CN1829713A - 3,5 disubstituted indazole compounds, pharmaceutical compositions and methods for mediating or inhibiting cell proliferation - Google Patents

Abstract

Translated fromChinese

描述了调节和/或抑制细胞增殖例如调节和/或抑制蛋白激酶活性的3，5二取代的吲唑化合物。这些化合物和含有它们的药物组合物能够介导CDK依赖性疾病，调节和/或抑制有害的细胞增殖。本发明还涉及含有这种化合物的药物组合物的治疗或预防用途、和通过给予有效量的这种化合物来治疗肿瘤以及其它与有害的血管生成和/或细胞增殖有关的疾病状态，例如糖尿病性视网膜病、新生血管性青光眼、类风湿性关节炎和牛皮癣的方法。3,5 Disubstituted indazole compounds that modulate and/or inhibit cell proliferation, such as modulate and/or inhibit protein kinase activity, are described. These compounds and pharmaceutical compositions containing them are capable of mediating CDK-dependent diseases, regulating and/or inhibiting unwanted cell proliferation. The invention also relates to the therapeutic or prophylactic use of pharmaceutical compositions containing this compound, and the treatment of tumors and other disease states associated with unwanted angiogenesis and/or cell proliferation, such as diabetic Approaches to retinopathy, neovascular glaucoma, rheumatoid arthritis, and psoriasis.

Description

Translated fromChinese

3，5二取代的吲唑化合物、药物组合物和介导 或抑制细胞增殖的方法3,5 disubstituted indazole compound, pharmaceutical composition and method for mediating or inhibiting cell proliferation

技术领域technical field

本发明涉及在3位具有取代的苯并咪唑的3，5二取代吲唑，其通过蛋白激酶的活性来介导和/或抑制细胞增殖，特别通过依赖细胞周期蛋白的激酶例如CDK1、CDK2、CDK4和CDK6的间介作用来介导和/或抑制细胞增殖。本发明进一步涉及含有这种化合物和组合物的药物组合物、和通过给予有效量的这种化合物来治疗肿瘤以及与有害的血管生成和/或细胞增殖有关的其它疾病状态的方法。The present invention relates to 3,5 disubstituted indazoles with a substituted benzimidazole at position 3, which mediate and/or inhibit cell proliferation through the activity of protein kinases, in particular cyclin-dependent kinases such as CDK1, CDK2, CDK4 and CDK6 to mediate and/or inhibit cell proliferation. The invention further relates to pharmaceutical compositions containing such compounds and compositions, and methods of treating tumors and other disease states associated with unwanted angiogenesis and/or cell proliferation by administering an effective amount of such compounds.

背景技术Background technique

细胞增殖在对于各种刺激源的应答中出现，并可以由细胞分裂周期(或细胞周期)失去调控而引起，通过这个过程细胞成倍增加和分裂。高度增殖性疾病状态包括肿瘤的特征在于由于例如损伤了直接或间接地调节周期进展的基因，而使细胞具有不受控制的茁壮长势、在整个细胞周期不能控制地蔓延。这样，调节细胞周期和这种高度增殖的药剂，可用于治疗各种与不受控制的或有害的细胞增殖有关的疾病状态。Cell proliferation occurs in response to various stimuli and can result from deregulation of the cell division cycle (or cell cycle), by which cells multiply and divide. Hyperproliferative disease states include tumors characterized by uncontrolled proliferation of cells through the cell cycle due to, for example, damage to genes that directly or indirectly regulate cycle progression. Thus, agents that modulate the cell cycle and such hyperproliferation are useful in the treatment of a variety of disease states associated with uncontrolled or deleterious cell proliferation.

在细胞和分子水平上的细胞增殖的机理正处于积极的研究中：对于信号途径失去调控、细胞周期控制的丧失、不加拘束的血管生成或炎性途径的刺激进行了细胞水平的研究，而在分子水平上，这些过程是通过各种蛋白调节的，在这些蛋白中，蛋白激酶是突出的疑似物。增殖的总体减少还可以由编程性细胞死亡或细胞程序死亡产生，同时借助于多重途径对其进行调节，一些途径涉及蛋白水解酶蛋白。在候选的调控蛋白中，蛋白激酶是一族催化蛋白中特定的酪氨酸、丝氨酸或苏氨酸残基的羟基磷酸化的酶家族。典型地，这种磷酸化作用显著地干扰蛋白质的功能，并且这种蛋白激酶在多种细胞过程的调控中是关键性的。例如，不希望被特定理论所束缚，人们相信作为蛋白激酶例如依赖细胞周期蛋白的激酶(″CDK″)的抑制剂，本发明的药剂可以调节细胞RNA和DNA的合成水平，并因此可望有效用于治疗病毒感染例如HIV、人类乳头状瘤病毒、疱疹病毒、EB病毒、腺病毒、辛德毕斯病毒、痘病毒等等。(参见Schang，等人，J.Virol.74，2107-2120(2000))。另外，CDK5已经被认为包含在tau蛋白的磷酸化中，认为其是治疗或预防阿尔茨海默氏病的潜在方法(Hosoi，等人，J.Biochem.(Tokyo)，117，741-749(1995))。CDKs是在调节细胞周期的不同阶段之间的转变中起关键作用的丝氨酸-苏氨酸蛋白激酶，例如从G1(在有丝分裂和新一轮细胞分裂的DNA复制的起始之间的间隙)中的休眠期至S(活性DNA合成的阶段)的发展，或从G2到M阶段的发展，在此阶段中出现活跃的有丝分裂和细胞分裂。通过调控性细胞周期蛋白(cyclin)亚型(例如，细胞周期蛋白A，B1，B2，D1，D2，D3和E)与催化激酶亚型(例如，CDK1，CDK2，CDK4，CDK5和CDK6)的联合而形成CDK复合物。顾名思义，为了磷酸化CDKs的靶向底物，CDKs显示了对于细胞周期蛋白亚型的绝对依赖性，并且不同的激酶/细胞周期蛋白对在贯穿细胞周期的特定阶段起到调节进展的作用。Mechanisms of cell proliferation at the cellular and molecular levels are under active investigation: deregulated signaling pathways, loss of cell cycle control, unfettered angiogenesis, or stimulation of inflammatory pathways are studied at the cellular level, while At the molecular level, these processes are regulated by various proteins, among which protein kinases are prominent suspects. The overall reduction in proliferation can also result from apoptosis, or apoptosis, which is regulated by means of multiple pathways, some of which involve proteolytic enzyme proteins. Among candidate regulatory proteins, protein kinases are a family of enzymes that catalyze the hydroxyl phosphorylation of specific tyrosine, serine, or threonine residues in proteins. Typically, this phosphorylation significantly interferes with protein function, and such protein kinases are critical in the regulation of a variety of cellular processes. For example, without wishing to be bound by a particular theory, it is believed that, as inhibitors of protein kinases such as cyclin-dependent kinases ("CDKs"), the agents of the invention can modulate the level of cellular RNA and DNA synthesis and are thus expected to have Effective for the treatment of viral infections such as HIV, human papilloma virus, herpes virus, Epstein-Barr virus, adenovirus, Sindbis virus, pox virus, etc. (See Schang, et al., J. Virol. 74, 2107-2120 (2000)). In addition, CDK5 has been considered to be involved in the phosphorylation of tau protein, which is considered to be a potential method for the treatment or prevention of Alzheimer's disease (Hosoi, et al., J.Biochem.(Tokyo), 117, 741-749( 1995)). CDKs are serine-threonine protein kinases that play a key role in regulating transitions between different phases of the cell cycle, for example from G1 (the gap between mitosis and the initiation of DNA replication for a new round of cell division) The development from dormancy to S (the phase of active DNA synthesis), or from G2 to M phase, in which active mitosis and cell division occur. Through the interaction of regulatory cyclin isoforms (e.g., cyclin A, B1, B2, D1, D2, D3, and E) with catalytic kinase isoforms (e.g., CDK1, CDK2, CDK4, CDK5, and CDK6) Combine to form the CDK complex. As the name implies, CDKs display an absolute dependence on cyclin isoforms in order to phosphorylate their target substrates, and different kinase/cyclin pairs function to regulate progression through specific phases of the cell cycle.

已经确定大量吲唑衍生物具有潜在的疗效：GB 2345486公开了作为酪氨酸激酶抑制剂的吲唑衍生物，EP0518805确定了具有sigma受体活性的哌啶取代的吲唑；WO 89/43969公开了用作HI V蛋白酶抑制剂的环状脲的吲唑；US 4,415,569确定了具有支气管扩张作用的吡唑并吲唑衍生物；US 5,208,248公开了治疗偏头痛的吲唑。吲唑衍生物的其它治疗应用在WO 96/20192、EP 04994774、JP 60/004184、EP0023633、US 4051145、JP59/228248、GB 1/376600、US4978603、EP0904769和De Lucca等人的文献Journal of Medicinal Chemistry，42，135-52(1999)中得到了讨论。制备吲唑衍生物的一般合成反应路线由Wentrup等人在Joumal Organic Chemistry，43，2037-41(1978)和Fugimura等人在Chemical Abstracts，1070，749(1987)中公开。更详细地，已经确定3，5取代的吲唑为蛋白激酶抑制剂：WIPOInternational Publication No.01/85726公开了被1，1-二氧代异四氢噻唑取代的化合物作为CDK抑制剂；WO 02/10137公开了作为JunN-末端激酶抑制剂的抑制剂的3，5取代的吲唑；和美国专利No.6,555,539和WO 03/004488公开了在3位具有苯并咪唑的3，5取代的吲唑。A large number of indazole derivatives have been identified as potentially therapeutic: GB 2345486 discloses indazole derivatives as tyrosine kinase inhibitors, EP0518805 identifies piperidine-substituted indazoles with sigma receptor activity; WO 89/43969 discloses Indazoles used as cyclic ureas for HIV protease inhibitors; US 4,415,569 identified pyrazoloindazole derivatives with bronchodilation; US 5,208,248 disclosed indazoles for the treatment of migraine. Other therapeutic applications of indazole derivatives are described in WO 96/20192, EP 04994774, JP 60/004184, EP0023633, US 4051145, JP59/228248, GB 1/376600, US4978603, EP0904769 and Journal of Medicinal Chemistry by De Lucca et al. , 42, 135-52 (1999) are discussed. General synthetic schemes for the preparation of indazole derivatives are disclosed by Wentrup et al. in Journal Organic Chemistry, 43, 2037-41 (1978) and Fugimura et al. in Chemical Abstracts, 1070, 749 (1987). In more detail, 3,5-substituted indazoles have been identified as protein kinase inhibitors: WIPO International Publication No. 01/85726 discloses compounds substituted by 1,1-dioxoisotetrahydrothiazoles as CDK inhibitors; WO 02 /10137 discloses 3,5 substituted indazoles as inhibitors of Jun N-terminal kinase inhibitors; and U.S. Patent No. 6,555,539 and WO 03/004488 disclose 3,5 substituted indazoles having a benzimidazole at the 3 position azole.

然而还需要更有效的CDK抑制剂，具体地说，需要对于靶向CDK激酶具有高亲合性以及相对于其它蛋白激酶具有高选择性的CDK抑制剂。本发明的化合物对于CDK抑制剂通常比先前出版物中所描述的化合物更具选择性。There is however a need for more potent CDK inhibitors, in particular CDK inhibitors with high affinity for targeting CDK kinases and high selectivity over other protein kinases. Compounds of the invention are generally more selective for CDK inhibitors than compounds described in previous publications.

发明内容Contents of the invention

本发明的目的是提供有效和有选择性的CDK抑制剂。相应地，本发明的一个目的是获得能够抑制CDK活性的化合物和药物组合物，或它们的细胞周期蛋白复合物。进一步的目的是提供通过CDK抑制来治疗肿瘤适应症的有效的方法。另一个目的是获得含有化合物的药物组合物，该化合物能够有效阻断癌细胞转变到它们的增生期。本发明的这些及其它目的和优点将根据下面的详细说明而变得很明显，可以通过使用如下所述的本发明的细胞周期控制剂来实现这些目的和优点。The object of the present invention is to provide potent and selective CDK inhibitors. Accordingly, it is an object of the present invention to obtain compounds and pharmaceutical compositions capable of inhibiting the activity of CDKs, or their cyclin complexes. A further object is to provide effective methods of treating tumor indications by CDK inhibition. Another object is to obtain pharmaceutical compositions containing compounds capable of effectively blocking the transition of cancer cells into their proliferative phase. These and other objects and advantages of the present invention will become apparent from the following detailed description, and can be achieved by using the cell cycle control agents of the present invention as described below.

根据这些目的，按照本发明提供了式I的化合物或药学可接受的盐或溶剂化物：According to these objects, according to the present invention there is provided a compound of formula I or a pharmaceutically acceptable salt or solvate:

其中R¹、R²、R³和R⁴选自H，卤素，氰基，硝基，三氟甲氧基，三氟甲基，叠氮基，羟基，C₁-C₆烷氧基，C₁-C₁₀烷基，C₂-C₆烯基，C₂-C₆炔基，-C(O)R⁵，-C(O)OR⁵，-OC(O)R⁵，-NR⁵C(O)R⁶，-C(O)NR⁵R⁶，-(CR⁵R⁶)NR⁷R⁸，-CR⁵R⁶NR⁷R⁸，-NR⁵OR⁶，-SO₂NR⁵R⁶，-S(O)_j(C₁-C₆烷基)、其中j是0到2的整数，-(CR⁵R⁶)_t(C₆-C₁₀芳基)，-(CR⁵R⁶)_t(C₃-C₁₀环烷基)，-(CR⁵R⁶)_t(4-10元杂环)，-(CR⁵R⁶)_qC(O)(CR⁷R⁸)_t(C₆-C₁₀芳基)，-(CR⁵R⁶)_qC(O)(CR⁷R⁸)_t(C₃-C₁₀环烷基)，-(CR⁵R⁶)_qC(O)(CR⁷R⁸)_t(4-10元杂环)，-(CR⁵R⁶)_tO(CR⁷R⁸)_q(C₆-C₁₀芳基)，-(CR⁵R⁶)_tO(CR⁷R⁸)_q(C₃-C₁₀环烷基)，-(CR⁵R⁶)_tO(CR⁷R^g)_q(4-10元杂环)，-(CR⁵R⁶)_qSO₂(CR⁷R⁸)_t(C₆-C₁₀芳基)，-(CR⁵R⁶)_qSO₂(CR⁷R⁸)_t(C₃-C₁₀环烷基)和-(CR⁵R⁶)_qSO₂(CR⁷R⁸)_t(4-10元杂环)，其中q和t每个独立地是从0到5的整数，上述R¹、R²、R³或R⁴基团的环烷基或杂环部分的1或2个环碳原子任选被一个氧代(＝O)基团取代，每个R⁵、R⁶、R⁷和R⁸独立地选自H、C₁-C₆烷基；且其中R¹、R²、R³和R⁴不同时是H。wherein R¹ , R² , R³ and R⁴ are selected from H, halogen, cyano, nitro, trifluoromethoxy, trifluoromethyl, azido, hydroxyl, C₁ -C₆ alkoxy, C₁ -C₁₀ alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, -C(O)R⁵ , -C(O)OR⁵ , -OC(O)R⁵ , -NR⁵ C(O)R⁶ , -C(O)NR⁵ R⁶ , -(CR⁵ R⁶ )NR⁷ R⁸ , -CR⁵ R⁶ NR⁷ R⁸ , -NR⁵ OR⁶ , -SO₂ NR⁵ R⁶ , -S(O)_j (C₁ -C₆ alkyl), wherein j is an integer from 0 to 2, -(CR⁵ R⁶ )_t (C₆ -C₁₀ aryl), -(CR⁵ R⁶ )_t (C₃ -C₁₀ cycloalkyl), -(CR⁵ R⁶ )_t (4-10 membered heterocycle), -(CR⁵ R⁶ )_q C(O)(CR⁷ R⁸ )_t (C₆ -C₁₀ aryl), -(CR⁵ R⁶ )_q C(O)(CR⁷ R⁸ )_t (C₃ -C₁₀ cycloalkyl), -(CR⁵ R⁶ )_q C(O)(CR⁷ R⁸ )_t (4-10 membered heterocycle), -(CR⁵ R⁶ )_t O(CR⁷ R⁸ )_q (C₆ -C₁₀ aryl), -(CR⁵ R⁶ )_t O(CR⁷ R⁸ )_q (C₃ -C₁₀ cycloalkyl), -(CR⁵ R⁶ )_t O(CR⁷ R^g )_q (4-10 membered heterocycle), -( CR⁵ R⁶ )_q SO₂ (CR⁷ R⁸ )_t (C₆ -C₁₀ aryl), -(CR⁵ R⁶ )_q SO₂ (CR⁷ R⁸ )_t (C₃ -C₁₀ cycloalkane base) and -(CR⁵ R⁶ )_q SO₂ (CR⁷ R⁸ )_t (4-10 membered heterocyclic ring), wherein q and t are each independently an integer from 0 to 5, the above R¹ , R^2. 1 or 2 ring carbon atoms of the cycloalkyl or heterocyclic portion of the R³ or R⁴ group are optionally substituted by an oxo (=O) group, each of R⁵ , R⁶ , R⁷ and R⁸ is independently selected from H, C₁ -C₆ alkyl; and wherein R¹ , R² , R³ and R⁴ are not H at the same time.

在一个实施方案中，R¹是-(CR⁵R⁶)NR⁷R⁸，R²、R³和R⁴独立地选自H或F。In one embodiment, R¹ is -(CR⁵ R⁶ )NR⁷ R⁸ , and R² , R³ and R⁴ are independently selected from H or F.

在一个实施方案中，R¹是乙氨基甲基，R³是H，R²和R⁴是F。In one embodiment,^R1 is ethylaminomethyl,^R3 is H,^R2 and^R4 are F.

在另一个实施方案中，R¹是乙氨基甲基，R²和R⁴是H，R³是F。In another embodiment,^R1 is ethylaminomethyl,^R2 and^R4 are H, and^R3 is F.

在进一步的实施方案中，本发明涉及选自下列的化合物In a further embodiment, the present invention relates to compounds selected from the group consisting of

或

or

本发明还提供了用于制备式I化合物的方法。The present invention also provides processes for the preparation of compounds of formula I.

按照本发明进一步提供了使用作为细胞周期控制剂的化合物用于治疗由抑制激酶来介导的疾病或障碍的方法，包括给予需要它们的患者式I的化合物或式I化合物的药学可接受的盐或溶剂化物。There is further provided according to the present invention a method of using a compound as a cell cycle control agent for the treatment of a disease or disorder mediated by inhibition of a kinase comprising administering a compound of formula I or a pharmaceutically acceptable salt of a compound of formula I to a patient in need thereof or solvates.

本发明进一步提供了治疗真菌感染、癌或肿瘤以及其它与有害的血管生成和/或细胞增殖有关的疾病状态的方法，包括给予需要这种治疗的患者有效量的式I的化合物或式I化合物的药学可接受的盐或溶剂化物。The present invention further provides methods of treating fungal infections, cancers or tumors, and other disease states associated with unwanted angiogenesis and/or cell proliferation, comprising administering to a patient in need of such treatment an effective amount of a compound of formula I or a compound of formula I pharmaceutically acceptable salts or solvates of .

本发明还提供了通过给予需要的患者式I的化合物或式I化合物的药学可接受的盐或溶剂化物，有选择地抑制CDK激酶活性的方法。The present invention also provides a method of selectively inhibiting CDK kinase activity by administering a compound of formula I or a pharmaceutically acceptable salt or solvate of a compound of formula I to a patient in need thereof.

按照本发明还提供了含有式I化合物或式I化合物的药学可接受的盐或溶剂化物的药物组合物，和该组合物在治疗由激酶活性介导的疾病例如肿瘤以及其它与有害的血管生成和/或细胞增殖有关的疾病状态例如糖尿病性视网膜病、新生血管性青光眼、类风湿性关节炎和牛皮癣中的治疗用途。According to the present invention, there is also provided a pharmaceutical composition containing a compound of formula I or a pharmaceutically acceptable salt or solvate of a compound of formula I, and the composition is effective in treating diseases mediated by kinase activity such as tumors and other harmful angiogenesis and/or cell proliferation related disease states such as diabetic retinopathy, neovascular glaucoma, rheumatoid arthritis and psoriasis.

本发明的药剂和含有这种药剂的组合物可以用于治疗与不受控制的或有害的细胞增殖有关的各种障碍或疾病状态，例如肿瘤、自身免疫障碍、病毒性疾病、真菌性疾病、神经变性障碍和心血管疾病。因此，本发明还涉及通过给予有效量的本发明的药剂而治疗这种疾病的方法。Agents of the present invention and compositions containing such agents can be used to treat various disorders or disease states associated with uncontrolled or unwanted cell proliferation, such as tumors, autoimmune disorders, viral diseases, fungal diseases, Neurodegenerative disorders and cardiovascular disease. Accordingly, the present invention also relates to methods of treating such diseases by administering an effective amount of an agent of the present invention.

本发明的其它方面、优点和特征将从下面的详细说明中变得显而易见的。Other aspects, advantages and features of the invention will become apparent from the following detailed description.

本发明的化合物和组合物用作抗增殖药剂和作为哺乳动物的激酶复合物、昆虫激酶或真菌激酶复合物的抑制剂。例如，可以抑制CDK复合物。这种化合物和组合物还可用于控制增殖、分化和/或细胞程序死亡。The compounds and compositions of the invention are useful as anti-proliferative agents and as inhibitors of mammalian, insect or fungal kinase complexes. For example, CDK complexes can be inhibited. Such compounds and compositions are also useful for controlling proliferation, differentiation and/or apoptosis.

除非另有陈述，本文中使用的术语“卤素”是指氟、氯、溴或碘。优选的卤素基团是氟、氯和溴。As used herein, unless otherwise stated, the term "halogen" refers to fluorine, chlorine, bromine or iodine. Preferred halo groups are fluorine, chlorine and bromine.

除非另有陈述，本文中使用的术语“烷基”包括具有直链或支链部分的饱和一价烃基。“C₁-C₆烷基”表明具有1至6个碳原子的直链或支链烷基部分，等等。As used herein, unless otherwise stated, the term "alkyl" includes saturated monovalent hydrocarbon groups having straight or branched chain portions. "C₁ -C₆ alkyl" denotes a straight or branched chain alkyl moiety having 1 to 6 carbon atoms, and the like.

术语“烯基”是指链中具有2至12个碳原子的直链或支链烯基。例证性的烯基包括丙-2-烯基，丁-2-烯基，丁-3-烯基，2-甲基丙-2-烯基，己-2-烯基，乙烯基，戊烯基，等等。The term "alkenyl" refers to straight or branched chain alkenyl groups having 2 to 12 carbon atoms in the chain. Exemplary alkenyl groups include prop-2-enyl, but-2-enyl, but-3-enyl, 2-methylprop-2-enyl, hex-2-enyl, vinyl, pentene base, wait.

术语“炔基”是指链中具有2至12个碳原子的直链或支链炔基。例证性的炔基包括丙-2-炔基，丁-2-炔基，丁-3-炔基，2-甲基丁-2-炔基，己-2-炔基，乙炔基，丙炔基，戊炔基等等。The term "alkynyl" refers to straight or branched chain alkynyl groups having 2 to 12 carbon atoms in the chain. Exemplary alkynyl groups include prop-2-ynyl, but-2-ynyl, but-3-ynyl, 2-methylbut-2-ynyl, hex-2-ynyl, ethynyl, propyne base, pentynyl, etc.

术语“环烷基”是指每个环具有3到12个环原子的饱和或部分饱和的、单环或稠合或螺多环的碳环。环烷基说明的例子包括下面的部分：The term "cycloalkyl" refers to a saturated or partially saturated, monocyclic or fused or spiro polycyclic carbocyclic ring having 3 to 12 ring atoms per ring. Examples of cycloalkyl specifications include the following:

，等等。,etc.

除非另有陈述，本文中使用的术语“芳基”包括通过去除一个氢而衍生自芳香族烃的有机基团，例如苯基或萘基。As used herein, unless otherwise stated, the term "aryl" includes organic groups derived from aromatic hydrocarbons by removal of one hydrogen, such as phenyl or naphthyl.

除非另有陈述，本文中使用的术语“4-10元杂环”，包括含有一到四个杂原子的芳烃和非芳烃的杂环基团，每个杂原子选自O、S和N，其中每个杂环基团在其环系中具有4-10个原子，并且条件是所述基团的环不含有两个邻接的O或S原子。非芳烃杂环基团包括在其环系中只具有4个原子的基团，但是芳族杂环基团必须在其环系中具有至少5个原子。杂环基团包括苯并稠环系统。4元杂环基团的例子是氮杂环丁烷基(衍生自氮杂环丁烷)。5元杂环基团的例子是噻唑基、10元杂环基团的例子是喹啉基。非芳族杂环基团的例子是吡咯烷基、四氢呋喃基、二氢呋喃基、四氢噻吩基、四氢吡喃基、二氢吡喃基、四氢硫代吡喃基、哌啶基、吗啉代，硫代吗啉代，噻噁烷基，哌嗪基，氮杂环丁烷基，氧杂环丁烷基，硫杂环丁烷基，高哌啶基，氧杂环庚烷基(oxepanyl)，硫杂环庚烷基(thiepanyl)，氧杂氮杂基，二氮杂基，硫杂氮杂基，1，2，3，6-四氢吡啶基，2-吡咯啉基，3-吡咯啉基，二氢吲哚基，2H-吡喃基，4H-吡喃基，二噁烷基，1，3-二氧戊环基，吡唑啉基，二噻烷基，二硫戊环基，二氢吡喃基，二氢噻吩基，二氢呋喃基，吡唑烷基，咪唑啉基，咪唑烷基，3-氮杂双环[3.1.0]己烷基，3-氮杂双环[4.1.0]庚烷基，3H-吲哚基和喹嗪基。芳香杂环基团的例子是吡啶基，咪唑基，嘧啶基，吡唑基，三唑基，吡嗪基，四唑基，呋喃基，噻吩基，异噁唑基，噻唑基，噁唑基，异噻唑基，吡咯基，喹啉基，异喹啉基，吲哚基，苯并咪唑基，苯并呋喃基，噌啉基，吲唑基，茚嗪基，酞嗪基，哒嗪基，三嗪基，异氮茚基，喋啶基，嘌呤基，噁二唑基，噻二唑基，呋咱基，苯并呋咱基，苯并噻吩基，苯并噻唑基，苯并噁唑基，喹唑啉基，喹喔啉基，萘啶基和呋喃并吡啶基。上述基团，当衍生自上面所列出的基团时，可以是C连接的或N连接的，当这样的连接是可能的情况下。例如，衍生自吡咯的基团可以是吡咯-1-基(N连接的)或吡啶-3-基(C连接的)。另外，衍生自咪唑的基团可以是咪唑-1-基(N连接的)或咪唑-3-基(C连接的)。4-10元杂环可以是任选在每个环的任何环碳、硫或氮原子上被一至两个氧代取代的。其中2个环碳原子被氧代部分取代的杂环基团的例子是1，1-二氧代-硫代吗啉基。4-10元杂环的其它例证性例子衍生自、但不局限于下面的基团：Unless otherwise stated, the term "4-10 membered heterocycle" as used herein includes aromatic and non-aromatic heterocyclic groups containing from one to four heteroatoms, each heteroatom selected from O, S and N, wherein each heterocyclic group has 4-10 atoms in its ring system, with the proviso that the ring of said group does not contain two adjacent O or S atoms. Non-aromatic heterocyclic groups include groups having only 4 atoms in their ring system, but aromatic heterocyclic groups must have at least 5 atoms in their ring system. Heterocyclic groups include benzofused ring systems. An example of a 4 membered heterocyclic group is azetidinyl (derived from azetidine). An example of a 5-membered heterocyclic group is thiazolyl, and an example of a 10-membered heterocyclic group is quinolinyl. Examples of non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuryl, dihydrofuryl, tetrahydrothiophenyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl , Morpholino, Thiomorpholino, Thioxanyl, Piperazinyl, Azetidinyl, Oxetanyl, Thietanyl, Homopiperidinyl, Oxepinyl Alkyl (oxepanyl), thiepanyl (thiepanyl), oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridyl, 2 -pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, di Thianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuryl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexyl Alkyl, 3-azabicyclo[4.1.0]heptanyl, 3H-indolyl and quinozinyl. Examples of aromatic heterocyclic groups are pyridyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl , isothiazolyl, pyrrolyl, quinolinyl, isoquinolyl, indolyl, benzimidazolyl, benzofuryl, cinnolinyl, indazolyl, indenazinyl, phthalazinyl, pyridazinyl , triazinyl, isoindolyl, pteridyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothienyl, benzothiazolyl, benzoxa Azolyl, quinazolinyl, quinoxalinyl, naphthyridinyl and furopyridyl. The above groups, when derived from the groups listed above, may be C-attached or N-attached, where such linkage is possible. For example, a group derived from pyrrole may be pyrrol-1-yl (N-attached) or pyridin-3-yl (C-attached). Additionally, a group derived from imidazole may be imidazol-1-yl (N-attached) or imidazol-3-yl (C-attached). The 4-10 membered heterocyclic rings may be optionally substituted with one to two oxo on any ring carbon, sulfur or nitrogen atom per ring. An example of a heterocyclic group in which 2 ring carbon atoms are substituted with an oxo moiety is 1,1-dioxo-thiomorpholinyl. Other illustrative examples of 4-10 membered heterocycles are derived from, but not limited to, the following groups:

和and

除非另有陈述，术语“氧代”是指＝O。Unless otherwise stated, the term "oxo" refers to =O.

术语“酰胺”是指基团-C(O)N(R′)(R″)，其中R′和R″每个独立地选自氢，烷基，烯基，炔基，-OH，烷氧基，环烷基，杂环烷基，杂芳基，芳基，如上所述；或R′和R″与氮一起环化形成如上所述的杂环烷基或杂芳基。The term "amide" refers to the group -C(O)N(R')(R"), wherein R' and R" are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, -OH, alkane Oxy, cycloalkyl, heterocycloalkyl, heteroaryl, aryl, as described above; or R' and R" are cyclized with nitrogen to form a heterocycloalkyl or heteroaryl as described above.

术语“取代的”是指带有一或多个取代基的指定的基团或部分。术语“未取代的”是指不带有取代基的指定的基团。The term "substituted" refers to a designated group or moiety bearing one or more substituents. The term "unsubstituted" refers to a designated group that bears no substituents.

在本发明中，很清楚式I的化合物可以显示出互变异构的现象，而且本说明书中的分子式图仅仅代表了可能的互变异构形式中的一种。应理解本发明包括任何调节和/或抑制激酶活性的互变异构形式，并且不被仅仅限制于所使用的分子式图中的任何一种互变异构形式。In the present invention, it is clear that compounds of formula I may exhibit the phenomenon of tautomerism and that the formula diagrams in this specification represent only one of the possible tautomeric forms. It is to be understood that the present invention encompasses any tautomeric form that modulates and/or inhibits kinase activity, and is not limited to any one tautomeric form in the formula schemes used.

本发明的一些化合物可以以单一立体异构体(即，基本上不含其它立体异构体)、消旋体、和/或对映体和/或非对映体的混合物的形态存在。所有这种单一立体异构体、消旋体和它们的混合物将被规定为在本发明的范围内。优选，以旋光纯的形式使用本发明的光学活性化合物。Some of the compounds of the present invention may exist as single stereoisomers (ie, substantially free of other stereoisomers), racemates, and/or mixtures of enantiomers and/or diastereomers. All such single stereoisomers, racemates and mixtures thereof are intended to be within the scope of this invention. Preferably, the optically active compounds according to the invention are used in optically pure form.

正如本领域技术人员通常所理解的那样，具有一个手性中心(即，一个不对称碳原子)的旋光纯化合物基本上由两个可能的对映体中的一个组成(即，对映体纯的)，并且具有一个以上手性中心的旋光纯的化合物既是非对映体纯的又是对映体纯的。优选，以至少90％旋光纯的形式使用本发明的化合物，即，含有至少90％单一异构体(80％对映体过量(“e.e.”)或非对映体过量(“d.e.”))，更优选至少95％(90％e.e.或d.e.)，更加优选至少97.5％(95％e.e.或d.e.)，最优选至少99％(98％e.e.或d.e.)的形式。As generally understood by those skilled in the art, an optically pure compound having one chiral center (i.e., an asymmetric carbon atom) consists essentially of one of two possible enantiomers (i.e., enantiomerically pure ), and optically pure compounds with more than one chiral center are both diastereomeric and enantiomerically pure. Preferably, the compounds of the invention are used in at least 90% optically pure form, i.e., containing at least 90% of a single isomer (80% enantiomeric excess ("e.e.") or diastereomeric excess ("d.e.")). , more preferably at least 95% (90% e.e. or d.e.), still more preferably at least 97.5% (95% e.e. or d.e.), most preferably at least 99% (98% e.e. or d.e.) form.

另外，通式I和II意在包括溶剂化物以及所确定结构的未溶剂化的形式。例如，通式I和II包括以水合与非水合形式的所示结构的化合物。溶剂化物的其它例子包括与异丙醇、乙醇、甲醇、DMSO、乙酸乙酯、乙酸或乙醇胺结合的结构。Additionally, Formulas I and II are intended to include solvates as well as unsolvated forms of the identified structures. For example, general formulas I and II include compounds of the shown structures in both hydrated and non-hydrated forms. Other examples of solvates include structures associated with isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, or ethanolamine.

术语“药学可接受的盐”是指保持具体化合物的游离酸和碱的生物有效性的盐，而且不是生物学不合需要的或其它不合需要的盐。本发明的化合物可以具备足够酸性、足够碱性的基团，或这两种官能团，并相应地与许多无机或有机碱、无机和有机酸的任一种反应，形成药学可接受的盐。典型的药学可接受的盐包括本发明的化合物与无机或有机酸或无机碱反应制备的盐，例如盐包括，硫酸盐，焦硫酸盐，硫酸氢盐，亚硫酸盐，亚硫酸氢盐，磷酸盐，磷酸一氢盐，磷酸二氢盐，偏磷酸盐，焦磷酸盐，氯化物，溴化物，碘化物，醋酸盐，丙酸盐，癸酸盐，辛酸盐，丙烯酸盐，甲酸盐，异丁酸盐，己酸盐，庚酸盐，丙炔酸盐，草酸盐，丙二酸盐，琥珀酸盐，辛二酸盐，癸二酸盐，富马酸盐，马来酸盐，丁炔-1，4-二酸盐，己炔-1，6-二酸盐，苯甲酸盐，氯苯甲酸盐，甲基苯甲酸盐，二硝基苯甲酸盐，羟基苯甲酸盐，甲氧基苯甲酸盐，邻苯二甲酸盐，磺酸盐，二甲苯磺酸盐，苯乙酸盐，苯丙酸盐，苯基丁酸盐，柠檬酸盐，乳酸盐，γ-羟基丁酸盐，乙醇酸盐，酒石酸盐，甲磺酸盐，丙磺酸盐，萘-1-磺酸盐，萘-2-磺酸盐，和扁桃酸盐。The term "pharmaceutically acceptable salt" refers to salts that retain the biological effectiveness of the free acids and bases of the specified compound and which are not biologically or otherwise undesirable. The compounds of the present invention may possess sufficiently acidic, sufficiently basic groups, or both functional groups, and accordingly react with any of a number of inorganic or organic bases, inorganic and organic acids to form pharmaceutically acceptable salts. Typical pharmaceutically acceptable salts include salts prepared by reacting the compounds of the present invention with inorganic or organic acids or inorganic bases, for example, salts include, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphoric acid Salt, Monohydrogen Phosphate, Dihydrogen Phosphate, Metaphosphate, Pyrophosphate, Chloride, Bromide, Iodide, Acetate, Propionate, Caprate, Caprylate, Acrylate, Formic Acid Salt, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate Butyne-1,4-dioate, Hexyne-1,6-dioate, Benzoate, Chlorobenzoate, Methylbenzoate, Dinitrobenzoate , Hydroxybenzoate, Methoxybenzoate, Phthalate, Sulfonate, Xylenesulfonate, Phenylacetate, Phenylpropionate, Phenylbutyrate, Citric Acid Salt, lactate, gamma-hydroxybutyrate, glycolate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, and mandelate .

如果本发明的化合物是一种碱，所需要的药学可接受的盐可以通过任何本领域现有的合适方法来制备，例如用无机酸处理游离碱，无机酸例如盐酸，氢溴酸，硫酸，硝酸，磷酸等等，或用有机酸处理，例如乙酸，马来酸，琥珀酸，扁桃酸，富马酸，丙二酸，pyrovicacid，草酸，羟基乙酸，水杨酸，吡喃糖苷酸例如葡糖醛酸或半乳糖醛酸，α-羟基酸例如柠檬酸或酒石酸，氨基酸例如天冬氨酸或谷氨酸，芳香酸例如苯甲酸或肉桂酸，磺酸例如对甲苯磺酸或乙磺酸，等等。If the compound of the present invention is a base, the desired pharmaceutically acceptable salt can be prepared by any suitable method known in the art, such as treatment of the free base with a mineral acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, Nitric acid, phosphoric acid, etc., or treated with organic acids such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyrovicacid, oxalic acid, glycolic acid, salicylic acid, pyranosidic acid such as glucosinolate Uronic acid or galacturonic acid, alpha-hydroxy acid such as citric acid or tartaric acid, amino acid such as aspartic acid or glutamic acid, aromatic acid such as benzoic acid or cinnamic acid, sulfonic acid such as p-toluenesulfonic acid or ethanesulfonic acid ,etc.

如果本发明的化合物是酸，所需要的药学可接受的盐可以通过任何合适的方法来制备，例如，用无机或有机碱例如胺(伯，仲或叔)、碱金属氢氧化物或碱土金属氢氧化物等等处理游离酸。合适的盐的说明例子包括：衍生自氨基酸例如甘氨酸和精氨酸、氨、伯、仲和叔胺和环胺比如哌啶、吗啉和哌嗪的有机盐，和衍生自钠、钙、钾、镁、锰、铁、铜、锌、铝和锂的无机盐。If the compound of the present invention is an acid, the desired pharmaceutically acceptable salt can be prepared by any suitable method, for example, with an inorganic or organic base such as an amine (primary, secondary or tertiary), an alkali metal hydroxide or an alkaline earth metal Hydroxides etc. treat free acids. Illustrative examples of suitable salts include: organic salts derived from amino acids such as glycine and arginine, ammonia, primary, secondary and tertiary amines and cyclic amines such as piperidine, morpholine and piperazine, and those derived from sodium, calcium, potassium , inorganic salts of magnesium, manganese, iron, copper, zinc, aluminum and lithium.

在药剂是固体的情况下，本领域技术人员可以知道，本发明的化合物和盐可以以不同的结晶或多晶型物存在，所有这些都被规定为在本发明和具体公式范围内。Where the agent is a solid, those skilled in the art will appreciate that the compounds and salts of the invention may exist in different crystalline or polymorphic forms, all of which are intended to be within the scope of the invention and the particular formulae.

按照本发明的细胞周期控制剂用作治疗哺乳动物特别是人类的增殖障碍的药物，这种障碍以有害的内原性组织增殖为标志。式I的化合物可以用于治疗患有与过量细胞增殖有关的病症的患者，这些病症为例如肿瘤、牛皮癣、涉及不希望有的白细胞增殖的免疫障碍和再狭窄及其它平滑肌障碍。此外，这种化合物可以用来预防有丝分裂后组织和/或细胞的解除分化。The cell cycle control agents according to the invention are useful as medicaments for the treatment of proliferative disorders in mammals, especially humans, which are marked by unwanted endogenous tissue proliferation. Compounds of formula I may be used in the treatment of patients suffering from disorders associated with excessive cell proliferation such as tumors, psoriasis, immune disorders involving unwanted proliferation of leukocytes and restenosis and other smooth muscle disorders. In addition, such compounds can be used to prevent dedifferentiation of post-mitotic tissues and/or cells.

与不受控制的或异常的细胞增殖有关的疾病或障碍包括但不局限于下列：Diseases or disorders associated with uncontrolled or abnormal cell proliferation include, but are not limited to the following:

-各种肿瘤包括但不限于癌、淋巴系统的生血肿瘤、骨髓系统的生血肿瘤、间质源肿瘤、中枢和周围神经系统肿瘤及其它肿瘤包括黑素瘤、精原细胞瘤和皮肤多发性出血性肉瘤等等。- Various tumors including but not limited to carcinoma, hematopoietic tumors of the lymphatic system, hematopoietic tumors of the myeloid system, tumors of mesenchymal origin, tumors of the central and peripheral nervous system and other tumors including melanoma, seminoma and multiple hemorrhages of the skin sarcoma etc.

-以异常细胞增殖为特征的疾病病变，例如良性前列腺肥大、家族性腺瘤息肉病、神经纤维瘤病、动脉粥样硬化、肺纤维化、关节炎、牛皮癣、肾小球肾炎、血管成形术或血管手术后的再狭窄、肥厚性瘢痕形成物、炎症性肠病、移植排斥、内毒素性休克和真菌感染。- Disease lesions characterized by abnormal cell proliferation, such as benign prostatic hypertrophy, familial adenomatous polyposis, neurofibromatosis, atherosclerosis, pulmonary fibrosis, arthritis, psoriasis, glomerulonephritis, angioplasty, or Restenosis, hypertrophic scar formation, inflammatory bowel disease, graft rejection, endotoxic shock, and fungal infection after vascular surgery.

-与有缺陷的细胞程序死亡关联的病症，例如肿瘤(包括但不局限于上文提及的那些类型)、病毒感染(包括但不局限于疱疹病毒、痘病毒、EB病毒、辛德毕斯病毒和腺病毒)、HI V感染个体中的AIDS发展的预防、自身免疫疾病(包括但不局限于系统性红斑狼疮、类风湿性关节炎、牛皮癣、自身免疫介导的肾小球肾炎、炎症性肠病和自身免疫糖尿病)、神经变性的障碍(包括但不局限于阿尔茨海默氏病、肌萎缩性侧索硬化、色素性视网膜炎、帕金森氏症、AIDS-相关的痴呆、脊髓性肌萎缩和小脑退化)、脊髓发育不良综合征、再生障碍性贫血、与心肌梗塞有关的缺血性损伤、中风和再灌注损伤、心律失常、动脉粥样硬化、毒素引起的或酒精相关的肝脏疾病。- Conditions associated with defective apoptosis such as tumors (including but not limited to those types mentioned above), viral infections (including but not limited to herpesviruses, poxviruses, Epstein-Barr virus, Sindbis virus and adenovirus), prevention of AIDS development in HIV-infected individuals, autoimmune diseases (including but not limited to systemic lupus erythematosus, rheumatoid arthritis, psoriasis, autoimmune-mediated glomerulonephritis, inflammatory bowel disease disease and autoimmune diabetes), neurodegenerative disorders (including but not limited to Alzheimer's disease, amyotrophic lateral sclerosis, retinitis pigmentosa, Parkinson's disease, AIDS-related dementia, spinal muscular atrophy and cerebellar degeneration), myelodysplastic syndrome, aplastic anemia, ischemic injury related to myocardial infarction, stroke and reperfusion injury, cardiac arrhythmia, atherosclerosis, toxin-induced or alcohol-related liver disease .

-血液学的疾病(包括但不局限于长期贫血和再生障碍性贫血)、肌骨胳系统的退行性疾病(包括但不局限于骨质疏松和关节炎)、阿斯匹林敏感性鼻窦炎、囊性纤维化、多发性硬化、肾脏疾病和肿瘤疼痛。- Hematological diseases (including but not limited to chronic anemia and aplastic anemia), degenerative diseases of the musculoskeletal system (including but not limited to osteoporosis and arthritis), aspirin-sensitive sinusitis , cystic fibrosis, multiple sclerosis, kidney disease and tumor pain.

本发明的活性剂还可以有效用于抑制侵入肿瘤的发展、肿瘤血管生成和转移。The agents of the invention are also effective in inhibiting the development of invasive tumors, tumor angiogenesis and metastasis.

此外，本发明的活性剂例如作为CDKs的抑制剂，可以调节细胞RNA和DNA合成的水平，并因此预计其可有效用于治疗病毒感染例如HIV、人类乳头状瘤病毒、疱疹病毒、EB病毒、腺病毒、辛德毕斯病毒、痘病毒等等。In addition, the active agent of the present invention, for example, as an inhibitor of CDKs, can regulate the level of cellular RNA and DNA synthesis, and thus it is expected to be effective in the treatment of viral infections such as HIV, human papilloma virus, herpes virus, Epstein-Barr virus, Adenovirus, Sindbis virus, poxvirus, etc.

本发明的化合物和组合物抑制例如CDK/细胞周期蛋白复合物的激酶活性，这种复合物为例如那些在细胞周期的G0或G1阶段的活性物，例如CDK2、CDK4和/或CDK6复合物。The compounds and compositions of the invention inhibit the kinase activity of, for example, CDK/cyclin complexes, such as those active in the G0 or G1 phase of the cell cycle, such as CDK2, CDK4 and/or CDK6 complexes.

为了获得治疗或抑制效果，所给予的细胞周期控制剂的具体剂量可以用本领域已知的方式、按照围绕病例的特定环境来确定，包括例如所给予的具体药剂、给药途径、所治疗的病症和所治疗的患者或宿主。可以以单一或多剂量给予细胞周期控制剂的示范性的总的日剂量，含有从约0.01mg/kg体重至约50mg/kg体重的剂量水平。To achieve a therapeutic or inhibitory effect, the specific dose of cell cycle control agent administered can be determined in a manner known in the art according to the particular circumstances surrounding the case, including, for example, the particular agent administered, the route of administration, the Condition and patient or host treated. Exemplary total daily dosages of cell cycle control agents may be administered in single or multiple doses, containing dosage levels of from about 0.01 mg/kg body weight to about 50 mg/kg body weight.

本发明的细胞周期控制剂可以通过多种合适途径的任何一种给予，例如口服、直肠、透皮、皮下、静脉内、肌肉内、或鼻内给予。优选，在给予之前，将细胞周期控制剂配制成为适合于所要求途径的组合物。The cell cycle control agents of the invention may be administered by any of a variety of suitable routes, such as oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, or intranasal administration. Preferably, the cell cycle control agent is formulated in a composition suitable for the desired route prior to administration.

按照本发明的药物组合物或制剂包括有效量的细胞周期控制剂、任选一或多种其它活性剂和药学可接受的载体，例如用于药剂的稀释剂或赋形剂；当载体作为稀释剂时，它可以是固体、半固体、或起赋形剂作用的液体物质、赋形剂、或活性组分的介质。按照本发明的组合物可以通过将活性组分与载体混合，或用载体将它稀释，或将它密封或封装在载体之内来制备，其可以以胶囊、小袋、纸容器等等的形式存在。典型的组分，除一或多种细胞周期控制剂和任何其它活性组分之外，包括微晶纤维素(微晶纤维素)，淀粉，乳糖，硫酸钙二水合物，石膏粉，蔗糖，滑石粉，明胶，琼脂，果胶，阿拉伯胶，硬脂酸镁，硬脂酸，花生油，橄榄油，单硬脂酸甘油酯，Tween 80(聚山梨酸酯80)，1，3-丁二醇，可可脂，蜂蜡，聚乙二醇，丙二醇，单硬脂酸山梨糖醇酐酯，聚山梨酸酯60，2-辛基十二烷醇，苯甲醇，甘氨酸，山梨酸，山梨酸钾，磷酸氢二钠，氯化钠，和水。The pharmaceutical composition or preparation according to the present invention includes an effective amount of a cell cycle control agent, optionally one or more other active agents and a pharmaceutically acceptable carrier, such as a diluent or excipient for a medicament; when the carrier is used as a diluent When administered, it may be a solid, semi-solid, or liquid substance that functions as a vehicle, excipient, or medium for the active ingredient. The compositions according to the invention can be prepared by admixing the active ingredient with a carrier, or diluting it with a carrier, or sealing or encapsulating it in a carrier, which may be in the form of a capsule, sachet, paper container, etc. . Typical ingredients, in addition to one or more cell cycle control agents and any other active ingredient, include microcrystalline cellulose (microcrystalline cellulose), starch, lactose, calcium sulfate dihydrate, terra alba, sucrose, Talc, Gelatin, Agar, Pectin, Gum Arabic, Magnesium Stearate, Stearic Acid, Peanut Oil, Olive Oil, Glyceryl Monostearate, Tween 80 (Polysorbate 80), 1,3-Butanedi Alcohol, Cocoa Butter, Beeswax, Macrogol, Propylene Glycol, Sorbitan Monostearate, Polysorbate 60, 2-Octyldodecanol, Benzyl Alcohol, Glycine, Sorbic Acid, Potassium Sorbate , disodium hydrogen phosphate, sodium chloride, and water.

组合物可以按照各种适合于所需要的给予方式的形式中的任一种来制备。例如，药物组合物可以以下列形式制备：片剂，药丸，粉末，糖锭，小袋，扁囊剂，酏剂，悬浮液，乳状液，溶液，糖浆，气雾剂(以固体或液体作为介质)，油膏(例如，按重量计算，含有至多10％的细胞周期控制剂)，软凝胶和硬凝胶胶囊，栓剂，无菌注射溶液，无菌包装粉末等等。The compositions can be prepared in any of a variety of forms suitable for the desired mode of administration. For example, pharmaceutical compositions can be prepared in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (with a solid or liquid medium) ), ointments (eg, containing up to 10% by weight of a cell cycle control agent), soft and hard gel capsules, suppositories, sterile injectable solutions, sterile packaged powders, and the like.

类似地，载体或稀释剂可以包括本领域已知的延时或按时释放的物质，例如单硬脂酸甘油酯或二硬脂酸甘油酯，其可以单独使用或与石蜡、乙基纤维素、羟丙基甲基纤维素、异丁烯酸甲脂等等混合。Similarly, the carrier or diluent may include delay or time release substances known in the art, such as glyceryl monostearate or glyceryl distearate, alone or with paraffin, ethyl cellulose, Hydroxypropyl methylcellulose, methyl methacrylate, etc. are mixed.

可以使用各种药物形式。因此，如果使用固体载体，制剂可以是片剂，以粉末或小丸的形式放置入硬明胶胶囊中，或是锭剂或糖锭的形式。固体载体的量可以改变，但通常从约25mg至约1g。如果使用液体载体，制剂可以是糖浆、乳状液、软明胶胶囊、放在安瓿或小瓶中的无菌注射溶液或悬浮液或非水液体悬浮液。Various drug forms are available. Thus, if a solid carrier is used, the preparation can be tableted, placed in a hard gelatine capsule in powder or pellet form, or in the form of a troche or lozenge. The amount of solid carrier will vary but will generally be from about 25 mg to about 1 g. If a liquid carrier is used, the preparation can be a syrup, emulsion, soft gelatin capsule, sterile injectable solution or suspension in ampoules or vials, or a non-aqueous liquid suspension.

为了得到稳定的水溶性剂量形式，将发明药剂的药学可接受的盐溶于有机或无机酸的水溶液中，例如0.3M琥珀酸或柠檬酸的溶液。如果可溶性盐的形式不适宜，可以将药剂溶于合适的共溶剂或共溶剂的组合中。合适的共溶剂的例子包括，但不局限于，浓度范围从总体积的0-60％的乙醇，丙二醇，聚乙二醇300，聚山梨酸酯80，甘油等等。式I的化合物可以溶于DMSO中并用水稀释。组合物还可以是在合适的含水赋形剂例如水或等渗盐水或葡萄糖溶液中的活性组分形成的盐的溶液形式。To obtain stable water-soluble dosage forms, a pharmaceutically acceptable salt of an inventive agent is dissolved in an aqueous solution of an organic or inorganic acid, such as a 0.3M solution of succinic or citric acid. If the form of a soluble salt is not suitable, the agent can be dissolved in a suitable co-solvent or combination of co-solvents. Examples of suitable co-solvents include, but are not limited to, ethanol, propylene glycol, polyethylene glycol 300, polysorbate 80, glycerol, and the like in concentrations ranging from 0-60% by total volume. Compounds of formula I can be dissolved in DMSO and diluted with water. The composition may also be in the form of a solution of a salt of the active ingredient in a suitable aqueous vehicle, such as water or isotonic saline or dextrose solution.

本发明的组合物可以用通常已知的制备药物组合物的方式来制备，例如，使用常规方法例如混合，溶解，造粒，生产糖衣丸，研磨，乳化，封装，收集或冷冻干燥。药物组合物可以用常规的方式、使用一或多种生理学可接受的载体来配制，该载体可以选自那些便于加工活性化合物成为药学可使用的制剂的赋形剂和助剂。The compositions of the present invention can be prepared in a generally known manner for the preparation of pharmaceutical compositions, for example, using conventional methods such as mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, collecting or freeze-drying. Pharmaceutical compositions may be formulated in a conventional manner using one or more physiologically acceptable carriers selected from excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically.

适当的制剂取决于所选择的给药途径。对于注射剂，可以将本发明的药剂配制成为水溶液，优选用生理学相容的缓冲液例如Hanks′s溶液，林格溶液，或生理盐水缓冲液。对于透粘膜给药，在制剂中使用对于所渗透的屏障合适的渗透剂。这样的渗透剂通常在本领域是已知的。Proper formulation is dependent on the route of administration chosen. For injection, the agent of the present invention can be formulated as an aqueous solution, preferably with a physiologically compatible buffer such as Hanks's solution, Ringer's solution, or physiological saline buffer. For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.

对于口服给药，可以容易地通过将活性化合物与本领域已知的药学可接受的载体混合来配制。这样的载体能够将本发明的化合物配制为片剂，药丸，糖衣丸，胶囊，液体，凝胶剂，糖浆，浆液，悬浮液等等，通过所治疗的患者进行口服摄取。口服使用的药物制剂可以按照下列方式得到：使用固体赋形剂与活性组分(药剂)的混合物，任选研磨所得到的混合物，加入合适的助剂之后加工颗粒剂的混合物，如果需要的话，得到片剂或糖衣丸芯。合适的赋形剂包括：填料例如糖，包括乳糖，蔗糖，甘露糖醇或山梨糖醇；纤维素制剂例如，玉米淀粉，小麦淀粉，玉米淀粉，马铃薯淀粉，明胶，树胶，羟丙基甲基-纤维素，羧甲基纤维素钠，甲基纤维素或聚乙烯吡咯烷酮(PVP)。如果需要的话，可以加入崩解剂，例如交联的聚乙烯基吡咯烷酮，琼脂或藻酸或其盐，例如藻酸钠。For oral administration, it can be formulated readily by combining the active compounds with pharmaceutically acceptable carriers known in the art. Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated. Pharmaceutical preparations for oral use can be obtained by using a mixture of a solid excipient and the active ingredient (medicament), optionally grinding the resulting mixture, processing the mixture of granules after adding suitable auxiliaries, if desired, Tablets or dragee cores are obtained. Suitable excipients include: fillers such as sugars, including lactose, sucrose, mannitol or sorbitol; cellulose preparations such as corn starch, wheat starch, corn starch, potato starch, gelatin, gums, hydroxypropylmethyl - cellulose, sodium carboxymethylcellulose, methylcellulose or polyvinylpyrrolidone (PVP). If desired, disintegrants, such as cross-linked polyvinylpyrrolidone, agar or alginic acid or a salt thereof, such as sodium alginate, may be added.

糖衣丸芯具有合适的包衣。为了这个目的，可以使用浓缩糖溶液，其可以任选地含有阿拉伯树胶，聚乙烯基吡咯烷酮，聚羧乙烯凝胶，聚乙二醇和/或二氧化钛，漆溶液，和合适的有机溶剂或溶剂混合物。为了鉴别或为了表征不同的活性剂的组合，可以将染料或颜料加入到片剂或糖衣丸包衣中。Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, polyvinylpyrrolidone, carbopol gel, polyethylene glycol and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments can be added to the tablets or dragee coatings for identification or to characterize different combinations of active agents.

可用于口服的药物制剂包括由明胶制成的推合座(push-fit)胶囊，以及由明胶和增塑剂例如甘油或山梨糖醇制成的软的密封胶囊。推合座胶囊可以含有活性组分与填料例如乳糖、粘合剂例如淀粉、和/或润滑剂例如滑石粉或硬脂酸镁、和任选的稳定剂的混合物。在软胶囊中，可以将活性剂溶解或悬浮在合适的液体例如脂肪族的油类、液体石蜡或液体聚乙二醇中。另外，可以加入稳定剂。所有用于口服的制剂应该按适合于这种给药的剂量。对于口腔含化给药，组合物可以采取以常规方式配制的片剂或糖锭的形式。Pharmaceutical preparations which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active agents may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. All formulations for oral administration should be in dosages suitable for such administration. For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner.

对于鼻内给药或通过吸入给药，按照本发明使用的化合物可以借助于合适的推进剂例如二氯二氟甲烷、三氯氟甲烷、二氯四氟乙烷、二氧化碳或其它合适的气体，由气溶胶包装或喷雾器以气溶胶喷射给予的形式方便地给予。在加压气雾剂的情况下，可以通过提供一种可递送计量量的阀来确定剂量单位。用于吸入器或吹入器等等的胶囊和明胶柱体可以被配制成含有化合物与合适的粉末基质例如乳糖或淀粉的粉末混合物。For intranasal administration or administration by inhalation, the compounds used according to the invention may be administered with the aid of suitable propellants such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gases, It is conveniently administered in the form of an aerosol spray from an aerosol pack or nebuliser. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve that delivers a metered amount. Capsules and gelatin cartridges for use in an inhaler or insufflator and the like may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.

可以将化合物配制成通过注射肠胃外给药的形式，例如，通过快速浓注或连续输液。用于注射的制剂可以存在于单位剂型中，例如在加入防腐剂的安瓿或多剂量容器中。组合物可以采用在油状或含水赋形剂中的悬浮液、溶液或乳状液的形式，并且可以含有调配试剂例如悬浮、稳定化和/或分散剂。The compounds may be formulated for parenteral administration by injection, eg, by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, eg, in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.

用于肠胃外给药的药学制剂包括水溶性形式的活性化合物的水溶液。另外，可以将活性剂的悬浮液制备成合适的油状注射悬浮液。合适的亲脂性溶剂或赋形剂包括脂肪族的油类例如芝麻油，或合成脂肪酸酯，例如油酸乙酯或甘油三酯，或脂质体。含水注射悬浮液中可以含有增加悬浮液粘度的物质，例如羧甲基纤维素钠，山梨糖醇或右旋糖酐。任选地，悬浮液还可以含有合适的稳定剂或增加化合物的溶解度的试剂，以允许高浓度溶液的制备。Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active agents may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include aliphatic oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.

对于眼部给药，活性剂是在药学可接受的眼用赋形剂中给予的，这样化合物可以与眼睛表面保持接触一段充分的时间，以使化合物渗入眼的角膜和内部区域，包括，例如，前房，后房，玻璃体，水状体，玻璃体液，角膜，虹膜/眼睫毛，晶状体，脉络膜/视网膜和巩膜。药学可接受的眼用赋形剂可以是油膏，植物油或密封材料。还可以将本发明的化合物直接注入到玻璃体和水状体内。For ocular administration, the active agent is administered in a pharmaceutically acceptable ophthalmic vehicle such that the compound remains in contact with the surface of the eye for a period of time sufficient to allow the compound to penetrate the cornea and inner regions of the eye, including, for example , anterior chamber, posterior chamber, vitreous, aqueous humor, vitreous humor, cornea, iris/eyelashes, lens, choroid/retina and sclera. Pharmaceutically acceptable ophthalmic excipients can be ointments, vegetable oils or sealants. The compounds of the invention may also be injected directly into the vitreous and aqueous humor.

或者，使用之前，活性组分可以是粉末形式，用于与合适的赋形剂例如无菌、无热原的水组合。还可以将化合物以直肠组合物例如栓剂或滞留灌肠剂的形式配制，例如，含有常规的栓剂基料例如可可脂或其它甘油脂。Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, eg sterile, pyrogen-free water, before use. The compounds may also be formulated in rectal compositions such as suppositories or retention enemas, eg, containing conventional suppository bases such as cocoa butter or other glycerides.

还可以将化合物配制为长效制剂。这种长效制剂可以通过植入法给予(例如，皮下或肌肉内)或通过肌肉注射给予。因此，例如，化合物可以与合适的聚合或疏水性材料(例如，在可接受的油中的乳状液)或离子交换树脂进行配制，或以微溶的衍生物，例如微溶的盐的形式。The compounds can also be formulated as a depot preparation. Such long-acting formulations may be administered by implantation (eg, subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (eg, as emulsions in acceptable oils) or ion exchange resins, or as sparingly soluble derivatives, eg, as sparingly soluble salts.

用于疏水化合物的药学载体是包括苯甲醇、非极性表面活性剂、与水可互溶的有机聚合物和水相的共溶剂系统。共溶剂系统可以是VPD共溶剂系统。VPD是3％w/v的苯甲醇、8％w/v的非极性表面活性剂聚山梨酸酯80和65％的w/v聚乙二醇300的溶液，用纯乙醇补偿体积的溶液。VPD共溶剂系统(VPD：5W)含有用5％葡萄糖水溶液稀释的1：1的VPD。这个共溶剂系统能很好地溶解疏水化合物，并且在全身给予时，其本身产生低毒性。自然地，在没有破坏其溶解度和毒性特征的条件下，共溶剂系统的比例可以显著地改变。此外，共溶剂组分的特性可以改变：例如，可以使用其它低毒性的非极性表面活性剂代替聚山梨酸酯80；聚乙二醇的片断大小可以改变；其它生物相容的聚合物可以替代聚乙二醇，例如聚乙烯基吡咯烷酮；其它糖或多糖可以代替葡萄糖。The pharmaceutical carrier for hydrophobic compounds is a co-solvent system comprising benzyl alcohol, non-polar surfactant, water-miscible organic polymer and an aqueous phase. The co-solvent system may be a VPD co-solvent system. VPD is a solution of 3% w/v benzyl alcohol, 8% w/v non-polar surfactant polysorbate 80 and 65% w/v polyethylene glycol 300, made up to volume with pure ethanol . The VPD co-solvent system (VPD: 5W) contained VPD diluted 1:1 with 5% dextrose in water. This co-solvent system dissolves hydrophobic compounds well and itself produces low toxicity when administered systemically. Naturally, the proportions of a co-solvent system can vary considerably without destroying its solubility and toxicity characteristics. In addition, the properties of the co-solvent components can be changed: for example, other less toxic non-polar surfactants can be used in place of polysorbate 80; the fragment size of polyethylene glycol can be changed; other biocompatible polymers can be Instead of polyethylene glycol, such as polyvinylpyrrolidone; other sugars or polysaccharides can replace glucose.

或者，可以使用其它用于疏水性药学化合物的递送系统。脂质体和乳状液是递送疏水性药物的赋形剂或载体的已知的例子。还可以使用某些有机溶剂例如二甲亚砜，尽管通常以更大的毒性为代价。另外，可以使用缓释系统递送化合物，例如含有治疗剂的固体疏水性聚合物的半透性基质。已经确定了各种缓释材料，并且为本领域技术人员所了解。根据缓释胶囊的化学性质，缓释胶囊可以释放化合物几周直到超过100天。根据治疗试剂的化学性质和生物学稳定性，可以使用其它使蛋白质稳定化的策略。Alternatively, other delivery systems for hydrophobic pharmaceutical compounds can be used. Liposomes and emulsions are known examples of vehicles or carriers for the delivery of hydrophobic drugs. Certain organic solvents such as dimethylsulfoxide can also be used, although usually at the expense of greater toxicity. Additionally, the compounds can be delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent. Various sustained release materials have been identified and are known to those skilled in the art. Depending on the chemical nature of the sustained release capsule, the sustained release capsule may release the compound for several weeks up to over 100 days. Depending on the chemical nature and biological stability of the therapeutic agent, other strategies for protein stabilization may be used.

药物组合物还可以包括合适的固体或凝胶相载体或赋形剂。这种载体或赋形剂的例子包括碳酸钙，磷酸钙，糖，淀粉，纤维素衍生物，明胶和聚合物例如聚乙二醇。The pharmaceutical composition may also include suitable solid or gel phase carriers or excipients. Examples of such carriers or excipients include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives, gelatin and polymers such as polyethylene glycol.

以与药学相容的相反离子所成的盐的形式，可以提供一些本发明的化合物。可以与许多酸包括盐酸、硫酸、乙酸、乳酸、酒石酸、苹果酸、琥珀酸等等形成药学相容的盐。盐比相应的游离碱形式倾向于更易溶于水或其它质子溶剂。Some of the compounds of the invention may be provided in the form of salts with pharmaceutically compatible counterions. Pharmaceutically compatible salts can be formed with many acids, including hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, and the like. Salts tend to be more soluble in water or other protic solvents than the corresponding free base forms.

按照本发明的药物组合物包括细胞周期控制剂和任选的一或多种其它活性组分，例如与细胞周期控制剂相容并适合于所治疗的适应症的已知的抗增殖药剂。A pharmaceutical composition according to the invention comprises a cell cycle control agent and optionally one or more other active ingredients, such as known anti-proliferative agents compatible with the cell cycle control agent and appropriate for the indication being treated.

该化合物用作抗血管生成药剂并作为调节和/或抑制蛋白激酶活性的药剂，从而为肿瘤或其它与蛋白激酶介导的细胞增殖有关的其它疾病提供治疗。The compounds are useful as anti-angiogenic agents and as agents that modulate and/or inhibit protein kinase activity, thereby providing therapy for tumors or other diseases associated with protein kinase-mediated cell proliferation.

可以使用治疗有效量的本发明药剂来治疗蛋白激酶的调整或调节所介导的疾病。“有效量”是指，当给予需要这种治疗的哺乳动物时，足以实施治疗一或多种激酶活性所介导的疾病的量。因此，例如，式I化合物、其盐、活性代谢物或前体药物的治疗有效量，是足够调整、调节或抑制一或多种激酶活性的数量，这样可以减轻或缓解由该活性所介导的疾病症状。Modulation of protein kinases or diseases mediated by modulation can be treated with therapeutically effective amounts of agents of the invention. "Effective amount"means an amount sufficient to effect treatment of a disorder mediated by the activity of one or more kinases when administered to a mammal in need of such treatment. Thus, for example, a therapeutically effective amount of a compound of formula I, a salt, active metabolite or prodrug thereof, is an amount sufficient to modulate, modulate or inhibit the activity of one or more kinases such that the activity mediated by that activity is alleviated or alleviated. disease symptoms.

“治疗”是指最低限度地缓解由一或多种激酶活性影响、至少部分影响的哺乳动物例如人类的疾病状况，包括：预防哺乳动物出现疾病状况，特别是当发现哺乳动物倾向于患有该疾病状况、但还没有做出诊断时；调节和/或抑制疾病状况；和/或减轻疾病状况。"Treatment" means minimally ameliorating a disease condition in a mammal, such as a human, that is affected, at least in part, by the activity of one or more kinases, including the prevention of a disease condition in a mammal, particularly when the mammal is found to be predisposed to the disease condition When a disease condition has not been diagnosed; modulates and/or inhibits a disease condition; and/or alleviates a disease condition.

在本文描述的本发明方法的任一项具体实施方案中，异常的细胞生长是癌，包括但不限于肺癌，骨癌，胰腺癌，皮肤癌，头或颈癌，皮肤或眼内的黑素瘤，子宫癌，卵巢癌，直肠癌，肛区癌，胃癌，结肠癌，乳腺癌，子宫癌，输卵管癌，子宫内膜癌，宫颈癌，阴道癌，外阴癌，淋巴肉芽肿病，食道癌，小肠癌，内分泌系统癌，甲状腺癌，甲状旁腺癌，肾上腺癌，软组织肉瘤，尿道癌，阴茎癌，前列腺癌，慢性或急性白血病，淋巴细胞性淋巴瘤，膀胱癌，肾或输尿管癌，肾细胞癌，肾盂癌，中枢神经系统(CNS)肿瘤，原发性CNS淋巴瘤，脊骨轴肿瘤，脑干神经胶质瘤，垂体腺瘤，或一或多种上述肿瘤的组合。在所述方法的另一个实施方案中，所述异常的细胞生长是良性增殖疾病，包括但不限于牛皮癣、良性前列腺肥大或restinosis。In any specific embodiment of the methods of the invention described herein, the abnormal cell growth is cancer, including but not limited to lung cancer, bone cancer, pancreatic cancer, skin cancer, head or neck cancer, melanoma of the skin or eye tumor, uterine cancer, ovarian cancer, rectal cancer, anal region cancer, stomach cancer, colon cancer, breast cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, lymphogranulomatous disease, esophageal cancer , small bowel cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal gland cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, chronic or acute leukemia, lymphocytic lymphoma, bladder cancer, kidney or ureter cancer, Renal cell carcinoma, renal pelvis carcinoma, central nervous system (CNS) tumor, primary CNS lymphoma, spinal axis tumor, brainstem glioma, pituitary adenoma, or a combination of one or more of the foregoing. In another embodiment of the method, the abnormal cell growth is a benign proliferative disease including but not limited to psoriasis, benign prostatic hypertrophy or restinosis.

在本文描述的任一项本发明方法的进一步具体实施方案中，该方法进一步包括给予哺乳动物一定量的一或多种选自抗肿瘤药剂、抗血管生成药剂、信号转导抑制剂和抗增殖药剂的物质，该数量在所述异常细胞生长的治疗中同时有效。本发明的化合物可以与其它抗肿瘤药剂相结合，这样的方法公开在WO038716、WO038717、WO038715、WO038730、WO038718、WO038665、WO037107、WO038786、WO038719中，以它们的全部将其内容引入本文中作为参考。抗肿瘤药剂的例子包括有丝分裂抑制剂，例如长春花生物碱衍生物例如长春花碱、长春瑞宾、长春地辛和长春新碱；秋水仙碱类allochochine、软海绵素(halichondrine)、N-苯甲酰基三甲基-秋水仙酸甲醚、多拉司他汀(dolastatin)10、美坦生、rhizoxine，紫杉烷类例如紫杉醇(太平洋紫杉醇)、多烯紫杉醇(泰索帝)、2′-N-[3-(二甲基氨基)丙基]戊二酸酯(紫杉醇衍生物)、硫代秋水仙碱、三苯甲基半胱氨酸、替尼泊苷、氨甲喋呤、硫唑嘌呤、氟苷、阿糖胞苷、2′2′-二氟脱氧胞苷(吉西他滨)、阿霉素和丝裂霉素。烷基化剂，例如顺铂、卡铂oxiplatin、异丙铂、N-乙酰基-DL-十二烷基肌氨酸钠-L-亮氨酸乙酯(Asaley或Asalex)、1，4-环己二烯-1，4-二氨基甲酸、2，5-二(1-氮丙啶基)-3，6-二氧代-二乙酯(地吖醌)、1，4-二(甲磺酰氧基)丁烷(bisulfan或leucosulfan)氯脲菌素、氯乙矾(clomesone)、氰基吗啉基阿霉素、cyclodisone、去水卫矛醇(dianhydroglactitol)、氟多潘、hepsulfam、丝裂霉素C、羟胺硫蒽酮丝裂霉素C、mitozolamide、1-(2-氯乙基)-4-(3-氯丙基)-哌嗪二盐酸盐、哌嗪二酮、双溴丙基哌嗪、波福霉素、螺妥因芥(spirohydantoin mustard)、替罗昔隆、奥马铂、硫替派、三乙烯亚胺三嗪、尿嘧啶氮芥、二(3-甲磺酰氧基丙基)胺盐酸盐、丝裂霉素、亚硝基脲药例如环己基-氯乙基亚硝基脲、甲基环己基-氯乙基亚硝基脲1-(2-氯乙基)-3-(2，6-二氧代-3-哌啶基)-1-亚硝基脲、二(2-氯乙基)亚硝基脲、普鲁苄肼、氮烯唑胺、氮芥相关的化合物例如盐酸氮芥、环磷酰胺、异环磷酰胺、苯丙氨酸氮芥、苯丁酸氮芥、雌氮芥磷酸钠、链脲霉素和替莫唑胺。DNA抗代谢物，例如5-氟尿嘧啶，阿糖胞苷，羟基脲，2-[(3-羟基-2-吡啶基(pyrinodinyl))亚甲基]-肼羰基硫酰胺，脱氧氟尿苷，5-羟基-2-甲酰吡啶缩氨基硫脲，α-2’-脱氧-6-硫鸟苷，阿非迪霉素甘氨酸盐，5-氮杂脱氧胞苷，β-硫鸟嘌呤脱氧核糖核苷，环胞苷，胍唑，肌苷乙二醇二醛，macbecin II，吡唑并咪唑(pyrazolimidazole)，克拉屈滨，喷司他丁，硫鸟嘌呤，巯基嘌呤，争光霉素，2-氯脱氧腺苷，胸苷酸合酶抑制剂例如雷替曲塞和培美曲唑二钠，clofarabine，5-氟脱氧尿苷和氟达拉滨。DNA/RNA代谢拮抗剂，例如：L-丙氨菌素，5-氮胞苷，阿西维辛，氨基蝶呤和它们的衍生物例如N-[2-氯-5-[[(2，4-二氨基-5-甲基-6-喹唑啉基)甲基]氨基]苯甲酰基]-L-天冬氨酸，N-[4-[[(2，4-二氨基-5-乙基-6-喹唑啉基)甲基]氨基]苯甲酰基]-L-天冬氨酸，N-[2-氯-4-[[(2，4-二氨基喋啶基)甲基]氨基]苯甲酰基]-L-天冬氨酸，可溶性三嗪苯酰胺，二氯烯丙基指甲花醌，布喹那，呋氟啶，二氢-5-氮胞苷，氨甲喋呤，N-(膦酰乙酰基)-L-天冬氨酸四钠盐，吡唑并呋喃，三甲曲沙，普卡霉素，放线菌素D，cryptophycin(一种缩酚酸肽类抗肿瘤药)，和类似物例如cryptophycin-52或，例如在欧洲专利申请No.239362中公开的优选的抗代谢物之一例如N-(5-[N-(3，4-二氢-2-甲基-4-氧代喹唑啉-6-基甲基)-N-甲基氨基)-2-噻吩甲酰)-L-谷氨酸；生长因子抑制剂；细胞周期抑制剂；嵌入抗生素(intercalating antibiotics)，例如阿霉素和争光霉素；蛋白，例如干扰素；和抗激素，例如抗雌激素比如Nolvadex^TM(三苯氧胺)或，例如抗雄激素比如Casodex^TM(4’-氰基-3-(4-氟苯基磺酰基)-2-羟基-2-甲基-3’-(三氟甲基)丙酰替苯胺)。这种联合治疗可以通过同时、顺序或分开剂量给予治疗的单独成分的方式实现。In a further specific embodiment of any one of the methods of the invention described herein, the method further comprises administering to the mammal an amount of one or more agents selected from the group consisting of antineoplastic agents, antiangiogenic agents, signal transduction inhibitors, and antiproliferative agents. A substance of a medicament, the amount simultaneously effective in the treatment of said abnormal cell growth. The compounds of the present invention may be combined with other antineoplastic agents, such methods are disclosed in WO038716, WO038717, WO038715, WO038730, WO038718, WO038665, WO037107, WO038786, WO038719, the contents of which are incorporated herein by reference in their entirety. Examples of antineoplastic agents include mitotic inhibitors such as vinca alkaloid derivatives such as vinblastine, vinorelbine, vindesine and vincristine; colchicines allochochine, halichondrine, N-benzene Formyltrimethyl-colchicate methyl ether, dolastatin (dolastatin)10, maytansin, rhizoxine, taxanes such as paclitaxel (paclitaxel), docetaxel (taxotere), 2′- N-[3-(dimethylamino)propyl]glutarate (paclitaxel derivative), thiocolchicine, tritylcysteine, teniposide, methotrexate, azathioprine, Fluoridine, cytarabine, 2'2'-difluorodeoxycytidine (gemcitabine), doxorubicin, and mitomycin. Alkylating agents such as cisplatin, carboplatin oxiplatin, isoproplatin, N-acetyl-DL-sarcosinate-L-leucine ethyl ester (Asaley or Asalex), 1,4- Cyclohexadiene-1,4-dicarbamic acid, 2,5-bis(1-aziridinyl)-3,6-dioxo-diethyl ester (deacroquinone), 1,4-bis( Methanesulfonyloxy)butane (bisulfan or leucosulfan), chlorurecin, clomesone, cyanomorpholino doxorubicin, cyclodisone, dianhydroglactitol, fludopan, hepsulfam , Mitomycin C, Lucanthone Mitomycin C, Mitozolamide, 1-(2-Chloroethyl)-4-(3-Chloropropyl)-Piperazine Dihydrochloride, Piperazine Dione , dibromopropylpiperazine, boformycin, spirohydantoin mustard, tiroxiron, omaplatin, thiotepa, triethyleneimine triazine, uracil mustard, two (3- Methanesulfonyloxypropyl)amine hydrochloride, mitomycin, nitrosourea drugs such as cyclohexyl-chloroethylnitrosourea, methylcyclohexyl-chloroethylnitrosourea 1-( 2-chloroethyl)-3-(2,6-dioxo-3-piperidinyl)-1-nitrosourea, bis(2-chloroethyl)nitrosourea, procarbazine, Dacarbazine, nitrogen mustard-related compounds such as mechlorethamine hydrochloride, cyclophosphamide, ifosfamide, melphalan, chlorambucil, estramustine, streptozotocin, and temozolomide. DNA antimetabolites such as 5-fluorouracil, cytarabine, hydroxyurea, 2-[(3-hydroxy-2-pyrinodinyl)methylene]-hydrazine carbonylsulfamide, deoxyfluridine, 5 -Hydroxy-2-formylpyridylthiosemicarbazone, α-2'-deoxy-6-thioguanosine, aphidicolin glycinate, 5-azadeoxycytidine, β-thioguanine deoxyribose glycoside, cyclocytidine, guanazole, inosine glycol dialdehyde, macbecin II, pyrazolimidazole (pyrazolimidazole), cladribine, pentostatin, thioguanine, mercaptopurine, bleomycin, 2- Chlorodeoxyadenosine, thymidylate synthase inhibitors such as raltitrexed and pemetrexole disodium, clofarabine, 5-fluorodeoxyuridine and fludarabine. Antagonists of DNA/RNA metabolism, such as: L-Alanamectin, 5-azacytidine, acivicin, aminopterin and their derivatives such as N-[2-chloro-5-[[(2, 4-Diamino-5-methyl-6-quinazolinyl)methyl]amino]benzoyl]-L-aspartic acid, N-[4-[[(2,4-diamino-5 -Ethyl-6-quinazolinyl)methyl]amino]benzoyl]-L-aspartic acid, N-[2-chloro-4-[[(2,4-diaminopteridinyl) Methyl]amino]benzoyl]-L-aspartic acid, soluble triazinebenzamide, dichloroallylmethanone, buquinal, furfluridine, dihydro-5-azacytidine, methotrexate , N-(phosphonoacetyl)-L-aspartic acid tetrasodium salt, pyrazolofuran, trimetrexate, plicamycin, actinomycin D, cryptophycin (a depsipeptide anti- tumor drug), and analogues such as cryptophycin-52 or, for example, one of the preferred antimetabolites disclosed in European Patent Application No. 239362 such as N-(5-[N-(3,4-dihydro-2- Methyl-4-oxoquinazolin-6-ylmethyl)-N-methylamino)-2-thienoyl)-L-glutamic acid; growth factor inhibitor; cell cycle inhibitor; intercalating antibiotic (intercalating antibiotics), such as doxorubicin and bleomycin; proteins, such as interferons; and antihormones, such as antiestrogens such as Nolvadex^™ (tamoxifen) or, such as antiandrogens such as Casodex^™ (4'-cyano- 3-(4-fluorophenylsulfonyl)-2-hydroxy-2-methyl-3'-(trifluoromethyl)propionanilide). Such combination therapy may be achieved by administering the individual components of the therapy simultaneously, sequentially or in divided doses.

抗血管生成药剂包括MMP-2(基质-金属蛋白酶2)抑制剂、MMP-9(基质-金属蛋白酶9)抑制剂和COX-II(环加氧酶II)抑制剂。有效的COX-II抑制剂的例子包括CELEBREX^TM(alecoxib)、伐地考昔和罗非考昔。有效的基质金属蛋白酶抑制剂的例子描述在下列文献中：WO 96/33172(1996年10月24日公开)，WO 96/27583(1996年3月7日公开)，欧洲专利申请No.97304971.1(1997年7月8日申请)，欧洲专利申请No.99308617.2(1999年10月29日申请)，WO 98/07697(1998年2月26日公开)，WO 98/03516(1998年1月29日公开)，WO98/34918(1998年8月13日公开)，WO 98/34915(1998年8月13日公开)，WO 98/33768(1998年8月6日公开)，WO 98/30566(1998年7月16日公开)，欧洲专利出版物EP 606,046(1994年7月13日公开)，欧洲专利出版物EP 931,788(1999年7月28日公开)，WO90/05719(1990年5月31日公开)，WO 99/52910(1999年10月21日公开)，WO 99/52889(1999年10月21日公开)，WO 99/29667(1999年6月17日公开)，PCT国际申请No.PCT/IB98/01113(1998年7月21日申请)，欧洲专利申请No.99302232.1(1999年3月25日申请)，大不列颠专利申请编号9912961.1(1999年6月3日申请)，美国临时申请No.60/148,464(1999年8月12日申请)，美国专利US5,863,949(1999年1月26日公告)，美国专利US 5,861,510(1999年1月19日公告)，和欧洲专利出版物EP 780,386(1997年6月25日公开)，所有这些以其全部引入本文中作为参考。优选的MMP-2和MMP-9抑制剂是那些具有很少或不具有抑制MMP-1活性的抑制剂。更更优选的是那些相对于其它基质-金属蛋白酶类(即MMP-1，MMP-3，MMP-4，MMP-5，MMP-6，MMP-7，MMP-8，MMP-10，MMP-11，MMP-12和MMP-13)选择性的抑制MMP-2和/或MMP-9的那些。Anti-angiogenic agents include MMP-2 (matrix-metalloproteinase 2) inhibitors, MMP-9 (matrix-metalloproteinase 9) inhibitors and COX-II (cyclooxygenase II) inhibitors. Examples of effective COX-II inhibitors include CELEBREX^™ (alecoxib), valdecoxib and rofecoxib. Examples of effective matrix metalloproteinase inhibitors are described in WO 96/33172 (published October 24, 1996), WO 96/27583 (published March 7, 1996), European Patent Application No. 97304971.1 ( filed on July 8, 1997), European Patent Application No. 99308617.2 (applied on October 29, 1999), WO 98/07697 (published on February 26, 1998), WO 98/03516 (on January 29, 1998 published), WO98/34918 (published on August 13, 1998), WO 98/34915 (published on August 13, 1998), WO 98/33768 (published on August 6, 1998), WO 98/30566 (published on August 1998), published on July 16, 1994), European Patent Publication EP 606,046 (published on July 13, 1994), European Patent Publication EP 931,788 (published on July 28, 1999), WO90/05719 (published on May 31, 1990 Publication), WO 99/52910 (published on October 21, 1999), WO 99/52889 (published on October 21, 1999), WO 99/29667 (published on June 17, 1999), PCT International Application No. PCT/IB98/01113 (filed July 21, 1998), European Patent Application No. 99302232.1 (filed March 25, 1999), Great Britain Patent Application No. 9912961.1 (filed June 3, 1999), U.S. Provisional Application No. .60/148,464 (applied August 12, 1999), U.S. Patent No. 5,863,949 (announced January 26, 1999), U.S. Patent No. 5,861,510 (announced January 19, 1999), and European Patent Publication EP 780,386 (published June 25, 1997), all of which are incorporated herein by reference in their entirety. Preferred MMP-2 and MMP-9 inhibitors are those that have little or no MMP-1 inhibiting activity. Even more preferred are those relative to other matrix-metalloproteases (i.e. MMP-1, MMP-3, MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, MMP-10, MMP- 11, MMP-12 and MMP-13) those that selectively inhibit MMP-2 and/or MMP-9.

信号转导抑制剂的例子包括可以抑制EGFR(表皮生长因子受体)反应的药剂，例如EGFR抗体、EGF抗体和EGFR抑制剂分子；VEGF(血管内皮生长因子)抑制剂；和erbB2受体抑制剂，例如与erbB2受体结合的有机分子或抗体，例如HERCEPTIN^TM(Genentech，Inc.of SouthSan Francisco，California，USA)。Examples of signal transduction inhibitors include agents that can inhibit EGFR (epidermal growth factor receptor) responses, such as EGFR antibodies, EGF antibodies, and EGFR inhibitor molecules; VEGF (vascular endothelial growth factor) inhibitors; and erbB2 receptor inhibitors , such as organic molecules or antibodies that bind to the erbB2 receptor, such as HERCEPTIN^™ (Genentech, Inc. of South San Francisco, California, USA).

EGFR抑制剂在例如下列文献中作出了描述：WO 95/19970(1995年7月27日公开)，WO 98/14451(1998年4月9日公开)，WO98/02434(1998年1月22日公开)，和美国专利US 5,747,498(1998年5月5日公告)。EGFR抑制剂包括但不局限于单克隆抗体C225和抗EGFR 22Mab(ImClone Systems incorporated of New York，New York，USA)，化合物ZD-1839(AstraZeneca)，BIBX-1382(BoehringerIngelheim)，MDX-447(Medarex Inc.of Annandale，New Jersey，USA)，和OLX-103(Merck&Co.of Whitehouse Station，New Jersey，USA)，VRCTC-310(Ventech Research)和EGF融合毒素(Seragen Inc.ofHopkinton，Massachusettes)。VEGF抑制剂，例如SU-5416和SU-6668，(Sugen Inc.of South San Francisco，California，USA)，也可以与式I的化合物合并或共同给予。VEGF抑制剂描述在例如下列文献中：WO 99/24440(1999年5月20日公开)，PCT国际申请PCT/IB99/00797(1999年5月3日申请)，WO 95/21613(1995年8月17日公开)，WO 99/61422(1999年12月2日公开)，美国专利US5,834,504(1998年11月10日公告)，WO98/50356(1998年11月12日公开)，美国专利US 5,883,113(1999年3月16日公告)，美国专利US 5,886,020(1999年3月23日公告)，美国专利US5,792,783(1998年8月11日公告)，WO 99/10349(1999年3月4日公开)，WO 97/32856(1997年9月12日公开)，WO 97/22596(1997年6月26日公开)，WO 98/54093(1998年12月3日公开)，WO98/02438(1998年1月22日公开)，WO 99/16755(1999年4月8日公开)，和WO 98/02437(1998年1月22日公开)，所有这些以其全部引入本文中作为参考。一些具体VEGF抑制剂的其它例子是IM862(CytranInc.of Kirkland，Washington，USA)；Genentech，Inc.of SouthSan Francisco，California的抗VEGF单克隆抗体；和angiozyme，一种源于核糖酶(Boulder，Colorado)和Chiron(Emeryville，California)的合成核糖酶。ErbB2受体抑制剂，例如GW-282974(GlaxoWelcome pic)，和单克隆抗体AR-209(Aronex Pharmaceuticals Inc.of The Woodlands，Texas，USA)和2B-1(Chiron)，可以与式I化合物的组合给予。这种erbB2抑制剂包括在下列文献中所描述的那些：WO 98/02434(1998年1月22日公开)，WO99/35146(1999年7月15日公开)，WO 99/35132(1999年7月15日公开)，WO 98/02437(1998年1月22日公开)，WO 97/13760(1997年4月17日公开)，WO95/19970(1995年7月27日公开)，美国专利US 5,587,458(1996年12月24日公告)，和美国专利US 5,877,305(1999年3月2日公告)，每篇以其整体引入到本文中作为参考。在本发明中有效的ErbB2受体抑制剂也描述在下列文献中：美国临时申请No.60/117,341，1999年1月27日申请，和1999年1月27日申请的美国临时申请No.60/117,346，所有这两篇以其全部引入本文中作为参考。EGFR inhibitors are described, for example, in WO 95/19970 (published July 27, 1995), WO 98/14451 (published April 9, 1998), WO98/02434 (published January 22, 1998) Open), and U.S. Patent US 5,747,498 (announced on May 5, 1998). EGFR inhibitors include but are not limited to monoclonal antibody C225 and anti-EGFR 22Mab (ImClone Systems incorporated of New York, New York, USA), compound ZD-1839 (AstraZeneca), BIBX-1382 (BoehringerIngelheim), MDX-447 (Medarex Inc. of Annandale, New Jersey, USA), and OLX-103 (Merck & Co. of Whitehouse Station, New Jersey, USA), VRCTC-310 (Ventech Research) and EGF fusion toxin (Seragen Inc. of Hopkinton, Massachusetts). VEGF inhibitors, such as SU-5416 and SU-6668, (Sugen Inc. of South San Francisco, California, USA), may also be combined or co-administered with compounds of formula I. VEGF inhibitors are described, for example, in the following documents: WO 99/24440 (published May 20, 1999), PCT International Application PCT/IB99/00797 (filed May 3, 1999), WO 95/21613 (published on August 1995), Published on November 17), WO 99/61422 (published on December 2, 1999), U.S. Patent No. 5,834,504 (announced on November 10, 1998), WO98/50356 (published on November 12, 1998), U.S. Patent US 5,883,113 (announced on March 16, 1999), US Patent US 5,886,020 (announced on March 23, 1999), US Patent US5,792,783 (announced on August 11, 1998), WO 99/10349 (announced on March 1999 4), WO 97/32856 (published on September 12, 1997), WO 97/22596 (published on June 26, 1997), WO 98/54093 (published on December 3, 1998), WO98/02438 (published on January 22, 1998), WO 99/16755 (published on April 8, 1999), and WO 98/02437 (published on January 22, 1998), all of which are incorporated herein by reference in their entirety. Other examples of some specific VEGF inhibitors are IM862 (Cytran Inc. of Kirkland, Washington, USA); an anti-VEGF monoclonal antibody from Genentech, Inc. of South San Francisco, California; and angiozyme, a ribozyme derived (Boulder, Colorado ) and Chiron (Emeryville, California) synthetic ribozymes. ErbB2 receptor inhibitors, such as GW-282974 (GlaxoWelcome pic), and monoclonal antibodies AR-209 (Aronex Pharmaceuticals Inc. of The Woodlands, Texas, USA) and 2B-1 (Chiron), can be combined with the compound of formula I give. Such erbB2 inhibitors include those described in the following documents: WO 98/02434 (published on January 22, 1998), WO 99/35146 (published on July 15, 1999), WO 99/35132 (published on July 1999), Published on January 15), WO 98/02437 (published on January 22, 1998), WO 97/13760 (published on April 17, 1997), WO95/19970 (published on July 27, 1995), U.S. Patent US 5,587,458 (issued December 24, 1996), and US Patent No. 5,877,305 (issued March 2, 1999), each of which is incorporated herein by reference in its entirety. ErbB2 receptor inhibitors useful in the present invention are also described in U.S. Provisional Application No. 60/117,341, filed January 27, 1999, and U.S. Provisional Application No. 60, filed January 27, 1999 /117,346, both of which are incorporated herein by reference in their entirety.

可以使用的其它抗增殖药剂包括法呢基蛋白质转移酶的酶抑制剂和受体酪氨酸激酶PDGFr的抑制剂，包括下面美国专利申请所公开和要求的化合物：09/221946(1998年12月28日申请)；09/454058(1999年12月2日申请)；09/501163(2000年2月9日申请)；09/539930(2000年3月31日申请)；09/202796(1997年5月22日申请)；09/384339(1999年8月26日申请)；和09/383755(1999年8月26日申请)；和下面的美国临时专利申请所公开和要求的化合物：60/168207(1999年11月30日申请)；60/170119(1999年12月10日申请)；60/177718(2000年1月21日申请)；60/168217(1999年11月30日申请)，和60/200834(2000年5月1日申请)。前面的专利申请和临时专利申请的每一篇以其整体引入本文中作为参考。Other antiproliferative agents that may be used include enzyme inhibitors of farnesyl protein transferase and inhibitors of the receptor tyrosine kinase PDGFr, including the compounds disclosed and claimed in the following U.S. Patent Application: 09/221946 (December 1998 28); 09/454058 (filed 2 December 1999); 09/501163 (filed 9 February 2000); 09/539930 (filed 31 March 2000); 09/202796 (filed 1997 09/384339 (filed August 26, 1999); and 09/383755 (filed August 26, 1999); and compounds disclosed and claimed in the following U.S. provisional patent applications: 60/ 168207 (filed November 30, 1999); 60/170119 (filed December 10, 1999); 60/177718 (filed January 21, 2000); 60/168217 (filed November 30, 1999), and 60/200834 (filed 1 May 2000). Each of the foregoing patent applications and provisional patent applications is incorporated herein by reference in its entirety.

式I的化合物也可以与其它在治疗异常细胞生长或肿瘤中有效的药剂一起使用，这种药剂包括但不限于：能够提高抗癌免疫反应的药剂，例如CTLA4(细胞毒性淋巴细胞(lymphocite)抗原4)抗体，及其它能够阻断CTLA4的药剂；和抗增殖药剂例如其它法呢基蛋白质转移酶抑制剂。可被用于本发明的具体CTLA4抗体包括美国临时申请60/113,647(1998年12月23日申请)中所描述的那些，将其全部引入本文中作为参考。Compounds of formula I may also be used with other agents that are effective in treating abnormal cell growth or tumors, such agents include, but are not limited to: agents that enhance anti-cancer immune responses, such as CTLA4 (cytotoxic lymphocyte (lymphocite) antigen 4) Antibodies, and other agents capable of blocking CTLA4; and antiproliferative agents such as other farnesyl protein transferase inhibitors. Specific CTLA4 antibodies that may be used in the present invention include those described in US Provisional Application 60/113,647 (filed December 23, 1998), which is incorporated herein by reference in its entirety.

本发明的详细说明和优选实施方案Detailed Description and Preferred Embodiments of the Invention

本发明的药剂可以使用如下所述的反应途径与合成路线、采用本领域可获得的技术、使用容易得到的起始原料来制备。The agents of the present invention can be prepared using the reaction pathways and synthetic routes described below, using techniques available in the art, and using readily available starting materials.

下面的实施例详细描述了本发明具体优选的化合物的制备。技术人员将会认识到所描述的化学反应可以容易适合于制备许多本发明的其它激酶抑制剂。例如，按照本发明的非例证性化合物的合成可以成功地通过对本领域技术人员显而易见的改进来进行，例如，通过恰当地保护干扰性的基团，通过变为本领域已知的其它合适的试剂，或通过进行反应条件的常规改进来进行。或者，本文中公开的或本领域已知的其它反应将被认可具有制备本发明的其它化合物的实用性。The following examples describe in detail the preparation of specific preferred compounds of the invention. The skilled artisan will recognize that the chemical reactions described can be readily adapted to prepare many other kinase inhibitors of the invention. For example, the synthesis of non-exemplary compounds according to the present invention can be successfully performed by modifications obvious to those skilled in the art, for example, by appropriate protection of interfering groups, by changing other suitable reagents known in the art , or by performing conventional modifications of the reaction conditions. Alternatively, other reactions disclosed herein or known in the art will be recognized as having utility for preparing other compounds of the invention.

在如下所述的实施例中，除非另有陈述，所有的温度以摄氏温度显示，而所有份数和百分数是用重量显示的。试剂是从商品供应商例如Aldrich化学公司或Lancaster Synthesis Ltd.购买的，而且可不经进一步纯化而使用，除非另有陈述。用氢化钙蒸馏的四氢呋喃(THF)和N，N-二甲基甲酰胺(DMF)是从Aldrich购买的，在可靠密封的瓶子中，并以收到的状态使用。所有的溶剂可使用本领域技术人员已知的标准方法纯化，除非另有陈述。In the examples described below, unless otherwise stated, all temperatures are expressed in degrees Celsius and all parts and percentages are expressed by weight. Reagents were purchased from commercial suppliers such as Aldrich Chemical Company or Lancaster Synthesis Ltd. and were used without further purification unless otherwise stated. Tetrahydrofuran (THF) and N,N-dimethylformamide (DMF) distilled with calcium hydride were purchased from Aldrich in securely sealed bottles and used as received. All solvents can be purified using standard methods known to those skilled in the art unless otherwise stated.

以下列出的反应通常是在下列条件下进行的：在氩气的正压下或带有一个干燥管，在室温(除非另有说明)，在无水溶剂中，且此反应烧瓶备有橡胶隔片，以通过注射器引入底物和试剂。玻璃器皿是烘干的和/或加热干燥的。分析性薄层色谱法(TLC)在玻璃背板的硅胶60F254平板Analtech(0.25mm)上进行，并用合适的溶剂比例(V/V)洗脱，和在合适的地方表示出来。通过TLC测定反应，并通过原料的消耗量判断反应终止。The reactions listed below are generally carried out under the following conditions: under a positive pressure of argon or with a drying tube, at room temperature (unless otherwise stated), in anhydrous solvents, and the reaction flask is equipped with a rubber Septa to introduce substrate and reagents via syringe. Glassware is oven dried and/or heat dried. Analytical thin layer chromatography (TLC) was performed on glass-backed silica gel 60F254 plates Analtech (0.25 mm) and eluted with appropriate solvent ratios (V/V) and indicated where appropriate. The reaction was assayed by TLC and terminated as judged by the consumption of starting material.

薄层色谱板的显色用对甲氧基苯甲醛喷显剂或磷钼酸试剂(Aldrich Chemical，20wt％，在乙醇中)来进行并加热活化。后处理典型地通过用反应溶剂或萃取溶剂使反应体积加倍，然后用所指明的水溶液洗涤来进行，使用按体积25％的提取体积量，除非另有陈述。将产品溶液在过滤之前用无水Na₂SO₄或MgSO₄干燥，并在旋转蒸发器上减压蒸发此溶剂，并当在真空中除去溶剂时加以注明。使用Baker级快速硅胶(47-61μm)和硅胶：原料的比例大约为20∶1至50∶1来进行快速柱色谱法(Still等人，J.Org.Chem.，43，2923(1978))，除非另有说明。在实施例表明的压力或环境压力下进行氢化。Color development of TLC plates was carried out with p-methoxybenzaldehyde spray developer or phosphomolybdic acid reagent (Aldrich Chemical, 20 wt% in ethanol) and heat activated. Workup was typically performed by doubling the reaction volume with reaction solvent or extraction solvent, followed by washing with the indicated aqueous solution, using an extraction volume of 25% by volume unless otherwise stated. The product solution was dried over anhydrous_Na2SO4 or_MgSO4 before filtration and the solvent was evaporated under reduced pressure on_a rotary evaporator and noted when the solvent was removed in vacuo. Flash column chromatography (Still et al., J.Org.Chem., 43, 2923 (1978)) was performed using Baker grade flash silica gel (47-61 μm) and a silica:raw material ratio of approximately 20:1 to 50:1 ,Unless otherwise indicated. The hydrogenation is carried out at the pressure indicated in the examples or at ambient pressure.

¹H-NMR谱是在300MHz或500MHz下运行的Bruker仪器上记录的，且¹³C-NMR谱是在75MHz下运行记录的。NMR波谱以CDCl₃溶液(以ppm报告)得到，使用氯仿作为参照标准(7.25ppm和77.00ppm)或CD₃OD(3.4ppm和4.8ppm和49.3ppm)，或在合适的时侯使用内标四甲基硅烷(0.00ppm)。如果需要可使用其它NMR溶剂。当报道峰值多重性时，使用下列缩写：s(单峰)，d(双峰)，t(三重峰)，m(多重峰)，br(宽的)，dd(双二重峰)，dt(双三重峰)。当得到偶合常数时，以赫兹(Hz)报道。¹ H-NMR spectra were recorded on a Bruker instrument operating at 300 MHz or 500 MHz, and¹³ C-NMR spectra were recorded operating at 75 MHz. NMR spectra were obtained as_CDCl3 solution (reported in ppm) using chloroform as reference standard (7.25ppm and 77.00ppm) or_CD3OD (3.4ppm and 4.8ppm and 49.3ppm), or internal standard IV when appropriate Methylsilane (0.00 ppm). Other NMR solvents can be used if desired. When peak multiplicity is reported, the following abbreviations are used: s (singlet), d (doublet), t (triplet), m (multiplet), br (broad), dd (doublet of doublets), dt (double triplet). When coupling constants are obtained, they are reported in Hertz (Hz).

红外(IR)光谱是以纯油或KBr压片的形式、在Perkin-ElmerFT-IR分光计上记录的，并且当给出谱时，以波数(cm^-1)来报道。质谱是使用LSIMS或电喷雾获得的。所有的熔点(mp)是未校正的。Infrared (IR) spectra were recorded in pure oil or KBr pellets on a Perkin-Elmer FT-IR spectrometer and, when spectra are given, are reported in wavenumber (cm⁻¹ ). Mass spectra were acquired using LSIMS or electrospray. All melting points (mp) are uncorrected.

在实施例中使用的起始原料是可商业购买的，和/或可以通过本领域已知的技术制备。Starting materials used in the examples are commercially available and/or can be prepared by techniques known in the art.

实施例1：{5-[3-(4，6-二氟-1H-苯并咪唑-2-基)-1H-吲唑-5-基]-4-甲基-吡啶-3-基甲基}-乙基-胺Example 1: {5-[3-(4,6-difluoro-1H-benzimidazol-2-yl)-1H-indazol-5-yl]-4-methyl-pyridin-3-ylmethyl base}-ethyl-amine

(a)中间体1a-(5-溴-4-甲基-吡啶-3-基甲基)-乙基-胺(a) Intermediate 1a-(5-bromo-4-methyl-pyridin-3-ylmethyl)-ethyl-amine

在氮气氛围下，将5-溴-4-甲基-吡啶-3-甲醛(6.74g，33.7mmol)[对于制备该化合物，见Reich，S.R.；Bleckman，T.M.；Kephart，S.E.；Romines，W.H.；Wallace，M.B.，US patent6,555,539，April 29，2003.]溶于甲醇(290mL)中。用30分钟滴加乙胺的甲醇溶液(2.0M，90ml，180mmol)。在室温下进一步持续搅拌30分钟。5-Bromo-4-methyl-pyridine-3-carbaldehyde (6.74 g, 33.7 mmol) [For the preparation of this compound, see Reich, S.R.; Bleckman, T.M.; Kephart, S.E.; Romines, W.H.; Wallace, M.B., US patent 6,555,539, April 29, 2003.] dissolved in methanol (290 mL). A solution of ethylamine in methanol (2.0M, 90ml, 180mmol) was added dropwise over 30 minutes. Stirring was continued for a further 30 minutes at room temperature.

在分开的烧瓶中，将氰基硼氢化钠(2.33g，37.1mmol)溶于甲醇(150mL)中。加入无水氯化锌(2.53g，18.5mmol)并在室温下持续搅拌20分钟。然后将此溶液(锌/氰基硼氢化物)慢慢地加入到上述醛/乙胺溶液中。用2.0M HCl/甲醇(120mL)将反应溶液酸化至pH值4，然后在室温下搅拌18小时。In a separate flask, sodium cyanoborohydride (2.33 g, 37.1 mmol) was dissolved in methanol (150 mL). Anhydrous zinc chloride (2.53 g, 18.5 mmol) was added and stirring was continued at room temperature for 20 minutes. This solution (zinc/cyanoborohydride) was then slowly added to the above aldehyde/ethylamine solution. The reaction solution was acidified to pH 4 with 2.0M HCl/methanol (120 mL), then stirred at room temperature for 18 hours.

通过旋转蒸发除去溶剂，并将残余物在乙酸乙酯和10％碳酸钠水溶液之间分配。用硫酸镁干燥有机提取物并浓缩，得到粗品胺1a(7.36g，95％)橙色油，不将其进一步纯化而在下一步中使用：The solvent was removed by rotary evaporation, and the residue was partitioned between ethyl acetate and 10% aqueous sodium carbonate. The organic extract was dried over magnesium sulfate and concentrated to give crude amine 1a (7.36 g, 95%) as an orange oil which was used in the next step without further purification:

                                                      ¹HNMR(CDCl₃)δ8.53(s，1H)，8.31(s，1H)，3.77(s，2H)，2.67(q，J＝7.0Hz，2H)，2.42(s，3H)，1.11(t，J＝7.0Hz，3H).¹ HNMR (CDCl₃ ) δ8.53(s, 1H), 8.31(s, 1H), 3.77(s, 2H), 2.67(q, J=7.0Hz, 2H), 2.42(s, 3H), 1.11( t, J=7.0Hz, 3H).

(b)中间体1b-(5-溴-4-甲基-吡啶-3-基甲基)-乙基-氨基甲酸叔丁基酯(b) Intermediate 1b-(5-bromo-4-methyl-pyridin-3-ylmethyl)-ethyl-carbamic acid tert-butyl ester

将二碳酸二叔丁基酯(10.43g，47.8mmol)加入到粗品胺1a(7.36g，32.1mmol)的THF(400mL)溶液中，而后加入氢氧化钠水溶液(1.0M，101mL)。在室温下将该双相性溶液大力搅拌20小时。将溶液在水和乙酸乙酯之间分配；用硫酸镁干燥有机提取物，过滤并浓缩。将如此获得的粗品黄色油通过硅胶色谱纯化(用10％至30％的乙酸乙酯/己烷进行梯度洗脱)，得到溴吡啶1b(5.37g，51％)黄色油：Di-tert-butyl dicarbonate (10.43 g, 47.8 mmol) was added to a solution of crude amine la (7.36 g, 32.1 mmol) in THF (400 mL), followed by aqueous sodium hydroxide (1.0 M, 101 mL). The biphasic solution was vigorously stirred at room temperature for 20 hours. The solution was partitioned between water and ethyl acetate; the organic extracts were dried over magnesium sulfate, filtered and concentrated. The crude yellow oil thus obtained was purified by chromatography on silica gel (gradient elution with ethyl acetate/hexanes from 10% to 30%) to afford pyridine bromide 1b (5.37 g, 51%) as a yellow oil:

                                          ¹H NMR(CDCl₃)δ8.58(s，1H)，8.22(s，1H)，4.47(s，2H)，3.17(br s，2H)，2.37(s，3H)，1.45(s，9H)，1.03(t，J＝7.2Hz，3H).¹ H NMR (CDCl₃ )δ8.58(s, 1H), 8.22(s, 1H), 4.47(s, 2H), 3.17(br s, 2H), 2.37(s, 3H), 1.45(s, 9H ), 1.03(t, J=7.2Hz, 3H).

(c)中间体1c-5-碘代-1-(四氢-吡喃-2-基)-1H-吲唑-3-羧酸甲氧基-甲基-酰胺(c) Intermediate 1c-5-iodo-1-(tetrahydro-pyran-2-yl)-1H-indazole-3-carboxylic acid methoxy-methyl-amide

按照Sun等人[Sun，J.-H.；Teleha，C.A.；Yan，J.-S.；Rogers，J.D.；and Nugiel，D.A.，J.Org.Chem.1997，62，5627]的方法，用二氢吡喃将5-碘代-1H-吲唑-3-羧酸甲氧基-甲基-酰胺[对于该化合物的制备，见Reich，S.R.；Bleckman，T.M.；Kephart，S.E.；Romines，W.H.；Wallace，M.B.，US patent 6,555,539 B2，April29，2003.]烷基化，得到酰胺1c(典型地＞90％)类白色粉末：According to the method of Sun et al. [Sun, J.-H.; Teleha, C.A.; Yan, J.-S.; Rogers, J.D.; and Nugiel, D.A., J.Org.Chem.1997,62,5627], use Dihydropyran 5-iodo-1H-indazole-3-carboxylic acid methoxy-methyl-amide [For the preparation of this compound, see Reich, S.R.; Bleckman, T.M.; Kephart, S.E.; Romines, W.H. ; Wallace, M.B., US patent 6,555,539 B2, April 29, 2003.] Alkylation affords amide 1c (typically >90%) off-white powder:

                                                                            ¹HNMR(DMSO-d₆)δ8.37(s，1H)，7.74(dd，J＝1.5，8.8Hz，1H)，7.68(d，J＝8.8Hz，1H)，5.97(dd，J＝2.3，9.0Hz，1H)，3.88(m，2H)，3.79(s，3H)，3.42(s，3H)，2.35(m，1H)，2.03(m，2H)，1.75(m，1H)，1.58(m，2H).¹ H NMR (DMSO-d₆ ) δ8.37 (s, 1H), 7.74 (dd, J=1.5, 8.8Hz, 1H), 7.68 (d, J=8.8Hz, 1H), 5.97 (dd, J=2.3 , 9.0Hz, 1H), 3.88(m, 2H), 3.79(s, 3H), 3.42(s, 3H), 2.35(m, 1H), 2.03(m, 2H), 1.75(m, 1H), 1.58 (m, 2H).

(d)中间体1d-5-碘代-1-(四氢-吡喃-2-基)-1H-吲唑-3-甲醛(d) intermediate 1d-5-iodo-1-(tetrahydro-pyran-2-yl)-1H-indazole-3-carbaldehyde

将氢化铝锂(1.2当量)分批加入至酰胺1c(1.0当量)的THF冷(＜5℃)溶液中。在＜5℃下持续搅拌，直到反应完成为止，典型地搅拌30分钟。在＜5℃的条件下，通过缓慢加入乙酸乙酯猝灭反应，将全部混合物倾倒入0.4N NaHSO₄中。用盐水洗涤有机层，用硫酸镁干燥，浓缩，用硅胶色谱纯化得到醛1d(典型地～70％)类白色粉末：Lithium aluminum hydride (1.2 equiv) was added portionwise to a cold (<5°C) solution of amide 1c (1.0 equiv) in THF. Stirring was continued at <5°C until the reaction was complete, typically 30 minutes. The reaction was quenched by the slow addition of ethyl acetate at <5°C and the entire mixture was poured into 0.4N_NaHSO4 . The organic layer was washed with brine, dried over magnesium sulfate, concentrated, and purified by silica gel chromatography to afford aldehyde 1d (typically -70%) as an off-white powder:

                                              ¹H NMR(CDCl₃)δ10.15(s，1H)，8.47(s，1H)，7.82(dd，J＝1.5，8.7Hz，1H)，7.78(d，J＝8.5Hz，1H)，6.04(dd，J＝2.3，9.28Hz，1H)，3.85(m，2H)，2.35(m，1H)，2.05(m，2H)，1.76(m，1H)，1.60(m，2H).¹ H NMR (CDCl₃ ) δ10.15(s, 1H), 8.47(s, 1H), 7.82(dd, J=1.5, 8.7Hz, 1H), 7.78(d, J=8.5Hz, 1H), 6.04 (dd, J=2.3, 9.28Hz, 1H), 3.85(m, 2H), 2.35(m, 1H), 2.05(m, 2H), 1.76(m, 1H), 1.60(m, 2H).

(e)中间体1e-乙基-{5-[3-甲酰基-1-(四氢-吡喃-2-基)-1H-吲唑-5-基]-4-甲基-吡啶-3-基甲基}-氨基甲酸叔丁基酯(e) intermediate 1e-ethyl-{5-[3-formyl-1-(tetrahydro-pyran-2-yl)-1H-indazol-5-yl]-4-methyl-pyridine- 3-ylmethyl}-tert-butyl carbamate

将碘代吲唑1d(3.56g，10.0mmol)、双(频哪醇酰)(pinacolato)二硼(2.79g，11mmol)、乙酸钾(2.74g，30mmol)和[1，1′-双(二苯基膦基)-二茂铁]二氯钯(II)与二氯甲烷(245mg，0.3mmol)的复合物溶于N，N-二甲基乙酰胺(60mL)中。通过抽真空将溶液脱气(直到溶剂开始鼓泡为止)，并用氩气(3个循环)吹扫，然后在80℃的油浴中加热2小时。略微冷却以后(至～50℃)，加入溴吡啶1b(3.62g，11mmol)的N，N-二甲基乙酰胺(40mL)溶液，而后加入去离子水(10mL)和磷酸钾(3.18g，15mmol)。将溶液脱气，加入四(三苯基膦)钯(O)(347mg，0.3mmol)，再次脱气。将混合物在90℃的油浴中搅拌4.5小时。冷却至室温以后，将混合物用乙酸乙酯(300mL)稀释，用去离子水(150mL)和饱和氯化钠(100mL)洗涤。用硫酸镁干燥有机层，过滤并浓缩至粗品红黑色油(9.43g)。通过硅胶色谱纯化(用50-100％乙酸乙酯/己烷洗脱)，得到偶合产物1e(2.9462g)橙色油。该产物的¹H NMR显示它被～1当量的频哪醇污染。用己烷研磨得到纯的1e(2.0853g，44％)细小黄色粉末：Iodoindazole 1d (3.56g, 10.0mmol), bis(pinacolatoyl) (pinacolato) diboron (2.79g, 11mmol), potassium acetate (2.74g, 30mmol) and [1,1′-bis( The complex of diphenylphosphino)-ferrocene]dichloropalladium(II) and dichloromethane (245 mg, 0.3 mmol) was dissolved in N,N-dimethylacetamide (60 mL). The solution was degassed by evacuation (until the solvent started bubbling) and flushed with argon (3 cycles), then heated in an oil bath at 80° C. for 2 hours. After cooling slightly (to ~50 °C), a solution of bromopyridine 1b (3.62 g, 11 mmol) in N,N-dimethylacetamide (40 mL) was added, followed by deionized water (10 mL) and potassium phosphate (3.18 g, 15mmol). The solution was degassed, tetrakis(triphenylphosphine)palladium(0) (347 mg, 0.3 mmol) was added and degassed again. The mixture was stirred in an oil bath at 90°C for 4.5 hours. After cooling to room temperature, the mixture was diluted with ethyl acetate (300 mL), washed with deionized water (150 mL) and saturated sodium chloride (100 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated to a crude magenta black oil (9.43g). Purification by silica gel chromatography (eluting with 50-100% ethyl acetate/hexanes) afforded the coupled product 1e (2.9462 g) as an orange oil.¹ H NMR of the product showed that it was contaminated with -1 equivalent of pinacol. Trituration with hexane gave pure 1e (2.0853 g, 44%) as a fine yellow powder:

             ¹H NMR(CDCl₃)δ10.25(s，1H)，8.39(s，1H)，8.34(s，1H)，8.22(s，1H)，7.74(d，J＝8.7Hz，1H)，7.38(dd，J＝1.5，8.5Hz，1H)，5.88(dd，J＝2.8，9.2Hz，1H)，4.53(s，2H)，4.03(m，1H)，3.81(m，1H)，3.24(br s，2H)，2.60(m，1H)，2.18(s，3H)，2.15(m，2H)，1.77(m，1H)，1.65(m，2H)，1.47(s，9H)，1.09(t，J＝7.0Hz，1H).¹ H NMR (CDCl₃ ) δ10.25(s, 1H), 8.39(s, 1H), 8.34(s, 1H), 8.22(s, 1H), 7.74(d, J=8.7Hz, 1H), 7.38 (dd, J=1.5, 8.5Hz, 1H), 5.88(dd, J=2.8, 9.2Hz, 1H), 4.53(s, 2H), 4.03(m, 1H), 3.81(m, 1H), 3.24( br s, 2H), 2.60(m, 1H), 2.18(s, 3H), 2.15(m, 2H), 1.77(m, 1H), 1.65(m, 2H), 1.47(s, 9H), 1.09( t, J=7.0Hz, 1H).

(f)中间体1f-{5-[3-(4，6-二氟-1H-苯并咪唑-2-基)-1-(四氢-吡喃-2-基)-1H-吲唑-5-基]-4-甲基-吡啶-3-基甲基}-乙基-氨基甲酸叔丁基酯(f) intermediate 1f-{5-[3-(4,6-difluoro-1H-benzimidazol-2-yl)-1-(tetrahydro-pyran-2-yl)-1H-indazole -5-yl]-4-methyl-pyridin-3-ylmethyl}-ethyl-tert-butyl carbamate

将醛1e(2.05克，4.28mmol)、1，2-二氨基-3，5-二氟代苯(617毫克，4.28mmol)和亚硫酸氢钠(891毫克，8.57mmol)溶于N，N-二甲基乙酰胺(43毫升)中，并在120℃的油浴中加热21小时。冷却至室温以后，将混合物用乙酸乙酯(100mL)稀释，并用半饱和氯化钠水溶液(75mL，去离子水和饱和氯化钠水溶液的1∶1混合物)洗涤。将水层用乙酸乙酯(2×100ml)反萃取。合并所有的有机提取物，用硫酸镁干燥，浓缩至褐色焦油(3.39g)。将粗品用硅胶色谱纯化(用70％至100％的乙酸乙酯/己烷进行梯度洗脱)，得到苯并咪唑产物1f(2.11g，81％)褐色泡沫：¹H NMR(CD₃OD)δ8.46(s，1H)，8.41(s，1H)，8.29(s，1H)，7.87(d，J＝8.6Hz，1H)，7.46(dd，J＝1.3，8.6Hz，1H)，7.13(m，1H)，6.84(m，1H)，5.99(dd，J＝2.3，9.9Hz，1H)，4.60(s，2H)，4.01(m，1H)，3.86(m，1H)，3.32(m，2H，被溶剂峰遮蔽)2.67(m，1H)，2.28(s，3H)，2.18(m，2H)，1.89(m，1H)，1.73(m，2H)，1.47(s，9H)，1.13(t，J＝7.1Hz，1H).元素分析：(C₃₃H₃₆F₂N₆O₃·0.4H₂O)C，H，N，F.Aldehyde 1e (2.05 g, 4.28 mmol), 1,2-diamino-3,5-difluorobenzene (617 mg, 4.28 mmol) and sodium bisulfite (891 mg, 8.57 mmol) were dissolved in N,N - dimethylacetamide (43 ml) and heated in an oil bath at 120°C for 21 hours. After cooling to room temperature, the mixture was diluted with ethyl acetate (100 mL) and washed with half-saturated aqueous sodium chloride (75 mL, 1:1 mixture of deionized water and saturated aqueous sodium chloride). The aqueous layer was back extracted with ethyl acetate (2 x 100ml). All organic extracts were combined, dried over magnesium sulfate and concentrated to a brown tar (3.39g). The crude product was purified by silica gel chromatography (gradient elution with ethyl acetate/hexanes from 70% to 100%) to give the benzimidazole product If (2.11 g, 81%) as a brown foam:¹ H NMR (CD₃ OD) δ8.46(s, 1H), 8.41(s, 1H), 8.29(s, 1H), 7.87(d, J=8.6Hz, 1H), 7.46(dd, J=1.3, 8.6Hz, 1H), 7.13 (m, 1H), 6.84(m, 1H), 5.99(dd, J=2.3, 9.9Hz, 1H), 4.60(s, 2H), 4.01(m, 1H), 3.86(m, 1H), 3.32( m, 2H, masked by solvent peak) 2.67(m, 1H), 2.28(s, 3H), 2.18(m, 2H), 1.89(m, 1H), 1.73(m, 2H), 1.47(s, 9H) , 1.13 (t, J=7.1Hz, 1H). Elemental analysis: (C₃₃ H₃₆ F₂ N₆ O₃ ·0.4H₂ O)C, H, N, F.

(g)实施例1-(5-[3-(4，6-二氟-1H-苯并咪唑-2-基)-1H-吲唑-5-基]-4-甲基-吡啶-3-基甲基}-乙基-胺(g) Example 1-(5-[3-(4,6-difluoro-1H-benzimidazol-2-yl)-1H-indazol-5-yl]-4-methyl-pyridine-3 -ylmethyl}-ethyl-amine

将三乙基硅烷(976毫克，8.40mmol)和三氟乙酸(12.9毫升，168mmol)加入到1f(2.02克，3.36mmol)的二氯甲烷(12.9毫升)溶液中。将混合物在室温下搅拌3.5小时。通过旋转蒸发除去挥发物，用环己烷(10mL)和氢氧化铵水溶液(2N，20mL)处理残余物。强烈搅拌15分钟以后，形成粉红色沉淀，通过抽吸过滤将其收集。用乙酸乙酯(3x 50mL)提取滤液。合并有机提取物，用硫酸镁干燥，过滤，浓缩至橙色的固体(～0.4g)。将该固体加入到上面获得的粉红色沉淀中，用柱层析纯化(用1％浓氨水-19％纯乙醇-80％二氯甲烷的混合物洗脱)。将如此获得的产物(1.23g类白色固体)进一步用环己烷研磨来纯化，得到纯的1(1.09g，74％)类白色固体：Triethylsilane (976 mg, 8.40 mmol) and trifluoroacetic acid (12.9 mL, 168 mmol) were added to a solution of 1f (2.02 g, 3.36 mmol) in dichloromethane (12.9 mL). The mixture was stirred at room temperature for 3.5 hours. The volatiles were removed by rotary evaporation and the residue was treated with cyclohexane (10 mL) and aqueous ammonium hydroxide (2N, 20 mL). After vigorous stirring for 15 minutes, a pink precipitate formed which was collected by suction filtration. The filtrate was extracted with ethyl acetate (3 x 50 mL). The organic extracts were combined, dried over magnesium sulfate, filtered, and concentrated to an orange solid (-0.4 g). This solid was added to the pink precipitate obtained above and purified by column chromatography (eluting with a mixture of 1% conc. ammonia-19% absolute ethanol-80% dichloromethane). The product thus obtained (1.23 g of off-white solid) was further purified by trituration with cyclohexane to give pure 1 (1.09 g, 74%) of off-white solid:

             ¹H NMR(DMSO-d₆)δ13.81(非常宽的s，1H)，8.46(s，1H)，8.35(s，2H)，7.76(d，J＝8.6Hz，1H)，7.44(dd，J＝1.3，8.6Hz，1H)，7.17(m，1H)，7.07(t of d，Jt＝1.5Hz，Jd＝10.6Hz，1H)3.78(s，2H)，2.63(q，J＝7.1Hz，2H)，2.25(s，3H)，1.07(t，J＝7.1Hz，3H).HRMS[M+H]⁺计算值：419.1791；测定值：419.1811.元素分析(C₂₃H₂₀F₂N₆·1.1H₂O)C，H，N，F.¹ H NMR (DMSO-d₆ ) δ13.81 (very broad s, 1H), 8.46 (s, 1H), 8.35 (s, 2H), 7.76 (d, J=8.6Hz, 1H), 7.44 (dd , J=1.3, 8.6Hz, 1H), 7.17(m, 1H), 7.07(t of d, Jt=1.5Hz, Jd=10.6Hz, 1H), 3.78(s, 2H), 2.63(q, J=7.1 Hz, 2H), 2.25(s, 3H), 1.07(t, J=7.1Hz, 3H). HRMS [M+H]⁺ calculated value: 419.1791; measured value: 419.1811. Elemental analysis (C₂₃ H₂₀ F₂ N₆ ·1.1H₂ O)C, H, N, F.

实施例2：乙基-{5-[3-(5-氟-1H-苯并咪唑-2-基)-1H-吲唑-5-基]-4-甲基-吡啶-3-基甲基}-胺Example 2: Ethyl-{5-[3-(5-fluoro-1H-benzimidazol-2-yl)-1H-indazol-5-yl]-4-methyl-pyridin-3-ylmethyl base}-amine

(a)中间体2a-乙基-{5-[3-(5-氟-1H-苯并咪唑-2-基)-1-(四氢-吡喃-2-基)-1H-吲唑-5-基]-4-甲基-吡啶-3-基甲基}-氨基甲酸叔丁基酯(a) intermediate 2a-ethyl-{5-[3-(5-fluoro-1H-benzimidazol-2-yl)-1-(tetrahydro-pyran-2-yl)-1H-indazole -5-yl]-4-methyl-pyridin-3-ylmethyl}-tert-butyl carbamate

使用与合成中间体1f相同的方法，在亚硫酸氢钠(894mg，8.59mmol)的存在下，将醛1e(2.06g，4.29mmol)与4-氟-1，2-苯二胺(542mg，4.29mmol)缩合，得到苯并咪唑2a(2.04g，78％)橙色泡沫：¹H NMR(DMSO-d₆，由于互变异构化，一些峰是双重的)Using the same method as for the synthesis of intermediate 1f, aldehyde 1e (2.06 g, 4.29 mmol) was combined with 4-fluoro-1,2-phenylenediamine (542 mg, 4.29 mmol) was condensed to give benzimidazole 2a (2.04 g, 78%) as an orange foam:¹ H NMR (DMSO-d₆ , some peaks are double due to tautomerization)

δ13.15和13.13(2s，1H一起)，8.42和8.41(2s，1H一起)，8.39(s，1H)，8.32(s，1H)，7.77(dd，J＝1.0，8.9Hz，1H)，(7.70(dd，J＝4.8，8.8Hz)和7.27(dd，J＝2.5，9.1Hz)1H一起]，7.52(m，2H)，7.07(m，1H)，6.07(d，J＝9.3Hz 1H)，4.53(s，2H)，3.96(m，1H)，3.86(m，1H)，3.32(m，2H)2.60(m，1H)，2.18(s，3H)，2.12(m，2H)，1.83(m，1H)，1.65(m，2H)，1.41(s，9H)，1.05(t，J＝7.0Hz，3H).元素分析：(C₃₃H₃₇FN₆O₃·0.5H₂O·0.2己烷)C，H，N，F.δ13.15 and 13.13 (2s, 1H together), 8.42 and 8.41 (2s, 1H together), 8.39 (s, 1H), 8.32 (s, 1H), 7.77 (dd, J=1.0, 8.9Hz, 1H), (7.70(dd, J=4.8, 8.8Hz) and 7.27(dd, J=2.5, 9.1Hz) 1H together], 7.52(m, 2H), 7.07(m, 1H), 6.07(d, J=9.3Hz 1H), 4.53(s, 2H), 3.96(m, 1H), 3.86(m, 1H), 3.32(m, 2H), 2.60(m, 1H), 2.18(s, 3H), 2.12(m, 2H) , 1.83(m, 1H), 1.65(m, 2H), 1.41(s, 9H), 1.05(t, J=7.0Hz, 3H). Elemental analysis: (C₃₃ H₃₇ FN₆ O₃ ·0.5H₂ O·0.2 hexane) C, H, N, F.

(b)实施例2-乙基-{5-[3-(5-氟-1H-苯并咪唑-2-基)-1H-吲唑-5-基]-4-甲基-吡啶-3-基甲基}-胺(b) Example 2-ethyl-{5-[3-(5-fluoro-1H-benzimidazol-2-yl)-1H-indazol-5-yl]-4-methyl-pyridine-3 -ylmethyl}-amine

用和1f的脱保护同样的方法，将中间体2a(1.95g，3.34mmol)转变为标题化合物2(1.04g，74％)灰白色固体：Intermediate 2a (1.95 g, 3.34 mmol) was transformed into the title compound 2 (1.04 g, 74%) as an off-white solid by the same method as the deprotection of 1f:

                                                  ¹H NMR(DMSO-d₆，¹ H NMR (DMSO-d₆ ,

由于互变异构化，一些峰是双重的)δ13.80(very br s，1H)，13.12(非常宽的s)1H)，8.46(s，1H)，8.39(s，1H)，8.34(s，1H)，7.69和7.25(2m，1H一起)，7.48(m，1H)，7.44(dd，J＝1.5，8.6Hz，1H)，7.05(m，1H)，3.77(s，2H)，2.62(q，J＝7.3Hz，2H)，2.25(s，3H)，1.07(t，J＝7.1Hz，3H).元素分析：(C₂₃H₂₁FN₆·1.1H₂O)C，H，N，F.Some peaks are double due to tautomerization) δ 13.80 (very br s, 1H), 13.12 (very broad s) 1H), 8.46 (s, 1H), 8.39 (s, 1H), 8.34 ( s, 1H), 7.69 and 7.25 (2m, 1H together), 7.48 (m, 1H), 7.44 (dd, J=1.5, 8.6Hz, 1H), 7.05 (m, 1H), 3.77 (s, 2H), 2.62(q, J=7.3Hz, 2H), 2.25(s, 3H), 1.07(t, J=7.1Hz, 3H). Elemental analysis: (C₂₃ H₂₁ FN₆ ·1.1H₂ O)C, H , N, F.

生物化学和生物学评价Biochemical and Biological Evaluation

依赖细胞周期蛋白的激酶的活性是通过放射性磷酸盐从[³²P]ATP或[³³P]ATP掺入到蛋白质底物的酶催化的、随时间而变的结合进行量化来测定的。除非另外指出，试验是在98孔培养皿中、以50μL的总体积、每个反应在10mM HEPES(N-[2-羟乙基]哌嗪-N’-[2-乙磺酸](pH 7.4)、10mM MgCl₂、25μM三磷酸腺苷(ATP)、1mg/mL卵清蛋白、5μg/mL亮肽素、1mM二硫苏糖醇、10mM β-甘油磷酸酯、0.1mM钒酸钠、1mM氟化钠、2.5mM乙二醇-双(β-氨乙基醚)-N，N，N′，N′-四乙酸(EGTA)、2％(v/v)二甲亚砜和0.03-0.4μCi[32/33P]ATP的存在下进行。用30℃培养的酶引发反应，20分钟以后，通过加入乙二胺四乙酸(EDTA)至250mM而终止反应。然后在硝化纤维素或磷酸纤维素膜上、使用96孔多孔过滤器捕获磷酸化基质，通过用0.85％磷酸重复洗涤来除去未结合的放射性。通过将干燥膜暴露于磷光影像扫描分析仪而将放射性量化。Cyclin-dependent kinase activity is determined by quantification of the enzyme-catalyzed, time-dependent incorporation of radioactive phosphate from [³² P]ATP or [³³ P]ATP incorporation into protein substrates. Unless otherwise noted, assays were performed in 98-well dishes in a total volume of 50 μL, with each reaction in 10 mM HEPES (N-[2-hydroxyethyl]piperazine-N'-[2-ethanesulfonic acid] (pH 7.4), 10mM MgCl₂ , 25μM adenosine triphosphate (ATP), 1mg/mL ovalbumin, 5μg/mL leupeptin, 1mM dithiothreitol, 10mM β-glycerophosphate, 0.1mM sodium vanadate, 1mM fluoride Sodium, 2.5 mM ethylene glycol-bis(β-aminoethyl ether)-N,N,N′,N′-tetraacetic acid (EGTA), 2% (v/v) dimethyl sulfoxide, and 0.03-0.4 μCi Carried out in the presence of [32/33P]ATP. The reaction was initiated with enzymes incubated at 30°C, and after 20 minutes, the reaction was terminated by adding ethylenediaminetetraacetic acid (EDTA) to 250mM. Then on nitrocellulose or phosphocellulose membrane Above, phosphorylated substrates were captured using a 96-well porous filter and unbound radioactivity was removed by repeated washing with 0.85% phosphoric acid.Radioactivity was quantified by exposing the dried membrane to a phosphorimager.

表观Ki值是通过下列方法测定的：在不同浓度抑制剂化合物的存在下测定的酶活性，减去不存在酶时测定的本底放射性。使用Kaleidagraph(Synergy Software)将抑制数据填入竞争性抑制方程式，或使用软件KineTic(BioKin，Ltd.)将其填入竞争性紧密结合抑制方程式。Apparent Ki values are determined by subtracting background radioactivity measured in the absence of enzyme from enzyme activity measured in the presence of various concentrations of inhibitor compound. Inhibition data were filled into competitive inhibition equations using Kaleidagraph (Synergy Software) or competitive tight-binding inhibition equations using the software KineTic (BioKin, Ltd.).

CDK4/Cyclin D成视网膜细胞瘤激酶活性的抑制Inhibition of CDK4/Cyclin D Retinoblastoma Kinase Activity

使用传统生化色谱技术，从已经同时感染相应的杆状病毒表达载体的昆虫细胞中提纯人类CDK4和细胞周期蛋白D3的复合物、或人类CDK4和基因截短的(1-264)细胞周期蛋白D3的复合物(见例如，Meijerand Kim，“Chemical Inhibitors of Cyclin-Dependent Kinases，”Methods in Enzymol，.vol.283(1997)，pp.113-128.)。用0.3-0.5微克纯化重组成视网膜细胞瘤蛋白片段(Rb)作为基质来测定酶复合物(5或50nM)。为了便于纯化，设计的Rb片段(天然成视网膜细胞瘤蛋白的残基386-928；62.3kDa)含有在天然106-kDa蛋白质中发现的大部分的磷酸化位点，以及六个组氨酸残基的标记。通过在硝化纤维素膜上进行微过滤来捕获磷酸化Rb基质，并使用如上所述的磷光影像扫描分析仪进行量化。为了测量紧密结合的抑制剂，酶复合物浓度低于5nM，测定持续时间延至60分钟，在此期间，产物的形成的时间依赖性是线形的。Purification of complexes of human CDK4 and cyclin D3, or human CDK4 and genetically truncated (1-264) cyclin D3, from insect cells that have been co-infected with the corresponding baculovirus expression vectors using conventional biochemical chromatography techniques (see, for example, Meijerand Kim, "Chemical Inhibitors of Cyclin-Dependent Kinases," Methods in Enzymol, .vol.283(1997), pp.113-128.). Enzyme complexes (5 or 50 nM) were assayed using 0.3-0.5 micrograms of purified recombinant retinoblastoma protein fragment (Rb) as a substrate. For ease of purification, the designed Rb fragment (residues 386-928 of the native retinoblastoma protein; 62.3 kDa) contains most of the phosphorylation sites found in the native 106-kDa protein, as well as six histidine residues base tag. Phosphorylated Rb substrates were captured by microfiltration on nitrocellulose membranes and quantified using a phosphorimager as described above. For the measurement of tightly bound inhibitors, the enzyme complex concentration was below 5 nM and the assay duration was extended to 60 minutes, during which time the time dependence of product formation was linear.

CDK2/Cyclin A成视网膜细胞瘤激酶活性的抑制Inhibition of CDK2/Cyclin A Retinoblastoma Kinase Activity

使用公开的方法(Rosenblatt等人，“Purification andCrystallization of Human Cyclin-dependent Kinase 2，”J.MoLBiol.，vol.230，1993，pp.1317-1319)、从已经感染上杆状病毒表达载体的昆虫细胞中提纯CDK2。从表达全长重组细胞周期蛋白A的大肠杆菌细胞中提纯细胞周期蛋白A，并通过限制性蛋白水解作用产生平截细胞周期蛋白A构成物，并按先前描述的方式进行提纯(Jeffrey等人，“Mechanism of CDK activation revealed by the structureof a cyclin A-CDK2 complex，”Nature，vol.376(27July 1995)，pp.313-320)。制备CDK2和蛋白水解的(proteolyzed)细胞周期蛋白A的复合物并通过凝胶过滤纯化。该试验的基质与用于CDK4试验的Rb基质片段相同，并且CDK2/细胞周期蛋白A和CDK4/细胞周期蛋白D3试验的方法基本上相同，除了CDK2以150nM或5nM提供之外。按如上所述测定Ki值。Using published methods (Rosenblatt et al., "Purification and Crystallization of Human Cyclin-dependent Kinase 2," J.MoLBiol., vol.230, 1993, pp.1317-1319), from insects that have been infected with a baculovirus expression vector Purification of CDK2 from cells. Cyclin A was purified from E. coli cells expressing full-length recombinant cyclin A and truncated cyclin A constructs were generated by restricted proteolysis and purified as previously described (Jeffrey et al. "Mechanism of CDK activation revealed by the structure of a cyclin A-CDK2 complex," Nature, vol.376(27July 1995), pp.313-320). Complexes of CDK2 and proteolyzed cyclin A were prepared and purified by gel filtration. The matrix for this assay was the same as the Rb matrix fragment used for the CDK4 assay, and the methods for the CDK2/cyclin A and CDK4/cyclin D3 assays were essentially the same, except that CDK2 was provided at 150 nM or 5 nM. Ki values were determined as described above.

通过生长因子例如VEGF及其它物质进行的细胞增殖的刺激，取决于它们诱导相应受体的酪氨酸激酶中的每一个的自动磷酸化。因此，通过这些生长因子所诱导的蛋白激酶抑制剂阻断细胞增殖的能力，直接与其阻断受体自动磷酸化的能力有关系。为了测定化合物的蛋白激酶抑制活性，使用下列结构。Stimulation of cell proliferation by growth factors such as VEGF and others depends on their induction of autophosphorylation of each of the tyrosine kinases of the corresponding receptors. Thus, the ability of protein kinase inhibitors induced by these growth factors to block cell proliferation is directly related to their ability to block receptor autophosphorylation. To determine the protein kinase inhibitory activity of the compounds, the following structures were used.

细胞生长的抑制：细胞毒性评价Inhibition of Cell Growth: Cytotoxicity Evaluation

使用四唑盐试验来测定细胞生长的抑制，其基于活细胞将溴化3-(4，5-二甲基噻唑-2-基)-2，5-[2H]-二苯基四唑(MTT)还原为甲(formazan)的能力。(Mossman，Journal of Immunological Methods，vol.65(1983)，pp.55-58)。然后用分光光度法检测不溶于水的紫色甲(forrmazan)产物。HCT 116细胞系生长在96孔培养皿中。在McCoy′s 5A介质中，将细胞以135μl/孔的体积在合适的介质中涂覆。在加入抑制剂化合物之前将平皿培养四个小时。在0.5％(v/v)二甲亚砜(15μL/孔)中加入不同浓度的抑制剂化合物，并将细胞在37℃(5％CO₂)下培养四至六天(根据细胞类型)。在培养结束时，加入MTT至0.2mg/mL的最后浓度，并将细胞在37℃下培养超过4小时。离心平皿并除掉介质后，甲(formazan)(溶解在二甲亚砜中)的吸光度可以在540纳米处测定。导致50％生长抑制的抑制剂化合物的浓度，是由抑制剂浓度对抑制百分数的半对数坐标图的线形部分来确定的。所有结果与只用0.5％(v/v)二甲亚砜处理的对照细胞相比。Inhibition of cell growth was determined using the tetrazolium salt assay, which is based on the conversion of 3-(4,5-dimethylthiazol-2-yl)-2,5-[2H]-diphenyltetrazolium bromide ( MTT) can be reduced to formazan. (Mossman, Journal of Immunological Methods, vol. 65 (1983), pp. 55-58). The water-insoluble purple formazan (forrmazan) product was then detected spectrophotometrically. The HCT 116 cell line was grown in 96-well dishes. Cells were plated in the appropriate medium at a volume of 135 [mu]l/well in McCoy's 5A medium. Plates were incubated for four hours prior to the addition of inhibitor compounds. Various concentrations of inhibitor compounds were added in 0.5% (v/v) dimethyl sulfoxide (15 μL/well), and cells were incubated at 37°C (5% CO₂ ) for four to six days (depending on cell type). At the end of the incubation, MTT was added to a final concentration of 0.2 mg/mL and the cells were incubated at 37°C for more than 4 hours. The absorbance of formazan (dissolved in dimethyl sulfoxide) can be measured at 540 nm after centrifuging the plate and removing the medium. The concentration of inhibitor compound that resulted in 50% growth inhibition was determined from the linear portion of a semi-log plot of inhibitor concentration versus percent inhibition. All results are compared to control cells treated with 0.5% (v/v) DMSO alone.

蛋白质激酶组protein kinase group

为了测定与各种蛋白质激酶相对照的CDK的抑制活性，本发明的化合物针对许多组蛋白激酶进行筛选。使用Davies，S等人在Specificity and Mechanism of Action of Some Commonly UsedProtein Kinase Inhibitors，Biochem J.351，95-105(2000)中描述的方法和物质来进行试验，它们的全部内容本文中引入作为参考。针对一组蛋白质激酶筛选化合物，蛋白质激酶包括：AMP-活化蛋白激酶(AMPK)，检验点激酶(CHK1)，酪蛋白激酶1和2(CK1和CK2)，胞质酪氨酸激酶(CSK)，双重丝氨酸/苏氨酸/酪氨酸激酶(DYRK1A)，糖原合酶激酶3(GSK3B)，c-Jun N-末端激酶(JNK)，淋巴细胞激酶(LCK)，促分裂原活化蛋白激酶2，K-1a，K2(MAPK2，MAPKAP-K1a和MAPKAP-K2)，MAPK激酶(MKK1，也称为MEK)，丝裂原和应激-活化蛋白激酶1(MSK1)，never-in-有丝分裂激酶6(NEK6)，p70核糖体蛋白S6激酶(P70s6K1)，3-磷酸肌醇-依赖性蛋白激酶1(PDK1)，磷酸化酶激酶(PHK)，蛋白激酶A(PKA)，蛋白激酶B(PKB，也称为Akt)，蛋白激酶C(PKCa)，p38-调节/活化激酶(PRAK)，Rho-依赖性蛋白激酶(ROCK-II)，应激-活化蛋白激酶2a、2b、3和4(SAPK-2A或p38，SAPK-2b或p38β2，SAPK3或p38γ，SAPK4或p38δ，分别地)，和血清-和糖皮质激素-诱导激酶(SGK)。将化合物活性划分为弱类型(＜50％)、中度类型(50-75％)和强烈抑制类型(＞75％)。正如下面表1所说明的那样，本发明的化合物是有效的CDK抑制剂，并且与摘自美国专利US No.6,555,539的3，5取代的吲唑相比较，具有意想不到的更好的CDK抑制剂选择性。To determine the inhibitory activity of CDKs compared to various protein kinases, the compounds of the invention were screened against a number of histone kinases. The assay was performed using the method and substances described by Davies, S et al., Specificity and Mechanism of Action of Some Commonly Used Protein Kinase Inhibitors, Biochem J. 351, 95-105 (2000), the entire contents of which are incorporated herein by reference. Screen compounds against a panel of protein kinases including: AMP-activated protein kinase (AMPK), checkpoint kinase (CHK1), casein kinases 1 and 2 (CK1 and CK2), cytoplasmic tyrosine kinase (CSK), Dual serine/threonine/tyrosine kinase (DYRK1A), glycogen synthase kinase 3 (GSK3B), c-Jun N-terminal kinase (JNK), lymphocyte kinase (LCK), mitogen-activated protein kinase 2 , K-1a, K2 (MAPK2, MAPKAP-K1a and MAPKAP-K2), MAPK kinase (MKK1, also known as MEK), mitogen and stress-activated protein kinase 1 (MSK1), never-in-mitotic kinase 6 (NEK6), p70 ribosomal protein S6 kinase (P70s6K1), 3-phosphoinositide-dependent protein kinase 1 (PDK1), phosphorylase kinase (PHK), protein kinase A (PKA), protein kinase B (PKB , also known as Akt), protein kinase C (PKCa), p38-regulated/activated kinase (PRAK), Rho-dependent protein kinase (ROCK-II), stress-activated protein kinases 2a, 2b, 3 and 4 ( SAPK-2A or p38, SAPK-2b or p38β2, SAPK3 or p38γ, SAPK4 or p38δ, respectively), and serum- and glucocorticoid-inducible kinases (SGKs). Compound activity was classified as weak (<50%), moderate (50-75%) and strongly inhibitory (>75%). As illustrated in Table 1 below, the compounds of the present invention are potent CDK inhibitors and are unexpectedly better CDK inhibitors than the 3,5 substituted indazoles taken from U.S. Patent No. 6,555,539 selective.

3，5吲唑化合物的激酶活性Kinase activity of 3,5 indazole compounds

表1   A^*   B^*   C^*   D^*   1   2   CDK2/A K₁(nM)   0.52   0.25   0.80   2.40   0.78   0.47   HCT-116IC₅₀(nM)   70   90   86   ＞500   120   22   Kinase   AMPK   ++   ++   ++   ++   ++   ++   CDK2/A   ++   ++   ++   ++   ++   ++   CHK1   +   +   -   -   -   -   CK1   -   -   -   -   -   -   CK2   -   -   -   -   -   -   CSK   -   -   -   -   -   -   DYRK1A   ++   ++   ++   ++   ++   ++   GSK3B   ++   ++   ++   ++   ++   ++   JNK   -   -   -   -   -   -   LCK   ++   ++   +   -   +   +   MAPK2   -   -   -   -   -   -   MAPKAP-K1a   ++   ++   ++   +   ++   -   MAPKAP-K2   -   -   -   -   -   -   MKK1   ++   +   +   +   -   -   MSK1   -   -   -   -   -   -   NEK6   -   -   -   -   -   -   P70s6K1   +   +   -   -   -   -   PDK1   +   -   -   -   -   -   PHK   ++   +   +   -   +   ++   PKA   ++   ++   +   -   -   -   PKB   -   -   -   -   -   -   PKCa   +   ++   +   -   -   -   PRAK   ++   +   ++   +   -   -   ROCK-II   ++   +   +   -   -   +   SAPK-2A   -   -   -   -   -   -   SAPK-2b   -   -   -   -   -   -   SAPK3   -   -   -   -   -   -   SAPK4   -   -   -   -   -   -   SGK   +   +   -   -   -   -

Table 1 A^* B^* C^* D^* 1 2 CDK2/A K₁ (nM) 0.52 0.25 0.80 2.40 0.78 0.47 HCT-116IC₅₀ (nM) 70 90 86 >500 120 twenty two Kinase AMPK ++ ++ ++ ++ ++ ++ CDK2/A ++ ++ ++ ++ ++ ++ CHK1 + + - - - - CK1 - - - - - - CK2 - - - - - - CSK - - - - - - DYRK1A ++ ++ ++ ++ ++ ++ GSK3B ++ ++ ++ ++ ++ ++ JNK - - - - - - LCK ++ ++ + - + + MAPK2 - - - - - - MAPKAP-K1a ++ ++ ++ + ++ - MAPKAP-K2 - - - - - - MKK1 ++ + + + - - MSK1 - - - - - - NEK6 - - - - - - P70s6K1 + + - - - - PDK1 + - - - - - PHK ++ + + - + ++ PKA ++ ++ + - - - PKB - - - - - - PKCa + ++ + - - - PRAK ++ + ++ + - - ROCK-II ++ + + - - + SAPK-2A - - - - - - SAPK-2b - - - - - - SAPK3 - - - - - - SAPK4 - - - - - - SGK + + - - - -

++强烈抑制＞75％++ strongly suppressed >75%

+中度抑制50-75％+ Moderate suppression 50-75%

-弱抑制＜50％- weak inhibition <50%

*化合物A、B、C和D在美国专利US No.6,555,539中描述。*Compounds A, B, C and D are described in US Patent No. 6,555,539.

为了测定式I化合物对其它激酶即VEGF或FGFR(成纤维细胞生长因子受体)激酶的CDK选择性，可以容易地进行额外的试验。这样的试验在美国专利US No.6,555,539和WO 03/004488中描述，并在本领域是已知的。Additional assays can readily be performed to determine the CDK selectivity of compounds of formula I for other kinases, namely VEGF or FGFR (fibroblast growth factor receptor) kinases. Such assays are described in U.S. Patent No. 6,555,539 and WO 03/004488 and are known in the art.

可以将如上所述的示范性化合物，按照下列通常的实施例配制成为药物组合物。The exemplary compounds described above can be formulated into pharmaceutical compositions according to the following general examples.

肠胃外的组合物Parenteral Compositions

为了制备适合于注射给药的肠胃外的药物组合物，可以将100mg的式I化合物的水溶盐溶于DMSO中，然后与10mL的0.9％无菌生理盐水混合。将混合物并入适合于注射给药的剂量单元剂型中。In order to prepare a parenteral pharmaceutical composition suitable for injection administration, 100 mg of the water-soluble salt of the compound of formula I can be dissolved in DMSO, and then mixed with 10 mL of 0.9% sterile physiological saline. The mixture is incorporated into dosage unit dosage forms suitable for administration by injection.

口服组合物oral composition

为了制备用于口服递送的药物组合物，可以将100mg的式I化合物与750mg乳糖混合。可以将混合物并入口服剂量单位，例如适合于口服的硬胶囊。To prepare a pharmaceutical composition for oral delivery, 100 mg of a compound of formula I may be mixed with 750 mg of lactose. The mixture can be incorporated into oral dosage units, such as hard capsules suitable for oral administration.

同时本发明已经引证了具体和优选的实施方案来举例说明，本领域技术人员将会认识到，通过常规实验和本发明的实践，可以进行改变和改进。因此，本发明不想通过上述说明书加以限制，但通过附加的权利要求书和它们的同等方式加以限定。While the invention has been illustrated by reference to specific and preferred embodiments, those skilled in the art will recognize that changes and modifications can be made through routine experimentation and practice of the invention. Accordingly, the invention is not intended to be limited by the foregoing description, but is defined by the appended claims and their equivalents.

Claims (9)

1. the compound of formula I or pharmacologically acceptable salts or solvate:

R wherein¹, R², R³And R⁴Be selected from H, halogen, cyano group, nitro, trifluoromethoxy, trifluoromethyl, azido-, hydroxyl, C₁-C₆Alkoxyl group, C₁-C₁₀Alkyl, C₂-C₆Thiazolinyl, C₂-C₆Alkynyl ,-C (O) R⁵,-C (O) OR⁵,-OC (O) R⁵,-NR⁵C (O) R⁶,-C (O) NR⁵R⁶,-(CR⁵R⁶) NR⁷R⁸,-CR⁵R⁶NR⁷R⁸,-NR⁵OR⁶,-SO₂NR⁵R⁶,-S (O)_j(C₁-C₆Alkyl), wherein j is 0 to 2 integer ,-(CR⁵R⁶)_t(C₆-C₁₀Aryl) ,-(CR⁵R⁶)_t(C₃-C₁₀Cycloalkyl) ,-(CR⁵R⁶)_t(4-10 unit heterocycle) ,-(CR⁵R⁶)_qC (O) (CR⁷R⁸)_t(C₆-C₁₀Aryl) ,-(CR⁵R⁶)_qC (O) (CR⁷R⁸)_t(C₃-C₁₀Cycloalkyl) ,-(CR⁵R⁶)_qC (O) (CR⁷R⁸)_t(4-10 unit heterocycle) ,-(CR⁵R⁶)_tO (CR⁷R⁸)_q(C₆-C₁₀Aryl) ,-(CR⁵R⁶)_tO (CR⁷R⁸)_q(C₃-C₁₀Cycloalkyl) ,-(CR⁵R⁶)_tO (CR⁷R⁸)_q(4-10 unit heterocycle) ,-(CR⁵R⁶)_qSO₂(CR⁷R⁸)_t(C₆-C₁₀Aryl) ,-(CR⁵R⁶)_qSO₂(CR⁷R⁸)_t(C₃-C₁₀Cycloalkyl) and-(CR⁵R⁶)_qSO₂(CR⁷R⁸)_t(4-10 unit heterocycle), wherein q and t each be from 0 to 5 integer independently, above-mentioned R¹, R², R³Or R⁴1 or 2 ring carbon atom of the cycloalkyl of group or heterocyclic moiety is optional by an oxo (=O) group replacement, each R⁵, R⁶, R⁷And R⁸Be independently selected from H, C₁-C₆Alkyl; And R wherein¹, R², R³And R⁴Not H simultaneously.

2. according to compound or pharmacologically acceptable salts or solvate, the wherein R of claim 1¹Be-(CR⁵R⁶) NR⁷R⁸, R², R³And R⁴Be independently selected from H or F.

3. according to compound or pharmacologically acceptable salts or solvate, the wherein R of claim 1¹Be the ethylamino methyl, R³Be H, R²And R⁴Be F.

4. according to compound or pharmacologically acceptable salts or solvate, the wherein R of claim 1¹Be the ethylamino methyl, R²And R⁴Be H, R³Be F.

5. be selected from following compound or pharmacologically acceptable salts or solvate:

Or

6. treatment is by the disease of kinase whose inhibition mediation or the method for obstacle, comprises patient that these needs are arranged compound or pharmacologically acceptable salts or the solvate according to claim 5.

7. a method for the treatment of fungi infestation, cancer or tumour and other and undesirable vasculogenesis and/or cell proliferation disease states associated comprises compound or pharmacologically acceptable salts or the solvate according to the claim 5 that give significant quantity.

8. by giving compound or pharmacologically acceptable salts or the solvate method that optionally suppress CDK kinase activity of son according to claim 5.

9. one kind contains according to the compound of claim 5 or the pharmaceutical composition of pharmacologically acceptable salts or solvate.