TW201231467A - Pyrazolopyridine kinase inhibitors - Google Patents

Abstract

The present invention relates to compounds useful as inhibitors of protein kinase. The invention also provides pharmaceutically acceptable compositions comprising said compounds and methods of using the compositions in the treatment of various disease, conditions, or disorders. The invention also provides processes for preparing compounds of the inventions.

Description

201231467 六、發明說明： 本申請案主張2010年1月27曰提出申請之美國臨時申請 案第61/298,649號、及2010年11月5日提出申請之美國臨時 申請案第61/41〇,426號的權利，其皆以引用方式併入本文 中。 【先前技術】 蛋白質激§#構成了負貝控制細胞内各種信號轉導過程之 結構相關性酶的大家族（參見Hardie，G及Hanks，S. The201231467 VI. INSTRUCTIONS: This application claims US Provisional Application No. 61/298,649, filed on January 27, 2010, and US Provisional Application No. 61/41, 426, filed on November 5, 2010. The rights of the number are incorporated herein by reference. [Prior Art] Protein §# constitutes a large family of structurally related enzymes that control the various signal transduction processes in cells (see Hardie, G and Hanks, S. The

Protein Kinase Facts B〇〇k? I及 II，Academic Press，SanProtein Kinase Facts B〇〇k? I and II, Academic Press, San

Diego, CA: 1995)。 通常，蛋白質激酶藉由影響自三磷酸核苷至蛋白質受體 之涉及信號傳導路徑的磷醯基轉移來調介細胞内信號傳 導。該等磷酸化事件用作可調節或調控靶蛋白生物功能的 分子導通/關斷開關。該等磷酸化事件最終因應各種細胞 外刺激及其他刺激而觸發。該等刺激之實例包含環境及化 學應力信號（例如衝擊、熱衝擊、紫外線輻射、細菌内毒 素、及H2〇2)、細胞因子（例如介白素]及腫瘤壞死 因子a(TNF-a))、及生長因子（例如粒巨噬系集落刺激因子 (GM-CSF)、及成纖維細胞生長因子（FGF)卜細胞外刺激可 影響一或多種與以下有關之細胞反應：細胞生長、遷移、 刀化、激素分泌、轉錄因子活化、肌肉收縮、葡萄糖代 謝、蛋白質合成之控制、細胞循環之存活及調控。 激酶可藉由其所磷酸化之基質（例如蛋白質_酪胺酸、蛋 白質-絲胺酸/蘇胺酸、脂質等）而分成諸多家族。人們已識 153786.doc 201231467 別出通常對應於該等激酶家族中之每一者的序列基元（參 見（例如）Hanks，S.K.，Hunter, T·，FASEB J. .1995，9，576-596 ; Knighton等人，Science 1991，253, 407-414 ; Hiles等 人，Cell 1992，70，419-429 ; Kunz等人，Cell 1993，73, 585-596 ; Garcia-Bustos等人，EMBO J 1994，13，2352- 2361)» 絲胺酸/蘇胺酸激酶（即蛋白質激酶C-θ (PKC-Θ))係新穎 鈣獨立性PKC亞家族成員，其在T細胞及骨骼肌中選擇性 表現。若干條證據表明PKC-Θ在T細胞活化中發揮關鍵作 用。在抗原刺激T細胞時，PKC-Θ(而非其他PKC亞型）迅速 自細胞質轉移至T細胞與抗原呈遞細胞（APC)間之細胞接觸 位點，在此其與T細胞受體（TCR)—起定位於稱作中央超分 子活化簇（cSMAC)之區域中（Monks等人，1997，Nature, 385: 83-86 ; Monks等人，1998, Nature, 395: 82-86)。 已報導，PKC-Θ選擇性活化轉錄因子AP-1及NF-κΒ並整 合TCR及CD28共刺激信號，從而活化IL-2啟動子中之 CD28 反應元件（CD28RE)(Baier-Bitterlich等人，1996，Mol· Cell. Biol., 16: 1842-1850 ; Coudronniere 等人，2000, PNAS，97: 3394-3399)。在激酶死亡PKC-Θ突變體、或反義 PKC-Θ之表現以劑量依賴性方式抑制CD3/CD28共刺激之 NF-κΒ活化（而非TNF-α刺激之NF-κΒ活化）的研究中，突出 展現了 PKC-Θ在T細胞之CD3/CD28共刺激中之具體作用。 在其他PKC亞型中並未發現此現象（Lin等人，2000，Mol. Cell. Biol” 20: 2933-2940)。據報導，PKC-Θ 至 SMAC 之募 153786.doc 201231467 集係由其N-末端調節結構域進行調介且此對於T細胞活化 而言係必需的，此乃因過度表現之PKC-Θ催化片段並不轉 移且不能活化NF-κΒ，而PKC-Θ催化結構域-Lck膜結合結 構域嵌合體能夠重構信號傳導（Bi等人’ 2001，Nat. Immunol·，2:556-563) 〇 將PKC-Θ易位至SMAC似乎係由涉及Vav及PI3-激酶之較 大PLC-Y/DAG-獨立性機構調介的（Villalba等人’ 2002, JCB 157: 253-263)，而PKC-Θ之活化需要來自包含Lck、 ZAP-70、SLP-76、PLC-γ、Vav及PI3-激酶在内之若干信號 傳導組份的信號輸入（Liu等人，2000，JBC，275·· 3606-3609 ; Herndon等人，2001，J. Immunol.，166: 5654-5664 ; Dienz等人，2002，J. Immunol·，169: 365-372 ; Bauer等 人，2001 JBC.，276: 31627-31634)。PKC-Θ基因剔除小鼠 中之研究已證實該等人類T細胞中之生化研究，其確認此 酶在T細胞功能中發揮關鍵作用。PKC-Θ-Λ小鼠係健康且 能育之小鼠，其具有正常發育之免疫系統，但在成熟T細 胞活化中展現明顯缺陷（Sun等人，200，Nature, 404:402-407)。如同抗原活體内反應一般來抑制TCR及TCR/CD28共 刺激之增殖反應（>90%)。與人類T細胞中之研究一致，可 去除轉錄因子AP-1及NF-κΒ之活化，從而導致在IL_2產生 及IL-2 R上調中產生嚴重缺陷（Baier-Bitterlich等人，1996, MBC，16，1842 ; Lin 等人，2000，MCB，20，2933 ; Courdonniere, 2000，97，3394) 〇 最近，PKC-Θ-缺陷小鼠中 之研究表明PKC-Θ在自身免疫性疾病之小鼠模型的發育中 153786.doc 201231467 發揮一定作用，該等自身免疫性疾病包含多發性硬化 (MS)、類風濕性關節炎（RA)及大腸激躁症（IBD)(Salek-Ardakani 等人，2006 ; Tan 等人，2006 ; Healy 等人， 2006 ; Anderson等人，2006)。在該等模型中，PKC-Θ-缺 陷小鼠顯示，與自體反應T細胞之發育及效應子功能中之 明顯缺陷有關的疾病嚴重程度顯著減小。 除在τ細胞活化中之作用外，據報導，pkc-θ可調介保 護T細胞免受Fas-及UV-誘導性細胞凋亡影響之佛波醇酯-引起之存活信號（Villalba 等人，2001, J. Immunol. 166: 5955-5963 ； Berttolotto 等人，2000，275: 37246-37250)° 此促存活作用備受關注，此乃因人類PKC-Θ基因定位於染 色體10 (10pl 5)上，該染色體10係與引起T細胞白血病及淋 巴瘤之突變有關的區域（Erdel等人，1995，Genomics 25: 295-297 ; Verma等人，1987，J. Cancer Res. Clin. Oncol., 113: 192-196)。 在活體内，PKC-Θ在感染免疫應答中之作用取決於所遇 到之病原體的類型。PKC-Θ缺陷小鼠可引起對於若干病毒 感染及原生動物寄生蟲碩大利什曼原蟲（Leishmania major) 之正常Thl及細胞毒性T細胞介導之反應，且會有效清除該 等感染（Marsland 等人，2004 ; Berg-Brown 等人，2004 ; Marsland等人，2005 ; Giannoni等人，2005)。然而，PKC-Θ 缺陷小鼠不能引起對於寄生蟲巴西鼠鉤蟲（Nippostrongylus brasiliensis)及某些過敏原之正常Th2 T細胞反應（Marsland 等人，2004 ; Salek-Ardakani等人，2004)且不能清除單核 153786.doc 201231467 細胞增生利斯特菌（Listeria monocytogenes)感染（Sakowicz-Burkiewicz等人，2008)。顯而易見’在一些1情況下’可省 去T細胞活化對於PKC-Θ之需求，且此情況很可能涉及自 先天性免疫系統細胞、或直接自呈病原體相關性分子圖案 (PAMP)形式之病原體向T細胞提供額外信號（Marsland等 人，2007)。 最近，PKC-Θ-缺陷小鼠中之研究表明，PKC-Θ在自身免 疫性疾病（包含多發性硬化、類風濕性關節炎及炎性腸病） 小鼠模型之發育中發揮一定作用。在所考察之所有情形 下，PKC-Θ-缺陷小鼠顯示，與新發現種類T細胞-Th 17細胞 之發育中之明顯缺陷有關的疾病嚴重程度顯著減小（Salek-Ardakani 等人，2006 ; Tan 等人，2006 ; Healy 等人， 2006 ; Anderson等人，2006 ; Nagahama等人 ’ 2008)。因 此，PKC-Θ似乎對於自身免疫背景中之致病自體反應Thl 7 細胞之發育較為重要。該等發現可支持以下觀點：靶向 PKC-Θ提供了靶向自身免疫性T細胞反應從而使許多T細胞 反應（例如，對於病毒感染）保持完整的方式。 除在T細胞活化中之作用外，PKC-Θ可調介保護T細胞免 受Fas-及UV-誘導性細胞凋亡影響之佛波醇酯-引起之存活 信號（Villalba 等人，2001，J. Immunol. 166: 5955-5963 ; Berttolotto等人，2000，275: 37246-37250)。此促存活作用 備受關注，此乃因人類PKC-Θ基因定位於染色體10 (1 Op 15) 上，該染色體10係與引起T細胞白血病及淋巴瘤之突變有 關的區域（Erdel等人，1995, Genomics 25: 295-297 ; Verma 153786.doc 201231467 荨人，1987，J. Cancer Res. Clin. Oncol·，1 13: 192-196)。 總之，該等數據表明’ PKC-Θ係炎性病症、免疫病症、 淋巴瘤及T細胞白血病中之治療性干預的吸引性把。 因此’業内迫切需要研發用作蛋白質激酶抑制劑之化合 物。特定而言’期望研發用作PKC-Θ抑制劑之化合物，尤 其在實施當前可用於大部分涉及其活化之病症之不適當治 療時。 【發明内容】 一般而言’本發明提供用作激酶抑制劑之化合物。 在一實施例中’本發明化合物由結構式j代表：Diego, CA: 1995). In general, protein kinases mediate intracellular signalling by affecting phosphonium-based transduction of signal transduction pathways from nucleoside triphosphates to protein receptors. These phosphorylation events are used as molecular on/off switches that modulate or modulate the biological function of the target protein. These phosphorylation events are ultimately triggered by a variety of extracellular stimuli and other stimuli. Examples of such stimuli include environmental and chemical stress signals (eg, shock, thermal shock, ultraviolet radiation, bacterial endotoxin, and H2〇2), cytokines (eg, interleukin), and tumor necrosis factor a (TNF-a). And growth factors (such as granulocyte-macrophage colony-stimulating factor (GM-CSF), and fibroblast growth factor (FGF) extracellular stimulation can affect one or more of the following cellular responses: cell growth, migration, knives Chemotherapy, hormone secretion, activation of transcription factors, muscle contraction, glucose metabolism, control of protein synthesis, survival and regulation of cell cycle. The kinase can be phosphorylated by its matrix (eg protein_tyrosine, protein-serine) /threonine, lipids, etc.) and divided into families. It is known that 153786.doc 201231467 excludes sequence motifs that usually correspond to each of these kinase families (see, for example, Hanks, SK, Hunter, T · FASEB J. . 1995, 9, 576-596; Knighton et al, Science 1991, 253, 407-414; Hiles et al, Cell 1992, 70, 419-429; Kunz et al, Cell 1993, 73, 585 -596 ; Garcia- Bustos et al, EMBO J 1994, 13, 2352-2361) » Serine/threonine kinase (ie protein kinase C-theta (PKC-Θ)) is a novel calcium-independent PKC subfamily member, which is in T cells. And selective expression in skeletal muscle. Several lines of evidence suggest that PKC-Θ plays a key role in T cell activation. When antigen-stimulated T cells, PKC-Θ (rather than other PKC isoforms) rapidly metastasize from cytoplasm to T cells a cell contact site between antigen presenting cells (APCs), which is localized to the T cell receptor (TCR) in a region called the central supramolecular activation cluster (cSMAC) (Monks et al., 1997, Nature, 385: 83-86; Monks et al., 1998, Nature, 395: 82-86) It has been reported that PKC-Θ selectively activates transcription factors AP-1 and NF-κΒ and integrates TCR and CD28 costimulatory signals to activate CD28 response element (CD28RE) in the IL-2 promoter (Baier-Bitterlich et al, 1996, Mol. Cell. Biol., 16: 1842-1850; Coudronniere et al, 2000, PNAS, 97: 3394-3399). Inhibition of CD3/CD28 costimulatory NF-κΒ activity in a dose-dependent manner in the expression of kinase-depleted PKC-Θ mutant, or antisense PKC-Θ (Not stimulated with TNF-α activation of NF-κΒ) study, the protruding show PKC-Θ specific role in the CD3 T cell / CD28 co-stimulation of. This phenomenon was not found in other PKC subtypes (Lin et al., 2000, Mol. Cell. Biol 20: 2933-2940). It is reported that PKC-Θ to SMAC was raised by 153786.doc 201231467 by its N - The terminal regulatory domain is mediated and this is necessary for T cell activation, as the overexpressed PKC-Θ catalytic fragment does not transfer and does not activate NF-κΒ, whereas the PKC-Θ catalytic domain-Lck Membrane-bound domain chimeras are capable of reconstituting signaling (Bi et al' 2001, Nat. Immunol., 2:556-563). The translocation of PKC-Θ to SMAC appears to be greater by Vav and PI3-kinase. PLC-Y/DAG-independent agency (Villalba et al. 2002, JCB 157: 253-263), and activation of PKC-Θ requires Lck, ZAP-70, SLP-76, PLC-γ, Signal input to several signaling components, including Vav and PI3-kinase (Liu et al., 2000, JBC, 275·3606-3609; Herndon et al., 2001, J. Immunol., 166: 5654-5664; Dienz Et al, 2002, J. Immunol, 169: 365-372; Bauer et al, 2001 JBC., 276: 31627-31634. Studies in PKC-Θ gene knockout mice have confirmed these Biochemical studies in T-like cells confirm that this enzyme plays a key role in T cell function. PKC-Θ-Λ mice are healthy and fertile mice with a normally developing immune system but at mature T cells Significant defects in activation (Sun et al, 200, Nature, 404: 402-407). Inhibition of TCR and TCR/CD28 co-stimulation proliferative responses (> 90%) as in vivo antigen reactions. In the study, the activation of the transcription factors AP-1 and NF-κΒ was removed, resulting in serious defects in IL_2 production and IL-2 R upregulation (Baier-Bitterlich et al., 1996, MBC, 16, 1842; Lin Et al, 2000, MCB, 20, 2933; Courdonniere, 2000, 97, 3394) Recently, studies in PKC-Θ-deficient mice have shown that PKC-Θ is involved in the development of a mouse model of autoimmune disease 153786. Doc 201231467 plays a role in these autoimmune diseases including multiple sclerosis (MS), rheumatoid arthritis (RA) and irritable bowel syndrome (IBD) (Salek-Ardakani et al., 2006; Tan et al., 2006). Healy et al., 2006; Anderson et al., 2006). In these models, PKC-Θ-deficient mice showed a significant reduction in the severity of the disease associated with the development of autoreactive T cells and significant defects in effector function. In addition to its role in the activation of tau cells, it has been reported that ppk-θ can mediate survival signals induced by phorbol esters that protect T cells from Fas- and UV-induced apoptosis (Villalba et al., 2001, J. Immunol. 166: 5955-5963; Berttolotto et al., 2000, 275: 37246-37250) ° This pro-survival effect is of concern because the human PKC-Θ gene is localized on chromosome 10 (10pl 5) This chromosome 10 is associated with a region that causes mutations in T cell leukemia and lymphoma (Erdel et al., 1995, Genomics 25: 295-297; Verma et al., 1987, J. Cancer Res. Clin. Oncol., 113: 192-196). In vivo, the role of PKC-Θ in the immune response to infection depends on the type of pathogen encountered. PKC-Θ deficient mice can cause normal Th1 and cytotoxic T cell-mediated responses to several viral infections and protozoan parasite Leishmania major, and will effectively eliminate such infections (Marsland et al. People, 2004; Berg-Brown et al., 2004; Marsland et al., 2005; Giannoni et al., 2005). However, PKC-Θ deficient mice did not cause normal Th2 T cell responses to the parasite Nippostrongylus brasiliensis and certain allergens (Marsland et al., 2004; Salek-Ardakani et al., 2004) and could not clear the list. Nuclear 153786.doc 201231467 Listeria monocytogenes infection (Sakowicz-Burkiewicz et al., 2008). It is obvious that 'in some cases' can eliminate the need for T cell activation for PKC-Θ, and this situation is likely to involve pathogens from congenital immune system cells, or directly from pathogen-associated molecular pattern (PAMP). T cells provide additional signals (Marsland et al., 2007). Recently, studies in PKC-Θ-deficient mice have shown that PKC-Θ plays a role in the development of mouse models of autoimmune diseases including multiple sclerosis, rheumatoid arthritis and inflammatory bowel disease. In all cases examined, PKC-Θ-deficient mice showed a significant reduction in disease severity associated with significant defects in the development of newly discovered T cell-Th 17 cells (Salek-Ardakani et al., 2006; Tan et al., 2006; Healy et al., 2006; Anderson et al., 2006; Nagahama et al. '2008). Therefore, PKC-Θ appears to be important for the development of Thl 7 cells in the autoimmune background of autoimmune responses. These findings may support the notion that targeting PKC-Θ provides a means to target autoimmune T cell responses to keep many T cell responses (e.g., for viral infections) intact. In addition to its role in T cell activation, PKC-Θ can mediate phorbol ester-induced survival signals that protect T cells from Fas- and UV-induced apoptosis (Villalba et al., 2001, J) Immunol. 166: 5955-5963; Berttolotto et al., 2000, 275: 37246-37250). This pro-survival effect is of concern because the human PKC-Θ gene is localized on chromosome 10 (1 Op 15), a region related to mutations that cause T-cell leukemia and lymphoma (Erdel et al., 1995). , Genomics 25: 295-297; Verma 153786.doc 201231467 Deaf, 1987, J. Cancer Res. Clin. Oncol·, 1 13: 192-196). Taken together, these data indicate the attractiveness of therapeutic interventions in 'PKC-lanthanide inflammatory disorders, immune disorders, lymphomas, and T-cell leukemias. Therefore, there is an urgent need in the industry to develop a compound for use as a protein kinase inhibitor. In particular, it is desirable to develop compounds for use as PKC-oxime inhibitors, particularly when implementing undue treatment currently available for most of the conditions involved in their activation. SUMMARY OF THE INVENTION Generally, the present invention provides compounds useful as kinase inhibitors. In one embodiment, the compound of the invention is represented by structural formula j:

或其醫藥上可接受之鹽。 T係-NH-或不存在。 每一 Jci 及 Jc2 皆獨立地係 _cn、-F、-Cl、-OR、-CH2〇R、 或-CF3。 每一 1)丨、U2、及u3皆獨立地係_H、z、或Jb，其中α、 U2、及U3中之至多一者係_Η ;或υ〗、U2、及U3中之兩者連 接至一起形成獨立地經一或多個Je取代之具有0-1個雜原子 153786.doc 201231467 的C1-C6環烷基環。 Z係 Y2-Q2。 Y2不存在或係視需要且獨立地經一或多個Jd取代之C1-6 烷基。 Q2不存在或係視需要且獨立地經一或多個Je取代之具有 0-1個雜原子的C3-C8環烷基，其中Y2及Q2二者不可同時 不存在（在U,、U2 '及U3係Z時）。 每一 Jb獨立地係-F、-OR、-CN、-CF3、_N(R)2、-C(0)N(R)2、 視需要且獨立地經一或多個Ja取代之C1 ·6烷基。 每一 Ja獨立地係-F、-OR、-N(R)2、或-C(0)N(R)2。 每一 Jd獨立地係-OR、-CN、-C(0)N(R)2、-N(R)2 或 F。 每一 Je獨立地係C1-C6烷基、-OR、_N(R)2 cf3、或F。 每一 R係-Η或C1-C6烷基。 其中由*指示之碳係對掌性中心。 在一實施例中，本發明係治療或預防個體之蛋白質激酶 介導之病狀之方法’其包括向個體投與有效量之本發明之 化合物、其醫藥上可接受之鹽、或組合物。 在實施例中，本發明係製備用於治療或預防個體之蛋 白質激酶介導之病狀的本發明之化合物、其醫藥上可接受 之鹽、或組合物。 在另-實施例中，本發明之化合物、其醫藥上可接受之 鹽、及組合物亦用於研究生物及病理學現象中之激酶、研 究由該等_調介之細胞㈣號料路彳t、及對比性評估 新穎激酶抑制劑。 153786.doc 201231467 【實施方式】 本發明係關於用作蛋白質激酶抑制劑之化合物、其醫藥 上可接受之鹽、及組合物（例如醫藥組合物）。 在一實施例中’本發明之化合物、其醫藥上可接受之 鹽、及組合物可有效地用作ρκχθ之抑制劑。 本發明化合物包含彼等概述於本文中者，且進一步由本 文所揭示之種類、子類、及物質予以闡釋。除非另有所 指，否則本文所用之本文所定義之定義應適用。出於本發 明之目的’根據元素週期表，CAS版，Handbook 〇f Chemistry and Physics，第75版來識別化學元素。此外， 有機化學之一般原則闡述於「Organic Chemistry」， Thomas Sorrell, University Science Books, Sausalito： 1999、及「March's AdvancedOrganic Chemistry」，第 5 版：Smith, M.B.及 March, J·，John Wiley & Sons，NewOr a pharmaceutically acceptable salt thereof. T-NH- or not present. Each Jci and Jc2 is independently _cn, -F, -Cl, -OR, -CH2〇R, or -CF3. Each 1) 丨, U2, and u3 are independently _H, z, or Jb, wherein at most one of α, U2, and U3 is _Η; or υ, U2, and U3 The C1-C6 cycloalkyl rings having 0-1 heteroatoms 153786.doc 201231467, which are independently substituted by one or more Je, are joined together. Z series Y2-Q2. Y2 is absent or C1-6 alkyl substituted with one or more Jd as needed. Q2 is a C3-C8 cycloalkyl group having 0-1 heteroatoms which is not present or which is optionally substituted by one or more Je, wherein neither Y2 nor Q2 are simultaneously absent (in U, U2' And when U3 is Z)). Each Jb is independently -F, -OR, -CN, -CF3, _N(R)2, -C(0)N(R)2, C1 substituted as needed and independently by one or more Jas. 6 alkyl. Each Ja is independently -F, -OR, -N(R)2, or -C(0)N(R)2. Each Jd is independently -OR, -CN, -C(0)N(R)2, -N(R)2 or F. Each Je is independently a C1-C6 alkyl group, -OR, _N(R)2 cf3, or F. Each R is a hydrazine or a C1-C6 alkyl group. The carbon line indicated by * is the palm center. In one embodiment, the invention is a method of treating or preventing a protein kinase mediated condition in an individual' which comprises administering to the subject an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof, or a composition. In the embodiments, the invention is a compound, a pharmaceutically acceptable salt, or a composition thereof, for use in the treatment or prevention of a protein kinase mediated condition in a subject. In another embodiment, the compounds of the present invention, pharmaceutically acceptable salts thereof, and compositions are also useful in the study of kinases in biological and pathological phenomena, and in the study of cells (four) t, and comparative evaluation of novel kinase inhibitors. 153786.doc 201231467 [Embodiment] The present invention relates to a compound for use as a protein kinase inhibitor, a pharmaceutically acceptable salt thereof, and a composition (e.g., a pharmaceutical composition). In one embodiment, the compound of the present invention, a pharmaceutically acceptable salt thereof, and a composition are effective as inhibitors of ρκχθ. The compounds of the present invention are included as they are summarized herein, and further exemplified by the classes, subclasses, and substances disclosed herein. Unless otherwise indicated, the definitions defined herein are intended to apply. For the purposes of the present invention, chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook 〇f Chemistry and Physics, 75th edition. In addition, the general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry", 5th edition: Smith, MB and March, J., John Wiley & Sons , New

York: 2001中，其全部内容皆以引用方式併入本文中。 在一實施例中，本發明化合物由如上所述之結構式I代 表。 在另一實施例中，對於式I化合物，U!係Z且U3係Jb，且 變量之剩餘部分如上所述。 在另一實施例中，對於式I化合物，U!及u2係z且u3係 Jb，且變量之剩餘部分如上所述。 在另一實施例中，對於式I化合物，Y2係視需要且獨立 地經一或多個Jd取代之C hC3烷基。Q2不存在或係視需要 且獨立地經一或多個Je取代之C3-C6院基。每一 Jd獨立地 153786.doc • 10· 201231467 係-OR、或F，且變量之剩餘部分如上所述。 在另一實施例中，對於式I化合物，Jb係-OH或-NH2，且 變量之剩餘部分如上所述。 在另一實施例中，對於式I化合物，Jb係-OH，且變量之 剩餘部分如上所述。 在另一實施例中，對於式I化合物，每一 Jcl及Jc2皆獨立 地係-CF3、-CN、-F、或-C1B，且變量之剩餘部分如上所 述0 在另—實施例中，對於式I化合物，每一 Jcl及Jc2皆獨立 地係-F、或_ci，且變量之剩餘部分如上所述。 在另一實施例中，對於式I化合物，每一 Jcl及Jc2皆 係-F ’且變量之剩餘部分如上所述。 在另一實施例中，對於式I化合物，Jcl係F且JC2係C1 ;或 Jci 係 C1 且 je2係 f。 在某些實施例中，式I化合物不為：York: 2001, the entire contents of which are incorporated herein by reference. In one embodiment, the compounds of the invention are represented by structural formula I as described above. In another embodiment, for the compound of formula I, U! is Z and U3 is Jb, and the remainder of the variables are as described above. In another embodiment, for the compound of formula I, U! and u2 are z and u3 is Jb, and the remainder of the variables are as described above. In another embodiment, for a compound of formula I, Y2 is optionally substituted with one or more Jd substituted ChC3 alkyl groups. Q2 does not exist or is optionally substituted with one or more Je substituted C3-C6 yards. Each Jd is independently 153786.doc • 10· 201231467 is -OR, or F, and the remainder of the variable is as described above. In another embodiment, for the compound of formula I, Jb is -OH or -NH2 and the remainder of the variables are as described above. In another embodiment, for the compound of formula I, Jb is -OH and the remainder of the variables are as described above. In another embodiment, for the compound of Formula I, each Jcl and Jc2 are independently -CF3, -CN, -F, or -C1B, and the remainder of the variables are as described above. In another embodiment, For the compounds of formula I, each Jcl and Jc2 are independently -F, or -ci, and the remainder of the variables are as described above. In another embodiment, for the compound of formula I, each Jcl and Jc2 is -F' and the remainder of the variables are as described above. In another embodiment, for a compound of formula I, Jcl is F and JC2 is C1; or Jci is C1 and je2 is f. In certain embodiments, the compound of Formula I is not:

在一實施例中’本發明化合物由結構式Π代表： I53786.doc -11 - 201231467 上In one embodiment, the compound of the invention is represented by the structural formula: I53786.doc -11 - 201231467

(」b)w 或其醫藥上可接受之鹽，其中： T係-CH2-、-CH(Jb)-、-C(Jb)2-、-NH-或-N(Jb)-。 t為 0、1、或2。 w為0或1。 每一八獨立地係 CN、F、Cl、-OR、-CH2OR、或 CF3。 U係Z或Jb。 Z係 Y2-Q2 〇 Y2不存在或係視需要且獨立地經一或多個jd取代之Cl_6 烷基。 Q2不存在或係視需要且獨立地經一或多個je取代之具有 0-1個雜原子的C3-C8環烷基；其中Y2及Q2二者不可同時 不存在。 每一 Jb獨立地係-F、-OR、-CN、-CF3、-N(R)2、-C(0)N(R)2、 視需要且獨立地經一或多個Ja取代之Cl-6烷基。 每一 Ja獨立地係-F、-OR、-N(R)2、或-C(0)N(R)2。 每一 Jd獨立地係-〇R、-CN、-C(0)N(R)2、-N(R)2 或 ρ。 每一 Je獨立地係-〇R、CF3、_N(R)2 或 F。 153786.doc •12· 201231467 每一 R係-Η或C1-C6烧基。 前提係該化合物不為：("b)w or a pharmaceutically acceptable salt thereof, wherein: T is -CH2-, -CH(Jb)-, -C(Jb)2-, -NH- or -N(Jb)-. t is 0, 1, or 2. w is 0 or 1. Each of the eight is independently CN, F, Cl, -OR, -CH2OR, or CF3. U series Z or Jb. Z-line Y2-Q2 〇 Y2 is absent or is optionally substituted with one or more jd-substituted Cl_6 alkyl groups. Q2 is a C3-C8 cycloalkyl group having 0-1 heteroatoms which is not present or which is optionally substituted by one or more je; wherein neither Y2 nor Q2 are simultaneously absent. Each Jb is independently -F, -OR, -CN, -CF3, -N(R)2, -C(0)N(R)2, optionally and independently substituted by one or more Ja -6 alkyl. Each Ja is independently -F, -OR, -N(R)2, or -C(0)N(R)2. Each Jd is independently - 〇R, -CN, -C(0)N(R)2, -N(R)2 or ρ. Each Je is independently - 〇R, CF3, _N(R)2 or F. 153786.doc •12· 201231467 Each R-based or C1-C6 alkyl group. The prerequisite is that the compound is not:

在一實施例中，結構式II之化合物具有下列結構式：In one embodiment, the compound of formula II has the formula:

如本文所述，原子之指定數字範圍包含其中之任一整 數。舉例而言，具有1-4個原子之基團可具有i、2、3、或 4個原子。 本文所用之術語「不存在 變量並不存在於該實施例中 及「鍵」可互換使用以意指 亦即該變量並不代表原子或 153786.doc •13- 201231467 原子基團。 本文所用之術語「穩定」係指如下化合物：在出於本文 所揭示之一或多個目的而經受其製備、檢測、回收、儲 存、純化、及使用之條件時，其並不發生實質性變化。在 一些實施例中，穩定化合物或化學上可行之化合物係如下 化合物：其在机或以下之溫度下、在不存在水分或其他 化學反應條件下保持至少一週時並不發生實質性變化。 本文所用之術語「脂肪族」或「脂肪族基團」意指完全 飽和或含有一或多個不飽和單元但並非芳族的直鏈（亦 即，無支鏈）、或具支鏈烴鏈。 除非另有所指，否則脂肪族基團含有1-20個脂肪族碳原 子。在一些實施例中，脂肪族基團含有卜1〇個脂肪族碳原 子。在其他實施例中，脂肪族基團含有丨_8個脂肪族碳原 子。在其他實施例中，脂肪族基團含有丨_6個脂肪族碳原 子，且在其他實施例中，脂肪族基團含有丨_4個脂肪族碳 原子。脂肪族基團可為直鏈或具支鏈烷基、烯基、或炔 基。具體實例包含但不限於曱基、乙基、異丙基、正丙 基第一-丁基、乙烯基、正丁醇、噻吩基、及第三·丁 基。 本文所用之術語「烷基」意指飽和直鏈或具支鏈烴。本 文所用之術語「烯基」意指包括一或多個雙鍵之直鏈或具 支鏈烴。本文所用之術語「炔基」意指包括一或多個三鍵 之直鏈或具支鏈烴。 術。。環知肪族」（或「碳環」）係指具有3至14個環碳 153786.doc -14- 201231467 ====’其可為•環或含有-或多個 該術語亦包含二 合、螺或橋接碳環系統。 .^ 厌衣 〇至—或多個非芳族碳環或雜jf $ -或多個芳環或其組合之多環系統或 點位於碳環上。稠合雙環系統包括兩二=連接 之環，螺共用3個或4個相鄰環原子 包〜二系統共用一個環原子。環脂肪族基團之實例 ::::於環院基及環縣。具體實例包含但不= 己基裱丙烯基、環丙基及環丁基。 本文所用之術語「雜環」（或「雜環 之」）係指具有3至14個環原 5 ”環 工G ,, 具中一或多個環碳由雜屌 歹,，N、s、或0)代替之非芳族單環，直可、 2有—或多個不飽和單元。該術語包含多科合、 橋接雜環系統。該術語亦包含雜環可稠合至—或多二 族碳環或雜環或-或多個芳環或其组合之多環系兑: 連接基團或連接點位於雜環上。 :’、 L “ 貫例包含但不限於 ^比絲m秦基、料咬基1。㈣基、㈣咬 二！：環庚院基、二氮雜環庚貌基、三氮雜環庚烧基、 啶某：、-氮％辛基、三氮環辛基、噁唾啶基、異噁唑 坐啶基、異噻唑啶基、氧氮環辛基、氧氮雜環庚 疋基、硫氮雜環庚院基、錢環辛基、苯并咪㈣嗣基、 四氮咬喃基、四氮售吩基、四氮笨硫基、嗎琳基(包：例 =基、4·嗎：基、2，嗎琳基、3•琉嗎琳基、4·硫 馬琳基)一咬基、2，各咬基、3*定基 153786.doc -15· 201231467 。比嗓基、2_六氫。比嗓基、3·六氫。比嗪基、^比哇钱、3 。比㈣基、4-W基、…咬基、卜六氫心、2: 六氫吡啶基、3_六氫吡啶基、4_六氫吡啶基、2_噻唑啶 基、3-嗟唾咬基、4_嗟„坐„定基、μ米心定基、2_味唑啶 基、4-咪唾啶基、5·咪唾啶基、二氫十朵基、四氫啥啉 基、四氫異啥琳基、苯并硫味基、苯并二嗟炫基、二氣_ 苯并米坐-2-酮基、及1，3_二氫m綱基、氮雜雙環戊 基氮雜雙環己基'氮雜雙環庚基、氮雜雙環辛基、氮雜 雙環壬基、氮雜雙環癸基、二氮雜雙環己基、二氮雜雙環 庚基一氫吲唑基、二氫苯并咪唑基、四氫n比啶基、二氫 吡啶基、四氫吡嗪基、二氫吡嗪基、四氫嘧啶基、二氫嘧 啶基、二氫吡咯基'二氫吡唑基、二氫咪唑基、八氫吡咯 并吡嗪基、八氫η比咯并吼啶基、八氫吡啶并吡嗪基、八氫 吡啶并吡啶基、二氮雜雙環辛基、二氮雜雙環壬基、及二 氮雜雙環癸基。 如本文所用，除非另有所述’否則雙環可為稠合、螺及 橋接環。 術語「雜原子」意指氧、硫、氮、磷、或矽中之—或多 者（包含：氮、硫、磷、或矽之任一氧化形式；任—驗性 氮之四級銨化形式或；雜環之可取代氮，例如Ν(如3,4_二 氫-2Η-吡咯基中）、ΝΗ(如吡咯啶基中）或NR+(如Ν-取代之 °比咯啶基中））。 本文所用之術語「不飽和」意指具有一或多個不飽和單 元之部分。 153786.doc •16- 201231467 本文所用之術5吾「烧氧基」、或「硫代炫基」係指經由 氧（「烷氧基」’例如，-〇_烷基）或硫（「硫代烷基」，例 如’ -S-烧基）原子連接至分子之如前文所定義的烷基。 術語「_代烷基」、「_代烯基」、「幽代脂肪族基團」、 及「函代烷氧基」（或「胺基烷基」、「羥基烷基」等）意指 視情形可經一或多個齒素原子取代的烷基、烯基或烷氧 基。此術語包含全氟烷基，例如_CF3及_CF2C；F3。 術語「函素」、「齒基」、及「hal」意指F、C1、Br、或 I。術語鹵代脂肪族基團及_〇(鹵代脂肪族基團）包含單_、 二-及三-齒基取代之脂肪族基團。 術語「芳基」（單㈣作為較大部分之一部分使用，如 方烷基」、「方基烷氧基」、「芳氧基烷基」、或「雜芳 基」中）係指碳環及/或雜環芳環系統。術語「芳基」可I 術語「芳環」互換使用。 /、 …環基團僅具有碳環原子(通常⑷相）， =芳環（例如苯基）及兩個或更多個碳環芳環相互稠合之 稠合多環芳環系統。實例包含 ^ 2貧其古“ I』匕3 “萘基、2-萘基、i•惠基及 2-蒽基。亦包含於術語「 去孫—垆细入 及衷方&」（如本文所用）範圍内 例如在二氫^ ^ 方族哀（敛環或雜環）之基團， 菲啶其、i卜 兑胺基'奈二甲醯亞胺基、 非啶基、或四氫萘基中，其中 上。 連接基團或連接點位於芳環 術雜芳基（heteroaryl)」、r 芳基（heteroaryi gr〇up)j 及「雜 雜芳族」 芳族基團 、「雜芳環」、「雜 」（單獨或作為較 153786.doc •17· 201231467 大部分之一As used herein, the specified numerical range of atoms includes any integer. For example, a group having 1-4 atoms may have i, 2, 3, or 4 atoms. As used herein, the term "non-existing variables" does not exist in this embodiment and "keys" are used interchangeably to mean that the variable does not represent an atom or an atomic group. The term "stable" as used herein, refers to a compound that does not undergo substantial changes when subjected to conditions for its preparation, detection, recovery, storage, purification, and use for one or more of the purposes disclosed herein. . In some embodiments, the stabilizing compound or chemically feasible compound is a compound that does not undergo substantial changes at or below the temperature, in the absence of moisture or other chemical reaction conditions for at least one week. The term "aliphatic" or "aliphatic group" as used herein, means a straight chain (ie, unbranched) or a branched hydrocarbon chain that is fully saturated or contains one or more unsaturated units but is not aromatic. . Unless otherwise indicated, the aliphatic group contains 1-20 aliphatic carbon atoms. In some embodiments, the aliphatic group contains one aliphatic carbon atom. In other embodiments, the aliphatic group contains 丨8 aliphatic carbon atoms. In other embodiments, the aliphatic group contains 丨6 aliphatic carbon atoms, and in other embodiments, the aliphatic group contains 丨4 aliphatic carbon atoms. The aliphatic group may be a linear or branched alkyl, alkenyl, or alkynyl group. Specific examples include, but are not limited to, mercapto, ethyl, isopropyl, n-propyl first-butyl, vinyl, n-butanol, thienyl, and tert-butyl. The term "alkyl" as used herein means a saturated straight or branched hydrocarbon. The term "alkenyl" as used herein means a straight or branched hydrocarbon chain comprising one or more double bonds. The term "alkynyl" as used herein means a straight or branched hydrocarbon comprising one or more triple bonds. Surgery. . "Circularly known as aliphatic" (or "carbon ring") means having 3 to 14 ring carbons 153786.doc -14- 201231467 ====' which may be • ring or contain - or more than one term also includes , screw or bridge carbon ring system. .^ 厌 〇 — — — — — — — — — — 或 — — 或 — — — — — — — — — — — — — 。 。 。 。 。 。 。 。 。 A fused bicyclic system consists of two or two = connected rings, and the snails share three or four adjacent ring atoms. The two systems share one ring atom. Examples of cycloaliphatic groups :::: Yuhuanyuan and Huanxian. Specific examples include, but are not = hexyl propylene, cyclopropyl and cyclobutyl. The term "heterocycle" (or "heterocyclic" as used herein, refers to a 5" ring G having from 3 to 14 ring atoms, having one or more ring carbons from a hydrazine, N, s, Or 0) instead of a non-aromatic monocyclic ring, straight, 2 or more unsaturated units. The term encompasses a multi-complexed, bridged heterocyclic ring system. The term also encompasses heterocyclic rings which may be fused to - or more than two. Polycyclic ring system of a carbocyclic or heterocyclic ring or a heterocyclic ring or a combination thereof: The linking group or the point of attachment is on the heterocyclic ring. : ', L " The example includes but is not limited to ^ 比丝姆秦基, bite base 1. (four) base, (four) bite two! : cycloheptyl, diazepine, triazepane, pyridine:, -nitrogen octyl, triazacyclooctyl, oxasulfinyl, isoxazolidine, Isothiazolidinyl, oxazolidinyl, oxazepine, thiazepine, hydroxycyclooctyl, benzopyrene, tetrazolium, tetrakis , tetrazophenylthiol, morphinyl (including: example = base, 4·?: base, 2, morphine, 3 • 琉 琳 基, 4 thiomarin) a bite base, 2, each bite Base, 3* fixed base 153786.doc -15· 201231467. Than thiol, 2_hexahydro. More than thiol, 3 · hexahydro. Biazinyl, ^ than wow money, 3 . Ratio (tetra), 4-W, ..., hexyl, hexahydrogen, 2: hexahydropyridyl, 3 hexahydropyridyl, 4 hexahydropyridyl, 2 thiazolidinyl, 3-indole Base, 4_嗟„ sit „定基, μ米心定基, 2_ oxazolidinyl, 4-amiridinyl, 5-meridinyl, dihydrododeto, tetrahydroporphyrin, tetrahydrogen Isoindolinyl, benzothiazepine, benzodiazepine, dioxo-benzoxan-2-one, and 1,3-dihydromethyl, azabicyclopentyl azabicyclo Hexyl 'azabicycloheptyl, azabicyclooctyl, azabicyclononyl, azabicyclononyl, diazabicyclohexyl, diazabicycloheptylmonohydrocarbazolyl, dihydrobenzimidazolyl Tetrahydron-pyridinyl, dihydropyridyl, tetrahydropyrazinyl, dihydropyrazinyl, tetrahydropyrimidinyl, dihydropyrimidinyl, dihydropyrrolyl 'dihydropyrazolyl, dihydroimidazolyl , octahydropyrrolopyrazinyl, octahydropyrolopyridinium, octahydropyridazinyl, octahydropyridinyl, diazabicyclooctyl, diazabicyclononyl, and Azabicyclononyl. As used herein, unless otherwise stated, the bicyclic ring may be a fused, spiro and bridged ring. The term "heteroatom" means - or more of oxygen, sulfur, nitrogen, phosphorus, or antimony (including: any of the oxidized forms of nitrogen, sulfur, phosphorus, or antimony; Formal or heterocyclic substituted nitrogen, such as hydrazine (such as in 3,4-dihydro-2-indole-pyrrolyl), hydrazine (such as in pyrrolidinyl) or NR+ (such as hydrazine-substituted in the ratio of pyridyl) )). The term "unsaturated" as used herein means a portion having one or more unsaturated units. 153786.doc •16- 201231467 As used herein, the term “alkoxy” or “thioxo” refers to the passage of oxygen (“alkoxy”, for example, —〇-alkyl) or sulfur (“sulfur” An alkyl group, such as an '-S-alkyl group, is attached to the alkyl group as defined above. The terms "_alkyl", "_alkenyl", "cosyl aliphatic", and "alkenyl alkoxy" (or "aminoalkyl", "hydroxyalkyl", etc.) mean An alkyl, alkenyl or alkoxy group which may be substituted with one or more dentate atoms, as appropriate. This term encompasses perfluoroalkyl groups such as _CF3 and _CF2C; F3. The terms "fun", "dental", and "hal" mean F, C1, Br, or I. The terms haloaliphatic group and hydrazine (halogenated aliphatic group) comprise mono-, di- and tri-dentate substituted aliphatic groups. The term "aryl" (single (four) is used as part of a larger part, such as a quaternary alkyl group, "arylalkoxy", "aryloxyalkyl", or "heteroaryl") means a carbocyclic ring. And / or heterocyclic aromatic ring system. The term "aryl" is used interchangeably with the term "aromatic ring". /, ... The ring group has only a carbon ring atom (usually the (4) phase), = an aromatic ring (such as a phenyl group), and a fused polycyclic aromatic ring system in which two or more carbocyclic aromatic rings are fused to each other. Examples include ^ 2 poor ancient "I" 匕 3 "naphthyl, 2-naphthyl, i. keithyl and 2-indenyl. Also included in the term "destiny - 垆 入 及 衷 衷 衷 衷 」 」 」 」 」 」 」 」 」 」 」 如 如 二 二 二 二 二 二 二 二 二 二 二 i i i i i i In the amine 'n-dimethylanilinium, non-pyridyl, or tetrahydronaphthyl, on which. The linking group or the linking point is located in a heteroaryl aryl group, a aryl group (heteroaryi gr〇up), a "heteroaromatic" aromatic group, a "heteroaryl ring", and a "hetero" ( Alone or as one of the most 153786.doc •17· 201231467

本文所用）範圍内者係芳環稠合至一 /丞」執，雜芳基烷氧 ?環基團’包含單環雜芳 匕芳環之多環芳環。雜芳 含於術語「雜芳基」（如 一或多個非芳族環（碳環 或雜環）之基團，#中連接基團或連接點位於芳環上。本 文所用之雙環6,5雜芳環係（例如）稠合至第二5員環之6員雜 芳環，其中連接基團或連接點位於6員環上。雜芳基之實 例包含吡啶基、吡嗪基、嘧啶基、噠嗪基、咪唑基、吡咯 基、吡唑基、***基、四唑基、噁唑基、異噁唑基、噁二 唑基、噻唑基、異噻唑基、或噻二唑基（包含例如2_呋喃 基、3-吱喃基）、N-咪°坐基、2-咪唾基、4-咪t»坐基、5-咪η坐 基、3-異噁唑基、4-異噁唑基、5-異噁唑基、2-噁二。坐 基、5-"惡二唑基' 2-噁唑基、4-噁唑基、5-噁唑基、3-〇比 唑基、4-吡唑基、1-吡咯基、2-吡咯基、3-吡咯基、2-吡 啶基、3-吡啶基、4-吡啶基、2-嘧啶基、4-嘧啶基、5-嘧 咬基、3-遂嗪基、2-°塞°坐基、4-。塞。坐基、5-嘆°坐基、2-三 唑基、5·***基、四唑基、2-噻吩基、3-噻吩基、咔唑 基、苯并咪唑基、苯并噻吩基、苯并呋喃基、吲哚基、苯 并***基、苯并噻唑基、苯并噁唑基、苯并咪唑基、異喹 啉基、吲哚基、異吲哚基、吖啶基、苯并異噁唑基、異噻 唑基、1，2,3-噁二唑基、1，2,5-噁二唑基、1，2,4-噁二唑 基、1，2,3-***基、1,2,3-噻二唑基、1,3,4-噻二唑基、 1，2,5-噻二唑基、嘌呤基、吡嗪基、1,3,5-三嗪基、喹啉基 153786.doc -18- 201231467 (例如，2-喹啉基、3-喹啉基' 4_喹啉基）、及異喹啉基（例 如，1-異喹啉基、3-異喹啉基、或4_異喹琳基）。 本文所用之術語「保護性基團」及「保護基團」可互換 使用，且係指用於暫時性封阻具有多個反應位點之化合物 中之一或多個期望官能團的試劑。在某些實施例中，保護 性基團具有一或多個、或較佳地所有下列特性：a)以良好 產率選擇性添加至官能團以得到經保護基質’該經保護基 質b)對於在一或多個其他反應位點處發生之反應比較穩 定，及c)可藉由並不攻擊重新生成之脫除保護基官能團之 試劑以良好產率選擇性去除。如熟習此項技術者所理解， 在一些情形下，該等試劑並不攻擊化合物中之其他反應性 基團。在其他情形下，該等試劑亦可與化合物中之其他反 應性基團發生反應。保護性基團之實例詳述於Greene， T.W·，Wuts，P. G，「Protective Groups in 〇rganic Synthesis」，第 3 版，John Wiley & Sons，New York: 1999(及該書之其他版本）中，其全部内容以引用方式併入 本文中。本文所用之術語「氮保護性基團」係指用於暫時 性封阻多官能化合物中之一或多個期望氮反應位點的試 劑。較佳氮保護性基團亦擁有上文針對保護性基團所例示 之特性，且某些實例性氮保護性基團亦詳述於第7章， Greene, T.W., Wuts, P. G > r Protective Groups in OrganicAs used herein, the aryl ring is fused to a monocyclic ring, and the heteroarylalkoxy ring group includes a polycyclic aromatic ring of a monocyclic heteroaryl aryl ring. Heteroaryl is contained in the term "heteroaryl" (such as one or more non-aromatic rings (carbocyclic or heterocyclic) groups, and the linking group or point of attachment in # is on the aromatic ring. Bicyclic rings 6, 5 as used herein. A heteroaryl ring is, for example, a 6-membered heteroaryl ring fused to a second 5-membered ring wherein the linking group or point of attachment is on a 6-membered ring. Examples of heteroaryl groups include pyridinyl, pyrazinyl, pyrimidinyl. , pyridazinyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, or thiadiazolyl ( Including, for example, 2-furanyl, 3-mercapto), N-miso-based, 2-meridino, 4-mi-t-spinyl, 5-imidinyl, 3-isoxazolyl, 4 -isoxazolyl, 5-isoxazolyl, 2-oxo. Sodium, 5-"oxadiazolyl-2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3- 〇比zolyl, 4-pyrazolyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl , 5-pyrimidinyl, 3-pyridazinyl, 2-°-plug-sitting, 4-cylinder, sitting group, 5-sinter sit, 2-triazolyl, 5. Azyl, tetrazolyl, 2-thienyl, 3-thienyl, oxazolyl, benzimidazolyl, benzothienyl, benzofuranyl, fluorenyl, benzotriazolyl, benzothiazolyl , benzoxazolyl, benzimidazolyl, isoquinolyl, decyl, isodecyl, acridinyl, benzoisoxazolyl, isothiazolyl, 1,2,3-oxadiazole 1,1,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiadiazolyl, 1,3,4 -thiadiazolyl, 1,2,5-thiadiazolyl, fluorenyl, pyrazinyl, 1,3,5-triazinyl, quinolyl 153786.doc -18- 201231467 (for example, 2-quinoline Lolinyl, 3-quinolinyl '4-quinolyl), and isoquinolinyl (eg, 1-isoquinolinyl, 3-isoquinolinyl, or 4-isoquinolinyl). The terms "protective group" and "protecting group" are used interchangeably and refer to an agent that is used to temporarily block one or more of the desired functional groups of a compound having multiple reactive sites. In certain embodiments Wherein the protective group has one or more, or preferably all, of the following characteristics: a) selective addition to the functional group in good yield To obtain a protected substrate 'the protected substrate b) is more stable to the reaction occurring at one or more other reaction sites, and c) may be good by not attacking the reconstituted reagent for removing the protecting group functional group The yield is selectively removed. As will be understood by those skilled in the art, in some instances, such agents do not attack other reactive groups in the compound. In other instances, such agents may also react with other reactive groups in the compound. Examples of protective groups are detailed in Greene, TW., Wuts, P. G, "Protective Groups in 〇rganic Synthesis", 3rd edition, John Wiley & Sons, New York: 1999 (and other versions of the book) The entire contents of this are incorporated herein by reference. The term "nitrogen protecting group" as used herein refers to a reagent used to temporarily block one or more desired nitrogen reactive sites in a polyfunctional compound. Preferred nitrogen protecting groups also possess the properties exemplified above for the protective group, and certain exemplary nitrogen protecting groups are also detailed in Chapter 7, Greene, TW, Wuts, P. G > r Protective Groups in Organic

Synthesis」’第 3版，j〇hn Wiley & Sons, New York: 1999 中’其全部内容以引用方式併入本文中。 在一些實施例中，其中顯示脂肪族鏈之亞甲基單元視需 153786.doc -19· 201231467 要經另一原子或基團代替。該等原子或基團之實例包含但 不限於 G，其包含-^4(11')-、-0-、-(：(0)-、-(：(=：^-0^)-、-C(=NR')- -C(=NOR，）-、-S-、-S(O)·、及-S(0)2-。該等 原子或基團可組合形成較大基團。該等較大基團之實例包 含但不限於-OC(O)-、-C(0)C0-、-C02-、-C(0)NR，'-、 -c(=n-cn)、-n(r’)c(o)-、-n(r)c(o)o-、-s(o)2n(r')- 、-N(R)S02-、-N(R)C(0)N(R')-、-0C(0)N(R’)-、 及-N(R)S02N(R·)-，其中R·定義於本文中。 僅涵蓋彼等產生穩定結構之代替及基團組合《可選代替 可發生於键内及/或鏈之任一端；亦即在連接點處及/或亦 在末端處。兩個可選代替亦可在鏈内彼此相鄰，只要產生 化學上穩定之化合物即可。 在一些實施例中，可選代替亦可完全代替鏈中之所有碳 原子。舉例而言’ C3脂肪族可視需要經-N(R')-、-C(O)-、 及-N(R’）-代替以形成_n(R')C(0)N(R，）-(脲），或C丨脂肪族可 視需要經（例如）_0-、NH-等代替。在該等實施例之某些情 形下，鏈係連接體。 除非另有所指，否則若代替發生於術端處，則代替原子 與術端處之Η結合。舉例而言，若_Cii2CH2CH視需要經-〇-代替’則所得化合物可為-〇CH2CH3、-CH2OCH3、 或-CH2CH2〇H’或若_CH2CH3視需要經-〇-代替，則所得化 合物可為-OCH3 ’或·0：Η2ΟΗ2ΟΗ，或若-CH2CH3視需要 經-c(o)-代替’則所得化合物可為_C(0)CH3、 或-ch2c(o)h。 153786.doc -20- 201231467 U文所指定之—替代性實施例中’多達3個（0-3)亞曱 基視需要經Μ/ϋ,、 、丹中 G 係-N(R’）-、_〇_、_c(〇)_、或 _s(〇)p_ G、中R及p如本文所定義））代替之脂肪族鏈需要在鏈中具 有至少個未經代替之亞曱基（颂取代基）_或_CH2_)。舉 ^ ° Cl脂肪族基團中之亞曱基不可經（例 如）-ΟΗ、·ΝΗ2等代替以得到作為取代基之_〇h及_NHy其 中在鍵中不含任—亞曱基）’或U)C2脂肪族基團中之兩個 亞曱基不可經_C(〇)_及_〇_代替以得到_c(〇)〇H。在該等替 代性實施例之某些情況下，冑並非連接體而是僅在一個位 置連接至分子其他部分的取代基。該等脂肪族基團進-步 如本文所定義經取代。 除非另有所指，否則本文所繪示之結構亦意欲包含該結 構之所有異構體（例如，對映異構體、非對映異構體、幾 何異構體、構象異構體、及旋轉異構體）形式。舉例而 言，每一不對稱中心之（R)及（S)構型、（2)及（£)雙鍵異構 體、及（Z)及（E)構象異構體皆包含於本發明中β本文結構 中（R)及（S)之使用代表立體化學，且與變量說明中之原子 硫s或變量R不同。熟習此項技術者應理解，取代基可在任 >ΛΛΛ/ 一可旋轉圍自由旋轉。舉例而言，繪示為〇之取代 基亦代表。 因此，本發明化合物之單一立體化學異構體以及對映異 構體、非對映異構體、幾何異構體、構象異構體、及旋轉 153786.doc -21- 201231467 異構體混合物均屬於本發明範圍内。 本發月化δ物之較佳構象係示於六氫吡嗪環中之⑻及^ 碳上之（R) » 可使用X-射線繞射、利用彼等熟習此項技術者已知之技 #來測定本發明分子之立體化學。在—替代性實施例中， 不期望X理♦約束’可根據本文所述分析中之pKc〇功效 來預測立體化學。 除非另有所心’否則本發明化合物之所有互變異構體形 式皆屬於本發明範圍内。 此外’除非另有所#，否則本文所繪示之結構亦意欲包 3僅在-或多個富含同位素之原子存在下不同之化合物。 丨=八有本發明結構之化合物（氫由氘或氚代替、 或炭由C或C-备集碳代替者除外）均屬於本發明範圍 内。該等化合物可用作（例如）生物分析中之分析工具或探 測物。 如本文所述，其中本發明所示之化合物可視需要經… 多個取代基取代’如本文所概述，或如由本發明之特定率 類、子類、及物質所例示。應瞭解，片語「視需要經耳 代」可與片語「經取代或未經取代」互換使用—般而t 術語「經取代」（不論前面是否存在術語「視需要」则 使用指絲代基基團代替給定結構中之氫基團。除非另有 所指，否則視需要經取代之基團可在該基團之每—可取代 位置處具有取代基，且在任—給定結構中之—個以上之位 置可經-個以上之選自指定基團的取代基取代時，在每一 153786.doc •22· 201231467 位置處之取代基可相同或不同。 僅涵蓋彼等產生穩定結構之選擇及取代基組合。該等選 擇及組合對於彼等熟習此項技術者而言顯而易見，且可在 無需過多實驗之情形下確定。 術語「環原子」係諸如C、N、0或S等位於芳族基團、 環烷基或非芳族雜環中之原子。 芳族或非芳族環基團中之「可取代環原子」係結合至氫 原子之環碳或氮原子。氫可視需要經適宜取代基基團代 替。因此’術語「可取代環原子」並不包含兩個環稠合時 共用之環氮或碳原子。此外，「可取代環原子」並不包含 在結構中繪示為已連接至除氫外之部分時的環碳或氮原 子。 如本文所定義之視需要經取代之芳基可含有一或多個可 取代環原子，其可結合至適宜取代基《位於芳基之可取代 環碳原子上之適宜取代基之實例包含R@。尺@係-Ra、-Br、 -C卜，I、-F、-ORa、-SRa、-O-CORa、-CORa、-CSRa、-CN、 -N02、-NCS、-S03H、-N(RaRb)、-COORa、-NRcNRcCORa、 -NRcNRcC02Ra、-CHO、-CON(RaRb)、-0C(0)N(RaRb)、 -CSN(RaRb)、-NRcCORa、-NRcCOORa、-NRcCSRa、 -NRcCON(RaRb)、_NRcNRcC(0)N(RaRb)、-NRcCSN(RaRb)、 -C(=NRc)-N(RaRb)、-C(=S)N(RaRb)、-NRd-C(=NRc)-N(RaRb)、 -NRcNRaRb、-S(0)pNRaRb、-NRcS02N(RaRb)、-NRcS(0)pRa、 -S(0)pRa、-0S(0)pNRaRb或-0S(0)pRa ;其中 p為 1 或 2。Synthesis", 3rd edition, j〇hn Wiley & Sons, New York: 1999, the entire disclosure of which is incorporated herein by reference. In some embodiments, wherein the methylene unit of the aliphatic chain is shown, 153786.doc -19. 201231467 is replaced by another atom or group. Examples of such atoms or groups include, but are not limited to, G, which includes -^4(11')-, -0-, -(:(0)-, -(:(=:^-0^)-, -C(=NR')- -C(=NOR,)-, -S-, -S(O)·, and -S(0)2-. The atoms or groups may be combined to form a larger group. Examples of such larger groups include, but are not limited to, -OC(O)-, -C(0)C0-, -C02-, -C(0)NR, '-, -c(=n-cn) , -n(r')c(o)-, -n(r)c(o)o-, -s(o)2n(r')-, -N(R)S02-, -N(R) C(0)N(R')-, -0C(0)N(R')-, and -N(R)S02N(R·)-, wherein R· is defined herein. Substitution of Structures and Group Combinations "Optional substitutions can occur at either end of the bond and/or chain; that is, at the point of attachment and/or also at the end. Two alternatives can also be used in the chain. Neighbor, as long as a chemically stable compound is produced. In some embodiments, the optional substitution may also completely replace all of the carbon atoms in the chain. For example, 'C3 aliphatics may need to pass -N(R')-, -C(O)-, and -N(R')- instead of forming _n(R')C(0)N(R,)-(urea), or C丨 aliphatic may be as needed (for example)_0 -, NH-, etc. instead. In some instances of these embodiments, the linker is a connector. Unless otherwise indicated, if the substitution occurs at the surgical end, the replacement atom is combined with the ridge at the surgical end. For example, if _Cii2CH2CH is needed By -〇-substituting 'the resulting compound may be -〇CH2CH3, -CH2OCH3, or -CH2CH2〇H' or if _CH2CH3 is replaced by -〇-, the resulting compound may be -OCH3' or ·0:Η2ΟΗ2ΟΗ, Or if -CH2CH3 is replaced by -c(o)- as needed, the resulting compound may be _C(0)CH3, or -ch2c(o)h. 153786.doc -20- 201231467 U-specified-alternative In the examples, 'up to three (0-3) fluorene groups are required to pass through ϋ/ϋ, ,, Danzhong G system-N(R')-, _〇_, _c(〇)_, or _s (〇) p_G, where R and p are as defined herein)) The substituted aliphatic chain needs to have at least one unsubstituted sulfhydryl group (颂 substituent)_ or _CH2_) in the chain. The fluorenyl group in the aliphatic group of the ^ ° Cl may not be replaced by, for example, -ΟΗ, ·ΝΗ2, etc. to obtain _〇h and _NHy as substituents, wherein the bond does not contain any -indenyl group) Or two of the U) C2 aliphatic groups may not be replaced by _C(〇)_ and _〇_ to obtain _c(〇)〇H. In some instances of such alternative embodiments, hydrazine is not a linker but a substituent that is attached to other portions of the molecule only at one position. These aliphatic groups are further substituted as defined herein. Unless otherwise indicated, structures depicted herein are also intended to include all isomers of the structure (eg, enantiomers, diastereomers, geometric isomers, conformers, and Rotamer) form. For example, the (R) and (S) configurations, (2) and (£) double bond isomers, and (Z) and (E) conformational isomers of each asymmetric center are encompassed by the present invention. The use of (R) and (S) in the structure of β represents the stereochemistry and is different from the atomic sulfur s or the variable R in the variable description. It will be understood by those skilled in the art that the substituents can be freely rotated in the >ΛΛΛ/ a rotatable enclosure. For example, the substituents depicted as oxime are also represented. Thus, the single stereochemical isomers of the compounds of the invention as well as the enantiomers, diastereomers, geometric isomers, conformational isomers, and the 153786.doc -21 - 201231467 isomer mixture It is within the scope of the invention. The preferred conformation of the present δ-derivatives is shown in (8) and on the carbon in the hexahydropyrazine ring (R) » X-ray diffraction can be used, and those skilled in the art can be used. The stereochemistry of the molecules of the invention is determined. In an alternative embodiment, the X ♦ Constraint ' is not expected to predict stereochemistry according to the pKc 〇 efficacy in the analysis described herein. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention. Further, unless otherwise stated, the structures depicted herein are also intended to encompass compounds that differ only in the presence of one or more isotope-rich atoms.丨 = eight compounds having the structure of the present invention (except that hydrogen is replaced by ruthenium or osmium or carbon is replaced by C or C-collected carbon) are within the scope of the present invention. Such compounds can be used, for example, as analytical tools or probes in biological assays. As described herein, wherein the compounds of the invention may be substituted, as desired, by a plurality of substituents, as outlined herein, or as exemplified by the particular classes, subclasses, and materials of the invention. It should be understood that the phrase "as needed" can be used interchangeably with the phrase "substituted or unsubstituted" - the term "substitution" (regardless of whether the term "as needed" is used before A group replaces a hydrogen group in a given structure. Unless otherwise indicated, a substituted group may have a substituent at each -substitutable position of the group, and in any given structure Where more than one position may be substituted by more than one substituent selected from the specified group, the substituents at each position of 153786.doc • 22·201231467 may be the same or different. The choices and combinations of substituents are obvious to those skilled in the art and can be determined without undue experimentation. The term "ring atom" is such as C, N, 0 or S, etc. An atom located in an aromatic group, a cycloalkyl group or a non-aromatic heterocyclic ring. A "substitutable ring atom" in an aromatic or non-aromatic ring group is bonded to a ring carbon or a nitrogen atom of a hydrogen atom. Need to be substituted by a suitable substituent Therefore, the term 'substitutable "substitutable ring atom" does not include the ring nitrogen or carbon atom shared by the two rings when fused. In addition, the "substitutable ring atom" is not included in the structure and is shown as being connected to the dehydrogenation. a ring carbon or a nitrogen atom in a portion thereof. The optionally substituted aryl group as defined herein may contain one or more substitutable ring atoms which may be bonded to a suitable substituent "substitutable ring carbon atom at the aryl group" Examples of suitable substituents include R@. 尺@系-Ra, -Br, -C, I, -F, -ORa, -SRa, -O-CORa, -CORa, -CSRa, -CN, - N02, -NCS, -S03H, -N(RaRb), -COORa, -NRcNRcCORa, -NRcNRcC02Ra, -CHO, -CON(RaRb), -0C(0)N(RaRb), -CSN(RaRb), -NRcCORa , -NRcCOORa, -NRcCSRa, -NRcCON(RaRb), _NRcNRcC(0)N(RaRb), -NRcCSN(RaRb), -C(=NRc)-N(RaRb), -C(=S)N(RaRb) -NRd-C(=NRc)-N(RaRb), -NRcNRaRb, -S(0)pNRaRb, -NRcS02N(RaRb), -NRcS(0)pRa, -S(0)pRa, -0S(0) pNRaRb or -0S(0)pRa; where p is 1 or 2.

Ra-Rd各自獨立地係-Η、月旨肪族基團、芳族基團、非芳 I53786.doc •23· 201231467 族碳環或雜環基團或一起形成非芳族雜環基團 之-N(RaRb)。由Ra-R代表之脂肪族、芳族及非芳族雜環基 團及由-N(RaRb)代表之非芳族雜環基團各自視需要且獨立 地經一或多個由R#代表之基團取代。較佳地，Ra-Rd未經 取代。 以係 _ 素、R+、-OR+、-SR+、-N〇2、-CN、-N(R+)2、-COR+、 -COOR+ ' -NHC02R+ ' -NHC(0)R+ ' -NHNHC(0)R+ ' -nhc(o)n(r+)2、-NHNHC(0)N(R+)2、-nhnhco2r+、 -C(0)N(R + )2、-0C(0)R+、-oc(o)n(r+)2、-S(0)2R+、 -so2n(r+)2、-s(o)r+、-nhso2n(r+)2、-nhso2R+、 -C(=S)N(R+)2、或-C(=NH)-N(R+)2。 R+係-H、C1-C4烷基、單環芳基、非芳族碳環或雜環基 團，其各自視需要經烷基、齒代烷基、烷氧基、齒代烷氧 基、鹵素、-CN、-N02、胺、烷基胺或二烷基胺取代。較 佳地，R+未經取代。 本文所用之視需要經取代之脂肪族或非芳族雜環或碳環 基團可含有一或多個取代基。用於脂肪族基團或非芳族雜 環基團之環碳之適宜取代基之實例係R"。R"包含彼等上文 針對R@所列示之取代基及=0、=S、=NNHR**、 =NN(R**)2、=NNHC(0)R"、=NNHC02(烧基）、 =NNHS02(烷基）、=NR**、螺環烷基或稠合環烷基。每一 R**獨立地選自氫、未經取代之烷基或經取代之烷基。烷 基上由R**代表之取代基實例包含胺基、烷基胺基、二烷 基胺基、胺基羰基、鹵素、烷基、烷基胺基羰基、二烷基 153786.doc •24- 201231467 胺基幾基、烷基胺基羰基氧基、二烷基胺基羰基氧基、烷 氧基、硝基、氰基、羧基'烷氧基羰基、烷基羰基、羥 基、齒代烷氧基、或i代烷基。 在雜環基、雜芳基、或雜芳烷基含有氮原子時，其可經 取代或未經取代。在雜芳基之芳環中之氮原子具有取代基 時’氮可為四級氮。 非芳族含氮雜環基團之較佳取代位置係氮環原子。非芳 族雜環基團或雜芳基之氮上的適宜取代基包含_RA、_N(R〇2、 C(0)RA . c〇2Ra . -C(0)C(0)RA ^ -S02Ra ' S02N(RA)2 > C(=S)N(RA)2、C(=NH)-N(Ra)2、及-NRASC^RA ;其中 RA係 氫、脂肪族基團、經取代脂肪族基團、芳基、經取代芳 基、雜環或碳環或經取代雜環或碳環。基團上由代表之 取代基之實例包含烷基、自代烷氧基、_代烷基、烷氧基 炫基、磺醯基、烷基磺醯基、函素、硝基、氰基、羥基、 芳基、碳環或雜環、側氧基、胺基、烷基胺基、二烷基胺 基、胺基羰基、烷基胺基羰基、二烷基胺基羰基氧基、烷 氧基缓基、院氧基幾基、或烧基幾基。較佳地，RA未經 取代。 在J衣氮上經取代且在環碳原子處連接至分子之剩餘部分 之非芳族含氮雜環稱為N取代β舉例而言，N烷基六氫吡 啶基在六氫咄啶基環之2、3或4位處連接至分子之剩餘部 分且在環氮處經烷基取代。在一個環氮上經取代且在第二 環氮原子處連接至分子之剩餘部分之非芳族含氮雜環（例 如吡嗪基）稱作Ν’取代-N-雜環。舉例而言，N，醯基N_吡嗪 153786.doc -25· 201231467 基在一個環氮原子處連接至分子之剩餘部分且在第二環氮 原子處經醯基取代。 如本文所使用，視需要經取代之芳烷基可在烷基及芳基 部分上經取代。除非另有所指，否則本文所用之視需要經 取代之务烧基視需要在芳基部分上經取代。 本發明化合物在本文中係藉由其化學結構及/或化學名 稱來定義。若藉由化學結構及化學名稱來提及化合物，且 化學結構與化學名稱相衝突，則化學結構決定化合物之身 份。 本發明化合物可以用於處理之游離形式存在，或若適 宜，呈醫藥上可接受之鹽形式。 本文所用之術語「醫藥上可接受之鹽」係指在正確醫學 判斷範圍内適用於接觸人類及低等動物組織而不會產生過 度副作用（例如毒性、刺激、過敏反應及諸如此類）且具有 相應之合理效益/風險比的化合物鹽。 醫藥上可接受之鹽為業内所熟知。舉例而言，s M.Ra-Rd are each independently a fluorene group, an aromatic group, an aromatic group, a non-aryl I53786.doc • 23· 201231467 group carbocyclic or heterocyclic group or together form a non-aromatic heterocyclic group. -N(RaRb). The aliphatic, aromatic and non-aromatic heterocyclic groups represented by Ra-R and the non-aromatic heterocyclic groups represented by -N(RaRb) are each optionally and independently represented by R# by one or more Replaced by the group. Preferably, Ra-Rd is unsubstituted. _ 素, R+, -OR+, -SR+, -N〇2, -CN, -N(R+)2, -COR+, -COOR+ ' -NHC02R+ ' -NHC(0)R+ ' -NHNHC(0)R+ ' -nhc(o)n(r+)2, -NHNHC(0)N(R+)2, -nhnhco2r+, -C(0)N(R + )2, -0C(0)R+, -oc(o) n(r+)2, -S(0)2R+, -so2n(r+)2, -s(o)r+, -nhso2n(r+)2, -nhso2R+, -C(=S)N(R+)2, or -C(=NH)-N(R+)2. R+ is -H, C1-C4 alkyl, monocyclic aryl, non-aromatic carbocyclic or heterocyclic groups, each of which is optionally substituted via an alkyl group, a chiral alkyl group, an alkoxy group, a dentate alkoxy group, Halogen, -CN, -N02, amine, alkylamine or dialkylamine substitution. Preferably, R+ is unsubstituted. As used herein, an optionally substituted aliphatic or non-aromatic heterocyclic or carbocyclic group may contain one or more substituents. An example of a suitable substituent for a ring carbon of an aliphatic group or a non-aromatic heterocyclic group is R". R" contains the substituents listed above for R@ and =0, =S, =NNHR**, =NN(R**)2, =NNHC(0)R", =NNHC02(alkyl ), =NNHS02(alkyl), =NR**, spirocycloalkyl or fused cycloalkyl. Each R** is independently selected from hydrogen, unsubstituted alkyl or substituted alkyl. Examples of the substituent represented by R** on the alkyl group include an amine group, an alkylamino group, a dialkylamino group, an aminocarbonyl group, a halogen group, an alkyl group, an alkylaminocarbonyl group, a dialkyl group 153786.doc •24 - 201231467 Aminomethyl, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkoxy, nitro, cyano, carboxy 'alkoxycarbonyl, alkylcarbonyl, hydroxy, dentate Oxy, or i-alkyl. When the heterocyclic group, heteroaryl group or heteroaralkyl group contains a nitrogen atom, it may be substituted or unsubstituted. When the nitrogen atom in the aromatic ring of the heteroaryl group has a substituent, the 'nitrogen may be a quaternary nitrogen. Preferred substitution positions for the non-aromatic nitrogen-containing heterocyclic group are nitrogen ring atoms. Suitable substituents on the nitrogen of the non-aromatic heterocyclic group or heteroaryl group include _RA, _N(R〇2, C(0)RA. c〇2Ra . -C(0)C(0)RA ^ - S02Ra ' S02N(RA)2 > C(=S)N(RA)2, C(=NH)-N(Ra)2, and -NRASC^RA; wherein RA is hydrogen, aliphatic group, substituted An aliphatic group, an aryl group, a substituted aryl group, a heterocyclic ring or a carbocyclic ring or a substituted heterocyclic ring or a carbocyclic ring. Examples of the substituent represented by the group include an alkyl group, a self alkoxy group, an alkylene group. Alkyl, alkoxy, sulfonyl, alkylsulfonyl, cyclin, nitro, cyano, hydroxy, aryl, carbocyclic or heterocyclic, pendant oxy, amine, alkylamino, a dialkylamino group, an aminocarbonyl group, an alkylaminocarbonyl group, a dialkylaminocarbonyloxy group, an alkoxy group, an alkoxy group, or an alkyl group. Preferably, RA is not Substituted. A non-aromatic nitrogen-containing heterocycle substituted on the J-nitrogen and attached to the remainder of the molecule at the ring carbon atom is referred to as N-substituted β. For example, an N-alkyl hexahydropyridinyl group in hexahydroacridine The 2, 3 or 4 position of the base ring is attached to the remainder of the molecule and is substituted at the ring nitrogen by an alkyl group. A non-aromatic nitrogen-containing heterocycle (e.g., pyrazinyl) which is substituted and attached to the remainder of the molecule at the second ring nitrogen atom is referred to as a Ν'-substituted-N-heterocycle. For example, N, fluorenyl N _ pyrazine 153786.doc -25· 201231467 The group is attached to the remainder of the molecule at one ring nitrogen atom and is substituted with a thiol group at the second ring nitrogen atom. As used herein, the substituted aralkyl group may be optionally substituted. Substituted on the alkyl and aryl moieties. Unless otherwise indicated, the substituted mercapto as used herein is optionally substituted on the aryl moiety. The compounds of the invention are herein employed by their chemistry. Structural and/or chemical name is defined. If a compound is referred to by chemical structure and chemical name, and the chemical structure conflicts with the chemical name, the chemical structure determines the identity of the compound. The compound of the present invention can be used in the free form of the treatment. Or, where appropriate, in the form of a pharmaceutically acceptable salt. The term "pharmaceutically acceptable salt" as used herein means that it is suitable for exposure to humans and lower animal tissues within the correct medical judgment. Compound salts which are subject to side effects (e.g., toxicity, irritation, allergic reactions, and the like) and which have a corresponding reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, s M.

Berge專人在 J. Pharmaceutical Sciences, 1977，ό6. 1-19 中 詳細闡述醫藥上可接受之鹽，其係以引用方式併入本文 中。本發明化合物之醫藥上可接受之鹽包含彼等衍生自適 宜無機及有機酸及鹼者。該等鹽可在化合物之最終分離及 純化期間原位製得β酸加成鹽可藉由以下方式製得·· 1 )使 游離基形式之純化化合物與適宜有機或無機酸進行反應， 及2)分離由此形成之鹽。 醫藥上可接受之無毒酸加成鹽之實例係無機酸（例如， I53786.doc -26- 201231467 鹽酸、氫溴酸、磷酸、硫酸及高氯酸）或與有機酸（例如， 乙酸、草s文、馬來酸、酒石酸、捧檬酸、破珀酸或丙二 酸）或藉由使用業内所用之其他方法（例如，離子交換）與胺 基形成之鹽。其他醫藥上可接受之鹽包含己二酸鹽、藻酸 鹽、抗壞血酸鹽、天冬胺酸鹽、苯續酸鹽、苯曱酸鹽、碰 酸氫鹽、侧酸醋、丁酸鹽、樟腦酸鹽、樟腦續酸鹽、檸檬 酸鹽、環戊烷丙酸鹽、二葡萄糖酸鹽、十二烷基硫酸鹽、 乙烧靖酸鹽、曱酸鹽、富馬酸鹽、葡庚糖酸鹽、甘油碟酸 鹽、經乙S文鹽、葡萄糖酸鹽、經乙酸鹽、半硫酸鹽、庚酸 鹽、已酸鹽、鹽酸鹽、氫溴酸鹽、氫碘酸鹽、2_羥基-乙烷 磺酸鹽、乳糖酸鹽、乳酸鹽、月桂酸鹽、月桂基硫酸鹽、 蘋果酸鹽、馬來酸鹽、丙二酸鹽、曱績酸鹽、2-萘續酸 鹽、菸酸鹽、硝酸鹽、油酸鹽、草酸鹽、棕櫚酸鹽、雙羥 萘酸鹽、果膠酸鹽、過硫酸鹽、3 -笨基丙酸鹽、磷酸鹽、 苦味酸鹽、新戊酸鹽、丙酸鹽、水揚酸鹽、硬脂酸鹽、琥 珀酸鹽、硫酸鹽、酒石酸鹽、硫氰酸鹽、對-曱苯磺酸 鹽、十一烷酸鹽、戊酸鹽、及諸如此類。 鹼加成鹽可藉由以下方式製得：1)使呈酸形式之純化化 合物與適宜有機或無機鹼進行反應，及2)分離由此形成之 鹽。自適宜鹼衍生之鹽包含鹼金屬（例如鈉、鋰、及鉀）、 鹼土金屬（例如鎂及鈣）、銨及N'Cu烷基）4鹽。本發明亦 期望本文所揭示化合物之任一鹼性含氮基團的四級銨化作 用。藉由該四級銨化作用，可獲得水或油可溶性或可分散 性產物。 153786.doc •27· 201231467 若適宜，其他醫藥上可接受之鹽包含無毒銨、四級錄、 及胺陽離子，其係使用諸如齒離子、氫氧根、叛酸根、硫 酸根、磷酸根、硝酸根、低碳烷基磺酸根及芳基續酸根等 抗衡離子來形成。其他酸及鹼儘管自身並非醫藥上可接 受，但亦可用於製備在獲得本發明化合物及其醫藥上可接 受之酸或鹼加成鹽時可用作中間體之鹽。 應理解，本發明包含不同醫藥上可接受之鹽之混人物/ 組合以及游離形式化合物與醫藥上可接受之鹽的混人物/ 組合。 除本發明化合物外，本發明化合物之醫藥上可接受之六 劑合物（例如，水合物）及晶籠化合物亦可用於組合物中來 治療或預防本文所識別的病症。 本文所用之術語「醫藥上可接受之溶劑合物」係自締合 一或多種醫藥上可接受之溶劑分子與本發明化合物中之一 者形成的溶劑合物。術語溶劑合物包含水合物（例如，半 水合物、單水合物、二水合物、三水合物、四水合物、及 諸如此類）。 本文所用之術語「水合物」意指進一步包含化學計量或 非化學計量量之由非共價分子間作用力結合之水的本發明 化合物或其鹽。 本文所用之術語「晶籠化合物」意指呈含有空間（命 如，通道）之晶格形式的本發明化合物或其鹽，該等空間 内捕獲有客體分子（例如，溶劑或水）。 除本發明化合物外，本發明化合物之醫藥上可接受之衍 153786.doc -28- 201231467 生物或前藥、及酯亦可用於組合物中來治療或預防本文所 識別之病症。 如本文所使用且除非另有所指，否則術語「前藥」意指 可水解、氧化或另外在生物條件下（活體外或活體内）發生 反應以提供本發明化合物的化合物衍生物。前藥可在生物 條件下發生該反應時變得具有活性，或其可在其未反應形 式時具有活性。本發明所涵蓋前藥之實例包含但不限於包 括生物可水解之部分之本發明化合物的類似物或衍生物， 該等生物可水解之部分係（例如）生物可水解之醯胺、生物 可水解之酯、生物可水解之胺基甲酸酯、生物可水解之碳 酸酯、生物可水解之醯脲、及生物可水解之磷酸酯類似 物。前藥之其他實例包含包括-NO、-N02、-ΟΝΟ、 或-0Ν02部分之本發明化合物的衍生物。前藥通常可使用 熟知方法製得，例如彼等由BURGER'S MEDICINAL CHEMISTRY AND DRUG DISCOVERY (1995) 172-178, 949-982 (Manfred E. Wolff編輯，第 5版）闡述者。 「醫藥上可接受之衍生物」係在投與有需要之患者時能 夠直接或間接提供本文原本所述化合物、或其代謝物或殘 餘物的加合物或衍生物。醫藥上可接受之衍生物之實例包 含但不限於酯及該等酯之鹽。 「醫藥上可接受之衍生物或前藥」包含本發明化合物之 任一醫藥上可接受之酯、酯鹽或其其他衍生物或鹽，其在 投與接受者後能夠直接或間接提供本發明化合物或其活性 受到抑制之代謝物或殘餘物。尤其有利之衍生物或前藥係 153786.doc -29· 201231467 彼等如下衍生物或前藥：其在將該等化合物投與串者時舍 增加本發明化合物之生物可用性（例如，藉由使 之化合物更易於吸收至血液申 T)或相對於母體物質會辨 加母體化合物至生物脉$彳曰 生物腔至(例如’腦或淋巴系統)之遞送。 本發明化合物之醫藥上可桩典— J接$之剛樂包含（不限於）酯、 胺基酸酯、磷酸酯、金屬鹽及磺酸酯。 本文所用之片語「副作用」涵蓋治療劑（例如，預防性 或治療性藥劑）之不期望且 不利之作用。副作用總是不期 仁不期望之作用不一定不利。來自治療劑⑽如，預 防性或治療性藥劑）之不利作用可有害或不合意或具有風 險。副作用包含但不限於發掉 、發燒寒冷、昏睡、胃腸道毒性 (匕含胃及腸潰瘍及糜爛卜惡心…區吐、神經毒性 性腎損害、腎毒性（自合# t q (匕3諸如乳頭壞死及慢性間質性腎炎 等病狀）、肝毒性（包含血、主拉 > 貝丨王F灸 π肝鉍含量升高）、骨髓中毒性 (包含白血球減少症、骨髄女 月髓抑制、血小板減少症及貧血）、 D腔㈣' 金屬味 '孕期延長 '虛弱、嗜睡、疼痛（包含 肌肉痛、骨痛及頭痛）、脫强 .^ 貝屌J脫髮、無力、頭暈、錐體外系症 狀、靜衫能、心血管障礙及性功能障礙。 實施例中’本發明係包括本發明化合物及醫藥上可 接受之載劑、稀釋劑、佐劑或媒劑之醫藥組合物。在一實 施例中，本發明係包括有效量之本發明化合物及醫藥上可 接又之載劑、稀釋劑、佐劑或媒劑的醫藥組合物。醫藥上 。又之載d包3 (例如）適於根據預期投與形式進行選 擇且符e s用邊藥實踐之醫藥稀釋劑、賦形劑或載劑。 153786.doc 201231467 醫藥上可接受之載劑可含有不會不恰當地抑制化合物之 生物活性之惰性成份。醫藥上可接受之載劑應具有生物相 容性，例如在投與個體時無毒、非炎性、非免疫原性或沒 有其他不期望反應或副作用。可採用標準醫藥調配技術。 如本文所使用，醫藥上可接受之載劑、佐劑、或媒劑包 含適用於所需特定劑型之任一種及所有溶劑、稀釋劑、或 其他液體媒劑、分散或懸浮助劑、表面活性劑、等滲劑、 增稠或乳化劑、防腐劑、固體黏合劑、潤滑劑及諸如此 類。Remington's Pharmaceutical Sciences，第 16版，E wThe pharmaceutically acceptable salts are described in detail by Berge, in J. Pharmaceutical Sciences, 1977, pp. 6. 1-19, which is incorporated herein by reference. The pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. The salts can be prepared in situ during the final isolation and purification of the compound. The beta acid addition salt can be prepared by: 1) reacting the purified compound in free form with a suitable organic or inorganic acid, and 2 The salt thus formed is separated. Examples of pharmaceutically acceptable non-toxic acid addition salts are inorganic acids (for example, I53786.doc -26-201231467 hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid) or with organic acids (for example, acetic acid, grass s Salt, maleic acid, tartaric acid, citric acid, saprotic acid or malonic acid) or a salt formed with an amine group by using other methods (eg, ion exchange) used in the art. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzoate, benzoate, hydrogen citrate, vinegar, butyrate, camphor Acid salt, camphor hydrochloride, citrate, cyclopentane propionate, digluconate, lauryl sulfate, acetylate, decanoate, fumarate, glucoheptonic acid Salt, glycerin disc salt, s-S salt, gluconate, acetate, hemi-sulphate, heptanoate, acid salt, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyl -ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, acid salt, 2-naphthoate, smoke Acid, nitrate, oleate, oxalate, palmitate, pamoate, pectate, persulphate, 3-phenylpropionate, phosphate, picrate, neopentyl Acid salt, propionate, salicylate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, And so on. The base addition salt can be obtained by 1) reacting the purified compound in acid form with a suitable organic or inorganic base, and 2) isolating the salt thus formed. Salts derived from suitable bases include alkali metal (e.g., sodium, lithium, and potassium), alkaline earth metal (e.g., magnesium and calcium), ammonium and N'Cu alkyl) 4 salts. The present invention also contemplates the quaternization of any of the basic nitrogen-containing groups of the compounds disclosed herein. By this quaternization, water or oil soluble or dispersible products are obtained. 153786.doc •27· 201231467 Where applicable, other pharmaceutically acceptable salts include non-toxic ammonium, quaternary, and amine cations such as dentate, hydroxide, tetherate, sulfate, phosphate, nitric acid It is formed by a counter ion such as a root, a lower alkyl sulfonate or an aryl sulfonate. Other acids and bases, although not themselves pharmaceutically acceptable, are also useful in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid or base addition salts. It will be understood that the invention encompasses a mixed person/combination of different pharmaceutically acceptable salts and a mixed character/combination of the free form compound with a pharmaceutically acceptable salt. In addition to the compounds of the invention, pharmaceutically acceptable hexapods (e.g., hydrates) and caged compounds of the compounds of the invention may also be used in the compositions to treat or prevent the conditions identified herein. The term "pharmaceutically acceptable solvate" as used herein is a solvate formed by association of one or more pharmaceutically acceptable solvent molecules with one of the compounds of the present invention. The term solvate comprises hydrates (e.g., hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, and the like). The term "hydrate" as used herein means a compound of the present invention or a salt thereof further comprising a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces. The term "cage compound" as used herein means a compound of the present invention or a salt thereof in the form of a crystal lattice containing a space (for example, a channel) in which a guest molecule (e.g., a solvent or water) is trapped. In addition to the compounds of the invention, the pharmaceutically acceptable derivatives of the compounds of the invention 153786.doc -28-201231467 may also be used in compositions for the treatment or prevention of the conditions identified herein. As used herein and unless otherwise indicated, the term "prodrug" means a derivative of a compound which hydrolyzes, oxidizes or otherwise reacts under biological conditions (in vitro or in vivo) to provide a compound of the invention. A prodrug can become active upon occurrence of the reaction under biological conditions, or it can be active in its unreacted form. Examples of prodrugs encompassed by the present invention include, but are not limited to, analogs or derivatives of the compounds of the invention comprising a biohydrolyzable moiety, such as biohydrolyzable guanamine, biohydrolyzable Esters, biohydrolyzable urethanes, biohydrolyzable carbonates, biohydrolyzable guanidine ureas, and biohydrolyzable phosphate analogs. Other examples of prodrugs include derivatives of the compounds of the invention including the -NO, -N02, -ΟΝΟ, or -OΝ02 moiety. Prodrugs can generally be prepared using well known methods, such as those described by BURGER'S MEDICINAL CHEMISTRY AND DRUG DISCOVERY (1995) 172-178, 949-982 (edited by Manfred E. Wolff, 5th Edition). "Pharmaceutically acceptable derivatives" are adducts or derivatives which, when administered to a patient in need thereof, are capable of providing, directly or indirectly, the compounds described herein, or their metabolites or residues. Examples of pharmaceutically acceptable derivatives include, but are not limited to, esters and salts of such esters. "Pharmaceutically acceptable derivative or prodrug" includes any pharmaceutically acceptable ester, ester salt or other derivative or salt thereof of the compound of the invention which, after administration to a recipient, provides the invention, either directly or indirectly A compound or a metabolite or residue whose activity is inhibited. Particularly advantageous derivatives or prodrugs 153786.doc -29-201231467 such derivatives or prodrugs which, when administered to the compounds, increase the biological availability of the compounds of the invention (for example, by The compound is more readily absorbed into the bloodstream T) or the parent compound is added to the delivery of the parent compound to the biological cavity (eg, 'brain or lymphatic system'). The medicinal composition of the compound of the present invention includes, without limitation, esters, amino acid esters, phosphate esters, metal salts and sulfonates. As used herein, the phrase "side effects" encompasses the undesirable and unfavorable effects of a therapeutic agent (e.g., a prophylactic or therapeutic agent). Side effects are always unsatisfactory. Adverse effects from therapeutic agents (10) such as prophylactic or therapeutic agents can be detrimental or undesirable or risky. Side effects include, but are not limited to, hair loss, fever, drowsiness, gastrointestinal toxicity (stomach and intestinal ulcers and sputum sputum sputum... vomiting, neurotoxic renal damage, nephrotoxicity (self-contained #tq (匕3 such as nipples) Necrosis and chronic interstitial nephritis (hepatitis), hepatotoxicity (including blood, main pull > Beckham King F moxibustion π liver sputum increased), bone marrow toxicity (including leukopenia, osteophytes, medullary inhibition, Thrombocytopenia and anemia), D cavity (four) 'Metal taste' prolonged during pregnancy 'weakness, lethargy, pain (including muscle pain, bone pain and headache), strong. ^ Bellow J hair loss, weakness, dizziness, extrapyramidal symptoms In the present invention, the invention includes a pharmaceutical composition of a compound of the invention and a pharmaceutically acceptable carrier, diluent, adjuvant or vehicle. In one embodiment The present invention includes an effective amount of a compound of the present invention and a pharmaceutically acceptable carrier, diluent, adjuvant or vehicle. The pharmaceutical composition is further provided, for example, according to Expected form of investment Pharmaceutically acceptable carrier, excipient or carrier. 153786.doc 201231467 A pharmaceutically acceptable carrier may contain inert ingredients which do not unduly inhibit the biological activity of the compound. The carrier to be received should be biocompatible, for example non-toxic, non-inflammatory, non-immunogenic or have no other undesired reactions or side effects when administered to an individual. Standard pharmaceutical formulation techniques can be employed. As used herein, medically An acceptable carrier, adjuvant, or vehicle comprises any of the specific dosage forms desired and all solvents, diluents, or other liquid vehicles, dispersion or suspension aids, surfactants, isotonic agents, and additional agents. Thick or emulsifiers, preservatives, solid binders, lubricants, and the like. Remington's Pharmaceutical Sciences, 16th Edition, E w

Martin (Mack Publishing公司，Easton，pa，198〇)揭示用於 調配醫藥上可接受之組合物之各種載劑及製備其之已知技 術。任一習用載劑介質之使用皆涵蓋於本發明範圍内，但 若該習用載劑介質與本發明化合物不相容則屬例外，例如 產生任何不期望之生物效應或另外以有害方式與醫藥上可 接雙之組合物中的任何其他組份相互作用。 —些可用作醫藥上可接受之載劑的材料之實例包含但不 限於離子父換劑、氧化铭、硬脂酸銘、卵磷脂、血清蛋白 (例如，人類血清白蛋白）、緩衝物質（例如，磷酸鹽、甘胺 酸山梨酸或山梨酸鉀）、飽和植物脂肪酸之部分甘油酯 混合物、水、鹽或電解質（例如硫酸魚精蛋白、磷酸氫二 鈉碟酸氫卸、氯化鈉、辞鹽、膠態二氧化;g夕、三石夕酸 鎂）、聚乙烯基吡咯啶酮、聚丙烯酸酯、蠟、聚乙烯-聚氧 丙烯-嵌段聚合物、羊毛脂、糖（例如，乳糖、葡萄糖及蔗 糖）；澱粉，例如玉米澱粉及馬鈴薯澱粉；纖維素及其衍 153786.doc 31 201231467 生物’例如羧甲基纖維素鈉、乙基纖維素及乙酸纖維素； 粉末狀磺蓍膠；麥芽；明膠；滑石粉；賦形劑，例如可可 油及栓劑蠟；油，例如花生油、棉籽油；紅花油；芝麻 油；撖欖油；玉米油及大豆油；二醇；例如丙二醇或聚乙 二醇；醋’例如油酸乙酯及月桂酸乙酯；瓊脂；緩衝劑， 例如氫氧化鎂及氫氧化鋁；海藻酸；無致熱源之水；等渗 鹽水；林格氏溶液（Ringer’s solution);乙醇、及磷酸鹽緩 衝溶液、以及其他無毒相容潤滑劑（例如，月桂基硫酸鈉 及硬脂酸鎂）’且根據配方設計師之判斷’該組合物中亦 可存在著色劑、釋放劑、塗覆劑、甜味劑、矯味劑及芳香 劑、防腐劑及抗氧化劑。 可將蛋白質激酶抑制劑或其醫藥鹽調配成用於投與至如 本文所定義之個體的醫藥組合物。該等醫藥組合物（包括 有效治療或預防蛋白質激酶介導之病狀之一定量蛋白質抑 制劑及醫藥上可接受之載劑）係本發明之另一實施例。 在一實施例中，本發明係治療或預防有需要之個體之蛋 白質激酶介導之病症的方法，其包括向該個體投與有效量 之如本文所述的本發明化合物、組合物或醫藥上可接受之 鹽β在另一實施例中，本發明係有效量之本文所述化合 物、組合物或醫藥上可接受之鹽在治療或預防有需要之個 體中本文所述疾病或病症中的用途。在又一實施例中，本 發明係有效量之本文所述化合物、組合物或醫藥上可接受 之鹽之用途，其用於製備用於治療或預防有需要之個體之 本文所述疾病或病症的藥劑。在一實施例中，蛋白質激酶 153786.doc •32- 201231467 介導之疾病係蛋白暂.紅& ^ 龙白貝激it c (PKC)介導之疾病。在另一實 施例中i白質激酶介導之疾病係蛋白質激酶c㊀（pkc〇) 介導之疾病。 本文所用之術語「個^^ Γ i r ϋ °個體」、「患者」及「哺乳動物」可互 換使用。術語「個體」及「患者」係指動物（例如，鳥（例 如小雞♦鳥鶉或火雞），或哺乳動物），較佳係哺乳動物， 包含非靈長類動物（例如，牛、豬、馬、綿羊 '兔、荷蘭 豬、大鼠、1替、狗、及小鼠）及靈長類動物（例如，狼子、 ,,、、裡獲及人類）’更佳係人類。在—實施例中，個體係非 人類動物例如農場動物(例如’馬、牛、豬或綿羊）、或 寵物（例如’狗、1苗、荷蘭豬或兔）。在-較佳實施例中， 個體係人類。 本文所用之有效量」係指足以引起期望生物反應之 量。在本發明中，期望生物反應係減輕或改善蛋白質激酶 介導之病狀之嚴重程度、持續時間、進展、或開始，預防 蛋白質激酶介導之病狀之發展，使蛋白質激酶介導之病狀 消退，預防與蛋白質激酶介導之病狀有關之症狀的復發、 發展、開始或進展，或增強或改進另一療法之預防性或治 療性效應。投與個體之化合物的確切量取決於投與模式、 疾病或病狀之類型及嚴重程度及個體特性（例如一般健康 狀況、年齡、性別、體重及藥物耐受性）。其亦取決於蛋 白質激酶介導之病狀之程度、嚴重程度及類型、及投與模 式。熟習此項技術者能夠端視該等及其他因素來確定適當 劑量。在與其他藥劑一起共投與時，例如在與蛋白質激酶 153786.doc -33- 201231467 介導之病狀藥劑一起共投與時，第二藥劑之「有效量」將 取決於所用藥物之類型。適宜劑量對於批准之藥劑而言已 眾所周知’且可由熟習此項技術者根據個體之病狀、所治 療之病狀類型及所使用本發明化合物之量來加以調節。在 並未明確標注用量之情形下，應假定一定有效量。 本文所用之術語「治療」（「treat」、Γ treatment」及 「treating」）係指減小或改善蛋白質激酶介導之病狀之進 展、嚴重程度及/或持續時間，或改善因投與一或多種治 療齊j (例如，一或多種治療性藥劑，例如本發明化合物）引 起之蛋白質激酶介導之病狀的一或多個症狀（較佳地，一 或多個可辨別症狀）。在具體實施例中，術語「治療」 (treat」、treatment」及「treating」）係指改善蛋白質激 酶介導之病狀<至少一個可量測物理參數。纟其他實施例 中’術語「治療」（「treat」、「treatment」及「t制㈣」） 係指以物理方式藉由（例如）穩定可辨別症狀、以生理學方 式藉由（例如）穩定物理參數、或以此兩種方式來抑制蛋白 質激酶介導之病狀的進展。在其他實施例中，術語「治 療」（「treat」、「treatment」及「⑽㈣」）係指減輕或穩 定蛋白質激酶介導之病狀。 「本文所用之術語「治療」（「t刚」、及 treatmg」）係指減小獲得或發生既定蛋白質激酶介導之 病狀之風險，或減小或抑制蛋白質激酶介導之病狀的復 發。在—實施例中’將本發明化合物作為肋性措施投與 患者、較佳人類，該患者具有本文所述任—病狀、疾病或 153786.doc • 34· 201231467 病症之遺傳素質。 本文所用之術語「疾病」、「病症」及「病狀」在本文中 可互換使用以係指蛋白質激酶介導之病狀。 在I樣中，本發明提供治療疾病、病狀、或病症（其 中蛋白質激酶與疾病狀態有關）或減輕其嚴重程度的方 法。在另一態樣中，本發明提供治療激酶疾病、病狀、或 病症（〃中酶活性之抑制與疾病治療有關）或減輕其嚴重程 度的方法。在另一態樣中，本發明提供使用藉由結合至蛋 白質激酶來抑制酶活性之化合物治療疾病、病狀、或病症 或減輕其嚴重程度的方法。另—態樣提供藉由使用蛋白質 酶抑制劑抑制激酶之酶活性來治療激酶疾病、病狀、或 病症或減輕其嚴重程度的方法。在一些實施例中，該蛋白 質激酶抑制劑係PKC0抑制劑。 本文所用之術語「蛋白質激酶介導之病狀」意指蛋白質 激ϋ在其+發揮作用之任何疾病或其他有害病狀。該等病 狀匕3 (不限於）自身免疫性疾病、炎性疾病、增殖性及過 ^增殖性疾病、免疫介導之疾病、免疫缺陷病症、免疫調 節或免疫抑制性病症、骨疾病、代謝疾病、神經及神經退 疾病〜血官疾病、激素相關性疾病' 糖尿病、過 哮黑及阿爾次海默病（Alzheimer's disease)。 本文所用之術語「PKC介導之病狀」意指pKC在其中發 揮作用之任何疾病或其他有害病狀^該等病狀包含（不限 於）彼等上述病狀及（特定而言）T-細胞介導之疾病（包含（不 於）自身免疫性疾病、慢性或急性炎性疾病、及增殖性 153786.doc -35- 201231467 及過度增殖性疾病）。 本文所用之術語「ΡΚΧΘ介導之病狀」意指ΡΚΧΘ在其中 發揮作用之任何疾病或其他有害病狀。該等病狀包含（不 限於）彼等上述疾病及（特定而言）自身免疫性疾病、慢性或 急性炎性疾病、及增殖性及過度增殖性疾病。 本文所用之術語「炎性疾病」或「炎性病症」係指會導 致炎症之病理學狀態’其通常係由白細胞浸潤引起。該等 病症之實例包含炎性皮膚病，包含（不限於）乾癬及特應性 皮炎；全身性硬皮病及硬化症；與炎性腸病（IBD)有關之 反應（例如克羅恩氏病（Crohn's disease)及潰瘍性結腸炎）； 局部缺血再灌注病症’包含外科組織再灌注損傷、心肌局 部缺血病狀（例如心肌梗塞）、心臟停搏、心臟外科手術後 之再灌注及經皮腔内冠狀動脈成形術後之收縮、中風、及 腹部主動脈瘤；中風繼發性腦部水腫；顱創傷、低血容量 性休克；窒息；成人呼吸窘迫症候群；急性肺損傷；貝赫 切特氏病（Behcet’sdisease);皮肌炎；多肌炎；多發性硬化 (MS);皮膚炎；髓膜炎；腦炎；葡萄膜炎；骨關節炎；狼 瘡性腎炎；自身免疫性疾病，例如類風濕性關節炎（RA)、 薛格連氏症候群（Sjorgen's syndrome)、血管炎；涉及白細 胞血細胞滲出之疾病；中樞神經系統（CNS)炎性病症、敗 血病或創傷繼發性多器官損傷症候群；酒精性肝炎；細菌 性肺炎；抗原抗體複合物介導之疾病，包含腎小球腎炎； 敗血病，結節病，組織或器官移植之免疫病理學反應；肺 炎症’包含胸膜炎、肺泡炎、血管炎、肺炎、慢性支氣管 153786.doc • 36 · 201231467 炎、支氣管擴張症、彌漫性全細支氣管炎、過敏性肺炎、 特發性肺纖維化（IPF)、及囊性纖維化；等。 增瘦性或過度增殖性疾病之特徵在於過度或不正常細胞 增殖。該等疾病包含（不限於）癌症及骨髓增殖性病症。 術語「癌症」包含但不限於下列癌症：類表皮口、心 臟、肺、胃腸道、泌尿生殖道、肝、骨、神經系統、婦科 學、血液學、曱狀腺及腎上腺癌。血液學癌症包含下列 癌：血液（髓樣白血病[急性及慢性]、急性成淋巴細胞性白 血病、慢性淋巴細胞白血病、骨髓增殖性疾病、多發性骨 髓瘤、骨髓增生異常症候群）、霍奇金病（H〇dgkinis disease)、非霍奇金淋巴瘤（non_H〇dgkin，s lymphoma)[惡性 淋巴瘤]毛細胞；淋巴病症；皮膚：惡性黑素瘤、基底細 胞癌、鱗狀細胞癌、卡波西氏肉瘤（Karp〇si，s sarcoma)、 角化棘皮瘤、癌（發月異常癌）、脂肪瘤、血管瘤、皮膚纖 維瘤、瘢痕瘤、及乾癬。因此，本文所提供之術語「癌細 胞」包含受上文所識別病狀中之任一者影響之細胞。 術語「骨髓增殖性病症」包含諸如以下病症：真性紅細 胞增多症、血小板增多症、伴有骨髓纖維變性之髓樣化 生、高嗜酸粒細胞症候群、青少年骨髓單核細胞性白血 病、全身性肥大細胞病、及造血系統病，特定而言係急 性-髓性白血病（AML)、慢性-趙性白血病（CML)、急性·前 髓細胞性白血病（APL)、及急性淋巴細胞白血病。 神經退化性疾病之實例包含（不限於）阿爾茨海默病、亨 廷頓氏病（Huntington's disease)、帕金森病（parkins〇n，s 153786.doc •37· 201231467 disease)、AIDS相關性癡呆、及雙相情感病症。 在實施例中，PKce介導之疾病包含（不限於）慢性炎 症、自身免疫性糖尿病、類風濕性關節炎（RA)、類風濕性 脊柱炎、痛風性關節炎及其他關節炎病狀、多發性硬化 (MS)、哮喘、全身性紅斑狼瘡、成人呼吸窘迫症候群、貝 赫切特氏病、乾癬、慢性肺部炎性疾病、移植物抗宿主反 應 '克羅恩氏病、潰瘍性結腸炎、炎性腸病（IBD)(包含脂 瀉病及刺激性腸症候群）；阿爾茨海默病、τ_細胞白血病、 淋巴瘤、移植排斥、癌症及輕癱、以及與炎症及相關病症 有關之任一疾病或病症。 在一實施例中，PKC0介導之疾病包含（例如）關節炎、類 風濕性關節炎、骨關節炎、關節炎症、狼瘡、多發性硬 化、哮喘、乾癖、癌症、Τ-細胞淋巴瘤、白血病、1或11型 糖尿病、及炎性腸病、移植排斥、克羅恩氏病及結腸炎。 自身免疫性疾病之實例包含（不限於）多發性硬化、類風 濕性關節炎及大腸激躁症。 根據所治療感染之嚴重程度，本發明之醫藥上可接受之 組合物可以下列方式投與人類及其他動物：經口、經直 腸、非經腸、腦池内、***内、腹膜腔内、局部（以於 劑、軟膏、或滴劑形式）、經口腔（以經口或鼻噴霧形式）咬 諸如此類。 用於經口投與之液體劑型包含但不限於醫藥上可接成之 乳液、微乳液、溶液、懸浮液、糖漿及酏劑。除活性化人 物外’液體劑型可含有業内通常使用之惰性稀釋劑㈠列如 153786.doc -38 - 201231467 水或其他溶劑）、增溶劑及乳化劑，例# 醇、破酿r ώ # 異丙 -曰、乙酸乙酯、苯曱醇、苯曱酸苄 醇、1 q __ _ j — 、，-一醇、二甲基甲醯胺、油（尤其係棉籽油、花生 油玉f油、胚芽油、撖揽油、萬麻油及芝麻油）、甘 油、四氫糠醇、聚乙二醇及山梨糖醇肝之脂肪酸酿、及其 混合物。除惰性稀釋劑外，口服組合物亦可包含佐劑，例 如η潤濕劑、乳化及懸浮劑、甜味劑、端味劑及芳香劑。 可根據已知技術使用適宜分散劑或潤濕劑及懸浮劑來 配可注射㈣’例如，無菌可注射水性或油㈣浮液^ 菌可注射製劑亦可為存於無毒非腸道可接受之稀釋劑或^ 劑中的無菌可注射溶液、懸浮液或乳液，例如存於^丁 二醇中之溶液。可採用之可接受媒劑及溶劑尤其為水、林 格氏'合液、u.s.p•及等滲氯化鈉溶液。此外，ϋ常採用無 菌不揮發性油作為溶劑或懸浮介質。出於此目可採用 包含合成甘油單酸酯或甘油二酸酯之任何溫和的不揮發性 油此外’在可注射製劑中可使用諸如油酸等脂肪酸。 可注射調配物可（例如）藉由經由細菌截留㈣器過Μ 藉由納入殺菌劑來進行滅菌，該等殺菌劑呈可在使用前溶 解或分散於無菌水或其他無菌可注射介質中之無菌固體組 合物形式。 為延長本發明化合物之效應，通常期望自皮下或肌内注 射來減緩該化合物之吸收。此可藉由使用具有較差水㈣ 之結晶或非晶形材料之液體懸浮液來達成。因此，化合物 之吸收速率取決於其溶解速率，且此溶解速率進而可取決 153786.doc -39- 201231467 ’可藉由將化合物溶 於晶體尺寸及結晶形式》另一選擇為 解或懸洋於油性媒劑中來達成非經腸投與化合物形式之延 遲吸收。可藉由在生物可降解聚合物（例如，聚交酯·聚乙 醇酸交酯）中形成化合物之微囊基質來製備可注射之儲積 形式。端視化合物與聚合物之比例及所用特定聚合物之性 質 ，可控制化合物之釋放速率。 其他生物可降解聚合物之 實例包含聚（原酸酯）及聚（酐）。儲積注射用調配物亦可藉 由將化合物俘獲人與身體組織相容之脂質體或微乳液中^ 製備》 用於直腸或***投與之組合物較佳為栓劑，其可藉由將 本發明化合物與適宜無刺激性賦形劑或載劑（例如可可 油、聚乙二醇或栓劑蠟）進行混合來製備，該等賦形劑或 載劑在環境溫度下為固體但在體溫下為液體且因此其可在 直腸或***腔内融化並釋放活性化合物。 經口投與之固體劑型包含膠囊、錠劑、丸劑、粉劑及顆 粒。在該等固體劑型中，活性化合物系與至少一種醫藥上 可接丈之惰性賦形劑或載劑（例如，檸檬酸鈉或磷酸二鈣） 及/或以下物質混合：a)填充劑或擴充劑，例如，澱粉、乳 糖、蔗糖、葡萄糖、甘露醇及矽酸，b)黏合劑，例如羧甲 基酸纖維素、藻酸鹽、明膠、聚乙烯基吡咯啶酮、蔗糖及 ***膠’ c)保濕劑，例如甘油，d)崩解劑，例如瓊脂、 碳酸鈣、馬鈴薯或木薯澱粉、海藻酸、某些矽酸鹽、及碳 酸鈉，e)溶液阻滞劑，例如石蠟，f)吸收促進劑，例如四 級敍化合物，g)潤濕劑，例如鯨蠟醇及甘油單硬脂酸酯， 153786.doc •40· 201231467 h)吸收劑’例如高嶺土及膨潤土，及i)潤滑劑，例如滑石 粉、硬脂酸鈣、硬脂酸鎂、固體聚乙二醇、月桂基硫酸 納、及其混合物。若為膠囊、錠劑及丸劑，則劑型亦可包 括緩衝劑。 在使用諸如乳糖（lactose或milk sugar)以及高分子量聚乙 二醇及諸如此類等賦形劑之軟質及硬質填充明膠膠囊中， 亦可採用類似類型之固體組合物作為填充劑。固體劑型之 鍵劑、糖衣藥丸、膠囊、丸劑及顆粒可使用包膜及包殼製 備’例如腸溶包膜及醫藥調配技術中熟知之其他包膜。其 可視需要含有遮光劑且亦可為視需要以延遲方式僅（或優 先）在腸道之某一部分中釋放活性成份的組合物。可使用 之包埋用組份的實例包含聚合物質及蠟。在使用諸如乳糖 (lactose或milk sugar)以及高分子量聚乙二醇及諸如此類等 賦形劑的軟質及硬質填充明膠膠囊中，亦可採用相似類型 之固體組合物作為填充劑。 活性化合物亦可呈具有一或多種上述賦形劑之微囊封化 形式。可使用諸如腸溶包膜、釋放控制包膜及醫藥調配技 術中熟知之其他包膜等包膜及包殼來製備錠劑、糖衣藥 丸、膠囊、丸劑及微粒之固體劑型。在該等固體劑型中， 可將活性化合物與至少一種惰性稀釋劑（例如，蔗糖、乳 糖或澱粉）混合。該等劑型除惰性稀釋劑以外亦可包含如 同通常實踐一般之額外物質，例如壓片潤滑劑及其他壓片 助劑（例如硬脂酸鎂及微晶纖維素卜在膠囊、錠劑及丸劑 之情形下，該等劑型亦可包括緩衝#卜其可視需要含有遮 153786.doc •41· 201231467 光劑且亦可為視需要以延遲方式僅（或優先）在腸道之某一 邛刀中釋放活性成份的組合物。可使用之包埋用組份的實 例包含聚合物質及徵。 用於局。卩或經皮投與本發明化合物之劑型包含軟膏、膏 糊乳膏、洗劑、凝膠、粉末、溶液、喷霧劑、吸入劑或 貼片若需要，可在無菌條件下將活性組份與醫藥上可接 受之載劑及任一所需防腐劑或緩衝劑混合。眼用調配物、 滴耳齊丨及滴眼劑亦涵蓋於本發明範圍内。此外，本發明 涵蓋使用透皮貼片，其具有提供化合物至身體之控制遞送 的額外優點。可藉由將化合物溶解或分配於合適介質中來 製備該等劑型。亦可使用吸收增強劑來增加化合物經過皮 膚之通量。速率可藉由提供速率控制膜或藉由將化合物分 配於聚合物基質或凝膠中來控制。 本發明組合物可經口、非經腸、藉由吸入喷霧、經局 部、經直腸、經鼻、經口腔、經***或經由植入型藥盒投 與。本文所用之術語「非經腸」包含但不限於皮下：；脈 内n關節内、滑膜内、胸骨内、鞠内、肝内、病灶 内及顱内注射或輸注技術。較佳地經口、腹膜内或靜脈 内投與該等組合物。 本發明組合物之無菌可注射形式可為水性或油性之懸浮 液°該等懸浮液可根據業内已知技術使用適宜之分散或％ 潤劑及懸浮劑進行調配。無菌可注射製劑亦可為存於益毒 非經腸可接受之稀釋劑或溶劑中之無菌可注射溶液或縣浮 液，例如，呈存於仏丁二醇中之溶液。可採用的可接受 153786.doc •42- 201231467 媒劑及溶劑@t、& 外，通當r #格氏溶液及等滲氯化納溶液。此 此目的，二無菌不揮發性油作為溶劑或懸浮介質。出於 二甘油r知用任—溫和不揮發性油，包含合成之單-或 一甘油知。脂肪酸（例如 注射物，例如天然之醫藥上;及，於可 藥麻油，其貞’例如撖视油或 液亦Π*八士 形式。該等油溶液或懸浮 類=長Γ稀釋劑或分散劑，例如叛甲基纖維素或 — 彳Ί常用於調配包含乳液及料液在内之醫 =受之劑型。亦可將其他常用表面活性劑用於調= 歹如丁ween、Spans及其他通常用於製備醫藥上可接 :之固體、液體、或其他劑型的乳化劑或生物可用性增強 本發明之醫藥組合物可以任何 ，，— V T«:人’用尘經口投 與’該等劑型包含但不限於膠囊、錠劑、水性懸浮液或容 液。在供口服使用之錠劑之情形中，常用載劑包含但不限 於乳糖及玉米澱粉。通常亦添加潤滑劑，例如硬脂酸鎮。 對於以膠囊形式經口投與而言，有用稀釋劑包含乳糖及乾 玉米殿粉。當f 口服使时性懸浮料，可將活性成份與 乳化劑及懸浮劑加以組合m，亦可添加某些甜味 劑、矯味劑或著色劑。 另-選擇為，本發明之醫藥組合物可以直腸投與之检劑 形式投與。可藉由將藥劑與適宜非刺激性賦形劑混合來製 備該等組合物，該賦形劑在室溫下為固體但在直腸溫度下 為液體，2因此可在直腸中融化而釋放藥物。該等材二包 I53786.doc -43- 201231467 含但不限於可可油、蜂蠟及聚乙二醇。 本發明之醫藥組合物亦可經局部投與，尤其當治療標乾 包含可藉由局部施加易於達到之區域或器官（包含眼睛、 皮膚或下腸道之疾病）時。很容易針對各該等區域或器官 製備適宜之局部調配物。 可採用直腸栓劑調配物（參見上文）或適宜灌腸調配物局 部施加至下腸道。亦可使用局部經皮貼片。 用於局部施加時，可將醫藥組合物調配於含有懸浮或溶 解於一或多種載劑中之活性組份的適宜軟膏中。用於局部 投與本發明化合物之載劑包含但不限於：礦物油、液體石 蠟、白軟石蠟、丙二醇、聚乙二醇、聚氧丙烯化合物、乳 化蠟及水。另一選擇為，可將醫藥組合物調配於含有懸浮 或溶解於一或多種醫藥上可接受載劑中之活性組份的適宜 洗劑或乳膏中。適宜載劑包含但不限於礦物油、山梨糠醇 酐單硬脂酸酯、聚山梨醇酯6〇、十六烷基酯蠟、鯨蠟硬脂 醇、2-辛基十二烷醇、苯甲醇及水。 用於眼睛時，可將醫藥組合物於等滲、經調整pH之無菌 鹽水中調酉己成微粒化懸料，或較佳為於等滲、經調整沖 ^無菌鹽水中調配成溶液，其含有或不含防腐劑，例如氣 苄烷銨。另—選擇為，用於眼睛時，可將醫藥組合物調配 於軟膏（例如礦脂）中。 亦可藉由經鼻氣溶膠或吸入劑來投與本發明之醫藥組合 物。根據醫藥調配領域熟知之技術來製備該等組合物且可 於生理食鹽水中製成溶液，其中採用苯f醇或其他適宜防 153 786.doc 201231467 腐劑、吸收促進劑（用於增強生物可用性）、碳氟化合物、 及/或其他習用增溶劑或分散劑。 可根據各種因素來選擇使用結構式1及π之化合物的劑量 方案’該等因素包含所治療病症及該病症之嚴重程度；所 用具體化合物之活性；所用具體組合物；患者之年齡、體 重、一般健康狀況、性別及飲食；投與時間、投與途徑、 及所用具體化合物之分泌速率；個體之腎及肝功能；及所 用之特疋化合物或其鹽、治療持續時間；與所用具體化合 物組合或同時使用之藥物、及醫藥技術中熟知之類似因 素。熟習此項技術者很容易決定並開立所需有效量之結構 式I及II化合物，以（例如）治療、預防、抑制（完全或部分 地）或阻止疾病之進展。 結構式I及II之化合物的劑量可介於約〇 〇1至約i卯 mg/kg體重/日、約〇.〇1至約5〇 mg/kg體重/日、約〇」至約5〇 mg/kg體重/日、或約！至約25 mg/kg體重/日之間。應理 解，可以單一劑量投與每天钠詈忐 六· π八心〜置，或可以多次劑量（例 如每天兩次、3次或4次）進行投與。 用於本發明方法之化合物可調配成單位劑型。術狂「單 位劑型」係指適於作為單劑型用於經受治療之個體的物理 離散單位’其中每—單位含有經計算可視需要與適宜醫藥 載劑組合產生期望治療效應之預定量活性材料。單位劑型 可為單-曰劑量或多次曰劑量(例如，每天約…欠或更 多次）之一。在使用多次曰劑量時’每—劑量 / 可相同或不同。 胃 153786.doc •45- 201231467 在本發明之方法或醫藥組合物中，可單獨使用結構式i 及II之化合物或其醫藥上可接受之鹽或溶劑合物（例如，水 合物）或與額外適宜治療劑（例如，癌症_治療劑）組合使用 來達成有效量。在採用組合療法時，可使用第一量之結構 式I及II之化合物或其醫藥上可接受之鹽或溶劑合物（例 如水η物）及第二量的額外適宜治療劑來達成有效量。 在貫施例中，分別以有效量（亦即，分別以單獨投與 時治療有效之量）來投與結構式〗及Ϊ J之化合物及額外治療 劑。在另一實施例中，分別以單獨投與時並不提供治療效 應之量（亞治療劑量）來投與結構式I及II之化合物及額外治 療劑。在再一實施例中，以有效量投與結構式〖及π之化合 物，而以亞治療劑量投與額外治療劑。在另一實施例中， 可以亞治療劑量投與結構式！及π之化合物，而以有效量投 與額外治療劑（例如，適宜癌症_治療劑）。 本文所用之術語「組合」或「共投與」可互換使用以係 才曰使用一種以上之治療劑（例如，一或多種預防性藥劑及/ 或治療性藥劑）^該等術語之使用並不限制向個體投與治 療劑（例如’預防性藥劑及/或治療性藥劑）之順序。 共投與涵蓋以基本上同時之方式投與第一及第二量之共 技與化合物，例如以單一醫藥組合物形式（例如，具有固 定比率之第一及第二量之膠囊或錠劑）、或以多次且每次 呈分開之膠囊或錠劑形式。此外，該共投與亦涵蓋以依序 方式以任一順序來使用每一化合物。 在共投與涉及分開投與第一量之結構式〗及U之化合物及 153786.doc • 46 · 201231467 第二量之額外治療劑時，在足夠接近之時間内投與化合物 以產生期望治療效應。舉例而言’可產生期望治療效應之 每次投與間之時間可介於數分鐘至數小時之間且可考慮每 一化合物的性質來確定，該等性質係（例如）功效、溶解 度、生物可用性、血漿半衰期及動力學特徵。舉例而言， 結構式I及II之化合物及第二治療劑可以任一順序在約24小 時内、約16小時内、約8小時内、約4小時内、約丨小時内 或約3 0分鐘内先後投與。 更具體而言，第一治療劑（例如，預防性或治療性藥 劑，例如本發明化合物）可在向個體投與第二治療劑（例 如，預防性或治療性藥劑，例如抗癌藥）之前（例如，在5分 鐘、15分鐘、30分鐘、45分鐘、1小時、2小時、4小時、6 小時、12小時、24小時、48小時、72小時、％小時、i 週2週、3週、4週、5週、6週、8週、或12週前）、同 時、或在之後（例如，在5分鐘、15分鐘、3〇分鐘、45分 鐘、1小時、2小時、4小時、6小時、12小時、24小時、48 小時、72小時、96小時、！週、2週、3週、4週、5週、6 週、8週、或I2週後）投與。 應理解，共投與第一量之結構式1及11之化合物及第二量 之額外治療劑之方法可產生增強或協同治療效應，其中組 口效應大於自分開投與第一量之結構式〗及π之化合物及第 二量之額外治療劑所產生的加和效應。 本文所用之術語「協同」係指本發明化合物與另一治療 劑（例如，預防性或治療性藥劑）之組合，其有效性大於各 153786.doc -47- 201231467 治療劑之加和效應。治療劑組合(例如，預防性或治療性 藥劑之組合）之協同效應允許使用較低劑量之一或多種治 療劑及/或以較低頻率向個體投與該等治療劑。利用較低 劑量治療劑（例如’預防性或治療性藥劑）及/或以較低頻率 投與該治療劑之能力彳減小與向個體投與該治療劑有關的 毒性，且不會減小該治療劑預防、管控或治療病症之效 能。此外，協同效應可改進藥劑在預防、管控或治療病症 中之效能。最後，治療劑組合（例如，預防性或治療性藥 劑之組合）之協同效應可避免或減小與使用僅任一治療劑 有關之不利或不期望的副作用。 可使用適用於評價藥物相互作用之方法來確定協同效應 之存在。適且方法包含（例如）Sigm〇id-Emax方程（H〇lf〇rd, N.H.G·及 Scheiner，L.B·，Clin. Pharmacokinet. 6: 429-453 (1981))、Loewe加和性方程（Loewe，SiMuischnek, h.， Arch. Exp. Pathol Pharmacol. 114: 313-326 (1926))及中效 方程（Chou, T.C.及丁alalay，P., Adv. Enzyme Regul· 22. 27_ 55 (1984))。可使用實驗數據來應用上文提及之每一方程 以產生相應圖式來幫助評價藥物組合之效應。與上文提及 之方程有關之相應圖式分別係濃度-效應曲線、等效線圖 曲線及合併係數曲線。 在一些實施例中’該額外治療劑選自癌症-治療劑，例 如，抗癌藥、抗增殖藥、或化學治療劑。 在一些實施例中’該額外治療劑選自喜樹驗 (camptothecin)、MEK抑制劑：U0126、KSP(驅動蛋白紡錘 153786.doc -48- 201231467 體蛋白）抑制劑、阿黴素（adriamycin)、干擾素、及翻衍生 物（例如順舶（Cisplatin))。 在其他實施例中，該額外治療劑選自紫杉烷；bcr-ab抑 制劑（例如格列衛（Gleevec)、達沙替尼（dasatinib)、及尼羅 替尼（nilotinib)) ; EGFR抑制劑（例如塔西法（Tarceva)及易 瑞沙（Iressa)) ; DNA損傷劑（例如順鉑、奥沙利鉑 (oxaliplatin)、卡# (carboplatin)、招撲異構酶抑制劑、及 蒽環）；及抗代謝藥（例如AraC及5-FU)。 在其他實施例中，該額外治療劑選自喜樹鹼、多柔比星 (doxorubicin)、伊達比星（idarubicin)、順翻、紅豆杉醇、 泰素帝（taxotere)、長春新驗（vincristine)、塔西法、MEK 抑制劑、U0126、KSP抑制劑、伏立諾他（vorinostat)、格 列衛、達沙替尼、及尼羅替尼。 在另一實施例中，該額外治療劑選自Hei*-2抑制劑（例如 赫赛汀（Herceptin))、HDAC抑制劑（例如伏立諾他 (vorinostat))、VEGFR抑制劑（例如阿瓦斯丁（Avastin))、 c-KIT及FLT-3抑制劑（例如舒尼替尼（sunitinib))、BRAF抑 制劑（例如Bayer之BAY 43-9006)、MEK抑制劑（例如Pfizer 之PD0325901)、及紡錘體毒劑（例如埃坡黴素 (Epothilones))及紫杉齡（paclitaxel)蛋白質結合顆粒（例如 Abraxane®) 〇 可與本發明藥劑組合使用之其他療法或抗癌藥包含外科 手術、放射療法（僅在少數實例中，γ-放射療法、中子束放 射療法、電子束放射療法、質子療法、近距放射療法、及 1537S6.doc -49- 201231467 全身放射性同位素療法，僅舉幾個例子）、内分泌療法、 生物反應調節劑（干擾素、介白素及腫瘤壞死因子（TNF)， 僅舉幾個例子）、高溫療法及冷凍療法、消弱任何副作用 之藥劑（例如，止吐藥）及其他經批准化學治療藥物，包含 但不限於烷基化藥物（氮芥、苯丁酸氮芥、環磷醯胺、美 法侖（Melphalan)、異環磷醯胺）、抗代謝藥物（甲胺蝶呤 (Methotrexate))、嘌呤拮抗劑及嘧啶拮抗劑（6-巯基嘌呤、 5-氟尿嘲咬、阿糖胞苷（Cytarabile)、二氟胞。密咬 (Gemcitabine))、紡錘體毒素（長春驗（Vinblastine)、長春新 驗、長春瑞賓（Vinorelbine)、紫杉醇（Paclitaxel))、鬼臼毒 素（podophyllotoxin)(表鬼臼毒素（Etoposide)、伊立替康 (Irinotecan)、拓撲替康（Topotecan))、抗生素（多柔比星 (Doxorubicin)、博萊黴素（Bleomycin)、絲裂黴素 (Mitomycin))、亞确基腺（亞硕基腺氮芥（Carmustine)、羅 氮芥（Lomustine))、無機離子（順鉑、卡鉑）、酶（天冬醢胺 酶）、及激素（他莫昔芬（Tamoxifen)、亮丙瑞林 (Leuprolide)、氟利坦（Flutamide)、及曱地孕綱（Megestrol))、 Gleevec™、阿黴素、***（dexamethasone)、及環磷酿 胺。 本發明化合物亦可與下列治療劑中之任一者組合用於治 療癌症：阿巴瑞克（abarelix)(Plenaxis depot®);阿地白介 素（aldesleukin)(Prokine®);阿地白介素（Proleukin®);阿 來祖馬（Alemtuzumabb)(Campath®);阿曲諾英（alitretinoin) (Panretin®);別嗓呤醇（allopurinol)(Zyloprim®);六甲嘴 153786.doc -50- 201231467 胺（altretamine)(Hexalen®);胺填汀（amifostine)(Ethyol®); 阿那曲唾（anastrozole)(Arimidex®);三氧化二石申（Trisenox®); 天冬酿胺酶（Elspar®);阿紮胞普（azacitidine) (Vidaza®);貝 法古自馬（bevacuzimab)(Avastin®);貝沙羅汀（bexarotene) 膠囊（Targretin®);貝沙羅汀凝膠（Targretin®);博萊黴素 (Blenoxane®);波替單抗（bortezomib)(Velcade®);靜脈内 使用之白消安（busulfan)(Busulfex®) ; 口服白消安（Myleran®); 卡普睪酮（calusterone)(Methosarb®);卡培他濱（capecitabine) (Xeloda®);卡銘（Paraplatin®);卡莫司汀(carmustine)(BCNU®、 BiCNU®);卡莫司汀（Gliadel®);卡莫司汀與聚苯丙生20 植入物（Gliadel Wafer®);塞利西菌（celecoxib)(Celebrex®); 西土西單抗（cetuximab)(Erbitux®); 苯丁酸氮芬 (Leukeran®);順始（Platinol®);克拉屈濱（cladribine) (Leustatin®、2-CdA®);氯苯吩唤（clofarabine)(Clolar®); 環填酿胺（Cytoxan®、Neosar®);環構酿胺（Cytoxan Injection®);環峨酿胺（Cytoxan Tablet®);阿糖胞苦 (Cytosar-U®);阿糖胞苷脂質體（DepoCyt®);達卡巴嗪 (dacarbazine)(DTIC，Dome®);更生黴素（dactinomycin)、 放線菌素 D(actinomycin D)(Cosmegen®);達貝泊汀 a(Darbepoetin alfa)(Aranesp®);柔紅徽素（daunorubicin)脂 質體（DanuoXome®);柔紅黴素、道諾黴素（daunomycin) (daunorubicin®);柔紅黴素、道諾黴素（Cerubidine®);地 尼白介素 2(Denileukin diftitox)(Ontak®);右雷佐生 (dexrazoxane)(Zinecard®);多西他赛（docetaxel)(taxotere®); 153786.doc -51- 201231467 多柔比星（Adriamycin PFS®);多柔比星（Adriamycin®、 Rubex®);多柔比星（Adriamycin PFS Injection®);多柔比 星脂質體（Doxil®);丙酸甲雄烧酮（dromostanolone®);丙 酸甲雄烧酮（masterone injection®);愛立特氏（Elliott's)B 溶液（Elliott's B Solution®):表柔比星（epirubicin) (Ellence®);阿法依伯、;丁（Epoetin alfa)(epogen®);埃羅替 尼（erlotinib)(Tarceva®);雌莫司汀（estramustine)(Emcyt®); 磷·酸依託泊苦（etoposide phosphate)(Etopophos®);依託泊 苦（etoposide)，VP-16(Vepesid®);依西美坦（exemestane) (Aromasin®);非格司亭（Filgrastim)(Neupogen®);銳尿苦 (intraarterial)(FUDR®) ; IL 達拉濱（fludarabine)(Fludara®); 氟尿嘧啶、5-FU(Adrucil®);氟維司群（fulvestrant) (Faslodex®)；吉非替尼（gefitinib)(Iressa®);吉西他濱 (gemcitabine)(Gemzar®);吉姆單抗奥佐米星（gemtuzumab ozogamicin)(Mylotarg®);乙酸戈舍瑞林（goserelin acetate)(Zoladex Implant®);乙酸戈舍瑞林（Zoladex®); 乙酸組胺瑞林（histrelin acetate)(Histrelin implant®);經基 腺（Hydrea®);替坦異貝莫單抗（Ibritumomab Tiuxetan) (Zevalin®);伊達比星（Idamycin®);異環填醯胺（IFEX®); 甲續酸伊馬替尼（imatinib mesylate)(Gleevec®);干擾素α 2a(Roferon A®);干擾素 a-2b(Intron A®);伊立替康 (Camptosar®);勒鈉度胺（lenalidomide)(Revlimid®);來曲 唑（letrozole)(Femara®);甲醯四氫葉酸（leucovorin) (Wellcovorin®、leucovorin®);乙酸亮丙瑞林（Eligard®); 153786.doc -52- 201231467 左旋四0米°坐（16乂3!1113〇16)(£^&11113〇1©);羅氮芥（1〇1111131^116)、 CCNU(CeeBU®);雙氯乙基曱胺（meclorethamine)、氮芥 (Mustargen®);乙酸甲地孕酮（Megace®);美法侖、L-PAM (Alkeran®);疏基0票0令、6-MP(Purinethol®);美司鈉 (mesna)(Mesnex®);美司鈉（Mesnex tabs®);胺曱蝶吟 (Methotrexate®);曱氧沙林（methoxsalen)(Uvadex®);絲 裂黴素C(Mutamycin®);米托坦（mitotane)(Lysodren®);米 托蒽醒（mitoxantrone)(Novantrone®);苯丙酸諾龍（nandrolone phenpropionate)(Durabolin-50®);对拉濱（nelarabine) (Arranon®);諾非單抗（Nofetumomab)(Verluma®);奥普瑞 白介素（〇prelvekin)(Neumega®);奥沙利銘（Eloxatin®); 紫杉醇（Paxene®);紫杉醇（taxol®);紫杉醇蛋白質結合顆 粒（Abraxane®);帕利非明（palifermin)(Kepivance®);帕米 膦酸二納（pamidronate)(Aredia®);培加酶（pegademase) (Adagen(Pegademase Bovine)®);培加帕酶（pegaspargase) (Oncaspar®);培非拉斯替（Pegfilgrastim)(Neulasta®);培 美曲塞二鈉（pemetrexed disodium)(Alimta®);噴托他丁 (pentostatin)(Nipent®) ; 0辰泊漠烧（pipobroman)(Vercyte®); 普卡黴素（plicamycin)、米拉黴素（mithramycin)(Mithracin®); σ卜吩姆納（porfimer sodium)(Photofrin®);丙卡巴肼 (procarbazine)(Matulane®);奎納克林（quinacrine)(Atabrine®); 拉布立酶（Rasburicase)(Elitek®);利妥昔單抗（Rituximab) (Rituxan®);沙格莫 丁（sargramostim)(Leukine®);沙格莫 丁（Prokine®);索拉非尼（sorafenib)(Nexavar®);鍵腺黴素 153786.doc -53- 201231467 (streptozocin)(Zanosar®);馬來酸蘇尼替尼（sunitinib maleate) (Sutent®);滑石粉（Sclerosol®);他莫昔芬（Nolvadex®); 替莫 °坐胺（temozolomide)(Temodar®);替尼泊苦（teniposide)、 VM-26(Vumon®);睪内酯（Teslac®);硫烏嘌呤、6-TG (Thioguanine®) ; »塞替派（thiotepa)(Thioplex®);拓撲替康 (Hycamtin®);托瑞米芬（toremifene)(Fareston®);托西莫 單抗（Tositumomab)(Bexxar®);托西莫單抗八-13 1托西莫單 抗（Bexxar®);曲司佐單抗（Trastuzumab)(Herceptin®);維 甲酸（tretinoin)、ATRA(Vesanoid®);尿嘲咬氮芥（Uracil Mustard)(Uracil Mustard Capsules®);伐蘆比星（valrubicin) (Valstar®);長春驗（Velban®);長春新驗（Oncovin®);長 春瑞濱（Navelbine®) ; °坐來膦酸鹽（zoledronate)(Zometa®) 及福瑞斯達（vorinostat)(Zolinza®)。 關於更新之癌症療法之深入論述，可參見 http://www.nci.nih.gov/，一系列FDA批准之腫瘤學藥物可 參見 http://www.fda.gov/cder/cancer/druglistframe.htm、及 The Merck Manual，第17版，1999，其全部内容皆以引用 方式併入本文中。 亦可與本發明化合物組合使用之其他藥劑實例包含（不 限於）：用於阿爾茨海默病之治療劑，例如Aricept®及 Excelon® ；用於帕金森病之治療劑，例如L-D0PA/卡比多 巴（carbidopa)、恩他卡朋（entacapone)、羅B比尼洛 (ropinrole)、普拉克索（pramipexole)、演隱亭 (bromocriptine)、培高利特（pergolide)、苯海索 153786.doc -54- 201231467 (trihexephendyl)、及金剛院胺；用於治療多發性硬化（MS) 之藥劑，例如β干擾素（例如’ Avonex®及Rebif®)、 Copaxone®、及米托蒽S昆；用於哮喘之治療劑，例如沙丁 胺醇（albuterol)及Singulair® ;用於治療精神***症之藥 劑，例如再普樂（zyprexa)、維思通（risperdal)、思瑞康 (seroquel)、及氟旅咬醇（haloperidol);抗炎劑，例如皮質 類固醇、TNF封阻劑、IL:1 RA、硫唑嘌呤（azathioprine)、 環攝醯胺、及柳氬確胺比咬（sulfasalazine);免疫調節及免 疫阻抑性藥劑’例如環抱素（cyclosporine)、他羅利姆 (tacrolimus)、雷帕黴素（rapamycin)、麥考酿酸嗎乙醋 (mycophenolate mofetil)、干擾素、皮質類固醇、環鱗醯 胺、硫唑嘌呤、及柳氮磺胺吡啶；神經營養因子，例如， 乙醯膽鹼酯酶抑制劑、MAO抑制劑、干擾素、抗驚厥藥、 離子通道封阻劑、利產嗟吐（riluzole)、及抗帕金森病藥； 用於治療心血管疾病之藥劑，例如β·封阻劑、ace抑制 劑、利尿藥、硝酸鹽、鈣通道封阻劑、及他汀類藥物 (statins);用於治療肝病之藥劑，例如皮質類固醇、考來 烯胺（cholestyramine)、干擾素、及抗病毒藥；用於治療血 液病症之藥劑，例如皮質類固醇、抗白血病藥、及生長因 子；及用於治療免疫缺陷病症之藥劑，例如γ-球蛋白。 作為蛋白質激酶抑制劑，本發明之化合物及組合物亦可 用於生物試樣中。本發明一態樣係關於抑制生物試樣中之 蛋白質激酶活性，該方法包括使該生物試樣與式I及Π化合 物或包括該化合物之組合物接觸。本文所用之術語「生物 153786.doc •55- 201231467 試樣」意指活體外或離體試樣包含(不限於)細胞培養 物或其提取物’自哺乳動物獲得之活檢組織材料或其提取 物；及企液、唾液、尿、翼便、***、眼淚或其他體液或 其提取物。 抑制生物試樣中之蛋白質激酶活性可用於熟習此項技術 . 者已知之各種目的。此等目的之實例包含但不限於輸血、 器官移植、及生物標本儲存。 本發明之另-態樣係關於研究生物學及病理學現象中之 蛋白質激酶；研究由該等蛋白質激酶調介之細胞内信號轉 導路徑；及對比性評估新顆蛋白質激酶抑制劑。該等用途 之實例包含但不限於生物分析，例如酶分析及細胞基分 析。 作為蛋白質激酶抑制劑之化合物之活性可在活體外、活 體内或細胞系中進行分析。活體外分析包含測定經活化激 酶之激酶活性或ATPase活性之抑制的分析。替代性活體外 分析可量化抑制劑結合蛋白質激酶之能力，且可藉由以下 方式進行#測：在結合前放射性標記抑制劑，分離抑制劑/ 激酶複合物並測定所結合放射性標記之量，或實施將新穎 抑制劑與結合至已知放射性配體之激酶一起培育之競爭實 . 驗。分析本發明所用化合物之詳細條件闡述於下文實例 中。 本發明之另一態樣係關於本文所述化合物（尤其係彼等 對於生物化學鈀具有中等觀察親和力者（IC5〇丨_1〇 μΜ))作 為起點在化學優化中的用途。特定而言，本發明一態樣係 153786.doc •56· 201231467 關於對於化學優化用纪酶之常規抑制研究。 本發明之另一態樣係關於本文所述化合物在晶體學（尤 其係彼等對於生物化學鈀具有中等觀察親和力者）中之用 途：特定而言，本發明一態樣係關於使用本文所述化合物 來產生共複合物晶體結構。 本發明之另一態樣係關於本文所述化合物作為化學工具 在活體外及活體内探究把生物學之用途：特定而士， 用在生物化學分析中具有中等親和力之抑制劑來探究二制 細胞及整體動物疾病模型中之把酶的生物影塑。 本發明之另一態樣提供藉由使式之化合物與蛋白質 激酶接觸來調節酶活性的方法。 缩寫 使用下列縮寫： DMSO 二曱基亞颯 TCA 三氯乙酸 ATP 三磷腺苷 BSA 牛血清白蛋白 DTT 二硫蘇糖醇 MOPS 4 -嗎*丙酸 NMR 核磁共振 HPLC 尚效液相層析 LCMS 液相層析-質譜 TLC 薄層層析 Rt 保留時間 在一些實施例中，本發明化合物展示於表丨中。在某此 實施例中，本文所用之變量如表丨中所示之具體實施= 153786.doc -57- 201231467 所定義。Martin (Mack Publishing Company, Easton, pa, 198 〇) discloses various carriers for formulating pharmaceutically acceptable compositions and known techniques for preparing the same. The use of any conventional carrier medium is encompassed within the scope of the invention, except where the conventional carrier medium is incompatible with the compounds of the invention, for example, to produce any undesirable biological effects or otherwise in a deleterious manner with the pharmaceutical Any other component in the composition that can be combined can interact. - Examples of materials useful as pharmaceutically acceptable carriers include, but are not limited to, ion parent, oxidized, stearic acid, lecithin, serum proteins (eg, human serum albumin), buffer substances ( For example, phosphate, sorbic acid sorbate or potassium sorbate), a mixture of glycerides of saturated plant fatty acids, water, salts or electrolytes (eg protamine sulfate, disodium hydrogen phosphate, sodium chloride, Salt, colloidal dioxide; g, three magnesium sulfate, polyvinylpyrrolidone, polyacrylate, wax, polyethylene-polyoxypropylene-block polymer, lanolin, sugar (for example, lactose , glucose and sucrose); starch, such as corn starch and potato starch; cellulose and its derivative 153786.doc 31 201231467 biological 'such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered sulfonate; Malt; gelatin; talcum powder; excipients such as cocoa butter and suppository wax; oils such as peanut oil, cottonseed oil; safflower oil; sesame oil; eucalyptus oil; corn oil and soybean oil; diol; Polyethylene glycol; vinegar 'such as ethyl oleate and ethyl laurate; agar; buffer, such as magnesium hydroxide and aluminum hydroxide; alginic acid; water without pyrogen; isotonic saline; Ringer's solution ( Ringer's solution; ethanol, and phosphate buffer solutions, and other non-toxic compatible lubricants (eg, sodium lauryl sulfate and magnesium stearate)' and, depending on the formulator's color, may also be present in the composition. , release agents, coating agents, sweeteners, flavoring and fragrances, preservatives and antioxidants. The protein kinase inhibitor or a pharmaceutical salt thereof can be formulated into a pharmaceutical composition for administration to an individual as defined herein. Such pharmaceutical compositions, including one that effectively treats or prevents a protein kinase mediated condition, a quantitative protein inhibitor and a pharmaceutically acceptable carrier, are another embodiment of the invention. In one embodiment, the invention is a method of treating or preventing a protein kinase-mediated disorder in an individual in need thereof, comprising administering to the individual an effective amount of a compound, composition or medicinal invention of the invention as described herein. Acceptable Salts β In another embodiment, the invention is an effective amount of a compound, composition or pharmaceutically acceptable salt described herein for use in treating or preventing a disease or condition described herein in an individual in need thereof . In still another embodiment, the invention is an use of an effective amount of a compound, composition or pharmaceutically acceptable salt described herein for the manufacture of a disease or condition described herein for the treatment or prevention of an individual in need thereof Pharmacy. In one embodiment, the protein kinase 153786.doc • 32-201231467 mediated disease is a protein temporarily. Red & ^ Longbaibeiji it c (PKC) mediated disease. In another embodiment, the i-white kinase mediated disease is a protein kinase c- (pkc〇) mediated disease. The terms "a ^ Γ i r ϋ ° individual", "patient" and "mammal" are used interchangeably herein. The terms "individual" and "patient" mean an animal (eg, a bird (eg, a chicken ♦ guanine or turkey), or a mammal), preferably a mammal, and includes a non-primate (eg, cow, pig) Horses, sheep 'rabbits, Dutch pigs, rats, 1 pair, dogs, and mice) and primates (eg, wolves, ,,,, and humans) are better humans. In an embodiment, the system is a non-human animal such as a farm animal (e.g., 'horse, cow, pig or sheep), or a pet (e.g., 'dog, 1 seedling, Dutch pig or rabbit). In the preferred embodiment, the system is human. An effective amount as used herein refers to an amount sufficient to cause a desired biological response. In the present invention, it is expected that the biological response system reduces or improves the severity, duration, progression, or initiation of a protein kinase-mediated condition, prevents the development of a protein kinase-mediated condition, and causes a protein kinase-mediated condition. Regression, prevention of recurrence, progression, onset or progression of symptoms associated with protein kinase mediated conditions, or enhancement or amelioration of the prophylactic or therapeutic effects of another therapy. The exact amount of a compound administered to an individual will depend on the mode of administration, the type and severity of the disease or condition, and the individual characteristics (e.g., general health, age, sex, weight, and drug tolerance). It also depends on the extent, severity and type of the condition mediated by the protein kinase, and the mode of administration. Those skilled in the art will be able to determine these and other factors to determine the appropriate dosage. When co-administered with other agents, such as when co-administered with a pathogenic agent mediated by protein kinase 153786.doc-33-201231467, the "effective amount" of the second agent will depend on the type of drug being used. Suitable dosages are well known to the approved pharmaceutical agents and can be adjusted by those skilled in the art based on the condition of the individual, the type of condition being treated, and the amount of the compound of the invention employed. In cases where the amount is not clearly indicated, an effective amount should be assumed. The term "treat", "treatment" and "treating" as used herein means reducing or improving the progression, severity and/or duration of a protein kinase-mediated condition, or improving the administration of a disease. One or more symptoms (preferably, one or more discernible symptoms) of a protein kinase-mediated condition caused by a plurality of treatments (eg, one or more therapeutic agents, such as a compound of the invention). In the specific examples, the terms "treat", "treatment" and "treating" refer to amelioration of protein kinase-mediated conditions. <At least one measurable physical parameter. In other embodiments, 'the term 'treatment' ("treat", "treatment" and "t system (4)") refers to physically, for example, by stabilizing a discernible symptom, physiologically by, for example, stabilizing Physical parameters, or both, inhibit the progression of protein kinase-mediated conditions. In other embodiments, the term "treat", "treatment" and "(10) (d)") refers to alleviating or stabilizing a protein kinase-mediated condition. "The term "treatment" ("t-gang", and treatmg" as used herein refers to reducing the risk of acquiring or developing a disease-mediated pathogen, or reducing or inhibiting the recurrence of a protein kinase-mediated condition. . In the present invention, the compound of the present invention is administered to a patient, preferably a human, as a ribing measure, and the patient has any of the conditions, diseases or 153786 described herein. Doc • 34· 201231467 The genetic quality of the condition. The terms "disease", "condition" and "condition" as used herein are used interchangeably to refer to a protein kinase-mediated condition. In a sample, the invention provides a method of treating or lessening the severity of a disease, condition, or condition in which a protein kinase is associated with a disease state. In another aspect, the invention provides methods of treating or lessening the severity of a kinase disease, condition, or condition (inhibition of enzyme activity in a sputum associated with treatment of a disease). In another aspect, the invention provides a method of treating or lessening the severity of a disease, condition, or condition by a compound that inhibits enzymatic activity by binding to a protein kinase. Another aspect provides a method of treating a kinase disease, condition, or condition or reducing the severity thereof by inhibiting the enzymatic activity of the kinase using a proteinase inhibitor. In some embodiments, the protein kinase inhibitor is a PKCO inhibitor. As used herein, the term "protein kinase mediated condition" means any disease or other deleterious condition in which a protein is active at its action. Such conditions 匕3 (not limited to) autoimmune diseases, inflammatory diseases, proliferative and hyperproliferative diseases, immune-mediated diseases, immunodeficiency disorders, immunomodulatory or immunosuppressive disorders, bone diseases, metabolism Disease, neurological and neurodegenerative diseases ~ blood disease, hormone-related diseases 'diabetes, black stagnation and Alzheimer's disease. The term "PKC-mediated condition" as used herein means any disease or other deleterious condition in which pKC functions (including, but not limited to) the above-mentioned conditions and (specifically) T- Cell-mediated disease (including (not) autoimmune disease, chronic or acute inflammatory disease, and proliferative 153,786. Doc -35- 201231467 and hyperproliferative diseases). The term "sputum-mediated condition" as used herein means any disease or other deleterious condition in which a sputum plays a role. Such conditions include, without limitation, the above-mentioned diseases and (particularly) autoimmune diseases, chronic or acute inflammatory diseases, and proliferative and hyperproliferative diseases. The term "inflammatory disease" or "inflammatory disorder" as used herein refers to a pathological condition that causes inflammation, which is usually caused by leukocyte infiltration. Examples of such conditions include inflammatory skin diseases including, without limitation, cognac and atopic dermatitis; systemic scleroderma and sclerosis; reactions associated with inflammatory bowel disease (IBD) (eg, Crohn's disease) (Crohn's disease) and ulcerative colitis); ischemia-reperfusion disorders include surgical tissue reperfusion injury, myocardial ischemic conditions (eg myocardial infarction), cardiac arrest, reperfusion after cardiac surgery, and Contraction, stroke, and abdominal aortic aneurysm after intracortical coronary angioplasty; secondary brain edema of stroke; cranial trauma, hypovolemic shock; asphyxia; adult respiratory distress syndrome; acute lung injury; Behcet's disease; dermatomyositis; polymyositis; multiple sclerosis (MS); dermatitis; meningitis; encephalitis; uveitis; osteoarthritis; lupus nephritis; autoimmune disease For example, rheumatoid arthritis (RA), Sjorgen's syndrome, vasculitis; diseases involving leukocyte blood cell exudation; central nervous system (CNS) inflammatory disease, septicemia or invasive Secondary multiple organ injury syndrome; alcoholic hepatitis; bacterial pneumonia; antigen-antibody complex-mediated disease, including glomerulonephritis; septicemia, sarcoidosis, immunopathological response to tissue or organ transplantation; pulmonary inflammation 'Contains pleurisy, alveolitis, vasculitis, pneumonia, chronic bronchi 153786. Doc • 36 · 201231467 Inflammation, bronchiectasis, diffuse panbronchiolitis, allergic pneumonia, idiopathic pulmonary fibrosis (IPF), and cystic fibrosis; A lean or hyperproliferative disorder is characterized by excessive or abnormal cell proliferation. Such diseases include, without limitation, cancer and myeloproliferative disorders. The term "cancer" includes, but is not limited to, the following cancers: epidermis, heart, lung, gastrointestinal tract, genitourinary tract, liver, bone, nervous system, gynecology, hematology, sputum gland, and adrenal cancer. Hematological cancer includes the following cancers: blood (myeloid leukemia [acute and chronic], acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disease, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease (H〇dgkinis disease), non-H〇dgkin, s lymphoma [malignant lymphoma] hair cells; lymphoid disorders; skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kappa Western sarcoma (Karp〇si, s sarcoma), keratoacanthoma, cancer (abnormal cancer of the moon), lipoma, hemangioma, cutaneous fibroids, keloid, and cognac. Accordingly, the term "cancer cell" as provided herein encompasses a cell that is affected by any of the conditions identified above. The term "myeloproliferative disorder" encompasses conditions such as polycythemia vera, thrombocytopenia, myeloid metaplasia with myelofibrosis, high eosinophilic syndrome, adolescent bone marrow monocytic leukemia, systemic hypertrophy Cytopathic and hematopoietic diseases, in particular, acute-myeloid leukemia (AML), chronic-directed leukemia (CML), acute promyelocytic leukemia (APL), and acute lymphocytic leukemia. Examples of neurodegenerative diseases include, without limitation, Alzheimer's disease, Huntington's disease, Parkinson's disease (parkins〇n, s 153786. Doc •37·201231467 disease), AIDS-related dementia, and bipolar disorder. In embodiments, PKce-mediated diseases include, without limitation, chronic inflammation, autoimmune diabetes, rheumatoid arthritis (RA), rheumatoid spondylitis, gouty arthritis, and other conditions of arthritis, multiple Sclerosing (MS), Asthma, Systemic Lupus Erythematosus, Adult Respiratory Distress Syndrome, Behcet's Disease, Cognac, Chronic Pulmonary Inflammatory Disease, Graft Anti-Host Response 'Crohn's Disease, Ulcerative Colitis Inflammatory bowel disease (IBD) (including celiac disease and stimulating bowel syndrome); Alzheimer's disease, τ-cell leukemia, lymphoma, transplant rejection, cancer and convulsions, and inflammation and related disorders Any disease or condition. In one embodiment, the PKC0 mediated disease comprises, for example, arthritis, rheumatoid arthritis, osteoarthritis, joint inflammation, lupus, multiple sclerosis, asthma, cognac, cancer, sputum-cell lymphoma, Leukemia, type 1 or 11 diabetes, and inflammatory bowel disease, transplant rejection, Crohn's disease, and colitis. Examples of autoimmune diseases include, without limitation, multiple sclerosis, rheumatoid arthritis, and irritable bowel syndrome. Depending on the severity of the infection being treated, the pharmaceutically acceptable compositions of the present invention can be administered to humans and other animals in the following manner: orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, locally ( In the form of a dose, ointment, or drops), biting through the mouth (in the form of an oral or nasal spray), and the like. Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the activated person, the liquid dosage form may contain inert diluents commonly used in the industry (1), such as 153786. Doc -38 - 201231467 Water or other solvents), solubilizers and emulsifiers, example #醇,破酿r ώ #isopropyl-曰, ethyl acetate, benzofuran, benzyl benzoate, 1 q __ _ j —,,--ol, dimethylformamide, oil (especially cottonseed oil, peanut oil jade oil, germ oil, oil, sesame oil and sesame oil), glycerin, tetrahydrofurfuryl alcohol, polyethylene glycol and The fatty acid of sorbitol liver, and mixtures thereof. Besides the inert diluent, the oral compositions may also contain adjuvants such as η wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents, and perfuming agents. Suitable dispersing agents or wetting agents and suspending agents can be used according to the known art. (4) For example, sterile injectable aqueous or oily (IV) floating liquid injectable preparations may also be non-toxic and non-intestinal acceptable A sterile injectable solution, suspension or emulsion in a diluent, for example, a solution in a solution of butyl diol. The acceptable vehicles and solvents that can be used are, in particular, water, Ringer's liquid, u. s. p• and isotonic sodium chloride solution. In addition, sterile non-volatile oils are often employed as solvents or suspending media. Any mild, fixed oil containing synthetic mono- or diglycerides may be employed for this purpose. Further, fatty acids such as oleic acid may be used in the injectable preparations. Injectable formulations can be sterilized, for example, by incorporating a bactericidal agent by sterilizing the bactericidal agent, which is sterilized by dissolving or dispersing in sterile water or other sterile injectable medium before use. In the form of a solid composition. To prolong the effects of the compounds of the invention, it is generally desirable to inject from subcutaneous or intramuscular to slow the absorption of the compound. This can be achieved by using a liquid suspension of crystalline or amorphous material with poor water (iv). Therefore, the rate of absorption of the compound depends on its rate of dissolution, and this rate of dissolution may in turn depend on 153,786. Doc-39-201231467' can be achieved by dissolving or relaxing in an oily vehicle by dissolving the compound in crystal size and crystalline form to achieve delayed absorption of the parenterally administered compound form. Injectable depot forms can be made by forming microencapsule matrices of the compound in a biodegradable polymer (e.g., polylactide/polyglycolide). The release rate of the compound can be controlled by looking at the ratio of the compound to the polymer and the nature of the particular polymer used. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). The composition for the storage injection may also be prepared by rectal or vaginal administration by liposome or microemulsion in which the compound is captured by humans and body tissues, preferably as a suppository, which can be used by the present invention. The compound is prepared by mixing with a suitable non-irritating excipient or carrier, such as cocoa butter, polyethylene glycol or a suppository wax, which is solid at ambient temperature but liquid at body temperature And thus it can melt in the rectum or vaginal cavity and release the active compound. The solid dosage form for oral administration comprises capsules, troches, pills, powders and granules. In such solid dosage forms, the active compound is mixed with at least one pharmaceutically acceptable inert excipient or carrier (for example, sodium citrate or dicalcium phosphate) and/or the following: a) filler or extender Agents such as starch, lactose, sucrose, glucose, mannitol and citric acid, b) binders such as carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic a humectant such as glycerin, d) a disintegrant such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain citrates, and sodium carbonate, e) solution blockers such as paraffin, f) absorption Promoters, such as quaternary compounds, g) wetting agents, such as cetyl alcohol and glyceryl monostearate, 153,786. Doc • 40· 201231467 h) absorbents such as kaolin and bentonite, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, lozenges and pills, the dosage form may also include a buffer. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage form of the key, dragee, capsule, pill and granules can be prepared using envelopes and encapsulants' such as enteric coatings and other coatings well known in the art of pharmaceutical formulation. It may optionally contain an opacifying agent and may also be a composition which, if desired, releases the active ingredient only in a certain portion of the intestinal tract in a delayed manner. Examples of embedding components that can be used include polymeric substances and waxes. Solid and similar types of solid compositions can also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The active compound may also be in microencapsulated form with one or more of the above-mentioned excipients. Solid dosage forms of lozenges, dragees, capsules, pills, and microparticles can be prepared using coatings and coatings such as enteric coatings, release control coatings, and other coatings well known in the art. In such solid dosage forms, the active compound may be mixed with at least one inert diluent (for example, sucrose, lactose or starch). These dosage forms may contain, in addition to the inert diluent, additional substances as are conventional practice, such as tableting lubricants and other tableting aids (such as magnesium stearate and microcrystalline cellulose in capsules, lozenges and pills). In case, the dosage forms may also include a buffer. Doc •41· 201231467 A light agent can also be a composition that releases the active ingredient only in one of the intestines in a delayed manner, if desired, in a delayed manner. Examples of embedding components that can be used include polymeric materials and signs. Used for bureau. The dosage form of the compound of the present invention, which is administered orally or transdermally, comprises an ointment, a cream, a lotion, a gel, a powder, a solution, a spray, an inhalant or a patch, if necessary, the active ingredient can be obtained under aseptic conditions. Mix with a pharmaceutically acceptable carrier and any desired preservative or buffer. Ophthalmic formulations, ear drops, and eye drops are also contemplated as being within the scope of the invention. Moreover, the present invention contemplates the use of transdermal patches that have the added advantage of providing controlled delivery of the compound to the body. Such dosage forms can be prepared by dissolving or dissolving the compound in a suitable medium. Absorption enhancers can also be used to increase the flux of the compound through the skin. The rate can be controlled by providing a rate controlling membrane or by dispensing the compound into a polymer matrix or gel. The compositions of the present invention can be administered orally, parenterally, by inhalation spray, transdermally, rectally, nasally, orally, vaginally or via an implantable kit. The term "parenteral" as used herein includes, but is not limited to, subcutaneous: intravascular n-articular, intrasynovial, intrasternal, intraorbital, intrahepatic, intralesional, and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally or intravenously. The sterile injectable form of the compositions of the present invention may be aqueous or oily suspensions. The suspensions may be formulated according to techniques known in the art using suitable dispersions or dispersing agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or a preservative solution in a parenterally acceptable diluent or solvent, for example, as a solution in the butylene glycol. Acceptable 153786. Doc •42- 201231467 Vehicles and solvents @t, & In addition, the common r #格氏溶液 and isotonic sodium chloride solution. For this purpose, the second sterile fixed oil is used as a solvent or suspending medium. Known for the use of di-glycerol, a mild, non-volatile oil, including synthetic mono- or monoglycerol. Fatty acids (such as injectables, such as natural medicines; and, in medicinal sesame oils, such as sputum oils or liquids, * octagonal forms. These oils or suspensions = long sputum thinners or dispersants For example, methyl cellulose or 彳Ί is often used to formulate emulsions and liquids. Other commonly used surfactants can also be used for adjustments such as butyl ween, Spans and others. Emulsifiers or bioavailability enhancements in the preparation of medicinal solids, liquids, or other dosage forms can enhance any of the pharmaceutical compositions of the present invention, - VT «: human's use of dust by oral administration of 'these dosage forms include but It is not limited to capsules, troches, aqueous suspensions or liquids. In the case of tablets for oral use, conventional carriers include, but are not limited to, lactose and corn starch. Lubricants are also usually added, such as stearic acid. In the case of oral administration in the form of a capsule, the useful diluent comprises lactose and dry corn powder. When f is orally administered as a suspension, the active ingredient may be combined with an emulsifier and a suspending agent, and some sweetness may be added. Flavor, Flavoring or coloring agent. Alternatively, the pharmaceutical composition of the present invention can be administered in the form of a rectal administration of the test composition, which can be prepared by mixing the agent with a suitable non-irritating excipient. The excipient is solid at room temperature but liquid at rectal temperature, 2 so it can be thawed in the rectum to release the drug. This material is in two packs I53786. Doc -43- 201231467 Includes, but is not limited to, cocoa butter, beeswax and polyethylene glycol. The pharmaceutical compositions of this invention may also be administered topically, especially when the therapeutic stem comprises areas or organs readily accessible by topical application, including diseases of the eye, skin or lower intestinal tract. It is easy to prepare suitable topical formulations for each of these regions or organs. The rectal suppository formulation (see above) or a suitable enema formulation can be applied locally to the lower intestinal tract. Local transdermal patches can also be used. For topical application, the pharmaceutical compositions can be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid paraffin, white soft paraffin, propylene glycol, polyethylene glycol, polyoxypropylene compound, emulsified wax, and water. Alternatively, the pharmaceutical composition can be formulated in a suitable lotion or cream containing the active ingredient in suspension or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 6 oxime, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol And water. When used in the eye, the pharmaceutical composition can be adjusted into a micronized suspension in an isotonic, pH-adjusted sterile saline solution, or preferably in an isotonic, adjusted, sterile saline solution. With or without preservatives such as benzylammonium chloride. Alternatively, when used in the eye, the pharmaceutical composition can be formulated in an ointment such as petrolatum. The pharmaceutical composition of the present invention can also be administered by nasal aerosol or inhalation. The compositions are prepared according to techniques well known in the art of pharmaceutical formulation and can be made into solutions in physiological saline using phenyl alcohol or other suitable anti-153 786. Doc 201231467 Fertilizers, absorption enhancers (for enhanced bioavailability), fluorocarbons, and/or other conventional solubilizers or dispersants. Dosage regimens for the use of compounds of structural formula 1 and π can be selected based on a variety of factors including the condition being treated and the severity of the condition; the activity of the particular compound employed; the particular composition employed; the age, weight, and general Health status, gender and diet; time of administration, route of administration, and rate of secretion of the particular compound used; kidney and liver function of the individual; and the particular compound or salt thereof used, duration of treatment; in combination with the particular compound used or The drugs used at the same time, and similar factors well known in the medical technology. Those skilled in the art will readily be able to determine and prescribe the desired effective amount of a compound of formula I and II to, for example, treat, prevent, inhibit (completely or partially) or prevent progression of the disease. The dose of the compound of formula I and II may range from about 〇1 to about i卯 mg/kg body weight/day, about 〇. 〇1 to about 5〇 mg/kg body weight/day, about 〇” to about 5〇 mg/kg body weight/day, or about! Up to about 25 mg/kg body weight/day. It should be understood that sodium 詈忐 · π 八 心 ～ can be administered in a single dose, or can be administered in multiple doses (e.g., twice daily, three times or four times). The compounds used in the methods of the invention can be formulated into unit dosage forms. By "unit dosage form" is meant a physical discrete unit suitable for use as a single dosage form for the subject to be treated' wherein each unit contains a predetermined amount of active material calculated to provide the desired therapeutic effect in combination with a suitable pharmaceutical carrier. The unit dosage form can be one of a single-twist dose or multiple doses (e.g., about owe or more times per day). 'every doses' may be the same or different when multiple doses of sputum are used. Stomach 153786. Doc • 45- 201231467 In the method or pharmaceutical composition of the present invention, a compound of the formulae i and II or a pharmaceutically acceptable salt or solvate thereof (for example, a hydrate) or an additional suitable therapeutic agent may be used alone. (eg, cancer-therapeutic agents) are used in combination to achieve an effective amount. In the case of combination therapy, a first amount of a compound of formula I and II, or a pharmaceutically acceptable salt or solvate thereof (e.g., water η), and a second amount of an additional suitable therapeutic agent can be used to achieve an effective amount. . In the examples, the compounds of the formulas and formulas and the additional therapeutic agents are administered in an effective amount (i.e., in an amount effective to be administered separately upon administration). In another embodiment, the compounds of structural formula I and II and additional therapeutic agents are administered in amounts that do not provide a therapeutic effect (sub-therapeutic dose) when administered separately, respectively. In still another embodiment, the compound of the formula 〖and π is administered in an effective amount, and the additional therapeutic agent is administered at a subtherapeutic dose. In another embodiment, the sub-therapeutic dose can be administered to the structural formula! And a compound of π, and an additional therapeutic agent (e.g., a suitable cancer-therapeutic agent) is administered in an effective amount. The terms "combination" or "co-administered" as used herein are used interchangeably to mean the use of more than one therapeutic agent (eg, one or more prophylactic agents and/or therapeutic agents). The order in which a therapeutic agent (e.g., 'prophylactic agent and/or therapeutic agent') is administered to an individual is limited. Co-injection encompasses the administration of first and second amounts of a combination of compounds and compounds in a substantially simultaneous manner, for example, in the form of a single pharmaceutical composition (eg, a first or second amount of capsule or lozenge having a fixed ratio) Or in the form of capsules or lozenges that are separated multiple times and each time. In addition, the co-administration also encompasses the use of each compound in either order, in a sequential manner. In the co-investment involves the separation of the first amount of the structural formula and the compound of U and 153786. Doc • 46 · 201231467 When a second amount of additional therapeutic agent is administered, the compound is administered in close enough proximity to produce the desired therapeutic effect. For example, the time between each administration that produces the desired therapeutic effect can range from a few minutes to several hours and can be determined by considering the nature of each compound, such as efficacy, solubility, biological Usability, plasma half-life and kinetic characteristics. For example, the compounds of formulas I and II and the second therapeutic agent can be in any order within about 24 hours, within about 16 hours, within about 8 hours, within about 4 hours, within about ten hours, or about 30 minutes. It has been voted in successively. More specifically, a first therapeutic agent (eg, a prophylactic or therapeutic agent, eg, a compound of the invention) can be administered prior to administering to a subject a second therapeutic agent (eg, a prophylactic or therapeutic agent, eg, an anticancer drug) (for example, at 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, % hours, 2 weeks 2 weeks, 3 weeks) , 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks ago), at the same time, or after (for example, at 5 minutes, 15 minutes, 3 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, Administration was performed at 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, weeks, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or after I2 weeks. It will be appreciated that a method of co-administering a first amount of a compound of structural formula 1 and 11 and a second amount of an additional therapeutic agent may produce an enhanced or synergistic therapeutic effect, wherein the group mouth effect is greater than the structural formula of the first amount separately from the separation And the additive effect produced by the compound of π and the second amount of additional therapeutic agent. The term "synergistic" as used herein, refers to a combination of a compound of the invention and another therapeutic agent (e.g., a prophylactic or therapeutic agent) that is more effective than each of 153,786. Doc -47- 201231467 The additive effect of therapeutic agents. The synergistic effect of a combination of therapeutic agents (e.g., a combination of prophylactic or therapeutic agents) allows for the administration of one or more therapeutic agents at a lower dose and/or administration of such therapeutic agents to the subject at a lower frequency. The ability to administer the therapeutic agent with a lower dose of a therapeutic agent (eg, a 'prophylactic or therapeutic agent') and/or at a lower frequency, reduces the toxicity associated with administering the therapeutic agent to the individual, and does not decrease The effectiveness of the therapeutic agent in preventing, managing or treating a condition. In addition, synergistic effects can improve the efficacy of the agent in preventing, managing, or treating a condition. Finally, the synergistic effect of a combination of therapeutic agents (e.g., a combination of prophylactic or therapeutic agents) can avoid or reduce adverse or undesirable side effects associated with the use of only any of the therapeutic agents. Methods suitable for evaluating drug interactions can be used to determine the presence of synergistic effects. Suitable methods include, for example, the Sigm〇id-Emax equation (H〇lf〇rd, N. H. G· and Scheiner, L. B., Clin.  Pharmacokinet.  6: 429-453 (1981)), Loewe's additive equation (Loewe, SiMuischnek, h. , Arch.  Exp.  Pathol Pharmacol.  114: 313-326 (1926)) and the intermediate effect equation (Chou, T. C. Ding alalay, P. , Adv.  Enzyme Regul· 22.  27_ 55 (1984)). Experimental data can be used to apply each of the equations mentioned above to generate a corresponding pattern to help evaluate the effects of the drug combination. The corresponding figures relating to the equations mentioned above are the concentration-effect curve, the equivalent line graph curve and the combined coefficient curve, respectively. In some embodiments the additional therapeutic agent is selected from the group consisting of a cancer-therapeutic agent, for example, an anticancer drug, an antiproliferative drug, or a chemotherapeutic agent. In some embodiments, the additional therapeutic agent is selected from the group consisting of camptothecin, MEK inhibitors: U0126, KSP (kinesin spindle 153786. Doc -48- 201231467 Body protein inhibitors, adriamycin, interferons, and retinoesis (eg, Cisplatin). In other embodiments, the additional therapeutic agent is selected from the group consisting of a taxane; a bcr-ab inhibitor (eg, Gleevec, dasatinib, and nilotinib); EGFR inhibition Agents (eg, Tarceva and Iressa); DNA damaging agents (eg, cisplatin, oxaliplatin, carboplatin, piperomerase inhibitors, and anthracyclines) ); and antimetabolites (such as AraC and 5-FU). In other embodiments, the additional therapeutic agent is selected from the group consisting of camptothecin, doxorubicin, idarubicin, cisplatin, taxol, taxotere, and vincristine (vincristine) ), Taxifa, MEK inhibitor, U0126, KSP inhibitor, vorinostat, Gleevec, dasatinib, and nilotinib. In another embodiment, the additional therapeutic agent is selected from the group consisting of a Hei*-2 inhibitor (eg, Herceptin), an HDAC inhibitor (eg, vorinostat), a VEGFR inhibitor (eg, Avas) Avastin), c-KIT and FLT-3 inhibitors (eg, sunitinib), BRAF inhibitors (eg Bayer's BAY 43-9006), MEK inhibitors (eg Pfizer's PD0325901), and Spindle poisons (e.g., Epothilones) and paclitaxel protein binding particles (e.g., Abraxane®). Other therapies or anticancer drugs that can be used in combination with the agents of the present invention include surgery, radiation therapy ( In only a few examples, gamma-radiation therapy, neutron beam radiation therapy, electron beam radiation therapy, proton therapy, brachytherapy, and 1537S6. Doc -49- 201231467 Systemic radioisotope therapy, to name a few), endocrine therapy, biological response modifiers (interferon, interleukin and tumor necrosis factor (TNF), to name a few), hyperthermia and cryotherapy Therapies, agents that attenuate any side effects (eg, antiemetics) and other approved chemotherapeutic drugs, including but not limited to alkylating drugs (nitrogen mustard, chlorambucil, cyclophosphamide, melphalan ( Melphalan), metacyclic phosphoniumamine, antimetabolite (Methotrexate), sputum antagonist and pyrimidine antagonist (6-mercaptopurine, 5-fluorouridine, Cytarabile) , difluorocytology, gemcitabine, spindle toxin (Vinblastine), Changchun new test, vinorelbine (Vinorelbine), paclitaxel (Paclitaxel), podophyllotoxin (podophyllotoxin) (Etoposide), Irinotecan, Topotecan, Antibiotics (Doxorubicin, Bleomycin, Mitomycin), Argentine Glands Adenosine (Carmustine), Lomustine, inorganic ions (cisplatin, carboplatin), enzymes (aspartate), and hormones (Tamoxifen, Leuprolide, Flutamide, Megestrol, GleevecTM, doxorubicin, dexamethasone, and cyclophosphamide. The compounds of the invention may also be used in combination with any of the following therapeutic agents for the treatment of cancer: aparex (Plenaxis depot®); aldesleukin (Prokine®); aldileukin (Proleukin®) ); Alemtuzumabb (Campath®); altretinoin (Panretin®); allopurinol (Zyloprim®); Liujiazui 153786. Doc -50- 201231467 Alkretamine (Hexalen®); Amiostostine (Ethyol®); Anastrozole (Arimidex®); Trisenox®; Aspartame Enzyme (Elspar®); azacitidine (Vidaza®); bevacuzimab (Avastin®); bexarotene capsule (Targretin®); besarudine gel (Targretin) ®); Bleoxane®; bortezomib (Velcade®); busulfan (Busulfex®) for intravenous use; oral administration of Mysteran®; Calusterone (Methosarb®); capecitabine (Xeloda®); Paraplatin®; carmustine (BCNU®, BiCNU®); carmustine (Gliadel®) Carmustine and polyphenylene phenyl 20 implants (Gliadel Wafer®); celecoxib (Celebrex®); cetuximab (Erbitux®); phenylbutyrate Leukeran®); Platinol®; cladribine (Leustatin®, 2-CdA®); clofarabine (Clolar®); ring-filled amine (Cytoxan®, Neosar®) Circulation Cytoxan Injection®; Cytoxan Tablet®; Cytosar-U®; DepoCyt®; dacarbazine (DTIC, Dome®) ); dactinomycin, actinomycin D (Cosmegen®); Darbepoetin alfa (Aranesp®); daunorubicin liposome (DanuoXome®); Daunorubicin, daunomycin (daunorubicin®); daunorubicin, erinomycin (Cerubidine®); denileukin diftitox (Ontak®); dexrazoxane (Zinecard®); docetaxel (taxotere®); 153786. Doc -51- 201231467 Adriamycin PFS®; Adriamycin®, Rubex®; Adriamycin PFS Injection®; Doxil®; Dromostanolone®; masterone injection®; Elliott's B Solution®: epirubicin (Ellence®); Epoetin alfa (epogen®); erlotinib (Tarceva®); estramustine (Emcyt®); phospho-acid etoposide phosphate (Etopophos®); etoposide, VP-16 (Vepesid®); exemestane (Aromasin®); filsrastim (Neupogen®); acute urinary (intraarterial) (FUDR®); IL fludarabine (Fludara®); fluorouracil, 5-FU (Adrucil®); fulvestrant (Faslodex®); gefitinib (Iressa®) ; gemcitabine (Gemzar®); gemtuzumab ozogamicin (Mylotarg®); goserelin acetate (Zoladex Implant®) ; Zoladex® acetate; Histrelin acetate® (Histrelin implant®); basal gland (Hydrea®); Ibritumomab Tiuxetan (Zevalin®); Idamycin®; Isoprofen (IFEX®); imatinib mesylate (Gleevec®); interferon alpha 2a (Roferon A®); interferon a-2b (Intron A®); Campitosar®; lenalidomide (Revlimid®); letrozole (Femara®); leucovorin (Wellcovorin®, leucovorin®) ; leuprolide acetate (Eligard®); 153786. Doc -52- 201231467 左旋四米米°Sit (16乂3!1113〇16)(£^&11113〇1©);Romanium mustard (1〇1111131^116), CCNU(CeeBU®); Dichloro Meclorethamine, nitrogen mustard (Mustargen®); megestrol acetate (Megace®); melphalan, L-PAM (Alkeran®); sparse base 0 votes 0, 6-MP (Purinethol® ); Mesnex®; Mesnex tabs®; Methotrexate®; methoxsalen (Uvadex®); Mitomycin C ®); mitotane (Lysodren®); mitoxantrone (Novantrone®); nandrolone phenpropionate (Durabolin-50®); for nelarabine (Arranon) ®); Nofetumomab (Verluma®); 〇prelvekin (Neumega®); Oxalin (Eloxatin®); Paxene®; Taxol®; Paclitaxel Protein binding particles (Abraxane®); palifermin (Kepivance®); pamidronate (Aredia®); pegademase (Adagen (Pegademase Bovine)®); Pegaspargase (Oncaspar®); Peifei Pegfilgrastim (Neulasta®); pemetrexed disodium (Alimta®); pentostatin (Nipent®); pipobroman (Vercyte®); Picamycin, mithramycin (Mithracin®); porfimer sodium (Photofrin®); procarbazine (Matulane®); quinacrine ( Quinacrine) (Atabrine®); Rasburicase (Elitek®); Rituximab (Rituxan®); sargramostim (Leukine®); Shagmodine (Prokine) ®); sorafenib (Nexavar®); adeninemycin 153786. Doc -53- 201231467 (streptozocin)(Zanosar®); sunitinib maleate (Sutent®); talcum powder (Sclerosol®); tamoxifen® (Nolvadex®); (temozolomide) (Temodar®); teniposide, VM-26 (Vumon®); terpene lactone (Teslac®); thioindigo, 6-TG (Thioguanine®); » thiotepa (Thioplex®); topotecan (Hycamtin®); toremifene (Fareston®); tositumomab (Bexxar®); tosimozumab-13-13 Tossi Berxar®; Trastuzumab (Herceptin®); tretinoin, ATRA (Vesanoid®); Uracil Mustard (Uracil Mustard Capsules®); Valrubicin (Valstar®); Changchun test (Velban®); Changchun new test (Oncovin®); vinorelbine (Navelbine®); ° selledronate (Zometa®) and Furui Vorinostat (Zolinza®). For an in-depth discussion of updated cancer therapies, see http://www. Nci. Nih. Gov/, a series of FDA-approved oncology drugs available at http://www. Fda. Gov/cder/cancer/druglistframe. Htm, and The Merck Manual, 17th Edition, 1999, the entire contents of which are incorporated herein by reference. Examples of other agents which may also be used in combination with the compounds of the invention include, without limitation: therapeutic agents for Alzheimer's disease, such as Aricept® and Excelon®; therapeutic agents for Parkinson's disease, such as L-D0PA/ Carbidopa, entacapone, ropinrole, pramipexole, bromocriptine, pergolide, trihexemene 153786 . Doc -54- 201231467 (trihexephendyl), and Physician; a drug used to treat multiple sclerosis (MS), such as beta interferon (eg 'Avonex® and Rebif®'), Copaxone®, and mitoxantrone; Therapeutic agents for asthma, such as albuterol and Singulair®; agents for the treatment of schizophrenia, such as zyprexa, risperdal, seroquel, and fluoride travel Haloperidol; anti-inflammatory agents, such as corticosteroids, TNF blockers, IL:1 RA, azathioprine, guanidine, and sulfasalazine; immunomodulation and Immunosuppressive agents such as cyclosporine, tacrolimus, rapamycin, mycophenolate mofetil, interferon, corticosteroids, cyclosporine Amine, azathioprine, and sulfasalazine; neurotrophic factors, for example, acetylcholinesterase inhibitors, MAO inhibitors, interferons, anticonvulsants, ion channel blockers, riluzole ), and anti-Parkinson's disease drugs; Agents for treating cardiovascular diseases, such as beta blockers, ace inhibitors, diuretics, nitrates, calcium channel blockers, and statins; agents for treating liver diseases, such as corticosteroids , cholestyramine, interferon, and antiviral agents; agents for treating blood disorders, such as corticosteroids, anti-leukemia drugs, and growth factors; and agents for treating immunodeficiency disorders, such as gamma- globulin. As protein kinase inhibitors, the compounds and compositions of the invention can also be used in biological samples. One aspect of the invention pertains to inhibiting protein kinase activity in a biological sample, the method comprising contacting the biological sample with a compound of formula I and a hydrazine compound or a composition comprising the compound. The term "biological 153786." is used herein. Doc • 55- 201231467 "sample" means that an ex vivo or ex vivo sample comprises, without limitation, a cell culture or an extract thereof, a biopsy tissue material obtained from a mammal or an extract thereof; and a liquid, saliva, urine , flank, semen, tears or other body fluids or their extracts. Inhibition of protein kinase activity in biological samples can be used to familiarize the art.  Various purposes are known. Examples of such purposes include, but are not limited to, blood transfusion, organ transplantation, and biological specimen storage. Another aspect of the invention relates to the study of protein kinases in biological and pathological phenomena; the study of intracellular signal transduction pathways mediated by such protein kinases; and the comparative evaluation of novel protein kinase inhibitors. Examples of such uses include, but are not limited to, biological assays such as enzyme assays and cell-based assays. The activity of a compound as a protein kinase inhibitor can be assayed in vitro, in vivo or in a cell line. In vitro assays include assays that determine the inhibition of kinase activity or ATPase activity by activated kinases. An alternative in vitro assay can quantify the ability of the inhibitor to bind to a protein kinase and can be performed by: measuring the inhibitor/kinase complex prior to binding and determining the amount of bound radiolabel, or The competition to develop novel inhibitors with kinases that bind to known radioligands is implemented.  Test. Detailed conditions for analyzing the compounds used in the present invention are set forth in the Examples below. Another aspect of the invention is the use of the compounds described herein, especially those having a medium affinity for biochemical palladium (IC5〇丨_1〇μΜ), as a starting point for chemical optimization. In particular, one aspect of the present invention is 153786. Doc •56· 201231467 A study on the conventional inhibition of chemically optimized enzymes. Another aspect of the invention pertains to the use of the compounds described herein in crystallography, especially among those having a medium affinity for biochemical palladium: in particular, one aspect of the invention pertains to the use of The compound produces a co-complex crystal structure. Another aspect of the present invention relates to the use of the compounds described herein as a chemical tool for in vitro and in vivo exploration of biological uses: specific, inhibitors of medium affinity for use in biochemical analysis to explore secondary cells And biofilming of enzymes in the overall animal disease model. Another aspect of the invention provides a method of modulating enzyme activity by contacting a compound of the formula with a protein kinase. The abbreviations use the following abbreviations: DMSO Dimercaptopurine TCA Trichloroacetic acid ATP ATP ABS BSA Bovine serum albumin DTT Dithiothreitol MOPS 4 -?* Propionic acid NMR Nuclear magnetic resonance HPLC Liquid chromatography LCMS Liquid Chromatography-Mass Spectrometry TLC Thin Layer Chromatography Rt Retention Time In some embodiments, the compounds of the invention are shown in the surface. In some embodiments, the variables used herein are as shown in the table 153786. Doc -57- 201231467 defined.

153786.doc 58- 201231467153786.doc 58- 201231467

153786.doc 59- 201231467 25 26 27153786.doc 59- 201231467 25 26 27

2929

31 32 33 ci31 32 33 ci

ClCl

34 35 3634 35 36

QQ

153786.doc 60· 201231467153786.doc 60· 201231467

一般合成方法 -61 · 153786.doc 201231467 本發明化合物可根據說明書使用彼等熟習此項技術者通 常已知之步驟製得。彼等化合物可藉由已知方法進行分 析，包含但不限於LCMS(液相層析質譜）HPLC及nmr(核 磁共振）。應理解，下文所示之具體條件僅係實例，且並 不意欲限制可用於製備本發明化合物之條件範圍。而是， 本發明亦包含彼等熟習此項技術者根據用於製備本發明化 合物之此說明書所顯而易見之條件。除非另有所指，否則 下列反應圖中之所有變量皆如本文所定義。一般反應圖： 實例 在以單一 MS模式使用電喷射離子化作業之Micr〇Mass Quamo Micro質譜儀上分析質譜試樣。使用層析將試樣引 入質譜儀中。用於所有質譜分析之流動相係由1〇 mM pH 7 乙酸銨及1:1之乙腈·甲醇混合物組成。方法A:管柱梯度 條件係5%-100%乙腈·曱醇，梯度時間為3 5爪比，且在 ACE5C8 3.0x75 mm管柱上運行4.8 min之時間。流速2 ml/min。方法B :管柱梯度係5%_100%乙腈-甲醇，梯度時 間為10 min，且在ACE5C8 4.6x150 mm管柱上運行12 min 之時間。流速為1.5 ml/min。本文所用之術語「Rt(min)」 係指與化合物有關之HPLC保留時間（以分鐘表示）。除非另 有所指’否則用於獲得所報告保留時間之LCMS*法如上 文所詳述。若Rt(min)<5 min，則使用方法A，若Rt(min)>5 min，則使用方法B。 在400 MHz下使用Bmker DPX 400儀器記錄汨小^^光 譜。 153786.doc 62- 201231467General Synthetic Methods -61 · 153786.doc 201231467 The compounds of the present invention can be prepared according to the instructions using procedures generally known to those skilled in the art. These compounds can be analyzed by known methods including, but not limited to, LCMS (liquid chromatography mass spectrometry) HPLC and nmr (nuclear magnetic resonance). It is to be understood that the specific conditions shown below are merely examples and are not intended to limit the range of conditions that can be used to prepare the compounds of the invention. Rather, the invention also includes those which are apparent to those skilled in the art from this disclosure. Unless otherwise indicated, all variables in the following reaction schemes are as defined herein. General Reaction Diagram: Example Mass spectrometry samples were analyzed on a Micr(R) Mass Quamo Micro mass spectrometer using electrospray ionization in a single MS mode. The sample was introduced into the mass spectrometer using chromatography. The mobile phase for all mass spectrometry consisted of 1 mM pH 7 ammonium acetate and a 1:1 mixture of acetonitrile and methanol. Method A: Column Gradient Conditions were 5%-100% acetonitrile-decyl alcohol with a gradient time of 3 5 claw ratio and run on an ACE5C8 3.0 x 75 mm column for 4.8 min. Flow rate 2 ml/min. Method B: The column gradient was 5%-100% acetonitrile-methanol with a gradient time of 10 min and run on an ACE5C8 4.6 x 150 mm column for 12 min. The flow rate was 1.5 ml/min. The term "Rt(min)" as used herein refers to the HPLC retention time (expressed in minutes) associated with a compound. Unless otherwise indicated, the LCMS* method used to obtain the reported retention time is as detailed above. If Rt(min) < 5 min, method A is used, and if Rt(min) > 5 min, method B is used. The small ^^ spectrum was recorded at 400 MHz using a Bmker DPX 400 instrument. 153786.doc 62- 201231467

可如下所述來製備並分析式I及II之下列化合物： 反應圖IThe following compounds of Formulas I and II can be prepared and analyzed as follows: Reaction Scheme I

”式劑及條件：a) η-BuLi或格氏試劑（Grignard reagent)，_78t：至(^，THF ; b) NH2NH2，thf，8〇它； c) K2C03，DMF ’ 11(rc 或 Pd(〇Ae)2，Na⑽u dme，配 體，90°C。 上文之反應圖I展示用於製備式E化合物之一般途徑，其 中各變量如本文所定義且N(w)2形成如本文所定義之六氫 吡嗪/吡咯啶環。使weinreb醯胺A與化合物3在正丁基鋰或 格氏D式劑存在下進行偶合以形成式c化合物。然後將化合 在肼存在下加熱以得到中間體D。藉由視需要經保護 ^胺在適宜驗（例如，碳酸卸、二異丙基乙基胺（dipea)、 三乙胺、1，8·二氮雜雙環[5.4.〇]十一·：烯^^⑺等）存在下 在適宜溶劑（例如’二曱基甲酿胺、二甲基亞硬（DMSO)、 153786.doc -63· 201231467 正丁醇（n-Bu-OH)等）中在約70°C至約ll〇°C、約80°C至約 10(TC、約90。(：至約100°C下來置換式D化合物以形成胺取 代之雜芳醯基吡唑并吡啶。另一選擇為，可使用Buchwa11 型條件使用Pd作為觸媒及彼等熟習此項技術者熟知之一系 列鹼及配體來實施此置換。"Formula and conditions: a) η-BuLi or Grignard reagent, _78t: to (^, THF; b) NH2NH2, thf, 8 〇 it; c) K2C03, DMF ' 11 (rc or Pd ( 〇Ae) 2, Na(10)u dme, ligand, 90 ° C. Reactions above Figure I shows a general route for the preparation of compounds of formula E, wherein each variable is as defined herein and N(w) 2 is formed as defined herein a hexahydropyrazine/pyrrolidine ring. The weinreb guanamine A is coupled with the compound 3 in the presence of n-butyllithium or Grignard D to form a compound of formula c. The compound is then heated in the presence of hydrazine to give an intermediate Body D. Appropriate test by protecting the amine as needed (for example, carbonic acid unloading, diisopropylethylamine (dipea), triethylamine, 1,8-diazabicyclo[5.4.〇] eleven ·: in the presence of alkene (7), etc. in a suitable solvent (eg 'dimercaptoacetamide, dimethyl sulfite (DMSO), 153786.doc -63 · 201231467 n-butanol (n-Bu-OH), etc. In the range of from about 70 ° C to about 11 ° C, from about 80 ° C to about 10 (TC, about 90 ° (: to about 100 ° C to replace the compound of formula D to form an amine substituted heteroaryl mercapto pyrazole) And pyridine. Another option May be used Buchwa11 type condition using Pd as catalyst and their well known to those skilled in the art, and one series of base ligands embodiment this substitution.

反應圖IIReaction diagram II

試劑及條件：a) LDA，-78°c 至 0°C，THF ; b) NH2NH2， 二。惡院，室溫；c) K2C03，DMF，110°C 或 Pd(OAc)2， NaOtBu，DME，配體，9〇〇c。 上文之反應圖II展示用於製備式K化合物之一般途徑， 其中各變量如本文所定義。使Weinreb醯胺A與化合物G在 一異丙基胺化鐘（LDA)存在下進行偶合以形成式η化合 物。然後使用肼處理化合物Η以得到中間體〗。藉由視需要 經保護之胺在適宜鹼（例如，碳酸鉀、二異丙基乙基胺 (DIPEA)、三乙胺、Μ-二氮雜雙環[5.4.0]十一-7-烯（DBU) 等)存在下在適宜溶劑(例如，二甲基甲醯胺、二甲基亞砜 153786.doc • 64 - 201231467 (DMS〇)、正丁醇（n-Bu-OH)等）中在約70〇C至約11〇〇c下來 置換式I化合物以形成胺取代之雜芳醯基吡唑并吡啶。另 一選擇為，可使用Buchwald型條件使用pd作為觸媒及彼等Reagents and conditions: a) LDA, -78 °c to 0 ° C, THF; b) NH2NH2, II. House, room temperature; c) K2C03, DMF, 110 ° C or Pd (OAc) 2, NaOtBu, DME, ligand, 9 〇〇 c. Reaction Scheme II above shows a general route for the preparation of compounds of formula K, wherein each variable is as defined herein. Weinreb decylamine A is coupled with compound G in the presence of an isopropylation clock (LDA) to form a compound of formula η. The compound is then treated with hydrazine to give the intermediate. By suitably protecting the amine in a suitable base (for example, potassium carbonate, diisopropylethylamine (DIPEA), triethylamine, hydrazine-diazabicyclo[5.4.0]undec-7-ene ( DBU), etc. in the presence of a suitable solvent (eg dimethylformamide, dimethyl sulfoxide 153786.doc • 64 - 201231467 (DMS〇), n-butanol (n-Bu-OH), etc.) Substituting the compound of formula I from about 70 〇C to about 11 〇〇c to form an amine-substituted heteroaryl-p-pyrazolopyridine. Another option is to use Buchwald type conditions to use pd as a catalyst and their

熟習此項技術者熟知之一系列鹼及配體來實施此置換。 反應圖IIIOne such base and ligand are well known to those skilled in the art to carry out this substitution. Reaction diagram III

試劑及條件：a) Pd催化Suzuki偶合；b) NH2NH2，二噪 烷’室溫；c) i. K2C03，DMF，110°C 或 Pd(〇Ac)2， NaOtBu，DME，配體，90〇C ; ii.脫除保護基。 上文之反應圖III展示用於製備式〇化合物之一般途經， 其中各變量如本文所定義。將硼酸酯衍生物L與吡唆衍生 物L在Pd觸媒存在下在Suzuki偶合反應中進行偶合以形成 式N化合物。然後藉由視需要經保護之胺在適宜鹼（例如， 碳酸鉀、二異丙基乙基胺（DIPEA)、三乙胺、i，8_二氣雜 雙環[5.4.0]十一 _7_烯（DBU)等）存在丁在適宜溶劑（例如， 二甲基曱醯胺、二甲基亞砜（DMSO)、正丁醇（η·Βιι-〇Η)、 153786.doc •65· 201231467 N-甲基η比咯啶酮（NMP)等）中在約7〇°c至約11 〇。(3下來置換 化合物N以形成胺取代之雜芳醯基吡唑并吡啶。另一選擇 為’可使用Buchwald型條件使用Pd作為觸媒及彼等熟習此 項技術者熟知之一系列鹼及配體來實施此置換。最終脫除 保護基可得到通式〇之化合物。Reagents and conditions: a) Pd catalyzed Suzuki coupling; b) NH2NH2, dioxin' room temperature; c) i. K2C03, DMF, 110 ° C or Pd (〇Ac) 2, NaOtBu, DME, ligand, 90 〇 C; ii. Removal of the protecting group. Reactions above Figure III shows a general route for the preparation of a hydrazine compound wherein each variable is as defined herein. The boronic acid ester derivative L is coupled with pyridoxine derivative L in the presence of a Pd catalyst in a Suzuki coupling reaction to form a compound of formula N. Then, by a suitable amine in the appropriate base (for example, potassium carbonate, diisopropylethylamine (DIPEA), triethylamine, i,8_di-heterobicyclo[5.4.0] eleven_7 _ene (DBU), etc. exist in a suitable solvent (for example, dimethyl decylamine, dimethyl sulfoxide (DMSO), n-butanol (η·Βιι-〇Η), 153786.doc •65· 201231467 N-methyl η is more than 7 ° C to about 11 Torr in the case of pyrrolidone (NMP). (3) Substituting compound N to form an amine-substituted heteroaryl-p-pyrazolopyridine. Another option is to use Pd as a catalyst using Buchwald-type conditions and one of the series of bases and ligands well known to those skilled in the art. This substitution is carried out to obtain a compound of the formula 最终.

反應圖IVReaction Diagram IV

試劑及條件：a) DIPEA，NMP，130。(： ； b) Pd(Ph3)4， Κ3Ρ04 ’ 二噁烷，水，i〇0〇c，pd 催化之 Suzuki偶合；c) TFA ’ TES ’ DCM，脫除保護基。 上文之反應圖IV展示用於製備式r化合物之一般途徑’ 153786.doc -66 - 201231467 其中各變量如本文所定義。使用視需要經保護之胺在適宜 鹼（例如碳酸鉀、二異丙基乙基胺（DIPEA)、三乙胺、丨，8_ 二氮雜雙環[5.4.0]十一 _7_烯（DBU)等）存在下在適宜溶劑 (例如，二甲基曱醯胺、二甲基亞砜（DMSO)、正丁醇 (n-Bu-OH)、N-甲基吡咯啶酮（nmp))中在約loot至約 130°C下置換Μ以形成胺取代之吡啶p。使硼酸酯衍生物[ 與°比啶衍生物Ρ在Pd觸媒存在下在Suzuki偶合反應中進行 偶合以形成式Q化合物。最終脫除保護基可得到通式R之 化合物。 實例1，化合物1 (R)-(+)-3-甲基-2-(吼嗓 _2_ 基）丁烧-2-醇Reagents and conditions: a) DIPEA, NMP, 130. (: ; b) Pd(Ph3)4, Κ3Ρ04 'dioxane, water, i〇0〇c, pd-catalyzed Suzuki coupling; c) TFA 'TES 'DCM, deprotection group. Reaction Scheme IV above shows a general route for the preparation of compounds of formula r 153 786. doc - 66 - 201231467 wherein the variables are as defined herein. Use a protected amine as appropriate in a suitable base (eg potassium carbonate, diisopropylethylamine (DIPEA), triethylamine, hydrazine, 8-diazabicyclo [5.4.0] eleven-7-ene (DBU) In the presence of a suitable solvent (eg, dimethyl decylamine, dimethyl sulfoxide (DMSO), n-butanol (n-Bu-OH), N-methylpyrrolidone (nmp)) The hydrazine is displaced at about loot to about 130 ° C to form an amine substituted pyridine p. The boronic acid ester derivative [coupling with the pyridine derivative hydrazine in the presence of a Pd catalyst in a Suzuki coupling reaction to form a compound of formula Q. Final removal of the protecting group provides the compound of formula R. Example 1, Compound 1 (R)-(+)-3-Methyl-2-(indol-2-yl)butan-2-ol

將存於無水THF (1.400 L)中之2,2,6,6-四甲基六氫吡啶 (282.2 g，337.2 mL，1.998 mol)的溶液在氮下冷卻 至-35°C。經30分鐘添加nBuLi(2.5 Μ，存於己烧中）（799.2 mL，2.5 Μ，1.998 mol)，同時將内部溫度保持於_25。〇 與-35°C之間。將混合物升溫至0。（+/_丨。）並授拌1〇分鐘。 然後將混合物冷卻至-78。(：並在此溫度下保持20分鐘。然 後將存於無水THF(200.0 mL)中之吡嗪（80 g，998.9 mmol) 的溶液導入胺化鍾混合物中，同時將内部溫度保持於低 於JOt。將深紅色混合物攪拌20分鐘，然後盡可能迅速 153786.doc 67- 201231467 地添加 3-甲基丁烧-2-酮（430.1 g，534.3 mL，4.994 mol)(在·78°C浴中冷卻），同時將内部溫度保持於低 於-60。。然後將混合物在_78°C(+/- 5°C)下攪拌2 hr»此時 間後之Lc/Ms顯示沒有吡嗪剩餘。在-78°C下，藉由緩慢添 加2 M HC1(2 L)來終止反應。然後添加乙酸乙酯（800 mL)。將混合物升溫至環境溫度且分離有機相。混合物極 暗但各相易於分離。使用乙酸乙酯（2x500 ml)萃取水相。 使用飽和NaHC03(800 ml)、然後水（1 L)然後鹽水（500 ml) 洗滌合併之有機物。然後將混合物濃縮。將殘餘物溶於汽 油（1.2 L)中。存在一些固體。添加MgS〇4並乾燥混合物， 過;慮並濃縮。粗製物係暗紅色油狀物（260 g) »在使用 0-50%乙酸乙酯/汽油洗脫之矽膠上純化粗製物。獲得淺黃 色油狀物形式之標題化合物（1〇3 2 g，62%) ; iH NMR (CDC13) 0.74 (3H, d), l.oi (3h, d), 2.07 (1H, m), 4.19 (1H, s)，8.52 (2H, s)，8.73 (1H，s) ; MS ES(+) 167.35 (M+l)。 藉由對掌[4SFC層析使用纖維素_2管柱（phenornenex)來 分離（R)-(+)-對映異構體（1〇% AcCN，5 ml/min，100 巴， 35°C ’ 220 nm ;保留時間為 1.54 min)[a]D+23.80 (C=5.15, EtOH)。 (2R)-3-曱基-2-(六氫吨嗓·2_基）丁烷·2·醇A solution of 2,2,6,6-tetramethylhexahydropyridine (282.2 g, 337.2 mL, 1.998 mol) in dry THF (1.400 L) was cooled to -35 °C under nitrogen. nBuLi (2.5 Μ, stored in hexane) (799.2 mL, 2.5 Μ, 1.998 mol) was added over 30 minutes while maintaining the internal temperature at _25. 〇 Between -35 °C. The mixture was warmed to zero. (+/_丨.) and mix for 1 minute. The mixture was then cooled to -78. (: and kept at this temperature for 20 minutes. Then a solution of pyrazine (80 g, 998.9 mmol) in anhydrous THF (200.0 mL) was introduced into the amination clock mixture while keeping the internal temperature below JOt The dark red mixture was stirred for 20 minutes, then 3-methylbutyrol-2-one (430.1 g, 534.3 mL, 4.994 mol) was added as quickly as possible 153786.doc 67-201231467 (cooled in a 78 ° C bath) At the same time, the internal temperature was kept below -60. Then the mixture was stirred at _78 ° C (+/- 5 ° C) for 2 hr»Lc/Ms after this time showed no pyrazine remaining. The reaction was stopped by slowly adding 2 M HCl (2 L) at 78 ° C. Then ethyl acetate (800 mL) was added. The mixture was warmed to ambient temperature and the organic phase was separated. The mixture was very dark but the phases were easily separated. The aqueous phase was extracted with ethyl acetate (2×500 ml). The combined organics were washed with saturated NaHC03 (800 ml) then water (1 L) then brine (500 ml). The mixture was then concentrated. In L), some solids are present. Add MgS〇4 and dry the mixture, pass through; The title compound (1 〇 3 2 g, 62%) was obtained as a pale yellow oil. ; iH NMR (CDC13) 0.74 (3H, d), l.oi (3h, d), 2.07 (1H, m), 4.19 (1H, s), 8.52 (2H, s), 8.73 (1H, s) MS ES (+) 167.35 (M+l). Separation of the (R)-(+)-enantiomer by the use of a cellulose-2 column (phenornenex) for 4SFC chromatography (1%) AcCN, 5 ml/min, 100 bar, 35 ° C '220 nm; retention time 1.54 min) [a] D + 23.80 (C = 5.15, EtOH). (2R)-3-mercapto-2- (six) Hydrogen ton 嗓·2_yl)butane·2·alcohol

153786.doc •68- 201231467 將氧化韵（4.673 g，20.58 mmol)放置於Parr瓶中。在氮 氣氛下添加甲醇（140 mL)，隨後添加（R)-(+)-3-甲基-2-(吡 嗪·2-基）丁烷-2-醇（17.1 g，102.9 mmol)。在 60 psi之氫壓 力下，將反應混合物在PARR氫化器中振動過夜。此時間 後之Lc/Ms表明反應已完成。在氮氣氛下，經由矽藻土墊 過濾懸浮液，使用曱醇沖洗。在真空中濃縮粗製混合物。 將殘餘物再次溶於二氯甲烷中，藉由MgS04乾燥，過濾並 在真空中濃縮以提供黏性淺黃色油狀物形式之標題化合物 (16.6 g » 93%) ； !H NMR (CDC13) 0.82-1.08 (9H, m), 1.81 (1H，m)，2.20-3.17 (10H，m); MS ES(+) 173.0 (M+l)。 4-(第三-丁基二甲基甲矽烷基）-2,3,5-三氟吡啶153786.doc •68- 201231467 Place the oxidation rhyme (4.673 g, 20.58 mmol) in a Parr bottle. Methanol (140 mL) was added under a nitrogen atmosphere, followed by (R)-(+)-3-methyl-2-(pyrazine-2-yl)butan-2-ol (17.1 g, 102.9 mmol). The reaction mixture was shaken overnight in a PARR hydrogenator under a hydrogen pressure of 60 psi. The Lc/Ms after this time indicates that the reaction has been completed. The suspension was filtered through a pad of diatomaceous earth under a nitrogen atmosphere and rinsed with methanol. The crude mixture was concentrated in vacuo. The residue was redissolved in EtOAc (EtOAc) (EtOAc) (EtOAc) -1.08 (9H, m), 1.81 (1H, m), 2.20-3.17 (10H, m); MS ES (+) 173.0 (M+l). 4-(Third-butyldimethylformamidinyl)-2,3,5-trifluoropyridine

將存於THF(1.350 L)中之二異丙基胺（98.85 g，136.9 mL，976.9 mmol)的溶液冷卻至-65°C。經由套管經i h以維 持反應溫度低於-60°C之速率逐滴添加n-BuLi(2.5 Μ，存於 己烧中）（375.8 mL ’ 2.5 Μ，939.4 mmol)。添加完成後， 去除冷卻浴且將反應混合物升溫至。將反應混合物在 〇°C下攪拌15 min ’然後再次冷卻至-78°C。經由套管經2〇 min以維持反應溫度低於_69°C之速率逐滴添加2,3,5_三氟 153786.doc •69· 201231467 °比啶（100 g ’ 751.5 mmol)。將反應混合物在·78°(：下攪拌 45 min，在此期間溶液變成橙褐色。然後經由套管經3〇 min添加存於THF( 150 mL)中之第三-丁基-氯-二甲基-矽烷 (147.2 g，976.9 mmol)的溶液。將反應混合物在_78°C下攪 拌90分鐘，在此期間，溶液變暗。此時間後之Lc/ms表明 反應已完成。然後添加飽和氣化銨溶液（3〇〇 ml)且將混合 物升溫至室溫。使用水（1 〇〇 ml)稀釋反應混合物並使用A solution of diisopropylamine (98.85 g, 136.9 mL, 976.9 mmol) in THF (1.350 L) was cooled to -65 °C. n-BuLi (2.5 Torr, stored in hexane) (375.8 mL '2.5 Μ, 939.4 mmol) was added dropwise via a cannula via i h at a rate to maintain the reaction temperature below -60 °C. After the addition was complete, the cooling bath was removed and the reaction mixture was warmed to. The reaction mixture was stirred at 〇 ° C for 15 min ′ then cooled again to -78 ° C. 2,3,5-trifluoro 153786.doc •69·201231467 ° pyridine (100 g '751.5 mmol) was added dropwise via a cannula at a rate to maintain the reaction temperature below _69 °C for 2 〇 min. The reaction mixture was stirred at -78 ° (: 45 min, during which time the solution turned orange-brown. then the third-butyl-chloro-dimethyl group in THF (150 mL) was added via a cannula over 3 min. A solution of benzyl-decane (147.2 g, 976.9 mmol). The reaction mixture was stirred at -78 ° C for 90 minutes, during which time the solution became dark. After this time Lc/ms indicated that the reaction was complete. Ammonium solution (3 〇〇 ml) and warm the mixture to room temperature. Dilute the reaction mixture with water (1 〇〇ml) and use

EtOAc(1.5 L ’ 然後2x500 ml)萃取。使用飽和NaHCO (500 ml)及鹽水（4〇〇 ml)洗滌合併之有機物。將粗製混合物在真 空中部分地濃縮，藉由硫酸鎂乾燥，過濾並在真空中濃縮 成/由狀物。藉由急驟層析（CombiFlash Companion XL，1.5 kg管柱，存於石油醚中之〇·2〇%乙酸乙酯）純化粗製物。此 可提供無色油狀物形式之標題化合物（136.2 g，73%) ; if!Extract with EtOAc (1.5 L ' then 2 x 500 mL). The combined organics were washed with saturated NaHCO (500 mL) and brine (4 mL). The crude mixture was partially concentrated in vacuo, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (CombiFlash Companion XL, 1.5 kg column, EtOAc EtOAc EtOAc). This provides the title compound (136.2 g, 73%) as a colorless oil;

NMR (CDC13) 0.34 (6H，s)，0.89 (9H，s)，7.73 (1H，s) ; MS ES(+) 248.25 (M+l)。 (4_(第二· 丁基二甲基甲發烧基）-3,5,6-三氟吼咬-2-基）(2-氟 吡啶-3-基）甲酮NMR (CDC13) 0.34 (6H, s), 0.89 (9H, s), 7.73 (1H, s); MS ES (+) 248.25 (M+l). (4_(t-Butyldimethylmethanone)-3,5,6-trifluoroindol-2-yl)(2-fluoropyridin-3-yl)methanone

將存於THF(1.360 L)中之二異丙基胺（66 78 g，％ 49 153786.doc •70· 201231467 mL，659.9 mm〇l)的溶液在氮下冷卻至_2〇<t。經由套管以 維持内部溫度低於_15°c之速率逐滴添加nBuLi(2 5 Μ，存 於己烷中）(253.0 mL，2.5 Μ，632.4 mmol)。將溶液升溫 至〇 c然後立即再次冷卻至_90〇c。經由套管以維持内部溫 度低於-85。(：之速率逐滴添加第三_丁基_二甲基_(2,3,5三 氟-4-吡啶基）矽烷（136 g，549 9 mm〇1)。完成添加後，溶 液變成燈色懸浮液。將反應混合物在_85它下攪拌丨h，然 後經1 h逐滴添加2-氟-N-曱氧基·Ν_甲基吡啶_3_甲醯胺 (116,5 g ’ 632.4 mmol)，同時保持内部溫度低於_85<)(：。混 合物在添加期間變成暗綠色然後變成暗紅色。將混合物 在-85°C下攪拌45 min，此後，Lc/Ms表明反應已完成。去 除冷卻浴並將混合物升溫至_50°c。添加飽和氯化銨溶液 NH4C1(300 mL)並將混合物升溫至室溫。使用Et〇Ac (2.5 L)稀釋混合物。分離水相並使用額外Et〇Ac (500 ml)進行 萃取。使用鹽水洗務合併之有機物並在真空中部分地濃 縮。藉由硫酸鎂乾燥溶液，過濾並在真空中濃縮成褐色油 狀物。在使用存於石油醚中之0-20%乙酸乙酯洗脫的矽膠 上純化粗製物。此可得到黃色油狀物形式之標題化合物， 該化合物在靜置時會發生固化（159.6 g，78%);NMR (CDC13) 0.35 (6H, s), 0.88 (9H, s), 7.29 (1H, m), 8.13 (1H, m), 8.37 (1H, m) ; 19F NMR(去偶合）-112.47, -106.7, -89.3, -61.95 ; MS ES (+) 371.14 (M+l)。 3-(4-(第三-丁基二甲基f矽炫基）-3,5,6-三氟》比啶·2-基）-1H-吡唑并【3,4-b】吡啶 153786.doc •71 - 201231467A solution of diisopropylamine (66 78 g, % 49 153786.doc • 70·201231467 mL, 659.9 mm 〇l) in THF (1.360 L) was cooled to _2 〇 <t under nitrogen. nBuLi (25 Μ in hexane) (253.0 mL, 2.5 Μ, 632.4 mmol) was added dropwise via a cannula at a rate to maintain the internal temperature below _15 °C. The solution was warmed to 〇 c and then immediately cooled again to _90 〇 c. Via the sleeve to maintain the internal temperature below -85. (: The rate was added dropwise to the third _butyl-dimethyl-(2,3,5-trifluoro-4-pyridyl) decane (136 g, 549 9 mm 〇1). After the addition, the solution became a lamp. Color suspension. The reaction mixture was stirred at _85 under 丨h, then 2-fluoro-N-decyloxy·Ν-methylpyridine_3_formamide (116,5 g ' was added dropwise over 1 h. 632.4 mmol) while keeping the internal temperature below _85<) (:. The mixture turned dark green and then turned dark red during the addition. The mixture was stirred at -85 °C for 45 min, after which Lc/Ms indicated that the reaction was complete Remove the cooling bath and warm the mixture to _50 ° C. Add saturated ammonium chloride solution NH4C1 (300 mL) and warm the mixture to room temperature. Dilut the mixture with Et 〇Ac (2.5 L). Extraction with Et EtOAc (500 mL). EtOAc (EtOAc m. The crude product was purified by chromatography on EtOAc (EtOAc) The compound solidified upon standing (159.6 g, 78%); NMR (CDC13) 0.35 (6H, s), 0.88 (9H, s), 7.29 (1H, m), 8.13 (1H, m), 8.37 ( 1H, m); 19F NMR (decoupling) - 112.47, -106.7, -89.3, -61.95; MS ES (+) 371.14 (M+l). 3-(4-(t-butyl dimethyl-f)矽炫)-3,5,6-trifluoro"pyridin-2-yl)-1H-pyrazolo[3,4-b]pyridine 153786.doc •71 - 201231467

將[4-[第三-丁基（二曱基）曱石夕烧基]_3,5，6-三敗-2-n比咬 基]-(2-IL-3-0比咬基）甲 g同（159 g，429.2 mmol)溶於二0惡貌 (1.6 L)中且添加碳酸約（85.91 g，858.4 mmol)。在冰浴中 進行反應且經30分鐘逐滴添加水合肼（107.4 g，104.4 mL，2.146 mol)。將所得混合物攪拌過夜’此後，稠懸浮 液變成不均勻之紅色溶液。經由矽藻土墊過濾反應混合 物，使用 EtOAc/MeOH 7:1 (2x500 mL)及少量水（100 mL) 充分洗滌。將濾液分配於EtOAc (1 L)與水（500 ml)之間。 使用NaHC〇3飽和水溶液（5〇〇 mL)洗滌有機相。使用EtOAc (2x200 ml)反萃取合併之水層且使用鹽水（4〇〇 ml)洗滌合併 之有機物’藉由MgS〇4乾燥且過濾並濃縮成橙色固體。使 用一氣甲烧研磨固體並過濾，使用二氯甲烷及汽油洗滌。 此可得到灰白色固體形式之標題化合物（1〇3 8 g)。在減壓 下濃縮濾液。再次研磨所得固體並過濾，使用額外汽油洗 滌以得到灰白色固體（36 7 g)。獲得灰白色固體形式之標 題化 s 物（總重為 i4〇.5g，90%) ; !H NMR (CDC13) 0.55 (6H’ s)’ 1.02 (9H，s)，7.21 (1H，m)，8.69 (1H，m)，8.91 (1H， s), Π.69 (1H, brs) ； MS ES (+) 365.18 (M+l) 〇 153786.doc -72· 201231467[4-[Third-butyl (di-decyl) fluorene]_3,5,6-tri-f--2-n ratio base]-(2-IL-3-0 ratio bite base) G-g (159 g, 429.2 mmol) was dissolved in dioxin (1.6 L) and about (85.91 g, 858.4 mmol) was added. The reaction was carried out in an ice bath and hydrazine hydrate (107.4 g, 104.4 mL, 2.146 mol) was added dropwise over 30 min. The resulting mixture was stirred overnight. After that, the thick suspension became a non-uniform red solution. The reaction mixture was filtered through a pad of celite, and washed thoroughly with EtOAc/MeOH 7:1 (2×500 mL) and water (100 mL). The filtrate was partitioned between EtOAc (1 L) and water (500 mL). The organic phase was washed with a saturated aqueous solution of NaHC 3 (5 mL). The combined aqueous layers were back-extracted with EtOAc (2.times.2 mL) and washed with brine (4 mL). The solid was triturated with a gas and filtered, and washed with dichloromethane and petrol. This gave the title compound (1 〇 3 8 g) as a white solid. The filtrate was concentrated under reduced pressure. The resulting solid was triturated again and filtered and washed with additional pets to give an off-white solid (3,7 g). Obtained the titled s material (yield: i4 〇.5g, 90%); !H NMR (CDC13) 0.55 (6H's)' 1.02 (9H, s), 7.21 (1H, m), 8.69 (1H,m), 8.91 (1H, s), Π.69 (1H, brs) ; MS ES (+) 365.18 (M+l) 〇153786.doc -72· 201231467

3-甲基-2-(三甲基甲矽烷基氧基）丁烷_2基）六氫吡嗪·ι基）3-methyl-2-(trimethylformamidooxy)butan-2-yl)hexahydropyrazine·m base)

(19 g，110·3 mmol)、THF (53 mL)及咪唑-卜基·三甲基 _矽 院（51.57 g，53.72 mL，367.7 mmol)。並行實施相同實 驗。密封容器且加熱混合物並在95。(：下攪拌過夜。此時間 後之Lc/Ms顯示混合物由73%之期望（S，R)-非對映異構體及 180/。之（R，R)-非對映異構體組成。冷卻反應混合物，合併 並使用EtOAc (500 ml)稀釋。使用飽和碳酸氫鈉（2x2〇〇 ml) 洗滌溶液。使用乙酸乙酯（200 ml)將合併之水層萃取3次。 使用鹽水（200 ml)洗滌合併之有機物，藉由MgS04乾燥， 過濾並在真空中濃縮以得到丨63.874 g黏性褐色油狀物。在 153786.doc -73- 201231467 矽膠（使用存於含有2%三乙胺之石油醚中之ι〇 95%乙酸乙(19 g, 110·3 mmol), THF (53 mL), and imidazole-bry-trimethyl _ 矽 ( (51.57 g, 53.72 mL, 367.7 mmol). Implement the same experiment in parallel. The vessel was sealed and the mixture was heated at 95. (: stirring overnight. Lc/Ms after this time shows that the mixture consists of 73% of the desired (S,R)-diastereomer and 180/(R,R)-diastereomer. The reaction mixture was cooled, diluted with EtOAc EtOAc EtOAc EtOAc (EtOAc) The combined organics were washed with MgSO4, filtered and concentrated in vacuo to give EtOAc EtOAc EtOAc s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s Ι〇95% acetic acid B in petroleum ether

酯洗脫）上分離非對映異構體。此可得到需要之燈色發泡 體形式的（S，R)·非對映異構體（60.1 g，69%) ; iH NMR (CDCls) 0.001 (9H, s), 0.32 (6H, s), 0.76-0.84 (9H, m), 1.11 (4H, m), 1.45 (4H, m), 1.72 (1H, m), 1.90 (1H, s), 2.61 (1H, m), 2.74 (2H, m), 2.97 (1H, m), 3.11 (1H, m), 3.64 (1H, m), 3.82 (1H, m), 3.96 (1H, m), 7.09 (1H, m), 8.48 (1H, m), 8.74 (1H, m)，11.31 (1H，brs) ; 19F NMR(去偶合）-113.45, -108·3 9 I MS ES(+) 589.3 (M+l)。分離出橙色發泡體形式 之（R，R)-非對映異構體（22%) ; NMR(CDC13) 0.001 (9H， s), 0.33 (6H, s), 0.72-0.88 (10H, m), 1.07 (3H, m), 1.45 (5H, m)5 1.86 (1H, m), 2.54 (1H, m), 2.74 (2H, m), 2.94 (1H, m), 3.07 (1H, m), 3.63 (1H, m), 3.73 (1H, m), 3.96 (1H, m), 7.04 (1H, m), 8.46 (1H, m), 8.69 (1H, m), 11.35 (1H，brs) ; 19F NMR(去偶合）.113.78，-108.4 ; MS ES(+) 589.3 (M+l)。 (R)-2-((S)-4-(3,5 -二氟峻并[3,4-b]®* 咬-3·基）°ifc 啶-2-基）六氫吡嗪-2-基）-3_甲基丁烷_2-醇Separation of the diastereomers on the ester elution). This gives the desired (S,R)·diastereomer (60.1 g, 69%) in the form of a light-colored foam; iH NMR (CDCls) 0.001 (9H, s), 0.32 (6H, s) , 0.76-0.84 (9H, m), 1.11 (4H, m), 1.45 (4H, m), 1.72 (1H, m), 1.90 (1H, s), 2.61 (1H, m), 2.74 (2H, m ), 2.97 (1H, m), 3.11 (1H, m), 3.64 (1H, m), 3.82 (1H, m), 3.96 (1H, m), 7.09 (1H, m), 8.48 (1H, m) , 8.74 (1H, m), 11.31 (1H, brs); 19F NMR (decoupling) - 113.45, -108·3 9 I MS ES (+) 589.3 (M+l). The (R,R)-diastereomer (22%) in the form of an orange foam was isolated; NMR (CDC13) 0.001 (9H, s), 0.33 (6H, s), 0.72-0.88 (10H, m ), 1.07 (3H, m), 1.45 (5H, m)5 1.86 (1H, m), 2.54 (1H, m), 2.74 (2H, m), 2.94 (1H, m), 3.07 (1H, m) , 3.63 (1H, m), 3.73 (1H, m), 3.96 (1H, m), 7.04 (1H, m), 8.46 (1H, m), 8.69 (1H, m), 11.35 (1H, brs) ; 19F NMR (decoupling). 113.78, -108.4; MS ES (+) 589.3 (M+l). (R)-2-((S)-4-(3,5-difluorobenzo[3,4-b]®* 2-3-yl)°ifc pyridine-2-yl)hexahydropyrazine- 2-yl)-3_methylbutane-2-ol

153786.doc •74- 201231467 在室溫下，將第三-丁基-[2-[(3S)-3-[(lR)-l，2-二曱基-1-三曱基曱矽烷基氧基-丙基]六氫吡嗪-1-基]-3,5-二 氟-6·(1Η-吡唑并[3,4-b]吡啶-3-基）-4-吡啶基]-二甲基-矽烷 (60 g ’ 1〇1_9 mmol)溶於THF (216.0 mL)中。經由套管經45 分鐘向褐色溶液中逐滴添加存於THF中之TBAF(214.0 mL，1 Μ，214.0 mmol)。將反應液攪拌過夜，此後，藉由 Lc/Ms脫除保護基。使用EtOAc(600 ml)稀釋混合物並使用 NaHC03飽和水溶液（1〇〇 mi ’然後2x200 ml)洗條。使用 飽和鹽水：水（100 ml)之2:3混合物進一步洗滌有機相直至在 Lc/Ms分析中觀察到不再剩餘如^十鹽為止。藉由MgS〇4 乾燥有機相，過濾並在真空中濃縮以得到褐色固體。使用 二***研磨固體，過濾並乾燥以得到橙褐色固體04.5呂， 84。/。)。自異丙醇使固體重結晶。此可提供淺褐色固體形式 之標題化合物（23 g) ; 4 NMR (d6-DMS〇) 〇 84 (3H，队 0.90 (3H, d), 1.06 (3H, s), 1.83 (2H, m)j 2.?4 (2H d)153786.doc •74- 201231467 Third-butyl-[2-[(3S)-3-[(lR)-l,2-didecyl-1-tridecylfluorenyl) at room temperature Oxy-propyl]hexahydropyrazin-1-yl]-3,5-difluoro-6·(1Η-pyrazolo[3,4-b]pyridin-3-yl)-4-pyridyl] Dimethyl-decane (60 g '1〇1_9 mmol) was dissolved in THF (216.0 mL). TBAF (214.0 mL, 1 Μ, 214.0 mmol) in THF was added dropwise to the brown solution via a cannula over 45 min. The reaction solution was stirred overnight, after which the protecting group was removed by Lc/Ms. The mixture was diluted with EtOAc (600 mL) and was washed with NaH.sub.3, sat. The organic phase was further washed with a 2:3 mixture of saturated brine: water (100 ml) until no residue was observed in the Lc/Ms analysis. The organic phase was dried with MgSO4, filtered and concentrated in vacuo The solid was triturated with diethyl ether, filtered and dried to give an orange-brown solid. /. ). The solid was recrystallized from isopropanol. This provides the title compound (23 g) as a light brown solid. 4 NMR (d6-DMS 〇) 〇 84 (3H, vol. 0.90 (3H, d), 1.06 (3H, s), 1.83 (2H, m)j 2.?4 (2H d)

(2H，d)，3.〇9(1H，d)，3.78(1H，d)，4〇4(iHdHi3’（iH s)，7.30 (1H，dd)，7.92 (1H，dd)，8.6〇 (ih，_ 8 π (ih ⑽，n.99 (1H，b亦 4 NMR(去偶合）_128 ;，_124」；， MS ES(+) 403.0 (M+l)。 ’ · ’ 自濾液獲得第二批產物（5·3 g)且其具右 、“頁相同光譜數據。 實例2，化合物9 153786.doc -75- 201231467(2H,d), 3.〇9(1H,d),3.78(1H,d),4〇4(iHdHi3'(iH s), 7.30 (1H,dd),7.92 (1H,dd),8.6〇 (ih, _ 8 π (ih (10), n.99 (1H, b also 4 NMR (decoupling) _128;, _124";, MS ES (+) 403.0 (M+l). ' · ' Two batches of product (5·3 g) and having the right, "page identical spectral data. Example 2, compound 9 153786.doc -75- 201231467

LDA, THF, -90*CLDA, THF, -90*C

n2h4.h2o C03,二噁炫 0·<!至室溫 rNr^55^CI LDA, THF,-78eC TBDMSiCI 72% θθ%N2h4.h2o C03, dioxin 0·<! to room temperature rNr^55^CI LDA, THF, -78eC TBDMSiCI 72% θθ%

"BuU. ΤΘΜΕ -78*Ct MeCO^r"BuU. ΤΘΜΕ -78*Ct MeCO^r

^ 1)TMP, "BuU.THF 2) MeCC^Pr, .78*C^ 1) TMP, "BuU.THF 2) MeCC^Pr, .78*C

υ對映分難 2) Pt〇2. Hj. MeOH (βϊ： = +23.8* (c»5.15e/1〇0ml, EtOH) (S)： [ej^ s _22.8* (c=5.15〇/100ml. Et〇H)υ υ 分 2 2) Pt〇2. Hj. MeOH (βϊ: = +23.8* (c»5.15e/1〇0ml, EtOH) (S): [ej^ s _22.8* (c=5.15〇 /100ml. Et〇H)

將存於無水THF (1.400 L)中之2,2,6,6-四曱基六氫吡啶 (282·2 g ’ 337.2 mL，1.998 mol)的溶液在氮下冷卻 至-3 5t。經30分鐘添加nBuLi(2.5 Μ，存於己烷中）(799.2 mL·，2·5 M，1.998 mol) ’同時將内部溫度保持於_25°C 與-35°C之間。將混合物升溫至〇。(+/_ 1。）並攪拌1〇分鐘。 然後將混合物冷卻至-78。(：並在此溫度下保持20分鐘。然 後將存於無水THF (200.0 mL)中之吡嗪（80 g，998.9 mmol) 的溶液導入胺化鋰混合物中，同時將内部溫度保持於低 於-70°C。將深紅色混合物攪拌20分鐘，然後盡可能迅速 地添加 3-曱基丁烷 _2·酮（43〇1 g，534.3 mL，4.994 153786.doc -76- 201231467 mol)(在-78°C浴中冷卻），同時將内部溫度保持於低 於-60。然後將混合物在_78 C (+/- 5 C )下授掉2 hr。此時 間後之Lc/Ms顯示沒有吡嗪剩餘。在-78X：下，藉由緩慢添 加2 M HC1 (2 L)來終止反應。然後添加乙酸乙醋（8〇〇 mL)。將混合物升溫至環境溫度且分離有機相。混合物極 暗但各相易於分離。使用乙酸乙酯（2x500 ml)萃取水相。 使用飽和NaHC03(800 ml)、然後水（1 L)然後鹽水（500 ml) 洗滌合併之有機物。然後將混合物濃縮。將殘餘物溶於汽 油（1.2 L)中》存在一些固體。添加MgS〇4並乾燥混合物， 過濾並濃縮。粗製物係暗紅色油狀物（260 g) ^在使用 0-50°/。乙酸乙酯/汽油洗脫之矽膝上純化粗製物。獲得淺黃 色油狀物形式之標題化合物（103.2 g，62%) ; 4 NMR (CDC13) 0.74 (3H, d), 1.01 (3H, d), 2.07 (1H, m), 4.19 (1H, s), 8·52 (2H，s)，8.73 (1H，s) ; MS ES(+) 167.35 (M+l)。 藉由對掌性SFC層析使用纖維素-2管柱（Phenomenex)來 分離（R)-(+)_對映異構體（10% AcCN，5 ml/min，100巴， 35°C，220 nm ;保留時間為 1.54 min)[a]D+23_80(c=5.15, EtOH)。 (2R)-3-甲基-2·(六氫吡嗪-2-基）丁烷-2-醇A solution of 2,2,6,6-tetradecylpiperidine (282.2 g '337.2 mL, 1.998 mol) in dry THF (1.400 L) was cooled to -3 5t under nitrogen. nBuLi (2.5 Torr in hexane) (799.2 mL·, 2. 5 M, 1.998 mol) was added over 30 minutes while maintaining the internal temperature between _25 ° C and -35 ° C. The mixture was warmed to hydrazine. (+/_ 1.) and stir for 1 minute. The mixture was then cooled to -78. (: and kept at this temperature for 20 minutes. Then a solution of pyrazine (80 g, 998.9 mmol) in anhydrous THF (200.0 mL) was introduced into the lithium alkoxide mixture while keeping the internal temperature below - 70 ° C. The dark red mixture was stirred for 20 minutes, then 3-mercaptobutane 2 · ketone (43 〇 1 g, 534.3 mL, 4.994 153786.doc -76 - 201231467 mol) was added as quickly as possible (at - Cool at 78 ° C in the bath while maintaining the internal temperature below -60. The mixture was then allowed to give 2 hr at _78 C (+/- 5 C). After this time Lc/Ms showed no pyrazine The reaction was terminated by slowly adding 2 M HCl (2 L) at -78 X. Then ethyl acetate (8 〇〇 mL) was added. The mixture was warmed to ambient temperature and the organic phase was separated. The phases were easily separated. The aqueous phase was extracted with ethyl acetate (2×500 ml). The combined organics were washed with saturated NaHC03 (800 ml) then water (1 L) then brine (500 ml). Dissolved in gasoline (1.2 L). Some solids were present. Add MgS〇4 and dry the mixture, filter and concentrate. The crude material was obtained as a dark red oil ( EtOAc). 62%) ; 4 NMR (CDC13) 0.74 (3H, d), 1.01 (3H, d), 2.07 (1H, m), 4.19 (1H, s), 8·52 (2H, s), 8.73 (1H, s) ; MS ES (+) 167.35 (M+l). Separation of the (R)-(+)-enantiomer by using a cellulose-2 column (Phenomenex) for palm SFC chromatography (10) % AcCN, 5 ml/min, 100 bar, 35 ° C, 220 nm; retention time 1.54 min) [a] D + 23_80 (c = 5.15, EtOH). (2R)-3-methyl-2·( Hexahydropyrazin-2-yl)butan-2-ol

將氧化鉑（4.673 g，20.58 mmol)放置於Parr瓶中。在氮 153786.doc -77· 201231467 氣氛下添加曱醇（140 mL)，隨後添加（R)-(+)_3-曱基-2-(<»比 嗓-2-基）丁烧-2-醇（17.1 g，102.9 mmol)。在 60 psi 之氫壓 力下’將反應混合物在PARR氮化器中振動過夜。此時間 後之Lc/Ms表明反應已完成。在氮氣氛下，經由矽藻土塾 過濾懸浮液，使用曱醇沖洗。在真空中濃縮粗製混合物。 .將殘餘物再次溶於二氯甲烷中，藉由MgS04乾燥，過遽並 在真空中濃縮以提供黏性淺黃色油狀物形式之標題化合物 (16.6 g，非對映異構體之3:1混合物，93%) ; 4 NMR (CDC13) 0.82-1.08 (9H，m)，1.81 (1H，m)，2.20-3.17 (10H， m); MS ES(+) 173.0 (M+1)。 4-(第三-丁基二甲基甲矽烷基）-3-氣-2,5-二氟吡啶Platinum oxide (4.673 g, 20.58 mmol) was placed in a Parr bottle. Add sterol (140 mL) under nitrogen atmosphere 153786.doc -77· 201231467, followed by addition of (R)-(+)_3-mercapto-2-(<»比嗓-2-yl)butane-2 - Alcohol (17.1 g, 102.9 mmol). The reaction mixture was shaken overnight in a PARR nitrider under a hydrogen pressure of 60 psi. The Lc/Ms after this time indicates that the reaction has been completed. The suspension was filtered through diatomaceous earth under a nitrogen atmosphere and rinsed with methanol. The crude mixture was concentrated in vacuo. The residue was redissolved in dichloromethane, EtOAc (EtOAc m. 1 mixture, 93%); 4 NMR (CDC13) 0.82-1.08 (9H, m), 1.81 (1H, m), 2.20-3.17 (10H, m); MS ES (+) 173.0 (M+1). 4-(Third-butyldimethylformamidinyl)-3-aero-2,5-difluoropyridine

將存於THF(1.205 L)中之二異丙基胺（78.52 g，108.8 mL，776.0 mmol)的溶液冷卻至-20°C。經由套管經30 min 以將溫度保持於低於-15°C之速率逐滴添加n-BuLi(2.5 Μ， 存於己烧中）（298.4 mL，2.5 Μ，746· 1 mmol)。添加完成 後，立即去除冷卻浴且將反應混合物升溫至0°C。將反應 混合物在0°C下攪拌15 min，然後再次冷卻至_78°C。經由 套管經20 min以將溫度保持於低於-70°C之速率逐滴添加3-氣-2,5-二氟-吡啶（95.963 g’ 596.9 mmol)。將反應混合物 153786.doc •78· 201231467 在-7 8 C下擾摔4 5 m i η ’在此期間，溶液變成燈紅色。經由 套管以維持反應溫度低於-70°C之速率添加存於thF (1 3 3.9 mL)中之第三-丁基氣-二曱基-矽烷（117.0 g，776.0 mmol) 的溶液。將反應混合物在-78°C下攪拌90分鐘，在此期 間，溶液變成深紅色。此時間後之Lc/Ms表明反應已完 成。然後添加飽和氯化敍溶液（3 00 ml)且將混合物升溫至 環境溫度。使用水（200 ml)及碳酸氮納飽和水溶液（5〇〇 稀釋反應混合物，並使用乙酸乙酯（1.5 L，然後5 00 ml)萃 取。使用鹽水（400 ml)洗蘇合併之有機物，藉由硫酸錢乾 燥，過濾、並在真空中濃縮成油狀物（18 7 g)。藉由急驟層析 (CombiFlash Companion XL，1.5 kg管柱，存於石油 _ 中 之0.5-10%乙酸乙酯）純化粗製物。此可提供淺黃色油狀物 形式之標題化合物（113.8 g，72%) ; 4 NMR (CDC13) 0.46 (6H，d)，0.93 (9H，s)，7.84 (1H，d) ; 19F NMR(去偶合） -112.8, -74.6 ; MS ES (+) 264.95 (M+l) » 2-氟-N-曱氧基-N-甲基吡啶-3-甲醯胺A solution of diisopropylamine (78.52 g, 108.8 mL, 776.0 mmol) in THF (1.205 L) was cooled to -20 °C. n-BuLi (2.5 Torr, stored in hexane) (298.4 mL, 2.5 Μ, 746·1 mmol) was added dropwise via a cannula over 30 min to maintain the temperature below -15 °C. Immediately after the addition was completed, the cooling bath was removed and the reaction mixture was warmed to 0 °C. The reaction mixture was stirred at 0 °C for 15 min and then cooled again to _78 °C. 3-Gas-2,5-difluoro-pyridine (95.963 g' 596.9 mmol) was added dropwise via a cannula over 20 min at a rate to maintain the temperature below -70 °C. The reaction mixture 153786.doc •78· 201231467 was disturbed at -7 8 C by 4 5 m i η ' during which the solution turned red. A solution of the third-butyl gas-dimercapto-nonane (117.0 g, 776.0 mmol) in thF (1 3 3.9 mL) was added via a cannula at a rate to maintain the reaction temperature below -70 °C. The reaction mixture was stirred at -78 °C for 90 minutes, during which time the solution turned dark red. The Lc/Ms after this time indicates that the reaction has been completed. Saturated chlorinated solution (300 ml) was then added and the mixture was allowed to warm to ambient temperature. Use water (200 ml) and a saturated aqueous solution of sodium bicarbonate (5 〇〇 dilute the reaction mixture and extract with ethyl acetate (1.5 L, then 5 00 ml). Wash the combined organics with brine (400 ml). The sulphuric acid was dried, filtered, and concentrated in vacuo to an oil (1,7 g). EtOAc (EtOAc) The crude product was purified from EtOAc (EtOAc: EtOAcjjjjjjjjjjjjjjjjjjjjjjjj 19F NMR (decoupling) -112.8, -74.6; MS ES (+) 264.95 (M+l) » 2-fluoro-N-decyloxy-N-methylpyridine-3-carboxamide

將 2-氟 n 比咬-3_甲酸（1〇〇 g，708.7 mmol)溶於 THF (1.5 L) 中。添加DMAP (86.58 g，708.7 mmol)，隨後添加鹽酸N-甲氧基曱胺（76.05 g，779.6 mmol)。將混合物冷卻至 l〇°C ，然後添加 DIPEA (100.8 g，135.8 mL，779.6 153786.doc ·79· 201231467 mmol)，隨後逐份添加 EDC (149.5 g，779.6 mmol)。將混 合物攪拌30分鐘，然後迅速升溫至環境溫度（22°C)並授拌 過夜。此時間後之Lc/Ms顯示沒有酸剩餘。使用乙酸乙西旨 (1 L)及水（1.5 L)稀釋反應混合物。將混合物授拌1〇分鐘， 然後分離有機相。使用乙酸乙酯（2x500 ml)萃取水溶液並 將使用鹽水洗蘇合併之有機物，藉由硫酸鎮乾燥，過遽並 濃縮。經由使用50-70°/。乙酸乙酯/汽油洗脫之二氧化石夕塞 純化粗製物。此可提供淺黃色油狀物形式之標題化合物 (81 g . 62%) ； ]H NMR (CDC13) 3.39 (3H, s), 3,68 (3H, brs), 7.29 (1H, m), 7.92 (1H, m), 8.32 (1H, m) ； MS ES (+) 184.9 (M+l)。 (4-(第三-丁基二甲基甲矽烷基）_5_氣_3,6_二氟吡咬·2_ 基）（2-氟吡啶-3-基）甲酮2-Fluorine was dissolved in THF (1.5 L) than bit-3-carboxylic acid (1 g, 708.7 mmol). DMAP (86.58 g, 708.7 mmol) was added followed by N-methoxydecylamine hydrochloride (76.05 g, 779.6 mmol). The mixture was cooled to 10 ° C, then DIPEA (100.8 g, 135.8 mL, 779.6 153 786. doc · 79 · 201231 467 mmol) was added, then EDC (149.5 g, 779.6 mmol) was added portionwise. The mixture was stirred for 30 minutes and then rapidly warmed to ambient temperature (22 ° C) and stirred overnight. Lc/Ms after this time showed no acid residue. The reaction mixture was diluted with ethyl acetate (1 L) and water (1.5 L). The mixture was stirred for 1 minute and then the organic phase was separated. The aqueous solution was extracted with ethyl acetate (2 x 500 ml) and the combined organics were washed with brine, dried over sodium sulfate, dried and concentrated. Via use 50-70 ° /. Ethyl acetate/gasoline eluted sulphur dioxide was used to purify the crude material. This provides the title compound (81 g. 62%) in the form of a pale yellow oil; ]H NMR (CDC13) 3.39 (3H, s), 3,68 (3H, brs), 7.29 (1H, m), 7.92 (1H, m), 8.32 (1H, m) ; MS ES (+) 184.9 (M+l). (4-(Third-butyldimethylformamidinyl)_5_gas_3,6-difluoropyridinyl-2-yl)(2-fluoropyridin-3-yl)methanone

將存於THF(967.3 mL)中之二異丙基胺（52.41 g，72.59 mL ’ 517.9 mmol)的溶液冷卻至-20°C。經15分鐘經由套管 逐滴添加n-BuLi (2.5 Μ，存於己烷中）（198.5 mL，2.5 Μ， 496.3 mmol)同時維持内部溫度低於_15。(：。將溶液升溫至 〇°C然後立即再次冷卻至_90°C。經2〇 min經由套管以將内 部溫度保持於低於-85°C之速率逐滴添加存於thf(85 35 153786.doc -80- 201231467 mL)中之第三-丁基_(3_氯-2,5-二氟-4-吡啶基）-二曱基-矽燒 (113.84 g ’ 43 1.6 mmol)的溶液。在添加期間，溶液首先變 成亮黃色然後緩慢變成橙色懸浮液。將反應混合物 在-8 5 °C下撥拌1 h。經15分鐘經由套管以將内部溫度保持 於低於-80.7°C (理想情形為低於-85°C )之速率逐滴添加存 於THF(85.3 5 mL)中之2-氟-N-曱氧基-N-甲基吡啶-3-甲酿 胺（91.40 g，496.3 mmol)的溶液。添加後，混合物變成暗 撥褐色。將混合物在-85 C下授摔90分鐘，此後，Lc/Ms表 明反應已完成。去除冷卻浴且將混合物升溫至_5〇°c。添 加飽和氣化銨溶液（400 mL)且將混合物升溫至室溫。使用 乙酸乙酯（1.5 L)稀釋混合物。分離水相並使用額外乙酸乙 酯（300 ml)進行萃取。使用鹽水（300 ml)洗滌合併之有機 物’藉由硫酸鎂乾燥’過濾並在真空中濃縮成褐色油狀 物。在石夕膠（CombiFlash Companion XL，1.5 kg管柱，存 於石油醚中之0.5-1 〇%乙酸乙醋，存於石油趟中之乙 酸乙酯）上純化粗製物。此可得到黃色油狀物形式之標題 化合物’该化合物在靜置時會發生固化（159.6 g，95%); 'Η NMR (CDC13) 0.60 (6H, d), 1.07 (9H, s), 7.47 (1H, m), 8.33 (1H，m)，8.52 (1H，m) ; 19F NMR(去偶合）·107.2, 72.4, ·61.8 ; MS ES (+) 387.04 (M+l)。 3-(4-(第三-丁基二甲基甲矽烷基）_5_氣_3 6_二氟吡啶_2_ 基比唾并[3,4-b]&quot;比咬 153786.doc -81 * 201231467A solution of diisopropylamine (52.41 g, 72.59 mL '517.9 mmol) in THF (967.3 mL) was cooled to -20 °C. n-BuLi (2.5 Μ in hexane) (198.5 mL, 2.5 Μ, 496.3 mmol) was added via cannula over 15 min while maintaining the internal temperature below _15. (: The solution was warmed to 〇 ° C and then immediately cooled again to _90 ° C. After 2 〇 min via a cannula to keep the internal temperature at a rate below -85 ° C added dropwise to thf (85 35 153786.doc -80-201231467 mL) of the third-butyl-(3-chloro-2,5-difluoro-4-pyridyl)-dimercapto-oxime (113.84 g '43 1.6 mmol) Solution. During the addition, the solution first turned bright yellow and then slowly turned into an orange suspension. The reaction mixture was stirred at -8 5 ° C for 1 h. The inner temperature was kept below -80.7 via a sleeve for 15 minutes. 2-Fluoro-N-methoxy-N-methylpyridine-3-cartoamine (91.40) in THF (85.3 5 mL) was added dropwise at a rate of C (ideally below -85 °C). g, 496.3 mmol) of the solution. After the addition, the mixture became dark brown. The mixture was dropped at -85 C for 90 minutes, after which Lc/Ms indicated that the reaction was completed. The cooling bath was removed and the mixture was warmed to _5 〇 Add a saturated solution of ammonium sulphate (400 mL) and warm the mixture to room temperature. Dilute the mixture with ethyl acetate (1.5 L). Separate the aqueous phase and use additional ethyl acetate (300 ml) Extraction. The combined organics were washed with brine (300 ml) and dried <RTI ID=0.0></RTI> <RTI ID=0.0> The crude compound was purified by the addition of 0.5-1% EtOAc (EtOAc EtOAc) 95%); 'Η NMR (CDC13) 0.60 (6H, d), 1.07 (9H, s), 7.47 (1H, m), 8.33 (1H, m), 8.52 (1H, m); 19F NMR (decoupling) ) 107.2, 72.4, ·61.8 ; MS ES (+) 387.04 (M+l) 3-(4-(T-butyldimethylmethylmethanyl)_5_gas_3 6_difluoropyridine 2_ 基比唾和[3,4-b]&quot;比比153786.doc -81 * 201231467

將[4-[第三-丁基（二甲基）甲矽烷基]_5_氣_3 6二氟_2吡 啶基]-(2-氟-3-吡啶基）曱酮（294.86 g，762 2 mm〇1)溶於 二°惡院（2.212 L)中且添加碳酸詞（152.5 g，1.524 mol)。在 冰浴中冷卻反應且經15分鐘經由套管向黃色懸浮液中逐滴 添加水合肼（190.8 g ’ 185.4 mL，3.811 mol)，同時保持内 部溫度低於1 0 °C。在添加期間，内部溫度降至7 · 1 °c且顏 色自淺黃色變為芒果撥色。將所得混合物升溫至環境溫度 過夜。此後之Lc/Ms表明反應已完成《經由矽藻土墊過渡 反應混合物，使用二氣曱烷（約2.5 L)充分洗滌。向濾液中 添加水（400 ml)，隨後添加碳酸氫鈉飽和溶液（4〇〇 mL)。 分離有機相並使用碳酸氫鈉飽和水溶液（350 mL)再次洗 滌。使用二氣甲烷（2x400 ml)反萃取合併之水層。藉由硫 酸鎂乾燥合併之有機物，過濾並在真空中濃縮。將所得固 體在石油中製成漿液，過渡並乾燥（8 1 g)。使用7:1之二 氣甲烷/曱醇（3x800 ml)及4 L4:l之二氣曱烷/甲醇進一步洗 滌矽藻土直至在TLC上觀察到沒有化合物剩餘為止。在真 空中濃縮濾液。如上所述，使用石油醚研磨殘餘固體（185 g)。合併固體並在4(TC及真空下乾燥。此可得到灰白色固 體形式之標題化合物（260.5 g，89%);NMR (CDC13) 0.63 (6H，d)，1·〇7 (9H，s)，7.44 (1H，m)，8.76 (1H，m)， 9.07 (1H, m), 13.31 (1H，brs) ; 19F NMR(去偶合） 153786.doc -82- 201231467 -104.7, -73.8 ; MS ES (+) 381.1 (Μ+l)。 3_(4-(第三-丁基二甲基甲梦炫基）-5-氣-3-氟-6-((8)-3-((尺)· 3 -甲基-2-(三甲基甲梦炫基氧基）丁燒基）六氫吼嗪-1-基） 吡啶-2·基）-1Η-吡唑并[3,4-b】吡啶[4-[Third-butyl(dimethyl)metholyl]_5_gas_3 6 difluoro-2-pyridyl]-(2-fluoro-3-pyridinyl)fluorenone (294.86 g, 762 2 mm 〇 1) was dissolved in two broth (2.212 L) and added with the word carbonic acid (152.5 g, 1.524 mol). The reaction was cooled in an ice bath and hydrazine hydrate (190.8 g &apos; 185.4 mL, 3.811 mol) was added dropwise via a cannula to the yellow suspension over 15 minutes while maintaining the internal temperature below 10 °C. During the addition, the internal temperature dropped to 7 · 1 °c and the color changed from light yellow to mango. The resulting mixture was allowed to warm to ambient temperature overnight. Thereafter, Lc/Ms indicates that the reaction has been completed. The transition reaction mixture was passed through a diatomaceous earth pad and washed thoroughly with dioxane (about 2.5 L). Water (400 ml) was added to the filtrate, followed by a saturated solution of sodium hydrogencarbonate (4 mL). The organic phase was separated and washed again using a saturated aqueous solution of sodium bicarbonate (350 mL). The combined aqueous layers were back extracted using di-methane (2 x 400 ml). The combined organics were dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting solid was slurried in petroleum, transitioned and dried (8 1 g). The diatomaceous earth was further washed with 7:1 hexane methane/nonanol (3 x 800 ml) and 4 L 4:1 dioxane/methanol until no compound remained observed on TLC. The filtrate was concentrated in the air. The residual solid (185 g) was triturated with petroleum ether as described above. The solids were combined and dried with EtOAc EtOAcjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH 7.44 (1H,m), 8.76 (1H,m), 9.07 (1H, m), 13.31 (1H,brs) ;19F NMR (decoupling) 153786.doc -82- 201231467 -104.7, -73.8 ; MS ES ( +) 381.1 (Μ+l). 3_(4-(Third-butyl dimethylmethanthyl)-5-gas-3-fluoro-6-((8)-3-((foot)· 3-Methyl-2-(trimethylmethylammonyloxy)butanyl)hexahydropyridazin-1-yl)pyridine-2·yl)-1Η-pyrazolo[3,4-b] Pyridine

將3-(4-(第三-丁基二甲基曱矽烷基）-5-氣-3,6-二氟吡啶-2-基）-1Η-π 比嗤并[3,4-b]e 比咬（132.7 g，348 mmol)溶於無水 THF (265 mL)中。添加咪唑-1-基（三曱基）矽烷（254 mL)， 隨後添加（2R)-3-甲基-2-(六風α比。秦-2-基）丁院-2-醇（90 g， 522 mmol)。將混合物分配至4個玻璃壓力器皿中，且加熱 密封之容器並在95°C下攪拌48小時。冷卻粗製混合物，合 併並使用乙酸乙酯（1.7 L)稀釋。使用飽和碳酸氫鈉（2x500 ml)洗滌溶液。使用乙酸乙酯（500 ml)反萃取合併之水層。 使用鹽水（500 ml)洗滌合併之有機物，藉由MgS04乾燥， 過濾並在真空中濃縮以得到黏性褐色油狀物。在矽膠（存 於石油醚中之含有2%三乙胺之1 〇-1 〇〇%乙酸乙酯）上分離 非對映異構體。此可得到需要之黃色發泡體形式之（S，R)_ 非對映異構體（125.3 g，59%) ; NMR (CDC13) 0.01 (9H， 153786.doc -83 - 201231467 s)，0.42 (6H，s)，0.78-0.89 (15H，m)，1.09-1.13 (3H， 1.74 (1H，m)，2.61 (1H，m)，2.80-2.99 (4H，m)，3.12 (lH m), 3.45 (1H, d), 3.69 (1H, d), 7.12 (1H, m), 8.55 (1H, m) 8·81 (1H，m)，12.75 (1H，brs) ; 19F NMR(去偶合）-108.9 ; MS ES 605.2 (M+)。分離出黃色發泡體形式之3-(4-(Third-butyldimethylmethylalkyl)-5-gas-3,6-difluoropyridin-2-yl)-1Η-π is 嗤[3,4-b] e is more soluble than bite (132.7 g, 348 mmol) in anhydrous THF (265 mL). Add imidazol-1-yl(tridecyl)decane (254 mL), followed by addition of (2R)-3-methyl-2-(hexa-pyrene ratio: Qin-2-yl)butan-2-ol (90 g, 522 mmol). The mixture was dispensed into 4 glass pressure vessels and the sealed container was heated and stirred at 95 ° C for 48 hours. The crude mixture was cooled, combined and diluted with ethyl acetate (1L). The solution was washed with saturated sodium bicarbonate (2 x 500 ml). The combined aqueous layers were back extracted with ethyl acetate (500 mL). The combined organics were washed with EtOAc (EtOAc)EtOAc. The diastereomers were separated on silica gel (1 〇 -1 〇〇% ethyl acetate containing 2% triethylamine in petroleum ether). This gave the desired (S,R)-diastereomer in the form of a yellow foam (125.3 g, 59%); NMR (CDC13) 0.01 (9H, 153786.doc -83 - 201231467 s), 0.42 (6H, s), 0.78-0.89 (15H, m), 1.09-1.13 (3H, 1.74 (1H, m), 2.61 (1H, m), 2.80-2.99 (4H, m), 3.12 (lH m), 3.45 (1H, d), 3.69 (1H, d), 7.12 (1H, m), 8.55 (1H, m) 8·81 (1H, m), 12.75 (1H, brs); 19F NMR (decoupling) - 108.9 ; MS ES 605.2 (M+). Isolated in the form of a yellow foam

映異構體（27.5 g，13%) ; 4 NMR (CDC13) 0.00 (9H，s) 0.38 (6H，m)，0.76-0.80 (15H，m)，0.85 (3H，s)，1.85 (iH m)，2.50 (1H，m)，2.90-3.13 (4H，m)，3.42 (1H，m)，3.56 (1H，m)，3.91 (1H，m)，7.08 (1H，m)，8.51 (1H，m)，8·76 (1H，m)，12.70 (1H，brs) ; 19F NMR(去偶合）-109.0 ; MS ES 605.2 (M+)。 (R)-2-((S)-4-(3_ 氣-5-氟-6-(lH-吡唑并【3,4-b]吡啶-3-基）吨 啶-2-基）六氫咕嗪-2-基）-3-甲基丁烷-2-醇Enantiomer (27.5 g, 13%); 4 NMR (CDC13) 0.00 (9H, s) 0.38 (6H, m), 0.76-0.80 (15H, m), 0.85 (3H, s), 1.85 (iH m ), 2.50 (1H, m), 2.90-3.13 (4H, m), 3.42 (1H, m), 3.56 (1H, m), 3.91 (1H, m), 7.08 (1H, m), 8.51 (1H, m), 8·76 (1H, m), 12.70 (1H, brs); 19F NMR (decoup)-109.0; MS ES 605.2 (M+). (R)-2-((S)-4-(3_ gas-5-fluoro-6-(lH-pyrazolo[3,4-b]pyridin-3-yl)ton-2-yl)6 Hydropyridazin-2-yl)-3-methylbutan-2-ol

HN-N FHN-N F

在環境溫度下，將3-(4-(第三-丁基二甲基甲矽烷基）-5-氯-3-氟-6-((S)-3-((R)-3-甲基-2·(三曱基曱矽烷基氧基）丁 烧-2-基）六氫&quot;比嘻-1-基）《&gt;比淀-2-基）-1Η-°比》坐并[3,4-b]°比咬 (125 g，206.5 mmol)溶於THF中（450 mL)。經由套管向黃 色溶液中逐滴添加四丁基氟化銨（433.6 mL，1 M THF溶 液，433.6 mmol)。内部溫度自21.3°C升至27.7°C。將反應 153786.doc •84· 201231467 液攪拌48小時》然後使用乙酸乙酯（ι·5 L)稀釋混合物並使 用碳酸氫鈉飽和水溶液與水之1:1混合物（3 X 600 ml)洗務。 使用乙酸乙酯（2x600 ml)反萃取合併之水相。然後使用雎 水（600 ml)洗滌合併之有機相，藉由MgS〇4乾燥，過濾並 在真空中部分地濃縮直至標題產物開始沉澱為止。添加數 滴曱醇並將混合物在環境溫度下攪拌過夜。然後過渡產 物，使用最少量之乙酸乙酯及石油醚沖洗以得到灰白色固 體’在真空下乾燥過夜（40°C及1.5毫巴）。此可提供白色固 體形式之標題化合物（73.1 g，84%) ; mp (DSC)開始溫度為 215.3°C ’ 峰溫為 218.1°C ; NMR (400.0 MHz，DMSO) 0.91 (d，3H)，0.94 (d，3H)，1.10 (s，3H), 1.83 (b quint，2H), 2.72 (t, 1H), 2.80-2.94 (m, 3H), 3.14-3.17 (m, 1H), 3.62 (d, 1H), 3.88 (d, 1H), 4.14 (s, 1H), 7.37 (dd, 1H), 8.16 (d, 1H), 8.65 (dd，1H), 8.86 (dd, 1H)，14.12 (bs，1H) ; 19F NMR(去 偶合）-127.9 ; MS ES(+) 419.1 (M+l);對映異構體超量 &gt;98% (Minigram SFC, ODH 250x10 mm, 20% MeOH (0.1% TEA)，5 mg/ml。 實例3，化合物36 6-((R)-3-((S)-l-胺基-2-甲基丙基洛咬 _i_ 基）_2_ 氯 _5·ι 菸腈3-(4-(Third-butyldimethylformamido)-5-chloro-3-fluoro-6-((S)-3-((R)-3-) at ambient temperature Base-2·(trimethylsulfonylalkyloxy)butan-2-yl)hexahydro&quot;by 嘻-1-yl) "&gt; bicyan-2-yl)-1Η-° ratio The [3,4-b]° bite (125 g, 206.5 mmol) was dissolved in THF (450 mL). Tetrabutylammonium fluoride (433.6 mL, 1 M THF solution, 433.6 mmol) was added dropwise to the yellow solution via a cannula. The internal temperature rose from 21.3 ° C to 27.7 ° C. The reaction was stirred for 48 hours, then the mixture was diluted with ethyl acetate (1·5 L) and washed with a 1:1 mixture of saturated aqueous sodium hydrogen carbonate and water (3×600 ml). The combined aqueous phases were back extracted with ethyl acetate (2 x 600 ml). The combined organic phases were then washed with hydrazine (600 mL), dried over EtOAc EtOAc EtOAc. A few drops of sterol were added and the mixture was stirred at ambient temperature overnight. The product was then transferred, rinsed with a minimum of ethyl acetate and petroleum ether to afford an off-white solid, which was dried overnight (40 ° C and 1.5 mbar). This provides the title compound as a white solid (73.1 g, 84%); mp (DSC), starting at 215.3 ° C, peak temperature of 218.1 ° C; NMR (400.0 MHz, DMSO) 0.91 (d, 3H), 0.94 (d, 3H), 1.10 (s, 3H), 1.83 (b quint, 2H), 2.72 (t, 1H), 2.80-2.94 (m, 3H), 3.14-3.17 (m, 1H), 3.62 (d, 1H), 3.88 (d, 1H), 4.14 (s, 1H), 7.37 (dd, 1H), 8.16 (d, 1H), 8.65 (dd, 1H), 8.86 (dd, 1H), 14.12 (bs, 1H) 19F NMR (decoupling)-127.9; MS ES(+) 419.1 (M+l); enantiomeric excess &gt; 98% (Minigram SFC, ODH 250x10 mm, 20% MeOH (0.1% TEA) , 5 mg/ml. Example 3, compound 36 6-((R)-3-((S)-l-amino-2-methylpropyl octazone_i_yl)_2_ chloro_5·ι nicotinonitrile

153786.doc -85- 201231467 將存於NMP (3 mL)中之2-甲基-i-[(3S)-吡咯啶-3-基]丙 烷-1-胺（3 10 mg ’ 1.98 mmol)、2,6-二氣-5-氟-吡啶-3·甲腈 (378.7 mg，1.98 mmol)及 DIPEA (512.6 mg，690.8 pL ’ 3.97 mmol)的混合物在13(TC及微波條件下加熱20分鐘。此 後’將反應混合物冷卻至環境溫度並使用EtOAc、水及 NaHC03飽和水溶液稀釋。分離有機層並使用鹽水洗滌， 乾燥（Na2S04)，過濾並在真空中濃縮。藉由管柱層析 (ISCO CompanionTM，40 g管柱，使用 MeOH/DCM洗脫）純 化粗製混合物以得到油狀物形式之子標題化合物（506.3 mg，產率為86%)。 6-((3S)-3-(l -胺基-2_甲基丙基）°Λ嘻咬-1-基）-5-氟·2·(1-三 苯甲基-1Η-吡唑并p，4-b】”比啶-3-基）菸腈153786.doc -85- 201231467 2-Methyl-i-[(3S)-pyrrolidin-3-yl]propan-1-amine (3 10 mg ' 1.98 mmol) in NMP (3 mL), A mixture of 2,6-di-gas-5-fluoro-pyridine-3.carbonitrile (378.7 mg, 1.98 mmol) and DIPEA (512.6 mg, 690.8 pL ' 3.97 mmol) was heated at 13 (TC and microwave for 20 min). After that, the reaction mixture was cooled to ambient temperature and diluted with EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc. The crude mixture was purified to give the subtitle compound (506.3 mg, yield 86%). 2_Methylpropyl)°Λ嘻1-yl)-5-fluoro·2·(1-trityl-1Η-pyrazolo p,4-b]”pyridin-3-yl) Nicotinonitrile

將3-(4,4,5,5-四甲基-1，3,2-二氧硼咮-2-基）-卜三苯甲基_ °比唾并[5,4-1&gt;]°比°定（1.45 g，2_98 mmol)、6-[(3S)-3-(l-胺 基-2-曱基-丙基）吡咯啶_ι_基]_2_氯-5-氟-吡啶-3-甲腈（506 153786.doc • 86 · 201231467 mg，1.71 mmol)、Κ3Ρ〇4(1·45 g，6.82 mmol)及 Pd(PPh3)4 (98.51 mg，0.09 mmol)懸浮於二。惡烧（18 mL)及水（1.8 mL) 中，並在100°C下加熱2小時。此後，將反應混合物冷卻至 環境溫度並使用EtOAc、水及NaHC03飽和水溶液稀釋，且 經由矽藻土墊過濾。分離有機層，使用飽和鹽水水溶液洗 滌’乾燥（Na2S04)，過濾並在真空中濃縮。藉由管柱層析 (ISCO Companion™，40 g管柱，使用 NH4OH:MeOH/DCM 洗脫）純化粗製混合物以得到油狀物形式之子標題化合物 (762.1 mg，產率為 72%)。 6-((3S)-3_(l-胺基-2-甲基丙基）吡咯啶-1-基）-5-氟-2_(1H-吡 唑并[3,4-b】&quot;*啶-3-基）菸腈 Η3-(4,4,5,5-tetramethyl-1,3,2-dioxaborin-2-yl)-b-trityl- _ ° ratio [5, 4-1] ° ° ° (1.45 g, 2_98 mmol), 6-[(3S)-3-(l-amino-2-mercapto-propyl)pyrrolidine_ι_yl]_2_chloro-5-fluoro- Pyridine-3-carbonitrile (506 153786.doc • 86 · 201231467 mg, 1.71 mmol), Κ3Ρ〇4 (1·45 g, 6.82 mmol) and Pd(PPh3)4 (98.51 mg, 0.09 mmol) were suspended in two. The mixture was burned (18 mL) and water (1.8 mL) and heated at 100 ° C for 2 hours. Thereafter, the reaction mixture was cooled to ambient temperature and diluted with EtOAc EtOAc. The organic layer was separated, washed with aq. EtOAc (EtOAc) The crude mixture was purified by EtOAc EtOAc EtOAc (EtOAc) 6-((3S)-3_(l-Amino-2-methylpropyl)pyrrolidin-1-yl)-5-fluoro-2_(1H-pyrazolo[3,4-b]&quot;* Pyridin-3-yl) nicotinamide

將存於DCM (20 mL)中之2-[(38)-3-(1-胺基_2_甲基-丙基） 吡咯啶-1-基&gt;5-氟-6-(1-三苯曱基吡唑并[3,4_b]吡啶_3_基） 0比咬-3-曱腈（762 mg，1.27 mmol)的溶液在〇。〇下冷卻，且 使用三乙基矽烷（142.6 mg’ 195.9 μί，1.23 mmol)及TFA (2.80 g ’ 1.89 mL ’ 24.52 mmol)進行處理。將反應混合物 經18小時升溫至環境溫度。此後’在真空中濃縮反應混合 153786.doc • 87 · 201231467 物。藉由反相製備型 HPLC [ Waters Sunfire C18，5 μΜ， 100 A管柱，梯度l〇%-95% B(溶劑A :存於水中之〇 〇5% TFA ;溶劑B : CH3CN)，經16分鐘，25 mL/min]來純化殘 餘物。收集來自峰1之部分並凍乾以得到標題化合物之 單-TFA鹽固體（58.8 mg，產率為 19.4%)。H1 NMR (400.0 MHz, DMSO) δ 14.19 (s, 1H), 8.72 (dd, J=1.3, 8.1 Hz, 1H), 8.62 (dd, J=1.5, 4.5 Hz, 1H), 8.03 (s, 1H), 7.88 (d, J=3.0 Hz, 3H), 7.32 (dd, J=4.5, 8.1 Hz, 1H), 4.05-4.00 (m, 2H), 3.75-3.11 (m, 3H), 2.60-2.50 (m, 1H), 2.26-2.18 (m, 1H), 2.01-1.74 (m，2H), 1.06 (d，J=6.9 Hz，3H)及 1.00 (d, J=7.0 Hz，3H) ppm ; MS (ES+) 3 80.0。收集來自峰2之部分並凍 乾以得到標題化合物異構體之單-TFA鹽固體（47.0 mg，產 率為 15.2%)。H1 NMR (400.0 MHz，DMSO) δ 14.18 (s，1H)， 8.74 (dd, J=1.3, 8.1 Hz, 1H), 8.62 (dd, J=1.5, 4.5 Hz, 1H), 8.04 (s，1H)，8.00 (s，3H)，7.34 (dd，J=4.5，8.2 Hz, 1H)， 4.13-4.07 (m, 1H), 4.00-3.92 (m, 1H), 3.81-3.71 (m, 1H), 3.59-3.54 (m, 1H), 3.20-3.09 (m, 1H), 2.59-2.50 (m, 1H), 2.21-1.99 (m, 2H), 1.89-1.75 (m, 1H), 1.07 (d, J=7.0 Hz, 3H)及0.97 (d，J=7.0 Hz, 3H) ppm ; MS (ES+) 380.0。 化合物9，替代性合成 153786.doc -88 - 2012314672-[(38)-3-(1-Amino-2-methyl-propyl)pyrrolidin-1-yl&gt; 5-fluoro-6-(1-) in DCM (20 mL) A solution of triphenylsulfonylpyrazolo[3,4_b]pyridine-3-yl) 0 is more than a solution of bitten-3-carbonitrile (762 mg, 1.27 mmol). It was cooled under the agitation and treated with triethyl decane (142.6 mg &apos;&lt;RTIID=0.0&gt;&gt;&&&&&&&&&&&&&& The reaction mixture was warmed to ambient temperature over 18 hours. Thereafter, the reaction mixture was concentrated in a vacuum 153786.doc • 87 · 201231467. Prepared by reverse phase preparative HPLC [Waters Sunfire C18, 5 μΜ, 100 A column, gradient l〇%-95% B (solvent A: 5% TFA in water; solvent B: CH3CN), 16 The residue was purified by minute, 25 mL/min. The fraction from peak 1 was collected and lyophilized to give the title compound as a mono-TFA salt solid (58.8 mg, yield 19.4%). H1 NMR (400.0 MHz, DMSO) δ 14.19 (s, 1H), 8.72 (dd, J=1.3, 8.1 Hz, 1H), 8.62 (dd, J=1.5, 4.5 Hz, 1H), 8.03 (s, 1H) , 7.88 (d, J=3.0 Hz, 3H), 7.32 (dd, J=4.5, 8.1 Hz, 1H), 4.05-4.00 (m, 2H), 3.75-3.11 (m, 3H), 2.60-2.50 (m , 1H), 2.26-2.18 (m, 1H), 2.01-1.74 (m, 2H), 1.06 (d, J = 6.9 Hz, 3H) and 1.00 (d, J = 7.0 Hz, 3H) ppm ; MS (ES+ ) 3 80.0. The fraction from peak 2 was collected and lyophilized to give the title compound as a mono-TFA salt solid (47.0 mg, yield 15.2%). H1 NMR (400.0 MHz, DMSO) δ 14.18 (s, 1H), 8.74 (dd, J = 1.3, 8.1 Hz, 1H), 8.62 (dd, J=1.5, 4.5 Hz, 1H), 8.04 (s,1H) , 8.00 (s, 3H), 7.34 (dd, J = 4.5, 8.2 Hz, 1H), 4.13-4.07 (m, 1H), 4.00-3.92 (m, 1H), 3.81-3.71 (m, 1H), 3.59 -3.54 (m, 1H), 3.20-3.09 (m, 1H), 2.59-2.50 (m, 1H), 2.21-1.99 (m, 2H), 1.89-1.75 (m, 1H), 1.07 (d, J= 7.0 Hz, 3H) and 0.97 (d, J = 7.0 Hz, 3H) ppm; MS (ES+) 380.0. Compound 9, alternative synthesis 153786.doc -88 - 201231467

Pt02 H2 (40 psi) EtOH 40 °C/3d 大致定量 HCHO (aq) MeOH 60 °C/8 h 大致定量Pt02 H2 (40 psi) EtOH 40 °C/3d Approximate Quantification HCHO (aq) MeOH 60 °C/8 h Approximate Quantification

号OCOC

e Ηe Η

Β〇〇2〇 DC Μ RT/1 h &amp; 大致定量 約70:30 (7?,S人丫尺巧 b:c 穿ocΒ〇〇2〇 DC Μ RT/1 h &amp; roughly Quantitative about 70:30 (7?, S people 丫 巧 b:c wear oc

Si02層析 a〇Ac/己烷 62% (R,S) 17% (RtR) (3步） 号ocSi02 chromatography a〇Ac/hexane 62% (R,S) 17% (RtR) (3 steps) No. oc

TfOH(2.1 當量） BuOAcTfOH (2.1 eq.) BuOAc

ΝΗ2ΟΗ·ΗΟΙ MeOH 60 °Cy20 h 然後 K2C〇3 &gt;90% (蒸餾）ΝΗ2ΟΗ·ΗΟΙ MeOH 60 °Cy20 h then K2C〇3 &gt;90% (distillation)

甲oc f 0-10°C/1 h 然後 3M NaOH/DCM 81 - 85% HA oc f 0-10 ° C / 1 h then 3M NaOH / DCM 81 - 85% H

藉由首先使用Boc20保護無阻礙氮在5個步驟中來拆分 (尺,3):(11,11)-六氫吡嗪1)/(：之70:30混合物以提供（11，8):(11，11)-N-Boc六氫°比。秦d/e的混合物。使用HCHO水溶液處理此混 合物以提供（尺,8):(11,尺)-&gt;1-：8〇(：-°惡°坐咬以§之混合物。經由 Si02管柱層析分離非對映異構體混合物。使用TfOH對純非 對映異構體依次脫除保護基以形成（R,S)-噁唑啶h或（R,R)-噁唑啶，且然後使用NH2OH«HCl加熱[或藉由加熱h或 (R，R)-噁唑啶之雙-(三氟曱磺酸）鹽]以分別提供（R，S)-i或 (R，R)-六氫°比嘹。 153786.doc -89- 201231467The unblocked nitrogen was first resolved in 5 steps by using Boc20 (foot, 3): (11,11)-hexahydropyrazine 1)/(: 70:30 mixture to provide (11,8) :(11,11)-N-Boc hexahydrogen ratio. Mixture of Qin d/e. This mixture was treated with an aqueous solution of HCHO to provide (foot, 8): (11, ft.) - &gt; 1-: 8 〇 ( :-°°°Sit with a mixture of §. Separation of the mixture of diastereomers by SiO 2 column chromatography. The pure diastereomers were used to remove the protecting groups in order to form (R,S)- using TfOH. Oxazolidine h or (R,R)-oxazolidine, and then heated with NH2OH «HCl [or by heating h or (R,R)-oxazolidine bis-(trifluoromethanesulfonate) salt] To provide (R,S)-i or (R,R)-hexahydrogen ratio 嘹. 153786.doc -89- 201231467

FF

TBDMSTBDMS

HN一N FHN-N F

TBAFTBAF

THF 0-10 °C/1〇 min 98% 使反應燒瓶配備有磁力搜拌器、熱電偶、加熱套、及n2 入口。將j以及THF裝填至燒瓶中。將懸浮液在〇_1〇β(：下冷 卻。經5 min 添加存於 THF中之 1.〇 μ TBAF(65.6 mL ; 66 mmol ; 1.0當量）。將所得溶液升溫至室溫。使用水（25〇 mL ; 10 V)稀釋反應溶液，此會產生白色稠懸浮液。陳化1 h後’藉由過濾（紙）收集固體。使用水（3x50 mL)、EtOH (2x50 mL)洗滌濾餅’並風乾以提供精細黃色粉末形式之 k 〇 化合物9THF 0-10 °C / 1 〇 min 98% The reaction flask was equipped with a magnetic stirrer, thermocouple, heating mantle, and n2 inlet. j and THF were loaded into the flask. The suspension was cooled under 〇1 〇β (:. 1μ TBAF (65.6 mL; 66 mmol; 1.0 eq.) in THF was added over 5 min. The solution was warmed to room temperature. 25 〇mL ; 10 V) dilute the reaction solution, which will produce a white thick suspension. After 1 h of aging, 'collect the solid by filtration (paper). Wash the filter cake with water (3 x 50 mL), EtOH (2 x 50 mL) And air dried to provide a k 〇 compound 9 in the form of a fine yellow powder

使反應燒瓶配備有磁力授拌器、熱電偶、加熱套、及 入口。將k裝填至燒瓶中。在NMP (19.2 mL ; 8 V)中添加i 之溶液（2.33 g; 13.5 mmol ; 1 _5當量）。將所得黃色懸浮液 在90eC下加熱10 h。冷卻至室溫後，使用水（96 mL ; 4〇 v) 及1.0 M NaOH(9.9 mL ; 9.9 mmol ; 1.1當量）稀釋所得懸浮 液。將懸浮液陳化30 min。藉由過濾（緩慢過渡）收集固 體。使用水（2x60 mL)洗滌濾餅並簡單風乾。將濕滤餅轉 153786.doc -90· 201231467 移至適宜燒瓶中並藉由CAN稀釋物/濃縮物（2 x2〇〇 mL)去除 剩餘水。添加新鮮ACN (60 mL)並在80°C及攪動下升溫。 將懸浮液冷卻至室溫且藉由過濾收集固體。使用ACN (2x10 mL)洗滌濾餅並風乾以提供精細白色粉末9。 HPLC : 98.7% AUC (1.3%之單一雜質） 4 NMR(DMSO-d6):符合結構；CAN有剩餘。 化合物9之晶體結構 在配備有密封管Cu Κα源及Apex η CCD檢測器之Bruker Apex II繞射儀上獲得繞射數據。 使用 SHELX程式（Sheldrick，G.M.，Acta Cryst”（2008) A64, 112-122)來解析及精修結構。 根據系統消光及強度統計學，在斜方晶單位晶胞及離心 P2PJ空間群_來解析及精修結構。 使用-0.005(0.014) Flack絕對構型因子來可靠地測定絕 對構型》所測值極其接近〇且具有較小標準偏差^此表示 能可靠地測定絕對構型。 在不對稱單元_具有一個分子。 存在Ζ字形一維無限鏈，且將R 2,2(9)圖式設定用於氫鍵 結合成子結構。在該等鏈之間不存在氫鍵，僅存在范德華 (van der Waals)相互作用。 比對模擬圖案與計算圖案時，顯示該結構即代表該批化 合物。 該結構完全有序化，且具有2 3%之低R因子。我們針對 結構品質指定A—個得分值。 153786.doc -91 · 201231467 實驗 將20 mg化合物9溶於1 mL曱醇、4 mL乙醇中，添加晶 種，在80°C下於密封小瓶中加熱。過夜後獲得針型晶體。 選擇尺寸為〇.3〇χ〇. 10x0.05 mm3之無色刀片型晶體，將 其安置於MicroMount上並使其位於Bruker APEX II繞射儀 (VO 115 10)中心處。獲得在倒晶格空間中分離之3批40個框 架，以提供取向矩陣及初始晶胞參數。收集最終晶胞參數 並根據全資料集完成精修。 使用0.5°步長以106° 2Θ角之解析度獲得倒晶格空間的繞 射數據集合，其中對於低角度框架而言，每一框架之曝露 時間為10秒，且對於高角度框架而言，每一框架之曝露時 間為60秒。在100 (2) K溫度下收集數據。使用APEXII軟體 對強度進行積分並精修晶胞參數。 在具有Cu Κα輻射及Highstar檢測器之Bruker D8 Discover繞射儀上收集粉末X-射線繞射數據。 精修 結構完全有序化。使用騎式模型來精修氩原子。 計算細節 數據收集：Apex II ;晶胞精修：Apex II ;數據簡化： Apex II;用於拆分結構之程式：SHELXS97 (Sheldrick， 1990);用於精修結構之程式：SHELXL97 (Sheldrick， 1997);分子圖形：汞；用於準備公開材料之軟體： publCIF 。 晶體數據 153786.doc -92- 201231467 晶體數據 C20Hj4ClFN6O Dx=1.340Mgm° Mr=418.90 CuKa輻射，λ=1·54178 A 斜方晶，P2A2 來自5449個反射之晶胞參數 a=15.0138(8)A 0=3.4-52.8° b=24.9923 (14) A μ=1.91 mm'1 c=5.5319(3) A T=100K V=2075.7 (2) A3 刀片型，無έ Z=4 0.3〇x〇.l〇x〇.〇5 mm F(000)=880 數據收集The reaction flask was equipped with a magnetic stirrer, thermocouple, heating mantle, and inlet. Load k into the flask. A solution of i (2.33 g; 13.5 mmol; 1 _5 equivalent) was added to NMP (19.2 mL; 8 V). The resulting yellow suspension was heated at 90 °C for 10 h. After cooling to room temperature, the resulting suspension was diluted with water (96 mL; 4 〇 v) and 1.0 M NaOH (9.9 mL; 9.9 mmol; 1.1 eq.). The suspension was aged for 30 min. The solids are collected by filtration (slow transition). The filter cake was washed with water (2 x 60 mL) and air dried briefly. The wet cake was transferred to 153786.doc -90· 201231467 and transferred to a suitable flask and the remaining water was removed by CAN dilution/concentrate (2 x 2 〇〇 mL). Fresh ACN (60 mL) was added and warmed at 80 ° C with stirring. The suspension was cooled to room temperature and the solid was collected by filtration. The filter cake was washed with ACN (2 x 10 mL) and air dried to provide a fine white powder. HPLC: 98.7% AUC (1.3% single impurity) 4 NMR (DMSO-d6): conforms to structure; CAN has remaining. Crystal Structure of Compound 9 The diffraction data was obtained on a Bruker Apex II diffractometer equipped with a sealed tube Cu Κα source and an Apex η CCD detector. Analyze and refine the structure using the SHELX program (Sheldrick, GM, Acta Cryst (2008) A64, 112-122). Analyze the orthorhombic unit cell and the centrifugal P2PJ space group according to the system extinction and intensity statistics. And intensive structure. Using -0.005 (0.014) Flack absolute configuration factor to reliably determine the absolute configuration" measured values are extremely close to 〇 and have a small standard deviation ^ This means that the absolute configuration can be reliably determined. Unit _ has one molecule. There is a 一-shaped one-dimensional infinite chain, and the R 2,2(9) pattern is set for hydrogen bonding to form a substructure. There is no hydrogen bond between the chains, only van der Waals (van) Der Waals). When comparing the simulated pattern with the calculated pattern, it shows that the structure represents the batch of compounds. The structure is completely ordered and has a low R factor of 23.3%. We specify A for the structural quality. 153786.doc -91 · 201231467 Experiment 20 mg of compound 9 was dissolved in 1 mL of decyl alcohol, 4 mL of ethanol, seeded, and heated in a sealed vial at 80 ° C. Needle crystals were obtained overnight. Choose a size of 〇.3〇χ A colorless blade crystal of 10x0.05 mm3 was placed on the MicroMount and placed at the center of the Bruker APEX II diffractometer (VO 115 10). Three batches of 40 frames were separated in the inverted lattice space. To provide an orientation matrix and initial unit cell parameters, collect the final unit cell parameters and complete the refinement according to the full data set. Use a 0.5° step size to obtain a diffraction data set of the inverted lattice space with a resolution of 106° 2 , angle, where For low-angle frames, each frame has an exposure time of 10 seconds, and for high-angle frames, each frame has an exposure time of 60 seconds. Data is collected at 100 (2) K. Use APEXII software for intensity Integrate and refine the unit cell parameters. Collect powder X-ray diffraction data on a Bruker D8 Discover diffractometer with Cu Κα radiation and Highstar detector. The refinement structure is fully ordered. Use the ride model to refine Argon atom. Computational details data collection: Apex II; cell refinement: Apex II; data simplification: Apex II; program for splitting structures: SHELXS97 (Sheldrick, 1990); program for finishing structures: SHELXL97 ( Sh Eldrick, 1997); Molecular Graphics: Mercury; Software for the preparation of published materials: publCIF. Crystal Data 153786.doc -92- 201231467 Crystal Data C20Hj4ClFN6O Dx=1.340Mgm° Mr=418.90 CuKa Radiation, λ=1·54178 A Square crystal, P2A2 unit cell parameter from 5449 reflections a=15.0138(8)A 0=3.4-52.8° b=24.9923 (14) A μ=1.91 mm'1 c=5.5319(3) AT=100K V=2075.7 (2) A3 blade type, no έ Z=4 0.3〇x〇.l〇x〇.〇5 mm F(000)=880 Data collection

Bruker APEX-II CCD 繞射儀 2283個反射，其中Ι&gt;2σ(Ι) 輻射源：細聚焦密封管 Rint=0.030 石墨 emax=52.9°, 9min=3.4° ~ φ及ω掃描 h=-15—&gt;13 8508個量測反射 k=-25—25 &quot; ~ 2382個獨立反射 1=-5- 精修 F2精修 氫位點位置：自相鄰位點推f 最小二乘法矩陣：充分 藉由獨立精修與強制性精修之 組合來處理Η原子 R[F2&gt;2〇(F2)]=0.023 w=l/[a2(F02)+(〇〇336P)2+〇.3794P] 其中 PKFj+SF。2)/〗 wR(F2)=0.059 (Δ/σ)腿=0_004 S=1.04 A&gt;max=〇.12 e A'3 2382個反射 A&gt;min=-〇.ll e A'3 359個參數 消光校正：SHELXL，Fc*=kFc [l+O.OOlxFcV/sin(20)r1/4 0限制 消光係數：0.00037(14) 主要原子位點定位：結構不變 量直接方法 絕對結構：Flack H D (1983)， Acta Cryst. A39, 876-881 次要原子位點定位：差值傅裏 葉圖 ---- Flack參數：-0.005 (14) 153786.doc -93· 201231467 具體細節 幾何結構。使用全協方差矩陣來估計所有esd(兩個l.s.平 面間之雙面角中的esd除外）。在估計距離、角度及扭轉角 度之esd時，應單獨考慮晶胞esd ;晶胞參數esd間之關聯僅 用於該等關聯係由晶體對稱性界定時。使用晶胞esd之近 似（各向同性）處理來估計涉及1. s.平面之esd。 精修。針對所有反射來精修F2。加權R-因子wR及擬合S 優度係基於F2，習用R-因子R係基於F，其中負F2之F設定 為零。F2&gt;2o(F2)之閾值表徵僅用於計算R-因子（gt)等且與 用於精修之反射的選擇無關。基於F2之R-因子在統計學上 比彼等基於F者大約兩倍，且基於所有數據之R-因子甚至 更大。 表A.分級原子坐標及各向同性或等效各向同性位移參數 (A2) X y Z uiso*/ueq C11 1.04404 (4) 0.58029 (2) 0.34143 (10) 0.03616(19) F1 1.20454 (8) 0.66248 (5) 1.0451 (2) 0.0366 (3) 01 0.68641 (11) 0.57143 (6) 0.4801 (3) 0.0272 (4) N6 0.74240 (12) 0.67589 (7) 0.2358 (4) 0.0249 (5) N1 0.99956(11) 0.70617 (7) 0.7671 (3) 0.0247 (4) N2 1.14128(12) 0.75283 (7) 1.2551 (3) 0.0285 (5) N5 0.91316(11) 0.67077 (7) 0.4524 (3) 0.0237 (4) C1 1.07209(13) 0.70611 (9) 0.9140 (4) 0.0239 (5) C2 0.86382 (16) 0.72146 (9) 0.4486 (4) 0.0254 (5) C3 0.79085 (14) 0.62439 (9) 0.2451 (4) 0.0236 (5) N3 1.12675 (12) 0.79799 (8) 1.3849(4) 0.0282 (5) C4 0.98751 (13) 0.66811 (9) 0.6028 (4) 0.0233 (5) 153786.doc • 94· 201231467 C5 1.05189 (14) 0.62702 (8) 0.5716 (4) 0.0271 (5) C6 0.84970 (15) 0.62586 (9) 0.4687 (4) 0.0246 (5) Cl 0.72662 (13) 0.57558 (9) 0.2458 (4) 0.0256 (5) C8 1.07779 (13) 0.75034 (8) 1.0867(4) 0.0240 (5) N4 1.02367 (11) 0.87124 (7) 1.3936 (3) 0.0288 (5) C9 1.05411 (14) 0.82485 (9) 1.3027 (4) 0.0253 (5) CIO 0.78037 (15) 0.52250 (9) 0.2120 (4) 0.0272 (6) Cll 0.94497 (14) 0.81731 (9) 0.9897 (4) 0.0285 (6) C12 1.13329 (13) 0.66481 (9) 0.8951 (4) 0.0270 (5) C13 1.12472 (15) 0.62587 (10) 0.7230 (4) 0.0293 (6) C14 0.65471 (15) 0.58205 (11) 0.0558 (4) 0.0286 (5) C15 0.95206 (15) 0.88963 (9) 1.2770 (4) 0.0327 (6) C16 1.01947(13) 0.79594 (9) 1.1065 (4) 0.0247 (5) C17 0.80485 (15) 0.72167 (9) 0.2276 (4) 0.0269 (6) C18 0.72073 (19) 0.47349 (12) 0.2330 (7) 0.0439 (7) C19 0.91192(16) 0.86462 (9) 1.0796 (4) 0.0324 (6) C20 0.83300 (19) 0.52023 (12) -0.0247 (5) 0.0398 (7) HI 0.8284(13) 0.6202 (8) 0.108 (4) 0.014 (5)* H2 0.8286(13) 0.7276 (8) 0.603 (4) 0.021 (6)* H3 0.8822(12) 0.5928 (8) 0.486 (3) 0.010(5)* H4 0.6810(15) 0.5897 (9) -0.100(5) 0.035 (6)* H5 0.6204 (14) 0.5493 (9) 0.044 (4) 0.030 (6)* H6 0.7118(14) 0.6754 (9) 0.102 (4) 0.023 (6)* H7 0.7682(13) 0.7558 (8) 0.218(3) 0.014(5)* H8 0.9025 (14) 0.7517(9) 0.432 (4) 0.023 (6)* H9 0.8398 (14) 0.7190 (8) 0.080 (4) 0.017(5)* H10 0.8252(14) 0.5220 (7) 0.353 (4) 0.017(5)* Hll 0.6125(15) 0.6120 (9) 0.096 (4) 0.032 (6)* H12 0.8104(14) 0.6294 (8) 0.618(4) 0.022 (5)* H13 0.6865 (19) 0.4754 (10) 0.378 (5) 0.052 (8)* H14 1.1690(15) 0.5983 (9) 0.697 (4) 0.032 (6)* H15 0.684 (2) 0.4701 (12) 0.097 (6) 0.064 (9)* H16 0.9303 (14) 0.9226 ⑼ 1.342 (4) 0.033 (6)* 153786.doc •95- 201231467 H17 0.9200 (14) 0.8009 (8) 0.854 (4) 0.027 (6)* H18 0.882 (2) 0.5493 (13) -0.039 (6) 0.082 (10)* H19 0.8631 (15) 0.4848 (10) -0.038 (4) 0.033 (6)* H20 0.6366 (19) 0.5853 (12) 0.489 ⑹ 0.061 (10)* H24 0.7569(15) 0.4408 (10) 0.243 (4) 0.032 (6)* H22 0.8643 (15) 0.8801 (9) 1.003 (4) 0.034 (6)* H21 1.1660(19) 0.8064(11) 1.524 (5) 0.058 (8)* H23 0.7900 (17) 0.5223 (9) -0.164(5) 0.047 (7)* 表Β·原子位移參數（A2)Bruker APEX-II CCD diffractometer 2283 reflections, where Ι&gt;2σ(Ι) Radiation source: fine focus sealed tube Rint=0.030 Graphite emax=52.9°, 9min=3.4° ~ φ and ω scan h=-15—&gt ; 13 8508 measurement reflections k = -25 - 25 &quot; ~ 2382 independent reflections 1 = -5 - Refinement F2 refinement hydrogen position: Pushing from the adjacent sites f - Least squares matrix: Fully The combination of independent refinement and mandatory refinement to deal with helium atom R[F2>2〇(F2)]=0.023 w=l/[a2(F02)+(〇〇336P)2+〇.3794P] where PKFj+SF . 2)/〗 wR(F2)=0.059 (Δ/σ) Leg=0_004 S=1.04 A&gt;max=〇.12 e A'3 2382 reflection A&gt;min=-〇.ll e A'3 359 parameters Extinction correction: SHELXL, Fc*=kFc [l+O.OOlxFcV/sin(20)r1/4 0 limiting extinction coefficient: 0.00037(14) Primary atomic site localization: structural invariant direct method absolute structure: Flack HD (1983) ), Acta Cryst. A39, 876-881 Secondary Atomic Site Positioning: Difference Fourier Diagram---- Flack Parameters: -0.005 (14) 153786.doc -93· 201231467 Specific Detail Geometry. Use the full covariance matrix to estimate all esd (except for esd in the double-sided corner between the two l.s. planes). When estimating the esd of distance, angle and torsion angle, the unit cell esd should be considered separately; the correlation between the unit cell parameters esd is only used when the correlation is defined by crystal symmetry. The approximate (isotropic) processing of the unit cell esd is used to estimate the esd involving the 1. s. plane. refine. Refine F2 for all reflections. The weighted R-factor wR and the fitted S-goodness are based on F2, and the conventional R-factor R is based on F, where F of negative F2 is set to zero. The threshold characterization of F2 &gt; 2o (F2) is only used to calculate the R-factor (gt) and the like and is independent of the choice of reflection for refinement. The R-factor based on F2 is statistically approximately twice as large as those based on F, and the R-factor based on all data is even larger. Table A. Hierarchical atomic coordinates and isotropic or equivalent isotropic displacement parameters (A2) X y Z uiso*/ueq C11 1.04404 (4) 0.58029 (2) 0.34143 (10) 0.03616(19) F1 1.20454 (8) 0.66248 (5) 1.0451 (2) 0.0366 (3) 01 0.68641 (11) 0.57143 (6) 0.4801 (3) 0.0272 (4) N6 0.74240 (12) 0.67589 (7) 0.2358 (4) 0.0249 (5) N1 0.99956 (11 0.70617 (7) 0.7671 (3) 0.0247 (4) N2 1.14128(12) 0.75283 (7) 1.2551 (3) 0.0285 (5) N5 0.91316(11) 0.67077 (7) 0.4524 (3) 0.0237 (4) C1 1.07209( 13) 0.70611 (9) 0.9140 (4) 0.0239 (5) C2 0.86382 (16) 0.72146 (9) 0.4486 (4) 0.0254 (5) C3 0.79085 (14) 0.62439 (9) 0.2451 (4) 0.0236 (5) N3 1.12675 (12) 0.79799 (8) 1.3849(4) 0.0282 (5) C4 0.98751 (13) 0.66811 (9) 0.6028 (4) 0.0233 (5) 153786.doc • 94· 201231467 C5 1.05189 (14) 0.62702 (8) 0.5716 ( 4) 0.0271 (5) C6 0.84970 (15) 0.62586 (9) 0.4687 (4) 0.0246 (5) Cl 0.72662 (13) 0.57558 (9) 0.2458 (4) 0.0256 (5) C8 1.07779 (13) 0.75034 (8) 1.0867 (4) 0.0240 (5) N4 1.02367 (11) 0.87124 (7) 1.3936 (3) 0.0288 (5) C9 1.05411 (14 ) 0.82485 (9) 1.3027 (4) 0.0253 (5) CIO 0.78037 (15) 0.52250 (9) 0.2120 (4) 0.0272 (6) Cll 0.94497 (14) 0.81731 (9) 0.9897 (4) 0.0285 (6) C12 1.13329 ( 13) 0.66481 (9) 0.8951 (4) 0.0270 (5) C13 1.12472 (15) 0.62587 (10) 0.7230 (4) 0.0293 (6) C14 0.65471 (15) 0.58205 (11) 0.0558 (4) 0.0286 (5) C15 0.95206 (15) 0.88963 (9) 1.2770 (4) 0.0327 (6) C16 1.01947(13) 0.79594 (9) 1.1065 (4) 0.0247 (5) C17 0.80485 (15) 0.72167 (9) 0.2276 (4) 0.0269 (6) C18 0.72073 (19) 0.47349 (12) 0.2330 (7) 0.0439 (7) C19 0.91192(16) 0.86462 (9) 1.0796 (4) 0.0324 (6) C20 0.83300 (19) 0.52023 (12) -0.0247 (5) 0.0398 (7) ) HI 0.8284(13) 0.6202 (8) 0.108 (4) 0.014 (5)* H2 0.8286(13) 0.7276 (8) 0.603 (4) 0.021 (6)* H3 0.8822(12) 0.5928 (8) 0.486 (3) 0.010(5)* H4 0.6810(15) 0.5897 (9) -0.100(5) 0.035 (6)* H5 0.6204 (14) 0.5493 (9) 0.044 (4) 0.030 (6)* H6 0.7118(14) 0.6754 (9 ) 0.102 (4) 0.023 (6)* H7 0.7682(13) 0.7558 (8) 0.218(3) 0.014(5)* H8 0.9025 (14) 0.7517(9) 0.432 (4) 0.023 (6)* H9 0.8398 (14 ) 0.7190 (8) 0.080 (4) 0.017(5)* H10 0.8252(14) 0.5220 (7) 0.353 (4) 0.017(5)* Hll 0.6125(15) 0.6120 (9) 0.096 (4) 0.032 (6)* H12 0.8104(14) 0.6294 (8) 0.618(4) 0.022 (5)* H13 0.6865 (19) 0.4754 (10) 0.378 (5) 0.052 (8)* H14 1.1690(15) 0.5983 (9) 0.697 (4) 0.032 ( 6)* H15 0.684 (2) 0.4701 (12) 0.097 (6) 0.064 (9)* H16 0.9303 (14) 0.9226 (9) 1.342 (4) 0.033 (6)* 153786.doc •95- 201231467 H17 0.9200 (14) 0.8009 (8) 0.854 (4) 0.027 (6)* H18 0.882 (2) 0.5493 (13) -0.039 (6) 0.082 (10)* H19 0.8631 (15) 0.4848 (10) -0.038 (4) 0.033 (6)* H20 0.6366 (19) 0.5853 (12) 0.489 (6) 0.061 (10)* H24 0.7569(15) 0.4408 (10) 0.243 (4) 0.032 (6)* H22 0.8643 (15) 0.8801 (9) 1.003 (4) 0.034 (6) ) * H21 1.1660(19) 0.8064(11) 1.524 (5) 0.058 (8)* H23 0.7900 (17) 0.5223 (9) -0.164(5) 0.047 (7)* Table Β·Atomic displacement parameter (A2)

Un u22 U33 U12 u13 u23 C11 0.0319(3) 0.0383 (3) 0.0383 (3) 0.0041 (3) 0.0019(3) -0.0099 (3) F1 0.0253 (7) 0.0380 (8) 0.0465 (8) 0.0030 (6) -0.0099 (6) -0.0001 (7) 01 0.0256 (9) 0.0357(10) 0.0202 (8) 0.0003 (8) 0.0018(7) 0.0010 (7) N6 0.0251 (11) 0.0279 (12) 0.0216(11) 0.0006 (9) -0.0032 (9) 0.0011 (9) N1 0.0217(10) 0.0266(11) 0.0256(10) -0.0037 (8) 0.0005 (9) 0.0018(9) N2 0.0254(11) 0.0312(11) 0.0290(11) -0.0024 (8) -0.0017(9) 0.0020(10) N5 0.0228 (10) 0.0239(10) 0.0244 (9) 0.0001 (8) -0.0006 (8) 0.0010(8) Cl 0.0201 (12) 0.0271 (13) 0.0244 (12) -0.0027 (9) 0.0001 (10) 0.0042(11) C2 0.0254(13) 0.0249 (14) 0.0258 (14) -0.0002(11) 0.0006(11) 0.0011 (11) C3 0.0253 (12) 0.0298 (14) 0.0156(12) 0.0053 (10) 0.0034(11) 0.0014(10) N3 0.0255 (11) 0.0323 (11) 0.0268 (11) -0.0009 (9) -0.0031 (9) -0.0005 (10) C4 0.0198(12) 0.0273 (12) 0.0226 (12) -0.0028 (10) 0.0027 (10) 0.0047(11) C5 0.0244 (12) 0.0263 (12) 0.0305 (13) -0.0013 (10) 0.0039 (11) 0.0008 (10) C6 0.0242 (13) 0.0255 (14) 0.0240(13) 0.0013 (10) -0.0003 (11) 0.0017(11) C7 0.0259 (12) 0.0297 (13) 0.0214(12) 0.0014(10) 0.0014(9) -0.0016(10) C8 0.0187(12) 0.0292 (13) 0.0239 (13) -0.0043 (10) -0.0004(10) 0.0050(10) N4 0.0225 (11) 0.0351 (12) 0.0288 (10) -0.0035 (9) 0.0044 (8) -0.0029 (9) C9 0.0219(12) 0.0301 (13) 0.0240 (12) -0.0043 (11) 0.0036(11) 0.0032(11) CIO 0.0254(13) 0.0306 (14) 0.0257 (13) 0.0008 (10) -0.0045 (11) -0.0015(11) Cll 0.0237(13) 0.0323 (14) 0.0296 (13) -0.0060(11) -0.0028 (12) 0.0009(11) C12 0.0189(12) 0.0321 (14) 0.0300(13) -0.0038(11) -0.0062(11) 0.0047 (12) C13 0.0234(13) 0.0290 (14) 0.0354(14) 0.0025 (11) 0.0031 (12) 0.0039 (12) 153786.doc -96- 201231467 C14 0.0265 (13) 0.0340(15) 0.0252 (14) 0.0008(13) -0.0043 (11) -0.0036 (12) C15 0.0279 (14) 0.0305 (15) 0.0397(15) 0.0003 (12) 0.0052(13) -0.0042 (12) C16 0.0196(13) 0.0291 (13) 0.0254 (12) -0.0047(10) 0.0019(10) 0.0028(11) C17 0.0275 (14) 0.0287(15) 0.0244 (14) 0.0036(11) 0.0025 (12) 0.0041 (11) C18 0.0374 (17) 0.0312(17) 0.063 (2) 0.0016(13) -0.0040 (17) -0.0067(15) C19 0.0235 (13) 0.0330(15) 0.0408 (15) 0.0017(11) -0.0040 (12) 0.0010(12) C20 0.0493 (17) 0.0403 (18) 0.0299(15) 0.0156(14) 0.0038 (14) -0.0062(13) 表c.幾何參數（A，°)Un u22 U33 U12 u13 u23 C11 0.0319(3) 0.0383 (3) 0.0383 (3) 0.0041 (3) 0.0019(3) -0.0099 (3) F1 0.0253 (7) 0.0380 (8) 0.0465 (8) 0.0030 (6) - 0.009 (6) -0.0001 (7) 01 0.0256 (9) 0.0357(10) 0.0202 (8) 0.0003 (8) 0.0018(7) 0.0010 (7) N6 0.0251 (11) 0.0279 (12) 0.0216(11) 0.0006 (9) ) -0.0032 (9) 0.0011 (9) N1 0.0217(10) 0.0266(11) 0.0256(10) -0.0037 (8) 0.0005 (9) 0.0018(9) N2 0.0254(11) 0.0312(11) 0.0290(11) - 0.0024 (8) -0.0017(9) 0.0020(10) N5 0.0228 (10) 0.0239(10) 0.0244 (9) 0.0001 (8) -0.0006 (8) 0.0010(8) Cl 0.0201 (12) 0.0271 (13) 0.0244 ( 12) -0.0027 (9) 0.0001 (10) 0.0042(11) C2 0.0254(13) 0.0249 (14) 0.0258 (14) -0.0002(11) 0.0006(11) 0.0011 (11) C3 0.0253 (12) 0.0298 (14) 0.0156(12) 0.0053 (10) 0.0034(11) 0.0014(10) N3 0.0255 (11) 0.0323 (11) 0.0268 (11) -0.0009 (9) -0.0031 (9) -0.0005 (10) C4 0.0198(12) 0.0273 (12) 0.0226 (12) -0.0028 (10) 0.0027 (10) 0.0047(11) C5 0.0244 (12) 0.0263 (12) 0.0305 (13) -0.0013 (10) 0.0039 (11) 0.0008 (10) C6 0.0242 (13) ) 0.0255 (14) 0. 0240(13) 0.0013 (10) -0.0003 (11) 0.0017(11) C7 0.0259 (12) 0.0297 (13) 0.0214(12) 0.0014(10) 0.0014(9) -0.0016(10) C8 0.0187(12) 0.0292 ( 13) 0.0239 (13) -0.0043 (10) -0.0004(10) 0.0050(10) N4 0.0225 (11) 0.0351 (12) 0.0288 (10) -0.0035 (9) 0.0044 (8) -0.0029 (9) C9 0.0219( 12) 0.0301 (13) 0.0240 (12) -0.0043 (11) 0.0036(11) 0.0032(11) CIO 0.0254(13) 0.0306 (14) 0.0257 (13) 0.0008 (10) -0.0045 (11) -0.0015(11) Cll 0.0237(13) 0.0323 (14) 0.0296 (13) -0.0060(11) -0.0028 (12) 0.0009(11) C12 0.0189(12) 0.0321 (14) 0.0300(13) -0.0038(11) -0.0062(11) 0.0047 (12) C13 0.0234(13) 0.0290 (14) 0.0354(14) 0.0025 (11) 0.0031 (12) 0.0039 (12) 153786.doc -96- 201231467 C14 0.0265 (13) 0.0340(15) 0.0252 (14) 0.0008 (13) -0.0043 (11) -0.0036 (12) C15 0.0279 (14) 0.0305 (15) 0.0397(15) 0.0003 (12) 0.0052(13) -0.0042 (12) C16 0.0196(13) 0.0291 (13) 0.0254 ( 12) -0.0047(10) 0.0019(10) 0.0028(11) C17 0.0275 (14) 0.0287(15) 0.0244 (14) 0.0036(11) 0.0025 (12) 0.0041 (11) C18 0.0374 (17) 0.0312(17) 0 .063 (2) 0.0016(13) -0.0040 (17) -0.0067(15) C19 0.0235 (13) 0.0330(15) 0.0408 (15) 0.0017(11) -0.0040 (12) 0.0010(12) C20 0.0493 (17) 0.0403 (18) 0.0299(15) 0.0156(14) 0.0038 (14) -0.0062(13) Table c. Geometric parameters (A, °)

Cll—C5 1.732 (2) C3—C7 1.555 (3) FI—C12 1.355 (2) N3—C9 1.359 (3) 01—C7 1.434 (2) C4—C5 1.421 (3) N6—C3 1.479 (3) C5—C13 1.377 (3) N6—C17 1.480(3) C7—C14 1.515 (3) Nl—C4 1.328 (3) C7—C10 1.564 (3) Nl—Cl 1.359 (3) C8—C16 1.441 (3) N2—C8 1.334(3) N4—C15 1.335 (3) N2—N3 1.355 (3) N4—C9 1.344(3) N5—C4 1.394(3) C9—C16 1.404(3) N5—C2 1.468 (3) CIO—C18 1.522 (3) N5—C6 1.475 (3) CIO—C20 1.530 (3) Cl—C12 1.386 (3) Cll—C19 1.375 (3) Cl—C8 1.463 (3) Cll—C16 1.398 (3) C2—C17 1.509 (3) C12—C13 1.368 (3) C3—C6 1.520 (3) C15—C19 1.395 (3) C3—N6—C17 111.23(17) 01—C7—CIO 105.31 (17) C4—Nl—Cl 121.17(17) C14—C7—CIO 112.04(18) C8—N2—N3 107.09(17) C3—C7—CIO 110.19(17) C4—N5—C2 116.98(17) N2—C8—C16 110.11 (18) C4—N5—C6 116.39(16) N2—C8—Cl 122.21 (18) C2—N5—C6 109.38(17) C16—C8—Cl 127.68(18) Nl—Cl—C12 119.15(19) C15—N4—C9 112.96(19) 153786.doc •97- 201231467 N1—Cl—C8 115.88(18) N4—C9—N3 125.0 (2) C12—Cl—C8 124.96 (19) N4—C9—C16 127.4 (2) N5—C2—C17 108.08(18) N3—C9—C16 107.57(19) N6—C3—C6 107.03 (18) C18—CIO—C20 109.8 (2) N6—C3—C7 112.19(17) C18—CIO—C7 111.72(19) C6—C3—C7 112.17(17) C20—CIO—C7 113.59(19) N2—N3—C9 111.29(18) C19—Cll—C16 116.7(2) N1—C4—N5 118.91 (18) FI—C12—C13 118.04(19) N1—C4—C5 120.54(18) FI—C12—Cl 120.60 (19) N5—C4—C5 120.45 (18) C13—C12—Cl 121.3 (2) C13—C5—C4 118.8(2) C12—C13—C5 118.9(2) C13—C5—C11 119.12(17) N4—C15—C19 124.9 (2) C4—C5—C11 122.03 (16) Cll—C16—C9 117.2 (2) N5—C6—C3 110.12(18) Cll—Cl 6—C8 138.8 (2) 01—C7—C14 109.56(17) C9—C16—C8 103.93 (18) 01—C7—C3 108.67(16) N6—C17—C2 110.14(18) C14—C7—C3 110.88(18) Cll—C19—C15 120.8 (2) 一般而言，可根據與實例1、2及3、化合物2-8、10-35 及37-45中所述相似之途徑來合成下列化合物。 相似方法闡述於2009年7月22日提出申請且標題為「TRICYCLIC PYRAZOLOPYRIDINE KINASE INHIBITORS」 之 PCT 申請案第PCT/US2009/051437號中，其全部内容以引用方 式併入本文中。 表2展示通常藉由與上述實例中所述相似之途徑製得之 某些實例性化合物的數據。 153786.doc • 98 · 201231467 表2 編號 M+l (obs) RT (min) ^-NMR 1 403 7.47 1H NMR (400 MHz, DMSO) d 13.99 (s, 1H), 8.77 (dd, J=8.1} 1.4 Hz, 1H), 8.60 (dd, J=4.4,1.5 Hz, 1H), 7.92 (dd, J=12.1, 9.8 Hz, 1H), 7.30 (dd, J=8.1,4.5 Hz, 1H), 4.14 (s, 1H), 4.04 (d, J=7.9 Hz, 1H), 3.77 (d, J=8.6 Hz, 1H), 3.09 (d, J=8.9 Hz, 1H), 2.84 (d, J=9.1 Hz, 2H), 2.74 (d, J=7.4 Hz, 2H), 1.81 (dt, J=13.5,6.8 Hz, 2H), 1.05 (s, 3H), 0.87 (dd, J=23.8,6.7 Hz, 6H) 〇 2 401.2 2.36 1H (DMSO) d 0.15 (d, 1H), 0.20 (d, 1H), 0.89 (s, 3H), 0.96 (s, 3H), 1.53 (bs, 1H, NH), 2.24-2.31 (m, 1H), 2.64-2.72 (m, 2H), 2.79 (t, 1H), 2.91 (d, 1H), 3.58-3.63 (m, 2H), 4.70 (s, 1H, OH), 7.10 (dd, 1H), 7.72 (dd, 1H), 8.40 (dd, 1H), 8.55 (1H, dd), 13.80 (bs, lH),NH)ppm 3 403 7.67 4 401 7.42 5 401 7.52 6 389 7.17 1HNMR (CD30D) 1.05 (3H, t), 1.28-1.32 (4H, m), 1.60-1.85 (2H, m), 2.98 (3H, m), 3.10-3.15 (2H, m), 4.05-4.10 (1H, m), 4.30-4.35 (1H, m), 7.40-7.45 (lH,dd), 7.70-7.80 (1H, dd), 8.70 (1H, d), 9.00 (1H, d). 7 389 1.68 (CD30D) 1.01 (6H, d), 1.25-1.35 (1H, m), 1.85-1.95 (1H, m), 1.85-1.90 (1H, m), 2.95-3.10 (2H, m), 3.20 (1H, M), 3.70 (1H, s), 3.92-3.97 (1H, m), 4.20-4.25 (1H, d), 7.33-7.36 (1H, dd), 7.59-7.64 (1H, m), 8.57-8.59 (1H, d), 8.87-8.89 (1H, d). 8 375 6.91 DMSO-d6 0.89-0.93 (3H, m), 1.3-1.4 (1H, m), 1.55-1.60 (1H, m), 2.65-2.70 (2H, m) 2.80-3.00 (2H, m), 3.02-3.07 (1H, m), 3.25-3.30 (1H, m), 3.50 (1H, s), 3.75-3.80 (1H, m), 4.03-4.08 (1H, m), 4.59-4.61 (1H, m), 7.29-7.32 (1H, d), 7.90-7.95 (1H, dd), 8.59-8.60 (1H, d), 8.76-8.79 (1H, d), 13.95-13.90 (1H, s). 9 419 8.27 (CD30D) 0.97-1.03 (6H, dd), 1.21 (3H, s), 1.93-1.94 (1H, m), 2.80-2.86 (1H, t), 3.00-3.08 (2H, m), 3.22-3.25 (1H, m), 3.71-3.75 (1H, d), 3.99-4.03 (1H, d), 7.32-7.35 (1H, d), 7.83-7.86 (1H, d), 8.58-8.59 (1H, d), 8.90-8.92 (1H, d). 10 (DMSO, 400MHz) 0.83 (3H, s), 0.94 (3H, s), 1.09 (3H, s), 1.87 (1H, sept), 3.15-3.50 (5H, m), 4.18 (1H, d), 4.38 (1H, d), 7.37 (1H, dd), 8.46 (1H, d), 8.66 (1H, dd), 8.71 (1H, d), 14.40 (lH,brs). 153786.doc -99_ 201231467 編號 M+l (obs) RT (min) ^-NMR 11 421.2 2.35 1H (DMSO) d 1.24 (d, 3H), 1.36 (d, 3H), 1.42 (d, 3H), 2.59-2.67 (m, 1H), 2.88-2.93 (m, 2H), 2.98 (dd, 1H), 3.14 (d, 1H), 3.78 (d, 1H), 4.09 (d, 1H), 4.86 (s, 1H, OH), 7.25 (dd, 1H), 7.92 (dd, 1H), 8.58 (dd, 1H), 8.74 (dd, 1H), 13.99 (bs, 1H, NH) ppm 12 421.2 2.31 1H (DMSO) d 1.21 (s, 3H), 1.40 (t, 6H), 1.97 (bs, 1H, NH), 2.75-2.95 (m, 4H), 3.06 (d, 1H), 3.76 (d, 1H), 4.16 (d, 1H), 4.77 (s, 1H, OH), 7.30 (dd, 1H), 7.92 (dd, 1H), 8.59 (dd, 1H), 8.82 (dd, 1H), 13.97 (bs, 1H, NH) ppm 13 429 0.77 (d6-DMSO, 400 MHz) 1.49 (3H, s), 3.15-3.20 (1H, m), 3.21-3.45 (3H, m), 3.78 (1H, brs), 4.11 (1H, d), 4.19 (1H, d), 7.30 (1H, dd), 7.45 (brs), 8.08 (1H, dd), 8.62-8.64 (2H, m), 8.92 (1H, brs), 9.09 (1H, brs), 14.09 (1H, brs) 14 429 0.73 (d6-DMSO, 400 MHz) 1.49 (3H, s), 3.18 (1H, t), 3.27-3.33 (1H, m), 3.37-3.45 (2H, m), 3.79 (1H, t), 4.11 (1H, d), 4.19 (1H, d), 7.29 (1H, dd), 7.44 (1H, s), 8.09 (1H, dd), 8.62 (2H, m), 8.91 (1H, brs), 9.05 (1H, brs), 14.09 (1H, brs) 15 443 8.35 1HNMR(CD30D) 1.30 (3H, s), 2.30-2.60 (1H, m), 2.65-2.80 (1H, m), 2.85-2.95 (2H, m), 3.00-3.10 (1H, m), 3.80-3.85 (1H, m), 4.05-4.10 (1H, m), 7.25 (1H, d), 7.50-7.55 (1H, m), 8.46-8.48 (1H, d), 8.73-8.76 (1H, d). 16 405 6.97 1HNMR(CD30D) 1.32 (3H, s), 3.20-3.25 (lHt), 3.30-3.45(5H，隱蔽)，3.63-3.67 (1H，m), 4.21-4.25 (1H，m)， 4.35-4.39 (1H, m), 7.32-7.35 (1H, dd), 7.71-7.76 (1H, dd), 8.60-8.62 (1H, d), 8.74-8.76 (1H, d). 17 405 6.89 H NMR (400.0 MHz, DMSO) d 13.99 (s, 1H, NH), 8.79 (dd, J=1.4, 8.1 Hz, 1H), 8.60 (dd, J=1.5, 4.5 Hz, 1H), 7.93 (dd, ]=9.9, 12.0 Hz, 1H), 7.30 (dd, J=4.5, 8.1 Hz, 1H), 3.98-3.92 (m, 1H), 3.80-3.77 (m, 1H), 3.77 (s, 1H, OH), 3.38-3.32 (m, 1H), 3.27-3.24 (m, 4H), 3.08 (d, 1H), 2.87-2.67 (m, 4H), 2.15 (bs，1H, NH)及 1.16 (s，3H) ppm 18 391 7.44 19 391 7.48 H NMR (400.0 MHz，DMSO) d 0.92 (t，3H), 1.34(七重峰， 1H), 1.56-1.65 (m, 1H), 2.61 (t, 1H), 2.67-2.72 (m, 1H), 2.82-2.92 (m，2H)，3.03-3.06 (m, 1H), 3.26-3.34 (隱蔽信號，1H)， 3.58 (d, 1H), 3.87 (d, 1H), 4.56 (d, 1H), 7.34 (dd, 1H), 8.11 (d, 1H)，8.61 (dd，1H), 8_81 (dd，1H)及 14.10 (brs，1H) ppm 20 405 1.05 1H (DMSO-d6) 0.89-0.96 (6H, dd), 1.85-1.90 (1H, m), 2.60-2.65 (1H, m), 2.78-2.82 (1H, m), 2.88-2.93 (1H, m), 3.10-3.15 (1H, m), 3.20 (1H, m), 3.65-3.67 (1H, m), 3.92-3.95 (1H, m), 4.54-4.54 (1H, m), 7.40-7.43 (1H, m), 8.14-8.16 (1H, d), 8.70 (1H, s), 8.75 (1H, d), 153786.doc -100- 201231467 編號 M+l (obs) RT (min) ^-NMR 21 405 1.06 1H (DMSO-d6) 0.91-0.95 (6H, m), 1.80-1.85 (1H, m), 2.70-2.75 (1H, m), 2.85-3.00 (2H, m), 3.10-3.20 (2H, m),3.65-3.67 (2H, m), 4.65-4.68 (1H, m), 7.37-7.40 (1H, m), 8.15-8.18 (1H, d), 8.64-8.66 (1H, d), 8.81 (1H, d), 14.1-1.2 (1H, br s) 22 373 2.42 (d6-DMSO, 400 MHz) 0.99 (3H, d), 1.06 (3H, d), 1.75-1.80 (1H, m), 1.93-1.96 (1H, m), 2.16-2.21 (1H, m), 3.07-3.17 (2H, m), 3.43 (1H, t), 3.62-3.66 (1H, m), 3.83 (2H, brs), 7.28 (1H, dd), 7.81-7.88 (4H, m), 8.59 (1H, dd), 8.76 (1H, d), 13.96 (1H, brs) 23 389.17 2.54 HNMR (400.0 MHz, DMSO) d 0.99 (d,3H), 1.06 (d, 3H), 1.71-1.79 (m, 1H), 1.91-1.99 (m, 1H), 2.20 (qn, 1H), 3.13-3.20 (m, 1H), 3.59 (t, 2H), 3.73-3.85 (m, 3H), 7.29 (dd, 1H), 7.89 (br s, ΝΉ3+, 3H), 7.99 (d, 1H), 8.60 (dd, 1H), 8.76 (dd, lH)&amp;14.07(s，lH)ppm 24 389.17 2.6 H NMR (400.0 MHz, DMSO) d 0.96 (d, 3H), 1.06 (d, 3H), 1.79 (五重峰，1H)，2.01-2.15 (m, 2H), 3.14 (br m, 1H)，3.20-3.60(隱蔽信號，1H)，3.63 (t，1H)，3.71 (t，1H)，3.79-3.86 (m， 2H), 7.32 (dd, 1H), 7.83 (s, NH3+, 3H), 8.00 (d, 1H), 8.61 (dd, 1H)，8.76 (dd，1H)及 14.07 (s，1H) ppm 25 375.2 2.28 1H NMR (400.0 MHz, DMSO) d 14.00 (bs, 1H, NH), 8.73 (dd，J=1.5, 8.1 Hz，1H), 8.60 (dd，J=1.5, 4.5 Hz，1H), 7.93 (dd， J=9.9,12.1 Hz, 1H), 7.30 (dd, J=4.5, 8.1 Hz, 1H), 4.67 (d, J=5.6 Hz, 1H), 3.82-3.74 (m, 2H), 3.35-3.30 (m, 2H), 3.09-3.03 (m, 1H), 2.98-2.91 (m, 1H), 2.86-2.80 (m, 1H), 2.73-2.68 (m, 2H), 2.33-2.28 (bs, ΙΗ,ΝΗ), 1.57-1.53 (m, 1H), 1.38-1.34 (m, 1H)及0.92 (t, J=7.4 Hz, 3H) ppm 26 419 8.69 lHNMR(dmso-d6) 0.98 (9H, s), 2.80-3.00 (4H, m), 3.10-3.25 (2H, m), 3.60-3.64 (1H, m), 3.82-3.85 (1H, m), 7.34-7.38 (1H, dd), 8.13-8.16 (1H, d), 8.64-8.66 (1H, dd), 8.85-8.88 (1H, dd)., 27 403 8.23 1HNMR(CD30D) 1.01 (9H, s), 2.95-3.20 (56H, m), 3.90-3.95 (1H, d), 4.10-.4-15 (1H, d), 7.29-7.32 (1H, d), 7.59 (1H, dd), 8.55-8.57 (1H, d), 8.83-8.84 (1H, d) 28 373.18 2.44 HNMR(400.0 MHz, DMSO) d 0.87 (d, 3H), 0.95 (d, 3H), 1.58-1.60 (m, 1H), 1.69-1.76 (m, 1H), 2.13-2.28 (m, 2H), 2.46 (dd，1H)，3.32-3.36(隱蔽信號，1均,3.57-3.64(111，111)，3.70-3.80 (m，2H)，7.29 (dd，1H)，7.79 (dd, 1H)，8.57 (dd, 1H)及 8.75 (dd, 1H) ppm 153786.doc -101 - 201231467 編號 M+l (obs) RT (min) !h-nmr 29 387 1.77 1H NMR(dmso) 0.28-.029 (2H, s), 0.35-0.37 (1H, m), 0.39-0.40 (1H, m), 0.97-0.99 (1H, m), 2.80-2.95 (5H, m), 3.06-3.09 (1H, m), 3.77-3.79 (1H, m), 4.04-4.0 (1H, m), 4.72 (1H, s), 7.28-7.31 (1H, d), 7.90-7.96 (1H, dd), 8.59-8.60 (1H, d), 8.78-8.80 (1H, m), 13.90-1.40 (1H, s). 30 417 0.64 (d6-DMSO, 400 MHz) 0.26-0.30 (3H, m), 0.45-0.48 (1H, m), 0.93-1.03 (1H, m), 1.11 (3H, s), 2.75-2.93 (3H, m), 3.12 (1H, d), 3.63 (1H, d), 3.92 (1H, d)5 4.10 (1H, brs), 7.32 (1H, dd), 8.13 (1H, d), 8.62 (1H, dd), 8.85 (1H, dd), 14.10 (1H, brs) 31 403 1.91 lHNMR(DMSO-d6) 0.0-0.05 (2H, m), 0.07-0.10 (1H, m), 0.20-0.25 (1H, m), 0.70-0.80 (2H, m), 2.50-2.70 (4H, m), 2.82-2.90 (1H, m), 3.30-3.40 (1H, m), 3.60-3.65 (1H, m), 7.07-7.10 (1H, d), 7.85-7.88 (1H, m), 8.36-8.37 (1H, d), 8.57-8.59 (1H, d). 32 401 0.51 (d6-DMSO, 400 MHz) 0.84 (3H, d), 0.94 (3H, d), 1.09 (2H, s), 1.76-1.88 (1H, m), 2.89 (1H, t), 3.13-3.20 (1H, m), 3.27-3.39 (3H, m), 4.08 (1H, d), 4.33 (1H, d), 5.20 (1H, brs), 7.17 (1H, d), 7.26 (1H, dd), 8.33-8.40 (1H, m), 8.55-8.59 (2H, m), 8.66 (1H, dd), 11.00 (1H, brs), 13.83 (1H, brs) 33 421.1 2.35 H NMR (400.0 MHz, DMSO) d 14.10 (bs, 1H, NH), 8.83 (dd, J=1.6, 8.1 Hz, 1H), 8.62 (dd, J=1.5,4.5 Hz, 1H), 8.12 (d, J=9.8 Hz, 1H), 7.33 (dd, J=4.5, 8.1 Hz, 1H), 4.57 (s, 1H), 3.77 (d, J=11.3 Hz, 1H), 3.61 (d, J=9.0 Hz, 1H), 3.35 (d, J=11.0 Hz, 1H), 3.28-3.23 (m, 4H), 3.11-3.08 (m, 1H), 2.86-2.79 (m, 3H), 2.73-2.67 (m，1H), 2_12 (bs，1H，NH)及 1.16 (s，3H) ppm 34 410 0.98 H NMR (400.0 MHz, DMSO) d 14.28 (s, 1H), 8.80-8.57 (m, 3H), 8.28 (d, 1H), 7.35 (dd, J=4.5, 8.1 Hz, 1H), 4.81-4.37 (m, 2H), 3.57-3.21 (m, 5H), 1.96-1.81 (m, 1H), 1.06 (d, J=4.9 Hz, 3H)，0.93 (d, J=6.6 Hz，3H)及0.67 (d，J=6.8 Hz，3H) ppm 35 410 0.98 H NMR (400.0 MHz, DMSO) d 14.28 (s, 1H), 8.85-8.53 (m, 4H), 8.28 (s, 1H), 7.34 (dd, J=4.5, 8.1 Hz, 1H), 4.70-4.47 (m, 2H), 3.56-3.21 (m，5H)，1.14 (s, 3H)及0.88-0.79 (m，6H) ppm 36 380 0.59 H NMR (400.0 MHz, DMSO) d 14.19 (s, 1H), 8.72 (dd, J=1.3, 8.1 Hz, 1H), 8.62 (dd, J=1.5, 4.5 Hz, 1H), 8.03 (s, 1H), 7.88 (d, J=3.0 Hz, 3H), 7.32 (dd, J=4.5, 8.1 Hz, 1H), 4.05-4.00 (m, 2H), 3.75-3.11 (m, 3H), 2.60-2.50 (m, 1H), 2.26-2.18 (m, 1H), 2.01-1.74 (m，2H)，1.06 (d，J=6_9 Hz, 3H)及 1.00 (d，J=7.0 Hz, 3H) ppm 153786.doc -102- 201231467 編號 M+1 (obs) RT (min) !h-nmr 37 380 0.59 HNMR(400.0 MHz, DMSO) d 14.31 (s, 1H), 8.79 (d, 1H), 8.65 (m, 1H), 8.25 (d, 1H), 7.85 (brs, 3H), 7.35 (dd, 1H), 4.04-3.94 (m, 2H), 3.82-3.71 (m, 1H), 3.62-3.15 (m, 2H), 2.71-2.44 (m，1H)，2.29-2.18 (m，1H), 2.01-1.75 (m, 2H), 1.08 (d，3H)及 1.01 (d, 3H) ppm 38 419 0.67 (d6-DMSO, 400 MHz) 0.91 (6H, dd), 1.07 (3H, s), 1.91-1.98 (1H, m), 2.63-2.71 (1H, m), 2.88-2.93 (2H, m), 3.18 (1H, d), 3.63 (1H, d), 3.78 (1H, d), 4.13 (1H, s), 7.37 (1H, dd), 8.15 (1H, d), 8.65 (1H, dd), 8.83 (1H, d), 14.12 (1H, brs) 39 419 1.77 40 419 2 41 419 2.05 42 435 2.54 43 (DMSO, 400MHz) 0.77 (3H, d), 0.89 (3H, d), 1.05 (3H, s), 1.83 (1H, sept), 2.70-3.20 (5H, m), 4.31 (1H, d), 4.65 (1H, d), 7.34 (1H, dd), 8.11 (1H, d), 8.63 (1H, d), 8.70 (1H, d), 14.22 (1H, br s). 44 415.2 2.05 H NMR (400.0 MHz, DMSO) d 14.01 (bs, 1H, NH), 8.82 (d, 1H), 8.60 (dd, 1H), 7.79 (d, 1H), 7.30 (d, 1H), 5.54 (t, 1H), 4.60-4.50 (m, 2H), 4.28 (bs, 1H), 3.48-3.36 (m, 2H), 3.18-3.13 (m, 1H), 2.98-2.89 (m, 2H), 2.73-2.66 (m, 1H), 1.83-1.76 (m, 1H)，1.06 (s，3H), 0.91 (d，3H)及0.85 (d，3H) ppm 45 435 2.23 一般而言，本發明化合物（包含表1中之化合物）可有效 抑制piece。測試本發明化合物抑制ρκχθ之選擇性，且結 果示於下列實例中。所獲得數據藉由展示關於ρκχθ、 PKCa及PKCa之Ki功效來展示關於ΡΚΧΘ亞型選擇性的值。 實例4 PKC0 製備分析緩衝液，其係由100 mM HEPES (pH 7.5)、10 mM MgCl2、25 mM Na(M、0.1 mM EDTA 及 0.01% Brij 組 成。在分析缓衝液中製備含有下列最終分析濃度試劑之酶 153786.doc -103 - 201231467 緩衝液：0.00001% Triton X-100、200 pg/mL構脂酿絲胺 酸、20 pg/mL二醯甘油、360 μΜ NADH、3 mM填酸婦醇 丙酿I酸、70 pg/mL丙酮酸激酶、24 pg/mL乳酸脫氫酶、2 mM DTT、100 μΜ受質肽（ERMRPRKRQGSVRRRV SEQ ID NO. 1)及18 nM PKC0激酶。向存於384孔板中之60 μί此酶 緩衝液中添加2 μί存於DMSO中之VRT儲備溶液。將混合 物在30°C下平衡1〇 min。藉由添加5 μι在分析緩衝液中製 得之儲備ATP溶液直至最終分析濃度為240 μΜ來引發酶反 應。在30°C下，自340 ηΜ下吸光度之改變率（對應於NADH 之化學計量消耗）使用Molecular Devices Spectramax板讀數 儀（Sunnyvale，CA)經15 min來測定初始速率數據。對於每 次Ki測定，一式兩份獲得涵蓋〇-20 μΜ之VRT濃度範圍之 12個數據點（自初始1 〇 mM VRT儲備液、隨後進行1:2連續 稀釋來製備DMSO儲備液）。藉由非線性回歸使用Prism軟 體包（Prism 4.0a，Graphpad Software, San Diego, CA)自初 始速率數據來計算Ki值。Ki值表示為A*&lt;0.001 μΜ ’ A**&lt;0.01 μΜ，A&lt;〇 〇5 μΜ，Β&lt;0·5 μΜ，Β*&gt;0.7 μΜ， C*&gt;1.25 μΜ，C**&gt;2.0 μΜ，C&lt;2_8 μΜ，D&gt;2.8 μΜ，D*&gt;4 μΜ ο Α化合物係：10、16-18、21-22、24-25、33-34、37-39及 43 ° A*化合物係：1、2、3-9、11-15、19-20、23、26-32、40-42、及44。 B化合物係：35、36及45。 153786.doc -104- 201231467 PKCa 製備分析緩衝液，其係由100 mM HEPES (pH 7.5)、10 mM MgCh、25 mM NaCl、0.1 mM EDTA及 0.01% Brij組 成。在分析緩衝液中製備含有下列最終分析濃度試劑之酶 緩衝液：0.002% Triton X-100、200 pg/mL填脂醯絲胺 酸、20 pg/mL二醢甘油、360 μΜ NADH、3 mM填酸婦醇 丙酮酸、70 pg/mL丙酮酸激酶、24 pg/mL乳酸脫氫酶、2 mM DTT、150 μΜ受質肽（ERMRPRKRQGSVRRRV SEQ ID NO. 2)及46 nM PKCa激酶。向存於384孔板中之16 μί此酶 緩衝液中添加1 pL存於DMSO中之VRT儲備溶液。將混合 物在30 °C下平衡10 min。藉由添加16 pL在分析緩衝液中 製得之儲備ATP溶液直至最終分析濃度為150 μΜ來引發酶 反應。在30°C下，自340 ηΜ下吸光度之改變率（對應於 NADH之化學計量消耗）使用 Molecular Devices Spectramax 板讀數儀（Sunnyvale, CA)經15 min來測定初始速率數據。 對於每次Ki測定’一式兩份獲得涵蓋〇_2〇 μΜ之VRT濃度 範圍之12個數據點（自初始1 〇 mM VRT儲備液、隨後進行 1:2連續稀釋來製備DMSO儲備液）^藉由非線性回歸使用 Prism軟體包（Prism 4.0a，Graphpad Software, San Diego, CA)自初始速率數據來計算Ki值。 A 化合物係：1、5-9、12、15、19-20、23、28、29、31、 40及 42。 A**化合物係：2、11 ' 26、27、30、32、及 44。 B 化合物係 _· 3-4、10、13·14、16-18、21-22、24、25、 153786.doc -105· 201231467 33 、 37 、 38 、 39及41 ° C*化合物係：34-36、43、及45 〇 PKCa 製備分析緩衝液，其係由100 mM HEPES (pH 7.5)、10 mM MgCl2、25 mM NaC卜 0.1 mM EDTA、100 μΜ CaCl2 及0.01% Brij組成。在分析缓衝液中製備含有下列最終分 析濃度試劑之酶緩衝液：0.002°/。Triton X-100、100 pg/mL填月旨醢絲胺酸、20 pg/mL二酿甘油、360 μΜ NADH、3 mM磷酸烯醇丙酮酸、70 pg/mL丙酮酸激酶、24 pg/mL乳酸脫氫酶、2 mM DTT、150 μΜ受質肽 (RRRRRKGSFKRKA SEQ ID NO. 1)及 4.5 nM PKCa激酶。 向存於384孔板中之16 μΐ^此酶緩衝液中添加1 pL存於 DMSO中之VRT儲備溶液。將混合物在30°C下平衡10 min。藉由添加16 μι在分析緩衝液中製得之儲備ATP溶液 直至最終分析濃度為130 μΜ來引發酶反應。在30°C下，自 340 nM下吸光度之改變率（對應於NADH之化學計量消耗） 使用 Molecular Devices Spectramax板讀數儀（Sunnyvale, CA)經15 min來測定初始速率數據。對於每次Ki測定，一 式兩份獲得涵蓋0-20 μΜ之VRT濃度範圍之12個數據點（自 初始10 mM VRT儲備液、隨後進行1:2連續稀釋來製備 DMSO儲備液）。藉由非線性回歸使用Prism軟體包（Prism 4.0a，Graphpad Software，San Diego，CA)自初始速率數據 來計算Ki值。 B化合物係：1、2、5、7、9、12、15、20、23 ' 26-30、 153786.doc - 106- 201231467 32、40、41 ' 及44 ° C化合物係：3、6、8、11、13-14、1 7、19、21 -22、3 1、 37、38、及 42。 C*化合物係：4、10、16、18、24、25、33-36、39、43及 45 » 儘管已對本發明之許多實施例進行了闡述，但顯而易 見’可對我們之基本實例加以修改以提供可利用發明化合 物、方法及過程之其他實施例。因此，應瞭解，本發明之 範圍將由隨附申請專利範圍而非由本文實例所代表之具體 實施例界定。 【圖式簡單說明】 圖1展示化合物9之模擬及實驗XRD圖案的對比。 153786.doc •107·Cll—C5 1.732 (2) C3—C7 1.555 (3) FI—C12 1.355 (2) N3—C9 1.359 (3) 01—C7 1.434 (2) C4—C5 1.421 (3) N6—C3 1.479 (3) C5 —C13 1.377 (3) N6—C17 1.480(3) C7—C14 1.515 (3) Nl—C4 1.328 (3) C7—C10 1.564 (3) Nl—Cl 1.359 (3) C8—C16 1.441 (3) N2— C8 1.334(3) N4—C15 1.335 (3) N2—N3 1.355 (3) N4—C9 1.344(3) N5—C4 1.394(3) C9—C16 1.404(3) N5—C2 1.468 (3) CIO—C18 1.522 (3) N5—C6 1.475 (3) CIO—C20 1.530 (3) Cl—C12 1.386 (3) Cll—C19 1.375 (3) Cl—C8 1.463 (3) Cll—C16 1.398 (3) C2—C17 1.509 (3) C12—C13 1.368 (3) C3—C6 1.520 (3) C15—C19 1.395 (3) C3—N6—C17 111.23(17) 01—C7—CIO 105.31 (17) C4—Nl—Cl 121.17(17 C14—C7—CIO 112.04(18) C8—N2—N3 107.09(17) C3—C7—CIO 110.19(17) C4—N5—C2 116.98(17) N2—C8—C16 110.11 (18) C4—N5— C6 116.39(16) N2—C8—Cl 122.21 (18) C2—N5—C6 109.38(17) C16—C8—Cl 127.68(18) Nl—Cl—C12 119.15(19) C15—N4—C9 112.96(19) 153786.doc •97- 201231467 N1 Cl—C8 115.88(18) N4—C9—N3 125.0 (2) C12—Cl—C8 124.96 (19) N4—C9—C16 127.4 (2) N5—C2—C17 108.08(18) N3—C9—C16 107.57 ( 19) N6—C3—C6 107.03 (18) C18—CIO—C20 109.8 (2) N6—C3—C7 112.19(17) C18—CIO—C7 111.72(19) C6—C3—C7 112.17(17) C20—CIO —C7 113.59(19) N2—N3—C9 111.29(18) C19—C11—C16 116.7(2) N1—C4—N5 118.91 (18) FI—C12—C13 118.04(19) N1—C4—C5 120.54(18 FI—C12—Cl 120.60 (19) N5—C4—C5 120.45 (18) C13—C12—Cl 121.3 (2) C13—C5—C4 118.8(2) C12—C13—C5 118.9(2) C13—C5— C11 119.12(17) N4—C15—C19 124.9 (2) C4—C5—C11 122.03 (16) Cll—C16—C9 117.2 (2) N5—C6—C3 110.12(18) Cll—Cl 6—C8 138.8 (2 01—C7—C14 109.56(17) C9—C16—C8 103.93 (18) 01—C7—C3 108.67(16) N6—C17—C2 110.14(18) C14—C7—C3 110.88(18) Cll—C19— C15 120.8 (2) In general, the following compounds can be synthesized according to the procedures similar to those described in Examples 1, 2 and 3, Compounds 2-8, 10-35 and 37-45. A similar method is set forth in PCT Application No. PCT/US2009/051437, filed on Jan. 22, 2009,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, Table 2 shows data for certain exemplary compounds typically made by routes analogous to those described in the above examples. 153786.doc • 98 · 201231467 Table 2 No. M+l (obs) RT (min) ^-NMR 1 403 7.47 1H NMR (400 MHz, DMSO) d 13.99 (s, 1H), 8.77 (dd, J=8.1} 1.4 Hz, 1H), 8.60 (dd, J=4.4, 1.5 Hz, 1H), 7.92 (dd, J=12.1, 9.8 Hz, 1H), 7.30 (dd, J=8.1, 4.5 Hz, 1H), 4.14 ( s, 1H), 4.04 (d, J=7.9 Hz, 1H), 3.77 (d, J=8.6 Hz, 1H), 3.09 (d, J=8.9 Hz, 1H), 2.84 (d, J=9.1 Hz, 2H), 2.74 (d, J=7.4 Hz, 2H), 1.81 (dt, J=13.5, 6.8 Hz, 2H), 1.05 (s, 3H), 0.87 (dd, J=23.8, 6.7 Hz, 6H) 〇 2 401.2 2.36 1H (DMSO) d 0.15 (d, 1H), 0.20 (d, 1H), 0.89 (s, 3H), 0.96 (s, 3H), 1.53 (bs, 1H, NH), 2.24-2.31 (m , 1H), 2.64-2.72 (m, 2H), 2.79 (t, 1H), 2.91 (d, 1H), 3.58-3.63 (m, 2H), 4.70 (s, 1H, OH), 7.10 (dd, 1H ), 7.72 (dd, 1H), 8.40 (dd, 1H), 8.55 (1H, dd), 13.80 (bs, lH), NH)ppm 3 403 7.67 4 401 7.42 5 401 7.52 6 389 7.17 1HNMR (CD30D) 1.05 (3H, t), 1.28-1.32 (4H, m), 1.60-1.85 (2H, m), 2.98 (3H, m), 3.10-3.15 (2H, m), 4.05-4.10 (1H, m), 4.30 -4.35 (1H, m), 7.40-7.45 (lH, dd), 7.70-7.80 (1H, dd), 8.70 (1H, d), 9.00 (1H, d). 7 389 1. 68 (CD30D) 1.01 (6H, d), 1.25-1.35 (1H, m), 1.85-1.95 (1H, m), 1.85-1.90 (1H, m), 2.95-3.10 (2H, m), 3.20 (1H , M), 3.70 (1H, s), 3.92-3.97 (1H, m), 4.20-4.25 (1H, d), 7.33-7.36 (1H, dd), 7.59-7.64 (1H, m), 8.57-8.59 (1H, d), 8.87-8.89 (1H, d). 8 375 6.91 DMSO-d6 0.89-0.93 (3H, m), 1.3-1.4 (1H, m), 1.55-1.60 (1H, m), 2.65- 2.70 (2H, m) 2.80-3.00 (2H, m), 3.02-3.07 (1H, m), 3.25-3.30 (1H, m), 3.50 (1H, s), 3.75-3.80 (1H, m), 4.03 -4.08 (1H, m), 4.59-4.61 (1H, m), 7.29-7.32 (1H, d), 7.90-7.95 (1H, dd), 8.59-8.60 (1H, d), 8.76-8.79 (1H, d), 13.95-13.90 (1H, s). 9 419 8.27 (CD30D) 0.97-1.03 (6H, dd), 1.21 (3H, s), 1.93-1.94 (1H, m), 2.80-2.86 (1H, t ), 3.00-3.08 (2H, m), 3.22-3.25 (1H, m), 3.71-3.75 (1H, d), 3.99-4.03 (1H, d), 7.32-7.35 (1H, d), 7.83-7.86 (1H, d), 8.58-8.59 (1H, d), 8.90-8.92 (1H, d). 10 (DMSO, 400MHz) 0.83 (3H, s), 0.94 (3H, s), 1.09 (3H, s) , 1.87 (1H, sept), 3.15-3.50 (5H, m), 4.18 (1H, d), 4.38 (1H, d), 7.37 (1H, dd), 8.46 (1H, d), 8.66 (1H, dd ), 8.71 (1H, d), 14.40 (l H, brs). 153786.doc -99_ 201231467 No. M+l (obs) RT (min) ^-NMR 11 421.2 2.35 1H (DMSO) d 1.24 (d, 3H), 1.36 (d, 3H), 1.42 (d , 3H), 2.59-2.67 (m, 1H), 2.88-2.93 (m, 2H), 2.98 (dd, 1H), 3.14 (d, 1H), 3.78 (d, 1H), 4.09 (d, 1H), 4.86 (s, 1H, OH), 7.25 (dd, 1H), 7.92 (dd, 1H), 8.58 (dd, 1H), 8.74 (dd, 1H), 13.99 (bs, 1H, NH) ppm 12 421.2 2.31 1H (DMSO) d 1.21 (s, 3H), 1.40 (t, 6H), 1.97 (bs, 1H, NH), 2.75-2.95 (m, 4H), 3.06 (d, 1H), 3.76 (d, 1H), 4.16 (d, 1H), 4.77 (s, 1H, OH), 7.30 (dd, 1H), 7.92 (dd, 1H), 8.59 (dd, 1H), 8.82 (dd, 1H), 13.97 (bs, 1H, NH) ppm 13 429 0.77 (d6-DMSO, 400 MHz) 1.49 (3H, s), 3.15-3.20 (1H, m), 3.21-3.45 (3H, m), 3.78 (1H, brs), 4.11 (1H, d), 4.19 (1H, d), 7.30 (1H, dd), 7.45 (brs), 8.08 (1H, dd), 8.62-8.64 (2H, m), 8.92 (1H, brs), 9.09 (1H, brs ), 14.09 (1H, brs) 14 429 0.73 (d6-DMSO, 400 MHz) 1.49 (3H, s), 3.18 (1H, t), 3.27-3.33 (1H, m), 3.37-3.45 (2H, m) , 3.79 (1H, t), 4.11 (1H, d), 4.19 (1H, d), 7.29 (1H, dd), 7.44 (1H, s), 8.09 (1H, dd), 8.62 (2H, m) , 8.91 (1H, brs), 9.05 (1H, brs), 14.09 (1H, brs) 15 443 8.35 1HNMR(CD30D) 1.30 (3H, s), 2.30-2.60 (1H, m), 2.65-2.80 (1H, m), 2.85-2.95 (2H, m), 3.00-3.10 (1H, m), 3.80-3.85 (1H, m), 4.05-4.10 (1H, m), 7.25 (1H, d), 7.50-7.55 ( 1H, m), 8.46-8.48 (1H, d), 8.73-8.76 (1H, d). 16 405 6.97 1HNMR(CD30D) 1.32 (3H, s), 3.20-3.25 (lHt), 3.30-3.45 (5H, Concealed), 3.63-3.67 (1H, m), 4.21-4.25 (1H, m), 4.35-4.39 (1H, m), 7.32-7.35 (1H, dd), 7.71-7.76 (1H, dd), 8.60- 8.62 (1H, d), 8.74-8.76 (1H, d). 17 405 6.89 H NMR (400.0 MHz, DMSO) d 13.99 (s, 1H, NH), 8.79 (dd, J=1.4, 8.1 Hz, 1H) , 8.60 (dd, J=1.5, 4.5 Hz, 1H), 7.93 (dd, ]=9.9, 12.0 Hz, 1H), 7.30 (dd, J=4.5, 8.1 Hz, 1H), 3.98-3.92 (m, 1H) ), 3.80-3.77 (m, 1H), 3.77 (s, 1H, OH), 3.38-3.32 (m, 1H), 3.27-3.24 (m, 4H), 3.08 (d, 1H), 2.87-2.67 (m , 4H), 2.15 (bs, 1H, NH) and 1.16 (s, 3H) ppm 18 391 7.44 19 391 7.48 H NMR (400.0 MHz, DMSO) d 0.92 (t, 3H), 1.34 (seven peak, 1H), 1.56-1.65 (m, 1H), 2.61 (t, 1H), 2.67-2.72 (m, 1H), 2.82-2.92 (m 2H), 3.03-3.06 (m, 1H), 3.26-3.34 (concealed signal, 1H), 3.58 (d, 1H), 3.87 (d, 1H), 4.56 (d, 1H), 7.34 (dd, 1H), 8.11 (d, 1H), 8.61 (dd, 1H), 8_81 (dd, 1H) and 14.10 (brs, 1H) ppm 20 405 1.05 1H (DMSO-d6) 0.89-0.96 (6H, dd), 1.85-1.90 ( 1H, m), 2.60-2.65 (1H, m), 2.78-2.82 (1H, m), 2.88-2.93 (1H, m), 3.10-3.15 (1H, m), 3.20 (1H, m), 3.65- 3.67 (1H, m), 3.92-3.95 (1H, m), 4.54-4.54 (1H, m), 7.40-7.43 (1H, m), 8.14-8.16 (1H, d), 8.70 (1H, s), 8.75 (1H, d), 153786.doc -100- 201231467 No. M+l (obs) RT (min) ^-NMR 21 405 1.06 1H (DMSO-d6) 0.91-0.95 (6H, m), 1.80-1.85 ( 1H, m), 2.70-2.75 (1H, m), 2.85-3.00 (2H, m), 3.10-3.20 (2H, m), 3.65-3.67 (2H, m), 4.65-4.68 (1H, m), 7.37-7.40 (1H, m), 8.15-8.18 (1H, d), 8.64-8.66 (1H, d), 8.81 (1H, d), 14.1-1.2 (1H, br s) 22 373 2.42 (d6-DMSO , 400 MHz) 0.99 (3H, d), 1.06 (3H, d), 1.75-1.80 (1H, m), 1.93-1.96 (1H, m), 2.16-2.21 (1H, m), 3.07-3.17 (2H , m), 3.43 (1H, t), 3.62-3.66 (1H, m), 3.83 (2H, brs), 7.28 (1H, dd), 7.81-7.88 (4H, m), 8.59 (1H, Dd), 8.76 (1H, d), 13.96 (1H, brs) 23 389.17 2.54 HNMR (400.0 MHz, DMSO) d 0.99 (d, 3H), 1.06 (d, 3H), 1.71-1.79 (m, 1H), 1.91-1.99 (m, 1H), 2.20 (qn, 1H), 3.13-3.20 (m, 1H), 3.59 (t, 2H), 3.73-3.85 (m, 3H), 7.29 (dd, 1H), 7.89 ( Br s, ΝΉ3+, 3H), 7.99 (d, 1H), 8.60 (dd, 1H), 8.76 (dd, lH)&amp;14.07(s,lH)ppm 24 389.17 2.6 H NMR (400.0 MHz, DMSO) d 0.96 (d, 3H), 1.06 (d, 3H), 1.79 (five peaks, 1H), 2.01-2.15 (m, 2H), 3.14 (br m, 1H), 3.20-3.60 (hidden signal, 1H), 3.63 (t,1H), 3.71 (t,1H), 3.79-3.86 (m, 2H), 7.32 (dd, 1H), 7.83 (s, NH3+, 3H), 8.00 (d, 1H), 8.61 (dd, 1H) ), 8.76 (dd, 1H) and 14.07 (s, 1H) ppm 25 375.2 2.28 1H NMR (400.0 MHz, DMSO) d 14.00 (bs, 1H, NH), 8.73 (dd, J=1.5, 8.1 Hz, 1H) , 8.60 (dd, J=1.5, 4.5 Hz, 1H), 7.93 (dd, J=9.9, 12.1 Hz, 1H), 7.30 (dd, J=4.5, 8.1 Hz, 1H), 4.67 (d, J=5.6 Hz, 1H), 3.82-3.74 (m, 2H), 3.35-3.30 (m, 2H), 3.09-3.03 (m, 1H), 2.98-2.91 (m, 1H), 2.86-2.80 (m, 1H), 2.73-2.68 (m, 2H), 2.33-2.28 (bs, ΙΗ, ΝΗ), 1.57-1.53 (m, 1H), 1.38-1.34 (m, 1H) and 0.92 (t, J=7.4 Hz, 3H) ppm 26 419 8.69 lHNMR(dmso-d6) 0.98 (9H, s), 2.80-3.00 (4H, m), 3.10-3.25 ( 2H, m), 3.60-3.64 (1H, m), 3.82-3.85 (1H, m), 7.34-7.38 (1H, dd), 8.13-8.16 (1H, d), 8.64-8.66 (1H, dd), 8.85-8.88 (1H, dd)., 27 403 8.23 1HNMR(CD30D) 1.01 (9H, s), 2.95-3.20 (56H, m), 3.90-3.95 (1H, d), 4.10-.4-15 (1H , d), 7.29-7.32 (1H, d), 7.59 (1H, dd), 8.55-8.57 (1H, d), 8.83-8.84 (1H, d) 28 373.18 2.44 HNMR (400.0 MHz, DMSO) d 0.87 ( d, 3H), 0.95 (d, 3H), 1.58-1.60 (m, 1H), 1.69-1.76 (m, 1H), 2.13-2.28 (m, 2H), 2.46 (dd, 1H), 3.32-3.36 ( Concealed signals, 1 average, 3.57-3.64 (111, 111), 3.70-3.80 (m, 2H), 7.29 (dd, 1H), 7.79 (dd, 1H), 8.57 (dd, 1H) and 8.75 (dd, 1H) ) ppm 153786.doc -101 - 201231467 No. M+l (obs) RT (min) !h-nmr 29 387 1.77 1H NMR(dmso) 0.28-.029 (2H, s), 0.35-0.37 (1H, m) , 0.39-0.40 (1H, m), 0.97-0.99 (1H, m), 2.80-2.95 (5H, m), 3.06-3.09 (1H, m), 3.77-3.79 (1H, m), 4.04-4.0 ( 1H, m), 4.72 (1H, s), 7.28-7.31 (1H, d), 7.90-7.96 (1H, dd), 8.59-8.60 (1H, d), 8.78-8.80 (1H, m), 13.90-1.40 (1H, s). 30 417 0.64 (d6-DMSO, 400 MHz) 0.26-0.30 (3H, m), 0.45-0.48 (1H, m), 0.93-1.03 (1H, m), 1.11 (3H, s), 2.75-2.93 (3H, m), 3.12 (1H, d), 3.63 (1H, d), 3.92 (1H, d)5 4.10 (1H, brs), 7.32 (1H, dd), 8.13 (1H, d), 8.62 (1H, dd), 8.85 (1H, dd), 14.10 (1H, brs) 31 403 1.91 lHNMR(DMSO-d6) 0.0 -0.05 (2H, m), 0.07-0.10 (1H, m), 0.20-0.25 (1H, m), 0.70-0.80 (2H, m), 2.50-2.70 (4H, m), 2.82-2.90 (1H, (m), 3.30-3.40 (1H, m) 8.59 (1H, d). 32 401 0.51 (d6-DMSO, 400 MHz) 0.84 (3H, d), 0.94 (3H, d), 1.09 (2H, s), 1.76-1.88 (1H, m), 2.89 ( (1H, d) , 7.26 (1H, dd), 8.33-8.40 (1H, m), 8.55-8.59 (2H, m), 8.66 (1H, dd), 11.00 (1H, brs), 13.83 (1H, brs) 33 421.1 2.35 H NMR (400.0 MHz, DMSO) d 14.10 (bs, 1H, NH), 8.83 (dd, J=1.6, 8.1 Hz, 1H), 8.62 (dd, J=1.5, 4.5 Hz, 1H), 8.12 (d, J =9.8 Hz , 1H), 7.33 (dd, J=4.5, 8.1 Hz, 1H), 4.57 (s, 1H), 3.77 (d, J=11.3 Hz, 1H), 3.61 (d, J=9.0 Hz, 1H), 3.35 (d, J=11.0 Hz, 1H), 3.28-3.23 (m, 4H), 3.11-3.08 (m, 1H), 2.86-2.79 (m, 3H), 2.73-2.67 (m,1H), 2_12 (bs , 1H, NH) and 1.16 (s, 3H) ppm 34 410 0.98 H NMR (400.0 MHz, DMSO) d 14.28 (s, 1H), 8.80-8.57 (m, 3H), 8.28 (d, 1H), 7.35 ( Dd, J=4.5, 8.1 Hz, 1H), 4.81-4.37 (m, 2H), 3.57-3.21 (m, 5H), 1.96-1.81 (m, 1H), 1.06 (d, J=4.9 Hz, 3H) , 0.93 (d, J = 6.6 Hz, 3H) and 0.67 (d, J = 6.8 Hz, 3H) ppm 35 410 0.98 H NMR (400.0 MHz, DMSO) d 14.28 (s, 1H), 8.85-8.53 (m, 4H), 8.28 (s, 1H), 7.34 (dd, J=4.5, 8.1 Hz, 1H), 4.70-4.47 (m, 2H), 3.56-3.21 (m, 5H), 1.14 (s, 3H) and 0.88 -0.79 (m,6H) ppm 36 380 0.59 H NMR (400.0 MHz, DMSO) d 14.19 (s, 1H), 8.72 (dd, J=1.3, 8.1 Hz, 1H), 8.62 (dd, J=1.5, 4.5 Hz, 1H), 8.03 (s, 1H), 7.88 (d, J=3.0 Hz, 3H), 7.32 (dd, J=4.5, 8.1 Hz, 1H), 4.05-4.00 (m, 2H), 3.75-3.11 (m, 3H), 2.60-2.50 (m, 1H), 2.26-2.18 (m, 1H), 2.01-1.74 (m, 2H), 1.06 (d, J = 6_9 Hz, 3H) and 1. 00 (d, J=7.0 Hz, 3H) ppm 153786.doc -102- 201231467 No. M+1 (obs) RT (min) !h-nmr 37 380 0.59 HNMR (400.0 MHz, DMSO) d 14.31 (s, 1H ), 8.79 (d, 1H), 8.65 (m, 1H), 8.25 (d, 1H), 7.85 (brs, 3H), 7.35 (dd, 1H), 4.04-3.94 (m, 2H), 3.82-3.71 ( m, 1H), 3.62-3.15 (m, 2H), 2.71-2.44 (m, 1H), 2.29-2.18 (m, 1H), 2.01-1.75 (m, 2H), 1.08 (d, 3H) and 1.01 ( d, 3H) ppm 38 419 0.67 (d6-DMSO, 400 MHz) 0.91 (6H, dd), 1.07 (3H, s), 1.91-1.98 (1H, m), 2.63-2.71 (1H, m), 2.88- 2.93 (2H, d), 3.18 (1H, d), 3.63 (1H, d), 3.78 (1H, d), 4.13 (1H, s), 7.37 (1H, dd), 8.15 (1H, d), 8.65 (1H, dd), 8.83 (1H, d), 14.12 (1H, brs) 39 419 1.77 40 419 2 41 419 2.05 42 435 2.54 43 (DMSO, 400MHz) 0.77 (3H, d), 0.89 (3H, d) , 1.05 (3H, s), 1.83 (1H, sept), 2.70-3.20 (5H, m), 4.31 (1H, d), 4.65 (1H, d), 7.34 (1H, dd), 8.11 (1H, d ), 8.63 (1H, d), 8.70 (1H, d), 14.22 (1H, br s). 44 415.2 2.05 H NMR (400.0 MHz, DMSO) d 14.01 (bs, 1H, NH), 8.82 (d, 1H ), 8.60 (dd, 1H), 7.79 (d, 1H), 7.30 (d, 1H), 5.54 (t, 1H), 4.6 0-4.50 (m, 2H), 4.28 (bs, 1H), 3.48-3.36 (m, 2H), 3.18-3.13 (m, 1H), 2.98-2.89 (m, 2H), 2.73-2.66 (m, 1H) ), 1.83-1.76 (m, 1H), 1.06 (s, 3H), 0.91 (d, 3H) and 0.85 (d, 3H) ppm 45 435 2.23 In general, the compounds of the invention (comprising the compounds in Table 1) Can effectively suppress the piece. The compounds of the present invention were tested for their selectivity for inhibition of ρκχθ, and the results are shown in the following examples. The data obtained shows values for the ΡΚΧΘ subtype selectivity by showing the Ki efficacy for ρκχθ, PKCa and PKCa. Example 4 PKC0 Preparation assay buffer consisting of 100 mM HEPES (pH 7.5), 10 mM MgCl2, 25 mM Na (M, 0.1 mM EDTA, and 0.01% Brij. Prepare reagents containing the following final assay concentrations in assay buffer Enzyme 153786.doc -103 - 201231467 Buffer: 0.00001% Triton X-100, 200 pg/mL fatty acid, 20 pg/mL diglycerin, 360 μΜ NADH, 3 mM acid-filled progesterone I acid, 70 pg/mL pyruvate kinase, 24 pg/mL lactate dehydrogenase, 2 mM DTT, 100 μM receptor peptide (ERMRPRKRQGSVRRRV SEQ ID NO. 1) and 18 nM PKC0 kinase. Stored in 384-well plates. Add 60 μL of this enzyme buffer to 2 μί of VRT stock solution in DMSO. The mixture was equilibrated at 30 ° C for 1 〇 min. Add 5 μιη of the stock ATP solution prepared in assay buffer until final The concentration of 240 μΜ was analyzed to initiate the enzymatic reaction. At 30 ° C, the rate of change in absorbance from 340 ηΜ (corresponding to the stoichiometric consumption of NADH) was determined using a Molecular Devices Spectramax plate reader (Sunnyvale, CA) for 15 min. Initial rate data. For each Ki determination, the culvert was obtained in duplicate. 12 data points of the VRT concentration range of 〇-20 μΜ (from the initial 1 〇 mM VRT stock solution followed by 1:2 serial dilution to prepare the DMSO stock solution). The Prism software package was used by nonlinear regression (Prism 4.0) a, Graphpad Software, San Diego, CA) Calculate the Ki value from the initial rate data. The Ki value is expressed as A*&lt;0.001 μΜ ' A**&lt;0.01 μΜ, A&lt;〇〇5 μΜ,Β&lt;0·5 μΜ,Β*&gt;0.7 μΜ, C*&gt;1.25 μΜ, C**&gt;2.0 μΜ, C&lt;2_8 μΜ, D&gt;2.8 μΜ, D*&gt;4 μΜ ο Α compound: 10, 16-18 , 21-22, 24-25, 33-34, 37-39 and 43 ° A* compound systems: 1, 2, 3-9, 11-15, 19-20, 23, 26-32, 40-42, And 44. Compound B: 35, 36 and 45. 153786.doc -104- 201231467 PKCa Preparation assay buffer consisting of 100 mM HEPES (pH 7.5), 10 mM MgCh, 25 mM NaCl, 0.1 mM EDTA and 0.01 % Brij. Prepare an enzyme buffer containing the following final assay concentration reagents in assay buffer: 0.002% Triton X-100, 200 pg/mL fat-filled lysine, 20 pg/mL diterpene glycerol, 360 μΜ NADH, 3 mM fill Glycolyl pyruvate, 70 pg/mL pyruvate kinase, 24 pg/mL lactate dehydrogenase, 2 mM DTT, 150 μM receptor peptide (ERMRPRKRQGSVRRRV SEQ ID NO. 2) and 46 nM PKCa kinase. To 16 μί of this enzyme buffer stored in a 384-well plate, 1 pL of VRT stock solution in DMSO was added. The mixture was equilibrated at 30 °C for 10 min. The enzyme reaction was initiated by adding 16 pL of the stock ATP solution prepared in assay buffer until the final assay concentration was 150 μΜ. At 30 ° C, the rate of change in absorbance from 340 η ( (corresponding to the stoichiometric consumption of NADH) was determined using a Molecular Devices Spectramax plate reader (Sunnyvale, CA) for 15 min to determine initial rate data. For each Ki assay, 12 data points covering the VRT concentration range of 〇_2〇μΜ were obtained in duplicate (from the initial 1 〇 mM VRT stock solution, followed by 1:2 serial dilution to prepare the DMSO stock solution) Ki values were calculated from the initial rate data by nonlinear regression using a Prism software package (Prism 4.0a, Graphpad Software, San Diego, CA). A compound system: 1, 5-9, 12, 15, 19-20, 23, 28, 29, 31, 40 and 42. A** compound system: 2, 11 '26, 27, 30, 32, and 44. B compound system _· 3-4, 10, 13·14, 16-18, 21-22, 24, 25, 153786.doc -105· 201231467 33, 37, 38, 39 and 41 ° C* compound system: 34 -36, 43, and 45 〇PKCa Preparation assay buffer consisting of 100 mM HEPES (pH 7.5), 10 mM MgCl2, 25 mM NaCb 0.1 mM EDTA, 100 μΜ CaCl2, and 0.01% Brij. An enzyme buffer containing the following final concentration reagents was prepared in assay buffer: 0.002°/. Triton X-100, 100 pg/mL filled with lysine, 20 pg/mL diglyceride, 360 μΜ NADH, 3 mM phosphoenolpyruvate, 70 pg/mL pyruvate kinase, 24 pg/mL lactic acid Dehydrogenase, 2 mM DTT, 150 μM receptor peptide (RRRRRKGSFKRKA SEQ ID NO. 1) and 4.5 nM PKCa kinase. 1 pL of VRT stock solution in DMSO was added to 16 μM of this enzyme buffer in a 384-well plate. The mixture was equilibrated at 30 ° C for 10 min. The enzymatic reaction was initiated by the addition of 16 μl of the stock ATP solution prepared in assay buffer until the final assay concentration was 130 μΜ. Rate of change in absorbance from 340 nM at 30 ° C (corresponding to stoichiometric consumption of NADH) Initial rate data was determined using a Molecular Devices Spectramax plate reader (Sunnyvale, CA) over 15 min. For each Ki assay, 12 data points covering the VRT concentration range of 0-20 μΜ were obtained in duplicate (from the initial 10 mM VRT stock solution followed by a 1:2 serial dilution to prepare the DMSO stock solution). Ki values were calculated from the initial rate data by nonlinear regression using a Prism software package (Prism 4.0a, Graphpad Software, San Diego, CA). Compound B: 1, 2, 5, 7, 9, 12, 15, 20, 23 ' 26-30, 153786.doc - 106- 201231467 32, 40, 41 ' and 44 ° C compound: 3, 6, 8, 11, 13-14, 1, 7, 19, 21 -22, 3 1, 37, 38, and 42. C* compound series: 4, 10, 16, 18, 24, 25, 33-36, 39, 43 and 45 » Although many embodiments of the invention have been described, it is obvious that 'we can modify our basic examples Other embodiments for providing the compounds, methods, and processes of the invention are provided. Therefore, it is to be understood that the scope of the invention is defined by the appended claims BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 shows a comparison of the simulated and experimental XRD patterns of Compound 9. 153786.doc •107·

Claims (1)

201231467 七、申請專利範圍·· 1 · 一種由下列結構式代表之化合物，201231467 VII. Scope of Application for Patent·· 1 · A compound represented by the following structural formula, 或其醫藥上可接受之鹽，其中： T係-NH-或不存在； 每一 JC1 及 Jc2 皆獨立地係 _CN、-F、、_〇R、&lt;Η2〇κ 或-CF3 ; 每一 U!、U2、及IJ3皆獨立地係_H、z、或凡，其中 川、U2、及U3中之至多一者係_H;或^、〜、及U3中之 兩者連接至一起形成具有0-1個雜原子且獨立地經一或多 個Je取代之C1-C6環烷基環； Z係 Y2-Q2 ; Y2不存在或係視需要且獨立地經一或多個。取代之 C1-6烷基； Q2不存在或係視需要且獨立地經一或多個尺取代之具 有〇-1個雜原子的C3-C8環烷基，其中Y2&amp;Q2二者不可同 時不存在； 每一 Jb獨立地係-F、-OR、_CN、-CF3、-N(R)2、-C(0)N(R)2、 153786.doc 201231467 視需要且獨立地經一或多個ja取代之C1-6烷基； 每一 Ja獨立地係-F、-OR、-N(R)2、或-C(0)N(R)2 ; 每一 Jd獨立地係-OR、-CN、-C(0)N(R)2、-N(R)2或 F ; 每一 Je獨立地係（M-C6烷基、-OR、-N(R)2 CF3、或F ; 每一 R係-H或C1-C6烷基；且 其中由*指示之碳係對掌性中心。 2·如請求項1之化合物，其中且υ3係Jb。 3 ·如請求項1至2中任一項之化合物，其中u!及U2係Z且U3 係Jb。 4. 如請求項1至3中任一項之化合物，其中 Y2係視需要且獨立地經一或多個Jd取代之C1_C3烷 基； Q2不存在或係視需要且獨立地經一或多個Je取代之 C3-C6貌基；且 每一 Jd獨立地係-〇R、或F。 5. 如請求項！至4中任一項之化合物，其中l係_〇h 或-NH2 〇 6. 如請求項1至5中任一項之化合物，其中Jb係_〇H。 7. 如請求項1至6中任一項之化合物，其中每一 Jci&amp;Jc2皆獨 立地係-CF3、-CN、-F、或-C1。 8. 如請求項1至7中任一項之化合物，其中每_ I及“皆獨 立地係-F、或_c卜 9. 如請求項1至8中任一項之化合物，其中每一 k及L皆 係-F。 153786.doc 201231467 10.如請求項1至9中任—項之化合物，其中Jci係F且Jc2係 C1 ;或 Je_Cl且 Jc2係 ρ。 11 · 一種由下列結構式代表之化合物，Or a pharmaceutically acceptable salt thereof, wherein: T-series-NH- or absent; each JC1 and Jc2 are independently _CN, -F, _〇R, &lt; Η2〇κ or -CF3; A U!, U2, and IJ3 are each independently _H, z, or 凡, where at most one of Chuan, U2, and U3 is _H; or two of ^, ~, and U3 are connected together. A C1-C6 cycloalkyl ring having 0-1 heteroatoms independently substituted with one or more Je; Z-line Y2-Q2; Y2 is absent or optionally one or more depending on the need. Substituted C1-6 alkyl; Q2 is absent or optionally substituted by one or more ruthenium C3-C8 cycloalkyl groups having 〇-1 heteroatoms, wherein neither Y2 &amp; Q2 is simultaneously Existence; each Jb is independently -F, -OR, _CN, -CF3, -N(R)2, -C(0)N(R)2, 153786.doc 201231467 as needed and independently through one or more a ja substituted C1-6 alkyl group; each Ja is independently -F, -OR, -N(R)2, or -C(0)N(R)2; each Jd is independently -OR, -CN, -C(0)N(R)2, -N(R)2 or F; each J is independently (M-C6 alkyl, -OR, -N(R)2 CF3, or F; Each R is -H or C1-C6 alkyl; and wherein the carbon is indicated by * to the palm center. 2. The compound of claim 1, wherein υ3 is Jb. 3 · as in claims 1 to 2 A compound of any one, wherein u! and U2 are Z and U3 is Jb. 4. A compound according to any one of claims 1 to 3, wherein Y2 is optionally substituted by one or more Jd C1_C3 Alkyl; Q2 is absent or optionally substituted by one or more J's C3-C6 topographical groups; and each Jd is independently -〇R, or F. 5. As requested; A compound according to any one of claims 1 to 6, wherein the compound is a compound of any one of claims 1 to 5, wherein Jb is _〇H. 7. And a compound of any one of claims 1 to 7, wherein each of _I and "all" The compound of any one of claims 1 to 8, wherein each of k and L is -F. 153786.doc 201231467 10. As claimed in claims 1 to 9 a compound of the formula wherein Jci is F and Jc2 is C1; or Je_Cl and Jc2 is ρ. 11 · A compound represented by the following structural formula, 或其醫藥上可接受之鹽，其中： T係-CH2-、-CH(Jb)-、-C(Jb)2-、-NH-或-N(Jb)-; t為 〇、1、或 2 ; w為0或1 ; 每一 Jc獨立地係 CN、F、Cl、-OR、-CH2OR、或 CF3 ; u係Z或Jb z係 Y2-Q2 ; Y2不存在或係視需要且獨立地經一或多個Jd取代之 C1-6烷基； Q2不存在或係視需要且獨立地經一或多個、取代之具 有〇-1個雜原子的C3-C8環烷基；其中Y2及Q2二者不可同 時不存在； 每一 Jb獨立地係-F、-OR、-CN、-CF3、-N(R)2、-C(0)N(R)2、 視需要且獨立地經一或多個Ja取代之Cl-6烷基； 每一 Ja獨立地係-F、-OR、-N(R)2、或-C(0)N(R)2 ; 153786.doc 201231467 每一 Jd獨立地係-OR、_CN、-C(0)N(R)2、-N(R)2 或 F。 每一 Je獨立地係-OR、CF3、-N(R)2或F ;且 每一 R係-Η或C1-C6烷基； 前提係該化合物不為：Or a pharmaceutically acceptable salt thereof, wherein: T is -CH2-, -CH(Jb)-, -C(Jb)2-, -NH- or -N(Jb)-; t is 〇, 1, or 2 ; w is 0 or 1 ; each Jc is independently CN, F, Cl, -OR, -CH2OR, or CF3; u is Z or Jb z is Y2-Q2; Y2 is absent or is required and independently a C1-6 alkyl group substituted by one or more Jd; Q2 is absent or optionally substituted by one or more, C3-C8 cycloalkyl groups having 〇-1 heteroatoms; wherein Y2 and Q2 may not exist at the same time; each Jb is independently -F, -OR, -CN, -CF3, -N(R)2, -C(0)N(R)2, as needed and independently One or more Ja substituted Cl-6 alkyl groups; each Ja is independently -F, -OR, -N(R)2, or -C(0)N(R)2; 153786.doc 201231467 each Jd is independently -OR, _CN, -C(0)N(R)2, -N(R)2 or F. Each Je is independently -OR, CF3, -N(R)2 or F; and each R is -Η or C1-C6 alkyl; provided that the compound is not: 或or 12· —種由選自表1之結構式代表之化合物，或其醫藥上可 接受之鹽。 13. —種組合物，其包括如請求項丨至12 或醫藥上可接受之其鹽、及醫藥上可接受 劑、或媒劑。 14. -種治療或預防個體之蛋白f激酶介導之病狀之方法， 其包括向該個體投與有效量之如請求項m2中任一項 之化合物或其醫藥上可接受之鹽或組合物。 15. 如凊求項14之方法’其中該蛋白質激 之病狀 153786.doc -4- 201231467 PKC介導之病狀。 16.如請求項15之方法’其中該pKc介導之病狀係Ρκχθ介導 之病狀。 17·如请求項16之方法’其中該PKC0介導之病狀係自身免疫 性疾病、炎性疾病或增殖性或過度增殖性疾病。 18. 如請求項17之方法’其中該卩尺以介導之病狀選自由以下 組成之群：哮喘、乾癣、關節炎、類風濕性關節炎、關 節炎症、多發性硬化、糖尿病、炎性腸病、移植排斥、 Τ-細胞白血病、淋巴瘤、及狼瘡。 19. 如請求項17之方法，其中該ρκχθ介導之病狀係自身免疫 性疾病。 20. 如請求項19之方法，其中該自身免疫性疾病選自由多發 性硬化、類風濕性關節炎、大腸激躁症組成之群。 2 1 _如請求項19之方法，其中該自身免疫性疾病係多發性硬 化。 22.如請求項19之方法，其中該自身免疫性疾病係類風濕性 關節炎。 23·如請求項19之方法，其中該自身免疫性疾病係大腸激躁 症。 24. 如請求項18之方法，其中該ρκχθ介導之病狀選自由丁_細 胞白金病及淋巴瘤組成之群。 25. 一種製備由結構式I代表之化合物之方法，其包括以下步 153786.doc 20123146712. A compound represented by a structural formula selected from Table 1, or a pharmaceutically acceptable salt thereof. 13. A composition comprising as claimed in claim 12 to 12 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable agent, or vehicle. 14. A method of treating or preventing a protein f-kinase mediated condition in an individual, comprising administering to the individual an effective amount of a compound of any one of claims m2, or a pharmaceutically acceptable salt or combination thereof Things. 15. The method of claim 14, wherein the protein is provoked by a condition 153786.doc -4- 201231467 PKC mediated condition. 16. The method of claim 15 wherein the pKc-mediated condition is mediated by Ρκχθ. 17. The method of claim 16, wherein the PKC0 mediated condition is an autoimmune disease, an inflammatory disease, or a proliferative or hyperproliferative disease. 18. The method of claim 17, wherein the condition mediated by the condition is selected from the group consisting of asthma, cognac, arthritis, rheumatoid arthritis, joint inflammation, multiple sclerosis, diabetes, inflammation Enteropathy, transplant rejection, sputum-cell leukemia, lymphoma, and lupus. 19. The method of claim 17, wherein the ρκχθ is mediated by a pathological autoimmune disease. 20. The method of claim 19, wherein the autoimmune disease is selected from the group consisting of multiple sclerosis, rheumatoid arthritis, and irritable bowel syndrome. The method of claim 19, wherein the autoimmune disease is multiplely hardened. 22. The method of claim 19, wherein the autoimmune disease is rheumatoid arthritis. The method of claim 19, wherein the autoimmune disease is irritable bowel syndrome. 24. The method of claim 18, wherein the ρκχθ-mediated condition is selected from the group consisting of D-cell leukocytosis and lymphoma. 25. A method of preparing a compound represented by structural formula I, comprising the steps of 153786.doc 201231467 其中： T係-NH-或不存在； -F、-α、-OR、-CH2OR、 每一 Jcl及Jc2皆獨立地係·〇Ν 或-CF3 ， 每一 Ui、U2、及U3皆獨立地係_H、z、或Jb，其中 U】、U2、及U3中之至多一者係屮；或^、U2、及U3中之 兩者連接至一起形成具有04個雜原子且獨立地經一或多 個Je取代之C1-C6環烷基環； Z係 Y2-Q2 ; Y2不存在或係視需要且獨立地經一或多個jd取代之 C1-6烷基； 153786.doc -6 - 201231467 Q2不存在或係視需要且獨立地經一或多個八取代之具 有〇-1個雜原子的C3-C8環烷基，其中Y2及Q2二者不可同 時不存在； 每—Jb獨立地係-F、-OR、-CN、-CF3、-N(R)2、-C(0)N(R)2、 視需要且獨立地經一或多個Ja取代之C丨_6烷基； 每一 ja獨立地係-F、-OR、-N(R)2、或-C(0)N(R)2 ; 每一 Jd獨立地係 _OR、-CN、-C(0)N(R)2、-N(R)2 或 F ; 每—Je獨立地係 C1-C6烷基、-〇R、-N(R)2 CF3、或F ; 每一 R係-H或C1-C6烷基；且 其中由*指示之碳係對掌性中心； a) 合併醯胺Α與G以形成C ; b) 在肼存在下加熱C以形成D;及 c) 使用胺J置換D上之鹵素以形成I。 26.如請求項25之方法，其中步驟a)係在二異丙基胺化鋰 (LDA)存在下實施。 27·如請求項25之方法，其中步驟c)中之該胺經保護。 28. 如請求項25之方法，其中步驟匀係在選自包括碳酸鉀、 二異丙基乙基胺（DIPEA)、三乙胺、或丨，8•二氮雜雙環 [5.4.0]十一-7-烯（DBU)之群之適宜鹼存在下，在選自包 括二甲基曱醯胺、二曱基亞碾(DMS〇)、或正丁醇 之群之適宜溶劑中實施。 29. 如請求項25之方法，其中步驟c)係在7〇t&gt;c至11〇它下進 行。 3〇.如請求項25之方法，其中步驟c)係使用Pd作為觸媒進 153786.doc 201231467 行。 3 1. —種製備由 驟： 其包括以下步Wherein: T-series-NH- or non-existent; -F, -α, -OR, -CH2OR, each Jcl and Jc2 are independently 〇Ν or -CF3, each Ui, U2, and U3 are independently a system of _H, z, or Jb, wherein at most one of U], U2, and U3 is 屮; or two of ^, U2, and U3 are joined together to form a 04 heteroatom and independently Or a plurality of J1 substituted C1-C6 cycloalkyl rings; Z series Y2-Q2; Y2 is absent or C1-6 alkyl substituted with one or more jd as needed; 153786.doc -6 - 201231467 Q2 is a C3-C8 cycloalkyl group having 〇-1 heteroatoms which is absent or independently substituted by one or more eight, wherein neither Y2 nor Q2 are simultaneously absent; each -Jb independently -F, -OR, -CN, -CF3, -N(R)2, -C(0)N(R)2, C丨_6 alkyl optionally substituted with one or more Ja Each ja is independently -F, -OR, -N(R)2, or -C(0)N(R)2; each Jd is independently _OR, -CN, -C(0)N (R) 2, -N(R) 2 or F; each -Je is independently a C1-C6 alkyl group, -〇R, -N(R)2 CF3, or F; each R-system -H or C1- C6 alkyl; and wherein indicated by * Based chiral center; A) Amides Α combined to form C and G; B) of hydrazine was heated in the presence of C to D form; and c) the displacement of the halogen with an amine of D J to form I. 26. The method of claim 25, wherein step a) is carried out in the presence of lithium diisopropylamide (LDA). 27. The method of claim 25, wherein the amine in step c) is protected. 28. The method of claim 25, wherein the step is homogenously selected from the group consisting of potassium carbonate, diisopropylethylamine (DIPEA), triethylamine, or hydrazine, 8 diazabicyclo[5.4.0] In the presence of a suitable base of the group of -7-ene (DBU), it is carried out in a suitable solvent selected from the group consisting of dimethyl decylamine, dimercapto (DMS), or n-butanol. 29. The method of claim 25, wherein step c) is performed at 7〇t&gt;c to 11〇. 3. The method of claim 25, wherein step c) uses Pd as a catalyst to enter the line 153786.doc 201231467. 3 1. Preparation of the preparation: It includes the following steps 結構式I代表 之化合物之方法 其中： T係-NH-或不存在； 每- Jel 及 Je2 皆獨立地係、.CN、_F、、_〇R、CH2〇R、 或-CF3 ， 每一 U〗、l；2、及U3皆獨立地係_H、z、或Jb，其中 u】、u2、及u3中之至多一者係汨；或。、U2、及U3中之 兩者連接至一起形成具有0-i個雜原子且獨立地經一或多 個Je取代之C1-C6環烷基環； Z係 Y2-Q2 ; 153786.doc 201231467 Y2不存在或係視需要且獨立地經一或多個Jd取代之 C1-6烷基； Q2不存在或係視需要且獨立地經一或多個^取代之具 有0-1個雜原子的C3-C8環烷基，其中Y2及Q2二者不可同 時不存在； 每一 Jb獨立地係-F、-OR、-CN、-CF3、-N(R)2、-C(0)N(R)2、 視需要且獨立地經一或多個Ja取代之C1_6烷基； 每一 Ja獨立地係-F、-OR、-N(R)2、或-C(0)N(R)2 ; 每一 獨立地係-OR、-CM、-C(0)N(R)2、-N(R)2 或 F ; 每一 Je獨立地係 C1-C6烷基、-〇R、-N(R)2 CF3、或F ; 每一 R係-H或C1-C6烷基； Pr係保護基團；且 其中由*指示之碳係對掌性中心； a) 合併L與Μ以形成N ;及 b) 使用胺J置換Ν上之鹵素以形成I。 32. 如請求項31之方法，其中在^觸媒存在下合併[與]^。 33. 如請求項31之方法，其中在步驟…中，該胺經保護。 34. 如請求項31之方法，其中步驟…係在選自包括碳酸鉀、 二異丙基乙基胺（DIPEA)、三乙胺、或1}8_二氮雜雙環 [5.4.0]十一_7_烯（DBU)之群之適宜鹼存在下，在選自包 括一甲基曱酿胺、三甲基亞;ε風(DMS〇)、正丁醇（n_Bu_〇H)、 或N-曱基吡咯啶酮（NMP)之群之適宜溶劑中進行。 35. 如請求項31之方法，其中步驟b)係在7〇ι至} 艺下進 行0 153786.doc 201231467 36. 如清求項31之方法，其中步驟b)係使用pd作為觸媒進 行。 37. —種製備由結構式丨代表之化合物之方法，其包括以下步The method of the compound represented by the formula I wherein: T---- or non-existent; each - Jel and Je2 are independently, .CN, _F, _〇R, CH2〇R, or -CF3, each U 〖, l; 2, and U3 are each independently _H, z, or Jb, wherein at most one of u], u2, and u3 is 汨; , two of U2, and U3 are joined together to form a C1-C6 cycloalkyl ring having 0-i heteroatoms independently substituted with one or more Je; Z-line Y2-Q2; 153786.doc 201231467 Y2 a C1-6 alkyl group which is not present or which is optionally substituted with one or more Jd; Q2 is absent or C3 having 0-1 heteroatoms which are optionally and independently substituted by one or more -C8 cycloalkyl, wherein neither Y2 nor Q2 are simultaneously absent; each Jb is independently -F, -OR, -CN, -CF3, -N(R)2, -C(0)N(R 2) a C1_6 alkyl group substituted with one or more Ja as needed; each Ja is independently -F, -OR, -N(R)2, or -C(0)N(R)2 Each independently is -OR, -CM, -C(0)N(R)2, -N(R)2 or F; each Je is independently a C1-C6 alkyl group, -〇R, -N (R) 2 CF3, or F; each R-based or H- or C1-C6 alkyl; a Pr-protecting group; and wherein the carbon-paired palm-center is indicated by *; a) combining L with hydrazine to form N And b) replacing the halogen on the crucible with an amine J to form I. 32. The method of claim 31, wherein [and] is combined in the presence of a catalyst. 33. The method of claim 31, wherein in step ... the amine is protected. 34. The method of claim 31, wherein the step ... is selected from the group consisting of potassium carbonate, diisopropylethylamine (DIPEA), triethylamine, or 1}8-diazabicyclo[5.4.0] In the presence of a suitable base of a group of _7-ene (DBU), selected from the group consisting of monomethylamine, trimethyl amide, ε wind (DMS〇), n-butanol (n_Bu_〇H), or This is carried out in a suitable solvent for the group of N-decylpyrrolidone (NMP). 35. The method of claim 31, wherein step b) is performed at 7 〇 至 至 0 0 0 0 0 0 0 0 31 31 31 31 31 31 31 2012 2012 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 。 。 。 。 。 。 。 。 。 。 。 。 37. A method of preparing a compound represented by the structural formula, comprising the steps 其中： T係-NH-或不存在； 每一 Jci 及 Jc2 皆獨立地係-CN、-F、-Cl、-OR、-CH2OR、 或-CF3 ; 每一 U!、、及U3皆獨立地係_H、z、或Jb，其中 Ui、U2、及U3中之至多一者係-H ;或u,、U2、及U3中之 兩者連接至一起形成具有〇-1個雜原子且獨立地經一或多 個Je取代之C1-C6環烷基環； Z係 Y2-Q2 ; 153786.doc -10- 201231467 Y2不存在或係視需要且獨立地經一或多個jd取代之 C1-6烷基； Q2不存在或係視需要且獨立地經一或多個夂取代之具 有〇-1個雜原子的C3-C8環烷基，其中Y2及Q2二者不可同 •時不存在； -每一 Jb獨立地係-F、-OR、-CN、-CF3、-N(R)2、-C(0)N(R)2、 視需要且獨立地經一或多個ja取代之Cl-6烷基； 每一 Ja獨立地係-F、-OR、-N(R)2、或-C(0)N(R)2 ; 每一 Jd獨立地係-OR、-CN、-C(0)N(R)2、-N(R)2或 F ; 每一 Je獨立地係 C1-C6烷基、-OR、-N(R)2 CF3、或F ; 每一 R係-H或C1-C6烷基； Pr係保護基團；且 其中由*指示之碳係對掌性中心； a) 合併J與Μ以形成P ; b) 合併Ρ與l以形成q ;及 c) 脫除Q之保護基以形成I。 3 8.如請求項37之方法，其中步驟幻係在選自包括碳酸鉀、 一異丙基乙基胺（DIPEA)、三乙胺、或丨，8_二氮雜雙環 . [5.4·0]十—·7·烯（DBU)之群之適宜鹼存在下，在選自包 括二甲基曱醯胺、二甲基亞砜(DMS〇)、正丁醇（n_Bu_〇H)、 • 或1^•甲基°比咯啶酮（NMP)之群之適宜溶劑中進行。 39·如凊求項37之方法，其中步驟a)係在1〇〇。匚至13〇。〇下進 行。 4〇’如凊求項37之方法，其中步驟b)係在Pd觸媒存在下進 行。 153786.doc • 11 -Wherein: T-NH- or non-existent; each Jci and Jc2 are independently -CN, -F, -Cl, -OR, -CH2OR, or -CF3; each U!, and U3 are independently a system of _H, z, or Jb, wherein at most one of Ui, U2, and U3 is -H; or two of u, U2, and U3 are joined together to form a heteroatom having -1 hetero atom C1-C6 cycloalkyl ring substituted by one or more Je; Z series Y2-Q2; 153786.doc -10- 201231467 Y2 is not present or is optionally substituted by one or more jd C1- a C3-C8 cycloalkyl group having 〇-1 heteroatoms which is absent or which is optionally substituted by one or more hydrazines, wherein Y2 and Q2 are not the same; - each Jb is independently -F, -OR, -CN, -CF3, -N(R)2, -C(0)N(R)2, optionally substituted with one or more jas Cl-6 alkyl; each Ja is independently -F, -OR, -N(R)2, or -C(0)N(R)2; each Jd is independently -OR, -CN, - C(0)N(R)2, -N(R)2 or F; each Je is independently a C1-C6 alkyl group, -OR, -N(R)2CF3, or F; each R-system- H or C1-C6 alkyl; Pr-protecting group; The carbon-to-palm center indicated by *; a) combines J and Μ to form P; b) combines Ρ and l to form q; and c) removes the protecting group of Q to form I. 3. The method of claim 37, wherein the step is selected from the group consisting of potassium carbonate, monoisopropylethylamine (DIPEA), triethylamine, or hydrazine, 8-diazabicyclo. [5.4·0 In the presence of a suitable base of the group of deuterium (DBU), selected from the group consisting of dimethyl decylamine, dimethyl sulfoxide (DMS hydrazine), n-butanol (n_Bu_〇H), Or in a suitable solvent for the group of 1^•methyl-pyrrolidone (NMP). 39. The method of claim 37, wherein step a) is at 1 〇〇.匚 to 13〇. Let's go under your arm. The method of claim 37, wherein step b) is performed in the presence of a Pd catalyst. 153786.doc • 11 -