyl chloride (1 mL) was added slowly. The reaction was stirred at 0°C for 15 minutes, then at room temperature for 19 hours. The reaction was quenched with water (10 mL) and concentrated in vacuo. The reaction was partitioned between ethyl acetate (50 mL) and water (50 mL), the organics dried ( _MgSO4 ), filtered and concentrated in vacuo to give the desired material (1.68 g) as a white solid.

NMR谱： ¹H NMR(DMSO-d₆)δ3.52(6H，s)，3.87(3H，s)，7.58(1H，d)，7.94-7.97(1H，m)，8.10(1H，d) NMR spectrum: ¹ H NMR (DMSO-d ₆ ) δ 3.52 (6H, s), 3.87 (3H, s), 7.58 (1H, d), 7.94-7.97 (1H, m), 8.10 (1H, d)

质谱：M+H⁺386。 Mass spectrum: M+H ⁺ 386.

2-氯-4-(甲基磺酰基甲基)-6-吗啉-4-基-嘧啶的制备描述如下。The preparation of 2-chloro-4-(methylsulfonylmethyl)-6-morpholin-4-yl-pyrimidine is described below.

2-氯-4-(甲基磺酰基甲基)-6-吗啉-4-基-嘧啶2-Chloro-4-(methylsulfonylmethyl)-6-morpholin-4-yl-pyrimidine

将2，4-二氯-6-(甲基磺酰基甲基)嘧啶(10.56g)的DCM(230mL)悬浮液进行磁性搅拌(在氮气氛围中)，并冷却至-5℃。加入三乙胺(6.78mL)，而后逐滴加入吗啉(3.85mL)的DCM(30mL)溶液，保持反应温度低于-5℃。在室温下搅拌反应1小时，而后用水(300mL)洗涤有机混合物。干燥(MgSO4)有机相，过滤，蒸发至褐色固体，对其利用硅胶色谱，用50％乙酸乙酯/DCM洗脱，得到所需要的物质(6.81g)白色固体。A suspension of 2,4-dichloro-6-(methylsulfonylmethyl)pyrimidine (10.56 g) in DCM (230 mL) was magnetically stirred (under nitrogen) and cooled to -5°C. Triethylamine (6.78 mL) was added followed by a solution of morpholine (3.85 mL) in DCM (30 mL) dropwise, keeping the reaction temperature below -5°C. The reaction was stirred at room temperature for 1 hour, then the organic mixture was washed with water (300 mL). The organic phase was dried (MgSO4), filtered and evaporated to a brown solid which was chromatographed on silica gel eluting with 50% ethyl acetate/DCM to give the desired material (6.81 g) as a white solid.

NMR谱： ¹H NMR(DMSO-d₆)δ3.12(3H，s)，3.63(4H，s)，3.68-3.70(4H，m)，4.45(2H，s)，6.96(1H，s) NMR spectrum: ¹ H NMR (DMSO-d ₆ ) δ3.12 (3H, s), 3.63 (4H, s), 3.68-3.70 (4H, m), 4.45 (2H, s), 6.96 (1H, s)

质谱：MH+292。 Mass spectrum: MH+292.

2，4-二氯-6-(甲基磺酰基甲基)嘧啶2,4-Dichloro-6-(methylsulfonylmethyl)pyrimidine

将6-(甲基磺酰基甲基)-1H-嘧啶-2，4-二酮(12.72g)悬浮在三氯氧磷(125mL)中，在氮气氛围中回流加热14小时。将溶液冷却，并真空浓缩。将冰水(250mL)慢慢地加入到残余物中，然后用DCM(3x200mL)提取产物。真空浓缩有机物，得到所需要的物质，褐色固体(10.56g)。6-(Methylsulfonylmethyl)-1H-pyrimidine-2,4-dione (12.72 g) was suspended in phosphorus oxychloride (125 mL), and heated under reflux for 14 hours under nitrogen atmosphere. The solution was cooled and concentrated in vacuo. Ice water (250 mL) was slowly added to the residue, then the product was extracted with DCM (3x200 mL). The organics were concentrated in vacuo to give the desired material as a tan solid (10.56g).

NMR谱： ¹H NMR(DMSO-d₆)δ3.14(3H，s)，4.79(2H，s)，7.88(1H，s) NMR spectrum: ¹ H NMR (DMSO-d ₆ ) δ 3.14 (3H, s), 4.79 (2H, s), 7.88 (1H, s)

质谱：(M-H)-239。 Mass spectrum: (MH)-239.

6-(甲基磺酰基甲基)-1H-嘧啶-2，4-二酮6-(Methylsulfonylmethyl)-1H-pyrimidine-2,4-dione

将6-(氯甲基)尿嘧啶(10.00g)溶于DMF(300mL)中，加入甲亚磺酸(methanesulphinic)钠盐(7.64g)。将反应在125℃加热1小时。冷却反应，过滤，真空浓缩滤液，得到所需要的物质，黄色固体(12.72g)。6-(Chloromethyl)uracil (10.00 g) was dissolved in DMF (300 mL), and methanesulphinic sodium salt (7.64 g) was added. The reaction was heated at 125°C for 1 hour. The reaction was cooled, filtered and the filtrate concentrated in vacuo to give the desired material as a yellow solid (12.72g).

NMR谱： ¹H NMR(DMSO-d₆)δ3.10(3H，s)，4.27(2H，s)，5.63(1H，s)，10.94(1H，s)，11.16(1H，s)。 NMR spectrum: ¹ H NMR (DMSO-d ₆ ) δ 3.10 (3H, s), 4.27 (2H, s), 5.63 (1H, s), 10.94 (1H, s), 11.16 (1H, s).

实施例2：Example 2:

N-[[4-[4-(甲基磺酰基甲基)-6-吗啉-4-基-嘧啶-2-基]苯基]甲基]甲磺酰胺N-[[4-[4-(methylsulfonylmethyl)-6-morpholin-4-yl-pyrimidin-2-yl]phenyl]methyl]methanesulfonamide

将[4-[4-(甲基磺酰基甲基)-6-吗啉-4-基-嘧啶-2-基]苯基]甲胺(72mg)悬浮在DCM(4mL)中，并用三乙胺(0.056mL)处理。然后逐滴加入甲磺酰氯(0.024mL)，并在RT下搅拌反应过夜。加入水(2mL)来猝灭反应，分离各层。用DCM(2x2mL)提取水层，干燥合并的有机物，过滤，蒸发至绿油，将其在碱式制备HPLC系统上纯化。将包含产物的馏份装填到甲醇预先洗脱的SCX柱上，用甲醇洗涤，然后用7N氨/甲醇洗脱。真空蒸发所需要的馏份，得到所需要的物质，白色固体(20mg)。[4-[4-(Methylsulfonylmethyl)-6-morpholin-4-yl-pyrimidin-2-yl]phenyl]methanamine (72 mg) was suspended in DCM (4 mL) and washed with triethyl Treat with amine (0.056 mL). Methanesulfonyl chloride (0.024 mL) was then added dropwise and the reaction was stirred overnight at RT. Water (2 mL) was added to quench the reaction and the layers were separated. The aqueous layer was extracted with DCM (2x2 mL), the combined organics were dried, filtered and evaporated to a green oil which was purified on a basic preparative HPLC system. Fractions containing product were loaded onto a methanol pre-eluted SCX column, washed with methanol, and then eluted with 7N ammonia/methanol. The desired fractions were evaporated in vacuo to give the desired material as a white solid (20mg).

LCMS谱：MH+441.58，保留时间1.41方法：监控酸法 LCMS spectrum: MH+441.58, retention time 1.41 Method: monitoring acid method

NMR谱： ¹H NMR(300.132MHz，DMSO-d₆)δ2.89(s，3H)，3.20(s，3H)，3.71(s，8H)，4.25(d，2H)，4.51(s，2H)，6.91(s，1H)，7.45(m，2H)，7.62(m，1H)，8.34(m，2H)。 NMR spectrum: ¹ H NMR (300.132MHz, DMSO-d ₆ ) δ2.89(s, 3H), 3.20(s, 3H), 3.71(s, 8H), 4.25(d, 2H), 4.51(s, 2H ), 6.91 (s, 1H), 7.45 (m, 2H), 7.62 (m, 1H), 8.34 (m, 2H).

试验(a)平均IC₅₀值6.8μM。Assay (a) had an average _IC50 value of 6.8 μM.

起始原料[4-[4-(甲基磺酰基甲基)-6-吗啉-4-基-嘧啶-2-基]苯基]甲胺制备如下。The starting material [4-[4-(methylsulfonylmethyl)-6-morpholin-4-yl-pyrimidin-2-yl]phenyl]methanamine was prepared as follows.

[4-[4-(甲基磺酰基甲基)-6-吗啉-4-基-嘧啶-2-基]苯基]甲胺[4-[4-(Methylsulfonylmethyl)-6-morpholin-4-yl-pyrimidin-2-yl]phenyl]methanamine

将2-甲基硫基-4-(甲基磺酰基甲基)-6-吗啉-4-基-嘧啶(228mg)、[4-(氨甲基)苯基]硼酸(310mg)、噻吩-2-羧酸铜(I)(373mg)和Pd(PPh₃)₄(35mg)加入到微波容器中，然后加入1，4-二噁烷(5mL)。密封系统，在微波反应器中、在130℃加热1小时。进一步加入Pd(PPh₃)₄(10mg)，并将反应加热到130℃，保持20分钟。将混合物转入预先用甲醇洗脱的SCX柱中。然后用甲醇冲洗SCX柱，而后用7N氨/甲醇洗脱所需要的物质。蒸发馏份，得到所需要的化合物，乳膏状固体(129mg)。2-Methylthio-4-(methylsulfonylmethyl)-6-morpholin-4-yl-pyrimidine (228mg), [4-(aminomethyl)phenyl]boronic acid (310mg), thiophene - Copper (I) 2-carboxylate (373 mg) and Pd(PPh ₃ ) ₄ (35 mg) were added to a microwave vessel, followed by 1,4-dioxane (5 mL). The system was sealed and heated at 130° C. for 1 hour in a microwave reactor. Further Pd(PPh ₃ ) ₄ (10 mg) was added and the reaction was heated to 130° C. for 20 minutes. The mixture was transferred to an SCX column pre-eluted with methanol. The SCX cartridge was then flushed with methanol before the desired material was eluted with 7N ammonia/methanol. Fractions were evaporated to give the desired compound as a cream solid (129mg).

LCMS谱：MH+363.55，保留时间0.83方法：监控酸法 LCMS spectrum: MH+363.55, retention time 0.83 Method: monitoring acid method

2-甲基硫基-4-(甲基磺酰基甲基)-6-吗啉-4-基-嘧啶2-Methylthio-4-(methylsulfonylmethyl)-6-morpholin-4-yl-pyrimidine

将2-甲基硫基-6-(甲基磺酰基甲基)嘧啶-4-醇(15g，63.97mmol)在氯氧化亚磷(100ml)中回流加热大约1小时。蒸发氯氧化亚磷，用氢氧化钠溶液中和残余物，并提取到乙酸乙酯中。然后用硫酸镁将得到的混合物干燥，过滤，蒸干，得到粗品氯代产物。然后将其溶于DCM中，加入吗啉(319mmol，28ml)，在室温下搅拌反应。一旦完成，收集得到的沉淀，白色固体。浓缩滤液，得到更多固体，得到合并产率13.7g。2-Methylthio-6-(methylsulfonylmethyl)pyrimidin-4-ol (15 g, 63.97 mmol) was heated at reflux in phosphorous oxychloride (100 mL) for about 1 hour. The phosphorous oxychloride was evaporated, the residue was neutralized with sodium hydroxide solution and extracted into ethyl acetate. The resulting mixture was then dried over magnesium sulfate, filtered and evaporated to dryness to give the crude chlorinated product. It was then dissolved in DCM, morpholine (319mmol, 28ml) was added, and the reaction was stirred at room temperature. Once complete, the resulting precipitate was collected as a white solid. The filtrate was concentrated to give more solids giving a combined yield of 13.7g.

NMR谱： ¹H NMR(300.132MHz，DMSO)δ2.45(s，3H)，3.49-3.74(m，8H)，4.37(s，2H)，6.66(s，1H)ppm.。 NMR spectrum: ¹ H NMR (300.132 MHz, DMSO) δ 2.45 (s, 3H), 3.49-3.74 (m, 8H), 4.37 (s, 2H), 6.66 (s, 1H) ppm.

LCMS谱：MH+304.50，保留时间1.49min，方法：监控碱法。 LCMS spectrum: MH+304.50, retention time 1.49min, method: monitoring alkali method.

2-甲基硫基-6-(甲基磺酰基甲基)嘧啶-4-醇2-Methylthio-6-(methylsulfonylmethyl)pyrimidin-4-ol

将6-(氯甲基)-2-甲基硫基-嘧啶-4-醇(19.07g，100mmol)悬浮在乙腈(400mL)中。向该搅拌悬浮液中加入甲亚磺酸钠盐(12.255g，120mmol)和DMF(100mL)。然后将反应加热到100℃，得到黑色的悬浮液，用LCMS监控。一旦完成，除去溶剂，并将所得产品加入到1∶1MeOH∶DCM(200ml)中，用乙酸(10ml)酸化。收集得到的沉淀，用水(200ml)和MeOH(100ml)洗涤，真空干燥过夜，得到标题化合物，白色固体16.45g。6-(Chloromethyl)-2-methylsulfanyl-pyrimidin-4-ol (19.07 g, 100 mmol) was suspended in acetonitrile (400 mL). To this stirred suspension was added methanesulfinic acid sodium salt (12.255 g, 120 mmol) and DMF (100 mL). The reaction was then heated to 100 °C to give a black suspension which was monitored by LCMS. Once complete, the solvent was removed and the resulting product was taken up in 1:1 MeOH:DCM (200ml) and acidified with acetic acid (10ml). The resulting precipitate was collected, washed with water (200ml) and MeOH (100ml) and dried under vacuum overnight to give the title compound as a white solid, 16.45g.

NMR谱： ¹H NMR(300.132MHz，DMSO)δ2.50(s，3H)，3.12(s，3H)，4.39(s，2H)，6.25(s，1H)，13.09(s，1H)ppm.。 NMR spectrum: ¹ H NMR (300.132MHz, DMSO) δ2.50(s, 3H), 3.12(s, 3H), 4.39(s, 2H), 6.25(s, 1H), 13.09(s, 1H) ppm. .

LCMS谱：MH+235.2，保留时间0.5分钟，方法：5分钟前期碱式方法。 LCMS spectrum: MH+235.2, retention time 0.5 min, method: 5 min pre-basic method.

6-(氯甲基)-2-甲基硫基-嘧啶-4-醇6-(Chloromethyl)-2-methylthio-pyrimidin-4-ol

将S-甲基-2-硫代假脲硫酸酯(20g，71.85mmol)、4-氯乙酰醋酸乙酯(10.755mL，79.04mmol)和碳酸钠(13.925g，107.78mmol)溶于水(100mL)中，并在室温下搅拌过夜。用TLC监控反应，一旦完成，收集反应沉淀，用6N盐酸中和上清液，得到更多反应沉淀，同样将其收集。然后用水(x3)洗涤聚集的沉淀，获得类白色固体。在60℃将其真空干燥48小时，得到所需要的化合物，浅黄色/白色固体43.2g。Dissolve S-methyl-2-thiopseudourea sulfate (20 g, 71.85 mmol), ethyl 4-chloroacetoacetate (10.755 mL, 79.04 mmol) and sodium carbonate (13.925 g, 107.78 mmol) in water (100 mL ) and stirred overnight at room temperature. The reaction was monitored by TLC and upon completion the reaction pellet was collected and the supernatant was neutralized with 6N hydrochloric acid to give more reaction pellet which was also collected. The aggregated precipitate was then washed with water (x3) to obtain an off-white solid. It was dried under vacuum at 60°C for 48 hours to obtain the desired compound as a pale yellow/white solid 43.2 g.

NMR谱： ¹H NMR(300.132MHz，CDCl₃)δ2.59(s，3H)，4.35(s，2H)，6.41(s，1H)，12.70(s，1H)ppm NMR spectrum: ¹ H NMR (300.132MHz, CDCl ₃ ) δ 2.59(s, 3H), 4.35(s, 2H), 6.41(s, 1H), 12.70(s, 1H) ppm

质谱：M⁺190 Mass spectrum: M ⁺ 190

实施例3：Example 3:

N-[4-[4-(甲基磺酰基甲基)-6-吗啉-4-基-嘧啶-2-基]苯基]环丙磺酰胺N-[4-[4-(methylsulfonylmethyl)-6-morpholin-4-yl-pyrimidin-2-yl]phenyl]cyclopropanesulfonamide

向4-[4-(甲基磺酰基甲基)-6-吗啉-4-基-嘧啶-2-基]苯胺(52mg)的吡啶(4mL)溶液中加入环丙磺酰氯(53mg)，并在RT下搅拌反应过夜。然后向反应混合物中加入PS-三羟甲基氨基甲烷树脂(200mg)，摇动混合物2小时，然后过滤，用甲醇洗涤。将合并的有机物蒸干，而后溶于DMSO(1mL)中，用制备HPLC纯化，使用Phenomenex‘Gemini’制备反相柱(5微米硅胶，21.2mm直径，100mm长度)，使用水和乙腈(包含2％甲酸)的极性渐减的混合物作为洗脱液，得到标题化合物(33mg)。To a solution of 4-[4-(methylsulfonylmethyl)-6-morpholin-4-yl-pyrimidin-2-yl]aniline (52 mg) in pyridine (4 mL) was added cyclopropanesulfonyl chloride (53 mg), And the reaction was stirred overnight at RT. PS-tris resin (200 mg) was then added to the reaction mixture, the mixture was shaken for 2 hours, then filtered and washed with methanol. The combined organics were evaporated to dryness then dissolved in DMSO (1 mL) and purified by preparative HPLC using a Phenomenex 'Gemini' preparative reverse phase column (5 micron silica gel, 21.2 mm diameter, 100 mm length) with water and acetonitrile containing 2 % formic acid) as eluents to afford the title compound (33 mg).

LCMS谱：M+H⁺453.45；保留时间2.59方法：监控酸法 LCMS spectrum: M+H ⁺ 453.45; retention time 2.59 Method: monitoring acid method

试验(a)平均IC₅₀值0.88μM。Assay (a) had an average _IC50 value of 0.88 μM.

使用合适的磺酰氯，用类似方式制备下列化合物。The following compounds were prepared in an analogous manner using the appropriate sulfonyl chloride.

实施例3a：试验(a)平均IC₅₀值1.4μM。Example 3a: Experiment (a) Average _IC50 value 1.4 μM.

实施例3b：试验(a)平均IC₅₀值4μM。Example 3b: Experiment (a) Average _IC50 value 4 μM.

实施例3c：试验(a)平均IC₅₀值6μM。Example 3c: Experiment (a) Average _IC50 value 6 μM.

实施例3d：试验(a)平均IC₅₀值7.1μM。Example 3d: Experiment (a) The average _IC50 value was 7.1 μM.

4-[4-(甲基磺酰基甲基)-6-吗啉-4-基-嘧啶-2-基]苯胺的制备描述如下：The preparation of 4-[4-(methylsulfonylmethyl)-6-morpholin-4-yl-pyrimidin-2-yl]aniline is described as follows:

4-[4-(甲基磺酰基甲基)-6-吗啉-4-基-嘧啶-2-基]苯胺4-[4-(Methylsulfonylmethyl)-6-morpholin-4-yl-pyrimidin-2-yl]aniline

将2-甲基硫基-4-(甲基磺酰基甲基)-6-吗啉-4-基-嘧啶(1.00g，3.3mmol)、4-氨基苯基硼酸(904mg，6.60mmol)、噻吩-2-羧酸铜(I)(1.64g，8.58mmol)、Pd(PPh₃)₄(153mg，0.04当量，0.13mmol)加入到微波容器中，并加入1，4-二噁烷(20mL)。用N₂将系统脱气，密封并在微波反应器中、在130℃加热1小时。一旦冷却，将反应物倒入水中，过滤收集得到的沉淀，真空干燥，得到标题化合物，类白色固体(988mg)。2-Methylthio-4-(methylsulfonylmethyl)-6-morpholin-4-yl-pyrimidine (1.00g, 3.3mmol), 4-aminophenylboronic acid (904mg, 6.60mmol), Copper(I) thiophene-2-carboxylate (1.64 g, 8.58 mmol), Pd(PPh ₃ ) ₄ (153 mg, 0.04 equiv, 0.13 mmol) were added to a microwave vessel, and 1,4-dioxane (20 mL ). The system was degassed with _N2 , sealed and heated in a microwave reactor at 130 °C for 1 h. Once cooled, the reaction was poured into water and the resulting precipitate collected by filtration and dried in vacuo to give the title compound as an off-white solid (988 mg).

LCMS谱：MH+349.41，保留时间1.43，方法：监控酸法 LCMS spectrum: MH+349.41, retention time 1.43, method: monitoring acid method

NMR谱： ¹H NMR(300.132MHz，DMSO-d₆)δ3.20(3H，s)，3.61-3.83(8H，m)，4.43(2H，s)，5.57(1H，s)，6.60(2H，d)，6.70(1H，s)，8.04(2H，d) NMR spectrum: ¹ H NMR (300.132 MHz, DMSO-d ₆ ) δ3.20 (3H, s), 3.61-3.83 (8H, m), 4.43 (2H, s), 5.57 (1H, s), 6.60 (2H ,d), 6.70(1H,s), 8.04(2H,d)

实施例4：Example 4:

N-[4-[4-(甲基磺酰基甲基)-6-吗啉-4-基-嘧啶-2-基]苯基]甲磺酰胺N-[4-[4-(methylsulfonylmethyl)-6-morpholin-4-yl-pyrimidin-2-yl]phenyl]methanesulfonamide

向4-[4-(甲基磺酰基甲基)-6-吗啉-4-基-嘧啶-2-基]苯胺(53mg，0.15mmol))的吡啶(3mL)溶液中加入甲磺酰氯(21mg，0.18mmol)，并在RT下搅拌反应2小时。将水(10mL)加入到混合物中，过滤收集沉淀。用制备HPLC纯化该固体，得到所需要的物质，白色固体(29mg)。To a solution of 4-[4-(methylsulfonylmethyl)-6-morpholin-4-yl-pyrimidin-2-yl]aniline (53 mg, 0.15 mmol)) in pyridine (3 mL) was added methanesulfonyl chloride ( 21 mg, 0.18 mmol), and the reaction was stirred at RT for 2 hours. Water (10 mL) was added to the mixture, and the precipitate was collected by filtration. The solid was purified by preparative HPLC to give the desired material as a white solid (29mg).

LCMS谱：M+H⁺427.4；保留时间1.38，方法：监控酸法 LCMS spectrum: M+H ⁺ 427.4; retention time 1.38, method: monitoring acid method

NMR谱： ¹H NMR(300.132MHz，DMSO-d₆)δ3.08(3H，s)，3.22(3H，s)，3.75(8H，s)，4.57(2H，s)，6.93(1H，s)，7.33(2H，d)，8.30(2H，d)，10.12(1H，s) NMR spectrum: ¹ H NMR (300.132 MHz, DMSO-d ₆ ) δ 3.08 (3H, s), 3.22 (3H, s), 3.75 (8H, s), 4.57 (2H, s), 6.93 (1H, s ), 7.33(2H,d), 8.30(2H,d), 10.12(1H,s)

试验(a)平均IC₅₀值2.6μM。Assay (a) had an average _IC50 value of 2.6 μM.

实施例5：Example 5:

N-[[4-[4-[(3S)-3-甲基吗啉-4-基]-6-(甲基磺酰基甲基)嘧啶-2-基]苯基]甲N-[[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(methylsulfonylmethyl)pyrimidin-2-yl]phenyl]methyl 基]甲磺酰胺base] methanesulfonamide

将三乙胺(0.038mL，0.27mmol)加入到[4-[4-[(3S)-3-甲基吗啉-4-基]-6-(甲基磺酰基甲基)嘧啶-2-基]苯基]甲胺(100mg，0.27mmol)的DCM(5mL)溶液中。加入甲磺酰氯(0.021mL，0.27mmol)，并在室温下搅拌反应2小时。用水(5mL)洗涤有机物，干燥(MgSO₄)，真空浓缩。在硅胶上纯化粗品，用0-5％甲醇/DCM洗脱，得到所需要的物质，白色固体(90mg)。Triethylamine (0.038 mL, 0.27 mmol) was added to [4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(methylsulfonylmethyl)pyrimidine-2- yl]phenyl]methylamine (100 mg, 0.27 mmol) in DCM (5 mL). Methanesulfonyl chloride (0.021 mL, 0.27 mmol) was added and the reaction was stirred at room temperature for 2 hours. The organics were washed with water (5 mL), dried ( _MgSO4 ), and concentrated in vacuo. The crude was purified on silica gel eluting with 0-5% methanol/DCM to give the desired material as a white solid (90 mg).

LCMS谱：M+H⁺455；保留时间1.61，方法：监控碱法 LCMS spectrum: M+H ⁺ 455; retention time 1.61, method: monitoring alkali method

NMR谱： ¹H NMR(400.132MHz，CDCl₃)δ1.36(d，3H)，2.89(s，3H)，3.08(s，3H)，3.35(m，1H)，3.60(t，1H)，3.79(m，2H)，4.05(d，1H)，4.18(d，1H)，4.27(s，2H)，4.39(d，2H)，4.49(s，1H)，4.80(s，1H)，6.52(s，1H)，7.43(d，2H)，8.36(d，2H)。 NMR spectrum: ¹ H NMR (400.132 MHz, CDCl ₃ ) δ1.36 (d, 3H), 2.89 (s, 3H), 3.08 (s, 3H), 3.35 (m, 1H), 3.60 (t, 1H), 3.79(m, 2H), 4.05(d, 1H), 4.18(d, 1H), 4.27(s, 2H), 4.39(d, 2H), 4.49(s, 1H), 4.80(s, 1H), 6.52 (s, 1H), 7.43 (d, 2H), 8.36 (d, 2H).

试验(a)平均IC₅₀值4.5μM。Assay (a) had an average _IC50 value of 4.5 μM.

[4-[4-[(3S)-3-甲基吗啉-4-基]-6-(甲基磺酰基甲基)嘧啶-2-基]苯基]甲胺的制备描述如下。The preparation of [4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(methylsulfonylmethyl)pyrimidin-2-yl]phenyl]methanamine is described below.

[4-[4-[(3S)-3-甲基吗啉-4-基]-6-(甲基磺酰基甲基)嘧啶-2-基]苯基]甲胺[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(methylsulfonylmethyl)pyrimidin-2-yl]phenyl]methanamine

将2-氯-4-[(3S)-3-甲基吗啉-4-基]-6-(甲基磺酰基甲基)嘧啶(1.0g，3.27mmol)溶于18％DMF的7∶3∶2 DME∶水∶乙醇(9mL)的混合物溶液中。然后将4-氨基甲基苯基硼酸盐酸盐(0.92g，4.91mmol)、2M碳酸钠溶液(3mL)和二氯双(三苯基膦)钯催化剂(115mg，0.16mmol)加入到溶液中，在氮气氛中，在90℃回流16小时。使反应冷却至室温，然后在乙酸乙酯和水之间分配。用硫酸镁干燥有机物，过滤，浓缩至干。对粗品油利用硅胶色谱，用0-5％甲醇/DCM洗脱，得到所需要的物质，乳膏状固体(400mg)。2-Chloro-4-[(3S)-3-methylmorpholin-4-yl]-6-(methylsulfonylmethyl)pyrimidine (1.0 g, 3.27 mmol) was dissolved in 18% DMF in 7: 3:2 DME:water:ethanol (9mL) mixture solution. 4-Aminomethylphenylborate hydrochloride (0.92 g, 4.91 mmol), 2M sodium carbonate solution (3 mL) and dichlorobis(triphenylphosphine)palladium catalyst (115 mg, 0.16 mmol) were then added to the solution reflux at 90° C. for 16 hours in a nitrogen atmosphere. The reaction was cooled to room temperature, then partitioned between ethyl acetate and water. The organics were dried over magnesium sulfate, filtered, and concentrated to dryness. Chromatography on silica gel eluting with 0-5% methanol/DCM on the crude oil gave the desired material as a cream solid (400 mg).

LCMS谱：M-H-375；保留时间1.58，方法：监控碱法 LCMS spectrum: MH-375; retention time 1.58, method: monitoring alkali method

NMR Spectrum： ¹H NMR(400.132MHz，CDCl₃)δ1.36(d，3H)，3.08(s，3H)，3.34(m，1H)，3.60(m，1H)，3.75(m，1H)，3.83(d，1H)，3.94(s，2H)，4.05(m，1H)，4.18(m，1H)，4.26(s，2H)，4.49(m，1H)，6.50(s，1H)，7.40(d，2H)，8.33(d，2H)。 NMR Spectrum: ¹ H NMR (400.132MHz, CDCl ₃ ) δ1.36(d, 3H), 3.08(s, 3H), 3.34(m, 1H), 3.60(m, 1H), 3.75(m, 1H), 3.83(d, 1H), 3.94(s, 2H), 4.05(m, 1H), 4.18(m, 1H), 4.26(s, 2H), 4.49(m, 1H), 6.50(s, 1H), 7.40 (d,2H), 8.33(d,2H).

2-氯-4-[(3S)-3-甲基吗啉-4-基]-6-(甲基磺酰基甲基)嘧啶2-Chloro-4-[(3S)-3-methylmorpholin-4-yl]-6-(methylsulfonylmethyl)pyrimidine

将2，4-二氯-6-(甲基磺酰基甲基)嘧啶(30g，0.13mol)溶于二氯甲烷中，在-5℃搅拌(在氮气氛围中)。加入三乙胺(17.4mL，0.13mol)，得到澄清的褐色溶液。将(3S)-3-甲基吗啉溶于二氯甲烷中，逐滴加入，保持反应低于-5℃。然后除去冷却浴，搅拌混合物1小时。回流加热反应混合物2小时，然后用水洗涤反应混合物，干燥，然后蒸发。用制备HPLC纯化粗品，得到所需要的物质，固体(19.3g)。2,4-Dichloro-6-(methylsulfonylmethyl)pyrimidine (30 g, 0.13 mol) was dissolved in dichloromethane and stirred at -5°C (under nitrogen atmosphere). Triethylamine (17.4 mL, 0.13 mol) was added to give a clear brown solution. (3S)-3-Methylmorpholine was dissolved in dichloromethane and added dropwise keeping the reaction below -5°C. The cooling bath was then removed and the mixture was stirred for 1 hour. The reaction mixture was heated at reflux for 2 hours, then the reaction mixture was washed with water, dried and evaporated. The crude was purified by preparative HPLC to give the desired material as a solid (19.3g).

NMR谱： ¹H NMR(400.13MHz，DMSO-d₆)δ1.21-1.23(m，3H)，3.11(s，3H)，3.19-3.26(m，1H)，3.42-3.49(m，1H)，3.58-3.62(1H，m)，3.73(d，1H)，3.92-3.96(m，2H)，4.27-4.31(m，1H)，4.45(s，2H)，6.92(s，1H) NMR spectrum: ¹ H NMR (400.13 MHz, DMSO-d ₆ ) δ1.21-1.23 (m, 3H), 3.11 (s, 3H), 3.19-3.26 (m, 1H), 3.42-3.49 (m, 1H) , 3.58-3.62(1H, m), 3.73(d, 1H), 3.92-3.96(m, 2H), 4.27-4.31(m, 1H), 4.45(s, 2H), 6.92(s, 1H)

LCMS谱：MH+306，保留时间1.42分钟，方法：5分钟酸式法 LCMS spectrum: MH+306, retention time 1.42 minutes, method: 5 minutes acid method

先前描述了2，4-二氯-6-(甲基磺酰基甲基)嘧啶的制备。The preparation of 2,4-dichloro-6-(methylsulfonylmethyl)pyrimidine was previously described.

实施例6：Embodiment 6:

N-[4-[4-[(3S)-3-甲基吗啉-4-基]-6-(甲基磺酰基甲基)嘧啶-2-基]苯基]甲N-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(methylsulfonylmethyl)pyrimidin-2-yl]phenyl]methyl 磺酰胺Sulfonamide

将2-氯-4-[(3S)-3-甲基吗啉-4-基]-6-(甲基磺酰基甲基)嘧啶(150mg，0.49mmol)溶于18％DMF的7∶3∶2 DME∶水∶乙醇(1.5mL)的混合物溶液中。然后将4-氨基甲基苯基硼酸盐酸盐(0.74mmol)、2M碳酸钠溶液(0.5mL)和二氯双(三苯基膦)钯催化剂(18mg，0.02mmol)加入到溶液中，在氮气氛中，在90℃回流16小时。使反应冷却至室温，然后在乙酸乙酯和水之间分配。用硫酸镁干燥有机物，过滤，浓缩至干。将粗品固体溶于DCM中，过滤除去不溶性杂质，然后用制备HPLC纯化滤液，得到所需要的化合物，白色固体(87mg)。2-Chloro-4-[(3S)-3-methylmorpholin-4-yl]-6-(methylsulfonylmethyl)pyrimidine (150 mg, 0.49 mmol) was dissolved in 18% DMF 7:3 : 2 in a mixture solution of DME: water: ethanol (1.5 mL). 4-Aminomethylphenylborate hydrochloride (0.74 mmol), 2M sodium carbonate solution (0.5 mL) and dichlorobis(triphenylphosphine) palladium catalyst (18 mg, 0.02 mmol) were then added to the solution, Under nitrogen atmosphere, reflux at 90°C for 16 hours. The reaction was cooled to room temperature, then partitioned between ethyl acetate and water. The organics were dried over magnesium sulfate, filtered, and concentrated to dryness. The crude solid was dissolved in DCM, filtered to remove insoluble impurities, and the filtrate was purified by preparative HPLC to give the desired compound as a white solid (87mg).

NMR 谱： ¹H NMR(400.13MHz，DMSO-d₆)δ1.24(3H，d)，293(3H，s)，3.21(3H，s)，3.24(1H，m)，3.50(1H，m)，3.65(1H，m)，3.78(1H，d)，3.98(1H，m)，4.16(1H，d)，4.43(1H，s)，4.48(2H，s)，6.76(1H，s)，7.17(2H，d)，8.21(2H，d) NMR spectrum: ¹ H NMR (400.13 MHz, DMSO-d ₆ ) δ1.24 (3H, d), 293 (3H, s), 3.21 (3H, s), 3.24 (1H, m), 3.50 (1H, m ), 3.65(1H,m), 3.78(1H,d), 3.98(1H,m), 4.16(1H,d), 4.43(1H,s), 4.48(2H,s), 6.76(1H,s) , 7.17(2H,d), 8.21(2H,d)

LCMS谱：M+H⁺441；保留时间1.45，方法：监控酸法 LCMS spectrum: M+H ⁺ 441; retention time 1.45, method: monitoring acid method

试验(a)平均IC₅₀值1μM。Assay (a) Mean _IC50 value 1 μM.

Claims

1. Compounds of formula (I):

Formula (I)

or its pharmaceutically acceptable salt; where

m is 0, 1, 2, 3 or 4;

¹ Y and Y ² are independently N or CR ⁸ , with the proviso that one of ¹ Y and Y ² is N, and the other is CR ⁸ ;

X is a linker selected from the group consisting of: -CR ⁴ =CR ⁵ -, -CR ⁴ =CR ⁵ CR ⁶ R ⁷ -, -CR ⁶ R ⁷ CR ⁵ =CR ⁴ -, -C≡C-, -C≡C- CCR ⁶ R ⁷ -, -CR ⁶ R ⁷ C≡C-, -NR ⁴ CR ⁶ R ⁷ -, -OCR ⁶ R ⁷ -, -SCR ⁶ R ⁷ -, -S(O)CR ⁶ R ⁷ -, -S(O) ₂ CR ⁶ R ⁷ -, -C(O)NR ⁴ CR ⁶ R ⁷ -, -NR ⁴ C(O)CR ⁶ R ⁷ -, -NR ⁴ C(O)NR ⁵ CR ⁶ R ⁷ -, -NR ⁴ S(O) ₂ CR ⁶ R ⁷ -, -S(O) ₂ NR ⁴ CR ⁶ R ⁷ -, -C(O)NR ⁴ -, -NR ⁴ C(O)-, - NR ⁴ C(O)NR ⁵ -, -S(O) ₂ NR ⁴ - and -NR ⁴ S(O) ₂ -;

^R is a group selected from the group consisting of hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, carbocyclyl, carbocyclic C _1-6 alkyl, heterocyclyl and Heterocyclyl C _1-6 alkyl, which is optionally substituted by one or more substituents selected from the following groups: halogen, cyano, nitro, R ⁹ , -OR ⁹ , -SR ⁹ , -SOR ⁹ , -SO ₂ R ⁹ , -COR ⁹ , -CO ₂ R ⁹ , -CONR ⁹ R ¹⁰ , -NR ⁹ R ¹⁰ , -NR ⁹ COR ¹⁰ , -NR ⁹ CO ₂ R ¹⁰ , -NR ⁹ CONR ¹⁰ R ¹⁵ , -NR ⁹ COCONR ¹⁰ R ¹⁵ and -NR ⁹ SO ₂ R ¹⁰ ;

R ² is a group selected from the group consisting of C _1-6 alkyl, carbocyclyl and heterocyclyl, which is substituted by -NR ¹⁷ SO ₂ R ¹⁸ , and optionally one or more independently selected from The following substituent groups are substituted: halogen, cyano, nitro, -R ¹¹ , -OR ¹¹ , -SR ¹¹ , -SOR ¹¹ , -SO ₂ R ¹¹ , -COR ¹¹ , -CO ₂ R ¹¹ , -CONR ¹¹ R ¹² , -NR ¹¹ R ¹² , -NR ¹¹ COR ¹² and -NR ¹¹ COCONR ¹² R ¹⁶ ; when present, each R ³ is independently selected from halogen, cyano, nitro, -R ¹³ , -OR ¹³ , -SR ¹³ , -SOR ¹³ , -SO ₂ R ¹³ , -COR ¹³ , -CO ₂ R ¹³ , -CONR ¹³ R ¹⁴ , -NR ¹³ R ¹⁴ , -NR ¹³ COR ¹⁴ , -NR ¹³ CO ₂ R ¹⁴ and -NR ¹³ SO ₂ R ¹⁴ ;

R ⁴ and R ⁵ are independently hydrogen or C _1-6 alkyl;

Or R ¹ and R ⁴ form a 5- to 10-membered carbocyclic or heterocyclic ring together with the atoms to which they are attached, wherein 1, 2 or 3 ring carbon atoms are optionally replaced by N, O or S, and the ring is optionally Optionally substituted by one or more substituent groups selected from the group consisting of: halogen, cyano, nitro, hydroxyl, C _1-6 alkyl, C _1-6 alkoxy, halogen C _1-6 alkyl, halogen C _1-6 alkoxy, hydroxy C _1-6 alkyl, hydroxy C 1-6 alkoxy, C _1-6 alkoxy C _1-6 _alkyl , C _1-6 alkoxy C _1-6 alkane Oxygen, amino, C _1-6 alkylamino, two (C _1-6 alkyl) amino, amino C _1-6 alkyl, (C _1-6 alkyl) amino C _1-6 alkyl, two ( C _1-6 alkyl) amino C _1-6 alkyl, cyano C _{1-6 alkyl, C 1-6} _{alkylsulfonyl} , C _1-6 alkylsulfonylamino, C _1-6 alkylsulfonyl Acyl (C _1-6 alkyl) amino, sulfamoyl, C _1-6 alkyl sulfamoyl, di(C _1-6 alkyl) sulfamoyl, C _1-6 alkanoylamino, C _1-6 Alkanoyl (C _1-6 alkyl) amino, carbamoyl, C _1-6 alkyl carbamoyl and two (C _1-6 alkyl) carbamoyl;

R ⁶ and R ⁷ are independently selected from hydrogen, halogen, cyano, nitro and C _1-6 alkyl;

^R is selected from hydrogen, halogen, cyano and C _1-6 alkyl;

R ⁹ and R ¹⁰ are independently hydrogen or a group selected from the group consisting of C _1-6 alkyl, carbocyclyl, carbocyclic C _1-6 alkyl, heterocyclyl and heterocyclyl C _1-6 alkyl , the group is optionally substituted by one or more substituents selected from the group consisting of: halogen, cyano, nitro, hydroxyl, C _1-6 alkyl, C _1-6 alkoxy, halogen C _1-6 Alkyl, halogen C _1-6 alkoxy, hydroxy C 1-6 alkyl _, hydroxy C _1-6 alkoxy, C _1-6 alkoxy C _1-6 alkyl, C _1-6 alkoxy C _1-6 alkoxy, amino, C _{1-6 alkylamino, di(C 1-6} _alkyl ) amino, amino C _1-6 alkyl, (C _1-6 alkyl) amino C _1-6 Alkyl, di(C _1-6 alkyl)amino C _1-6 alkyl, cyano C _1-6 alkyl, C _1-6 alkylsulfonyl, C _1-6 alkylsulfonylamino, C _{1 -6} alkylsulfonyl (C _1-6 alkyl)amino, sulfamoyl, C _1-6 alkylsulfamoyl, di(C _1-6 alkyl)sulfamoyl, C _1-6 alkanoylamino , C _1-6 alkanoyl (C _1-6 alkyl) amino, carbamoyl, C _1-6 alkyl carbamoyl and two (C _1-6 alkyl) carbamoyl;

R ¹¹ , R ¹² and R ¹⁷ are independently hydrogen or a group selected from the group consisting of C _1-6 alkyl, carbocyclyl, carbocyclic C _1-6 alkyl, heterocyclyl and heterocyclyl C _{1- 6} alkyl, which is optionally substituted by one or more substituents selected from the group consisting of halogen, cyano, nitro, hydroxyl, C _1-6 alkyl, C _1-6 alkoxy, halogen C _1-6 alkyl, halogen C _1-6 alkoxy _, hydroxy C _1-6 alkyl, hydroxy C 1-6 alkoxy, C _1-6 alkoxy C _1-6 alkyl, C _1-6 Alkoxy C _1-6 alkoxy, amino, C _1-6 alkylamino, two (C _1-6 alkyl) amino, amino C _1-6 alkyl, (C _1-6 alkyl) amino C _1-6 alkyl, two (C _1-6 alkyl) amino C _1-6 alkyl, cyano C _1-6 alkyl, C _1-6 alkylsulfonyl, C _1-6 alkanoylamino, C _1-6 alkanoyl (C _1-6 alkyl) amino, carbamoyl, C _1-6 alkyl carbamoyl and two (C _1-6 alkyl) carbamoyl;

R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ and R ¹⁸ are independently hydrogen or a group selected from the group consisting of C _1-6 alkyl, carbocyclyl, carbocyclic C _1-6 alkyl, heterocyclyl and Heterocyclyl C _1-6 alkyl, which is optionally substituted by one or more substituents selected from the group consisting of halogen, cyano, nitro, hydroxyl, C _1-6 alkyl, C _1-6 Alkoxy, halogen C _1-6 alkyl, halogen C 1-6 alkoxy _, hydroxy C _1-6 alkyl, hydroxy C _1-6 alkoxy, C _1-6 alkoxy C _1-6 alk Base, C _1-6 alkoxy C _1-6 alkoxy, amino, C _1-6 alkylamino, two (C _1-6 alkyl) amino, amino C _1-6 alkyl, (C _{1-6 6} alkyl) amino C _1-6 alkyl, di(C _1-6 alkyl) amino C _1-6 alkyl, cyano C _1-6 alkyl, C _1-6 alkylsulfonyl, C _{1- 6} alkyl sulfonylamino, C _1-6 alkyl sulfonyl (C _1-6 alkyl) amino, sulfamoyl, C _1-6 alkyl sulfamoyl, di(C _1-6 alkyl) sulfamoyl Acyl, C _1-6 alkanoylamino, C _1-6 alkanoyl(C _1-6 alkyl)amino, carbamoyl, C _1-6 alkylcarbamoyl and di(C _1-6 alkyl)amino formyl.

2. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (Ia) or (Ib)

or a pharmaceutically acceptable salt thereof, wherein R ¹ , R ² , R ³ , X, Y ¹ and Y ² are as defined for the compound of formula (I) as claimed in claim 1.

3. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein ^R3 is methyl.

4. The compound according to any one of claims 1 to 3, wherein ^Y1 is ^CR8 , and ^Y2 is N, or a pharmaceutically acceptable salt thereof.

5. A compound according to claim 4, or a pharmaceutically acceptable salt thereof, wherein ^Y1 is CH, and ^Y2 is N.

6. A compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein X is a linker selected from the group consisting of: -NR ⁴ CR ⁶ R ⁷ -, -OCR ⁶ R ⁷ -, -SCR ⁶ R ⁷ -, -S(O)CR ⁶ R ⁷ -, -S(O) ₂ CR ⁶ R ⁷ -, -C(O)NR ⁴ CR ⁶ R ⁷ -, -NR ⁴ C(O)NR ⁵ CR ⁶ R ⁷ -, -S(O) ₂ NR ⁴ CR ⁶ R ⁷ , -C(O)NR ⁴ - and -NR ⁴ C(O)-.

7. The compound according to claim 6, or a pharmaceutically acceptable salt thereof, wherein X is a linker selected from the group consisting of: -NR ⁴ CR ⁶ R ⁷ -, -OCR ⁶ R ⁷ -, -SCR ⁶ R ⁷ -, -S (O)CR ⁶ R ⁷ -, -S(O) ₂ CR ⁶ R ⁷ -, -C(O)NR ⁴ - and -NR ⁴ C(O)-.

8. The compound according to claim 7, or a pharmaceutically acceptable salt thereof, wherein X is a linker selected from the group consisting of: ^-NR4CH2- , _-OCH2- _, -OCH( _CH3 )-, -OC( _CH3 ) ₂ -, -SCH ₂ -, -SCH(CH ₃ )-, -SC(CH ₃ ) ₂ -, -S(O)CH ₂ -, -S(O)CH(CH ₃ )-, -S( O)C(CH ₃ ) ₂ -, -S(O) ₂ CH ₂ -, -S(O) ₂ CH(CH ₃ )-, -S(O) ₂ C(CH ₃ ) ₂ -, -C( O)NR ⁴ - and -NR ⁴ C(O)-.

9. The compound according to claim 8, or a pharmaceutically acceptable salt thereof, wherein X is -S(O) ₂ CH ₂ -, -S(O) ₂ CH(CH ₃ )- or -S(O) ₂ C(CH ₃ ) _2- .

10. The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein ^R is a group selected from the group consisting of adamantyl, methyl, ethyl, propyl, butyl, isobutyl Base, tert-butyl, cyclopentyl, cyclohexyl, phenyl, benzyl, phenethyl, pyrrolidinyl, pyrrolyl, imidazolyl, pyrazolyl, furyl, thienyl, pyridyl, pyrimidyl, pyrimidyl Azinyl, pyrrolidinylmethyl, pyrrolidinylethyl, pyrrolylmethyl, pyrrolylethyl, imidazolylmethyl, imidazolylethyl, pyrazolylmethyl, pyrazolylethyl, furylmethyl base, furylethyl, thienylmethyl, thienylethyl, pyridylmethyl, pyridylethyl, pyrimidinylmethyl, pyrimidinylethyl, pyrazinylmethyl and pyrazinylethyl, the The group is optionally substituted with 1, 2 or 3 substituents selected from the group consisting of: halogen, cyano, nitro, R ⁹ , -OR ⁹ , -COR ⁹ , -CONR ⁹ R ¹⁰ , -NR ⁹ R ¹⁰ and -NR ⁹ COR ¹⁰ .

11. The compound or pharmaceutically acceptable salt thereof according to claim 10, wherein ^R is a group selected from the group consisting of methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, cyclopropyl, Cyclopentylcyclohexyl, phenyl, benzyl, phenethyl, pyridyl, pyrazolylethyl, furylmethyl, thienylmethyl, thiazolylmethyl, thiadiazolylmethyl, and pyrazinyl Ethyl, which is optionally substituted by 1 or 2 substituents selected from the group consisting of amino, halogen, cyano, methyl, methoxy, trifluoromethyl, trifluoromethoxy, _-NHCOCH , -CONH ₂ and -CONHCH ₃ .

12. The compound according to claim 11 or a pharmaceutically acceptable salt thereof, wherein R ¹ is a group selected from the group consisting of methyl, isopropyl, cyclopropyl, cyclohexyl, -CH ₂ CH ₂ OH, -CH ₂ CH ₂ NC(O)CH ₃ , phenyl, 4-fluorophenyl, 2-chlorophenyl, 2-trifluoromethylphenyl, 2-methoxyphenyl, 2-methylphenyl, 4- Acetamidophenyl, 4-aminophenyl, pyridin-4-yl, pyridin-2-yl, 2-oxopyrrolidin-3-yl,, thiazol-2-yl, 4-methylthiazol-2-yl and 3-methyl-1,3,4-thiadiazol-2-yl.

13. A compound according to claim 12, or a pharmaceutically acceptable salt thereof, wherein ^R1 is methyl.

14. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 13, wherein ^R is selected from: 5 or 6 membered carbocyclic or heterocyclic groups, which are substituted by -NR ¹⁷ SO ₂ R ¹⁸ , and optionally substituted by one or more substituents independently selected from the following substituent groups: halogen, cyano, nitro, -R ¹¹ , -OR ¹¹ , -COR ¹¹ , -CONR ¹¹ R ¹² , -NR ¹¹ R ¹² and -NR ¹¹ COR ¹² .

15. The compound or pharmaceutically acceptable salt thereof according to claim 14, wherein R ² is selected from 6-membered aryl and 5 or 6-membered heteroaryl, which is substituted by -NR ¹⁷ SO ₂ R ¹⁸ , and optionally Substituted by one or more substituent groups independently selected from the following: halogen, cyano, nitro, -R ¹¹ , -OR ¹¹ , -COR ¹¹ , -CONR ¹¹ R ¹² , -NR ¹¹ R ¹² and -NR ¹¹ ^COR12 .

16. The compound according to claim 15 or a pharmaceutically acceptable salt thereof, wherein R ^is selected from phenyl, pyrrolyl, imidazolyl, pyrazolyl, furyl, thienyl, pyridyl, pyrimidinyl, pyridazinyl, thiazole group, which is substituted by -NR ¹⁷ SO ₂ R ¹⁸ , and optionally substituted by one or more substituents independently selected from the group consisting of: halogen, cyano, nitro, -R ¹¹ , -OR ¹¹ , -COR ¹¹ , -CONR ¹¹ R ¹² , -NR ¹¹ R ¹² and -NR ¹¹ COR ¹² .

17. According to the compound or pharmaceutically acceptable salt thereof of claim 16, wherein R is ^selected from phenyl, pyrrolyl, imidazolyl, pyrazolyl, furyl, thienyl, pyridyl, pyrimidyl, pyridazinyl, thiazole group, which is substituted by -NR ¹⁷ SO ₂ R ¹⁸ , and optionally substituted by one or more substituents independently selected from the group consisting of fluoro, methyl, methoxy, hydroxymethyl, cyanomethyl group, -CONH ₂ , -CONHCH ₃ and -CON(CH ₃ ) ₂ .

18. The compound according to claim 17 or a pharmaceutically acceptable salt thereof, wherein R ² is phenyl substituted by -NR ¹⁷ SO ₂ R ¹⁸ and optionally substituted by one or more substituents independently selected from the following substituents Or pyridyl: fluoro, methyl, methoxy, hydroxymethyl, cyanomethyl, -CONH ₂ , -CONHCH ₃ and -CON(CH ₃ ) ₂ .

19. The compound according to claim 18, or a pharmaceutically acceptable salt thereof, wherein R ² is

wherein ^A1 and ^A2 are selected from CH or N, with the proviso that at least one ^A1 or ^A2 is CH.

20. A compound according to any one of claims 14 to 19, or a pharmaceutically acceptable salt thereof, wherein ^R17 is hydrogen.

21. The compound or pharmaceutically acceptable salt ^thereof according to any one of claims 1 to 20, wherein R is hydrogen or a group selected from the group consisting of: C _1-6 alkyl, C _3-6 cycloalkyl, aryl radical, heteroaryl, aryl C _1-6 alkyl and heteroaryl C _1-6 alkyl, the group is optionally substituted by one or more substituents selected from the group consisting of: halogen, cyano, nitro radical, hydroxy, C _1-6 alkyl, C _1-6 alkoxy, halogen C _1-6 alkyl, halogen C _1-6 alkoxy, hydroxy C _1-6 alkyl, hydroxy C _1-6 alk Oxygen, C _1-6 alkoxy C _1-6 alkyl, C _1-6 alkoxy C 1-6 alkoxy, amino, _{C 1-6} _alkylamino , two (C _1-6 alkyl ) amino, amino C _1-6 alkyl, (C _1-6 alkyl) amino C _1-6 alkyl, di(C _1-6 alkyl) amino C _1-6 alkyl, cyano C _1-6 Alkyl, C _1-6 alkylsulfonyl, C _1-6 alkylsulfonylamino, C _1-6 alkylsulfonyl (C _1-6 alkyl) amino, sulfamoyl, C _1-6 alkyl Sulfamoyl, di(C _1-6 alkyl) sulfamoyl, C _1-6 alkanoylamino, C _1-6 alkanoyl (C _1-6 alkyl) amino, carbamoyl, C _1-6 alkane Carbamoyl and di(C _1-6 alkyl)carbamoyl.

22. The compound or pharmaceutically acceptable salt thereof according to claim 21, wherein R is ^hydrogen or a group selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl Base, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, thienyl, imidazolylmethyl, isoxazolyl, pyrazolyl, pyridyl and pyrimidinyl, the group is optional Substituted by one or more substituent groups selected from the group consisting of: halogen, cyano, nitro, hydroxyl, C _1-6 alkyl, C _1-6 alkoxy, halogen C _1-6 alkyl, halogen C _{1 -6} alkoxy, hydroxy C _1-6 alkyl, hydroxy C 1-6 alkoxy _, C _1-6 alkoxy C _1-6 alkyl, C _1-6 alkoxy C _1-6 alkoxy Base, amino, C _1-6 alkylamino, two (C _1-6 alkyl) amino, amino C _1-6 alkyl, (C _1-6 alkyl) amino C _1-6 alkyl, two (C _1-6 alkyl) amino C _1-6 alkyl, cyano C _1-6 alkyl, C _1-6 alkylsulfonyl, C _1-6 alkylsulfonylamino, C _1-6 alkylsulfonyl (C _1-6 alkyl) amino, sulfamoyl, C _1-6 alkyl sulfamoyl, di(C _1-6 alkyl) sulfamoyl, C _1-6 alkanoylamino, C _1-6 alkane Acyl(C _1-6 alkyl)amino, carbamoyl, C _1-6 alkylcarbamoyl and di(C _1-6 alkyl)carbamoyl.

23. The compound or pharmaceutically acceptable salt thereof according to claim 22, wherein R is ^hydrogen or a group selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl radical, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH ₂ (cyclopropyl), -CH ₂ CH ₂ NMe ₂ , -CH(CH ₃ )CH ₂ OH, -C( CH ₃ ) ₂ CH ₂ OH, -CH ₂ CH ₂ OH, -CH ₂ CH ₂ CH ₂ OH, 4-methylphenyl, 4-chlorophenyl, 4-trifluoromethylphenyl, 4-fluorobenzene Base, 4-methoxyphenyl, 3,4-difluorophenyl, thiophen-2-yl, -CH ₂ (imidazol-2-yl), -CH ₂ (imidazol-3-yl), isoxazole Base-3-yl, 6-oxo-1H-pyridin (pryrdin)-2-yl, 5-methylisoxazol-3-yl, 1-methylpyrazol-4-yl, 6-methoxy Pyridin-3-yl, 5-fluoropyridin-2-yl, pyrimidin-2-yl and 1H-pyrazol-3-yl.

24. A compound according to claim 23, or a pharmaceutically acceptable salt thereof, wherein ^R18 is hydrogen or a group selected from the group consisting of methyl, ethyl, propyl, butyl, cyclopropyl and 4-fluorophenyl.

25. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from any one of the examples or a pharmaceutically acceptable salt thereof.

26. A compound of formula (I) according to any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof, for use as a medicament in the treatment of proliferative diseases.

27. Use of a compound of formula (I) as defined in any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of proliferative diseases.

28. Use of a compound of formula (I) as defined in any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof, to produce an antiproliferative effect in a warm-blooded animal, such as a human.

29. Use of a compound of formula (I) as defined in any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for producing an antiproliferative effect in a warm-blooded animal, such as a human.

30. A method for producing an antiproliferative effect in a warm-blooded animal such as a human in need of such treatment, the method comprising administering to said animal an effective amount of a compound of formula (I) as defined in any one of claims 1 to 25 or a compound thereof Pharmaceutically acceptable salt.

31. A method of treating cancer, inflammatory disease, obstructive respiratory disease, immune disease or cardiovascular disease in a warm-blooded animal such as a human in need of such treatment, the method comprising administering an effective amount of any one of claims 1 to 25 A compound of formula (I) as defined in Item 1 or a pharmaceutically acceptable salt thereof.

32. A pharmaceutical composition comprising a compound of formula (I) as defined in any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable diluent or carrier.

33. A compound of formula (I) as defined in any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof, for use as a medicament.