TWI283678B - Pyrazolo[3,4-b]pyridine compounds, and their use as phosphodiesterase inhibitors - Google Patents

Pyrazolo[3,4-b]pyridine compounds, and their use as phosphodiesterase inhibitors Download PDF

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TWI283678B
TWI283678B TW92125497A TW92125497A TWI283678B TW I283678 B TWI283678 B TW I283678B TW 92125497 A TW92125497 A TW 92125497A TW 92125497 A TW92125497 A TW 92125497A TW I283678 B TWI283678 B TW I283678B
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ethyl
pyridine
methyl
ylamino
tetrahydro
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TW92125497A
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TW200404801A (en
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David George Allen
Diane Mary Coe
Caroline Mary Cook
Michael Dennis Dowle
Christopher David Edlin
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Glaxo Group Ltd
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Priority claimed from GB0308017A external-priority patent/GB0308017D0/en
Priority claimed from GB0319708A external-priority patent/GB0319708D0/en
Priority claimed from GB0321074A external-priority patent/GB0321074D0/en
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Abstract

The invention relates to a compound of formula (I) or a salt thereof: wherein: R1 is C1-4alkyl, C1-3fluoroalkyl, -CH2CH2OH or -CH2CH2CO2C1-2alkyl; R2 is a hydrogen atom (H), methyl or C1 fluoroalkyl; R3 is optionally substituted C3-8cycloalkyl or optionally substituted mono-unsaturated-C5-7cycloalkenyl or an optionally substituted heterocyclic group of sub-formula (aa), (bb) or (cc); in which n1 and n2 independently are 1 or 2; and in which Y is O, S, SO2, or NR10; or R3 is a bicyclic group (dd) or (ee); and wherein X is NR4R5 or OR5a. The compounds are phosphodiesterase (PDE) inhibitors, in particular PDE4 inhibitors. Also provided is the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment and/or prophylaxis of an inflammatory and/or allergic disease in a mammal such as a human, for example chronic obstructive pulmonary disease (COPD), asthma, or allergic rhinitis.

Description

1283678 玖、發明說明： 【發明所屬之技術領域】 本發明係關於吡唑并吡啶化合物，其製法，可用於此等方 法中之中間物，及含有該化合物之醫藥組合物。本發明亦 關於吡唑并吡啶化合物在治療上之用途，例如作為磷酸二 酉旨酶之抑制劑及/或用於治療及/或預防炎性及/或過= 性疾病，譬如慢性阻塞肺病（C0PD)、氣喘或過敏性鼻炎。 【先前技術】 US 3,979,399、US 3，_，546 及 US 3,966,746 (E.R.Sq祕 & 示吡唑并[3,4-b]吡啶_5_甲醯胺之4-胺基衍生物，其中‘胺基 NRsR4可為非環狀胺基，其中心與&可各為氫、低碳烷基（例 如丁基）、苯基等；NR3 R4可替代地為3_6_員雜環族基團，嬖 如四氫p比哈基、六氫吡啶基及六氫峨畊基。此等化合物係 被揭示為中樞神經系統壓抑劑，可作為精神安定、止痛及 低血壓劑使用。 US 3,925,388 、US 3,856,799 、US 3,833,594 及 US 3,755,340 (E.R·Squibb & Sons)係揭示p比峻并[3，4-b]峨咬-5-幾酸類與酯類之 4-胺基衍生物。此4-胺基NR3R4可為非環狀胺基，其中化與 R4可各為氫、低碳烷基（例如丁基）、苯基等；Nr3 r4可替代 地為5-6-貝雜％族基團’其中存在另一個氮，譬如四氫p比洛 基、六氫吡啶基、吡唑基、嘧啶基、嗒畊基或六氫吡畊 基。此等化合物係被提及為中樞神經系統壓抑劑，可作為 精神安定藥劑或鎮定劑使用，具有消炎與止痛性質。此等 化合物被提及會增加腺苷-3，，5，-環狀單磷酸鹽之胞内濃度，及 87841-960303-中.doc -10- 1283678 減輕氣喘之病徵。 H. Hoehn 等人，/· //eteraqyc/· C7^m·，1972, 9(2)，235-253 揭示一系列 1H-吡唑并[3,4七]吡啶-5_羧酸衍生物，具有4-羥基、4-氯基、 4-烷氧基、4-肼基及4-胺基取代基。 CA 1003419 、 CH 553 799 及 T· Denzel, Archiv der Pharmazie， 1974, 307(3)，177-186揭示在1-位置上未經取代之4,5-二取代1H-叶匕吐并[3,4-b]p比淀類。 2002年1月23日公告之日本特許公開專利申請案圯-2002-20386-A (Ono Yakuhin Kogyo KK)揭示下式p比吐并批淀化合物：1283678 发明Invention Description: TECHNICAL FIELD The present invention relates to pyrazolopyridine compounds, which are produced by the intermediates in the methods, and pharmaceutical compositions containing the compounds. The invention also relates to the use of pyrazolopyridine compounds in therapy, for example as inhibitors of diterpene phosphate enzymes and/or for the treatment and/or prevention of inflammatory and/or over-sex diseases, such as chronic obstructive pulmonary disease ( C0PD), asthma or allergic rhinitis. [Prior Art] US 3,979,399, US 3,_, 546 and US 3,966,746 (ERSq secret & The amine group NRsR4 may be a non-cyclic amine group, the center of which may be hydrogen, a lower alkyl group (e.g., butyl group), a phenyl group, etc.; and NR3 R4 may alternatively be a 3-6-membered heterocyclic group. For example, tetrahydrop-biheptyl, hexahydropyridyl and hexahydroquinone. These compounds are disclosed as central nervous system depressants and can be used as a neuroleptic, analgesic and hypotensive agent. US 3,925,388, US 3,856,799 US 3,833,594 and US 3,755,340 (ER·Squibb & Sons) are 4-amino-based derivatives of p-suppressive [3,4-b] bite-5-acids and esters. NR3R4 may be a non-cyclic amine group, wherein R4 may be each hydrogen, lower alkyl (e.g., butyl), phenyl, etc.; Nr3r4 may alternatively be a 5-6-shell hetero-group There is another nitrogen, such as tetrahydrop-pyrrolyl, hexahydropyridyl, pyrazolyl, pyrimidinyl, hydrazine or hexahydropyrryl. These compounds are mentioned as central nervous system depression. It can be used as a neuroleptic or tranquilizer with anti-inflammatory and analgesic properties. These compounds are mentioned to increase the intracellular concentration of adenosine-3,5,-cyclic monophosphate, and 87841-960303- .doc -10- 1283678 to alleviate the symptoms of asthma. H. Hoehn et al., // //eteraqyc/· C7^m·, 1972, 9(2), 235-253 Reveal a series of 1H-pyrazolo[3, 4-7] Pyridine-5-carboxylic acid derivative having 4-hydroxy, 4-chloro, 4-alkoxy, 4-indenyl and 4-amino substituents. CA 1003419, CH 553 799 and T· Denzel , Archiv der Pharmazie, 1974, 307(3), 177-186 discloses unsubstituted 4,5-disubstituted 1H-leaf and [3,4-b]p ratios at the 1-position. 2002 Japanese Laid-Open Patent Application No. -2002-20386-A (Ono Yakuhin Kogyo KK), published on January 23, discloses a compound of the formula p:

JP-2002-20386-A (Ono) 其中R1表示1)基團-OR6，2)基團-SR7，3) C2-8決基，4)硝基， 5)氰基，6)被羥基或C1-8烷氧基取代之C1-8烷基，7)苯基， 8)基團-C(0)R8，9)基團-S02NR9R10，10)基團 _NRuS02R12，11) 基團-NR13C(0)R14或12)基團-CH=NR15。R6與R7表示i)氫原 子，ii)Cl-8烷基，iii)被C1-8烷氧基取代之C1-8烷基，iv)三鹵 甲基，v) C3-7環烷基，vi)被苯基取代之C1-8烷基或vii) 3-15員 單-、二-或三環狀雜環，含有1-4個氮原子、1-3個氧原子及 /或1-3個硫原子。R2表示1)氫原子或2) C1-8烷氧基。R3表示 1)氫原子或2) C1-8烷基。R4表示1)氫原子，2) C1-8烷基， 3)C3-7環烷基，4)被C3-7環烷基取代之C1-8烷基，5)可被1-3 87841-960303-中.doc •11 - 1283678 個_原子取代之苯基，或6) 3-15員單-、二-或三環狀雜環， 含有Μ個氮原子、1-3個氧原子及/或1-3個硫原子。R5表示 1)氫原子，2)Cl-8烷基，3)C3-7環烷基，4)被C3_7環燒基取代 之C1-8烷基，或5)可被1-3個取代基取代之苯基。在基團R3 中，氫原子為較佳。在基團R4中，甲基、乙基、環丙基、 環丁基或環戊基為較佳。JP-2002-20386-A之化合物係被敛述 為具有PDE4抑制活性，且可用於預防及/或治療炎性疾病 及許多其他疾病。 EP 0 076 035 A1 (ICI美國公司）揭示吡唑并[3,4_b]吡啶衍生物作 為中樞神經系統壓抑劑，可作為鎮定劑或精神安定藥劑， 用於舒解焦慮與緊張狀態。 化合物卡它唑酯（cartazolate)，4-(正·丁基胺基）+乙基·1H_吡 吨并[3,4-b]-外b淀-5-叛酸乙酯，係為已知。j w· Daly等 人，Med· Chem·及饥，1994, 4, 293-306 與 D· Shi 等人，襄# 發廣呀 宏，1997,42, 41-56揭示一系列4-(胺基）取代之1H吡唑并[3,4七]吡 啶-5-羧酸衍生物，包括4-環戊基胺基+甲基_1H_吡唑并[3,4_b] 吡啶-5-羧酸乙酯及其在A〗-與八2 a-腺苷受體處之親和力與拮 抗活性，且後述論文揭示其在GABAa-受體通道之各種結合 位置上之親和力。S· Schenone等人，及⑽叹从汉/. CTzem. jLeii.， 2001，11，2529-2531 與 F.Bondavalli 等人，2002,第 45 卷 (2002年10月22,24日發表，依其所述公告於網站上， 09/24/2002)，第4875-4887頁，揭示一系列4-胺基-1-(2-氯基-2-苯基 乙基）-1Η·吡唑并[3,4-b]吡啶-5-羧酸乙酯類，作為Ai -腺苷受體 配位體。 87841-960303·中.doc •12- 1283678 WO 02/060900 A2呈現出揭示一系列雙環雜環族化合物，作 為用於治療過敏性、炎性或自身免疫病症或疾病之MCP-1拮 抗劑，該化合物具有-C(0)-NR4-C(0>NR5R6取代基，包括異啰 峻并[5,4-b]吡啶類與1H_吡唑并[3,4七]吡啶類（命名為吡唑并[5,4-b]吡啶類），具有-C(0)-NR4-C(0)-NR5 R6基團，作為5-取代基， 且視情況在1-，3-，4-及/或6-位置上經取代。具有_c(0)NH2取 代基代替-C⑼-NR4-C(0)-NR5R6取代基之雙環雜環族化合物， 係被主張揭示於WO 02/060900中，作為-C(0)_NR4 -C(0)-NR5R6取 代化合物之合成上之中間物。 一般期望發現結合至且較佳為抑制磷酸二酯酶類型IV (PDE4)之新穎化合物。 【發明内容】 本發明係提供式（I)化合物或其鹽（特別是其藥學上可接受 之鹽）：JP-2002-20386-A (Ono) wherein R1 represents 1) a group -OR6, 2) a group -SR7,3) a C2-8 group, 4) a nitro group, 5) a cyano group, 6) a hydroxy group or C1-8 alkoxy substituted C1-8 alkyl, 7) phenyl, 8) group -C(0)R8,9) group -S02NR9R10,10) group_NRuS02R12,11) group-NR13C (0) R14 or 12) group -CH=NR15. R6 and R7 represent i) a hydrogen atom, ii) a C8-8 alkyl group, iii) a C1-8 alkyl group substituted by a C1-8 alkoxy group, iv) a trihalomethyl group, v) a C3-7 cycloalkyl group, Vi) C1-8 alkyl substituted by phenyl or vii) 3-15 membered mono-, di- or tricyclic heterocyclic ring containing 1-4 nitrogen atoms, 1-3 oxygen atoms and/or 1- 3 sulfur atoms. R2 represents 1) a hydrogen atom or 2) a C1-8 alkoxy group. R3 represents 1) a hydrogen atom or 2) a C1-8 alkyl group. R4 represents 1) a hydrogen atom, 2) a C1-8 alkyl group, 3) a C3-7 cycloalkyl group, 4) a C1-8 alkyl group substituted by a C3-7 cycloalkyl group, and 5) can be 1-3 87841- 960303-中.doc •11 - 1283678 _Atom substituted phenyl, or 6) 3-15 member mono-, di- or tricyclic heterocyclic ring containing 氮 one nitrogen atom, 1-3 oxygen atoms and / Or 1-3 sulfur atoms. R5 represents 1) a hydrogen atom, 2) a C8-8 alkyl group, 3) a C3-7 cycloalkyl group, 4) a C1-8 alkyl group substituted by a C3_7 cycloalkyl group, or 5) may be substituted by 1 to 3 substituents. Substituted phenyl. In the group R3, a hydrogen atom is preferred. In the group R4, a methyl group, an ethyl group, a cyclopropyl group, a cyclobutyl group or a cyclopentyl group is preferred. The compound of JP-2002-20386-A is converged to have PDE4 inhibitory activity and can be used for the prevention and/or treatment of inflammatory diseases and many other diseases. EP 0 076 035 A1 (ICI USA) discloses that pyrazolo[3,4_b]pyridine derivatives act as central nervous system depressants and act as tranquilizers or neuroleptic agents for relieving anxiety and stress. Compound carbazole (cartazolate), 4-(n-butylamino)+ethyl·1H_pyridox[3,4-b]-external b-yt-5-deoxyethyl ester know. Jw· Daly et al., Med·Chem·and Hunger, 1994, 4, 293-306 and D· Shi et al., 襄# 发广呀宏, 1997, 42, 41-56 Reveal a series of 4-(amino) Substituted 1H pyrazolo[3,4-7]pyridine-5-carboxylic acid derivative, including 4-cyclopentylamino + methyl-1H-pyrazolo[3,4_b]pyridine-5-carboxylic acid B Ester and its affinity and antagonistic activity at the A- and octa-ag-adenosine receptors, and the affinities of the various binding positions of the GABAa-receptor channel are revealed in the following papers. S. Schenone et al., and (10) Sin Han/. CTzem. jLeii., 2001, 11, 2529-2531 and F. Bondavalli et al., 2002, vol. 45 (published on October 22, 2002, according to The publication is published on the website, 09/24/2002), pages 4875-4887, revealing a series of 4-amino-1-(2-chloro-2-phenylethyl)-1Η·pyrazolo[ Ethyl 3,4-b]pyridine-5-carboxylate as an Ai-adenosine receptor ligand. 87841-960303·中.doc • 12-1283678 WO 02/060900 A2 presents the disclosure of a series of bicyclic heterocyclic compounds as MCP-1 antagonists for the treatment of allergic, inflammatory or autoimmune disorders or diseases, The compound has a -C(0)-NR4-C (0>NR5R6 substituent, including isoindole [5,4-b]pyridine and 1H-pyrazolo[3,4-7]pyridine (designated as pyridyl) Zoxao[5,4-b]pyridines, having a -C(0)-NR4-C(0)-NR5 R6 group as a 5-substituent, and optionally 1-, 3-, 4- And/or substituted at the 6-position. A bicyclic heterocyclic compound having a _c(0)NH2 substituent in place of the -C(9)-NR4-C(0)-NR5R6 substituent is disclosed in WO 02/060900 As a synthetic intermediate of -C(0)-NR4 -C(0)-NR5R6 substituted compound. It is generally desired to find a novel compound which binds to, and preferably inhibits, phosphodiesterase type IV (PDE4). The present invention provides a compound of formula (I) or a salt thereof (particularly a pharmaceutically acceptable salt thereof):

R1 為 Ch烷基、Cu 氟烷基、-CH2CH2〇H或烷 基； R2為氫原子（H)、甲基或q氟烷基； R3為視情況經取代之c3_8環烷基或視情況經取代之單不飽 和-C5_7環埽基，或亞式（aa)、（bb)或（ec)之視情況經取代之雜 87841-960303-中.doc -13- 1283678 環族基團；R1 is a Ch alkyl group, a Cu fluoroalkyl group, -CH2CH2〇H or an alkyl group; R2 is a hydrogen atom (H), a methyl group or a q-fluoroalkyl group; R3 is optionally substituted c3_8 cycloalkyl group or, as the case may be Substituted monounsaturated-C5_7 cyclodecyl, or substituted as a subtype (aa), (bb) or (ec), substituted 87841-960303-medium.doc-13- 1283678 cyclodyl group;

㈣ (bb) (cc)(iv) (bb) (cc)

η2 其中nl與η2係獨立為1或2;且其中Y為〇、S、S02或NR10 ; 其中R10為氫原子（η)、q·4烷基（例如甲基或乙基）' Cl-2氟 燒基、ch2c(o)nh2、c(0)Nh2、c(0)_Ci-2烷基、c(〇)_Cl氟烷基 或烷基； 且其中在R3中，（^8環烷基或亞式（aa)、（bb)或（cc)之雜環族 基團’係視情況被一或兩個取代基取代，取代基獨立為（例 如為）酮基（=〇); OH; Ci-2烷氧基；Ci-2氟基烷氧基（例如三 氟甲氧基）；NHR21，其中R21為氫原子(H)或Ci-5直鏈烷基（例 如Η或Ci _4直鏈烷基）；q ·2烷基；C! -2氟烷基（例如Ci氟烷 基’譬如-CH2F 或-CHF2); ·αΐ2ΟΗ; -CH2CH2OH; -CH2NHR22， 其中 R22 為 H 或（V2烷基；-C(0)0R23，其中 R23 為 基；-C(0)NHR24，其中 R24 為 Η 或 Ci-2 烷基；_c(〇)r25，其中 烷基；氟基；羥亞胺基（=N-〇H);或（Ci-4烷氧基）亞 胺基（=N-OR26，其中R26為c卜4烷基）；且其中任何OH、烷氧 基、氟基燒氧基或NHR21取代基不會在連接（結合）至式(I) _ NH-基團之R3環碳處經取代，且不會在結合至雜環族基團 (aa)、（bb)或（cc)之Y基團之任一個R3環碳處經取代； 且其中當R3為視情況經取代之單不飽和_C5-7環烯基時，則 環缔基係視情況被一或兩個為氟基或C1-2燒基之取代基取 87841-960303-中.doc -14 - 1283678 代，其條件是，若有兩個取代基，則其不得皆以燒基 且結合至式①-勝基團之R3環碳不會參與環缔基雙鍵；Η2 wherein nl and η2 are independently 1 or 2; and wherein Y is 〇, S, S02 or NR10; wherein R10 is a hydrogen atom (η), q·4 alkyl (eg methyl or ethyl) 'Cl-2 Fluoroalkyl, ch2c(o)nh2, c(0)Nh2, c(0)_Ci-2 alkyl, c(〇)_Cl fluoroalkyl or alkyl; and wherein in R3, (^8 cycloalkyl Or a heterocyclic group of the formula (aa), (bb) or (cc) is optionally substituted with one or two substituents, the substituent being independently (for example) a keto group (=〇); OH; Ci-2 alkoxy; Ci-2 fluoroalkoxy (e.g., trifluoromethoxy); NHR21, wherein R21 is a hydrogen atom (H) or a Ci-5 linear alkyl group (e.g., hydrazine or Ci _4 linear) Alkyl); q · 2 alkyl; C! -2 fluoroalkyl (e.g., Ci fluoroalkyl ' such as -CH2F or -CHF2); ?αΐ2ΟΗ; -CH2CH2OH; -CH2NHR22, wherein R22 is H or (V2 alkyl ;-C(0)0R23, wherein R23 is a group; -C(0)NHR24, wherein R24 is Η or Ci-2 alkyl; _c(〇)r25, wherein alkyl; fluoro; hydroxyimino (= N-〇H); or (Ci-4 alkoxy)imino (=N-OR26, wherein R26 is c 4 alkyl); and any OH, alkoxy, fluoroalkyloxy or NHR21 Replace The group is not substituted at the R3 ring carbon attached (bonded) to the formula (I) _ NH- group, and is not bonded to the heterocyclic group (aa), (bb) or (cc) Y Wherein any one of the R3 ring carbons of the group is substituted; and wherein when R3 is an optionally substituted monounsaturated _C5-7 cycloalkenyl group, then the ring link is optionally one or two fluoro groups or The substituent of the C1-2 alkyl group is 87841-960303-medium doc -14 - 1283678, provided that if there are two substituents, they are not all calcined and bonded to the formula 1-win group R3 ring carbon does not participate in the ring-bonded double bond;

(dd) 或R3為亞式（dd): 基團：(dd) or R3 is subtype (dd): group:

之雙環狀 其中Y1、Y2及Y3係獨立為Ch2或氧（〇)，其條件是，γΐ、 Υ2及Υ3中不超過一個為氧（0); 且X為NR4R5或〇R5a，其中： 9 R為氫原子（H) , 基；（：卜3氟燒基；燒基，被一 個取代基R11取代；且 R為氫原子（H)，（：卜8燒基；Ch氣:ί完基；视情況被Ci-2燒基 取代之C3·8環烷基；或_(αί2)Λ(：3·8環烷基，視情況在 -(CH2)n4-部份基團或在C3_8環烷基部份基團中，被2烷基 取代，其中η4為1、2或3 ; 或R為C；2 ·6燒基’被一或兩個獨立取代基ri 1取代； | 其中各取代基R11，與任何其他存在之Ri 1取代基無關，係 為：經基(OH); Ch烷氧基；苯氧基；苄氧基；_nr12ri3 ; 视15-c(〇)Rl6 ; -NR15-C(0)_0-R16 ;视15-C(0)-祕R15 ^ SC^R16 ;且其中任何Ri 1取代基，其係為〇H、烷氧基或 -NRl 2r1 3 ’不會在任何R4或R5取代之烷基（其係結合至NR4R5 之氮）之任何碳原子處經取代； 或以為#!^)/1-^；。)!^6;#!!；^12·^。)]^12!^3;-^^19-C(0)NR12R13 ; .(CH2)n12-C(0)0R16 ； -(CH2)n12-C(0)0H ； -CHR19- 87841-960303-中.doc -15- 1283678 c^6；.chr19^ 二，或 _(CH2)nl2-CN;其中n11為0、1、2、3或4，且nl2 曷丄、2、3或4 ; 或 R5為 <CH2)ni3_Het，其中 nl3 5 十 1 2、3 或 4，且 Het 為 4- ，或7-周飽和或部份飽和雜環，含有_或兩個獨立， ^ 之環雜原子；其中存在之任何環雜原子，當 日、’不會結合至-(CH2)n"-部份基圏，而當η13為〇時，不备 2至之氮4中存在且不為不飽和（意即其不^ 雙鍵）之任何環氮，係以存在，其中Rl7係如本文定義； 且其中一或兩個碳環原子係獨立视情況被Ci2烷基取代； 或尺為苯基’視情況被獨立之一、二或三個下列基圈取 代._原子；C!·6烷基（例如Q·4烷基或Cl·2烷基）；Ci2氟烷 基（例如三氟甲基）；Cl·4烷氧基（例如Cl_2烷氧基）；Ci2氟基 燒氧基（例如三氟甲氧基）； C3-6 環烷基氧基；_C(0)Rl6a ; -C(〇)〇r30 ; -S(〇)2_Rl6a(例如 烷基磺醯基或Cl -2烷基_S〇2 ; R1 6 a_s(〇)厂NR! 5 a-(例如q 烷 基-S02-NH-) ; R7R8N-S(〇)2· ; q 烷基 _c(〇>Rl5aN_s(〇)2_ ; 烷基-S(0)-、Ph-S(O)-、R7R8N-CO· ; -NR15-C(0)R16 ; R7R8N ; OH; C卜4烷氧基甲基；Cl-4烷氧基乙基；Cb2 ;1171181^(0)2<：112-;(：卜2烷基-8(0)2-观15&-〇12-;-(：112-(^; -ch2ch2-oh； -ch2-nr7r8 ； -CH2-CH2-NR7R8 ； -CH2-C(0)OR30 ； 其中n14為o或1 ;氰基（CN) ; Ar5a ;或笨基、吡啶基或嘧啶 基，其中苯基、吡啶基或嘧啶基係獨立視情況被一或兩個 87841-960303-中.doc •16- 1283678 氟基、氯基、c^2烷基、Cl氟烷基、Ci 2烷氧基或。氟基烷 氧基取代，或其中兩個相鄰取代基一起採用為办^“％)-^ 或 _0-(CH2 )n 14 -0-，其中 ηι 4 為 1 或 2 ; 其中R7與R8係獨立為氫原子（H); Ci_4烷基（例如Ci2烷基， 譬如甲基）；（：3_6環烷基；或苯基，視情況被一或兩個下列 基團取代·氟基、氯基、q·2烷基、q氟烷基、（^-2烷氧基 或Ci氟基烷氧基；或R7與R8 一起為_(CH2凫叭或·c(〇)_(CH2)n7_ 或-c(o)-(ch2 )n 7 -c(0> 或 _(Ch2 )Λχ7 _(CH2 )Λ 或 ’其中：n6為3、4、5或6, n7為2、3、4或5 (n7較佳為2、 3或4)，η8與η9及ηι〇係獨立為2或3(較佳係獨立為2)，且乂7 為Ο或NR14，其中Ri4為H、Ci_2烷基或c(〇)Me(較佳為η或 Ci - 2挺基）； 或R5具有亞式（X)、（y)、（yl)或⑻：The bicyclic ring wherein Y1, Y2 and Y3 are independently Ch2 or oxygen (〇), provided that no more than one of γΐ, Υ2 and Υ3 is oxygen (0); and X is NR4R5 or 〇R5a, wherein: 9 R is a hydrogen atom (H), a group; (: a trifluoroalkyl group; a pyridyl group, which is substituted by a substituent R11; and R is a hydrogen atom (H), (: a group of 8 groups; a gas of CH: ί a C3·8 cycloalkyl group substituted by a Ci-2 alkyl group; or _(αί2)Λ (:3·8 cycloalkyl group, optionally in the -(CH2)n4- moiety or in the C3_8 ring In the alkyl moiety, substituted by 2 alkyl, wherein η4 is 1, 2 or 3; or R is C; 2·6 alkyl is substituted by one or two independent substituents ri 1 ; The group R11, irrespective of any other Ri 1 substituents present, is: trans group (OH); Ch alkoxy; phenoxy; benzyloxy; _nr12ri3; 15-c(〇)Rl6; -NR15- C(0)_0-R16; 15-C(0)-secret R15^SC^R16; and any of the Ri 1 substituents, which are 〇H, alkoxy or -NRl 2r1 3 'will not be in any Any carbon atom substituted by R4 or R5 substituted alkyl (which is bound to the nitrogen of NR4R5) is substituted; or as #!^)/1-^;.)!^6;#!!;^12 ^.)]^12!^3;-^^19-C(0)NR12R13 ; .(CH2)n12-C(0)0R16 ; -(CH2)n12-C(0)0H ; -CHR19- 87841- 960303-中.doc -15- 1283678 c^6;.chr19^ 2, or _(CH2)nl2-CN; where n11 is 0, 1, 2, 3 or 4, and nl2 曷丄, 2, 3 or 4 Or R5 is <CH2)ni3_Het, where nl3 5 is 1, 2, 3 or 4, and Het is 4-, or a 7-week saturated or partially saturated heterocyclic ring containing _ or two independent, ^ ring An atom; any ring hetero atom present therein, on the same day, 'will not bind to the -(CH2)n"- partial base, and when η13 is 〇, it is not present in the nitrogen 4 and is not unsaturated Any ring nitrogen (meaning that it is not a double bond) is present, wherein Rl7 is as defined herein; and wherein one or two of the carbon ring atoms are independently substituted by Ci2 alkyl as appropriate; or the phenyl is ' Substituting one, two or three of the following base rings as appropriate. Atom; C!.6 alkyl (eg Q.4 alkyl or Cl.2 alkyl); Ci2 fluoroalkyl (eg trifluoromethyl) Cl 4 alkoxy (eg Cl 2 alkoxy); Ci 2 fluoro alkoxy (eg trifluoromethoxy); C 3-6 cycloalkyloxy; _C (0) Rl6a ; -C(〇)〇r30 ; -S(〇)2_Rl6a (eg alkylsulfonyl or Cl -2 alkyl _S〇2; R1 6 a_s(〇) plant NR! 5 a- (eg q alkane --S02-NH-) ; R7R8N-S(〇)2· ; q alkyl-c(〇>Rl5aN_s(〇)2_ ; alkyl-S(0)-, Ph-S(O)-, R7R8N -CO15; -NR15-C(0)R16; R7R8N; OH; C 4 alkoxymethyl; Cl-4 alkoxyethyl; Cb2; 1171181^(0)2<:112-; 2 alkyl-8(0)2-View 15&-〇12-;-(:112-(^;-ch2ch2-oh;-ch2-nr7r8;-CH2-CH2-NR7R8; -CH2-C(0 OR30; wherein n14 is o or 1; cyano (CN); Ar5a; or stupid, pyridyl or pyrimidinyl, wherein phenyl, pyridyl or pyrimidinyl is independently one or two 87481-960303- Medium .doc • 16-1283678 Fluoro, chloro, c^2 alkyl, Cl fluoroalkyl, Ci 2 alkoxy or. Fluoroalkoxy substituted, or wherein two adjacent substituents are taken together as "%"-^ or _0-(CH2)n 14 -0-, wherein ηι 4 is 1 or 2; wherein R7 and R8 Is independently a hydrogen atom (H); a Ci_4 alkyl group (for example, a Ci2 alkyl group such as a methyl group); (: a 3-6 cycloalkyl group; or a phenyl group, optionally substituted by one or two of the following groups: a fluorine group, a chlorine group Base, q.2 alkyl, q fluoroalkyl, (^-2 alkoxy or Ci fluoroalkoxy; or R7 together with R8 is _(CH2凫 or ·c(〇)_(CH2)n7_ Or -c(o)-(ch2)n 7 -c(0> or _(Ch2 )Λχ7 _(CH2 )Λ or 'where: n6 is 3, 4, 5 or 6, and n7 is 2, 3, 4 or 5 (n7 is preferably 2, 3 or 4), η8 and η9 and ηι〇 are independently 2 or 3 (preferably independently 2), and 乂7 is Ο or NR14, wherein Ri4 is H, Ci_2 alkyl Or c(〇)Me (preferably η or Ci-2 quinone); or R5 has the subtype (X), (y), (yl) or (8):

其中在亞式（X)中，n = 〇、liu;在亞式(y)與⑹中，瓜叫或 2;及在亞式（z)中，1^==0、1或2; 其中在亞式（X)與（y)及(yl)中，A、B、D、E及F之中沒有或 一或兩個，係獨立為氮或氮_氧化物"+_〇-)，其條件是A、 B、D、E及F中不超過一個為氮-氧化物；而其餘a、b、 D、E及F係獨立為CH或CR6 ; 其條件是，當在亞式（X)中之η為〇時，則一或兩個A、B、 87841-960303-nfi.doc -17- 1283678Wherein in subtype (X), n = 〇, liu; in subtypes (y) and (6), melon or 2; and in subtype (z), 1^==0, 1 or 2; In the subtypes (X) and (y) and (yl), none or one or two of A, B, D, E and F are independently nitrogen or nitrogen oxides "+_〇-) , the condition is that no more than one of A, B, D, E and F is nitrogen-oxide; and the remaining a, b, D, E and F are independently CH or CR6; the condition is that when in the subtype ( When η in X) is 〇, then one or two A, B, 87841-960303-nfi.doc -17- 1283678

D、E及F係獨立為氮或氮-氧化物^^_〇-)，且a、b、d、E 及F中不超過一個為氮-氧化物； 其中各R6，與存在之任何其他R6無關，係為··鹵原子；Ο — 烷基（例如C! ·4烷基或q j烷基）；q _4氟烷基（例如q _2氟烷 基）；c1M烷氧基（例如Cl·2烷氧基）；Ci 2氟基烷氧基；。^環 烷基氧基；-C(0)R16a ; -C(0)0R3() ; -S(0)2-R16a(例如Cu 烷基 磺醯基，意即（：卜2烷基-S02_); Ri6a_S(0)厂服151(例如〇12烷 基-S02_NH_) ; R7r8n_S(0)2- ; c卜2 烷基-C⑼-R15aN-S(0)2- ; Ch 烷基-S(0)·、Ph-S(o)-、R7R8N-CO- ; -NR15-(:(0)1116 ; r7r8n ; 〇H; Ch燒氧基甲基；烷氧基乙基；〇：卜2烷基_8(〇)2_(：112- ，R7R8N-S(0)2-CH2_ ; Ci.2 燒基-S(0)2-NR15a-CH2- ; -CH2-0H ; -CH2CH2-OH ； -CH2-NR7R8 ； -CH2-CH2-NR7R8 ； -CH2-C(0)0R3 0 ; 其中n14為0或1;氰基（CN) ; Ar5b ;或苯基、吡啶基或嘧啶 基’其中苯基、吡啶基或嘧啶基係獨立視情況被一或兩個 氟基、氯基、烷基、q氟烷基、Q-2烷氧基或〇1氟基烷 氧基取代；或其中兩個相鄰R6 —起採用為_Q_(CMe2 或 (CH2)n14-0-，其中^為“戈二； 其中R7與R8均如本文定義； 其中亞式（y)與（yl)係獨立視情況在相鄰6-員芳族環之環碳處D, E and F are independently nitrogen or nitrogen-oxide ^^_〇-), and no more than one of a, b, d, E and F is a nitrogen-oxide; wherein each R6, and any other present R6 is irrelevant, is a halogen atom; Ο-alkyl group (such as C! · 4 alkyl or qj alkyl); q _4 fluoroalkyl (such as q _2 fluoroalkyl); c1M alkoxy (such as Cl · 2 alkoxy); Ci 2 fluoroalkoxy; ^cycloalkyloxy; -C(0)R16a; -C(0)0R3(); -S(0)2-R16a (eg Cu alkylsulfonyl, meaning (: 2 alkyl-S02_ Ri6a_S(0) Factory service 151 (eg 〇12 alkyl-S02_NH_); R7r8n_S(0)2-; cBu 2 alkyl-C(9)-R15aN-S(0)2-; Ch alkyl-S(0 ··, Ph-S(o)-, R7R8N-CO-; -NR15-(:(0)1116; r7r8n; 〇H; Ch alkoxymethyl; alkoxyethyl; 〇: 卜2 alkyl _8(〇)2_(:112-, R7R8N-S(0)2-CH2_; Ci.2 alkyl-S(0)2-NR15a-CH2-; -CH2-0H; -CH2CH2-OH; -CH2 -NR7R8; -CH2-CH2-NR7R8; -CH2-C(0)0R3 0 ; wherein n14 is 0 or 1; cyano (CN); Ar5b; or phenyl, pyridyl or pyrimidinyl' wherein phenyl, pyridine The yl or pyrimidinyl group is independently substituted with one or two fluoro, chloro, alkyl, q fluoroalkyl, Q-2 alkoxy or fluorenyl 1 fluoroalkoxy groups; or two adjacent R 6 - is adopted as _Q_(CMe2 or (CH2)n14-0-, where ^ is "Ge 2; where R7 and R8 are as defined herein; wherein sub- (y) and (yl) are independent depending on the situation 6-member aromatic ring ring carbon

被酮基（=0)取代（例如亞式（y)，可視情況為 87841-960303-中.doc -18- 1283678Substituted by a keto group (=0) (for example, subtype (y), as the case may be 87841-960303-medium.doc -18- 1283678

ϋ ，或亞式（yl)可視情況為Jj 或/ 〆）· 其中在亞式⑻中，G為0或S或NR9，其中R9為氫原子（H)、 Ci- 4燒基或Q- 4氟燒♦基；J、L、Μ及Q之中沒有或一、一或 三個為氮；而其餘J、L、Μ及Q係獨立為CH或CR6，其中 R6，與存在之任何其他R6無關，係如本文定義； 或 R4 與 R5 —起採用為-(CHJp1-或-C(0)-(CH2)p2_ 或 _(CH2)p3_x5-(CH2)p[或-C(〇)-x5-(CH2)p5_，其中：pl = 3、4、5或6(較佳 P = 4或5)，p2為2、3、4或5(p2車交佳為2、3或4)，且p3與及 P5係獨立為2或3(較佳係獨立為2)，且X5為〇或NR17 ; 且其中，當R4與R5—起採用為-(CHJp1·或_C(〇HCH2)/_時， NR4R5雜環係視情況被一個R18取代基取代，其中1^8為：Ci4 鍵•基（例如Cl - 2燒基）；Cl - 2氣健基，C3 - 6壤燒基；Cl 2垸》氧基 (未在結合至nr4r5環氮之環碳處經取代）；q氟基烷氧基（未 在結合至NR4R5環氮之環碳處經取代）；0H(未在結合至 NR4R5環氮之環碳處經取代）；-(CH2)p7-C(0)R16，其中P7為〇、 1、2 或 3(p7 較佳為 0 或 1) ; -((：Η2)ρ7<(0)0ί116 ; -(CH2)p7-0C(0)R16 ； -(CH2)p7-C(0)NR12R13 ； -(CH2 )p 7-NR15 C^R16 ; -(CH2)p7-NR15C(0)NR12R13 ； -(CH2 )p 7-NR15 CCOPR16 ； -(CH2)p7-S02R16 ； -(CH2)p7-S02NR12R13 ； -(CH2)p7-NR15S02R16 ； -(CH2)p7-OH ; -(CHd^-OR16 ;或苯基，視情況被一或兩個下列基團取 代：自原子、（^-2烷基、q氟烷基、Ck烷氧基或(^氟基烷 氧基； 87841-960303-中.doc -19- 1283678 或R4與R5 —起採用為如本文中定義之或_c(〇)_ (CH2)p2-或-(CH2)p3_x5_(CH2)p4_ 或七(〇)·χ5_(α^ρ5_，且其中 NR4R5雜環係稠合至苯環，視情況在苯基上被一或兩個下列 基團取代：_原子、Cm烷基、Cl氟烷基、Ci 2烷氧基或^ 氟基烷氧基；且 烷基，Cu 氟烷基；（]3_8環烷基；_(CH2)n4a-C3-6 環 烷基，其中n a為1或2 ;苯基，視情況被一或兩個下列基團 取代：卣原子、（:卜2烷基、三氟甲基、Ci 2烷氧基或三氟甲 氧基；或R5a具有如本文中定義之亞式⑻、⑼或⑻ 且其中： R12與R13係獨立為Η; (ν5烷基（例如Cl-3烷基）；c36環烷 基；或苯基，視情況被一或兩個下列基團取代：卣原子、 q·2燒基、（^氟烷基、烷氧基或心氟基烷氧基； 或 R12 與 R13 — 起為 _(CH2)n6-或·〇：(〇)-(αί2)η7-或-C(0)_(CH2)n7- <^(〇)-或-(012)1180^2-((：112)119-或-(：(0)-又12-((：112)1110-，其中：116 為3、4、5或6(116較佳為4或5)，117為2、3、4或5(117較佳為 2、3或4)，η8與η9及ηι〇係獨立為2或3(較佳係獨立為2)，且 X12為0或NR14a，其中Ri4a為H、Ci 2烷基或c(〇)Me(較佳為 Η或（^-2燒基）； R為風原子（Η)，C〗_4燒基（例如tBu或Q ·2燒基，例如甲 基）；A —環烷基；或苯基，視情況被一或兩個下列基團取 代：自原子、Q-2烷基、心氟烷基、烷氧基或心氟基烷 氧基； R15a，與其他R15a無關，係為氫原子（H)或（V4烷基（例如η、 87841·96〇3〇3-中 doc -20- 1283678ϋ , or subtype (yl) may be Jj or / 〆)) wherein in sub-formula (8), G is 0 or S or NR9, wherein R9 is a hydrogen atom (H), a Ci-4 group or a Q-4 Fluorine-based; none, one, one or three of J, L, hydrazine and Q are nitrogen; and the remaining J, L, Μ and Q are independently CH or CR6, of which R6, and any other R6 present Irrelevant, as defined herein; or R4 and R5 are taken as -(CHJp1- or -C(0)-(CH2)p2_ or _(CH2)p3_x5-(CH2)p[or-C(〇)-x5 -(CH2)p5_, where: pl = 3, 4, 5 or 6 (preferably P = 4 or 5), p2 is 2, 3, 4 or 5 (p2 is preferably 2, 3 or 4), and The p3 and P5 lines are independently 2 or 3 (preferably independently 2), and X5 is 〇 or NR17; and wherein R4 and R5 are taken as -(CHJp1· or _C(〇HCH2)/_ When the NR4R5 heterocyclic ring is optionally substituted by an R18 substituent, wherein 1^8 is: Ci4 bond group (for example, Cl-2 base group); Cl-2 gas group, C3-6 soil base; Cl 2垸"oxy (not substituted at the ring carbon bonded to the nr4r5 ring nitrogen); q fluoroalkoxy (not substituted at the ring carbon bonded to the NR4R5 ring nitrogen); 0H (not bound to the NR4R5 ring) Nitrogen ring carbon Substituted); -(CH2)p7-C(0)R16, wherein P7 is 〇, 1, 2 or 3 (p7 is preferably 0 or 1); -((:Η2)ρ7<(0)0ί116 ; (CH2)p7-0C(0)R16; -(CH2)p7-C(0)NR12R13; -(CH2)p 7-NR15 C^R16 ; -(CH2)p7-NR15C(0)NR12R13 ; -(CH2 p 7-NR15 CCOPR16; -(CH2)p7-S02R16; -(CH2)p7-S02NR12R13; -(CH2)p7-NR15S02R16; -(CH2)p7-OH; -(CHd^-OR16; or phenyl, Substituted by one or two of the following groups: from an atom, (^-2 alkyl, q-fluoroalkyl, Ck alkoxy or (^fluoroalkoxy; 87841-960303-.doc -19- 1283678 or R4 and R5 are employed as defined herein or _c(〇)_(CH2)p2- or -(CH2)p3_x5_(CH2)p4_ or seven (〇)·χ5_(α^ρ5_, and wherein The NR4R5 heterocyclic ring is fused to a phenyl ring, optionally substituted on the phenyl group with one or two of the following groups: _ atom, Cm alkyl, Cl fluoroalkyl, Ci 2 alkoxy or fluoroalkoxy And alkyl, Cu fluoroalkyl; () 3-8 cycloalkyl; _(CH2)n4a-C3-6 cycloalkyl, wherein na is 1 or 2; phenyl, optionally with one or two of the following groups Substitution: Helium atom, (: 2 alkyl, trifluoromethyl, Ci 2 alkane Or a trifluoromethoxy group; or R5a has the formula (8), (9) or (8) as defined herein and wherein: R12 and R13 are independently oxime; (ν5 alkyl (eg Cl-3 alkyl); c36 naphthenic Or a phenyl group, optionally substituted with one or two of the following groups: a halogen atom, a q2 alkyl group, a (fluoroalkyl group, an alkoxy group or a cardinylfluoroalkoxy group; or R12 and R13 Is _(CH2)n6- or ·〇:(〇)-(αί2)η7- or -C(0)_(CH2)n7- <^(〇)- or -(012)1180^2-(( : 112) 119- or -(:(0)- and 12-((:112)1110-, where: 116 is 3, 4, 5 or 6 (116 is preferably 4 or 5), and 117 is 2, 3 4 or 5 (117 is preferably 2, 3 or 4), η8 and η9 and ηι〇 are independently 2 or 3 (preferably independently 2), and X12 is 0 or NR14a, wherein Ri4a is H, Ci 2 alkyl or c(〇)Me (preferably Η or (^-2 alkyl); R is a wind atom (Η), C _4 alkyl (such as tBu or Q · 2 alkyl, such as methyl) A-cycloalkyl; or phenyl, optionally substituted with one or two of the following groups: from atom, Q-2 alkyl, heart fluoroalkyl, alkoxy or heart fluoroalkoxy; R15a, Irrespective of other R15a, it is a hydrogen atom (H) or (V) 4 alkyl (eg η, 87841·96〇3〇3-中 doc -20- 1283678

Wu或Cu烷基，譬如甲基；R15a較佳為Η或Cu烷基，更佳 為H);Wu or Cu alkyl, such as methyl; R15a is preferably hydrazine or Cu alkyl, more preferably H);

Rl6與R1U係獨立為：Rl6 and R1U are independent:

Cb6烷基（例如（：卜4烷基或(^·2烷基）； C3·6環烷基（例如C5-6環烷基），視情況被一個酮基（=〇)、 0H或Q ·2烷基取代基取代（例如視情況在c5 -6環烷基環之3-或4_位置上經取代；及/或較佳為未經取代之c3_6環烷基）； C3 - 6環烷基-CH2 -(例如C5 _ 6環烷基-CH2 ; 吡啶基（例如吡啶-2-基），視情況在環碳原子上被以下之一 取代：_原子、烷基、心氟烷基、Cl-2烷氧基或心氟基 烷氧基；Cb6 alkyl (eg (: 4 alkyl or (^. 2 alkyl); C 3 · 6 cycloalkyl (eg C5-6 cycloalkyl), optionally a keto group (=〇), 0H or Q a 2 alkyl substituent (for example, substituted at the 3- or 4-position of the c5 -6 cycloalkyl ring; and/or preferably unsubstituted c3-6 cycloalkyl); C3-6 ring Alkyl-CH2- (for example C5-6 cycloalkyl-CH2; pyridinyl (for example pyridin-2-yl), optionally substituted on one of the ring carbon atoms by one of the following: _ atom, alkyl, heart fluoroalkyl , Cl-2 alkoxy or heart fluoride alkoxy;

Ar5c ； 苯基，視情況被一或兩個下列基團取代：_原子、Ci 2燒 基、（^氟烷基、烷氧基或心氟基烷氧基； 苄基’視情況在芳族碳原子處被一或兩個下列基團取代： 鹵原子、Ci·2烷基、Ci氟烷基、Ci·2烷氧基或q氟基烷氧 基；或 4·，5-，6-或7-員飽和雜環，在環·碳處經連接，且含有一或兩 個獨立選自0、S及N之環雜原子；其中存在之任何環·氮係 以NR27存在，其中R27為η、Cl·2烷基或-C(〇)Me;且其中該環 係視情況在碳處被一個^·2烷基或酮基（=〇)取代基取代，其 條件是’任何酮基（=〇)取代基係在結合至環-氮之環_碳原子 處經取代； 其中AP、Ar5b及Ar5c係獨立為5_員芳族雜環，含有一個〇、 87841_96〇3〇3_中 d〇c 21 - 1283678 S或NR15&在5-員環中，其中5-員環可視情況另外含有一或兩 個N原子，且其中雜環係視情況在環碳原子上被下列之一取 代：鹵原子、Cu烷基、（^氟烷基、-CH2OH、-CHrOC^烷 基、OH(包括其酮基互變異構物）或-CH2-NR28R29，其中R28 與R29係獨立為Η或甲基； 且R17為氫原子（H); CV4烷基（例如（：卜2烷基）；CV2氟烷 基；〇3_6環烷基；-(CH2)p6-C(0)R16，其中 p6為 〇、1、2 或 3(p6 較佳為0); -(CH2)P6-C(0)NR12R13 ； -(CH2)p6-C(0)0R16 ； -(CH2)p6-C(0)0H ； -S02 R16 ; -C(0)_CH2 -NR12 R13 ； -C(0)-CH2 -NR15 a - 3 烷 基；-CXCO-CIVO-Cu烷基；或苯基或爷基，其中苯基或苄基 係視情況在芳族碳原子處被一或兩個下列基團取代：鹵原 子、烷基、（^氟烷基、Ci-2烷氧基或(^氟基烷氧基； R1 9 為 Ci -4 燒基；-(CH2 )n2 0 -OR2 〇，其中 η20為 1、2、3或4，且 R2G 為氫原子（Η)或 Ch烷基；-CH(Me)-OH ; -CH2-SH ; _CH2-CH2-S-Me ;苄基；或（4-羥苯基）甲基（意即4·羥基·爷基）；且 R3 〇 ’與其他R3 G無關，係為氫原子（H)、Ci -4烷基或c3 _6環烷 基；且Ar5c ; phenyl, optionally substituted by one or two of the following groups: _ atom, Ci 2 alkyl, (^ fluoroalkyl, alkoxy or heart fluoroalkoxy; benzyl 'in the case of aromatic The carbon atom is substituted by one or two of the following groups: a halogen atom, a Ci 2 alkyl group, a Ci fluoroalkyl group, a Ci 2 alkoxy group or a q fluoro alkoxy group; or 4·, 5-, 6- Or a 7-membered saturated heterocyclic ring, which is attached at the ring carbon and contains one or two ring heteroatoms independently selected from 0, S and N; any ring nitrogen present therein is present as NR27, wherein R27 is η, Cl·2 alkyl or -C(〇)Me; and wherein the ring is optionally substituted at the carbon with a ^2 alkyl or keto (=〇) substituent, provided that the 'any keto group The (=〇) substituent is substituted at the ring-nitrogen ring-bonded to the carbon atom; wherein AP, Ar5b and Ar5c are independently 5_membered aromatic heterocycles, containing one 〇, 87841_96〇3〇3_ D〇c 21 - 1283678 S or NR15&in a 5-membered ring wherein the 5-membered ring may additionally contain one or two N atoms, and wherein the heterocyclic ring is optionally substituted on the ring carbon atom by one of the following : halogen atom, Cu alkyl group, (^ Fluoroalkyl, -CH2OH, -CHrOC^alkyl, OH (including keto tautomers thereof) or -CH2-NR28R29, wherein R28 and R29 are independently oxime or methyl; and R17 is a hydrogen atom (H) CV4 alkyl (eg (: 2 alkyl); CV2 fluoroalkyl; 〇3_6 cycloalkyl; -(CH2)p6-C(0)R16, wherein p6 is 〇, 1, 2 or 3 (p6 Preferably, it is 0); -(CH2)P6-C(0)NR12R13; -(CH2)p6-C(0)0R16; -(CH2)p6-C(0)0H; -S02 R16 ; -C(0) _CH2 -NR12 R13 ; -C(0)-CH2 -NR15 a - 3 alkyl; -CXCO-CIVO-Cu alkyl; or phenyl or aryl, wherein phenyl or benzyl is optionally in the aromatic carbon atom Substituted by one or two of the following groups: a halogen atom, an alkyl group, (^fluoroalkyl, Ci-2 alkoxy or (^fluoroalkoxy; R1 9 is a Ci -4 alkyl; -(CH2) N2 0 -OR2 〇, wherein η20 is 1, 2, 3 or 4, and R2G is a hydrogen atom (Η) or a Ch alkyl group; -CH(Me)-OH; -CH2-SH; _CH2-CH2-S- Me ; benzyl; or (4-hydroxyphenyl)methyl (ie, 4 hydroxy hydroxy); and R 3 〇 ' is independent of other R 3 G, is a hydrogen atom (H), Ci -4 alkyl or C3 _6 cycloalkyl;

Het1 ’與其他Het1無關，係為4-，5-，6-或7-員飽和雜環，在環· 碳處經連接，且含有一或兩個獨立選自〇、s及N之環雜原 子；其中存在之任何環-氮係以存在，其中RS1為Η、Ci 2 烷基或-C(0)Me ;且其中該環係視情況在碳處被一個Ci 2烷基 或酮基（=0)取代基取代，其條件是，任何酮基（=〇)取代基係 在結合至環-氮之環-碳原子處經取代； 87841_96〇3〇3_ 中.doc -22- 1283678 其條件是： 當R3為亞式（bb)雜環族基團，η1為1，且Y為NR1 G時，則： 無論是⑷R1 G不為q -4烷基、q -2氟烷基或CH2C(0)NH2 ;或 (b) R1 Q為甲基，且化合物為：4-[(1-甲基六氫吡啶冬基）胺基]-1-乙基·1Η-吡唑并p，4-b]吡啶-5-羧酸乙酯、1-乙基-N-(2-乙基丁基）_ 4_[(1_甲基六氫吡啶-4-基）胺基]·1Η_吡唑并[3,4_b]吡淀·5_甲醯 胺、1-乙基-Ν-(4_氟苯基）-4-[(1-甲基六氫ρ比淀-4-基）胺基]-lH-p比 唑并[3,4七]吡啶-5-甲醯胺或Ν-苄基小乙基-4-[〇甲基六氫吡啶-4-基）胺基]-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺。 在X為OR5a之情況下，化合物較佳係不為其中Ri為曱基，X 為OEt，且R3為環戊基之化合物。 在本發明之一項選用具體實施例中，Ri為Cl_4烷基或Cl-2 氟烷基。 替代或另外地，在本發明之一項選用具體實施例中，R2為 氫原子（H)。 替代或另外地，在本發明之一項選用具體實施例中，R3為 C3-8環烷基或為Het1 'is not related to other Het1, is a 4-, 5-, 6- or 7-membered saturated heterocyclic ring, is attached at the ring carbon, and contains one or two ring heterocycles independently selected from 〇, s and N. An atom; wherein any ring-nitrogen system is present, wherein RS1 is deuterium, Ci 2 alkyl or -C(O)Me; and wherein the ring is optionally a Ci 2 alkyl or keto group at the carbon ( =0) Substituent substitution, provided that any keto (=〇) substituent is substituted at the ring-carbon atom bonded to the ring-nitrogen; 87841_96〇3〇3_.doc -22- 1283678 Yes: When R3 is a subgroup of the (bb) heterocyclic group, η1 is 1, and Y is NR1 G, then: (4) R1 G is not q-4 alkyl, q-2 fluoroalkyl or CH2C ( 0) NH2; or (b) R1 Q is methyl, and the compound is: 4-[(1-methylhexahydropyridyl)amino]-1-ethyl·1Η-pyrazole p,4- b] pyridine-5-carboxylate ethyl ester, 1-ethyl-N-(2-ethylbutyl)-4-[(1-methylhexahydropyridin-4-yl)amino]]1Η_pyrazole And [3,4_b]pyridine·5-formamide, 1-ethyl-indole-(4-fluorophenyl)-4-[(1-methylhexahydrop-butylide-4-yl)amino group ]-lH-p-pyrazolo[3,4-pyridinium-5-carboxamide or Ν-benzyl Small ethyl-4-[indolylmethylhexahydropyridin-4-yl)amino]-1Η-pyrazolo[3,4-b]pyridine-5-carboxamide. In the case where X is OR5a, the compound is preferably not a compound wherein Ri is a fluorenyl group, X is OEt, and R3 is a cyclopentyl group. In an alternative embodiment of the invention, Ri is a Cl 4 alkyl group or a Cl-2 fluoroalkyl group. Alternatively or additionally, in an alternative embodiment of the invention, R2 is a hydrogen atom (H). Alternatively or additionally, in an alternative embodiment of the invention, R3 is C3-8 cycloalkyl or

广Y 或雜環族基團，其中Y為 〇、S、S〇2或NR10 ;其中R10為氫、Ch烷基、Ci-2氟烷基、 αοΚκ烷基或 c(o)-cf3 ; 且其中在R3中’ C3 - 8壤燒基或雜環族基團係視情況被一或雨 個OH、q ·2烷氧基、三甲氧基或C! -2烷基之取代基取代；JL 其中任何ΟΗ、烷氧基或三甲氧基取代基不會在連接（結合） 至式（I) -ΝΗ-基團之（R3)環碳處經取代，且不會在結合至雜環 87841_96〇3〇3-中.doc -23- 1283678 族基團之γ基團之任—個(r3)環碳處經取代。 曰代或另外地，在本發明之一項選用具體實施例中，圮為 氫、烷基或(：1-2氟燒基。 替代或另外地，在本發明之一項選用具體實施例中，於為 ^ 1-8烷基Cl_8氟烷基或C3·8環烷基；或苯基，视情況 被一或兩個下列基團取代：齒原子、CW充基、三氟甲基〆、 Cl 氧基或二氟甲氧基；或R5具有亞式⑻、⑼或㈦： _(CH2)na broad Y or heterocyclic group wherein Y is 〇, S, S〇2 or NR10; wherein R10 is hydrogen, Ch alkyl, Ci-2 fluoroalkyl, αοΚκ alkyl or c(o)-cf3; Wherein the 'C3-8' or the heterocyclic group in R3 is optionally substituted by a substituent of OH, q.2 alkoxy, trimethoxy or C!-2 alkyl; Wherein any of the hydrazine, alkoxy or trimethoxy substituents are not substituted at the (R3) ring carbon attached (bonded) to the formula (I)-ΝΗ- group, and are not bonded to the heterocycle 87841_96〇 Any of the (r3) ring carbons of the γ group of the 3〇3-中.doc -23- 1283678 group is substituted. Deuterated or otherwise, in an alternative embodiment of the invention, hydrazine is hydrogen, alkyl or (: 1-2 fluoroalkyl). Alternatively or additionally, in an embodiment of the invention selected Is a ^ 1-8 alkyl Cl_8 fluoroalkyl or C 3 · 8 cycloalkyl; or a phenyl group, optionally substituted with one or two of the following groups: a tooth atom, a CW group, a trifluoromethyl hydrazine, Cl oxy or difluoromethoxy; or R 5 has the subtype (8), (9) or (7): _(CH2)n

(X)(X)

-(CH2-(CH2

(z) 其中在亞式（X)中，n=l或2;在亞式（y)中，m叫或2;及在 亞式（z)中，r = 1或2 ; 其中在亞式（X)與（y)中，A、b、D、E及F之中没有或一或 兩個為氮；而其餘A、B、D、E及F為CH或CR6,其中於為 鹵原子、燒基、Cl_4說燒基、Ci2燒氧基、Ci2氣基燒氧 基、Ch燒基磺醯基（Ci·2燒基妈-)、Ci 2燒基、 C1_4烷氧基甲基或(z) where in the subtype (X), n = 1 or 2; in the subtype (y), m is called 2 or 2; and in the subformula (z), r = 1 or 2; In (X) and (y), none or one or two of A, b, D, E and F are nitrogen; and the remaining A, B, D, E and F are CH or CR6, wherein in the halogen atom , calcination base, Cl_4, calcination group, Ci2 alkoxy group, Ci2 gas-based alkoxy group, Ch-alkylsulfonyl group (Ci·2 calcination mother-), Ci 2 alkyl group, C1_4 alkoxymethyl group or

R7R8N-S02_、R7R8N-CO·、R7R8n、OH q·2烷基_S(VCH2·，其中R7與R8係獨立為氫或Ci 2烷基； 其中在亞式（z)中，G為o或S或NR9，其中R9*Ci_4烷基或 Ch氟燒S ; J、L、M及Q之中沒有或一或兩個為氮，·而其 餘J、L、Μ及Q為CH或CR6，其中R6係如本文定義。 在上文R4及/或R5選用具體實施例之替代方式中，於本發 明之一項選用具體實施例中，圮與圮一起採用可為_(cH2) ，其中P1 = 3、4或5(較佳為p1==4或5)。 87841-960303-中.doc -24- 1283678 在本發明之一項選用具體實施例中，R3為視情況經取代之 C3·8環燒基或亞式（aa)、（bb)或（cc)之視情況經取代之雜環族 基團；R7R8N-S02_, R7R8N-CO·, R7R8n, OH q·2 alkyl_S(VCH2·, wherein R7 and R8 are independently hydrogen or Ci 2 alkyl; wherein in subformula (z), G is o or S or NR9, wherein R9*Ci_4 alkyl or Ch fluorocarbon S; none or one or two of J, L, M and Q are nitrogen, and the remaining J, L, Μ and Q are CH or CR6, wherein R6 is as defined herein. In the alternatives to the specific embodiments of R4 and/or R5 above, in an alternative embodiment of the invention, 圮 and 圮 may be used together as _(cH2), where P1 = 3, 4 or 5 (preferably p1 == 4 or 5) 87841-960303-中.doc -24- 1283678 In an alternative embodiment of the invention, R3 is optionally replaced by C3·8 a heterocyclic group substituted with a cycloalkyl group or an Asian formula (aa), (bb) or (cc);

其中η1與n2係獨立為1或2 ;且其中γ為〇、s、8〇2或>丨1110 ; 其中R10為氫原子（H)、Q -4烷基（例如甲基或乙基）、q -2氟 _ 燒基、ch2c(o)nh2、C(0)NH2、C(〇KV2烷基或 ¢:(0)-(^ 氟烷基； 且其中在R3中’ C3 - 8環燒基或亞式（aa)、（bb)或（cc)之雜環 族基團’係視情況被一或兩個酮基（=〇)、〇H、Ci 2烷氧基、 ci_2氟基烷氧基（例如三氟甲氧基）或Cl-2烷基之取代基取 代；且其中任何0H、烷氧基或氟基烷氧基取代基不會在連 接（結合）至式（I) -NH-基團之R3環碳處經取代，且不會在結合 至雜環族基图（aa)、（bb)或（cc)之Y基團之任一個R3環碳處經 取代。 馨 替代或另外地對上文選用之R3定義而言，在本發明之一項 選用具體實施例中，X為NR4R5或0R5a，其中： R4為氫原子（H); Cle6烷基；Cu氟烷基；或C2-6烷基，被一 個取代基R11取代；且 R5為氫原子（H); 烷基；氟烷基；视情況被Cl-2烷基 取代之C3·8環烷基；或_(CH2)n4-C3·8環烷基，視情況在-(CH2)n4 -邵份基團或在c3 _8環燒基部份基團中，被q _2燒基取 87841_96〇3〇3_ 中.doc -25- 1283678 代，其中η4為1、2或3 ; 或R5為C2-6烷基，被一或兩個獨立取代基Rii取代； 其中各取代基R11，與任何其他存在之Rii取代基無關，係 為：羥基（OH) ; CV6烷氧基；苯基氧基；苄氧基； -NR12R13 ; -NR15-C(0)R16 ； -NR15-C(0)-0-R16 ； -NR15-C(0)-NH-R15 ;或-NR15-S〇2R16 ;且其中任何R11取代基，其係為0H、 烷氧基或-NR12R13，不會在任何R4或R5取代之烷基（其係結 合至NR4 R5之氮）之任何碳原子處經取代； 或 R5 為-(CH2)n"-C(0)R16 ; -(CH2)n12-C(0)NR12R" ; -CHR19. C(0)NR12 R13 ； -(CH2 )n 12 -C^OR16 ; -CHR19 -^(Ο)ΟΚ1 6 ； -(CH2 )n 12 S〇2-NR12R13 ; -(CHdnU-SC^RM ;或 _(CH2)ni2-CN;其中 nll 為 〇、1、2、3或4，且n12為 1、2、3或4; 或R5為-(CH2)ni3_Het ’其中nu為〇、1、2、3或4，且此為斗 5-，6-或7-員飽和或部份飽和雜環，含有一或兩個獨立選自 〇、S及Ν之環雜原子；其中存在之任何環雜原子，當y3為 1時，不會結合至仰2)/3^份基團，而當nU為〇時，不會 結合至NR4R5之氮；其中存在且不為不飽和（意即其不參^ 雙鍵）之任何環氮，係以NR17存在，其中Rw係如本文定義； 且其中一或兩個碳環原子係獨立視情況被C12烷基取代； 或R5為苯基，視情況被一或兩個下列基團取代：鹵原子； C1M烷基（例如烷基）；Cl·2氟烷基（例如三氟甲基广c 燒氧基（例如Cl-2燒氧基）；Cl_2氟基燒氧基（例如^甲^ 基）；CW完基續酿基（Cl_2燒基.s〇2_); Ci 2^_sn R7R«N-S02- ； R7R3N-CO-； -NR15-C(0)R16 ； r7rsn; 〇h； Ci 87841-960303-中.doc -26 - 1283678 氧基甲基；A·4烷氧基乙基；Cl-2烷基_s〇2_CH2_;氰基（CN); 或苯基，视情況被一或兩個氟基、氯基、Cij烷基、Ci氟烷 基、Q-2烷氧基或^氟基烷氧基取代； 其中R7與R8係獨立為氫原子（H); Cl_4烷基（例如Cl-2烷基， 譬如甲基）；C3_6環烷基；或苯基，視情況被一或兩個下列 基團取代：氟基、氯基、Cl_2烷基、（^氟烷基、Ci-2烷氧基 或Q氟基燒氧基；或R7與R8 一起為_(CH2)n6-或_c(〇)_(CH2)n7· 或-C(0)-(CH2 )n 7 -c(0)·或-(CH2 )n 8 -X7 -(CH2 )n 9 -或-c(0)-x7 -(叫 ^ ，其中：n6為3、4、5或6，n7為2、3、4或5(n7較佳為2、3 或4)，η8與η9及ηι〇係獨立為2或3，且χ7為〇或，其中 R14為Η或C!-2烷基； 或R5具有亞式⑻、（y)或（z):Wherein η1 and n2 are independently 1 or 2; and wherein γ is 〇, s, 8〇2 or >丨1110; wherein R10 is a hydrogen atom (H), a Q-4 alkyl group (e.g., methyl or ethyl) , q -2 fluoro-alkyl, ch2c(o)nh2, C(0)NH2, C(〇KV2 alkyl or ¢:(0)-(^ fluoroalkyl; and wherein 'C3-8 ring in R3 A halogenated group or a heterocyclic group of the formula (aa), (bb) or (cc) is optionally treated with one or two keto groups (=〇), 〇H, Ci 2 alkoxy, ci 2 fluoro group Substituted with alkoxy (eg, trifluoromethoxy) or Cl-2 alkyl; and wherein any 0H, alkoxy or fluoroalkoxy substituent is not attached (bonded) to formula (I) The R3 ring carbon of the -NH- group is substituted and is not substituted at any R3 ring carbon bonded to the Y group of the heterocyclic group diagram (aa), (bb) or (cc). Alternatively or additionally to the definition of R3 selected above, in an alternative embodiment of the invention, X is NR4R5 or 0R5a, wherein: R4 is a hydrogen atom (H); Cle6 alkyl; Cu fluoroalkyl Or a C2-6 alkyl group, substituted by a substituent R11; and R5 is a hydrogen atom (H); an alkyl group; a fluoroalkyl group; a l-2 alkyl-substituted C3.8 cycloalkyl group; or a _(CH2)n4-C3.8 cycloalkyl group, optionally in the -(CH2)n4-shornyl group or in the c3-8 ring group In the group, by the q 2 _2 alkyl group 87841_96 〇 3 〇 3 _ .doc -25 - 1283678 generation, wherein η4 is 1, 2 or 3; or R5 is C2-6 alkyl, by one or two independent substituents Rii substituted; wherein each substituent R11, irrespective of any other Rii substituent present, is: hydroxy (OH); CV6 alkoxy; phenyloxy; benzyloxy; -NR12R13; -NR15-C(0 R16; -NR15-C(0)-0-R16; -NR15-C(0)-NH-R15; or -NR15-S〇2R16; and any R11 substituent thereof, which is 0H, alkoxy Or -NR12R13, which is not substituted at any carbon atom of any R4 or R5 substituted alkyl group which is bonded to the nitrogen of NR4 R5; or R5 is -(CH2)n"-C(0)R16;(CH2)n12-C(0)NR12R"; -CHR19. C(0)NR12 R13 ; -(CH2 )n 12 -C^OR16 ; -CHR19 -^(Ο)ΟΚ1 6 ; -(CH2 )n 12 S 〇2-NR12R13 ; -(CHdnU-SC^RM ; or _(CH2)ni2-CN; where nll is 〇, 1, 2, 3 or 4, and n12 is 1, 2, 3 or 4; or R5 is - (CH2)ni3_Het 'where nu is 〇, 1, 2, 3 or 4, And this is a 5-, 6- or 7-membered saturated or partially saturated heterocyclic ring containing one or two ring heteroatoms independently selected from the group consisting of ruthenium, S and iridium; any ring hetero atom present therein, when y3 is At 1 o'clock, it does not bind to the 2)/3^ group, and when nU is 〇, it does not bind to the nitrogen of NR4R5; where it is present and not unsaturated (meaning it does not participate in the double bond) Any ring nitrogen is present as NR17 wherein Rw is as defined herein; and wherein one or two carbon ring atoms are independently substituted by C12 alkyl as appropriate; or R5 is phenyl, optionally one or two of the following groups Group substitution: a halogen atom; a C1M alkyl group (e.g., an alkyl group); a Cl. 2 fluoroalkyl group (e.g., a trifluoromethyl group c alkoxy group (e.g., Cl-2 alkoxy group); a C 2 fluoro group alkoxy group (e.g. ^甲^基); CW complete base (Cl_2 base.s〇2_); Ci 2^_sn R7R«N-S02- ; R7R3N-CO-; -NR15-C(0)R16 ; r7rsn; h; Ci 87841-960303-中.doc -26 - 1283678 oxymethyl; A·4 alkoxyethyl; Cl-2 alkyl _s〇2_CH2_; cyano (CN); or phenyl, as appropriate By one or two fluoro, chloro, Cij alkyl, Ci fluoroalkyl, Q-2 alkoxy or ^ Alkenyloxy substituted; wherein R7 and R8 are independently a hydrogen atom (H); Cl_4 alkyl (eg, Cl-2 alkyl, such as methyl); C3_6 cycloalkyl; or phenyl, optionally one or two Substituted by the following groups: fluoro, chloro, Cl 2 alkyl, (fluoroalkyl, Ci-2 alkoxy or Q fluoroalkyloxy; or R7 together with R8 is _(CH2)n6- or _ c(〇)_(CH2)n7· or -C(0)-(CH2)n 7 -c(0)· or -(CH2 )n 8 -X7 -(CH2 )n 9 -or-c(0) -x7 - (called ^, where: n6 is 3, 4, 5 or 6, n7 is 2, 3, 4 or 5 (n7 is preferably 2, 3 or 4), η8 and η9 and ηι〇 are independent 2 Or 3, and χ7 is 〇 or wherein R14 is Η or C!-2 alkyl; or R5 has the formula (8), (y) or (z):

及在 其中在亞式⑻中’ n=M2;在亞式（y)中，m=1或2; 亞式（z)中，r = 〇、i或2; 其中在亞式（X)與（y)中，A、B、D、E&F之中沒有或一或雨 個為氮，而其餘A、B、D、E及F係獨立為CH或CR6 ; 其中R為_原子；Cw烷基（例如Cm烷基）；Cw氟烷基（例 如4·2氟烷基）；Cl_4烷氧基（例如q·2烷氧基）；氟基烷氧 基·’ c〗-2烷基磺醯基（Ci-2烷基_s〇2-); 烷基名〇厂__ ; R7R8N-so2.； r^r«n-co-； -NR^-C(0)R16 ； r7R8N; oh; Ci 氧基甲基，cw烷氧基乙基；Ci_2燒基_s〇2_CH2_;氰基（CN); 87841·96〇3〇3_ 中.d〇c -27- 1283678 或苯基，視情況被一或兩個氟基、氯基、Ci 2烷基、q氟俨 基、Ck烷氧基或心氟基烷氧基取代；其中^與圮均如本文 定義； 其中在亞式（z)中，G為0或S或NR9，其中r9為氫原子⑻、 Ci-4燒基或Ch氟燒基；J、L、Μ及Q之中沒有或一、一 L ^^4 三個為氮；而其餘J、L、Μ及Q係獨立為CH或CR6，其中R6 係如本文定義； 或 R4 與 R5 —起採用為-(CHJp1·或-C(〇HCH2)p2_ 或-(αΪ2)ρ3_χ5_ (CH2)p4-或-C(0>X5_(CH2)p5_，其中：pl = 3、4、5或6(較佳 P = 4或5)，P2為2、3、4或5(p2較佳為2、3或4)，且p3與？4及 P5係獨立為2或3 (較佳獨立為2)，且X5為〇或NR1 7 ; 其中R17為氫原子（H) ; C! ·4燒基（例如Q j燒基）；q ·2氟燒 基；C3-6環烷基；-(CH2)p6-C(0)R16，其中 ρ6為 〇、i、2或 3(ρ6 較佳為 0) ; -(CH2)p6-C(0)NR12R13 ; -(CH2)p6-C(0)〇Ri6 ; -S〇2 R1 6 ;或苯基或苄基，其中苯基或苄基係視情況在芳族 碳原子處被一或兩個下列基困取代：齒原子、Cl-2烷基、Ci 氟烷基、Cij烷氧基或心氟基烷氧基； 且其中當R4與R5—起採用為-(CHJp1-或-C(0)-(CH2)p2-時， NR4R5雜環係視情況被一個Ris取代基取代，其中Ris為：Ci 4 燒基（例如（V2烷基）；Cm氟烷基；C3-6環烷基；CV2烷氧基 (未在結合至NR4R5環-氮之環-碳處經取代）；Cl氟基烷氧基 (未在結合至NR4R5環-氮之環-碳處經取代）；〇H (未在結合 至NR4R5環-氮之環-碳處經取代）；-(CH2)p7_c⑼Ri 6，其中p7 為 〇、1、2或 3(p7較佳為 〇 或 1); -(CH2)p7-C(0)0R16 ; -(CH2)p7- 87841·96〇3〇3·中.doc -28 - 1283678 OC^R1 6 ； -(CH2 )p 7 -C(0)NR12 R13 ； -(CH2 )p 7 -NR15 C(0)R!6 ； -(CH2)P7-NR15C(0)NR12R13 ； -(CH2)p7-NR15C(0)0R16 ; .(CH2)p7· so2r16 ； -(CH2)p7.S02NR12R13 ； -(CH2)p7-NR15S02R16 ； -(CH2)p7-OH ; -(CH2 )p 7 -OR1 6 ;或苯基，視情況被一或兩個下列基團取 代：_原子、C^2烷基、C!氟烷基、Q-2烷氧基或(^氟基烷 氧基； 或R4與R5 —起採用為如本文中定義之_(CH2)pl-或<(〇)_ (CH2)p2-或 _(CH2)p3-X5-(CH2)p4-或-(：(0)-Χ5_((：Η2)ρ5·，且其中 NR4R5雜環係稠合至苯環，視情況在苯基上被一或兩個下列 基團取代：卣原子、Ci-2烷基、（^氟烷基、（^-2烷氧基或(^ 氟基烷氧基；且 R為Cl· 8纟元基’ Cl-8氟燒基；C3-8環健》基；苯基，视情況被 一或兩個下列基團取代：_原子、cl-2烷基、三氟甲基、 Cl _2燒乳基或三氟甲氧基；或R5 a具有如本文中定義之亞式 ⑻、（y)或(z) 且其中： R12與R13係獨立為H; Cu烷基（例如c卜3烷基）；C3_6環燒 基；或苯基，視情況被一或兩個下列基團取代：鹵原子、 Ci-2燒基、Ci氟烷基、q-2烷氧基或心氟基烷氧基； 或 R12 與 Ri3 一起為-(αΐ2)Λ 或-C(〇>(CH2)n7_ 或 _c(〇)_(CH2)n7· C(o)-或-(ch2 )n 8-χΐ 2 _(Ch2 )n 9 或 _c(0>xl 2-(Ch2 )n i 〇 …其中·· n6 為3、4、5或6(n6較佳為4或5)，n7為2、3 ' 4或5(n7較佳為 2、3或4)，η8與η9及ηι〇係獨立為2或3(較佳係獨立為2)，且 X12為0或NR14，其中RM為η或Cl-2烷基； 87841-96〇3〇3·中.doc -29- 1283678And in which in the subtype (8) 'n=M2; in the subtype (y), m=1 or 2; in the subtype (z), r = 〇, i or 2; wherein in the subtype (X) (y), among the A, B, D, E & F, none or one or the rain is nitrogen, and the remaining A, B, D, E and F are independently CH or CR6; wherein R is _ atom; Cw Alkyl (e.g., Cm alkyl); Cw fluoroalkyl (e.g., 4·2 fluoroalkyl); Cl_4 alkoxy (e.g., q. 2 alkoxy); fluoroalkoxy·'c>-2 alkyl Sulfhydryl (Ci-2 alkyl _s〇2-); alkyl name 〇 factory __ ; R7R8N-so2.; r^r«n-co-; -NR^-C(0)R16 ; r7R8N; Oh; Ci oxymethyl, cw alkoxyethyl; Ci_2 alkyl _s〇2_CH2_; cyano (CN); 87841·96〇3〇3_中.d〇c -27- 1283678 or phenyl, depending The condition is substituted by one or two fluoro, chloro, Ci 2 alkyl, q fluoroindolyl, Ck alkoxy or cardinyl fluoroalkoxy; wherein both hydrazine and hydrazine are as defined herein; Wherein G is 0 or S or NR9, wherein r9 is a hydrogen atom (8), a Ci-4 alkyl group or a Ch fluoroalkyl group; and none of J, L, Μ and Q is one or one L ^^4 three Nitrogen; while the remaining J, L, Μ and Q are independently CH or CR6, of which R6 As defined herein; or R4 and R5 are taken as -(CHJp1· or -C(〇HCH2)p2_ or -(αΪ2)ρ3_χ5_(CH2)p4- or -C(0>X5_(CH2)p5_, where: Pl = 3, 4, 5 or 6 (preferably P = 4 or 5), P2 is 2, 3, 4 or 5 (p2 is preferably 2, 3 or 4), and p3 is independent of ?4 and P5 2 or 3 (preferably independently 2), and X5 is 〇 or NR1 7 ; wherein R17 is a hydrogen atom (H); C! · 4 alkyl (for example, Q j alkyl); q · 2 fluoroalkyl; C3 -6 cycloalkyl; -(CH2)p6-C(0)R16, wherein ρ6 is 〇, i, 2 or 3 (p6 is preferably 0); -(CH2)p6-C(0)NR12R13; -( CH2)p6-C(0)〇Ri6; -S〇2 R1 6 ; or phenyl or benzyl, wherein the phenyl or benzyl group is optionally substituted with one or two of the following groups at the aromatic carbon atom: a tooth atom, a Cl-2 alkyl group, a Ci fluoroalkyl group, a Cij alkoxy group or a heart fluoroalkoxy group; and wherein R4 and R5 are taken together as -(CHJp1- or -C(0)-(CH2) When p2-, the NR4R5 heterocyclic ring is optionally substituted by a Ris substituent, wherein Ris is: Ci 4 alkyl (for example (V2 alkyl); Cm fluoroalkyl; C3-6 cycloalkyl; CV2 alkoxy ( Not substituted at the NR4R5 ring-nitrogen ring-carbon; Cl fluoroalkoxy a group (not substituted at the ring to the ring of NR4R5 ring-nitrogen-carbon); 〇H (not substituted at the ring-carbon bonded to NR4R5 ring-nitrogen); -(CH2)p7_c(9)Ri 6, where p7 is 〇 1, 2 or 3 (p7 is preferably 〇 or 1); -(CH2)p7-C(0)0R16; -(CH2)p7- 87841·96〇3〇3·中.doc -28 - 1283678 OC ^R1 6 ; -(CH2 )p 7 -C(0)NR12 R13 ; -(CH2 )p 7 -NR15 C(0)R!6 ; -(CH2)P7-NR15C(0)NR12R13 ; -(CH2) p7-NR15C(0)0R16; .(CH2)p7·so2r16; -(CH2)p7.S02NR12R13; -(CH2)p7-NR15S02R16; -(CH2)p7-OH; -(CH2)p7-OR1 6 ; Or phenyl, optionally substituted by one or two of the following groups: _Atom, C^2 alkyl, C! fluoroalkyl, Q-2 alkoxy or (^fluoroalkoxy; or R4 and R5 - used as _(CH2)pl- or <(〇)_(CH2)p2- or _(CH2)p3-X5-(CH2)p4- or -(:(0)-Χ5_ as defined herein ((:Η2)ρ5·, and wherein the NR4R5 heterocyclic ring is fused to the benzene ring, optionally substituted with one or two of the following groups on the phenyl group: a halogen atom, a Ci-2 alkyl group, a (fluoroalkyl group) , (^-2 alkoxy or (^ fluoroalkylalkoxy; and R is Cl. 8 fluorene-based 'Cl-8 fluoroalkyl; C3-8 ring Phenyl group, optionally substituted with one or two of the following groups: _ atom, cl-2 alkyl, trifluoromethyl, Cl _2 succinyl or trifluoromethoxy; or R5 a has a definition as defined herein Sub-formula (8), (y) or (z) and wherein: R12 and R13 are independently H; Cu alkyl (eg c-3 alkyl); C3_6 cycloalkyl; or phenyl, optionally one or two Substituted by a halogen atom, a Ci-2 alkyl group, a Ci fluoroalkyl group, a q-2 alkoxy group or a heart fluoroalkoxy group; or R12 together with Ri3 is -(αΐ2)Λ or -C(〇&gt ;(CH2)n7_ or _c(〇)_(CH2)n7·C(o)- or -(ch2)n 8-χΐ 2 _(Ch2 )n 9 or _c(0>xl 2-(Ch2 ) Ni 〇... where n6 is 3, 4, 5 or 6 (n6 is preferably 4 or 5), n7 is 2, 3' 4 or 5 (n7 is preferably 2, 3 or 4), η8 and η9 and Ηι〇 is independently 2 or 3 (preferably independently 2), and X12 is 0 or NR14, wherein RM is η or Cl-2 alkyl; 87841-96〇3〇3·中.doc -29- 1283678

Rl 5為氫原子（Η) ; Ci -4烷基（例如tBu或q ·2烷基，例如甲 基）；C3 -6環烷基；或苯基，視情況被一或兩個下列基團取 代：自原子、C1-2烷基、Ci氟烷基、Ci-2烷氧基或(^氟基烷 氧基； 汉為cle4燒基（例如C!-2燒基）；C3_6環燒基；？比咬基（例如峨 淀-2-基）；或苯基，視情況被一或兩個下列基图取代：鹵原 子、Cl_2烷基、Ci氟烷基、Q-2烷氧基或(^氟基烷氧基；且 Rl9為cw烷基；-(CH2)n20-OR20，其中η20為 1、2、3或4，且 R 為氫原子（Η)或 Ch烷基；-(：Η(]ν^)-ΟΗ ; -CH2-SH ; -CH2-CH2-;苄基；或（4_羥苯基）甲基（意即4-羥基_爷基）。 在化合物中，例如在式（I)(或式（IA)或式（IB)，參閱後述）化 合物中’ ”烷基”基團或部份基團可為直鏈或分枝狀。可被 採用之烷基，例如Cl-s烷基或Ci·6烷基或Ci4烷基或烷基 或^_2燒基’包括Ci0烷基或Ci4烷基或Ci3烷基或烷 土 $如甲基、乙基、正-丙基、正_ 丁基、正·戊基或正-己 基或其任何分枝狀異構物，譬如異丙基、第三_ 丁基、第 土 〃、丁基、3-甲基丁 -2_基、2-乙基丁 -1·基或其類似 相應意義係意欲針對，，燒Rl 5 is a hydrogen atom (Η); Ci -4 alkyl (such as tBu or q · 2 alkyl, such as methyl); C 3 -6 cycloalkyl; or phenyl, optionally with one or two of the following groups Substituted: from atom, C1-2 alkyl, Ci fluoroalkyl, Ci-2 alkoxy or (^fluoroalkoxy; Han cle4 alkyl (eg C!-2 alkyl); C3_6 cycloalkyl Or a phenyl group, or a phenyl group, optionally substituted with one or two of the following base diagrams: a halogen atom, a C 2 alkyl group, a Ci fluoroalkyl group, a Q 2 alkoxy group or (^fluoroalkoxy; and Rl9 is cw alkyl; -(CH2)n20-OR20, wherein η20 is 1, 2, 3 or 4, and R is a hydrogen atom (Η) or a Ch alkyl group; Η(]ν^)-ΟΗ; -CH2-SH; -CH2-CH2-; benzyl; or (4-hydroxyphenyl)methyl (ie 4-hydroxy-yl). In compounds, for example The alkyl group or partial group of the formula (I) (or formula (IA) or formula (IB), as described later) may be linear or branched. The alkyl group which may be employed, for example Cl-s alkyl or Ci.6 alkyl or Ci4 alkyl or alkyl or ^2 alkyl 'includes Ci0 alkyl or Ci4 alkyl or Ci3 alkyl or alkane $ such as methyl, ethyl, -propyl, n-butyl, n-pentyl or n-hexyl or any of its branched isomers, such as isopropyl, tert-butyl, terpene, butyl, 3-methylbutyl -2_yl, 2-ethylbutan-1-yl or the like is intended to be targeted,

烷氧基”、”次烷基，，及衍生自烷基 或Ci·2燒氧基，包Alkoxy", "alkylene," and derived from alkyl or Ci. 2 alkoxy, packaged

曱磺醯基（曱烷磺醯基）、乙 少元基之其他基围。 譬如Ci·6烷氧基或^^烷氧基 乳基、乙氧基、丙氧基及上文列示燒 I基績醯基"，譬如4-4燒基績醯基，包 酿基）、乙基績醢基及衍生自上文列示 烷基磺醯氧基"，譬如(^-4烷基磺醯氧 87841-960303-中.doc 1283678 基，包括甲烷磺醯氧基（甲磺醯基氧基）、乙烷磺醯氧基等 等。 π環烷基”，例如c：3_8環烷基，包括環丙基、環丁基、環戊 基、環己基、環庚基、環辛基等。C3-8環烷基較佳為c3-6環 烷基或C：5·6環烷基，其含有3-6員或5-6員碳環。 π氟烷基”包括具有一、二、三、四、五或更多個氟取代基 之烷基，例如氟烷基或^」氟烷基或Ci_2氟烷基，譬如 單氟甲基、二氟甲基、三氟甲基、五氟乙基、2,2,2-三氟乙 基（CF3CH2-)、2,2_ 二氟乙基（CHF2CH2-)、2-氟基乙基（CH2FCH2- )等。"氟基烷氧基"包括C^4氟基烷氧基或c1-2氟基烷氧 基，譬如三氟甲氧基、五氟乙氧基、單氟甲氧基、二氟甲 氧基等。"氟烷基磺醯基"，譬如(^_4氟烷基磺醯基，包括三 氟曱燒績醯基、五氟乙基績醯基等。 存在於化合物中之自原子（”齒基”），例如在式①化合物 中，可為氟、氯、溴或碘原子（”氟基"、”氯基"、”溴基，，或 ”碘基”）。 當本專利說明書陳述原予或部份基團A係”結合"或，，連接，， 至原子或部份基團B時，其係意謂原子/部份基團A通常係 利用一或多個共價鍵，直接結合至原子/部份基團B，且排 除A係經由一或多個中間原子/部份基團，間接連接至 B (例如排除A-C-B);除非内文明顯意欲包含另一種意義。 R1較佳為_4烷基（例如甲基、乙基、正-丙基、異丙基或 正_丁基）、〇：1-3氟烷基或-〇12(：112〇11;111更佳為(：：1_3烷基（例 如甲基、乙基或正_丙基）、Cl-2氟烷基或-Ch2CH2〇h ;又更 87841-960303-中.doc -31- 1283678 佳為Ci -3 基、C2氣燒•基或-CH2 CH2 OH，譬如曱基、乙基、 正-丙基或-CH2CH2〇H。R1又再更佳為c2_3烷基（例如乙基或 正-丙基）、氟烷基（例如q氟烷基-CH2-，譬如CF3-CH2-)或 -CH2CH2〇H ;特別是乙基、正-丙基或_CH2cH2〇H。R1最佳為 乙基。 R2較佳為氫原子（H)或甲基，更佳為氫原子（H)。 在R3中，較佳係有一個取代基或無取代基。 在一項選用具體實施例中，R3為视情況經取代之C3環烷 基或亞式（aa)、（bb)或（cc)之視情況經取代之雜環族基團。在 此具體實施例中’視情況而定，在R3中，C3 _ 8環烷基或亞式 (aa)、（bb)或（cc)之雜環族基團係視情況被一或兩個取代基取 代，取代基獨立為（例如係為）酮基（==〇)、〇H、Ci 2燒氧基、 Ci _2氟基k乳基（例如二氟甲氧基）或q 2燒基；且其中任何 OH、燒氧基或氟基燒氧基取代基不會在連接（結合）至式①_ NH-基團之R3環碳處經取代，且不會在結合至雜環族基團 (aa)、（bb)或㈣之Y基圈之任一個R3環碳處經取代。 在一項選用具體實施例中，其中R3為視情況經取代之C3i 環烷基，其不為視情況經取代之Cs環烷基，意即不為视情 況經取代之環戊基。於此情況中，圮更佳為視情況經取代 之C6 _ 8環燒基。 在R3為視情況經取代之A·8環烷基之情況下，更佳為视情 況經取代之A環烷基（意即環己基）；例如Q環烷基，視情況 被一或兩個取代基取代，取代基獨立為（例如係為）酮基 (=0)、OH、C卜2燒氧基、C卜2氣基烷氧基（例如三氟甲氧基） 87841-960303·中.doc -32- 1283678 或4-2烷基，且其中任何0H、烷氧基或氟基烷氧基取代基 不會在連接（結合）至式（1) -NH-基團之R3環碳處經取代。 在R3為視情況經取代之C^8環烷基之情況下，一或兩個選 用取代基較佳係包括（例如係為或獨立為（何如係為》酮基 H)); OH; Cl烷氧基；Cl氟基烷氧基（例如三氟甲氧基）； NHR21，其中R21為氫原子（HhiLCM直鏈烷基；Ci2烷基，譬 如甲基’ C!氟烷基，譬如_Cjj2f或_CHp2 ; _CH2〇H ; -CH2NHR22，其中R22 為 H; _c(〇)〇R23，其中R23為 Η或甲基； •C(0)NHR24，其中R24為Η或甲基；_c(〇)R25，其中r25為甲 基；氟基；羥亞胺基（=N-OH);或（cle2烷氧基）亞胺基（=N_ OR2 6，其中r2 6為Ci 2烷基）；且其中任何〇H、烷氧基、氟基 烷氧基或NHR21取代基不會在連接（結合）至式①基團之 R3環碳處經取代，且不會在結合至雜環族基團（aa)、（bb)或 (cc)之Y基團之任一個R3環碳處經取代。 更佳是在R3為視情況經取代之c>8環烷基之情況下，一或 兩個選用取代基係包括（例如係為或獨立為（例如係為））酮基 (=0) ; OH ; NHR21，其中為氫原子⑻；Ci 2烷基，譬如甲 基；q氟烷基，譬如-CI^F或-CHF2 ; _C(0)0R23，其中R23為H或 甲基；-C(0)NHR24，其中r24為H或甲基；氟基；羥亞胺基（=乂 0Η);或（Cu烷氧基)亞胺基(=N_OR26，其中2烷基）。 又更佳是在R3為視情況經取代之(：3-8環烷基之情況下，一 或兩個選用取代基係包括（例如係為或獨立為（例如係為））酮 基（=0) ; OH ; NHR21，其中r2 1為氫原子（H);甲基卜; _CHF2卜C(0)0R23 ’其中R23為η;氟基；羥亞胺基（塔〇11); 87841-960303-中.doc -33- 1283678 或（(V2烷氧基）亞胺基(=n_OR26，其中R26為Ci_2烷基）。 又再更佳是在R3為视情況經取代之q·8環烷基之情況下， 一或兩個選用取代基係包括（例如係為或獨立為（例如係為）） 酮基（=0); 0H;甲基；氟基；羥亞胺基（=N_〇H);或（Cl?烷氧 基）亞胺基（=N-OR26，其中R26為c1-2烷基）。 最佳是在R3為視情況經取代之A·8環烷基之情況下，一或 兩個選用取代基係包括（例如係為或獨立為（例如係 為））0H、酮基（=〇)或肟基（=n-〇h)。例如，一或兩個選用取 代基可包括（例如係為）〇H及/或酮基（=0)。 視情沉而定，在R3中，A-8環烷基可為未經取代。 在R3為視情況經取代之A-8環烷基之情況下，例如視情況 經取代之A-8環烷基，譬如视情況經取代之C6環烷基（視情 況經取代之環己基），一或兩個選用取代基，若存在時，較 佳係包括R3環烷基環之3-、4-或5-位置上之取代基（例如一 或多個取代基）。（就此而論，R3環烷基環之μ位置係被視為 是對式（I)中-ΝΗ-之連接點）。 在R3為視情況經取代之C：3·8環烷基之情況下，任何ΟΗ、烷 氧基、氟基烷氧基、-ch2oh、-ch2ch2oh、-ch2nhr22、 _〇Χ〇ρκ23 > -C(0)NHR24、-C(0)R25或氟基取代基（特別是任何 0H取代基）更佳係在R3環烷基（例如C6 8環烷基）環之、4_ 或5-位置，例如3-或5-位置上。例如，任何〇H、烷氧基、 氟基燒氧基、-CH20H、-CH2CH2OH、-CH2NHR22、 _CX〇X)K23、_C(0)NHR24、-C(0)R25或氟基取代基（特別是任何 OH取代基），可在R3Cs環烷基（環戊基）環之3-位置上，或在 87841-960303-中.doc -34- 1283678 汉C6 $衣^元基（環己基）壤之3_、4-或5-位置，例如3-或5-位置 上（就此點以及下文而論’ R3環基環之1-位置係被視為是 對式（I)中-NH-之連接點）。 在R為視情況經取代之C3 _8環燒基之情況下，任何npjr2 1 取代基較佳係在R3環烷基（例如C0_8環烷基，例如環己基）環 之2-，3-，4-或5-位置上，較佳為2-或3-位置，或更佳為3_位置。 在R3為視情況經取代之A _8環烷基之情況下，任何烷基或 氟燒基取代基較佳係在R3環燒基（例如C6 · 8環燒基，例如環 己基）環之1-，2-，3-，4-或5-位置上，更佳為1-，2-，3-或5-位置， 又更佳為1-或3-位置。 在R3為視情況經取代之C3 _ 8環燒基之情況下，任何酮基 (=0)、羥亞胺基（=N-OH)或似_4烷氧基）亞胺基（=N-OR26)取代 基，較佳係在R3環烷基（例如C6-8環烷基，例如環己基）環之 3-或4-位置上，較佳係在4-位置上。 在R3為視情況經取代之C3_8環烷基之情況下，R3較佳為環 己基（意即未經取代），或被一個酮基(=〇)、〇H、NHR21、q _2 烷基、（V2 氟烷基、-CH20H、-C(0)0R23、-C(0)NHR24、 _C(0)R25、氟基、羥亞胺基（=N-〇H)、（Ch烷氧基）亞胺基（=N-OR26)取代基取代之環己基，或被兩個氟基取代基取代之環 己基。R3更佳為環己基（意即未經取代），或被一個酮基 (=9、OH、NHR21、Cu烷基、Cu氟烷基、-C(0)OR23、氟 基、羥亞胺基（=N-0H)或（Ch烷氧基）亞胺基（=N-OR26)取代基 取代之環己基，或被兩個氟基取代基取代之環己基。R3又 更佳為環己基（意即未經取代），或被一個酮基（=〇)、羥亞胺 87841-960303-中.doc -35- 1283678 基（=N-OH)、C! _2烷基或OH取代基取代之環己基。選用取代 基可在R3環己基環之3-或4-位置上，例如3-位置；更佳為任 何OH取代基較佳係在R3環己基環之3-位置處，及/或任何 酮基（=0)、羥亞胺基（=N-OH)或（C! -4烷氧基）亞胺基（=：N-OR26) 取代基較佳係在R3環己基環之4-位置上。 在R3為視情況經取代之C6環烷基之情況下，R3可為例如4_ 幾基-環己基（意即4-經基環己燒-1-基），但R3更佳為環己基 (意即未經取代）、3-羥基-環己基（意即3-羥基環己烷-1-基）、 4·酮基·環己基（意即4_酮基環己燒-1-基）、4-(經亞胺基）環己基 (意即4-(經亞胺基）環己-1-基）、4_((^-2烷氧基亞胺基）環己 基、1-甲基環己基或3-甲基環己基。在R3為視情況經取代之 C6環燒基之情沉下’ R3最佳為環己基（意即未經取代）、4-酮 基-環己基（意即4-酮基環己烷-1-基）或4-(羥亞胺基）環己基（意 即4-(羥亞胺基）環己小基）。 在R3為視情況經取代之C5環烷基（視情況經取代之環戊基） 之h況下’ R可例如為％戊基（意即未經取代）或經基-環戊 基。 在R3為視情況經取代之單不飽和<：5_7環缔基之情況下，其 較佳為視彳Θ況經取代之早不飽和-C5 _ 6環缔基，更佳為視情 況經取代之單不飽和-C0環晞基（意即視情況經取代之單不飽 和環己烯基=視情況經取代之環己烯基）。R3環己烯基又更 佳為視情況經取代之環己-3_烯小基。 在R3為視情沉經取代之單不飽和_C5_7環缔基之情況下，R3 環晞基較佳係視情況被一或兩個氟基或甲基之取代基取 87841-%〇3〇3-中.doc -36- 1283678 代，其條件是，若有兩個取代基，則其不得皆為甲基。R3 環晞基較佳係視情況被一個氟基或-2燒基（例如甲基）之取 代基取代；R3環缔基更佳係被一個氟基取代基取代或為未 經取代。對R3環晞基而言，選用取代基可在環晞基環之1_，2-， 3-，4-或5-位置上。 在R3為亞式（aa)、（bb)或（cc)之雜環族基團之情況下，則γ 較佳為0、S、S〇2、NH或N-C(O)甲基，更佳為〇、NH或N· C(0)甲基，又更佳為〇或N-C(O)甲基，最佳為〇。（當丫為^ 或N-C(O)甲基時，則RM為Η或C(0)甲基）。 R 0較佳為氣原子（H)、甲基、乙基、c(0)NH2、C(0)甲基或 C(0)-CF3。R1 0可視情況為氫原子（η)、甲基、乙基、c(q)甲基 或C(0)_CF3，更佳為Η、C(0)甲基或C(0)-CF3，又更佳為Η或 c(o)甲基。 在R3為亞式（aa)、（bb)或（cc)之雜環族基圈之情況^，則R3 較佳為亞式（aa)或（bb)，更佳為亞式（bb)之雜環族基團。 在亞式（bb)中，ηι較佳為i。在亞式（ce)中，#較佳為i。意 即’在R3雜環族基團中較佳為六員環。 在R3中，亞式（aa)、（bb)或（cc)之雜環族基團係適當地為未 經取代（就此而論，在γ為Nrm之情況下，Rl〇不被分類為取 代基）。 在亞式（aa)、（bb)或（CC)<R3雜環族基團中，一或兩個選用 取代基較佳係包括（例如係為或獨立為（(例如係為）)〇h;網 基（=〇); (V2燒基（例如甲基）或〇12氟燒基（例如 譬如-CH2 F或彻2)。在亞式㈣、（bb)或㈣之R3雜環ς基困 8784 卜 96〇3〇3_ 中.doc -37- 1283678 原子上 ’一或兩個選用取代基更佳係包括（例如係為或獨立為 ((例如係為））OH及/或酮基；一或兩個選用取代基最佳係包 (如係為）酮基（=Q)。在亞式（㈣、㈣）或（⑶）之R3雜環族 基團中，任何酮基（=〇)取代基較佳係在結合（鄰近）至X之碳 及/或可在R3雜環之2-，3-，4-或5-位置上。（就此而 淪，R3雜環之μ位置係被视是為對式①中之連接點）。 备R3為亞式（aa)之雜環族基團，且γ為nrI 〇時，則較佳Rl 0 不為C(〇)-Me。更佳情況是，當r3為亞式（aa)雜環族基團，且 Y為NR10時，則Ri〇較佳係不為c(〇)R，意即或例如Rl〇較佳係 不為C(〇)NH2、CXOK：〗·2烷基或(：(0)%氟烷基。於一項具體實 施例中，當R3為亞式（aa)之雜環族基團時，γ為〇、S、s〇2 或NH 〇Other bases of sulfonyl sulfhydryl (decanesulfonyl) and acetaminophen. For example, Ci.6 alkoxy or alkoxyl, ethoxy, propoxy, and the above-listed sulphur-based thiol groups, such as 4-4, ), ethyl oxime and derived from the above alkyl sulfonyloxy group, such as (^-4 alkylsulfonyloxy 87481-960303-中.doc 1283678 base, including methanesulfonyloxy ( Methanesulfonyloxy), ethanesulfonyloxy, etc. πcycloalkyl", for example c: 3-8 cycloalkyl, including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl , cyclooctyl, etc. The C3-8 cycloalkyl group is preferably a c3-6 cycloalkyl group or a C: 5·6 cycloalkyl group, which contains a 3-6 member or a 5-6 membered carbocyclic ring. Included are alkyl groups having one, two, three, four, five or more fluorine substituents, such as fluoroalkyl or fluoroalkyl or Ci 2 fluoroalkyl, such as monofluoromethyl, difluoromethyl, tri Fluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl (CF3CH2-), 2,2-difluoroethyl (CHF2CH2-), 2-fluoroethyl (CH2FCH2-), etc. "Fluoroalkoxy" includes C^4 fluoroalkoxy or c1-2 fluoroalkoxy, such as trifluoromethoxy, pentafluoroethoxy, Fluoromethoxy, difluoromethoxy, etc. "fluoroalkylsulfonyl", such as (^_4 fluoroalkylsulfonyl, including trifluorosulfonate fluorenyl, pentafluoroethyl fluorenyl The self-atoms ("dentate groups") present in the compound, for example, in the compounds of formula 1, may be fluorine, chlorine, bromine or iodine atoms ("fluoro-based", "chloro-based", "bromo-based, , or "iodo". When this patent specification states that the original or part of the group A "combines" or ",", connects to an atom or a part of a group B, it means an atom / part The group A is usually bonded directly to the atom/partial group B by means of one or more covalent bonds, and the A system is indirectly linked to B via one or more intermediate atoms/partial groups (eg excluding ACB) Unless otherwise expressly intended to contain another meaning, R1 is preferably _4 alkyl (eg methyl, ethyl, n-propyl, isopropyl or n-butyl), hydrazine: 1-3 fluorocarbon Or -〇12(:112〇11;111 is more preferably (::1_3 alkyl (such as methyl, ethyl or n-propyl), Cl-2 fluoroalkyl or -Ch2CH2〇h; yet more 87841 -960303-中.doc -31- 12836 78 is preferably a Ci -3 group, a C 2 gas group or a -CH 2 CH 2 OH group such as a mercapto group, an ethyl group, a n-propyl group or a -CH 2 CH 2 〇H. R 1 is more preferably a c 2 _ 3 alkyl group (for example, ethyl or N-propyl), fluoroalkyl (eg q fluoroalkyl-CH2-, such as CF3-CH2-) or -CH2CH2〇H; especially ethyl, n-propyl or _CH2cH2〇H. R1 is most preferably ethyl. R2 is preferably a hydrogen atom (H) or a methyl group, more preferably a hydrogen atom (H). In R3, it is preferred to have one substituent or no substituent. In a preferred embodiment, R3 is optionally substituted C3 cycloalkyl or an optionally substituted heterocyclic group of the formula (aa), (bb) or (cc). In this particular embodiment, as the case may be, in R3, a heterocyclic group of C3-8 cycloalkyl or subtype (aa), (bb) or (cc) is optionally one or two Substituted by a substituent, the substituent is independently (for example) a keto group (==〇), 〇H, a Ci 2 alkoxy group, a Ci 2 fluoro-based ke group (for example, a difluoromethoxy group) or a q 2 alkyl group. And any of the OH, alkoxy or fluoroalkyl alkoxy substituents are not substituted at the R3 ring carbon attached (bonded) to the formula 1_NH- group, and are not bonded to the heterocyclic group Any one of the R 3 ring carbons of the Y base ring of (aa), (bb) or (d) is substituted. In a preferred embodiment, wherein R3 is optionally substituted C3i cycloalkyl, which is not optionally substituted Cs cycloalkyl, meaning that it is not optionally substituted cyclopentyl. In this case, ruthenium is preferably a C6 -8 ring group which is optionally substituted. In the case where R3 is an optionally substituted A.8 cycloalkyl group, it is more preferably an optionally substituted A cycloalkyl group (ie, cyclohexyl group); for example, a Q cycloalkyl group, as the case may be one or two Substituted by a substituent, the substituent is independently (for example, ketone group (=0), OH, C 2 alkoxy, C 2 alkoxy (for example, trifluoromethoxy) 87841-960303· .doc -32- 1283678 or 4-2 alkyl, and any of the 0H, alkoxy or fluoroalkoxy substituents are not attached (bonded) to the R3 ring carbon of the formula (1) -NH- group Replaced by. In the case where R3 is an optionally substituted C^8 cycloalkyl group, one or two of the optional substituents preferably include (for example, whether or independently (as if it is a "keto group H)); OH; Cl Alkoxy; Cl fluoroalkoxy (e.g., trifluoromethoxy); NHR21, wherein R21 is a hydrogen atom (HhiLCM linear alkyl; Ci2 alkyl, such as methyl 'C! fluoroalkyl, such as _Cjj2f Or _CHp2; _CH2〇H; -CH2NHR22, wherein R22 is H; _c(〇)〇R23, wherein R23 is Η or methyl; • C(0)NHR24, wherein R24 is Η or methyl; _c(〇) R25, wherein r25 is methyl; fluoro; hydroxyimino (=N-OH); or (cle2 alkoxy)imide (=N_OR2 6, wherein r2 6 is Ci 2 alkyl); Any hydrazine H, alkoxy, fluoroalkoxy or NHR21 substituent will not be substituted at the R3 ring carbon attached (bonded) to the group of formula 1, and will not be bonded to the heterocyclic group (aa) Any one of the Y groups of the Y group of (bb) or (cc) is substituted with a R3 ring carbon. More preferably, in the case where R3 is optionally substituted c>8 cycloalkyl, one or two optional substitutions The base system includes (for example, is or is independent (for example, for) Keto group (=0); OH; NHR21, wherein is a hydrogen atom (8); Ci 2 alkyl, such as methyl; q fluoroalkyl, such as -CI^F or -CHF2; _C(0)0R23, wherein R23 is H Or methyl; -C(0)NHR24, wherein r24 is H or methyl; fluoro; hydroxyimino (=乂0Η); or (Cu alkoxy)imide (=N_OR26, wherein 2 alkyl More preferably, in the case where R3 is optionally substituted (: 3-8 cycloalkyl), one or two selected substituents include (for example, are or independently (for example)) a keto group. (=0) ; OH ; NHR21, wherein r 2 1 is a hydrogen atom (H); methyl b; _CHF 2 b C(0) 0R23 'where R 23 is η; a fluoro group; a hydroxyimino group (Ta 〇 11); 87841 -960303-中.doc -33- 1283678 or ((V2 alkoxy)imino (=n_OR26, wherein R26 is Ci_2 alkyl). Still more preferably in R3 is optionally substituted q.8 ring In the case of an alkyl group, one or two optional substituents include (for example, are or independently (for example)) a keto group (=0); 0H; a methyl group; a fluoro group; a hydroxyimino group (=N) _〇H); or (Cl? alkoxy)imido group (=N-OR26, wherein R26 is c1-2 alkyl). The best is in the case of R3 In the case of a substituted A.8 cycloalkyl group, one or two of the optional substituents include (for example, or independently (for example)) 0H, keto (=〇) or sulfhydryl (=n-〇) h). For example, one or two alternative substituents can include, for example, 〇H and/or keto groups (=0). Depending on the sinking, in R3, the A-8 cycloalkyl group can be unsubstituted. In the case where R3 is optionally substituted A-8 cycloalkyl, for example, optionally substituted A-8 cycloalkyl, such as optionally substituted C6 cycloalkyl (optionally substituted cyclohexyl) One or two optional substituents, if present, preferably include a substituent at the 3-, 4- or 5-position of the R3 cycloalkyl ring (e.g., one or more substituents). (In this connection, the μ position of the R3 cycloalkyl ring is regarded as the point of attachment to -ΝΗ- in the formula (I). In the case where R3 is optionally substituted C:3·8 cycloalkyl, any oxime, alkoxy, fluoroalkoxy, —ch2oh, —ch2ch2oh, —ch2nhr22, _〇Χ〇ρκ23 > C(0)NHR24, -C(0)R25 or a fluoro substituent (particularly any OH substituent) is more preferably at the 4 or 5 position of the R3 cycloalkyl (eg C6 8 cycloalkyl) ring, For example, at the 3- or 5-position. For example, any hydrazine H, alkoxy, fluoroalkyl alkoxy, -CH20H, -CH2CH2OH, -CH2NHR22, _CX〇X)K23, _C(0)NHR24, -C(0)R25 or a fluoro substituent (specific Is any OH substituent), may be in the 3-position of the R3Cs cycloalkyl (cyclopentyl) ring, or in 87841-960303-.doc -34- 1283678 Han C6 $ clothing ^ yuan base (cyclohexyl) soil 3_, 4- or 5-position, for example 3- or 5-position (as far as this and below is concerned, the 1-position of the R3 ring-based ring is considered to be the connection of -NH- in formula (I) point). In the case where R is optionally substituted C3-8 cycloalkyl, any npjr2 1 substituent is preferably 2-, 3-, 4 in the R3 cycloalkyl (eg, C0-8 cycloalkyl, eg cyclohexyl) ring. In the - or 5-position, preferably a 2- or 3-position, or more preferably a 3_ position. In the case where R3 is optionally substituted A-8 cycloalkyl, any alkyl or fluoroalkyl substituent is preferably attached to the R3 cycloalkyl (eg, C6-8 cycloalkyl, eg cyclohexyl) ring. In the -, 2-, 3-, 4- or 5-position, more preferably a 1-, 2-, 3- or 5-position, and still more preferably a 1- or 3-position. In the case where R3 is optionally substituted C3-8 cycloalkyl, any keto (=0), hydroxyimino (=N-OH) or _4 alkoxy) imine (=N) The -OR26) substituent is preferably at the 3- or 4-position of the R3 cycloalkyl (e.g., C6-8 cycloalkyl, e.g., cyclohexyl) ring, preferably at the 4-position. In the case where R3 is an optionally substituted C3_8 cycloalkyl group, R3 is preferably a cyclohexyl group (ie, unsubstituted), or a keto group (=〇), 〇H, NHR21, q _2 alkyl group, (V2 fluoroalkyl, -CH20H, -C(0)0R23, -C(0)NHR24, _C(0)R25, fluoro, hydroxyimino (=N-〇H), (Ch alkoxy) a cyclohexyl group substituted with an imido group (=N-OR26), or a cyclohexyl group substituted with two fluoro substituents. R3 is more preferably a cyclohexyl group (ie, unsubstituted), or a keto group (= 9. OH, NHR21, Cu alkyl, Cu fluoroalkyl, -C(0)OR23, fluoro, hydroxyimino (=N-0H) or (Ch alkoxy)imide (=N-OR26 a cyclohexyl group substituted with a substituent or a cyclohexyl group substituted with two fluoro substituents. R3 is more preferably a cyclohexyl group (ie, unsubstituted), or a keto group (=〇), hydroxyimine 87841 -960303-中.doc -35- 1283678 (=N-OH), C! _2 alkyl or OH substituent substituted cyclohexyl. The substituent may be selected at the 3- or 4-position of the R3 cyclohexyl ring, For example, 3-position; more preferably any OH substituent is preferably at the 3-position of the R3 cyclohexyl ring, and/or any keto group =0), hydroxyimino (=N-OH) or (C!-4 alkoxy)imido (=:N-OR26) The substituent is preferably at the 4-position of the R3 cyclohexyl ring. In the case where R3 is an optionally substituted C6 cycloalkyl group, R3 may be, for example, a 4-methyl-cyclohexyl group (that is, a 4-cyclohexyl-1-yl group), but R3 is more preferably a cyclohexyl group ( That is, unsubstituted), 3-hydroxy-cyclohexyl (ie 3-hydroxycyclohexane-1-yl), 4-keto-cyclohexyl (meaning 4-ketocyclohexan-1-yl) , 4-(imido)cyclohexyl (ie 4-(imido)cyclohex-1-yl), 4-((^-2 alkoxyimino)cyclohexyl, 1-methyl Cyclohexyl or 3-methylcyclohexyl. When R3 is optionally substituted by a C6 cycloalkyl group, 'R3 is preferably cyclohexyl (ie unsubstituted), 4-keto-cyclohexyl (meaning That is, 4-ketocyclohexan-1-yl) or 4-(hydroxyimino)cyclohexyl (ie, 4-(hydroxyimino)cyclohexyl). In R3, C5 is optionally substituted. The cycloalkyl group (optionally substituted cyclopentyl group) can be, for example, a % pentyl group (ie, unsubstituted) or a benzyl-cyclopentyl group. In the case of saturating <:5_7 ring-bonding group, it is preferably an early-unsaturated-C5 -6 ring-bonding group which is substituted depending on the condition, and more preferably a monounsaturated-C0 ring fluorenyl group which may be optionally substituted. (Immediately substituted monounsaturated cyclohexenyl = optionally substituted cyclohexenyl). R3 cyclohexenyl is more preferably a cyclohex-3-enyl group which is optionally substituted. In the case where R3 is a monounsaturated _C5_7 cycloalkyl group substituted by the apparent sinking, the R3 cyclodecyl group is preferably taken by one or two substituents of a fluoro group or a methyl group as 87841-% 〇3〇. 3-中.doc -36- 1283678, provided that if there are two substituents, they must not be methyl. The R3 cyclodecyl group is preferably substituted by a substituent of a fluoro group or a -2 alkyl group (e.g., methyl group); the R3 ring group is more preferably substituted by a fluoro group substituent or unsubstituted. For the R3 cyclodecyl group, the substituent may be selected at the 1-, 2-, 3-, 4- or 5-position of the cycloalkyl ring. In the case where R3 is a heterocyclic group of the formula (aa), (bb) or (cc), γ is preferably 0, S, S〇2, NH or NC(O)methyl, more preferably It is preferably an anthracene, NH or N.C(0)methyl group, more preferably an anthracene or an NC(O)methyl group. (When 丫 is ^ or N-C(O)methyl, RM is Η or C(0) methyl). R 0 is preferably a gas atom (H), a methyl group, an ethyl group, a c(0)NH2, a C(0) methyl group or a C(0)-CF3 group. R1 0 may be hydrogen atom (η), methyl group, ethyl group, c(q) methyl group or C(0)_CF3, more preferably Η, C(0) methyl or C(0)-CF3, and More preferably Η or c(o) methyl. In the case where R3 is a heterocyclic ring of subtype (aa), (bb) or (cc), then R3 is preferably subtype (aa) or (bb), more preferably subtype (bb). A heterocyclic group. In the subtype (bb), ηι is preferably i. In the subtype (ce), # is preferably i. That is, it is preferably a six-membered ring in the R3 heterocyclic group. In R3, the heterocyclic group of the formula (aa), (bb) or (cc) is suitably unsubstituted (in this case, in the case where γ is Nrm, R1〇 is not classified as a substitution. base). In the subunit (aa), (bb) or (CC) < R3 heterocyclic group, one or two of the optional substituents preferably include (for example, or are independently ((for example))) 〇 h; net group (=〇); (V2 alkyl (such as methyl) or fluorene 12 fluoroalkyl (such as, for example, -CH2 F or T2). R3 heterocyclic ring in subtype (4), (bb) or (d)基困8784 卜96〇3〇3_中.doc -37- 1283678 More preferably one or two substituents on the atom include (for example, or independently (for example)) OH and/or ketone groups One or two of the preferred tethers (for example) are keto groups (=Q). In the R3 heterocyclic group of the subtype ((4), (4)) or ((3)), any keto group (= Preferably, the substituent is bonded to the carbon adjacent to X and/or may be at the 2-, 3-, 4- or 5-position of the R3 heterocycle. (In this case, the position of the R3 heterocycle It is regarded as the point of attachment in Formula 1. When R3 is a heterocyclic group of the formula (aa), and γ is nrI 〇, it is preferred that R10 is not C(〇)-Me. More preferably, when r3 is a subgroup (aa) heterocyclic group and Y is NR10, then Ri 〇 is preferably not c(〇)R. That is, or for example, Rl is preferably not C(〇)NH2, CXOK: 2 alkyl or (:(0)% fluoroalkyl. In a specific embodiment, when R3 is subtype (aa) In the case of a heterocyclic group, γ is 〇, S, s〇2 or NH 〇

視情況而定，根據本發明之一項具體實施例，_皮3不為 HN 。更佳情況是，當R3為亞式（bb)之雜環族基團，且 Y為NR1G時，及視情況當一為i時，則較佳尺1()係不為甲基。 更佳情況是，當R3為亞式（bb)之雜環族基團，且¥為观1〇， 及視情況當η1為1時，則較佳Ri〇係不為烷基或經取代之烷 基，意即或例如R10較佳係不為ClM烷基（例如甲基或乙 基）、q _2氟燒基或CH2C(0)NH2。於一項具體實施例中，當 R3為亞式（bb)之雜環族基團時’ γ較佳為〇、s、s〇2或 NR"，其中 Ri〇為 Η、C(0)NH2、C(〇KV2烷基或 c(0)_Cl 氟烷 基，或更佳Y為Η或C(0)Me。對亞式（bb)而言，更佳γ為〇或 NR1 G。在R3為亞式（dd)或（ee)之雙環狀基團之情況下，其較佳 87841-960303-中.doc -38 - 1283678 為亞式（ee)。在亞式（ee)中，較佳Υ1、Y2及Y3係皆為CH2。 較隹情況是，NHR3 為亞式（a)，(al)，(b)，(c)，(cl)，(c2)，(c3)，（c4)， (c5)5 (c6)5 (c7)5 (d)5 (e)5 (f)5 (g)? (gl)? (g2)? (g3)? (g4)? (h)5 (i)5 〇, (k)5 (kl)5 (L), (m)，(ml)，(m2)，(m3)，(m4)，(m5)，⑻，(〇)，(〇1)，(〇2)，(〇3)，(〇4)，(〇5)，(p)，(pl)， (p2)，(p3)，(p4)，(p5)，(p6)，(p7)，(p8)或(q):As the case may be, according to a particular embodiment of the invention, _皮3 is not HN. More preferably, when R3 is a heterocyclic group of the formula (bb), and Y is NR1G, and if the case is i, it is preferred that the ruler (1) is not a methyl group. More preferably, when R3 is a heterocyclic group of the formula (bb), and ¥ is 1 〇, and optionally η1 is 1, the preferred Ri 〇 is not alkyl or substituted. Alkyl, meaning or or, for example, R10 is preferably not a ClM alkyl group (e.g., methyl or ethyl), q2 fluoroalkyl or CH2C(0)NH2. In a specific embodiment, when R3 is a heterocyclic group of the formula (bb), 'γ is preferably 〇, s, s〇2 or NR", wherein Ri〇 is Η, C(0)NH2 , C (〇KV2 alkyl or c(0)_Cl fluoroalkyl, or more preferably Y is hydrazine or C(0)Me. For the subtype (bb), more preferably γ is 〇 or NR1 G. At R3 In the case of a bicyclic group of the formula (dd) or (ee), it is preferably 87841-960303-medium doc -38 - 1283678 is a subtype (ee). In the subtype (ee), Jiayu 1, Y2 and Y3 are both CH2. In other cases, NHR3 is subtypes (a), (al), (b), (c), (cl), (c2), (c3), (c4). ), (c5)5 (c6)5 (c7)5 (d)5 (e)5 (f)5 (g)? (gl)? (g2)? (g3)? (g4)? (h)5 (i) 5 〇, (k)5 (kl)5 (L), (m), (ml), (m2), (m3), (m4), (m5), (8), (〇), (〇 1), (〇2), (〇3), (〇4), (〇5), (p), (pl), (p2), (p3), (p4), (p5), (p6) , (p7), (p8) or (q):

(d) (e)(d) (e)

(f)(f)

ΗΝΰ (9)ΗΝΰ (9)

(k) (k1) (L)(k) (k1) (L)

HNHN

HN (h) (i) ⑴HN (h) (i) (1)

(m) (m2)(m) (m2)

HNHN

(n) NH0(n) NH0

<V0H r^vNHz ilN^^ HN^ (P) (P1) (P2)<V0H r^vNHz ilN^^ HN^ (P) (P1) (P2)

(P3) (p4) 87841-960303-中.doc -39- 1283678(P3) (p4) 87841-960303-中.doc -39- 1283678

在上文亞式（a)至（q)等之中，NHR3基團對式（I)吡唑并吡啶 4-位置之-NH-連接點係被劃底線。 較佳 NHR3 為亞式（C)，(cl)，(C2)，(C3)，(C4)，(C5)，(C6)，(C7)，(d)，(e)，(f)， (gl)，(g4)，⑻，(i)，①，(k)，(kl)，(L)，(m)，(ml)，(m2)，(m3)，(m5)，⑻，(〇)，(〇1)， (〇2)，(〇3)，(〇4)，(〇5)，(p)，(P2)，(P3)，(P5)，(P6)，(p7)或（q)。更佳 NHR3 為 亞式（c)，(cl)，(c4)，(c5)，⑻，⑴，①，(k)，(ml)，(m2)，⑻，⑻，(〇2)，(〇3)，(P2)， (p5)，(p6)或（q)。又更佳 NHR3 為亞式（c)，(h)，(k)，⑻，（ο)或（〇2);例 如（c)，(h)，（ο)或（〇2)。最佳R3為四氫-2Η-哌喃-4-基；意即NHR3最 佳為亞式（h)，如上文所示。 根據一項具體實施例 ，NHR3 為亞式 (a)，(b)，(c)，(d)，（e)，①，(g)，(gl)，(g2)，(g3)，(h)，⑴，①，(k)，(L)，(m)，(ml)，⑹， (〇)，（〇1)，(p)或（q)。在此具體實施例中，較佳NHR3為亞式 (c)，(d)，⑷，(f)，(gl)，(h)，(i)，G)，(k)，（m)，(ml)，(n)，(〇)，(〇1)，(p)或（q);且 在此具體實施例中，NHR3更佳為亞式（c)，(h)，(i)，G)， (k)，（ml)，⑻，（ο)或（q)。在此具體實施例中，NHR3又更佳為亞 式（c)，（h)，（k)，（η)或（〇)。最佳R3為四氫_2H_哌喃斗基；意即NHR3 最佳為亞式（h)，如上文所示。 根據另一項具體實施例，NHR3為亞式（a)，(b)，（c)，⑷，⑷， 87841-96〇3〇3_ 中.doc -40- 1283678 (f)，（g)，（h)，(〇,①或（k)。在此具體實施例中，NHR3較佳為亞式 (c)，（d)，（e)，（f)，⑻，（i)，①或（k);且在此具體實施例中，NHR3更 佳為亞式（c)，（h)，⑴，①或（k)。最佳R3為四氫-2H-哌喃_4_基；意 即NHR3最佳為亞式（h)，如上文所示。 較佳X為NR4R5。 在圮為心―烷基之情況下，則其較佳為Cl_4烷基或(^〈烷 基。在圮為^」氟烷基之情況下，則其較佳為Cl-2氟烷基。 R4最佳為氫原子（H)。 在R4為被一個取代基R11取代之C2_6烷基之情況下，則R4較 佳為被一個取代基R11取代之C2-4烷基（例如C2_3烷基）。R4更 佳為-(CH2)n3-Rn，其中η3為2、3或4。又更佳情況是，η3為2 及 / 或 R4為-(CH2)n3-〇H。 當R5為被一或兩個獨立取代基R11取代之〇2-6烷基時，R5較 佳為被一或兩個獨立取代基Ri 1取代之C2-4烷基（例如C2-3烷 基）。當R5為被一或兩個獨立取代基RU取代之C2-6烷基（例 如A·4燒基或C2·3燒基）時，R5較佳為被一個取代基ri 1取代 之C2·6烷基（例如（：2·4烷基或C2-3烷基）。R5更佳為_(CH2)n5_ R11，其中η5為2、3或4。η5較佳為2或3，更佳為2。 各取代基R11，與存在之任何其他R11取代基無關，較佳 為：經基（OH); Cm燒氧基（例如Ci·4燒氧基，譬如第三-丁 基氧基、乙氧基或甲氧基）；苯基氧基；苄氧基；eNRi2Ri3 ; -NR15 -(:(0)1116 ; -NR15 -CXCO-NH-R15 ;或-NRi 5 _s〇2 R16 (更佳為 Cm 烷氧基、-NR15-C(0)-NH-R15 或-NRi5_s〇2Ri6 ;最佳為 _^15_ S〇2R16)。在所有情況中，任何R"取代基，其係為〇H、燒 87841-960303-中.doc -41- 1283678 氧基或-NR12R13，不會在任何R4或R5取代之烷基（其係結合 至NR4R5之氮）之任何碳原子處經取代。 在烷基之情況下，則其較佳為Cl·5烷基或燒 基。在R5為Ci_8氟烷基之情況下，則其較佳為Cl·3氟燒基或 Ci -2氣纟元基。在R為視情況被Ci -2纟充基取代之C3 -8環燒基之 情況下，則C：3·8環烷基較佳係不會在結合至NR4R5氮之環_碳 處經取代。在R5為視情況經取代之C3_8環烷基之情況下，則 其更佳為C3-8環烷基（意即未經取代）。 當R5為視情況經取代之-(CH2)n4-C3_8環烷基時，其中n4為 1、2或3，則η4較佳為1或2，或更佳為1，及/或R5較佳為 視情況經取代之-(CH2)n4-C5_6環说基或視情況經取代之 -(CH；2 )n 4 -C6環燒基。當R5為视情況經取代之_(CH2 )n 4 -C3 _ 8環燒 基時，其較佳為未經取代。R5最佳為（環己基）甲基-，意即 -CH2-環己基。 當尺”為心-4烷基時，則其較佳為異丁基、第二·丁基或Cl-3烷基，譬如甲基或異丙基。當R19為-(CH2)n2G-〇R20時，則其 較佳為n2G為1，及/或R2G較佳為氫原子（H)。 C(0)NR12R13 ； -(CH2)n12-C(0)0R16 ； -CHR19-C(0)0R16 ; -(CH2)n12-S02-NR12R13 ; -(CH2)n12-S02R16 ;或-(CH2)n12-CN 時； 則在本發明之一項具體實施例中，R5可為：_(CH2)nu-C(0)R16 ； -(CH2 )n 12 -CCCONR12 R13 ； -(CH2 )n 12 -QOpR16 ; -(CH2)n12-S02-NR12R13 ; -(CH2)n12-S02R16 ;或-(CH2)n12-CN。 當 R5 為-(CH2)nn-C(0)R16;-(CH2)n12-C(0)NR12R13;-(CH2)n12· 87841-96〇3〇3-中.doc -42- 1283678 C_R^ 偶)nl2-S〇2W2Rl3 ;偶)nl2妈RU ^ -(CH2)n12-CN# ; ^R5?T4^^.(CH2)ni,.C(〇)Rl6 . _(CH2)ni2. C_^R";或-(CH2)nl2-CN;較佳為 _(cH2)nii_c(〇)Ri6。 π較佳為卜2、3或4;n11更佳為…。…可有利地為i 或2 〇 當m(CH2)n"_Het時，nu較佳為〇、_，更佳為_。In the above sub-formulas (a) to (q) and the like, the NHR3 group is delineated to the -NH-attachment point of the pyrazolopyridine 4-position of the formula (I). Preferably, NHR3 is subtypes (C), (cl), (C2), (C3), (C4), (C5), (C6), (C7), (d), (e), (f), (gl), (g4), (8), (i), 1, (k), (kl), (L), (m), (ml), (m2), (m3), (m5), (8), (〇), (〇1), (〇2), (〇3), (〇4), (〇5), (p), (P2), (P3), (P5), (P6), ( P7) or (q). More preferably, NHR3 is subtypes (c), (cl), (c4), (c5), (8), (1), 1, (k), (ml), (m2), (8), (8), (〇2), ( 〇3), (P2), (p5), (p6) or (q). More preferably NHR3 is subtype (c), (h), (k), (8), (o) or (〇2); for example (c), (h), (o) or (〇2). The most preferred R3 is tetrahydro-2-indole-piperidin-4-yl; that is, NHR3 is most preferably sub-formula (h) as shown above. According to a specific embodiment, NHR3 is subtypes (a), (b), (c), (d), (e), 1, (g), (gl), (g2), (g3), ( h), (1), 1, (k), (L), (m), (ml), (6), (〇), (〇1), (p) or (q). In this embodiment, preferably NHR3 is subtypes (c), (d), (4), (f), (gl), (h), (i), G), (k), (m), (ml), (n), (〇), (〇1), (p) or (q); and in this embodiment, NHR3 is more preferably sub-formula (c), (h), (i) , G), (k), (ml), (8), (ο) or (q). In this embodiment, NHR3 is more preferably subtype (c), (h), (k), (η) or (〇). The most preferred R3 is tetrahydro-2H-piperidin; meaning that NHR3 is most preferably subtype (h) as shown above. According to another specific embodiment, NHR3 is subtypes (a), (b), (c), (4), (4), 87841-96〇3〇3_. doc -40-1283678 (f), (g), (h), (〇, 1 or (k). In this particular embodiment, NHR3 is preferably subtypes (c), (d), (e), (f), (8), (i), 1 or (k); and in this particular embodiment, NHR3 is more preferably subtype (c), (h), (1), 1 or (k). The most preferred R3 is tetrahydro-2H-pyran-4-yl; That is, NHR3 is preferably subtype (h), as shown above. Preferably, X is NR4R5. In the case where oxime is a heart-alkyl group, it is preferably a C 4 alkyl group or a (alkyl group). In the case where 圮 is a fluoroalkyl group, it is preferably a Cl-2 fluoroalkyl group. R4 is preferably a hydrogen atom (H). In the case where R4 is a C2_6 alkyl group substituted by a substituent R11, R4 is preferably a C2-4 alkyl group substituted by a substituent R11 (e.g., C2_3 alkyl). R4 is more preferably -(CH2)n3-Rn, wherein η3 is 2, 3 or 4. More preferably, , η3 is 2 and/or R4 is -(CH2)n3-〇H. When R5 is 〇2-6 alkyl substituted by one or two independent substituents R11, R5 is preferably one or two independent Substituent R a C2-4 alkyl group substituted by i 1 (for example, C2-3 alkyl). When R 5 is a C 2-6 alkyl group substituted by one or two independent substituents RU (for example, A·4 alkyl or C 2·3 alkyl) When R5 is preferably a C2.6 alkyl group substituted by a substituent ri 1 (for example, (: 2·4 alkyl or C2-3 alkyl). R5 is more preferably _(CH2)n5_R11, wherein η5 Is 2, 3 or 4. η5 is preferably 2 or 3, more preferably 2. Each substituent R11 is independently of any other R11 substituent present, preferably: via (OH); Cm alkoxy ( For example, Ci. 4 alkoxy, such as tri-butyloxy, ethoxy or methoxy); phenyloxy; benzyloxy; eNRi2Ri3; -NR15-(:(0)1116; -NR15 - CXCO-NH-R15; or -NRi 5 _s〇2 R16 (more preferably Cm alkoxy, -NR15-C(0)-NH-R15 or -NRi5_s〇2Ri6; best _^15_ S〇2R16) In all cases, any R" substituent, which is 〇H, burn 87841-960303-medium.doc-4121283678 oxy or -NR12R13, will not be substituted at any R4 or R5 alkyl group Any carbon atom bonded to the nitrogen of NR4R5 is substituted. In the case of an alkyl group, it is preferably a Cl.5 alkyl group or an alkyl group. In the case of Ci_8 fluoroalkyl group, it is preferably a Cl.3 fluoroalkyl group or a Ci-2 gas group. In the case where R is a C3-8 cycloalkyl group optionally substituted by Ci-2, the C:3·8 cycloalkyl group is preferably not substituted at the ring-carbon attached to the NR4R5 nitrogen. . In the case where R5 is an optionally substituted C3_8 cycloalkyl group, it is more preferably a C3-8 cycloalkyl group (i.e., unsubstituted). When R5 is optionally substituted -(CH2)n4-C3_8 cycloalkyl, wherein n4 is 1, 2 or 3, then η4 is preferably 1 or 2, or more preferably 1, and/or R5 is preferred. The -(CH2)n4-C5_6 ring group or the optionally substituted -(CH;2)n 4 -C6 cycloalkyl group is optionally substituted. When R5 is optionally substituted _(CH2)n 4 -C3 -8 cycloalkyl, it is preferably unsubstituted. R5 is most preferably (cyclohexyl)methyl-, meaning -CH2-cyclohexyl. When the ruler is a heart-4 alkyl group, it is preferably an isobutyl group, a second butyl group or a Cl-3 alkyl group such as a methyl group or an isopropyl group. When R19 is -(CH2)n2G-〇 When R20, it is preferably n2G is 1, and/or R2G is preferably a hydrogen atom (H). C(0)NR12R13; -(CH2)n12-C(0)0R16; -CHR19-C(0) 0R16; -(CH2)n12-S02-NR12R13; -(CH2)n12-S02R16; or -(CH2)n12-CN; then in a specific embodiment of the invention, R5 can be: _(CH2) nu-C(0)R16; -(CH2)n 12 -CCCONR12 R13 ; -(CH2 )n 12 -QOpR16 ; -(CH2)n12-S02-NR12R13 ; -(CH2)n12-S02R16 ; or -(CH2) n12-CN. When R5 is -(CH2)nn-C(0)R16; -(CH2)n12-C(0)NR12R13;-(CH2)n12· 87841-96〇3〇3-中.doc -42 - 1283678 C_R^ even) nl2-S〇2W2Rl3; even) nl2 mom RU ^ -(CH2)n12-CN# ; ^R5?T4^^.(CH2)ni,.C(〇)Rl6 . _(CH2) Ni2. C_^R"; or -(CH2)nl2-CN; preferably _(cH2)nii_c(〇)Ri6. π is preferably Bu 2, 3 or 4; n11 is more preferably.... advantageously For i or 2 m when m(CH2)n"_Het, nu is preferably 〇, _, and more preferably _.

Het較佳為5-或6-員飽和或部份飽和雜環，及/或較佳為4_， 5-，6-或7-員飽和雜環。雜環Het較佳係含有一個選自〇、8及 N之環雜原子。在Het中之碳環原子較佳為未經取代。此最 佳為下列之一：Het is preferably a 5- or 6-membered saturated or partially saturated heterocyclic ring, and/or is preferably a 4-, 5-, 6- or 7-membered saturated heterocyclic ring. The heterocyclic Het preferably contains a ring hetero atom selected from the group consisting of ruthenium, 8 and N. The carbon ring atom in Het is preferably unsubstituted. This is best for one of the following:

當R5為視情況經取代之苯基時，則其較佳為視情況被一或 兩個本文定義之取代基取代之苯基。 當R5為視情況經取代之苯基時，則R5較佳為视情況獨立被 一、二或三個（較佳為一或兩個；或一個）下列基團取代之 苯基：_原子（較佳為氟基及/或氣基）；Ci2烷基；Ci2‘ 烷基（例如三氟甲基）；Q ·2烷氧基（例如甲氧基）；三氟曱氧 基；燒基續醢基（Cu燒基-so2_) ; cle2燒基-S02-NH-; R7R8N-S02- ; R7r8n-CO-; -NR15-C(0)R16 ; ; 〇H; c卜2 燒 氧基甲基；C1-2燒基-S〇2-CH2_ ;氰基（CN);或苯基，視情況 被氟基、C!·2烷基、q氟烷基、Ck烷氧基或〇1氟基烷氧基 87841-96〇3〇3-中.doc -43- 1283678 之一取代。R5更佳為視情況被—或兩個（較佳為一個）下列基 團取代之苯基：爵原子、Cl·2烷基、三氟甲基、Ci 2烷氧 基、三氟甲氧基、r7r8n-S〇2_、R7RSN_c〇_ 或 Ci 2 烷基 _s〇2_ CH2_❶當R5為视情況經取代之苯基時，則較佳為一或兩個 選用取代基之一或全部係在苯環之間_(3_及/或5_)及/或 對_ (4·)位置上經取代，相對於結合至^尺5氮之苯環-碳而 言。 R7及/或R8較佳係獨立為氫原子⑻；q _2烷基，譬如甲 基；C：3·6環烷基；或視情況被下列基團之一取代之苯基：氟 基、氯基、q-2烷基、（^氟烷基、Cl-2烷氧基或（^氟基烷氧 基；或R7 與 R8—起為—(CH2)n6_ 或 _(CH2)n8-X7-(CH2)n9-，其中X7 為NR14，或較佳為〇。 當R7為環烷基或視情況經取代之苯基時，則r8較佳係既非 環烷基，亦非視情況經取代之苯基。 R7及/或R8最佳係獨立為氫原子（H)或Ci_2烷基。R7較佳為 氫原子(H)。 η較佳為4或5。η7較佳為2、3或4。η8、η9及/或η1 〇較佳 係獨立為2。 一般而言，R5較佳係具有亞式（X)或⑺或（yl)或⑻。 當R5具有亞式（X)或（y)或(yl)或⑻時，則R5較佳係具有亞式 ⑻或（y)或（yl)或具有亞式（X)或（y)或⑻。r5更佳係具有亞式 ⑻或（y)，最佳為（X)。 η較佳為1或2。更佳n=l。較佳m=l。較佳r=l或2，更佳 87841-960303-中.doc -44- 1283678 在亞式（x)、（y)及/或（yi)中，較佳為a、b、d、e及f之 中沒有或-或兩個為氮；A、B、c、E*F之中沒有或一、 二或三個4 CR6 ;而其餘A、B、D、E及F為CH。更佳為 B D E及F之中沒有或一或兩個為氮；α、β、〇、ε 及F之中沒有或一或兩個*CR6 ;而其餘A、B、D、e&f為 CH。 在亞式⑻、⑺及/或（yi)中，較佳為沒有或其中一個a、 B、D、E及F為氮，及/或較佳為沒有、一或兩個A、B、 D、E 及 F 為 CR6。 · 亞式⑻較佳為：芊基；苯乙基苄基，在苯環上 被一或兩個R6取代基取代；苯乙基，在苯環上被 一或兩個R6取代基取代；或下列之一：When R5 is optionally substituted phenyl, it is preferably a phenyl group optionally substituted with one or two substituents as defined herein. When R5 is optionally substituted phenyl, then R5 is preferably a phenyl group optionally substituted by one, two or three (preferably one or two; or one) of the following groups: Preferred is a fluoro group and/or a gas group; a Ci2 alkyl group; a Ci2' alkyl group (e.g., a trifluoromethyl group); a Q2 alkoxy group (e.g., a methoxy group); a trifluoromethoxy group; Sulfhydryl (Cu alkyl-so2_); cle2 alkyl-S02-NH-; R7R8N-S02-; R7r8n-CO-; -NR15-C(0)R16; ;〇H; c卜2 alkoxymethyl ; C1-2 alkyl-S〇2-CH2_; cyano (CN); or phenyl, optionally as a fluorine group, C!·2 alkyl group, q fluoroalkyl group, Ck alkoxy group or 〇1 fluoro group One of the alkoxy 87841-96〇3〇3-中.doc-43- 1283678 is substituted. R5 is more preferably a phenyl group which is optionally substituted with two or more (preferably one) of the following groups: a ruthenium atom, a Cl 2 alkyl group, a trifluoromethyl group, a Ci 2 alkoxy group, a trifluoromethoxy group. , r7r8n-S〇2_, R7RSN_c〇_ or Ci 2 alkyl_s〇2_CH2_❶ When R5 is optionally substituted phenyl, it is preferred that one or both of the substituents are attached to benzene The _(3_ and/or 5_) and/or the _(4·) positions between the rings are substituted with respect to the benzene ring-carbon bonded to the 尺5 nitrogen. R7 and/or R8 are preferably independently a hydrogen atom (8); q _2 alkyl, such as methyl; C: 3·6 cycloalkyl; or phenyl substituted by one of the following groups: fluoro, chloro Base, q-2 alkyl, (^fluoroalkyl, Cl-2 alkoxy or (^fluoroalkoxy; or R7 and R8 - (CH2)n6_ or _(CH2)n8-X7- (CH2)n9-, wherein X7 is NR14, or preferably 〇. When R7 is cycloalkyl or optionally substituted phenyl, then r8 is preferably neither cycloalkyl nor optionally substituted. R7 and/or R8 are preferably independently a hydrogen atom (H) or a Ci_2 alkyl group. R7 is preferably a hydrogen atom (H). η is preferably 4 or 5. η7 is preferably 2, 3 or 4. η8, η9 and/or η1 〇 are preferably independently 2. In general, R5 preferably has the subtype (X) or (7) or (yl) or (8). When R5 has the subtype (X) or ( When y) or (yl) or (8), then R5 preferably has the formula (8) or (y) or (yl) or has the formula (X) or (y) or (8). R5 preferably has the subtype (8) or (y), preferably (X). η is preferably 1 or 2. More preferably n = 1. Preferred m = 1. Preferred r = 1 or 2, more preferably 87841-960303 - medium. doc - 44 - 1283678 in the Asian style (x) (y) and/or (yi), preferably none or - or two of a, b, d, e and f are nitrogen; none of A, B, c, E*F or one or two Or three 4 CR6; and the remaining A, B, D, E and F are CH. More preferably none or one or two of BDE and F are nitrogen; none of α, β, 〇, ε and F or One or two *CR6; and the remaining A, B, D, e&f are CH. In sub-forms (8), (7) and/or (yi), preferably none or one of a, B, D, E and F is nitrogen, and/or preferably no, one or two of A, B, D, E and F are CR 6. · Subtype (8) is preferably: fluorenyl; phenethylbenzyl, which is on the phenyl ring Substituted with one or two R6 substituents; phenethyl, substituted on the phenyl ring by one or two R6 substituents; or one of the following:

其中R6a為無論是如本文中定義之R6或（較佳為）氫。 亞式（X)最佳為苄基或吡啶基甲基 •CH2Y^i [例如吡啶冬基甲基（意即 、吡啶-3-基甲基， -ch2 丫、 或較佳為吡啶-2-基甲基（意即 )]。 87841-96〇3〇3_ 中.doc -45- 1283678 亞式（y)較Wherein R6a is R6 or (preferably) hydrogen as defined herein. The subtype (X) is most preferably benzyl or pyridylmethyl•CH2Y^i [e.g. pyridylmethylmethyl (i.e., pyridin-3-ylmethyl, -ch2, or preferably pyridin-2-) Methyl group (meaning)] 87841-96〇3〇3_中.doc -45- 1283678 Asian (y)

佳為Good for

其中R6a.為或獨立為無論是如本文中定義之 / — 4為氫亞式（y)較佳係不會在介於&員芳族環與結 合至nr4r5氮之碳間之碳上被酮基取代。Wherein R6a. is or independently such that, as defined herein, / 4 is a hydrogen subtype (y) preferably does not be on the carbon between the & aromatic ring and the carbon bonded to the nr4r5 nitrogen. Keto group substitution.

其中為或獨立為無論是如本文中定義之R0或較佳為氫。 在亞式（Z)中’較佳為沒有或一或兩個J、L、Μ及Q為氮。 在亞式（X)、（力及/或⑻中，各R6，與存在之任何其他R6 播關，較佳為氟、氣、溴或破原子、甲基、乙基、正-丙 基、異丙基、A烷基、三氟甲基、_CH2〇H、甲氧基、乙氧 基、q氟基烷氧基（例如三氟甲氧基或二氟甲氧基）、〇H、 Cl - 3燒基S(〇)2 -(譬如甲基橫酿基，其係為MeS(0)2 -)，q _ 3燒 基8(〇)2_·-，譬如甲基-S02-NH-，Me2N-S(0)2-、H2N_S(〇)2-、 -CONH2、-CONHMe、-C02H、氰基（CN)、NMe2、第三-丁氧基 甲基，或Cb3烷基S(0)2-CH2-，譬如甲基-S02-CH2-。各於， 與存在之任何其他R6無關，更佳為氟、氣、溴或碘原子、 甲基、乙基、正-丙基、異丙基、異丁基、三氣甲基、 87841-960303-φ^〇〇 -46 - 1283678 -CH2 OH、甲氧基、乙氧基、q氟基烷氧基（例如三氟甲氧基 或二氟甲氧基），C^-3烷基S(0)2-，譬如甲基磺醯基，Ci_3烷 基 S(0)2-NIl·，譬如甲基-S02-NH-，Me2N-S(0)2-、H2N-S(0)2-、 _conh2，或Ci-3烷基s(o)2-ch2-，譬如甲基-so2-ch2。各R6， 與存在之任何其他R6無關，又更佳為氟、氯或溴原子、甲 基、乙基、正-丙基、異丙基、三氟甲基、-CH2 OH、甲氧 基、二氟甲氧基、甲基磺醯基、甲基-S02-NH-或甲基-S02-CH2- ο 上文較佳R6取代基亦獨立為關於在r5為視情況經取代苯基 之情況下之較佳苯基選用及獨立取代基。 在亞式（X)及/或（y)中，較佳為一、二或三個R6取代基存 在於B、D及/或E中；以致例如在亞式（X)中，一、二或三 個R取代基係存在於間_ (3-及/或5_)及/或對_ (4_)位置中， 相對於-((:巧允側鏈而言。 在亞式⑻及/或（y)中，任何選用R6取代基可視情況僅存 在於B、D及/或E中，以致在亞式（χ)中，任何選用r6取代 基僅存在於間-(3-及/或5_)及/或對_(4_)位置中，相對於 -(〇^)0侧鏈而言。或者，在亞式⑻中，任何選用r0取代基可 ，在於鄰-(2-及/或6-)位i，相對於偶χ側鏈而言，無論 單獨或與一或多個其他選用R6取代基併用。 對R5整體而言Wherein or independently is R0 or preferably hydrogen as defined herein. In the subtype (Z), it is preferred that none or one or two of J, L, oxime and Q are nitrogen. In the formula (X), (force and / or (8), each R6, and any other R6 present, preferably fluorine, gas, bromine or atomic, methyl, ethyl, n-propyl, Isopropyl, Aalkyl, trifluoromethyl, _CH2〇H, methoxy, ethoxy, q-fluoroalkoxy (eg trifluoromethoxy or difluoromethoxy), 〇H, Cl - 3 alkyl S (〇) 2 - (such as methyl cross-linking, which is MeS (0) 2 -), q _ 3 alkyl 8 (〇) 2_·-, such as methyl-S02-NH- ,Me2N-S(0)2-, H2N_S(〇)2-, -CONH2, -CONHMe, -C02H, cyano (CN), NMe2, tri-butoxymethyl, or Cb3 alkyl S(0 2-CH2-, such as methyl-S02-CH2-, each, independently of any other R6 present, more preferably a fluorine, gas, bromine or iodine atom, methyl, ethyl, n-propyl, iso Propyl, isobutyl, trimethyl, 87841-960303-φ^〇〇-46 - 1283678 -CH2 OH, methoxy, ethoxy, q-fluoroalkoxy (eg trifluoromethoxy or Difluoromethoxy), C^-3 alkyl S(0)2-, such as methylsulfonyl, Ci_3 alkyl S(0)2-NIl·, such as methyl-S02-NH-, Me2N- S(0)2-, H2N-S(0)2-, _conh2, or Ci-3 The group s(o)2-ch2-, such as methyl-so2-ch2. Each R6, independently of any other R6 present, is more preferably a fluorine, chlorine or bromine atom, methyl, ethyl or n-propyl. , isopropyl, trifluoromethyl, -CH 2 OH, methoxy, difluoromethoxy, methylsulfonyl, methyl-S02-NH- or methyl-S02-CH2- ο The R6 substituent is also independently a preferred phenyl moiety and an independent substituent in the case where the phenyl group is optionally substituted at r5. In the subtypes (X) and/or (y), preferably one or two. Or three R6 substituents are present in B, D and/or E; such that, for example, in subformula (X), one, two or three R substituents are present in the intermediate _ (3- and / or 5 _) and / or in the _ (4_) position, relative to - ((: Qiao Yun side chain. In the subtype (8) and / or (y), any choice of R6 substituents may only exist in B, D and / Or E, such that in the subtype (χ), any optional r6 substituent is present only in the inter-(3- and/or 5_) and/or in the _(4_) position, relative to -(〇^)0 In the case of a side chain, or in the subtype (8), any r0 substituent may be selected, in the o-(2- and/or 6-) position i, relative to the even side For, either alone or in combination with one or more other substituent groups R6 selected and used. Overall for R5

Cl - 6燒基（例如Cj，2或 R5較佳為氫原子田）； 、環烷基（例如c5_6環烷 ’视情況被一或兩個下列基 二氣甲基、甲氧基或三氟甲 燒基或（：3·6燒基）；cle4氟烷基 基）、（C5·6環烷基）甲基·，苯基 團取代··氟或氯原子、甲基、 87841·96〇3〇3_ 中.doc •47- 1283678 氧基；或R5具有亞式（X)、（y)或（z)，例如，如上述者。 R5又更佳為氫原子（H)、甲基、乙基、正-丙基、異丙基、 2-乙基丁 -1-基、環戊基、環己基、（環己基）甲基_，视情況經 取代之本基’例如氟苯基’例如4-氟苯基，視情況經取代之 苄基或視情況經取代之吡啶基甲基。R5可視情況為爷基、 p比淀基甲基（例如p比淀-4-基曱基、p比淀-3-基甲基，或較佳為 吡啶-2-基甲基）或4-氟苯基。 NR4R5較佳係不為NH2。R5較佳係不為氫原子（H)。 當R4與R5 —起採用為視情況經取代之_(CH2)p 1 _或視情況經 取代之-C(0)-(CH2)p2-或-(CH2)P3-X5-(CH2)P4·或-C(0)-X5-(CH2)p5-或 任何前 述之部 份不飽 和衍生 物時， R4 與 R5 較佳係 一起採 用為視情況經取代之-(CHJp1-或視情況經取代之_C(0)-(CH2 )p 2 -或-(CH2 )p 3 -X5 -(CH2 )p 4 -或-C⑼_X5 -(CH2 )p 5 -(意即不為任 何此等之部份不飽和衍生物）。 當R4與R5—起採用為視情況被Ri8取代之-(CHJp1-，或视情 況被 R18 取代之-C(〇HCH2)p2-或-(ch2)p3-x5-(ch2)p4-時，nr4r5 可例如為：一<3，視情況被R18取代，或：N0，視情況被 R18取代，或，視情況被R18取代，或：一(意即r4 、、_r~\ 與 R5 —起採用為-(CHA-NCR17)-((：112)2-)或：(意即 R4 與 R5 一起採用為-(ch2)2-o-(ch2)2·)。 R17較佳為氫原子（H); Ci-4烷基（例如Q-2烷基）；C3·6環坑 基；-(ch2)p6-c(o)r16或視情況經取代之苯基或芊基° R更佳 為H;(：卜2烷基；-(CH2)P6-C(0)R16或視情況經取代之苯基。 87841-96〇3〇3_中 doc -48 - 1283678 當R4與R5 一起採用為偶)Λ或-C(〇HCH2)p2-時，nrW雜 環較佳係未被R1 8取代。 當R4與R5一起採用為偶)Λ或-c(oHCh2)p2_，且若nr4r5 雜環係被Rl8取代時，則Rl8视情況不會在結合至nr4r5環-氮 之環•碳上經取代。 當R4與R5 -起採用為_(αί2)Λ或部>(CH2)p2_或偶)ρ3_χ5· (CH2)/-或-C(0>x5_(CH2)p5_或任何此等之部份不飽和衍生 物，且其中NR4R5雜環係稠合至苯環，视情況在苯基上被一 或兩個下列基團取代時：齒原子、C12烷基、。氟烷基、 q-2烷氧基或心氟基烷氧基；則在本發明之一項具體實施例 中，NR4R5為Cl - 6 alkyl (for example, Cj, 2 or R5 is preferably a hydrogen atom field); a cycloalkyl group (for example, c5_6 cycloalkane' is optionally substituted by one or two of the following dimethyl, methoxy or trifluoro Methyl group or (:3·6 alkyl); cle4 fluoroalkyl group, (C5·6 cycloalkyl)methyl group, phenyl group substitution · fluorine or chlorine atom, methyl group, 87841·96〇 3〇3_中.doc •47-1283678 oxy; or R5 has the formula (X), (y) or (z), for example, as described above. More preferably, R5 is a hydrogen atom (H), methyl, ethyl, n-propyl, isopropyl, 2-ethylbutan-1-yl, cyclopentyl, cyclohexyl, (cyclohexyl)methyl_ An optionally substituted base such as a fluorophenyl group such as 4-fluorophenyl, optionally substituted benzyl or optionally substituted pyridylmethyl. R5 may optionally be a genomic group, p is more than a benzyl group (e.g., p is more than benzyl-4-yl fluorenyl, p is more than -3-methylmethyl, or preferably pyridin-2-ylmethyl) or 4- Fluorophenyl. NR4R5 is preferably not NH2. R5 is preferably not a hydrogen atom (H). When R4 and R5 are used together, _(CH2)p 1 _ or optionally substituted -C(0)-(CH2)p2- or -(CH2)P3-X5-(CH2)P4 Or -C(0)-X5-(CH2)p5- or any of the foregoing partially unsaturated derivatives, R4 and R5 are preferably employed together as an optionally substituted -(CHJp1- or optionally substituted _C(0)-(CH2)p 2 - or -(CH2 )p 3 -X5 -(CH2 )p 4 - or -C(9)_X5 -(CH2 )p 5 - (meaning not part of any of these Unsaturated derivatives). When R4 and R5 are used, they are substituted by Ri8 as appropriate (CHJp1-, or -C(〇HCH2)p2- or -(ch2)p3-x5-(substituted by R18) When ch2)p4-, nr4r5 may be, for example, a <3, optionally replaced by R18, or: N0, as the case may be replaced by R18, or, if appropriate, by R18, or: one (meaning r4, _r ~\ Use with R5 as -(CHA-NCR17)-((:112)2-) or :(meaning that R4 and R5 together are -(ch2)2-o-(ch2)2·). R17 Preferred is a hydrogen atom (H); a Ci-4 alkyl group (e.g., Q-2 alkyl group); a C3·6 ring pit group; -(ch2)p6-c(o)r16 or an optionally substituted phenyl group or芊 base ° R is more preferably H; (: 2 2 alkyl; - (CH2) P6-C (0) R16 or a substituted phenyl group. 87841-96〇3〇3_中 doc -48 - 1283678 When R4 and R5 are used together as an oxime or -C(〇HCH2)p2-, the nrW heterocyclic ring is preferably not R1 8 is substituted. When R4 is combined with R5 as Λ) or -c(oHCh2)p2_, and if the nr4r5 heterocyclic ring is substituted by Rl8, then Rl8 is not bound to the nr4r5 ring-nitrogen ring. The upper is substituted. When R4 and R5 are taken as _(αί2)Λ or part>(CH2)p2_ or even)ρ3_χ5·(CH2)/- or -C(0>x5_(CH2)p5_ or any Part of the unsaturated derivative, wherein the NR4R5 heterocyclic ring is fused to the phenyl ring, optionally substituted on the phenyl group with one or two of the following groups: a tooth atom, a C12 alkyl group, a fluoroalkyl group. , q-2 alkoxy or heart fluoroalkoxy; in a particular embodiment of the invention, NR4R5 is

或 取代：鹵原子、 /中苯基係視情況被一或兩個下列基團 Cl·2烷基、Cl氟烷基、Q-2烷氧基或。氟基 烷氧基。 於本發明之一項具體實施，中’ 及/或可例 如獨立為卜Ο或卜n/ -NR14 或或\一1〜，或 一 (意 21 2 與 R1 3 —起或 R7 與 R8 一起為 <CH2 _N(Rl 4 ^CH2 D 或 (意即 R12 與 R13 — 起或 r7 與 R8 一起為 _(CH2 )2 _〇_(cH2 )2 _)Or substituted: a halogen atom, / a phenyl group is optionally one or two of the following groups: Cl.2 alkyl, Cl fluoroalkyl, Q-2 alkoxy or. Fluoroalkyloxy. In a specific implementation of the present invention, 'and/or may be independently Ο or 卜 n/-NR14 or or ～1~, or one (meaning 21 2 together with R1 3 or R7 and R8 together <CH2 _N(Rl 4 ^CH2 D or (that is, R12 and R13 or r7 and R8 together are _(CH2)2 _〇_(cH2)2 _)

:―N ρ 或 NMe2 R15較佳為氫原子（Η)或q _4烷基（例如tBu或Ci 2虎基，例如 甲基）；R15更佳為氫原子（H)。 但是，R4與R5較佳係未一起採用，意即並未一起採用以形 87841-960303-中.doc -49- 1283678 成本文中所述之NR4R5環系統。 (類似優先性係如同關於R5，適用於R5a，惟115&不能為氫 原子。R5a最佳為乙基）。 在尤佳具體實施例中，NR4R5係如以下任一實例中所定義 之 NR4R5 :實例 21-98, 100-182, 187-188, 191-200, 201-203,210-353, 355-651，653-658 及 660-664。 特佳式⑴化合物或其鹽為： 4-(環戊基胺基）-1·乙基-lH-p比峻并[3,4-b]p比嗓_5·叛酸乙酿， 4-(環己胺基）-1-乙基-1H-吡唑并[3,4-b]吡啶-5-羧酸乙酯， 1-乙基-4-(四氫-2H-喊喃-4-基胺基）-1Η-ρ比峻并[3,4-b]外b淀-5-叛酸 乙酯， 4-[(1-甲基六氫吡啶-4-基）胺基]-1-乙基-1H-吡唑并[3,4-b]吡啶-5-羧 酸乙酯， 4-[(1·乙醯基六氫吡啶-4-基）胺基]小乙基_1H-吡唑并[3,4-b]吡啶-5-羧酸乙酯， 4_(環戊基胺基）-1-甲基-1H-P比嗤并[3,4-b>比淀-5-叛酸乙酿， 1-甲基-4-(四氫-2H·哌喃斗基胺基）-1Η-吡唑并[3,4_b]吡啶-5-羧酸 乙酯， 1-乙基-4_[(3S)-四氫呋喃1基胺基]-1H-吡唑并[3,4-b]吡啶-5-羧酸 乙酯， 1_乙基-4_[(3R)-四氳呋喃冰基胺基]411_吡唑并[3,4七]吡啶羧酸 乙酯， 1-乙基-4-(四氫-2H-硫代哌喃4-基胺基）-1Η_吡唑并[3,4-b]吡啶-5- 羧酸乙酯， 87841-96〇3〇3_ 中.doc -50- 1283678 1-乙基-4-(四氫嘧吩-3-基胺基)-1Η-吡唑并[3,4_b]吡啶-5-羧酸乙酯， 4_(環丙胺基）小乙基-1H-吡唑并[3,4-b]吡啶-5-羧酸乙酯， 4- [(1，1-二氧化四氫嘧吩·3-基）胺基]-1·乙基-1H-吡唑并[3,4-b]吡啶- 5- 羧酸乙酯， 4_[(1，1_二氧化四氫-2H_硫代哌喃_4_基）胺基]-1-乙基_1H-吡唑并 [3,4-b]吡啶-5-羧酸乙酯， N-苄基小乙基(四氫·2Η-哌喃-4-基胺基）·1Η_吡唑并[3,4-b]吡啶· 5-甲醯胺， 1-乙基-N_(4-氟苯基）-4-(四氫-2H-哌喃斗基胺基）-1Η-吡唑并[3,4-b] 外匕淀-5-甲醯胺， N-環戊基-4-(環戊基胺基)_1_乙基-1H-吡唑并[3,4-b]吡啶-5-甲醯胺， 4-(環己胺基）環戊基-1-乙基-1H-吡唑并[3,4七>比啶-5-甲醯胺， N-環戊基小乙基冰(四氫-2H-哌喃-4·基胺基）-1Η-吡唑并[3,4-b]吡 啶-5-甲醯胺， 4-[(1-乙醯基六氫吡啶-4-基）胺基]-N·環戊基-1-乙基-1H-吡唑并 [3,4-b]吡啶-5-甲醯胺， N_環戊基-1_乙基_5-(四氫吡咯·μ基羰基）_1H_吡唑并[3,4七]吡啶冬 胺， N-環己基-1乙基-5-(四氫吡咯+基羰基）-1Η·吡唑并[3,4七]吡啶冬 胺， 1-乙基-5_(四氫峨咯-丨·基羰基）况四氫_211_哌喃斗基_m-吡唑并 [3,4-b]吡啶-4-胺， 4- (¾:戊基胺基）_1_乙基-N七比啶-4_基甲基）_1H_吡唑并[3,州吡咬· 5- 甲醯胺， 87841-96〇3〇3·中.doc -51 - 1283678 4-(環己胺基）小乙基-Ν-O比啶-4-基甲基）-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺， 1-乙基-N-(吡啶-4-基甲基）-4-(四氫-2H-哌喃-4_基胺基）-1Η-吡唑并 [3,4-b]吡啶-5-甲醯胺， 4-(環戊基胺基）-1-乙基-1H-吡唑并P，4-b]吡啶-5-甲醯胺， 4-(環己胺基）-1-乙基-1H-吡唑并[3,4-b]吡啶-5·甲醯胺， 1·乙基_4_(四氫-2H-哌喃-4_基胺基）_1H-吡唑并[3,4-b]吡啶_5_甲醯 胺， N_芊基_4-(環戊基胺基）小乙基-1H-吡唑并[3,4-b]吡啶_5_甲醯胺， 芊基_4-(環己胺基）小乙基-1H-吡唑并[3,4_b]吡啶-5-甲醯胺， 4-[(1-乙醯基六氫？比攻-4_基）胺基]-1^-爷基-1-乙基-111-叶1：吐并[3,4-b]p比攻-5-甲酿胺， 4-(環戊基胺基）小乙基-N-(2_乙基丁基）·1Η-吡唑并[3,4-b]吡啶-5- 甲醯胺， 4-(環己胺基）小乙基-N-(2-乙基丁基）-1Η-吡唑并[3,4_b]吡啶-5-曱 醯胺， 1-乙基-N-(2-乙基丁基）-4_(四氮-2H-喊喃-4-基胺基）-1Η-ρ比吨并 [3,4-b]吡啶-5-甲醯胺， 1-乙基-N-(2-乙基丁基）-4-[(1-甲基六氫吡啶-4-基）胺基]-1H-吡唑 并[3,4-b]吡啶-5-甲醯胺， 4-[(1-乙醯基六氫吡啶斗基）胺基]_1·乙基-N_(2-乙基丁基）-1Η-吡 唑并[3,4-b]吡啶-5-甲醯胺， 4-(環戊基胺基）小乙基-N-(4_氟苯基）-1H-p比唾并[3,4-b]外b淀-5-甲 醯胺， 87841-960303-中.doc -52· 1283678 4-(環己胺基）小乙基-N-(4-氟苯基）-1Η-外b唆并[3,4-b]峨淀-5-甲醯 胺， 1-乙基-N-(4-氟苯基）-4-[(1-曱基六氫吡啶冰基）胺基]-1H_吡唑并 [3,4-b]吡啶-5-甲醯胺， 4-[(1-乙酸基穴氯p比咬-4-基）胺基]-1-乙基-N-(4-氣苯基）-1H-p比也 并[3,4-b]吡啶-5-甲醯胺， 4-(環戊基胺基）-1-乙基-N-正-丙基-1H-P比唆并[3,4-b]外b淀-5-甲酿 胺， 癱 4-(環己胺基）-1-乙基-N-正-丙基_1H-吡唑并[3,4-b]吡啶-5-甲醯胺， 1-乙基-N-正-丙基_4-(四氫_2Η·哌喃-4-基胺基）_1Η-吡唑并[3,4-b]吡 啶-5-甲醯胺， 4-[(1-乙酿基穴鼠p比淀-4-基）胺基]-1-乙基-N-正-丙基-lH-p比唆并 [3,4-b]外b違_5_甲酿胺， N-苄基小乙基-4-[(l-甲基六氫吡啶-4-基）胺基]-1H-吡唑并[3,4-b] 外匕淀-5-甲酿胺， 4- [(1-乙醯基六氫吡啶-4-基）胺基]-1-乙基-N-(吡啶-4-基甲基）-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺， N-苄基-4-(環戊基胺基）-1_甲基-1H-吡唑并[3,4-b]吡啶_5·甲醯胺， N-芊基-4_(環己胺基）-1_甲基-1H-吡唑并[3,4-b]吡啶-5-甲醯胺， N-苄基_1·甲基斗(四氫-2H-哌喃-4-基胺基）-1Η-吡唑并[3,4-b]吡啶- 5- 甲醯胺， 4-(環戊基胺基）-N-(2-乙基丁基）-1-甲基-1H-吡唑并[3,4七]吡啶-5-甲醯胺， 4-(環己胺基）-N-(2-乙基丁基）-1·甲基-1H-吡唑并[3,4-b]吡啶_5_甲 87841-9603〇3·中.doc -53- 1283678 醯胺， N-(2-乙基丁基）-1_甲基_4_(四氫-2H-哌喃-4-基胺基）·1Η-吡唑并 [3,4-b]p比咬-5_甲醯胺， 4-(環戊基胺基）-N-(4-氟苯基）小甲基-1H-吡唑并[3,4-b]吡啶-5-甲 醯胺， 4·(環己胺基）·Ν_(4·氟苯基）-1-甲基-1H-吡唑并[3,4-b]吡啶-5_甲醯 胺， N-(4-氟苯基）-1-甲基·4-(四氫-2H-哌喃-4-基胺基）-1Η_吡唑并[3,4七] 外匕淀-5-甲酸胺， 4-(環戊基胺基）·1-甲基-1H-P比嗅并[3,4-b>比淀_5_甲酸胺， 4_(環己胺基）小甲基-1H-P比峻并[3,4-b]p比淀-5-甲醯胺， 1-甲基-4-(四氳-2H_哌喃斗基胺基）-1Η-吡唑并[3,4-b]吡啶-5-甲醯 胺， 4-[(1-乙醯基六氫吡啶_4_基）胺基]-N-苄基-1_甲基-1H-吡唑并[3,4-b>比淀-5-甲醯胺， 4-[(1-乙醯基六氫吡啶-4-基）胺基]-N-(2-乙基丁基）-1-甲基-1H-外匕 吐并[3,4-b]p比淀-5-甲酿胺’ 4- [(1·乙醯基六氫吡啶-4-基）胺基]-N-(4_氟苯基）_1_甲基_1H-吡唑 并[3,4-b]p比淀-5-甲酿胺’ 1_乙基-N-甲基-4_(四氫-2H·哌喃冰基胺基）-iH-吡唑并[3,4七>比啶- 5- 甲醯胺， 1-乙基-N，N-二甲基-4-(四氫-2H-哌喃-4-基胺基）·1Η-吡唑并[3,4-b] 吡淀-5-甲醯胺， 1-乙基-N-乙基-4-(四氫-2H-哌喃-4-基胺基）-1Η-吡唑并[3,4_b]吡啶- 87841-960303-中.doc -54- 1283678 5-甲醯胺， 1-乙基-N-異丙基-4-(四氫-2H-哌喃_4_基胺基）-1Η-吡唑并[3,4-b]吡 淀_5_甲Si胺， N·苄基-1-乙基-4-[(3S)-四氫呋喃-3-基胺基]-1H-吡唑并[3,4-b]吡啶· 5-甲酿胺， N-卞基-1-乙基-4-[(3R)-w氮吹喃·3_基胺基]-lH_T^b峻并[3,4-b]p比淀- 5-甲酿胺， N-卞基-1-乙基-4_(四氫p塞吩-3-基胺基）_1Η·ρ比吐并[3,4-b]p比淀-5-甲 醯胺， N-爷基-4-(環丙胺基）小乙基-IHh?比峻并[3,4-b]p比淀·5_甲醯胺， N-亨基·4-[(1，1-二氧化四氫ρ塞吩_3_基）胺基]小乙基-iH-p比吐并 [3,4-b]吡啶-5-甲醯胺， N-苄基-4-[(1，1-二氧化四氫-2H-硫代喊喃_4·基）胺基]-1_乙基_ih_ 外匕峻并[3,4-b>比淀-5-甲醯胺， N-苄基_1_乙基冰(四氫-；2H-硫代哌喃_4_基胺基）-1Η-吡唑并[3,4-b] 外匕淀-5-甲醯胺， 1_乙基-Ν·(4·氟苯基）-4-[(3S)-w氫呋喃冬基胺基]_1Η·吡唑并[3,4-b] 吡淀-5-甲醯胺， 1·乙基·Ν-(4-氟苯基）冰[(3R)_四氫呋喃各基胺基].吡唑并p，4-b] 外匕淀-5-甲酿胺^ 1-乙基-N-(4-氟苯基）-4_(四氫-2H-硫代哌喃_4·基胺基>m_吡唑并 [3,4-b]p比淀-5-甲酿胺， 1-乙基-N-(4-氟苯基）-4-(四氫噻吩·3_基胺基）_1H_吡唑并[3,4七]吡 淀-5-甲酿胺， 87841-96〇3〇3-中.doc -55- 1283678 4-(環丙胺基）-1_乙基_Ν·⑷氟苯基）_1H_吡唑并[3,4_b]吡啶-5_甲醯 胺， 4-[(1山二氧化四氫嘍吩_3_基）胺基]-1-乙基-N-(4-氟苯基）-1Η-吡唑 并[3,4-b]p比淀-5-甲酿胺，或 4-[(1，1_二氧化四氫-2H_硫代哌喃斗基）胺基]乙基_N_(4_氟苯 基HH-吡唑并[3,4七]吡啶_5_甲醯胺； 處》其鹽，例如其藥學上可接受之鹽。 此等特定化合物之結構係示於後文實例1_98中。 或者，式（I)化合物或其鹽特佳為： 1-乙基-N-[4_(甲磺醯基）爷基]冰(四氫_2H-哌喃-4-基胺基）_1H-吡 唑并[3,4-b]吡啶-5-甲醯胺， (1-{[1-乙基_4_(四氫-2H-哌喃斗基胺基）-1Η-吡唑并[3,4_b]吡啶-5-基]羰基}六氫吡啶-3-基）甲基胺基甲酸第三·丁酯， 1-乙基_N_[3-(甲磺醯基）爷基]_4-(四氫-2H-哌喃-4-基胺基）-1Η-吡 唑并P，4_b]吡啶-5-甲醯胺， 1-乙基-5-{[5_甲氧基_6·(三氟甲基）·2,3_二氫-1H-吲哚-1_基]羧基}-Ν-四氫-2Η_哌喃-4-基-1Η_吡唑并[3,4_b]吡啶-4_胺， N-[(5-氯基吡啶-2-基）甲基]_1_乙基-4_(四氫-2H-喊喃-4-基胺基）-1Η-吡也并[3,4-b]吡淀-5-甲醯胺， N-(4-氣苄基）_1_乙基-N-異丙基-4-(四氫_2H-旅喃-4·基胺基>1H-吡 唑并[3,4-b]吡啶-5-甲醯胺， N-(3-氯苄基）_1·乙基_Ν·(2·羥乙基）-4-(四氫-2H-哌喃_4_基胺基）·1Η-ρ比也并[3,4-b]外t咬-5-甲醯胺， 1-乙基-Ν-[(5·甲基-3-苯基異17号峻·4-基）甲基]-4-(四氮-2H_喊喃-4_ 87841-960303-中.doc -56- 1283678 基胺基）-1Η-ρ比也并[3,4-b>比嗓-5-甲酸胺， N-(2-弟二-丁乳基乙基）-1_乙基_4-(四氯-2H-旅喃-4_基胺基）-1Η-ρ比 唑并[3,4-b]吡啶-5-甲醯胺， 1-乙基-4_(四氫-2H-哌喃-4-基胺基）-Ν-(1，3-嶁唑_2_基甲基）-1Η-吡 唑并[3,4-b]吡啶-5-甲醯胺， 1-乙基-N-(嘧啶-4-基甲基）_4·(四氫-2H-哌喃-4-基胺基）-1Η_吡唑并 [3,4-b]吡啶-5-甲醯胺， 1-乙基-N-[(2_甲基·1，3-嘧唑-4-基）甲基]-4-(四氫-2H-哌喃斗基胺 基）_1H-吡也并[3,4-b]吡啶-5-甲醯胺， Ν·[3-(第三-丁氧基甲基）亨基]-1_乙基冬(四氫-2H-哌喃-4-基胺 基）_1Η-ρ比吐并[3,4-b]外t;淀-5_甲酸胺， 1-乙基-N-{2-[甲基（甲磺醯基）胺基]乙基}-4-(四氫-2H-哌喃-4-基 胺基比峻并[3,4-b]p比淀-5-甲酿胺， 1-乙基-N-(吡畊-2-基甲基）-4-(四氫-2H·哌喃-4-基胺基）-1Η-吡唑并 [3,4-b]吡啶-5-甲醯胺， 1-乙基-5-{[4-(吡啶-2-基羰基）六氫吡畊-1-基]羰基}_N-四氫-2H-哌 喃-4-基-1H-吡唑并[3,4-b]吡啶-4_胺， Ν·(2-氯基-6-氟基苄基）小乙基·4-(四氫_2H_哌喃-4-基胺基）-1Η-吡 唑并[3,4-b]吡啶-5-甲醯胺， 1-乙基-Ν·[(6-酬基-1，6-^ —鼠ρ比淀-3-基）甲基]-4-(四氯-2Η-喊喃_4_基 胺基）-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺， N-[3-(胺基羰基）芊基]小乙基-4-(四氫-2H-哌喃-4-基胺基）-1Η-吡 唑并[3,4-b]吡啶-5-甲醯胺， 1-乙基-N-{4-[(甲胺基）羰基]苯基}-4-(四氫-2H-哌喃-4-基胺基）-1Η- 87841-96〇303-中.doc -57- 1283678 外匕吐并[3,4-b]叶b邊-5-甲醯胺， 1·乙基-N-[2-(l-甲基-1H-味峻-4-基）乙基]-4-(四氫_2H_旅喃-4-基胺 基）-1Η-ρ比峻并[3,4-b]p比淀_5_甲酿胺， Ν-{2·[(苯胺基羰基）胺基]乙基}小乙基-4-(四氫_2H_旅喃_4_基胺 基）-1Η_吡唑并[3,4-b]吡啶-5-甲醯胺， 1·乙基-N-(1H-四也-5-基甲基）-4-(四氯-2H_^喃-4-基胺基）-1Η-ϊτ比唆 并[3,4_b]吡啶_5_甲醯胺， 1- 乙基-4-(四氮-2H-喊喃-4-基胺基）-Ν-[2-(1Η-1，2,4_三峻小基）乙基]-1H·吡唑并[3,4-b]吡啶-5-甲醯胺， 2- [{[1-乙基_4-(四氫-2H_喊喃-4-基胺基）-1Η-ρ比也并[3,4-1小比淀-5-基]羰基}(甲基）胺基]乙基胺基甲酸第三-丁酯， 1-乙基-4-(四氫·2Η·哌喃-4-基胺基）-N-[4-(三氟甲基）苯基]_1H-吡 唑并[3,4-b]吡啶-5-甲醯胺， 4-({[1-乙基·4-(四氫-2H·哌喃·4·基胺基）-1Η-吡唑并[3,4_b]吡啶-5-基]羰基}胺基）六氫吡啶小羧酸第三-丁酯， 1-乙基-N-{3-[(甲績醯基）胺基]丙基}-4-(四氫-2H-味喃-4-基胺基）-1H-吡唑并[3,4-b]吡啶-5-甲醯胺， N-[2-(二甲胺基）芊基]-1_乙基冬(四氫-2H-哌喃斗基胺基）-iH-吡 唑并[3,4-b]吡啶-5-甲醯胺， 1-乙基-Ν-[(1·乙基四氫吡咯-2-基）甲基]_4-(四氫-2H-哌喃-4_基胺 基）-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺， 1-乙基-N-(四氫呋喃-2-基甲基）冰(四氫-2H-哌喃-4_基胺基）-iH-吡 唑并[3,4-b]吡啶-5-甲醯胺， 1_乙基-N-四氫-2H-喊喃_4_基-4_(四氫-2H-旅喃-4-基胺基）_ih-吡吐 87841-960303-中.doc - 58 - 1283678 并[3,4-b]吡啶-5-甲醯胺， N-{4-[(二甲胺基）磺醯基]苄基}小乙基斗(四氫-2H-哌喃-4_基胺 基）-1Η-吡峻并[3,4-b]吡啶-5-甲醯胺， 1-乙基-N-{3-[(甲磺醯基）胺基]爷基}-4-(四氫_2Η·哌喃斗基胺基）_ 1Η-ρ比峻并[3,4-b]p比淀·5-甲醯胺， M[l-乙基_4·(四氫-2Η-哌喃-4-基胺基）_1Η-吡唑并P，4-b]吡啶-5_基] 羰基}六氫吡啶-2-曱醯胺， 1·乙基-Ν·(4-甲氧苯基）-4_(四氫-2H-哌喃-4-基胺基）-1Η-吡唑并 [3,4-b]吡啶-5-甲醯胺， 1-乙基·N-[3_(2-酮基四氫p比洛_1·基）丙基]-4-(四氫-2Η-»派喃·4-基胺 基）-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺， 1-乙基-N-[2-(l_甲基四氫吡咯-2_基）乙基]_4-(四氫-2H-哌喃-4-基胺 基）_1Η-ρ比峻并[3,4_b]外1：違-5-甲縫胺， 1-乙基_N七比啶-3-基甲基）-4_(四氫-2H-喊喃_4_基胺基）-1Η-吡唑并 [3,4-b]吡啶-5-甲醯胺， 1-乙基-N-(l-甲基六氫吡啶_4·基）-4-(四氫_2H-味喃-4-基胺基）_1Η· 吡吐并[3,4-b]吡啶-5-甲醯胺， 1-乙基-N-(l-乙基丙基)-4-(四氫-2H-喊喃-4-基胺基）-1Η-吡嗅并 P，4_b]吡啶-5-甲醯胺， 1_乙基-N_(2_六氫吡啶小基乙基）_4·(四氫_2H_哌喃-4-基胺基）-1Η-ρ比峻并[3,4-b]吡啶-5-甲醯胺， 1-乙基-N-(3-嗎福淋-4-基丙基）-4-(四氫_2H-喊喃-4·基胺基）-1Η-外匕 吐并[3,4-b]吡啶-5-甲醯胺， N-(3-乙氧基丙基）小乙基-4-(四氫-2H_喊喃_4_基胺基比吨并 87841-96〇303-中.doc -59- 1283678 [3,4-b>比淀-5-甲醯胺， N_(環己基甲基）-1_乙基冰(四氫-2H_哌喃-4-基胺基）-1Η-吡唑并 [3,4-b]p比淀-5-甲酿胺， N-[3-(二甲胺基）丙基]小乙基冰(四氫-2H-哌喃-4-基胺基）-1Η-吡 唑并[3,4七]吡啶-5_甲醯胺， 1-乙基-N_新戊基-4-(四氫_2H-哌喃_4·基胺基）-1Η_吡唑并[3,4-b]吡 淀-5-甲酿胺》 1_乙基-N_(4_甲氧基苄基）-4_(四氫_2H-喊喃-4-基胺基）-1Η·峨唆并 [3,4_b]外1：淀-5-甲酸胺， 1-乙基-N_{2-[(苯磺醯基）胺基]乙基}冰(四氫-2H-哌喃-4-基胺基）-1Η_ρ比也并[3,4-b]外1：淀-5·甲醯胺， N-〇(乙醯胺基）乙基]_1_乙基_4_(四氫·2Η_哌喃-4-基胺基）·1Η-吡 唑并[3,4-b]吡啶-5-甲醯胺， 1-乙基_N-{2_[(甲磺醯基）胺基]乙基}-4-(四氫-2H-哌喃-4-基胺基）-1H-峨唑并[3,4-b]吡啶_5_甲醯胺， 1·乙基-N-甲基-N七比啶-4_基甲基）-4-(四氫-2H-哌喃-4-基胺基）·1Η_ 吡吨并[3,4-b]吡啶-5-甲醯胺， 1-乙基-Ν·{2-[(2-甲氧苯基）(甲基）胺基]乙基}-4-(四氫-2H·哌喃-4-基胺基）-1Η-ρ比嗅并[3,4-b]吡啶·5·甲醯胺， 1-乙基-Ν-(2-ϊ同基-2-苯基乙基）-4-(四氫-2Η_^喃-4-基胺基）_1Η-ρ比 唑并[3,4-b]吡咱：-5-甲醯胺， N-(2,5-二氟爷基）-1-乙基-4-(四氫-2H-旅喃-4·基胺基）-1H-p比吨并 |；3,4-b]吡啶-5-甲醯胺， 1·乙基冰(四氫-2H_哌喃-4-基胺基）-N-[4-(三氟甲基）爷基]-1H-吡 87841-960303·中.doc -60- 1283678 唑并[3,4-b]吡啶-5-甲醯胺， N，l-二乙基-N-丙基-4_(四氫_2H-旅喃-4-基胺基）-1Η-吡唑并[3,4-b] p比淀-5-甲醯胺， N_環丙基-1_乙基-4_(四氫_2H_喊喃-4-基胺基）·1Η_ρ比峻并[3,4-b]外匕 淀-5-甲酸胺， N_(2-胺基-2-酮基乙基>1-乙基_4_(四氫-2H-旅喃-4-基胺基）-lH-外b 唑并[3,4-b]吡啶-5-甲醯胺， 1"·乙基_N-(3_甲乳冬基）-4-(四氮·2Η_喊喃-4-基胺基）-1Η_ρ比也并 P，4-b]吡啶_5·甲醯胺， Ν"·(3,4_<一氣卞基）-1-乙基-4-(四氮_2Η_^喃-4-基胺基）_1Η-ρ比吨并 [3,4-b]吡啶-5-甲醯胺， 3-({[1-乙基-4·(四氫·2Η-哌喃-4-基胺基）-1Η-吡唑并[3,4-b]吡啶-5- 基]羰基}胺基）丙酸乙酯， N-(l-苄基六氫外匕啶-4-基）·1·乙基-4-(四氫-2H-略喃-4·基胺基）-1Η-吡吨并[3,4-b]吡啶-5-甲醯胺， N-丁基-4·{[1-乙基-4-(四氯-2H_^喃-4-基胺基比也并[3,4-b]外匕 啶-5-基]羰基}六氫吡畊-1-甲醯胺， 1_乙基-4_(四氯-2H-喊喃-4·基胺基）-Ν-(1，3,4-ρ塞二吐_2-基）-1H-p比峻 并[3,4-b]吡啶-5-甲醯胺， Ν-(2,3·二氯-1H-雖-2-基）-1-乙基-4-(四氮-2H-旅喃-4-基胺基比 唑并[3,4-b]吡啶-5-甲醯胺， 1-乙基-N-[2-(2-嗣基味攻p林淀小基）乙基]-4-(四氣_2H-旅喃-4-基胺 基）_1H-吡唑并[3,4-b]吡啶-5-甲醯胺， N-(3,4-二甲氧基爷基）小乙基-4-(四氫-2H-»7瓜喃-4-基胺基比 87841-960303-中.doc -61 · 1283678 唑并[3,4-b]吡啶-5-甲醯胺， N-(3-氯苄基）-1_乙基-4-(四氫-2H_哌喃-4_基胺基）_ih-吡唑并[3,4_b] 12比淀-5-甲酿胺， 1-乙基-5·[(4_甲基六氫吡畊_1_基）羰基]-N四氫如_哌喃_冬基_lH_ 吡唑并[3,4-b]吡啶斗胺， 1-乙基善(2-羥乙基）冰(四氫-2H-哌喃斗基胺基）-lH-吡唑并[3,4七] 口比淀-5-甲酿胺， 1-乙基-5·{[4·(4-甲氧苯基）六氫吡畊-1-基]羰基卜N_四氫·2H_哌喃_ 4-基-lHwb吨并[3,4-b>比淀_4_胺， 1-乙基-N-{4-[(甲續醯基）甲基]苯基卜4-(四氫_2Η·ϊ痕喃_4_基胺基）_ 1H-吡唑并[3,4-b]吡啶-5_甲醯胺， N-[3-(二甲胺基）_3_酮基丙基]_1_乙基冰(四氫-211_哌喃·4_基胺基）-lHw比峻并[3,4_b]外b淀-5-甲醯胺， 1-乙基-N-[(l-甲基_1Η·咪唑-5-基）甲基]_4-(四氫-2H·喊喃-4-基胺 基）-1Η·ρ比峻并[3,4-b>比淀-5-甲醯胺， 1·乙基_Ν_{4·[(甲胺基）續醯基]苯基}冰(四氫-2H碌喃-4-基胺基）-1Η-吡唑并[3,4-b]吡啶·5·甲醯胺， Ν_(2-氰基乙基）-1_乙基_4-(四氫-2Η-喊喃-4-基胺基）·1Η-ρ比吨并 [3,4-b>比淀-5·甲醯胺， 1-乙基甲基-Ν-[(5·甲基号二峻-2-基）甲基]-4-(四氫-2H-口底 喃-4-基胺基）_1Η·ρ比吐并[3,4-b]外b淀-5-甲酿胺， 1-乙基-N-[(l_甲基·1Η·吡唑-4_基）甲基]冰(四氫-2H-哌喃-4-基胺 基）_1H-外b峻并[3,4-b>比攻·5-甲醯胺， 1-乙基-Ν-甲基-N-[(l-甲基_1Η-味峻_2_基）甲基]-4-(四氫-2Η-旅喃-4_ 87841-96〇3〇3·中.doc -62- 1283678 基胺基）_1H-p比峻并[3,4-b]p比淀_5_甲醯胺， 1-乙基-4-(四氣-2H-喊喃-4-基胺基）-N-(2-p塞吩-2-基乙基比吐 并[3,4_b>比淀-5-甲醯胺， N-[2-(4-鼠私基）乙基]-1-乙基-4-(四氫-2H-^底喃_4_基胺基）-lH>比吨 并[3,4-b]吡淀-5-甲醯胺， 1·乙基-N-[2-(2-甲氧苯基）乙基]-4·(四氫-2H碌喃-4·基胺基）·1Η>比 唑并[3,4-b]吡啶-5-甲醯胺， 4- (環己胺基）小(3-乙氧基_3_酮基丙基比吐并[3,4-b]p比淀-5·魏 酸乙酯， 1-正-丙基_4-(四氫-2H-喊喃-4-基胺基）-1Η·ρ比唆并[3,4-b]p比淀-5-叛 酸乙酯， 1-(2_羥乙基）_4-(四氫-2H-哌喃斗基胺基）-1Η-吡唑并[3,4-b]吡啶-5- 羧酸乙酯， N-[4-(甲磺醯基）苄基]小正-丙基-4-(四氫-2H-哌喃-4-基胺基）-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺， Ν-(4·氟苯基）-1正-丙基-4_(四氫·2Η_哌喃-4-基胺基）-1Η·吡唑并 [3,4-b]吡啶-5-甲醯胺， 1-乙基-6-甲基·4_(四氫-2H_哌喃斗基胺基）-1Η-吡唑并[3,4-b]吡啶- 5- 羧酸乙酯， 4-(環己胺基）_1_乙基-6-甲基-1H-吡唑并[3,4-b]吡啶-5-羧酸乙酯， 4-(環己胺基）小乙基-6-甲基_N-[4-(甲磺醯基）芊基]-1Η-吡唑并 [3,4-b]吡啶-5-甲醯胺， N-苄基-4-(環己胺基）小乙基-6-甲基-1H-吡唑并[3,4_b]吡啶-5-甲醯 胺， 87841-960303-中.doc -63- 1283678 4- (環己胺基）-1•乙基-N-(4-氣苯基）-6-甲基比吐并[3,4_b]P比淀- 5- 甲醯胺， 4-(環己胺基）-1-乙基-6-曱基-N_[4_(三氟甲基）爷基吡唑并 [3,4-b>比淀-5-甲醯胺， 4-(環己胺基）-N-(2,3-二氫-1H-雜_2_基）_1_乙基_6_甲基-1H-P比吐并 [3,4七>比淀-5-甲醯胺， N-卞基-1-乙基-6-甲基-4-(四氫_2H-喊喃基胺基）_1Η·ρ比峻并[3,4-b]p比淀-5-甲醯胺， N-芊基小乙基-4-[(2·酮基一氮七圜烷-3-基）胺基]-1H-吡唑并[3,4-b>比淀-5-甲醯胺， N-苄基-1-乙基_4_[(3_輕基環己基）胺基]_1H_吡唑并[3,4-b]吡淀-5_ 曱醯胺， N-苄基-1-乙基_4-[(4-經基環己基）胺基]_ih_吡唑并[3,4-b]吡啶_5_ 曱si胺， N-苄基小乙基-4_[(3-經基環戊基）胺基]-1H-吡唑并[3,4_b]吡啶-5-甲醯胺， N_苄基_1_乙基·4-[(4-酮基環己基）胺基]_1H吡唑并[3,4_b]吡啶_5_ 甲醯胺； 盛《其鹽，例如其藥學上可接受之鹽。 此等特定化合物之結構係示於後文實例100—201中。 或者，式（I)化合物或其鹽可為： 1_乙基-N-(2_羥基-1-甲基乙基>4_(四氫-2H-哌喃-4-基胺基）-1Η-叶匕峻并[3,4-b]吡啶·5-甲醯胺或 (2S)_2-({[1_乙基_4_(四氫-2Η·哌喃-4-基胺基）-1Η-咄唑并[3,4_b]吡 87841-96〇3〇3_ 中.doc -64 - 1283678 淀-5-基]幾基}胺基）-3-經基丙酸甲酯； 或其鹽，例如其藥學上可接受之鹽（參閱，例如實⑽ 或者，式（I)化合物或其鹽特佳係選自 A人n 貝1 至664，作為 θ物或其鹽，例如其藥學上可接受之鹽” 二 物之結構係示於後文實例204至664中。 争疋化e 學本上發可=Γ刚式_物或其鹽(特別是其藥: "N ρ or NMe2 R15 is preferably a hydrogen atom (Η) or a q _4 alkyl group (e.g., tBu or Ci 2, for example, methyl); and R15 is more preferably a hydrogen atom (H). However, R4 and R5 are preferably not used together, meaning that the NR4R5 ring system described herein is not used together in the form of 87841-960303-中.doc -49-1283678. (Like the preference is as for R5, for R5a, but 115& cannot be a hydrogen atom. R5a is preferably ethyl). In a particularly preferred embodiment, NR4R5 is NR4R5 as defined in any of the following examples: Examples 21-98, 100-182, 187-188, 191-200, 201-203, 210-353, 355-651, 653- 658 and 660-664. The compound of the formula (1) or a salt thereof is: 4-(cyclopentylamino)-1·ethyl-lH-p is more than [3,4-b]p than 嗓_5·reactive acid, 4 -(cyclohexylamino)-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester, 1-ethyl-4-(tetrahydro-2H- shouting- 4-aminoamino)-1Η-ρ is more than [3,4-b]external b--5-deoxyethyl ester, 4-[(1-methylhexahydropyridin-4-yl)amino] Ethyl 1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate, 4-[(1·ethinylhexahydropyridin-4-yl)amino]ethyl _1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester, 4-(cyclopentylamino)-1-methyl-1H-P than 嗤[3,4-b> ratio -5-5-Repulsive B, 1-methyl-4-(tetrahydro-2H·piperidinyl)-1Η-pyrazolo[3,4_b]pyridine-5-carboxylic acid ethyl ester, 1 -ethyl-4_[(3S)-tetrahydrofuran-1-ylamino]-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester, 1-ethyl-4_[(3R)-tetra Ethylfuranylamino]411_pyrazolo[3,4-hexa]pyridinecarboxylic acid ethyl ester, 1-ethyl-4-(tetrahydro-2H-thiopiperan 4-ylamino)-1Η_ Ethyl pyrazolo[3,4-b]pyridine-5-carboxylate, 87841-96〇3〇3_中.doc -50- 1283678 1-ethyl-4-(tetrahydropyrimidin-3-ylamine -1Η-pyrazole [3,4_b]ethyl pyridine-5-carboxylate, ethyl 4-(cyclopropylamino)ethylethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate, 4- [(1 ,1-dihydrotetramethylene sulfonate-3-yl)amino]-1·ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate, 4_[(1,1 _Dihydrotetrahydro-2H-thiopiperan-4-yl)amino]-1-ethyl_1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester, N-benzyl Small ethyl (tetrahydro-2-indolyl-pyran-4-ylamino)·1Η-pyrazolo[3,4-b]pyridine·5-carboxamide, 1-ethyl-N_(4-fluoro Phenyl)-4-(tetrahydro-2H-piperidinylamino)-1Η-pyrazolo[3,4-b] oxime-5-carbamide, N-cyclopentyl-4- (cyclopentylamino)_1_ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide, 4-(cyclohexylamino)cyclopentyl-1-ethyl-1H -pyrazolo[3,4-7>pyridin-5-carbamide, N-cyclopentyl small ethyl ice (tetrahydro-2H-piperidin-4-ylamino)-1Η-pyrazole [3,4-b]pyridine-5-formamide, 4-[(1-ethylhydrazinohexahydropyridin-4-yl)amino]-N·cyclopentyl-1-ethyl-1H-pyridyl Zoxa[3,4-b]pyridine-5-carboxamide, N_cyclopentyl-1_ethyl_5-(tetrahydropyrrole·μ-ylcarbonyl)_1H_pyrazolo[3,4-7] Pyridinium, N-cyclohexane -1ethyl-5-(tetrahydropyrrole+ylcarbonyl)-1Η·pyrazolo[3,4-7]pyridinium, 1-ethyl-5-(tetrahydrofuran-fluorenylcarbonyl) Hydrogen_211_piperidinyl-m-pyrazolo[3,4-b]pyridin-4-amine, 4-(3⁄4:pentylamino)_1_ethyl-N-pyridin-4-yl Methyl)_1H_pyrazolo[3,state pyridine 5-pyridylamine, 87841-96〇3〇3·中.doc -51 - 1283678 4-(cyclohexylamino)ethylidene-Ν- O-pyridin-4-ylmethyl)-1Η-pyrazolo[3,4-b]pyridine-5-carboxamide, 1-ethyl-N-(pyridin-4-ylmethyl)-4- (tetrahydro-2H-piperidin-4-ylamino)-1Η-pyrazolo[3,4-b]pyridine-5-carboxamide, 4-(cyclopentylamino)-1-ethyl -1H-pyrazolo P,4-b]pyridine-5-carboxamide, 4-(cyclohexylamino)-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5· Formamidine, 1·ethyl_4_(tetrahydro-2H-piperidin-4-ylamino)_1H-pyrazolo[3,4-b]pyridine_5-formamide, N_mercapto 4-(cyclopentylamino)ethylidene-1H-pyrazolo[3,4-b]pyridine-5-carbamimidyl, fluorenyl-4-(cyclohexylamino)ethylidene-1H- Pyrazolo[3,4_b]pyridine-5-carboxamide, 4-[(1-ethylhydrazine hexahydro? Specific attack-4_yl)amino]-1^-y-yl-1-ethyl-111-leaf 1: spit[3,4-b]p than attack-5-cartoamine, 4-(ring Amylamino)ethyl-N-(2-ethylbutyl)·1Η-pyrazolo[3,4-b]pyridine-5-carboxamide, 4-(cyclohexylamine) small B --N-(2-ethylbutyl)-1 Η-pyrazolo[3,4_b]pyridine-5-decylamine, 1-ethyl-N-(2-ethylbutyl)-4_(four Nitrogen-2H-pyran-4-ylamino)-1Η-ρ than ton[3,4-b]pyridine-5-carboxamide, 1-ethyl-N-(2-ethylbutyl) 4-[(1-methylhexahydropyridin-4-yl)amino]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide, 4-[(1-ethenyl) Hexahydropyridyl)amino]_1·ethyl-N-(2-ethylbutyl)-1Η-pyrazolo[3,4-b]pyridine-5-carboxamide, 4-(cyclopentyl) Amino) small ethyl-N-(4-fluorophenyl)-1H-p than salino[3,4-b]exyl b--5-carbamamine, 87841-960303-中.doc-52· 1283678 4-(Cyclohexylamino)ethylidene-N-(4-fluorophenyl)-1Η-exo b唆[3,4-b]indole-5-formamide, 1-ethyl- N-(4-fluorophenyl)-4-[(1-mercaptohexahydropyridyl)-yl]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide, 4- [(1-acetic acid-based chloro-p-buty-4-yl)amino]-1-ethyl- N-(4-Phenylphenyl)-1H-p ratio also [3,4-b]pyridine-5-carboxamide, 4-(cyclopentylamino)-1-ethyl-N-positive- propyl-1H-P is more than 唆[3,4-b]externate b-5-cartoamine, 瘫4-(cyclohexylamino)-1-ethyl-N-n-propyl_1H- Pyrazolo[3,4-b]pyridine-5-carboxamide, 1-ethyl-N-n-propyl-4-(tetrahydro-2-indole-piperidin-4-ylamino)_1Η-pyridyl Zoxao[3,4-b]pyridine-5-carboxamide, 4-[(1-ethyl acanthoprum p-precipitate-4-yl)amino]-1-ethyl-N-n-propyl Base-lH-p is more than 唆[3,4-b], b is _5_cartotenamine, N-benzyl small ethyl-4-[(l-methylhexahydropyridin-4-yl)amine -1H-pyrazolo[3,4-b] oxime--5-cartoamine, 4-[(1-ethenylhexahydropyridin-4-yl)amino]-1-ethyl -N-(pyridin-4-ylmethyl)-1Η-pyrazolo[3,4-b]pyridine-5-carboxamide, N-benzyl-4-(cyclopentylamino)-1_ Methyl-1H-pyrazolo[3,4-b]pyridine_5.carbamamine, N-mercapto-4_(cyclohexylamino)-1_methyl-1H-pyrazolo[3,4 -b]pyridine-5-carboxamide, N-benzyl-1·methyl pipe (tetrahydro-2H-piperazin-4-ylamino)-1Η-pyrazolo[3,4-b]pyridine - 5-Protonamine, 4-(cyclopentylamino)-N-(2-ethylbutyl)-1-methyl-1H-pyrazolo[3,4 Pyridine-5-carbamide, 4-(cyclohexylamino)-N-(2-ethylbutyl)-1.methyl-1H-pyrazolo[3,4-b]pyridine_5_ A 87841-9603〇3·中.doc -53- 1283678 decylamine, N-(2-ethylbutyl)-1_methyl_4_(tetrahydro-2H-piperazin-4-ylamino)· 1Η-pyrazolo[3,4-b]p ratio bit-5-carbamamine, 4-(cyclopentylamino)-N-(4-fluorophenyl)sodiummethyl-1H-pyrazole [3,4-b]pyridine-5-formamide, 4·(cyclohexylamino)·Ν_(4·fluorophenyl)-1-methyl-1H-pyrazolo[3,4-b] Pyridine-5-formamide, N-(4-fluorophenyl)-1-methyl·4-(tetrahydro-2H-piperazin-4-ylamino)-1Η-pyrazolo[3,4 VII] external yttrium-5-formic acid amine, 4-(cyclopentylamino)·1-methyl-1H-P than olfactory [3,4-b> butyl _5-formic acid amine, 4_(ring Hexylamino)methanol-1H-P is more than [3,4-b]p than pent-5-carbamide, 1-methyl-4-(tetramethylene-2H-piperidinylamino) -1Η-pyrazolo[3,4-b]pyridine-5-carboxamide, 4-[(1-ethylhydrazinium hexahydropyridin-4-yl)amino]-N-benzyl-1_ Methyl-1H-pyrazolo[3,4-b>pyramid-5-carbamide, 4-[(1-ethylhydrazinohexahydropyridin-4-yl)amino]-N-(2- Ethyl butyl)-1-methyl-1H-exopurin and [3,4-b]p ratio -5-Artemisamine' 4-[(1·Ethyl hexahydropyridin-4-yl)amino]-N-(4-fluorophenyl)_1_methyl_1H-pyrazolo[3, 4-b]p butyl-5-cartoamine ' 1 -ethyl-N-methyl-4_(tetrahydro-2H·pipelanylamino)-iH-pyrazole[3,4-7] Bis-5-carbamamine, 1-ethyl-N,N-dimethyl-4-(tetrahydro-2H-piperidin-4-ylamino)·1Η-pyrazolo[3,4 -b] pyridin-5-formamide, 1-ethyl-N-ethyl-4-(tetrahydro-2H-piperidin-4-ylamino)-1Η-pyrazolo[3,4_b] Pyridine - 87841-960303-中.doc -54- 1283678 5-Protonamine, 1-ethyl-N-isopropyl-4-(tetrahydro-2H-pyran-4-ylamino)-1Η- Pyrazolo[3,4-b]pyrrolidine-5-SiSiamine, N.benzyl-1-ethyl-4-[(3S)-tetrahydrofuran-3-ylamino]-1H-pyrazole [3,4-b]pyridine· 5-cartoamine, N-mercapto-1-ethyl-4-[(3R)-w-nitropyran-3-ylamino]-lH_T^b 3,4-b]p-precipitate- 5-cartoamine, N-mercapto-1-ethyl-4_(tetrahydro-p-phenant-3-ylamino)_1Η·ρ ratio spit [3,4 -b]p-precipitate-5-formamide, N-yl--4-(cyclopropylamino)ethylidene-IHh? than succinyl[3,4-b]p than 5·carbamamine , N-Henki·4-[(1,1-dioxytetrahydrocyclopropenyl-3-yl)amino]] Base-iH-p ratio spitting [3,4-b]pyridine-5-methanamine, N-benzyl-4-[(1,1-dioxytetrahydro-2H-thiopyranyl-4) Amino group]-1_ethyl_ih_ 匕 匕 并 [3,4-b> 淀 -5-5-formamide, N-benzyl-1-ethyl ice (tetrahydro-; 2H-sulfur Desmodium-4-ylamino)-1Η-pyrazolo[3,4-b] oxime-5-carbamide, 1_ethyl-Ν·(4·fluorophenyl)-4- [(3S)-w-hydrofuranylamino]]Η·pyrazolo[3,4-b]pyrazine-5-carboxamide, 1·ethyl·Ν-(4-fluorophenyl) ice [ (3R)_tetrahydrofuranylamino]pyrazolop,4-b] oxime-5-cartoamine^1-ethyl-N-(4-fluorophenyl)-4_(tetrahydro- 2H-thiopiperan-4 amino group >m_pyrazolo[3,4-b]p than lake-5-cartoamine, 1-ethyl-N-(4-fluorophenyl) -4-(tetrahydrothiophene-3-ylamino)_1H_pyrazolo[3,4-7]pyridine-5-cartoamine, 87841-96〇3〇3-中.doc -55- 1283678 4 -(cyclopropylamino)-1_ethyl_Ν·(4)fluorophenyl)_1H_pyrazolo[3,4_b]pyridine-5-carbamimidamine, 4-[(1山二氧化tetrahydrothiophene _ 3_yl)amino]-1-ethyl-N-(4-fluorophenyl)-1Η-pyrazolo[3,4-b]p than lake-5-cartoamine, or 4-[( 1,1_dihydrotetrahydro-2H-thiopiperine Amino] ethyl _N_ (4_ fluorophenyl HH- pyrazolo [3,4 seven] pyridine _5_ A Amides; the "salt thereof, for example the pharmaceutically acceptable salts thereof. The structures of these specific compounds are shown in Examples 1 - 98 below. Alternatively, the compound of the formula (I) or a salt thereof is particularly preferably: 1-ethyl-N-[4_(methylsulfonyl) aryl] ice (tetrahydro-2H-piperidin-4-ylamino)_1H- Pyrazolo[3,4-b]pyridine-5-carboxamide, (1-{[1-ethyl_4_(tetrahydro-2H-piperidinyl)-1Η-pyrazolo[3 ,4_b]pyridin-5-yl]carbonyl}hexahydropyridin-3-yl)methylcarbamic acid, third butyl ester, 1-ethyl_N_[3-(methylsulfonyl) aryl]_4- (tetrahydro-2H-piperazin-4-ylamino)-1Η-pyrazolo P,4_b]pyridine-5-formamide, 1-ethyl-5-{[5-methoxy_6· (trifluoromethyl)·2,3_dihydro-1H-indole-1_yl]carboxy}-indole-tetrahydro-2-indole-pyran-4-yl-1Η-pyrazolo[3,4_b] Pyridine-4_amine, N-[(5-chloropyridin-2-yl)methyl]_1_ethyl-4_(tetrahydro-2H-pyran-4-ylamino)-1Η-pyridyl [3,4-b]pyrazine-5-formamide, N-(4-gasbenzyl)_1_ethyl-N-isopropyl-4-(tetrahydro-2H- brit-4) Amine Group>1H-pyrazolo[3,4-b]pyridine-5-carboxamide, N-(3-chlorobenzyl)_1·ethyl_Ν·(2·hydroxyethyl)-4- (tetrahydro-2H-pyran-4-ylamino)·1Η-ρ ratio also [3,4-b]external t-bend-5-formamide, 1-ethyl-Ν-[(5· Methyl-3-phenyliso-17 Jun-4-yl)methyl]-4 -(tetranitro-2H_ shouting-4_ 87841-960303-medium.doc -56- 1283678 arylamino)-1Η-ρ ratio also [3,4-b> than 嗓-5-carboxylic acid amine, N- (2-di-di-butyl-butylethyl)-1_ethyl_4-(tetrachloro-2H-Butan-4-ylamino)-1Η-ρ-pyrazolo[3,4-b]pyridine -5-Protonamine, 1-ethyl-4_(tetrahydro-2H-piperidin-4-ylamino)-indole-(1,3-oxazol-2-ylmethyl)-1Η-pyrazole And [3,4-b]pyridine-5-formamide, 1-ethyl-N-(pyrimidin-4-ylmethyl)_4·(tetrahydro-2H-piperidin-4-ylamino)- 1Η_pyrazolo[3,4-b]pyridine-5-carboxamide, 1-ethyl-N-[(2-methyl·1,3-pyrazol-4-yl)methyl]-4 -(tetrahydro-2H-piperidinylamino)_1H-pyrido[3,4-b]pyridine-5-carboxamide, Ν·[3-(T-butoxymethyl)hen Base]-1-ethyl winter (tetrahydro-2H-piperidin-4-ylamino)_1Η-ρ ratio spit [3,4-b] outer t; lake-5-formic acid amine, 1-ethyl -N-{2-[methyl(methylsulfonyl)amino]ethyl}-4-(tetrahydro-2H-piperazin-4-ylamino group than sir[3,4-b]p ratio Ding-5-cartoamine, 1-ethyl-N-(pyroxy-2-ylmethyl)-4-(tetrahydro-2H-piperidin-4-ylamino)-1Η-pyrazolo[ 3,4-b]pyridine-5-formamide, 1-ethyl-5-{[4-(pyridin-2-ylcarbonyl) Hexahydropyranin-1-yl]carbonyl}_N-tetrahydro-2H-piperidin-4-yl-1H-pyrazolo[3,4-b]pyridine-4-amine, Ν·(2-chloro 5--6-fluorobenzyl)ethylidene 4-(tetrahydro-2H-piperidin-4-ylamino)-1Η-pyrazolo[3,4-b]pyridine-5-carboxamide , 1-ethyl-Ν·[(6-费基-1,6-^-rho-p-but-3-yl)methyl]-4-(tetrachloro-2Η-喊喃_4_ylamino -1Η-pyrazolo[3,4-b]pyridine-5-carboxamide, N-[3-(aminocarbonyl)indenyl]sodiumethyl-4-(tetrahydro-2H-pyran- 4-aminoamino)-1Η-pyrazolo[3,4-b]pyridine-5-carboxamide, 1-ethyl-N-{4-[(methylamino)carbonyl]phenyl}-4 -(tetrahydro-2H-piperazin-4-ylamino)-1Η- 87841-96〇303-中.doc -57- 1283678 外匕吐和[3,4-b]叶叶边-5-甲Indoleamine, 1·ethyl-N-[2-(l-methyl-1H-mist-4-yl)ethyl]-4-(tetrahydro-2H-bran-4-ylamino)- 1Η-ρ比峻和[3,4-b]p ratio _5_甲甲胺,Ν-{2·[(anilinocarbonyl)amino]ethyl}sodiumethyl-4-(tetrahydro- 2H_旅喃_4_ylamino)-1Η_pyrazolo[3,4-b]pyridine-5-carboxamide, 1·ethyl-N-(1H-tetra-5-ylmethyl )-4-(tetrachloro-2H-^py-4-ylamino)-1Η-ϊτ is more than [3,4_b]pyridine_5_A Indoleamine, 1-ethyl-4-(tetrazol-2H-pyran-4-ylamino)-indole-[2-(1Η-1,2,4_trisinyl)ethyl]-1H ·pyrazolo[3,4-b]pyridine-5-carboxamide, 2- [{[1-ethyl_4-(tetrahydro-2H_ shomo-4-ylamino)-1Η-ρ Ratio is also [3,4-1 small ratio of 5-amino]carbonyl}(methyl)amino]ethylaminocarbamic acid tert-butyl ester, 1-ethyl-4-(tetrahydro-2Η· Piperaz-4-ylamino)-N-[4-(trifluoromethyl)phenyl]_1H-pyrazolo[3,4-b]pyridine-5-carboxamide, 4-({[1 -ethyl·4-(tetrahydro-2H·piperidin-4-ylamino)-1Η-pyrazolo[3,4_b]pyridin-5-yl]carbonyl}amino)hexahydropyridine small carboxylic acid Tri-butyl ester, 1-ethyl-N-{3-[(polymethyl)amino]propyl}-4-(tetrahydro-2H-mum-4-ylamino)-1H-pyridyl Zoxa[3,4-b]pyridine-5-carboxamide, N-[2-(dimethylamino)indolyl]-1-ethyl winter (tetrahydro-2H-piperidinylamino) -iH-pyrazolo[3,4-b]pyridine-5-carboxamide, 1-ethyl-indole-[(1·ethyltetrahydropyrrol-2-yl)methyl]_4-(tetrahydrogen) -2H-pyran-4-ylamino)-1Η-pyrazolo[3,4-b]pyridine-5-carboxamide, 1-ethyl-N-(tetrahydrofuran-2-ylmethyl) ice (tetrahydro-2H-piperidin-4-ylamino)-iH-pyrazolo[3 ,4-b]pyridine-5-methanamine, 1_ethyl-N-tetrahydro-2H-methylene-4-yl-4-(tetrahydro-2H-hamo-4-ylamino)_ih- Pyridin 87841-960303-中.doc - 58 - 1283678 and [3,4-b]pyridine-5-formamide, N-{4-[(dimethylamino)sulfonyl]benzyl} small B Base (tetrahydro-2H-piperidin-4-ylamino)-1Η-pyrido[3,4-b]pyridine-5-carboxamide, 1-ethyl-N-{3-[( Methanesulfonyl)amino]yl}-4-(tetrahydro-2-indole·piperidinylamino)_1Η-ρ is more than [3,4-b]p than 5-Metamine , M[l-ethyl_4.(tetrahydro-2Η-piperidin-4-ylamino)_1Η-pyrazolo P,4-b]pyridin-5-yl]carbonyl}hexahydropyridin-2- Indoleamine, 1·ethyl-indole (4-methoxyphenyl)-4_(tetrahydro-2H-piperazin-4-ylamino)-1Η-pyrazolo[3,4-b]pyridine -5-Protonamine, 1-ethyl·N-[3_(2-ketotetrahydrop-pyryl-1)propyl]-4-(tetrahydro-2Η-»派喃·4-yl Amino)-1Η-pyrazolo[3,4-b]pyridine-5-carboxamide, 1-ethyl-N-[2-(l-methyltetrahydropyrrole-2-yl)ethyl] _4-(tetrahydro-2H-piperidin-4-ylamino)_1Η-ρ ratio and [3,4_b] outside 1: Violation-5-methylamide, 1-ethyl-N-pyridin-3 -ylmethyl)-4_(tetrahydro-2H-pyro- 4-ylamino -1Η-pyrazolo[3,4-b]pyridine-5-carboxamide, 1-ethyl-N-(l-methylhexahydropyridin-4-yl)-4-(tetrahydro-2H- Miso-4-ylamino)_1Η·pyrido[3,4-b]pyridine-5-carboxamide, 1-ethyl-N-(l-ethylpropyl)-4-(tetrahydrogen) -2H- 喃 -4--4-ylamino)-1Η-pyrrolidino P,4_b]pyridine-5-carboxamide, 1-ethyl-N-(2-hexahydropyridine small ethyl)_4·( Tetrahydro 2H-piperazin-4-ylamino)-1Η-ρ is more than [3,4-b]pyridine-5-carboxamide, 1-ethyl-N-(3-moffone- 4-ylpropyl)-4-(tetrahydro-2H-pyran-4)ylamino)-1Η-exopurin and [3,4-b]pyridine-5-carboxamide, N-(3 -ethoxypropyl)sodiumethyl-4-(tetrahydro-2H_ shouting _4_ylamine-based ton and 87841-96〇303-中.doc-59- 1283678 [3,4-b> Bishen-5-carbamamine, N_(cyclohexylmethyl)-1_ethyl ice (tetrahydro-2H-piperidin-4-ylamino)-1Η-pyrazolo[3,4-b] P-Phenan-5-cartoamine, N-[3-(dimethylamino)propyl]sodiumethyl pentyl (tetrahydro-2H-piperidin-4-ylamino)-1Η-pyrazolo[ 3,4-7]pyridine-5-carbamamine, 1-ethyl-N-neopentyl-4-(tetrahydro-2H-pyran-4-ylamino)-1Η-pyrazolo[3, 4-b]Pyramid-5-cartoamine 1_Ethyl-N_(4 _Methoxybenzyl)-4_(tetrahydro-2H-pyran-4-ylamino)-1Η·峨唆[3,4_b]External 1: Ammonium-5-formic acid amine, 1-ethyl- N_{2-[(phenylsulfonyl)amino]ethyl}ice (tetrahydro-2H-piperidin-4-ylamino)-1Η_ρ ratio also [3,4-b] outer 1: lake- 5. Myramine, N-indole (ethylamino)ethyl]_1_ethyl_4_(tetrahydro-2Η-piperidin-4-ylamino)·1Η-pyrazolo[3,4- b]pyridine-5-carboxamide, 1-ethyl_N-{2_[(methylsulfonyl)amino]ethyl}-4-(tetrahydro-2H-piperazin-4-ylamino) -1H-carbazolo[3,4-b]pyridine-5-carbamamine, 1·ethyl-N-methyl-N heptaidine-4-ylmethyl)-4-(tetrahydro-2H -piperazin-4-ylamino)·1Η_pyrido[3,4-b]pyridine-5-carboxamide, 1-ethyl-Ν·{2-[(2-methoxyphenyl)( Methyl)amino]ethyl}-4-(tetrahydro-2H.piperidin-4-ylamino)-1Η-ρ than oleno[3,4-b]pyridine·5·carbamidine, 1 -ethyl-indole-(2-indolyl-2-phenylethyl)-4-(tetrahydro-2Η-^an-4-ylamino)_1Η-ρ-pyrazolo[3,4-b] Pyridoxine: 5-carbamamine, N-(2,5-difluoroaryl)-1-ethyl-4-(tetrahydro-2H-bungan-4-ylamino)-1H-p ratio Tons of |; 3,4-b]pyridine-5-formamide, 1·ethyl ice (tetrahydro-2H _piperazin-4-ylamino)-N-[4-(trifluoromethyl)-yl]-1H-pyry 87841-960303·中.doc -60- 1283678 oxazo[3,4-b]pyridine -5-Mergamine, N,l-diethyl-N-propyl-4_(tetrahydro-2H-bran-4-ylamino)-1Η-pyrazolo[3,4-b] p Bishen-5-formamide, N_cyclopropyl-1_ethyl-4_(tetrahydro-2H_ shout-4-ylamino)·1Η_ρ ratio and [3,4-b] Ammonium-5-formic acid amine, N_(2-amino-2-ketoethyl)> 1-ethyl_4_(tetrahydro-2H-bran-4-ylamino)-lH-exo bazole [3,4-b]pyridine-5-carboxamide, 1"·ethyl_N-(3_methyllactosyl)-4-(tetrazo 2 Η 喊 -4- -4-ylamino)- 1Η_ρ ratio is also P,4-b]pyridine_5·carbamamine, Ν"·(3,4_<one gas sulfhydryl)-1-ethyl-4-(tetrazine 2 Η^^ -4-ylamine Base)_1Η-ρ than ton[3,4-b]pyridine-5-formamide, 3-({[1-ethyl-4·(tetrahydro-2-indolyl-4-ylamino)) -1Η-pyrazolo[3,4-b]pyridin-5-yl]carbonyl}amino)propionic acid ethyl ester, N-(l-benzylhexahydroexoacridin-4-yl)·1·B 4-(tetrahydro-2H-sulphant-4-ylamino)-1Η-pyrido[3,4-b]pyridine-5-carboxamide, N-butyl-4·{[1 -ethyl-4-(tetrachloro-2H-^py-4-ylamino) And [3,4-b]exoazin-5-yl]carbonyl}hexahydropyrazine-1-carboxamide, 1_ethyl-4_(tetrachloro-2H-pyran-4-ylamino) -Ν-(1,3,4-ρ2,2,2-yl)-1H-p, benzo[3,4-b]pyridine-5-carboxamide, Ν-(2,3·dichloride -1H-Is-2-yl)-1-ethyl-4-(tetrazine-2H-bromo-4-ylaminobispyrazolo[3,4-b]pyridine-5-carboxamide, 1 -ethyl-N-[2-(2-mercapto-paste), ethyl]-4-(tetrahydro-2H-bromo-4-ylamino)_1H-pyrazolo[3 , 4-b]pyridine-5-carbamide, N-(3,4-dimethoxyaryl)ethylethyl-4-(tetrahydro-2H-»7 guran-4-ylamine ratio 87841-960303-中.doc -61 · 1283678 oxazo[3,4-b]pyridine-5-carboxamide, N-(3-chlorobenzyl)-1_ethyl-4-(tetrahydro-2H _piperidin-4_ylamino)_ih-pyrazolo[3,4_b] 12 than lake-5-cartoamine, 1-ethyl-5·[(4_methylhexahydropyrazine_1_ Carbonyl]-N tetrahydrogen such as _pyranyl-winter _lH_pyrazolo[3,4-b]pyridinium, 1-ethyl benzo(2-hydroxyethyl) ice (tetrahydro-2H- Piperidinylamino)-lH-pyrazolo[3,4-7]pyramid-5-cartoamine, 1-ethyl-5·{[4·(4-methoxyphenyl)hexahydro Pyridin-1-yl]carbonylbu N_tetrahydro·2H_pyran-4-yl-lHwb ton[3, 4-b>Biprecipitate_4_amine, 1-ethyl-N-{4-[(methylsulfonyl)methyl]phenyl b 4-(tetrahydro-2-indole) Base) _ 1H-pyrazolo[3,4-b]pyridine-5-formamide, N-[3-(dimethylamino)_3-ketopropyl]_1_ethyl ice (tetrahydro- 211_pyran-4-ylamino)-lHw is more than [3,4_b] external b-precipitate-5-formamide, 1-ethyl-N-[(l-methyl_1Η·imidazole-5 -yl)methyl]_4-(tetrahydro-2H· shout-4-ylamino)-1Η·ρ ratio and [3,4-b>pyramid-5-formamide, 1·ethyl _Ν_{4·[(Methylamino) hydrazino]phenyl} ice (tetrahydro-2H-furan-4-ylamino)-1Η-pyrazolo[3,4-b]pyridine·5· Formamide, Ν_(2-cyanoethyl)-1_ethyl_4-(tetrahydro-2Η- sher-4-ylamino)·1Η-ρ 比吨[3,4-b> Bishen-5·carbamamine, 1-ethylmethyl-indole-[(5·methyl-di-n-butyl-2-yl)methyl]-4-(tetrahydro-2H-mouth -4- Amino group)_1Η·ρ ratio spit[3,4-b]external b-precipitate-5-cartoamine, 1-ethyl-N-[(l-methyl·1Η·pyrazole-4_yl) Methyl] ice (tetrahydro-2H-piperazin-4-ylamino)_1H-external b-[3,4-b> than attack·5-formamide, 1-ethyl-fluorene-methyl -N-[(l-methyl_1Η-味峻_2_yl)methyl]-4-(tetrahydro-2 -旅喃-4_ 87841-96〇3〇3·中.doc -62- 1283678 胺amino)_1H-p is more than [3,4-b]p than _5_carbamamine, 1-B Base-4-(tetraqi-2H-pyran-4-ylamino)-N-(2-p-cephen-2-ylethyl than spit [3,4_b> butyl-5-carbamide , N-[2-(4-ratyl)ethyl]-1-ethyl-4-(tetrahydro-2H-^-endo- 4-ylamino)-lH> than tons [3,4 -b]pyrazine-5-formamide, 1·ethyl-N-[2-(2-methoxyphenyl)ethyl]-4·(tetrahydro-2H-furan-4-ylamino) ·1Η>Bizozolo[3,4-b]pyridine-5-carboxamide, 4-(cyclohexylamino) small (3-ethoxy-3-butanylpropyl than spit [3,4 -b]p-precipitate-5·heric acid ethyl ester, 1-n-propyl-4-(tetrahydro-2H-fluoren-4-ylamino)-1Η·ρ than 唆[3,4- b]p-precipitate-5-oleic acid ethyl ester, 1-(2-hydroxyethyl)-4-(tetrahydro-2H-piperidinylamino)-1Η-pyrazolo[3,4-b] Pyridine-5-carboxylic acid ethyl ester, N-[4-(methylsulfonyl)benzyl]sodium n-propyl-4-(tetrahydro-2H-piperidin-4-ylamino)-1Η-pyridyl Oxazo[3,4-b]pyridine-5-carboxamide, Ν-(4.fluorophenyl)-1 n-propyl-4_(tetrahydro-2-indolyl-4-ylamino)- 1Η·pyrazolo[3,4-b]pyridine-5-formamide, 1-ethyl-6-methyl· 4_(tetrahydro-2H_piperidinylamino)-1Η-pyrazolo[3,4-b]pyridine-5-carboxylate ethyl ester, 4-(cyclohexylamino)_1_ethyl-6 -ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester, 4-(cyclohexylamino)ethylethyl-6-methyl_N-[4-(methylsulfonate) Indenyl) fluorenyl]-1Η-pyrazolo[3,4-b]pyridine-5-carboxamide, N-benzyl-4-(cyclohexylamino)ethyl-6-methyl-1H -pyrazolo[3,4_b]pyridine-5-carboxamide, 87841-960303-中.doc -63- 1283678 4- (cyclohexylamino)-1•ethyl-N-(4-phenylphenyl) -6-Methyl to benzo[3,4_b]P than y- 5-carbamamine, 4-(cyclohexylamino)-1-ethyl-6-fluorenyl-N_[4_(trifluoromethyl) Base) syl-pyrazolo[3,4-b>pyramid-5-carbamide, 4-(cyclohexylamino)-N-(2,3-dihydro-1H-hetero-2-yl) _1_ethyl_6_methyl-1H-P is more than spit [3,4-7> bis--5-carbamamine, N-mercapto-1-ethyl-6-methyl-4-( Tetrahydro 2H-h-ylamino)1Η·ρ ratio and [3,4-b]p than pent-5-carbamide, N-fluorenyl small ethyl-4-[(2·keto) Nitros-7-ylamino)amino]-1H-pyrazolo[3,4-b>pyramid-5-carbamide, N-benzyl-1-ethyl_4_[(3_ Light-based cyclohexyl)amino]_1H_pyrazolo[3,4-b]pyridine- 5_ decylamine, N-benzyl-1-ethyl_4-[(4-cyclocyclohexyl)amino]]ih-pyrazolo[3,4-b]pyridine_5_ 曱siamine, N- Benzyl small ethyl-4_[(3-carbylcyclopentyl)amino]-1H-pyrazolo[3,4_b]pyridine-5-carboxamide, N_benzyl_1_ethyl·4 -[(4-Ketylcyclohexyl)amino]]H-pyrazolo[3,4-b]pyridine-5-carbamimid; a salt thereof, for example, a pharmaceutically acceptable salt thereof. The structures of these specific compounds are shown in Examples 100-201 below. Alternatively, the compound of the formula (I) or a salt thereof may be: 1-ethyl-N-(2-hydroxy-1-methylethyl>4-(tetrahydro-2H-piperazin-4-ylamino)- 1Η-叶匕峻和[3,4-b]pyridine·5-formamide or (2S)_2-({[1_ethyl_4_(tetrahydro-2Η·piperidin-4-ylamino)-1Η) - oxazolo[3,4_b]pyr 87841-96〇3〇3_中.doc-64 - 1283678 ound-5-yl]amino}amino)-3-methylpropionic acid methyl ester; or a salt thereof, For example, a pharmaceutically acceptable salt thereof (see, for example, (10) or a compound of the formula (I) or a salt thereof is selected from the group consisting of A human n shells 1 to 664, as a θ substance or a salt thereof, for example, which is pharmaceutically acceptable The structure of the two substances is shown in the following examples 204 to 664. The escaping e-learning can be Γ 式 式 _ _ _ _ _ _ _ _ _ _ _ _ _ _

X (ΙΑ) 其中：X 為 NR4 R5 或 a，其中··R為氫、c!-2燒基或Ci 2氟燒基，且 R為氫Cl.8：ki基、Cl·8氟燒基或c3.8環燒基，苯基’视情 況被一或兩個下列基團取代：齒原子、Cl_2燒基、三氟甲 基、Cl·2燒氡基或三氟甲氧基，·或R5具有亞式⑻、（y)或⑻： _(CH2)n Γ R'D . 、eJ -(叫 L (y) (z) 其中在亞式(x)與⑻中，n=1或2;且在亞式(y)中，㈣或2; 其中在亞式（X)與(y)中，沒有或一或兩個A、B、D、E&F 為氮’而其餘A、b、d、e及F為⑶或⑽，其中r6為卣原 (X)X (ΙΑ) where: X is NR4 R5 or a, wherein R is hydrogen, c!-2 alkyl or Ci 2 fluoroalkyl, and R is hydrogen Cl. 8: ki, Cl·8 fluoroalkyl Or c3.8 cycloalkyl, phenyl 'optionally substituted with one or two of the following groups: a tooth atom, a C 2 alkyl group, a trifluoromethyl group, a Cl 2 decyl group or a trifluoromethoxy group, or R5 has the subtype (8), (y) or (8): _(CH2)n Γ R'D . , eJ - (called L (y) (z) where in the subtypes (x) and (8), n = 1 or 2 And in the subtype (y), (d) or 2; wherein in the subtypes (X) and (y), no or one or two of A, B, D, E & F are nitrogen' and the remaining A, b , d, e and F are (3) or (10), where r6 is 卣原(X)

子、Ch燒基、c 卜4 氟烷基Sub, Ch alkyl, c 4 fluoroalkyl

Cl-2燒氧基、Q-2氟基燒氧基、 87841_96〇3〇3_ 中.doc -65- 1283678 燒基續酿基（Cl_2燒基·S(V)、Ci 2燒基碼權_、尺物-s〇2-、RWca、r7r8n、0H、Ci 4燒氧基甲基或 Ci 2燒 基-s〇2_CH2_，其中R7與R8係獨立為氫或Cu烷基； 其中在亞式(Z)中，G為〇或8或服9，其中燒基或 Ch氟燒基；沒有或一或兩個卜L、為氮；而其餘 J、L、Μ及Q為CH或CR6，其中R6係如本文定義； 或R4與R5—起採用為_(CH2)p-，其中p = 3、4或5(較佳p = 4); R a為Ch燒基；Cl-8氟烷基；c3 8環燒基；苯基，视情況被 一或兩個下列基團取代：函原子' Ci_2烷基、三氟甲基、 Α-2烷氧基或三氟甲氧基；或RSa具有如本文中定義之亞式 ⑻、（y)或（z); R3為C3_8環烷基或雜環族基團為Cl-2 alkoxy group, Q-2 fluoroalkyl alkoxy group, 87841_96〇3〇3_中.doc-65- 1283678 烧基根根(Cl_2 alkyl·S(V), Ci 2 alkyl base code _ , the rule -s〇2-, RWca, r7r8n, 0H, Ci 4 alkoxymethyl or Ci 2 alkyl-s〇2_CH2_, wherein R7 and R8 are independently hydrogen or Cu alkyl; In Z), G is hydrazine or 8 or service 9, wherein the alkyl group or Ch fluoroalkyl group; no or one or two of L, is nitrogen; and the remaining J, L, Μ and Q are CH or CR6, wherein R6 Is as defined herein; or R4 and R5 are taken as _(CH2)p-, wherein p = 3, 4 or 5 (preferably p = 4); R a is a Ch alkyl group; Cl-8 fluoroalkyl; C3 8 cycloalkyl; phenyl, optionally substituted by one or two of the following groups: a functional atom 'Ci-2-alkyl, trifluoromethyl, Α-2 alkoxy or trifluoromethoxy; or RSa has Sub-formula (8), (y) or (z) as defined herein; R3 is a C3_8 cycloalkyl or heterocyclic group

其中Y為0、S、SOpiLNR10 ;其中Rl〇為氫、Ci-4烷基、Ci 2 氟烷基、¢:(0)4 _2烷基或c(o)-cf3 ; 且其中在R3中’（：3·8環烷基或雜環族基團係視情沉被一或兩 個OH、q·2烷氧基、三甲氧基或烷基之取代基取代；且 其中任何0H、烷氧基或三甲氧基取代基不會在連接至式 (IA) -NH-基團之環碳處經取代，且不會在結合至雜環族基團 之Y基團之任一個環碳處經取代；&ri = Ci_4烷基4Ci-2氟烷 基。 在式（IA)中，於亞式（X)及/或⑺中，較佳為沒有或一或兩 個A、B、D、E及F為氮；A、B、D、E及F之中沒有或 一、二或三個為CR6;而其餘A、：B、D、E及F為CH。更佳 87841·96〇3〇3·中.doc -66- 1283678 為沒有或一或兩個A、B、D、E及F為氮；沒有或一或兩個 A、B、D、E及F為CR6;而其餘A、B、D、E及F為CH。 在式（IA)中，於亞式（X)及/或(y)中，較佳為沒有或其中一個 八、8、〇、£及？為氮。 在式(IA)中，亞式⑻較佳為：芊基；苯乙基（Ph_c2H4_);爷 基或苯乙基係在苯環上被單一 R6取代基或下列之一取代··Wherein Y is 0, S, SOpiLNR10; wherein R1〇 is hydrogen, Ci-4 alkyl, Ci 2 fluoroalkyl, ¢:(0)4 _2 alkyl or c(o)-cf3; and wherein in R3 (: 3·8 cycloalkyl or heterocyclic group is optionally substituted by one or two substituents of OH, q·2 alkoxy, trimethoxy or alkyl; and any of 0H, alkoxy The benzyl or trimethoxy substituent is not substituted at the ring carbon attached to the -NH- group of formula (IA), and is not bonded to any of the ring carbons of the Y group bonded to the heterocyclic group. Substituting; &ri = Ci_4 alkyl 4Ci-2 fluoroalkyl. In the formula (IA), in the subformula (X) and/or (7), preferably no or one or two A, B, D, E and F are nitrogen; none, one, two or three of A, B, D, E and F are CR6; and the remaining A, B, D, E and F are CH. Better 87841·96〇3 〇3·中.doc -66- 1283678 is no or one or two of A, B, D, E and F are nitrogen; no or one or two of A, B, D, E and F are CR6; , B, D, E and F are CH. In the formula (IA), in the subtypes (X) and/or (y), it is preferred that none or one of the eight, eight, 〇, £ and ? In formula (IA), Preferably ⑻ formula: Qian group; phenethyl (Ph_c2H4_); Ye based or phenethyl substituted on the phenyl ring or one of the following groups a single substituent R6 ·

-CH-CH

-CH-CH

其中R6a為無論是如本文中定義之R6或（較佳為）氫。 在式（IA)中，亞式（y)較佳為： 論是如本文中定義之R6或較佳為Wherein R6a is R6 or (preferably) hydrogen as defined herein. In formula (IA), subformula (y) is preferably: R6 or preferably as defined herein

其中R6a為無 氫。Wherein R6a is hydrogen free.

實例1-99係為本發明第二方面（式（IA))之化合物或鹽之實例。 本發明之第三方面係提供式（IB)化合物或其鹽（特別是其 學上可接受之鹽）： ^ HN^ 0Examples 1-99 are examples of compounds or salts of the second aspect of the invention (formula (IA)). According to a third aspect of the present invention, there is provided a compound of the formula (IB) or a salt thereof (particularly a salt thereof): ^ HN^ 0

(IB) 87841-960303-φ.άοο -67- 1283678 其中： RICh 燒基、（：卜3 氟烷基、-CH2CH2OH 或-CI^CH^CC^Cu 烷 基； R2為氫原子（H)、曱基或Ci氟烷基； R為視N況經取代之C；3 ·8壤燒基，或亞式（aa)、（bb)或（cc)之 視情況經取代之雜環族基團；(IB) 87841-960303-φ.άοο -67- 1283678 where: RICh alkyl, (: 3 fluoroalkyl, -CH2CH2OH or -CI^CH^CC^Cu alkyl; R2 is a hydrogen atom (H), Mercapto or Ci fluoroalkyl; R is a substituted C in the case of N; 3 · 8 calcoxy, or optionally substituted heterocyclic group of subtype (aa), (bb) or (cc) ;

(aa) _ (CC) 其中η1與η2係獨立為1或2 ;且其中γ為〇、s、802或>况10 ; 其中R10為氫原子（Η)、C! _4烷基（例如甲基或乙基）、q 氟 燒基、CH2C(0)NH2、c(o)nh2、¢:(0)4-2烷基或(：(0)々氟烷基； 且其中在R3中，C3 -8環燒基或亞式（aa)、（bb)或（CC)之雜環族 基圈，係視情況被一或兩個酮基（=〇)、〇H、q -2烷氧基、 Ci ·2氟基烷氧基（例如三氟甲氧基）或q _2烷基之取代基取 代；且其中任何0H、烷氧基或氟基烷氧基取代基不會在連 接（結合）至式（IB) -NH-基團之R3環碳處經取代，且不會在任 一個結合至雜環族基團（aa)、（bb)或（CC)之Y基團之R3環碳處 經取代； 且X為NR4R5或0R5a，其中： R4為氫原子（H) ; Ci-6烷基；（V3氟烷基；或C2-6烷基，被一 個取代基R11取代；且 R5為氫原子（H) ; Cu烷基；Cu氟烷基；視情況被Ci -2燒基 87841-960303-中.doc -68 - 1283678 取代之C3_8環烷基；或_(CH2)n4-c3_8環烷基，視情況在 -(CH2)n4-部份基團或在C3 8環烷基部份基團中，被(^·2烷基 取代，其中η4為1、2或3 ; 或R5為C2_6燒基，被一或兩個獨立取代基R"取代； 其中各取代基R11，與任何其他存在之Ri 1取代基無關，係 為··幾基（0H) ; (^·6烷氧基；苯基氧基；芊氧基； -NR12R13 ； ^15-0(0)^6 ； -NR15-C(0>0-R16 ； -NR15-C(0)-NH-R1 5 ;或-NR1 ISC^R1 6 ;且其中任何Ri 1取代基，其係為〇H、 烷氧基或-NR12R13，不會在任何圮或化5取代之烷基（其係結 合至NR4R5之氮）之任何碳原子處經取代； 或 R5 為-(CH2)n 11 <：(0奸 6 ; ; chr19- C(0)NR12R13 ;-(CH2)n12-C(0)0R16 ; -CHR19-C(0)0R16 ; -(CH2)n12· S〇2-NR12R13 ; -(CH2)n12-S02R16 ;或-(CH2)ni2_CN;其中 nll 為 0、1、2、3或4，且 n12為 1、2、3 或4; 或 R5為-(CH2)n"_Het，其中 nl3為 〇、1、2、3 或4，且此為 4_， 5-，6-或7·員飽和或部份飽和雜環，含有一或兩個獨立選自 Ο、S及N之環雜原子；其中存在之任何環雜原子，當^為 1時’不會結合至-(CH2)ni3-部份基團，而當nl3為〇時，不會 結合至NRW之氮；纟中存在且不為不飽和（意即其不參盘 雙鍵）之任何環氮係以NR17存在，其中RU係如本文定 其中一或兩個碳環原子係獨立視情況被Ci2烷基取代； 或R5為苯基，視情況被-或兩個下列基图取代：㈣子； Ch烷基（例如Ck烷基）；Cl_2氟烷基（例如三氟甲其广c 燒氧基（例如CW完氧基）；Cl.2氟基Μ基⑼如^甲1氧4 87841-960303-中.doc •69- 1283678 基）； <：卜2烷基磺醯基（Ci-2烷基-S02_); Ci-2烷基-so2-nh·; R7R8N-S〇2-; R7R8N-CO-; -NR15-C(0)R16 ; R7R8N; OH; Ch烷 氧基甲基；c卜4烷氧基乙基；c1-2烷基_so厂Ch2_ ;氰基（CN); 或苯基’視情況被一或兩個氟基、氣基、q _2燒基、q氟烷 基、Cl - 2燒*乳基或Q氟基燒氧基取代； 其中R7與R8係獨立為氫原子⑻；Cl_4烷基（例如Ci-2烷基， 譬如甲基）；C：3·6環烷基；或苯基，視情沉被一或兩個下列 基團取代：氟基、氣基、Q-2烷基、（^氟烷基、Cle2烷氧基 或Ci氟基燒氧基；或R7與R8 一起為^设^-或^⑺^%)/ — 或-C(0)-(CH2 )n 7 -C(0)-或-(CH2 )n 8 -X7 -(ch2 )n 9 -或-c(o)-x7 -(CH2 )n 10 - ，其中：n6為3、4、5或6，n7為2、3、4或5(n7較佳為2、3 或4)，n8與n9及ni〇係獨立為2或3，且χ7為〇或]^14，其中 R14為11或（：1-2烷基； 或R5具有亞式（X)、（y)或⑻：(aa) _ (CC) wherein η1 and η2 are independently 1 or 2; and wherein γ is 〇, s, 802 or > Case 10; wherein R10 is a hydrogen atom (Η), C! _4 alkyl (such as A Or ethyl), q fluoroalkyl, CH2C(0)NH2, c(o)nh2, ¢: (0)4-2 alkyl or (:(0) fluorinylalkyl; and wherein in R3, a C3-8 cycloalkyl or a heterocyclic ring of the formula (aa), (bb) or (CC), optionally taken by one or two keto groups (=〇), 〇H, q-2 alkoxy Substituted with a substituent of Ci 2 fluoroalkoxy (eg, trifluoromethoxy) or q _2 alkyl; and wherein any 0H, alkoxy or fluoroalkoxy substituent is not attached (bonded To the R3 ring carbon of the formula (IB)-NH- group substituted by the R3 ring carbon and not bonded to the Y group of the heterocyclic group (aa), (bb) or (CC) Substituted; and X is NR4R5 or 0R5a, wherein: R4 is a hydrogen atom (H); Ci-6 alkyl; (V3 fluoroalkyl; or C2-6 alkyl, substituted by a substituent R11; and R5 is a hydrogen atom (H); a Cu alkyl group; a Cu fluoroalkyl group; a C3_8 cycloalkyl group substituted by a Ci-2 former base 87841-960303-中.doc-68-1283678; or _(CH2)n4-c3_ 8-cycloalkyl, optionally in the -(CH2)n4- moiety or in the C3 8 cycloalkyl moiety, substituted by (^.2 alkyl, wherein η4 is 1, 2 or 3; or R5 is a C2_6 alkyl group substituted by one or two independent substituents R" wherein each substituent R11, irrespective of any other Ri 1 substituent present, is a group of (0H); Oxyl; phenyloxy; anthraceneoxy; -NR12R13; ^15-0(0)^6; -NR15-C(0>0-R16; -NR15-C(0)-NH-R1 5 ; -NR1 ISC^R1 6 ; and any of the Ri 1 substituents, which are 〇H, alkoxy or -NR12R13, are not substituted at any of the oxime or substituted 5-alkyl groups (which are bonded to the nitrogen of NR4R5) Any carbon atom is substituted; or R5 is -(CH2)n 11 <:(0 rape 6 ; ; chr19- C(0)NR12R13 ; -(CH2)n12-C(0)0R16 ; -CHR19-C( 0) 0R16 ; -(CH2)n12· S〇2-NR12R13 ; -(CH2)n12-S02R16 ; or -(CH2)ni2_CN; where nll is 0, 1, 2, 3 or 4, and n12 is 1, 2 , 3 or 4; or R5 is -(CH2)n"_Het, where nl3 is 〇, 1, 2, 3 or 4, and this is a 4_, 5-, 6- or 7-membered saturated or partially saturated heterocyclic ring Containing one or two independent choices from Ο, S and N a ring heteroatom; any ring hetero atom present therein, when ^ is 1 'will not bind to the -(CH2)ni3- moiety, and when nl3 is 〇, it will not bind to the nitrogen of NRW; Any cyclic nitrogen present in and not unsaturated (ie, which does not participate in a double bond) is present as NR17 wherein the RU is as defined herein wherein one or two of the carbon ring atoms are independently substituted with Ci2 alkyl as appropriate; Or R5 is phenyl, optionally substituted by - or two of the following base diagrams: (iv) sub; Ch alkyl (eg Ck alkyl); Cl 2 fluoroalkyl (eg trifluoromethyl) c alkoxy (eg CW finished氧基); Cl. 2 fluoro fluorenyl (9) such as methoxy 1 87841-960303-中 .doc • 69- 1283678 base; <: 2 alkyl sulfonyl (Ci-2 alkyl-S02_) Ci-2 alkyl-so2-nh·; R7R8N-S〇2-; R7R8N-CO-; -NR15-C(0)R16; R7R8N; OH; Ch alkoxymethyl; c 4 alkoxy Base ethyl; c1-2 alkyl _so plant Ch2_; cyano (CN); or phenyl 'as appropriate by one or two fluoro, gas, q _2 alkyl, q fluoroalkyl, Cl - 2 a calcined * or a fluoroalkyl alkoxy group; wherein R 7 and R 8 are independently a hydrogen atom (8); a C 4 alkyl group (for example, a Ci-2 alkyl group, Such as methyl); C: 3·6 cycloalkyl; or phenyl, as the case is replaced by one or two of the following groups: fluoro, gas, Q-2 alkyl, (^ fluoroalkyl, Cle2 Alkoxy or Ci fluoroalkyl alkoxy; or R7 together with R8 is ^- or ^(7)^%)/- or -C(0)-(CH2)n 7 -C(0)- or -( CH2)n 8 -X7 -(ch2 )n 9 - or -c(o)-x7 -(CH2 )n 10 - , wherein: n6 is 3, 4, 5 or 6, and n7 is 2, 3, 4 or 5 (n7 is preferably 2, 3 or 4), n8 and n9 and ni〇 are independently 2 or 3, and χ7 is 〇 or ]^14, wherein R14 is 11 or (:1-2 alkyl; or R5 has Subtype (X), (y) or (8):

其中在亞式（X)中，n=l或2;在亞式（y)中，m=l或2;及在 亞式（z)中，r = 〇、i或2; 其中在亞式（X)與（y)中，沒有或一或兩個A、B、D、E及F為 氮；而其餘A、B、D、E及F係獨立為CH或CR6 ; 其中R6為自原子；Cl_4烷基（例如Ci 2烷基）；Ci 4氟烷基（例 如4_2氟燒基）；Cw烷氧基（例如Ci 2烷氧基）；Ci 2氟基烷氧 基；Ci·2燒基磺醯基（c卜2烷基-S〇2_) ; Ci 2烷基_s〇2-NH_ ; 87841·96〇3〇3_ 中.doc •70- 1283678 R7R8N-S〇2- ； R7R8N-CO-； -NR15-C(0)R16 ； R7R8N； oh； 氣基甲基；（^1-4燒氧基乙基；（111-2燒基-8〇2-(1!112-;氰基（。1^); 或苯基，視情況被一或兩個氟基、氯基、C! _2燒基、Ci敦燒 基、C!-2烷氧基或心氟基烷氧基取代；其中R7與R8均如本文 定義； 其中在亞式（Z)中，G為Ο或S或NR9，其中R9為氫原子(H)、 Ci -4燒基或Ci _4氟燒基；J、L、Μ及Q之中沒有或一、二或 三個為氮；而其餘J、L、Μ及Q係獨立為CH或CR6，其中R6 係如本文定義； 或 R4 與 R5 —起採用為-(CHdp1-或-C(〇MCH2)p2_ 或-(αί2)ρ3_χ5- (CH2)p4_ 或-C(0)_X5_(CH2)p5-，其中：Ρι = 3、4、5或6(較佳為 P = 4或5)，p2為2、3、4或5(p2較佳為2、3或4)，且p3與p4及 P5係獨立為2或3 (較佳獨立為2)，且X5為〇或NR1 7 ; 其中R17為氫原子（H); Q-4烷基（例如(^·2烷基）；（：卜2氟烷 基；C3_6環烷基；-(CH2)p6_C(0)R16，其中 p6為 〇、！、2 或 3(p6 較佳為 0) ; -(ch2)p6-c(o)nr12r13 ; -(ch2)p6-c(o)〇r16 ; -S〇2 R ’或+基或卞基，其中苯基或爷基係視情況在芳族 碳原子處被一或兩個下列基團取代：_原子、C1-2烷基、Ci 氟烷基、Ck烷氧基或(^氟基烷氧基； 且其中，當R4與R5 —起採用為-(CH2)pi-或-C(0)-(CH2)p2-時，NR4 R5雜環係視情況被一個Ri 8取代基取代，其中r1 s 為：Ch烷基（例如Cm烷基）；（^-2氟烷基；C3-6環烷基； ci ·2燒氧基（未在結合至NR4R5環-氮之環-碳處經取代）；Ci氟 基燒氧基（未在結合至Nr4r5環-氮之環·碳處經取代）； 87841-96〇3〇3-中.doc •71 - 1283678 OH(未在結合至nr4r5環-氮之環-碳處經取代）；_(CH2)p7_ CXCOR1 6，其中p7為〇、丄、2或3 (p7較佳為^或^;^^^^ C(0)0R16 ； -(CH2)p^〇c(〇)Ri6 ； .(CH2)p7-C(0)NR12R13 ； -(CH2)p7-NR1 5 C(0)R1 6 ； -(CH2 )p 7 -NR15 C(0)NR12 R13 ； -(CH2)P7- NR15C(0)0R16 ； _(CH2 )p 7 _S02 R1 6 ; -(CH2 )p 7 -S02 NR12 R13 ; -(ch2)p7-nr15so2r!6 ; _(CH2)p7_OH; ·(αΐ2)ρ7-〇κ16 ;或苯基， 視情況被一或兩個下列基團取代··卣原子、Ci -2烷基、Ci氟 烷基、Q-2烷氧基或心氟基烷氧基； 或R4與R5 —起採用為如本文中定義之-(CH2)pi_或_c(〇)_ (CH2)p2-或 _(CH2)p3_x5_(CH2)p4-或-C(0)-X5-(CH2)p5-，且其中 NR4 R5雜環係稠合至苯環，視情況在苯基上被一或兩個下列 基團取代：_原子、烷基、q氟烷基、Ck烷氧基或。 氟基燒氧基；且 r5Hs燒基；Cu氟烷基；c3_8環烷基；苯基，視情況被 一或兩個下列基图取代：齒原子、Ci-2烷基、三氟曱基、 Q·2燒氧基或三氟甲氧基；或R5a具有如本文中定義之亞式 ⑻、（y)或(Z); 且其中： R12與R13係獨立為H; Ch烷基（例如C卜3烷基）；c3-6環烷 基；或苯基，視情況被一或兩個下列基團取代··齒原子、 Ci-2烷基、C!氟烷基、Q-2烷氧基或心氟基烷氧基； 或 R12 與 R13 — 起為 _(〇ί2)Λ 或-C(〇HCH2)n7-或 _C(〇HCH2)n7· 為3、4、5或6(n6較佳為4或5)，η7為2、3、4或5(n7較佳為 87841-960303-中.doc •72- 1283678 2、3或4)，η與η及η1 〇係獨互為2或3 (較佳獨立為2)，且 X12為0或NR14，其中R14為Η或Cb2烷基； R15為氫原子（H); ¢^4燒基（例如或Ci_2烷基，例如甲 基）；C3-6環烷基；或苯基，視情況被一或兩個下列基團取 代：鹵原子、Cufe基、q氟燒基、Cl_2燒氧基或心氟基燒 氧基； ^ 烷基（例如(^_2烷基）；（：3_6環烷基；吡啶基（例如吡 啶-2-基”或苯基，视情況被一或兩個下列基團取代：自原 子、Q·2燒基、心氟燒基、c卜2燒氧基或〇1氟基烷氧基；且 R19為氫原子（H) ; Q _4燒基（例如異丁基、第二_丁其或匸^ 基，譬如甲基或異丙基）；-(CH2 )n2 0 -〇R2 〇，其中 3或4(較佳為i) ’且尺^為氯原子（11)或〇1_4燒基（較佳為圮〇為 H) ; -CH_-OH ; -CH2-SH ; -CH2-CH2_S_Me ; τ 基；或㈣苯 基）甲基（意即4-羥基-爷基）。 在式（ffi)中’於R3為視情況經取代之C38環烷基之情況 下’-或兩個選用取代基較佳係包括（例如係為）〇h及/或 嗣基㈣。在式㈣中’於亞式㈣、㈣或（cc)之圮雜環族基 團中，-或兩個選用取代基較佳係包括（例如係為輝及/ 或酮基。 實例剛係為本發明第三方面（式_之化合物或鹽之實 例0 關於式（IAH匕合物或鹽與式（IBM匕合物或鹽之較佳或選用 特徵，係與關於式（1)化合物或鹽之較佳或選用特徵相同或 類似，其中所有必要改變（例如對化學式、對R基團及/或 S7841 _96〇3〇3·中 d〇c -73- 1283678 對取代基）已被施行。一般而言，無論何時在本文中提及式 (I)時’則在替代具體實施例中，提及式①之陳述係適用於 式（IA)或式（IB)，其中所有必要改變已被施行。 鹽、溶劑合物、異構物、互變異構形式、分子量等 由於其在醫藥上之潛在用途，故式①化合物之鹽較佳為藥 學上可接受。適當藥學上可接受之鹽可包括酸或鹼加成 鹽蕖學上可接受之酸加成鹽，可藉由式（I)化合物與適當 無機或有機酸（譬如氫溴酸、鹽酸、硫酸、硝酸、磷酸、琥 珀缸、順丁缔二酸、醋酸、反丁雄二酸、擰檬酸、酒石 酸、苯甲酸、對-甲苯磺酸、甲烷磺酸或莕磺酸）之反應而 形成，視情況在適當溶劑中，譬如有機溶劑，獲得鹽，其 ，系係藉由例如結晶化作用及過濾而分離。式①化合物之 藥子上可接支之酸加成鹽，可為例如氫溴酸鹽、鹽酸鹽、 硫酸鹽、硝酸鹽、磷酸鹽、琥_酸鹽、順丁缔二酸酿、酷 酸鹽、反丁埽二酸鹽、擰檬酸鹽、酒石酸鹽、I甲酸鹽、曰 對-甲苯磺酸鹽、甲烷磺酸鹽或萘磺酸鹽。藥學上可接典之 驗加成鹽可藉由式（1)化合物與適當無機或有機驗之反= 二成並视情況在適當溶劑中，譬如有機溶劑1得鹼加成 ^其通常係藉由例如結晶化作用及過滤而分冑。其 當藥學上可接受之B®，句括蘊與 /、、 浓取 &amp;括樂學上可接受之金屬鹽，例如 柒學上可接受之鹼金屬或鹼土金屬蹄，座 鎂鹽；特別是可存在於式①化合物中“：、：、句或 基團之藥學上可接受金屬鹽。 &lt; 個叙酸邵份 其他非藥學上可接受之鹽，例 例如卓鉍鹽，可用於例如本發 87841-960303.^.d〇c -74- 1283678 明化合物之單離中，且係包含在本發明之範圍内。 =明在其範園内’係包括式①化合物鹽之所有可能化學 計I與非化學計量形式。 亦包含在本發明之範圍内者，係為本發明化合物與鹽之所 有落劑合物、水合物及複合物。 包含在本發明中之某些基圏、取代基、化合物或鹽，可以 異構物存在。本發明在其範圍内’係包括所有此種異構 物，包括外消旋物、對掌異構物及其混合物。 被包含在式①化合物或其鹽中之某些基圏，例如雜芳族環 系、·克可以-或多種互變異構形式存在。本發明在其範圍 内，係包括所有此種互變異構形式，包括混合物。 尤其是當欲供口服醫藥利用時，式（1)化合物可視情況具有 分子量為1000或較低，例如800或較低，特定言之為65〇或 較低，或600或較低。此處之分子量係指未溶劑化合&quot;自由 態鹼”化合物之分子量，意.即排除由任何加成鹽、溶劑（例 如水）分子等所貢獻之任何分子量。 合成方法途徑 下述方法可用以製造本發明化合物：Wherein in the subtype (X), n = 1 or 2; in the subtype (y), m = 1 or 2; and in the subtype (z), r = 〇, i or 2; In (X) and (y), no or one or two of A, B, D, E and F are nitrogen; and the remaining A, B, D, E and F are independently CH or CR6; wherein R6 is a self atom ; C 4 alkyl (for example, Ci 2 alkyl); Ci 4 fluoroalkyl (for example, 4 2 fluoroalkyl); C alkoxy (for example, Ci 2 alkoxy); Ci 2 fluoroalkoxy; Ci · 2 Sulfosyl (c 2 alkyl-S〇2_); Ci 2 alkyl _s〇2-NH_; 87841·96〇3〇3_中.doc •70- 1283678 R7R8N-S〇2- ; R7R8N- CO-; -NR15-C(0)R16; R7R8N; oh; gas methyl; (^1-4 alkoxyethyl; (111-2 alkyl-8〇2-(1!112-; cyanide) Base (.1^); or phenyl, optionally substituted by one or two fluoro, chloro, C! _2 alkyl, Ci butyl, C!-2 alkoxy or heart fluoroalkoxy Wherein R7 and R8 are as defined herein; wherein in the subtype (Z), G is hydrazine or S or NR9, wherein R9 is a hydrogen atom (H), a Ci-4 alkyl group or a Ci_4 fluoroalkyl group; None, one, two or three of L, Μ and Q are nitrogen; and the remaining J, L, Μ and Q Independently CH or CR6, where R6 is as defined herein; or R4 and R5 are taken as -(CHdp1- or -C(〇MCH2)p2_ or -(αί2)ρ3_χ5- (CH2)p4_ or -C(0) _X5_(CH2)p5-, wherein: Ρι = 3, 4, 5 or 6 (preferably P = 4 or 5), p2 is 2, 3, 4 or 5 (p2 is preferably 2, 3 or 4), And p3 and p4 and P5 are independently 2 or 3 (preferably independently 2), and X5 is 〇 or NR1 7 ; wherein R17 is a hydrogen atom (H); Q-4 alkyl (for example, (^.2 alkyl) (;: 2 fluoroalkyl; C3_6 cycloalkyl; -(CH2)p6_C(0)R16, wherein p6 is 〇, !, 2 or 3 (p6 is preferably 0); -(ch2)p6-c (o) nr12r13; -(ch2)p6-c(o)〇r16; -S〇2 R ' or + or fluorenyl, wherein phenyl or aryl is optionally one or two at the aromatic carbon atom Substituting the following groups: _Atom, C1-2 alkyl, Ci fluoroalkyl, Ck alkoxy or (fluoroindolyl); and wherein, when R4 is combined with R5, it is -(CH2)pi- Or -C(0)-(CH2)p2-, the NR4 R5 heterocyclic ring is optionally substituted by a Ri 8 substituent, wherein r1 s is: Ch alkyl (eg Cm alkyl); (^-2 halothane) C3-6 cycloalkyl; ci · 2 alkoxy (not bound to NR4R5 ring-nitrogen Ring-carbon substituted); Ci-fluoroalkoxy (not substituted at the ring bonded to Nr4r5 ring-nitrogen); 87841-96〇3〇3-中.doc •71 - 1283678 OH (not Substituted to nr4r5 ring-nitrogen ring-carbon; _(CH2)p7_CXCOR1 6, wherein p7 is 〇, 丄, 2 or 3 (p7 is preferably ^ or ^; ^^^^ C(0 ) 0R16 ; -(CH2)p^〇c(〇)Ri6 ; .(CH2)p7-C(0)NR12R13 ; -(CH2)p7-NR1 5 C(0)R1 6 ; -(CH2 )p 7 - NR15 C(0)NR12 R13 ; -(CH2)P7- NR15C(0)0R16 ; _(CH2 )p 7 _S02 R1 6 ; -(CH2 )p 7 -S02 NR12 R13 ; -(ch2)p7-nr15so2r!6 ; _(CH2)p7_OH; ·(αΐ2)ρ7-〇κ16; or phenyl, optionally substituted by one or two of the following groups: 卣 atom, Ci-2 alkyl, Ci fluoroalkyl, Q-2 Alkoxy or cardinylalkoxy; or R4 and R5 are taken as -(CH2)pi_ or _c(〇)_(CH2)p2- or _(CH2)p3_x5_(CH2 as defined herein) P4- or -C(0)-X5-(CH2)p5-, and wherein the NR4 R5 heterocyclic ring is fused to the phenyl ring, optionally substituted on the phenyl group with one or two of the following groups: _ atom, Alkyl, q-fluoroalkyl, Ck alkoxy or. Fluoroalkyl alkoxy; and r5Hs alkyl; Cu fluoroalkyl; c3_8 cycloalkyl; phenyl, optionally substituted by one or two of the following base diagrams: a tooth atom, a Ci-2 alkyl group, a trifluoromethyl group, Q. 2 alkoxy or trifluoromethoxy; or R5a having the formula (8), (y) or (Z) as defined herein; and wherein: R12 and R13 are independently H; Ch alkyl (eg C a 3 alkyl group; a c3-6 cycloalkyl group; or a phenyl group, optionally substituted by one or two of the following groups: a tooth atom, a Ci-2 alkyl group, a C! fluoroalkyl group, a Q-2 alkoxy group Or a fluoroalkoxy group; or R12 and R13 are _(〇ί2)Λ or -C(〇HCH2)n7- or _C(〇HCH2)n7· is 3, 4, 5 or 6 (n6 Preferably, 4 or 5), η7 is 2, 3, 4 or 5 (n7 is preferably 87841-960303-medium.doc • 72-1283678 2, 3 or 4), and η and η and η1 are each 2 or 3 (preferably independently 2), and X12 is 0 or NR14, wherein R14 is hydrazine or Cb2 alkyl; R15 is a hydrogen atom (H); ¢^4 alkyl (for example or a Ci_2 alkyl group such as methyl a C3-6 cycloalkyl group; or a phenyl group, optionally substituted with one or two of the following groups: a halogen atom, a Cufe group, a q fluoroalkyl group, a C 2 alkoxy group or a heart fluoride alkoxy group; ^alkyl (for example (^ 2 alkyl); (: 3_6 cycloalkyl; pyridyl (eg pyridin-2-yl) or phenyl, optionally substituted with one or two of the following groups: from atom, Q· 2 alkyl, fluoroalkyl, c 2 alkoxy or fluorenyl 1 fluoroalkoxy; and R 19 is a hydrogen atom (H); Q _ 4 alkyl (eg isobutyl, second butyl or oxime) ^基, such as methyl or isopropyl); -(CH2)n2 0 -〇R2 〇, wherein 3 or 4 (preferably i) ' and the ruler ^ is a chlorine atom (11) or a 〇1_4 alkyl group Preferably, it is H); -CH_-OH; -CH2-SH; -CH2-CH2_S_Me; τ group; or (tetra)phenyl)methyl (meaning 4-hydroxy-yl). In formula (ffi) 'In the case where R3 is optionally substituted C38 cycloalkyl, '- or the two optional substituents preferably include (for example, 〇h and/or fluorenyl (IV). In the formula (d), 'in the subtype In the heterocyclic group of (d), (d) or (cc), the substituent or the two substituents preferably include (for example, a fluorene and/or a keto group. The example is the third aspect of the invention (formula_) Example 0 of a compound or salt. Regarding the formula (IAH complex or salt and formula (IBM compound or salt) Preferred or optional characteristics, which are the same or similar to those of the compound or salt of formula (1), all of which are necessary (for example, for the chemical formula, for the R group and/or for S7841 _96〇3〇3·d 〇c -73- 1283678 for substituents) has been implemented. In general, whenever reference is made to Formula (I) herein, then in the alternative embodiments, the reference to Formula 1 applies to Formula (IA) or Formula (IB), where all necessary changes have been Implementation. Salts, solvates, isomers, tautomeric forms, molecular weights, etc. The salts of the compounds of formula 1 are preferably pharmaceutically acceptable due to their potential use in medicine. Suitable pharmaceutically acceptable salts may include acid- or base-addition salts, which are pharmaceutically acceptable acid addition salts, which may be obtained by reacting a compound of formula (I) with a suitable inorganic or organic acid (such as hydrobromic acid, hydrochloric acid, sulfuric acid, Formed by the reaction of nitric acid, phosphoric acid, amber cylinder, cis-dibasic acid, acetic acid, trans-tert-bic acid, citric acid, tartaric acid, benzoic acid, p-toluenesulfonic acid, methanesulfonic acid or sulfonic acid, depending on the situation In a suitable solvent, such as an organic solvent, a salt is obtained which is isolated by, for example, crystallization and filtration. The acid addition salt of the compound of the formula 1 may be, for example, a hydrobromide, a hydrochloride, a sulfate, a nitrate, a phosphate, a succinate, a succinic acid, and a cool An acid salt, a sulfonate, a citrate, a tartrate, a formate, a p-toluenesulfonate, a methanesulfonate or a naphthalenesulfonate. The pharmaceutically acceptable salt addition salt can be obtained by reacting a compound of the formula (1) with a suitable inorganic or organic compound = 20% and optionally adding a base in an appropriate solvent such as an organic solvent. For example, crystallization and filtration are separated. It is a pharmaceutically acceptable B®, a sentence containing and/or, a concentrate and a musically acceptable metal salt, such as a drop-off of an alkali metal or alkaline earth metal hoof, a magnesium salt; Is a pharmaceutically acceptable metal salt of a ":,:, or a group" which may be present in the compound of Formula 1. < </ RTI> Other non-pharmaceutically acceptable salts, such as, for example, a sulfonium salt, may be used, for example, The present invention is in the form of a single compound of the present invention and is included in the scope of the present invention. I and non-stoichiometric forms. Also included within the scope of the invention are all falling compositions, hydrates and complexes of the compounds and salts of the invention. Certain bases, substituents included in the invention , a compound or a salt, which may be present as an isomer. The invention in its scope includes all such isomers, including racemates, palmomerisomers and mixtures thereof. Certain bases in the salt, such as heteroaromatic rings, - or a plurality of tautomeric forms are present. Within the scope of the invention, all such tautomeric forms, including mixtures, are included. In particular, when intended for oral pharmaceutical use, the compound of formula (1) may optionally have a molecular weight of 1000. Or lower, such as 800 or lower, specifically 65 〇 or lower, or 600 or lower. The molecular weight here refers to the molecular weight of the unsolvated compound &quot;free base" compound, meaning Any molecular weight contributed by any addition salt, solvent (eg, water) molecules, and the like. Synthetic Method Pathways The following methods can be used to make the compounds of the invention:

R1 大部份下述合成方法係為其中R2為氫原子（Η)之式①化合 物實例。但疋，一邵份或全邵此等方法亦可與例如起始物 87841-960303-中.doc -75- 1283678 質與試劑之適當修正一起使用，以製造其中R2不為Η之式① 化合物。Most of the following synthesis methods of R1 are examples of the compound of the formula 1 wherein R2 is a hydrogen atom (Η). However, the method of 邵, 邵, or 邵 邵 can also be used together with appropriate corrections such as starting material 87841-960303-中.doc-75-1283678 for the preparation of a compound of formula 1 wherein R2 is not ruthenium. .

方法A 式（I)化合物，其中X==0R5a，可根據由Yu等人在 J Λ^/C/zem·，2001，44, 1025-1027中所述之方法，經由使式⑼化 合物與式R3NH2之胺反應而製成。此反應較佳係於鹼存在 下，譬如三乙胺或N，N-二異丙基乙胺，及/或在有機溶劑譬 如乙醇、二氧陸圜或乙腈中進行。此反應可能需要加熱至 例如約60-10(TC，例如約80_9(rc :Process A A compound of formula (I) wherein X = 0R5a can be obtained by formulating a compound of formula (9) according to the method described by Yu et al., J Λ^/C/zem., 2001, 44, 1025-1027. It is prepared by reacting an amine of R3NH2. This reaction is preferably carried out in the presence of a base such as triethylamine or N,N-diisopropylethylamine, and/or in an organic solvent such as ethanol, dioxane or acetonitrile. This reaction may require heating to, for example, about 60-10 (TC, such as about 80-9 (rc:

(I) 式（π)化合物亦描述於上文參考資料中，且可經由使式（ΙΠ) 化合物與例如乙氧基亞甲基丙二酸二乙酯（其中R5a= Et)反 應，並加熱，接著與氯化磷醯反應，再一次加熱而製成：(I) The compound of the formula (π) is also described in the above reference, and can be reacted by heating a compound of the formula (ΙΠ) with, for example, diethyl ethoxymethylenemalonate (wherein R5a= Et) and heating , then reacted with phosphine chloride and heated again to produce:

式III 1)Formula III 1)

在所要之式（III)胺基吡唑不為市購可得之情況下（例如 R^CHJh)，製備可使用由Dorgan等人在又〇^紅8〇(：.， Perkin Trans. 1，（4)，938-42 ; 1980中所述之方法，經由使氰基乙 87841-960303-中.doc -76- 1283678 基肼與式㊇咖之適當越，在溶劑譬如乙醇中反應，並加 熱，接著以例如納在溶劑譬如第三-丁醇中還原而達成。r4〇 應經選擇，以致能夠含有比以少—個碳原子，例如r4 基將獲得R1^乙基。In the case where the desired formula (III) is not commercially available (for example, R^CHJh), the preparation can be carried out by Dorgan et al. in 〇^红8〇(:., Perkin Trans. 1, (4), 938-42; The method described in 1980, by reacting cyanoethyl 87841-960303-medium doc-76-1283678 base with a suitable formula, in a solvent such as ethanol, and heating This is then achieved, for example, by reduction in a solvent such as a third-butanol. The r4 oxime should be chosen such that it will contain more than one carbon atom, for example an r4 group.

H2NH2N

CNCN

1) R40CHO EtOH1) R40CHO EtOH

2) Na / t-BuOH2) Na / t-BuOH

方法B 式（I)化合物，其中X = NR4R5，可經由使式（IV)化合物與式 R3NH2胺反應而製成。此反應較佳係於鹼存在下，譬如三乙 胺或N，N-二異丙基乙胺，及/或在有機溶劑譬如乙醇、 THF、二氧陸圜或乙腈中進行。此反應可能需要加熱至例如 約60-100°C或約80-90°C，例如歷經8-48或12-24小時：Process B A compound of formula (I) wherein X = NR4R5 can be prepared by reacting a compound of formula (IV) with an amine of formula R3NH2. This reaction is preferably carried out in the presence of a base such as triethylamine or N,N-diisopropylethylamine, and/or in an organic solvent such as ethanol, THF, dioxane or acetonitrile. This reaction may require heating to, for example, about 60-100 ° C or about 80-90 ° C, for example over 8-48 or 12-24 hours:

式（IV)化合物可以兩步驟程序，按照由Bare等人在ju C7^w. 1989, 32, 2561-2573中所述製成。此方法首先涉及使式（v) 化合物與二氯化亞硫醯（或另一種適合從叛酸形成氯化醯之 作用劑），無論是在有機溶劑譬如氣仿或THF中，或以不含 溶劑之溶液反應。此反應可能需要加熱，且如此形成之中 87841-960303-中.doc -77- 1283678 間物可以或可以不分離。步_ -在、本 T驟一係涉及與式R4R5NH胺，在 有機溶劑譬如THF或氯仿中反鹿， ^ 、 T夂應且耶可涉及鹼，譬如三乙 胺或二異丙基乙胺之利用：The compound of formula (IV) can be prepared in two steps, as described by Bare et al., ju C7^w. 1989, 32, 2561-2573. This method first involves the compound of formula (v) and sulfinium dichloride (or another agent suitable for the formation of ruthenium chloride from tickic acid), whether in an organic solvent such as gas or THF, or Solvent solution reaction. This reaction may require heating, and the formation of 87841-960303-medium doc-77- 1283678 may or may not be separated. Step _ - In this T, it relates to the formula R4R5NH amine, in the organic solvent such as THF or chloroform, anti-deer, ^, T 夂 and yoke may involve a base, such as triethylamine or diisopropylethylamine use:

式VFormula V

NFTR3 式（V)化口物可根據由Yu等人在又偏㈤所，獅丨〆4,廳· 1027中所述之方法，藉由式⑻g旨之水解作用製成。此程序 較佳係涉及與驗，譬如氫氧化鋼或氫氧化鉀，在溶劑，例 如水性洛劑，譬如•含水乙醇或含水二氧陸圜中反應：The NFTR3 formula (V) can be produced by the hydrolysis of the formula (8) g according to the method described by Yu et al., V. 4, Hall 1027. Preferably, the procedure involves the reaction, such as the oxidation of steel or potassium hydroxide, in a solvent such as a waterborne agent such as aqueous ethanol or aqueous dioxin:

方法C 式（I)化合物亦可根據由Bare等人在《/· C/zem· 1989, 32, 2561-2573中所述之方法製成，其係涉及使式（VI)化合物，其中-0-R為-OA·4烷基，特別是_〇_扮，與式r3nh2胺反應。反應可 使用或未使用溶劑進行，且可能需要加熱。 R\Process C The compound of formula (I) can also be prepared according to the method described by Bare et al., /C/zem. 1989, 32, 2561-2573, which relates to a compound of formula (VI) wherein -0 -R is -OA.4 alkyl, especially _〇_, reacted with an amine of the formula r3nh2. The reaction can be carried out with or without a solvent and may require heating. R\

R1R1

式VIFormula VI

OR5a 87841_960303·中.doc -78- 1283678 式（VI)化合物（亦描述於上文參考資料中）可經由使式（VII) 化合物與式Ri -X之適當烷基化劑反應而製成，其中X為脫離 基，譬如自素。此反應應於驗存在下，譬如碳酸鉀，在無 水溶劑譬如DMF中進行：OR5a 87841_960303·中.doc -78- 1283678 The compound of formula (VI) (also described in the above references) can be prepared by reacting a compound of formula (VII) with a suitable alkylating agent of formula Ri-X, wherein X is a detached base, such as self-priming. This reaction should be carried out in the presence of a solvent such as potassium carbonate in an anhydrous solvent such as DMF:

OROR

式VIIFormula VII

OROR

R1-X K2C03 DMF 式VII化合物藉由式VIII化合物之氧化性***之製備，係由R1-X K2C03 DMF The preparation of a compound of formula VII by oxidative cleavage of a compound of formula VIII

Bare 等人在 MM. C/zem· 1989, 32, 2561-2573 中（進一步依據 Zuleski 等人，在 J· Drug· Metab· Dispos.，1985, 13, 139 中）描述。Bare et al. are described in MM. C/zem. 1989, 32, 2561-2573 (further according to Zuleski et al., J. Drug. Metab. Dispos., 1985, 13, 139).

式 VIIIFormula VIII

式VII 方法D : 為形成式⑴化合物，其中X = NR4R5，可使式（I)化合物，但 其中X = OH(羧酸）轉化成經活化之式（I)化合物，但其中X = 可被胺取代之脫離基；接著，可使經活化之化合物與式 R4R5NH胺反應。 例如，經活化之化合物可為氯化醯，意即經活化之式（I)化 合物，但其中脫離基X = C1。其可製自羧酸(X = OH)，例如藉 由與二氯化亞硫酿反應。參閱，例如實例81-85。或者，經 87841-960303-中.doc -79- 1283678 活化之化合物可為經活化酯，其中脫離基X為Formula VII Method D: To form a compound of formula (1) wherein X = NR4R5, a compound of formula (I), but wherein X = OH (carboxylic acid), can be converted to an activated compound of formula (I), but wherein X = The amine is substituted for the cleavage group; then, the activated compound can be reacted with the formula R4R5NH amine. For example, the activated compound can be cesium chloride, meaning an activated compound of formula (I), but wherein the cleavage group X = C1. It can be prepared from a carboxylic acid (X = OH), for example by reaction with thionous chloride. See, for example, Examples 81-85. Alternatively, the compound activated by 87841-960303-.doc-79-1283678 may be an activated ester wherein the cleavage group X is

後述經活化之化合物可製自羧酸（χ = 0H)，無論是： ⑻經由使羧酸與碳化二亞胺譬如EDC反應，其係為1-乙基-3-(3 - —甲胺基丙基）碳化二亞胺’且亦為1-(3-二甲胺基丙基）_3_ 乙基碳化二亞胺或其鹽，例如鹽酸鹽，接著使所形成之產 物與1-羥基苯并***(HOBT)反應；反應⑷通常係於溶劑存在 下’譬如二甲基甲醯胺（DMF)，及/或通常在室溫下（例如 約20至約25°C )進行； (b)經由與四氟硼酸2_(1H-苯并***小基）-ΐ，ι，3,3-四甲基錁 (TBTU)或六氟磷酸0-(7·氮苯并***-1-基）_\，&gt;^，，&gt;1，-四甲基錁 (HATU)反應，於鹼存在下，譬如二異丙基乙胺 (ipr^NetsDIPEA)，且通常於溶劑存在下，譬如二甲基甲醯胺 (DMF)，及/或通常在室溫下（例如約2〇至約25°C )。 因此，本發明亦提供製備式（I)化合物或其鹽之方法，其包括 (a) 關於式（I)化合物，其中X = OR5a，為式⑼化合物與式 R3NH2胺之反應，或 (b) 關於式⑴化合物’其中X = nr4r5，為式（IV)化合物與式 R3NH2胺之反應，或 (c) 式（VI)化合物，其中烷基，與式r3^胺之 反應； 87841-960303-中.doc -80- 1283678 (d)為形成式（I)化合物’其中X = NR4R5，係使式①化合物， 但其中X = OH(羧酸），轉化成經活化之式①化合物，但其中 X==可被胺取代之脫離基（經活化之化合物較佳可為氯化醯， 意即經活化之式（I)化合物，但其中X = C1)，接著是經活化之 化合物與式R4R5NH胺之反應； 且視情況使式⑴化合物轉化成鹽，例如藥學上可接受之鹽。 醫藥用途 本發明亦提供式（I)化合物或其藥學上可接受之鹽，在哺乳 動物譬如人類中，作為活性治療物質之用途。此化合物或 鹽可用於治療及/或預防本文中所述之任何症狀（例如，在 哺乳動物中用於治療及/或預防炎性及/或過敏性疾病）， 及/或作為磷酸二酯酶抑制劑使用，例如作為磷酸二酯酶4 (PDE4)抑制劑使用。&quot;治療”可包括治療處理及/或預防。 亦提供式（I)化合物或其藥學上可接受之鹽於藥劑製造上之 用途（例如醫藥組合物），該藥劑係在哺乳動物譬如人類中 治療及/或預防炎性及/或過敏性疾病。 亦提供一種在有需要之哺乳動物（例如人類）中治療及/或 預防炎性及/或過敏性疾病之方法，其包括對哺乳動物（例 如人類）投予治療上有效量之如本文中定義之式（1)化合物或 其藥學上可接受之鹽。 鱗酸二酿酶4抑制劑被認為可在哺乳動物譬如人類中用於 治療及/或預防多種疾病，尤其是炎性及/或過敏性疾 病，例如：氣喘、慢性枝氣管炎、氣腫、異位性皮炎、蓴 麻療過敏性鼻炎、過敏性結合膜炎、春季結合膜炎、嗜 87841-96〇3〇3-中.d〇c -81 - 1283678 伊紅肉芽瘤、牛皮癖、風濕性關節炎、敗血性休克、潰瘍 性結腸炎、克隆氏病、心肌與腦部之再灌注傷害、慢性絲 球體性腎炎、内毒素休克、成人呼吸困難徵候簇或多發性 硬化。 在治療及/或預防方面，炎性及/或過敏性疾病較佳為哺 乳動物（例如人類）中之慢性阻塞肺病（c〇pD)、氣喘或過敏性 鼻炎。更佳為在哺乳動物（例如人類）中治療及/或預防 COPD或氣喘。PDE4抑制劑被認為有效用於治療氣喘（例如， 參閱 M.A.GiembyCZ，i&gt;.,2000 年 2 月，59(2)，193_212 ; Z-Huang 等 人，允荸4 ##之趨疔！庳，2001，5 : 432-438 ;及其中所引用之 參考資料）與COPD (例如，參閱S L W〇Wa，孕趨之襄 2〇00, 5(3)，309-319 ; Z· Huang等人，必學立勒荸之尽穿龙 摩，2001，5 : 432-438 ;及其中所引用之參考資料）。c〇pD通常 之特徵為氣流阻塞之存在，此係由於慢性枝氣管炎及/或氣 腫所致（SLWolda，2000)。 醫藥組合物與服藥 對於在醫藥上之用途而言，本發明化合物通常係以醫藥組 合物投藥。 因此，於另一方面，本發明係提供一種醫藥組合物，其包 含式（I)化合物或其藥學上可接受之鹽，及一或多種藥學上 可接受之載劑及/或賦形劑。 醫藥組合物可用於治療及/或預防本文中所述之任何症狀。 式（I)化合物及/或醫藥組合物可例如藉由口服、非經腸 (例如靜脈内、皮下或肌内）、吸入或鼻投藥法進行投藥。 87841-960303-中.doc -82- 1283678 因此，此醫藥組合物較佳係適合口 内、由μ 口口服、非經腸（例如靜脈 ★头組合物更佳係適 口例如對哺乳動物譬如人類之吸入， 你、止 a 口服投樂。吸入投藥 #、以及對肺臟之局部投藥，例如藉由 iin 叫乳，合膠或乾粉組合 物。對人類之口服投藥係為最佳。 適於口服投藥之醫藥組合物，可為液體或固體；例如，其 可為糖漿、懸浮液或乳化液、片劑、膠囊或鍵劑。 液體配方通常係包含此化合物或藥學上可接受之鹽在適當 藥學上可接受之液體載劑中之懸浮液或溶液，該=體載: 例如水性溶劑’譬如水、乙醇或甘油，或非水性溶劑，譬 如聚乙二醇或油。此配方亦可含有懸浮劑、防腐劑、矯味 及/或著色劑。 適於口服投藥且為片劑之醫藥組合物，可包含一或多種適 用於製備片劑配方之藥學上可接受載劑及/或賦形劑。此 種載劑之實例包括乳糖與纖維素。片劑亦可或替代地含有 一或多種藥學上可接受之賦形劑，例如黏合劑，潤滑劑，籲 譬如硬脂酸鎂，及/或片劑崩解劑。 適於口服投藥且為膠囊之醫藥組合物，可使用包膠程序製 成。例如，含有活性成份之丸粒，可使用適當藥學上可接 受之載劑製成，然後填入硬明膠膠囊中。或者，分散液或 懸浮液可使用任何適當藥學上可接受之載劑製成，例如含 水膠質或油’然後將此分散液或懸浮液填入軟明膠膠囊中。 組合物較佳係呈單位劑量形式，譬如供口服投藥之片劑或 膠囊，例如供口服投藥至人類。 87841-960303-中.doc -83- 1283678 非經腸組合物可包含化合物或藥學上可接受鹽在無菌水性 載劑或非經腸上可接受油中之溶液或懸浮液。或者’可使 溶液凍乾；已凍乾之非經腸醫藥組合物可在即將投藥之 前，以適當溶劑重配。 供鼻或吸入投藥之組合物，可合宜地被調配成氣溶膠、滴 劑、凝膠或乾粉。 氣溶膠配方，例如供吸入投藥，可包含活性物質在藥學上 可接受《水性或非水性溶劑中之溶液或微細懸浮液。氣溶 膠配方可以在密封容器中呈無菌形式之單一或多劑量之數 量呈現’胃容器可採取藥筒或再充填形式，以與霧化裝置 或吸^器—起使用。或者，密封容器可為單-分配裝置， S 士單d量鼻吸入器或裝有計量閥之氣溶膠分配器（經計 量义劑量吸人器）’—旦容器之内容物已被耗盡，其係欲予 被棄置。 在劑量形式包含氣滚膠八两 、 口乳/合修刀配器乏情況下，較佳係含有在壓 力下《適當推進劑’譬如壓縮空氣、二氧化碳，或有機推 進蜊5如氯氟化碳（CFC)或氫氟化碳(HFC)。適當CFC推進 劑包括二氯二氟甲焓、— &gt; 产 二虱氟甲烷及二氯四氟乙烷。適當 HFC推進劑包括 ’ ’，2,3,3,3_七氟基丙烷與m2-四氟基乙烷。 氣各膠劑1Γ形式亦可接抱 』j杈取泵_霧化器形式。 Ά 口及/或配合碉整以供吸入投藥之醫藥組合物而 β式（I)化口物或鹽較佳係呈粒子大小降低形式，且此大 小降低形式更佳俏兹&amp;似 精由彳政粉化作用而獲得或可獲得。微粉 化作用通常係涉及蚀几 便化合物/鹽在經常包含旋風器組件之 87841-960303-^.doc -84- 1283678 快速流動環狀/密閉路徑空氣流中，接受磨擦力。大小降 低（例如微粉化）之化合物或鹽之粒子大小（例如D50數值）較 佳為約0.5至約10微米，例如約1至約5微米（例如當使用雷射 繞射度量時）。例如，式（I)化合物或鹽較佳係具有以下所界 定之粒子大小：D10為約0_3至約3微米（例如約1微米），及/ 或D50為約1至約5微米（例如約2-3微米），及/或D90為約3 至約10微米（例如約5-6微米）；例如當使用雷射繞射度量 時。現在給予較佳微粉化方法之說明而非限制之實例： 微粉化實例：實例518或518A之微粉化 •目的：為利用JetpharmaMCI微粉化器，使大約600-1000毫克 之實例518或51δΑ (於後文所述）微粉化。 •藉由雷射繞射分析母體（未經微粉化）與已微粉化物質之 粒子大小，及藉由PXRD分析結晶度。 設備與物質 設備/物質 JetpharmaMCl微粉化器 分析天平 上方充填器天平 數值測徑器 振動刮勺 欲被微粉化之物質 程序： 說明與規格 亂供應·空氣槽桶’具有 275 psi速率管件The activated compound described later can be prepared from a carboxylic acid (χ = 0H), either: (8) by reacting a carboxylic acid with a carbodiimide such as EDC, which is 1-ethyl-3-(3-methylamino) Propyl)carbodiimide' and also 1-(3-dimethylaminopropyl)_3_ethylcarbodiimide or a salt thereof, such as the hydrochloride salt, followed by the resulting product and 1-hydroxybenzene And a triazole (HOBT) reaction; the reaction (4) is usually carried out in the presence of a solvent such as dimethylformamide (DMF), and/or usually at room temperature (for example, about 20 to about 25 ° C); ) via 2-(1H-benzotriazole small)-indole, iota, 3,3-tetramethylguanidine (TBTU) or hexafluorophosphate 0-(7.nitrobenzotriazole-1- Base)__,&gt;^,,&gt;1,-tetramethylguanidine (HATU) reaction, in the presence of a base, such as diisopropylethylamine (ipr^NetsDIPEA), and usually in the presence of a solvent, such as Dimethylformamide (DMF), and/or usually at room temperature (eg, from about 2 Torr to about 25 ° C). Accordingly, the present invention also provides a process for the preparation of a compound of formula (I) or a salt thereof, which comprises (a) a compound of formula (I) wherein X = OR5a is a reaction of a compound of formula (9) with an amine of formula R3NH2, or (b) With respect to the compound of the formula (1) wherein X = nr4r5 is a reaction of a compound of the formula (IV) with an amine of the formula R3NH2, or (c) a compound of the formula (VI) wherein an alkyl group is reacted with an amine of the formula r3; 87841-960303- .doc -80- 1283678 (d) is a compound of formula (I) wherein X = NR4R5, which is a compound of formula 1, but wherein X = OH (carboxylic acid), is converted to an activated compound of formula 1, but wherein X == a cleavage group which may be substituted by an amine (the activated compound may preferably be ruthenium chloride, meaning activated compound of formula (I), but X = C1), followed by activated compound and formula R4R5NH amine The reaction of the compound of formula (1), if appropriate, is converted to a salt, such as a pharmaceutically acceptable salt. Pharmaceutical Use The present invention also provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as an active therapeutic substance in a mammal, such as a human. The compound or salt can be used to treat and/or prevent any of the symptoms described herein (eg, for use in treating and/or preventing inflammatory and/or allergic diseases in a mammal), and/or as a phosphodiesterase Inhibitors are used, for example, as phosphodiesterase 4 (PDE4) inhibitors. &quot;Treatment&quot; may include therapeutic treatment and/or prevention. Also provided is the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament, such as a pharmaceutical composition, in a mammal, such as a human. Treating and/or preventing inflammatory and/or allergic diseases. Also provided is a method of treating and/or preventing inflammatory and/or allergic diseases in a mammal, such as a human, in need thereof, including to a mammal ( For example, human) is administered a therapeutically effective amount of a compound of formula (1), or a pharmaceutically acceptable salt thereof, as defined herein. A bisphosphonate 4 inhibitor is believed to be useful in the treatment of mammals, such as humans. / or prevent a variety of diseases, especially inflammatory and / or allergic diseases, such as: asthma, chronic bronchitis, emphysema, atopic dermatitis, urticaria allergic rhinitis, allergic membranous inflammation, spring combined membrane Inflammation, addiction 87841-96〇3〇3-中.d〇c -81 - 1283678 Eosin granuloma, psoriasis, rheumatoid arthritis, septic shock, ulcerative colitis, Crohn's disease, myocardium and brain Reperfusion injury Chronic glomerulonephritis, endotoxin shock, adult dyspnea syndrome or multiple sclerosis. In the treatment and / or prevention, inflammatory and / or allergic diseases are preferably chronic obstructive pulmonary disease in mammals (such as humans) (c〇pD), asthma or allergic rhinitis. More preferably, it treats and/or prevents COPD or asthma in mammals such as humans. PDE4 inhibitors are considered to be effective for the treatment of asthma (see, for example, MAGiembyCZ, i&gt) ;., February 2000, 59(2), 193_212; Z-Huang et al., 荸4##之疔!庳, 2001, 5: 432-438; and references cited therein) and COPD (For example, see SLW〇Wa, Pregnancy 襄2〇00, 5(3), 309-319; Z·Huang et al., must learn to stand up and wear Longmo, 2001, 5: 432-438; And references cited therein.) c〇pD is usually characterized by the presence of airflow obstruction due to chronic bronchitis and/or emphysema (SLWolda, 2000). Pharmaceutical compositions and medications for medicine For the purposes of use, the compounds of the invention are usually administered in a pharmaceutical composition. In another aspect, the invention provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers and/or excipients. The compounds can be used to treat and/or prevent any of the symptoms described herein. The compounds of formula (I) and/or pharmaceutical compositions can be administered, for example, orally, parenterally (eg, intravenously, subcutaneously or intramuscularly), inhaled or nasally. According to the administration method, 87841-960303-中.doc-82- 1283678 Therefore, the pharmaceutical composition is preferably suitable for oral administration, oral administration by mu, and parenteral (for example, the intravenous composition of the head is better, for example, for breastfeeding. Animals such as human inhalation, you, stop a orally. Inhaled dosing #, as well as topical administration to the lungs, for example by iin called milk, gelatin or dry powder compositions. Oral administration to humans is optimal. A pharmaceutical composition suitable for oral administration may be a liquid or a solid; for example, it may be a syrup, a suspension or an emulsion, a tablet, a capsule or a key. A liquid formulation will generally comprise a suspension or solution of such a compound or a pharmaceutically acceptable salt in a suitable pharmaceutically acceptable liquid carrier, such as an aqueous solvent such as water, ethanol or glycerol, or nonaqueous A solvent such as polyethylene glycol or oil. The formulation may also contain suspending agents, preservatives, flavoring and/or coloring agents. A pharmaceutical composition suitable for oral administration and in the form of a tablet may comprise one or more pharmaceutically acceptable carriers and/or excipients suitable for the preparation of a tablet formulation. Examples of such carriers include lactose and cellulose. Tablets may also or alternatively contain one or more pharmaceutically acceptable excipients such as binders, lubricants, such as magnesium stearate, and/or tablet disintegrants. A pharmaceutical composition suitable for oral administration and in capsules can be prepared using an encapsulation procedure. For example, a pellet containing the active ingredient can be prepared using a suitable pharmaceutically acceptable carrier and then filled into a hard gelatin capsule. Alternatively, the dispersion or suspension may be prepared using any suitable pharmaceutically acceptable carrier, for example, a hydrocolloid or oil&apos; and then the dispersion or suspension is filled into a soft gelatin capsule. Preferably, the compositions are in unit dosage form, such as tablets or capsules for oral administration, for example, for oral administration to humans. 87841-960303-中.doc-83- 1283678 The parenteral composition can comprise a solution or suspension of the compound or pharmaceutically acceptable salt in a sterile aqueous carrier or parenterally acceptable oil. Alternatively, the solution may be lyophilized; the lyophilized parenteral pharmaceutical composition may be reconstituted with a suitable solvent just prior to administration. Compositions for nasal or inhalation administration may conveniently be formulated as aerosols, drops, gels or dry powders. Aerosol formulations, for example for administration by inhalation, may comprise a solution or suspension of the active substance in a pharmaceutically acceptable aqueous or nonaqueous solvent. The aerosol formulation can be presented in a single or multiple doses in sterile form in a sealed container. The gastric container can be in the form of a cartridge or refill for use with an atomizing device or aspirator. Alternatively, the sealed container may be a single-distribution device, a single-dose nasal inhaler or an aerosol dispenser with a metering valve (a metered dose inhaler) - once the contents of the container have been exhausted, It is intended to be abandoned. In the case where the dosage form comprises a gas-filled gel or a mouth-washing/repairing knife, it is preferred to contain a "proper propellant" such as compressed air, carbon dioxide, or an organic propellant such as chlorofluorocarbon under pressure (for example). CFC) or hydrofluorocarbon (HFC). Suitable CFC propellants include dichlorodifluoromethane, - &gt; difluorofluoromethane and dichlorotetrafluoroethane. Suitable HFC propellants include '', 2,3,3,3-heptafluoropropane and m2-tetrafluoroethane. The gas can be held in the form of a Γ 杈 泵 pump _ atomizer. Preferably, the β-form (I) hydration or salt is in a reduced particle size, and the reduced size is better in the form of a medicinal composition for inhalation administration. Obtained or obtained by the use of granules. Micronization typically involves the application of a frictional compound/salt in a fast flowing annular/closed path air stream that often contains a cyclone assembly 87841-960303-^.doc-84- 1283678. The particle size (e.g., D50 value) of the compound or salt of reduced size (e.g., micronized) is preferably from about 0.5 to about 10 microns, such as from about 1 to about 5 microns (e.g., when using laser diffraction metrics). For example, the compound or salt of formula (I) preferably has a particle size as defined below: D10 is from about 0-3 to about 3 microns (e.g., about 1 micron), and/or D50 is from about 1 to about 5 microns (e.g., about 2). -3 microns), and/or D90 is from about 3 to about 10 microns (e.g., about 5-6 microns); for example when using a laser diffraction metric. Examples of preferred micronization methods are now given instead of limitations: Micronization Example: Micronization of Example 518 or 518A • Purpose: To utilize the Jetpharma MCI micronizer to give an example of 518 or 51 δ 600 of about 600-1000 mg (after Said) micronization. • Analysis of the particle size of the parent (unmicronized) and micronized material by laser diffraction and analysis of crystallinity by PXRD. Equipment and Substance Equipment/Substance JetpharmaMCl Micronizer Analytical Balance Upper Filler Balance Numerical Caliper Vibrating Scraper Substances to be micronized Procedure: Description and Specifications Indiscriminate supply · Air tank barrels with 275 psi rate fittings

Sartorius 分析Sartorius analysis

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實例518或518A 將微粉化器組裝在一起。將與輸入口之細腰突出距離，個 別調整至1.0公分，並以微測徑器度量，以確定其已正確地 ***。將環（R)與細腰(V)壓力根據實驗設計中所指定之數值 87841_96〇3〇3_ 中.doc -85- 1283678 (參照下文實驗段落）作調整，其方式是調整微粉化器上之 壓力计上之氣閥。藉由觀察壓力計讀數中是否有任何波 動’檢查裝置是否滲漏。 應注意的是，將細腰⑺壓力保持大於環（R)壓力至少2 巴，以防止物質逆流。 以校準法碼檢查天平性能。將所指定量之母體物質（參閱 實驗操作段落）稱重置於塑膠製稱重船形物中。然後，在指 定進料速率下，將物質使用振動刮勺餵入微粉化器中。在 微粉化程序期間，監測物質餵入時間與設備壓力。 於微粉化操作完成時，關閉氮供應，並輕拍收集袋，以允 弄粒子沉降至微粉化器底部之回收容器中。移離收集袋， 並放在一旁。將回收容器與旋風器（於回收容器上方）上之 已微粉化粉末，個別收集至不同之經稱重+經標識收集小玻 瓶中。i己錄已微粉化物質之重量。拆解微粉化器，並將微 粉化器内部表面上之殘留PDE4化合物以7〇/3〇異丙醇/水沖 洗，且收集至燒瓶中。然後，在進行後續操作之前，經由 沖洗，並以適當溶劑擦栻，及乾燥，將微粉化器徹底清潔。 實驗操作 母體（未經微粉化）物質··實例518或518A 所使用之天平·· Sartorius分析 細腰出口***深度：1〇·〇毫米 操作#物質輸 細腰(V)/意欲 進料所需實際 入量（克）環(R)壓力進料速率要之時間進料速率 (巴） （分鐘+秒）（克/分鐘) 1 0.8795 克 V=10 巴 200 毫克 4 分鐘 51 〇·181 克 / -86- 87841-960303-中.doc 1283678 R = 6巴 /分鐘 秒 分鐘 結果及/或觀察 /產率-[(知自容器之物質+得自旋風器之物質物質輸人量] 一般而言，使用此方法可達成極接近7〇%產率。 替代具體實施例··可使實例518或S1SA以外之本發明化合物 /鹽之實例微粉化。 對適合及/或配合碉整以供吸入投藥之醫藥組合物而言， 醫藥組合物較佳為乾粉可吸入組合物。此種組合物可包含 粉末基料，譬如乳糖或澱粉，式（I)化合物或其鹽（較佳係呈 粒子大小降低形式，例如呈微粉化形式），及選用之一種性 能改質劑，譬如L-白胺酸、甘露醇、海藻糖及/或硬脂酸 鎂。乾粉可吸入組合物較佳係包含乳糖與式⑴化合物或其 鹽之乾粉末摻合物。乳糖較佳為乳糖水合物，例如乳糖單 水合物’及/或較佳為吸入級及/或微細級乳糖。乳糖之 粒子大小較佳係被定義為90%或更多（重量比或體積比）之乳 糖粒子於直徑上小於1〇〇〇微米（例如10_1000微米，例如3〇-1000微米），及/或50%或更多乳糖粒子於直徑上小於5〇〇微 米（例如10-500微米）。乳糖之粒子大小更佳係被定義為9〇% 或更多乳糖粒子於直徑上小於300微米（例如10-300微米，例 如50-300微米），及/或50%或更多乳糖粒子於直徑上小於 100微米。乳糖之粒子大小係視情況被定義為90%或更多乳 糖粒子於直徑上小於100-200微米，及/或50%或更多乳糖粒 子於直徑上小於40-70微米。最重要的是，較佳為約3至約30 % (例如約10% )(重量比或體積比）之粒子小於50微米或小於 87841-960303-中.doc -87- 1283678 20微米直徑。例如，而非限制，適當吸入級乳糖係為E9334 乳糖（10 % 微細粉末 XBorculoDomo Ingredients，Hanzeplein 25， 8017 JD Zwolle,Example 518 or 518A assembled the micronizers together. The distance from the thin waist of the input port will be adjusted to 1.0 cm each and measured with a micro caliper to determine that it has been properly inserted. Adjust the ring (R) and the waist (V) pressure according to the value specified in the experimental design 87841_96〇3〇3_.doc -85-1283678 (refer to the experimental paragraph below) by adjusting the micronizer Air valve on the pressure gauge. Check for leaks by observing any fluctuations in the pressure gauge readings. It should be noted that the pressure of the waist (7) is kept at least 2 bar above the ring (R) pressure to prevent backflow of material. Check the balance performance with the calibration code. Reset the specified amount of parent material (see the experimental operating section) to a plastic weighing boat. The material is then fed into the micronizer using a vibratory spatula at a specified feed rate. Material feed time and equipment pressure are monitored during the micronization process. Upon completion of the micronization operation, the nitrogen supply is turned off and the collection bag is tapped to allow the particles to settle into the recovery vessel at the bottom of the micronizer. Remove the collection bag and set aside. The micronized powder on the recovery vessel and cyclone (above the recovery vessel) was individually collected into different weighed + labeled collection vials. i has recorded the weight of the micronized material. The micronizer was disassembled, and the residual PDE4 compound on the inner surface of the micronizer was washed with 7 〇 / 3 〇 isopropanol / water and collected into a flask. The micronizer is then thoroughly cleaned by rinsing, rubbing with a suitable solvent, and drying before proceeding. Experimental operation of the parent (not micronized) substance · Example 518 or 518A used in the balance · Sartorius analysis of the fine waist outlet insertion depth: 1 〇 · 〇 mm operation # material delivery waist (V) / intended to feed Actual intake (g) ring (R) pressure feed rate time feed rate (bar) (minutes + seconds) (g / min) 1 0.8795 g V = 10 bar 200 mg 4 minutes 51 〇 · 181 g / -86- 87841-960303-中.doc 1283678 R = 6 bar/minute second minute result and / or observation / yield - [(material from the container + material input from the cyclone)] Using this method, a yield of very close to 7〇% can be achieved. Alternative Embodiments Examples of the compounds/salts of the invention other than Example 518 or S1SA can be micronized. Suitable and/or compatible for inhalation administration In the case of a pharmaceutical composition, the pharmaceutical composition is preferably a dry powder inhalable composition. Such a composition may comprise a powder base such as lactose or starch, a compound of formula (I) or a salt thereof (preferably having a reduced particle size) Form, for example in micronized form, and a performance change A granule, such as L-leucine, mannitol, trehalose and/or magnesium stearate. The dry powder inhalable composition preferably comprises a dry powder blend of lactose with a compound of formula (1) or a salt thereof. It is a lactose hydrate such as lactose monohydrate' and/or preferably inhaled grade and/or fine grade lactose. The particle size of lactose is preferably defined as 90% or more (weight ratio or volume ratio) of lactose. The particles are less than 1 micron in diameter (eg, 10 to 1000 microns, such as 3 to 1000 microns), and/or 50% or more of the lactose particles are less than 5 microns in diameter (eg, 10-500 microns). Lactose. Preferably, the particle size is defined as 9% or more of the lactose particles being less than 300 microns in diameter (eg, 10-300 microns, such as 50-300 microns), and/or 50% or more of the lactose particles in diameter. Less than 100 microns. The particle size of lactose is defined as 90% or more of the lactose particles being less than 100-200 microns in diameter, and/or 50% or more of the lactose particles being less than 40-70 microns in diameter. Importantly, preferably from about 3 to about 30% (e.g., about 10%) (by weight or The volume ratio of the particles is less than 50 microns or less than 87841-960303 - medium .doc -87 - 1283678 20 microns diameter. For example, but not by limitation, the appropriate inhalation grade lactose is E9334 lactose (10% fine powder XBorculoDomo Ingredients, Hanzeplein 25, 8017 JD Zwolle,

Netherlands) o 在乾粉可吸入組合物中，式⑴化合物或其鹽較佳係以組合 物重量之約0.1%至約70% (例如約1%至約50%，例如約5%至 約40%，例如約20至約30% )存在。 乾粉可吸入組合物之說明而非限制性實例，如下： 乾粉配方實例-乾粉乳糖摻合物製備 使用大小降低例如微粉化形式之式（I)化合物或其鹽（例 如，在上文微粒化實例中製成者），乾粉末摻合物係經由將 所需要量之化合物/鹽（例如10毫克，1% w/w)與含有10%微 細粉末之吸入級乳糖（例如990毫克，99 % w/w)，在 Tefl〇nTM(聚四氟乙烯）罐筒中，於Mikro-分解器球磨機（但未帶 有球）中，於3/4速度（約2000-2500rpm)下，在各掺合物濃度 下，混合約4小時而製成。Mikro-分解器球磨機（未具有 球）（可得自 B. Braun Biotech 國際 &amp;3，SchwarzenbergerWeg73-79，D-34212 Melsungen, Germany ； www.bbraunbiotech.com)包含一個底 座，其具有TeflonTM罐筒所連接之向上凸出且側面可振動 臂。此臂之振動會達成掺合。 其他掺合物·· 10% w/w化合物/鹽（50毫克）+ 90% w/w乳糖 (450毫克，吸入級乳糖，含有10%微細粉末）。 1% w/w掺合物之連續稀釋可達成例如0.1%與0.3% w/w掺合 物。 87841-960303-中.doc -88 - 1283678 視情況，特別是對於乾粉可吸入組合物而言，供吸入投藥 ^醫藥組合物，可被摻入多個密封劑量容器（例如含有乾粉 組合物）中，其係以縱向方式裝載在適當吸入裝置内部之片 條或τ狀物中。此容器係為可斷裂或可剝離開啟，依需求 而定，且例如乾粉組合物之劑量可經由裝置，藉吸入投 丁，譬如由 GlaxoSmithKline 銷售之 DISKUSTM裝置。diskustμ吸 入裝置通常係實質上如在(3]82,242，134八中所述者。在此種裝 置中，對於呈粉末形式之醫藥組合物之至少一個容器（該至 J 個各器較佳為多個密封劑量容器，以縱向方式裝載在 片條或帶狀物中），係被界定在互相固定之兩個可剝離構件 之間，此裝置包括：界定該至少一個容器之開口位置之設 置’在開口位置用於使構件剝離分開以打開容器之設置； 及一個出口，與已打開之容器相通，經過此出口，使用者 可從已打開之容器吸入呈粉末形式之醫藥組合物。 在醫藥組合物中，供口服或非經腸投藥用之一個或每一個 劑量單位，較佳係含有0·01至3〇〇〇毫克，更佳為〇 5至1〇〇〇毫 克式（I)化合物或其藥學上可接受之鹽，以自由態鹼計算而 得。供鼻或吸入投藥用之一個或每一個劑量單位，較佳係 含有0.001至50毫克，更佳為0.01至5毫克式①化合物或其藥 學上可接受之鹽，以自由態鹼計算而得。 本發明藥學上可接受之化合物或鹽，較佳係以每日口服或 非經腸劑量為每公斤體重每天0.001毫克至5〇毫克（毫克/公 斤/天），例如0.01至20毫克/公斤/天，或〇〇3至10毫克/ 公斤/天，或0.1至2毫克/公斤/天之式①化合物或其藥學 87841 -96〇3〇3_ 中,d〇c -89- 1283678 上可接受之鹽’以自由態鹼計算而得，投予哺乳動物（例如 人類）。 本發明藥學上可接受之化合物或鹽，較佳係以下列每日鼻 或吸入劑量投予哺乳動物（例如人類）：〇〇〇〇1至5毫克/公斤 /天，例如0.001至1毫克/公斤/天，或〇 005至〇 3毫克/公 斤/天之式（I)化合物或其藥學上可接受之鹽，以自由態鹼 計算而得。 本發明藥學上可接受之化合物或鹽，較佳係以日服劑量 ^對成年病患而言）投予，例如口服或非經腸劑量為每天 笔克至3000毫克或每天〇 5至1〇〇〇毫克，例如每天2至獅毫 2，或鼻或吸入劑量為每天〇〇〇1至3〇〇毫克或每天〇〇〇1至％ 笔克或每天0·01至30毫克或每天〇 〇1至5毫克之式①化合物 或其藥學上可接受之鹽，Μ自由態驗計算而得。 組合 根據本發明《化合物、鹽及/或醫藥組合物，亦可n 種治療活性劑併用，例如 ，、 胺、抗過敏或消炎劑。 素又體催動劑、抗組織 因此，於另-方面，本發明係提供一 化合物或其藥學上可接受之鹽，伴隨著另一種::式① 消夾劑或防止傳染劑。 %戶“ 广腎上腺素受體催動劑之實例，包 Mmeterol)(例如作成外 美特鮮 掌異構物)、舒喘*(salbut:U對拿異構物’譬如對 舒而呈（__)、弗莫 87841 -960303 -中.doc -90- 1283678 莫（salmefamol)、芬忒醇或間經第三丁腎上腺素，及其鹽，例 如沙美特醇（salmeterol)之愛克辛那弗酸鹽、舒喘靈之硫酸鹽 或自由態驗或弗莫特醇之反丁烯二酸鹽。長效给-腎上腺素 受體催動劑係為較佳，尤其是具有治療效果超過24小時期 間者，譬如沙美特醇(salmeterol)或弗莫特醇。 較佳長效/32-腎上腺素受體催動劑，包括WO02/066422A、 WO 03/024439、WO 02/070490 及 WO 02/076933 中所述者。 尤佳之長效庆-腎上腺素受體催動劑，包括式（XX)化合物 (描述於 WO 02/066422 中）：Netherlands) o In a dry powder inhalable composition, the compound of formula (1) or a salt thereof is preferably from about 0.1% to about 70% by weight of the composition (e.g., from about 1% to about 50%, such as from about 5% to about 40%). , for example, from about 20 to about 30%) is present. Illustrative, but non-limiting examples of dry powder inhalable compositions are as follows: Dry Powder Formulation Example - Dry Powdered Lactose Blend Preparation The use of a compound of formula (I) or a salt thereof in reduced size, eg, micronized form (eg, in the above micronized example) The dry powder blend is obtained by adding the required amount of the compound/salt (for example, 10 mg, 1% w/w) to the inhaled grade lactose containing 10% of the fine powder (for example, 990 mg, 99% w /w), in a Tefl〇nTM (polytetrafluoroethylene) canister, in a Mikro-decomposer ball mill (but without a ball) at 3/4 speed (about 2000-2500 rpm) in each blend It was prepared by mixing for about 4 hours at a concentration. The Mikro-Decomposer ball mill (without the ball) (available from B. Braun Biotech International &amp; 3, Schwarzenberger Weg 73-79, D-34212 Melsungen, Germany; www.bbraunbiotech.com) contains a base with a TeflonTM canister The connection protrudes upward and the side can vibrate the arm. The vibration of this arm will achieve blending. Other blends·· 10% w/w compound/salt (50 mg) + 90% w/w lactose (450 mg, inhaled lactose, containing 10% fine powder). Serial dilutions of the 1% w/w blend can achieve, for example, 0.1% and 0.3% w/w blends. 87841-960303-中.doc -88 - 1283678 Depending on the circumstances, particularly for dry powder inhalable compositions, the pharmaceutical composition for inhalation administration can be incorporated into a plurality of sealed dose containers (e.g., containing a dry powder composition). It is loaded longitudinally into a strip or tau inside the appropriate inhalation device. The container is rupturable or peelable open, as desired, and for example, the dosage of the dry powder composition can be dosed via a device, such as a DISKUSTM device sold by GlaxoSmithKline. The diskustμ inhalation device is generally substantially as described in (3) 82, 242, 134. In such a device, at least one container of the pharmaceutical composition in powder form (these are preferably more than J devices) a sealed dose container, longitudinally loaded between the strips or strips, defined between two peelable members that are secured to each other, the device comprising: a setting defining an opening position of the at least one container The opening position is used to separate the members apart to open the container; and an outlet is communicated with the opened container, through which the user can inhale the pharmaceutical composition in powder form from the opened container. Or one or each dosage unit for oral or parenteral administration, preferably containing from 0. 01 to 3 mg, more preferably from 5 to 1 mg of the compound of formula (I) or A pharmaceutically acceptable salt, calculated as a free base. One or each dosage unit for nasal or inhalation administration, preferably containing from 0.001 to 50 mg, more preferably from 0.01 to 5 mg of the compound of formula 1 A pharmaceutically acceptable salt thereof, calculated as a free base. The pharmaceutically acceptable compound or salt of the present invention is preferably administered in a daily oral or parenteral dose of from 0.001 mg to 5 mg per kg of body weight per day. (mg/kg/day), for example 0.01 to 20 mg/kg/day, or 〇〇3 to 10 mg/kg/day, or 0.1 to 2 mg/kg/day of the compound of formula 1 or its pharmacy 87841-96〇 In 3〇3_, d〇c -89-1283678 The acceptable salt 'is calculated as a free base and administered to a mammal (for example, a human). The pharmaceutically acceptable compound or salt of the present invention is preferably the following A daily nasal or inhaled dose is administered to a mammal (eg human): 〇〇〇〇1 to 5 mg/kg/day, eg 0.001 to 1 mg/kg/day, or 〇005 to 〇3 mg/kg/day A compound of the formula (I) or a pharmaceutically acceptable salt thereof, calculated as a free base. The pharmaceutically acceptable compound or salt of the present invention is preferably administered in a daily dose to an adult patient. For example, an oral or parenteral dose of 3,000 mg per day or 5 to 1 per day 〇〇〇mg, for example, 2 to lion 2 per day, or nasal or inhaled dose of 1 to 3 mg per day or 1 to % pg per day or 0. 01 to 30 mg per day or daily A compound of formula 1 or a pharmaceutically acceptable salt thereof in an amount of from 1 to 5 mg, calculated as a free state. Combinations In accordance with the "compounds, salts and/or pharmaceutical compositions of the present invention, n therapeutically active agents may also be used in combination, for example, an amine, an antiallergic or an anti-inflammatory agent. Further, the present invention provides a compound or a pharmaceutically acceptable salt thereof, accompanied by another: a formula 1 deodorant or an anti-infective agent. % household "an example of a broad-adrenergic receptor stimulant, including Mmeterol" (for example, made as a foreign special isomer), and a sedative (salbut: U to an isomer) such as 舒舒(__ ), 弗莫87841 -960303 -中.doc -90- 1283678 Mo (salmefamol), fentanol or osmectin, and its salts, such as salbutol (salmeterol) Salt, salbutamol sulfate or free state or fumarate fumarate. Long-acting-adrenergic receptor stimulant is preferred, especially for therapeutic effects over a 24-hour period For example, salmeterol or fluoterol. Preferred long-acting/32-adrenergic receptor agonists, including WO02/066422A, WO 03/024439, WO 02/070490 and WO 02/076933 The above-mentioned long-acting-adrenergic receptor agonist, including the compound of formula (XX) (described in WO 02/066422):

或其鹽或溶劑合物，其中在式（XX)中： mx為2至8之整數； nx為3至11之整數， 其附帶條件是，mx+ nx為5至19， R11X 為-XSC^NRMXrHX，其中烯基； R16X與R17X係獨立選自氫、Cu烷基、c3_7環烷基、 c(o)nr18Xr19X、苯基及苯基（Cl_4烷基）_， 或R16X與R17X和彼等所結合之氮，一起形成、6_或7-員含氮 環，且R1 6X與R1 7X各視情況被一或兩個基團取代，取代基選自 鹵基、（V6烷基、c!·6 _烷基、cv6烷氧基、羥基取代之cw 烷氧基、-C02R18X、_S02NR18XR19X 、-conr18Xr19X 、 ，或 5_，6_或7-員雜環； 87841-960303-中.doc -91- 1283678 R18X與RBX係獨立選自氫、Ci6烷基、C36環烷基、苯基及 苯基（Ci_4烷基）-;且 px為0至6之整數，較佳為〇至4; R12X與RUX係獨立選自氫、Ci6烷基、Ci6烷氧基、齒基、 苯基及Ci-6 _烷基；且 R14X與R15X係獨立選自氫與Ci 4烷基，其附帶條件是rmx與 R15X中之碳原子總數不超過4。 揭示於W0 02/066422中之較佳屄-腎上腺素受體催動劑包括： 3-(4_{[6-({(2R)-2-#f基-2·[4_羥基-3-(經甲基)-苯基]乙基}胺基）己基] 氧基} 丁基）苯續酿胺，與 3- (3_{[7-({(2R)-2-羥基_2-[4_羥基_3_羥甲基）苯基]乙基}胺基）庚基] 氧基}丙基）苯磺醯胺。 揭示於WO 03/024439中之較佳戾-腎上腺素受體催動劑為·· 4- {(lR)_2-[(6_{2-[(2,6-二氯节基）氧基]乙氧基}己基）胺基龜乙 基}-2-(羥甲基）酚。 抗組織胺之實例包括麥沙非林（methapyriiene)或羅拉他疗 (loratadin) ° 於另一方面，本發明亦提供一種組合，其包含式①化合物 或其藥學上可接受之鹽，伴隨著抗膽鹼能化合物，例如蠅 蕈鹼(M)受體拮抗劑，特別是叫、％、Mi/M2或m3受體拮抗 劑。關於抗膽驗能化合物/蠅蕈鹼受體拮抗劑與pDE4抑 制劑之組合，可參閱例如W〇〇3/〇11274A2與w〇〇2/〇69945 A2 / US 20〇2/〇193393 A1 及 US 20〇2/052312 A1，且此等公報之一 部份或全部均給予可與式①化合物或鹽一起使用之抗膽鹼 8784· 1-960303-中.doc -92- 1283678 能化合物/蠅蕈鹼(Μ)受體拮抗劑之實例。 其他適當組合，包括例如其他消炎劑，例如NSAID (例如 白三晞素拮抗劑、iNOS抑制劑、類胰朊酶與彈性蛋白酶抑 制劑、/3-2整合素拮抗劑及腺苷2a催動劑）或防止傳染劑（例 如抗生素、抗病毒劑）。 上文所指之組合可合宜地以醫藥組合物形式呈現，以供使 用，且因此，一種醫藥組合物，其包含如上文定義之組 合，伴隨著一或多種藥學上可接受之載劑及/或賦形劑， 係代表本發明之另一方面。 此種組合之個別化合物可無論是相繼或同時地，以個別或 合併之醫藥組合物投藥。 生物學試驗方法 PDE 3, PDE 4B，PDE 4D，PDE 5, PDE 6 初步檢測方法 化合物之活性可以下文所示之檢測方法度量。較佳之本發 明化合物係為選擇性PDE4抑制劑，意即其會抑制PDE4 (例如 PDE4B及/或PDE4D，較佳為PDE4B)比其抑制PDE3更強烈， 及/或比其抑制PDE5更強烈，及/或比其抑制PDE6更強烈。 PDE酶來源與文獻參考資料 人類重組體PDE4D，特別是其2B接合變型（HSPDE4B2B)，係 揭示於W0 94/20079，以及M.M. McLaughlin等人，&quot;得自人類腦部 之低Km，羅利普蘭（rolipram)-敏感性，cAMP專一之磷酸二酿 酶：cDNA之無性繁殖與表現，重組蛋白質之生物化學特徵 蓉定，及 mRNA 之組織分佈&quot;，/· 5zW· C/zem·，1993, 268, 6470-6476 中。人類重組體PDE4B係表現於PDE-缺乏之釀酒酵母菌種 87841-960303-中.doc -93- 1283678 GL62中。酵母細胞溶胞產物之100,000 χ克上層清液離份，係 用於PDE4B檢測與抑制劑研究。 人類重組體PDE4D (HSPDE4D3A)係揭示於P. A· Baecker等人，，， 將會使人類羅利普蘭（rolipram)-敏感性環AMP磷酸二醋酶 (PDEIVD )編碼之 cDNA 單離&quot;，（¾呢 1994,138, 253_256 中。 人類重組體PDE5係揭示於K. Loughney等人，，，使PDE5A編碼 之cDNA之單離與特徵鑒定，該PDE5A為一種人類cGMP-結 合，cGMP-專一之 3’，5f-環核苷酸磷酸二酯酶 ’’，1998, 216, 139-147 中。 PDE3係按照由H. Coste與P. Grondin，&quot;類型V磷酸二酯酶之新 穎有效且專一抑制劑之特徵黎定’’，P/zarmaco/·，1995, 50， 1577-1585所述，自牛主動脈純化。 PDE6係按照以下所述，自牛視網膜純化：P. Catty與 P. Deterre，”視網膜cGMP-專一嶙酸二酯酶藉由有限蛋白水解之 活化作用與增溶作用&quot;，五wr· ·/·所1991，199, 263-269 ; A· Tar等 人π牛視網膜cGMP磷酸二酯酶之純化π，錄學才法，1994, 238, 3-12 ;及/或D· Srivastava等人”鎂對於藉由牛視網膜棒環狀GMP 磷酸二酯酶之環狀GMP水解作用之作用’’，所oc/zem.人1995, 308, 653-658。 PDE 3, PDE 4B，PDE 4D，PDE S 或 PDE 6 活性之抑制 化合物在PDE4B或4D (人類重組體）、PDE3 (得自牛主動 脈）、PDE5 (人類重組體）或PDE6 (得自牛視網膜）上抑制催化 活性之能力，係在96-井格式中，藉由閃爍親近檢測（SPA)測 定。使待測化合物於環境溫度（室溫）下，在Wallac同型板（代 87841-96〇3〇3-中.doc -94- 1283678 碼 1450-514)中，以5〇111]\0^-11(：1緩衝劑（?117.5)、8.3111]^1^(：12、 1.7mMEGTA、0.05%(w/v)牛血清白蛋白中之PDE酶，預培養logo 分鐘 （ 通常為 30 分鐘 ） 。 調整 酶濃度 ，以致 在培養 期間， 於未具有化合物之對照井中，下文所定義之受質發生不超 過20%之水解作用。對PDE3、PDE4B及PDE4D檢測，係添加 [5f，8-3H]腺芬 3'5’_ 環狀磷酸鹽（Amersham Pharmacia Biotech，代碼 TRK.559)，獲得每井0.05 uCi，及〜ΙΟηΜ最後濃度。對PDE5與 PDE6檢測，係添加[8-3H]鳥嘌呤核糖甞31，環狀磷酸鹽 (Amersham Pharmacia Biotech，代碼 TRK.392)，獲得每井 0.05 uCi， 及〜36nM最後濃度。將板在軌道振盪器上混合5分鐘，並於 環境溫度下培養1小時。添加（每井〜1毫克）磷酸二酯酶SPA 珠粒（Amersham Pharmacia Biotech，代碼 RPNQ 0150)，以使檢測終 止。將板密封並振盪，且使其在環境溫度下靜置35分鐘至1 小時（較佳為35分鐘），以允許珠粒沉降。使用 WALLAC TRILUX 1450 Microbeta閃爍計數器度量已結合之放射 性產物。檢測各化合物之10種濃度（L5nM - 30uM)，以提供抑 制作用曲線。曲線係使用ActivityBase與XLfit (ID商業解法有限 公司）分析。結果係以PIC〗〇值表TF。 關於一些實例所獲得之生物學數據(PDE4B抑制活性，無論 是一個讀數或為約2-6個讀數之平均）如下，僅以現行度量法 為基礎。絕對準確度是不可能的，且所予之讀數僅準確至 高達約± 0.5個對數單位，依所施行並平均之讀數數目而定： 實例編號 PDE4B pIC5〇 2 8.0 3 7.8 87841-960303-中.doc -95- 1283678 6 6.6 11 7.4 21 8.5 22 7.9 32 7.7 40 8.3 63 6.9 1，36, 39, 41，42, 43, 44, 47， 48, 63, 83, 109, 178, 187 及 600 7.0 7.9 100, 155, 165, 167, 201，260， 261，263, 265, 266, 267, 271， 493, 494, 495, 498, 518, 518A， 551，575, 581，584, 619, 622， 624-626, 628, 630, 636, 638， 643-645 及 653 8.2 至 9.6 196 7.9 198 8.5 排除參考實例19-20，此等實例具有PDE4B抑制活性在 pICs 0 =約5·5 (土約〇·5)至約9.6 (土約0·5)之範圍内。大部份（約95 %或更多）實例，排除參考實例19-20，具有PDE4B抑制活性 在約6 (土約〇·5)至約9.6 (土約0.5)之範圍内。 其中R3=環己基（NHR3=亞式（c))、四氫_2H_哌喃-4-基（NHR3 = 基團（h))、4-酮基環己基_3=亞式（0))或某些其他類型之經 取代環己基或某些雜環之實例，當在上述酶抑制檢測中 量時，與其中R3 =環丙基_3=亞式（b))之可比較實例之 擇性比較，通常或經常（尤其是關於Rl=乙基）對PDE4B具 較高程度之選擇性，勝過PDE5。例如，僅以現行度量^ 基礎，且受累積檢測不準確性支配： 87841»960303^.doc •96- 1283678 -實例21、4〇、90、19δ及201 (其中njjr3個別=亞式（h)、 (c)、①、⑻及（ο)，R1 =乙基）對pDE4B具有勝過pDE5之選擇 性’在約3至20或更多倍之範園内，多於其中R3=環丙基 (NHR3 =亞式（b))之相當實例39所達成之選擇性； -實例43與44 (其中NHR3個別=亞式⑷與⑻)對pDE4B具有勝 過PDE5之選擇性，在約4至8或更多倍之範圍内，多於相當 之R3 =環丙基實例42所達成之選擇性； -實例22與48 (其中NHR3個別=亞式⑻與（c))對pDE4B具有勝 過PDE5之選擇性，在約2.5至1〇或更多倍之範圍内，多於相 當之R3 =環丙基實例47所達成之選擇性；及 -實例2與3 (其中NHR3個別=亞式⑹與⑻)對pDE4B具有勝過 PDE5之選擇性，在約2至5或更多倍之範圍内，多於相當之 R3 =環丙基實例1所達成之選擇性。 勘 誤 表 喱吐：一些已知PDE4抑制劑可能會造成嘔吐及/或惡 心，達較大或較小程度（例如參閱z· Huang等人，必學立#學 之趨疔龙庳，2001，5 : 432-438,尤其是參閱第433_434頁及其中所 引用之參考資料）。因此，若本發明之pDE4抑制化合物或鹽 僅會造成有限或容易處理之致吐副作用，則其係為較佳， 但非必須。當投予雪貂時，致吐副作用可藉由例如化合物 或鹽之產生呕吐潛力度量；例如，吾人可於口服或非經腸 投予化合物或鹽之後，在雪貂中度量嘔吐、乾嘔及/或痛 告之展開時間、私度、頻率及/或延續時間。參閱，例如 A· Robichaud等人，，’在雪貂中藉由[PDE IV]抑制劑所引致之嘔吐 M， Neuropharmacology, 1999,3 8,289-297 87841-960303-中.doc -97- 1283678 2001，40, 465-465。但是，更佳為大白鼠中之 致吐副作用與治療指數可於本發明化合物或鹽投藥後，合 宜地經由監測大白鼠之異食癖進食行為度量（參閱下文活體 内檢測2)。 真越琢作蓆：一些已知PDE4抑制劑可能會造成其他副作 用，譬如頭痛及其他中樞神經系統（CNS-)所媒介之副作用； 及/或胃腸（GI)道失調。因此，若本發明之特定PDE4抑制化 合物或鹽僅會造成一或多種此等副作用種類之有限或容易 處理之副作用，則其係為較佳，但非必須。 活體内生物學檢測 上述活體外酵素PDE4B抑制檢測，應被認為是生物學活性 之初步試驗。但是，下文係描述選用且並非功效或副作用 之必須度量方式之其他活體内生物學試驗。 活體内檢測1. 在大白鼠中LPS-所引致之肺嗜中性白血球增 多症：經口投予PDE4抑制劑之作用 肺嗜中性白血球流入已被証實是肺病族群之重要成份，例 如慢性阻塞肺病（COPD)，其可涉及慢性枝氣管炎及/或氣腫 (G.F· Filley，2000 ; 117(5) ; 251 s-260s)。此嗜中性白血球模式 之目的，係為研究經口投予之PDE4抑制劑，對於藉由氣溶 膠化脂多糖（LPS)之吸入所引致之嗜中性白血球增多症之活 體内潛在消炎作用，以製作COPD之嗜中性白血球炎性成份 之模型。關於科學背景，可參閱以下文獻段落。 將體重大約300-400克之雄性路易士大白鼠（Charles River， Raleigh，NC，USA)，以無論是⑻懸浮於水中之0.5%甲基纖維素 87841-960303-中.doc -98- 1283678 (可得自Sigma_Aldrich, St Louis，MO, USA)内之待測化合物，或（b) 只有媒劑預處理，以10毫升/公斤之劑量體積經口傳輸。 一般而言，劑量回應曲線係使用下列PDE4抑制劑之劑量產 生：1〇·〇、2.0、0.4、0.08及0.016毫克/公斤。在預處理後三 十分鐘，使大白鼠曝露至由含有100微克/毫升LPS溶液之 霧化器產生之氣溶膠化LPS (血清型大腸桿菌026 ·· B6，藉由 一鼠醋fel萃取物製成’可得自Sigma_ Aldrich，St Louis， MO, USA)。在4升/分鐘之速率下，使大白鼠曝露至]^”氣 落膠20分鐘。LPS曝露係在具有内部尺寸為45公分長度X 24 公分寬度x20公分高度之密閉室中進行。霧化器與曝露室係 被包含在經檢定合格之煙霧通風櫥中。於Lps曝露4小時 後’在90毫克/公斤下’藉由腹膜腔内方式投予過度劑量 &lt;戊巴比妥，使大白鼠安樂死。枝氣管與肺胞灌洗（BAL)係 經過14號鈍針，進入外露之氣管中，預先形成。進行五次5 毫升洗滌，以收集總計25毫升之BAL流體。對BAL流體進行 總細胞計數與白血球差別，以計算嗜中性白血球至肺臟之 泥入量。計算各劑量（參閱媒劑）下之百分比嗜中性白血球 抑制，而產生一條可變斜率、s形劑量回應曲線，通常使用 PrismGraph-Pad。使用此劑量回應曲線，以計算關於藉由pDE4 抑制劑抑制LPS-所引致嗜中性白血球增多症之£〇5〇值（以每 公斤體重之毫克數表示）。 …果·以現行度量法為基礎，實例22、及⑸之化合 物，在上述程序中以經口方式投藥，顯示嗜中性白血球增 多症抑制ED50值在約0.5毫克/公斤至約2毫克/公斤之範圍 87841_96〇3〇3_ 中.doc -99- 1283678 内。 替汽才法輿潜耒··在此程序之一項替代具體實施例中，係 對大白鼠投予單一口服劑量之10毫克/公斤或1.0毫克/公 斤之PDE4抑制劑（或媒劑），並計算百分比嗜中性白血球抑 制，且報告該特定劑量。於此具體實施例中，以現行度量 法為基礎，實例21、100、109、167、172及600之化合物， 在上述程序中，於單一劑量L0毫克/公斤下，以經口方式 投藥，顯示百分比嗜中性白血球增多症抑制，係在約19%至 約69%之範圍内（或在約32%至約69%之範圍内，對實例21、 100、109、167 及 600 而言）。 文齔··Or a salt or solvate thereof, wherein in the formula (XX): mx is an integer of 2 to 8; nx is an integer of 3 to 11, with the proviso that mx+nx is 5 to 19, and R11X is -XSC^NRMXrHX Wherein alkenyl; R16X and R17X are independently selected from the group consisting of hydrogen, Cu alkyl, c3-7 cycloalkyl, c(o)nr18Xr19X, phenyl and phenyl (Cl-4 alkyl)_, or R16X in combination with R17X and the like. The nitrogen, together formed, 6- or 7-membered nitrogen-containing ring, and R1 6X and R1 7X are each optionally substituted by one or two groups, the substituent being selected from a halogen group, (V6 alkyl, c!·6) _Alkyl, cv6 alkoxy, hydroxy substituted cw alkoxy, -C02R18X, _S02NR18XR19X, -conr18Xr19X, or 5_,6_ or 7-membered heterocyclic ring; 87841-960303-中.doc -91- 1283678 R18X Independently selected from the group consisting of hydrogen, Ci6 alkyl, C36 cycloalkyl, phenyl and phenyl (Ci_4 alkyl)-; and px is an integer from 0 to 6, preferably from 〇 to 4; R12X is independent of RUX It is selected from the group consisting of hydrogen, Ci6 alkyl, Ci6 alkoxy, dentyl, phenyl and Ci-6-alkyl; and R14X and R15X are independently selected from hydrogen and Ci 4 alkyl, with the proviso that rmx and R15X The total number of carbon atoms does not exceed 4. Revealed on W0 02/066422 Preferred sputum-adrenergic receptor motivators include: 3-(4_{[6-({(2R)-2-#f-based-2·[4-hydroxy-3-(methyl))- Phenyl]ethyl}amino)hexyl]oxy} butyl)benzene extender, with 3-(3_{[7-({(2R)-2-hydroxy_2-[4_hydroxy_3_ Hydroxymethyl)phenyl]ethyl}amino)heptyl]oxy}propyl)benzenesulfonamide. A preferred sputum-adrenergic receptor mobilizer disclosed in WO 03/024439 is 4-{(lR)_2-[(6_{2-[(2,6-dichlorobenzyl)oxy]] Ethoxy}hexyl)amine-based turtle ethyl}-2-(hydroxymethyl)phenol. Examples of antihistamines include mesapyriiene or lolatatin. In another aspect, the invention also provides a combination comprising a compound of formula 1, or a pharmaceutically acceptable salt thereof, with an anti-antibiotic Cholinergic compounds, such as muscarine (M) receptor antagonists, in particular, %, Mi/M2 or m3 receptor antagonists. For a combination of an anti-cholinergic compound/musbine receptor antagonist and a pDE4 inhibitor, see, for example, W〇〇3/〇11274A2 and w〇〇2/〇69945 A2 / US 20〇2/〇193393 A1 and US 20 〇 2/052312 A1, and some or all of these publications are given anticholinergic 8784·1960303-medium doc-92- 1283678 compound/fly that can be used with the compound or salt of formula 1 An example of a muscarinic receptor antagonist. Other suitable combinations include, for example, other anti-inflammatory agents such as NSAIDs (eg, white triterpene antagonists, iNOS inhibitors, tryptase and elastase inhibitors, /3-2 integrin antagonists, and adenosine 2a agonists) or Prevent infectious agents (such as antibiotics, antiviral agents). The combination referred to above may conveniently be presented in the form of a pharmaceutical composition for use, and thus, a pharmaceutical composition comprising a combination as defined above, along with one or more pharmaceutically acceptable carriers and/or Or an excipient, representing another aspect of the invention. The individual compounds of such combination may be administered in separate or combined pharmaceutical compositions, either sequentially or simultaneously. Biological Test Methods PDE 3, PDE 4B, PDE 4D, PDE 5, PDE 6 Preliminary Detection Methods The activity of the compounds can be measured by the detection methods shown below. Preferably, the compound of the invention is a selective PDE4 inhibitor, meaning that it inhibits PDE4 (e.g., PDE4B and/or PDE4D, preferably PDE4B) more strongly than it inhibits PDE3, and/or is more potent than its inhibition of PDE5, and / or more intense than its inhibition of PDE6. PDE enzyme source and literature reference human recombinant PDE4D, especially its 2B junction variant (HSPDE4B2B), is revealed in W0 94/20079, and MM McLaughlin et al., &quot;low Km from human brain, rolipram (rolipram)-sensitive, cAMP-specific phosphodimerase: asexual reproduction and expression of cDNA, biochemical characteristics of recombinant proteins, and tissue distribution of mRNA&quot;, /· 5zW· C/zem·, 1993 , 268, 6470-6476. The human recombinant PDE4B line is expressed in the PDE-deficient Saccharomyces cerevisiae strain 87841-960303-中.doc-93- 1283678 GL62. The 100,000 gram supernatant of the yeast cell lysate is used for PDE4B detection and inhibitor studies. The human recombinant PDE4D (HSPDE4D3A) line, disclosed in P. A. Baecker et al., will separate the cDNA encoded by the human rolipram-sensitive cyclic AMP phosphodiacetase (PDEIVD). (3⁄4? 1994, 138, 253_256. The human recombinant PDE5 line is disclosed in K. Loughney et al., the individualization and characterization of the cDNA encoded by PDE5A, a human cGMP-binding, cGMP-specific 3', 5f-cyclic nucleotide phosphodiesterase '', 1998, 216, 139-147. PDE3 is novel, effective and specific according to H. Coste and P. Grondin, &quot; type V phosphodiesterase Inhibitors were characterized by Liding'', P/zarmaco/, 1995, 50, 1577-1585, purified from bovine aorta. PDE6 was purified from bovine retina as described below: P. Catty and P. Deterre , "Retina cGMP-specific citrate diesterase activation and solubilization by limited proteolysis", five wr · · · · 1991, 199, 263-269; A · Tar et al π bovine retinal cGMP Purification of phosphodiesterase π, recorded method, 1994, 238, 3-12; and / or D · Srivastava et al. The role of cyclic GMP hydrolysis of bovine retinal rod cyclic GMP phosphodiesterase '', oc/zem. human 1995, 308, 653-658. PDE 3, PDE 4B, PDE 4D, PDE S or PDE 6 activity The ability of the inhibitory compound to inhibit catalytic activity in PDE4B or 4D (human recombinant), PDE3 (from bovine aorta), PDE5 (human recombinant) or PDE6 (from bovine retina) in the 96-well format By scintillation proximity detection (SPA) determination, the test compound is allowed to be at ambient temperature (room temperature) on the Wallac isoform plate (generation 87841-96〇3〇3-medium.doc-94-1283678 code 1450-514) In the middle, 5:111]\0^-11 (:1 buffer (?117.5), 8.3111]^1^(:12, 1.7 mM EGTA, 0.05% (w/v) PDE enzyme in bovine serum albumin, Pre-culture logo minutes (usually 30 minutes) Adjust the enzyme concentration so that during the culture, in the control well without compound, the hydrolysis defined below does not exceed 20% hydrolysis. Detection of PDE3, PDE4B and PDE4D , adding [5f,8-3H] gland phenanthrene 3'5'_ cyclic phosphate (Amersham Pharmacia Biotech, code TRK.559), obtained each 0.05 uCi, and the final concentration ~ΙΟηΜ. For PDE5 and PDE6 assays, [8-3H] guanine riboside 31, cyclic phosphate (Amersham Pharmacia Biotech, code TRK.392) was added to obtain a final concentration of 0.05 uCi per well and ~36 nM. The plates were mixed on an orbital shaker for 5 minutes and incubated for 1 hour at ambient temperature. Phosphodiesterase SPA beads (Amersham Pharmacia Biotech, code RPNQ 0150) were added (~1 mg per well) to stop the assay. The plate is sealed and shaken and allowed to stand at ambient temperature for 35 minutes to 1 hour (preferably 35 minutes) to allow the beads to settle. The combined radioactive product was measured using a WALLAC TRILUX 1450 Microbeta scintillation counter. Ten concentrations of each compound (L5nM - 30 uM) were tested to provide a inhibition curve. The curves were analyzed using ActivityBase and XLfit (ID Business Solutions, Inc.). The results are based on the PIC 〇 value table TF. The biological data obtained for some of the examples (PDE4B inhibitory activity, either a reading or an average of about 2-6 readings) are as follows, based only on current metrics. Absolute accuracy is not possible and the readings are only accurate up to approx. ± 0.5 log units, depending on the number of readings performed and averaged: Example number PDE4B pIC5〇2 8.0 3 7.8 87841-960303-medium. Doc -95- 1283678 6 6.6 11 7.4 21 8.5 22 7.9 32 7.7 40 8.3 63 6.9 1,36, 39, 41,42, 43, 44, 47, 48, 63, 83, 109, 178, 187 and 600 7.0 7.9 100, 155, 165, 167, 201, 260, 261, 263, 265, 266, 267, 271, 493, 494, 495, 498, 518, 518A, 551, 575, 581, 584, 619, 622, 624- 626, 628, 630, 636, 638, 643-645 and 653 8.2 to 9.6 196 7.9 198 8.5 Excluding reference examples 19-20, these examples have PDE4B inhibitory activity at pICs 0 = about 5·5 (earth 〇·5 ) to a range of approximately 9.6 (about 0. 5). The majority (about 95% or more) of the examples, excluding Reference Examples 19-20, have a PDE4B inhibitory activity in the range of from about 6 (about 〇·5) to about 9.6 (about 0.5). Wherein R3 = cyclohexyl (NHR3 = subtype (c)), tetrahydro-2H-piperazin-4-yl (NHR3 = group (h)), 4-ketocyclohexyl_3 = subtype (0) Or some other type of substituted cyclohexyl or some of the heterocyclic rings, when measured in the above enzyme inhibition assay, with a comparable example wherein R3 = cyclopropyl_3 = subformula (b)) Selective comparisons, usually or often (especially with respect to Rl = ethyl), have a higher degree of selectivity for PDE4B than PDE5. For example, it is based only on the current measurement and is subject to cumulative detection inaccuracy: 87841»960303^.doc •96- 1283678 - Examples 21, 4〇, 90, 19δ and 201 (where njjr3 is individual = subtype (h) , (c), 1, (8) and (ο), R1 = ethyl) have a selectivity for pDE4B over pDE5 'in about 3 to 20 or more times, more than R3 = cyclopropyl ( NHR3 = substrate (b)) is equivalent to the selectivity achieved by Example 39; - Examples 43 and 44 (where NHR3 is individual = subtypes (4) and (8)) have a selectivity over pDE5 for pDE4B, at about 4 to 8 or More than the range, more than equivalent R3 = selectivity achieved by cyclopropyl example 42; - Examples 22 and 48 (where NHR3 is individual = subtypes (8) and (c)) have a preference for pDE4B over PDE5 Sex, in the range of about 2.5 to 1 or more times, more than equivalent R3 = selectivity achieved by cyclopropyl example 47; and - examples 2 and 3 (where NHR3 is individual = subtypes (6) and (8)) The selectivity for pDE4B over PDE5 is greater than the equivalent of R3 = cyclopropyl Example 1 in the range of about 2 to 5 or more. Errata gel spit: Some known PDE4 inhibitors may cause vomiting and/or nausea, to a greater or lesser extent (see, for example, z·Huang et al., must learn to learn #学之疔疔, 2001, 5: 432-438, especially refer to page 433_434 and references cited therein). Therefore, if the pDE4 inhibiting compound or salt of the present invention causes only a limited or easy to treat vomiting side effect, it is preferred, but not essential. When ferrets are administered, the side effects of vomiting can be measured by, for example, the vomiting potential of the compound or salt; for example, we can measure vomiting, retching and vomiting in ferrets after oral or parenteral administration of the compound or salt. / or the time, privateness, frequency and/or duration of the warning. See, for example, A. Robichaud et al., 'Vegetation caused by [PDE IV] inhibitors in ferrets M, Neuropharmacology, 1999, 3 8, 289-297 87841-960303-中.doc-97- 1283678 2001, 40, 465-465. However, it is more preferred that the vomiting side effects and therapeutic index in the rats are administered after the administration of the compound or salt of the present invention, preferably by monitoring the eating behavior of the eclipse in the rats (see in vivo assay 2 below). It is true that some PDE4 inhibitors may cause other side effects, such as headaches and other side effects of the central nervous system (CNS-); and/or gastrointestinal (GI) disorders. Thus, it is preferred, but not required, that a particular PDE4 inhibiting compound or salt of the present invention will only result in limited or easy to treat side effects of one or more of these side effect types. In vivo biological assays The above-mentioned in vitro enzyme PDE4B inhibition assay should be considered as a preliminary test for biological activity. However, the following are other in vivo biological assays that are selected and are not a measure of efficacy or side effects. In vivo detection 1. LPS-induced pulmonary neutropenia in rats: oral administration of PDE4 inhibitors Lung neutrophil influx has been shown to be an important component of the pulmonary disease group, such as chronic obstruction Pulmonary disease (COPD), which may involve chronic bronchitis and/or emphysema (GF· Filley, 2000; 117(5); 251 s-260s). The purpose of this neutrophil model is to study the potential anti-inflammatory effects of dermal neutropenia caused by inhalation of aerosolized lipopolysaccharide (LPS) in the study of oral administration of PDE4 inhibitors. To make a model of neutrophil inflammatory components of COPD. For the scientific background, please refer to the following passages. Male Lewisian rats (Charles River, Raleigh, NC, USA) weighing approximately 300-400 grams, either as (8) suspended in water, 0.5% methylcellulose 87841-960303-medium.doc -98-1283678 ( The test compound was obtained from Sigma_Aldrich, St Louis, MO, USA), or (b) was pretreated with vehicle and delivered orally in a dose volume of 10 ml/kg. In general, dose response curves were generated using the following PDE4 inhibitor doses: 1 〇·〇, 2.0, 0.4, 0.08, and 0.016 mg/kg. Thirty minutes after pretreatment, the rats were exposed to aerosolized LPS (serotype E. coli 026 ··B6) produced by an atomizer containing 100 μg/ml LPS solution, prepared by a rat vinegar fel extract Cheng ' is available from Sigma_Aldrich, St Louis, MO, USA). At a rate of 4 liters per minute, the rats were exposed to a gas gel for 20 minutes. The LPS exposure was carried out in a closed chamber having an internal dimension of 45 cm length X 24 cm width x 20 cm height. The exposure chamber is contained in a certified ventilated fume hood. After 4 hours of exposure to Lps, 'at 90 mg/kg', the dose is administered by intraperitoneal administration of excessive dose &lt; pentobarbital. Euthanasia. The tracheal trachea and lung lavage (BAL) were pre-formed through a 14-gauge blunt needle into an exposed trachea. Five 5 ml washes were performed to collect a total of 25 ml of BAL fluid. Total cells were injected into the BAL fluid. Count the difference from white blood cells to calculate the amount of neutrophil to the lungs. Calculate the percentage of neutrophil inhibition under each dose (see vehicle) and produce a variable slope, sigmoidal dose response curve, usually used PrismGraph-Pad. This dose response curve was used to calculate the value of 〇5〇 (expressed in milligrams per kilogram of body weight) for inhibition of LPS-induced neutropenia by pDE4 inhibitors. Based on the current metrics, the compounds of Examples 22 and (5) were administered orally in the above procedure, showing that neutropenia inhibits an ED50 value of from about 0.5 mg/kg to about 2 mg/kg. The range is 87841_96〇3〇3_中.doc -99- 1283678. In the alternative embodiment of this procedure, a single oral dose of 10 mg/kg is administered to the rats. Or 1.0 mg/kg of PDE4 inhibitor (or vehicle) and calculate percent neutrophil septicemia and report the specific dose. In this particular example, based on current metrics, Examples 21, 100, 109 Compounds of 167, 172 and 600, in the above procedure, administered orally at a single dose of L0 mg/kg, showing a percent inhibition of neutropenia, ranging from about 19% to about 69% Internal (or in the range of about 32% to about 69%, for examples 21, 100, 109, 167, and 600).

Filley G.F. COPD與氣喘之結構與炎性特徵之比較· C%如.2000 ; 117(5) 251 s-260s。Filley G.F. Comparison of the structure and inflammatory characteristics of COPD and asthma. C% is .2000; 117(5) 251 s-260s.

Howell RE，Jenkins LP，Fielding LE 及 Grimes D·在褐色 Norway 大白 鼠中抗原引致之肺嗜伊紅血球過多與嗜中性白血球增多症 藉由磷酸二酯酶類型3與4之選擇性抑制劑之抑制·#桌理 1995 ; 8 : 83-89。Howell RE, Jenkins LP, Fielding LE and Grimes D· In the brown Norway rats, antigen-induced pulmonary eosinophilia and neutropenia are inhibited by selective inhibitors of phosphodiesterase types 3 and 4. · #桌理1995 ; 8 : 83-89.

Spond J, Chapman R, Fine J, Jones H, Kreutner W, Kung TT? Minnicozzi, M. 在肺嗜中性白血球增多症之大白鼠模式中PDE4抑制劑、羅 利普蘭及SB207499(ArifloTM)之比較·摩桌理#與治# #.2001 ; 14 ·· 157-164 〇Spond J, Chapman R, Fine J, Jones H, Kreutner W, Kung TT? Minnicozzi, M. Comparison of PDE4 inhibitors, rolipram and SB207499 (ArifloTM) in the rat model of pulmonary neutropenia摩桌理#和治# #.2001 ; 14 ·· 157-164 〇

Underwood DC, Osborn RR? Bochnowicz S5 Webb EF, Rieman DJ, Lee JC, Romanic AM，Adams JL，Hay DWP 及 Griswold DE. SB 239063 ， p38MAPK抑制劑在肺臟中減少嗜中性白血球、炎性細胞活素、 87841-960303-中.doc -100- 1283678 MMP-9 及纖維變性· ^/尸Cfe&quot; M^/ 戶/抑/〇/. 2000 ; 279 : L895-L902 。 活體內檢測2. 嗔吐之大白鼠異食癖模式 f # ··選擇性PDE4抑制劑，已在各種活體外與活體内模 式中，藉由增加許多免疫細胞（例如淋巴細胞、單細胞）之 cAMP之胞内含量，被証實會抑制發炎。但是，一些pDE4抑 制劑在許多物種中之副作用是嘔吐。由於發炎之許多大白 氣模式係經良好地特徵鑒定，故其已被使用於程序（參閱， 上文例如活體内檢測1)中，以証實PDE4抑制劑之有利消炎 作用。但是，大白鼠無致吐回應（其沒有嘔吐反射），以致 難以直接在大白鼠中研究PDE4抑制劑之有利消炎作用與嘔 吐間之關係。 但是，於1991年，Takeda等人（參閱下文之文獻段落）証實 大白鼠中之異食癖進食回應係類似嘔吐。 白鼠中是-種對疾病之行為回應，其中大μ係進 養物質，譬如泥土或特別是黏土（例如高嶺土），其可繫助 及收母素。異食癖進食可藉由運動與化學品（尤其是在人類 中域吐敎化學㈠謗發，且可使騎在人財抑制唱吐 《藥物”乂樂理學万式抑制。大白鼠異食癖模式，活體内 檢測2，可測定在藥理學 予上有關聯之劑量下，大白鼠對PDE4 抑制之異食癖回應程度， 消炎檢測(例如上文活另—組)大白鼠中之活體内 m 舌1&quot;内檢測G平行進行。於相同物種中 &lt;消犬與異食癖檢測，可一 i ^ ^ 起棱供本發明化合物/鹽對# 大白鼠中之”治療指數” 于於 (Ο砭數據。大白鼠耵可例如 87841-96〇3〇3·中.doc -101- 1283678 自檢測2之潛在致吐異食癖回應ED5〇劑量，對b)大白鼠消炎 ED50劑量（例如藉由在活體内檢測1中之大白鼠嗜中性白血 球增多症抑制度量）之比例計算而得，其中在許多消炎劑量 下，較大TI比例可能指示較低嘔吐。這或許允許具有消炎 作用之本發明化合物或鹽之非致吐或最低致吐醫藥劑量之 種選擇。但是，應明瞭達成低致吐PDE4抑制化合物並非 必須。 禮多··於實驗之第一天，將大白鼠個別飼養在未具有舖蓋 或π加強物”之籠子中。藉由金屬網，使大白鼠保持遠離籠 子地板。將含有標準大白鼠食物與黏土顆粒之經預稱重食 物杯放置在籠子中。可得自Languna黏土公司（工業 城，CA，USA)之黏土顆粒，係與食物顆粒相同大小與形狀。 使大白鼠適應黏土 72小時，於此段時間内，每日在能夠度 量至最接近0·1克之電子天平上稱量得自籠子之杯子與食物 及黏土碎屑。於72小時適應期間結束時，大白鼠係一般性 地顯示不對黏土顆粒感興趣。 於72小時結束時，將大白鼠置於乾淨籠子中，並稱量食物 杯。將仍然規則地消耗黏土之大白鼠移離研究。就在暗循 環（動物係為活動的且應正在進食時）之前，將動物分成數 個治療組，並以經口方式服用本發明化合物/鹽之劑量（不 同治療組不同劑量）或單獨媒劑，在2毫升/公斤之劑量體 積下。於此經口服藥時，化合物/鹽係呈水中〇·5%甲基^ 維素（可得自Sigma-Aldrich，St Louis, MO, USA)内之懸浮液形式。 隔天，將食物與黏土杯與籠子碎屑稱重，並計算當晚被每 87841-96〇3〇弘中 d〇c -102- 1283678 一隻動物消耗之總黏土與食物量。 計算劑量回應，其方式是首先使數據轉化成量子回應，其 中動物對異食癖回應係為無論是陽性或陰性。若大白鼠消 耗超過通常使用藉由Statistica統計套裝軟體進行之計算術回 歸所計算之平均值，大於或等於0.3克黏土，則大白鼠係為” 異食癖陽性π。於是可計算異食癖回應ED50值，以每公斤體 重之毫克數表示。 果··使用上述程序，並根據現行度量法，實例22、83及 155之化合物顯示異食癖回應ED50在約4.8毫克/公斤至大於 或等於約40毫克/公斤之範圍内。可見及的是，此等異食 癖回應ED50劑量，係高於對此三個實例之嗜中性白血球增 多症抑制ED50值（參閱上文活體内檢測1)，以致大白鼠中之 治療指數&gt;2，當藉由檢測1+2，且根據現行度量法度量時， 乍看之下對此三個實例似乎已被達成。 文獻··Underwood DC, Osborn RR? Bochnowicz S5 Webb EF, Rieman DJ, Lee JC, Romanic AM, Adams JL, Hay DWP and Griswold DE. SB 239063, p38MAPK inhibitors reduce neutrophils, inflammatory cytokines in the lungs, 87841-960303-中.doc -100- 1283678 MMP-9 and fibrosis·^/corpse Cfe&quot; M^/ household////〇/. 2000; 279: L895-L902. In vivo detection 2. The sputum of the white rat heterotrophic sputum mode f # · · Selective PDE4 inhibitor, has increased cAMP by many immune cells (such as lymphocytes, single cells) in various in vitro and in vivo modes The intracellular content has been shown to inhibit inflammation. However, some of the side effects of pDE4 inhibitors in many species are vomiting. Since many of the inflamed large white gas patterns are well characterized, they have been used in procedures (see, for example, in vivo assay 1 above) to confirm the beneficial anti-inflammatory effects of PDE4 inhibitors. However, the rats did not respond to vomiting (there was no vomiting reflex), making it difficult to study the relationship between the beneficial anti-inflammatory effects of PDE4 inhibitors and vomiting directly in rats. However, in 1991, Takeda et al. (see the passage below) confirmed that the eclipse feeding response in rats was similar to vomiting. In white mice, there is a response to the behavior of the disease, in which large μ is a feeding material, such as soil or especially clay (such as kaolin), which can help and collect the parent. Eating with different foods can be achieved by exercise and chemicals (especially in the human body, spitting chemistry (1), and can make riding in the human capital to suppress the singer "drugs", music theory, inhibition. In vivo detection 2, can determine the degree of response to PDE4 inhibition of ecstasy in rats at pharmacologically relevant doses, anti-inflammatory test (such as the above live-group) in vivo in the mouse m tongue 1 &quot; The internal detection G is carried out in parallel. In the same species, the detection of the canine and the eclipse can be used to provide the therapeutic index of the compound/salt of the invention in the white rat (于). White sputum can be, for example, 87841-96〇3〇3·中.doc -101-1283678. The potential vomiting of the self-test 2 is ED5〇 dose, and b) the dose of anti-inflammatory ED50 of the mouse (for example, by in vivo detection 1) The ratio of the neutropenia inhibition measure in rats is calculated by the fact that at many anti-inflammatory doses, a larger TI ratio may indicate lower vomiting. This may allow for the anti-inflammatory effects of the compounds or salts of the present invention. Cause spitting or minimal vomiting The choice of dosage is. However, it should be understood that it is not necessary to achieve a low vomiting PDE4 inhibitory compound. On the first day of the experiment, the rats were individually housed in a cage without a tiling or π reinforcement. The rat is kept away from the cage floor by a metal mesh. A pre-weighed food cup containing standard rat food and clay granules is placed in a cage. Clay available from Languna Clay Company (Industrial City, CA, USA) The granules are the same size and shape as the food granules. The rats are adapted to the clay for 72 hours. During this time, the cups and foods from the cage are weighed daily on an electronic balance that can be measured to the nearest 0.1 gram. Clay debris. At the end of the 72-hour adaptation period, the rats generally showed no interest in clay granules. At the end of 72 hours, the rats were placed in clean cages and the food cups were weighed. The mice that consumed the clay were removed from the study. Just before the dark cycle (the animal is active and should be eating), the animals were divided into several treatment groups and orally With the dose of the compound/salt of the present invention (different doses of different treatment groups) or a separate vehicle at a dose volume of 2 ml/kg, the compound/salt is 〇·5% methyl in water. The suspension in the form of vitamins (available from Sigma-Aldrich, St Louis, MO, USA). The next day, weighed the food and clay cups and cage debris, and calculated that every night was 87411-96〇3〇 D〇c -102- 1283678 The total amount of clay and food consumed by an animal. The dose response is calculated by first converting the data into a quantum response, in which the animal responds to the eclipse as either positive or negative. The consumption is more than the average calculated using the computational regression of the Statistica statistical suite software, greater than or equal to 0.3 grams of clay, and the rat is "pigmented 癖 positive π. The ED50 value of the eclipse can then be calculated and expressed in milligrams per kilogram body weight. Using the above procedure, and according to the current metric, the compounds of Examples 22, 83 and 155 show that the eclipse responds to an ED50 in the range of from about 4.8 mg/kg to greater than or equal to about 40 mg/kg. It can be seen that these ecstasy respond to the ED50 dose, which is higher than the ED50 value of the three cases of neutropenia (see above in vivo test 1), so that the therapeutic index in rats> 2. When by measuring 1+2 and measuring according to the current metric, at first glance it seems that the three instances have been reached. literature··

Beavo JA，Contini，Μ·，Heaslip，R.J.多重環核嘗酸磷酸二酉旨酶· Mol Pharmacol. 1994 ; 46 : 399-405。Beavo JA, Contini, Μ·, Heaslip, R.J. Multiple Cyclic Nucleic Acid Diterpenoids Mol Pharmacol. 1994; 46: 399-405.

Spond J5 Chapman R? Fine J5 Jones H3 Kreutner W, Kung TT5 Minnicozzi M. 在肺嗜中性白血球增多症之大白鼠模式中PDE4抑制劑、羅 利普蘭及SB207499(ArifloTM)之比較·肺藥理學與治療 學.2001 ; 14 : 157-164。Spond J5 Chapman R? Fine J5 Jones H3 Kreutner W, Kung TT5 Minnicozzi M. Comparison of PDE4 Inhibitor, Rolipram and SB207499 (ArifloTM) in Rat Model of Pulmonary Leukocytosis • Lung Pharmacology and Treatment Learning .2001 ; 14 : 157-164.

Takeda N，Hasegawa S，Morita Μ 及 Matsunaga T·大白鼠中之異食癖 係類似嘔吐：嘔吐研究上之動物模式.藥理學，生物化學及行 為.1991 ; 45 : 817-821。 87841-960303-中.doc -103- 1283678Takeda N, Hasegawa S, Morita Μ and Matsunaga T· White rats are similar to vomiting: animal model of vomiting research. Pharmacology, biochemistry and behavior. 1991; 45: 817-821. 87841-960303-中.doc -103- 1283678

Takeda N，Hasegawa S，Morita M，Horii A，Uno A，Yamatodani A 及 Matsunaga，1&gt;區吐之神經藥理學機制· I.大白鼠中之止吐藥物對 運動-與阿樸嗎啡-所引致異食癖之作用.C/如 1995 ; 17(9)589-596。Takeda N, Hasegawa S, Morita M, Horii A, Uno A, Yamatodani A and Matsunaga, 1&gt; The pharmacological mechanism of vomiting in the area · I. Antiemetic drugs in rats - exercise - and apomorphine - induced eclipse The role of 癖. C / as in 1995; 17 (9) 589-596.

Takeda N，Hasegawa S，Morita M，Horii A，Uno A，Yamatodani A 及 Matsunaga 1&gt;區吐之神經藥理學機制· II.大白鼠中之止吐藥物對 順氯胺銘-所引致異食癖之作用· Mei/z Wm/Exp C7z&gt;2尸/zarmaco/. 1995 ; 17(9)647-652。 活體内檢測3. 在大白鼠中LPS所引致之肺嗜中性白血球增 多症··經氣管内投予PDE4抑制劑之作用 此項檢測為肺中發炎-明確言之為藉由脂多糖（LPS)所謗發 之嗜中性白血球增多症-之動物模式，並允許研究此種嗜中 性白血球增多症藉由氣管内（i.t)投予PDE4抑制劑之推斷抑制 (消炎作用）。PDE4抑制劑較佳係呈乾粉或潤濕懸浮液形 式。氣管内投藥為一種吸入投藥之模式，允許局部傳輸至 肺臟。 愈 # :將由 Charles River，Raleigh，NC，USA 供應之雄性 CD (史泊 格多利（Sprague Dawley)所衍生）大白鼠，以數組每個籠子各5 隻大白鼠飼養，在交付至少7天後，使其適應規則地更換之 舖蓋/棲息材料，以無限制給予之SDS飲食R1粒狀食物餵 食，及供應每日更換之巴斯德滅菌之動物級飲用水。 #粉授襄届之袁I ··於服藥針頭與注射器間之用後即棄3-向接口。將3-向無菌接口（Vycon參考876.00)稱重，然後將藥 物摻合物或吸入級乳糖（媒劑對照物）添加至接口中，關閉 87841-960303-中.doc -104- 1283678 接口以防止藥物流失，並將接口再稱重，以測定接口中之 藥物重量。絲藥後，再—次將接p稱重，以測定留在接 口中《藥物重量。將此針頭，SigmaZ21934々注射器針頭⑼ 號’ 152毫米(6英吋)長，具有魯厄氏輪轂，#由工程切判成 大約丨32毫米（5·2英吋），製成鈍端，以防止其傷害大白鼠之 氣管，並在藥物傳輸之前與之後，稱量針頭，以確認服藥 後沒有藥物殘留在針頭中。 涿濕憑孕旋犮桌蓆之袭I..其係類似上文所述，但使用鈍 服藥針頭，其前端對針軸稍微呈一角度，具有被***針頭 中之可撓性塑膠把持套管。 桌#與## ··使脂多糖（LPS)(血清型：〇127: B8)(L3129批號 61K4075)溶於磷酸鹽緩衝鹽水(PBS)中。]?]〇]&amp;4抑制劑係以大小 降低（例如微粉化）形式使用，例如根據上文所予之微粉化 實例。對藥物之乾粉投藥而言，可使用上文所予包含藥物 與吸入級乳糖之乾粉配方實例。通常使用之吸入級乳糖（批 號E98L4675批次845120)具有10%微細粉末（1〇%之物質，在藉 由Malvern粒子大小度量之15微米粒子大小下）。藥物之潤濕 懸浮液可經由將所需要體積之媒劑，添加至藥物中而製 成；所使用之媒劑為鹽水/ Tween (0.2% Tween 80)之混合物。 在使用之前，使潤濕懸浮液音振10分鐘。 製備及服用pde4抑制劑：後电掩韌蜘11象餐銬兔m塑 膠室中，並使其曝露至異氟燒（isoflourane)(4.5% )、氧化亞氮（3 升/分鐘）及氧（1升/分鐘）之氣態混合物，使大白鼠麻醉。 一旦已麻醉，將動物置於不銹鋼製氣管内服藥承載桌上。 87841_96〇3〇3_ 中.doc -105- 1283678 以其背部，將其以大約35。角放置。使光線對著咽喉外部呈 某一角度，以照亮氣管。打開口部，並使氣道之開口得以 見及。此程序係如下述，針‘對PDE4抑制劑之潤濕懸浮液及 乾粉投藥作改變： 以謂濕廢孕旋赝襄··經由已小心地***大白鼠氣管中之兹屯 金屬服藥針頭，引進把持套管。經由具有用於各不同藥物 組之新内部套管之服藥針頭，使動物以氣管内方式服用媒 劑或PDE4抑制劑。使用連接至服藥針頭之注射器，使配方 慢慢地（10秒）月良用至氣管。 以#粉赝藥··將三向接口裝置與針頭***大白鼠氣管中， 達到經建立以被定位在主要分叉上方大約1公分處之預定 點。另一位操作者係在指定位置握住針頭，同時傳輸毫 升空氣經過三向接口，經由施壓注射器（理想上係與動物吸 氣一致），目的在於從接口逐出全部藥物量。於服藥後，自 氣道移除針頭與接口，並關閉接口，以防止任何殘留之藥 物離開接口。在以無論是潤濕懸浮液或乾粉服藥後，接著 將動物移離桌子，並不斷地觀察，直到其已自麻醉作用恢 復。使動物返回容納籠，並給予自由獲取食物與水；觀察 彼等，並記下任何不尋常行為改變。 镙虞至1把··於氣管内服用媒劑對照物或PDE4抑制劑後約2 小時，將大白鼠置於密封透明塑膠容器中，並曝露至Lps之 氣溶膠（霧化器濃度150微克/毫升），歷經15分鐘。Lps之氣 溶膠係藉由霧化器（DeVilbiSS，USA)產生，並將其導入透明塑膠 曝露室中。在15-分鐘LPS-曝露期間之後，使動物返回容納 87841·96〇3〇3_ 中.doc -106 - 1283678 籠，並允許自由獲取食物與水。 [在一項替代具體實施例中，可使大白鼠於氣管内服藥 後，曝露至LPS低於2小時。在另一項替代具體實施例中， 可使大白鼠在藉由媒劑或PDE4抑制劑之氣管内服藥後，曝 露至LPS超過2小時（例如約4或約6小時），以測試PDE4抑制 劑是否具有長作用期（這並非必須）]。 犮扃f庳游虑灌洗·· LPS曝露後4小時，藉由劑量過度之 戊巴比酮鈉（腹膜腔内）殺死動物。將氣管以套管***聚丙 烯管件，並以3 X 5毫升肝燐脂化（25單位/毫升）磷酸鹽緩衝 之鹽水(PBS)灌洗（洗除）肺臟。 嗦户從白▲球加應妒歲··使枝氣管與肺胞灌洗（BAL)試樣 在1300rpm下離心7分鐘。移除上層清液，並使所形成之細胞 丸粒再懸浮於1毫升PBS中。經由將1〇〇微升再懸浮之BAL流 體置入細胞旋轉保持器中，製備再懸浮流體之細胞載玻 片，然後於5000rpm下旋轉5分鐘。使載玻片風乾，接著以 Leishmans染料染色（20分鐘），以允許差別細胞計數。亦自再 懸浮液計數全部細胞。從此兩種計數，測得嗜中性白血球 在BAL中之總數。為度量嗜中性白血球增多症之pDE4_抑制 劑引致之抑制，進行嗜中性白血球計數在以媒劑處理之大 白鼠與以PDE4抑制劑處理之大白鼠中之比較。 經由改變使用於服藥步驟中之PDE4抑制劑劑量（例如每八 斤體重〇·2或0.1毫克之PDE4抑制劑，降至例如〇 毫克/八 斤），可產生劑量回應曲線。 於本專利說明書中引述之所有公報，包括但不限於專利與 87841_96〇3〇3·中.doc -107- 1283678 專利申請案， 且個別地顯示 提出一般。 均併於本文供參考，猶如各個別公報係詳細 、并入本文供參考，就如同完整地於此處 【實施方式】 實例 見在本發明《各方面將參考下述實例加以 例係僅只是說明而p ^ μ k 此寺I 而非欲被解釋為限制本發明之r 圍。在此段落中，”中間 ^ 中之中間化合物合成。 貫例合治 於本文中使用之縮窝·· DCM 二氯甲烷 EtOAc 醋酸乙酿 Et20 ***Takeda N, Hasegawa S, Morita M, Horii A, Uno A, Yamatodani A and Matsunaga 1&gt; The pharmacological mechanism of vomiting in the area · II. The effect of antiemetics in rats on cisplatin-induced ecstasy · Mei/z Wm/Exp C7z&gt; 2 corpse/zarmaco/. 1995; 17(9)647-652. In vivo detection 3. Lung-induced neutropenia caused by LPS in rats · The effect of intratracheal administration of PDE4 inhibitor This test is inflammation in the lungs - specifically by lipopolysaccharide (LPS) An animal model of neutropenia that has been developed and allowed to investigate the putative inhibition (anti-inflammatory effect) of this neutrophilic leukemia by intratracheal (it) administration of a PDE4 inhibitor. Preferably, the PDE4 inhibitor is in the form of a dry powder or a wet suspension. Intratracheal administration is a mode of inhaled administration that allows local delivery to the lungs. Yu #: Male CDs (derived from Sprague Dawley) supplied by Charles River, Raleigh, NC, USA, in an array of 5 rats per cage, after delivery for at least 7 days, It is adapted to regularly replace the covering/habiting material, feeding the unrestricted SDS diet R1 granulated food, and supplying the daily replacement of pasteurized animal-grade drinking water. #粉授襄的袁I ·· After the use of the needle and the syringe, the 3-way interface is discarded. Weigh the 3-way sterile interface (Vycon reference 876.00), then add the drug blend or inhaled lactose (vehicle control) to the interface, close the 87841-960303-medium.doc-104-1283678 interface to prevent The drug is lost and the interface is weighed again to determine the weight of the drug in the interface. After the silk medicine, the p weight will be weighed again to determine the weight of the drug left in the interface. This needle, SigmaZ21934 々 syringe needle (9) number '152 mm (6 inches) long, with Luer's wheel hub, # is cut into approximately 毫米32 mm (5.2 ft) by engineering, made into a blunt end, Prevent it from damaging the trachea of the rats, and weigh the needle before and after the drug is delivered to confirm that no drug remains in the needle after taking the drug.涿 凭 凭 凭 凭 凭 凭 凭 凭 凭 . I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I . Table ####·························································· Inhibitors are used in the form of reduced size (e.g., micronized), for example, according to the micronization examples given above. For the dry powder administration of the drug, an example of a dry powder formulation of the above-mentioned drug and inhaled lactose may be used. The commonly used inhaled lactose (batch E98L4675 lot 845120) has 10% fine powder (1% by weight of material at a 15 micron particle size as measured by Malvern particle size). Wetting of the drug The suspension can be prepared by adding the required volume of vehicle to the drug; the vehicle used is a mixture of saline / Tween (0.2% Tween 80). The wetted suspension was sonicated for 10 minutes before use. Preparation and administration of pde4 inhibitor: post-tapping the 11-like meal in the rabbit plastic chamber and exposing it to isoflourane (4.5%), nitrous oxide (3 liters/min) and oxygen ( A gaseous mixture of 1 liter per minute was used to anesthetize the rats. Once anesthetized, the animals were placed in a stainless steel trachea on a drug carrying table. 87841_96〇3〇3_中.doc -105- 1283678 With its back, it is about 35. The corner is placed. Light the light at an angle to the outside of the throat to illuminate the air tube. Open the mouth and allow the opening of the airway to be seen. This procedure is as follows, the needle 'changes to the wet suspension of the PDE4 inhibitor and the dry powder administration: it is said to be wet and pregnant. · Through the needle of the metal medicinal drug that has been carefully inserted into the trachea of the rat, introduced Hold the sleeve. Animals were administered the vehicle or PDE4 inhibitor intratracheally via via needles with new internal cannulas for each of the different drug groups. Use a syringe attached to the medication needle to allow the formulation to slowly (10 seconds) to the trachea. The three-way interface device and the needle were inserted into the trachea of the rat to reach a predetermined point that was established to be positioned approximately 1 cm above the main bifurcation. Another operator holds the needle at the designated location while delivering milliliters of air through the three-way interface, via a pressurized syringe (ideally in line with the animal's inhalation), with the goal of expelling the entire amount of drug from the interface. After taking the drug, remove the needle and the interface from the airway and close the interface to prevent any residual drug from leaving the interface. After taking the drug, either wetted suspension or dry powder, the animal is then removed from the table and continuously observed until it has recovered from anesthesia. Return the animals to the containment cage and give them free access to food and water; observe them and note any unusual behavioral changes.镙虞到1····································································································· ML), after 15 minutes. The aerosol of Lps is produced by a nebulizer (DeVilbiSS, USA) and introduced into a transparent plastic exposure chamber. After the 15-minute LPS-exposure period, the animals were returned to accommodate the 87841·96〇3〇3_.doc -106 - 1283678 cage and allowed free access to food and water. [In an alternative embodiment, the rats can be exposed to LPS for less than 2 hours after administration in the trachea. In another alternative embodiment, the rats can be exposed to LPS for more than 2 hours (e.g., about 4 or about 6 hours) after intratracheal administration by vehicle or PDE4 inhibitor to test PDE4 inhibitors. Whether it has a long duration (this is not necessary)].犮扃f庳要过洗洗·· 4 hours after LPS exposure, the animals were killed by an overdose of sodium pentobarbitone (intraperitoneal cavity). The trachea was cannulated into a polypropylene tube and the lungs were lavaged (washed out) with 3 x 5 ml of hepatic lipidified (25 units/ml) phosphate buffered saline (PBS). Seto was centrifuged at 1300 rpm for 7 minutes from the white ▲ ball plus the sputum sputum. The supernatant was removed and the resulting cell pellet was resuspended in 1 ml of PBS. The cell slide of the resuspended fluid was prepared by placing 1 liter microliter of the resuspended BAL fluid into the cell rotation holder and then rotating at 5000 rpm for 5 minutes. The slides were air dried and then stained with Leishmans dye (20 minutes) to allow for differential cell counting. All cells were also counted from the resuspension. From these two counts, the total number of neutrophils in the BAL was measured. To measure inhibition by pDE4_inhibitors of neutrophilia, neutrophil counts were compared between vehicle-treated rats and PDE4 inhibitor-treated rats. A dose response curve can be generated by varying the dose of the PDE4 inhibitor used in the dosing step (e.g., down to 2 mg or 0.1 mg of PDE4 inhibitor per ounce of body weight, for example to 〇 mg/8 kg). All publications cited in this patent specification, including, but not limited to, the patents and the patent application Serial No. s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s The disclosures of each of the entire publications are hereby incorporated by reference herein in their entirety in the entireties in the the the the the the the the the the the While p ^ μ k this temple I is not intended to be construed as limiting the invention. In this paragraph, the synthesis of the intermediate compound in the middle ^. The combined use of the condensate used in this article · DCM dichloromethane EtOAc acetic acid Et20 ether

DMF MeOH 二甲基甲醯胺 甲醇 HPLC 高壓液相層析法 SPE 固相萃取 鲁DMF MeOH dimethylformamide methanol HPLC high pressure liquid chromatography SPE solid phase extraction

核磁共振（其中：s=單重峰，d==雙重峰，t〜一 重峰，q=四重峰，dd=二重峰之-舌您 — —1重峰，多 重峰，H=質子數）Nuclear magnetic resonance (where: s = singlet, d = = doublet, t ~ one heavy peak, q = quadruple peak, dd = doublet - tongue you - 1 heavy peak, multiple peak, H = number of protons)

LCMS TLC 液相層析法/質量光譜 薄層層析法LCMS TLC liquid chromatography / mass spectroscopy thin layer chromatography

BEMP 2-第三-丁基亞胺基·2·二乙胺基]少二甲基全氫 1，3,2-« —氮鱗赌 87841-960303-中.doc -108 - 1283678 EDC l-(3_二甲胺基丙基）-3-乙基碳化二亞胺鹽酸鹽 HATU 六氟磷酸〇-(7-氮苯并***小基）-N，N，N’，N’-四甲基錁 HBTU 六氟磷酸〇-(苯并***小基）_N，N，N’，N’-wT*# HOBT 羥基苯并*** h 小時 DIPEA 二異丙基乙胺（iPr2NEt) Tret 滯留時間 THF 四氫呋喃BEMP 2-Tertiary-butylimido·2·diethylamino]Less dimethylhydrogen 1,3,2-«—Nitrogen gambling 87041-960303-中.doc -108 - 1283678 EDC l- (3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride HATU hexafluorophosphate-(7-azobenzotriazole small)-N,N,N',N'- Tetramethyl hydrazine HBTU bismuth hexafluorophosphate-(benzotriazole small group)_N,N,N',N'-wT*# HOBT hydroxybenzotriazole h hour DIPEA diisopropylethylamine (iPr2NEt) Tret Residence time THF tetrahydrofuran

Lawesson氏試劑2,4-雙（4_甲氧苯基）_1，3·二硫-2,4_二磷四圜-2,4-二 硫化物 室溫 其通常在約20至約25°C之範圍内 於本文中使用之機械方法： lcms (液相層析法/質量光譜)Lawesson's reagent 2,4-bis(4-methoxyphenyl)_1,3·dithio-2,4-diphosphonium tetraindole-2,4-disulfide is usually at room temperature of from about 20 to about 25°. Mechanical methods used herein within the scope of C: lcms (liquid chromatography / mass spectroscopy)

Waters ZQ質譜儀，以正離子電噴霧模式操作，質量範圍100-1000 amu UV波長：215-330毫微米Waters ZQ mass spectrometer operating in positive ion electrospray mode with mass range 100-1000 amu UV wavelength: 215-330 nm

管柱：3.3公分x4.6毫米内徑，3微米ABZ + PLUS 流率：3毫升/分鐘 注射體積：5微升 溶劑A : 95%乙腈+ 0.05%甲酸 溶劑B : 0.1%甲酸+10毫莫耳濃度醋酸銨 梯度液：〇% A/0.7 分鐘，0-100% A/3.5 分鐘，100% A/U 分鐘，100-0 % A/0.2分鐘Column: 3.3 cm x 4.6 mm id, 3 μm ABZ + PLUS Flow rate: 3 ml/min Injection volume: 5 μl Solvent A: 95% acetonitrile + 0.05% formic acid solvent B: 0.1% formic acid + 10 mmol Ear concentration ammonium acetate gradient: 〇% A/0.7 minutes, 0-100% A/3.5 minutes, 100% A/U minutes, 100-0 % A/0.2 minutes

質量導引之自預備HPLC 87841-96〇3〇3_ 中.doc -109- 1283678 所使用之預備管柱為Supelcosil ABZplus (10公分χ 2·12公分） (通常為10公分χ2·12公分微米） UV波長：200-320微毫米 流量：20毫升/分鐘 注射體積：1毫升；或更佳為0.5毫升 溶劑A : 0.1%甲酸 溶劑B : 95%乙腈+ 5%甲酸；或更通常為99.95%乙腈+ 0.05% 甲酸 梯度液：100% A/1 分鐘，100-80% A/9 分鐘，80-1% A/3.5 分鐘，1% A/1.4 分鐘，MOO% A/0.1 分鐘 中間物輿實例 所有未在以下内文中詳述之試劑，係可市購得自已建立之 供應商，譬如Sigma-Aldrich。關於下文中間物與實例中所提 及之一些起始物質之供應商之地址，如下：The quality-guided preparative HPLC 87841-96〇3〇3_中.doc -109- 1283678 The preparatory column used is Supelcosil ABZplus (10 cm χ 2·12 cm) (usually 10 cm χ 2·12 cm micron) UV wavelength: 200-320 micrometers Flow: 20 ml/min Injection volume: 1 ml; or better 0.5 ml solvent A: 0.1% formic acid solvent B: 95% acetonitrile + 5% formic acid; or more usually 99.95% acetonitrile + 0.05% formic acid gradient: 100% A/1 min, 100-80% A/9 min, 80-1% A/3.5 min, 1% A/1.4 min, MOO% A/0.1 min Intermediate 舆 Example Reagents not detailed in the following texts are commercially available from established suppliers such as Sigma-Aldrich. The addresses of the suppliers of the starting materials mentioned in the following intermediates and examples are as follows:

-ABCR GmbH 公司，KG，P.O· Box 21 01 35, 76151 Karlsruhe，Germany -Aceto Color Intermediates (目錄名稱），Aceto 公司，One Hollow Lane， Lake Success，NY，11042-1215, USA-ABCR GmbH, KG, P.O. Box 21 01 35, 76151 Karlsruhe, Germany - Aceto Color Intermediates (catalog name), Aceto, One Hollow Lane, Lake Success, NY, 11042-1215, USA

-Acros 有機物，Fisher 科學公司之部門，500 American Road, Morris Plains，NJ 07950, USA -Apin 化學品公司，82 C Milton Park，Abingdon，Oxon 0X14 4RY， United Kingdom -Apollo 科學公司，Unit 1A，Bingswood Industrial Estate，Whaley Bridge，-Acros Organics, Division of Fisher Scientific, 500 American Road, Morris Plains, NJ 07950, USA -Apin Chemicals, 82 C Milton Park, Abingdon, Oxon 0X14 4RY, United Kingdom -Apollo Scientific, Unit 1A, Bingswood Industrial Estate, Whaley Bridge,

Derbyshire SK23 7LY，United KingdomDerbyshire SK23 7LY, United Kingdom

Aldrich (目錄名稱），Sigma-Aldrich 公司，Dorset，United Kingdom,電 87841-960303-中.doc -110- 1283678 話：+44 1202 733114; Fax: +44 1202 715460; [email protected];或 -Aldrich (目錄名稱），Sigma-Aldrich 公司，P.O. Box 14508, St· Louis， MO 63178-9916, USA;電話：314-771-5765; fax: 314-771-5757; [email protected];或 -Aldrich (目錄名稱），Sigma·Aldrich ChemieGmbh，Munich，Germany; 電話：+49 89 6513 0; Fax: +49 89 6513 1169; [email protected].Aldrich (catalog name), Sigma-Aldrich, Dorset, United Kingdom, electric 87841-960303-medium.doc-110- 1283678 words: +44 1202 733114; Fax: +44 1202 715460; [email protected]; Or - Aldrich (catalog name), Sigma-Aldrich, PO Box 14508, St. Louis, MO 63178-9916, USA; telephone: 314-771-5765; fax: 314-771-5757; [email protected]; Or - Aldrich (catalog name), Sigma Aldrich ChemieGmbh, Munich, Germany; Tel: +49 89 6513 0; Fax: +49 89 6513 1169; [email protected].

-Alfa Aesar，A Johnson Matthey 公司，30 Bond Street，Ward Hill, MA 01835-8099, USA -Array Biopharma 公司，1885 33rd Street，Boulder，CO 80301，USA -AstaTech 公司，8301 Torresdale Ave” 19C，Philadelphia，PA 19136, USA -Austin 化學公司，1565 Barclay Blvd·，Buffalo Grove, IL 60089, USA - Avocado 研究，Shore Road，Port of Heysham Industrial Park，Heysham Lancashire LA3 2XY，United Kingdom -Bayer AG, Business Group Basic and Fine Chemicals, D-513 68 Leverkusen, Germany-Alfa Aesar, A Johnson Matthey, 30 Bond Street, Ward Hill, MA 01835-8099, USA - Array Biopharma, 1885 33rd Street, Boulder, CO 80301, USA - AstaTech, 8301 Torresdale Ave" 19C, Philadelphia, PA 19136, USA - Austin Chemical Company, 1565 Barclay Blvd,, Buffalo Grove, IL 60089, USA - Avocado Research, Shore Road, Port of Heysham Industrial Park, Heysham Lancashire LA3 2XY, United Kingdom -Bayer AG, Business Group Basic and Fine Chemicals , D-513 68 Leverkusen, Germany

Berk Univar plc，Berk House，P.O.Box 56, Basing View，Basingstoke， Hants RG21 2E6, United Kingdom -Butt Park 公司，Braysdown Works，Peasedown St· John，Bath BA2 8LL， United Kingdom -化學結構單位（目錄名稱），Ambinter，46 quai Louis Bleriot，Paris, F-75016, France -ChemBridge Europe, 4 Clarkfs Hill Rise, Hampton Wood, Evesham, Worcestershire WR11 6FW, United KingdomBerk Univar plc, Berk House, POBox 56, Basing View, Basingstoke, Hants RG21 2E6, United Kingdom - Butt Park, Braysdown Works, Peasedown St. John, Bath BA2 8LL, United Kingdom - Chemical Structure Unit (catalog name), Ambinter, 46 quai Louis Bleriot, Paris, F-75016, France -ChemBridge Europe, 4 Clarkfs Hill Rise, Hampton Wood, Evesham, Worcestershire WR11 6FW, United Kingdom

-ChemService 公司，P.O.Box 3108, West Chester，PA 19381，USA 87841-960303-中.doc -111- 1283678-ChemService, P.O.Box 3108, West Chester, PA 19381, USA 87841-960303-中.doc -111- 1283678

-Combi-Blocks 公司，7949 Silverton Avenue，Suite 915, San Diego, CA 92126, USA -Dynamit Nobel GmbH，Germany;亦可得自：Saville Whittle Ltd (UK agents of Dynamit Nobel), Vickers Street, Manchester M40 8EF, United Kingdom -E. Merck，Gennany;或 E. Merck (Merck Ltd)，Hunter Boulevard，Magna Park, Lutterworth, Leicestershire LEI7 4XN, United Kingdom-Combi-Blocks, Inc., 7949 Silverton Avenue, Suite 915, San Diego, CA 92126, USA - Dynamit Nobel GmbH, Germany; also available from: Saville Whittle Ltd (UK agents of Dynamit Nobel), Vickers Street, Manchester M40 8EF, United Kingdom -E. Merck,Gennany; or E. Merck (Merck Ltd), Hunter Boulevard, Magna Park, Lutterworth, Leicestershire LEI7 4XN, United Kingdom

_ Esprit 化學公司，Esprit Plaza，7680 Matoaka Road，Sarasota，FL 34243， USA -探索圖書館（目錄名稱），Ambinter，46 quai Louis Bleriot，Paris， F-75016, France -Fluka Chemie AG，Industriestrasse 25, P.O. Box 260, CH-9471 Buchs， Switzerland -Fluorochem 公司，Wesley Street，Old Glossop，Derbyshire SK13 7RY， United Kingdom_ Esprit Chemical Company, Esprit Plaza, 7680 Matoaka Road, Sarasota, FL 34243, USA - Discovery Library (catalog name), Ambinter, 46 quai Louis Bleriot, Paris, F-75016, France - Fluka Chemie AG, Industriestrasse 25, PO Box 260, CH-9471 Buchs, Switzerland -Fluorochem Company, Wesley Street, Old Glossop, Derbyshire SK13 7RY, United Kingdom

-ICN 生物醫學公司，3300 Hyland Avenue，Costa Mesa，CA 92626, USA -Interchim Intermediates (目錄名稱），Interchim，213 Avenue Kennedy， BP 1140, Montlucon，Cedex，03103, France 關鍵有機物公司，3, Highfield Indusrial Estate, Camelford，Cornwall PL32 9QZ，United Kingdom-ICN Biomedical Company, 3300 Hyland Avenue, Costa Mesa, CA 92626, USA - Interchim Intermediates (catalog name), Interchim, 213 Avenue Kennedy, BP 1140, Montlucon, Cedex, 03103, France Key Organics, 3, Highfield Indusrial Estate , Camelford, Cornwall PL32 9QZ, United Kingdom

Lancaster 合成公司，Newgate，White Lund，Morecambe，Lancashire LA3 3DY，United Kingdom -Manchester 有機物公司，Unit 2, Ashville Industrial Estate，Sutton Weaver, Runcorn, Cheshire WA7 3PF, United Kingdom 87841-960303-中.doc -112- 1283678 -Matrix Scientific，Ρ·0· Box 25067, Columbia，SC 29224-5067, USA -Maybridge 化學公司，Trevillett，Tintagel，Cornwall PL34 OHW，UnitedLancaster Synthetic Company, Newgate, White Lund, Morecambe, Lancashire LA3 3DY, United Kingdom -Manchester Organics, Unit 2, Ashville Industrial Estate, Sutton Weaver, Runcorn, Cheshire WA7 3PF, United Kingdom 87841-960303-中.doc -112- 1283678 -Matrix Scientific,Ρ·0· Box 25067, Columbia, SC 29224-5067, USA -Maybridge Chemical Company, Trevillett, Tintagel, Cornwall PL34 OHW,United

Kingdom -Maybridge反應性中間物（目錄名稱），Maybridge化學公司， Trevillett, Tintagel, Cornwall PL34 OHW, United Kingdom -微量化學結構單位（目錄名稱），MicroChemistry-RadaPharma， Shosse Entusiastov 56, Moscow，111123, Russia -Miteni S.p.A.，Via Mecenate 90, Milano, 20138, Italy -N.D· Zelinsky 研究所，有機化學，Leninsky prospect 47, 117913 Moscow B-334, RussiaKingdom -Maybridge Reactive Intermediate (catalog name), Maybridge Chemical Company, Trevillett, Tintagel, Cornwall PL34 OHW, United Kingdom - Microchemical Structure Unit (catalog name), MicroChemistry-RadaPharma, Shosse Entusiastov 56, Moscow, 111123, Russia - Miteni SpA, Via Mecenate 90, Milano, 20138, Italy -ND· Zelinsky Institute, Organic Chemistry, Leninsky prospect 47, 117913 Moscow B-334, Russia

-Optimer 結構單位（目錄名稱），Array BioPharma，3200 Walnut Street， Boulder，CO 80301，USA -Peakdale 分子 &amp;3，PeakdaleSciencePark，SheffieldRoad，Chapel-en- le-Frith，High Peak SK23 0PG，United Kingdom -Pfaltz &amp; Bauer 公司，172 East Aurora Street，Waterbury，CT 06708, USA -稀有化學品（目錄名稱），Rare Chemicals GmbH, Schulstrasse 6， 24214 Gettorf, Germany -SALOR (目錄名稱）(Sigma Aldrich稀有化學品資料庫），Aldrich 化學公司，1001 West Saint Paul Avenue，Milwaukee，WI 53233, USA -Sigma (目錄名稱），Sigma-Aldrich 公司，P.O. Box 14508, St. Louis， MO 63178-9916, USA;參閱上文關於&quot;Aldrich”之其他非美國地址 及其他接觸細節 -SIGMA-RBI, One Strathmore Road, Natick, ΜΑ 01760-1312, USA -Synchem OHG Heinrich-Plett-Strasse 40, Kassel, D-34132, Germany 87841-960303-中.doc -113- 1283678 -Syngene 國際 Pvt &amp;3，Hebbagodi，HosurRoad，Bangalore，India·-Optimer structural unit (directory name), Array BioPharma, 3200 Walnut Street, Boulder, CO 80301, USA -Peakdale Molecular &amp; 3, PeakdaleSciencePark, SheffieldRoad, Chapel-en-le-Frith, High Peak SK23 0PG, United Kingdom -Pfaltz &amp; Bauer, 172 East Aurora Street, Waterbury, CT 06708, USA - Rare Chemicals (Catalogue Name), Rare Chemicals GmbH, Schulstrasse 6, 24214 Gettorf, Germany - SALOR (Catalogue Name) (Sigma Aldrich Rare Chemicals Database) ), Aldrich Chemical Company, 1001 West Saint Paul Avenue, Milwaukee, WI 53233, USA - Sigma (catalog name), Sigma-Aldrich, PO Box 14508, St. Louis, MO 63178-9916, USA; see above for &quot Other non-US addresses and other contact details of Aldrich" - SIGMA-RBI, One Strathmore Road, Natick, ΜΑ 01760-1312, USA -Synchem OHG Heinrich-Plett-Strasse 40, Kassel, D-34132, Germany 87841-960303-中.doc -113- 1283678 -Syngene International Pvt &amp; 3, Hebbagodi, HosurRoad, Bangalore, India·

-TCI America，9211 North Harborgate Street，Portland，OR 97203, USA -TimTec 結構單位八，111111^，111〇.，？0 8〇父8941，\6\¥&amp;±，0£19714-8941，USA-TCI America,9211 North Harborgate Street, Portland, OR 97203, USA -TimTec Structural Unit Eight, 111111^, 111〇.,? 0 8〇父8941,\6\¥&amp;±, 0£19714-8941,USA

-Trans World 化學品公司，14674 Southlawn Lane，Rockville，MD 20850, USA 細Ubichem PLC，Mayflower Close，Chandlers Ford Industrial Estate， Eastleigh，Hampshire S053 4AR，United Kingdom - Ultrafine (UFC 公司），Synergy House，Guildhall Close，Manchester Science Park，Manchester Ml5 6SY，United Kingdom 中間物表 中間物 編號 名稱 1 4-氯基_1_乙基-1H-吡唑并[3,4-b]吡啶-5-羧酸乙酯 2 4·乙氧基-1H-吡唑并[3,4-b]吡啶-5-羧酸乙酯 3 1-曱基-4_乙氧基-1H-吡唑并[3,4-b]吡啶·5-羧酸乙酯 4 1_爷基-4_乙氧基-1Η_ρ比吨并[3,4-b&quot;Kb淀-5-幾酸乙酉旨 5 4-氯基-1-苯基-1H-P比峻并[3,4-b]p比咬-5-叛酸乙酉旨 6 1_乙醯基-4-胺基六氫峨淀 7 1-甲基斗胺基六氫吡啶 8 4-胺基四氯喊喃 8A 四氫-2H-哌喃-4_胺鹽酸鹽=4-胺基四氫哌喃鹽酸鹽 9 (R)-(+)-3-胺基四氫吱喃4-甲苯續酸鹽 10 (S)-(-)-3-胺基四氫吱喃4_甲苯續酸鹽 11 四氫-211_硫代哌喃-4_胺 12 四氫-3-嘧吩胺 87841-960303-中.doc -114- 1283678 13 四氫-3-嘧吩胺l，i-二氧化物鹽酸鹽 14 四氫-2H-硫代哌喃_4-胺_1，1_二氧化物鹽酸鹽 15 4-氯基小乙基_1Η-ρ比唾并[3,4_b]吡淀-5-羧酸 16 4-氯基-1-乙基-1H_吡唑并[3,4-b]吡啶_5_羰基氯 17 N_苄基-4-氯基-1-乙基-1H·吡唑并[3,4-b]吡啶-5_甲醯胺 18 4-乳基-1-乙基-N-(2-乙基丁基）_1H-p比吐并[3,4-b]p比淀-5_ 甲醯胺 19 4_氯基_1·乙基-N-(4-氟苯基）·1Η·吡唑并[3,4-b]吡啶-5-甲 醯胺 20 4-氟-N-環戊基-1-乙基-lH-p比峻并[3,4-b]p比淀-5·甲醯胺 21 4_氯基-1-乙基_5_(四氫吡咯_1_基羰基）-iH-吡唑并[3,4-b&gt;比淀 22 4-氯基-1·乙基_N-(吡啶冰基甲基）-1Η-吡唑并[3,4七]吡 啶-5-甲醯胺 23 4-氯基小乙基丙基-1H-P比峻并[3,4_b]p比淀-5-甲醯胺 24 4-氯基-1-乙基-1H-P比峻并[3,4-b]p比淀-5-甲醯胺 25 4-氯基-1-甲基-1H-吡唑并[3,4-b]吡啶-5-羧酸乙酯 26 4·氯基·1·曱基-1H·吡唑并[3,4-b]吡啶_5-羧酸 27 4-氯基-1_甲基-1H-吡唑并[3,4-b]吡啶-5-羰基氯 28 N-节基-4-氣基-1-甲基-lH-p比哇并[3,4-b]峨咬-5-甲醯胺 29 4_氯基-1-甲基_Ν·(4_氟苯基）_1H-吡唑并[3,4_b]吡啶-5_甲 醯胺 30 4-氯基小甲基-Ν·(2-乙基丁基）-1Η-吡唑并[3,4_b]吡啶_5_ 甲醯胺 31 4·氯基小甲基-1H-吡唑并[3,4-b]吡啶-5-甲醯胺 32 1-乙基冰(四氫-2H-哌喃-4·基胺基）-1Η-吡唑并[3,4七]吡 啶-5-羧酸乙酯 33 1-乙基·4·(四氫-2H-哌喃·4·基胺基）-1Η-吡唑并[3,4-b]吡 啶-5-羧酸 34 1-乙基斗[(3S)_四氫呋喃-3-基胺基]-1H·吡唑并[3,4-b]吡 啶-5-羧酸乙酯 87841-96〇3〇3·中.doc -115- 1283678 35 1_乙基_4_[(3R)_四氫呋喃_3_基胺基]-1H-吡唑并[3,4七]吡 啶-5-羧酸乙酯 36 1·乙基-4_(四氫-2H-硫代嗓喃-4-基胺基）-1Η-ρ比峻并 |；3,4-b]吡啶-5-羧酸乙酯 37 1-乙基冰(四氫嘧吩·3-基胺基）_iH_吡唑并[3,4-b]吡啶· 5-羧酸乙酯 38 4-(環丙胺基)-1•乙基-lH-p比峻并[3,4-b]p比咱：-5-叛酸乙酯 39 4-[(1，1-二氧化四氫噻吩-3-基）胺基]-1-乙基·1Η-吡唑并 [3,4-b]吡啶-5-羧酸乙酯 40 4-[(1，1-二氧化四氫-2H-硫代哌喃斗基）胺基]-1-乙基-1H-吡唑并[3,4-b&gt;比啶_5_羧酸乙酿 41 1-乙基-4_[(3S)-四氫呋喃-3_基胺基]-1H-吡唑并[3,4-bH 啶-5-羧酸 42 乙基1 -乙基-4-[(3R)-四氫呋喃-3-基胺基]-1H-吡唑并 [3,4_b]外匕淀-5-幾酸 43 1-乙基冰(四氫-2H-硫代哌喃-4-基胺基）-1Η-吡唑并 [3,4-b]吡啶-5-羧酸 44 1-乙基-4·(四氫嘧吩-3-基胺基）-1Η-吡唑并[3,4-b]吡啶· 5-羧酸 45 4-(環丙胺基）-1_乙基-1H-吡唑并[3,4-b]吡啶-5-羧酸 46 4-[(1，1-二氧化四氫嘧吩-3-基）胺基]小乙基-1H-吡唑并 [3,4-b]吡啶_5_複酸 47 4-[(1，1-二氧化四氫-2H-硫代哌喃_4_基）胺基]小乙基-1H-吡唑并[3,4_b]吡啶-5-羧酸 48 4-(環己胺基比也并[3,4-b&gt;比淀-5-叛酸乙酯 49 4-(環己胺基）-1Η-吡唑并[3+b]吡啶-5-羧酸 50 1-正·丙基-4-(四氫-2H-哌喃-4-基胺基）_1H-吡唑并[3,4七] 吨匕咬 -5-叛酸 51 4-乳基-1-乙基·6_甲基-1H-P比岐并[3,4-b]p比淀·5_ 羧酸乙酯 52 4-(J幕己胺基）-1-乙基-6-甲基-1Η-外b吐并[3,4-b]r比淀_5-. 羧酸 87841-960303-中.doc -116- 1283678 53 1_乙基-6_甲基-4-(四氫-2H-哌喃冰基胺基）-1Η-吡唑并 [3,4-b]吡啶-5-羧酸 54 4-胺基環己酮鹽酸鹽 中間物1 : 4-氣基小乙基-1H-吡唑并P，4-b】吡啶-5-羧酸乙酯 製自市購可得之5-胺基-1-乙基吡唑，如由G· Yu等人在 «/· Μ以/ 2001，44, 1025-1027 中所述：-Trans World Chemicals, 14674 Southlawn Lane, Rockville, MD 20850, USA Fine Ubichem PLC, Mayflower Close, Chandlers Ford Industrial Estate, Eastleigh, Hampshire S053 4AR, United Kingdom - Ultrafine (UFC), Synergy House, Guildhall Close, Manchester Science Park, Manchester Ml5 6SY, United Kingdom Intermediate Table Intermediate No. Name 1 4-Chloro-1_ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester 2 4 · Ethoxy-1H-pyrazolo[3,4-b]pyridine-5-carboxylate ethyl ester 3- 1-indolyl-4_ethoxy-1H-pyrazolo[3,4-b]pyridine · 5-Carboxylic acid ethyl ester 4 1_Yoyl-4_ethoxy-1Η_ρ than tons [3,4-b&quot; Kb lake-5-acid acid ethyl 5-methylchloro-1-phenyl- 1H-P is more than [3,4-b]p than bite-5-repulsive oxime. 6 1_Ethyl-4-amino hexahydroindole 7 1-methylindole-based hexahydropyridine 8 4-aminotetrachloromethane 8A tetrahydro-2H-pyran-4-amine hydrochloride = 4-aminotetrahydropyran hydrochloride 9 (R)-(+)-3-aminotetrahydro 4-Methyl 4-toluene hydrochloride 10 (S)-(-)-3-Aminotetrahydrofurfuryl 4-toluene hydrochloride 11 Tetrahydro-211_thiopipene-4-amine 12 Tetrahydro-3 - thiophene 87841-960303-中.doc -114- 1283678 13 Tetrahydro-3-sulfenylamine 1,i-dioxide hydrochloride 14 Tetrahydro-2H-thiopipene_4-amine_1,1_2 Oxide hydrochloride 15 4-chloro-based small ethyl Η Η-ρ than salido [3,4_b] pyridin-5-carboxylic acid 16 4-chloro-1-ethyl-1H-pyrazolo[3 ,4-b]pyridine_5_carbonyl chloride 17 N-benzyl-4-chloro-1-ethyl-1H·pyrazolo[3,4-b]pyridine-5-formamide 18 4-milk -1-ethyl-N-(2-ethylbutyl)_1H-p than spit[3,4-b]p than pent-5-carbamamine 19 4 _ chloroyl-1 ethyl-N -(4-fluorophenyl)·1Η·pyrazolo[3,4-b]pyridine-5-formamide 20 4-fluoro-N-cyclopentyl-1-ethyl-lH-p ratio [3,4-b]p ratio -5-5·carbamamine 21 4 _ chloro-1-ethyl _5_(tetrahydropyrrole_1-ylcarbonyl)-iH-pyrazolo[3,4-b&gt ; 比淀22 4-chloro-1(ethyl)-N-(pyridyl)methyl-pyrido[3,4-pyridin-5-carboxamide 23 4-chloro-based small ethyl propyl-1H-P is more than [3,4_b]p than yt-5-carbamide 24 4-chloro-1-ethyl-1H-P than [3,4-b]p -5-Mergamine 25 4-chloro-1-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester 26 4 ·Chloryl·1·decyl-1H· Pyrazolo[3,4-b]pyridine-5-carboxylate 27 4-Chloro-1-methyl-1H-pyrazolo[3,4-b]pyridine-5-carbonyl chloride 28 N-nodyl-4-yl-1-methyl-lH-p than wow And [3,4-b]bite-5-carbamamine 29 4_chloro-1-methyl-Ν·(4_fluorophenyl)_1H-pyrazolo[3,4_b]pyridine-5_ Formamide 30 4-Chloromethyl-methyl-(2-ethylbutyl)-1Η-pyrazolo[3,4_b]pyridine_5_carbamimidamide 31 4·Chloromethylmethyl-1H- Pyrazolo[3,4-b]pyridine-5-formamide 32 1-ethyl ice (tetrahydro-2H-piperidin-4-ylamino)-1Η-pyrazolo[3,4-7] Pyridine-5-carboxylate ethyl ester 33 1-ethyl·4·(tetrahydro-2H-pyran-4-ylamino)-1Η-pyrazolo[3,4-b]pyridine-5-carboxylic acid 34 1-ethyl chloro[(3S)_tetrahydrofuran-3-ylamino]-1H·pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester 87841-96〇3〇3·中. Doc -115- 1283678 35 1_Ethyl_4_[(3R)_tetrahydrofuran_3_ylamino]-1H-pyrazolo[3,4-7]pyridine-5-carboxylic acid ethyl ester 36 1·ethyl -4_(tetrahydro-2H-thiopyran-4-ylamino)-1Η-ρ ratio 并||3,4-b]pyridine-5-carboxylic acid ethyl ester 37 1-ethyl ice (four Hydrogen thiophene-3-ylamino)_iH_pyrazolo[3,4-b]pyridine·5-carboxylate ethyl ester 38 4-(cyclopropylamino)-1•ethyl-lH-p ratio [3,4 -b]p than 咱:-5-oleic acid ethyl ester 39 4-[(1,1-dihydrotetraphenylthio-3-yl)amino]-1-ethyl·1Η-pyrazolo[3, 4-b]pyridine-5-carboxylic acid ethyl ester 40 4-[(1,1-dihydrotetrahydro-2H-thiopiperidinyl)amino]-1-ethyl-1H-pyrazolo[ 3,4-b&gt;bipyridine_5_carboxylic acid ethyl 41 1-ethyl-4_[(3S)-tetrahydrofuran-3-ylamino]-1H-pyrazolo[3,4-bH pyridine-5 -carboxylic acid 42 ethyl 1-ethyl-4-[(3R)-tetrahydrofuran-3-ylamino]-1H-pyrazolo[3,4_b]external deuterium-5-acids 43 1-ethyl Ice (tetrahydro-2H-thiopiperazin-4-ylamino)-1Η-pyrazolo[3,4-b]pyridine-5-carboxylic acid 44 1-ethyl-4·(tetrahydrofuran -3-ylamino)-1Η-pyrazolo[3,4-b]pyridine·5-carboxylic acid 45 4-(cyclopropylamino)-1_ethyl-1H-pyrazolo[3,4- b]pyridine-5-carboxylic acid 46 4-[(1,1-dihydrotetramethylenesulfon-3-yl)amino]ethylethyl-1H-pyrazolo[3,4-b]pyridine_5 _Fusic acid 47 4-[(1,1-dihydrotetrahydro-2H-thiopiperan-4-yl)amino]]ethylethyl-1H-pyrazolo[3,4_b]pyridine-5-carboxylate Acid 48 4-(cyclohexylamine ratio also [3,4-b>pyramid-5-oleic acid ethyl ester 49 4-(cyclohexylamino)-1Η-pyrazolo[3+b]pyridine- 5-carboxylic acid 50 1-n-propyl -4-(tetrahydro-2H-piperazin-4-ylamino)_1H-pyrazolo[3,4-7] ton bite-5-rebel 51 4-milyl-1-ethyl·6_ Methyl-1H-P is more than [3,4-b]p than ethyl 5-carboxylate 52 4-(J-hexylamino)-1-ethyl-6-methyl-1Η-external b Sodium [3,4-b]r ratio _5-. carboxylic acid 87841-960303-中.doc-116- 1283678 53 1_ethyl-6-methyl-4-(tetrahydro-2H-pyran Ice-based amino)-1Η-pyrazolo[3,4-b]pyridine-5-carboxylic acid 54 4-aminocyclohexanone hydrochloride intermediate 1 : 4-vapor-based small ethyl-1H-pyridyl Zymbly P,4-b]pyridine-5-carboxylate ethyl ester available from commercially available 5-amino-1-ethylpyrazole, as by G·Y et al. in «/· Μ / 2001 , 44, 1025-1027:

C02Et 中間物2 : 4-乙氧基_1H-吡唑并[3,4-b】吡啶-5-羧酸乙酯 可藉由1-呋喃基甲基衍生物之氧化性***（Se02)製成，如 由 Τ·Μ· Bare 等人在 J· C/zem·, 1989, 32,2561-2573 中所述，（進一 步參考 Zuleski，F. R·，Kirkland，K.R.，Melgar，M· D· ; Malbica, J. Drag, Metab. Dispos,, 1985? 13, 139)C02Et Intermediate 2: 4-Ethoxy-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester can be prepared by oxidative cleavage (Se02) of 1-furylmethyl derivative Cheng, as described by Τ·Μ·Bare et al., J. C/zem., 1989, 32, 2561-2573 (for further reference to Zuleski, F. R., Kirkland, KR, Melgar, M·D· Malbica, J. Drag, Metab. Dispos,, 1985? 13, 139)

t間物3· : 1-甲基-4-乙氧基-1H·吡唑并[3,4-b]吡啶-5-羧酸乙酯tIntermediate 3· : ethyl 1-methyl-4-ethoxy-1H·pyrazolo[3,4-b]pyridine-5-carboxylate

C02Et 將中間物2 (0.47克）與無水碳酸鉀（0.83克）（預先經由在l〇〇°C 下加熱而乾燥）在無水二甲基甲醯胺（DMF)(4毫升）中之混合 物’以碘甲烷（0.26毫升）處理，並激烈攪拌3小時。然後過 -117- 87841·96〇3〇3_中 d〇c 1283678 滤混合物，並使濾液在真空中濃縮，而得殘留油’使其在 二氯甲烷（DCM)(25毫升）與水(25毫升）之間作分液處理。分離 液層，並將水相以另外之DCM (2x25毫升）萃取。使合併之有 機萃液以無水硫酸鈉脫水乾燥，並蒸發成橘色固體，將其 施加至SPE藥筒（矽膠，20克）。使藥筒相繼以EtOAc ·•輕油 (1 : 4、1 : 2及1 : 1)，然後以氯仿：甲醇（49 : 1、19 : 1及 9 : 1)溶離。將含有所要物質之溶離份合併，並在真空中濃 縮，而得中間物 3 (0.165 克）。LCMS 顯示 MH+ = 250 ; Tret = 2.59 分鐘。 ί—間物4 : 1-苄基-4·乙氧基-1Η-吡唑并[3,4-b】吡啶-5-羧酸乙酯C02Et a mixture of Intermediate 2 (0.47 g) and anhydrous potassium carbonate (0.83 g) (previously dried by heating at 10 ° C) in anhydrous dimethylformamide (DMF) (4 mL) Treat with methyl iodide (0.26 mL) and stir vigorously for 3 h. Then, the mixture was filtered through EtOAc-EtOAc (EtOAc) (EtOAc) 25 ml) for liquid separation. The layers were separated and the aqueous extracted with EtOAc EtOAc. The combined organic extracts were dried over anhydrous sodium sulfate and evaporated to an orange solid which was applied to &lt;RTIgt; The cartridges were successively eluted with EtOAc · • light oil (1:4, 1: 2, and 1:1), then chloroform:methanol (49:1, 19:1, and 9:1). The fractions containing the desired material were combined and concentrated in vacuo to give intermediate 3 (0.165 g). LCMS showed MH+ = 250; Tret = 2.59 min. —-Intermediate 4: ethyl 1-benzyl-4-ethoxy-1Η-pyrazolo[3,4-b]pyridine-5-carboxylate

將中間物2 (0.47克）與無水碳酸鉀（0.83克）(預先經由在l〇〇°C 下加熱而乾燥）在無水DMF (4毫升）中之混合物，以溴化苄 (〇·72克）處理，然後激烈攪拌，並於mi下加熱4·5小時。.使 混合物冷卻，接著過濾，並使濾液在真空中濃縮，·而得殘 留油，使其在DCM (25毫升）與水(25毫升）之間作分液處理。 分離液層，並將水相以另外之DCM (2x25毫升）萃取。使合併 之有機萃液以無水硫酸鈉脫水乾燥，並蒸發成黃色油性固 體，使其溶於DCM中，並施加至SPE藥筒（矽膠，20克）。將 藥筒以EtOAc :輕油梯度液（1 : 4、1 : 2及1 : 1)，然後以氯仿 甲醇（49: 1、19 : 1及9: 1)溶離。將含有所要物質之溶離份 合併，並於真空中濃縮，而得中間物4 (〇·33克）。LCMS顯示 87841-%〇3〇3-中.doc -118- 1283678 MH =326; tret==3.24分鐘。 +聞物5_ : 氣基小苯基_1H-吡唑并[3,4_b]吡啶_5_羧酸乙酯Mixture of intermediate 2 (0.47 g) with anhydrous potassium carbonate (0.83 g) (previously dried by heating at 10 ° C) in dry DMF (4 ml) to benzyl bromide (72 g) ), then vigorously stirred and heated at mi for 4.5 hours. The mixture was allowed to cool, then filtered, and the filtrate was concentrated in vacuo to afforded oil, which was partitioned between DCM (25 mL) and water (25 mL). The layers were separated and the aqueous extracted with EtOAc EtOAc. The combined organic extracts were dried over anhydrous sodium sulfate and evaporated to a yellow oily solid, which was dissolved in DCM and applied to the SPE cartridge (20 g). The cartridge was eluted with EtOAc:light oil gradients (1:4, 1:2, and 1:1) then chloroform methanol (49:1, 19:1 and 9:1). The fractions containing the desired material were combined and concentrated in vacuo to give Intermediate 4 (······ LCMS showed 87841-% 〇3 〇3-med. doc -118-1283678 MH = 326; tret == 3.24 min. + smell 5_ : gas-based small phenyl_1H-pyrazolo[3,4_b]pyridine-5-carboxylic acid ethyl ester

將5-胺基_丨_苯基吡唑（2〇克）與乙氧基亞甲基丙二酸二乙酯 (2·54毫升）之混合物，於Dean Stark條件下，在120°C下加熱16 小時。使落液冷卻，然後添加氯化磷醯（16毫升），並將混合 物於回泥下再加熱20小時。在真空中移除過量氯化磷醯， 並使殘留物於***與水之間作分液處理，於添加水時，極 ‘田心地進行。將含醚層以另外之水洗條，接著以硫酸鍰 脫水乾燥，及在真空中濃縮，而得孓氯基小苯基_1H_吡唑并 [3,4七]批淀_5-羧酸乙酯（2.〇9克）。〇：]\48顯示]\411+=302; Tret= 3.80 分鐘。 中W—物6 : 1-乙醯基_4_胺基六氫吡啶 I自市購可得之N1-爷基-4-胺基六氫p比淀，如由Yama(ja等人 在WO 00/42011中所述：a mixture of 5-amino-p-phenylpyrazole (2 g) and diethyl ethoxymethylenemalonate (2. 54 ml) under Dean Stark conditions at 120 ° C Heat for 16 hours. The falling liquid was allowed to cool, then cesium chloride (16 ml) was added, and the mixture was further heated under reflux for 20 hours. Excess phosphorus ruthenium chloride was removed in vacuo, and the residue was partitioned between diethyl ether and water. When water was added, it was carried out in a very strong manner. The ether-containing layer is washed with additional water, followed by dehydration drying with barium sulfate, and concentration in vacuo to give a chloro-phenyl small phenyl-1H-pyrazole [3,4] batch of _5-carboxylic acid. Ethyl ester (2. 〇 9 g). 〇:]\48 shows]\411+=302; Tret= 3.80 minutes. W-form 6: 1-Ethyl 4-_aminopyridinium I commercially available N1-aryl-4-amine hexahydro-p-precipitate, as by Yama (ja et al. in WO As stated in 00/42011:

中間物7 : 1_甲基_4_胺基六氫吡啶 製自市購可得之N-甲基_4_六氫吡啶酮，如由CM. An(jersson 等人在WO 01/66521中所述： 87841_96〇3〇3·中.doc -119- 1283678Intermediate 7 : 1 -methyl 4 -aminohexahydropyridine is commercially available from N-methyl 4 -hexahydropyridone as obtained by CM. An (jersson et al. in WO 01/66521 Said: 87841_96〇3〇3·中.doc -119- 1283678

中間物8 : 4-胺基四氫哌喃 可市賭得自 Combi_Blocks 公司，7949 Silverton Avenue，Suite 915, San Diego, CA5 92126, USA (CAS 38041-19-9) H2N- 土^閑物8A ：四氫-2H-哌喃-4-胺鹽酸鹽=4_胺基四氫哌喃鹽酸里Intermediate 8: 4-Aminotetrahydropyranone available from Combi_Blocks, Inc., 7949 Silverton Avenue, Suite 915, San Diego, CA5 92126, USA (CAS 38041-19-9) H2N- Soils 8A: Tetrahydro-2H-piperazin-4-amine hydrochloride = 4_aminotetrahydropyranidine hydrochloride

步驟1 : N^f-二苄基四氫-2H-哌喃斗胺 於0°C至5°C下，將二芊胺（34.5克）與醋酸（6.7毫升）添加至四 氫-4H·哌喃-4-酮（16.4克，可市購得自例如Aldrich)在二氣甲烷 (260毫升）中之經攪拌溶液内。於〇〇c至5。〇下2.5小時後，分 次添加三乙醯氧基硼氫化鈉（38·9克），並使混合物溫熱至室 溫。在室溫下攪拌過夜後，將反應混合物連續以2Μ-氫氧化 鈉（200毫升與50毫升）、水(2x50毫升）及鹽水（50毫升）洗滌， 然後脫水乾燥，並蒸發，獲得黃色油（45克）。於4°C下，將 此油與甲醇（50毫升）一起攪拌30分鐘，而得產物，為白色固 體（21.5 克）。LCMS顯示 MH+=282; Tret=1.98 分鐘。 步驟2 ··四氬戒喃+胺盪酸螫 在100 psi及室溫下，使n，N-二苄基四氫-2H-哌喃-4-胺（20.5克） 溶於乙醇（210毫升）與氫化10%鈀/碳觸媒（4克）中，歷經72 87841-96〇3〇3·中.doc -120- 1283678 小時。過濾反應混合物，並以在***中之2M-氯化氫’將濾 液調整至pH值1。蒸發溶劑，獲得固體，將其以***研製， 獲得產物，為白色固體（9.23克）。d6-DMSO 中，27°C，5 ppm)8.24(寬廣 s，3H)，3.86(dd，12,4Hz，2H)，3.31(dt，2, 2Hz，2H)，3.20 (m，1H)，1.84 (m，2H)，1.55 (dq，4, 12Hz，2H)· 中間物9 : (R)-(+)-3-胺基四氫呋喃4_甲苯磺酸鹽 可市購得自 FlukaChemieAG，Germany (CAS 111769-27-8)Step 1: N^f-dibenzyltetrahydro-2H-piperidinamine Diamine (34.5 g) and acetic acid (6.7 ml) were added to tetrahydro-4H at 0 ° C to 5 ° C. Piper-4-one (16.4 g, commercially available, for example, from Aldrich) in a stirred solution of di-methane (260 mL). From 〇〇c to 5. After 2.5 hours of sputum, sodium triethoxysulfonate (38.9 g) was added in portions and the mixture was allowed to warm to room temperature. After stirring at room temperature overnight, the reaction mixture was washed successively with EtOAc EtOAc EtOAc (EtOAc (EtOAc) 45 grams). This oil was stirred with methanol (50 ml) at 4 ° C for 30 minutes to give a white solid (21.5 g). LCMS showed MH+ = 282; Tret = 1.98 min. Step 2 ····················································· And with hydrogenated 10% palladium/carbon catalyst (4 g), after 72 87841-96 〇 3 〇 3 · medium .doc -120 - 1283678 hours. The reaction mixture was filtered, and the filtrate was adjusted to pH 1 with 2M-hydrogen chloride in diethyl ether. The solvent was evaporated to give a crystal. In d6-DMSO, 27 ° C, 5 ppm) 8.24 (broad s, 3H), 3.86 (dd, 12, 4 Hz, 2H), 3.31 (dt, 2, 2 Hz, 2H), 3.20 (m, 1H), 1.84 (m, 2H), 1.55 (dq, 4, 12 Hz, 2H) · Intermediate 9: (R)-(+)-3-Aminotetrahydrofuran 4-tosylate is commercially available from FlukaChemie AG, Germany (CAS 111769-27-8)

中間物10 : (S)&lt;-)_3_胺基四氨咬响4·甲苯確酸鹽 可市講得自 Ε· Merck，Germany ;或 Ε· Merck (Merck 公司），Hunter Boulevard，Magna Park，Lutterworth，Leicestershire，LEI7 4XN，United Kingdom (CAS 104530-80-5)Intermediate 10: (S)&lt;-)_3_Amino-Ammonia Bitter 4·Toluene-deposited acid can be obtained from Merck, Germany; or Ε· Merck (Merck), Hunter Boulevard, Magna Park , Lutterworth, Leicestershire, LEI7 4XN, United Kingdom (CAS 104530-80-5)

中間物11 :四氫-2H-硫代哌喃·4_胺 製自市購可得之四氫硫代喊喃-4_酮，如由Subramanian等人， ·/· Og· 1981，46,4376-4383中所述。其鹽酸鹽之後績製備可 藉習用方式達成。Intermediate 11: tetrahydro-2H-thiopiperan-4-amine is commercially available from tetrahydrothiopyran-4-one, as by Subramanian et al., /. Og. 1981, 46, Said in 4376-4383. The preparation of the hydrochloride salt can be achieved by conventional means.

中間物12 :四氫-3_，塞吩胺 87841-960303-中.doc -121 - 1283678 以類似中間物11之方式，製自市購可得之四氫達吩-4-酮。 月亏形成係由Grigg等人，及的心办叫1991，47,4477-4494描述，而月亏 還原作用係由 Unterhalt 等人，drc/z. 1990, 317-318 描述。Intermediate 12: tetrahydro-3_, phenoxyamine 87841-960303-中.doc -121 - 1283678 Prepared from commercially available tetrahydrodaphen-4-one in a manner similar to intermediate 11. The formation of the monthly deficit is described by Grigg et al., and the heart is called 1991, 47, 4477-4494, and the monthly reduction is described by Unterhalt et al., drc/z. 1990, 317-318.

土間物13 :四氫_3_嘧吩胺1，1_二氧化物鹽酸鹽 可市購得自稀有化學品之Sigma Aldrich資料庫（SALOR)(CAS-6338-70-1)。胺鹽酸鹽之製備可藉習用方式達成。Interstitial 13: Tetrahydro-3-pyrimidinamine 1,1-dioxide hydrochloride Commercially available from the Sigma Aldrich database of rare chemicals (CASLOR) (CAS-6338-70-1). The preparation of the amine hydrochloride can be achieved by conventional means.

_中間物14 :四氫-211_硫代哌喃·4-胺-1，1-二氧化物鹽酸鹽 以類似中間物11之方式，製自市購可得之四氫嘧吩斗酮。 氧化成1，1-二S同基·四氮-1 λ6-硫代喊喃-4-嗣，係由Rule等人在 J· Org· C/zem·，1995, 60,1665-1673 中描述。肟形成係由 Truce 等人在 */· Og· C/zem·，1957, 617, 620 中描述，而妨還原作用係由 Barkenbus 等人，dm· &amp;c·，1955, 77, 3866描述。胺鹽酸鹽之後續製備 可藉習用方式達成。_ Intermediate 14: tetrahydro-211-thiopipene 4-amine-1,1-dioxide hydrochloride in a similar manner to intermediate 11 from commercially available tetrahydropyrimidin . Oxidation to 1,1-di-S-synyltetraki-1 λ6-thiopyran-4-yl is described by Rule et al., J. Org. C/zem., 1995, 60, 1665-1673. . The 肟 formation system is described by Truce et al. in */· Og·C/zem·, 1957, 617, 620, and the reduction is described by Barkenbus et al., dm· &amp;c., 1955, 77, 3866. Subsequent preparation of the amine hydrochloride can be accomplished by conventional means.

中間物15 : 4-氣基-1_乙基·1Η·竹I;攻并[3,4_b】p比咬_5·•叛酸 87841-960303-中.doc -122- 1283678Intermediate 15: 4-gasyl-1_ethyl·1Η·Bamboo I; attack and [3,4_b]p ratio bite_5·•rebel acid 87841-960303-中.doc -122- 1283678

N^Tl&quot;C〇2HN^Tl&quot;C〇2H

Et 將中間物明克）在二氧陸圜（28毫升）中之溶液，以氫氧 化钾⑹克）作成在水(2〇毫升）中之溶液處理。將混合㈣摔 、J時”、：後於真空中丨辰縮，以2M鹽酸水溶液酸化至阳3， 並乂醋酸乙酉曰萃取。分離液層，使有機層以硫酸鈉脫水乾 燥接著在真2中濃縮，而得中間物15，為白色固體（2.4 克）。LCMS 顯示 MH+=226; Tret = 2.62 分鐘。 土-MA1Z · N-子基_4·氣醛，三氣乙醛-乙基_1H_吡唑并[3,4-b】吡 淀-5-甲酿胺Et was treated with a solution of the intermediate in dimethylamine (28 ml) in the form of potassium hydroxide (6 g) in water (2 mL). Mixing (four) falls, J time", and then squeezing in a vacuum, acidifying to a positive 3 with a 2M aqueous solution of hydrochloric acid, and extracting with acetonitrile. The liquid layer is separated, and the organic layer is dried with sodium sulfate and then dried. Concentrated to give intermediate 15 as a white solid (2.4 g). LCMS: MH+ = 226; T ret = 2.62 min. s. 1H_pyrazolo[3,4-b]pyrazine-5-cartoamine

使中間物15 (3.5克）以五氧化二磷脫水乾燥1小時，然後以 二氯化亞硫醯（47克）處理。攪拌混合物，並於75°c下加熱L3 小時。於真空中移除過量二氯化亞硫醯，並使殘留油與二 氣甲燒(DCM) —起共沸，而得中間物16，假設為中間物15之 氣化醯衍生物，為白色固體（3·3克）。 使中間物16 (0.473克）溶於四氫呋喃（THF)(4毫升）中，並以 N，N_二異丙基乙胺（dipea)(0.509毫升），然後以苄胺（0.209克） 處理，且將混合物於氮氣下攪拌0.5小時。使混合物在真空 87841-960303-中.doc -123- 1283678 中濃縮，然後於二氯甲烷與水之間作分液處理。分離液層， 並使有機物質於真空中濃縮，而得中間物17 (0.574克）。 LCMS 顯示MH+=315; Tret = 2.90 分鐘。 以類似方式製備下列物質：Intermediate 15 (3.5 g) was dehydrated and dried with phosphorus pentoxide for 1 hour and then treated with sulfinium dichloride (47 g). The mixture was stirred and heated at 75 ° C for 3 hours. Excess ruthenium dichloride was removed in vacuo, and the residual oil was azeotroped with dimethyl ketone (DCM) to give intermediate 16 which was assumed to be a gasified hydrazine derivative of intermediate 15 in white. Solid (3.3 g). Intermediate 16 (0.473 g) was dissolved in THF (4 mL) EtOAc (EtOAc) The mixture was stirred under nitrogen for 0.5 hours. The mixture was concentrated in vacuo 87841-960303-M. doc-123-1283678 and then partitioned between dichloromethane and water. The layers were separated and the organic material was concentrated in vacuo to afford Intermediate 17 (0.574 g). LCMS showed MH+ = 315; Tret = 2.90 min. The following materials were prepared in a similar manner:

NR4R5 胺試劑 MH+離子 TreiT(分鐘） 中間物18 2-乙基丁基胺 309 3.07 中間物19 4-氟苯胺 319 3.08 中間物20 广广NH 環戊胺 293 2.76 中間物21 四氫吡咯 279 2.46 中間物22 : 4_氣基-1_乙基(吡啶-4_基甲基）·1Η_吡唑并[3,4-b]吡 啶-5-甲醯胺NR4R5 Amine Reagent MH+ Ion TreiT (min) Intermediate 18 2-Ethylbutylamine 309 3.07 Intermediate 19 4-Fluoroaniline 319 3.08 Intermediate 20 Wide NH Cyclopentylamine 293 2.76 Intermediate 21 Tetrahydropyrrole 279 2.46 Intermediate 22: 4_gas- 1 -ethyl (pyridin-4-ylmethyl)·1Η-pyrazolo[3,4-b]pyridine-5-carboxamide

氯化醯中間物16係使用上文關於中間物π所示之方法，合 成自中間物15。使中間物16 (0.473克）溶於THF (4毫升）中，並 以二異丙基乙胺（DIPEA)(0.509毫升），然後以4-(胺基曱基）外b啶 (0.211克）處理，且將混合物於氮氣下攪拌〇·5小時。使混合物 在真空中濃縮，接著於DCM與水之間作分液處理。分離液 層，並於真空中濃縮有機物質，然後施加至SPE藥筒（矽 膠，1〇克），將其以環己烷：EtOAc梯度液(2 : 1，逐步漸增高 87841-96〇3〇3_ 中.doc -124- 1283678 至〇 : 1)，接著以MeOH : EtOAc (5 : 95,然後10 : 90)溶離。將含 有所要物質之溶離份合併，並於真空中濃縮，而得中間物 22 (0.086 克）。LCMS 顯示MH+=316; Tret=1.84 分鐘。 土間物23 · 4-氣基_1_乙基-N-正-丙基-1H_p比唆并[3,4-b]〃比淀-5-甲 醯胺The ruthenium chloride intermediate 16 is synthesized from the intermediate 15 using the method shown above for the intermediate π. Intermediate 16 (0.473 g) was dissolved in THF (4 mL) eluted with diisopropylethylamine (DIPEA) (0.509 mL) and then 4-(amino thiol) b-pyridine (0.211 g) Treated and the mixture was stirred under nitrogen for 5 hours. The mixture was concentrated in vacuo and then partitioned between DCM and water. The layers were separated and the organic material was concentrated in vacuo and then applied to a EtOAc EtOAc EtOAc (EtOAc) 3_中.doc -124-1283678 to 〇: 1), followed by dissolution with MeOH: EtOAc (5: 95, then 10: 90). The fractions containing the desired material were combined and concentrated in vacuo to give intermediate 22 (0.086 g). LCMS showed MH+ = 316; Tret = 1.84 min. Interstitial 23 · 4-Alkyl_1_ethyl-N-n-propyl-1H_p is more than [3,4-b]pyrene~-5-methylamine

氯化醯中間物16係使用上文關於中間物17所示之方法，合 成自中間物15。使中間物16 (0.473克）溶於THF (4毫升）中，並 以DIPEA (0.509毫升），然後以正-丙基胺（0.115克）處理，且將 混合物於氮氣下攪拌0.5小時。接著添加另一份正-丙基胺 (0.023克），並持續攪拌18小時。使混合物在真空中濃縮，然 後於DCM與水之間作分液處理。分離液層，並使有機物質 在真空中濃縮，而得中間物23 (0.405克）。LCMS顯示 MH+ = 267 ; TRET = 2.54 分鐘。 中間物24 : 4-氣基·1·乙基-1H-吡唑并[3,4_b]吡啶_5_甲醯胺The ruthenium chloride intermediate 16 is synthesized from the intermediate 15 using the method described above for the intermediate 17. Intermediate 16 (0.473 g) was dissolved in THF (4 mL) EtOAc (EtOAc) Then another portion of n-propylamine (0.023 g) was added and stirring was continued for 18 hours. The mixture was concentrated in vacuo and then partitioned between DCM and water. The layers were separated and the organic material was concentrated in vacuo to afford Intermediate 23 (0.405 g). LCMS showed MH+ = 267; TRET = 2.54 min. Intermediate 24: 4-Alkyl·1·Ethyl-1H-pyrazolo[3,4_b]pyridine_5-carboxamide

氯化醯中間物16係使用上文關於中間物17所示之方法，合 成自中間物15。使中間物16 (0.30克）溶於THF (3毫升）中，並 以氨在二氧陸圜中之0.5M溶液（4.92毫升）處理。將混合物於 氮氣下攪拌18小時。添加另一份二氧陸圜中之〇·5Μ氨(4.92毫 87841-96〇3〇3-中.doc -125- 1283678 升），並持續攪拌72小時。在真空中濃縮混合物，並使殘留 物於DCM與2M氫氧化鈉溶液之間作分液處理。分離液層， 並濃縮有機物質，而得中間物24 (0.278克）。LCMS顯示 MH — 225 &gt; Tr e τ = 2.10 分鐘。 土··間物25 : 4-氣基-1_甲基-1H-吡唑并[3,4-b]吡啶-5-羧酸乙酯The ruthenium chloride intermediate 16 is synthesized from the intermediate 15 using the method described above for the intermediate 17. Intermediate 16 (0.30 g) was dissolved in THF (3 mL) and EtOAc (EtOAc) The mixture was stirred under nitrogen for 18 hours. Add another portion of hydrazine in the dioxane to 5 Μ ammonia (4.92 mM 87841-96 〇 3 〇 3-中 .doc -125-1283678 liters) and continue to stir for 72 hours. The mixture was concentrated in vacuo and the residue was partitioned between DCM and 2M sodium hydroxide. The layers were separated and the organic material was concentrated to give intermediate 24 (0.278 g). LCMS showed MH - 225 &gt; Tr e τ = 2.10 minutes. Earth··Interstitial 25 : 4-methyl-l-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester

將5-胺基-1-甲基吡唑（4.〇克）與乙氧基亞甲基丙二酸二乙酯 (9.16當升）之混合物，在i5〇°c下，於Dean Stark條件下加熱5小 時。將氯化磷醯（55毫升）小心添加至混合物中，並將所形成 之溶液於130。(：及回流下加熱18小時。於真空中濃縮混合 物，然後使殘留油在冰浴中冷卻，並小心地以水（100毫升） 處理（注意：放熱）。以DCM (3x100毫升）萃取所形成之混合 物’並使合併之有機萃液以無水硫酸鈉脫水乾燥，及在真 空中濃縮。使殘留固體藉Biotage層析（碎膠，90克）純化，以 EbO :輕油（1 : 3)溶離。將含有所要物質之溶離份合併，並 於真空中濃縮，而得中間物25 (4.82克）。LCMS顯示 = 240 ; TRET = 2.98 分鐘。 土間物26 : 4-氣基小甲基-1H-〃比攻并[3,4-b】P比咬-5-叛酸Mixture of 5-amino-1-methylpyrazole (4. gram) with diethyl ethoxymethylenemalonate (9.16 liters) at i5 ° C under Dean Stark conditions Heat for 5 hours. Phosphine chloride (55 ml) was carefully added to the mixture, and the resulting solution was at 130. (: and heating under reflux for 18 hours. The mixture was concentrated in vacuo, then the residue was evaporated in EtOAc EtOAc EtOAc (EtOAc) And the combined organic extracts were dried over anhydrous sodium sulfate and concentrated in vacuo. The residual solid was purified by Biotage chromatography (gels, 90 g) eluting with EbO: light oil (1:3) The fractions containing the desired material were combined and concentrated in vacuo to give Intermediate 25 (················ 〃比攻和[3,4-b]P than bite-5-rebel

將中間物25 (4.0克）在二氧陸圜（3〇毫升）中溶液，以氫氧化 87841-960303-中.doc -126 - 1283678 鉀（7.54克）作成在水(20毫升）中之溶液處理。將混合物攪拌 16小時，然後以水（150毫升）稀释，並以5M鹽酸水溶液酸化 至pH3。將混合物於冰浴中攪拌15分鐘，接著藉過濾收集， 以冰冷水洗滌，及在真空中以五氧化二磷脫水乾燥，而得 中間物26，為白色固體（2.83克）。LCMS顯示MH+=212 ; Tret = 2.26 分鐘。 _也間物28 ·· N-爷基-4·氣基_1_甲基比峻并[3,4-b】峨淀_5_甲酿 胺A solution of the intermediate 25 (4.0 g) in dioxane (3 mL) was used as a solution in water (20 mL) with a solution of 78,418-960, 303 - doc - 126 - 1283 678 (7.54 g). deal with. The mixture was stirred for 16 hours, then diluted with water (150 mL) and acidified to pH 3 with 5M aqueous hydrochloric acid. The mixture was stirred in an ice-bath for 15 min then EtOAc (EtOAc)EtOAc. LCMS showed MH+ = 212; Tret = 2.26 min. _also a substance 28 ··································

將中間物26 (2.5克）（預先以五氧化二磷脫水乾燥）以二氯化 亞硫醯（25毫升）處理，並將混奋物於回流下加熱1小時。於 真空中移除過量二氯化亞硫醯，而得中間物27，假設為中 間物26之氣化醯衍生物，為白色固體（2 7克）。 使中間物27 (0.68克）溶於THF (10毫升）中，並以DIPEA (0.77 毫升）’然後以苄胺（0.339克）處理，且將混合物在氮氣下攪 拌3小時。於真空中濃縮混合物，然後於dcm (20毫升）與水 (10毫升）之間作分液處理。分離液層，並使有機物質在真空 中濃縮’而得中間物28(0.90克）。LCMS顯示MH+= 301 ; Tret= 2.72 分鐘。 以類似方式製備下列物質： 87841-960303-中.doc -127- 1283678The intermediate 26 (2.5 g) (dehydrated in advance with phosphorus pentoxide) was treated with sulfinium dichloride (25 ml), and the mixture was heated under reflux for 1 hour. Excess ruthenium dichloride was removed in vacuo to give intermediate 27 as a gasified hydrazine derivative of intermediate 26 as a white solid (27 g). Intermediate 27 (0.68 g) was dissolved in THF (10 mL) eluting with EtOAc (EtOAc) The mixture was concentrated in vacuo and then partitioned between dcm (20 mL) and water (10 mL). The liquid layer was separated and the organic material was concentrated in vacuo to afford Intermediate 28 (0.90 g). LCMS showed MH+ = 301; Tret = 2.72 min. The following materials were prepared in a similar manner: 87841-960303-中.doc -127- 1283678

nr4r5 胺試劑 MH+離子 Tret(分鐘） 中間物29 4-氟苯胺 305 2.91 中間物30 hn^j^ 2-乙基丁基胺 295 2.97 ί__間物31 : 4-氯基-1·甲基-1Η_峨咬并[3,4-b】峨違_5-甲酿胺Nr4r5 amine reagent MH+ ion Tret (minutes) intermediate 29 4-fluoroaniline 305 2.91 intermediate 30 hn^j^ 2-ethylbutylamine 295 2.97 ί__interstitial 31 : 4-chloro-1 -methyl 1Η_峨bit and [3,4-b]峨 violation_5-甲甲胺

'Γ ^ Me νη2 氯化醯中間物27係使用上文關於中間物28所示之方法，合 成自中間物26。然後，將中間物27 (0.68克）以氨在二氧陸圜 中之0.5M溶液（17.7毫升）處理。接著添加二異丙基乙胺（0 51 毫升），並將混合物攪拌21小時。然後，使混合物於 DCM (100毫升）與水(30毫升）之間作分液處理。藉過濾移除不 溶性固體，以水（20毫升）洗滌，及在真空中以五氧化二磷脫 水乾燥，而得中間物31 (0.544克）。LCMS顯示MH+ = 211 ; Tret=1.84 分鐘。 土間物32 (=實例3) : 1-乙基斗(四氫_2H-哌喃斗基胺基）-1Η-吡唑 并[3,4-b】吡啶-5_羧酸乙酯'Γ ^ Me νη2 ruthenium chloride intermediate 27 was synthesized from the intermediate 26 using the method shown above for the intermediate 28. Intermediate 27 (0.68 g) was then treated with a 0.5 M solution (17.7 mL) of ammonia in dioxane. Then diisopropylethylamine (0 51 ml) was added and the mixture was stirred for 21 hours. Then, the mixture was subjected to liquid separation between DCM (100 ml) and water (30 ml). The insoluble solid was removed by filtration, washed with water (20 mL) and dried with EtOAc EtOAc EtOAc LCMS showed MH+ = 211; Tret = 1.84 min. Soil 32 (=Example 3): 1-ethylidene (tetrahydro-2H-piperidinylamino)-1Η-pyrazole and [3,4-b]pyridine-5-carboxylic acid ethyl ester

C〇2EtC〇2Et

87841-960303-ψ.άοο 128- 1283678 使中間物1 (0·20克）與三乙胺（0.55毫升）懸浮於乙醇（8毫升） 中，並添加4-胺基四氫哌喃（0.088克）。將混合物於氮氣及8〇 °C下攪拌加熱16小時，然後在真空中濃縮。使殘留物於 DCM與水之間作分液處理。分離液層，並將有機層直接裝 填於SPE藥筒（矽膠，5克）上，將其相繼以；（i)DCM，(ii) DCM: Et20(2: l)，(iii)DCM: Et20(l: l)，(iv)Et20 及（v)EtOAc 溶 離。將含有所要物質之溶離份合併，並於真空中濃縮，而 得中間物32(0.21克）。1^]^顯示腿+=319;1^丁 = 2.93分鐘。 土^物33 : 1_乙基-4-(四氫-2H-喊喃-4-基胺基比吐并[3,4-b] 吡啶-5-羧酸87841-960303-ψ.άοο 128- 1283678 Intermediate 1 (0·20 g) and triethylamine (0.55 ml) were suspended in ethanol (8 ml) and 4-aminotetrahydropyran (0.088 g) was added. ). The mixture was heated with stirring under nitrogen at 8 ° C for 16 hours and then concentrated in vacuo. The residue was subjected to liquid separation between DCM and water. The liquid layer was separated and the organic layer was directly loaded onto an SPE cartridge (5 g), which was successively used; (i) DCM, (ii) DCM: Et20 (2: 1), (iii) DCM: Et20 (l: l), (iv) Et20 and (v) EtOAc were dissolved. The fractions containing the desired material were combined and concentrated in vacuo to afford Intermediate 32 (0.21 g). 1^]^ shows the leg += 319; 1 ^ Ding = 2.93 minutes. Soil 33: 1_ethyl-4-(tetrahydro-2H- sher-4-ylamino)pyrazine[3,4-b]pyridine-5-carboxylic acid

將中間物32 (0.21克）在乙醇：水（95 : 5，10毫升）中之溶 液’以氮乳化鋼（0.12克）處理。將混合物於5〇。〇下加熱8小 時，然後在真空中濃縮，溶於水中，及以酷酸酸化至pH 4。 藉過滤移除所形成之白色固體，並於真空下乾燥，而得中 間物33，為灰白色固體（0.156克）。LCMS顯示MH+ = 291 ; Tret= 2.11 分鐘。 土.間物34 (=.宜例.g) : 1_乙基-4_[(38)_四氫呋喃-3-基胺基】-1H-吡唑 并[3,4_b]吡啶-5-羧酸乙酯 87841_960303·中.doc -129- 1283678The solution of Intermediate 32 (0.21 g) in ethanol: water (95: 5, 10 mL) was treated with nitrogen emulsified steel (0.12 g). The mixture was taken at 5 Torr. Heated under the arm for 8 hours, then concentrated in vacuo, dissolved in water, and acidified to pH 4 with EtOAc. The white solid which formed was removed by filtration and dried under vacuo to give intermediate material 33 as pale white solid (0.156 g). LCMS showed MH+ = 291; Tret = 2.11 min. Soil. 34 (=.1.): 1_Ethyl-4_[(38)_tetrahydrofuran-3-ylamino]-1H-pyrazolo[3,4_b]pyridine-5-carboxylic acid Ethyl ester 87841_960303·中.doc -129- 1283678

NHRJNHRJ

C〇2Et 中間物 34 NHR3= HN.n..&lt;Qj 使中間物1 (0.05克）與（S)_㈠_3_胺基四氫呋喃冬曱苯磺酸鹽 (0.052克）懸浮於乙醇（1毫升）中，並添加三乙胺（〇14毫升）。 將混合物於氮氣下攪拌，並在8(rc下加熱24小時。於冷卻至 室溫後，在氮氣流下藉蒸發移除4，並使殘留物於觀(2 毫升）與水（1.5毫升）之間作分液處埋。分離液層，並使有機 層濃縮至乾酒。使用SPE藥筒（矽膠，5克）進行純化，以 EtOAc:環己烷梯度液（1: 16,然後1: 8l: 4i: 21: 1及1: 〇)溶離。將含有所要物質之溶離份合併，並於真空中濃縮， 而得中間物34匕^^(0.052克）。LCMS顯示; Tret= 2.70 分鐘。 以類似方式製備下列物質： NHR3C〇2Et Intermediate 34 NHR3= HN.n..&lt;Qj. Intermediate 1 (0.05 g) and (S)_(I)_3_Aminotetrahydrofuran oxime sulfonate (0.052 g) were suspended in ethanol (1 ml) Medium and add triethylamine (〇 14 ml). The mixture was stirred under nitrogen and heated at 8 (rc) for 24 hours. After cooling to room temperature, 4 was removed by evaporation under a stream of nitrogen, and the residue was taken from (2 mL) and water (1. The mixture was separated and the layers were separated and the organic layer was concentrated to dryness. Purified using EtOAc EtOAc: EtOAc (EtOAc) : 4i: 21: 1 and 1: 〇) Dissolution. The fractions containing the desired material were combined and concentrated in vacuo to give EtOAc (EtOAc: EtOAc) The following materials were prepared in the same manner: NHR3

胺試劑 MH+離子 Tr E T (分 、 中間物35 ί=實例9) /NH —----- (R)-(+&gt;3_胺基四 氫呋喃4-甲笨 磺酸鹽 305 JIX JCi X ' ^SEm / 2.73 中間物36 0=實例10) ηνΌ 中間物11 335 3.21 中間物37 (=實例11) ΝΗ 中間物12 321 3.10 87841-960303-中.doc -130- 1283678 中間物38 (=會例12) 久NH 環丙基胺 275 2.98 _中間物39(= Ui 13) ·· 4_[(1，[二氧化四氫嘧吩-3-基）胺基]小乙 基-1H_吡唑并[3,4-b】吡啶_5_羧酸乙酯Amine reagent MH+ ion Tr ET (minute, intermediate 35 ί=Example 9) /NH —----- (R)-(+&gt;3_Aminotetrahydrofuran 4-methyl sulfonate 305 JIX JCi X ' ^SEm / 2.73 Intermediate 36 0 = Example 10) ηνΌ Intermediate 11 335 3.21 Intermediate 37 (=Example 11) 中间 Intermediate 12 321 3.10 87841-960303-中.doc -130- 1283678 Intermediate 38 (=Meetings 12) long NH cyclopropylamine 275 2.98 _ intermediate 39 (= Ui 13) ··· 4_[(1,[tetrahydropyrimidin-3-yl)diamine]ethylethyl-1H-pyrazole [3,4-b]pyridine-5-carboxylic acid ethyl ester

使中間物1 (〇·〇5克）與中間物13 (0.027克）懸浮於乙醇（1毫升） 中，並添加三乙胺（0.14毫升）。將混合物於氮氣下攪拌，並 在80°C下加熱24小時。於冷卻至室溫後，在氮氣流下藉蒸發 移除乙醇，並使殘留物於DCM(2毫升）與水（ι·5毫升）之間作 分液處理。分離液層，並使有機層濃縮至乾涸。使用SPE藥 筒（矽膠，5克）進行純化，以EtOAc :環己烷梯度液（1 : 8,然 後1 : 4, 1 : 2, 1 : 1及1 : 〇)溶離。將含有所要物質之溶離份合 併，並於真空中濃縮，而得中間物39 (=實例13V0.045克），為 對掌異構物之混合物。LCMS顯示MH+= 3纟3 ; TRET= 2.60分鐘。 以類似方式製備下列物質： NHR3Intermediate 1 (5 g of 〇·〇) and intermediate 13 (0.027 g) were suspended in ethanol (1 ml) and triethylamine (0.14 ml) was added. The mixture was stirred under nitrogen and heated at 80 ° C for 24 hours. After cooling to room temperature, the ethanol was removed by evaporation under a stream of nitrogen, and the residue was partitioned between DCM (2 mL) and water (1·5 mL). The layers were separated and the organic layer was concentrated to dryness. Purification was carried out using a SPE cartridge (silica gel, 5 g) eluting with a gradient of EtOAc: hexanes (1:8, then 1:4, 1:2, 1:1 and 1: s). The fractions containing the desired material were combined and concentrated in vacuo to give intermediate 39 (= </ RTI> <RTIgt; LCMS showed MH+ = 3 纟 3; TRET = 2.60 min. The following materials were prepared in a similar manner: NHR3

C〇2Et NHR3 胺試劑 MH+離子 Tr^et(分鐘） 中間物40 (=實例14、 中間物14 367 2.64 ί·間物41 : 1-乙基-4-[(3S)_四氫咬喃·3_基胺基]-111_吡也并[3,4-b] 87841_96〇3〇3_ 中.doc -131- 1283678 吡啶-5-羧酸 NHR3C〇2Et NHR3 Amine reagent MH+ ion Tr^et (minutes) Intermediate 40 (=Example 14, Intermediate 14 367 2.64 ί·Interstitial 41: 1-Ethyl-4-[(3S)_Tetrahydrocyanate· 3_ylamino]-111_pyrido[3,4-b] 87841_96〇3〇3_中.doc -131- 1283678 pyridine-5-carboxylic acid NHR3

n^yVc〇2H 中間物 41 NHR3= HN…·· 將中間物34 (0.037克）在r _ 、技故 兄）在乙鮮••水（95: 5，3¾升）中之溶液 、、氣氧化納（0_019克）處理。將混合物於犹下加熱16小時， :,在真2中濃縮。使殘留物溶於水(ι·5毫升)中，並以醋 酸酸化至ρΗ4。藉過滤移除所形成之白色固體沉殿物，並於 真空下乾燥。以醋酸乙酯萃取濾液，並收集有機層，及在 真2中濃縮，而得另一份白色固體。合併兩份固體，而得 中間物 41 (0.033 克）。LCMS 顯示 MH+=277 ; Tret=2.05 分鐘。 以類似方式製備下列物質：n^yVc〇2H Intermediate 41 NHR3= HN...·· The solution of the intermediate 34 (0.037 g) in r _ , the skill brother in Ethyl • Water (95: 5, 33⁄4 liter), gas Oxidation of sodium (0_019 g). The mixture was heated under a heat for 16 hours: :, concentrated in True 2. The residue was dissolved in water (1 mL) and acidified to pH. The formed white solid sink was removed by filtration and dried under vacuum. The filtrate was extracted with ethyl acetate and the organic layer was collected and concentrated in EtOAc to give a white solid. The two solids were combined to give intermediate 41 (0.033 g). LCMS showed MH+ = 277; Tret = 2.05 min. The following materials were prepared in a similar manner:

NHR3 起始物質 MH+離子 Tret(分鐘） 中間物 42 /NH 中間物35 277 2.05 中間物 43 HN-~~( &gt; 中間物36 307 2.40 中間物 44 /NH 中間物37 293 2.59 中間物 45 久NH 中間物38 247 2.24 中間物 HN. 中間物39 325 2.05 87841-960303·中.doc -132- 1283678 _46 中間物 __47 中間物40 339 2.05 : 4_(環己胺基）_1H-吡唑并[3,4_b]P比啶_s_羧酸乙酯NHR3 Starting material MH+ ion Tret (minutes) Intermediate 42 /NH Intermediate 35 277 2.05 Intermediate 43 HN-~~( &gt; Intermediate 36 307 2.40 Intermediate 44 /NH Intermediate 37 293 2.59 Intermediate 45 Long NH Intermediate 38 247 2.24 Intermediate HN. Intermediate 39 325 2.05 87841-960303·中.doc -132- 1283678 _46 Intermediate __47 Intermediate 40 339 2.05 : 4_(cyclohexylamino)_1H-pyrazolo[3 , 4_b]P than pyridine_s_carboxylic acid ethyl ester

C02Et Η 使中間物2 (0_69克）懸浮於環己胺（ι·〇ι毫升）中，並將混合 物在90°C下加熱3小時。使殘留混合物冷卻至室溫，並於氯 仿（25毫升）與水（25毫升）之間作分液處理。分離液相，並使 有機相蒸發至乾涸。以Et2〇 (25毫升）研製殘留物，並收集不 溶性固體，及乾燥，而得中間物48，為米黃色固體（0·58 克）。LCMS 顯 tf ΜΗ+ = 289，Tr ε τ = 2.91 分鐘。 土間物49 : 4_(環己胺基）_1H_吡峻并[3,4_b]吡啶-5_叛酸C02Et 中间 Intermediate 2 (0-69 g) was suspended in cyclohexylamine (ι·〇ι ml), and the mixture was heated at 90 ° C for 3 hours. The residual mixture was cooled to room temperature and partitioned between chloroform (25 mL) and water (25 mL). The liquid phase is separated and the organic phase is evaporated to dryness. The residue was triturated with EtOAc (25 mL). LCMS showed tf ΜΗ+ = 289, Tr ε τ = 2.91 min. Interstitial 49 : 4_(cyclohexylamino)_1H_pyrido[3,4_b]pyridine-5-rebel

Η co2h 將2Μ-氫氧化鈉溶液（〇·5毫升）添加至中間物48 (0.2克）在二 氧陸圜（4毫升）與水（〇·5毫升）中之經攪拌懸浮液内。於室溫 下揽摔過夜後’將反應混合物在4〇°c下加熱8小時。添加另 一數量之2M-氫氧化鈉溶液（15毫升），並將反應混合物於40 87841-960303·中.doc -133 - 1283678 °C下加熱48小時。使反應溶液濃縮，以水（10毫升）稀釋，並 以冰醋酸酸化。藉過濾收集所形成之沉澱物，以水洗條， 及乾燥，獲得中間物49(0.18克）。LCMS顯示MH+ = 261 ;Η co2h 2 Μ-NaOH solution (〇·5 ml) was added to a stirred suspension of intermediate 48 (0.2 g) in dioxane (4 mL) and water (5 mL). After the overnight fall at room temperature, the reaction mixture was heated at 4 ° C for 8 hours. Another amount of 2M-sodium hydroxide solution (15 ml) was added, and the reaction mixture was heated at 40 87841-960303···doc -133 - 1283678 °C for 48 hours. The reaction solution was concentrated, diluted with water (10 mL), and evaporated. The precipitate formed was collected by filtration, washed with water, and dried to give Intermediate 49 (0.18 g). LCMS showed MH+ = 261;

Tret= 2.09 分鐘。 中間物50 ·· 1_正-丙基-4-(四風-2H_喊喃_4_基胺基）_1H-p比峻并[3,4· b]吡啶-5-羧酸Tret = 2.09 minutes. Intermediate 50 ·· 1_正-propyl-4-(四风-2H_叫喃_4_ylamino)_1H-p ratio 峻[3,4· b]pyridine-5-carboxylic acid

將2M_氫氧化鈉溶液（0.7毫升）添加至實例185 (0.23克，於後 文描述）在乙醇（5毫升）與水（1·5毫升）中之經攪拌懸浮液内。 於室溫下攪拌過夜後，添加另一數量之2Μ-氫氧化鈉溶液 (〇·7毫升），並將反應混合物在43°C下加熱2.5小時。使反應 溶液濃縮，以水（5毫升）稀釋，並以2M-鹽酸酸化。藉過濾收 集所形成之沉澱物，以水洗滌，及乾燥，而得中間物50， 為白色固體（〇·14克）。LCMS顯示MH+=305 ; Tret=2.42分鐘。 中間物ϋ : ‘氣基-1-乙基_6_甲基-1Η-吡唑并[3,4-b】吡啶-5-羧酸 乙酯 87841-960303-中.doc -134- 1283678A 2 M solution of sodium hydroxide (0.7 mL) was added to a stirred suspension of EtOAc (5. <RTI ID=0.0></RTI> </RTI> <RTIgt; After stirring at room temperature overnight, another amount of 2 Μ-sodium hydroxide solution (〇·7 mL) was added, and the reaction mixture was heated at 43 ° C for 2.5 hours. The reaction solution was concentrated, diluted with water (5 mL) The precipitate formed by filtration was collected, washed with water, and dried to give Intermediate 50 as a white solid (14 g). LCMS showed MH+ = 305; T rt = 2.42 min. Intermediate ϋ : ‘Alkyl-1-ethyl_6-methyl-1Η-pyrazolo[3,4-b]pyridine-5-carboxylic acid Ethyl ester 87841-960303-中.doc -134- 1283678

將5-胺基-1-乙基p比峻（1.614克，14·5毫莫耳）與2-(1-乙氧基亞 乙基）丙二酸二乙酯（3.68克，16·〇毫莫耳，如由 P.P.T. Sah5 /. Amen Ckm· 1931，fl，1836 所述）之混合物，在 150 C下’於Dean Stark條件下加熱5小時。將氯化鱗酿（25毫升） 小心添加至混合物中，並將所形成之溶液於130°C及回流下 加熱18小時。於真空中濃縮混合物，然後將殘留油小心添 加至水（100毫升）中，並冷卻。以DCM (3x100毫升）萃取所形 成之混合物，並使合併之有機萃液以無水硫酸鈉脫水乾 燥，及在真空中濃縮。使殘留油藉Biotage層析（矽膠，90克） 純化，以醋酸乙酯-輕油（1 : 19)溶離。將含有所要產物之溶 離份合併，並在真空中濃縮，而得中間物51(115克）。lcms 顯示 MH+ = 268; Tret= 3.18 分鐘。 +間物52 : 4-(環己胺基）小乙基_6_甲基_1H-吡唑并[3,4-b】吡啶-5-羧酸5-Amino-1-ethyl p ratio (1.614 g, 14.5 mmol) with diethyl 2-(1-ethoxyethylidene)malonate (3.68 g, 16·〇 A mixture of millimolars, as described by PPT Sah5 /. Amen Ckm. 1931, fl, 1836, was heated at 150 C under Dean Stark conditions for 5 hours. Chlorinated scale (25 ml) was carefully added to the mixture, and the resulting solution was heated at 130 ° C for 18 hours under reflux. The mixture was concentrated in vacuo and the residual oil was carefully added to water (100 mL) and cooled. The resulting mixture was extracted with EtOAc (EtOAc)EtOAc. The residual oil was purified by Biotage chromatography (silica gel, 90 g) and dissolved in ethyl acetate-light oil (1: 19). The fractions containing the desired product were combined and concentrated in vacuo to afford Intermediate <RTI ID=0.0> Lcms shows MH+ = 268; Tret = 3.18 minutes. +Interstance 52 : 4-(cyclohexylamino)ethylidene-6-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid

87841-960303-中.doc -135- 1283678 毫升）中之實例190(0.128克，〇·39毫莫耳，於後文描述）内， 並將混合物於50°C下加熱16小時。濃縮反應混合物，並以 2M鹽版使所形成之水溶液中和，以使固體沉澱，將其藉過 濾收集。將濾液施加至OASIS®親水性_親油性平衡(hlb值）萃 取藥筒*(1克），將其以水，接著以甲醇溶離。蒸發甲醇溶離 份，獲得固體，將其與最初沉澱之固體合併，而得中間物 52 (0.083克），為白色固體，假設為羧酸。 *OASIS®HLB萃取藥筒可得自Waters公司，34MapleS打邮， Milford，MA01757, USA。藥筒包含管柱，含有共聚物吸著 劑，具有HLB值，以致當水溶液經過管柱溶離時，溶質會被 吸收或被吸附進入吸著劑中或在其上，且致使當溶離有機 /表劑（例如甲醇）時’溶質係以有機（例如甲醇）溶液釋出。這 是一種分離溶質與含水溶劑之方法。 史$ # 53 : 1-乙基各曱基冰(四氫_2Η_哌喃-4_基胺基）-1Η_吡唑 并[3,4-b】吡啶_5羧酸Example 190 (0.128 g, 〇·39 mmol, described later) in 87841-960303-中.doc-135- 1283678 ml), and the mixture was heated at 50 ° C for 16 hours. The reaction mixture was concentrated, and the resulting aqueous solution was neutralized with a 2M salt plate to precipitate a solid which was collected by filtration. The filtrate was applied to an OASIS® hydrophilic _ lipophilic balance (hlb value) extraction cartridge* (1 gram) which was dissolved in water followed by methanol. Evaporation of the MeOH afforded a solid which was combined with the solid that was initially precipitated to afford Intermediate 52 (0.083 g) as a white solid as a carboxylic acid. * OASIS® HLB extraction cartridges are available from Waters, 34 MapleS, Milford, MA01757, USA. The cartridge comprises a column containing a copolymer sorbent having an HLB value such that when the aqueous solution is dissolved through the column, the solute is absorbed or adsorbed into or onto the sorbent and causes dissolution of the organic/table In the case of a reagent such as methanol, the solute is released as an organic (e.g., methanol) solution. This is a method of separating solute from aqueous solvent. History $ # 53 : 1-ethyl fluorenyl ice (tetrahydro-2-indole-piperidin-4-ylamino)-1Η-pyrazole and [3,4-b]pyridine-5carboxylic acid

將2M-氫氧化鈉溶液（0.75毫升，1.5毫莫耳）添加至乙醇（2毫 升）中之實例189(0.248克，0.75毫莫耳，於後文描述）内，並 將混合物於回流下加熱16小時。使反應混合物濃縮，以水（1 毫升）稀釋，並以2M-鹽酸（0.75毫升）酸化，以使固體沉殿， 87841-960303-中.doc -136- 1283678 將其藉過濾收集，而得中間物53 (0·168克）。LCMS顯示 MH+=305; Tret=1.86 分鐘。 中間物54 : 4-胺基環己酮鹽酸鹽2M-sodium hydroxide solution (0.75 ml, 1.5 mmol) was added to 189 (0.248 g, 0.75 mmol, as described below) in ethanol (2 mL) and the mixture was heated under reflux. 16 hours. The reaction mixture was concentrated, diluted with water (1 mL), and then acidified with 2M-hydrochloric acid (0.75 ml) to allow the solid to be dissolved, 87841-960303-medium doc-136-1283678. Matter 53 (0·168 g). LCMS showed MH+ = 305; Tret = 1.86 min. Intermediate 54 : 4-Aminocyclohexanone hydrochloride

NH..HCI 將氯化氫在二氧陸圜（0.5毫升，2.0毫莫耳，4M)中之溶液 添加至4-酮基環己基胺基甲酸第三-丁酯（0.043克，0.20毫莫 耳，可市購得自Astatech公司，Philadelphia，USA)在二氧陸圜（0.5 毫升）中之經攪拌溶液内，並於室溫下攪拌混合物。1小時 後，蒸發反應混合物，獲得中間物54，為乳黃色固體（34毫 克）。1HNMR(400MHz 在 d6-DMSO 中，27°C，5 ppm)8.09(寬廣 s，3H)，3.51 (tt，11，3.5Hz，1H)，2.45 (m，2H，部份被遮蔽），2_29 (m，2H)， 2.16(m, 2H), 1.76(m，2H). 中間物54A : N-苄基-4-(環己胺基)-1Η-吡唑并[3,4-b]吡啶-5-甲醯 胺NH..HCI A solution of hydrogen chloride in dioxane (0.5 ml, 2.0 mmol, 4 M) was added to the 4-keto-cyclohexylaminocarbamic acid tert-butyl ester (0.043 g, 0.20 mmol). It is commercially available from Astatech, Philadelphia, USA in a stirred solution of dioxane (0.5 ml) and the mixture is stirred at room temperature. After 1 hour, the reaction mixture was evaporated to give a m. 1H NMR (400MHz in d6-DMSO, 27°C, 5 ppm) 8.09 (broad s, 3H), 3.51 (tt, 11, 3.5Hz, 1H), 2.45 (m, 2H, partially masked), 2_29 ( m, 2H), 2.16 (m, 2H), 1.76 (m, 2H). Intermediate 54A: N-benzyl-4-(cyclohexylamino)-1 Η-pyrazolo[3,4-b]pyridine -5-formamide

將芊胺（0.16毫升）添加至中間物49 (0_13克）、DIPEA (0.26毫 升）及HATU(0_285克）在DMF(3毫升）中之經攪拌混合物内。將 87841-960303-中.doc -137- 1283678 所形成之混合物加熟’並於85°C下揽掉16小時。添加另一份 HATU(〇.H克）、DIPEA(0.13毫升）及苄胺（0.082毫升），並將混 合物於88°C下加熱16小時。使所形成之溶液濃縮，以二氯甲 烷（20毫升）稀釋，並以飽和碳酸氫鈉溶液(20毫升）洗滌，藉 疏水性玻料分離’及濃縮有機層。使殘留物於spE藥筒（碎 膠，20克）上純化，以環己烷中之60_80%醋酸乙酯溶離。使 殘留物進一步於SPE藥筒（Isolute SCX續酸藥筒，5克χ2)上純 化，以甲醇(2x20毫升）與甲醇中之10%氨(4x20毫升）溶離；將 驗性溶離份合併，並濃縮，而得中間物54Α，為白色固體 (0.07 克）。LCMS 顯示 MH+=350; Tret = 2.99 分鐘。 中間物55 : 4_氣基小乙基-N-{[4_(甲氧基）苯基]甲基卜iH_吡唑并 [3,4-b]竹li咬-5-甲酿胺The decylamine (0.16 mL) was added to a stirred mixture of intermediate 49 (0-13 g), DIPEA (0.26 mL) and HATU (0-285 g) in DMF (3 mL). The mixture formed by 87841-960303-中.doc -137-1283678 was cooked and removed at 85 ° C for 16 hours. Another portion of HATU (〇.H), DIPEA (0.13 mL), and benzylamine (0.082 mL) were added and the mixture was heated at 88 °C for 16 hours. The resulting solution was concentrated, diluted with methylene chloride (EtOAc) (EtOAc) The residue was purified on a spE cartridge (eluent, 20 g) eluting with 60-80% ethyl acetate in cyclohexane. The residue was further purified on an SPE cartridge (Isolute SCX acid cartridge, 5 g χ2), dissolved in methanol (2 x 20 mL) and 10% ammonia (4 x 20 mL) in methanol; Concentrate to give the intermediate as a white solid (0.07 g). LCMS showed MH+ = 350; Tret = 2.99 min. Intermediate 55 : 4_ gas-based small ethyl-N-{[4_(methoxy)phenyl]methyl iH_pyrazolo[3,4-b] bamboo li bite-5-cartoamine

將中間物15 (1·04克）以二氯化亞硫酸（13.22克）處理。將混合 物揽拌’並於75 C下加熱2小時。於真空中移除過量二氯化 亞硫醯，並使殘留油與甲苯一起共沸，而得中間物16，假 設為中間物15之氯化醯衍生物，為乳黃色固體（112克）。 使中間物16 (0.997克）溶於四氫呋喃（THF)(25毫升）中，並以 N，N_二異丙基乙胺（1.07毫升），然後以ι_[4_(甲氧基）苯基]甲胺 - 4-甲氧基苄胺(〇·54毫升）（可得自例如Aldrich，Acros或 87841-960303-φ.(1οο -138- 1283678Intermediate 15 (1.04 g) was treated with sulfuric acid dichloride (13.22 g). The mixture was stirred and heated at 75 C for 2 hours. Excess ruthenium dichloride was removed in vacuo and the residual oil was azeotroped with toluene to give intermediate 16 which was taken to be a yttrium chloride derivative of intermediate 15 as a creamy solid (112 g). Intermediate 16 (0.997 g) was dissolved in tetrahydrofuran (THF) (25 mL) eluted with N,N-diisopropylethylamine (1.07 ml), then ι_[4-(methoxy)phenyl] Methylamine 4-methoxybenzylamine (〇·54 ml) (available, for example, from Aldrich, Acros or 87841-960303-φ. (1οο -138-1283678)

Lett, 20025 43 (48), 8735 ；或 Meindl 等人，J； M以/· C〜m·, 1984, 27 (9)， 1111 ;或 Leiters，2002, 4 (12)，2055)處理，並將混合物攪:拌 3小時。在真空中濃縮溶液，然後於DCM與水之間作分液處 理。分離液層，並使有機物質在真空中濃縮。接著，將固 體在1 : 1醋酸乙酯：環己烷中研製，而得中間物55 (1.27 克）。LCMS 顯示 MH+=345，Tret = 2.86 分鐘。 以類似方式製備下列物質：Lett, 20025 43 (48), 8735; or Meindl et al, J; M by /· C~m·, 1984, 27 (9), 1111; or Leiters, 2002, 4 (12), 2055), and Stir the mixture: mix for 3 hours. The solution was concentrated in vacuo and then separated between DCM and water. The layers were separated and the organic material was concentrated in vacuo. Next, the solid was triturated in 1:1 ethyl acetate: cyclohexane to give Intermediate 55 ( 1.27 g). LCMS showed MH+=345 and Tret = 2.86 minutes. The following materials were prepared in a similar manner:

nr4r5 HNR4R5之來源 MH+離子 Tret(分鐘） 中間物56 [J Λ· Lis等人， J· Med· Chem” 1990, 33 (10)， 2883,參閱圖式 III與參考資料 24 408 2.60 中間物57 nh~C〇 Maybridge-Int ; 或 Aldrich ;或 TCI-America 341 3.08 中間物58 : 1-乙基-4-[(4-酮基環己基）胺基]-1Η-吡唑并[3,4-b]吡 啶-5-羧酸Source of nr4r5 HNR4R5 MH+ ion Tret (minutes) Intermediate 56 [J Λ· Lis et al., J. Med·Chem" 1990, 33 (10), 2883, see Figure III and reference 24 408 2.60 Intermediate 57 nh ~C〇Maybridge-Int ; or Aldrich ; or TCI-America 341 3.08 Intermediate 58 : 1-ethyl-4-[(4-ketocyclohexyl)amino]-1Η-pyrazolo[3,4- b]pyridine-5-carboxylic acid

87841-960303-中.doc -139- 1283678 將氫氧化鈉（0.053克’ 1.32毫莫耳）在水（〇 41毫升）中之溶 液，添加至實例205((U克，〇.303毫莫耳）在乙醇（1毫升）中之 經攪拌溶液内，並於5(TC下加熱所形成之混合物。丨小時 後，將已冷卻之反應混合物以2M鹽酸調整至pH3，並以 EtOAc (2x6毫升）萃取。使合併之有機萃液脫水乾燥 (Na^O4) ’並蒸發，而得中間物58(〇〇72克），為白色固體。 LCMS 顯不 MH+= 303 ; Tret^S.IS 分鐘。 胃中間物58A :乙基1-乙基_4-(四氫-2Εμ痕喃_3_基胺基）-1Η-吡唑并 [3,4-b]吡啶_5_羧酸乙酯87841-960303-中.doc -139- 1283678 A solution of sodium hydroxide (0.053 g ' 1.32 mmol) in water (〇 41 ml) was added to Example 205 ((U g, 〇.303 mmol) The resulting mixture was heated in 5 (TC) in EtOAc (1 mL). EtOAc (2 EtOAc) The combined organic extracts were dehydrated (Na^O4) and evaporated to give Intermediate <RTI ID=0.0>#</RTI> </RTI> <RTI ID=0.0></RTI> <RTIgt; Intermediate 58A: ethyl 1-ethyl- 4-(tetrahydro-2 Εμ trace _3_ ylamino)-1 Η-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester

使中間物1(0_76克，3.0毫莫耳）溶於乙腈（1〇毫升）中。添加 四氫_2H-哌喃-3_胺鹽酸鹽（〇·5克，3.6毫莫耳，如.如以 1988, 84, 148)與N，N_二異丙基乙胺（3.14愛升，18.0毫莫耳），並 將混合物於85°C下攪拌24小時。24小時後，添加另一份四 氫-2H-哌喃-3-胺鹽酸鹽（0.14克，1.02毫莫耳），並在85〇c下持 續授掉。再8小時後，於真空中濃縮混合物。使殘留物於 DCM (20毫升）與水（12毫升）之間作分液處理。分離液層，並 將水層以另外之DCM(12毫升）萃取。使合併之有機萃液脫水 乾燥（NajO4)，及在真空中濃縮，獲得褐色固體，使其在 SPE藥筒（矽膠，20克）上純化，以醋酸乙酯：環己烷梯度液 (1 : 16, 1 : 8, 1 : 4, 1 : 2, 1 : 1，1 : 0)溶離。將含有所要物質之 87841-960303-中.doc -140- 1283678 溶離份合併，並蒸發，而得中間物58八(〇.89克）。lcms顯示 MH+=319; Tret = 2.92 分鐘。 中間_:卜乙基冰(四氫抓哌喃各基胺基）_1H_吡唑并[3,4_b】 外b淀幾酸Intermediate 1 (0-76 g, 3.0 mmol) was dissolved in acetonitrile (1 mL). Add tetrahydro-2H-piperidin-3-amine hydrochloride (〇·5 g, 3.6 mmol, eg. as 1988, 84, 148) with N,N-diisopropylethylamine (3.14 Love) Liter, 18.0 mmol, and the mixture was stirred at 85 ° C for 24 hours. After 24 hours, another portion of tetrahydro-2H-piperidin-3-amine hydrochloride (0.14 g, 1.02 mmol) was then weighed and continued at 85 〇c. After a further 8 hours, the mixture was concentrated in vacuo. The residue was partitioned between DCM (20 mL) and water (12 mL). The layers were separated and the aqueous extracted with EtOAc EtOAc. The combined organic extracts were dried (Naj.sub.4) and concentrated in vacuo to afford a brown solid which was purified on EtOAc EtOAc EtOAc 16, 1 : 8, 1 : 4, 1 : 2, 1 : 1,1 : 0) Dissolution. The 87841-960303-medium doc-140-1283678-soluble fractions containing the desired material were combined and evaporated to give intermediate 58 (yield: 89 g). Lcms shows MH+=319; Tret = 2.92 minutes. Intermediate _: Buethyl ice (tetrahydropyridinylamino)_1H_pyrazolo[3,4_b]

將中間物58A (0.89克，2.79毫莫耳）在乙醇（16.7毫升）中之溶 液，以氫氧化鈉（0.47克，11.7毫莫耳）作成在水中之溶液（31 耄升）處理。於50°C下攪拌混合物。12小時後，使反應混合 物在真空中濃縮，獲得殘留油，使其溶於水（16毫升）中，然 後冷卻，並以2M鹽酸酸化至PH3。在0。(：下攪拌30分鐘後， 藉過濾收集所形成之沉澱物，以冷卻水（2毫升）洗滌，及在 真空中乾燥，而得中間物59，為白色固體（0.73克）。LCMS顯 示 MH+=291 ; Tret = 2.19 分鐘。 中間物60 : 4-[(1-乙醯基_4_六氫吡啶基）胺基]-1-乙基-1H_吡唑并 [3,4_b] 〃比淀-5-幾酸A solution of the intermediate 58A (0.89 g, 2.79 mmol) in ethanol (16.7 mL) was then taken up in sodium hydroxide (0.47 g, 11.7 mmol) in water (31 liters). The mixture was stirred at 50 °C. After 12 hours, the reaction mixture was evaporated EtOAc mjjjjjjjjj At 0. (After stirring for 30 minutes, the formed precipitate was collected by filtration, washed with EtOAc EtOAc (EtOAc) 291 ; Tret = 2.19 min. Intermediate 60 : 4-[(1-Ethyl-4_hexahydropyridyl)amino]-1-ethyl-1H-pyrazolo[3,4_b] -5-acid

-141- 87841-960303-中.doc 1283678 將氫氧化鈉水溶液（8·55毫升，2M)添加至實例207 (1.55克） 在EtOH (13毫升）中之溶液内。將混合物於5〇。〇下加熱18小 時’然後使用鹽酸水溶液中和，及在真空中蒸發，而得丨_乙 基-4-(4-六氫吡啶基胺基）-1Η-吡唑并[3,4_b&gt;比啶-5-羧酸與4-[(1-乙 醯基-4_穴氫p比淀基）胺基]小乙基比吐并[3,4_b]u比咬_5_羧酸 之混合物。 將醋酸（0·36毫升）添加至HATU (2.41克）與N，N-二異丙基乙胺 (2.21毫升）在N，N-二甲基甲醯胺（65毫升）中之經攪拌混合物 内。於攪拌15分鐘後’將混合物添加至μ乙基本(4_六氫p比淀 基胺基）_1Η-吡唑并[3,4-b]吡啶_5_羧酸與4-[(1-乙醯基-4-六氫吡淀 基）胺基]-1_乙基-1H·吡唑并[3,4七]吡啶_5-羧酸之混合物中，並 將反應物攪拌15小時。於真空中蒸發反應混合物，並使殘 留物藉層析，使用Biotage (矽膠，90克）純化，以DCM : MeOH (0% -5% MeOH)溶離，而得中間物60 (136克），為白色固 體。LCMS 顯示 MH+334; Tret=2.06 分鐘。 土間物61 . 4·(環己胺基）小乙基_1H·^比也并[3,4_b]v比淀-5-羧酸-141- 87841-960303-中.doc 1283678 Aqueous sodium hydroxide (8.55 mL, 2M) was added to a solution of 207 (l. The mixture was taken at 5 Torr. Heating under the arm for 18 hours' then neutralized with aqueous hydrochloric acid and evaporating in vacuo to give 丨-ethyl-4-(4-hexahydropyridylamino)-1 Η-pyrazole [3,4_b> ratio Mixture of pyridine-5-carboxylic acid with 4-[(1-ethylindolyl-4_hydrogen p-pyryl)amino]diethyl-pyrolo[3,4_b]u ratio biting_5-carboxylic acid . Add acetic acid (0. 36 ml) to a mixture of HATU (2.41 g) and N,N-diisopropylethylamine (2.21 ml) in N,N-dimethylformamide (65 ml) Inside. After stirring for 15 minutes, the mixture was added to μethyl (4-6 hexa-p-decylamino)-indole-pyrazolo[3,4-b]pyridine-5-carboxylic acid and 4-[(1- To a mixture of ethionyl-4-hexahydropyridyl)amino]-1-ethyl-1H.pyrazolo[3,4hepta]pyridine-5-carboxylic acid, the reaction was stirred for 15 h. The reaction mixture was evaporated in vacuo <mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj White solid. LCMS showed MH+ 334; Tret = 2.06 min. Soil 61.6 (cyclohexylamino) small ethyl_1H·^ ratio also [3,4_b]v than lake-5-carboxylic acid

將實例2 (5.37克’ 17耄莫耳）在乙醇（3〇毫升）中之溶液，以 氣乳化鋼（2.72克’ 68毫莫耳）在水（2〇毫升）中之溶液處理， 87841-960303-中 _doc -142- 1283678 並將所形成之混合物於50°C下攪拌3小時。使反應混合物在 真空中濃縮’溶於水（250耄升）中，並以5M-鹽酸使已冷卻之 溶液酸化至pH 1。藉過濾收集所形成之固體，並於真空中乾 燥，而得中間物61 ，為白色固體（4·7克）。LCMS顯示 MH+ = 289 ; Tr e τ = 2.83 分鐘。 土間物岐:(4,4-二氟環己基）胺基甲酸1，1-二甲基乙酯A solution of Example 2 (5.37 g of '17 Torr) in ethanol (3 mL) was treated with a solution of air-emulsified steel (2.72 g '68 mmol) in water (2 mL), 87841- 960303-Medium_doc-142- 1283678 The resulting mixture was stirred at 50 ° C for 3 hours. The reaction mixture was concentrated in vacuo to dissolve in water (250 liters) and the cooled solution was acidified to pH 1 with 5M hydrochloric acid. The solid which formed was collected by filtration and dried in vacuo to give Intermediate <RTIgt; LCMS showed MH+ = 289; Tr e τ = 2.83 min. Soil material: 1,1-dimethylethyl (4,4-difluorocyclohexyl)carbamate

將三氟化（二乙胺基）硫(DAST)(〇.〇6毫升，〇·47毫莫耳）添加至 (4-酉同基環己基）胺基甲酸ι，ΐ-二甲基乙酯（25〇毫克，U7毫莫 耳，可市購得自AstaTech公司，Philadelphia，USA)在無水二氣甲 燒（5毫升）中之經攪拌溶液内，並於氮氣及2〇。〇下攪拌混合 物。22小時後，使反應混合物冷卻至〇〇c，以飽和碳酸氫鈉 落液（4毫升）處理，然後使其溫熱至環境溫度。藉由經過疏 水性玻料分離液相，並將水相再以DCM (5毫升）萃取。使合 併之有機相於真空中濃縮，而得橘色固體（369毫克），使其 進一步藉層析，使用SPE藥筒（矽膠，1〇克）純化，以DCM溶 離’而得中間物62 (140毫克），含有20% (4·氟基-3-環己烯-1-基）胺基甲酸1，1-二甲基乙酯。iHNMR(400MHz，在CDC13中，27 C，5 ppm)較少成份：δ 5.11(dm，16Hz，lH)，4.56(br，lH)，3.80 (br，lH) 2.45-1.45 (m’s，6H 過量），l.43(s，9H).主要成份： 87841-960303-中,doc -143 - 1283678 54.43 (br，1H)，3·58 (br，1H)，2.45-1.45 (m，s，8H 過量），1.45(s，9H)· 史間物63 : (4,4_二氟環己基）胺鹽酸鹽Adding (diethylamino)sulfur trifluoride (DAST) (〇.〇6 ml, 〇·47 mmol) to (4-酉-ylcyclohexyl)urethane, ι,ΐ-dimethyl The ester (25 mg, U7 mmol, commercially available from AstaTech, Philadelphia, USA) in a stirred solution of anhydrous gas (5 mL) in nitrogen and 2 Torr. Stir the mixture under the arm. After 22 hours, the reaction mixture was cooled to EtOAc EtOAc (EtOAc) The liquid phase was separated by a water-repellent glass and the aqueous phase was extracted with DCM (5 mL). The combined organics were concentrated in vacuo to give EtOAc (EtOAc: EtOAc). 140 mg), containing 1,1,1-dimethylethyl (4. fluoro-3-cyclohexen-1-yl)carbamate. iHNMR (400MHz, in CDC13, 27 C, 5 ppm) less components: δ 5.11 (dm, 16 Hz, lH), 4.56 (br, lH), 3.80 (br, lH) 2.45-1.45 (m's, 6H excess) , l.43(s, 9H). Main components: 87841-960303-中, doc -143 - 1283678 54.43 (br,1H),3·58 (br,1H),2.45-1.45 (m,s,8H excess ), 1.45(s,9H)· Intermediary 63 : (4,4-difluorocyclohexyl)amine hydrochloride

於20°C下，將氣化氫在二氧陸圜中之溶液(4M，1.6毫升）添 加至中間物62 (140毫克，0.6毫莫耳）在二氧陸圜（ι·6毫升）中 之經攪拌溶液内。3小時後，使反應混合物在真空中濃縮， 而得中間物63 (96.5毫克），含有4_氟基-3-環己浠小胺。A solution of hydrogen sulfide in dioxane (4M, 1.6 ml) was added to intermediate 62 (140 mg, 0.6 mmol) in dioxane (1·6 mL) at 20 °C. It is stirred in the solution. After 3 hours, the reaction mixture was concentrated in vacuo to give titled <RTI ID=0.0></RTI> <RTIgt;

1H NMR (400 MHz 在 dg -DMSO 中，27 °C，5 ppm)較少成份：占 8.22(br，3H 過量），5.18(dm，16Hz，lH)，3.28-3.13(m，lH 過量），2.41_ 1·53 (m’s，6H 過量）·主要成份：58.22 (br，3H 過量），3.28-3.13 (m，1H 過量），2.41-1.53 (mfs，8H過量）·亦存在不純物。 土 ·間物64 · 4-氣-1-乙基甲基-1H·〃比峻并[3,4-b】外b咬_5_甲酿胺1H NMR (400 MHz in dg-DMSO, 27 °C, 5 ppm) less components: 8.22 (br, 3H excess), 5.18 (dm, 16 Hz, lH), 3.28-3.13 (m, lH excess), 2.41_ 1·53 (m's, 6H excess) · Main components: 58.22 (br, 3H excess), 3.28-3.13 (m, 1H excess), 2.41-1.53 (mfs, 8H excess) · Impurities are also present. Soil · Interstitial 64 · 4-gas-1-ethylmethyl-1H·〃比峻和[3,4-b] 外b bit_5_甲甲胺

將中間物15 (0.06克，0.266毫莫耳）以二氯化亞硫醯（〇·48毫 升）處理。將混合物擾摔’並於75°C下加熱2小時。於真空中 移除過量二氯化亞硫醯，並使殘留油與二氯甲烷（DCM) 一起 共沸，而得中間物16，假設為中間物15之氯化醯衍生物， 為白色固體。使中間物16溶於無水四氫吱喃（thF)(2毫升） 中，並以N，N-二異丙基乙胺（DIPEA)(0.069毫升），然後以甲胺 (2M，在四氫呋喃中，〇·ΐ5毫升）處理，且將混合物在氮氣下 87841-960303-中.doc •144· 1283678 攪拌16小時。添加另外〇 〇5毫升甲胺（2M，在ΤΗρ中），並將 落液攪拌2小時。使混合物在真空中濃縮，接著於二氯甲烷 (2毫升）與氫氧化鈉水溶液（2M，2毫升）之間作分液處理， 然後以水（2耄升）洗務有機層。分離液層，並於真空中濃縮 有機物質，而得中間物64 (0.052克）。LCMS顯示MH+ = 239 ; Tret=2.17 分鐘。 土間物65_ :叫⑴⑽上二甲基乙基）氧基]凝基}_4_六氫吡啶基)胺 基]_1_乙基_1H-吡唑并[3,4-b】峨啶-5_羧酸乙酯Intermediate 15 (0.06 g, 0.266 mmol) was treated with sulfinium dichloride (〇·48 mL). The mixture was disturbed and heated at 75 ° C for 2 hours. Excess ruthenium dichloride was removed in vacuo and the residual oil was azeotroped with dichloromethane (DCM) to afford intermediate 16 which was assumed to be the ruthenium chloride derivative of intermediate 15 as a white solid. Intermediate 16 was dissolved in dry tetrahydrofuran (th) (2 mL) and taken to N,N-diisopropylethylamine (DIPEA) (0.069 mL) then methylamine (2M in tetrahydrofuran) , 〇·ΐ 5 ml) was treated, and the mixture was stirred under a nitrogen atmosphere of 87481-960303-media.doc • 144·1283678 for 16 hours. An additional 〇 5 ml of methylamine (2M in ΤΗρ) was added and the solution was stirred for 2 hours. The mixture was concentrated in vacuo then EtOAc (2 mL) EtOAc. The layers were separated and the organic material was concentrated in vacuo to afford Intermediates <RTIgt; LCMS showed MH+ = 239; Tret = 2.17 min. Interstitial 65_: called (1) (10) upper dimethylethyl)oxy] condensyl}_4_hexahydropyridyl)amino]_1_ethyl_1H-pyrazolo[3,4-b]acridine-5 _carboxylic acid ethyl ester

將中間物17(2.0克，6_37毫莫耳）、1，1-二甲基乙基4_胺基 六氫吡啶羧酸鹽（2.04克，10.2毫莫耳）及N，N-二異丙基乙胺 (5.54毫升，3L9毫莫耳）在MeCN(40毫升）中之混合物，於85°c 下加熱42小時。蒸發反應物，並使殘留物於DCM與水之間 作分液處理。使有機相脫水乾燥(MgS04)，然後於真空中蒸 發。使殘留物於矽膠（Biotage，90克）上層析，以環己烷： EtOAc (1 : 1)溶離，獲得中間物65，為白色固體（2·7〇克）。 LCMS 顯示 MH+=479; Tret=3.37 分鐘。 _中間物67 : 3-胺基-N-環己基-N-甲基苯曱醯胺Intermediate 17 (2.0 g, 6-37 mmol), 1,1-dimethylethyl 4-aminopyridinium carboxylate (2.04 g, 10.2 mmol) and N,N-diisopropyl A mixture of ethylamine (5.54 mL, 3 L 9 mmol) in MeCN (40 mL). The reaction was evaporated and the residue was partitioned between DCM and water. The organic phase was dried (MgS04) and then evaporated in vacuo. The residue was chromatographed on EtOAc (EtOAc) (EtOAc) LCMS showed MH+ = 479; Tret = 3.37 min. _ Intermediate 67: 3-Amino-N-cyclohexyl-N-methylbenzamide

87841·96〇3〇3·中.doc -145- 1283678 於20°C下’將3-氯化硝基苯甲醯（2 〇克，1〇 78毫莫耳）在 DCM (20毫升）中之溶液，逐滴添加至N_甲基環己胺⑽毫 升，14.01耄莫耳）、n，N-二異丙基乙胺（3/76毫 耳）及N，N-二甲胺基吡啶（〇·〇ι克）在dcm中之 升，21.56毫莫 經攪拌混合物 内。將反應混合物攪拌56小時，然後在真空中蒸發。使殘 留物於醋酸乙酯與水之間作分液處理。將有機相以Ηα水溶 液洗滌，接著脫水乾燥（MgS〇4),及在真空中蒸發。使殘留 物於矽膠上藉層析純化，以環己烷：Et〇Ac (9 :丨，接著2 ·· ^ 落離’而得N-環己基-N-甲基-3-硝基苯甲醯胺（14〇克）。MS顯 示 ΜΗ+=263· 將Ν-環己基-Ν·甲基-3-硝基苯甲醯胺（ι·4〇克，5·35毫莫耳）與 I巴/碳（5%，0.140克）在乙醇（10毫升）中之混合物，於氫大氣 下攪拌1小時。使反應混合物經過矽藻土過濾，並蒸發滤 液，而得中間物67，為褐色固體（0.107克）。LCMS顯示 MH+= 233 ; TRET= 2.56 分鐘。 中間物68 : N-乙基_4_酮基-1-六氫吡啶甲醯胺 〇87841·96〇3〇3·中.doc -145- 1283678 '3-Chloronitrobenzoquinone (2 g, 1〇78 mmol) in DCM (20 ml) at 20 °C The solution was added dropwise to N_methylcyclohexylamine (10 ml, 14.01 mmol), n,N-diisopropylethylamine (3/76 mil) and N,N-dimethylaminopyridine. (〇·〇ι克) The rise in dcm, 21.56 mmol was stirred in the mixture. The reaction mixture was stirred for 56 hours and then evaporated in vacuo. The residue was subjected to liquid separation between ethyl acetate and water. The organic phase was washed with a Ηα aqueous solution, followed by dehydration drying (MgS 〇 4), and evaporation in vacuo. The residue was purified by chromatography on silica gel to give N-cyclohexyl-N-methyl-3-nitrobenzoate as cyclohexane:Et〇Ac (9: 丨, then 2 ·· ^ falling off ' Indoleamine (14 g). MS shows ΜΗ+=263· Ν-cyclohexyl-Ν·methyl-3-nitrobenzamide (Ig 4 g, 5.35 mmol) and I A mixture of bar/carbon (5%, 0.140 g) in EtOAc (EtOAc) (EtOAc) (0.107 g) LCMS showed MH+ = 233; TRET = 2.56 min. Intermediate 68: N-ethyl- 4- keto-1-hexahydropyridinamide

N 入^ Η 於下，將異氰酸乙酯（2·31克，32.5毫莫耳）在DCM(40毫 升）中之溶液，在15分鐘内，逐滴添加至4-六氫批淀酮單水 合物鹽酸鹽（5.0克，32.5毫莫耳，可市購得自Aldrich)與碳酸 87841-960303-ψ.άοο -146- 1283678 氫鈉（8.2克，97·5毫莫耳）在水（6〇毫升）中之經激烈攪拌溶液 内。將反應混合物在室溫下攪拌20小時。將氯化鈉（7〇克） 添加至反應混合物中，並分離有機相。以另外之Dcm (3 X 75 毫升）萃取水相。使合併之有機萃液脫水乾燥^s〇4)，及 在真空中蒸發，獲得白色固體（4·〇克）。自醋酸乙酯：環己 k (10 · 1)再結晶，提供中間物68，為白色固體（2 J克）。 TLC(矽膠）獲得Rf=〇.24(醋酸乙酯）·分析實測值：c，56.7 ; H，8.3，N，16.35. C8H14N2〇2 需要 c，56.5 ; Η，8·3 ; N，16.5. 土間物69 · 4-胺基_Ν·乙基-1-六氫峨淀甲醜胺 νη2 ό Λ、 使中間物68 (u克，8.8毫莫耳）與芊胺（1〇4克，9 7毫莫耳） 在無水乙醇（60亳升）中之溶液，於預還原之1〇%鈀/炭觸媒 (0.6克）上，在乙醇（2〇毫升）中氫化，直到已停止氫吸收為止 (22小時）。使反應混合物經過濾劑（矽藻土），然後經過矽膠 (100笔升）過濾，以乙醇：〇 88氨_ :丨）溶離獲得黑色 油。使此油溶於乙醇(30毫升)中，並以氯化氫在乙醇中之溶 液（3M)處理’直到溶液呈酸性為止，蒸發溶劑，並以乙醇研 製殘留物，而得中間物69，為白色固體（1〇9克）。TLc(矽 膠）’獲得Rf=0.73(醋酸乙酯：曱醇，1〇: 1}.分析實測值： C, 45.9，H’8.4’ N，19.8. C8印 8ClN3〇 需要 Q 46.3; H，8.7; N，20.2. 87841-96〇3〇3·中.doc •147- 1283678 中間物: ({4-[(環丙胺基）談基]苯基}甲基）胺基甲酸14-二甲 基乙酯a solution of ethyl isocyanate (2·31 g, 32.5 mmol) in DCM (40 mL) was added dropwise to 4-hexahydromethanol in 15 min. Monohydrate hydrochloride (5.0 g, 32.5 mmol, commercially available from Aldrich) and carbonic acid 87481-960303-ψ.άοο -146- 1283678 sodium hydride (8.2 g, 97·5 mmol) in water (6 〇 ml) in a vigorously stirred solution. The reaction mixture was stirred at room temperature for 20 hours. Sodium chloride (7 g) was added to the reaction mixture, and the organic phase was separated. The aqueous phase was extracted with a further Dcm (3 X 75 mL). The combined organic extracts were dried (MgSO4) and evaporated in vacuo to give a white solid. Recrystallization from ethyl acetate: cyclohexane k (10 · 1) afforded Intermediate 68 as a white solid (2 J). TLC (silicone) obtained Rf = 〇.24 (ethyl acetate) · Analytical value: c, 56.7; H, 8.3, N, 16.35. C8H14N2 〇 2 requires c, 56.5; Η, 8·3; N, 16.5. Soil 69 · 4-Amino-Ν·Ethyl-1-hexahydroindole A ugly amine νη2 ό Λ, intermediate 68 (u gram, 8.8 mmol) with guanamine (1 〇 4 g, 9 7 mmoles of a solution in absolute ethanol (60 liters) on a pre-reduced 1% palladium on carbon catalyst (0.6 g) in hydrogen (2 mL) until hydrogen absorption has ceased So far (22 hours). The reaction mixture was passed through a filter (diatomaceous earth), and then filtered through a silica gel (100 liters), and dissolved in ethanol: 〇 88 ammonia _ : 丨) to obtain a black oil. The oil was dissolved in ethanol (30 ml) and treated with a solution of hydrogen chloride in ethanol (3M) until the solution was acidic. The solvent was evaporated and the residue was crystallised from ethanol to give intermediate 69 as a white solid. (1〇9g). TLc (矽胶)' obtained Rf = 0.73 (ethyl acetate: decyl alcohol, 1 〇: 1}. Analytical values: C, 45.9, H'8.4' N, 19.8. C8 printed 8ClN3 〇 requires Q 46.3; H, 8.7 N,20.2. 87841-96〇3〇3·中.doc •147- 1283678 Intermediate: ({4-[(Cyclopropylamino)-based]phenyl}methyl)carbamic acid 14-dimethyl Ethyl ester

將環丙基胺（0.136克，2·39毫莫耳）與二異丙基乙胺（〇68毫 升’ 3.9毫莫耳）添加至4·[({[(1，1_二甲基乙基）氧基]羰基}胺基) 甲基]苯甲酸（0.501克，2.0毫莫耳）、EDC (0.612克，3.2毫莫 耳）及ΗΟΒΤ (0.35克，2.6毫莫耳）在DMF (2毫升）中之經攪拌溶 液内。將所形成之混合物於室溫下攪拌過夜。在真空中移 除溶劑，並使殘留物溶於醋酸乙酯（2〇毫升）中，且以〇·5Μ-鹽 酸（3 χ20毫升）洗滌。使有機相脫水乾燥,及在真空 中蒸發’獲得粗產物，使其藉Biotage層析（碎膠）純化，以醋 酸乙酿：環己烷（1.3 : 1)溶離，而得中間物7〇，為白色固體 (0.512 克）。LCMS 顯示 MH+=291; Tret=2.75 分鐘。 土-間物71 : 4_(胺基甲基)環丙基苯甲醯胺里酸鹽Add cyclopropylamine (0.136 g, 2.39 mmol) to diisopropylethylamine (〇68 mL '3.9 mmol) to 4·[({[(1,1_dimethyl) Alkyloxy]carbonyl}amino)methyl]benzoic acid (0.501 g, 2.0 mmol), EDC (0.612 g, 3.2 mmol) and hydrazine (0.35 g, 2.6 mmol) in DMF (2) In a stirred solution in milliliters). The resulting mixture was stirred at room temperature overnight. The solvent was removed in vacuo and the residue was crystalljjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj The organic phase is dehydrated and dried, and evaporated in vacuo to give a crude product which is purified by Biotage chromatography (separation) and eluted with ethyl acetate: cyclohexane (1.3:1) to give an intermediate. As a white solid (0.512 g). LCMS showed MH+ = 291; Tret = 2.75 min. Soil-intermediate 71 : 4_(Aminomethyl)cyclopropylbenzamide

AA

•HCI 於氮氣下，使中間物70(0.506克，1J4毫莫耳）溶於氯化童 在二氧陸圜中之溶液(20毫升，4M)内。1小時後，將甲醇 毫升）添加至混合物中，並在室溫下持續攪拌過夜。在真竺 中移除溶劑，而得中間物71，為白色固體（〇416克）^ lcmj 87841 -960303-φ .doc -148- 1283678 顯示 MH+= 191 ; TRET= 0·82 分鐘。 中間物72• HCI Under nitrogen, intermediate 70 (0.506 g, 1 J4 mmol) was dissolved in a solution of chlorinated children in dioxane (20 mL, 4 M). After 1 hour, methanol (ml) was added to the mixture and stirring was continued at room temperature overnight. The solvent was removed in hexane to give Intermediate 71 as a white solid ( 416 g) </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; Intermediate 72

使中間物33 (1.36克，4·7毫莫耳）、EDC (1·26克，6.57毫莫 耳）及ΗΟΒΤ (0.76克，5.62毫莫耳）懸浮於DMF (5〇毫升）中，並 在罜溫下激烈攪拌0.5小時，然後添加4_(胺基甲基）六氫吡 呢羧酸1，1-二甲基乙酯（1.3克，6·07毫莫耳，可市購得自 Maybridge化學公司）。於室溫下攪拌過夜後，將另一數量之车 (胺基甲基）-ι-六氫吡啶羧酸u_二甲基乙酯（1〇1克，4·7毫莫 耳）添加至反應混合物中，然後將其在5〇〇c下加熱。6小時 後，添加二異丙基乙胺（〇·25毫升，144毫莫耳），並將混合 物於50 C下再保持6小時。在真空中移除溶劑，並使殘留物 於DCM(100毫升）與水（1〇〇毫升）之間作分液處理。藉由經過 疏水性玻料分離液相，並使有機相在真空中蒸發，獲得粗 產物。使用SPE藥筒（胺基丙基，接著矽膠）進一步純化，獲 得中間物72，為乳黃色固體（1.24克）。LCMS顯示_+==487 ,· Tret = 2·97 分鐘。 中間物73 中間物73係當場使用在關於實例360-414之一般程序中。 也^’物74 : ({3·[(乙醯胺基）甲基】苯基}甲基）胺基甲酸14-二甲 87841-960303-nf3.d〇c -149- 1283678 基乙酯Intermediate 33 (1.36 g, 4.7 mmol), EDC (1. 26 g, 6.57 mmol) and hydrazine (0.76 g, 5.62 mmol) were suspended in DMF (5 mL). Stir vigorously at room temperature for 0.5 hours, then add 1,1-dimethylethyl 4-(aminomethyl)hexahydropyranoate (1.3 g, 6.07 mmol, commercially available from Maybridge Chemical company). After stirring at room temperature overnight, another quantity of car (aminomethyl)-ι-hexahydropyridinecarboxylic acid u-dimethylethyl ester (1 〇 1 g, 4.7 mmol) was added to The reaction mixture was then heated at 5 °c. After 6 hours, diisopropylethylamine (25 ml, 144 mmol) was added and the mixture was kept at 50 C for an additional 6 hours. The solvent was removed in vacuo and the residue was partitioned between DCM (100 mL) and water (1 mL). The crude product is obtained by separating the liquid phase through a hydrophobic glass and evaporating the organic phase in vacuo. Further purification was carried out using an SPE cartridge (aminopropyl, followed by silica gel) to afford intermediate 72 as a creamy solid (1.24 g). LCMS showed _+==487, · Tret = 2.97 minutes. Intermediate 73 Intermediate 73 is used on the spot in the general procedure for examples 360-414. Also ^'74: ({3·[(ethylamino)methyl]phenyl}methyl)carbamic acid 14-dimethyl 87841-960303-nf3.d〇c -149- 1283678 ethyl ester

殘留物於EtOAc與水之間作分液處理。 。使有機相脫水乾燥 (MgS04)，及在真空中蒸發。使殘留物於珍膠上層析，以己 烷· EtOAc(l · 1)，接著以Et〇Ac溶離，而得中間物74(12 克）’為播色油。分析實測值：c，64 79 ; H，7 93 ; 1^10.10.(^5¾2]^3 需要 c，64 73 ; Η, 7.97 ； Ν, 10.06. MS (M+Na)+301. 电間物75 : N-{[3-(胺基甲基）苯基]甲基}乙醯胺鹽酸鹽The residue was partitioned between EtOAc and water. . The organic phase was dried (MgS04) and evaporated in vacuo. The residue was chromatographed on EtOAc (EtOAc) (EtOAc) Analytical measured values: c, 64 79 ; H, 7 93 ; 1^10.10. (^53⁄42]^3 Requires c, 64 73 ; Η, 7.97 ; Ν, 10.06. MS (M+Na)+301. 75 : N-{[3-(Aminomethyl)phenyl]methyl}acetamide hydrochloride

將二氧陸圜中之氯化氳（4毫升，4M)添加至中間物74 (1.0 克，3.6毫莫耳）在二氧陸圜（10毫升）中之溶液内，並於20°C 下將所形成之混合物攪拌6小時。將反應物以Et20 (20毫升） 稀釋，並過濾，而得中間物75 (0·7克），為白色固體。 MSMH+179. iHNMROOOMHz，在 d6-DMSO *，27°C，（5ppm)(5 8.6-8·4 (br m，3H)， 7.38-7.26 (m5 3H)，7·22 (bm，1H)，4.24 (d，J = 5·7Ηζ，2H)， 87841-960303-中.doc -150- 1283678 3.95 (dd，J = 11.6，5·7Ηζ，2H)，1.87 (s，3H)· 實例表 實例 編號 名稱 1 4-(環戊基胺基）-1·乙基-1H-吡唑并[3,4-b]吡啶-5_羧酸乙酯 2 4-(環己胺基）-1•乙基_1Η·吡唑并『3,4-b]吡啶-5-羧酸乙酯 3 1-乙基-4-(四氫-2H-哌喃斗基胺基）-1Η-吡唑并[3,4-b]吡啶-5-羧酸乙酯 4 4-[(1-甲基六氫吡啶-4_基）胺基]小乙基-1H-吡唑并[3,4_b] 吡啶-5-羧酸乙酯 5 4_[(1-乙醯基六氫吡啶-4-基）胺基]-1-乙基-1H-吡唑并[3,4-b]吡啶-5-羧酸乙酯 6 4-(環戊基胺基）·1_甲基-ih_p比吐并[3,4_b]p比淀-5·叛酸乙酉旨 7 1-甲基·4_(四氫-2H-哌喃-4-基胺基）-1Η-吡唑并[3,4-b]吡啶-5-羧酸乙酯 8 1-乙基-4-[(3S)-四氫呋喃-3·基胺基]-1H-吡唑并[3,4-b]吡啶-5-羧酸乙酯 9 1-乙基-4-[(3R)-四氫呋喃；基胺基]·1Η·吡唑并[3,4七]吡啶-5-羧酸乙酯 10 1-乙基_4-(四氫_2Η-硫代哌喃-4-基胺基）-1Η-吡唑并[3,4-b] 吡啶-5·羧酸乙酯 11 1-乙基-4-(四氫噻吩_3_基胺基）_1H•吡唑并[3,4_b⑽啶_5_羧 酸乙酯 12 土^環丙)+乙基吡唑并[3,4_b]吡啶_5_羧酸乙酯 13 ‘叽，1·二氧化四氫嘧吩_3_基）胺基]-1-乙基-1H-吡唑并 [3,4-b]吡啶羧酸乙酯 14 4-[(1，1_一氧化四氫_2H_硫代哌喃_4基）胺基]―丨·乙基_ih_ 吡啶-5-羧酸乙酯 21 下基-1·乙基+(四氫-2H-哌喃-4_基胺基）-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺 8784l-96〇3〇3-中.doc 151- 22 ' ..... ..... 1·乙基-N_(4-氣苯基&gt;4-(四氫-2Η·旅喃-4·基胺基）_1H_吡唑 并[3,4-b]吡啶-5-甲醯胺 23 N_環戊基-4_(環戊基胺基）+乙基_1H—吡唑并[3,4_b]吡啶一 5-甲醯胺 24 4_(環己胺基）-N_環戊基-1-乙基_1H_吡唑并[3,4七&gt;比啶-5- 甲醯胺 25 N-環戊基-1-乙基-4-(四氫痕喃-4-基胺基）_1H〜比峻并 [3,4-b]吡啶-5-甲醯胺 27 4-[(1-乙醯基六氫吡啶-4-基）胺基]環戊基-1-乙基-1H-叶匕峻并[3,4-b]p比淀-5-甲醯胺 28 N_環戊基_1_乙基-5·(四氫吡咯-1-基羰基）_1H_吡唑并[3,4-b]吡啶-4-胺 29 N_環己基-1-乙基-5-(四氫吡咯-μ基羰基）_1H_吡唑并[3,4-b]p比淀-4-胺 30 1-乙基-5-(四鼠p比洛-1-基窥基）-N_四氯-2H-成喃-4-基·1Η_ 外匕峻并[3,4-b]e比淀-4-胺 31 4-(環戊基胺基）小乙基-N七比啶-4-基甲基）-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺 32 4-(環己胺基）·1_乙基-N-(吡啶冬基甲基）_1H-吡唑并[3,4-b] 吡啶-5-甲醯胺 33 1-乙基-N-(吡啶斗基甲基）冰(四氫-2H-哌喃-4-基胺基）_1Η· 吡唑并[3,4-b]吡啶-5-甲醯胺 34 4·(環戊基胺基）-1-乙基-1H-吡唑并[3,4-b]吡啶-5-甲醯胺 35 4-(環己胺基）小乙基比峻并[3,4-b]外(：淀-5-甲酿胺 36 1_乙基-4-(四氮-2H-旅喃-4-基胺基比嗤并[3,4_b]p比淀- 5-甲醯胺 39 N-宇基-4-(環戊基胺基）-1-乙基-1H-P比唆并[3,4-b]p比淀-5- 甲醯胺 40 N_苄基-4-(環己胺基）小乙基-1H-吡唑并[3,4七]吡啶-5-甲 醯胺 41 4-[(1-乙酸基六氯p比淀-4-基）胺基]_^1_爷基_1_乙基_1H-外匕 唑并[3,4-b]吡啶-5-甲醯胺 87841-960303-中.doc -152- 1283678The ruthenium chloride (4 ml, 4 M) in dioxane was added to a solution of intermediate 74 (1.0 g, 3.6 mmol) in dioxane (10 mL) at 20 ° C The resulting mixture was stirred for 6 hours. The reaction was diluted with EtOAc (20 mL). MSMH+179. iHNMROOOMHz, in d6-DMSO*, 27°C, (5ppm) (5 8.6-8·4 (brm, 3H), 7.38-7.26 (m5 3H), 7·22 (bm, 1H), 4.24 (d, J = 5·7Ηζ, 2H), 87841-960303-中.doc -150- 1283678 3.95 (dd, J = 11.6, 5·7Ηζ, 2H), 1.87 (s, 3H)· Example table instance number Name 1 4-(cyclopentylamino)-1·ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester 2 4-(cyclohexylamino)-1•B Ethyl-1-pyrido[3,4-b]pyridine-5-carboxylic acid ethyl ester 3- 1-ethyl-4-(tetrahydro-2H-piperidinylamino)-1Η-pyrazolo[ Ethyl 3,4-b]pyridine-5-carboxylate 4 4-[(1-methylhexahydropyridin-4-yl)amino]ethylethyl-1H-pyrazolo[3,4_b]pyridine- 5-carboxylic acid ethyl ester 5 4_[(1-ethylhydrazinylhexahydropyridin-4-yl)amino]-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid Ethyl 6 4-(cyclopentylamino)·1_methyl-ih_p than spit[3,4_b]p than y-5-repulsive oxime 7 1-methyl·4_(tetrahydro-2H- Ethyl pyl-4-ylamino)-1 Η-pyrazolo[3,4-b]pyridine-5-carboxylate 8 1-ethyl-4-[(3S)-tetrahydrofuran-3-ylamino -1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester 9 1-ethyl-4-[(3R)-tetrahydrofuran Alkylamino]·1Η·pyrazolo[3,4hepta]pyridin-5-carboxylic acid ethyl ester 10 1-ethyl_4-(tetrahydro-2-indole-thiopiperazin-4-ylamino) -1Η-pyrazolo[3,4-b]pyridine-5-carboxylate ethyl ester 11 1-ethyl-4-(tetrahydrothiophene-3-ylamino)_1H•pyrazolo[3,4_b(10)pyridine _5_Carboxylic acid ethyl ester 12 Earth^cyclopropyl)+ethylpyrazolo[3,4_b]pyridine_5_carboxylic acid ethyl ester 13 '叽,1·tetrahydropyrimidine _3_yl)amine Ethyl 1-ethyl-1H-pyrazolo[3,4-b]pyridinecarboxylic acid ethyl ester 14 4-[(1,1_monotetrahydro-2-H-thiopiperan-4-yl)amine Base]-丨·ethyl_ih_pyridine-5-carboxylate ethyl ester 21 lower group-1·ethyl+(tetrahydro-2H-piperidin-4-ylamino)-1Η-pyrazolo[3, 4-b]pyridine-5-carboxamide 8874l-96〇3〇3-中.doc 151- 22 ' ..... ..... 1·ethyl-N_(4-gasphenyl) 4-(tetrahydro-2Η·jol-4'ylamino)_1H_pyrazolo[3,4-b]pyridine-5-carboxamide 23 N_cyclopentyl-4_(cyclopentylamino) )+ethyl_1H-pyrazolo[3,4_b]pyridine-5-methalamine 24 4_(cyclohexylamino)-N-cyclopentyl-1-ethyl_1H-pyrazolo[3, 4-7&gt;bipyridine-5-carbamidamine 25 N-cyclopentyl-1-ethyl-4-(tetrahydroindol-4-ylamino)_1H~ [3,4-b]pyridine-5-carbamidamine 27 4-[(1-ethylhydrazinylhexahydropyridin-4-yl)amino]cyclopentyl-1-ethyl-1H- 匕 匕 并 [3 , 4-b]p, butyl-5-carbamamine 28 N_cyclopentyl_1_ethyl-5·(tetrahydropyrrole-1-ylcarbonyl)_1H-pyrazolo[3,4-b] Pyridin-4-amine 29 N_cyclohexyl-1-ethyl-5-(tetrahydropyrrole-μ-ylcarbonyl)_1H-pyrazolo[3,4-b]p-precipitate-4-amine 30 1-B -5-5-(tetra-m mouse p-l-l-l-pyrenyl)-N-tetrachloro-2H-forman-4-yl·1Η_ 外匕峻[3,4-b]e ratio -4- Amine 31 4-(cyclopentylamino)ethylidene-N-pyridin-4-ylmethyl)-1Η-pyrazolo[3,4-b]pyridine-5-carboxamide 32 4-( Cyclohexylamino)·1-ethyl-N-(pyridylmethyl)_1H-pyrazolo[3,4-b]pyridine-5-carboxamide 33 1-ethyl-N-(pyridine bucket Methyl) ice (tetrahydro-2H-piperidin-4-ylamino)_1Η·pyrazolo[3,4-b]pyridine-5-carbamimid 34 4·(cyclopentylamino)- 1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 35 4-(cyclohexylamino)ethylidene than benzo[3,4-b] -5-Artemisylamine 36 1_ethyl-4-(tetrazine-2H-bromo-4-ylaminol 嗤[3,4_b]p than yttrium- 5-carbamide 39 N-Yuji -4-(cyclopentylamino)-1-ethyl -1H-P is more than [3,4-b]p than pent-5-carbamamine 40 N-benzyl-4-(cyclohexylamino)ethylidene-1H-pyrazolo[3,4 VII]pyridin-5-formamide 41 4-[(1-acetoxyhexachlorop-precipitate-4-yl)amino]]^1_yl-1_1-ethyl_1H-exocarbazole 3,4-b]pyridine-5-methamine amine 87841-960303-中.doc -152- 1283678

42 4-(環戊基胺基）小乙基-Ν_(2·乙基丁基）-1Η-吡唑并[3,4-b] 吡啶-5-甲醯胺 43 4-(環己胺基）小乙基-N-(2-乙基丁基）-1Η-吡唑并[3,4-b]吡 淀-5-甲酿胺 44 1-乙基-N-(2-乙基丁基）-4-(四氫-2H_旅喃-4-基胺基）·1Η-口比 唑并『3,4-b]吡啶-5-甲醯胺 45 1-乙基-N-(2-乙基丁基）-4-[(1_甲基六氫吡啶-4-基）胺基]-1H-吡唑并[3,4-b]吡啶-5-甲醯胺 46 4-[(1-乙酿基六氫p比淀-4-基）胺基]-1-乙基-N-(2-乙基丁 基）-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺 47 4-(環戊基胺基）-1-乙基-Ν·(4-氣苯基）-1Η-ρ比嗅并[3,4-b] 口比 淀-5-甲酸胺 48 4- (環己胺基）小乙基-Ν-(4·氟苯基）-1Η·吡唑并[3,4-b]吡啶- 5- 甲醯胺 49 1-乙基-N-(4-氟苯基）-4-[(1-甲基六氫吡啶-4-基）胺基]-1H_ 吡唑并[3,4-b]吡啶-5-甲醯胺 50 4-[(1-乙醯基六氫吡啶-4-基）胺基]小乙基-N-(4-氟苯基）-1H-吡唑并[3,4-b]吡啶·5_甲醯胺 51 4- (環戊基胺基）-1-乙基-Ν·正-丙基-1Η-吡唑并[3,4-b]吡啶- 5- 甲醯胺 52 4-(環己胺基）小乙基-N-正-丙基-1H-吡唑并[3,4-b]吡啶-5- 甲醯胺 53 1-乙基-N-正_丙基-4-(四氫-2H-哌喃_4·基胺基）-1Η-吡唑并 [3,4-b]吡啶-5-甲醯胺 55 4-[(1-乙醯基六氫吡啶_4-基）胺基]-1-乙基-N-正·丙基-1H-吡唑并[3,4-b]吡啶-5-甲醯胺 56 N-爷基-1-乙基-4·[(1-甲基六氫p比淀-4-基）胺基]-1H-P比峻 并[3,4-b]吡啶-5-甲醯胺 57 4-[(1-乙醯基六氫吡啶-4-基）胺基]-1-乙基-N-(吡啶冰基甲 基）-1Η-ρ比吐并[3,4-b]外b淀-5-甲疏胺 61 N-苄基-4-(環戊基胺基）-1_甲基-1H-吡唑并[3,4-b]吡啶-5- 甲醯胺 87841-960303-中.doc -153- 1283678 62 Ν·苄基-4-(環己胺基）小甲基-1H-吡唑并[3，4-b]吡啶-5-甲 醯胺 63 N_苄基-1-甲基·4-(四氫-2H-哌喃-4-基胺基）-lH-吡唑并[3,4-b]吡啶-5-甲醯胺 64 4-(環戊基胺基）-N-(2-乙基丁基）小甲基-1H-吡唑并[3,4七] 吡啶-5-甲醯胺 65 4-(環己胺基）-N-(2-乙基丁基）小甲基-1H-吡唑并[3,4-b]吡 淀-5-甲酿胺 66 汴(2_乙基丁基）-1-甲基-4-(四氫-2H-哌喃·4_基胺基）-1Η-吡 唑并[3,4-b]吡啶-5-甲醯胺 67 4-(環戊基胺基）-N-(4-氟苯基）-1-甲基-1H-吡唑并[3,4-b]吡 淀-5-甲酿胺 68 4·(環己胺基）-N-(4-氟苯基）小甲基·1Η-吡唑并[3,4-b]吡啶-5-甲醯胺 69 N-(4_氟苯基）-1•甲基-4-(四氯-2H_喊喃_4_基胺基比峡 并[3,4-b]吡啶-5-甲醯胺 70 4-(環戊基胺基）小甲基-1H-吡唑并[3,4-b]吡啶-5-甲醯胺 71 4-(環己胺基）-1-甲基-1H-吡唑并[3,4-b]吡啶-5-甲醯胺 72 1-甲基冬(四氫-2H-哌喃-4·基胺基）-1Η-吡唑并[3,4-b]吡啶- 5-甲醯胺 74 4·[(1-乙醯基六氫吡啶_4_基）胺基]-N-苄基小甲基-1H-吡 唑并[3,4-b]吡啶-5-甲醯胺 76 4-[(1·乙醯基六氫吡啶-4-基）胺基]-N-(2-乙基丁基）-1-甲 基-1H-外b唆并[3,4-b&gt;比咬-5-甲醯胺 78 4-[(1-乙醯基六氫吡啶-4-基）胺基]-N-(4-氟苯基）-1·甲基-1H-外1：也并[3,4-b]p比淀-5_甲醯胺 81 1-乙基-N-甲基冬(四氫-2H-哌喃斗基胺基）-1Η·吡唑并[3,4-比淀-5-甲醯胺 82 1-乙基_N，N-二甲基-4·(四氫-2H-哌喃-4-基胺基）-1Η-吡唑 并[3,4-b]吡啶-5-甲醯胺 83 1-乙基-N-乙基-4_(四氯_2H-旅喃-4-基胺基）-1Η-ρ比峻并[3,4-b]吡啶-5-甲醯胺 87841-960303-中.doc -154- 1283678 84 1_乙基-N-異丙基_4-(四氫-2H-哌喃-4_基胺基）_111_吡唑并 [3,4-b]p比淀-5-甲酿胺 85 N-苄基-1-乙基-4-[(3S)-四氫呋喃_3_基胺基]-1H吡唑并 [3,4-b]p比淀-5-甲酸胺 86 N-苄基-1-乙基·4·[(3Κ&gt;四氫呋喃基胺基]-1H-吡唑并 [3,4七]吡啶-5-甲醯胺 87 Ν-芊基-1-乙基_4-(四氫嘧吩_3_基胺基）_ΐΗ_吡唑并[3,4-b] 吡啶-5-甲醯胺 88 N-苄基-4-(環丙胺基）-1-乙基吡唑并[3,4-b]吡啶-5-甲 醯胺 89 N·苄基_4-[(1，1-二氧化四氫嘧吩_3_基）胺基]小乙基]凡吡 唑并[3,4-b]吡啶-5-甲醯胺 90 N-苄基-4-[(1，1-二氧化四氫-2H-硫代哌喃_4·基）胺基]-1-乙 基-1H-吡唑并[3,4-b]吡啶-5-甲醯胺 91 N-苄基_1_乙基-4-(四氫_2H-硫代喊喃_4·基胺基）-1Η-吡唑 并[3,4-b]p比淀-5-甲酿胺 92 1·乙基-N-(4-氟苯基）-4-[(3S)-四氫呋喃-3-基胺基]·1Η-吡唑 并[3,4-b]口比淀-5-甲酿胺 93 1-乙基_N-(4-氟苯基）-4-[(311)_四氫呋喃-3-基胺基]-1H-吡唑 并[3,4-b]p比淀-5-甲酿胺 94 1·乙基-N-(4_氟苯基）_4_(四氫-2H_硫代喊喃-4-基胺基）-1Η- 吡唑并[3,4-b]吡啶-5_甲醯胺 95 1-乙基-N-(4-氟苯基）-4·(四氫p塞吩-3-基胺基）_ih-p比峻并 [3,4-b]外匕咬·5·甲醯胺 96 4- (環丙胺基）小乙基-Ν-(4_氟苯基）_1Η_吡唑并[3,4-b]吡咬- 5- 甲醯胺 97 4_[(1，1_二氧化四氫嘧吩-3-基）胺基]-i_乙基_N_(4_氟苯基）_ 1H-吡唑并[3,4-b]吡啶-5-甲醯胺 98 4-[(1，1_二氧化四氫-2H·硫代喊喃-4_基）胺基]-1·乙基·Ν_(4_ 氟苯基）-1Η4也并[3,4_b]p比違-5-甲醯胺 87841-960303-中.doc -155- 1283678 實例 編號 名稱 100 1-乙基-N-[4-(甲續縫基）爷基]_4-(四氫底喃-4-基胺基）-1Η_吡唑并[3,4-b]吡啶-5_甲醯胺 101 (1-{[1_乙基冰(四氫-2H-哌喃_4_基胺基）-1Η-吡唑并[3,4七] 口比淀-5-基]羰基}六氫峨淀-3-基）甲基胺基甲酸第三-丁酯 102 1-乙基·Ν_[3-(甲績酸基）辛基]-4-(四氫-2H-喊喃-4-基胺基）-1H-吡唑并[3,4-b]吡啶-5-甲醯胺 103 1-乙基_5-{[5-甲氧基-6-(三氟甲基）-2,3-二氫-1H-巧丨哚-1-基] 数基}-N四氫-2H-喊喃-4-基-1H-P比峻并[3,4-b]峨淀-4-胺 104 N_[(5-氯基吡啶-2-基）甲基]·1_乙基-4-(四氫-2H-哌喃-4_基 胺基）·1Η_吡唑并[3,4-b]吡啶-5-甲醯胺 105 N_(4_氟卞基）-1_乙基-N_異丙基-4_(四氫-2H-峰喃-4_基胺 基）-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺 106 N-(3-氯苄基）-1-乙基_N_(2-羥乙基）冬(四氫-2H-哌喃-4_基 胺基比吐并[3,4_b]p比淀甲酿胺 107 1-乙基_N_[(5_甲基-3-苯基異吟吨_4_基）甲基]-4-(四氫-2H-哌喃-4-基胺基）-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺 108 Ν-(2·第三·丁氧基乙基）小乙基-4·(四氫_2Η·喊喃-4-基胺 基）-1Η-ρ比峻并[3,4-b]p比淀-5-甲酿胺 109 1-乙基-4-(四氫-2H-哌喃·4·基胺基）-Ν-(1，3-嘧唑-2-基甲基）-lH-ρ比也并[3,4-b]p比淀-5-甲醯胺 110 1-乙基-N七密啶_4_基甲基）-4-(四氫_2H-哌喃_4·基胺基）-1Η-口比峻并[3,4-b]p比淀-5-甲酿胺 111 1·乙基-N-[(2-甲基塞唆-4-基）甲基]_4_(四氫_2Η4喃_4_ 基胺基）-1Η-ρ比吐并[3,4-b]p比淀-5_甲醯胺 112 N_[3-(第三-丁氧基甲基）爷基]小乙基-4-(四氫-2H_喊喃-4-基胺基ΗΗ-ρ比峻并[3,4-b&gt;比淀-5-甲醯胺 113 1-乙基-Ν·{2-[甲基（甲磺醯基）胺基]乙基}-4_(四氫_211_哌 喃-4-基胺基）_1Η_ρ比吐并[3,4-b]p比淀-5_甲驢胺 114 1·乙基·Ν-(ρ比哨1 _2·基甲基）-4-(四氫-2H-喊喃-4-基胺基）-1Η-外匕吐并[3,4-b]峨淀-5-甲酸胺 87841-960303-中.doc -156- 115 1-乙基-5-{[4-(吡啶-2-基羰基）六氫吡畊-1-基]羰基}-N-四 氫-2H-哌喃·4-基-1H-吡唑并[3,4-b]吡啶-4-胺 116 N-(2-氯基-6-氟基苄基）小乙基-4_(四氫-2H-哌喃-4_基胺 基）-1Η-吡唑并[3,4-b]吡啶-5_甲醯胺 117 1_乙基-N_[(6-酬基_1，6_二鼠p比淀-3-基）甲基]-4-(四氯-2H-口底 喃-4-基胺基）-1Η-ρ比峻并[3,4-b]p比淀-5-甲酿胺 118 N-[3-(胺基羰基）苄基]小乙基·4_(四氫-2H-哌喃_4_基胺基)-1Η-吡唑并P，4-b]吡啶-5-甲醯胺 119 1-乙基-N-{4-[(甲胺基）羰基]苯基卜4-(四氫-2H-哌喃冰基 胺基）-1Η·吡唑并[3,4_b]吡啶-5-甲醯胺 120 1-乙基-N-[2-(l-甲基·1Η-味吐-4_基）乙基]-4-(四氮-2H_旅喃· 4-基胺基）-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺 121 N-{2-[(苯胺基魏基）胺基]乙基}-1-乙基_4-(四氫-2H-喊喃_ 4-基胺基）-1Η-吡唑并[3,4-b]吡啶_5_甲醯胺 122 1-乙基-N-(1H-四吐-5-基甲基）-4-(四氮-2H-略喃-4-基胺基）-1H·吡唑并[3,4-b]吡啶-5-甲醯胺鹽酸鹽 123 I-乙基-4-(四氮-2H-旅喃-4-基胺基）-Ν-[2-(1Η-1，2,4-三嗤·1_ 基）乙基]-1Η·吡唑并[3,4-b]吡啶-5-甲醯胺 124 2-[{[1-乙基-4·(四氮-2H-旅喃_4_基胺基比吨并[3,4-b] 吡啶-5-基]羰基}(甲基）胺基]乙基胺基甲酸第三-丁酯 125 1-乙基-4-(四氣-2Η_ρ底喃-4-基胺基）-N_[4_(三氟1甲基）苯基]一 1H-吡唑并|；3,4-b]吡啶-5-甲醯胺 126 4_({[1-乙基-4-(四氮-2H-旅喃-4-基胺基）-1Η-ρ比峻并[3,4-b] 吡淀·5_基]羰基}胺基）六氫p比淀小叛酸第三-丁酯 127 1-乙基_Ν-{3-[(甲績醯基）胺基]丙基}-4-(四氫-2Η-旅喃_4· 基胺基）-1Η_外b吐并[3,4-b]外b淀-5_甲酿胺 128 N-[2_(二甲胺基）爷基]小乙基_4_(四氫_2Η-ϊ痕喃-4-基胺基）_ 1Η-吡唑并[3,4-b]吡啶_5_甲醯胺 129 1-乙基-Ν-[(1·乙基四氫ρ比洛-2·基）甲基]-4-(四氫-2H-喊喃-4-基胺基）-1Η-ρ比吐并[3,4-b&gt;比淀-5_甲醯胺 130 1-乙基-N-(四氫呋喃-2-基甲基）-4-(四氫-2H-哌喃-4_基胺 基）-1Η·吡唑并[3,4-b]吡啶-5·甲醯胺 87841-960303-中.doc -157- 131 1-乙基-N-四氯-2H-喊喃·4-基-4-(四氯-2H-旅喃-4·基胺基） 1Η-吡唑并[3,4-b]吡啶-5_甲醯胺 132 N-{4_[(二甲胺基）磺醯基]爷基}小乙基冬(四氫_2H-哌喃-4-基胺基）-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺 133 1-乙基_N-{3-[(甲磺醯基）胺基]苄基}-4-(四氫-2H-哌喃-4-基胺基）-1Η&gt;比也并[3,4-b]外b淀-5-甲醯胺 134 M[l_乙基-4-(四氫-2H-哌喃-4-基胺基）·1Η-吡唑并[3,4_b]吡 啶_5_基]羰基}六氫吡啶-2-甲醯胺 135 1-乙基-N-(4-甲氧苯基）冰(四氫-2H-哌喃-4_基胺基）-1Η-毗 吐并[3,4-b&gt;比淀-5-甲酸胺 136 1-乙基-Ν-[3·(2·酮基四氫吡咯-1_基）丙基]-4-(四氫-2H_哌 喃-4-基胺基）-1Η-ρ比吐并[3,4-b]p比淀-5-甲酿胺 137 1-乙基-N-[2-(l-甲基四氫吡咯-2_基）乙基]-4-(四氫-2H-哌 喃-4_基胺基）-1Η-ρ比峻并[3,4-b]p比淀-5-甲酿胺 138 1-乙基-Ν-(ρ比淀-3-基甲基）-4_(四氯-2H-喊喃-4_基胺基）-1Η· 吡唑并[3,4-b]吡啶-5-甲醯胺 139 1_乙基-N-(l-甲基穴氮外b淀-4-基）-4-(四氯-2H-喊喃_4·基胺 基）-1Η-吡唑并[3,4-b]吡啶_5_甲醯胺 140 1-乙基-N-(l-乙基丙基）-4-(四氫-2H-哌喃-4-基胺基）_1H-毗 唑并[3,4-b]吡啶-5-甲醯胺 141 1-乙基-N-(2-六氯ρ比淀-1-基乙基）-4-(四氮-2H-喊喃-4-基胺 基）-1Η_ρ比哇并[3,4_b]p比淀-5·甲酿胺 142 1-乙基-N-(3-嗎福淋-4-基丙基）-4_(四氣·2Η_喊喃-4-基胺 基）-1Η-^嗅并[3,4~b]p比淀-5·甲酿胺 143 N-(3-乙氧基丙基）-1-乙基-4-(四氫喃_4_基胺基）-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺 144 N-(環己基甲基）小乙基-4-(四氫-2H-喊喃-4-基胺基）-1Η-ρ比 唑并[3,4-b]吡啶-5-甲醯胺 145 N-[3_(二甲胺基）丙基]-1·乙基斗(四氫_2H-哌喃-4_基胺基）-1H-吡唑并[3,4-b]吡啶_5_甲醯胺 146 1-乙基-N-新戊基-4-(四氯-2H·喊喃-4_基胺基）-1Η-^比吐并 [3,4-b]p比淀-5-甲醯胺 87841-96〇3〇3·中.doc -158 - 1283678 147 1-乙基-Ν·(4-甲氧基字基）-4-(四氫派喃-4-基胺基）-1Η-吡唑并[3,4_b]吡啶_5_甲醯胺 148 1-乙基·Ν_{2·[(苯續酸基）胺基]乙基}-4-(四氫-2H碌喃-4-基胺基）·1Η-吡唑并[3,4-b]吡啶-5-甲醯胺 149 N-[2-(乙醯胺基）乙基]小乙基_4-(四氫-2H-哌喃-4-基胺基）-1H-吡唑并[3,4_b]吡啶-5-甲醯胺 150 1-乙基-N-{2_[(甲續酿基）胺基]乙基}-4-(四氫_2H«^底喃-4-基胺基）-1Η-ρ比峻并[3,4-b]p比淀-5-甲酿胺 151 1·乙基-N-甲基-N-(p比症·4_基甲基）-4-(四氫-2H-喊喃-4-基 胺基比吐并[3,4-b&gt;比啶-5-甲醯胺 152 1-乙基-Ν·{2·[(2·甲氧苯基）(甲基）胺基]乙基卜4-(四氫-2H-喊喃-4_基胺基）-1Η-ρ比峻并[3,4-b]p比淀-5-甲醯胺 153 1-乙基-N-(2-酮基-2-苯基乙基）-4-(四氫-2H-喊喃-4-基胺 基）-1H-p比峻并[3,4-b]p比淀_5_甲酿胺 154 N-(2,5-二氟苄基）小乙基-4-(四氫-2H-哌喃·4-基胺基）_1H_ 吡唑并[3,4-b]吡啶-5-甲醯胺 155 1_乙基_4-(四氫-2H-哌喃-4·基胺基）-N-[4-(三氟甲基）爷基]-lH-p比峻并[3,4_b&gt;比淀-5_甲醯胺 156 N，l_二乙基-N-丙基-4-(四氫-2H-哌喃-4-基胺基）-1Η-吡唑 并[3,4-b]吡啶-5-甲醯胺 157 N-環丙基_1_乙基-4-(四氫-2H&gt;展喃-4_基胺基）-1Η-ρ比峻并 [3,4-b]吡啶-5-甲醯胺 158 N-(2-胺基-2-酮基乙基）-1_乙基_4_(四氫-2H-略喃_4_基胺 基）-1Η-吡唑并[3,4-b]吡啶-5·甲醯胺 159 1-乙基-N-(3-甲氧苯基）-4_(四氫-2H_哌喃-4_基胺基）_ih-吡 唑并[3,4-b]吡啶-5-甲醯胺 160 N-(3,4-二氟爷基）·1_乙基-4-(四氫·2Η_略喃-4_基胺基）_iH-吡唑并[3,4-b]吡啶-5-甲醯胺 161 3-({[1-乙基-4-(四氫-2H-哌喃·4_基胺基）_1Η·吡唑并[3,4-b] 外匕淀-5-基]羰基}胺基）丙酸乙酯 162 N-(l_卞基7T比咬-4-基）-1-乙基-4-(四氫-2H-口底喃《4-基胺 基）-1Η-吡唑并[3,4-b]吡啶-5-曱醯胺 87841-960303-中.doc -159- 1283678 163 N_丁基-4-{[l-乙基-4-(四氫-2H-哌喃-4_基胺基）-1Η-吡唑并 [3，4-b]吡啶-5-基]羰基}六氫吡畊小甲醯胺 164 1-乙基-4·(四氫-2H-哌喃-4-基胺基）-Ν-(1，3,4_嘧二唑-2_基）_ 1H-吡唑并[3,4七]吡啶-5-甲醯胺 165 Ν·(2,3-二氯-1H-節·2-基）_1_乙基-4-(四氯-2H-喊喃-4_基胺 基）-1Η_吡唑并[3,4-b]吡啶-5-甲醯胺 166 1_乙基-N-[2-(2-酮基咪唑啉啶-1-基）乙基]-4-(四氫-2H-哌 喃-4-基胺基）-1Η_吡唑并[3,4-b]吡啶-5-甲醯胺 167 N-(3,4-二甲氧基苄基）小乙基-4-(四氫-2Ημ派喃-4-基胺基）-1Η·吡唑并[3,4_b]吡啶-5_甲醯胺 168 N-(3-氯爷基）-1-乙基_4-(四氮-211-0瓜喃_4·基胺基）-111-0比峻 并[3,4-b]吡啶-5-曱醯胺 169 1-乙基-5-[(4·甲基六氫吡畊-1-基）羰基]_N_四氫-2H-哌喃斗 基-1H-吡唑并[3,4-b]吡啶-4-胺 170 1-乙基-N-(2_經乙基）-4_(四氯-2H-略喃-4-基胺基比峻 并[3,4-b]吡啶-5-甲醯胺 171 1-乙基-5-{[4-(4-甲氧苯基）六氫吡畊-1-基]羰基}-N-四氳-2H_哌喃-4-基-1H-吡唑并[3,4-b]吡啶-4_胺 172 1-乙基-N-{4-[(甲磺醯基）甲基]苯基}-4-(四氫-2H-哌喃-4-基胺基）-1Η-ρ比峻并[3,4_b]外b咬-5_甲醯胺 173 N-[3-(二甲胺基）·3-酮基丙基]小乙基_4-(四氫_2H_哌喃-4-基胺基）-1Η-ρ比吐并[3,4-b]外b淀-5-甲醯胺 174 1-乙基_N-[(1-甲基-1H-咪唑-5-基）甲基]-4-(四氫-2H·哌喃-4-基胺基HH-吡唑并[3,4-b]吡啶-5-甲醯胺 175 1-乙基-N-{4_[(甲胺基）績醯基]苯基卜4-(四氫-2H-哌喃-4-基胺基HH-吡唑并[3,4-b]吡啶-5_甲醯胺 176 N_(2_氯基乙基）_1_乙基_4-(四氯-2H-略喃-4·基胺基）-1Η-口比 唑并[3,4-b]吡啶-5-甲醯胺 177 1-乙基-N_甲基-N-[(5-甲基-1，3,4·咩二唑-2-基）甲基]-4-(四 氫-2H-旅喃-4-基胺基）_1H-吡唑并[3,4-b]吡啶-5-甲醯胺 178 1-乙基-Ν-[(1·甲基-1H_吡唑-4-基）甲基]-4-(四氫-2Ημ派喃-4_ 基胺基）_1Η-吡唑并[3,4-b]吡啶-5-甲醯胺 87841-960303-中.doc -160- 1283678 179 1-乙基-N-甲基·Ν-[(1-甲基-1H-咪唑-2-基）甲基]-4-(四氫，2H-旅喃-4-基胺基）-iH-吡唑并[3,4-b]吡啶-5-甲醯胺 180 1-乙基-4-(四氫-2H-哌喃-4-基胺基）-N-(2-嘧吩-2-基乙基）-1H-吡唑并[3,4七]吡啶-5-甲醯胺 181 Ν-[2·(4-氯苯基）乙基]—1-乙基冰(四氫-2H-哌喃-4-基胺基）_ 1Η-ρ比吐并[3,4-b]p比遠-5-甲酿胺 182 1-乙基-Ν·[2-(2-甲氧苯基）乙基]·4·(四氫-2H-哌喃-4-基胺 基）-1Η-吡唑并[3,4-b]吡啶_5_甲醯胺 183 4-(環己胺基）_1-(3-乙氧基-3-酮基丙基）-1Η-吡唑并[3,4-b] 吡啶-5-羧酸乙酯 185 1-正-丙基-4-(四氯-2H-»1 辰喃-4-基胺基比峻并[3,4-b]p比 啶-5-羧酸乙酯 186 1-(2-羥乙基）-4-(四氫-2H-哌喃_4_基胺基）-1Η-吡唑并[3,4七] 吡啶-5-羧酸乙酯 187 N-[4_(甲續酸基）爷基]_1_正-丙基-4-(四氫-2H_喊喃-4-基胺 基）_1H-吡唑并[3,4-b]吡啶-5-甲醯胺 188 N-(4-氟苯基）小正-丙基-4-(四氫-2H-喊喃-4-基胺基）·1Η-ρ比 唑并[3,4-b]吡啶-5-甲醯胺 189 1·乙基-6-甲基_4-(四氫-2H-哌喃_4_基胺基）_1H-吡唑并[3,4-b]吡啶-5-羧酸乙酯 190 4-(環己胺基）-1-乙基-6·甲基也并[3,4-b]p比淀-5-叛酸 乙酉旨 191 4-(環己胺基）-1•乙基-6-甲基-N-[4-(甲續醯基）爷基]比 唑并[3,4-b]吡啶-5-甲醯胺 192 N-爷基·4-(環己胺基）-1-乙基_6_甲基-1H-P比吐并[3,4-b]口比 淀-5-甲酿胺 193 4-(環己胺基）小乙基-N-(4-氟苯基）·6-甲基-1H-1T比也并[3,4_ b]外ti淀-5-甲縫胺 194 4-(環己胺基）-1·乙基-6·甲基抓[4-(三氟甲基）爷基]·1Η-吡 吐并[3,4-b]p比淀-5-甲酿胺 195 4-(環己胺基）_N-(2,3-二氫·1Η_雖-2-基）小乙基各甲基 吡唑并[3,4-b]吡啶-5-甲醯胺 87841-960303-中.doc •161- 1283678 196 N-芊基_1·乙基-6-甲基_4-(四氫-2H-哌喃_4_基胺基）-1Η-吡 唑并[3,4-b]吡啶-5-甲醯胺 197 N-爷基-1-乙基-4-[(2·酬基一氮七圜健-3-基）胺基]-lH-p比 唑并[3，4七]吡啶-5-甲醯胺 198 Ν·苄基-1-乙基-4·[(3-羥基環己基）胺基；ΜΗ-吡唑并[3,4-b] p比淀-5-甲酿胺，亦稱為N-爷基-1-乙基-4-[(3-經基壤己 烷小基）胺基]-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺 199 N·芊基-1·乙基-4-[(4-羥基環己基）胺基]-1H-吡唑并[3,4-b] 1(7比淀-5-甲酸胺，亦稱為N-卞基-1-乙基-4-[(4-裡基稼己 烷小基）胺基]-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺 200 N-苄基-1-乙基-4-[(3-羥基環戊基）胺基]_1H-吡唑并[3,4-b] p比淀-5-甲酸胺，亦稱為N-卞基-1-乙基-4-[(3·乡呈基壤戊 烷小基）胺基]-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺 201 N_苄基小乙基冰[(4_酮基環己基）胺基；MH-吡唑并[3,4_b] p比淀-5-甲酿胺，亦稱為N-卞基-1_乙基-4-[(4-嗣基J幕己 烷小基）胺基]_1H-吡唑并[3,4-b]吡啶-5-甲醯胺 202 1-乙基_N-(2-羥基小甲基乙基）-4-(四氫-2H-哌喃斗基胺 基）-1Η-吡唑并[3,4-b]吡啶-5·甲醯胺 203 (2S)-2-({[l-乙基-4-(四氮-2H-旅喃-4-基胺基）-1Η-ρ比吐并 [3,4-b]吡啶-5-基]羰基}胺基）-3-羥基丙酸甲酯 實例 編號 名稱 204 1-乙基4-[(4-羥基環己基）胺基]-1H-吡唑并[3,4七]吡啶-5·羧 酸乙酯 205 1-乙基4-[(4-酮基環己基）胺基]-1H-吡唑并[3,4-b]吡啶-5-羧 酸乙酯 207 4·[(1-乙醯基-4-六氫吡啶基）胺基]-1-乙基_1H-吡唑并[3,4-b]吡啶-5_羧酸乙酯 209 4-[(4-胺基環己基）胺基]-1-乙基_1Η·吡唑并[3,4_b]吡啶-5- 羧酸乙酯 8784l-96〇3〇3-中.doc -162- 1283678 210 乙基_N-[(1-氧化-3-吡啶基）甲基]_4_(四氫-2H-哌喃斗基胺 基）-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺 211 1·乙基-N-[(l-氧化-2-吡啶基）甲基]冬(四氫_2Η-哌喃斗基 胺基）-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺 212 1-乙基-Ν-[(1·氧化-4-外b淀基）甲基M-(四氫-2H-派喃-4-基 胺基）-1Η-吡唑并[3,4-b]吡啶-5_甲醯胺 214 4-[(順式-4-胺基環己基）胺基]小乙基善(苯基甲基&gt;1H_吡 唑并[3,4-b]吡啶-5_甲醯胺 221 4·(環丁基胺基）小乙基(苯基甲基）_1H-吡唑并p，4_b]吡 啶-5-甲醯胺 222 4-(環庚基胺基）小乙基(苯基甲基）_1Η-ρ比嗅并[3,4-b]^比 啶-5-甲醯胺 223 1-乙基-4-[(4-甲基環己基）胺基]-N-(苯基甲基）-iH_吡唑并^ [3,4七]吡啶-5-甲醯胺 224 1-乙基-4-[(3-甲基環己基）胺基]-Ν-(苯基甲基）-iH-吡唑并 [3,4-b]吡啶_5_甲醯胺 225 1-乙基-4-[(l-甲基壤己基）胺基](苯基曱基比吨并 [3,4-b]吡啶-5-甲醯胺 226 4-[(lR，2R，4S)-雙環并[2.2.1]庚-2-基胺基]-1-乙基-N-(苯基甲 基）-1Η·吡唑并[3,4-b]吡啶-5_甲醯胺 227 4-[(lR，2S，4S)_雙環并[2.2.1]庚-2-基胺基H-乙基-N-(苯基甲 基）-1Η_吡唑并[3,4-b]吡啶-5-甲醯胺 228 1-乙基-4-{[(3S)-2-酮基-3·四氫吡咯基]胺基}_N-(苯基甲 基）_1H-吡唑并[3,4-b]吡啶-5-甲醯胺 229 4-[(2,5-二酮基-3-四氧吡咯基）胺基]-1-乙基-N-(苯基甲基）-1H-吡唑并[3,4-b]吡啶-5-甲醯胺 230 4-(1-氮雙環并[2·2·2]辛-3-基胺基）-1·乙基-N_(苯基甲基）-1H-吡唑并[3,4-b]吡啶-5-甲醯胺 231 1-乙基-4-[(l-甲基環己基）胺基]-Ν·{[4-(甲氧基）苯基]甲 基}-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺 233 4-(環丁基胺基）小乙基-N_{[4-(甲氧基）苯基]甲基卜1Η-吡 唑并[3,4-b]吡啶-5-甲醯胺 87841-960303·中.doc -163- 1283678 234 4-(環庚基胺基）小乙基_N-{[4-(甲氧基）苯基]甲基}_ιη·吡 唑并[3,4-b]吡啶-5-甲醯胺 235 4-[(lR，2R，4S)-雙環并[2·2·1]庚-2-基胺基 H-乙基-Ν·{[4-(甲氧 基）苯基]甲基}_1H#比峻并[3,4_b]p比淀-5_甲醯胺 236 1-乙基4-[(4-甲基環己基）胺基]-N-{[4-(甲氧基）苯基]甲 基比峻并[3,4-b]p比淀-5-甲酸胺 237 1-乙基-4-[(3-甲基環己基）胺基]-N-{[4-(甲氧基）苯基]甲 基}-1Η-吡唑并[3,4_b]吡啶·5_甲醯胺 238 4-[(lR，2S，4S)-雙環并ρ·2·1]庚-2_基胺基]小乙基-Ν-{[4-(甲氧 基）苯基]甲基}-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺 239 4-[(順式·4_胺基環己基)胺基]小乙基-N-{[4-(甲氧基）苯基] 甲基}-1Η-外b峻并[3,4-b&gt;比咬-5-甲醯胺 240 4·(環庚基胺基）-1·乙基-Ν·({4-[(甲磺醯基）胺基]苯基}甲 基）-1Ημ比也并[3,4-b]p比淀_5_甲醯胺 241 4-(環丁基胺基）-1·乙基-Ν·({4_[(甲磺醯基）胺基]苯基}甲 基）-1Η-ρ比唆并[3,4-b]吡淀-5-甲醯胺 242 4-[(lR，2R，4S)-雙環并 P.2.1]庚-2-基胺基]-1-乙基-N-({4-[(甲 磺醯基）胺基]苯基}甲基）-1Η_吡唑并[3,4-b]吡啶-5-甲醯胺 243 4-[(lR，2S，4S)·雙環并[2_2.1]庚-2-基胺基]小乙基-N-({4_[(甲 磺醯基）胺基]苯基}甲基）-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺 244 1_乙基-4-[(4·甲基環己基)胺基]_Ν-({4·[(甲磺醯基）胺基]苯 基}甲基）-1Η-竹b也并[3,4-b]r比淀-5-甲酿胺 245 1·乙基_4_[(3-甲基環己基)胺基]·Ν-({4-[(甲磺醯基）胺基]苯 基}甲基）·1Η-ρ比峻并[3,4-b]p比淀-5-甲酿胺 247 1-乙基-4-[(l-甲基環己基）胺基]-N_({4_[(甲磺醯基）胺基]苯 基}甲基比吐并[3,4-b]p比淀_5_甲酿胺 248 4-[(順式-4-胺基環己基）胺基]-1-乙基-N-({4-[(甲磺醯基）胺 基]苯基}甲基比吐并[3,4-b]p比淀-5-甲酸胺 249 4-(環己胺基）-1-乙基-N-({4-[(甲績醯基）胺基]苯基}甲基）-1H-P比峻并[3,4-b]p比淀-5-曱酿胺 250 4-(環庚基胺基）-Ν-(2,3·二氫-1H-雖-2-基）-1-乙基-1H-P比峻 并[3,4-b]吡啶-5-甲醯胺 87841-96〇3〇3_ 中.doc •164- 1283678 251 4-(環丁基胺基）-N-(2,3_二氫_1H-茚-2-基）-1-乙基·1Η-吡唑 并[3,4-b]吡啶-5-甲醯胺 253 N-(2,3-二氮-1H-印_2_基）·1-乙基-4-[(3_甲基環己基）胺基]_ 1Η-吡唑并[3,4-b]吡啶-5-甲醯胺 254 N-(2,3-二氫-1H-雖-2·基）小乙基·4-[(4-甲基環己基）胺基]-IH-p比峻并[3,4-b]W：淀-5-甲醯胺 255 4-[(lR，2R，4S)-雙環并[2·2·1]庚 基胺基]_N-(2,3_二氫-1H-茚-2_基）-1-乙基-1H-吡唑并[3,4-b]吡啶-5-甲醯胺 256 4-[(lR，2S，4S)-雙壤并[2·2·1]庚 基胺基]-N-(2,3-二氯-1H-節-2-基）-1•乙基-1H·吡唑并[3,4_b]吡啶-5-甲醯胺 257 Ν·(2,3_二氫_1H-茚-2-基）小乙基-4-[(l-甲基環己基）胺基]-lEMb峡并[3,4-b]p比淀-5-甲醯胺 258 4-[(順式·4_胺基環己基）胺基]-N-(2,3-二氫-1H-茚-2-基）小 乙基_1H-吡唆并[3,4-b]p比淀-5-甲醯胺 259 1_乙基-N-{4-[(甲磺醯基）甲基]苯基}·4-[(4-酮基環己基）胺 基]-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺 260 N-[(2,4_二甲基苯基）甲基]-1-乙基冬[(4·酮基環己基）胺 基]-1H-吡唑并[3,4_b]吡啶-5-甲醯胺 261 Ν_[(3,4·二甲基苯基）甲基]小乙基-4-[(4_酮基環己基）胺 基]-lH-p比唑并[3,4-b]吡啶_5_甲醯胺 262 N-[(3,4-二氯苯基）甲基]-1-乙基_4-[(4-酮基環己基）胺基]-1H-吡唑并[3,4-b]吡啶-5_甲醯胺 263 1_乙基-N-{[4-(甲氧基）苯基]甲基卜4_[(4_酮基環己基）胺 基]-1H-吡唑并[3,4-b]吡啶_5_甲醯胺 264 1-乙基-N-({4-[(甲磺醯基）胺基]苯基}曱基）-4_[(4-酮基環 己基）胺基HH_p比吐并[3,4-b]外t淀-5-甲醯胺 265 N-{[4-(二甲胺基）苯基]甲基卜μ乙基_4-[(4-酮基環己基）胺 基]-lH-p比峻并[3,4-b]p比淀_5_甲醯胺 266 N-({4-[(二氟甲基）氧基]苯基}甲基乙基冬[(4-酮基環 己基）胺基]-1H-吡唑并[3,4-b]吡啶-5-甲醯胺 267 1-乙基-4-[(4_酮基環己基）胺基]·ν·{[4-(三氟基甲基）苯基] 甲基HH-吡唑并[3,4-bl吡啶-5·甲醯胺 87841-960303-中.doc -165- 1283678 268 1-乙基-N-{[4-(甲磺醯基）苯基]甲基}·4-[(4-酮基環己基）胺 基]-1Η_吡唑并[3,4-b]吡啶-5-甲醯胺 269 1-乙基-N-(4-氟苯基）·4-[(4-嗣基環己基）胺基]-1H_p比唆并 j；3,4-b]吡啶-5-甲醯胺 270 1-乙基斗[(4-酮基環己基）胺基]-N-(2-吡啶基甲基）-1Η-吡 唑并[3,4_b]吡啶-5-甲醯胺三氟醋酸鹽 271 N-(2,3-二氫-1H-茚_2_基）小乙基-4-[(4-酮基環己基）胺基]-1H-吡唑并[3,4-b]吡啶-5·甲醯胺 272 N-(l-乙醯基-4_六氫吡啶基）-1-乙基-4-[(4-酮基環己基）胺 基]-1H-吡唑并[3,4-b]吡啶-5-甲醯胺 273 1-乙基-N_[(l-甲基-1H-吡唑-4-基）甲基]-4-[(4-酮基環己基） 胺基]·1Η-吡唑并[3,4-b]吡啶-5·甲醯胺 274 N，l-二乙基_4-[(4-酮基環己基）胺基]-1H-吡唑并[3,4-b]吡 咬-5-甲酿胺 275 1-乙基-4-[(4-酮基環己基）胺基]-N-(l，3-嘍唑_2·基甲基）-1Η-p比峻并[3,4七&gt;比淀-5-甲醯胺 276 1-乙基-N_(苯基甲基）-4-(四氫-2H_哌喃-3-基胺基）·1Η-吡唑 并[3,4-b]吡啶-5-甲醯胺 277 N-({4-[(二氟甲基）氧基]苯基}甲基）-1_乙基_4_(四氫-2H-哌 喃_3_基胺基）-1Η_ρ比也并[3,4-b&gt;比淀-5-曱醯胺 278 1-乙基-4-(四氫-2H-哌喃-3-基胺基）_N-{[4-(三氟基甲基）苯 基]甲基}-1Η_外b吐并[3,4-b&gt;比淀-5-甲醯胺 279 1-乙基-N-{[4-(甲磺醯基）苯基]甲基}-4-(四氫-2H-哝喃-3-基胺基）_1H-吡唑并[3,4-b]吡啶-5-甲醯胺 280 1-乙基-N_{4·[(甲磺醯基）甲基]苯基卜4-(四氫-2H-呱喃-3-基胺基）-1Η-吡唑并[3,4_b]吡啶_5_甲醯胺 281 1-乙基-N-(4-氟苯基）-4-(四氫-2H-哌喃-3-基胺基）-1Η-吡唑 并[3,4-b&gt;比淀-5-甲醯胺 282 1-乙基-N-(2-吡啶基甲基）-4-(四氫-2H-哌喃_3_基胺基）·1Η-吡唑并[3，4-b]吡啶-5-甲醯胺三氟醋酸鹽 283 Ν·(2,3·二氫-1H-茚基）-1_乙基_4_(四氫-2H-旅喃-3-基胺 基）-1Η-吡唑并[3,4-b]吡啶_5_甲醯胺 87841-960303-中.doc -166 - 1283678 284 N-(l-乙酿基-4-ττ氮p比淀基）-1-乙基-4-(四氯-2Η-ϊ派喃_3_基 胺基）_1H-吡唑并[3,4-b]吡啶-5·甲醯胺 285 1-乙基_N-[(1-甲基-1H-吡唑-4-基）甲基]-4-(四氫_2H_喊喃_3_ 基胺基）_1H-吡唑并[3,4-b]吡啶-5-甲醯胺 286 N，l-二乙基-4-(四氫-2H-旅喃-3-基胺基）_1Η-ρ比嗅并[3,4-b] 1(7比咬-5-甲酿胺 287 1-乙基-4_(四氫-2H-旅喃-3-基胺基）-N-(l，3-p塞吐-2-基曱基）_ 1H-吡唑并[3,4-b]吡啶-5-甲醯胺 288 4_[(4,4-二氟環己基）胺基]·1-乙基-N_(苯基甲基）-lH-吡唑 并[3,4-b]吡啶-5-甲醯胺 289 1-乙基-4-[(4·氟基-3-環己晞-1-基）胺基]-N-(苯基甲基）_1H_ 吡唑并[3,4-b]吡啶-5-甲醯胺 290 4_[(1-乙醯基-4-六氫吡啶基）胺基]·Ν-(2,3-二氫-1H·茚-2-基）-1-乙基-1Η-Ρ比哇并[3,4-b]p比淀-5-甲酸胺 291 4-[(1-乙醯基-4_六氫吡啶基）胺基]-Ν-[(3,4·二氯苯基）甲 基]小乙基-1Η-吡唑并[3,4-b]吡啶_5_甲醯胺 292 4-[(1-乙醯基-4-六氫吡啶基）胺基]-1-乙基-N-[(3-氟苯基） 甲基]-1H-吡唑并[3,4-b]吡啶-5-甲醯胺 293 4-[(1·乙醯基-4-六氫吡啶基）胺基]-N-[(3,4-二氟苯基）曱 基]-1_乙基-1H-吡唑并[3,4-b]吡啶-5-甲醯胺 294 4-[(1-乙醯基-4-六氫吡啶基）胺基]-N-[(2,5-二氟苯基）甲 基]-1-乙基-1H·吡唑并[3,4-b]吡啶_5_甲醯胺 295 4-[(1-乙醯基-4·六氫吡啶基）胺基]小乙基-N_{[3-(三氟f 基）苯基]甲基}-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺 296 4-[(1-乙醯基-4-六氫吡啶基）胺基]小乙基·Ν-{[4-(三氟甲 基）苯基]甲基}-1Η-吡唑并[3,4_b]吡啶_5_甲醯胺 297 4-[(1-乙醯基_4·六氳吡啶基）胺基]-N-[(2,6-二氟苯基）甲 基]-1-乙基-1H-吡唑并[3,4-b]吡啶-5-甲醯胺 298 4-[(1-乙醯基-4·六氫吡啶基）胺基]-N-[(3-氣苯基）甲基]-1-乙基-1H-吡也并[3,4-b]外b淀-5-甲醯胺 299 4-[(1·乙醯基-4-六氫吡啶基）胺基]-1-乙基-N-{[4-(甲氧基） 苯基]甲基HH-吡唑并[3,4-b]吡啶-5-甲醯胺 87841·96〇3〇3·中.doc -167- 1283678 300 4_[〇乙醯基-4-六氫吡啶基）胺基]-1-乙基-N-[4-(甲氧基） 苯基]-1Η_ρ比吐并[3,4-b&gt;比淀-5-甲醯胺 301 4-[(1-乙醯基-4-六氫吡啶基）胺基]-N-({4-[(二甲胺基）磺醯 基]苯基}甲基）-1-乙基-lH-p比峻并[3,4-b]p比淀-5-甲酿胺 302 4-[(1_乙醯基-4-六氫吡啶基）胺基]-1_乙基-N-(l，2,3,4-四氫-1-萘基）_1H-吡唑并[3,4_b]吡啶_5_甲醯胺 303 4-[(1-乙醯基-4-六氫吡啶基）胺基]-N-{[2_(二甲胺基）苯基] 甲基}小乙基-1H-吡唑并[3,4-b]吡啶-5-甲醯胺 304 4-[(1_乙醯基-4-六氫吡啶基）胺基]-N-[(2,4-二氯苯基）甲 基]-1-乙基比吐并[3,4-b]p比度-5_甲酿胺 305 4-[(1-乙醯基-4-六氫吡啶基）胺基]小乙基-N-[(2-氟苯基） 甲基]-1H-吡唑并[3,4-b]吡啶-5_甲醯胺 306 4-[(1-乙酸基-4-六氫p比淀基）胺基]-N-[(2-氯基·6·氟苯基） 甲基]小乙基·1Η·吡唑并[3,4-b]吡啶-5-甲醯胺 307 4·[(1_乙醯基·4_六氫吡啶基）胺基]-N-({4-[(二氟甲基）氧基] 苯基}甲基）小乙基-1H-吡唑并[3,4-b]吡啶-5-甲醯胺 308 4-[(1·乙醯基-4-六氫吡啶基）胺基]-N-{[3-氣基·4-(甲氧基） 苯基]甲基}-1-乙基-ΙΗ-ρ比峻并[3,4-b]p比淀-5-甲酿胺 309 4-[(1-乙酿基-4-六氮p比淀基）胺基]-N-[(5-氣基-2·^比淀基） 甲基]小乙基-1H-吡唑并[3,4-b]吡啶-5-甲醯胺 310 4-[(1·乙酸基-4-六氮p比咬基）胺基]-N-(5-氯基-2,3_二氫-1H_ 茚-2-基）-1-乙基-1H·吡唑并[3,4-b]吡啶-5-曱醯胺 311 4-[(1-乙醯基-4-六氫吡啶基）胺基]小乙基-N-(l，3-嘍唑-2-基甲基）_1H-吡唑并[3,4-b]吡啶-5-甲醯胺 312 4-[(1-乙酿基-4-六氫p比淀基）胺基]-1·乙基-N-{[4-(甲續酿 基）苯基]甲基卜1H·吡唑并[3,4-b]吡啶-5-甲醯胺 313 4-[〇乙醯基-4-六氫吡啶基）胺基]-N-(2,2-二苯基乙基）+ 乙基-1H-吡唑并[3,4-b]吡啶_5_甲醯胺 314 4-[(1-乙酿基-4·六氫p比症基）胺基]-1-乙基_N-({4-[(甲續酿 基）胺基]苯基}甲基）-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺 315 4-[(1-乙酿基-4-六氫p比喊基）胺基]-1_乙基-N_({4-[(甲月矣基） 羰基]苯基}甲基）-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺 87841_96〇3〇3·中.doc -168 - 1283678 316 4-[(l-乙醯基-4-六氫吡啶基）胺基]-N-{[4-(胺基磺醯基）苯 基]甲基}小乙基-1H·吡唑并[3,4-b]吡啶-5-甲醯胺 317 4-[(1-乙醯基斗六氫吡啶基）胺基]小乙基-N-({3-[(甲胺基） 羰基]苯基}甲基）-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺 318 4-[(1-乙醯基-4_六氫吡啶基）胺基]-N-{[4-(胺基羰基）苯基] 甲基}-1_乙基-1H-吡唑并[3,4-b]吡啶_5_甲醯胺 319 4-[(1-乙酿基-4-六氯p比淀基）胺基]-1·乙基-Ν-{[6·(甲氧基）· 3-吡啶基]甲基}-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺 320 1-乙基-N-4-六氫吡啶基-4-(四氫-2H-哌喃-4-基胺基）-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺 321 1-乙基-N-(4-六氫吡啶基甲基）外(四氫-2H-哌喃斗基胺 基）-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺 322 1-乙基_Ν-[1-(乙基績酿基）-4-ττ氯p比淀基]-4-(四氮-2H-喊 喃_4_基胺基）-1Η_吡唑并[3,4-b]吡啶-5_甲醯胺 323 1-乙基-N-{1_[(1-甲基乙基）續酿基]_4-穴氮p比淀基}-4-(四 氫-2H_哌喃-4-基胺基）-1Η-吡唑并[3,4_b]吡啶-5·甲醯胺 324 哀戊基績酸基）-4-ττ氯p比淀基]-1-乙基-4-(四氣-2H-哌喃斗基胺基）-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺 325 乙基-Ν_[1·(甲績酿基）-4-ττ氮ρ比淀基]-4-(四氯_2H-p底喃_ 4-基胺基）-1Η-吡唑并[3,4-b]吡啶-5·甲醯胺 326 1-乙基-N-{1-[(苯基甲基）磺醯基]-4-六氫吡啶基}-4-(四氫-2H-哌喃斗基胺基）_1H-吡唑并[3,4-b]吡啶-5-甲醯胺 327 1-乙基-Ν-[1·(苯續酿基）-4-ττ氮外b淀基]-4-(四氣-2H-喊喃· 4-基胺基）·1Η-吡唑并[3,4-b]吡啶-5_甲醯胺 328 1_乙基-N-[l-(丙基續酿基）-4-ττ氯p比淀基]-4-(四氮-2H-口底 喃斗基胺基）-1Η-吡唑并[3,4-b]吡啶_5_甲醯胺 329 N-[l-(壤丙基談基）-4-六氮外b淀基]-1-乙基-4-(四氮-2H-P瓜 喃-4-基胺基）-1Η-吡唑并[3,4-b]吡啶_5·甲醯胺 330 1-乙基-Ν-[1·(3-咬喃基談基）-4-穴氮卩比淀基]-4-(四氮-2Η-^ 喃-4-基胺基）_1Η·ρ比吐并[3,4-b]外b淀-5-甲酿胺 331 N-[l-(3,3-二甲基丁醯基）-4-六氫吡啶基]-1-乙基-4-(四氫-2H-哌喃斗基胺基）-1Η-吡唑并[3,4_b]吡啶-5_甲醯胺 87841·96〇3〇3_ 中.doc -169- 1283678 332 1-乙基-N-[l-(2-乙基丁酸基）-4-六氮p比淀基]-4·(四氯-2H_^ 喃-4-基胺基比吐并[3,4-b]p比淀_5_甲酿胺 333 N-[l-(環戊基乙酸基氯p比淀基]小乙基_4-(四氫_2H_ 旅喃-4-基胺基比嗅并[3,4-b]p比淀-5·甲酿胺 334 1-乙基-N-[l-(2-甲基丙酸基）-4-六氯叶b淀基]-4-(四氯-2H-喊 喃_4·基胺基）-1Η_ρ比峻并[3,4-b]p比淀-5_甲酿胺 335 1-乙基-4·(四氣-2H_喊喃-4-基胺基）-Ν-[1_(四氯-2H-P底喃_4_ 基羰基）-4·六氫吡啶基]_1H-吡唑并[3,4-b]吡啶-5_甲醯胺 336 1-乙基·Ν·(1-丙酿基-4-TT氮外b淀基）_4-(四氯-2H-p辰喃-4-基 胺基）-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺 337 N-[1-(N-乙酸基甘胺酸基）·4-六氯p比淀基]-1-乙基·4-(四氫一 2Η-哌喃-4-基胺基）-1Η_吡唑并[3,4-b]吡啶-5_甲醯胺 338 1-乙基-N-[l-(4-嗎福p林基乙酸基）-4-六氯p比淀基]-4-(四氫-211-0底喃-4-基胺基比吐并[3,4-b]p比淀-5-甲酸胺 339 1-乙基-Ν-{1-[(4-酮基環己基）羰基]-4-六氬吡啶基}-4-(四 氮-2H-旅喃-4-基胺基比峻并[3,4-b]p比淀-5-甲酸胺 340 1-乙基-N-[l-(l-六氫吡啶基乙醯基）-4-六氫吡啶基]-4-(四 氮·2Η_略喃-4-基胺基比峻并[3,4-b]p比淀-5-甲酿胺 341 1-乙基-N-{1_[(1-甲基-5·酮基-3-四氫吡咯基）羰基]冰六^ 外匕淀基}-4-(四氯-2H-喊喃-4-基胺基）-1Η-ρ比峻并[3,4-b]p比 啶-5-甲醯胺 342 1-乙基-Ν·{1-[(3-甲基-3-環氧丙烷基）羰基]-4-六氫吡7 基}-4-(四氫-2Η-哌喃-4-基胺基）-1Η_吡唑并|；3,4-b]吡啶j 甲醯胺 343 1-乙基-Ν-{1-[(4-^苯基）乙酿基]-4-六氫外b咬基}-4-(四氧· 2H·哌喃-4-基胺基）-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺 344 Ν-{[1-(3,3-二甲基丁醯基）-4-六氫p比淀基]甲基}-1_乙基7 (四氫_2H-喊喃-4-基胺基）-1H-p比峻并[3,4-b]p比淀-5-甲酿胺 345 Ν-{[1-(環戊基乙醯基）-4-六氫吡啶基]甲基}-1-乙基-4-(^ 氫-2H&gt;辰喃-4-基胺基比也并[3,4-b&gt;比淀-5-甲醯胺 346 Ν-{[1-(環丙基羰基）-4-六氫吡啶基]甲基}小乙基-4-(四$ 2H_哌喃-4_基胺基）_1H-吡唑并[3,4-b]吡啶-5-甲醯胺 87841-960303•中.doc -170- 1283678 347 1-乙基·Ν-({1-[(4-酮基環己基）羰基]-4-六氫吡啶基}甲基）-4·(四氯·2Η-旅喃-4-基胺基比吐并[3,4-b]p比淀_5•甲酿 胺 348 1-乙基-Ν-({1-[(4-氟苯基）乙醯基]-4-六氫吡啶基}甲基）-4-(四氫-2H-哌喃_4_基胺基）-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺 349 1-乙基·Ν-({1-[(1-甲基同基_3_四氮p比洛基）数基]_4·ττ鼠 吡啶基}甲基）-4-(四氫-2Η-哌喃-4-基胺基）-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺 350 甲基3_[(1_乙基-5-{[(苯基甲基）胺基]羰基}_1Η·吡唑并[3,4-b]吡啶-4-基）胺基]環己烷羧酸酯 351 3-[(1-乙基-5-{[(苯基甲基）胺基]羰基}_1H_吡唑并[3,4-b]吡 啶斗基）胺基]環己烷羧酸 352 1-乙基-N-(苯基甲基）-4-(4-六氫吡啶基胺基）-1Η-吡唑并 [3,4-b]外b沒-5·甲酿胺 353 1_乙基-4-({l-[(甲氧基）乙醯基]-4-六氫p比淀基}胺基）-1Η-吡唑并[3,4-b]吡啶-5-羧酸乙酯 354 1-(1-甲基乙基）-4_(四氫·2Η_^喃-4-基胺基）-1Ηπ比唆并[3,4-b]吡啶-5-羧酸乙酯 355 4-(環己胺基）小乙基-N-甲基-1H-吡唑并[3,4-b]吡啶-5-甲 醯胺 356 1-乙基-N-(4-氟苯基）-6-甲基-4-(四氫-2H-哌喃-4-基胺基）· 1H_p比峻并[3,4-b]p比淀-5-甲醯胺 357 1-乙基-6-甲基_N-{[4-(甲磺醯基）苯基]甲基}-4-(四氫-2H-哌喃-4_基胺基）-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺 358 N-(2,3_二氫-1H-雖·2_基）_1_乙基-6-甲基-4-(四氫-2H·旅喃-4-基胺基）-1Η-峨峻并[3,4_b]外b淀-5_甲醯胺 360 1-乙基-N_[3-(l-六氫ρ比淀基羰基）苯基]-4-(四氫-2H_p瓜喃-4-基胺基）-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺 361 1-乙基·Ν-[4-(1甲基乙基）苯基]_4·(四氫-2Ιϋ喃-4-基胺 基）-1Η-外b峻并[3,4-b]外b淀-5-甲酿胺 362 1-乙基-Ν·(2-氟苯基）-4-(四氫-2H-喊喃-4_基胺基）·ιη_ρ比也 并[3,4-b]p比淀-5-甲酿胺 87841-960303-中.doc -171- 1283678 363 N-{3-[(二甲胺基）羰基]苯基}-l-乙基-4_(四氫_2Η·喊喃-4-基胺基）-1Η-ρ比吐并[3,4-b&gt;比淀-5_甲醯胺 364 Ν-{4-[(二氟甲基）氧基]苯基}-1_乙基冰(四氫—2Η-旅喃-4-基胺基）_1Η·吡唑并[3,4-b]吡啶-5-甲醯胺 365 N-{4-[乙醯基（甲基）胺基]苯基}-1_乙基-4-(四氳-2H-喊喃-4-基胺基）-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺 366 1-乙基-N-(4-經苯基）-4-(四氫-2H-喊喃-4-基胺基）-1Η-ρ比吨 并[3,4-b]吡啶-5-甲醯胺 367 1-乙基_N-[4_(4-嗎福琳基）-2_(三氟甲基）苯基]_φ·(四氫-2H_ p底喃-4-基胺基）_1H-p比唆并[3,4-b]p比淀-5-甲酿胺 368 1-乙基-N-4-p比淀基-4-(四氫-2H-派喃-4-基胺基）-1Η-外b峻 并[3,4-b]吡啶-5-甲醯胺 369 1-乙基_N_{4-[(4-甲基-1-六氫外b p井基）羰基]苯基}-4-(四氫-2H-旅喃-4-基胺基）-1Η-峨峻并[3,4-b]p比淀-5-甲醯胺 370 1-乙基-N-[2_(2-酮基-1-四氫？比p各基）苯基]_4-(四氫-2H_旅 喃-4-基胺基）-1Η-^比也并[3,4-b]p比淀-5-曱酿胺 371 1-乙基-N_[3-(甲績酿基）苯基]_4-(四氫-2H-喊喃-4-基胺基）-1H-P比吐并[3,4-b]外b淀·5_甲醢胺 372 Ν·{3_[乙醯基（甲基）胺基]苯基}-1_乙基_4-(四氫-2Η·ϊ派喃-4-基胺基比峻并[3,4-bp比淀-5-甲醯胺 373 1-乙基-N-{3-[(甲續酸基）胺基]苯基}_4·(四氫-2H-喊喃-4_ 基胺基比吐并[3,4_b]p比淀-5-甲醯胺 374 1-乙基-Ν·(4-氟基-2-#呈苯基）-4-(四氫-2H-喊喃-4_基胺基）-1Η·β比吨并[3,4-b]外b淀-5-甲酶胺 375 N-(4-氯苯基）_1·乙基-4-(四氫-2H-喊喃-4-基胺基比吨 并[3,4-b]吡啶-5-甲醯胺 376 N-(3_氯基-2-氰基苯基）小乙基-4-(四氫_2H_^喃_4_基胺 基）-1Η-ρ比吐并[3,4_b&gt;比淀-5_甲酸胺 377 1·乙基-Ν-[3-(1·六氫外b喊基續醯基）苯基]·4-(四氫-2H-旅 喃-4-基胺基）-1Η-ρ比嗅并[3,4-b]p比淀·5·甲酿胺 379 1-乙基-Ν_[2·(甲續酸基）苯基]-4-(四氫-2Η-喊喃-4-基胺基）_ | IH-p比咬并[3,4_b]p比淀-5_甲酿胺 8784l-960303-中.doc -172- 380 N-{2-[乙醯基（甲基）胺基]苯基}小乙基-4-(四氫-211-哌喃-4-基胺基）_1H-吡唑并[3,4-b]吡啶-5-甲醯胺 381 1-乙基_N-[3-(4-嗎福ρ林基談基）苯基]_4-(四氮-2H4辰喃-4-基 胺基）-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺 382 N_(4-氯基-3-氯基苯基）-1_乙基-4-(四氮-2H-喊喃-4-基胺 基）-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺 383 1-乙基-N_(3-羥苯基）-4-(四氫-2H-哌喃-4-基胺基）-1Η-吡唑 并[3,4-b]吡啶-5-甲醯胺 384 N-(3-氯苯基）小乙基-4-(四氫-2H-哌喃-4-基胺基）-1Η-吡唑 并[3,4-b]吡啶-5-甲醯胺 386 Ν-[3·[(乙醯胺基）甲基]-4-(甲氧基）苯基]-1-乙基冬(四氫-2H-哌喃斗基胺基）_1Η·吡唑并[3,4-b]吡啶-5-甲醯胺 387 1_乙基-N-[4-(l-六氫吡啶基磺醯基）苯基]-4·(四氫-2H-哌 喃_4_基胺基）-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺 388 N-(3-{[環己基（甲基）胺基]羰基}苯基）小乙基4-(四氫-2H-旅喃-4-基胺基）-1Η-吡唑并[3,4-b]吡啶_5_甲醯胺 389 1·乙基-N-[2-(4•嗎福啉基）苯基]-4-(四氫-2H-哌喃-4-基胺 基）-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺 390 N_{3-[(乙醯胺基）磺醯基]苯基}-1·乙基-4-(四氫·2Η-哌喃-4-基胺基）-1Η-吡唑并[3,4-b]吡啶-5_甲醯胺 391 N-(3_氯基_4_經苯基）-1-乙基_4-(四氣-2H·喊喃-4_基胺基）-1H-吡唑并[3,4_b]吡啶-5-甲醯胺 392 1-乙基-Ν·{4-[(甲磺醯基）胺基]苯基}冰(四氫-2H-哌喃-4-基胺基峻并[3,4-b]外b淀-5-甲酿胺 393 1-乙基-N-{3-[(甲胺基）羰基]苯基}-4-(四氫-2H-哌喃_4_基 胺基）-1Η_吡哇并[3,4-b]吡啶-5-甲醯胺 394 1-乙基-4-(四氫-2H-旅喃-4-基胺基）-N-[3-(三氟甲基）苯基]-1H-吡唑并[3,4七]吡啶-5-甲醯胺 395 1-乙基-Ν·3-ρ比淀基-4-(四氮-2H-喊喃-4-基胺基比吐 并[3,4-b]吡啶-5-甲醯胺 396 N-(3,4-二氣苯基）-1-乙基-4-(四氫-2H-喊喃-4-基胺基）-1Η-吡唑并[3,4-b]吡啶-5-曱醯胺 87841-9603〇3_ 中.doc -173- 1283678 397 Ν·[3-(胺基續醯基）-4-氯苯基]-1_乙基-4-(四氫-2H-喊喃-4-基胺基）-1Η-吡唆并[3,4-b&gt;比淀-5_甲醯胺 398 1-乙基-N-[3-(4-嗎福淋基）苯基]_4-(四氫-2H-喊喃冰基胺 基比峻并[3,4七&gt;比淀_5_甲醯胺 399 1-乙基-N_[4_(4_嗎福淋基續驢基）苯基]_4-(四氫_2H_t派喃-4-基胺基比峻并[3,4_b]p比淀-5·甲醯胺 400 1-乙基-Ν·{2-[(4-甲基小六氫吡啡基）羰基]苯基卜4_(四氫-2Η-Ϊ派喃-4-基胺基）·1Η·ρ比吐并[3,4-b]p比淀_5_甲醯胳 401 [(二甲胺基）羰基]苯基}小乙基-4-(四氫-2H-味喃_4_ 基胺基）-1Η«^比吨并[3,4-b]p比淀-5-甲醯胺 402 N-[2-氯基-4-(三氟甲基）苯基]-1-乙基-4-(四氫-2H-喊喃-4-基胺基）-1Η-ρ比峻并[3,4-b&gt;比淀-5-甲醯胺 403 N-{2-[(乙醯胺基）甲基]苯基}小乙基斗(四氫-2迅味喃斗 基胺基）-1Η-ρ比唆并[3,4-b]外b咬-5_甲醯胺 404 N-(2-氣苯基）-1-乙基-4-(四氫-2H-派喃-4-基胺基）-1Η·ρ比也 并[3,4-b]吡啶-5-甲醯胺 405 N-(3-氯基-2-氟苯基）-1-乙基-4-(四氫-2H-喊喃·4-基胺基）-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺 406 1-乙基-N-(3_說苯基）-4-(四氫-2H-喊喃·4_基胺基）-ιη·外b也 并[3,4-b]吡啶-5-甲醯胺 407 N-(2_氰基-3-氟苯基）-1-乙基-4-(四氫-2H-喊喃-4-基胺基）-1H-吡唑并[3,4-b]吡啶-5-甲醯胺 408 1-乙基-N_[4_(丙基橫醯基）苯基]冰(四氫々Η-喊喃-4-基胺 基比唆并[3,4-b]外ti淀·5_甲醯胺 409 Ν-{4-[(二甲胺基）羰基]苯基}_1_乙基冰(四氫-2fj_喊喃本 基胺基）_1Η-吡唑并[3,4-b]吡啶-5-甲醯胺 411 1_乙基-N-[4·(甲續醢基）苯基]_4_(四氫_2Η_ι派喃_4_基胺基）_ 1H-吡唑并[3,4_b]吡啶-5-甲醯胺 413 N-{4-[(乙酿胺基）甲基]琴基}·1-乙基_4_(四氮辰喃-4_ 基胺基）-1Η-ρ比+并[3,4-b]p比淀-5-甲酿胺 414 1-乙基-4-(四氫-2H-旅喃-3-基胺基比峻并[3,4-b]p比淀_ 5-甲醯胺 87841-96〇3〇3·中.doc -174- 1283678 415 N-[2-(胺基磺醯基）乙基]_4_(環己胺基）-1-乙基-1H-吡唑并 [3,4-b]吡啶-5-甲醯胺 416 N-(2-胺基-2-酮基乙基）-4·(環己胺基）小乙基-1H-吡唑并 [3,4-b]吡啶-5-甲醯胺（非較佳名稱） 417 4-(環己胺基）-1-乙基-N-{2-[(甲磺醯基）胺基]乙基}-1Η-吡 唑并[3,4-b]吡啶-5-甲醯胺 418 4-(環己胺基）-1-乙基(四氫-2H-哌喃-4-基）_1H-吡唑并 |；3,4-b]峨淀-5-甲醯胺 419 4_(環己胺基）_1_乙基-N-[(l-甲基-1H_吡唑-4-基）甲基]-1H-叶匕吐并[3,4-b]咐淀-5-甲醯胺 420 4-(環己胺基）_1_乙基-N-{[3-(甲磺醯基）苯基]甲基}-1Η_吡 也并[3,4-b]外b遠-5-甲醯胺 421 N-{[3-(胺基羰基）苯基]甲基卜4_(環己胺基）-1-乙基-1H-吡 峻并[3,4-b&gt;比咬-5-甲醯胺 422 4-(環己胺基）_1_乙基-N-(四氫-2-呋喃基甲基）-1Η-吡唑并 [3,4-b]p比淀·5-甲酿胺 423 4-(環己胺基）-Ν-({4-[(二甲胺基）磺醯基]苯基}甲基）-1-乙 基-1H-吡唑并[3,4-b]吡啶-5-甲醯胺 424 N-[(5_氯基-2·吡啶基）甲基]-4·(環己胺基）-1-乙基-1H-吡唑 并[3,4-b]吡啶-5-甲醯胺 425 4-(環己胺基）-1-乙基-N-{[4-(甲磺醯基）苯基]甲基}·1Η-吡 也并[3,4-b]外b淀-5-甲醯胺 426 4-(環己胺基）-1-乙基-N_{[6-(甲氧基）_3_吡啶基]甲基}-1Η-外匕嗅并[3,4-b&gt;比淀-5-甲醯胺 427 4-(環已胺基）小乙基·Ν-{4-[(甲胺基）羰基]苯基}-1Η-吡唑 并[3,4-b]吡啶-5-甲醯胺 428 4_(環己胺基）-1-乙基·Ν-({3-[(甲胺基）羰基]苯基}甲基）-1Η-吡唑并[3,4-b]吡啶-5_甲醯胺 429 Ν-{[4-(胺基羰基）苯基]甲基}-4-(環己胺基）-1-乙基-1Η-吡 唑并[3,4-b]吡啶-5-甲醯胺 430 4-(環己胺基）-1-乙基-N-[(4-羥苯基）甲基]-1H-吡唑并[3,4七] 吡啶-5-甲醯胺 87841-9603〇3_ 中.doc -175- 1283678 431 4-(環己胺基）-1-乙基-N-{[4-(甲氧基）苯基]甲基卜ih_吡唑 并[3,4-b]吡啶-5-甲醯胺 432 4-(環己胺基）-N-[(3,4-二氟苯基）甲基H-乙基-1H-吡唑并 [3,4-b]吡啶-5-甲醯胺 433 4-(環己胺基）小乙基-N-{[4-(三氟甲基）苯基]甲基卜1H_吡 峻并[3,4-b]p比淀-5-甲酸胺 434 4-(環己胺基）小乙基-N-({3-[(甲磺醯基）胺基]苯基}甲基）_ 1H·吡唑并[3,4_b]吡啶-5-甲醯胺 435 4-(環己胺基）-N-[(2,5-二氟苯基）甲基]-1-乙基-1H-外b峻并 [3,4-b]吡啶-5-甲醯胺 436 4-(環己胺基）-1·乙基-N_[(4-甲基苯基）甲基]-iH_外b峻并 [3,4-b]毗啶-5-甲醯胺 438 4-(環己胺基）小乙基-N-(2_{4-[(甲續醯基）胺基]苯基}乙 基）-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺 439 4-(環己胺基）·1·乙基-N-[(2-蠢苯基）甲基]-iH-p比峻并[3,4-b] 外匕淀-5-甲酸胺 440 4-(壤己胺基）-N_[(3,4- 一乳本基）甲基]-1-乙基-1H-P比也并 [3,4-b]竹1：淀-5-甲醯胺 441 4-(環己胺基）-N-[(3,5-二氯苯基）甲基]-1-乙基-1H-吡唑并 [3,4-b]吡啶-5-甲醯胺 442 4-(環己胺基）-1-乙基-N-(2-苯基乙基比峻并[3,4-b]外匕 淀-5-甲醯胺 443 4-(環己胺基）-1·乙基_N_(1，2,3,4-四氫小蕃基比吐并 [3,4-b]p比读；-5-甲醯胺 444 4-(環己胺基）小乙基-N-{[2-(甲基亞續醯基）苯基]甲基卜 ΙΗ-外!:峻并[3,4-b]外b淀-5-甲醯胺 445 4-(環己胺基）小乙基-N-[2_(4-幾苯基）乙基]比峻并[3,4_ b]外t違-5_甲醯胺 446 N]2-[4-(胺基磺醯基）苯基]乙基}_4-(環己胺基）-1-乙基「 1H-吡唑并[3,4-b]吡啶-5-甲醯胺 447 4_(環己胺基）小乙基-N-({2-[(甲胺基）羰基]苯基}甲基）_1H_ ρ比吐并[3,4-b]p比淀-5-甲酿胺 87841-960303-中.doc •176- 1283678 448 4-(環己胺基）-1-乙基-N-{[2_(甲續醯基）苯基]甲基卜iH-外匕 唑并[3,4-b]吡啶-5-甲醯胺 449 2-[({[4-(環己胺基）-1乙基_1H_p比峻并[3,4-b]p比淀_5_基]後 基}胺基）甲基]苯甲酸甲酯 450 4-(環己胺基）-1·乙基-Ν·{2-[4-(甲續醯基）苯基]乙基 吡唑并[3,4-b]吡啶-5-甲醯胺 451 N-[4,5-雙（甲氧基）-2,3-二氫-1H·茚-2-基]_4-(環己胺基）小乙 基-1H-P比峻并[3,4-b]外b淀甲酿胺 452 4-(環己胺基）小乙基-N_{[2_氟基-3-(三氟甲基）苯基]甲 基比峻并[3,4-b&gt;比淀-5-甲酸胺 453 4-(環己胺基）·Ν-[(3,4-二甲基苯基）甲基]小乙基-1H-吡唑 并[3,4-b]外b咬-5_甲酿胺 454 4-(環己胺基）-1-乙基-Ν-[2·(4_氟苯基）乙基]-1H-吡唑并[3,4-b]吡啶-5-甲醯胺 455 4-(環己胺基）-1-乙基-N-[2-(4-甲基苯基）乙基]_1H-吡唑并 [3,4-b]p比淀-5-曱酿胺 456 4·(環己胺基）-1-乙基-N-{2-[4-(甲氧基）苯基]乙基}-1Η-吡 唑并[3,4-b]吡啶-5-甲醯胺 457 4-(環己胺基）小乙基-N_(2-吡啶基甲基）-1Η-吡唑并[3,4-b] 吡啶-5-甲醯胺三氟醋酸鹽 458 4-(環己胺基）-N-[(3,5-二氟苯基）甲基]小乙基-1H-吡唑并 [3,4-b]吡啶-5-甲醯胺 459 4-(環己胺基）-N-(2,3-二氫-1H-茚-1-基）小乙基-1H-吡唑并 [3,4-b]吡啶-5-曱醯胺 460 4-(環己胺基）_N-{[4-(二曱胺基）苯基]甲基}小乙基-1H-吡 唑并[3,4-b]吡啶_5_甲醯胺三氟醋酸鹽 461 4-(環己胺基）-1-乙基-N-[(2-氟苯基）甲基]-1Η·吡唑并[3,4-b] 外1：咬-5-甲醯胺 462 N-{[2,4-雙（甲氧基）苯基]甲基卜4-(環己胺基）-1-乙基-1H-吡唑并[3,4-b]吡啶_5_甲醯胺 463 N-[(6-氯基-2-吡啶基）甲基]_4-(環己胺基）-1-乙基-1H-吡唑 并[3,4-b&gt;比啶-5-甲醯胺三氟醋酸鹽 87841-960303·中.doc -177- 1283678 464 [乙酿基（甲基）胺基]苯基}甲基）-4-(環己胺基乙 基-1H·叶b峻并[3,4-b]p比淀-5-甲酸胺三氟醋酸驗 465 4-(環己胺基）-1-乙基_Ν_{[4·氟基-3-(三氟甲基）苯基]甲 基}-1Η_ρ比吐并[3,4-b]峨淀-5-甲醯胺 466 4-(環己胺基）-N-[(lR)-2,3-二氫-1H_茚-1_基H•乙基_1H-吡唑 并[3,4-b]吡啶-5-甲醯胺 467 4_(環己胺基）-N-[(2,6-二氯苯基）甲基]-1-乙基_ih_p比岭并 [3,4-b]吡啶-5-甲醯胺 468 3_[({[4-(環己胺基）-1-乙基-1H-P比吐并[3,4_b]p比淀_5_基]談 基}胺基）甲基]苯甲酸甲酯 469 4-(餐己胺基）-N-(2,3-二氯-1H-雖-2_基）_1_乙基-iH-p比峻并 [；3,4-b&gt;比啶-5-甲醯胺 470 4·[({[4_(環己胺基）-1-乙基-1H-P比峻并[3,4-b]p比淀-5-基]魏 基}胺基）甲基]苯甲酸甲酯 471 4-(J哀己胺基）-1·乙基-N-(1H-四唆-5-基甲基）-1Η-ρ比峻并 [；3,4-b&gt;比淀-5-甲醯胺 472 4-(環己胺基）-N-({4-[(二氟甲基）氧基]苯基}甲基）小乙基-1H-吡吐并[3,4-b]吡啶-5-甲醯胺 473 4-(壤己胺基）_1_乙基-N-[(2-甲基·1，3·ρ塞也-4·基）甲基]-1H_ 吡唑并[3,4-b]吡啶-5-甲醯胺 474 N-[(2-氯基-6-氟苯基）甲基]-4-(環己胺基）-1•乙基-1H_吡唑 并[3,4-b]吡啶-5-甲醯胺 475 N-{[2-(胺基羰基）苯基]甲基}·4-(環己胺基）小乙基-1H-吡 唑并[3,4-b]吡啶-5-甲醯胺 477 4-(環己胺基）-N-{[2-(二甲胺基）苯基]甲基}-1-乙基_1H-吡 峻并[3,4-b]p比淀-5-甲酿胺 478 4-(環己胺基）-1-乙基-N-[(4-氟苯基）甲基]-1Η-吡唑并[3,4七] 吡啶-5-甲醯胺 479 4-(餐己胺基）-1-乙基-N-{[3-(三氣甲基）各基]甲基比 峻并[3,4-b&gt;比矣-5-甲醯胺 480 4-(環己胺基）-N-[(2,6-二氟苯基）甲基H-乙基-1H-吡唑并 [3,4-b]吡啶-5-甲醯胺 87841-960303-中.doc -178- 1283678 481 4-(環己胺基）小乙基-N-[(3-氟苯基）甲基]-1Η-吡唑并[3,4-b] 吡啶-5-甲醯胺 482 4-(環己胺基）小乙基-N-{[2-(三氟甲基）苯基]甲基}-1Η-说 唑并[3,4-b]吡啶-5-甲醯胺 483 N-(5-氯基-2,3-二氫-1H-茚-2-基）-4-(環己胺基）小乙基·1Η-ρ比峻并[3,4-b]p比淀-5-甲醯胺 484 4-(環己胺基）小乙基-N-({4_[(甲胺基）羰基]苯基}甲基）-1Η-外匕吐并[3,4-b]外b淀-5-甲醯胺 485 4-(環己胺基）小乙基-N-[4-(甲氧基）苯基]-1Η-吡唑并[3,4-b] 吡啶-5-甲醯胺 486 4-(環己胺基）-1-乙基-N-[(6-酉同基-1，6-二氯-3-p比淀基）甲基]-1H-吡唑并[3,4_b]吡啶-5-甲醯胺 487 4-(環己胺基）-1·乙基-Ν·(3_吡啶基甲基）·1Η_吡唑并[3,4-b] 吡啶-5-甲醯胺 488 4-[({[4-(環己胺基）-1·乙基-1H-吡唑并[3,4-b]吡啶-5-基]羰 基}胺基）甲基]苯甲酸 489 3_[({[4-(環己胺基）小乙基·1Η_吡唑并[3,4-b]吡啶-5-基]羰 基}胺基）甲基]苯甲酸 490 4-(壤己胺基）_N-(2,3_二氮_1H-印-2·基）-1-乙基-1Η_ρ比'^并 [3,4-b]p比淀-5-甲酸胺鹽酸鹽 491 4-(環己胺基）-N-(2,3-二氫-1H-茚-2-基）小乙基-1H-吡唑并 [3，4-b]吡啶-5-甲醯胺甲烷磺酸鹽 492 Ν-({2-[(1，1·二甲基乙基）氧基]-3-吡啶基}甲基）小乙基_4_ (四氫-2Η-哌喃斗基胺基）-1Η_吡唑并[3,4_b]吡啶-5-甲醯胺 三氟醋酸鹽 493 N-[(3-氣基-4-甲基苯基）甲基]小乙基斗(四氫-2H·哌喃-4· 基胺基）-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺 494 N_[(4-氣基-2-甲基苯基）甲基]-1-乙基-4·(四氫-2H-哌喃-4-基胺基）-1Η_吡唑并[3,4-b]吡啶-5-甲醯胺 495 N-({2-[(二氟甲基）氧基]苯基}甲基）小乙基_4-(四氫-2H-哌 喃-4-基胺基）-1Η-吡唑并[3,4_b]吡啶-5-甲醯胺 87841·96〇3〇3·中.doc -179- 1283678 496 1-乙基-Ν_({2·[(1-甲基乙基）氧基]苯基}甲基）_4_(四氫·2Η_ 旅喃-4_基胺基）·1Η-外b也并[3,4七&gt;比淀-5-甲酸胺 497 1-乙基_N_({3-[(1-甲基乙基）氧基]苯基}甲基）_4_(四氫_2h_ 旅喃-4-基胺基比唆并[3,4_b]p比淀_5_甲醯胺 498 N-({3_[(二敦甲基）氧基]苯基}甲基）小乙基_4·(四氫-2H-T派 喃-4-基胺基比吐并[3,4_b]p比淀_5_甲酿胺 499 1_乙基-N_{[4·#呈基-3-(甲氧基）苯基]甲基}_4_(四氫-2H-旅 喃-4-基胺基比峻并[3,4-b]p比淀_5_甲酸胺 500 N-[(5-乙醯基-2-羥苯基）甲基]小乙基-4·(四氫-2H-哌喃-4-基胺基）-1Η-吡唑并[3,4-b]吡啶-5_甲醯胺 501 1-乙基-4-(四氫_2H-旅喃-4-基胺基）_Ν·{2·[3_(三氟甲基）苯 基]乙基比峻并[3,4-b]p比淀-5-甲酿胺 502 N-{[4_(乙酿胺基）苯基]甲基}_1_乙基_4-(四氯-2H-旅喃-4_ 基胺基）_1H_吡唑并[3,4-b]吡啶-5-甲醯胺 503 1_乙基-N-[2-(3-喪苯基）乙基]-4-(四氫-2H-^展喃-4-基胺基）_ 1H-吡唑并[3,4-b]吡啶-5-甲醯胺 504 N-[2-(3-氯苯基）乙基]-1-乙基-4-(四氫-2H-味喃-4-基胺基）_ 1H-吡唑并[3,4-b]吡啶·5_甲醯胺 505 1-乙基-4-(四氫-2Η-17底喃-4-基胺基）-Ν-(2-{4-[(三氟甲基）氧 基]苯基}乙基）-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺 506 1-乙基-N-{2-[3-(甲氧基）苯基]乙基}-4-(四氫-2H·哌喃-4-基 胺基）-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺 507 N-[2-(4-乙醯基苯基）乙基]-1-乙基-4-(四氫-2H-喊喃-4-基胺 基）_1H_吡唑并[3,4_b]吡啶-5·甲醯胺 508 N-[2-(3,4-二氯苯基）乙基]小乙基-4-(四氫-2H_哌喃冬基胺 基）-1Η-吡唑并[3,4-b]吡啶-5_甲醯胺 509 N-{2-[3-(胺基磺醯基）苯基]乙基卜1-乙基-4-(四氫-2H-哌 喃-4·基胺基）-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺 510 N-{2-[3,4-雙（甲氧基）苯基]乙基}小乙基-4-(四氫-2H-哌喃-4-基胺基）-1Η-吡唑并[3,4-b]吡啶-5·甲醯胺 512 N-[2-(2,3-二氯苯基）乙基]小乙基-4-(四氫-2H-哌喃-4-基胺 基）-1Η_吡唑并[3,4-b]吡啶_5_甲醯胺 87841-96〇3〇3-中.doc -180 - 1283678 513 N-{2-[3,5-雙（甲氧基）苯基]乙基}_1-乙基·4_(四氫_2Η·哌喃-4-基胺基）-1Η-ρ比峻并[3,4-b]p比淀-5-甲酿胺 514 1-乙基-N-{2-[3-甲基冰(甲氧基）苯基]乙基}冰(四氫-2H-哌 喃-4-基胺基）_1H-吡唑并[3,4-b]吡啶-5-甲醯胺 515 N· [2-(2,6-.一氣丰基）乙基]·1_乙基-4-(四氮-2H-旅喃-4-基胺 基）-1Η_ρ比咬并[3,4-b]p比淀-5-甲醢胺 516 N-{2_p，6-雙（甲氧基）苯基]乙基}-1_乙基_4_(四氫-2H-喊喃_ 4-基胺基）-1Η·吡唑并[3,4-b]吡啶-5-甲醯胺 517 1-乙基-N-[2_(2-甲基苯基）乙基]-4-(四氫底喃-4-基胺 基）-1H-p比唆并[3,4七&gt;比淀-5-甲醯胺 518 Ν-[(3,4-二甲基苯基）甲基]小乙基-4-(四氫-2Η-喊喃-4-基胺 基）-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺 519 N-[4,5-雙（甲乳基）_2,3_二鼠-1H-印-2-基]·1_ 乙基-4-(四氯-2H_ 喊喃-4-基胺基）-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺 521 N-{2-[4-(胺基續醯基）苯基]乙基}·1_乙基-4-(四氫_2H-旅 喃-4-基胺基）·1Η_ρ比吐并[3,4-b]p比淀-5-甲醯胺 522 1_乙基_N-{[2-(甲基亞磺醯基）苯基]甲基}_4-(四氫_2H_哌 喃-4-基胺基）·1Η-吡唑并[3,4-b]吡啶-5-甲醯胺 523 1-乙基-N-(2-苯基乙基）-4-(四氫-2H-喊喃-4_基胺基比 唑并[3,4-b]吡啶-5-甲醯胺 524 N-{[4-(二甲胺基）苯基]甲基}小乙基冬(四氫_2H_哌喃-4-基胺基比吐并[3,4-b&gt;比淀-5-甲醯胺 525 1_乙基-N-[2_(4_氟苯基）乙基]-4-(四氫-2Η4喃-4_基胺基）-1Η·吡唑并[3,4-b]吡啶-5_甲醯胺 526 1-乙基_Ν-[2·(4-甲基苯基）乙基]-4-(四氫-2H-喊喃_4_基胺 基）·1Η_外1：吐并[3,4-b]外b淀-5_甲醯胺 527 N-{[3-(胺基續醯基）苯基]甲基}小乙基-4-(四氫_2Η-ϊ痕喃-4-基胺基）-1Η-ρ比唆并[3,4-b]p比淀-5-甲酸胺 528 1·乙基-N-[(4-甲基苯基）甲基]-4-(四氫-2H-略喃-4-基胺基）-1H_p比峻并[3,4-b]p比嗓·5-甲醯胺 530 1·乙基_Ν-{[4·氣基_3_(三氟甲基）苯基]甲基卜4-(四氫-2Η-旅喃-4-基胺基比吐并[3,4-b&gt;比淀-5·甲醯胺 87841-96〇3〇3_ 中.doc •181 - 1283678 531 2-[({[l-乙基-4-(四氫-2H-旅喃-4-基胺基比唆并[3,4-b] 吡啶-5-基]羰基}胺基）甲基]苯甲酸甲酯 532 N-[(6-氯基-2-叶b淀基）甲基]-1-乙基-4-(四氫-2H-喊喃-4-基 胺基）-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺三氟醋酸鹽 533 N-(2,3-二氯-1Η-Θ -1-基）小乙基-4-(四氣_2H-喊喃-4_基胺 基）-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺 534 N-({2-[乙醯基（甲基）胺基]苯基}甲基）-卜乙基-4-(四氫-2H-哌喃-4-基胺基）-1Η_吡唑并[3,4七]吡啶-5-甲醯胺 535 N-[(1S)_2,3-二氫-1H-莽-1-基]-1-乙基 _4·(四氫 _2H-味喃-4-基 胺基）-1Η-吡唑并[3,4-b]吡啶_5_甲醯胺 536 N-[(lR)-2,3-二氯-1H-印-1-基]-1-乙基 _4_(四氯 _2H-喊喃-4-基 胺基）_1Η·吡唑并[3,4-b]吡啶-5·甲醯胺 537 1-乙基-N-({3-[(甲磺醯基）胺基]苯基}甲基）-4-(四氫_2H-哌 喃-4-基胺基）-1H-p比吐并[3,4-b&gt;比淀-5-甲醯胺 538 1-乙基-N-(苯基甲基）_N-丙基-4-(四氯-2H-旅喃-4-基胺基）-1H-吡唑并[3,4-b]吡啶-5-甲醯胺 540 N-[2_(二甲胺基）乙基]-1_乙基-N-(苯基甲基）_4-(四氫-2H-哌喃-4-基胺基）-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺 541 N-丁基·1·乙基-N-(苯基甲基）-4-(四氫-2H-喊喃·4-基胺基）-lH-ρ比吨并[3,4-b]叶b淀-5_甲醯胺 542 N，l-二乙基-N-(苯基甲基）·4-(四氫-2H-喊喃-4-基胺基）-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺 544 1-乙基-N-(l-苯基-4-氣p比淀基）-4-(四氣展喃-4-基胺 基）_1H-吡唑并[3,4-b]吡啶-5_甲醯胺 545 1-乙基-N-{1-[(乙胺基）羰基]-4-六氫吡啶基}-4-(四氫-2H-喊喃-4_基胺基）-1Η-ρ比吐并[3,4-b]p比淀_5-甲酿胺 546 甲酸-1·乙基-N-[l-甲基-2-(4-甲基-1-六氯外b呼基）乙基]·4· (四氫-2Η-哌喃-4-基胺基）-1Η-吡唑并P，4-b]吡啶-5-甲醯胺 (1:1) 547 [4-({[1·乙基-4-(四氯-2H_^喃-4_基胺基）_1Η_ρ比峻并[3,4-b] 吡啶-5-基]羰基}胺基）-1-六氫吡啶基]酷酸甲酯 87841-9603〇3_ 中.doc -182- 1283678 548 1·乙基-N-{[4-(4•嗎福琳基甲基）苯基]甲基}-4·(四氫-2Hh派 喃斗基胺基）_1Η-吡唑并[3,4-b]吡淀-5-甲醯胺三氟醋酸鹽 549 1-乙基-N-({3-[(4-甲基-1-六氫吡畊基）甲基]苯基}甲基）-4-(四氫-2H-哌喃-4-基胺基）-1Η-吡唑并[3,4-b]吡啶-5_甲醯胺 三氟醋酸鹽 550 N-{[5-(胺基談基）-3_p比淀基]甲基}·1·乙基-4·(四氫_2H-喊 喃-4-基胺基）_1H-吡唑并[3,4-b]吡啶-5-甲醯胺三氟醋酸鹽 551 1-乙基-Ν-{[4-(1-甲基乙基）苯基]甲基卜4-(四氫-2H-哌喃-4-基胺基）-1Η-吡唑并[3,4七]吡啶-5-甲醯胺 552 N_{[3-(環戊氧基)-4-(甲氧基）苯基]甲基}_1_乙基-4-(四氫_ 2H-喊喃-4-基胺基）-1Η-ρ比哇并[3,4-b]p比淀-5-甲酿胺 553 1-乙基-N-({4-[(4-甲基-1-六氫吡畊基）甲基]苯基}甲基）冰 (四氫-2H-哌喃-4-基胺基）-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺 三氟醋酸鹽 554 Ν·[(2,4·二氣苯基）甲基]-1-乙基-4-(四氫-2H-喊喃-4-基胺 基）-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺 555 N-[(2,4_二氟苯基）甲基]-1-乙基冬(四氫-2H-哌喃斗基胺 基）_1Η·吡唑并[3,4_b]吡啶-5-甲醯胺 556 N-[(2_氯基-4_氟苯基）甲基]-1-乙基-4·(四氫-2H_旅喃·4_基 胺基比唆并[3,4-b]p比淀-5-甲酿胺 557 N-{2_[2_氯基-3-(甲氧基）苯基]乙基}·1·乙基-4-(四氮-2H-口辰 喃-4-基胺基）·1Η·外b吐并[3,4-b]p比淀-5_甲酿胺 558 3-[({[1-乙基4-(四氫-2H-旅喃_4_基胺基比也并[3,4_b] 吡啶-5_基]羰基}胺基）甲基]苯甲酸甲酯 559 1-乙基-N_{[3-(1-四氫吡咯基甲基）苯基]甲基}斗(四氫_2H-哌喃-4-基胺基）-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺三氟醋 酸鹽 560 1-乙基N-(2-{4-[(甲磺醯基）胺基]苯基}乙基）-4-(四氫^： 旅喃-4-基胺基）-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺 561 N-{[2,5-雙（甲氧基）苯基]甲基}小乙基冬(四氫-2H-哌喃-4-基胺基）-1Η-吡唑并[3,4-b]吡啶_5_甲醯胺 87841·96〇303·中.doc -183- 1283678 562 N-{[2,6-雙（甲氧基)苯基]甲基卜丨乙基冰(四氫-2H-哌喃-4-基胺基）-1Η-峨峻并[3,4-b&gt;比淀_5_甲醯胺 563 1-乙基-N-[(2_氣苯基）甲基]-4-(四氯-2H-喊喃-4-基胺基）_ 1Η·ρ比吐并[3,4-b]p比啶-5-甲醯胺 564 N-[(3,5-一氣表基）甲基]_1_乙基_4-(四氯-211-0底喃-4-基胺 基）-1Η-吡唑并[3,4-b]吡啶_5_甲醯胺 565 N-[(4-亂冬基）甲基]-1-乙基_4-(四氯-211-0底喃-4-基胺基）_ 1H-吡唑并[3,4-b]吡啶-5-甲醯胺 567 N_環己基小乙基_4·(四氫-2H-哌喃-4_基胺基）-1Η-吡唑并 [3,4-b]吡啶-5-甲醯胺 568 1-乙基-N-{2-[4-(甲磺醯基）苯基]乙基}-4-(四氫-2H-哌喃·4-基胺基）-1Η_吡唑并[3,4-b]吡啶_5·甲醯胺 569 1-乙基-Ν·{[2·氣基-3·(三氟甲基）苯基]甲基}-4-(四氫_2Η-旅喃-4-基胺基）-1Η^比吐并[3,4-b&gt;比淀-5-甲酿胺 570 N_({4-[(環丙胺基）羰基]苯基}甲基）-1_乙基-4·(四氫-2H-哌 喃-4_基胺基）-1H_p比吐并[3,4-b]p比淀-5-甲醯胺 571 1·乙基-Ν-{[4·(4_甲基-1-六氫外b啡基）苯基]甲基}-4-(四氫· 2H-喊喃-4_基胺基）-1Η-外b峻并[3,4-b]p比淀-5·甲醯胺 572 1-乙基-N-{[4-(l_w氫u比洛基甲基）苯基]甲基卜4-(四氫-2H-喊喃-4-基胺基比哇并[3,4-b]p比淀-5-甲醯胺 573 1-乙基-N-[6-(甲氧基）小酮基_2,3_二氫·1Η-雖-2-基]-4-(四 氫-2H-哌喃-4-基胺基）_1H-吡唑并[3,4-b]吡啶_5_甲醯胺 574 N-[(2,5-二氯苯基）甲基]-1-乙基-4-(四氫-2H-喊喃-4-基胺 基）·1Η_吡唑并[3,4-b]吡啶_5-甲醯胺 575 N-[(3,5-二乙基苯基）甲基]-1·乙基·4·(四氫_2Η_»派喃-4-基胺 基）-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺 576 N-[(2,3-二氟苯基）甲基]_1_乙基-4-(四氫-2H-嗓喃-4-基胺 基）-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺 577 1-乙基-N_{[2-(甲續酿基）苯基]甲基}_4-(四氫-2H-喊喃-4-基胺基）-1Η·吡唑并[3,4-b]吡啶-5-甲醯胺 578 1-乙基-Ν-[(3·輕苯基）甲基]-4-(四氳-2H-旅喃-4·基胺基）-1H-吡唑并[3,4-b]吡啶·5-甲醯胺 87841-960303-中.doc -184 - 1283678 579 N-{[3,5-雙（甲氧基）苯基]甲基卜丨_乙基-4-(四氫-2H_哌喃-4-基胺基）-1Η-吡峻并[3,4-b&gt;比啶-5-甲醯胺 580 1-乙基-N-[2-(4-羥苯基）乙基]-4-(四氫-2H-哌喃-4-基胺基）-1H-吡唑并[3,4-b]吡啶-5-甲醯胺 581 N-[(3,5-一乱苯基）甲基]-1-乙基-4-(四氯-211-0底喃-4-基胺 基）-1Η-吡唑并[3,4-b]吡啶_5_甲醯胺 582 N-{[2,4-雙（甲氧基）苯基]甲基卜；[_乙基·4·(四氫-2H-哌喃-4-基胺基）-1Η·吡峻并[3,4-b]p比淀-5-甲醯胺 583 1-乙基·Ν-{[2-(甲乳基）丰基]甲基卜4-(四氯-2H·*7底喃-4-基 胺基）_11]&gt;比峻并[3,4-b&gt;比淀-5-甲醯胺 584 N-[(2,4-二甲基苯基）甲基]小乙基冰(四氫_2H-哌喃-4-基胺 基）-1Η&gt;比吨并[3,4-b]p比淀-5-甲酸胺 585 1-乙基_N-({2-[(甲胺基）羰基]苯基}甲基）冬(四氫-2H-哌喃-4-基胺基）-1Η-吡唑并[3,4_b]吡啶-5-甲醯胺 586 1-乙基-N_{2_[4-(甲氧基）苯基]乙基}-4-(四氫-2H-旅喃-4-基 胺基）·1Η-吡唑并[3,4-b]吡啶-5-甲醯胺 587 N-[(2-氯苯基）甲基]小乙基-4-(四氫-2H-哌喃-4-基胺基）-1H-吡唑并[3,4_b]吡啶-5_甲醯胺 588 1-乙基_N_[(2_經苯基）甲基]-4-(四氫-2H-旅喃-4-基胺基）-1H-吡唑并[3,4-b]吡啶-5_甲醯胺 589 N-(l，3-苯并二氧伍圜晞-5-基甲基）·1_乙基·4-(四氫-2H-峰 喃-4-基胺基）-1Η-ρ比唆并[3,4_b]p比淀·5-甲醯胺 590 1-乙基_Ν-[3-(甲氧基）苯基]-4-(四氫-2Η-旅喃-4-基胺基）-1H-P比峻并[3,4_冲比淀-5-甲醯胺 591 N-(環己基甲基）小乙基-4-(四氫-2H-哌喃-4-基胺基比 唑并[3,4-b]吡啶-5-甲醯胺 592 1-乙基-N-(l，2,3,4-四氫小萘基）-4_(四氫-2H-喊喃-4·基胺 基）-1Η·^吐并[3,4_b]p比淀-5-甲酿胺 593 4-[({[1-乙基_4-(四氫-2H-哌喃-4-基胺基）·1Η-吡唑并[3,4-b] 外匕淀-5-基]談基}胺基）甲基]苯甲酸甲酉旨 594 N-[(3,4-二氣苯基）甲基]_1_乙基-4-(四氫-2H_^喃-4_基胺 基比也并[3,4-b]p比淀-5-甲酿胺 87841-960303-中.doc -185- 1283678 595 Ν·{[4-(胺基羰基）苯基]甲基}_1-乙基-4-(四氫-2H-喊喃-4_ 基胺基）-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺 596 N-[(2,6-.一'氣尽基）甲基]-1_乙基-4-(四氯-2H-^喃-4-基胺 基比吨并[3,4-b]p比淀_5_甲酿胺 597 N-{[3_(胺基魏基）苯基]甲基}_1_乙基·4_(四氫-2H·略喃_4_ 基胺基）-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺 598 1-乙基-Ν-[(4·幾苯基）甲基]-4-(四氫-2H-喊喃-4-基胺基）_ 1Η·ρ比唆并|；3,4帅比淀-5-甲醯胺 599 1-乙基-N-{[6-(甲氧基）_3_?比淀基]甲基}-4·(四氫-2H-p底喃_ 4-基胺基）-1Η-ρ比吐并[3,4-b]外b淀-5-甲驗胺 600 1-乙基比淀基甲基）-4-(四氫-2H-p底喃-4-基胺基）_1H_ 吡唑并[3,4-b]吡啶-5-甲醯胺 601 1-乙基-4-(四氫-2Η-Ϊ痕喃-4-基胺基）·Ν-{[3_(三氟1甲基）苯基] 甲基}-1Η-吡吐并[3,4-b&gt;比症·5_甲醯胺 602 Ν-[4-(2•胺基-2-酮基乙基）苯基]_1-乙基·4-(四氫-2Η-Τ痕喃冰 基胺基比峻并[3,4-b]外b淀-5-甲龜胺 603 1-乙基-N-({4-[(甲胺基）羰基]苯基}甲基）-4-(四氫-2H-喊喃_ 4-基胺基）-1Η·ρ比峻并[3,4-b]p比淀-5-甲酿胺 604 1-乙基-N-{4-[2-(甲胺基）-2-酮基乙基]苯基}_4-(四氫-2H-喊 喃-4-基胺基）-1Η_ρ比唆并[3,4-1小比淀-5-甲酸胺 605 1-乙基-N-[(3-氟苯基）甲基]-4-(四氫-2H-喊喃-4-基胺基）-1H-吡唑并[3,4-b]吡啶-5-甲醯胺 606 1-乙基-N-({4_[(甲續酿基）胺基]苯基}甲基）_4_(四氫-2H_略 喃-4-基胺基比唆并[3,4-b]p比淀-5_甲酿胺 607 N-{[4-(胺基磺醯基）苯基]甲基）-1·乙基-4-(四氫-2Ημ痕喃-4-基胺基）-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺 608 N-{[2-(胺基羰基）苯基]甲基卜1-乙基_4_(四氫·2Η-哌喃斗 基胺基）-1Η_ρ比唆并[3,4-b]p比淀-5_甲酿胺 609 N-({4_[(二氟甲基）氧基]苯基}甲基）-1-乙基_4-(四氫-2H-旅 喃-4-基胺基比岐并[3,4-b]p比淀-5-甲酿胺 610 N-({3-[(二甲胺基）甲基]苯基}甲基）小乙基-4-(四氫-2H-哌 喃-4-基胺基）-1Η-吡唑并[3,4-b]吡啶-5-曱醯胺 87841-960303-中.doc -186- 611 N_{[3-氯基-4-(甲氧基）苯基]甲基}-l-乙基-4-(四氳_2H-口底 喃-4-基胺基比唾并[3,4-b]p比淀-5-甲酿胺 612 N-(l_乙酿基-4_ττ氣ρ比淀基）-1乙基-4-(四氯-2H·喊喃-4-基 胺基）-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺 613 1-乙基-4-(四氫-2H-喊喃-4-基胺基）-N_{[2_(三氟甲基）苯基] 甲基HH-吡唑并[3,4_b]吡啶-5-甲醯胺 615 N_(5-氯基_2,3-二氯-1H-雜_2_基）小乙基_4·(四氯-2H-喊喃-4· 基胺基）-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺 616 N-({3-[(乙酸胺基）甲基]苯基}甲基）-1_乙基_4-(四氫-2H-水 喃-4-基胺基）-1Η-ρ比峻并[3,4-b]p》b淀-5-甲酿胺 617 1-乙基-N-[(4-氟苯基）甲基]-4·(四氫-2H·旅喃-4-基胺基）-1H-P比峻并[3,4-b]p比咬-5-甲醯胺 618 1-乙基-N-{[4-氟基·2·(三氟甲基）苯基]甲基}·4_(四氫-2H-哌喃-4-基胺基）-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺 619 1-乙基-N_[(2-乙基苯基）甲基]-4-(四氫-2H-哌喃-4-基胺基）-1H_吡唑并[3,4-b]吡啶-5-甲醯胺 620 1-乙基-N-{[2-氟基-5-(三氟甲基）苯基]甲基}-4-(四氮_2H_ 哌喃-4-基胺基）-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺 621 1-乙基-4-(四氫_2H-哌喃-4_基胺基）_N-[(2,3,4-三氟苯基）甲 基]-1H-吡唑并[3,4-b]吡啶-5-甲醯胺 622 N-[(4-鼠基_2_氣苯基）甲基]-1-乙基-4·(四氯-2H-P辰喃-4-基 胺基）_1Η·吡唑并[3,4-b]吡啶-5-甲醯胺 623 N-[(4-溴基-2-氟苯基）甲基]小乙基-4-(四氫-2H-哌喃_4_基 胺基）-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺 624 Ν-[(3,5-二甲基苯基）甲基]小乙基-4-(四氫-2H-哌喃_4_基胺 基）-1Η-吡唑并[3,4七]吡啶-5-甲醯胺 625 N-[(2,3-二甲基苯基）甲基]-1-乙基斗(四氫-2H-哌喃_4_基胺 基）-1Η-吡唑并[3,4七]吡啶_5_甲醯胺 626 N-[(2,3-二氣苯基）甲基]-1-乙基斗(四氫-2H·哌喃-4-基胺 基）-1Η-吡唑并[3,4_b]吡啶-5-甲醯胺 627 N-[(4-氛基冬基）甲基]·1_乙基-4_(Έ5氯-2H-旅喃-4-基胺基）_ 1Η-吡唑并[3,4-b]吡啶-5_甲醯胺 87841-960303-中.doc -187- 1283678 628 Ν·[(4-溴苯基）甲基]_i_乙基-4-(四氫_2H_哌喃-4_基胺基）_ 1H-吡唑并[3,4-b]吡啶-5-甲醯胺 629 1-乙基-N_{[5-氟基-2-(三氟甲基）苯基]甲基}-4-(四氫_2H-哌喃-4-基胺基）-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺 630 1-乙基-N-[(4_碘苯基）甲基]-4_(四氫-2H-哌喃-4-基胺基）-1H-吡唑并[3,4-b]吡啶-5-甲醯胺 631 Ν-{[4-(1，1-二甲基乙基）苯基]甲基}_1_乙基·4-(四氫-2H-哌 喃-4-基胺基）-1Η-吡唑并[3,4-b]吡啶-5_甲醯胺 632 N-[(3-氰基苯基）甲基]-1-乙基-4-(四氫-2H-哌喃-4-基胺基）-1Η·ρ比峻并[3,4-b&gt;比淀-5-甲龜胺 633 N-[(2,6_二氯苯基）甲基]-1-乙基冬(四氫-2H-哌喃斗基胺 基）-111_吡唑并[3,4-b]吡啶-5-甲醯胺 634 N-[(5-氯基-2-甲基苯基）甲基]-1-乙基·4·(四氯-2H-喊喃-4· 基胺基）-1Η_吡唑并i3,4-b]吡啶-5-甲醯胺 635 Ν-[(3,5·二溪苯基）甲基]-1_乙基·4-(四氯-2H-喊喃-4-基胺 基）-1Η-吡唑并[3,4_b]吡啶-5-甲醯胺 636 1-乙基-N-[(4-乙基苯基）甲基]-4-(四氫-2H-哌喃-4-基胺基）-lH-ρ比也并[3,4-b]外I：淀-5-甲龜胺 637 1-乙基-Ν·{[3-氟基-4-(三氟甲基）苯基]甲基}-4-(四氫-2H· 哌喃-4-基胺基）-1Η-吡唑并[3,4_b]吡啶-5-曱醯胺 638 1-乙基-N-[(2_蛾苯基）甲基]-4-(四氯-2H-喊喃_4_基胺基）_ 1H-吡唑并[3,4-b]吡啶-5-甲醯胺 639 N-[(2-溴苯基）甲基]-1_乙基-4_(四氫-2H-略喃-4_基胺基）_ 1H-吡唑并[3,4-b]吡啶-5-甲醯胺 640 1-乙基-N-{[4-(叛甲基）苯基]甲基}-4-(四氫_2H_喊喃-4-基 胺基）-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺 641 1-乙基-N-{[3-(經甲基）苯基]甲基}-4-(四氫-2H-喊喃-4-基 胺基）-111_吡唑并[3,4-b]吡啶-5_甲醯胺 642 1_乙基-N-{[3-(羥甲基）_2_甲基苯基]甲基}冰(四氫_2H-哌 喃-4-基胺基）-111-0比峻并[3,4-b]p比淀-5-甲酿胺 643 Ν·{[2,3-二氯-6-(經甲基）苯基]甲基}小乙基-4-(四氫-2H-哌 喃-4-基胺基）-1Η-ρ比峻并[3,4_b&gt;比淀-5-甲醯胺 8784l-960303-中.doc -188- 1283678 644 N-[(2,4_二氯-6-甲基苯基）甲基]小乙基冰(四氫^ 基胺基）-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺 645 1_乙基_N-{[4_(2-甲基丙基）苯基]甲基}_4_(四氫-2H碌喃-4_ 基胺基）-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺 646 N-[(2,5-一·甲基+基）甲基]-1-乙基-4-(四氯-2H-P底喃基胺 基）-1H-P比峻并[3,4_b]p比淀·5_甲酿胺 647 1-乙基-4-(四氫-2Η-哌喃-4-基胺基）-Ν_[(2,4,5-三氟苯基）甲 基]-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺 648 1-乙基-N-{[2_氟基_4_(三氟甲基）苯基]甲基}·4_(四氫·2H_ 旅喃-4-基胺基）-1Η^比峻并[3,4-b&gt;比淀-5-甲酿胺 649 N-[(2_氯基-6-甲基苯基）甲基]_1_乙基冰(四氫-2H-哌喃_4_ 基月:基）·1Η-ρ比也并[3,4-b]p比淀-5-甲酸胺 650 4_[({[1_乙基-4-(四氫-2H-喊喃_4_基胺基）-1H-p比吱并[3,4-b] 吡啶-5-基]羰基}胺基）甲基]苯甲酸鈉鹽 651 3-[({[1-乙基-4·(四氫_2H_喊喃-4_基胺基）-1Η-外b峡并[3,4-b] 吡啶-5-基]羰基}胺基）甲基]苯甲酸 652 1-乙基-4·{[4_(經亞胺基）環己基]胺基}_1H-吡唑并[3,4-b]吡 啶-5-羧酸乙酯 653 1_乙基_4-{[4-(羥亞胺基）環己基]胺基}-N-{[4-(甲氧基）苯 基]甲基}-1Η-ρ比唾并[3,4-b]吡淀-5-甲醯胺 654 N-{[4-(二甲胺基）苯基]甲基}-1_乙基·4-{[4-(羥亞胺基）環 己基]胺基}-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺 655 1-乙基-4_({4-[(乙氧基）亞胺基]環己基}胺基）-N-{[4-(甲氧 基）苯基]甲基}-1Η·吡吐并[3,4-b&gt;比啶_5_甲醯胺 656 1_乙基-4-({4-[(甲氧基）亞胺基]環己基）胺基）-N-{[4-(甲氧 基）苯基]甲基卜1H-吡唑并[3,4-b]吡啶-5-甲醯胺 657 4-[(4-{[(1，1·二甲基乙基）氧基]亞胺基}環己基）胺基]·1·乙 基-Ν-{[4-(甲氧基）苯基]甲基卜1Η-吡唑并[3,4-b]吡啶-5-甲 醯胺 658 1_乙基-N-{[4_(甲氧基）苯基]甲基}-4-[(7_酮基六氫_1H— 氣七圜晞-4-基）胺基]比吐并[3,4-b]p比淀-5-甲酿胺 8784l-960303-中.doc -189- 1283678 659 1_乙基_4-[(7-酮基六氫-1H—氮七圜烯-4_基）胺基]_1Η·吡 唑并[3,4-b]吡淀-5-羧酸乙酯 660 4-{[順式-4·(丁基胺基）環己基]胺基卜n_(2,3-二氫-1H-茚-2-基）_1_乙基-1Η·ρ比峻并[3,4-b]峨淀-5-甲醯胺 661 4_[(反式-4-胺基J承己基）胺基]-i-乙基(苯基甲基比 唑并[3,4-b]吡啶-5-甲醯胺 662 4_[(反式-2-胺基環己基）胺基]小乙基·Ν_(苯基曱基）_1]9[_吡 唑并[3,4-b]吡啶-5-甲醯胺 663 4-[(順式-2-胺基環己基）胺基]_1_乙基_N_(苯基甲基 唑并[3,4-b]吡啶-5-甲醯胺 664 4-[(3·胺基壤己基）胺基]-1-乙基(苯基甲基）_1Η-ρ比唆并 [3,4-b]p比淀-5-甲酸胺 免例1 : 4_(環戊基胺基）-1-乙基-111_吡峻并[3,4-b]吡啶-5_叛酸乙酯42 4-(Cyclopentylamino)ethylidene-indole_(2·ethylbutyl)-1Η-pyrazolo[3,4-b]pyridine-5-carboxamide 43 4-(cyclohexylamine Small ethyl-N-(2-ethylbutyl)-1Η-pyrazolo[3,4-b]pyrrol-5-cartoamine 44 1-ethyl-N-(2-ethyl Butyl)-4-(tetrahydro-2H-bran-4-ylamino)·1Η-benzazolo-3,4-b]pyridine-5-carboxamide 45 1-ethyl-N- (2-ethylbutyl)-4-[(1-methylhexahydropyridin-4-yl)amino]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 46 4 -[(1-Ethyl hexahydrop-precipitate-4-yl)amino]-1-ethyl-N-(2-ethylbutyl)-1Η-pyrazolo[3,4-b] Pyridine-5-formamide 47 4-(cyclopentylamino)-1-ethyl-indole (4-phenylphenyl)-1Η-ρ ratio ol[3,4-b] 5-carboxylic acid amine 48 4-(cyclohexylamino)ethylidene-indole-(4.fluorophenyl)-1Η·pyrazolo[3,4-b]pyridine-5-carbamimidium 49 1-B -N-(4-fluorophenyl)-4-[(1-methylhexahydropyridin-4-yl)amino]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 50 4-[(1-Ethyl hexahydropyridin-4-yl)amino]picethyl-N-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine·5 _Metamine 51 4- (cyclopentylamino)-1-ethyl-hydrazine -propyl-1Η-pyrazolo[3,4-b]pyridine-5-carbamoyl 52 4-(cyclohexylamino)ethylidene-N-n-propyl-1H-pyrazolo[3 ,4-b]pyridine-5-carboximine 53 1-ethyl-N-n-propyl-4-(tetrahydro-2H-pyran-4-ylamino)-1Η-pyrazolo[3 ,4-b]pyridine-5-carboxamide 55 4-[(1-ethylhydrazinohexahydropyridin-4-yl)amino]-1-ethyl-N-n-propyl-1H-pyrazole And [3,4-b]pyridine-5-methanamine 56 N-ylidene-1-ethyl-4·[(1-methylhexahydrop-predative-4-yl)amino]-1H- P is more than [3,4-b]pyridine-5-carbamidamine 57 4-[(1-ethenylhexahydropyridin-4-yl)amino]-1-ethyl-N-(pyridine ice Methyl)-1Η-ρ ratio spit[3,4-b]external b-position-5-methaneamine 61 N-benzyl-4-(cyclopentylamino)-1_methyl-1H- Pyrazolo[3,4-b]pyridine-5-carbamidamine 87841-960303-中. Doc -153- 1283678 62 苄·benzyl-4-(cyclohexylamino)smallmethyl-1H-pyrazolo[3,4-b]pyridine-5-carbamimid 63 N-benzyl-1- Methyl 4-(tetrahydro-2H-piperazin-4-ylamino)-lH-pyrazolo[3,4-b]pyridine-5-carbamimidyl 64 4-(cyclopentylamino) -N-(2-ethylbutyl)小methyl-1H-pyrazolo[3,4-7]pyridine-5-carboxamide 65 4-(cyclohexylamino)-N-(2-ethyl Butyl) small methyl-1H-pyrazolo[3,4-b]pyrrol-5-ylamine 66 汴(2-ethylbutyl)-1-methyl-4-(tetrahydro-2H -pyran-4-ylamino)-1Η-pyrazolo[3,4-b]pyridine-5-methanamine 67 4-(cyclopentylamino)-N-(4-fluorophenyl) 1-methyl-1H-pyrazolo[3,4-b]pyrazole-5-cartoamine 68 4·(cyclohexylamino)-N-(4-fluorophenyl)small methyl·1Η -pyrazolo[3,4-b]pyridine-5-carboxamide 69 N-(4-fluorophenyl)-1•methyl-4-(tetrachloro-2H_pyranyl-4-ylamino) Bis[3,4-b]pyridine-5-carbamide 70 4-(cyclopentylamino)methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 71 4-(Cyclohexylamino)-1-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 72 1-methyl winter (tetrahydro-2H-pyran-4 ·Amino)-1Η-pyrazolo[3,4-b]pyridine-5 -Metformamide 74 4·[(1-Ethyl hexahydropyridinyl-4-yl)amino]-N-benzyl small methyl-1H-pyrazolo[3,4-b]pyridine-5- Methionine 76 4-[(1·ethinylhexahydropyridin-4-yl)amino]-N-(2-ethylbutyl)-1-methyl-1H-exo b唆[3, 4-b&gt;Bite-5-Protonamine 78 4-[(1-Ethylhexahydropyridin-4-yl)amino]-N-(4-fluorophenyl)-1·methyl-1H -External 1: also [3,4-b]p than lake -5-carbamamine 81 1-ethyl-N-methyl winter (tetrahydro-2H-piperidinylamino)-1Η·pyridyl Zoxa[3,4-Pentyl-5-carbamimidyl 82 1-ethyl-N,N-dimethyl-4·(tetrahydro-2H-piperidin-4-ylamino)-1Η-pyridyl Zoxao[3,4-b]pyridine-5-carboxamide 83 1-ethyl-N-ethyl-4_(tetrachloro-2H-bran-4-ylamino)-1Η-ρ ratio [3,4-b]pyridine-5-methanamine 87841-960303-中. Doc -154- 1283678 84 1_Ethyl-N-isopropyl_4-(tetrahydro-2H-piperidin-4-ylamino)_111_pyrazolo[3,4-b]p ratio- 5-cartoamine 85 N-benzyl-1-ethyl-4-[(3S)-tetrahydrofuran-3-ylamino]-1H pyrazolo[3,4-b]p than lake-5-formic acid Amine 86 N-benzyl-1-ethyl·4·[(3Κ&gt;tetrahydrofurylamino]-1H-pyrazolo[3,4-7]pyridine-5-carboxamide 87 Ν-mercapto-1- Ethyl_4-(tetrahydrosulfonyl-3-ylamino)-indole-pyrazolo[3,4-b]pyridine-5-carboxamide 88 N-benzyl-4-(cyclopropylamino)- 1-ethylpyrazolo[3,4-b]pyridine-5-carboxamide 89 N·benzyl_4-[(1,1-dihydrotetramethylenesulfonyl-3-yl)amino] Ethyl]-pyrazolo[3,4-b]pyridine-5-carboxamide 90 N-benzyl-4-[(1,1-dihydrotetrahydro-2H-thiopiperan-4) Amino]-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 91 N-benzyl_1_ethyl-4-(tetrahydro-2H-thio Shouting _4·ylamino)-1Η-pyrazolo[3,4-b]p than lake-5-cartoamine 92 1·ethyl-N-(4-fluorophenyl)-4-[ (3S)-Tetrahydrofuran-3-ylamino]·1Η-pyrazolo[3,4-b] hydroxyp--5-cartoamine 93 1-ethyl-N-(4-fluorophenyl)- 4-[(311)_tetrahydrofuran-3-ylamino]-1H-pyridyl And [3,4-b]p is more than 5-aminoamine 94 1·ethyl-N-(4-fluorophenyl)_4_(tetrahydro-2H-thiopyran-4-ylamino) -1Η-pyrazolo[3,4-b]pyridine-5-formamide 95 1-ethyl-N-(4-fluorophenyl)-4·(tetrahydro-p-s-phen-3-ylamino ) _ih-p is more than [3,4-b] outer bite · 5 · methotrexate 96 4- (cyclopropylamino) small ethyl-fluorene-(4_fluorophenyl)_1Η_pyrazole [ 3,4-b]pyridine- 5-carbamamine 97 4_[(1,1_dihydrotetramethylene-4-yl)amino]-i-ethyl_N_(4-fluorophenyl) _ 1H-pyrazolo[3,4-b]pyridine-5-formamide 98 4-[(1,1-dihydrotetrahydro-2H·thiopyran-4-yl)amino]-1 · Ethyl·Ν_(4_fluorophenyl)-1Η4 is also [3,4_b]p is more than 5--5-carbamamine 87841-960303-. Doc -155- 1283678 Example No. Name 100 1-Ethyl-N-[4-(methyl sulphonyl) aryl] 4-(tetrahydroendan-4-ylamino)-1Η-pyrazole[3 , 4-b]pyridine-5-carboxamide 101 (1-{[1_ethyl ice (tetrahydro-2H-piperidin-4-ylamino)-1Η-pyrazolo[3,4-7] Mouth-butyl-5-yl]carbonyl}hexahydroindole-3-yl)methylaminocarbamic acid tert-butyl ester 102 1-ethyl·Ν_[3-(methicic acid)octyl]-4 -(tetrahydro-2H-fluoren-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 103 1-ethyl_5-{[5-methoxy -6-(trifluoromethyl)-2,3-dihydro-1H-acidyl-1-yl]}}N-hydrogen-2H-pyran-4-yl-1H-P ratio And [3,4-b]indole-4-amine 104 N_[(5-chloropyridin-2-yl)methyl]·1_ethyl-4-(tetrahydro-2H-pyran-4) Amino)·1Η_pyrazolo[3,4-b]pyridine-5-formamide 105 N_(4-fluoroindolyl)-1_ethyl-N-isopropyl-4_(tetrahydro- 2H-Flan-4-ylamino)-1Η-pyrazolo[3,4-b]pyridine-5-carboxamide 106 N-(3-chlorobenzyl)-1-ethyl_N_(2 -Hydroxyethyl) Winter (tetrahydro-2H-pyran-4-ylamino) than spit[3,4_b]p is more than decylamine 107 1-ethyl_N_[(5-methyl-3- Phenylisoindole _4_yl)methyl]-4-(tetrahydro-2H -piperazin-4-ylamino)-1Η-pyrazolo[3,4-b]pyridine-5-carbamimidyl 108 Ν-(2·t-butoxyethyl) small ethyl-4 ·(tetrahydro 2 Η· shout-4-ylamino)-1Η-ρ ratio 并[3,4-b]p than pent-5-cartoamine 109 1-ethyl-4-(tetrahydrogen) -2H-pyran-4-ylamino)-indole-(1,3-pyrazol-2-ylmethyl)-lH-ρ ratio also [3,4-b]p than y-5-A Indoleamine 110 1-ethyl-N-sevenidine _4_ylmethyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1Η-mouth ratio and [3,4-b ]p butyl-5-cartoamine 111 1·ethyl-N-[(2-methylthiazol-4-yl)methyl]_4_(tetrahydro 2 Η 4 _ 4 4 ylamino)-1 Η- ρ 比吐和[3,4-b]p 比盐-5_Metformamide 112 N_[3-(T-butoxymethyl)-yl]-diethyl-4-(tetrahydro-2H_喃 -4- 基 基 基 基 基 ρ ρ ρ [ [3,4-b> 淀 -5 -5-carbamide 113 1-ethyl- Ν · {2-[methyl (methylsulfonyl) amine Ethyl]ethyl}-4_(tetrahydro-211-pyran-4-ylamino)_1Η_ρ than spit[3,4-b]p than lake-5-formamide 114 1·ethyl·Ν- (ρ whistle 1 _2·ylmethyl)-4-(tetrahydro-2H-fluoren-4-ylamino)-1Η-exopurin and [3,4-b]indole-5-carboxylic acid amine 87841-960303-中. Doc -156- 115 1-ethyl-5-{[4-(pyridin-2-ylcarbonyl)hexahydropyrrolidin-1-yl]carbonyl}-N-tetrahydro-2H-pyran-4-yl- 1H-pyrazolo[3,4-b]pyridin-4-amine 116 N-(2-chloro-6-fluorobenzyl)ethylidene-4_(tetrahydro-2H-pyran-4) Amino)-1Η-pyrazolo[3,4-b]pyridine-5-carbamimidamine 117 1_ethyl-N_[(6-paid base_1,6_two-mouse p-predyl-3-yl) )methyl]-4-(tetrachloro-2H-cyclopentan-4-ylamino)-1Η-ρ is more than [3,4-b]p than pent-5-cartoamine 118 N-[ 3-(Aminocarbonyl)benzyl]sodiumethyl 4-(tetrahydro-2H-piperidin-4-ylamino)-1Η-pyrazolo P,4-b]pyridine-5-carboxamide 119 1-ethyl-N-{4-[(methylamino)carbonyl]phenyl b 4-(tetrahydro-2H-piperanylamino)-1Η·pyrazolo[3,4_b]pyridine-5 -Procarbamide 120 1-ethyl-N-[2-(l-methyl·1Η-味吐-4_yl)ethyl]-4-(tetrazo-2H_ brityl 4-ylamino -1Η-pyrazolo[3,4-b]pyridine-5-methanamine 121 N-{2-[(anilinylweiyl)amino]ethyl}-1-ethyl_4-(four Hydrogen-2H- 喊 _ 4-ylamino)-1 Η-pyrazolo[3,4-b]pyridine_5-formamide 122 1-ethyl-N-(1H-tetras-5-yl) Methyl)-4-(tetrazo-2H-monopyran-4-ylamino)-1H·pyrazolo[3,4-b Pyridine-5-carbamide hydrochloride 123 I-ethyl-4-(tetrazine-2H-bran-4-ylamino)-oxime-[2-(1Η-1,2,4-three嗤·1_yl)ethyl]-1Η·pyrazolo[3,4-b]pyridine-5-formamide 124 2-[{[1-ethyl-4·(tetrazo-2H- brim) 4_ylamino-based ton[3,4-b]pyridin-5-yl]carbonyl}(methyl)amino]ethylaminocarbamic acid tert-butyl ester 125 1-ethyl-4-(four Η-2Η_ρ底喃-4-ylamino)-N_[4_(trifluoromethyl)phenyl]- 1H-pyrazolo-; 3,4-b]pyridine-5-carboxamide 126 4_( {[1-ethyl-4-(tetrazol-2H-bromo-4-ylamino)-1Η-ρ is more than [3,4-b] pyridinium-5-yl]carbonyl}amino) Hexahydro-p-precipitate small-reactive acid third-butyl ester 127 1-ethyl-Ν-{3-[(A)-amino-propyl]-4-(tetrahydro-2-indole-branches _4 · Amino group)-1Η_External b spit [3,4-b]External b-precipitate-5_Artemisamine 128 N-[2_(Dimethylamino)-yl]Sodiumethyl_4_(tetrahydrogen) Η2 - ϊ 喃 -4-ylamino) Η 1 Η-pyrazolo[3,4-b]pyridine _5-formamide 129 1-ethyl-fluorene-[(1·ethyltetrahydro ρ Bilo-2·yl)methyl]-4-(tetrahydro-2H-fluoren-4-ylamino)-1Η-ρ ratio spit [3,4-b> butyl--5-carbamide 130 1-ethyl-N-(tetrahydrofuran-2-ylmethyl) )-4-(tetrahydro-2H-piperidin-4-ylamino)-1Η·pyrazolo[3,4-b]pyridine-5·carbamamine 87841-960303-中. Doc -157- 131 1-Ethyl-N-tetrachloro-2H-pyranyl 4-yl-4-(tetrachloro-2H-bungan-4-ylamino) 1Η-pyrazolo[3,4 -b]pyridine-5-carbamamine 132 N-{4_[(dimethylamino)sulfonyl] aryl} winter ethyl (tetrahydro-2H-piperidin-4-ylamino)-1Η -pyrazolo[3,4-b]pyridine-5-carboxamide 133 1-ethyl_N-{3-[(methylsulfonyl)amino]benzyl}-4-(tetrahydro-2H -piperazin-4-ylamino)-1Η&gt; ratio also [3,4-b]external b-position-5-formamide 134 M[l-ethyl-4-(tetrahydro-2H-pyran 4-ylamino)·1Η-pyrazolo[3,4_b]pyridine-5-yl]carbonyl}hexahydropyridine-2-carboxamide 135 1-ethyl-N-(4-methoxyphenyl ) ice (tetrahydro-2H-piperidin-4-ylamino)-1Η-pyrazine and [3,4-b> butyl--5-formic acid amine 136 1-ethyl-Ν-[3·(2 ·Ketyltetrahydropyrrole-1_yl)propyl]-4-(tetrahydro-2H-piperidin-4-ylamino)-1Η-ρ than spit[3,4-b]p ratio- 5-cartoamine 137 1-ethyl-N-[2-(l-methyltetrahydropyrrole-2-yl)ethyl]-4-(tetrahydro-2H-pyran-4-ylamino) -1Η-ρ比峻和[3,4-b]p 比淀-5-甲含胺138 1-ethyl-Ν-(ρ比淀-3-ylmethyl)-4_(tetrachloro-2H- Shouting -4_ylamino)-1Η·pyrazolo[3,4-b]pyridine-5-formamidine 139 1_Ethyl-N-(l-methylazide external b-butyl-4-yl)-4-(tetrachloro-2H-pyro- 4-ylamino)-1Η-pyrazolo[3, 4-b]pyridine_5_formamide 140 1-ethyl-N-(l-ethylpropyl)-4-(tetrahydro-2H-piperidin-4-ylamino)_1H-pyrazole [3,4-b]pyridine-5-formamide 141 1-ethyl-N-(2-hexachloro-p-pred-1-ylethyl)-4-(tetrazine-2H- shouting-4 -ylamino)-1Η_ρ than wow and [3,4_b]p than yt-5·ylamine 142 1-ethyl-N-(3-isofo-4-ylpropyl)-4_(four gases ·2Η_叫喃-4-ylamino)-1Η-^ sniff [3,4~b]p than yt-5·enamin 143 N-(3-ethoxypropyl)-1-B 4-(tetrahydropyran-4-ylamino)-1Η-pyrazolo[3,4-b]pyridine-5-carboxamide 144 N-(cyclohexylmethyl)succinyl-4- (tetrahydro-2H-fluoren-4-ylamino)-1Η-ρ-pyrazolo[3,4-b]pyridine-5-carboxamide 145 N-[3_(dimethylamino)propyl] -1·ethyl phenyl (tetrahydro-2H-piperidin-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carbamimid 146 1-ethyl-N-new Pentyl-4-(tetrachloro-2H· shoutin-4_ylamino)-1Η-^ than spit[3,4-b]p than lake-5-formamide 87841-96〇3〇3 ·in. Doc -158 - 1283678 147 1-ethyl-indole (4-methoxy-yl)-4-(tetrahydropyran-4-ylamino)-1Η-pyrazolo[3,4_b]pyridine_ 5_Metformamide 148 1-ethyl·Ν_{2·[(benzoic acid)amino]ethyl}-4-(tetrahydro-2H-furan-4-ylamino)·1Η-pyrazole And [3,4-b]pyridine-5-formamide 149 N-[2-(ethylguanidino)ethyl]sodiumethyl 4-(tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo[3,4_b]pyridine-5-carboxamide 150 1-ethyl-N-{2_[(methyl succinyl)amino]ethyl}-4-(tetrahydro-2H «^Butyl-4-ylamino)-1Η-ρ is more than [3,4-b]p than pent-5-cartoamine 151 1·ethyl-N-methyl-N-(p ratio 44_ylmethyl)-4-(tetrahydro-2H-pyran-4-ylamino group than spit [3,4-b>pyridin-5-carbamide 152 1-ethyl-hydrazine ·{2·[(2-methoxyphenyl)(methyl)amino]ethyl b 4-(tetrahydro-2H-pyran-4-ylamino)-1Η-ρ is more than [3, 4-b]p-precipitate-5-formamide 153 1-ethyl-N-(2-keto-2-phenylethyl)-4-(tetrahydro-2H-pyran-4-ylamine -1H-p is more than [3,4-b]p than _5_cartoamine 154 N-(2,5-difluorobenzyl)succinyl-4-(tetrahydro-2H- Piperan-4-ylamino)_1H_pyrazolo[3,4-b]pyridine-5-carboxamide 155 1_Ethyl_4-(tetrahydro-2H-piperidin-4-ylamino)-N-[4-(trifluoromethyl)-yl]-lH-p ratio [3,4_b&gt;碧丁-5_Mercaptoamine 156 N,l-Diethyl-N-propyl-4-(tetrahydro-2H-piperidin-4-ylamino)-1Η-pyrazolo[3,4- b]pyridine-5-methanamine 157 N-cyclopropyl_1_ethyl-4-(tetrahydro-2H&gt;anthracen-4-ylamino)-1Η-ρ ratio 并[3,4- b] Pyridine-5-formamide 158 N-(2-Amino-2-ketoethyl)-1_ethyl_4_(tetrahydro-2H-furan-4-ylamino)-1Η- Pyrazolo[3,4-b]pyridine-5·carbamidamine 159 1-ethyl-N-(3-methoxyphenyl)-4_(tetrahydro-2H-pyran-4-ylamino) _ih-pyrazolo[3,4-b]pyridine-5-carboxamide 160 N-(3,4-difluoroaryl)·1_ethyl-4-(tetrahydro-2-indolyl-4 _i-amino))iH-pyrazolo[3,4-b]pyridine-5-formamide 161 3-({[1-ethyl-4-(tetrahydro-2H-pyran-4-ylamine) Base)_1Η·pyrazolo[3,4-b]exodecyl-5-yl]carbonyl}amino)propionic acid ethyl ester 162 N-(l_mercapto 7T to bit-4-yl)-1- Ethyl-4-(tetrahydro-2H-cyclobutanyl 4-amino-amino)-1Η-pyrazolo[3,4-b]pyridine-5-decylamine 87841-960303-中. Doc -159- 1283678 163 N-butyl-4-{[l-ethyl-4-(tetrahydro-2H-piperidin-4-ylamino)-1Η-pyrazolo[3,4-b] Pyridin-5-yl]carbonyl}hexahydropyrazine small formamide 164 1-ethyl-4·(tetrahydro-2H-piperidin-4-ylamino)-indole-(1,3,4-pyrimidine Diazol-2_yl)_ 1H-pyrazolo[3,4h7]pyridin-5-formamide 165 (·(2,3-dichloro-1H- isomer·2-yl)_1_ethyl- 4-(tetrachloro-2H-pyran-4-ylamino)-1Η-pyrazolo[3,4-b]pyridine-5-carboxamide 166 1_ethyl-N-[2-(2 -ketoimidazolinidin-1-yl)ethyl]-4-(tetrahydro-2H-piperidin-4-ylamino)-1Η-pyrazolo[3,4-b]pyridine-5- Indoleamine 167 N-(3,4-dimethoxybenzyl)ethylethyl-4-(tetrahydro-2Ημpyran-4-ylamino)-1Η·pyrazolo[3,4_b]pyridine- 5_Metamine 168 N-(3-chloro-aryl)-1-ethyl_4-(tetrazo-211-0 guar- 4-ylamino)-111-0 is more than [3,4 -b]pyridine-5-decylamine 169 1-ethyl-5-[(4·methylhexahydropyrrolidin-1-yl)carbonyl]_N_tetrahydro-2H-piperidinyl-1H-pyridyl Zydro[3,4-b]pyridin-4-amine 170 1-ethyl-N-(2-ethyl)-4((tetrachloro-2H-chloropyran-4-ylamino) ,4-b]pyridine-5-formamide 171 1-ethyl-5-{[4-(4-methoxybenzene) Hexahydropyranin-1-yl]carbonyl}-N-tetrahydro-2H-piperidin-4-yl-1H-pyrazolo[3,4-b]pyridine-4_amine 172 1-ethyl- N-{4-[(methylsulfonyl)methyl]phenyl}-4-(tetrahydro-2H-piperidin-4-ylamino)-1Η-ρ is more than [3,4_b] external b Bite-5_carbamamine 173 N-[3-(dimethylamino)-3-ketopropyl]sodiumethyl 4-(tetrahydro-2H-piperidin-4-ylamino)-1Η -ρ ratio vomit [3,4-b] outer b-position-5-formamide 174 1-ethyl_N-[(1-methyl-1H-imidazol-5-yl)methyl]-4- (tetrahydro-2H-piperazin-4-ylamino HH-pyrazolo[3,4-b]pyridine-5-carbamimid 175 1-ethyl-N-{4_[(methylamino) Thiophene]phenyl 4-(tetrahydro-2H-piperazin-4-ylamino HH-pyrazolo[3,4-b]pyridine-5-formamide 176 N_(2-chloroethyl )_1_Ethyl_4-(tetrachloro-2H-l-amyl-4-ylamino)-1Η-b-pyrazolo[3,4-b]pyridine-5-formamide 177 1-ethyl- N-methyl-N-[(5-methyl-1,3,4·oxadiazol-2-yl)methyl]-4-(tetrahydro-2H-bran-4-ylamino)_1H -pyrazolo[3,4-b]pyridine-5-formamide 178 1-ethyl-indole-[(1·methyl-1H-pyrazol-4-yl)methyl]-4-(four Hydrogen-2Ημ派喃-4_ylamino)_1Η-pyrazolo[3,4-b]pyridine-5-formamide 87841-960303-中. Doc -160- 1283678 179 1-Ethyl-N-methyl-indole-[(1-methyl-1H-imidazol-2-yl)methyl]-4-(tetrahydro, 2H- brim-4- Amino-based)-iH-pyrazolo[3,4-b]pyridine-5-carboxamide 180 1-ethyl-4-(tetrahydro-2H-piperidin-4-ylamino)-N- (2-pyrimidin-2-ylethyl)-1H-pyrazolo[3,4-7]pyridine-5-carboxamide 181 Ν-[2·(4-chlorophenyl)ethyl]-1- Ethyl ice (tetrahydro-2H-piperazin-4-ylamino)_ 1Η-ρ ratio spit [3,4-b]p ratio far-5-cartoamine 182 1-ethyl-Ν·[ 2-(2-methoxyphenyl)ethyl]·4·(tetrahydro-2H-piperidin-4-ylamino)-1Η-pyrazolo[3,4-b]pyridine_5_ formazan Amine 183 4-(cyclohexylamino)_1-(3-ethoxy-3-ketopropyl)-1 Η-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester 185 1- N-propyl-4-(tetrachloro-2H-»1 phenan-4-ylamino group is more than [3,4-b]p than pyridine-5-carboxylic acid ethyl ester 186 1-(2-hydroxyl Ethyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1Η-pyrazolo[3,4-7]pyridine-5-carboxylic acid ethyl ester 187 N-[4_(methyl-acid Base]_1_正-propyl-4-(tetrahydro-2H_ shout-4-ylamino)_1H-pyrazolo[3,4-b]pyridine-5-carboxamide 188 N -(4-fluorophenyl) small n-propyl-4-(tetrahydro-2H-pyran-4-ylamine )·ΗΗ-ρ-pyrazolo[3,4-b]pyridine-5-formamide 189 1·ethyl-6-methyl_4-(tetrahydro-2H-pyranyl-4-ylamino) 1-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester 190 4-(cyclohexylamino)-1-ethyl-6-methyl-[3,4-b]p ratio盐-5- 叛 酉 酉 191 4-(cyclohexylamino)-1•ethyl-6-methyl-N-[4-(methyl sulfhydryl) aryl]pyrazole[3,4- b] Pyridin-5-formamide 192 N-yote·4-(cyclohexylamino)-1-ethyl-6-methyl-1H-P than spit[3,4-b] -5-Artemisamine 193 4-(cyclohexylamino)ethylidene-N-(4-fluorophenyl)·6-methyl-1H-1T ratio also [3,4_b]external ti- 5-Methylamide 194 4-(cyclohexylamino)-1·ethyl-6·methyl-[4-(trifluoromethyl)-yl]1Η-pyrido[3,4-b] p 比盐-5-甲含胺195 4-(cyclohexylamino)_N-(2,3-dihydro·1Η_ although-2-yl) small ethyl methylpyrazolo[3,4- b] Pyridine-5-formamide 87841-960303-中. Doc •161- 1283678 196 N-Mercapto-1·ethyl-6-methyl_4-(tetrahydro-2H-pyran-4-ylamino)-1Η-pyrazolo[3,4-b Pyridine-5-carbamamine 197 N-ylidene-1-ethyl-4-[(2·费基一氮七圜健-3-yl)amino]-lH-p-pyrazole[3, 4-7]pyridin-5-formamide 198 Ν·benzyl-1-ethyl-4·[(3-hydroxycyclohexyl)amine; ΜΗ-pyrazolo[3,4-b] p-precipitate- 5-mercaptoamine, also known as N-Germanyl-1-ethyl-4-[(3-carbyl hexane small)amino]-1Η-pyrazolo[3,4-b]pyridine -5-Mergamine 199 N·indolyl-1·ethyl-4-[(4-hydroxycyclohexyl)amino]-1H-pyrazolo[3,4-b] 1 (7 than D-5 - formic acid amine, also known as N-mercapto-1-ethyl-4-[(4- ricottine propyl)amino]-1 Η-pyrazolo[3,4-b]pyridine-5 -carbamamine 200 N-benzyl-1-ethyl-4-[(3-hydroxycyclopentyl)amino]_1H-pyrazolo[3,4-b] p than ammonium-5-formate, Also known as N-mercapto-1-ethyl-4-[(3. sylylene pentane) amino]-1 Η-pyrazolo[3,4-b]pyridine-5- formazan Amine 201 N_benzylic small ethyl sorb [(4-ketocyclohexyl)amine; MH-pyrazolo[3,4_b] p than pent-5-cartoamine, also known as N-fluorenyl- 1_ethyl-4-[(4-fluorenyl J curtain) Alkyl) Amino]_1H-pyrazolo[3,4-b]pyridine-5-carboxamide 202 1-ethyl-N-(2-hydroxysodiummethylethyl)-4-(tetrahydrogen) -2H-piperidinylamino)-1Η-pyrazolo[3,4-b]pyridine-5·carboxamide 203 (2S)-2-({[l-ethyl-4-(tetraz) -2H-Bucer-4-ylamino)-1Η-ρ than spit [3,4-b]pyridin-5-yl]carbonyl}amino)-3-hydroxypropanoic acid methyl ester Example No. Name 204 1 -ethyl 4-[(4-hydroxycyclohexyl)amino]-1H-pyrazolo[3,4-7]pyridine-5.carboxylic acid ethyl ester 205 1-ethyl 4-[(4-keto ring) Ethyl)amino]-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester 207 4·[(1-ethylindenyl-4-hexahydropyridinyl)amino]-1- Ethylethyl 1-H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester 209 4-[(4-Aminocyclohexyl)amino]-1-ethyl-1Η·pyrazolo[ 3,4_b]pyridine-5-carboxylate ethyl ester 8784l-96〇3〇3-中. Doc -162- 1283678 210 Ethyl-N-[(1-oxo-3-pyridyl)methyl]_4_(tetrahydro-2H-piperidinylamino)-1Η-pyrazolo[3,4- b]pyridine-5-carbamimid 211 1·ethyl-N-[(l-oxy-2-pyridyl)methyl]dong (tetrahydro-2-indole-piperidinyl)-1Η-pyrazole And [3,4-b]pyridine-5-formamide 212 1-ethyl-indole-[(1. oxidized-4-exo b-decyl)methyl M-(tetrahydro-2H-pyran-4 -ylamino)-1Η-pyrazolo[3,4-b]pyridine-5-carbamimidyl 214 4-[(cis-4-aminocyclohexyl)amino]xiaoethyl good (phenyl Methyl &gt; 1H_pyrazolo[3,4-b]pyridine-5-formamide 221 4·(cyclobutylamino)ethylidene(phenylmethyl)_1H-pyrazolop,4_b Pyridine-5-formamide 222 4-(cycloheptylamino)ethylidene(phenylmethyl)_1Η-ρ than oleno[3,4-b]^pyridin-5-carboxamide 223 1-ethyl-4-[(4-methylcyclohexyl)amino]-N-(phenylmethyl)-iH-pyrazolo[3,4-7]pyridine-5-carboxamide 224 1 -ethyl-4-[(3-methylcyclohexyl)amino]-indole-(phenylmethyl)-iH-pyrazolo[3,4-b]pyridine-5-carbamimid 225 1- Ethyl-4-[(l-methyl-trihexyl)amino](phenylindole-based ton[3,4-b]pyridine-5-formamide 226 4 -[(lR, 2R, 4S)-bicyclic and [2. 2. 1]hept-2-ylamino]-1-ethyl-N-(phenylmethyl)-1Η·pyrazolo[3,4-b]pyridine-5-formamide 227 4-[(lR , 2S, 4S) _ double loop and [2. 2. 1]hept-2-ylamino H-ethyl-N-(phenylmethyl)-1Η-pyrazolo[3,4-b]pyridine-5-carbamimidyl 228 1-ethyl-4- {[(3S)-2-keto-3-tetrahydropyrrolyl]amino}_N-(phenylmethyl)_1H-pyrazolo[3,4-b]pyridine-5-carboxamide 229 4 -[(2,5-diketo-3-tetraoxapyrryl)amino]-1-ethyl-N-(phenylmethyl)-1H-pyrazolo[3,4-b]pyridine- 5-Protonamine 230 4-(1-Azabicyclo[2·2·2]oct-3-ylamino)-1·ethyl-N-(phenylmethyl)-1H-pyrazolo[3 , 4-b]pyridine-5-formamide 231 1-ethyl-4-[(l-methylcyclohexyl)amino]-indole·{[4-(methoxy)phenyl]methyl} -1Η-pyrazolo[3,4-b]pyridine-5-carbamimid 233 4-(cyclobutylamino)ethylidene-N_{[4-(methoxy)phenyl]methyl b 1Η-pyrazolo[3,4-b]pyridine-5-carboxamide 87841-960303·中. Doc -163- 1283678 234 4-(cycloheptylamino)ethylidene_N-{[4-(methoxy)phenyl]methyl}_ιη·pyrazolo[3,4-b]pyridine- 5-Protonamine 235 4-[(lR,2R,4S)-bicyclo[2·2·1]heptan-2-ylamino H-ethyl-anthracene {[4-(methoxy)benzene Base]methyl}_1H# is more than [3,4_b]p than lake-5_formamamine 236 1-ethyl4-[(4-methylcyclohexyl)amino]-N-{[4- (Methoxy)phenyl]methyl is more than [3,4-b]p than ammonium 5-carboxylate 237 1-ethyl-4-[(3-methylcyclohexyl)amino]-N -{[4-(Methoxy)phenyl]methyl}-1Η-pyrazolo[3,4_b]pyridine·5-formamide 238 4-[(lR,2S,4S)-bicyclo and ρ· 2·1]heptan-2-ylamino]picethyl-indole-{[4-(methoxy)phenyl]methyl}-1Η-pyrazolo[3,4-b]pyridine-5- Methotrexate 239 4-[(cis.4-aminocyclohexyl)amino]ethylidene-N-{[4-(methoxy)phenyl]methyl}-1Η-external b-[ 3,4-b&gt;Bite-5-Protonamine 240 4·(Cycloheptylamino)-1·ethyl-Ν·({4-[(methylsulfonyl)amino]phenyl} A Base)-1Ημ ratio also [3,4-b]p ratio _5_methalamine 241 4-(cyclobutylamino)-1·ethyl-Ν·({4_[(methylsulfonyl) Amino]phenyl}methyl)-1Η-ρ Comparative 唆[3,4-b]pyrazine-5-formamide 242 4-[(lR,2R,4S)-bicyclic and P. 2. 1]hept-2-ylamino]-1-ethyl-N-({4-[(methylsulfonyl)amino]phenyl}methyl)-1Η-pyrazolo[3,4-b Pyridine-5-formamide 243 4-[(lR,2S,4S)·bicyclo[2_2. 1]hept-2-ylamino]picethyl-N-({4_[(methylsulfonyl)amino]phenyl}methyl)-1Η-pyrazolo[3,4-b]pyridine- 5-Proline 244 1 1-ethyl-4-[(4·methylcyclohexyl)amino]-Ν-({4·[(methylsulfonyl)amino]phenyl}methyl)-1Η- Bamboo b also [3,4-b]r than lake-5-cartoamine 245 1·ethyl_4_[(3-methylcyclohexyl)amino]·Ν-({4-[(methylsulfonate) Indenyl)amino]phenyl}methyl)·1Η-ρ is more than [3,4-b]p than pent-5-ylamine 247 1-ethyl-4-[(l-methyl ring) Hexyl)amino]-N_({4_[(methylsulfonyl)amino]phenyl}methyl is more than spit[3,4-b]p than _5_甲甲胺2484-[(顺4-Aminocyclohexyl)amino]-1-ethyl-N-({4-[(methylsulfonyl)amino]phenyl}methylpyrano[3,4-b]p Bismuth-5-formic acid amine 249 4-(cyclohexylamino)-1-ethyl-N-({4-[()-amino)phenyl}methyl)-1H-P ratio And [3,4-b]p is more than 5-aminoamine 250 4-(cycloheptylamino)-indole-(2,3·dihydro-1H-but-2-yl)-1-B Base-1H-P is more than [3,4-b]pyridine-5-formamide 87841-96〇3〇3_. Doc •164- 1283678 251 4-(Cyclobutylamino)-N-(2,3-dihydro-1H-indol-2-yl)-1-ethyl·1Η-pyrazolo[3,4- b]pyridine-5-methanamine 253 N-(2,3-diaza-1H-indox-2-yl)·1-ethyl-4-[(3-methylcyclohexyl)amino]_ 1Η -pyrazolo[3,4-b]pyridine-5-carboxamide 254 N-(2,3-dihydro-1H- although -2.yl)-p-ethyl 4-[(4-methylcyclo) Hexyl)amino]-IH-p is more than [3,4-b]W: yt-5-carbamide 255 4-[(lR,2R,4S)-bicyclo[2·2·1]g Amino]]N-(2,3-dihydro-1H-indol-2-yl)-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 256 4- [(lR, 2S, 4S)-double soil and [2·2·1]heptylamino]-N-(2,3-dichloro-1H- is-2-yl)-1•ethyl-1H ·pyrazolo[3,4_b]pyridine-5-formamide 257 Ν·(2,3-dihydro-1H-indol-2-yl)sodiumethyl-4-[(l-methylcyclohexyl) Amino]-lEMb gorge[3,4-b]p is more than 5-amylamine 258 4-[(cis.4-aminocyclohexyl)amino]-N-(2,3-di Hydrogen-1H-indol-2-yl)sodiumethyl-1H-pyrido[3,4-b]p than yt-5-carbamide 259 1_ethyl-N-{4-[(methane) Mercapto)methyl]phenyl}·4-[(4-ketocyclohexyl)amino]-1Η-pyrazolo[3,4-b]pyridine-5-carboxamide 260 N- [(2,4-dimethylphenyl)methyl]-1-ethyl winter [(4. ketocyclohexyl)amino]-1H-pyrazolo[3,4_b]pyridine-5- formazan Amine 261 Ν_[(3,4·dimethylphenyl)methyl]sodiumethyl-4-[(4-ketocyclohexyl)amino]-lH-p-pyrazolo[3,4-b] Pyridine_5_formamidine 262 N-[(3,4-dichlorophenyl)methyl]-1-ethyl_4-[(4-ketocyclohexyl)amino]-1H-pyrazole [3,4-b]pyridine-5-formamide 263 1_ethyl-N-{[4-(methoxy)phenyl]methyl b 4_[(4-ketocyclohexyl)amino] -1H-pyrazolo[3,4-b]pyridine_5-formamide 264 1-ethyl-N-({4-[(methylsulfonyl)amino]phenyl}fluorenyl)-4_ [(4-Ketylcyclohexyl)amine HH_p is more than spit[3,4-b]externate-5-formamide 265 N-{[4-(dimethylamino)phenyl]methyl b Μethyl_4-[(4-ketocyclohexyl)amino]-lH-p is more than [3,4-b]p than _5_carbamamine 266 N-({4-[( Difluoromethyl)oxy]phenyl}methylethyl winter [(4-ketocyclohexyl)amino]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 267 1 -ethyl-4-[(4-ketocyclohexyl)amino]]ν·{[4-(trifluoromethyl)phenyl]methylHH-pyrazolo[3,4-blpyridine- 5. Myramine 87841-960303-中. Doc-165- 1283678 268 1-Ethyl-N-{[4-(methylsulfonyl)phenyl]methyl}·4-[(4-ketocyclohexyl)amino]-1Η-pyrazole [3,4-b]pyridine-5-formamide 269 1-ethyl-N-(4-fluorophenyl)·4-[(4-fluorenylcyclohexyl)amino]-1H_p ;3,4-b]pyridine-5-carbamimid 270 1-ethylidene [(4-ketocyclohexyl)amino]-N-(2-pyridylmethyl)-1Η-pyrazolo[ 3,4_b]pyridine-5-carbamidamine trifluoroacetate 271 N-(2,3-dihydro-1H-indole-2-yl)ethylethyl-4-[(4-ketocyclohexyl)amine -1H-pyrazolo[3,4-b]pyridine-5.carbamamine 272 N-(l-ethinyl-4-hexahydropyridinyl)-1-ethyl-4-[(4 -ketocyclohexyl)amino]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 273 1-ethyl-N_[(l-methyl-1H-pyrazole-4- Methyl]-4-[(4-ketocyclohexyl)amino]·1Η-pyrazolo[3,4-b]pyridine-5·carboxamide 274 N,l-diethyl_4 -[(4-ketocyclohexyl)amino]-1H-pyrazolo[3,4-b]pyrodo-5-cartoamine 275 1-ethyl-4-[(4-ketocyclohexyl) Amino]-N-(l,3-oxazol-2-ylmethyl)-1Η-p is more than [3,4-7] than dian-5-carbamide 276 1-ethyl-N_ (phenylmethyl)-4-(tetrahydro-2H_per pipe喃-3-ylamino)·1Η-pyrazolo[3,4-b]pyridine-5-formamide 277 N-({4-[(difluoromethyl)oxy]phenyl}methyl -1_ethyl_4_(tetrahydro-2H-pyranyl-3-ylamino)-1Η_ρ ratio also [3,4-b> butyl-5-nonylamine 278 1-ethyl-4 -(tetrahydro-2H-piperidin-3-ylamino)_N-{[4-(trifluoromethyl)phenyl]methyl}-1Η_external b spit [3,4-b> ratio -5-5-Metaguanamine 279 1-ethyl-N-{[4-(methylsulfonyl)phenyl]methyl}-4-(tetrahydro-2H-indol-3-ylamino)_1H -pyrazolo[3,4-b]pyridine-5-formamide 280 1-ethyl-N_{4·[(methylsulfonyl)methyl]phenyl b 4-(tetrahydro-2H-indole喃-3-ylamino)-1Η-pyrazolo[3,4_b]pyridine_5-formamide 281 1-ethyl-N-(4-fluorophenyl)-4-(tetrahydro-2H- Piperidin-3-ylamino)-1Η-pyrazolo[3,4-b>pyramid-5-formamide 282 1-ethyl-N-(2-pyridylmethyl)-4-( Tetrahydro-2H-piperidin-3-ylamino)·1Η-pyrazolo[3,4-b]pyridine-5-formamide trifluoroacetate 283 Ν·(2,3·dihydro-1H -mercapto)-1_ethyl_4_(tetrahydro-2H-bromo-3-ylamino)-1Η-pyrazolo[3,4-b]pyridine_5-formamide 87841-960303- in. Doc -166 - 1283678 284 N-(l-Ethyl-4-ylτ nitrogen p-precipitate)-1-ethyl-4-(tetrachloro-2Η-ϊ派喃_3_ylamino)_1H- Pyrazolo[3,4-b]pyridine-5.carbamamine 285 1-ethyl-N-[(1-methyl-1H-pyrazol-4-yl)methyl]-4-(tetrahydrogen) _2H_ shouting _3_ arylamino)_1H-pyrazolo[3,4-b]pyridine-5-carboxamide 286 N,l-diethyl-4-(tetrahydro-2H- britant- 3-aminoamino)_1Η-ρ ratio ol[3,4-b] 1 (7 than bite-5-cartoamine 287 1-ethyl-4_(tetrahydro-2H-nican-3-ylamine) -N-(l,3-psec-2-ylindenyl)_ 1H-pyrazolo[3,4-b]pyridine-5-carboxamide 288 4_[(4,4-difluoro Cyclohexyl)amino]·1-ethyl-N-(phenylmethyl)-lH-pyrazolo[3,4-b]pyridine-5-carboxamide 289 1-ethyl-4-[(4 ·Fluoro-3-cyclohexan-1-yl)amino]-N-(phenylmethyl)_1H_pyrazolo[3,4-b]pyridine-5-carboxamide 290 4_[(1- Acetyl-4-hexahydropyridyl)amino]·Ν-(2,3-dihydro-1H·indol-2-yl)-1-ethyl-1Η-Ρ比哇和[3,4- b]p-precipitate-5-formic acid amine 291 4-[(1-ethylindolyl-4_hexahydropyridinyl)amino]-indole-[(3,4·dichlorophenyl)methyl] Base-1Η-pyrazolo[3,4-b]pyridine_5_methamine 292 4-[(1-acetamidine) 4-tetrahydropyridyl)amino]-1-ethyl-N-[(3-fluorophenyl)methyl]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 293 4-[(1·Ethyl-4-pyropyridyl)amino]-N-[(3,4-difluorophenyl)indolyl]-1_ethyl-1H-pyrazolo[ 3,4-b]pyridine-5-methanamine 294 4-[(1-ethylindolyl-4-hexahydropyridinyl)amino]-N-[(2,5-difluorophenyl)methyl ]-1-ethyl-1H·pyrazolo[3,4-b]pyridine_5-formamide 295 4-[(1-ethylindolyl-4·hexahydropyridinyl)amino]ethyl -N_{[3-(trifluorofyl)phenyl]methyl}-1Η-pyrazolo[3,4-b]pyridine-5-carboxamide 296 4-[(1-ethenyl-4 -hexahydropyridyl)amino]]iethyl-indole-{[4-(trifluoromethyl)phenyl]methyl}-1 oxime-pyrazolo[3,4_b]pyridine_5-carbamimid 297 4-[(1-Ethyl _4·hexafluoridyl)amino]-N-[(2,6-difluorophenyl)methyl]-1-ethyl-1H-pyrazolo[3 ,4-b]pyridine-5-formamide 298 4-[(1-ethylindolyl-4·hexahydropyridinyl)amino]-N-[(3-phenylphenyl)methyl]-1- Ethyl-1H-pyrido[3,4-b]external b-position-5-formamide 299 4-[(1·ethinyl-4-hexahydropyridinyl)amino]-1-ethyl -N-{[4-(methoxy)phenyl]methylHH-pyrazolo[3,4-b]pyridyl Pyridin-5-carbamamine 87841·96〇3〇3·中. Doc-167- 1283678 300 4_[〇乙醯-4-Pyridine)amino]-1-ethyl-N-[4-(methoxy)phenyl]-1Η_ρ than spit [3, 4-b&gt;Bisodium-5-carbamamine 301 4-[(1-Ethyl-4-pyridinyl)amino]-N-({4-[(dimethylamino))sulfonyl) ]phenyl}methyl)-1-ethyl-lH-p is more than [3,4-b]p than pent-5-cartoamine 302 4-[(1_ethenyl-4-hexahydro) Pyridyl)amino]-1 -ethyl-N-(l,2,3,4-tetrahydro-1-naphthalenyl)_1H-pyrazolo[3,4_b]pyridine-5-carbamimidyl 303 4 -[(1-ethylindolyl-4-hexahydropyridinyl)amino]-N-{[2-(dimethylamino)phenyl]methyl}sodiumethyl-1H-pyrazolo[3,4 -b]pyridine-5-carbamide 304 4-[(1-ethenyl-4-hexahydropyridinyl)amino]-N-[(2,4-dichlorophenyl)methyl]-1 -ethyl to benzo[3,4-b]p ratio-5-y-amine 305 4-[(1-ethylindol-4-hexahydropyridinyl)amino]ethyl-N-[ (2-fluorophenyl)methyl]-1H-pyrazolo[3,4-b]pyridine-5-formamide 306 4-[(1-acetoxy-4-hexahydrop-decyl)amine ]]-N-[(2-Chloro-6-fluorophenyl)methyl]sodiumethyl·1Η·pyrazolo[3,4-b]pyridine-5-carboxamide 307 4·[(1 _ Ethyl 4·hexahydropyridyl)amino]-N-({4- [(Difluoromethyl)oxy]phenyl}methyl)sodiumethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 308 4-[(1·Ethyl)- 4-hexahydropyridyl)amino]-N-{[3-carbyl·4-(methoxy)phenyl]methyl}-1-ethyl-ΙΗ-ρ is more than [3,4- b]p bis-5-cartoamine 309 4-[(1-ethyl-bromo-4-hexanitro-p-aryl)amino]-N-[(5-alkyl-2·^ ratio decyl group) Methyl]sodiumethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 310 4-[(1.Acetyl-4-pyridinium p-butyl)amino]- N-(5-Chloro-2,3-dihydro-1H-indol-2-yl)-1-ethyl-1H·pyrazolo[3,4-b]pyridine-5-decylamine 311 4- [(1-Ethyl-4-pyridinyl)amino]ethyl-N-(l,3-oxazol-2-ylmethyl)_1H-pyrazolo[3,4-b] Pyridine-5-formamide 312 4-[(1-ethyl-bromo-4-hexahydrop-decyl)amino]-1·ethyl-N-{[4-(methyl aryl)phenyl ]methyl b 1H·pyrazolo[3,4-b]pyridine-5-formamide 313 4-[indolyl-4-hexahydropyridyl)amino]-N-(2,2- Diphenylethyl)+ethyl-1H-pyrazolo[3,4-b]pyridine_5-formamide 314 4-[(1-Ethyl-4,hexahydro-p-pyryl)amine ]]-1-ethyl_N-({4-[(methyl aryl))]yl}methyl}methyl )-1Η-pyrazolo[3,4-b]pyridine-5-formamide 315 4-[(1-ethyl-bromo-4-hexahydrop-pyryl)amino]-1_ethyl- N_({4-[(Mercurinyl)carbonyl]phenyl}methyl)-1Η-pyrazolo[3,4-b]pyridine-5-carboxamide 87841_96〇3〇3·中. Doc -168 - 1283678 316 4-[(l-Ethyl-4-pyropyridinyl)amino]-N-{[4-(aminosulfonyl)phenyl]methyl}methylethyl- 1H·pyrazolo[3,4-b]pyridine-5-carbamimid 317 4-[(1-ethylhydrazine) hexahydropyridyl)amino]N-ethyl-N-({3-[( Methylamino)carbonyl]phenyl}methyl)-1Η-pyrazolo[3,4-b]pyridine-5-formamide 318 4-[(1-ethylindolyl-4-hexahydropyridinyl) Amino]-N-{[4-(aminocarbonyl)phenyl]methyl}-1_ethyl-1H-pyrazolo[3,4-b]pyridine_5-formamide 319 4-[ (1-Ethyl-4-pyridyl p-pyrifosyl)amino]-1·ethyl-indole-{[6·(methoxy)·3-pyridyl]methyl}-1Η-pyrazole And [3,4-b]pyridine-5-formamide 320 1-ethyl-N-4-hexahydropyridyl-4-(tetrahydro-2H-piperidin-4-ylamino)-1Η- Pyrazolo[3,4-b]pyridine-5-formamide 321 1-ethyl-N-(4-hexahydropyridylmethyl)-(tetrahydro-2H-piperidinylamino)- 1Η-pyrazolo[3,4-b]pyridine-5-carbamimid 322 1-ethyl-indole-[1-(ethyl distillyl)-4-ττ chloride p ratio benzyl]-4- (tetrazol-2H-methylene-4-ylamino)-1Η-pyrazolo[3,4-b]pyridine-5-carbamimid 323 1-ethyl-N-{1_[(1-A Base ethyl) continuation base]_4-hole nitrogen p ratio }}-4-(tetrahydro-2H-piperazin-4-ylamino)-1Η-pyrazolo[3,4_b]pyridine-5·carbamimid 324 succinyl acid)-4-ττ Chlorine p ratio benzyl]-1-ethyl-4-(tetraqi-2H-piperidinylamino)-1 Η-pyrazolo[3,4-b]pyridine-5-carbamimid 325 ethyl -Ν_[1·(())-4-ττ nitrogen ρ ratio decyl]-4-(tetrachloro-2H-p-endan-4-ylamino)-1Η-pyrazolo[3,4 -b]pyridine-5-carbamamine 326 1-ethyl-N-{1-[(phenylmethyl)sulfonyl]-4-hexahydropyridinyl}-4-(tetrahydro-2H-piperidin Cyclopropylamino)_1H-pyrazolo[3,4-b]pyridine-5-carboxamide 327 1-ethyl-indole-[1·(benzoic)-4-ττ nitrogen outer b-precipitate 4-(4-gas-2H-pyran-4-ylamino)·1Η-pyrazolo[3,4-b]pyridine-5-carbamimid 328 1_ethyl-N-[l -(propyl continuation)-4-ττ chlorop ratio butyl]-4-(tetrazine-2H-cyclopentanylamino)-1Η-pyrazolo[3,4-b]pyridine_ 5_Mercaptoamine 329 N-[l-(Lactinyl)-4-hexanitro-b-butyl]-1-ethyl-4-(tetrazine-2H-P guolate-4-ylamine ))-Η-pyrazolo[3,4-b]pyridine_5·carbamamine 330 1-ethyl-indole-[1·(3-咬基基基基)-4-azepine yttrium -4-(tetrazol-2Η-^ -4--4-ylamino)_1 ·ρ ratio vomit [3,4-b]external b-precipitate-5-cartoamine 331 N-[l-(3,3-dimethylbutylidene)-4-hexahydropyridyl]-1-ethyl -4-(tetrahydro-2H-piperidinylamino)-1Η-pyrazolo[3,4_b]pyridine-5-carbamamine 87841·96〇3〇3_ Doc -169- 1283678 332 1-Ethyl-N-[l-(2-ethylbutylidene)-4-hexanitrogen p-butyl]-4·(tetrachloro-2H-^-an-4-ylamine比比吐和[3,4-b]p比淀_5_甲甲胺333 N-[l-(cyclopentylacetate chloride p than decyl) small ethyl _4-(tetrahydro-2H_ brig喃-4-ylamino group than oleno[3,4-b]p than yt-5-ylamine 334 1-ethyl-N-[l-(2-methylpropionate)-4-hexa Chlorophyllin b benzyl]-4-(tetrachloro-2H-fluorenyl-4'ylamino)-1Η_ρ比峻[3,4-b]p ratio -5-5_甲甲胺335 1-ethyl -4·(Four gas-2H_ shout-4-ylamino)-indole-[1_(tetrachloro-2H-P-pyranyl-4-ylcarbonyl)-4·hexahydropyridyl]_1H-pyrazole [3,4-b]pyridine-5-formamide 336 1-ethyl·Ν·(1-propanyl-4-TT nitrogen external b-position) 4-(tetrachloro-2H-p-butyl- 4-aminoamino)-1Η-pyrazolo[3,4-b]pyridine-5-carboxamide 337 N-[1-(N-acetoxyglycine)·4-hexachloropyp 1-ethyl 4-(tetrahydro-2-pyrano-4-ylamino)-1Η-pyrazolo[3,4-b]pyridine-5-formamide 338 1-ethyl -N-[l-(4-?-fu-p- phenylacetate)-4-hexachloro-p-butyl]-4-(tetrahydro-211-0-decano-4-ylamino) than spit[3 ,4-b]p, butyl-5-formic acid amine 339 1-ethyl-indole-{1-[(4-keto) Hexyl)carbonyl]-4-hexafluoropyridinyl}-4-(tetrazine-2H-bucky-4-ylamino group is more than [3,4-b]p than lake-5-formate 340 1- Ethyl-N-[l-(l-hexahydropyridinyl)-4-hexahydropyridinyl]-4-(tetrazo 2 Η 略 喃 -4-ylamino) is more than [3, 4-b]p butyl-5-cartoamine 341 1-ethyl-N-{1_[(1-methyl-5. keto-3-tetrahydropyrrolyl)carbonyl] }}-4-(tetrachloro-2H-fluoren-4-ylamino)-1Η-ρ is more than [3,4-b]p than pyridine-5-carbamid 342 1-ethyl-fluorene {1-[(3-Methyl-3-epoxypropenyl)carbonyl]-4-hexahydropyridinyl 7-yl}-4-(tetrahydro-2-indole-piperidin-4-ylamino)-1Η_ Pyrazolo-; 3,4-b]pyridine j-carbamamine 343 1-ethyl-indole-{1-[(4-(phenyl)ethenyl]-4-hexahydro outside b-bityl}- 4-(tetraoxane 2H·piperidin-4-ylamino)-1Η-pyrazolo[3,4-b]pyridine-5-carbamimid 344 Ν-{[1-(3,3-di Methylbutylidene)-4-hexahydrop-pyrifosyl]methyl}-1_ethyl 7 (tetrahydro-2H-fluoren-4-ylamino)-1H-p is more than [3,4- b]p butyl-5-cartoamine 345 Ν-{[1-(cyclopentylethyl fluorenyl)-4-hexahydropyridyl]methyl}-1-ethyl-4-(^ hydride-2H&gt ; Chenan-4-ylamine ratio also [3,4-b> butyl--5-carbamamine 346 Ν-{[1-(Cyclopropylcarbonyl)-4-hexahydropyridyl]methyl}sodiumethyl-4-(tetra$2H_pyran-4-ylamino)_1H-pyrazolo[ 3,4-b]pyridine-5-methamine amine 87841-960303•中. Doc -170- 1283678 347 1-ethyl·Ν-({1-[(4-ketocyclohexyl)carbonyl]-4-hexahydropyridinyl}methyl)-4·(tetrachloro·2Η-jum -4-ylamino-aminopyrazine[3,4-b]p is more than _5•cartoamine 348 1-ethyl-indole-({1-[(4-fluorophenyl)ethenyl]- 4-Hexidopyridinyl}methyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1Η-pyrazolo[3,4-b]pyridine-5-carboxamide 349 1 -ethyl·Ν-({1-[(1-methyliso)_3_tetrazine p-l-yl)-based group]_4·ττ-rat pyridyl}methyl)-4-(tetrahydro-2Η- Piperazin-4-ylamino)-1Η-pyrazolo[3,4-b]pyridine-5-carboxamide 350 methyl 3_[(1_ethyl-5-{[(phenylmethyl)) Amino]carbonyl}_1Η·pyrazolo[3,4-b]pyridin-4-yl)amino]cyclohexanecarboxylate 351 3-[(1-ethyl-5-{[(phenyl) Amino]carbonyl]_1H_pyrazolo[3,4-b]pyridinyl)amino]cyclohexanecarboxylic acid 352 1-ethyl-N-(phenylmethyl)-4-(4 - hexahydropyridylamino)-1 Η-pyrazolo[3,4-b]external b--5-cartoamine 353 1_ethyl-4-({l-[(methoxy)ethetidine) Ethyl]-4-hexahydrop-pyrifosyl}amino)-1Η-pyrazolo[3,4-b]pyridine-5-carboxylate ethyl ester 354 1-(1-methylethyl)-4_( Tetrahydro- 2Η_^--4-yl Base)-1Ηπ 唆[3,4-b]pyridine-5-carboxylic acid ethyl ester 355 4-(cyclohexylamino)ethylidene-N-methyl-1H-pyrazolo[3,4- b] Pyridin-5-formamide 356 1-ethyl-N-(4-fluorophenyl)-6-methyl-4-(tetrahydro-2H-piperidin-4-ylamino)· 1H_p ratio并[3,4-b]p than yt-5-carbamide 357 1-ethyl-6-methyl_N-{[4-(methylsulfonyl)phenyl]methyl}-4- (tetrahydro-2H-piperidin-4-ylamino)-1Η-pyrazolo[3,4-b]pyridine-5-formamide 358 N-(2,3-dihydro-1H- though 2_yl)_1_ethyl-6-methyl-4-(tetrahydro-2H·jol-4-ylamino)-1Η-峨峻和[3,4_b] 外乙淀-5_甲醯Amine 360 1-ethyl-N-[3-(l-hexahydrop-decylcarbonyl)phenyl]-4-(tetrahydro-2H-p-guanosyl-4-ylamino)-1Η-pyrazolo[3 ,4-b]pyridine-5-carbamimid 361 1-ethyl·indole-[4-(1methylethyl)phenyl]_4·(tetrahydro-2-indol-4-ylamino)-1Η -External b and [3,4-b]external b-precipitate-5-cartoamine 362 1-ethyl-indole (2-fluorophenyl)-4-(tetrahydro-2H- shouting-4_ The amino group)·ιη_ρ ratio is also [3,4-b]p than the lake-5-cartoamine 87841-960303-中. Doc -171- 1283678 363 N-{3-[(Dimethylamino)carbonyl]phenyl}-l-ethyl-4_(tetrahydro-2Η· 喃 -4--4-ylamino)-1Η-ρ ratio Spit and [3,4-b> butyl-5-carbamamine 364 Ν-{4-[(difluoromethyl)oxy]phenyl}-1_ethyl ice (tetrahydro-2 Η- brim 4--4-aminoamino)_1Η·pyrazolo[3,4-b]pyridine-5-carboxamide 365 N-{4-[ethylidene(methyl)amino]phenyl}-1_B 4-(tetrahydro-2H-pyran-4-ylamino)-1Η-pyrazolo[3,4-b]pyridine-5-carboxamide 366 1-ethyl-N-(4- Phenyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1Η-ρ than ton[3,4-b]pyridine-5-carboxamide 367 1-ethyl_N -[4_(4-moffinyl)-2_(trifluoromethyl)phenyl]_φ·(tetrahydro-2H_p-decyl-4-ylamino)_1H-p is more than [3,4- b]p than yt-5-cartoamine 368 1-ethyl-N-4-p than decyl-4-(tetrahydro-2H-pyran-4-ylamino)-1Η-external b [3,4-b]pyridine-5-formamide 369 1-ethyl_N_{4-[(4-methyl-1-hexahydro-exo bp) carbonyl]phenyl}-4-(four Hydrogen-2H-Bucer-4-ylamino)-1Η-峨君[3,4-b]p than yt-5-carbamide 370 1-ethyl-N-[2_(2-keto -1-tetrahydro? ratio p) phenyl]_4-(tetrahydro-2H_bromo-4-ylamine )-1Η-^ ratio is also [3,4-b]p than dian-5-anthracene amine 371 1-ethyl-N_[3-(methyl-branched)phenyl]_4-(tetrahydro-2H - 喃 -4- 基 基 ) ) -1 -1 -1 -1 [ [ 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 淀 { { { { { { { { { { { }}-1_ethyl_4-(tetrahydro-2Η·ϊ派喃-4-ylamino group is more than [3,4-bp than yt-5-carbamide 373 1-ethyl-N- {3-[(methyl acid)amino]phenyl}_4·(tetrahydro-2H-pyran-4-ylamino group than spit[3,4_b]p than lake-5-formamide 374 1 -ethyl-Ν·(4-fluoro-2-# is phenyl)-4-(tetrahydro-2H-fluoren-4-ylamino)-1Η·β than tons of [3,4-b Exo b-precipitate-5-methylamine 375 N-(4-chlorophenyl)_1·ethyl-4-(tetrahydro-2H- sher-4-ylamino group than ton[3,4-b Pyridine-5-formamide 376 N-(3-chloro-2-cyanophenyl)succinyl-4-(tetrahydro-2H_^anyl-4-ylamino)-1Η-ρ ratio spit And [3,4_b&gt;Bisho-5-formic acid amine 377 1·ethyl-Ν-[3-(1·hexahydro outside b) phenyl] 4-(tetrahydro-2H-brum喃-4-ylamino)-1Η-ρ than oleno[3,4-b]p ratio ··5·甲含胺379 1-ethyl-Ν_[2·(methyl acid) phenyl] -4-(tetrahydro-2Η- sher-4-ylamino)_ | IH-p ratio bite [3, 4_b]p than the lake -5 - brewing amine 8784l-960303-zhong. Doc -172- 380 N-{2-[Ethyl(methyl)amino]phenyl}sodiumethyl-4-(tetrahydro-211-piperidin-4-ylamino)_1H-pyrazole [3,4-b]pyridine-5-formamide 381 1-ethyl_N-[3-(4-?-fusinyl)-phenyl]_4-(tetrazine-2H4-c-butyl-4 -ylamino)-1Η-pyrazolo[3,4-b]pyridine-5-carbamimid 382 N_(4-chloro-3-chlorophenyl)-1_ethyl-4-(four Nitrogen-2H-pyran-4-ylamino)-1Η-pyrazolo[3,4-b]pyridine-5-carboxamide 383 1-ethyl-N-(3-hydroxyphenyl)-4- (tetrahydro-2H-piperazin-4-ylamino)-1Η-pyrazolo[3,4-b]pyridine-5-carboxamide 384 N-(3-chlorophenyl)succinyl-4 -(tetrahydro-2H-piperazin-4-ylamino)-1Η-pyrazolo[3,4-b]pyridine-5-carboxamide 386 Ν-[3·[(acetamido) A 4-(methoxy)phenyl]-1-ethyl winter (tetrahydro-2H-piperidinylamino)_1Η·pyrazolo[3,4-b]pyridine-5-formamidine Amine 387 1_ethyl-N-[4-(l-hexahydropyridylsulfonyl)phenyl]-4·(tetrahydro-2H-piperidin-4-ylamino)-1Η-pyrazole [3,4-b]pyridine-5-carbamimid 388 N-(3-{[cyclohexyl(methyl)amino]carbonyl}phenyl)succinyl 4-(tetrahydro-2H- britant- 4-aminoamino)-1Η-pyrazolo[3,4-b]pyridin Acridine_5_formamide 389 1·ethyl-N-[2-(4•morpholinyl)phenyl]-4-(tetrahydro-2H-piperidin-4-ylamino)-1Η- Pyrazolo[3,4-b]pyridine-5-formamide 390 N_{3-[(acetamido)sulfonyl]phenyl}-1·ethyl-4-(tetrahydro-2Η- Piperazin-4-ylamino)-1Η-pyrazolo[3,4-b]pyridine-5-carbamimid 391 N-(3-chloro- 4-phenyl)-1-ethyl_ 4-(four gas-2H· shouting-4_ylamino)-1H-pyrazolo[3,4_b]pyridine-5-carbamimid 392 1-ethyl-Ν·{4-[(methane) Mercapto)amino]phenyl}ice (tetrahydro-2H-piperidin-4-ylamine)[3,4-b]externate-5-cartoamine 393 1-ethyl-N- {3-[(Methylamino)carbonyl]phenyl}-4-(tetrahydro-2H-piperidin-4-ylamino)-1Η_pyva[3,4-b]pyridine-5-A Indoleamine 394 1-ethyl-4-(tetrahydro-2H-bran-4-ylamino)-N-[3-(trifluoromethyl)phenyl]-1H-pyrazolo[3,4 VII] Pyridin-5-formamide 395 1-ethyl-Ν·3-ρ ratio decyl-4-(tetrazol-2H-pyran-4-ylamino group than spit[3,4-b] Pyridine-5-formamide 396 N-(3,4-diphenyl)-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1Η-pyrazolo[ 3,4-b]pyridine-5-decylamine 87841-9603〇3_. Doc -173- 1283678 397 Ν·[3-(Aminothiol)-4-chlorophenyl]-1_ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1Η -pyridinium[3,4-b>pyramid-5-carbamamine 398 1-ethyl-N-[3-(4-?-fusyl)phenyl]_4-(tetrahydro-2H- shout喃冰基胺基比峻和[3,4七&gt; 比淀_5_Mercaptoamine 399 1-ethyl-N_[4_(4_?), 驴 基 ) )) phenyl]_4- (four Hydrogen 2H_t-Pan-4-ylamino group is more than [3,4_b]p than yt-5-carbamamine 400 1-ethyl-anthracene {2-[(4-methyl hexahydropyridinolate) ))carbonyl]phenyl bromide 4_(tetrahydro-2Η-Ϊ派喃-4-ylamino)·1Η·ρ than spit[3,4-b]p than _5_甲醯 401 [( Dimethylamino)carbonyl]phenyl}sodiumethyl-4-(tetrahydro-2H-isan-4-ylamino)-1Η«^ than ton[3,4-b]p than pent-5- Methionine 402 N-[2-chloro-4-(trifluoromethyl)phenyl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1Η-ρ比峻和[3,4-b&gt; 比丁-5-Metformamide 403 N-{2-[(ethylamino)methyl]phenyl} small ethyl bucket (tetrahydro-2 Amino group)-1Η-ρ ratio 唆[3,4-b]external b bit-5-carbamamine 404 N-(2-phenylphenyl)-1-ethyl-4-(tetrahydro-2H -Pantan-4-ylamino)-1Η·ρ ratio And [3,4-b]pyridine-5-formamide 405 N-(3-chloro-2-fluorophenyl)-1-ethyl-4-(tetrahydro-2H-pyran-4-yl Amino)-1Η-pyrazolo[3,4-b]pyridine-5-formamide 406 1-ethyl-N-(3_phenylene)-4-(tetrahydro-2H- shouting 4_ylamino)-ιη·external b and [3,4-b]pyridine-5-formamide 407 N-(2-cyano-3-fluorophenyl)-1-ethyl-4- (tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-formamide 408 1-ethyl-N_[4_(propyl fluorenyl) Phenyl] ice (tetrahydroanthracene-throm-4-ylamino group 唆[3,4-b]externate ti 5·carbamamine 409 Ν-{4-[(dimethylamino) Carbonyl]phenyl}_1_ethyl ice (tetrahydro-2fj_pyranylamino)_1Η-pyrazolo[3,4-b]pyridine-5-methalamine 411 1_ethyl-N -[4·(甲 continued 醢)phenyl]_4_(tetrahydro-2Η_ι派喃_4_ylamino)_ 1H-pyrazolo[3,4_b]pyridine-5-formamide 413 N-{ 4-[(Ethylamino)methyl]yl}}1-ethyl_4_(tetrazepin-4-ylamino)-1Η-ρ ratio+[3,4-b]p ratio -5-Artemisamine 414 1-ethyl-4-(tetrahydro-2H-bungan-3-ylamino) than succinyl [3,4-b]p than yt-5-carbamamine 87841-96 〇3〇3·中. Doc -174- 1283678 415 N-[2-(Aminosulfonyl)ethyl]_4_(cyclohexylamino)-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5- Methionamine 416 N-(2-Amino-2-ketoethyl)-4·(cyclohexylamino)ethylidene-1H-pyrazolo[3,4-b]pyridine-5-formamidine Amine (non-preferred name) 417 4-(cyclohexylamino)-1-ethyl-N-{2-[(methylsulfonyl)amino]ethyl}-1Η-pyrazolo[3,4 -b]pyridine-5-methanamine 418 4-(cyclohexylamino)-1-ethyl(tetrahydro-2H-pyran-4-yl)_1H-pyrazolo[;3,4-b]峨丁-5-Metamine 419 4_(cyclohexylamino)_1_ethyl-N-[(l-methyl-1H-pyrazol-4-yl)methyl]-1H-leaf sputum and [ 3,4-b]indole-5-formamide 420 4-(cyclohexylamino)_1_ethyl-N-{[3-(methylsulfonyl)phenyl]methyl}-1Η_pyridyl Also [3,4-b]exo b far-5-carbamide 421 N-{[3-(aminocarbonyl)phenyl]methyl b 4_(cyclohexylamino)-1-ethyl-1H -pyrido[3,4-b> than bite-5-formamide 422 4-(cyclohexylamino)_1-ethyl-N-(tetrahydro-2-furanylmethyl)-1Η-pyridyl Azolo[3,4-b]p ratio ·5-cartoamine 423 4-(cyclohexylamino)-indole-({4-[(dimethylamino)sulfonyl]phenyl}methyl )-1-ethyl-1H-pyrazolo[3,4 -b]pyridine-5-methanamine 424 N-[(5-chloro-2-pyridyl)methyl]-4·(cyclohexylamino)-1-ethyl-1H-pyrazolo[3 ,4-b]pyridine-5-formamide 425 4-(cyclohexylamino)-1-ethyl-N-{[4-(methylsulfonyl)phenyl]methyl}·1Η-pyridyl And [3,4-b]external b-position-5-formamide 426 4-(cyclohexylamino)-1-ethyl-N_{[6-(methoxy)_3_pyridyl]methyl} -1Η-外匕 匕和[3,4-b&gt; 比淀-5-Methylamine 427 4-(cyclohexylamino)ethylidene·Ν-{4-[(methylamino)carbonyl]phenyl }-1Η-pyrazolo[3,4-b]pyridine-5-formamide 428 4_(cyclohexylamino)-1-ethyl·indole-({3-[(methylamino)carbonyl)benzene }}methyl)-1Η-pyrazolo[3,4-b]pyridine-5-carbamimid 429 Ν-{[4-(aminocarbonyl)phenyl]methyl}-4-(cyclohexylamine 1-ethyl-1-indole-pyrazolo[3,4-b]pyridine-5-methamine 430 4-(cyclohexylamino)-1-ethyl-N-[(4-hydroxybenzene) Methyl]-1H-pyrazolo[3,4-7]pyridine-5-carboxamide 87841-9603〇3_ Doc -175- 1283678 431 4-(cyclohexylamino)-1-ethyl-N-{[4-(methoxy)phenyl]methyl b ih_pyrazolo[3,4-b]pyridine -5-Protonamine 432 4-(cyclohexylamino)-N-[(3,4-difluorophenyl)methyl H-ethyl-1H-pyrazolo[3,4-b]pyridine- 5-Proline 433 4-(cyclohexylamino)ethylidene-N-{[4-(trifluoromethyl)phenyl]methyl b 1H_pyrido[3,4-b]p ratio -5-5-formic acid amine 434 4-(cyclohexylamino)ethylidene-N-({3-[(methylsulfonyl)amino]phenyl}methyl)_ 1H·pyrazolo[3, 4_b]pyridine-5-methanamine 435 4-(cyclohexylamino)-N-[(2,5-difluorophenyl)methyl]-1-ethyl-1H-external b s[3, 4-b]pyridine-5-formamide 436 4-(cyclohexylamino)-1·ethyl-N_[(4-methylphenyl)methyl]-iH_external b[3,4 -b] pyridin-5-formamide 438 4-(cyclohexylamino)ethylidene-N-(2_{4-[(methylsulfonyl)amino]phenyl}ethyl)-1Η- Pyrazolo[3,4-b]pyridine-5-formamide 439 4-(cyclohexylamino)·1·ethyl-N-[(2-stupyl)methyl]-iH-p ratio并[3,4-b] 匕 匕-5-formic acid amine 440 4-(lorylhexylamino)-N_[(3,4-monolacyl)methyl]-1-ethyl-1H- P ratio also [3,4-b] bamboo 1: lake-5-carbamide 4 41 4-(Cyclohexylamino)-N-[(3,5-dichlorophenyl)methyl]-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-formamidine Amine 442 4-(cyclohexylamino)-1-ethyl-N-(2-phenylethyl than benzo[3,4-b]external oxime-5-formamide 443 4-(cyclohexane Amino)-1·ethyl_N_(1,2,3,4-tetrahydrofuranylpyrazine[3,4-b]p ratio read;-5-formamide 444 4-(cyclohexyl) Amino) small ethyl-N-{[2-(methyl sulfenyl)phenyl]methyl bromide-external!: succinyl[3,4-b]external b-precipitate-5-carboxamide 445 4-(cyclohexylamino)ethylidene-N-[2_(4-phenylphenyl)ethyl] is more than [3,4_b], and t is -5-carbamamine 446 N]2- [4-(Aminosulfonyl)phenyl]ethyl}_4-(cyclohexylamino)-1-ethyl" 1H-pyrazolo[3,4-b]pyridine-5-carboxamide 447 4-(cyclohexylamino)ethylidene-N-({2-[(methylamino)carbonyl)phenyl}methyl)_1H_ ρ than spit[3,4-b]p than pent-5-A Amine amine 87841-960303-zhong. Doc •176- 1283678 448 4-(cyclohexylamino)-1-ethyl-N-{[2_(methylsulfonyl)phenyl]methylid iH-exocarbazolo[3,4-b] Pyridine-5-formamide 449 2-[({[4-(cyclohexylamino)-1ethyl_1H_p is more than [3,4-b]p than _5_yl]) Methyl]methyl]benzoate 450 4-(cyclohexylamino)-1·ethyl-oxime {2-[4-(methyl-decyl)phenyl]ethylpyrazolo[3,4 -b]pyridine-5-methanamine 451 N-[4,5-bis(methoxy)-2,3-dihydro-1H·indol-2-yl]_4-(cyclohexylamino) small B -1-1H-P is more than [3,4-b], and it is 452 4-(cyclohexylamino)ethylidene-N_{[2_fluoro-3-(trifluoromethyl) Phenyl]methyl is more than [3,4-b>pyramid-5-formic acid amine 453 4-(cyclohexylamino)·Ν-[(3,4-dimethylphenyl)methyl] Ethyl-1H-pyrazolo[3,4-b]external b-bend-5_cartoamine 454 4-(cyclohexylamino)-1-ethyl-indole-[2·(4-fluorophenyl) Ethyl]-1H-pyrazolo[3,4-b]pyridine-5-formamide 455 4-(cyclohexylamino)-1-ethyl-N-[2-(4-methylbenzene Ethyl)ethyl]_1H-pyrazolo[3,4-b]p than yt-5-anthracene amine 456 4·(cyclohexylamino)-1-ethyl-N-{2-[4-( Methoxy)phenyl]ethyl}-1Η-pyrazolo[3,4-b]pyridyl Pyridin-5-formamide 457 4-(cyclohexylamino)ethylidene-N-(2-pyridylmethyl)-1Η-pyrazolo[3,4-b]pyridine-5-carboxamide III Fluoroacetate 458 4-(cyclohexylamino)-N-[(3,5-difluorophenyl)methyl]sodiumethyl-1H-pyrazolo[3,4-b]pyridine-5- Indoleamine 459 4-(cyclohexylamino)-N-(2,3-dihydro-1H-indol-1-yl)sodiumethyl-1H-pyrazolo[3,4-b]pyridine-5- Indoleamine 460 4-(cyclohexylamino)_N-{[4-(didecylamino)phenyl]methyl}sodiumethyl-1H-pyrazolo[3,4-b]pyridine_5_ Methionine trifluoroacetate 461 4-(cyclohexylamino)-1-ethyl-N-[(2-fluorophenyl)methyl]-1Η·pyrazolo[3,4-b] :Bite-5-carbamide 462 N-{[2,4-bis(methoxy)phenyl]methyl b 4-(cyclohexylamino)-1-ethyl-1H-pyrazolo[3 , 4-b]pyridine_5_formamide 463 N-[(6-chloro-2-pyridyl)methyl]_4-(cyclohexylamino)-1-ethyl-1H-pyrazolo[ 3,4-b&gt;bipyridin-5-carbamide trifluoroacetate 87481-960303·中. Doc -177- 1283678 464 [Ethyl (meth)amino]phenyl}methyl)-4-(cyclohexylaminoethyl-1H·leafb[3,4-b]p -5-formic acid amine trifluoroacetic acid 465 4-(cyclohexylamino)-1-ethyl_Ν_{[4·fluoro-3-(trifluoromethyl)phenyl]methyl}-1Η_ρ ratio spit And [3,4-b]峨丁-5-methamine 466 4-(cyclohexylamino)-N-[(lR)-2,3-dihydro-1H_茚-1_yl H•B Base_1H-pyrazolo[3,4-b]pyridine-5-formamide 467 4_(cyclohexylamino)-N-[(2,6-dichlorophenyl)methyl]-1-B Base _ih_p bilis[3,4-b]pyridine-5-methanamine 468 3_[({[4-(cyclohexylamino)-1-ethyl-1H-P ratio vomit [3,4_b ] p 淀 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _1_ethyl-iH-p ratio 峻[[3,4-b&gt; pyridine-5-carbamide 470 4·[({[4_(cyclohexylamino)-1-ethyl-1H-P)峻 并 [3,4-b]p than yt-5-yl]-Wenyl}amino)methyl]benzoic acid methyl ester 471 4-(J succinylamino)-1·ethyl-N-( 1H-tetrakis-5-ylmethyl)-1Η-ρ ratio 并[[3,4-b&gt; butyl--5-carbamide 472 4-(cyclohexylamino)-N-({4- [(Difluoromethyl)oxy]phenyl}methyl) small keto-1H-pyrido[3,4-b]pyridine-5-formamide 473 4-(diacylamino)_1_ethyl-N-[(2-methyl·1,3·ρ plug Also -4·yl)methyl]-1H_pyrazolo[3,4-b]pyridine-5-formamide 474 N-[(2-chloro-6-fluorophenyl)methyl]-4- (cyclohexylamino)-1•ethyl-1H-pyrazolo[3,4-b]pyridine-5-formamide 475 N-{[2-(aminocarbonyl)phenyl]methyl}· 4-(cyclohexylamino)ethylidene-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 477 4-(cyclohexylamino)-N-{[2-(dimethyl Amino)phenyl]methyl}-1-ethyl_1H-pyrido[3,4-b]p than lake-5-cartoamine 478 4-(cyclohexylamino)-1-ethyl -N-[(4-fluorophenyl)methyl]-1Η-pyrazolo[3,4-7]pyridine-5-carboxamide 479 4-(anilinoyl)-1-ethyl-N- {[3-(Trimethyl)yl]methyl is more than [3,4-b&gt; than 矣-5-carbamide 480 4-(cyclohexylamino)-N-[(2,6) -Difluorophenyl)methyl H-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 87841-960303-中. Doc -178- 1283678 481 4-(cyclohexylamino)ethylidene-N-[(3-fluorophenyl)methyl]-1 oxime-pyrazolo[3,4-b]pyridin-5-carboxamidine Amine 482 4-(cyclohexylamino)ethylidene-N-{[2-(trifluoromethyl)phenyl]methyl}-1 fluorene-r-oxazolo[3,4-b]pyridine-5-- Indoleamine 483 N-(5-Chloro-2,3-dihydro-1H-indol-2-yl)-4-(cyclohexylamino)ethylidene·1Η-ρ ratio Jun [3,4- b]p-precipitate-5-formamide 484 4-(cyclohexylamino)ethylidene-N-({4_[(methylamino)carbonyl]phenyl}methyl)-1Η- [3,4-b]external b-position-5-formamide 485 4-(cyclohexylamino)ethylidene-N-[4-(methoxy)phenyl]-1Η-pyrazolo[3 ,4-b]pyridine-5-methanamine 486 4-(cyclohexylamino)-1-ethyl-N-[(6-indolyl-1,6-dichloro-3-p ratio decyl) )methyl]-1H-pyrazolo[3,4_b]pyridine-5-formamide 487 4-(cyclohexylamino)-1·ethyl-oxime·(3_pyridylmethyl)·1Η_ Pyrazolo[3,4-b]pyridin-5-formamide 488 4-[({[4-(cyclohexylamino)-1·ethyl-1H-pyrazolo[3,4-b] Pyridyl-5-yl]carbonyl}amino)methyl]benzoic acid 489 3_[({[4-(cyclohexylamino))ethyl)1Η_pyrazolo[3,4-b]pyridine-5- Carbonyl}amino)methyl]benzoic acid 49 0 4-(lorylhexylamino)_N-(2,3_diaza_1H-indol-2-yl)-1-ethyl-1Η_ρ ratio '^ and [3,4-b]p than the lake-5 -formic acid amine hydrochloride 491 4-(cyclohexylamino)-N-(2,3-dihydro-1H-indol-2-yl)sodiumethyl-1H-pyrazolo[3,4-b] Pyridine-5-formamide methanesulfonate 492 Ν-({2-[(1,1·dimethylethyl)oxy]-3-pyridyl}methyl)small ethyl_4_ (tetrahydro) -2Η-piperidinylamino)-1Η-pyrazolo[3,4_b]pyridine-5-carbamidamine trifluoroacetate 493 N-[(3-carbyl-4-methylphenyl)- A small ethyl benzene (tetrahydro-2H·pyran-4 ylamino)-1 Η-pyrazolo[3,4-b]pyridine-5-carboxamide 494 N_[(4-carbyl- 2-methylphenyl)methyl]-1-ethyl-4·(tetrahydro-2H-piperidin-4-ylamino)-1Η-pyrazolo[3,4-b]pyridine-5- Methionine 495 N-({2-[(difluoromethyl)oxy)phenyl}methyl)methylethyl 4-(tetrahydro-2H-piperidin-4-ylamino)-1Η- Pyrazolo[3,4_b]pyridine-5-carboxamide 87841·96〇3〇3·中. Doc -179- 1283678 496 1-Ethyl-indole_({2·[(1-methylethyl)oxy)phenyl}methyl)_4_(tetrahydro·2Η_ 喃尔-4_ylamino)· 1Η-External b is also [3,4-7] butylate-5-formic acid amine 497 1-ethyl_N_({3-[(1-methylethyl)oxy)phenyl}methyl)_4_ (tetrahydro-2h_ bhak-4-ylamino group is more than 唆[3,4_b]p than _5_carbamamine 498 N-({3_[(di-methyl)oxy)phenyl} Base) small ethyl _4·(tetrahydro-2H-T-pyran-4-ylamino group than spit[3,4_b]p than _5_cartoamine 499 1_ethyl-N_{[4 ·#Pretyl-3-(methoxy)phenyl]methyl}_4_(tetrahydro-2H-bran-4-ylamino group is more than [3,4-b]p than _5_carboxylic acid Amine 500 N-[(5-Ethyl-2-hydroxyphenyl)methyl]sodiumethyl-4·(tetrahydro-2H-piperidin-4-ylamino)-1Η-pyrazolo[3 ,4-b]pyridine-5-formamide 501 1-ethyl-4-(tetrahydro-2H-bran-4-ylamino)_Ν·{2·[3_(trifluoromethyl)phenyl Ethyl thiophene [3,4-b]p is more than 5-aminoamine 502 N-{[4_(ethinyl)phenyl]methyl}_1_ethyl_4-(tetrachloro -2H- brim-4-ylamino)_1H_pyrazolo[3,4-b]pyridine-5-carboxamide 503 1_ethyl-N-[2-(3- phenyl)ethyl ]-4-(tetrahydro-2H-^exan-4-yl) Amino)_1H-pyrazolo[3,4-b]pyridine-5-carboxamide 504 N-[2-(3-chlorophenyl)ethyl]-1-ethyl-4-(tetrahydrogen) -2H-misan-4-ylamino)_1H-pyrazolo[3,4-b]pyridine·5-formamide 505 1-ethyl-4-(tetrahydro-2Η-17-decane- 4-ylamino)-indole-(2-{4-[(trifluoromethyl)oxy]phenyl}ethyl)-1Η-pyrazolo[3,4-b]pyridine-5-formamidine Amine 506 1-ethyl-N-{2-[3-(methoxy)phenyl]ethyl}-4-(tetrahydro-2H·piperidin-4-ylamino)-1Η-pyrazole [3,4-b]pyridine-5-formamide 507 N-[2-(4-ethylhydrazinophenyl)ethyl]-1-ethyl-4-(tetrahydro-2H- shouting-4 -ylamino)_1H_pyrazolo[3,4_b]pyridine-5.carbamamine 508 N-[2-(3,4-dichlorophenyl)ethyl]sodiumethyl-4-(tetrahydro) -2H_pipelanylamino)-1Η-pyrazolo[3,4-b]pyridine-5-formamide 509 N-{2-[3-(aminosulfonyl)phenyl]B Keb 1-ethyl-4-(tetrahydro-2H-piperidin-4-ylamino)-1Η-pyrazolo[3,4-b]pyridine-5-formamide 510 N-{2- [3,4-bis(methoxy)phenyl]ethyl}ethylethyl-4-(tetrahydro-2H-piperidin-4-ylamino)-1Η-pyrazolo[3,4-b Pyridine-5·carbamamine 512 N-[2-(2,3-dichlorophenyl)ethyl]sodiumethyl-4-(tetrahydrogen) -2H-piperazin-4-ylamino)-1Η-pyrazolo[3,4-b]pyridine_5-formamide 87841-96〇3〇3-中. Doc -180 - 1283678 513 N-{2-[3,5-bis(methoxy)phenyl]ethyl}_1-ethyl·4_(tetrahydro-2-indole-piperidin-4-ylamino)- 1Η-ρ比峻和[3,4-b]p 比淀-5-甲甲胺514 514 1-ethyl-N-{2-[3-methyl-ice (methoxy)phenyl]ethyl} Ice (tetrahydro-2H-piperazin-4-ylamino)_1H-pyrazolo[3,4-b]pyridine-5-carboxamide 515 N· [2-(2,6-. Esteryl)ethyl]·1_ethyl-4-(tetrazine-2H-bran-4-ylamino)-1Η_ρ than bite [3,4-b]p than pent-5-formamidine Amine 516 N-{2_p,6-bis(methoxy)phenyl]ethyl}-1_ethyl_4_(tetrahydro-2H-pyran-4-ylamino)-1Η·pyrazolo[ 3,4-b]pyridine-5-formamide 517 1-ethyl-N-[2_(2-methylphenyl)ethyl]-4-(tetrahydroendan-4-ylamino)- 1H-p is more than 唆[3,4-7&gt; bis--5-carbamide 518 Ν-[(3,4-dimethylphenyl)methyl]sodiumethyl-4-(tetrahydro-2-indole) - 喃 -4--4-ylamino)-1Η-pyrazolo[3,4-b]pyridine-5-carbamimid 519 N-[4,5-bis(methyllacyl)_2,3_two mice -1H-indol-2-yl]·1_ethyl-4-(tetrachloro-2H_pyran-4-ylamino)-1Η-pyrazolo[3,4-b]pyridine-5-carboxamide 521 N-{2-[4-(Aminothiol)phenyl]ethyl}·1_ethyl-4-(tetrahydro-2H-bran-4-ylamino)·1Η_ρ ratio [3,4-b]p ratio -5-5-formamide 522 1_ethyl_N-{[2-(methylsulfinyl)phenyl]methyl}_4-(tetrahydro-2H_ Piperid-4-ylamino)·1Η-pyrazolo[3,4-b]pyridine-5-carbamimid 523 1-ethyl-N-(2-phenylethyl)-4-(four Hydrogen-2H- shouting-4_ylaminobispyrazolo[3,4-b]pyridine-5-formamidine 524 N-{[4-(Dimethylamino)phenyl]methyl}methylethyl (tetrahydro-2H-pyran-4-ylamino) than spit[3,4-b> butyl- 5-Mercaptoamine 525 1_ethyl-N-[2_(4-fluorophenyl)ethyl]-4-(tetrahydro-2Η4-an-4-ylamino)-1Η·pyrazolo[3, 4-b]pyridine-5-carbamimid 526 1-ethyl-indole-[2·(4-methylphenyl)ethyl]-4-(tetrahydro-2H-pyranyl-4-ylamino )·1Η_外1: spit[3,4-b]externate b--5-carbamamine 527 N-{[3-(amino sulfhydryl)phenyl]methyl}methylene-4 -(tetrahydro-2-indole-scarred-4-ylamino)-1Η-ρ is more than [3,4-b]p than ammonium 5-carboxylate 528 1·ethyl-N-[(4 -methylphenyl)methyl]-4-(tetrahydro-2H-chloropyran-4-ylamino)-1H_p is more than [3,4-b]p than 嗓·5-formamide 530 1 ·ethyl_Ν-{[4·glycol_3_(trifluoromethyl)phenyl]methyl b 4-(tetrahydro-2Η-jol-4-ylamino group than spit[3,4- b&gt;Bidian-5·carbamamine 87841-96〇3〇3_ in. Doc •181 - 1283678 531 2-[({[l-ethyl-4-(tetrahydro-2H-bromo-4-ylamino)-indeno[3,4-b]pyridin-5-yl]carbonyl }amino)methyl]benzoic acid methyl ester 532 N-[(6-chloro-2-ylidene)methyl]-1-ethyl-4-(tetrahydro-2H- shouting-4- Amino)pyr-pyrazolo[3,4-b]pyridine-5-carboxamide trifluoroacetate 533 N-(2,3-dichloro-1Η-indol-1-yl) small ethyl -4-(tetraqi_2H-pyran-4-ylamino)-1Η-pyrazolo[3,4-b]pyridine-5-formamide 534 N-({2-[ethyl fluorenyl) Methyl)amino]phenyl}methyl)-ethylethyl-4-(tetrahydro-2H-piperidin-4-ylamino)-1Η-pyrazolo[3,4-7]pyridine-5-formamidine Amine 535 N-[(1S)_2,3-dihydro-1H-indol-1-yl]-1-ethyl_4·(tetrahydro-2H-misan-4-ylamino)-1Η-pyridyl Oxazo[3,4-b]pyridine_5-formamide 536 N-[(lR)-2,3-dichloro-1H-indol-1-yl]-1-ethyl_4_(tetrachloro_ 2H-Suppressed 4-ylamino)1Η·pyrazolo[3,4-b]pyridine-5·carboxamide 537 1-ethyl-N-({3-[(methylsulfonyl))amine Phenyl]phenyl}methyl)-4-(tetrahydro-2H-piperidin-4-ylamino)-1H-p than spit[3,4-b>pyramid-5-carbamide 538 1 -ethyl-N-(phenylmethyl)_N-propyl-4-(tetrachloro-2H-l-butan-4-yl -1H-pyrazolo[3,4-b]pyridine-5-carboxamide 540 N-[2-(dimethylamino)ethyl]-1_ethyl-N-(phenylmethyl) _4-(tetrahydro-2H-piperazin-4-ylamino)-1Η-pyrazolo[3,4-b]pyridine-5-carbamimid 541 N-butyl·1·ethyl-N- (phenylmethyl)-4-(tetrahydro-2H-pyran-4-ylamino)-lH-ρ than ton[3,4-b]lead b--5-carbamimid 542 N, l-Diethyl-N-(phenylmethyl)·4-(tetrahydro-2H-pyran-4-ylamino)-1Η-pyrazolo[3,4-b]pyridine-5-A Indoleamine 544 1-ethyl-N-(l-phenyl-4-p-p-decyl)-4-(tetraxan-4-ylamino)_1H-pyrazolo[3,4-b Pyridine-5_formamide 545 1-ethyl-N-{1-[(ethylamino)carbonyl]-4-hexahydropyridinyl}-4-(tetrahydro-2H- shout-4) Amino)-1Η-ρ ratio spit[3,4-b]p ratio _5-cartoamine 546 formic acid-1·ethyl-N-[l-methyl-2-(4-methyl- 1-hexachloro-exo- b-yl)ethyl]·4·(tetrahydro-2Η-piperidin-4-ylamino)-1Η-pyrazolo-P,4-b]pyridine-5-carboxamide 1:1) 547 [4-({[1·Ethyl-4-(tetrachloro-2H_^)-4-ylamino)_1Η_ρ比比[3,4-b]pyridin-5-yl]carbonyl }Amino)-1-hexahydropyridinyl]succinate methyl ester 87481-9603〇3_ Medium. Doc -182- 1283678 548 1·Ethyl-N-{[4-(4•hufolinylmethyl)phenyl]methyl}-4·(tetrahydro-2Hh-pyridylamino)_1Η- Pyrazolo[3,4-b]pyrrol-5-carbamidamine trifluoroacetate 549 1-ethyl-N-({3-[(4-methyl-1-hexahydropyrryl)) Phenyl]phenyl}methyl)-4-(tetrahydro-2H-piperazin-4-ylamino)-1Η-pyrazolo[3,4-b]pyridine-5-formamide trifluoroacetate 550 N-{[5-(Amino-based)-3_p ratio benzyl]methyl}·1·ethyl-4·(tetrahydro-2H-pyran-4-ylamino)_1H-pyrazole [3,4-b]pyridine-5-carbamidamine trifluoroacetate 551 1-ethyl-indole-{[4-(1-methylethyl)phenyl]methyl b 4-(tetrahydro- 2H-piperazin-4-ylamino)-1Η-pyrazolo[3,4hepta]pyridin-5-formamide 552 N_{[3-(cyclopentyloxy)-4-(methoxy) Phenyl]methyl}_1_ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1Η-ρ than wow [3,4-b]p than pent-5- Amine 553 1-ethyl-N-({4-[(4-methyl-1-hexahydropyrrolidinyl)methyl]phenyl}methyl) ice (tetrahydro-2H-pyran-4-yl) Amino)-1Η-pyrazolo[3,4-b]pyridine-5-formamide trifluoroacetate 554 Ν·[(2,4·diphenyl)methyl]-1-ethyl- 4-(tetrahydro-2H-pyran-4-ylamine -1Η-pyrazolo[3,4-b]pyridine-5-carboxamide 555 N-[(2,4-difluorophenyl)methyl]-1-ethyl winter (tetrahydro-2H -piperidinylamino)_1Η·pyrazolo[3,4_b]pyridine-5-carbamimid 556 N-[(2-nitro-4-fluorophenyl)methyl]-1-ethyl- 4·(tetrahydro-2H_ britium·4_ylamino-p-[3,4-b]p than pent-5-cartoamine 557 N-{2_[2_chloro-3-(A Oxy)phenyl]ethyl}·1·ethyl-4-(tetrazine-2H-mouth oxime-4-ylamino)·1Η·external b-[3,4-b]p -5_Artemisamine 558 3-[({[1-ethyl4-(tetrahydro-2H- brityl-4-ylamino)-[3,4_b]pyridin-5-yl]carbonyl}amine Methyl]methyl]benzoate 559 1-ethyl-N_{[3-(1-tetrahydropyrrolylmethyl)phenyl]methyl}yl (tetrahydro-2H-pyran-4-ylamine) -1Η-pyrazolo[3,4-b]pyridine-5-carbamidamine trifluoroacetate 560 1-ethyl N-(2-{4-[(methylsulfonyl)amino]benzene }}ethyl)-4-(tetrahydro^: bromo-4-ylamino)-1 Η-pyrazolo[3,4-b]pyridine-5-formamide 561 N-{[2,5 - bis(methoxy)phenyl]methyl}sodiumethyl (tetrahydro-2H-piperidin-4-ylamino)-1Η-pyrazolo[3,4-b]pyridine_5_A Indoleamine 87841·96〇303·中. Doc -183- 1283678 562 N-{[2,6-Bis(methoxy)phenyl]methyl bromide ethyl ice (tetrahydro-2H-piperidin-4-ylamino)-1Η-峨峻And [3,4-b> butyl _5_methalamine 563 1-ethyl-N-[(2- phenyl)methyl]-4-(tetrachloro-2H--pyran-4-yl Amino)_1Η·ρ ratio spit[3,4-b]p than pyridine-5-carbamimid 564 N-[(3,5-a-epoxy)methyl]_1_ethyl_4-( Tetrachloro-211-0 decyl-4-ylamino)-1 Η-pyrazolo[3,4-b]pyridine_5-carbamimid 565 N-[(4-乱冬基)methyl]- 1-ethyl_4-(tetrachloro-211-0-endan-4-ylamino)_ 1H-pyrazolo[3,4-b]pyridine-5-carboxamide 567 N_cyclohexyl small B Base_4·(tetrahydro-2H-piperidin-4-ylamino)-1Η-pyrazolo[3,4-b]pyridine-5-carboxamide 568 1-ethyl-N-{2- [4-(Methanesulfonyl)phenyl]ethyl}-4-(tetrahydro-2H-pyran-4-ylamino)-1Η-pyrazolo[3,4-b]pyridine_5· Methionamine 569 1-ethyl-Ν·{[2·glycol-3·(trifluoromethyl)phenyl]methyl}-4-(tetrahydro-2-indole-hamo-4-ylamino) -1Η^比吐和[3,4-b&gt; 比淀-5-甲含胺570 N_({4-[(cyclopropylamino)carbonyl]phenyl}methyl)-1_ethyl-4·( Tetrahydro-2H-piperidin-4-ylamino)-1H_p than spit[3,4-b]p Precipitate-5-carbamamine 571 1·ethyl-Ν-{[4·(4_methyl-1-hexahydro-b-phenyl)phenyl]methyl}-4-(tetrahydro-2H- shout -4-4_ylamino)-1Η-external b s[3,4-b]p than yt-5-carbamamine 572 1-ethyl-N-{[4-(l_w hydrogen u than 洛基Methyl)phenyl]methyl b 4-(tetrahydro-2H-pyran-4-ylaminobipyrano[3,4-b]p than lake-5-formamide 573 1-ethyl- N-[6-(Methoxy)succinyl 2,3-dihydro·1Η- although-2-yl]-4-(tetrahydro-2H-piperidin-4-ylamino)_1H-pyridyl Zoxa[3,4-b]pyridine_5-formamide 574 N-[(2,5-dichlorophenyl)methyl]-1-ethyl-4-(tetrahydro-2H- shouting- 4-ylamino)·1Η_pyrazolo[3,4-b]pyridine_5-formamide 575 N-[(3,5-diethylphenyl)methyl]-1·ethyl· 4·(tetrahydro-2Η_»派喃-4-ylamino)-1Η-pyrazolo[3,4-b]pyridine-5-carboxamide 576 N-[(2,3-difluorophenyl) )methyl]_1_ethyl-4-(tetrahydro-2H-indol-4-ylamino)-1Η-pyrazolo[3,4-b]pyridine-5-carboxamide 577 1-B --N_{[2-(Metholyl)phenyl]methyl}_4-(tetrahydro-2H-pyran-4-ylamino)-1Η·pyrazolo[3,4-b]pyridine -5-Protonamine 578 1-ethyl-indole-[(3·light phenyl)methyl]-4-(tetraindole-2H- brim-4) Amino) lH-pyrazolo [3,4-b] pyridine-5-Amides of 87841-960303-. Doc -184 - 1283678 579 N-{[3,5-bis(methoxy)phenyl]methyldoxime-ethyl-4-(tetrahydro-2H-piperidin-4-ylamino)-1Η -pyrido[3,4-b&gt;pyridin-5-formamide 580 1-ethyl-N-[2-(4-hydroxyphenyl)ethyl]-4-(tetrahydro-2H-piperidin喃-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 581 N-[(3,5-disorganophenyl)methyl]-1-ethyl -4-(tetrachloro-211-0 decyl-4-ylamino)-1 Η-pyrazolo[3,4-b]pyridine_5-carbamimid 582 N-{[2,4-double ( Methoxy)phenyl]methyl b; [_ethyl·4·(tetrahydro-2H-piperidin-4-ylamino)-1Η·pyrano[3,4-b]p ratio- 5-Proline 583 1-ethyl·Ν-{[2-(Methyl)-fundyl]methyl b 4-(tetrachloro-2H·*7-endan-4-ylamino)_11]&gt ;比峻和[3,4-b&gt; 比淀-5-carbamide 584 N-[(2,4-dimethylphenyl)methyl]sodiumethyl ice (tetrahydro-2H-pyran) 4-aminoamino)-1Η&gt; ton[3,4-b]p than ammonium-5-formic acid amine 585 1-ethyl-N-({2-[(methylamino)carbonyl)phenyl} Methyl) Winter (tetrahydro-2H-piperidin-4-ylamino)-1Η-pyrazolo[3,4_b]pyridine-5-formamide 586 1-ethyl-N_{2_[4-( Methoxy)phenyl]ethyl}-4-(tetrahydro-2H-bran-4-ylamine ))·1Η-pyrazolo[3,4-b]pyridine-5-formamide 587 N-[(2-chlorophenyl)methyl]sodiumethyl-4-(tetrahydro-2H-pyran 4-ylamino)-1H-pyrazolo[3,4_b]pyridine-5-carbamimid 588 1-ethyl_N_[(2_phenyl)methyl]-4-(tetrahydro- 2H-Bucer-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carbamimid 589 N-(l,3-benzodioxan-5-yl Methyl)·1_ethyl·4-(tetrahydro-2H-peak-2-ylamino)-1Η-ρ is 唆[3,4_b]p than ·5-methylamine 590 1- Ethyl-Ν-[3-(methoxy)phenyl]-4-(tetrahydro-2Η-jol-4-ylamino)-1H-P is more than [3,4_冲比淀- 5-Protonamine 591 N-(cyclohexylmethyl)sodiumethyl-4-(tetrahydro-2H-piperidin-4-ylaminobispyrazolo[3,4-b]pyridine-5-formamidine Amine 592 1-ethyl-N-(l,2,3,4-tetrahydrosapinyl)-4_(tetrahydro-2H-pyran-4-ylamino)-1Η·^ spit and [3, 4_b]p Bishen-5-cartoamine 593 4-[({[1-ethyl_4-(tetrahydro-2H-piperidin-4-ylamino)·1Η-pyrazolo[3,4 -b] 匕 匕 -5 - 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基Tetrahydro-2H_^-an-4-ylamine-based ratio also [3,4-b]p is more than 5--5 87841-960303- in. Doc -185- 1283678 595 {·{[4-(Aminocarbonyl)phenyl]methyl}_1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1Η-pyrazole [3,4-b]pyridine-5-methanamine 596 N-[(2,6-. A 'exhaust base' methyl]-1_ethyl-4-(tetrachloro-2H-^an-4-ylamine group than ton[3,4-b]p ratio _5_甲甲胺597 N-{[3_(Amino-Williyl)phenyl]methyl}_1_ethyl·4_(tetrahydro-2H.pyrano-4-ylamino)-1Η-pyrazolo[3,4-b Pyridine-5-formamide 598 1-ethyl-indole-[(4·monophenyl)methyl]-4-(tetrahydro-2H-fluoren-4-ylamino)_ 1Η·ρ ratio唆和|;3,4 Shuai Ding-5-carbamamine 599 1-ethyl-N-{[6-(methoxy)_3_? than decyl]methyl}-4·(tetrahydro-2H -p bottom _ 4-ylamino)-1Η-ρ than spit [3,4-b]external b--5-methine 600 1-ethyl than decylmethyl)-4-(four Hydrogen-2H-p-endo-4-ylamino)_1H_pyrazolo[3,4-b]pyridine-5-carboxamide 601 1-ethyl-4-(tetrahydro-2Η-scarred- 4-ylamino)·Ν-{[3_(trifluoromethyl)phenyl]methyl}-1Η-pyrido[3,4-b>ratio·5-carbamamine 602 Ν-[ 4-(2•Amino-2-ketoethyl)phenyl]_1-ethyl·4-(tetrahydro-2-indole-scarred ylamino group is more than sir[3,4-b] Precipitate-5-cartosamine 603 1-ethyl-N-({4-[(methylamino)carbonyl]phenyl}methyl)-4-(tetrahydro-2H-pyran-4-ylamino) )-1Η·ρ比峻和[3,4-b]p 比淀-5-甲甲胺604 1 -ethyl-N-{4-[2-(methylamino)-2-ketoethyl]phenyl}_4-(tetrahydro-2H-pyran-4-ylamino)-1Η_ρ is 唆[3,4-1 Xiaobiyan-5-formic acid amine 605 1-ethyl-N-[(3-fluorophenyl)methyl]-4-(tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo[3,4-b]pyridine-5-carbamimid 606 1-ethyl-N-({4_[(methyl aryl)amino]phenyl}methyl)_4_( Tetrahydro-2H_bromo-4-ylamino group 唆[3,4-b]p ratio -5-5_甲甲胺607 N-{[4-(aminosulfonyl)phenyl]- Base)-1·ethyl-4-(tetrahydro-2Ημ trace-4-ylamino)-1Η-pyrazolo[3,4-b]pyridine-5-formamide 608 N-{[2 -(Aminocarbonyl)phenyl]methyl-i-ethyl_4_(tetrahydro-2Η-piperidinylamino)-1Η_ρ is 唆[3,4-b]p than -5-5_甲Amine amine 609 N-({4_[(difluoromethyl)oxy)phenyl}methyl)-1-ethyl_4-(tetrahydro-2H-bran-4-ylamino) 3,4-b]p than yt-5-cartoamine 610 N-({3-[(dimethylamino)methyl]phenyl}methyl) succinyl-4-(tetrahydro-2H- Piperazin-4-ylamino)-1Η-pyrazolo[3,4-b]pyridine-5-decylamine 87841-960303-中. Doc -186- 611 N_{[3-Chloro-4-(methoxy)phenyl]methyl}-l-ethyl-4-(tetramethylene-2H-cyclopentan-4-ylaminol ratio Salivation [3,4-b]p is more than pent-5-cartoamine 612 N-(l_ethyl-branched-4_ττ gas ρ than decyl)-1 ethyl-4-(tetrachloro-2H· shout -4-ylamino)-1Η-pyrazolo[3,4-b]pyridine-5-carbamimid 613 1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino) -N_{[2_(trifluoromethyl)phenyl]methylHH-pyrazolo[3,4_b]pyridine-5-carbamimid 615 N_(5-chloro-2,3-dichloro-1H- Hetero-2_yl)small ethyl_4·(tetrachloro-2H-pyran-4)ylamino)-1Η-pyrazolo[3,4-b]pyridine-5-carboxamide 616 N- ({3-[(Acetylamino)methyl)phenyl}methyl)-1_ethyl_4-(tetrahydro-2H-hydropyran-4-ylamino)-1Η-ρ ratio 并[ 3,4-b]p"b-precipitate-5-cartoamine 617 1-ethyl-N-[(4-fluorophenyl)methyl]-4.(tetrahydro-2H. britylene-4-yl Amino)-1H-P is more than [3,4-b]p than bite-5-formamide 618 1-ethyl-N-{[4-fluoroyl·2·(trifluoromethyl)benzene Methyl}·4_(tetrahydro-2H-piperidin-4-ylamino)-1Η-pyrazolo[3,4-b]pyridine-5-carboxamide 619 1-ethyl-N_[ (2-ethylphenyl)methyl]-4-(tetrahydro-2H-piperidin-4-ylamino)-1H-pyrazole [3,4-b]pyridine-5-formamide 620 1-ethyl-N-{[2-fluoro-5-(trifluoromethyl)phenyl]methyl}-4-(tetrazine_ 2H_piperazin-4-ylamino)-1Η-pyrazolo[3,4-b]pyridine-5-carboxamide 621 1-ethyl-4-(tetrahydro-2H-pyran-4) Amino)_N-[(2,3,4-trifluorophenyl)methyl]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 622 N-[(4-muryl) _2_gasphenyl)methyl]-1-ethyl-4·(tetrachloro-2H-P-Chen-2-ylamino)_1Η·pyrazolo[3,4-b]pyridine-5- Methionamine 623 N-[(4-bromo-2-fluorophenyl)methyl]sodiumethyl-4-(tetrahydro-2H-piperidin-4-ylamino)-1Η-pyrazolo[ 3,4-b]pyridine-5-carbamimid 624 Ν-[(3,5-dimethylphenyl)methyl]sodiumethyl-4-(tetrahydro-2H-pyran-4-ylamine Base)-1Η-pyrazolo[3,4-7]pyridine-5-carbamimid 625 N-[(2,3-dimethylphenyl)methyl]-1-ethylindole (tetrahydro-2H -piperidin-4-ylamino)-1Η-pyrazolo[3,4-7]pyridine_5_formamide 626 N-[(2,3-diphenyl)methyl]-1-ethyl Base (tetrahydro-2H.piperazin-4-ylamino)-1Η-pyrazolo[3,4_b]pyridine-5-carbamimid 627 N-[(4-ylyl-methylene)methyl] ·1_Ethyl-4_(Έ5-chloro-2H-bran-4-ylamino)_ 1Η-pyrazolo[3 , 4-b]pyridine-5-formamide 87841-960303-中. Doc -187- 1283678 628 Ν·[(4-bromophenyl)methyl]_i_ethyl-4-(tetrahydro-2H-pyran-4-ylamino)_ 1H-pyrazolo[3, 4-b]pyridine-5-carbamimid 629 1-ethyl-N-{[5-fluoro-2-(trifluoromethyl)phenyl]methyl}-4-(tetrahydro-2H-pyran -4-ylamino)-1Η-pyrazolo[3,4-b]pyridine-5-methamine 630 1-ethyl-N-[(4-iodophenyl)methyl]-4_(four Hydrogen-2H-piperazin-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-formamide 631 Ν-{[4-(1,1-dimethylethyl) Phenyl]methyl}_1_ethyl·4-(tetrahydro-2H-piperidin-4-ylamino)-1Η-pyrazolo[3,4-b]pyridine-5-carbamimid 632 N-[(3-cyanophenyl)methyl]-1-ethyl-4-(tetrahydro-2H-piperidin-4-ylamino)-1Η·ρ ratios [3,4-b&gt碧丁-5-甲甲胺 633 N-[(2,6-Dichlorophenyl)methyl]-1-ethyl winter (tetrahydro-2H-piperidinyl)-111_pyrazole And [3,4-b]pyridine-5-formamide 634 N-[(5-chloro-2-methylphenyl)methyl]-1-ethyl·4·(tetrachloro-2H- shout -4-4·ylamino)-1Η-pyrazolo and i3,4-b]pyridine-5-carbamimid 635 Ν-[(3,5·二溪phenyl)methyl]-1_ethyl· 4-(tetrachloro-2H-pyran-4-ylamino)-1Η-pyrazolo[3,4_b]pyridine -5-Protonamine 636 1-ethyl-N-[(4-ethylphenyl)methyl]-4-(tetrahydro-2H-piperidin-4-ylamino)-lH-ρ ratio And [3,4-b] outside I: lake-5-cartosamine 637 1-ethyl-hydrazine·{[3-fluoro-4-(trifluoromethyl)phenyl]methyl}-4- (tetrahydro-2H.piperazin-4-ylamino)-1Η-pyrazolo[3,4_b]pyridine-5-decylamine 638 1-ethyl-N-[(2_mothyl)) -4-(tetrachloro-2H-fluorenyl-4-ylamino)_ 1H-pyrazolo[3,4-b]pyridine-5-carboxamide 639 N-[(2-bromophenyl) )methyl]-1_ethyl-4_(tetrahydro-2H-furan-4-ylamino)_ 1H-pyrazolo[3,4-b]pyridine-5-carboxamide 640 1-B -N-{[4-(demethyl)phenyl]methyl}-4-(tetrahydro-2H_ sher-4-ylamino)-1Η-pyrazolo[3,4-b] Pyridine-5-formamide 641 1-ethyl-N-{[3-(methyl)phenyl]methyl}-4-(tetrahydro-2H-pyran-4-ylamino)-111 _pyrazolo[3,4-b]pyridine-5-formamide 642 1_ethyl-N-{[3-(hydroxymethyl)_2-methylphenyl]methyl} ice (tetrahydro _ 2H-piperidin-4-ylamino)-111-0 is more than [3,4-b]p than pent-5-ylamine 643 Ν·{[2,3-dichloro-6-( Methyl)phenyl]methyl}sodiumethyl-4-(tetrahydro-2H-piperidin-4-ylamino)-1Η-ρ is more than [3,4_b&Gt; butyl--5-carbamamine 8784l-960303-zhong. Doc -188- 1283678 644 N-[(2,4-dichloro-6-methylphenyl)methyl]sodiumethyl pentyl (tetrahydroamino)-1Η-pyrazolo[3,4- b]pyridine-5-formamide 65 1_ethyl_N-{[4_(2-methylpropyl)phenyl]methyl}_4_(tetrahydro-2H-furan-4-ylamino)-1Η -pyrazolo[3,4-b]pyridine-5-formamide 646 N-[(2,5-monomethyl)methyl]-1-ethyl-4-(tetrachloro-2H -P-carbylamino)-1H-P than succinyl [3,4_b]p than 5·7-bristamine 647 1-ethyl-4-(tetrahydro-2-indole-pyran-4-ylamine Base)-Ν_[(2,4,5-trifluorophenyl)methyl]-1Η-pyrazolo[3,4-b]pyridine-5-carboxamide 648 1-ethyl-N-{[ 2_Fluoro- 4_(trifluoromethyl)phenyl]methyl}·4_(tetrahydro-2H_ 喃 -4-ylamino)-1Η^比峻[3,4-b&gt; 5-cartoamine 649 N-[(2-chloro-6-methylphenyl)methyl]_1_ethyl ice (tetrahydro-2H-pyranyl-4) base: base)·1Η-ρ ratio Also [3,4-b]p than yt-5-formic acid amine 650 4_[({[1_ethyl-4-(tetrahydro-2H- sulphonyl) 4-H-p ratio) Indolo[3,4-b]pyridin-5-yl]carbonyl}amino)methyl]benzoic acid sodium salt 651 3-[({[1-ethyl-4·(tetrahydro-2H_ shouting-4) _ylamino)-1Η-external b gorge[3,4-b]pyridin-5-yl] 】}amino)methyl]benzoic acid 652 1-ethyl-4·{[4_(imido)cyclohexyl]amino}_1H-pyrazolo[3,4-b]pyridine-5-carboxylate Ethyl acetate 653 1_ethyl_4-{[4-(hydroxyimino)cyclohexyl]amino}-N-{[4-(methoxy)phenyl]methyl}-1Η-ρ ratio Salivation [3,4-b]pyrazine-5-formamide 654 N-{[4-(dimethylamino)phenyl]methyl}-1_ethyl·4-{[4-(hydroxy Imino)cyclohexyl]amino}-1Η-pyrazolo[3,4-b]pyridine-5-formamide 655 1-ethyl-4_({4-[(ethoxy))imido) Cyclohexyl}amino)-N-{[4-(methoxy)phenyl]methyl}-1Η·pyrido[3,4-b>pyridyl-5-carbamide 656 1_B 4-({4-[(methoxy)imino]cyclohexyl)amino)-N-{[4-(methoxy)phenyl]methyl b 1H-pyrazolo[3, 4-b]pyridine-5-formamide 657 4-[(4-{[(1,1·dimethylethyl)oxy]imino]cyclohexyl)amino]·1·ethyl- Ν-{[4-(Methoxy)phenyl]methyl b 1Η-pyrazolo[3,4-b]pyridine-5-carboxamide 658 1_ethyl-N-{[4_(methoxy Phenyl]methyl}-4-[(7-ketohexahydro_1H-qi-7-yl-4-yl)amino]pyrazine[3,4-b]p than lake-5- A brewing amine 8784l-960303-zhong. Doc -189- 1283678 659 1_Ethyl_4-[(7-ketohexahydro-1H-azadecen-4-yl)amino]_1Η·pyrazolo[3,4-b]pyridine -5-Carboxylic acid ethyl ester 660 4-{[cis-4.(butylamino)cyclohexyl]aminophenyl n_(2,3-dihydro-1H-indol-2-yl)_1_ethyl -1Η·ρ比峻和[3,4-b]峨盐-5-Proline 661 4_[(trans-4-AminoJ-hexyl)amino]-i-ethyl (phenylmethyl) Bisazo[3,4-b]pyridine-5-carbamimid 662 4_[(trans-2-aminocyclohexyl)amino]xiaoethyl·Ν_(phenylindenyl)_1]9[_ Pyrazolo[3,4-b]pyridine-5-formamide 663 4-[(cis-2-aminocyclohexyl)amino]_1_ethyl_N_(phenylmethyloxazolidine [3] ,4-b]pyridine-5-methanamine 664 4-[(3·Amino- hexyl)amino]-1-ethyl(phenylmethyl)_1Η-ρ than 唆[3,4-b ]p-precipitate-5-formic acid amine free example 1: 4_(cyclopentylamino)-1-ethyl-111_pyrido[3,4-b]pyridine-5-oleic acid ethyl ester

使中間物1 (0.051克）與環戊胺（0.019克）懸浮於乙醇（2毫升） 中，並添加三乙胺（0.14毫升）。將混合物於氮氣下攪拌，並 在80°C下加熱16小時。於冷卻至室溫後，在氮氣流下藉蒸發 移除乙醇，並使殘留物於二氣甲烷（DCM)與水之間作分液處 理。分離液層，並將有機層直接裝填於固相萃取（SPE)藥筒 (矽膠，5克）上，將其相繼以；（i)DCM，⑼DCM : Et2〇 (2 : 1)， (iii) DCM : Et2 Ο (1 : 1)，(iv) Et2 0, (v) EtOAc，(vi) MeOH 溶離。將含有 87841-960303·中.doc -190- 1283678 所要物質之溶離份合併，並於真空中濃縮，而得實例丨（〇 〇74 克）。LCMS 顯示 MH+=303; Tret=3.45 分鐘0 以類似方式製備下列物質： NHR3Intermediate 1 (0.051 g) and cyclopentylamine (0.019 g) were suspended in ethanol (2 mL) and triethylamine (0.14 mL). The mixture was stirred under nitrogen and heated at 80 ° C for 16 hours. After cooling to room temperature, the ethanol was removed by evaporation under a stream of nitrogen, and the residue was partitioned between di-methane (DCM) and water. The liquid layer was separated, and the organic layer was directly loaded on a solid phase extraction (SPE) cartridge (silicone, 5 g), which was successively used; (i) DCM, (9) DCM: Et2 (2: 1), (iii) DCM : Et 2 Ο (1 : 1), (iv) Et 2 0, (v) EtOAc, (vi) MeOH. The fractions containing the desired material of 87841-960303···doc -190-1283678 were combined and concentrated in vacuo to give an example 丨(〇 〇 74 g). LCMS shows MH+ = 303; Tret = 3.45 min. 0 The following materials were prepared in a similar manner: NHR3

NHR3 胺試劑 ΜΗ+離子 TRET(分鐘） 實例2 hn-〇 環己胺 317 3.65 實例3 ηνΌ 4-胺基四氫哌喃 319 2.93 實例4 ΗΝ 乂）ι 一 中間物7 332 2.17 實例5 中間物6 360 3.20 复惠《1(=中間物32) : 1-乙基冬(四氮-2Η·ι痕喃_4_基胺基)-iH_吡唑 并[3,4_b]峨淀_5_羧酸乙酯NHR3 amine reagent ΜΗ+ion TRET (minutes) Example 2 hn-cyclohexylamine 317 3.65 Example 3 ηνΌ 4-aminotetrahydropyran 319 2.93 Example 4 ΗΝ 乂)ι an intermediate 7 332 2.17 Example 5 Intermediate 6 360 3.20 Rehabilitation "1 (= intermediate 32): 1-ethyl winter (tetrazol-2 Η·ι 喃 _4_ ylamino)-iH_pyrazolo[3,4_b] 峨 ___ Ethyl carboxylate

代替上文所示之方法（稱為方法A)，實例3之化合物亦可 使用下述方法製成： 實例3,方法B :使中間物1 (2 5克）溶於乙腈（15毫升）中。添 加4-胺基四氫哌喃鹽酸鹽（11克）與N，N_二異丙基乙胺（9 4毫 升）’並將混合物於氮氣及85艽下攪拌16小時。殘留微量之 起始物質’故添加另一份冬胺基四氫哌喃鹽酸鹽（〇11克）， 並於85 C下再持續攪拌16小時。然後，在真空中濃縮混合 物。使殘留物於DCM與水之間作分液處理。分離液層，並 87841_960303·中.doc •191- 1283678 將有機層以另外之水（2x20毫升）洗滌，接著脫水乾燥 (Na2S04)，及在真空中濃縮。使殘留物進一步藉層析，使用 Biotage (碎膠，90克）純化，以環己燒：酷酸乙酯溶離，而得 實例 21 (2.45 克）。LCMS 顯示 MH+=319 ; Tret = 2.90 分鐘。 實例6 : 4-(環戊基胺基)_1_甲基_1H-吡唑并[3,4-b]吡啶-5-羧酸乙酯 X)Instead of the method shown above (referred to as Method A), the compound of Example 3 can also be prepared using the following procedure: Example 3, Method B: Intermediate 1 (25 g) was dissolved in acetonitrile (15 mL) . 4-Aminotetrahydropyran hydrochloride (11 g) and N,N-diisopropylethylamine (9 4 mL) were added and the mixture was stirred under nitrogen and EtOAc for 16 hr. A trace amount of the starting material was left. Thus, another portion of the amidotetrahydropyran hydrochloride (〇 11 g) was added, and stirring was continued at 85 C for further 16 hours. The mixture was then concentrated in vacuo. The residue was partitioned between DCM and water. The layers were separated, and the organic layer was washed with water (2.times.20 mL), then dried (Na2S04) and concentrated in vacuo. The residue was further chromatographed, purified using EtOAc (EtOAc) (EtOAc) LCMS showed MH+ = 319; Tret = 2.90 min. Example 6: Ethyl 4-(cyclopentylamino)_1-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate X)

將中間物3 (0.045克）放置在ReactivialTM中，並以環戊胺（〇_〇7 毫升）處理。將混合物在90°C下加熱2小時，然後使其冷卻至 室溫，並於氯仿（2毫升）與水（1毫升）之間作分液處理。分離 液層，並使有機相蒸發成褐色固體，使其藉質量導引之自 預備HPLC純化，而得實例6，為白色固體（0·008克）。LCMS 顯示 MH+=289; Tret=3.22 分鐘。 f例7 : 1-甲基_4_(四氫_2H4喃-4-基胺基)-1Η_吡唑并[3,4-b]吡 啶-5-羧酸乙酯Intermediate 3 (0.045 g) was placed in ReactivialTM and treated with cyclopentylamine (〇_〇 7 mL). The mixture was heated at 90 °C for 2 hours, then cooled to room temperature and partitioned between chloroform (2 mL) and water (1 mL). The layers were separated and the organic phase was evaporated to a white solid. LCMS showed MH+ = 289; Tret = 3.22 min. f Example 7: 1-methyl_4_(tetrahydro-2H4py-4-ylamino)-1Η-pyrazolo[3,4-b]pyridin-5-carboxylic acid ethyl ester

將中間物3 (0.035克）放置在ReactivialTM中，並以本胺基四氫 哌喃（0.06毫升）處理。將混合物於9(rc下加熱2小時，然後使 其冷卻至室溫，並於氯仿(2毫升）與水㈣升）之間作分液處 87841_96〇3〇3·中.doc -192- 1283678 理。分離液層，並使有機相濃縮，接著施加至預備之TLC板 (矽膠，20公分x20公分xl毫米），將其以醋酸乙酯溶離。自 板移除所需要之吸收帶，龙以醋酸乙酯（2 χ 15毫升）洗滌矽 膠。於真空中濃縮醋酸乙酯溶液，獲得實例7，為白色固體 (0.008 克）。LCMS 顯示MH+==:305，Tret = 2.67 分鐘。 竟肩: 1-乙基-4-[(3S)-四氛17夫喃各基胺基】比峻并丨3,4_b】p比 啶-5-羧酸乙酯Intermediate 3 (0.035 g) was placed in ReactivialTM and treated with the present amine tetrahydropyran (0.06 mL). The mixture was heated at 9 (rc for 2 hours, then allowed to cool to room temperature and separated between chloroform (2 ml) and water (4) liters) 87041_96〇3〇3·中.doc -192-1283678 Reason. The liquid layer was separated and the organic phase was concentrated, then applied to a preparative TLC plate (tank, 20 cm x 20 cm x 1 mm), which was dissolved in ethyl acetate. The absorbent tape required for the removal of the plate was washed with ethyl acetate (2 χ 15 ml). The ethyl acetate solution was concentrated in vacuo to afford crystals as a white solid (0.008 g). LCMS showed MH+==:305 and Tret = 2.67 min. Actually shoulder: 1-ethyl-4-[(3S)-four atmospheres of 17-propanylamino group] than 丨 丨 3,4_b]p ratio pyridine-5-carboxylic acid ethyl ester

Ο 使中間物1 (0.05克）與（S)_(+3-胺基四氫吱喃4_甲苯續酸鹽 (0·052克）懸浮於乙醇（丨毫升）中，並添加三乙胺（〇14毫升）。 將混合物於氮氣下攪拌，並在80°c下加熱24小時。於冷卻至 至/里後’在氮氣流下藉蒸發移除乙醇，並使殘留物於dCM (2 笔升）與水（1.5毫升）之間作分液處理。分離液層，並使有機 層濃縮至乾涸。使用SPE藥筒（矽膠，5克）進行純化，以 EtOAc :環己燒梯度液（1 : 16，然後i : 8, i : 4, i : 2, i : 1及工： 〇)溶離。將含有所要物質之溶離份合併，並於真空中濃縮， 而得實例8 (0·〇52克）。LCMS顯示顧+= 3〇5 ; 丁纽=2·7〇分鐘。 以類似方式製備下列物質： 87841-960303-ψ.άοο -193- 1283678中间 Suspend Intermediate 1 (0.05 g) and (S)_(+3-aminotetrahydrofurfuryl 4-toluene hydrochloride (0·052 g) in ethanol (丨 ml) and add triethylamine (〇 14 ml). The mixture was stirred under nitrogen and heated at 80 ° C for 24 hours. After cooling to / after - the ethanol was removed by evaporation under a stream of nitrogen, and the residue was taken in dCM (2 liters) Separate the mixture with water (1.5 ml). The layers were separated and the organic layer was concentrated to dryness. Purified with EtOAc (EtOAc: EtOAc) 16, then i: 8, i: 4, i: 2, i: 1 and work: 〇) Dissolution. The dissolved fractions containing the desired substances are combined and concentrated in vacuo to give Example 8 (0·〇52 g LCMS shows Gu += 3〇5; Ding New = 2·7〇 minutes. The following materials were prepared in a similar manner: 87841-960303-ψ.άοο -193- 1283678

NHR3 胺試劑 MH+ 離子 Tret(分鐘） 實例9 (R)-(+)-3_胺基四氫吱 喃4-甲苯磺酸鹽 305 2.73 實例10 中間物11 335 3.21 實例11 (對掌異構物 之混合物） 中間物12 321 3.10 實例12 ΝΗ 環丙基胺 275 2.98 童-例:本队1-二氧化四氫嘧吩基）胺基Η-乙基-1H-吡唑并 [3,4_b】吡啶_5_羧酸乙酯NHR3 Amine Reagent MH+ Ion Tret (minutes) Example 9 (R)-(+)-3_Aminotetrahydrofurfuryl 4-toluenesulfonate 305 2.73 Example 10 Intermediate 11 335 3.21 Example 11 Mixture) Intermediate 12 321 3.10 Example 12 ΝΗ Cyclopropylamine 275 2.98 Child-Example: Our team 1-dihydropyrimidinylamino) hydrazine-ethyl-1H-pyrazolo[3,4_b] Pyridine-5-carboxylic acid ethyl ester

使中間物1 (0.05克）與中間物13 (0.027克）懸浮於乙醇（1毫升） 中，並添加三乙胺（0.14毫升）。將混合物於氮氣下攪拌，並 在80°C下力η熱24小時。於冷卻至室溫後，在氮氣流下藉蒸發 移除乙醇，並使殘留物於DCM (2毫升）與水（1.5毫升）之間作 分液處理。分離液層，並使有機層濃縮至乾涸。使用SPE藥 筒（矽膠，5克）進行純化，以EtOAc :環己烷梯度液；（1 : 8, 然後1 : 4, 1 : 2,1 ·· 1及1 ·· 0)溶離。將含有所要物質之溶離份 合併，並於真空中濃縮，而得實例13 (0.045克），為對掌異構 87841-960303-中.doc -194- 1283678 物之混合物。LCMS顯示MH+=353 ; Tret = 2.60分鐘。 以類似方式製備下列物質： NHR3Intermediate 1 (0.05 g) and intermediate 13 (0.027 g) were suspended in ethanol (1 mL) and triethylamine (0.14 mL). The mixture was stirred under nitrogen and heated at 80 ° C for 24 hours. After cooling to room temperature, the ethanol was removed by evaporation under a nitrogen stream, and the residue was partitioned between DCM (2 mL) and water (1.5 mL). The layers were separated and the organic layer was concentrated to dryness. Purification was carried out using a SPE cartridge (silica gel, 5 g) eluting with a gradient of EtOAc: hexanes; (1:8, then 1:4, 1:2,1··1 and 1··0). The fractions containing the desired material were combined and concentrated in vacuo to give EtOAc (EtOAc: EtOAc) LCMS showed MH+ = 353; Tret = 2.60 min. The following materials were prepared in a similar manner: NHR3

C〇2Et NHR3 胺試劑 MH+離子 TRET(分鐘） 實例14 hnXDsC 中間物14 367 2.64 免例I9 (參考J例，作為中間物）:4-(環戊基胺基）-1Η-吡唑并 [3,4-b]p比淀-5_幾酸乙酿C〇2Et NHR3 Amine reagent MH+ ion TRET (minutes) Example 14 hnXDsC Intermediate 14 367 2.64 Free Example I9 (Refer to J case, as intermediate): 4-(cyclopentylamino)-1Η-pyrazolo[3 , 4-b]p than the lake -5 - acid

實例 19 NHR3 = hn-〇 將中間物2 (0.035克）放置在ReactivialTM中，並以環戊胺（〇·〇5 毫升）處理。將混合物在90°C下加熱1·5小時，然後使其冷卻 至室溫’並於氯仿（2毫升）與水（1毫升）之間作分液處理。分 離液層’並使有機相濃縮。以Et〗Ο研製殘留固體，並收集 不溶性灰白色固體’及風乾，而得實例19 (0.016克）。LCMS 顯示 MH+=275 ; Tret=2.58 分鐘。 t例2〇(參考實免L··作為中間物)·· 4_(四氫-2H-哌喃-4-基胺基）_ 1H_吡唑并[3,4-b]吡啶-5-羧酸乙酯 87841-960303-φ.άοο -195- 1283678Example 19 NHR3 = hn-〇 Intermediate 2 (0.035 g) was placed in ReactivialTM and treated with cyclopentylamine (〇·〇 5 mL). The mixture was heated at 90 ° C for 1.5 hours, then allowed to cool to room temperature and was partitioned between chloroform (2 mL) and water (1 mL). The liquid layer was separated&apos; and the organic phase was concentrated. The residual solid was triturated with Et, and an insoluble off-white solid was collected and dried to give Example 19 (0.016 g). LCMS showed MH+ = 275; Tret = 2.58 min. t Example 2〇 (Refer to L.· as an intermediate)································ Ethyl carboxylate 87841-960303-φ.άοο -195- 1283678

將中間物2 (0.035克）放置在ReactiviaiTM中，並以i胺美四氮 喊喃（0·05毫升）處理。將混合物在9〇它下加熱15小時，然後 使其冷卻至室溫，並於氯仿（2毫升）與水（1毫升）之間作分液 處理。分離液層，並使有機相濃縮。使粗產物藉質量導引 之自預備HPLC純化，而得實例2〇，為灰白色固體（〇 〇11 克）。LCMS 顯示MH+==291; Tret=2.08 分鐘。 關於實例20之替代合成方法： 使中間物2 (2克）懸浮於4-胺基四氫哌喃（2克）中，並將混 合物在90°C下加熱6小時。使殘留混合物冷卻至室溫，並於 氯仿（50毫升）與水（50毫升）之間作分液處理。分離液相，並 使有機相蒸發至乾涸。以％0 (30毫升）研製殘留物，並收集 不溶性固體，及乾燥，而得實例20，為乳黃色固體（2·24 克）。LCMS 顯示 MH+=291; Tret=2.19 分鐘。 m 21· : N-苄基小乙基冬(四氫-扭娘喃冰基胺基）·1Η-Ρ比吐并 [3,4-b】吡啶-5-甲醯胺 196· 87841_96〇3〇3·中 d〇c 1283678Intermediate 2 (0.035 g) was placed in ReactiviaiTM and treated with i-amine meglumine (0. 05 mL). The mixture was heated under 9 Torr for 15 hours, then cooled to room temperature and partitioned between chloroform (2 mL) and water (1 mL). The layers were separated and the organic phase was concentrated. The crude product was purified by preparative HPLC eluting with EtOAc EtOAc (EtOAc) LCMS showed MH+ == 291; Tret = 2.08 min. Alternative Synthetic Method for Example 20: Intermediate 2 (2 g) was suspended in 4-aminotetrahydropyran (2 g) and the mixture was heated at 90 °C for 6 hours. The residual mixture was cooled to room temperature and partitioned between chloroform (50 ml) and water (50 ml). The liquid phase is separated and the organic phase is evaporated to dryness. The residue was triturated with EtOAc (3 mL). LCMS showed MH+ = 291; Tret = 2.19 min. m 21· : N-benzyl small ethyl winter (tetrahydro-tornyl amyl) · 1Η-Ρ than spit [3,4-b]pyridine-5-carbamide 196· 87841_96〇3 〇3·中d〇c 1283678

nrV 料_5=^0 NHR3= m^y 三種替代方法A、B及C已被用以製造實例21，如下述： 實例21，方法A : 將4-氯基中間物17 (0.031克，〇·1毫莫耳）在乙醇（L9毫升）中 之溶液’以三乙胺（0.07毫升，0.5毫莫耳），接著以4_胺基四 氫喊喃之〇·1Μ甲醇性溶液（中間物8，U毫升，01M含乙醇 溶液= 〇·11毫莫耳）處理。將混合物於回流（8(rc)下加熱18小 時。然後添加另一份4-胺基-四氫喊喃（〇·〇ι毫升未經稀釋胺， 非其溶液），並再持續加熱24小時。於真空中移除揮發性物 質，並使殘留物溶於二氯甲烷（DCM)中，接著施加至固相萃 取（SPE)藥筒（胺基丙基，1克），將其首先以DCM，然後以甲 醇溶離。在真空中濃縮含有所要物質之溶離份，而得實例 21 (0.004 克）。1^：]\48顯示_+=380;1^了=2.92分鐘。 實例21，方法B : 使中間物17(0.031克，0.1毫莫耳）溶於乙腈（1毫升）中。添 加4-胺基四氫哌喃鹽酸鹽（中間物8A，〇 〇15克，〇11毫莫耳） 與N，N-二異丙基乙胺（〇.〇8毫升，〇·5毫莫耳），並將混合物於 氮氣及85 C下攪拌16小時，然後在真空中濃縮。使殘留物於 87841-96〇3〇3·中.doc -197- 1283678 二氯甲燒（DCM)與水之間作分液處理。分離液層，並使有機 層在真空中濃縮，而得實例21 (0.027克）。LCMS顯示 MH+= 380 ; TRET= 2.92 分鐘。 實例21，方法C : 實例21之此種替代途徑c係涉及實例3酯=中間物32nrV material _5=^0 NHR3= m^y Three alternative methods A, B and C have been used to make Example 21, as follows: Example 21, Method A: 4-Chloro intermediate 17 (0.031 g, 〇 · 1 millimolar) solution in ethanol (L9 ml) 'with triethylamine (0.07 ml, 0.5 mmol), followed by 4-aminotetrahydropyrene oxime · 1 Μ methanol solution (intermediate 8, U ml, 01M with ethanol solution = 〇 · 11 millimoles). The mixture was heated under reflux (8 (rc) for 18 hours. Then another portion of 4-amino-tetrahydrofuran (〇·〇ι ml undiluted amine, not a solution) was added and heating was continued for another 24 hours. The volatiles were removed in vacuo and the residue was dissolved in dichloromethane (DCM) then applied to a solid phase extraction (SPE) cartridge (aminopropyl, 1 gram) which was firstly taken in DCM Then, it was dissolved in methanol, and the fractions containing the desired substance were concentrated in vacuo to give Example 21 (0.004 g). 1^:]\48 showed _+=380;1^== 2.92 min. Example 21, Method B : Intermediate 17 (0.031 g, 0.1 mmol) was dissolved in acetonitrile (1 mL). 4-Aminotetrahydropyran hydrochloride (Intermediate 8A, 15 g, 〇11 mmol) And N,N-diisopropylethylamine (8 ml, 〇·5 mmol), and the mixture was stirred under nitrogen and 85 C for 16 hr then concentrated in vacuo. 87841-96〇3〇3·中.doc -197- 1283678 Dichloromethane (DCM) was partitioned between water and water. The liquid layer was separated and the organic layer was concentrated in vacuo to give Example 21 (0) .027 g) LCMS showed MH+ = 380; TRET = 2.92 min. Example 21, Method C: This alternative route c of Example 21 relates to Example 3 Ester = Intermediate 32

)之形成’使用上述方法之^- ’使用上文關於中 間物33所予之方法，使實例3之酯/中間物32轉化成羧酸 (中間物33)，然後使用下文實例81-84之方法，進行醯胺鍵結 形成，以形成實例21。 下列化合物可使用一或多種上文方法A、B或c，較佳為 方法A或B，以類似方式製成：Formation of 'Using the above method' - using the method described above for Intermediate 33, the ester/intermediate 32 of Example 3 was converted to the carboxylic acid (Intermediate 33), and then the following Examples 81-84 were used. Method, a guanamine bond formation was made to form Example 21. The following compounds can be prepared in a similar manner using one or more of the above methods A, B or c, preferably Process A or B:

NR4R5 NHR3 起始 物質 胺試劑 ΜΗ+ —離子 384 Tret (分鐘） 3.09 實例 22 ηνΌ 中間物19 4_胺基四氫味喃 實例 23 ονη ΗΝΌ 中間物20 環戊胺 342 3.29 實例 24 crNH ηνΌ 中間物20 環己胺 356 3.47 87841-960303-^.doc -198- 1283678 實例 25 CrHH~ ην-〇 中間物20 ------- 4·胺基四氫喊喃 358 2.79 實例 27 CrNH Μ 中間物20 中間物6 400 2.64 實例 28 Ο ην^ο 中間物21 環戊胺 328 2.69 實例 29 RT ηνΌ 中間物21 環己胺 342 2.87 實例 30 ό ΗΝ-^ )〇 中間物21 4-胺基四氫哌喃 344 2.33 實例 31 ην^ο 中間物22 環戊胺 365 2.38 實例 32 ην~0 中間物22 環己基 379 2.54 實例 33 ΗΝ々γ^ι ηνΌ 中間物22 4-胺基四氫哌喃 381 2.09 實例 34 νη2 ΗΝ^ 中間物24 環戊胺 274 2.59 實例 35 νη2 ην-〇 中間物24 環己胺 288 2.79 實例 36 νη2 ΗΝ—^ ^0 中間物24 4-胺基四氫哌喃 290 2.22 兔例.39 : N-苄基斗(環戊基胺基)小乙基-1H-吡唑并[3,4七】吡啶-5-甲醯胺 87841-96〇3〇3_ 中.doc -199- 1283678NR4R5 NHR3 Starting material Amine reagent ΜΗ+-ion 384 Tret (minutes) 3.09 Example 22 ηνΌ Intermediate 19 4_Amino tetrahydro sulphonate Example 23 ονη ΗΝΌ Intermediate 20 Cyclopentylamine 342 3.29 Example 24 crNH ηνΌ Intermediate 20 Cyclohexylamine 356 3.47 87841-960303-^.doc -198- 1283678 Example 25 CrHH~ ην-〇 intermediate 20 ------- 4·Amino tetrahydrogen 358 2.79 Example 27 CrNH Μ Intermediate 20 Intermediate 6 400 2.64 Example 28 Ο ην^ο Intermediate 21 Cyclopentylamine 328 2.69 Example 29 RT ηνΌ Intermediate 21 Cyclohexylamine 342 2.87 Example 30 ό ΗΝ-^ ) 〇 Intermediate 21 4-Aminotetrahydropyran 344 2.33 Example 31 ην^ο Intermediate 22 Cyclopentylamine 365 2.38 Example 32 ην~0 Intermediate 22 Cyclohexyl 379 2.54 Example 33 ΗΝ々γ^ι ηνΌ Intermediate 22 4-Aminotetrahydropyran 381 2.09 Example 34 Ηη2 ΗΝ^ Intermediate 24 Cyclopentylamine 274 2.59 Example 35 νη2 ην-〇 Intermediate 24 Cyclohexylamine 288 2.79 Example 36 νη2 ΗΝ—^ ^0 Intermediate 24 4-Aminotetrahydropyran 290 2.22 Rabbit Example.39 : N-benzyl bucket (cyclopentylamino) small ethyl-1H-pyrazole [3,4-7] Pyridine-5-formamide 87841-96〇3〇3_中.doc -199- 1283678

nr4r5 其中 NR4R5=： NHR3= 將中間物17 (0.031克，〇】吝苗1+ 、一、 笔莫耳）在乙醇（1毫升）中之溶液， 以二乙胺（0.07耄升，〇_5毫墓耳、，接！ 二、、 笔莫耳）接奢以環戊胺之0.1M含乙 醇溶液（1.1毫升，（^说含乙醇溶 π /合/從u.u笔莫耳）處理。將混 合物於回流（_)下加熱1Μ、時。然後添加另—份環戊胺 _9毫升未經稀釋胺，非其溶液），並再持續加熱％小時。 於真空中移除揮發性物質，並使殘留物溶於Dcm中，接著 施加至SPE藥筒（胺基丙基，1克），將其首先以DCM，然後 以甲醇溶離。在真空中濃縮DCM溶離份，接著施加至spE藥 筒（矽膠’ 0.5克），將其相繼以①DCM，⑼Et2 0, (iii) EtOAc及（iv) MeOH溶離。合併含有所要物質之溶離份，而得實例39 (0·0〇7 克）。LCMS 顯示 ΜΗ+=364; Tret=3.38 分鐘。 以類似方式製備下列物質：Nr4r5 where NR4R5=: NHR3= a solution of intermediate 17 (0.031 g, 〇 吝 seedling 1+, 、, 莫莫) in ethanol (1 ml) with diethylamine (0.07 liters, 〇_5 The ear of the tomb, and the second!, the pen Moer) is connected with a 0.1M ethanol solution of cyclopentylamine (1.1 ml, (^ said ethanol containing π / combined / from uu pen Moer). Heating under reflux (_) for 1 Torr, then adding another portion of cyclopentylamine _9 ml of undiluted amine, not a solution thereof, and heating was continued for an additional hour. The volatiles were removed in vacuo and the residue was taken up in Dcm then applied to &lt;RTI ID=0.0&gt;&gt;&gt; The DCM fractions were concentrated in vacuo, then applied to a spE cartridge (yield: &lt;RTI ID=0.0&gt;&gt; The fractions containing the desired material were combined to give Example 39 (0·0〇7 g). LCMS showed ΜΗ+=364; Tret=3.38 min. The following materials were prepared in a similar manner:

87841-960303-中.doc -200- 1283678 nr4r5 NHR3 起始 物質 胺試劑 MH+ 離子 Tret (分鐘） 實例 40 HNT) 中間物17 環己胺 378 3.43 實例 41 HNT) hn-〇^° 中間物17 中間物6 42 1 2.75 實例 42 HN. HN~O 中間物18 環戊胺 358 3.63 實例 43 HN. &quot;Ο 中間物18 環己胺 372 3.79 實例 44 HN. hn~0 中間物18 4-胺基四氯 旅喃 374 3.13 實例 45 HN. HN—^ yj— 中間物18 中間物7 387 2.37 實例 46 HN. HN—^ 中間物18 中間物6 415 2.92 實例 47 F hn^O 中間物19 環戊胺 368 3.61 實例 48 HN—F hn-〇 中間物19 環己胺 382 3.76 實例 49 F hn—CZ/*~ 中間物19 中間物7 397 2.29 實例 50 F --0-Λ0 中間物19 中間物6 425 2.88 實例 51 HN，^ HN-〇 中間物23 環戊胺 316 3.05 實例 52 hn&lt;3 中間物23 環己胺 330 3.26 實例 53 HN 八'^ HN—^ \) 中間物23 4_胺基四氯 喊喃 332 2.58 實例 55 hn{M〇 中間物23 中間物6 373 2.46 87841-960303-中.doc -201 - 1283678 實处發· N•爷基+乙基甲基六氫吡啶-4-基）胺基]_1H-吡唑 并[3,4_b]吡啶-5-甲醯胺87841-960303-中.doc -200- 1283678 nr4r5 NHR3 Starting material Amine reagent MH+ Ion Tret (minutes) Example 40 HNT) Intermediate 17 Cyclohexylamine 378 3.43 Example 41 HNT) hn-〇^° Intermediate 17 Intermediate 6 42 1 2.75 Example 42 HN. HN~O Intermediate 18 Cyclopentylamine 358 3.63 Example 43 HN. &quot;Ο Intermediate 18 Cyclohexylamine 372 3.79 Example 44 HN. hn~0 Intermediate 18 4-Amino Tetrachloride L. 374 3.13 Example 45 HN. HN—^ yj—Intermediate 18 Intermediate 7 387 2.37 Example 46 HN. HN—^ Intermediate 18 Intermediate 6 415 2.92 Example 47 F hn^O Intermediate 19 Cyclopentylamine 368 3.61 Example 48 HN-F hn-〇 intermediate 19 cyclohexylamine 382 3.76 Example 49 F hn-CZ/*~ Intermediate 19 Intermediate 7 397 2.29 Example 50 F --0-Λ0 Intermediate 19 Intermediate 6 425 2.88 Example 51 HN,^HN-〇 intermediate 23 cyclopentylamine 316 3.05 Example 52 hn&lt;3 intermediate 23 cyclohexylamine 330 3.26 Example 53 HN 八'^ HN-^ \) Intermediate 23 4_Amino tetrachloro 332 2.58 Example 55 hn{M〇Intermediate 23 Intermediate 6 373 2.46 87841-960303-中.doc -201 - 1283678 Realization · N•Yuji+Ethyl Yl -piperidin-4-yl) amino] _1H- pyrazolo [3,4_b] pyridine-5-Amides

將中間物17 (0.031克，〇·ι毫莫耳）在乙醇（1毫升）中之溶 液’以二乙胺（〇.〇7毫升〇·5毫莫耳），接著以中間物7之〇.1M[ 含乙醇落液（1.1毫升溶液==0.U毫莫耳）處理。將混合物於回 流（80 C )下加熱18小時。然後添加另一份中間物7 (〇.〇1毫 升’未經稀釋胺），並再持續加熱24小時。於真空中移除揮 發性物質’並使殘留物溶於DCM中，接著施加至SPE藥筒 (胺基丙基，1克），將其首先以DCM，然後以甲醇溶離。於 真空中濃縮DCM溶離份，接著施加至SPE藥筒（矽膠，0.5 克），將其相繼以（i) DCM，(ii) Et2 0,（iii) EtOAc 及（iv) MeOH 溶離。 使甲醇溶離份濃縮，及進一步藉SPE (矽膠，0.5克）純化，以 (i)DCM，（ii) EtOAc及(iii)氣仿：甲醇（從99: 1至高達4: 1)之階 式梯度溶離。合併含有所要物質之溶離份，而得實例 56(0.004 克）。1^]^8顯示]^+=393;1^^=2.26分鐘。 ΐ例57 : 4-[(1_乙醯基六氩吡啶_4_基）胺基]小乙基-Ν-(ρ比咬-4-基 甲基）_1Η-吡峻并[3,4-b]吡啶_5_甲醯胺 87841·96〇3〇3_ 中.doc -202- 1283678 ΛA solution of the intermediate 17 (0.031 g, ι·ι mmol) in ethanol (1 mL) was taken as diethylamine ( 〇 〇 〇 〇 〇 5 5 5 5 5 5 5 5 5 5 .1M [containing ethanol drop (1.1 ml solution = 0. U millimoles). The mixture was heated under reflux (80 C) for 18 hours. Then another intermediate 7 (〇.〇1 ml) of undiluted amine was added and heating was continued for another 24 hours. The volatile material was removed in vacuo and the residue was dissolved in DCM then applied to a SPE cartridge (aminopropyl, 1 gram) which was first eluted with DCM then methanol. The DCM fractions were concentrated in vacuo and then applied to a EtOAc EtOAc (EtOAc) (EtOAc) The methanol fractions were concentrated and further purified by SPE (silica gel, 0.5 g) in steps of (i) DCM, (ii) EtOAc and (iii) EMI:MeOH (from 99:1 up to 4:1) Gradient dissolution. The fractions containing the desired material were combined to give Example 56 (0.004 g). 1^]^8 shows]^+=393; 1^^=2.26 minutes. Example 57: 4-[(1_Ethyl hexafluoropyridinyl-4-yl)amino]]ethylethyl-hydrazine-(ρ 咬-4-ylmethyl)_1Η-pyrene[3,4 -b]pyridine_5_formamamine 87841·96〇3〇3_中.doc -202- 1283678 Λ

EtEt

NR4r5 其中 NR4R5 =NR4r5 where NR4R5 =

NHR3= HN 〇 將中間物22_克’約w毫莫耳)在乙醇㈣升)中之洽 液，以三乙胺（_毫升，0.5毫莫耳），接著是巾間物^ o.im含乙醉溶液(u毫升溶液=〇11毫莫耳)處理。將混合物 於回流下加熱1M、時。難添加另—份中間物6_ 毫升’未經稀釋）’並再持續加熱24小時^真空中移除揮 發性物質，並使殘留物溶於DCM中，接著施加至spE藥筒 (胺基丙基，1克），將其首先以DCM ,然後以甲醇溶離。於 真空中丨展縮DCM溶離份，接著施加至spE藥筒（矽膠，〇 5 克），以（i)DCM，（ii)EtOAc及（出）氯仿：甲醇（從99: 1至高達4: 1)階式梯度溶離。合併含有所要物質之溶離份，而得實例 57(0.003 克）。LCMS 顯示 MH+= 422; TRET = 2.1 分鐘。 免例61 ·· N-苄基_4-(環戊基胺基）小甲基]Η-吡唑并[3,4-b】吡啶_5_ 甲酿胺NHR3 = HN 〇 The intermediate 22_g 'about w millimoles' in ethanol (four) liters, to triethylamine (_ml, 0.5 millimolar), followed by the towel ^ o.im Treatment with B solution (u ml solution = 〇 11 mmol). The mixture was heated at reflux for 1 M. It is difficult to add another intermediate 6-ml 'undiluted' and continue heating for 24 hours. The volatiles are removed in vacuo and the residue is dissolved in DCM, then applied to the spE cartridge (aminopropyl) , 1 g), which was first dissolved in DCM and then methanol. The DCM fractions were decanted in vacuo and applied to a spE cartridge (矽, 5 g) to (i) DCM, (ii) EtOAc and (out) chloroform:methanol (from 99:1 up to 4: 1) Step gradient elution. The fractions containing the desired material were combined to give Example 57 (0.003 g). LCMS showed MH+ = 422; TRET = 2.1 min. Free of Example 61 ·········································

87841-960303-nfJ.doc -203 - 1283678 將中間物28(0.03克，(U毫莫耳)在乙醇(ι毫升)中之溶液以 環戊胺之0.1M含乙醇溶液（u毫升溶液= 〇ιι毫莫耳）處理。 然後添加三乙胺_毫升，〇.5毫莫耳），並將混合物於回流 (85。〇及氮氣下加熱124今接著添加另—份環戊胺(議9毫 升’未經稀釋），並再持續加熱36小時。在真空中濃縮混合 物，並以氯仿處理殘留物。藉過遽收集少量不溶性物質’ 然後將濾液施加至SPE藥筒（胺基丙基，1克），將其首先以 觀，接著以f醇溶離。合併含有所要物質之溶離份，而 得實例Μ (〇.〇39克）。LCMS顯示廳+= MO ; Tret = 2別分鐘。 以類似方式製備下列物質··87841-960303-nfJ.doc -203 - 1283678 A solution of intermediate 28 (0.03 g, (U millimolar) in ethanol (1 ml) with a solution of cyclopentylamine in 0.1 M ethanol (u ml solution = 〇 Then, add triethylamine _ml, 〇.5 mM), and the mixture is heated under reflux (85 〇 and under nitrogen), then add another portion of cyclopentylamine (9 ml) 'Undiluted' and heating for an additional 36 hours. Concentrate the mixture in vacuo and treat the residue with chloroform. Collect a small amount of insoluble material by hydrazine' and then apply the filtrate to the SPE cartridge (aminopropyl, 1 g ), which is first viewed in a view, followed by elution with the f alcohol. The dissolved fractions containing the desired material are combined to give an example Μ (〇.〇 39 g). LCMS shows hall += MO; Tret = 2 minutes. In a similar manner Prepare the following substances··

NR4R5 NHR3 起始 物質 胺試劑 ΜΗ+ 離子 Tret (分鐘） 實例 62 HN^〇 ηνΟ 中間物28 環己胺 364 3.05 實例 63 HNXi ηνΓ&quot; ΗΝ·~^ )〇 中間物28 4·胺基四氫 喊喃 366 2.52 實例 64 ΗΝ. -——— 中間物30 環戊胺 344 3.06 實例 65 ηνΙ~ '— ηνΌ 中間物30 環己胺 358 3.23 實例 66 ην~Ό 中間物30 1----- 4_胺基四氫 旅喃 360 2.69 87841-96〇3〇3·中.doc -204 - 1283678 實例 67 F HNO 中間物29 環戊胺 354 3.17 實例 68 ΗΝ—^^κ-F hnhO 中間物29 環己胺 368 3.33 實例 69 HN—F hnO 中間物29 4-胺基四氫 旅喃 370 2.72 實例 70 nh2 中間物31 環戊胺 260 2.10 實例 71 nh2 中間物31 環己胺 274 2.29 實例 72 nh2 hnO 中間物31 4-胺基四氫 喊喃 276 1.86 實例74 : 4-[(1_乙醯基六氫吡啶冰基）胺基]苄基小甲基-1H-吡 唑并[3,4-b]吡啶-5_甲醯胺NR4R5 NHR3 Starting material Amine reagent ΜΗ+ Ion Tret (minutes) Example 62 HN^〇ηνΟ Intermediate 28 Cyclohexylamine 364 3.05 Example 63 HNXi ηνΓ&quot; ΗΝ·~^ ) 〇Intermediate 28 4·Amino tetrahydron 366 2.52 Example 64 ΗΝ. -——— Intermediate 30 Cyclopentylamine 344 3.06 Example 65 ηνΙ~ '- ηνΌ Intermediate 30 Cyclohexylamine 358 3.23 Example 66 ην~Ό Intermediate 30 1----- 4_amine Base tetrahydrogenethane 360 2.69 87841-96〇3〇3·中.doc -204 - 1283678 Example 67 F HNO Intermediate 29 cyclopentylamine 354 3.17 Example 68 ΗΝ—^^κ-F hnhO Intermediate 29 Cyclohexylamine 368 3.33 Example 69 HN-F hnO Intermediate 29 4-Aminotetrahydro brigade 370 2.72 Example 70 nh2 Intermediate 31 Cyclopentylamine 260 2.10 Example 71 nh2 Intermediate 31 Cyclohexylamine 274 2.29 Example 72 nh2 hnO Intermediate 31 4-Aminotetrahydropyrene 276 1.86 Example 74: 4-[(1_Ethyl hexahydropyridyl) yl]benzyl small methyl-1H-pyrazolo[3,4-b]pyridine -5_Metamine

其中I NR4R5 = NHR3 =Where I NR4R5 = NHR3 =

將中間物28 (0.03克，0·1毫莫耳）在乙醇（1毫升）中之溶液， 以中間物6之0_1M含乙醇溶液（U毫升溶液=011毫莫耳）處 理。然後添加三乙胺（0.07毫升，〇.5毫莫耳），並將混合物於 回流（85°C )及氮氣下加熱12小時。接著添加另一份中間物 6 (0.1毫莫耳），並再持續加熱36小時。使混合物於真空中濃 87841-96〇3〇3_ 中.doc -205 - 1283678 縮，並以氯仿處理殘留物。藉過濾收集少量不溶性物質， 然後將濾液施加至SI&gt;E藥筒（胺基丙基，丨克），將其首先以 DCM，接著以甲醇溶離。將含有所要物質之溶離份合併， 並於真空中濃縮。使殘留物進一步藉spE (矽膠，〇·5克）純 化以⑴DCM，⑼乳仿，（iii) EtOAc及（iv)氯仿：甲醇（從99 : 1至 同達4 · 1)之階式梯度溶離。合併含有所要物質之溶離份， 而得實例74(0.029克）。LCMS顯示mh+^術；Tret = 2 57分 鐘。 以類似方式製備下列物質：A solution of Intermediate 28 (0.03 g, 0.1 mmol) in ethanol (1 mL) was taken and taken from &lt;RTI ID=0.0&gt;&gt; Then triethylamine (0.07 ml, 〇. 5 mmol) was added, and the mixture was heated under reflux (85 ° C) and nitrogen for 12 hr. An additional intermediate 6 (0.1 mmol) was then added and heating was continued for an additional 36 hours. The mixture was concentrated in a vacuum of 87841-96 〇 3 〇 3 _ doc - 205 - 1283 678 and the residue was treated with chloroform. A small amount of insoluble material was collected by filtration, and then the filtrate was applied to a SI&gt;E cartridge (aminopropyl, gram) which was first dissolved in DCM followed by methanol. The fractions containing the desired material were combined and concentrated in vacuo. The residue was further purified by step-wise gradient elution of (1) DCM, (9) milk, (iii) EtOAc and (iv) chloroform:methanol (from 99:1 to the same 4·1). . The fractions containing the desired material were combined to give Example 74 (0.029 g). LCMS showed mh+^ surgery; Tret = 2 57 minutes. The following materials were prepared in a similar manner:

nr4r5 hn、 NHR3 起始 物質 胺試劑 MH+ 離子 Tret (分鐘） 實例 76 HN—^ 中間物30 中間物6 401 2.74 實例 78 hn^C3~~f 中間物29 中間物6 411 2.69 實羞· 1-乙基各甲基冬(四氫_2H-略喃-4-基胺基）-1Η-吡咬并 [3,4-b]吡啶_5_甲醯胺Nr4r5 hn, NHR3 starting material amine reagent MH+ ion Tret (minutes) Example 76 HN—^ Intermediate 30 Intermediate 6 401 2.74 Example 78 hn^C3~~f Intermediate 29 Intermediate 6 411 2.69 Really Shame·1-B Methyl methyl winter (tetrahydro-2H-chloropyran-4-ylamino)-1Η-pyrido[3,4-b]pyridine-5-carbamide

實例 81 NR4R5 = NHMe 87841-960303-中.doc •206· 1283678 於中間物33(0·025克，約㈣至_毫莫耳）在氯仿（2毫幻 中《經攪拌懸浮液内，$加二氯化亞硫醯_5毫升），並將 混合物於室溫下攪拌丨小時。使混合物冷卻至〇χ：，並添加 甲胺（在THF中之2M溶液，〇·69毫升=U8毫莫耳）。返回室溫 後，將混合物再攪拌丨小時，然後藉由添加水（4毫升）使反 應淬滅，並分離液層。使有機層濃縮，接著施加至spE藥筒 (矽膠，1 克），將其以（i)DCM，⑼ Et2〇(2: 1}，㈣ Et〇Ac，㈣Example 81 NR4R5 = NHMe 87841-960303-中.doc • 206· 1283678 in the intermediate 33 (0·025 g, approx. (4) to _mole) in chloroform (2 mAh in the stirred suspension, $plus Thionine ruthenium chloride (5 ml), and the mixture was stirred at room temperature for a few hours. The mixture was cooled to hydrazine: and methylamine (2M solution in THF, EtOAc &lt;RTI ID=0.0&gt; After returning to room temperature, the mixture was stirred for an additional hour, then the reaction was quenched by the addition of water (4 mL) and the layers were separated. The organic layer was concentrated and then applied to a spE cartridge (silicone, 1 g), which was (i) DCM, (9) Et2 (2: 1}, (iv) Et〇Ac, (d)

MeOH : EtOAc(l : 9)溶離。合併含有所要物質之溶離份，而 仔實例81(0.019克）。1^^18顯示1^111+=304;1^£；1^=2.19分鐘。 以類似方式製備下列物質：MeOH : EtOAc (1:9) was dissolved. The fractions containing the desired material were combined and Example 81 (0.019 g) was obtained. 1^^18 shows 1^111+=304; 1^£;1^=2.19 minutes. The following materials were prepared in a similar manner:

nr4r5 胺試劑 MH+ 離子 Tret (分鐘） 實例82 NMe2 二甲胺(2M，在THF中） 318 2.06 實例83 NHEt 乙胺（2M，在THF中） 318 2.31 實例84 NHiPr 異丙胺（2M，在THF中） 332 2.44 f例83 : N，l-二乙基-4-(四氫-2H-哌喃-4_基胺基）-1Η_吡唑并[3,4-b]吡啶_5_甲醯胺；亦被稱為1-乙基-N_乙基-4-(四氫-2H·哌喃_4_ 基胺基）-1Η_吡唑并[3,4_b]吡啶-5-甲醯胺 87841-960303-ψ.άοο -207- 1283678Nr4r5 amine reagent MH+ ion Tret (minutes) Example 82 NMe2 dimethylamine (2M in THF) 318 2.06 Example 83 NHEt ethylamine (2M in THF) 318 2.31 Example 84 NHiPr isopropylamine (2M in THF) 332 2.44 f Example 83: N,l-diethyl-4-(tetrahydro-2H-piperidin-4-ylamino)-1Η-pyrazolo[3,4-b]pyridine_5_ formazan Amine; also known as 1-ethyl-N-ethyl-4-(tetrahydro-2H.piperidin-4-ylamino)-1Η-pyrazolo[3,4_b]pyridine-5-carboxamide 87841-960303-ψ.άοο -207- 1283678

在一項關於上述實例81-84方法之替代具體實施例中，實例 83可根據下述方法製成：將中間物33 (3 〇克，1〇·33毫莫 耳）、EDC(2.25 克，11.7 毫莫耳）及 ΗΟΒΤ(1·68 克，12.4 毫莫耳） 之混合物於室溫下攪拌1小時。添加乙胺（6·2毫升，12_4毫莫 耳，在THF中之2Μ-溶液），並在室溫下持續攪拌22小時。於 真空中移除溶劑，並使殘留固體溶於氯仿（250毫升）中，且 連續以水（70毫升）與5% -碳酸氫鈉溶液（70毫升）洗滌。以無 水硫酸鈉脫水乾燥後，使有機溶液在真空中蒸發，獲得淡 橘色固體（4·15克）。使此固體溶於二氯甲烷（15毫升）與氣仿 (5毫升）之混合物中，並藉管柱層析（Biotage，矽膠，100克） 純化，首先以EtOAc·環己烷（2 : 1)，且最後以純EtOAc溶離。 將含有產物之溶離份合併，並蒸發，而得實例83，為淡黃 色固體（3.05 克）。LCMS 顯示 MH+=318 ; Tret=2.33 分鐘。 ^NMR (400 MHz 在 d6-DMSO 中，27 °C，（5 ppm) 9.76 (d，1H) 8.35 (s，1H) 7.94 (s， 1H) 5.99 (br m，1H) 4.47 (q，2H) 4.16-4.01 (m，s，3H) 3.62 (m， 2H) 3.48 (m，2H) 2.13 (m，2H) 1.77 (m，2H) 1·49 (t，3H) 1.28 (t，3H)· 實例85 : N-苄基-1-乙基-4-[(3S)-四氫呋喃_3-基胺基]_1H-吡唑并 [3,4_b]吡啶-5-甲醯胺 87841-960303-中.doc -208 - 1283678In an alternative embodiment to the above examples 81-84, Example 83 can be made according to the following method: intermediate 33 (3 gram, 1 〇 33 millimoles), EDC (2.25 gram, A mixture of 11.7 millimoles) and hydrazine (1. 68 grams, 12.4 millimoles) was stirred at room temperature for 1 hour. Ethylamine (6.2 ml, 12_4 mmol, 2 Μ in THF) was added and stirring was continued at room temperature for 22 hours. The solvent was removed in vacuo and the residual solid was dissolved in chloroform (250 mL). After dehydration and drying with anhydrous sodium sulfate, the organic solution was evaporated in vacuo to give a pale orange solid (4·15 g). This solid was dissolved in a mixture of dichloromethane (15 mL) and EtOAc (5 mL). ) and finally dissolved in pure EtOAc. The product-containing fractions were combined and evaporated to give a crystallite. LCMS showed MH+ = 318; Tret = 2.33 min. ^NMR (400 MHz in d6-DMSO, 27 °C, (5 ppm) 9.76 (d,1H) 8.35 (s,1H) 7.94 (s, 1H) 5.99 (br m,1H) 4.47 (q,2H) 4.16-4.01 (m, s, 3H) 3.62 (m, 2H) 3.48 (m, 2H) 2.13 (m, 2H) 1.77 (m, 2H) 1·49 (t, 3H) 1.28 (t, 3H)· Example 85 : N-benzyl-1-ethyl-4-[(3S)-tetrahydrofuran-3-ylamino]_1H-pyrazolo[3,4_b]pyridine-5-carboxamide 87841-960303-中. Doc -208 - 1283678

使中間物41 (0.017克，0.062毫莫耳）溶於DMF (2毫升）中，然 後以HATU (0.023克），接著以二異丙基乙胺（0·021毫升）處理， 並將混合物攪拌10分鐘。接著添加苄胺（0.007毫升），並再持 續攪拌64小時。在真空中濃縮混合物，並使殘留物溶於 DCM (1.5毫升）中，然後以飽和碳酸氫鈉水溶液（1.5毫升）處 理。將此混合物攪拌30分鐘，接著分離液層，並將有機層 施加至SPE藥筒（矽膠，1克），將其相繼以醋酸乙酯：環己 烷梯度液（1 ·· 4,然後1 : 2, 1 : 1，2 : 1及1 : 0)溶離。在真空中 濃縮含有所要物質之溶離份，而得實例85 (0.017克）。LCMS 顯示 MH+=366; Tret = 2.80 分鐘。 以類似方式製備下列物質：Intermediate 41 (0.017 g, 0.062 mmol) was dissolved in DMF (2 mL) then EtOAc (EtOAc: EtOAc) 10 minutes. Then benzylamine (0.007 ml) was added and stirring was continued for a further 64 hours. The mixture was concentrated in vacuo and EtOAc EtOAc m. The mixture was stirred for 30 minutes, then the layers were separated and the organic layer was applied to a SPE cartridge (tank, 1 g), which was successively taken in ethyl acetate: cyclohexane gradient (1 ··4, then 1: 2, 1 : 1, 2 : 1 and 1: 0) Dissolution. The fractions containing the desired material were concentrated in vacuo to give Example 85 (0.017 g). LCMS showed MH+ = 366; Tret = 2.80 min. The following materials were prepared in a similar manner:

87841-960303-中.doc -209 - 1283678 NHR3 起始物質 子 Tre τ (分鐘） 實例86 中間物42 366 2.80 實例87 ΝΗ 中間物44 382 3.11 實例88 ^ΝΗ LJM —----- 中間物45 336 3.00 實例89 ΠΙΝ^ XX 0 中間物46 414 2.69 實例90 hM0&lt; 中間物47 428 2.75 i·例91 : N-苄基士乙基_4_(四氫·2Η_硫代哌喃_4_基胺基）_1H-吡 唑并[3,4_b]吡啶_5_甲醯胺87841-960303-中.doc -209 - 1283678 NHR3 Starting material Tre τ (minutes) Example 86 Intermediate 42 366 2.80 Example 87 中间 Intermediate 44 382 3.11 Example 88 ^ΝΗ LJM —----- Intermediate 45 336 3.00 Example 89 ΠΙΝ^ XX 0 Intermediate 46 414 2.69 Example 90 hM0&lt; Intermediate 47 428 2.75 i·Example 91 : N-Benzylethyl_4_(tetrahydro-2Η_thiopipene_4_yl Amino)_1H-pyrazolo[3,4_b]pyridine_5-formamide

使中間物43(0.019克）溶於DMF (2毫升）中，然後以 HATU(0.024克），接著以二異丙基乙胺（〇〇22毫升）處理，並將 混合物攪拌10分鐘。然後添加苄胺（〇 〇〇7毫升），並再持續攪 拌64小時。在真空中濃縮混合物，並使殘留物溶於DCM (15 毫升）中’接著以飽和碳酸氫鈉水溶液（丨.5毫升）處理。此將 混合物攪拌30分鐘，然後分離液層，並將有機層施加至SpE 藥筒（梦膠，1克），將其相繼以醋酸乙酯：環己烷梯度液 (1 : 4,然後1 : 2, 1 : 1及1 ·· 〇)溶離。在真空中濃縮含有所要 物質之溶離份，而得實例91 (0·〇23克）。LCMS顯示MH+= 396 ; Tret= 3.26 分鐘。 兔例92 :[乙基氟苯基）-4_[(3S)-四氫呋喃-3-基胺基】-1H-吡 -210- 87841-960303-cjn,doc 1283678 唑并[3,4七]吡啶_5_甲醯胺Intermediate 43 (0.019 g) was dissolved in DMF (2 mL) thenEtOAc (EtOAc) Then benzylamine (7 ml) was added and stirring was continued for another 64 hours. The mixture was concentrated in EtOAc (EtOAc m. This mixture was stirred for 30 minutes, then the layers were separated, and the organic layer was applied to a SpE cartridge (m.m., 1 g), which was successively taken in ethyl acetate: cyclohexane gradient (1:4, then 1: 2, 1 : 1 and 1 ·· 〇) Dissolution. The fractions containing the desired material were concentrated in vacuo to give Example 91 (0·23 g). LCMS showed MH+ = 396; Tret = 3.26 min. Rabbit Example 92: [Ethylfluorophenyl]-4_[(3S)-tetrahydrofuran-3-ylamino]-1H-pyridyl-210- 87841-960303-cjn, doc 1283678 oxazo[3,4-7]pyridine _5_Metamine

使中間物41(0.017克）溶於DMF(2毫升）中，然後以 HATU(0.023克），接著以二異丙基乙胺（〇〇21毫升）處理，並將 混合物攪拌10分鐘。接著添加4_氟苯胺（〇 〇〇6毫升），並再持 續攪拌64小時。在真空中濃縮混合物，並使殘留物溶於 DCM (1.5耄升）中，然後以飽和碳酸氫鈉水溶液（15毫升）處 理。將此混合物攪拌3〇分鐘，接著分離液層，並使有機層 於真空中濃縮。使粗製混合物藉質量導引之自預備HPLC純 化，而得實例 92 (0.013 克）。LCMS 顯示 ΜΗ+=370 ; Tret=2.91 分鐘。 以類似方式製備下列物質：Intermediate 41 (0.017 g) was dissolved in DMF (2 mL) thenEtOAc (EtOAc:EtOAc) Then, 4-fluoroaniline (〇6 ml) was added, and stirring was continued for another 64 hours. The mixture was concentrated in vacuo and EtOAc EtOAc m. The mixture was stirred for 3 minutes, then the layers were separated and the organic layer was concentrated in vacuo. The crude mixture was purified by preparative HPLC by mass guidance to give Example 92 (0.013 g). LCMS showed ΜΗ+=370; Tret=2.91 min. The following materials were prepared in a similar manner:

87841-96〇3〇3·中.doc -211 · 1283678 NHR3 起始物質 ΜΗ+離子 Tret (分鐘） 實例93 實例94 實例9S 實例96 貫例97 ---^ NH 中間物42 370 2.91 ηνΌ 中間物43 400 -----— 3.37 中間物44 386 3.27 Λ. \ΝΗ 中間物45 340 3.21 ΗΝ、 η 中間物46 418 2.80 實例98 -- ηνΚ^Χ 中間物47 432 &quot;----- 2.84 實例99 於所有實例22至98中’在下式I之4-胺基5·甲醯 ----- --——1 胺實例已從 4_氯基衍生物合成之情況下，則替代之最後步驟合成係如下 述：87841-96〇3〇3·中.doc -211 · 1283678 NHR3 Starting material ΜΗ+ion Tret (minutes) Example 93 Example 94 Example 9S Example 96 Example 97 ---^ NH Intermediate 42 370 2.91 ηνΌ Intermediate 43 400 ----- 3.37 Intermediate 44 386 3.27 Λ. \ΝΗ Intermediate 45 340 3.21 ΗΝ, η Intermediate 46 418 2.80 Example 98 -- ηνΚ^Χ Intermediate 47 432 &quot;----- 2.84 Example 99 In all of Examples 22 to 98, in the case where the 4-amino-5-carbamyl-------1 amine of the following formula I has been synthesized from a 4-chloro derivative, The final step of synthesis is as follows:

使上文式IV中間物（Q1毫莫耳）溶於乙腈Q毫升）中。添加 式R^NH2胺（0.U笔莫耳，u莫耳當量）與略二異❻基乙胺 (笔莫耳’ 5莫耳當量），並將混合物於氮氣及饥下擾摔 J寺在真二中〉辰縮後，使殘留物於二氯甲烷（DCM)與水 (間作刀液處理。分離液層，並使有機層在真空中濃縮， 而得式I之實例。 實例100 -212- 87841-96〇3〇3_ 中.doc 1283678The intermediate of formula IV above (Q1 millimolar) was dissolved in acetonitrile (Q mL). Add R^NH2 amine (0.U penmoule, u molar equivalent) and slightly diisodecylethylamine (pen Moer '5 molar equivalent), and mix the mixture under nitrogen and hunger After the reduction in the true two, the residue was treated with dichloromethane (DCM) and water (intermediate with a knife solution. The liquid layer was separated and the organic layer was concentrated in vacuo to give an example of formula I. Example 100 -212- 87841-96〇3〇3_ Medium.doc 1283678

使中間物33 (0.048毫莫耳）溶於DMF (0.5毫升）中，然後以 HATU (0.048毫莫耳），接著以二異丙基乙胺（0.096毫莫耳）處 理，並將混合物攪拌10分鐘。接著添加4-甲磺醯基苄胺 (0.052毫莫耳，可得自Acros有機物質），並再持續攪拌16小 時。於真空中濃縮混合物。使粗製混合物藉質量導引之自 預備HPLC純化，而得實例100(0.013克）。LCMS顯示 MH+ = 458 ; TRET= 2.22 分鐘。 下列化合物係以類似方式製成，但以相同或類似莫耳數之 另一種胺R4R5NH置換4-甲磺醯基芊胺：Intermediate 33 (0.048 mmol) was dissolved in DMF (0.5 mL) then treated with HATU (0.048 mmol) followed by diisopropylethylamine (0.096 m) and mixture was stirred 10 minute. Next, 4-methanesulfonylbenzylamine (0.052 mmol, available from Acros organic) was added and stirring was continued for an additional 16 hours. The mixture was concentrated in vacuo. The crude mixture was purified by preparative HPLC eluting with mass to give Example 100 (0.013 g). LCMS showed MH+ = 458; TRET = 2.22 min. The following compounds were prepared in a similar manner except that the other amine, R4R5NH, of the same or similar molar number was substituted for 4-methanesulfonylguanamine:

87841·96〇3〇3·中.doc -213 - 1283678 NR4R5(連 結R4與R5 至-CO-吡 唑并-吡啶 部份基困 之N原子係 被劃底線） r4r5nh 之來源 起始 物質 MH+ 離子 Tret (分鐘） 實例101 CX/N °VCH3 Th36 CH3 AstaTech 公司 8301 Torresdale Ave. 19C，Philadelphia， PA，19136， USA 中間物33 487 2.29 實例102 /、、〇 J. Chem. Soc.} 1945, 633 中間物33 458 2.2 實例103 C〇^F ch3 WO 98/52943 中間物33 490 2.66 實例104 J· Org· Chem” \9Ί9, 44(3)，396 中間物33 415 2.28 實例105 Seriya Khimicheskaya^ 1989, ⑺，1694 中間物33 456 2.65 實例106 H〇/^cl SALOR (Aldrich) 中間物33 458 2.32 實例107 H3C、 Maybridge化學公司 Trevillett Tintagel Cornwall PL34 0HW United Kingdom 中間物33 461 2.5 實例108 MicroChemistry-RadaPharma Shosse Entusiastov 56 Moscow, 111123 Russia 中間物33 390 2.28 實例109 MicroChemistry-RadaPharma Shosse Entusiastov 56 Moscow, 111123 Russia 中間物33 387 2.13 -214- 87841-960303-中.doc 1283678 實例110 Bulletin des Societes Chimiques Beiges， (1982)，91(2)，153 中間物33 382 1.98 實例111 ΗΝ/Χ^Ν、 &quot;XVch3 \s MicroChemistry-RadaPharma Shosse Entusiastov 56 Moscow, 111123 Russia 中間物33 401 2.14 實例112 HNn^O^〇XCH3 h3c ch3 中間物33 466 2.67 實例113 V CH3 ch3 Ultrafine(UFC 公司)， 參閱上文地址 中間物33 425 2 實例114 Austin化學公司 1565 Barclay Blvd. Buffalo Grove, IL，60089 USA 中間物33 382 2 實例115 0¾ WO 02/83624 中間物33 464 1.97 實例116 cr Fluka Chemie AG 中間物33 432 2.52 實例117 H MicroChemistry-RadaPharma Shosse Entusiastov 56 Moscow，111123 Russia 中間物33 397 1.96 實例118 0 WO 02/85860 中間物33 423 2.09 實例119 0 Butt Park公司 Braysdown Works Peasedown St. John Bath，BA2 8LL， United Kingdom 中間物33 423 2.19 實例120 N^/ Sigma 中間物33 398 1.77 實例121 y~N\ 。b US 4562184 中間物33 452 2.21 實例122 n、n// Dynamit Nobel GmbH, Germany;或 Saville Whittle Ltd (UK agents of Dynamit Nobel), Vickers Street, Manchester M40 8EF, United Kingdom 中間物33 372 1.93 87841-960303-中.doc -215- 1283678 實例123 N^/ WO 02/66470 中間物33 385 1.93 實例124 Η υΜ3 J. Med. Chem., 1990, 33(1), 97 中間物33 447 2.17 實例125 Aldrich 中間物33 434 2.84 實例126 ^χν：； AstaTech，公司 8301 Torresdale Ave. 19C5 Philadelphia, PA，19136, USA 中間物33 473 2.5 實例127 hn^^n.s^ch3 中間物33 425 1.99 實例128 H3C/N、CH3 J. Org. Chem., 2001, 66(6), 1999 中間物33 423 1.97 實例129 ΗΝ. (|}Ν、Η3 Acros有機物 中間物33 401 1.82 實例130 〆 Aldrich 中間物33 374 2.08 實例131 idN. n Combi-Blocks 公司 7949 Silverton Av.5 Suite 915, San Diego， CA 92126, USA (亦 參閱中間物8A) 中間物33 374 2.04 實例132 〇◊、〇 J. Org· Chem,，1955, 20,1657 中間物33 487 2.39 實例133 HN. 〇1、ch3 0 J. Med. Chem., 1999, 42(14)，2504; 或變型：Lis等人·，/· Med. Chem., 1990, 33(10)，2883,參閱圖 式III參考資料24 中間物33 473 2.24 實例134 0 Tetrahedron, 1992, 48(29)，6161 中間物33 401 1.97 實例135 Aldrich 中間物33 396 2.4287841·96〇3〇3·中.doc -213 - 1283678 NR4R5 (N atomic system linked to R4 and R5 to -CO-pyrazolo-pyridine partial base is drawn to the bottom line) Source of starting material MH+ ion of r4r5nh Tret (minutes) Example 101 CX/N °VCH3 Th36 CH3 AstaTech Corporation 8301 Torresdale Ave. 19C, Philadelphia, PA, 19136, USA Intermediate 33 487 2.29 Example 102 /, 〇J. Chem. Soc.} 1945, 633 Middle Object 33 458 2.2 Example 103 C〇^F ch3 WO 98/52943 Intermediate 33 490 2.66 Example 104 J· Org·Chem” \9Ί9, 44(3), 396 Intermediate 33 415 2.28 Example 105 Seriya Khimicheskaya^ 1989, (7) , 1694 Intermediate 33 456 2.65 Example 106 H〇/^cl SALOR (Aldrich) Intermediate 33 458 2.32 Example 107 H3C, Maybridge Chemical Company Trevillett Tintagel Cornwall PL34 0HW United Kingdom Intermediate 33 461 2.5 Example 108 MicroChemistry-RadaPharma Shosse Entusiastov 56 Moscow, 111123 Russia Intermediate 33 390 2.28 Example 109 MicroChemistry-RadaPharma Shosse Entusiastov 56 Moscow, 111123 Russia Intermediate 33 387 2.13 -214- 87841-960303-中.doc 1283678 Examples 110 Bulletin des Societes Chimiques Beiges, (1982), 91(2), 153 Intermediate 33 382 1.98 Example 111 ΗΝ/Χ^Ν, &quot;XVch3 \s MicroChemistry-RadaPharma Shosse Entusiastov 56 Moscow, 111123 Russia Intermediate 33 401 2.14 Example 112 HNn^O^〇XCH3 h3c ch3 Intermediate 33 466 2.67 Example 113 V CH3 ch3 Ultrafine (UFC), see above address intermediate 33 425 2 Example 114 Austin Chemical Company 1565 Barclay Blvd. Buffalo Grove, IL, 60089 USA Intermediate 33 382 2 Example 115 03⁄4 WO 02/83624 Intermediate 33 464 1.97 Example 116 cr Fluka Chemie AG Intermediate 33 432 2.52 Example 117 H MicroChemistry-RadaPharma Shosse Entusiastov 56 Moscow, 111123 Russia Intermediate 33 397 1.96 Example 118 0 WO 02/85860 Intermediate 33 423 2.09 Example 119 0 Butt Park Braysdown Works Peasedown St. John Bath, BA2 8LL, United Kingdom Intermediate 33 423 2.19 Example 120 N^/ Sigma Intermediate 33 398 1.77 Example 121 y~N\ . b US 4562184 Intermediate 33 452 2.21 Example 122 n, n// Dynamit Nobel GmbH, Germany; or Saville Whittle Ltd (UK agents of Dynamit Nobel), Vickers Street, Manchester M40 8EF, United Kingdom Intermediate 33 372 1.93 87841-960303 - 中.doc -215-1283678 Example 123 N^/WO 02/66470 Intermediate 33 385 1.93 Example 124 Η υΜ3 J. Med. Chem., 1990, 33(1), 97 Intermediate 33 447 2.17 Example 125 Aldrich Intermediate Object 33 434 2.84 Example 126 ^χν:; AstaTech, Inc. 8301 Torresdale Ave. 19C5 Philadelphia, PA, 19136, USA Intermediate 33 473 2.5 Example 127 hn^^ns^ch3 Intermediate 33 425 1.99 Example 128 H3C/N, CH3 J. Org. Chem., 2001, 66(6), 1999 Intermediate 33 423 1.97 Example 129 ΗΝ. (|}Ν,Η3 Acros Organic Intermediate 33 401 1.82 Example 130 〆Aldrich Intermediate 33 374 2.08 Example 131 idN. n Combi-Blocks, Inc. 7949 Silverton Av. 5 Suite 915, San Diego, CA 92126, USA (see also Intermediate 8A) Intermediate 33 374 2.04 Example 132 〇◊, 〇 J. Org·Chem,, 1955, 20, 1657 Intermediate 33 487 2.39 Example 133 HN. 〇1, ch3 0 J. M Ed. Chem., 1999, 42(14), 2504; or variant: Lis et al., /. Med. Chem., 1990, 33(10), 2883, see Figure III Reference 24 Intermediate 33 473 2.24 Example 134 0 Tetrahedron, 1992, 48(29), 6161 Intermediate 33 401 1.97 Example 135 Aldrich Intermediate 33 396 2.42

87841-960303-中.doc -216- 1283678 實例136 HN. &quot;V Aldrich 中間物33 415 2.03 實例137 ch3 Aldrich 中間物33 401 1.78 實例138 Aldrich 中間物33 381 1.81 實例139 MicroChemistry-RadaPharma Shosse Entusiastov 56 Moscow, 111123 Russia 中間物33 387 1.74 實例140 CH. \ch3 Aldrich 中間物33 360 2.16 實例141 Aldrich 中間物33 401 1.81 實例142 HNv^ 0 Aldrich 中間物33 417 1.75 實例143 ldik^^〇vCH3 Aldrich 中間物33 376 2.16 實例144 Aldrich;或 Baruah 等 人，1999, 4， 409 中間物33 386 2.59 實例145 ch3 观^^n、ch3 Aldrich 中間物33 375 1.73 實例146 H3C\/CH3 M^&lt;CH3 Fluorochem 公司 Wesley Street Old Glossop Derbyshire SK13 7RY United Kingdom 中間物33 360 2.16 87841-960303-中.doc 217- 1283678 實例147 —% Aldrich;或 Acros;或 Jung等人， Tetrahedron Lett., 2002, 43(48)，8735;或Meindl 等人，J. Med. Chem., 1984, 27(9)，1111;或 Organic Lett,, 2002, 4(12)，2055 中間物33 410 2.4 實例148 Η Ό Berk Univar pic Berk House P.O.Box 56 Basing View Basingstoke Hants RG21 2E6， United Kingdom 中間物33 473 2.26 實例149 人 CH3 Η 3 Aldrich 中間物33 375 1.9 實例150 MicroChemistry-RadaPharma Shosse Entusiastov 56 Moscow, 111123 Russia 中間物33 411 1.95 實例151 h3c Array Biopharma Inc. 1885 33rd Street Boulder，CO 80301 USA 中間物33 395 1.73 實例152 ΗΝ^ If Nippon Kagaku Zasshi.^ I960, 81 p.962. 中間物33 453 1.96 實例153 Aldrich 中間物33 408 2.35 實例154 F Aldrich 中間物33 416 2.5 實例155 mJ〇^ Aldrich;或 Meindl 等人， J. Med. Chem., 1984, 27(9)，11Λ1;或 Organic Letters, 2002, 4(12), 2055 中間物33 448 2.68 218- 87841-960303-中.doc 1283678 實例156 广3 N、^ch3 AlfaAesar， A Johnson Matthey 公司 30 Bond Street Ward ΗιΙΙ,ΜΑ 01835-8099 USA 中間物33 360 2.16 實例157 V Aldrich 中間物33 330 2.04 實例158 〇 -\^nh2 Aldrich 中間物33 347 1.83 實例159 〇、ch3 Aldrich 中間物33 396 2.49 實例160 HN\ F Aldrich 中間物33 416 2.53 實例161 Aldrich 中間物33 390 2.18 實例162 Aldrich 中間物33 463 1.96 實例163 〇 ^ch3 US 4987132 中間物33 458 2.13 實例164 Aldrich 中間物33 374 2.22 實例165 Aldrich;或 TCI-America;或 Maybridge-Int. 中間物33 406 2.53 實例166 Maybridge化學公司 Trevillett Tintagel Cornwall PL34 0HW United Kingdom 中間物33 402 1.9387841-960303-中.doc-216- 1283678 Example 136 HN. &quot;V Aldrich Intermediate 33 415 2.03 Example 137 ch3 Aldrich Intermediate 33 401 1.78 Example 138 Aldrich Intermediate 33 381 1.81 Example 139 MicroChemistry-RadaPharma Shosse Entusiastov 56 Moscow , 111123 Russia Intermediate 33 387 1.74 Example 140 CH. \ch3 Aldrich Intermediate 33 360 2.16 Example 141 Aldrich Intermediate 33 401 1.81 Example 142 HNv^ 0 Aldrich Intermediate 33 417 1.75 Example 143 ldik^^〇vCH3 Aldrich Intermediate 33 376 2.16 Example 144 Aldrich; or Baruah et al., 1999, 4, 409 Intermediate 33 386 2.59 Example 145 ch3 View ^^n, ch3 Aldrich Intermediate 33 375 1.73 Example 146 H3C\/CH3 M^&lt;CH3 Fluorochem Wesley Street Old Glossop Derbyshire SK13 7RY United Kingdom Intermediate 33 360 2.16 87841-960303-中.doc 217- 1283678 Example 147 —% Aldrich; or Acros; or Jung et al, Tetrahedron Lett., 2002, 43(48), 8735; Or Meindl et al, J. Med. Chem., 1984, 27(9), 1111; or Organic Lett,, 2002, 4(12), 2055 Intermediate 33 410 2.4 Example 148 Η Ό Berk Univar pic Ber k House POBox 56 Basing View Basingstoke Hants RG21 2E6, United Kingdom Intermediate 33 473 2.26 Example 149 Human CH3 Η 3 Aldrich Intermediate 33 375 1.9 Example 150 MicroChemistry-RadaPharma Shosse Entusiastov 56 Moscow, 111123 Russia Intermediate 33 411 1.95 Example 151 H3c Array Biopharma Inc. 1885 33rd Street Boulder, CO 80301 USA Intermediate 33 395 1.73 Example 152 If^ If Nippon Kagaku Zasshi.^ I960, 81 p.962. Intermediate 33 453 1.96 Example 153 Aldrich Intermediate 33 408 2.35 Example 154 F Aldrich Intermediate 33 416 2.5 Example 155 mJ〇^ Aldrich; or Meindl et al, J. Med. Chem., 1984, 27(9), 11Λ1; or Organic Letters, 2002, 4(12), 2055 Intermediate 33 448 2.68 218- 87841-960303-中.doc 1283678 Example 156 Guang 3 N, ^ch3 AlfaAesar, A Johnson Matthey Company 30 Bond Street Ward ΗιΙΙ, ΜΑ 01835-8099 USA Intermediate 33 360 2.16 Example 157 V Aldrich Intermediate 33 330 2.04 Example 158 〇-\^nh2 Aldrich Intermediate 33 347 1.83 Example 159 〇, ch3 Aldrich Intermediate 33 396 2.49 Example 160 HN\ F Aldrich Intermediate 33 4 16 2.53 Example 161 Aldrich Intermediate 33 390 2.18 Example 162 Aldrich Intermediate 33 463 1.96 Example 163 〇^ch3 US 4987132 Intermediate 33 458 2.13 Example 164 Aldrich Intermediate 33 374 2.22 Example 165 Aldrich; or TCI-America; or Maybridge- Int. Intermediate 33 406 2.53 Example 166 Maybridge Chemical Company Trevillett Tintagel Cornwall PL34 0HW United Kingdom Intermediate 33 402 1.93

87841-960303-中.doc -219- 1283678 實例167 HN^ φι。㈣ h3c/0 Aldrich;或 Barnah 等 人，办《/价，1999, 4， 409 中間物33 440 2.3 實例168 idN^ Aldrich;或 Meindl 等 又，J· Med. Chem.， 1984, 27(9)，1111;或 Organic Letters, 2002, 4(12)，2055 中間物33 414 2.58 實例169 〇 Aldrich 中間物33 373 1.64 實例170 -^-ΟΗ Aldrich 中間物33 334 1.85 實例171 % h3c Aldrich 中間物33 465 2.29 實例172 CH3 EP 666258 中間物33 458 2.25 實例173 ?η3 -^YN-ch3 J. Chem. Soc., 1954, 1171 中間物33 389 1.98 實例174 ΗΝ-^\ /CH3 Peakdale分子公司， Peakdale Science Park, Sheffield Road, Chapel-en-le-Frith, High Peak SK23 OPQ United Kingdom 中間物33 384 1.76 實例175 Χλλ〇η3 οΛ〇 Fluorochem 公司 Wesley Street Old Glossop Derbyshire SK13 7RY United Kingdom 中間物33 459 2.36 實例176 Lancaster合成公司， Newgate, White Lund, Morecambe，Lancashire LA3 3DY，United Kingdom 中間物33 343 2.01 實例177 h3C\ Ά〇η3 ChemBridge Europe, 4 Clark’s Hill Rise, Hampton Wood， Evesham， Worcestershire WR11 6FW5 United 1 Kingdom 中間物33 400 1.92 87841-960303-中.doc -220- 1283678 實例178 Λ Ν—Ν Nch3 TimTec公司 PO Box 8941 Newark，DE，19714-8941 USA 中間物33 384 2.03 實例179 ch3 1CH NW^CH3 ChemBridge Europe, 4 Clark’s Hill Rise， Hampton Wood, Evesham， Worcestershire WR11 6FW，United Kingdom 中間物33 398 1.70 實例180 Aldrich 中間物33 400 2.41 實例181 &quot;^aCI Aldrich 中間物33 428 2.61 實例182 ^^6 Aldrich 中間物33 424 2.49 實例167 : Ν·{[3,4·雙（甲氧基）苯基】甲基}小乙基-4-(四氫_2H-哌 喃-4-基胺基）-1Η-吡唑并[3,4_b]吡啶-5_甲醯胺87841-960303-中.doc -219-1283678 Example 167 HN^ φι. (iv) h3c/0 Aldrich; or Barnah et al., “/Price, 1999, 4, 409 Intermediate 33 440 2.3 Example 168 idN^ Aldrich; or Meindl et al., J. Med. Chem., 1984, 27(9) , 1111; or Organic Letters, 2002, 4(12), 2055 Intermediate 33 414 2.58 Example 169 〇Aldrich Intermediate 33 373 1.64 Example 170 -^-ΟΗ Aldrich Intermediate 33 334 1.85 Example 171 % h3c Aldrich Intermediate 33 465 2.29 Example 172 CH3 EP 666258 Intermediate 33 458 2.25 Example 173 ?η3 -^YN-ch3 J. Chem. Soc., 1954, 1171 Intermediate 33 389 1.98 Example 174 ΗΝ-^\ /CH3 Peakdale Corporation, Peakdale Science Park , Sheffield Road, Chapel-en-le-Frith, High Peak SK23 OPQ United Kingdom Intermediate 33 384 1.76 Example 175 Χλλ〇η3 οΛ〇Fluorochem Wesley Street Old Glossop Derbyshire SK13 7RY United Kingdom Intermediate 33 459 2.36 Example 176 Lancaster Synthesis Company, Newgate, White Lund, Morecambe, Lancashire LA3 3DY, United Kingdom Intermediate 33 343 2.01 Example 177 h3C\Ά〇η3 ChemBridge Europe, 4 Clark's Hill Rise, Hampton Wood, Evesham, Worcestershire WR11 6FW5 United 1 Kingdom Intermediate 33 400 1.92 87841-960303-中.doc -220- 1283678 Example 178 Λ Ν-Ν Nch3 TimTec PO Box 8941 Newark, DE, 19714-8941 USA Intermediate 33 384 2.03 Example 179 ch3 1CH NW^CH3 ChemBridge Europe, 4 Clark's Hill Rise, Hampton Wood, Evesham, Worcestershire WR11 6FW, United Kingdom Intermediate 33 398 1.70 Example 180 Aldrich Intermediate 33 400 2.41 Example 181 &quot;^aCI Aldrich Intermediate 33 428 2.61 Example 182 ^^6 Aldrich Intermediate 33 424 2.49 Example 167: Ν·{[3,4·Bis(methoxy)phenyl]methyl}ethylethyl-4-(tetrahydro-2H-pyran-4-yl) Amino)-1Η-pyrazolo[3,4_b]pyridine-5-formamide

在一項關於上述實例100-182方法之替代具體實施例中，實 例167可根據下述方法製成： 將中間物33 (0.498克，1.72毫莫耳）、EDC (0.46克，2.41毫莫 耳）及ΗΟΒΤ(0·278克，1.68毫莫耳）之混合物於室溫下攪拌0.25 小時。添加藜蘆基胺（3,4-二甲氧基苄胺，0.31毫升，2.05毫 莫耳，可得自Aldrich或5^/时，1999, 4, 409)，並在室溫下持續攪 拌22小時。使反應混合物於Et20與水之間作分液處理。以 87841-9603〇3·中.doc -221 - 1283678In an alternative embodiment to the above examples 100-182, Example 167 can be made according to the following procedure: Intermediate 33 (0.498 g, 1.72 mmol), EDC (0.46 g, 2.41 mmol) A mixture of hydrazine (0. 278 g, 1.68 mmol) was stirred at room temperature for 0.25 hours. Add cucurbitamine (3,4-dimethoxybenzylamine, 0.31 ml, 2.05 mmol, available from Aldrich or 5^/hr, 1999, 4, 409) and continue stirring at room temperature 22 hour. The reaction mixture was partitioned between Et20 and water. To 87841-9603〇3·中.doc -221 - 1283678

Et：2 Ο年取水相’並將合併之有機相以鹽水洗滌，脫水乾燥 (MgS〇4)，及在真空中蒸發。使殘留物藉層析（Bi〇tage，矽膠 40克）純化，以EtOAc ··環己烷（2 : 1)溶離。使物質進一步藉 SPE (SCX-2，10克）純化，以甲醇，然後以甲醇中之氨（〇·5Μ) &gt;谷離。將氣甲if·落離份合併’並於真空中蒸發，而得實例 167 ’為白色泡沫物（0.633克）。LCMS顯示MH+ = 440 ; Tret = 2.65 分鐘。iH NMR(400MHz，在 CDC13 中，27°C，5 ppm) 9·78 (d，1H) 8_37 (s，1H) 7.94 (s，1H) 6.94-6.82 (m，3H) 6.29 (br m，1H) 4.56 (d，2H) 4.46 (q，2H) 4.15-4.01 (m，3H) 3.89 (s，6H) 3.63 (m，2H) 2.15 (m， 2H) 1.78 (m，2H) 1.49 (t，3H). 實&quot;例183 : 4_(環己胺基）-l-(3_乙氧基_3_酮基丙基比峻并[3,4-b]吡啶-5_羧酸乙酯Et: 2 water phase was taken in the next year' and the combined organic phases were washed with brine, dehydrated (MgS〇4), and evaporated in vacuo. The residue was purified by EtOAc (EtOAc) eluting eluting The material was further purified by SPE (SCX-2, 10 g) with methanol, then with ammonia (? 5 Μ) &gt; The gas, if, and the mixture were combined and evaporated in vacuo to give a white foam (0.633 g). LCMS showed MH+ = 440; Tret = 2.65 min. iH NMR (400MHz, in CDC13, 27°C, 5 ppm) 9·78 (d,1H) 8_37 (s,1H) 7.94 (s,1H) 6.94-6.82 (m,3H) 6.29 (br m,1H 4.56 (d,2H) 4.46 (q,2H) 4.15-4.01 (m,3H) 3.89 (s,6H) 3.63 (m,2H) 2.15 (m, 2H) 1.78 (m,2H) 1.49 (t,3H Example: 183: 4_(cyclohexylamino)-l-(3_ethoxy-3- ketopropyl-p-[3,4-b]pyridine-5-carboxylic acid ethyl ester

C〇2Et C〇2Et 將中間物48 (40毫克）、無水碳酸鉀（57毫克）及溴基丙酸 乙酯（0.027毫升）在無水DMF(i毫升）中之經激烈攪拌混合 物’於65°C下加熱過夜。濃縮反應混合物，並使殘留物於二 氣甲燒（5當升）與水（5毫升）之間作分液處理。分離液相，並 使有機相蒸發成殘留油，使其藉質量導引之自預備純 化，而得實例183 (5毫克）。LCMS顯示mh+= 389 ; T = 3 87841-960303-中.doc -222- 1283678 分鐘。 實例: 1-正-丙基-4-(四氫底喃-4-基胺基）-1Η_峨峻并[3,4-b】 吡啶-5-羧酸乙酯C〇2Et C〇2Et The mixture of intermediate 48 (40 mg), anhydrous potassium carbonate (57 mg) and ethyl bromopropionate (0.027 ml) in anhydrous DMF (1 mL) Heat at C overnight. The reaction mixture was concentrated, and the residue was partitioned between methylene chloride (5 liters) and water (5 ml). The liquid phase was separated and the organic phase was evaporated to a residual oil which was purified by preparative purification to give 183 (5 mg). LCMS showed mh+ = 389; T = 3 87841-960303 - medium .doc - 222 - 1283678 min. Example: 1-n-propyl-4-(tetrahydroendan-4-ylamino)-1Η_峨君[3,4-b]pyridine-5-carboxylic acid ethyl ester

將氫化鈉（0.067克，於油中之6〇%分散液）添加至實例 20 (0.47克）在DMF (19毫升）中之經攪拌溶液内，接著是碘化 正-丙：Μ〇·17笔升）。將混合物於抑下揽掉％小時，然後濃 縮，以氣仿（3〇毫升）稀釋，並以1: 1水：鹽水溶液（30毫升） 洗;條’刀離’及;辰縮有機層。使殘留物於弧藥筒（珍膠， H)克）上純化，以1〇毫升體積之二氣甲烷、ι: 1***：環己 燒及***/合離。使合併之丨·· i***：環己烷與***溶離份 /辰細，而4于實例185，為透明膠（0.23克）。LCMS顯示 MH+=333; TRET= 3.14 分鐘。 ^ ^ lg6 · 1-(2_經乙基）·4_(四氫_2H_哌喃-4-基胺基）-1Η-吡唑并 [3,4-b]吡啶_5_羧酸乙酯 87841·96〇3〇3·中.doc -223 - 1283678Sodium hydride (0.067 g, 6% dispersion in oil) was added to a stirred solution of Example 20 (0.47 g) in DMF (19 mL), followed by i-propyl iodide: Μ〇·17 Pen rise). The mixture was shaken off for 1 hour, then concentrated, diluted with air (3 mL) and washed with a 1:1 water: brine solution (30 mL); The residue was purified on an arc cartridge (Ji, H), hexanes, m. The combined hydrazines: diethyl ether: cyclohexane and diethyl ether were separated from the mixture, and 4 was used in Example 185 as a clear gum (0.23 g). LCMS showed MH+ = 333; TRET = 3.14 min. ^ ^ lg6 · 1-(2_Ethyl)·4_(tetrahydro-2H-piperidin-4-ylamino)-1Η-pyrazolo[3,4-b]pyridine_5_carboxylic acid B Ester 87841·96〇3〇3·中.doc -223 - 1283678

將2-溴基乙醇（0·008毫升）與2-第三_丁基亞胺基_2_二乙胺基_ 1,3_一甲基β全氫-1，3,2-二氮磷烷（經聚合體結合，2.3毫莫耳/ 克裝填量’ 0·045克），一起添加至實例20 (0.03克）在無水DMF (15毫升）中之溶液内。使混合物於23〇c下振盪16小時，然後 使溶液自樹脂流乾，並以DMF洗滌樹脂。濃縮合併之有機 物免’並使殘留物於SPE藥筒（矽膠，1克）上純化，以環己 燒中之70·1〇〇%醋酸乙酯溶離。使合併之溶離份濃縮，而得 實例186，為白色固體（o.oii克）。LCMS顯示]^+=335 ; Tret= 2.47 分鐘。 3L例187_ : N_[4-(甲績酿基）辛基]_1_正丙基_4_(四氫_2Η·旅喃-4-基 胺基）-1Η_峨吐并[3,4-b】吡啶甲醯胺2-Bromoethanol (0. 008 ml) and 2-tris-butylimido-2-diethylamino-1,3-monomethyl-β-hydrogen-1,3,2-diazo The phosphane (polymerized, 2.3 mmol/g loading &lt; 0 045 g) was added together to a solution of Example 20 (0.03 g) in dry DMF (15 mL). The mixture was shaken at 23 ° C for 16 hours, then the solution was allowed to dry from the resin, and the resin was washed with DMF. The combined organics were concentrated and the residue was purified on EtOAc EtOAc (EtOAc) The combined fractions were concentrated to give mp mp (m. LCMS showed]^+=335; Tret = 2.47 min. 3L Example 187_ : N_[4-(4-) Alkyl]_1_-n-propyl_4_(tetrahydro-2-indole·t-but-4-ylamino)-1Η_峨吐和[3,4- b]pyridine carbenamide

將中間物50 (0.03克）在DMF (1毫升）中，與DIPEA (0.035毫升） 87841-960303-中.doc -224· 1283678 及HATU(〇.〇38克）一起攪拌20分鐘。將4_(甲磺醯基）苄胺鹽酸 鹽（0.024克）添加至混合物中，並將溶液於23〇c下攪拌8小 時。濃縮溶液，並使殘留物溶於二氯甲烷（6毫升）中，然後 以飽和碳酸氫鈉溶液（6毫升）與1 :丨鹽水：水（6毫升）洗務， 藉疏水性玻料分離。使有機層濃縮，而得實例187，為白色 固體（0.039 克）。LCMS 顯示 MH+=472 ; Tret = 2.67 分鐘。 免例188 : N-(4-氟苯基)-1-正·丙基(四氫-2H_^喃-4-基胺基)_ lH-Ptb峻并[3,4-b]p比淀-S·甲酿胺Intermediate 50 (0.03 g) was stirred in DMF (1 mL) with DIPEA (0.035 mL) &lt;RTI ID=0.0&gt;&gt;&gt; 4_(Methanesulfonyl)benzylamine hydrochloride (0.024 g) was added to the mixture, and the solution was stirred at 23 ° C for 8 hours. The solution was concentrated, and the residue was evaporated mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj The organic layer was concentrated to give 187 (m. LCMS showed MH+ = 472; Tret = 2.67 min. 188: N-(4-Fluorophenyl)-1-n-propyl (tetrahydro-2H-(pyridin-4-ylamino)- lH-Ptb s[3,4-b]p -S·Artemisamine

合成方法係按實例187中所述，惟替代4-(甲磺醯基）爷胺鹽 酸鹽，將4-氟苯胺（0.01毫升）添加至混合物中。所形成產物 需要進一步純化，其係藉由質量導引之自預備HPLC進行， 獲得實例1S8，為透明膠（0.〇3克）。LCMS顯示MH+=398 ; Tret= 3.13 分鐘。 會例189 : 1-乙基_6_甲基-4-(四氫_2H-哌喃-4_基胺基）-iH-吡唑并 [3,4-b】吡啶-5·羧酸乙酯 87841-960303-中.doc -225- 1283678 αThe synthesis was carried out as described in Example 187 except that 4-(methylsulfonyl)myramine hydrochloride was added and 4-fluoroaniline (0.01 mL) was added to the mixture. The product formed required further purification by mass-directed preparative HPLC to give Example 1S8 as a clear gum (0. 〇 3 g). LCMS showed MH+ = 398; Tret = 3.13 min. EXAMPLE 189: 1-Ethyl_6-methyl-4-(tetrahydro-2H-piperidin-4-ylamino)-iH-pyrazolo[3,4-b]pyridine-5.carboxylic acid Ethyl ester 87841-960303-中.doc -225-1283678 α

、將4_胺基四氫哌喃鹽酸鹽（中間物8Α，0.413克，3.0毫莫 耳）添加至中間物51 (().268克，㈣莫耳）與n，n-二異丙基乙 胺（0.87毫升5.0毫莫耳）在乙腈(3毫升）中之混合物内。將所形 成之此&amp;物於85 C下加熱24小時。在真空中移除揮發性物 質，並使殘留物溶於氯仿（1.5毫升）中，及施加至spE藥筒 (珍膠’ 5克）。將藥筒連續以％〇、Et〇Ac及(9八） 溶離。將含有所要產物之溶離份合併，並於真空中濃縮， 而得所要之產物，受起始物質（中間物51)污染。使用SPE藥 筒（矽膠，5克）進一步純化，以醋酸乙酯_環己烷（1/3)溶離， 獲得實例 189(0.248 克）。LCMS 顯示 MH+=333 ; Tret=2.75 分 鐘。 兔例190 : 4-(環己胺基）-1_乙基-6-甲基-1H_吡唑并[3,4七】吡啶冬 羧酸乙酯Add 4-aminotetrahydropyran hydrochloride (intermediate 8 Α, 0.413 g, 3.0 mmol) to intermediate 51 ((). 268 g, (d) Mo) and n, n-diisopropyl Ethylethylamine (0.87 ml 5.0 mmol) in a mixture of acetonitrile (3 mL). The &amp; formed material was heated at 85 C for 24 hours. The volatiles were removed in vacuo and the residue dissolved in chloroform (1. 5 mL) and applied to spE cartridge (5 g). The cartridge was continuously dissolved in % 〇, Et 〇 Ac and (9). The fractions containing the desired product are combined and concentrated in vacuo to give the desired material which is eluted from starting material (intermediate 51). Further purification was carried out using an SPE cartridge (yellow gel, 5 g), eluting with ethyl acetate-cyclohexane (1/3) to give the Example 189 (0.248 g). LCMS showed MH+ = 333; Tret = 2.75 min. Rabbit Example 190: 4-(cyclohexylamino)-1_ethyl-6-methyl-1H-pyrazolo[3,4-7]pyridine winter carboxylic acid ethyl ester

將環己胺（O.H9克’ 1.5毫莫耳）添加至中間物51 (0.201克， 87841_96〇3〇3·中.doc -226- 1283678 〇·75毫莫耳）與N，N-二異丙基乙胺（〇·65毫升，3.73毫莫耳）在乙 腈（3毫升）中之混合物内。將所形成之混合物於8yc下加熱 40小時。在真空中移除揮發性物質，並使殘留物溶於氣仿 (1.5毫升）中，及施加至SpE藥筒（矽膠，5克以Et2〇、 EtOAc及MeOH連續溶離藥筒。將含有所要產物之溶離份合 併，並在真空中濃縮，而得實例19〇 (0j28克）。LCMS顯示 K4H 331 ’ Treτ = 3·64 分鐘。 [例191 : 4_(環己胺基乙基·6-曱基_Ν-[4-(甲磺醯基）爷基】_1Η-ρ比哇并[3,4-b]外1;淀_5_甲酿胺Add cyclohexylamine (O.H9 g '1.5 mmol) to Intermediate 51 (0.201 g, 87841_96〇3〇3·中.doc -226-1283678 〇·75 mmol) and N,N-II Isopropylethylamine (〇·65 ml, 3.73 mmol) in a mixture of acetonitrile (3 mL). The resulting mixture was heated at 8 yc for 40 hours. The volatiles were removed in vacuo and the residue was taken up in EtOAc (1 mL) and applied to a SpE cartridge (5 g of EtOAc, EtOAc and MeOH). The solute fractions were combined and concentrated in vacuo to give EtOAc (EtOAc: EtOAc). _Ν-[4-(Methanesulfonyl) aryl] Η Η-ρ than wow [3,4-b] outside 1; _____

使中間物 52(0.014 克，0.046 毫莫耳）、HATU (0.018 克，0.048 毫莫耳）及DIPEA (0.022毫升，0.125毫莫耳）在DMF (1毫升）中 之混合物，於室溫下振盪1〇分鐘。然後添加（甲磺醯基） 苯基]甲胺（0.009克，0.046毫莫耳），並使混合物振盪數分 鐘’獲得溶液。將此溶液在室溫下儲存16小時。在真空中 濃縮溶液，並使殘留物溶於氣仿（0 5毫升）中，及施加至SPE 藥筒（胺基丙基，0·5克）。將藥筒連續以氯仿（1·5毫升）、 EtOAc(1.5毫升）及EtOAoMeOH(9: 1，υ毫升）溶離。於真空 中濃縮含有所要產物之溶離份，而得實例191 (〇 〇〇5克）。 87841-960303-中.doc -227- 1283678 LCMS 顯示 MH+=470; Tret=2.54 分鐘。 實例192 : N_苄基-4-(環己胺基）-1-乙基_6-甲基_1H-吡唑并[3,4_b] 吡啶-5_甲醯胺A mixture of intermediate 52 (0.014 g, 0.046 mmol), HATU (0.018 g, 0.048 mmol) and DIPEA (0.022 mL, 0.125 mmol) in DMF (1 mL). 1 minute. Then (methanesulfonyl)phenyl]methylamine (0.009 g, 0.046 mmol) was added and the mixture was shaken for a few minutes to obtain a solution. This solution was stored at room temperature for 16 hours. The solution was concentrated in vacuo and the residue was taken in EtOAc (EtOAc)EtOAc. The cartridge was continuously dissolved in chloroform (1.5 mL), EtOAc (1.5 mL) and Et. The fractions containing the desired product were concentrated in vacuo to give Example 191 (5 g). 87841-960303-中.doc -227- 1283678 LCMS shows MH+=470; Tret=2.54 min. Example 192: N-benzyl-4-(cyclohexylamino)-1-ethyl-6-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide

實例192係使用類似實例191之方法，製自中間物52。 LCMS 顯示 MH+=392: Tret = 2.43· 實例193 : 4-(環己胺基）-1乙基_Ν·(4-氟苯基）·6_甲基_1H_吡唑并 [3,4_b】吡啶-5-甲醯胺Example 192 was prepared from Intermediate 52 using a procedure analogous to Example 191. LCMS showed MH+ = 392: Tret = 2.43. Example 193: 4-(cyclohexylamino)-1 ethyl hydrazide (4-fluorophenyl)·6-methyl-1H-pyrazolo[3,4_b Pyridine-5-carboxamide

實例193係使用類似實例191之方法，製自中間物52。 LCMS 顯示 MH+=396; Tret = 2.6 分鐘。 實例194 : 4-(環己胺基）_1_乙基-6-甲基-Ν-[4·(三氟曱基）爷基】-1H· 吡唑并[3,4-b]吡啶-5-甲醯胺 87841-960303-中.doc -228- 1283678Example 193 was prepared from Intermediate 52 using a procedure analogous to Example 191. LCMS showed MH+ = 396; Tret = 2.6 min. Example 194: 4-(cyclohexylamino)_1-ethyl-6-methyl-indole-[4.(trifluoromethyl)-yl-1H-pyrazolo[3,4-b]pyridine- 5-carbamamine 87841-960303-中.doc -228- 1283678

實例194係使用類似實例191之方法，製自中間物52。 LCMS 顯示 MH+ = 460; Tret=2.74 分鐘。 實例195 : 4-(環己胺基）_N-(2,3-二氫-1H-茚-2-基）小乙基-6-曱基· 1H-吡唑并[3,4-b]吡啶_5·曱醯胺Example 194 was prepared from Intermediate 52 using a procedure analogous to Example 191. LCMS showed MH+ = 460; Tret = 2.74 min. Example 195: 4-(Cyclohexylamino)-N-(2,3-dihydro-1H-indol-2-yl)succinylethyl-6-fluorenyl-1H-pyrazolo[3,4-b] Pyridine _5·guanamine

實例195係使用類似實例191之方法，製自中間物52。 LCMS 顯示 MH+ = 418; Tret=2.55 分鐘。 實例196 : N_苄基_1_乙基-6-甲基-4-(四氫-2H-哌喃-4-基胺基）_1H-吡唑并[3,4-b]吡啶-5-甲醯胺Example 195 was prepared from Intermediate 52 using a procedure analogous to Example 191. LCMS showed MH+ = 418; Tret = 2.55 min. Example 196: N-Benzyl_1-ethyl-6-methyl-4-(tetrahydro-2H-piperidin-4-ylamino)_1H-pyrazolo[3,4-b]pyridine-5 -Procarbamide

實例196係使用類似實例191之方法，製自中間物53。 87841-96〇3〇3_ 中.doc -229- 1283678 LCMS 顯示MH+=394; Tret = 2.02 分鐘。 t例197 : N-苄基小乙基-4-[(2-酮基一氮七圜燒-3_基）胺基]_扭_ 吡唑并[3,4-b】吡啶-5-甲醯胺Example 196 was prepared from Intermediate 53 using a procedure analogous to Example 191. 87841-96〇3〇3_中.doc -229- 1283678 LCMS shows MH+=394; Tret = 2.02 min. Example 197: N-benzylic small ethyl-4-[(2-keto-nitros-7-indole-3-yl)amino]-Twisted-pyrazolo[3,4-b]pyridine-5- Formamide

將3-胺基一氮七圜烷-2-酮（0.043克，0.335毫莫耳，可市講得 自Sigma-Aldrich公司）添加至中間物17 (0.021克，〇·067毫莫耳） 與DIPEA(0.058毫升，0.335毫莫耳）在乙腈（0·5毫升）中之混合 物内。將所形成之混合物於85°C下加熱48小時。在真空中移 除揮發性物質，並使殘留物溶於氯仿（〇·5毫升）中，及施加 至SI&gt;E藥筒（矽膠，〇.5克），將其連績以***（ι·5毫升）、醋酸 乙酯（1.5毫升）及醋酸乙酯_甲醇（9/1，15毫升）溶離。使含有 所要物質之溶離份於真空中濃縮，而得實例197_9:)。 LCMS顯示 MH+ = 407; Tret=2.81 分鐘。 下列化合物係以類似方式製成，俨 衣堞1一以相冋或類似莫耳數之 另一種胺R3NH2置換3-胺基—氮七圜烷务酮：3-Amino-adenositane-2-one (0.043 g, 0.335 mmol, commercially available from Sigma-Aldrich) was added to Intermediate 17 (0.021 g, 〇·067 mmol) and DIPEA (0.058 mL, 0.335 mmol) in acetonitrile (0.5 mL). The resulting mixture was heated at 85 ° C for 48 hours. The volatiles were removed in vacuo and the residue was dissolved in chloroform (5 mL) and applied to &lt;&lt;&gt;&gt; 5 ml), ethyl acetate (1.5 ml) and ethyl acetate-methanol (9/1, 15 ml) were dissolved. The fractions containing the desired material were concentrated in vacuo to give Example 197_9:). LCMS showed MH+ = 407; Tret = 2.81 min. The following compounds were prepared in a similar manner. The oxime 1 replaced the 3-amino-naphthyl sulphonate with another amine, R3NH2, which is equivalent to a molar number:

87841-96〇3〇3-中·doc -230- 1283678 實例 編號 NHR3 R3NH2之來源 起始物質 MH+ 離子 Tret (分鐘） 實例 198 OH hn{5 J. Chem. Soc” Perkin Trans· 1， 1994, 537 中間物17 394 2.75 實例 199 HN-/ V-OH Aldrich ;或 TCI-America 中間物17 394 2.82 實例 200 ，~cr0H US 4219660 中間物17 380 2.70 實例201 : N-苄基-1_乙基-4-[(4_酮基環己基）胺基】-1H-吡唑并[3,4· b]吡啶_5_甲醯胺87841-96〇3〇3-中·doc -230- 1283678 Example No. NHR3 Source of R3NH2 Starting material MH+ Ion Tret (minutes) Example 198 OH hn{5 J. Chem. Soc" Perkin Trans· 1, 1994, 537 Intermediate 17 394 2.75 Example 199 HN-/V-OH Aldrich; or TCI-America Intermediate 17 394 2.82 Example 200, ~cr0H US 4219660 Intermediate 17 380 2.70 Example 201: N-Benzyl-1_ethyl-4 -[(4-ketocyclohexyl)amino]-1H-pyrazolo[3,4·b]pyridine_5-formamide

將中間物54 (0.048克，0.32毫莫耳）添加至中間物17 (0.050 克，0.16毫莫耳）與DIPEA (0·17毫升，0.98毫莫耳）在乙腈（3毫 升）中之混合物内。將所形成之混合物於回流下加熱。12小 時後，將另一數量之中間物54 (0.044克，0·29毫莫耳）、 DIPEA (0.17毫升0.98毫莫耳）及乙腈（1毫升）添加至反應混合物 中，使其保持於回流下。36小時後，在真空中濃縮反應混 合物，並使殘留油溶於二氯甲烷（8毫升）中，且以5%碳酸氫 鋼溶液（2毫升）洗滌。蒸發有機溶液，獲得黏稠油，使其溶 於二氯甲烷（2毫升）中，並施加至SPE藥筒（矽膠，5克）。將 藥筒連續以醋酸乙酯-環己烷梯度液（1 : 16,然後1 : 8, 1 : 87841-960303-中.doc -231 - 1283678 4, 1 : 2, 1 : 1及1 : 0)溶離。使含有所要物質之溶離份在真空 中濃縮’而得實例201 (0.018克）。LCMS顯示MH+=392 ;Intermediate 54 (0.048 g, 0.32 mmol) was added to a mixture of intermediate 17 (0.050 g, 0.16 mmol) and DIPEA (0·17 mL, 0.98 mmol) in acetonitrile (3 mL) . The resulting mixture was heated under reflux. After 12 hours, another quantity of intermediate 54 (0.044 g, 0·29 mmol), DIPEA (0.17 mL 0.98 mmol) and acetonitrile (1 mL) were added to the reaction mixture and kept at reflux. under. After 36 hours, the reaction mixture was evaporated EtOAcjjjjjjjjj The organic solution was evaporated to give a viscous oil, which was taken in dichloromethane (2 mL) and applied to a SPE cartridge (5 g). The cartridge was continuously treated with ethyl acetate-cyclohexane gradient (1: 16, then 1:8, 1:87841-960303-medium.doc-231-1283678 4, 1 : 2, 1 : 1 and 1: 0 ) Dissolution. Example 201 (0.018 g) was obtained by concentrating the fractions containing the desired material in vacuo. LCMS showed MH+=392;

Tret =2.95 分鐘。 實例202 : 1-乙基具(2-羥基小甲基乙基）_4-(四氫_211_哌喃_4•基胺 基）_1Η_吡唑并[3,4-b]吡啶-5_甲醯胺Tret = 2.95 minutes. Example 202: 1-ethyl(2-hydroxysodiummethylethyl)-4-(tetrahydro-211-pyran-4-ylamino)_1Η-pyrazolo[3,4-b]pyridine-5 _mercaptoamine

使中間物33 (0.1克，0.34毫莫耳）、EDC (0.066克，0.34毫莫 耳）及ΗΟΒΤ (0·05克，0.37毫莫耳）懸浮於DMF (2毫升）中，並 在室溫及氮氣下攪拌15分鐘。添加2-胺基丙小醇（0.026克， 〇·34毫莫耳）與三乙胺（0.036克，0.36毫莫耳），並將混合物於 至溫及氮氣下擾掉6小時。在真空中移除溶劑，並使殘留物 於DCM與水之間作分液處理。使有機層濃縮，並施加至SPE 藥筒（胺基丙基，5克），將其以甲醇溶離。於真空中濃縮， 獲得實例 202 (0.095 克）。LCMS 顯示]VlH+= 348, TRET= 2.15 分鐘。 ^ 203 : (2S)-2-({[l-乙基_4-(四氫-2H_哌喃_4_基胺基）-1Η-吡唑并 [3,4-b]v比淀-5-基】談基}胺基)_3·趣基丙酸甲酿 -232- 87841_96〇3〇3·中 doc 1283678Intermediate 33 (0.1 g, 0.34 mmol), EDC (0.066 g, 0.34 mmol) and hydrazine (0.05 g, 0.37 mmol) were suspended in DMF (2 mL) at room temperature Stir under nitrogen for 15 minutes. 2-Aminopropanol (0.026 g, 〇·34 mmol) and triethylamine (0.036 g, 0.36 mmol) were added, and the mixture was stirred for 6 hours under warm nitrogen. The solvent was removed in vacuo and the residue was partitioned between DCM and water. The organic layer was concentrated and applied to a SPE cartridge (amine propyl, 5 g) which was eluted with methanol. Concentrate in vacuo to give Example 202 (0.095 g). LCMS showed] VlH+ = 348, TRET = 2.15 min. ^ 203 : (2S)-2-({[l-ethyl_4-(tetrahydro-2H_pyran-4-ylamino)-1Η-pyrazolo[3,4-b]v -5-基】谈基}Amino)_3·趣基丙酸甲酿-232- 87841_96〇3〇3·中 doc 1283678

X OH C02Me 反應圖式：X OH C02Me reaction pattern:

co2h 中間物33 H2N又C02Me 鹽酸鹽Co2h intermediate 33 H2N and C02Me hydrochloride

EDC, HOBT, Et3N, DMFEDC, HOBT, Et3N, DMF

使中間物33 (0_1克，0.34毫莫耳）、edc (0.066克，〇·34毫莫 耳）及HOBT (0.05克，0·37毫莫耳）懸浮於DMF (2毫升）中，並 在A &amp;及氮氣下擾摔15分鐘。添加L-絲胺酸甲目旨鹽酸鹽 (0.054克，0.34毫莫耳）與三乙胺（〇·〇36克，0.36毫莫耳），並將 混合物於室溫及氮氣下攪拌18小時。在真空中移除溶劑， 並使殘留物於DCM與水之間作分液處理。使有機層於真空 中濃縮，並施加至SPE藥筒（胺基丙基，5克），將其以甲醇 溶離。在真空中濃縮，獲得不純殘留物，使其進一步藉SPE 藥筒（矽膠，5克）純化，以醋酸乙酯，接著以5%甲醇/醋 酸乙酯溶離。使所要之溶離份於真空中濃縮，而得實例 203 (0.055 克）。1^^8顯示丽+=393;!^了 = 2.22分鐘。 實例204 :乙基1-乙基-4-[(4-羥基環己基)胺基】-1Η-吡唑并[3,4-b] 87841-960303-中.doc -233 - 1283678 吡啶-5-羧酸乙酯Intermediate 33 (0_1 g, 0.34 mmol), edc (0.066 g, 〇·34 mmol) and HOBT (0.05 g, 0·37 mmol) were suspended in DMF (2 mL) and A &amp; and nitrogen under the disturbance for 15 minutes. L-Amino acid methyl ester hydrochloride (0.054 g, 0.34 mmol) and triethylamine (36 g, 0.36 mmol) were added, and the mixture was stirred at room temperature under nitrogen for 18 hours. . The solvent was removed in vacuo and the residue was partitioned between DCM and water. The organic layer was concentrated in vacuo and applied to a sep. Concentration in vacuo gave an impure residue which was purified further eluted with EtOAc EtOAc (EtOAc) The desired fraction was concentrated in vacuo to give EtOAc (EtOAc: EtOAc). 1^^8 shows 丽+=393;!^ = 2.22 minutes. Example 204: Ethyl 1-ethyl-4-[(4-hydroxycyclohexyl)amino]-1Η-pyrazolo[3,4-b] 87841-960303-中 .doc -233 - 1283678 Pyridine-5 -carboxylic acid ethyl ester

使中間物1(1.5克，5·9毫莫耳）溶於乙腈（8〇毫升）中。添加 反式冰胺基環己醇（〇·817克，71毫莫耳，可市購得自 America;或者，（例如為Ηα鹽）得自Aidrich)與二異丙基乙胺 (6.18笔升，35.5耄莫耳），並將混合物於85。〇下攪拌16小時。 使混合物在真空中濃縮，並使殘留物於DCM(12〇毫升）與水 (3〇毫升）之間作分液處理。分離液相，並使有機相脫水乾燥 (NaaSO4)，及蒸發，而得淡黃色固體。使固體溶於dcm(i〇毫 升）與氯仿（3毫升）之混合物中，並以等份施加至兩個spE藥 筒（矽膠，20克），將其相繼以Et〇Ac :環己烷梯度液（1 : %， 然後1 ·· 8， 1 · 4, 1 · 2, 1 · 1及1 : 〇)溶離。將含有所要物質之溶離份合 併’並於真空中蒸發，獲得實例2〇4 (1 893克），為白色固 體。LCMS 顯示 MH+=333; Tret=2.79 分鐘。 艾例205 :乙基[乙基_4_[(4_酮基環己基）胺基】-1H-吡唑并[3,4_b] 吡啶_5·羧酸乙酯Intermediate 1 (1.5 g, 5.9 mmol) was dissolved in acetonitrile (8 mL). Add trans-alurylcyclohexanol (〇817 g, 71 mmol, commercially available from America; or, for example, Ηα salt) from Aidrich) and diisopropylethylamine (6.18 liters) , 35.5 耄 Mo ear), and the mixture at 85. Stir under the arm for 16 hours. The mixture was concentrated in vacuo and the residue was crystallised between DCM (12 mL) and water (3 mL). The liquid phase was separated, and the organic phase was dried (Na.sub.2SO.sub.4) and evaporated to give a pale yellow solid. The solid was dissolved in a mixture of dcm (1 mL) and chloroform (3 mL) and applied in aliquots to two spE cartridges (tank, 20 g) successively in Et. Liquid (1: %, then 1 ·· 8, 1 · 4, 1 · 2, 1 · 1 and 1 : 〇) Dissolution. The dissolved fractions containing the desired material were combined and evaporated in vacuo to afford Example 2 4 (1 893 g) as a white solid. LCMS showed MH+ = 333; Tret = 2.79 min. Example 205: Ethyl [ethyl_4_[(4-ketocyclohexyl)amino]-1H-pyrazolo[3,4_b]pyridine_5·carboxylate

使實例204 (1.893克，5.7毫莫耳）懸浮於丙酮（12毫升）中，並 87841_96〇3〇3·中.doc -234- 1283678 在〇 C下，以jones試劑（1·81耄升）處理經攪拌之懸浮液。3〇分 鐘。後，將另一數量之J〇nes試劑（1.81毫升）添加至反應混合 物中，使其保持在0 C下。再2小時後，將最後一份J〇nes試 对J (1.44耄升）添加至反應混合物中、並持續在下攪拌i小 時。將異丙醇（3·8毫升）添加至反應混合物中，接著是水（15 毫升）。以酷酸乙酯（2x40毫升）萃取所形成之混合物。將合 併之有機萃液以水（8毫升）洗滌，脫水乾燥，及蒸發 成灰色固體。使固體溶於DCM(10毫升）中，並以等份施加至 兩個SPE藥筒（碎膠’ 20克）’將其相繼以醋酸乙酯：環己燒 梯度液（1 · 16,然後1 : 8, 1 : 4, 1 : 2及1 : 1)溶離。將含有所要 物質之溶離份合併，並於真空中蒸發，而得實例2〇5 (1893 克）’為白色固體。LCMS顯示MH+=331 ; Tret=2.84分鐘。 宜_例2〇7 : 4_[(1_乙醯基-4-六氫吡啶基）胺基]_1_乙基-1H-吡唑并 [3,4_b]p比咬-5-叛酸乙酿Example 204 (1.893 g, 5.7 mmol) was suspended in acetone (12 mL), and 87481_96〇3〇3·中.doc-234-1283678 at 〇C, with jones reagent (1·81 liters) The stirred suspension is treated. 3 minutes. Thereafter, another amount of J〇nes reagent (1.81 ml) was added to the reaction mixture to keep it at 0 C. After a further 2 hours, the last J〇nes test J (1.44 liters) was added to the reaction mixture and stirring was continued for an hour. Isopropanol (3.8 mL) was added to the reaction mixture followed by water (15 mL). The resulting mixture was extracted with ethyl oleate (2 x 40 mL). The combined organic extracts were washed with water (8 mL), dried and evaporated. The solid was dissolved in DCM (10 mL) and applied in aliquots to two SPE cartridges (a mixture of 20 g). : 8, 1 : 4, 1 : 2 and 1: 1) Dissolution. The fractions containing the desired material were combined and evaporated in vacuo to give EtOAc (m. LCMS showed MH+ = 331; T rt = 2.84 min. _Example 2〇7 : 4_[(1_Ethyl-4-pyridinyl)amino]_1_ethyl-1H-pyrazolo[3,4_b]p ratio bite-5-rebel B wine

使中間物1 (2.58克）、中間物6 (2.0克）及N，N-二異丙基乙胺 (8.9毫升）溶於乙腈（98毫升）中。將反應混合物於85°C下加熱 24小時，然後添加另一份中間物6 ((U8克），並再持續加熱 10小時。在真空中濃縮反應物，並使殘留物於DCM與水之 間作分液處理。分離液相，並使有機相於真空中蒸發。使 87841-960303-中.doc -235 - 1283678 殘留物藉層析純化，使用Biotage (矽膠90克），以DCM : Me〇H(5% )溶離，而得實例207(1.55克），為白色固體。LCMS 顯不 MH+ 360，Tret=2.71 分鐘。 1例209 : 4-[(4_胺基環己基）胺基】小乙基-1H-吡唑并[3,4-b]吡啶-5-羧酸乙酯Intermediate 1 (2.58 g), intermediate 6 (2.0 g) and N,N-diisopropylethylamine (8.9 ml) were dissolved in acetonitrile (98 ml). The reaction mixture was heated at 85 ° C for 24 hours, then another portion of intermediate 6 ((8 g) was added and heating was continued for a further 10 hours. The reaction was concentrated in vacuo and the residue was taken between DCM and water. The liquid phase was separated, and the liquid phase was separated, and the organic phase was evaporated in vacuo. The residue of 87841-960303-M.doc-235 - 1283678 was purified by chromatography using Biotage (90 g), DCM: Me〇 H (5%) was dissolved, and Example 207 (1.55 g) was obtained as a white solid. LCMS showed MH+ 360, Tret = 2.71 min. 1 209: 4-[(4-aminocyclohexyl)amino] Ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate

實例209係使用類似用於製備實例207之方法，製自中間物 1與（4-胺基環己基）胺。LCMS顯示MH+=332 ; Tret = 2.18分鐘。 t例210 : 1-乙基_Ν·[(1_氧化_3-吡啶基）甲基]·4_(四氫-2H_哌喃·4_ 基胺基）-1Η_吡唑并[3,4_b】吡啶_5_甲醯胺Example 209 was prepared from the intermediate 1 and (4-aminocyclohexyl)amine using a procedure analogous to that used for the preparation of Example 207. LCMS showed MH+ = 332; Tret = 2.18 min. Example 210: 1-ethyl-Ν·[(1_oxidation_3-pyridyl)methyl]·4_(tetrahydro-2H-pyran-4-ylamino)-1Η-pyrazolo[3, 4_b]pyridine_5_formamide

於〇°C下，將間·氣過氧苯甲酸（45毫克，〇·26毫莫耳）在氯 仿（1毫升）中之溶液，逐滴添加至實例138 (0.1克，〇·26毫莫 耳）在氯仿（1.5毫升）中之經攪拌溶液内。在〇°c下ι·5小時 後，添加另一數量在氯仿（1毫升）中之間-氯過氧苯甲酸（45 毫克，0.26毫莫耳），並於〇°C下持續攪拌1.5小時。殘留微量 87841-960303-中.doc -236- !283678 起始物質，故添加另一數量在氯仿（0·6毫升）中之間-氯過氧 苯甲酸（22毫克，0.13毫莫耳）。於0°c下3·5小時後，將2Μ碳 納么液（1毫升）添加至反應混合物中。藉由經過疏水性玻 料分離液相，並以更多氯仿（2毫升）萃取水相。使合併之有 機萃液蒸發成殘留泡沫物，使其藉質量導引之自預備HPLC 純化，而得實例210(44毫克）。LCMS顯示MH+=397 ; Tret= 2.13 分鐘。 免例211 : 1乙基-N-[(l_氧化_2_吡啶基）甲基]-4-(四氫·2Η_哌喃-4-基胺基）_1Η_吡唑并[3,4-b】吡啶-5-甲醯胺A solution of m-benzoic acid (45 mg, 〇·26 mmol) in chloroform (1 mL) was added dropwise to Example 138 (0.1 g, 〇·26 mmol) Ear) in a stirred solution in chloroform (1.5 ml). After 5 hours at 〇 °c, another amount of chloroperoxybenzoic acid (45 mg, 0.26 mmol) was added between chloroform (1 ml) and stirring was continued for 1.5 hours at 〇 ° C. . Residual trace 87841-960303-中.doc -236- !283678 Starting material, so add another amount in chloroform (0.6 ml) -chloroperoxybenzoic acid (22 mg, 0.13 mmol). After 3 hours at 0 ° C, 2 Μ of carbonic acid (1 ml) was added to the reaction mixture. The liquid phase was separated by passing through a hydrophobic glass and the aqueous phase was extracted with more chloroform (2 mL). The combined organic extracts were evaporated to a residual foam which was purified by preparative HPLC eluting with EtOAc. LCMS showed MH+ = 397; Tret = 2.13 min. Exception 211 : 1 ethyl-N-[(l_oxy-2-pyridyl)methyl]-4-(tetrahydro-2-indolyl-4-ylamino)-1Η-pyrazolo[3, 4-b]pyridine-5-carboxamide

實例211係使用類似用於製備實例210之方法，製自實例 600。LCMS 顯示 MH+=397; Tret = 2.20 分鐘。 實例212 : 1-乙基-N-[(l-氧化_4·ρ比咬基）甲基]-4-(四氫_2H-略哺冬 基胺基比并[3,4_b】〃比呢-5-甲酿胺Example 211 was prepared from Example 600 using a procedure similar to that used to prepare Example 210. LCMS showed MH+ = 397; Tret = 2.20 min. Example 212: 1-ethyl-N-[(l-oxidation_4·ρ ratio) methyl]-4-(tetrahydro-2H-succinylamine-based ratio [3,4_b]pyr ratio 5--5-armamamine

實例212係使用類似用於製備實例210之方法，製自實例 33。LCMS 顯示 MH+=397; Tret=2.13 分鐘。 87841-960303-中.doc -237- 1283678 實例214至230Example 212 was prepared from Example 33 using a procedure similar to that used to prepare Example 210. LCMS showed MH+ = 397; Tret = 2.13 min. 87841-960303-中.doc -237- 1283678 Examples 214 to 230

一般程序 將中間物17 (0.15毫莫耳）以得自乙腈（〇.2M)與N，N_二異丙基 乙胺（0.24毫莫耳）中之儲備溶液之一液份胺（〇·95毫升，相當 於0.19毫莫耳）處理。將混合物於回流下加熱2〇小時，然後籲 在真空中丨辰縮。使殘留物藉SPE (碎膠）純化，而得所要之產 物。The general procedure is to use intermediate 17 (0.15 mmol) as one of the stock solutions from acetonitrile (〇.2M) and N,N-diisopropylethylamine (0.24 mmol). 95 ml, equivalent to 0.19 mmoles). The mixture was heated under reflux for 2 hrs and then quenched in a vacuum. The residue is purified by SPE (crushed) to obtain the desired product.

-238 - 87841-960303-中.doc 1283678 實例編號 NHR3 R3 NH2 之來源 起始物質 MH 十 離子 LC-MC 滯留時間 214 J. Med· Chem” 1994, 37(17)， 2360 中間物17 393 2.16 221 力 Mi Aldrich 中間物17 350 3.18 222 Aldrich 中間物17 392 3.62 223 H,exx Aldrich 中間物17 392 3.63,3.68 224 Pfaltz-Bauer 中間物17 392 3.61,3.66 225 J. Org. Chem., 1985, 50(11)， 1859 中間物17 392 3.54 226 h6k Η、业 Aldrich 中間物17 390 3.56 227 h Aldrich 中間物17 390 3.52 228 0 WO 99/12933 中間物17 379 2.66 229 0 EP 1188744 中間物17 393 2.58 230 mhQJ) Aldrich 中間物17 405 2.19 實例225 : 1-乙基-4-[(l-甲基環己基）胺基】·Ν·(苯基甲基)-1Η-吡唑 并[3,4-b]吡啶-5_曱醯胺-238 - 87841-960303-中.doc 1283678 Example No. NHR3 R3 Source of NH2 Starting material MH Ten ion LC-MC Retention time 214 J. Med·Chem" 1994, 37(17), 2360 Intermediate 17 393 2.16 221 Force Mi Aldrich Intermediate 17 350 3.18 222 Aldrich Intermediate 17 392 3.62 223 H, exx Aldrich Intermediate 17 392 3.63, 3.68 224 Pfaltz-Bauer Intermediate 17 392 3.61, 3.66 225 J. Org. Chem., 1985, 50 ( 11), 1859 Intermediate 17 392 3.54 226 h6k Η, industry Aldrich Intermediate 17 390 3.56 227 h Aldrich Intermediate 17 390 3.52 228 0 WO 99/12933 Intermediate 17 379 2.66 229 0 EP 1188744 Intermediate 17 393 2.58 230 mhQJ Aldrich Intermediate 17 405 2.19 Example 225: 1-Ethyl-4-[(l-methylcyclohexyl)amine]·Ν·(phenylmethyl)-1Η-pyrazolo[3,4-b Pyridine-5_guanamine

-239 87841-96〇3〇3-中.doc 1283678 關於製備實例225且涉及1-甲基環己胺與較長反應時間之 較佳方法，係如下述： 攪拌中間物17 (46毫克）、μ甲基環己胺（26毫克）及二異丙 基乙胺（94毫克）在乙腈（丨毫升）中之溶液，並於回流下加熱 77小時。添加更多丨-甲基環己胺（1〇2毫克）、二異丙基乙胺 (93毫克）及乙腈（丨毫升），並將反應混合物於回流下再加熱 68小時。使溶液冷卻，並於真空中濃縮。將殘留物在醋酸 乙酿中研製，並過濾。使濾液藉質量導引之自預備HPLC純 化’獲得實例 225 (19 毫克）。LCMS 顯示 MH+=392 ; Tret=3.46 分鐘。 不於下文且亦涉及1-甲基環己胺之實例231、247及257，亦 可較佳地以類似方式製成。 實例 231_239-239 87841-96〇3〇3-中.doc 1283678 A preferred method for the preparation of Example 225 and involving 1-methylcyclohexylamine with a longer reaction time is as follows: stirring intermediate 17 (46 mg), A solution of μmethylcyclohexylamine (26 mg) and diisopropylethylamine (94 mg) in acetonitrile (m. More 丨-methylcyclohexylamine (1 〇 2 mg), diisopropylethylamine (93 mg) and acetonitrile (m) were added, and the reaction mixture was heated under reflux for a further 68 hours. The solution was allowed to cool and concentrated in vacuo. The residue was triturated in acetic acid and filtered. The filtrate was purified by preparative HPLC by mass guidance to give Example 225 (19 mg). LCMS showed MH+ = 392; Tret = 3.46 min. Examples 231, 247 and 257, which are not hereinafter and also involve 1-methylcyclohexylamine, may also preferably be made in a similar manner. Example 231_239

一般程序 將中間物55 (0.15毫莫耳）以得自乙腈（〇·2Μ)與N，N_二異丙基 乙胺（0.24毫莫耳）中之儲備溶液之一液份胺（〇·95毫升，相當 於0·19毫莫耳）處理。將混合物於回流下加熱2()小時，然後 在真空中濃縮。使殘留物藉SPE(矽膠）純化，而得所要之產 嶋-960303-中.doc -秦 1283678 實例編號 NHRJ R3 ΝΗ2 之來源 起始物質 MH 十 離子 LC-MC 滯留時間 231 J. Org, Chem” 1985, 50(11)， 1859 中間物55 422 3.43 233 Aldrich 中間物55 380 3.20 234 Aldrich 中間物55 422 3.58 235 | Η 此 Aldrich 中間物55 420 3.52 236 Aldrich 中間物55 422 3.57,3.64 ΊΠ Pfaltz-Bauer 中間物55 422 3.56,3.62 238 Η〜 Aldrich 中間物55 420 3.48 239 J. Med. Chem.y 1994,37(17), 2360 中間物55 423 2.16 實例 240-249The general procedure is to use the intermediate 55 (0.15 mmol) as one of the stock solutions from acetonitrile (〇·2Μ) and N,N-diisopropylethylamine (0.24 mmol). 95 ml, equivalent to 0. 19 millimoles). The mixture was heated under reflux for 2 () hours and then concentrated in vacuo. The residue was purified by SPE (Silver) to obtain the desired 嶋-960303-中.doc-Qin 1283678 Example No. NHRJ R3 ΝΗ2 Source of starting material MH Ten ion LC-MC Retention time 231 J. Org, Chem" 1985, 50(11), 1859 Intermediate 55 422 3.43 233 Aldrich Intermediate 55 380 3.20 234 Aldrich Intermediate 55 422 3.58 235 | Η This Aldrich Intermediate 55 420 3.52 236 Aldrich Intermediate 55 422 3.57, 3.64 ΊΠ Pfaltz-Bauer Intermediate 55 422 3.56, 3.62 238 Η~ Aldrich Intermediate 55 420 3.48 239 J. Med. Chem.y 1994, 37(17), 2360 Intermediate 55 423 2.16 Example 240-249

NHS02Me 一般程序 將中間物56 (0·15毫莫耳）以得自乙腈（0.2M)與N，N-二異丙基 乙胺（0.24毫莫耳）中之儲備溶液之一液份胺（0.95毫升，相當 於0.19毫莫耳）處理。將混合物於回流下加熱20小時，然後 在真空中濃縮。使殘留物藉SPE (碎膠）純化，獲得所要之產 物。 -241 - 87841-960303-中.doc 1283678 實例編號 NHR' R3 ΝΗ2 之來源 起始物質 MH + 離子 LC-MC 滯留時間 240 乂） Aldrich 中間物56 485 3.26 241 X7 m Aldrich 中間物56 443 2.94 242 Η、扯l Aldrich 中間物56 483 3.20 243 H Aldrich 中間物56 483 3.14 244 Ά Aldrich 中間物56 485 3.25,3,33 245 Pfatlz-Bauer 中間物56 485 3.24,3.31 247 J. Org. Chem,, 1985,50(11), 1859 中間物56 483 3.10 248 J. Med, Chem.y 1994, 37(17), 2360 中間物56 486 2.05 249 cx Aldrich t間物56 471 .3.21 實例 250-258NHS02Me General procedure Intermediates 56 (0.15 mmol) are obtained as a liquid amine from one of the stock solutions of acetonitrile (0.2 M) and N,N-diisopropylethylamine (0.24 mmol). 0.95 ml, equivalent to 0.19 millimoles). The mixture was heated under reflux for 20 hours and then concentrated in vacuo. The residue is purified by SPE (crushed) to obtain the desired product. -241 - 87841-960303-中.doc 1283678 Example number NHR' R3 ΝΗ2 Source Starting material MH + ion LC-MC Retention time 240 乂) Aldrich Intermediate 56 485 3.26 241 X7 m Aldrich Intermediate 56 443 2.94 242 Η Aldrich Intermediate 56 483 3.20 243 H Aldrich Intermediate 56 483 3.14 244 Ά Aldrich Intermediate 56 485 3.25,3,33 245 Pfatlz-Bauer Intermediate 56 485 3.24,3.31 247 J. Org. Chem,, 1985, 50(11), 1859 Intermediate 56 483 3.10 248 J. Med, Chem.y 1994, 37(17), 2360 Intermediate 56 486 2.05 249 cx Aldrich t-space 56 471 .3.21 Example 250-258

一般程序 將中間物57 (0·15毫莫耳）以得自乙腈（0.2M)與N，N-二異丙基 乙胺（〇·24毫莫耳）中之儲備溶液之一液份胺（0.95毫升，相當 -242- 87841-960303-中.doc 1283678 於0.19毫莫耳）處理。將混合物於回流下加熱20小時，然後 在真空中濃縮。使殘留物藉SPE(矽膠）純化，而得所要之產 物。 實例編號 NHR3 R3 NH2 之來源 起始物質 MH 離子 LC-MC 滯留時間 250 Aldrich 中間物57 418 3.78 251 Aldrich 中間物57 376 3.42 253 Pfaltz-Bauer 中間物57 418 3.78,3.84 254 Aldrich 中間物57 418 3.82,3.86 255 Η Aldrich 中問物57 416 3.66 256 H &quot;tJtl Aldrich 中間物57 416 3.77 257 J, Org, Chem,, 1985, 50(11), 1859 中間物57 418 3.74 258 H,Nv^ i J. Med. Chem.y 1994,37(17), 2360 中間物57 419 2.38 實例 259-275The general procedure is to use intermediate 57 (0.15 mmol) as one of the stock solutions from acetonitrile (0.2 M) and N,N-diisopropylethylamine (〇·24 mmol). (0.95 ml, equivalent -242- 87841-960303-medium.doc 1283678 at 0.19 mmol). The mixture was heated under reflux for 20 hours and then concentrated in vacuo. The residue is purified by SPE (gelatin) to obtain the desired product. Example No. NHR3 R3 NH2 Source Starting material MH ion LC-MC Retention time 250 Aldrich Intermediate 57 418 3.78 251 Aldrich Intermediate 57 376 3.42 253 Pfaltz-Bauer Intermediate 57 418 3.78, 3.84 254 Aldrich Intermediate 57 418 3.82, 3.86 255 Η Aldrich Intermediate 57 416 3.66 256 H &quot;tJtl Aldrich Intermediate 57 416 3.77 257 J, Org, Chem,, 1985, 50(11), 1859 Intermediate 57 418 3.74 258 H, Nv^ i J. Med. Chem.y 1994, 37(17), 2360 Intermediate 57 419 2.38 Examples 259-275

一般程序 使中間物58 (0.1毫莫耳）、HATU(0.1毫莫耳）及DIPEA(0.4毫 莫耳）在DMF (0.4毫升）中之混合物於室溫下振盪10分鐘。然 -243 - 87841-960303-中.doc 1283678 後添加胺（0·1毫莫耳）在DMF (0·2毫升）中之溶液，並將混合物 攪拌數分鐘，獲得溶液。將溶液在室溫下儲存16小時，接 著於真空中濃縮。使殘留物溶於氯仿（0.5毫升）中，並施加 至SI&gt;E藥筒（胺基丙基，0.5克）。將藥筒連續以氯仿（1.5毫 升）、EtOAc (1.5 毫升）及 EtOAc : MeOH (9 : 1，1_5 毫升）溶離。 於真空中濃縮含有所要產物之溶離份，並使殘留物藉質量 導引之自預備HPLC純化。 實例編號 NR4^ r3nh2 之來源 起始物質 MH + 離子 LC-MC 滯留時間 201 Aldrich 中間物58 392 2.60 259 EP 666258 中間物58 470 2.44 260 Salor;或 ICN 生物醫藥 公司；或 Synthesis f 1982, 12,1036 中間物58 420 3.09 261 CHMSRV-AS; 或 Matrix 科學；或 Chem. Ber., 1969, 102, 2770 中間物58 420 3.09 244- 87841_96〇3〇3·中.doc 1283678 262 Aldrich;或 Meindl 等人，/· Med, Chem·， 1984,27(9), 1111. 中間物58 454 3.20 263 CH, Acros;或 Aldrich; Tetrahedron Lett., 2002, 43(48), 8735;或 J. Med. Chem., 1984, 27(9), 1111;或 Org. Lett., 2002, 4(12), 2055 中間物58 422 2.86 264 Lis ¥ 人，J· Med. Chem., 1990, 33(10), 900a. 參閲h式111與 參考資料24 中間物58 485 2.64 265 1 Aldrich 中間物58 435 2.54 266 Fluorochem;或 WO 98/45268 中間物58 458 2.81 267 Aldrich;或 Meindl 等人,/ Med, Chem” 1984,27(9), 1111;或 Org. Lett, 2002, 4(12), 2055 中間物58 460 2,96 268 &quot;-o-f Peakdale 中間物58 470 2.39 269 Aldrich 中間物58 396 2.80 270 (為 cf3 co2h 鹽） Aldrich 中間物58 393 1.89 271 TCI-America; 或 Aldrich;或 Maybridge-Int 中間物58 418 2.77 272 WO 99/38877 中間物58 427 2.13 87841-960303·中.doc 245 - 1283678 273 \^N N.D. Zelinsky 學會 中間物58 396 2.15 274 Aldrich 中間物58 330 2.10 275 Matrix 科學 中間物58 399 2.29 實例 276-287General Procedure A mixture of intermediate 58 (0.1 mmol), HATU (0.1 mmol) and DIPEA (0.4 mmol) in DMF (0.4 mL) was shaken for 10 min. Then -243 - 87841-960303-中.doc 1283678 A solution of the amine (0.1 mole) in DMF (0.2 mL) was added and the mixture was stirred for a few minutes to give a solution. The solution was stored at room temperature for 16 hours and then concentrated in vacuo. The residue was dissolved in chloroform (0.5 mL) and applied to a &lt;&gt;&gt;&gt;E cartridge (aminopropyl, 0.5 g). The cartridge was lysed in chloroform (1.5 mL), EtOAc (1.5 mL) and EtOAc:EtOAc (EtOAc (EtOAc) The fractions containing the desired product were concentrated in vacuo and the residue was purified by preparative HPLC with mass. Example No. NR4^ r3nh2 Source Starting material MH + ion LC-MC Retention time 201 Aldrich Intermediate 58 392 2.60 259 EP 666258 Intermediate 58 470 2.44 260 Salor; or ICN Biopharmaceutical Company; or Synthesis f 1982, 12, 1036 Intermediate 58 420 3.09 261 CHMSRV-AS; or Matrix Science; or Chem. Ber., 1969, 102, 2770 Intermediate 58 420 3.09 244- 87841_96〇3〇3·中.doc 1283678 262 Aldrich; or Meindl et al, /· Med, Chem·, 1984, 27(9), 1111. Intermediate 58 454 3.20 263 CH, Acros; or Aldrich; Tetrahedron Lett., 2002, 43(48), 8735; or J. Med. Chem., 1984, 27(9), 1111; or Org. Lett., 2002, 4(12), 2055 Intermediate 58 422 2.86 264 Lis ¥ Person, J. Med. Chem., 1990, 33(10), 900a. See h formula 111 and reference 24 Intermediate 58 485 2.64 265 1 Aldrich Intermediate 58 435 2.54 266 Fluorochem; or WO 98/45268 Intermediate 58 458 2.81 267 Aldrich; or Meindl et al, / Med, Chem" 1984, 27 (9), 1111; or Org. Lett, 2002, 4(12), 2055 Intermediate 58 460 2,96 268 &quot;-of Peakdale Intermediate 58 470 2.39 269 Aldrich Medium Interstitial 58 396 2.80 270 (for cf3 co2h salt) Aldrich Intermediate 58 393 1.89 271 TCI-America; or Aldrich; or Maybridge-Int Intermediate 58 418 2.77 272 WO 99/38877 Intermediate 58 427 2.13 87841-960303· .doc 245 - 1283678 273 \^N ND Zelinsky Society Intermediate 58 396 2.15 274 Aldrich Intermediate 58 330 2.10 275 Matrix Scientific Intermediate 58 399 2.29 Example 276-287

一般程序 使中間物59 (0.1毫莫耳）、HATU (0.1毫莫耳）及DIPEA (0.4毫 莫耳）在DMF (0.4毫升）中之混合物於室溫下振盪10分鐘。然 後添加胺（0.1毫莫耳）在DMF (0.2毫升）中之溶液，並將混合物 攪拌數分鐘，而得溶液。將溶液在室溫下儲存16小時，接 著於真空中濃縮。使殘留物溶於氯仿（0.5毫升）中，並施加 至SPE藥筒（胺基丙基，0.5克）。將藥筒連續以氯仿（1.5毫 升）、EtOAc (1.5 毫升）及 EtOAc ·· MeOH (9 : 1，1.5 毫升）溶離。 於真空中濃縮含有所要產物之溶離份，並使殘留物藉質量 導引之自預備HPLC純化。 87841-960303·中.doc -246- 1283678 實例編號 NR4R' hnr4r5 之來源 起始物質 MH+ 離子 LC-MC 滯留時間 276 Aldrich 中間物59 392 2.60 277 F Fluorochem;或 WO 98/45268 中間物59 446 2.84 278 Aldrich;或 Meindl 等人，J. Med. Chem., 1984, 27(9), 1111;或 Og. Lett,, 2002, 4(12), 2055 中間物59 448 3.0 279 Acros 中間物59 458 2.40 * 280 EP 382570 中間物59 458 2.47 1 i i 281 Aldrich 中間物59 384 2.85 282 (為 cf3 co2h 鹽） Aldrich 中間物59 381 1.89 j i i 1 283 TCI-America; 或 Aldrich;或 Maybridge-Int 中間物59 406 2.80 1 1 284 WO 99/38877 中間物59 415 2.14 285 \s^N N.D. Zelinsky 學會 中間物59 384 2.16 286 Aldrich 中間物59 318 2.11 287 %:〕 Matrix 科學· 中間物59 399 2.29 會例288 : 4-[(4,4-二氟環己基）胺基】_1•乙基-Ν·(苯基曱基）-1Η-吡 唑并[3,4-b]吡啶-5-甲醯胺與實例289 : 1-乙基-4-[(4-氟基-3-環己 晞-1-基)胺基]-Ν-(苯基甲基)-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺 -247- 87841-960303-中.doc 1283678General Procedure A mixture of intermediate 59 (0.1 mmol), HATU (0.1 mmol) and DIPEA (0.4 mmol) in DMF (0.4 mL) was shaken at room temperature for 10 min. A solution of the amine (0.1 mmol) in DMF (0.2 mL) was then added and the mixture was stirred for a few minutes to give a solution. The solution was stored at room temperature for 16 hours and then concentrated in vacuo. The residue was dissolved in chloroform (0.5 mL) and applied to EtOAc (EtOAc: The cartridge was continuously dissolved in chloroform (1.5 mL), EtOAc (1.5 mL) and EtOAc······· The fractions containing the desired product were concentrated in vacuo and the residue was purified by preparative HPLC with mass. 87841-960303·中.doc -246-1283678 Example Number NR4R' hnr4r5 Source Starting Material MH+ Ion LC-MC Retention Time 276 Aldrich Intermediate 59 392 2.60 277 F Fluorochem; or WO 98/45268 Intermediate 59 446 2.84 278 Aldrich; or Meindl et al, J. Med. Chem., 1984, 27(9), 1111; or Og. Lett,, 2002, 4(12), 2055 Intermediate 59 448 3.0 279 Acros Intermediate 59 458 2.40 * 280 EP 382570 Intermediate 59 458 2.47 1 ii 281 Aldrich Intermediate 59 384 2.85 282 (for cf3 co2h salt) Aldrich Intermediate 59 381 1.89 jii 1 283 TCI-America; or Aldrich; or Maybridge-Int Intermediate 59 406 2.80 1 1 284 WO 99/38877 Intermediate 59 415 2.14 285 \s^N ND Zelinsky Society Intermediate 59 384 2.16 286 Aldrich Intermediate 59 318 2.11 287 %:] Matrix Science · Intermediate 59 399 2.29 Case 288 : 4-[ (4,4-Difluorocyclohexyl)amino] _1 </ RTI> ethyl-indole (phenylphenyl)-1 hydrazinopyrazolo[3,4-b]pyridine-5-carboxamide and Example 289: 1-ethyl-4-[(4-fluoro-3-cyclohexan-1-yl)amino]-indole-(phenylmethyl)-1Η-pyrazolo[3,4-b]pyridine -5-carbamamine-247- 8784 1-960303-中.doc 1283678

實例289 將一^異丙基乙胺（〇·113毫升，〇·65毫莫耳）添加至中間物 7 (40笔克，〇j3笔莫耳）與中間物幻⑷毫克，〇·26毫莫耳）在 乙知（2笔升）中之經攪拌混合物内。於85。〇下攪拌混合物。 18小時後’將另一份中間物63 (22.5毫克，0·13毫莫耳）與二 異丙基乙胺（0.113毫升，〇·65毫莫耳）添加至反應混合物中， 並於90 C下持續攪拌24小時。然後在真空中濃縮混合物，並 使殘留物於DCM (20毫升）與水（5毫升）之間作分液處理。分 離液相，並以另外之DCM (10毫升）萃取水相。使合併之有機 萃液脫水乾燥(Na2S04)，並於真空中蒸發，獲得褐色油（65毫 克），其係在SPE藥筒（矽膠，1〇克）上部份純化，以醋酸乙 酯··石油醚（1 : 8 ; 1 ·· 4 ; 1 : 2 ; 1 : 1及1 : 0)溶離。藉質量 導引自預備之HPLC分離所形成之兩份淡褐色油（34毫克）’ 而得實例288 (19毫克），為白色泡沫物（LCMS顯示MH+ = 414 ; TRET= 3.24分鐘）與實例2δ9 (9毫克），為白色固體（LCMS顯示 MH+=394; Tret=3.21 分鐘）。 實例 290-319 87841-960303-中.doc -248 - 1283678Example 289 Add isopropylethylamine (〇·113 ml, 〇·65 mmol) to Intermediate 7 (40 gram, 〇j3 mp) and intermediate illusion (4) mM, 〇·26 毫Mohr) is stirred in a mixture of B (2 pens). At 85. The mixture was stirred under the arm. After 18 hours, add another intermediate 63 (22.5 mg, 0·13 mmol) to diisopropylethylamine (0.113 mL, 〇·65 mmol) to the reaction mixture and at 90 C Stirring was continued for 24 hours. The mixture was then concentrated in vacuo and the residue was crystallised eluted eluted eluted The liquid phase was separated and the aqueous phase was extracted with additional DCM (10 mL). The combined organic extracts were dried (Na2SO4) and evaporated in vacuo to afford a brown oil (65 mg) which was partially purified on a SPE cartridge (yel. Petroleum ether (1:8; 1 ·· 4 ; 1 : 2 ; 1 : 1 and 1: 0) is dissolved. Example 288 (19 mg) was obtained as a white foam (LCMS: MH+ = 414; TRET = 3.24 min) and Example 2 δ 9 by mass separation of two portions of pale brown oil (34 mg). (9 mg) as a white solid (LCMS: MH+= 394; Example 290-319 87841-960303-中.doc -248 - 1283678

nr4r5 一般程序 使中間物60 (0.1毫莫耳）、HATU (0.1毫莫耳）及DIPEA (0.4毫 莫耳）在DMF (0·4毫升）中之混合物於室溫下振盪10分鐘。然 後添加胺（0.1毫莫耳）在DMF (0.2毫升）中之溶液，並將混合物 攪拌數分鐘，獲得溶液。將溶液在室溫下儲存16小時，接 著於真空中濃縮。使殘留物溶於氯仿（0.5毫升）中，並施加 至SPE藥筒（胺基丙基，0.5克）。將藥筒連續以氯仿（1.5毫 升）、EtOAc(1.5 毫升）及 EtOAc: MeOH(9: 1，1.5 毫升）溶離。 在真空中濃縮含有所要產物之溶離份，並使殘留物藉質量 導引之自預備HPLC純化。 實例編號 nr4r&quot; hnr4r5 之來源 起始物質 MH+ 離子 LC-MC 滯留時間 290 Aldrich;或 TCI-America; 或 Maybridge-Int 中間物60 447 2.96 291 Aldrich;或 Meindl 等人，/ Med. Chem.9 1984, 27(9)， 1111. 中間物60 488/ 490 3.16 292 Aldrich;或 Meindl 等人，/ Med, Chem.y 1984, 27(9), 1111;或 Org· Lett, 2002, 4(12), 2055 中間物60 439 2.84 -249- 87841-960303-中.doc 1283678 293 Aldrich 中間物60 457 2.92 294 F Aldrich 中間物60 457 2.87 295 Aldrich;或 Meindl 等人，乂 Med. Chem·， 1984, 27(9), 1111. 中間物60 489 3.06 296 Aldrich;或 Meindl 等人，乂 Med. Chem., 1984, 27(9)， 1111;或抑. Lett., 2002, 4(12), 2055 中間物60 489 3.08 297 / Aldrich 中間物60 457 2.82 298 Aldrich;或 Meindl 等人，*/· Med. Chem.t 1984, 27(9), 1111;或 Lett., 2002, 4(12), 2055 中間物60 455 2.98 299 Aldrich;或 Acros;或 Jung 等 尺、Tetrahedron Lett., 2002, 43(48), 8735;或 Meindl 等人，/ Med, Chem·, 1984, 27(9), 1111;或 Org· Lett,, 2002, 4(12), 2055 中間物60 451 2.79 300 m^Qr' Aldrich 中間物60 437 2,82 301 Peakdale 分子公司 中間物60 528 2.76 302 NH C0 Aldrich 中間物60 461 3.00 303 Peakdale 分子公司 中間物60 464 2.31 -250- 87841-960303-中.doc 1283678 •304 Cl Aldrich;或 Meindl 等人， J. Med. Chem., 1984, 27(9), 1111. 中間物60 489 3.16 305 F Aldrich;或 Og. Lett., 2002, 4(12), 2055 中間物60 439 2.84 306 F Fluka 中間物60 473 2,92 307 Fluorochem 公司；或 WO 98/45268 中間物60 487 2.95 308 W。、 Apin 中間物60 485 2,94 309 Key 有k物公司 中間物60 456 2.65 310 -or J, Med. Chern., 2001,44(26), 4628 中間物60 481 3.16 311 Manchester 有機物公司 「中間物60 428 2.28 312 &quot;-OF Acres Chimica. 中間物60 499 2.37 313 Aldrich 中間物60 511 3.18 314 Lis.等人，《«/· Med. Chem.y 1990, 33(10), 9〇Q*3 參閲’圖式III與 參考資料24 中間物60 514 2.60 315 WO 94/17035 中間物60 478 2.47 316 ^ζ： 0 Sigma 中間物60 500 2.50 317 Peakdale 分子 公司 中間物60 478 2.49 -251- 87841-960303-中.doc 1283678 318 WO 02/85860 中間物60 464 2.42 319 1 Syngene 中間物60 452 2.45 兔例320 1_乙基_N-4_六氫吡啶基冬(四氫-2H-哌喃_4_基胺基）-iH_ 吡唑并[3,4-b】吡啶_5_甲醯胺Nr4r5 General Procedure A mixture of intermediate 60 (0.1 mmol), HATU (0.1 mmol) and DIPEA (0.4 mmol) in DMF (0.4 mL) was shaken at room temperature for 10 min. Then a solution of the amine (0.1 mmol) in DMF (0.2 mL) was added and the mixture was stirred for a few minutes to give a solution. The solution was stored at room temperature for 16 hours and then concentrated in vacuo. The residue was dissolved in chloroform (0.5 mL) and applied to EtOAc (EtOAc: The cartridge was lysed in chloroform (1.5 mL), EtOAc (1.5 mL) andEtOAcEtOAcEtOAc The fractions containing the desired product were concentrated in vacuo and the residue was purified by preparative HPLC with mass. Example number nr4r&quot; hnr4r5 source starting material MH+ ion LC-MC retention time 290 Aldrich; or TCI-America; or Maybridge-Int intermediate 60 447 2.96 291 Aldrich; or Meindl et al, / Med. Chem. 9 1984, 27(9), 1111. Intermediate 60 488/490 3.16 292 Aldrich; or Meindl et al, / Med, Chem.y 1984, 27(9), 1111; or Org· Lett, 2002, 4(12), 2055 Intermediate 60 439 2.84 -249- 87841-960303-中.doc 1283678 293 Aldrich Intermediate 60 457 2.92 294 F Aldrich Intermediate 60 457 2.87 295 Aldrich; or Meindl et al., 乂 Med. Chem., 1984, 27 (9 ), 1111. Intermediate 60 489 3.06 296 Aldrich; or Meindl et al., 乂 Med. Chem., 1984, 27(9), 1111; or inhibit. Lett., 2002, 4(12), 2055 Intermediate 60 489 3.08 297 / Aldrich Intermediate 60 457 2.82 298 Aldrich; or Meindl et al, */· Med. Chem.t 1984, 27(9), 1111; or Lett., 2002, 4(12), 2055 Intermediate 60 455 2.98 299 Aldrich; or Acros; or Jung et al., Tetrahedron Lett., 2002, 43(48), 8735; or Meindl et al, / Med, Chem., 1984, 27(9), 1111; or Org· Lett, , 20 02, 4(12), 2055 Intermediate 60 451 2.79 300 m^Qr' Aldrich Intermediate 60 437 2,82 301 Peakdale Molecular Company Intermediate 60 528 2.76 302 NH C0 Aldrich Intermediate 60 461 3.00 303 Peakdale Molecular Company Intermediate 60 464 2.31 -250- 87841-960303-中.doc 1283678 •304 Cl Aldrich; or Meindl et al, J. Med. Chem., 1984, 27(9), 1111. Intermediate 60 489 3.16 305 F Aldrich; or Og. Lett., 2002, 4(12), 2055 Intermediate 60 439 2.84 306 F Fluka Intermediate 60 473 2,92 307 Fluorochem Company; or WO 98/45268 Intermediate 60 487 2.95 308 W. , Apin Intermediate 60 485 2,94 309 Key There is a k company intermediate 60 456 2.65 310 -or J, Med. Chern., 2001,44(26), 4628 Intermediate 60 481 3.16 311 Manchester Organic Company "Intermediate 60 428 2.28 312 &quot;-OF Acres Chimica. Intermediate 60 499 2.37 313 Aldrich Intermediate 60 511 3.18 314 Lis. et al., «/· Med. Chem.y 1990, 33(10), 9〇Q*3 See 'Form III and Reference 24 Intermediate 60 514 2.60 315 WO 94/17035 Intermediate 60 478 2.47 316 ^ζ: 0 Sigma Intermediate 60 500 2.50 317 Peakdale Molecular Company Intermediate 60 478 2.49 -251- 87841- 960303-中.doc 1283678 318 WO 02/85860 Intermediate 60 464 2.42 319 1 Syngene Intermediate 60 452 2.45 Rabbit Example 320 1_Ethyl_N-4_hexahydropyridyl Winter (tetrahydro-2H-pyranose _ 4_ylamino)-iH_pyrazolo[3,4-b]pyridine_5-formamide

將氯化氫在二氧陸圜中之溶液(30毫升，4M，0.12莫耳）添 加至實例126 (1.3克，2.75毫莫耳）在二氧陸圜（10毫升）中之懸 浮液内’並將混合物於室溫下攪拌6小時。將反應混合物留 置14小時，然後使溶液蒸發，與DCm —起共沸，獲得白色 固體，其鹽酸鹽。使固體懸浮於醋酸乙酯（5〇毫升）中，並以 氫氧化鈉溶液（2N，50毫升）洗滌。使有機層以脫水乾 燥，並於真空中濃縮，而得實例318，為白色固體（995毫 克）。LCMS 顯示 MH+=373; Tret=1.89 分鐘。 f 例3211_乙基具(4-六氫吡啶基甲基)-4-(四氫_2Εμ痕喃_4-基胺 基）_1Η-ρ比峻并[3,4-b】峨淀-5_甲酿胺A solution of hydrogen chloride in dioxane (30 mL, 4 M, 0.12 mol) was added to a suspension of Example 126 (1.3 g, 2.75 mmol) in dioxane (10 mL) and The mixture was stirred at room temperature for 6 hours. The reaction mixture was allowed to stand for 14 hours, then the solution was evaporated and then azeotroped with DCm to afford a white solid. The solid was suspended in ethyl acetate (5 mL) and washed with sodium hydroxide (2N, 50 mL). The organic layer was dried with EtOAc (EtOAc m. LCMS showed MH+ = 373; Tret = 1.89 min. f Example 3211_ethyl with (4-hexahydropyridylmethyl)-4-(tetrahydro-2Εμ trace 4-ylamino)_1Η-ρ ratio and [3,4-b]峨- 5_甲甲胺

87841_96〇303_ 中.doc •252- 1283678 將氯化氫在二氧陸圜中之溶液（30毫升，4M，012莫耳）添 加至中間物72 (1.2，2.5莫耳）在二氧陸圜（10毫升）中之懸浮液 内，並將混合物於室溫下攪拌6小時。將反應混合物留置14 小時，然後使溶液蒸發，與DCM —起共沸，獲得白色固體 (1·24克）。使一部份之固體（68毫克）懸浮於醋酸乙酯中，並 以2Μ-氫氧化鈉溶液洗滌。使有機層以Ν々8〇4脫水乾燥，並 在真空中濃縮，而得實例321，為白色固體（60毫克）。[CMS 顯示 MH+=387; Tret=1.92 分鐘。 jT例322 1-乙基-N-[l_(乙基續酿基)_4_六氫u比淀基】_4_(四氫_2jj&lt; 喃_4_基胺基）-1Η-吡峻并[3,4-b】吡淀-5-甲醯胺87841_96〇303_中.doc •252- 1283678 A solution of hydrogen chloride in dioxane (30 ml, 4M, 012 mol) was added to intermediate 72 (1.2, 2.5 mol) in dioxane (10 ml) The suspension was placed in the mixture and the mixture was stirred at room temperature for 6 hours. The reaction mixture was allowed to stand for 14 hours, then the solution was evaporated and evaporated to dryness with DCM to give a white solid (1·24 g). A portion of the solid (68 mg) was suspended in ethyl acetate and washed with a 2? sodium hydroxide solution. The organic layer was dried with EtOAc EtOAc (EtOAc) [CMS shows MH+=387; Tret=1.92 minutes. jT Example 322 1-Ethyl-N-[l_(ethyl continuation)_4_hexahydrou-pyrylate] _4_(tetrahydro-2jj&lt; __4_ylamino)-1Η-pyridin[ 3,4-b]pyramidine-5-formamide

將三乙胺（0.023毫升，0.16毫莫耳）添加至實例320 (0.043克， 0·115莫耳）在DCM(1毫升）中之溶液内。使混合物冷卻（冰/ 水浴，歷經10分鐘），並添加氯化乙燒績醯（0.014毫升，0138 毫莫耳）。將所形成之溶液於室溫下攪拌18小時，然後以氮 蒸汽移除溶劑。使殘留物溶於二氯甲烷（1.5毫升）中，並與 水（1.5毫升）一起授拌。分離有機層，並以氮向下吹，及施 加至SPE藥筒（矽膠，2克），以環己烷中之60% -100%醋酸乙 酯溶離。使所要之溶離份於真空中濃縮，而得實例322，為 白色固體（32毫克）。LCMS顯示MH+=465 ; Tret = 2.52分鐘。 下列係以類似方式製成 87841-960303-中.doc -253 - 1283678Triethylamine (0.023 mL, 0.16 mmol) was added to a solution of Example 320 (0.043 g, EtOAc) The mixture was allowed to cool (ice/water bath over 10 min) and chlorobenzene (0.014 mL, 0138 m. The resulting solution was stirred at room temperature for 18 hours and then the solvent was removed with nitrogen vapor. The residue was dissolved in dichloromethane (1. 5 mL) and EtOAc (EtOAc) The organic layer was separated and sparged with nitrogen and applied to a SPE cartridge (2 g), eluting with 60% to 100% ethyl acetate in cyclohexane. The desired fractions were concentrated in vacuo to afford EtOAc EtOAc (EtOAc: LCMS showed MH+ = 465; T rt = 2.52 min. The following are made in a similar manner. 87841-960303-中.doc -253 - 1283678

實例編號 NR'R' 氯化磺醯 氱化磺醢 之來源 MH+ 離子 LC-MC 滯留時間 323 Η，々α A Aldrich 479 2.58 324 J. Org. Chem.y 1952,17, 1529 505 2.75 325 H3C、// rcx H3C //° 〇々、α Aldrich 451 2.41 •326 〇o 、cx 9 Aldrich 527 2.90 327 0. y0 σ&lt;α Aldrich 513 2.66 328 Η,Ο-Χ Aldrich 479 2.42Example No. NR'R' Source of sulfonated sulfonated sulfonium MH+ ion LC-MC Retention time 323 々, 々α A Aldrich 479 2.58 324 J. Org. Chem.y 1952,17, 1529 505 2.75 325 H3C, // rcx H3C //° 〇々,α Aldrich 451 2.41 •326 〇o ,cx 9 Aldrich 527 2.90 327 0. y0 σ&lt;α Aldrich 513 2.66 328 Η,Ο-Χ Aldrich 479 2.42

實例329 N-丨1-(環丙基羰基)_4_六氫峨淀基]小乙基冬(四氫々Η-喊 喃_4_基胺基）-1Η-吡唑并[3,4-b]吡啶-5_甲醯胺Example 329 N-丨1-(cyclopropylcarbonyl)_4_hexahydroindenyl] small ethyl winter (tetrahydroanthracene-pyro- 4-ylamino)-1Η-pyrazolo[3,4 -b]pyridine-5-carbamamine

使環丙燒羧酸（0.011毫升，0.138毫莫耳）、EDC (0.031克， 0.161毫莫耳）及HOBT (0.019克，0.138毫莫耳）懸浮於DMF (2毫 -254- 87841-960303-中.doc 1283678 升）中，並在室溫下攪拌1小時。添加實例320 (0 043克，0.115 毫莫耳），並將混合物於室溫下攪拌16小時。使用氮氣流移 除大部份溶劑，並使殘留物於DCM (3毫升）與水(3毫升）之間 作分液處理。將有機層以氮向下吹送，並施加至SPE藥筒 (胺基丙基，1克），將其以甲醇溶離。經由以氮向下吹送而 濃縮，獲得不純殘留物，使其進一步藉SPE藥筒（矽膠，1 克）純化，以環己烷中之50-100% EtOAc，接著以EtOAc中之5 %甲醇溶離。於真空中濃縮所要之溶離份，而得實例329， 為白色固體（49毫克）。LCMS顯示MH+=441 ; Tret = 2.23分 鐘。 以類似方式，使用相同或類似莫耳數之試劑與溶劑體積， 並使用實例320作為起始物質，以製造實例330至343，但使 用實例321 (類似莫耳數）代替實例320作為起始物質，以施行 實例344至349，製備下列物質： 87841-96〇3〇3·中.doc 255- 1283678Cyclopropanecarboxylic acid (0.011 ml, 0.138 mmol), EDC (0.031 g, 0.161 mmol) and HOBT (0.019 g, 0.138 mmol) were suspended in DMF (2 mM -254 - 87841-960303- Medium .doc 1283678 liters) and stirred at room temperature for 1 hour. Example 320 (0 043 g, 0.115 mmol) was added and the mixture was stirred at room temperature for 16 h. Most of the solvent was removed using a stream of nitrogen and the residue was partitioned between DCM (3 mL) and water (3 mL). The organic layer was blown down with nitrogen and applied to an SPE cartridge (aminopropyl, 1 g) which was dissolved in methanol. Concentration by nitrogen downwards to give an impure residue which was further purified by a SPE cartridge (cluster, 1 g) eluting with 50-100% EtOAc in cyclohexane followed by 5% MeOH in EtOAc. . The desired fractions were concentrated in vacuo to give a crystallite. LCMS showed MH+ = 441; Tret = 2.23 min. In a similar manner, the same or similar molar number of reagents and solvent volumes were used, and Example 320 was used as the starting material to make Examples 330 to 343, but using Example 321 (similar to the molar number) instead of Example 320 as the starting material. To carry out Examples 344 to 349, the following materials were prepared: 87841-96〇3〇3·中.doc 255- 1283678

實例編號 NR4R&quot; 羧酸 羧酸之來 源 MH+ 離子 LC-MC 滯留時間 330 Cr^〇H Aldrich 467 2.50 331 Aldrich 471 2.73 332 、ch3 Aldrich 471 2.72 333 oa^ ολ0Η Aldrich 483 2.81 334 Ία HjCY^oh CH, Aldrich 443 2.27 335 οΛχ cA Combi-Blocks 485 2.17 336 Aldrich 429 2.38 337 Η·ναα 町丫以。« Aldrich 472 2.20 338 °Λχ Oa. Synchem OHG 500 1.91 339 #cx Xt^ J. Med. Chem., 1998,41(5), 760 497 2.17 87841-960303-中.doc -256- 1283678 340 0人 微量化學結 構單位 498 1.94 341 H^C Interchim 中間物 498 2.07 342 〇0^°« DE 3618135 471 2.33 343 Aldrich 509 2.75 344 扯I H，c4^〇H Aldrich 485 2.78 345 m 〇a0H Aldrich 497 2.85 346 /CUm Λ Aldrich 455 2.50 347 〇x/w J. Med. Chem.y 1998,41(5)， 760 511 2.42 348 mi X)UL Aldrich 523 2.78 349 Vcu H,C H,C Interchim 中間物 512 2.29Example No. NR4R&quot; Source of Carboxylic Acid MH+ Ion LC-MC Retention Time 330 Cr^〇H Aldrich 467 2.50 331 Aldrich 471 2.73 332, ch3 Aldrich 471 2.72 333 oa^ ολ0Η Aldrich 483 2.81 334 Ία HjCY^oh CH, Aldrich 443 2.27 335 οΛχ cA Combi-Blocks 485 2.17 336 Aldrich 429 2.38 337 Η·ναα 丫 丫. « Aldrich 472 2.20 338 °Λχ Oa. Synchem OHG 500 1.91 339 #cx Xt^ J. Med. Chem., 1998,41(5), 760 497 2.17 87841-960303-中.doc -256- 1283678 340 0 people Chemical structural units 498 1.94 341 H^C Interchim Intermediate 498 2.07 342 〇0^°« DE 3618135 471 2.33 343 Aldrich 509 2.75 344 Pull IH, c4^〇H Aldrich 485 2.78 345 m 〇a0H Aldrich 497 2.85 346 /CUm Λ Aldrich 455 2.50 347 〇x/w J. Med. Chem.y 1998,41(5), 760 511 2.42 348 mi X)UL Aldrich 523 2.78 349 Vcu H,CH,C Interchim Intermediate 512 2.29

實例350 3-丨(1•乙基_5-{[(苯基甲基）胺基】羰基}_1H-吡唑并[3,4-b]吡 啶-4-基）胺基]環己烷羧酸甲酯Example 350 3-丨(1•Ethyl_5-{[(phenylmethyl)amino]carbonyl}_1H-pyrazolo[3,4-b]pyridin-4-yl)amino]cyclohexane Methyl carboxylate

實例350係製自中間物17，並使用類似用於製備實例207之 -257- 87841-960303-中.doc 1283678 方法。LCMS 顯示 MH+=436; Tret=3.20. 复企1^1&gt;[(1-乙基-5-{[(苯基甲基)胺基]羰基}-1Η-吡唑并[3,4-b]吡 啶_4_基）胺基]環己烷羧酸Example 350 was prepared from Intermediate 17, and a method similar to that used in Preparation Example 207 -257- 87841-960303-.doc 1283678 was used. LCMS showed MH+=436; Tret=3.20. Recombination 1^1&gt;[(1-ethyl-5-{[(phenylmethyl)amino]carbonyl}-1Η-pyrazolo[3,4-b Pyridine-4-yl)amino]cyclohexanecarboxylic acid

將2M_氫氧化鈉溶液（0.5毫升）添加至實例350 (0·12克，0.275 毫莫耳）在曱醇（3.5毫升）與水（0.8毫升）中之經攪拌懸浮液 内。於室溫下攪拌過夜後，使反應溶液濃縮，以水（3毫升） 稀釋，並以2Μ-鹽酸酸化。藉過濾收集所形成之沉澱物，以 水洗條’及乾燥，獲得實例351，為白色固體（〇1〇5克）。 LCMS 顯示 MH+ = 422; Tret = 2.95 分鐘。 复例352 : ^乙基_N_(苯基甲基）-4-(4-六氫吡啶基胺基）-1Η-吡唑 并[3,4_bp比咬_5·甲醯胺A 2M solution of sodium hydroxide (0.5 mL) was added to a stirred mixture of EtOAc (EtOAc &lt;RTI ID=0.0&gt;&gt; After stirring at room temperature overnight, the reaction solution was concentrated, diluted with water (3 ml) and acidified with 2? The precipitate formed was collected by filtration, washed with water and dried to give s. LCMS showed MH+ = 422; Tret = 2.95 min. Example 352: ^Ethyl_N_(phenylmethyl)-4-(4-hexahydropyridylamino)-1Η-pyrazole and [3,4_bp ratio biting_5·carbamidine

將鹽酸水落液（20毫升，5M)添加至中間物65 (2.58克，5.40 φ莫耳.）在四氣吱喃（1〇毫升）中之溶液内。將反應混合物於 20 C下揽拌22小時，然後在真空中蒸發。使殘留物於DCM與 水 &lt; 間作分液處理。以氫氧化鈉水溶液（2M)使水相鹼化，並 87841-960303-中.doc -258· 1283678 以***萃取。在真空中蒸發有機相，而得實例352，為白色 固體（2.04 克）。LCMS顯示 MH+=379 ; Tret=2.1〇 分鐘。 娃353: H基斗…七甲氧基）乙醯基]_4_六氫吡啶基}胺基）-1H-吡唑并[3,4b】吡啶-5-羧酸乙酯Hydrochloric acid aqueous solution (20 mL, 5 M) was added to a solution of intermediate 65 (2.58 g, 5.40 <RTIgt; The reaction mixture was stirred at 20 C for 22 h then evaporated in vacuo. The residue was subjected to liquid separation between DCM and water &lt; The aqueous phase was basified with aqueous sodium hydroxide (2M) and extracted with EtOAc &lt;RTI ID=0.0&gt;&gt; The organic phase was evaporated <RTI ID=0.0> LCMS showed MH+ = 379; Tret = 2.1 〇 min.娃: H base bucket...heptamethoxy)ethinyl]_4_hexahydropyridyl}amino)-1H-pyrazolo[3,4b]pyridine-5-carboxylic acid ethyl ester

將氯化甲氧基乙醯（0.016毫克，OJ44毫莫耳）與三乙胺（002 莫耳’ 0·144毫莫耳）添加至Reactivial中之實例352 (〇 〇46克， 0.122晕莫耳）在DCM中之溶液内。將反應物於2〇〇c下攪拌22 小時，然後以DCM稀釋，並以碳酸氫鈉水溶液洗滌。分離 有機相，並直接施加至SPE藥筒（矽膠2克）。將藥筒以 DCM : MeOH(l%，接著3% )溶離，獲得實例353，為白色固體 (0.05 克）。LCMS 顯示 MH+=451; Tret = 2.66 分鐘。 宜J 354 : Μ1-甲基乙基）四氫JH-t痕喃斗基胺基）-1Η-吡唑并 [3,4-b]吡啶_5_羧酸乙酯Add methoxyethyl hydrazine chloride (0.016 mg, OJ 44 mmol) and triethylamine (002 Mohr '0·144 mmol) to Example 352 in Reactivial (〇〇46 g, 0.122 VOM) ) in solution in DCM. The reaction was stirred at 2 ° C for 22 h then diluted with DCM and washed with aqueous NaHCI. The organic phase was separated and applied directly to the SPE cartridge (2 g of silicone). The cartridge was dissolved in DCM: MeOH (1% EtOAc) LCMS showed MH+ = 451; Tret = 2.66 min. Yi J 354 : Μ 1-methylethyl) tetrahydro JH-t-indoleylamino)-1Η-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester

以類似實例186之方式製成，使用實例2〇 (〇 〇3克，〇1毫莫 耳）與2-溴丙烷（1〇微升，〇11毫莫耳），16小時後，添加另外 87841-960303-中.doc -259- 1283678 0·11毫莫耳烷基化劑。所形成之最後化合物為透明膠質（16毫 克）。LCMS 顯示 MH+=333; Tret=3.16 分鐘。 實例355 : 4-(環己胺基）-1_乙基甲基-1H-吡唑并[3,4-b】吡啶_5_ 甲醯胺Made in a similar manner to Example 186, using Example 2 (〇〇3 g, 〇1 mmol) with 2-bromopropane (1 〇 microliter, 〇11 mmol), after 16 hours, add another 87841 -960303-中.doc -259- 1283678 0·11 millimolar alkylating agent. The final compound formed was a clear gum (16 mg). LCMS showed MH+ = 333; Tret = 3.16 min. Example 355: 4-(cyclohexylamino)-1 -ethylmethyl-1H-pyrazolo[3,4-b]pyridine_5-carbamimidamine

使中間物64 (0.02克，0.084毫莫耳）與二異丙基乙胺（〇〇44毫 升，0.252毫莫耳）懸浮於N-甲基四氫吡咯酮（1毫升）中，並添 加環己胺（0.012毫升，0.1毫莫耳）。將混合物於85〇c下加熱， 並在ReactivialTM中攪拌8小時，然後在真空中濃縮。使殘留 物於DCM (2毫升）與水(2毫升）之間作分液處理。分離液層， 並使有機層在真空中濃縮’接著藉質量導引之自預備HPLC 純化’而得實例355 (0.012克）。LCMS顯示MH+= 302 ;Intermediate 64 (0.02 g, 0.084 mmol) and diisopropylethylamine (44 ml, 0.252 mmol) were suspended in N-methyltetrahydropyrrolidone (1 mL) and added. Hexylamine (0.012 ml, 0.1 mmol). The mixture was heated at 85 ° C and stirred in a ReactivialTM for 8 hours then concentrated in vacuo. The residue was partitioned between DCM (2 mL) and water (2 mL). The liquid layer was separated and the organic layer was concentrated <RTI ID=0.0></RTI> to <RTI ID=0.0> LCMS showed MH+ = 302;

Tret= 2.85 分鐘。 實..例3發.:乙基-Ν·(4-氟苯基）-6-甲基_4_(四氫々Η-喊喃-4-基胺 基）-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺Tret = 2.85 minutes. Example 3. Example 3. Ethyl-indole (4-fluorophenyl)-6-methyl_4_(tetrahydroindole-pyran-4-ylamino)-1Η-pyrazolo[3 ,4-b]pyridine-5-carboxamide

實例356係使用類似實例191之方法，製自中間物％。 LCMS 顯示 MH+=398; Tret=2.18 分鐘。 87841-960303-中.doc -260- 1283678 t·例357 : 1-乙基-6_甲基-N-{[4-(甲磺醯基）苯基】甲基丨冰(四氮 2H_哌喃_4_基胺基）_1H_吡唑并[3,4-b]吡啶-5_甲酿胺Example 356 was prepared using a method analogous to Example 191 from % of intermediate. LCMS showed MH+ = 398; Tret = 2.18 min. 87841-960303-中.doc -260-1283678 t·Example 357 : 1-ethyl-6-methyl-N-{[4-(methylsulfonyl)phenyl]methylhydrazine ice (tetranitro 2H_ Piperidine_4_ylamino)_1H_pyrazolo[3,4-b]pyridine-5-cartoamine

實例3S7係使用類似實例191之方法，製自中間物％。 LCMS 顯示 MH+=472; Tret=2.15 分鐘。 复例358 :队(2,3-二氫I基H_乙基各甲基_4_(四氫-2H-哌 喃_4_基胺基）-1H_p比峻并[3,4七】峨淀-5_甲酿胺Example 3S7 was prepared using a method similar to that of Example 191 from % of intermediate. LCMS showed MH+ = 472; Tret = 2.15 min. Example 358: Team (2,3-dihydrol-based H_ethylmethylmethyl_4_(tetrahydro-2H-pyran-4-ylamino)-1H_p ratio and [3,4-7]峨淀-5_甲甲胺

實例35δ係使用類似實例191之方法，製自中間物％。 LCMS 顯示 MH+=394 ; Tret=2.04 分鐘。 籲 實例 360-414Example 35δ was prepared using a method analogous to Example 191 from % of intermediate. LCMS showed MH+ = 394; Tret = 2.04 min. Call example 360-414

nr4r5 一般程序 以二氯化亞硫醯（10 *升）處理中間物33 (1 89克），並將混合 87841·96〇3〇3_ 中.doc -261 - 1283678 物於回流下加熱2小時。於真空中移除過量二氯化亞硫醯， 而得中間物73，假設為中間物33之氯化醯，為乳黃色固 體。使固體懸浮於四氫呋喃（32.5毫升）中，並將一份懸浮液 添加至胺（0.11毫莫耳）與N，N-二異丙基乙胺（0.165-0.22毫莫耳） 在THF (0.5毫升）中之混合物内。將反應混合物攪拌24小時， 並在真空中移除溶劑。使殘留物藉質量導引之自預備HPLC 純化。 實例編號 NR4R^ hnr4r5 之來源 起始物質 MH+ 離子 LC-MC 滯留時間 360 ΟγΟ. Interchim 中間物 中間物33 477 2.98 361 MU Aldrich 中間物33 408 3.45 362 α： Aldrich 中間物33 384 3.09 363 0 Butt Park 公司 中間物33 437 2.69 364 丫 χχ Aldrich 中間物33 432 3.21 365 Maybridge 化學公司 中間物33 437 2.72 366 Aldrich 中間物33 382 2.67 367 f Interchim 中間物 中間物33 519 3.01 368 Aldrich +間物33 367 2.19 369 Butt Park 公司 中間物33 492 2.21 370 。心 J. Chem, Soc. C， 1969, 1444 中間物33 449 2.72 87841-960303-中.doc -262- 1283678 371 Peakdale 技術有限 公司Μ 中間物33 444 2.81 372 VX J. Heterocycl Chem., 1975, 12(2), 225 中間物33 437 2.74 373 。’ Interchim 中間物 中間物33 459 2.79 374 Xx: Apollo 科學公司 中間物33 400 2.99 375 a Aldrich 中間物33 400 3.35 376 6r Lancaster 中間物33 425 3.07 377 Maybridge CombiChem 中間物33 513 3.33 379 T° Peakdale 技術有限 公司 中間物33 444 2.99 380 〇丫 N、 J. Heterocycl. Chem” 1975， 12(2)，225 中間物33 437 2.64 381 ΟγΟ-MU Interchim 中間物 中間物33 479 2.68 382 Aceto公司 中間物33 425 3.38 383 Aldrich 中間物33 382 2.78 384 Aldrich 中間物33 400 3.38Nr4r5 General procedure Intermediate 33 (1 89 g) was treated with sulfinium dichloride (10 * liter) and the mixture of 87841·96 〇 3 〇 3 _ .doc - 261 - 1283 678 was heated under reflux for 2 hours. Excess ruthenium dichloride was removed in vacuo to give intermediate 73, which was assumed to be the ruthenium chloride of intermediate 33, which was a cream solid. The solid was suspended in tetrahydrofuran (32.5 ml) and a portion of the suspension was added to the amine (0.11 mmol) and N,N-diisopropylethylamine (0.165-0.22 mmol) in THF (0.5 ml In the mixture. The reaction mixture was stirred for 24 hours and the solvent was removed in vacuo. The residue was purified by preparative HPLC by mass guidance. Example No. NR4R^ hnr4r5 Source Starting material MH+ Ion LC-MC Retention time 360 ΟγΟ. Interchim Intermediate Intermediate 33 477 2.98 361 MU Aldrich Intermediate 33 408 3.45 362 α: Aldrich Intermediate 33 384 3.09 363 0 Butt Park Company Intermediate 33 437 2.69 364 丫χχ Aldrich Intermediate 33 432 3.21 365 Maybridge Chemical Company Intermediate 33 437 2.72 366 Aldrich Intermediate 33 382 2.67 367 f Interchim Intermediate Intermediate 33 519 3.01 368 Aldrich + Interstitial 33 367 2.19 369 Butt Park company intermediate 33 492 2.21 370. Heart J. Chem, Soc. C, 1969, 1444 Intermediate 33 449 2.72 87841-960303-中.doc -262- 1283678 371 Peakdale Technology Co., Ltd. 中间 Intermediate 33 444 2.81 372 VX J. Heterocycl Chem., 1975, 12 (2), 225 Intermediate 33 437 2.74 373. 'Interchim Intermediate Intermediate 33 459 2.79 374 Xx: Apollo Scientific Company Intermediate 33 400 2.99 375 a Aldrich Intermediate 33 400 3.35 376 6r Lancaster Intermediate 33 425 3.07 377 Maybridge CombiChem Intermediate 33 513 3.33 379 T° Peakdale Technology Limited Company Intermediate 33 444 2.99 380 〇丫N, J. Heterocycl. Chem” 1975, 12(2), 225 Intermediate 33 437 2.64 381 ΟγΟ-MU Interchim Intermediate Intermediate 33 479 2.68 382 Aceto Intermediate 33 425 3.38 383 Aldrich Intermediate 33 382 2.78 384 Aldrich Intermediate 33 400 3.38

87841-960303-中.doc -263 - 1283678 •386 丫0 HN、 WO 03/32986 中間物33 467 2,65 387 Ο、/ Maybridge 化學公司 中間物33 513 3.35 388 中間物67 中間物33 505 3.23 389 0 Lancaster 中間物33 451 3.17 390 EP 538945 中間物33 487 2.80 391 Aldrich 中間物33 416 2.99 392 Interchim 中間物 中間物33 459 2.74 393 Butt Park 公司 中間物33 423 2.66 394 r F Aldrich 中間物33 434 3.43 395 N^nh Aldrich 中間物33 367 2.40 396 Aldrich;或 Reetz, Synthesis^ 1999, 9, 1555 中間物33 434 3,67 397 Η,-Lo Bayer AG 中間物33 479 2.89 398 η 探索圖書館 中間物33 451 2.91 399 ο./ Maybridge 化學公司 中間物33 515 3.0287841-960303-中.doc -263 - 1283678 •386 丫0 HN, WO 03/32986 Intermediate 33 467 2,65 387 Ο, / Maybridge Chemical Company Intermediate 33 513 3.35 388 Intermediate 67 Intermediate 33 505 3.23 389 0 Lancaster Intermediate 33 451 3.17 390 EP 538945 Intermediate 33 487 2.80 391 Aldrich Intermediate 33 416 2.99 392 Interchim Intermediate Intermediate 33 459 2.74 393 Butt Park Company Intermediate 33 423 2.66 394 r F Aldrich Intermediate 33 434 3.43 395 N^nh Aldrich Intermediate 33 367 2.40 396 Aldrich; or Reetz, Synthesis^ 1999, 9, 1555 Intermediate 33 434 3,67 397 Η,-Lo Bayer AG Intermediate 33 479 2.89 398 η Explore Library Intermediate 33 451 2.91 399 ο./ Maybridge Chemical Company Intermediate 33 515 3.02

87841-960303-中.doc -264- 1283678 400 9- 0 TimTec 中間物33 492 2.20 401 探索圖書館 中間物33 437 2.68 402 α Lancaster 中間物33 468 3.53 403 0丄NH 〇1 Heterocycles, 1983 20(3), 445 中間物33 437 2.70 404 α： Aldrich 中間物33 400 3.09 405 &amp; Aldrich 中間物33 418 3.21 406 Aldrich 中間物33 384 3.19 407 ά： Aldrich 中間物33 409 2.95 408 Helv, Chim. Actay 1983 66(4), 1046 中間物33 472 3.07 409 Αχ Butt Park 公司 中間物33 437 2.68 411 VCH* Salor 中間物33 444 2.69 413 Peakdale 分子 有限公司 中間物33 437 2.3587841-960303-中.doc -264-1283678 400 9- 0 TimTec Intermediate 33 492 2.20 401 Exploring the library intermediate 33 437 2.68 402 α Lancaster Intermediate 33 468 3.53 403 0丄NH 〇1 Heterocycles, 1983 20(3 ), 445 Intermediate 33 437 2.70 404 α: Aldrich Intermediate 33 400 3.09 405 &amp; Aldrich Intermediate 33 418 3.21 406 Aldrich Intermediate 33 384 3.19 407 ά: Aldrich Intermediate 33 409 2.95 408 Helv, Chim. Actay 1983 66 (4), 1046 Intermediate 33 472 3.07 409 Αχ Butt Park Company Intermediate 33 437 2.68 411 VCH* Salor Intermediate 33 444 2.69 413 Peakdale Molecular Co., Ltd. Intermediate 33 437 2.35

會例414 : 1-乙基-4-(四氫-2H-哌喃-3-基胺基）-1Η^比吐并[3,4-b]竹b 啶-5-甲醯胺 -265 - 87841-960303-中.doc 1283678Example 414: 1-Ethyl-4-(tetrahydro-2H-piperidin-3-ylamino)-1Η^ than spit [3,4-b]bambob-5-carboxamide-265 - 87841-960303-中.doc 1283678

nh2 實例414係使用關於實例360-413方法所述之一般方法，製 自中間物 59。LCMS 顯示MH+=398 ; Tret = 2.90 分鐘。 實例 415-487The nh2 instance 414 was prepared from the intermediate 59 using the general method described in relation to the example 360-413 method. LCMS showed MH+ = 398; Tret = 2.90 min. Example 415-487

一般程序 使中間物61 (0.1毫莫耳）、HATU(0.1毫莫耳）及DIPEA(0.4毫 莫耳）在DMF (0.4毫升）中之混合物於室溫下振盪10分鐘。然 後添加胺（〇·1毫莫耳）在DMF(0.2毫升）中之溶液，並將混合物 攪拌數分鐘，獲得溶液。將溶液在室溫下儲存16小時，接 著於真空中濃縮。使殘留物溶於氯仿（0.5毫升）中，並施加 至SPE藥筒（胺基丙基，0.5克）。將藥筒連續以氯仿（1.5毫 升）、EtOAc(1.5 毫升）及EtOAc: MeOH(9: 1，1.5 毫升）溶離。 在真空中濃縮含有所要產物之溶離份，並使殘留物藉質量 導引之自預備HPLC純化。 實例編號 nr4r5 hnr4r5 之來源 起始物質 MH+ 離子 LC-MC 滯留時間 415 h2n 々〇 稀有化學品 GmbH 中間物61 395 2.80 416 Aldrich 中間物61 345 2.64 4Π 0 Ultrafine (UFC公司） 中間物61 409 2.84 87841-960303-中.doc -266- 1283678 418 中間物8Α ; 或中間物8 (Combi-Blocks) 中間物61 372 3.03 419 -CTm N.D. Zelinsky 學會 有機化學 中間物61 382 2.96 420 Peakdale 分子公司 中間物61 456 3.22 421 Peakdale 分子公司 中間物61 421 3.03 422 ζ-j^m Aldrich 中間物61 372 3.09 423 J. Org. Chem.y 1955, 20,1657 中間物61 485 3.44 424 Key有機物 公司 中間物61 413 3.39 425 ^^S02Me Acros 中間物61 456 3.19 426 OMe WO 00/17163 中間物61 409 3,3 427 0 Peakdale 分子公司 中間物61 421 3.23 428 關· Peakdale 分子公司 中間物61 435 3-07 429 0 Peakdale 分子公司 中間物61 421 2.97 430 織Η Apin 中間物61 394 3.25 431 Acros;或 Aldrich;或 Jung等人， Tetrahedron Lett., 2002, 43(48), 8735; 或Meindl等 人，J.細. Chem., 1984, 27(9)，1111;或 Org, Lett” 2002, 4,2055 中間物61 408 3.51General Procedure A mixture of intermediate 61 (0.1 mmol), HATU (0.1 mmol) and DIPEA (0.4 mmol) in DMF (0.4 mL) was shaken at room temperature for 10 min. Then, a solution of an amine (〇·1 mmol) in DMF (0.2 ml) was added, and the mixture was stirred for several minutes to obtain a solution. The solution was stored at room temperature for 16 hours and then concentrated in vacuo. The residue was dissolved in chloroform (0.5 mL) and applied to EtOAc (EtOAc: The cartridge was lysed in chloroform (1.5 mL), EtOAc (1.5 mL) and EtOAc: MeOH (9:1, 1.5 mL). The fractions containing the desired product were concentrated in vacuo and the residue was purified by preparative HPLC with mass. Example No. nr4r5 Source of hnr4r5 Starting material MH+ Ion LC-MC Retention time 415 h2n 々〇 Rare chemical GmbH Intermediate 61 395 2.80 416 Aldrich Intermediate 61 345 2.64 4Π 0 Ultrafine (UFC) Intermediate 61 409 2.84 87841- 960303-中.doc -266- 1283678 418 Intermediate 8Α; or Intermediate 8 (Combi-Blocks) Intermediate 61 372 3.03 419 -CTm ND Zelinsky Society of Organic Chemistry 61 382 2.96 420 Peakdale Molecular Company Intermediate 61 456 3.22 421 Peakdale Molecular Company Intermediate 61 421 3.03 422 ζ-j^m Aldrich Intermediate 61 372 3.09 423 J. Org. Chem.y 1955, 20,1657 Intermediate 61 485 3.44 424 Key Organics Intermediate 61 413 3.39 425 ^ ^S02Me Acros Intermediate 61 456 3.19 426 OMe WO 00/17163 Intermediate 61 409 3,3 427 0 Peakdale Molecular Company Intermediate 61 421 3.23 428 Off · Peakdale Molecular Company Intermediate 61 435 3-07 429 0 Peakdale Molecular Company Middle Object 61 421 2.97 430 woven Apin intermediate 61 394 3.25 431 Acros; or Aldrich; or Jung et al, Tetrahedron Lett., 2002, 43(48), 8735; or Meindl . Al., J Fine Chem, 1984, 27 (9), 1111;. Or Org, Lett "2002, 4,2055 Intermediate 61 408 3.51

87841-960303-中.doc 267- 1283678 432 -xc； Aldrich 中間物61 414 3.68 433 德5 Aldrich; A Meindl 等人，/ Med. Chem.t 1984,27(9)， 1111. 中間物61 446 3.81 434 J. Med. Chem.y 1999, 42(14), 2504 中間物61 471 3.23 435 F Aldrich 中間物61 414 3.66 436 JX&quot; Aldrich;或 Organic Letters, 2002, 4(12), 2055 中間物61 392 3.69 438 Key有機物 公司 中間物61 485 3.25 439 Buttpark 中間物61 394 3.52 440 ΙίΧ- Aldrich;或 Meindl 等人，·/. Med. Chern., 1984, 27(9), 1111· 中間物61 446 4 441 aXpr^ Cl Lancaster;或 Meindl 等人，/ Med, Chem” 1984, 27(9), 1111. 中間物61 446 4.08 442 Aldrich 中間物61 392 3.62 443 ςο m Aldrich 中間物61 418 3.83 444 U &quot; WO 01/38323 中間物61 440 3.07 445 Aldrich 中間物61 408 3.31 446 H,N、/ Acros 中間物61 471 3.13 87841-960303-中.doc 268 - 1283678 447 分。 〇r- Peakdale 分子公司 中間物61 435 3.13 448 CH, 〇 = R=〇 u &quot; Peakdale 分子公司 中間物61 456 3.32 449 CH, u &quot; Peakdale 分子公司 中間物61 436 3.56 450 M、/ Aldrich 中間物61 471 2.79 451 Ί H3c_0 ^ Na J, Med, Chem., 1982, 25(12), 1442 中間物61 465 3.11 452 ABCR 中間物61 464 3.47 453 Matrix 科學；或 Chem. Ber” 1969, 102, 2770 中間物61 407 3.35 454 Aldrich 中間物61 411 3.18 455 &quot;X)u. Aldrich 中間物61 407 3.3 456 Aldrich 中間物61 423 3.09 457 (為 CF3 C(0)OH 鹽） CT&quot; Aldrich 中間物61 379 2.92 458 FX^Tm F Aldrich 中間物61 414 3.68 459 Aldrich 中間物61 404 3.72 460 (為 CF3 C(0)0H 鹽） in, Aldrich 中間物61 421 3.29 87841-960303-中.doc -269- 1283678 461 Aldrich 中間物61 396 3.58 462 H，c、0 CH, Aldrich 中間物61 438 3.53 463 (為 CF3 C(0)0H 鹽） Inorganic Chemistry, 1997, 36(9), 1967 中間物61 413 3.4 464(為 cf3 c(〇)〇h 鹽） CH, 人A Peakdale 分子公司 中間物61 449 3.18 465 ABCR 中間物61 422 3.77 466 (5^ Aldrich 中間物61 404 3.72 467 Pfaltz-Bauer; 或Meindl等 人，J, Med· Chem.t 1984, 27(9),1111. 中間物61 446 3.85 468 CH, Peakdale 分子公司 中間物61 436 3.53 469 Aldrich 中間物61 404 3.66 470 Aldrich 中間物61 435 3.52 471 Esprit 中間物61 370 2.82 472 λΤ Apollo 中間物61 444 3.63 473 MicroChemist ry- RadaPharma π中間物61 399 3.16 87841-960303-中.doc -270- 1283678 474 0C Fluka 中間物61 430 3.72 475 J. Am. Chem. Socty 1977, 99, 3075 中間物61 421 3.04 477 H,C、n/CH3 J. Org. Chem., 2001, 66(6), 1999 中間物61 421 2.89 478 FJX&quot; Aldrich 中間物61 396 3.59 479 Aldrich;或 Meindl 等人，/ Med, Chem., 1984,27(9)， 1111. 中間物61 446 3.80 480 6c Aldrich 中間物61 414 3.57 481 Aldrich;或 Meindl 等人,/ Med. Chem” 1984, 27(9)， 1111. 中間物61 396 3.62 482 Aldrich 中間物61 446 3.82 483 1 Med. Chem., 2001, 44(26), 4628 中間物61 438 3.95 484 WO 9417035 中間物61 485 ，〇&quot;〇、 Aldrich 中間物61 394 3.61 486 MicroChemist ry- RadaPharma 中間物61 395 2.78 487 Aldrich 中間物61 379 2.7187841-960303-中.doc 267- 1283678 432 -xc; Aldrich Intermediate 61 414 3.68 433 De 5 Aldrich; A Meindl et al, / Med. Chem.t 1984, 27(9), 1111. Intermediate 61 446 3.81 434 J. Med. Chem.y 1999, 42(14), 2504 Intermediate 61 471 3.23 435 F Aldrich Intermediate 61 414 3.66 436 JX&quot;Aldrich; or Organic Letters, 2002, 4(12), 2055 Intermediate 61 392 3.69 438 Key Organics Intermediate 61 485 3.25 439 Buttpark Intermediate 61 394 3.52 440 ΙίΧ- Aldrich; or Meindl et al., Med. Chern., 1984, 27(9), 1111· Intermediate 61 446 4 441 aXpr^ Cl Lancaster; or Meindl et al, / Med, Chem" 1984, 27(9), 1111. Intermediate 61 446 4.08 442 Aldrich Intermediate 61 392 3.62 443 ςο m Aldrich Intermediate 61 418 3.83 444 U &quot; WO 01/38323 Intermediate 61 440 3.07 445 Aldrich Intermediate 61 408 3.31 446 H,N, / Acros Intermediate 61 471 3.13 87841-960303-中.doc 268 - 1283678 447 points 〇r- Peakdale Molecular Company Intermediate 61 435 3.13 448 CH, 〇= R=〇u &quot; Peakdale Molecular Company Intermediate 61 456 3.32 449 CH, u &quot; Peakdale Molecular Company Intermediate 61 436 3.56 450 M, / Aldrich Intermediate 61 471 2.79 451 Ί H3c_0 ^ Na J, Med, Chem., 1982, 25(12), 1442 Intermediate 61 465 3.11 452 ABCR Intermediate 61 464 3.47 453 Matrix Science; or Chem. Ber" 1969, 102, 2770 Intermediate 61 407 3.35 454 Aldrich Intermediate 61 411 3.18 455 &quot;X)u. Aldrich Intermediate 61 407 3.3 456 Aldrich Intermediate 61 423 3.09 457 ( CF3 C(0)OH salt) CT&quot; Aldrich Intermediate 61 379 2.92 458 FX^Tm F Aldrich Intermediate 61 414 3.68 459 Aldrich Intermediate 61 404 3.72 460 (for CF3 C(0)0H salt) in, Aldrich Middle Object 61 421 3.29 87841-960303-中.doc -269- 1283678 461 Aldrich Intermediate 61 396 3.58 462 H,c,0 CH, Aldrich Intermediate 61 438 3.53 463 (for CF3 C(0)0H salt) Inorganic Chemistry, 1997, 36(9), 1967 Intermediate 61 413 3.4 464 (for cf3 c(〇)〇h salt) CH, Human A Peakdale Molecular Company Intermediate 61 449 3.18 465 ABCR Intermediate 61 422 3.77 466 (5^ Aldrich Middle Object 61 404 3.72 467 Pfaltz-Bauer; or Meindl et al, J, Med·Che Mt 1984, 27(9), 1111. Intermediate 61 446 3.85 468 CH, Peakdale Molecular Company Intermediate 61 436 3.53 469 Aldrich Intermediate 61 404 3.66 470 Aldrich Intermediate 61 435 3.52 471 Esprit Intermediate 61 370 2.82 472 λΤ Apollo Intermediate 61 444 3.63 473 MicroChemist ry- RadaPharma π Intermediate 61 399 3.16 87841-960303-中.doc -270- 1283678 474 0C Fluka Intermediate 61 430 3.72 475 J. Am. Chem. Socty 1977, 99, 3075 Intermediate 61 421 3.04 477 H, C, n/CH3 J. Org. Chem., 2001, 66(6), 1999 Intermediate 61 421 2.89 478 FJX&quot; Aldrich Intermediate 61 396 3.59 479 Aldrich; or Meindl et al., / Med , Chem., 1984, 27(9), 1111. Intermediate 61 446 3.80 480 6c Aldrich Intermediate 61 414 3.57 481 Aldrich; or Meindl et al, / Med. Chem" 1984, 27(9), 1111. Intermediate 61 396 3.62 482 Aldrich Intermediate 61 446 3.82 483 1 Med. Chem., 2001, 44(26), 4628 Intermediate 61 438 3.95 484 WO 9417035 Intermediate 61 485 , 〇&quot;〇, Aldrich Intermediate 61 394 3.61 486 MicroChemist ry- RadaPharma Intermediate 61 395 2.78 487 Aldric h Intermediate 61 379 2.71

會例488 : 4-[({[4_(環己胺基）-1-乙基-1H-吡唑并[3,4-b]吡啶-5-基] 羰基}胺基）甲基]苯甲酸 -271 - 87841-960303-中.doc 1283678Example 488: 4-[({[4-(cyclohexylamino)-1-ethyl-1H-pyrazolo[3,4-b]pyridin-5-yl]carbonyl}amino)methyl]benzene Formic acid -271 - 87841-960303-中.doc 1283678

將2M-氫氧化鈉溶液（29微升，0.058毫莫耳）添加至實例 470 (6毫克，0.014毫莫耳）在甲醇(28微升）與水(2微升）中之經 攪拌溶液内。於50°C及氮氣下攪拌所形成之溶液。16小時 後’將混合物以水（0.5毫升）稀釋，並以醋酸調整至pjj4。藉 過滤收集已沉殿之固體，並在真空中乾燥，而得實例， 為白色固體（4·5毫克）。LCMS顯示MH+=422 ; Tret=3.26分 鐘。 實例489 : 3_[({[冬(環己胺基）小乙基吡唑并[3 4七】〃比啶冬基】 羰基}胺基）甲基】苯甲酸2M-sodium hydroxide solution (29 microliters, 0.058 millimoles) was added to a stirred solution of example 470 (6 mg, 0.014 mmol) in methanol (28 microliters) and water (2 microliters) . The resulting solution was stirred at 50 ° C under nitrogen. After 16 hours, the mixture was diluted with water (0.5 ml) and adjusted to pjj4 with acetic acid. The solids from the sinking chamber were collected by filtration and dried in vacuo to give a white solid (4.5 mg). LCMS showed MH+ = 422; Tret = 3.26 min. Example 489: 3_[({[Winter (cyclohexylamino))ethylethylpyrazolo[3 4-7]indolepyridinyl]carbonyl}amino)methyl]benzoic acid

將2M-氫氧化鈉溶液（83微升，〇·ΐ66毫莫耳）添加至實例468 (18毫克，0.042毫莫耳）在甲醇（88微升）與水(5微升）中之經攪 拌溶液内。於50°C及氮氣下攪拌所形成之溶液。16小時後， 將另一數量之2M-氫氧化鈉溶液(29微升，〇·〇58毫莫耳）添加 87841-960303-中.doc -272- 1283678 至反應混合物中。24小時後，將反應混合物以水（〇·5毫升） 稀釋，並以醋酸調整至pH 4。以醋酸乙酯（2 X 0.5毫升）萃取混 合物，並使合併之萃液脫水乾燥（Na2S〇4),及在真空中蒸 發’獲得固體（21毫克）。使此固體於SPE藥筒（矽膠，1克）上 純化，以醋酸乙酯：環己烷（1 : 1)，接著以甲醇溶離。將含 有所要產物之溶離份合併，及濃縮，而得實例489，為白色 固體（4.6 毫克）。LCMS 顯示 MH+= 422 ; TRET= 3.22 分鐘。 复: 4_(環己胺基）_N_(2,3_二氫_111_茚_2_基）小乙基-1H_吡唑 并[3,4七]吡啶-5-甲醯胺里酸鹽2M-sodium hydroxide solution (83 μL, 〇·ΐ 66 mmol) was added to Example 468 (18 mg, 0.042 mmol) stirred in methanol (88 μL) and water (5 μL) In solution. The resulting solution was stirred at 50 ° C under nitrogen. After 16 hours, another quantity of 2M-sodium hydroxide solution (29 μL, 〇·〇 58 mmol) was added to the reaction mixture from 87841-960303-medium.doc-272-1283678. After 24 hours, the reaction mixture was diluted with water (5 mL) and adjusted to pH 4 with acetic acid. The mixture was extracted with ethyl acetate (2×0.5 mL), and then evaporated and evaporated. This solid was purified on a SPE cartridge (silica gel, 1 g) eluting with ethyl acetate: cyclohexane (1:1) followed by methanol. The fractions containing the desired product were combined and concentrated to give a white solid (4.6 mg). LCMS showed MH+ = 422; TRET = 3.22 min. Complex: 4_(cyclohexylamino)_N_(2,3_dihydro_111_茚_2_yl) small ethyl-1H-pyrazolo[3,4-7]pyridine-5-carboxamide salt

將實例469 (71毫克，0.17毫莫耳）在無水THF (2毫升）中之溶 液，以二氧陸圜中之氯化氫（4M，〇·3毫升）處理。於環境溫 度下靜置16小時後，藉過濾收集所形成之固體，並於真空 下乾燥，獲得實例490，為棒狀結晶（36毫克）。LCMS顯示 - 404 , Tr e τ = 3.60 分鐘。 免例491 : 4_(環己胺基）具(2,3_二氫_1H-茚_2_基）小乙基-iH_吡唑 并[3,4七】吡啶-5-甲醯胺甲烷磺酸鹽 87841_96〇3〇3-中.doc -273 - 1283678Example 469 (71 mg, 0.17 mmol) in EtOAc (2 mL) After standing at ambient temperature for 16 hours, the solid which formed was collected by filtration and dried under vacuum to afford s. LCMS shows -404, Tr e τ = 3.60 minutes. Free 491 : 4_(cyclohexylamino) with (2,3-dihydro-1H-茚_2-yl) small ethyl-iH-pyrazolo[3,4-7]pyridine-5-carboxamide Methanesulfonate 87841_96〇3〇3-中.doc -273 - 1283678

將實例469C71毫克，0.17毫莫耳）在無水_(2毫升）中之溶 液，以無水甲烷磺酸（11·4微升， 0.17毫莫耳）處理。於環境溫 度下靜置16小時後，藉過濾收集所形成之固體，並於真空 下乾燥’而得實例491 ’為棒狀結晶（23毫克）。lcms顯示 MH+= 404 ; TRET= 3.59 分鐘。 、 實例 492-649An example solution of 469 C 71 mg, 0.17 mmol, in anhydrous EtOAc (2 mL). After standing at ambient temperature for 16 hours, the solid which formed was collected by filtration and dried under vacuum to give </ RTI> </ RTI> as a rod crystal (23 mg). Lcms shows MH+= 404; TRET= 3.59 minutes. , example 492-649

一般程序 使中間物33(0.1毫莫耳）、_((U毫莫耳）&amp;DIpEA(〇4毫 莫耳）在DMF(0.4毫升）中之混合物於室溫下振盪1〇分鐘。然 後添加胺（0.1毫莫耳）在DMF(0.2毫升）中之溶液，並將混合物 攪拌數分鐘’獲得溶液。將溶液在室溫下儲存16小時，接 著在真空中濃縮。使殘留物溶於氯仿（0.5毫升）中，並施加 至SPE藥筒（胺基丙基，〇·5克）。將藥筒連續以氣仿（1·5毫 升）、EtOAc(1.5 毫升）及EtOAc: MeOH(9: 1，15 毫升）溶離。 於真空中濃縮含有所要產物之溶離份，並使殘留物藉質量 導引之自預備HPLC純化。 87841-960303-中.doc -274- 1283678 實例編號 NR4R5 hnr4r5 之來源 起始物質 MH+ 離子 LC-MC 滯留時間 492 (為 CF3 C(0)0H 鹽） OC&quot; Peakdale 分子公司 中間物33 453 2.90 493 XT- Maybridge 化學公司； 或 WO 01/30745 中間物33 428 2.92 494 Trans World 化學品 公司；或DE 1953059 中間物33 428 2.91 495 (V&quot; Fluorochem 公司 中間物33 446 2.70 496 Peakdale 分子公司 中間物33 438 2.83 497 qrm r Peakdale 分子公司 中間物33 438 2.79 498 ςτ&quot; Fluorochem 公司 中間物33 446 2.73 499 Aldrich 中間物33 426 2.50 500 Nippon Kagaku Zasshi] 1952, 73; 393 中間物33 438 2.62 87841-960303-中.doc 275 - 1283678 501 Apollo 科學公司 中間物33 462 2.88 502 Apin 化學品 公司 中間物33 437 2.19 503 Sigma 中間物33 410 2.60 504 Aldrich 中間物33 428 2.80 505 七。tx^ Miteni S.p.A. 中間物33 478 2.97 506 Aldrich 中間物33 424 2.58 507 J, Med· Chem.9 1997, 20(9), 1210 中間物33 436 2.44 508 也m Fluorochem 公司 中間物33 462 2.99 509 JP 11080156 中間物33 473 2.2 510 /0 Aldrich 中間物33 454 2.41 512 Synchem OHG 中間物33 462 2.96 513 Apin 化學品公司 中間物33 454 2.59 514 J. Chem, Soc. Perkin Trans. 1, 1977, 386 中間物33 438 2.75 515 9C^ F SIGMA-RBI 中間物33 430 2.65 516 /0 WO 9303022 中間物33 454 2.67 517 cc^ SIGMA-RBI 中間物33 408 2.73 87841-960303-中.doc 276- 1283678 518 Matrix 科學；或 Chem, Ber,、 1969, 102, 2770 中間物33 408 3.2 519 H,C-0广幽 J, Med, Chem.t 1982 25(12), 1442 中間物33 466 3 521 〇々々〇 Acros 中間物33 473 2.62 522 〇:； ch3 WO 01/38323 中間物33 445 2.55 523 Aldrich 中間物33 394 3 524 CH, Aldrich 中間物33 423 2.51 525 Fxx^. Aldrich :中間物33 412 3.06 526 Aldrich 中間物33 408 3.16 527 ςτ- Η,Ν-^=0 0 Yakugaku Zasshi; 1950 70,71 中間物33 459 2.6 528 .xr- Aldrich;或 Organic Letters, 2002, 4(12), 2055 中間物33 394 3.08 530 Lancaster 中間物33 466 3.31 531 o；r H3c〆0 J, Am, Chem, Soc.} 1976, 78(22), 6978 中間物33 438 3 532 (為 CF3 C(0)0H 鹽） ςτ^ Cl Inorganic Chemistry, 1997,36(9), 1967 中間物33 415 2,82 87841-960303-中.doc -277- 1283678 533 0^ Aldrich 中間物33 406 3.14 534 CC- Peakdalc 分子公司 中間物33 451 2.71 535 Aldrich 中間物33 406 3.15 536 Aldrich 中間物33 406 3.15 537 J. Med. Chem., 1999, 42(14), 2504 中間物33 473 2.58 538 ςο ch3 化學結構 單位 中間物33 422 2.92 540 9 Ν s Wn、Ch3 Aldrich 中間物33 451 2.13 541 9 V Aldrich 中間物33 436 .3.15 542 CP Aldrich 中間物33 408 • 2.85 544 j〇〇 Janssen 酱藥 中間物33 449 2.67 545 jO1— 中間物 69 中間物33 444 2.34 546 (為 H-C(0)0H 鹽 =甲酸加成 鹽） 〇, Arzneimittel Forschungt 1974, 24(4a), 584 中間物33 430 1.95General Procedure A mixture of Intermediate 33 (0.1 mmol), _ ((U Mill) &amp; DIpEA (〇 4 mmol) in DMF (0.4 mL) was shaken at room temperature for 1 Torr. A solution of the amine (0.1 mmol) in DMF (0.2 mL) was added and the mixture was stirred for a few minutes to give a solution. The solution was stored at room temperature for 16 hours, then concentrated in vacuo. The residue was dissolved in chloroform. (0.5 ml) and applied to the SPE cartridge (aminopropyl, 〇·5 g). The cartridge was continuously vented (1·5 mL), EtOAc (1.5 mL) and EtOAc: MeOH (9: 1.15 ml) Dissolve. Dissolve the fractions containing the desired product in vacuo and purify the residue by preparative HPLC by mass guidance. 87841-960303-中.doc -274- 1283678 Example No. NR4R5 Source of hnr4r5 MH+ ion LC-MC retention time 492 (for CF3 C(0)0H salt) OC&quot; Peakdale Molecular Company Intermediate 33 453 2.90 493 XT- Maybridge Chemical Company; or WO 01/30745 Intermediate 33 428 2.92 494 Trans World Chemical company; or DE 1953059 Intermediate 33 428 2.91 495 (V&q Uot; Fluorochem Intermediary 33 446 2.70 496 Peakdale Molecular Company Intermediate 33 438 2.83 497 qrm r Peakdale Molecular Company Intermediate 33 438 2.79 498 ςτ&quot; Fluorochem Intermediary 33 446 2.73 499 Aldrich Intermediate 33 426 2.50 500 Nippon Kagaku Zasshi 1952, 73; 393 Intermediate 33 438 2.62 87841-960303-中.doc 275 - 1283678 501 Apollo Scientific Company Intermediate 33 462 2.88 502 Apin Chemical Company Intermediate 33 437 2.19 503 Sigma Intermediate 33 410 2.60 504 Aldrich Middle 33 428 2.80 505 VII. tx^ Miteni SpA Intermediate 33 478 2.97 506 Aldrich Intermediate 33 424 2.58 507 J, Med·Chem.9 1997, 20(9), 1210 Intermediate 33 436 2.44 508 Also m Fluorochem Company Intermediate Substance 33 462 2.99 509 JP 11080156 Intermediate 33 473 2.2 510 /0 Aldrich Intermediate 33 454 2.41 512 Synchem OHG Intermediate 33 462 2.96 513 Apin Chemical Company Intermediate 33 454 2.59 514 J. Chem, Soc. Perkin Trans. 1 , 1977, 386 Intermediate 33 438 2.75 515 9C^ F SIGMA-RBI Intermediate 33 430 2.65 516 /0 WO 9303022 Intermediate 33 454 2.67 517 cc^ SIGMA-RBI Intermediate 33 408 2.73 87841-960303-中.doc 276- 1283678 518 Matrix Science; or Chem, Ber,, 1969, 102, 2770 Intermediate 33 408 3.2 519 H, C-0 wide J, Med, Chem.t 1982 25(12), 1442 Intermediate 33 466 3 521 〇々々〇Acros Intermediate 33 473 2.62 522 〇:; ch3 WO 01/38323 Intermediate 33 445 2.55 523 Aldrich Intermediate 33 394 3 524 CH, Aldrich Intermediate 33 423 2.51 525 Fxx^. Aldrich : Intermediate 33 412 3.06 526 Aldrich Intermediate 33 408 3.16 527 ςτ- Η, Ν-^=0 0 Yakugaku Zasshi; 1950 70,71 Intermediate 33 459 2.6 528 .xr- Aldrich; or Organic Letters, 2002, 4(12), 2055 Intermediate 33 394 3.08 530 Lancaster Intermediate 33 466 3.31 531 o;r H3c〆0 J, Am, Chem, Soc.} 1976, 78 (22), 6978 Intermediate 33 438 3 532 (for CF3 C(0)0H salt) ςτ^ Cl Inorganic Chemistry, 1997,36(9), 1967 Intermediate 33 415 2,82 87841-960303-中.doc - 277- 1283678 533 0^ Aldrich Intermediate 33 406 3.14 534 CC- Peakdalc Molecular Company Intermediate 33 451 2.71 535 Aldrich Intermediate 33 406 3.15 536 Aldrich Middle 33 406 3.15 537 J. Med. Chem., 1999, 42(14), 2504 Intermediate 33 473 2.58 538 ςο ch3 Chemical structure unit intermediate 33 422 2.92 540 9 Ν s Wn, Ch3 Aldrich Intermediate 33 451 2.13 541 9 V Aldrich Intermediate 33 436 .3.15 542 CP Aldrich Intermediate 33 408 • 2.85 544 j〇〇Janssen Potion Intermediate 33 449 2.67 545 jO1—Intermediate 69 Intermediate 33 444 2.34 546 (for HC(0)0H Salt = Formic acid addition salt) 〇, Arzneimittel Forschungt 1974, 24(4a), 584 Intermediate 33 430 1.95

87841-960303-中.doc -278- 1283678 547 WO 97/25323 中間物33 445 1.96 548(為 CF3C(0)0H 鹽） OjCT&quot; WO 03/32980 中間物33 479 2.21 549 (為 CF3 C(0)0H 鹽） WO 03/32980 中間物33 492 2.24 550 (為 CF3 C(0)0H 鹽） WO 02/85860 中間物33 424 2.33 551 Salor 中間物33 422 3.36 552 9 WO 95/00516 中間物33 494 3.22 553 (為 CF3C(0)0H 鹽） XuD^ WO 03/32980 中間物33 492 2.21 554 1 ct^ Aldrich;或 Mdndl等人， J, Med. Chem., 1984, 27(9), 1111. 中間物33 448 3.4 555 Aldrich 中間物33 416 3.06 556 FiVm Salor 中間物33 432 3.21 557 h，c、。^ ο DE 2300018 中間物33 458 3.12 558 4 Pcakdale 分子公司 中間物33 436 3.41 87841-960303-中.doc •279- 1283678 559 (為 CF3 C(0)OH 鹽） oJ JP 10045736 中間物33 463 2.28 560 WO 02/16318 EP 338793 中間物33 487 2.74 561 H,。、 H,〆 Maybridge 化學公司 中間物33 440 2.99 562 H，C CH, Lancaster 中間物33 440 3,00 563 Aldrich 中間物33 398 3.01 564 F Aldrich;或 Meindl 等人， J. Med. Chem.y 1984, 27(9), 1111. 中間物33 416 3.11 565 Aldrich;或 Organic Letters, 2002, 4(12), 2055 中間物33 414 3,19 567 Aldrich 中間物33 372 3.01 568 7. Biol Chem,, 1997,272(3), 1493 中間物33 472 2.69 569 Fluorochem 公司 中間物33 466 3.29 570 utW=\^° 中間物 71 中問物33 463 2.66 571 Maybridge Sih 中間物 中間物33 478 2.2587841-960303-中.doc -278-1283678 547 WO 97/25323 Intermediate 33 445 1.96 548 (for CF3C(0)0H salt) OjCT&quot; WO 03/32980 Intermediate 33 479 2.21 549 (for CF3 C(0) 0H salt) WO 03/32980 Intermediate 33 492 2.24 550 (for CF3 C(0)0H salt) WO 02/85860 Intermediate 33 424 2.33 551 Salor Intermediate 33 422 3.36 552 9 WO 95/00516 Intermediate 33 494 3.22 553 (for CF3C(0)0H salt) XuD^ WO 03/32980 Intermediate 33 492 2.21 554 1 ct^ Aldrich; or Mdndl et al, J, Med. Chem., 1984, 27(9), 1111. Intermediate 33 448 3.4 555 Aldrich Intermediate 33 416 3.06 556 FiVm Salor Intermediate 33 432 3.21 557 h, c,. ^ ο DE 2300018 Intermediate 33 458 3.12 558 4 Pcakdale Molecular Company Intermediate 33 436 3.41 87841-960303-中.doc • 279- 1283678 559 (for CF3 C(0)OH salt) oJ JP 10045736 Intermediate 33 463 2.28 560 WO 02/16318 EP 338793 Intermediate 33 487 2.74 561 H,. , H, 〆 Maybridge Chemical Company Intermediate 33 440 2.99 562 H, C CH, Lancaster Intermediate 33 440 3,00 563 Aldrich Intermediate 33 398 3.01 564 F Aldrich; or Meindl et al, J. Med. Chem.y 1984 , 27(9), 1111. Intermediate 33 416 3.11 565 Aldrich; or Organic Letters, 2002, 4(12), 2055 Intermediate 33 414 3,19 567 Aldrich Intermediate 33 372 3.01 568 7. Biol Chem,, 1997 , 272(3), 1493 Intermediate 33 472 2.69 569 Fluorochem Company Intermediate 33 466 3.29 570 utW=\^° Intermediate 71 Middle Question 33 463 2.66 571 Maybridge Sih Intermediate Intermediate 33 478 2.25

87841-960303-中.doc 280 - 1283678 572 WO 99/67204 中間物33 463 2.24 573 4ϊΤ、丨 Eur. J, Med. Chem” 1987， 22(5),417 中間物33 450 2.90 574 Cl Lancaster 中間物33 446/ 448/ 450 3.35 575 Eur. J, Med. Chem.y 1987, 33(5), 363 中間物33 436 3.48 576 Avocado 中間物33 416 3.06 577 WO 02/30930 中間物33 458 2.80 578 ^0H Apin 中間物33 458 2.80 579 0— Aldrich 中間物33 458 2.80 580 Aldrich 中間物33 581 Cl Lancaster;或 J, Med. Chem.9 1984, 27(9), 1111. 中間物33 446/ 448/ 450 2.80 582 Aldrich 中間物33 440 2.96· 583 Aldrich 中間物33 410 2.98 584 ICN 生物酱藥公 司；或Salor; 良 Synthesis、 1982, 12, 1036 中間物33 408 3.1887841-960303-中.doc 280 - 1283678 572 WO 99/67204 Intermediate 33 463 2.24 573 4ϊΤ, 丨Eur. J, Med. Chem” 1987, 22(5), 417 Intermediate 33 450 2.90 574 Cl Lancaster Intermediate 33 446/ 448/ 450 3.35 575 Eur. J, Med. Chem.y 1987, 33(5), 363 Intermediate 33 436 3.48 576 Avocado Intermediate 33 416 3.06 577 WO 02/30930 Intermediate 33 458 2.80 578 ^0H Apin Intermediate 33 458 2.80 579 0—Aldrich Intermediate 33 458 2.80 580 Aldrich Intermediate 33 581 Cl Lancaster; or J, Med. Chem. 9 1984, 27(9), 1111. Intermediate 33 446/ 448/ 450 2.80 582 Aldrich Intermediate 33 440 2.96· 583 Aldrich Intermediate 33 410 2.98 584 ICN Biological Sauce Company; or Salor; Good Synthesis, 1982, 12, 1036 Intermediate 33 408 3.18

87841-960303-中.doc 281 - 1283678 585 Η— WO 03/32986 中間物33 437 2.62 586 Aldrich 中間物33 424 3.05 587 Aldrich 中間物33 414/ 416 3.13 588 Buttpark 中間物33 396 2.14 589 Aldrich 中間物33 424 2.76 590 Lancaster 中間物33 396 2.95 591 Aldrich;或 Synlett, 1999, 4,409 中間物33 386 3.10 592 &amp; Aldrich 中間物33 593 Apin 中間物33 438 2.82 594 Aldrich;或 Meindl 等人， J. Med, Chem.j 1984, 27(9), 1111. 中間物33 448/ 450/ 452 3.26 595 WO 02/85860 中間物33 423 2.29 596 F Aldrich 中間物33 416 3.0 597 Aldrich 中間物33 423 2.56 598 Apin 中問物33 396 2.54 599 WO 00/17163 中間物33 411 2.72 600 Aldrich;或 J. Med. Chem.t 2003, 中間物33 381 1,8987841-960303-中.doc 281 - 1283678 585 Η- WO 03/32986 Intermediate 33 437 2.62 586 Aldrich Intermediate 33 424 3.05 587 Aldrich Intermediate 33 414/ 416 3.13 588 Buttpark Intermediate 33 396 2.14 589 Aldrich Intermediate 33 424 2.76 590 Lancaster Intermediate 33 396 2.95 591 Aldrich; or Synlett, 1999, 4, 409 Intermediate 33 386 3.10 592 &amp; Aldrich Intermediate 33 593 Apin Intermediate 33 438 2.82 594 Aldrich; or Meindl et al, J. Med, Chem .j 1984, 27(9), 1111. Intermediate 33 448/ 450/ 452 3.26 595 WO 02/85860 Intermediate 33 423 2.29 596 F Aldrich Intermediate 33 416 3.0 597 Aldrich Intermediate 33 423 2.56 598 Apin 33 396 2.54 599 WO 00/17163 Intermediate 33 411 2.72 600 Aldrich; or J. Med. Chem.t 2003, Intermediate 33 381 1,89

87841-960303-中.doc -282- 1283678 46(4), 461. 601 Aldrich;或 Meindl等人， J, Med. Chem.y 1984, 27(9), 1111. 中間物33 448 2.96 602 Peakdale 分子 有限公司 中間物33 423 2.28 603 WO 94/17035 中間物33 437 2.28 604 J.Pharm Sci.t 1987, 76(1), 18-20 中間物33 437 2,34 605 Mbvj0^F Aldrich;或 Meindl 等人， J. Med. Chem., 1984, 27(9), 1111; A Organic Letters^ 2002, 4(12), 2055 中間物33 398 2.71 606 &quot;Ί&gt;ηΛ〇 Lis等人，/ Med. Chem.y 1990, 33(10), 2883,參閱 囷式III與 參考資料24 中間物33 473 2.40 607 Sigma 中間物33 459 2.31 608 Η,Ν^Ο Peakdale 分子公司 中間物33 423 2.55 609 %人 Fluorochem 公司 中間物33 · 446 2.82 610 -Ί〇ΓΎ DE 19937494 中間物33 437 1.86 611 1 FluorochemL 士間物33 444 2.80 612 Τγ WOOO/72834 中間物33 415 2.12 613 F^F Aldrich 中間物33 448 2.96 87841-960303-中.doc 283 - 1283678 615 m J, Med, Chem,y 2001, 44(26), 4628 中間物33 440 3.03 616 中間物75 (為HC1鹽） 中間物33 451 2.62 617 Aldrich;或 Organic Letters, 2002, 4(12), 2055 中間物33 398 2.90 618 Alfa 中間物33 466 2.98 619 Energy &amp; Fuels, (1994), 8(4), 990-1001 中間物33 408 2.86 620 Alfa 中間物33 466 2.94 621 Apollo 中間物33 434 2.82 622 Acros 中間物33 432 2.9 623 Acros 中間物33 476 2.95 624 Apollo;或 Eur. J. Med, Chem.y 1998, 33(5), 363 中間物33 408 2.88 625 ^ir Maybridgc 中間物33 408 2.83 626 Lancaster 中間物33 448 3.02 627 Apin 中間物33 405 2.56 628 &quot;Π. Ubi-Chem 中W物33 458 2.89 87841-960303-中.doc 284- 1283678 629 F ABCR 中間物33 466 2.97 630 Lancaster 中間物33 505. 9 2.97 63 i Apollo 中間物33 436 3.11 632 WO 98/33767;或 Meindl 等人， J. Med. Chem.f 1984, 27(9),1111. 中間物33 405 2.55 633 Pfaltz-Bauer; 或Meindl等 Med, Chem.t 1984, 27 ⑼，1111 中間物33 448 2.88 634 a Transworld 中間物33 428 3.22 635 B- Apin (作為HC1鹽 使用） 中間物33 536 3.47 636 Matrix 中間物33 408 3.18 637 &quot;XC Avocado 中間物33 466 3.25 638 Pfaltz-Bauer 中間物33 505. 9 2.92 639 Alfa 中間物33 458 3.10 640 OH WO 03/35621 (作為HC1鹽 使用） 中間物33 410 2.49 641 WO 03/35621 (作為HC1鹽 使用） 中間物33 410 2.51 642 DE 2136624 (作為HC1鹽 使用） 中間物33 424 2.5587841-960303-中.doc-282- 1283678 46(4), 461. 601 Aldrich; or Meindl et al, J, Med. Chem.y 1984, 27(9), 1111. Intermediate 33 448 2.96 602 Peakdale Molecules Intermediary 33 423 2.28 603 WO 94/17035 Intermediate 33 437 2.28 604 J. Pharm Sci.t 1987, 76(1), 18-20 Intermediate 33 437 2,34 605 Mbvj0^F Aldrich; or Meindl et al Human, J. Med. Chem., 1984, 27(9), 1111; A Organic Letters^ 2002, 4(12), 2055 Intermediate 33 398 2.71 606 &quot;Ί&gt;ηΛ〇Lis et al., / Med. Chem .y 1990, 33(10), 2883, see 囷Form III and Reference 24 Intermediate 33 473 2.40 607 Sigma Intermediate 33 459 2.31 608 Η,Ν^Ο Peakdale Molecular Company Intermediate 33 423 2.55 609 % Human Fluorochem Intermediate 33 · 446 2.82 610 - Ί〇ΓΎ DE 19937494 Intermediate 33 437 1.86 611 1 FluorochemL Scorpion 33 444 2.80 612 Τ γ WOOO/72834 Intermediate 33 415 2.12 613 F^F Aldrich Intermediate 33 448 2.96 87841-960303 - 中.doc 283 - 1283678 615 m J, Med, Chem, y 2001, 44(26), 4628 Intermediate 33 440 3.03 616 Intermediate 75 (for HC1 salt) Middle 33 451 2.62 617 Aldrich; or Organic Letters, 2002, 4(12), 2055 Intermediate 33 398 2.90 618 Alfa Intermediate 33 466 2.98 619 Energy &amp; Fuels, (1994), 8(4), 990-1001 Intermediate 33 408 2.86 620 Alfa Intermediate 33 466 2.94 621 Apollo Intermediate 33 434 2.82 622 Acros Intermediate 33 432 2.9 623 Acros Intermediate 33 476 2.95 624 Apollo; or Eur. J. Med, Chem.y 1998, 33(5) , 363 Intermediate 33 408 2.88 625 ^ir Maybridgc Intermediate 33 408 2.83 626 Lancaster Intermediate 33 448 3.02 627 Apin Intermediate 33 405 2.56 628 &quot;Π. Ubi-Chem W object 33 458 2.89 87841-960303-中. Doc 284- 1283678 629 F ABCR Intermediate 33 466 2.97 630 Lancaster Intermediate 33 505. 9 2.97 63 i Apollo Intermediate 33 436 3.11 632 WO 98/33767; or Meindl et al, J. Med. Chem.f 1984, 27 (9), 1111. Intermediate 33 405 2.55 633 Pfaltz-Bauer; or Meindl et al Med, Chem.t 1984, 27 (9), 1111 Intermediate 33 448 2.88 634 a Transworld Intermediate 33 428 3.22 635 B- Apin (as HC1 Salt use) Intermediate 33 536 3.47 636 Matrix Intermediate 33 408 3.18 637 &quot;XC Avocado Intermediate 33 466 3.25 638 Pfaltz-Bauer Intermediate 33 505. 9 2.92 639 Alfa Intermediate 33 458 3.10 640 OH WO 03/35621 (used as HC1 salt) Intermediate 33 410 2.49 641 WO 03/35621 (Used as HC1 salt) Intermediate 33 410 2.51 642 DE 2136624 (used as HC1 salt) Intermediate 33 424 2.55

87841-960303-中.doc -285 - 1283678 643 Q (作為HC1鹽 使用） 中間物33 478 2.96 644 Aldrich 中間物33 462 3.13 645 Λ 中間物33 436 3.18 646 Matrix 中間物33 408 2.84 647 F Apollo 中間物33 434 2.80 648 ABCR 中間物33 466 2.99 649 Lancaster 中間物33 428 2.87 例518 ·· N-[(3,4_二甲基苯基）甲基】_1_乙基-4-(四氫_2H_哌喃_4-基胺基）-1Η_吡唑并[3,4-b】吡啶_5_甲醯胺；亦稱為：n_(3,4-二甲 基苄基）-1_乙基_4_(四氫·2Η_哌喃-4_基胺基）_ih-吡唑并[3,4_b】吡 啶-5-甲醯胺87841-960303-中.doc -285 - 1283678 643 Q (used as HCl salt) Intermediate 33 478 2.96 644 Aldrich Intermediate 33 462 3.13 645 中间 Intermediate 33 436 3.18 646 Matrix Intermediate 33 408 2.84 647 F Apollo Intermediate 33 434 2.80 648 ABCR Intermediate 33 466 2.99 649 Lancaster Intermediate 33 428 2.87 Example 518 ·· N-[(3,4-dimethylphenyl)methyl]_1_ethyl-4-(tetrahydro-2H _piperan-4-ylamino)-1Η-pyrazolo[3,4-b]pyridine_5-formamide; also known as: n_(3,4-dimethylbenzyl)-1_ Ethyl_4_(tetrahydro-2Η-piperidin-4-ylamino)_ih-pyrazolo[3,4_b]pyridine-5-carboxamide

一種用以製備實例518之替代方法係示於下文：於中間物 33 (3.5克’ 12.07毫莫耳）在DMF (500毫升）中之溶液内，添加 -286- 87841-960303-中.doc 1283678 HATU (4.5克，12.07毫莫耳），並將混合物在室溫下攪拌30分 鐘。添加3,4-二甲基苄胺（1.63克，12.07毫莫耳，可得自Mstrix 科學，Clumbia，USA或藉由C/^m.价r·，1969, 102, 2770中所述之方 法），接著是DIPEA(4.5毫升，26.55毫莫耳），並將溶液在室 溫下攪拌16小時。於減壓下移除溶劑，並使殘留物於飽和 NaHC03水溶液（200毫升）與醋酸乙酯（250毫升）之間作分液處 理，以醋酸乙酯（2x200毫升）再萃取水相，將有機萃液合 併，脫水乾燥（Na2S04)，及蒸發。使所形成之黏稠油自熱醋 酸乙酯（約100毫升）再結晶，而得標題化合物，為白色結晶 性固體（3.36 克，80% )。LCMS 顯示 MH+ = 408 ; Tret=3.06 分 鐘。5 η (D6 DMSO) 1 ·36 (3H，t)，1 ·51 (2H，m)，2.00 (2H，m)，2· 18 (3H，s)， 2·19 (3H，s)，2.50 (2H，m)，3.61 (2H，m)，3.83 (2H，m)，4·17 (1H，m)，4·36 (2H， q)，4·38 (2H，d)，7.02-7.09 (3H，m)，8.17 (1H，s)，8.62 (1H，s)，8.93 (1H，t)，9.96 (lH，d) : 5 c(D6DMSO) 14.65, 18.91，19.33, 32.81，41.06, 41.86, 48.57, 4.94, 101.69, 102.18, 124.44, 128.22, 129.24, 133.28, 134.31，135.78, 136.91，1 49.26, 149.59, 151.36, 168.81 實例518A : N-[(3,4_二甲基苯基）甲基]-1_乙基-4·(四氫-2H·哌喃-4-基胺基）-1Η_吡唑并[3,4-b]吡啶-5-甲醯胺鹽酸鹽；亦稱為：N-(3,4-二甲基爷基）-1-乙基-4-(四氮-2H-旅喃-4_基胺基）-111-¾1比也并 [3,4-b]吡啶-5-甲醯胺鹽酸鹽 8784 卜9603〇3_ 中.doc -287- 1283678 ο)An alternative method for the preparation of Example 518 is shown below: in a solution of Intermediate 33 (3.5 g ' 12.07 mmol) in DMF (500 mL), add -286- 87841-960303-中.doc 1283678 HATU (4.5 g, 12.07 mmol) and the mixture was stirred at room temperature for 30 min. Add 3,4-dimethylbenzylamine (1.63 g, 12.07 mmol, available from Mstrix Scientific, Clumbia, USA or by C/^m. price r., 1969, 102, 2770) ), followed by DIPEA (4.5 mL, 26.55 mmol), and the solution was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure and the residue was crystallised eluted eluted eluted eluted The extracts were combined, dehydrated (Na2S04), and evaporated. The resulting viscous oil was recrystallized from EtOAc (EtOAc:EtOAc) LCMS showed MH+ = 408; Tret = 3.06 min. 5 η (D6 DMSO) 1 ·36 (3H,t),1 ·51 (2H,m), 2.00 (2H,m),2· 18 (3H,s), 2·19 (3H,s), 2.50 (2H,m), 3.61 (2H,m),3.83 (2H,m),4·17 (1H,m),4·36 (2H, q),4·38 (2H,d),7.02-7.09 (3H, m), 8.17 (1H, s), 8.62 (1H, s), 8.93 (1H, t), 9.96 (lH, d): 5 c (D6DMSO) 14.65, 18.91, 19.33, 32.81, 41.06, 41.86 , 48.57, 4.94, 101.69, 102.18, 124.44, 128.22, 129.24, 133.28, 134.31, 135.78, 136.91, 1 49.26, 149.59, 151.36, 168.81 Example 518A: N-[(3,4-dimethylphenyl)methyl ]-1_ethyl-4·(tetrahydro-2H·piperidin-4-ylamino)-1Η-pyrazolo[3,4-b]pyridine-5-carboxamide hydrochloride; also known as Is: N-(3,4-dimethyl-aryl)-1-ethyl-4-(tetrazine-2H-bran-4-ylamino)-111-3⁄41 ratio also [3,4- b] Pyridine-5-methanamine hydrochloride 8878 卜9603〇3_中.doc -287-1283678 ο)

將實例518 (1,3克，3.19毫莫耳）在無水四氫呋喃（200毫升）中 之溶液，以氯化氫在二氧陸圜中之溶液(4M，8毫升）處理， 並將混合物於環境溫度下攪拌16小時。藉過濾收集所形成 之白色沉澱物，並自熱甲醇（100毫升）再結晶，而得標題化 合物實例518A，為白色結晶性固體（U2克，79% )。LCMS顯 示 MH+ = 408; Tret=3.21 分鐘。（5H(D6DMSO)1.39(3H，t)，1.59(2H， m)，2.01 (2H，m)，2.19 (3H，s)，2·20 (3H，s)，3·64 (2H，t)，3·83 (2H，m)，4·28 (1H ，m)5 4.40 (2H，d)，4.50 (2H，q)，7·04·7· 11 (3H，m)5 9.40 (1H, s (br))，10.72 (1H，s (br))· .實例650 : 4·丨({丨1·乙基_4_(四氫痕喃_4_基胺基）_ιη·吡唑并[3,4-b】吡啶-5-基】羰基}胺基）甲基】苯甲酸鈉里A solution of Example 518 (1,3 g, 3.19 mmol) in anhydrous tetrahydrofuran (200 mL) eluted with hydrogen chloride in dioxane (4M, 8 mL) and mixture at ambient temperature Stir for 16 hours. The resulting white solid was collected by EtOAc (EtOAc:EtOAc) LCMS showed MH+ = 408; Tret = 3.21 min. (5H(D6DMSO) 1.39 (3H, t), 1.59 (2H, m), 2.01 (2H, m), 2.19 (3H, s), 2·20 (3H, s), 3·64 (2H, t) ,3·83 (2H,m),4·28 (1H ,m)5 4.40 (2H,d),4.50 (2H,q),7·04·7· 11 (3H,m)5 9.40 (1H, s (br)), 10.72 (1H, s (br))·. Example 650: 4·丨({丨1·ethyl_4_(tetrahydro-s-furyl-4-ylamino)_ιη·pyrazolo[ 3,4-b]pyridin-5-yl]carbonyl}amino)methyl]benzoic acid

將2M-氫氧化鈉溶液（98微升，0.196毫莫耳）添加至實例593 (22毫克，0.049毫莫耳）在甲醇（1〇4微升）與水（6微升）中之經 攪拌溶液内。於50°C及氮氣下攪拌所形成之溶液。16小時 -288- 87841-960303-中.doc 1283678 後，將反應混合物以水（0.5毫升）稀釋，並以酷酸調整至 ΡΗ4。以醋酸乙酯（2x0.5毫升）萃取混合物，並使合併之萃液 脫水乾燥（NasSO4)，及在真空中蒸發，獲得固體（15毫克）。 使此固體懸浮於水（0.5毫升）中，並以2M-氫氧化鈉溶液（15微 升）處理。於真空中蒸發溶劑，獲得實例65〇，為白色固體 (11 毫克）。LCMS 顯示 MH+=425 ; Tret=2.69 分鐘。 复例651 : 3_[({[1-乙基_4-(四氫-2Η-ϊ痕喃-4_基胺基比也并[3,4-叫吡啶-5-基】羰基}胺基）甲基]苯甲酸2M-sodium hydroxide solution (98 μL, 0.196 mmol) was added to Example 593 (22 mg, 0.049 mmol) stirred in methanol (1 〇 4 μL) and water (6 μL) In solution. The resulting solution was stirred at 50 ° C under nitrogen. After 16 hours - 288 - 87841 - 960303 - medium .doc 1283678, the reaction mixture was diluted with water (0.5 ml) and adjusted to ΡΗ4 with a cool acid. The mixture was extracted with ethyl acetate (2x 0.5 mL). This solid was suspended in water (0.5 ml) and treated with a 2M- sodium hydroxide solution (15 liter). The solvent was evaporated in vacuo to give mp. LCMS showed MH+ = 425; Tret = 2.69 min. Replicate 651 : 3_[({[1-ethyl_4-(tetrahydro-2Η-scarred-4-ylamino)-[3,4-pyridin-5-yl]carbonyl}amine Methyl]benzoic acid

將2M-氫氧化鈉溶液（98微升，0.196毫莫耳）添加至實例558 (22毫克，0.049毫莫耳）在甲醇（1〇4微升）與水（6微升）中之經 攪拌溶液内。於50°C及氮氣下攪拌所形成之溶液。16小時 後，將反應混合物以水（0.5毫升）稀釋，並以醋酸調整至 pH4。藉過濾收集已沉澱之固體，並在真空中乾燥，而得實 例651，為白色固體（15毫克）。LCMS顯示MH+=425 ; Tret=2.72 分鐘。 實例652 : 1_乙基_4_{[4-(經亞胺基）環己基]胺基}·1Η-吡唑并[3,4-b]吡啶-5-羧酸乙酯 87841-960303-中.doc -289- 12836782M-sodium hydroxide solution (98 μL, 0.196 mmol) was added to Example 558 (22 mg, 0.049 mmol) in methanol (1 〇 4 μl) and water (6 μL). In solution. The resulting solution was stirred at 50 ° C under nitrogen. After 16 hours, the reaction mixture was diluted with water (0.5 mL) and adjusted to pH 4 with acetic acid. The solid which had been precipitated was collected by filtration and dried in vacuo to give a white solid (15 mg). LCMS showed MH+ = 425; Tret = 2.72 min. Example 652: 1_Ethyl_4_{[4-(imido)cyclohexyl]amino}·1Η-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester 87841-960303- Medium.doc -289- 1283678

將實例205 (200毫克）、羥胺鹽酸鹽（50毫克）及無水碳酸鉀 (420晕克）在乙腈（1〇毫升）中之混合物攪拌，並於回流下加熱 17小時。使溶液冷卻，並於真空中濃縮。使殘留物於Et〇Ac 與水之間作分液處理。分離有機相，以Na2 S04脫水乾燥，及 在真空中濃縮，獲得實例652，為白色粉末（2〇3毫克）。LCMS 顯示 MH+=346; Tret = 2.84 分鐘。 實一例653 : 1-乙基-4_{[4_(羥亞胺基）環己基】胺基卜N-{[4-(甲氧基） 苯基】曱基}_1H-吡唑并[3,4-b】吡啶_5_甲醯胺A mixture of 205 (200 mg), hydroxyamine hydrochloride (50 mg) and EtOAc (EtOAc) (EtOAc) The solution was allowed to cool and concentrated in vacuo. The residue was partitioned between Et〇Ac and water. The organic phase was separated, dried with EtOAc EtOAc EtOAc EtOAc LCMS showed MH+ = 346; Tret = 2.84 min. Example 653: 1-ethyl-4_{[4_(hydroxyimino)cyclohexyl]amino-based N-{[4-(methoxy)phenyl]fluorenyl}_1H-pyrazolo[3, 4-b]pyridine_5_formamide

將實例263 (217毫克）、羥胺鹽酸鹽（43毫克）及無水碳酸鉀 (355毫克）在乙腈（1〇毫升）中之混合物攪拌，並於回流下加熱 17小時。使溶液冷卻，並在真空中濃縮。使殘留物於Et〇Ac 與水之間作分液處理。分離有機相，以Na2S〇4脫水乾燥，及 在真空中濃縮，而得實例653，為黃色固體（186毫克）。LCMS 顯示 MH+= 437 ; TRET= 2.82 分鐘。5 H(CDC13) 1.49 (3H，t)，1·80 (2H， m)，2.2-2.4 (4H，m)，2·54 (1H，m)，3.13 (1H，dt)，3.81 (3H，s)，4·13 (1H，m)， 4.46 (2¾ q)，4·54 (2H，d)，6.28 (1H，t)，6.90 + 7·28 (4H，AA，BB，)，7.98 (1H，s)， 87841-960303-中.doc -290- 1283678 8·36 (1H，s)，9·84 (1H，d).羥基質子不可見及。 下述實例係藉由類似程序製成：A mixture of 263 (217 mg), hydroxyamine hydrochloride (43 mg), EtOAc (EtOAc) The solution was allowed to cool and concentrated in vacuo. The residue was partitioned between Et〇Ac and water. The organic phase was separated, dried with EtOAc EtOAc EtOAc LCMS showed MH+ = 437; TRET = 2.82 min. 5 H(CDC13) 1.49 (3H, t), 1·80 (2H, m), 2.2-2.4 (4H, m), 2·54 (1H, m), 3.13 (1H, dt), 3.81 (3H, s),4·13 (1H,m), 4.46 (23⁄4 q),4·54 (2H,d), 6.28 (1H,t),6.90 + 7·28 (4H,AA,BB,), 7.98 ( 1H, s), 87841-960303-中.doc -290- 1283678 8·36 (1H, s), 9.84 (1H, d). Hydroxy protons are not visible. The following examples are made by similar procedures:

實例編號 NR4R5 hnr4r5 之來源 起始物質 MH+ 離子 LC-MC 滯留時間 654 Aldrich 實例619 450 2.35 复例655_ : 1-乙基_4-({4·[(乙氧基）亞胺基】環己基}胺基）-Ν-{[4·(甲 氧基）苯基】甲基卜1Η-吡峻并[3,4-b]吡淀-5-甲醯胺Example No. NR4R5 Source of hnr4r5 Starting material MH+ Ion LC-MC Retention time 654 Aldrich Example 619 450 2.35 Replica 655_ : 1-ethyl_4-({4·[(ethoxy)imino]cyclohexyl} Amino)-Ν-{[4·(methoxy)phenyl]methyl b 1Η-pyrido[3,4-b]pyridine-5-carboxamide

將實例263 (25毫克）、乙氧基胺鹽酸鹽（r26〇nh2，其中 R26==Et ’ 20毫克）及二異丙基乙胺（30毫克）在乙腈（3毫升）中 之混合物攪拌，並於回流下加熱3.25小時。使溶液冷卻，並 於真空中濃縮。將殘留物施加至SPE藥筒（5克）。以Et0Ae溶 離藥筒。使含有所要產物之溶離份在真空中濃縮，而得實 例 655，為無色膠（2〇 毫克）。LCMS 顯示 _+=465 ; Tret==3 28 分鐘。 下述實例係藉由類似程序製成·· 87841-960303-φ.ά〇〇 -291- 1283678Stir a mixture of Example 263 (25 mg), ethoxylamine hydrochloride (r26 〇nh2, </ RTI> </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> 20 mg) and diisopropylethylamine (30 mg) in acetonitrile (3 mL) And heated under reflux for 3.25 hours. The solution was allowed to cool and concentrated in vacuo. The residue was applied to an SPE cartridge (5 grams). Dissolve the cartridge with Et0Ae. The fractions containing the desired product were concentrated in vacuo to give s. s. LCMS shows _+=465; Tret==3 28 minutes. The following examples are made by a similar procedure. · 87841-960303-φ.ά〇〇 -291- 1283678

實例編號 R26 r26onh2 之來源 起始物質 MH+ 離子 LC-MC 滯留時間 656 Me Aldrich 實例263 451 2.52 657 tBu Aldrich 實例263 493 3.66 竟: 1-乙基-N_{[4_(甲氧基）苯基】甲基h-[(7-酮基六氫_1H-一氮七園烯冬基）胺基]-1H-吡唑并[3,4七]吡啶-5-甲醯胺Example No. R26 r26onh2 Source Starting material MH+ Ion LC-MC Retention time 656 Me Aldrich Example 263 451 2.52 657 tBu Aldrich Example 263 493 3.66 Actual: 1-ethyl-N_{[4_(methoxy)phenyl] A H-[(7-ketohexahydro-1H-nitrohayrostenylene)amino]-1H-pyrazolo[3,4-7]pyridine-5-carboxamide

OMe 將三聚氯化氰（150毫克）在DMF (0.2毫升）中之懸浮液攪拌3〇 分鐘。以DMF將此懸浮液稀釋至7毫升，並攪拌。移除ι·〇毫 升部份之所形成懸浮液，並添加至實例653 (52毫克）中。將 所形成之溶液攪拌90小時，然後在真空中濃縮。使殘留物 於EtOAc與水之間作分液處理。分離有機相，並連續以飽和 碳酸鈉、10% w/v擰檬酸及飽和鹽水洗滌，以Na2 S04脫水乾 燥，及在真空中濃縮。將殘留物施加至SPE藥筒（2克）。將藥 筒連續以EtOAc :環己燒（1 : 1)，EtOAc，然後以二氯甲燒、 乙醇及氨之（100 : 8 : 1)混合物溶離。於真空中濃縮含有所要 87841-960303-中.doc -292- 1283678 產物之溶離份（在含氨溶液中溶離），而得實例658，為無色 油（11 毫克）。LCMS 顯示 MH+ = 437 ; Tret=2.50 分鐘。 實例659 : 1-乙基冬[(7-酮基六氫-1H-—氮七園烯_4_基)胺基】-1H-吡唑并[3,4-b]吡啶-5-羧酸乙酯OMe A suspension of cyanuric chloride (150 mg) in DMF (0.2 mL) was stirred for 3 min. The suspension was diluted to 7 ml with DMF and stirred. The resulting suspension was removed and added to Example 653 (52 mg). The resulting solution was stirred for 90 hours and then concentrated in vacuo. The residue was partitioned between EtOAc and water. The organic phase was separated and washed successively with saturated sodium bicarbonate, 10% w/v EtOAc and saturated brine, dried over Na? The residue was applied to an SPE cartridge (2 grams). The cartridge was continuously lyophilized with EtOAc: cyclohexane (1:1), EtOAc then EtOAc (EtOAc:EtOAc) The fractions containing the desired product of 87841-960303-Meso.doc-292-1283678 (dissolved in an ammonia-containing solution) were concentrated in vacuo to give Example 658 as a colorless oil (11 mg). LCMS showed MH+ = 437; Tret = 2.50 min. Example 659: 1-Ethyl Winter [(7-ketohexahydro-1H--azopentylene-4-yl)amino]-1H-pyrazolo[3,4-b]pyridine-5-carboxylate Ethyl acetate

實例659係使用實例658所用之相同程序，製自實例652。 LCMS顯示MH+=346; Tret = 2.56 分鐘。 : 4·{[順式冰(丁基胺基）環己基]胺基卜N-(2,3_二氫-1H_ 茚：基）-1-乙基-1H_吡唑并[3,4_b]吡啶_5_甲醯胺Example 659 was prepared using the same procedure as used in Example 658 from Example 652. LCMS showed MH+ = 346; Tret = 2.56 min. : 4·{[cis-ice (butylamino)cyclohexyl]amine-based N-(2,3-dihydro-1H-indole:yl)-1-ethyl-1H-pyrazolo[3,4_b Pyridine_5_formamide

將實例258 (25毫克）、丁醛（5毫克）及冰醋酸（3〇毫克）在 DCM (3毫升）中之溶液攪拌1〇分鐘。添加三乙醯氧基硼氫化 鈉（21毫克）。將反應混合物攪拌U小時。逐滴添加碳酸氫 鈉（1·〇莫耳，莫耳濃度，3毫升），並攪拌。攪拌5分鐘後，分 離液相。使有機相以Na2 S〇4脫水乾燥，並施加至SpE藥筒（5 克）。以二氣甲烷、乙醇及氨之（100 : 8 : 混合物溶離藥 筒。使含有所要產物之溶離份在真空中濃縮，而得實例 87841-960303-中.doc -293 - 1283678 660，為非晶質乳黃色固體（19毫克）。LCMS顯示MH+=346 ; Tret = 2.56 分鐘。 實例661至664 nhr3oA solution of 258 (25 mg), butyraldehyde (5 mg) and glacial acetic acid (3 mg) in DCM (3 mL) was stirred for 1 min. Sodium triethoxy borohydride (21 mg) was added. The reaction mixture was stirred for U hours. Sodium bicarbonate (1·molar, molar concentration, 3 ml) was added dropwise and stirred. After stirring for 5 minutes, the liquid phase was separated. The organic phase was dried over Na 2 S 〇 4 and applied to a SpE cartridge (5 g). Dissolve the cartridge with di-methane, ethanol and ammonia (100:8: mixture). The fraction containing the desired product is concentrated in vacuo to obtain the example 87841-960303-medium doc-293-1283678 660, which is amorphous. A creamy yellow solid (19 mg). LCMS showed MH+ = 346; Tret = 2.56 min. Examples 661 to 664 nhr3o

一般程序： 將乙腈（1毫升）中之中間物17 (0.16毫莫耳），以乙腈（1毫升） 中之R3NH2. (0.8毫莫耳）與N，N_二異丙基乙胺（0.8毫莫耳）處 理。於50°C下，將混合物加熱18小時，然後在真空中濃縮。 將殘留物以水（3毫升）稀釋，並以二氯甲烷（2 X 5毫升）萃取。 蒸發合併之有機萃液，並使殘留物藉質量導引之自預備 HPLC純化，而得所要之產物，含有甲酸。使此物質溶於氯 仿-甲醇（10/1，5.5毫升）中，並以5%碳酸氫鈉溶液（1毫升）洗 滌，蒸發溶劑後，獲得純產物。 實例 編號 NHR3 r3nh2 之來源 起始物質 MH+ 離子 LC-MC 滯留時間 214 H2N-^^NH J· Med. Chem·, 1994, 37 (17)， 2360 中間物17 393 2.16 661 Aldrich 中間物17 393 2.16 662 ^^、λ'、νη2 Aldrich 中間物17 393 2.29 663 Aldrich 中間物17 393 2.30 87841-96〇3〇3·中.doc -294- 1283678 664 h2K Peakdale 分子 公司 中間物17 393 2.21 對實例214與661-663中之NHR3而言，NHR3係如所示為順式 或反式異構物。對實例662-664而言，NHR3為3-胺基_或2_胺 基-環己-1-基胺基，呈外消旋形式。 复例6651·乙基_4-{[(lSR，3RS)_3-經基環己基】胺基}_1H^比峻并[3 4 叫峨啶-5-羧酸乙酯General Procedure: Intermediate 17 (0.16 mmol) in acetonitrile (1 mL) in EtOAc (1 mL) EtOAc (EtOAc &lt;RTI ID=0.0&gt; Molly) processing. The mixture was heated at 50 ° C for 18 hours and then concentrated in vacuo. The residue was diluted with water (3 mL) andEtOAc. The combined organic extracts were evaporated and the residue purified by preparative HPLC eluting with EtOAc. This material was dissolved in chloroform-methanol (10/1, 5.5 mL) eluted elute Example No. NHR3 r3nh2 Source Starting material MH+ Ion LC-MC Retention time 214 H2N-^^NH J· Med. Chem·, 1994, 37 (17), 2360 Intermediate 17 393 2.16 661 Aldrich Intermediate 17 393 2.16 662 ^^,λ',νη2 Aldrich Intermediate 17 393 2.29 663 Aldrich Intermediate 17 393 2.30 87841-96〇3〇3·中.doc -294- 1283678 664 h2K Peakdale Molecular Company Intermediate 17 393 2.21 For Examples 214 and 661 For NHR3 in -663, NHR3 is shown as a cis or trans isomer. For Examples 662-664, NHR3 is a 3-amino- or 2-amino-cyclohexan-1-ylamino group in racemic form. Example 6651·Ethyl_4-{[(lSR,3RS)_3-p-cyclohexyl]amino}_1H^ is more complex [3 4 is acridine-5-carboxylic acid ethyl ester

[順式-(3-羥基環己-1-基）胺基，外消旋] 於室溫下，將乙腈（10毫升）與乙醇（1毫升）中之3-胺基環己 醇（0.677 克，5.9 毫莫耳，如在 J C/zem· PerhVz 7hz似 i，1994, 537 中所述者），添加至中間物1 (1.24克，4·9毫莫耳）與二異丙基 乙胺（4.26毫升，24.5毫莫耳）在乙腈(25毫升）中之經攪摔溶液 内。將所形成之混合物於85°C下攪拌17小時。在真空中濃縮 混合物，並使殘留物於DCM (50毫升）與水（1〇毫升）之間作分 液處理。分離液相，並使有機相脫水乾燥（Na2 S04)，及蒸 發，而得橘褐色油。使此油藉Biotage層析（矽膠1〇〇克）純 化，以環己燒中之30·50% EtOAc溶離，而得實例665，為白色 泡沫物（0.681 克）。LCMS 顯示 MH+=333 ; Tret=2.76 分鐘。 實例 666-676 87841-960303-中.doc -295 - 1283678[cis-(3-hydroxycyclohex-1-yl)amine, racemic] 3-aminocyclohexanol (0.677) in acetonitrile (10 mL) and ethanol (1 mL) at room temperature克, 5.9 millimolar, as described in JC/zem·PerhVz 7hz like i, 1994, 537), added to intermediate 1 (1.24 g, 4·9 mmol) and diisopropylethylamine (4.26 ml, 24.5 mmol) in acetonitrile (25 mL) in a stirred solution. The resulting mixture was stirred at 85 ° C for 17 hours. The mixture was concentrated in vacuo and the residue was crystallised eluted eluting eluting eluting The liquid phase was separated, and the organic phase was dried (Na2SO4) and evaporated to give an orange-brown oil. The oil was purified by EtOAc (EtOAc EtOAc) (EtOAc) LCMS showed MH+ = 333; Tret = 2.76 min. Examples 666-676 87841-960303-中.doc -295 - 1283678

OHOH

[順式-(3-¾基環己-1-基）胺基，外消旋] 一般裎年： 使中間物76(0.1毫莫耳）、HATU(0.1毫莫耳）&amp;DIpEA(〇4毫 莫耳）在DMF (0.5毫升）中之混合物於室溫下振盪1〇分鐘。然 後添加胺HNR4R5(0.12毫莫耳）在DMF (0.5毫升）中之溶液，並 將混合物攪拌數分鐘，獲得溶液。將溶液在室溫下 Γ埼存16 小時，接著在真空中濃縮。使殘留物藉質量導引之自 印頂備 HPLC純化。 87841-960303·中.doc -296- 1283678 實例編號 nr4r&quot; HNR4 R5 之來源 起始物質 MH十 離子 LC-MC 滯留時間 666 Aldrich 中間物76 332 2.35 667 Aldrich 中間物76 398 2.96 668 Μ) Manchester 有機物公司 中間物76 401 2.48 669 Aldrich 中間物76 412 2.88 670 Acros 中間物76 472 2.57 671 Aldrich 中間物76 454 2.67 672 1 M3 Aldrich 中問物76 395 2.15 673 \^N N.D. Zelinsky 學會 中間物76 398 2,35 674 Matrix 科學；或 Chem· Ber” 1969,102、 2770 中間物76 422 3.08 675 Aldrich 中間物76 424 2.81 676 ICN 生物醫藥公 司；或 Salor; 良 Synthesis、 1982,12,1036 中間物76 422 3.08 實例26〇(替代程序） Ν-[(2,4·二甲基苯基）甲基】小乙基-4-[(4-酮基環己基）胺基]_1H-吡 吐并[3,4-b]峨淀-5-甲酿胺[cis-(3-3⁄4-ylcyclohex-1-yl)amino, racemic] General leap year: intermediate 76 (0.1 mmol), HATU (0.1 mmol) &amp; DIpEA (〇 A mixture of 4 mmoles in DMF (0.5 mL) was shaken at room temperature for 1 min. Then a solution of the amine HNR4R5 (0.12 mmol) in DMF (0.5 mL) was added and the mixture was stirred for a few minutes to give a solution. The solution was stored at room temperature for 16 hours and then concentrated in vacuo. The residue was purified by HPLC on a mass-guided HPLC. 87841-960303·中.doc -296-1283678 Example No. nr4r&quot; Source of HNR4 R5 Starting material MH Dec. LC-MC Retention time 666 Aldrich Intermediate 76 332 2.35 667 Aldrich Intermediate 76 398 2.96 668 Μ) Manchester Organics Intermediate 76 401 2.48 669 Aldrich Intermediate 76 412 2.88 670 Acros Intermediate 76 472 2.57 671 Aldrich Intermediate 76 454 2.67 672 1 M3 Aldrich Intermediate 76 395 2.15 673 \^N ND Zelinsky Learning Intermediate 76 398 2,35 674 Matrix Science; or Chem· Ber” 1969, 102, 2770 Intermediate 76 422 3.08 675 Aldrich Intermediate 76 424 2.81 676 ICN Biopharmaceutical Company; or Salor; Good Synthesis, 1982, 12, 1036 Intermediate 76 422 3.08 Example 26 〇 (alternative procedure) Ν-[(2,4·Dimethylphenyl)methyl]sodiumethyl-4-[(4-ketocyclohexyl)amino]_1H-pyrido[3,4- b]峨淀-5-甲甲胺

-297 87841-960303-中.doc 1283678 關於製備實例260之替代程序： 將中間物58 (45毫克）、11\1!；(63毫克）及〇正£八(39毫克）在乙 腈（5毫升）中之溶液攪拌10分鐘。添加2,4-二甲基苄胺（24毫 克X可得自Salor ;或ICN生物醫學公司；或 办故/^此，1982, 12, 1036)在乙腈（1毫升）中之溶液。將反應混合 物攪拌18小時。濃縮溶液，並使殘留物於醋酸乙酯（25毫升） 與0·5Μ碳酸氫鈉（20毫升）之間作分液處理。分離有機相，以 水（20毫升）洗滌，以Na2 S04脫水乾燥，及濃縮，留下膠質， 將其施加至SPE藥筒（5克）。以醋酸乙酯溶離藥筒。將含有所 要化合物之溶離份合併，並於真空中濃縮，獲得實例260 (32 毫克）〇 LC-MS 顯示 MH+=420 ; Tret=3.16 分鐘。511(0〇(：13)·· 1.49(3H，t)，2.11(2H，m)，2.33 (3H，s)，2.35 (3H，s)，2·40 (2H，m)，2·52 (2H，m)，2·61 (2H，m)，4·36 (1H，m)， 4·47 (2H，q)，4·55 (2H，d)，6·14 (1H，t)，7.01 + 7.18 (2H，ΑΑΉΒ，)，7.04 (1H，s)， 8.01 (1H，s)，8·36 (1H，s)，9.96 (1H，d). 下列實例677-679後以類似實例260之方式（上述替代程序） 製成，例如使用相同或類似莫耳數之試劑與相同或類似體 積之溶劑：-297 87841-960303-中.doc 1283678 Alternative procedure for Preparation Example 260: Intermediate 58 (45 mg), 11\1!; (63 mg) and 〇正八八(39 mg) in acetonitrile (5 ml) The solution in the solution was stirred for 10 minutes. A solution of 2,4-dimethylbenzylamine (24 mg X available from Sallor; or ICN Biomedical; or ICP/1982, 12, 1036) in acetonitrile (1 mL) was added. The reaction mixture was stirred for 18 hours. The solution was concentrated and the residue was partitioned between ethyl acetate (25 ml) and EtOAc. The organic phase was separated, washed with water <RTI ID=0.0>(20 </RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; </RTI> <RTIgt; Dissolve the cartridge with ethyl acetate. The fractions containing the desired compound were combined and concentrated in vacuo to afford </RTI> </RTI> <RTIgt; </RTI> <RTIgt; 511 (0〇(:13)·· 1.49(3H,t), 2.11(2H,m), 2.33 (3H,s), 2.35 (3H,s),2·40 (2H,m),2·52 (2H,m),2·61 (2H,m),4·36 (1H,m), 4·47 (2H,q),4·55 (2H,d),6·14 (1H,t) , 7.01 + 7.18 (2H, ΑΑΉΒ,), 7.04 (1H, s), 8.01 (1H, s), 8.36 (1H, s), 9.96 (1H, d). The following examples are similar examples after 677-679 The method of 260 (the above alternative procedure) is made, for example, using the same or similar molar reagents with the same or similar volume of solvent:

87841-96〇3〇3-中.doc -298- 1283678 實例編號 NR4R? HNR4 R5 之來源 起始物質 MH+ 離子 LC-MC 滯留時間 677 -m5rci Lancaster 中間物58 460 3.28 678 NH Maybridge 化學公司； 或 W0 01/30745 中間物58 440 3.25 679 丁 nms Wc^rld 化學品公司 或 DE 19^059 中間物58 440 3.24 實例 680-686 實例680-686係藉由類似上文關於實例653所示之程序製 成，例如使用相同或類似莫耳數之試劑與相同或類似體積 之溶劑：87841-96〇3〇3-中.doc -298-1283678 Example No. NR4R? HNR4 Source of R5 Starting material MH+ Ion LC-MC Retention time 677 -m5rci Lancaster Intermediate 58 460 3.28 678 NH Maybridge Chemical Company; or W0 01/30745 Intermediate 58 440 3.25 679 butyl nm Wc^rld Chemical Company or DE 19^059 Intermediate 58 440 3.24 Example 680-686 Example 680-686 is made by a procedure similar to that shown above for Example 653 For example, using the same or similar molar reagents with the same or similar volumes of solvent:

實例編號 NR^ HNR4 R5 之來源 起始物質 MH+ 離子 LC-MC 滯留時間 680 Salor;或 ICN 生物酱糙 公司；或 Synthesis， 1982,12, 1036 實例260 435 3.10 87841-960303·中.doc 299- 1283678 681 CHMSRV-AS;或 Matrix 科學；或 Cherru Ber^ 1969,102, 2770 實例261 435 3.08 682 Lancaster 實例677 475 3.20 683 V:, Maybridge 化學公司； 或 W001/30745 實例678 455 3.17 684 %。 Trans World 化學品 公司彡或DE 1953059 實例679 455 3.17 685 Fluorochcxn; 或WO 98/45268 實例266 473 3.00 686 Aldrich;或 Mcindl 等人，/ MccL Chcnu% 1984,27(9), 1111;或 〇，· Lett,, 2002, 4(12), 2055 實例267 475 3.13 t例681 : N-[(3,4-二甲基苯基）甲基】_1-乙基-4-{[4-(羥亞胺基）環 己基]胺基卜1H-吡唑并[3,4-b]吡啶-5-甲醯胺之替代製備 χχΗ。Example No. NR^ HNR4 R5 Source Starting Material MH+ Ion LC-MC Retention Time 680 Salor; or ICN Bio-salt Rough Company; or Synthesis, 1982, 12, 1036 Example 260 435 3.10 87841-960303·中.doc 299- 1283678 681 CHMSRV-AS; or Matrix Science; or Cherru Ber^ 1969, 102, 2770 Example 261 435 3.08 682 Lancaster Example 677 475 3.20 683 V:, Maybridge Chemical Company; or W001/30745 Example 678 455 3.17 684 %. Trans World Chemicals 彡 or DE 1953059 Example 679 455 3.17 685 Fluorochcxn; or WO 98/45268 Example 266 473 3.00 686 Aldrich; or Mcindl et al, / MccL Chcnu% 1984, 27(9), 1111; or 〇, · Lett,, 2002, 4(12), 2055 Example 267 475 3.13 t Example 681: N-[(3,4-Dimethylphenyl)methyl]_1-ethyl-4-{[4-(hydroxy Preparation of hydrazine by the substitution of amino)cyclohexyl]aminopyr 1H-pyrazolo[3,4-b]pyridine-5-carboxamide.

將實例261 (35毫克）、羥胺鹽酸鹽（10毫克）及二異丙基乙胺 (26毫克）在乙腈（4毫升）中之混合物攪拌，並於回流下加熱 2·5小時。使溶液冷卻，並於真空中濃縮。使殘留物於EtOAc 與水之間作分液處理。分離有機相，以Na2S04脫水乾燥，及 -300- 87841_96〇303_ 中.doc 1283678 在真空中濃縮。將殘留物施加至SPE藥筒（10克）。將藥筒以 EtOAc :環己烷（1 : 1)，然後以EtOAc溶離。合併含有所要化 合物之溶離份，並在真空中濃縮，而得實例681，為白色非 晶質固體（18毫克）。LCMS顯示MH+=435 ; Tret=3.08分鐘。 δ η (CDC13) 1.49 (3H，t)，1·79 (2Η，m)，2.24 (6Η，s)，2.19-2.38 (4Η，m)，2.56 (2H，dt)，4.13 (1H，m)，4.46 (2H，q)，4.53 (2H，d)，6·36 (1H，t)，7.09 (2H，t)5 7.1 2 (1H，s)，7.98 (1H，s)，8·38 (1H，s)，9·79 (1H，d)·羥基質子不可見及。 87841-960303-中.doc 301 -A mixture of 261 (35 mg), EtOAc (EtOAc) (EtOAc) The solution was allowed to cool and concentrated in vacuo. The residue was partitioned between EtOAc and water. The organic phase was separated, dried over Na2SO4, and concentrated in vacuo. The residue was applied to an SPE cartridge (10 grams). The cartridge was EtOAc (EtOAc): EtOAc (EtOAc) The fractions containing the desired compound were combined and concentrated in vacuo to afford crystals (yield: 18 mg). LCMS showed MH+ = 435; T rt = 3.08 min. δ η (CDC13) 1.49 (3H, t), 1.79 (2Η, m), 2.24 (6Η, s), 2.19-2.38 (4Η, m), 2.56 (2H, dt), 4.13 (1H, m) , 4.46 (2H, q), 4.53 (2H, d), 6.36 (1H, t), 7.09 (2H, t) 5 7.1 2 (1H, s), 7.98 (1H, s), 8.38 ( 1H, s), 9.79 (1H, d)· Hydroxy protons are not visible. 87841-960303-中.doc 301 -

Claims (1)

12气養^哲举j 拾、範園： 1. 一種式（I)化合物或其鹽， /R3 HN 012 气养^哲举j Pick up, Fan Yuan: 1. A compound of formula (I) or its salt, /R3 HN 0 n^n^^r2 (I) R1 r1為Ci-3燒基、Ci_2氟烷基或-CH2CH2OH ; R2為氫原子（Η)、曱基或q氟烷基； R3為經取代之C3 - 8環燒基或亞式（aa)、肿）或（cc)之視情況經 取代之雜環族基團；N^n^^r2 (I) R1 r1 is Ci-3 alkyl, Ci_2 fluoroalkyl or -CH2CH2OH; R2 is a hydrogen atom (hydrazine), a fluorenyl group or a q-fluoroalkyl group; R3 is a substituted C3-8 a heterocyclic group substituted by a cycloalkyl group or a subtype (aa), swollen) or (cc); (aa)(aa) r^)n2r^)n2 (cc) 或 (⑽ 或 其中η1與η2係獨立為1或2 ;且其中γ為ο、s、S〇2或NR10 ;其中R10為氫原子（Η)、甲基、乙基、c(0)NH2、C(O)甲基 或 c(o)-cf3 ; 且其中當R3為經取代之C：3·8環烷基時，則R3為被一取代基 取代之環己基，取代基為酮基（=〇)、〇H、NHr2 1，其中R2 i 為氮原子⑻或Ci -5直鍵悦基、-CH2 OH、-C(0)0R2 3，其中r2 3 為Η或甲基、-C(0)NHR24，其中R24為Η、羥亞胺基（=N_〇h) 或（Ch烷氧基）亞胺基(=N-OR26,其中R26為Ch烷基）；且其 中任何0H或NHR21取代基不會在連接（結合）至式①___ 基團之R3環碳處取代； 87841-960303.doc 1283678 且其中亞式（aa)、（bb)或（cc)之R3雜環族基團視情況被一或 兩個酮基（==〇)取代基取代； 且X為NR4R5或〇R5a，其中： R4為氫原子（H);且 R5為(^_8烷基；Ch氟烷基；視情況被(^_2烷基取代之C3_8 環垸基；或烷基，視情況在-(CH2)n4-部份基 團或在C：3_8環烷基部份基團中被（^_2烷基取代，其中n4為1 、2或 3 ; 或R5為C2_6烷基，被一或兩個獨立取代基Rn取代； 其中各取代基R11，與任何其他存在之Ri 1取代基無關，係 為：羥基（0H); (ν6烷氧基；苯基氧基；苄氧基； ;-NR1 5 ((COR1 6 ; -NRi 5 _c(〇)_〇 ri 6 ; -NRi 5 ·0(〇)-Ν]ΗμΚι 5 ;或 -NR1 5 -SC^R16 ;且其中任何Ri 1取代基，其係為〇H、烷氧基 或-NR12Ri3，不會在任何圮或^取代之烷基（其係結合至 NR4R5之氮）之任何碳原子處經取代； 或 R5 為 _(CH2)n&quot;-C(0)RH ； _(CH2)ni2_c(0)0Rl6 ； -(CH2)n12-C(0)0H ； -CHR19-C(0)0R^ ； -CHR19-C(0)0H ； -(CH2)n^-S02.NR^Ri3 ; .(CH2)ni2.s〇2Ri6 ； .(Ch2),12.CN ； 其中n11為1、2、3或4，且n12為1、2、3或4; 2、3或4，且Het為 或 R5 為-(CH2 )n 1 3 -Het，其中 ηι 3 為 〇、 4-，5_，6-或7-員飽和或部份飽和雜環，含有一或兩個獨立選 自O S及&gt;1之％雜原子；其中存在之任何環雜原子，當打13 為工時，不會結合至_(CH2)nl3_部份基團，而當nl3為〇時， 不會結合至NR4R5之氮；其中存在且不 為不飽和（意即其不 87841-960303.doc -2 - I283678 參與雙鍵）之任何環氮，係以NR17存在，其中R17係如本文 定義；且其中一或兩個碳環原子係獨立視情況被C! _2烷基 取代； 或R5為苯基，視情況獨立被一、二或三個下列基團取代： 鹵原子；燒基；（^_2氟烷基；Ch烷氧基；氟基烷 氧基；C3_6環烷基氧基；-C(0)R16a ; _C(0)OR30 ; ·8(0)2-Ι116&amp; ;R16 a-S(0)2 -NR15 a-; R7R8N-S(0)2 ; q -2 烷基-(XCO-R1 5 aN-S(0)2 ;q.4 烷基-s(0)-、Ph-S(O)-、R7R8N-CO-; -NR15-(:(0)1116 ; R7R8N ’〇此（^1-4燒氧基甲基，（^_4健乳基乙基；（111-2燒基-8(0)2-(1!112- ;R7 R8 N-S(0)2 -CH2 - ; C卜 2 烷基-S(0)2 -NR15 a -CH2 - ; -CH2 ·0Η ; ch2ch2_oh; -ch2_nr7r8 ; -ch2-ch2-nr7r8 ; -ch2-c(o)or3〇 ;-CH2-C(0)-NR7R8 ; -CH2-NR15a-C(0)-C卜 3 烷基；-(CHOnU-Het1 ’其中n14為0或1;氰基(CN)或苯基，其中苯基視情況被一 或兩個氟基、氯基、（^_2烷基、q氟烷基、Ck烷氧基或 Q氟基烷氧基取代； 或其中在R5視情況經取代苯基上之兩個相鄰取代基一 起採用為-0-(CMe2)-a或-〇-(CH2)n14a-0-，其中1114&amp;為1 或2; 其中R7與R8係獨立為氫原子（H) ; q-4烷基或C3_6環烷基 ;或 R7 與 R8 —起為-(CH2)n6-或-C(0)-(CH2)n'或 -C(〇HCH2)n7-C(0&gt; 或 _(CH2 )n 8 -X7 -(CH2 )n 9 _ 或 -C(0)-X7-(CH2)n10-，其中：n6為3、4、5或6，n7為2、3、4 或5，η8與η9及ηι〇係獨立為2或3，且X7為0或NR14，其中rH 為Η、C卜2燒》基或C(0)Me ; 或R5具有亞式（X)、（y)、（yl)或（z): 87841-960303.doc 1283678 -(CH2)n(cc) or ((10) or wherein η1 and η2 are independently 1 or 2; and wherein γ is ο, s, S〇2 or NR10; wherein R10 is a hydrogen atom (Η), a methyl group, an ethyl group, a c(0) NH2, C(O)methyl or c(o)-cf3; and wherein when R3 is a substituted C:3·8 cycloalkyl group, then R3 is a cyclohexyl group substituted by a substituent, and the substituent is Keto group (=〇), 〇H, NHr2 1, wherein R2 i is a nitrogen atom (8) or Ci -5 straight bond, -CH2 OH, -C(0)0R2 3, wherein r2 3 is Η or methyl, -C(0)NHR24, wherein R24 is hydrazine, hydroxyimino (=N_〇h) or (Ch alkoxy)imido (=N-OR26, wherein R26 is aCh alkyl); and any The 0H or NHR21 substituent is not substituted at the R3 ring carbon attached (bonded) to the formula 1___ group; 87841-960303.doc 1283678 and wherein the R3 heterocyclic group of the subtype (aa), (bb) or (cc) The group is optionally substituted by one or two keto (==〇) substituents; and X is NR4R5 or 〇R5a, wherein: R4 is a hydrogen atom (H); and R5 is (^_8 alkyl; Ch halothane a C3_8 cyclodecyl group substituted by a ^2 alkyl group; or an alkyl group, optionally in the -(CH2)n4- moiety or in a C:3_8 cycloalkyl group a moiety substituted by (^_2 alkyl, wherein n4 is 1, 2 or 3; or R5 is C2_6 alkyl, substituted by one or two independent substituents Rn; wherein each substituent R11, and any other present The Ri 1 substituent is irrelevant and is: hydroxy (0H); (ν6 alkoxy; phenyloxy; benzyloxy; ;-NR1 5 ((COR1 6 ; -NRi 5 _c(〇)_〇ri 6 ; -NRi 5 ·0(〇)-Ν]ΗμΚι 5 ; or -NR1 5 -SC^R16 ; and any of the Ri 1 substituents, which are 〇H, alkoxy or -NR12Ri3, will not be in any oxime or ^Substituted alkyl (which is bonded to the nitrogen of NR4R5) is substituted at any carbon atom; or R5 is _(CH2)n&quot;-C(0)RH;_(CH2)ni2_c(0)0Rl6;CH2)n12-C(0)0H;-CHR19-C(0)0R^;-CHR19-C(0)0H;-(CH2)n^-S02.NR^Ri3; .(CH2)ni2.s〇 2Ri6 ; .(Ch2), 12.CN ; where n11 is 1, 2, 3 or 4, and n12 is 1, 2, 3 or 4; 2, 3 or 4, and Het is or R5 is -(CH2)n 1 3 -Het, wherein ηι 3 is an anthracene, 4-, 5-, 6- or 7-membered saturated or partially saturated heterocyclic ring containing one or two heteroatoms independently selected from OS and &gt;1; Any ring hetero atom, when When 13 is working, it will not bind to the _(CH2)nl3_ moiety, and when nl3 is 〇, it will not bind to the nitrogen of NR4R5; it exists and is not unsaturated (meaning it is not 87841- 960303.doc -2 - I283678 Any ring nitrogen involved in a double bond) is present as NR17, wherein R17 is as defined herein; and one or two of the carbon ring atoms are independently substituted by C! _2 alkyl as appropriate; R5 is phenyl, optionally substituted by one, two or three of the following groups: halogen atom; alkyl group; (^2 fluoroalkyl; Ch alkoxy; fluoroalkoxy; C3_6 cycloalkyloxy ;-C(0)R16a ; _C(0)OR30 ; ·8(0)2-Ι116&amp;;R16 aS(0)2 -NR15 a-; R7R8N-S(0)2 ; q -2 alkyl-( XCO-R1 5 aN-S(0)2; q.4 alkyl-s(0)-, Ph-S(O)-, R7R8N-CO-; -NR15-(:(0)1116 ; R7R8N '〇 This (^1-4 alkoxymethyl, (^_4 健乳基乙; (111-2 alkyl-8(0)2-(1!112-; R7 R8 NS(0)2 -CH2 - ; C 2 2 alkyl-S(0) 2 -NR15 a -CH2 - ; -CH2 ·0Η ; ch2ch2_oh; -ch2_nr7r8 ; -ch2-ch2-nr7r8 ; -ch2-c(o)or3〇;-CH2-C (0)-NR7R8; -CH2-NR15a-C(0)-CBu 3 alkyl; -(CHOnU-Het1 'where n14 is 0 Or 1; cyano (CN) or phenyl, wherein the phenyl group is optionally one or two fluoro, chloro, (2, alkyl, q, fluoroalkyl, Ck alkoxy or Q fluoroalkoxy Substituting; or wherein two adjacent substituents on the substituted phenyl group in R5 are taken together as -0-(CMe2)-a or -〇-(CH2)n14a-0-, wherein 1114& is 1 or 2 Wherein R7 and R8 are independently a hydrogen atom (H); q-4 alkyl or C3_6 cycloalkyl; or R7 and R8 are -(CH2)n6- or -C(0)-(CH2)n' Or -C(〇HCH2)n7-C(0&gt; or _(CH2)n 8 -X7 -(CH2 )n 9 _ or -C(0)-X7-(CH2)n10-, wherein: n6 is 3, 4, 5 or 6, n7 is 2, 3, 4 or 5, η8 and η9 and ηι〇 are independently 2 or 3, and X7 is 0 or NR14, wherein rH is Η, C卜2 burning base or C ( 0) Me ; or R 5 has the subtype (X), (y), (yl) or (z): 87841-960303.doc 1283678 -(CH2)n (x)(x) 仰2)Yang 2) (2) G(2) G 其中在亞式(x)中，n = 0、；!或2;在亞式⑺與㈤中，㈣ 或2，及在亞式⑻中，r==〇、1或2; 其中在亞式（x)與（y)及（y1)中，沒有或一或兩個a、B、D E及F係獨立為氮或氮_氧化物（Ν+-0·)，其條件是A、B 、D、E及F中不超過一個為氮-氧化物；而其餘a、b、d 、E及F係獨立為CH或Cr6 ; 其條件是，當η在亞式（X)中為〇時，則一或兩個A、b、D 、E及F係獨立為氮或氮-氧化物⑼+_〇-)，且a、b、D、E 及F中不超過一個為氮-氧化物； 其中各R6，與存在之任何其他R6無關，係為：自原子； 燒基，Cw氟烷基；Q-4烷氧基；氟基烷氧基；〇3-6環 烷基氧基；-C(0)R16a ; -C(0)0R3° ； .S(0)2.R^a ； R16a-S(0)2-NRl5a_; R7R8N_s(〇)2_; Ci2 烷基 _c(〇&gt;Rl5aN_s(〇)2_ ;q_4烷基-s(0)-、R7R8N-CO-; -NR15-C(0)R16 ; r7r8n ; OH ;Ci-4烷氧基甲基；cw烷氧基乙基；（：卜2烷基-s(o)2-ch2_ ;R7 R8 N-S(0)2 -CH2 - ; C卜 2 烷基-S(0)2 -NR15 a -CH2 - ; -CH2 -OH ; •ch2ch2-oh; -ch2-nr7r8 ; _CH2-CH2-NR7R8 ; -CH2-C(0)OR3〇 ，其中n14為0或1;氰基(CN)或苯基，其中苯基視情況被一 或兩個氟基、氯基、q-2烷基、Q氟烷基、Ci-2烷氧基或 87841-960303.doc -4 - 1283678 q氟基烷氧基取代； 或其中兩個相鄰R6 —起採用為-〇_(CMe2)_〇_或 _〇-(CH2)n14a-〇-，其中n14a為 1 或2; 其中R7與R8均如本文定義； 其中亞式（y)與（yi)係獨立視情況在鄰近6-員芳族環之環碳 處被酮基（=〇)取代； 其中在亞式（z)中，G為0或S或NR9，其中R9為氫原子（H) 、G - 4燒基或Ci - 4氣燒基；沒有或一、二或三個j、l、Μ 及Q為氮；而其餘J、L、Μ及Q係獨立為ch或CR6，其中 R6，與存在之任何其他R6無關，係如本文定義；且 1^為&lt;^-8烷基或C!-8氟烷基； 且其中： R與R 3係獨互為H ; c卜5燒基；或苯基，視情況被一或兩 個齒原子' Ci—2烷基、Q氟烷基、cl-2烷氧基或心氟基烷 氧基取代； 或 R12 與 R13 — 起為 _(CH2)n6_ 或 _c(〇)_(CH2)n7_ 或 -C(0)-(CH2 )n 7 -C(0)- 或 -(CH2 )n 8 -X12 -(CH2 )n 9 - 或 -C(0)-X12-(CH2)n10-，其中：n6為3、4、5或6，n7為2 ' 3、 4或5 ’ n8與n9及ni 〇係獨立為2或3，且χι 2為〇或抓1 4 a，其 中 R 為基或 C(0)Me ; R15為氫原子（Η) ; CV4烷基；或苯基，視情況被一或兩個 下列基團取代：鹵原子、Ci 2烷基、〇1氟烷基、Ci -2烷氧 基或Q氟基燒氧基； R15a，與其他R15a無關，係為氫原子（H)或Ci4烷基； 87841-960303.doc 1283678 R16與1116&amp;係獨立為： Ci.6烷基； C3·6環烷基，視情況被一個酮基(=〇)、烷基取 代基取代； C3_6環烷基-CH2-; 吡啶基，視情況在環碳原子上被以下基團之一取代： 鹵原子、q_2烷基、Cl氟烷基、烷氧基或(^氟基烷氧 基； Ar5c ； 苯基，視情況被一或兩個下列基團取代：鹵原子、Ci 烷基、4氟烷基、（^-2烷氧基或心氟基烷氧基； 苄基，視情況在芳族碳原子處被一或兩個下列基图取 代：卣原子、C^2烷基、q氟烷基、Ck烷氧基或（^氟基 烷氧基；或 4-，5-，6-或7-員飽和雜環，在環-碳處經連接，且含有一 或兩個獨立選自0、S及N之環雜原子；其中存在之任何 環·氮係以NR27存在，其中圮7為η、c^2烷基或·€(〇)Μ6 ; 且其中該環係視情況在碳處被一個q ·2燒基或酮基（=〇)取 代基取代，其條件是，任何酮基(=〇)取代基係在結合至環 -氮之環-碳原子處經取代； 其中Ar5。為5-員芳族雜環，含有一個〇、s或NR15 a在5-員環 中，其中5-員環可視情況另外含有一或兩個n原子，且其 中雜環係视情況在環碳原子上被以下基團之一取代··函原 子、Ci-2*元基、Ci 氟燒基、-CH2OH、-CH2-OCi.2燒基、〇H( 87841-960303.doc 1283678 包括其酮基互變異構物）或_CH2-NR28R29取代，其中R28與 R29係獨立為Η或甲基； 且R1 7為氫原子(H); Ch烷基；C卜2氟烷基；-(012)/-(:(0)1116 ，其中 P6 為 0、1、2 或 3; -(CH2)p6-C(0)NR12R13 ; -(CH2)P6-C(0)0R16 ； -(CH2 )p 6 -C(0)0H ； -S02 R16 ； -C(0)-CH2 -NR12 R13 ; -C(0)-CH2 -NR15 a -C(0)_U完基； 燒基；或苯基或苄基，其中苯基或芊基係 视情況在芳族碳原子處被一或兩個下列基團取代：鹵原子 、Ci_2燒基、Q氟烷基、Ci-2烷氧基或心氟基烷氧基； 1119為 Ci-4烷基；-(CH2)n20-〇R20，其中 n2〇為 1、2、3 或4， 且R20為氫原子（H)或（：卜4烷基；-CH(Me)-0H ; -CH2_SH或 -CH2 -CH〗 -S-Me ;且 R3〇，與其他r3〇無關，係為氳原子(H)、Ci_4烷基或 烷基；且 Het1，與其他Het1無關，係為4-，5_，6-或7-員飽和雜環，在環 -碳處經連接，且含有一或兩個獨立選自〇、S及N之環雜 原子；其中存在之任何環-氮係以NR31存在，其中R31為η 、Q ·2烷基或-C(0)Me ;且其中該環係視情況在碳處被一個 Q -2坑基或酮基(=0)取代基取代，其條件是，任何酮基(=〇) 取代基係在結合至壤氮之壤-碳原子處經取代； 其條件是：當R3為亞式（aa)之雜環族基團且Y為NR10時， 則 R1 Q 不為 C(0)NH2、C(0)甲基或 C(0)-CF3 ; 其條件是： 當R3為亞式（bb)之雜環族基團，η1為1，且γ為nrI 〇時，則 87841-960303.doc -7- 1283678 :無論是（a) R10不為甲基或乙基；或（b)R10為甲基，且化合 物為：4-[(1-甲基六氫吡啶冰基）胺基]小乙基-1H-吡唑并[3,4-b] 比咬-5·«^故乙酿、1-乙基-N-(2-乙基丁基）-4-[(l-甲基穴氯p比咬 -4-基）胺基]_ih-吡唑并[3,4-b]吡啶-5-甲醯胺、1-乙基-N-(4-氟苯 基）·4-[(1-甲基六氫吡啶_4-基）胺基]-1H_吡唑并[3,4-b]吡啶-5·甲 醯胺，或N-芊基-1-乙基冰[(1-甲基六氫吡啶-4·基）胺基]-1H-外匕唑并[3,4七]吡啶-5·甲醯胺； 其條件是：當R3為亞式（cc)之雜環族基團時，則NHR3為亞 式（L)、（m)、（ml)或（m2)，其中NHR3基團對式⑴吡唑并吡 啶4-位置之-NH-連接點係被劃底線：Wherein in subtype (x), n = 0, ;! or 2; in sub-forms (7) and (5), (iv) or 2, and in sub-formula (8), r ==〇, 1 or 2; (x) and (y) and (y1), none or one or two of a, B, DE and F are independently nitrogen or nitrogen_oxide (Ν+-0·), provided that A, B, No more than one of D, E and F is nitrogen-oxide; and the remaining a, b, d, E and F are independently CH or Cr6; provided that when η is 〇 in sub-form (X), Then one or two of A, b, D, E and F are independently nitrogen or nitrogen-oxide (9) + _ 〇 -), and no more than one of a, b, D, E and F is a nitrogen-oxide; Wherein each R6, irrespective of any other R6 present, is: from an atom; a decyl group, a Cw fluoroalkyl group; a Q-4 alkoxy group; a fluoroalkoxy group; a fluorene 3-6 cycloalkyloxy group; C(0)R16a; -C(0)0R3°; .S(0)2.R^a ; R16a-S(0)2-NRl5a_; R7R8N_s(〇)2_; Ci2 alkyl_c(〇&gt;Rl5aN_s(〇)2_;q_4alkyl-s(0)-,R7R8N-CO-;-NR15-C(0)R16;r7r8n;OH; Ci-4 alkoxymethyl; cw alkoxyethyl; (: 2 alkyl-s(o)2-ch2_; R7 R8 NS(0)2 -CH2 - ; CBu 2 alkyl-S(0)2 -NR15 a -CH2 - ; CH2-OH; •ch2ch2-oh; -ch2-nr7r8; _CH2-CH2-NR7R8; -CH2-C(0)OR3〇, where n14 is 0 or 1; cyano (CN) or phenyl, wherein phenyl is The condition is substituted by one or two fluoro, chloro, q-2 alkyl, Q fluoroalkyl, Ci-2 alkoxy or 87841-960303.doc -4 - 1283678 q fluoroalkoxy; or two of them The adjacent R6 is taken as -〇_(CMe2)_〇_ or _〇-(CH2)n14a-〇-, where n14a is 1 or 2; wherein R7 and R8 are as defined herein; And (yi) are independently substituted by a ketone group (=〇) at the ring carbon of the adjacent 6-membered aromatic ring; wherein in the subtype (z), G is 0 or S or NR9, wherein R9 is Hydrogen atom (H), G-4 alkyl group or Ci-4 gas group; no or one, two or three j, l, Μ and Q are nitrogen; and the remaining J, L, Μ and Q are independently ch Or CR6, wherein R6, independently of any other R6 present, is as defined herein; and 1^ is &lt;^-8 alkyl or C!-8 fluoroalkyl; and wherein: R and R3 are each H ; c 5 5 alkyl; or phenyl, optionally taken by one or two tooth atoms ' Ci-2 alkyl, Q fluoroalkyl, cl-2 alkoxy or heart fluoroalkoxy ; or R12 and R13 are _(CH2)n6_ or _c(〇)_(CH2)n7_ or -C(0)-(CH2)n 7 -C(0)- or -(CH2 )n 8 - X12 -(CH2)n 9 - or -C(0)-X12-(CH2)n10-, where: n6 is 3, 4, 5 or 6, and n7 is 2' 3, 4 or 5 ' n8 and n9 and ni The oxime is independently 2 or 3, and χι 2 is 〇 or grabs 14 a, where R is a group or C(0)Me; R15 is a hydrogen atom (Η); CV4 alkyl; or phenyl, as the case may be Or two of the following groups are substituted: a halogen atom, a Ci 2 alkyl group, a fluorenyl 1 fluoroalkyl group, a Ci 2 alkoxy group or a Q fluoroalkyl alkoxy group; R 15a, which is independent of other R 15a, is a hydrogen atom (H) Or Ci4 alkyl; 87841-960303.doc 1283678 R16 and 1116&amp; are independently: Ci.6 alkyl; C3·6 cycloalkyl, optionally substituted by a keto group (=〇), alkyl substituent; C3_6 Cycloalkyl-CH2-; pyridyl, optionally substituted on the ring carbon atom by one of the following groups: halogen atom, q_2 alkyl group, Cl fluoroalkyl group, alkoxy group or (^fluoroalkoxy group; Ar5c Phenyl group, optionally substituted by one or two of the following groups: a halogen atom, a Ci alkyl group, a 4-fluoroalkyl group, a (^-2 alkoxy group or a heart-fluorenyl alkoxy group; a group, optionally substituted with one or two of the following base diagrams at the aromatic carbon atom: a halogen atom, a C 2 alkyl group, a q fluoroalkyl group, a Ck alkoxy group or a (fluoroalkyl alkoxy group; or 4- a 5-, 6- or 7-membered saturated heterocyclic ring which is attached at the ring-carbon and which contains one or two ring heteroatoms independently selected from 0, S and N; wherein any ring nitrogen is present NR27 is present, wherein 圮7 is η, c^2 alkyl or □(〇)Μ6; and wherein the ring is optionally substituted at the carbon by a q·2 alkyl or keto (=〇) substituent, Provided that any keto (= oxime) substituent is substituted at the ring-carbon atom bonded to the ring-nitrogen; wherein Ar5. a 5-membered aromatic heterocyclic ring containing a ruthenium, s or NR15a in a 5-membered ring, wherein the 5-membered ring may additionally contain one or two n atoms, and wherein the heterocyclic ring is optionally in the ring carbon The atom is substituted by one of the following groups: a functional atom, a Ci-2* group, a Ci fluoroalkyl group, a -CH2OH, a -CH2-OCi.2 alkyl group, and a hydrazine H (87841-960303.doc 1283678 including its ketone) Substituent) or _CH2-NR28R29 substituted, wherein R28 and R29 are independently hydrazine or methyl; and R1 7 is a hydrogen atom (H); Ch alkyl; C bis 2 fluoroalkyl; - (012) /-(:(0)1116 where P6 is 0, 1, 2 or 3; -(CH2)p6-C(0)NR12R13; -(CH2)P6-C(0)0R16; -(CH2)p 6 -C(0)0H; -S02 R16; -C(0)-CH2-NR12 R13; -C(0)-CH2-NR15 a -C(0)_U complete group; alkyl group; or phenyl or benzyl group Wherein the phenyl or fluorenyl group is optionally substituted at the aromatic carbon atom with one or two of the following groups: a halogen atom, a Ci 2 alkyl group, a Q fluoroalkyl group, a Ci-2 alkoxy group or a heart fluoride alkoxy group. 1119 is Ci-4 alkyl; -(CH2)n20-〇R20, wherein n2〇 is 1, 2, 3 or 4, and R20 is a hydrogen atom (H) or (: 4 alkyl; -CH ( Me)-0H ; -CH2_SH or -CH2 -CH -S-Me; and R3〇, independent of other r3〇, is a halogen atom (H), Ci_4 alkyl or alkyl; and Het1, independent of other Het1, is 4-,5_,6- Or a 7-membered saturated heterocyclic ring, attached at the ring-carbon, and containing one or two ring heteroatoms independently selected from the group consisting of hydrazine, S and N; wherein any ring-nitrogen present therein is present as NR31, wherein R31 is η, Q · 2 alkyl or -C(0)Me ; and wherein the ring is optionally substituted at the carbon by a Q-2 pit or a keto (=0) substituent, provided that any keto group (=〇) The substituent is substituted at the carbon-bonded to the soil of the soil nitrogen; the condition is: when R3 is a heterocyclic group of the formula (aa) and Y is NR10, then R1 Q is not C(0)NH2, C(0)methyl or C(0)-CF3; the conditions are: when R3 is a heterocyclic group of the formula (bb), η1 is 1, and γ is nrI 〇, Then 87841-960303.doc -7- 1283678: whether (a) R10 is not methyl or ethyl; or (b) R10 is methyl, and the compound is: 4-[(1-methylhexahydropyridine ice Amino]aminoethyl-1H-pyrazolo[3,4-b] is more than a bit of -5-", 2-ethyl-N-(2-ethylbutyl)-4- [(l-A Chloride p is more than -4-yl)amino]_ih-pyrazolo[3,4-b]pyridine-5-carboxamide, 1-ethyl-N-(4-fluorophenyl)·4- [(1-Methylhexahydropyridine-4-yl)amino]-1H-pyrazolo[3,4-b]pyridin-5-carboxamide, or N-mercapto-1-ethyl ice [ (1-methylhexahydropyridin-4-yl)amino]-1H-exocarbazo[3,4-7]pyridin-5-carbamamine; the condition is: when R3 is a subtype (cc) In the case of a heterocyclic group, NHR3 is a subtype (L), (m), (ml) or (m2) wherein the NHR3 group is bonded to the 4-position of the pyrazolopyridine 4-position Bottom line: 且其條件為：在R3為經取代之C3_8環烷基之情況下，則任何 0H ' ·&lt;：Η2ΟΗ、-C⑼OR23、-C(0)NHR24或-C(0)R25取代基位於 r3 環己基環之3-、4-或5-位置（其中，在此r3環烷基環之^位 置視為對式（I)中-NH-之連接點）。 2· —種式（IA)化合物或其鹽，And the condition is: in the case where R3 is a substituted C3_8 cycloalkyl group, then any 0H '·&lt;:Η2ΟΗ, -C(9)OR23, -C(0)NHR24 or -C(0)R25 substituent is located in the r3 ring. The 3-, 4- or 5-position of the hexyl ring (wherein the position of the r3 cycloalkyl ring is regarded as the point of attachment to -NH- in the formula (I)). 2. A compound of the formula (IA) or a salt thereof, 其中： X為NR4R5或〇R5a，其中： 87841-960303.doc 1283678 R4為氣，且 化5為&lt;^-8烷基、Cl-S氟烷基或心^環烷基，苯基，視情況被 一或兩個下列基團取代：鹵原子、c1-2烷基、三氟甲基、Cl_2 燒氧基或三氟甲氧基；或R5具有亞式（幻、（幻或（z):Wherein: X is NR4R5 or 〇R5a, wherein: 87841-960303.doc 1283678 R4 is a gas, and 5 is &lt;^-8 alkyl, Cl-S fluoroalkyl or heart^cycloalkyl, phenyl, The situation is replaced by one or two of the following groups: a halogen atom, a c1-2 alkyl group, a trifluoromethyl group, a Cl_2 alkoxy group or a trifluoromethoxy group; or R5 has an Asian form (phantom, (magic or (z) : 其中在亞式⑻與（z)中，n=l或2;且在亞式（y)中，my 或2 ; 其中在亞式⑻與（y)中，沒有或一或兩個A、B、D、E 及F為氮；而其餘A、B、D、E及F為CH或CR6，其中R6 為鹵原子、Q-4烷基、Cm氟烷基、Q-2烷氧基、q _2氟基 燒氧基、q ·2烷基磺醯基（(：卜2烷基-S02-)、（：卜2烷基-SCVNH-、R7R8N-S02_、R7R8N-CO_、R7R8N、OH、Cw烷氧基甲基 或c卜2烷基_S02-CH2-，其中R7與R8係獨立為氫或c卜2烷基； 其中在亞式（z)中，G為0或8或&gt;^19，其中妒為心^烷基 或匸卜4氟烷基；沒有或一或兩個j、L、M及Q為氮；而其 餘J、L、Μ及Q為CH或CR6，其中R6係如本文定義； R為Ci- 8燒基或〇ι- 8氣燒基； R3為經取代之c3_8環烷基或為Wherein in the subtypes (8) and (z), n = 1 or 2; and in the subtype (y), my or 2; wherein in the subtypes (8) and (y), there is no or one or two A, B , D, E and F are nitrogen; and the remaining A, B, D, E and F are CH or CR6, wherein R6 is a halogen atom, Q-4 alkyl, Cm fluoroalkyl, Q-2 alkoxy, q _2 fluoroalkyl alkoxy, q · 2 alkylsulfonyl ((: 2 alkyl-S02-), (: 2 alkyl-SCVNH-, R7R8N-S02_, R7R8N-CO_, R7R8N, OH, Cw Alkoxymethyl or c 2 alkyl _S02-CH2- wherein R 7 and R 8 are independently hydrogen or c 2 alkyl; wherein in subformula (z), G is 0 or 8 or &gt; 19, wherein 妒 is a heart ^ alkyl or 4 4 fluoroalkyl; no or one or two of j, L, M and Q are nitrogen; and the remaining J, L, Μ and Q are CH or CR6, wherein R6 As defined herein; R is Ci-8 alkyl or 〇ι-8 gas; R3 is substituted c3_8 cycloalkyl or 之雜環 族基團，其中Y為0、8、802或1^10;其中111〇為氫、甲基 、乙基、C(0)甲基或c(o)-cf3 ; 且其中在R3中，C3-8環烷基係被一個OH取代基取代之環己 87841 -960303 .doc 1283678 基；且其中任何OH取代基不會在連接至式（ία) -NH-基團之 環碳處取代；且 RLCu烷基或(^_2氟烷基；a heterocyclic group wherein Y is 0, 8, 802 or 1^10; wherein 111〇 is hydrogen, methyl, ethyl, C(0)methyl or c(o)-cf3; and wherein in R3 Wherein a C3-8 cycloalkyl group is substituted by an OH substituent to a cyclohexane 87841-960303.doc 1283678 group; and wherein any OH substituent is not attached to the ring carbon of the formula (ία)-NH- group Substituted; and RLCu alkyl or (^2 fluoroalkyl; 其條件是：當R3為、、 之雜環族基團，且Y為NR10時，則 R1()不為 C(O)甲基或 C(0)-CF3 ; 其條件是：The condition is: when R3 is a heterocyclic group of , , and Y is NR10, then R1() is not C(O)methyl or C(0)-CF3; the conditions are: 之雜環族基團，且Y為NR10時，則：無論 是（a)R10為氫、C(O)甲基或C(0)-CF3 ;或（b)R10為甲基，且化 合物為：4-[(1-甲基六氫吡啶-4-基）胺基]-1-乙基-1H-吡唑并 [3,4-b]吡啶-5-羧酸乙酯、1-乙基-N-(2-乙基丁基）-4-[(1-甲基六 氫吡啶-4-基）胺基]_1H-吡唑并[3,4-b]吡啶-5-甲醯胺、1-乙基 -N-(4-氟苯基）_4-[(1·甲基六氫吡啶-4-基）胺基]-1H-吡唑并[3+b] 吡啶-5-甲醯胺或N-苄基_1_乙基-4-[(l-甲基六氫吡啶·4_基）胺 基]-1Η-吡唑并[3,4_b]吡啶-5-甲醯胺； 且其條件是：在R3為經取代之C3_8環烷基之情況下，則此 一取代基為位於R3環烷基環之3-、4-或5-位置之取代基（ 其中，在此R3環烷基環之1-位置視為對式（IA)中-NH-之連 接點）。 3· —種式（IB)化合物或其鹽， 87841-960303.doc -10- 1283678 ,R〇a heterocyclic group, and when Y is NR10, then: (a) R10 is hydrogen, C(O)methyl or C(0)-CF3; or (b) R10 is methyl, and the compound is : 4-[(1-Methylhexahydropyridin-4-yl)amino]-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester, 1-B --N-(2-ethylbutyl)-4-[(1-methylhexahydropyridin-4-yl)amino]_1H-pyrazolo[3,4-b]pyridine-5-formamidine Amine, 1-ethyl-N-(4-fluorophenyl)_4-[(1·methylhexahydropyridin-4-yl)amino]-1H-pyrazolo[3+b]pyridine-5- Formamide or N-benzyl-1-ethyl-4-[(l-methylhexahydropyridin-4-yl)amino]-1Η-pyrazolo[3,4_b]pyridine-5-formamidine An amine; and the condition is: in the case where R3 is a substituted C3_8 cycloalkyl group, then the substituent is a substituent at the 3-, 4- or 5-position of the R3 cycloalkyl ring (wherein The 1-position of this R3 cycloalkyl ring is considered to be the point of attachment to -NH- in formula (IA). 3. A compound of the formula (IB) or a salt thereof, 87841-960303.doc -10- 1283678, R〇 其中： 烷基、Cl-2氟烷基或-CH2CH2〇H ; R2為氫原子（η)、曱基或q氟烷基； R為經取代之C3 _ 8環燒基或亞式（aa)、（bb)或（cc)之視情況經 取代之雜環族基團；Wherein: alkyl, Cl-2 fluoroalkyl or -CH2CH2〇H; R2 is a hydrogen atom (η), a fluorenyl group or a q-fluoroalkyl group; R is a substituted C3 -8 cycloalkyl group or a subtype (aa) a heterocyclic group substituted as appropriate by (bb) or (cc); 其中η1與n2係獨立為1或2 ;且其中γ為〇、s、S02或NR10 :其中R10為氫原子（H)、甲基、乙基、c(0)NH2、CX〇)甲基 或 c(o)-cf3 ; 且其中當R3為經取代之C3-8環烷基時，R3為被一個酮基（=〇) 或0H取代基取代之環己基；且其中任何〇H取代基不會在 連接（結合）至式（ΙΒ)-ΝΗ-基團之R3環碳處取代； 且其中亞式（aa)、（bb)或（cc)之R3雜環族基團視情況被一或 兩個酮基（=0)取代基取代； 且X為NR4R5或0R5a，其中： R4為氫原子（H);且 R5為4-8烷基；〇ν8氟烷基；視情況被Cl-2烷基取代之c3_8 環烷基；或-(CH2)n4-C3-8環烷基，視情況在-(CH2)n4_部份基 87841-960303.doc -11 - 1283678 團或在C3-8環烷基部份基團中被C^2烷基取代，其中η4為1 、2或 3 ; 或R5為C2_6烷基，被一或兩個獨立取代基R11取代； 其中各取代基R11，與任何其他存在之R11取代基無關，係 為：羥基（〇H); Ch烷氧基；苯基氧基；苄氧基； ;-NR15-C(0)R16 ; NR15-Q〇)-0-R16 ; -NRB.qpyNH-Ris ;或 -NR15-S02R16 ;且其中任何Rii取代基，其係為0H、燒氧基 或-NR12R13，不會在任何R4或R5取代之烷基（其係結合至 NR4R5之氮）之任何碳原子處經取代； 或 R5 為-(CH2 )/4(0)1116 ; -(CH2 )^2-0(0)0^6 ； -CHR19-C(0)0R16 ; -(CH2)n12-S02-NR12R13 ; -(CH2)n12-S02RU ;4_(CH2)n12-CN;其中【、2、3或4，且nl2為 i2 、3 或4 ; 或 R5 為-(CH2 )n 13 -Het，其中n13為〇、1、2、3或4，且 Het 為 4-，5-，6-或7-員飽和或部份飽和雜環，含有一或兩個獨立選 自0、S及N之環雜原子；其中存在之任何環雜原子，當〆3 為1時，不會結合至-(CH2)ni3_部份基團，而當nn為〇時， 不會結合至NR4R5之氮；其中存在且不為不飽和之任何環 氮（意即其不參與雙鍵）係以存在，其中RW係如本文 疋義，且其中一或兩個碳環原子係獨立視情況被A _2烷基 取代； 或R5為苯基，视情況被_或兩個下列基團取代：_原子，· Ch燒基；Cl.2氟燒基；Ch燒氧基；Ci2氟基燒氧基,· c&quot; 燒基續醯基（Cl_成基外）；燒基，视_; r7r8n_S(V 87841-960303.doc -12- 1283678 ;R7R8N-CO-; -NRU-CXO)!^ ; R7R8N; 0H; c卜4烷氧基曱基 ，4反氧基乙基，q_2燒基-S02-CH2-;氰基（CN);或苯基 ，視情況被一或兩個氟基、氯基、Cl_2烷基、（^氟烷基、 Cl-2烷氧基或心氟基燒氧基取代； 其中R7與R8係獨立為氫原子(H) ; Cl -4烷基或C3 6環烷基 ;或 R7 與 R8 — 起為 _(οη2)Λ 或-C(0&gt;(CH2)n7-或 -C(0&gt;(CH2)n7-C(0&gt; 或 -(CH2 )n 8 -χ7 -(CH2 )n 9 - 或 -C(O)-X7-(CH2)n10_，其中：n6為3、4、5或6，n7為2、3、4 或5，n8與n9及η1 〇係獨立為2或3，且X7為〇或NRi 4，其中 R14為Η或(V2烷基； 或R5具有亞式（X)、（y)或（z):Wherein η1 and n2 are independently 1 or 2; and wherein γ is 〇, s, S02 or NR10: wherein R10 is a hydrogen atom (H), methyl, ethyl, c(0)NH2, CX〇)methyl or c(o)-cf3; and wherein when R3 is a substituted C3-8 cycloalkyl group, R3 is a cyclohexyl group substituted by a keto group (=〇) or a 0H substituent; and wherein any 〇H substituent is not Substituting at the R3 ring carbon attached (bonded) to the formula (ΙΒ)-ΝΗ-group; and wherein the R3 heterocyclic group of the subtype (aa), (bb) or (cc) is optionally taken Substituted by two keto (=0) substituents; and X is NR4R5 or 0R5a, wherein: R4 is a hydrogen atom (H); and R5 is 4-8 alkyl; 〇ν8 fluoroalkyl; optionally by Cl-2 Alkyl substituted c3_8 cycloalkyl; or -(CH2)n4-C3-8 cycloalkyl, optionally in the group -(CH2)n4_part 87841-960303.doc -11 - 1283678 or in C3-8 a cycloalkyl moiety substituted by C^2 alkyl, wherein η4 is 1, 2 or 3; or R5 is C2_6 alkyl, substituted by one or two independent substituents R11; wherein each substituent R11, Any other R11 substituent present is: hydroxy (〇H); Ch alkoxy; phenyloxy;氧基; NR15-C(0)R16; NR15-Q〇)-0-R16; -NRB.qpyNH-Ris; or -NR15-S02R16; and any of the Rii substituents, which are 0H, oxygenated a group or -NR12R13, which is not substituted at any carbon atom of any R4 or R5 substituted alkyl group which is bonded to the nitrogen of NR4R5; or R5 is -(CH2)/4(0)1116; -(CH2 )^2-0(0)0^6 ; -CHR19-C(0)0R16 ; -(CH2)n12-S02-NR12R13 ; -(CH2)n12-S02RU ;4_(CH2)n12-CN; 2, 3 or 4, and nl2 is i2, 3 or 4; or R5 is -(CH2)n 13 -Het, where n13 is 〇, 1, 2, 3 or 4, and Het is 4-, 5-, 6 Or a 7-membered saturated or partially saturated heterocyclic ring containing one or two ring heteroatoms independently selected from 0, S and N; any ring heteroatoms present therein, when 〆3 is 1, do not bind to -(CH2)ni3_partial group, and when nn is 〇, it does not bind to the nitrogen of NR4R5; any ring nitrogen which is present and not unsaturated (that is, it does not participate in the double bond) is present, Wherein RW is as defined herein, and wherein one or two carbon ring atoms are independently substituted by A _2 alkyl as appropriate; or R 5 is phenyl, optionally _ or two Substituted by the following groups: _ atom, · Ch alkyl; Cl. 2 fluoroalkyl; Ch alkoxy; Ci2 fluoro alkoxy, · c &quot; burnt thiol (Cl_ into the base); , _; r7r8n_S (V 87841-960303.doc -12- 1283678; R7R8N-CO-; -NRU-CXO)!^; R7R8N; 0H; c 4 alkoxycarbonyl, 4-epoxyethyl, Q_2alkyl-S02-CH2-; cyano (CN); or phenyl, optionally with one or two fluoro, chloro, Cl 2 alkyl, (fluoroalkyl, Cl-2 alkoxy or heart) Fluoroalkyl alkoxy substituted; wherein R7 and R8 are independently a hydrogen atom (H); Cl-4 alkyl or C3 6 cycloalkyl; or R7 and R8 are _(οη2)Λ or -C(0&gt; (CH2)n7- or -C(0&gt;(CH2)n7-C(0&gt; or -(CH2)n 8 -χ7 -(CH2)n 9 - or -C(O)-X7-(CH2)n10_, Wherein: n6 is 3, 4, 5 or 6, n7 is 2, 3, 4 or 5, n8 and n9 and η1 are independently 2 or 3, and X7 is 〇 or NRi 4, wherein R14 is Η or (V2 Alkyl; or R5 has the subtype (X), (y) or (z): 其中在亞式（X)中，n=l或2;在亞式（y)中，^=1或2;及在 亞式（z)中，r = 〇、1或2; 其中在亞式（x)與(y)中，沒有或一或兩個A、B、D、E及F 為氮；而其餘A、B、D、E及F係獨立為CH或CR6 ; 其中尺6為_原子；cw燒基；（：卜4氟烷基；Ci-4燒氧基；&amp; 氟基燒氧基；c^2烷基磺醯基（Cl_2烷基名〇2〇; Ci_2烷基 -S〇2-NH- , R7R8N-S02. ; R7R8N-CO- ； -NR15-C^R16 ； R7R8n ，OH, Cw燒氧基甲基；q_4烷氧基乙基；A。烷基_s〇2_CH2_ •，氰基（CN);或苯基，视情況被一或兩個氟基、氯基、A 坑基、q氟坑基、Ci·2烷氧基或^氟基烷氧基取代；其中 87841-960303.doc -13 - 1283678 R7與R8均如本文定義； 其中在亞式（z)中，G為0或S或NR9,其中R9為氫原子（Η) Cl- 4彡元基或C卜4說悦基；沒有或一、二或三個J、L、Μ 及Q為氮；而其餘j、L、M及Q係獨立為CH或CR6，其中 R6係如本文定義；且 烷基或(：;1-8氟烷基； 且其中： R12與R13係獨立為H; q-5烷基；或苯基，視情況被一或兩 個下列基團取代：卣原子、Cl-2烷基、^氟烷基、烷 氧基或q氟基烷氧基； 或 R12 與 R13 一起為 _(CH2)n6_ 或-C(〇)-(CH2)n7_ 或 -C(〇HCH2)n7-C(0&gt; 或 _(CH2 )n 8 -X12 -(CH2 )n 9 - 或 -C(0)-X12-(CH2)n10-，其中：n6為3、4、5或6，n7為 2、3、 4或5，η8與n9&amp;niG係獨立為2或3，且χΐ2為osnrH，其 中R14為Η或（V2烷基； R15為氫原予（H); q-4烷基；或苯基，視情況被一或兩個 下列基團取代：函原子、Ci-2烷基、（^氟烷基、烷氧 基或q氟基烷氧基； R為Ci - 4燒基；C3 - 6環婉*基；1^比淀基，或苯基’視情況被 一或兩個下列基團取代：南原子、Ci-2烷基、（^氟烷基、 Ci-2烷氧基或(^氟基烷氧基； R17為氫原子(H) ; Ch烷基；Cu氟烷基；-(CH2)p6-C(0)R16 ，其中 P6為 0、1、2或 3 ; -(CH2)p6-C(0)NR12R13 ; -(CH2)p6-C(0)0R16 ; -so2r16 ;或苯基或苄基，其中苯基 87841-960303.doc -14- 1283678 或苄基之一個芳香碳原子視情況被一或兩個自原子、c 烷基、Ci氟烷基、Ci-2烷氧基或(^氟基烷氧基取代；且 R19 為Ch烷基；-(CH2)n20-OR20，其中#〇為 i、2、3或 4， 且R2G為氫原子（H)或C卜4燒基；-CH(Me)-OH ; -CH2_SH或 CH〕-CH〗-S-Me ; 其條件是：當R3為亞式（aa)之雜環族基團且γ為nrIG時， 則 R10 不為 C(0)NH2、C(0)甲基或 C(0)-CF3 ; 其條件是： 當R3為亞式（bb)之雜環族基團，η1為1，且Y為NR10時，則 :無論是(a)R1G不為甲基或乙基； 或（b)R1G為甲基，且化合物為：4-[(1-甲基六氫吡啶-4-基）胺 基]小乙基-1H-吡唑并[3,4-b]吡啶-5-羧酸乙酯、1-乙基-N-(2-乙 基丁基）-4-[(1-甲基六氫吡啶斗基）胺基]-1Η-吡唑并[3,4-b]吡啶 -5-曱醯胺、1-乙基·Ν-(4-氟苯基）-4-[(1-甲基六氫吡啶-4-基）胺 基]-lH-p比吐并[3,4-b]p比淀-5-甲酿胺或Ν-子基_1_乙基_4-[(1-甲 基六氫吡啶-4-基）胺基]-1H-吡唑并[3,4-b]吡啶-5-甲醯胺； 其條件是：當R3為亞式（aa)之雜環族基團，則NHR3為亞式 (L)、（m)或（ml)，其中NHR3基團對式（IB)外1：峻并p比淀4-位 置之-NH-連接點係被劃底線：Wherein in the subtype (X), n=l or 2; in the subtype (y), ^=1 or 2; and in the subformula (z), r = 〇, 1 or 2; wherein in the subtype (x) and (y), none or one or two of A, B, D, E and F are nitrogen; and the remaining A, B, D, E and F are independently CH or CR6; Atom; cw alkyl; (: 4 fluoroalkyl; Ci-4 alkoxy; &amp; fluoroalkyl alkoxy; c 2 alkyl sulfonyl (Cl 2 alkyl 〇 2 〇; Ci 2 alkyl - S〇2-NH- , R7R8N-S02. ; R7R8N-CO- ; -NR15-C^R16 ; R7R8n , OH, Cw alkoxymethyl; q_4 alkoxyethyl; A. Alkyl_s〇2_CH2_ • cyano (CN); or phenyl, optionally substituted by one or two fluoro, chloro, A, hydroxy, hydroxy, chloro, or fluoroalkoxy; 87841-960303.doc -13 - 1283678 R7 and R8 are as defined herein; wherein in the subtype (z), G is 0 or S or NR9, wherein R9 is a hydrogen atom (Η) Cl-4 atomic group or C卜4说悦基; no or one, two or three J, L, Μ and Q are nitrogen; and the remaining j, L, M and Q are independently CH or CR6, wherein R6 is as defined herein; Or (:; 1-8 fluoroalkyl; and : R12 and R13 are independently H; q-5 alkyl; or phenyl, optionally substituted by one or two of the following groups: a halogen atom, a Cl-2 alkyl group, a fluoroalkyl group, an alkoxy group or a q Fluoroalkoxy; or R12 together with R13 is _(CH2)n6_ or -C(〇)-(CH2)n7_ or -C(〇HCH2)n7-C(0&gt; or _(CH2)n 8 -X12 -(CH2)n 9 - or -C(0)-X12-(CH2)n10-, wherein: n6 is 3, 4, 5 or 6, n7 is 2, 3, 4 or 5, η8 and n9 &amp; niG Independently 2 or 3, and χΐ2 is osnrH, wherein R14 is oxime or (V2 alkyl; R15 is hydrogen atom to (H); q-4 alkyl; or phenyl, optionally with one or two of the following groups Substituted: a functional atom, a Ci-2 alkyl group, a (fluoroalkyl group, an alkoxy group or a q-fluoroalkoxy group; R is a Ci-4 alkyl group; a C3-6 ring 婉* group; Or a phenyl group' is optionally substituted with one or two of the following groups: a south atom, a Ci-2 alkyl group, a (fluoroalkyl group, a Ci-2 alkoxy group or a fluoroalkyl alkoxy group; (H); Ch alkyl; Cu fluoroalkyl; -(CH2)p6-C(0)R16 wherein P6 is 0, 1, 2 or 3; -(CH2)p6-C(0)NR12R13; CH2)p6-C(0)0R16; -so2r16; or phenyl or benzyl, of which phenyl 8784 1-960303.doc -14- 1283678 or an aromatic carbon atom of a benzyl group is optionally one or two from an atom, a c alkyl group, a Ci fluoroalkyl group, a Ci-2 alkoxy group or a (fluoroalkyl alkoxy group). Substituting; and R19 is a Ch alkyl group; -(CH2)n20-OR20, wherein #〇 is i, 2, 3 or 4, and R 2 G is a hydrogen atom (H) or a C 4 alkyl group; -CH(Me)- OH; -CH2_SH or CH]-CH--S-Me; provided that when R3 is a heterocyclic group of the formula (aa) and γ is nrIG, then R10 is not C(0)NH2, C (0) methyl or C(0)-CF3; the conditions are: when R3 is a heterocyclic group of the formula (bb), η1 is 1, and Y is NR10: then: (a) R1G Not methyl or ethyl; or (b) R1G is methyl, and the compound is: 4-[(1-methylhexahydropyridin-4-yl)amino]ethylidene-1H-pyrazolo[ Ethyl 3,4-b]pyridine-5-carboxylate, 1-ethyl-N-(2-ethylbutyl)-4-[(1-methylhexahydropyridyl)amino]-1Η -pyrazolo[3,4-b]pyridine-5-decylamine, 1-ethyl-indole-(4-fluorophenyl)-4-[(1-methylhexahydropyridin-4-yl) Amino]-lH-p than spit[3,4-b]p than yt-5-cartoamine or oxime-yl-1_ethyl_4-[(1-methylhexahydropyridine-4 -yl)amino]-1H- Zizo[3,4-b]pyridine-5-formamide; provided that when R3 is a heterocyclic group of the formula (aa), NHR3 is a subtype (L), (m) or ( Ml), wherein the NHR3 group is paired with the formula (IB): the ratio of the Jun-p and the 4-position-NH-linkage is bottomed: X^NH NH Ο (m) (m1); 且其條件為：在R3為經取代之C3_8環烷基之情況下，則此一 87841-960303.doc -15- 1283678 取代基為位於R3環烷基環之3-、4-或5-位置之取代基（其中， 在此R3環烷基環之1 -位置視為對式（IB)中-NH-之連接點）。 4·根據申請專利範圍第1或3項之化合物或鹽，其中R2為氫原 子⑻。 5·根據申請專利範圍第1至3項中任一項之化合物或鹽，其 中R1為乙基、正·丙基、（：2氟烷基或-CH2CH2〇H。 6.根據申請專利範圍第1項之化合物或鹽，其中Ri為乙基。 7·根據申請專利範圍第3項之化合物或鹽，其中Ri為乙基。 8·根據申請專利範圍第1至3項中任一項之化合物或鹽，其 中在R3中有一個取代基或沒有取代基。 9·根據申請專利範圍第1項之化合物或鹽，其中在r3為經取 代之A -8環燒基之情況下，則此一取代基為：g同基（=〇); OH; NHR21，其中R2i為氫原子⑻；-C⑼OR23，其中圮3為η :羥亞胺基（=N-OH);或（Cu烷氧基）亞胺基(=N-OR26,其中 κ26*(ν2烷基）。 1〇·根據申請專利範圍第1項之化合物或鹽，其中在R3為經取 代之C：3 - s環捉基之情況下，則此一取代基為qh、酮基（=〇) 或羥亞胺基（=Ν-ΟΗ)。 11 ·根據申請專利範圍第1項之化合物或鹽，其中在r3為經取 代之C：3環烷基之情況下，則此一取代基係為在R3環烷基 環之3-，4-或5-位置上之取代基（其中，在此R3環烷基環之^ 位置係被視為是對式（I)或（ΙΑ)或中-ΝΗ—之連接點）。 12·根據申請專利範圍第1至3項中任一項之化合物或鹽，其 中在R3為經取代之C：6環烷基之情況下，則R3為3_羥基_環己 87841_960303.doc -16- 1283678 基（意即3-羥基環己烷+基）、4_酮基_環己基（意即4-酮基環 己燒基）、4_(經亞胺基）環己基（意即4-(羧亞胺基）環己烷小 基）或4-((^ _2烷氧基亞胺基）環己基。 13·根據申請專利範圍第1至3項中任一項之化合物或鹽，其 中在R3為亞式（aa)、㈣）或（cc)雜環族基團之情況下，則γ 為〇、NH或N-C(O)甲基。 14·根據申請專利範圍第1至3項中任一項之化合物或鹽，其 中在R3為亞式（aa)、（bb)或（cc)雜環族基團之情況下，則γ 為0 〇 15·根據申請專利範圍第1至3項中任一項之化合物或鹽，其 中R1 G為氫原子(H)或C(0)甲基。 16·根據申請專利範圍第！至3項中任一項之化合物或鹽，其 中在R3為亞式（aa)、（bb)或（cc)雜環族基團之情況下，則R3 為亞式（bb)雜環族基團，且ηι為1。 17_根據申請專利範圍第1至3項中任一項之化合物或鹽，其 中在R3中，亞式（aa)、（bb)或（cc)雜環族基團為未經取代（其 中，在此Y為NR1G之情況下，rig不被分類為取代基）。 18.根據申請專利範圍第i至3項中任一項之化合物或鹽，其中 當R3為亞式（aa)之雜環族基團時，則γ為〇、s、s〇2或 NH，而 當R3為亞式（bb)之雜環族基團，且時，則Rl〇不 為甲基或乙基。 19·根據申請專利範圍第i項之化合物或鹽，其中·· R3為亞式（bb)之雜環族基團，^為丨，且¥為〇或^10，其 87841-960303.doc -17- 1283678 中 R1G為 Η、c(o)nh2、c(o)甲基或 c(o)-cf3， 其中在R3中，亞式（bb)之雜環族基團為未經取代（其中， 在此Y為NR1G之情況下，R1G不被分類為取代基）； 或R3為經取代之C6環烷基且為：3-羥基-環己基（即3-羥 基環己烷-1-基）、4-酮基_環己基（即4-酮基-環己烷-1-基） 、4-(羥亞胺基）環己基（即4-(羥亞胺基）環己烷-卜基）或 ((Cm烷氧亞胺基）環己基。 20.根據申請專利範圍第1至3項中任一項之化合物或鹽，其 中 NHR3 為亞式⑷，(e)，(f)，(g)，(gl)，(g2)，(g3)，(g4)，(h)，⑴，①，(k)， (kl)，(L)，(m)，(ml)，(m2)，(m3)，(n)，(〇)，(〇1)，(〇2)，(〇3)，(〇4)，(〇5)，(p)，(pi) ，(p2)，(p3)，（p4)，(p7)或(p8)，其中 NHR3基團對式（I)或（ΙΑ)或 (IB)吡唑并吡啶4-位置之-ΝΗ-連接點係被劃底線：X^NH NH Ο (m) (m1); and the condition is: in the case where R3 is a substituted C3_8 cycloalkyl group, then the 87041-960303.doc -15-1283678 substituent is located at R3 naphthenic A substituent at the 3-, 4- or 5-position of the base ring (wherein the 1-position of the R3 cycloalkyl ring is regarded as the point of attachment to -NH- in the formula (IB)). 4. A compound or salt according to claim 1 or 3 wherein R2 is a hydrogen atom (8). The compound or salt according to any one of claims 1 to 3, wherein R1 is ethyl, n-propyl, (: 2fluoroalkyl or -CH2CH2〇H. 6. According to the scope of the patent application A compound or a salt, wherein Ri is an ethyl group. 7. A compound or a salt according to claim 3, wherein Ri is an ethyl group. 8. A compound according to any one of claims 1 to 3 Or a salt, wherein there is a substituent or no substituent in R3. 9. A compound or salt according to item 1 of the patent application, wherein in the case where r3 is a substituted A-8 cycloalkyl group, then The substituent is: g homo group (=〇); OH; NHR21, wherein R2i is a hydrogen atom (8); -C(9)OR23, wherein 圮3 is η: hydroxyimino group (=N-OH); or (Cu alkoxy group) Imino group (=N-OR26, wherein κ26*(ν2 alkyl). 1〇· The compound or salt according to Item 1 of the patent application, wherein R3 is a substituted C:3 - s ring Next, the substituent is qh, a keto group (=〇) or a hydroxyimino group (=Ν-ΟΗ). 11 · A compound or a salt according to the scope of claim 1 wherein r3 is taken In the case of a C:3 cycloalkyl group, the substituent is a substituent at the 3-, 4- or 5-position of the R3 cycloalkyl ring (wherein the R3 cycloalkyl ring is present) The position is considered to be a point of attachment to the formula (I) or (ΙΑ) or to - ΝΗ - 12. The compound or salt according to any one of claims 1 to 3, wherein In the case of a substituted C:6 cycloalkyl group, R3 is a 3-hydroxyl-cyclohexyl 87841_960303.doc-16-283830 base (ie 3-hydroxycyclohexane+yl), 4-keto-cyclohexyl ( That is, 4-ketocyclohexanyl), 4-(imido)cyclohexyl (meaning 4-(carboxyimino)cyclohexane) or 4-((^ _2 alkoxyimine) The compound or salt according to any one of claims 1 to 3, wherein, in the case where R3 is a subgroup (aa), (4) or (cc) heterocyclic group, Then γ is 〇, NH or NC(O)methyl. The compound or salt according to any one of claims 1 to 3, wherein R3 is a subtype (aa), (bb) or (cc) In the case of a heterocyclic group, γ is 0 〇15. The compound or salt of any one of the above items, wherein R1 G is a hydrogen atom (H) or a C(0) methyl group. 16. A compound or salt according to any one of claims 3 to 3 Wherein in the case where R3 is a subgroup (aa), (bb) or (cc) heterocyclic group, then R3 is a subgroup (bb) heterocyclic group, and ηι is 1. 17_According to the application The compound or salt of any one of clauses 1 to 3, wherein in R3, the heterocyclic group of the formula (aa), (bb) or (cc) is unsubstituted (wherein Y is In the case of NR1G, rig is not classified as a substituent). The compound or salt according to any one of claims 1 to 3, wherein when R3 is a heterocyclic group of the formula (aa), γ is 〇, s, s〇2 or NH, When R3 is a heterocyclic group of the formula (bb), and R1 is not a methyl group or an ethyl group. 19. The compound or salt according to item i of the patent application, wherein R3 is a heterocyclic group of the subtype (bb), ^ is 丨, and ¥ is 〇 or ^10, which is 87841-960303.doc - 17- 1283678 wherein R1G is Η, c(o)nh2, c(o)methyl or c(o)-cf3, wherein in R3, the heterocyclic group of the subtype (bb) is unsubstituted (wherein In the case where Y is NR1G, R1G is not classified as a substituent); or R3 is a substituted C6 cycloalkyl group and is: 3-hydroxy-cyclohexyl (ie 3-hydroxycyclohexane-1-yl) , 4-keto-cyclohexyl (ie 4-keto-cyclohexane-1-yl), 4-(hydroxyimino)cyclohexyl (ie 4-(hydroxyimino)cyclohexane-b Or a compound or a salt according to any one of claims 1 to 3, wherein NHR3 is a subtype (4), (e), (f), (g), (gl), (g2), (g3), (g4), (h), (1), 1, (k), (kl), (L), (m), (ml), (m2 ), (m3), (n), (〇), (〇1), (〇2), (〇3), (〇4), (〇5), (p), (pi), (p2) , (p3), (p4), (p7) or (p8), wherein the NHR3 group is attached to the formula (I) or (ΙΑ) or (IB) pyrazole The pyridine 4-position-ΝΗ-joining point is underlined: 87841-960303.doc -18 - 128367887841-960303.doc -18 - 1283678 (〇1) (〇2) (o3) (〇4) (〇5) 21. 根據申請專利範圍第2 0項之化合物或鹽，其中NHR3為亞 式（d)，⑷，(f)，(g4)，(h)，⑴，G)，(k)，(kl)，(L)，(m)，(ml)，(m2)，(m3)，⑻，⑹， (ol)，(o2)，(o3)，(o4)，（o5)，(p)，(p2)，(p3^(p7)。 22. 根據申請專利範圍第2 0項之化合物或鹽，其中NHR3為亞 式⑷，(e)，(f)，⑻，(i)，G)，⑻，(m)，(ml)，⑹，(〇)，(〇1)或⑹。 23. 根據申請專利範圍第2 1項之化合物或鹽，其中NHR3為亞 式(h)，⑴，(j)，(k)，(ml)，(m2)，⑹，(〇)，(〇2)，(〇3)或(p2)。 24. 根據申請專利範圍第2 1項之化合物或鹽，其中NHR3為亞 式(h)，(k)，⑻，⑹或(〇2) 〇 25. 根據申請專利範圍第2 0項之化合物或鹽，其中R3為四氫 -2H-哌喃-4-基；意即NHR3為亞式（h)。 26. 根據申請專利範圍第1項之化合物或鹽，其中X為NR4R5。 27. 根據申請專利範圍第26項之化合物或鹽，其中R3為四氫 87841-960303.doc -19- 1283678(〇1) (〇2) (o3) (〇4) (〇5) 21. The compound or salt according to item 20 of the scope of the patent application, wherein NHR3 is subtype (d), (4), (f), ( G4), (h), (1), G), (k), (kl), (L), (m), (ml), (m2), (m3), (8), (6), (ol), (o2 ), (o3), (o4), (o5), (p), (p2), (p3^(p7). 22. A compound or salt according to item 20 of the patent application, wherein NHR3 is a subtype (4) , (e), (f), (8), (i), G), (8), (m), (ml), (6), (〇), (〇1) or (6). 23. A compound or salt according to claim 21, wherein NHR3 is subtype (h), (1), (j), (k), (ml), (m2), (6), (〇), (〇 2), (〇3) or (p2). 24. A compound or salt according to claim 21, wherein NHR3 is a subtype (h), (k), (8), (6) or (〇2) 〇 25. a compound according to claim 20 or a salt wherein R3 is tetrahydro-2H-piperidin-4-yl; that is, NHR3 is a subtype (h). 26. A compound or salt according to claim 1 wherein X is NR4R5. 27. A compound or salt according to claim 26, wherein R3 is tetrahydro 87841-960303.doc -19- 1283678 -2H-哌喃-4-基；即NHR3為亞式（h):— 。 v (h) 28·根據申請專利範圍第27項之化合物或鹽，其中R1為乙基。 29·根據申請專利範圍第2項之化合物或鹽，其中X為NR4R5。 30_根據申請專利範圍第3項之化合物或鹽，其中X為NR4R5。 31·根據申請專利範圍第30項之化合物或鹽，其中R1為乙基。 32·根據申請專利範圍第19項之化合物或鹽，其中又為服士5 〇 33·根據申請專利範圍第32項之化合物或鹽，其中Ri為乙基。 34·根據申請專利範圍第1至3、6、7、9、1〇、η、19或26 至33項中任一項之化合物或鹽，其中R5為： ci-8烷基； Cl - 3氟燒基； C3-8環烷基（未經取代）； 未經取代之-(CH2)n4-C5-6環烷基，其中η4為1或2; h其中η5為2或3，且各取代基Rii，與存在 之任何其他R11取代基無關，係為（^-4烷氧基、 -NR15 -C⑼-NH-R15 或视15 捣 Ri 6 ; 或 -(CH2 )n n -CXCOR16 ； -(CH2 )n 12 _C(0)NR12 Rl 3 ； -(cH2 )n12 -C(0)0R16 ； -(CH2 )n12 -S°2 -NR12 R13 ； -(CH2 )n 12 -S〇2 R1 6 •，或-(CH2)n12-CN，其中 n11為 1 或 2，且 ni2 為 i 或 2。 35.根據申請專利範圍第i至3、6、7、9、10、11、19或26 至33項中任一項之化合物或鹽，其中R5為_(CH2)n13-Het，η13 87841-960303.doc -20- 1283678 為 〇、1 或 9， tl ττ » 且Het為5-或6-員飽和雜環，其包含一選自ο 、切雜原予，其中Het中之碳環原予為未^取代。 36·根據申請專利範園第1至3、6、7、9、1〇、u、19或26 至33項中任―项之化合物或鹽，其中r5為苯基，視情況獨 立被-或兩個下列基團取代：函原子；h烷基；CM氟 烷基；h燒氧基；三氟甲氧基；Ci 2燒基磺酿基燒 基-S〇2_);(：卜2 烷基 _§〇2_勝；r7r8n s〇2_ ; r7r8n c〇_ ; -NR15-C(0)Ri 6 ; r7rsn . 〇H . Q-2烷氧基甲基；C^2烷基 S〇2-CH2_，氰基（CN);或苯基，視情況被氟基、Ck烷基、 Cl氟烷基、C1_2烷氧基或（^氟基烷氧基之一取代。 37·根據中請專利範圍第36項之化合物或鹽，其中❻苯基， 視情況被一或兩個下列基團取代：自原子、烷基、三 氟甲基、c卜2烷氧基、三氟甲氧基、R7R8N_s〇2_、r7r8n_c〇_ 或 Ci - 2 燒基-S〇2 -。 38·根據申請專利範圍第1至3、6、7、9、10、11、19或26 至33項中任一項之化合物或鹽，其中R5具有亞式⑻或（y) 或(yl)或(z)。 39·根據申请專利範圍第1至3、6、7、9、10、11、19或26 至33項中任一項之化合物或鹽，其中R5具有亞式（X)。 40·根據申請專利範圍第38項之化合物或鹽，其中n=i，m=1 ，且 r = 1 〇 41·根據申請專利範圍第1至3、6、7、9、10、11、19或26 至33項中任一項之化合物或鹽，其中在亞式⑻、⑼及（yl) 中：沒有或一或兩個A、B、D、E及F為氮；沒有或一、 87841-960303.doc -21- 1283678 二或三個A、B、D、E及F為（：聚6;而其餘A、B、D、E 及F為CH。 42·根據申請專利範圍第41項之化合物或鹽，其中在亞式⑻ 、（y)及/或（yl)中，沒有或其中一個A、B、D、E及F為 氮。 43·根據申請專利範圍第i至3、6、7、9、1〇、U、19或26 至33項中任一項之化合物或鹽，其中在亞式（χ)、（y)、（yl) 及⑻中，各R6，與存在之任何其他r6無關，係為氟、氣、 漠或硪原子’或甲基、乙基、正-丙基、異丙基、匸4烷基 、三氟甲基、-CH2〇H、甲氧基、乙氧基、q氟基烷氧基、 OH、（V3 烷基 s(0)2_、（：卜3 烷基 S(0)2-NH- ' Me2N-S(0)2-、 H2N-S(0)2-、-CONH2、-CONHMe、-C02H ' 氰基（CN)、NMe2 、第三-丁氧基甲基或Ci-3烷基s(o)2-ch2-。 44·根據申請專利範圍第43項之化合物或鹽，其中在亞式⑻ ' (y)、（yi)及/或（Ζ)中，、各R6，與存在之任何其他R6無關 ’係為氟、氯或漠原子，或甲基、乙基、正-丙基、異丙 基、三氟甲基、-CH2〇H、甲氧基、二氟甲氧基、甲基磺醯 基、甲基-so2_nh_或甲基-S02-CH2·。 45·根據申請專利範圍第1至3、6、7、9、10、11、19或26 至33項中任一項之化合物或鹽，其中r5為亞式（χ)，且係為 :苄基、（單烷基-苯基）甲基、[單（氟烷基）_苯基]甲基、（單 卣基苯基）甲基、（單烷氧基·苯基）甲基、[單（氟基烷氧基）_ 苯基]甲基、[單(Ν，Ν-二甲胺基)-苯基]甲基、[單（甲基 苯基）甲基、[單（甲基-SCV)-苯基]甲基/ (二烷基-苯基）甲基 87841-960303.doc -22- 1283678 、（單烷基·單卣基苯基）曱基、[單（氟烷基）_單_基苯基]甲基 、（二自基苯基）甲基、（二_基_單烷基_苯基）甲基、[二_基 -單（#i甲基)-苯基]甲基或（二烷氧基_苯基）甲基。 46·根據申請專利範圍第45項之化合物或鹽，其中RS為：（單 Cu烷基-苯基）甲基；（單Cl氟烷基_苯基）甲基；（單2烷氧 基-苯基）甲基；[單（C!氟基烷氧基)_苯基]甲基；（二Ci2燒基 -苯基）甲基；（單(^_2烷基-單_基苯基）甲基；（二卣基·苯基） 曱基；（二_基單ci _2烷基-苯基）甲基；或[二鹵基-單懷曱 基）-苯基]甲基。 47. 根據申請專利範圍第46項之化合物或鹽，其中r5為··（4_c^ 坑基-苯基）甲基；（4-Q氟烷基·苯基）甲基；（4-Ck烷氧基_ 苯基）甲基；（4-Q氟基烷氧基·苯基）甲基；（3,4_二甲基_苯基） 甲基；（2,4-二甲基-苯基）甲基；（3,5_二甲基_苯基）甲基；（2,3· 二甲基-苯基）甲基；（2,5-二甲基-苯基）甲基；（4_甲基-3_氯苯 基）甲基；（3-甲基-4-氯苯基）甲基；（2-甲基_4_氯苯基）甲基； (2-氯基_4·氟苯基）甲基；（2,4-二氟苯基）甲基；（4_溴基氟苯 基）甲基；（4-氯基-2-氟苯基）甲基；（3,4·二氯-苯基）曱基；（2,4-二氯-苯基）甲基；（2,6-二氯-苯基）甲基；（2,3-二氯-苯基）甲基 ，（2,4-二氯-6_甲基-苯基）甲基；或[2,3-二氣冬(經甲基）-苯基] 甲基。 48. 根據申請專利範圍第1至3、6、7、9、1〇、11、19或26 至33項中任一項之化合物或鹽，其中r5具有亞式（z)，1&lt;為i ，沒有或其中一個j、l、M或Q為CR6,而若j、L、M或Q 之一為CR6，則R6為甲基或c!氟烷基，且R9為氫原子（H)或 87841-960303.doc -23 - 1283678 甲基。 49·根據申請專利範圍第45項之化合物或鹽，其中Rl為乙基且 X 為 NR4R5 〇 50.根據申請專利範圍第40項之化合物或鹽，其中Rl為乙基且 X 為 NR4R5 〇 51_根據申請專利範圍第1項之化合物或鹽，其係為： 1-乙基-4-(四氫_2H-哌喃_4·基胺基）-1Η-吡唑并[3,4-b]吡啶-5_羧 酸乙酯， 4·[(1-甲基六氫吡啶斗基）胺基]-1—乙基-1H-吡唑并[3,4-b]吡啶 -5-羧酸乙酯， 4-[(1-乙醯基六氫吡啶-4-基）胺基]-1-乙基-1H-吡唑并[3,4七]吡 啶-5-羧酸乙酯， 1-甲基-4-(四氫_2H-旅喃_4·基胺基）-lH-吡唑并[3,4-b]吡啶-5-羧 酸乙酯， 1-乙基-4-[(3S)-四氫呋喃-3-基胺基]-1H-吡唑并[3,4-b]吡啶-5-羧 酸乙酯， 1-乙基斗[(3R)-四氫呋喃基胺基]·1Η·吡唑并[3,4-b]吡啶-5-羧 酸乙酯， 1-乙基冰(四氫-2H-硫代哌喃-4-基胺基）-1Η-吡唑并[3,4_1小比啶 •5-叛酸乙酉旨， 1·乙基冰(四氫嘧吩-3-基胺基）_ih_吡唑并[3,4七]吡啶-5-羧酸 乙酯， 4-(環丙胺基）小乙基-1H-吡唑并[3,4_b]吡啶-5-羧酸乙酯， 4_[(1，1-二氧化四氫嘧吩-3-基）胺基]-μ乙基-1H-吡唑并|；3,4七]吡 87841-960303.doc •24- 1283678 啶-5-羧酸乙酯， 4-[(1，1-二氧化四氫-2H-硫代哌喃斗基）胺基]小乙基_1H_吡唑 并[3,4-b]吡啶-5-羧酸乙酯， N-苄基小乙基斗(四氫-2H-哌喃斗基胺基）·1Η_吡唑并[3,4仰比 啶-5-甲醯胺， 1-乙基-Ν-(4-氟苯基）-4·(四氫·2Η-哌喃-4-基胺基）·1Η-吡唑并 [3,4-b&gt;比淀-5·甲醯胺， N-環戊基-1-乙基-4-(四氫-2H&gt;底喃-4-基胺基）-1Η-吡唑并[3,4-b] 吡啶-5-甲醯胺， 4-[(1-乙醯基六氫吡淀-4-基）胺基]_N-環戊基小乙基-1H_吡唑 并[3,4-b]p比淀-5-甲酸胺， 1-乙基-N七比啶-4_基甲基）_4-(四氫_2H_哌喃-4-基胺基）-1Η-吡唑 并[3,4-b]外b淀-5-甲醢胺， 4-[(1-乙醯基六氫吡啶-4-基）胺基]-N·苄基-1-乙基-1H-吡唑并 |；3,4-b]p比淀-5-甲醯胺， 1-乙基-N-(2-乙基丁基）-4-(四氫_2Η-哌喃-4-基胺基）-1Η-吡唑并 [3,4-b]p比淀-5·甲醯胺， 1-乙基-N-(2-乙基丁基）_4-[(1-甲基六氫吡啶-4-基）胺基]-1H-吡 唑并[3，4七]吡啶-5-甲醯胺， 4-[(1_乙醯基六氫吡啶-4-基）胺基]_1_乙基-Ν·(2-乙基丁基）_1H-p比唑并[3,4七]吡啶-5-甲醯胺， 1-乙基-N-(4-氟苯基）-4-[(1-甲基六氫吡啶-4-基）胺基]-1H-吡唑 并[3,4-b]吡啶-5_甲醯胺， 4-[(1-乙酿基穴鼠π比淀-4-基）胺基]-1-乙基-N-(4-氣苯·基比 87841-960303.doc -25- 1283678 唑并[3,4-b]吡啶-5-甲醯胺， 1-乙基-N-正-丙基-4-(四氯-211-0辰喃_4*·基胺基比吐并[3,4-b] 吡啶-5-甲醯胺， 4-[(1-乙醯基六氫吡啶-4-基）胺基]_1_乙基正丙基-1H-吡唑 并[3,4-b]吡啶-5-甲醯胺， N-爷基_1_乙基-4-[(l-甲基六氫ρ比咬-4-基）胺基]_1Η_ρ比吨并 [3,4-b]吡啶-5-甲醯胺， 4-[(1-乙醯基六氫吡啶-4-基）胺基]_1_乙基-N_〇比啶_4·基甲基 )-1Η-吡峻并[3,4-b]外b淀-5-甲醯胺， N_爷基-1-甲基-4-(四氫-2H-喊喃-4_基胺基比咬并[3,4_b]口比 咬-5-甲醯胺， N-(2-乙基丁基）·1-曱基-4-(四氫_2H-t痕喃-4-基胺基）-1Η-外b吨并 [3,4-b]p比淀-5-甲酸胺’ N-(4_氟苯基）·1-甲基_4-(四氫-2H_哌喃-4-基胺基）-1Η-吡唆并 [3,4-b]p比咬-5-甲酸胺^ 4-[(1-乙醯基六氫吡啶_4_基）胺基]_n_苄基-1-甲基-1H-吡吨并 [3,4-b]峨淀-5-甲酿胺’ 1-乙基-N-甲基-4-(四氫-2H-哌喃·4_基胺基）-1Η-吡唑并[3,4_b]吡 淀-5-甲酿胺， - 1_乙基-N-乙基_4-(四氫-2H-哌喃-4·基胺基）-1Η-吡唑并[3,4-b]吡 啶-5-甲醯胺， 1-乙基-N-異丙基-4-(四氫-2H_哌喃-4·基胺基）-1Η-吡唑并[3,4-b] 吡啶-5-甲醯胺， N-苄基-1-乙基_4-[(3S)-四氫呋喃-3-基胺基]_1H-吡唑并[3,4-b]吡 87841-960303.doc •26- 1283678 淀-5-甲酿胺， N_苄基小乙基-4-[(3R)-四氫呋喃_3_基胺基]-1H-吡唑并[3,4七&gt;比 淀-5-甲酿胺， N-苄基-1-乙基冬(四氳嘧吩_3_基胺基）_1Η_吡唑并[3,4_b]吡啶 -5-甲酿胺， N-爷基·4-[(1，1-二氧化四氫嘧吩_3_基）胺基]-丨·乙基-1H-吡唑并 [3,4-b]吡啶-5_甲醯胺， N-芊基-4·[(1，1_二氧化四氫硫代哌喃斗基）胺基]小乙基 -1Η-吡唑并[3,4-b]吡啶_5_甲醯胺， N-苄基-1-乙基-4-(四氫-2H-硫代哌喃-4-基胺基）-1Η·吡唑并 P，4-b]吡啶-5-甲醯胺， 1-乙基-N-(4_氟苯基）-4_[(3S)·四氫呋喃-3-基胺基]_1H_吡唑并 [3,4-b]吡啶-5-甲醯胺， 1-乙基_N-(4-氟苯基）_4-[(3R)_四氫呋喃-3_基胺基]-1H-吡唑并 [3,4-b]p比淀-5-甲酿胺， 1-乙基-N-(4-氟苯基）-4-(四氫_2H-硫代哌喃-4·基胺基）-1Η·吡唑 并[3,4-b]吡啶-5-甲醯胺， 1_乙基-N-(4-氟苯基）-4·(四氫嘧吩-3-基胺基）-1Η-吡唑并[3,4-b] p比淀-5-甲酿胺， 4-[(1，1-二氧化四氫嘍吩-3-基）胺基]_1_乙基·ν_(4-氟苯基）_1H-吡 峻并[3,4-b]p比淀-5-甲醯胺， 4-[(1，1·一氧化四氫-2H-硫代喊喃-4-基）胺基]-1-乙基-N-(4-氟苯 基）-1Η·外b峻并[3,4-b]p比淀-5_甲醯胺， 1-乙基·Ν-[4-(甲磺醯基）爷基]_4_(四氫·2Η_哌喻-4-基胺基）-1Η_ 87841-960303.doc •27- 1283678 吡唑并[3,4-b]吡啶-5-甲醯胺， 1-乙基-N-[3-(甲磺醯基）爷基]-4-(四氫_2H-哌喃-4-基胺基）-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺， N-[(5_氯基吡啶-2-基）甲基]小乙基冬(四氫-2H-喊喃_4_基胺基 )-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺， 1-乙基-N-[(5-甲基-3-苯基異嘮唑-4-基）甲基]-4-(四氫-2H-哌喃 -4-基胺基）_1H-吡唑并[3,4_b]吡啶_5_甲醯胺’ N-(2-第三-丁氧基乙基）-1-乙基-4-(四鼠-2H-喊喃-4-基胺基）-1Η_ 外I：唑并[3,4-b]吡啶-5-甲醯胺， 1-乙基-4-(四氫-2H-哌喃-4-基胺基）-Ν-(1，3-嘧唑-2-基甲基）-1Η-毗唑并[3,4-b]吡啶-5_甲醯胺， 1_乙基-N_(p密淀-4-基甲基）-4·(四氣-2H_喊喃-4-基胺基）·1Η-ρ比峻 并[3,4-b]吡啶-5-甲醯胺， 1-乙基-Ν·[(2_甲基_l，3-p塞峻_4_基）甲基]-4-(四氫_2Η·»痕喃-4-基胺 基）-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺， N-[3-(第三丁氧基甲基）辛基]-1-乙基-4-(四氫-2H-旅喃-4-基胺 基）-1H-吡唑并[3,4-b]吡啶·5_甲醯胺， 1-乙基-Ν-{2_[甲基（甲橫醯基）胺基]乙基}-4-(四氫-2Η-喊喃-4-基胺基比峻并[3,4-b]竹b淀-5-甲酿胺， 1-乙基_ -2-基甲基）-4-(四氫-2Η-Ϊ派喃-4_基胺基比唆 并[3,4-b]外b淀-5-甲酿胺， N-(2-氯基-6-氟基爷基）-1-乙基-4-(四氫-2Η-Ϊ痕喃-4-基胺基）-1Η- 外1：唑并[3,4-b]p比啶-5·甲醯胺， 1-乙基-N-[(6_酮基-1，6-二氫叶b淀-3-基）甲基]_4_(四氯派喃_4_ 87841-960303.doc -28- 1283678 基胺基）-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺， N-[3-(胺基羰基）芊基]小乙基-4-(四氫-2H-哌喃-4-基胺基）-1Η-峨峻并[3,4-b&gt;比淀-5-甲醢胺， 1-乙基-N-{4-[(甲胺基）觀基]苯基}-4-(四氯_2H-峰喃-4-基胺基 )-1Η-吡唑并P，4_b]吡啶·5·甲醯胺， 1-乙基-Ν-[2·(1_甲基-1Η·咪唑-4-基）乙基]冰(四氫-2Η-哌喃-4·基 胺基）-1Η-吡唑并[3,4-b]吡啶-5·甲醯胺， N-{2-[(冬胺基談基）胺基]乙基}_1_乙基-4-(四氯-2H-旅喃_4_基 胺基）-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺， 1_乙基-N-(1H-四唑-5-基甲基）_4-(四氫_2Η·哌喃·4_基胺基）-1Η-外b唑并[3,4-b]吡啶-5-甲醯胺， 1_乙基-4-(四氯-2H-喊喃-4-基胺基）·Ν-[2-(1Η-1，2,4-三峻-1_基）乙 基]-1Η·吡唑并[3,4-b]吡啶-5_甲醯胺， 1-乙基-4_(四氯-211-0底喃·4·基胺基）_N-[4_(三氟甲基）苯基]-1H-外b哇并P，4-b&gt;比淀-5-甲酸胺， 4-({[1-乙基-4-(四氫·2Η_^喃-4_基胺基）-1Η-ρ比唆并[3,4_b]p比咬 •5-基]羰基}胺基）六氫吡啶-1-羧酸第三·丁酯， 1-乙基_N-{3-[(甲續酿基）胺基]丙基}-4-(四氫-2H·喊喃·4·基胺 基）-1Η_ρ比吨并[3,4七&gt;比淀-5-甲醯胺， Ν-[2-(二甲胺基）爷基]-1-乙基-4-(四氫-2Η-喊喃_4_基胺基）-1Η-峨唑并[3,4-b]吡啶-5-甲醯胺， 1-乙基_N-[(1-乙基四氫吡咯_2_基）甲基]_4-(四氫-2H-哌喃-4·基 胺基）-lH&gt;比吐并[3,4-b]叶b淀-5_甲酿胺， 1-乙基_N-(izg氫咬喃-2_基甲基）_4_(四氫-2H·旅喃-4-基胺基）-1Η- 87841-960303.doc -29- 1283678 吡唑并[3,4-b]吡啶-5-甲醯胺， 1-乙基-N-四氫-2H-喊喃-4-基-4-(四氫-2H-喊喃-4-基胺基）_1Η-ρ比 唑并[3,4-b]吡啶-5-甲醯胺， N-{4-[(二甲胺基）磺醯基]苄基}小乙基-4-(四氬-2H-哌喃-4-基 胺基）·1Η·ρ比峻并[3,4-b]^比淀-5-甲酿胺， 1·乙基-N-{3-[(甲磺醯基）胺基]苄基}-4_(四氫-2H_哌喃-4·基胺 基）-1H_p比峻并[3,4-b]p比淀-5-甲酿胺， 1-乙基-N-(4-甲氧苯基）-4-(四氣-2H-喊喃-4-基胺基比峻并 [3,4-b]吡啶-5-甲醯胺， 1-乙基-Ν-[3-(2·酮基四氫吡咯小基）丙基]-4-(四氫-2H-哌喃-4-基胺基比吨并[3,4-b]p》b淀_5_甲酿胺》 1-乙基-N-[2-(l-甲基四氳卩比洛-2-基）乙基]-4-(四氮_2H-浪喃-4-基胺基）-1Η-吡唑并[3,4-b]吡啶-5_甲醯胺， 1-乙基_N-(p比淀-3-基甲基）-4-(四氯-2H-略喃-4-基胺基）-1Η_ρ比峻 并[3,4_b]吡啶-5_甲醯胺， 1-乙基-N-(l-甲基六氳外b淀-4-基）-4-(四氫-2H-喊喃-4-基胺基 )-lH-^b吐并[3,4-b]p比淀-5·甲酿胺， 1-乙基·Ν-(1-乙基丙基）_4·(四氮-2Η-»痕喃-4-基胺基比峻并 [3,4-b]吡啶-5-甲醯胺， 1-乙基-N-(2-六氫叶b淀-1·基乙基）-4_(四氫-2H-旅喃-4-基胺基 )-1Η_π比峻并[3,4-b]外b淀_5_甲醯胺， 1_乙基·Ν-(3-嗎福淋-4-基丙基）-4-(四氫-2Η_ϊ痕喃-4-基胺基）-1Η-吡唑并[3，4七]吡啶-5·甲醯胺， N-(3-乙氧基丙基）小乙基-4_(四氫-2H-t痕喃-4·基胺基）-1Η·ρ比峻 87841-960303.doc -30- 1283678 并[3,4_b]吡淀-5-甲醯胺， N-(環己基甲基）_1_乙基_4-(四氫-2H-哌喃_4_基胺基）-1Η-吡唑 并[3,4-b]p比淀-5-甲酿胺&gt; N-[3-(二甲胺基）丙基]_1_乙基斗(四氫-2H-哌喃-4-基胺基）-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺， 1-乙基-N-新戊基-4-(四氫_2H_哌喃-4-基胺基）_1H-吡唑并[3,4-b] 外匕淀-5-甲酸胺^ 1-乙基-N_(4_甲氧基苄基）-4-(四氫-2H-哌喃-4-基胺基）-1Η-吡唑 并[3,4-b]p比淀-5-甲酸胺》 1-乙基-N-{2-[(苯磺醯基）胺基]乙基}冬(四氫·2Η_哌喃-4-基胺 基）-1Η_ρ比吃并[3,4_1&gt;&gt;比淀-5-甲酿胺， Ν-[2-(乙醯胺基）乙基]-1_乙基-4·(四氫-2Η-哌喃-4-基胺基）-1Η-外匕也并[3,4-b]^比咬-5-甲酿胺， 1-乙基-N-{2-[(甲磺醯基）胺基]乙基}-4·(四氫-2H_哌喃-4-基胺 基）_1Η·ρ比峻并|；3,4-b]吡啶-5_甲醯胺， 1_乙基-N-{2-[(2-甲氧苯基）(甲基）胺基]乙基}-4-(四氫·2Η_哌喃 -4-基胺基）-1Η·吡唑并[3,4-b]吡啶-5-甲醯胺， 1-乙基-Ν-(2·ϊ同基-2-苯基乙基）_4-(四氮-2H-旅喃-4-基胺基）-1Η_ 外匕唑并[3，4-b]吡啶-5-甲醯胺， N-(2,5-二氟芊基）小乙基_4-(四氫-2H-哌喃-4-基胺基）-1Η·吡唑 并[3,4-b]吡啶-5-甲醯胺， 1-乙基-4-(四氯-2H-喊喃-4-基胺基）_N_[4-(三氣甲基）爷基]-1H-p比哇并[3,4七&gt;比咬-5-甲醯胺， N-環丙基小乙基-4-(四氫-2H-哌喃-4-基胺基）-1Η-吡唑并[3,4-b] 87841-960303.doc -31- 1283678 峨啶-5-甲醯胺， N-(2-胺基I酮基乙基乙基斗(四氫_2H_哌喃斗基胺基）_m_ 吡唑并[3,4-b]吡啶-5-甲醯胺， 1-乙基-N-(3-曱氧苯基）-4-(四氫-2H_哌喃斗基胺基）_1H_吡唑并 [；3,4-b]吡攻_5_甲醯胺， N-(3,4-二氟苄基）_1_乙基_4·(四氫-2H-哌喃-4-基胺基）-1Η-吡唑 并[3,4-b]p比淀-5-甲酸胺， 3-({[1-乙基-4-(四氫-21¾喃-4_基胺基）-1Η-吡唑并[3,4-b&gt;比啶 -5-基]談基}胺基）丙酸乙酉旨， Ν-(1·苄基六氳吡啶-4-基）小乙基-4-(四氫_2H-哌喃-4-基胺基 )-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺， 1_乙基_4_(四氫-2H_喊喃-4-基胺基）-Ν-(1，3,4-嘍二唑-2-基）-1Η-吡 峻并[3,4-b&gt;比淀-5-甲醯胺， N-(2,3-二氫_1H-茚·2·基）·1-乙基_4_(四氫-2H-哌喃-4-基胺基）_1Η· p比唆并[3,4-b]p比嗅-5-曱酿胺’ 1·乙基-N-[2-(2-酮基味峻琳淀_1_基）乙基]-4-(四氫-2H-喊喃-4-基胺基）-1Η-吡唑并p，4-b]吡啶-5-甲醯胺， N-(3,4-二1氧基爷基）-1-乙基-4-(四氫-2H-喊喃-4-基胺基）-1Η_ 吡唑并[3,4-b]吡啶-5·甲醯胺， N-(3-乳卞基）·1-乙基_4·(四氮-2H-喊喃-4-基胺基yiH-p比并 [3,4-b]吡皮-5-甲醯胺， 1-乙基-N-(2-輕乙基）-4-(四氮-2H-喊喃-4-基胺基）-1Η-ρ比嗤并 [3,4-b]吡走-5-甲醯胺， 1-乙基-Ν-{4·[(甲磺醯基）甲基]苯基}·4-(四氫-2H_哌喃冰基胺 87841-960303.doc -32- 1283678 基）-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺， Ν-[3·(二甲胺基）-3-酮基丙基]-1-乙基冬(四氫-2H·哌喃·4·基胺 基）-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺， 1-乙基_N-[(1-甲基-1H-咪唑-5-基）甲基]-4-(四氫-2H-哌喃-4-基胺 基）-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺， 1-乙基-N-{4-[(甲胺基）磺醯基]苯基}-4-(四氫·2Η·哌喃-4-基胺 基）-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺， N-(2-氰基乙基）-1_乙基-4-(四氫-2H-哌喃_4_基胺基）-1Η·吡唑并 [3,4-b]吡啶-5-甲醯胺， 1-乙基-N-[(l-甲基-1H-吡唑-4-基）甲基]-4-(四氫-211_哌喃-4-基胺 基）-1Η-吡唑并[3,4_b]吡啶-5·甲醯胺， 1-乙基-4-(四氯-2H-旅喃-4-基胺基）-N-(2-p塞吩-2-基乙基）-1Η-口比 唑并[3,4-b]吡啶-5-甲醯胺， Ν-[2-(4·氯苯基）乙基]-1-乙基-4-(四氫-2H-派喃-4-基胺基）-1Η-吡 唑并[3,4-b]吡啶-5-甲醯胺， 1-乙基-N-[2-(2-甲氧苯基）乙基]-4-(四氫-2H-哌喃冬基胺基）-1Η-外b峻并[3,4-b]外ti淀_5_甲酿胺， 1-正-丙基-4_(四氫_2H-哌喃-4-基胺基）-1Η-吡唑并[3,4-b]吡啶_5_ 羧酸乙酯， 1-(2-經乙基）-4-(四氫·2Η_旅喃-4-基胺基）·1Η-ρ比吐并[3,4-b]p比淀 -5-梭酸乙酿’ N-[4_(甲績酿基）爷基]-l-正_丙基-4-(四氫-2H-喊喃-4-基胺基 比吐并[3,4-b]p比嗓-5-甲酿胺， N-(4-氟苯基）小正-丙基-4-(四氫—2Η-Ϊ痕喃-4-基胺基）-1Η_ρ比峻并 87841-960303.doc -33 - 1283678 [3,4-b]吡啶-5-甲醯胺， 1-乙基各甲基-4-(四氫-2H-哌喃-4-基胺基）_1沁吡唑并[3,4-b]吡 啶-5·羧酸乙酯， N-苄基-1-乙基-6-甲基-4-(四氫-2H-哌喃-4-基胺基）-1Η_吡唑并 [3,4-b]吡啶-5-甲醯胺， N_苄基-1-乙基-4_[(2_酮基一氮七圜烷-3-基）胺基]-lH-吡唑并 [3,4-b]吡啶-5-甲醯胺， N-苄基-1-乙基-4-[(3-羥基環己基）胺基]-1H_吡唑并[3,4-b]吡啶 -5-甲醯胺， N-苄基小乙基-4-[(4-羥基環己基）胺基]-1H-吡唑并[3,4-b]吡啶 -5-甲醯胺， N-芊基小乙基-4-[(4·酮基環己基）胺基]·1Η_吡唑并[3,4-b]吡啶 -5-甲醯胺， 1-乙基-N_(2_羥基小甲基乙基）-4-(四氫-2H·哌喃-4-基胺基）_1H-吡唑并[3,4七]吡啶_5_甲醯胺， (2S)-2-({[l_乙基_4-(四氫-2H-哌喃斗基胺基）-1Η-吡唑并[3,4_b]吡 啶-5-基]羰基}胺基）-3-羥基丙酸甲酯， 1_乙基-4-[(4-羥基環己基）胺基]·1Η-吡唑并p，4-b]吡啶-5-羧酸 乙酯， 1-乙基-4-[(4-酮基環己基）胺基]-1H-毗唑并[3,4-b]吡啶-5·羧酸 乙酯， 4·[(1-乙醯基-4-六氳吡啶基）胺基]小乙基-1H-吡唑并[3,4-b]吡 啶-5-羧酸乙酯， 4-[(4_胺基環己基）胺基]小乙基-1H-吡唑并p，4-b]吡啶_5·羧酸 87841-960303.doc -34- 1283678 乙酯， N-[(l_氧化_3-p比咬基）甲基]-4-(四氯-2H-喊喃·4-基胺基）-1Η-ρ比 唑并[3,4-b]吡啶-5-甲醯胺， 1-乙基-N-[(l-氧化-2-p比淀基）曱基]-4-(四氮-2H-喊喃-4-基胺基 )-1Η-ρ比峻并[3,4-b]p比度-5-甲酿胺， 1-乙基-N_[(l-氧化-4-p比淀基）甲基]-4-(四氫_2H-喊喃-4-基胺基 )-1Η-ρ比峻并[3,4-b]p比淀-5-甲酿胺， 4-[(順式-4-胺基環己基）胺基]-1_乙基-N-(苯基甲基）-1Η-ρ比峻 并[3,4-b]吡啶-5_甲醯胺， 1-乙基-4-{[(3S)-2-酮基-3-四氫吡咯基]胺基卜N-(苯基甲基）-1Η-毗唑并[3,4-b]吡啶-5-甲醯胺， 4-[(2,5-二酮基-3-四氫吡咯基）胺基]-1-乙基-N-(苯基甲基）-1Η-外匕也并[3,4-b&gt;比淀_5·甲醯胺， 4-[(順式-4-胺基環己基）胺基]-1-乙基-Ν-{[4-(甲氧基）苯基]甲 基}-1Η-ρ比吨并[3,4-b&gt;比淀-5-甲酿胺， 4-[(順式-4-胺基壤己基）胺基]-1-乙基-N-({4_[(甲績酿基）胺基] 苯基}甲基）_1Η-ρ比吐并[3,4-b]外b淀-5-甲醯胺， 4-[(順式-4-胺基環己基）胺基]_Ν·(2,3·二氫-1H-茚-2_基）-1-乙基 -1H-吡唑并[3,4-b]吡啶_5_甲醯胺， 1-乙基-N-{4-[(甲磺醯基）甲基]苯基}-4-[(4-酮基環己基）胺基 ]-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺， N-[(2,4-一甲基苯基）甲基]-1-乙基-4-[(4-鋼基環己基）胺基]-1H_ 外匕唑并[3，4-b]吡啶-5-甲醯胺， N-[(3,4-二甲基苯基）甲基]小乙基·4-[(4-酮基環己基）胺基]-1H- 87841-960303.doc -35· 1283678 外匕峻并[3，4-b]吡啶-5-甲醯胺， N-[(3,4_二氯苯基）曱基]-1-乙基_4_[(4_嗣基環己基）胺基]·ΐΗ-ρ比 ♦并[3,4-b]吡啶-5-甲醯胺， 1_乙基-N-{[4·(甲氧基）苯基]甲基卜4_[(4_酮基環己基）胺基]-1H-外匕峻并[3，4七]吡啶-5-甲醯胺， 1-乙基-N-({4-[(甲磺醯基）胺基]苯基}甲基）-4-[(4-酮基環己基） 胺基]-ΙΗ-ρ比峻并[3,4_b]p比淀-5-甲酸胺， N-{[4-(二甲胺基）苯基]甲基}小乙基-4-[(4-酮基環己基）胺基 比吐并[3,4七&gt;比淀-5-甲醯胺， N-({4-[(二氟曱基）氧基]苯基}甲基）小乙基-4-[(4-酮基環己基） 胺基]-1H-吡唑并[3,4七]毗啶-5-甲醯胺， 1-乙基-4-[(4-酮基環己基）胺基]-N-{[4-(三氟基甲基）苯基]甲基 }-1Η-ρ比峻并[3,4-b&gt;比淀-5-甲酸胺， 1-乙基-N-{[4-(甲績醯基）苯基]曱基}-4-[(4-酮基環己基）胺基 ]-1Η-吡也并[3,4-b]吡啶-5-甲醯胺， 1-乙基-Ν·(4-氟苯基）-4-[(4-酮基環己基）胺基]-1H-吡唑并[3,4-b] 吡啶_5-甲醯胺， 1-乙基·4·[(4-酮基環己基）胺基]-Ν-(2·吡啶基甲基）-iH-吡唑并 [3,4-b]p比淀-5-甲酿胺三氟醋酸鹽， N-(2,3-二氫-1H·雖-2-基）·1-乙基-4-[(4-酮基環己基）胺基]-iH-p比 也并[3,4-b]吡啶-5-甲醯胺， N-(l-乙醯基-4-六氫吡啶基）-1-乙基-4-[(4-酮基環己基）胺基 ]-1Η-ρ比嗅并[3，‘b]外1：淀-5-甲醯胺， 1-乙基-N-[(l-甲基-1Η_ρ比咬-4-基）甲基]-4-[(4-嗣基環己基）胺基 87841-960303.doc -36- 1283678 ]-1Η-峨峻并[3,4-b]吡啶-5-甲醯胺， N，l-二乙基_4_[(4_酮基環己基）胺基]-1H-吡唑并[3,4-b]吡啶_5_ 甲醯胺， 1-乙基-4-[(4,基環己基）胺基]-N_(1，3_嘧唑_2_基甲基）_1H_吡唑 并[3,4-b]吡啶-5-甲醯胺， 1-乙基(苯基甲基&gt;4-(四氫-2H-哌喃-3-基胺基）·1Η·吡唑并 [；3,4-b]吡淀-5-甲醯胺， N-({4-[(二氟甲基）氧基]苯基}甲基)小乙基冬(四氫-2凡哌喃-3-基胺基）-1Η-吡唑并[3,4_b]吡啶-5_甲醯胺， 1-乙基-4-(四氫·2Η_哌喃_3_基胺基）-N-{[4-(三氟甲基）苯基]甲 基}-1Η-吡唑并[3,4-b]吡啶-5_甲醯胺， 1_乙基-N-{[4_(甲磺醯基）苯基]甲基}·‘(四氫-2H-哌喃-3-基胺 基）-1Η-ρ比峡并[3,4_b]p比淀-5-甲酿胺， 1_乙基-N]4·[(甲磺醯基）甲基]苯基}_4-(四氫·2H_哌喃_3_基胺 基）-1Η-ρ比峻并[3,4-b]峨咬-5-甲醯胺， 1-乙基-N-(4-氟苯基）-4-(四氫·2Η·哌喃-3-基胺基）-1Η-吡唑并 [3,4-b]吡啶-5-曱醯胺， 1-乙基-Ν·(2_吡啶基曱基）_4-(四氫·2Ιϋ喃-3-基胺基）_1H-p比唑 并[3,4-b]吡啶-5-甲醯胺三氟醋酸鹽， Ν-(2,3·二氫-1H-茚·2_基&gt;1-乙基冰(四氫JH-哌喃-3_基胺基）-1Η-p比峻并[3,4-b]外1：咬-5-甲醯胺， N_〇乙醯基-4-六氫吡啶基&gt;1·乙基_4-(四氫-2H-略喃-3-基胺基 )-1Η-ρ比峻并[3,4-b]外b淀-5·甲醯胺， 1-乙基-N-[(l_甲基-1H4唾冰基）甲基]·4_(四氫_2H哌喃斗基胺 87841-960303.doc • 37 · 1283678 基）-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺， N，l-二乙基-4-(四氫-2H-旅喃·3-基胺基）-1Η-吡唑并[3,4-b]吡啶 -5-甲驢胺， 1-乙基-4-(四氫-2H_哌喃-3-基胺基）-Ν-(1，3-嘧唑-2-基甲基）_1H-叶匕峻并[3,4-b]p比淀-5-甲醯胺， 4-[(1-乙酿基-4-六氮p比淀基）胺基]-N-(2,3_二氮-1H-印-2-基）-1-乙 基-1H-吡唑并[3,4-b]吡啶-5-甲醯胺， 4·[(1·乙酿基-4_：ττ氯1(7比症基）胺基]_N-[(3,4-二乳冬基）甲基]-1· 乙基-1H-吡唑并p，4-b]吡啶-5-甲醯胺， 4-[(1-乙醯基-4-六氫吡啶基）胺基]-1-乙基-N-[(3-氟苯基）甲基 ]-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺， 4-[(1-乙醯基斗六氫吡啶基）胺基]-Ν-[(3,4·二氟苯基）甲基]小 乙基-1Η-Ρ比吐并[3,4-b]p比淀-5-甲酸胺， 4-[(1-乙醯基-4-六氫吡啶基）胺基]-N-[(2,5-二氟苯基）甲基]-1-乙基-lH-p比吐并[3,4-b]p比淀-5-甲酿胺， 4-[(1·乙酿基氯p比淀基）胺基]·1-乙基-Ν-{[3·(三氣甲基）苯 基]甲基}-1Η-吡唑并[3,4-b]吡啶-5_甲醯胺， 4_[(1_乙醯基_4·六氫吡啶基）胺基]-1-乙基_Ν·{[4-(三氟甲基）苯 基]甲基}·1Η-ρ比吐并[3,4七&gt;比淀_5_甲酿胺， 4_[(1_乙醯基_4_六氫吡啶基）胺基]·Ν·[(2,6-二氟苯基）甲基]+ 乙基_1Η_外b峻并[3,4-b]p比淀-5-甲酿胺， 4-[(1-乙酸基-4-六氫p比淀基）胺基]-N-[(3-氯苯基）甲基]_ι·乙基 -1H-吡峻并[3,4-b]外b啶-5-甲酸胺、 4·[(1-乙酸基-4-六氫外b攻基）胺基]-1-乙基-Ν-{[4-(曱氧基）苯基] 87841-960303.doc -38- 1283678 甲基}-1Η-吡唑并|；3,4-b]吡啶-5-甲醯胺， 4-[(1-乙醯基-4-六氫吡啶基）胺基]-1-乙基-N-[4-(甲氧基）苯基 ]-1Η-毗也并[3,4-b]吡啶-5-甲醯胺， 4-[(1-乙醯基-4-六氫吡啶基）胺基]-N-({4-[(二甲胺基）續醯基] 苯基}甲基）-1-乙基-1H-吡唑并[3,4-b]吡啶-5-甲醯胺， 乙酿基-4-穴氯p比淀基）胺基]-1-乙基-N-(l，2,3,4_四氫-1-茶 基）-1Η-β比峡并[3,4-b&gt;比淀-5-甲醯胺， 4-[(1-乙醯基_4_六氫吡啶基）胺基]-N_{[2-(二甲胺基）苯基]曱基 }小乙基-1H-吡唑并[3,4-b]吡啶-5-甲醯胺， 4-[(1-乙酿基·4-τ^氯p比淀基）胺基]-N-[(2,4-二氯苯基）甲基]-1-乙基-1H-吡唑并P，4-b]吡啶-5-甲醯胺， 4-[(1-乙醯基-4·六氫吡啶基)胺基]小乙基-N-[(2-氟苯基)甲基 ]-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺， 4-[(1-乙酸基-4-六氫蚱b淀基）胺基]-Ν-[(2-氣基-6-氟苯基）甲基 ]-1_乙基_1Η-吡唑并[3,4-b]吡啶-5-甲醯胺， 4-[(1-乙醯基-4_六氫吡啶基）胺基]-N-({4-[(二氟甲基）氧基]苯 基}甲基）-1-乙基-1H-吡唑并[3,4-b]吡啶_5_曱醯胺， 4·[(1-乙酸基-4-六氫叶b淀基）胺基]-N-{[3-氣基斗(甲氧基）苯基] 甲基}·1-乙基-1H-吡唑并[3,4-b]吡啶-5_甲醯胺， 4-[(1-乙醯基-4-六氫吡啶基）胺基]·Ν-[(5-氣基-2_吡啶基）甲基 ]-1-乙基-1Η-0比唑并|；3,4-b]吡啶-5·甲醯胺， 4-[(1-乙醯基-4-六氫吡啶基）胺基]-N-(5-氯基_2,3_二氫-1H_^ _2_ 基H_乙基-1H-吡唑并[3,4七]吡啶_5_甲醯胺， 4-[(1-乙酸基-4-穴氮p比淀基）胺基]-1_乙基-N-(l，3-p塞峻_2•基甲 87841-960303.doc -39- 1283678 基）-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺， 4-[(1-乙醯基-4-六氫吡啶基）胺基]小乙基-Ν_{[4·(甲磺醯基）苯 基]甲基ΗΗ-吡唑并[3,4-b]吡啶-5-甲醯胺， 4-[(1-乙醯基-4-六氫吡啶基）胺基]-Ν·(2,2-二苯基乙基）-1-乙基 -1H-吡唑并[3,4-b]吡啶-5-甲醯胺， 4-[(1_乙醯基-4-六氫吡啶基）胺基]-1-乙基-N-({4-[(甲磺醯基）胺 基]苯基}甲基）_1H-吡唑并[3,4-b]吡啶-5-甲醯胺， 4-[(1-乙醯基冰六氫吡啶基）胺基]小乙基-Ν·({4-[(甲胺基）羰基] 苯基}甲基）-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺， 4-[(1-乙醯基_4·六氫吡啶基）胺基]-Ν_{[4·(胺基磺醯基）苯基]甲 基}小乙基_lHw比峻并[3,4-b]吡淀·5·甲醯胺， 4-[(1-乙醯基_4_六氫吡啶基）胺基]_1·乙基-Ν-({3-[(甲胺基）羰基] 苯基}甲基）-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺， 4-[(1-乙醯基-4-六氫吡啶基）胺基]-N-{[4-(胺基羰基）苯基]甲基 }小乙基_1Η·吡唑并[3,4-b]吡啶-5-甲醯胺， 4-[(1-乙醯基-4-六氫吡啶基）胺基]-1-乙基-Ν·{[6-(甲氧基）-3-吡 啶基]甲基}-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺， 1-乙基-N-4-六氫外1：淀基-4-(四氫-2H-喊喃-4-基胺基）-1Η-β比吨 并[3,4-b]吡啶-5-甲醯胺， 1-乙基-N-(4-六氫吡啶基甲基）-4-(四氫-2H-哌喃-4-基胺基）-1Η-p比吐并[3,4-b]吡淀-5-甲醯胺， 1-乙基-N-[l-(乙基續酿基）-4-六氫外1：淀基]-4·(四氫-2H-旅喃-4-基胺基）-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺， 1-乙基-N-{1_[(1_甲基乙基）續醯基]冬六氫吡啶基卜4-(四氩-2H- 87841-960303.doc -40- 1283678 哌喃-4-基胺基）-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺， N-[l_(環戊基磺醯基）_4_六氫吡啶基]-1·乙基-4-(四氫-2H-來喃 -4-基胺基）-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺， 1-乙基-N-[l-(甲磺醯基）-4_六氫吡啶基]-4-(四氫-2H-哌喃冬基 胺基）·1Η-吡唑并[3,4_b]吡啶-5_甲醯胺， 1-乙基-Ν-{1-[(苯基甲基）磺醯基]-4-六氫吡啶基}-4-(四氫-2H-哌喃冬基胺基）-1Η_吡唑并[3,4_b]吡啶-5-甲醯胺， 1-乙基-N-[l-(苯磺醯基）-4-六氫吡啶基]-4-(四氫-2H-哌喃-4-基 胺基）_1H-吡唑并[3,4-b]吡啶_5-甲醯胺， I-乙基-Ν·[1-(丙基續酸基）-4-六氯外b淀基]-4-(四氯-2H-17底喃-4-基胺基）_1H-吡唑并[3,4_b]吡啶-5-甲醯胺， Ν-[1·(環丙基羰基）冬六氫吡啶基]小乙基_4-(四氫-2H-哌喃-4· 基胺基）-1Η_吡唑并[3,4-b]吡啶-5-甲醯胺， 1-乙基-Ν-[1-(3·呋喃基羰基）-4-六氫吡啶基]-4-(四氫-2H-哌喃 -4-基胺基比唆并[3,4-b]p比淀-5-甲酿胺， Ν-[1·(3,3·二甲基丁醯基）_4_六氬吡啶基]-1-乙基斗(四氫-2H-哌 喃-4-基胺基）_1Η·吡唑并[3,4-b]吡啶-5-甲醯胺， 1-乙基-N-[l-(2-乙基丁酿基）-4-六氯外b淀基]-4-(四氯-2H-旅喃 -4-基胺基）-1Η-吡唑并[3,4-b]吡啶_5_甲醯胺， N-[l-(壤戊基乙酿基）-4-六氯p比淀基]-1-乙基-4-(四氮-2H-旅喃 -4·基胺基）-1Η-ρ比吨并[3,4-b]p比淀-5·甲酿胺’ 1-乙基-N-[l-(2-甲基丙酸基）·4-ττ氮卩比攻基]-4-(四氮-2H_旅喃 -4-基胺基比咬并[3,4-b]p比淀-5-甲酿胺， 1·乙基-4-(四氫-2H-喊喃-4-基胺基）-Ν-[1-(四氫-2H-喊喃-4_基談 -41 - 87841-960303.doc 1283678 基）-4-六氫吡啶基]-1H-吡唑并[3,4-b]吡啶-5-甲醯胺， 1-乙基丙龜基·4-ττ氯ρ比淀基）-4-(四鼠底喃-4-基胺基 )-1Η-吡唑并|；3,4-b]吡啶-5-甲醯胺， N-[1-(N-乙醯基甘胺醯基）-4_六氫吡啶基]-1-乙基-4-(四氫-2H-哌喃-4-基胺基）-1Η-吡唑并|；3,4-b]吡啶-5-甲醯胺， 1-乙基-N_[l-(4-嗎福淋基乙酿基）-4-六氯p比淀基]-4-(四氮-2H-哌喃-4-基胺基）-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺， 1-乙基-Ν-{1·[(4-酮基環己基）羰基]-4-六氫吡啶基}-4-(四氫-2H-哌喃-4-基胺基）-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺， 1-乙基-N-[l-(l-六氫ρ比淀基乙酸基）-4-六氫p比淀基]-4-(四氫 -2H-哌喃-4-基胺基）-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺， 1-乙基-N_{1-[(1-甲基-5-酮基-3-四氫吡咯基）羰基]-4-六氫吡啶 基}-4·(四氫-2H-哌喃-4_基胺基）-1Η·吡唑并[3,4七]吡啶-5-甲醯 胺， 1-乙基-Ν-{1-[(3-甲基-3·環氧丙烷基）羰基]-4-六氫吡啶基}-4-( 四氫-2Η-哌喃·4-基胺基）-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺， 1-乙基·Ν-{1-[(4-氟苯基）乙醯基]_4_六氫吡啶基}-4-(四氫-2H-哌 喃·4-基胺基）-1Η-ρ比吐并[3,4-b]p比淀-5-甲酿胺， Ν_{[1-(3,3·二甲基丁酿基）-4-六氫外b淀基]甲基}-1-乙基_4_(四氫 -2H-旅喃-4-基胺基）-1Η_^也并[3,4-b]外b淀-5-甲醯胺， Ν-{[1-(環戊基乙醯基）-4-六氫叶b淀基]甲基}-1_乙基-4-(四氫 -2H-旅喃-4_基胺基）_1Η-ρ比吨并[3,4-b]p比淀-5-甲醯胺， Ν-{[1-(環丙基羰基）-4_六氫吡啶基]甲基}小乙基-4-(四氫-2H-哌喃-4-基胺基）-1Η-吡唑并[3,4_b]吡啶-5-甲醯胺， 87841-960303.doc -42- 1283678 1-乙基_Ν-({1-[(4-嗣基環己基）談基]-4-ττ氯竹b淀基}甲基）-4_(四 氫-2H-哌喃冬基胺基）-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺， 1-乙基-Ν-({1-[(4-氣苯基）乙酸基]-4-六氯p比淀基}甲基）-4-(四氫 -2H-哌喃-4-基胺基）-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺， 1_乙基-Ν-({1·[(1-甲基-5·酬基-3-四氮外b洛基）談基]&quot;4-六氯p比淀 基}甲基）冰(四氫-2H-哌喃_4·基胺基）-1Η-吡唑并[3,4_b]吡啶-5-曱醯胺， 3-[(1-乙基-5-{[(苯基甲基）胺基]羰基}-1Η·吡唑并[3,4七&gt;比淀-4-基）胺基]環己烷羧酸甲酯， 3-[(1-乙基-5-{[(苯基甲基）胺基]羰基}·1Η·吡唑并[3,4-b]吡啶-4_ 基）胺基]環己烷羧酸， 1-乙基-N-(苯基甲基）-4-(4•六氫吡啶基胺基）-1Η-吡唑并[3,4-b] 吡啶-5-甲醯胺， 1-乙基-4-({l-[(甲氧基）乙醯基]-4-六氫吡啶基}胺基）-1Η-吡唑 并[3,4_b]吡啶-5-羧酸乙酯， 1-(1·甲基乙基）-4-(四氫-2H-哌喃-4-基胺基）-1Η-吡唑并[3,4-b]吡 啶-5-羧酸乙酯， 1·乙基-Ν·(4-氟苯基）_6_甲基-4-(四氫-2H-喊喃-4·基胺基）-1Η-ρ比 唑并[3,4七]吡啶·5_甲醯胺， 1-乙基-6-甲基-Ν-{[4-(甲橫酿基）苯基]甲基}-4-(四氫-2Η-喊喃 -4-基胺基）-1Η-吡唑并[3,4_b]吡啶-5-甲醯胺， N-(2,3-二氫-1Η·β _2·基）-1-乙基-6-甲基-4-(四氫-2H-旅喃-4-基胺 基）·1Η-ρ比吨并[3,4_b]p比淀-5-甲酿胺， 1-乙基-N-[3-(l-六氫吡啶基羧基）苯基]_4·(四氫—2H-旅喃-4-基 87841-960303.doc -43 - 1283678 胺基）-1Η-吡唑并[3,4七]吡啶-5-甲醯胺， 1-乙基-N-[4_(l-甲基乙基）苯基]·4-(四氫-2H-t派喃-4-基胺基）-1Η-峨唑并[3，4七]吡啶-5-甲醯胺， 1-乙基-N-(2-氟苯基）-4-(四氫-2H-喊喃-4_基胺基）_1H-p比峻并 [3,4-b]吡啶-5-甲醯胺， N-{3__[(二甲胺基）羰基]苯基}小乙基冰(四氫-211_喊喃-4-基胺 基）-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺， N-{4_[(二氟甲基）氧基]苯基}小乙基冰(四氫_2H-喊喃-4-基胺 基）-1Η-ρ比峻并[3,4-b]p比淀_5_甲酸胺， N_{4-[乙醯基（甲基）胺基]苯基}小乙基_4-(四氫_2IK喃-4-基 胺基）-1Η-ρ比峻并[3,4_b]p比淀-5-甲酿胺， 1_乙基-N-(4_經苯基）-4-(四氫·2Η·喊喃-4-基胺基）_1Η-ρ比峻并 [3,4-b]p比淀-5-甲酿胺， 1_乙基-N-[4-(4-嗎福淋基）_2_(三氟甲基）苯基]_4_(四氫-2H-旅喃 -4-基胺基）·1Η-ρ比峻并[3,4-b]外b淀-5-甲醯胺， 1-乙基-N-4-p比淀基-4-(四氫-2H-喊喃-4-基胺基比吨并 [3,4-b]吡啶-5-甲醯胺， 1-乙基-Ν·{4·[(4-甲基-1_六氫吡畊基）羰基]苯基卜4-(四氫-2H-i派 喃-4-基胺基）·1Η·外b吨并[3,4_b]p比淀_5_甲醯胺， 1-乙基-N_[2-(2-酮基小四氫外t洛基）苯基]_4_(四氫-2H-旅喃-4-基胺基）·1Η-ρ比吐并[3,4-b]吡啶-5-甲醯胺， 1-乙基-N-[3_(甲磺醯基）苯基]-4-(四氫-2H-哌喃-4-基胺基）-1Η-巧匕♦并[3,4-b]外b淀-5·甲醯胺， N-{3_[乙酿基（甲基）胺基]苯基}_1_乙基四氫底喃冬基 87841-960303.doc -44- 1283678 胺基）-1Η-吡唑并[3,4-b]吡啶·5_甲醯胺， 1-乙基-Ν-{3-[(甲續醯基）胺基]苯基}冰(四氫-2Η·喊喃-4-基胺 基）-1Η-吡唑并p，4-b]吡啶-5-甲醯胺， 1-乙基-Ν·(4-氟基-2_#至苯基）-4-(四氫-2H-喊喃-4-基胺基）-1Η-外匕 峻并[3,4-b]吡啶-5-甲醯胺， N-(4-氯苯基）-1-乙基·4_(四氫_211_喊喃-4_基胺基比峻并 [3,4-b]吡啶-5-甲醯胺， N-(3-氯基-2-氰基苯基）_1_乙基-4-(四氫-2Η-Ϊ痕喃-4·基胺基）-iH_ 峨峻并[3，4七]吡啶-5-甲醯胺， 1-乙基-N-[3-(l-六氫ρ比咬基續醯基）苯基]-4-(四氫-2H-派喃冬 基胺基）&quot;·1Η-ρ比也并[3,4-b]p比淀_5_甲酿胺， 1_乙基-Ν·[2-(甲續酸基）苯基]-4-(四氫-2H-P底喃_4_基胺基）-lH_ 外匕吃并[3,4-b]p比淀-5_甲醯胺， N-{2_[乙酸基（甲基）胺基]苯基}小乙基-4-(四氫-2H-喊喃-4_基 胺基）_1H-p比哇并[3,4-b]p比淀_5_甲酿胺， 1-乙基_N-[3-(4-嗎福琳基談基）苯基]-4-(四氫-2H-旅喃-4·基胺 基）-1H-p比峻并[3,4-b&gt;比淀-5·甲醯胺， N-(4-氯基-3-氯基苯基）-1-乙基-4-(四氫-2H·喊喃-4-基胺基）_1H_ 外匕吨并[3，4七]吡啶-5-甲醯胺， 1-乙基_N-(3-輕苯基）-4-(四氫·2Η-喊喃-4-基胺基）-1Η-ρ比峡并 [3,4-b]吡啶_5_甲醯胺， N_(3-氯苯基）-1-乙基-4·(四氫-2H_^喃-4-基胺基）-lH_叶b峻并 [3,4-b]吡啶-5-甲醯胺， Ν-[3·[(乙醯胺基）甲基]-4-(甲氧基）苯基]-l_乙基冰(四氫-2H_哌 87841-960303.doc -45- 1283678 喃-4-基胺基）_1H-吡唑并[3,4-b]吡啶-5-曱醯胺， 1-乙基鼠外b淀基㉟'酿基）丰基]-4-(四氯-2H-17瓜喃-4-基胺基）-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺， N-(3-{[環己基（甲基）胺基]羰基}苯基)-1-乙基-4-(四氫-2H-哌喃 -4-基胺基）_1H-吡唑并[3,4-b]吡啶-5_甲醯胺， 1-乙基-N-[2-(4-嗎福p林基）苯基]-4-(四氯辰喃-4-基胺基）-1Η-外匕峻并[3,4-b]外b違-5-甲醯胺， Ν-{3·[(乙醯胺基）磺醯基]苯基}-1-乙基-4·(四氫-2H-哌喃-4-基 胺基）_1Η-ρ比峻并[3,4-b]p比淀-5-甲酿胺， N-(3-氯基-4-經苯基）-1-乙基-4-(四氫-2H-喊喃-4-基胺基）-1Η-叶匕 唑并[3,4-b]吡啶-5-甲醯胺， 1-乙基-N-{4-[(甲磺醯基）胺基]苯基}-4-(四氫-2H-哌喃-4-基胺 基）-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺， 1-乙基-Ν-{3·[(甲胺基）談基]苯基}_4-(四氫-2H-喊喃_4_基胺基 )_1Η-吡唑并[3,4-b]吡啶·5·甲醯胺， 1-乙基-4-(四氫-2Η_旅喃-4-基胺基）·Ν-[3-(三氟甲基）苯基]-1Η-外匕吐并[3,4-b&gt;比啶-5-甲醯胺， 1-乙基-N-3-外b淀基-4-(四氫-2H_喊喃-4_基胺基）-1H-p比峻并 [3,4-b&gt;比淀-5-甲醯胺， N-(3,4-二氣苯基）-1-乙基-4·(四氫-2H-喊喃-4-基胺基）-1Η-ρ比魂 并[3，4七]吡啶-5-甲醯胺， N-[3-(胺基續酿基）-4-氯苯基]小乙基_4_(四氫-2H_旅喃-4-基胺 基）-1H-外t峻并P，4-b&gt;比淀-5_甲醯胺， 1-乙基-N-[3-(4_嗎福琳基）苯基]-4_(四氫-2H&gt;底喃-4-基胺基)-1Η· 87841-960303.doc -46- 1283678 冲匕峻并[3，4-b]峨淀-5-甲酸胺， 1-乙基-N-[4-(4-嗎福p林基續醯基）苯基]-4-(四氫-2H-味喃_冬基 胺基）-1Η-吡唑并[3,4-b]吡啶_5_甲醯胺， 1·乙基-N-{2_[(4-曱基-1-7T氮卩比p井基）窥基]麥基}-4-(四氫_2η·口底 喃·4_基胺基）-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺， N-{2-[(二甲胺基）羰基]苯基}-1·乙基-4·(四氫-2H_^喃_4-基胺 基）-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺， N-[2-氯基-4-(三氟甲基）苯基]小乙基_4_(四氫-2H-旅喃_4_基胺 基）-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺， N-{2_[(乙酸胺基）甲基]苯基}-1-乙基-4-(四氫·2Η_^喃冰基胺 基）-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺， N-(2-氯苯基）小乙基-4-(四氮-2H-喊喃-4-基胺基比吐并 [3,4_b]吡啶-5-甲醯胺， N-(3_氯基-2-氟苯基）-1•乙基-4-(四氫-2H·喊喃_4_基胺基）·ιη_ρ比 唑并[3，4七]吡啶-5-甲醯胺， 1-乙基-Ν-(3-氟苯基）-4-(四氳-2Η-旅喃-4-基胺基）-1Η_ρ比峻并 [3,4-b]吡啶-5-甲醯胺， N-(2-氰基·3_氟苯基）_1_乙基-4-(四氫_2H_喊喃-4-基胺基）-1Η-ρ比 唑并[3，4七]吡啶-5-甲醯胺， 1-乙基-Ν-[4-(丙基續酿基）苯基]-4-(四氯-2Η·。底ρ南-4-基胺基 )-1Η-吡唑并[3,4-b]吡啶·5_甲醯胺， Ν-{4-[(二甲胺基）羰基]苯基}-1·乙基-4-(四氫-2Η-喊喃-4-基胺 基）-lHw比吨并[3,4_b&gt;比淀_5_甲酸胺， 1-乙基-N-[4-(甲橫醯基）苯基]冰(四氫_2H_^喃-4-基胺基）-1Η- 87841-960303.doc -47- 1283678 峨峻并[3,4七]外b淀-5-甲醯胺， N-{4-[(乙酸胺基）甲基]冬基}-1-乙基-4-(四氯-2H-喊喃-4-基胺 基）-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺， N-({2_[(1，1-二甲基乙基）氧基]_3-ρ比淀基}甲基）-1-乙基-4_(四氫 -211-喊喃_4-基胺基）-1Η·吡峻并[3,4-b]吡淀_5_甲醯胺三氟酷酸 鹽， Ν-[(3·氯基-4-甲基苯基）甲基]小乙基冰(四氫_2H-喊喃-4-基胺 基）·1Η_ρ比峻并[3,4-b&gt;比淀-5-甲醯胺， N-[(4-氯基-2-甲基苯基）甲基]小乙基_4-(四氫-2H碌喃-4-基胺 基）·1Η-ρ比峻并[3,4-b]p比淀-5-甲酿胺， Ν·({2_[(一氣甲基）乳基]本基}甲基）-1-乙基-4_(四氯-211*^底喃_4_ 基胺基）-1Η-ρ比吨并[3,4七&gt;比&lt; -5-甲醯胺， 1-乙基-Ν_({2_[(1-甲基乙基）氧基]苯基}甲基）_4_(四氫々Η-派喃 _4·基胺基）-1Η-ρ比峻并[3,4-b]p比淀_5_甲酿胺， 1-乙基-Ν·({3·[(1·甲基乙基）氧基]苯基}甲基）冰(四氫-2H-派喃 -4-基胺基）·1Η-ρ比唆并[3,4-b]p比淀_5_甲酿胺， N-({3-[(二氟甲基）氧基]苯基}甲基）·1·乙基冬(四氫-2H娘喃·4_ 基胺基）-1Η-ρ比峻并[3,4-b&gt;比淀-5_甲酿胺， 1-乙基-Ν_{[4-#呈基-3-(甲氧基）苯基]甲基}_4-(四氫-2Η-旅喃-4_ 基胺基）-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺， N-[(5-乙醯基-2-羥苯基）甲基]小乙基_4-(四氫-2H-哌喃_4_基胺 基）·1Η-ρ比峻并[3,4-b&gt;比淀-5-甲醯胺， 1-乙基-4-(四氫-2H-喊喃-4-基胺基）·Ν-{2_[3_(三氟甲基）苯其]乙 基}-1Η_ρ比吨并[3,4-b&gt;比淀-5_甲醯胺， 87841-960303.doc -48- 1283678 N-{[4-(乙醯胺基）苯基]甲基}小乙基_4_(四氫-2H-哌喃-4-基胺 基）-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺， 1-乙基-N-[2-(3-羥苯基）乙基]-4-(四氫-2H-哌喃-4-基胺基）-1Η-吡 唑并[3,4-b]吡啶_5_甲醯胺， 1^-[2-(3_鼠冬基）乙基]_1_乙基-4-(四氮底喃-4-基胺基）-1Η-ρ比 吐并[3,4-b]吡啶-5-甲醯胺， 1-乙基-4-(四氫-2H-哌喃-4-基胺基）-N-(2-{4-[(三氟甲基）氧基] 苯基}乙基HH-吡唑并[3,4-b]吡啶-5·甲醯胺， 1_乙基·Ν-{2-[3_(甲氧基）苯基]乙基}-4-(四氫-2H-哌喃-4-基胺基 )-1Η-ρ比峻并[3,4-b&gt;比咬_5_甲醯胺， Ν-[2·(4-乙酿基苯基）乙基]-1-乙基-4-(四氯·2Η-ρ底喃-4-基胺基 )-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺， N-[2-(3,4-二氯苯基）乙基]-1-乙基-4·(四氫-2H-哌喃-4-基胺基 )-1Η-吡唑并[3,4_b]吡啶-5-甲醯胺， N-{2-[3-(胺基磺醯基）苯基]乙基}小乙基-4-(四氫_2H-哌喃_4_基 胺基）-1Η-吡唑并[3,4-b]吡啶_5_甲醯胺， N-{2-[3,4-雙（曱氧基）苯基]乙基}小乙基_4-(四氫-211_哌喃-4-基 胺基）-1Η·吡唑并[3,4-b]吡啶-5-甲醯胺， N-[2-2,3-二氯苯基）乙基]-1-乙基-4-(四氫_2H-哌喃-4-基胺基 )-1Η-吡唑并[3,4_b]吡啶-5-甲醯胺， N-{2-[3,5-雙（甲氧基）苯基]乙基}小乙基_4-(四氫-2H-哌喃-4-基 胺基）-1Η-毗唑并[3,4-b]吡啶-5_甲醯胺， 1-乙基-N-{2-[3-甲基-4-(甲氧基）苯基]乙基}-4-(四氫-2H-哌喃-4-基胺基）_1H-吡唑并[3,4-b]吡啶-5-甲醯胺， 87841-960303.doc -49- 1283678 N-[2_(2,6-二氟苯基）乙基]-1_乙基-4-(四氫-2H-旅喃_4_基胺基 )-1H-p比嗅并[3,4-b扣比淀-5-甲酿胺， N_{2-[2,6_雙（甲氧基）苯基]乙基}_1_乙基_4_(四氫-2H4喃-4-基 胺基）-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺， 1_乙基-N-[2-(2-甲基苯基）乙基]-4-(四氫_2H_喊喃-4-基胺基）-1Η- 外匕峻并[3,4-b]p比淀-5-甲醯胺， N-[(3,4_二甲基苯基）甲基]-1-乙基-4-(四氫—2H-旅喃_4_基胺基 )-1Η-吡唑并[3,4-b]吡啶_5_甲醯胺， N-[4,5-雙（甲氧基）-2,3-二氫-1H-茚-2-基H-乙基_4-(四氫_211_喊 喃-4-基胺基）-1Η-外b吐并[3,4-b]外b淀-5-甲酸胺， Ν-{2·[4-(胺基續醯基）苯基]乙基}-1-乙基-4-(四氫_2H_旅喃-4-基 胺基）-1Η-吡唑并[3,4-b]吡啶_5_甲醯胺， 1-乙基-N-{[2-(甲基亞續酿基）苯基]甲基}·4-(四氫-2H-旅喃-4-基胺基）·1Η-吡唑并[3,4_b]吡啶_5_甲醯胺， 1_乙基-N-(2-苯基乙基）-4-(四氯-2H-旅喃·4-基胺基）-1Η-ρ比唆并 [3,4-b]吡啶-5-甲醯胺， Ν·{[4-(二甲胺基）苯基]甲基}小乙基-4-(四氫-2H-哌喃_4-基胺 基）-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺， 1_乙基-Ν_[2-(4·氟苯基）乙基]-4-(四氫-2H-哌喃_4_基胺基）·1Η_吡 也并[3,4-b]p比淀-5-甲醢胺， 1-乙基-Ν·[2-(4-甲基苯基）乙基]-4-(四氫-2H_^喃-4-基胺基）-1Η-p比吐并[3,4七&gt;比喊_5_甲酿胺， N_{[3-(胺基磺醯基）苯基]甲基}小乙基·4-(四氫-211_哌喃斗基 胺基)-1Η_ρ比峻并[3,4-b]p比淀-5-甲酿胺， 87841-960303.doc -50· 1283678 1- 乙基_N-[(4-甲基苯基）甲基]-4-(四氫-2H·略喃·4·基胺基）-1Η-被吃并[3,4-b]吡啶-5-甲醯胺， 1·乙基-N_{[4-敦基-3-(三氣甲基）苯基]曱基}-4-(四氫底喃 -4-基胺基）·1Η·吡唑并[3,4-b]吡啶-5-甲醯胺， 2- [({[1_乙基-4·(四氫-2H-喊喃_4_基胺基比峻并[3,4-b]p比淀 -5-基]魏基}胺基）甲基]苯甲酸甲酉旨， N-[(6-鼠基-2-ρ比淀基）甲基]-1-乙基-4_(四氯展喃-4-基胺基 )-1Η·吡唑并[3,4-b]吡啶-5-甲醯胺三氟醋酸鹽， N-(2,3-二氯-1H-葬-1·基）_1_乙基-4-(四氯_2H·^底喃-4_基胺基）_1H_ 外1：咬并[3,4-b]吡啶-5-甲醯胺， N_({2-[乙醯基（甲基）胺基]苯基}甲基）小乙基-4-(四氫-2H-哌喃 -4-基胺基）-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺， N-[(lS)-2,3-二氯_111_印_1_基]-1-乙基-4-(四氯_2H-喊喃-4-基胺基 )-1Η-ρ比也并[3,4_b]叶匕淀-5-甲酿胺， N-[(lR)-2,3-二氫-1H·茚-1-基]小乙基-4·(四氫-2H-哌喃-4-基胺基 )-1Η·吡唑并|；3,4-b]吡啶_5_甲醯胺， 1-乙基-N-({3-[(甲磺醯基）胺基]苯基}甲基）-4-(四氫-2H-哌喃-4-基胺基）_1H-吡唑并[3,4-b]吡啶_5_甲醯胺， 1_乙基·N-(l-苯基_4_六氫吡啶基）-4-(四氫-2H-哌喃-4·基胺基 )-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺， 1_乙基-N-{1_[(乙胺基）羰基]-4-六氫吡啶基}-4-(四氫-2H-哌喃 -4-基胺基）-1Η-吡唑并[3,4-b]吡啶-5·甲醯胺， 甲酸小乙基-N-[l-甲基-2-(4-曱基-1-六氫吡畊基）乙基]4-(四氫 -2H-喊喃-4-基胺基）-1Η-吡唑并p，4-b]吡啶_5·甲醯胺（1 : 1)， 87841-960303.doc -51- 1283678 [4-({[l-乙基-4-(四氫-2H·旅喃-4-基胺基）-1Η_ρ比唾并[3,4-b]p比淀 -5-基]羰基}胺基）-1-六氫吡啶基]醋酸甲酯， 1-乙基-N-{[4-(4-嗎福淋基甲基）苯基]甲基}_4-(四氫_2H-旅喃-4-基胺基）-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺三氟醋酸鹽， 1-乙基-N_({3-[(4-甲基小六氫吡畊基）甲基]苯基}甲基）-4·(四氫 -2H·喊喃-4-基胺基）-1H-p比峻并[3,4-b&gt;比淀·5_甲酸胺三氟醋酸 ητΛ£ 鹽 ， Ν-{[5-(胺基獄基）-3-p比淀基]甲基}-1-乙基-4_(四氯-2Η-0底喃-4_ 基胺基）-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺三氟醋酸鹽， 1-乙基-N_{[4-(1-甲基乙基）苯基]甲基}_4-(四氫-2H-喊喃-4-基胺 基）_1H-吡唑并[3,4-b]吡啶-5-甲醯胺， N-{[3-(環戊氧基)_4-(甲氧基）苯基]甲基}小乙基-4-(四氫_2H-哌 喃斗基胺基）_1H_吡唑并[3,4-b]吡啶-5·甲醯胺， 1_乙基-Ν·({4-[(4-甲基小六氫吡畊基）甲基]苯基}甲基）冰(四氫 -2Η-略喃-4-基胺基）-1Η-ρ比峻并[3,4-b]p比淀-5-甲酿胺三氟醋酸 鹽， N-[(2,4-二氯苯基）甲基]-1-乙基-4-(四氫-2H_哌喃-4-基胺基）_1H-吡唑并[3,4-b]吡啶-5·甲醯胺， Ν·[(2,4-二氟苯基）甲基]小乙基-4-(四氫·2Η-哌喃-4_基胺基）_1Η· 吡也并[3,4-b]吡啶-5-甲醯胺， N-[(2-氣基-4-氟苯基）甲基]-1-乙基-4-(四氫-2H-喊喃-4-基胺基 )-1Η·吡峻并[3,4-b]吡啶-5-甲醯胺， N-{2-[2-乳基_3-(甲氧基）苯基]乙基}-1-乙基-4-(四氣-2H_喊喃_4_ 基胺基）-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺， 87841-960303.doc -52- 1283678 3-[({[l-乙基冰(四氫_2H-哌喃-4-基胺基）-1Η-吡唑并[3,4-b]吡啶 -5-基]羰基}胺基）甲基]苯甲酸甲酯， 1-乙基-Ν-{[3-(1-四氫p比洛基甲基）苯基]甲基}-4-(四氫-2H-^喃 -4-基胺基）-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺三氟醋酸鹽， 1-乙基-N-(2-{4-[(甲續酸基）胺基]苯基}乙基）-4-(四氫-2H-喊喃 -4-基胺基）-1Η·ρ比吐并[3,4_b]p比淀-5-甲酿胺， N-{[2,5-雙（甲氧基）苯基]甲基}-1-乙基-4-(四氮-2H-喊喃-4-基胺 基）-1Η-外b峻并[3,4-b]p比淀-5-甲酿胺， N-{[2,6_雙（甲氧基）苯基]甲基}_1_乙基-4_(四氫-2H_旅喃-4-基胺 基）-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺， 1-乙基·Ν-[(2-氟苯基）甲基]-4·(四氫-2H·喊喃_4_基胺基）-1Η-外匕 唑并[3,4-b]吡啶-5-甲醯胺， N-[(3,5-二氟苯基）甲基]-1-乙基-4-(四氫_2Hh派喃-4-基胺基）-1Η_ 吡唑并[3,4-b]吡啶-5-甲醯胺， N_[(4-氯苯基）甲基]-1-乙基-4-(四氫·2Η-喊喃-4-基胺基）-1Η-峨 峻并[3,4-b]外1：淀-5-甲醯胺， N-環己基_1-乙基-4-(四氳-2H·哌喃_4_基胺基&gt;1H-吡唑并[3,4_b] 竹匕淀-5-甲酿胺， 1-乙基·Ν_{2·[4-(甲績酿基）苯基]乙基}-4-(四氫_2H_喊喃-4·基胺 基）-1Η·吡唑并[3,4-b]吡啶-5_甲醯胺， 1_乙基-Ν_{[2_氟基-3-(三氟甲基）苯基]甲基卜4_(四氫jH-喊喃 -4·基胺基）-1Η-ρ比唆并[3,4-b]p比咬-5-甲酿胺， N_({4-[(環丙胺基）羰基]苯基}甲基）_1_乙基_4_(四氫喃冰 基胺基比峻并[3,4-b]p比淀-5-甲酿胺， 87841-960303.doc -53 - 1283678 1-乙基-N-{[4-(4-甲基_1·六氫吡畊基）苯基]甲基卜4-(四氫-2H-哌 喃-4·基胺基）-1Η-吡唑并[3,4-b]吡啶-5_甲醯胺， 1-乙基-N_{[4-(1•四氫吡咯基甲基）苯基]甲基卜4-(四氫-2H-哌喃 _4_基胺基）·1Η·吡唑并[3,4_b]吡啶-5-甲醯胺， 1_乙基-N_[6-(甲氧基）-1-酮基·2,3-二氫_1Η·茚-2-基]·4-(四氫-2H-哌喃-4-基胺基）·1Η-吡唑并[3,4-b]吡啶-5-甲醯胺， N-[(2,5_&lt;一乳卒基）甲基]-1-乙基-4-(四氣底喃-4-基胺基）_1H_ 吡唑并[3,4-b]吡啶-5-甲醯胺， N-[(3,5-二乙基苯基）甲基]_1_乙基_4_(四氫-2H_哌喃-4-基胺基 比峻并[3,4-b]外匕淀-5-甲醯胺， N-[(2,3_一氣麥基）甲基]_1_乙基-4·(四氯-2H-旅喃-4·基胺基）-1Η_ 吡唑并[3,4_b]吡啶-5·甲醯胺， 1-乙基_N-{[2_(甲磺醯基）苯基]甲基}-4·(四氫-2H-哌喃-4-基胺 基）_1H_吡唑并[3,4-b]吡啶-5-甲醯胺， 1-乙基_N_[(3-羥苯基）甲基]-4·(四氫-2H_哌喃-4-基胺基）-1Η-吡 唑并[3,4_b]吡啶-5-甲醯胺， N-{[3,5-雙（甲氧基）苯基]甲基卜丨乙基冬(四氫-2H_哌喃_4_基胺 基HH-吡唑并[3,4-b]吡淀-5-甲醯胺， 1-乙基-N-[2_(4_經苯基）乙基]-4-(四氫_2H-喊喃_4_基胺基）-1Η-吡 峻并[3,4-b]ii比淀-5-甲酿胺， N-[(3,5-一氣苯基）甲基]小乙基-4-(四氫-2Η_ϊ痕喃·4-基胺基）-1Η_ 吡唑并[3,4_b]吡啶-5-甲醯胺， N-{[2,4-雙（甲氧基）苯基]甲基乙基_4·(四氫-2Η_ϊ痕喃冬基胺 基）_1Η-吡峻并[3,4-b]吡啶-5-甲醯胺， 87841.960303.doc -54- 1283678 1-乙基-N-{[2-(甲氧基）苯基]甲基}-4-(四氫-2H-喊喃-4_基胺基 )-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺， N-[(2,4-二甲基苯基）甲基]小乙基-4-(四氫-2H-哌喃斗基胺基 )-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺， 1-乙基-Ν·({2-[(甲胺基）羰基]苯基}甲基）-4_(四氫_2H_喊喃-4-基 胺基）-1Η·吡唑并[3,4-b]吡啶-5_甲醯胺， 1-乙基-N-{2-[4-(甲氧基）苯基]乙基}-4-(四氫-2Η-Ϊ痕喃-4-基胺基 )-1Η^比峻并[3,4-b&gt;比淀-5-甲醯胺， N-[(2_氯苯基）甲基]-1_乙基-4-(四氫-2H-喊喃-4-基胺基比 处并[3,4-b]p比咬-5-甲酸胺’ 1-乙基-N-[(2_#呈苯基）甲基]-4-(四氫-2H-喊喃-4-基胺基）·1Η-外b 峻并[3,4-b&gt;比淀-5-甲醯胺， N-(l，3-苯并二氧伍圜烯-5-基甲基）-1-乙基-4·(四氫_2H_哌喃-4-基胺基）-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺， 1-乙基·Ν-[3-(甲氧基）苯基]-4-(四氬·2Η-哌喃-4-基胺基）-1Η-吡 吐并[3,4-b]p比淀-5-甲酿胺， N-(環己基甲基）小乙基-4-(四氫-2H_喊喃-4-基胺基）-1H-p比峻 并[3,4-b]吡啶-5-甲醯胺， 1-乙基·Ν·(1，2,3,4·四氫-1_莕基）_4-(四氫-2H-哌喃冬基胺基）-1Η-p比吐并[3,4-b]p比淀-5-甲酸胺， 4_[({|&gt;乙基-4·(四氫-211-旅喃-4-基胺基）-1Η_吡唑并[3,4-b]竹b啶 基]羰基}胺基）甲基]苯甲酸甲酯， Ν-[(3,4·二氯苯基）甲基]小乙基_4-(四氫-2H_哌喃-4-基胺基）-1Η-吡唑并[3,4-b&gt;比啶-5-甲醯胺 87841-960303.doc -55- 1283678 N-{[4-(胺基羰基）苯基]甲基}-1-乙基-4-(四氫-2H-哌喃-4_基胺 基）-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺 N-[(2,6-二氟苯基）甲基]-1_乙基-4-(四氫-2H-略喃-4-基胺基）_iH_ 吡唑并[3,4-b]吡啶-5-甲醯胺 N-{[3-(胺基談基）苯基]甲基}小乙基-4-(四氬_2H-喊喃-4-基胺 基）-1Η·吡唑并[3,4-b]吡啶·5·甲醯胺 1-乙基-Ν-[(4-每苯基）甲基]-4-(四氫-2Η-*7瓜喃-4-基胺基）-1Η-ρ比 唑并[3,4-b]吡啶-5-甲醯胺， 1-乙基-N-{[6-(甲氧基）-3-外b淀基]甲基}-4-(四氫_2H-旅喃-4-基 胺基）-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺 1-乙基比淀基甲基）-4-(四氯-2H-P底喃-4-基胺基）-1Η-ρ比吐 并[3,4-b]吡啶-5-甲醯胺 1-乙基-4-(四氫-2H-哌喃-4-基胺基）·Ν-{[3_(三氟曱基）苯基]甲 基}-1Η-吡峻并[3,4-b]吡啶-5-甲醯胺 Ν·[4-(2-胺基-2-酮基乙基）苯基]小乙基-4-(四氫-2H-哌喃-4-基 胺基）-1Η_吡唑并[3,4-b]吡啶_5_甲醯胺 1-乙基-Ν·({4-[(甲胺基）羰基]苯基}甲基）-4-(四氫-2H-哌喃_4_基 胺基）_1H_毗唑并[3,4-b]吡啶_5_甲醯胺 1_乙基-Ν·{4-[2-(甲胺基）-2·酮基乙基]苯基}冬(四氫-2H-哌喃-4-基胺基HH-吡唑并[3,4-b]吡啶-5-甲醯胺 1-乙基-N-[(3-氟苯基）甲基]-4-(四氫-2H·哌喃4-基胺基）-1Η-吡 唑并[3,4-b]吡啶—5-甲醯胺 1_乙基_N-({4-[(甲磺醯基）胺基]苯基}甲基）_4_(四氫-2H-哌喃斗 基胺基）-1Η-吡唑并[3,4-b]吡啶-5_甲醯胺 87841-960303.doc -56- 1283678 N-{[4-(胺基續縫基）苯基]甲基}-l-乙基-4·(四氣底喃-4-基 胺基）·1Η-吡唑并[3,4_b]吡啶_5_甲醯胺 N-{[2-(胺基魏基）苯基]甲基}_1_乙基-4-(四氯·2Η_^喃-4-基胺 基）-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺 N-({4-[(二氟甲基）氧基]苯基}甲基）_1_乙基·4-(四氫底喃-4-基胺基）·1Η_吡唑并[3,4七]吡啶-5-甲醯胺 Ν-({3-[(二甲胺基）甲基]苯基}甲基）-1•乙基-4-(四氫-2Η-哌喃冰 基胺基）-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺 N-{[3-氯基-4-(甲氧基）苯基]甲基}小乙基-4-(四氯-2H-喊喃-4-基胺基）-1Η-吡唑并p，4-b]吡啶-5-甲醯胺 Ν-(1·乙酿基-4-TT氮ρ比淀基乙基-4-(四氣-211·^底喃-4-基胺基 )-1Η-ρ比峻并p，4-b]批淀-5-甲醯胺 1-乙基-4-(四氫-2H-旅喃·4_基胺基）-N-{[2-(三氟甲基）苯基]甲 基}·1Η-吡唑并[3,4_b]吡啶-5-甲醯胺 N_(5·氯基-2,3-二氫-1H_雜_2·基）-1•乙基-4-(四氣_2Η_ι派喃_4_基胺 基）-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺 N-({3-[(乙酿胺基）甲基]苯基}甲基）·1_乙基_4-(四氫·2Η&gt;底喃-4-基胺基）-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺 1-乙基·Ν-[(4-氟苯基）甲基]-4-(四氫-2H-哌喃_4_基胺基）-1Η_吡 唑并[3,4_b]吡啶-5-甲醯胺 1-乙基-Ν-{[4-|^基-2-(三氟甲基）苯基]甲基}_4_(四氫_2H_喊喃 -4-基胺基）_1Η-ρ比吐并[3,4-b]外b淀-5_甲酸胺 1·乙基-N-[(2-乙基苯基）甲基]-4-(四氫_2H-喊喃-4-基胺基）-1Η-竹1：唑并[3,4-b]吡啶-5-甲醯胺 87841-960303.doc -57- 1283678 1-乙基-N-{[2_氟基-5-(三氟甲基）苯基]甲基}-4-(四氫-2H-喊喃 -4-基胺基比咬并[3,4-b]p比咬-5-甲酸胺 1-乙基-4_(四氫_2H_喊喃_4_基胺基）-N-[(2,3,4-三氟苯基）甲基 ]-1Η-ρ比也并[3,4-b]p比淀-5-甲酿胺 N-[(4-氯基_2_氟苯基）甲基]-1·乙基-4-(四氫-2H-喊喃-4-基胺基 比峻并[3,4-b]?比淀-5-甲疏胺 N-[(4-溴基-2-氟苯基）甲基]-1-乙基-4-(四氫-2H-喊喃-4-基胺基 )-1Η-吡峻并[3,4-b]吡啶-5-甲醯胺 N-[(3,5-二甲基苯基）甲基]-1-乙基-4-(四氫_2H-旅喃-4-基胺基 )-1Η-吡唑并[3,4_b]吡啶-5-甲醯胺 N-[(2,3-二甲基苯基）甲基]-1-乙基-4-(四氫-2H-派喃-4-基胺基 )-1Η-吡峻并[3,4-b]吡啶-5-甲醯胺 N-[(2,3-二氣苯基）甲基]-1-乙基·4-(四氫-2Η-Ϊ痕喃-4-基胺基）-1Η-吡唑并[3,4_b]吡啶-5-甲醯胺 N-[(4-氰基苯基）甲基]_1·乙基-4-(四氫-2H-旅喃_4_基胺基）-1Η-外匕峻并[3,4-b]外1：淀-5-甲酸胺 N-[(4-溴苯基）甲基]-1-乙基-4-(四氫-2H-喊喃_4_基胺基）-lH-口比 唑并[3,4-b]吡啶-5-甲醯胺 1-乙基-N-{[5-氟基-2_(三氟甲基）苯基]甲基卜4-(四氫—2H-喊喃 -4-基胺基）-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺 1-乙基-N-[(4-破苯基）甲基]·4-(四氫-2H_喊喃-4-基胺基）-1Η_叶匕 唑并[3,4-b]吡啶-5-甲醯胺 Ν-{[4-(1，1-二甲基乙基）苯基]甲基}小乙基-4-(四氫-2H-哌喃-4_ 基胺基）-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺 87841-960303.doc -58 - 1283678 N_[(3-散基苯基）甲基]-1-乙基-4-(四氫-2H-喊喃-4_基胺基）-1Η-p比唆并[3,4-b]p比淀-5-甲酿胺 N-[(2,6-二氯苯基）甲基]小乙基_4-(四氫_2凡哌喃-4-基胺基）-1Η-峨唑并[3,4-b]吡啶-5-甲醯胺 N-[(5-氯基-2-甲基苯基）甲基]-1_乙基-4-(四氫-2H-喊喃-4·基胺 基比吐并[3,4-b]吡咱：-5-甲醯胺 N-[(3,5_二溴苯基）甲基;μΐ_匕基-4-(四氫_2H-喊喃-4-基胺基）-1Η_ 吡唑并[3,4-b]吡啶-5-甲醯胺 1_乙基·Ν-[(4_乙基苯基）甲基]-4-(四氫-2H-喊喃_4_基胺基）-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺 1-乙基_N-{[3_氟基-4-(三氟甲基）苯基]甲基}-4-(四氫-2H-喊喃 -4-基胺基）-1Η_吡唑并[3,4-b]吡啶-5-甲醯胺 1-乙基-N-[(2-蛾苯基）甲基]-4-(四氫-2H_^喃-4_基胺基）_1H-p比 唑并[3，4七]吡啶-5-甲醯胺 N-[(2-溴苯基）甲基]-1_乙基-4·(四氫-2H&gt;辰喃_4·基胺基）-iH_外匕 也并[3,4-b&gt;比淀-5-甲醯胺 1-乙基-Ν-{[4·(幾甲基）苯基]甲基}-4-(四氫-2H-喊喃冬基胺基 )-1Η-吡嗤并[3,4-b]p比咬-5-甲醯胺 1-乙基-N-{[3-(羥甲基）苯基]甲基}_4-(四氫_2H_喊喃_4_基胺基 )-1Η-吡峻并[3,4-b]吡啶-5-甲醯胺 1-乙基-N-{[3-(羥甲基）-2-甲基苯基]甲基卜4-(四氫-2H_p展喃-4-基胺基）-1Η-吡唑并[3,4-b]吡啶_5_甲醯胺 N-{[2&gt;二氯_6_(經甲基）苯基]甲基}小乙基斗(四氫_2迅喊喃冬 基胺基）-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺 87841-960303.doc -59- 1283678 N-[(2,4-二氯-6-甲基苯基）甲基]-1-乙基-4-(四氫-2H&gt;底喃-4-基胺 基）-1Η-ρ比峻并[3,4-b]外b咬-5_甲酸胺 1-乙基-N-{[4-(2-甲基丙基）苯基]甲基}-4·(四氫-2Η·哌喃_4-基胺 基）-1Η-ρ比唆并[3,4_b&gt;比淀-5_甲酿胺 N-[(2,5-二甲基苯基）甲基]-1-乙基-4-(四氫-2H-喊喃-4-基胺基 )-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺 1-乙基-4-(四氫-2H-旅喃_4_基胺基）-N-[(2,4,5_三氟苯基）甲基 ]-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺 1-乙基-N-{[2-氟基-4-(三氟甲基）苯基]甲基}-4-(四氫-2H-哌喃 -4-基胺基）-1Η_ρ比峻并[3,4-b]p比攻-5-甲酸胺 N-[(2-氯基-6-甲基苯基）甲基]-1-乙基-4-(四氫-2H&gt;底喃-4-基胺 基）·1Η-β比也并[3,4-b]p比淀-5-曱酿胺 4_[({[1_乙基·4·(四氫-2H-哌喃·4-基胺基）-1Η-吡唑并[3,4-b]吡啶 -5-基]羰基}胺基）甲基]苯甲酸鈉鹽 3-[({[1-乙基-4-(四氫-2H-哌喃-4-基胺基）-1Η-吡唑并卩，4七]吡啶 -5-基]羰基}胺基）甲基]苯甲酸 1-乙基_4-{[4-(羥亞胺基）環己基]胺基}_1H-吡唑并[3,4-b]吡啶 -5-羧酸乙酯 1-乙基-4_{[4-(羥亞胺基）環己基]胺基}-N-{[4_(甲氧基）苯基]甲 基}-1Η_ρ比岐并[3,4-b]p比淀-5-甲酿胺 N-{[4-(二甲胺基）苯基]甲基}小乙基-4-{[4-(羥亞胺基）環己基] 胺基}-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺 1_乙基-4-({4-[(乙氧基）亞胺基]環己基}胺基）-N-{[4-(甲氧基）苯 基]甲基卜1H-吡唑并[3,4七]吡啶-5-甲醯胺 87841-960303.doc -60- 1283678 1_乙基_4-({4-[(甲氧基）亞胺基]環己基}胺基）-Ν-{[4·(甲氧基）苯 基]甲基HH-吡唑并[3,4-b]吡啶-5-甲醯胺 4_[(4-{[(1，1-二甲基乙基）氧基]亞胺基}環己基）胺基]-1-乙基 -N_{[4-(曱氧基）苯基]甲基}_ih-吡唑并[3,4-b]吡啶-5-甲醯胺 1_乙基_N-{[4_(甲氧基）苯基]甲基}-4-[(7_酮基六氫-1H-—氮七 圜烯-4_基）胺基]_1H_吡唑并p，4_b]吡啶-5-甲醯胺 1-乙基-4-[(7-酮基六氫-1H-—氮七圜烯-4·基）胺基]-1H-吡唑并 [3,4-b]吡啶-5-羧酸乙酯 4-{[順式-4-(丁基胺基）環己基]胺基卜N-(2,3-二氫-1H-茚-2-基 )_1_乙基-lH-p比吐并[3,4-b]竹b淀-5-甲酸胺 4·[(反式冰胺基環己基）胺基]小乙基-N-(苯基甲基）-1Η-吡唑 并[3,4-b]吡啶-5-甲醯胺 4-[(反式-2-胺基環己基）胺基1-1-乙基(苯基甲基）-1Η-吡唑 并[3,4-b]吡啶-5-甲醯胺 4-[(順式-2-胺基環己基）胺基]-1-乙基-N-(苯基甲基）-1Η-吡唑 并[3,4-b]吡啶-5-甲醯胺， 4-[(3_胺基環己基)胺基H-乙基-N-(苯基甲基）_1H_吡唑并[3,4七] 吡啶-5-甲醯胺， 1-乙基-4{[(lSR，3RS)-3-經基環己基]胺基比吐并[3,4-b]p比 啶-5-羧酸乙酯， N，l-二乙基-4-{[(lSR，3RS)-3-經基環己基]胺基卜iH-ρ比吐并[3,4-b] 吡啶-5-甲醯胺， 1_乙基-Ν·(4-氟苯基）-4_{[(lSR，3RS)-3_#呈基環己基]胺基卜ih_口比 唑并[3，4七]吡啶-5-甲醯胺， 87841-960303.doc -61 - 1283678 1-乙基-4-{[(lSR，3RS)_3-羥基環己基]胺基}-Ν·(1，3-嘧唑_2_基甲 基）-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺， 1-乙基-N-[(4-氟苯基）甲基]-4-{[(lSR，3RS)-3_羥基環己基]胺基 }-1Η-叶b峻并P，4-b]外I：淀-5-甲酸胺， 1-乙基_4_{[(lSR，3RS)-3-羥基環己基]胺基}-N-{[4_(甲磺醯基）苯 基]甲基卜1H-吡唑并[3,4_b]吡啶-5-甲醯胺， N-{[3,4-雙（甲氧基）苯基]甲基}小乙基-4-{[(lSR，3RS)-3-羥基環 己基]胺基}_1H-吡唑并[3,4_b]吡啶-5-甲醯胺， 1-乙基-4-{[(lSR，3RS)_3-羥基環己基]胺基卜N-(2-吡啶基甲基 )-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺， 1-乙基-4-{[(lSR，3RS)-3-羥基環己基]胺基}-Ν-[(1-甲基-1H-吡唑 -4-基）甲基]-1H·吡唑并[3,4-b]吡啶-5-甲醯胺， N-[(3,4-二甲基苯基）甲基]-1-乙基-4_{[(1SR，3RS)_3-羥基環己基] 胺基}-1Η·吡唑并[3,4-b]吡啶-5-甲醯胺， 1_乙基-4-{[(lSR，3RS)-3-羥基環己基]胺基卜N-{[4-(甲氧基）苯基] 甲基}-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺， N-[(2,4-二曱基苯基）甲基]小乙基-4-{[(lSR，3RS)-3-羥基環己基] 胺基}-1Η·吡唑并[3,4-b]吡啶-5-甲醯胺， N-[(2,3-二氯苯基）甲基]-1-乙基-4-[(4_酮基環己基）胺基]比 唑并[3,4-b)吡啶-5-甲醯胺， N-[(3-氯基-4-甲基苯基）甲基]小乙基-[(4_酮基環己基）胺基 ]-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺， N-[(4-氣基-2-甲基苯基）甲基]小乙基-4-[(4-酮基環己基）胺基 ]-1Η-吡唑并[3,4-b]吡啶-5·甲醯胺， 87841-960303.doc -62- 1283678 N-[(2,4-二甲基苯基）甲基]-1-乙基-4-{[4-(羥亞胺基）環己基]胺 基}-1Η_吡唑并[3,4_b]吡啶-5-甲醯胺， Ν·[(3,4-二甲基苯基）甲基]-1-乙基-4-{[4-(羥亞胺基）環己基]胺 基}-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺， N-[(2,3_二氯苯基）甲基]小乙基斗{[羥亞胺基）環己基]胺基 }-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺， Ν-[(3·氯基_4_甲基苯基）甲基]小乙基-4_{[4_(經亞胺基）環己基] 胺基}-1Η-吡唑并[3,4-b]吡啶-5-甲醯胺， N-[(4-氯基-2-甲基苯基）甲基]-1-乙基-4-{[4·(羥亞胺基）環己基] 胺基}-1Η-吡唑并[3,4-b]吡啶_5_甲醯胺， N-({4-[(二氟甲基）氧基]苯基}甲基)小乙基·4-{[4-(經亞胺基）環 己基]胺基}·1Η-吡唑并[3,4-b]吡啶-5-甲醯胺，或 1-乙基冰{[4-(經亞胺基）環己]胺基}_Ν_{[4·(三氟甲基）苯基]甲 基}·1Η_吡唑并[3,4-b]吡啶-5-甲醯胺； 或其鹽。 52·根據申請專利範圍第1項之化合物或鹽，其係為： N-[(2,4-二曱基苯基）甲基]小乙基-4-[(4_酮基環己基）胺基]-1H-峨唑并[3,4-b]吡啶-5-甲醯胺， N-[(3,4-二甲基苯基）甲基]_1_乙基-4·[(4·酮基環己基）胺基]-1H-峨唑并[3,4-b]吡淀·5_甲醯胺， 1-乙基_Ν-{[4·(甲氧基）苯基]甲基}-4-[(4-酮基環己基）胺基]-1Η-毗唑并[3,4-b]吡啶-5-甲醯胺， N-({4·[(二氟甲基）氧基]苯基}甲基）小乙基·4-[(4-酮基環己基） 胺基]-1Η-吡唑并[3,4-b]吡啶_5_甲醯胺， 87841-960303.doc -63- 1283678 4-(環己胺基）-1-乙基-N-{[4-(甲氧基）苯基]甲基}-1Η-ρ比峡并 [3,4-b]吡啶-5-甲醯胺， N_[(3-氯基冬甲基苯基）甲基]_1_乙基-4_(四氫-2H-哌喃-4-基胺 基）-1Η-吡唑并[3,4-b]吡啶_5·甲醯胺， N-[(4-氯基-2·甲基苯基）甲基]-1-乙基冬(四氫-2H·哌喃斗基胺 基）_1Η-吡唑并[3,4-b]吡啶_5-甲醯胺， N-[(3,4_二甲基苯基）甲基]小乙基-4_(四氫-2H-哌喃斗基胺基 )-1Η-吡唑并P，4-b]吡啶-5-甲醯胺， 1_乙基-N-[(4-甲基苯基）甲基]·4-(四氫_2H-哌喃-4-基胺基）-m-被唑并[3,4-b]吡啶-5-甲醯胺， N-[(2,4-二甲基苯基）甲基]-1-乙基_4·(四氮-2H-喊喃-4-基胺基 比吐并[3,4-b]外1：淀-5-甲酿胺， N-[(2,3_二氣苯基）甲基]-1·乙基-4-(四氬-；2H-哌喃-4-基胺基）-1Η-外匕哇并[3，4-b]吡啶-5-甲醯胺， N_{[2,3-二氯-6·(經甲基）苯基]甲基}-1-乙基-4-(四氫-2H-哌喃-4-基胺基）-1Η·吡唑并[3,4-b]吡啶-5-甲醯胺， 1-乙基-4-{[4_(羥亞胺基）環己基]胺基}-N-{[4-(甲氧基）苯基]甲 基}-1Η_ρ比唆并[3,4-b]p比淀_5·甲醯胺， N-[(4-氣-2-甲基苯基）甲基]-1-乙基-4-[(4-酮基環己基）胺 基]·1Η-吡唑并[3,4-b]吡啶-5-叛醯胺， N-[(2,4 - 一甲基苯基）甲基]-1-乙基-4·{[4-(經亞胺基）環己 基]胺基}-1Η-吡唑并[3,4-b]吡啶-5-羧醯胺， N-[(3,4-一甲基苯基）甲基]-1-乙基_4-{[4-(經亞胺基）環己 基]胺基}·1Η-ρ比唆并[3,4-b]^：咬-5_幾醯胺， 87841-960303.doc -64- 1283678 N-[(2,3-二氯苯基）甲基]-丨-乙基_心{[4_(羥亞胺基）環己基] 胺基}-1Η^比峻并[3,4-b]p比淀-5-羧醯胺， N-[(3-氯-4-甲基苯基）甲基]乙基_心{[4-(羥亞胺基）環己 基]胺基}-1Η-吡唑并[3,4-b]吡啶-5-羧醯胺， Ν·[(4-氯-2-甲基苯基）甲基]_丨-乙基_4-{[4-(羥亞胺基）環己 基]胺基}-1Η·吡唑并[3,4-b]吡啶-5-羧醯胺， N-({4-[(二氟甲基）氧基]苯基}甲基）-1_乙基-4-{[4-(羥亞胺 基）環己基]胺基}·1Η-ρ比4并[3,4-b]p比淀-5-叛酿胺，或 1-乙基-4-{[4-(羥亞胺基）環己基]胺基}-N_{[4-(三氟曱基） 苯基]甲基}-1Η-吡唑并[3,4-b]吡啶-5-羧醯胺； 或其鹽。 53·根據申請專利範圍第1項之化合物或鹽，其係為： N-苄基-1-乙基-4_(四氫_2Η·哌喃-4-基胺基）-1Η-吡唑并 [3,4-b]p比淀-5_幾酿胺， 1_乙基-Ν·(4·氟苯基）-4-(四氫-2H_^喃_4_基胺基）-1Η-吡 唑并[3,4-b]吡啶-5-羧醯胺， 1-乙基_N_乙基-4-(四氫-2H_哌喃_4_基胺基）-1Η-吡唑并 [3,4_b]吡啶-5-羧醯胺， 1-乙基-Ν-[4·(甲基磺醯基）爷基]·4_(四氫-2H-哌喃_4_基胺 基）-1Η-吡唑并[3,4-b]吡啶-5-羧醯胺， 1-乙基-4_(四氫-：2H-旅喃-4-基胺基）-Ν-(1，3-達也-2基甲基 )-1Η-吡唑并[3,4-b]吡啶-5-羧醯胺， N-(3,4-二甲氧基苄基）1_乙基-4_ (四氫-2H_旅喃-4-基胺基 )_1H-吡唑并[3,4-b]吡啶-5_羧醯胺， 87841-960303.doc -65- 1283678 卜乙基_N-{4-[(甲基磺醯基）甲基]苯基}-4-(四氫-2H-哌喃 -4-基胺基）-1Η-吡唑并[3,4-b]吡啶-5-羧醯胺， 1·乙基-Ν·[(1_甲基- iH-p比吨_4_基）〒基]-4-(四氫-2H-喊喃 -4-基胺基）-1Η-ρ比峻并[3,4_b]p比淀-5_羧酸胺，或 卜乙基-N-(2-吡啶基甲基）-4-(四氫-2H·旅喃_4_基胺基 )-1Η-吡唑并[3,4-b]吡啶-5-羧醯胺； 或其鹽。 54·根據申請專利範圍第1至3、6、7、9、10、11、19、26 至33、51、52或53項中任一項之化合物或鹽，其係為化合 物或其藥學上可接受之鹽。 55·根據申請專利範圍第1至3、6、7、9、10、11、19、26 至33、51、52或53項中任一項之化合物或鹽，其係呈粒子 大小降低形式。 56·根據申請專利範圍第55項之化合物或鹽，其中大小降低之 化合物或鹽之粒子大小（D5〇值）為〇.5至1〇微米。 57·根據申請專利範圍第1至3、6、7、9、10、u、19、％ 至33、51、52或53項中任一項之化合物或鹽，其係作為人 類磷酸二酯酶4抑制劑。 58. —種醫藥組合物，其包含如申請專利範圍第1至3、6、7 、9、10、11、19、26至33、5卜52或53項中任一項所定 義 &lt; 式（I)或（IA)或（IB)化合物，或其藥學上可接受之鹽，及 一或多種藥學上可接受之載劑及/或賦形劑，其中此組合 物係作為磷酸二酯酶4抑制劑以治療及/或預防：人類氣喘 、慢性枝氣管炎、氣腫、異位性皮炎、蓴麻疹、過敏性鼻 87841-960303.doc -66- 1283678 炎、過敏性結合膜炎、春季結合膜炎、唁伊紅肉芽瘤、牛 皮癖風“、f生關節炎、敗血性休克、溃療性結腸炎、克隆 氏病、心肌與腦部之再灌注傷害、慢性絲球體性腎炎、内 毒素休克、成人呼吸困難徵候簇或多發性硬化。 59· —種醫藥組合物，其包含如申請專利範圍第1至3、6、7 、9、10、11、19、26至33、5卜52或兄項中任一項所定 義·^式（I)或（IA)或（IB)化合物，或其藥學上可接受之鹽，及 一或多種藥學上可接受之載劑及/或賦形劑，其中該組合 物係用於治療及/或預防人類炎性及/或過敏性疾病。 60· —種根據申請專利範圍第i至3、6、7、9、1〇、u、19 、26至33' 5卜52或53項之中任一項所定義之式①或（ia) 或（IB)化合物或其藥學上可接受之鹽之用途，其係用於製 造治療及/或預防人類炎性及/或過敏性疾病之藥劑。 61·根據申請專利範園第59項之組合物，其中組合物係用於治 療及/或預防人類慢性阻塞肺病（C〇pd)、氣喘或過敏性鼻 炎。 62.根據申請專利範圍第60項之用途，其中藥劑係用於治療及 /或預防人類fe性阻塞肺病（COPD)、氣喘或過敏性鼻炎。 63· —種組合，其包含根據申請專利範圍第1至3、6、7、9 、10、11、19、26至33、51、52或53項中任一項所定義之 式（I)或（IA)或（IB)化合物或其藥學上可接受之鹽，以及 腎上腺素受體催動劑、抗組織胺、抗過敏或消炎劑。 64· —種組合，其包含根據申請專利範圍第丨至3、6、7、9 、10、11、19、26至33、51、52或53項中任一項所定義之 87841-960303.doc -67 - 1283678 式（I)或（ΙΑ)或（IB)化合物或其藥學上可接受之鹽，以及蠅蕈 鹼(M)受體拮抗劑。 65.根據申請專利範圍第64項之組合，其中蠅蕈鹼（M)受體拮 抗劑為M3受體拮抗劑。 87841-960303.doc 68--2H-piperidin-4-yl; that is, NHR3 is subtype (h):-. v (h) 28. A compound or salt according to claim 27, wherein R1 is ethyl. 29. A compound or salt according to claim 2, wherein X is NR4R5. 30. A compound or salt according to item 3 of the patent application, wherein X is NR4R5. 31. A compound or salt according to claim 30, wherein R1 is ethyl. 32. A compound or salt according to item 19 of the scope of the patent application, wherein it is also a compound or a salt according to claim 32, wherein Ri is an ethyl group. 34. A compound or salt according to any one of claims 1 to 3, 6, 7, 9, 1 , η, 19 or 26 to 33, wherein R 5 is: ci-8 alkyl; Cl - 3 Fluoroalkyl; C3-8 cycloalkyl (unsubstituted); unsubstituted -(CH2)n4-C5-6 cycloalkyl, wherein η4 is 1 or 2; h wherein η5 is 2 or 3, and each The substituent Rii, independently of any other R11 substituent present, is (^-4 alkoxy, -NR15-C(9)-NH-R15 or -15 捣Ri 6 ; or -(CH 2 ) nn -CXCOR16 ; -( CH2)n 12 _C(0)NR12 Rl 3 ; -(cH2 )n12 -C(0)0R16 ; -(CH2 )n12 -S°2 -NR12 R13 ; -(CH2 )n 12 -S〇2 R1 6 • , or -(CH2)n12-CN, where n11 is 1 or 2, and ni2 is i or 2. 35. According to the scope of the patent application, i- to 3, 6, 7, 9, 10, 11, 19 or 26 to 33 A compound or salt according to any one of the preceding claims, wherein R5 is _(CH2)n13-Het, η13 87841-960303.doc -20- 1283678 is 〇, 1 or 9, tl ττ » and Het is 5- or 6-member a saturated heterocyclic ring comprising a compound selected from the group consisting of ο and π, wherein the carbocyclic ring in Het is unsubstituted. 36. According to the patent application No. 1 to 3, 6, 7, 9, 1 A compound or a salt of any one of 〇, u, 19 or 26 to 33, wherein r5 is phenyl, optionally substituted by - or two of the following groups: a functional atom; an alkyl group; a CM fluoroalkyl group; h alkoxy; trifluoromethoxy; Ci 2 alkyl sulfoalkyl-S〇2_); (: 2 alkyl § § 〇 2 _ win; r7r8n s 〇 2 _; r7r8n c 〇 _ ; NR15-C(0)Ri 6 ; r7rsn . 〇H. Q-2 alkoxymethyl; C^2 alkyl S〇2-CH2_, cyano (CN); or phenyl, optionally as a fluorine group, a Ck alkyl group, a Cl fluoroalkyl group, a C1 _2 alkoxy group or a fluoroalkyl alkoxy group. 37. A compound or salt according to claim 36, wherein the fluorenylphenyl group is optionally taken. Two of the following groups are substituted: from an atom, an alkyl group, a trifluoromethyl group, a c a 2 alkoxy group, a trifluoromethoxy group, a R7R8N_s〇2_, a r7r8n_c〇_ or a Ci-2 alkyl group-S〇2-. 38. A compound or salt according to any one of claims 1 to 3, 6, 7, 9, 10, 11, 19 or 26 to 33, wherein R5 has the formula (8) or (y) or (yl) Or (z). 39. A compound or salt according to any one of claims 1 to 3, 6, 7, 9, 10, 11, 19 or 26 to 33 wherein R5 has the formula (X). 40. A compound or salt according to item 38 of the patent application, wherein n = i, m = 1, and r = 1 〇 41. According to the patent claims 1 to 3, 6, 7, 9, 10, 11, 19 Or a compound or salt of any one of items 26 to 33, wherein in the subtypes (8), (9) and (yl): no or one or two of A, B, D, E and F are nitrogen; no or one, 87841 -960303.doc -21- 1283678 Two or three A, B, D, E and F are (: poly 6; while the remaining A, B, D, E and F are CH. 42. According to the scope of claim 41 a compound or a salt, wherein in the subtypes (8), (y) and/or (yl), none or one of A, B, D, E and F is nitrogen. 43. According to the scope of claims i to 3, 6 a compound or salt of any one of clauses 7, 9, 1 , U, 19 or 26 to 33, wherein in the subtypes (χ), (y), (yl) and (8), each R6, and the presence thereof Irrespective of any other r6, is a fluorine, gas, desert or halogen atom 'or methyl, ethyl, n-propyl, isopropyl, decyl 4, trifluoromethyl, -CH 2 〇 H, methoxy Ethoxy, q-fluoroalkoxy, OH, (V3 alkyl s(0)2_, (:3 alkyl S(0)2-NH - ' Me2N-S(0)2-, H2N-S(0)2-, -CONH2, -CONHMe, -C02H 'Cyano (CN), NMe2, T-butoxymethyl or Ci-3 Base s(o)2-ch2-. 44. A compound or salt according to claim 43 of the patent application, wherein in the sub-formula (8) '(y), (yi) and/or (Ζ), each R6, and Any other R6-independent 'as a fluorine, chlorine or adipose atom, or methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, -CH2〇H, methoxy, difluoromethoxy Base, methylsulfonyl, methyl-so2_nh_ or methyl-S02-CH2·. 45. According to the scope of patent application No. 1 to 3, 6, 7, 9, 10, 11, 19 or 26 to 33 A compound or salt of any one, wherein r5 is a subfamily (χ) and is: benzyl, (monoalkyl-phenyl)methyl, [mono(fluoroalkyl)-phenyl]methyl, ( Monodecylphenyl)methyl, (monoalkoxyphenyl)methyl, [mono(fluoroalkoxy)-phenyl]methyl, [mono(indole, fluorenyl-dimethylamino)- Phenyl]methyl, [mono(methylphenyl)methyl, [mono(methyl-SCV)-phenyl]methyl/(dialkyl-phenyl)methyl 87841-960303.doc -22- 1283678, (monoalkyl· Nonylphenyl)fluorenyl, [mono(fluoroalkyl)-mono-phenyl]methyl, (di-phenylphenyl)methyl, (di-yl-monoalkyl-phenyl)methyl, [Di-yl-mono(#imethyl)-phenyl]methyl or (dialkoxy-phenyl)methyl. 46. A compound or salt according to claim 45, wherein RS is: (mono-Cu alkyl-phenyl)methyl; (mono-C fluoroalkyl-phenyl)methyl; (mono-2-alkoxy- Phenyl)methyl; [mono(C! fluoroalkoxy)-phenyl]methyl; (di-Ci2-alkyl-phenyl)methyl; (mono(^_2alkyl-mono-phenyl)) Methyl; (didecyl phenyl) fluorenyl; (di-yl mono ci -2-alkyl-phenyl)methyl; or [dihalo-mono-indenyl)-phenyl]methyl. 47. A compound or salt according to claim 46, wherein r5 is (4_c^ phenyl-phenyl)methyl; (4-Q fluoroalkyl phenyl) methyl; (4-Ck alkane) Oxy-phenyl)methyl; (4-Q-fluoroalkoxy-phenyl)methyl; (3,4-dimethyl-phenyl)methyl; (2,4-dimethyl-benzene Methyl); (3,5-dimethyl-phenyl)methyl; (2,3·dimethyl-phenyl)methyl; (2,5-dimethyl-phenyl)methyl; (4-methyl-3-chlorophenyl)methyl; (3-methyl-4-chlorophenyl)methyl; (2-methyl-4-chlorophenyl)methyl; (2-chloro) _4·fluorophenyl)methyl; (2,4-difluorophenyl)methyl; (4-bromofluorophenyl)methyl; (4-chloro-2-fluorophenyl)methyl; (3,4·dichloro-phenyl)indenyl; (2,4-dichloro-phenyl)methyl; (2,6-dichloro-phenyl)methyl; (2,3-dichloro- Phenyl)methyl, (2,4-dichloro-6-methyl-phenyl)methyl; or [2,3-dioxan (methyl)-phenyl]methyl. 48. A compound or salt according to any one of claims 1 to 3, 6, 7, 9, 1 , 11 , 19 or 26 to 33 wherein r 5 has the subtype (z), 1 &lt;is i, no or one of j, l, M or Q is CR6, and if one of j, L, M or Q is CR6, then R6 is methyl or c! fluoroalkyl, and R9 is a hydrogen atom (H) or 87841-960303. Doc -23 - 1283678 Methyl. 49. A compound or salt according to claim 45, wherein R1 is ethyl and X is NR4R5 〇 50. A compound or salt according to claim 40, wherein R1 is ethyl and X is NR4R5 〇51_ according to the compound or salt of claim 1 of the patent application, which is: 1-ethyl-4-(tetrahydrogen) _2H-pyran-4-ylamino)-1Η-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester, 4·[(1-methylhexahydropyridyl)amino group -1 -ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester, 4-[(1-ethylhydrazinohexahydropyridin-4-yl)amino]-1 -ethyl-1H-pyrazolo[3,4hepta]pyridin-5-carboxylic acid ethyl ester, 1-methyl-4-(tetrahydro-2H-bromo- 4-ylamino)-lH-pyridyl Ethylzolo[3,4-b]pyridine-5-carboxylate, 1-ethyl-4-[(3S)-tetrahydrofuran-3-ylamino]-1H-pyrazolo[3,4-b Pyridine-5-carboxylic acid ethyl ester, 1-ethyl chloro[(3R)-tetrahydrofurylamino]·1Η·pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester, 1-B Base ice (tetrahydro-2H-thiopiperazin-4-ylamino)-1Η-pyrazolo[3,4_1 small pyridine-5-rebel acid, 1·ethyl ice (tetrahydrofuran) -3-ylamino))ih-pyrazolo[3,4hepta]pyridin-5-carboxylic acid ethyl ester, 4-(cyclopropylamino)ethylidene-1H-pyrazolo[3,4_b]pyridine- 5-carboxylic acid ethyl ester, 4_[(1,1-di) Tetrahydrofurfuryl pyrimidin-3-yl) amino] ethyl - [mu] -1H- pyrazolo |; 3,4- seven] pyrazol 87841-960303. Doc •24- 1283678 ethyl 5-pyridinecarboxylate, 4-[(1,1-dihydrotetrahydro-2H-thiopiperidinyl)amino]]ethylethyl-1H-pyrazolo[3 , 4-b]pyridine-5-carboxylate ethyl ester, N-benzyl small ethyl bucket (tetrahydro-2H-piperidinylamino)·1Η_pyrazolo[3,4 aspirin-5 -Procarbamide, 1-ethyl-indole-(4-fluorophenyl)-4·(tetrahydro-2-indolyl-4-ylamino)·Η-pyrazolo[3,4-b&gt; Bishen-5-carbamamine, N-cyclopentyl-1-ethyl-4-(tetrahydro-2H&gt; decyl-4-ylamino)-1 Η-pyrazolo[3,4-b] Pyridine-5-formamide, 4-[(1-ethylhydrazinhexahydropyridin-4-yl)amino]_N-cyclopentylethylethyl-1H-pyrazolo[3,4-b] p-Phase-5-formic acid amine, 1-ethyl-N heptaidine-4-ylmethyl)_4-(tetrahydro-2H-piperidin-4-ylamino)-1Η-pyrazolo[3 ,4-b]external b-position-5-formamide, 4-[(1-ethylhydrazinylhexahydropyridin-4-yl)amino]-N-benzyl-1-ethyl-1H-pyrazole And 3,4-b]p than yt-5-carbamide, 1-ethyl-N-(2-ethylbutyl)-4-(tetrahydro-2-indole-pyran-4-ylamine Base)-1Η-pyrazolo[3,4-b]p ratio -5-5·carbamamine, 1-ethyl-N-(2-ethylbutyl)_4-[(1-methylhexahydro) Pyridin-4-yl)amino]-1H-pyrazole And [3,4-7]pyridine-5-formamide, 4-[(1_ethinylhexahydropyridin-4-yl)amino]_1_ethyl-oxime (2-ethylbutyl) _1H-p-pyrolo[3,4-pyridinium-5-carboxamide, 1-ethyl-N-(4-fluorophenyl)-4-[(1-methylhexahydropyridin-4-yl) Amino]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide, 4-[(1-ethyl-based acicular π-precipitate-4-yl)amino]-1- Ethyl-N-(4- gas benzene·base ratio 87841-960303. Doc -25- 1283678 oxazo[3,4-b]pyridine-5-carboxamide, 1-ethyl-N-n-propyl-4-(tetrachloro-211-0 butyl _4*·yl Aminopyrazine[3,4-b]pyridine-5-carboxamide, 4-[(1-ethenylhexahydropyridin-4-yl)amino]_1_ethyl-n-propyl-1H- Pyrazolo[3,4-b]pyridine-5-carboxamide, N-yl-1_1-ethyl-4-[(l-methylhexahydrop-buty-4-yl)amino]_1Η_ρ More than tons of [3,4-b]pyridine-5-formamide, 4-[(1-ethylhydrazinium hexahydropyridin-4-yl)amino]_1_ethyl-N-indenyl pyridine ·Methyl-)-Η-pyrido[3,4-b]external b-position-5-carbamamine, N_yryl-1-methyl-4-(tetrahydro-2H- shouting-4 _ ylamino group bite and [3,4_b] mouth bite -5-carbamamine, N-(2-ethylbutyl)·1-mercapto-4-(tetrahydro-2H-t trace- 4-aminoamino)-1Η-external b ton[3,4-b]p than ammonium-5-formic acid amine 'N-(4-fluorophenyl)·1-methyl_4-(tetrahydro- 2H_piperazin-4-ylamino)-1Η-pyridox[3,4-b]p ratio biting-5-formic acid amine 4-[(1-ethenylhexahydropyridine_4_yl) Amino]_n_benzyl-1-methyl-1H-pyrido[3,4-b]indole-5-caramin' 1-ethyl-N-methyl-4-(tetrahydro- 2H-pyran-4-ylamino)-1Η-pyrazolo[3,4_b]pyrazine-5-cartoamine, - 1_ethyl-N-ethyl_4-(tetrahydro-2H-piperidin-4-ylamino)-1Η-pyrazolo[3,4-b]pyridine-5-carboxamide, 1 -ethyl-N-isopropyl-4-(tetrahydro-2H-piperidin-4-ylamino)-1Η-pyrazolo[3,4-b]pyridine-5-carboxamide, N- Benzyl-1-ethyl_4-[(3S)-tetrahydrofuran-3-ylamino]_1H-pyrazolo[3,4-b]py 87841-960303. Doc •26- 1283678 D--5-armamamine, N-benzyl small ethyl-4-[(3R)-tetrahydrofuran-3-ylamino]-1H-pyrazolo[3,4-7]盐-5-甲含胺, N-benzyl-1-ethyl winter (tetramethylene sulfonyl-3-ylamino) Η 吡 pyrazolo[3,4_b]pyridine-5-cartoamine, N-爷基·4-[(1,1-dihydrotetramethylene sulfonyl-3-yl)amino]-indole·ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide , N-Mercapto-4·[(1,1_dihydrotetrahydrothiopyranyl)amino]]ethylethyl-1Η-pyrazolo[3,4-b]pyridine_5_ formazan Amine, N-benzyl-1-ethyl-4-(tetrahydro-2H-thiopiperazin-4-ylamino)-1Η·pyrazolo P,4-b]pyridine-5-carboxamide , 1-ethyl-N-(4-fluorophenyl)-4_[(3S)·tetrahydrofuran-3-ylamino]_1H-pyrazolo[3,4-b]pyridine-5-carboxamide, 1-ethyl_N-(4-fluorophenyl)_4-[(3R)_tetrahydrofuran-3-ylamino]-1H-pyrazolo[3,4-b]p Amine, 1-ethyl-N-(4-fluorophenyl)-4-(tetrahydro-2H-thiopiperan-4-ylamino)-1Η·pyrazolo[3,4-b]pyridine -5-Mergamine, 1_ethyl-N-(4-fluorophenyl)-4·(tetrahydropyrimidin-3-ylamino)-1Η-pyrazolo[3,4-b] p Bishen-5-cartoamine, 4-[ (1,1-dihydrotetrazole-3-yl)amino]_1_ethyl·ν_(4-fluorophenyl)_1H-pyrido[3,4-b]p than lake-5- Methionamine, 4-[(1,1·tetrahydro-2H-thiopyran-4-yl)amino]-1-ethyl-N-(4-fluorophenyl)-1Η· b峻和[3,4-b]p 比淀-5_carbamamine, 1-ethyl·Ν-[4-(methylsulfonyl)-yl]_4_(tetrahydro-2Η_pipefi-4 -ylamino)-1Η_ 87841-960303. Doc •27- 1283678 Pyrazolo[3,4-b]pyridine-5-carboxamide, 1-ethyl-N-[3-(methylsulfonyl)-yl]-4-(tetrahydro-2H -piperazin-4-ylamino)-1Η-pyrazolo[3,4-b]pyridine-5-carboxamide, N-[(5-chloropyridin-2-yl)methyl] Radix (tetrahydro-2H-fluorenyl-4-ylamino)-1Η-pyrazolo[3,4-b]pyridine-5-carboxamide, 1-ethyl-N-[(5-A) 3-phenylisoxazol-4-yl)methyl]-4-(tetrahydro-2H-piperidin-4-ylamino)_1H-pyrazolo[3,4_b]pyridine_5_A Indoleamine 'N-(2-Terti-butoxyethyl)-1-ethyl-4-(four-rat-2H-pyran-4-ylamino)-1Η_Exo I: oxazo[3, 4-b]pyridine-5-carboxamide, 1-ethyl-4-(tetrahydro-2H-piperidin-4-ylamino)-indole-(1,3-pyrazol-2-ylmethyl) )-1Η-pyrazolo[3,4-b]pyridine-5-formamide, 1_ethyl-N_(p-melt-4-ylmethyl)-4·(four gas-2H_ shouting -4-ylamino)·1Η-ρ is more than [3,4-b]pyridine-5-formamide, 1-ethyl-Ν·[(2_methyl_l,3-p _4_yl)methyl]-4-(tetrahydro-2Η·»-s--4-ylamino)-1Η-pyrazolo[3,4-b]pyridine-5-carboxamide, N- [3-(Tertibutoxymethyl)octyl]-1-ethyl-4-(tetrahydro-2H-l-butan-4-yl Amino)-1H-pyrazolo[3,4-b]pyridine·5-carboxamide, 1-ethyl-hydrazine-{2_[methyl(methylylidene)amino]ethyl}-4 -(tetrahydro-2-indole-pyran-4-ylamino group is more than [3,4-b] bamboo b-precipitate-5-cartoamine, 1-ethyl--2-ylmethyl)-4- (Tetrahydro-2Η-Ϊ派喃-4_ylamino-amino-[3,4-b]ex-b-butyl-5-cartoamine, N-(2-chloro-6-fluoroyl) 1-ethyl-4-(tetrahydro-2-indole-scarred-4-ylamino)-1Η-exo 1: oxazolo[3,4-b]ppyridin-5-carbamamine, 1 -ethyl-N-[(6-keto-1,6-dihydrofolate b-butyl-3-yl)methyl]_4_(tetrachloropyran_4_ 87841-960303. Doc -28- 1283678 arylamino)-1 Η-pyrazolo[3,4-b]pyridine-5-carboxamide, N-[3-(aminocarbonyl)indolyl] small ethyl-4-( Tetrahydro-2H-piperazin-4-ylamino)-1Η-峨君[3,4-b>pyramid-5-carbamide, 1-ethyl-N-{4-[(methylamine) Base) phenyl}-4-(tetrachloro-2H-peak-2-ylamino)-1Η-pyrazolo P,4_b]pyridine·5·carbamidine, 1-ethyl-hydrazine -[2·(1_methyl-1Η·imidazol-4-yl)ethyl]ice (tetrahydro-2-indole-piperidin-4-ylamino)-1Η-pyrazolo[3,4-b] Pyridin-5-carbamamine, N-{2-[(Tetralamyl)amino]ethyl}_1_ethyl-4-(tetrachloro-2H-bromo- 4-ylamino)- 1Η-pyrazolo[3,4-b]pyridine-5-formamide, 1-ethyl-N-(1H-tetrazol-5-ylmethyl)_4-(tetrahydro-2-indole·pyran 4_ylamino)-1Η-exo-bazolo[3,4-b]pyridine-5-carboxamide, 1-ethyl-4-(tetrachloro-2H-pyran-4-ylamino) ·Ν-[2-(1Η-1,2,4-Trisyl-1_yl)ethyl]-1Η·pyrazolo[3,4-b]pyridine-5-formamide, 1-ethyl -4_(tetrachloro-211-0 succinyl-4 ylamino)_N-[4_(trifluoromethyl)phenyl]-1H-external bww and P,4-b&gt; Amine, 4-({[1-ethyl-4-(tetrahydro-2Η_^)-4-ylamine )-1Η-ρ is more than [3,4_b]p than biting •5-yl]carbonyl}amino)hexahydropyridine-1-carboxylic acid tert-butyl ester, 1-ethyl_N-{3- [(甲), Amino] propyl}-4-(tetrahydro-2H· shouting 4·ylamino)-1Η_ρ 比吨[3,4七&gt; 比淀-5-甲醯Amine, Ν-[2-(dimethylamino) aryl]-1-ethyl-4-(tetrahydro-2 Η-喊 _ _4_ ylamino)-1 Η-carbazolo[3,4- b]pyridine-5-carboxamide, 1-ethyl-N-[(1-ethyltetrahydropyrrole-2-yl)methyl]-4-(tetrahydro-2H-pyran-4-ylamino) )-lH&gt; than vomiting [3,4-b] leaf b-precipitate-5_cartoamine, 1-ethyl_N-(izg hydrogen sulfan-2-ylmethyl)_4_(tetrahydro-2H·喃 -4--4-ylamino)-1Η- 87841-960303. Doc -29- 1283678 Pyrazolo[3,4-b]pyridine-5-carboxamide, 1-ethyl-N-tetrahydro-2H-pyran-4-yl-4-(tetrahydro-2H- Shoutin-4-ylamino))Η-ρ-pyrazolo[3,4-b]pyridine-5-carboxamide, N-{4-[(dimethylamino)sulfonyl]benzyl} small Ethyl-4-(tetra-argon-2H-piperazin-4-ylamino)·1Η·ρ is more than [3,4-b]^ dian-5-cartoamine, 1·ethyl-N -{3-[(methylsulfonyl)amino]benzyl}-4_(tetrahydro-2H-piperidin-4-ylamino)-1H_p is more than [3,4-b]p-precipitate- 5-mercaptoamine, 1-ethyl-N-(4-methoxyphenyl)-4-(tetraqi-2H-methane-4-ylamino)pyrano[3,4-b]pyridine- 5-carbalamine, 1-ethyl-indole-[3-(2·ketotetrahydropyrroleyl)propyl]-4-(tetrahydro-2H-pyran-4-ylamino) [3,4-b]p"b-deposition_5_cartoamine" 1-ethyl-N-[2-(l-methyltetradecylo-2-yl)ethyl]-4-( Tetranitro 2H-propan-4-ylamino)-1Η-pyrazolo[3,4-b]pyridine-5-formamide, 1-ethyl-N-(p-but-3-yl Methyl)-4-(tetrachloro-2H-chloropyran-4-ylamino)-1Η_ρ比比[3,4_b]pyridine-5-carbamamine, 1-ethyl-N-(l-A氲6氲)4 ))-4-(tetrahydro-2H- sher-4-ylamino)-lH-^b spit [3 , 4-b]p than yt-5. ketoamine, 1-ethyl Ν-(1-ethylpropyl) _4·(tetrazo-2 Η-» δ -4-ylamino group [3,4-b]pyridine-5-carboxamide, 1-ethyl-N-(2-hexahydrofolate b-butyl-1-ylethyl)-4_(tetrahydro-2H- britium-4-胺 ) π π π π π π 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 Tetrahydro-2Η-scaridin-4-ylamino)-1Η-pyrazolo[3,4-7]pyridine-5·carboxamide, N-(3-ethoxypropyl)ethylethyl-4_( Tetrahydro-2H-t-norm-4-ylamino)-1Η·ρ ratio Jun 87841-960303. Doc -30- 1283678 and [3,4_b]pyrazine-5-formamide, N-(cyclohexylmethyl)_1_ethyl_4-(tetrahydro-2H-piperan-4-ylamino) -1Η-pyrazolo[3,4-b]p than lake-5-cartoamine&gt; N-[3-(dimethylamino)propyl]_1_ethyl bucket (tetrahydro-2H-piperider喃-4-ylamino)-1Η-pyrazolo[3,4-b]pyridine-5-carboxamide, 1-ethyl-N-neopentyl-4-(tetrahydro-2H-pyran -4-ylamino)_1H-pyrazolo[3,4-b] oxime-5-formic acid amine 1-ethyl-N-(4-methoxybenzyl)-4-(tetrahydro- 2H-piperazin-4-ylamino)-1Η-pyrazolo[3,4-b]p than ammonium-5-formate amine 1-ethyl-N-{2-[(phenylsulfonyl) Amino]ethyl}winter (tetrahydro-2Η-piperidin-4-ylamino)-1Η_ρ is more than eaten [3,4_1&gt;&gt; bis--5-cartoamine, Ν-[2-(B Amidino)ethyl]-1_ethyl-4·(tetrahydro-2-indole-piperazin-4-ylamino)-1Η-exopurine and [3,4-b]^ than bite-5- Amine, 1-ethyl-N-{2-[(methylsulfonyl)amino]ethyl}-4·(tetrahydro-2H-pyran-4-ylamino)_1Η·ρ ratio And 3,4-b]pyridine-5-formamide, 1-ethyl-N-{2-[(2-methoxyphenyl)(methyl)amino]ethyl}-4-( Tetrahydro-2Η-piperazin-4-ylamino)-1Η·pyrazolo[3,4-b Pyridine-5-formamide, 1-ethyl-indole-(2.indolyl-2-phenylethyl)-4-(tetrazo-2H-bran-4-ylamino)-1Η_ Oxazo[3,4-b]pyridine-5-carboxamide, N-(2,5-difluoroindolyl) small ethyl 4-(tetrahydro-2H-pyran-4-ylamino) )-1Η·pyrazolo[3,4-b]pyridine-5-carboxamide, 1-ethyl-4-(tetrachloro-2H-pyran-4-ylamino)_N_[4-(three Gas methyl) genomic]-1H-p than wow [3,4 VII] than bite-5-carbamide, N-cyclopropyl small ethyl-4-(tetrahydro-2H-pyran- 4-ylamino)-1Η-pyrazolo[3,4-b] 87841-960303. Doc -31- 1283678 Acridine-5-carbamide, N-(2-Amino-1-ketoethylethyl) (tetrahydro-2H_piperidinyl)_m_pyrazolo[3,4 -b]pyridine-5-carboxamide, 1-ethyl-N-(3-indolylphenyl)-4-(tetrahydro-2H-piperidinylamino)_1H_pyrazolo[;3 ,4-b]pyrazine_5_carbamamine, N-(3,4-difluorobenzyl)_1_ethyl_4·(tetrahydro-2H-piperidin-4-ylamino)-1Η -pyrazolo[3,4-b]p than ammonium-5-formate, 3-({[1-ethyl-4-(tetrahydro-213⁄4-an-4-ylamino)-1Η-pyrazole And [3,4-b>pyridin-5-yl]-yl}amino)propionic acid, Ν-(1·benzylhexylpyridin-4-yl)-ethyl-4-(tetrahydro) _2H-piperazin-4-ylamino)-1Η-pyrazolo[3,4-b]pyridine-5-carboxamide, 1_ethyl_4_(tetrahydro-2H_ shouting-4- Amino)-indole-(1,3,4-oxadiazol-2-yl)-1Η-pyridin[3,4-b>pyramid-5-carbamide, N-(2,3 -dihydro_1H-茚·2·yl)·1-ethyl_4_(tetrahydro-2H-piperidin-4-ylamino)_1Η·p is more than [3,4-b]p than olfactory -5-Acantylamine '1·Ethyl-N-[2-(2-keto-Sensage)-ethyl)-4-(tetrahydro-2H--pyran-4-ylamine -1Η-pyrazolop,4-b]pyridine-5-carboxamide, N-(3,4- Di-oxy-yl)-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1Η-pyrazolo[3,4-b]pyridine-5-carboxamide N-(3-lactyl)·1-ethyl_4·(tetrazo-2H-pyran-4-ylamino yiH-p than [3,4-b]pyrazine-5-formamidine Amine, 1-ethyl-N-(2-lightethyl)-4-(tetrazol-2H-pyran-4-ylamino)-1Η-ρ than 嗤[3,4-b]pyridyl -5-Mergamine, 1-ethyl-indole-{4.[(methylsulfonyl)methyl]phenyl}.4-(tetrahydro-2H-pentanylamine 87041-960303. Doc -32- 1283678 base)-1Η-pyrazolo[3,4-b]pyridine-5-carboxamide, Ν-[3·(dimethylamino)-3-ketopropyl]-1- Ethyl winter (tetrahydro-2H.piperidin-4-ylamino)-1Η-pyrazolo[3,4-b]pyridine-5-carboxamide, 1-ethyl_N-[(1- Methyl-1H-imidazol-5-yl)methyl]-4-(tetrahydro-2H-piperidin-4-ylamino)-1Η-pyrazolo[3,4-b]pyridine-5- Indoleamine, 1-ethyl-N-{4-[(methylamino)sulfonyl]phenyl}-4-(tetrahydro-2Η·piperidin-4-ylamino)-1Η-pyrazole [3,4-b]pyridine-5-formamide, N-(2-cyanoethyl)-1_ethyl-4-(tetrahydro-2H-piperidyl-4-ylamino)-1Η Pyrazolo[3,4-b]pyridine-5-carboxamide, 1-ethyl-N-[(l-methyl-1H-pyrazol-4-yl)methyl]-4-(four Hydrogen-211_piperazin-4-ylamino)-1Η-pyrazolo[3,4_b]pyridine-5·carboxamide, 1-ethyl-4-(tetrachloro-2H-jum-4- Amino)-N-(2-p-cephen-2-ylethyl)-1 oxime-borazolo[3,4-b]pyridine-5-carboxamide, Ν-[2-(4· Chlorophenyl)ethyl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1Η-pyrazolo[3,4-b]pyridine-5-carboxamide , 1-ethyl-N-[2-(2-methoxyphenyl)ethyl]-4-(tetrahydro-2H-piperidinylamine )-1Η-External b and [3,4-b]External ti_5_Artemis, 1-n-propyl-4_(tetrahydro-2H-piperidin-4-ylamino)-1Η -pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester, 1-(2-ethyl)-4-(tetrahydro-2Η-bran-4-ylamino)·1Η-ρ More than spit and [3,4-b]p than D--5-haloic acid brewing 'N-[4_(A))-l-n-propyl-4-(tetrahydro-2H-喃 -4- 基 基 胺 比 [ [ 3 [3,4-b]p than 嗓-5- amide, N-(4-fluorophenyl) small n-propyl-4-(tetrahydro-2 Η - keloid-4-ylamino)-1Η_ρ ratio jun and 87841-960303. Doc -33 - 1283678 [3,4-b]pyridine-5-carbamide, 1-ethylmethylmethyl-4-(tetrahydro-2H-piperidin-4-ylamino)_1 沁pyrazole Ethyl [3,4-b]pyridine-5.carboxylate, N-benzyl-1-ethyl-6-methyl-4-(tetrahydro-2H-piperidin-4-ylamino)-1Η _pyrazolo[3,4-b]pyridine-5-carboxamide, N-benzyl-1-ethyl-4_[(2-ketoprazin-7-yl)amino]- lH-pyrazolo[3,4-b]pyridine-5-carboxamide, N-benzyl-1-ethyl-4-[(3-hydroxycyclohexyl)amino]-1H-pyrazolo[ 3,4-b]pyridine-5-carboxamide, N-benzyl small ethyl-4-[(4-hydroxycyclohexyl)amino]-1H-pyrazolo[3,4-b]pyridine- 5-carboxamide, N-fluorenylethylidene-4-[(4. ketocyclohexyl)amino]·1Η_pyrazolo[3,4-b]pyridine-5-carboxamide, 1 -ethyl-N-(2-hydroxylethylethyl)-4-(tetrahydro-2H-piperidin-4-ylamino)_1H-pyrazolo[3,4-7]pyridine_5_ formazan Amine, (2S)-2-({[l_ethyl_4-(tetrahydro-2H-piperidinyl)-1Η-pyrazolo[3,4_b]pyridin-5-yl]carbonyl} Methylamino)-3-hydroxypropionate, ethyl 1-ethyl-4-[(4-hydroxycyclohexyl)amino]·1Η-pyrazolop,4-b]pyridine-5-carboxylate , 1-ethyl-4-[(4- Ethyl cyclohexyl)amino]-1H-azolo[3,4-b]pyridine-5·carboxylate ethyl ester, 4·[(1-ethylindolyl-4-hexapyridine)amino] Ethyl 1-H-pyrazolo[3,4-b]pyridine-5-carboxylate, 4-[(4-aminocyclohexyl)amino]ethylethyl-1H-pyrazolo p,4 -b]pyridine_5·carboxylic acid 87841-960303. Doc -34- 1283678 Ethyl ester, N-[(l_oxidation_3-p ratio) methyl]-4-(tetrachloro-2H-pyran-4-ylamino)-1Η-ρ-pyrazole And [3,4-b]pyridine-5-formamide, 1-ethyl-N-[(l-oxidized-2-p-butylated) fluorenyl]-4-(tetrazo-2H- shout -4-ylamino)-1Η-ρ is more than [3,4-b]p ratio-5-cartoamine, 1-ethyl-N_[(l-oxidation-4-p ratio) Methyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1Η-ρ is more than [3,4-b]p than pent-5-cartoamine, 4-[( 4-Aminocyclohexyl)amino]-1_ethyl-N-(phenylmethyl)-1Η-ρ is more than [3,4-b]pyridine-5-formamide, 1- Ethyl-4-{[(3S)-2-keto-3-tetrahydropyrrolyl]amino-based N-(phenylmethyl)-1Η-azolo[3,4-b]pyridine-5 -Procarbamide, 4-[(2,5-diketo-3-tetrahydropyrrolyl)amino]-1-ethyl-N-(phenylmethyl)-1Η-external oxime [3 , 4-b&gt; phage_5·carbamidine, 4-[(cis-4-aminocyclohexyl)amino]-1-ethyl-indole-{[4-(methoxy)phenyl ]methyl}-1Η-ρ 吨和[3,4-b&gt; bicyan-5-cartoamine, 4-[(cis-4-aminocarbamoyl)amino]-1-ethyl- N-({4_[())amino]phenyl}methyl)_1Η-ρ ratio spit [3,4-b Exo b-position-5-carbamamine, 4-[(cis-4-aminocyclohexyl)amino]-Ν·(2,3·dihydro-1H-indol-2-yl)-1-B -1H-pyrazolo[3,4-b]pyridine-5-carbamamine, 1-ethyl-N-{4-[(methylsulfonyl)methyl]phenyl}-4-[( 4-ketocyclohexyl)amino]-1Η-pyrazolo[3,4-b]pyridine-5-carboxamide, N-[(2,4-methylphenyl)methyl]-1 -ethyl-4-[(4-Steylcyclohexyl)amino]-1H_ Outocarbazolo[3,4-b]pyridine-5-carboxamide, N-[(3,4-dimethyl) Phenyl)methyl]sodiumethyl 4-[(4-ketocyclohexyl)amino]-1H- 87841-960303. Doc -35· 1283678 外匕君[3,4-b]pyridine-5-carbamimidamine, N-[(3,4-dichlorophenyl)indolyl]-1-ethyl_4_[(4 _嗣-cyclohexyl)amino] ΐΗ-ρ ratio ♦ [3,4-b]pyridine-5-methanamine, 1-ethyl-N-{[4·(methoxy)phenyl] Methyl b 4_[(4-ketocyclohexyl)amino]-1H-exoquinone [3,4-7]pyridine-5-carboxamide, 1-ethyl-N-({4-[( Methanesulfonyl)amino]phenyl}methyl)-4-[(4-ketocyclohexyl)amino]-ΙΗ-ρ is more than [3,4_b]p than ammonium-5-formate, N-{[4-(dimethylamino)phenyl]methyl}methylethyl-4-[(4-ketocyclohexyl)amine group is more than spit [3,4-7] than dian-5- Methionamine, N-({4-[(difluoroindolyl)oxy]phenyl}methyl))ethylethyl-4-[(4-ketocyclohexyl)amino]-1H-pyrazole [3,4-7]pyridin-5-carbamide, 1-ethyl-4-[(4-ketocyclohexyl)amino]-N-{[4-(trifluoromethyl)phenyl ]methyl}-1Η-ρ is more than [3,4-b> butyl--5-formic acid amine, 1-ethyl-N-{[4-(methylphenyl)phenyl]fluorenyl}- 4-[(4-Ketylcyclohexyl)amino]-1Η-pyrido[3,4-b]pyridine-5-carboxamide, 1-ethyl-anthracene (4-fluorophenyl)- 4-[(4-ketocyclohexyl) Amino]-1H-pyrazolo[3,4-b]pyridine_5-formamide, 1-ethyl·4·[(4-ketocyclohexyl)amino]-indole-(2·pyridine Methyl)-iH-pyrazolo[3,4-b]p than lake-5-caraamine trifluoroacetate, N-(2,3-dihydro-1H· although-2-yl) 1-ethyl-4-[(4-ketocyclohexyl)amino]-iH-p is also a ratio of [3,4-b]pyridine-5-carboxamide, N-(l-ethenyl- 4-hexahydropyridyl)-1-ethyl-4-[(4-ketocyclohexyl)amino]-1Η-ρ than oleno[3, 'b] outer 1: lake-5-carboxamide , 1-ethyl-N-[(l-methyl-1Η_ρ 咬-4-yl)methyl]-4-[(4-fluorenylcyclohexyl)amine 87841-960303. Doc -36- 1283678 ]-1Η-峨君[3,4-b]pyridine-5-carbamimidamine, N,l-diethyl_4_[(4-ketocyclohexyl)amino]-1H -pyrazolo[3,4-b]pyridine_5_carbamidamine, 1-ethyl-4-[(4,ylcyclohexyl)amino]-N_(1,3-pyrazole-2-yl) Base)_1H_pyrazolo[3,4-b]pyridine-5-carboxamide, 1-ethyl(phenylmethyl&gt;4-(tetrahydro-2H-piperazol-3-ylamino) ·1Η·pyrazolo[;3,4-b]pyrazine-5-formamide, N-({4-[(difluoromethyl)oxy]phenyl}methyl)succinyl winter ( Tetrahydro-2fanipan-3-ylamino)-1Η-pyrazolo[3,4_b]pyridine-5-carbamimid, 1-ethyl-4-(tetrahydro-2-indolyl_3 —N-amino]-N-{[4-(trifluoromethyl)phenyl]methyl}-1Η-pyrazolo[3,4-b]pyridine-5-formamide, 1-ethyl- N-{[4_(methylsulfonyl)phenyl]methyl}·'(tetrahydro-2H-piperidin-3-ylamino)-1Η-ρ than gorge[3,4_b]p ratio- 5-mercaptoamine, 1_ethyl-N]4·[(methylsulfonyl)methyl]phenyl}_4-(tetrahydro-2H-pyranyl-3-ylamino)-1Η-ρ ratio并[3,4-b] bite-5-carbamamine, 1-ethyl-N-(4-fluorophenyl)-4-(tetrahydro-2-indolyl-3-ylamino) -1Η-pyrazolo[3,4-b]pyridine-5-decylamine 1-ethyl-indole (2-pyridine-1-yl)-4-(tetrahydro-2-indol-3-ylamino)_1H-p-pyrazolo[3,4-b]pyridine-5-carboxamide Trifluoroacetate, Ν-(2,3·dihydro-1H-茚·2_yl)&gt; 1-ethyl ice (tetrahydro JH-pyran-3-ylamino)-1Η-p [3,4-b]External 1: Bite-5-carbamamine, N_indolyl-4-hexahydropyridyl&gt;1·Ethyl 4-(tetrahydro-2H-slightly-3 -ylamino)-1Η-ρ ratio 并[3,4-b]external b-position-5-carbamamine, 1-ethyl-N-[(l-methyl-1H4 salivyl)methyl ]·4_(tetrahydro-2H piperidinylamine 87841-960303. Doc • 37 · 1283678 base)-1Η-pyrazolo[3,4-b]pyridine-5-carboxamide, N,l-diethyl-4-(tetrahydro-2H- britylene·3-yl Amino)-1Η-pyrazolo[3,4-b]pyridine-5-carboxamide, 1-ethyl-4-(tetrahydro-2H-piperidin-3-ylamino)-indole-( 1,3-pyrazol-2-ylmethyl)_1H-leaf sulphate [3,4-b]p than yam-5-carbamamine, 4-[(1-ethyl-bromo-4-hexa-nitro-p ratio Amyl)-amino]-N-(2,3-dinitro-1H-indol-2-yl)-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide , 4·[(1·乙牛基-4_:ττ氯1 (7 症基基) Amino]_N-[(3,4-dilactosyl)methyl]-1·ethyl-1H-pyridyl Zymbly p,4-b]pyridine-5-carboxamide, 4-[(1-ethylindolyl-4-hexahydropyridinyl)amino]-1-ethyl-N-[(3-fluorobenzene) Methyl]-1Η-pyrazolo[3,4-b]pyridine-5-carboxamide, 4-[(1-ethylhydrazine) hexahydropyridinyl]-anthracene-[(3 ,4·difluorophenyl)methyl]sodiumethyl-1Η-Ρ than spit[3,4-b]p than ammonium-5-formate, 4-[(1-ethylindol-4-6 Hydropyridyl)amino]-N-[(2,5-difluorophenyl)methyl]-1-ethyl-lH-p than spit[3,4-b]p than pent-5-A Amine amine, 4-[(1·ethyl-brown chlorine p-butyl group) amine group]·1-ethyl-Ν-{[3·( Tris-methyl)phenyl]methyl}-1Η-pyrazolo[3,4-b]pyridine-5-formamide, 4_[(1_ethinyl-4)hexahydropyridyl) ]-1-ethyl-Ν·{[4-(trifluoromethyl)phenyl]methyl}·1Η-ρ ratio spitting [3,4-7] than precipitation _5_cartoamine, 4_[ (1_Ethylidene_4_hexahydropyridyl)amino]·Ν·[(2,6-difluorophenyl)methyl]+ethyl_1Η_external b][3,4-b ]p-precipitate-5-cartoamine, 4-[(1-acetoxy-4-hexahydrop-decyl)amino]-N-[(3-chlorophenyl)methyl]_ι·ethyl -1H-pyrido[3,4-b]exo b-pyridine-5-carboxylate, 4·[(1-acetoxy-4-hexahydro-b-)amino]-1-ethyl-fluorene -{[4-(decyloxy)phenyl] 87841-960303. Doc -38- 1283678 methyl}-1Η-pyrazolo-; 3,4-b]pyridine-5-carbamimid, 4-[(1-ethylindenyl-4-hexahydropyridinyl)amino] 1-ethyl-N-[4-(methoxy)phenyl]-1Η-pyrazolo[3,4-b]pyridine-5-carboxamide, 4-[(1-ethenyl- 4-hexahydropyridyl)amino]-N-({4-[(dimethylamino) hydrazino]phenyl}methyl)-1-ethyl-1H-pyrazolo[3,4- b]pyridine-5-carbamamine, ethyl 4-phosphoryl p-pyrifosyl)amino]-1-ethyl-N-(l,2,3,4-tetrahydro-1-yl )-1Η-β is more than gorge [3,4-b&gt; bis--5-carbamamine, 4-[(1-ethylindolyl_4-hexahydropyridinyl)amino]-N_{[2- (dimethylamino)phenyl]fluorenyl}small ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide, 4-[(1-ethyl aryl 4-ch^) Chlorine p ratio aryl)amino]-N-[(2,4-dichlorophenyl)methyl]-1-ethyl-1H-pyrazolo P,4-b]pyridine-5-carboxamide , 4-[(1-ethylindolyl-4·hexahydropyridinyl)amino]ethylidene-N-[(2-fluorophenyl)methyl]-1Η-pyrazolo[3,4-b Pyridine-5-formamide, 4-[(1-acetoxy-4-hexahydroindole b-butyl)amino]-indole-[(2-carbyl-6-fluorophenyl)methyl]- 1_Ethyl-1Η-pyrazolo[3,4-b]pyridine-5-carboxamide, 4-[(1-acetamidine) -4_hexahydropyridyl)amino]-N-({4-[(difluoromethyl)oxy)phenyl}methyl)-1-ethyl-1H-pyrazolo[3,4- b]pyridine_5_decylamine, 4·[(1-acetoxy-4-hexahydrofolate b-aryl)amino]-N-{[3-gasyl (methoxy)phenyl] A 1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carbamimidyl, 4-[(1-ethylindolyl-4-hexahydropyridinyl)amino] -[(5-carbyl-2-pyridyl)methyl]-1-ethyl-1Η-0-pyrazolo-; 3,4-b]pyridine-5-carbamamine, 4-[(1- Ethyl-4-pyridinyl)amino]-N-(5-chloro-2,3-dihydro-1H_^_2_yl H-ethyl-1H-pyrazolo[3,4-7] Pyridine_5_formamidine, 4-[(1-acetoxy-4-atomium nitrogen-pyridyl)amino]-1_ethyl-N-(l,3-p-Sen_2• base 87841-960303. Doc -39- 1283678 base)-1Η-pyrazolo[3,4-b]pyridine-5-methanamine, 4-[(1-ethylindolyl-4-hexahydropyridinyl)amino] Ν-Ν_{[4·(Methanesulfonyl)phenyl]methylindole-pyrazolo[3,4-b]pyridine-5-carboxamide, 4-[(1-ethenyl-4- Hexahydropyridyl)amino]-indole·(2,2-diphenylethyl)-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide, 4- [(1_Ethyl-4-pyridinyl)amino]-1-ethyl-N-({4-[(methylsulfonyl)amino]phenyl}methyl)_1H-pyrazole And [3,4-b]pyridine-5-formamide, 4-[(1-ethylindenyl hexahydropyridinyl)amino]ethylidene-Ν·({4-[(methylamino)) Carbonyl]phenyl}methyl)-1Η-pyrazolo[3,4-b]pyridine-5-carboxamide, 4-[(1-ethylindolyl-4'hexahydropyridinyl)amino]- Ν_{[4·(Aminosulfonyl)phenyl]methyl}small ethyl _lHw is more than [3,4-b]pyridine·5·carbamamine, 4-[(1-acetamidine) _4_hexahydropyridyl)amino]_1·ethyl-indole-({3-[(methylamino)carbonyl)phenyl}methyl)-1Η-pyrazolo[3,4-b] Pyridine-5-formamide, 4-[(1-ethylindolyl-4-hexahydropyridinyl)amino]-N-{[4-(aminocarbonyl)phenyl]methyl}methyl} 1Η·pyrazole And [3,4-b]pyridine-5-formamide, 4-[(1-ethylindolyl-4-hexahydropyridinyl)amino]-1-ethyl-Ν·{[6-(A Oxy)-3-pyridyl]methyl}-1Η-pyrazolo[3,4-b]pyridine-5-carboxamide, 1-ethyl-N-4-hexahydro outside 1: decyl- 4-(tetrahydro-2H-fluoren-4-ylamino)-1Η-β is more than ton[3,4-b]pyridine-5-carboxamide, 1-ethyl-N-(4-hexa) Hydropyridylmethyl)-4-(tetrahydro-2H-piperidin-4-ylamino)-1Η-p than spit [3,4-b]pyridine-5-carbamidamine, 1-B --N-[l-(ethyl continuation)-4-hexahydro outside 1: decyl]-4·(tetrahydro-2H-bran-4-ylamino)-1Η-pyrazolo[ 3,4-b]pyridine-5-carboxamide, 1-ethyl-N-{1_[(1-methylethyl) hydrazino] winter hexahydropyridyl-4- 4-tetrahydro-2H- 87841-960303. Doc -40- 1283678 Piperazin-4-ylamino)-1Η-pyrazolo[3,4-b]pyridine-5-carboxamide, N-[l_(cyclopentylsulfonyl)_4_6 Hydropyridyl]-1·ethyl-4-(tetrahydro-2H-indol-4-ylamino)-1Η-pyrazolo[3,4-b]pyridine-5-carboxamide, 1- Ethyl-N-[l-(methylsulfonyl)-4-hexahydropyridyl]-4-(tetrahydro-2H-piperidinylamino)·1Η-pyrazolo[3,4_b]pyridine 5-5-carbamamine, 1-ethyl-indole-{1-[(phenylmethyl)sulfonyl]-4-hexahydropyridinyl}-4-(tetrahydro-2H-piperidinylamine Base)-1Η_pyrazolo[3,4_b]pyridine-5-formamide, 1-ethyl-N-[l-(phenylsulfonyl)-4-hexahydropyridyl]-4-(four Hydrogen-2H-piperazin-4-ylamino)_1H-pyrazolo[3,4-b]pyridine-5-carbamimid, I-ethyl-oxime [1-(propyl acid) 4--4-hexachloro-b-butyl]-4-(tetrachloro-2H-17-endan-4-ylamino)_1H-pyrazolo[3,4_b]pyridine-5-carboxamide, Ν-[ 1·(cyclopropylcarbonyl)donghexahydropyridyl]sodiumethyl 4-(tetrahydro-2H-pyran-4-ylamino)-1Η-pyrazolo[3,4-b]pyridine- 5-carbalamine, 1-ethyl-indole-[1-(3·furylcarbonyl)-4-hexahydropyridinyl]-4-(tetrahydro-2H-piperidin-4-ylaminopyridinium And [3,4-b]p than the lake -5-Artemisamine, Ν-[1·(3,3·dimethylbutanyl)_4_hexafluoropyridyl]-1-ethylyl (tetrahydro-2H-pyran-4-ylamino) Η 吡 · pyrazolo[3,4-b]pyridine-5-formamide, 1-ethyl-N-[l-(2-ethylbutyryl)-4-hexachloro-b-butyl]- 4-(tetrachloro-2H-bromo-4-ylamino)-1Η-pyrazolo[3,4-b]pyridine-5-carbamimidamine, N-[l-(p-amylethyl) )-4-hexachlorop ratio benzyl]-1-ethyl-4-(tetrazine-2H-bungan-4-ylamino)-1Η-ρ ratio ton[3,4-b]p ratio盐-5·甲甲胺' 1-Ethyl-N-[l-(2-methylpropionate)·4-ττ卩卩 ratio]-4-(tetrazo-2H_旅喃-4 -Amino group ratio bite [3,4-b]p than lake-5-cartoamine, 1 ·ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-Ν-[ 1-(tetrahydro-2H- shouting-4_ base talk-41 - 87841-960303. Doc 1283678 yl)-4-hexahydropyridyl]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide, 1-ethylpropanyl group, 4-ττ chloropyranyl -4-(tetrasanosyl-4-ylamino)-1Η-pyrazolo[,3,4-b]pyridine-5-carboxamide, N-[1-(N-ethinylamine) Indenyl)-4_hexahydropyridyl]-1-ethyl-4-(tetrahydro-2H-piperidin-4-ylamino)-1Η-pyrazolo[;3,4-b]pyridine- 5-Mercaptoamine, 1-ethyl-N_[l-(4-moffyl-ethyl)-4-hexachloro-p-butyl]-4-(tetrazine-2H-pyran-4- Amino)-1Η-pyrazolo[3,4-b]pyridine-5-carboxamide, 1-ethyl-fluorene-{1·[(4-ketocyclohexyl)carbonyl]-4-hexa Hydropyridyl}-4-(tetrahydro-2H-piperidin-4-ylamino)-1Η-pyrazolo[3,4-b]pyridine-5-carboxamide, 1-ethyl-N- [l-(l-hexahydrop to decylacetate)-4-hexahydrop than decyl]-4-(tetrahydro-2H-piperidin-4-ylamino)-1Η-pyrazolo[ 3,4-b]pyridine-5-carboxamide, 1-ethyl-N_{1-[(1-methyl-5-keto-3-tetrahydropyrrolyl)carbonyl]-4-hexahydropyridine }}-4·(tetrahydro-2H-piperidin-4-ylamino)-1Η·pyrazolo[3,4-7]pyridine-5-carboxamide, 1-ethyl-Ν-{1- [(3-methyl-3. epoxypropenyl)carbonyl]-4-hexahydro Pyridyl}-4-(tetrahydro-2-indole-piperidin-4-ylamino)-1Η-pyrazolo[3,4-b]pyridine-5-carboxamide, 1-ethyl·Ν-{ 1-[(4-fluorophenyl)ethenyl]_4_hexahydropyridinyl}-4-(tetrahydro-2H-pyran-4-ylamino)-1Η-ρ ratio spitting [3,4 -b]p butyl-5-cartoamine, Ν_{[1-(3,3·dimethylbutyryl)-4-hexahydrodopyl]methyl}-1-ethyl_4_ (tetrahydro-2H-bran-4-ylamino)-1Η_^ also [3,4-b]external b-position-5-carbamamine, Ν-{[1-(cyclopentylethenyl) )-4-hexahydrofolate b benzyl]methyl}-1_ethyl-4-(tetrahydro-2H-bran-4-ylamino)_1Η-ρ than ton[3,4-b] p 淀-5-carbamamine, Ν-{[1-(cyclopropylcarbonyl)-4_hexahydropyridyl]methyl}sodiumethyl-4-(tetrahydro-2H-pyran-4- Amino)-1Η-pyrazolo[3,4_b]pyridine-5-carboxamide, 87841-960303. Doc -42- 1283678 1-Ethyl-Ν-({1-[(4-fluorenylcyclohexyl)-yl]-4-ττ-chlorinated bamboo b-position}methyl)-4_(tetrahydro-2H-piperidin Isoamylamino)-1Η-pyrazolo[3,4-b]pyridine-5-carboxamide, 1-ethyl-indole-({1-[(4-phenylphenyl)acetate)- 4-hexachloro-p-predyl}methyl)-4-(tetrahydro-2H-piperidin-4-ylamino)-1Η-pyrazolo[3,4-b]pyridine-5-carboxamide , 1_ethyl-Ν-({1·[(1-methyl-5·费基-3-tetrazine-exo-l-l-yl)-based]&quot;4-hexachloro-p-butyl}methyl) Ice (tetrahydro-2H-pyran-4-ylamino)-1Η-pyrazolo[3,4_b]pyridine-5-decylamine, 3-[(1-ethyl-5-{[(benzene) Methyl)amino]carbonyl]}Η·pyrazolo[3,47>p-but-4-yl)amino]cyclohexanecarboxylic acid methyl ester, 3-[(1-ethyl-5) -{[(phenylmethyl)amino]carbonyl}·1Η·pyrazolo[3,4-b]pyridin-4-yl)amino]cyclohexanecarboxylic acid, 1-ethyl-N-(benzene Methyl)-4-(4•hexahydropyridylamino)-1Η-pyrazolo[3,4-b]pyridine-5-carboxamide, 1-ethyl-4-({l-[ (Methoxy)ethinyl]-4-hexahydropyridinyl}amino)-1Η-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester, 1-(1·methylethyl) -4-(tetrahydro-2H-pyran Ethyl 4-aminoamino)-1Η-pyrazolo[3,4-b]pyridine-5-carboxylate, 1·ethyl-indole·(4-fluorophenyl)-6-methyl-4- (tetrahydro-2H-pyran-4-ylamino)-1Η-ρ-biazo[3,4-7]pyridine·5-formamide, 1-ethyl-6-methyl-Ν-{[ 4-(methyl-branched)phenyl]methyl}-4-(tetrahydro-2Η- shode-4-ylamino)-1Η-pyrazolo[3,4_b]pyridine-5-carboxamide , N-(2,3-Dihydro-1Η·β _2-yl)-1-ethyl-6-methyl-4-(tetrahydro-2H-hamo-4-ylamino)·1Η-ρ More than tons of [3,4_b]p than yt-5-cartoamine, 1-ethyl-N-[3-(l-hexahydropyridylcarboxy)phenyl]_4·(tetrahydro-2H- brim -4-based 87841-960303. Doc -43 - 1283678 Amino)-1Η-pyrazolo[3,4-7]pyridine-5-carboxamide, 1-ethyl-N-[4_(l-methylethyl)phenyl]·4 -(tetrahydro-2H-t-Pentan-4-ylamino)-1Η-oxazolo[3,4-7]pyridine-5-carboxamide, 1-ethyl-N-(2-fluorophenyl) )-4-(tetrahydro-2H-pyran-4-ylamino)_1H-p is more than [3,4-b]pyridine-5-carboxamide, N-{3__[(dimethylamino) Carbonyl]phenyl}sodium ethyl ice (tetrahydro-211_ shout-4-ylamino)-1Η-pyrazolo[3,4-b]pyridine-5-carboxamide, N-{4_ [(Difluoromethyl)oxy]phenyl} small ethyl ice (tetrahydro-2H-fluoren-4-ylamino)-1Η-ρ ratio and [3,4-b]p ratio _ 5_carboxylic acid amine, N_{4-[ethinyl(methyl)amino]phenyl}succinyl_4-(tetrahydro-2-oxan-4-ylamino)-1Η-ρ ratio and [ 3,4_b]p than pent-5-cartoamine, 1_ethyl-N-(4_phenyl)-4-(tetrahydro-2Η· sher-4-ylamino)_1Η-ρ ratio并和[3,4-b]p 比淀-5-甲含胺, 1_ethyl-N-[4-(4-)-based)_2_(trifluoromethyl)phenyl]_4_(four Hydrogen-2H-Bucer-4-ylamino)·1Η-ρ ratio 并[3,4-b]external b-position-5-carbamamine, 1-ethyl-N-4-p ratio -4-(tetrahydro-2H-pyran-4-ylaminol ratio Tons of [3,4-b]pyridine-5-formamide, 1-ethyl-Ν·{4·[(4-methyl-1_hexahydropyrrolidinyl)carbonyl]phenyl b-4-( Tetrahydro-2H-ipyran-4-ylamino)·1Η·external b ton[3,4_b]p ratio _5_formamidine, 1-ethyl-N_[2-(2-ketone) Small tetrahydro outside t-lyl)phenyl]_4_(tetrahydro-2H-bran-4-ylamino)·1Η-ρ than spit[3,4-b]pyridine-5-carboxamide, 1-ethyl-N-[3_(methylsulfonyl)phenyl]-4-(tetrahydro-2H-piperidin-4-ylamino)-1Η-巧匕♦[3,4-b] External b-position -5-carbamamine, N-{3_[ethyl-bromo (methyl)amino]phenyl}_1_ethyltetrahydroendanyl 87041-960303. Doc -44- 1283678 Amino)-1Η-pyrazolo[3,4-b]pyridine·5-carbamimidamine, 1-ethyl-indole-{3-[(methylsulfonyl)amino]benzene Base} ice (tetrahydro-2Η· shout-4-ylamino)-1Η-pyrazolop,4-b]pyridine-5-carboxamide, 1-ethyl-fluorene (4-fluoro group) -2_# to phenyl)-4-(tetrahydro-2H-fluoren-4-ylamino)-1Η-exo-[3,4-b]pyridin-5-carboxamide, N-( 4-Chlorophenyl)-1-ethyl·4_(tetrahydro-211_ shoutin-4_ylamino-pyrimido[3,4-b]pyridine-5-carboxamide, N-(3- Chloro-2-cyanophenyl)_1_ethyl-4-(tetrahydro-2indole-scarred-4-ylamino)-iH_ 峨 并[3,4-7]pyridine-5- formazan Amine, 1-ethyl-N-[3-(l-hexahydro-p-butyryl)-phenyl]-4-(tetrahydro-2H-pyranylamino)&quot;·1Η-ρ Ratio of [3,4-b]p to _5_甲甲胺,1_ethyl-Ν·[2-(methylsulfonate)phenyl]-4-(tetrahydro-2H-P __4_ylamino)-lH_ external oxime and [3,4-b]p than lake-5-carbamamine, N-{2_[acetoxy (methyl)amino]phenyl} small B 4-(tetrahydro-2H-fluoren-4-ylamino)_1H-p than wow[3,4-b]p than _5_cartoamine, 1-ethyl_N-[ 3-(4-moffolinyl)phenyl]-4-(tetrahydro- 2H-Brigan-4-ylamino)-1H-p is more than [3,4-b>pyramid-5.carbamamine, N-(4-chloro-3-chlorophenyl)- 1-ethyl-4-(tetrahydro-2H.pyran-4-ylamino)_1H_ outer xanthene[3,4-7]pyridine-5-carboxamide, 1-ethyl_N-(3 -light phenyl)-4-(tetrahydro-2Η- sher-4-ylamino)-1Η-ρ than gorge[3,4-b]pyridine-5-carbamamine, N_(3-chloro Phenyl)-1-ethyl-4·(tetrahydro-2H-^an-4-ylamino)-lH_leafb[3,4-b]pyridin-5-carboxamide, Ν-[ 3·[(Acetylamino)methyl]-4-(methoxy)phenyl]-l-ethyl ice (tetrahydro-2H_pipe 87841-960303. Doc -45- 1283678 -4--4-ylamino)_1H-pyrazolo[3,4-b]pyridine-5-decylamine, 1-ethyl-mole external b-precipitate 35'-branched base] -4-(tetrachloro-2H-17Guano-4-ylamino)-1Η-pyrazolo[3,4-b]pyridine-5-carboxamide, N-(3-{[cyclohexyl ( Methyl)amino]carbonyl}phenyl)-1-ethyl-4-(tetrahydro-2H-piperidin-4-ylamino)_1H-pyrazolo[3,4-b]pyridine-5_ Formamidine, 1-ethyl-N-[2-(4-indolyl)-phenyl]-4-(tetrachloro-n-butyl-4-ylamino)-1Η-外匕峻和[3 , 4-b]External b is 5--5-carbamamine, Ν-{3·[(acetamido)sulfonyl]phenyl}-1-ethyl-4·(tetrahydro-2H-pyran -4-ylamino)) Η-ρ 峻 并 [3,4-b]p than pent-5-cartoamine, N-(3-chloro-4-phenyl)-1-ethyl- 4-(tetrahydro-2H-fluoren-4-ylamino)-1Η-ylidene[3,4-b]pyridine-5-carboxamide, 1-ethyl-N-{4-[ (Methanesulfonyl)amino]phenyl}-4-(tetrahydro-2H-piperidin-4-ylamino)-1Η-pyrazolo[3,4-b]pyridine-5-carboxamide , 1-ethyl-indole-{3·[(methylamino)-based]phenyl}_4-(tetrahydro-2H-pyro- 4-ylamino)_1Η-pyrazolo[3,4- b]pyridine·5·carbamamine, 1-ethyl-4-(tetrahydro-2Η-bran-4-ylamino group )·Ν-[3-(trifluoromethyl)phenyl]-1Η-exopurin and [3,4-b>pyridin-5-formamide, 1-ethyl-N-3-external b Precipitate-4-(tetrahydro-2H-pyran-4-ylamino)-1H-p is more than [3,4-b>pyramid-5-carbamide, N-(3,4- Diphenylphenyl)-1-ethyl-4·(tetrahydro-2H-pyran-4-ylamino)-1Η-ρ ratio [3,4-7]pyridine-5-carboxamide, N -[3-(Amino aryl)-4-chlorophenyl]succinyl_4_(tetrahydro-2H-bran-4-ylamino)-1H-external T and P,4-b&gt ; 比盐-5_Metaguanamine, 1-ethyl-N-[3-(4-norfosinyl)phenyl]-4_(tetrahydro-2H&gt;endan-4-ylamino)-1Η · 87841-960303. Doc -46- 1283678 匕 匕 并 [3,4-b] 峨 -5 -5 - carboxylic acid amine, 1-ethyl-N-[4-(4- 福 p 林 林 ) )) phenyl]- 4-(tetrahydro-2H-isanyl-furylamino)-1Η-pyrazolo[3,4-b]pyridine-5-carbamamine, 1·ethyl-N-{2_[(4- Mercapto-1-7T 卩 卩 p ) ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] Pyridine-5-formamide, N-{2-[(dimethylamino)carbonyl]phenyl}-1·ethyl-4·(tetrahydro-2H_^an-4-ylamino)-1Η -pyrazolo[3,4-b]pyridine-5-carboxamide, N-[2-chloro-4-(trifluoromethyl)phenyl]succinyl_4_(tetrahydro-2H-britt __4_ylamino)-1Η-pyrazolo[3,4-b]pyridine-5-carboxamide, N-{2_[(acetic acid amino)methyl]phenyl}-1-ethyl 4-(tetrahydro-2Η-^anylamino)-1Η-pyrazolo[3,4-b]pyridine-5-carboxamide, N-(2-chlorophenyl)succinyl-4 -(tetranitro-2H-pyran-4-ylaminolpyrazine[3,4_b]pyridin-5-carboxamide, N-(3-chloro-2-fluorophenyl)-1•ethyl -4-(tetrahydro-2H. sulphonyl-4-ylamino)·ιη_ρbiazo[3,4-7]pyridin-5-carboxamide, 1-ethyl-indole-(3-fluorophenyl) )-4-(tetraindole-2Η-jol-4-ylamine )-1Η_ρ比比和[3,4-b]pyridine-5-carboxamide, N-(2-cyano-3-phenylphenyl)_1_ethyl-4-(tetrahydro-2H_ shout -4-ylamino)-1Η-ρ-pyrazolo[3,4-pyridin-5-carboxamide, 1-ethyl-indole-[4-(propyl aryl)phenyl]-4 -(tetrachloro-2Η.. ρ南-4-ylamino)-1Η-pyrazolo[3,4-b]pyridine·5-formamide, Ν-{4-[(dimethylamino) )carbonyl]phenyl}-1·ethyl-4-(tetrahydro-2-indole-ytyl-4-ylamino)-lHw than ton[3,4_b> butyl _5-formic acid amine, 1-B --N-[4-(methyl fluorenyl) phenyl] ice (tetrahydro-2H_^ -4-ylamino)-1Η- 87841-960303. Doc -47- 1283678 峨 并 [3,4 七] 外 b丁-5-carbamamine, N-{4-[(acetic acid amino)methyl]-meryl}-1-ethyl-4-( Tetrachloro-2H-pyran-4-ylamino)-1Η-pyrazolo[3,4-b]pyridine-5-carboxamide, N-({2_[(1,1-dimethyl) ))oxy]_3-ρ ratio decyl}methyl)-1-ethyl-4_(tetrahydro-211-anthracene-4-ylamino)-1Η·pyridin[3,4-b] Pyridinium_5_carbamamine trifluorocurate, Ν-[(3·chloro-4-methylphenyl)methyl]sodiumethylidene (tetrahydro-2H-pyran-4-ylamine Base)·1Η_ρ比峻和[3,4-b&gt; 比丁-5-carbamamine, N-[(4-chloro-2-methylphenyl)methyl]succinyl_4-(four Hydrogen-2H-furan-4-ylamino)·1Η-ρ is more than [3,4-b]p than pent-5-ylamine, Ν·({2_[(monomethyl))) Benki}methyl)-1-ethyl-4_(tetrachloro-211*^ 喃 _4_ ylamino)-1Η-ρ ratio ton [3,4 VII] ratio &lt;-5-Proline, 1-ethyl-indole_({2_[(1-methylethyl)oxy)phenyl}methyl)_4_(tetrahydroanthracene-pyranyl-4) Base)-1Η-ρ ratio and [3,4-b]p ratio _5_甲甲胺, 1-ethyl-Ν·({3·[(1·methylethyl)oxy)benzene }) methyl) ice (tetrahydro-2H-pyran-4-ylamino)·1Η-ρ than 唆[3,4-b]p than _5_甲甲胺, N-({3 -[(difluoromethyl)oxy]phenyl}methyl)·1·ethyl winter (tetrahydro-2H n-yl 4-ylamino)-1Η-ρ ratio [3,4-b&gt;比丁-5_甲甲胺, 1-ethyl-Ν_{[4-#methyl-3-(methoxy)phenyl]methyl}_4-(tetrahydro-2-indole-bran-4-ylamine -1 Η-pyrazolo[3,4-b]pyridine-5-carboxamide, N-[(5-ethinyl-2-hydroxyphenyl)methyl]succinyl 4- 4- Hydrogen-2H-pyranyl-4-ylamino)·1Η-ρ ratio Jun [3,4-b> butyl--5-carbamamine, 1-ethyl-4-(tetrahydro-2H- shouting喃-4-ylamino)·Ν-{2_[3_(trifluoromethyl)benzene its]ethyl}-1Η_ρ 比吨[3,4-b> butyl--5-carbamamine, 87841- 960303.doc -48- 1283678 N-{[4-(Acetylamino)phenyl]methyl}sodiumethyl_4_(tetrahydro-2H-piperidin-4-ylamino)-1Η-pyrazole And [3,4-b]pyridine-5-A Indoleamine, 1-ethyl-N-[2-(3-hydroxyphenyl)ethyl]-4-(tetrahydro-2H-piperidin-4-ylamino)-1Η-pyrazolo[3, 4-b]pyridine_5_formamide, 1^-[2-(3_murine)ethyl]_1-ethyl-4-(tetrazalida-4-ylamino)-1Η- ρ 比 并[3,4-b]pyridine-5-carboxamide, 1-ethyl-4-(tetrahydro-2H-piperidin-4-ylamino)-N-(2-{4- [(Trifluoromethyl)oxy]phenyl}ethyl HH-pyrazolo[3,4-b]pyridine-5.carboxamide, 1_ethyl·Ν-{2-[3_(methoxy Phenyl]ethyl}-4-(tetrahydro-2H-piperidin-4-ylamino)-1Η-ρ is more than [3,4-b> than biting _5_formamide, Ν -[2·(4-Ethylphenyl)ethyl]-1-ethyl-4-(tetrachloro-2Η-ρ-decyl-4-ylamino)-1Η-pyrazolo[3,4 -b]pyridine-5-carboxamide, N-[2-(3,4-dichlorophenyl)ethyl]-1-ethyl-4.(tetrahydro-2H-pyran-4-ylamine -1Η-pyrazolo[3,4_b]pyridine-5-carboxamide, N-{2-[3-(aminosulfonyl)phenyl]ethyl}ethylethyl-4-(four Hydrogen 2H-pyran-4-ylamino)-1Η-pyrazolo[3,4-b]pyridine-5-carbamimidamine, N-{2-[3,4-bis(decyloxy) Phenyl]ethyl}sodiumethyl_4-(tetrahydro-211-piperidin-4-ylamino)-1Η·pyrazolo[3,4-b]pyridine-5- Indoleamine, N-[2-2,3-dichlorophenyl)ethyl]-1-ethyl-4-(tetrahydro-2H-piperidin-4-ylamino)-1Η-pyrazolo[ 3,4_b]pyridine-5-formamide, N-{2-[3,5-bis(methoxy)phenyl]ethyl}sodiumethyl 4-(tetrahydro-2H-pyran-4 -ylamino)-1Η-pyrazolo[3,4-b]pyridine-5-formamide, 1-ethyl-N-{2-[3-methyl-4-(methoxy)benzene Ethyl]ethyl}-4-(tetrahydro-2H-piperidin-4-ylamino)_1H-pyrazolo[3,4-b]pyridine-5-carboxamide, 87841-960303.doc -49 - 1283678 N-[2_(2,6-Difluorophenyl)ethyl]-1_ethyl-4-(tetrahydro-2H-bromo-4-ylamino)-1H-p ratio olfactory [ 3,4-b deductive pentane-5-cartoamine, N_{2-[2,6-bis(methoxy)phenyl]ethyl}_1_ethyl_4_(tetrahydro-2H4-an-4 -ylamino)-1Η-pyrazolo[3,4-b]pyridine-5-carboxamide, 1-ethyl-N-[2-(2-methylphenyl)ethyl]-4- (tetrahydro-2H_ shout-4-ylamino)-1Η- 匕 匕 并 [3,4-b]p than lake 5-carbamide, N-[(3,4-dimethyl) Phenyl)methyl]-1-ethyl-4-(tetrahydro-2H-bromo- 4-ylamino)-1Η-pyrazolo[3,4-b]pyridine-5-carbamimidamine, N-[4,5-bis(methoxy)-2,3-dihydro-1H-indol-2-yl H-ethyl_4-(tetrahydro-211_ shouting- 4-Aminoamino)-1Η-external b ox[3,4-b]external b-position-5-formic acid amine, Ν-{2·[4-(amino sulfhydryl)phenyl]ethyl} 1-ethyl-4-(tetrahydro-2H-bromo-4-ylamino)-1Η-pyrazolo[3,4-b]pyridine-5-carbamimid, 1-ethyl-N -{[2-(methyl succinyl)phenyl]methyl}·4-(tetrahydro-2H-bran-4-ylamino)·1Η-pyrazolo[3,4_b]pyridine_ 5_Mercaptoamine, 1_ethyl-N-(2-phenylethyl)-4-(tetrachloro-2H-bran-4-ylamino)-1Η-ρ is 唆[3,4 -b]pyridine-5-carboxamide, Ν·{[4-(dimethylamino)phenyl]methyl}sodiumethyl-4-(tetrahydro-2H-pyran-4-ylamino) -1Η-pyrazolo[3,4-b]pyridine-5-carboxamide, 1-ethyl-indole-[2-(4-fluorophenyl)ethyl]-4-(tetrahydro-2H-piperidin __4_ylamino)·1Η_pyrido[3,4-b]p than lake-5-formamide, 1-ethyl-Ν·[2-(4-methylphenyl) Base]-4-(tetrahydro-2H-^an-4-ylamino)-1Η-p ratio spit [3,4-7] than _5_甲甲胺, N_{[3-(amino group Sulfhydryl)phenyl]methyl}sodiumethyl 4-(tetrahydro-211-piperidinylamino)-1Η_ρ比比[3,4-b]p than lake-5-cartoamine , 87841-960303.doc -50· 1283678 1-ethyl_N-[(4-methylphenyl) Methyl]-4-(tetrahydro-2H.pyran-4-ylamino)-1Η-is eaten [3,4-b]pyridine-5-carboxamide, 1·ethyl-N_{[ 4-Denyl-3-(trimethylmethyl)phenyl]indolyl}-4-(tetrahydroendan-4-ylamino)·1Η·pyrazolo[3,4-b]pyridine-5- Formamidine, 2-[({[1_ethyl-4·(tetrahydro-2H- 喊 __4_ylamino) is more than [3,4-b]p than pent-5-yl] N-[(6-murine-2-pyranyl)methyl]-1-ethyl-4_(tetrachlorohexan-4-ylamine) Base)-1Η·pyrazolo[3,4-b]pyridine-5-carbamidamine trifluoroacetate, N-(2,3-dichloro-1H-buri-1 base)_1_ethyl- 4-(tetrachloro-2H·^-endan-4-ylamino)_1H_ outer 1: bite [3,4-b]pyridine-5-carboxamide, N_({2-[ethyl fluorenyl (A) Amino]phenyl}methyl)methylethyl-4-(tetrahydro-2H-piperidin-4-ylamino)-1Η-pyrazolo[3,4-b]pyridine-5- Indoleamine, N-[(lS)-2,3-dichloro-111_in-1-yl]-1-ethyl-4-(tetrachloro-2H-pyran-4-ylamino)-1Η -ρ ratio is also [3,4_b] 匕 匕 -5 - 酿 胺, N-[(lR)-2,3-dihydro-1H·茚-1-yl] small ethyl-4·(four Hydrogen-2H-piperazin-4-ylamino)-1Η·pyrazolo®; 3,4-b]pyridine_5-carbamamine, 1- -N-({3-[(methylsulfonyl)amino]phenyl}methyl)-4-(tetrahydro-2H-piperidin-4-ylamino)_1H-pyrazolo[3, 4-b]pyridine-5_carbamamine, 1_ethyl·N-(l-phenyl_4_hexahydropyridyl)-4-(tetrahydro-2H-piperidin-4ylamino) -1Η-pyrazolo[3,4-b]pyridine-5-carboxamide, 1-ethyl-N-{1_[(ethylamino)carbonyl]-4-hexahydropyridyl}-4-( Tetrahydro-2H-piperazin-4-ylamino)-1Η-pyrazolo[3,4-b]pyridine-5·carboxamide, formic acid small ethyl-N-[l-methyl-2- (4-mercapto-1-hexahydropyridinyl)ethyl]4-(tetrahydro-2H-pyran-4-ylamino)-1Η-pyrazolop,4-b]pyridine_5· Methionamine (1: 1), 87841-960303.doc -51- 1283678 [4-({[l-ethyl-4-(tetrahydro-2H·bromo-4-ylamino)-1Η_ρ) And [3,4-b]p is more than 5-amino]carbonyl}amino)-1-hexahydropyridinyl]acetate, 1-ethyl-N-{[4-(4-? Methyl)phenyl]methyl}_4-(tetrahydro-2H-bran-4-ylamino)-1Η-pyrazolo[3,4-b]pyridine-5-carbenamide trifluoroacetic acid Salt, 1-ethyl-N_({3-[(4-methyl hexahydropyranyl)methyl]phenyl}methyl)-4·(tetrahydro-2H· sher-4-ylamine) Base)-1H-p ratio and [3,4-b&gt; 5_ formic acid amine trifluoroacetic acid ητΛ£ salt, Ν-{[5-(amine-based)-3-p ratio benzyl]methyl}-1-ethyl-4_(tetrachloro-2Η-0 -4_ylamino)-1Η-pyrazolo[3,4-b]pyridine-5-carbamimid trifluoroacetate, 1-ethyl-N_{[4-(1-methylethyl)benzene Methyl}_4-(tetrahydro-2H-pyran-4-ylamino)_1H-pyrazolo[3,4-b]pyridine-5-carboxamide, N-{[3-(ring Pentyloxy)-4-(methoxy)phenyl]methyl}sodiumethyl-4-(tetrahydro-2H-piperidinylamino)_1H_pyrazolo[3,4-b]pyridine- 5. Myramine, 1_ethyl-Ν·({4-[(4-methyl hexahydropyranyl)methyl]phenyl}methyl) ice (tetrahydro-2Η-slightly-4 -ylamino)-1Η-ρ ratio and [3,4-b]p than pent-5-caraamine trifluoroacetate, N-[(2,4-dichlorophenyl)methyl]- 1-ethyl-4-(tetrahydro-2H-piperazin-4-ylamino)_1H-pyrazolo[3,4-b]pyridine-5.carboxamide, Ν·[(2,4- Difluorophenyl)methyl]sodiumethyl-4-(tetrahydro-2Η-piperidin-4-ylamino)_1Η·pyrido[3,4-b]pyridine-5-carboxamide, N -[(2-Alkyl-4-fluorophenyl)methyl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1Η·pyrine[3,4 -b]pyridine-5-carbamamine, N-{2- [2-lacyl-3-(methoxy)phenyl]ethyl}-1-ethyl-4-(tetraqi-2H_ shouting _4_ylamino)-1Η-pyrazolo[3, 4-b]pyridine-5-carboxamide, 87841-960303.doc -52- 1283678 3-[({[1-ethyl ice(tetrahydro-2H-piperidin-4-ylamino)-1Η- Methyl pyrazolo[3,4-b]pyridin-5-yl]carbonyl}amino)methyl]benzoate, 1-ethyl-indole-{[3-(1-tetrahydro-p-l-l-yl) Phenyl]methyl}-4-(tetrahydro-2H-(anthyl-4-ylamino)-1Η-pyrazolo[3,4-b]pyridine-5-carboxamide trifluoroacetate , 1-ethyl-N-(2-{4-[(sudecanoyl)amino]phenyl}ethyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1Η ·ρ ratio spit [3,4_b]p than lake-5-cartoamine, N-{[2,5-bis(methoxy)phenyl]methyl}-1-ethyl-4-(four Nitrogen-2H-yt-4-ylamino)-1Η-external b-[3,4-b]p than pent-5-cartoamine, N-{[2,6-bis(methoxy) Phenyl]methyl}_1_ethyl-4_(tetrahydro-2H-bran-4-ylamino)-1Η-pyrazolo[3,4-b]pyridine-5-carboxamide, 1 -ethyl·Ν-[(2-fluorophenyl)methyl]-4·(tetrahydro-2H· 喃 __4_ylamino)-1Η-exocarbazo[3,4-b]pyridine -5-Mergamine, N-[(3,5-difluorophenyl)methyl]-1-ethyl- 4-(tetrahydro-2Hh-Pentan-4-ylamino)-1Η-pyrazolo[3,4-b]pyridine-5-carboxamide, N_[(4-chlorophenyl)methyl]-1 -ethyl-4-(tetrahydro-2-indolyl-oxan-4-ylamino)-1Η-峨君[3,4-b]external 1:precipitate-5-formamide, N-cyclohexyl_ 1-ethyl-4-(tetramethylene-2H-piperan-4-ylamino)&gt;1H-pyrazolo[3,4_b] 竹匕盐-5-甲含胺, 1-ethyl·Ν_{ 2·[4-(A)-phenyl]ethyl}-4-(tetrahydro-2H_pyran-4-ylamino)-1Η·pyrazolo[3,4-b]pyridine- 5_Mercaptoamine, 1_ethyl-Ν_{[2-fluoro-3-(trifluoromethyl)phenyl]methyl b 4_(tetrahydrojH-pyran-4-ylamino)-1Η -ρ is more than [3,4-b]p than bite-5-cartoamine, N_({4-[(cyclopropylamino)carbonyl]phenyl}methyl)_1_ethyl_4_(tetrahydrogen)喃冰基基基比比和[3,4-b]p 比淀-5-甲含胺, 87841-960303.doc -53 - 1283678 1-ethyl-N-{[4-(4-methyl _1·Hexahydropyrrole)Phenyl]methyl b 4-(tetrahydro-2H-piperidin-4-ylamino)-1Η-pyrazolo[3,4-b]pyridine-5-A Indoleamine, 1-ethyl-N_{[4-(1•tetrahydropyrrolylmethyl)phenyl]methyl b 4-(tetrahydro-2H-pyran-4-ylamino)·1Η·pyridyl Zoxa[3,4_b]pyridine-5-A Indoleamine, 1_ethyl-N-[6-(methoxy)-1-keto-2,3-dihydro_1Η·indol-2-yl]·4-(tetrahydro-2H-pyran- 4-ylamino)·1Η-pyrazolo[3,4-b]pyridine-5-carboxamide, N-[(2,5_ &lt;One milk base) methyl]-1-ethyl-4-(tetramethane-4-ylamino)_1H_pyrazolo[3,4-b]pyridine-5-carboxamide, N -[(3,5-diethylphenyl)methyl]_1_ethyl_4_(tetrahydro-2H-piperazin-4-ylamino) is more than [3,4-b] 5-carbamimidamine, N-[(2,3-mono-methacrylic)methyl]_1_ethyl-4·(tetrachloro-2H-bungan-4-ylamino)-1Η_pyrazolo[3 , 4_b]pyridine-5-carbamamine, 1-ethyl_N-{[2_(methylsulfonyl)phenyl]methyl}-4·(tetrahydro-2H-piperazin-4-ylamino )_1H_pyrazolo[3,4-b]pyridine-5-formamide, 1-ethyl_N_[(3-hydroxyphenyl)methyl]-4·(tetrahydro-2H-pyran) 4-ylamino)-1Η-pyrazolo[3,4_b]pyridine-5-carboxamide, N-{[3,5-bis(methoxy)phenyl]methyl bromide ethyl winter ( Tetrahydro-2H_pyran-4-ylamino HH-pyrazolo[3,4-b]pyrazine-5-carboxamide, 1-ethyl-N-[2_(4_phenyl) Ethyl]-4-(tetrahydro-2H-fluorenyl-4-ylamino)-1Η-pyridin[3,4-b]ii than pent-5-cartoamine, N-[(3, 5-monophenyl)methyl]sodiumethyl-4-(tetrahydro-2indole-scarred-4-ylamino)-1Η_pyrazolo[3,4_b]pyridine-5-carboxamide, N-{ [2,4-bis(methoxy)phenyl]methyl b _4·(tetrahydro-2Η_scarredanylamino)_1Η-pyrido[3,4-b]pyridine-5-carboxamide, 87841.960303.doc -54- 1283678 1-ethyl-N-{[ 2-(Methoxy)phenyl]methyl}-4-(tetrahydro-2H-pyran-4-ylamino)-1Η-pyrazolo[3,4-b]pyridine-5-formamidine Amine, N-[(2,4-dimethylphenyl)methyl]sodiumethyl-4-(tetrahydro-2H-piperidinylamino)-1Η-pyrazolo[3,4-b Pyridine-5-formamide, 1-ethyl-fluorenyl ({2-[(methylamino)carbonyl)phenyl}methyl)-4_(tetrahydro-2H-pyran-4-ylamino) -1Η·pyrazolo[3,4-b]pyridine-5-formamide, 1-ethyl-N-{2-[4-(methoxy)phenyl]ethyl}-4-( Tetrahydro-2Η-scaridin-4-ylamino)-1Η^ is more than [3,4-b>pyramid-5-formamide, N-[(2-chlorophenyl)methyl] -1_ethyl-4-(tetrahydro-2H-fluoren-4-ylamino group ratio and [3,4-b]p ratio bite-5-formic acid amine' 1-ethyl-N-[( 2_# is phenyl)methyl]-4-(tetrahydro-2H- sher-4-ylamino)·1Η-external b and [3,4-b> butyl--5-carbamamine, N-(l,3-benzodioxolan-4-ylmethyl)-1-ethyl-4·(tetrahydro-2H-piperidin-4-ylamino)-1Η-pyrazole [3,4-b]pyridine-5-formamide, 1-ethyl·Ν-[3-( Oxy)phenyl]-4-(tetrahydro-2-indolyl-4-ylamino)-1Η-pyrido[3,4-b]p than pent-5-cartoamine, N-( Cyclohexylmethyl)sodiumethyl-4-(tetrahydro-2H_ycyl-4-ylamino)-1H-p is more than [3,4-b]pyridine-5-carboxamide, 1- Ethyl·Ν·(1,2,3,4·tetrahydro-1_fluorenyl)_4-(tetrahydro-2H-piperidinylamino)-1Η-p ratio spitting [3,4-b ]p-precipitate-5-formic acid amine, 4_[({|&gt;ethyl-4·(tetrahydro-211-hamo-4-ylamino)-1Η-pyrazolo[3,4-b] Bamboo b-pyridyl]carbonyl}amino)methyl]benzoic acid methyl ester, Ν-[(3,4·dichlorophenyl)methyl]sodiumethyl 4-(tetrahydro-2H-pyran-4 -ylamino)-1Η-pyrazolo[3,4-b>pyridin-5-formamide 87841-960303.doc -55- 1283678 N-{[4-(aminocarbonyl)phenyl]- -1-}-1-ethyl-4-(tetrahydro-2H-piperidin-4-ylamino)-1Η-pyrazolo[3,4-b]pyridine-5-carboxamide N-[(2 ,6-difluorophenyl)methyl]-1_ethyl-4-(tetrahydro-2H-furan-4-ylamino)_iH_pyrazolo[3,4-b]pyridine-5-A Indoleamine N-{[3-(amino)phenyl]methyl}methylethyl-4-(tetrahydro-2-H-pyran-4-ylamino)-1Η·pyrazolo[3, 4-b]pyridine·5·carbamidine 1-ethyl-hydrazine-[(4-per benzene) Methyl]-4-(tetrahydro-2Η-*7 guolate-4-ylamino)-1Η-ρ-pyrazolo[3,4-b]pyridine-5-carboxamide, 1-B --N-{[6-(methoxy)-3-exo b-butyl]methyl}-4-(tetrahydro-2H-bran-4-ylamino)-1Η-pyrazolo[3 , 4-b]pyridine-5-formamide 1-ethyl than decylmethyl)-4-(tetrachloro-2H-P-decano-4-ylamino)-1Η-ρ ratio spit[3 ,4-b]pyridine-5-carbamimidamine 1-ethyl-4-(tetrahydro-2H-piperidin-4-ylamino)·Ν-{[3_(trifluoromethyl)phenyl]- }}-1Η-pyrido[3,4-b]pyridine-5-carbamimidoxime [4-(2-amino-2-ketoethyl)phenyl]pyridin-4-( Tetrahydro-2H-piperazin-4-ylamino)-1Η-pyrazolo[3,4-b]pyridine_5-carbamimidamine 1-ethyl-oxime ({4-[(methylamino) )carbonyl]phenyl}methyl)-4-(tetrahydro-2H-piperidin-4-ylamino)_1H-pyrazolo[3,4-b]pyridine_5-carbamimidamine 1-ethyl -Ν·{4-[2-(Methylamino)-2. ketoethyl]phenyl} Winter (tetrahydro-2H-piperazin-4-ylamino HH-pyrazolo[3,4- b] Pyridin-5-formamide 1-ethyl-N-[(3-fluorophenyl)methyl]-4-(tetrahydro-2H-piperidin-4-ylamino)-1Η-pyrazole [3,4-b]pyridine-5-carbamamine 1_ethyl_N-({4-[(methylsulfonyl)amino]phenyl} Base)_4_(tetrahydro-2H-piperidinylamino)-1Η-pyrazolo[3,4-b]pyridine-5-formamide 87841-960303.doc -56- 1283678 N-{[4 -(Amino sulphonyl)phenyl]methyl}-l-ethyl-4·(tetramethane-4-ylamino)·1Η-pyrazolo[3,4_b]pyridine_5_A Indoleamine N-{[2-(aminowei)phenyl]methyl}_1_ethyl-4-(tetrachloro-2-indolyl-4-ylamino)-1Η-pyrazolo[3, 4-b]pyridine-5-carboxamide N-({4-[(difluoromethyl)oxy)phenyl}methyl)_1_ethyl·4-(tetrahydropyran-4-ylamine) Base)·1Η_pyrazolo[3,4-7]pyridine-5-carbamimidoxime-({3-[(dimethylamino)methyl]phenyl}methyl)-1•ethyl-4 -(tetrahydro-2-indole-pyranylamino)-1Η-pyrazolo[3,4-b]pyridine-5-carboxamide N-{[3-chloro-4-(methoxy) Phenyl]methyl}sodiumethyl-4-(tetrachloro-2H-methane-4-ylamino)-1Η-pyrazolop,4-b]pyridine-5-carbamimidoxime-(1 ·Ethyl-based 4-TT nitrogen ρ than decyl ethyl-4-(tetraqi-211·^-decano-4-ylamino)-1Η-ρ ratio and p,4-b] 5-carboxamide 1-ethyl-4-(tetrahydro-2H-bran-4-ylamino)-N-{[2-(trifluoromethyl)phenyl]methyl}·1Η-pyridyl Zoxa[3,4_b]pyridine-5-carboxamide N_(5·Chloro-2,3-dihydro-1H-hetero-2·yl)-1•ethyl-4-(tetraqi_2Η_ι派喃_4_ylamino)-1Η-pyrazole [3,4-b]pyridine-5-formamide N-({3-[(ethylamino)methyl]phenyl}methyl)·1_ethyl_4-(tetrahydro·2Η&gt; Decano-4-ylamino)-1Η-pyrazolo[3,4-b]pyridine-5-carboxamide 1-ethyl·Ν-[(4-fluorophenyl)methyl]-4- (tetrahydro-2H-pyran-4-ylamino)-1Η-pyrazolo[3,4_b]pyridine-5-carboxamide 1-ethyl-indole-{[4-|^yl-2- (trifluoromethyl)phenyl]methyl}_4_(tetrahydro-2H_ shout-4-ylamino)_1Η-ρ than spit [3,4-b]externate b-5-carboxylic acid amine 1 Ethyl-N-[(2-ethylphenyl)methyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1Η-竹1: oxazo[3,4-b Pyridine-5-formamide 87041-960303.doc -57- 1283678 1-ethyl-N-{[2-fluoro-5-(trifluoromethyl)phenyl]methyl}-4-(four Hydrogen-2H--pyran-4-ylamino group is more than bite [3,4-b]p than bite-5-formic acid amine 1-ethyl-4_(tetrahydro-2H_pyranyl-4-ylamino) )-N-[(2,3,4-trifluorophenyl)methyl]-1Η-ρ ratio also [3,4-b]p than pent-5-cartoamine N-[(4-chloro Base 2_fluorophenyl)methyl]-1·ethyl-4-(tetrahydro-2H- sher-4-ylamino group is more than [3,4-b] ?比盐-5-Medralamine N-[(4-bromo-2-fluorophenyl)methyl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino) -1Η-pyrido[3,4-b]pyridine-5-formamide N-[(3,5-dimethylphenyl)methyl]-1-ethyl-4-(tetrahydro-2H -Nam-4-ylamino)-1Η-pyrazolo[3,4_b]pyridine-5-carboxamide N-[(2,3-dimethylphenyl)methyl]-1-ethyl -4-(tetrahydro-2H-pyran-4-ylamino)-1Η-pyrido[3,4-b]pyridine-5-carboxamide N-[(2,3-diphenyl) )methyl]-1-ethyl·4-(tetrahydro-2-indole-indole-4-ylamino)-1Η-pyrazolo[3,4_b]pyridine-5-carboxamide N-[( 4-cyanophenyl)methyl]_1·ethyl-4-(tetrahydro-2H-jum- 4-ylamino)-1Η-external 并[[,4-b] 外 1 : -5-formic acid amine N-[(4-bromophenyl)methyl]-1-ethyl-4-(tetrahydro-2H-fluorenyl-4-ylamino)-lH-mouth-pyrazole[3 ,4-b]pyridine-5-carboxamide 1-ethyl-N-{[5-fluoro-2-((trifluoromethyl)phenyl]methyl b 4-(tetrahydro-2H- shouting- 4-Aminoamino)-1Η-pyrazolo[3,4-b]pyridine-5-carboxamide 1-ethyl-N-[(4-phenylphenyl)methyl]·4-(tetrahydrogen) -2H_ shout-4-ylamino)-1Η_f-oxazolo[3,4-b]pyridine-5-carbamimidoxime-{[4-(1,1-dimethylethyl) Phenyl]methyl}sodiumethyl-4-(tetrahydro-2H-piperidin-4-ylamino)-1Η-pyrazolo[3,4-b]pyridine-5-carboxamide 87841- 960303.doc -58 - 1283678 N_[(3-Phenylphenyl)methyl]-1-ethyl-4-(tetrahydro-2H-fluoren-4-ylamino)-1Η-p is 唆[3,4-b]p bis--5-cartoamine N-[(2,6-dichlorophenyl)methyl]sodiumethyl 4-(tetrahydro-2-vanopan-4-yl Amino)-1Η-oxazolo[3,4-b]pyridine-5-formamide N-[(5-chloro-2-methylphenyl)methyl]-1_ethyl-4- (tetrahydro-2H-pyran-4)-amino-aminopyrazine[3,4-b]pyridinium-5-carbamimidamine N-[(3,5-dibromophenyl)methyl; _Mercapto-4-(tetrahydro-2H-pyran-4-ylamino)-1Η_pyrazolo[3,4-b]pyridine-5-carboxamide 1_ethyl·Ν-[(4 _Ethylphenyl)methyl]-4-(tetrahydro-2H-fluorenyl-4-ylamino)-1Η-pyrazolo[3,4-b]pyridine-5-carboxamide 1-B -N-{[3_Fluoro-4-(trifluoromethyl)phenyl]methyl}-4-(tetrahydro-2H-pyran-4-ylamino)-1Η-pyrazolo[ 3,4-b]pyridine-5-carboxamide 1-ethyl-N-[(2-molyl)methyl]-4-(tetrahydro-2H-^an-4-ylamino)_1H- P-pyrazolo[3,4-7]pyridine-5-carboxamide N-[(2-bromophenyl)methyl]-1_ethyl-4 ·(tetrahydro-2H&gt; chen _4·ylamino)-iH_external oxime also [3,4-b> butyl--5-carbamamine 1-ethyl-Ν-{[4·( Methyl)phenyl]methyl}-4-(tetrahydro-2H-fluorenylamino)-1Η-pyrido[3,4-b]p than bite-5-carboxamide-1 Ethyl-N-{[3-(hydroxymethyl)phenyl]methyl}_4-(tetrahydro-2H_pyran-4-ylamino)-1Η-pyrido[3,4-b] Pyridine-5-carbamimidamine 1-ethyl-N-{[3-(hydroxymethyl)-2-methylphenyl]methyl b 4-(tetrahydro-2H_p-exan-4-ylamino) -1Η-pyrazolo[3,4-b]pyridine_5_carbamimidamine N-{[2&gt;dichloro-6-(methyl)phenyl]methyl}small ethyl benzene (tetrahydro-2)迅 喃 喃 ) ) Η Η Η Η Η Η 吡 吡 878 878 878 878 878 878 878 878 878 878 878 878 878 878 878 878 878 878 878 878 878 878 878 878 878 878 878 878 878 878 878 878 878 878 878 878 878 878 Methylphenyl)methyl]-1-ethyl-4-(tetrahydro-2H&gt; oxa-4-ylamino)-1Η-ρ is more than [3,4-b] external b bit-5 _ formic acid amine 1-ethyl-N-{[4-(2-methylpropyl)phenyl]methyl}-4·(tetrahydro-2Η·piperan-4-ylamino)-1Η-ρ唆和[3,4_b&gt; 比淀-5_甲甲胺N-[(2,5-Dimethylphenyl)methyl]-1-ethyl-4-(tetrahydro-2H- shouting - 4-ylamino)-1Η-pyrazolo[3,4-b]pyridine-5-methanamine 1-B 4-(tetrahydro-2H-bromo-4-ylamino)-N-[(2,4,5-trifluorophenyl)methyl]-1Η-pyrazolo[3,4-b Pyridine-5-formamide 1-ethyl-N-{[2-fluoro-4-(trifluoromethyl)phenyl]methyl}-4-(tetrahydro-2H-pyran-4- Amino group)-1Η_ρ ratio Jun [3,4-b]p ratio attack-5-formic acid amine N-[(2-chloro-6-methylphenyl)methyl]-1-ethyl-4 -(tetrahydro-2H&gt; decyl-4-ylamino)·1Η-β ratio also [3,4-b]p than dian-5-anthracene 4_[({[1_ethyl·4 · (tetrahydro-2H-pyran-4-ylamino)-1Η-pyrazolo[3,4-b]pyridin-5-yl]carbonyl}amino)methyl]benzoic acid sodium salt 3-[( {[1-ethyl-4-(tetrahydro-2H-piperazin-4-ylamino)-1Η-pyrazoloindole, 4-7]pyridin-5-yl]carbonyl}amino)methyl]benzene 1-ethyl-4-{[4-(hydroxyimino)cyclohexyl]amino}_1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester 1-ethyl-4_ {[4-(Hydroxyimino)cyclohexyl]amino}-N-{[4_(methoxy)phenyl]methyl}-1Η_ρ is 岐[3,4-b]p than 淀-5 -cartosamine N-{[4-(dimethylamino)phenyl]methyl}methylethyl-4-{[4-(hydroxyimino)cyclohexyl]amino}-1Η-pyrazole [3,4-b]pyridine-5-carboxamide 1_ethyl-4-({4-[(ethoxy) Imino]cyclohexyl}amino)-N-{[4-(methoxy)phenyl]methyl b 1H-pyrazolo[3,4-7]pyridine-5-carboxamide 87841-960303. Doc -60- 1283678 1_Ethyl_4-({4-[(methoxy)imino]cyclohexyl}amino)-indole-{[4·(methoxy)phenyl]methyl HH -pyrazolo[3,4-b]pyridine-5-carboxamide 4_[(4-{[(1,1-dimethylethyl)oxy]imino]cyclohexyl)amino]- 1-ethyl-N_{[4-(decyloxy)phenyl]methyl}_ih-pyrazolo[3,4-b]pyridine-5-carboxamide 1_ethyl_N-{[4_ (Methoxy)phenyl]methyl}-4-[(7-ketohexahydro-1H--azadecen-4-yl)amino]_1H_pyrazolop,4_b]pyridine-5 -Procarbamide 1-ethyl-4-[(7-ketohexahydro-1H--azepten-4-yl)amino]-1H-pyrazolo[3,4-b]pyridine- 5-carboxylic acid ethyl ester 4-{[cis-4-(butylamino)cyclohexyl]aminobine N-(2,3-dihydro-1H-indol-2-yl)_1_ethyl- lH-p ratio spit [3,4-b] bamboo b-precipitate-5-formic acid amine 4·[(trans-amylcyclohexyl)amino]ethyl-N-(phenylmethyl)-1Η -pyrazolo[3,4-b]pyridine-5-carbamimid-4-[(trans-2-aminocyclohexyl)amino)1-1-ethyl(phenylmethyl)-1Η-pyridyl Zoxa[3,4-b]pyridine-5- Indole 4-[(cis-2-aminocyclohexyl)amino]-1-ethyl-N-(phenylmethyl)-1Η-pyrazolo[3,4-b]pyridine-5- Formamide, 4-[(3-aminocyclohexyl)amino H-ethyl-N-(phenylmethyl)_1H-pyrazolo[3,4-7]pyridine-5-carboxamide, 1 -ethyl-4{[(lSR,3RS)-3-ylcyclohexyl]amine-based ox[3,4-b]p-pyridyl-5-carboxylic acid ethyl ester, N,l-diethyl -4-{[(lSR,3RS)-3-ylcyclohexyl]amino group iH-ρ than spit [3,4-b]pyridine-5-carboxamide, 1_ethyl-Ν·( 4-fluorophenyl)-4_{[(lSR,3RS)-3_# is based on cyclohexyl]amino group ih_ borazo[3,4-7]pyridine-5-carboxamide, 87841-960303. Doc -61 - 1283678 1-Ethyl-4-{[(lSR,3RS)_3-hydroxycyclohexyl]amino}-Ν·(1,3-pyrazole-2-ylmethyl)-1Η-pyrazole And [3,4-b]pyridine-5-formamide, 1-ethyl-N-[(4-fluorophenyl)methyl]-4-{[(lSR,3RS)-3-hydroxycyclohexyl Amino}-1Η-leaf b and P,4-b]exo I: ammonium-5-formic acid amine, 1-ethyl_4_{[(lSR,3RS)-3-hydroxycyclohexyl]amino} -N-{[4_(methylsulfonyl)phenyl]methyl b 1H-pyrazolo[3,4_b]pyridine-5-carboxamide, N-{[3,4-bis(methoxy) Phenyl]methyl} Small ethyl-4-{[(lSR,3RS)-3-hydroxycyclohexyl]amino}_1H-pyrazolo[3,4_b]pyridine-5-carboxamide, 1-ethyl-4-{[ (lSR,3RS)_3-hydroxycyclohexyl]aminopyridyl N-(2-pyridylmethyl)-1Η-pyrazolo[3,4-b]pyridine-5-carboxamide, 1-ethyl- 4-{[(lSR,3RS)-3-hydroxycyclohexyl]amino}-indole-[(1-methyl-1H-pyrazol-4-yl)methyl]-1H·pyrazolo[3, 4-b]pyridine-5-carboxamide, N-[(3,4-dimethylphenyl)methyl]-1-ethyl-4_{[(1SR,3RS)_3-hydroxycyclohexyl]amine }}-1Η·pyrazolo[3,4-b]pyridine-5-carboxamide, 1_ethyl-4-{[(lSR,3RS)-3-hydroxycyclohexyl]amine b-N-{ [4-(Methoxy)phenyl]methyl}-1Η-pyrazolo[3,4-b]pyridine-5-carboxamide, N-[(2,4-didecylphenyl) A Small ethyl-4-{[(lSR,3RS)-3-hydroxycyclohexyl]amino}-1Η·pyrazolo[3,4-b]pyridine-5-carboxamide, N-[( 2,3-Dichlorophenyl)methyl]-1-ethyl-4-[(4-ketocyclohexyl)amino]pyrazolo[3,4-b)pyridine-5-carboxamide, N-[(3-Chloro-4-methylphenyl)methyl]sodiumethyl-[(4-ketocyclohexyl)amino]-1Η-pyrazolo[3,4-b]pyridine- 5-carbamamine, N-[(4-carbyl-2-methylphenyl) Methyl]sodiumethyl-4-[(4-ketocyclohexyl)amino]-1Η-pyrazolo[3,4-b]pyridine-5·carboxamide, 87841-960303.doc -62- 1283678 N-[(2,4-Dimethylphenyl)methyl]-1-ethyl-4-{[4-(hydroxyimino)cyclohexyl]amino}-1Η_pyrazolo[3 , 4_b]pyridine-5-carbamide, Ν·[(3,4-dimethylphenyl)methyl]-1-ethyl-4-{[4-(hydroxyimino)cyclohexyl]amine }}-Η-pyrazolo[3,4-b]pyridine-5-formamide, N-[(2,3-dichlorophenyl)methyl]small ethyl bucket {[hydroxyimino) Cyclohexyl]amino}-1Η-pyrazolo[3,4-b]pyridine-5-formamide, Ν-[(3·chloro-4-4-methylphenyl)methyl] succinate- 4_{[4_(Imino)cyclohexyl]amino}-1Η-pyrazolo[3,4-b]pyridine-5-carboxamide, N-[(4-chloro-2-methyl) Phenyl)methyl]-1-ethyl-4-{[4·(hydroxyimino)cyclohexyl]amino}-1Η-pyrazolo[3,4-b]pyridine_5-formamide , N-({4-[(difluoromethyl)oxy)phenyl}methyl)methylethyl 4-{[4-(imido)cyclohexyl]amino}·1Η-pyrazole And [3,4-b]pyridine-5-formamide, or 1-ethyl ice {[4-(transamido)cyclohexyl]amino}_Ν_{[4·(trifluoromethyl)benzene Methyl}·1Η _ pyrazolo[3,4-b]pyridine-5-formamide; or a salt thereof. 52. A compound or salt according to claim 1 of the patent application, which is: N-[(2,4-dimercaptophenyl)methyl]sodiumethyl-4-[(4-ketocyclohexyl) Amino]-1H-indolo[3,4-b]pyridine-5-carboxamide, N-[(3,4-dimethylphenyl)methyl]_1_ethyl-4·[( 4-ketocyclohexyl)amino]-1H-indazolo[3,4-b]pyridyl-5-carbamamine, 1-ethyl-Ν-{[4·(methoxy)phenyl ]methyl}-4-[(4-ketocyclohexyl)amino]-1Η-azolo[3,4-b]pyridine-5-carboxamide, N-({4·[(difluoro) Methyl)oxy]phenyl}methyl)methylethyl 4-[(4-ketocyclohexyl)amino]-1Η-pyrazolo[3,4-b]pyridine_5-carboxamide , 87841-960303.doc -63- 1283678 4-(cyclohexylamino)-1-ethyl-N-{[4-(methoxy)phenyl]methyl}-1Η-ρ than gorge [3 ,4-b]pyridine-5-methanamine, N_[(3-chlorobendenylmethyl)methyl]_1_ethyl-4_(tetrahydro-2H-piperazin-4-ylamino) -1Η-pyrazolo[3,4-b]pyridine_5. formamide, N-[(4-chloro-2-methylphenyl)methyl]-1-ethyl winter (tetrahydro- 2H·piperidinylamino)_1Η-pyrazolo[3,4-b]pyridine-5-carbamimidamine, N-[(3,4-dimethylphenyl)methyl]butylethyl- 4 _(tetrahydro-2H-piperidinylamino)-1Η-pyrazolo P,4-b]pyridine-5-carboxamide, 1-ethyl-N-[(4-methylphenyl) Methyl]·4-(tetrahydro-2H-piperidin-4-ylamino)-m-oxazolo[3,4-b]pyridine-5-carboxamide, N-[(2,4- Dimethylphenyl)methyl]-1-ethyl_4·(tetrazo-2H-pyran-4-ylamino group than spit[3,4-b] outside 1:di-5-branched Amine, N-[(2,3-diphenyl)methyl]-1.ethyl-4-(tetra-argon-; 2H-piperidin-4-ylamino)-1Η-external oxime [ 3,4-b]pyridine-5-carboxamide, N_{[2,3-dichloro-6.(methyl)phenyl]methyl}-1-ethyl-4-(tetrahydro-2H -piperazin-4-ylamino)-1Η·pyrazolo[3,4-b]pyridine-5-carboxamide, 1-ethyl-4-{[4_(hydroxyimino)cyclohexyl] Amino}-N-{[4-(methoxy)phenyl]methyl}-1Η_ρ is 唆[3,4-b]p than _5·carbamamine, N-[(4-气-2-methylphenyl)methyl]-1-ethyl-4-[(4-ketocyclohexyl)amino]·1Η-pyrazolo[3,4-b]pyridine-5-rebel Amine, N-[(2,4-methylphenyl)methyl]-1-ethyl-4·{[4-(imido)cyclohexyl]amino}-1Η-pyrazolo[ 3,4-b]pyridine-5-carboxamide, N-[(3,4-methylphenyl)methyl]-1-ethyl_4-{ [4-(transamido)cyclohexyl]amino}}1Η-ρ is 唆[3,4-b]^: bite-5-myramine, 87841-960303.doc -64- 1283678 N- [(2,3-dichlorophenyl)methyl]-oxime-ethyl_heart {[4_(hydroxyimino)cyclohexyl]amino}}Η^^^^[3,4-b]p Bishen-5-carboxamide, N-[(3-chloro-4-methylphenyl)methyl]ethyl_heart {[4-(hydroxyimino)cyclohexyl]amino}-1Η- Pyrazolo[3,4-b]pyridine-5-carboxamide, Ν·[(4-chloro-2-methylphenyl)methyl]_丨-ethyl_4-{[4-(hydroxy Imino)cyclohexyl]amino}-1Η·pyrazolo[3,4-b]pyridine-5-carboxyguanamine, N-({4-[(difluoromethyl)oxy]phenyl} Methyl)-1_ethyl-4-{[4-(hydroxyimino)cyclohexyl]amino}}1Η-ρ ratio 4 and [3,4-b]p than lake-5-rebel amine Or 1-ethyl-4-{[4-(hydroxyimino)cyclohexyl]amino}-N_{[4-(trifluoromethyl)phenyl]methyl}-1Η-pyrazolo[ 3,4-b]pyridine-5-carboxyguanamine; or a salt thereof. 53. A compound or salt according to claim 1 of the patent application, which is: N-benzyl-1-ethyl-4_(tetrahydro-2-indole-piperidin-4-ylamino)-1Η-pyrazole [3,4-b]p is more than a 5-amine, 1_ethyl-Ν·(4·fluorophenyl)-4-(tetrahydro-2H_^-yl-4-ylamino)-1Η -pyrazolo[3,4-b]pyridine-5-carboxamide, 1-ethyl-N-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1Η-pyridyl Zoxa[3,4_b]pyridine-5-carboxamide, 1-ethyl-indole-[4·(methylsulfonyl)-yl]·4_(tetrahydro-2H-pyran-4-ylamine -1Η-pyrazolo[3,4-b]pyridine-5-carboxyguanamine, 1-ethyl-4_(tetrahydro-:2H-hamo-4-ylamino)-Ν-(1 , 3-Deta-2-ylmethyl)-1Η-pyrazolo[3,4-b]pyridine-5-carboxamide, N-(3,4-dimethoxybenzyl)1-ethyl- 4_(tetrahydro-2H_bromo-4-ylamino)_1H-pyrazolo[3,4-b]pyridine-5-carboxyguanamine, 87841-960303.doc -65- 1283678 卜乙_N-{ 4-[(Methylsulfonyl)methyl]phenyl}-4-(tetrahydro-2H-piperidin-4-ylamino)-1Η-pyrazolo[3,4-b]pyridine-5 - Carboxylamamine, 1 · Ethyl-hydrazine·[(1_Methyl-iH-p to ton-4-yl) fluorenyl]-4-(tetrahydro-2H-pyran-4-ylamino) -1Η-ρ比峻和[3,4 _b]p than lake-5-carboxylic acid amine, or puethyl-N-(2-pyridylmethyl)-4-(tetrahydro-2H·jungan-4-ylamino)-1Η-pyrazolo[ 3,4-b]pyridine-5-carboxyguanamine; or a salt thereof. 54. A compound or salt according to any one of claims 1 to 3, 6, 7, 9, 10, 11, 19, 26 to 33, 51, 52 or 53 which is a compound or a pharmaceutical thereof Acceptable salt. 55. A compound or salt according to any one of claims 1 to 3, 6, 7, 9, 10, 11, 19, 26 to 33, 51, 52 or 53 which is in the form of a particle size reduction. 56. A compound or salt according to claim 55, wherein the reduced size of the compound or salt has a particle size (D5〇) of from 0.5 to 1 μm. 57. A compound or salt according to any one of claims 1 to 3, 6, 7, 9, 10, u, 19, % to 33, 51, 52 or 53 as a human phosphodiesterase 4 inhibitors. 58. A pharmaceutical composition comprising as defined in any one of claims 1 to 3, 6, 7, 9, 10, 11, 19, 26 to 33, 5, 52 or 53 &lt; Compound of Formula (I) or (IA) or (IB), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers and/or excipients, wherein the composition is as a phosphoric acid Diesterase 4 inhibitors for treatment and/or prevention: human asthma, chronic bronchitis, emphysema, atopic dermatitis, urticaria, allergic nasal 87841-960303.doc -66- 1283678 inflammation, allergic binding membrane Inflammation, spring combined with membranous inflammation, sputum red granuloma, psoriasis, f arthritis, septic shock, ulcerative colitis, Crohn's disease, myocardial and brain reperfusion injury, chronic spheroid Nephritis, endotoxin shock, adult dyspnea syndrome or multiple sclerosis. 59. A pharmaceutical composition comprising, as claimed in claims 1 to 3, 6, 7, 9, 10, 11, 19, 26 to 33 a compound of formula (I) or (IA) or (IB), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, as defined in any one of 5, 52 or / or an excipient wherein the composition is for the treatment and/or prevention of inflammatory and/or allergic diseases in humans. 60. - Formula 1 or (ia) as defined in any of the i-third to three, six, seven, nine, one, u, 19, 26 to 33' 5, 52 or 53 patent applications. Or the use of the (IB) compound or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment and/or prevention of inflammatory and/or allergic diseases in humans. 61. According to the combination of the patent application No. 59 The composition, wherein the composition is for the treatment and/or prevention of chronic obstructive pulmonary disease (C〇pd), asthma or allergic rhinitis in humans. 62. The use according to claim 60, wherein the medicament is for treatment and/or Prevention of human fecal obstructive pulmonary disease (COPD), asthma or allergic rhinitis. 63. A combination comprising 1 to 3, 6, 7, 9, 10, 11, 19, 26 to 33, 51 according to the scope of the patent application. a compound of formula (I) or (IA) or (IB), or a pharmaceutically acceptable salt thereof, as defined in any one of 52 or 53 above, and an adrenergic receptor agonist, an antihistamine, an antiallergic or Anti-inflammatory agent. 64. A combination comprising, according to the scope of the patent application No. 3, 6, 7, 9, 10, 11, 19, 26 to 33, 51, 52 87841-960303.doc -67 - 1283678, or a compound of formula (I) or (IB) or a pharmaceutically acceptable salt thereof, and a muscarine (M) receptor, as defined in any one of 53 Antagonist. 65. A combination according to claim 64, wherein the muscarine (M) receptor antagonist is an M3 receptor antagonist. 87841-960303.doc 68-
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