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TW200524877A - Pharmaceutical compounds - Google Patents

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TW200524877A
TW200524877A TW093121972A TW93121972A TW200524877A TW 200524877 A TW200524877 A TW 200524877A TW 093121972 A TW093121972 A TW 093121972A TW 93121972 A TW93121972 A TW 93121972A TW 200524877 A TW200524877 A TW 200524877A
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TW093121972A
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TWI356823B (en
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Valerio Berdini
Michael Alistair O'brien
Maria Grazia Carr
Theresa Rachel Early
Adrian Liam Gill
Gary Trewartha
Alison Jo-Anne Woolford
Andrew James Woodhead
Paul Graham Wyatt
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Astex Technology Ltd
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    • C04B35/00—Shaped ceramic products characterised by their composition; Ceramics compositions; Processing powders of inorganic compounds preparatory to the manufacturing of ceramic products
    • C04B35/622—Forming processes; Processing powders of inorganic compounds preparatory to the manufacturing of ceramic products
    • C04B35/626—Preparing or treating the powders individually or as batches ; preparing or treating macroscopic reinforcing agents for ceramic products, e.g. fibres; mechanical aspects section B
    • C04B35/63—Preparing or treating the powders individually or as batches ; preparing or treating macroscopic reinforcing agents for ceramic products, e.g. fibres; mechanical aspects section B using additives specially adapted for forming the products, e.g.. binder binders
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    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
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    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D231/38—Nitrogen atoms
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    • C07D231/40—Acylated on said nitrogen atom
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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    • C07—ORGANIC CHEMISTRY
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    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
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    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
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    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
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    • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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  • Structural Engineering (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Enzymes And Modification Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

The invention provides compounds of the formula (0) or salts or tautomers or N-oxides or solvates thereof for use in the prophylaxis or treatment of disease states and conditions such as cancers mediated by cyclin-dependent kinase and glycogen synthase kinase-3. In formula (0): X is a group R1-A-NR4-or a 5-or 6-membered carbocyclic or heterocyclic ring; A is a bond, SO2, C=O, NRg(C=O) or O(C=O) wherein Rg is hydrogen or C1-4 hydrocarbyl optionally substituted by hydroxy or C1-4 alkoxy; Y is a bond or an alkylene chain of 1, 2 or 3 carbon atoms in length; R1 is hydrogen; a carbocyclic or heterocyclic group having from 3 to 12 ring members; or a C1-8 hydrocarbyl group optionally substituted by one or more substituents selected from halogen (e.g. fluorine), hydroxy, C1-4 hydrocarbyloxy, amino, mono- or di-C1-4 hydrocarbylamino, and carbocyclic or heterocyclic groups having from 3 to 12 ring members, and wherein 1 or 2 of the carbon atoms of the hydrocarbyl group may optionally be replaced by an atom or group selected from O, S, NH, SO, SO2; R2 is hydrogen; halogen; C1-4 alkoxy (e.g. methoxy); or a C1-4 hydrocarbyl group optionally substituted by halogen (e.g. fluorine), hydroxyl or C1-4 alkoxy (e.g. methoxy); R3 is selected from hydrogen and carbocyclic and heterocyclic groups having from 3 to 12 ring members; and R4 is hydrogen or a C1-4 hydrocarbyl group optionally substituted by halogen (e.g. fluorine), hydroxyl or C1-4 alkoxy (e.g. methoxy).

Description

200524877 (1) 九、發明說明 【發明所屬之技術領域】 本發明係關於吡唑化合物，彼可抑制或調節環素依賴 型激酶（CDK)及糖原合成酶激酶-3(GSK-3)的活力，關於將 該化合物用於治療或預防環素依賴型激酶及糖原合成酶激 酶-3仲介的疾病狀態或症狀，以及關於新穎具有環素依賴 型激酶或糖原合成酶激酶-3抑制活性或調節活性的化合物 。本發明也提供藥學組成物，彼含有如上述的化合物及新 穎化學中間物。 【先前技術】 蛋白質激酶構築一個在結構上相關的酶的大家族，該 酶負責控制各式各樣的在細胞內的信號轉導程序（Hardie ’ G . and Hanks，S . ( 1 9 9 5 )The Protein Kinase Facts Book.I and II Academic Press，San Diego，CA)。激酶藉其磷酸 化的酶作用物被分類成家族（例如蛋白質-酪胺酸、蛋白 質-絲胺酸/蘇胺酸、脂質等）。序列圖形業已被鑑別，彼通 常符合這些激酶家族中的各種（例如Hanks，S.K.，Hunter ，T. ， FASEB J.9 : 5 76-5 96( 1 995 ) ； Knighton ， et al..Science » 2 5 3 ： 407-414(1991) ； Hi]es，ei aI.，Cell，70 ：419_429( 1 992) ； Kunz，et aI.，Ce]l，7 3 : 585-596(1993) ;Garcia-Bustos，et al.，EMBO J.，13 : 2352-236 1 (1994)) o 蛋白質激酶可被彼之調節機制特徵化。這些機制包括 -6 - 200524877 (2) :例如：自磷酸化作用、其他激酶的轉磷酸化作用、蛋白 質-蛋白質相互作用、蛋白質-脂質相互作用、蛋白質-多 核苷酸相互作用。個別的蛋白質激酶可被一種以上的機制 調節。 激酶藉由將磷酸根絡加至標的蛋白質的方式調節許多 不同的細胞程序，該册胞程序包括（但不限於）：增殖作用 、分化作用、細胞凋亡、自動能力、轉錄作用、轉譯作用 及其他的信號程序。這些磷酸化作用擔任分子的開關，彼 可以修飾或調節標的蛋白質的生物機能。標的蛋白質的憐 酸化作用響應下列而發生：各式各樣的細胞外信號（激素 、神經傳遞物、生長及分化因子等）、細胞週期、環境或 營養壓迫等。合適的蛋白質激酶在信號通道中起作用使下 列活化或滅活（直接或間接地）、代謝作用酶、調節蛋白質 、受體、細胞骨骼蛋白質、離子通道或泵浦、或轉錄作用 因子。肇因於蛋白質磷酸化作用控制不完全的未被控制的 信號業已和許多的疾病有關聯，該疾病包括：炎症、癌、 過敏/氣喘、免疫系統的疾病及症狀、中樞神經系統的疾 病的疾病及症狀，以及血管生成。 真核狀態的細胞分裂程序可大槪地被分成一系列名爲 Gl、S、G2及Μ的連續期。正確的進展業已透過細胞週期 不同的分裂期被證實彼決定性地取決於一個蛋白質家族（ 被稱爲環素依賴型激酶（CDKs))及一不同的彼之同系蛋白 質夥伴組（被稱爲環素）的時間及空間的調節作用。C D K s 是cdc2(也被稱爲CDK1)同系絲胺酸-蘇胺酸激酶蛋白質， 200524877 (3) 在本說明書中彼可以將ATP當成各種多肽磷酸化作用的 酶作用物。環素是一個蛋白質家族’彼之特徵在於同系區 域（含有大約1 0 0種胺基酸），被稱爲 ''環素盒子〃，該環 素盒子在與特異的CDK參與蛋白質結合及定義選擇性的 場合中被使用。 在整個細胞週期的不同CDK類及環素類的表現水平 、降解速率及活化水平導致一系列CDK/環素複合物的循 環形成，其中CDK類是酶活潑的。這些複合物的形成控 制經過分散的細胞週期檢查點的通道，使得細胞分裂作用 的程序能夠持續。不能滿足在已知的細胞週期檢查點上首 要的生物化學標準（即不能形成所需的CDK/環素複合物） 可以導致細胞週期中止及/或細胞脫噬。迷亂的細胞增殖 作用（如在癌中所示的）經常被歸因於正確細胞週期的喪失 控制。抑制C D K酶活性提供一種方法，藉由該方法異常 分裂的細胞可中止其之分裂作用及/或被殺死。在仲介細 胞週期的場合中CDK類及CDK複合物類的多樣性及其之 決定性的角色提供許多根據已定義的生物化學基本原則所 選擇的可能的治療標的。 從細胞週期的G 1期進展至S期主要經由與D及E型 環素成員的聯合被CDK2、CDK3、CDK4及CDK6調節。D 型環素類似乎是能越過G1限制點的通道，然而CDK2/環 素E複合物是從G 1期轉換至S期的鑰匙。吾人認爲S期 接下來進展到G2期需要CDK2/環素A複合物。有絲分裂 及觸發有絲分裂的G 2期至Μ期的轉換皆被C D K 1及A及 200524877 (4) B型環素的複合物調節。 在G1期間，視網膜母細胞瘤蛋白質（Rb)及相關的囊 狀蛋白質（如P130)是CDK(2，4&6)/環素複合物的酶作用 物。G1的進展部份被過度磷酸化促進，所以藉CDK(4/6)/ 環素-D複合物使Rb及pi 30滅活。Rb及pi 30的過度磷酸 化造成轉錄因子（如E2F)釋出，所以基團的表現是從G1期 進展到S期所必需的（如供環素e用的基因）。環素e的表 現促進CDK2/環素E複合物的形成，該複合物經由進一步 的使Rb磷酸化來放大或維持E2F的水平。CDK2/環素E 複合物也使DNA複製必需的其他蛋白質如NPAT，彼涉及 組蛋白生物合成磷酸化。G 1進展及G 1 /S轉換也經由被有 絲分裂原激活的Myc通道（送到CDK2/環素E通道）被調節 。CDK2也經由p53調節p21水平的作用而與仲介DNA損 壞反應通道的P53連接。P21是一種CDK2/環素E的蛋白 質抑制劑，所以可以中斷或延後G 1 / S轉換。C D K 2 /環素 E複合物可代表一個點，在該點來自Rb、M y c及p 5 3通道 的生物化學興奮劑有某些程度的合而爲一。所以CDK2及/ 或CDK2/環素E複合物代表供在中止或回復在異常分裂的 細胞的細胞週期的控制上被設計的治療用的良好標的。 CDK3在細胞週期中的正確角色並不淸楚。由於尙沒 有同源的環素夥伴被鑑定，但是顯性的負型式的CDK3使 在G 1期的細胞延後，所以暗示c D K 3在調節g 1 / S轉換的 場合中扮演一個角色。 儘管大多數的CDK類涉及細胞週期的調節作用，然 200524877 (5)200524877 (1) IX. Description of the invention [Technical field to which the invention belongs] The present invention relates to pyrazole compounds, which can inhibit or regulate cyclin-dependent kinase (CDK) and glycogen synthase kinase-3 (GSK-3). Vitality, regarding the use of the compound in the treatment or prevention of disease states or symptoms mediated by cyclin-dependent kinases and glycogen synthase kinase-3, and about novel cyclin-dependent kinases or glycogen synthase kinase-3 inhibitory Or compounds that modulate activity. The present invention also provides a pharmaceutical composition containing a compound as described above and a novel chemical intermediate. [Prior art] Protein kinases construct a large family of structurally related enzymes that are responsible for controlling a variety of intracellular signal transduction programs (Hardie 'G. and Hanks, S. (1 9 9 5 ) The Protein Kinase Facts Book. I and II Academic Press, San Diego, CA). Kinases are classified into families by their phosphorylated enzyme substrates (eg, protein-tyrosine, protein-serine / threonine, lipids, etc.). Sequence patterns have been identified, and they generally conform to a variety of these kinase families (eg, Hanks, SK, Hunter, T., FASEB J. 9: 5 76-5 96 (1 995); Knighton, et al .. Science »2 53: 407-414 (1991); Hi] es, ei aI., Cell, 70: 419_429 (1 992); Kunz, et al., Ce] 1, 7: 585-596 (1993); Garcia- Bustos, et al., EMBO J., 13: 2352-236 1 (1994)) o Protein kinases can be characterized by their regulatory mechanisms. These mechanisms include -6-200524877 (2): for example: autophosphorylation, transphosphorylation of other kinases, protein-protein interactions, protein-lipid interactions, protein-polynucleotide interactions. Individual protein kinases can be regulated by more than one mechanism. Kinases regulate many different cellular programs by adding phosphate to the target protein. The cellular programs include (but are not limited to): proliferation, differentiation, apoptosis, autonomic ability, transcription, translation, and Other signal procedures. These phosphorylation acts as a molecular switch, which can modify or regulate the biological function of the target protein. Phosphorylation of the target protein occurs in response to a variety of extracellular signals (hormones, neurotransmitters, growth and differentiation factors, etc.), cell cycle, environment, or nutritional stress. Appropriate protein kinases function in signaling pathways to activate or inactivate (directly or indirectly), metabolize enzymes, regulatory proteins, receptors, cytoskeletal proteins, ion channels or pumps, or transcription factors. Uncontrolled signals due to incomplete control of protein phosphorylation have been linked to many diseases including: inflammation, cancer, allergies / asthma, diseases and symptoms of the immune system, diseases of the central nervous system And symptoms, and angiogenesis. The eukaryotic cell division program can be largely divided into a series of consecutive phases called G1, S, G2, and M. The correct progression has been demonstrated through different divisions of the cell cycle. They depend decisively on a family of proteins (known as cyclin-dependent kinases (CDKs)) and a different group of other homologous protein partners (called cyclins ) Time and space regulation. CDKs is a cdc2 (also known as CDK1) homologue serine-threonine kinase protein. 200524877 (3) In this specification, ATP can be used as an enzyme substrate for phosphorylation of various polypeptides. Cyclins are a family of proteins. They are characterized by homologous regions (containing about 100 amino acids) and are called `` cyclin boxes '', which are involved in protein binding and specific selection with specific CDKs. Used in sexual situations. The expression level, degradation rate and activation level of different CDKs and cyclins throughout the cell cycle lead to the formation of a series of CDK / cyclin complexes, in which CDKs are enzymatically active. The formation of these complexes controls the passage through discrete cell cycle checkpoints, allowing the process of cell division to continue. Failure to meet the primary biochemical criteria at known cell cycle checkpoints (ie, inability to form the required CDK / cyclin complex) can result in cell cycle arrest and / or cell phagocytosis. Disorganized cell proliferation (as shown in cancer) is often attributed to loss of control of the correct cell cycle. Inhibiting CDK enzyme activity provides a method by which cells that divide abnormally can stop their division and / or be killed. The diversity of CDKs and CDK complexes and their decisive role in the context of intervening cell cycles provides a number of possible therapeutic targets selected based on defined basic principles of biochemistry. Progression from the G 1 phase to the S phase of the cell cycle is mainly regulated by CDK2, CDK3, CDK4, and CDK6 through a combination with D and E type cyclin members. D-type cyclins seem to be able to cross the G1 limit, but the CDK2 / Cyclin E complex is the key to switch from G 1 to S phase. We believe that the CDK2 / Cyclin A complex is needed for the S phase to progress to the G2 phase. Both mitosis and G 2 to M transitions that trigger mitosis are regulated by the complexes of CD K 1 and A and 200524877 (4) type B cyclin. During G1, retinoblastoma protein (Rb) and related cystic proteins (such as P130) are enzymes of the CDK (2,4 & 6) / cyclin complex. The progress of G1 is partly promoted by hyperphosphorylation, so the CDK (4/6) / cyclin-D complex inactivates Rb and pi 30. Excessive phosphorylation of Rb and pi 30 results in the release of transcription factors (such as E2F), so the performance of the group is necessary to progress from G1 to S (such as genes for cyclin e). The expression of cyclin e promotes the formation of a CDK2 / cycline E complex that amplifies or maintains E2F levels by further phosphorylation of Rb. The CDK2 / Cyclin E complex also makes other proteins necessary for DNA replication, such as NPAT, which are involved in the phosphorylation of histone biosynthesis. G 1 progression and G 1 / S conversion are also regulated via a Myc channel (sent to CDK2 / cyclin E channel) activated by mitogens. CDK2 is also linked to P53, an intermediate DNA damage response channel, through the role of p53 in regulating p21 levels. P21 is a protein inhibitor of CDK2 / cyclin E, so it can interrupt or delay G 1 / S conversion. The C D K 2 / cycline E complex can represent a point at which biochemical stimulants from the Rb, Myc, and p 5 3 channels are unified to some extent. So CDK2 and / or CDK2 / Cyclin E complexes represent a good target for treatments designed to stop or restore control of the cell cycle of abnormally dividing cells. The correct role of CDK3 in the cell cycle is not unclear. Since no homologous cyclin partners have been identified, but the dominant negative form of CDK3 delays cells in the G 1 phase, it is implied that c D K 3 plays a role in regulating g 1 / S conversion. Although most CDKs are involved in cell cycle regulation, 200524877 (5)

而有證據證明CDK家族的特定成員介入其他的生物化學 程序。這被CDK5舉例說明，CDK5是正確的神經元發展所 必需並且涉及如下的數種神經元蛋白質的磷酸化作用： Tau、NUDE-1、突觸素 1、DARPP32及 Muncl8/SyntaxinlA 複合物。視經元CDK5在傳統上藉由與P35/p39蛋白質結 合被活化。然而CDK5活性可藉由p25(p35的被截斷的版 本）的結合被去調節。p35至p25的轉換及接下來的CDK5 活性的去調節作用可以被局部缺血、刺激毒性及/5 -澱粉 樣肽誘發。因此p2 5涉及神經變性病（如阿茲海默病）的發 病機制，所以有供抗這些疾病的治療用的標的之意義。There is evidence that specific members of the CDK family are involved in other biochemical procedures. This is exemplified by CDK5, which is necessary for correct neuron development and involves the phosphorylation of several neuronal proteins: Tau, NUDE-1, synaptophysin 1, DARPP32, and Muncl8 / SyntaxinlA complex. Apoptotic CDK5 is traditionally activated by binding to the P35 / p39 protein. However, CDK5 activity can be deregulated by binding to p25, a truncated version of p35. Conversion of p35 to p25 and subsequent deregulation of CDK5 activity can be induced by ischemia, stimulating toxicity, and / 5-amyloid peptide. Therefore, p2 5 is involved in the pathogenesis of neurodegenerative diseases (such as Alzheimer's disease), so it has a significance as a target for the treatment of these diseases.

CDK7是一種核蛋白，彼有cdc2 CAK活性及與環素Η 結合。CDK7被鑑定爲TFIIH轉錄複合物的組成份，該複 合物有RNA聚合酶IIC-末端功能域（CTD)活性。這與經由 Tat所仲介的生物化學通道來調節HIV-1轉換作用有關。 CDK8與環素C結合及涉及RNA聚合酶II的CTD磷酸化 作用。同樣地，CDK9/環素-T1複合物（P-TEFb複合物）涉 及RNA聚合酶II的延長控制。PTEF-b也是下面所需：透 過病毒協調子Tat與環素T1的相互作用使HIV-1基因組的 轉錄作用活化。所以CDK7、CDK8、CDK9及P-TEFb複合 物是抗病毒性治療的可能的標的。 在分子水平下，CDK/環素複合物活性的仲介作用需 要一系列的激活及抑制磷酸化作用或去磷酸化作用事件。 CDK磷酸化作用的進行是藉由一組CDK活化激酶（CAK) 及/或激酶（如 W e e 1 · M y t】及M i k 1 )。去磷酸化作用的進行 -10- 200524877 (6) 是藉由憐酸化酶（如cdc25(a&c)、pp2a或KAP。 CDK/環素複合物活性可進一步被二個內源的細胞蛋 白性抑制劑家族調節：Kip/Cip家族，或INK家族。INK 蛋白質專一地結合 CDK4及 CDK6。pl6ink4(也被稱爲 Μ T S 1) τη 一種可#的腫瘤抑制子基因，彼在許多的一·期癌 中被突變或消除。Kip/Cip 家族含有蛋白質，如 P2 1eip’Wafl，P2 7KiPi 及 P5 7KiP2。如先前所討論的，P21 被 p53誘發並且可以使 CDK2/環素（E/A)及 CDK4/環素 (D1/D2/D3)複合物滅活。P27表現的非典型的低水平在乳 癌、結腸癌及前列腺癌中被觀察到。在實體腫瘤中環素E 的相反的過度表現被證實與不良的患者預後有關係。環素 D 1的過度表現與下列有關：食管癌、乳癌、鱗狀細胞癌 及非小型細胞肺癌。 CDK類及彼之相關的蛋白質在協調及驅使增殖中的 細胞的細胞週期場合中的重要角色業已在上文中被槪述。 某些生物化學通道（其中CDK扮演一個關鍵角色）也已被 描述。處理增殖性疾病（如癌）的單一療法（使用標的在 CDK或在特定的CDK上的遺傳工程療法的發展是可以高 度期望的。CDK抑制劑也可被用來處理其他的症狀，如 病毒感染、自體免疫疾病及神經變性病。標的CDK的治 療也可提供在處理前述疾病的臨床上的益處（當被使用於 與現有的或新式的治療藥劑綜合的療法時）。標的CDK的 抗癌療法的益處勝於許多現有的抗癌藥劑’因爲他們不會 直接與D N A起相互作用，所以降低二期癌發展的風險。 200524877 (7) 糖原合成酶激酶-3 ( G S K 3 )是一種絲胺酸蘇胺酸激酶， 彼以二種被普遍表現的異構形式存在於人體中（G S K 3 α & β GSK3/3PGSK3涉及在下列場合中有個角色：胚原發 展、蛋白質合成、細胞增殖、細胞分化、微管動力、細胞 能動性及細胞脫噬作用。GSK3涉及下列疾病狀態的進展 :糖尿病、癌、阿茲海默氏病、中風、癲癎、運動神經元 疾病及/或頭創傷。種系發育的 GSK3與環素依賴型激酶 (CDK類）最密切相關。 一般被GSK3識別的肽酶作用物序列是（Ser/Thr(-X-X-X-(pSer/pThr)，其中 X是任何的胺基酸（在位置（n+1)、 (n + 2)、（n + 3)，pSer及pThr分別是磷絲胺酸及磷蘇胺酸 (n + 4)。GSK3使在位置（η)上的第一個絲胺酸或蘇胺酸磷酸 化。在位置（η + 4)的磷絲胺酸或磷蘇胺酸對引動GSK3得到 最大的酶作用物更新而言似乎是必需的。在 Ser21的 GSK3a或在Ser9的GSK3冷的磷酸化作用導致GSK3的抑 制作用。遺傳突變與肽競爭硏究導致GSK3的磷酸化的N-末端經由自體抑制機制可以與磷肽酶作用物 (S/TXXXPS/PT)競爭的模型。也有資料提出：GSK3 a及 GSKP分別被酪胺酸279及2 16的磷酸化作用微妙調節。這 些基團突變成Phe造成在活體內的激酶活性下降。GSK3 泠的X射線結晶照相的結構有助於遮蔽在GSK3活化及調 節的所有的方面的光線。 GSK3構成哺乳動物胰島素反應通道的一部份及可以 磷酸化，因而使糖原合成酶滅活。由於糖原合成酶活性的 -12- 200524877 (8) 向上調節，所以糖原合成酶（透過GSK3的抑制作用）被認 爲是一種抗II型或非胰島素依賴型糖尿病（N〗DDM)( 一種 症狀，身體組織變得對胰島素活化作用有抗性）的可能的 方法。在肝、脂肪或肌肉組織內的細胞胰島素反應被與細 胞外胰島素受體結合的胰島素觸發。這觸發造成胰島素受 體酶作用物（IRS)蛋白質的磷酸化作用及接下來的細胞膜 募集。IRS蛋白的進一步的磷酸化作用把磷酸肌醇-3激酶 (PI3K)的募集引到細胞膜，在該處可以釋放第二個信使3 ，4，5-三磷酸磷酸醯肌醇酯（PIP3)。這促進3-磷酸肌醇依 賴型蛋白激酶1(PDK1)及蛋白激酶B(PKB或Akt)共同定位 於細胞膜，在該處PDK1使PKB活化。PKB可以分別透過 Ser9或Ser21的磷酸化作用被磷酸化、，藉以抑制GSK3 α及 /或GSKyS。GSK3的抑制作用接下來觸發糖原合成酶活性 的向上調節。所以可以抑制GSK3的治療藥劑可以誘發類 似在胰島素激活作用上可見的細胞反應的紐胞反應。 GSK3的另一個在活體內的酶作用物是真核蛋白質合成作 用啓動因子2B(eIF2B)。eIF2B經由磷酸化作用被滅活， 因而可以抑制蛋白質生物合成作用。利用 ''利巴黴素 (rapamycin)使哺乳動物標的〃蛋白質（mTOR)滅活來抑制 G S K 3可以使蛋白質生物合成作用向上調節。最後，有一 些G S K 3活性的調節作用的證據：經由使有絲分裂原活化 的蛋白質激酶（M A PK)通道透過GSK3被激酶（如使被有絲 分裂原活化的蛋白質激酶活化的蛋白質激酶1 (M A P K A P -K]或RSK)磷酸化來調節GSK3活性。這些資料提出GSK3 200524877 (9) 活性可被促有絲分裂的胰島素及/或胺基酸刺激物調節。 以下也已被證實：GSK3 /3在脊椎動物Wnt信號通道 中是一個關鍵的組成份。這個生物化學通道已被證實對正 常的胚原發展很重要，並且彼可調節在正常組織中的細胞 增殖作用。GSK3變得可抑制Wnt刺激物。這可導致GSK3 酶作用物（如A X i η)、腺瘤息肉病大腸（A P C )基因產物及冷-卡特素（c a t e n i η)的去碟酸化。W n t通道異常的調節作用與 許多癌有關。在APC及/或/3 -卡特素（catenin)中的突變作 用常見於結腸直腸癌及其他的癌。泠-卡特素（catenin)已 被證實在細胞黏連中的重要性。所以GSK3也可把細胞黏 連程序調節至若干程度。除了已經被描述的生物化學通道 以外，還有如下的資料：GSK3涉及細胞分裂作用的調節（ 經由環素_D 1的磷酸化作用），涉及轉錄作用因子，如c· Jun，CCAAT/促進子結合蛋白質α (C/ΕΒΡα )，c-Myc及/ 或其他的酶作用物（如被活化的T細胞的核因子（NFATc)， 熱休克因子-l(HSF-l)及 c-AMP反應元素結合蛋白質 (CREB))的磷酸化作用。雖然有組織專一性，但GSK3似 乎在調節細胞脫噬作用的場合中扮演一個角色。GSK3在 調節細胞脫噬作用的角色（經由一個前脫噬機制）與醫學上 的症狀（其中神經元脫噬作用可以發生）尤其有關。這些症 狀的實例是頭創傷、中風、癲癎、阿茲海默氏病及運動神 經元疾病、進行性核上性麻痺、基底皮質變性及Pick氏 病。以下在玻管中業已被證實：GSK3可以使微管相關的 蛋白質Tail過度磷酸化。Tail的過度磷酸化破壞彼與微管 -14- 200524877 (10) 的正常結合，也導致細胞內Tau分絲的生成。吾人咸信： 這些分絲的進行性積累導致最後的神經元機能障礙及變性 。所以Tau磷酸化作用的抑制（透過GSK3的抑制）可提供 一種限制及/或防止神經變性效果的方法。 杜邦（Du Pont)的WO 02/3 4 72 1掲示一種充作環素依賴 型激酶抑制劑的茚並[1，2-c]吡唑-4-酮。CDK7 is a nuclear protein that has cdc2 CAK activity and binds to cyclin IX. CDK7 was identified as a component of the TFIIH transcription complex, which has RNA polymerase IIC-terminal domain (CTD) activity. This is related to the regulation of HIV-1 conversion via biochemical channels mediated by Tat. CDK8 binds to cyclin C and is involved in CTD phosphorylation by RNA polymerase II. Similarly, the CDK9 / Cyclin-T1 complex (P-TEFb complex) is involved in the extension control of RNA polymerase II. PTEF-b is also required to activate the transcription of the HIV-1 genome through the interaction of the viral coordinator Tat and cyclin T1. Therefore, CDK7, CDK8, CDK9 and P-TEFb complexes are possible targets for antiviral therapy. At the molecular level, the mediating effect of CDK / cycline complex activity requires a series of events that activate and inhibit phosphorylation or dephosphorylation. CDK phosphorylation proceeds through a set of CDK-activated kinases (CAK) and / or kinases (such as We e 1 · My T] and Mi k 1). Dephosphorylation is carried out-10-200524877 (6) by phosphoacidases such as cdc25 (a & c), pp2a or KAP. CDK / cyclin complex activity can be further characterized by two endogenous cellular proteins Inhibitor family regulation: Kip / Cip family, or INK family. INK protein specifically binds CDK4 and CDK6. Pl6ink4 (also known as M TS 1) τη is a # tumor suppressor gene, which is in many stages Mutated or eliminated in cancer. The Kip / Cip family contains proteins such as P2 1eip'Wafl, P2 7KiPi and P5 7KiP2. As previously discussed, P21 is induced by p53 and can make CDK2 / cyclin (E / A) and CDK4 / Cycline (D1 / D2 / D3) complex inactivation. Atypically low levels of P27 expression were observed in breast, colon, and prostate cancers. The opposite overexpression of cyclin E in solid tumors was confirmed to be associated with The prognosis of poor patients is related. The overexpression of cyclin D 1 is related to the following: esophageal cancer, breast cancer, squamous cell carcinoma, and non-small cell lung cancer. CDKs and related proteins coordinate and drive proliferating cells. Important roles in cell cycle situations Described above. Certain biochemical pathways, in which CDK plays a key role, have also been described. Monotherapy for the treatment of proliferative diseases (such as cancer) (using targeted genetic engineering on CDK or on specific CDKs) The development of therapies can be highly expected. CDK inhibitors can also be used to deal with other symptoms, such as viral infections, autoimmune diseases and neurodegenerative diseases. Targeted CDK treatments can also be provided in the clinical treatment of the aforementioned diseases Benefits (when used in combination with existing or new therapeutic agents). The benefits of the targeted CDK anti-cancer therapies outweigh the many existing anti-cancer agents' because they do not interact directly with DNA, they reduce Risk of the development of secondary cancer. 200524877 (7) Glycogen synthase kinase-3 (GSK 3) is a serine threonine kinase that exists in the human body in two widely expressed isomeric forms (GSK 3 α & β GSK3 / 3PGSK3 involves a role in the following situations: embryonic development, protein synthesis, cell proliferation, cell differentiation, microtubule motility, cell motility, and fine Phagocytosis. GSK3 is involved in the progression of the following disease states: diabetes, cancer, Alzheimer's disease, stroke, epilepsy, motor neuron disease, and / or head trauma. Germline-developed GSK3 and cyclin-dependent kinases ( CDKs) are most closely related. The sequence of peptidases generally recognized by GSK3 is (Ser / Thr (-XXX- (pSer / pThr), where X is any amino acid (at position (n + 1), ( n + 2), (n + 3), pSer and pThr are respectively phosphosenic acid and phosphothreonine (n + 4). GSK3 phosphorylates the first serine or threonine at position (η). Phosphatide or phosphothreonate at position (η + 4) seems to be necessary to induce GSK3 to obtain maximum enzyme substrate renewal. Cold phosphorylation of GSK3a in Ser21 or GSK3 in Ser9 leads to GSK3 inhibition. Genetic mutations and peptide competition have investigated models that lead to phosphorylation of the N-terminus of GSK3 via an autoinhibitory mechanism that can compete with phosphopeptidase substrates (S / TXXXPS / PT). Data also suggest that GSK3 a and GSKP are subtlely regulated by the phosphorylation of tyrosine 279 and 2 16 respectively. Mutation of these groups into Phe results in a decrease in kinase activity in vivo. The structure of X-ray crystallography of GSK3 helps to block light in all aspects of GSK3 activation and adjustment. GSK3 forms part of the mammalian insulin response channel and can be phosphorylated, thereby inactivating glycogen synthase. Because glycogen synthase activity is -12-200524877 (8) up-regulated, glycogen synthase (through the inhibition of GSK3) is considered to be an anti-type II or non-insulin-dependent diabetes mellitus (N〗 DDM) (a Symptoms, body tissues become resistant to insulin activation) possible methods). The cellular insulin response in liver, fat or muscle tissue is triggered by insulin binding to extracellular insulin receptors. This triggers phosphorylation of insulin receptor enzyme substrate (IRS) proteins and subsequent cell membrane recruitment. Further phosphorylation of the IRS protein directs the recruitment of phosphoinositide-3 kinase (PI3K) to the cell membrane, where a second messenger 3,4,5-triphosphate phosphate inositol phosphate (PIP3) is released. This promotes the co-localization of inositol 3-phosphate-dependent protein kinase 1 (PDK1) and protein kinase B (PKB or Akt) to the cell membrane, where PDK1 activates PKB. PKB can be phosphorylated by Ser9 or Ser21 phosphorylation, respectively, thereby inhibiting GSK3 α and / or GSKyS. Inhibition of GSK3 then triggers up-regulation of glycogen synthase activity. Therefore, a therapeutic agent that can inhibit GSK3 can induce a neoplasm response similar to the cellular response seen in insulin activation. Another in vivo enzyme of GSK3 is eukaryotic protein synthesis initiation factor 2B (eIF2B). eIF2B is inactivated through phosphorylation, and thus can inhibit protein biosynthesis. The use of rapamycin to inactivate mammalian target tadpole protein (mTOR) to inhibit G S K 3 can up-regulate protein biosynthesis. Finally, there is some evidence for the regulation of GSK 3 activity: via GSK3 via kinases that activate mitogen-activated protein kinase (MA PK) channels (such as protein kinase 1 (MAPKAP-K), which activates mitogen-activated protein kinases) Or RSK) phosphorylation to regulate GSK3 activity. These data suggest that GSK3 200524877 (9) activity can be regulated by mitogenic insulin and / or amino acid stimulators. The following has also been confirmed: GSK3 / 3 in vertebrate Wnt signaling channels Is a key component. This biochemical pathway has been shown to be important for normal embryogenic development, and it can regulate cell proliferation in normal tissues. GSK3 becomes able to inhibit Wnt stimuli. This can lead to GSK3 Enzymes (such as AX i η), adenoma polyposis large intestine (APC) gene products and cold-catenin (cateni η) de-acidification. The abnormal regulation of Wnt channels is associated with many cancers. In APC and / Mutation in or / 3-catenin is common in colorectal cancer and other cancers. Ling-catenin has been shown to be involved in cell adhesion Importance. So GSK3 can also regulate the cell adhesion process to a certain degree. In addition to the biochemical channels already described, there is the following information: GSK3 is involved in the regulation of cell division (via phosphorylation of cyclin D 1) Role), involving transcription factors such as c · Jun, CCAAT / promoter binding protein α (C / ΕΒΡα), c-Myc and / or other enzymatic agents (such as nuclear factor of activated T cells (NFATc) Phosphorylation of heat shock factor-l (HSF-1) and c-AMP response element binding protein (CREB). Although tissue-specific, GSK3 appears to play a role in regulating cell dephasing. The role of GSK3 in regulating cell dephagy (via a pre-phagy mechanism) is particularly relevant to medical symptoms (where neuron dephagy can occur). Examples of these symptoms are head trauma, stroke, epilepsy, az Heimer's disease and motor neuron disease, progressive supranuclear palsy, basal cortical degeneration, and Pick's disease. The following has been confirmed in glass tubes: GSK3 can make the microtubule-related protein Tail excessive Acidification. Tail's excessive phosphorylation disrupts the normal binding of microtubules to microtubules 14-200524877 (10), and also leads to the generation of Tau filaments in the cell. I am convinced that the progressive accumulation of these filaments leads to the final neuronal function Obstacles and degeneration. So inhibition of Tau phosphorylation (inhibition through GSK3) can provide a way to limit and / or prevent the effects of neurodegeneration. Du Pont's WO 02/3 4 72 1 shows a kind of cyclin Indeno [1,2-c] pyrazol-4-one, which is a dependent kinase inhibitor.

Bristol Myers Squibb 的 W0 0 1 /8 1 348 揭示把 5-硫代-，亞磺醯-及磺醯吡唑並[3，4-b]-吡啶當成環素依賴型激 酶抑制劑使用。W0 0 1/8 1 348 by Bristol Myers Squibb revealed the use of 5-thio-, sulfenyl- and sulfopyrazolo [3,4-b] -pyridine as cyclin-dependent kinase inhibitors.

Bristol Myers Squibb 的 W0 00/62778 揭示一種蛋白 質酪胺酸激酶抑制劑。…WO 00/62778 by Bristol Myers Squibb reveals a protein tyrosine kinase inhibitor. ...

Cyclacel的WO 01/72745A1描述2-經取代的4 -雜芳基-嘧啶及彼之製造，含有彼之藥學組成物，以及彼充當環素 依賴型激酶（CDKs)的抑制劑使用，因而用於處理增殖性病 症，如癌、白血病、乾癬等。 八8〇111*〇11的〜0 99/2 1 845描述供抑制環素依賴型激酶 (CDKs)(如 CDK1、CDK2、CDK4 及 CDK6)用的 4 -胺基噻唑 衍生物。本發明也指示含有這類化合物的藥學組成物的治 療或預防用途及利用投給有效藥量的這類化合物的方式來 處理惡性的或其他的疾病的方法。 八8〇111*〇11的〜0 0 1 /5 3 2 74揭示充作（：1)1<：激酶抑制劑的 一種化合物，彼可以包含與含氮的雜環基團連接的經酿胺 取代的苯環。 -15- 200524877 (11) WO 0 1 /9 82 90(Pharmacia & Upjohn)揭示一種充作蛋白 質激酶抑制劑的3-胺基羰基-2-甲醯胺基噻吩衍生物。WO 01 / 72745A1 by Cyclacel describes 2-substituted 4-heteroaryl-pyrimidines and their manufacture, containing their pharmaceutical compositions, and their use as inhibitors of cyclin-dependent kinases (CDKs), and are therefore used in Dealing with proliferative disorders such as cancer, leukemia, psoriasis, etc. Eight 008111 * 〇11 ~ 0 99/2 1 845 describes 4-aminothiazole derivatives for inhibiting cyclin-dependent kinases (CDKs) such as CDK1, CDK2, CDK4 and CDK6. The invention also indicates the therapeutic or prophylactic use of pharmaceutical compositions containing such compounds and methods of treating malignant or other diseases by administering an effective amount of such compounds. 8 ~ 0111 * 〇11 ~ 0 0 1/5 3 2 74 reveals a compound acting as (: 1) 1 <: kinase inhibitor, which may include a fermented amine linked to a nitrogen-containing heterocyclic group Substituted benzene ring. -15- 200524877 (11) WO 0 1/9 82 90 (Pharmacia & Upjohn) discloses a 3-aminocarbonyl-2-formamidinethiophene derivative serving as a protein kinase inhibitor.

Agouron 的 W0 01/53268 及 wo 01/02369 揭示透過蛋 白質激酶（如環素依賴型激酶或酪胺酸激酶）的抑制來仲介 或抑制細胞增殖作用的化合物。該Agouron化合物具有一 個直接或透過CH = CH或CH = N基團與吲唑環的3取代位置 連接的芳基或雜芳基環。 杜邦製藥（Du Pont Pharmaceuticals)的 WO 00/39108 及WO 02/0 06 5 1描述雜環化合物，彼是類胰朊酶的絲胺酸 蛋白酶（尤其因子Xa及凝血酶）的抑制劑。據描述：該化 合物可充作制凝藥使用或用於預防血栓性插塞病。 US 2002/0091116(Zhu 等人）、WO 01/19798 及 WO 0 1 /64642個別揭示充作因子Xa的抑制劑的不同的雜環化 合物群組。若干1 -經取代的吡唑甲醯胺被揭示及舉例說明 〇W0 01/53268 and wo 01/02369 by Agouron disclose compounds that mediate or inhibit cell proliferation through inhibition of protein kinases, such as cyclin-dependent kinases or tyrosine kinases. The Agouron compound has an aryl or heteroaryl ring connected directly or through a CH = CH or CH = N group to the 3 substitution position of the indazole ring. WO 00/39108 and WO 02/0 06 5 1 of Du Pont Pharmaceuticals describe heterocyclic compounds, which are inhibitors of trypsin-like serine proteases, especially factor Xa and thrombin. It is described that the compound can be used as a coagulant or for the prevention of thromboembolic disease. US 2002/0091116 (Zhu et al.), WO 01/19798 and WO 0 1/64642 each disclose different groups of heterocyclic compounds acting as inhibitors of factor Xa. Several 1-substituted pyrazolidines are disclosed and exemplified.

Allergan 的 US6，1 2 7,3 8 2 ， W00 1 /70668 ， WOAllergan's US6, 1 2 7, 3 8 2, W00 1/70668, WO

00/68 1 9 1，WO 97/48672，WO97/ 1 9052 及 WO97/1 9062 個 別描述具有似樹脂作用的化合物，彼可用於處理各種過度 增殖性疾病（包括癌）。 WO 02/0705 1 0(Bayer)描述一種可用於處理心血管疾 病的胺基二羧酸化合物。儘管吡唑被一般性地提及，然而 在此文件中沒有吡唑的特例。 WO 9 7/03 0 7 1 (KnolI AG)揭示一種雜環基一甲醯胺衍 生物，彼可用於處理中樞神經系統病症。吡唑類被廣泛地 -16- 200524877 (12) 提及作爲雜環基團的實例，但沒有特異的吡唑化合物被揭 示或舉例說明。 WO 97/40017(Novo Nordisk)描述蛋白質酪胺酸磷酸 化酶的調節劑。 W0 0 3/02 02 1 7 (康乃狄格大學）揭示一種吡唑3-甲醯胺 ，彼可充作處理神經病症的類大麻鹼受體調節劑。據描述 (第1 5頁）：該化合物可被用於癌的化學治療，但不淸楚該 化合物是否像抗癌藥劑般作用或彼是否被投藥作其他的用 途。 WO 0 1 /5 8 8 69(Bristol Myers Squibb)揭示特別可被用 來處理各式各樣的疾病的類大麻鹼受體調節劑。其被正視 的主要用途是處理呼吸疾病，儘管參考例是處理癌。 WO 0 1 /02 3 8 5 (Aventis Crop Science)揭示充作殺黴菌 劑的1-(喹啉-4-基）-lH-Dtt唑衍生物。1-未被取代的吡唑類 被揭示彼充作合成的中間物。 WO 2 004/03 9 7 9 5 (Fujisawa)揭示充作脫脂蛋白B分泌 作用抑制劑的醯胺類，彼含有1 -經取代的吡唑基團。把描 述：該化合物可用於處理像高脂血症的症狀。 WO 2004/0003 1 8(Cellular Genomics)揭示充作激酶調 節劑的各種被胺基取代的單環。所舉例說明的化合物中無 一是吡唑類。 【發明內容】 本發明提供一種化合物，彼具有環素依賴型激酶抑制 -17- 200524877 (13) 活性或調節活性，彼被假想將可用於預防或治療由激酶仲 介的疾病狀態或症狀。 所以，舉例來說，據假想：本發明之化合物可用於減 輕或減少癌的發病率。 於是，本發明之一方面提供一種化合物，彼可用於製 造預防或治療由環素依賴型激酶所仲介的疾病狀態或症狀 的藥劑，該化合物具有如式（〇)之結構：00/68 1 9 1, WO 97/48672, WO 97/1 9052, and WO 97/1 9062 each describe resin-like compounds that can be used to treat a variety of hyperproliferative diseases, including cancer. WO 02/0705 1 0 (Bayer) describes an amino dicarboxylic acid compound that can be used to treat cardiovascular diseases. Although pyrazole is mentioned generically, there are no special cases of pyrazole in this document. WO 9 7/03 0 7 1 (KnolI AG) discloses a heterocyclic group, methylformamide derivative, which can be used for treating central nervous system disorders. Pyrazoles are widely mentioned as examples of heterocyclic groups -16-200524877 (12), but no specific pyrazole compound has been disclosed or exemplified. WO 97/40017 (Novo Nordisk) describes modulators of protein tyrosine phosphorylase. W0 0 3/02 02 1 7 (University of Connecticut) revealed a pyrazole 3-methylamidine, which can be used as a cannabinoid receptor modulator for neurological disorders. It is described (p. 15): The compound can be used for chemotherapy of cancer, but it is not clear whether the compound acts like an anti-cancer agent or whether it is administered for other purposes. WO 0 1/5 8 8 69 (Bristol Myers Squibb) discloses cannabinoid receptor modulators that can be used particularly to treat a wide variety of diseases. Its main use being addressed is to treat respiratory diseases, although the reference example is to treat cancer. WO 0 1/02 3 8 5 (Aventis Crop Science) discloses a 1- (quinolin-4-yl) -lH-Dttazole derivative serving as a fungicide. 1-Unsubstituted pyrazoles are revealed to act as synthetic intermediates. WO 2 004/03 9 7 9 5 (Fujisawa) discloses amidines that act as inhibitors of the secretion of apolipoprotein B, which contain 1-substituted pyrazole groups. Description: The compound can be used to treat symptoms like hyperlipidemia. WO 2004/0003 18 (Cellular Genomics) discloses various amine-substituted monocyclic rings that act as kinase regulators. None of the exemplified compounds are pyrazoles. [Summary of the Invention] The present invention provides a compound which has a cyclin-dependent kinase inhibition -17- 200524877 (13) activity or modulation activity, which is supposed to be useful for preventing or treating a disease state or symptom mediated by a kinase. So, for example, it is hypothesized that the compounds of the present invention can be used to reduce or reduce the incidence of cancer. Accordingly, one aspect of the present invention provides a compound that can be used for the manufacture of a medicament for the prevention or treatment of a disease state or symptom mediated by a cyclin-dependent kinase, the compound having the structure of formula (0):

H ⑼ 或彼之鹽類或互變異構物類或N-氧化物類； 其中 X是一種R^A-NR4-基團或5或6員的碳環或雜環； A 是一個鍵、S02、C = 0、NRg(C = 0)或 〇(C = 〇)，其中 Rg是氫或C】.4烴基（被羥基或Cb4烷氧基任意取代）； Y是一個鍵或長度1、2或3個碳原子的伸烷基； R1是氫；有3至12個環原子的碳環或雜環基團；或Cl_ 8烴基，（彼被一或多個選自下列的取代基任意取代鹵素 (例如氟）、羥基、C ! ·4烴氧基、胺基、一或二-C】·4烴胺基 、有3至1 2個環原子的碳環或雜環基團，其中烴基的碳原 子中的]或2個可被選自〇、S、ΝΗ、SO、S02之中的原子 或基團任意替代； R2是氫；鹵素；C!-4烷氧基（例如甲氧基）；或被鹵素（ -18- 200524877 (14) 例如氟）、羥基或C! .4烷氧基（例如甲氧基）任意取代； R3是選自氫及有3至12個環原子的碳環及雜環基團； R4是氫或C].4烴基（被鹵素（例如氟）、羥基或C】_4烷氧 基（例如甲氧基）任意取代）。 在一個體現中，本發明提供一種化合物，彼可用於製 造預防或治療由環素依賴型激酶所仲介的疾病狀態或症狀 的藥劑，該化合物具有如式（I ^)之結構：H ⑼ or its salts or tautomers or N-oxides; where X is a R ^ A-NR4- group or a 5- or 6-membered carbocyclic or heterocyclic ring; A is a bond, S02 , C = 0, NRg (C = 0) or 〇 (C = 〇), where Rg is hydrogen or C]. 4 hydrocarbon group (optionally substituted by hydroxyl or Cb4 alkoxy group); Y is a bond or length 1, 2 Or an alkylene group of 3 carbon atoms; R1 is hydrogen; a carbocyclic or heterocyclic group having 3 to 12 ring atoms; or a Cl-8 hydrocarbon group, which is optionally substituted by one or more substituents selected from Halogen (e.g. fluorine), hydroxyl, C! · 4 alkoxy, amine, mono- or di-C] · 4 hydrocarbon amine, carbocyclic or heterocyclic group having 3 to 12 ring atoms, in which the hydrocarbon group ] Or 2 of the carbon atoms of can be arbitrarily replaced by an atom or a group selected from 0, S, NH, SO, S02; R2 is hydrogen; halogen; C! -4 alkoxy (for example, methoxy ); Or optionally substituted with halogen (-18-200524877 (14) such as fluorine), hydroxyl or C! .4 alkoxy (such as methoxy); R3 is selected from hydrogen and carbon having 3 to 12 ring atoms Ring and heterocyclic groups; R4 is hydrogen or C] .4 hydrocarbon group (by halogen (such as fluorine), hydroxyl Or C] _4 alkoxy (such as methoxy) is optionally substituted). In one embodiment, the present invention provides a compound that can be used for the manufacture of a medicament for the prevention or treatment of a disease state or condition mediated by a cyclin-dependent kinase The compound has a structure of formula (I ^):

或彼之鹽類或互變異構物類或N-氧化物類或溶劑化物類； 其中 X是一種R]-A-NR4-基團或5或6員的碳環或雜環；Or its salts or tautomers or N-oxides or solvates; where X is a R] -A-NR4- group or a 5- or 6-membered carbocyclic or heterocyclic ring;

A是一個鍵、C = 0、NRg(C = 0)或0(00) ’其中Rg是氫 或Ci.4烴基（被羥基或 &lt;：】_4烷氧基任意取代）； Y是一個鍵或1、2或3個碳原子的伸烷基； R1是氫；碳環或雜環基團（有3至12個環原子）；或c!.8 烴基，彼被一或多個選自下列基團的取代基任意取代：鹵 素（例如氟）、羥基、C】·4烴氧基、胺基、一或二- 烴胺 基、及有3至]2個環原子的碳環或雜環基團，其中烴基的 碳原子中的1或2個可被選自〇、S、NH、SO、S02的原子 或基團任意替代； R2是氫；鹵素；c】-4烷氧基（例如甲氧基）；或C !. 4烴 -19- 200524877 (15) 基（被下列基團任意取代：鹵素（例如氟）、羥基或Cl_4烷氧 基（例如甲氧基））； R3選自：氫及有3至12個環原子的碳環及雜環基團； R4是氫或C】_4烴基（被下列基團任意取代：鹵素（例如 氟）、羥基或Ci-4烷氧基（例如甲氧基））。 本發明也提供一種化合物，彼可用於製造預防或治療 由環素依賴型激酶所仲价的疾病狀態或症狀的藥劑，該化 合物具有如式⑴之結構：A is a bond, C = 0, NRg (C = 0) or 0 (00) 'where Rg is hydrogen or Ci.4 hydrocarbon group (optionally substituted by hydroxyl or <4: alkoxy group); Y is a bond Or an alkylene group of 1, 2, or 3 carbon atoms; R1 is hydrogen; a carbocyclic or heterocyclic group (with 3 to 12 ring atoms); or a c! .8 hydrocarbon group, which is selected from one or more The substituents of the following groups are arbitrarily substituted: halogen (for example, fluorine), hydroxyl, C] · 4 alkoxy, amine, mono- or di-hydrocarbamino, and carbocyclic or heterocyclic having 3 to 2 ring atoms A cyclic group in which 1 or 2 of the carbon atoms of the hydrocarbon group can be arbitrarily replaced by an atom or group selected from 0, S, NH, SO, S02; R2 is hydrogen; halogen; c] -4 alkoxy ( (Such as methoxy); or C!. 4 hydrocarbon-19- 200524877 (15) group (optionally substituted by: halogen (such as fluorine), hydroxyl or Cl_4 alkoxy (such as methoxy)); R3 selected From: hydrogen and carbocyclic and heterocyclic groups having 3 to 12 ring atoms; R4 is hydrogen or C] _4 hydrocarbon group (optionally substituted by the following groups: halogen (such as fluorine), hydroxyl or Ci-4 alkoxy (E.g. methoxy)). The present invention also provides a compound that can be used for the manufacture of a medicament for the prevention or treatment of a disease state or symptom secondary to a cyclin-dependent kinase, the compound having the structure as shown in Formula (I):

或彼之鹽類或互變異構物類或N-氧化物類或溶劑化物類； 其中 X是一種基團Ri-A-NR4-; A是一個鍵、C = 0、NRg(C = 0)或0(C = 0)，其中Rg是氫 或Ch烴基（被羥基或Cm烷氧基任意取代）； Y是一個鍵或長度1、2或3個碳原子的伸烷基； R】是氫；有3至1 2個環原子的碳環或雜環基團；或c j _ 8烴基，彼被一或多個選自下列的取代基任意取代：鹵素（ 例如氟）、羥基、C!_4烴氧基、胺基、一或二- ClM烴胺基 、有3至12個環原子的碳環或雜環基團，其中烴基的碳原 子中的1或2個可被選自〇、S、NH、SO、S02的原子或基 團任意替代； -20- 200524877 (16) R2是氫；鹵素；Cm烷氧基（例如甲氧基）；或Ci.4烴 基（被下列基團任意取代：鹵素（例如氟）、羥基或Cl_4烷氧 基（例如甲氧基））； R3選自··氫及有3至12個環原子的碳環及雜環基團； R4是氫或c!.4烴基（被下列基團任意取代：鹵素（例如 氟）、羥基或C ! _ 4烷氧基（例如甲氧基））。 在下面的任意的但書中的任何一或多項（以任何的綜 合形式）可應用於如式（0)、（IG)、（I)之化合物及彼之副族 (a-i)當A是一個鍵及γ-R3是一種烷基、環烷基、被任意取 代的苯基或被任意取代的苯烷基時，則R 1不代表一個被取 代的或未被取代的二氫萘、二氫色滿、二氫硫代色滿、四 氫喹啉或四氫苯並呋喃基團。 (a-ii)X及R3各不代表一個含有馬來醯亞胺基團的基團，其 中該馬來醯亞胺基團有氮原子連接在彼之3及4的位置上。 (a-iii )111不代表一個含有嘌呤核苷基團的基團。 (a-iv)X及R3各不代表一個含有環丁烯」’ 2_二酮基團的基 團’其中該環丁烯，2 -二酮基團有氮原子連接在彼之3 及4的位置上。 (a-v)R不代表一個含有4 -被單取代的或4，5 -被雙取代的 2 -吼D疋基或2 -嚼啶基或5 -被單取代的或5，6 -被雙取代的1 2 4 ~嗦-3-基或3-嗟嗦基的基團。 (a - v 1) X及R3各不代表一個基團，該基團含有一個與被取代 的或未被取代的吡啶、二嗪或三嗦基團連接的被取代的或 200524877 (17) 未被取代的吡唑-3 _基胺基團。 (a-vii)當a是c = 0及γ-R3是一種烷基、環烷基、被任意取 代的苯基或被任意取代的苯烷基時，則R 1不代表一個被取 代的或未被取代的四氫萘、四氫D奎啉、四氫色滿或四氫硫 代色滿基團。 U-viii)當R3是h&amp;a是一個鍵時，R1不代表一個含有一個 二-芳基、二-雜芳基或芳基雜芳基的基團。 (a-ix)R3不代表—個含有1，2，8，8a-四氫-7-甲基-環丙 [c]吡咯並[3，2，e]吲哚-4-(5h)__基團的基團。 (a-x)當Y是一個鍵時，R3是氫，A是CO及R1是一個被取代 的苯基，在苯基上的各取代基不代表基團CH2-P(0)RxRy， 其中Rx及Ry各自選自院氧基及苯基。 (a-xi)X不代表4-(第三丁氧羯基胺基）-3 -甲基咪哇_2·基端 基胺基。 本發明之另一個方面提供一個（用於製造藥劑的）如式 (I)之化合物的副族，以通式（Ia)代表：Or its salts or tautomers or N-oxides or solvates; where X is a group Ri-A-NR4-; A is a bond, C = 0, NRg (C = 0) Or 0 (C = 0), where Rg is hydrogen or Ch hydrocarbon (optionally substituted by hydroxyl or Cm alkoxy); Y is a bond or an alkylene group of 1, 2 or 3 carbon atoms in length; R] is hydrogen ; A carbocyclic or heterocyclic group having 3 to 12 ring atoms; or a cj _ 8 hydrocarbon group, which is optionally substituted with one or more substituents selected from the group consisting of halogen (for example, fluorine), hydroxyl, C! _4 Hydrocarbyloxy, amine, mono- or di-ClM hydrocarbylamine, carbocyclic or heterocyclic group having 3 to 12 ring atoms, wherein 1 or 2 of the carbon atoms of the hydrocarbon group may be selected from 0, S , NH, SO, S02 atom or group arbitrary substitution; -20- 200524877 (16) R2 is hydrogen; halogen; Cm alkoxy group (such as methoxy group); or Ci.4 hydrocarbyl group (optionally substituted by the following groups) : Halogen (such as fluorine), hydroxyl or Cl_4 alkoxy (such as methoxy)); R3 is selected from ... hydrogen and carbocyclic and heterocyclic groups having 3 to 12 ring atoms; R4 is hydrogen or c! .4 hydrocarbyl (optionally substituted by: halogen (eg Fluoro), hydroxy, or C! _ 4 alkoxy (e.g. methoxy)). Any one or more (in any comprehensive form) of any of the following provisos can be applied to compounds of formula (0), (IG), (I) and their subgroups (ai) when A is a When the bond and γ-R3 are an alkyl group, a cycloalkyl group, an optionally substituted phenyl group, or an optionally substituted phenalkyl group, then R 1 does not represent a substituted or unsubstituted dihydronaphthalene, dihydro Chroman, dihydrothiochroman, tetrahydroquinoline or tetrahydrobenzofuran groups. (a-ii) X and R3 each does not represent a group containing a maleimide group, in which the maleimide group has a nitrogen atom attached to the 3 and 4 positions. (a-iii) 111 does not represent a group containing a purine nucleoside group. (a-iv) X and R3 each does not represent a cyclobutene-containing "2-diketone group" in which the cyclobutene, 2-diketone group has a nitrogen atom attached to each of 3 and 4 Position. (av) R does not represent a group containing 4 -monosubstituted or 4,5 -disubstituted 2 -pyridyl or 2 -pyridinyl or 5 -monosubstituted or 5,6 -disubstituted 1 2 4 ~ fluoren-3-yl or 3-fluorenyl. (a-v 1) X and R3 each does not represent a group containing a substituted or 200524877 (17) unattached or substituted with a substituted or unsubstituted pyridine, diazine, or trifluorene group A substituted pyrazole-3-ylamine group. (a-vii) When a is c = 0 and γ-R3 is an alkyl, cycloalkyl, optionally substituted phenyl, or optionally substituted phenylalkyl, then R1 does not represent a substituted or Unsubstituted tetrahydronaphthalene, tetrahydro D quinoline, tetrahydrochroman or tetrahydrothiochroman groups. U-viii) When R3 is h &amp; a is a bond, R1 does not represent a group containing a di-aryl, di-heteroaryl or arylheteroaryl group. (a-ix) R3 does not represent-one containing 1,2,8,8a-tetrahydro-7-methyl-cyclopropyl [c] pyrrolo [3,2, e] indole-4- (5h) _ _ Group of groups. (ax) When Y is a bond, R3 is hydrogen, A is CO and R1 is a substituted phenyl group, each substituent on the phenyl group does not represent the group CH2-P (0) RxRy, where Rx and Ry is each selected from the group consisting of oxo and phenyl. (a-xi) X does not represent 4- (third butoxyfluorenylamino) -3 -methylimido_2. Another aspect of the present invention provides a subgroup of a compound of formula (I) (for manufacturing a medicament) represented by the general formula (Ia):

H (la) 或彼之鹽類或互變異構物類或N-氧化物類或溶劑化物類； 其中 X是基團 r1-a_nr4~ ; A是一個鍵、C = 0、NRg(C = 〇)或〇(c = 0)’其中是氫 -22- 200524877 (18) 或C|4烴基（被羥基或Ch4烷氧基任意取代）； Y是一個鍵或長度1、2或3個碳原子的伸烷基； R1是有3至12個環原子的碳環或雜環基團；或（^_8烴 基，彼被一或多個選自下列的取代基任意取代：氟、經基 、Cm烴氧基、胺基、一或二-Cm烴胺基、及有3至12個 環原子的碳環或雜環基團，其中烴基的碳原子中的丨或2個 可被選自〇、S、NH、SO、S02的原子或基團任意替代； R2是氫；鹵素；C!.4烷氧基（例如甲氧基）；或Ci.4· 基（被下列基團任意取代··鹵素（例如氟）、經基或C ! . 4院氧 基（例如甲氧基））； R3選自：氫及有3至12個環原子的碳環及雜環基團； R·4是氫或C!.4烴基（被下列基團任意取代：鹵素（例如 氟）、羥基或~·4烷氧基（例如甲氧基））。 在下面的任意的但書中的任何一或多項（以任何的綜 合形式）可應用於如式（la)之化合物及彼之副族：上面的但 書（a-i)至（a-xi)。 (b-i)R3不代表一個被橋連的氮雜二環基團。 (b-ii)當A是一個鍵時’則R3不代表一個含有一個未被取代 的或被取代的苯基的基團，在苯基之鄰位有一種被取代的 或未被取代的胺基甲醯或硫代胺基甲醯基團連接。 (b - i i i)當A是一個鍵時，則R3不代表一個含有異喹啉基或 〇奎噁啉基的基團，其各有一個被取代的或未被取代的哌啶 環或哌嗪環連接。 (b - i v)當A是一個鍵及R 1是一個烷基時，則R 3不代表一個 200524877 (19) 含有噻三嗪基團的基團。 (b-v)當R1或R3含有一個有s(-0)2環原子的雜環與碳環稠合 的基團時，該碳環不代表一個被取代的或未被取代的苯環 (b-vi)當A是一個鍵時，R1不代表一個芳烷基、雜芳烷基 或哌啶基烷基，其各有選自氰基 '被取代的或未被取代的 胺基、胺烷基、脒基、胍基及胺基甲醯基團的取代基連接 〇 (b-vii)當X是一個基團Rj-AsNR4-，A是一個鍵及R1是一個 非芳香基團時，則R3不代表一個6員的單環芳基或雜芳基（ 直接被5，6 -被稠合的二環雜芳基連接）。 本發明又一方面提供一種如式（I)及（la)之新穎化合物 的副族，該新穎化合物被化學式（lb)代表：H (la) or its salts or tautomers or N-oxides or solvates; where X is a group r1-a_nr4 ~; A is a bond, C = 0, NRg (C = 〇 ) Or 〇 (c = 0) 'where is hydrogen-22- 200524877 (18) or C | 4 hydrocarbon group (optionally substituted by hydroxyl or Ch4 alkoxy group); Y is a bond or 1, 2 or 3 carbon atoms in length R1 is a carbocyclic or heterocyclic group having 3 to 12 ring atoms; or (^ _8 hydrocarbon group, which is optionally substituted by one or more substituents selected from the group consisting of: fluorine, meridian, Cm Hydrocarbyloxy, amine, mono- or di-Cm hydrocarbylamine, and carbocyclic or heterocyclic groups having 3 to 12 ring atoms, wherein 1 or 2 of the carbon atoms of the hydrocarbon group may be selected from 0, S, NH, SO, S02 atoms or groups are arbitrarily substituted; R2 is hydrogen; halogen; C! .4 alkoxy (such as methoxy); or Ci.4 · group (optionally substituted by the following groups ... Halogen (such as fluorine), mesityl or C!. 4 (oxy) (such as methoxy); R3 is selected from: hydrogen and carbocyclic and heterocyclic groups having 3 to 12 ring atoms; R · 4 is Hydrogen or C! .4 hydrocarbyl (optionally substituted by: halogen (eg, fluorine), hydroxyl Group or ~ · 4 alkoxy group (for example, methoxy group). Any one or more (in any comprehensive form) of any of the following provisos can be applied to compounds such as formula (la) and their secondary groups. Family: The above provisos (ai) to (a-xi). (Bi) R3 does not represent a bridged azabicyclic group. (B-ii) When A is a bond, then R3 does not represent A group containing an unsubstituted or substituted phenyl group with a substituted or unsubstituted aminoformamidine or thioaminoformamidine group adjacent to the phenyl group. (B -iii) When A is a bond, then R3 does not represent a group containing isoquinolinyl or quinoxaline, each of which has a substituted or unsubstituted piperidine ring or piperazine ring attached (B-iv) When A is a bond and R 1 is an alkyl group, R 3 does not represent a 200524877 (19) group containing a thiatriazine group. (Bv) When R 1 or R 3 contains a group When the heterocyclic ring of s (-0) 2 ring is fused with a carbocyclic ring, the carbocyclic ring does not represent a substituted or unsubstituted benzene ring (b-vi). When A is a bond, R1 Does not represent an aralkyl, Aralkyl or piperidinylalkyl, each of which is attached by a substituent selected from the group consisting of cyano 'substituted or unsubstituted amine, amine alkyl, fluorenyl, guanidino, and aminoformamidine groups. (b-vii) When X is a group Rj-AsNR4-, A is a bond and R1 is a non-aromatic group, then R3 does not represent a 6-membered monocyclic aryl or heteroaryl group (directed by 5 , 6-is connected by a fused bicyclic heteroaryl). Another aspect of the present invention provides a subfamily of a novel compound such as formula (I) and (la), which is represented by the chemical formula (lb):

或彼之鹽類或互變異構物類或N -氧化物類或溶劑化物類； 其中 X是一種基團R]-A-NR4-; A是一個鍵、〇〇、NRg(C = 〇)或〇(〇〇)，其中Rg是氫 或C!.4烴基（被羥基或C^4烷氧基任意取代）； Y是一個鍵或長度1、2或3個碳原子的伸垸基； R1是一種有3至12個環原子的碳環或雜環基團；或 -24- 200524877 (20) 烴基，彼被一或多個選自下列的取代基任意取代··氣、經 基、Ci-4烴氧基、胺基、一或二-Cm烴胺基、及有3至12 個環原子的碳環或雜環基團，其中烴基碳原子中的1或2個 可被選自〇、S、NH、SO、S02的原子或基團任意替代； R2是氫；鹵素；Cm烷氧基（例如甲氧基）；或Cl 4烴 基（被下列基團任意取代：鹵素（例如氟）、羥基或Cl 4院氧 基（例如甲氧基））； R3選自：有3至12個環原子的碳環及雜環基團； R4是氫或C!_4烴基（被下列基團任意取代：鹵素（例如 氟）、羥基或Cm烷氧基（例如甲氧基））。 在下面的任意的但書中的任何一或多項（以任何的綜 合形式）可應用於如式（lb)之化合物及彼之副族： 但書（a-i)至（a-vii) ， （a-ix)及（a，xi)。 但書（b-i)至（b-vii)。 (c-i)當A是一個鍵時，R1不代表一個被取代的芳烷基、雜 芳烷基或哌啶烷基。 (c - i i)當X是一個胺基或烷胺基及γ是一個鍵時，R 3不代表 一個被雙取代的噻唑基，其中取代基中的一個選自氰基及 氟代烷基。 在但書（a-iii)中嘌呤核苷基團的引用文指的是被取代 的及未被取代的嘌呤基團，其上連接單糖化物基團（例如 戊糖或己糖）或單糖化物基團的衍生物，例如脫氧單糖化 物基團或被取代的單糖化物基團。 在但書（b-i)中被橋接的氮雜二環基團的引用文指的是 200524877 (21) 二環烷的被橋接的環系統，其中二環烷的碳原子中的一個 業己被氮原子替代。在被橋接的環系統中，二個環共享二 個以上的原子，見 Advanced Organic Chemistry，by Jerry March，4th Edition，Wiley Interscience，pages 131-133 ，1992° 本發明也提供一種如式（la)或（lb)之化合物，彼用於 製造預防或治療由環素依賴型激酶所仲介的疾病狀態或症 狀的藥劑。 在化學式（I)，（la)及（lb)中的但書（a-i)至（a-x)、（b-i) 至（b-vii)、（c-i)及（c-ii)指的是在下面的先前技藝文件中 的揭示。 (a-i)US 2003/0166932，US 6，127,382，US6，093,838 (a-ii)WO 03/03 1 440 (a-iii)WO 03/014137 (a-iv)WO 02/0 8 3 624 (a-v)WO 02/0645 86 (a-vi)WO 02/22 60 8，WO 02/22605，WO 02/22603 &amp;WO 02/22601 (a-vii)WO 97/4 8 672，WO 97/ 1 905 2 (a-viii)WO 00/06 1 69 (a-ix)US 5,5 02,06 8 (a-x)JP 07188269 (b-i) WO 03/040 147 (b-ii)WO 01/70671 -26- 200524877 (22) (b-iii)WO 0 1 /3 2 62 6 (bMv)WO 98/08845 (b-v)WO 00/59902 (b-vi)US 6,020,357，WO 99/32454 &amp; WO 98/28269 (b-vii)WO 2004/012736 (c])US 6,0 2 0,3 5 7，WO 9 7/3 2 4 5 4 &amp;WO 9 8 /2 8 2 6 9 (c - i i)U S 2 0 0 4/00 8 2 62 9 在前面的任意的但書至（a-xi)、（b-i)至（b-vii)、 (c-i)至（c-Π)中的任何一或多項（以任何的綜合形式）也可靡 用於如式（lb)、（II)、（III)、（IV)、（IVa)、（Va)、（Vb)、 (Via)、（VIb)、（VII)或（VIII)之化合物及其中所定義的副 族。 本發明也提供： •使用一種如式（la)、（lb)、（II)、（III)、（IV)、（IVa)、 (Va)、（Vb)、（Via)、（VIb)、（VII)或（VIII)之化合物及其 中所定義的副族於製造預防或治療由環素依賴型激酶所仲 介的疾病狀態或症狀的藥劑。 •一種供緩和或減少疾病或症狀的發生率用的方法，該疾 病或症狀包含或起源於哺乳動物體內異常的細胞生長，該 方法包含給哺乳動物投服有效抑制異常的細胞生長的份量 的如式（0) ' (1〇)、（I)、（la)、（lb)、（II)、(III)、（IV)、 (IA’a)、（Va)、（Vb)、（Via)、（VIb)、（VII)或（VIII)之化合 物及其中所定義的副族。 •一種供緩和或減少由環素依賴型激酶或糖原合成酶激 一 27- 200524877 (23) 酶-3所仲介的疾病狀態或症狀用的方法，該方法包含給有 需要的患者投服如式（〇)、（1°)、（I)、（la)、（lb)、（II)、 (III)、（IV)、（IVa)、（Va)、（Vb)、（via)、（VIb)、（VII)或 (VIII)之化合物及其中所定義的副族。 * 一種供預防或治療由環素依賴型激酶所仲介的疾病狀態 或症狀用的方法，該方法包含給有需要的患者投服如式 (0)、（I0)、（I)、（la)、（lb)、（II)、（III)、（IV)、（IVa)、 (Va)、（Vb)、（Via)、（VIb)、（VII)或（VIII)之化合物及其 中所定義的副族。 •一種供處理疾病或症狀用的方法，該疾病或症狀包含或 起源於哺乳動物體內異常的細胞生長，該方法包含給哺乳 動物投服有效抑制異常的細胞生長的份量的如式（0)、（1% 、⑴、（la)、（lb)、（II)、（III)、（IV)、（IVa)、（Va)、（Vb) 、（Via)、（VIb)、（VII)或（VIII)之化合物及其中所定義的 副族。 •一種供處理疾病或症狀用的方法，該疾病或疾狀包含或 起源於哺乳動物體內異常的細胞生長，該方法包含給哺乳 動物投服有效抑制環素依賴型激酶（例如CDK2)的份量的 如式（0)、（I0)、（I)、（la)、（lb)、（II)、（III)、（IV)、（IVa) 、（Va)、（Vb)、（Via)、（VIb)、（VII)或（VIII)之化合物及 其中所定義的副族。 •一種抑制環素依賴型激酶的方法，該方法包含使激酶的 如式（0)、（I0)、（I)、（la)、（lb)、（II)、（III)、（IV)、（IVa) 、（Va)、（Vb)、（Via)、（VIb)、（VII)或（VIII)之抑制激酶 200524877 (24) 化合物及其中所定義的副族接觸。 •一種調節細胞程序（例如細胞分裂作用）的方法，該方法 藉由使用如式（〇)、（1〇)、（I)、（la)、（lb)、（II)、（III)、 (IV)、（Va)、（Vb)、（Via)、（VIb)、（VII)或（VIII)之化合物 及其中所定義的副族來抑制環素依賴型激酶的活性。Or its salts or tautomers or N-oxides or solvates; where X is a group R] -A-NR4-; A is a bond, 〇〇, NRg (C = 〇) Or 〇 (〇〇), where Rg is hydrogen or C! .4 hydrocarbon group (optionally substituted by hydroxy or C ^ 4 alkoxy group); Y is a bond or a fluorenyl group of 1, 2 or 3 carbon atoms in length; R1 is a carbocyclic or heterocyclic group having 3 to 12 ring atoms; or -24-200524877 (20) hydrocarbon group, which is optionally substituted with one or more substituents selected from the group consisting of: Ci-4 hydrocarbyloxy, amine, mono- or di-Cm hydrocarbylamine, and carbocyclic or heterocyclic groups having 3 to 12 ring atoms, wherein 1 or 2 of the hydrocarbyl carbon atoms may be selected from 〇, S, NH, SO, S02 atoms or groups are arbitrarily substituted; R2 is hydrogen; halogen; Cm alkoxy (such as methoxy); or Cl 4 hydrocarbon (optionally substituted by the following groups: halogen (such as fluorine ), Hydroxyl or Cl 4 (such as methoxy); R3 is selected from: carbocyclic and heterocyclic groups having 3 to 12 ring atoms; R4 is hydrogen or C! _4 hydrocarbon group (by the following groups Any substitution: halogen (eg fluorine), hydroxyl or Cm alkane Group (e.g. methoxy)). Any one or more of the following provisos (in any comprehensive form) can be applied to compounds of formula (lb) and their subfamilies: provisos (ai) to (a-vii), (a -ix) and (a, xi). But the books (b-i) to (b-vii). (c-i) When A is a bond, R1 does not represent a substituted aralkyl, heteroaralkyl or piperidinyl. (c-i i) When X is an amine or alkylamino group and γ is a bond, R 3 does not represent a disubstituted thiazolyl group, wherein one of the substituents is selected from the group consisting of cyano and fluoroalkyl. The references to purine nucleoside groups in Daniel (a-iii) refer to substituted and unsubstituted purine groups to which a monosaccharide group (such as pentose or hexose) is attached or mono Derivatives of saccharification groups, such as deoxymonosaccharification groups or substituted monosaccharification groups. The reference to the bridged azabicyclic group in Daniel (bi) refers to 200524877 (21) the bridged ring system of bicycloalkanes, in which one of the carbon atoms of the bicycloalkane has been nitrogenated Atomic substitution. In a bridged ring system, two rings share more than two atoms, see Advanced Organic Chemistry, by Jerry March, 4th Edition, Wiley Interscience, pages 131-133, 1992 ° The present invention also provides a formula (la) Or (lb) compounds that are useful in the manufacture of a medicament for the prevention or treatment of a disease state or condition mediated by a cyclin-dependent kinase. The provisos (ai) to (ax), (bi) to (b-vii), (ci) and (c-ii) in chemical formulas (I), (la) and (lb) refer to the following Revelations from previous art files. (ai) US 2003/0166932, US 6,127,382, US 6,093,838 (a-ii) WO 03/03 1 440 (a-iii) WO 03/014137 (a-iv) WO 02/0 8 3 624 (av ) WO 02/0645 86 (a-vi) WO 02/22 60 8, WO 02/22605, WO 02/22603 &amp; WO 02/22601 (a-vii) WO 97/4 8 672, WO 97/1 905 2 (a-viii) WO 00/06 1 69 (a-ix) US 5,5 02,06 8 (ax) JP 07188269 (bi) WO 03/040 147 (b-ii) WO 01/70671 -26- 200524877 (22) (b-iii) WO 0 1/3 2 62 6 (bMv) WO 98/08845 (bv) WO 00/59902 (b-vi) US 6,020,357, WO 99/32454 &amp; WO 98/28269 ( b-vii) WO 2004/012736 (c)) US 6,0 2 0,3 5 7, WO 9 7/3 2 4 5 4 &amp; WO 9 8/2 8 2 6 9 (c-ii) US 2 0 0 4/00 8 2 62 9 Any one or more of the preceding provisos to (a-xi), (bi) to (b-vii), (ci) to (c-Π) Any comprehensive form) can also be used for formulae (lb), (II), (III), (IV), (IVa), (Va), (Vb), (Via), (VIb), (VII ) Or (VIII) compounds and the subgroups defined therein. The invention also provides: • using a formula (la), (lb), (II), (III), (IV), (IVa), (Va), (Vb), (Via), (VIb), The compound of (VII) or (VIII) and a subgroup thereof defined therein are used for the manufacture of an agent for preventing or treating a disease state or symptom mediated by a cyclin-dependent kinase. • A method for alleviating or reducing the incidence of a disease or symptom that includes or originates from abnormal cell growth in a mammal, the method comprising administering to the mammal an amount effective to inhibit abnormal cell growth such as Formula (0) '(1〇), (I), (la), (lb), (II), (III), (IV), (IA'a), (Va), (Vb), (Via ), (VIb), (VII) or (VIII) compounds and the subgroups defined therein. A method for alleviating or reducing a disease state or symptom mediated by a cyclin-dependent kinase or glycogen synthase 27-200524877 (23) enzyme-3, the method comprising administering to a patient in need such as (0), (1 °), (I), (la), (lb), (II), (III), (IV), (IVa), (Va), (Vb), (via), Compounds of (VIb), (VII) or (VIII) and the subgroups defined therein. * A method for preventing or treating a disease state or symptom mediated by a cyclin-dependent kinase, which method comprises administering to a patient in need such formulas (0), (I0), (I), (la) , (Lb), (II), (III), (IV), (IVa), (Va), (Vb), (Via), (VIb), (VII) or (VIII) compounds and their definitions Of the tribe. A method for treating a disease or symptom, the disease or symptom comprising or originating from abnormal cell growth in a mammal, the method comprising administering to the mammal an effective amount of inhibiting abnormal cell growth as shown in formula (0), (1%, ⑴, (la), (lb), (II), (III), (IV), (IVa), (Va), (Vb), (Via), (VIb), (VII) or Compounds of (VIII) and the subgroups defined therein. A method for treating a disease or condition comprising or originating from abnormal cell growth in a mammal, the method comprising administering to a mammal effective Inhibition of the amount of cyclin-dependent kinases (eg, CDK2) is as follows: (0), (I0), (I), (la), (lb), (II), (III), (IV), (IVa) , (Va), (Vb), (Via), (VIb), (VII) or (VIII) compounds and the subgroups defined therein. A method for inhibiting a cyclin-dependent kinase, the method comprising making a kinase The formula is (0), (I0), (I), (la), (lb), (II), (III), (IV), (IVa), (Va), (Vb), (Via) , VIb), (VII), or (VIII) inhibitory kinase 200524877 (24) compounds and their defined subfamily contacts. • A method for modulating cellular processes, such as cell division, by using the formula (〇 ), (10), (I), (la), (lb), (II), (III), (IV), (Va), (Vb), (Via), (VIb), (VII) Or a compound of (VIII) and a subfamily defined therein to inhibit the activity of a cyclin-dependent kinase.

本發明之化合物也被認爲是糖原合成酶激酶-3 (GSK3) 的抑制劑，於是本發明也提供如式（〇)、（”）、（I)、（la)、 (lb)、（II)、（III)、（IV)、（IVa)、（Va)、（Vb)、（Via)、 (VIb)、（VII)或（VIII)之化合物及其中所定義的副族的激酶 抑制劑或調節劑的方法及用途（但其中的激酶是糖原合成 酶激酶-3 )。 本發明的又一方面提供：The compounds of the present invention are also considered to be inhibitors of glycogen synthase kinase-3 (GSK3), so the present invention also provides formulae such as (0), ("), (I), (la), (lb), Compounds of (II), (III), (IV), (IVa), (Va), (Vb), (Via), (VIb), (VII) or (VIII) and their subfamily kinases as defined therein Methods and uses of inhibitors or modulators (but where the kinase is glycogen synthase kinase-3). Another aspect of the invention provides:

•一*種藥學組成物，彼包含一種如式（la)、（lb)、（II)、 (III)、（IV)、（IVa)、（Va)、（Vb)、（Via)、（VIb)、（VII)或 (VIII)之化合物及其中所定義的副族及一種藥學上可接受 的載體。 •用於藥劑中的如式（lb)、（II)、（III)、（IV)、（IVa)、（Va) 、（Vb)、（Via)、（VIb)、（VII)或（VIII)之化合物及其中所 定義的副族。 •使用如式（〇)、（1〇)、（I)、（la)、（lb)、（II)、（III)、（IV) 、（IVa)、（Va)、（Vb)、（Via)、（VIb)、（VII)或（VIII)之化 合物及其中所定義的副族於製造預防或治療在本說明書中 所揭不的疾病狀悲或症狀中的任何一'種用的藥劑。 •一種供處理或預防在本說明書中所揭示的疾病狀態或症 -29- 200524877 (25) 狀中的任何一種用的方法，該方法包含給有需要的患者投 服治療上有效份量的如式（0)、（IG)、（I)、（la)、（lb)、（II) 、（III)、（IV)、（iva)、（Va)、（Vb)、（Via)、（VIb)、（VII) 或（VIII)之化合物及其中所定義的副族。 •一種供緩和或減少在本說明書中所揭示的疾病狀態或症 狀的發生率用的方法，該方法包含給有需要的患者投服治 療上有效份量的如式（〇)、（IG)、（I)、（la)、（lb)、（II)、 (III) 、（IV)、（IVa)、（Va)、（Vb)、（Via)、（VIb)、（VII)或 (VIII)之化合物及其中所定義的副族。 •一種供診斷及處理由環素依賴型激酶所仲介的疾病狀態 或症狀用的方法，該方法包含··（i)篩選患者以確定是否患 者正或可能正患有的疾病或症狀可以有抗環素依賴型激酶 活性的化合物處理；（ii)確定患者所患的疾病或症狀所顯 示的徵兆’接著給患者投服如式（〇)、（IG)、⑴、（Ia)、 (lb)、（II)、（in)、（IV)、（IVa)、（Va)、（Vb)、（VIa)、 (VIb)、（VII)或（VIII)之化合物及其中所定義的副族。 •使用一種如式（〇)、（I。）、⑴、（Ia)、（Ib)、（11)、（111)、 (IV) 、（IVa)、（Va)、（Vb)、（Via)、（VIb)、（VII)或（VIH) 之化合物及其中所定義的副族於製造藥劑，該藥劑可以處 理或預防業已被篩選及確定患有可以有抗環素依賴型激酶 的活性的化合物處理的疾病或症狀或有患有該疾病或症狀 的風險的患者體內的疾病或症狀。 在各種前述的本發明之使用、方法及其他的方面，以 及在下面被陳述的本發明之任何的方面及體現中，如式 -30- 200524877 (26) (0)、（I0)、（I)、（la)、（lb)、（II)、（ΠΙ)、（IV)、（IVa)、 (Va)、（Vb)、（Via)、（VIb)、（VII)或（VIII)之化合物及其 中所定義的副族的引用包括在其之範圍內的本發明之化合 物的鹽類或溶劑化物類或互變異構物類或N-氧化物類。 泛用的參考例及定義 在下面的泛用的參考例及定義要應用於X、Y、Rg、 R 1至R4部份及彼之任可的副定義、副族或體現中的每一·個 ，除非另有指示。 在本說明書中，如式（1)之化合物的參考例包括：化 學式（〇)、（I。）、（la)、（lb)、（II)、（III)、（IV)、（IVa)、 (Va)、（Vb)、（Via)、（VIb)、（VII)或（VIII)及副族，以及 如式（0)、（I0)、（la) ' (lb)、（II)、（III)、（IV)、（IVa)、 (Va)、（Vb)、（Via)、（VIb)、（VII)或（VIII)之實例或體現 ，除非另有指示。 所以（舉例而言），特別在治療用途、藥學調和物及製 造化合物（指的是式（I)之化合物）的方法的參考例上，其也 表示化學式（〇)、（IG)、（la)、（lb)、（II)、（III)、（IV)、 (IVa)、（Va)、（Vb)、（Via)、（VIb)、（VII)或（VIII)及副族 ，以及如式（〇)、（I〇)、（la)、（lb)、（II)、（III)、（IV)、 (IVa)、（Va)、（Vb)、（Via)、（VIb)、（VII)或（VIII)之實例 或體現。 同樣地，在如式（I)之化合物的參考例、體現及實例 的場合中，其也可應用於化學式（〇)、（1G)、（la)、（lb)、 -31 - 200524877 (27) (II)、（III)、（IV)、（IVa)、（Va)、（Vb)、（Via)、（VIb)、 (VII)或（VIII)及副族，以及如式（0)、（IG)、（la)、（Ib)、 (II)、（III)、（IV)、（IVa)、（Va)、（Vb)、（Via)、（VIb)、 (VII)或（VIII)之實例或體現，除非另有指示。 在本說明書中所使用的 ''碳環基〃及 ''雜環基〃的參 考例要（除非另外指定）包括芳香環系統及非芳香環系統二 者。所以 ''碳環及雜環基團〃包括：芳香的、非芳香的、 未被飽和的，被部份飽和的及被完全飽和的碳環及雜環系 統。通常，這樣的基團可能是單環的或雙環的，可能含有 (例如3至12個環原子，較常含有5至10個環原子。單環基 團的實例是含有3、4、5、6、7及8個環原子（較常含有3至 7個，較佳5或6個環原子）的單環基團。雙環基團的實例是 含有8、9、10、11及12個環原子（較常含有9或10個環原子 )的雙環基團。 碳環或雜環基團可以是芳基或雜芳基，彼有5至12個 環原子，較常有5至1 〇個環原子。、'芳基〃代表有芳香特 徵的碳環基團，、、雜芳基〃代表有芳香特徵的雜環基團。 ''芳基〃及 '、雜芳基〃包含多環的（例如雙環的）環系統， 其中一或多個環是非芳香的，條件是至少一個環是芳香的 。在這樣的多環系統中，基團被芳香環或被非芳香環連接 。芳基或雜芳基可以是單環的或雙環的基團，可以是未被 取代的或被一或多個取代基（例如一或多個R 1 G)取代。 ''非芳香基團〃包含不飽和的環系統（無芳香特徵）， 部份飽和的及完全飽和的碳環及雜環系統。 '、不飽和的環 -32- 200524877 (28) &quot;及'v部份飽和的環〃代表環結構含有共用一個以上的共 價鍵的原子，即環含有至少一個多重鍵，例如C = C，C三C 或N = C鍵。 '、完全飽和的環〃代表環原子之間沒有多重鍵 。飽和的碳環基團包括下面所定義的環烷基。部份飽和的 碳環基團包括下面所定義的環烯基，例如環戊烯基、環庚 儲基及環辛嫌基。環燦基的一個更進一步的實例是環己嫌 基〇 雜芳基的實例是單環基團及雙環基團，彼含有5至12 個環原子（較常含有5至10個環原子）。雜芳基可以是5員或 6員的單環或雙環（由稠合的5員環及6員環或二個稠合的6 員環或例如二個稠合的5員環）。各環可含有至多約4個雜 原子（一般選自氮、硫及氧）。一般雜芳基環會含有至多4 個雜原子，較典型含有至多3個雜原子，較常含有至多2個 雜原子。例如一個雜原子。在一個體現中，雜芳基環含有 至少一個氮原子環原子。在雜芳基環中的氮原子可以是鹼 性的（在咪唑或吡啶中），或非鹼性的（在吲哚或吡咯氮中） 。通常在雜芳基中存在的鹼性的氮原子的數·，目（包括環的 任何胺基取代基）會小於5。 5員的雜芳基的實例包括（但不限於）：吡略、I]夫喃、 噻吩、咪唑、呋咱、噁唑、噁二唑、噁三唑、異噁唑、噻 唑、異噻唑、吡唑、三唑及四唑基團。 6員的雜芳基的實例包括（但不限於）··吡啶、吡嗪、 噠嗪、嘧啶及三嗪。 一種雙環的雜芳基可以是（例如）一個選自下列的基團 -33- 200524877 (29) a)苯環，彼與5員或6員的環（含有1、2或3個環雜原子）稠合 b) 吡啶環，彼與5員或6員的環（含有1、2或3個環雜原子） 稠合； c) 嘧啶環，彼與5員或6員的環（含有1或2個環雜原子）稠合• A * pharmaceutical composition, which contains a formula such as (la), (lb), (II), (III), (IV), (IVa), (Va), (Vb), (Via), ( VIb), (VII) or (VIII) compounds and their subgroups as defined therein and a pharmaceutically acceptable carrier. • Formulas (lb), (II), (III), (IV), (IVa), (Va), (Vb), (Via), (VIb), (VII) or (VIII) used in pharmaceuticals ) Compounds and the subgroups defined therein. • Use formulas (〇), (10), (I), (la), (lb), (II), (III), (IV), (IVa), (Va), (Vb), ( Via), (VIb), (VII) or (VIII) compounds and the subgroups defined therein for the manufacture or prevention of any one of the symptoms or symptoms of diseases not disclosed in this specification . A method for treating or preventing any one of the disease states or conditions disclosed in the present specification 29-200524877 (25), the method comprising administering to a patient in need thereof a therapeutically effective amount of the formula (0), (IG), (I), (la), (lb), (II), (III), (IV), (iva), (Va), (Vb), (Via), (VIb ), (VII) or (VIII) compounds and the subgroups defined therein. A method for alleviating or reducing the incidence of a disease state or symptom disclosed in this specification, which method comprises administering to a patient in need thereof a therapeutically effective amount of formulae (0), (IG), ( I), (la), (lb), (II), (III), (IV), (IVa), (Va), (Vb), (Via), (VIb), (VII), or (VIII) Compounds and the subgroups defined in them. A method for diagnosing and managing a disease state or symptom mediated by a cyclin-dependent kinase, the method comprising: (i) screening patients to determine if the patient is or may be suffering from a disease or symptom that is resistant Compound treatment with cyclin-dependent kinase activity; (ii) determining signs of disease or symptoms exhibited by the patient 'and then administering the patient to formulae (0), (IG), ⑴, (Ia), (lb) , (II), (in), (IV), (IVa), (Va), (Vb), (VIa), (VIb), (VII) or (VIII) compounds and the subgroups defined therein. • Use a formula such as (0), (I.), ⑴, (Ia), (Ib), (11), (111), (IV), (IVa), (Va), (Vb), (Via ), (VIb), (VII), or (VIH) compounds and their subgroups defined in the manufacture of pharmaceuticals that can treat or prevent patients who have been screened and identified to have anti-cyclin-dependent kinase activity A disease or condition treated by a compound, or a disease or condition in a patient at risk for the disease or condition. In each of the foregoing uses, methods, and other aspects of the invention, as well as in any aspect and embodiment of the invention set forth below, such as the formula -30- 200524877 (26) (0), (I0), (I ), (La), (lb), (II), (ΠΙ), (IV), (IVa), (Va), (Vb), (Via), (VIb), (VII), or (VIII) The references to the compounds and their defined subgroups include within their scope salts or solvates or tautomers or N-oxides of the compounds of the invention. General reference examples and definitions The following general reference examples and definitions are to be applied to each of X, Y, Rg, R 1 to R4 and any of its sub-definitions, sub-families, or manifestations. Unless otherwise instructed. In this specification, reference examples of the compound of formula (1) include: Chemical formulas (〇), (I.), (la), (lb), (II), (III), (IV), (IVa) , (Va), (Vb), (Via), (VIb), (VII) or (VIII) and the subgroups, and formulas (0), (I0), (la) '(lb), (II) (III), (IV), (IVa), (Va), (Vb), (Via), (VIb), (VII), or (VIII) unless otherwise indicated. So (for example), especially in reference examples of therapeutic uses, pharmaceutical blends, and methods of making compounds (referring to compounds of formula (I)), they also represent chemical formulas (0), (IG), (la ), (Lb), (II), (III), (IV), (IVa), (Va), (Vb), (Via), (VIb), (VII) or (VIII) and subgroups, and Such as formula (〇), (I〇), (la), (lb), (II), (III), (IV), (IVa), (Va), (Vb), (Via), (VIb) , (VII) or (VIII) Examples or Embodiments. Similarly, in the case of the reference example, embodiment and example of the compound of formula (I), it can also be applied to the chemical formulas (〇), (1G), (la), (lb), -31-200524877 (27 ) (II), (III), (IV), (IVa), (Va), (Vb), (Via), (VIb), (VII) or (VIII) and the subgroups, and as shown in formula (0) , (IG), (la), (Ib), (II), (III), (IV), (IVa), (Va), (Vb), (Via), (VIb), (VII), or ( Examples or manifestations of VIII), unless otherwise indicated. The reference examples of `` carbocyclyl '' and `` heterocyclyl '' used in this specification include (unless otherwise specified) both aromatic ring systems and non-aromatic ring systems. Therefore, "carbocyclic and heterocyclic groups" include: aromatic, non-aromatic, unsaturated, partially saturated and fully saturated carbocyclic and heterocyclic systems. In general, such groups may be monocyclic or bicyclic and may contain (for example, 3 to 12 ring atoms, and more often 5 to 10 ring atoms. Examples of monocyclic groups are those containing 3, 4, 5, Monocyclic groups of 6, 7, and 8 ring atoms (more often containing 3 to 7, preferably 5 or 6 ring atoms). Examples of bicyclic groups are 8, 9, 10, 11 and 12 rings A bicyclic group of atoms (commonly containing 9 or 10 ring atoms). A carbocyclic or heterocyclic group can be an aryl or heteroaryl group, which has 5 to 12 ring atoms and more often 5 to 10 Ring atoms. '' Aryl 'represents a carbocyclic group with aromatic characteristics, and heteroaryl' represents a heterocyclic group with aromatic characteristics. '' Aryl 'and', heteroaryl 'contain polycyclic (Eg bicyclic) ring systems in which one or more rings are non-aromatic, provided that at least one ring is aromatic. In such polycyclic systems, the groups are connected by an aromatic ring or by a non-aromatic ring. An aryl or Heteroaryl groups can be monocyclic or bicyclic groups and can be unsubstituted or substituted with one or more substituents (eg, one or more R 1 G). '' Non-aromatic Group 〃 contains unsaturated ring systems (without aromatic characteristics), partially saturated and fully saturated carbocyclic and heterocyclic systems. ', Unsaturated ring-32- 200524877 (28) &quot; and' v partially saturated The ring 〃 represents that the ring structure contains atoms that share more than one covalent bond, that is, the ring contains at least one multiple bond, such as C = C, C triple C, or N = C bond. ', A fully saturated ring 〃 represents the ring atom. There are no multiple bonds between them. Saturated carbocyclic groups include cycloalkyl groups as defined below. Partially saturated carbocyclic groups include cycloalkenyl groups as defined below, such as cyclopentenyl, cycloheptyl and cyclooctyl A further example of cyclocanyl is cyclohexyl. Examples of heteroaryl are monocyclic and bicyclic groups, which contain 5 to 12 ring atoms (more often 5 to 10 rings) Atoms). Heteroaryl can be a 5- or 6-membered monocyclic or bicyclic ring (consisting of a fused 5-membered ring and a 6-membered ring or two fused 6-membered rings or, for example, two fused 5-membered rings) Each ring can contain up to about 4 heteroatoms (typically selected from nitrogen, sulfur and oxygen). Generally heteroaryl rings will contain up to 4 heterogens , More typically contains up to 3 heteroatoms, and more often contains up to 2 heteroatoms. For example, a heteroatom. In one embodiment, the heteroaryl ring contains at least one nitrogen atom ring atom. The nitrogen in the heteroaryl ring Atoms can be basic (in imidazole or pyridine) or non-basic (in indole or pyrrole nitrogen). The number of basic nitrogen atoms usually present in heteroaryl groups, including rings Any amine substituent) will be less than 5. Examples of 5-membered heteroaryl groups include (but are not limited to): pyriole, I] furan, thiophene, imidazole, furan, oxazole, oxadiazole, oxatriazole Azole, isoxazole, thiazole, isothiazole, pyrazole, triazole, and tetrazole groups. Examples of 6-membered heteroaryl include, but are not limited to, pyridine, pyrazine, pyridazine, pyrimidine, and triazine . A bicyclic heteroaryl group can be, for example, a group selected from the group -33- 200524877 (29) a) a benzene ring, which has a 5- or 6-membered ring (containing 1, 2 or 3 ring heteroatoms) ) Fused b) pyridine ring, which is fused with a 5- or 6-membered ring (containing 1, 2 or 3 ring heteroatoms); c) pyrimidine ring, which is with a 5- or 6-membered ring (containing 1 or 2 ring heteroatoms) fused

d) 吡咯環，彼與5員或6員的環（含有1、2或3個環雜原子) 稠合； e) 吡唑環，彼與5員或6員的環（含有1或2個環雜原子）稠合 Ο咪唑環，彼與5員或6員的環（含有1或.2個環雜原子）稠合 g) 噁唑環，彼與5員或6員的環（含有1或2個環雜原子）稠合d) pyrrole ring, which is fused to a 5- or 6-membered ring (containing 1, 2 or 3 ring heteroatoms); e) pyrazole ring, which is to a 5- or 6-membered ring (containing 1 or 2 members) A ring heteroatom) is fused to a 0-imidazole ring, which is fused to a 5- or 6-membered ring (containing 1 or .2 ring heteroatoms) g) An oxazole ring, which is fused to a 5- or 6-membered ring (containing 1 Or 2 ring heteroatoms) condensed

h) 異噁唑環，彼與5員或6員的環（含有1或2個環雜原子）稠 合； i) 噻唑環，彼與5員或6員的環（含有1或2個環雜原子）稠合 j) 異噻唑環，彼與5員或6員的環（含有1或2個環雜原子）稠 合； k) 噻吩環，彼與5員或6員的環（含有1、2或3個環雜原子） 稠合； l) 呋喃環，彼與5員或6員的環（含有]、2或3個環雜原子）稠 -34- 200524877 (30) 么 · Ο ， m)噁唑環，彼與5員或6員的環（含有1或2個環雜原子）稠合 η)異噁唑環，彼與5員或6員的環（含有1或2個環雜原子）稠 合； 〇)環己基環，彼與5員或6員的環（含有1、2或3個環雜原子 )稠合；h) Isoxazole ring, which is fused with a 5- or 6-membered ring (containing 1 or 2 ring heteroatoms); i) Thiazole ring, which is with a 5- or 6-membered ring (containing 1 or 2 rings) Heteroatom) fused j) Isothiazole ring, which is fused with a 5- or 6-membered ring (containing 1 or 2 ring heteroatoms); k) Thiophene ring, which is fused with a 5- or 6-membered ring (containing 1 , 2 or 3 ring heteroatoms) fused; l) a furan ring, which is fused to a 5- or 6-membered ring (containing), 2 or 3 ring heteroatoms -34- 200524877 (30) m) oxazole ring, which is fused to a 5- or 6-membered ring (containing 1 or 2 ring heteroatoms) η) isoxazole ring, which is fused to a 5- or 6-membered ring (containing 1 or 2 rings) Heteroatoms) are fused; o) a cyclohexyl ring, which is fused with a 5- or 6-membered ring (containing 1, 2 or 3 ring heteroatoms);

Ρ)環戊基環，彼與5員或6員的環（含有1、2或3個環雜原子 )稠合； 雙環的雜芳基（含有一個5員環，彼與另一個5員環稠 合）的特例包括（但不限於）：咪唑並噻唑（例如咪唑並[2， Ι-b]噻唑）及咪唑並咪唑（例如咪唑並[1，2-a]咪唑）。P) a cyclopentyl ring, which is fused with a 5- or 6-membered ring (containing 1, 2 or 3 ring heteroatoms); a bicyclic heteroaryl (containing one 5-membered ring, which is in contact with another 5-membered ring) Specific examples of fused) include (but are not limited to): imidazothiazolyl (eg, imidazo [2, 1-b] thiazole) and imidazomidazole (eg, imidazo [1,2-a] imidazole).

雙環的雜芳基（含有一個6員環，彼與另一個5員環稠 合）的特例包括（但不限於）：苯並呋喃、苯並噻吩、苯並 咪唑、苯並噁唑、異苯並噁唑、苯並異噁唑、苯並噻唑、 苯並異噻D坐、異苯並呋喃、吲哚、異吲哚、吲哚嗪、吲哚 滿、異吲哚滿、嘌呤（例如腺嘌呤、鳥嘌呤）、吲唑、吡唑 並呢、啶（例如吡唑並[1，5 - a]嘧啶）、三唑並嘧啶（例如[]， 2 ’ 4]二唑並[丨，5 _a]嘧啶）、苯並二噁茂及吡唑並吡啶（例 如吡唑並[1，5-a]吡啶）基團。 雙環的雜芳基（含有二個稠合的6員環）的特例包括（但 不限於）：鸣啉、異鸣啉、色滿、硫代色滿、色烯、異色 烯、色滿、異色滿、苯並二噁烷、鸣嗪、苯並噁嗪、苯並 二嗪、吡啶缒吡啶、_噁啉、喹唑啉、噌啉、酞嗪、萘啶 -35 - 200524877 (31) 及蝶啶基團。Specific examples of bicyclic heteroaryl groups (containing one 6-membered ring that are fused with another 5-membered ring) include (but are not limited to): benzofuran, benzothiophene, benzimidazole, benzoxazole, isobenzene Benzoxazole, benzoisoxazole, benzothiazole, benzoisothiazine, isobenzofuran, indole, isoindole, indoxazine, indolin, isoindolin, purine (eg gland Purines, guanines), indazoles, pyrazolones, pyrimides (for example, pyrazolo [1,5-a] pyrimidine), triazolopyrimidines (for example, [], 2 '4] diazolo [丨, 5 (a) pyrimidine), benzodioxo, and pyrazolopyridine (eg, pyrazolo [1,5-a] pyridine) groups. Specific examples of bicyclic heteroaryls (containing two fused 6-membered rings) include (but are not limited to): Hematophylline, Isomaline, Color Manganese, Thiochrome Manganese, Trypene, Isoprenene, Manganese, Heterochromatic Manganese, benzodioxane, songazine, benzoxazine, benzodiazine, pyridinium pyridine, _oxoline, quinazoline, oxoline, phthalazine, naphthyridine-35-200524877 (31) and butterfly Pyridine group.

雜芳基的一個亞群包含：吼Π定基、吼咯基、D夫喃基、 噻吩基、咪唑基、噁唑基、噁二唑基、噁三唑基、異噁唑 基、噻唑基、異噻唑基、吡唑基、吡嗪基、噠嗪基、嚼陡 基、三嗪基、三唑基、四唑基、喹啉基、異喹啉基、苯並 口夫喃基、苯並噻吩基、色滿基、硫代色滿基、苯並咪D坐基 、苯並噁唑基、苯並異噁唑基、苯並噻唑基、苯並異噻口坐 基、異苯並呋喃基、吲哚基、異吲哚基、吲哚嗪基、巧丨D朵 滿基、異吲哚滿基、嘌呤基（例如腺嘌呤、鳥嘌D令y、间^ 基、苯並二D惡茂基、色嫌基、異色燃基、異色滿基、苯並 二噁烷基、喹嗪基、苯並噁嗪基、苯並二嗪基、1¾ D定並口比 啶基、喹噁啉基、曈唑啉基、噌啉基、酞嗪基、萘Β定基&amp; 蝶啶基。A subgroup of heteroaryls includes: sulfonyl, sulfolyl, D-furanyl, thienyl, imidazolyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, Isothiazolyl, pyrazolyl, pyrazinyl, pyridazinyl, glutamyl, triazinyl, triazolyl, tetrazolyl, quinolinyl, isoquinolinyl, benzohuffanyl, benzo Thienyl, chromanyl, thiochromanyl, benzimidyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, isobenzofuran Group, indolyl, isoindolyl, indolazinyl, d-allyl, isoindolyl, purine (for example, adenine, guanine, D, y, m-, benzo, D) Oxacenyl, chromoyl, heterochromic, heterochroman, benzodioxanyl, quinazinyl, benzoxazinyl, benzodiazinyl, 1¾D aziridinyl, quinoxaline Group, oxazoline group, fluorenyl group, phthalazinyl group, naphthalene group B &amp; pteridinyl group.

多環的芳基及雜芳基（含有一個芳香環及〜個非男：胃 環）的實例包括：四氫萘、四氫異喹啉、四氫嗖啉.、二胃 苯並噻嗯、二氫苯並呋喃、2，3 -二氫-苯並[】，4 μ二氧雜 環己烯基、苯並[1，3]-二噁茂、4，5，6，7-四氫苯並〇夫 喃、吲哚滿及茚滿基團。 碳環的芳基的實例包括：苯基、萘基、茚_、四氯蔡 基。 非芳香雜環基團的實例包括··未被取代的或被取代白勺 (被一或多個基團R1G)雜環基（有3至12個環原子、〜般$至 12個環原子、較常有5至1〇個環原子）。非芳香雜瓚基團可 以是單的或雙環的（例如），一般有〗至5個雜原子環原子 -36- 200524877 (32) (較常有〗，2 ’ 3或4個雜原子環原子），雜原子環原子一般 選自氮、氧及硫。 當硫存在時，在鄰近的原子及基團的特性允許之下’ 硫可以- S-’-S(O) -或-S(0)2 -存在。 ， 雜環基團可以含有（例如）：環狀的醚基團（例如在四 氫呋喃及二噁烷中的）、環狀的硫醚基團（例如在四氫噻吩 及二噻烷中的）、環狀的胺基團（例如在吡咯烷中的）、環 狀的醯胺基團（例如在吡咯烷酮中的）、環狀的硫醯胺、環 狀的硫酯、環狀的酯基團（例如在丁內酯中的）、環狀的硕 (例如在硫烷及硫烯中的）、環狀的亞硕、環狀的磺胺及彼 之綜合（例如嗎啉及硫代嗎啉及彼之S-氧化物及S，S-二氧 化物）。雜環基團的進一步實例是含有環狀的脲基團的基 團（例如在咪唑烷-2-酮中的）。 在雜環基團的一個亞組中’雜環基團含有環狀的醚基 團（例如在四氫呋喃及二噁烷中的）、環狀的硫醚基團（例 如在四氫噻吩及二噻烷中的）、環狀的胺基團（例如在吡咯 烷中的）、環狀的硕（例如在硫烷及硫烯中的）、環狀的亜 砸、環狀的磺胺及彼之綜合（例如硫代嗎啉）° 單環的非芳香雜環基團的實例包括：5、6及7員的單 環的雜環基。彼之特別包括··嗎啉、_ 0定（例如1 - _啶基 、2 -哌啶基、3 -哌啶基及4 -哌啶基、）、批咯院（例如1 -毗 咯烷基、2-吡咯烷基及3-吡咯烷基）、_咯院酮、吼喃（2H-吡喃或4H-毗喃）、二氫噻吩 '二氫吡喃、二氫呋喃、二氫 噻哇、四氫呋喃、四氫噻吩、二噁院、四氫吡喃（例如[ -37- 200524877 (33) 四氫吡喃基）、咪唑啉、咪唑啉酮、噁唑啉、噻哇啉、2_ 吡唑啉、吼唑烷、哌嗪及N -烷基I派嗪（如N -甲基哌嗪）°另 外的實例包括硫代嗎啉及彼之S -氧化物及S，S -二氧化物（ 尤其硫代嗎啉）。又另外的實例包括··吖丁啶、_ D定酮、 哌腙、N-烷基哌啶（如N-甲基哌啶）。Examples of polycyclic aryl and heteroaryl groups (containing an aromatic ring and ~ non-male: gastric ring) include: tetrahydronaphthalene, tetrahydroisoquinoline, tetrahydropyridoline, digastric benzothion, Dihydrobenzofuran, 2,3-dihydro-benzo [], 4 μdioxelenyl, benzo [1,3] -dioxo, 4,5,6,7-tetrahydro Benzofuran, indole and indane groups. Examples of the carbocyclic aryl group include: phenyl, naphthyl, indene, and tetrachlorozetyl. Examples of non-aromatic heterocyclic groups include ... unsubstituted or substituted (by one or more groups R1G) heterocyclic groups (having 3 to 12 ring atoms, ~ $ 12 to 12 ring atoms) , More often 5 to 10 ring atoms). Non-aromatic heterofluorene groups can be mono- or bicyclic (for example), and generally have 5 to 5 heteroatom ring atoms -36- 200524877 (32) (more often, 2 '3 or 4 heteroatom ring atoms ), Heteroatom ring atoms are generally selected from nitrogen, oxygen and sulfur. When sulfur is present, &apos; sulfur may be -S- &apos; -S (O)-or -S (0) 2 &lt; &quot; &gt;, as allowed by the properties of adjacent atoms and groups. , Heterocyclic groups may contain (for example): cyclic ether groups (for example in tetrahydrofuran and dioxane), cyclic thioether groups (for example in tetrahydrothiophene and dithiane), Cyclic amine groups (such as in pyrrolidine), cyclic amido groups (such as in pyrrolidone), cyclic thiostilamine, cyclic thioesters, cyclic ester groups ( For example in butyrolactone), cyclic masters (such as in sulfanes and thioenes), cyclic sub-masters, cyclic sulfonamides, and combinations thereof (such as morpholine and thiomorpholine and other S-oxides and S, S-dioxides). A further example of a heterocyclic group is a group containing a cyclic urea group (e.g., in imidazolidin-2-one). In a subgroup of heterocyclic groups, 'heterocyclic groups contain cyclic ether groups (such as in tetrahydrofuran and dioxane), cyclic thioether groups (such as in tetrahydrothiophene and dithia In alkane), cyclic amine groups (such as in pyrrolidine), cyclic masters (such as in sulfane and sulfene), cyclic thorium, cyclic sulfonamide, and combinations thereof (Eg, thiomorpholine) ° Examples of monocyclic non-aromatic heterocyclic groups include: 5, 6 and 7-membered monocyclic heterocyclic groups. In particular, they include ... morpholine, _ 0 (such as 1-_ pyridyl, 2-piperidinyl, 3-piperidinyl and 4-piperidinyl, etc.), batches (such as 1-pyrrolidine Group, 2-pyrrolidinyl and 3-pyrrolidinyl), _rocodone, cynan (2H-pyran or 4H-pyran), dihydrothiophene 'dihydropyran, dihydrofuran, dihydrothio Wow, tetrahydrofuran, tetrahydrothiophene, dioxin, tetrahydropyran (eg [-37- 200524877 (33) tetrahydropyranyl), imidazoline, imidazolinone, oxazoline, thiawaline, 2-pyridine Oxazoline, oxazolidine, piperazine, and N-alkyl I piperazine (such as N-methylpiperazine). Other examples include thiomorpholine and its S-oxides and S, S-dioxides. (Especially thiomorpholine). Yet other examples include ... acridine, -D-didone, piperidine, N-alkylpiperidine (such as N-methylpiperidine).

非芳香的雜環基團的一個合宜的亞組的組成如下：飽 和的基團（如吖丁啶、吡咯烷、哌啶、嗎啉、硫代嗎啉、 硫代嗎啉S，S-二氧化物、哌嗪、N-烷基哌嗪、及N-烷基 _ U定。 非芳香的雜環基團的另一個亞組的組成如下：吡咯烷 、哌啶嗎啉、硫代嗎啉、硫代嗎啉S，S -二氧化物、哌嗪 及N -烷基哌嗪（如‘ N 甲：基哌嗪）。 雜環基團的一個特別的亞組的組成如下：吡咯烷、哌 啶、嗎啉及N -烷基哌嗪（例如N -甲基哌嗪）及任意的硫代嗎 啉。A suitable subgroup of non-aromatic heterocyclic groups is composed of: saturated groups (such as azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine, thiomorpholine S, S-di Oxides, piperazines, N-alkylpiperazines, and N-alkyl_U. Other subgroups of non-aromatic heterocyclic groups are composed as follows: pyrrolidine, piperidine morpholine, thiomorpholine , Thiomorpholine S, S-dioxide, piperazine and N-alkylpiperazine (such as' N methyl: ylpiperazine). A special subgroup of heterocyclic groups is composed as follows: pyrrolidine, Piperidine, morpholine and N-alkylpiperazine (eg N-methylpiperazine) and any thiomorpholine.

非芳香的雜環基團的實例包括：環烷基（如環己基及 環戊基）、環烯基（如環戊烯基、環己烯基、環庚烯基及環 辛烯基），以及環己二烯基、環辛四烯基、四氫蔡基及蔡 烷基。 合宜的非芳香的碳環基團是單環的環，最佳飽和的單 環的環。 典型的實例是3、4、5及6員的飽和的碳環，例如被任 意取代的環戊基及環己基環。 非芳香的碳環基團的一個亞組包括：未被取代的或被 -38- 200524877 (34) 取代的（被一或多個基團R1Q)單環基團及特別的飽和的單 環基團’例如環烷基。這類環烷基的實例包括：環丙基、 環丁基、環戊基、環己基及環庚基；較典型包括：環丙基 、環丁基、環戊基及環己基，尤其環己基。 非芳香的環狀基團的另一實例包括：被橋接的環系統 ’如二環的烷及氮雜二環的烷，即使該被橋接的環系統一 般較不合宜。 ''被橋接的環系統〃代表環系統中的二個環 共享二個以上的原子，見（例如）Adv a need Organic Chemicstry ， by Jerry March， 4thEdition ， Wiley Interscience，pages 131-133，1992。被橋接的環系統的 實例包括：二環[2·2·1]庚烷、氮雜二環[2·2·1]庚烷、二環 [2.2.2]辛烷、氮雜二環[2.2.2]辛烷、二環[3.2.：1]辛烷及氮 雜二環[32·2. 1]辛烷。被橋接的環系統的一個特例是1-氮 雜-二環[2·2.2]辛-3-基。 在碳環及雜環基團的參考例中，碳環或雜環可以（除 非另外指定）是未被取代的或被選自下列的取代基取代： 一或多個選自下列的取代基R 1 G :鹵素 '羥基、三氟甲基 、氰基、硝基、殘基、胺基、一或二-C】.4烴胺基、有3至 12個環原子的碳環及雜環基團；基團Ra-Rb’其中Ra是一 個鍵、〇、CO、X】C(X2)、c(x2)x】、X】C(X2)X】、s、so、 s〇2、NRC、S02NRc或NRcS02 ; Rb選自：氫、有3至12個環 原子的碳環及雜環基團，C ! .8烴基被一或多個選自下列的 取代基任意取代：羥基、合氧基、鹵素、氰基、硝基、羧 基、胺基、一或二烴胺基、有3至I 2個環原子的碳環 -39- 200524877 (35) 及雜環基團’其中C !· 8烴基的一或多個碳原子可被下列基 任意替代：0、S、s〇、S02、NRC、X】C(X2)、CCX^X1 或 X】C(X2)X】；Examples of non-aromatic heterocyclic groups include: cycloalkyl (such as cyclohexyl and cyclopentyl), cycloalkenyl (such as cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl), As well as cyclohexadienyl, cyclooctatetraenyl, tetrahydrozekienyl, and cholenyl. A suitable non-aromatic carbocyclic group is a monocyclic ring, preferably a saturated monocyclic ring. Typical examples are saturated carbocyclic rings of 3, 4, 5 and 6 members, such as cyclopentyl and cyclohexyl rings which are optionally substituted. A subgroup of non-aromatic carbocyclic groups includes: monocyclic groups that are unsubstituted or substituted with -38- 200524877 (34) (by one or more groups R1Q) and special saturated monocyclic groups Group 'is, for example, cycloalkyl. Examples of such cycloalkyl include: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl; more typical include: cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, especially cyclohexyl . Another example of a non-aromatic cyclic group includes a bridged ring system such as a bicyclic alkane and an azabicyclic alkane, even though the bridged ring system is generally less suitable. '' Bridged ring system 〃 represents two rings in a ring system sharing more than two atoms, see (for example) Adv a need Organic Chemicstry, by Jerry March, 4th Edition, Wiley Interscience, pages 131-133, 1992. Examples of bridged ring systems include: bicyclo [2 · 2 · 1] heptane, azabicyclo [2 · 2 · 1] heptane, bicyclo [2.2.2] octane, azabicyclo [ 2.2.2] octane, bicyclo [3.2.:1] octane and azabicyclo [32 · 2.1.1] octane. A specific example of a bridged ring system is 1-aza-bicyclo [2.2.2] oct-3-yl. In the reference examples of carbocyclic and heterocyclic groups, the carbocyclic or heterocyclic ring (unless otherwise specified) may be unsubstituted or substituted with one or more of the following substituents: 1 G: halogen 'hydroxyl, trifluoromethyl, cyano, nitro, residue, amine, mono- or di-C]. 4 hydrocarbon amine, carbocyclic and heterocyclic group having 3 to 12 ring atoms Group Ra-Rb 'where Ra is a bond, 0, CO, X] C (X2), c (x2) x], X] C (X2) X], s, so, s02, NRC , S02NRc or NRcS02; Rb is selected from the group consisting of hydrogen, carbocyclic and heterocyclic groups having 3 to 12 ring atoms, and C! .8 hydrocarbon groups are optionally substituted with one or more substituents selected from: hydroxyl, oxygen Group, halogen, cyano, nitro, carboxyl, amine, mono- or di-hydrocarbon amine, carbocyclic ring-39-200524877 (35) with 3 to 12 ring atoms and heterocyclic group 'wherein C! 8 One or more carbon atoms of the hydrocarbon group may be arbitrarily substituted by: 0, S, so, S02, NRC, X] C (X2), CCX ^ X1 or X] C (X2) X];

Re選自··氫及C^4烴基； x1是 〇、S或 NRC，x2是=〇、=8或=^11。。 在取代基R 1G包含或包括一個碳環基或雜環基的場合 中’該碳環基或雜環基可以是未被取代的或本身可以被一 或多個另外的取代基RiQ取代。在如式（1)之化合物的一個 亞群中’該另外的取代基可包括碳環基或雜環基，一 般彼本身不被進一步取代。在如式之化合物的另一個 亞群中’該另外的取代基不包括碳環基或雜環基，但另外 選自上面的在的定義中所列出的基團。 取代基R 1G可被選擇，使得彼含有至多2 〇個非氫的原 子’例如至多1 5個非氫的原子，例如至多1 2、或1 1、或1 〇 、或9、或8、或7、或6、或5個非氫的原子。 在碳環及雜環基團在相鄰的環原子上有一對取代基的 場合中’該二個取代基，可被連接形成一個環狀基團。所 以’二個相鄰的基團Ri〇連同其所連接的碳原子或雜原子 可形成~個5員的雜芳基環或一個5或6員的非芳香碳環或 雜環’其中該雜芳基或雜環基含有至多3個選自N、〇及S 的雜原子環原子。舉例來說，在環的相鄰的碳原子上的相 鄰的一對取代基可經由一或多個雜原子或被任意取代的嫌 基連接形成一個稠合的氧雜、二氧雜、氮雜、二氮雜或氧 雜一氮雜的環烷基。 -40- 200524877 (36) 被這樣連接的取代基的實例包括： X〕 X〉 )0Re is selected from the group consisting of hydrogen and C ^ 4 hydrocarbon groups; x1 is 0, S, or NRC, and x2 is = 0, = 8, or = ^ 11. . Where the substituent R 1G contains or includes a carbocyclyl or heterocyclyl, the carbocyclyl or heterocyclyl may be unsubstituted or may itself be substituted with one or more additional substituents RiQ. In a subgroup of the compounds of formula (1), the additional substituent may include a carbocyclyl or heterocyclic group, and is generally not further substituted by itself. In another subgroup of compounds of the formula, the additional substituent does not include carbocyclyl or heterocyclyl, but is further selected from the groups listed in the definition above. The substituent R 1G may be selected such that it contains up to 20 non-hydrogen atoms', such as up to 15 non-hydrogen atoms, such as up to 12, 2, or 1, 1, or 10, or 9, or 8, or 7, or 6, or 5 non-hydrogen atoms. In the case where the carbocyclic and heterocyclic group have a pair of substituents on adjacent ring atoms, the two substituents may be linked to form a cyclic group. So 'two adjacent groups Ri0 together with the carbon or heteroatom to which they are attached can form a 5-membered heteroaryl ring or a 5- or 6-membered non-aromatic carbocyclic or heterocyclic ring', where the hetero An aryl or heterocyclic group contains up to 3 heteroatom ring atoms selected from N, 0 and S. For example, an adjacent pair of substituents on an adjacent carbon atom of a ring may be connected via one or more heteroatoms or optionally substituted substituents to form a fused oxa, dioxa, nitrogen Hetero, diaza or oxa-azacycloalkyl. -40- 200524877 (36) Examples of the substituents thus attached include: X] X〉) 0

A XX 鹵素取代基的實例包括：氟、氯、溴及碘。氟及氯尤 其合宜。 在上文及下文所使用的如式（I)之化合物的定義中， A烴基&quot;是泛用的名稱，彼包含脂族的、脂環族的及芳香 族的基團，彼有全碳的主幹及由碳原子及氫原子組成，除 非另外敍述。 在某些場合中，組成碳主幹的碳原子中的一或多個可 被特定的原子或原子的基團替代。 烴基的實例包括：烷基、環烷基、環烯基、碳環的芳 基、烯基、炔基、環烷基烷基、環烯基烷基、碳環的芳烷 ®、芳烯基及芳炔基。這類基團可以是未被取代的或被一 或多個如本說明書中所定義的取代基取代。下文所表現的 實例及參考例適用於在如式（I)之化合物的取代基的各種 的定義中所提及的各個烴基取代基或含有烴基的取代基， 除非另外指示。 合宜的非芳香的烴基是飽和的基團，如烷基及環烷基 〇 一般，舉例說明，烴基可以有至多8個碳原子，除非 -41 - 200524877 (37) 另有需要。在有1至8個碳原子的烴基的亞群中，特 Cu烴基，如C】.4烴基（例如Ci.3烴基或C】.2烴基），專 實例（彼是任何的個別的値或値的綜合）選自：c !，C2 ，c4，c5，c6，c7及 c8烴基。 ''烷基〃涵蓋直鏈及分枝的鏈的烷基。烷基的實 括：甲基、乙基、丙基、異丙基、正丁基、異丁基、 丁基、正戊基、2-戊基、3-戊基、2-甲基丁基、3-甲 基、正己基及彼之異構物。在有1至8個碳原子的烷基 群中，特例是C 1 _ 6院基5如C 1 _ 4院基（例如C 1 · 3垸基惑 烷基）。 環烷基的實例選自：環丙基、環丁基、環戊基、 基及環庚基。在環烷基的亞群中，環烷基有3至.8個碳 ，特別是C3_6環烷基。 烯基的實例包括（但不限於）：乙烯基、1 -丙烯基 丙烯基、異丙烯基、丁烯基、丁 1，4-二烯基、戊烯 己烯基。在烯基的亞群中，烯基有2至8個碳原子，特 C2_6烯基，如C2_4烯基。 環烯基的實例包括（但不限於）：環丙烯基、環丁 、環戊烯基、環戊二烯基及環己烯基。在環烯基的亞 ，環烯基有3至8個碳原子，特例是C3.6環烯基。 炔基的實例包括（但不限於）：乙炔基及2-丙炔基 有2至8個碳原子的炔基的亞組中，特例是C2.6炔基，《 4炔基。 碳環的芳基的實例包括被取代的及未被取代的苯； 例是 一的 ，C3 例包 第三 基丁 的亞 ;C 1 _ 2 環己 原子 、2- 基及 例是 烯基 組中 。在 ；Π c2- -42- 200524877 (38) 環烷基烷基、環烯基烷基、碳環的芳烷基、芳烯基及 芳炔基的實例包括：苯乙基、苄基、苯乙烯基、苯乙炔基 、環己基甲基、環戊基甲基、環丁基甲基、環丙基甲基及 環戊嫌基甲基。 在說明時及在描述的場合中，烴基可被一或多個選自 下列的取代基任意取代··羥基、合氧基、烷氧基、羧基、 鹵素、氰基、硝基、胺基、一或二-Ci.4烴胺基、單環或二 環的碳環及雜環基團（有3至12個，一般有3至1〇個，較常 有5至1 0個環原子）。合宜的取代基包括鹵素，如氟。所以 ’舉例說明’被取代的烴基可以是被部份氟化的或被全氟 化的基團，如二氟代甲基或三氟代甲基。在一個體現中， 合宜的取代基包括單環的碳環或雜環基團，彼有3 _ 7個環 原子，較常有3、4、5或6個環原子。 在說明的場合中，烴基的一或多個碳原子可被下列任 意替代：Ο、S、SO、S02、NRC、xkfX2)、C(X2)X】或 Xiixyx、或彼之亞組），其中χι及χ2如前文所定義的， 件是烴基的至少一個碳原子保留。舉例來說，烴基的1、2 、3或4個碳原子可被所列出的原子或基團中的一個替代， 該替代的原子或基團可以是相同的或不同的。一般而言，. 被替代的直鏈的或主幹的碳原子數目要符合在取代碳原子 的基團中的直鏈的或主幹的原子的數目。基團（其中烴基 的一或多個碳原子己被上文所定義的替代原子或替代基替 代）的實例包括：醚類及硫醚類（C被氧或硫替代）、醯胺類 、酯類、硫醯胺類及硫酯類（C-C被X!C(X2)或c(x2)x]替代 200524877 (39) )、硕類及亞碾類（c被S 0或S Ο 2替代）、胺類（C被N R。替代） 。另外的實例包括：脲類、碳酸酯類及胺基甲酸酯類（C _ c-c被 替代）。 在胺基有2個烴基取代基的場合中，烴基可連同所連 接的氣原子’及任思與另一個雜原子（如氮、硫或氧）連接 形成4至7個環原子，較常爲5至6個環原子的環結携。 ''氮雜-環烷基〃代表一種環烷基，其中碳環原子中 的一個被氮原子替代。所以氮雜-環烷基的實例包括哌啶 及吡咯烷。、氮雜-環烷基〃代表一種環烷基，其中碳環 原子中的一個被氧原子替代。氧雜-環烷基的實例包括四 氫呋喃及四氫吡喃。在一個類似的方式中， ''二氮雜-環 烷基〃、 ''二氧雜-環烷基〃及 ''氮雜-氧雜-環烷基〃個 別代表環烷基，其中二個碳環原子被下列替代：二個氮原 子、二個氧原子、或一個氮原子及一個氧原子。 'Ra-Rb 〃（關於在碳環或雜環基團上存在的取代基或 關於在如式（I)之化合物上的其他位置上存在的其他的取 代基）包括其他的化合物，其中Ra選自：一個鍵、〇，C Ο ，OC(O)，SC(O)，NRcC(0)，OC(S)，SC(S)，NRcC(S)， OC(NRc) ， SC(NRC) ，NRcC(NRc) ，C(0)0 ， C(0)S ， C(0)NRe，C(S)0，C(S)S，C(S)NRc，C(NRc)0，C(NRc)S ，（:（NRC)NRC，0C(0)0，SC(0)0，NRcC(0)0，0C(S)0 ’ SC(S)0，NRcC(S)0，0C(NRc)0，S C (N Rc) Ο，N Rc C (N Rc) 0 ，0C(0)S，SC(0)S ，NRcC(0)S ，〇C(S)S， SC(S)S， 200524877 (40) NRcC(S)S ， OC(NRc)S ， S C (N Rc) S ， N Rc C (N Rc) S ， 0C(0)NRc，SC(0)NRc ’ N Rc C (0 )N Re，0 C ( S ) N Rc， SC(S)NRC，NRcC(S)NRc，〇C(NRc)NRc，SC(NRc)NRc， NRcC(NRc)NRc，S，SO，SP2，NRC，S02NRc 及 NRcS02， 其中Re如同前面所定義的。 基團Rb可以是氫或可以是選自下列的基團：有3至12 個環原子（一般3至10個環原子，較常5至10個環原子）的碳 環及雜環基團，及烴基（如上文所定義的被任意取代） 。烴基碳環及雜環基團的實例在上文中被陳述。 當Ra是0，Rb是0：】_8烴基時，Ra及Rb—起形成一個烴 氧基。合宜的烴氧基包括：飽和的烴氧基（如烷氧基(例如 1-6烷氧基，較、常爲C!_4烷氧基，如乙氧基及甲氧基，尤其 甲氧基）、環院氧基（例如C 3 · 6環院氧基，如環丙氧基、環 丁氧基、環戊氧基及環己氧基）及環烷基烷氧基（例如C3_6 環烷基-Cu烷氧基，如環丙基甲氧基）。 烴氧基可以如本說明書所定義的被各種取代基取代。 舉例來說，院氧基可以被下列取代：鹵素（例如在二氟甲 氧基及三氟甲氧基中的），羥基（例如在羥基乙氧基中的） 、C 1 · 2院氧基（例如在甲氧基及乙氧基中的），經基_ C ! _ 2院 基（例如在羥基乙氧基乙氧基中的）或環狀的基團（例如環 烷基或非芳香雜環基團中的）。烷氧基的實例（帶有一個非 芳香雜環基團的取代基）的基團。其中雜環基團是飽和的 環狀的妝’如嗎啉帳呢、吼D各院、哌嗪、C】· 4 ·院基-_ 嗉、（：3.7_環烷基嗪、四氫吡喃或四氫呋喃，烷氧基是 -45- 200524877 (41) C】·4烷氧基，較典型是Cl.3烷氧基，如甲氧基、乙氧基或 正丙氧基。 烷氧基被下列取代：單環的基團，如吡咯烷、哌啶、 嗎啉及哌嗪及彼之N-被取代的衍生物，如N-苄基、N-C+4 醯基及N-Ch烷氧羰基。特例包括：吡咯烷並乙氧基、_ 啶並乙氧基及哌嗪並乙氧基。 當1^是一個鍵及Rb是一個C!_8烴基時，烴基Ra-Rb的實 例如同前文中所定義的。烴基可以是飽和的基團，如環烷 基及烷基’彼之特例包括：甲基、乙基及環丙基。烴基（ 例如烷基）可以被本說明書中所定義的各種原子及基團取 代。被取代的烷基的實例包括：被下列取代的烷基：一或 多個鹵素原子（如氟及氯，特別包括溴代乙基、氯代乙基 及三氟甲基）、或羥基（例如羥甲基及羥乙基）、Ci 8醯氧基 (例如醋酸甲基及韦氧甲基）、胺基及一及二烷基胺基（例 如胺乙基、甲胺基、乙基、二甲胺基甲基、二甲胺基乙基 及第三丁胺基甲基）、烷氧基（例如c】_2烷氧基、如甲氧基 一如在甲氧乙基中的），及環狀的基團，如環烷基、芳基 雜方基及非方香雜垣基（如前文中所定義的）。 被環狀的基團取代的烷基的特例是烷基，其中環狀的 基團是飽和的環狀的胺，如嗎啉、哌啶、吡咯烷、_嗪、 C 1 - 4 -《το基-哌嗪、C 3 · 7 -環院基-_嗪、四氫卩比喃或四氫咲喃 ’該院基是一種Cm烷基、較典型是Cl·3烷基，如甲基、 乙基或正丙基。被環狀的基團取代的烷基的特例包括：吼 啶烷並甲基、吡啶烷並丙基、嗎啉代甲基、嗎啉代乙基、 -46- 200524877 (42) 嗎啉代丙基、哌啶甲基、哌嗉並甲基及彼之N -被取代的型 式（如本說明書中所定義的）。 被芳基及雜芳基取代的烷基的特例包括苄基及D(t啶甲 基。當R a是S Ο 2 N Re，R b可以是（例如）氫或被任意取代的 C】·8烴基或碳環或雜環基團。R、Rb的實例（其中是 S〇2NRe)包括：胺磺醯、Cl_4烷基胺磺醯及二-Cle4烷基胺 磺醯’由環狀的胺基形成的磺胺類，如哌啶、嗎啉、吡咯 烷或任意的N-被取代的哌嗪，如N-甲基-哌嗪。 基團Ra-Rb的實例（其中；^是s〇2)包括：烷基磺醯、雜 芳基擴醯及芳基磺醯基團，尤其單環的芳基及雜芳基磺醯 基團。特例括：甲磺醯、苯硫醯及甲苯磺醯。 當R/是NRe時，，Rb可以是（例如）：氫或被任意取代的 C】-8烴基，或碳環或雜環的基團。R、Rb(其中^是^^^的 實例包括：胺基、Cl·4烷胺基（例如甲胺基、乙胺基、丙胺 基異丙胺基、第二丁胺基）、二· c】4烷胺基（例如二甲胺 基及二乙胺基）及環烷胺基（例如環丙胺基、環戊胺基及環 己胺基）。 體現及參考例Examples of A XX halogen substituents include: fluorine, chlorine, bromine and iodine. Fluorine and chlorine are particularly suitable. In the definitions of the compounds of formula (I) used above and below, A hydrocarbyl is a generic name that includes aliphatic, cycloaliphatic, and aromatic groups, and that they have all carbons. The backbone of and is composed of carbon and hydrogen atoms, unless stated otherwise. In some cases, one or more of the carbon atoms that make up the carbon backbone may be replaced by a particular atom or group of atoms. Examples of hydrocarbyl groups include: alkyl, cycloalkyl, cycloalkenyl, carbocyclic aryl, alkenyl, alkynyl, cycloalkylalkyl, cycloalkenylalkyl, carbocyclic aralkyl®, aralkenyl And arylalkynyl. Such groups may be unsubstituted or substituted with one or more substituents as defined in this specification. The examples and reference examples shown below apply to each of the hydrocarbyl substituents or hydrocarbyl-containing substituents mentioned in the various definitions of the substituents of the compound of the formula (I), unless otherwise indicated. A suitable non-aromatic hydrocarbon group is a saturated group, such as an alkyl group and a cycloalkyl group. Generally, for example, a hydrocarbon group may have up to 8 carbon atoms, unless -41-200524877 (37) otherwise required. In the subgroup of hydrocarbyl groups having 1 to 8 carbon atoms, special Cu hydrocarbyl groups, such as C] .4 hydrocarbyl (such as Ci.3 hydrocarbyl or C] .2 hydrocarbyl), specific examples (these are any individual Synthesis of）) selected from the group consisting of: c !, C2, c4, c5, c6, c7, and c8 hydrocarbon groups. '' Alkyl '' encompasses both straight and branched chain alkyl groups. Examples of alkyl: methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methylbutyl , 3-methyl, n-hexyl and their isomers. In the group of alkyl groups having 1 to 8 carbon atoms, a special case is a C 1-6 alkyl group 5 such as a C 1-4 alkyl group (for example, a C 1 · 3 alkyl group). Examples of cycloalkyl are selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, and cycloheptyl. In the subgroup of cycloalkyl, cycloalkyl has 3 to .8 carbons, especially C3-6 cycloalkyl. Examples of alkenyl include, but are not limited to: vinyl, 1-propenylpropenyl, isopropenyl, butenyl, but 1,4-dienyl, pentenhexenyl. In the subgroup of alkenyl, alkenyl has 2 to 8 carbon atoms, and is especially C2-6 alkenyl, such as C2_4 alkenyl. Examples of cycloalkenyl include, but are not limited to: cyclopropenyl, cyclobutyl, cyclopentenyl, cyclopentadienyl, and cyclohexenyl. In the cycloalkenyl group, the cycloalkenyl group has 3 to 8 carbon atoms, and a specific example is a C3.6 cycloalkenyl group. Examples of alkynyl include (but are not limited to): ethynyl and 2-propynyl. In the subgroup of alkynyl groups having 2 to 8 carbon atoms, specific examples are C2.6 alkynyl and "4 alkynyl. Examples of carbocyclic aryl groups include substituted and unsubstituted benzene; the examples are one, C3 includes the tertiary butylene; C 1 _ 2 cyclohexyl, 2-yl, and examples are alkenyl groups in. Π c2- -42- 200524877 (38) Examples of cycloalkylalkyl, cycloalkenylalkyl, carbocyclic aralkyl, arylalkenyl and aralkynyl include: phenethyl, benzyl, benzene Vinyl, phenylethynyl, cyclohexylmethyl, cyclopentylmethyl, cyclobutylmethyl, cyclopropylmethyl, and cyclopentylmethyl. In the description and in the occasions described, the hydrocarbyl group may be arbitrarily substituted with one or more substituents selected from the group consisting of hydroxyl, alkoxy, alkoxy, carboxyl, halogen, cyano, nitro, amine, Mono- or di-Ci.4 hydrocarbon amine groups, monocyclic or bicyclic carbocyclic and heterocyclic groups (3 to 12, usually 3 to 10, and more often 5 to 10 ring atoms) . Suitable substituents include halogens, such as fluorine. So the 'exemplified' substituted hydrocarbon group may be a partially fluorinated or perfluorinated group, such as a difluoromethyl group or a trifluoromethyl group. In one embodiment, suitable substituents include monocyclic carbocyclic or heterocyclic groups, which have 3 to 7 ring atoms, more often 3, 4, 5, or 6 ring atoms. In the illustrated context, one or more carbon atoms of the hydrocarbyl group may be replaced by any of the following: 0, S, SO, S02, NRC, xkfX2), C (X2) X] or Xiixyx, or another subgroup thereof), where χι and χ2 are as defined above, and at least one carbon atom of the hydrocarbon group is retained. For example, one, two, three, or four carbon atoms of a hydrocarbyl group may be replaced by one of the atoms or groups listed, which substituted atoms or groups may be the same or different. In general, the number of straight or backbone carbon atoms to be replaced should match the number of straight or backbone atoms in the carbon-substituted group. Examples of groups in which one or more carbon atoms of a hydrocarbon group have been replaced by a substituted atom or a substituent as defined above include: ethers and thioethers (C is replaced by oxygen or sulfur), amidines, esters Class, thioxamines and thioesters (CC replaced by X! C (X2) or c (x2) x] 200524877 (39)), master class and sub-mill (c replaced by S 0 or S Ο 2) Amines (C is replaced by NR.). Additional examples include: ureas, carbonates, and urethanes (C_c-c is replaced). Where the amine group has 2 hydrocarbyl substituents, the hydrocarbyl group can be joined with the attached gas atom 'and Rens to another heteroatom (such as nitrogen, sulfur or oxygen) to form 4 to 7 ring atoms, more commonly Ring attachment of 5 to 6 ring atoms. '' Aza-cycloalkylfluorene represents a cycloalkyl group in which one of the carbocyclic atoms is replaced by a nitrogen atom. Therefore, examples of aza-cycloalkyl include piperidine and pyrrolidine. Aza-cycloalkylfluorene represents a cycloalkyl group in which one of the carbocyclic atoms is replaced by an oxygen atom. Examples of oxa-cycloalkyl include tetrahydrofuran and tetrahydropyran. In a similar manner, `` diaza-cycloalkyl '', `` dioxa-cycloalkyl '' and `` aza-oxa-cycloalkyl '' each represent a cycloalkyl, two of which Carbocyclic atoms are replaced by two nitrogen atoms, two oxygen atoms, or one nitrogen atom and one oxygen atom. 'Ra-Rb 〃 (with regard to substituents present on carbocyclic or heterocyclic groups or with respect to other substituents present at other positions on compounds such as formula (I)) includes other compounds in which Ra is selected From: one bond, 0, C 0, OC (O), SC (O), NRcC (0), OC (S), SC (S), NRcC (S), OC (NRc), SC (NRC), NRcC (NRc), C (0) 0, C (0) S, C (0) NRe, C (S) 0, C (S) S, C (S) NRc, C (NRc) 0, C (NRc ) S, (: (NRC) NRC, 0C (0) 0, SC (0) 0, NRcC (0) 0, 0C (S) 0 'SC (S) 0, NRcC (S) 0, 0C (NRc) 0, SC (N Rc) 0, N Rc C (N Rc) 0, 0C (0) S, SC (0) S, NRcC (0) S, 0C (S) S, SC (S) S, 200524877 (40) NRcC (S) S, OC (NRc) S, SC (N Rc) S, N Rc C (N Rc) S, 0C (0) NRc, SC (0) NRc 'N Rc C (0) N Re, 0 C (S) N Rc, SC (S) NRC, NRcC (S) NRc, OC (NRc) NRc, SC (NRc) NRc, NRcC (NRc) NRc, S, SO, SP2, NRC, S02NRc And NRcS02, where Re is as previously defined. The group Rb may be hydrogen or may be a group selected from 3 to 12 ring atoms (generally 3 to 10 ring atoms, more often 5 to 10 rings Atomic) carbocyclic and hetero Groups, and hydrocarbyl groups (arbitrarily substituted as defined above). Examples of hydrocarbyl carbocyclic and heterocyclic groups are stated above. When Ra is 0 and Rb is 0:]-8 hydrocarbon group, Ra and Rb— An alkoxy group is formed. Suitable alkoxy groups include: saturated alkoxy groups (such as alkoxy groups (for example, 1-6 alkoxy groups, more commonly C! _4 alkoxy groups, such as ethoxy and methyl) Oxy, especially methoxy), cyclohodooxy (such as C 3 · 6 cyclohodooxy, such as cyclopropoxy, cyclobutoxy, cyclopentyloxy and cyclohexyloxy) and cycloalkylalkanes (For example, C3_6 cycloalkyl-Cu alkoxy, such as cyclopropylmethoxy). The alkoxy group may be substituted with various substituents as defined in this specification. For example, the oxo group may be substituted with the following : Halogen (for example, in difluoromethoxy and trifluoromethoxy), hydroxyl (for example, in hydroxyethoxy), C 1 · 2 alkyloxy (for example, in methoxy and ethoxy) ), Via a radical _ C! _ 2 courtyard (for example in a hydroxyethoxyethoxy group) or a cyclic group (for example in a cycloalkyl or non-aromatic heterocyclic group). An example of an alkoxy group (a substituent with a non-aromatic heterocyclic group). Wherein the heterocyclic group is a saturated cyclic make-up such as morpholine tent, d-D, D, piperazine, C] · 4-D--嗉, (: 3.7_ cycloalkylazine, tetrahydropyridine Or tetrahydrofuran, the alkoxy group is -45- 200524877 (41) C] · 4 alkoxy group, which is more typically Cl.3 alkoxy group, such as methoxy group, ethoxy group, or n-propoxy group. Substituted by: monocyclic groups such as pyrrolidine, piperidine, morpholine, and piperazine and their N-substituted derivatives, such as N-benzyl, N-C + 4 fluorenyl, and N-Ch Alkoxycarbonyl. Specific examples include: pyrrolidinoethoxy, pyridinoethoxy and piperazinoethoxy. When 1 ^ is a bond and Rb is a C! _8 hydrocarbon group, examples of hydrocarbon groups Ra-Rb As defined above. Hydrocarbon groups can be saturated groups, such as cycloalkyl and alkyl. Specific examples include: methyl, ethyl, and cyclopropyl. Hydrocarbon groups (such as alkyl) can be used in this specification. Various types of atoms and groups as defined. Examples of substituted alkyl groups include: alkyl groups substituted by: one or more halogen atoms (such as fluorine and chlorine, especially bromoethyl, chloroethyl and tri Fluoromethyl ), Or hydroxy (such as hydroxymethyl and hydroxyethyl), Ci 8 methoxy (such as methyl acetate and veoxymethyl), amine and mono- and dialkylamino (such as amine ethyl, methylamine Methyl, ethyl, dimethylaminomethyl, dimethylaminoethyl and tertiary butylaminomethyl), alkoxy (eg c) _2alkoxy, such as methoxy as in methoxyethyl ), And cyclic groups, such as cycloalkyl, arylheterosyl, and non-spherical heterocyclyl (as defined above). Specific examples of alkyl substituted by cyclic groups Is an alkyl group, where the cyclic group is a saturated cyclic amine, such as morpholine, piperidine, pyrrolidine, _azine, C 1-4-"τοyl-piperazine, C 3 · 7-ring Radical-tetrazine, tetrahydropyran or tetrahydropyran. The radical is a Cm alkyl group, more typically a Cl3 alkyl group, such as methyl, ethyl or n-propyl. A cyclic group Specific examples of group-substituted alkyl groups include: pyrimidinylmethyl, pyridinopropyl, morpholinomethyl, morpholinoethyl, -46- 200524877 (42) morpholinopropyl, piperidine Group, piperidino methyl group and other N-substituted form (such as this As defined in the specification). Specific examples of alkyl substituted with aryl and heteroaryl include benzyl and D (t-pyridylmethyl. When Ra is S Ο 2 N Re, R b can be, for example, hydrogen Or optionally substituted C] · 8 hydrocarbyl or carbocyclic or heterocyclic group. Examples of R and Rb (which is So2NRe) include: sulfamidine, Cl_4 alkylamine sulfonium and di-Cle4 alkylamine Sulfonium sulfonamides formed from cyclic amine groups, such as piperidine, morpholine, pyrrolidine, or any N-substituted piperazine, such as N-methyl-piperazine. Examples of groups Ra-Rb (Wherein ^ is so2) include: alkylsulfonium, heteroaryl fluorene and arylsulfonyl groups, especially monocyclic aryl and heteroarylsulfonyl groups. Specific examples include: mesylate, sulfenium, and toluensulfonium. When R / is NRe, Rb may be, for example, hydrogen or an optionally substituted C] -8 hydrocarbon group, or a carbocyclic or heterocyclic group. R, Rb (where ^ is ^^^ Examples include: amino groups, Cl · 4 alkylamino groups (such as methylamino, ethylamino, propylaminoisopropylamino, second butylamino), di · c] 4 Alkylamino (such as dimethylamino and diethylamino) and cycloalkylamino (such as cyclopropylamino, cyclopentylamino, and cyclohexylamino). Embodiments and reference examples

X、Y、A、Rg、的專— X 碳環或雜 在式（I)中，X是基團RI-A_Nr4_或5或6員的 在一個體現中，X是基團 在另一個體現中，X是一個6 g 4 b貝的碳環或雜環 -47- 200524877 (43)X, Y, A, Rg, special-X carbocyclic or hetero in formula (I), X is a group RI-A_Nr4_ or 5 or 6 members in one embodiment, X is a group in another embodiment In the formula, X is a carbocyclic or heterocyclic ring of 6 g 4 b shell-47- 200524877 (43)

A 在式⑴中，A是一個鍵，C = 0、NRg(C = 〇)或〇(C = 0)。 以下將被重視：連接吡唑環的4位置的基團R 1 - A -N R4可以 成下列形式：胺R]-NR4醯胺Ri-C( = 0)NR4 .，脲R1-NRg(C = 0)NR4或胺基甲酸根絡RLoqCONR4。A In formula (1), A is a bond, C = 0, NRg (C = 0), or 0 (C = 0). The following will be emphasized: the group R 1-A -N R4 which connects the 4-position of the pyrazole ring can be in the following form: amine R] -NR4 amine Ri-C (= 0) NR4. = 0) NR4 or urethane RLoqCONR4.

在本發明之化合物的一個合宜的基團中，A是C = 0， 基團R^A-NR4成醯胺RLcbCONR4形式。在本發明之化合 物的另一個基團中，A是一個鍵，基團Ri-A-NR4成胺 NR4形式。 R4 ， R4是氫或C^4烴基，彼被下列任意取代：鹵素（例如氟 )、羥基或Cm烷氧基（例如甲氧基）。 在烴基上的任意的取代基的數目典型上會依照取代基 的特性而不同。舉例來說，在取代基是g素的場合中，或 許有1至3個鹵素原子存在（較佳2或3個）。在取代基是羥基 或烷氧基的場合中，典型上只有一個取代基存在 R且爲氫或C〗.3院基，較佳氫或甲基，㈢ 取佳氯/。In a suitable group of the compounds of the present invention, A is C = 0 and the group R ^ A-NR4 is in the form of amidamine RLcbCONR4. In another group of the compounds of the present invention, A is a bond and the group Ri-A-NR4 forms the amine NR4. R4 and R4 are hydrogen or C ^ 4 hydrocarbon group, which are substituted by any of the following: halogen (such as fluorine), hydroxyl or Cm alkoxy (such as methoxy). The number of arbitrary substituents on the hydrocarbyl group will typically differ depending on the characteristics of the substituents. For example, where the substituent is g, there may be 1 to 3 halogen atoms (preferably 2 or 3). In the case where the substituent is a hydroxy group or an alkoxy group, typically only one of the substituents is present in R and is hydrogen or C. 3, preferably hydrogen or methyl, and 佳 is preferably chlorine.

Rg R g是氫或C ! . 4烴基 烷氧基（例如甲氧基）。 當Rg是被羥基或C 彼被下列任意取 代：羥基或C 1 · 4Rg Rg is hydrogen or C! .4 alkyl alkoxy (e.g. methoxy). When Rg is replaced by hydroxyl or C, it is replaced by any of the following: hydroxyl or C 1 · 4

• 4院氧基取代的G ^烴基的場合中 -48- 200524877 (44) ，典型上只有一個取代基存在。 …宜爲氫或CU3烷基，較佳氫或甲基，最佳Rg是氫。 R2 R2是氫、鹵素、C^4烷氧基或（^-4烴基（被鹵素、羥基 或C 1 -4垸氧基任意取代）。 當R2是鹵素時，R2宜選自氯及氟，較佳氟。 當^^是心·4烷氧基時，R2可以是（例如）(^.3烷氧基， 較佳Ci-2院氧基，最佳甲氧基。 當R2是一個被任意取代的匕_4烴基時，烴基宜爲Cl.3 烴基，較佳C】.2烴基，例如被任意取代的甲基。供被任意 取代的烴基用的任意的取代基宜選自：氟、·羥基及甲氧基 〇 在烴基上的任意的取代基的數目典型會根據取代基的 特性而不同。舉例來說，在取代基是鹵素的場合中，或許 有1至3個鹵素原子存在（較佳2或3個）。在取代基是羥基或 甲氧基的場合中，典型上只有一個取代基存在。 構築R2的烴基宜爲飽和的烴基。飽和的烴基的實例包 括：甲基、乙基、正丙基、異丙基及環丙基。 在另一個體現中，R2是氫、鹵素、Cle4烷氧基、或Cm 烴基，彼被下列任意取代：鹵素、羥基或Cl .4烷氧基。 在另一個體現中，R2是氫、氟、氯、甲氧基、或Ci-3 烴基，彼被氟、羥基或甲氧基任意取代。 在一個合宜的體現中，R2是氫或甲基，最佳氫。 -49- 200524877 (45) R】 R1是氫，有3至12個環原子的碳環或雜環基團，或Cl_ 8烴基，彼被一或多個選自下列的取代基任意取代：鹵素（ 例如氟）、羥基、C〗.4烴氧基、胺基、一或二-C^烴胺基 、有3至12個環原子的碳環或雜環基團，其中烴基的碳原 子中的1或2個可被選自下列的原子或基團任意替代：〇、 S、NH、SO、S02。碳環或雜環基團及羥基的實例及參考 例如同在上文的泛用的參考例及定義章節及下文中所陳述 的。 在一個體現中，R1是芳基或雜芳基。 當R 1是--個雜芳基時，特別的雜芳基包括單環的雜芳 基（含有至多3個選自0、S及N的雜原子環原子），及二環的 雜芳基（含有至多2個選自0、S及N的雜原子環原子，其中 二個環皆是芳香環）。 雜芳基的實例包括：呋喃基（例如2 -呋喃基或3 -咲喃 基）、吲哚基（例如3-吲哚基、6-吲哚基）、2，3-二氫-苯並 [1，4]-二氧雜環己烯基基（例如2，3-二氫-苯並[1，4]·二 氧雜環己烯基· 5 -基）、吡唑基（例如吡唑-5 -基）、吡唑並[1 ’ 5-a]吡啶基（例如吡唑並[1，5-a]吡啶-3_基），噁唑基、 例如異噁唑基（例如異噁唑-4-基）、吡啶基（例如2-吡啶基 、3 -吡啶基、4 -吡啶基、）、D奎啉基（例如2 -喧啉基）、吡咯 基（例如3-吡略基）、咪唑基及噻吩基（例如2-噻吩基、3-噻 吩基）。 -50- 200524877 (46) 雜芳基R 1的一個亞群是由下列組成：呋喃基（例如2 _ 咲喃基或3 -呋喃基）、吲哚基、噁唑基、異噁唑基、吡陡 基、D奎啉基、吡咯基、咪唑基及噻吩基。 雜方基R 1是一個合宜的亞組包括：2 -呋喃基、3 ·咲喃 基、吡咯基、咪唑基及噻吩基。 合宜的芳基R1是苯基。 基團R 1可以是一個不飽和的或飽和的碳環或雜環基團 ’其中一或多個取代基可以選自前文中所定義的基團Rl〇 。在一個體現中’在R1上的取代基可選自由下列組成的基 團R1Ga :鹵素、羥基、三氟甲基、氰基、硝基、羥基、基 團 R、Rb，其中 Ra是一個鍵、〇、co、x3c(x4)、c(x4)x3 、X3C(X4)X3、s' so 或 S02，Rb選自：氫及 Ci.8 烴基，彼 被一或多個選自下列的取代基任意取代：羥基、合氧基、 鹵素、氰基、硝基、羧基、有3至6個環原子的單環的非芳 香碳環或雜環基團；其中（^.8烴基的一或多個碳原子可任 意被下列替代·· 0、s、so、so2、x3c(x4)、c(x4)x3 或 X3C(X4)X3 ; x3是 o或 s ; X4 是=〇、=s。 在碳環及雜環基團在相鄰的環原子上有一對取代基的 場合中，該二個取代基可連接形成一個環狀的基團。所以 ，二個相鄰的基團R 1 G連同所連接的碳原子或雜原子可形 成一個5員的雜芳基環或一個5或6員的非芳香碳環或雜環 ，其中該雜芳基及雜環基團含有至多3個選自N、0及S的 雜原子環原子。特別地，2個相鄰的基團R 1 G連同所連接的 碳原子或雜原子可形成一個6員的非芳香雜環，彼含有至 -51 - 200524877 (47) 多3個（尤其2個）選自N、Ο及S的雜原子環原子。較特別地 ，二個相鄰的基團R ^可形成一個6員的非芳香雜環，彼含 有2個選自Ν或0的雜原子環原子，如二卩惡院’例如[1，4 -二噁烷]。在一個體現中，R 1是一個碳環基團（例如苯基） ，彼在相鄰的環原子上有一對取代基相連接形成2，3 -二 氫-苯並[1，4]-二氧雜環己烯基。 較特別地，在R1上的取代基可選自：鹵素、羥基、三 氟甲基、基團Ra-Rb，其中Ra是一個鍵或〇，Rb選自：氫及 C; _4烴基，彼被一或多個選自下列的取代基任意取代：羥 基、鹵素（較佳氟）、5或6員的飽和的碳環及雜環基團（例 如含有至多2個選自0、S及N的雜原子的基團’如未被取 ’代的_啶、吡咯烷並、嗎啉代、哌嗪並及N -甲基哌嗪並） 〇 基團R1可被一個以上的取代基取代。所以’（例如）可 以有1或2或3或4個取代基。在一個體現中，其中R1是一種 6員的環（例如碳環，如苯環），在環的2、3、4或6位置上 有、2或3個取代基。舉例來說，苯基R 1可以是2 -被單取代 的、3 -被單取代的、2，6 -被雙取代的、2，3 -被雙取代的 、2，4_被雙取代的、2，5-被雙取代的、2，3，6-被三取 伐的或2，4 ’ 6 -被三取代的。較特別地，苯基R 1可在2位 置被單取代或在2及6位置被雙取代，取代基選自：氟、氯 及RlRb，其中Μ是〇，…是烷基（例如甲基或乙基）。 在一個體現中’氟是一個合宜的取代基。在另一個體現中 ，合宜的取代基（選自：氟、氯及甲氧基。 -52- 200524877 (48) 非芳香取代基R 1的特例包括未被取代的或被取代的（ 被一或多個基團RIG)單環的環烷基。該環烷基的實例包括 :環丙基、環丁基、環戊基、環己基及環庚基；較常是環 丙基、環丁基、環戊基及環己基，尤其環己基。 非芳香基團R1的另例包括未被取代的或被取代的（被 一或多個基團R1G)雜環基團，彼有3至12個環原子，典型4 至12個環原子，較常有5至10個環原子）。該基團可以是單 環或二環的（例如）典型上有1至5個雜原子環原子（較常有1 、2、3或4個雜原子環原子），而雜原子選自氮、氧及硫。 當硫存在時，在相鄰的原子及基團的特性允許的場合 中，硫可以-S-、-S(O)-或-S(0)2-的形式存在。 ‘ 雜環基團可以含有（例如）：環狀的醚基團（例如在四 氫呋喃及二噁烷中的）、環狀的硫醚基團（例如在四氫噻吩 及二噻烷）、環狀的胺基團（例如在吡咯烷中的）、環狀的 醯胺類（例如在吡咯烷酮中的）、環狀的酯類（例如在丁內 酯中的）、環狀的硫醯胺及硫酯、環狀的硕（例如在磺烷及 磺烯中的）、環狀的亞硕、環狀的磺胺及彼之綜合（例如嗎 啉及硫代嗎啉及彼之S -氧化物及S ’ S -二氧化物）° 在雜環基團R1的一個亞組中’雜環基團含有環狀的醚 基團（例如在四氫呋喃及二噁烷中的）、環狀的硫醚基團（ 例如在四氫噻吩及二噻烷中的）、環狀的胺基團（例如在口比 略烷中的）、環狀的硕（例如在磺烷及磺烯中的）、環狀的 亞硕、環狀的磺胺及彼之綜合（例如硫代嗎啉）° 單環的非芳香雜環基團R1的實例包括：5、6及7員的 -53- 200524877 (49) 單環的雜環基團，如嗎啉、_啶（例如1-哌啶基、2 -哌啶 基、3 -1派D定基及4 -哌'D定基、）、吼咯院（例如1 -吼略院基、• In the case of 4-oxy-substituted G ^ alkyl, -48-200524877 (44), typically only one substituent is present. ... is preferably hydrogen or CU3 alkyl, preferably hydrogen or methyl, and most preferably Rg is hydrogen. R2 R2 is hydrogen, halogen, C ^ 4 alkoxy or (^ -4 hydrocarbon group (optionally substituted by halogen, hydroxy or C 1-4 alkoxy). When R2 is halogen, R2 is preferably selected from chlorine and fluorine, Preferable fluorine. When ^^ is alkoxy group, R2 can be (for example) (^ .3 alkoxy group, preferably Ci-2 alkyloxy group, most methoxy group. When R2 is a In the case of an optionally substituted alkyl group, the hydrocarbon group is preferably a Cl.3 hydrocarbon group, preferably C] .2 hydrocarbon group, such as an optionally substituted methyl group. The optional substituent for the optionally substituted hydrocarbon group is preferably selected from: fluorine The number of arbitrary substituents on the hydrocarbyl group of the hydroxyl group and methoxy group typically varies depending on the characteristics of the substituent. For example, when the substituent is a halogen, there may be 1 to 3 halogen atoms (Preferably 2 or 3). In the case where the substituent is a hydroxyl group or a methoxy group, typically only one substituent exists. The hydrocarbon group constituting R2 is preferably a saturated hydrocarbon group. Examples of the saturated hydrocarbon group include: methyl, Ethyl, n-propyl, isopropyl, and cyclopropyl. In another embodiment, R2 is hydrogen, halogen, Cle4 alkoxy, or Cm hydrocarbyl. Columns are optionally substituted: halogen, hydroxyl, or Cl.4 alkoxy. In another embodiment, R2 is hydrogen, fluorine, chlorine, methoxy, or Ci-3 alkyl, which is optionally substituted with fluorine, hydroxyl, or methoxy In a suitable embodiment, R2 is hydrogen or methyl, preferably hydrogen. -49- 200524877 (45) R] R1 is hydrogen, a carbocyclic or heterocyclic group having 3 to 12 ring atoms, or Cl_ 8 hydrocarbyl groups, which are optionally substituted with one or more substituents selected from the group consisting of halogen (e.g., fluorine), hydroxy, C. 4 alkoxy, amine, mono- or di-C ^ hydrocarbon amine, 3 to A carbocyclic or heterocyclic group of 12 ring atoms, in which 1 or 2 of the carbon atoms of the hydrocarbon group may be arbitrarily replaced by an atom or group selected from the group consisting of: 0, S, NH, SO, S02. Carbocyclic or Examples and references of heterocyclic groups and hydroxyl groups are as described above in the general reference examples and definitions sections, and in the following. In one embodiment, R1 is aryl or heteroaryl. When R1 is- In the case of a heteroaryl group, the special heteroaryl group includes a monocyclic heteroaryl group (containing up to 3 heteroatom ring atoms selected from 0, S, and N), and a bicyclic heteroaryl group (containing up to 2 A heteroatom ring atom selected from 0, S, and N, both of which are aromatic rings. Examples of heteroaryl groups include: furyl (such as 2-furyl or 3-pyranyl), indolyl ( Such as 3-indolyl, 6-indolyl), 2,3-dihydro-benzo [1,4] -dioxelenyl (such as 2,3-dihydro-benzo [1 , 4] · Dioxane (5-yl), pyrazolyl (such as pyrazol-5-yl), pyrazolo [1 '5-a] pyridyl (such as pyrazolo [1, 5-a] pyridin-3-yl), oxazolyl, such as isoxazolyl (such as isoxazol-4-yl), pyridyl (such as 2-pyridyl, 3-pyridyl, 4-pyridyl, ), D quinolinyl (such as 2-nolinyl), pyrrolyl (such as 3-pyrrolyl), imidazolyl, and thienyl (such as 2-thienyl, 3-thienyl). -50- 200524877 (46) A subgroup of heteroaryl R 1 is composed of the following: furyl (such as 2- fluoranyl or 3-furanyl), indolyl, oxazolyl, isoxazolyl, Pyridyl, Dquinolyl, pyrrolyl, imidazolyl, and thienyl. Heterosquare R 1 is a suitable subgroup including: 2-furyl, 3-pyranyl, pyrrolyl, imidazolyl, and thienyl. A suitable aryl group R1 is phenyl. The group R 1 may be an unsaturated or saturated carbocyclic or heterocyclic group 'wherein one or more substituents may be selected from the group R 10 previously defined. In one embodiment, the substituent on R1 may be selected from the group consisting of R1Ga: halogen, hydroxy, trifluoromethyl, cyano, nitro, hydroxy, groups R, Rb, where Ra is a bond, 〇, co, x3c (x4), c (x4) x3, X3C (X4) X3, s' so or S02, Rb is selected from: hydrogen and Ci.8 hydrocarbon group, which is selected by one or more substituents selected from Arbitrary substitution: hydroxy, oxy, halogen, cyano, nitro, carboxyl, monocyclic non-aromatic carbocyclic or heterocyclic group having 3 to 6 ring atoms; wherein (^ .8 hydrocarbon group is one or more Each carbon atom can be arbitrarily replaced by 0, s, so, so2, x3c (x4), c (x4) x3, or X3C (X4) X3; x3 is o or s; X4 is = 0, = s. When carbocyclic and heterocyclic groups have a pair of substituents on adjacent ring atoms, the two substituents may be connected to form a cyclic group. Therefore, two adjacent groups R 1 G together with The attached carbon or heteroatom may form a 5-membered heteroaryl ring or a 5- or 6-membered non-aromatic carbocyclic or heterocyclic ring, wherein the heteroaryl and heterocyclic group contain up to 3 selected from N Heteroatom ring atoms of 0, S and S In particular, two adjacent groups R 1 G together with the attached carbon or heteroatom can form a 6-membered non-aromatic heterocyclic ring, which contains up to -51-200524877 (47) 3 more (especially 2 ) A heteroatom ring atom selected from N, O and S. More specifically, two adjacent groups R ^ may form a 6-membered non-aromatic heterocyclic ring, which contains 2 heteroatoms selected from N or 0 A ring atom, such as a dioxin, such as [1,4-dioxane]. In one embodiment, R 1 is a carbocyclic group (eg, phenyl), which has a pair of substitutions on adjacent ring atoms Groups are connected to form a 2,3-dihydro-benzo [1,4] -dioxelenyl group. More specifically, the substituent on R1 may be selected from the group consisting of halogen, hydroxy, trifluoromethyl, Group Ra-Rb, where Ra is a bond or O, Rb is selected from: hydrogen and C; _4 hydrocarbon group, which is optionally substituted with one or more substituents selected from: hydroxyl, halogen (preferably fluorine), 5 Or 6-membered saturated carbocyclic and heterocyclic groups (for example, groups containing up to 2 heteroatoms selected from 0, S and N, such as unsubstituted pyridine, pyrrolidino, morpholino Piperazino and N-methyl The piperazino) group R1 may be substituted with more than one substituent. So '(for example) may have 1 or 2 or 3 or 4 substituents. In one embodiment, where R1 is a 6-membered ring (for example A carbocyclic ring, such as a benzene ring), which has 2, 2 or 3 substituents at the 2, 3, 4 or 6 position of the ring. For example, phenyl R 1 may be 2-mono-substituted, 3-mono-substituted , 2, 6-double-substituted, 2, 3-double-substituted, 2, 4_ double-substituted, 2, 5- double-substituted, 2, 3, 6-triplicated or 2 , 4 '6-replaced by three. More specifically, phenyl R 1 may be mono-substituted at the 2-position or di-substituted at the 2 and 6 positions. The substituents are selected from the group consisting of fluorine, chlorine and R1Rb, where M is 0, ... is an alkyl group (for example, methyl or ethyl) base). In one embodiment, 'fluoro is a suitable substituent. In another embodiment, suitable substituents (selected from: fluorine, chlorine, and methoxy. -52- 200524877 (48) Special examples of the non-aromatic substituent R 1 include unsubstituted or substituted ( RIG) a monocyclic cycloalkyl group. Examples of the cycloalkyl group include: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl; more commonly, cyclopropyl, cyclobutyl , Cyclopentyl and cyclohexyl, especially cyclohexyl. Other examples of non-aromatic groups R1 include unsubstituted or substituted (by one or more groups R1G) heterocyclic groups, each having 3 to 12 Ring atoms, typically 4 to 12 ring atoms, and more often 5 to 10 ring atoms). The group may be monocyclic or bicyclic (for example) typically having 1 to 5 heteroatom ring atoms (more often 1, 2, 3 or 4 heteroatom ring atoms), and the heteroatom is selected from nitrogen, Oxygen and sulfur. When sulfur is present, sulfur may exist in the form of -S-, -S (O)-, or -S (0) 2- where the characteristics of adjacent atoms and groups permit. 'Heterocyclic groups can contain, for example: cyclic ether groups (such as in tetrahydrofuran and dioxane), cyclic thioether groups (such as in tetrahydrothiophene and dithiane), cyclic Amine groups (such as in pyrrolidine), cyclic amidoamines (such as in pyrrolidone), cyclic esters (such as in butyrolactone), cyclic thiamidine and sulfur Esters, cyclic masters (for example, in sulfanes and sulfenes), cyclic masters, cyclic sulfonamides, and combinations thereof (for example, morpholine and thiomorpholine and their S-oxides and S 'S-Dioxide) ° In a subgroup of heterocyclic group R1, the' heterocyclic group contains a cyclic ether group (such as in tetrahydrofuran and dioxane), a cyclic thioether group (Such as in tetrahydrothiophene and dithiane), cyclic amine groups (such as in orbiorane), cyclic masters (such as in sulfane and sulfene), cyclic ASUS, cyclic sulfa and their combination (such as thiomorpholine) ° Examples of monocyclic non-aromatic heterocyclic groups R1 include: 5,53 and 7-membered -53- 200524877 (49 ) Monocyclic heterocyclic groups, such as morpholine, pyridine (such as 1-piperidinyl, 2-piperidinyl, 3 -1 D-Dyl and 4-piperyl D-, etc.) 1-Hou Lue Yuan Ji,

2 -吡咯烷基及3 -吡咯烷基）、咄咯烷酮、吡喃（2 H -吡喃或 4 Η - D比喃）、二氫噻吩、二氫吼喃、二氫呋喃、二氫噻唑、 四氫呋喃、四氫噻吩、二噁烷、四氫吡喃（例如4 -四氫毗 喃基）、咪唑啉、咪唑啉酮、噁唑啉、噻唑啉、2 -观唑啉 、吡唑烷、哌嗪及Ν -烷基_嗪（如Ν -甲基哌嗪）。另外的實 例包括硫代嗎啉及彼之S -氧化物及S，S -二氧化物（尤其硫 代嗎啉）。又一個實例包括Ν -烷基哌啶，如Ν -甲基哌啶。2-pyrrolidinyl and 3-pyrrolidinyl), pyrrolidone, pyran (2 H -pyran or 4 Η -D ratio), dihydrothiophene, dihydroroan, dihydrofuran, dihydro Thiazole, tetrahydrofuran, tetrahydrothiophene, dioxane, tetrahydropyran (eg 4-tetrahydropyranyl), imidazoline, imidazolinone, oxazoline, thiazoline, 2-spectazoline, pyrazolidine , Piperazine, and N-alkyl_azine (such as N-methylpiperazine). Additional examples include thiomorpholine and its S-oxides and S, S-dioxides (especially thiomorpholine). Yet another example includes N-alkylpiperidine, such as N-methylpiperidine.

非芳香雜環基團R 1的一個亞群包括：未被取代的或被 取代的（被一或多個基團R1G)5、6及7員的單環的雜環基團 ，'如嗎Π林、口浪口定（例如1HD定基、2_ 口JR D定基、3-D底0定基、4-_啶基、）、吡咯烷（例如1 -吡咯烷基、2 -吡咯烷基及3 -吡 咯烷基）、吡咯酮、哌嗪及N -烷基哌嗪（如N _甲基哌嗪）， 其中特別的亞組是由下列組成：吡咯烷、呢啶、嗎啉、硫 代嗎啉及N -甲基哌嗪。 一般，合宜的非芳香雜環基團包括：吡咯烷、哌啶、 嗎啉、硫代嗎啉、S，S-二氧化物、_嗪、N-烷基哌嗪及 N -烷基哌啶。 雜環基團的另一個特別的亞組是由下列組成：吡咯烷 、哌啶、嗎啉、N-烷基_嗪、任意的N-甲基_嗪及硫代嗎 琳。 當R]是一種被碳環或雜環基團取代的G.s烴基時，碳 環及雜環基團可以是芳香的或非芳香的，彼可以選自上文 -54- 200524877 (50) 中所陳述的該類基團的實例。被取代的烴基典型上是一種 飽和的c!.4烴基（如烷基），較佳〇]^2或CH2CH2基團。在被 取代的烴基是C2Μ烴基的場合中，碳原子及彼之相關的氫 原子中的一個可被磺醯替代（例如在基團S02CH2中的）。 在與（^.8烴基連接的碳環或雜環基團是芳香性時，該 基團的實例包括：單環的芳基與單環的雜芳基（含有至多4 個雜原子環原子，而雜原子選自〇、S及N)及二環的雜芳 基（含有至多2個選自〇、S及N的雜原子環原子），其中二個 環是芳香的。· 該基團的實例在上文的 ''泛用的參考例及定義〃章節 中被陳述。 '該基團的特例包括呋喃基（例如2 -呋喃基或3 -呋喃 基）、吲哚基、噁唑基、異噁唑基、吡啶基、喹啉基、毗 咯基、咪唑基及噻吩基。充當Ch8烴基的取代基的芳基及 雜芳基的特例包括：苯基、咪唑基、四唑基、噻唑基、吲 哚基、2 -呋喃基、3 -呋喃基、吡咯基及噻吩基。該基團可 被一或多個如本說明書中所定義的取代基R1()或尺1()3取代 〇 當R1是一種被非芳香碳環或雜環基團取代的C!_8烴基 時，非芳香的或雜環的基團可以是選自在前文中所陳述的 該類基團的名單的基團。舉例來說，非芳香基團可以是一 種單環的基團，彼有4至7個環原子，例如5至7個環原子， 典型有〇至3個（較典型有0、1或2個）選自〇、S及N的雜原子 環原子。當環狀的基團是一種碳環基團時’彼另外可選自 -55- 200524877 (51) 有3個環原子的單環基團。特例包括：單環的環院基，如 環丙基、環丁基、環戊基、環己基及環戊基、及5、6及7 員的單環的雜環基團，如嗎啉、暖啶（例如1 -哌D定基、2 _ 哌啶基、3 -哌啶基及4 -1派啶基、）、吡咯烷（例如丨_吼略院 基、2 - D比略丨兀基及-批略丨兀基）、吼略院酬、呢j]秦及n _院 基_嗪（如N -甲基_嗦）。一般’合宜的非芳香雜環基團包 括··吡咯烷、哌啶、嗎啉、硫代嗎啉及N-甲基哌嗪。 當R 1是一種被任意取代的c 1 ·8煙基時，烴基可以如前 · 文中所定義的，較佳長度至多4個碳原子，較常爲長度至 多3個碳原子，例如長度1或2個碳原子。 在一個體現中，烴基是飽和的，彼可以是與環的或環 '•狀的，例如無環的。無環的飽和的烴基（即烷基）可以是直 鏈的或分枝的烷基。 直鏈烷基R 1的實例包括：甲基、乙基、丙基及丁基。 分枝鏈的烷基R 1的實例包括：異丙基、異丁基、第三 丁基及2，2-二甲基丙基。 φ 在一個實例中，烴基是一種直鏈的飽和基團，彼有Ιό 個碳 原子， 較常有 1 - 4 個 碳原子 ，例如 1- 3 個 碳原子 ，例 如1、2或3個碳原子。當烴基被取代時，特例是被取代的（ 例如被碳環或雜環基團）甲基及乙基。 C】·8烴基R1可以被一至多個選自下列的取代基任意取 代：鹵素（例如氟）、羥基、Cy烴氧基、胺基、一或二_ -4烴胺基、有3至12個環原子的碳環或雜環基團，其中 烴基的碳原子中的]或2個可被選自〇、S、NH、SO、S〇2 -56- 200524877 (52) 的原子或基團任意替代。烴基的特別的取代基包括：羥基 、氯、氟（例在在三氟甲基中的）、甲氧基、乙氧基、胺基 、甲胺基及二甲胺基，合宜的取代基是羥基及氟。 當A是C = Ο時，特別的基團R 1 - C 0是在下面的表〗中所 陳述的基團。 在表1中，與吡唑-4-胺基的氮原子連接的基團的連接 點是由從羰基延伸的末端的單鍵表示。所以，作爲說明’A subgroup of the non-aromatic heterocyclic group R 1 includes: unsubstituted or substituted (by one or more groups R1G) 5, 6, and 7-membered monocyclic heterocyclic groups, 'such as? Lin Lin, Oral Mouth (such as 1HD acryl, 2-D JR D, a 3-D bottom 0 amid, 4-pyridyl, etc.), pyrrolidine (eg 1-pyrrolidinyl, 2-pyrrolidinyl and 3 -Pyrrolidinyl), pyrrolidone, piperazine, and N-alkylpiperazine (such as N-methylpiperazine), among which a special subgroup consists of the following: pyrrolidine, morphine, morpholine, thio? And N-methylpiperazine. In general, suitable non-aromatic heterocyclic groups include: pyrrolidine, piperidine, morpholine, thiomorpholine, S, S-dioxide, _azine, N-alkylpiperazine, and N-alkylpiperidine . Another particular subgroup of heterocyclic groups consists of the following: pyrrolidine, piperidine, morpholine, N-alkyl_azine, any N-methyl_azine, and thiomorphine. When R] is a Gs hydrocarbon group substituted with a carbocyclic or heterocyclic group, the carbocyclic and heterocyclic group may be aromatic or non-aromatic, and they may be selected from the above-54-200524877 (50) Examples of such groups are stated. The substituted hydrocarbon group is typically a saturated c! .4 hydrocarbon group (such as an alkyl group), preferably a ^ 2 or CH2CH2 group. In the case where the substituted hydrocarbon group is a C2M hydrocarbon group, one of the carbon atom and its related hydrogen atom may be replaced by sulfonium (for example, in the group S02CH2). When a carbocyclic or heterocyclic group connected to a hydrocarbon group is aromatic, examples of the group include: a monocyclic aryl group and a monocyclic heteroaryl group (containing up to 4 heteroatom ring atoms, The heteroatom is selected from 0, S, and N) and a bicyclic heteroaryl group (containing up to 2 heteroatom ring atoms selected from 0, S, and N), of which two rings are aromatic. Examples are set out in the "General Reference Examples and Definitions" section above. 'Specific examples of this group include furyl (such as 2-furyl or 3-furyl), indolyl, oxazolyl, Isoxazolyl, pyridyl, quinolinyl, pyrrolyl, imidazolyl, and thienyl. Specific examples of aryl and heteroaryl groups that serve as substituents for the Ch8 hydrocarbon group include: phenyl, imidazolyl, tetrazolyl, and thiazole Group, indolyl, 2-furanyl, 3-furanyl, pyrrolyl, and thienyl. This group may be substituted by one or more substituents R1 () or R1 () 3 as defined in this specification. 〇 When R1 is a C! _8 hydrocarbon group substituted with a non-aromatic carbocyclic or heterocyclic group, the non-aromatic or heterocyclic group may be selected from the group described in the foregoing. A list of similar groups. For example, a non-aromatic group can be a monocyclic group, which has 4 to 7 ring atoms, such as 5 to 7 ring atoms, and typically 0 to 3 ( More typically there are 0, 1 or 2) heteroatom ring atoms selected from 0, S, and N. When the cyclic group is a carbocyclic group, 'the other can be selected from -55- 200524877 (51) have A monocyclic group of 3 ring atoms. Specific examples include: monocyclic cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cyclopentyl, and 5, 6, and 7-membered monocyclic groups Heterocyclic groups, such as morpholine, warming (such as 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, and 4 -1 pyridinyl), pyrrolidine (such as 丨 _ Base, 2-D ratio (Woody base and-Criticized base (Woody base)), Rouer Academy pay, j] Qin and n _ Yuan base_ hydrazine (such as N -methyl_ 嗦). Generally 'appropriate non- Aromatic heterocyclic groups include ······································································ When the R 1 is an optionally substituted c 1 · 8 nicotinyl group, the hydrocarbon group may be as before · As defined in the text, the preferred length is up to 4 carbon atoms, more often the length Up to 3 carbon atoms, such as 1 or 2 carbon atoms in length. In one embodiment, the hydrocarbyl group is saturated, which may be cyclic or cyclic, such as acyclic. Acyclic saturated hydrocarbon groups ( (I.e., alkyl) may be a linear or branched alkyl group. Examples of the linear alkyl group R 1 include methyl, ethyl, propyl, and butyl. Examples of the branched chain alkyl group R 1 include: Isopropyl, isobutyl, third butyl, and 2,2-dimethylpropyl. Φ In one example, a hydrocarbyl group is a straight-chain saturated group with 1 carbon atom and more often 1 -4 carbon atoms, such as 1 to 3 carbon atoms, such as 1, 2 or 3 carbon atoms. When a hydrocarbyl group is substituted, special cases are substituted (such as by a carbocyclic or heterocyclic group) methyl and ethyl base. C] · 8 hydrocarbon group R1 may be arbitrarily substituted with one or more substituents selected from the group consisting of halogen (for example, fluorine), hydroxyl group, Cy alkyloxy group, amine group, mono- or di-4 hydrocarbon alkyl group, 3 to 12 Carbocyclic or heterocyclic group of a ring atom, of which a carbon atom of a hydrocarbon group] or 2 atoms or groups which may be selected from 0, S, NH, SO, S02-56-200524877 (52) Arbitrary substitution. The special substituents of hydrocarbyl include: hydroxyl, chlorine, fluorine (such as in trifluoromethyl), methoxy, ethoxy, amine, methylamino and dimethylamine. Suitable substituents are Hydroxyl and fluorine. When A is C = 0, the special groups R 1-C 0 are the groups stated in the table below. In Table 1, the connection point of the group attached to the nitrogen atom of the pyrazole-4-amino group is represented by a single bond at the terminal extending from the carbonyl group. So as an illustration ’

在表中的基團B是三氟乙醯基團，在表中的基團10是苯乙 醯基團，在表中的基團I是3-(4-氯代苯基）丙釀基團。The group B in the table is a trifluoroacetamidine group, the group 10 in the table is a phenethylamidine group, and the group I in the table is a 3- (4-chlorophenyl) propanyl group. group.

-57- 200524877 (53)-57- 200524877 (53)

-58- 200524877 (54)-58- 200524877 (54)

-59- 200524877 (55)-59- 200524877 (55)

-60- 200524877(56)-60- 200524877 (56)

Me 0 HN Λ MeO 丨 £ Me o MeJ Me^Me BU BV BW BX 專 Cl rj^N Me^y^OMe A BY BZ BAA BAB [Γ^Ί 〇r〇Et 〇〇5 分？ BAC BAD BAE BAF CLBr \〇V (&gt;0. X Me Me 0 MeO \ Λ BAG BAH BAI BAJ C，^cl .Cl Me 'r Ο， BAK BAL BAM BANMe 0 HN Λ MeO 丨 £ Me o MeJ Me ^ Me BU BV BW BX Special Cl rj ^ N Me ^ y ^ OMe A BY BZ BAA BAB [Γ ^ Ί 〇r〇Et 〇〇5 points? BAC BAD BAE BAF CLBr \ 〇V (&gt; 0. X Me Me 0 MeO \ Λ BAG BAH BAI BAJ C, ^ cl .Cl Me 'r Ο, BAK BAL BAM BAN

-61 - 200524877 (57)-61-200524877 (57)

基團R^-CO的一個亞群是由在上文的表1中的基團A至 BF組成。 基團R^-CO的另一個亞群是由在上文的表1中的基團A 至BS組成。 合宜的基團R^CO的一組是由基團J、AB、AH、AJ、· AL、AS、AX、AY、AZ、BA、BB、BD、BH、BL、BQ、 BS及BAI組成。A subgroup of the groups R ^ -CO is composed of the groups A to BF in Table 1 above. Another subgroup of the group R ^ -CO is composed of the groups A to BS in Table 1 above. A suitable group of groups R ^ CO is composed of the groups J, AB, AH, AJ, · AL, AS, AX, AY, AZ, BA, BB, BD, BH, BL, BQ, BS and BAI.

合宜的基團R^CO的另一組是由基團J、AB、AH、AJ 、AL、AS、AX、AY、AZ、BA、BB、BD、BH、BL、BQAnother group of suitable groups R ^ CO is composed of groups J, AB, AH, AJ, AL, AS, AX, AY, AZ, BA, BB, BD, BH, BL, BQ

及B S組成。 更合宜的基團R^CO—是AJ、AX、BQ、BS及BAI。 基團R^CO的一個特別合宜的亞組是由AJ、BQ及BS 組成。 基團R^CO的一個特別合宜的亞組是由AJ及BQ組成。 當X是R^A-NR4及A是C = 0，及R1是在4的位置上帶有 取代基的苯基環時，在4的位置上的取代基宜不代表在鄰 位有基團S02NH2或S02Me的苯基。 在一個泛用的體現中，R 1可不代表一個被取代的或未 -62- 200524877 (58) 被取代的四氫喹啉、色滿、色烯、硫代色滿、硫代色烯、 二氫萘或四氫萘基團。較特別地，可不代表一個被取代 的或未被取代的四氫鸣啉、色滿、色烯、硫代色滿、硫 代色燒、二氫萘或四氫萘基團（被彼之芳香環連結成基團 A-NR4·)。 在另一個泛用的體現中，當R】是一個被取代的或未被 取代的苯基時，基團Y„R3可不代表氫、未被取代的〇燒 基未被取代的C 5 - 1 0環院基、未被取代的苯基、未被取代 的CbM烷苯基或未被取代的苯基_CiiG烷基。 在基團RJ-A-NR4-中，當R1是一個被任意取代的烴基 ’該烴基包含或含有一個被取代的或未被取代的嫌基時， 吾人較佳烯基的碳-碳雙鍵不直接與基團A鍵接。 在基團R^A-NR4-中，當R1是一個被任意取代的烴基 時，該烴基可不代表烯基。 在另一個泛用的體現中，當Y是一個鍵、R3是氫、A 是C Ο、R 1是一個被取代的苯基時，在苯基上的各取代基 可不代表基團CH2-P(〇)RxRy，其中Rx及Ry各選自烷氧基及 苯基。And B S composition. More suitable groups R ^ CO- are AJ, AX, BQ, BS and BAI. A particularly suitable subgroup of the group R ^ CO is composed of AJ, BQ and BS. A particularly suitable subgroup of the group R ^ CO is composed of AJ and BQ. When X is R ^ A-NR4 and A is C = 0, and R1 is a phenyl ring having a substituent at the 4 position, the substituent at the 4 position should not represent a group in the ortho position SO2NH2 or SO2Me's phenyl. In a generalized embodiment, R 1 may not represent a substituted or un-62- 200524877 (58) substituted tetrahydroquinoline, chroman, chromene, thiochroman, thiochromene, di Hydronaphthalene or tetrahydronaphthalene groups. More specifically, it may not represent a substituted or unsubstituted tetrahydropyridine, chroman, chromene, thiochroman, thiochroman, dihydronaphthalene or tetrahydronaphthalene group (which is aromatic The ring is linked to form the group A-NR4 ·). In another universal embodiment, when R] is a substituted or unsubstituted phenyl group, the group Y „R3 may not represent hydrogen, and the unsubstituted alkynyl group is unsubstituted C 5-1 0 ring courtyard, unsubstituted phenyl, unsubstituted CbM alkylphenyl, or unsubstituted phenyl_CiiG alkyl. In the group RJ-A-NR4-, when R1 is an optionally substituted When the hydrocarbon group contains or contains a substituted or unsubstituted alkyl group, the carbon-carbon double bond of our preferred alkenyl group is not directly bonded to the group A. In the group R ^ A-NR4- However, when R1 is an optionally substituted hydrocarbon group, the hydrocarbon group may not represent an alkenyl group. In another universal embodiment, when Y is a bond, R3 is hydrogen, A is C0, and R1 is a substituted In the case of phenyl, each substituent on the phenyl may not represent the group CH2-P (0) RxRy, where Rx and Ry are each selected from alkoxy and phenyl.

Y 在如式（I)之化合物中，Y是一個鍵或長度1，2或3個 碳原子的伸烷基鏈。 ''伸烷基〃有彼之一般的意義及代表一個二價飽和無 環的烴鏈。烴鏈可以是分枝的或不分枝的。在伸烷基鏈是 -63 - 200524877 (59) 分枝的場合中，伸烷基鏈可有一或多個甲基側鏈。伸烷基 的實例包括：-ch2-、-CH2CH2-、-CH2-CH2-CH2-、 CH(CH3)-、C(CH3)2-、-CHrCHn)-、-CH2-C(CH3)2-及 -CH(CH3)-CH(CH3)-。 在一個體現中，Y是一個鍵。 在另一個體現中，Y是一個伸院基鏈。 當γ是一個伸烷基鏈時，較佳γ是不分枝的，較特別 地含有1或2個碳原子，較佳1個碳原子。所以，合宜的基 團Y是- ch2-及-ch2-ch2-，最合宜的基團是（ch2)-。 在Y是一個分枝的鏈的場合中，較佳Y有至多2個甲基 側鏈。例如，Y可有一個單一的甲基側鏈。在一個體現中 ，Ύ是一個基團-CH(Me)_ 〇 在化合物的一個亞群中，Y是一個鍵、CH2、CH2CH2 或 ch2ch(ch3)。 R3 基團R3選自氫及有3至12個環原子的碳環及雜環基團 〇 在化合物的一個亞群中，Y是一個鍵及R3是氫。 在化合物的另·一個亞群中，Y是如前文中所定義的伸 烷基鏈及R3是氫。 在化合物的另一個亞群中，Y是一個鍵或伸烷基鏈（例 如基團-C(CH2)-及R3是一個碳環或雜環基團。 在化合物的另一個亞群中，Y是一個鍵及R3是一個碳 -64- 200524877 (60) 環或雜環基團。 在化合物的又一個亞群中，γ是一個伸烷基鏈（例如基 團-(CH2)-及R3是一個碳環或雜環基團。 碳環或雜環基團R3可以是芳基、雜芳基、非芳香碳環 或非芳香雜環基團，彼之實例在上文的泛用的參考例及定 義及下文中被詳細陳述。 合宜的芳基R3是未被取代的及被取代的苯基。 雜芳基R3的實例包括單環的雜芳基，彼含有至多3個（ 較佳至多2個）的選自◦、S及N的雜原子環原子。合宜.的雜 芳基包括5員環（含有至多一或二個雜原子環原子）及$員環 (含有一個雜原子環原子，最佳氮）。雜芳基之特例包括： 未被取代的或被取代的吡陡基、咪I]坐、吡哇、噻d坐、異噻 唑、異噁唑、噁唑、呋喃基及噻吩基。 特別的雜芳基是未被取代的及被取代的吡碇基，例如 2 -吡啶基' 3 -吡啶基及4 -吡啶基，尤其3 -吡啶基及4 -吡啶 基。當吡啶基被取代時，彼可以帶有一或多個取代基（一 般至多2個’較一般1個），取代基選自：C ! _4烷基（例如甲 基）、鹵素（例如氟或氯、較佳氯）及C ! - 4院氧基（例如甲氧 基）。在吡啶基上的取代基另可選自··胺基、二-C ! _4烷胺 基及二-G.4烷胺基，尤其胺基。 在一個體現中，當R3是一個芳基（例如苯基）或雜芳基 時，在碳環或雜環基團上的取代基可選自：基團R IG a，彼 由下列組成：鹵素、羥基、三氟甲基、氰基、單環的碳環 及雜環基團（有3至7個（一般5至6個環原子），及基團RLRb -65- 200524877 (61) ，其中 Ra 是一個鍵、〇、CO、Χ4(Χ2)、C^X^X1、 XIC(X2)X1、S、SO、S02、NRC、S02NRC或NRCS02 ;…選 自：氫、有3-7個環原子的碳環或雜環基團及C^8烴基，彼 被一或多個選自下列的取代基任意取代：羥基、合氧基、 鹵素、氰基、硝基、羧基、胺基、一或二烴胺基、有 3-7個環原子的碳環或雜環基團，其中Ci-8烴基的一或多個 碳原子可被下列任意替代：〇、S、SO、S02、NRe、 Χ4(Χ2)、C^XMX1 或 ; Re、X1 及 X2如同上文中 所定義的。 非芳香基團R3的實例包括：被任意取代（被R1()或R1Ga) 的環烷基、氧雜-環烷基、氮雜-環烷基、二氮雜-環烷基 、二氧雜-環烷基、及氮雜-氧雜-環院基。另外的實例包 括C7_】G氮雜-二環烷基，如1-氮雜-二環[2.2.2]辛-3-基。 R3的特例包括：未被取代的及被取代的環丙基、環丁 基、環戊基、環己基、四氫吼喃、嗎啉、四氫D夫喃、（]很Π定 及吡咯烷基團。 非芳香基團R3的一個亞組是由下列組成：環丙基、環 丁基、環戊基、環己基、四氫吡喃、四氫呋喃、_卩定及吡 咯烷基團。 合宜的非芳香基團R3包括：未被取代的或被取代的環 戊基、環己基、四氫吡喃、四氫呋喃、哌啶及吡咯烷基團 〇 非芳香基團可以是未被取代的或被一或多個如上文中 所定義的基團R1()或R1()a取代。 -66* 200524877 (62) R3的特別的取代其（你丨力n ,.、a 3 基（例如⑴® R是一個芳基或雜芳基 時或（i i)當R3是一個非芳香某圓 外万曰巻圑日寸）選自··基團R】Ga，彼由 下列組成··鹵素；羥基.罝標的m 1 巷’单環的碳壞或雜環基團（有3至6 個環原子，含有至多2個、、盟白η \Τ ΤΧ η 個k自〇、Ν及s的雜原子環原子）； 基團Ra-Rb，其中Ra是— 疋 10 踺 〇 ' CO &gt; c〇2 ' S〇2 ' NH ' S〇2 NH或NHS02，Rb選自··氫、碳環或雜環基團（有w 個環原子，含有至多2個選自〇、N&amp;s的雜原子環原子）；Y In the compound of formula (I), Y is a bond or an alkylene chain of 1, 2 or 3 carbon atoms in length. The term "alkylene" has its ordinary meaning and represents a divalent saturated acyclic hydrocarbon chain. The hydrocarbon chain may be branched or unbranched. Where the alkylene chain is -63-200524877 (59) branched, the alkylene chain may have one or more methyl side chains. Examples of alkylene include: -ch2-, -CH2CH2-, -CH2-CH2-CH2-, CH (CH3)-, C (CH3) 2-, -CHrCHn)-, -CH2-C (CH3) 2- And -CH (CH3) -CH (CH3)-. In one embodiment, Y is a key. In another embodiment, Y is an extension chain. When γ is an alkylene chain, it is preferred that γ is unbranched and more particularly contains 1 or 2 carbon atoms, preferably 1 carbon atom. Therefore, the suitable group Y is -ch2- and -ch2-ch2-, and the most suitable group is (ch2)-. Where Y is a branched chain, it is preferred that Y has at most two methyl side chains. For example, Y may have a single methyl side chain. In one embodiment, Ύ is a group -CH (Me) _ 〇 In a subgroup of the compound, Y is a bond, CH2, CH2CH2, or ch2ch (ch3). The R3 group R3 is selected from hydrogen and carbocyclic and heterocyclic groups having 3 to 12 ring atoms. In a subgroup of compounds, Y is a bond and R3 is hydrogen. In another subgroup of compounds, Y is an alkylene chain as defined above and R3 is hydrogen. In another subgroup of compounds, Y is a bond or an alkylene chain (for example, the group -C (CH2)-and R3 is a carbocyclic or heterocyclic group. In another subgroup of compounds, Y Is a bond and R3 is a carbon-64- 200524877 (60) ring or heterocyclic group. In yet another subgroup of compounds, γ is an alkylene chain (eg, the group-(CH2)-and R3 is A carbocyclic or heterocyclic group. The carbocyclic or heterocyclic group R3 may be an aryl, heteroaryl, non-aromatic carbocyclic or non-aromatic heterocyclic group, examples of which are in the general reference examples above. And its definition and detailed description below. Suitable aryl groups R3 are unsubstituted and substituted phenyl. Examples of heteroaryl groups R3 include monocyclic heteroaryl groups, which contain up to 3 (preferably up to 2) A) heteroatom ring atoms selected from ◦, S and N. Convenient heteroaryl groups include 5-membered rings (containing up to one or two heteroatom ring atoms) and $ membered rings (containing a heteroatom ring atom, Optimal nitrogen). Specific examples of heteroaryl groups include: unsubstituted or substituted pyrachyl, pyrimidine, pyridine, thiazole, isothiazole, isoxazole, , Furyl and thienyl. Special heteroaryl groups are unsubstituted and substituted pyridosyl, such as 2-pyridyl '3-pyridyl and 4-pyridyl, especially 3-pyridyl and 4-pyridyl When pyridyl is substituted, it may bear one or more substituents (generally up to 2 'more generally 1), the substituents are selected from: C! _4 alkyl (such as methyl), halogen (such as fluorine Or chlorine, preferably chlorine) and C!-4 alkoxy (such as methoxy). The substituent on the pyridyl group may be further selected from the group consisting of ·· amino, di-C! -4 alkylamino and di-G .4 alkylamino groups, especially amino groups. In one embodiment, when R3 is an aryl group (such as phenyl) or a heteroaryl group, the substituents on the carbocyclic or heterocyclic group may be selected from the group: R IG a, which consists of the following: halogen, hydroxyl, trifluoromethyl, cyano, monocyclic carbocyclic and heterocyclic groups (with 3 to 7 (usually 5 to 6 ring atoms), and groups RLRb -65- 200524877 (61), where Ra is a bond, 0, CO, χ4 (χ2), C ^ X ^ X1, XIC (X2) X1, S, SO, S02, NRC, S02NRC or NRCS02; ... select From: hydrogen, with 3-7 ring atoms Ring or heterocyclic group and C ^ 8 hydrocarbon group, which are arbitrarily substituted with one or more substituents selected from the group consisting of hydroxyl, oxy, halogen, cyano, nitro, carboxy, amine, mono or dihydrocarbon An amine group, a carbocyclic or heterocyclic group having 3-7 ring atoms, in which one or more carbon atoms of a Ci-8 hydrocarbon group may be replaced by any of the following: 0, S, SO, S02, NRe, X4 (X2 ), C ^ XMX1 or; Re, X1 and X2 are as defined above. Examples of the non-aromatic group R3 include: cycloalkyl, oxa-cycloalkyl substituted arbitrarily (by R1 () or R1Ga) , Aza-cycloalkyl, diaza-cycloalkyl, dioxa-cycloalkyl, and aza-oxa-cycloalkyl. Additional examples include C7_] Gaza-bicycloalkyl, such as 1-aza-bicyclo [2.2.2] oct-3-yl. Specific examples of R3 include: unsubstituted and substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuran, morpholine, tetrahydro Dfuran, (?) And pyrrolidine A subgroup of the non-aromatic group R3 is composed of the following groups: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyran, tetrahydrofuran, pyridine, and pyrrolidinyl groups. Non-aromatic group R3 includes: unsubstituted or substituted cyclopentyl, cyclohexyl, tetrahydropyran, tetrahydrofuran, piperidine, and pyrrolidinyl group. Non-aromatic group may be unsubstituted or substituted by a Or more than one of the groups R1 () or R1 () a as defined above. -66 * 200524877 (62) A special substitution of R3 which (you n, n,., A 3 group (eg ⑴® R is When an aryl or heteroaryl group or (ii) when R3 is a non-aromatic outer circle, it is selected from the group R] Ga, which consists of the following: halogen; hydroxyl. m 1 lane's monocyclic carbon bad or heterocyclic group (has 3 to 6 ring atoms, contains up to 2 and M η \ Τ Τχ η heteroatom ring atoms from k, 0 and s Group Ra-Rb, where Ra is-疋 10 踺 〇 'CO &gt; c〇2' S〇2 'NH' S〇2 NH or NHS02, Rb is selected from the group consisting of hydrogen, carbocyclic or heterocyclic group (Has w ring atoms and contains up to 2 heteroatom ring atoms selected from 0, N &amp;s);

C ! - 6烴基，彼被一或多個選自下列的取代基任意取代：羥 基、σ氧基、鹵素、羧基、胺基、—或二_Ci_4烴胺基、碳 環或雜環基團（有3-6個環原子，含有至多2個選自〇、^^及8 的雜原子環原子）；其中Cl-0烴基的一或二個碳原子可被下C! -6 hydrocarbon group, which is arbitrarily substituted with one or more substituents selected from: hydroxyl, sigmaoxy, halogen, carboxyl, amine, or -Ci_4 hydrocarbon amine, carbocyclic or heterocyclic (3-6 ring atoms, containing up to 2 heteroatom ring atoms selected from 0, ^^, and 8); where one or two carbon atoms of the Cl-0 hydrocarbon group can be replaced

列任思取代：〇、s、so、S02或NH 在~個體現中，合宜的在R3上的取代基R 1 G a (例如⑴ §R是一個芳基或雜芳基時或（丨”當…是一個非芳香基團 時）包括：鹵素、基團R、Rb，其中Ra是一個鍵、〇、c〇、Lenz substitution: 0, s, so, S02, or NH In ~ embodiments, a suitable substituent R 1 G a on R 3 (for example, when § § R is an aryl or heteroaryl or When ... is a non-aromatic group) includes: halogen, groups R, Rb, where Ra is a bond, 0, co,

C(X2)Xl，Rt^自：氫、有3-7個環原子的雜環基團、Cl.4烴 基’彼被一或多個選自下列的取代基任意取代：羥基、羧 基、胺基、一或二-C】.4烴胺基、有3-7個環原子的雜瓌基 團。 特別合宜的在R3上的取代基R1Ga(例如⑴當R3是一個 芳基或雜芳基時或（ii)當R3是一個非芳香基團時）包括：_ 素（尤其氟）、Cw烷氧基（如甲氧基）、C10烴基，彼被下列 任意取代：氟、羥基（例如羥甲基）、Cl.2烷氧基或5員或6 員的飽和的雜環（如哌啶並、嗎啉代、哌嗪並及N -甲基_ -67- 200524877 (63) 嗪並）。 在另一個體現中，R3的取代基（芳香的或非芳香的）選 自： •鹵素（例如氟及氯） • Ch4烷氧基（例如甲氧基及乙氧基），彼被一或多個選自 下列的取代基任意取代：鹵素、羥基、Cm烷氧基及5員 及6員的飽和的雜環（含有1或2個選自0、N及S的雜原子）， 雜環進一步被一或多個C ! _4基團（例如甲基）任意取代，其 中S(當存在時）可以S、SO或S02的形式存在； • C ! 4烴基，彼被一或多個選自下列的取代基任意取代，： 鹵素、羥基、C!·4烷氧基、胺基、C!-4烷基磺醯胺基' 3至 6員的環烷基（例如環丙基）、苯基（被一或多個選自鹵素、 甲基、甲氧基及胺基的取代基任意取代）、5員及6員的飽 和雜環（含有1或2個選自〇、N及S的雜原子），該雜環進一 步被一或多個C!-4基團（例如甲基）任意取代，其中s(當存 在時）可以S、S 0或S 0 2的形式存在； •羥基； •胺基、一 -C!·4烷胺基、二_Cl.4烷胺基、苄氧羰基胺基 及Cm烷氧羰基胺基； •羧基及Cb4烷氧羰基； • Cb4烷胺基磺醯及c!.4烷磺醯胺基； • 6·4烷磺醯； •基團0-HetlNH-Hets’其中Hets是一個5員或6員的飽和 的雜環’彼（含有1或2個選自〇、N及S的雜原子，該雜環 200524877 (64) 進一步被一或多個C】·4基團（例如甲基）任意取代，其中s( 當存在時）可以s、so或so2的形式存在； • 5員及6員的飽和的雜環，彼含有]或2個選自Ο、N及s的 雜原子，該雜環進一步被一或多個C ^4基團（例如甲基）任 意取代，其中S(當存在時）可以S、SO或so2的形式存在； •合氧基； • 6員的芳基及雜芳基環，彼含有至多2個氮環原子，彼被 一或多個選自鹵素、甲基及甲氧基的取代基任意取代。 在化合物的一個合宜的亞群中，R3是一個碳環或雜環 基團R3a，彼選自··苯基；C3_6環烷基；5及6員的飽和的非 芳香雜環，彼含有至多2個選自N、0、S及S02的雜原子環 原子；6員的雜芳基環，彼含有1、2或3個氮環原子；5員 的雜芳基環，彼有至多3個選自N、0及S的雜原子環原子 其中各碳環或雜環基團R3a被至多4個，較佳至多3個，較 佳至多2個（例如1個）選自下列的取代基任意取代：胺基； 經基，合氧基；氟；氯；Ci_4院基- (0)〇·，其中q是0或1， Ci-4丨兀基基團被氟、經基或Ci.2院氧基任意取代；一 -Ci-4 垸胺基；二-Cy烷胺基；Ch烷氧羰基；羧基；基團Re-R16，其中Re是一個鍵或Cl_3伸烷基鏈，選自Ci 4烷基 石貝釀，C 1 . 4丨兀肢基礦釀；C 1 · 4院基礦釀胺基；胺基；一 -C ]-4火兀fe：基，一 -C 4院胺基；c 1 . 7烴氧鑛基胺基；6員的芳香 基團（含有至多3個氮環原子）；C 3 · 6環院基；5或6員的飽和 的非芳香雜環基團，彼含有]或2個選自N、0、S及s 0 2的 200524877 (65) 雜原子環原子，基團R!6(當飽和的非芳香基團被一或多個 甲基任意取代），基團R16(當芳香基團被一或多個選自下 列的基團任意替代：氟、氯、羥基、Cm烷氧基及Ci 2烷 基）。 π 在另一個體現中，R3選自： •單環的芳基，彼被丨“個（例如丨_2個，例如丨個）取代基 R10或R1。3任意取代； 之 • C3-C7環烷基，彼被1-4個（例如丨」個，例如丨個）取代_ R10或意取代； •飽和的5員的雜環，彼含有i個選自〇、s的雜原子及 被一個合氧基及/或被1 _ 4個（例如1 _ 2個，例如1個）取代基 R1G或R1Ga任意取代； •飽和的6員的雜環，彼含有丨或2個選自〇、N及s的雜原 子及被一個合氧基及/或被1 _4個（例如1 _ 2個，例如1個）取 代基R1G或R1Ga任意取代； • 5員的雜芳基，彼含有〗或2個選自〇、N及s的雜原子及 被1-4個（例如1-2個，例如1個）取代基以^或…^任意取代 • 0員的雜芳基環，彼含有丨個或2個氮環原子（較佳1個氮 i哀原子）及被1 - 4個（例如1 - 2個，例如1個）取代基R】0或R】0 a 任意取代； •一 -氮雜二環烷基及二氮雜二環烷基各有7至9個環原子 及被]-4個（例如】-2個’例如1個）取代基R i G或R I 0 a任意取 代。 -70 - 200524877 (66) 基團Y-R3的特例在表2中被陳述。在表2中，與吡唑-3 -甲醯胺基團的氮原子連接的基團的連接點是由從該基團 延伸的末端的單鍵表示。所以，作爲說明，在表中的基團 CA是4-氟代苯基、在表中的基團CB是4-甲氧基苄基、在 表中的基團CC是4-(4-甲基哌嗪並）-苯基甲基。C (X2) X1, Rt ^ from: hydrogen, heterocyclic group having 3-7 ring atoms, Cl.4 hydrocarbon group which is optionally substituted with one or more substituents selected from: hydroxyl, carboxyl, amine Group, mono- or di-C]. 4 hydrocarbon amine group, a heterofluorene group having 3-7 ring atoms. Particularly suitable substituents R1Ga on R3 (for example, when R3 is an aryl or heteroaryl group or (ii) when R3 is a non-aromatic group) include: _ (especially fluorine), Cw alkoxy (Such as methoxy), C10 hydrocarbyl, which are substituted by any of the following: fluorine, hydroxyl (such as methylol), Cl.2 alkoxy, or a 5- or 6-membered saturated heterocyclic ring (such as piperido, Morpholino, piperazino and N-methyl- -67- 200524877 (63) azino). In another embodiment, the substituents (aromatic or non-aromatic) of R3 are selected from: • halogens (such as fluorine and chlorine) • Ch4 alkoxy (such as methoxy and ethoxy), which are substituted by one or more Any substituent selected from the following: halogen, hydroxyl, Cm alkoxy, and 5-membered and 6-membered saturated heterocyclic ring (containing 1 or 2 heteroatoms selected from 0, N, and S), the heterocyclic ring is further Arbitrarily substituted with one or more C! _4 groups (such as methyl), where S (when present) can exist in the form of S, SO or S02; • C! 4 hydrocarbon group, which is selected from one or more of the following Arbitrarily substituted by: halogen, hydroxyl, C! · 4 alkoxy, amine, C! -4 alkylsulfonamido '3 to 6 membered cycloalkyl (such as cyclopropyl), phenyl (Optionally substituted by one or more substituents selected from halogen, methyl, methoxy and amine), 5-membered and 6-membered saturated heterocyclic rings (containing 1 or 2 heterocyclic groups selected from 0, N and S Atom), the heterocyclic ring is further optionally substituted with one or more C! -4 groups (such as methyl), where s (when present) may exist in the form of S, S 0 or S 0 2; Amine , Mono-C! · 4 alkylamino, di-Cl.4 alkylamino, benzyloxycarbonylamino and Cm alkoxycarbonylamino; • carboxyl and Cb4 alkoxycarbonyl; • Cb4 alkylaminosulfonyl and c ! .4 Alkylsulfonylamino groups; • 6.4 Alkylsulfonyl groups; • Group 0-HetlNH-Hets' where Hets is a 5- or 6-membered saturated heterocyclic ring (containing 1 or 2 members selected from 〇, N and S heteroatoms, the heterocycle 200524877 (64) is further optionally substituted by one or more C] · 4 groups (such as methyl), where s (when present) may be s, so or so2 Exists in the form; • 5 and 6-membered saturated heterocyclic ring, which contains] or 2 heteroatoms selected from 0, N, and s, and the heterocyclic ring is further substituted by one or more C ^ 4 groups (such as methyl ) Arbitrary substitution, where S (when present) can exist in the form of S, SO or so2; • Hexy; • 6-membered aryl and heteroaryl rings, which contain up to 2 nitrogen ring atoms, which are replaced by a Or a plurality of substituents selected from halogen, methyl, and methoxy are optionally substituted. In a suitable subgroup of compounds, R3 is a carbocyclic or heterocyclic group R3a, which is selected from the group consisting of phenyl; C3_6 Cycloalkyl; 5 and 6 member saturation Non-aromatic heterocycle, which contains up to 2 heteroatom ring atoms selected from N, 0, S, and S02; 6-membered heteroaryl ring, which contains 1, 2 or 3 nitrogen ring atoms; 5-membered heteroaryl Basic ring, which has up to 3 heteroatom ring atoms selected from N, 0 and S. Among them, each carbocyclic or heterocyclic group R3a is up to 4, preferably up to 3, preferably up to 2 (for example 1 ) Arbitrarily substituted by a substituent selected from the group consisting of: amine; trisoxy, alkoxy; fluorine; chlorine; Ci_4--(0) 〇, where q is 0 or 1, Ci-4 group is Arbitrarily substituted by fluorine, via a group or Ci.2 oxygen; mono-Ci-4 fluorenylamino; di-Cy alkylamino; Ch alkoxycarbonyl; carboxyl; group Re-R16, where Re is a bond or Cl_3 The alkylene chain is selected from Ci 4 alkyl stone shellfish, C 1. 4 丨 limulus base; C 1 · 4 courtyard base amine; amine; mono-C] -4 , A -C 4 amine group; c 1.7 hydrocarbyl amine group; 6-membered aromatic group (containing up to 3 nitrogen ring atoms); C 3 · 6-ring compound; 5 or 6 member saturation Non-aromatic heterocyclic group, which contains] or 2 200524877 (65) heteroatom ring atoms selected from N, 0, S and s 0 2 , Group R! 6 (when the saturated non-aromatic group is arbitrarily substituted by one or more methyl groups), group R16 (when the aromatic group is arbitrarily replaced by one or more groups selected from the group: fluorine, chlorine , Hydroxy, Cm alkoxy, and Ci 2 alkyl). π In another embodiment, R3 is selected from: • a monocyclic aryl group, which is optionally substituted with one or more (eg, two or two) substituents R10 or R1. 3; C3-C7 ring Alkyl, which is substituted by 1-4 (for example, 丨 ", such as 丨) _ R10 or intended; • saturated 5-membered heterocyclic ring, which contains i heteroatoms selected from 0, s and by Oxygen and / or arbitrarily substituted with 1 to 4 (eg 1 to 2, for example 1) substituents R1G or R1Ga; • saturated 6-membered heterocyclic ring, which contains 丨 or 2 selected from 0, N And s heteroatoms and are optionally substituted with one oxy group and / or with 1 to 4 (for example 1 to 2 for example 1) substituents R1G or R1Ga; • 5-membered heteroaryl groups, which contain or 2 Heteroatoms selected from 0, N and s and optionally substituted with 1-4 (eg 1-2, such as 1) ^ or… ^ 0-membered heteroaryl rings, each of which contains 丨Or 2 nitrogen ring atoms (preferably 1 nitrogen atom) and arbitrarily substituted with 1 to 4 (for example 1 to 2 for example 1) substituents R] 0 or R] 0 a; Heterobicycloalkyl and diazabicycloalkyl each have 7 to 9 rings Atom and arbitrarily substituted by] -4 (e.g. -2 ', e.g. 1) substituents R i G or R I 0 a. -70-200524877 (66) Specific examples of the group Y-R3 are stated in Table 2. In Table 2, the point of attachment of the group attached to the nitrogen atom of the pyrazole-3-methylamidine group is represented by a single bond at the terminal extending from the group. Therefore, as an illustration, the group CA in the table is 4-fluorophenyl, the group CB in the table is 4-methoxybenzyl, and the group CC in the table is 4- (4-methyl Piperazino) -phenylmethyl.

-71 - 200524877 (67) 表2-基團Y-R3的實例 CA CB ^&quot;N、Me cc Ό CD O〇 CE CF CG Η CH xxo Cl X5^oh CJ ^Ci CK Xi Me CL Όι CM T^Me ^Me CN Ό CO ΎΧΟ CP ^ XI CQ XV 0 CR X^.〇H 0 cs-71-200524877 (67) Table 2- Examples of group Y-R3 CA CB ^ &quot; N, Me cc Ό CD O〇CE CF CG Η CH xxo Cl X5 ^ oh CJ ^ Ci CK Xi Me CL CL CM T ^ Me ^ Me CN Ό CO ΎΧΟ CP ^ XI CQ XV 0 CR X ^ .〇H 0 cs

-72- 200524877 (68)-72- 200524877 (68)

-73- 200524877(69)-73- 200524877 (69)

DN 3 N DO 8 DP 8 N」 DQ ό Me DR DS DT DU DV Ό丫， DW V1 DX όό DY Ol. DZ Ό、 cf3 EA EB &quot;n EC Ό·, HN、sf XX Smh rS vn XI ^N、Me ^ Me ED EE EF EGDN 3 N DO 8 DP 8 N ”DQ ό Me DR DS DT DU DV Ό 丫, DW V1 DX ό DY Ol. DZ Ό, cf3 EA EB &quot; n EC Ό ·, HN, sf XX Smh rS vn XI ^ N , Me ^ Me ED EE EF EG

-74- 200524877(70)-74- 200524877 (70)

Ό丫 Me^^O pMe Me EH A OH El Ol 以〇 EJ XX广 1 Me EK X) MeO^ EL XV EM u；° EN Ό.， HN 丫。 r° Ph EO XX/ 〇々b、Me EP XX〗 nh2 EQ όί ό ER 、、、'，〇h ES 、n ET Xl〇 EU EV A EW EX Xr° EY EZ Me /O Me FAΌ ^ Me ^^ O pMe Me EH A OH El Ol to 〇 EJ XX wide 1 Me EK X) MeO ^ EL XV EM u; ° EN Ό., HN ya. r ° Ph EO XX / 〇々b, Me EP XX〗 nh2 EQ ό ER 、、、 '， 〇h ES ， n ET Xl〇 EU EV A EW EX Xr ° EY EZ Me / O Me FA

-75- 200524877 (71)-75- 200524877 (71)

FB /NO FC Me FD FE FF FG /0 FH FI FJ FK tx FL N FM FNFB / NO FC Me FD FE FF FG / 0 FH FI FJ FK tx FL N FM FN

選自表2的基團的一個亞組是由基團CA至EL組成。 選自表2的基團的另一個亞組是由基團C A至CV組成。 選自表2的合宜的基團包括基團CL、CM、ES、ET、 FC、FG及 FH。 選自表2的特別合宜的基團包括基團CL、CM及ES， 最佳CL及CM。 在另一個泛用的體現中，當R3是一個氮雜-環烷基時 ，在如式（I)之化合物中的基團X宜爲R^A-NR4，其中A是 CO、NRg(C = 0)或0(00)。另外，當R3是一個氮雜-環烷基 時，氮雜-環烷基的氮原子宜不被與2，3-二氫-苯並[1，4] -76- 200524877 (72) 二氧雜環己烯基或四氫萘基團連接的伸烷基鏈取代。 在另一個泛用的體現中，當Y是長度1個碳原子的伸 烷基鏈時，R3不代表被任意取代的苯基，彼帶有一個被取 代的或未被取代的環己氧基或環己硫基。 在另一個泛用的體現中，R3不代表一個含有5員的雜 芳基環的基團，該雜芳基環由一個單鍵直接與單環的或雙 環的芳基連接或R3不代表一個含有2個雜芳基的基團，該2 個雜芳基包含由一個單鍵連接在一起的二個5員的雜芳基 環。 在另一個泛用的體現中，R1不代表一個含有5員的雜 芳基環的基團，該雜芳基環由一個單鍵直接與單環的或雙 環的芳基連接或R3不代表一個含有2個雜芳基的基團，該 二個雜芳基包含由一個單鍵連接在一起的二個5員的雜芳 基環。 在另一個泛用的體現中，當Y-R3是一個烷基、環烷基 、被任意取代的苯基或被任意取代的苯烷基時，R]-A-NR4 不代表一個被任意取代的薛醯-胺基或；醯-胺基。 當A是一個鍵（及任意地當A是CO、NRg(C = 0)或 0(C = 0))時，Y-R3可不代表在位置”皮烴基鏈（同時帶有一 個氧基，如羥基）、芳基及二唑及三唑取代的環烷基。 合宜地，R1或R3各不代表一個基團，彼含有一個被取 代的苯基，在苯基環的3至4位置上有硫及/或氧取代基， 如羥基、烷氧基及烷硫代。 在另一個泛用的體現中，當γ - R3是未被取代的或被取 -77- 200524877 (73) 代的苄基或苯乙基或萘甲基時，X可不代表cU5院胺基或 Cm醯胺基。 基團Y-R3較佳不包括一個苯並稠合的內醯胺基團，彼 有一個未被取代的或被取代的咪唑基團與其連接。 基團Y-R3較佳不包括基團_CH = C(C02Rq)-S_，其中Rq 是氫或院基。 在另一個泛用的體現中，既不是R1也不是R3含有—個 基團，其中一個5員的含氮雜芳基直接與或經由一個伸院 基氧雜-伸烷基、硫雜-伸烷基或氮雜-伸烷基與未被取代 的吡啶基或被取代的芳基、雜芳基或哌啶環連接，各環有 一個選自下列的取代基與其連接··氰基、被取代的或未被 取代的胺基、胺烷基、脒基、胍基及胺基甲_。 在另一個泛用的體現中，R1及R3各不代表—個不飽和 的含氮雜環基團或含氮雜芳基、或苯並呋喃或苯並嚷吩基 團，其中該含氮雜環基團、含氮雜芳基、二環的苯並咲喃 或苯並噻吩基團藉由一個單鍵與被取代的吡啶基或苯基直 接連接。 在另一個泛用的體現中，既不是Rl也不是R3含有〜個 基團’其中一個5員的含氮雜芳基直接與或經由一個伸院 基、氧雜·伸烷基、硫雜-伸烷基或氮雜-伸烷基與未被取 代的吼D定基或被取代的芳基、雜芳基或哌[J定基連接。 一般’吾人較佳本發明之化合物含有一個羧酸基團， 含有至多1個羧酸基團。 -78- 200524877 (74) 式（1)、（la)及（lb)的特別的及合宜的亞群 本發明之化合物的一個特別的群被式（II)表示：A subgroup of groups selected from Table 2 is composed of the groups CA to EL. Another subgroup of groups selected from Table 2 consists of the groups CA to CV. Suitable groups selected from Table 2 include the groups CL, CM, ES, ET, FC, FG and FH. Particularly suitable groups selected from Table 2 include the groups CL, CM and ES, most preferably CL and CM. In another universal embodiment, when R3 is an aza-cycloalkyl group, the group X in the compound of formula (I) is preferably R ^ A-NR4, where A is CO, NRg (C = 0) or 0 (00). In addition, when R3 is an aza-cycloalkyl group, the nitrogen atom of the aza-cycloalkyl group should preferably not be combined with 2,3-dihydro-benzo [1,4] -76- 200524877 (72) dioxane Hexenyl or tetralin groups are connected by an alkylene chain. In another universal embodiment, when Y is an alkylene chain of 1 carbon atom in length, R3 does not represent an arbitrarily substituted phenyl group, which carries a substituted or unsubstituted cyclohexyloxy group. Or cyclohexylthio. In another generalized embodiment, R3 does not represent a 5-membered heteroaryl ring group, the heteroaryl ring is directly connected to a monocyclic or bicyclic aryl group by a single bond or R3 does not represent a A group containing 2 heteroaryl groups, the 2 heteroaryl groups comprising two 5-membered heteroaryl rings connected together by a single bond. In another generalized embodiment, R1 does not represent a 5-membered heteroaryl ring group, the heteroaryl ring is directly connected to a monocyclic or bicyclic aryl group by a single bond or R3 does not represent a A group containing 2 heteroaryl groups, the two heteroaryl groups comprising two 5-membered heteroaryl rings connected together by a single bond. In another universal embodiment, when Y-R3 is an alkyl, cycloalkyl, optionally substituted phenyl, or optionally substituted phenalkyl, R] -A-NR4 does not represent an optionally substituted Xylamine-amino group; or fluorene-amino group. When A is a bond (and arbitrarily when A is CO, NRg (C = 0) or 0 (C = 0)), Y-R3 may not represent the position of the "pipinyl chain (with an oxy group, such as Hydroxyl), aryl, and diazole and triazole substituted cycloalkyl groups. Conveniently, R1 or R3 each does not represent a group, which contains a substituted phenyl group and has 3 to 4 positions on the phenyl ring. Sulfur and / or oxygen substituents, such as hydroxyl, alkoxy, and alkylthio. In another generalized embodiment, when γ-R3 is unsubstituted or taken as -77- 200524877 (73) In the case of phenyl or phenethyl or naphthylmethyl, X may not represent cU5 or amine. The group Y-R3 preferably does not include a benzo-fused lactam group. A substituted or substituted imidazole group is attached to it. The group Y-R3 preferably does not include the group _CH = C (C02Rq) -S_, where Rq is hydrogen or a radical. In another universal embodiment, Neither R1 nor R3 contains a group, one of which is a 5-membered nitrogen-containing heteroaryl group directly or via an alkylene oxa-alkylene, thia-alkylene, or aza-alkylene Unsubstituted pyridyl Or substituted aryl, heteroaryl, or piperidine rings, each ring having a substituent selected from the following attached to it: cyano, substituted or unsubstituted amine, amine alkyl, fluorenyl , Guanidino, and aminomethyl. In another universal embodiment, R1 and R3 each do not represent an unsaturated nitrogen-containing heterocyclic group or nitrogen-containing heteroaryl group, or benzofuran or benzofluorene. A phen group in which the nitrogen-containing heterocyclic group, nitrogen-containing heteroaryl, bicyclic benzopyran or benzothiophene group is directly connected to the substituted pyridyl or phenyl group through a single bond. In another universal embodiment, neither Rl nor R3 contains ~ groups. One of the five members of the nitrogen-containing heteroaryl group is directly or via an alkylene group, oxa · alkylene group, or thia-ene group. Alkyl or aza-alkylene is attached to an unsubstituted alkyl group or a substituted aryl, heteroaryl or piperidine group. Generally, the compound of the present invention preferably contains a carboxylic acid group, Contains at most 1 carboxylic acid group. -78- 200524877 (74) Special and suitable subgroups of formula (1), (la) and (lb) The compounds of the present invention A special group is of formula (II) represented by:

或彼之鹽類或互變異構物類或N -氧化物類或溶劑化物類， 其中R1、R2、R3及Y各獨立選自如本說明書中所定義的R】 ' R2、R3及 Y。 在式（Π)中，吾人較佳R2是氫或C!.4烷基（例如Cu燒 基）），較佳R2是氫。 在如式（11)之化合物的一^個亞群中，R1是： (i)苯基，彼被一或多個（例如i、2或3個）選自下列的取代 基任意取代··氟；氯；羥基；5及6員的飽和的雜環基團彼 含有1個或2個選自〇、N及S的雜原子，該雜環基團被一或 多個c】.4烷基任意取代；Ci4烴氧基；Ci4烴基；其中 烴基及C^4烴氧基被一或多個選自下列的取代基任意取代 :經基、氟、C!·2烷氧基、胺基、一及二-Ci·4烷胺基、苯 基、鹵苯基、飽和的碳環基團（有3至7個環原子，較佳4、 5或6個環原子、例如5或6個環原子）或飽和的雜環基團（有 5或6個環原子及含有至多2個選自〇、S及N的雜原子）；或 2，一氫_本並[1，4]二氧雜環己烯基；或 (ii)一個單環的雜芳基，彼含有一或二個選自〇、§及N的 200524877 (75) 雜原子；或一個二環的雜芳基，彼含有一個選自〇、S及N 的雜原子；單環的及二環的雜芳基，各被一或多個選自下 列的取代基任意取代：氟；氯；Ci〇烴氧基及Ci 3烴基， 彼被下列任意取代：羥基、氟、甲氧基或5員或6員的飽和 的碳環或雜環基團（含有至多2個選自〇、3及N的雜原子）； 或 (iii) 一個被取代的或未被取代的有3至6個環原子的環烷基 j (iv) —個C^4烴基，彼被一或多個選自下列的取代基任意 取代：讓；羥基；Cm烴氧基；胺基；一或二-Cl4烴胺基 ;有3至12個環原子的碳環或雜環基團，其中烴基的碳原 子中的一個可被選自下列的原子或基團任意替代：〇、NH 、so及 so2 〇 在基團（i)中，基團R】的一個亞群是由下列組成··苯基 ’彼被一或多個選自下列的取代基任意取代：氟；氯；羥 基；C!·3烴氧基；Ci.4烴基，其中Ci_3烴基被一或多個選自 下列的取代基任意取代：羥基、氟、C 1 .2烷氧基、胺基、 一及二- CL4烷胺基、飽和的碳環基團（有3至7個環原子， 較佳4、5或6個環原子，例如5或6個環原子）或飽和的雜環 基團（有5或6個環原子及含有至多2個選自0、S及N的雜原 子）。 在如式（II)之化合物的另一個亞群中，R1選自：上文 的⑴及（iii)及亞組（aii)，其中（aii)是由下列組成：2-呋喃 基、3 -呋喃基、咪唑基、2 _吡啶基、吲哚基、2 _噻吩基及 -80- 200524877 (76) 3-噻吩基，各被一或多個選自下列的取代基任意取代：氟 、氯、烴氧基、C!_3烴基（被羥基、氟或甲氧基任意取 代）。Or its salts or tautomers or N-oxides or solvates, wherein R1, R2, R3 and Y are each independently selected from R] 'R2, R3 and Y as defined in this specification. In formula (Π), it is preferred that R2 is hydrogen or a C! .4 alkyl group (such as a Cu alkyl group), and R2 is preferably hydrogen. In a subgroup of compounds of formula (11), R1 is: (i) phenyl, which is optionally substituted with one or more (eg, i, 2 or 3) substituents selected from the following ... Fluorine; chlorine; hydroxyl; 5 and 6-membered saturated heterocyclic groups each containing 1 or 2 heteroatoms selected from 0, N, and S, the heterocyclic group being one or more c]. 4 alkyl Ci4 hydrocarbyloxy; Ci4 hydrocarbyl; wherein hydrocarbyl and C ^ 4 hydrocarbyl are arbitrarily substituted with one or more substituents selected from: via radical, fluorine, C! · 2 alkoxy, amine , Mono- and di-Ci · 4 alkylamino groups, phenyl, halophenyl, saturated carbocyclic groups (having 3 to 7 ring atoms, preferably 4, 5 or 6 ring atoms, such as 5 or 6 Ring atom) or a saturated heterocyclic group (having 5 or 6 ring atoms and containing up to 2 heteroatoms selected from 0, S and N); or 2, a hydrogen_benzo [1,4] dioxy Heterocyclohexenyl; or (ii) a monocyclic heteroaryl group that contains one or two 200524877 (75) heteroatoms selected from 0, §, and N; or a bicyclic heteroaryl group that contains A heteroatom selected from 0, S, and N; monocyclic and bicyclic heteroaryl, each A plurality of substituents selected from the following are optionally substituted: fluorine; chlorine; Ci0 alkoxy and Ci 3 hydrocarbon groups, each of which is optionally substituted by: hydroxyl, fluorine, methoxy, or a 5- or 6-membered saturated carbocyclic or Heterocyclic group (containing up to 2 heteroatoms selected from 0, 3 and N); or (iii) a substituted or unsubstituted cycloalkyl group having 3 to 6 ring atoms j (iv) — Each C ^ 4 hydrocarbon group is arbitrarily substituted with one or more substituents selected from: Let; hydroxyl; Cm alkyloxy; amine; mono- or di-Cl4 alkylamino; having 3 to 12 ring atoms A carbocyclic or heterocyclic group in which one of the carbon atoms of a hydrocarbyl group can be arbitrarily replaced by an atom or group selected from the group consisting of: 0, NH, so, and so2. In the group (i), the group R] A subgroup is composed of the following: phenyl is optionally substituted with one or more substituents selected from the group consisting of: fluorine; chlorine; hydroxyl; C! 3 hydrocarbyloxy; Ci.4 hydrocarbyl, wherein Ci_3 hydrocarbyl is Any one or more substituents selected from the group consisting of: hydroxy, fluorine, C 1.2 alkoxy, amine, mono- and di-CL4 alkylamino, saturated carbocyclic groups (with 3 to 7 rings atom , Preferably 4, 5, or 6 ring atoms, such as 5 or 6 ring atoms, or a saturated heterocyclic group (having 5 or 6 ring atoms and containing up to 2 heteroatoms selected from 0, S, and N) ). In another subgroup of compounds of formula (II), R1 is selected from: ⑴ and (iii) above and subgroup (aii), wherein (aii) is composed of: 2-furyl, 3- Furyl, imidazolyl, 2-pyridyl, indolyl, 2-thienyl and -80- 200524877 (76) 3-thienyl, each optionally substituted with one or more substituents selected from the group consisting of fluorine, chlorine , Hydrocarbyloxy, C! _3 hydrocarbyl (optionally substituted by hydroxy, fluoro or methoxy).

在如式（II)之化合物的基團中，其中R1是⑴一個被任 意取代的苯基，彼可以是未被取代的苯基或2-被單取代白勺 、3 -被單取代的、2，3 -被雙取代的、2，5 -被雙取代的或 2 ’ 6_被雙取代的苯基或2，3 -二氫-苯並[1，4]-二氧雜環 己烯基，其中取代基選自··鹵素；羥基；Ci·3烷氧基Cm 烷基，其中Cu烷基被下列任意取代：羥基、氟、 氧基、胺基、一或二-cη烷胺基、或飽和的碳環基團（有3 至6個環原子）及/或飽和雜環基團（有5或6個環原子及含有】 或2個選自Ν及Ο的雜原子）。In the group of the compound of formula (II), wherein R1 is ⑴an optionally substituted phenyl group, which may be unsubstituted phenyl group or 2-monosubstituted group, 3-monosubstituted group, 2, 3 -disubstituted, 2,5 -disubstituted or 2 '6_disubstituted phenyl or 2,3-dihydro-benzo [1,4] -dioxelenyl, Wherein the substituent is selected from the group consisting of halogen; hydroxy; Ci · 3 alkoxy Cm alkyl, wherein Cu alkyl is substituted with any of the following: hydroxy, fluorine, oxy, amine, mono- or di-cη alkylamino, A saturated carbocyclic group (with 3 to 6 ring atoms) and / or a saturated heterocyclic group (with 5 or 6 ring atoms and containing [] or 2 heteroatoms selected from N and O).

在一個體現中，Rl選自：未被取代的苯基、h氟代 基、2-羥基苯基、2-甲氧基苯基、甲基苯基、-吡 烷-1-基）乙氧基）-苯基、3-氟代苯基、3_甲氧基苯基、2 6-二氟代苯基、2-氟代羥基苯基、^氟代甲氧基 基、2-氟代甲氧基苯基、厂氯代_6_甲氧基苯基、厂 代-6-甲氧基苯基、2，二氯代苯基及^氯代氟代苯 ’及任意選自5-氟代甲氧基苯基。 在另-個體現中，Ri選自：未被取代的苯基、2_氟 苯基、2·經基苯基、甲氧基苯基、2_甲基苯s 咯烷-1-基）乙氧基）-苯基' 3_氟代苯基、％甲氧基苯基、 ，6-二氟代苯基、2_氟代_6_羥基苯基及、2•氟代甲： 基苯基及2 -氟代-5-甲氧基苯基。 -81 - 200524877 (77) 特別的基團R1是2，6-二氟代苯基、2-氟代-6-甲氧基 苯基及2，6 -二氯代苯基。 一個特別合宜的基團R1是2，卜二氟代苯基。 另一個特別合宜的基團R 1是2，6 —二氯代苯基。 當R】是（H)—個單環的雜芳基（含有1或2個選自〇、S及 N的雜原子）或一個雙環的雜芳基（含有一個雜原子），單環 的及雙環的雜芳基的實例包括：呋喃基（例如2-呋喃基及 3 -呋喃基）、咪唑基、吡啶基（例如2 -批B定基）、吲哚基、噻 吩基（例如2-噻吩基及3-噻吩基）。V的任意的取代基可以 包括：氯、氟、甲基、甲氧基、羥甲基、甲氧基甲基、嗎 啉代甲基、哌嗪並甲基、N -甲基_嗪並甲基及哌啶基甲基 。基團（i i)的特例包括··未被取代的2 -呋喃基、3 -甲基-2 -呋喃基、未被取代的4·(1Η)-咪唑基、未被取代的5-(1Η)-咪唑基、未被取代的3 -呋喃基、未被取代的3 -噻吩基、2-甲基-3 -噻吩基及未被取代的3 - D[t略基，另外的實例包括 :4 -甲氧基-3-噻吩基、5-(1-吡咯烷基）甲基-2-呋喃基及5-(4 -嗎啉代）甲基-2 -呋喃基。 當R 1是（i i i) 一個被任意取代的環烷基時，R 1可以是一 個被取代的或未被取代的環丙基、環丁基、環戊基或環己 基。當環烷基被取代時’合宜的取代基包括：甲基、氟及 控基。環ί兀基的特例包括：1 -甲基環丙基、^羥基環丙基 及未被取代的環己基、環戊基及環丁基。 在式（π)及基團的說明中，被任意取代的烴基的特 例疋被任思取代的甲基 '乙基、丙基，其中烴基的碳原子 -82* 200524877 (78) 中的一個被下列任意替代：Ο、Ν Η、S 0或S Ο2。烴基的特 例包括·甲基、乙基二氟甲基、被一個有3至12個環原子 的碳環或雜環基團取代的甲基及乙基、被一個有3至12個 環原子的碳環或雜環基團取代的磺驢甲基、羥甲基、羥乙 基、3-羥基-2-丙基、丙基、異丙基、丁基及第三丁基。 烴基及碳環或雜環基團的實例在上文中的泛用的定義中被 陳述。特別的碳環或雜環基團包括：未被取代的或被取代 的苯基、吲哚基、四唑基、三唑基、哌啶基、嗎啉基、呃 嗪基、Ν -甲基哌嗪基、咪唑基，其中任意的取代基可選自 基團R1()及彼之亞群。 在如式（II)之化合物的另一個亞群中，R1是一個Cl_4 烴基，彼被一或多個選自下列的取代基任意取代：氟、經 基、C^4烴氧基胺基、一或二-Cm烴胺基，有3至1 2個環 原子的碳環或雜環基團，其中烴基的碳原子中的一個可被 選自下列的原子或基團任意替代：Ο、NH、SO及S02。 在一個體現中，R1是基團R】-(V)n-，其中： φ η是0或1 ; V選自：CH2、CH2CH2及 S02CH2 ; 1^13是一個選自苯基的碳環或雜環基團； 5員的雜芳基環，彼有至多4個選自Ν、Ο及S的雜原子環原 子； 6員的雜芳基環（含有1或2個氮環原子）； 5或6員的飽和的非芳香雜環（含有1或2個選自〇、N、S及 S〇2的雜原子環原子）； -83- 200524877 (79) C 3 ·6環烷基；吲哚；及D奎啉； 其中各碳環及雜環基團R】a可以被一或多個選自下列的取 代基任意取代_· 5或6員的飽和的非芳香碳環及雜環基團（ 含有至多2個選自N、〇、S及s 02的雜原子環原子）；羥基 ’月女基’合氧基；—· C 1 _ 4院胺基；一 -C 1 · 4院胺基；藥， 氣’硝基，C】_4院基- (0)q-，其中q是0或1，Ci_4院基被下 列任意取代：氟、羥基、Cl_2烷氧基、或5或6員的飽和的 非芳香碳環或雜環基團，彼含有至多2個選自N、0、S及 S〇2的雜原子環原子；苯基及（^_2-伸烷基二氧基。 在式（II)中的基團rLCO-的特別在上文的表1中被陳述 〇 合宜的基團R 1 - C Ο -的一個亞群是由下列組成：基團J 、AB、AH、AJ、AL、AS、AX、AY、AZ、BA、BB、BD 、BH、BL、BQ 及 BS。In one embodiment, R1 is selected from the group consisting of: unsubstituted phenyl, hfluoro, 2-hydroxyphenyl, 2-methoxyphenyl, methylphenyl, -pyridin-1-yl) ethoxy Group) -phenyl, 3-fluorophenyl, 3-methoxyphenyl, 2 6-difluorophenyl, 2-fluorohydroxyphenyl, ^ fluoromethoxy, 2-fluoro Methoxyphenyl, plant chloro-6-methoxyphenyl, plant-6-methoxyphenyl, 2, dichlorophenyl, and ^ chlorofluorobenzene 'and any one selected from 5- Fluoromethoxyphenyl. In another embodiment, Ri is selected from the group consisting of: unsubstituted phenyl, 2-fluorophenyl, 2-methylphenyl, methoxyphenyl, 2-methylbenzenes, and so on. (Ethoxy) -phenyl '3-fluorophenyl,% methoxyphenyl, 6-difluorophenyl, 2-fluoro-6-hydroxyphenyl, and 2 • fluoromethyl: Phenyl and 2-fluoro-5-methoxyphenyl. -81-200524877 (77) Special groups R1 are 2,6-difluorophenyl, 2-fluoro-6-methoxyphenyl and 2,6-dichlorophenyl. A particularly suitable group R1 is 2, didifluorophenyl. Another particularly suitable group R 1 is 2,6-dichlorophenyl. When R] is (H) —a monocyclic heteroaryl group (containing 1 or 2 heteroatoms selected from 0, S and N) or a bicyclic heteroaryl group (containing one heteroatom), monocyclic and Examples of bicyclic heteroaryl groups include: furyl (such as 2-furanyl and 3-furanyl), imidazolyl, pyridyl (such as 2-Branyl), indolyl, thienyl (such as 2-thienyl) And 3-thienyl). Any substituent of V may include: chloro, fluoro, methyl, methoxy, hydroxymethyl, methoxymethyl, morpholinomethyl, piperazinomethyl, N-methyl_azinomethyl And piperidinylmethyl. Specific examples of the group (ii) include unsubstituted 2-furanyl, 3-methyl-2-furanyl, unsubstituted 4 · (1Η) -imidazolyl, and unsubstituted 5- (1Η ) -Imidazolyl, unsubstituted 3-furanyl, unsubstituted 3-thienyl, 2-methyl-3-thienyl, and unsubstituted 3-D [t acryl, additional examples include: 4-methoxy-3-thienyl, 5- (1-pyrrolidinyl) methyl-2-furanyl and 5- (4-morpholino) methyl-2-furanyl. When R 1 is (i i i) an optionally substituted cycloalkyl group, R 1 may be a substituted or unsubstituted cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group. When cycloalkyl is substituted 'suitable substituents include: methyl, fluorine, and control. Specific examples of cyclopentyl include 1-methylcyclopropyl, ^ hydroxycyclopropyl, and unsubstituted cyclohexyl, cyclopentyl, and cyclobutyl. In the description of formula (π) and the group, a special case of an arbitrarily substituted hydrocarbyl group: methyl 'ethyl, propyl substituted with any one, wherein one of the carbon atom of the hydrocarbyl group -82 * 200524877 (78) is Any of the following alternatives: 0, NΗ, S 0, or S 02. Specific examples of hydrocarbon groups include methyl, ethyldifluoromethyl, methyl and ethyl substituted with a carbocyclic or heterocyclic group having 3 to 12 ring atoms, and methyl substituted with 3 to 12 ring atoms. Carbocyclic or heterocyclic group substituted sulfomethyl, hydroxymethyl, hydroxyethyl, 3-hydroxy-2-propyl, propyl, isopropyl, butyl and tert-butyl. Examples of hydrocarbyl and carbocyclic or heterocyclic groups are stated above in the general definitions. Specific carbocyclic or heterocyclic groups include: unsubstituted or substituted phenyl, indolyl, tetrazolyl, triazolyl, piperidinyl, morpholinyl, erazinyl, N-methyl Piperazinyl and imidazolyl, any of which may be selected from the group R1 () and its subgroup. In another subgroup of compounds of formula (II), R1 is a Cl_4 hydrocarbon group, which is arbitrarily substituted with one or more substituents selected from the group consisting of fluorine, meridian, C ^ 4 alkyloxyamine, A mono- or di-Cm hydrocarbon amine group, a carbocyclic or heterocyclic group having 3 to 12 ring atoms, wherein one of the carbon atoms of the hydrocarbon group can be arbitrarily replaced by an atom or group selected from the group consisting of: 0, NH , SO and S02. In one embodiment, R1 is a group R]-(V) n-, wherein: φ η is 0 or 1; V is selected from: CH2, CH2CH2 and S02CH2; 1 ^ 13 is a carbocyclic ring selected from phenyl or Heterocyclic groups; 5-membered heteroaryl rings each having up to 4 heteroatom ring atoms selected from N, O, and S; 6-membered heteroaryl rings (containing 1 or 2 nitrogen ring atoms); 5 Or 6-membered saturated non-aromatic heterocyclic ring (containing 1 or 2 heteroatom ring atoms selected from 0, N, S, and S02); -83- 200524877 (79) C 3 · 6 cycloalkyl; ind Indole; and D quinoline; wherein each carbocyclic and heterocyclic group R] a may be arbitrarily substituted with one or more substituents selected from the group of 5 or 6-membered saturated non-aromatic carbocyclic and heterocyclic groups Group (containing up to 2 heteroatom ring atoms selected from N, 0, S, and s 02); hydroxyl 'moonyl' oxygen;-· C 1 _ 4 amine group;--C 1 · 4 ward Amine group; drug, nitro, C] _4 courtyard-(0) q-, where q is 0 or 1, Ci_4 courtyard is substituted by any of the following: fluorine, hydroxyl, Cl_2 alkoxy, or 5 or 6 Member is a saturated non-aromatic carbocyclic or heterocyclic group, which contains at most 2 heterocyclic groups selected from N, 0, S and S〇2 Sub-ring atoms; phenyl and (^ _2-alkylenedioxy). The group rLCO- in formula (II) is stated in particular in Table 1 above. Suitable groups R 1-C Ο A subgroup of-is composed of the following groups: groups J, AB, AH, AJ, AL, AS, AX, AY, AZ, BA, BB, BD, BH, BL, BQ, and BS.

基團R^CO的另一個亞群是由下列組成··基團A至BF 〇Another subgroup of the group R ^ CO is composed of the groups A to BF.

基團Rj-CO的另一個亞群是由下列組成：基團A至BS 〇 特別合宜的基團是在表1中的基團AJ、BQ及BS ’例如 由AJ及BQ組成的亞組。 本發明之化合物的另一個基團被式（111)表示： 200524877 (80)Another subgroup of the group Rj-CO is composed of the following groups: Groups A to BS. Particularly suitable groups are the groups AJ, BQ and BS 'in Table 1 such as the subgroup consisting of AJ and BQ. Another group of the compounds of the present invention is represented by formula (111): 200524877 (80)

或彼之鹽類或互變異構物類或N-氧化物類或溶劑化物類； 其中R1、R2、R3及Y如同本說明書中所定義的。 基團R1、R2、R3及Y的實施例及參考例如同上文的如 式（0)、（IG)、（I)、（la)、（lb)及（III)之化合物中所陳述的 ，除非另外指定。 如式（III)之化合物的特別的亞群包括： ⑴化合物，其中R1是一個雜芳基，彼含有1、2或3個選自 Ο、N及S的雜原子環原子； (ii) 化合物，其中R1是一個Cu烴基，彼被一或多個選自 下列的取代基任意取代：氟、羥基、C ! .4烴氧基、胺基、 一或二- Cl4烴胺基、有3至12個環原子的碳環或雜環基團 ，其中烴基的碳原子中的一個可被一個選自0、NH、SO 及S02的原子或基團任意替代； (iii) 化合物，其中R1是一個有3至12個環原子的非芳香碳 環或雜環基團。 如式（III)之化合物的實例（其中R1是⑴一個雜芳基）包 括：5員及6員的單環的雜芳基，例如含有1或2個選自0、 N及S的雜原子環原子。在一個體現中，雜芳基是一個有1 或2個氮環原子的單環基團。在另一個體現中，雜芳基選 自含有]或2個氮環原子的6員環，例如吡啶、嘧啶、吡嗪 -85- 200524877 (81) 及噠11秦基團，一個特別的亞群是由吼嗪基及D[；t D定基組成。 雜芳基可以是未被取代的或被一或多個如本說明書中 所定義的基團R1()取代。 如式（ΠΙ)之化合物的實例（其中R1是（ii)一個被任意取 代的Cl6烴基）包括：基團，其中烴基是未被取代的烴基， 例如未被取代的烷基，如甲基、乙基、丙基、異丙基、丁 基、異丁基、第三丁基、1-戊基、2-戊基及3-戊基。 化合物（其中R1是一個非芳香碳環或雜環基團）的實例 包括：基團，其中碳環或雜環基團是單環的及含有至多2 個選自氧及氮的雜原子。特例是環己基及哌啶並。 如式（I)之化合物的另一個亞群可以被式（IV)代表：Or its salts or tautomers or N-oxides or solvates; wherein R1, R2, R3 and Y are as defined in the present specification. Examples and references of the groups R1, R2, R3 and Y are for example the same as stated above for the compounds of formula (0), (IG), (I), (la), (lb) and (III) Unless otherwise specified. Specific subgroups of compounds such as formula (III) include: ⑴ compounds, wherein R1 is a heteroaryl group, which contains 1, 2 or 3 heteroatom ring atoms selected from 0, N and S; (ii) compounds , Where R1 is a Cu hydrocarbon group, which is optionally substituted by one or more substituents selected from the group consisting of fluorine, hydroxyl, C! .4 alkoxy, amine, mono- or di-Cl4 hydrocarbon amine, 3 to A carbocyclic or heterocyclic group of 12 ring atoms, in which one of the carbon atoms of the hydrocarbon group may be arbitrarily replaced by an atom or group selected from 0, NH, SO and S02; (iii) a compound in which R1 is a Non-aromatic carbocyclic or heterocyclic groups having 3 to 12 ring atoms. Examples of compounds of formula (III) (where R1 is a heteroaryl group) include: 5-membered and 6-membered monocyclic heteroaryl groups, such as containing 1 or 2 heteroatoms selected from 0, N, and S Ring atom. In one embodiment, a heteroaryl is a monocyclic group having 1 or 2 nitrogen ring atoms. In another embodiment, the heteroaryl group is selected from a 6-membered ring containing] or 2 nitrogen ring atoms, such as pyridine, pyrimidine, pyrazine-85-200524877 (81) and pyridin group, a special subgroup It is composed of a hydrazine group and D [; t D definite group. Heteroaryl may be unsubstituted or substituted with one or more groups R1 () as defined in this specification. Examples of compounds of formula (III) (where R1 is (ii) an optionally substituted Cl6 hydrocarbon group) include: groups in which the hydrocarbon group is an unsubstituted hydrocarbon group, such as an unsubstituted alkyl group such as methyl, Ethyl, propyl, isopropyl, butyl, isobutyl, third butyl, 1-pentyl, 2-pentyl, and 3-pentyl. Examples of compounds where R1 is a non-aromatic carbocyclic or heterocyclic group include groups in which the carbocyclic or heterocyclic group is monocyclic and contains up to 2 heteroatoms selected from oxygen and nitrogen. Specific examples are cyclohexyl and piperidino. Another subgroup of compounds such as formula (I) can be represented by formula (IV):

I~丨U IV) /|\I ~ 丨 U IV) / | \

或彼之鹽類或互變異構物類或N-氧化物類或溶劑化物類； 其中R1及R2如同本說明書中所定義的； 任意的次鍵或許存在於碳原子1及2之間； U及T中的一個選自：CH2、CHR13、CR]】R】3、NR】4、 N(0)R】5、C^s(〇)t; U及丁中的另一個選自：NR14、0、CH2、CHR】】、C(RU)2 、c = o ; 1是 0、；[、2、3 或 4 ; t 是 0、1或 2 ; -86 - 200524877 (82) R11選自：氫、鹵素（尤其氟）、Cy烷基（例如甲基）及Cl_3 烷氧基（例如甲氧基）； R13選自：氫、NHR14、NOH、NOR14及 Ra-Rb ; R14選自：氫及Rd-Rb ;Or its salts or tautomers or N-oxides or solvates; where R1 and R2 are as defined in this specification; any secondary bonds may exist between carbon atoms 1 and 2; U And one of T is selected from: CH2, CHR13, CR]] R] 3, NR] 4, N (0) R] 5, C ^ s (〇) t; the other of U and D is selected from: NR14 , 0, CH2, CHR]], C (RU) 2, c = o; 1 is 0, [, 2, 3, or 4; t is 0, 1, or 2; -86-200524877 (82) R11 is selected from : Hydrogen, halogen (especially fluorine), Cy alkyl (such as methyl) and Cl_3 alkoxy (such as methoxy); R13 is selected from: hydrogen, NHR14, NOH, NOR14, and Ra-Rb; R14 is selected from: hydrogen And Rd-Rb;

Rd 選自：一個鍵、CO、C(X2)X】、302及30以1^;Rd is selected from: a bond, CO, C (X2) X], 302 and 30 with 1 ^;

Ra、Rb及Re如同前文中所定義的；Ra, Rb and Re are as defined above;

R 15選自C ! _4飽和的烴基，彼被下列任意取代：羥基C ! _2烷 氧基、鹵素或單環的5或6員的碳環或雜環基團，條件是U 及T不可以同時是Ο。 基團R1及R2的實例及參考例在上文中的如式（I)、（la) 、（lb)及（III)之化合物中所陳述的，除非另外指定。 在式（IV)中，r可以是0、1、2、3或4。在一個體現中 ，！*是0。在另一個體現中，r是2，在另一個體現中，r是4 在式（IV)中，合宜的化合物的一個亞組是化合物只有 一個單鍵介於碳原子1及2之間。 然而，在化合物的另一個亞群中，有一個雙鍵介於碳 原子1及2之間。 另一個亞組的化合物之特徵在於在2 -碳（當有一個單 鍵介於碳原子1及2之間時）及/或6-碳上的偕雙取代。合宜 的偕雙取代基包括二氟代及二甲基。 另一個亞組的化合物之特徵在於烷氧基（例如甲氧基） 存在於碳原子3上，即基團T的α位置。 在式（IV)中，R3選自下面的環系統中的任何〜個： -87- 200524877 (83)R 15 is selected from C! _4 saturated hydrocarbon groups, which are optionally substituted by: hydroxyl C! _2 alkoxy, halogen, or monocyclic 5 or 6 membered carbocyclic or heterocyclic group, provided that U and T are not allowed Also 0. Examples and reference examples of the groups R1 and R2 are stated above in the compounds of the formulae (I), (la), (lb) and (III), unless otherwise specified. In formula (IV), r may be 0, 1, 2, 3, or 4. In one embodiment,! * It is 0. In another embodiment, r is 2 and in another embodiment, r is 4 In formula (IV), a subgroup of suitable compounds is that the compound has only one single bond between carbon atoms 1 and 2. However, in another subgroup of the compounds, there is a double bond between carbon atoms 1 and 2. Another subgroup of compounds is characterized by fluorene double substitution on 2-carbon (when there is a single bond between carbon atoms 1 and 2) and / or on 6-carbon. Suitable fluorene disubstituents include difluoro and dimethyl. Another subgroup of compounds is characterized by the presence of an alkoxy group (such as a methoxy group) on carbon atom 3, the alpha position of the group T. In formula (IV), R3 is selected from any of the following ring systems: -87- 200524877 (83)

合宜的環系統包括G1及G3。 如式（Iv )之化合物的一個合宜的亞群可以被式（IV a)代Suitable ring systems include G1 and G3. A suitable subgroup of compounds of formula (Iv) can be replaced by formula (IVa)

或彼之鹽類或互變異構物類或N -氧化物類或溶劑化物類’ 其中R1及R2如同前文中所定義的； 11及T中的一個選自：CH2、CHR】3、CR】】R】3 ; 、 ^0)1115、0及 S(〇)t ; U及 T中的另一個選自：CH2、CHR11、C(rU)2、C = 〇 ; r是 -88- 200524877 (84) 0、1或 2; t是 〇、1或 2; R11選自：氫及Cy烷基； R13選自··氫及R、Rb ; R14選自：氫及Rd-Rb ; 以選自：一個鍵、co、qxyx1、S02&amp;S02NRc;Or its salts or tautomers or N-oxides or solvates' wherein R1 and R2 are as defined above; one of 11 and T is selected from: CH2, CHR] 3, CR] ] R] 3;, ^ 0) 1115, 0, and S (〇) t; the other of U and T is selected from: CH2, CHR11, C (rU) 2, C = 〇; r is -88- 200524877 ( 84) 0, 1 or 2; t is 0, 1 or 2; R11 is selected from: hydrogen and Cy alkyl; R13 is selected from ... hydrogen and R, Rb; R14 is selected from: hydrogen and Rd-Rb; : One key, co, qxyx1, S02 &amp;S02NRc;

Ra、…及1^如同前文中所定義的； R 15選自Cb4飽和的羥基，彼被下列任意取代：烴基、C! -2 烷氧基、鹵素或單環的5或6員的碳環或雜環基團。 基團11]及R2的實例及參考例在上文中的如式（0)、（1°) 、（I)、（la)、（lb)及（II)之化合物中被陳述，除非另外指定 在式（IVa)中，T宜選自：CH2、CHR13、CHHR13、 NR14、N(0)R15、Ο及 S(0)t ; U宜選自：CH2、CHR11、 C(R】】）2及C = 0。 在取代基RH及R14的定義中，Rb宜選自：氫；單環的 碳環或雜環基團（有3至7個環原子）；C】.4烴基（較佳無環的 飽和的G.4基團），彼被一或多個選自下列的取代基任意取 代：羥基、合氧基、鹵素、胺基、一或二-C!.4烴胺基、單 環的碳環或雜環基團（有3至7個環原子，較佳3至6個環原 子），其中C ! .4烴基的一或多個碳原子可被下列任意替代： 0、S、SO、S02、NRC、xAx2)、C(x2)x】；Ra, ... and 1 ^ are as defined above; R 15 is selected from Cb4 saturated hydroxyl groups, which are substituted by any of the following: hydrocarbyl, C! -2 alkoxy, halogen or monocyclic 5 or 6 membered carbocyclic ring Or heterocyclic group. Examples and reference examples of groups 11] and R2 are stated above in compounds such as formulas (0), (1 °), (I), (la), (lb), and (II), unless otherwise specified In formula (IVa), T is preferably selected from: CH2, CHR13, CHHR13, NR14, N (0) R15, 0, and S (0) t; U is preferably selected from: CH2, CHR11, C (R)] 2 And C = 0. In the definitions of the substituents RH and R14, Rb is preferably selected from: hydrogen; a monocyclic carbocyclic or heterocyclic group (with 3 to 7 ring atoms); C]. 4 hydrocarbon group (preferably acyclic saturated G.4 group), which are arbitrarily substituted with one or more substituents selected from the group consisting of hydroxyl, oxy, halogen, amine, mono- or di-C! .4 hydrocarbon amine, monocyclic carbocyclic ring Or heterocyclic group (having 3 to 7 ring atoms, preferably 3 to 6 ring atoms), in which one or more carbon atoms of the C! .4 hydrocarbon group may be replaced by any of the following: 0, S, SO, S02 , NRC, xAx2), C (x2) x];

Re選自：氫及Cm烴基； X1是 0、S或 NR。，X2 是=0、=S 或=NRC。 R1]宜選自氫及甲基，最佳氫。 -89- 200524877 (85) R】3宜選自：氫；鹵素；羥基；氰基；胺基；一 -Cm 飽和的烴胺基；二-C μ飽和的烴胺基；單環的5或6員的碳 環及雜環基團；c ! .4飽和的烴基’彼被下列任意取代：羥 基、C!」烷氧基、鹵素或單環的5或6員的碳環或雜環基團 〇 R13的特別是氫、經基、胺基、c 1」院胺基（例如甲胺 基）Cl·4院基（例如甲基、乙基、丙基及丁基）、Ci_2院氧基（ 例如甲氧基）、Cu烷基磺胺基（例如甲磺胺基）、羥基_Cl 2 ；(：完基（例如經甲基）、c 1 ·2院氧基-c 1 ·2院基（例如甲氧甲基及 甲氧乙基）、羧基、C】_4烷氧羰基（例如乙氧羰基）及胺基_ Ch2烷基（例如胺甲基）。 R 14的特別是氫；C!_4烴基，彼被下列任意取代：氧或 5或6員的飽和雜環基團（例如基團，彼選自··（i)甲基、乙 基、正丙基、異丙基、丁基、2，2，2 -三氟乙基及四氫呋 喃基甲基；及/或（ii)2 -氟代乙基及2，2 -二氟代乙基）；環 丙基甲基；被取代的或未被取代的吡啶基-Cl.2烷基（例如 2 -吡啶基甲基）；被取代的或未被取代的苯基_ c】_2烷基（例 如卡基）’ Ci·4；(:兀氧擬基（例如乙氧鑛基及第三丁氧鑛基）、 被取代的及未被取代的苯基-Cl.2烷氧羰基（例如卡氧鑛基） ，·被取代的及未被取代的5及6員的雜芳基，如吡啶基（例 如2-吡啶基及6·氯代-2_批啶基）及嘧啶基（例如2_嘧啶基）； C!-2-烷氧基-Ci·2烷基（例如甲氧甲基及甲氧乙基Cl 4烷 磺醯（例如甲磺醯）。 合宜的化合物包括··化合物，其中（丨）1;是（:9]113(較佳 -90- 200524877 (86) CH2)及 T及 NR14，（ii)T是 CHR13 (較佳 CH2)及 U 是 NR】4。 如式（IV)之化合物的一個特別合宜的亞群可以被式 (V a)代表：Re is selected from: hydrogen and Cm hydrocarbon groups; X1 is 0, S or NR. , X2 is = 0, = S or = NRC. R1] is preferably selected from hydrogen and methyl, most preferably hydrogen. -89- 200524877 (85) R] 3 is preferably selected from: hydrogen; halogen; hydroxyl; cyano; amine; mono-Cm saturated hydrocarbon amine; di-C μ saturated hydrocarbon amine; monocyclic 5 or 6-membered carbocyclic and heterocyclic groups; c! .4 saturated hydrocarbon groups are substituted by any of the following: hydroxyl, C! "Alkoxy, halogen or monocyclic 5 or 6-membered carbocyclic or heterocyclic groups In the group 〇13, especially hydrogen, mesityl, amine, c 1 "amine (for example, methylamine) Cl · 4 (for example, methyl, ethyl, propyl and butyl), Ci_2 and oxy (For example, methoxy), Cu alkylsulfonyl (for example, methylsulfonyl), hydroxy_Cl 2; (: end group (for example, via methyl), c 1 · 2 alkyloxy-c 1 · 2 alkyl ( For example methoxymethyl and methoxyethyl), carboxyl, C] _4 alkoxycarbonyl (such as ethoxycarbonyl) and amine_Ch2 alkyl (such as aminemethyl). R 14 is especially hydrogen; C! _4 Hydrocarbyl, which is optionally substituted by: oxygen or a 5 or 6-membered saturated heterocyclic group (eg, a group selected from (i) methyl, ethyl, n-propyl, isopropyl, butyl, 2,2,2-trifluoroethyl and tetrahydrofurylmethyl; and / or (ii) 2-fluoroethyl and 2,2-difluoroethyl); cyclopropylmethyl; substituted or unsubstituted pyridyl-Cl.2 alkyl (eg 2-pyridylmethyl); Substituted or unsubstituted phenyl_c] _2 alkyl (such as carbo) 'Ci · 4; (: oxoamido (such as ethoxy group and third butoxy group), substituted And unsubstituted phenyl-Cl.2 alkoxycarbonyl (such as peroxo), and substituted and unsubstituted 5 and 6-membered heteroaryl, such as pyridyl (such as 2-pyridyl and 6. · Chloro-2_pyridinyl) and pyrimidinyl (such as 2-pyrimidinyl); C! -2-alkoxy-Ci · 2 alkyl (such as methoxymethyl and methoxyethyl Cl 4 alkane Sulfonium (such as methanesulfonium). Suitable compounds include compounds of which (丨) 1; is (: 9] 113 (preferably -90- 200524877 (86) CH2) and T and NR14, (ii) T Is CHR13 (preferably CH2) and U is NR] 4. A particularly suitable subgroup of compounds of formula (IV) can be represented by formula (V a):

或彼之鹽類或互變異構物類或N-氧化物類或溶劑化物類； 其中R14a選自：氫、Cl_4烷基，彼被氟任意取代（例如甲基 、乙基、正丙基、異丙基、丁基及2，2，2-三氟乙基）、 環丙基甲基、苯基-C】.2烷基（例如苄基）、1.4烷氧羰基（例 如乙氧羰基及第三丁氧羰基）、苯基烷氧羰基（例如苄 氧羰基）、Ci.2-烷氧基- C^2烷基（例如甲氧甲基及甲氧乙基 )、C】_4烷基磺醯（例如甲磺醯），其中苯基（當存在時）被1 至3個選自下列的取代基任意取代··氟、氯、C 1 -4院氧基（ 被氟或c^2-烷氧基任意取代）、Cl.4烷基（被氟或C】.2-氧基 任意取代）； w是 0，1，2或 3 ; R2是氫或甲基，最佳氫； R11及r如同上文中所定義的； R19選自：氟；；C].4烷氧基（被氟或（^·2烷氧基任意取代） ;C ! · 4烷基（被氟或C !」烷氧基任意取代）。 -91 - 200524877 (87) 如式（IV)之化合物的另一個特別合宜的亞群可以被式 (Vb)代表：Or its salts or tautomers or N-oxides or solvates; where R14a is selected from: hydrogen, Cl_4 alkyl, which is optionally substituted by fluorine (eg methyl, ethyl, n-propyl, Isopropyl, butyl and 2,2,2-trifluoroethyl), cyclopropylmethyl, phenyl-C] .2 alkyl (such as benzyl), 1.4 alkoxycarbonyl (such as ethoxycarbonyl and Third butoxycarbonyl), phenylalkoxycarbonyl (such as benzyloxycarbonyl), Ci.2-alkoxy-C ^ 2 alkyl (such as methoxymethyl and methoxyethyl), C] _4 alkyl Sulfonium (such as methanesulfonium) where phenyl (when present) is arbitrarily substituted with 1 to 3 substituents selected from fluorine, chlorine, C 1-4 oxo (by fluorine or c ^ 2 -Alkoxy optionally substituted), Cl.4 alkyl (optionally substituted by fluorine or C]. 2-oxy); w is 0, 1, 2 or 3; R2 is hydrogen or methyl, optimal hydrogen; R11 And r are as defined above; R19 is selected from: fluorine; C]. 4 alkoxy (optionally substituted by fluorine or (^ · 2 alkoxy); C! · 4 alkyl (substituted by fluorine or C! "Alkoxy is optionally substituted). -91-200524877 (87) Another characteristic of compounds of formula (IV) An inappropriate subgroup can be represented by (Vb):

或彼之鹽類或互變異構物類或N -氧化物類或溶劑化物類； 其中11143選自：氫、被氟任意取代的烷基（例如甲基、 乙基、正丙基、異丙基、丁基及2，2，2-三氟乙基）、環 丙基甲基、苯基-C!.2烷基（例如苄基）、c】_4烷氧羰基（例如 乙氧羰基及第二丁氧鑛基）、苯基- 烷氧羰基（例如苄氧 簾基）、Cy院氧基- Ci·2院基（例如甲氧甲基及甲氧乙基） 、C^4丨兀基擴醯（例如甲石貝醯）’其中苯基（當存在時）被1至 3個選自下列的取代基任意取代：氟、氯、烷氧基（被 氟或CnjC完氧基任意取代）、CV4烷基（被氟或Ci 2烷氧基 任意取代）； w 是 0，1，2 或 3 ; R2是氫或甲基，最佳氫； R11及r如同上文定義的； R19選自：氟；氯；Ci_4院氧基（被氟或〔 代）；C !.4院基（被氟或C 1，2院氧基任意耳又 Μ烷氧基任意 代）。 取 -92- 200524877 (88) 在式（Va)及（Vb)中，當w是1、2或3時，吾人較佳：苯 基環是2-被單取代的、3_被單取代的、2，6_被雙取代的 、2 ’ 3-被雙取代的、2，4_被雙取代的、2，5_被雙取代 的、2，3，6 -被三取代的或2，4，6 -被三取代的。最佳苯 基環在位置2及6上被選自氟、氯及甲氧基的取代基雙取代 R1 1宜爲氫（或r是〇)。 R14a最宜爲氫或甲基。 如式（Va)之化合物的一個合宜的亞群可以被式（Via) 代表：Or its salts or tautomers or N-oxides or solvates; where 11143 is selected from: hydrogen, alkyl optionally substituted with fluorine (such as methyl, ethyl, n-propyl, isopropyl Butyl, butyl and 2,2,2-trifluoroethyl), cyclopropylmethyl, phenyl-C! .2 alkyl (such as benzyl), c] -4alkoxycarbonyl (such as ethoxycarbonyl and Second butoxy group), phenyl-alkoxycarbonyl group (such as benzyloxy curtain group), Cy-oxy-Ci · 2 group (such as methoxymethyl and methoxyethyl), C ^ 4 Radical expansion (eg, methotrexate) where phenyl (when present) is arbitrarily substituted with 1 to 3 substituents selected from fluorine, chlorine, alkoxy (optionally substituted by fluorine or CnjC endoxy) ), CV4 alkyl (optionally substituted by fluorine or Ci 2 alkoxy); w is 0, 1, 2 or 3; R2 is hydrogen or methyl, optimal hydrogen; R11 and r are as defined above; R19 is selected From: Fluorine; Chlorine; Ci_4 courtyard oxygen (by fluorine or [generation); C!. 4 courtyard base (by fluorine or C 1, 2 courtyard oxygen arbitrary ear and M alkoxy arbitrary generation). Take -92- 200524877 (88) In formulas (Va) and (Vb), when w is 1, 2 or 3, we are better: the phenyl ring is 2- monosubstituted, 3_ monosubstituted, 2 , 6_ double substituted, 2 '3-double substituted, 2, 4_ double substituted, 2, 5_ double substituted, 2, 3, 6-triple substituted, or 2, 4, 6-Replaced by three. The most preferred phenyl ring is disubstituted at positions 2 and 6 with a substituent selected from fluorine, chlorine and methoxy. R1 1 is preferably hydrogen (or r is 0). R14a is most preferably hydrogen or methyl. A suitable subgroup of the compound of formula (Va) can be represented by formula (Via):

N-氧化物類或溶劑化物類； 個不是氯、甲氧基、乙氧基 或彼之鹽類或互變異構物類或 其中R20選自氫及甲基； R21選自氟及氯； R22選自氟、氯及甲氧基；或 R21及R22中的一個是氫，另一 二氟甲氧基、三氟甲氧基及爷與基° r-j _____•彳〇 A亩的®群可以被式 如式（Va)之化合物的另個《且扪i m ^ - 93- 200524877 (89) (VIb)代表：N-oxides or solvates; not chlorine, methoxy, ethoxy or their salts or tautomers or wherein R20 is selected from hydrogen and methyl; R21 is selected from fluorine and chlorine; R22 Selected from fluorine, chlorine, and methoxy; or one of R21 and R22 is hydrogen, and the other difluoromethoxy, trifluoromethoxy, and aryl group ° rj _____ • 彳 〇A acres of ® group can be Another compound of the compound of formula (Va) is the same as: 扪 im ^-93- 200524877 (89) (VIb) represents:

或彼之鹽類或互變異構物類或N-氧化物類或溶劑化物類； 其中R2G選自氫及甲基； R21a選自氟及氯； R22a選自氟、氯及甲氧基。 合宜的如式（VIb)之化合物包括： 4-(2，6-二氟代-苄醯胺基）-lH-D比唑-3-羧酸哌啶-4-基醯胺 4-(2，6-二氟代-苄醯胺基）-imt唑-3-羧酸（1-甲基-哌啶- 4-基)-醯胺； · 4-(2，6-二氯代-苄醯胺基唑-3·羧酸哌啶-4-基醯胺 4-(2氟代-6-甲氧基-苄醯胺基）-lH-Dtt唑-3-羧酸哌啶-4-基 醯胺；或彼之鹽類或互變異構物類或氧化物類或溶劑化 物類。 本發明之化合物的另一個基團被式（V 11)代表： -94- 200524877 (90) 9 οOr its salts or tautomers or N-oxides or solvates; wherein R2G is selected from hydrogen and methyl; R21a is selected from fluorine and chlorine; R22a is selected from fluorine, chlorine and methoxy. Suitable compounds of formula (VIb) include: 4- (2,6-difluoro-benzylamido) -lH-D-pyrazole-3-carboxylic acid piperidin-4-ylamidoamine 4- (2 , 6-difluoro-benzylamido) -imtazole-3-carboxylic acid (1-methyl-piperidin-4-yl) -amidamine; 4- (2,6-dichloro-benzyl Amidinazole-3 · piperidin-4-carboxylic acid amide 4- (2fluoro-6-methoxy-benzylamidoamine) -lH-Dttazole-3-carboxylic acid piperidin-4- Methylamine; or its salts or tautomers or oxides or solvates. Another group of the compounds of the present invention is represented by formula (V 11): -94- 200524877 (90) 9 ο

ίΓΝ N’Y、R3 Η (VII) 或彼之鹽類或互變異構物類或Ν -氧化物類或溶劑化物類； 其中R2' R3及Υ如同前文中所定義的，G是一個5或6貝的 碳環或雜環。 基團G可以是未被取代的碳環或雜環或彼可以是一個 被取代的碳環或雜環，彼帶有一或多個選自如前文中所定 義的基團R1G及R1Ga的取代基。 碳環或雜環可以是芳香的或非芳香的’雜環的實例在 上文中被陳述。在基團G中，合宜的雜環是含有氮環原子 的雜環，透過該氮環原子基團G被連接至吡唑環上。特別 的雜環是飽和的雜環，彼含有至多3個氮原子（較常有至多 2個，例如1個）及任意的1個氧原子。特例是6員的環，如 哌啶、哌嗪、N -甲基哌嗪及嗎啉。 當基團G是一個碳環基團時，g可以是一個6員的芳基 環。舉例來說，基團G可以是一個未被取代的苯基或可以 是一個被取代的苯基，彼帶有一或多個選自如前文中所定 義的基團R1G及111()3的取代基。取代基（當存在時）是小型取 代基’如羥基、鹵素（例如氟及氯）、Ci “烴基（甲基、乙基 及環丙基）’彼被下列任意取代：氟（例如三氟甲基）或羥 基（例如羥甲基）。 在一個泛用的體現中，當χ是一個非芳香雜環基團時 ’以不是6員的單環的芳基或雜芳基（與$，6_稠合的二環 -95- 200524877 (91) 的雜芳基直接連接）。 本發明之化合物的另一個基團被式（VIΠ)代表··ΓΓN N'Y, R3 Η (VII) or its salts or tautomers or N-oxides or solvates; where R2 'R3 and Υ are as defined above, G is a 5 or 6 carbocyclic or heterocyclic ring. The group G may be an unsubstituted carbocyclic or heterocyclic ring or it may be a substituted carbocyclic or heterocyclic ring carrying one or more substituents selected from the groups R1G and R1Ga as defined above. Examples of carbocyclic or heterocyclic rings which may be aromatic or non-aromatic are stated above. In the group G, a suitable heterocyclic ring is a heterocyclic ring containing a nitrogen ring atom, and the group G is connected to the pyrazole ring through the nitrogen ring atom group. A particular heterocyclic ring is a saturated heterocyclic ring, which contains up to 3 nitrogen atoms (more often up to 2 such as 1) and any 1 oxygen atom. Specific examples are 6-membered rings such as piperidine, piperazine, N-methylpiperazine and morpholine. When the group G is a carbocyclic group, g may be a 6-membered aryl ring. For example, the group G may be an unsubstituted phenyl group or may be a substituted phenyl group with one or more substituents selected from the groups R1G and 111 () 3 as defined above . Substituents (when present) are small substituents such as hydroxy, halogen (such as fluorine and chlorine), Ci "hydrocarbyl (methyl, ethyl, and cyclopropyl) ', and they are optionally substituted with: Group) or hydroxyl group (such as hydroxymethyl). In a generalized embodiment, when χ is a non-aromatic heterocyclic group, 'is not a 6-membered monocyclic aryl or heteroaryl group (with $, 6 _The fused biaryl-95-200524877 (91) heteroaryl group is directly connected.) Another group of the compound of the present invention is represented by the formula (VIΠ) ··

或彼之鹽類或互變異構物類或N-氧化物類或溶劑化物類； 其中R1、R2、R3及Y如同本說明書中所定義的。 合宜的基團R1、R2、Y及R3是在上文中的 ''泛用的參 考例及定義〃章節中被陳述的基團及與如式（Ό及（Π)之化 合物及彼之在本說明書中所定義的亞群。Or its salts or tautomers or N-oxides or solvates; wherein R1, R2, R3 and Y are as defined in the present specification. Suitable groups R1, R2, Y, and R3 are the groups stated in the `` General Reference Examples and Definitions '' section above, and compounds with formulae (Ό and (Π), and Subgroups as defined in the description.

爲避免懷疑，以下待了解：基團R1的各泛用的及專一 的參考例、體現及實例可與本說明書中的基團R2及/或R3 及/或R4及/或RIG及/或Y及/或…及/或彼之亞群的各泛用的 及專一的參考例、體現及實例綜合，該類的綜合皆被包含 在本申請案中。 構成如式（I)之化合物的各種官能基及取代基被典型 地選擇使得如式（I)之化合物的分子量不超過1 000。較常 見地，化合物之分子量小於7 5 0，例如小於7 0 0，或小於 65〇 ’或小於600，或小於5 5 0。較合宜地，分子量小於525 ，例如5 0 〇以下。 本發明之特別化合物在下面的實例中被舉例說明。 -96- 200524877 (92) 鹽類，溶劑化物類、互變異構物類、異構物類、N-氧化物 類、酯類、前藥類及同位素類 除非另外指定，特別化合物的一個參考例也包括在下 文中被討論的彼之離子的、鹽的、溶劑化物的及被保護的 形式。In order to avoid doubt, the following should be understood: the general and specific reference examples, embodiments and examples of the group R1 can be compared with the groups R2 and / or R3 and / or R4 and / or RIG and / or Y in this description. And / or ... and / or each subgroup of general and specific reference examples, manifestations and example synthesis, this type of synthesis is included in this application. Various functional groups and substituents constituting the compound of the formula (I) are typically selected so that the molecular weight of the compound of the formula (I) does not exceed 1,000. More commonly, the molecular weight of a compound is less than 750, such as less than 700, or less than 650 'or less than 600, or less than 550. Conveniently, the molecular weight is less than 525, such as less than 500. Specific compounds of the invention are illustrated in the following examples. -96- 200524877 (92) Salts, solvates, tautomers, isomers, N-oxides, esters, prodrugs and isotopes Unless otherwise specified, a reference example of a special compound Also included are the ionic, salt, solvate, and protected forms discussed below.

許多如式（I)之化合物可以鹽類的形式存在，例如酸 式加成鹽、在特定場合中的有機鹼及無機鹼的鹽類（如羧 酸鹽、磺酸鹽及磷酸鹽）。這類鹽類全部在本發明之範圍 中，如式（I)之化合物的參考例包括化合物的鹽形式。在 本申請案的前面的章節中，式（I)之參考例全部指的是式 (0)、（I0)、（I)、（la)、（lb)、（II)、（III)、（IV)、（IVa)、 (Va)、（Vb)、（Via)、（VIb)、（VII)或（VIII)及彼之亞群， 除非另有指定。Many compounds of formula (I) can exist in the form of salts, such as acid addition salts, salts of organic and inorganic bases (such as carboxylates, sulfonates, and phosphates) in specific applications. Such salts are all within the scope of the present invention, and reference examples of the compound of formula (I) include salt forms of the compounds. In the previous sections of this application, the reference examples of formula (I) all refer to formulas (0), (I0), (I), (la), (lb), (II), (III), (IV), (IVa), (Va), (Vb), (Via), (VIb), (VII) or (VIII) and their subgroups, unless otherwise specified.

鹽形式可被選擇及依照在下面文獻中所描述的方法被 製造：Pharmaceutical Salt : Properties，Selection，and Use，P.Heinrich Stahl(Editor)，Camille G.Wermuth( Editor)，ISBN ： 3-90639-026-8，Hardcover，3 8 8 pages， August 2002 o 酸式加成鹽可由許多種酸類（無機的及有機的）製成。 酸式加成鹽的實例包括由選自下列的酸所製成的鹽類：醋 酸、2，2-二氯醋酸、己二酸、藻朊酸、抗壞血酸（例如L-抗壞血酸）、L-丁胺二酸、苯磺酸、苯甲酸、心乙醯胺基 苯甲酸、丁酸、（+ )梓腦酸、梓腦-磺酸、（+ )-(13)-梓腦-10-磺酸、癸酸、己酸、辛酸、肉桂酸、檸檬酸、環醯胺 -97- 200524877 (93) 酸、十二烷基硫酸、乙烷-1，2 -二磺酸、乙烷磺酸、2 -經 基乙烷磺酸、甲酸、富馬酸、乳酸、龍膽酸、葡庚糖酸、 D-葡糖酸、葡糖醛酸（例如D-葡糖醛酸）、榖胺酸（例如L-穀胺酸）、α -合氧基戊二酸、乙酸、馬尿酸、氫溴酸、氫 氯酸、氫磺酸、羥乙基磺酸、（ + )-L-乳酸、（±)-DL-乳酸 、乳糖醛酸、馬來酸、蘋果酸、（-)-L-蘋果酸、丙二酸、（ ± )-DL-苯乙醇酸、甲烷磺酸、萘-2-磺酸、萘-1 , 二磺 酸、1-羥基-2·萘酸、菸酸、硝酸、油酸、乳淸酸、草酸 、棕櫚酸、棕櫚醯酸、磷酸、丙酸、L-焦榖胺酸、水楊酸 、4-胺基-水楊酸、癸二酸、硬脂酸、丁二酸、硫酸、丹 寧酸、（ + )-L-酒石酸、硫氰酸、對甲苯磺酸、十一碳烯酸 及戊酸，以及醯化的胺基酸及陽離子交換樹脂。 特別的一群鹽類是由下列的酸所製成的鹽組成：鹽酸 、氫碘酸、磷酸、硝酸、硫酸、檸檬酸、乳酸、丁二酸、 馬來酸、蘋果酸、羥乙基磺酸、富馬酸、苯磺酸、甲苯磺 酸、甲烷磺酸、乙烷磺酸、萘磺酸、戊酸、醋酸、丙酸、 丁酸、丙二酸、葡糖醛酸及乳糖醛酸。 合宜的一群鹽類是由下列的酸所製成的鹽組成：鹽酸 、醋酸、己二酸、L-丁胺二酸及DL-乳酸。 特別合宜的鹽類是鹽酸鹽。 舉例來說，如果化合物是陰離子型，或有陰離子型官 能基（例如-C Ο Ο Η可以是-C Ο 0 -)的話，則鹽可由適合的陽 離子製成。適合的無機陽離子的實例包括（但不限於）：鹼 金屬離子（如Na +及Κ + )、鹼土族陽離子（如Ca2 +及Mg2 + )，以 200524877 (94) 及其他的陽離子（如A 13 +)。合適的有機陽 但不限於）：銨離子（即NH4 + )及被取代 NH3R+、NH2R2+、nhr3+、nh4 + )。某些合The salt form can be selected and manufactured according to the methods described in the following literature: Pharmaceutical Salt: Properties, Selection, and Use, P. Heinrich Stahl (Editor), Camille G. Wermuth (Editor), ISBN: 3-90639- 026-8, Hardcover, 3 8 8 pages, August 2002 o Acid addition salts can be made from many acids (inorganic and organic). Examples of the acid addition salt include salts made of an acid selected from the group consisting of acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid (such as L-ascorbic acid), and L-butane Amino acid, benzene sulfonic acid, benzoic acid, acetoamido benzoic acid, butyric acid, (+) catalic acid, catalic-sulfonic acid, (+)-(13) -azina-10-sulfonic acid , Capric acid, hexanoic acid, octanoic acid, cinnamic acid, citric acid, cyclohexylamine-97- 200524877 (93) acid, dodecyl sulfate, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2 -Ethanesulfonic acid, formic acid, fumaric acid, lactic acid, gentisic acid, glucoheptanoic acid, D-gluconic acid, glucuronic acid (such as D-glucuronic acid), ammonium acid (such as L-Glutamic acid), α-Hydroxyglutaric acid, acetic acid, hippuric acid, hydrobromic acid, hydrochloric acid, hydrosulfonic acid, isethionic acid, (+)-L-lactic acid, (±) -DL-lactic acid, galacturonic acid, maleic acid, malic acid, (-)-L-malic acid, malonic acid, (±) -DL-phenylglycolic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, Naphthalene-1, disulfonic acid, 1-hydroxy-2 · naphthoic acid, nicotinic acid, nitric acid, oleic acid, lactic acid, oxalic acid, palm , Palmitic acid, phosphoric acid, propionic acid, L-pyropic acid, salicylic acid, 4-amino-salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+ ) -L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid, undecylenic acid and valeric acid, as well as tritiated amino acids and cation exchange resins. A special group of salts are salts made of the following acids: hydrochloric acid, hydroiodic acid, phosphoric acid, nitric acid, sulfuric acid, citric acid, lactic acid, succinic acid, maleic acid, malic acid, isethionate , Fumaric acid, benzenesulfonic acid, toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, naphthalenesulfonic acid, valeric acid, acetic acid, propionic acid, butyric acid, malonic acid, glucuronic acid, and lacturonic acid. A suitable group of salts is composed of the following acids: hydrochloric acid, acetic acid, adipic acid, L-butyric acid and DL-lactic acid. Particularly suitable salts are the hydrochloride salts. For example, if the compound is anionic or has an anionic functional group (for example, -C OO Ο can be -C OO 0-), the salt can be made from a suitable cation. Examples of suitable inorganic cations include (but are not limited to): alkali metal ions (such as Na + and K +), alkaline earth cations (such as Ca 2+ and Mg 2+), 200524877 (94) and other cations (such as A 13 +). Suitable organic cations are not limited to: ammonium ions (ie, NH4 +) and substituted NH3R +, NH2R2 +, nhr3 +, nh4 +). Certain combination

離子的實例是由下列所衍生：乙胺、二乙 三乙胺、丁胺 '乙二胺、乙醇胺、二乙醇 、苯基苄胺、膽鹼、葡甲胺、胺基丁三I 如離胺酸及精胺酸）。常見的季胺離子的 〇 在如式（I)之化合物含有胺官能基的 於此藝人士所熟悉的方法與烷化劑起反應 該季銨化合物在式（I)的範圍之內。 本發明之化合物的鹽形式一般是藥學 ’彼之實例在下面文獻中被討論：Berge Pharmaceuticalyy Acceptable Salts &quot; ，Examples of ions are derived from the following: ethylamine, diethylenetriethylamine, butylamine 'ethylenediamine, ethanolamine, diethanol, phenylbenzylamine, choline, meglumine, aminobutanetriol such as ionamine Acid and arginine). Common quaternary ammonium ions are reacted with alkylating agents in a method familiar to those skilled in the art as compounds of formula (I) contain amine functional groups. The quaternary ammonium compounds are within the scope of formula (I). The salt forms of the compounds of the present invention are generally pharmacological. 'An example of this is discussed in the following literature: Berge Pharmaceuticalyy Acceptable Salts &quot;,

Vol.66，ΡΡ·1-19。然而，藥學上不可接受 成中間物的形式，接著被轉變成藥學上可 類非藥學上可接受的鹽形式（可用於提純: 化合物）也構成本發明的一部份。 含有一個胺官能基的如式（I)之化合1 化物。 在化合物含有幾種胺官能基的場合中 原子可被氧化形成N-氧化物。N-氧化物的 含氮的雜環的氮原子的N·氧化物。 N -氧化物可以由以氧化劑（如過氧化ί 離子的實例包括（ 的銨離子（例如 適的被取代的銨 胺、二環己胺、 胺、_嗪、苄胺 ί享、以及胺基酸（ 實例是n(ch3)4 + 場合中，依照精 可形成季銨鹽。 上可接受的鹽類 et al·，1 9 7 7，、、 J . P h ar m . S c i.， 的鹽類也可被製 接受的鹽類。這 或分離本發明之 吻也可形成N-氧 ，一個以上的氮 特別是第三胺或 ΐ或過酸（例如過 -99- 200524877 (95) 氧殘酸）處理對應的胺被製成’見Advanced Organic Chemistry ， by Jerry March ， 4thEdition ， Wiley Interscience ， pages.More particularly ， N-oxides can made by the procedure of L.W.Deady(Syn.Comm.1977，7 ，5 0 9 - 5 1 4)，其中胺化合物在惰性溶劑（如二氯甲烷）中被 間氯代過氧苯甲酸（MCPBA)反應。 如式（I)之化合物可以許多不同的幾何異構物及互變 異構物形式存在，如式（I)之化合物的參考例包括所有的 該類形式。爲避免懷疑，在化合物可以數種幾何異構物或 互變異構物形式中的一種形式存在，只有一種形式被專一 地描述或展示，其他的形式皆依然被包含在式（I)中。 舉例來說，在如式（I)之化合物中，吡唑基團可以是 下面的二種互變異構物形式A及B中的任何一種。爲簡單 起見，通式（I)說明A形式，但化學式包含二種互變異構物 形式。Vol.66, PP · 1-19. However, pharmaceutically unacceptable intermediate forms and subsequent conversion to pharmaceutically acceptable non-pharmaceutically acceptable salt forms (usable for purification: compounds) also form part of the present invention. A compound of formula (I) containing an amine functional group. Where the compound contains several amine functions, the atoms can be oxidized to form N-oxides. N-oxide N-oxide of a nitrogen atom of a nitrogen-containing heterocyclic ring. Examples of N-oxides can be obtained from oxidants such as peroxide ions, including ammonium ions (such as suitable substituted ammonium amines, dicyclohexylamine, amines, hydrazines, benzylamines, and amino acids (An example is n (ch3) 4 + where quaternary ammonium salts can be formed according to fines. The acceptable salts et al ·, 197, 7, J, Pharm, Sci., Salts can also be made acceptable salts. This or separation of the kiss of the present invention can also form N-oxygen, more than one nitrogen, especially a third amine or amidine or peracid (for example per-99- 200524877 (95) oxygen Residual acid) treatment corresponding amines are made 'See Advanced Organic Chemistry, by Jerry March, 4th Edition, Wiley Interscience, pages. More particularly, N-oxides can made by the procedure of LWDeady (Syn. Comm. 1977, 7,, 5 0 9-5 1 4), in which the amine compound is reacted with m-chloroperoxybenzoic acid (MCPBA) in an inert solvent (such as dichloromethane). The compound of formula (I) can have many different geometric isomers And tautomeric forms, such as the reference examples of compounds of formula (I) include all the Forms. To avoid doubt, compounds can exist in one of several geometric isomer or tautomeric forms, and only one form is specifically described or shown, and other forms are still included in formula (I) For example, in compounds such as formula (I), the pyrazole group can be any of the following two tautomeric forms A and B. For simplicity, the general formula (I) illustrates A Form, but the chemical formula contains two tautomeric forms.

互變異構物形式的其他的實例包括（例如酮基、烯醇 及烯醇根絡的形式）下面的互變異構物對··酮/烯醇（在下文 中被舉例說明），亞胺/烯胺、醯胺/亞胺醇、脒/脒、亞硝 基/问、硫酸/烯硫赶及硝基/酸硝酸。 -100- 200524877 (96) I ,〇 \ ,0H H+ \ /0· —c-c 兰 C=C、 =^=: c=c I \ / \ H+ / \ 酮基 烯醇 烯醇根絡 在如式（I)之化合物含有一或多個對掌中心及可以二 或多種旋光異構物的形式存在的場合中，如式（1)之化合 物的參考例包括所有的彼之旋光異構物形式（例如對掌異 構物、差位異構物、及非對映立體異構物），以個別的旋 光異構物或混合物（例如外消旋混合物）或二或多種的旋光 異構物的形式，除非另外指定。 旋光異構物可被彼之旋光度（即+及-異構物，或d及1 異構物）特徵化及鑑定或彼可以彼之絕對的立體化學使用 &gt; R及S 〃命名法被特徵化，該命名法是下列所發展的： Cahn ， Ingold and Prelog ， see Advanced Organic Chemistry by Jerry March ? 4th Edition » John Wiley &amp; Sons ， New York ， 1992 ， pages 109-114 ， and see alsoOther examples of tautomeric forms include (e.g. keto, enol and enol complexes) the following tautomer pairs: ketone / enol (illustrated below), imine / ene Amines, amidines / imines, amidines / amidines, nitrosos / ammonium, sulfuric acid / enesulfur, and nitro / acid nitric acids. -100- 200524877 (96) I, 〇 \, 0H H + \ / 0 · —cc blue C = C, = ^ =: c = c I \ / \ H + / \ ketoenol enol complex in the formula Where the compound of (I) contains one or more palm centers and can exist in the form of two or more optical isomers, the reference examples of the compound of formula (1) include all the other optical isomer forms ( Such as paraisomers, epimers, and diastereoisomers), in the form of individual optical isomers or mixtures (such as racemic mixtures) or two or more optical isomers Unless otherwise specified. Optical isomers can be characterized and identified by their optical rotations (ie, + and-isomers, or d and 1 isomers) or they can be used in their absolute stereochemistry &gt; R and S 〃 nomenclature Characterized, the nomenclature was developed as follows: Cahn, Ingold and Prelog, see Advanced Organic Chemistry by Jerry March? 4th Edition »John Wiley &amp; Sons, New York, 1992, pages 109-114, and see also

Cahn，Ingo 1 d &amp; Pre 1 o g，Auge w · Chem . I nt. Ed · EngI.，1 9 6 6 ，5 ， 385-415° 旋光異構物可以被許多技術分開，該技術包括對掌性 層離（在對掌性支架上層離），這類的技術是精於此藝的人 士所熟悉的。 在如式（I)之化合物以二或多種的旋光異構物形式存 在的場合中，一對對掌異構物中的一個對掌異構物會展現 比其他的對掌異構物更多的益處，例如生物活性。所以， 在若干情況下，可以一對對掌異構物中的一個或眾多非對 -101 - 200524877 (97) 映立體異構物中的一個充當治療藥劑使用。於是，本發明 提供含有如式（1)之化合物的組成物，該如式（1)之化合物 有一或多個對掌中心，其中至少55%(例如至少60%、65% 、70%、75%、80%、85%、90°/〇 或 95%)的如式（I)之化合物 是以單一的旋光異構物（例如對掌異構物或非對映立體異 構物）的形式存在。在一個泛用的體現中，如式（I)之化合 物的總量的9 9 %以上（例如實質地全部）可以單一的旋光異 構物（例如對掌異構物或非對映立體異構物）的形式存在。 本發明之化合物包括有一或多種同位素取代的化合物 ，特別元素的參考例包括在彼之範圍內的元素的全部的同 位素。例如，氫的參考例包括：j、2H(D)及3H(T)。同樣 地，碳及氧的參考例分別包括：12C、13c及14c及160及180 〇 同位素可以是放射性的或非放射性的。在本發明的一 個體現中，化合物不含放射性同位素。這類化合物適於治 療使用。在另一個體現中，然而，化合物可含有一或多種 同位素。含有這類放射性同位素的化合物可用於診斷方面 〇 酯類（如帶有羧酸基團或羥基的如式（I)之化合物的羧 一酸酯類及醯氧基酯類）也被包含於式（I)中。酯類的實 例是含有基團-C ( = 0)0R的化合物，其中R是一種酯取代 基，例如C】.7烷基' (：3·2〇雜環基、或C5-20芳基，較佳 C!-7烷基。酯基團的特例包括（但不限於）：-c( = o)och3 、-C( = 0)0CH2CH3、·ί：( = 0)0(：((：Η3)3 及-C( = 〇)〇Ph。醯氧基（ -102- 200524877 (98) 逆轉的酯）基團的實例被-0C( = 0)R代表，其中R是一種醯氧基 取代基，例如，C!_7烷基、C3-2G雜環基、或C5_2G芳基，較佳 C!-7烷基。醯氧基之特別包括（但不限於）：-〇C( = 0)CH3(乙醯 氧基）、-〇C( = 〇)CH2CH3、-0C( = 0)C(CH3)3、-0C( = 0)Ph 及-0C(=0)CH2Ph 。 式（I)所包含的還有化合物的任何的多晶形式、化合 物的溶劑化物（例如水合物）、錯合物（例如化合物（如環糊 精）的包含錯合物或籠形物，或與金屬的錯合物）.及化合物 的前藥。 ''前藥〃表示任何的化合物，彼在活體內被轉變 成生物活性的如式（I)之化合物。 舉例來說，若干前藥是活性化合物的酯類（例如生理 上可接受的代謝不穩定的酯）。在代謝作用期間，酯基（-C( = 0) OR)被分裂成活性的藥物。這類酯類可由以（合適的） 在親代化合物中存在的任何其他的反應基團的前保護作用 使在親代化合物中的羧酸基團（-C( = 0) OH)中的任何一個酯 化製成，接著去保護（視需要而定）。 這類代謝不穩定的酯類的實例包括如式-C( = 0)0R的 酯基團，其中R是： C】-7烷基（例如甲基、乙基、正丙基、異丙基、正丁基、另 丁基、異丁基、第三丁基）； C】-7胺烷基（例如胺乙基；2-(N，N-二乙胺基）乙基；2-(4-嗎啉代）乙基）；醯氧基- Ch7烷基（例如醯氧基甲基；醯氧 基乙基；特戊醯氧基甲基；乙醯氧基甲基；】-乙醯氧基乙 基；1-(1-甲氧基-卜甲基）乙基-羰氧乙基；（卜苄醯氧基）乙 -103- 200524877 (99) 基；異丙氧基-羰氧甲基；1-異丙氧基-羰氧乙基；環己基-羥氧甲基；1-環己基-羰氧乙基；環己氧基-羰氧甲基；b 環己氧基-羰氧乙基；四氫吡嘲氧基）羰氧甲基；1_(4-四氫吡喃氧基）羰氧乙基；（4-四氫吡喃基）羰氧甲基；及b (4-四氫吡喃基）羰氧乙基）。 若干前藥也被酶催化活化成活性化合物，或化合物（ 彼進一步化學反應成活性化合物（例如ADEPT、GDEPT、 LID EPT等）。舉例來說，前藥可以是糖衍生物或其他的苔 共軛物，或可以是胺基酸酯衍生物。 生物活性 如式（〇)、（1〇)、（I)、（la)、（lb)、（II)、（III)、（IV)、 (IVa)、（Va)、（Vb)、（Via)、（VIb)、（VII)或（VIII)之化合 物及彼之亞群是環素依賴型激酶的抑制劑，尤其環素依賴 激酶選自·· CDK1、CDK2、CDK3、CDK4、CDK5 及 CDK6 〇 合宜的化合物是抑制一或多種選自下列的CDK激酶的 化合物·· CDK1、CDK2、CDK4 及 CDK5，例如 CDK1 及 / 或 CDK2。 本發明之化合物也被考慮爲糖原合成酶激酶- 3(GSK3) 的抑制劑。 由於上述的化合物及彼之亞群在調節或抑制CDK激酶 及糖原合成酶激酶的活性方面的結果，吾人期待彼在提供 一種中止或回復在異常分裂的細胞的細胞週期的控制的方 -104- 200524877 (100) 法中有用。所以吾人預期該化合物類會證明彼可用於處理 或預防增殖性疾病（如癌）。經本發明硏究得知：本發明之 化合物可用於處理下列症狀：病毒感染、11型或非胰島素 型依賴型糖尿病、自體免疫病、頭創傷、中風、癲癎、神 經變性病（如阿茲海默氏病）、運動神經元病、進行性核上 性麻痺、基底皮質變性及P i c k氏病。經本發明者硏究得知 :本發明之化合物可使用的疾病狀態及症狀的一個亞群是 由下列組成··病毒性感染、自體免疫病及神經變性病。 CDK類在調節細胞週期、脫噬作用、轉錄作用、分化 作用及中樞神經系統機能的場合中扮演一個角色。所以 C D K抑制劑可用於處理增殖作用、、脫噬作用或分化作用 的疾病（如癌）。尤其RB + Ve腫瘤可能對CDK抑制劑特別敏 感。RB + Ve腫瘤也可能對CDK抑制劑敏感。 可被抑制的癌的實例包括（但不限於）：膀胱癌、乳癌 '結腸癌（例如結腸直腸癌，如結腸腺癌及結腸腺瘤）、腎 癌、表皮癌、肝癌、肺癌（如小型細胞肺癌及非小型細胞 肺癌）、食管癌、膽囊癌、卵巢癌、胰臟癌（例如外分泌胰 腺癌）、胃癌、項癌、甲狀腺癌、前列腺癌、皮膚癌（例如 鱗狀細胞癌）；造血性淋巴癌（例如白血病、急性淋巴細胞 白血病、B細胞淋巴癌、T細胞淋巴癌、Hodgkin氏淋巴癌 、非Η 〇 d g k i η氏淋巴癌、毛髮細胞淋巴癌或B u r 1 k e 11氏淋巴 癌、）；造血性骨髓癌（例如急性及慢性骨髓性白血病、骨 髓發育不良徵候群、或前骨細胞性白血病）；甲狀腺濾泡 癌；間質起端癌（例如纖維肉瘤或肌肉瘤）；中樞或周圍神 -105- 200524877 (101) 經系統癌（例如星形細胞癌、神經母細胞癌、神經膠質癌 或神經鞘癌）；黑色素癌；精原細胞癌；畸胎癌；骨肉癌 ;乾皮色素反質癌；角質癌；甲狀腺濾泡癌；或Kao osi氏 肉瘤。 癌可以是對任何的一或多種選自下列的環素依賴型激 酶的抑制作用敏感的癌：C D K 1、C D K 2、C D K 3、C D K 4、 C D K 5及C D K 6，例如一或多種選自下列的C D K激酶： CDK1、CDK2、CDK3、CDK4、CDK5，例如 CDK1 及 / 或 CDK2。 專一的癌是否是可被環素依賴型激酶抑制的癌可借助 於在實施例2 5 0中所陳述的細胞生長分析的方法或藉由在 標題爲 ''診斷的方法〃的章節中所陳述的方法被確定。 CD K類也被認爲在脫噬作用、增殖作用、分化作用及 轉錄作用中扮演一個角色，所以C D K抑制劑也可用於處理 下面的疾病（除癌以外）：病毒性感染，例如疱疹病毒、梅 素病毒、Epstein-Barr病毒、Sindbis病毒、腺病毒、HIV 、HPV、HCV及HCMV;防止在被HIV感染的個體體內的 A IDS發展；慢性炎病，例如全身性紅斑狼瘡、自體免疫 所仲介的腎小球性腎炎、類風濕性關節炎、銀屑病、炎性 腸病、自體免疫糖尿病；心血管病，例如心臟肥大、再狹 窄、動脈粥樣硬化；神經變性病，例如阿茲海默氏病、 A I D S相關的癡默、帕金森氏病、肌萎縮脊髓側索硬化、 視網膜色素變性、脊髓肌萎縮及小腦變性、腎小球性腎炎 ;骨髓發育不良徵候群、缺血性創傷伴髓的心肌梗塞、中 -106- 200524877 (102) 風及再灌注創傷、心律不整、動脈粥樣硬化、毒素誘發的 或酒精相關的肝病、血液病，例如慢性貧血及發育不全性 貧血；肌及骨骼系統變性病，例如骨質疏鬆及關節炎、阿 司匹林感受性鼻竇炎、胰囊性纖維變性、多發性硬化、腎 病及癌疼痛。 以下業已被發現：某些環素依賴型激酶抑制劑可與其 他的抗癌藥劑聯合被使用。舉例來說，環素依賴型激酶抑 制劑夫匹力朵（flavopiridol)業已與其他的抗癌藥劑綜合被 使用於綜合性治療中。 所以，在一個使用本發明之藥學組成物或方法處理包 含異常的細胞生長的疾病或症狀的體現中，該包含異常的 細胞生長的疾病或症狀是癌。 癌的一群包括：人乳癌（例如原發性乳癌、結負性乳 癌、乳腺的侵入性導管腺癌、非子宮內膜樣乳癌）；外膜 細胞淋巴癌。此外，其他的癌是結腸直腸癌及子宮內膜癌 〇 癌的另一亞組包括：乳癌、卵巢癌、結腸癌、前列腺 癌、食管癌、鱗狀細胞癌、非小型細胞肺癌。 充當環素依賴型激酶及糖原合成酶激酶-3的抑制劑的 本發明之化合物的活性可以使用在下面的實施例中所陳述 的分析被量測，由已知化合物所展現的活性水平可被定義 成1C 5 0値。本發明之合宜的化合物是1C 50値小於1mm 〇1， 較佳小於〇 . 1 m m ο 1的化合物。 -107- 200524877 (103) 製造本發明之化合物的方法 依照精於此藝的人士熟悉的合成法製造如式（I)之化 合物及彼之各種的亞群。除非另有指定，否則，R 1、R2、 R3、Y、X及A如同前文中所定義的。 在本章節中，如同在本申請案的所有的其他的章節中 ，式⑴之參考例也代表式（0)、（I0)、（I)、（la)、（lb)、（II) 、（III)、（IV)、（IVa)、（Va)、（Vb)、（Via)、（VIb)、（VII) 或（VIII)及彼之亞群，除非另有指定。 如式（I)之化合物（其中R^A-形成一個醯基R^CO-)可 以下列方式被製造：如反應計劃1中所示的以被適當取代 的4-胺基-吡唑使如式R^CC^H之羧酸或彼之被活化的衍生 物起反應。Cahn, Ingo 1 d &amp; Pre 1 og, Aug w · Chem. Sexual delamination (delamination on the palmar scaffold), this type of technology is familiar to those skilled in the art. Where compounds of formula (I) exist as two or more optical isomers, one paraisomer of a pair of paraisomers will exhibit more than the other paraisomer Benefits, such as biological activity. Therefore, in several cases, one or more of the non-paraisomeric -101-200524877 (97) enantiomeric stereoisomers can be used as a therapeutic agent. Thus, the present invention provides a composition containing a compound of formula (1) having one or more palmar centers, of which at least 55% (for example, at least 60%, 65%, 70%, 75%) %, 80%, 85%, 90 ° / 0 or 95%) of the compound of formula (I) is in the form of a single optical isomer (such as a para-isomer or a diastereo-isomer) presence. In a generalized embodiment, more than 99% (eg substantially all) of the total amount of compounds of formula (I) can be single optical isomers (eg, paraisomers or diastereoisomers) Exist). The compounds of the present invention include compounds substituted with one or more isotopes, and reference examples of specific elements include all isotopes of the elements within the range. For example, reference examples of hydrogen include: j, 2H (D), and 3H (T). Similarly, reference examples of carbon and oxygen include: 12C, 13c, and 14c, and 160 and 180, respectively. Isotope may be radioactive or non-radioactive. In one embodiment of the invention, the compound is free of radioisotopes. Such compounds are suitable for therapeutic use. In another embodiment, however, the compound may contain one or more isotopes. Compounds containing such radioisotopes are useful in diagnostics. Ester esters (such as the carboxylic acid esters and methoxy esters of compounds of formula (I) with carboxylic acid groups or hydroxyl groups) are also included in the formula (I). Examples of esters are compounds containing the group -C (= 0) OR, where R is an ester substituent, such as C] .7 alkyl '(: 3.20 heterocycle, or C5-20 aryl , Preferably C! -7 alkyl. Specific examples of ester groups include (but are not limited to): -c (= o) och3, -C (= 0) 0CH2CH3, · ί: (= 0) 0 (: (( : Η3) 3 and -C (= 〇) 〇Ph. An example of a methoxy group (-102- 200524877 (98) reversed ester) group is represented by -0C (= 0) R, where R is a fluorenyl group Substituents, for example, C! _7 alkyl, C3-2G heterocyclyl, or C5_2G aryl, preferably C! -7 alkyl. Specific examples of alkoxy include (but are not limited to): -0C (= 0 ) CH3 (ethoxy), -〇C (= 〇) CH2CH3, -0C (= 0) C (CH3) 3, -0C (= 0) Ph, and -0C (= 0) CH2Ph. Formula (I) Also included are any polymorphic forms of compounds, solvates of compounds (such as hydrates), complexes (such as compounds (such as cyclodextrin) containing complexes or clathrates, or metal complexes ) And prodrugs of compounds. "Prodrugs" means any compound that is converted into a biologically active compound of formula (I) in vivo. For example, several prodrugs are esters of active compounds (such as physiologically acceptable metabolically unstable esters). During metabolism, the ester group (-C (= 0) OR) is cleaved into the active drug. Such esters can be pre-protected by any suitable reactive group present in the parent compound to any of the carboxylic acid groups (-C (= 0) OH) in the parent compound. One is made by esterification, followed by deprotection (as needed). Examples of such metabolically unstable esters include ester groups of formula -C (= 0) OR, where R is: C] -7 alkane (Such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, isobutyl, third butyl); C] -7 amine alkyl (such as amine ethyl; 2- (N, N-diethylamino) ethyl; 2- (4-morpholino) ethyl); fluorenyl-Ch7 alkyl (e.g. fluorenylmethyl; fluorenylethyl; pentamidine Ethoxymethyl; ethoxymethyl;]-ethoxymethyl; 1- (1-methoxy-methyl) ethyl-carbonyloxyethyl; (phenylbenzyloxy) ethyl-103 -200524877 (99) group; isopropoxy-carbonyloxymethyl ; 1-isopropoxy-carbonyloxyethyl; cyclohexyl-hydroxyoxymethyl; 1-cyclohexyl-carbonyloxyethyl; cyclohexyloxy-carbonyloxymethyl; b cyclohexyloxy-carbonyloxyethyl Group; tetrahydropyridyloxy) carbonyloxymethyl; 1- (4-tetrahydropyranyloxy) carbonyloxyethyl; (4-tetrahydropyranyl) carbonyloxymethyl; and b (4-tetrahydropyranyl) carbonyloxymethyl; Hydropyranyl) carbonyloxyethyl). Several prodrugs are also activated by enzymes to catalyze active compounds, or compounds (which are further chemically reacted into active compounds (such as ADEPT, GDEPT, LID EPT, etc.). For example, the prodrug may be a sugar derivative or other moss conjugate, or it may be an amino acid derivative. The biological activity is as follows: (0), (10), (I), (la), (lb), (II), (III), (IV), (IVa), (Va), (Vb), ( Via), (VIb), (VII) or (VIII) compounds and their subgroups are inhibitors of cyclin-dependent kinases, especially cyclin-dependent kinases are selected from the group consisting of CDK1, CDK2, CDK3, CDK4, CDK5 and CDK6. Suitable compounds are compounds that inhibit one or more CDK kinases selected from the group consisting of CDK1, CDK2, CDK4, and CDK5, such as CDK1 and / or CDK2. The compounds of the present invention are also considered as inhibitors of glycogen synthase kinase-3 (GSK3). Due to the results of the above compounds and their subgroups in regulating or inhibiting the activity of CDK kinase and glycogen synthase kinase, we look forward to providing a way to stop or restore control of the cell cycle in abnormally dividing cells. -200524877 (100) method. So I expect this compound to prove that it can be used to treat or prevent proliferative diseases such as cancer. The present invention has revealed that the compounds of the present invention can be used to treat the following symptoms: viral infection, type 11 or non-insulin-dependent diabetes mellitus, autoimmune disease, head trauma, stroke, epilepsy, neurodegenerative diseases (such as Aziz Hemmer's disease), motor neuron disease, progressive supranuclear palsy, basal cortical degeneration, and Pick's disease. The inventors have learned that a subgroup of disease states and symptoms that can be used with the compounds of the present invention is composed of the following: viral infections, autoimmune diseases, and neurodegenerative diseases. CDKs play a role in regulating cell cycle, dephagy, transcription, differentiation, and central nervous system function. Therefore, CDK inhibitors can be used to treat diseases such as cancer, such as proliferation, dephagocytosis, or differentiation. In particular, RB + Ve tumors may be particularly sensitive to CDK inhibitors. RB + Ve tumors may also be sensitive to CDK inhibitors. Examples of cancers that can be inhibited include (but are not limited to): bladder cancer, breast cancer, colon cancer (eg colorectal cancer, such as colon adenocarcinoma and colon adenoma), kidney cancer, epidermal cancer, liver cancer, lung cancer (such as small cells Lung cancer and non-small cell lung cancer), esophageal cancer, gallbladder cancer, ovarian cancer, pancreatic cancer (such as exocrine pancreatic cancer), gastric cancer, neck cancer, thyroid cancer, prostate cancer, skin cancer (such as squamous cell carcinoma); hematopoietic Lymphoma (such as leukemia, acute lymphocytic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Ηdgki η lymphoma, hair cell lymphoma, or Bur 1 ke 11 lymphoma, ; Hematopoietic bone marrow cancer (eg, acute and chronic myeloid leukemia, myelodysplastic syndrome, or preosteoblastic leukemia); thyroid follicular cancer; interstitial cancer (eg fibrosarcoma or myoma); central or surrounding Shen-105- 200524877 (101) Systemic cancer (such as astrocytic, neuroblastic, glial, or schwann cancer); melanoma; spermatogonia ; Teratocarcinoma; osteosarcoma cancer; anti-dry skin pigment quality cancer; horny cancer; thyroid follicular cancer; Kao osi or sarcoma. The cancer may be a cancer susceptible to the inhibition of any one or more cyclin-dependent kinases selected from the group consisting of: CDK 1, CDK 2, CDK 3, CDK 4, CDK 5 and CDK 6, such as one or more selected from CDK kinases: CDK1, CDK2, CDK3, CDK4, CDK5, such as CDK1 and / or CDK2. Whether a specific cancer is a cancer that can be inhibited by a cyclin-dependent kinase can be aided by the method of cell growth analysis stated in Example 250 or by the method described in the section entitled `` Methods of diagnosis '' The method was determined. CD K is also considered to play a role in dephagocytosis, proliferation, differentiation, and transcription, so CDK inhibitors can also be used to treat the following diseases (in addition to cancer): viral infections, such as herpes virus, Syphilis virus, Epstein-Barr virus, Sindbis virus, adenovirus, HIV, HPV, HCV and HCMV; prevent the development of A IDS in HIV-infected individuals; chronic inflammatory diseases such as systemic lupus erythematosus, autoimmune Intervening glomerulonephritis, rheumatoid arthritis, psoriasis, inflammatory bowel disease, autoimmune diabetes; cardiovascular diseases such as cardiac hypertrophy, restenosis, atherosclerosis; neurodegenerative diseases such as Arab Zheimer's disease, AIDS-related obesity, Parkinson's disease, amyotrophic lateral sclerosis, retinal pigment degeneration, spinal muscular atrophy and cerebellar degeneration, glomerulonephritis; myelodysplastic syndromes, ischemic Trauma with myeloid infarction, medium-106- 200524877 (102) wind and reperfusion trauma, arrhythmia, atherosclerosis, toxin-induced or alcohol-related liver disease, blood Such as chronic anemia and hypoplastic anemia; muscular and skeletal system degenerative disease, such as osteoporosis and arthritis, aspirin sensitivity sinusitis, cystic fibrosis, multiple sclerosis, kidney diseases and cancer pain. It has been discovered that certain cyclin-dependent kinase inhibitors can be used in combination with other anticancer agents. For example, flavopiridol, a cyclin-dependent kinase inhibitor, has been used in combination with other anticancer agents in a comprehensive treatment. Therefore, in the embodiment of using the pharmaceutical composition or method of the present invention to treat a disease or symptom including abnormal cell growth, the disease or symptom including abnormal cell growth is cancer. A group of cancers includes: human breast cancer (eg, primary breast cancer, nodular breast cancer, invasive ductal adenocarcinoma of the breast, non-endometrioid breast cancer); adventitial cell lymphoma. In addition, other cancers are colorectal cancer and endometrial cancer. Another subgroup of cancers includes: breast cancer, ovarian cancer, colon cancer, prostate cancer, esophageal cancer, squamous cell carcinoma, and non-small cell lung cancer. The activity of the compounds of the invention, which act as inhibitors of cyclin-dependent kinases and glycogen synthase kinase-3, can be measured using the assays set forth in the examples below. The level of activity exhibited by known compounds can be Is defined as 1C 5 0 値. A suitable compound of the present invention is a compound having a 1C 50 値 of less than 1 mm 0, preferably less than 0.1 mm 1. -107- 200524877 (103) Method for producing the compound of the present invention The compound such as formula (I) and its various subgroups are produced according to synthetic methods familiar to those skilled in the art. Unless otherwise specified, R1, R2, R3, Y, X, and A are as defined above. In this section, as in all other sections of this application, the reference examples of formula (i) also represent formulas (0), (I0), (I), (la), (lb), (II), (III), (IV), (IVa), (Va), (Vb), (Via), (VIb), (VII) or (VIII) and their subgroups, unless otherwise specified. Compounds of formula (I) (wherein R ^ A- forms a fluorenyl group R ^ CO-) can be prepared in the following manner: as shown in Reaction Scheme 1 with 4-amino-pyrazole substituted as appropriate A carboxylic acid of the formula R ^ CC ^ H or an activated derivative thereof reacts.

反應計劃1 (XII) 在反應計劃1中所示的合成途徑用的起始物是4-硝基-吡唑-3-羧酸（X)，彼可以商業上取得或使對應的4-未被取 代的吡唑羧基化合物硝化製成。 -108- 200524877 (104) 以胺H2N-Y-R3使4-硝基吡唑羧酸（X)或彼之反應衍生 物起反應，得4-硝基-醯胺（CI)。在羧酸（X)及胺之間的偶 合反應宜在常在製造肽鏈結中被使用的型式的試劑的存在 下被進行。該類試劑的貫例包括I ’ 3 - 一環己基碳化一亞 胺（DCC)(Sheehan et al.，J.Amer.Chem Soc. 1 9 5 5 ’ 77 ’ 1067)，1-乙基- 3-(3二甲胺基丙基）-碳化二亞胺（在本說 明書中被稱爲EDC或EDAC，但在此藝中也被稱爲DECI及 WSCDI)(Sheehan et al.5J.Org.Chem 1961，26，25 2 5 )，尿 鐘爲主的偶合劑，如〇 · (7 -氮雜苯並三唑· 1 -基）-N，N，N · ，N’-四甲基尿_六氟磷酸鹽（HA TU)及鱗爲主的偶合劑， 如1 -苯並-三唑氧基三-(吡咯烷並）鱗六氟磷酸鹽 (PyBOP)(Castro et al. ?Tetrahedron Letters，1 990，3 1， 205)。碳化二亞胺爲主的偶合劑與1-羥基-7-氮雜苯並三唑 (HOAt)綜合被有利地使用（L.A.Carpino，J. Amer.Chem. Soc.1 99 3，115，4 3 97)或 1-羥基苯並三唑（HOBt)(Konig et al·，Che m.Ber.103，708，2024-2034)。合宜的偶合試劑包 括：EDC(EDAC)及DCC連同HOAt或HOBt的綜合。 偶合反應一般在非水性的、對質子呈惰性的溶劑（如 乙腈、二噁烷、二甲亞碾、二氯甲烷、二甲替甲醯胺或N-甲基吡咯烷）中，或在水性溶劑（任意地連同一或多種的可 溶混合潛溶劑）中被進行。反應可以在下列條件被進行： 在室溫下或在合適地提高的溫度下，其中反應劑是反應性 較差的（例如在帶有電子撤回基團（如磺胺基團）的電子少 量的苯胺的場合）。反應可在無干擾性鹼，例如第三胺（如 -109- 200524877 (105) 三乙胺或N，N-二異丙基乙胺）的存在下被進行。 另外，羧酸的反應衍生物（例如酐或醯基氯）可被使用 。與反應衍生物（如酐）的反應一般利用下列方面被實施： 在室溫下在驗（如D比11定）的存在下攪拌胺及酐。 如式H2N-Y-R3之胺類可取得自商業來源或利用許多精 於此藝的人士熟悉的標準的合成法中的任何一個被製造： Advanced Organic Chemistry ’ by Jerry March ， 4th Edition ， John Wiley &amp; Sons ， 1 992 ， and OrganicReaction Scheme 1 (XII) The starting material for the synthetic pathway shown in Reaction Scheme 1 is 4-nitro-pyrazole-3-carboxylic acid (X), which can be obtained commercially or the corresponding Substituted pyrazole carboxyl compounds by nitration. -108- 200524877 (104) 4-nitropyrazolecarboxylic acid (X) or its reaction derivative is reacted with amine H2N-Y-R3 to obtain 4-nitro-amidamine (CI). The coupling reaction between the carboxylic acid (X) and the amine is preferably performed in the presence of a reagent of the type often used in the production of peptide chains. Examples of such reagents include I '3 -cyclohexylcarbodiimide (DCC) (Sheehan et al., J. Amer. Chem Soc. 1 9 5 5' 77 '1067), 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide (referred to as EDC or EDAC in this specification, but also referred to herein as DECI and WSCDI) (Sheehan et al. 5J. Org. Chem 1961 , 26, 25 2 5), urinary clock-based coupling agents, such as 0 · (7-azabenzotriazole · 1-yl) -N, N, N ·, N'-tetramethyluria_hexa Fluorophosphate (HA TU) and scale-based coupling agents, such as 1-benzo-triazoloxytri- (pyrrolidino) scale hexafluorophosphate (PyBOP) (Castro et al.? Tetrahedron Letters, 1 990, 3 1, 205). A carbodiimide-based coupling agent combined with 1-hydroxy-7-azabenzotriazole (HOAt) is advantageously used (LACarpino, J. Amer. Chem. Soc. 1 99 3, 115, 4 3 97) or 1-hydroxybenzotriazole (HOBt) (Konig et al., Che m. Ber. 103,708, 2024-2034). Suitable coupling reagents include: EDC (EDAC) and DCC combined with HOAt or HOBt. Coupling reactions are generally in non-aqueous, proton-inert solvents (such as acetonitrile, dioxane, dimethyl arylene, dichloromethane, dimethylformamide or N-methylpyrrolidine), or Solvents (arbitrarily connected with the same or more soluble mixed subsolvents) are performed. The reaction can be carried out under the following conditions: at room temperature or at an appropriately elevated temperature, in which the reactant is less reactive (for example, in the case of occasion). The reaction can be carried out in the presence of a non-interfering base such as a third amine such as -109- 200524877 (105) triethylamine or N, N-diisopropylethylamine. In addition, reactive derivatives of carboxylic acids (such as anhydride or fluorenyl chloride) can be used. The reaction with a reactive derivative (such as an anhydride) is generally carried out using the following aspects: Agitate the amine and anhydride at room temperature in the presence of a test (such as D than 11). Amines of the formula H2N-Y-R3 can be obtained from commercial sources or manufactured using any of the standard synthetic methods familiar to many skilled in the art: Advanced Organic Chemistry 'by Jerry March, 4th Edition, John Wiley &amp; Sons, 1 992, and Organic

Syntheses ， V olumnes 1-8 ’ John Wiley ， edited bySyntheses, V olumnes 1-8 ’John Wiley, edited by

Jeremiah P.Freeman(ISBN : 0-47 1 -3 1 1 92-8)，1 995，以及 在下文的實驗章節中被描述的方法。 .硝基-Π比唑醯胺（XI)被還原成對應的如式（XII)之4-胺 基化合物。反應可藉由標準方法（如觸媒氫化）在室溫下在 鈀/活性碳的存在下在極性的溶劑（如乙醇或二甲替甲醯胺） 中被進行。另外，還原作用可使用還原劑（如氯化亞鍚之 乙醇溶液）在加熱（例如使溶劑回流的溫度）下被進行。 接著以如式R^CC^H之羧酸或彼之反應衍生物使4-胺 基-吡唑化合物（ΧΠ)起反應，其中使用在上文中製造醯胺 (XI)的方法及條件，得如式（I)之化合物。 如式R^CC^H之羧酸可取得自商業來源或依照精於此 藝的人士熟悉的被合成，見Advanced Organic Chemistry and Organic Syntheses，詳情請見上文。 如式（I)之化合物（其中X是一個基團R^A-NR4，A是一 個鍵可以許多的方法由如式（XII)之4-胺基化合物製成。與 -110- 200524877 (106) 被適當地取代的醛或酮的還原胺化作用可以在各式各樣的 還原劑存在下被進行（見Advanced Organic Chemistry，by Jerry March，4th Edition，John Wiley &amp; Sons，1992， PP 8 9 8 - 9 00 )。例如，還原胺化作用可以在或接近周遭溫度 下在對質子呈惰性的溶劑（如二氯甲烷）中在三醋酸硼氫化 鈉的存在下被進行。 化合物（其中X是基團R^A-NR4，其中A是一個鍵）也 可以下列方式被製造：在親核取代反應中以如式R]-L之化 合物（其中L是一個離去基，如鹵素）使4_胺基吡唑化合物 (XII)起反應。 另外，如式（I)之化合物可以下列方式被製造：以如 式R3-Y-NH2之化合物使如式（XIII)之化合物起反應。反應 可以使用上文中的醯胺偶合條件被進行。Jeremiah P. Freeman (ISBN: 0-47 1 -3 1 1 92-8), 1 995, and the method described in the experimental section below. Nitro-II-pyrazolamine (XI) is reduced to the corresponding 4-amine compound of formula (XII). The reaction can be carried out by standard methods (such as catalyst hydrogenation) at room temperature in the presence of palladium / activated carbon in a polar solvent (such as ethanol or dimethylformamide). Alternatively, the reduction can be carried out using a reducing agent (such as an ethanol solution of thallium chloride) under heating (for example, a temperature at which the solvent is refluxed). The 4-amino-pyrazole compound (XΠ) is then reacted with a carboxylic acid of the formula R ^ CC ^ H or a reactive derivative thereof, in which the method and conditions for producing sulfonamide (XI) above are used to obtain Such as compounds of formula (I). For example, carboxylic acids of the formula R ^ CC ^ H can be obtained from commercial sources or synthesized in accordance with those familiar with the art, see Advanced Organic Chemistry and Organic Syntheses, see above for details. Compounds of formula (I) (where X is a group R ^ A-NR4 and A is a bond can be made from a 4-amino compound such as formula (XII) in many ways. And -110- 200524877 (106 Reductive amination of appropriately substituted aldehydes or ketones can be performed in the presence of a wide variety of reducing agents (see Advanced Organic Chemistry, by Jerry March, 4th Edition, John Wiley &amp; Sons, 1992, PP 8 9 8-9 00). For example, reductive amination can be performed at or near ambient temperature in a solvent that is inert to protons, such as dichloromethane, in the presence of sodium triacetoxyborohydride. Compounds (where X Is a group R ^ A-NR4, where A is a bond) can also be produced in the following manner: In a nucleophilic substitution reaction, a compound of formula R] -L (where L is a leaving group such as halogen) is used 4-Aminopyrazole compound (XII) reacts. In addition, a compound such as formula (I) can be produced by reacting a compound such as formula (XIII) with a compound such as R3-Y-NH2. Reaction It can be performed using the amidine coupling conditions described above.

(XIII) 如式（I)之化合物（其中八是NH(C = 0)可以使用合成脲的 標準方法被製造。例如，這類化合物可利用下列方式被製 造：在極性溶劑（如DMF)中以被適當取代的異氰酸苯酯使 如式（XII)之胺基吡唑化合物起反應。反應一般在室溫下 被進行。 如式（I)之化合物（其中A是〇(〇0))可以使用下列的合 &gt;111 - 200524877 (107) 成胺基甲酸酯的標準方法：在精於此藝的人士熟悉的條件 下，以如式R^qOhCl的氯甲酸酯衍生物使如式（XII)之胺 基吡唑化合物起反應。 如式（I)之化合物（其中A是S02)可以製造磺胺的標準 方法由如式（ΧΠ)之胺基化合物製成。例如，如式（XII)之 化合物可以被如式I^SC^Cl之磺醯氯或如式（11402)20之酐 反應。反應一般在與干擾性鹼（如第三胺（例如三乙胺）或 吡啶或二異丙基乙胺（Hunig氏鹼））的存在下在對質子呈惰 性的溶劑（如乙腈或被氯化的烴（如二氯甲烷））中被進行。 另外，在鹼是液體的場合中，如以吡啶的場合中，鹼本身 可被當成反應的溶劑使用。 化合物（其中X是一個5或6員的環，彼含有一個與吡唑 基團連接的碳原子環原子）可以在反應計劃2中所陳述的反 應順序被製造。 如在反應計劃2中所示，以丙二腈使醛（XIV)(其中X是 一個C-被連接的芳基或雜芳基，如苯基）縮合，得炔（χνΐ) 。反應一般在加熱下在鹼（如哌啶）存在下在極性溶劑（如 乙醇）中被進行。接著炔（XVI)在烷基鋰（如丁基鋰）存在下 被三甲基甲矽烷基重氮甲烷反應，得5 -三甲基甲矽烷基吡 唑-3-腈（XVII)。反應在降溫（-78 °C )的保護氣氛（氮氣）下在 無水的對質子呈惰性的溶劑（如THF)中被進行。 以鹼金屬氫氧化物（如氫氧化鉀）使腈（XVII)水解，得 酸（XIX)及/或醯胺（XVII)。在酸及醯胺的混合物被製造的 場合中，該混合物可以依照標準方法（如層離）被分開。接 -112- 200524877 (108) 著在上文中所述的類型的典型醯胺偶合條件下使酸（XIX) 與如式r3-y-nh2之胺偶合，得如式（I)之化合物。 人 CN + 〈 X CN —- \_/ CN CN (XIV) (XV) (XVI)(XIII) Compounds of formula (I) (where eight is NH (C = 0) can be manufactured using standard methods for the synthesis of urea. For example, such compounds can be manufactured using: in a polar solvent such as DMF) An aminopyrazole compound of formula (XII) is reacted with a suitably substituted phenyl isocyanate. The reaction is generally carried out at room temperature. A compound of formula (I) (wherein A is 0 (00)) ) The following standard method of forming a carbamate can be used: 111-200524877 (107): Under conditions familiar to those skilled in the art, using a chloroformate derivative of the formula R ^ qOhCl Aminopyrazole compounds such as formula (XII) react. Standard compounds such as formula (I) (where A is S02) can be made from amine compounds such as formula (XΠ). For example, if The compound of (XII) can be reacted with sulfohydrazine such as formula I ^ SC ^ Cl or an anhydride such as formula (11402) 20. The reaction is generally performed with an interfering base such as a third amine (such as triethylamine) or pyridine or Diisopropylethylamine (Hunig's base)) in a solvent that is inert to protons (such as acetonitrile or chlorinated (Such as dichloromethane)). In addition, where the base is liquid, such as pyridine, the base itself can be used as a solvent for the reaction. Compounds (where X is a 5 or 6 membered ring , Which contains a carbon atom ring atom attached to a pyrazole group) can be manufactured in the reaction sequence stated in Reaction Scheme 2. As shown in Reaction Scheme 2, the aldehyde (XIV) (wherein X is a C-linked aryl or heteroaryl group, such as phenyl, which is condensed to give an alkyne (χνΐ). The reaction is generally carried out in a polar solvent (such as ethanol) under heating in the presence of a base (such as piperidine). Then, the alkyne (XVI) is reacted with trimethylsilyldiazomethane in the presence of an alkyl lithium (such as butyl lithium) to obtain 5-trimethylsilylpyrazole-3-carbonitrile (XVII). The reaction is carried out in a protective atmosphere (nitrogen) at a reduced temperature (-78 ° C) in an anhydrous proton-inert solvent (such as THF). The nitrile (XVII) is made with an alkali metal hydroxide (such as potassium hydroxide). Hydrolysis to obtain acid (XIX) and / or amidine (XVII). In the field where the mixture of acid and amidine is manufactured In this case, the mixture can be separated according to standard methods such as delamination. Then -112- 200524877 (108) The acid (XIX) is combined with the formula r3-y under typical amidine coupling conditions of the type described above. -nh2 amine coupling to obtain compounds of formula (I). Human CN + <X CN —- \ _ / CN CN (XIV) (XV) (XVI)

Me3Si一CHN2 BuLiMe3Si-CHN2 BuLi

XX

conh2 N (XVIII)conh2 N (XVIII)

XX

P〇2H N R3-Y-NH? --(I) (XIX) 反應計劃2 另外，如式（I)之化合物（其中X是一個c-被連接的芳 基或雜芳基（如苯基））可由如式（XX)之化合物製成： -113- 200524877 (109) 〇 r1VvVy、r3P〇2H N R3-Y-NH?-(I) (XIX) Reaction Scheme 2 In addition, compounds of formula (I) (where X is a c-linked aryl or heteroaryl (such as phenyl )) Can be made from compounds of formula (XX): -113- 200524877 (109) 〇r1VvVy, r3

N-N M H (XX) 其中'' Hal〃是鹵素，如氯、溴或碘，借助於Suzuki偶合 反應利用合適的芳基或雜芳基硼酸鹽。反應可以在鈀觸媒 (如二（三-第三丁基膦）鈀）及鹼（例如碳酸鹽，如碳酸鉀）的 存在下在典型的Suzuki偶合條件下被進行。反應可以在水 性溶劑系統（例如乙醇）中被進行，混合物一般被加熱至 100°c以上。 如式（XX)之化合物可以借助於下列方式由如式（XII) 之胺基-D比口坐化合物製成 Advanced Organic Chemistry，4th edition，by，Jerry March，John Wiley &amp; Sons，1 992， page723 )，其中胺基被亞硝酸反應轉變成重氮基團，接著 的鹵化亞銅（如CuCl或Cul)起反應。 一旦製成，使用此藝中眾所周知的標準化學步驟將一 種如式（I)之化合物轉變成另一種如式（I)之化合物。官能 基互變的實例見：Fiesersf Reagents for Organic Synthesis ，Volumes 1-17 ， John Wiley ， edited by MaryN-N M H (XX) where `` Hal '' is a halogen such as chlorine, bromine or iodine, using a suitable aryl or heteroarylborate by means of a Suzuki coupling reaction. The reaction can be carried out in the presence of a palladium catalyst (such as di (tri-third-butylphosphine) palladium) and a base (such as a carbonate such as potassium carbonate) under typical Suzuki coupling conditions. The reaction can be carried out in an aqueous solvent system (such as ethanol), and the mixture is generally heated above 100 ° C. Compounds of formula (XX) can be made from amine-D specific compounds such as formula (XII) by the following methods: Advanced Organic Chemistry, 4th edition, by, Jerry March, John Wiley &amp; Sons, 1 992, page723), in which the amine group is converted into a diazo group by the reaction of nitrous acid, and then a cuprous halide (such as CuCl or Cul) reacts. Once prepared, a compound of formula (I) is converted into another compound of formula (I) using standard chemical procedures well known in the art. For examples of functional group interconversion, see: Fiesersf Reagents for Organic Synthesis, Volumes 1-17, John Wiley, edited by Mary

Fieser(ISBN : 0-471-58283-2)，and Organic Syntheses，Fieser (ISBN: 0-471-58283-2), and Organic Syntheses,

Volumes 1-8 ， John Wiley ， edited by Jeremiah P.Freeman(ISBN: 0-47 卜 31192-8)，1 995。 在上文的反應計劃中所示的合成途徑用的起始物，例 如如式（X)之吡唑，可以取得自商業來源或藉由精於此藝 的人士熟悉的方法被製造。他們可以使用已知的方法被製 -114- 200524877 (110) 造，例如由酮類，在下列文獻中所描述的方法： EP3 0 8 3 2 0(Merck)，H e 1 v · C h i m . A c t a. 1 9 5 6，39，9 86-99 1 及 Helv.Chim.Acta.1958，41，306-309。另外，他們可以 i辱 自：利用精於此藝的人士熟悉的標準方法把商業上可取得 的吡唑（例如含有鹵素、硝基、酯或醯胺官能基）轉變成含 有所需的官能基的吡唑。例如，在3 -羧基-4-硝基吡唑中 ，硝基被標準方法還原成胺。4-硝基-吡唑-3-羧酸（XII)可 以取得自商業來源或利用下列方式被製造：使對應的4-未 被取代的吡唑羧化合物硝化，含有一個鹵素的吡唑被用於 偶合反應中（利用錫或鈀化學）。 保護基 在許多的上述的反應中，保護一或多個基團防止反應 發生在分子上的不希望的位置上。保護基的實例及把官能 基保護及去保護的方法可在下面被找到：Protective Groups in Organic S y n t h e s i s ( T . G r e e n and P.Wuts ； 3rd Edition; John Wiley and Sons，1999)。 羥基可被保護成：醚（-OR)或酯（-0C( = 0)R)，如第三 丁醚，四氫吡喃基（THP)醚；苄基醚、二苯甲基醚、或三 苯甲基醚；三甲基甲矽烷基醚或第三丁基二甲基甲矽烷基 醚；或乙醯酯（-0C( = 0)CH3，-OAc)。 酉签基或酮基可分別被保護成縮醒（R-CH(0R)2或縮酮 (R2COR)2)其中羰基（&gt;c = o)被第一醇反應轉變成二醚 (&gt;C(OR)2)。在酸存在下使用大量過量的水使醛基或酮基 -115- 200524877 (111) 水解再生。 胺基可被保護成：醯胺（-NRCO-R)或尿烷（-NRCO-OR) ’如甲基醯胺（-NHCO-CH3);苄氧基醯胺（-&gt;^&lt;：0-〇CH2C6H5，-NH-CbZ 或 NH-Z);第三丁氧基醯胺（-&gt;^(：0-〇C(CH3)3，-NH-Boc); 2-聯苯基-2-丙氧基醯胺（-NHCO — 〇C(CH3)2C6H4C6H5，-NH-Bpoc)，9-芴基甲氧基醯胺（-1^-Fmoc)，6-硝基二甲氧苄基醯胺（-NH-Vvoc)，2-三甲基甲 矽烷基乙氧基醯胺（-NH-Teoc)，2，2，2-三氯乙氧基醯胺 (-NH-Troc)，條丙氧基醯胺（-NH-Alloc)，或2-(苯磺醯）乙 氰基醯胺（-NH-Psec)。 在上文的反應計劃1中，當在胺H2N-Y-R3中的R3基團 含有一個第二胺基團，如環狀的胺基例如哌啶基或吡咯烷 基時，該第二胺基可被上文中所定義的保護基保護，一個 合宜的基團是第三丁氧羰基（Bo c)基團。在第二胺基不需 要接下來的修飾的場合中，保護基可以透過反應順序被進 行得到如式（I)之化合物的N-被保護的形式，接著以標準 方法（例如以酸處理）去保護，得如式（I)之化合物。 胺（如環狀的胺及雜環的N-H基團）的其他的保護基包 括：甲苯磺醯（tosly)、甲烷磺醯（mesyl)、苄基，如對甲氧 基苄基（PMB)、四氫吡喃基（THP)。 羧酸基團可被保護成如下的基團：烷基酯（例如甲 酯；第三丁酯）；（^·7鹵烷基酯（例如C^7三鹵烷基酯）；三 Ci-7院基甲砂院基-Ci-7院基醋；或Cs_2G芳基- Ci.7院基酯（ 例如苄基酯；硝基苄基酯）；或醯胺，例如甲醯胺。硫赶 -116- 200524877 (112) 基團可被保護成硫醚（-SR)，例如：苄基硫醚；乙醯胺基 甲醚（-s，ch2nhc( = o)ch3)。 單離及提純本發明之化合物 本發明之化合物可以依照精於此藝的人士熟悉的標準 方法被單離及提純。特別用於提純本發明之化合物的一種 方法是製備性液相層離，彼使用質譜偵測從層離管柱中流 出的經提純的化合物。 製備性LC-MS是一種用於提純小型有機分子（如在本 說明書中所描述的化合物）的標準有效的方法。供液相層 離（LC)及質譜（MS)用的方法可以被改變來提供粗製的物質 較佳的分離（藉由MS改善樣本的偵測）。製備性梯度LC法 的最適化會包括改變管柱，揮發性洗提液及調節劑及梯度 。使製備性LC-MS法最適化，接著使用他們提純化合物的 方法是此藝中眾所周知的。這類方法在下列文獻中被描述 :Rosentreter U，Huber U. ； Optimal fraction collecting in preparataive LC/MS ; J Comb Chem. ; 2004 ; 6(2)， 1 5 9-64 and Leister W，Strauss K，Wisnoski D，Zhao Z， Lindsley C.，Development of a custom high-throughput preparative liquid chromatography /mass spectrometer platform for the preoparati ve purification and analytical analysis of compound libraries ; J Comb Chem. ; 2003 ； 5 (3 )3 22-9。一個經由製備性LC/MS提純化合物的系統的實 例在下文的實施例章節中（ 質量指示的提純LC/MS系統 -117- 200524877 (113) )被描述。然而，以下將被明白：所描述的另外的系統 及方法可以被使用。尤其，以正常相製備性LC爲主的方 法可被使用來替代逆相式製備性L C。大多數的製備性L C -M S系統使用逆相式L c及揮發性酸性調節劑，因爲這個系 統對提純子型分子非常有效並且彼之洗提液與正離子電噴 射質譜相容。使用如在下文中被描述的分析方法中被槪述 的其他的層離溶液（例如正常相L C )，另外經緩衝的移動相 、鹼性調節劑等可以被用來提純化合物。 藥學組成物 儘管活性化合物可以被單獨投藥，然而藥學組成物的 形式（例如調和物）卻是較合宜的，藥學組成物包含：至少 一種的本發明之活性化合物連同一或多種藥學上可接受的 載體，佐藥、賦形藥、稀釋劑、塡料、緩衝劑、安定劑、 防腐劑、潤滑劑或精於此藝人士熟悉的其他的物質及任意 的其他的治療藥劑或預防藥劑。 所以，本發明另外提供上述的藥學組成物，以及製造 該藥學組成物的方法，該方法包含：把至少一種的如上述 的活性化合物連同一或多種藥學上可接受的載體、賦形藥 、稀釋劑、緩衝劑、佐藥、安定劑或其他的物質（如本說 明書中所述的）。 ''藥學上可接受的〃係關於化合物、物質、組成物及 /或劑量形式，彼在正確的醫學判斷範圍內適合用於與患 者（例如人）的組織接觸的場合，彼沒有過量的毒性、刺激 -118- 200524877 (114) 、過敏反應或其他的問題或倂發症（與合宜的利益/風險比 一致）。各載體、賦形藥等在與調和物中的其他的拚料相 容的方面也必須是、、可接受的〃。 所以’本發明另一方面提供如式（0)之化合物及彼之 如式（I。）、（I)、（la)、（lb)、（II)、（III)、（IV)、（IVa)、 (Va)、（Vb)、（Via)、（VIb)、（VII)或（VIII)之亞群及彼之 如本說明書中的藥學組成物中所定義的亞群。 藥學組成物可以是適合下列的任何形式··口服、腸胃 外投服、局部投藥、鼻內投藥、眼投藥、耳投藥、直腸投 藥、陰道內投藥、經皮投藥。在企圖使組成物適合腸胃外 投服的場合中，組成物可以被調和以供靜脈內投藥、肌內 投藥、腹膜腔內投藥、皮下投藥用的或以注射、輸注或其 他的輸送方式被直接送入器官或組織中。 在本發明的一個合宜的體現中，藥學組成物是適合以 注射或輸注作靜脈內投藥的形式。 在本發明的另一個合宜的體現中，藥學組成物是適合 皮下（S.C)投藥的形式。 適合口服的藥學劑量形式包括：藥錠、膠囊、小九粒 、藥九、藥片、糖漿劑、溶液、粉末、顆粒、酏劑及懸浮 液、舌下藥錠、糯米紙囊劑或貼片及頰側貼片。 含有如式（I)之化合物的藥學組成物可以依照已知的 方法被調製，見 Pharmaceutical Sciences’ Mack Publishing Company 5 Easton，PA，USA0 所以，藥錠組成物可以含有單位劑量的活性化合物連 -119- 200524877 (115) 同惰性稀釋劑或載體（如糖或糖醇，例如乳糖、蔗糖、山 梨糖醚或甘露糖醇）；及/或非糖衍化的稀釋劑，如碳酸鈉 、磷酸鈣、碳酸鈣，或纖維素或彼之衍生物（如甲基纖維 素 '乙基纖維素、羥丙基甲基纖維素）及激粉（如玉米粉） 。藥錠也可含有如下的標準拚料：黏合成粒劑（如聚乙烯 吡咯烷酮）、崩解劑（例如可膨脹的交聯的聚合物，如交聯 的羧甲基纖維素）、潤滑劑（例如硬脂酸鹽）、防腐劑（例如 巴拉發（paraben))、抗氧化劑（例如BHT)、緩衝劑（例如磷 酸鹽或檸檬酸鹽緩衝劑）及發泡劑（如檸檬酸鹽/碳酸氫鹽混 合物）。這類賦形藥是眾所周知的，不需在說明書中被詳 加討論。 膠囊調和物可由硬質明膠或軟質明膠製成，彼可以含 有固體、半固體或液體形式的活性組成份。明膠膠囊可以 由動物性明膠彼之人工或合成的或植物衍化的同等物製成 〇 固體劑量形式（例如：藥錠、膠囊等）可以是被覆的或 未被覆的形式，但典型有一層被覆，例如保護膜被覆（例 如蠟或淸漆）或控制釋出式被覆。被覆（例如 聚合物）被設計成可在胃腸道中的所需的位置釋出活性化 合物。所以，被覆可被選擇以便在胃腸道中特定的pH條 件下降解’藉以在胃或在迴腸或十二指腸中選擇性地釋出 活性化合物。 代替被覆’或除了被覆之外，藥劑可以存在於固體基 質中，該固體基質包含一種控制釋出式藥劑，例如一種延 200524877 (116) 後釋出式藥劑，彼可被改變來適合在胃腸道中不同酸度或 鹼度的條件下選擇性地釋出化合物。另外，基質物質或阻 滯釋出性被覆可以採用腐蝕性聚合物（例如馬來酐聚合物） 的形式，彼在通過胃腸道時被實質持續地侵蝕（如劑量形 式）。另外’活性化合物可以輸送系統的形式被調製，該 輸送系統提供釋出化合物的滲透控制。滲透釋出式及其他 的延後釋出式或持續釋出式調和物可依照精於此藝的人士 熟悉的方法被製造。 局部投藥用組成物包括：軟膏、乳膏、噴劑、貼片、 凝膠、液體滴劑、插入物（例如眼球內插入物）。這類組成 物可以依照已知的方法調製。 腸胃外投藥用組成物典型上以無菌的水性或油性溶液 或精細懸浮液的形式被呈現，或以臨時以供注射用的無菌 的水處理的精細的無菌粉末的形式被提供。 供直腸投藥或陰道內投藥用的調和物的實例包括：陰 道栓劑及栓劑’彼可由含有活性化合物的可模製的或蠟質 的材料製成。 供吸入投藥用的組成物可採用可吸入式粉末組成物或 液體噴劑或粉體噴劑的形式，彼可以使用粉體吸入器或氣 溶膠分配器的標準形式被投藥。這類器具是眾所周知的。 就吸入投藥而言，粉體調和物典型包含活性化合物及一種 惰性固體粉體稀釋劑（如乳糖）。 本發明之化合物一般會以劑量形式被呈現，彼典型會 含有足夠的化合物提供所需的生物活性水平。例如，口服 -121 - 200524877 (117) 用調和物可含有0.1 mg至2g的活性拼料，較常含有l〇mg至 1 g ,例如 50mg至 500mg。 活性化合物會以足以達到所需的治療效果的份量被投 給有需要的患者（例如人或動物）。 處理的方法 經本發明者硏究得知··如式（0)之化合物及彼之如式 (I0)、（I)、（la)、（lb)、（II)、（III)、（IV)、（IVa)、（Va)、 (Vb)、（Via)、（VIb)、（VII)或（VIII)之亞群及彼之如本說 明書中所定義的亞群可用於預防或治療由環素依賴型激酶 仲介的疾病狀態或症狀的範圍中。這類疾病狀態及症狀的 實例在上文中被陳述。 化合物一般被投給需要這類投服的患者，例如人或動 物，較佳人。 化合物典型以治療或預防上有用的及一般是無毒的份 量被投藥。然而，在特定的情況中（例如在威脅生命的疾 病中），投服如式（I)之化合物的益處勝過任何的毒性效果 或副效果的缺點，在某些場合中考慮投服會帶來些許毒性 的劑量的化合物也是可以的。 化合物可長期被投藥維持有益的治療效果或僅短期被 投藥。另外，化合物可以脈衝方式或連續方式被投藥。 儘管較高或較低的劑量可被投藥（視需要而定），然而 化合物典型的每日劑量可以是100微微克至100毫克/公斤 體重，較典型是5毫微克至2 5毫克/公斤體重，較常見是1 0 -122- 200524877 (118) 毫微克至15毫克（例如1〇毫微克至10毫克）/公斤體重。最後 ，被投藥的化合物的份量及所使用的組成物的類型會與被 處理的疾病或生理症狀的特性一致，並且是隨醫師的意。 如式（I)之化合物可以單一治療藥劑的形式被投藥或 彼可以與一或多種其他的供處理特殊的疾病狀態（例如腫 瘤，如前文中所定義的癌）用的化合物綜合治療的形式被 投藥。其他可以與如式（I)之化合物被投藥（同時或不同時） 的治療藥劑的實例包括（但不限於）：局部異構轉化酶抑制 劑類、烷化劑類、抗代謝物類、DNA黏合劑類及微管抑制 劑類（微管蛋白標的劑）、如順鉑、環磷酸醯胺、阿黴素、 衣利諾康（irinotecan)、夫達拉賓（fludarabine)、5FU、他 杉烷（tax a ne)、絲裂黴素C或放射性治療。另外，如式（I) 之化合物可以與單細胞系抗體或信號轉導作用抑制劑綜合 治療的形式被投藥。就與其他的綜合治療的CDK抑制劑而 言，二或多種處理可依照個別變化的劑量時間表及經由不 同的途徑被給予。 在如式（I)之化合物與一、二、三、四或多種的其他 的治療藥劑（較佳一或二種，較佳一種）綜合治療的形式被 投藥的場合中，化合物可以同時或先後被投藥。當先後被 投藥時，化合物可以緊密的間隔（例如5-10分鐘）或以較長 的間隔（例如1、2、3、4或多個小時，或視需要而定以更 長的間隔）被投藥，精確的劑量攝生法與治療藥劑的特性 一致。 本發明之化合物也可連同如下的非化學治療的處理被 -123- 200524877 (119) 投藥：放射療法、光動力療法、基團療法、外科手術及控 制飮食。 就與另一種化學治療藥劑綜合治療的使用而言，如 (I)之化合物及一、二、三、四或多種的其他的治療藥劑 可以一種含有二、三、四或多種治療藥劑的劑量形式被調 製在一起。另外，個別的治療藥劑可分開被調製及以套件 的形式被一起調製（任意地利用彼之使用指示）。 精於此藝的人士透過彼之常識會知道所使用的劑量攝 生法及綜合療法。 診斷的方法 在投服如式（I)之化合物之前，患者被篩選以確定是 否患者正或可能正罹患的疾病或症狀是可以抗環素依賴型 激酶活性的化合物處理的疾病或症狀。 舉例來說，從患者身上採取的生物樣本被分析以確定 是否患者正或可能正罹患的疾病或症狀（如癌）是特徵如下 的疾病或症狀：基因異常或異常的蛋白質表現，彼導致 CDK類的過度活潑或導致正常CDK活性通道的致敏作用。 這類異常（造成CDK2信號活化或致敏）的實例包括：環素E 的向上調節（Harwell RM，Mull BB，Porter DC， Keyomarsi K.，J Biol Chem.2004(Mar 26 ; 279(13) 12695-705)或p21或p27的喪失，或CDC4變異體的出現Volumes 1-8, John Wiley, edited by Jeremiah P. Freeman (ISBN: 0-47 Bu 31192-8), 1 995. The starting materials for the synthetic pathways shown in the above reaction schemes, such as pyrazoles of formula (X), can be obtained from commercial sources or made by methods familiar to those skilled in the art. They can be made using known methods, such as -114- 200524877 (110), for example from ketones, as described in the following literature: EP3 0 8 3 2 0 (Merck), He 1 v · C him. A ct a. 1 9 5 6, 39, 9 86-99 1 and Helv. Chim. Acta. 1958, 41, 306-309. In addition, they can use the standard methods familiar to those skilled in the art to convert commercially available pyrazoles (for example, containing halogen, nitro, ester, or amido functional groups) to contain the required functional groups Of pyrazole. For example, in 3-carboxy-4-nitropyrazole, the nitro group is reduced to an amine by standard methods. 4-Nitro-pyrazole-3-carboxylic acid (XII) can be obtained from commercial sources or manufactured by nitrating the corresponding 4-unsubstituted pyrazole carboxylic compound, and pyrazole containing a halogen is used In coupling reactions (using tin or palladium chemistry). Protecting Groups In many of the above reactions, one or more groups are protected from reactions occurring at undesirable locations on the molecule. Examples of protecting groups and methods for protecting and deprotecting functional groups can be found below: Protective Groups in Organic Synt s i s (T. Green and P. Wuts; 3rd Edition; John Wiley and Sons, 1999). Hydroxyl groups can be protected as: ether (-OR) or ester (-0C (= 0) R), such as tertiary butyl ether, tetrahydropyranyl (THP) ether; benzyl ether, benzhydryl ether, or Trityl ether; trimethylsilyl ether or third butyldimethylsilyl ether; or acetamyl ester (-0C (= 0) CH3, -OAc). The fluorenyl or keto group can be protected to awake (R-CH (0R) 2 or ketal (R2COR) 2), respectively, where the carbonyl group (&gt; c = o) is converted into the diether by the reaction of the first alcohol (&gt; C (OR) 2). Hydrolysis and regeneration of aldehyde or keto-115-200524877 (111) using a large excess of water in the presence of an acid. The amine group can be protected as: amine (-NRCO-R) or urethane (-NRCO-OR) 'such as methyl amine (-NHCO-CH3); benzyloxy amine (-&gt; ^ &lt;: 0-〇CH2C6H5, -NH-CbZ or NH-Z); tertiary butoxyfluorenamine (-&gt; ^ (: 0-〇C (CH3) 3, -NH-Boc); 2-biphenyl- 2-propoxyfluorenamine (-NHCO — OC (CH3) 2C6H4C6H5, -NH-Bpoc), 9-fluorenylmethoxyfluorenamine (-1 ^ -Fmoc), 6-nitrodimethoxybenzyl Ammonium (-NH-Vvoc), 2-trimethylsilylethoxyfluorenamine (-NH-Teoc), 2,2,2-trichloroethoxyfluorenamine (-NH-Troc), strip Propoxyfluorenamine (-NH-Alloc), or 2- (benzenesulfonium) ethanocyanamide (-NH-Psec). In Reaction Scheme 1 above, when in the amine H2N-Y-R3 When the R3 group contains a second amine group, such as a cyclic amine group such as piperidinyl or pyrrolidinyl group, the second amine group can be protected by the protecting group defined above. A suitable group is The third butoxycarbonyl (Bo c) group. Where the second amine group does not require subsequent modification, the protecting group can be carried out through the reaction sequence to obtain the N-protected form of the compound of formula (I) , Followed by the standard Deprotection (for example, by acid treatment) to obtain compounds of formula (I). Other protecting groups of amines (such as cyclic amines and heterocyclic NH groups) include: tosly, methanesulfonate Mesyl, benzyl, such as p-methoxybenzyl (PMB), tetrahydropyranyl (THP). The carboxylic acid group can be protected into the following groups: alkyl esters (such as methyl esters; Tributyl ester); (^ · 7 haloalkyl esters (such as C ^ 7 trihaloalkyl esters); three Ci-7 Yuan Jisha Yuan Ji-Ci-7 Yuan Ji vinegar; or Cs_2G aryl-Ci. 7 alkyl esters (such as benzyl esters; nitrobenzyl esters); or amidines, such as formamidine. Thiol -116- 200524877 (112) groups can be protected as thioethers (-SR), such as: Benzyl sulfide; acetamidomethyl ether (-s, ch2nhc (= o) ch3). Isolation and purification of the compounds of the present invention The compounds of the present invention can be isolated and purified according to standard methods familiar to those skilled in the art. Purification. One method that is particularly useful for purifying compounds of the present invention is preparative liquid phase separation, which uses mass spectrometry to detect purified compounds that flow out of a separation column. Preparative LC-MS is a Standard effective method for purification of small organic molecules (such as compounds described in this specification). Methods for liquid phase separation (LC) and mass spectrometry (MS) can be changed to provide better separation of crude material (Improve sample detection by MS.) Optimization of preparative gradient LC methods will include changes to the column, volatile eluent, modifier, and gradient. Methods for optimizing preparative LC-MS methods and then using them to purify compounds are well known in the art. Such methods are described in the following literatures: Rosentreter U, Huber U .; Optimal fraction collecting in preparataive LC / MS; J Comb Chem .; 2004; 6 (2), 1 5 9-64 and Leister W, Strauss K, Wisnoski D, Zhao Z, Lindsley C., Development of a custom high-throughput preparative liquid chromatography / mass spectrometer platform for the preoparati ve purification and analytical analysis of compound libraries; J Comb Chem.; 2003; 5 (3) 3 22- 9. An example of a system for the purification of compounds via preparative LC / MS is described in the Examples section below (LC / MS Purification System with Quality Indication -117- 200524877 (113)). However, it will be understood that the additional systems and methods described can be used. In particular, a method based on normal phase preparative LC can be used instead of reverse phase preparative LC. Most preparative LC-MS systems use reverse-phase LC and volatile acidity regulators because this system is very effective at purifying submolecules and its eluent is compatible with positive ion electrospray mass spectrometry. Other delamination solutions (e.g., normal phase LC), as described in the analytical method described below, and a buffered mobile phase, alkaline regulator, etc. can be used to purify the compound. Pharmaceutical composition Although the active compound can be administered alone, the form of the pharmaceutical composition (such as a blend) is more suitable. The pharmaceutical composition includes: at least one active compound of the present invention and one or more pharmaceutically acceptable Carriers, adjuvants, excipients, diluents, condiments, buffers, stabilizers, preservatives, lubricants or other substances familiar to those skilled in the art and any other therapeutic or preventive agents. Therefore, the present invention additionally provides the above-mentioned pharmaceutical composition, and a method for manufacturing the same, the method comprising: connecting at least one active compound as described above with the same or more pharmaceutically acceptable carriers, excipients, dilutions Agents, buffers, adjuvants, stabilizers, or other substances (as described in this specification). '' Pharmaceutically acceptable compounds are compounds, substances, compositions, and / or dosage forms that are suitable for use in contact with the tissues of patients (such as humans) within the scope of correct medical judgment, and that they do not have excessive toxicity , Irritation-118-200524877 (114), allergic reactions or other problems or eruption (in line with the appropriate benefit / risk ratio). Each carrier, excipient, etc. must also be acceptable in terms of compatibility with other ingredients in the blend. So 'another aspect of the present invention provides compounds of formula (0) and compounds of formula (I.), (I), (la), (lb), (II), (III), (IV), ( IVa), (Va), (Vb), (Via), (VIb), (VII) or (VIII) subgroups and subgroups as defined in the pharmaceutical composition in the present specification. The pharmaceutical composition may be in any form suitable for oral administration, parenteral administration, topical administration, intranasal administration, eye administration, ear administration, rectal administration, intravaginal administration, or transdermal administration. Where an attempt is made to make the composition suitable for parenteral administration, the composition can be blended for intravenous, intramuscular, intraperitoneal, subcutaneous or direct injection, infusion or other delivery methods Into organs or tissues. In a convenient embodiment of the invention, the pharmaceutical composition is in a form suitable for intravenous administration by injection or infusion. In another convenient embodiment of the invention, the pharmaceutical composition is in a form suitable for subcutaneous (S.C) administration. Suitable pharmaceutical dosage forms for oral administration include: tablets, capsules, small tablets, tablets, tablets, syrups, solutions, powders, granules, tinctures and suspensions, sublingual tablets, sticky rice capsules or patches and cheeks Side patch. Pharmaceutical compositions containing compounds of formula (I) can be prepared according to known methods, see Pharmaceutical Sciences' Mack Publishing Company 5 Easton, PA, USA. Therefore, the tablet composition can contain a unit dose of the active compound even -119 -200524877 (115) Same inert diluents or carriers (such as sugar or sugar alcohols, such as lactose, sucrose, sorbitol or mannitol); and / or non-sugar derived diluents, such as sodium carbonate, calcium phosphate, carbonic acid Calcium, or cellulose or its derivatives (such as methyl cellulose 'ethyl cellulose, hydroxypropyl methyl cellulose), and powder (such as corn flour). Tablets can also contain standard ingredients such as viscose granules (such as polyvinylpyrrolidone), disintegrants (such as expandable crosslinked polymers such as crosslinked carboxymethyl cellulose), and lubricants ( Such as stearates), preservatives (such as paraben), antioxidants (such as BHT), buffers (such as phosphate or citrate buffers), and foaming agents (such as citrate / carbonic acid) Hydrogen salt mixture). Such excipients are well known and need not be discussed in detail in the instructions. Capsule blends can be made of hard gelatin or soft gelatin, which can contain active ingredients in solid, semi-solid or liquid form. Gelatin capsules can be made from animal or synthetic or plant-derived equivalents. Solid dosage forms (eg, tablets, capsules, etc.) can be coated or uncoated, but typically have a coating. Examples are protective film coatings (such as wax or lacquer) or controlled release coatings. Covers (such as polymers) are designed to release the active compound at a desired location in the gastrointestinal tract. Therefore, the coating can be chosen to degrade under specific pH conditions in the gastrointestinal tract, thereby selectively releasing the active compound in the stomach or in the ileum or duodenum. Instead of or in addition to coating, the agent may be present in a solid matrix that contains a controlled release agent, such as a post-release drug that extends from 200524877 (116), which can be modified to fit in the gastrointestinal tract Compounds are selectively released under different acidity or alkalinity conditions. In addition, the matrix material or retarded release coating may take the form of a corrosive polymer (such as a maleic anhydride polymer) that is substantially continuously eroded (such as a dosage form) as it passes through the gastrointestinal tract. Alternatively, the &apos; active compound may be formulated in the form of a delivery system that provides osmotic control of the released compound. Osmotic release and other delayed release or continuous release blends can be manufactured according to methods familiar to those skilled in the art. Topical compositions include: ointments, creams, sprays, patches, gels, liquid drops, and inserts (eg, eyeball inserts). Such a composition can be prepared according to a known method. Parenteral pharmaceutical compositions are typically presented in the form of sterile aqueous or oily solutions or fine suspensions, or in the form of fine sterile powders temporarily provided by sterile water treatment for injection. Examples of blends for rectal or intravaginal administration include vaginal suppositories and suppositories', which may be made of a moldable or waxy material containing an active compound. The composition for administration by inhalation may be in the form of an inhalable powder composition or a liquid spray or powder spray, which may be administered in a standard form using a powder inhaler or an aerosol dispenser. Such appliances are well known. For inhaled administration, powder blends typically contain the active compound and an inert solid powder diluent (such as lactose). The compounds of the invention will generally be presented in dosage form, which will typically contain sufficient compounds to provide the desired level of biological activity. For example, oral -121-200524877 (117) blends may contain 0.1 mg to 2 g of active ingredient, more often 10 mg to 1 g, such as 50 mg to 500 mg. The active compound is administered to a patient in need (e.g., a human or animal) in a portion sufficient to achieve the desired therapeutic effect. The method of treatment has been learned by the inventors of the present invention. Compounds of formula (0) and their formulas (I0), (I), (la), (lb), (II), (III), (IV) ), (IVa), (Va), (Vb), (Via), (VIb), (VII) or (VIII) and other subgroups as defined in this specification can be used for prevention or treatment by Cyclin-dependent kinases mediate a range of disease states or symptoms. Examples of such disease states and symptoms are set out above. The compound is generally administered to a patient, such as a human or animal, preferably a human who requires such administration. The compounds are typically administered in therapeutically or prophylactically useful and generally non-toxic amounts. However, in certain situations (such as in life-threatening diseases), the benefits of administering a compound of formula (I) outweigh any disadvantages of toxic or side effects, and in some cases considering administering A slightly toxic dose of the compound is also possible. Compounds can be administered for long periods to maintain beneficial therapeutic effects or only for short periods. In addition, the compounds can be administered in a pulsed or continuous manner. Although higher or lower doses can be administered (depending on need), typical daily doses of the compounds can range from 100 picograms to 100 mg / kg body weight, more typically 5 nanograms to 25 mg / kg body weight The more common is 10-122- 200524877 (118) nanograms to 15 milligrams (for example, 10 nanograms to 10 milligrams) per kilogram of body weight. Finally, the amount of the compound to be administered and the type of composition used will be consistent with the characteristics of the disease or physiological condition being treated and will be at the discretion of the physician. Compounds of formula (I) may be administered in the form of a single therapeutic agent or they may be administered in combination with one or more other compounds for the treatment of a particular disease state (e.g., a tumor, as defined in the foregoing). Medication. Examples of other therapeutic agents that can be administered (simultaneously or simultaneously) with a compound of formula (I) include (but are not limited to): topical isomerizing invertase inhibitors, alkylating agents, antimetabolites, DNA Adhesives and microtubule inhibitors (tubulin-based agents), such as cisplatin, cyclophosphamide, doxorubicin, irinotecan, fludarabine, 5FU, and tamarix (Tax a ne), mitomycin C or radiotherapy. In addition, a compound such as formula (I) can be administered in the form of a combination therapy with a single cell line antibody or a signal transduction inhibitor. In the case of CDK inhibitors in combination with other treatments, two or more treatments can be administered according to individually varying dosage schedules and via different routes. Where the compound of formula (I) is administered in combination with one, two, three, four or more other therapeutic agents (preferably one or two, preferably one), the compounds may be administered simultaneously or sequentially Being administered. When administered successively, the compounds can be administered at closely spaced intervals (e.g. 5-10 minutes) or at longer intervals (e.g. 1, 2, 3, 4 or more hours, or longer intervals as needed) Dosing, precise dose inoculation is consistent with the characteristics of the therapeutic agent. The compounds of the present invention may also be administered with the following non-chemotherapy treatments: -123- 200524877 (119): radiation therapy, photodynamic therapy, group therapy, surgery, and control of food intake. For use in combination with another chemotherapeutic agent, the compound of (I) and one, two, three, four or more other therapeutic agents may be in a dosage form containing two, three, four or more therapeutic agents Were modulated together. In addition, individual therapeutic agents can be prepared separately and together in the form of a kit (arbitrarily using their instructions). Those who are skilled in this art will know through their common sense the dosimetry and comprehensive therapy used. Methods of diagnosis Prior to administration of a compound of formula (I), a patient is screened to determine whether the disease or condition that the patient is or may be suffering from is a disease or condition that can be treated with a compound that is resistant to cyclin-dependent kinase activity. For example, a biological sample taken from a patient is analyzed to determine whether the disease or symptom (such as cancer) that the patient is or may be suffering from is a disease or symptom characterized by a genetic abnormality or abnormal protein expression that leads to a CDK class Overactive or lead to sensitization of normal CDK active channels. Examples of such abnormalities (causing CDK2 signal activation or sensitization) include: Upregulation of cyclin E (Harwell RM, Mull BB, Porter DC, Keyomarsi K., J Biol Chem. 2004 (Mar 26; 279 (13) 12695 -705) or loss of p21 or p27, or the presence of a CDC4 variant

(Rajagopalan Η，Jallepalli PV，Rago C，Velculescu VE ，Kinzler KW，Vogelstein B，Lengauer C. ; Nature.2004 200524877 (120)(RajagopalanΗ, Jallepalli PV, Rago C, Velculescu VE, Kinzler KW, Vogelstein B, Lengauer C .; Nature. 2004 200524877 (120)

Mar 4 ; 42 8 (6 97 8 ) : 77- 8 ]。 '、向上調節&quot;包括被提高的表 現或過度表現，彼包括基因放大作用（即多重基因複製）及 被轉錄作用的效果提高的表現，及過度活潑及活化（包括 被突變作用活化）。所以，患者受到診斷性試驗以檢測如 下特徵的標記子：環素E的向上調節，或P2 1或p27的喪失 ，或CDC4變異體的存在。、診斷〃包括篩選。 ''標記子〃包括基因標記子，彼包括量測DNA組成物 來鑑定CDC4的突變。 ''標記子〃也包括特徵如下的標記 子：環素E的向上調節，彼包括前述蛋白質的酶活性、酶 水平、酶狀態（例如被磷酸化或未被磷酸化）及mRN A水平 〇 具有環素E的向上調節、P21或P2 7的喪失的腫瘤對 CDK抑制劑特別敏感。腫瘤在處理之前優先就環素E的向 訌調節，p21或P27的喪失等條件被篩選。所以，患者受到 診斷試驗以檢測如下特徵的標記子；環素E的向上調節， 或p2 1或P27的喪失。診斷性試驗典型在選自下列的生物樣 品上被實施：腫瘤活組織檢查樣本、血液樣本（離析及使 脫落腫瘤細胞營養豐富）糞便活組織檢查、痰、染色體分 析、胸膜液、腹膜液或尿液。Mar 4; 42 8 (6 97 8): 77- 8]. 'Up-regulation' includes improved expression or over-expression, which includes gene amplification (ie multiple gene replication) and performance of transcriptional effects, as well as over-activity and activation (including activation by mutation). Therefore, patients are subjected to diagnostic tests to detect markers that are characteristic of: upregulation of cyclin E, or loss of P21 or p27, or the presence of CDC4 variants. Diagnostics include screening. '' Markers '' include genetic markers, which include measuring DNA composition to identify mutations in CDC4. '' Labelers also include markers that are characterized by the upregulation of cyclin E, which includes the enzyme activity, enzyme level, enzyme state (eg, phosphorylated or unphosphorylated) of the aforementioned protein, and mRN A levels. Tumors with up-regulation of cyclin E and loss of P21 or P2 7 are particularly sensitive to CDK inhibitors. Prior to treatment, tumors were preferentially screened for cyclin E, and the loss of p21 or P27 was screened. Therefore, the patient is subjected to a diagnostic test to detect markers characterized by upregulation of cyclin E, or loss of p21 or P27. Diagnostic tests are typically performed on biological samples selected from: tumor biopsy samples, blood samples (isolating and enriching exfoliated tumor cells), stool biopsies, sputum, chromosome analysis, pleural fluid, peritoneal fluid, or urine liquid.

Rajagopalan 等人（Nature，2 004 Mar 4 ； 428 (6978)： 77-81)已發現在人結腸直腸癌及子宮的膜癌（Spruck et al·， ，Cancer Res.2002Aug 15; 62 ( 1 6)4 5 3 5 -9)中的 CDC4(也被 稱爲Fbw7或Archipelago)有突變存在。帶有在CDC4中突變 的個體的鑑定顯示患者特別適合以C D K抑制劑處理。腫瘤 200524877 (121) 在處理之前優先就c D C 4變異體的存在被篩選。篩選程序 典型會涵括··直接順序分析、寡核苷酸、微陣列分析或突 變體特異抗體。 鑑定及分析蛋白質的突變及向上調節的方法是精於此 藝的人士熟悉的。篩選的方法可包括（但不限於）標準的方 法’如逆轉錄酶聚合酶鏈反應（R τ - P C R)或就位雜交。 在被RT-PCR篩選的場合中，在腫瘤中的mRNA水平被 下列方式評估：建立mRNA的cDNA複製體，接著以PCR使 cDNA放大。 PCR放大的方法，引子的選擇及放大的條件是精於此 藝的人士熟悉的。核酸操作及PCR藉由下列文獻中所描述 的標準方法被進行：Ausubel，F.M.et al.，eds.Curent Protocols in Molecular Biology ^ 2004 &gt; John Wiley &amp; Sons Inc.，or Innis，M.A.et-al.，eds.PCR Protocols ·· a guede to methods and applications ， 1 990 ， AcademicRajagopalan et al. (Nature, 2 004 Mar 4; 428 (6978): 77-81) have been found in human colorectal and uterine membrane cancers (Spruck et al., Cancer Res. 2002 Aug 15; 62 (1 6) There is a mutation in CDC4 (also known as Fbw7 or Archipelago) in 4 5 3 5 -9). Identification of individuals with mutations in CDC4 shows that patients are particularly suitable for treatment with CDK inhibitors. Tumor 200524877 (121) was preferentially screened for the presence of c D C 4 variants before treatment. Screening procedures typically include direct sequence analysis, oligonucleotide, microarray analysis, or mutant-specific antibodies. Methods for identifying and analyzing protein mutations and up-regulation are familiar to those skilled in the art. Screening methods may include, but are not limited to, standard methods &apos; such as reverse transcriptase polymerase chain reaction (Rτ-PCR) or in situ hybridization. In the case of screening by RT-PCR, the mRNA level in a tumor is evaluated by establishing a cDNA replica of the mRNA and then amplifying the cDNA by PCR. The PCR amplification method, primer selection and amplification conditions are familiar to those skilled in the art. Nucleic acid manipulation and PCR are performed by standard methods described in the following literatures: Ausubel, FMet al., Eds. Curent Protocols in Molecular Biology ^ 2004 &gt; John Wiley &amp; Sons Inc., or Innis, MAet-al ., Eds.PCR Protocols ·· a guede to methods and applications, 1 990, Academic

Press，San Diego。包括核酸技術的反應及操作也在下面 被描述：Sambrook et al.，200 1，3rd Ed，Molecular Cloning : A Laboratory Manual ， Cold Spring Harbor Labpratory Press o 另外，供RT-PCR用的商業上可取得的套件（例如 Roche Molecular Biochemicals)可被使用，或如在美國專 利 4,6 6 6,828 ; 4,683,202 ； 4，8 0 1 ,5 3 1 ； 5,1 92,65 9 ； 5，2 72,0 57 ;5 ,8 8 2,8 64及6,2〗8，5 2 9中所陳述的方法論被倂入本說明書 中以供參考。 -126- 200524877 (122) 供評定mRN A表現用的就位雜交技術的一個實例是螢 光就位雜交（FISH)(見 Angerer，1987，Meth.Enzymol.， 152 ： 649) ° 一般，就位雜交包含如下的主要步驟：（1)使待分析 的組織固定；（2)使樣本預先雜交提高標的核酸的可取得 性及減少非特異性結合；（3)使核酸類的混合物雜交至在 生物結構中或在組織中的核酸上；（4)在雜交後淸洗去除 未在雜交中結合的核酸片段；及（5)檢測被雜交的核酸片 段。在這類應用中所使用的探針被下列典型地標記：放射 性同位素或螢光報告子。合宜的探針是足夠長的，例如， 從大約50，100或200個核苷酸至大約1000或多個核苷酸， 能夠在嚴苛的條件下與標的核酸特異雜交。供進行FISH用 的標準方法在下面文獻中被描述：Ausubel，F.M.et al.5eds.Current Protocols in Molecular Biology，2004，Press, San Diego. Reactions and manipulations including nucleic acid technology are also described below: Sambrook et al., 200 1, 3rd Ed, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Labpratory Press o In addition, commercially available RT-PCR Kits (eg, Roche Molecular Biochemicals) can be used, or as in US Patents 4,6 6 6,828; 4,683,202; 4,8 0 1, 5 3 1; 5,1 92,65 9; 5,2 72,0 57; The methodologies stated in 5,8 8 2,8 64 and 6,2〗 8,5 2 9 are incorporated in this specification for reference. -126- 200524877 (122) An example of an in situ hybridization technique for assessing the performance of mRN A is fluorescent in situ hybridization (FISH) (see Angerer, 1987, Meth. Enzymol., 152: 649) ° In general, in situ Hybridization includes the following main steps: (1) fixing the tissue to be analyzed; (2) pre-hybridizing the sample to improve the availability of the target nucleic acid and reducing non-specific binding; (3) hybridizing the nucleic acid mixture to the living organism Structure or on the nucleic acid in the tissue; (4) washing after the hybridization to remove the nucleic acid fragments that are not bound in the hybridization; and (5) detecting the hybridized nucleic acid fragments. Probes used in this type of application are typically labeled with the following: radioisotopes or fluorescent reporters. Convenient probes are sufficiently long, for example, from about 50, 100, or 200 nucleotides to about 1000 or more nucleotides to specifically hybridize to the target nucleic acid under severe conditions. Standard methods for performing FISH are described in the following literature: Ausubel, F.M.et al. 5eds. Current Protocols in Molecular Biology, 2004,

John Wiley &amp; Sons Inc and Fluorescence In Situ Hybridization ^ Technical Overview by John M.S.Bartlett in Molecular Diaagnosis of Cancer ， Methods and Protocols，2nd ed. ； ISBN ： 1-59259-760-2 ； March 2004 5 pps.077-088 i Series · Methods in Molecular Medicine 另外，由mRNA表現的蛋白質產物可藉由下列方式被 分析：腫瘤樣本的免疫組織化學，利用微滴定培養板的固 相免疫分析、西方印漬法、2-二維SDS-聚丙烯醯胺凝膠電 泳、E L I S A、在偵測特異蛋白質的技藝中眾所周知的其他 -127- 200524877 (123) 方法。偵測法包括使用部位特異抗體。精於此藝的人士會 明白所有的這類偵測下列眾所周知的方法可應用於本申請 案中：環素E的向上調節，或p21或p27的喪失、或CDC4變 異體。 所以這些方法全部可以被用來鑑定腫瘤，尤其是適合 以CD K抑制劑處理的腫瘤。有外膜細胞淋巴瘤（MCL)的患 者可以被選擇（使用診斷性試驗的）以CDK抑制劑處理。 MCL是一種非Hodgkin氏淋巴瘤的確切的臨床病理學實體 ，彼被下列特徵化：小型至中型的淋巴球的增殖作用（有 CD 5及CD20的共同表現）、一種攻擊性的及不治的臨床程 序、頻時（t(ll ; 14)(ql3 ; q32)移位。在外膜細胞淋巴瘤 (MCL)中被發現的環素D1 mRNA的過度表現是一個重要的 診斷上的標記子。Yatabe 等人（Blood，2000 Apr 1 : 95(7) :22 5 3 -6 1 )提議環素D1-正性應被包括在內，作爲供MCL 用的標準中的一個標準，供此不治之症用的創新的療法應 根據新的標準被探突。Jones等人（J Mol Diagn.2004 May ;6(2): 84-9)發展一個供環素D〗（CCN D1)表現用的確實 的時間、定量的、逆轉錄PCR分析以幫助外膜細胞淋巴瘤 (MCL)的診斷。Howe 等人（Clin Chem.2004 Jan; 50(1): 8 0-7)使用確實時間定量11丁-?〇11評估環素〇11111^八表現及 發現供正常化成CD19 mRNA的環素D1 mRNA用的定量RT-PCR可被用於血液、髓及組織中的MCL的診斷中。另外， 患有乳癌的患者可被選擇以CDK抑制劑處理（使用上述的 診斷性試驗）。癌細胞常過度表現環素E，以下業已被證實 -128- 200524877 (124) ••環素E在乳癌中被過度表現（HarwelI)等人，Cancei. Res ’ 2 0 0 0 ’ 6 0，4 8 1 - 4 8 9 )。所以乳癌尤其可被c D K抑制劑； 處理。 抗黴菌用途 在另一個方面，本發明提供使用如式（〇)、（ IG)、（ I)、 (la)、（lb)、（II)、（III)、（IV)、（IVa)、（Va)、（Vb)、（Via) 、（VIb)、（VII)或（VIII)之化合物及彼之亞群充當抗黴菌劑 〇 化合物可被用於動物醫學（例如處理哺乳動物，如人） ，或處理植物（例如農業及園藝），或充當泛用的抗黴菌劑 ，例如充當防腐劑及消毒劑。 在一個體現中，本發明提供一種如式（0)之化合物及 彼之如式（I0)、（I)、（la)、（lb)、（II)、（III)·、（IV)、（IVa) 、（Va)、（Vb)、（Via)、（VIb)、（VII)或（VIII)之亞群及彼 之如本說明書中所定義的亞群，彼用於預防或治療哺乳動 物（如人）體內的黴菌感染。 本發明也提供使用一種如式（〇)之化合物及彼之如式 (I0)、（I)、（la)、（lb)、（II)、（III)、（IV)、（IVa)、（Va)、 (Vb)、（Via)、（VIb)、（VII)或（VIII)之亞群及彼之如本說 明書中所定義的亞群於製造用於預防或治療哺乳動物（如 人）體內的黴菌感染的藥劑。 舉例來說，本發明之化合物可給正罹患或在被黴菌感 染的風險上，局部黴菌感感由如下的其他生物體引起：念 -129- 200524877 (125) 珠菌種、髮癖菌屬、小孢子癖菌屬、或表皮癬菌屬，或在 由白色念珠菌（例如鵝口瘡及陰道念珠菌病）引起的黏膜感 染中的人類患者投服。本發明之化合物也可以被投藥來處 理或預防由白色念珠菌屬、新生隱球菌屬、黃麯菌屬、煙 黴菌屬、球黴菌屬、副隱球菌屬、組織胞漿菌屬或芽生菌 屬引起的全身性黴菌感染。 在另一個方面，本發明提供一種供農業（包括園藝）上 使用的抗黴菌組成物，該組成物包含一種如式（1%之化合 物及彼之如前文中所定義如式⑴、（la)、（lb)、（II)、（III) 、（IV)、（V)、（VI)及（VII)之亞群連同農業上可接受的稀 釋劑或載體。 本發明另外提供一種處理有黴菌感染的動物（包括哺 乳動物，如人）、植物或種子的方法，該方法包含以有效 份量的如式（1%之化合物及彼之如前文所定義的如式（I)、 (la)、（lb)、（II)、（III)、（IV)、（V)、（VI)及（VII)之亞群處 理前述的動物，植物或種子、或前述的植物或種子的基因 位。 本發明也提供一種處理植物或種子內的黴菌感染的方 法，該方法包含以抗黴菌有效份量的如前文中所定義的抗 黴菌組成物處理植物或種子。 差示篩選分析可被用來選擇有供非ACDK酶用的專一 性的本發明之化合物。對真核病原的CDK酶發生專一性作 用的化合物可被當成抗黴菌劑或抗寄生菌劑使用。念珠菌 CDK激酶（CKSI)的抑制劑可被用於處理念珠菌病。抗黴菌 200524877 (126) 劑可被用來抗如前文中所定義的類型的感染，或在如下的 患者身上常發生的機會性感染：衰弱的及免疫抑制的患者 (如有白血病及淋巴瘤的患者）、接受免疫抑制治療的人、 有素質性症狀（如糖尿病或AIDS)的患者，以及非免疫抑制 的患者。 在技藝中被描述的分析可以被用於篩選藥劑，該藥劑 可被用來抑制至少一種的涉及如下的黴菌病的黴菌：念珠 菌病、麯黴病、毛黴病、芽生黴病、地絲菌病、隱球菌病 、產色黴菌病、球黴菌病、分生孢子病、組織胞漿菌病、 黴菌腫、鼻孢子菌病、土壤絲菌病、假放線菌病、青黴病 '念球菌病、孢子絲菌病。差示篩選分析可被用來鑑定抗 黴菌劑，該抗黴菌劑在使用由酵母（如煙麯菌、黃麯菌、 黑麯菌、小巢狀、麯菌或土麯菌）複製的CDK基因處理麯 徽病上有治療的價値，或在黴菌感染是mucon-nycosis的 場合中，CDK分析可衍化自酵母，如酒麯菌屬（Rhizopus arrhizus)、酒麯菌屬（Rhizopus oryzae)、棘子鬚黴菌屬 (Absidiacorymbifera)、棘子鬚黴菌屬、（Absidiaramosa) 或微小毛黴菌屬。其他CDK酶的來源包括病原卡林肺囊蟲 〇 舉例來說，化合物之抗黴菌活性的玻管內評估可以藉 由確定最小抑制濃度（Μ · I · C ·)的方式被實施，最小抑制濃 度是在合適的培養基中的試驗化合物的濃度，在該濃度下 特定的微生物不會生長。實際上，一系列的瓊脂培養板（ 各有在特定的濃度下被倂入的試驗化合物）被白色念珠菌 -131 - 200524877 (127) 的標準培養物接種，接下來各培養板在2 7 °C下被溫育合適 的期間。接著培養板被檢查黴菌的生長是否存在，合適 M.I.C.値被特別注意。 化合物的活體內評估可以在一系列的劑量水平下被進 行，借助於對被接種黴菌（例如白色念珠菌或黃麯菌的菌 種）的小鼠死亡後根據一被被處理的小鼠施以腹膜內注射 或靜脈內注射或口服的方式。化合物活性可以在一群未被 處理的小鼠死亡後根據一群被處理的小鼠的殘存者被評估 。化合物的活性可以劑量水平的形式被量測，在該劑量水 平下化合物提供抗感染的致死效果的50 %保護（PD 5〇)。 就人抗黴菌的使用而言，化合物可以被單獨投藥或以 與依照所需的投藥途徑及標準藥學實作被選擇的藥學上的 載體的混合物被投藥。所以，化合物可以藉由在上文的、' 藥學調和物〃中被描述的調和物被口服、胃腸外投藥、靜 脈內投藥、肌肉投藥或皮下投藥。 就給人類患者口服及胃腸外投藥而言，本發明之抗黴 菌化合物的每日劑量水平可以自〇·〇 1至1 〇mg/kg(分次）， 彼取決於在口服或胃腸外投藥當時化合物的效價強度。化 合物的藥錠或膠囊可含有5 m g至0 · 5 g的活性化合物，彼視 需要被一次或二次或多次投藥。無論如何醫師會確定真實 的劑量（有效的份量），該劑量將最適合個別的患者，並且 會隨年齡、體重及特定患者的反應而變化。 另外’抗黴菌化合物可以栓劑或子宮托的形式被投藥 ’或可以下列形式被局部抗藥：洗劑、溶液、乳膏、軟膏 -132- 200524877 (128) 或撒粉。舉例來說，化合物可以被倂入由聚乙二醇或液體 石蠟的含水乳化液組成的乳膏中；或彼可以在介於1及 1 0 %之間的濃度下被倂入由白蠟或白色軟質石蠟基底組成 的軟膏（視需要而定連同安定劑及防腐劑）中。 除了上述的治療使用之外，與差示篩選分析發展的抗 黴菌劑可以當作下列被使用：食品中的防腐劑、促進家畜 體重增加的食物補充劑、或處理無生命物用的消毒劑調和 物，例如消毒醫院設施及病房。同樣地，哺乳動物CDK及 昆蟲CDK(如果蠅CDK5基因的交互比對（Hellmich et al.5(l 994)FEBS L e 11 3 5 6 ·· 3 1 7 - 2 1)會容許在抑制劑化合物（ 彼分別人/哺乳動物酶及昆蟲酶）之中的的選擇。於是，本 發明特別期待在殺蟲劑中本發明之化合物的使用及調和物 ，如在像果蠅之類的昆蟲的管理中使用。 在又一個體現中，若干患者CDK抑制劑可以根據供與 哺乳動物酶相關的植物CDK用的抑制專一性被選擇。例如 ，使植物CDK與一或多種的人類酶類被配置在差示篩中來 選擇供抑制植物酶用的最大的選擇性的化合物。所以，本 發明特別期待供農業應用的患者C D K抑制劑的調和物（如 以落葉劑等的形式）。 爲了農業及園藝的目的，本發明之化合物可以視特殊 用途及目的的需要被調製的組成物的形式被使用。所以化 合物可以下列形式被使用：撒粉、顆粒、種子敷料、含水 的溶液、分散體或乳劑、浸劑、噴劑、氣溶膠或煙。組成 物也可以下列形式被供應：可分散的粉末、顆粒、或使用 -133- 200524877 (129) 前先稀釋的濃體。這類組成物可含有在農業中及園藝中已 知的及可接受的傳統的載體、稀釋劑或佐藥，組成物依照 傳統的步驟被製造。組成物也可合倂其他的活性拼料，例 如有除草性的或殺昆蟲性的或殺黴菌性的化合物。化合物 及組成物可以許多的方式被應用，例如彼可以被直接應用 到下列之上：植物葉、莖、枝、種子、根、土壤、或其他 的生長培養基，彼不僅可被用來根除疾病，也可預防保護 植物或種子免受攻擊。舉例來說，組成物可以含有0.0 1至 1 wt °/〇的活性拼料。就田地使用而言，活性拼料的近似應 .用率是50至5 00g/公頃。 本發明也期待使用如式（0)之化合物及彼之如式（IG)、 (I)、（la)、（lb)、（II)、（III)、（IV)、（IVa)、（Va)、（Vb)、 (Via)、（VIb)、（VII)或（VIII)之亞群及彼之如本說明書中 所定義的亞群於控制樹木腐爛性黴菌及於處理植物生長的 土壤、育苗的稻田、或灌漑用水。本發明也期待使用如式 (〇)之化合物及彼之如式（IG)、（I)、（la)、（lb)、（II)、（ΠΙ) 、（IV)、（IVa)、（Va)、（Vb)、（Via)、（VIb)、（VII)或 (VIII)之亞群及彼之如本說明書中所定義的亞群於保護被 貯藏的榖物及其他的非植物場所、免受黴菌的侵害。 實施方式 實施例 現在本發明將藉由在下面的實施例中所描述的特定的 體現作爲參考而被舉例說明（但不被限制）。 在實施例中，所製造的化合物被使用在下面所陳述的 -134- 200524877 (130) 系統及操作條件的液相層離及質譜（L C _ M S ))予以特徵化。 在氯存在及單一質量數被引用的場合中，化合物所引用的 質量數是針對35C1。上述的兩種系統被裝備以相同的層離 管柱以及被設定在相同的操作條件下進行。所使用的操作 條件也在下文中被描述。在實施例中，滯留時間以分鐘表 示0 平台系統John Wiley &amp; Sons Inc and Fluorescence In Situ Hybridization ^ Technical Overview by John MSBartlett in Molecular Diaagnosis of Cancer, Methods and Protocols, 2nd ed .; ISBN: 1-59259-760-2; March 2004 5 pps.077-088 i Series · Methods in Molecular Medicine In addition, protein products expressed by mRNA can be analyzed by: immunohistochemistry of tumor samples, solid-phase immunoassay using microtiter plates, Western blotting, 2-dimensional SDS-polyacrylamide gel electrophoresis, ELISA, other -127-200524877 (123) methods well known in the art of detecting specific proteins. Detection involves the use of site-specific antibodies. Those skilled in the art will understand that all such well-known methods of detection can be applied in this application: up-regulation of cyclin E, or loss of p21 or p27, or CDC4 variants. So all of these methods can be used to identify tumors, especially tumors suitable for treatment with CD K inhibitors. Patients with adventitial cell lymphoma (MCL) can be selected (using diagnostic tests) for treatment with a CDK inhibitor. MCL is an exact clinicopathological entity of non-Hodgkin's lymphoma, which is characterized by the following: small to medium-sized lymphoproliferative effects (common manifestations of CD 5 and CD20), an aggressive and incurable clinical Program, frequency (t (ll; 14) (ql3; q32) shift. Overexpression of cyclin D1 mRNA found in adventitial cell lymphoma (MCL) is an important diagnostic marker. Yatabe et al. Human (Blood, 2000 Apr 1: 95 (7): 22 5 3 -6 1) proposed that cyclin D1-positivity should be included as one of the criteria for MCL for this incurable disease Innovative therapies should be explored in accordance with new standards. Jones et al. (J Mol Diagn. 2004 May; 6 (2): 84-9) develop a definitive time for the performance of cyclic D [CCN D1] , Quantitative, reverse transcription PCR analysis to assist in the diagnosis of adventitial cell lymphoma (MCL). Howe et al. (Clin Chem. 2004 Jan; 50 (1): 8 0-7) use exact time to quantify 11- ?. 11 Assessing the performance of cycline 〇11111 ^ 8 and discovering the use of quantitative RT-PCR for cyclin D1 mRNA normalized to CD19 mRNA can be used for blood, marrow and tissue In the diagnosis of MCL. In addition, patients with breast cancer can be selected to be treated with CDK inhibitors (using the diagnostic test described above). Cancer cells often overexpress cyclin E, the following has been confirmed -128- 200524877 (124 ) •• Cyclin E is overexpressed in breast cancer (HarwelI) et al., Canceri. Res '2 0 0 0' 6 0, 4 8 1-4 8 9). So breast cancer can be treated especially by CDK inhibitors. Antimycotic uses In another aspect, the present invention provides the use of formulae such as (0), (IG), (I), (la), (lb), (II), (III), (IV), (IVa), (Va), (Vb), (Via), (VIb), (VII) or (VIII) compounds and their subgroups act as antimycotic agents. Compounds can be used in veterinary medicine (such as the treatment of mammals such as humans ), Or treating plants (such as agriculture and horticulture), or acting as a general antifungal agent, such as acting as a preservative and disinfectant. In one embodiment, the present invention provides a compound such as formula (0) and other compounds such as formula (I0), (I), (la), (lb), (II), (III), (IV), (IVa), (Va), (Vb), (Via), (VIb), (VII) or (VIII) subgroups and subgroups as defined in the present specification, which are used to prevent or treat breastfeeding Fungal infections in animals such as humans. The present invention also provides the use of a compound such as formula (0) and other compounds of formula (I0), (I), (la), (lb), (II), (III), (IV), (IVa), Subgroups of (Va), (Vb), (Via), (VIb), (VII) or (VIII) and other subgroups as defined in this specification are manufactured for the prevention or treatment of mammals (such as humans) ) Agents for mold infections in the body. For example, the compounds of the present invention may be given to other organisms that are suffering from or at the risk of being infected by molds: Nian-129- 200524877 (125) Candida species, Hydratia, Microsporidia, or Epidermophyton, or human patients in mucosal infections caused by Candida albicans, such as thrush and vaginal candidiasis. The compounds of the present invention can also be administered to treat or prevent genus Candida, Cryptococcus neoformans, Aspergillus, Fugillus, Coccus, Paracoccus, Histoplasma, or Spores Caused by systemic fungal infections. In another aspect, the present invention provides an antifungal composition for use in agriculture (including horticulture), the composition comprising a compound of formula (1%) and a compound of formula (1) , (Lb), (II), (III), (IV), (V), (VI), and (VII) together with agriculturally acceptable diluents or carriers. The invention also provides a treatment with mold A method for infecting an animal (including a mammal, such as a human), a plant, or a seed, the method comprising, in an effective portion, a compound such as formula (1%) and a compound as defined above (I), (la), The subgroups of (lb), (II), (III), (IV), (V), (VI) and (VII) deal with the aforementioned animals, plants or seeds, or the aforementioned plant or seed loci. The invention also provides a method of treating a fungal infection in a plant or seed, the method comprising treating a plant or seed with an anti-mold effective amount of an anti-mold composition as defined above.Differential screening analysis can be used to select available Specific compounds of the invention for non-ACDK enzymes. For eukaryotic cells Compounds that specifically act on pathogenic CDK enzymes can be used as antimycotics or antiparasitic agents. Inhibitors of Candida CDK kinase (CKSI) can be used to treat candidiasis. Antifungal 200524877 (126) Agents can It is used to fight the type of infection as defined above, or opportunistic infections that often occur in patients: debilitated and immunosuppressed patients (such as patients with leukemia and lymphoma), Humans, patients with qualitative symptoms (such as diabetes or AIDS), and non-immunosuppressive patients. The analysis described in the art can be used to screen for agents that can be used to inhibit at least one mold that involves the following Diseased molds: candidiasis, aspergillosis, mucormycosis, blastomycosis, earthworm, cryptococcosis, chromomycosis, coccidiosis, conidia, histoplasmosis, mycosis , Rhinosporidiosis, soil filariasis, pseudo actinomycosis, penicillium 'candidiasis, sporotomycosis. Differential screening analysis can be used to identify antimycotic agents, which are in use Yeast (such as Aspergillus flavus, Aspergillus flavus, Aspergillus niger, Aspergillus niger, Aspergillus or Aspergillus) replicated CDK gene treatment is valuable in treating aspergillosis, or where mold infection is mucon-nycosis CDK analysis can be derived from yeasts such as Rhizopus arrhizus, Rhizopus oryzae, Absidiacorymbifera, Absidiaramosa, or Mucor. Other sources of CDK enzymes include the pathogen Carinella pneumoniae. For example, an intra-glass tube assessment of the antifungal activity of a compound can be performed by determining the minimum inhibitory concentration (M · I · C ·). Is the concentration of the test compound in a suitable culture medium at which a particular microorganism will not grow. In fact, a series of agar plates (each containing a test compound incorporated at a specific concentration) were inoculated with a standard culture of Candida albicans-131-200524877 (127), followed by each plate at 2 7 ° C was incubated for a suitable period. The plates were then checked for the presence of mold growth and appropriate M.I.C. 値 was given special attention. In vivo assessment of compounds can be performed at a range of dosage levels by means of administering to a treated mouse after death of a mouse inoculated with a mold (such as Candida albicans or Aflatoxin strain) Intraperitoneal or intravenous or oral. Compound activity can be assessed on the survivors of a group of treated mice after the death of a group of untreated mice. Compound activity can be measured in the form of a dose level at which the compound provides 50% protection against the lethal effect of infection (PD 50). For use with human antifungals, the compounds can be administered alone or in admixture with a pharmaceutically acceptable carrier selected according to the desired route of administration and standard pharmaceutical practice. Therefore, the compounds can be administered orally, parenterally, intravenously, intramuscularly, or subcutaneously through the blends described in the above, "Pharmaceutical Blends". For oral and parenteral administration to human patients, the daily dosage level of the antimycotic compound of the present invention may be from 0.001 to 10 mg / kg (divided), depending on the time of oral or parenteral administration The potency of a compound. The tablets or capsules of the compounds may contain 5 mg to 0.5 g of the active compound, which may be administered one or two or more times as needed. Regardless, the physician will determine the actual dose (effective amount), which will be best suited for the individual patient and will vary with age, weight and the response of the particular patient. In addition, 'antimycotic compounds can be administered in the form of suppositories or pessaries' or can be topically resistant in the following forms: lotions, solutions, creams, ointments -132- 200524877 (128) or dusting. For example, the compound can be incorporated into a cream consisting of an aqueous emulsion of polyethylene glycol or liquid paraffin; or it can be incorporated into a white wax or white at a concentration between 1 and 10% In an ointment consisting of a soft paraffin base (as needed, together with stabilizers and preservatives). In addition to the above-mentioned therapeutic uses, antifungal agents developed with differential screening analysis can be used as preservatives in food, food supplements that promote weight gain in livestock, or disinfectants for the treatment of inanimate substances Such as disinfecting hospital facilities and wards. Similarly, mammalian CDK and insect CDK (if cross-comparison of the fly CDK5 gene (Hellmich et al. 5 (l 994) FEBS L e 11 3 5 6 ·· 3 1 7-2 1) will allow (These are human / mammalian enzymes and insect enzymes). Therefore, the present invention particularly looks forward to the use of compounds of the present invention in insecticides and their blends, such as the management of insects such as fruit flies In another embodiment, several patient CDK inhibitors can be selected based on the specificity of inhibition of plant CDKs associated with mammalian enzymes. For example, plant CDKs can be configured with one or more human enzymes. The sieve is used to select the compound with the greatest selectivity for inhibiting plant enzymes. Therefore, the present invention particularly looks forward to the use of CDK inhibitor blends (such as in the form of deciduous agents) for patients in agricultural applications. For agriculture and horticulture Purpose, the compound of the present invention can be used in the form of a composition to be prepared according to the needs of a particular application and purpose. Therefore, the compound can be used in the following forms: dusting, granules, seed dressings, aqueous Liquids, dispersions or emulsions, infusions, sprays, aerosols or smoke. Compositions can also be supplied in the form of dispersible powders, granules, or concentrates that are diluted before use -133- 200524877 (129). Such compositions may contain conventional carriers, diluents or adjuvants known and acceptable in agriculture and horticulture. The composition is manufactured according to conventional procedures. The composition may also be combined with other active ingredients, For example, there are herbicidal or insecticidal or fungicidal compounds. The compounds and compositions can be applied in many ways, for example, they can be directly applied to the following: plant leaves, stems, branches, seeds, roots, Soil, or other growth media, can be used not only to eradicate disease, but also to prevent the protection of plants or seeds from attack. For example, the composition can contain 0.0 1 to 1 wt ° / 〇 active ingredients. For field use, the approximate application of active ingredients. The utilization rate is 50 to 500 g / ha. The present invention also expects to use compounds such as formula (0) and other formulas (IG), (I), (la). , (Lb), (II), (III), Subgroups (IV), (IVa), (Va), (Vb), (Via), (VIb), (VII), or (VIII) and other subgroups as defined in this specification are used to control tree decay Sex mold and soil for treating plant growth, paddy field for raising seedlings, or water for irrigation. The present invention also anticipates the use of compounds of formula (0) and their use as formulas (IG), (I), (la), (lb). , (II), (ΠΙ), (IV), (IVa), (Va), (Vb), (Via), (VIb), (VII), or (VIII) and as described in this specification The defined subgroups are used to protect stored pupae and other non-plant areas from mold. Embodiments Examples The present invention will now be exemplified (but not limited) by reference to specific embodiments described in the following examples. In the examples, the manufactured compounds were characterized using liquid phase ionization and mass spectrometry (LC_MS) of the -134- 200524877 (130) system and operating conditions stated below. Where chlorine is present and a single mass is cited, the mass cited for the compound is for 35C1. The two systems described above are equipped with the same delamination string and are set up under the same operating conditions. The operating conditions used are also described below. In embodiments, the residence time is expressed in minutes. 0 Platform system

系統·· Waters 2790/Platform LC 質譜檢測器：Micromass Platform LC PDA 檢測器：Waters 996 PDA 分析的條件： 洗提液A : 5%乙腈之95%水（0· 1 %甲酸）溶液 洗提液B :乙腈（0.1 %甲酸） 梯度洗提：10-95%洗提液B 流速：1 . 2 m 1 / m i η 管柱：Synergi 4//m Max-RP Ci2，80Α，50 x46mm (Phenomenex) MS條件：System · Waters 2790 / Platform LC Mass Detector: Micromass Platform LC PDA Detector: Waters 996 PDA Conditions for analysis: Eluent A: 95% water (0.1% formic acid) solution 5% acetonitrile Eluent B : Acetonitrile (0.1% formic acid) Gradient elution: 10-95% Eluent B Flow rate: 1.2 m 1 / mi η Column: Synergi 4 // m Max-RP Ci2, 80A, 50 x 46mm (Phenomenex) MS condition:

毛細管電壓：3 .5kV 錐形管電壓：30V 來源溫度：]2 0 °C -135- 200524877 (131)Capillary voltage: 3.5kV Conical tube voltage: 30V Source temperature:] 2 0 ° C -135- 200524877 (131)

FractionLynx 系統FractionLynx system

系統：Waters FractionLynx(分析/製備雙效） 質譜檢測器：W a t e r s - M i c r o m a s s Z Q PDA 檢測器：Waters 2996 PDA 分析的條件： 洗提液A :水（0 . 1 %甲酸）System: Waters FractionLynx (Analytical / Preparative Dual Effect) Mass Detector: Water s-M i c r o m a s s Z Q PDA Detector: Waters 2996 PDA Conditions for Analysis: Eluent A: Water (0.1% formic acid)

洗提液B ··乙腈（〇 . 1 %甲酸） 梯度洗提：5-95%洗提液B 流速：1 . 5 m 1 / m i η 管柱：Synergi 4// m Max-RP C12，80Α，50Χ4 (Phenomenex) MS條件：Eluent B ·· acetonitrile (0.1% formic acid) Gradient elution: 5-95% Eluent B Flow rate: 1.5 m 1 / mi η Column: Synergi 4 // m Max-RP C12, 80Α 50 × 4 (Phenomenex) MS conditions:

毛細管電壓：3 .5kVCapillary voltage: 3.5 kV

錐形管電壓：30V 來源溫度：1 2 (TC 去溶劑化作用溫度：3 0 0 °C LC-MS分析系統 如下面所描述的方法使用幾種系統，這些系統被裝備 及被設定在極相似的操作條件下進行。所使用的操作條件 也在下文中被描述。 -136- 200524877 (132) HPLC 系統：Waters 2795Conical tube voltage: 30V Source temperature: 1 2 (TC desolvation temperature: 3 0 ° C LC-MS analysis system The method described below uses several systems, these systems are equipped and set to be very similar The operating conditions used are also described below. -136- 200524877 (132) HPLC system: Waters 2795

質譜檢測器：M i c r o m a s s P 1 a t f o r m L CMass detector: M i c r o m a s s P 1 a t f o r m L C

P D A 檢測器：W a t e r s 2 9 9 6 P D A 酸性的分析條件：P D A Detector: Wa t e r s 2 9 9 6 P D A Acidic Analysis Conditions:

洗提液A :水（〇 · 1 %甲酸） 洗提液B :乙腈（〇 · 1 %甲酸） 梯度洗提：5-9 5 %洗提液B，花3. 5分鐘 流速：〇.8ml/min 管柱：Phenomenex Synergi 4 μ m MAX-RP，80A，2·0χ 5 0 mm 驗性的分析條件：Eluent A: water (0.1% formic acid), eluent B: acetonitrile (0.1% formic acid), gradient elution: 5-95% eluent B, 3.5 minutes flow rate: 0.8ml / min column: Phenomenex Synergi 4 μm MAX-RP, 80A, 2 · 0χ 50 mm Test conditions:

洗提液A :水（10mM NH4HC03緩衝液，被氫氧化銨調整成 pH = 9.5) 洗提液B :乙腈 梯度洗提：5-95%洗提液B，花3.5分鐘 流速·· 〇 . 8 m 1 / m i η 管柱：Thermo Hypersil-Keystone BetaBasic-18 5 μ m 2.1 x 5 0 m m 或 管柱：Phenomenex Luna C18(2) 5// m 2.0x50mm - 137- 200524877 (133) 極性的分析條件： 洗提液A :水（0 · 1 %甲酸） 洗提液B :乙腈（〇 . 1 %甲酸） 梯度洗提：〇 - 5 0 %洗提液B，花3分鐘 流速：〇 . 8 m 1 / m i η 管柱：Thermo Hypersil-Keystone HyPurity Aquastar，5 /1 2.1x50mm 或 管柱：Phenomenex Synergi 4// MAX-RP 80A 2.0x50mm 較久的分析條件： 洗提液A :水（0 · 1 %甲酸） 洗提液B :乙腈（0 . 1 %甲酸） 梯度洗提：5-95 %洗提液B，花15分鐘 流速：〇.4ml/min 管柱：Phenomenex Synergi 4 β MAX-RP 80A，2.0 15 0mm M S條件： 毛細管電壓：3.6kV 錐形管電壓：30V 來源溫度：1 2 0 °C 掃描範圍：1 6 5 - 7 0 0 a m u 離子化模式：電噴射正離子或 -138- 200524877 (134) 電噴射負離子或 電噴射正離子&amp;負離子 質量 下面的製備性層離系統可被用來提純本發明之化合物 •硬體： _Eluent A: water (10 mM NH4HC03 buffer, adjusted to pH = 9.5 by ammonium hydroxide) Eluent B: Acetonitrile gradient elution: 5-95% Eluent B, take 3.5 minutes flow rate ·· 0.8 m 1 / mi η column: Thermo Hypersil-Keystone BetaBasic-18 5 μm 2.1 x 50 mm or column: Phenomenex Luna C18 (2) 5 // m 2.0x50mm-137- 200524877 (133) Polarity analysis conditions : Eluent A: water (0.1% formic acid), eluent B: acetonitrile (0.1% formic acid), gradient elution: 0-50% eluent B, 3 minutes flow rate: 0.8 m 1 / mi η Column: Thermo Hypersil-Keystone HyPurity Aquastar, 5/1 2.1x50mm or Column: Phenomenex Synergi 4 // MAX-RP 80A 2.0x50mm Longer analysis conditions: Eluent A: Water (0 · 1 % Formic acid) eluent B: acetonitrile (0.1% formic acid) gradient elution: 5-95% eluent B, 15 minutes flow rate: 0.4ml / min column: Phenomenex Synergi 4 β MAX-RP 80A , 2.0 15 0mm MS conditions: Capillary voltage: 3.6kV Conical tube voltage: 30V Source temperature: 1 2 0 ° C Scanning range: 1 6 5-7 0 0 amu Ionization mode: Electrospray positive ion -138-200524877 (134) or electrospray negative ion electrospray positive &amp; negative ion mass from the following preparative layer system may be used to purify the compounds of the present invention • Hardware: _

Waters Fractionlynx 系統： 2767自動採樣/級份收集器 2 5 25製備泵 CFO (管柱流體組織器），供管柱選擇用 RMA(WaterS試劑管理器），如組成泵 Waters ZQ質譜儀 Waters2 9 96發光二極體陣列偵檢器 •軟體：Masslynx 4.0 •管柱： 1. 低的 Ph 層離·· Phenomenex Synergy MAX-RP，1 0 β， 150x15mm (或使用相同型式管柱100x2 1.2mm)。 2. 高的 pH 層離：Phenomenex Luna C18(2)，1 0 // ，1 0 0 x 21.2 mm (或使用 Therm e Hypersil Keystone BetaBasic C18 ，5 β ，1 0 0 x 2 1 . 2 m m ) -139· 200524877 (135) •洗提液： 1 .低的pH層離： 溶劑A :水+ 0 . 1 %甲酸，ρ Η 1 . 5 溶劑Β :乙腈+0.1 %甲酸 2. 高的pH層離： 溶劑 A :水 +10mM NH4HC03 + NH40H，pH9.5 溶劑B :乙腈 3. 組成溶劑：甲醇+0.1 %甲酸（供二種型式的層離用） •方法： 在把製備性層離用於單離及提純產物化合物之前，首 先分析型LC-MS(見上文）可以被用來確定供製備性層離用 的最適合的條件。一個典型的慣例是使用最適合化合物結 構的層離類型（高的或低的pH)來進行分析型LC-MS。一 旦分析痕跡顯示爲良好的層離，則可以選擇相同類型的合 適的製備型層離方法。典型的供低的及高的pH層離方法 用的進行條件是： 流速：2 4 m 1 / m i η 梯度洗提：一般所有的梯度皆有最初的0.4分鐘洗提階段（ 以95%Α + 5 0°/〇Β洗提）。接著根據分析痕跡，爲了達到良好 的分離而選擇3.6分鐘洗提（例如，對最早滯留的化合物使 用5%至50%Β ;對中間滯留的化合物等使用35%至80%Β) 沖洗：在梯度洗提的末後進行1分鐘沖洗 再平衡：對系統爲下一次進行作準備而進行2 .】分鐘的再 -140- 200524877 (136) 平衡 組成流速：1 ηι 1 / m i η •溶劑： 或 1 0 0 % D M S 0 一般所有的化合物皆被溶於1 〇〇%甲醇 中 • M S進行條件： 毛細管電壓：3.2kV 錐形管電壓：2 5 V 來源溫度：120°C 放大器：500V 掃描範圍：1 25 - 8 00 amu 離子化模式：電噴射正離子 取得的，除非 供每一個實施例用的起始物是商業上 另外說明。 實施例1 4 -胺基-1 Η -吡唑-3 -羧酸苯醯胺 1 Α.4-硝基-1Η-吡唑-3-羧酸苯醯胺 -141 - 200524877 (137)Waters Fractionlynx system: 2767 automatic sampling / fraction collector 2 5 25 preparation pump CFO (column fluid organizer), for RMA (WaterS reagent manager) for column selection, such as the pump Waters ZQ mass spectrometer Waters2 9 96 luminescence Diode Array Detector • Software: Masslynx 4.0 • Tubing: 1. Low Ph delamination · Phenomenex Synergy MAX-RP, 10 β, 150x15mm (or use the same type of column 100x2 1.2mm). 2. High pH delamination: Phenomenex Luna C18 (2), 1 0 //, 1 0 x 21.2 mm (or use Thermo e Hypersil Keystone BetaBasic C18, 5 β, 1 0 x 2 1.2 mm)- 139 · 200524877 (135) • Eluent: 1. Low pH delamination: Solvent A: water + 0.1% formic acid, ρ Η 1.5 Solvent B: acetonitrile + 0.1% formic acid 2. High pH delamination : Solvent A: Water + 10mM NH4HC03 + NH40H, pH9.5 Solvent B: Acetonitrile 3. Composition Solvent: Methanol + 0.1% Formic Acid (for two types of delamination) • Method: Use preparative delamination for single Before isolating and purifying the product compounds, first analytical LC-MS (see above) can be used to determine the most suitable conditions for preparative delamination. A typical practice is to perform analytical LC-MS using the type of separation (high or low pH) that is most suitable for the structure of the compound. Once traces of analysis show good delamination, the same type of suitable preparative delamination method can be selected. Typical conditions for low and high pH delamination methods are: Flow rate: 2 4 m 1 / mi η Gradient elution: Generally all gradients have an initial 0.4 minute elution phase (with 95% Α + 50 ° / 〇Β elution). Then according to the analysis traces, choose a 3.6-minute elution in order to achieve a good separation (for example, use 5% to 50% B for the earliest retained compounds; 35% to 80% B for intermediate retained compounds, etc.) Rinse: In the gradient Rinse for 1 minute at the end of the elution and re-equilibrate: Prepare the system for the next run. 2.]-Minute re-140- 200524877 (136) Equilibration Composition Flow rate: 1 η 1 / mi η • Solvent: or 1 0 0% DMS 0 Generally all compounds are dissolved in 100% methanol • Conditions for MS: Capillary voltage: 3.2kV Conical tube voltage: 2 5 V Source temperature: 120 ° C Amplifier: 500V Scanning range: 1 25 -8 00 amu ionization mode: obtained by electrospray positive ion, unless the starting material for each example is commercially stated otherwise. Example 1 4 -Amino-1 fluorene-pyrazole-3-benzoxamine carboxylic acid 1 A.4-nitro-1 fluorene-pyrazole-3-carboxylic acid benzoxamine -141-200524877 (137)

將4-硝基-吡唑-3-羧酸（2.5g ; 15.9mmol)加入經攪拌 的苯胺（1.6ml ; 17.5mmol)、E D C (3 . 7 g ； 19.1mmol)及 HOBt(2.6g;19.1mmol)2 N，N-二甲替甲醯胺（DMF)(25 ml)溶液中，接著在室溫下攪拌一整夜。在減壓下蒸發去 除溶劑，將醋酸乙酯/飽和碳酸氫鈉溶液與殘渣硏磨。過 濾收集所得的固體，以及乙醚沖洗，在真空下乾燥，得黃 /棕色固體狀標題化合物（鈉鹽）（2.85g)。（LC/MS : Rt2.78[M + H] + 2 3 2.9 5 )。 胺基-1H-吡唑-3-羧酸苯醯胺4-Nitro-pyrazole-3-carboxylic acid (2.5 g; 15.9 mmol) was added to stirred aniline (1.6 ml; 17.5 mmol), EDC (3.7 g; 19.1 mmol), and HOBt (2.6 g; 19.1) mmol) 2 N, N-dimethylformamide (DMF) (25 ml) solution, followed by stirring at room temperature overnight. The solvent was removed by evaporation under reduced pressure, and the ethyl acetate / saturated sodium bicarbonate solution was triturated with the residue. The resulting solid was collected by filtration, washed with ether, and dried under vacuum to give the title compound (sodium salt) (2.85 g) as a yellow / brown solid. (LC / MS: Rt2.78 [M + H] + 2 3 2.9 5). Amino-1H-pyrazole-3-carboxylic acid benzamidine

使4·硝基-1H-D比唑-3-羧酸苯醯胺（l〇〇mg ; 0.43mmol) 溶於乙醇（5ml)中，以氯化亞錫二水合物（500mg ; 2 · 1 5 m m ο 1)處理，在回流狀態下加熱一整夜。冷卻，蒸發 。使殘渣分配於醋酸乙酯及溴之間，分出醋酸乙酯層，以 硫酸鎂乾燥，過濾，蒸發。先後以1 : 1醋酸乙酯/石油醚 -142- 200524877 (138) ’ 5 °/。甲醇/二氯甲烷洗提提純粗製的產物行快速管柱層離 。蒸發，製備性LC/MS，得非純白色固體狀產物（i5mg)。 (LC/MS: Rt1.40[M + H] + 202.95)〇 實施例2 4-乙醯胺基- lH-Dtt唑-3-羧酸（4-氟代-苯基）-醯胺 2 A .4-硝基-1H-吡唑-3-羧酸（4-氟代-苯基）_醯胺4 · nitro-1H-D-pyrazole-3-carboxylic acid benzidine (100 mg; 0.43 mmol) was dissolved in ethanol (5 ml), and stannous chloride dihydrate (500 mg; 2.1 5 mm ο 1) treatment, heating under reflux overnight. Cool and evaporate. The residue was partitioned between ethyl acetate and bromine, and the ethyl acetate layer was separated, dried over magnesium sulfate, filtered, and evaporated. 1: 1 ethyl acetate / petroleum ether -142- 200524877 (138) ′ 5 ° /. The crude product was purified by methanol / dichloromethane and subjected to flash column delamination. Evaporation, preparative LC / MS, gave the product as an impure white solid (i5 mg). (LC / MS: Rt1.40 [M + H] + 202.95) Example 2 4-Ethamido-lH-Dttazole-3-carboxylic acid (4-fluoro-phenyl) -amidoamine 2 A .4-Nitro-1H-pyrazole-3-carboxylic acid (4-fluoro-phenyl) _amidine

把4 -硝基吡唑-3 -羧酸（1 0 g ; 6 3 · 6 6 m m ο 1)加入經攪拌的 4-氟代苯胺（6.7ml; 70mmol)、EDC(14.6g; 76. 4mmol )及 HOBt (10.3g; 76.4mmol)之 DMF(25ml)溶液中，接著在室 溫下攪拌一整夜。在減壓下蒸發除去溶劑，將醋酸乙酯/ 飽和鹽溶液與殘渣硏磨。過濾收集所得的黃色固體，以 2M鹽酸沖洗，在真空中乾燥，得標題化合物（15.5g)。 (LC/MS: Rt2.92[M + H] + 2 5 0.89)〇 2Β·4-胺基吼唑-3-羧酸（4-氟代-苯基）·醯胺 -143- 2005248774 -Nitropyrazole-3 -carboxylic acid (10 g; 6 3 · 6 6 mm ο 1) was added to stirred 4-fluoroaniline (6.7ml; 70mmol), EDC (14.6g; 76.4mmol ) And HOBt (10.3 g; 76.4 mmol) in DMF (25 ml), followed by stirring at room temperature overnight. The solvent was removed by evaporation under reduced pressure, and the ethyl acetate / saturated salt solution was honed with the residue. The resulting yellow solid was collected by filtration, rinsed with 2M hydrochloric acid, and dried in vacuo to give the title compound (15.5 g). (LC / MS: Rt2.92 [M + H] + 2 5 0.89) 〇 2B · 4-Aminopyrazole-3-carboxylic acid (4-fluoro-phenyl) · Amidine -143- 200524877

使4-硝基-1H-吡唑-3-羧酸（4-氟代苯基）-醯胺（15g)溶 於乙醇（200ml)中，在氮氣氛下以10%鈀/活性碳（1.5g)處理 ，在室溫及加壓下氫化一整夜。以矽藻土過濾除去觸媒， 使濾液蒸發。使粗製的產物溶於丙酮/水（1 0 0 m 1 : 1 0 0 m 1) 中，徐徐使丙酮蒸發，過濾收集產物，得棕色結晶固狀 (8.1g)。（LC/MS: Rt1.58[M + H] + 220.95)。 2C.4-乙醯胺基-1H-吡唑-3-羧酸（4-氟代苯基）_醯胺4-Nitro-1H-pyrazole-3-carboxylic acid (4-fluorophenyl) -fluorenamine (15 g) was dissolved in ethanol (200 ml) under a nitrogen atmosphere at 10% palladium / activated carbon (1.5 g) Treat and hydrogenate overnight at room temperature and under pressure. The catalyst was removed by filtration through celite, and the filtrate was evaporated. The crude product was dissolved in acetone / water (100 m 1: 100 m 1), the acetone was slowly evaporated, and the product was collected by filtration to obtain a brown crystal solid (8.1 g). (LC / MS: Rt1.58 [M + H] + 220.95). 2C.4-acetamido-1H-pyrazole-3-carboxylic acid (4-fluorophenyl) _amidoamine

使心胺基-1H-吡唑-3-羧酸（4·氟代苯基）_醯胺（5〇〇mg ;2.27mmol)溶於吡啶（5ml)中’以醋酸酐（240 # I，2 5 mmol)處理，在室溫下攪拌一整夜。蒸發除去溶劑，加入 二氯甲烷（20ml)及2M鹽酸（20ml)。過濾收集未溶的固體 ，以更多的二氯甲烷及水沖洗，在真空下乾燥。單離得非 純白色固體狀產物（2 7 5 mg)。（LC/MS : ]^2.96[Μ + Η] + -144- 200524877 (140) 262.91)。 實施例3 4 - ( 2，2，2 -三氟代-乙醯胺基）…1 Η -吼唑-3 -羧酸（4 -氟代-苯基）-醯胺Dissolve cardioamino-1H-pyrazole-3-carboxylic acid (4-fluorophenyl) -amidoamine (500 mg; 2.27 mmol) in pyridine (5 ml). Acetic anhydride (240 # 1, 2 5 mmol), and stirred at room temperature overnight. The solvent was removed by evaporation, and dichloromethane (20 ml) and 2M hydrochloric acid (20 ml) were added. The undissolved solid was collected by filtration, washed with more dichloromethane and water, and dried under vacuum. The product was isolated as an impure white solid (275 mg). (LC / MS: ^ 2.96 [M + Η] + -144- 200524877 (140) 262.91). Example 3 4-(2,2,2-trifluoro-acetamido) ... 1 fluorene-imidazol-3-carboxylic acid (4-fluoro-phenyl) -amidamine

使4-胺基-1H-D1±唑-3-羧酸（4-氟代苯基）-醯胺（實施例 2B)(5 00mg ； 2.27mmol)溶於吡啶（5ml)中，以三氟醋酸酐 (320// 1，2.5mmol)，在室溫下攪拌一整夜。蒸發除去溶 劑，使殘渣分配於醋酸乙酯（50ml)及2M鹽酸（50ml)之間 ，分出醋酸乙酯層，以鹽溶液（50ml)沖洗，以硫酸鎂乾燥 ，過濾，蒸發，得棕色固體狀產物（5 60mg)。（LC/MS : [M + H] + 3 1 7)。 實施例4 4-[(5-合氧基-吡咯烷-2-羰基）-胺基]-11^-吡唑-3-羧酸（4-氟 代-苯基）-醯胺 -145- 200524877 (141)4-Amino-1H-D1 ± azole-3-carboxylic acid (4-fluorophenyl) -amidamine (Example 2B) (500 mg; 2.27 mmol) was dissolved in pyridine (5 ml), and trifluoro Acetic anhydride (320 // 1, 2.5 mmol) was stirred at room temperature overnight. The solvent was removed by evaporation, and the residue was partitioned between ethyl acetate (50 ml) and 2M hydrochloric acid (50 ml). The ethyl acetate layer was separated, washed with a salt solution (50 ml), dried over magnesium sulfate, filtered, and evaporated to obtain a brown solid. The product (5 60 mg). (LC / MS: [M + H] + 3 1 7). Example 4 4-[(5-Hydoxy-pyrrolidin-2-carbonyl) -amino] -11 ^ -pyrazole-3-carboxylic acid (4-fluoro-phenyl) -amidamine-145- 200524877 (141)

把2 -合氧基脯肢酸（3 3 m g ; 〇 · 2 5 m m ο 1)加入經攪拌的4 -胺基“Η-吡唑-3-羧酸（4-氟代苯基卜醯胺（實施例2B)(5〇mg ;〇.23mmol) 、 EDAC(52mg ; 〇.2 7mmol)及 HOBt(37mg ; 0.27mmol)之DMF(5ml)溶液中，在室溫下靜置一整夜。蒸 發，以製備性LC/MS提純殘渣，得白色固體狀產物 (24mg)(LC/MS : Rt2.27[M + H] + 3 3 2)。 實施例5 4-苯基乙醯胺基-1H-吡唑-3-羧酸（4_氟代-苯基）_醯胺2-Hydroxyprolimic acid (33 mg; 0.25 mm ο 1) was added to the stirred 4-amino "fluorene-pyrazole-3-carboxylic acid (4-fluorophenylbutanamine) (Example 2B) (50 mg; 0.23 mmol), EDAC (52 mg; 0.27 mmol) and HOBt (37 mg; 0.27 mmol) in a solution of DMF (5 ml), and allowed to stand at room temperature overnight. Evaporation and purification of the residue by preparative LC / MS gave the product (24 mg) as a white solid (LC / MS: Rt2.27 [M + H] + 3 3 2). Example 5 4-phenylacetamido- 1H-pyrazole-3-carboxylic acid (4-fluoro-phenyl) _amidine

以類似實施例4的方法進行反應，但使用苯醋酸（34mg ;0.23mmol)當起始物。標題化合物（14mg)被單離成白色 固體。（LC/MS : Rt3.24[M + H] + 3 3 9)。 實施例6 -146- 200524877 (142) 4-(2-1 Η-吲哚，3-基-乙醯胺基）-1 Η-吡唑-3-羧酸（4-氟代.苯 基）-醯胺The reaction was performed in a similar manner to Example 4 except that phenylacetic acid (34 mg; 0.23 mmol) was used as a starting material. The title compound (14 mg) was isolated as a white solid. (LC / MS: Rt3.24 [M + H] + 3 3 9). Example 6 -146- 200524877 (142) 4- (2-1 Amidine-indole, 3-yl-acetamido) -1 Amidine-pyrazole-3-carboxylic acid (4-fluoro.phenyl) -Amidamine

(44 mg ; 0.23mm 〇1)當起始物。標題化合物（14mg)被單離成 白色固體。（LC/MS: Rt3.05[M + H] + 378)。 實施例7 4-(2-苯磺醯-乙醯胺基）-lH-吡唑-3-羧酸（4-氟代-苯基）·醯 胺(44 mg; 0.23 mm) as the starting material. The title compound (14 mg) was isolated as a white solid. (LC / MS: Rt3.05 [M + H] + 378). Example 7 4- (2-benzenesulfonyl-acetamido) -lH-pyrazole-3-carboxylic acid (4-fluoro-phenyl) · fluorenamine

以類似實施例4的方法進行反應，但使用2-(苯磺醯） 醋酸（50m g ; 0.23m mol)當起始物。標題化合物（29mg)被單 離成白色固體。（LC/MS: Rt3.00[M + H] + 403)。 -147- 200524877 (143) 實施例8 4-[2-(5-胺基-四唑-1-基）-乙醯胺基]-1 Η-吼唑-3-羧酸（4-氟 代苯基）-醯胺The reaction was performed in a manner similar to that of Example 4, except that 2- (benzenesulfonium) acetic acid (50 mg; 0.23 m mol) was used as a starting material. The title compound (29 mg) was isolated as a white solid. (LC / MS: Rt3.00 [M + H] + 403). -147- 200524877 (143) Example 8 4- [2- (5-Amino-tetrazol-1-yl) -acetamidinyl] -1 hydrazone-oxazole-3-carboxylic acid Phenyl) -amidine

以類似實施例4的方法進行反應，但使用5 -胺基四唑_ 1-醋酸（3 6mg ; 0.2 3mmol)當起始物。標題化合物（23mg)被 單離成白色固體。（LC/MS : Rt2.37[M + H] + 346)。 實施例9 N-[3-(4-氟代-苯基胺基甲醯）-lH-D比唑-4-基]-6-羥基-菸醯 胺The reaction was performed in a similar manner to Example 4, except that 5-aminotetrazole-1-acetic acid (36 mg; 0.2 3 mmol) was used as a starting material. The title compound (23 mg) was isolated as a white solid. (LC / MS: Rt2.37 [M + H] + 346). Example 9 N- [3- (4-Fluoro-phenylaminoformamidine) -lH-D-pyrazol-4-yl] -6-hydroxy-nicotinamine

以類似實施例4的方法進行反應’但使用6-羥基菸酸 (3 8 m g ; 0 · 2 3 m m ο 1)當起始物’標題化合物（1 7 m g)被單離成 -148- 200524877 (144) 白色固體 D (LC/MS: Rt2.32[M + H] + 342)。 實施例1 〇 4-[3-(4-氯代-苯基）-丙醯胺基]-1 H-吡唑-3-羧酸（4-氟代苯 基）-醯胺The reaction was performed in a manner similar to Example 4 except that 6-hydroxynicotinic acid (38 mg; 0.23 mm ο 1) was used as the starting material. The title compound (17 mg) was isolated into -148- 200524877 ( 144) White solid D (LC / MS: Rt2.32 [M + H] + 342). Example 1 4- [3- (4-Chloro-phenyl) -propylamido] -1 H-pyrazole-3-carboxylic acid (4-fluorophenyl) -amidoamine

以類似實施例4的方法進行反應，但使用3-(4-氯代苯 基）丙酸（46mg; 0.23mmol)當起始物。標題化合物（40mg) 被單離成白色固體。（LC/MS ·· Rt3.60[M + H] + 3 8 8 )。 實施例1 1 # 4-(3-4Η-[1，2，4]三唑-3-基-丙醯胺基）-1Η-吼唑-3-羧酸 (4-氟代-苯基）-醯胺 -149- 200524877 (145)The reaction was performed in a similar manner to that in Example 4 except that 3- (4-chlorophenyl) propionic acid (46 mg; 0.23 mmol) was used as a starting material. The title compound (40 mg) was isolated as a white solid. (LC / MS ·· Rt3.60 [M + H] + 3 8 8). Example 1 1 # 4- (3-4Η- [1,2,4] triazol-3-yl-propanamido) -1Η-oxazole-3-carboxylic acid (4-fluoro-phenyl) -Amine-149- 200524877 (145)

以類似實施例4的方法進行反應，但使用3-三唑-3 _基 丙酸（3611^;0.23111111〇1)當起始物。標題化合物（1811^)被單 離成白色固體。（LC/MS:Rt2.39[M + H] + 344)。 _ 實施例1 2 4-[2-(1-甲基-1-H吲哚-3·基）-乙醯胺基]-1H-卩比唑-3-羧酸 (4-氟代-苯基）-醯胺The reaction was carried out in a manner similar to that in Example 4, except that 3-triazol-3-ylpropionic acid (3611 ^; 0.23111111101) was used as a starting material. The title compound (1811 ^) was isolated as a white solid. (LC / MS: Rt2.39 [M + H] + 344). _ Example 1 2 4- [2- (1-Methyl-1-Hindol-3 · yl) -acetamido] -1H-pyrazole-3-carboxylic acid (4-fluoro-benzene ) -Amidine

以類似實施例4的方法進行反應’但使用N-甲基吲 哚-3 -醋酸（4 8 m g ; 〇 · 2 3 m m ο 1)當起始物。標題化合物 (2 0mg)被單離成白色固體。（LC/MS ·· Rd.34[M + H] + 3 92)。 實施例1 3 4-[(]-羥基-環丙羰基）·胺基]•吡唑-3-羧酸（4_氟代-苯基 -150- 200524877 (146) )-醯胺The reaction was carried out in a manner similar to that of Example 4 except that N-methylindole-3 -acetic acid (48 mg; 0.23 mm 1) was used as a starting material. The title compound (20 mg) was isolated as a white solid. (LC / MS ·· Rd.34 [M + H] + 3 92). Example 1 3 4-[(]-Hydroxy-cyclopropylcarbonyl) · amino] · pyrazole-3-carboxylic acid (4-fluoro-phenyl-150- 200524877 (146)) -fluorenamine

以類似實施例4的方法進行反應，但使用1 -羥S環丙 烷羧酸（26mg ; 0.23mmol)當起始物。標題化合物（24mg)被 單離成白色固體。（LC/MS: Rt2.55[M + H] + 305)。 實施例1 4 1-乙醯-哌啶-4-羧酸[3-(4-氟代-苯基胺基甲醯）-1Η-吡唑- 4-基]-醯胺The reaction was performed in a similar manner to Example 4, except that 1-hydroxyS-cyclopropanecarboxylic acid (26 mg; 0.23 mmol) was used as a starting material. The title compound (24 mg) was isolated as a white solid. (LC / MS: Rt2.55 [M + H] + 305). Example 1 4 1-Acetyl-piperidine-4-carboxylic acid [3- (4-fluoro-phenylaminoformamidine) -1'-pyrazole-4-yl] -fluorenamine

以類似實施例4的方法進行反應，但使用N -乙醯哌啶 醋酸（4 3 mg ; 0.2 3 mmol)當起始物。標題化合物（1 9mg)被單 離成白色固體。（LC/MS: 1^2.49[1^ + ：9] + 374)。 -151 - 200524877 (147) 實施例1 5 4 - [ 3 - ( 4 -甲基-哌嗪-1-基）_丙醯胺基丨η _吼唑-3 -羧酸（4 -氟 代-苯基）-醯胺The reaction was performed in a manner similar to that of Example 4, except that N-acepiperidine acetic acid (43 mg; 0.23 mmol) was used as a starting material. The title compound (19 mg) was isolated as a white solid. (LC / MS: 1 ^ 2.49 [1 ^ +: 9] + 374). -151-200524877 (147) Example 1 5 4-[3-(4-methyl-piperazin-1-yl) -propanamido η η-azole-3 -carboxylic acid (4-fluoro- Phenyl) -amidine

以類似實施例4的方法進行反應，但使用4 -N -甲基哌 嗪_ 1 - N -丙酸（3 1 m g ; 〇 · 2 3 m m ο 1)當起始物。標題化合物 (191^)被單離成白色固體。（[(：/1^:1^1.77[1^ + 11] + 375)。The reaction was performed in a similar manner to Example 4, except that 4-N-methylpiperazine-1-N-propionic acid (31 mg; 0.23 mm 1) was used as a starting material. The title compound (191 ^) was isolated as a white solid. ([(: / 1 ^: 1 ^ 1.77 [1 ^ + 11] + 375).

實施例1 6 4-(2-1Η -咪口坐-4-基-乙醯胺基）_ih-口比哇-3-殘酸（4-氟代苯 基）-醯胺Example 1 6 4- (2-1fluorene-imidazo-4-yl-acetamido) _ih-orbiwa-3-residue (4-fluorophenyl) -amidamine

以類似實施例4的方法進行反應，但使用咪0坐-4-醋酸 (32 mg; 0.23 mmol)當起始物。標題化合物（35 mg)被單離成 白色固體。（LC/MS: Rt1.82[M + H] + 329)。 -152- 200524877 (148) 實施例1 7 4-(3-嗎啉_4_基-丙醯胺基）-1 Η-吡唑-3-羧酸（4_氟代苯 醯胺The reaction was performed in a similar manner as in Example 4 except that mito-4-acetic acid (32 mg; 0.23 mmol) was used as the starting material. The title compound (35 mg) was isolated as a white solid. (LC / MS: Rt1.82 [M + H] + 329). -152- 200524877 (148) Example 1 7 4- (3-morpholin-4-yl-propanamido) -1 hydrazone-pyrazole-3-carboxylic acid (4-fluorophenylhydrazone)

以類似實施例4的方法進行反應，但使用3-嗎啉-4-基-丙酸（4〇11^;0.23111111〇1)當起始物。標題化合物（1511^)被單 離成白色固體。（LC/MS: Rt1.84[M + H] + 362)。 實施例1 8 4-(3-哌啶-1-基-丙醯胺基）-1Η-吡唑-3-羧酸（4-氟代-苯基）-醯胺The reaction was carried out in a similar manner to Example 4, except that 3-morpholin-4-yl-propionic acid (40.1 ?; 0.23111111101) was used as a starting material. The title compound (1511 ^) was isolated as a white solid. (LC / MS: Rt1.84 [M + H] + 362). Example 1 8 4- (3-piperidin-1-yl-propanamido) -1A-pyrazole-3-carboxylic acid (4-fluoro-phenyl) -amidamine

以類似實施例4的方法進行反應，但使用3_哌啶_4_基-丙酸（3 9mg ; 〇.23mmol)當起始物。標題化合物（19nig)被單 離成白色固體。（LC/MS: Rtl.92[M + H] + 360)。 -153- 200524877 (149) 實施例1 9 4-環己基胺基-1 Η-吡唑-3-羧酸（4-氟代-苯基）-醯胺The reaction was performed in a similar manner to Example 4, except that 3-piperidin-4-yl-propionic acid (39 mg; 0.23 mmol) was used as a starting material. The title compound (19nig) was isolated as a white solid. (LC / MS: Rtl.92 [M + H] + 360). -153- 200524877 (149) Example 1 9 4-Cyclohexylamino-1 fluorene-pyrazole-3-carboxylic acid (4-fluoro-phenyl) -amidamine

把3A 分子篩（lg)及三醋酸硼氫化鈉（315mg ; 1.5mmol)加入4-胺基-1H-D比唑-3-羧酸（4-氟代-苯基）-醯胺 (200mg ; lmmol)及環己酮（107mg ; l.lmmol)之二氯甲院 (10ml)溶液中，在室溫下攪拌一個週末。以矽藻土過濾， 以醋酸乙酯稀釋，以鹽溶液沖洗，以硫酸鎂乾燥，蒸發， 得灰色膠體狀產物（48mg)。（LC/MS : Rt2.95，[M + H] + 2 8 5 ) ο 實施例2 0 4-異丙胺基-1 Η-批唑-3-羧酸（4-氟代-苯基）-醯胺Add 3A molecular sieves (lg) and sodium borohydride triacetate (315mg; 1.5mmol) to 4-amino-1H-D-pyrazole-3-carboxylic acid (4-fluoro-phenyl) -amidamine (200mg; lmmol) ) And cyclohexanone (107 mg; 1.1 mmol) in a solution of dichloromethane (10 ml), and stirred at room temperature over the weekend. Filter through celite, dilute with ethyl acetate, rinse with saline solution, dry over magnesium sulfate, and evaporate to obtain a gray colloidal product (48 mg). (LC / MS: Rt2.95, [M + H] + 2 8 5) ο Example 2 0 4-isopropylamino-1 fluorene-pyrazole-3-carboxylic acid (4-fluoro-phenyl)- Amidine

-154- 200524877 (150) 以類似實施例1 9的方法製造標題化合物’但使用丙嗣 替代環己酮。（LC/MS: Rt 2.08’ [M + H] + 245)° 實施例2 1 4 - (2 -羥基-1 ·甲基-乙胺基）-1 Η -吡唑-3 -羧酸（4 -氟代苯基）- 醯胺-154- 200524877 (150) The title compound was prepared in a similar manner to that described in Example 19 except that propionamidine was used in place of cyclohexanone. (LC / MS: Rt 2.08 '[M + H] + 245) ° Example 2 1 4-(2 -Hydroxy-1 · methyl-ethylamino) -1 hydrazone-pyrazole-3 -carboxylic acid (4 -Fluorophenyl)-Amidine

以類似實施例1 9的方法製造標題化合物，但使用羥基 丙酮替代環己酮。1HNMR(4〇〇MHz，D6-DMSO): 9·9(1Η，br s)，7.8(2H，dd)，7·3(1Η，s)，7·15(2Η，t)， 5.15(1H，d)，4·7(1Η’ brs)，3·4(2Η，m)，3·2(1Η，m)， 1 . 1 (3H，d)。 實施例2 2 4-(1-乙基-丙胺基）-1 H-Dtt唑-3-羧酸（4-氟代-苯基）_醯胺The title compound was prepared in a similar manner to that described in Example 19 except that hydroxyacetone was used in place of cyclohexanone. 1HNMR (400 MHz, D6-DMSO): 9.9 (1Η, br s), 7.8 (2H, dd), 7.3 (1Η, s), 7.15 (2Η, t), 5.15 (1H , D), 4 · 7 (1Η 'brs), 3.4 · (2Η, m), 3.2 · (1Η, m), 1.1 (3H, d). Example 2 2 4- (1-Ethyl-propylamino) -1 H-Dttazole-3-carboxylic acid (4-fluoro-phenyl) _amidine

K 以類似實施例1 9的方法製造標題化合物，但使用3 _戊 200524877 (151) 酮替代環己酮。1 HNMR(400MHz，D6-DMSO): 12.85(lh，br s)，9.9(1H，br s)，7·8(2Η，br t)， 7.3(1H，s)，7.15(2H，t)，5·0(1Η，d)，2.9(1ϋ，br 1.5(4H，m)，3.2(1H，m)，0·9(6Η，t)。 實施例2 3 4-(3-氯代-吡嗪-2-基胺基）-lH-Dth唑-3-羧酸（仁氟代-苯基 醯胺K The title compound was prepared in a similar manner to that described in Example 19, except that 3-pentyl 200524877 (151) ketone was used instead of cyclohexanone. 1 HNMR (400MHz, D6-DMSO): 12.85 (lh, br s), 9.9 (1H, br s), 7.8 (2Η, br t), 7.3 (1H, s), 7.15 (2H, t), 5.0 (1 Η, d), 2.9 (1 1.5, br 1.5 (4H, m), 3.2 (1H, m), 0.9 (6 Η, t). Example 2 3 4- (3-chloro-pyridine Azin-2-ylamino) -1H-Dthazole-3-carboxylic acid (enfluoro-phenylphosphonium amine

在CEM DiscoverTM微波合成器中在]50°C(50W)下將 把4·胺基-1H-D比唑-3-羧酸（4-氟代-苯基）-醯胺（50mg ; 0 · 2 3 m m ο 1)及 2，3 -二氯代吡嗪（1 4 0 m g ; 0.9 2 ni m ο 1)的混合 物加熱2 0分鐘。以醋酸乙酯/己烷（1 : 3 — 1 : 2 )洗提行快速 管柱層離提純粗製的反應混合物。把含有產物的級份複合 5蒸發，得白色固體狀標題化合物（15mg)。（LC/MS : Rt4.06[M + H] + 3 3 2)。 實施例2 4 4 - (〇tt嗪-2 -基胺基）-1 Η -吼D坐· 3 -殘酸（4 -氟代-苯基）-醯胺 -156- 200524877 (152)In a CEM DiscoverTM microwave synthesizer, 4 · amino-1H-D-pyrazole-3-carboxylic acid (4-fluoro-phenyl) -amidamine (50mg; 0 · A mixture of 2 3 mm ο 1) and 2,3-dichloropyrazine (140 mg; 0.9 2 ni m ο 1) was heated for 20 minutes. The crude reaction mixture was purified by eluent stripping with ethyl acetate / hexane (1: 3-1: 2). The product containing fractions were evaporated to give the title compound (15 mg) as a white solid. (LC / MS: Rt4.06 [M + H] + 3 3 2). Example 2 4 4-(〇ttazin-2 -ylamino) -1 hydrazone-succinyl 3 -residue acid (4-fluoro-phenyl) -amidamine -156- 200524877 (152)

以類似實施例23的方法製造標題化合物，但使用2-氯 代吼嗪替代2，3-二氯代吡嗪。（LC/MS : Rt3.28[M + H] + 299) 實施例2 5 4_(2_甲氧基-苯甲醯胺基）-1H-批唑_3_羧酸（4_氟代_苯基 醯胺之合成The title compound was prepared in a similar manner to that described in Example 23, except that 2-chloropyrazine was used instead of 2,3-dichloropyrazine. (LC / MS: Rt3.28 [M + H] + 299) Example 2 5 4_ (2_methoxy-benzylamido) -1H-pyrazole_3_carboxylic acid (4_fluoro_ Synthesis of Phenylamine

把2_甲氧基-苯甲酸（38nig; 0·25mmol)加入4-胺基-lH-吡唑-3-羧酸（4-氟代-苯基）-醯胺（50mg;0·23mmOl)， EDC(53mg ; 〇.27mmol)及 HOBt(37mg ; 0.27mmol)之 DM F(5 ml)溶液中。在室溫下攪拌24小時。在減壓下除去 溶劑。以製備性LC/M S提純殘渣，使含產物的級份蒸發 ’得略帶淡紅色的固體狀產物（12]1^，15%)。（1(：/1^· Ri4.00，[M + H] + 3 54.67)。 -157- 200524877 (153) 實施例26 4-苯甲醯胺基-ΙΗ-Dtt唑-3 -殘酸（4_氟代-苯基）_醯胺之合成2-Methoxy-benzoic acid (38nig; 0.25mmol) was added to 4-amino-1H-pyrazole-3-carboxylic acid (4-fluoro-phenyl) -amidamine (50mg; 0.23mmOl) , EDC (53 mg; 0.27 mmol) and HOBt (37 mg; 0.27 mmol) in a solution of DMF (5 ml). Stir at room temperature for 24 hours. The solvent was removed under reduced pressure. The residue was purified by preparative LC / MS, and the fractions containing the product were evaporated to give a slightly reddish solid product (12, 1 ^, 15%). (1 (: / 1 ^ · Ri4.00, [M + H] + 3 54.67). -157- 200524877 (153) Example 26 4-Benzamidoamino-l-Dttazole-3 -residue ( Synthesis of 4_fluoro-phenyl) _amidamine

以類似實施例2 5的方法進行實驗，使用苯甲酸（3 1 m g ，0.25mmol)當起始的酸。產物被單離成淡紅色固體（26mg ，35 0/〇)。（LC/MS: Rt3.96[M + H] + 324.65)° 實施例2 7 4-(環己烷羰基-胺基）-]H-吡唑-3-羧酸（4-氟代-苯基）-醯胺 之合成Experiments were performed in a similar manner to Example 25, using benzoic acid (31 mg, 0.25 mmol) as the starting acid. The product was isolated as a pale red solid (26 mg, 35 0 / 〇). (LC / MS: Rt3.96 [M + H] + 324.65) ° Example 2 7 4- (Cyclohexanecarbonyl-amino)-] H-pyrazole-3-carboxylic acid (4-fluoro-benzene ) -Amine Synthesis

以類似實施例2 5的方法進行實驗，使用環己烷羧酸 (3 2 m g ; 0.2 5 m m ο 1)當起始的酸。產物被卓離成淡紅色固體 (28mg，37%)。（LC/MS : Rt4.16[M + H] + 3 3 0.7 0)。 實施例2 8 -158- 200524877 (154) 4-[(1-甲基-環丙烷羰基）-胺基]-1 Η-吡唑-3-羧酸（4-氟代··苯 基）-醯胺之合成The experiment was carried out in a similar manner to that of Example 25, using cyclohexanecarboxylic acid (32 mg; 0.25 mm as 1) as the starting acid. The product was isolated as a pale red solid (28 mg, 37%). (LC / MS: Rt4.16 [M + H] + 3 3 0.7 0). Example 2 8 -158- 200524877 (154) 4-[(1-methyl-cyclopropanecarbonyl) -amino] -1 hydrazone-pyrazole-3-carboxylic acid (4-fluoro ·· phenyl)- Synthesis of sulfonamide

以類似實施例25的方法進行實驗，使用1 -甲基-環丙 院殘酸（2 5 m g ; 0.2 5 m m ο 1)當起始的酸。產物被單離成淡紅 色固體（24mg，35%)。（LC/MS: Rt3.72[M + H] + 302.68)。 實施例29 4-(2-羥基-乙醯胺基）-1 Η-吡唑-3-羧酸（4-氟代·苯基醯胺 之合成The experiment was carried out in a similar manner to that of Example 25, using 1-methyl-cyclopropaneuronic acid (25 m g; 0.2 5 m m ο 1) as the starting acid. The product was isolated as a pale red solid (24 mg, 35%). (LC / MS: Rt3.72 [M + H] + 302.68). Example 29 Synthesis of 4- (2-hydroxy-acetamido) -1 hydrazone-pyrazole-3-carboxylic acid (4-fluoro · phenylamidoamine)

以類似實施例2 5的方法進行實驗，使用羥基gg酸 (19mg，0.25 mmol)當起始的酸。產物被單離成白色固體 (26mg ^ 41%) ° (LC/MS ： Rt 2.6 5 [ M +Η ] + 2 7 8.6 1 ) 〇 實施例3 0 4-(2，2_二甲基-丙醯胺基）…IH-Dtt唑-3_羧酸（4_氟代-苯基 )-醯胺之合成 -159 &gt; 200524877 (155)Experiments were performed in a similar manner to Example 25, using hydroxygg acid (19 mg, 0.25 mmol) as the starting acid. The product was isolated as a white solid (26 mg ^ 41%) ° (LC / MS: Rt 2.6 5 [M + Η] + 2 7 8.6 1) 〇 Example 3 0 4- (2,2-Dimethyl-propanyl) Amine) ... IH-Dttazole-3_carboxylic acid (4-fluoro-phenyl) -amidine synthesis-159 &gt; 200524877 (155)

以類似實施例25的方法進行實驗，使用2，2-二甲基-丙酸（2 6 m g，0.2 5 m m ο 1)當起始的酸。產物被單離成淡紅色 固體（21mg，30°/〇)。（LC/MS: Rt3.83[M + H] + 3 04.68)。 實施例3 1 4-(3-羥基-丙醯胺基）-1Η-吡唑-3-羧酸（4-氟代-苯基）-醯胺 之合成 ΟExperiments were performed in a similar manner to Example 25, using 2,2-dimethyl-propionic acid (2 6 mg, 0.2 5 m m 1) as the starting acid. The product was isolated as a pale red solid (21 mg, 30 ° / 0). (LC / MS: Rt3.83 [M + H] + 3 04.68). Example 3 1 Synthesis of 4- (3-hydroxy-propanamido) -1H-pyrazole-3-carboxylic acid (4-fluoro-phenyl) -fluorenamine 〇

以類似實施例2 5的方法進行實驗，使用3 -羥基-丙酸 (75.1mg ; 0.25mm〇l)當起始的酸。產物被單離成灰棕色固 體（5mg，8%)。（LC/MS : Rt2.58[M + H] + 292.65)。 實施例3 2 1(2-氟代-苯甲醯胺基）-1Η-吡唑-3-羧酸（4_氟代-苯基）_醯 胺之合成 -160- 200524877 (156)Experiments were performed in a similar manner to Example 25, using 3-hydroxy-propionic acid (75.1 mg; 0.25 mm) as the starting acid. The product was isolated as a gray-brown solid (5 mg, 8%). (LC / MS: Rt2.58 [M + H] + 292.65). Example 3 Synthesis of 2 1 (2-Fluoro-benzylamido) -l-pyrazole-3-carboxylic acid (4-fluoro-phenyl) -fluorenamine -160- 200524877 (156)

把2-氟代苯甲酸（36mg，0.25mmol)加入4-胺基-1H-吡 唑-3-羧酸（4-氟代·苯基）-醯胺（50mg，0.23mmol)， EDC(53mg ， 0.27mmol)及 HOBt(37mg ， 0.27mmol)之 DMSO( lml)溶液中。在室溫下攪拌24小時，以製備性 LC/MS提純。把含有產物的級份蒸發得白色固體狀產物 (15mg，19%)。(LC/MS ： Rt 3 · 9 1 [ Μ + Η ] + 3 4 2.6 6 )。 實施例3 3 4-(3-氟代-苯甲醯胺基）-1 Η-吡唑-3 ·羧酸（4-氟代-苯基）_醯 胺之合成Add 2-fluorobenzoic acid (36 mg, 0.25 mmol) to 4-amino-1H-pyrazole-3-carboxylic acid (4-fluoro · phenyl) -amidamine (50 mg, 0.23 mmol), EDC (53 mg , 0.27 mmol) and HOBt (37 mg, 0.27 mmol) in DMSO (1 ml). Stir at room temperature for 24 hours and purify by preparative LC / MS. The product containing fractions were evaporated to give the product as a white solid (15 mg, 19%). (LC / MS: Rt 3 · 9 1 [Μ + Η] + 3 4 2.6 6). Example 3 3 Synthesis of 4- (3-fluoro-benzylamino) -1 -pyridazole-3 · carboxylic acid (4-fluoro-phenyl) _fluorene

以類似實施例3 2的方式進行反應，使用3 -氟代苯甲酸 (36mg，0.25mmol)當起始的酸。產物被單離成白色固體 (19mg，2 4%) 〇 (LC/MS ： Rt4 · 0 3 [ Μ+ H ] + 3 4 2 · 6 7)。 實施例3 4 4-(3-甲氧基-苯甲醯胺基）-1 Η-吡唑·3-羧酸（4-氟代-苯基） -161 - 200524877 (157) 醯胺之合成The reaction was performed in a similar manner to Example 32 using 3-fluorobenzoic acid (36 mg, 0.25 mmol) as the starting acid. The product was isolated as a white solid (19 mg, 24%). (LC / MS: Rt4 · 0 3 [M + H] + 3 4 2 · 6 7). Example 3 4 Synthesis of 4- (3-methoxy-benzylamido) -1 hydrazone-pyrazole · 3-carboxylic acid (4-fluoro-phenyl) -161-200524877 (157) Synthesis of amine

以類似實施例32的方法進行反應’使用3_甲氧基-苯 甲酸（3 9mg ; 0.2 5mmol)當起始的酸。產物被單離成白色固 體（20mg，25%)。（LC/MS : Rt3.97[M + H] + 3 54.6 8)。 實施例3 5 4-(2-硝基-苯甲醯胺基）_1H-吡唑-3-羧酸（4-氟代-苯基）-醯 胺The reaction was carried out in a similar manner to Example 32 'using 3-methoxy-benzoic acid (39 mg; 0.2 5 mmol) as the starting acid. The product was isolated as a white solid (20 mg, 25%). (LC / MS: Rt3.97 [M + H] + 3 54.6 8). Example 3 5 4- (2-Nitro-benzylideneamino) _1H-pyrazole-3-carboxylic acid (4-fluoro-phenyl) -fluorenamine

以類似實施例32的方法進行反應，使用2_硝基苯甲酸 (43mg ; 〇.25mmol)當起始的酸。產物被單離成白色固體 (17mg. 20%)° (LC/MS: R,3.67[M + H] + 369.66)〇 實施例3 6 硝基-苯甲醯胺基吼哩竣酸（4_氟代-苯基）_酿 胺之合成 -162- 200524877 (158)The reaction was performed in a similar manner to Example 32, using 2-nitrobenzoic acid (43 mg; 0.25 mmol) as the starting acid. The product was isolated as a white solid (17 mg. 20%) ° (LC / MS: R, 3.67 [M + H] + 369.66). Example 3 6 Nitro-benzylamine glutamic acid (4-fluoro -Phenyl) _Synthesis of Fermented Amine-162- 200524877 (158)

Μ 以類似實施例3 2的方式進行反應’使用4 -硝基苯甲酸 (43mg，0.25mmol)當起始的酸。產物被單離成白色固II (15mg，18%)。（LC/MS : Rt3.98[M + H] + 3 69.63 )。 實施例3 7 4-[(3·甲基-呋喃-2_羰基）-胺基]-1Η·批唑_3·羧酸（4-氟代· 苯基）-醯胺之合成The reaction was performed in a manner similar to that of Example 32 'using 4-nitrobenzoic acid (43 mg, 0.25 mmol) as the starting acid. The product was isolated as a white solid II (15 mg, 18%). (LC / MS: Rt3.98 [M + H] + 3 69.63). Example 3 7 Synthesis of 4-[(3 · methyl-furan-2_carbonyl) -amino] -1Η · pyrazole-3 · carboxylic acid (4-fluoro · phenyl) -amidamine

以類似實施例3 2的方式進行反應，使用3 ·甲基-2-呋 喃羧酸（32mg，0.25mmol)當起始的酸。產物被單離成白色 固體（15mg，20%)。（LC/MS: Rt3.86[M + H] + 3 2 8.6 8)。 實施例3 8 4_[(呋喃-2-羰基）-胺基]-1Η-吡唑-3-羧酸（4-氟代-苯基）·醯 胺之合成 -163- 200524877 (159)The reaction was carried out in a similar manner to Example 32 using 3-methyl-2-furancarboxylic acid (32 mg, 0.25 mmol) as the starting acid. The product was isolated as a white solid (15 mg, 20%). (LC / MS: Rt3.86 [M + H] + 3 2 8.6 8). Example 3 8 Synthesis of 4 _ [(furan-2-carbonyl) -amino] -1'-pyrazole-3-carboxylic acid (4-fluoro-phenyl) · fluorene -163- 200524877 (159)

以類似實施例3 2的方式進行反應，使用2 -呋喃羧酸 (29mg，0.25mmol)當起始的酸。產物被單離成白色固體 (18mg，2 5 0/〇)。（LC/MS: Rt3.56[M + H] + 314.64)。 實施例3 9 4-[(3H-咪唑-4-羰基）-胺基]-1H-吼唑-3-羧酸（4-氟代-苯基 )-醯胺之合成The reaction was performed in a similar manner to Example 32 using 2-furancarboxylic acid (29 mg, 0.25 mmol) as the starting acid. The product was isolated as a white solid (18 mg, 250/0). (LC / MS: Rt3.56 [M + H] + 314.64). Example 3 9 Synthesis of 4-[(3H-imidazole-4-carbonyl) -amino] -1H-nizol-3-carboxylic acid (4-fluoro-phenyl) -amidamine

以類似實施例32的方式進行反應，使用1H-咪唑-4-羧 酸（29mg，0.25mmol)當起始的酸。產物被單離成白色固體 (16mg，22%)。（LC/MS : Rt 2.5 9 [ M + Η ] + 3 1 4.6 5 )。 實施例40The reaction was performed in a similar manner to Example 32, using 1H-imidazole-4-carboxylic acid (29 mg, 0.25 mmol) as the starting acid. The product was isolated as a white solid (16 mg, 22%). (LC / MS: Rt 2.5 9 [M + Η] + 3 1 4.6 5). Example 40

4-(4-氟代-苯甲醯胺基）-ΐΗ-吡唑-3-羧酸（4-氣 胺之合成 -164- 200524877 (160)Synthesis of 4- (4-fluoro-benzylamino) -pyridine-pyrazole-3-carboxylic acid (4-aminoamine -164- 200524877 (160)

以類似實施例3 2的方式進行反應，使用4 -氟代衆 、本申酸 (36mg，0.25mmol)當起始的酸。產物被單離成淡酱任 -、边囱體 (23mg，29%)。（LC/MS : Rt4 · 00 [M + H]+ 3 42.67)。 實施例4 1 4-(2，6_二氟代-苯甲醯胺基）·1Η-吡唑_3·羧酸（扣氟代％ 基）-醯胺之合成The reaction was carried out in a manner similar to Example 32, using 4-fluoroazepine and Bensonic acid (36 mg, 0.25 mmol) as the starting acid. The product was isolated into a mild sauce, a side body (23mg, 29%). (LC / MS: Rt4 · 00 [M + H] + 3 42.67). Example 4 Synthesis of 1 4- (2,6_difluoro-benzamidino) · 1Η-pyrazole_3 · carboxylic acid (% fluorinated) -amidamine

以類似實施例3 2的方式進行反應，使用2，6-二氟代 苯甲酸（40mg，0.25mmol)當起始的酸。產物被單離成淡黃 色固體（25mg，30%)。（LC/MS: Rt3.76[M + H] + 3 60.66)。 實施例4 2 4-(3-硝基-苯甲醯胺基）-1 Η-吡唑-3-羧酸（4-氟代-苯基）-醯 胺之合成 •165- 200524877 (161)The reaction was performed in a similar manner to Example 32 using 2,6-difluorobenzoic acid (40 mg, 0.25 mmol) as the starting acid. The product was isolated as a pale yellow solid (25 mg, 30%). (LC / MS: Rt3.76 [M + H] + 3 60.66). Example 4 2 Synthesis of 4- (3-nitro-benzylideneamino) -1 fluorene-pyrazole-3-carboxylic acid (4-fluoro-phenyl) -fluorenamine • 165- 200524877 (161)

以類似實施例32的方式進行反應，使用3-硝基苯甲酸 (43mg，0.25mmol)當起始的酸。產物被單離成淡黃色固體 (15mg，18%)。（LC/MS : R t 3.9 4 [ M + Η ] + 3 6 9 · 6 5 )。 實施例4 3 1 Η-D弓丨哚-3-羧酸[3-(4-氟代-苯基胺基甲醯）-1 Η-吼唑-4-基]- 醯胺之合成The reaction was performed in a manner similar to Example 32, using 3-nitrobenzoic acid (43 mg, 0.25 mmol) as the starting acid. The product was isolated as a pale yellow solid (15 mg, 18%). (LC / MS: R t 3.9 4 [M + Η] + 3 6 9 · 6 5). Example 4 3 1 Synthesis of fluorene-D bowline indole-3-carboxylic acid [3- (4-fluoro-phenylaminomethylformamidine) -1 fluorene-amidazol-4-yl] -fluorenamine

以類似實施例32的方式進行反應，使用吲哚_ (4lmg，0.25mmol)當起始的酸。產物被單離成鐵銹色固於 (14mg，17%)。(LC/MS ： R13 · 6 0 [ Μ + Η ] + 3 6 3 · 6 6)。 實施例4 4 4-(4 -羥基甲基-苯甲醯胺基）-1 Η-吡唑羧酸（4_氟代 )-醯胺之合成 -166- 200524877 (162)The reaction was performed in a similar manner to Example 32, using indole (4lmg, 0.25mmol) as the starting acid. The product was isolated to a rust-colored solid (14 mg, 17%). (LC / MS: R13.60 [M + Η] + 3 6 3 · 6 6). Example 4 4 Synthesis of 4- (4-hydroxymethyl-benzylamido) -1 -pyridazolecarboxylic acid (4-fluoro) -amidamine -166- 200524877 (162)

OHOH

〇〇

F 以類似實施例3 2的方式進行反應，使用4 -羥基甲基苯 甲酸（39mg，0.25mmol)當起始的酸。產物被單離成白色固 體（19mg，23%)。（LC/MS: Rt3.12[M + H] + 3 54.68)。 實施例45 4-(3-甲基-苯甲醯胺基唑-3·羧酸（4-氟代-苯基）_醯 胺之合成F The reaction was performed in a similar manner to Example 32 using 4-hydroxymethylbenzoic acid (39 mg, 0.25 mmol) as the starting acid. The product was isolated as a white solid (19 mg, 23%). (LC / MS: Rt3.12 [M + H] + 3 54.68). Example 45 Synthesis of 4- (3-methyl-benzylamidominazole-3 · carboxylic acid (4-fluoro-phenyl) _amidine

以類似實施例3 2的方式進行反應，使用3 -甲基苯甲酸 (3 5m g，0.2 5 mmol)當起始的酸。產物被單離成非純白色固 體（21mg，27%)。（LC/MS: Rt4.13[M + H] + 3 3 8.7 l)。 實施例4 6 4-(2-甲基-苯甲醯胺基）-1 Η-吡唑-3-羧酸（4-氟代-苯基）-醯 胺之合成 -167- 200524877 (163)The reaction was performed in a similar manner to Example 32 using 3-methylbenzoic acid (35 mg, 0.2 5 mmol) as the starting acid. The product was isolated as a non-pure white solid (21 mg, 27%). (LC / MS: Rt4.13 [M + H] + 3 3 8.7 l). Example 4 6 Synthesis of 4- (2-methyl-benzylideneamino) -1 hydrazone-pyrazole-3-carboxylic acid (4-fluoro-phenyl) -fluorenamine -167- 200524877 (163)

以類似實施例32的方式進行反應，使用2-甲基苯甲酸 (35mg，0.25mmol)當起始的酸。產物被單離成非純白色固 體（20mg，26%)。（LC/MS: Rt4.05[M + H] + 3 3 8.6 9)。 實施例4 7 4-(4 -甲基-苯甲醯胺基）-1Η-吼唑-3-羧酸（4-氟代-苯基）-醯 胺之合成The reaction was performed in a similar manner to Example 32, using 2-methylbenzoic acid (35 mg, 0.25 mmol) as the starting acid. The product was isolated as a non-pure white solid (20 mg, 26%). (LC / MS: Rt4.05 [M + H] + 3 3 8.6 9). Example 4 7 Synthesis of 4- (4-methyl-benzylideneamino) -1Η-oxazol-3-carboxylic acid (4-fluoro-phenyl) -fluorenamine

以類似實施例3 2的方式進行反應，使用4 -甲基苯甲酸 (35mg，0.25mmol)當起始的酸。產物被單離成非純白色固 體（19mg，24%)。（LC/MS: Rt4.16[M + H] + 3 3 8.70)。 實施例4 8 4_[(2·甲基-噻吩- &gt; 羰基）·胺基]·1Η_吡唑羧酸（4-氟代 苯基）-醯胺之合成 -168- 200524877 (164)The reaction was performed in a similar manner to Example 32 using 4-methylbenzoic acid (35 mg, 0.25 mmol) as the starting acid. The product was isolated as a non-pure white solid (19 mg, 24%). (LC / MS: Rt4.16 [M + H] + 3 3 8.70). Example 4 8 4 _ [(2 · methyl-thiophene- &gt; carbonyl) · amino] · 1Η-pyrazolecarboxylic acid (4-fluorophenyl) -amidine synthesis -168- 200524877 (164)

把2 -甲基_3_噻吩羧酸（36mg，0.25mmol)加入4-胺基-1 Η -吡唑-3 -羧酸（4 -氟代-苯基）_醯胺（實施例2 b ) ( 5 〇 m g， 0.23mmol) ， EDC(53mg ， 0.27mmol)及 HOBt(37mg ， 0.27mmol)之D M S O (1 m 1)溶液中。在室溫下攪拌2 4小時。 把反應混合物滴入水（3 〇ml)中，過濾收集所得到的固體， 以水沖洗，將水吸乾。得到米色固體（1 5 m g，1 9 %)。 (LC/MS : Rt4.08[M + H] + 344.67) 〇 實施例4 9 D奎啉-2 -羧酸[3 - (4 -氟代-苯基胺基甲醯）-1 Η -吼唑-4 -基]-醯 胺之合成2-Methyl-3-thiophenecarboxylic acid (36 mg, 0.25 mmol) was added to 4-amino-1 fluorene-pyrazole-3 -carboxylic acid (4-fluoro-phenyl) -fluorenamine (Example 2 b ) (50 mg, 0.23 mmol), EDC (53 mg, 0.27 mmol) and HOBt (37 mg, 0.27 mmol) in DMSO (1 ml) solution. Stir at room temperature for 24 hours. The reaction mixture was dropped into water (30 ml), and the resulting solid was collected by filtration, washed with water, and blotted with water. Obtained as a beige solid (15 mg, 19%). (LC / MS: Rt4.08 [M + H] + 344.67) 〇 Example 4 9 Dquinoline-2 -carboxylic acid [3-(4-fluoro-phenylaminomethylformamidine) -1 hydrazone Synthesis of azole-4 -yl] -amidamine

以類似實施例4 8的方式進行反應’使用D奎哪啶酸 (44mg，0.25m mol)當起始的酸。產物被單離成棕色固體 (16mg，19%)。（LC/MS: Rt4.29[M + H] + 3 7 5.6 6 )。 實施例5 0 -169- 200524877The reaction was performed in a manner similar to Example 48 using D-quinalac acid (44 mg, 0.25 m mol) as the starting acid. The product was isolated as a brown solid (16 mg, 19%). (LC / MS: Rt4.29 [M + H] + 3 7 5.6 6). Example 5 0 -169- 200524877

XX 以類似實施例48的方式進行反應，使用噻吩-3 __ _ (33mg，0.25mmol)當起始的酸。產物被單離成米色固於 (15mg，20%)。（LC/MS : Rt3.77[M + H] + 3 3 0.6 1 )。 實施例5 1 4_(2_氟代_3_甲氧基-苯甲醯胺基）-1Η-吡唑-3-羧酸（4_氟代 苯基）-醯胺之合成XX The reaction was performed in a manner similar to Example 48, using thiophene-3 (33 mg, 0.25 mmol) as the starting acid. The product was isolated as a beige solid (15 mg, 20%). (LC / MS: Rt3.77 [M + H] + 3 3 0.6 1). Example 5 1 Synthesis of 4_ (2_fluoro_3_methoxy-benzylamido) -1′-pyrazole-3-carboxylic acid (4-fluorophenyl) -amidamine

K—N 在室溫下在DMSO(1.25ml)中把2-氟代-3-甲氧基苯甲 酸（0.047g，〇.28mmol)，4-胺基-1H-口比唑-3-羧酸（4-氟代· 苯基）-醯胺（實施例 2B)(0.0 5 5 g，0.25mmol)，EDC(0.58g， 〇 . 3 0 m ηι ο 1)及 Η Ο B t ( 0.0 4 1 g，0 · 3 0 m m ο 1)攪拌 5 小時。把反應 混合物倒入水（3 〇ml)中。過濾收集所得到的固體，在真空 -170- 200524877 (166) 爐中乾燥，得灰色固體狀標題化合物（0.0 5 8 g，63%)。 (LC/MS : Rt3.99[MH] + 3 72.9 8 )。 實施例5 2 4-[2-(2-吡咯烷-卜基-乙氧基）-苯甲醯胺基]_11^吡唑-3-羧 酸-4-氟代苯基醯胺之合成 52A 2-(2-吡咯烷-卜基-乙氧基）·苯甲酸甲酯K—N is 2-fluoro-3-methoxybenzoic acid (0.047 g, 0.28 mmol), 4-amino-1H-orbizol-3-carboxylate in DMSO (1.25 ml) at room temperature. Acid (4-fluoro · phenyl) -amidamine (Example 2B) (0.0 5 5 g, 0.25 mmol), EDC (0.58 g, 0.30 m η 1) and Η Ο B t (0.0 4 1 g, 0 · 30 mm ο 1) Stir for 5 hours. The reaction mixture was poured into water (30 ml). The resulting solid was collected by filtration and dried in a vacuum-170-200524877 (166) oven to give the title compound (0.0 5 8 g, 63%) as a gray solid. (LC / MS: Rt3.99 [MH] + 3 72.9 8). Example 5 2 Synthesis of 4- [2- (2-pyrrolidine-butyl-ethoxy) -benzamidinyl] _11 ^ pyrazole-3-carboxylic acid-4-fluorophenylphosphonium amine 52A 2- (2-Pyrrolidine-butyl-ethoxy) · methyl benzoate

把偶氮羧酸二異丙酯（〇.4〇4g，2mmol)滴入三苯膦 (〇.5 24g，2mmol)之 THF(lOml)溶液中。滴入水楊酸甲酯 (〇.3 04g，2mmol)，在室溫下攪拌1小時。滴入1，2-羥基 乙基吡咯烷（0.2 3 0g，2mmol)，在室溫下攪拌1 .5小時。在 真空中濃縮，以己烷：醋酸乙酯（5 : 1，1 : 1 )，醋酸乙酯 :甲醇（4 : 1 )洗提行快速管柱層離，得澄淸黃色油體狀產 物（0.104g，21%)。（LC/MS : Rt0.69，1·62，[Μ + Η] + 250·02Diisopropyl azocarboxylate (0.404 g, 2 mmol) was added dropwise to a solution of triphenylphosphine (0.524 g, 2 mmol) in THF (10 ml). Methyl salicylate (0.304 g, 2 mmol) was added dropwise, and the mixture was stirred at room temperature for 1 hour. 1,2-Hydroxyethylpyrrolidine (0.2 3 0 g, 2 mmol) was added dropwise, and the mixture was stirred at room temperature for 1.5 hours. Concentrate in vacuo, elute with hexane: ethyl acetate (5: 1, 1: 1), ethyl acetate: methanol (4: 1), and perform rapid column delamination to obtain a clear yellow oily product ( 0.104 g, 21%). (LC / MS: Rt 0.69, 1.62, [Μ + Η] + 250 · 02

52Β 4-[2-(2-吡咯烷-卜基-乙氧基）·苯甲醯胺基]比唑_ 3 -殘酸心氟代苯基醯胺 -171 - 200524877 (167)52B 4- [2- (2-Pyrrolidine-butyl-ethoxy) · benzylamido] pyrazole_ 3 -residue acid fluorophenylamidamine -171-200524877 (167)

FF

以2M氫氧化鈉水溶液（20ml)及水（20ml)處理2-(2-D比 咯烷-1-基-乙氧基）_苯甲酸甲酯（〇」〇4g，〇.42mmol)。在室 溫下攪拌20小時，在真空中濃縮，與甲苯（3 X 5ml)共沸。 加入水（5 0 m 1 )，以1 Μ鹽酸使混合物酸化至ρ Η 5。在真空 中濃縮，與甲苯（3x5ml)共沸，得白色固體，把固體與4_ 胺基-1H-吡唑-3-羧酸（4-氟代-苯基）-醯胺（實施例 2B)(0.05 5 g ， 0.25mmol) ， EDC(0.05 8g ， 0.3mmol)及 HOBt(0.04 1 g，0.3mmol)複合，在室溫下在 DMSO(3ml)中 攪拌20小時。把反應混合物倒入水（3 0ml)中，過濾收集所 得到的固體，在真空爐中乾燥，得灰色固體狀標題化合物 (0.015g，14%)。（LC/MS : Rt2.I8[MH]+43 8.06)。The 2- (2-D-rrolidin-1-yl-ethoxy) -benzoic acid methyl ester (0.44 g, 0.42 mmol) was treated with a 2M aqueous sodium hydroxide solution (20 ml) and water (20 ml). It was stirred at room temperature for 20 hours, concentrated in vacuo and azeotroped with toluene (3 X 5 ml). Water (50 m 1) was added and the mixture was acidified to ρ Η 5 with 1 M hydrochloric acid. Concentrated in vacuo and azeotroped with toluene (3x5ml) to give a white solid. The solid was mixed with 4-amino-1H-pyrazole-3-carboxylic acid (4-fluoro-phenyl) -amidamine (Example 2B) (0.05 5 g, 0.25 mmol), EDC (0.05 8 g, 0.3 mmol) and HOBt (0.04 1 g, 0.3 mmol) were combined, and stirred in DMSO (3 ml) at room temperature for 20 hours. The reaction mixture was poured into water (30 ml), and the resulting solid was collected by filtration and dried in a vacuum oven to obtain the title compound (0.015 g, 14%) as a gray solid. (LC / MS: Rt2.I8 [MH] +43 8.06).

實施例5 3 4-(2，6-二氟代-苯甲醯胺基唑-3-羧酸（1-甲基-哌 啶-4-基）-醯胺之合成Example 5 3 Synthesis of 4- (2,6-difluoro-benzimidazol-3-carboxylic acid (1-methyl-piperidin-4-yl) -amidamine

N Η -172- 200524877 (168) 在週遭溫度下把4 - ( 2，6 -二氟代苯甲醯胺基）d H _吡 唑-3 -羧酸（1 3 4 m g，0.5 0 m m ο 1)，4 -胺基-Ν -甲基哌啶（5 0.0 // 1 ， 0.45mmol) ， ED AC( 1 04mg ， 〇. 5 4mmol)及 Η〇B t ( 7 3 . 0 m g，0.5 4 m m o 1)之D M F ( 3 m 1)溶液的混合物攪拌 1 6小時。在真空中濃縮，使殘渣溶於醋酸乙醋中，依序以 飽和碳酸氫鈉水溶液、水及鹽溶液沖洗。以硫酸鎂乾燥有 機的部份，在真空中濃縮有機的部份，得白色固體狀4_(2 ’ 6 -二氟代-苯甲醯胺基）-1 Η -吡唑-3 -羧酸（1 -甲基-哌啶烷_ 4 -基）-醯胺（113mg，69%)。（LC/MS: Rt2.52[M + H] + 364.19 實施例5 4 4-(環己基-甲基-胺基比嗅-3-殘酸（4-氟代-苯基）_醯胺 之合成N Η -172- 200524877 (168) Put 4-(2,6-difluorobenzylamine) d H _pyrazole-3 -carboxylic acid (1 3 4 mg, 0.5 0 mm) at ambient temperature 1), 4-amino-N-methylpiperidine (5 0.0 // 1, 0.45 mmol), ED AC (104 mg, 0.54 mmol) and Η〇t (7.3. 0 mg, 0.5 4 A mixture of mmo 1) in DMF (3 ml) was stirred for 16 hours. Concentrate in vacuo, dissolve the residue in ethyl acetate, and rinse sequentially with a saturated sodium bicarbonate aqueous solution, water, and a saline solution. The organic portion was dried with magnesium sulfate, and the organic portion was concentrated in vacuo to obtain 4_ (2 '6-difluoro-benzylamido) -1Η-pyrazole-3-carboxylic acid ( 1-methyl-piperidin-4-yl) -amidamine (113 mg, 69%). (LC / MS: Rt2.52 [M + H] + 364.19 Example 5 4 4- (Cyclohexyl-methyl-amino group than ol-3-residual acid (4-fluoro-phenyl) _amidine synthesis

以類似實施例1 9的化合物的方式製造此化合物，先使 用環己酮，後使用甲醛行連續的還原胺化作用。（LC/MS :Rt2.77[MH] + 3 1 6·7 1 )。 實施例5 5 -173- 200524877 (169) 4 -(吡啶-2 -基胺基）-1 Η -吼唑-3 -羧酸（4 _氟代-苯基）_醯胺This compound was prepared in a manner similar to the compound of Example 19, using cyclohexanone first, and then continuous reductive amination using formaldehyde. (LC / MS: Rt2.77 [MH] + 3 1 6 · 7 1). Example 5 5 -173- 200524877 (169) 4-(Pyridin-2-ylamino) -1 hydrazone-imidazole-3 -carboxylic acid (4-fluoro-phenyl) -fluorenamine

以類似實施例2 3之化合物的方式製造標題化合物。 (LC/MS : Rt2.07[MH] + 29 8.03 )。 籲 實施例56-81 在表3中被陳述的化合物係利用下列方式被製造：遵 循在前面的實施例或其之類似的方法中所描述的步驟，或 使用在上面的實施例及精於此藝的人士所熟悉的合成方法 中所描述的化合物進行化學變化。 -174- 200524877 (170) 表3 實施例 編號 結構式 使用類似下 列實施例的 方式製造 與下列實施 例的差異？ LCMS 56 HN〆^。 Φ F 4 Rt 3.20 min [M+Hf 406.07 57 HN〆^。 Φ F 4 如在實施例82 中所描述的方 式以TFA去除 第三丁氧羰基 保護基團 Rt 2.35 min m/z 343.72 58 ΗΝ^^Ο φ F 4 使用DMS〇 替代DMF當 溶劑 Rt 3.51 min m/z 314.62 59 Φ F — 4 使用DMS0 替代DMF當 溶劑 1^3.79 min m/z 363.67 60 Ν—Ν μ SM 0 丫 ΜΗ 0 崎。\ 48 以醋酸乙酯 :石油醚洗 提行管柱層 離提純 Rt 3.68 min m/z 384.69 61 ΗΝ^^Ο Φ F 48 以醋酸乙酯 :石油醚洗 提行管柱層 離提純 Rt 3.61 min m/z 326.10The title compound was prepared in a similar manner to the compound of Example 23. (LC / MS: Rt2.07 [MH] + 29 8.03). Example 56-81 The compounds stated in Table 3 were prepared by following the steps described in the previous example or a similar method, or using the examples above and their refinements. The chemical compounds described in the synthetic methods are familiar to those skilled in the art. -174- 200524877 (170) Table 3 Examples No. Structural formula Manufactured in a manner similar to the following examples Differences from the following examples? LCMS 56 HN〆 ^. Φ F 4 Rt 3.20 min [M + Hf 406.07 57 HN〆 ^. Φ F 4 The third butoxycarbonyl protecting group Rt was removed by TFA in the manner described in Example 82. Rt 2.35 min m / z 343.72 58 ΗΝ ^^ Ο φ F 4 DMS was used instead of DMF as the solvent Rt 3.51 min m / z 314.62 59 Φ F — 4 Use DMS0 instead of DMF as the solvent 1 ^ 3.79 min m / z 363.67 60 Ν—Ν μ SM 0 λMΗ 0 Saki. \ 48 Ethyl acetate: petroleum ether elution and column purification Rt 3.68 min m / z 384.69 61 ΗΝ ^^ 〇 Φ F 48 Ethyl acetate: petroleum ether elution and column purification Rt 3.61 min m / z 326.10

- 175- 200524877 (171) 實施例 編號 結構式 使用類似下 列實施例的 方式製造 以下列實施 例的差異？ LCMS 62 ΟγΝΗ ° 48 以醋酸乙酯 :石油醚洗 提行管柱層 離提純 Rt 3.51 min m/z387.11 63 ΗΝ|/^0 Φ F 48 Rt 3.11 min m/z 313.65 64 οκ 0 丫 ΝΗ 〇 48 以醋酸乙酯 :石油醚洗 提行管柱層 離提純 Rt 2.20 min m/z 455.19 65 Ν—Ν Η SVO ΟγΝΗ U FtrF 53 Rt 3.95 min m/z 349.09 66 Ν一Ν μ 〜 ντο ΟγΝΗ ϋ FtrF 48 以醋酸乙酯 :石油醚洗 提行管柱層 離提純 Rt 2.39 min m/z 351.07-175- 200524877 (171) Example No. Structural formula Manufactured in a manner similar to the following examples Differences in the following examples? LCMS 62 ΟγΝΗ ° 48 Rt 3.51 min m / z387.11 63 with ethyl acetate: petroleum ether extraction column purification ΗΝ | / ^ 0 Φ F 48 Rt 3.11 min m / z 313.65 64 οκ 0 丫 ΝΗ 〇 48 Ethyl acetate: petroleum ether stripping column purification Rt 2.20 min m / z 455.19 65 Ν—Ν Η SVO ΟγΝΗ U FtrF 53 Rt 3.95 min m / z 349.09 66 Ν 一 Ν μ ~ ντο ΟγΝΗ ϋ FtrF 48 Ethyl acetate: petroleum ether stripping column purification Rt 2.39 min m / z 351.07

-176- 200524877 (172) 實施例 編號 結構式 使用類似下 列實施例的 方式製造 以下列實施 例的差異？ LCMS 67 Η Π ΟγΝΗ 〇 ☆ 48 以醋酸乙酯 :石油醚洗提 行管柱層離 提純 Rt2.83 min m/z 365.13 68 Ν—Ν VST ΟγΝΗ 〇 以TFA-苯甲 醚從如實施 例62的化合 物除去PMB 某團 Rt 2.10 min m/z 266.97 69 〇^/Νη 0 48 使DMF替代 DMSO當溶 劑 Rt 3.22 min m/z 363.10 70 Ν—Ν μ ΟγΝΗ ° 48 Rt 4.48 min m/z 358.96 71 ΟγΝΗ U ΗΌ 48 Rt 3.93 rain m/z 340.96 72 Ν—Ν μ 〜 ΟγΝΗ ϋ A 48 Rt4.11 min m/z 373.01 -177- 200524877(173) 實施例 編號 結構式 使用類似下 列實施例的 方式製造 以下列實施 例的差異？ LCMS 73 N—N H V^iNO 丫Η 又 48 使用DMF替 代DMS0當 溶劑 Rt 2.56 min m/z 373.05 74 如實施例73 的方式先後 以氧丨b還原 胺化作用製 得 Rt 1.99 min m/z 442.09 75 ΟγΝΗ ° FXrF 53 以DCM:MeOH 〇V至 19··1) 洗提行管柱 層離提純 Rt3.65 min m/z 335.03 76 β—Ν Η VYO ΟγΝΗ ° FtrF 25 以管柱層離提 純以飽和醋酸 乙酯/鹽酸除去 第三丁氣羰基 Rt 1.57 min m/z 350.10 77 HN '0 ό 53 Rt 5.05 min m/z 405.14-176- 200524877 (172) Examples No. Structural formula Manufactured in a manner similar to the following examples Differences in the following examples? LCMS 67 Η Π ΟγΝΗ 〇 ☆ 48 Ethyl acetate: petroleum ether stripping and column purification Rt2.83 min m / z 365.13 68 Ν—Ν VST ΟγΝΗ〇 Using TFA-anisole from Example 62 Compound removal of PMB Rt 2.10 min m / z 266.97 69 〇 ^ / Νη 0 48 Make DMF replace DMSO as solvent Rt 3.22 min m / z 363.10 70 Ν—Ν μ 〇γΝΟ ° 48 Rt 4.48 min m / z 358.96 71 ΟγΝΗ U ΗΌ 48 Rt 3.93 rain m / z 340.96 72 Ν—Ν μ ~ ΟγΝΗ 48 A 48 Rt4.11 min m / z 373.01 -177- 200524877 (173) Example No. The structural formula is manufactured using a method similar to the following example. Case difference? LCMS 73 N—NHV ^ iNO 丫 Η and 48 use DMF instead of DMS0 as solvent Rt 2.56 min m / z 373.05 74 As in Example 73, Rt 1.99 min m / z 442.09 75 was obtained by reductive amination with oxygen and b. ΟγΝΗ ° FXrF 53 DCM: MeOH 〇V to 19 ·· 1) Elution purification column column purification Rt3.65 min m / z 335.03 76 β-Ν Η VYO 〇γΝΗ ° FtrF 25 Purification by column separation to saturation Ethyl acetate / hydrochloric acid removes third butyl carbonyl Rt 1.57 min m / z 350.10 77 HN '0 ό 53 Rt 5.05 min m / z 405.14

-178- 200524877(174) 實施例 編號 結構式 使用類似下 列實施例的 方式製造 與下列實施 例的差異？ LCMS 78 53 Rt 2.87 min m/z416.07 79 °γΝΗ ° 53 以醋酸乙酯 :石油醚(1:1) 洗提行管柱 層離提純 Rt3.41 min m/z 321.03 80 Ν—N u ΟγΝΗ 。 Fw 2A, 2B &amp; 53 把商業^上可取 得的5-甲基-吡.1H各羧 酸當成起始物 ii用。 以醋酸乙酯： 己燒(1:3至1:]) 冼提行管柱層 離提純 Rt 3.42 min m/z 375.05 81 ΗΝ 乂 Φ F 2C 以醋酸乙酯： 己院(1:1至 1:0)洗提行管 柱層離提純 1^2,37 min m/z 277.04-178- 200524877 (174) Example No. Structural formula Manufactured in a manner similar to the following examples Differences from the following examples? LCMS 78 53 Rt 2.87 min m / z416.07 79 ° γΝΗ ° 53 Ethyl acetate: petroleum ether (1: 1) was used for column separation and purification Rt3.41 min m / z 321.03 80 Ν—N u ΟγΝΗ . Fw 2A, 2B &amp; 53 used commercially available 5-methyl-pyridine. 1H carboxylic acids as starting materials ii. Ethyl acetate: hexane (1: 3 to 1:]) 冼 Liquid column separation purification Rt 3.42 min m / z 375.05 81 ΗΝ 乂 Φ F 2C Ethyl acetate: house (1: 1 to 1 : 0) Elution purification column column purification 1 ^ 2, 37 min m / z 277.04

-179- 200524877 (175) 實施例8 2 4_[(心胺基-;ι_甲基_1H_咪唑_2_羰基）_胺基]_1H-吡唑_3_羧 酸（4_氟代-苯基）_醯胺-179- 200524877 (175) Example 8 2 4 _ [(cardioamino-; ι_methyl_1H_imidazole_2_carbonyl) _amino] _1H-pyrazole_3_carboxylic acid (4-fluoro -Phenyl) _amidine

F 把三氟醋酸（200 // 1)加入經攪拌的{2_[3_(4-氟代-苯基 胺基甲醯）-1Η-吡唑-4-基胺基甲醯甲基]H_咪唑基 卜胺基甲酸第三丁酯（30mg)之二氯甲烷（5ml)懸浮液中， 在室溫下攪拌2小時。把溶劑蒸發，接著以甲苯（2 χ i ⑺1) 再次蒸發。把殘渣與乙醚硏磨，過濾收集所得到的固體。 以乙醚沖洗固體，在真空中乾燥，得非純白色固體狀4_ [(4 -胺基-1-甲基-1H -咪唑-2-羰基）-胺基μΐΗ -吼唑-3-羧酸 (4-氟代-苯基）-醯胺（15mg)。（LC/MS: [Μ + Η] + 3 3 43·72)。 實施例8 3 4-{[4-(2’ 6 -一氟代-苯甲酿胺基）-1Η -咪卩坐·3 -羯基]-胺基卜 環己烷羧酸之合成 83Α 4-{[4-(2，6 -二氟代-苯甲醯胺基-吡唑-3-羰基]- 胺基卜環己烷羧酸乙酯 -180- 200524877F Add trifluoroacetic acid (200 // 1) to the stirred {2_ [3_ (4-fluoro-phenylaminomethylformamidine) -1Η-pyrazol-4-ylaminoformylmethyl] H_ A suspension of imidazolyl tertiary butyl tricarboxylic acid (30 mg) in dichloromethane (5 ml) was stirred at room temperature for 2 hours. The solvent was evaporated and then evaporated again with toluene (2 x i ⑺1). The residue was triturated with ether, and the resulting solid was collected by filtration. The solid was washed with diethyl ether and dried in vacuo to give 4 _ [(4-amino-1-methyl-1H-imidazole-2-carbonyl) -amino μΐΗ-oxazole-3-carboxylic acid ( 4-Fluoro-phenyl) -amidamine (15 mg). (LC / MS: [Μ + Η] + 3 3 43 · 72). Example 8 3 Synthesis of 4-{[4- (2 '6-monofluoro-benzylamino) -1Η-imidazine · 3 -fluorenyl] -aminocyclocyclohexanecarboxylic acid 83A 4 -{[4- (2,6-difluoro-benzylideneamino-pyrazole-3-carbonyl] -ethylaminocyclohexanecarboxylate-180- 200524877

把亞硫醯氯（〇.321111，4.4〇111111〇1)徐徐加入4-胺基環己 烷羧酸（572mg，4.00mmol)之乙醇混合物中’在週 遭溫度下攪拌1 6小時。在真空中濃縮，把殘渣與甲苯共沸 ，得淡白色固體狀對應的乙酯（65 Omg)。 在週遭溫度下把乙酯（1 〇3mg，0.60mmol)，4-(2，6-二氯代-苯甲醯胺基）-1Η· 口比唑-3-羧酸（134mg，0.50mmol) ，EDC(115mg，0.60mmol)及 H0Bt(81mg，0.60mmol)之 DMF( 5 ml)混合物攪拌16小時。在真空中濃縮，使殘渣溶 於醋酸乙酯中，依序以飽和碳酸氫鈉水溶液，水及鹽水沖 洗。以硫酸鎂乾燥有機的部份，在真空中濃縮，得4-{[4-(2，6 -二氟代-苯甲醯胺基）-1 Η -吡唑-3 -羰基]-胺基}-環己 烷羧酸乙酯（1 12mg)。 83B 4-{[4-(2’ 6 -一氛代·本甲醮胺基）-lH-D[：tn坐-3 -羯基卜胺 基}-環己烷羧酸Thionyl chloride (.321111, 4.4010111101) was gradually added to an ethanol mixture of 4-aminocyclohexanecarboxylic acid (572mg, 4.00mmol) 'and stirred at ambient temperature for 16 hours. It was concentrated in vacuo and the residue was azeotroped with toluene to give the corresponding ethyl ester (65 Omg) as a pale white solid. At ambient temperature, ethyl ester (103 mg, 0.60 mmol), 4- (2,6-dichloro-benzylideneamino) -1, oripizol-3-carboxylic acid (134 mg, 0.50 mmol) A mixture of EDC (115 mg, 0.60 mmol) and HOBt (81 mg, 0.60 mmol) in DMF (5 ml) was stirred for 16 hours. Concentrate in vacuo, dissolve the residue in ethyl acetate, and wash with saturated aqueous sodium bicarbonate solution, water and brine in this order. The organic portion was dried over magnesium sulfate and concentrated in vacuo to give 4-{[4- (2,6-difluoro-benzamidoamino) -1 hydrazone-pyrazole-3-carbonyl] -amino } -Ethyl cyclohexanecarboxylate (112 mg). 83B 4-{[4- (2 '6-monofluorobenzylamino) -lH-D [: tn-3-3-methylpropylamino} -cyclohexanecarboxylic acid

-181 - 200524877 (177) 在週遭溫度下把酯（45mg)(來自83A)之甲醇（2.5ml)及 2M氫氧化鈉水溶液（2.5ml)混合物攪拌16小時。在真空中 去除揮發物，加入水（l〇ml)，以1M鹽酸酸化至pH5。過 濾收集所形成的沈澱物，以醋酸乙酯/甲醇（1 : 0-9 :行 管柱層離提純，得白色固體狀4-{[4-(2，6 -二氟代-苯甲醯 胺基吡唑-3-羰酸]-胺基卜環己烷羧酸（1 1 mg)及順式/ 反式異構物的混合物 。（LC/MS ： Rt2.78及 2.96[Μ + Η] + 3 93·09)。-181-200524877 (177) A mixture of an ester (45 mg) (from 83A) in methanol (2.5 ml) and a 2M aqueous sodium hydroxide solution (2.5 ml) was stirred at ambient temperature for 16 hours. The volatiles were removed in vacuo, water (10 ml) was added and acidified to pH 5 with 1M hydrochloric acid. The formed precipitate was collected by filtration, and purified by ethyl acetate / methanol (1: 0-9: column separation to obtain 4-{[4- (2,6-difluoro-benzidine) as a white solid. Aminopyrazole-3-carbonyl acid]-A mixture of aminocyclohexylcarboxylic acid (11 mg) and cis / trans isomers. (LC / MS: Rt2.78 and 2.96 [Μ + Η ] + 3 93 · 09).

實施例8 4 - 1 5 2 泛用步驟A 由吡唑羧酸製造醯胺Example 8 4-1 5 2 Extensive Step A Production of Amines from Pyrazolecarboxylic Acids

在週遭溫度下把合適的苯甲醯胺基-1H-吡唑-3-羧酸 (0.50mmol)，EDAC(104mg，0.54mmol)，HOBt(73.0mg， 0.54mmol)及對應的胺（〇.45mmol)之DMF(3ml)混合物攪拌The appropriate benzamidine-1H-pyrazole-3-carboxylic acid (0.50 mmol), EDAC (104 mg, 0.54 mmol), HOBt (73.0 mg, 0.54 mmol) and the corresponding amine (. 45mmol) in DMF (3ml)

1 6小時。在真空中濃縮，使殘渣溶於醋酸乙醋中，依序以 飽和碳酸氫鈉水溶液，水及鹽水沖洗。以硫酸鈉乾燥有機 的部份，在真空中濃縮，得所需的產物。 -182- 200524877 (178) 泛用步驟B 由胺基吡唑製造醯胺16 hours. Concentrate in vacuo, dissolve the residue in ethyl acetate, and rinse with saturated aqueous sodium bicarbonate solution, water and brine in this order. The organic portion was dried over sodium sulfate and concentrated in vacuo to give the desired product. -182- 200524877 (178) General step B Manufacturing amidoamine from aminopyrazole

把對應的羧酸（0.2 5mm 〇1)加入經攪拌的合適的4-胺基-1H- D比唑-3-羧酸醯胺（0.23mmol) ， EDAC(52mg ，Add the corresponding carboxylic acid (0.2 5mm 〇1) to the appropriate 4-amino-1H-D-pyrazole-3-carboxylic acid amidoamine (0.23mmol), EDAC (52mg,

0.27mmol)及 HOBt(37mg，0.27mmol)之 Ν，Ν·二甲替甲醯 胺（5ml)溶液中，在室溫下靜置一整夜。蒸發，以製備性 LC/MS提純殘渣，得產物。 泛用步驟C 把第三丁氧羰基去除使哌啶環的氮去保護 以飽和醋酸乙酯/鹽酸處理步驟A或步驟b的產物（含 有哌啶基團，而該哌啶基團帶有第三丁氧羰基（t-Bo c) 保護基）（4 0 m g ’在室溫下攪拌1小時。過濾出沈澱的固體 ，以乙醚沖洗，乾燥，得產物（25mg)。（LC/MS : [M + H] + 3 64)。0.27 mmol) and HOBt (37 mg, 0.27 mmol) in a solution of N, N-dimethylformamide (5 ml), and left at room temperature overnight. Evaporation and purification of the residue by preparative LC / MS gave the product. Use step C to remove the third butoxycarbonyl group to deprotect the piperidine ring nitrogen. Treat the product from step A or step b with saturated ethyl acetate / hydrochloric acid (containing a piperidine group, and the piperidine group bears the first Tributoxycarbonyl (t-Bo c) protecting group) (40 mg 'stirred at room temperature for 1 hour. The precipitated solid was filtered off, washed with ether, and dried to give the product (25 mg). (LC / MS: [ M + H] + 3 64).

步驟L 製造胺起始物 下面的方法被用來製造下面的胺類： -183- 200524877 (179) 4-硫代嗎啉-4-基-環己胺； 4-(1，卜二合氧基-硫代嗎啉-4-基）-環己胺； N -(四氫-口比喃-4 -基）-環己烷-1，4 -二胺； 4-(4-甲基-哌嗪-1-基）-環己胺； 1’-甲基-[1，4’]聯哌啶基-4-基胺； 4-嗎啉-4-基-環己胺。Step L Manufacture of amine starter The following method was used to make the following amines: -183- 200524877 (179) 4-thiomorpholin-4-yl-cyclohexylamine; 4- (1, budioxy -Thiomorpholin-4-yl) -cyclohexylamine; N- (tetrahydro-pyran-4-yl) -cyclohexane-1,4-diamine; 4- (4-methyl- Piperazin-1-yl) -cyclohexylamine; 1'-methyl- [1,4 '] bipiperidinyl-4-ylamine; 4-morpholin-4-yl-cyclohexylamine.

以合適的胺（例如硫代嗎啉（〇.23 6g，2.3mmol)，三醋 酸硼氫化鈉（〇.715g，2.76mniol)及醋酸（0.182ml)處理 N-4-丁氧羰基-胺基環己酮（〇.5g，2.3 mmol)之THF(lOml)溶液 。在室溫下攪拌一整夜，以二氯甲烷稀釋，以飽和碳酸鈉 溶液沖洗。在硫酸鎂上乾燥有機層，蒸發，得白色固體， 彼不被提純即在下一階段被使用。以飽和鹽酸/醋酸乙酯 處理該白色固體，在室溫下攪拌1小時，蒸發成乾的，與 甲苯被再次蒸發。所得到的胺被單離成鹽酸鹽。（LC/MS :Rtl ·75[Μ + Η] + 201 )。Treat the N-4-butoxycarbonyl-amino group with a suitable amine (e.g. thiomorpholine (0.236 g, 2.3 mmol), sodium triacetoxyborohydride (0.715 g, 2.76 minol) and acetic acid (0.182 ml) A solution of cyclohexanone (0.5 g, 2.3 mmol) in THF (10 ml). Stir overnight at room temperature, dilute with dichloromethane, rinse with saturated sodium carbonate solution. Dry the organic layer over magnesium sulfate, evaporate, A white solid was obtained, which was used in the next stage without purification. The white solid was treated with saturated hydrochloric acid / ethyl acetate, stirred at room temperature for 1 hour, evaporated to dryness, and evaporated again with toluene. The obtained amine The sheet was isolated into the hydrochloride salt. (LC / MS: Rtl · 75 [Μ + Η] + 201).

在表4中被陳述的化合物乃利用下面的泛用步驟a，Β ’ C及L(在被說明的地方被修飾）予以製造。 -184- 200524877 (180) 表4 實施例 編號 製造方法 LCMS 84 Vn h a SV …0。 0丫 n'h 0 FtrF 步驟A [M+H]+380 Rtl.42 85 ΚΝ—N Η °υα·η ° 步驟A [M+H]+426 Rtl.93 86 HN—N Η 0丫〜 FxrF 步驟A [M+H]+440 Rtl.87 87 HN-N h k 〇丫〜 步驟A [M+H]+406 Rt2.78 88 xxf 。从々 hN~N H \ 步驟A [M+H]+406 Rt2.55 -185- 200524877 (181) 實施例 編號 製造方法 LCMS 89 H C) 〇丫％ 0 FtxF 步驟A 以DMSO替代DMF [M+H]+358 Rtl.98 90 0丫n、h 〇 步驟A 以DMSO替代DMF [M+H]+357 Rt3.37 91 H Ν—Ν Η y sv^ 0 丫 ν·η 〇 FtrF 步驟A 以DMS◦替代DMF [M+H]+391 Rt3.16 92 Η VSr^V °γΝΉ 〇 步驟A 以DMSO替代DMF [M+H]+375 Rt3.02 -186- 200524877 (182) 實施例 編號 製造方法 LCMS 93 K N—N H t / FtrF 步驟A 以DMSO替代DMF [M+H]+425 Rt3.27 94 H. svW 0丫％ 0 FtrF 步驟A 以DMS◦替代DMF [M+H]+393 Rt3.01 95 Η Π/-\ H Κί〇&gt;_^Λ_/ΌΗ /N-h 步驟A 以DMSO替代DMF [M+H]+365 Rt2.22 96 H N—N H y sv々 0丫 n.h 〇 步驟A 以DMSO替代DMF [M+H]+387 Rt3.05 97 N—N H \ 0丫 n、h \ 步驟A 以DMSO替代DMF [M+H]+464 Rt3.17The compounds stated in Table 4 were prepared using the following general steps a, B'C and L (modified where indicated). -184- 200524877 (180) Table 4 Example No. Manufacturing method LCMS 84 Vn h a SV… 0. 0 丫 n'h 0 FtrF Step A [M + H] +380 Rtl.42 85 ΚΝ—N Η ° υα · η ° Step A [M + H] +426 Rtl.93 86 HN—N Η 0YA ~ FxrF Step A [M + H] +440 Rtl.87 87 HN-N hk 〇 Ya ~ Step A [M + H] +406 Rt2.78 88 xxf. From 々hN ~ NH \ Step A [M + H] +406 Rt2.55 -185- 200524877 (181) Example No. Manufacturing Method LCMS 89 HC) 〇 %% 0 FtxF Step A Replace DMF with DMSO [M + H] +358 Rtl.98 90 0 λn, h 〇 Step A replace DMF with DMSO [M + H] +357 Rt3.37 91 H Ν—Ν Η y sv ^ 0 λ ν η 〇FtrF Step A replace with DMS◦ DMF [M + H] +391 Rt3.16 92 Η VSr ^ V ° γΝΉ 〇 Step A Replace DMF with DMSO [M + H] +375 Rt3.02 -186- 200524877 (182) Example No. Manufacturing method LCMS 93 KN —NH t / FtrF Step A replaces DMF with DMSO [M + H] +425 Rt3.27 94 H. svW 0 %% 0 FtrF Step A replaces DMF with DMS◦ [M + H] +393 Rt3.01 95 Η Π /-\ H Κί〇 &gt; _ ^ Λ_ / ΌΗ / Nh Step A Replace DMF with DMSO [M + H] +365 Rt2.22 96 HN—NH y sv々0λnh 〇 Step A Replace DMF with DMSO [M + H] +387 Rt3.05 97 N—NH \ 0y n, h \ Step A Replace DMF with DMSO [M + H] +464 Rt3.17

-187- 200524877 (183) 實施例 編號 製造方法 LCMS 98 Η Ο 0 丫 νή 〇 FtrF 步驟C，使用如實 施例97的產物當 起始物 [M+H]+364 Rtl.76 99 ΚΝ-Ν η 0 丫 ν*η 〇 步驟A 以DMS◦替代DMF [M+H]+389 Rt2.36 100 ΚΝ-Ν η Ο 〇γΝ.Η A 步驟A 以DMS0替代DMF [M+H]+351 Rt2.55 101 ΚΝ-Ν η 0丫νή 〇 步驟A 以DMS◦替代DMF [M+H]+362 Rt2.63 102 Η Ν—Ν Η u sva; °γΝΉ Η 方 步驟A 以DMS0替代DMF 依照步驟L製造起 始的胺 [M+H]+364 Rtl.75 -188- 200524877 (184) 實施例 編號 製造方法 LCMS 103 Η 〇 Ν—Ν Η jy 〇丫％ 〇 FtrF 步驟A 以DMSO替代DMF [M+H]+358 Rt3.2 104 HN-N h £ j °γΝ·Η 〇 步驟A 以DMSO替代DMF [M+H]+358 Rtl.77 105 KN-N H N WO 〇丫n，h 步驟A 以DMSO替代DMF [M+H]+344 Rt2.71 106 H Ν—Ν H VWY 〇丫％ \ 步驟A 以DMSO替代DMF [M+H]+392 Rt2.57 107 步驟A 以DMSci替代DMF [M+H]+347 Rt2.8-187- 200524877 (183) Example No. Manufacturing method LCMS 98 Η 〇 0 丫 νή 〇FtrF Step C, using the product as in Example 97 as the starting material [M + H] +364 Rtl.76 99 KN-N η 0 ya ν * η 〇 Step A replaces DMF with DMS◦ [M + H] +389 Rt2.36 100 ΚΝ-Ν η 〇 〇γΝ.Η A Step A replaces DMF with DMS0 [M + H] +351 Rt2.55 101 ΚΝ-Ν η 0 丫 νή 〇 Step A Replace DMF with DMS◦ [M + H] +362 Rt2.63 102 Η Ν—Ν Η u sva; ° γΝΉ Η Step A Replace DMF with DMS0 Follow steps L to manufacture Starting amine [M + H] +364 Rtl.75 -188- 200524877 (184) Example No. Manufacturing method LCMS 103 〇〇Ν-Ν Η jy 〇 ％％ 〇FtrF Step A Replace DMF with DMSO [M + H] +358 Rt3.2 104 HN-N h £ j ° γΝ · Η 〇 Step A replaces DMF with DMSO [M + H] +358 Rtl.77 105 KN-N HN WO 〇 Yan, h Step A replaces DMF with DMSO [M + H] +344 Rt2.71 106 H Ν—Ν H VWY 〇 %% \ Step A Replace DMF with DMSO [M + H] +392 Rt2.57 107 Step A Replace DMF with DMSci [M + H] + 347 Rt2.8

-189- 200524877 (185) 實施例 編號 製造方法 LCMS 108 Η Π svf ουνή 〇 步驟A 以DMSO替代DMF [M+H]+371 Rt3.1 109 ΚΝ-Ν Η _ ^ ΫΤΟ, 0 丫 ν·η FtrF 步驟A 三乙胺(1當量)，以DM SO替代DMF [M+H]+404 Rt2.7 110 〜人0 F ό Ν人Ν U 步驟A 三乙胺(2當量)，以 H〇At替代H〇Bt,以 DMS〇替代DMF [M+H]+428 Rt 2.63 111 Η 〇Η ν—ν η \ y SV” 〇丫％ 〇 FtrF 先步驟A，接著步驟C 三乙胺(2當量)，以 H〇At替代H〇Bt，以DMS 〇替代DMF [M+H]+364 Rt 1.75-189- 200524877 (185) Example No. Manufacturing method LCMS 108 Η Π svf ουνή 〇 Step A Replace DMF with DMSO [M + H] +371 Rt3.1 109 ΚΝ-Ν Η _ Ϋ ΫΤΟ, 0 νν · η FtrF Step A Triethylamine (1 equivalent), replace DMF with DM SO [M + H] +404 Rt2.7 110 ~ person 0 F ΝΝΝΝ U Step A Triethylamine (2 equivalent), replace with H〇At H〇Bt, replace DMF with DMS〇 [M + H] +428 Rt 2.63 111 Η 〇 ν—ν η \ y SV ”〇 ％％ 〇FtrF First step A, then step C triethylamine (2 equivalents), Replace H〇Bt with H〇At, DMF with DMS [M + H] +364 Rt 1.75

-190- 200524877 (186) 實施例 編號 製造方法 LCMS 112 先步驟A 三乙胺(2當量)，以 H〇At替代H〇Bt，以DMS 〇替代DMF [M+H]+427 Rt2.71 113 ΚΝ—Ν Η sva 0丫ν、η ☆ 先步驟A 以H〇At替代H〇Bt，以D MS0替代DMF [M+H]+363 Rt3.34 114 Vn 4 〜 vrox 0丫 νή FtrF 先步驟A 三乙胺(2當量)，以 H〇At替代H〇Bt,以DMS 〇替代DMF [M+H]+432 Rt 2.63 115 h、NA〇 F ό άα 步驟A [M+H]+461 Rt3.3 -191 - 200524877 (187) 實施例 編號 製造方法 LCMS 116 Η. 〇 F\ Chiral Η'Ν^^Ο Q 步驟A 以DMS0替代DMF， 三乙胺(2當量)，依照 步驟L製造的起始的 胺 [M+H]+448 Rtl.87 117 Η 0 F\ Chira, ΗΆ〇 F a ΓΗ 0 1 步驟A 以DMS0替代DMF， 三乙胺(2當量)，依照 步驟L製造的起始的 胺 [M+H]+447 Rtl.65 118 H. 〇 Fy Chiral 全φ a ：H 0 N 1 步驟A 以DMS0替代DMF， 三乙胺(2當量),依照 步驟L製造的起始的 胺 [M+H]+447 Rtl.72 119 N—N H 。丨 /n.h 0 步驟B [M+H]+462 Rt2.97-190- 200524877 (186) Example No. Manufacturing method LCMS 112 First step A Triethylamine (2 equivalents), replace 〇Bt with H〇At, replace DMF with DMS 〇 [M + H] +427 Rt2.71 113 ΚΝ—Ν Η sva 0āν, η ☆ First step A Replace H〇Bt with H〇At, DMF with D MS0 [M + H] +363 Rt3.34 114 Vn 4 ～ vrox 0 PM FtrF First step A Triethylamine (2 equivalents), replace H〇Bt with H〇At, DMF with DMS [M + H] +432 Rt 2.63 115 h, NA〇 άα Step A [M + H] +461 Rt 3. 3 -191-200524877 (187) Example No. Manufacturing method LCMS 116 Η. 〇F \ Chiral Η'N ^^ Ο Q Step A Replace DMF with DMS0, triethylamine (2 equivalents), and follow the start of manufacturing in Step L Amine [M + H] +448 Rtl.87 117 Η 0 F \ Chira, ΗΆ〇F a ΓΗ 0 1 Step A Replace DMS with DMS0, triethylamine (2 equivalents), follow the starting amine produced in step L [M + H] +447 Rtl.65 118 H. 〇Fy Chiral Total φ a: H 0 N 1 Step A Replace DMF with DMS0, triethylamine (2 equivalents), and start amine produced according to step L [M + H] +447 Rtl.72 119 N—NH.丨 /n.h 0 Step B [M + H] +462 Rt2.97

-192- 200524877 (188) 實施例 編號 製造方法 LCMS 120 ΚΝ-Ν η 4ϋΗν&quot;〇^°、η 0丫ν、η ☆ 步驟A N-乙基 ^pff(NEM) 2當量 [M+H]+379 Rt 2.45 121 η、ν^^^ο φ 0 步驟A 以HOAt替代H〇Bt， 三乙胺(2當量)，依照 步驟L製造的起始的 胺 [M+H]+450 Rt1.97 122 ΗΆ0 ό 步驟B [M+H]+387 Rt3.83 123 Η Ν—Ν Η ντο^ 0丫 ν、η / 步驟B [M+H]+417 Rt3.65 -193- 200524877 (189) 實施例 編號 製造方法 LCMS 124 KN-N h h chiral 0丫n、h \ ☆ 步驟A 以H〇At替代H〇Bt， 三乙胺(2當量） [M+H]+392 Rtl.85 125 H N—N H 0丫n、h 步驟A 以HOAt替代H〇Bt， 三乙胺(2當量） [M+H]+408 Rtl.82 126 h 卜 )° 步驟B [M+H]+403 Rt4.02 127 1 H、丨 c 步驟B [M+H]+369 Rt3.78 -194- 200524877 (190) 實施例 編號 製造方法 LCMS 128 卜 H&gt; ) 步驟B [M+Hf435 Rt3.83 129 H-丨 C 步驟B [M+H]+405 Rt3.96 130 \Kf h^n Ο^γΗ 0 hT \rH Chiral 步驟A 以H〇At替代H〇Bt [M+H]+512 Rt3.1 -195- 200524877 (191) 實施例 編號 製造方法 LCMS 131 ό 0=S=0 ，步驟A 以H〇At替代H〇Bt， [M+H]+428 Rt2.45 132 K 〇 \ Chira, η*ν/^ο Q 步驟A 以H〇Ati代H〇Bt， 三乙胺(2當量）。 在醯胺偶合步驟後 順式及反式異構物 分開依照步驟L製 造的起始的胺 [M+H]+482 Rtl.96 133 ΚΝ—Ν &lt;〇\ ντο-° 0 丫 νή 步驟A 以H〇At替代H〇Bt， 以DMS〇替代 DMF [M+H]+434 Rt2.3 134 :^ΤΙ。 ηΆο ό 步驟B [M+H]+442 Rt2.39-192- 200524877 (188) Example No. Manufacturing method LCMS 120 KN-N η 4ϋΗν &quot; 〇 ^ °, η 0γ, η ☆ Step A N-ethyl ^ pff (NEM) 2 equivalents [M + H] + 379 Rt 2.45 121 η, ν ^^^ ο φ 0 Step A Replace HOAt with HOAt, triethylamine (2 equivalents), and start the amine [M + H] +450 Rt1.97 122 produced in step L ΗΆ0 ό Step B [M + H] +387 Rt3.83 123 Η Ν—Ν Η ντο ^ 0 γ, η / Step B [M + H] +417 Rt3.65 -193- 200524877 (189) Example number Manufacturing method LCMS 124 KN-N hh chiral 0 y n, h \ ☆ Step A Replace H 〇Bt with H〇At, triethylamine (2 equivalents) [M + H] +392 Rtl.85 125 HN—NH 0 y n, h Step A replace HOBt with HOAt, triethylamine (2 equivalents) [M + H] +408 Rtl.82 126 h Bu) ° Step B [M + H] +403 Rt4.02 127 1 H,丨 c Step B [M + H] +369 Rt3.78 -194- 200524877 (190) Example No. Manufacturing Method LCMS 128 BU H &gt;) Step B [M + Hf435 Rt3.83 129 H- 丨 C Step B [M + H] +405 Rt3.96 130 \ Kf h ^ n Ο ^ γΗ 0 hT \ rH Chiral Step A Replace H〇Bt with H〇At [M + H] +512 Rt3.1 -195- 200524877 (191) Implementation example No. manufacturing method LCMS 131 ό 0 = S = 0, step A replaces H〇Bt with H〇At, [M + H] +428 Rt2.45 132 K 〇 \ Chira, η * ν / ^ ο Q Step A uses H 〇Ati HOBt, triethylamine (2 equivalents). After the amidine coupling step, the cis and trans isomers are separated according to step L. The starting amine [M + H] +482 Rtl.96 133 KN—N &lt; 〇 \ ντο- ° 0 λνή Step A Replace HoBt with HoAt and DMF with DMS [M + H] +434 Rt2.3 134: ^ ΤΙ. ηΆο ό step B [M + H] +442 Rt2.39

-196- 200524877(192) 實施例 編號 製造方法 LCMS 135 \ 步驟Β [M+Hf 458 Rt 2.26 136 H’N—Ν Η V F 步驟Β ^(H〇At替代H〇Bt， [M+H]+468 Rt3.07 137 Ην-ν η η _ chira， 〇丫％ 步驟A 三乙胺(2當量)， 以H〇At替代H〇Bt, [M+H]+379 Rt2.6 138 卜 r H&gt; 步驟Β [M+H]+472 Rt 2.40 139 Ην-ν η μ Chira, °&lt;ϊγ^Ν*Η Η ☆ 步驟A 三乙胺(2當量)， 以H〇At替代H〇Bt， 以DMS0替代DMF [M+H]+364 Rt2.1-196- 200524877 (192) Example No. Manufacturing method LCMS 135 \ Step B [M + Hf 458 Rt 2.26 136 H'N—N Η VF Step B ^ (H〇At instead of H〇Bt, [M + H] + 468 Rt3.07 137 Ην-ν η η _ chira, 〇 %% Step A triethylamine (2 equivalents), replace 〇Bt with H〇At, [M + H] +379 Rt2.6 138 BU H &gt; Step B [M + H] +472 Rt 2.40 139 Ην-ν η μ Chira, ° &lt; ϊγ ^ N * Η Η ☆ Step A Triethylamine (2 equivalents), replace H〇Bt with HAt and DMS0 Replace DMF [M + H] +364 Rt2.1

-197- 200524877 (193) 實施例 編號 製造方法 LCMS 140 ό Η 先步驟B,接著步驟C [M+H]+314 Rtl.78 141 Η &quot;Ο&quot; 〇γΝ、Η φ F 先步驟B，接著步驟C [M+H]+332 Rtl.89 142 0丫〜 先步驟B,接著步驟C [M+H]+362 Rtl.78 143 ΚΝ—Ν ^ VYU 0丫 ν.η φ CI 先步驟B,接著步驟C [M+H]+348 Rt2.01 144 ΗΝ—Ν Η 0丫％ 先步驟B,接著步驟C [M+H]+350 Rt1.97 -198- 200524877 (194) 實施例 編號 製造方法 LCMS 145 Wo. 0 丫 n.h φ γο F 先步驟Β,接著步驟C [M+H]+380 Rt 2.01 146 \ h、n 人。 ό Η 先步驟B,接著步驟C [M+H]+395 Rtl.94 147 r° ο Η 先步驟B,接著步驟C [M+H]+396 Rt2.11 148 Η Ν—Ν Η ντα 0 丫1S ν F 先步驟B，接著步驟C 以H〇A潜代H〇Bt [M+H]+368 Rt1.76 -199- 200524877 (195) 實施例 編號 製造方法 LCMS 149 Wo. 〇丫〜 先步驟Β,接著步驟C [M+H]+366 Rt 1.78 150 Η Ν—Ν Η 〜 VW—H °γΝ·Η XX 先步驟B，接著步驟C [M+H]+383 Rtl.87 151 H'N—Ν Η WO-H 〇Υν.η 0 先步驟B，接著步驟C [M+H]+433 Rtl.89 152 Η. Chiral 。W η 令. 先步驟A接著步驟C 以ΗΌΑι替f弋H〇.Bt [M+H]+350 Rt1.76 -200- 200524877 (196) 實施例1 5 3 - 1 6 5-197- 200524877 (193) Example No. Manufacturing method LCMS 140 ό Η First step B, then step C [M + H] +314 Rtl.78 141 Η &quot; 〇 &quot; 〇γΝ, Η φ F first step B, then Step C [M + H] +332 Rtl.89 142 0 Ah ~ First step B, then step C [M + H] +362 Rtl.78 143 ΚΝ—Ν ^ VYU 0 Ah ν.η φ CI First step B, Next step C [M + H] +348 Rt2.01 144 ΗΝ—Ν Η 0 ％% First step B, then step C [M + H] +350 Rt1.97 -198- 200524877 (194) Example No. Manufacturing Method LCMS 145 Wo. 0 λnh φ γο F First step B, then step C [M + H] +380 Rt 2.01 146 \ h, n people. ό 步骤 First step B, then step C [M + H] +395 Rtl.94 147 r ° ο 步骤 First step B, then step C [M + H] +396 Rt2.11 148 Η Ν—Ν Η ντα 0 ya 1S ν F First step B, then step C Substituting H〇A for H〇Bt [M + H] +368 Rt1.76 -199- 200524877 (195) Example No. Manufacturing method LCMS 149 Wo. 〇〜 Β, followed by step C [M + H] +366 Rt 1.78 150 Η Ν—Ν Η ~ VW—H ° γN · Η XX First step B, then step C [M + H] +383 Rtl.87 151 H'N —N Η WO-H 〇Υν.η 0 First step B, then step C [M + H] +433 Rtl. 89 152 Η. Chiral. W η Let. Step A followed by Step C Replace ΗΌΑι with fΗΌH〇.Bt [M + H] +350 Rt1.76 -200- 200524877 (196) Example 1 5 3-1 6 5

泛用步驟D 製造受保護的4-胺基-吼唑-3-基羧酸4_羥基-環己醯胺General Step D Manufacture of Protected 4-Amino-Amidazol-3-ylcarboxylic Acid 4-Hydroxy-cyclohexylamine

pg=保護基 步驟D(i): 在週遭溫度下把4-硝基-3 -吡唑羧酸（4.9 8g， 31.7mmol)，反式 4-胺基環己醇（3.65g，31.7mmol)， EDAC(6.68g， 34.8mmol)及 HOBt(4.7g， 34.8mmol)之 D M F (1 2 0 m 1)混合物攪拌1 6小時。在真空中濃縮，使殘渣 溶於二氯甲烷中，依序以5 %檸檬酸、飽和碳酸氫鈉水溶 液、水及鹽水沖洗。產物大部份在檸檬酸沖洗洗液中被發 現，以醋酸乙酯鹼化及萃取。在硫酸鎂上乾燥有機層，過 濾，蒸發，得白色固體，把白色固體與三氯甲烷硏磨，得 4-硝基- lH-tl比啶-3-羧酸4-羥基-環己醯胺（】.95g)(LC/MS : R】.62[M + H] + 2 5 5 )。 步驟D (i i): 導入四氫-吼喃-2-基保護基 -201 - 200524877 (197) 以 3，4-二氫- 2H_ 吼喃（1.54ml，15.43mmol)及對甲苯 磺酸一水合物（l〇〇mg)處理4-硝基-1H-D比唑-3-羧酸4-羥基-環己醯胺（1.95g，7.67mmol)之 T H F ( 5 0 m 1)及二氯甲烷 (100ml)混合物的溶液。在室溫下攪拌一整夜，把過量的 吡喃（0.9 ml)加入使反應完全。以二氯甲烷使反應混合物 稀釋，依序以飽和碳酸氫鈉水溶液、水及鹽水沖洗。在真 空中濃縮，先後以己烷（2管柱長）、30%醋酸乙酯：己烷 (10管柱長）、70%醋酸乙酯：己烷（10管柱長）洗提行 Biotage管柱層離，得4-硝基-1-(四氫-吼喃-2-基-1H-吼唑-3-羧酸[4-四氫-吡喃-2-基氧基]-環己基）·醯胺（1.25 gt)。 (LC/MS ： Rt2.97[M + H]+423 )。 步驟 D(III): 在室溫及加壓下以10%鈀/活性碳（30 mg)處理4-硝基-1-(四氫-吡喃-2-基）-1Η-批唑-3-羧酸[4-四氫-吡喃-2-基氧 基]••環己基]-醯胺（〇.3g; 0.71mmol)之甲醇（25ml)溶液，接 著氫化一整夜。過濾去除觸媒，以甲醇沖洗3次。蒸發濾 液，得所需的產物（〇.264g)。（LC/MS : Rt2.39[M + H] + 3 9 3 )pg = protecting group step D (i): 4-nitro-3 -pyrazolecarboxylic acid (4.9 8 g, 31.7 mmol), trans 4-aminocyclohexanol (3.65 g, 31.7 mmol) at ambient temperature , A mixture of EDAC (6.68 g, 34.8 mmol) and HOBt (4.7 g, 34.8 mmol) in DMF (120 m 1) was stirred for 16 hours. Concentrate in vacuo, dissolve the residue in dichloromethane, and rinse sequentially with 5% citric acid, saturated aqueous sodium bicarbonate solution, water and brine. Most of the product was found in citric acid washing lotion, alkalized and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and evaporated to give a white solid. The white solid was triturated with chloroform to give 4-nitro-lH-tl-pyridine-3-carboxylic acid 4-hydroxy-cyclohexylamine (] .95g) (LC / MS: R] .62 [M + H] + 2 5 5). Step D (ii): Introduce tetrahydro-roan-2-yl protecting group-201-200524877 (197) with 3,4-dihydro-2H-roan (1.54ml, 15.43mmol) and p-toluenesulfonic acid monohydrate (100 mg) treated 4-nitro-1H-D-pyrazole-3-carboxylic acid 4-hydroxy-cyclohexamidineamine (1.95 g, 7.67 mmol) in THF (50 m 1) and dichloromethane (100 ml) solution of the mixture. After stirring at room temperature overnight, excess pyran (0.9 ml) was added to complete the reaction. The reaction mixture was diluted with dichloromethane, and washed sequentially with a saturated aqueous sodium hydrogen carbonate solution, water, and brine. Concentrate in vacuum, and then elute the Biotage tube with hexane (2 column length), 30% ethyl acetate: hexane (10 column length), 70% ethyl acetate: hexane (10 column length) The column was delaminated to obtain 4-nitro-1- (tetrahydro-pyran-2-yl-1H-yrazol-3-carboxylic acid [4-tetrahydro-pyran-2-yloxy] -cyclohexyl ) · Amidine (1.25 gt). (LC / MS: Rt2.97 [M + H] +423). Step D (III): Treat 4-nitro-1- (tetrahydro-pyran-2-yl) -1Η-pyrazole-3 with 10% palladium / activated carbon (30 mg) at room temperature and under pressure -A solution of a carboxylic acid [4-tetrahydro-pyran-2-yloxy] • cyclohexyl] -fluorenamine (0.3 g; 0.71 mmol) in methanol (25 ml), followed by hydrogenation overnight. The catalyst was removed by filtration and rinsed 3 times with methanol. The filtrate was evaporated to give the desired product (0.264 g). (LC / MS: Rt2.39 [M + H] + 3 9 3)

泛用步驟E 去除四氫吡喃-2-基保護基的步驟 把對甲苯磺酸水合物（90mg，0.46mmol)加入4-(2 -甲 氧基-苯甲醯胺基）-1-(四氫-批喃-2-基-1H-吡啶-3-羧酸[4-( -202 - 200524877 (198) 四氫-吼喃-2-基氧基）-環己基]-醯胺（〇.125g，0.23 mmol)之 乙醇（10ml)懸浮液中。在70 °C下加熱30分鐘。以醋酸乙酯 稀釋，依序以飽和碳酸氫鈉水溶液，水及鹽水沖洗。在真 空中濃縮，得白色固體，彼含有痕量的對甲苯磺峻水合物 。使固體溶於醋酸乙酯中，先後以1 Μ氫氧化鈉、鹽水沖 洗。在真空中濃縮，將殘渣與乙醚/己烷硏磨，得所需的 產物（10mg)。（LC/MS: Rt2.29[M + H] + 3 5 9)。The step of removing the tetrahydropyran-2-yl protecting group in step E is generally used. Toluenesulfonic acid hydrate (90mg, 0.46mmol) is added to 4- (2-methoxy-benzylamido) -1- ( Tetrahydro-pyran-2-yl-1H-pyridine-3-carboxylic acid [4-(-202-200524877 (198) tetrahydro-anhydro-2-yloxy) -cyclohexyl] -fluorenamine (〇 .125 g, 0.23 mmol) in ethanol (10 ml) suspension. Heated at 70 ° C for 30 minutes. Diluted with ethyl acetate, washed sequentially with saturated aqueous sodium bicarbonate solution, water and brine. Concentrated in vacuo to obtain White solid, which contains trace amounts of p-toluenesulfonate hydrate. Dissolve the solid in ethyl acetate, rinse with 1 M sodium hydroxide, then brine. Concentrate in vacuo, and triturate the residue with ether / hexane. The desired product (10 mg) was obtained. (LC / MS: Rt2.29 [M + H] + 3 5 9).

泛用步驟F 由4-胺基-吼唑-3-羧酸醯胺製造脲General step F. Urea production from 4-amino-oxazol-3-carboxamide

把異氰酸苯酯（929mg，0.24mmol)加入4 -胺基-1-(四 氫-吼喃-2-基-ΙΗ-口比唑-3-羧酸[4-(四氫-批喃-2-基氧基）-環 己基]醯胺（8011^，0.211111)〇1)之甲苯（21111)溶液中。在70它 下加熱1小時。以醋酸乙酯稀釋，依序以水及鹽水沖洗。 在真空中濃縮，得黃色油體。該油體不進一步提純即被使 用。（LC/MS : Rt2.28[M + H] + 3 44)。Phenyl isocyanate (929 mg, 0.24 mmol) was added to 4-amino-1- (tetrahydro-roan-2-yl-lΗ-orbizole-3-carboxylic acid [4- (tetrahydro-pyran -2-yloxy) -cyclohexyl] fluorenamine (8011 ^, 0.211111) 〇1) in toluene (21111) solution. Heat it at 70 for 1 hour. Dilute with ethyl acetate and rinse with water and brine in that order. Concentrated in vacuo to give a yellow oil. This oil was used without further purification. (LC / MS: Rt2.28 [M + H] + 3 44).

泛用步驟G 由4 -胺基-D[t唑基轉變成4 -(嗎啉-4 -羰基胺基）-吡唑基 在-1 0 °C下把2 0 %碳醯氯之甲苯溶液滴入4 -胺基· 1 -(四 氫·吼喃-2 -基-1 Η · D比D坐-3 -殘酸[4 -(四氫-口比喃-2 -基氧基）-環 己基]-醯胺（O.lg，0.2 5 5 mmol)之二氯甲烷（5ml)溶液中。 在-1 0 °C下攪拌]5分鐘，加入嗎啉（〇 · 7 6 5 m m ο 1)。在室溫下 加溫1小時，在室溫下攬拌一整夜。以二氯甲烷稀釋，依 -203- 200524877 (199) 序以飽和碳酸氫鈉及鹽水沖洗。在真空中濃縮，得黃色油 體，彼不進一步提純即被使用。 (LC/MS: Rt1.68[M + H] + 3 3 8 )。 泛用步驟Η 製造Ν-氧化物類General step G: Conversion of 4-amino-D [tazolyl to 4- (morpholine-4-carbonylamino) -pyrazolyl at a temperature of -10 ° C in a 20% solution of carbochlorine in toluene Into the 4-amino group · 1-(tetrahydro · cyclonan-2 -yl-1 Η · D than D sitting -3 -residual acid [4-(tetrahydro-bipyran-2 -yloxy)- Cyclohexyl] -amidamine (0.1 g, 0.2 5 5 mmol) in a solution of dichloromethane (5 ml). Stir at -10 ° C] for 5 minutes and add morpholine (0.765 mm 1 ). Warm at room temperature for 1 hour, stir overnight at room temperature. Dilute with dichloromethane, rinse with saturated sodium bicarbonate and brine in the order of -203- 200524877 (199). Concentrate in vacuo, A yellow oil was obtained, which was used without further purification. (LC / MS: Rt1.68 [M + H] + 3 3 8). General procedure Η Manufacture of N-oxides

把間氯代過苯甲酸（MCPBA)(3.6mg0.02mmol)加入實 施例53之化合物（7.7mg，〇.〇2mmol)之二氯甲烷（0.5ml)懸 浮液中。在室溫下攪拌一整夜，蒸發。以製備性LC/MS 提純殘渣。得所需的產物（3mg) 。 （LC/MS :M-Chloroperbenzoic acid (MCPBA) (3.6 mg 0.02 mmol) was added to a suspension of the compound of Example 53 (7.7 mg, 0.02 mmol) in dichloromethane (0.5 ml). Stir overnight at room temperature and evaporate. The residue was purified by preparative LC / MS. The desired product (3 mg) was obtained. (LC / MS:

Rtl .83[M + H] + 3 8 0 )。 泛用步驟I 去除苄氧羰基保護基Rtl .83 [M + H] + 3 8 0). Extensive use of step I to remove benzyloxycarbonyl protecting group

在室溫及加壓下以10%鈀/活性碳（2 Omg)處理實施例 130之化合物（0.2g; 0.39mmol)之醋酸乙酯（40ml)溶液，接 著氫化3小時。過濾去除觸媒，以醋酸乙酯沖洗3次。蒸發 濾液，先後以10%甲醇-二氯甲烷、20%甲醇·二氯甲烷行 層離提純殘渣，得所需的產物（8〇mg)。（LC/MS : Rt 1 ·88[Μ + Η] + 3 7 8)。 泛用步驟J 胺的甲磺醯化作用 先後把甲烷-磺醯氯（〇.〇〇45 ，0.05 8 mmol)、H uni g -204- 200524877 (200) 氏鹼（0.0 18ml，0.1 mmol)加入實施例163之化合物（20mg， 0.05mmol)之乙腈（3ml)溶液中。在室溫下攪拌2小時。蒸 發。以製備性 LC/MS提純殘渣，得所需的產物（8mg)。 (LC/MS : Rt2.54[M + H] + 4 5 6)。 借助下面的步驟A至L，在表5中所陳述的化合物被 製造。A solution of the compound of Example 130 (0.2 g; 0.39 mmol) in ethyl acetate (40 ml) was treated with 10% palladium / activated carbon (20 mg) at room temperature and under pressure, followed by hydrogenation for 3 hours. The catalyst was removed by filtration and rinsed 3 times with ethyl acetate. The filtrate was evaporated, and the residue was separated and purified by 10% methanol-dichloromethane followed by 20% methanol · dichloromethane to obtain the desired product (80 mg). (LC / MS: Rt 1 · 88 [Μ + Η] + 3 7 8). In step J, the methanesulfonylation of the amine was followed by the addition of methane-sulfonyl chloride (0.0005, 0.05 8 mmol), H uni g -204- 200524877 (200) lye base (0.0 18ml, 0.1 mmol). A solution of the compound of Example 163 (20 mg, 0.05 mmol) in acetonitrile (3 ml). Stir at room temperature for 2 hours. Evaporate. The residue was purified by preparative LC / MS to obtain the desired product (8 mg). (LC / MS: Rt2.54 [M + H] + 4 5 6). With the following steps A to L, the compounds stated in Table 5 were produced.

-205- 200524877 (201) 表5 實施例 編號 製造方法 LCMS 153 Η N—N H u ^ SYtX 0丫 n、h 先後以步驟D,B，E製造 以H〇At替代H〇Bt, 以二氯甲烷替代DMF [M+H]+359 Rt 2.29 154 Η Ν—Ν Η u ^ VYtX 0丫 ν、η 先後以步驟D,B,E製造 以H〇At替代H〇Bt, 以二氯甲烷替代DMF [M+H]+377 Rt 2.22 -206- 200524877 (202) 實施例 編號 製造方法 LCMS 155 Η. Ν——Ν Η u 0 丫 ν'η 方1 先後以步驟D，B,E製造 以H〇At替代H〇Bt, 以二氯甲烷替代DMF [M+H]+381 Rt2.34 156 Η Ν—Ν Η u SVQ、 0丫ν、η σΝΗ 先後以步驟D,F，E製造 [M+H]+344 Rt2.28 157 Η Ν—Ν Η u 〇丫〜 /ΝΗ ό 先後以步驟D,F，E製造 [M+H]+358 Rt 2.22 158 Η Ν—Ν Η u 〜 〇Υν'η 4 先後以步驟D，B,E製造 以H〇At替代H〇Bt, 以二氯甲烷替代DMF [M+H]+365 Rt2.21 -207 - 200524877 (203)-205- 200524877 (201) Table 5 Example No. Manufacturing method LCMS 153 Η N—NH u ^ SYtX 0 y n, h Manufactured in steps D, B, and E in order to replace H 0 Bt with H 0 At, and dichloromethane Substitute DMF [M + H] +359 Rt 2.29 154 Η Ν—Ν Η u ^ VYtX 0 y ν, η Manufactured in steps D, B, and E in order to replace 〇Bt with H〇At and DMF with dichloromethane [ M + H] +377 Rt 2.22 -206- 200524877 (202) Example No. Manufacturing method LCMS 155 Η. Ν—Ν Η u 0 λν′η Square 1 is sequentially manufactured by steps D, B, E and Hα Instead of H〇Bt, replace DMF with dichloromethane [M + H] +381 Rt2.34 156 Η Ν—Ν Η u SVQ, 0 y ν, η σ Ν 制造 Manufactured in steps D, F, E [M + H] +344 Rt2.28 157 Η Ν—Ν Η u 〇 丫 ～ / ΝΗ ό Manufactured in steps D, F, E [M + H] +358 Rt 2.22 158 Η Ν—Ν Η u ~ 〇Υν'η 4 successively Manufactured in steps D, B, and E. Replace 〇Bt with H〇At and DMF with methylene chloride [M + H] +365 Rt2.21 -207-200524877 (203)

-208- 200524877 (204) 實施例 編號 ------- 製造方法 LCMS 163 Η N—N H u Chira, SVQ......λ °γΝ*Η 0 H 以步驟A(以HOAt替 代HOBt)製造，得實施 例130之化合物，接著以 步驟I製造 [M+H]+378 Rtl.78 164 _ F 〇八Ή δ Hi . 〇r=S=0 以步驟A(以HOAt替 代HOBt)及I製造，得 實施例163之化合物 ，接著以步驟I製造 [M+H]+456 Rt2.54 泛用步驟Μ 製成吡唑4 _醯胺基團-208- 200524877 (204) Example number ------- Manufacturing method LCMS 163 Η N-NH u Chira, SVQ ... λ ° γN * Η 0 H Step A (with HOAt instead of HOBt ) To obtain the compound of Example 130, and then produce [M + H] +378 Rtl.78 164 _ F 〇 八 Ή δ Hi. 〇r = S = 0 Step A (replace HOBt with HOAt) and I, to obtain the compound of Example 163, and then to produce [M + H] +456 Rt2.54 in step I, and then use step M to make a pyrazole 4-amidine group

νο2νο2

^y-c〇2H^ y-c〇2H

N-N Η 把4 -硝基吡唑-3 _羧酸（7 · 3 g ;丨5.9 m m 〇 1)加入經攪拌的 4 -月女基-1*•丁氧線基-定（i〇2mg; 51mmol)，EDC(10.7g; 55.8mmol)’ 及 H〇At(55.8g; 19.1mmol)之 DMF(l〇〇ml)溶 液中，在室溫下攪拌一整夜。在減壓下蒸發去除溶劑，把 殘渣與水（2 5 0ml)硏磨。過濾收集所得的淡黃色固體，以 水沖洗，在真空下乾燥，得4-[(4-硝基-1H-吡唑-3_羯基卜 -209- 200524877 (205) 胺基]-哌啶-卜羧酸第三丁酯（LC/MS: Rt2.50[M + H] + 340)。 在室溫及加壓下以1 0%鈀/活性碳（5 00m g)處理4-[(4-硝 基-1 Η -吼唑-3 -羰基）-胺基卜哌啶-；[-羧酸第三丁酯（1 3.0 5 g ) 之乙醇/DMF(3 00ml/75ml)溶液，接著氫化一整夜。透過矽 藻土過濾去除觸媒，蒸發濾液，連同甲苯再次蒸發。先後 以醋酸乙酯、2%甲醇/醋酸乙酯、5%甲醇/醋酸乙酯洗提 行快速管柱層離提純粗製的產物。使含有產物的級份複合 ’蒸發’得掠色泡沫體狀4-[(4 -胺基-1H-D比D坐-3-鑛基）-胺 基]-哌啶-卜羧酸第三丁酯（8.78 g)。 (LC/MS : Rt1.91[M + H] + 310)。 把對應的羧酸（0.25mm〇l)加入經攪拌的4-[(4-胺基-1H-口比唑-3·羰基）-胺基卜哌啶-卜羧酸第三丁酯（200mg ; 〇.65mmol)、EDAC(150mg ; 0.78mmol)及 HOBt(105mg ; 0.78 mmol)之N，N-二甲替甲醯胺（5 ml)溶液中，在室溫下 靜置一整夜。以飽和碳酸氫鈉水溶液稀釋，過濾收集產物 ，在真空下乾燥。使被丁氧羰基保護的化合物溶於飽和鹽 酸/醋酸乙酯中，在室溫下攪拌3小時。過濾收集產物，以 乙醚沖洗，在真空下乾燥。NN Η Add 4-nitropyrazole-3 carboxylic acid (7.3 g; 丨 5.9 mm 〇1) to the stirred 4-monthlyl-methyl-1 * • butoxyline-dio (12 mg; 51 mmol), EDC (10.7 g; 55.8 mmol) 'and HOAt (55.8 g; 19.1 mmol) in a DMF (100 ml) solution, and stirred at room temperature overnight. The solvent was removed by evaporation under reduced pressure, and the residue was triturated with water (250 ml). The resulting pale yellow solid was collected by filtration, washed with water, and dried under vacuum to give 4-[(4-nitro-1H-pyrazole-3_fluorenyl-209-200524877 (205) amino] -piperidine. -Tertiary butyl carboxylic acid (LC / MS: Rt2.50 [M + H] + 340). Treat 4-[(10% palladium / activated carbon (500 mg) at room temperature and under pressure. A solution of 4-nitro-1 fluorene-oxazole-3 -carbonyl) -aminopiperidine-; [-tert-butyl carboxylic acid (1 3.0 5 g) in ethanol / DMF (300 ml / 75 ml), then It was hydrogenated overnight. The catalyst was removed by filtration through diatomaceous earth, and the filtrate was evaporated. The toluene was evaporated again with toluene. The column was washed with ethyl acetate, 2% methanol / ethyl acetate, and 5% methanol / ethyl acetate. The crude product is isolated and purified. The fractions containing the product are compounded and 'evaporated' to obtain a color-picking foamy 4-[(4-amino-1H-D to D-sat-3-mine) -amino] -piperidine -Tert-butyl carboxylic acid (8.78 g). (LC / MS: Rt1.91 [M + H] + 310). The corresponding carboxylic acid (0.25 mm) was added to the stirred 4-[(4 -Amino-1H-orbitazole-3 · carbonyl) -aminobupiperidine-tricarboxylic acid tert-butyl ester (200mg; 0.65mmol), EDAC (150mg; 0.78mmol) and HOBt (105mg; 0.78m mol) of N, N-dimethylformamidine (5 ml) solution, and left at room temperature overnight. Dilute with saturated aqueous sodium bicarbonate solution, collect the product by filtration, and dry under vacuum. The oxycarbonyl-protected compound was dissolved in saturated hydrochloric acid / ethyl acetate and stirred at room temperature for 3 hours. The product was collected by filtration, washed with ether, and dried under vacuum.

泛用步驟N 製造1·第三丁基-哌啶·4_基胺 -210- 200524877 (206)Commonly used Step N to produce 1 · Tertiarybutyl-piperidine · 4-Amine -210- 200524877 (206)

νη2 步驟N(i) 在室溫下在水浴中以使溫度保持在3 (TC以下的速率把 甲基砩（15.5ml，0.25mol)加入1-乙基-4-合氧基哌啶（25g， 0.197mol)之丙酮（250ml)溶液中。過濾，以丙酮沖洗沈殿 物，乾燥，得1 -乙基-卜甲基-4-合氧基哌啶鑰碘化物 (45g)(LC/MS : Rt0.38[M + H] + 143)。 步驟N(ii) 把1-乙基-1-甲基-4-合氧基哌啶_碘化物（4〇g， 0.148mol)及碳酸氫鈉（1.245g ; 0.014mol)之水（60ml)溶液 加入第三丁基胺（78.2ml，0.74mol)之甲苯（400ml)溶液中 。在7 8 t下加熱6小時，冷卻至周遭的溫度。分開各層， 以醋酸乙酯沖洗含水層。使有機物複合，以鹽水沖洗，以 硫酸鎂乾燥，過濾，在真空中濃縮，得卜第三丁基-4-合 氧基哌啶（14g)(LC/MS : Rt0.39[M + H] + l 56)。 步驟N (i i i) 在用遭溫度下把1-第三丁基-4-合氧基哌啶（3.6g， 23.1mmol)，；基胺（5.1ml，46.8mmol)、醋酸（1.5ml)及三 醋酸硼氫化鈉（7.38g，34.8mmol)的溶液攪拌2曰。在真空 中濃縮，使殘渣分佈於碳酸鉀及醋酸乙酯之外。以硫酸鈉 -211 - 200524877 (207) 乾燥有機相，過濾，在真空中濃縮。以二氯甲烷/甲醇/氫 氧化銨（87/12/1)洗提行層離提純殘渣，得N-苄基-第三 丁 基哌啶-4-胺（1.5g)(LC/MS: Rt0.45[M + H] + 247)。 步驟N(iv) 在Parr搖盪器中在50psi下把N-苄基·卜第三丁基哌 啶·4-胺（l·56g)及10%鈀/活性碳（2g)之甲醇（2 5 0ml)溶液氫 化16小時。過濾，在真空中濃縮，得卜第三丁基哌啶-4-胺（0.64g)(LC/MS: Rt02.31，無[M + H].)。 實施例1 6 5 合成4-(2，6-二氟代-苯甲醯胺基）-lH-D比唑-3-羧酸[5-氟 代- 2-(1-甲基-哌啶-4·基氧基）-苯基]•醯胺 165A.合成4-硝基-1H-吡唑-3-羧酸'乙醋νη2 Step N (i) Add methyl hydrazone (15.5 ml, 0.25 mol) to 1-ethyl-4-hexyloxypiperidine (25 g in a water bath at room temperature at a rate to keep the temperature below 3 (TC) , 0.197 mol) in acetone (250 ml) solution. Filtered, rinsed the Shen Dian thing with acetone, and dried to obtain 1-ethyl-bumethyl-4-hexyloxypiperidine key iodide (45 g) (LC / MS: Rt0. 38 [M + H] + 143). Step N (ii) Add 1-ethyl-1-methyl-4-hexyloxypiperidine_iodide (40 g, 0.148 mol) and sodium bicarbonate (1.245 g; 0.014 mol) of water (60 ml) was added to a solution of tert-butylamine (78.2 ml, 0.74 mol) in toluene (400 ml). Heated at 7 8 t for 6 hours and cooled to the surrounding temperature. Separate the layers, The aqueous layer was washed with ethyl acetate. The organics were combined, washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to give tert-butyl-4-hexyloxypiperidine (14 g) (LC / MS: Rt 0.39 [M + H] + 56). Step N (iii) 1-Third-butyl-4-hexyloxypiperidine (3.6 g, 23.1 mmol); 5.1ml, 46.8mmol), acetic acid (1.5ml) and sodium borohydride triacetate (7.38g, 34.8mmol) The solution was stirred for 2 days. Concentrated in vacuo to distribute the residue outside potassium carbonate and ethyl acetate. The organic phase was dried over sodium sulfate -211-200524877 (207), filtered, and concentrated in vacuo. Dichloromethane / methanol / Ammonium hydroxide (87/12/1) was eluted and the residue was separated and purified to obtain N-benzyl-tert-butylpiperidine-4-amine (1.5g) (LC / MS: Rt0.45 [M + H] + 247). Step N (iv) In a Parr shaker, place N-benzylbuthyl tertiarybutylpiperidine · 4-amine (1.56 g) and 10% palladium / activated carbon (2 g) at 50 psi. ) In methanol (250 ml) for 16 hours. Filtered and concentrated in vacuo to give the third butylpiperidin-4-amine (0.64 g) (LC / MS: Rt02.31, without [M + H ].). Example 1 6 5 Synthesis of 4- (2,6-difluoro-benzylamido) -lH-D-pyrazole-3-carboxylic acid [5-fluoro-2- (1-methyl -Piperidine-4 · yloxy) -phenyl] • amine 165A. Synthesis of 4-nitro-1H-pyrazole-3-carboxylic acid 'ethyl acetate

irN 在週遭溫度下把亞硫醯氯（2.90ml，39.8mmol)徐徐加 入4·硝基-3-吼唑羧酸（5.68g，36.2mmol)之乙醇（l〇〇ml)混 合物中，攪拌4 8小時。在真空中濃縮，連同甲苯共沸乾燥 ’得白色固體狀4-硝基-1H-吡唑-3-羧酸乙酯（6.42g，96%) 。（】H NMR(400MHz，DMSO-d6)(5 14.4(s，1H)，9.0(s，1H)，4.4(q，2H)，1.3(t，3H)。 -212- 200524877 (208) 1 65 B.合成4-胺基-1H-吡唑-3-羧酸乙酯irN slowly add thionyl chloride (2.90ml, 39.8mmol) to a mixture of 4 · nitro-3-oxazolecarboxylic acid (5.68g, 36.2mmol) in ethanol (100ml) at ambient temperature, and stir for 4 8 hours. It was concentrated in vacuo and azeotropically dried with toluene to give 4-nitro-1H-pyrazole-3-carboxylic acid ethyl ester (6.42 g, 96%) as a white solid. (] H NMR (400 MHz, DMSO-d6) (5 14.4 (s, 1H), 9.0 (s, 1H), 4.4 (q, 2H), 1.3 (t, 3H). -212- 200524877 (208) 1 65 B. Synthesis of 4-amino-1H-pyrazole-3-carboxylic acid ethyl ester

rN 在氫氣氛下把4-硝基-1H-吡唑-3-羧酸乙醋（6.40g ’ 34.6mmol)及10%鈀/活性碳（6 5 0mg)之乙醇（150ml)混合物 攪拌20小時。透過矽藻土塞過濾，在真空中濃縮’連同甲 苯共沸乾燥，得淡紅色固體4-胺基-1H-吡挫-3-殘酸乙醋 (5.28g，98%)。（】H NMR(400MHz，DMSO-d6)(5 12.7(s，1H)，7.1(s，1H)，4.8(s，2H)，4.3(q，2H)， 1 .3(t，3H))。 165C.合成4-(2，6-二氟代-苯甲醯胺基）-lH-吡唑-3-羧酸乙 酯rN A mixture of 4-nitro-1H-pyrazole-3-carboxylic acid ethyl acetate (6.40 g '34.6 mmol) and 10% palladium / activated carbon (650 mg) in ethanol (150 ml) was stirred under a hydrogen atmosphere for 20 hours. . It was filtered through a plug of diatomaceous earth and concentrated in vacuo 'together with toluene to azeotropically dry to give 4-amino-1H-pyridine-3-residue ethyl acetate (5.28 g, 98%) as a pale red solid. (] H NMR (400MHz, DMSO-d6) (5 12.7 (s, 1H), 7.1 (s, 1H), 4.8 (s, 2H), 4.3 (q, 2H), 1.3 (t, 3H)) 165C. Synthesis of 4- (2,6-difluoro-benzylamido) -lH-pyrazole-3-carboxylic acid ethyl ester

OEt 在周遭溫度下把2，6-二氟代苯甲酸（6.32g， 40.0mmol) ，4 -胺基-1 Η -吡唑-3 -羧酸乙酯（5 · 9 6 g， 38.4mmol)、EDC(8.83g，46.1mmol)及 HOBt(6.23g ’ 4 6 . 1 m m ο 1)之D M F (] 0 0 m 1)混合物擅伴6小時。在真空下t辰 -213- 200524877 (209) 縮’加水’過爐收集固體’ i热乾丨栄’侍4 - (2，6 - __•氣代-苯甲醯胺基）-1Η-吡唑-3-羧酸乙酯爲主要成份的混合物 (15.3g)。（LC/MS: Rt3」l[M + H] + 295.99)。 1 6 5 D .合成4 - (2，6 -二氟代-苯甲醯胺基）-1 Η -吡唑· 3 -羧酸OEt converts 2,6-difluorobenzoic acid (6.32 g, 40.0 mmol), 4-amino-1, -pyrazole-3, carboxylic acid ethyl ester (5.99 g, 38.4 mmol) at ambient temperature , EDC (8.83g, 46.1mmol) and HOBt (6.23g '46. 1 mm ο 1) in DMF (] 0 0 m 1) mixture for 6 hours. Under the vacuum t-213- 200524877 (209) shrinking 'add water' in the furnace to collect solids' i heat dry 丨 栄 侍 侍 4-(2,6-_-• generation-benzamidine amine group)-1 -pyridine A mixture of ethyl azole-3-carboxylic acid as a main component (15.3 g). (LC / MS: Rt3 "l [M + H] + 295.99). 1 6 5 D. Synthesis of 4-(2,6-difluoro-benzylamido) -1 hydrazone -pyrazole · 3-carboxylic acid

在周遭溫度下把心（2，6-二氟代-苯甲醯胺基）_1Η-吡 唑-3-羧酸乙酯（10.2g)之2Μ氫氧化鈉水溶液/甲醇（1 : 1， 2 5 0 m 1)的混合物攪拌1 4小時。在真空中去除揮發性物質， 加水（3 00ml)，以1 Μ鹽酸酸化至pH5。過濾收集沈澱物， 連同甲苯共沸乾燥，得淡紅色固體4 - (2，6 -二氟代-苯甲醯 胺基）-1Η-吼唑-3-羧酸（5.7〇g) 。 （LC/MS ：Heart (2,6-difluoro-benzylamido) _1Η-pyrazole-3-carboxylic acid ethyl ester (10.2g) in 2M sodium hydroxide aqueous solution / methanol (1: 1, 2 at ambient temperature) The 50 m 1) mixture was stirred for 14 hours. The volatiles were removed in vacuo, water (300 ml) was added and acidified to pH 5 with 1 M hydrochloric acid. The precipitate was collected by filtration, and azeotropically dried with toluene to give 4- (2,6-difluoro-benzylamino) -1H-azolezol-3-carboxylic acid (5.70 g) as a pale red solid. (LC / MS:

Rt2.33[M + H] + 267.96)。 1 6 5 E ·合成5 -氟代-2 - (1-甲基-哌啶-4 -基氧基）-苯基胺Rt2.33 [M + H] +267.96). 1 6 5 E · Synthesis of 5-fluoro-2-(1-methyl-piperidine-4 -yloxy) -phenylamine

-214- 200524877 (210) 使3，4 -二硝基氟苯（1.86g，l〇m mol)及4 -羥基-卜甲基 哌啶（1 .3 8g，12mmol)溶於 THF(20ml)中，在周遭溫度下 攪拌，期間以少量多次的方式加入氫化鈉（在礦物油中60% 分散，0 · 4 0 g，1 〇 mm ο 1)。攪拌1小時，在真空中濃縮，使 殘渣分佈於醋酸乙酯及水二層，以鹽水沖洗有機相，以硫 酸鎂乾燥，在真空中濃縮。以5%甲醇/DCM洗提行管柱層 離提純殘渣，得黃色固體4-(3，4 -二硝基-苯氧基）-1-甲基-哌啶及4-(4-氟代-2-硝基-苯氧基）_1_甲基-哌啶（1.76g，2 : 1) 〇 在氮氣氛下使混合物產物（0.562g)溶於DMF(lOml)中 。加入IG /活性碳（1 0 %，0.0 5 6 g)，在氫氣氛下搖動4 0小時 。過濾去除固體’在真空中使濾液濃縮，使殘澄溶於醋酸 乙酯中，先後以飽和氯化銨水溶液、飽和食鹽水沖洗，以 硫酸鎂乾燥，在真空中濃縮，得棕色油體5-氟代-2(1-甲 基-哌啶-4 -基氧基）-苯胺（0.0 4 9 g，7 % )。 (】Η N M R (4 0 0 Μ Η ζ，Μ Ε Ο D d 4) δ 6.6(m，2Η)，6.4(m，1Η)，4.3(m，1Η)，2.7(m，2Η)， 2.3(m’ 2H)，1.9(m，2H)，1.7(m，2H)° 165F.合成4-(2，6_二氟代-苯甲醯胺基）_1H_吼唑-3-殘酸 [5-氟代- 2-(1-甲基-哌啶-4-基氧基）-苯基]-醯胺 -215- 200524877 (211)-214- 200524877 (210) Dissolve 3,4-dinitrofluorobenzene (1.86 g, 10 mol) and 4-hydroxy-p-methylpiperidine (1.3 8 g, 12 mmol) in THF (20 ml), Stir at ambient temperature, adding sodium hydride (60% dispersed in mineral oil, 0.40 g, 10 mm ο 1) in small portions multiple times. After stirring for 1 hour, the mixture was concentrated in vacuo. The residue was distributed in two layers of ethyl acetate and water. The organic phase was washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by column separation with 5% methanol / DCM to obtain 4- (3,4-dinitro-phenoxy) -1-methyl-piperidine and 4- (4-fluoro 2-nitro-phenoxy) _1-methyl-piperidine (1.76 g, 2: 1). The mixture product (0.562 g) was dissolved in DMF (10 ml) under a nitrogen atmosphere. Add IG / activated carbon (10%, 0.056 g) and shake for 40 hours under a hydrogen atmosphere. The solids were removed by filtration. The filtrate was concentrated in vacuo, the residue was dissolved in ethyl acetate, washed with saturated aqueous ammonium chloride solution, saturated brine, dried over magnesium sulfate, and concentrated in vacuo to obtain a brown oil body 5- Fluoro-2 (1-methyl-piperidine-4-yloxy) -aniline (0.0 4 9 g, 7%). () Η NMR (4 0 0 Μ Η ζ, Μ Ε Ο D d 4) δ 6.6 (m, 2Η), 6.4 (m, 1Η), 4.3 (m, 1Η), 2.7 (m, 2Η), 2.3 ( m '2H), 1.9 (m, 2H), 1.7 (m, 2H) ° 165F. Synthesis of 4- (2,6_difluoro-benzylamido) _1H_azolezol-3-residue acid [5 -Fluoro- 2- (1-methyl-piperidin-4-yloxy) -phenyl] -amidamine-215- 200524877 (211)

把5 -氟代-2 - (1 -甲基-哌啶-4 -基氧基）苯胺（〇 . 〇 4 9 g， 0.22mmol)及4-(2，6-二氟代-苯甲醯胺基）-iH-D比唑-3-羧酸 (0.0 5 3 g ， 0.20mmol) 、 EDC(0.048g ， Ο . 2 5 m m ο 1)、 HOBt(0.03 4g，0.25mm〇l)及 D M F (1 m 1)複合，在周遭溫度 下攪拌18小時。在真空中濃縮，以製備性LC/MS提純， 得淺黃色固體4-(2，6-二氟代·苯甲醯胺基）-1Η-吡唑-3-羧 酸[5-氟代- 2-(1-甲基-哌啶-4-基氧基）-苯基卜醯胺（0.01 Og ，11%)。（LC/MS : Rt2· 1 9[Μ + Η] + 474·27)。 實施例166 合成4-(2，6-二氟代-苯甲醯胺基）-1Η-吼唑-3-羧酸[5-氟 代- 2- (2 -D比略院-1-基·乙氧基）-苯基]-釀胺Add 5-fluoro-2-(1-methyl-piperidine-4 -yloxy) aniline (0.049 g, 0.22 mmol) and 4- (2,6-difluoro-benzidine) Amine group) -iH-D Pidazole-3-carboxylic acid (0.0 5 3 g, 0.20 mmol), EDC (0.048 g, 0. 25 mm ο 1), HOBt (0.03 4 g, 0.25 mm) and DMF (1 m 1) compounded and stirred at ambient temperature for 18 hours. Concentrated in vacuo and purified by preparative LC / MS to give 4- (2,6-difluoro · benzylamido) -1Η-pyrazole-3-carboxylic acid [5-fluoro- 2- (1-methyl-piperidin-4-yloxy) -phenylbutanamine (0.01 Og, 11%). (LC / MS: Rt2 · 19 [M + Η] + 474 · 27). Example 166 Synthesis of 4- (2,6-difluoro-benzylideneamino) -1hydrazone-oxazole-3-carboxylic acid [5-fluoro-2- (2-D · Ethoxy) -phenyl] -fermented amine

使3，4 -二硝基氟苯（0.9 3 g，5 in m ο 1)及1 - ( 2 -經乙基吼 -216- 200524877 (212) 咯烷（〇.69g，6mmol)溶於 THF(lOml)中，在周遭溫度下攪 拌’期間以少量數次的方式加入氫化鈉（在礦物油中60%分 散，〇.24g，6mmol)。攪拌5小時，以醋酸乙酯稀釋，以水 及鹽水沖洗經複合的有機物，以硫酸鎂乾燥，在真空中濃 縮。以5%甲醇/DCM洗提行管柱層離提純殘渣，得橙色油 體1-[2-(3，4-二硝基-苯氧基）-乙基]-吡咯烷及^[2-(4-氟' 代· 2 -硝基-苯氧基）-乙基]-吡咯烷（〇 . 9 4 g，1 : 1 )。 在氮氣氛下使混合物產物（0.2 8 1 g)溶於D M F ( 5 m 1)中。 加入鈀/活性碳（10%，0.028 g)，在氫氣氛下搖動20小時。 過濾去除固體，在真空中使濾液濃縮，把殘渣與4-(2，6-二氟代·苯甲醯胺基）-1Η-吡唑_3 -羧酸（0.134g，0.50mmol) 、EDC(0.116g，0.60mmol)、HOBt(0.081g，0.60mmol)及 DMF(2.5 ml)複合，在周遭溫度下攪拌18小時。在真空中濃 縮，使殘渣分佈於醋酸乙酯（5 Oml)及飽和碳酸氫鈉水溶液 (5 0 m 1)中。以鹽水沖洗有機層，以硫酸鎂乾燥，在真空中 濃縮，得中間物醯胺。加入醋酸（1 〇ml)，在回流狀態下加 熱3小時，在真空中濃縮。以製備性LC/MS把殘渣單離成 非純白色固體4 - (2，6 -二氟代-苯甲醯胺基）-丨η _吡唑-3 -羧 酸[5-氟代- 2-(2-吡咯烷-1-基-乙氧基）_苯基卜醯胺（〇.〇40g ，5.6%)。（LC/MS : R2 38[M + H] + 474.33。 實施例1 6 7 - 2 2 3 借助於上面所描述的步驟，在表6中所陳述的化合物 被製造。 -217- 200524877 (213) 表6 實施例 編號 結構式 方法 差異 LCMS 167 斤F 〇 ίΓΝ A 依據步驟: L製造起 始的胺 以HOA潜代 HOBiffiDMSO 當溶劑替代 DMF三乙胺（ 2當置)以HPLC 提純在胺製造 (L)之後把順 式/反式異構 物分開。 [M+H]M34 艮1.97 168 rj N-N A 依據步驟 L·製造起 始的胺 以HOAt替代 HOBtffiDMSO 當溶劑替代 DMF三乙胺（ 2當量)在胺製 造(L)之後把 順式/反式異 構物分開。 [M+H]+ 434 Rt 2.03 169 V^OH VN 先後以步 驟D、G、 E、製造 [M+H]+ 338 1^2.28 170 A 依據步驟 L·製造起 始的胺 把DMS〇當溶劑 替代DMF三乙胺 (2當董)在80°C下 加熱4小時，接著 在室溫下一整夜 在最後階段之後 以肌C提純分 開順式/反式異 構物 [M+H]+ 448 Rt1.973,4-Dinitrofluorobenzene (0.9 3 g, 5 in m ο 1) and 1-(2 -Ethyl-216- 200524877 (212) pyrrolidine (0.69 g, 6 mmol) were dissolved in THF (10 ml), add sodium hydride (60% dispersed in mineral oil, 0.24 g, 6 mmol) in small amounts several times while stirring at ambient temperature. Stir for 5 hours, dilute with ethyl acetate, and dilute with water and The combined organics were washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by column separation with 5% methanol / DCM to obtain an orange oil body 1- [2- (3,4-dinitro -Phenoxy) -ethyl] -pyrrolidine and ^ [2- (4-fluoro 'substituted · 2-nitro-phenoxy) -ethyl] -pyrrolidine (0.94 g, 1: 1 ). The mixture product (0.2 8 1 g) was dissolved in DMF (5 m 1) under a nitrogen atmosphere. Palladium / activated carbon (10%, 0.028 g) was added and shaken under a hydrogen atmosphere for 20 hours. The solids were removed by filtration, The filtrate was concentrated in vacuo, and the residue was mixed with 4- (2,6-difluoro · benzylamido) -1Η-pyrazole-3-carboxylic acid (0.134 g, 0.50 mmol) and EDC (0.116 g, 0.60 mmol), HOBt (0.081 g, 0.60 mmol) and DMF (2.5 ml), and stirred at ambient temperature for 18 hours Concentrated in vacuo, the residue was distributed in ethyl acetate (50 ml) and saturated aqueous sodium bicarbonate solution (50 m 1). The organic layer was washed with brine, dried over magnesium sulfate, and concentrated in vacuo to obtain the intermediate Amidine. Add acetic acid (10 ml), heat under reflux for 3 hours, and concentrate in vacuo. The residue was isolated into a non-pure white solid by preparative LC / MS 4-(2,6-difluoro- Benzamidine)-丨 η-pyrazole-3 -carboxylic acid [5-fluoro-2- (2-pyrrolidin-1-yl-ethoxy) -phenylbutanamine (0.040 g , 5.6%). (LC / MS: R2 38 [M + H] + 474.33. Example 1 6 7-2 2 3 With the procedure described above, the compounds stated in Table 6 were manufactured. -217 -200524877 (213) Table 6 Example No. Structural formula method difference LCMS 167 kg F 〇ΓΓΝ A According to the steps: L manufacture starting amine with HOA substituting HOBiffiDMSO as solvent instead of DMF triethylamine (2 units) and purification by HPLC Separate the cis / trans isomers after the amine production (L). [M + H] M34 Gen 1.97 168 rj NN A According to step L. Manufacture the starting amine with HOAt instead of HOBtffiDMSO as solvent The alternative DMF triethylamine (2 equivalents) separates the cis / trans isomers after the amine is made (L). [M + H] + 434 Rt 2.03 169 V ^ OH VN Manufactured in steps D, G, E, and [M + H] + 338 1 ^ 2.28 170 A According to step L, the starting amine was used as DMS. Substitute DMF triethylamine (2 dong) heated at 80 ° C for 4 hours, and then overnight at room temperature overnight after the final stage with muscle C purification to separate cis / trans isomers [M + H] + 448 Rt1.97

-218- 200524877 (214) 實施例 編號 結構式 方法 差異 LCMS 171 ：1^σ〇Η VN 先後以步 驟D、G、 E、製造 [Μ+Η]+ 365 Rt 0.34 172 Q 1 °Vp ^ VN B 以石油醚-醋 酸乙酯(ι:υ 洗提行管柱 層離提純 [M+H]+414.13 Rt 3.05 173 VN B 以石油醚-醋 酸乙酯(1:1) 洗提行管柱 層離提純 [M+H]+ 432.12 Rt3.12 174 Cl VN B 以石油醚-醋 酸乙酯(1:1) 洗提行管柱 層離提純 [M+H]+ 448.06 Rt 3.33 Π5 F々 0 Vn B 以石油醚-醋 酸乙酯(1:1) 洗提行管柱 層離提純 [M+H]+ 450.08 Rt 3.29 -219- 200524877 (215) 實施例 編號 結構式 方法 差異 LCMS 176 $ 。 Vn B 以石油醚-醋 酸乙酯(1:1)洗 提行管柱層離 提純 [M+H]+ 480.05 Rt3.18 177 λ^ρ η〆 Vn A 依據步驟 L製造起 始的胺 以HOAt替代 H〇Bt 把 DMS0 當溶劑替代 DMF 三乙胺(2當量） 以HPLC提純 製造鹽酸鹽 [M+H]+ 447 1^2.01 178 [TN B [M+Hf 343.05 Rt3.38 (極譜法） 179 ίΓΝ A 以步驟N 製造丁基 哌啶4-基胺 以HOAt替代 H〇Bt連同甲 醇硏磨提純 [M+H]+ 406 Rt1.85 180 B [M+H]+ 371.09 Ι〇·27 (極譜法） 181 〇 jCO^Srv !Tn B [M+H]+ 306.06 Rt 1.53-218- 200524877 (214) Example No. Structural Formula Method Difference LCMS 171: 1 ^ σ〇Η VN Manufactured in steps D, G, E, [M + Η] + 365 Rt 0.34 172 Q 1 ° Vp ^ VN B Purification with petroleum ether-ethyl acetate (ι: υ elution line column delamination [M + H] +414.13 Rt 3.05 173 VN B Purification with petroleum ether-ethyl acetate (1: 1) line column delamination Purification [M + H] + 432.12 Rt3.12 174 Cl VN B Purification with petroleum ether-ethyl acetate (1: 1) for column separation and purification [M + H] + 448.06 Rt 3.33 Π5 F々0 Vn B Petroleum ether-ethyl acetate (1: 1) was used for column delamination and purification [M + H] + 450.08 Rt 3.29 -219- 200524877 (215) Example No. Structural formula difference LCMS 176 $. Vn B to Petroleum ether-ethyl acetate (1: 1) column stripping purification [M + H] + 480.05 Rt3.18 177 λ ^ ρ η〆Vn A According to step L, the starting amine was manufactured and replaced with HOAt. Bt uses DMS0 as a solvent instead of DMF triethylamine (2 equivalents) to produce hydrochloride salt by purification by HPLC [M + H] + 447 1 ^ 2.01 178 [TN B [M + Hf 343.05 Rt3.38 (Polarography) 179 ΓΓΝ A In step N, butylpiperidin 4-ylamine is produced, and HOAt is substituted for 〇Bt. WH mill was purified with methanol [M + H] + 406 Rt1.85 180 B [M + H] + 371.09 Ι〇 · 27 (polarographic) 181 billion jCO ^ Srv! Tn B [M + H] + 306.06 Rt 1.53

-220 - 200524877(216) 實施例 編號 結構式 方法 差異 LCMS 182 O r B [M+H]+ 403.98 Rt 2.78 183 XnV^nh 0 B [M+Hf 345.05 Rt 3.03 184 Η B [M+H]+280.05 Rt 3.75 (基本法） 185 „&lt;^νη 〇 r^\ ° M-'〇H VN A 以HOAt替代 H〇Bt,接著以 醋酸乙酯/鹽 酸脫去保護 基 [M+H]+ 336 Rt 1.67 186 i&gt;c， F。 VN A [M+Hf 380.05 Rt1.78 187 ciO-c. 〇 Γ^^Ν〆 VN A [M+H]+ 396.02 Rt 1.86-220-200524877 (216) Example No. Structural formula method difference LCMS 182 O r B [M + H] + 403.98 Rt 2.78 183 XnV ^ nh 0 B [M + Hf 345.05 Rt 3.03 184 Η B [M + H] + 280.05 Rt 3.75 (basic method) 185 〈&lt; ^ νη 〇r ^ \ ° M-'〇H VN A Replace HOBt with HOAt, then remove the protective group [M + H] + 336 Rt with ethyl acetate / hydrochloric acid 1.67 186 i &gt; c, F. VN A [M + Hf 380.05 Rt1.78 187 ciO-c. 〇Γ ^^ Ν〆VN A [M + H] + 396.02 Rt 1.86

-221 - 200524877 (217) 實施例 編號 結構式 方法 差異 LCMS 188 ψ V A [Μ+Η]+386.10 Rt 1.88 189 n^n A [Μ+Η]+ 342.10 Rt 1.95 190 &amp; O’ NH n M,-Oh !ΤΝ Η Μ [Μ+Η]+ = 344 Rt = 1.87 191 ?0Η 0’ ΝΗ η ίΓΝ Η Μ [Μ+Η]+ = 330 Rt = 1.80 192 ?:〕 Ο^ΝΗ η M,Xjh Ν-Ν Η Μ [Μ+Η]+ = 372 Rt = 1.87 -222 - 200524877 (218) 實施例 編號 結構式 方法 差異 LCMS 193 N-N/^\ 〇r rN H M [M+H]+ - 354 Rt = 1.77 194 ci^y^ci O^NH n M,Xjh K-N H M 以二氯甲院（ 120ml),甲醇（ 15ml),醋酸(3 ml)，水(2ml)( DMAW120)洗 ;提行快速層 離提純 [M+H]+ = 383 / 385 Rt = 1.72 195 O^NH 〇 Λ^ν〇Η K-N H M 以 DMAW120 洗提行快速層 離提純 [M+H]+ = 393 / 395 Rt = 1.86 196 a. 。人 NH n M,Xjh N-N H M [M+H]+ = 398 Rt = 1.94 197 。MrCr !TN H M [M+H]+ = 330 Rt = 1.80 -223- 200524877 (219) 實施例 編號 結構式 方法 差異 LCMS 198 〇/ NH n ιγν Η M [M+H]+-358 Rt = 1.89 199 0¾。 ^rV〇H M [M+H]+ = 399 Rt = 1.88 200 O’ NH n M,Xjh N-N H M [M+H]+ = 420 Rt = 2.13 201 ?Br H M [M+H]+ = 392 / 394 Rt = 1.84 202 、。今F VN B 以二氯甲烷-甲醇-醋酸-水 (90:18:3:2)洗 提行快速層 離提純 [M+Hf 376.14 Rt 1.78 -224- 200524877(220) 實施例 編號 結構式 方法 差異 LCMS 203 VN B 以二氯甲院-甲醇-醋酸-水 (90:18:3:2)洗 提行快速層 離提純 [M+Hf 400.17 Rt 2.08 204 。。 VN B 以二氯甲烷-甲醇-醋酸-水 (90:18:3:2)洗 提行快速層 離提純 [M+H]+376.15 Rt1.92 205 VN B 以二氯甲烷-甲醇-醋酸冰 (90:18:3:2)洗 提行管柱層 離提純 [M+Hf 382.12 Rt1.77 206 斗/ 。。Vf VN B 以二氯甲烷-甲醇·醋酸-水 (90:18:3:2)洗 提行管柱層 離提純 [M+H]+388.18 Rt 1.73 207 /&gt;〇, VN A 以 DMA W120 ，行快速層離 提純 [M+H]+ = 397 / 399 Rt = 1.83-221-200524877 (217) Example No. Structural Formula Method Difference LCMS 188 ψ VA [Μ + Η] +386.10 Rt 1.88 189 n ^ n A [Μ + Η] + 342.10 Rt 1.95 190 &amp; O 'NH n M, -Oh! ΤΝ Μ Μ [Μ + Η] + = 344 Rt = 1.87 191? 0Η 0 'ΝΗ η ίΓΝ Μ Μ [Μ + Η] + = 330 Rt = 1.80 192?:] 〇 ^ ΝΗ η M, Xjh Ν -N Η Μ [Μ + Η] + = 372 Rt = 1.87 -222-200524877 (218) Example number Structural formula method difference LCMS 193 NN / ^ \ 〇r rN HM [M + H] +-354 Rt = 1.77 194 ci ^ y ^ ci O ^ NH n M, Xjh KN HM Wash with dichloromethane (120ml), methanol (15ml), acetic acid (3 ml), water (2ml) (DMAW120); extraction and rapid separation and purification [M + H] + = 383/385 Rt = 1.72 195 O ^ NH 〇Λ ^ ν〇Η KN HM Fast delamination purification with DMAW120 elution line [M + H] + = 393/395 Rt = 1.86 196 a. . Human NH n M, Xjh N-N H M [M + H] + = 398 Rt = 1.94 197. MrCr! TN HM [M + H] + = 330 Rt = 1.80 -223- 200524877 (219) Example No. Structural formula method difference LCMS 198 〇 NH n ιγν Η M [M + H] +-358 Rt = 1.89 199 0¾. ^ rV〇HM [M + H] + = 399 Rt = 1.88 200 O 'NH n M, Xjh NN HM [M + H] + = 420 Rt = 2.13 201? Br HM [M + H] + = 392/394 Rt = 1.84 202. Now F VN B is purified by dichloromethane-methanol-acetic acid-water (90: 18: 3: 2) for rapid delamination and purification [M + Hf 376.14 Rt 1.78 -224- 200524877 (220) Example No. Structural Formula Method Difference LCMS 203 VN B was purified by dichloromethane-methanol-acetic acid-water (90: 18: 3: 2) for rapid delamination and purification [M + Hf 400.17 Rt 2.08 204. . VN B was washed with methylene chloride-methanol-acetic acid-water (90: 18: 3: 2) for rapid delamination and purification [M + H] +376.15 Rt1.92 205 VN B with methylene chloride-methanol-acetic acid ice (90: 18: 3: 2) Stripping and purification of elution column [M + Hf 382.12 Rt1.77 206 bucket /. . Vf VN B was stripped and purified by dichloromethane-methanol · acetic acid-water (90: 18: 3: 2) [M + H] +388.18 Rt 1.73 207 / &gt; 〇, VN A was DMA W120 , Rapid delamination purification [M + H] + = 397/399 Rt = 1.83

-225- 200524877(221) 實施例 編碼 結構式 方法 差異 LCMS 208 〇 Λ ° Μ·&quot;° A 使用(S)-3-胺基. 小N-丁氧羰基 定偶合。 以步驟Μ脫去 保護基。 以二氯甲院-甲 醇-醋酸水(90: 18:3:2)洗提行管 柱層蠢提純。 [M+Hf 382,02 Rt 1.82 209 .° 〜。、 NN-n A [M+H]+ 440.22 Rt1.92 210 a%-·^ VN A [M-fH]+ 411.20 Rt2.97 211 a〇, VN A 在處理後以 製備性 LCMS提純 [M+H]+362.11 Rtl，91 212 c,^a〇, r A 在處理後以 製備性 LCMS提純 [M+H]+ 396.08 Rt2.06-225- 200524877 (221) Example Coding Structural Formula Method Difference LCMS 208 Λ ° M · &quot; ° A (S) -3-amino group. Small N-butoxycarbonyl group fixed coupling. The protecting group is removed in step M. The column layer was purified by dichloromethane-methanol-methanol-acetic acid water (90: 18: 3: 2). [M + Hf 382,02 Rt 1.82 209. ° ~. , NN-n A [M + H] + 440.22 Rt1.92 210 a%-· ^ VN A [M-fH] + 411.20 Rt2.97 211 a〇, VN A was purified by preparative LCMS after processing [M + H] +362.11 Rtl, 91 212 c, ^ a〇, r A, purified by preparative LCMS after processing [M + H] + 396.08 Rt2.06

-226- 200524877 (222) 實施例 編號 結構式 方法 差異 LCMS 213 α： VN A 在處理後以 製備性 LCMS提純 [M+H]+ 396.06 Rt2.04 214 VN B 在真空中濃縮 ，使殘渣溶於 醋酸乙酯中，依 序以飽和碳酸 鈉水溶叙水 及鹽水沖洗。 以硫酸鎂乾燥 有機部份，在真 空中濃縮，得所 需的產物 [M+H]+ 485 Rt2.59 215 Ci FV 。糾 VN B 在真空中濃縮 ，使殘渣溶於 醋酸乙酯中，依 序以飽和碳酸 氫鈉水溶液，水 及鹽水沖洗。 以硫酸鎂乾燥 有機部份，在真 空中濃縮，得所 需的產物 [M+H]+ 429 Rt2.25 216 F r A 以 DMAW120 洗提行快速 層離提純 [M+H]+ = 376 Rt = 1.85 •227- 200524877 (223) 實施例 編號 結構式 方法 差異 LCMS 217 發Λ VN A 以 DMAW120 洗提行快速 層離提純 [M+H]+ = 376 Rt-1.87 218 VN A 先後以5%, 10% 甲醇/DCM洗 提行快速層離 提純 [M+H]+ = 376 /378 Rt = 2.23 219 i&gt;c， °。 VN A 依照步驟 L製造起 始的胺 以DMAW90洗 提行快速層離 提純 [M+H]+ = 466/ 468 Rt = 1.98 220 c|j&gt;c, Vn A 先後以5%，10% 甲醇/DCM洗 提行快速層離 提純 [M+H]+ = 376 / 378 Rt = 2.09 221 !Tn A 依照步驟 L製造起 始的胺 以DMAW90洗 提行快速層離 提純 [M+H]+ = 434 Rt = 1.82 222 !Tn A 先後以5%,10% 甲醇/DCM洗 提行快速層離 提純 [M+H]+ = 356 Rt=2.11-226- 200524877 (222) Example No. Structural formula method difference LCMS 213 α: VN A is purified by preparative LCMS after processing [M + H] + 396.06 Rt2.04 214 VN B is concentrated in a vacuum to dissolve the residue in In ethyl acetate, rinse sequentially with saturated sodium carbonate in water and brine. The organic portion was dried over magnesium sulfate and concentrated in the air to obtain the desired product [M + H] + 485 Rt2.59 215 Ci FV. VN B was concentrated in vacuo, the residue was dissolved in ethyl acetate, and the solution was washed with saturated aqueous sodium hydrogen carbonate solution, water and brine in this order. The organic portion was dried with magnesium sulfate and concentrated in vacuo to obtain the desired product [M + H] + 429 Rt2.25 216 F r A. Fast delamination purification with DMAW120 eluent and purification [M + H] + = 376 Rt = 1.85 • 227- 200524877 (223) Example No. Structural formula method difference LCMS 217 issued Λ VN A DMAW120 elution line rapid delamination purification [M + H] + = 376 Rt-1.87 218 VN A successively by 5%, 10% methanol / DCM eluent for rapid delamination and purification [M + H] + = 376/378 Rt = 2.23 219 i &gt; c, °. VN A According to step L, the starting amine is produced by DMAW90 elution and rapid delamination purification [M + H] + = 466/468 Rt = 1.98 220 c | j &gt; c, Vn A successively with 5%, 10% methanol / DCM elution and rapid delamination and purification [M + H] + = 376/378 Rt = 2.09 221! Tn A Follow the step L to make the starting amine and use DMAW90 to desorb and quickly delaminate and refine [M + H] + = 434 Rt = 1.82 222! Tn A Fast delamination purification with 5%, 10% methanol / DCM, [M + H] + = 356 Rt = 2.11

-228- 200524877 (224) 實施例 編號 結構式 方法 差異 LCMS 223 ίΓΝ A 先後以5%，1〇% 甲醇/DCM洗 提行快速層離 提純 [M+H]+ = 344 Rt = 2.09 實施例224 4 - (4 -甲基-_ ϋ秦-1 -基）-1 Η - D比D坐-3 -殘酸（4 -氟代-苯基）酸胺-228- 200524877 (224) Example No. Structural Formula Method Difference LCMS 223 ΓΓΝ A Rapid delamination purification with 5%, 10% methanol / DCM elution [M + H] + = 344 Rt = 2.09 Example 224 4-(4 -methyl-_ hydrazone-1 -yl) -1 hydrazone-D ratio D to -3-residual acid (4-fluoro-phenyl) acid amine

把一（2 -氯代乙基）甲胺鹽酸鹽（97mg; 〇·5ιηηι〇ι)加入 經攪持的4 -胺基-1 η -吡唑-3 -羧酸（4 -氟代-苯基）-醯胺 (100mg ; 0.4 5mmol)、碘化四 丁基銨（20mg ; 〇 〇45111111()1)及 二異丙基乙胺（200// 1，1.13mmol)之DMF(5ml)溶液中， 在CEM DiscoverTM微波合成器中200°C(100W)下加熱30分 鐘。在真空下去除D M F，以二氯甲烷/甲醇/醋酸/水（9 〇 : 1 8 : 3 : 2)行快速管柱層離提純。使含有產物的級份複合 ，蒸發，以氯化氫之醋酸乙酯溶液處理，連同甲苯（2 X 20ml)再次蒸發，得非純白色固體（27mg。（LC/MS : Rtl ·64[Μ + Η] + 3 7 8 )。 229- 200524877 (225) 實施例2 2 5 4 -嗎啉-4 -基- 1H_D比唑羧酸（4_氟代-苯基）-醯胺Mono (2-chloroethyl) methylamine hydrochloride (97 mg; 0.5 μm) was added to the stirred 4-amino-1 η-pyrazole-3 -carboxylic acid (4-fluoro- Phenyl) -fluorenamine (100mg; 0.45mmol), tetrabutylammonium iodide (20mg; 0045111111 () 1) and diisopropylethylamine (200 // 1, 1.13mmol) in DMF (5ml) The solution was heated in a CEM DiscoverTM microwave synthesizer at 200 ° C (100W) for 30 minutes. DMF was removed under vacuum, and purified by flash column delamination with dichloromethane / methanol / acetic acid / water (90: 18: 3: 2). The product-containing fractions were combined, evaporated, treated with hydrogen chloride in ethyl acetate, and evaporated again with toluene (2 X 20 ml) to give a non-pure white solid (27 mg. (LC / MS: Rtl · 64 [M + Η]) + 3 7 8). 229- 200524877 (225) Example 2 2 5 4 -morpholin-4 -yl-1H_D-pyrazolecarboxylic acid (4-fluoro-phenyl) -amidamine

以類似貫施例2 2 4之方式製造標題化合物，但使用二 (2-氯代乙基）醚替代二（2-氯代乙基）甲胺鹽酸鹽。（LC/MS :Rt2.48[M + H] + 291)。 實施例226 4-(2，4-二氯代-苯基唑-3-羧酸4-(4 -甲基-哌嗪-1-基）-苄基醯胺The title compound was prepared in a similar manner to Example 2 2 4 except that bis (2-chloroethyl) ether was used instead of bis (2-chloroethyl) methylamine hydrochloride. (LC / MS: Rt2.48 [M + H] + 291). Example 226 4- (2,4-Dichloro-phenylazole-3-carboxylic acid 4- (4-methyl-piperazin-1-yl) -benzylfluorenamine

226A.製造4-(2，4-二氯代-苯基）-1Η-吡唑_3_羧酸 在60 t：下把4-(2，4-二氯代-苯基）-1Η-吼唑-3-羧酸乙 酯（205mg ; 0.72mmol)及氫氧化鋰-水合物（125mg ; 2.9mmol)之THF/水（10ml，1 : 1)溶液加熱一整夜。蒸發去 除T H F，以1 Μ鹽酸使含水相酸化，以醋酸乙酯（2 0 m 1)萃 取。以硫酸鎂乾燥醋酸乙酯層，過濾，蒸發，得4-(2，4- -230- 200524877 (226) 二氯代-苯基）-1 Η -吡唑· 3 -羧酸（2 0 0 m g)。 (LC/MS : [Μ + Η] + 25 6·85)。 226Β·製造4-(2 ’ 4-一氯代·苯基比D坐-3-殘酸4-(4 -甲 基-哌嗪-卜基）-苄基醯胺226A. Production of 4- (2,4-dichloro-phenyl) -1'-pyrazole-3_carboxylic acid at 60 t: 4- (2,4-dichloro-phenyl) -1'- A solution of oxazole-3-carboxylic acid ethyl ester (205 mg; 0.72 mmol) and lithium hydroxide-hydrate (125 mg; 2.9 mmol) in THF / water (10 ml, 1: 1) was heated overnight. The T H F was removed by evaporation, the aqueous phase was acidified with 1 M hydrochloric acid, and extracted with ethyl acetate (20 m 1). The ethyl acetate layer was dried over magnesium sulfate, filtered, and evaporated to give 4- (2,4- -230- 200524877 (226) dichloro-phenyl) -1 hydrazone-pyrazole · 3-carboxylic acid (2 0 0 mg). (LC / MS: [Μ + Η] + 25 6.85). 226B · Production of 4- (2'4-monochloro · phenyl ratio D-sat-3-residue 4- (4-methyl-piperazine-butyl) -benzylfluorenamine

在室溫下把4-(2，4-二氯代-苯基）_1H-吡唑-3-羧酸 (70mg ; 〇.27mmol)，4-(4-甲基-哌嗪-1-基）_ 苄胺（62mg ; 0.3mmol)EDHC(63mg ， 0.33mmol)及 HOBt(45mg ； 0.33 mmol)之DMF( 5 ml)溶液攪拌48小時。蒸發，使殘渣分佈 於醋酸乙酯及鹽水中把醋酸乙酯層分開，以硫酸鎂乾燥， 過濾，蒸發，在真空下進一步乾燥，得4-(2，4-二氯代-苯 基）-1Η -吡唑-3 -羧酸4_(4_甲基-哌嗪-1-基）-苄基醯胺 (34mg) 0 (LC/MS ： Rt2.42[M + H] + 444)。4- (2,4-dichloro-phenyl) _1H-pyrazole-3-carboxylic acid (70 mg; 0.27 mmol), 4- (4-methyl-piperazin-1-yl) at room temperature )-A solution of benzylamine (62 mg; 0.3 mmol) EDHC (63 mg, 0.33 mmol) and HOBt (45 mg; 0.33 mmol) in DMF (5 ml) was stirred for 48 hours. Evaporate and distribute the residue in ethyl acetate and brine. Separate the ethyl acetate layer, dry over magnesium sulfate, filter, evaporate, and dry under vacuum to give 4- (2,4-dichloro-phenyl)- 1H-pyrazole-3-carboxylic acid 4- (4-methyl-piperazin-1-yl) -benzylfluorenamine (34 mg) 0 (LC / MS: Rt2.42 [M + H] + 444).

實施例227 4-(2，4-二氯代-苯基）-1 Η-吼唑-3-羧酸4-甲基氨磺醯甲基-苄基醯胺Example 227 4- (2,4-dichloro-phenyl) -1 fluorene-amidazole-3-carboxylic acid 4-methylsulfamomethyl-benzylfluorenamine

以類似實施例226之方式製造標題化合物’但使用（4- 胺基甲基-苯基）-Ν -甲基-甲烷磺胺當作起始物。單離得到 -231 - 200524877 (227) 白色固體產物（6mg)。（LC/MS: Rt3.56[M + H] + 440)。 實施例228 4-苯基-1H-吡唑-3-羧酸醯胺The title compound 'was prepared in a similar manner to Example 226 except that (4-aminomethyl-phenyl) -N-methyl-methanesulfonamide was used as a starting material. Isolation gave -231-200524877 (227) as a white solid product (6 mg). (LC / MS: Rt3.56 [M + H] + 440). Example 228 4-phenyl-1H-pyrazole-3-carboxylic acid sulfonamide

2 2 8 A · 2 -苯亞甲基-丁 - 3 -炔腈 把哌啶（5滴）加入苯甲醛（2g ; 18.9mmol)及丙二腈 (1.37g; 20.7mmol)之乙醇（40m】）溶液中，在回流狀態下加 熱一整夜。冷卻，蒸發，以1 : 9醋酸乙酯/己烷洗提行快 速管柱層離提純，使含有產物的級份複合，蒸發，得2 -苯 亞甲基-丁 -3-炔腈（93 0mg)。 2 2 8 b . 4 -苯基-5 -三甲基甲矽烷基-η -吡唑-3 -腈 在-78 °C及氮氣氛下把正丁基鋰（2.7Μ之庚烷溶液 )(3.3ml.，9mmol)滴入經攪拌的三甲基甲矽烷基重氮基甲 烷（21^[之乙醚溶液）（4.5111卜9111111〇1)之無水丁1^(1〇1111)溶液 中，攪拌3 0分鐘。把2 -苯亞甲基-丁 - 3 -炔腈（9 2 0 m g ; 6mmol)之無水THF(5ml)溶液滴入，在-78°C下攪拌30分鐘 ，逐漸地加溫至室溫達一整夜。以醋酸乙酯（3 0ml)稀釋， 先後以飽和氯化銨溶液、鹽水沖洗。把醋酸乙酯層分開， 以硫酸鎂乾燥，過濾，蒸發。先後以]:8，1 : 4的醋酸乙 -232 - 200524877 (228) 醋/己院洗提行快速管柱層離，使含有產物的級份複合， 蒸發，得4-苯基-5-二甲基甲矽烷基吡唑-3_腈（1.0§)。 2 2 8 C · 4 -苯基-1 Η -吼唑-3 -羧酸醯胺 使4 -苯基· 5 -三甲基甲矽烷基-1 Η ·吡唑-3 -腈（5 0 0 m g ; 2.1mmol)溶於乙醇（lml)中，以氫氧化鉀（6〇〇mg)之水（3ml) 溶液處理，在CEM DiscoverTM微波合成器中先在150°C (100W)下30分鐘，後在170°C(100W)下20分鐘加熱。以濃 鹽酸酸化至pHl，以水（40ml)稀釋，接著以醋酸乙酯（2 X 4 0ml)萃取。把經複合的醋酸乙酯層分開，以硫酸鎂乾燥 ，過濾，蒸發，得4-苯基-1H-D比唑-3-羧酸及4-苯基-1H-吡 唑-3 -羧酸醯胺（3 : 1 )混合物。以5 %甲醇/二氯甲烷洗提行 快速管柱層離提純粗製的產物（5 Omg)，把經含有產物的級 份複合’蒸發，得白色固體的4 -苯基-1 Η -吡唑-3 -羧酸醯胺 (15mg)。（LC/MS : Rt2.15[M + H] + 188)。 實施例229 4-苯基-1H-吡唑-3-羧酸苯基醯胺2 2 8 A · 2-benzylidene-butane-3-acetylenitrile Piperidine (5 drops) was added to benzaldehyde (2g; 18.9mmol) and malononitrile (1.37g; 20.7mmol) in ethanol (40m) ) The solution is heated overnight under reflux. Cool, evaporate, and elute with 1: 9 ethyl acetate / hexane for rapid column separation and purification. The fractions containing the product are combined and evaporated to give 2-benzylidene-but-3-ynenitrile (93 0mg). 2 2 8 b. 4-Phenyl-5 -trimethylsilyl-η-pyrazole-3 -nitrile at -78 ° C under a nitrogen atmosphere to put n-butyllithium (2.7M solution in heptane) ( 3.3ml., 9mmol) was added dropwise to a stirred solution of trimethylsilyldiazomethane (21 ^ [in ether solution) (4.5111, 9111111〇1) in anhydrous butyl (1〇1111), and stirred. 30 minutes. A solution of 2-benzylidene-butyl-3 -acetylenenitrile (920 mg; 6 mmol) in anhydrous THF (5 ml) was added dropwise, stirred at -78 ° C for 30 minutes, and gradually warmed to room temperature to reach a whole night. Dilute with ethyl acetate (30ml), and rinse with saturated ammonium chloride solution and then brine. The ethyl acetate layer was separated, dried over magnesium sulfate, filtered, and evaporated. Ethyl acetate-232: 8,1: 4-200524877 (228) vinegar / Kiyuan elution was used for rapid column delamination to combine the product-containing fractions and evaporate to obtain 4-phenyl-5- Dimethylsilylpyrazole-3_nitrile (1.0§). 2 2 8 C · 4-Phenyl-1 hydrazone-oxazole-3-carboxylic acid hydrazine makes 4-phenyl · 5-trimethylsilyl-1-pyrazole-3-nitrile (50 0 0 mg; 2.1 mmol) dissolved in ethanol (1 ml), treated with a solution of potassium hydroxide (600 mg) in water (3 ml), and firstly at 150 ° C (100 W) in a CEM DiscoverTM microwave synthesizer for 30 minutes, After heating at 170 ° C (100W) for 20 minutes. It was acidified to pH 1 with concentrated hydrochloric acid, diluted with water (40 ml), and extracted with ethyl acetate (2 × 40 ml). The combined ethyl acetate layer was separated, dried over magnesium sulfate, filtered, and evaporated to obtain 4-phenyl-1H-D-pyrazole-3-carboxylic acid and 4-phenyl-1H-pyrazole-3-carboxylic acid. Amidine (3: 1) mixture. The crude product (50 mg) was purified by flash column separation with 5% methanol / dichloromethane. The fractions containing the product were combined and evaporated to give 4-phenyl-1 hydrazone-pyrazole as a white solid. -3-Ammonium carboxylate (15 mg). (LC / MS: Rt2.15 [M + H] + 188). Example 229 4-phenyl-1H-pyrazole-3-carboxylic acid phenylamidamine

在室溫下把4 -苯基-]η - Dtt嗤-3 -殘酸（7 5 m g ; 0 · 4 m m ο 1)( 依照實施例228 C的方法製造）、苯胺（45 g 1 ; 〇.48mmol)、 -233- 200524877 (229) EDAC(92mg ; 0.48mmol)及 HOBt(65mg ; 0.48mmol)之 DMF( 5 ml)溶液攪拌一整夜。蒸發先後以1 _· 3，1 : 2的醋 酸乙酯/己烷洗提行快速管柱層離提純殘渣。把含有產物 的級份複合，蒸發，得白色固體的4-苯基-1H-吡唑-3-羧酸 苯基醯胺（30mg)。（LC/MS: Rt3.12[M + H] + 264)。 實施例230 4-苯基-1H-吡唑-3-羧酸4-(4-甲基-哌嗪-卜基）-苄基醯胺4-Phenyl-] η-Dtt 嗤 -3-residual acid (75 mg; 0.4 mm ο 1) (manufactured according to the method of Example 228 C), aniline (45 g 1; 〇) at room temperature. .48 mmol), -233- 200524877 (229) A solution of DDAC (5 ml) of EDAC (92 mg; 0.48 mmol) and HOBt (65 mg; 0.48 mmol) was stirred overnight. After evaporation, the residue was purified by rapid column separation with ethyl acetate / hexane eluted with 1-3, 1: 2. The product-containing fractions were combined and evaporated to give 4-phenyl-1H-pyrazole-3-carboxylic acid phenylamidamine (30 mg) as a white solid. (LC / MS: Rt3.12 [M + H] + 264). Example 230 4-phenyl-1H-pyrazole-3-carboxylic acid 4- (4-methyl-piperazine-butyl) -benzylfluorenamine

以類似實施例229的方式製造標題化合物，但使用4_ (4-甲基-哌嗪-卜基）-苄基胺當成起始物。產物（6nig)被單 離成白色固體。（LC/MS: Rt2.〇5[M + H] + 376)。 實施例2 3 1 4-苯基-1H-吡唑-3-羧酸（6-甲氧基-吼唑-3-基）-醯胺The title compound was prepared in a manner similar to Example 229, but using 4- (4-methyl-piperazine-butyl) -benzylamine as the starting material. The product (6nig) was isolated as a white solid. (LC / MS: Rt 2.05 [M + H] + 376). Example 2 3 1 4-Phenyl-1H-pyrazole-3-carboxylic acid (6-methoxy-oxazol-3-yl) -amidamine

-234- 200524877 (230) 以類似實施例23 0的方式製造標題化合物，但使用3 -胺基-6 -甲氧基吡啶當作胺片段。產物（1 0 0 m g )被單離成淡 棕色固體。（LC/MS: Rt3.17[M + H] + 295)。 實施例2 3 2 4-(3-苄氧基-苯基）-1Η-吼唑-3-羧酸4-(4-甲基-哌嗪-卜基）- 苄基醯胺-234- 200524877 (230) The title compound was prepared in a similar manner to that described in Example 230 except that 3-amino-6-methoxypyridine was used as the amine fragment. The product (100 mg) was isolated into a light brown solid. (LC / MS: Rt3.17 [M + H] + 295). Example 2 3 2 4- (3-Benzyloxy-phenyl) -1H-zolazole-3-carboxylic acid 4- (4-methyl-piperazine-butyl) -benzylfluorenamine

以類似實施例226的方式製造標題化合物。產物被單 離成白色固體。（LC/MS: Rt2.65[M + H] + 482)。 實施例2 3 3 4-(3-羥基-苯基）-1Η-吼唑-3-羧酸4-(4-甲基-哌嗪-卜基）-苄 基醯胺The title compound was prepared in a similar manner to Example 226. The product was isolated as a white solid. (LC / MS: Rt2.65 [M + H] + 482). Example 2 3 3 4- (3-Hydroxy-phenyl) -1H-xylazole-3-carboxylic acid 4- (4-Methyl-piperazine-butyl) -benzylfluorenamine

在室溫及加壓下把10%鈀/活性碳（l〇mg)處理4-(3-苄 氧基-苯基）-lH-D比唑-3-羧酸4-(4-甲基-哌嗪-1-基）-苄基醯 -235- 200524877 (231) 胺（25mg ; 0.05mmol)之甲醇（5ml)溶液’接著氫化一整夜 。透過矽藻土過濾除去觸媒’使濾液蒸發。以製備性 LC/MS提純，得淡黃色固體的所需產物（8mg’）。（LC/MS :Rtl .67[M + H] + 3 92)。 實施例2 3 4 4-(5 -甲基_3 H-咪唑-4-基）-1Η-哦唑-3-羧酸（4-氟代-苯基）- 醯胺Treat 4- (3-benzyloxy-phenyl) -lH-D-pyrazole-3-carboxylic acid 4- (4-methyl) with 10% palladium / activated carbon (10 mg) at room temperature and under pressure. -Piperazin-1-yl) -benzylhydrazone-235- 200524877 (231) amine (25 mg; 0.05 mmol) in methanol (5 ml) followed by hydrogenation overnight. The catalyst was removed by filtration through diatomaceous earth, and the filtrate was evaporated. Purification by preparative LC / MS gave the desired product (8 mg ') as a pale yellow solid. (LC / MS: Rtl. 67 [M + H] + 3 92). Example 2 3 4 4- (5-methyl_3H-imidazol-4-yl) -1fluorene-oxazole-3-carboxylic acid (4-fluoro-phenyl) -fluorenamine

以類似實施例226的方式製造標題化合物，但在縮合 階段中使用4-甲基-5-甲醯咪唑當作起始物。產物（6mg)被 單離成白色固體。（LC/MS: Rt2.00[M + H] + 286)。 實施例2 3 5 4-(2，5-二甲基-吡咯-b基）-1H-吼唑-3-羧酸4·(4-氟代-苯 基）-醯胺 -236- 200524877 (232)The title compound was prepared in a manner similar to Example 226, except that 4-methyl-5-methylimidazole was used as the starting material in the condensation stage. The product (6 mg) was isolated as a white solid. (LC / MS: Rt2.00 [M + H] + 286). Example 2 3 5 4- (2,5-Dimethyl-pyrrole-byl) -1H-anizol-3-carboxylic acid 4 · (4-fluoro-phenyl) -amidamine-236- 200524877 ( 232)

在CEMDiscoverTM微波合成器中在ΐ2(Γ(：(50λν)下把 4 -胺基-1 Η -吼唑-3 -羧酸（4 -氟代-苯基）-醯胺（1 〇 〇 m g)及蒙脫 土 KSF黏土（100mg)之丙酮基丙酮（lml)混合物加熱15分鐘 。以5 %甲醇/二氯甲烷稀釋，過濾，蒸發。以1 ·· 2的醋酸 乙酯/己烷洗提行快速管柱層離提純粗製的產物，把含有 產物的級份複合，蒸發，得淡棕色固體的標的分子（6 5 mg) 。（LC/MS : Rt3.75[M + H] + 299)。 實施例2 3 6 4-(3-羥基甲基·苯基）-1Η-吡唑-3-羧酸苯基醯胺In the CEMDiscoverTM microwave synthesizer, 4-amino-1 fluorene-imidazol-3-carboxylic acid (4-fluoro-phenyl) -amidamine (1000 mg) was prepared at ΐ2 (Γ (:( 50λν)). And montmorillonite KSF clay (100mg) in a mixture of acetone acetone (1ml) for 15 minutes. Dilute with 5% methanol / dichloromethane, filter, and evaporate. Extract with ethyl acetate / hexane of 1 ·· 2 The crude product was purified by rapid column separation, and the fractions containing the product were combined and evaporated to give the target molecule (65 mg) as a light brown solid (LC / MS: Rt3.75 [M + H] + 299). Example 2 3 6 4- (3-Hydroxymethyl · phenyl) -1H-pyrazole-3-carboxylic acid phenylhydrazine

23 6 A·4-碘代-1H-吡唑-3-羧酸苯基醯胺 在〇°C下把亞硝酸鈉（760mg)之水（2ml)溶液滴入經攪 拌的4-胺基-1H-吡唑·3_羧酸苯基醯胺（2g ; 1〇mm〇1)之濃鹽 酸（2 0ml)懸浮液中，接著在〇。(：下攪拌6〇分鐘，以丙酮 (10ml)稀釋，接著以碘化鉀（1.8g)及碘化亞酮（21g)處理， -237- 200524877 (233) 在室溫下攪拌9 0分鐘。以鹽水及醋酸乙酯稀釋，以飽和硫 代硫酸鈉溶液沖洗。把醋酸乙酯層分開，以硫酸鎂乾燥， 過濾，蒸發，得得4-碘代-1H-吡唑-3-羧酸苯基醯胺 (6 8 0 m g) 〇 23 0B .4-碘代-1-(4-甲氧基-苄基）-1 Η-吡唑-3-羧酸苯基醯胺 先後以碳酸鉀（360mg; 2.57 mmol)，4 -甲氧基苄基氯 (320// 1; 2.35mmol)處理4-碘代-1H-I]比唑-3-羧酸苯基醯胺 (6 7 0mg ； 2.14mmol)之乙腈（10ml)溶液。在室溫下攪拌一 整夜，在減壓下蒸發。使殘渣分佈於醋酸乙酯及鹽水之中 ;把醋酸乙酯層分開，以硫酸鎂乾燥，過濾，蒸發。以1 :3的醋酸乙酯/己烷洗提行快速管柱層離提純，把含有產 物的級份複合，蒸發，得4-碘代-1-(4-甲氧基-苄基）-1Η-吡唑-3-羧酸苯基醯胺（660mg)。 236C.4-(3-羥基甲基-苯基）-1-(4-甲氧基-苄基）-1Η-吡唑- 3- 羧酸苯基醯胺 在CEM Discover微波合成器中在1 20°C (50W)下把4-碘代-1-(4-甲氧基·苄基）-1Η-吡唑-3-羧酸苯基醯胺（50m g ; O.llmmol)，二（三第三丁基膦）鈀（I2mg)，碳酸鉀（100mg ;0.66mmol)及3-(羥基甲基）苯硼酸（21mg; 0.14mmol)之乙 醇/甲苯/水（4 m 1 : 1 m 1 : 1 m 1)的混合物加熱1 5分鐘。蒸發， 使殘渣分佈於醋酸乙酯及鹽水之中。把醋酸乙酯層分開， 以硫酸鎂乾燥，過濾，蒸發，先後以1 : 2，2 : 1的醋酸乙 -238- 200524877 (234) 醋/己烷洗提行快速管柱層離提純。把含有產物的級份複 合，蒸發，得4-(3-羥基甲基-苯基）-1-(4-甲氧基-苄基）-1H-吼唑-3-羧酸苯基醯胺（60mg)。 236D.4-(3-羥基甲基-苯基比唑-3-羧酸苯基醯胺 在CEM Discover微波合成器中在120t(50W)下把4-(3-羥基甲基-苯基）_1-(4-甲氧基-苄基）_1H-哦唑-3-羧酸苯 基醯胺（20mg)及苯甲醚（20# 1)之三氟醋酸（lml)混合物加 熱1 5分鐘。蒸發以2 :丨的醋酸乙酯/己烷洗提行快速管柱 層離提純。把含有產物的級份複合，蒸發，得產物（5 mg) 。（LC/MS : Rt2.55[M + H] + 294)。 實施例237 製造4-(2，6-二氯代-苯甲醯胺基）-iH-吡唑-3-羧酸哌啶- 4- 基醯胺鹽酸鹽 2 3 7 A. 4-(2，6-二氯代-苯甲醯胺基）-iH-吼唑-3-羧酸 把2，6 -二氯代苯甲醯氯（8.2 g ; 3 9.0 5 m m ο 1)小心地加 入4-胺基-1 Η-吡唑-3-羧酸甲酯（以類似165B的方式製造 )(5g ; 35.5mmol)及三乙胺（5.95ml ; 42.6mmol)之二噁院 (50ml)溶液中，在室溫下攪拌5小時。過濾，以甲醇（5〇ml) 及2M氫氧化鈉溶液（l〇〇ml)處理濾液，在5(TC下加熱4小 時，蒸發。加入水（100ml)，以濃鹽酸酸化。過濾收集固 體，以水（100ml)沖洗，吸乾，得淡紫外固體4-(2，6-二氯 代-苯甲醯胺基）-1 Η -吡唑-3 -羧酸（1 0 . 〇 5 g)。 -239- 200524877 (235) 237Β.4-{[4·(2，6 -二氯代-苯甲醯胺基）_1H -口比唑-3 -羰基]-胺基}-哌啶-1-羧酸第三丁醋 在室溫下把4-(2，6-二氯代-苯甲醯胺基）-iH-吡唑- 3-羧酸（6.5g，2 1.6mmol，4-胺基 _；!_丁氧羰基-哌啶（4.76g， 23.8mmol) ， EDC(5.0g ， 25.9mmol) ， HOBt(3.5g ， 25.9mmol)之DMF(75ml)混合物攪拌20小時。在真空中濃 縮，使殘渣分佈於醋酸乙酯（100ml)及飽和碳酸氫鈉水溶 液（1 0 0ml)之中。以鹽水沖洗有機層，以硫酸鎂乾燥，在 真空中濃縮。使殘渣溶於5%甲醇-DCM(〜30ml)中。過濾收 集不溶物’以DCM沖洗，在真空中乾燥，得白色固體4-{[4-(2，6·二氯代-苯甲醯胺基唑-3-羰基]-胺基}-哌啶-1-羧酸第三丁酯（5.3 8g)。在真空中濃縮濾液，以1 : 2的醋酸乙酯/己烷至醋酸乙酯梯度洗提行管柱層離提純殘 渣，得額外的白色固體4-{[4-(2，6-二氯代-苯甲醯胺基）-1H-0比唑-3-羰基]-胺基卜哌啶-1-羧酸第三丁酯（2.54g)。 23 7C.4-(2，6-二氯代-苯甲醯胺基）-lH-D比唑-3-羧酸哌啶-4-基醯胺 以飽和氯化氫之醋酸乙酯（40m L)溶液處理4-{[4气2， 6-二氯代-苯甲醯胺基）-1Η-吡唑-3-羰基]-胺基}-哌啶q-殘 酸第三丁酯（7.9g)之甲醇（50mL)及醋酸乙酯（50ml)溶液， 接著在室溫下攪拌一整夜。因爲甲醇的存在，故產物不結 晶析出，蒸發，把殘澄連同醋酸乙酯硏磨。過濾、收集非純 -240- 200524877 (236) 白色固體，以醋酸乙酯沖洗，在多孔狀澱土上吸乾，得4-(2，6 -二氯代-苯甲醯胺基）-1 Η -吡唑-3 -羧酸哌啶-4 -基醯胺 鹽酸鹽（6.3g)。（LC/MS: Rt5.89[M + H] + 3 82/3 84)。 實施例2 3 8 4-甲烷磺醯胺基-1H-吡唑-3-羧酸（4-氟代-苯基醯胺23 6 A · 4-Iodo-1H-pyrazole-3-carboxylic acid phenylphosphonium amine A solution of sodium nitrite (760 mg) in water (2 ml) was dropped into the stirred 4-amine group at 0 ° C. A suspension of 1H-pyrazole · 3-carboxylic acid phenylamidamine (2 g; 10 mm) in concentrated hydrochloric acid (20 ml) was followed by 0. (: Stirred for 60 minutes, diluted with acetone (10 ml), and then treated with potassium iodide (1.8 g) and iodide (21 g), -237- 200524877 (233) stirred at room temperature for 90 minutes. Brine Dilute with ethyl acetate and rinse with saturated sodium thiosulfate solution. Separate the ethyl acetate layer, dry over magnesium sulfate, filter, and evaporate to obtain 4-iodo-1H-pyrazole-3-carboxylic acid phenylhydrazone. Amine (680 mg) 〇23 0B. 4-iodo-1- (4-methoxy-benzyl) -1 hydrazone-pyrazole-3-carboxylic acid phenylhydrazone followed by potassium carbonate (360mg; 2.57 mmol), 4-methoxybenzyl chloride (320 // 1; 2.35 mmol) treated 4-iodo-1H-I] pyrazole-3-carboxylic acid phenylamidamine (670 mg; 2.14 mmol) Acetonitrile (10ml) solution. Stir overnight at room temperature and evaporate under reduced pressure. Distribute the residue in ethyl acetate and brine; separate the ethyl acetate layer, dry over magnesium sulfate, filter, and evaporate. Ethyl acetate / hexane was used for 1: 3 flash column delamination and purification. The fractions containing the product were combined and evaporated to give 4-iodo-1- (4-methoxy-benzyl)- 1H-pyrazole-3-carboxylic acid phenylamidamine (660 mg). 236C.4- (3-hydroxymethyl-phenyl -1- (4-Methoxy-benzyl) -1'-pyrazole- 3-carboxylic acid phenylamidine was used in a CEM Discover microwave synthesizer to convert 4-iodo-1 at 120 ° C (50W) -(4-methoxy · benzyl) -1Η-pyrazole-3-carboxylic acid phenylamidamine (50 mg; 0.11 mmol), bis (tri-tert-butylphosphine) palladium (I2mg), potassium carbonate (100 mg; 0.66 mmol) and 3- (hydroxymethyl) phenylboronic acid (21 mg; 0.14 mmol) in a mixture of ethanol / toluene / water (4 m 1: 1 m 1: 1 m 1) was heated for 15 minutes. Evaporated, Distribute the residue in ethyl acetate and brine. Separate the ethyl acetate layer, dry over magnesium sulfate, filter, evaporate, and then use ethyl acetate-238- 200524877 (234) vinegar / hexane The alkane was extracted and purified by flash column delamination. The fractions containing the product were combined and evaporated to give 4- (3-hydroxymethyl-phenyl) -1- (4-methoxy-benzyl) -1H- Anthazol-3-carboxylic acid phenylamidamine (60mg). 236D.4- (3-hydroxymethyl-phenylpyrazole-3-carboxylic acid phenylamidamine in a CEM Discover microwave synthesizer at 120t (50W ), 4- (3-hydroxymethyl-phenyl) _1- (4-methoxy-benzyl) _1H-oxazole-3-carboxylic acid phenylamidamine (20mg) and anisole (20 # 1) Trifluoroacetate The acid (1 ml) mixture was heated for 15 minutes. Evaporate and elute with ethyl acetate / hexane in a 2: 1 column to purify the column. The product-containing fractions were combined and evaporated to give the product (5 mg). (LC / MS: Rt2.55 [M + H] + 294). Example 237 Production of 4- (2,6-dichloro-benzylamido) -iH-pyrazole-3-carboxylic acid piperidine-4-ylamidoamine hydrochloride 2 3 7 A. 4- ( 2,6-dichloro-benzylamido) -iH-azolezol-3-carboxylic acid Carefully add 2,6-dichlorobenzyl chloride (8.2 g; 3 9.0 5 mm ο 1) Diamine (50ml) solution of 4-amino-1 pyrene-pyrazole-3-carboxylic acid methyl ester (manufactured in a manner similar to 165B) (5g; 35.5mmol) and triethylamine (5.95ml; 42.6mmol) The mixture was stirred at room temperature for 5 hours. Filter, treat the filtrate with methanol (50 ml) and 2M sodium hydroxide solution (100 ml), heat at 5 (TC for 4 hours, evaporate. Add water (100 ml), acidify with concentrated hydrochloric acid. Collect the solid by filtration, Rinse with water (100ml) and blot dry to obtain a light ultraviolet solid 4- (2,6-dichloro-benzylideneamino) -1 hydrazone-pyrazole-3-carboxylic acid (1.05 g) -239- 200524877 (235) 237B.4-{[4 · (2,6-dichloro-benzylideneamino) _1H-orbitazole-3 -carbonyl] -amino} -piperidine-1 -Carboxylic acid tert-butyl vinegar 4- (2,6-dichloro-benzylamido) -iH-pyrazole-3-carboxylic acid (6.5 g, 2 1.6 mmol, 4-amine A mixture of di-butoxycarbonyl-piperidine (4.76 g, 23.8 mmol), EDC (5.0 g, 25.9 mmol), HOBt (3.5 g, 25.9 mmol) in DMF (75 ml) was stirred for 20 hours. Concentrated in vacuo The residue was distributed among ethyl acetate (100 ml) and saturated aqueous sodium bicarbonate solution (100 ml). The organic layer was washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was dissolved in 5% methanol-DCM (~ 30ml). The insolubles were collected by filtration, rinsed with DCM and dried in vacuo to give a white solid 4-{[4- (2,6 Dichloro-benzylamidozol-3-carbonyl] -amino} -piperidine-1-carboxylic acid tert-butyl ester (5.3 8 g). The filtrate was concentrated in vacuo to ethyl acetate 1: 2. Ester / hexane to ethyl acetate gradient elution column separation and purification of the residue to obtain an additional white solid 4-{[4- (2,6-dichloro-benzylamino) -1H-0 ratio Azole-3-carbonyl] -aminobupiperidine-1-carboxylic acid third butyl ester (2.54g). 23 7C.4- (2,6-dichloro-benzylamino) -lH-D Pyridazole-3-carboxylic acid piperidin-4-ylfluorenamine treated with saturated hydrogen chloride in ethyl acetate (40 ml) 4-{[4-gas 2, 6-dichloro-benzylamino) -1Η -Pyrazole-3-carbonyl] -amino} -piperidine q-residual acid third butyl ester (7.9 g) in methanol (50 mL) and ethyl acetate (50 ml) solution, followed by stirring at room temperature overnight .Because of the presence of methanol, the product does not crystallize out. Evaporate. Triturate the residue with ethyl acetate. Filter and collect the impure -240- 200524877 (236) white solid, rinse with ethyl acetate, and deposit in porous sediment Suction up and dry to give 4- (2,6-dichloro-benzylideneamino) -1 hydrazone-pyrazole-3 -piperidine-4 -ylamidoamine hydrochloride (6.3g). LC / MS: Rt5.89 [M + H] + 3 82/3 84). Example 2 3 8 4-Methanesulfonamido-1H-pyrazole-3-carboxylic acid (4-fluoro-phenylphosphonium amine

在室溫下把4_胺基-1H-吡唑-3-羧酸（4-氟代苯基卜酿 胺（5 0mg)(實施例2B)及甲烷磺酸酐（45mg)之吡啶（lml)溶液 攪拌一整夜，蒸發，以2 : 1的醋酸乙酯/己烷洗提行快速 管柱層離提純。把含有產物的級份蒸發，得檫題化合牛勿 (20mg)。（LC/MS : Rt2.87[M + H] + 299)。 實施例23 9至245 實施例23 9至245之化合物乃利用上面所描述的方法^ 類似上面所描述的方法的方法被製造。 實施例239 4-(2，6-二氟代-苯甲醯胺基）_1H-吼唑-3-羧酸[。（八氟代 乙基）-哌啶-4-基醯]-胺 -241 - 200524877 (237) Η.4-Amino-1H-pyrazole-3-carboxylic acid (4-fluorophenylbutanamine (50 mg) (Example 2B) and methanesulfonic anhydride (45 mg) of pyridine (1 ml) at room temperature) The solution was stirred overnight, evaporated, and purified by flash column dehydration with 2: 1 ethyl acetate / hexane. The fractions containing the product were evaporated to give the title compound Niuta (20mg). (LC / MS: Rt2.87 [M + H] + 299). Examples 23 9 to 245 The compounds of Examples 23 9 to 245 were prepared by a method similar to the method described above. Example 239 4- (2,6-difluoro-benzylideneamino) _1H-oxazol-3-carboxylic acid [(octafluoroethyl) -piperidin-4-ylhydrazone] -amine-241-200524877 (237) Alas.

實施例240Example 240

4-(2，6-二氯代-苯甲醯胺基）-1Η-吼唑-3-羧酸（6-氯代-吡 D定）-3 -基）-釀胺4- (2,6-dichloro-benzylideneamino) -1Η-oxazole-3-carboxylic acid (6-chloro-pyridine) -3 -yl) -vinylamine

實施例241Example 241

4-(2，6-二氯代-苯甲醯胺基）-1Η-吡唑-3-羧酸（6-胺基-吡 啶-3-基）-醯胺 H.4- (2,6-dichloro-benzylamido) -1, -pyrazole-3-carboxylic acid (6-amino-pyridin-3-yl) -amidamine H.

實施例242 4-(2，6-二氯代-苯甲醯胺基）-1Η-吼唑-3-羧酸（6 -甲氧基-吡啶-3-基）-醯胺 -242- 200524877 (238)Example 242 4- (2,6-dichloro-benzylideneamino) -1hydrazone-oxazole-3-carboxylic acid (6-methoxy-pyridin-3-yl) -amidoamine-242- 200524877 (238)

實施例243 4-[3-氯代- 5-(4-甲基-哌嗪-卜基）-苯甲醯胺基]-1 Η-吼唑- 3-Example 243 4- [3-Chloro-5- (4-methyl-piperazine-butyl) -benzamidinyl] -1 hydrazone-nizole-3

羧酸環己基醯胺Cyclohexylamine

KK

實施例244 4-(2，6-二氟代-苯甲醯胺基）-1Η-吼唑-3-羧酸[1-(2，2-二 氟代-乙基）-哌啶-4-基醯胺 φExample 244 4- (2,6-difluoro-benzylideneamino) -1 hydrazine-3-carboxylic acid [1- (2,2-difluoro-ethyl) -piperidine-4 -Methylamine φ

實施例245 4 - [ 3 - ( 4 -甲基-哌嗪-1-基）-苯甲醯胺基]-1 Η -吼唑-3 -羧酸環 己基醯胺 -243- 200524877 (239)Example 245 4-[3-(4 -Methyl-piperazin-1-yl) -benzamidinyl] -1 hydrazone -imidazole-3 -carboxylic acid cyclohexylamidoamine -243- 200524877 (239)

生物活性 實施例2 4 6 量測CD K2激酶抑制活性（ic5〇) 使用在下面的實驗方案或使用在實施例2 4 1中所描述 的經活化的CD K2/環素A激酶實驗方案來試驗本發明之 化合物抑制激酶的活性。 把經活化的 CD K2 /環素 A(Upstate Biotechnology， 10U/ Μ 1)(1 ·7 // 1)在分析緩衝液中稀釋（該分析緩衝液包含 :1 〇 倍強的分析緩衝液（2 5 0 μ 1) (2 0 0 m Μ Μ Ο P S p Η 7.2， 2 5 0mM yS-甘油磷酸鹽，50mM EDTA，150mM 氯化鎂）， 10mM ΑΤΡ(11·27μ1)，1MDTT(2.5//1)，lOOmM 原釩酸鈉 (25 // 1)，水（70 8.5 3 // 1)，把稀釋液10 // 1與組蛋白酶作用 物混合物（60 // 1 牛組蛋白 Hl(Upstate Biotechnology， 5mg/ml)，940 // I 水，35 // Ci γ 33P-ATP)1 0 β 1 混合，把 混合物連同5 // 1不同的試驗化合物之D M S Ο (至多2.5 % )稀 釋液加入96#培養板中。使反應進行5小時，接著以過量的 原磷酸（2%，30 # 1)使反應停止。 尙未被倂入組蛋白的殘留的7 33Ρ-ΑΤΡ與經磷酸化 200524877 (240) 的組蛋白 HI被Millipore MAPH濾菌器培養板分開。以 0.5%原磷酸潤濕MPAPH培養板上的穴井，以Millipore 真空過濾單元透過穴井過濾反應的結果。以200 // 1的 0.5%原磷酸沖洗殘渣2次。一旦濾菌器乾燥，加入25 // 1 的 Microscint20閃燦劑，接著在PackardTopcount上計數 3 0秒。 CDK2活性的抑芾[]百分率被計算及作圖，以便確定達 到抑制CDK2活性的50%所需的試驗化合物的濃度（1C 5〇)。 借助於在上面所陳述的實驗方案，吾人發現：實驗例 2C 至 87 ， 89-92 ， 94 ， 96-101 ， 104-105 ， 165 ， 166 ， 224 ，225，227，229，231，233，234 及 236之化合物各具有 2 0 // Μ以下的I C 5 〇値或提供在1 0 // Μ的濃度下可抑制 CDK2 活性至少 50%。實施例 88，93，226，22 8，23 0 及 2 3 5之化合物各具有7 5 0 // Μ以下的IC 5G値。 實施例2 4 7 CDK選擇性分析 使用在實施例239中所描述的泛用實驗方案（但如下面 所陳述被修飾）來試驗本發明之化合物對抗許多不同激酶 的激酶抑制活性。 把激酶在 20mM MOPS pH7.0，ImM EDTA，0.1%r-锍基乙醇，0.01% Brij-35，5%甘油，lmg/ml BSA中稀釋 成10倍的工作原液。一單位等於在30 °C下每分鐘把lnm ο 1 的磷酸鹽倂入〇.lmg/ml組蛋白HI，或CDK7酶作用物肽（ -245- 200524877 (241) 以最後的ATP濃度1 00 // Μ)中。 供所有的CDK分析（除CDK7之外）用的酶作用物是組 蛋白 Η1，彼在使用前被20mM MOPS ph7.4稀釋成10倍的 工作原液。供CDK7用的酶作用物是特g(J的肽（Upstate)， 彼被去離子水稀釋成1 0倍的工作原液。 供 CDK1/環素 B，CDK2/環素 A，CDK2/環素 E，CDK2/環 素E，CDK5/P35，CDK6/環素D3用的分析步驟： 在最終的反應體積25 // 1中，使酶（5-10mU)被8mM MOPS ρΗ7·0，〇.2mM EDTA，0.1mg/ml 組蛋白 HI，10mM 醋酸鎂及[r -33P-ATP](比活性大約50〇Cpm/pmol，濃度視 需要而定）溫育。加入Mg2 + [r-33P-ATP]啓始反應。在室 溫下溫育4 0分鐘，加入3 %磷酸溶液（5 μ 1)使反應停止。把 l〇ml反應液滴在 Ρ30濾墊上，以75mM磷酸沖洗3次（花5 分鐘），以甲醇沖洗一次，接著乾燥及計數。 在CDK3/環素E分析中，實施例150之化合物具有20 μ m以下的IC 5G値。 在CDK5/P35分析中，實施例41及150之化合物具有20 // m以下的IC5G値。 在CDK6/環素D3分析中，實施例150之化合物具有20 // m以下的I C 5 〇値。 供CDK7/環素H/MAT1用的分析步驟Biological activity Example 2 4 6 Measurement of CD K2 kinase inhibitory activity (ic50) Test using the following protocol or use the activated CD K2 / cyclin A kinase protocol described in Example 2 41 The compounds of the present invention inhibit kinase activity. The activated CD K2 / Cyclin A (Upstate Biotechnology, 10U / M 1) (1 · 7 // 1) was diluted in the analysis buffer (the analysis buffer contains: 10 times stronger analysis buffer (2 50 μ 1) (200 m Μ Μ Ο PS p Η 7.2, 250 mM yS-glycerol phosphate, 50 mM EDTA, 150 mM magnesium chloride), 10 mM ATP (11.27 μ1), 1 MDTT (2.5 // 1), lOOmM sodium orthovanadate (25 // 1), water (70 8.5 3 // 1), a dilution of 10 // 1 with a mixture of histone proteases (60 // 1 bovine histone Hl (Upstate Biotechnology, 5mg / ml), 940 // I water, 35 // Ci γ 33P-ATP) 1 0 β 1 mixed, add the mixture together with 5 // 1 DMS 0 (up to 2.5%) dilution of different test compounds to 96 # culture plate The reaction was allowed to proceed for 5 hours, and then the reaction was stopped with an excess of orthophosphoric acid (2%, 30 # 1). 尙 Residual 7 33P-ATP that was not incorporated with histones and the group phosphorylated 200524877 (240) The protein HI was separated by a Millipore MAPH filter culture plate. The wells on the MPAPH culture plate were wetted with 0.5% orthophosphoric acid, and the reaction was filtered through the wells with a Millipore vacuum filtration unit. 0 // 1 0.5% orthophosphoric acid rinses the residue 2 times. Once the bacteria filter is dry, add 25 // 1 Microscint20 Blinker, and then count on PackardTopcount for 30 seconds. The inhibition [] percentage of CDK2 activity is calculated And plot to determine the concentration of the test compound (1C 50) required to achieve 50% inhibition of CDK2 activity. With the experimental protocol stated above, we found that: Experimental Examples 2C to 87, 89-92, 94 , 96-101, 104-105, 165, 166, 224, 225, 227, 229, 231, 233, 234, and 236 each have an IC 5 〇 値 of 20 or less or provide 1 0 // CDK2 activity can be inhibited by at least 50% at the concentration of M. The compounds of Examples 88, 93, 226, 22 8, 23 0, and 2 35 each have an IC 5G 値 of 7 5 0 // M or less. Example 2 4 7 The CDK selective assay uses the general-purpose protocol described in Example 239 (but modified as stated below) to test the compounds of the invention against the kinase inhibitory activity of many different kinases. The kinase was diluted 10 times in 20 mM MOPS pH 7.0, ImM EDTA, 0.1% r-fluorenylethanol, 0.01% Brij-35, 5% glycerol, and 1 mg / ml BSA. One unit is equal to 0.1 mg / ml of histone HI, or CDK7 enzyme peptide (-245- 200524877 (241) at a final ATP concentration of 1 00 / / M). The enzyme used for all CDK analysis (except CDK7) was histone Η1, which was diluted 10-fold with 20 mM MOPS ph7.4 working stock solution before use. The enzyme used for CDK7 is the peptide (Upstate), which is diluted with deionized water to a 10-fold working stock solution. For CDK1 / Cyclin B, CDK2 / Cyclin A, and CDK2 / Cyclin E , CDK2 / Cyclin E, CDK5 / P35, CDK6 / Cyclin D3 Analytical steps: In the final reaction volume of 25 // 1, the enzyme (5-10mU) is subjected to 8mM MOPS ρΗ7.0, 0.2mM EDTA , 0.1mg / ml histone HI, 10mM magnesium acetate and [r -33P-ATP] (specific activity is about 50 Cpm / pmol, the concentration depends on need) incubation. Add Mg2 + [r-33P-ATP] to start Start the reaction. Incubate at room temperature for 40 minutes, add 3% phosphoric acid solution (5 μ 1) to stop the reaction. Drop 10 ml of the reaction solution on a P30 filter pad and rinse 3 times with 75 mM phosphoric acid (take 5 minutes) Rinse with methanol once, then dry and count. In the CDK3 / cycline E analysis, the compound of Example 150 has an IC 5G 5 below 20 μm. In the CDK5 / P35 analysis, the compounds of Examples 41 and 150 have IC5G 値 below 20 // m. In the CDK6 / cycline D3 analysis, the compound of Example 150 has an IC 5 〇 値 below 20 // m. Analytical steps for CDK7 / cycline H / MAT1.

在最終的反應體積25 // 1中，使酶（5-lOmU)被8mM -246- 200524877 (242) MOPSpH7,0，〇.2mMEDTA，500//M 肽，l〇mM 醋酸鎂及 [r -33P-ATP](比活性大約5 00cpm/pmol，濃度視需要而定） 溫育。加入Mg2 + [ 7 -33P-ATP]啓始反應。在室溫下溫育40 分鐘，加入3%磷酸溶液（5 // 1)使反應停止。把1〇 ml反應 液滴在P 3 0濾墊上，以7 5 mM磷酸沖洗3次（花5分鐘），以 甲醇沖洗一次，接著乾燥及計數。 實施例248In the final reaction volume of 25 // 1, the enzyme (5-lOmU) was subjected to 8mM -246- 200524877 (242) MOPS pH 7,0, 0.2mMEDTA, 500 // M peptide, 10mM magnesium acetate and [r- 33P-ATP] (specific activity is about 500 cpm / pmol, concentration is as needed) Incubation. Mg2 + [7 -33P-ATP] was added to start the reaction. Incubate at room temperature for 40 minutes. Add 3% phosphoric acid solution (5 // 1) to stop the reaction. 10 ml of the reaction solution was dropped on a P 30 filter pad, washed 3 times with 75 mM phosphoric acid (takes 5 minutes), washed once with methanol, then dried and counted. Example 248

A.量測經活化的CDK2/環素A激酶抑制活性分析（IC50) 使用在下面的實驗方案來試驗本發明之化合物抑制激 酶的活性。 使經活化的 CDK2/環素 A(Brown et al.，Nat.Cell Biol· ， 1 ， p p 4 3 8 -443 ， 1 999 ; Lowe ， E.D. ， etA. Measurement of Activated CDK2 / Cyclin A Kinase Inhibition Assay (IC50) The following experimental protocol was used to test the compounds of the present invention for inhibitory kinase activity. Activated CDK2 / Cyclin A (Brown et al., Nat. Cell Biol ·, 1, p p 4 3 8 -443, 1 999; Lowe, E.D., et

al.，Biochemistry，41，ppl 5 625 - 1 5 63 4，2002)在 2.5 倍強 的分析緩衝液中稀釋成1 2 5 P M (該分析緩衝液包含：5 0 m M MOPS pH7.2，62.5mM 冷甘油磷酸鹽，12.5mM EDTA， 37.5mM 氯化鎂，112.5mM ATP，2.5mM DTT，2.5mM 原 釩酸鈉，0.25 mg/ml牛血淸蛋白素）’把稀釋液1 〇 # 1與組 蛋白酶作用物混合物（60 # 1牛組蛋白 Hl(Upstateal., Biochemistry, 41, ppl 5 625-1 5 63 4, 2002) was diluted to 1 2 5 PM in 2.5 times stronger analysis buffer (the analysis buffer contains: 50 m M MOPS pH 7.2, 62.5 mM cold glycerol phosphate, 12.5 mM EDTA, 37.5 mM magnesium chloride, 112.5 mM ATP, 2.5 mM DTT, 2.5 mM sodium orthovanadate, 0.25 mg / ml bovine heparin)) Dilute the solution 1 〇 # 1 with histone Substance mixture (60 # 1 bovine histone Hl (Upstate

Biotechnology，5mg/nil) ’ 940// 1 水 ’ 35// Ci γ Ρ- ATP) 1 0 // 1混合，把混合物連同5 A 1的不同的試驗化合物 之D M S 0 (至多2 · 5 %)稀釋液加入9 6 #培養板中。使反應進 行2至4小時，接者以過量的原磷酸（2 %，5 // 1)加以停止。 尙未被倂入組蛋白Η1的殘留的r -33ρ-ατρ與經磷· -247- 200524877 (243) 酸化的組蛋白Η 1被M i 11 i p 0 r e M A Ρ Η濾菌器培養板分開。 以0.5%原磷酸潤濕ΜΑΡΗ培養板的井。以Maillipore真 空過濾單元透過穴井過濾反應的結果。以200 // 1的0.5% 原磷酸沖洗殘渣2次。一旦濾菌器乾燥，加入2 0 // 1的 Microscint 20閃爍劑，接著在 Packard Topcount 上計算 30 秒。 將CDK2活性抑制百分率計算及作圖，以便確定達到 抑制CDK2活性的50%所需的試驗化合物的濃度（IC5〇)。 借助於在上面所陳述的實驗方案，吾人發現：實施例 95，96，99- 1 04，106-121，1 23 - 1 2 5，1 3 0- 1 3 7，1 39， 1 42- 1 45，1 47- 1 5 0，1 5 2- 1 5 6，1 5 8 - 1 60，1 62- 1 64，167-173 ， 177-179 ， 181-182 ， 184-190 ， 194 ， 196-204 ， 208- 2 13及2 15之化合物各具有20// Μ以下的IC 5G値，並且大多 數具有100 // Μ以下的1C 5〇値。 B.CDK1/環素Β分析 CDK1/環素Β分析等同於上面的CDK2/環素Α，除了 以下的不问：使用CDK1/環素B(Upstate Discovery)，以 及酶被稀釋成6.25nM。 在如上述的方式或借助於實施例240中被陳述的實驗 方案所進行的C D K 1分析中，吾人發現：實施例2 c，4 1， 48 ’ 53 ， 64 ， 65 ， 66 ， 73 ， 76 ， 77 ， 91 ， 95 ， 102 ， 106 ， 117， 123， 125， 133， 137， 142， 150， 152， 154， 167， 186， 187， 189， 190， 193， 194， 196， 199， 202-204， -248- 200524877 (244) 207，208-213，215及218-223之化合物具有20//m以下的 IC5G値，而實施例188及206之化合物具有1 000 /zm以下的 1C 50値。 實施例249 供CD4用之分析步驟Biotechnology, 5mg / nil) '940 // 1 water' 35 // Ci γ ρ- ATP) 1 0 // 1 mixed, mix the mixture with 5 A 1 DMS of different test compounds 0 (up to 2.5%) Diluent was added to 9 6 # culture plate. The reaction was allowed to proceed for 2 to 4 hours, and then stopped with an excess of orthophosphoric acid (2%, 5 // 1). Residual r-33ρ-ατρ, which has not been incorporated into histone Η1, is separated from histone 1, which has been acidified with phosphorus -247-200524877 (243), and separated by a M i 11 i p 0 r e M A P 菌 filter plate. Wells of MAPY culture plates were wetted with 0.5% orthophosphoric acid. The results were filtered through a well with a Maillipore vacuum filtration unit. Rinse the residue twice with 0.5% orthophosphoric acid at 200 // 1. Once the bacteria filter is dry, add 20 // 1 Microscint 20 scintillator, and then count on the Packard Topcount for 30 seconds. The percentage inhibition of CDK2 activity was calculated and plotted to determine the concentration of the test compound (IC50) required to achieve 50% inhibition of CDK2 activity. With the experimental protocol stated above, we have found that: Examples 95, 96, 99-1 04, 106-121, 1 23-1 2 5, 1 3 0- 1 3 7, 1 39, 1 42-1 45, 1 47- 1 5 0, 1 5 2- 1 5 6, 1 5 8-1 60, 1 62- 1 64, 167-173, 177-179, 181-182, 184-190, 194, 196- The compounds of 204, 208- 2 13 and 2 15 each have an IC 5G 値 of 20 // M or less, and most have 1C 50 値 of 100 / M or less. B. CDK1 / Cyclin B analysis CDK1 / Cyclin B analysis is equivalent to the above CDK2 / Cyclin A, except for the following: Use CDK1 / Cycline B (Upstate Discovery), and the enzyme was diluted to 6.25 nM. In the CDK 1 analysis performed as described above or by means of the experimental protocol stated in Example 240, we found that: Example 2 c, 4 1, 48 '53, 64, 65, 66, 73, 76, 77, 91, 95, 102, 106, 117, 123, 125, 133, 137, 142, 150, 152, 154, 167, 186, 187, 189, 190, 193, 194, 196, 199, 202-204, -248- 200524877 (244) The compounds of 207, 208-213, 215 and 218-223 have an IC5G 値 of 20 // m or less, and the compounds of Examples 188 and 206 have a 1C 50 値 of 1 000 / zm or less. Example 249 Analysis steps for CD4

使用 Proqinase GmbH ’ Freiburg ’ Germany 專有的 33PanQinase®活性分析進行 CD4抑制活性分析。在96井 FlashPlatesTM(PerkinElmer)中進行分析。在各種場合中， 反應混合物（最終體積50 // 1)的組成如下：20 // 1分析緩衝 液（最終組成 60mM HEPES-NaOH，PH7.5，3mM 氯化鎂，3 μ Μ 原釩酸鈉，1.2mM DTT，50 // 1/ml PEG 2 0 0 0，5 // 1 ATP 溶液（最終濃度 1 // M[ r -33P]-ATP(大約 5 x l〇5cpm/井 ))，5 // 1試驗化合物之10%DMSO溶液，10 // 1酶作用物 /1 0 // 1酶溶液（預先混合）。酶及酶作用物的最終份量如下 所示。 激酶 激酶 酶作用物 酶作用物 ng/5 0 // 1 ng/5 0 // 1 CDK4/環素 D1 50 Ρ ο 1 y (A 1 a，G1 u，Lys 500 ，Tyr)6: 2: 5: 1 使反應混合物在3 0 °C下溫育8 0分鐘。以2 %磷酸溶液 (5 0 // 1)使反應停止，把培養板抽吸，以〇·9%鹽水（200 // 1) -249- 200524877 (245) 沖洗2次。以微培養板閃爍計數器確定33P的倂入。在計算 各井的殘留活性之前把數據扣除背景値。使用Prism 3.03 計算IC5〇値。 在這個分析中實施例1 5 0之化合物具有5 // m以下的 IC50 値。CD4 inhibitory activity analysis was performed using Proqinase GmbH ’Freiburg’ Germany ’s proprietary 33PanQinase® activity assay. Analysis was performed in a 96-well FlashPlatesTM (PerkinElmer). In various situations, the composition of the reaction mixture (final volume 50 // 1) is as follows: 20 // 1 analysis buffer (final composition 60 mM HEPES-NaOH, pH 7.5, 3 mM magnesium chloride, 3 μM sodium orthovanadate, 1.2 mM DTT, 50 // 1 / ml PEG 2 0 0 0, 5 // 1 ATP solution (final concentration 1 // M [r -33P] -ATP (approximately 5 x 105cpm / well)), 5 // 1 10% DMSO solution of the test compound, 10 // 1 enzyme substrate / 1 0 // 1 enzyme solution (premixed). The final amount of enzyme and enzyme substrate is shown below. Kinase kinase enzyme substrate ng / 5 0 // 1 ng / 5 0 // 1 CDK4 / Cyclo D1 50 ρ ο 1 y (A 1 a, G1 u, Lys 500, Tyr) 6: 2: 5: 1 The reaction mixture was maintained at 3 0 ° C Incubate for 80 minutes. Stop the reaction with 2% phosphoric acid solution (50 0 // 1), aspirate the culture plate, and rinse with 0.9% saline (200 // 1) -249- 200524877 (245) 2 The incubation of 33P was determined by a microplate scintillation counter. The background was subtracted from the data before calculating the residual activity of each well. The IC50 was calculated using Prism 3.03. In this analysis, the compound of Example 150 has 5 / / 50 IC50 以下.

實施例2 5 0 抗增殖作用分析Example 2 50 Analysis of antiproliferative effect

借助於對本發明之化合物在許多細胞系中的細胞生長 的抑制能力的量測來確定本發明之化合物抗增殖作用的活 性。使用 Alamar Blue 分析（Nociari，M.M，Shalev，A.， Benias，P.Russo，C. J o urnal of Immunological Methods 1 99 8，213，1 5 7- 1 67)量測細胞生長的抑制作用。該方法 係根據能存活的細胞把刃天青（resazurin)還原成彼之螢光 產物試鹵靈（res orufin)的能力。對各種增殖作用的分析而 言，細胞被置於9 6井培養板上，恢復1 6小時，接著加入抑 制劑達72小時。在溫育結束時，加入1 〇%(v/v)AIamar Blue ，溫育6小時，接著在5 3 5 nM ex/5 90nM em下確定螢光產 物。在非增殖性細胞分析的場合中，細胞被保持在融合狀 態下96小時，接著加入抑制劑達72小時。能存活的細胞數 且如先前般以A1 a m a r B 1 U e分析予以確定。所有的細胞系 皆取得自ECACC(歐洲細胞培養物收集所）。 在對抗人結腸癌細胞系HCT116(ECACC No.9 1 09 1 005 )的分析中，實施例 1〇，25-27，41 , 44，46，48，50，52 -250- 200524877 (246) ，53，60，62，64-67，6 9，73 - 77，79，80，83 A，86， 90-93 ， 95-98 ， 100-104 ， 106 ， 107 ， 109-121 ， 123-125 ， 13卜 134，1 3 6 - 1 43，1 47- 1 5 5，158，159，1 62- 1 64，166, 167， 178， 179， 185-190， 192-205， 207-215及218-223之 化合物具有20 // Μ以下的IC5G値，而實施例2C，3，29， 38， 39， 49， 51， 85， 89， 99， 108， 135， 160， 182, 183，206及216之化合物具有100// Μ以下的IC5G値。 實施例2 5 1 量測抗糖原合成酶激酶-3 (GSK-3)的抑制活性 使用下面的實驗方案A或B來確定充當GSK-3之抑 制劑的本發明之化合物的活性。The antiproliferative activity of the compounds of the present invention is determined by measuring the ability of the compounds of the present invention to inhibit cell growth in many cell lines. Alamar Blue analysis (Nociari, M.M, Shalev, A., Benias, P. Russo, C. Journal of Immunological Methods 1 99 8, 213, 15 7-1 67) was used to measure the inhibitory effect of cell growth. This method is based on the ability of viable cells to reduce resazurin to its fluorescent product, res orufin. For the analysis of various proliferation effects, the cells were placed on a 96-well culture plate, recovered for 16 hours, and then the inhibitor was added for 72 hours. At the end of the incubation, 10% (v / v) AIamar Blue was added, the incubation was performed for 6 hours, and then the fluorescent product was determined at 5 35 nM ex / 5 90 nM em. In the case of non-proliferative cell analysis, cells are kept in a confluent state for 96 hours, followed by the addition of inhibitors for 72 hours. The number of viable cells was determined as before by A1 ama r B 1 U e analysis. All cell lines were obtained from ECACC (European Cell Culture Collection). In the analysis against the human colon cancer cell line HCT116 (ECACC No. 9 1 09 1 005), Examples 10, 25-27, 41, 44, 46, 48, 50, 52 -250- 200524877 (246), 53, 60, 62, 64-67, 6 9, 73-77, 79, 80, 83 A, 86, 90-93, 95-98, 100-104, 106, 107, 109-121, 123-125, 13 Bu 134, 1 3 6-1 43, 1 47- 1 5 5, 158, 159, 1 62- 1 64, 166, 167, 178, 179, 185-190, 192-205, 207-215, and 218- The compound of 223 has an IC5G of 20 / M or less, while Examples 2C, 3, 29, 38, 39, 49, 51, 85, 89, 99, 108, 135, 160, 182, 183, 206, and 216 The compound has an IC5G 値 of 100 // M or less. Example 2 5 1 Measurement of inhibitory activity against glycogen synthase kinase-3 (GSK-3) The following protocol A or B was used to determine the activity of the compound of the present invention as an inhibitor of GSK-3.

實驗方案A 使 GSK3 - /3 (Upstate Di sco very)在下列溶劑中稀釋成 7.5 nM : 2 5 m M MOPS ， p Η 7.0 0 ， 2 5 m g / m 1 BSA ， 0.002 5 %Brij-35RTM，1 · 2 5 % 甘油，0.5 m Μ E D T A，2 5 m M 氯 化鎂，0.25% /5 -锍基乙醇，37.5mM ATP，把稀釋液10 # ：[ 與酶作用物1 〇 // 1混合。該酶作用物混合物是1 2 · 5 // Μ磷-糖原合成酶肽-2(Upstaate Discovery)之水（lml)溶液（具有 35 β Ci 7 -3 3 P-ATP)。把酶及酶作用物連同5 // 1各種的試 驗化合物之DM SO稀釋液（至多2.5%)加入96井培養板中。 使反應進行3小時，接著以過量的原碟酸（5 // 1，2 %)使反 應停止。過濾的步驟如同上面的經活化的CDK2/環素 a -251 - 200524877 (247) 分析。Protocol A Dilute GSK3-/ 3 (Upstate Disco very) to 7.5 nM in the following solvents: 2 5 m M MOPS, p ， 7.0 0, 2 5 mg / m 1 BSA, 0.002 5% Brij-35RTM, 1 · 25% glycerol, 0.5 mM EDTA, 2.5 mM magnesium chloride, 0.25% / 5-fluorenylethanol, 37.5mM ATP, and the diluted solution 10 #: [is mixed with the enzyme substrate 1 0 // 1. The enzyme substrate was a 1 2 · 5 // M phosphorus-glycogen synthase peptide-2 (Upstaate Discovery) solution in water (1 ml) (with 35 β Ci 7 -3 3 P-ATP). Add enzymes and enzyme substrates together with 5 // 1 DM SO dilutions (up to 2.5%) of various test compounds to a 96-well culture plate. The reaction was allowed to proceed for 3 hours, and then stopped with an excess of orthophosphoric acid (5 // 1, 2%). The filtration procedure was the same as for the activated CDK2 / cycline a -251-200524877 (247) analysis above.

實驗方案B 使G S K 3 $ (人）在下列溶劑中稀釋成1 〇倍的工作原液 :50mM Tris pH7.5，O.lmM EG T A，0 · 1 m Μ 釩酸鈉，0.1 °/〇 冷-锍基乙醇，lmg/ml BSA。一單位等於每分鐘把lnmol 磷酸鹽倂入磷糖原合成酶肽2中。 在最終反應體積25ml中，GSK3yS(5-10mU)被下列藥 劑溫育：8mM MOPS7.0 ， 0.2mM EDTA ， 20// Μ YRRAAVPPSPSLSRHSSPHQS(p)EDEEE(磷 GS2肽），1 OmM 醋酸錢及[T _3 3 P - A T P ](比活性大約5 Ο 0 c p m / p m ο 1，濃度視 需要而定）。加入Mg2 + [ 7 -33P-ATP]啓始反應。在室溫下 溫育40分鐘，加入3%磷酸溶液15 // 1)使反應停止。把反應 液（1 〇 // 1)滴在P3 0濾墊上，以50mM磷酸沖洗3次（花5分鐘 )’以甲醇沖洗一次，接著乾燥及計數。 從使用上面所陳述的二個實驗方案中的任一個所進行 的GSK3-B分析的結果中，吾人發現：實施例2c，26，48 ，53， 65， 76， 77， 84， 86， 95， 102， 106， 119， 122， 123， 126， 127， 128， 129， 131， 134， 135， 138， 140， 141，142，143，144，145，146，147，149，150及 151 之 化合物各具有10 // Μ以下的IC5G値。 藥學調和物 實施例2 5 2 200524877 (248) (i)藥錠調和物 含有如式（1)之化合物的藥錠組成物可利用下列方式 被製造：把如式（1)之化合物（50mg)及乳糖（BP)(197mg， 當作稀釋劑），硬脂酸鎂（3 mg，當作潤滑劑）混合，以已知 的方式壓製成錠。 (Π)膠囊調和物 膠囊調和物可利用下列方式被製造：把如式（1 )之化 合物（100mg)及乳糖（100mg)混合，把混合物充塡入標準的 不透明硬質明膠膠囊中。Protocol B: GSK 3 (human) was diluted to a 10-fold working stock solution in the following solvents: 50 mM Tris pH 7.5, 0.1 lmM EG TA, 0 · 1 m Μ sodium vanadate, 0.1 ° / 〇 cold- Fluorenyl alcohol, 1 mg / ml BSA. One unit is equivalent to scooping lnmol phosphate into phosphoglycogen synthase peptide 2 every minute. In the final reaction volume of 25ml, GSK3yS (5-10mU) was incubated with the following agents: 8mM MOPS7.0, 0.2mM EDTA, 20 // YRRAAVPPSPSLSRHSSPHQS (p) EDEEE (phosphorus GS2 peptide), 1 OmM acetate and [T _3 3 P-ATP] (specific activity is about 5 0 0 cpm / pm ο 1, the concentration depends on need). Mg2 + [7 -33P-ATP] was added to start the reaction. Incubate at room temperature for 40 minutes, add 3% phosphoric acid solution 15 // 1) to stop the reaction. The reaction solution (10 // 1) was dropped on a P30 filter pad, washed 3 times with 50 mM phosphoric acid (takes 5 minutes) ', washed once with methanol, then dried and counted. From the results of the GSK3-B analysis using any of the two experimental protocols stated above, we have found that: Example 2c, 26, 48, 53, 65, 76, 77, 84, 86, 95, 102, 106, 119, 122, 123, 126, 127, 128, 129, 131, 134, 135, 138, 140, 141, 142, 143, 144, 145, 146, 147, 149, 150, and 151 each of the compounds IC5G 値 with 10 // M or less. Example of a pharmaceutical blend 2 5 2 200524877 (248) (i) A pharmaceutical tablet composition containing a compound of formula (1) can be manufactured in the following way: Compound (50 mg) of formula (1) And lactose (BP) (197 mg, used as a diluent), magnesium stearate (3 mg, used as a lubricant), and pressed into tablets in a known manner. (Π) Capsule blends Capsule blends can be manufactured by mixing the compound (100 mg) and lactose (100 mg) of formula (1), and filling the mixture into standard opaque hard gelatin capsules.

(iii) 可注射的調和物I 注射用的腸胃外組成物可利用下列方式被製造：使如 式（1 )之化合物（例如鹽的形式）溶於1 0 %丙二醇之水溶液中 ，得濃度1.5 wt%的活心生化合物。過濾溶液加以殺菌，把 溶液充塡入管瓶中，密封。(iii) Injectable blends I Parenteral compositions for injection can be manufactured by dissolving a compound of formula (1) (for example in the form of a salt) in a 10% aqueous solution of propylene glycol to give a concentration of 1.5 wt% active compounds. Filter the solution for sterilization, fill the solution into a vial, and seal.

(iv) 可注射的調和物II 注射用腸胃外組成物可利用下列方式被製造：使如式 (1)之化合物（例如鹽的形式）（2mg/ml)及甘露糖醇 (50mg/ml)溶於水中，過濾溶液加以殺菌，把溶液充塡入 可密封的〗m 1管瓶中。 (v) 皮下注射調和物 -253- 200524877 (249) 皮下注射用組成物可利用下列方式被製造：把如式 (1)之化合物及藥劑級玉米油混合，得5mg/ml濃度。把組 成物殺菌，充塡入合適的容器中。 實施例2 5 3 抗黴菌活性的確定 使用下面的實驗方案來確定如式（1 )之化合物的抗黴 菌活性。 化合物被黴菌培養板測試，該黴菌培養板包括：近平 滑念珠菌（Candida parpsilosis)，熱帶念珠菌（Candida tropicalis)，白色念珠菌（Candida albicans-ATCC 3 608 2) 及新型隱球菌（Crypt〇c〇ccus ne〇f〇rmans)。把試驗黴菌保 持在4°c下的 Sab our ahd葡萄糖瓊脂斜面培養。各種黴菌 的單懸浮液可利用下列方式被製造：在2 7 °C下在旋轉的桶 上在酵母一氮基肉湯（YNB)(有胺基酸（Difco，Detroit， Mich.)pH7.〇及〇·〇5嗎啉丙烷磺酸（MOPS)中使酵母生長一 整夜。把懸浮液離心，以〇 · 8 5 %食鹽水沖洗2次，把經沖洗 的細胞懸浮液超音波4秒（Brans〇n s〇nifier ’ modei 3 5 0 ’ Danbury，Conn.)。在血球計中把單芽生胞子計數，以 0.8 5 %食鹽水調整成所需的濃度。 使用一種肉湯微稀釋法的修飾法來確定試驗化合物的 活性。使試驗化合物在DMS0中稀釋成1 .Omg/ml，接著在 YNB肉湯PH7.0及MOPS(Fluconazole被當成對照組使用） 中稀釋成6 4 # g / m 1，得各種化合物的工作原液。使用9 6井 -254- 200524877 (250) 培養板，井1及井3至12以YNB肉湯被準備，在井2至1 1中 製作化合物溶液的10倍稀釋液（濃度的範圍是64至0.125 // g/ml)。井1擔任分光光度計檢分析的無菌的對照組及空白 組。井1 2擔任生長對照組。微滴定培養板在井2到1 1中的 每一井中被接種1 〇 // 1 (最終的接種物大小是1 〇4個黴菌1) 。把經接種的培養板在3 5 °c ?下溫育4 8小時。以渦式混合 器 （V 〇 r t e - G e n i e 2 M i X e r ， Scientific Industries ，(iv) Injectable blends II Parenteral compositions for injection can be manufactured by using a compound (for example, in the form of a salt) of formula (1) (2 mg / ml) and mannitol (50 mg / ml) Dissolve in water, filter the solution for sterilization, and fill the solution into a sealable m 1 vial. (v) Subcutaneous injection blend -253- 200524877 (249) The composition for subcutaneous injection can be manufactured by mixing the compound of formula (1) and pharmaceutical grade corn oil to obtain a concentration of 5 mg / ml. The composition is sterilized and filled into a suitable container. Example 2 5 3 Determination of antifungal activity The following experimental protocol was used to determine the antifungal activity of a compound of formula (1). The compounds were tested on a mold plate that includes: Candida parpsilosis, Candida tropicalis, Candida albicans-ATCC 3 608 2 and Cryptoc (Ccus neomas). Sab our ahd glucose agar slant culture was maintained at 4 ° C. Single suspensions of various molds can be manufactured using yeast-nitrogen broth (YNB) (with amino acids (Difco, Detroit, Mich.) At pH 7) on a rotating bucket at 27 ° C. And 0.05 morpholine propane sulfonic acid (MOPS) to grow yeast overnight. Centrifuge the suspension, rinse twice with 0.85% saline, and sonicate the washed cell suspension for 4 seconds ( Brans〇ns〇nifier 'modei 3 5 0' Danbury, Conn.). Single bud spores were counted in a hemocytometer and adjusted to the required concentration with 0.85% saline. A modification method using a broth microdilution method To determine the activity of the test compound, the test compound was diluted to 1.0 mg / ml in DMS0, and then diluted to 6 4 # g / m 1 in YNB broth PH7.0 and MOPS (Fluconazole was used as a control group). A working stock solution of various compounds was obtained. Using 96-well-254-200524877 (250) culture plates, wells 1 and 3 to 12 were prepared with YNB broth, and a 10-fold dilution of the compound solution was prepared in wells 2 to 11. (Concentration range is 64 to 0.125 // g / ml). Well 1 serves as a sterile control group for spectrophotometric analysis Blank group. Wells 12 served as growth control groups. Microtiter culture plates were inoculated with 10 // 1 in each of wells 2 to 11 (final inoculum size was 104 molds 1). The inoculated plate was incubated at 35 ° C for 48 hours. Using a vortex mixer (Vorte-Genie 2 M i Xer, Scientific Industries,

Inc.Bolemia，N.Y·)攪拌培養板2分鐘，接著 MIC値之確 定是利用分光光度計（Automatic Micro plate Reader， Dupont Instruments，Wilmington，Del.)量測在 420nm 的 吸光被確定。MIC終點之定義是展現與對照井相比大約 5 0%(或以上）的生長降低的最低的藥劑濃度。濁度分析之 定義最低的藥劑濃度，在該條件下在穴井中的濁度是對照 井的50%(IC5G)以下。最小的溶細胞濃度（MCC)之確定是利 用：把從96井培養板到 Sabourahd葡萄糖瓊脂（SDA)培養 板上的所有的穴井施以次培養，在3 5 °C下溫育1至2日，接 著檢查生活力。 實施例2 5 4 供在活體內的整株植物黴菌感染控制的生物評估用的實驗 方案 使如式（1)之化合物溶於丙酮中，接著在丙酮中作成 一系列的所需的濃度範圍的稀釋液。最終的處理體積可利 用下列被得到：視病原而定加入9倍體積的0.0 5 % Tween- -255- 200524877 (251) 20^水溶液或 0.01 % Triton X-100TM。 接著利用下面的實驗方案把組成物用於試驗本發明之 化合物抗蕃茄枯萎病（phyt〇Phth〇ra infestans)之能力。使 蕃茄（Rutgers品種）在無土壤的泥炭苔基底的盆裁土混合 物中生長直到苗株有10-20公分高。以lOOppm的速率把試 驗化合物灑在蕃茄株上。經過24小時，以蕃茄枯萎病（馬 鈴薯疫病菌（Phytophthora infestans)的含水的芽胞囊懸浮 液噴灑在蕃茄上接種，把蕃茄保持在露水室中一整夜。接 著把蕃茄移至溫室中直到疾病在未經處理的對照組上發展 爲止。 把類似的實驗方案用來測試本發明之化合物抗下列的 植物害蟲病的活性：小麥褐斑病（Puccinia)，小麥粉狀黴 病（Ervsiphe vraminis)，小麥（Monon品種），小麥葉斑病 (Septoria tritici)，以及小麥莖衣斑病（Leptosphaeria nodorum) 〇 同等物 前面的實施例是爲了舉例說明本發明而被列舉，本發 明之範圍不受其限制。吾人將顯而易見：在上面被描述的 及在實施例中被舉例說明的本發明之特異的體現可能有許 多的修飾及變更，但他們都不可違反本發明之基本原則。 這類的修飾及變更都被包括在本申請案中。 -256-Inc. Bolemia, N.Y.) was stirred for 2 minutes, and then the MIC was determined by measuring the absorbance at 420 nm using a spectrophotometer (Automatic Micro plate Reader, Dupont Instruments, Wilmington, Del.). The MIC endpoint is defined as the lowest concentration of agent that exhibits approximately 50% (or more) reduced growth compared to control wells. The turbidity analysis defines the lowest concentration of medicament. Under this condition, the turbidity in the well is less than 50% (IC5G) of the control well. The determination of the minimum cytolytic concentration (MCC) is made by subculturing all the wells from the 96-well culture plate to the Sabourahd glucose agar (SDA) culture plate, and incubating at 35 ° C for 1 to 2 days. And then check viability. Example 2 5 4 Experimental protocol for biological evaluation of control of mold infection in whole plants in vivo A compound of formula (1) was dissolved in acetone, and then a series of desired concentration ranges were prepared in acetone. Diluent. The final processing volume can be obtained by adding 9 times the volume of 0.05% Tween- -255- 200524877 (251) 20 ^ aqueous solution or 0.01% Triton X-100TM depending on the pathogen. The composition was then used to test the ability of the compounds of the present invention to resist tomato phytophthora infestans using the following experimental protocol. Tomatoes (Rutgers) were grown in a soilless peat moss-based potting soil mix until the seedlings were 10-20 cm tall. The test compound was sprinkled on the tomato plants at a rate of 100 ppm. After 24 hours, the tomatoes were sprayed with an aqueous spore suspension of Phytophthora infestans, and the tomatoes were kept in the dew room overnight. Then the tomatoes were moved to the greenhouse until the disease A similar experimental protocol was used to test the activity of the compounds of the present invention against the following plant pests: wheat brown spot (Puccinia), wheat powdery mildew (Ervsiphe vraminis), wheat (Monon variety), wheat leaf spot (Septoria tritici), and wheat stem coat spot (Leptosphaeria nodorum). Equivalent The foregoing examples are listed for the purpose of illustrating the present invention, and the scope of the present invention is not limited thereto. It will be obvious to me: the specific embodiment of the present invention described above and exemplified in the examples may have many modifications and changes, but they must not violate the basic principles of the present invention. Such modifications and changes are all Included in this application.

Claims (1)

200524877 (1) 十、申請專利範圍 1 · 一種化合物於製造供預防或治療環素依賴型激酶所 仲介的疾病狀態或症狀用之藥劑的應用，該化合物有如式 (〇)之結構：200524877 (1) 10. Scope of patent application 1. The use of a compound for the manufacture of a medicament for the prevention or treatment of a disease state or symptom mediated by a cyclin-dependent kinase. The compound has the structure of formula (〇): 或彼之鹽類或互變異構物類或N-氧化物類或溶劑化物類； 其中 X是或6員的碳環或雜環； A 是一個鍵、S02、C = 0、NRg(C = 0)或 0(C = 0)，其中 Rg是氫或C!·4烴基（被羥基或烷氧基任意取代）； Y是一個鍵或長度1、2或3個碳原子的伸烷基； R1是氫；有3至12個環原子的碳環或雜環；或Cl_8烴 基，彼被一或多個選自下列的取代基任意取代：鹵素（例 如氟）、羥基、C〗_4烴氧基、胺基、一或二-Ci 烴胺基、 及有3至12個環原子的碳環或雜環，其中烴基的碳原子中 的1或2個可被選自氧、硫、NH、SO、S02之中的原子或基 團任意替代； R2是氫；鹵素；Ch烷氧基（例如甲氧基）；或Ci 4烴 基（被下列基團任意取代：鹵素（例如氟）、羥基或Ci_4烷氧 基（例如甲氧基））； R3選自：氫及有3至12個環原子的碳環及雜環基團·， -257 - 200524877 R 4是Μ或c 1 · 4煙基（被下列基團任意取代：鹵素（例如 氟）、羥基或匕_4烷氧基（例如甲氧基））。 2 · —種化合物於製造供預防或治療環素依賴型激_所 仲介的疾病狀態或症狀用之藥劑的應用，該化合物有如式 (Ια)之結構：Or its salts or tautomers or N-oxides or solvates; where X is a 6-membered carbocyclic or heterocyclic ring; A is a bond, S02, C = 0, NRg (C = 0) or 0 (C = 0), where Rg is hydrogen or C! · 4 hydrocarbon group (arbitrarily substituted by hydroxyl or alkoxy group); Y is a bond or an alkylene group of 1, 2 or 3 carbon atoms in length; R1 is hydrogen; a carbocyclic or heterocyclic ring having 3 to 12 ring atoms; or Cl_8 hydrocarbon group, which is optionally substituted with one or more substituents selected from the group consisting of halogen (for example, fluorine), hydroxyl, C_4 hydrocarbon oxygen Group, amine group, mono- or di-Ci hydrocarbon amine group, and carbocyclic or heterocyclic ring having 3 to 12 ring atoms, wherein 1 or 2 of the carbon atoms of the hydrocarbon group may be selected from oxygen, sulfur, NH, Any substitution of atoms or groups in SO, S02; R2 is hydrogen; halogen; Ch alkoxy (such as methoxy); or Ci 4 hydrocarbyl (optionally substituted by: halogen (such as fluorine), hydroxyl or Ci_4 alkoxy (eg methoxy)); R3 is selected from: hydrogen and carbocyclic and heterocyclic groups having 3 to 12 ring atoms, -257-200524877 R 4 is M or c 1 · 4 nicotyl (Arbitrarily selected by Generation: halo (e.g. fluoro), hydroxy or dagger _4 alkoxy (e.g. methoxy)). 2. The use of a compound for the manufacture of a medicament for the prevention or treatment of a disease state or symptom mediated by a cyclin-dependent stress, the compound has the structure of formula (Iα): 或彼之鹽類或互變異構物類或Ν-氧化物類或溶劑化物類； 其中 X是Ri-A-NR4-或5或6員的碳環或雜環； A是一個鍵、C = 0、NRg(C = 〇)或〇(c = 〇)，其中Rg是氫 或Cb4烴基（被羥基或（^.4烷氧基任意取代）； Y是一個鍵或長度1、2或3個碳原子的伸院基； R1是氫；有3至12個環原子的碳環或雜環；或烴 基，彼被一或多個選自下列的取代基任意取代：鹵素（例 如氟）、羥基、c〗·4烴氧基、胺基、一或二-c】· 4烴胺基、 及有3至12個環原子的碳環或雜環基團，其中烴基的碳原 子中的1或2個可被遠自氧、硫、NH、SO、S02的原子或基 團任意替代； R2是氫；鹵素；Cm烷氧基（例如甲氧基）；或Ci“烴 基（被下列基團任意取代：鹵素（例如氟）、羥基或Ci 4院氧 基（例如甲氧基））； -258 - 200524877 (3) R3選自：氫及有3至12個環原子的碳環及雜環基團； R4是氫或Cb4烴基（被下列基團任意取代：鹵素（例如 氟）、羥基或&lt;^_4烷氧基（例如甲氧基））。 3 ·如申請專利範圍第2項之應用，其中該化合物有如 式（I)之結構：Or its salts or tautomers or N-oxides or solvates; where X is Ri-A-NR4- or a 5- or 6-membered carbocyclic or heterocyclic ring; A is a bond, C = 0, NRg (C = 〇) or 〇 (c = 〇), where Rg is hydrogen or Cb4 hydrocarbyl (optionally substituted by hydroxyl or (^ .4 alkoxy); Y is a bond or a length of 1, 2 or 3 A carbon atom; R1 is hydrogen; a carbocyclic or heterocyclic ring having 3 to 12 ring atoms; or a hydrocarbon group which is optionally substituted with one or more substituents selected from the group consisting of halogen (e.g., fluorine), hydroxyl , C] · 4 alkoxy, amine, mono- or di-c] ·· 4 carbamino, and carbocyclic or heterocyclic groups having 3 to 12 ring atoms, in which 1 or 2 can be arbitrarily replaced by atoms or groups far from oxygen, sulfur, NH, SO, S02; R2 is hydrogen; halogen; Cm alkoxy (such as methoxy); or Ci "hydrocarbyl (optionally by any of the following groups) Substitution: halogen (such as fluorine), hydroxyl or Ci 4 (oxy) (such as methoxy); -258-200524877 (3) R3 is selected from: hydrogen and carbocyclic and heterocyclic groups having 3 to 12 ring atoms Group; R4 is hydrogen or Cb4 hydrocarbyl (below Column groups are optionally substituted: halogen (for example, fluorine), hydroxyl or <^ _ 4 alkoxy (for example, methoxy). 3 · As the application of the scope of patent application No. 2, wherein the compound has the formula (I) structure: ίί—Ν 或彼之鹽類或互變異構物類或N-氧化物類或溶劑化物類； 其中 X是 R】-A-NR4-; A是一個鍵、〇0、NRg(C = 0)或0(00)，其中Rg是氫 或Cim烴基（被羥基或烷氧基任意取代）； Y是一個鍵或長度1、2或3個碳原子的伸烷基； R1是氫；有3至12個環原子的碳環或雜環；或Cl 8· 基，彼被一或多個選自下列的取代基任意取代：鹵素、羥 基、Cm烴氧基、胺基、一或二_C μ烴胺基、及有3至12 個環原子的碳環或雜環，其中烴基的碳原子中的1或2個可 被選自氧、硫、ΝΗ、SO、S〇2的原子或基團任意替代； R2是氫；鹵素；Cm院氧基；或（^.4烴基（被鹵素、羥 基或（^_4烷氧基任意取代）； R3選自：氫及有3至12個環原子的碳環及雜環基團； R4是氫或C!.4烴基（被下列基團任意取代：鹵素、羥基 -259- 200524877 或C 1 _ 4院氧基）。 4 · 一種用於藥劑之化合物，該化合物有如式（la)之結ί-Ν or its salts or tautomers or N-oxides or solvates; where X is R] -A-NR4-; A is a bond, 0, NRg (C = 0) Or 0 (00), where Rg is hydrogen or Cim hydrocarbyl (arbitrarily substituted by a hydroxyl or alkoxy group); Y is a bond or an alkylene group of 1, 2 or 3 carbon atoms in length; R1 is hydrogen; there are 3 to Carbocyclic or heterocyclic ring of 12 ring atoms; or Cl 8 · group, which is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxyl, Cm hydrocarbyloxy, amine, mono- or di-C μ Hydrocarbyl amine groups, and carbocyclic or heterocyclic rings having 3 to 12 ring atoms, wherein 1 or 2 of the carbon atoms of the hydrocarbyl group may be an atom or group selected from the group consisting of oxygen, sulfur, NH, SO, and S02 Any substitution; R2 is hydrogen; halogen; Cm alkyloxy; or (^ .4 hydrocarbon group (optionally substituted by halogen, hydroxyl or (^ _4 alkoxy)); R3 is selected from: hydrogen and having 3 to 12 ring atoms Carbocyclic and heterocyclic groups; R4 is hydrogen or C! .4 hydrocarbon group (arbitrarily substituted by the following groups: halogen, hydroxyl-259-200524877 or C 1 _ 4 oxygen group). 4 · A compound for pharmaceutical use , The compound has the formula (la) Knot 或彼之鹽類或互變異構物類或N-氧化物類或溶劑化物類； 其中 X是 R】-A-NR4-; A是一個鍵、c = 0、NRg(C = 0)或〇(C = 0)，其中Rg是氫 或G.4烴基（被羥基或Cl_4烷氧基任意取代）； Y是一個鍵或長度1、2或3個碳原子的伸烷基； R1是有3至12個環原子的碳環或雜環；或Cu烴基， 彼被一或多個選自下列的取代基任意取代··氟、羥基、 Cm烴氧基、胺基、一或二-Cm烴胺基、及有3至12個環 原子的碳環或雜環，其中烴基的碳原子中的1或2個可被選 自氧、硫、NH、SO、S02的原子或基團任意替代； R2是氫；鹵素；Cm烷氧基；或C!_4烴基（被鹵素、羥 基或Cm烷氧基任意取代）； R3選自：氫及有3至12個環原子的碳環及雜環基團； 以及 R4是氫或(^.4烴基（被鹵素、羥基或（：！.4烷氧基任意取 代）。 -260- 200524877 (5) 5.—種如式（lb)化合物： 不ΟOr its salts or tautomers or N-oxides or solvates; where X is R] -A-NR4-; A is a bond, c = 0, NRg (C = 0) or 〇 (C = 0), where Rg is hydrogen or G.4 hydrocarbyl (arbitrarily substituted by hydroxyl or Cl_4 alkoxy); Y is a bond or alkylene of 1, 2 or 3 carbon atoms in length; R1 is 3 A carbocyclic or heterocyclic ring of up to 12 ring atoms; or a Cu hydrocarbon group, which is optionally substituted with one or more substituents selected from the group consisting of fluorine, hydroxyl, Cm alkoxy, amine, mono- or di-Cm hydrocarbon Amine groups, and carbocyclic or heterocyclic rings having 3 to 12 ring atoms, wherein 1 or 2 of the carbon atoms of the hydrocarbon group may be arbitrarily replaced by an atom or group selected from oxygen, sulfur, NH, SO, and S02; R2 is hydrogen; halogen; Cm alkoxy; or C! _4 hydrocarbon group (optionally substituted by halogen, hydroxyl, or Cm alkoxy); R3 is selected from: hydrogen and carbocyclic and heterocyclic groups having 3 to 12 ring atoms And R4 is hydrogen or (^ .4 hydrocarbon group (arbitrarily substituted with halogen, hydroxyl or (:!. 4 alkoxy group). -260- 200524877 (5) 5.-a compound such as formula (lb): not 〇 N/Y、R3 Η (lb) 或彼之鹽類或互變異構物類或N-氧化物類或溶劑化物類； 其中 X是 R】-A-NR4-; A是一個鍵、C = 0、NRg(C = 0)或0(C = 0)，其中Rg是氫 或C】_4烴基（被羥基或Cl.4烷氧基任意取代）； Y是一個鍵或長度1、2或3個碳原子的伸烷基； R1是有3至12個環原子的碳環或雜環；或Cb8烴基， 彼被一或多個選自下列的取代基任意取代：氟、羥基、 Cm烴氧基、胺基、一或二-Ci_4烴胺基、及有3至12個環 原子的碳環或雜環，其中烴基的1或2個碳原子可被選自氧 、硫、NH、SO、S02的原子或基團任意替代； R2是氫；鹵素；Cm烷氧基；或Cm烴基（被鹵素或C】-4院氧基任意取代）； R3選自：有3至12個環原子的碳環及雜環基團；以及 R4是氫或Ci.4烴基（被鹵素、羥基或Cu4烷氧基任意取 代）。 6·如申請專利範圍第5項之化合物，其中六是c =〇。 7 .如申請專利範圍第5項或第6項之化合物，其中R4是 氫。 8 ·如申請專利範圍第5至7項中的任何〜項之化合物， -261 - 200524877 (6) 其中R2是氫或甲基，較佳氫。 9 ·如申請專利範圍第5至8項中的任何一項之化合物， 其中Y是一個鍵。 1 〇 ·如申請專利範圍第5至8項中的任何一項之化合物 ’其中Y是一個伸烷基’彼含有1或2個碳原子（例如-(ch2)-)。 1 1 ·如申請專利範圍第5至1 0項中的任何一項之化合物 ，其中R1是一種有3至12個環原子（例如5至10個環原子的 碳環或雜環基團。 12·如申請專利範圍第5至10項中的任何一項之化合物 ，其中R 1是一種C ! . 8烴基（例如被任意取代的C i _ 4烴基，如 被羥基取代的C ! _4烴基），彼被一或多個選自下列的取代基 任意取代：氟、羥基、C!.4烴氧基、胺基，一或二-Cw烴 胺基，及有3至12個環原子的碳環或雜環基團，其中烴基 的碳原子中的1或2個可被選自0，S，NH，SO，S02的原 子或基團任意替代。 13.如申請專利範圍第12項之化合物，其中R1是一種 Ci-4烴基（例如甲基或乙基，較佳甲基），彼被一種有3至12 個環原子（例如5至10個環原子）的碳環或雜環基團取代。 1 4 .如申請專利範圍第1 1至1 3項中的任何一項之化合 物，其中該碳環及雜環基團是單環的基團。 1 5 .如申請專利範圍第1 1至1 3項中的任何一項之化合 物，其中該碳環及雜環基團是雙環的基團。 1 6 .如申請專利範圍第1 4項或第1 5項之化合物，其中 -262- 200524877 (7) 該單環及雙環的基團是芳基。 1 7 ·如申請專利範圍第1 6項之化合物，其中該芳基是 被取代的或未被取代的苯基。 1 8 ·如申請專利範圍第1 4項或第1 5項之化合物，其中 該單環或雙環的基團是雜芳基。 1 9 .如申請專利範圍第1 8項之化合物，其中該雜芳基 含有至多4個（例如至多3個）選自氮、硫及氧的雜原子，該 雜芳基選自：單環的5員環基團，單環的6員環基團，由稠 合的5員環及6員環形成的二環基團，由二個稠合的6員環 形成的二環基團。 2 0.如申請專利範圍第19項之化合物，其中該雜芳基 選自：呋喃基（例如2 -呋喃基或3 -呋喃基）、D引哚基（例3 -吲 哚基、6-吲哚基）、2，3-二氫-苯並[1，4]-二氧雜環己烯 基（例如2，3-二氫-苯並[1，4]·二氧雜環己烯-5 _基）、吡唑 基（例如吡唑-5-基）、吡唑並[1，5-a]吡啶基（例如吡唑並[1 ’ 5-a]吡啶-3-基），噁唑基、異噁唑基（例如異噁唑-4-基） 、吡啶基（例如2 -吡啶基、3 -吡啶基、心吡啶基、）、喹啉 基（例如2 -喹啉基）、吡咯基（例如3 -吡咯基）、咪唑基及噻 吩基（例如2-噻吩基、3-噻吩基）。 2 1 .如申請專利範圍第1 9項之化合物，其中該雜芳基 選自：吡啶基、吡咯基、呋喃基、噻吩基、咪唑基、噁唑 基、噁二唑基、噁三唑基、異噁唑基、噻唑基、異噻唑基 、吡唑基、吡嗪基、噠嗪基、嘧啶基、三嗪基、三唑基、 四唑基、D奎啉基、異D奎啉基、苯並呋喃基、苯並噻吩基、 -263- 200524877 (8) 色滿基、硫代色滿基、苯並咪唑基、苯並u惡唑基、苯並異 噁唑基、苯並噻唑基、苯並異噻唑基、異苯並呋喃基、吲 哚基、異吲哚基、吲晚滿嗪基、吲哚滿基、異吲哚滿基、 嘌呤基（例如腺嘌呤、鳥嘌呤）、吲唑基、苯並二噁茂基、 色烯基、異色烯基、異色滿基、苯並二噁院基、喹嗪基、 苯並噁嗪基、苯並二嗪基、吡啶並吡啶基、喹噁啉基、喹 唑啉基、噌啉基、酞嗪基、萘啶基及蝶啶基。 2 2 ·如申請專利範圍第2 1項之化合物，其中該雜芳基 選自··吲哚基、四唑基、吡啶基、三唑基、噁唑基、咪唑 基、呋喃基、噻吩基、喹啉基、吡咯基及吡嗪基。 2 3 .如申請專利範圍第1 4項或第1 5項之化合物，其中 該單環的及二環的基團是非芳香基團。 24.如申請專利範圍第23項之化合物，其中該非芳香 基團是雜環基（例如單環基團），彼含有1，2，3或4個（較 佳1或2個）選自氮、氧及硫的雜原子。 25 .如申請專利範圍第23項之化合物，其中該非芳香 基團選自： (i) 碳環基團，如未被取代的或被取代的單環的環烷基，例 如環丙基、環丁基、環戊基、環己基或環庚基（尤其環丙 基、環丁基、環戊基及環己基，例如環丙基及環己基）； (ii) 5，6及7員的單環的雜環基團，如嗎啉、哌啶（例如卜 哌啶基、2 -哌啶基、3 -哌啶基及4 -哌啶基）、吡咯烷（例如 1 **吡咯烷基、2 -吼咯烷基及3 -吡咯烷基）、吡咯烷酮 '吡喃 (2H-吡喃或4H-吡喃）、二氫噻吩、二氫吡喃、二氫呋喃、 -264- 200524877 (9) 二氫噻唑、四氫呋喃、四氫噻吩、二噁烷、四氫吼喃（例 如4 -四氫吡喃基）、咪唑啉、咪唑烷酮、螺哩啉、噻D坐啉 、2 -吡啉、吡唑院、哌嗪及N -院基哌嗪（如N -甲基哌嗪） (iii) 硫代嗎啉及彼之S-氧化物及S，S-二氧化物（尤其硫代 嗎啉）；以及 (iv) N-烷基哌啶（如N-甲基哌啶）。 2 6 .如申請專利範圍第2 3項之化合物，其中該雜環基 選自：嗎啉、哌啶、吡咯烷、吡咯烷酮、吡喃、二氫噻吩 、二氫吡喃、二氫呋喃、二氫噻唑、四氫呋喃、四氫噻吩 、二噁烷、四氫吡喃、咪唑啉、咪唑烷酮、噁唑啉、噻唑 啉、吡唑啉、吡唑烷、哌嗪、N-烷基哌嗪（如N-甲基哌嗪） ，尤其選自：哌啶、N-甲基哌嗪、嗎啉及咪唑烷酮。 2 7 .如申請專利範圍第1 1至2 6項中的任何一項之化合 物，其中該碳環及雜環的基團被一或多個（例如1或2或3或 4個）選自下列的取代基R1()取代：鹵素、羥基、三氟甲基 、氰基、硝基、羧基 '胺基、一或二- Cm烴胺基、有3至 12個環原子的碳環的及雜環的基團；R、Rb，其中Ra是一 個鍵、〇、co、x】c(x2)、c(x2)x】、xicxyx1、S、SO、 S〇2、NRe、S02NRe或NReS02; Rb 選自：氫、有 3至 12 個環 原子的碳環及雜環基團，以及Cb8烴基，彼被一或多個選 自下列的取代基任意取代：羥基、合氧基、鹵素、氰基、 硝基、羧基、胺基、一或二-C 4烴胺基、有3至1 2個環原 子的碳環及雜環基團，其中C】·8烴基的一或多個碳原子可 -265- 200524877 (10) 被下列基團任意替代：0、S、SO、S〇2、NRe、xkcx2)、 C(X2)Xi 或 Χ】（：（Χ2)χΐ ; Rc選自：氫及C】_4烴基； X1是 0、S 或 NR ，x^^o、或=NRC。 2 8 ·如申請專利範圍第2 7項之化合物，其中該取代基 RlG選自：基團RlQa，彼選自：鹵素、羥基、三氟甲基、 氰基、硝基、羧酸，基團Ra-Rb，其中Ra是一個鍵、〇、 CO、X1C(X )、（：(χ4)χ3、χ3(^(χ4)χ3、s、so 或 S〇2，Rb 選 自：氫及Cn煙基，彼被一或多個選自下列的取代基任意 取代··羥基、合氧基、鹵素、氰基、硝基、羧基及有3至6 個環原子的單環的非芳香碳環或雜環基團；其中CΜ烴基 的一或多個碳原子可被下列基團任意替代：0、S、S 0、 S〇2、χ3(：(χ4)、c(x4)x1 或 X1C(X2)X1 ; X1 是 0 或 S ; X2 是 =0 或=S 〇 2 9 ·如申g靑專利範圍第2 8項之化合物，其中該取代基 選自.鹵素、羥基、三氟甲基、基團R、Rb，其中Ra是一 個鍵或〇’ R ^自：氫及1_4烴基，彼被一或多個選自下 列的取代基任意取代：羥基、鹵素（較佳氟）及5及6員的飽 和碳環及雜環基團。 3 〇 ·如申請專利範圍第2 7至2 9項中的任何一項之化合 物，其中R疋在環的2，3，4，5或6的位置上有丨、2或3個 取代基的苯基。 -266 - 1 1 .如申請專利範圍第3 0項之化合物，其中該苯基是 2 2 -被單取代的、3 -被m 。 . „ 取卑取代的、2，6 -被雙取代的、2，3 - 200524877 被雙取代的、2N / Y, R3 Η (lb) or its salts or tautomers or N-oxides or solvates; where X is R] -A-NR4-; A is a bond, C = 0 , NRg (C = 0) or 0 (C = 0), where Rg is hydrogen or C] _4 hydrocarbon group (optionally substituted by hydroxyl or Cl.4 alkoxy group); Y is a bond or a length of 1, 2 or 3 Carbonyl alkylene; R1 is a carbocyclic or heterocyclic ring having 3 to 12 ring atoms; or Cb8 hydrocarbon group, which is optionally substituted with one or more substituents selected from the group consisting of fluorine, hydroxyl, and Cm hydrocarbyloxy , Amine group, mono- or di-Ci_4 hydrocarbon amine group, and carbocyclic or heterocyclic ring having 3 to 12 ring atoms, wherein 1 or 2 carbon atoms of the hydrocarbon group may be selected from oxygen, sulfur, NH, SO, S02 R2 is hydrogen; halogen; Cm alkoxy; or Cm hydrocarbyl (arbitrarily substituted by halogen or C] -4 alkoxy); R3 is selected from: carbons having 3 to 12 ring atoms Ring and heterocyclic groups; and R4 is hydrogen or Ci.4 hydrocarbyl (optionally substituted with halogen, hydroxyl, or Cu4 alkoxy). 6. The compound according to item 5 of the patent application, wherein six is c = 0. 7. A compound as claimed in item 5 or item 6, wherein R4 is hydrogen. 8 · If the compound in any of items 5 to 7 of the scope of application for a patent, -261-200524877 (6) wherein R2 is hydrogen or methyl, preferably hydrogen. 9-A compound according to any one of claims 5 to 8, wherein Y is a bond. 10. The compound according to any one of claims 5 to 8 of the scope of the patent application, 'wherein Y is an alkylene' which contains 1 or 2 carbon atoms (e.g.-(ch2)-). 1 1 · A compound according to any one of claims 5 to 10 in the scope of patent application, wherein R1 is a carbocyclic or heterocyclic group having 3 to 12 ring atoms (for example, 5 to 10 ring atoms. 12 · A compound as claimed in any one of claims 5 to 10, wherein R 1 is a C!. 8 hydrocarbon group (for example, an optionally substituted C i _ 4 hydrocarbon group, such as a C! _ 4 hydrocarbon group substituted with a hydroxyl group) , Which is optionally substituted by one or more substituents selected from the group consisting of fluorine, hydroxyl, C! .4 alkoxy, amine, mono- or di-Cw hydrocarbon amine, and carbon having 3 to 12 ring atoms A ring or heterocyclic group in which 1 or 2 of the carbon atoms of the hydrocarbon group can be arbitrarily replaced by an atom or group selected from 0, S, NH, SO, and S02. 13. The compound as claimed in item 12 of the scope of patent application , Where R1 is a Ci-4 hydrocarbon group (such as methyl or ethyl, preferably methyl), which is a carbocyclic or heterocyclic group having 3 to 12 ring atoms (for example, 5 to 10 ring atoms) Substituted. 1 4. The compound as claimed in any one of claims 11 to 13 in the scope of patent application, wherein the carbocyclic and heterocyclic group are monocyclic groups. 1 5. If applied for A compound according to any one of items 11 to 13 in which the carbocyclic and heterocyclic group are bicyclic groups. 16. The compound as claimed in item 14 or item 15 in the scope of patent application , Where -262- 200524877 (7) The monocyclic and bicyclic group is an aryl group. 1 7 · As the compound in the patent application No. 16 range, wherein the aryl group is a substituted or unsubstituted phenyl group 1 8 · If the compound in the scope of patent application No. 14 or 15 is applied, wherein the monocyclic or bicyclic group is a heteroaryl group. 19. If the compound in the scope of patent application No. 18 is applied, wherein Heteroaryl contains up to 4 (eg, up to 3) heteroatoms selected from nitrogen, sulfur, and oxygen, and the heteroaryl is selected from: a monocyclic 5-membered ring group, a monocyclic 6-membered ring group, A bicyclic group formed by a fused 5-membered ring and a 6-membered ring, a bicyclic group formed by two fused 6-membered rings. 2 0. The compound according to item 19 of the patent application scope, wherein the heteroaromatic The group is selected from the group consisting of furyl (such as 2-furyl or 3-furyl), D-indolyl (example 3-indolyl, 6-indolyl), 2,3-dihydro-benzo [1, 4] -Dioxin Heterocyclohexenyl (such as 2,3-dihydro-benzo [1,4] · dioxecyclo-5-enyl), pyrazolyl (such as pyrazol-5-yl), pyrazolo [1,5-a] pyridyl (such as pyrazolo [1 '5-a] pyridin-3-yl), oxazolyl, isoxazolyl (such as isoxazol-4-yl), pyridyl ( Such as 2-pyridyl, 3-pyridyl, cardiopyryl,), quinolinyl (such as 2-quinolinyl), pyrrolyl (such as 3-pyrrolyl), imidazolyl, and thienyl (such as 2-thienyl) , 3-thienyl). 2 1. The compound according to item 19 of the application, wherein the heteroaryl group is selected from the group consisting of pyridyl, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, oxadiazolyl, and oxatriazolyl , Isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, pyrazinyl, pyridazinyl, pyrimidinyl, triazinyl, triazolyl, tetrazolyl, Dquinolyl, isoDquinolyl , Benzofuranyl, benzothienyl, -263- 200524877 (8) chromanyl, thiochromanyl, benzimidazolyl, benzouoxazolyl, benzoisoxazolyl, benzothiazole Group, benzoisothiazolyl, isobenzofuranyl, indolyl, isoindolyl, indolazinyl, indolyl, isoindolinyl, purine (such as adenine, guanine) , Indazolyl, benzodioxoyl, chromenyl, isochromenyl, isochromanyl, benzodioxanyl, quinazinyl, benzoxazinyl, benzodiazinyl, pyridopyridyl , Quinoxaline, quinazolinyl, fluorazinyl, phthalazinyl, naphthyridinyl, and pteridinyl. 2 2 · The compound according to item 21 of the patent application range, wherein the heteroaryl group is selected from the group consisting of: · indolyl, tetrazolyl, pyridyl, triazolyl, oxazolyl, imidazolyl, furyl, and thienyl , Quinolinyl, pyrrolyl and pyrazinyl. 2 3. The compound according to item 14 or item 15 of the scope of patent application, wherein the monocyclic and bicyclic groups are non-aromatic groups. 24. The compound as claimed in claim 23, wherein the non-aromatic group is a heterocyclic group (such as a monocyclic group), which contains 1, 2, 3, or 4 (preferably 1 or 2) selected from nitrogen , Oxygen and sulfur heteroatoms. 25. The compound according to item 23 of the patent application, wherein the non-aromatic group is selected from: (i) carbocyclic groups, such as unsubstituted or substituted monocyclic cycloalkyl, such as cyclopropyl, cyclo Butyl, cyclopentyl, cyclohexyl or cycloheptyl (especially cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, such as cyclopropyl and cyclohexyl); (ii) 5, 6 and 7-membered monomers Ring heterocyclic groups such as morpholine, piperidine (such as piperidinyl, 2-piperidinyl, 3-piperidinyl, and 4-piperidinyl), pyrrolidine (such as 1 ** pyrrolidinyl, 2 -rotidinyl and 3-pyrrolidinyl), pyrrolidone'pyran (2H-pyran or 4H-pyran), dihydrothiophene, dihydropyran, dihydrofuran, -264- 200524877 (9) Dihydrothiazole, tetrahydrofuran, tetrahydrothiophene, dioxane, tetrahydrofuran (e.g. 4-tetrahydropyranyl), imidazoline, imidazolidinone, spiroline, thiazine, 2-pyroline, Pyrazine, piperazine, and N-cholylpiperazine (such as N-methylpiperazine) (iii) thiomorpholine and its S-oxides and S, S-dioxides (especially thiomorpholine) ); And (iv) N-alkylpiperidine (such as N-methyl Piperidine). 26. The compound according to item 23 of the application, wherein the heterocyclic group is selected from the group consisting of morpholine, piperidine, pyrrolidine, pyrrolidone, pyran, dihydrothiophene, dihydropyran, dihydrofuran, di Hydrothiazole, tetrahydrofuran, tetrahydrothiophene, dioxane, tetrahydropyran, imidazoline, imidazolidinone, oxazoline, thiazoline, pyrazoline, pyrazolidine, piperazine, N-alkylpiperazine ( Such as N-methylpiperazine), especially selected from: piperidine, N-methylpiperazine, morpholine and imidazolidone. 27. The compound according to any one of claims 11 to 26, wherein the carbocyclic and heterocyclic groups are selected from one or more (eg, 1 or 2 or 3 or 4) The following substituents R1 () are substituted: halogen, hydroxy, trifluoromethyl, cyano, nitro, carboxy'amino, mono- or di-Cm hydrocarbon amino, carbocyclic having 3 to 12 ring atoms, and Heterocyclic groups; R, Rb, where Ra is a bond, 0, co, x] c (x2), c (x2) x], xicxyx1, S, SO, S〇2, NRe, S02NRe or NReS02; Rb is selected from the group consisting of hydrogen, carbocyclic and heterocyclic groups having 3 to 12 ring atoms, and Cb8 hydrocarbon groups, which are optionally substituted with one or more substituents selected from the group consisting of hydroxyl, oxy, halogen, cyano A nitro group, a nitro group, a carboxyl group, an amine group, a mono- or di-C 4 hydrocarbon amine group, a carbocyclic ring and a heterocyclic group having 3 to 12 ring atoms, wherein C] · 8 hydrocarbon group has one or more carbon atoms Ke-265- 200524877 (10) is arbitrarily replaced by the following groups: 0, S, SO, S02, NRe, xkcx2), C (X2) Xi or X] (: (X2) χΐ; Rc is selected from: hydrogen And C] _4 hydrocarbon group; X1 is 0, S or NR, x ^^ o, or = NRC. 2 8 · The compound according to item 27 of the scope of patent application, wherein the substituent R1G is selected from the group R1Qa, which is selected from the group consisting of halogen, hydroxyl, trifluoromethyl, cyano, nitro, carboxylic acid, and group Ra-Rb, where Ra is a bond, 0, CO, X1C (X), (: (χ4) χ3, χ3 (^ (χ4) χ3, s, so, or S02), and Rb is selected from: hydrogen and Cn smoke Group, which is arbitrarily substituted with one or more substituents selected from the group consisting of: hydroxy, alkoxy, halogen, cyano, nitro, carboxy, and a monocyclic non-aromatic carbocyclic ring having 3 to 6 ring atoms or Heterocyclic groups; wherein one or more carbon atoms of a CM hydrocarbon group may be arbitrarily replaced by the following groups: 0, S, S 0, S〇2, χ3 (: (χ4), c (x4) x1, or X1C (X2 ) X1; X1 is 0 or S; X2 is = 0 or = S 〇 2 9 · As the compound of the 28th patent scope of the application, wherein the substituent is selected from halogen, hydroxyl, trifluoromethyl, Groups R, Rb, where Ra is a bond or O ′ R ^ from: hydrogen and 1-4 hydrocarbon groups, which are optionally substituted with one or more substituents selected from: hydroxyl, halogen (preferably fluorine) and 5 and 6 members Saturated carbocyclic and heterocyclic groups. 3 〇 · A compound according to any one of claims 27 to 29, wherein R 的 has a phenyl group with 2 or 3 or 2 substituents at the position of 2, 3, 4, 5 or 6 of the ring- 266-1 1. The compound according to item 30 of the scope of patent application, wherein the phenyl group is 2 2 -monosubstituted and 3 -substituted m. . „Substituted, 2,6-double replaced, 2,3-200524877 double replaced, 2 3 2 ·如申請專利範圍第3 1乂代的、2，5 -被雙取代的、2， 被三取代的基團。 ^ 3 1項之化合物，其中該苯基是3 2 · As in the 31st generation of the scope of the patent application, 2,5 -disubstituted, 2, and trisubstituted. ^ 31 compound of 1 wherein the phenyl is 在2及6的位置被雙取代， 取代基選自：氟、氯及R、Rb， 其中Ra是0，Rb是Cl_4烷基；或 ;被一或多 (Π)在2的位置被單取代，取代基選自··氟；氯；被一或 個氯原子任意取代的C!.4烷氧基；或在2及$的位置被選自 氟、氯及甲氧基的取代基雙取代。 3 3 ·如申請專利範圍第5至3 2項中的任何一項之化合物 ，其中八是0：〇，R^CO -選自在表！*所列出的基團，尤其 是基團 J、AB、AH、AJ、AL、AS、AX、AY、AZ、BA、 BB、BD、BH、BL、BQ 及 BS，更尤其是基團 AJ、AX、BQ 、BS及ΒΑΙ，較佳基團AJ及BQ。 3 4.如申請專利範圍第5項之化合物，彼有如式（II)之 結構：Is substituted at positions 2 and 6 and the substituents are selected from the group consisting of fluorine, chlorine, and R and Rb, where Ra is 0 and Rb is Cl_4 alkyl; or is mono-substituted by one or more (Π) at position 2, The substituent is selected from the group consisting of fluorine; chlorine; C! .4 alkoxy optionally substituted with one or one chlorine atom; or di-substituted at positions 2 and $ with substituents selected from fluorine, chlorine and methoxy. 3 3 · The compound according to any one of items 5 to 32 in the scope of patent application, wherein eight is 0: 0, R ^ CO-selected from the table! * Listed groups, especially groups J, AB, AH, AJ, AL, AS, AX, AY, AZ, BA, BB, BD, BH, BL, BQ and BS, and more especially group AJ , AX, BQ, BS and BAI, and the preferred groups AJ and BQ. 3 4. If the compound in the scope of patent application No. 5 has the structure of formula (II): 其中R1、R2、R3及Υ如同在申請專利範圍第5至3 3項中的 任何一項中所定義的。 -267- 200524877 (12) 3 5 .如申請專利範圍第3 4項之化合物，其中R】選自： (i) 苯基，彼被一或多個（例如1、2或3個）選自下列的取代 基任意取代：氟；氯；羥基；5員及6員的飽和雜環基團（ 含有1個或2個選自0、n及S的雜原子），該雜環基團被— 或多個C!_4烷基任意取代；Cl_4烴氧基·’ C!_4烴基；其中該 C〗_4烴基及C^4烴氧基被一或多個選自下列的取代基任意 取代：羥基、氟、Cu烷氧基、胺基、一或二-ClM烷基胺 基、苯基、鹵代苯基、飽和碳環基團（有3至7個環原子， 較佳4、5或6環原子、例如5或6個環原子）或飽和雜環基團 (有5或6個環原子；以及含有至多2個選自0、S及N的雜原 子）；或2，3-二氫-苯並[1，4]二氧雜環己烯基；或 (ii) 單環雜芳基團（含有一或二個選自〇、S及N的雜原子）； 或雙環雜芳基團（含有一個選自0、S及N的雜原子）；該單 環及雙環的雜芳基團各被一或多個選自下列的取代基任意 取代：氟；氯；C!.3烴氧基；C10烴基被下列基團任意取 代：經基、氟、甲氧基或5員或6員的飽和碳環或雜環基團 (含有至多2個選自0、S及N的雜原子）； (iii) 被取代的或未被取代的環烷基（有3至6個環原子）； (iv：^^4烴基，彼被一或多個選自下歹lj的取代基任意取代 :氟；羥基；Cw烴氧基；胺基；一或二-C】_4烴胺基；有 3至12個環原子的碳環或雜環基團，其中烴基的碳原子中 的一個可被選自〇、NH、SO及S〇2的原子或基團任意替代 〇 3 6 .如申請專利範圍第3 5項之化合物，其中R1選自取 -268- 200524877 (13) 代基（i) ’其中（i)是由下列所組成：苯基，彼被一或多個 選自下列的取代基任意取代：氟；氯；羥基；C&quot;烴氧基 ;C】-3烴基，其中C , _3烴基被一或多個選自下列的取代基 任意取代：羥基、氟、Cu烷氧基、胺基、—及二Cl_4院 胺基、飽和碳環基團（有3至7個環原子，較佳4、5或6個環 原子，例如5或6個環原子）或飽和雜環基團（有5或6個環原 子，以及含有至多2個選自〇、s及N的雜原子）。 3 7 ·如申請專利範圍第3 5項或第3 6項之化合物，其中 R1選自取代基（i)、（ii)及（iii)。 3 8 .如申請專利範圍第3 5項或第3 6項之化合物，其中 R1選自取代基（i)。 3 9 ·如申請專利範圍第3 8項之化合物，其中r 1是—種 2-被單取代的、3-被單取代的、2，3-被雙取代的、2，5-被雙取代的或2，6-被雙取代的苯基，或2，3-二氫-苯並[1 ，4]-二氧雜環己烯基，其中該取代基選自：鹵素；羥基 ;Cb3烷氧基，C!」烷基，其中該烷基被下列基團任意 取代··羥基、氟、Cu烷氧基、胺基、一及二-C!.4烷胺基 、或飽和碳環基團（有3至6個環原子）及/或飽和雜環基團（ 有5或6個環原子及含有1或2個選自N及Ο的雜原子）。 4 0 .如申請專利範圍第3 9項之化合物，其中R 1選自： 未被取代的苯基、2 -氟代苯基、2 -經基苯基、2_甲氧基苯 基、2_甲基苯基、2-(2-吡咯烷-1-基）乙氧基）-苯基、3-氟 代苯基、3-甲氧基苯基、2’ 6-二氟代苯基、2_氟代-6_羥 基苯基、2 -氟代-3-甲氧基苯基、2 -氟代-5-甲氧基苯基、 -269- 200524877 (14) 2-氯代-6-甲氧基苯基、2-氟代-6-甲氧基苯基、2’ 二氯 代苯基及2-氯代-6-氟代苯基；以及任意進一步地選自5-氯 代-2-甲氧基苯基。 4 1 .如申請專利範圍第4 0項之化合物，其中R 1選自：2 ，6-二氟代苯基、2-氟代-6-甲氧基苯基、2，6-二氯代苯 基及2 -氣代-6-親代苯基。 4 2.如申請專利範圍第5項之化合物，彼有如式（111)之 結構： R\ NH 〇Among them, R1, R2, R3 and Υ are as defined in any one of items 5 to 33 of the scope of patent application. -267- 200524877 (12) 3 5. The compound according to item 34 of the patent application scope, wherein R] is selected from: (i) phenyl, which is selected from one or more (eg 1, 2 or 3) The following substituents are arbitrarily substituted: fluorine; chlorine; hydroxyl; 5 and 6-membered saturated heterocyclic groups (containing 1 or 2 heteroatoms selected from 0, n and S), the heterocyclic group is- Or any C! _4 alkyl group; Cl_4 hydrocarbyloxy group; C! _4 hydrocarbyl group; wherein the C4 hydrocarbon group and C ^ 4 hydrocarbyl group are optionally substituted with one or more substituents selected from: hydroxyl , Fluorine, Cu alkoxy, amine, mono- or di-ClM alkylamino, phenyl, halophenyl, saturated carbocyclic group (with 3 to 7 ring atoms, preferably 4, 5 or 6 A ring atom, such as 5 or 6 ring atoms) or a saturated heterocyclic group (having 5 or 6 ring atoms; and containing up to 2 heteroatoms selected from 0, S and N); or 2,3-dihydro -Benzo [1,4] dioxane; or (ii) a monocyclic heteroaryl group (containing one or two heteroatoms selected from 0, S, and N); or a bicyclic heteroaryl group (Containing a heteroatom selected from 0, S and N); the monocyclic and bicyclic hetero Each group is optionally substituted with one or more substituents selected from: fluorine; chlorine; C! .3 alkoxy; C10 hydrocarbon is optionally substituted with: via a group, fluorine, methoxy, or 5-membered or 6-membered saturated carbocyclic or heterocyclic group (containing up to 2 heteroatoms selected from 0, S and N); (iii) substituted or unsubstituted cycloalkyl (having 3 to 6 ring atoms) ); (Iv: ^^ 4 hydrocarbon group, which is optionally substituted with one or more substituents selected from the following: l; fluoro; hydroxyl; Cw alkyloxy; amine group; mono- or di-C] -4 hydrocarbon amino group; A carbocyclic or heterocyclic group having 3 to 12 ring atoms, in which one of the carbon atoms of the hydrocarbon group may be arbitrarily replaced by an atom or group selected from 0, NH, SO, and S02. The 35th compound of the patent, wherein R1 is selected from -268- 200524877 (13) Substituent (i) 'where (i) is composed of: phenyl, which is selected from one or more of the following Substituents are optionally substituted: fluorine; chlorine; hydroxyl; C &quot;hydrocarbyloxy; C] -3 hydrocarbyl, wherein C, _3 hydrocarbyl is optionally substituted with one or more substituents selected from: hydroxy, fluorine, Cu alkoxy ,amine , — And di Cl_4 amine group, saturated carbocyclic group (with 3 to 7 ring atoms, preferably 4, 5 or 6 ring atoms, such as 5 or 6 ring atoms) or saturated heterocyclic group (with 5 or 6 ring atoms, and containing up to 2 heteroatoms selected from 0, s, and N) 37. For example, a compound in the scope of claim 35 or 36 in which R1 is selected from substituents ( i), (ii) and (iii). 3 8. The compound according to item 35 or item 36 of the scope of patent application, wherein R1 is selected from the substituent (i). 3 9 · The compound according to item 38 of the scope of patent application, wherein r 1 is a kind of 2-mono-substituted, 3-mono-substituted, 2,3-di-substituted, 2,5-di-substituted or 2,6-disubstituted phenyl, or 2,3-dihydro-benzo [1,4] -dioxelenyl, wherein the substituent is selected from: halogen; hydroxyl; Cb3 alkoxy "C!" Alkyl group, wherein the alkyl group is arbitrarily substituted by a hydroxyl group, a fluorine group, a Cu alkoxy group, an amine group, a mono- and di-C! .4 alkylamino group, or a saturated carbocyclic group ( There are 3 to 6 ring atoms) and / or saturated heterocyclic groups (having 5 or 6 ring atoms and containing 1 or 2 heteroatoms selected from N and O). 40. The compound according to item 39 of the scope of patent application, wherein R1 is selected from: unsubstituted phenyl, 2-fluorophenyl, 2-methoxyphenyl, 2-methoxyphenyl, 2 _Methylphenyl, 2- (2-pyrrolidin-1-yl) ethoxy) -phenyl, 3-fluorophenyl, 3-methoxyphenyl, 2 '6-difluorophenyl , 2-fluoro-6-hydroxyphenyl, 2-fluoro-3-methoxyphenyl, 2-fluoro-5-methoxyphenyl, -269- 200524877 (14) 2-chloro- 6-methoxyphenyl, 2-fluoro-6-methoxyphenyl, 2 'dichlorophenyl, and 2-chloro-6-fluorophenyl; and optionally further selected from 5-chloro Substituted for 2-methoxyphenyl. 4 1. The compound according to item 40 of the scope of patent application, wherein R 1 is selected from the group consisting of 2,6-difluorophenyl, 2-fluoro-6-methoxyphenyl, and 2,6-dichloro Phenyl and 2-Gas-6-parentyl. 4 2. If the compound in the scope of patent application No. 5 has the structure of formula (111): R \ NH 〇 Ν’丫、R3 Η (ΠΙ) 其中R1、R2、R3及Y如同在申請專利範圍第5至41頁中的 任何一項中所定義的。 43·如申請專利範圍第5至42項中的任何一項之化合物 ’其中R3選自有3至6個環原子的單環的碳環及雜環基團。 44.如申請專利範圓第43項之化合物，其中R3是芳基 或雜芳基。 4 5.如申請專利範園第44項之化合物，其中R3是未被 取代的或被取代的苯基。 4 6 ·如申請專利範_第4 4項之化合物，其中R 3是未被 取代的或被取代的吡啶基。 4 7 ·如申sra專利範_第5 8項或第5 9項之化合物，其中 該芳基或雜芳基被一或多個基團Ri〇(如同在申請專利範圍 -270- 200524877 (15) 第27項中所定義的）取代。 4 8 ·如申請專利範圍第4 7項之化合物，其中該芳基或 雜芳基被一或多個選自基團R1()a的取代基取代，基團R1Ga 是由下列組成：鹵素、羥基、三氟甲基、氰基、單環的碳 環及雜環基團（有3至7(典型地5或6)個環原子，以及基團 Ra_Rb，其中 Ra 是一個鍵、〇、C〇、χ1〇(χ2)、c(x2)xl、 xic(x2)xi、s、SO、so2、NRC、so2NR2或 nrcso2 ; Rb選 自：氫、碳環或雜環基團（有3-7個環原子），（^^烴基被一 或多個選自下列的取代基任意取代：羥基、合氧基、鹵素 、氰基、硝基、殘基、胺基、一或二- C^4烴胺基、碳環或 雜環基團（有3-7個環原子），其中Cb8烴基的一或多個碳原 子可被下列基團任意替代：0、S、SO、S02、NRe、 x】c(x2)、c^xqx1 或 xAxyx1。 4 9 ·如申請專利範圍第4 8項之化合物，其中該一或多 個取代基選自基團RI()a，基團R1()a是由下列組成：鹵素、 羥基、單環的碳環及雜環基團（有3至6個環原子及含有至 多2個選自0、N及S的雜原子環原子）；基團R、Rb，其中Ra 是一個鍵、0、CO、C02、S02、NH、S02-NH 或 NHS〇2; Rb選自：氫、碳環及雜環基團（有3-6個環原子及含有至多 2個選自Ο、N及S的雜原子環原子）；Cl_6烴基，彼被一或 多個選自下列的取代基任意取代··羥基、合氧基、鹵素、 羧基、胺基、一或二烴胺基、碳環及雜環基團（有3至 6個環原子及含有至多2個選自〇、N及S的雜原子環原子） •’其中C ! 4烴基的一或二個碳原子可被下列基團任意替代 -271 - 200524877 (16) :Ο、S、SO、S02 或 NH。 5 0 ·如申請專利範圍第4 9項之化合物，其中該耳又 R1Ga選自：鹵素、基團Ra_Rb，其中Ra是一個鍵、〇、 以又”乂1，Rb選自：氫、雜環基團（有3_7個環原子）， 烴基’彼被一或多個選自下列的取代基任意取代：羥 羧基、胺基、一或二-C1M烴胺基 '雜環基團（有3_7個 子）。 5 1 ·如申請專利範圍第5 〇項之化合物，其中該取 R】Ga選自：鹵素（尤其氟）、d_3烷氧基（如甲氧基）、c 基，彼被下列基團任意取代··氟、羥基（例如羥甲基） 2院氧基或5員或6員的飽和雜環基（如哌啶基、嗎啉基 嗪並及N-甲基哌嗪基。 5 2 .如申請專利範圍第4 7至5 1項中的任何一項之 物’其中該芳基或雜芳基被丨或2個取代基（例如1個取 )取代。 5 3 .如申請專利範圍第4 3項之化合物，其中R3選 芳香基團。 5 4 ·如申請專利範圍第5 3項之化合物，其中該非 基團選自··環烷基、氧雜-環烷基、氮雜-環烷基、 雜-環烷基、二氧雜-環烷基及氮雜-氧雜環烷基，以 意地選自C 7 〇氮雜二環烷基，其中該非芳香基團被一 個取代基R1C或R1Qa(如同在前面的申請專利範圍中的 一項中所定義的）任意取代。 55.如申請專利範圍第54項之化合物，其中該非 代基 C0、 C卜4 基、 環原 代基 1·3烴 、c】_ 、哌 化合 代基 自非 芳香 二氮 及任 或多 任何 芳香 -272 - 200524877 (17) 基團選自：被取代的及未被取代的環丙基、環丁基、環戊 基、環己基、四氫吡喃、嗎啉、四氫呋喃、哌啶及吡略烷 基團。 5 6 ·如申請專利範圍第5 5項之化合物，其中該非芳香 基團選自：環丙基、環丁基、環戊基、環己基、四氫吡喃 、四氫呋喃、哌啶及吡咯烷基團。 5 7 .如申g靑專利範圍第4 3至5 6項中的任何一項之化合 物，其中該碳環及雜環基團被1、2或3個（典型1或2個，例 如1個）選自下列的取代基取代： •鹵素（例如氟及氯） • C 4烷氧基（例如甲氧基及乙氧基），彼被一或多個選自 下列的取代基任意取代：鹵素、羥基、C ! _2烷氧基及5員 及6員的飽和雜環（含有丨或2個選自〇、n及s的雜原子），該 雜環進一步被一或多個C ! _4基團（例如甲基）任意取代，其 中S(存在時）可以S、SO或S02存在； • C4烴基，彼被一或多個選自下列的基團任意取代：鹵 素、經基、烷氧基、胺基、Cl_4烷基磺醯胺基、3至6 員的環烷基（例如環丙基）、苯基（被一或多個選自鹵素、 甲基、甲氧基及胺基的取代基任意取代）及5及6員的飽和 雜環（含有1或2個選自〇、n及S的雜原子），該雜環進一步 被一或多個C !·4基團（例如甲基）任意取代，其中s (存在時） 可以S、SO或S02存在； •羥基； •胺基、一 -C!-4烷胺基、二=Cl “烷胺基、苄氧羰基胺基 -273 - 200524877 (18) 及Cb4烷氧羰基胺基； •羧基及6.4烷氧羰基； • (^_4烷胺基磺醯及Cb4烷基磺醯胺基； • Cm烷基磺醯； •基團0-Hets或NH-Hets，其中Hets是一種5或6員的飽和雜 環（含有1或2個選自〇、N及S的雜原子），該雜環進一步被 一或多個Ci-4基團（例如甲基）任意取代，其中S(存在時）可 以S、SO或S02存在； • 5及6員的飽和雜環（含有1或2個選自〇、N及S的雜原子） ，該雜環進一步被一或多個C ! _4基團（例如甲基）任意取代 ，其中S(存在時）可以S、SO或S02存在； •合氧基； • 6員的芳基及雜芳基環（含有至多2個氮環原子），彼被一 或多個選自鹵素、甲基及甲氧基的取代基任意取代。 5 8 · —種如前面的申請專利範圍中的任何一項之化合 物，其中R3是一種碳環或雜環基團R3a，該R3a選自：苯基 ;C 3 _6環院基；5及6員的飽和非芳香族雜環（含有至多2個 選自N、0、S及S〇2的雜原子環原子）；6員的雜芳基環（含 有1、2或個热環原子），以及5貝的雜方基環（有至多3個 選自N、0及S的雜原子環原子）； 其中各個fci哀或雜環基團R3a被至多4個（較佳至多3個 ，更佳至多2個（例如1個）選自下列的取代基任意取代：胺 基’經基’合氧基，氛，氯，C!.4院基-(〇)q·，其中q是〇 或1 ’ C】-4院基部份被氟、羥基或c 2院氧基任意取代； 200524877 (19) 一 -C】_ 4院胺基；二-c】_ 4院胺基；C 1 · 4院氧鑛基；殘基；基 團Re-R】6，其中是一個鍵或Cl_3伸烷基，R】6選自：C卜4 烷基磺醯；Cm烷胺基擴酸；CL4烷基磺醯胺基；胺基； 一 -Cw烷胺基；二-C]_4^胺基；Cy烴氧基羰胺基；6員 芳香基團（含有至多三個氮環原子）；C3·6環院基；5或6貝 的飽和非芳香雜環基團（含有一或二個選自N、〇、S及S〇2 的雜原子環原子），基團ri6(當飽和非芳香基團被一或多 個甲基任意取代時），基團R16(當芳香基團被一或多個選 自下列的基團任意取代時：氟、氯、羥基、Ci_2烷氧基及 C】」烷基）。 5 9 · —種如前面的申請專利範圍中的任何一項之化合 物，其中R3選自： •單環的芳基，彼被1 _ 4個（例如2個，例如1個）取代基 RI()或R1Ga任意取代； • eve?環院基，彼被個（例如】-2個，例如1個）取代基 R1C)或R1Ga任意取代； •飽和的5員的雜環（含有1個選自Ο、N及S的雜原子），彼 可被一個合氧基及7或被丨-4個（例如1-2個，例如1個）取代 基或任意取代； 飽和的6貝的雜環（含有1個或2個選自〇、N及S的環雜原 卞）彼可被一個合氧基及/或被1-4個（例1-2個，例如j 個）取代基任意取代； 5貝的雜方基（含有 被1 - 4個（例如2個 -275- 1 或2個選自〇、N及S的雜原子），彼可 例如I個）取代基1^。或任意取代 200524877 (20) • 6貝的雜芳基（含有1或2個氮環原子（較佳1個氮環原子）） 彼可被I-4個（例如丨—2個，例如丨個）取代基尺1〇或111(^任意 取代； •單一氮雜二環烷基及二氮雜二環烷基（各有7至9個環原 子）’彼被1 - 4個（例如1 - 2個，例如1個）取代基r 1G或R 1G a任 意取代； 6 〇 ·如申請專利範圍第5至5 9項中的任何一項之化合物 ’其中基團Y-R3選自在表2中所陳述的基團。 6 1 .如申請專利範圍第6 0項之化合物，其中基團γ _ R3 選自：在表2中所陳述的基團CL、CM、ES、ET、FC、FG 及FH，較佳基團CL、CM及ES，最較佳CL及CM。 6 2.如申請專利範圍第5至61項中的任何一項之化合物 ，其中R1是基團Rla-(V)n-，其中： η是0或1 ; v選自 ch2、ch2ch2及 so2ch2; Rla是碳環或雜環基團，彼選自： 苯基； 5員的雜芳基環（有至多4個選自N、0及S的雜原子）； 6員的雜芳基環（含有1或2個氮環原子）； 5或6員的飽和的非芳香雜環（含有1或2個選自N、Ο、S及 S〇2的雜原子環原子）； C 3 - 6環烷基；吲哚；喹啉； 其中各個碳環及雜環基團R1 a可被一或多個選自下列的取 -276- 200524877 (21) 代基任意取代：5或6員的飽和的非芳香碳環及雜環基團（ 3有至多2個選自n、〇、s及S〇2的雜原子環原子）’淫基 ;胺基；合氧基；—_Ci4烷胺基；二_(：】_4烷胺基；氟； 氯；硝基；CU4烷基_(〇)q-，其中q是0或1，Cm烷基基團 被下列任意取代：氟、羥基、Cl_2烷氧基或5或6員的飽和 的非芳香碳環或雜環基團（含有至多2個選自N、0、S及 S〇2的雜原子環原子）；苯基及c】_2-伸烷基二氧基。 6 3 .如申請專利範圍第5至6 2項中的任何一項之化合物 ’其中 Y 是一個鍵、CH2、CH2CH2 或 CH2CH(CH3)。 64·如申請專利範圍第5至63項中的任何一項之化合物 ’其中Α是一個鍵，Ri是一個碳環或雜環基團（有3至7個環 原子）。 6 5 ·如申請專利範圍第5至6 4項中的任何一項之化合物 ’其中R2是氫、鹵素、甲氧基、或C!_3烴基（例如Ci_2煙基 )’彼被下列基團任意取代：氟、羥基或甲氧基。 6 6 .如申g靑專利範圍第5至6 5項中的任何一項之化合物 ，其中： (i) R1或R3均不含有被取代的四唑基團；及/或 (ii) Y-R3不代表被取代的或未被取代的嘧啶基團；及/或 (iii) X及R3各不代表含有雙環的經苯並稠合的基團，其中 經苯並稠合基團的苯環有一個另外的被單鍵連接的環基團 ;及/或 (iv) R2不代表第三丁基；及/或 (v) 當A是一個鍵及R1是一種烷基時，則R3不代表一種哌陡 •277- 200524877 (22) 基環或被伸烷基鏈（連接一個 及/或 環基團）取代的哌啶基環；Ν ′ 丫, R3 Η (ΠΙ) where R1, R2, R3, and Y are as defined in any one of pages 5 to 41 of the scope of patent application. 43. The compound according to any one of claims 5 to 42 in the scope of the patent application, wherein R3 is selected from a monocyclic carbocyclic ring and a heterocyclic group having 3 to 6 ring atoms. 44. The compound of claim 43 in the patent application, wherein R3 is aryl or heteroaryl. 4 5. The compound according to item 44 of the patent application park, wherein R3 is an unsubstituted or substituted phenyl group. 4 6 · The compound as claimed in claim No. 44, wherein R 3 is an unsubstituted or substituted pyridyl. 4 7 · As claimed in the sra patent range_item 58 or item 59, wherein the aryl or heteroaryl group is substituted by one or more groups Ri0 (as in the scope of the patent application -270- 200524877 (15 ) As defined in item 27). 48. The compound according to item 47 of the scope of patent application, wherein the aryl or heteroaryl group is substituted by one or more substituents selected from the group R1 () a, and the group R1Ga is composed of the following: halogen, Hydroxy, trifluoromethyl, cyano, monocyclic carbocyclic and heterocyclic groups (having 3 to 7 (typically 5 or 6) ring atoms, and the group Ra_Rb, where Ra is a bond, 0, C 〇, χ1〇 (χ2), c (x2) xl, xic (x2) xi, s, SO, so2, NRC, so2NR2 or nrcso2; Rb is selected from: hydrogen, carbocyclic or heterocyclic group (with 3-7 Ring atoms), (^^ hydrocarbon group is arbitrarily substituted with one or more substituents selected from: hydroxyl, oxy, halogen, cyano, nitro, residue, amine, one or two-C ^ 4 Hydrocarbon amine, carbocyclic or heterocyclic group (with 3-7 ring atoms), in which one or more carbon atoms of Cb8 hydrocarbon group can be arbitrarily replaced by the following groups: 0, S, SO, S02, NRe, x ] C (x2), c ^ xqx1, or xAxyx1. 4 9 · The compound according to item 48 of the patent application, wherein the one or more substituents are selected from the group RI () a, and the group R1 () a is Consists of: halogen, hydroxyl, monocyclic carbocyclic and heterocyclic Group (with 3 to 6 ring atoms and containing up to 2 heteroatom ring atoms selected from 0, N and S); groups R, Rb, where Ra is a bond, 0, CO, C02, S02, NH , S02-NH or NHS〇2; Rb is selected from: hydrogen, carbocyclic and heterocyclic groups (having 3-6 ring atoms and containing up to 2 heteroatom ring atoms selected from 0, N and S); Cl_6 Hydrocarbyl, which is optionally substituted with one or more substituents selected from the group consisting of: hydroxyl, alkoxy, halogen, carboxy, amine, mono- or di-hydrocarbyl, carbocyclic and heterocyclic groups (with 3 to 6 Ring atoms and containing up to 2 heteroatom ring atoms selected from 0, N, and S) • 'wherein one or two carbon atoms of the C! 4 hydrocarbon group may be arbitrarily replaced by the following groups -271-200524877 (16): 0, S, SO, S02 or NH. 50 0. The compound according to item 49 of the patent application, wherein the R1Ga is selected from the group consisting of halogen, a group Ra_Rb, where Ra is a bond, 0, and "" 1, Rb is selected from: hydrogen, heterocyclic group (with 3-7 ring atoms), the hydrocarbyl group is optionally substituted with one or more substituents selected from: hydroxycarboxyl, amine, mono- or di-C1M hydrocarbon amine Base 'Heterocyclic group (has 3-7 members). 5 1 · As the compound in the scope of the application for patent No. 50, where R] Ga is selected from: halogen (especially fluorine), d_3 alkoxy (such as methoxy) , C group, which are optionally substituted by the following groups: fluorine, hydroxyl (such as hydroxymethyl) 2-oxo or 5- or 6-membered saturated heterocyclic group (such as piperidinyl, morpholinyl and N -Methylpiperazinyl. 5 2. The substance according to any one of claims 47 to 51 in the scope of the patent application, wherein the aryl or heteroaryl is substituted with one or two substituents (for example, one). 53. The compound according to item 43 of the scope of patent application, wherein R3 is an aromatic group. 5 4 · The compound according to item 53 of the scope of patent application, wherein the non-group is selected from ... cycloalkyl, oxa-cycloalkyl, aza-cycloalkyl, hetero-cycloalkyl, dioxa- Cycloalkyl and aza-oxetanyl, intentionally selected from C 7 0 azabicycloalkyl, where the non-aromatic group is substituted by a substituent R1C or R1Qa (as in the scope of the previous patent application) (As defined in the item). 55. The compound according to item 54 of the application, wherein the non-substituted group C0, C4 group, cyclic primary group 1.3 hydrocarbon, c] _, piperidinyl group are from non-aromatic diazonium and any or more of any Aromatic-272-200524877 (17) Group selected from: substituted and unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyran, morpholine, tetrahydrofuran, piperidine and pyridine Slightly alkyl group. 56. The compound as claimed in claim 55, wherein the non-aromatic group is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyran, tetrahydrofuran, piperidine, and pyrrolidinyl group. 57. The compound according to any one of claims 43 to 56 of the patent scope, wherein the carbocyclic and heterocyclic group is 1, 2 or 3 (typically 1 or 2, such as 1 ) Substituents selected from: • halogens (such as fluorine and chlorine) • C 4 alkoxy (such as methoxy and ethoxy), which are optionally substituted with one or more substituents selected from: halogen , Hydroxyl, C! _2 alkoxy and 5- and 6-membered saturated heterocyclic rings (containing 丨 or 2 heteroatoms selected from 0, n and s), the heterocyclic ring is further substituted by one or more C! _4 groups Groups (such as methyl) are optionally substituted, where S (when present) may be S, SO or S02; C4 hydrocarbyl, which is optionally substituted by one or more groups selected from the group consisting of halogen, meridian, alkoxy , Amine, Cl_4 alkylsulfonamido, 3 to 6-membered cycloalkyl (such as cyclopropyl), phenyl (substituted with one or more members selected from halogen, methyl, methoxy, and amine Group is optionally substituted) and 5 and 6-membered saturated heterocyclic rings (containing 1 or 2 heteroatoms selected from 0, n, and S), the heterocyclic ring is further substituted by one or more C! · 4 groups (such as methyl ) Ren Substitution where s (when present) can be S, SO or S02; • hydroxyl; • amino, mono-C! -4 alkylamino, di = Cl "alkylamino, benzyloxycarbonylamino -273-200524877 (18) and Cb4 alkoxycarbonylamino groups; • Carboxyl and 6.4 alkoxycarbonyl groups; • (^ _4 alkylaminosulfonium and Cb4 alkylsulfonamido groups; • Cm alkylsulfonium groups; • groups 0-Hets Or NH-Hets, where Hets is a 5- or 6-membered saturated heterocyclic ring (containing 1 or 2 heteroatoms selected from 0, N, and S), and the heterocyclic ring is further substituted by one or more Ci-4 groups ( (Eg methyl) arbitrary substitution, where S (when present) can exist as S, SO or S02; • 5 and 6-membered saturated heterocyclic ring (containing 1 or 2 heteroatoms selected from 0, N and S), the hetero The ring is further arbitrarily substituted with one or more C! _4 groups (such as methyl), where S (when present) may exist as S, SO or S02; • Hoxy groups; • 6-membered aryl and heteroaryl rings (Containing up to 2 nitrogen ring atoms), which are arbitrarily substituted with one or more substituents selected from the group consisting of halogen, methyl, and methoxy. 5 8 · —A kind of any one of the scope of the previously applied patents Compound, wherein R3 is a carbocyclic or heterocyclic group R3a, the R3a is selected from: phenyl; C 3 -6 ring courtyard; 5 and 6-membered saturated non-aromatic heterocyclic ring (containing up to 2 selected from N, 0, S, and S0 2 heteroatom ring atoms); 6-membered heteroaryl ring (containing 1, 2 or hot ring atoms), and 5 shells heterocyclic ring (at most 3 selected from N, Heteroatoms ring atoms of 0 and S); wherein each fci or heterocyclic group R3a is arbitrarily substituted with up to 4 (preferably up to 3, more preferably up to 2 (for example 1)) selected from the following substituents: Amine radicals, amines, oxygen, chloro, C !. 4 radicals-(〇) q ·, where q is 0 or 1 'C]-4 radicals are fluorine, hydroxyl or c 2 Oxygen optionally substituted; 200524877 (19) mono-C] _ 4 amine group; di-c] _ 4 amine group; C 1 · 4 oxo group; residue; group Re-R] 6, where Is a bond or Cl_3 alkyl group, and R] 6 is selected from the group consisting of: C4 alkylsulfonaminium; Cm alkylaminosulfonic acid; CL4 alkylsulfonamido; amine; mono-Cw alkylamino; di- C] _4 ^ amino group; Cy alkoxycarbonylamino group; 6-membered aromatic group (containing up to three nitrogen ring atoms); C 3 · 6 ring courtyard group; 5 or 6 shell saturated non-aromatic heterocyclic group (containing one or two heteroatom ring atoms selected from N, 0, S and S02), group ri6 (when the saturated non- When the aromatic group is arbitrarily substituted by one or more methyl groups, the group R16 (when the aromatic group is arbitrarily substituted by one or more groups selected from the group consisting of fluorine, chlorine, hydroxyl, Ci_2 alkoxy, and C 】"alkyl). 5 9 · A compound as in any one of the scope of the previous patent application, wherein R3 is selected from: • a monocyclic aryl group, which is substituted by 1 to 4 (for example, 2 such as 1) substituent RI ( ) Or R1Ga arbitrarily substituted; • eve? Ring courtyard group, which is optionally substituted by one (for example) -2, such as 1 substituent R1C) or R1Ga; • saturated 5-membered heterocyclic ring (containing 1 selected from 0, N, and S heteroatoms), which may be substituted by a single oxy group and 7 or by 1-4 (such as 1-2, such as 1) substituents or arbitrarily substituted; Containing 1 or 2 cycloheterogenes selected from 0, N and S) which may be arbitrarily substituted with one oxy group and / or with 1-4 (eg 1-2, eg j) substituents; Heterocyclic group of 5 Å (containing 1 to 4 (for example, 2 -275-1 or 2 heteroatoms selected from 0, N and S), which may be, for example, 1). Or optionally substituted 200524877 (20) • 6 aryl heteroaryl (containing 1 or 2 nitrogen ring atoms (preferably 1 nitrogen ring atom)) can be 1 to 4 (eg 丨 -2, such as 丨) Substitute rule 10 or 111 (^ arbitrarily substituted; • single azabicycloalkyl and diazabicycloalkyl (each has 7 to 9 ring atoms) 'are each 1 to 4 (for example 1- 2, for example 1) the substituents r 1G or R 1G a are arbitrarily substituted; 6. The compound of any one of claims 5 to 59 in the scope of the patent application, wherein the group Y-R3 is selected from Table 2 6 1. The compound according to item 60 of the scope of patent application, wherein the group γ_R3 is selected from the group CL, CM, ES, ET, FC, FG and FH, preferred groups CL, CM and ES, most preferred CL and CM. 6 2. A compound as claimed in any one of claims 5 to 61, wherein R1 is the group Rla- (V) n -, Wherein: η is 0 or 1; v is selected from ch2, ch2ch2, and so2ch2; Rla is a carbocyclic or heterocyclic group selected from: phenyl; 5-membered heteroaryl ring (with up to 4 selected from Heteroatoms of N, 0 and S); 6-membered heteroaryl Ring (containing 1 or 2 nitrogen ring atoms); 5 or 6 membered saturated non-aromatic heterocyclic ring (containing 1 or 2 heteroatom ring atoms selected from N, 0, S and S02); C 3- 6-cycloalkyl; indole; quinoline; wherein each carbocyclic and heterocyclic group R1 a may be arbitrarily substituted by one or more -276- 200524877 (21) substituents: 5 or 6 members Saturated non-aromatic carbocyclic and heterocyclic groups (3 with up to 2 heteroatom ring atoms selected from n, 0, s, and S02) 's amine group; amine group; alkoxy group; -Ci4 alkylamino group ; Di _ (:) _ 4 alkylamino group; fluorine; chlorine; nitro; CU4 alkyl_ (〇) q-, where q is 0 or 1, Cm alkyl group is optionally substituted by: fluorine, hydroxyl, Cl_2 Alkoxy or 5- or 6-membered saturated non-aromatic carbocyclic or heterocyclic groups (containing up to 2 heteroatom ring atoms selected from N, 0, S and S02); phenyl and c] _2- Alkylene dioxy. 6 3. The compound as in any one of items 5 to 62 of the scope of patent application 'wherein Y is a bond, CH2, CH2CH2 or CH2CH (CH3). 64. A compound according to any one of 5 to 63, wherein A is Ri, is a carbocyclic or heterocyclic group (with 3 to 7 ring atoms). 6 5 · A compound such as any one of items 5 to 64 in the scope of patent application 'wherein R2 is hydrogen, halogen , Methoxy, or C! _3 hydrocarbyl (such as Ci_2 nicotinyl) 'are optionally substituted with the following groups: fluorine, hydroxyl, or methoxy. 66. A compound as claimed in any one of claims 5 to 65 in the patent scope, wherein: (i) R1 or R3 does not contain a substituted tetrazole group; and / or (ii) Y- R3 does not represent a substituted or unsubstituted pyrimidine group; and / or (iii) X and R3 each does not represent a benzo-fused group containing a bicyclic ring, wherein the benzene ring of the benzo-fused group Has another ring group connected by a single bond; and / or (iv) R2 does not represent a third butyl group; and / or (v) when A is a bond and R1 is an alkyl group, then R3 does not represent a Piperidine • 277- 200524877 (22) a base ring or a piperidinyl ring substituted by an alkylene chain (connecting one and / or a ring group); (v i) R不代表一 (v i i) R不代表一種，彼包 至4個氮環原子二環基團。 67·如申請專利範圍第5項之化合物，彼有如式（IV)之 化學式：(v i) R does not represent one (v i i) R does not represent one, which includes bicyclic groups of up to 4 nitrogen ring atoms. 67. If the compound in the scope of patent application No. 5 has the formula of formula (IV): 或彼之鹽類或互變異構物類或N-氧化物類或溶劑化物類； 其中R1及R2如同在前面的申請專利範圍中的任何一項中戶斤 定義的； 一種任意的第二鍵或許存在於碳原子1及2之間； U 及 T 中的一個選自：CH2、CHR13、CRHr13、NR14、 N(0)R15、0及 S(0)t; U及 T中的另一個選自：NR14、〇、 CH2、CHR11、C(RM)2 及 00; r是 〇、1、2、3或 4; t是 〇、 1或2 ; R1】選自：氫、鹵素（尤其氟）、Cl·3院基（例如甲基）及 烷氧基（例如甲氧基）； R13 選自氫、NHR】4、N〇H、N〇Rl4及 R、Rb; R14選自氫及Ra-Rb ; -278- 200524877 (23) Rd選自一個鍵、C0、C(X2)X】' S02 及 S02NRc ; Ra、…及Re是前面所定義的； R 15選自C ! -4飽和的烴基，彼被經基、C b 2院氧基、鹵素或 單環的5或6員的碳環或雜環基團任意取代；條件是u及丁 不能同時是氧。 68·如申請專利範圍第67項之化合物，彼有如式（IV a) 之結構·Or its salts or tautomers or N-oxides or solvates; where R1 and R2 are as defined in any of the previous patent applications; an arbitrary second bond May exist between carbon atoms 1 and 2; one of U and T is selected from: CH2, CHR13, CRHr13, NR14, N (0) R15, 0 and S (0) t; the other one of U and T From: NR14, 0, CH2, CHR11, C (RM) 2 and 00; r is 0, 1, 2, 3 or 4; t is 0, 1 or 2; R1] is selected from: hydrogen, halogen (especially fluorine) , Cl · 3 alkyl (such as methyl) and alkoxy (such as methoxy); R13 is selected from hydrogen, NHR] 4, NOH, NOR14 and R, Rb; R14 is selected from hydrogen and Ra- Rb; -278- 200524877 (23) Rd is selected from a bond, C0, C (X2) X] 'S02 and S02NRc; Ra, ... and Re are as defined above; R 15 is selected from C! -4 saturated hydrocarbon group , Which is arbitrarily substituted by a 5- or 6-membered carbocyclic or heterocyclic group via a radical, C b 2 alkoxy, halogen, or monocyclic; provided that u and butyl cannot be oxygen at the same time. 68 · If the compound in the scope of patent application No. 67 has the structure of formula (IV a) · (IV I—U(IV I-U 或彼之鹽類或互變異構物類或N -氧化物類或溶劑化物類； 其中 U及 T 中的一個選自：CH2、CHR13、CRHR13; NR14、 N(〇)R15、〇及3(〇)1; U及T中的另一個選自cH2、CHR1】、 C(RU)2及 C = 0; r是 〇、1或 2; t是 0、1或 2; R11選自氫及Ci_3院基； R】3選自氫及Ra-Rb ; R14選自氫及Ra-Rb ; Rd選自一個鍵、CO、C(x2)x】、S02 及 S〇2NRc; R15選自Cm飽和的羥基，彼被烴基、c] 2烷氧基、鹵素或 單環的5或6員的碳環或雜環基團任意取代； R]、R2、Ra、1^及Re如同在前面的申請專利範圍中的任何 一項中所定義的。 -279- 200524877 (24) 6 9 ·如申請專利範圍第6 8項之化合物，其中T選自： CH2、CHR13、CHHR13、NR14、N(〇)R15、〇及 S(0)t。 7 0 ·如申請專利範圍第6 8項或第6 9項之化合物，其中U 選自：CH2、CHR11、C(R&quot;)2 及 C = 0。 7 1.如申請專利範圍第68至70項中的任何一項之化合 物，其中R11選自氫及甲基（較佳氫）。 72 ·如申請專利範圍第6 8至7 1項中的任何一項之化合 物，其中R13選自：氫及Ra-Rb，其中，Rb選自：氫；有3 至7個環原子的單環的碳環及雜環基團；C ! _4烴基（較佳無 環的飽和C i _4基團），彼被一或多個選自下列的取代基任意 取代：羥基、合氧基、鹵素、胺基、一或二-(CL4烴胺基 、及有3至7個環原子（更佳3至6環原子）的單環的碳環及雜 環基團，其中C ! _4烴基中的一或多個碳原子可被下列任意 替代：Ο、S、SO、S02、NRC、X】C(X2)、C(X2)X】；Rc選 自氫及C】.4烴基；X是0、S或NRe及X2是=〇、=S或=NRC。 7 3 .如申請專利範圍第7 2項之化合物，其中R 13選自； 氫；羥基；鹵素；氰基；胺基；單-Cm飽和烴胺基；二-Cb4飽和烴胺基；單環的5或6員的碳環及雜環基團；Ci-4 飽和烴基，彼被下列任意取代：羥基、C, -2烷氧基、鹵素 或單環的5或6員的碳環或雜環基團。 7 4 ·如申請專利範圍第7 3項之化合物，其中R 13選自： 羥基、胺基、C】_2烷胺基（例如甲胺基）、Cl.4烷基（例如甲 基、乙基、丙基及丁基）、Ch2烷氧基（例如甲氧基）、Cm 烷基磺醯胺基（例如甲烷磺醯胺基）、羥基-C ^ 2烷基（例如 -280- 200524877 (25) 羥甲基）、Ci-2-烷氧基- 烷基（例如甲氧甲基及甲氧乙基 )、羧基、Ci.4烷氧羰基（例如乙氧羰基）及胺基-CL2烷基（ 例如胺甲基）。 7 5 ·如申請專利範圍第6 8至7 4項中的任何一項之化合 物，其中R14選自：氫及Rd-Rb，其中Rb選自：氫；有3至7 個環原子的單環的碳環及雜環基團；CL4烴基（較佳無環的 飽和C ! _4基團），彼被一或多個選自下列的取代基任意取代 :羥基、合氧基、鹵素、胺基、一或二- Ci.4烴胺基、有3 至7環原子（較佳3至6個環原子）的單環的碳環及雜環基團 ’其中C】-4烴基中的一或多個碳原子可被下列任意替代： 〇、S、SO、S02、NF/、χΐ(：(Χ2)、C(X2)X】；Rc選自氫及 Ci-4煙基，X 是 0、S或 NRe 及 χ2 是=〇、或=NRC。 7 6 .如申請專利範圍第7 5項之化合物，其中r】4選自： 氫、C】_4烴基’彼被下列任意取代：氟或5或6員的飽和雜 環基團（例如甲基、乙基、正丙基、異丙基、丁基、2，2 ’ 2-三氟乙基及四氫呋喃基甲基）、環丙基甲基、被取代 的或未被取代的吡啶基-C 2烷基（例如2 ·吡啶基甲基）、被 取代的或未被取代的苯基-Cl.2烷基（例如苄基）、Ci4烷氧 羰基（例如乙氧羰基及第三丁氧羰基）、被取代的及未被取 代的苯基-C】.2烷氧羰基（例如苄氧羰基）、被取代的及未被 取代的5及6員的雜芳基（如吡啶基（例如2 _吡啶基及6 _氯代-2_吡啶基）及嘧啶基（例如2-嘧啶基）、Ci^烷氧基_Ci2烷基 (例如甲氧基甲基及甲氧基乙基）、及〇1_4院基擴酿（例如= 院磺醯）。 -281 - 200524877 (26) 7 7 .如申請專利範圍第6 8至7 6項中的任何一項之化合 物，彼有如式（Va)之結構： (R )wOr its salts or tautomers or N-oxides or solvates; wherein one of U and T is selected from: CH2, CHR13, CRHR13; NR14, N (〇) R15, 0 and 3 ( 〇) 1; the other of U and T is selected from cH2, CHR1], C (RU) 2 and C = 0; r is 〇, 1 or 2; t is 0, 1 or 2; R11 is selected from hydrogen and Ci_3 College base; R] 3 is selected from hydrogen and Ra-Rb; R14 is selected from hydrogen and Ra-Rb; Rd is selected from a bond, CO, C (x2) x], S02 and S〇2NRc; R15 is selected from Cm saturated Hydroxyl group, which is optionally substituted by a hydrocarbon group, c] 2 alkoxy group, a halogen or a monocyclic 5- or 6-membered carbocyclic or heterocyclic group; R], R2, Ra, 1 ^ and Re are as in the previous patent application As defined in any one of the ranges. -279- 200524877 (24) 6 9 · The compound according to item 68 of the scope of patent application, wherein T is selected from: CH2, CHR13, CHHR13, NR14, N (〇) R15, 0, and S (0) t. 70. If the compound in the 68th or 69th of the scope of patent application, U is selected from: CH2, CHR11, C (R &quot;) 2 and C = 0. 7 1. The compound according to any one of claims 68 to 70, wherein R11 is selected from hydrogen and methyl (preferably hydrogen). 72. The compound according to any one of claims 68 to 71, wherein R13 is selected from: hydrogen and Ra-Rb, wherein Rb is selected from: hydrogen; a monocyclic ring having 3 to 7 ring atoms Carbocyclic and heterocyclic groups; C! _4 hydrocarbon group (preferably acyclic saturated Ci_4 group), which is optionally substituted with one or more substituents selected from the group consisting of hydroxyl, oxy, halogen, Amine group, mono- or di- (CL4 hydrocarbon amino group, and monocyclic carbocyclic and heterocyclic group having 3 to 7 ring atoms (more preferably 3 to 6 ring atoms), in which one of C! _4 hydrocarbon group Or more carbon atoms can be replaced by any of the following: 0, S, SO, S02, NRC, X] C (X2), C (X2) X]; Rc is selected from hydrogen and C]. 4 hydrocarbon group; X is 0, S or NRe and X2 are = 0, = S or = NRC. 7 3. The compound according to item 72 of the patent application range, wherein R 13 is selected from: hydrogen; hydroxyl; halogen; cyano; amine; mono-Cm Saturated hydrocarbon amine groups; Di-Cb4 saturated hydrocarbon amine groups; monocyclic 5 or 6-membered carbocyclic and heterocyclic groups; Ci-4 saturated hydrocarbon groups, which are substituted by any of the following: hydroxyl, C, -2 alkoxy , Halogen or monocyclic 5 or 6 membered carbocyclic or heterocyclic groups. 7 4 · As applied The compound in the scope of the patent No. 73, wherein R 13 is selected from the group consisting of hydroxyl, amine, C] _2 alkylamino (such as methylamino), Cl.4 alkyl (such as methyl, ethyl, propyl and butyl) Group), Ch2 alkoxy group (such as methoxy group), Cm alkylsulfonamido group (such as methanesulfonamido group), hydroxy-C ^ 2 alkyl group (such as -280- 200524877 (25) hydroxymethyl group) , Ci-2-alkoxy-alkyl (such as methoxymethyl and methoxyethyl), carboxyl, Ci.4 alkoxycarbonyl (such as ethoxycarbonyl), and amine-CL2 alkyl (such as aminemethyl ). 7 5 · The compound according to any one of claims 68 to 74, wherein R14 is selected from: hydrogen and Rd-Rb, wherein Rb is selected from: hydrogen; having 3 to 7 ring atoms Monocyclic carbocyclic and heterocyclic groups; CL4 hydrocarbon groups (preferably acyclic saturated C! _4 groups), which are optionally substituted with one or more substituents selected from the group consisting of: hydroxyl, oxy, halogen, Amine group, mono- or di-Ci.4 hydrocarbon amino group, monocyclic carbocyclic and heterocyclic group having 3 to 7 ring atoms (preferably 3 to 6 ring atoms) 'wherein C] -4 hydrocarbon group One or more carbon atoms can be Generation: 〇, S, SO, S02, NF /, χΐ (: (χ2), C (X2) X]; Rc is selected from hydrogen and Ci-4 nicotyl, X is 0, S or NRe and χ2 is = 〇 , Or = NRC. 7 6. The compound according to item 75 of the scope of patent application, wherein r] 4 is selected from: hydrogen, C] _4 alkyl group which is substituted by any of the following: fluorine or a 5- or 6-membered saturated heterocyclic group. Groups (such as methyl, ethyl, n-propyl, isopropyl, butyl, 2,2'2-trifluoroethyl, and tetrahydrofurylmethyl), cyclopropylmethyl, substituted or unsubstituted Pyridyl-C 2 alkyl (eg, 2-pyridylmethyl), substituted or unsubstituted phenyl-Cl.2 alkyl (eg, benzyl), Ci4 alkoxycarbonyl (eg, ethoxycarbonyl and Third butoxycarbonyl), substituted and unsubstituted phenyl-C] .2 alkoxycarbonyl (such as benzyloxycarbonyl), substituted and unsubstituted 5 and 6 membered heteroaryl (such as Pyridyl (such as 2-pyridyl and 6-chloro-2_pyridyl) and pyrimidinyl (such as 2-pyrimidyl), Ci ^ alkoxy_Ci2 alkyl (such as methoxymethyl and methoxy Ethyl), and 〇1_4 Yuanji expansion (for example = Yuan sulfonium). -281-200524877 (26) 7 7. If the compound of any one of items 68 to 76 in the scope of patent application, they have the structure of formula (Va): (R) w 或彼之鹽類或互變異構物類或N-氧化物類或溶劑化物類； 其中R14a選自：氫、被氟任意取代之C!_4烷基（例如甲基、 乙基、正丙基、異丙基、丁基及2，2，2-三氟乙基）、環 丙基甲基、苯基-Cm烷基（例如苄基）、Cb4烷氧羰基（例如 乙氧羰基及第三丁氧羰基）、苯基-Cw烷氧羰基（例如苄氧 羰基）、烷氧基-山_2烷基（例如甲氧基甲基及甲氧基乙 基）、及C ! -4烷基磺醯（例如甲烷磺醯），其中苯基部份（當 存在時）被一至三個選自下列的取代基任意取代：氟、氯 、C^4烷氧基（被氟或（：1-2_烷氧基任意取代）、及^.4烷基（被 氟或烷氧基任意取代）； W是 0，1，2或 3 ; R2是氫或甲基，最較佳氫； R 1 1及r如同在申請專利範圍第8 2至9 〇項中的任何一項中所 定義的； R 9選自：氟；氯；c14烷氧基（被氟或Ci 2烷氧基任意取 代）；院基（被氟或…」烷氧基任意取代）。 200524877 (27) 7 8 .如申請專利範圍第6 8至7 6項中的任一項之化合物 彼有如式（Vb)之結構：Or its salts or tautomers or N-oxides or solvates; where R14a is selected from: hydrogen, C! _4 alkyl (optionally substituted by fluorine, such as methyl, ethyl, n-propyl) , Isopropyl, butyl and 2,2,2-trifluoroethyl), cyclopropylmethyl, phenyl-Cm alkyl (such as benzyl), Cb4 alkoxycarbonyl (such as ethoxycarbonyl and tertiary Butoxycarbonyl), phenyl-Cw alkoxycarbonyl (such as benzyloxycarbonyl), alkoxy-san_2alkyl (such as methoxymethyl and methoxyethyl), and C! -4 alkyl Sulfonium (such as methanesulfonium) in which the phenyl moiety (when present) is arbitrarily substituted with one to three substituents selected from the group consisting of fluorine, chlorine, C ^ 4 alkoxy (by fluorine or (: 1- 2-alkoxy optionally substituted), and ^ .4 alkyl (optionally substituted by fluorine or alkoxy); W is 0, 1, 2 or 3; R2 is hydrogen or methyl, most preferably hydrogen; R 1 1 and r are as defined in any one of the scope of patent application Nos. 8 2 to 90; R 9 is selected from: fluorine; chlorine; c14 alkoxy (optionally substituted by fluorine or Ci 2 alkoxy) Yuanji (selected by fluorine or ... "alkoxy .) 200 524 877 (27) 78 The compound of any one of item 76 to 68 as the scope of patent application he like structural formula (Vb) of: 或彼之鹽類或互變異構物類或N -氧化物類或溶劑化物類； 其中R14a選自：氫、被氟任意取代之C!_4烷基（例如甲基、 乙基、正丙基、異丙基、丁基及2，2，2-三氟乙基）、環 丙基甲基、苯基- Ci-2院基（例如节基）、Ci-4院氧擬基（例如 乙氧羰基及第二丁氧鑛基）、本基-院氧羯基（例如卡氧 羰基）、CL2-烷氧基-Ci-2烷基（例如甲氧基甲基及甲氧基乙 基）、及C】_4烷基磺醯（例如甲烷磺醯），其中苯基部份（當 存在時）被一至三個選自下列的取代基任意取代：氟、氯 、Cw院氧基（被氟;或Cy院氧基任意取代）、及Cq院基（被 氟或6.2烷氧基任意取代）； w是 0，1，2 或 3 ; R2是氫或甲基，最較佳氫； R11及r如同前面所定義的； R】9選自··氟；氯；C ! “烷氧基（被氟或C 1 ·2烷氧基任意取 代）；及Cb4烷基（被氟或烷氧基任意取代）。 79·如申請專利範圍第77項或第78項之化合物，其中μ -283- 200524877 (28) 是〇或w是1、2或3，該苯基環是2_被單取代的、3、被％ 舉取 代的、2，6-被雙取代的、2，被雙取代的、2， 4 -被雙 取代的、2，5 -被雙取代的、2，3，6 _被三取伐的或之， ，6 -被三取代的。 8 0 .如申請專利範圍第7 9項之化合物，其中該苯其&amp; 在2及6的位置上被選自氟、氯及甲氧基的取代基雙取代 8 1 ·如申請專利範圍第6 8至8 0項中的任何一項之化a 物，其中R 1 1是氫。 8 2.如申請專利範圍第68至81項中的任何一項之$ 物其中R14a是氫或甲基。 83·—種如式（Via)之化合物：Or its salts or tautomers or N-oxides or solvates; wherein R14a is selected from: hydrogen, C! _4 alkyl optionally substituted by fluorine (eg methyl, ethyl, n-propyl , Isopropyl, butyl and 2,2,2-trifluoroethyl), cyclopropylmethyl, phenyl-Ci-2 (eg, benzyl), Ci-4 (oxy) Oxycarbonyl group and second butoxy group), Benzo-co-oxo group (such as carbocarbonyl), CL2-alkoxy-Ci-2 alkyl (such as methoxymethyl and methoxyethyl) , And C] _4 alkylsulfonium (such as methanesulfonium), in which the phenyl moiety (when present) is arbitrarily substituted with one to three substituents selected from the group consisting of fluorine, chlorine, Cw Or Cy optionally substituted), and Cq optionally substituted by fluorine or 6.2 alkoxy; w is 0, 1, 2 or 3; R2 is hydrogen or methyl, most preferably hydrogen; R11 and r is as defined above; R] 9 is selected from the group consisting of fluorine; chlorine; C! "alkoxy (optionally substituted by fluorine or C 1 · 2 alkoxy); and Cb4 alkyl (substituted by fluorine or alkoxy Optional replacement). 79. If the scope of patent application is 77 or The compound according to item 78, wherein μ -283- 200524877 (28) is 0 or w is 1, 2 or 3, and the phenyl ring is 2-substituted by mono, 3, substituted by%, 2,6-substituted Double substituted, 2, double substituted, 2, 4-double substituted, 2, 5-double substituted, 2, 3, 6 _ three triplicated or either,, 6-triple substituted 80. The compound according to item 79 of the scope of patent application, wherein the benzene is &amp; 2 substituted at positions 2 and 6 with a substituent selected from fluorine, chlorine and methoxy group 8 1 The compound of any one of items 68 to 80, wherein R 1 is hydrogen. 8 2. The product of any one of items 68 to 81 of the scope of patent application, wherein R 14a is hydrogen or formazan 83 · —A kind of compound of formula (Via): 或彼之鹽類或互變異構物類或N -氧化物類或溶劑化物類； 其中R2G選自氫及甲基； R21選自氟及氯； R22選自氟、氯及甲氧基；或 R2】及R22中的一個是氫，另一個選自：氯、甲氧基、乙氧 基、二氟甲氧基、二氟甲氧基及；氧基。 84.—種如式（VIb)之化合物： -284- 200524877 (29)Or its salts or tautomers or N-oxides or solvates; wherein R2G is selected from hydrogen and methyl; R21 is selected from fluorine and chlorine; R22 is selected from fluorine, chlorine and methoxy; or One of R2] and R22 is hydrogen, and the other is selected from the group consisting of chlorine, methoxy, ethoxy, difluoromethoxy, difluoromethoxy, and oxy. 84.—A compound such as formula (VIb): -284- 200524877 (29) 或彼之鹽類或互變異構物類或N-氧化物類或溶劑化物類； 其中r2G選自氫及甲基； R21a選自氟及氯； R22a選自氟、氯及甲氧基。 85，如申請專利範圍第84項之化合物，彼選自： 4-(2，6-二氟代-苯甲醯胺基）-1Η-吼唑-3-羧酸哌啶-4-基醯 胺； 4-(2，6-二氟代-苯甲醯胺基）_1H-口比唑-3-羧酸（1-甲基-哌 啶-4 -基）-醯胺； 4-(2，6-二氯代-苯甲醯胺基）-1Η-吼唑-3-羧酸哌啶-4-基醯 胺； 4 - ( 2 ·氟代-6 -甲氧基-苯甲醯胺基）-1 Η -吡唑-3 -羧酸哌啶-4 - 基醯胺。 8 6.—種如式（Ib)之化合物，其中該化合物如同在申請 專利範圍第5至8 5項中的任何一項中所定義的，條件是： (a-i)當A是一個鍵及Y_R3是一種烷基、環烷基、被任意取 代的苯基或被任意取代的苯烷基時，則R]不代表一個被取 代的或未被取代的二氫萘、二氫色滿、二氫硫代色滿、四 -285- 200524877 (30) 氫喹啉或四氫苯並呋喃基團；及/或 (a-ii)X及R3各不代表一個含有馬來醯亞胺基團的基團，其 中該馬來醯亞胺基團有氮原子連接在彼之3及4的位置上； 及/或 (a-iii)R1不代表一個含有嘌呤核苷基團的基團；及/或 (a-W)X及R3各不代表一個含有環丁烯-1，2-二酮基團的基 團，其中該環丁烯1，2_二酮基團有氮原子連接在彼之3 及4的位置上；及/或 (a-v)R3不代表一個基團，該基團含有4 -被單取代的或4， 5-被雙取代的2-吡啶基或2-嘧啶基或5-被單取代的或5，6_ 被雙取代的1，2，4-三嗪-3-基或3-噠嗪基；及/或 (a-vi)X及R3各不代表一個基團，該基團含有一個與被取代 的或未被取代的吡啶、二嗪、三嗪基團連接的被取代的或 未被取代的吡唑-3-基胺基團；及/或 (a-Wi)當A是C = 〇及γ-R3是一個烷基、環烷基、被任意取 代的苯基或被任意取代的苯烷基時，則R1不代表一個被取 代的或未被取代的四氫萘、四氫喹啉、四氫色滿或四氫硫 代色滿基團；及/或 (a-viii)當R3是Η及A是一個鍵時，R1不代表一個含有一個 二-芳基、二-雜芳基或芳基雜芳基的基團。 (a-x)當Y是一個鍵時，R3是氫，a是CO及R1是一個被取代 的苯基，在苯基上的各取代基不代表基團CH2-P(〇)RxR&gt;'， 其中Rx及Ry各自選自烷氧基及苯基。 (a-ix)R3不代表一個含有1，2，8，8a -四氫-7-甲基-環丙 -286- 200524877 (31) [c]吡咯並[3，2，e]吲哚- 4-(5 Η)-酮基團 (a-xi)X不代表4-(第三丁氧羰基胺基）-3 基胺基；及/或 (b-i)R3不代表一個被橋連的氮雜二環基 (b-ii)當A是一個鍵時，則R3不代表一個 的或被取代的苯基的基團，在該苯基之 的或未被取代的胺基甲醯或硫代胺基畔 或 (b-iii)當A是一個鍵時，則R3不代表一） 喹噁啉基的基團，其各有一個被取代的 或哌嗪環連接；及/或 (b - i v )當A是一個鍵及R 1是一個烷基時 含有噻三嗪基團的基團；及/或 (b-v)當R]或R3含有一個有S( = 〇)2環原子 的基團時，該碳環不代表一個被取代的 ;及/或 (b-vi)當A是一個鍵及R1是一個芳院基 烷基，其各有選自下列的取代基連接： 未被取代的胺基、胺垸基、脒基、胍基 及/或 (b-vii)當 X 是一個基團 RLa-NR4-，a是- 非芳香基團時，則：R3不代表〜個6員的骂 直接連接至5’ 6-被稠合的二環雜芳基）； (c - i)當A是一個鍵時’ R 1不代表一個被】 的基團；及/或 ，-甲基咪唑-2_基療 團；及/或 含有一個未被取代^ 鄰位有一種被取# 3醯基團連接；&amp; / _含有異喹啉基^ 或未被取代的哌D定 ，則R3不代表〜個 的雜環與碳環稠合 或未被取代的苯環 、雜芳烷基或哌Π定 氰基、被取代的或 及胺基甲醯基團； -個鍵及R1是一個 【環芳基或雜芳基（ 及/或 仅代的芳烷基、雜 -287- 200524877 (32) 芳烷基或哌啶烷基及/或 (c-ii)當X是一種胺基或烷胺基及γ是一個鍵時，R3不代表 一個被雙取代的噻唑基，其中取代基中的一個選自氰基及 氟代院基。 8 7 .如申請專利範圍第8 6項之化合物，其中化學式（I b ) 受但書（a-i)至（a-xi)、 （b-i)至（b-vii)、 （c-i)及（c-ii)全部約 束。 8 8 .如申請專利範圍第4至8 6項中的任何一項之化合物 ，其中該化合物是鹽的形式。 8 9 ·如申請專利範圍第3項中所定義式（I)化合物之用途 ，條件是： (a-i)當A是一個鍵及γ-R3是—種烷基、環烷基、被任意取 代的苯基或被任意取代的苯院基時，則R1不代表一個被取 代的或未被取代的二氫萘、二氫色滿、二氫硫代色滿、四 氫D奎啉或四氫苯並呋喃基團；及/或 (a-ii)X及R3各不代表一個含有馬來醯亞胺基團的基團，其 中該馬來醯亞胺基團有氮原子連接在彼之3及4的位置上； 及/或 (a-iii)R1不代表一個含有嘌呤核苷基團的基團；及/或 (a-iv)X及R3各不代表一個含有環丁烯“二酮基團的基 團’其中該環丁烯-1，2-二酮基團有氮原子連接在彼之3 及4的位置上；及/或 (a-v)R3不代表一個基團，該基團含有4_被單取代的或$， 5-被雙取代的2-吡啶基或2-嘧啶基或一種5_被單取代的或$ -288- 200524877 (33) ，6 -被雙取代的1，2，4 -三嗪-3-基或3 -噠 (a-vi)X及R3各不代表一個基團，該基團含 的或未被取代的基；吡啶、二嗪或三嗪基 的或未被取代的吡唑-3-基胺基團；及/或 (a-vii)當A是C = 〇及Y-R3是一種院基、環 代的苯基或被任意取代的苯院基時’則R1 代的或未被取代的四氫萘、四氫喹啉、四 代色滿基團；及/或 (a-viii)當R3是η及A是一個鍵時，Rl不代^ 二芳基、二雜芳基或芳基雜芳基）；及/或 (a-ix)R3不代表一個含有一種1，2，8，8a 丙[c]吡咯並[3，2，e]吲哚-4-( 5 Η)-酮基團 (a-x)當Υ是一個鍵時，R3是氫、八是（：0及 的苯基，在苯基上的各取代基不代表基團 其中Rx及Ry各選自烷氧基及苯基；及/或 (a-xi)X不代表4-(第三丁氧羰基胺基）_3_E 基胺基。 90·如申請專利範圍第89項之應用，： 化合物受但書（a - i)至（a - x i)約束。 9 1 · 一種如申請專利範圍第4項定義之 彼用於製藥上，條件是： U-i)當A是一個鍵及γ-R3是一個烷基、環 代的苯基或被任意取代的苯烷基，則Ri不 的或未取代的二氫萘、二氫色滿、二氫硫 嗪基；及/或 有一個與被取代 團連接的被取代 院基、被任意取 不代表一個被取 氫色滿或四氫硫 良一個基團（含有 -四氫-7-甲基-環 的基團；及/或 R1是一個被取代 CH2-P(0)RxRy， 戸基咪唑-2·基羰 其中該如式（I)之 .式（I a)化合物， 院基、被任意取 代表一個被取代 代色滿、四氫D奎 -289- 200524877 (34) 啉或四氫苯並呋喃基團；及/或 (a-ii)X及R3各不代表一個含有馬來醯亞胺基團的基團，其 中該馬來醯亞胺基團有氮原子連接在彼之3及4的位置上； 及/或 (a-iii)R1不代表一個含有嘌呤核苷基團的基團；及/或 (a-iv)X及R3各不代表一個含有環丁烯d，2_二酮基團的基 團’其中該環丁烯-1，2 -二酮基團有氮原子連接在彼之3 及4的位置上；及/或 (a-v)R3不代表一個基團，該基團含有4_被單取代的或4， 5-被雙取代的2-吡啶基或2_嘧啶基或5_被單取代的或5，6_ 被雙取代的1 ’ 2’ 4-三嗪-3 -基或3-嗟嗪基；及/或 (a-vl)X及R3各不代表一個基團，該基團含有一個與被取代 的或未被取代的吡啶、二嗪或三嗪基團連接的被取代的或 未被取代的吡唑-3-基胺基團；及/或 (a-vu)當A是C = 〇及W是—個烷基、環烷基、被任意取 代的本基或被任意取代的苯烷基時，則R 1不代表一個被取 代的或未被取代的四氫萘、四氫喹啉、四氫色滿或四氫硫 代色滿基團；及/或 (a-vlu)sR3是^及八是一個鍵時，…不代表一個基團（含有 一方基、一雜芳基或芳基雜芳基）；及/或 (a ix)R不代表一個含有1，2，8，8a -四氫-7·甲基-環丙 [c]吡咯並[3，2，e]吲哚_4_(5H卜酮基團的基團；及/或 (tx)當Y是一個鍵時，R3是氫、A是c〇&amp;R^ —個被取代 的本基’在苯基上的各取代基不代表基團CH2-P(〇)RxRy， -290- 200524877 (35) Rx及^各選自烷氧基及苯基；及/或 (a-xi)X不代表4-(第三丁氧羰基胺基）_3_甲基咪唑-2_基鑛 基胺基；及/或 (b-i)R3不代表一個被橋連的氮雜二環基團；及/或 (b-ii)當A是一個鍵時，則R3不代表一個含有未被取代的或 被取代的苯基的基團，在苯基之鄰位有一種被取代的或未 被取代的胺基甲醯或硫代胺基甲醯連接；及/或 (b-iii)當A是一個鍵時，則R3不代表一個含有異喹啉基或 D奎噁啉基的基團，其各有一個被取代基的或未被取代的脈 啶或哌嗪環連接；及/或 (b - i v )當A是一個鍵及R 1是一個烷基時，則R 3不代表一個 含有噻三嗪基團的基團；及/或 (b-v)當R1或R3含有一個有s( = 〇h環原子的雜環與碳環稠合 的基團時’該碳環不代表一個被取代的或未被取代的苯環 ;及/或 (b-W)當A是一個鍵時，R1不代表一個芳烷基、雜芳烷基 或哌啶院基，其各有選自下列的取代基連接：氰基、被取 代的或未被取代的胺基、胺烷基、脒基、胍基及胺基甲醯 基團；及/或 (b-vii)當X是一個基團Rj-A-NR4-，A是一個鍵及R1是一個 非芳香基團時，則R3不代表一個6員的單環芳基或雜芳基（ 直接連接至5，6 ·被稠合的二環雜芳基）。 9 2 ·如申請專利範圍第9 1項使用之化合物，其中如式 (la)之化合物受但書（a-i)至（a-xi)及（b-i)至（b-vii)全部約束 -291 - 200524877 (36) 9 3 .如申請專利範圍第4項使用之化合物，其中該化合 物如同在申請專利範圍第5至92項中的任何一項之化合物 所定義的。 9 4 ·如申請專利範圍第1至3項中的任何一項之化合物 的應用，其中該化合物如同在申請專利範圍第4至92項中 的任何一項中所定義的。 9 5 ·如申請專利範圍第1頂之應用，其中該化合物以化 學式（VII)表示：Or its salts or tautomers or N-oxides or solvates; wherein r2G is selected from hydrogen and methyl; R21a is selected from fluorine and chlorine; R22a is selected from fluorine, chlorine and methoxy. 85. The compound according to item 84 of the scope of patent application, which is selected from the group consisting of 4- (2,6-difluoro-benzylamido) -1Η-oxazol-3-carboxylic acid piperidin-4-yl 醯Amine; 4- (2,6-difluoro-benzylamido) _1H-orbitazol-3-carboxylic acid (1-methyl-piperidin-4-yl) -amidamine; 4- (2 , 6-dichloro-benzylamido) -1, -oxazol-3-carboxylic acid piperidin-4-ylamidoamine; 4-(2.fluoro-6-methoxy-benzamide Yl) -1 fluorene-pyrazole-3 -piperidine-4-carboxylic acid amine. 8 6.—A compound of formula (Ib), wherein the compound is as defined in any one of items 5 to 85 of the scope of patent application, provided that: (ai) when A is a bond and Y_R3 When it is an alkyl, cycloalkyl, optionally substituted phenyl, or optionally substituted phenylalkyl, then R] does not represent a substituted or unsubstituted dihydronaphthalene, dihydrochroman, dihydro Thiochroman, tetra-285-200524877 (30) hydroquinoline or tetrahydrobenzofuran group; and / or (a-ii) X and R3 each does not represent a group containing a maleimide group A group in which the maleimide group has a nitrogen atom attached to each of positions 3 and 4; and / or (a-iii) R1 does not represent a group containing a purine nucleoside group; and / or (aW) X and R3 each does not represent a group containing a cyclobutene-1,2-diketone group, wherein the cyclobutene-1,2-diketone group has a nitrogen atom attached to each of 3 and 4 And / or (av) R3 does not represent a group which contains 4--monosubstituted or 4,5-disubstituted 2-pyridyl or 2-pyrimidinyl or 5-monosubstituted Or 5,6_ double replaced by 1,2 4-triazin-3-yl or 3-pyridazinyl; and / or (a-vi) X and R3 each does not represent a group containing one group with a substituted or unsubstituted pyridine, di A substituted or unsubstituted pyrazol-3-ylamine group attached to a hydrazine, triazine group; and / or (a-Wi) when A is C = 0 and γ-R3 is an alkyl, ring Alkyl, optionally substituted phenyl, or optionally substituted phenylalkyl, R1 does not represent a substituted or unsubstituted tetrahydronaphthalene, tetrahydroquinoline, tetrahydrochroman, or tetrahydrothio Chroman groups; and / or (a-viii) when R3 is fluorene and A is a bond, R1 does not represent a group containing a di-aryl, di-heteroaryl, or arylheteroaryl group. (ax) When Y is a bond, R3 is hydrogen, a is CO and R1 is a substituted phenyl group, each substituent on the phenyl group does not represent the group CH2-P (〇) RxR> ', where Rx and Ry are each selected from alkoxy and phenyl. (a-ix) R3 does not represent a compound containing 1,2,8,8a-tetrahydro-7-methyl-cyclopropane-286- 200524877 (31) [c] pyrrolo [3,2, e] indole- 4- (5 Η) -one group (a-xi) X does not represent a 4- (third butoxycarbonylamino) -3 group; and / or (bi) R3 does not represent a bridged nitrogen Heterobicyclyl (b-ii) When A is a bond, then R3 does not represent a group of one or a substituted phenyl group, the amino group of which is unsubstituted or thiomethyl or thio Amino group or (b-iii) when A is a bond, then R3 does not represent a) quinoxaline group, each of which has a substituted or piperazine ring connection; and / or (b-iv ) A group containing a thiatriazine group when A is a bond and R 1 is an alkyl group; and / or (bv) when R] or R3 contains a group having a S (= 〇) 2 ring atom , The carbocyclic ring does not represent a substituted; and / or (b-vi) when A is a bond and R1 is an arylalkyl group, each of which is connected by a substituent selected from the group consisting of: an unsubstituted amine Group, amine group, fluorenyl group, guanidino group and / or (b-vii) when X is a group RLa-NR4- and a is-non-aromatic group, then: R3 is not substituted ~ 6 members are directly connected to 5 '6-fused bicyclic heteroaryl); (c-i) when A is a bond' R 1 does not represent a group]; and / or -Methylimidazole-2 group; and / or contains an unsubstituted ^ ortho position with a # 3 醯 group attached; &amp; / _ contains isoquinolinyl ^ or unsubstituted piperidine D, then R3 does not represent a heterocyclic ring with a carbocyclic ring fused or unsubstituted benzene ring, heteroaralkyl or piperidine cyano group, substituted or amine formamidine group; The bond and R1 is a [cycloaryl or heteroaryl (and / or substituted aralkyl, hetero-287- 200524877 (32) aralkyl or piperidinyl and / or (c-ii) when X When it is an amine group or an alkylamine group and γ is a bond, R3 does not represent a disubstituted thiazolyl group, and one of the substituents is selected from the group consisting of cyano and fluoroalkyl. 8 7 86. The compound of item 6, wherein the chemical formula (I b) is bound by the provisos (ai) to (a-xi), (bi) to (b-vii), (ci), and (c-ii). If any of the patent application scopes 4 to 86 is changed The compound is in the form of a salt. 8 9 · The use of a compound of the formula (I) as defined in item 3 of the scope of the patent application, provided that: (ai) when A is a bond and γ-R3 is a alkane Group, cycloalkyl, optionally substituted phenyl, or optionally substituted benzyl, R1 does not represent a substituted or unsubstituted dihydronaphthalene, dihydrochroman, dihydrothiochroman , Tetrahydro D quinoline or tetrahydrobenzofuran groups; and / or (a-ii) X and R3 each does not represent a group containing a maleimide group, wherein the maleimide group Groups have nitrogen atoms attached to positions 3 and 4 of them; and / or (a-iii) R1 does not represent a group containing a purine nucleoside group; and / or (a-iv) X and R3 each Represents a group containing a "diketone group" of cyclobutene wherein the cyclobutene-1,2-diketone group has a nitrogen atom attached to each of the 3 and 4 positions; and / or (av) R3 Does not represent a group which contains 4_ monosubstituted or $, 5-disubstituted 2-pyridyl or 2-pyrimidinyl or a 5_ monosubstituted or $ -288- 200524877 (33), 6-double substituted 1, 2 4-triazin-3-yl or 3-pyridyl (a-vi) X and R3 each does not represent a group, which group contains or is unsubstituted; pyridine, diazine, or triazine or not A substituted pyrazol-3-ylamine group; and / or (a-vii) when A is C = 0 and Y-R3 is a nodal group, a cyclic phenyl group, or an optionally substituted benzoin group 'Then R1 substituted or unsubstituted tetrahydronaphthalene, tetrahydroquinoline, quaternary chroman group; and / or (a-viii) when R3 is η and A is a bond, R1 is not substituted ^ two Aryl, diheteroaryl or arylheteroaryl); and / or (a-ix) R3 does not represent a propyl [c] pyrrolo [3,2, e] indine containing a 1,2,8,8a Indole-4- (5 Η) -one group (ax) When Υ is a bond, R3 is hydrogen, octa is (0 and phenyl groups, each substituent on phenyl does not represent a group where Rx And Ry are each selected from an alkoxy group and a phenyl group; and / or (a-xi) X does not represent a 4- (third butoxycarbonylamino) -3-E amino group. 90. If the application in the scope of patent application number 89 applies: The compounds are subject to the provisos (a-i) to (a-x i). 9 1 · It is used in pharmaceuticals as defined in item 4 of the scope of the patent application, provided that: Ui) when A is a bond and γ-R3 is an alkyl group, a cyclic phenyl group, or an optionally substituted benzone Group, then Ri is unsubstituted or unsubstituted dihydronaphthalene, dihydrochroman, dihydrothiazinyl group; and / or there is a substituted radical connected to the substituted group, and being taken arbitrarily does not represent a taken hydrogen A group of chroman or tetrahydrosulfan (a group containing -tetrahydro-7-methyl-ring; and / or R1 is a substituted CH2-P (0) RxRy, amidinoimidazole-2 · ylcarbonyl Wherein the compound of the formula (I), the compound of the formula (I a), the radical, is optionally substituted to represent a substituted chroman, tetrahydro D Kui-289- 200524877 (34) chloro or tetrahydrobenzofuran group ; And / or (a-ii) X and R3 each does not represent a group containing a maleimide group, wherein the maleimide group has a nitrogen atom attached to positions 3 and 4 of each other ; And / or (a-iii) R1 does not represent a group containing a purine nucleoside group; and / or (a-iv) X and R3 each does not represent a group containing a cyclobutene d, 2-diketone group The group 'where the cyclidine The -1,2-dione group has a nitrogen atom attached to each of its 3 and 4 positions; and / or (av) R3 does not represent a group containing 4_ monosubstituted or 4, 5- Di-substituted 2-pyridyl or 2-pyrimidinyl or 5-substituted mono or 5,6_ di-substituted 1 '2' 4-triazin-3-yl or 3-pyrazinyl; and / or ( a-vl) X and R3 each does not represent a group containing a substituted or unsubstituted pyrazole attached to a substituted or unsubstituted pyridine, diazine or triazine group- A 3-ylamine group; and / or (a-vu) when A is C = 0 and W is an alkyl group, a cycloalkyl group, an optionally substituted base, or an optionally substituted phenalkyl group, then R 1 does not represent a substituted or unsubstituted tetrahydronaphthalene, tetrahydroquinoline, tetrahydrochroman or tetrahydrothiochroman group; and / or (a-vlu) sR3 is ^ and eight is In a bond, ... does not represent a group (containing one-side, one heteroaryl, or arylheteroaryl); and / or (a ix) R does not represent a group containing 1,2,8,8a -tetrahydro- 7. A group of methyl-cyclopropyl [c] pyrrolo [3,2, e] indole-4_ (5H ketone group); and / or (tx) When Y is a bond, R3 is hydrogen, A is c0 &amp; R ^-each substituted substituent 'on the phenyl group does not represent the group CH2-P (〇) RxRy, -290- 200524877 (35) Rx and ^ are each selected from alkoxy and phenyl; and / or (a-xi) X does not represent 4- (third butoxycarbonylamino) _3-methylimidazole-2-ylamino And / or (bi) R3 does not represent a bridged azabicyclic group; and / or (b-ii) when A is a bond, then R3 does not represent an unsubstituted or substituted A substituted phenyl group having a substituted or unsubstituted aminoformamidine or thioaminoformamidine linkage adjacent to the phenyl group; and / or (b-iii) when A is a bond When R3 does not represent an isoquinolinyl or D quinoxaline-containing group, each of which has a substituted or unsubstituted pyrimidine or piperazine ring connection; and / or (b-iv ) When A is a bond and R 1 is an alkyl group, then R 3 does not represent a group containing a thiatriazine group; and / or (bv) when R 1 or R 3 contains a ring with s (= 〇h When a heterocycle of an atom is fused with a carbocyclic ring, the carbocyclic ring does not represent a substituted Or an unsubstituted benzene ring; and / or (bW) when A is a bond, R1 does not represent an aralkyl, heteroaralkyl, or piperidinyl group, each of which is connected by a substituent selected from the following: Cyano, substituted or unsubstituted amine, amine alkyl, fluorenyl, guanidino, and aminoformamidine groups; and / or (b-vii) when X is a group Rj-A-NR4 -When A is a bond and R1 is a non-aromatic group, then R3 does not represent a 6-membered monocyclic aryl or heteroaryl group (directly connected to 5, 6 · fused bicyclic heteroaryl group) . 9 2 · The compound used in item 91 of the scope of patent application, in which the compound of formula (la) is subject to all the constraints of (a) to (a-xi) and (bi) to (b-vii) -291- 200524877 (36) 9 3. The compound used in item 4 of the scope of patent application, wherein the compound is defined as the compound in any one of the scope of patent applications 5 to 92. 94. The use of a compound according to any one of claims 1 to 3, wherein the compound is as defined in any one of claims 4 to 92. 9 5 · As the application of the first item in the scope of patent application, wherein the compound is represented by chemical formula (VII): Μ， 其中R2、R3及Y如同在前面的申請專利範圍中的任何一項 中所定義的’ G是一種5或6員的碳環或雜環。 9 6 . —種如在申請專利範圍第9 5項中所定義的如式 (VII)之化合物（例如用於藥劑）。 9 7 · —種藥學組成物，彼含有一種如在前面的申請專 利範圍中的任何一項中所定義的化合物及一種藥學上可接 受的載體。 9 8 · —種供預防或治療由環素依賴型激酶所仲介的疾 病狀態或症狀用的方法，該方法包含給有需要的患者投服 一種如在申請專利範圍第1至9 5項中的任何一項中所定義 的化合物° -292- 200524877 (37) 9 9 . 一種抑制環素依賴型激酶的方法，該 該激酶與如在申請專利範圍第1至9 5項中的任 定義的激酶抑制性化合物接觸。 10 0.—種調節細胞程序（例如細胞分裂作j 該方法藉由使用如在申請專利範圍第1至95項 項中所定義之化合物抑制環素依賴型激酶的活 1 〇 1 . —種供治療一種疾病或症狀用的方法 症狀包含或起源於哺乳動物體內異常的細胞生 包含給該哺乳動物投服可有效抑制異常的細胞 的如在申請專利範圍第1至9 5項中的任何一項 化合物。 102.—種供治療疾病或症狀用的方法，該 包含或起源於哺乳動物體內異常的細胞生長， 給該哺乳動物投服可有效抑制CDK活性（例 CDK2活性）的份量的如在申請專利範圍第1至 何一項中所定義的化合物。 1 0 3 . —種如在申請專利範圍1至9 5項中的 所定義的化合物於製造藥劑的應用，該藥劑可 由糖原合成酶激酶-3所仲介的疾病狀態或症狀 1 0 4 . —種供預防或治療由糖原合成酶激酶 疾病狀態或症狀用的方法，該方法包含給有需 服一種如在申請專利範圍第1至9 5項中的任何 義的化合物。 1 0 5 . —種抑制糖原合成酶激酶-3的方法， 方法包含使 何一項中所 毛）的方法， 中的任何一 性。 ，該疾病或 長，該方法 生長之份量 中所定義的 疾病或症狀 該方法包含 j如CDK1或 9 5項中的任 任何一項中 預防或治療 〇 -3所仲介的 要的患者投 一項中所定 該方法包含 -293- 200524877 (38) 使該激酶與如在申請專利範圍第1至9 5項中的任何一項中 所定義的激酶抑制性化合物接觸。 1 〇 6 · —種調節細胞程序（例如細胞分裂作用）的方法， 該方法係使用如在申請專利範圍第1至9 5項中的任何一項 中所定義的化合物來抑制糖原合成酶激酶-3的活性。M, wherein R2, R3 and Y are as defined in any one of the scope of the previous patent application, and G is a 5- or 6-membered carbocyclic or heterocyclic ring. 9 6. A compound of formula (VII) as defined in item 95 of the scope of patent application (for example for use in pharmaceuticals). 97. A pharmaceutical composition comprising a compound as defined in any one of the preceding claims and a pharmaceutically acceptable carrier. 98.-A method for preventing or treating a disease state or symptom mediated by a cyclin-dependent kinase, which method comprises administering to a patient in need a drug as described in items 1 to 95 of the scope of patent application A compound as defined in any one of ° -292- 200524877 (37) 9 9. A method for inhibiting a cyclin-dependent kinase which is in combination with any of the kinases as defined in claims 1 to 95 Inhibiting compound exposure. 10 0.—regulatory cellular programs (eg, cell division operations). This method inhibits the activity of cyclin-dependent kinases by using compounds as defined in items 1 to 95 of the patent application. Method for treating a disease or symptom. Symptoms include or originate from abnormal cells in mammals. Including administration to the mammal can effectively inhibit abnormal cells as in any one of claims 1 to 95 of the scope of patent application. Compound 102. A method for treating a disease or symptom, comprising or originating from abnormal cell growth in a mammal, and administering to the mammal an amount effective to inhibit CDK activity (eg, CDK2 activity) as in the application Compounds defined in the first to any one of the patent scope. 1 0 3. —The use of a compound as defined in the patent scope 1 to 95 in the manufacture of a medicament, which can be made by glycogen synthase kinase -3 mediated disease state or symptom 104. A method for preventing or treating a disease state or symptom of glycogen synthase kinase, which method comprises A compound having any of the meanings in claims 1 to 95. 105. A method of inhibiting glycogen synthase kinase-3, the method includes any of the methods described above, One sex. , The disease or disease, the disease or symptom defined in the growing weight of the method, the method comprises j such as CDK1 or any one of the prevention or treatment of any one of the 5-5 items administered to the patient The method as defined in -293-200524877 (38) contacting the kinase with a kinase inhibitory compound as defined in any of claims 1 to 95 in the scope of the patent application. 106. A method for regulating a cellular program (for example, cell division) using a compound as defined in any one of claims 1 to 95 to inhibit glycogen synthase kinase -3 activity. 107·—種供治療一種疾病或症狀用的方法，該疾病或 症狀包含或起源於哺乳動物體內異常的細胞生長，該方法 包含給該哺乳動物投服可有效抑制糖原合成酶激酶-3的活 性的份量的如在申請專利範圍第1至9 5項中的任何一項中 所定義的化合物。 1 〇 8 . —種供如在前述申請專利範圍中的任何一項中所 定義的使用，應用或方法用的化合物，其中該疾病狀態或 症狀選自增殖性疾病（如癌）及症狀（如病毒性感染、自體 免疫病及神經變性毒）。107. A method for treating a disease or condition comprising or originating from abnormal cell growth in a mammal, the method comprising administering to the mammal an effective inhibitor of glycogen synthase kinase-3 An active portion of a compound as defined in any one of claims 1 to 95 of the scope of patent application. 1 08. A compound for use, application or method as defined in any one of the foregoing patent applications, wherein the disease state or symptom is selected from a proliferative disease (such as cancer) and symptoms (such as Viral infections, autoimmune diseases and neurodegenerative viruses). 109·—種供緩和或減少疾病或症戕的發生率用的方法 ，該疾病或症狀包含或起源於哺乳動物體內異常的細胞生 長，該方法包含給該哺乳動投服可有效抑制異常的細胞生 長的份量的如在前述申請專利範圍中的任一項中所定義的 如式（〇)、（IG)、（I)、（la)或（lb)之化合物。 1 1 〇 · —種供緩和或減少疾病狀態或症狀的發生率用的 方法，該疾病或症狀由一種環素依賴型激酶或糖原合成酶 激酶-3所仲介，該方法包含給有需要的患者投服如在前述 申請專利範圍中的任何一項中所定義的如式（0)、（IQ)、（I) 、（la)或（lb)之化合物。 -294- 200524877 (39) 1 11 · 一種供如在前述申請專利範圍中的任何一項的使 用、應用或方法用的化合物，其中該疾病狀態或症狀是一 種癌，彼選自··乳癌、卵巢癌、結腸癌、前列腺癌、食管 癌、鱗狀細胞癌及非小型細胞肺癌。 1 1 2 . —種製造如在前述申請專利圍中的任何一項中 所定義的化合物的方法’該方法包含： ⑴使如式（XII)之4-胺基-吡唑與如式R'CC^H之羧酸或彼 之被活化的衍生物起反應：109. A method for alleviating or reducing the incidence of a disease or disorder, the disease or symptom including or originating from abnormal cell growth in a mammal, the method comprising administering to the mammal to effectively inhibit abnormal cells A growing portion of a compound as defined in any one of the foregoing patent applications as defined by formula (0), (IG), (I), (la) or (lb). 1 1 〇-A method for alleviating or reducing the incidence of a disease state or symptom, which is mediated by a cyclin-dependent kinase or glycogen synthase kinase-3, the method comprising The patient administers a compound as defined in any one of the foregoing patent applications as formula (0), (IQ), (I), (la) or (lb). -294- 200524877 (39) 1 11 · A compound for use, application or method as in any one of the scope of the aforementioned patent application, wherein the disease state or symptom is a cancer selected from the group consisting of breast cancer, Ovarian, colon, prostate, esophageal, squamous cell, and non-small cell lung cancer. 1 1 2. A method of manufacturing a compound as defined in any one of the aforementioned patent applications 'The method comprises: ⑴ using 4-amino-pyrazole as formula (XII) and formula R' The CC ^ H carboxylic acid or its activated derivative reacts: 其中Y、R ]、R2及R3如同在前述申請專利範圍中的任何一 項中所定義的；或 (ii)使如式R3-Y-NH2之化合物與如式（XIII)之化合物起反 應：Where Y, R], R2 and R3 are as defined in any one of the scope of the aforementioned patent application; or (ii) react a compound of formula R3-Y-NH2 with a compound of formula (XIII): N (XIII) 其中X、R2及R3如同在前述申請專利範圍中的任何一項中 所定義的。 1 1 3 .如申請專利範圍第1至9 5項中的任何一項之化合 物，彼充當抗黴菌劑使用。 -295- 200524877 (40) 1 1 4 „ 一種供診斷及治療由環素依賴型激酶所仲介的疾 病狀態或症狀用的方法，該方法包含：（i)篩選患者以確定 是否患者正或可能正罹患的疾病或症狀可以用抗環素依賴 型激酶活性的化合物處理；（i i)確定患者罹患的疾病或症 狀所顯示的徵兆，接著給患者投服如在申請專利範圍第1 至9 5項中的任何一項中所定義的化合物。 1 1 5 .使用一種如在申請專利範圍第1至9 5項中的任何 一項中所定義的化合物於製造藥劑之應用，該藥劑可治療 或預防業己被篩選及確定患有可以抗環素依賴型激酶的活 性的化合物處理的疾病或症狀，或有患有該疾病或症狀的 風險的患者體內的疾病或症狀。 -296- 200524877 七 明 說 單 簡 ^ru 為符 圖件 表元 代之 定圖 指表 :案代 圖本本 表&gt; \ 代 定一二 匕曰 第 圖 八、本案若有化學式時，請揭示最能顯示發明特徵的化學 式：N (XIII) where X, R2, and R3 are as defined in any of the foregoing patent applications. 1 1 3. As a compound of any one of claims 1 to 95 in the scope of patent application, it is used as an antimycotic agent. -295- 200524877 (40) 1 1 4 „A method for diagnosing and treating a disease state or symptom mediated by a cyclin-dependent kinase, the method comprising: (i) screening patients to determine whether they are or may be The affected disease or symptom can be treated with a compound having anti-cyclin-dependent kinase activity; (ii) determine the signs that the patient suffers from the disease or symptom, and then administer the drug to the patient as in items 1 to 95 of the scope of patent application 1 1 5. Use of a compound as defined in any one of claims 1 to 95 for the manufacture of a medicament for the treatment or prevention of Diseases or symptoms that have been screened and identified for treatment with compounds that are active against cyclin-dependent kinases, or in patients at risk for the disease or symptom. -296- 200524877 Qiming said ^ ru is the symbolic designation table of the symbolic element table: the case and the table of this table> \ The table of the first and second daggers Figure 8. If there is a chemical formula in this case, please reveal the best display The next feature the formula: Η ^⑼Η ^ ⑼
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