TWI397528B - Tri(cyclo)substituted amide glucokinase activator compounds - Google Patents

Tri(cyclo)substituted amide glucokinase activator compounds Download PDF

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TWI397528B
TWI397528B TW93109372A TW93109372A TWI397528B TW I397528 B TWI397528 B TW I397528B TW 93109372 A TW93109372 A TW 93109372A TW 93109372 A TW93109372 A TW 93109372A TW I397528 B TWI397528 B TW I397528B
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cyclopentyl
alkyl
thiazol
compound
ylpropenylamine
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TW93109372A
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TW200514780A (en
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Matthew Colin Thor Fyfe
Lisa Sarah Gardner
Maseo Nawano
Martin James Procter
Chrystelle Marie Rasamison
Geoffrey Martyn Williams
David Witter
Kosuke Yasuda
Arlindo Castelhano
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Prosidion Ltd
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三(環)取代之醯胺類葡萄糖激酶活化劑化合物Tris(cyclo) substituted guanamine glucokinase activator compound

本發明係有關三(環)取代之醯胺化合物，特別是，本發明係有關醯胺化合物，其中i)其羰基碳經乙基/乙烯基所取代，而該乙基/乙烯基連結一含氮的六員雜芳環和一飽和或未飽和環，及ii)其胺基經帶有氮的雜芳環所取代，而該醯胺化合物是為葡萄糖激酶的調節子，且可用於預防或治療高血糖症和第II型糖尿病。The present invention relates to a tri(cyclo)substituted indoleamine compound, in particular, the present invention relates to a guanamine compound wherein i) its carbonyl carbon is substituted by an ethyl/vinyl group, and the ethyl/vinyl linkage is contained a six-membered heteroaryl ring of nitrogen and a saturated or unsaturated ring, and ii) an amine group substituted with a nitrogen-containing heteroaryl ring which is a regulator of glucokinase and which can be used for prevention or Treats hyperglycemia and type 2 diabetes.

吾人相信，葡萄糖激酶(“GK”)對身體中之血漿葡萄糖含量的調節極為重要。GK主要是發現於肝和胰臟內，為催化葡萄糖的初始代謝之四種己糖激酶中之一種。相較於其他己糖激酶途徑，GK途徑係在較高的葡萄糖含量的情況下被飽和(參見R.L.Printz et al.,Annu.Rev.Nutr.,13：463-496(1993))。GK對維持哺乳動物之葡萄糖的平衡極為重要。不會表現GK的動物在出生後會很快地因糖尿病而死亡，反之，過度表現GK的動物具有較佳的葡萄糖耐受量。GK的活化可導致胰島素過多性低血糖症(參見，例如，H.B.T.Christesen et al.,Diabetes,51：1240-1246(2002))。此外，第II型青春晚期糖尿病是由喪失GK基因的功能突變而導致，表示GK於人體內作為葡萄糖感受器(Y.Liang et al.,Biochem.J.309：167-173(1995))。因此，活化GK的化合物可增進 GK感覺系統的靈敏度，因此可用於治療高血糖症，特別是與第II型糖尿病相關的高血糖症。因此，提供可活化GK以治糖尿病的新穎化合物是所欲的。I believe that glucokinase ("GK") is extremely important for the regulation of plasma glucose levels in the body. GK is mainly found in the liver and pancreas and is one of the four hexokinases that catalyze the initial metabolism of glucose. The GK pathway is saturated at higher glucose levels compared to other hexokinase pathways (see R. L. Printz et al., Annu. Rev. Nutr., 13: 463-496 (1993)). GK is extremely important to maintain the balance of glucose in mammals. Animals that do not express GK will die rapidly from diabetes after birth. Conversely, animals that overexpress GK have better glucose tolerance. Activation of GK can lead to hyperinsulinemia of hypoinsulinemia (see, for example, H. B. T. Christesen et al., Diabetes, 51: 1240-1246 (2002)). In addition, type II puberty diabetes is caused by a loss of a functional mutation in the GK gene, indicating that GK acts as a glucose receptor in the human body (Y. Liang et al., Biochem. J. 309: 167-173 (1995)). Therefore, compounds that activate GK can be enhanced The sensitivity of the GK sensory system can therefore be used to treat hyperglycemia, especially hyperglycemia associated with type 2 diabetes. Therefore, it would be desirable to provide novel compounds that can activate GK to treat diabetes.

國際專利公開案WO 2001044216和US 6,353,111揭示作為GK活化劑之(E)-2,3-二取代的-N-雜芳基丙烯醯胺。國際專利公開案WO 2002014312和US 6,369,232、6,388,088、和6,441,180揭示四唑苯基乙醯胺GK活化劑。國際專利公開案WO 2000058293、歐洲專利申請案EP1169312和US 6,320,050揭示芳基環烷基丙醯胺GK活化劑。國際專利公開案WO 2002008209和US 6,486,184揭示作為抗糖尿病劑之α-醯基和α-雜原子取代的苯乙醯胺GK活化劑。國際專利公開案WO 2001083478揭示含乙內醯脲的GK活化劑。國際專利公開案WO 2001083465和US 6,388,071揭示炔苯基雜芳族GK活化劑。國際專利公開案WO 2001085707和US 6,489,485揭示對-胺取代的苯基醯胺GK活化劑。國際專利公開案WO 2002046173和US 6,433,188、6,441,184和6,448,399揭示稠合的雜芳族GK活化劑。國際專利公開案WO 2002048106和US 6,482,951揭示異吲哚啉-1-酮GK活化劑。國際專利公開案WO 2001085706揭示用於治療第II型糖尿病之經取代的苯基乙醯胺GK活化劑。US 6,384,220揭示對-芳基或雜芳基取代的苯基GK活化劑。法國專利案2,834,295揭示人類GK的純化及其晶狀結構，及揭示作為GK配位子之3-環戊基-2-吡啶-4-基-N-噻唑-2-基丙醯胺。國際專利公 開案WO 2003095438(在本案優先權日之後公開)揭示用於治療治療第II型糖尿病之作為GK活化劑之N-雜芳基苯基乙醯胺和相關的化合物。US 6,610,846揭示作為GK活化劑之環烷基雜芳基丙醯胺。國際專利公開案WO 2003000262揭示乙烯基苯基GK活化劑。國際專利公開案WO 2003000267揭示作為GK調節子之胺基菸酸衍生物。WO 2003015774(在本案優先權日之後公開)揭示作為GK調節子之化合物。國際專利公開案WO 2003047626(在本案優先權日之後公開)揭示併用GK活化劑以及葡萄朊拮抗劑以治療第II型糖尿病。國際專利公開案WO 2003055482(在本案優先權日之後公開)揭示作為GK活化劑之醯胺衍生物。國際專利公開案WO 2003080585(在本案優先權日之後公開)揭示用於治療糖尿病和肥胖之具有GK活性之胺基苯甲醯胺衍生物。國際專利公開案WO 2003097824(在本案優先權日之後公開)揭示人類肝臟GK晶體及其於以結構為基礎的藥物設計上之用途。國際專利公開案WO 2004002481(在本案優先權日之後公開)揭示作為GK活化劑之芳基羰基衍生物。The international patent publications WO 2001044216 and US 6,353,111 disclose (E)-2,3-disubstituted-N-heteroarylacrylamide as a GK activator. The international patent publications WO 2002014312 and US 6,369,232, 6,388,088, and 6,441,180 disclose tetrazole phenyl acetamide GK activators. The arylcycloalkyl decylamine GK activator is disclosed in the international patent publications WO 2000058293, the European patent application EP 1 169 312 and the US 6,320,050. The international patent publications WO 2002008209 and US 6,486,184 disclose alpha-mercapto and alpha-heteroatom substituted phenethylamine GK activators as anti-diabetic agents. International Patent Publication WO 2001083478 discloses GK activators containing intramethylene urea. The acetylene phenyl heteroaromatic GK activators are disclosed in the international patent publications WO 2001083465 and US 6,388,071. The international patent publications WO 2001085707 and US 6,489,485 disclose p-amine substituted phenylguanamine GK activators. Condensed heteroaromatic GK activators are disclosed in International Patent Publication No. WO 2002046173 and US Pat. Nos. 6,433,188, 6,441,184 and 6,448,399. International Patent Publication No. WO 2002048106 and US Pat. No. 6,482,951 disclose isoindoline-1-one GK activators. International Patent Publication WO 2001085706 discloses substituted phenylacetamide GK activators for the treatment of Type II diabetes. US 6,384,220 discloses p-aryl or heteroaryl substituted phenyl GK activators. French Patent No. 2,834,295 discloses the purification of human GK and its crystalline structure, and discloses 3-cyclopentyl-2-pyridin-4-yl-N-thiazol-2-ylpropionamide as a GK ligand. International patent The opening of WO 2003095438 (published after the priority date of the present application) discloses N-heteroarylphenylacetamide and related compounds as GK activators for the treatment of type 2 diabetes. US 6,610,846 discloses cycloalkylheteroarylamine as a GK activator. International Patent Publication WO 2003000262 discloses vinyl phenyl GK activators. International Patent Publication WO 2003000267 discloses amine nicotinic acid derivatives as GK regulators. WO 2003015774 (published after the priority date of the present application) discloses a compound which is a GK regulator. International Patent Publication WO 2003047626 (published after the priority date of the present application) discloses the use of a GK activator and a grape vine antagonist to treat Type II diabetes. International Patent Publication No. WO 2003055482 (published after the priority date of the present disclosure) discloses a guanamine derivative as a GK activator. International Patent Publication No. WO 2003080585 (published after the priority date of the present application) discloses a benzyl benzamide derivative having GK activity for the treatment of diabetes and obesity. International Patent Publication WO 2003097824 (published after the priority date of the present application) discloses human liver GK crystals and their use in the design of structure-based drugs. International Patent Publication No. WO 2004002481 (published after the priority date of the present disclosure) discloses aryl carbonyl derivatives as GK activators.

發明總論General theory of invention

一種如下式(I)所示之化合物 或其藥學上可接受之鹽或N-氧化物，其係用於預防和治療高血糖症或第II型糖尿病。a compound of the following formula (I) Or a pharmaceutically acceptable salt or N-oxide thereof for use in the prevention and treatment of hyperglycemia or type II diabetes.

發明之詳細說明Detailed description of the invention

一種如下式(I)所示之化合物 或其藥學上可接受之鹽或N-氧化物，其中：A1 、A2 、A3 、A4 和A5 中之一者是N，另一者是C-R5 ，另一者是C-R6 ，及另二者各自獨立地為N或CH；Q是C3-8 環烷基、5-或6-員雜芳基、或4-8員雜環；T與相連結的-N=C-形成雜芳環，或雜環(其中N=C 鍵是唯一的未飽和位置)；R1 和R2 各自獨立地為氫、鹵素、羥基、氰基、硝基、乙烯基、乙炔基、甲氧基、OCFn H3-n 、-N(C0-4 烷基)(C0-4 烷基)、CHO、或C1-2 烷基(任意地經1-5個各自獨立的鹵素、羥基、氰基、甲氧基、-N(C0-2 烷基)(C0-2 烷基)、SOCH3 或SO2 CH3 取代基所取代)；或R1 和R2 一起形成碳環或雜環；或R1 和R2 一起為經由雙鍵而與環相連結之氧原子；R3 和R4 各自獨立地為氫、鹵素、OCFn H3-n 、甲氧基、CO2 R77 、氰基、硝基、CHO、CONR99 R100 、CON(OCH3 )CH3 、或任意地經1-5個各自獨立的鹵素、羥基、氰基、甲氧基、-NHCO2 CH3 、或-N(C0-2 烷基)(C0-2 烷基)取代基所取代之C1-2 烷基、雜芳基、或C3-7 環烷基；或R3 和R4 一起形成5-8員芳族環、雜芳環、碳環或雜環；R5 和R6 各自獨立地為氫、羥基、鹵素、氰基、硝基、CO2 R7 、CHO、COR8 、C(OH)R7 R8 、C(=NOR7 )R8 、CONR9 R10 、SR7 、SOR8 、SO2 R8 、SO2 NR9 R10 、CH2 NR9 R10 、NR9 R10 、N(C0-4 烷基)SO2 R8 、NHCOR7 、或C1-4 烷基、C2-4 烯基、C2-4 炔基、C1-4 烷氧基、芳基、或雜芳基，其中各個基團任意地經1-6個各自獨立的鹵素、氰基、硝基、羥基、C1-2 烷氧基、-N(C0-2 烷基)(C0-2 烷基)、C1-2 烷基、CFn H3-n 、芳基、雜芳基、-COC1-2 烷基、-CON(C0-2 烷基)(C0-2 烷基)、SCH3 SOCH3 、SO2 CH3 、或-SO2 N(C0-2 烷基)(C0-2 烷基)取代基所取代；或R5 和R6 一起形成5-8員碳環或雜環；R7 和R77 各自獨立地為氫、或C1-4 烷基、C2-4 烯基、C2-4 炔基、C3-7 環烷基、芳基、雜芳基、或4-7員雜環基，其中各個基團任意地經1-6個各自獨立的鹵素、氰基、硝基、羥基、C1-2 烷氧基、-N(C0-2 烷基)(C0-2 烷基)、C1-2 烷基、C3-7 環烷基、4-7員雜環、CFn H3-n 、芳基、雜芳基、CO2 H、-COC1-2 烷基、-CON(C0-2 烷基)(C0-2 烷基)、SOCH3 、SO2 CH3 、或-SO2 N(C0-2 烷基)(C0-2 烷基)取代基所取代；R8 是C1-4 烷基、C2-4 烯基、C2-4 炔基、C3-7 環烷基、芳基、雜芳基、或4-7員雜環基，其中各個基團任意地經1-6個各自獨立的鹵素、氰基、硝基、羥基、C1-2 烷氧基、-N(C0-2 烷基)(C0-2 烷基)、C1-2 烷基、C3-7 環烷基、4-7員雜環、CFn H3-n 、芳基、雜芳基、CO2 H、-COC1-2 烷基、-CON(C0-2 烷基)(C0-2 烷基)、SOCH3 、SO2 CH3 、或-SO2 N(C0-2 烷基)(C0-2 烷基)取代基所取代；R9 、R10 、R99 、和R100 各自獨立地為氫、或C1-4 烷基、C3-7 環烷基、芳基、雜芳基、或4-7員雜環基，其中各個基團任意地經1-6個各自獨立的鹵素、氰基、硝基、羥基、C1-2 烷氧基、-N(C0-2 烷基)(C0-2 烷基)、C1-2 烷基、C3-7 環烷基、4-7員雜環、CFn H3-n 、芳基、雜芳基、-COC1-2 烷基、-CON(C0-2 烷基)(C0-2 烷基)、 SOCH3 、SO2 CH3 、或-SO2 N(C0-2 烷基)(C0-2 烷基)取代基所取代；或R9 和R10 或R99 和R100 一起形成6-8員雜雙環系統或4-8員雜環，而其任意地經1-2個各自獨立的C1-2 烷基、CH2 OCH3 、COC0-2 烷基、羥基、或SO2 CH3 取代基所取代；n是1、2或3；m是0或1；其中虛線和實線一起形成任意的雙鍵，及△表示雙鍵具有(E)構型；及其先決條件是式(I)所示之化合物不為3-環戊基-2-吡啶-4-基-N-噻唑-2-基丙醯胺。a compound of the following formula (I) Or a pharmaceutically acceptable salt or N-oxide thereof, wherein: one of A 1 , A 2 , A 3 , A 4 and A 5 is N, the other is CR 5 and the other is CR 6 And the other two are each independently N or CH; Q is a C 3-8 cycloalkyl, 5- or 6-membered heteroaryl, or a 4-8 membered heterocyclic ring; T is bonded to the -N=C - forming a heteroaromatic ring, or a heterocyclic ring (wherein N = C bond is the only unsaturated position); R 1 and R 2 are each independently hydrogen, halogen, hydroxy, cyano, nitro, vinyl, ethynyl, Methoxy, OCF n H 3-n , -N(C 0-4 alkyl)(C 0-4 alkyl), CHO, or C 1-2 alkyl (optionally 1-5 independent) Halogen, hydroxy, cyano, methoxy, -N(C 0-2 alkyl)(C 0-2 alkyl), SOCH 3 or SO 2 CH 3 substituent substituted; or R 1 and R 2 together Forming a carbocyclic or heterocyclic ring; or R 1 and R 2 together are an oxygen atom bonded to the ring via a double bond; R 3 and R 4 are each independently hydrogen, halogen, OCF n H 3-n , methoxy , CO 2 R 77 , cyano, nitro, CHO, CONR 99 R 100 , CON(OCH 3 )CH 3 , or optionally 1-5 each independently halogen, hydroxy, cyano, methoxy, - NHCO 2 CH 3 , or -N ( C 0-2 alkyl) (C 0-2 alkyl) substituents of C 1-2 alkyl, aryl, heteroaryl, or a C 3-7 cycloalkyl group; or R 3 and R together form a 45- 8 membered aromatic ring, heteroaryl ring, carbocyclic ring or heterocyclic ring; R 5 and R 6 are each independently hydrogen, hydroxy, halogen, cyano, nitro, CO 2 R 7 , CHO, COR 8 , C(OH R 7 R 8 , C(=NOR 7 )R 8 , CONR 9 R 10 , SR 7 , SOR 8 , SO 2 R 8 , SO 2 NR 9 R 10 , CH 2 NR 9 R 10 , NR 9 R 10 , N(C 0-4 alkyl)SO 2 R 8 , NHCOR 7 or C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, aryl, Or a heteroaryl group, wherein each group is optionally subjected to 1 to 6 independently halogen, cyano, nitro, hydroxy, C 1-2 alkoxy, -N(C 0-2 alkyl) (C 0 -2 alkyl), C 1-2 alkyl, CF n H 3-n , aryl, heteroaryl, -COC 1-2 alkyl, -CON(C 0-2 alkyl) (C 0-2 Alkenyl), SCH 3 SOCH 3 , SO 2 CH 3 , or -SO 2 N(C 0-2 alkyl)(C 0-2 alkyl) substituent; or R 5 and R 6 together form 5- 8 membered carbocyclic or heterocyclic; R 7 and R 77 are each independently hydrogen, or C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-7 cycloalkyl, aryl Base, heteroaryl, or 4-7 a heterocyclic group in which each group is optionally subjected to 1 to 6 independently halogen, cyano, nitro, hydroxy, C 1-2 alkoxy, -N(C 0-2 alkyl) (C 0 -2 alkyl), C 1-2 alkyl, C 3-7 cycloalkyl, 4-7 membered heterocyclic ring, CF n H 3-n , aryl, heteroaryl, CO 2 H, -COC 1- 2 alkyl, -CON(C 0-2 alkyl)(C 0-2 alkyl), SOCH 3 , SO 2 CH 3 , or -SO 2 N(C 0-2 alkyl) (C 0-2 alkane) Substituted by a substituent; R 8 is C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-7 cycloalkyl, aryl, heteroaryl, or 4-7 a heterocyclic group in which each group is optionally subjected to 1 to 6 independently halogen, cyano, nitro, hydroxy, C 1-2 alkoxy, -N(C 0-2 alkyl) (C 0 -2 alkyl), C 1-2 alkyl, C 3-7 cycloalkyl, 4-7 membered heterocyclic ring, CF n H 3-n , aryl, heteroaryl, CO 2 H, -COC 1- 2 alkyl, -CON(C 0-2 alkyl)(C 0-2 alkyl), SOCH 3 , SO 2 CH 3 , or -SO 2 N(C 0-2 alkyl) (C 0-2 alkane) Substituted by a substituent; R 9 , R 10 , R 99 , and R 100 are each independently hydrogen, or C 1-4 alkyl, C 3-7 cycloalkyl, aryl, heteroaryl, or 4 -7 membered heterocyclic group, wherein each group is arbitrarily passed through 1-6 Since independent halo, cyano, nitro, hydroxy, C 1-2 alkoxy, -N (C 0-2 alkyl) (C 0-2 alkyl), C 1-2 alkyl, C 3- 7 cycloalkyl, 4-7 membered heterocyclic ring, CF n H 3-n , aryl, heteroaryl, -COC 1-2 alkyl, -CON(C 0-2 alkyl) (C 0-2 alkane) Substituted with a SOCH 3 , SO 2 CH 3 , or —SO 2 N(C 0-2 alkyl)(C 0-2 alkyl) substituent; or R 9 and R 10 or R 99 together with R 100 Forming a 6-8 membered heterobicyclic ring system or a 4-8 membered heterocyclic ring, optionally exemplified by 1-2 independently C 1-2 alkyl groups, CH 2 OCH 3 , COC 0-2 alkyl groups, hydroxyl groups, or Substituted with a SO 2 CH 3 substituent; n is 1, 2 or 3; m is 0 or 1; wherein the dotted line and the solid line together form an arbitrary double bond, and Δ indicates that the double bond has the (E) configuration; The condition is that the compound represented by the formula (I) is not 3-cyclopentyl-2-pyridin-4-yl-N-thiazol-2-ylpropionamide.

當虛線和實線一起形成一單鍵時，連結芳基環和帶有Q的側鏈至羰基碳之碳原子是一對掌中心。因此，化合物可以外消旋物或(R)或(S)構型之單一鏡像異構物的形式存在。較佳的是(R)鏡像異構物。When the dotted line and the solid line together form a single bond, the carbon atom linking the aryl ring and the side chain having Q to the carbonyl carbon is a pair of palm centers. Thus, the compound may exist as a racemate or as a single mirror image isomer of the (R) or (S) configuration. Preferred are (R) mirror image isomers.

於第一態樣中，本發明係有關一種如下式(Ia)所示之化合物： 或其藥學上可接受之鹽或N-氧化物，其中A1 -A5 、Q、T、R1 -R4 、m、和△係如上式(I)中所定義。In a first aspect, the invention relates to a compound of formula (Ia): Or a pharmaceutically acceptable salt or N-oxide thereof, wherein A 1 -A 5 , Q, T, R 1 -R 4 , m, and Δ are as defined above in formula (I).

於第一態樣之一體系中，本發明係有關一種如式(Ia)所示之化合物，或其藥學上可接受之鹽或N-氧化物，其中：A3 是C-R5 ，A4 是C-R6 ，A1 、A2 和A5 中之一者是N，而另二者是CH。In one system of the first aspect, the invention relates to a compound of formula (Ia), or a pharmaceutically acceptable salt or N-oxide thereof, wherein: A 3 is CR 5 and A 4 is One of CR 6 , A 1 , A 2 and A 5 is N, and the other two are CH.

於第一態樣之另一體系中，本發明係有關一種如式(Ia)所示之化合物，或其藥學上可接受之鹽或N-氧化物，其中：A3 是C-R5 ，A4 是C-R6 ，A1 、A2 和A5 中之一者是N，而另二者是CH；Q是C3-8 環烷基。In another system of the first aspect, the invention relates to a compound of formula (Ia), or a pharmaceutically acceptable salt or N-oxide thereof, wherein: A 3 is CR 5 , A 4 Is CR 6 , one of A 1 , A 2 and A 5 is N, and the other two are CH; Q is a C 3-8 cycloalkyl group.

於第一態樣之另一體系中，本發明係有關一種如式(Ia)所示之化合物，或其藥學上可接受之鹽或N-氧化物，其中：A3 是C-R5 ，A4 是C-R6 ，A1 、A2 和A5 中之一者是N，而另二者是CH；Q是4-8員雜環。In another system of the first aspect, the invention relates to a compound of formula (Ia), or a pharmaceutically acceptable salt or N-oxide thereof, wherein: A 3 is CR 5 , A 4 Is CR 6 , one of A 1 , A 2 and A 5 is N, and the other two are CH; Q is a 4-8 member heterocyclic ring.

於第一態樣之另一體系中，本發明係有關一種如式(Ia)所示之化合物，或其藥學上可接受之鹽或N-氧化物，其中：A3 是C-R5 ，A4 是N，A1 、A2 和A5 中之一者是N， 而另二者是CH。In another system of the first aspect, the invention relates to a compound of formula (Ia), or a pharmaceutically acceptable salt or N-oxide thereof, wherein: A 3 is CR 5 , A 4 Is N, one of A 1 , A 2 and A 5 is N, and the other two are CH.

於第一態樣之另一體系中，本發明係有關一種如式(Ia)所示之化合物，或其藥學上可接受之鹽或N-氧化物，其中：A3 是C-R5 ，A4 是N，A1 、A2 和A5 中之一者是N，而另二者是CH；Q是C3-8 環烷基。In another system of the first aspect, the invention relates to a compound of formula (Ia), or a pharmaceutically acceptable salt or N-oxide thereof, wherein: A 3 is CR 5 , A 4 Is N, one of A 1 , A 2 and A 5 is N, and the other two are CH; Q is a C 3-8 cycloalkyl group.

於第二態樣中，本發明係有關一種如下式(Ib)所示之化合物： 或其藥學上可接受之鹽或N-氧化物，其中A1 -A5 、Q、T、R1 -R4 和m係如上式(I)中所定義。In a second aspect, the invention relates to a compound of formula (Ib): Or a pharmaceutically acceptable salt or N-oxide thereof, wherein A 1 -A 5 , Q, T, R 1 -R 4 and m are as defined above in formula (I).

於第二態樣之一體系中，本發明係有關一種如式(Ib)所示之化合物，或其藥學上可接受之鹽或N-氧化物，其中：A3 是C-R5 ，A4 是C-R6 ，A1 、A2 和A5 中之一者是N，而另二者是CH。In one system of the second aspect, the invention relates to a compound of formula (Ib), or a pharmaceutically acceptable salt or N-oxide thereof, wherein: A 3 is CR 5 and A 4 is One of CR 6 , A 1 , A 2 and A 5 is N, and the other two are CH.

於第二態樣之另一體系中，本發明係有關一種如式( Ib)所示之化合物，或其藥學上可接受之鹽或N-氧化物，其中：A3 是C-R5 ，A4 是C-R6 ，A1 、A2 和A5 中之一者是N，而另二者是CH；Q是C3-8 環烷基。In another system of the second aspect, the invention relates to a compound of formula (Ib), or a pharmaceutically acceptable salt or N-oxide thereof, wherein: A 3 is CR 5 , A 4 Is CR 6 , one of A 1 , A 2 and A 5 is N, and the other two are CH; Q is a C 3-8 cycloalkyl group.

式(I)所示之化合物的分子量宜低於800，更宜低於600，最宜低於500。The compound of the formula (I) preferably has a molecular weight of less than 800, more preferably less than 600, most preferably less than 500.

本發明中，A1 和A5 宜為CH。In the present invention, A 1 and A 5 are preferably CH.

本發明中，A2 宜為N。In the present invention, A 2 is preferably N.

本發明中，A3 宜為C-R5 。In the present invention, A 3 is preferably CR 5 .

本發明中，A4 宜為C-R6 或N；更宜為C-R6 。In the present invention, A 4 is preferably CR 6 or N; more preferably CR 6 .

本發明中，Q宜是環戊基、環己基、四氫吡喃基、四氫噻喃基、1-酮-四氫噻喃基、1,1-二酮-四氫噻喃基；更宜為環戊基、環己基、四氫吡喃基或四氫噻喃基；最宜為環戊基或環己基。In the present invention, Q is preferably a cyclopentyl group, a cyclohexyl group, a tetrahydropyranyl group, a tetrahydrothiopyranyl group, a 1-keto-tetrahydrothiopyranyl group, a 1,1-dione-tetrahydrothiopyranyl group; It is preferably a cyclopentyl group, a cyclohexyl group, a tetrahydropyranyl group or a tetrahydrothiopyranyl group; most preferably a cyclopentyl group or a cyclohexyl group.

當Q是雜芳基或雜環基時，其宜經由碳原子而連結至-(CH2 )m -基。When Q is a heteroaryl or heterocyclic group, it is preferably bonded to the -(CH 2 ) m - group via a carbon atom.

當Q是雜芳基時，其在與-(CH2 )m -基連結點相鄰的位置上宜不具有不為氫之取代基R1 或R2 。When Q is a heteroaryl group, it is preferred that it has no substituent R 1 or R 2 which is not hydrogen at a position adjacent to the -(CH 2 ) m - group attachment point.

本發明中，下式所示之基團 宜為單環雜芳基。更宜為噻唑基、噻二唑基、噁唑基、異 噁唑基、嘧啶基、吡嗪基、或吡啶基；更宜為2-噻唑基、5-〔1,2,4〕噻二唑基、2-〔1,3,4〕噻二唑基、4-嘧啶基、2-吡嗪基、3-異噁唑基、或2-吡啶基；最宜為2-噻唑基、5-〔1,2,4〕噻二唑基、或2-吡啶基。In the present invention, the group represented by the following formula It is preferably a monocyclic heteroaryl group. More preferably thiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, pyrimidinyl, pyrazinyl or pyridyl; more preferably 2-thiazolyl, 5-[1,2,4]thiadi Azolyl, 2-[1,3,4]thiadiazolyl, 4-pyrimidinyl, 2-pyrazinyl, 3-isoxazolyl, or 2-pyridyl; most preferably 2-thiazolyl, 5 - [1,2,4]thiadiazolyl, or 2-pyridyl.

下式所示之基團 更宜為2-噻唑基，例如2-噻唑基，其中R3 是5-鹵基(例如5-氟)，及R4 是氫。a group represented by the following formula More preferably, it is a 2-thiazolyl group, such as a 2-thiazolyl group, wherein R 3 is a 5-halo group (e.g., 5-fluoro), and R 4 is hydrogen.

本發明中，R1 和R2 宜為氫。In the present invention, R 1 and R 2 are preferably hydrogen.

本發明中，R3 宜是氫、鹵素和C1-2 烷基、或三氟甲基；更宜是氫、甲基、氟、氯或溴；更宜是氫、氟或氯；最宜是氫或氟。In the present invention, R 3 is preferably hydrogen, halogen and C 1-2 alkyl, or trifluoromethyl; more preferably hydrogen, methyl, fluorine, chlorine or bromine; more preferably hydrogen, fluorine or chlorine; It is hydrogen or fluorine.

本發明中，R4 宜是氫或甲基；更宜為氫。In the present invention, R 4 is preferably hydrogen or methyl; more preferably hydrogen.

本發明中，R5 宜是CF3 、SOR8 、SO2 R8 、SO2 NR9 R10 、NHSO2 R8 、***基或四唑基；更宜為SOR8 、SO2 R8 、SO2 NR9 R10 、或NHSO2 R8 ；最宜為SOR8 或SO2 R8 。In the present invention, R 5 is preferably CF 3 , SOR 8 , SO 2 R 8 , SO 2 NR 9 R 10 , NHSO 2 R 8 , triazolyl or tetrazolyl; more preferably SOR 8 , SO 2 R 8 , SO 2 NR 9 R 10 , or NHSO 2 R 8 ; most preferably SOR 8 or SO 2 R 8 .

本發明中，R6 宜是氫、氯、氟、或三氟甲基；更宜為氫。In the present invention, R 6 is preferably hydrogen, chlorine, fluorine or trifluoromethyl; more preferably hydrogen.

本發明中，R7 、R77 和R8 宜為C1-4 烷基、C3-7 環烷基、雜芳基、或4-8員雜環基；更宜為C1-4 烷基或C3-7 環烷基。In the present invention, R 7 , R 77 and R 8 are preferably a C 1-4 alkyl group, a C 3-7 cycloalkyl group, a heteroaryl group or a 4-8 membered heterocyclic group; more preferably a C 1-4 alkane Or a C 3-7 cycloalkyl group.

本發明中，R9 和R10 宜是C0-4 烷基，或一起形成4-8 員雜環。In the present invention, R 9 and R 10 are preferably a C 0-4 alkyl group or together form a 4-8 membered heterocyclic ring.

本發明中，R99 和R100 宜是C0-4 烷基。In the present invention, R 99 and R 100 are preferably a C 0-4 alkyl group.

本發明中，m宜是0。In the present invention, m is preferably 0.

本發明中，n是2或3。In the present invention, n is 2 or 3.

本發明之特別的化合物是實例所揭示的化合物，及其藥學上可接受之鹽或N-氧化物。Particular compounds of the invention are the compounds disclosed by the examples, and pharmaceutically acceptable salts or N-oxides thereof.

雖然各個變數的較佳基團已經分別地就各個變數列示於上文，然而本發明之較佳化合物包含式(I)中之數個或各個變數係選自所例示之各個變數之較宜、更宜、最宜、特別或特定的基團之化合物。因此，本發明包含所例示之較宜、更宜、最宜、特別或特定的基團之所有組合。Although the preferred groups of the various variables have been separately listed above for each variable, preferred compounds of the invention comprise several or individual variables of formula (I) selected from the various variables exemplified above. A compound that is more suitable, optimum, specific or specific. Accordingly, the present invention includes all combinations of the preferred, preferred, most suitable, specific or specific groups exemplified.

本文中，除非特別指明，“烷基”以及其他具有“alk”字首的基團，例如烷氧基、烷基、烯基、炔基等，係指可為直鏈或支鏈或其組合之碳鏈。烷基的例子包含甲基、乙基、丙基、異丙基、丁基、第二和第三丁基、戊基、己基、庚基等。“烯基”、“炔基”及其他類似的基團包含具有至少一個未飽和的碳-碳鍵之碳鏈。Herein, unless otherwise specified, "alkyl" and other groups having the "alk" prefix, such as alkoxy, alkyl, alkenyl, alkynyl, etc., are meant to be straight or branched or combinations thereof. The carbon chain. Examples of the alkyl group include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a second and a third butyl group, a pentyl group, a hexyl group, a heptyl group and the like. "Alkenyl", "alkynyl" and other similar groups include a carbon chain having at least one unsaturated carbon-carbon bond.

本文中，例如，“C0-4 烷基”意指於直鏈或支鏈結構中具有0至4(即0、1、2、3、或4)個碳原子之烷基。當烷基是末端基團時，不含碳的烷基是氫。當烷基是橋連基(連結基)時，不含碳的烷基是直接鍵。Herein, for example, "C 0-4 alkyl" means an alkyl group having 0 to 4 (i.e., 0, 1, 2, 3, or 4) carbon atoms in a linear or branched structure. When the alkyl group is a terminal group, the carbon-free alkyl group is hydrogen. When the alkyl group is a bridging group (linking group), the carbon-free alkyl group is a direct bond.

“環烷基”和“碳環”意指不含雜原子的碳環，包含單、雙或三環飽和碳環，以及稠合系統和橋連系統。此稠合環系統可包含一部份或完全未飽和的環，例如苯環，以形成 稠合環系統，例如苯並稠合的碳環。環烷基包含例如螺稠合環系統之稠合環系統。環烷基和碳環的例子包含C3-8 環烷基，例如環丙基、環丁基、環戊基、環己基、和萘烷、金剛烷、茚滿基、1,2,3,4-四氫萘等。"Cycloalkyl" and "carbocyclic" mean carbocyclic rings containing no heteroatoms, including mono-, di- or tricyclic saturated carbocycles, as well as fused systems and bridging systems. The fused ring system may comprise a partially or fully unsaturated ring, such as a benzene ring, to form a fused ring system, such as a benzofused carbocycle. Cycloalkyl groups contain a fused ring system such as a spiro fused ring system. Examples of cycloalkyl and carbocyclic rings include C 3-8 cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and decalin, adamantane, indanyl, 1,2,3, 4-tetrahydronaphthalene and the like.

“鹵素”乙辭包含氟、氯、溴、和碘原子。"Halogen" contains fluorine, chlorine, bromine, and iodine atoms.

“芳基”乙辭包含，例如，苯基和萘基。The term "aryl" includes, for example, phenyl and naphthyl.

除非特別指明，“雜環”包含含有1或2個選自氧、硫和氮的雜原子之4-8員飽和環。雜原子彼此不直接相連結。雜環的例子包含氧雜丁烷、四氫呋喃、四氫吡喃、氧雜環庚烷、氧雜環辛烷、硫雜環丁烷、四氫噻吩、四氫噻喃、硫雜環庚烷、硫雜環辛烷、氮雜環丁烷、吡咯烷、哌啶、氮雜環庚烷、氮雜環辛烷、〔1,3〕二噁烷、噁唑烷、哌嗪等。其他雜環的例子包含含硫環的氧化形式，因此，四氫噻吩1-氧化物、四氫噻吩1,1-二氧化物、四氫噻喃1-氧化物、四氫噻喃1,1-二氧化物亦視為雜環。Unless otherwise indicated, "heterocycle" embraces a 4-8 membered saturated ring containing one or two heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen. The heteroatoms are not directly linked to each other. Examples of the heterocyclic ring include oxabutane, tetrahydrofuran, tetrahydropyran, oxepane, oxeane, thietane, tetrahydrothiophene, tetrahydrothiopyran, thietane, Thiacyclooctane, azetidine, pyrrolidine, piperidine, azepane, azacyclooctane, [1,3]dioxane, oxazolidine, piperazine, and the like. Examples of other heterocyclic rings include an oxidized form of a sulfur-containing ring, and therefore, tetrahydrothiophene 1-oxide, tetrahydrothiophene 1,1-dioxide, tetrahydrothiopyran 1-oxide, tetrahydrothiopyran 1,1 - The dioxide is also considered to be a heterocyclic ring.

除非特別指明，“雜芳基”包含含有1-4個選自氧、硫和氮的雜原子之5或6員雜芳環。雜芳環的例子是呋喃基、噻吩基、吡咯基、吡唑基、咪唑基、噁唑基、異噁唑基、噻唑基、異噻唑基、***基、噁二唑基、噻二唑基、四唑基、吡啶基、噠嗪基、嘧啶基、吡嗪基、或三嗪基。Unless otherwise indicated, "heteroaryl" embraces a 5 or 6 membered heteroaryl ring containing from 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen. Examples of heteroaromatic rings are furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazole Base, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, or triazinyl.

上述化學式在某些位置上並無顯示出確定的立體化學。除非特別畫出或指明，本發明包含所有的立體異構物(例如幾何異構物、光學異構物、非鏡像異構物等)及其藥學上可接受之鹽或N-氧化物。此外，除非特別畫出或指 明，本發明亦涵蓋立體異構物的混合物和單離出的特定立體異構物。在進行用於製備上述化合物的合成步驟期間中，或在進行熟悉此項技術人士所習知的消旋或差向異構步驟時，上述步驟所產生的產物可為立體異構物的混合物。當上述化學式所示的化合物存在有互變異構物時，除非特別畫出或指明，本發明包含所有可能的互變異構物、及其藥學上可接受之鹽或N-氧化物、及其混合物。當上述化學式所示的化合物及其藥學上可接受之鹽或N-氧化物以溶劑化物或多晶型的形式存在時，本發明包含所有可能的溶劑化物及多晶型。形成溶劑化物的溶劑的類型並不特別限定，只要溶劑是藥學上可接受的溶劑。可使用，例如，水、乙醇、丙醇、丙酮等。The above chemical formula does not show a certain stereochemistry at certain positions. Unless specifically indicated or indicated, the invention encompasses all stereoisomers (e.g., geometric isomers, optical isomers, non-image isomers, etc.) and pharmaceutically acceptable salts or N-oxides thereof. In addition, unless specifically drawn or referred to It is to be understood that the invention also encompasses mixtures of stereoisomers and specific stereoisomers which are isolated. The product produced by the above steps may be a mixture of stereoisomers during the synthetic step used to prepare the above compounds, or when subjected to the racemic or epimeric step known to those skilled in the art. When a compound represented by the above formula is present in a tautomer, the present invention encompasses all possible tautomers, and pharmaceutically acceptable salts or N-oxides thereof, and mixtures thereof, unless otherwise specified or indicated. . When a compound of the above formula and a pharmaceutically acceptable salt or N-oxide thereof are present in the form of a solvate or polymorph, the invention encompasses all possible solvates and polymorphs. The type of the solvent forming the solvate is not particularly limited as long as the solvent is a pharmaceutically acceptable solvent. For example, water, ethanol, propanol, acetone, or the like can be used.

由於式(I)所示之化合物欲用於藥學的用途，其宜為實質上純質的形式，例如至少60%純度，宜為至少75%純度，特別是至少98%純度(%係以重量計)。Since the compound of formula (I) is intended for pharmaceutical use, it is preferably in a substantially pure form, for example at least 60% pure, preferably at least 75% pure, especially at least 98% pure (% by weight) meter).

本發明亦涵蓋一種藥學組成物，其包含式(I)所示之化合物、其藥學上可接受之鹽或N-氧化物、以及藥學上可接受之載體。The invention also encompasses a pharmaceutical composition comprising a compound of formula (I), a pharmaceutically acceptable salt or N-oxide thereof, and a pharmaceutically acceptable carrier.

組成物宜包含藥學上可接受之載體及無毒性之治療有效量之上述式(I)所示之化合物，或其藥學上可接受之鹽或N-氧化物。The composition preferably comprises a pharmaceutically acceptable carrier and a non-toxic therapeutically effective amount of a compound of the above formula (I), or a pharmaceutically acceptable salt or N-oxide thereof.

此外，在此較佳的體系中，本發明涵蓋一種藉由活化GK而預防或治療高血糖症和糖尿病之藥學組成物，其包含藥學上可接受之載體及無毒性之治療有效量之上述式( I)所示之化合物，或其藥學上可接受之鹽或N-氧化物。Further, in this preferred system, the present invention encompasses a pharmaceutical composition for preventing or treating hyperglycemia and diabetes by activating GK, comprising a pharmaceutically acceptable carrier and a non-toxic therapeutically effective amount of the above formula ( a compound of the formula I), or a pharmaceutically acceptable salt or N-oxide thereof.

本發明之化合物和組成物可有效地治療哺乳動物(例如人類)之高血糖症。The compounds and compositions of the present invention are effective in treating hyperglycemia in mammals such as humans.

本發明亦提供一種預防或治療GK的活化是所欲的病症之方法，其包含投服有效量之式(I)所示之化合物或其藥學上可接受之鹽之步驟。The present invention also provides a method for preventing or treating the activation of GK as a desired condition, which comprises the step of administering an effective amount of the compound of the formula (I) or a pharmaceutically acceptable salt thereof.

本發明亦提供一種預防或治療高血糖症或糖尿病之方法，其包含投服有效量之式(I)所示之化合物或其藥學上可接受之鹽之步驟。The present invention also provides a method for preventing or treating hyperglycemia or diabetes comprising the step of administering an effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt thereof.

本發明亦提供一種預防患有糖尿病前期性高血糖症或葡萄糖耐受不良之人類的糖尿病之方法，其包含投服預防有效量之式(I)所示之化合物或其藥學上可接受之鹽之步驟。The present invention also provides a method for preventing diabetes in a human having pre-diabetes hyperglycemia or glucose intolerance, comprising administering a prophylactically effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt thereof. The steps.

本發明亦提供式(I)所示之化合物或其藥學上可接受之鹽之作為GK活化劑的用途。The invention also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as a GK activator.

本發明亦提供式(I)所示之化合物或其藥學上可接受之鹽之用於預防或治療高血糖症或糖尿病的用途。The present invention also provides the use of a compound of the formula (I) or a pharmaceutically acceptable salt thereof for preventing or treating hyperglycemia or diabetes.

本發明亦提供式(I)所示之化合物或其藥學上可接受之鹽之用於預防患有糖尿病前期性高血糖症或葡萄糖耐受不良之人類的糖尿病之用途。The present invention also provides the use of a compound of the formula (I) or a pharmaceutically acceptable salt thereof for preventing diabetes in a human having pre-diabetes hyperglycemia or glucose intolerance.

本發明亦提供式(I)所示之化合物或其藥學上可接受之鹽之用於製造用於活化GK的藥物之用途。The invention also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for activating GK.

本發明亦提供式(I)所示之化合物或其藥學上可接受之鹽之用於製造用於預防或治療高血糖症或糖尿病的藥 物之用途。The present invention also provides a compound of the formula (I) or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for preventing or treating hyperglycemia or diabetes The use of the object.

本發明亦提供式(I)所示之化合物或其藥學上可接受之鹽之用於製造用於預防患有糖尿病前期性高血糖症或葡萄糖耐受不良之人類的糖尿病的藥物之用途。The present invention also provides the use of a compound of the formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for preventing diabetes in a human having pre-diabetes hyperglycemia or glucose intolerance.

本發明之化合物和組成物可任意地與一或多種其他的抗糖尿病劑或降血糖劑併用，其包含，例如，磺醯脲(例如伏降糖(glyburide)、格列美脲(glimepiride)、格列比特(glipyride)、格列吡嗪(glipizide)、氯磺丙脲(chlorpropamide)、格列濟特(gliclazide)、格列派特(glisoxepid)、醋磺環己脲(acetohexamide)、格列波脲(glibornuride)、甲苯磺丁脲(tolbutamide)、妥拉明(tolazamide)、胺磺丁脲(carbutamide)、格列喹酮(gliquidone)、格列己脲(glyhexamide)、苯磺丁脲(phenbutamide)、甲苯磺環己脲(tolcyclamide)等)、雙胍(例如二甲雙胍(metformin)、苯乙雙胍(phenformin)、丁雙胍(buformin)等)、糖原質拮抗劑(例如肽型或非肽型糖原質拮抗劑)、苷酶抑制劑(例如阿卡波糖(acarbose)、美格羅(miglitol)等)、胰島素促分泌素、胰島素增敏劑(例如曲格列酮(troglitazone)、羅格列酮(rosiglitazone)、皮格列酮(pioglitazone)等)等；或抗肥胖劑(例如諾美婷(sibutramine)、羅氏鮮(orlistat)等)等。本發明之化合物和組成物與其他的抗糖尿病劑或降血糖劑可同時、依序或個別地投服。The compounds and compositions of the present invention may optionally be used in combination with one or more other anti-diabetic or hypoglycemic agents, including, for example, sulfonium urea (e.g., glyburide, glimepiride, Glypyride, glipizide, chlorpropamide, gliclazide, glisoxepid, acetohexamide, greek Glbornuride, tolbutamide, tolazamide, carbutamide, gliquidone, glychexamide, phenylbutazone Phenbutamide), tolcyclamide, etc., biguanide (eg metformin, phenformin, buformin, etc.), glycogen antagonist (eg peptide or non-peptide) Glycogen antagonists, glycosidase inhibitors (eg, acarbose, miglitol, etc.), insulin secretagogues, insulin sensitizers (eg, troglitazone, ro Risoglitazone, pioglitazone, etc.; or anti-obesity agents (eg, novo Sibutramine, orlistat, etc.). The compounds and compositions of the present invention can be administered simultaneously, sequentially or individually with other anti-diabetic or hypoglycemic agents.

“藥學上可接受之鹽”乙辭意指由藥學上可接受之無毒 性的鹼或酸所製得的鹽。當本發明之化合物是酸性時，其對應的鹽可由藥學上可接受之無毒性的鹼(包含無機鹼和有機鹼)而簡單地製得。由此無機鹼所製得的鹽包含鋁鹽、銨鹽、鈣鹽、銅鹽、亞銅鹽、鐵鹽、亞鐵鹽、鋰鹽、鎂鹽、錳鹽、亞錳鹽、鉀鹽、鈉鹽、鋅鹽等。特別合宜的是銨鹽、鈣鹽、鎂鹽、鉀鹽和鈉鹽。由藥學上可接受之有機無毒性的鹼所製得的鹽包含一級、二級和三級胺，以及環狀胺和經取代的胺(例如天然發生和合成的胺)之鹽。其他可形成鹽之藥學上可接受的有機無毒性的鹼包含，例如，精胺酸、甜菜鹼、咖啡因、膽鹼、N’,N’-二苄基乙二胺、二乙胺、2-二乙胺基乙醇、2-二甲胺基乙醇、乙醇胺、乙二胺、N-乙基嗎啉、N-乙基哌啶、還原葡糖胺(glucamine)、葡糖胺(glucosamine)、組胺酸、異丙胺、賴胺酸、甲基還原葡糖胺(methylglucamine)、嗎啉、哌嗪、哌啶、多元胺樹脂、普魯卡因(procaine)、嘌呤、可可鹼(theobromine)、三乙胺、三甲胺、三丙胺、緩血酸胺(tromethamine)等。"Pharmaceutically acceptable salt" B means pharmaceutically acceptable non-toxic a salt prepared by a base or an acid. When the compound of the present invention is acidic, its corresponding salt can be simply prepared from a pharmaceutically acceptable non-toxic base comprising an inorganic base and an organic base. The salt prepared by the inorganic base comprises an aluminum salt, an ammonium salt, a calcium salt, a copper salt, a cuprous salt, an iron salt, a ferrous salt, a lithium salt, a magnesium salt, a manganese salt, a manganese salt, a potassium salt, and a sodium. Salt, zinc salt, etc. Particularly suitable are ammonium, calcium, magnesium, potassium and sodium salts. Salts prepared from pharmaceutically acceptable organic non-toxic bases include primary, secondary and tertiary amines, as well as salts of cyclic amines and substituted amines such as naturally occurring and synthetic amines. Other pharmaceutically acceptable organic non-toxic bases which form salts include, for example, arginine, betaine, caffeine, choline, N', N'-dibenzylethylenediamine, diethylamine, 2 - diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, Histamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resin, procaine, guanidine, theobromine, Triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.

當本發明之化合物是鹼性時，其對應的鹽可由藥學上可接受之無毒性的酸(包含無機酸和有機酸)而簡單地製得。此酸包含，例如，醋酸、苯磺酸、苯甲酸、樟腦磺酸、檸檬酸、乙磺酸、反丁烯二酸、葡糖酸、穀胺酸、氫溴酸、氫氯酸、2-羥基乙磺酸(isethionic acid)、乳酸、順丁烯二酸、蘋果酸、扁桃酸、甲磺酸、黏酸(mucic acid)、硝酸、雙羥萘酸(pamoic acid)、泛酸、磷酸、 琥珀酸、硫酸、酒石酸、對甲苯磺酸等。特別合宜的是檸檬酸、氫溴酸、氫氯酸、順丁烯二酸、磷酸、硫酸、甲磺酸、和酒石酸。When the compound of the present invention is basic, its corresponding salt can be simply prepared from a pharmaceutically acceptable non-toxic acid comprising a mineral acid and an organic acid. The acid comprises, for example, acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, 2- Isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid, Succinic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid, and the like. Particularly convenient are citric acid, hydrobromic acid, hydrochloric acid, maleic acid, phosphoric acid, sulfuric acid, methanesulfonic acid, and tartaric acid.

本發明之藥學組成物包含作為活性成份之式(I)所示之化合物或其藥學上可接受之鹽或N-氧化物、藥學上可接受之載體及任意的其他治療成份或助劑。雖然在任何的情況下最合宜的途徑是決定於活性成份所投服之特定的宿主和病況的性質和嚴重程度，組成物可包含適合經口、直腸、局部、和胃腸外(包含皮下、肌內和靜脈內)投服的組成物，以及經由吸入投服的組成物。藥學組成物可適當地以單位劑型的形式存在，且可以任何藥學界所習知的方法製得。The pharmaceutical composition of the present invention comprises, as an active ingredient, a compound of the formula (I), or a pharmaceutically acceptable salt or N-oxide thereof, a pharmaceutically acceptable carrier, and any other therapeutic ingredient or adjuvant. Although in any case the most appropriate route is determined by the nature and severity of the particular host and condition to which the active ingredient is administered, the composition may comprise suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular) Compositions administered internally and intravenously, as well as compositions administered via inhalation. The pharmaceutical composition may suitably be in the form of a unit dosage form and may be prepared by any method known in the pharmaceutical art.

本發明之藥學組成物較宜用於口服。The pharmaceutical composition of the present invention is preferably used orally.

實際上，本發明之式(I)所示之化合物，或其藥學上可接受之鹽或N-氧化物，可作為活性成份而與藥學載體利用習知的製藥混合技術而緊密地混合。載體可為各種形式，決定於適合於投服途徑(例如經口或胃腸外投服(包含靜脈內投服))的製劑的形式。因此，本發明之藥學組成物可為口服用之不連續的單位，例如膠囊、糯米紙藥包(cachet)、或錠劑，而其分別含有預定量之活性成份。此外，組成物可為粉劑、粒劑、溶液、水性液體的懸浮液、非水性液體的懸浮液、水包油乳液、或油包水液態乳液。除了上述之一般的劑型之外，式(I)所示之化合物，或其藥學上可接受之鹽或N-氧化物，亦可利用控釋裝 置及/或輸送裝置而投服。組成物可利用任何藥學界所習知的方法製備。通常，此方法包含令活性成份與構成一或多個必要成份之載體相混合之步驟。通常，組成物係藉由均勻且緊密地混合活性成份和液態載體或細分的固態載體或二者而製得。接著產物可適當地塑形成所欲的外觀。In fact, the compound of the formula (I) of the present invention, or a pharmaceutically acceptable salt or N-oxide thereof, can be intimately mixed as an active ingredient with a pharmaceutical carrier by a conventional pharmaceutical mixing technique. The carrier may be in a variety of forms depending on the form of the preparation suitable for the route of administration, such as oral or parenteral administration (including intravenous administration). Thus, the pharmaceutical compositions of the present invention may be discrete units for oral administration, such as capsules, wafers, or lozenges, each containing a predetermined amount of active ingredient. Further, the composition may be a powder, a granule, a solution, a suspension of an aqueous liquid, a suspension of a non-aqueous liquid, an oil-in-water emulsion, or a water-in-oil liquid emulsion. In addition to the above general dosage forms, the compound of formula (I), or a pharmaceutically acceptable salt or N-oxide thereof, may also be prepared by controlled release. Put on and/or transport the device and take it. The composition can be prepared by any method known in the pharmaceutical industry. Generally, the method comprises the step of mixing the active ingredient with a carrier which comprises one or more essential ingredients. Generally, the composition is prepared by uniformly and intimately mixing the active ingredient with a liquid carrier or a finely divided solid carrier or both. The product can then be suitably shaped to the desired appearance.

因此，本發明之藥學組成物可包含藥學上可接受之載體和式(I)所示之化合物，或其藥學上可接受之鹽或N-氧化物。式(I)所示之化合物，或其藥學上可接受之鹽或N-氧化物，亦可與一或多種其他的治療活性化合物一起混合而包含於藥學組成物中。Accordingly, the pharmaceutical composition of the present invention may comprise a pharmaceutically acceptable carrier and a compound of formula (I), or a pharmaceutically acceptable salt or N-oxide thereof. The compound of formula (I), or a pharmaceutically acceptable salt or N-oxide thereof, may also be included in the pharmaceutical composition by admixture with one or more other therapeutically active compounds.

本發明之藥學組成物包含含有式(I)所示之化合物或其藥學上可接受的鹽或N-氧化物之藥學上可接受的脂質體調合物。The pharmaceutical composition of the present invention comprises a pharmaceutically acceptable liposome blend containing a compound of the formula (I) or a pharmaceutically acceptable salt or N-oxide thereof.

所用之藥學載體可為，例如，固體、液體、或氣體。固態載體的的例子包含乳糖、石膏粉、蔗糖、滑石、明膠、瓊脂、果膠、金合歡膠、硬脂酸鎂、和硬脂酸。液態載體的的例子包含糖漿、花生油、橄欖油、和水。氣態載體的的例子包含二氧化碳和氮氣。The pharmaceutical carrier used can be, for example, a solid, a liquid, or a gas. Examples of solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. Examples of liquid carriers include syrup, peanut oil, olive oil, and water. Examples of gaseous carriers include carbon dioxide and nitrogen.

於製備口服劑型的組成物時，可使用任何適合的藥學介質。例如水、甘醇、油、醇、調味劑、防腐劑、色料等可用於形成口服液體製劑，例如懸浮液、酏劑和溶液；而例如澱粉、糖、微晶纖維素、稀釋劑、粒化劑、潤滑劑、黏合劑、崩散劑等載體可用於形成口服固體製劑單位，例如粉劑、膠囊和錠劑。由於投服的容易性，錠劑和膠囊是 為較合宜的口服劑型，因此使用固態藥學載體。任意地，錠劑可利用標準的水性或非水性技術而加以塗覆。For the preparation of compositions of oral dosage forms, any suitable pharmaceutical medium may be employed. For example, water, glycols, oils, alcohols, flavoring agents, preservatives, colorants and the like can be used to form oral liquid preparations such as suspensions, elixirs and solutions; for example, starch, sugar, microcrystalline cellulose, diluent, granules Carriers such as agents, lubricants, binders, disintegrators and the like can be used to form oral solid preparation units such as powders, capsules and lozenges. Due to the ease of administration, tablets and capsules are For a more convenient oral dosage form, a solid pharmaceutical carrier is therefore used. Optionally, the lozenge can be coated using standard aqueous or non-aqueous techniques.

含有本發明之組成物的錠劑可任意地與一或多種必要的成份或助劑利用壓製或模塑的方法而製備。壓製的錠劑可藉由於適合的機器中將呈自由流動形式(例如粉末或顆粒)的活性成份，任意地與結合劑、潤滑劑、惰性稀釋劑、表面活性劑或分散劑或其他此類的賦形劑混合壓製而獲致。賦形劑可為，例如，惰性稀釋劑例如碳酸鈣、碳酸鈉、乳糖、磷酸鈣或磷酸鈉；造粒劑和崩散劑例如玉米澱粉或藻酸；結合劑例如澱粉、明膠或金合歡膠；及潤滑劑例如硬脂酸鎂、硬脂酸或滑石。錠劑可為未經塗覆的或可利用習知的技術而被塗覆以延遲於胃腸道中的崩散和吸收如此以提供較長時間的持釋作用。例如，可使用時間延遲材料例如甘油單硬脂酸酯或甘油二硬脂酸酯。Tablets containing the compositions of the present invention can be prepared arbitrarily with one or more of the necessary ingredients or adjuvants by compression or molding. The compressed lozenge can be optionally combined with a binder, a lubricant, an inert diluent, a surfactant or a dispersant, or the like, in a suitable machine, in a free-flowing form (for example, a powder or granule). The excipients were mixed and pressed to obtain. The excipient can be, for example, an inert diluent such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; a granulating agent and a disintegrating agent such as corn starch or alginic acid; a binding agent such as starch, gelatin or acacia; And lubricants such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or may be coated by conventional techniques to delay disintegration and absorption in the gastrointestinal tract to provide a sustained release effect for a longer period of time. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed.

於硬明膠膠囊中，活性成份與惰性固態稀釋劑例如碳酸鈣、磷酸鈣或高嶺土混合。於軟明膠膠囊中，活性成份與水或油性介質例如花生油、液態石蠟或橄欖油混合。模塑的錠劑可藉由於適合的機器中模塑經以惰性液態稀釋劑潤濕粉狀化合物而得的混合物而製得。各個錠劑宜含有約0.05 mg至約5g的活性成份，而各個糯米紙藥包(cachet)或膠囊宜含有約0.05 mg至約5g的活性成份。In hard gelatin capsules, the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin. In soft gelatin capsules, the active ingredient is mixed with water or oily vehicles such as peanut oil, liquid paraffin or olive oil. Molded lozenges can be prepared by molding in a suitable machine a mixture obtained by wetting a powdered compound with an inert liquid diluent. Preferably, each lozenge will contain from about 0.05 mg to about 5 g of active ingredient, and each of the wafers or caches will contain from about 0.05 mg to about 5 g of active ingredient.

例如，人類用之口服調合物可含有約0.5 mg至約5g活性劑，以及適當及習用含量之載體物質(而其含量可為總組成物之約5%至約95%)。單位劑型通常含有約1 mg至約2g活性成份，通常為25 mg、50 mg、100 mg、200 mg、300 mg、400 mg、500 mg、600 mg、800 mg或1000 mg。For example, oral compositions for human use may contain from about 0.5 mg to about 5 g of active agent, as well as suitable and conventional amounts of carrier materials (which may range from about 5% to about 95% of the total composition). Unit dosage form usually contains about 1 From mg to about 2 g of active ingredient, usually 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg or 1000 mg.

適合於胃腸外投服之本發明的藥學組成物可於水中製成活性化合物的溶液或懸浮液的形式。可使用適合的表面活性劑，例如羥丙基纖維素。亦可於甘油、液態聚乙二醇及其於油中所形成的混合物中製成分散液。此外，可使用防腐劑以防止有害的微生物生長。The pharmaceutical compositions of the present invention which are suitable for parenteral administration can be prepared in the form of a solution or suspension of the active compound in water. A suitable surfactant such as hydroxypropylcellulose can be used. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof formed in oils. In addition, preservatives can be used to prevent the growth of harmful microorganisms.

適合於注射之本發明的藥學組成物包含無菌水溶液或分散液。此外，組成物可呈供臨時製備此無菌注射水溶液或分散液用之無菌粉末的形式。所有的情況中，最後的注射形式必須是無菌的且必須具有效的流動性而得以輕易地注射。藥學組成物在製備和貯存的條件下必須是安定的，因此，宜防腐以對抗微生物(例如細菌和黴菌)的污染作用。載體可為含有例如水、乙醇、多元醇(例如甘油、丙二醇和液態聚乙二醇)、植物油及其適合的混合物之溶劑或分散介質。Pharmaceutical compositions of the invention suitable for injection comprise sterile aqueous solutions or dispersions. Further, the composition may be in the form of a sterile powder for the temporary preparation of such a sterile injectable aqueous solution or dispersion. In all cases, the final form of injection must be sterile and must have effective fluidity for easy injection. The pharmaceutical composition must be stable under the conditions of manufacture and storage and, therefore, should be preserved against the contaminating action of microorganisms such as bacteria and mold. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol), vegetable oil, and suitable mixtures thereof.

本發明之藥學組成物可呈適合局部投服之形式，例如氣溶膠、乳霜、軟膏、乳液、撒粉等。此外，組成物可呈適用於經皮投服的裝置之形式。上述調合物可由式(I)所示之化合物，或其藥學上可接受之鹽或N-氧化物，藉由習知的加工方法而製得。例如，乳霜或軟膏之製法係將親水性物質和水與約5 wt%至約10 wt%化合物混合而製成具有所欲的黏度之乳霜或軟膏。The pharmaceutical composition of the present invention may be in a form suitable for topical administration, such as an aerosol, a cream, an ointment, an emulsion, a dusting or the like. Furthermore, the composition may be in the form of a device suitable for percutaneous administration. The above-mentioned complex can be obtained by a known method from the compound of the formula (I), or a pharmaceutically acceptable salt or N-oxide thereof. For example, a cream or ointment is prepared by mixing a hydrophilic material and water with from about 5 wt% to about 10 wt% of the compound to form a cream or ointment having a desired viscosity.

本發明之藥學組成物可呈適合經直腸投服之形式，其中載體是固體。混合物宜形成單位劑型的栓劑。適合的載體包含椰子油及其他先前技藝中習用的物質。栓劑可藉由先混合組成物與軟化或熔化的載體及繼之於模子中冷卻和模塑而輕易製得。The pharmaceutical compositions of the present invention may be in a form suitable for rectal administration wherein the carrier is a solid. The mixture preferably forms a suppository in unit dosage form. Suitable carriers include coconut oil and other materials conventionally used in the art. Suppositories can be readily prepared by first mixing the composition with a softened or molten carrier and subsequently cooling and molding in a mold.

本發明之藥學組成物可呈適合吸入投服之形式。此類投服可為多種形式及利用下列文獻所揭示之載體：例如，1)Particulate Interaction in Dry Powder Formulation for Inhalation,Xian Zheng et al,2000,Taylor and Francis,2)Pharmaceutical Inhalation Aerosol Technology,Anthony Hickey,1992,Marcel Dekker,3)Respiratory Drug Delivery,1990,Editor：P.R.Byron,CRC Press。The pharmaceutical composition of the present invention may be in a form suitable for inhalation. Such administration may be in a variety of forms and utilizes the carriers disclosed in the following documents: for example, 1) Particulate Interaction in Dry Powder Formulation for Inhalation, Xian Zheng et al, 2000, Taylor and Francis, 2) Pharmaceutical Inhalation Aerosol Technology, Anthony Hickey , 1992, Marcel Dekker, 3) Respiratory Drug Delivery, 1990, Editor: PRByron, CRC Press.

除了上述的載體成份之外，上述的藥學組成物適當的話可包含例如一或多種其他的載體成份例如稀釋劑、緩衝劑、調味劑、黏合劑、表面活性劑、增稠劑、潤滑劑、防腐劑(包含抗氧化劑)等。此外，可含有其他的助劑以使調合物與待治療對象的血液等滲透壓。含有式(I)所示之化合物或其藥學上可接受之鹽或N-氧化物之藥學組成物亦可製成粉末或濃縮液的形式。In addition to the above carrier components, the above pharmaceutical compositions may contain, for example, one or more other carrier ingredients such as diluents, buffers, flavoring agents, binders, surfactants, thickeners, lubricants, and preservatives. Agent (including antioxidants) and the like. In addition, other auxiliaries may be included to make the osmotic pressure of the conjugate and the blood of the subject to be treated. The pharmaceutical composition containing the compound of the formula (I) or a pharmaceutically acceptable salt or N-oxide thereof may also be in the form of a powder or a concentrate.

通常，每天約0.01 mg/公斤體重至約150 mg/公斤體重之劑量範圍(或者是每位患者每天約0.5 mg至約10g的劑量)可用於治療上述病狀。例如，每天每公斤體重約0.01 mg至100 mg化合物(或者是每位患者每天約0.5 mg至7g的劑量)可用於治療糖尿病。Generally, a dosage range of from about 0.01 mg/kg body weight to about 150 mg/kg body weight per day (or a dose of from about 0.5 mg to about 10 g per patient per day) can be used to treat the above conditions. For example, about 0.01 mg to 100 mg of compound per kilogram of body weight per day (or about 0.5 per patient per day) A dose of mg to 7 g) can be used to treat diabetes.

然而，須明白的是，特定患者的特殊劑量決定於各種因素，包含進行治療之特定糖尿病患者的年齡、體重、一般健康狀況、姓別、飲食、投服時間、投服途徑、***速率、藥物組合和疾病的嚴重程度。此外，須明白的是，於預防高血糖症的情況，本發明之化合物及其鹽或N-氧化物可以在低於治療劑量的情況下預防性地投服。However, it should be understood that the specific dosage of a particular patient depends on various factors, including the age, weight, general health, surname, diet, time of administration, route of administration, rate of excretion, drug, of the particular diabetic patient being treated. Combination and severity of the disease. Furthermore, it is to be understood that in the case of prevention of hyperglycemia, the compounds of the invention and their salts or N-oxides can be administered prophylactically below the therapeutic dose.

在糖尿病領域中已知：容易發展成糖尿病的人通常患有葡萄糖耐受不良或高血糖症。因此，本發明之化合物或其藥學上可接受之鹽或N-氧化物可投服預防性劑量以防止糖尿病的發生。是故，本發明包含一種用於預防高血糖症之方法，其包含投服有效量之本發明之化合物或其藥學上可接受之鹽或N-氧化物，以及一種用於預防患有糖尿病前期性高血糖症或葡萄糖耐受不良之人類的糖尿病之方法，其包含投服預防有效量之本發明之化合物或其藥學上可接受之鹽或N-氧化物。It is known in the field of diabetes that people who are prone to develop diabetes usually have glucose intolerance or hyperglycemia. Thus, a compound of the invention, or a pharmaceutically acceptable salt or N-oxide thereof, can be administered in a prophylactic dose to prevent the onset of diabetes. Accordingly, the present invention comprises a method for preventing hyperglycemia comprising administering an effective amount of a compound of the present invention or a pharmaceutically acceptable salt or N-oxide thereof, and a method for preventing pre-diabetes A method of diabetes in a human with hyperglycemia or glucose intolerance comprising administering a prophylactically effective amount of a compound of the invention, or a pharmaceutically acceptable salt or N-oxide thereof.

與已知的GK活化劑相比較，式(I)所示之化合物可展現有利的性質。The compound of formula (I) can exhibit advantageous properties as compared to known GK activators.

實驗部份Experimental part

根據本發明，式(Ia)所示之α,β-未飽和烯醯胺化合物可由下列反應圖1所示之流程製備： 其中：A1 -A5 、Q、T、R1 -R4 、m和△係如上所定義；R11 是C1-4 烷基；及X1 和X2 各自獨立地為溴或碘。According to the present invention, the α,β-unsaturated olefinamide compound represented by the formula (Ia) can be produced by the following reaction scheme shown in Figure 1: Wherein: A 1 -A 5 , Q, T, R 1 -R 4 , m and Δ are as defined above; R 11 is C 1-4 alkyl; and X 1 and X 2 are each independently bromine or iodine.

2-鹵基丙烯酸酯II係由有機銅化合物與丙炔酸的低級烷酯之反應所得的syn加成產物之鹵化反應而立即獲致(R.Rossi et al.,J Organomet.Chem.,1993,451,33-43)。鹵化的雜芳族物質III可由市面購得或利用習知的合成步驟而立即製得(參見，例如，R.N.guthikonda & F.P.DiNinno,US 5,409,920；X.Wang et al.,Tetrahedron Lett.,2000,41,4335-4338)。化合物II與活化的鋅反應以產生烯基鋅物質，其接著與鹵化物III在鉑(0)源的存在下於適合的溶劑(例如四氫呋喃)中在約40℃下進行交叉偶合反應(WO 01/44216)。所得的(E)-烯酸酯以例如氫氧化鈉於水性甲醇中在20℃至回流的溫度下進行皂化反應而得(E)-α,β-未飽和羧酸IV。2-halo acrylate II is obtained immediately by the halogenation reaction of a syn addition product obtained by the reaction of an organic copper compound with a lower alkyl ester of propiolic acid (R. Rossi et al., J Organomet. Chem., 1993, 451, 33-43). The halogenated heteroaromatic material III can be obtained commercially or immediately using conventional synthetic procedures (see, for example, RN Guthikonda & FP DiNinno, US 5,409,920; X. Wang et al., Tetrahedron Lett., 2000, 41). , 4335-4338). Compound II reacts with activated zinc to produce an ethylenyl zinc species, which is then cross-coupled with a halide III in the presence of a platinum (0) source in a suitable solvent (eg, tetrahydrofuran) at about 40 ° C (WO 01) /44216). The obtained (E)-enoic acid ester is subjected to a saponification reaction at, for example, sodium hydroxide in aqueous methanol at a temperature of from 20 ° C to reflux to obtain (E)-α,β-unsaturated carboxylic acid IV.

α,β-未飽和羧酸IV可與雜芳族胺V(許多是可購買 得到)利用各種偶合條件進行縮合而得到(Ia)，其中該縮合條件是例如經聚合物支撐的碳化二亞胺-1-羥基苯並***於N,N-二甲基甲醯胺在20℃下(代表性步驟請參見http：//www.argotech.com/PDF/resins/ps_carbodiimide.pdf及可由Argonaut Technologies,Inc.,Foster City,Califonia購買得到)。α,β-unsaturated carboxylic acid IV can be mixed with heteroaromatic amine V (many are commercially available Obtaining) (Ia) by condensation using various coupling conditions, wherein the condensation conditions are, for example, polymer supported carbodiimide-1-hydroxybenzotriazole to N,N-dimethylformamide at 20 At °C (for representative steps please see http://www.argotech.com/PDF/resins/ps_carbodiimide.pdf and available from Argonaut Technologies, Inc., Foster City, Califonia).

式(Ib)所示之飽和醯胺化合物可由下列反應圖2所示之流程製備： 其中：A1 -A5 、Q、T、R1 -R4 和m係如上所定義；V是CO2 R11 、CO2 CH2 Ph、或CN；及X3 是氯、溴、碘、或OSO2 R12 ；其中R11 係如上所定義，及R12 是C1-4 烷基，任意地經一或多個氟所取代，或是任意取代的芳基。The saturated guanamine compound of the formula (Ib) can be prepared by the following reaction scheme shown in Figure 2: Wherein: A 1 -A 5 , Q, T, R 1 -R 4 and m are as defined above; V is CO 2 R 11 , CO 2 CH 2 Ph, or CN; and X 3 is chlorine, bromine, iodine, Or OSO 2 R 12 ; wherein R 11 is as defined above, and R 12 is C 1-4 alkyl, optionally substituted by one or more fluorines, or an optionally substituted aryl.

鹵化物和磺酸酯VI可由市面購得或利用習知的合成步驟而立即製得。上述烷化劑可與乙酸酯或乙腈VII之α- 碳陰離子(在-78℃下於四氫呋喃中利用強鹼(例如三異丙基胺化鋰)而產生(WO 00/58293))反應而得到α-取代的酯和腈。羧酸VIII可藉由以例如氫氧化鈉於水性甲醇中在20℃至回流的溫度下皂化α-取代的酯及以例如水性硫酸在高溫下水解α-取代的腈而製得(R.Adams and A.F.Thal,Org.Synth.Coll.Vol.1,436)。Halides and sulfonate VIs are commercially available or can be prepared immediately using conventional synthetic procedures. The above alkylating agent can be combined with acetate or acetonitrile VII. The carbon anion (produced by a strong base (e.g., lithium triisopropylamide) in tetrahydrofuran (WO 00/58293) is reacted at -78 ° C to give an α-substituted ester and a nitrile. Carboxylic acid VIII can be obtained by saponifying an α-substituted ester with, for example, sodium hydroxide in aqueous methanol at a temperature of from 20 ° C to reflux and hydrolyzing an α-substituted nitrile at a high temperature, for example, aqueous sulfuric acid (R. Adams). And AFThal, Org. Synth. Coll. Vol. 1, 436).

羧酸VIII可與雜芳族胺V(許多是可購買得到)利用各種偶合條件進行縮合而得(Ib)，其中該縮合條件是例如四氟硼酸O-(1H-苯並***-1-基)-N,N,N’,N’-四甲脲鎓於N,N-二甲基甲醯胺在20℃下(R.Knorr et al.,Tetrahedron Lett.1989,30,1927-1930)。Carboxylic acid VIII can be condensed with heteroaromatic amine V (many commercially available) using various coupling conditions to give (Ib), wherein the condensation conditions are, for example, tetrafluoroboric acid O-(1H-benzotriazole-1- -N,N,N',N'-tetramethyluronium in N,N-dimethylformamide at 20 ° C (R. Knorr et al., Tetrahedron Lett. 1989, 30, 1927-1930 ).

式(Ib)所示之化合物具有不對稱的碳原子(連結醯胺羰基碳原子、芳環和含Q的側鏈)。根據本發明，不對稱中心之較佳的立體構型是(R)。The compound of the formula (Ib) has an asymmetric carbon atom (bonding a guanamine carbonyl carbon atom, an aromatic ring and a Q-containing side chain). According to the invention, the preferred stereo configuration of the asymmetric center is (R).

如果要單離出式(Ib)所示之化合物之純質的(R)-或(S)-立體異構物，可以利用傳統的化學方法解析對掌性羧酸前驅物VIII之外消旋混合物及繼之使用僅引起可忽略的外消旋化反應的試劑以縮合鏡像純質的羧酸與式V所示之胺。舉例說明，外消旋的VIII可與對掌性噁唑烷酮衍生物縮合(參見，例如，F.T.Bizzarro et al.WO 00/58293)以產生非鏡像異構的醯亞胺的混合物，而其可利用傳統的方法而分離例如管柱層析。純質醯亞胺的水解得到立體純質的(R)-和(S)-羧酸，而其可接著與雜環胺V使用可使對掌中心的外消旋化作用降至最低程度的 試劑(例如六氟磷酸苯並***-1-基氧基三(吡咯烷基)鏻(J.Coste et al.Tetrahedron Lett.1990,31,205-208))而進行縮合反應而得到式(Ib)所示之鏡像純質的(R)-或(S)-醯胺。或者，式(Ib)所示之醯胺的外消旋混合物可藉由對掌性高效能液相層析使用對掌性固相而單離，其中該掌性固相可購自，例如，Daicel Chemical Industries,Ltd,Tokyo,Japan。製備式(I)所示之化合物的其他細節請參見實施例。If the pure (R)- or (S)-stereoisomer of the compound of formula (Ib) is to be isolated, the conventional chemical method can be used to resolve the racemization of the palmitic carboxylic acid precursor VIII. The mixture and subsequent use of an agent which causes only a negligible racemization reaction condenses the mirror image of the pure carboxylic acid with the amine of formula V. By way of example, racemic VIII can be condensed with a palmitic oxazolidinone derivative (see, for example, FT Bizzarro et al. WO 00/58293) to produce a mixture of non-image mirror isomers, while Conventional methods can be used to separate, for example, column chromatography. Hydrolysis of the pure quinone imine gives stereoscopically pure (R)- and (S)-carboxylic acids, which can then be used with heterocyclic amines V to minimize racemization of the palm center. A reagent (for example, benzotriazol-1-yloxytris(pyrrolidinyl)phosphonium hexafluorophosphate (J. Coste et al. Tetrahedron Lett. 1990, 31, 205-208) is subjected to a condensation reaction to give a formula (Ib) Mirrored pure (R)- or (S)-guanamine shown. Alternatively, the racemic mixture of the guanamine of the formula (Ib) can be isolated by using a palmitic solid phase for palm-type high performance liquid chromatography, wherein the palm solid phase can be purchased, for example, Daicel Chemical Industries, Ltd, Tokyo, Japan. Further details of the preparation of the compounds of formula (I) can be found in the examples.

式(I)所示之化合物可單獨製備，或以含有至少2個，例如5至100個，更宜是10至100個，式(I)所示之化合物的化合物庫(compound libraries)的形式製備。化合物庫(compound libraries)可藉由組合式“分開和混合(split and mix)”途徑或利用多重平行合成法利用溶液或固相化學使用熟悉此項技術人士所習知的步驟而製得。The compound of formula (I) may be prepared separately or in the form of a compound library containing at least 2, for example 5 to 100, more preferably 10 to 100, compounds of formula (I). preparation. Compound libraries can be made by a combined "split and mix" route or by multiple parallel synthesis using solution or solid phase chemistry using procedures well known to those skilled in the art.

在合成式(I)所示之化合物的期間，中間化合物的不安定官能基，例如羥基、羧基和胺基，可加以保護。保護基可在式(I)所示之化合物之合成過程中的任何階段加以除去或者存在於最終之式(I)所示的化合物上。各種不安定官能基的保護和裂除所得之經保護的衍生物的方法之討論詳見於，例如，Protectivegroups in Organic Chemistry,T.W.greene and P.g.M.Wuts,(1991)Wiley-Interscience,New York,2nd edition。During the synthesis of the compound of formula (I), the labile functional groups of the intermediate compound, such as hydroxyl, carboxyl and amine groups, may be protected. The protecting group can be removed at any stage in the synthesis of the compound of formula (I) or present on the final compound of formula (I). A discussion of methods for the protection of various unstable functional groups and the removal of the resulting protected derivatives is described, for example, in Protective Groups in Organic Chemistry, TW Greene and Pg MWuts, (1991) Wiley-Interscience, New York, 2nd edition.

如上所定義的新穎中間物亦包含在本發明的範圍內。Novel intermediates as defined above are also included within the scope of the invention.

於本發明之另一態樣中，本發明亦提供一種式(IV)所示之化合物： 其中A1 -A5 、Q、R1 、R2 、m和△係如如式(I)所定義。In another aspect of the invention, the invention also provides a compound of formula (IV): Wherein A 1 -A 5 , Q, R 1 , R 2 , m and Δ are as defined in formula (I).

於本發明之另一態樣中，本發明亦提供一種式(VIII)所示之化合物： 其中A1 -A5 、Q、R1 、R2 和m係如如式(I)所定義。In another aspect of the invention, the invention also provides a compound of formula (VIII): Wherein A 1 -A 5 , Q, R 1 , R 2 and m are as defined in formula (I).

式(IV)和(VIII)所示之化合物中之各種取代基的較佳範圍是如式(I)所示之化合物中所定義者。A preferred range of the various substituents in the compounds of the formulae (IV) and (VIII) is as defined in the compound of the formula (I).

式(IV)和(VIII)所示之特定化合物包含製備例中所例示者。The specific compounds represented by the formulae (IV) and (VIII) are exemplified in the preparation examples.

本案說明書所引用之所有的文獻，包含(但不限於)專利和專利申請案，均併入本文以為參考，如同各個文獻是詳細且各自地被指明其內容全部併入本文以併參考。All documents cited in the present specification, including but not limited to, the patents and patent applications, are hereby incorporated by reference in their entirety in their entireties in the the the the theties

材料和方法Materials and Method

微波反應係於CEM Explorer system在100W下進行。管柱層析係於SiO2 (40-63篩孔)上進行。LCMS數據係藉由使用下列二種方法之一而獲致：方法A：Waters Symmetry 3.5μ C18 管柱(2.1 x 30.0 mm，流速=0.8mL min-1 )，洗提液：含0.1% HCO2 H之(5% MeCN/H2 O)-MeCN溶液，時間6分鐘及在220 nm下以UV檢測。梯度資訊：0.0-1.2分鐘：100%(5% MeCN/H2 O)；1.2-3.8分鐘：升至10%(5% MeCN/H2 O)-90% MeCN；3.8-4.4分鐘：維持在10%(5% MeCN/H2 O)-90% MeCN；4.4-5.5分鐘：升至100% MeCN；5.5-6.0分鐘：回至100%(5% MeCN/H2 O)。方法B：Phenomenex Mercury Luna 3μ C18 管柱(2.0 x 10.0 mm，流速=1.5mL/min)，洗提液：含0.1% HCO2 H之(5% MeCN/H2 O)-MeCN溶液(4：1-1：4)，時間2.95分鐘及使用二極體陣列檢測器。方法A和B之質譜係由電噴灑離子源以正離子(ES+ )或負離子(ES- )模式獲致。常壓化學離子化(APCI)光譜係由FinniganMat SSQ 7000C儀器測得。下列化合物的合成已經被報導過：(5-溴-2-吡啶基)亞胺二碳酸雙(第三丁基)酯：D.J.P.Pinto et al.,US 6,020,357；5-溴-2,3-二氯吡啶：EP 0136593；5-溴-2-乙硫基吡啶：WO 01/44243；2-溴-5-甲硫基吡啶：WO 01/64669；5-溴-2-甲硫基吡啶：X.Wang et al.,Tetrahedron Lett.2000,41,4335-4338；N-(5-溴吡啶-2-基)乙醯胺：M.Sollogoub et al.,Tetrahedron Lett.2002,43,3121-3123；5-溴-2-〔1,2,4〕***-1-基吡啶：WO 01/94342；(5-溴吡啶-2-基)甲基胺基甲酸第三丁酯：WO 99/30709；(6-氯吡啶-3-基)乙腈：WO 01/83475；碘化環戊甲基三苯基鏻：WO 01/44216；二環戊基二硫醚：E.Block et al.,J.Am.Chem.Soc.1992,114,3492-3499；(Z)-3-環戊基-2-碘丙烯酸甲酯：WO 01/44216。The microwave reaction was carried out at 100 W in a CEM Explorer system. Column chromatography was performed on SiO 2 (40-63 mesh). LCMS data was obtained by using one of two methods: Method A: Waters Symmetry 3.5 μ C 18 column (2.1 x 30.0 mm, flow rate = 0.8 mL min -1 ), eluent: 0.1% HCO 2 H (5% MeCN/H 2 O)-MeCN solution was detected by UV at 6 min and at 220 nm. Gradient information: 0.0-1.2 minutes: 100% (5% MeCN/H 2 O); 1.2-3.8 minutes: rise to 10% (5% MeCN/H 2 O)-90% MeCN; 3.8-4.4 minutes: maintained at 10% (5% MeCN/H 2 O)-90% MeCN; 4.4-5.5 min: rose to 100% MeCN; 5.5-6.0 min: back to 100% (5% MeCN/H 2 O). Method B: Phenomenex Mercury Luna 3μ C 18 column (2.0 x 10.0 mm, flow rate = 1.5 mL/min), eluent: (5% MeCN/H 2 O)-MeCN solution containing 0.1% HCO 2 H (4 :1-1:4), time 2.95 minutes and use a diode array detector. The mass spectra of methods A and B were obtained from an electrospray ion source in a positive ion (ES + ) or negative ion (ES - ) mode. Atmospheric pressure chemical ionization (APCI) spectroscopy was measured on a Finnigan Mat SSQ 7000C instrument. The synthesis of the following compounds has been reported: (5-bromo-2-pyridyl) imine di(tert-butyl) dicarbonate: DJPPinto et al., US 6,020,357; 5-bromo-2,3-dichloro Pyridine: EP 0136593; 5-bromo-2-ethylthiopyridine: WO 01/44243; 2-bromo-5-methylthiopyridine: WO 01/64669; 5-bromo-2-methylthiopyridine: X. Wang et al., Tetrahedron Lett. 2000, 41, 4335-4338; N-(5-bromopyridin-2-yl)acetamide: M. Sollogoub et al., Tetrahedron Lett. 2002, 43, 3121-3123; 5-bromo-2-[1,2,4]triazol-1-ylpyridine: WO 01/94342; (5-bromopyridin-2-yl)methylaminocarbamic acid tert-butyl ester: WO 99/30709 (6-chloropyridin-3-yl)acetonitrile: WO 01/83475; cyclopentylmethyltriphenylphosphonium iodide: WO 01/44216; dicyclopentyl disulfide: E. Block et al., J .Am. Chem. Soc. 1992, 114, 3492-3499; (Z) methyl 3-cyclopentyl-2-iodoacrylate: WO 01/44216.

縮寫和頭字語：Ac：乙醯基；ATP：腺苷5’-三磷酸；BINAP：2,2’-雙(二苯膦基)-1,1’-聯萘；n-Bu：正丁基；dba：二亞苄基丙酮；DBE：1,2-二溴乙烷；DMF：N,N-二甲基甲醯胺；DMSO：二甲亞碸；EDCI：1-(3-二甲胺基丙基)-3-乙基碳化二亞胺氫氯酸鹽；Et：乙基；FA：活化倍數；GK：葡萄糖激酶；Glc：葡萄糖；G6P：葡萄糖-6-磷酸酯；G6PDH：葡萄糖-6-磷酸酯脫氫酶；GST-GK：穀胱苷肽S-轉移酶-葡萄糖激酶融合蛋白；HMPA：六甲基磷醯胺；HOBt：1-羥基苯並***；IH：異己烷；KHMDS：雙(三甲基甲矽烷基)胺化鉀；LDA：二異丙基胺化鋰；LHMDS：雙(三甲基甲矽烷基)胺化鋰；mCPBA：3-氯過苯甲酸；Me：甲基；Ms：甲磺醯基；NADP(H)：β-菸醯胺腺嘌呤二核苷酸磷酸酯(還原的)；Ph：苯基；n-Pr：正丙基；PS：經聚合物支撐的； RP-HPLC：逆相高效能液相層析法；RT：遲滯時間；RTA ：方法A之遲滯時間；RTB ：方法B之遲滯時間；TBTU：四氟硼酸O-(1H-苯並***-1-基)-N,N,N’,N’-四甲脲鎓；Tf：三氟甲磺醯基；TFA：三氟醋酸；TFAA：三氟醋酸酐；THF：四氫呋喃；TMSCl：氯三甲基甲矽烷。Abbreviations and initial words: Ac: acetamidine; ATP: adenosine 5'-triphosphate; BINAP: 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl; n-Bu: n-butyl Dba: dibenzylideneacetone; DBE: 1,2-dibromoethane; DMF: N,N-dimethylformamide; DMSO: dimethyl hydrazine; EDCI: 1-(3-dimethyl Aminopropyl)-3-ethylcarbodiimide hydrochloride; Et: ethyl; FA: activation multiple; GK: glucokinase; Glc: glucose; G6P: glucose-6-phosphate; G6PDH: glucose -6-phosphate dehydrogenase; GST-GK: glutathione S-transferase-glucose kinase fusion protein; HMPA: hexamethylphosphonium; HOBt: 1-hydroxybenzotriazole; IH: isohexane KHMDS: bis(trimethylmethane alkyl) potassium amide; LDA: lithium diisopropylamide; LHMDS: lithium bis(trimethylmethyl decyl) amination; mCPBA: 3-chloroperbenzoic acid; Me: methyl; Ms: methanesulfonyl; NADP (H): β-nicotamine adenine dinucleotide phosphate (reduced); Ph: phenyl; n-Pr: n-propyl; PS: Polymer supported; RP-HPLC: reverse phase high performance liquid chromatography; RT: hysteresis time; RT A : method A hysteresis time; RT B : hysteresis time of method B; TBTU: O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; Tf: trifluoromethanesulfonate TFA: trifluoroacetic acid; TFAA: trifluoroacetic anhydride; THF: tetrahydrofuran; TMSCl: chlorotrimethylmethane.

製備例1：2-(6-氯吡啶-3-基)-3-環戊基丙酸Preparation Example 1: 2-(6-chloropyridin-3-yl)-3-cyclopentylpropionic acid

步驟1：在-78℃下，KHMDS(30.9mL之1mmolmL-1 的THF溶液，30.9mmol)加至攪拌中之由(6-氯吡啶-3-基)乙腈(4.40g,28.9mmol)於無水THF-HMPA(3：1,72mL)所形成的溶液中。30分鐘後，加入碘甲基環戊烷(1.46g,6.9mmol)。溶液在-78℃下攪拌4.5小時，接著使升溫至20℃，歷時16小時。於反應混合物中小心地加入飽和NH4 Cl水溶液(20mL)以使反應驟停，接著加入H2 O(100mL)。混合物經EtOAc萃取(3 x 50mL)，接著乾燥(Na2 SO4 )萃取液。過濾、蒸發溶劑和管柱層析(n-C6 H14 -EtOAc)得2-(6-氯吡啶-3-基)-3-環戊基丙腈：m/z(ES+ )=235.1〔M+H〕+ 。步驟2：所得化合物(2.30g,9.8mmol)與50% H2 SO4 水溶液(10mL)在130℃下攪拌加熱2小時。使混合物冷卻至20℃，歷時16小時，接著以飽和Na2 CO3 水溶液中和 及以CHCl3 萃取。有機萃取液經乾燥(Na2 SO4 )後，過濾及濃縮得標題化合物：m/z(ES+ )=254.2〔M+H〕+ 。Step 1: At -78 ° C, KHMDS (30.9 mL of 1 mmol mL -1 in THF, 30.9 mmol) was added to (6-chloropyridin-3-yl)acetonitrile (4.40 g, 28.9 mmol) THF-HMPA (3:1, 72 mL) in a solution formed. After 30 minutes, iodomethylcyclopentane (1.46 g, 6.9 mmol) was added. The solution was stirred at -78 °C for 4.5 hours and then allowed to warm to 20 °C for 16 hours. The reaction mixture was carefully added to a saturated aqueous solution of NH 4 Cl (20mL) to the reaction quenched, followed by H 2 O (100mL). The mixture was extracted with EtOAc (3 x 50mL) was followed by drying (Na 2 SO 4) extract. Filtered and the solvent was evaporated and column chromatography (nC 6 H 14 -EtOAc) to give 2- (6-chloro-3-yl) -3-cyclopentyl-propionitrile: m / z (ES +) = 235.1 [M +H〕 + . Step 2: The obtained compound (2.30 g, 9.8 mmol) and 50% H 2 SO 4 aqueous solution (10 mL) were stirred and heated at 130 ° C for 2 hours. The mixture was cooled to 20 ℃, for 16 hours followed by saturated aqueous Na 2 CO 3 and and extracted with CHCl 3. The organic extract was dried (Na 2 SO 4), filtered and concentrated to give the title compound: m / z (ES +) = 254.2 [M + H] +.

製備例2：3-環戊基-2-吡啶-3-基丙酸Preparation 2: 3-Cyclopentyl-2-pyridin-3-ylpropionic acid

步驟1：在-78℃下，LDA(5.1mL之1.5mmolmL-1 的c-C6 H12 溶液，7.6mmol)加至攪拌中之由3-吡啶基乙酸乙酯(1.15g,6.9mmol)於無水THF-HMPA(3：1,260mL)所形成的溶液中。30分鐘後，加入碘甲基環戊烷(1.46g,6.9mmol)。溶液在-78℃下繼續攪拌4.5小時。使混合物升溫至20℃，接著攪拌16小時。於反應混合物中小心地加入飽和NH4 Cl水溶液(20mL)以使反應驟停，接著加入H2 O(100mL)。混合物經EtOAc萃取(3 x 50mL)，接著乾燥(Na2 SO4 )萃取液。過濾、蒸發溶劑和管柱層析(n-C6 H14 -EtOAc)得3-環戊基-2-吡啶-3-基丙酸乙酯：m/z(ES+ )=248.3〔M+H〕+ 。步驟2：所得化合物(0.73g,3.0mmol)於THF(3mL)所形成的溶液在攪拌的情況下經2 M NaOH(3mL,6.0mmol)處理。在20℃下16小時後，在低壓下除去有機溶劑，接著調整殘餘溶液至pH 6.5，之後以EtOAc萃取。EtOAc萃取液經乾燥(Na2 SO4 )、過濾和濃縮後得標題化合物：m/z( ES+ )=220.2〔M+H〕+ 。Step 1: To a -78 ℃, LDA (cC 5.1mL of 1.5mmolmL -1 6 H 12 the solution, 7.6mmol) was added to a stirred solution of ethyl 3-pyridyl (1.15g, 6.9mmol) in dry THF-HMPA (3:1, 260 mL) in a solution formed. After 30 minutes, iodomethylcyclopentane (1.46 g, 6.9 mmol) was added. The solution was stirred at -78 ° C for an additional 4.5 hours. The mixture was allowed to warm to 20 ° C and then stirred for 16 hours. The reaction mixture was carefully added to a saturated aqueous solution of NH 4 Cl (20mL) to the reaction quenched, followed by H 2 O (100mL). The mixture was extracted with EtOAc (3 x 50mL) was followed by drying (Na 2 SO 4) extract. Filtered and the solvent was evaporated and column chromatography (nC 6 H 14 -EtOAc) to give 3-cyclopentyl-2-pyridin-3-yl propionate: m / z (ES +) = 248.3 [M + H] + . Step 2: A solution of EtOAc (3 mL, EtOAc. After 16 hours at 20 ° C, the organic solvent was removed at low pressure, then the residual solution was adjusted to pH 6.5 then extracted with EtOAc. The EtOAc extract was dried (Na 2 SO 4), filtered, and concentrated to give the title compound: m / z (ES +) = 220.2 [M + H] +.

製備例3：(E)-3-環戊基-2-(6-甲硫基吡啶-3-基)丙烯酸Preparation 3: (E)-3-Cyclopentyl-2-(6-methylthiopyridin-3-yl)acrylic acid

步驟1：DBE(345 μL,4.0mmol)加至由Zn粉(2.62g,40.0mmol)於無水THF(4mL)所形成的懸浮液中。加熱混合物至沸騰，接著使之冷卻至20℃。重覆此步驟三次，接著在20℃下攪拌混合物2小時，接著以TMSCl(380 μL,3.0mmol)處理。繼續攪拌1.5小時，接著加入由(Z)-3-環戊基-2-碘丙烯酸甲酯(2.52g,9.0mmol)於無水THF(8mL)所形成的溶液中，歷時3分鐘。混合物在40℃下攪拌2小時，接著在20℃下攪拌16小時，最後靜置4小時。於另一個反應容器中，PPh3 (315 mg,1.2mmol)和Pd2 (dba)3 (150 mg,0.5mmol)於無水THF(15mL)所形成的溶液在20℃下攪拌2小時，接著以由5-溴-2-甲硫基吡啶(2.76g,13.5mmol)於無水THF(10mL)所形成的溶液處理。接著利用插管加入新鮮製備的有機鋅化合物的溶液，混合物在40℃下攪拌68小時。蒸發溶劑和管柱層析(4：1,IH-Et2 O)得3-環戊基-2-(6-甲硫基吡啶-3-基)丙烯酸甲酯：m/z(ES+ )=278.1〔M+H〕+ 。步驟2：所得化合物( 1.12g,4.0mmol)於MeOH(5.5mL)所形成的溶液經1 M NaOH(8.9mL,8.9mmol)處理。混合物在65℃下攪拌3小時，接著在20℃下攪拌16小時。在低壓下除去MeOH，接著加入H2 O(10mL)和1 M NaOH(10mL)。所得之混合物經Et2 O(25mL)沖洗，接著以2 M HCl酸化以調節至pH 1。所得之懸浮液經EtOAc萃取(2 x 50mL)，接著萃取液經鹽水(20mL)沖洗，及乾燥(MgSO4 )。過濾、蒸發溶劑和再結晶(EtOAc-IH)得標題化合物：m/z(ES+ )=264.1〔M+H〕+ 。Step 1: DBE (345 μL, 4.0 mmol) was added to a suspension of Zn powder (2.62 g, 40.0 mmol) in anhydrous THF (4 mL). The mixture was heated to boiling and then allowed to cool to 20 °C. This step was repeated three times, then the mixture was stirred at 20 ° C for 2 hours, then treated with TMSCl (380 μL, 3.0 mmol). Stirring was continued for 1.5 hours, then a solution of methyl (Z)-3-cyclopentyl-2-iodoacrylate (2.52 g, 9.0 mmol) in dry THF (8 mL) The mixture was stirred at 40 ° C for 2 hours, then at 20 ° C for 16 hours and finally allowed to stand for 4 hours. In a separate reaction vessel, a solution of PPh 3 (315 mg, 1.2 mmol) and Pd 2 (dba) 3 (150 mg, 0.5 mmol) in anhydrous THF (15 mL) was stirred at 20 ° C for 2 h then Treatment with a solution of 5-bromo-2-methylthiopyridine (2.76 g, 13.5 mmol) in dry THF (10 mL). A freshly prepared solution of the organozinc compound was then added using a cannula, and the mixture was stirred at 40 ° C for 68 hours. Evaporation of solvent and column chromatography (4:1, IH-Et 2 O) gave methyl 3-cyclopentyl-2-(6-methylthiopyridin-3-yl)acrylate: m/z (ES + ) =278.1[M+H] + . Step 2: A solution of EtOAc (EtOAc, EtOAc. The mixture was stirred at 65 ° C for 3 hours and then at 20 ° C for 16 hours. Under low pressure to remove MeOH, followed by H 2 O (10mL) and 1 M NaOH (10mL). The resulting mixture (25mL) rinsed Et 2 O, followed by 2 M HCl to adjust acidified to pH 1. The resulting suspension was extracted with EtOAc sum (2 x 50mL), followed by extraction with brine solution (20mL) rinsed, and dried (MgSO 4). Filtered and the solvent was evaporated and recrystallized (EtOAc-IH) gave the title compound: m / z (ES +) = 264.1 [M + H] +.

表1所列示的化合物係根據製備例3所揭示的方法由(Z)-3-環戊基-2-碘丙烯酸甲酯和適合的雜芳基溴化合物而製得，除非另外指明。The compounds listed in Table 1 were prepared according to the procedure disclosed in Preparation 3 from methyl (Z)-3-cyclopentyl-2-iodoacrylate and a suitable heteroaryl bromide compound, unless otherwise indicated.

製備例9：(E)-3-環戊基-2-〔6-(5-甲基四唑-1-基)吡啶-3-基〕丙烯酸Preparation 9: (E)-3-Cyclopentyl-2-[6-(5-methyltetrazol-1-yl)pyridin-3-yl]acrylic acid

步驟1：NaN3 (13.69g,210.6mmol)和Tf2 O(33mL, 196.5mmol)在0℃下加至攪拌中之N-(5-溴吡啶-2-基)乙醯胺(8.31g,38.6mmol)於無水MeCN(200mL)所形成的溶液中。2.5小時後，升溫至45℃，並繼續攪拌16小時。在低壓下除去溶劑，接著殘餘物於CH2 Cl2 (250mL)和飽和NaHCO3 水溶液(250mL)間分配。水層再經CH2 Cl2 (250mL)萃取，接著合併的有機萃取液經H2 O(200mL)和鹽水(200mL)沖洗，接著乾燥(MgSO4 )。過濾及蒸發溶劑得殘餘物，殘餘物經快速層析純化(CH2 Cl2 -THF，1：0至15：1)。所得的物質再經第二次快速層析純化(IH-EtOAc，10：1至3：2)得5-溴-2-(5-甲基四唑-1-基)吡啶：δH (CDCl3 )：2.95(s,3H)，7.95(d,1H),8.10(dd,1H),8.65(d,1H)。步驟2：DBE(310 μL,3.5mmol)加至由Zn粉(1.49g,22.5mmol)於無水THF(4mL)所形成的懸浮液中。加熱混合物至沸騰，接著使之冷卻至20℃。重覆此步驟三次，接著加入TMSCl(300 μL,2.3mmol)。反應混合物在20℃下攪拌70分鐘，接著加入由(Z)-3-環戊基-2-碘丙烯酸甲酯(1.31g,5.0mmol)於無水DMF(6mL)所形成的溶液。混合物在45℃(浴)攪拌65分鐘，接著在25℃下置放16小時。加入無水THF(13mL)，接著靜置混合物。在攪拌的情況下，將有機鋅化合物的溶液加至由Pd(PPh3 )2 Cl2 (0.38g,0.5mmol)和5-溴-2-(5-甲基四唑-1-基)吡啶(1.58g,7.0mmol)於無水DMF(10mL)所形成的懸浮液中。混合物在45℃(浴)攪拌72小時，接著於反應中 加入少量的MeOH以使反應驟停，並於EtOAc(75mL)和飽和NH4 Cl水溶液(50mL)間分配。水層再經EtOAc(75mL)萃取。過濾合併的有機萃取液，接著以H2 O(50mL)和鹽水(50mL)沖洗。乾燥(MgSO4 )後，溶液經過濾及濃縮得殘餘物，殘餘物經快速層析純化(CH2 Cl2 -THF，1：0至16：1)得(E)-3-環戊基-2-〔6-(5-甲基四唑-1-基)吡啶-3-基〕丙烯酸甲酯：m/z(ES+ )=314.1〔M+H〕+ 。步驟3：根據製備例3之步驟2所例示之步驟，皂化所得的酯(271 mg,865 μmol)，得標題化合物：m/z(ES+ )=300.1〔M+H〕+ 。Step 1: NaN 3 (13.69 g, 210.6 mmol) and Tf 2 O (33 mL, 196.5 mmol) were added to the stirred N-(5-bromopyridin-2-yl)acetamide (8.31 g, 38.6 mmol) in a solution of anhydrous MeCN (200 mL). After 2.5 hours, the temperature was raised to 45 ° C and stirring was continued for 16 hours. The solvent was removed under low pressure, then the residue in CH 2 Cl 2 (250mL) and between saturated aqueous NaHCO 3 (250 mL) allocation. And then (250 mL) The aqueous layer was extracted with CH 2 Cl 2, and then the combined organic extracts were 2 O (200mL) and brine (200mL) rinsed H, then dried (MgSO 4). Filtered, and the solvent was evaporated to give the residue, and the residue was purified by flash chromatography (CH 2 Cl 2 -THF, 1 : 0 to 15: 1). The obtained material was purified by a second flash chromatography (IH-EtOAc, 10:1 to 3:2) to give 5-bromo-2-(5-methyltetrazol-1-yl)pyridine: δ H (CDCl) 3 ): 2.95 (s, 3H), 7.95 (d, 1H), 8.10 (dd, 1H), 8.65 (d, 1H). Step 2: DBE (310 μL, 3.5 mmol) was added to a suspension of Zn powder (1.49 g, 22.5 mmol) in anhydrous THF (4 mL). The mixture was heated to boiling and then allowed to cool to 20 °C. This step was repeated three times, followed by the addition of TMSCl (300 μL, 2.3 mmol). The reaction mixture was stirred at 20 ° C for 70 min then a solution of &lt;RTI ID=0.0&gt;&gt; The mixture was stirred at 45 ° C (bath) for 65 minutes and then placed at 25 ° C for 16 hours. Anhydrous THF (13 mL) was added, followed by a mixture. A solution of the organozinc compound was added to Pd(PPh 3 ) 2 Cl 2 (0.38 g, 0.5 mmol) and 5-bromo-2-(5-methyltetrazol-1-yl)pyridine with stirring. (1.58 g, 7.0 mmol) in a suspension of anhydrous DMF (10 mL). The mixture was stirred at 45 deg.] C (bath) for 72 hours followed by addition of a small amount of MeOH in the reaction to the reaction quenched and partitioned between an aqueous solution (50mL) 4 Cl EtOAc (75mL ) and saturated NH. The aqueous layer was extracted with EtOAc (75 mL). The combined organic extracts were filtered, then rinsed with H 2 O (50mL) and brine (50mL). After drying (MgSO 4), filtered and the solution was concentrated to give a residue which was purified by flash chromatography (CH 2 Cl 2 -THF, 1 : 0 to 16: 1) to give (E) -3- cyclopentyl - Methyl 2-[6-(5-methyltetrazol-1-yl)pyridin-3-yl]acrylate: m/z (ES + ) = 314.1 [M+H] + . The title compound: m/z (ES + ) = 300.1 [M+H] + < / RTI></RTI></RTI></RTI></RTI><RTIgt;

製備例10：(E)-2-(5-氯-6-丙硫基吡啶-3-基)-3-環戊基丙烯酸Preparation 10: (E)-2-(5-chloro-6-propylthiopyridin-3-yl)-3-cyclopentylacrylic acid

步驟1：5-溴-2,3-二氯吡啶(4.47g,19.7mmol)和NaOH(867 mg,21.7mmol)於DMSO(50mL)所形成的混合物經足量的H2 O處理以溶解。加入n-PrSH(1.96mL,21.7mmol)，接著反應混合物在20℃下攪拌4小時。將混合物倒於碎冰(200g)上，接著以CH2 Cl2 萃取(2 x 100mL)。合併的CH2 Cl2 萃取液經H2 O(3 x 100mL)和鹽水(3 x 100mL)沖洗，接著乾燥(MgSO4 )。過濾、蒸發溶劑和管柱層析(IH)得5-溴-3-氯-2-丙硫基吡啶： m/z(ES+ )=268.0〔M+H〕+ 。步驟2：根據製備例9之步驟2所揭示之交叉偶合條件，令所得的溴基吡啶(2.73g,10.2mmol)與(Z)-3-環戊基-2-碘丙烯酸甲酯(1.84g,6.6mmol)進行反應，得(E)-2-(5-氯-6-丙硫基吡啶-3-基)-3-環戊基丙烯酸甲酯：m/z(ES+ )=340.1〔M+H〕+ 。步驟3：根據製備例3之步驟2所揭示之方法，皂化所得的酯(770 mg,2.3mmol)，得標題化合物：δH (CDCl3 )：1.05(t,3H),1.40-1.85(m,10H),2.45-2.60(m,1H),3.20(t,2H),7.15(d,1H),7.40(d,1H),8.15(d,1H)。Step 1: 5-Bromo-2,3-dichloropyridine (4.47g, 19.7mmol) and NaOH (867 mg, 21.7mmol) by a sufficient amount of the mixture in DMSO (50mL) formed by H 2 O treatment to dissolve. n-PrSH (1.96 mL, 21.7 mmol) was added, and the reaction mixture was stirred at 20 ° C for 4 hr. The mixture was poured onto crushed ice (200g), followed by CH 2 Cl 2 and extracted (2 x 100mL). The combined CH 2 Cl 2 extracts were washed with H 2 O (3×100 mL) and brine (3×100 mL) and then dried (MgSO 4 ). Filtered and the solvent was evaporated and column chromatography (IH) to give 5-bromo-3-chloro-2-propylthio-pyridine: m / z (ES +) = 268.0 [M + H] +. Step 2: According to the cross-coupling conditions disclosed in Step 2 of Preparation 9, the obtained bromopyridine (2.73 g, 10.2 mmol) and (Z)-3-cyclopentyl-2-iodoacrylate (1.84 g). , 6.6 mmol) was carried out to give (E)-2-(5-chloro-6-propylthiopyridin-3-yl)-3-cyclopentyl acrylate: m/z (ES + )=340.1 M+H] + . The title compound: δ H (CDCl 3 ): 1.05 (t, 3H), 1.40-1.85 (m), m.p. , 10H), 2.45-2.60 (m, 1H), 3.20 (t, 2H), 7.15 (d, 1H), 7.40 (d, 1H), 8.15 (d, 1H).

表2所列示的化合物係根據製備例10所揭示之步驟而製備。The compounds listed in Table 2 were prepared according to the procedure disclosed in Preparation 10.

製備例13：碘化三苯基(四氫吡喃-4-基甲基)鏻Preparation Example 13: Triphenyl(tetrahydropyran-4-ylmethyl)phosphonium iodide

在攪拌的情況下，4-碘甲基四氫吡喃(3.43g,15.2mmol)和PPh3 (3.98g,15.2mmol)於無水MeCN(10mL)所形成的溶液經回流加熱19小時，冷卻至20℃後加入Et2 O(50mL)。收集所形成的沉澱物，以Et2 O(150mL)沖洗，及再結晶(MeCN)，得標題化合物：m/z(ES+ )=361.2〔M〕+ 。A solution of 4-iodomethyltetrahydropyran (3.43 g, 15.2 mmol) and PPh 3 (3.98 g, 15.2 mmol) in anhydrous MeCN (10 mL) was stirred with stirring for 19 hr. After 20 ° C, Et 2 O (50 mL) was added. The precipitate formed was collected to Et 2 O (150mL) washing and recrystallization (MeCN), to give the title compound: m / z (ES +) = 361.2 [M] +.

製備例14：(E)-3-(四氫吡喃基)-2-(6-甲硫基吡啶-3-基)丙烯酸Preparation 14: (E)-3-(tetrahydropyranyl)-2-(6-methylthiopyridin-3-yl)acrylic acid

步驟1：在-78℃下，將n-BuLi(32.9mL之2.6 M的己烷溶液，102mmol)加至攪拌中之由2,5-二溴吡啶(23.7g,100mmol)於Et2 O(800mL)所形成的溶液中，歷時15分鐘。20分鐘後，加入草酸二乙酯(16.4mL,120mmol)，歷時15分鐘，接著在-78℃下繼續攪拌30分鐘，及在0℃下繼續攪拌3小時。將反應混合物倒在冰冷的飽和NH4 Cl水溶液中，接著以Et2 O萃取。有機層經H2 O和鹽水沖洗、乾燥(Na2 SO4 )、過濾及在真空下濃縮。層析純化(EtOAc-n-C6 H14 ,1：6)得(6-溴吡啶-3-基) 二羥醋酸乙酯：m/z(APCI+ )=276〔M+H2 O+H〕+ 。步驟2：在0℃下，在由所得的化合物(11.6g,44.9mmol)於DMF(200mL)所形成的溶液中加入NaSMe(3.15g,44.9mmol)，歷時5分鐘。混合物在20℃下攪拌24小時，接著在真空下濃縮。殘餘物於EtOAc和H2 O間分配。有機層經H2 O和鹽水沖洗、乾燥(Na2 SO4 )、過濾及濃縮。層析純化(EtOAc-n-C6 H14 ,1：10)得(6-甲硫基吡啶-3-基)二羥醋酸乙酯：m/z(APCI+ )=226〔M+H〕+ 。步驟3：在0℃下，LHMDS(6.25mL之1.0 M的THF溶液，6.3mmol)加至攪拌中之由碘化三苯基(四氫吡喃-4-基甲基)鏻(製備例13，3.18g，8.5mmol)於THF(10mL)所形成的懸浮液中。1小時後，加入(6-甲硫基吡啶-3-基)二羥醋酸乙酯(1.13g,5.0mmol)於THF(4mL)所形成的溶液，歷時5分鐘。反應混合物在0℃下攪拌1小時，接著先以H2 O處理，繼之以10% HCl水溶液處理以調節至pH 6。混合物在20℃下攪拌1小時，接著在真空下除去THF。殘餘物經Et2 O(50mL)處理及過濾。收集的沉澱物經Et2 O沖洗。濾液和洗液經Et2 O萃取(3 x 10mL)。合併的有機層經鹽水沖洗、乾燥(Na2 SO4 )、過濾及濃縮。殘餘物經層析純化(EtOAc-n-C6 H14 ,1：3)得3-(四氫吡喃基)-2-(6-甲硫基吡啶-3-基)丙烯酸乙酯之(E)-和(Z)-異構物之2：1的混合物：m/z(APCI+ )=308〔M+H〕+ 。步驟4：在0℃下，將2 M NaOH(1.5mL,3.0mmol)加至由所得的酯(615 mg,2.0mmol)於 EtOH(3mL)所形成的溶液中。混合物在20℃下攪拌24小時，接著在真空下濃縮。殘餘物經以H2 O(5mL)稀釋，以2M HCl酸化，及以EtOAC萃取。合併的有機層經鹽水沖洗、乾燥(Na2 SO4 )、過濾及在真空下濃縮。再結晶(EtOAc)得標題化合物：m/z(ES- )=278〔M-H〕- 。Step 1: To a -78 ℃, the (32.9mL of hexane solution of 2.6 M, 102mmol) n-BuLi was added to a stirred solution of 2,5-dibromopyridine (23.7g, 100mmol) in Et 2 O ( 800 mL) of the resulting solution lasted 15 minutes. After 20 minutes, diethyl oxalate (16.4 mL, 120 mmol) was added over 15 minutes, then stirring was continued at -78 °C for 30 minutes and stirring was continued at 0 °C for 3 hours. The reaction mixture was poured onto ice-cold saturated aqueous NH 4 Cl, followed by Et 2 O to extraction. The organic layer was dried over H 2 O and brine, dried (Na 2 SO 4), filtered and concentrated in vacuo. Chromatography (EtOAc-nC 6 H 14 , 1 : 6) to give (6-bromopyridin-3-yl) hydroxyacetic acid ethyl ester: m/z (APCI + ) = 276 [M+H 2 O+H] + . Step 2: NaSMe (3.15 g, 44.9 mmol) was added to a solution of the obtained compound (11.6 g, 44.9 mmol) in DMF (200 mL). The mixture was stirred at 20 ° C for 24 hours and then concentrated under vacuum. The residue was partitioned between EtOAc and H 2 O. The organic layer was dried over H 2 O and brine, dried (Na 2 SO 4), filtered, and concentrated. Purified by chromatography (EtOAc-nC 6 H 14, 1: 10) to give (6-methylsulfanyl-pyridin-3-yl) glyoxylic acid ethyl ester: m / z (APCI +) = 226 [M + H] +. Step 3: LHMDS (6.25 mL of a 1.0 M solution in THF, 6.3 mmol) was added to a stirred solution of triphenyl(tetrahydropyran-4-ylmethyl)phosphonium iodide at 0 ° C (Preparation Example 13) , 3.18 g, 8.5 mmol) in a suspension of THF (10 mL). After 1 h, a solution of (6-methylthiopyridin-3-yl)dihydroxyacetate (1.13 g, 5.0 mmol) in THF (4 mL) The reaction mixture was stirred at 0 ℃ 1 hour, followed by treatment first with H 2 O, followed by 10% aqueous HCl to adjust to pH 6. The mixture was stirred at 20 ° C for 1 hour, then the THF was removed in vacuo. The residue was purified by Et 2 O (50mL) and filter processing. The collected precipitate was rinsed with Et 2 O. The filtrate and washings were extracted with Et 2 O (3 x 10 mL). The combined organic layers were rinsed with brine, dried (Na 2 SO 4), filtered, and concentrated. The residue was purified by chromatography (EtOAc-nC 6 H 14, 1: 3) was obtained 3- (tetrahydropyran-yl) -2- (6-methylsulfanyl-pyridin-3-yl) acrylate of (E) a mixture of - and (Z)-isomers of 2:1: m/z (APCI + ) = 308 [M+H] + . Step 4: 2 M NaOH (1.5 mL, 3.0 mmol) was added to a solution of EtOAc (EtOAc) The mixture was stirred at 20 ° C for 24 hours and then concentrated under vacuum. The residue was diluted with H 2 O (5mL), acidified with 2M HCl, and extracted with EtOAC. The combined organic layers were rinsed with brine, dried (Na 2 SO 4), filtered and concentrated in vacuo. Recrystallization (EtOAc) to give the title compound: m / z (ES -) = 278 [MH] -.

製備例15：(E)-3-環戊基-2-(6-環丙基硫基吡啶-3-基)丙烯酸Preparation 15: (E)-3-Cyclopentyl-2-(6-cyclopropylthiopyridin-3-yl)acrylic acid

在0℃下，將SO2 Cl2 (9.8mL,122.0mmol)緩緩地加至二環丙基二硫化物(17.0g,116.2mmol)中。混合物在20℃下攪拌2小時，接著以無水PhMe(100mL)稀釋以得環丙烷亞磺醯氯的PhMe溶液。於另一個容器內，在-78℃下，將n-BuLi(153mL之1.6 M的己烷溶液，244.8mmol)加至攪拌中之由2,5-二溴吡啶(55.1g,232.4mmol)於無水PhMe(1 L)所形成的溶液中。在-78℃下3小時後，於混合物中緩緩加入上述之環丙烷亞磺醯氯溶液。1小時後，在-20℃下，於混合物中加入飽和NH4 Cl水溶液(1L)以使反應驟停，接著在20℃下攪拌16小時。分離出有機層，接著水層經Et2 O萃取(3 x 500mL)。合併有機層，乾燥(MgSO4 )，過濾，濃縮，及快速管柱層析純化(IH-Et2 O,98.5：1.5)，得5-溴-2-環 丙基硫基吡啶：m/z(ES+ )=232.0〔M+H〕+ 。於所得的化合物(22.0g,95.6mmol)進行溴-鋰交換反應，及繼之根據製備例14之步驟1所揭示的方法，與草酸二乙酯反應，得(6-環丙基硫基吡啶-3-基)酮基乙酸乙酯：m/z(ES+ )=252.2〔M+H〕+ 。根據製備例14之步驟3所揭示的方法，令所得的酮基酯(11.09g,44.1mmol)與碘化環戊甲基三苯鏻(33.00g,75.0mmol)反應，得3-環戊基-2-(6-環丙基硫基吡啶-3-基)丙烯酸乙酯之(E)-和(Z)-異構物之約2：1的混合物：m/z(ES+ )=318.2〔M+H〕+ 。根據製備例14之步驟4所揭示的步驟，水解所得的酯(13.21g,41.6mmol)，得標題化合物：m/z(ES+ )=290.3〔M+H〕+ 。SO 2 Cl 2 (9.8 mL, 122.0 mmol) was slowly added to dicyclopropyl disulfide (17.0 g, 116.2 mmol) at 0 °C. The mixture was stirred at 20 ° C for 2 hours, then diluted with anhydrous PhMe (100 mL) to give a solution of cyclopropanesulfinium chloride in PhMe. In a separate vessel, n-BuLi (153 mL of a 1.6 M solution in hexane, 244.8 mmol) was added to a stirred mixture of 2,5-dibromopyridine (55.1 g, 232.4 mmol) at -78 °C An aqueous solution of PhMe (1 L) was formed. After 3 hours at -78 ° C, the above cyclopropane sulfinium chloride solution was slowly added to the mixture. After 1 hour, a saturated aqueous solution of NH 4 Cl (1 L) was added to the mixture at -20 ° C to quench the reaction, followed by stirring at 20 ° C for 16 hours. The organic layer was separated, then the aqueous layer was extracted with Et 2 O (3 x 500 mL). The organic layers were combined, dried (MgSO 4), filtered, concentrated, and purified by flash column chromatography (IH-Et 2 O, 98.5 : 1.5), to give 5-bromo-2-cyclopropyl-pyridyldithio: m / z (ES + ) = 232.0 [M+H] + . The obtained compound (22.0 g, 95.6 mmol) was subjected to a bromine-lithium exchange reaction, and then reacted with diethyl oxalate according to the method disclosed in Step 1 of Preparation Example 14 to give (6-cyclopropylthiopyridine). Ethyl -3-yl) ketoacetate: m/z (ES + ) = 252.2 [M+H] + . The obtained ketoester (11.09 g, 44.1 mmol) was reacted with cyclopentylmethyltriphenylphosphonium iodide (33.00 g, 75.0 mmol) according to the method disclosed in Step 3 of Preparation 14 to give 3-cyclopentyl. Mixture of about 2:1 of (E)- and (Z)-isomers of ethyl 2-(6-cyclopropylthiopyridin-3-yl)acrylate: m/z (ES + ) = 318.2 [M+H] + . According to Step 4 of Preparation 14 disclosed, the resulting hydrolysis of the ester (13.21g, 41.6mmol), to give the title compound: m / z (ES +) = 290.3 [M + H] +.

製備例16：3-環戊基-2-(6-氟吡啶-3-基)丙酸Preparation 16: 3-cyclopentyl-2-(6-fluoropyridin-3-yl)propanoic acid

步驟1：根據製備例9之步驟2所揭示之交叉偶合條件，令5-溴-2-氟吡啶(1.50g,8.5mmol)與3-環戊基-2-碘丙烯酸甲酯(2.60g,9.3mmol)反應，得(E)-3-環戊基-2-(6-氟吡啶-3-基)丙烯酸甲酯：m/z(ES+ )=250.1〔M+H〕+ 。步驟2：所得的α,β-未飽和酯(1.50g,6.0mmol)於EtOAc所形成的溶液經Pd(10%於碳上，300 mg，0.3mmol)於EtOH(0.5mL)所形成的懸浮液處 理。反應混合物在H2 下攪拌4天，接著以寅氏鹽過濾。在低壓下除去溶劑，接著殘餘物經管柱層析純化，得3-環戊基-2-(6-氟吡啶-3-基)丙酸甲酯：m/z(ES+ )=252.2〔M+H〕+ 。步驟3：所得的酯(1.48g,5.9mmol)和LiOH．H2 O(0.49g,11.8mmol)於THF-H2 O(5：1,24mL)所形成的溶液在20℃下攪拌18小時。在真空下除去THF，接著殘餘物於飽和Na2 CO3 水溶液(150mL)和Et2 O(75mL)間分配。水層經以2 M HCl調整至pH 3。殘餘物經EtOAc萃取(100mL+75mL)。合併的有機萃取液經鹽水沖洗、乾燥(MgSO4 )、過濾和濃縮，得標題化合物：m/z(ES+ )=238.1〔M+H〕+ 。Step 1: According to the cross-coupling conditions disclosed in Step 2 of Preparation 9, 5-bromo-2-fluoropyridine (1.50 g, 8.5 mmol) and methyl 3-cyclopentyl-2-iodoacrylate (2.60 g, Methyl (E)-3-cyclopentyl-2-(6-fluoropyridin-3-yl)acrylate: m/z (ES + ) = 250.1 [M+H] + . Step 2: Suspension of a solution of the obtained α,β-unsaturated ester (1.50 g, 6.0 mmol) in EtOAc over Pd (10% over carbon, 300 mg, 0.3 mmol) in EtOH (0.5 mL) Liquid treatment. The reaction mixture was stirred under H 2 for 4 days and then filtered to Celite. The solvent was removed under low pressure, then the residue was purified by column to afford 3-cyclopentyl-2- (6-fluoropyridin-3-yl) propanoate: m / z (ES +) = 252.2 [M +H〕 + . Step 3: The obtained ester (1.48 g, 5.9 mmol) and LiOH. A solution of H 2 O (0.49 g, 11.8 mmol) in THF-H 2 O (5:1, 24 mL) was stirred at 20 ° C for 18 hours. THF was removed in vacuo, and then the residue between Et 2 O (75mL) partitioned between aqueous saturated Na 2 CO 3 (150mL). The aqueous layer was adjusted to pH 3 with 2 M HCl. The residue was extracted with EtOAc (100 mLEtOAc) The combined organic extracts were rinsed with brine, dried (MgSO 4), filtered and concentrated to give the title compound: m / z (ES +) = 238.1 [M + H] +.

製備例17：3-環戊基-2-(6-環丙烷磺醯基吡啶-3-基)丙酸Preparation 17: 3-Cyclopentyl-2-(6-cyclopropanesulfonylpyridin-3-yl)propionic acid

根據實例35所揭示的步驟，氧化(E)-3-環戊基-2-(6-環丙基硫基吡啶-3-基)丙烯酸(製備例15，9.63g，33.3mmol)，得(E)-3-環戊基-2-(6-環丙烷磺醯基吡啶-3-基)丙酸：δH (CDCl3 )：1.05-1.20(m,2H),1.35-1.85(m,10H),2.40-2.50(m,1H),2.80-2.90(m,1H),7.25(d,1H),7.80(dd,1H),8.05(d,1H), 8.60(d,1H)。根據製備例16之步驟2所揭示的步驟，還原所得的α,β-未飽和羧酸，得標題化合物：m/z(ES+ )=324.2〔M+H〕+ 。According to the procedure disclosed in Example 35, (E)-3-cyclopentyl-2-(6-cyclopropylthiopyridin-3-yl)acrylic acid (Preparation 15, 9.63 g, 33.3 mmol) was obtained. E)-3-Cyclopentyl-2-(6-cyclopropanesulfonylpyridin-3-yl)propionic acid: δ H (CDCl 3 ): 1.05-1.20 (m, 2H), 1.35 - 1.85 (m, 10H), 2.40-2.50 (m, 1H), 2.80-2.90 (m, 1H), 7.25 (d, 1H), 7.80 (dd, 1H), 8.05 (d, 1H), 8.60 (d, 1H). The resulting α,β-unsaturated carboxylic acid was purified according to the procedure obtained in Step 2 of Preparation 16 to give the title compound: m/z (ES + )=324.2 [M+H] + .

表3所列示的化合物係根據實例5所揭示之方法藉由偶合適合的羧酸和噻唑-2-基胺而製得。The compounds listed in Table 3 were prepared according to the procedure disclosed in Example 5 by coupling the appropriate carboxylic acid and thiazol-2-ylamine.

製備例21：5-氟噻唑-2-基胺氫氯酸鹽Preparation 21: 5-fluorothiazol-2-ylamine hydrochloride

NEt3 (63.4mL,455mmol)加至攪拌中之由5-溴噻唑-2-基胺氫溴酸鹽(102.7g,379mmol)於CH2 Cl2 (1.5 L)所形成的懸浮液中。1小時後，在0℃下逐滴加入TFAA (64.2mL,455mmol)，歷時15分鐘。使混合物升溫至20℃，歷時1小時，接著繼續攪拌2小時。加入H2 O(600mL)，及收集所得的沉澱物。分離出濾液的水層，並以CHCl3 萃取(3 x 300mL)。合併的有機萃取液經鹽水沖洗、乾燥(Na2 SO4 )、過濾及濃縮。合併收集的沉澱物和殘餘的固體，並以EtOAc-n-C6 H14 碾製，得N-(5-溴噻唑-2-基)-2,2,2-三氟乙醯胺：δH (CDCl3 )：7.45(s,1H)，13.05(br,1H)。在-78℃下，將n-BuLi(253mL之1.58 M己烷溶液，403mmol)逐滴加至攪拌中之由所得醯胺(50.0g,183mmol)於無水THF(1.3 L)所形成的溶液中，歷時50分鐘。1.5小時後，逐滴加入N-氟苯磺醯亞胺(86.0g,275mmol)於無水THF(250mL)所形成的溶液，歷時30分鐘。攪拌混合物30分鐘，接著使升溫至-30℃。加入H2 O(300mL)，以寅氏鹽墊過濾混合物。收集的固體和寅氏鹽經Et2 O(400mL)和H2 O(400mL)沖洗。分離出濾液的有機層，並以水萃取(2 x 400mL)。合併的水層經Et2 O(400mL)沖洗，接著以2M HCl酸化至pH 6.5，及以EtOAc萃取(2 x 400mL)。合併的有機萃取液經H2 O(2 x 400mL)和鹽水沖洗，接著乾燥(MgSO4 )、過濾及濃縮。管柱層析(EtOAc-n-C6 H14 ，1：3至1：2)得N-(5-氟噻唑-2-基)-2,2,2-三氟乙醯胺：δH (CDCl3 )：7.13(d,1H)。在0℃下，將AcCl(12.6mL,175mmol)逐滴加至攪拌中之由所得的醯胺(15.7g,73mmol)於MeOH(300mL)所形成的溶液中。混合物在 20℃下攪拌30分鐘，回流加熱1小時，及最後在真空下濃縮。殘餘的固體經THF碾製得標題化合物：δH (D2 O)：7.00(d,1H)。NEt 3 (63.4mL, 455mmol) was added to a stirred solution of the 5-bromo-thiazol-2-ylamine hydrobromide (102.7g, 379mmol) was suspended in CH 2 Cl 2 (1.5 L) is formed. After 1 hour, TFAA (64.2 mL, 455 mmol) was added dropwise at 0 °C over 15 min. The mixture was allowed to warm to 20 ° C for 1 hour, then stirring was continued for 2 hours. H 2 O (600 mL) was added, and the resulting precipitate was collected. The aqueous layer of the filtrate was separated, and is extracted with CHCl 3 (3 x 300mL). The combined organic extracts were rinsed with brine, dried (Na 2 SO 4), filtered, and concentrated. The collected precipitate and the residual solid were combined and triturated with EtOAc-n C 6 H 14 to give N-(5-bromothiazol-2-yl)-2,2,2-trifluoroacetamide: δ H ( CDCl 3 ): 7.45 (s, 1H), 13.05 (br, 1H). n-BuLi (253 mL of a 1.58 M solution in hexane, 403 mmol) was added dropwise to a solution of the obtained decylamine (50.0 g, 183 mmol) in anhydrous THF (1.3 L). It took 50 minutes. After 1.5 hours, a solution of N-fluorobenzenesulfonimide (86.0 g, 275 mmol) in dry THF (250 mL) was added dropwise over 30 min. The mixture was stirred for 30 minutes and then allowed to warm to -30 °C. H 2 O (300 mL) was added and the mixture was filtered thru a pad. The collected solid and strontium salt were rinsed with Et 2 O (400 mL) and H 2 O (400 mL). The organic layer of the filtrate was separated and extracted with water (2 x 400 mL). The combined aqueous layers were Et 2 O (400mL) washing, followed by acidification with 2M HCl to pH 6.5, and extracted with EtOAc (2 x 400mL). The combined organic extracts were rinsed with brine and H 2 O (2 x 400mL) , then dried (MgSO 4), filtered, and concentrated. Column chromatography (EtOAc-nC 6 H 14 , 1:3 to 1:2) gave N-(5-fluorothiazol-2-yl)-2,2,2-trifluoroacetamide: δ H (CDCl) 3 ): 7.13 (d, 1H). AcCl (12.6 mL, 175 mmol) was added dropwise to a solution of the obtained decylamine (15.7 g, 73 mmol) in MeOH (300 mL). The mixture was stirred at 20 ° C for 30 minutes, heated at reflux for 1 hour, and finally concentrated under vacuum. The residual solid was triturated THF to give the title compound: δ H (D 2 O) : 7.00 (d, 1H).

實例1Example 1

2-(6-氯吡啶-3-基)-3-環戊基-N-噻唑-2-基丙醯胺2-(6-chloropyridin-3-yl)-3-cyclopentyl-N-thiazol-2-ylpropanamide

2-(6-氯吡啶-3-基)-3-環戊基丙酸(製備例1，0.56g，2.2mmol)、TBTU(1.41g,4.4mmol)、HOBt(0.45g,3.3mmol)、NEt3 (0.31mL,2.2mmol)、和噻唑-2-基胺(0.44g,4.4mmol)於無水DMF(23mL)所形成的溶液在20℃下攪拌16小時。反應混合物經EtOAc稀釋，接著以2M Na2 CO3 、H2 O和鹽水沖洗。乾燥(Na2 SO4 )後，過濾及濃縮有機層，得標題化合物：RTA =3.82分鐘；m/z(ES+ )=336.1〔M+H〕+ 。2-(6-chloropyridin-3-yl)-3-cyclopentylpropionic acid (Preparation Example 1, 0.56 g, 2.2 mmol), TBTU (1.41 g, 4.4 mmol), HOBt (0.45 g, 3.3 mmol), NEt 3 (0.31mL, 2.2mmol), and thiazol-2-yl-amine (0.44g, 4.4mmol) in solution in dry DMF (23mL) was stirred at 20 ℃ 16 hours. The reaction mixture was diluted with EtOAc, followed by 2M Na 2 CO 3, H 2 O and brine. After drying (Na 2 SO 4), filtered, and the organic layer was concentrated to give the title compound: RT A = 3.82 minutes; m / z (ES +) = 336.1 [M + H] +.

實例2Example 2

3-環戊基-2-(6-苯基吡啶-3-基)-N-噻唑-2-基丙醯胺3-cyclopentyl-2-(6-phenylpyridin-3-yl)-N-thiazol-2-ylpropanamide

2-(6-氯吡啶-3-基)-3-環戊基-N-噻唑-2-基丙醯胺(實例1，100 mg，297μmol)、Pd(PPh3 )4 (5 mg,4μmol)、(R)-(+)-BINAP(5 mg,8μmol)、K2 CO3 (100 mg,724 μmol)、和苯硼酸(100mg,820μmol)於DMF(1mL)所形成的混合物在150℃下攪拌加熱48小時。冷卻後的反應混合物經EtOAc(50mL)稀釋，接著以H2 O沖洗(3 x 20mL)。在低壓下除去溶劑，接著殘餘物經RP-HPLC純化得標題化合物：RTA =3.93分鐘；m/z(ES+ )=378.2〔M+H〕+ 。2-(6-chloropyridin-3-yl)-3-cyclopentyl-N-thiazol-2-ylpropanamide (Example 1, 100 mg, 297 μmol), Pd(PPh 3 ) 4 (5 mg, 4 μmol a mixture of (R)-(+)-BINAP (5 mg, 8 μmol), K 2 CO 3 (100 mg, 724 μmol), and phenylboronic acid (100 mg, 820 μmol) in DMF (1 mL) at 150 ° C The mixture was heated under stirring for 48 hours. The reaction mixture was cooled (50mL) diluted with EtOAc, followed by H 2 O rinse (3 x 20mL). The solvent was removed under low pressure, then the residue was purified by RP-HPLC to give the title compound: RT A = 3.93 minutes; m / z (ES +) = 378.2 [M + H] +.

實例3Example 3

3-環戊基-N-噻唑-2-基-2-(6-噻吩-3-基吡啶-3-基)丙醯胺3-cyclopentyl-N-thiazol-2-yl-2-(6-thiophen-3-ylpyridin-3-yl)propanamide

根據實例2所揭示的步驟，令2-(6-氯吡啶-3-基)-3-環戊基-N-噻唑-2-基丙醯胺(實例1，100mg，297 μmol)與噻吩-3-硼酸(100mg,781μmol)進行交叉偶合反應，得標題化合物：RTA =3.83分鐘；m/z(ES+ )=384.2〔M+H〕+ 。According to the procedure disclosed in Example 2, 2-(6-chloropyridin-3-yl)-3-cyclopentyl-N-thiazol-2-ylpropionamide (Example 1, 100 mg, 297 μmol) and thiophene- 3-Baconic acid (100 mg, 781 μmol) was subjected to a cross-coupling reaction to give the title compound: RT A = 3.83 min; m/z (ES + ) = 384.2 [M+H] + .

實例4Example 4

3-環戊基-2-吡啶-3-基-N-噻唑-2-基丙醯胺3-cyclopentyl-2-pyridin-3-yl-N-thiazol-2-ylpropanamide

根據實例1所揭示的方法，令3-環戊基-2-吡啶-3-基丙酸(製備例2，0.96g，4.4mmol)與噻唑-2-基胺(0.88g,8.8mmol)進行縮合反應，得標題化合物：RTA =3.05分鐘；m/z(ES+ )=302.2〔M+H〕+ 。3-cyclopentyl-2-pyridin-3-ylpropanoic acid (Preparation Example 2, 0.96 g, 4.4 mmol) and thiazol-2-ylamine (0.88 g, 8.8 mmol) were obtained according to the procedure of Example 1. condensation reaction, to give the title compound: RT A = 3.05 minutes; m / z (ES +) = 302.2 [m + H] +.

實例5Example 5

(E)-3-環戊基-2-(6-甲硫基吡啶-3-基)-N-噻唑-2-基丙烯醯胺(E)-3-cyclopentyl-2-(6-methylthiopyridin-3-yl)-N-thiazol-2-ylpropenylamine

PS-碳化二亞胺(1.08g，負載1.32mmolg-1 ，1.42mmol)、(E)-3-環戊基-2-(6-甲硫基吡啶-3-基)丙烯酸(製備例3，125 mg，475 μmol)、和HOBt(128mg,949μmol)於無水DMF(8mL)所形成的懸浮液在20℃下攪拌15分鐘。加入噻唑-2-基胺(48mg,475μmol)，接著混合物在20℃下攪拌14小時。LCMS顯示反應未完成，因此再加入更多的噻唑-2-基胺(95mg,950μmol)。再繼續攪拌混合物64小時，接著過濾。所收集的樹脂經CH2 Cl2 沖洗，接著合併的濾液和洗液在低壓下濃縮 。管柱層析(2：1 IH-EtOAc)得標題化合物：RTA =3.85分鐘；m/z(ES+ )=346.1〔M+H〕+ 。PS-carbodiimide (1.08 g, load 1.32 mmolg -1 , 1.42 mmol), (E)-3-cyclopentyl-2-(6-methylthiopyridin-3-yl)acrylic acid (Preparation Example 3, A suspension of 125 mg, 475 μmol) and HOBt (128 mg, 949 μmol) in dry DMF (8 mL) was stirred at 20 ° C for 15 min. Thiazol-2-ylamine (48 mg, 475 μmol) was added, and the mixture was stirred at 20 ° C for 14 hours. LCMS showed the reaction was not complete, so more thiazol-2-ylamine (95 mg, 950 [mu]mol) was added. The mixture was further stirred for a further 64 hours, followed by filtration. The collected resin was rinsed 2 Cl 2 CH, then the combined filtrate and washings were concentrated under reduced pressure. Column chromatography (2: 1 IH-EtOAc) to give the title compound: RT A = 3.85 minutes; m / z (ES +) = 346.1 [M + H] +.

根據實例5所揭示之步驟，製備表4所列示的化合物。The compounds listed in Table 4 were prepared according to the procedure disclosed in Example 5.

實例12Example 12

(E)-3-環戊基-2-(5-甲硫基吡啶-2-基)-N-噻唑-2-基丙 烯醯胺(E)-3-Cyclopentyl-2-(5-methylthiopyridin-2-yl)-N-thiazole-2-ylpropane Enamine

(E)-3-環戊基-2-(5-甲硫基吡啶-2-基)丙烯酸(製備例5，1.00g，3.8mmol)、EDCI(0.95g,4.9mmol)、HOBt(0.67g,4.9mmol)和噻唑-2-基胺(1.52g,15.2mmol)於無水THF(62mL)和DMF(50mL)所形成的溶液在20℃下攪拌4天。在低壓下除去溶劑，接著殘餘物於CH2 Cl2 和飽和Na2 CO3 水溶液間分配。有機層經H2 O和鹽水沖洗，接著乾燥(MgSO4 )。過濾、蒸發溶劑和管柱層析(7：3 IH-EtOAc)得標題化合物：RTA =3.96分鐘；m/z(ES+ )=346.1〔M+H〕+ 。(E)-3-Cyclopentyl-2-(5-methylthiopyridin-2-yl)acrylic acid (Preparation Example 5, 1.00 g, 3.8 mmol), EDCI (0.95 g, 4.9 mmol), HOBt (0.67 g) A solution of 4.9 mmol) and thiazol-2-ylamine (1.52 g, 15.2 mmol) in dry THF (EtOAc) (EtOAc) The solvent was removed under low pressure, then the residue between in CH 2 Cl 2 CO 3 and aqueous saturated Na 2 distribution. The organic layer was dried over H 2 O and brine, then dried (MgSO 4). Filtered and the solvent was evaporated and column chromatography (7: 3 IH-EtOAc) to give the title compound: RT A = 3.96 minutes; m / z (ES +) = 346.1 [M + H] +.

表5所列示的化合物係根據實例12所揭示之方法而製備。The compounds listed in Table 5 were prepared according to the method disclosed in Example 12.

實例16Example 16

(E)-3-(4-四氫吡喃基)-2-(6-甲硫基吡啶-3-基)-N-噻唑-2-基丙烯醯胺(E)-3-(4-tetrahydropyranyl)-2-(6-methylthiopyridin-3-yl)-N-thiazol-2-ylpropenylamine

在-25℃下，將(E)-3-(四氫吡喃基)-2-(6-甲硫基吡啶-3-基)丙烯酸(製備例14，280 mg，1.0mmol)於THF(4mL)所形成的溶液加至由DMF(126 μL,1.6mmol)和草醯氯(280mg,1.0mmol)於THF(3mL)所形成的懸浮液中。混合物在0℃下攪拌1小時，接著在20℃下攪拌1小時。在-45℃下加入由噻唑-2-基胺(320mg,3.2mmol)和NEt3 (446 μL,3.2mmol)於THF(2mL)所 形成的溶液，歷時10分鐘，接著混合物在0℃下攪拌1小時。加入飽和NaHCO3 水溶液，及以寅氏鹽過濾混合物。濾液的水層經EtOAc萃取。合併的有機層經鹽水沖洗、乾燥(Na2 SO4 )、過濾及在真空下濃縮。管柱層析純化(先EtOAc-n-C6 H14 ，1：3至1：1，接著CHCl3 -MeOH，99：1)得標題化合物：δH (CDCl3 )：1.46-1.56(m,4H),2.22-2.40(m,1H),2.54(s,3H),3.17-3.29(m,2H),3.80(dt,2H),6.78(d,1H),7.22(d,1H),7.34(dd,1H),7.50(d,1H),7.52(dd,1H),8.27(dd,1H),12.19(s,1H)；m/z(APCI+ )=362〔M+H〕+ 。(E)-3-(Tetrahydropyranyl)-2-(6-methylthiopyridin-3-yl)acrylic acid (Preparation 14, 280 mg, 1.0 mmol) in THF (br.) 4 mL) of the resulting solution was added to a suspension of DMF (126 uL, 1.6 mmol) The mixture was stirred at 0 ° C for 1 hour and then at 20 ° C for 1 hour. Joined by thiazol-2-amine (320mg, 3.2mmol) and NEt 3 (446 μL, 3.2mmol) at -45 ℃ solution in THF (2mL) is formed, over 10 minutes, and then the mixture was stirred at 0 ℃ 1 hour. A saturated aqueous solution of NaHCO 3 was added and the mixture was filtered with brine. The aqueous layer of the filtrate was extracted with EtOAc. The combined organic layers were rinsed with brine, dried (Na 2 SO 4), filtered and concentrated in vacuo. Purified by column chromatography (first EtOAc-nC 6 H 14, 1 : 3 to 1: 1, followed by CHCl 3 -MeOH, 99: 1) to give the title compound: δ H (CDCl 3): 1.46-1.56 (m, 4H ), 2.22-2.40 (m, 1H), 2.54 (s, 3H), 3.17-3.29 (m, 2H), 3.80 (dt, 2H), 6.78 (d, 1H), 7.22 (d, 1H), 7.34 ( Dd, 1H), 7.50 (d, 1H), 7.52 (dd, 1H), 8.27 (dd, 1H), 12.19 (s, 1H); m/z (APCI + ) = 362 [M+H] + .

根據實例16所揭示之步驟，製備表6所列示的化合物。The compounds listed in Table 6 were prepared according to the procedure disclosed in Example 16.

實例35Example 35

(E)-3-環戊基-2-(6-甲磺醯基吡啶-3-基)-N-噻唑-2-基丙烯醯胺(E)-3-Cyclopentyl-2-(6-methylsulfonylpyridin-3-yl)-N-thiazol-2-ylpropenylamine

mCPBA(65%純度，60mg，226μmol)加至攪拌中之由(E)-3-環戊基-2-(6-甲硫基吡啶-3-基)-N-噻唑-2-基丙烯醯胺(實例5，39mg，113μmol)於CH2 Cl2 (3mL)所形成的溶液中。16小時後，反應混合物在低壓下濃縮。加入EtOAc(15mL)和飽和NaHCO3 水溶液(5mL)，接著劇烈攪拌反應混合物20分鐘。分離出有機層，接著以鹽水(5mL)沖洗，及乾燥(MgSO4 )。過濾、蒸發溶劑和管柱層析(1：1 IH-EtOAc)得標題化合物：RTA =3.49分鐘；m/z(ES+ )=419.2〔M+MeCN+H〕+ 。mCPBA (65% purity, 60 mg, 226 μmol) was added to the stirred (E)-3-cyclopentyl-2-(6-methylthiopyridin-3-yl)-N-thiazol-2-ylpropene oxime amine (example 5,39mg, 113μmol) in CH solution (3mL) 2 Cl 2 formed in. After 16 hours, the reaction mixture was concentrated under reduced pressure. Was added EtOAc (15mL) and saturated aqueous NaHCO 3 (5mL), followed by vigorously stirring the reaction mixture for 20 minutes. The organic layer was separated, followed by brine (5mL) rinsed, and dried (MgSO 4). Filtered and the solvent was evaporated and column chromatography (1: 1 IH-EtOAc) to give the title compound: RT A = 3.49 minutes; m / z (ES +) = 419.2 [M + MeCN + H] +.

根據實例35所揭示之步驟，製備表7所列示的化合物。The compounds listed in Table 7 were prepared according to the procedure disclosed in Example 35.

實例40Example 40

(E)-N-(5-溴噻唑-2-基)-3-環戊基-2-(6-甲磺醯基吡啶-3-基)丙烯醯胺(E)-N-(5-bromothiazol-2-yl)-3-cyclopentyl-2-(6-methylsulfonylpyridin-3-yl)propenylamine

根據實例5所揭示之方法，縮合(E)-3-環戊基-2-(6-甲硫基吡啶-3-基)丙烯酸(製備例3，64mg，0.24mmol)與5-溴噻唑-2-基胺(218 mg,1.22mmol)，得(E)-N-(5-溴噻唑-2-基)-3-環戊基-2-(6-甲硫基吡 啶-3-基)丙烯醯胺：RTA =4.28分鐘；m/z(ES+ )=426.2〔M+H〕+ 。根據實例35所揭示之步驟，氧化所得的化合物(61mg,144μmol)，得標題化合物：RTA =3.91分鐘；m/z(ES+ )=499.2〔M+MeCN+H〕+ 。Condensation of (E)-3-cyclopentyl-2-(6-methylthiopyridin-3-yl)acrylic acid (Preparation Example 3, 64 mg, 0.24 mmol) and 5-bromothiazole according to the method disclosed in Example 5. 2-Amine (218 mg, 1.22 mmol) gave (E)-N-(5-bromothiazol-2-yl)-3-cyclopentyl-2-(6-methylthiopyridin-3-yl) Acrylamide: RT A = 4.28 min; m/z (ES + ) = 426.2 [M+H] + . According to the disclosed example 35 step, the resulting compound oxide (61mg, 144μmol), to give the title compound: RT A = 3.91 minutes; m / z (ES +) = 499.2 [M + MeCN + H] +.

根據實例12和35所揭示之步驟，製備表8所列示的化合物。The compounds listed in Table 8 were prepared according to the procedures disclosed in Examples 12 and 35.

實例44Example 44

(E)-2-〔3-環戊基-2-(6-環丙烷磺醯基吡啶-3-基)丙烯醯基胺基〕噻唑-5-甲酸甲醯胺(E)-2-[3-cyclopentyl-2-(6-cyclopropanesulfonylpyridin-3-yl)propenylamino]thiazol-5-carboxylic acid carbenamide

根據實例12所揭示之方法，令(E)-3-環戊基-2-(6-環丙基硫基吡啶-3-基)丙烯酸(製備例15，250 mg，0.86mmol)與2-胺基噻唑-5-甲酸乙酯(297 mg,1.73mmol)進行縮合，得2-〔3-環戊基-2-(6-環丙基硫基吡啶-3-基)丙烯醯基胺基〕噻唑-5-甲酸乙酯：m/z(ES+ )=444.3〔M+H〕+ 。根據製備例16之步驟3所揭示之步驟，皂化所得的酯，得2-〔3-環戊基-2-(6-環丙基硫基吡啶-3-基)丙烯醯基胺基〕噻唑-5-甲酸：m/z(ES+ )=416.1〔M+H〕+ 。根據實例35所揭示之方法，氧化所得的硫醚，得2-〔3-環戊基-2-(6-環丙烷磺醯基吡啶-3-基)丙烯醯基胺基〕噻唑-5-甲酸：m/z(ES+ )=448.2〔M+H〕+ 。根據實例12所揭示之一般步驟，在NEt3 的存在下，令所得的羧酸(52 mg,116 μmol)與MeNH2 ．HCl進行縮合，得標題化合物：RTA =3.29分鐘；m/z(ES+ )=461.3〔M+H〕+ 。According to the method disclosed in Example 12, (E)-3-cyclopentyl-2-(6-cyclopropylthiopyridin-3-yl)acrylic acid (Preparation 15, 250 mg, 0.86 mmol) and 2- Ethyl thiazole-5-carboxylate (297 mg, 1.73 mmol) was condensed to give 2-[3-cyclopentyl-2-(6-cyclopropylthiopyridin-3-yl)propenylamino Ethyl thiazole-5-carboxylate: m/z (ES + ) = 444.3 [M+H] + . The resulting ester was saponified according to the procedure disclosed in Step 3 of Preparation 16 to give 2-[3-cyclopentyl-2-(6-cyclopropylthiopyridin-3-yl)propenylamino]thiazole. -5-carboxylic acid: m/z (ES + ) = 416.1 [M+H] + . The resulting thioether was oxidized according to the method disclosed in Example 35 to give 2-[3-cyclopentyl-2-(6-cyclopropanesulfonylpyridin-3-yl)propenylamino]thiazol-5- Formic acid: m/z (ES + ) = 448.2 [M+H] + . The resulting carboxylic acid (52 mg, 116 μmol) was combined with MeNH 2 in the presence of NEt 3 according to the general procedure disclosed in Example 12. HCl condensation, to give the title compound: RT A = 3.29 minutes; m / z (ES +) = 461.3 [M + H] +.

實例45和46Examples 45 and 46

(E)-N-(5-氯噻唑-2-基)-3-環戊基-2-(5-甲磺醯基吡啶-2-基)丙烯醯胺和(E)-N-(5-氯噻唑-2-基)-3-環戊基-2-(5-甲亞磺醯基吡啶-2-基)丙烯醯胺(E)-N-(5-chlorothiazol-2-yl)-3-cyclopentyl-2-(5-methylsulfonylpyridin-2-yl)propenylamine and (E)-N-(5 -Chlorothiazole-2-yl)-3-cyclopentyl-2-(5-methylsulfinylpyridin-2-yl)propenamide

mCPBA(65%純度，158 mg，548μmol)加至由(E)-N-(5-氯噻唑-2-基)-3-環戊基-2-(5-甲硫基吡啶-2-基)丙烯醯胺(實例13，200 mg，525 μmol)於CH2 Cl2 (10mL)所形成的溶液中。混合物在20℃下攪拌16小時，接著加入更多的mCPBA(65%純度，53 mg，184μmol)。30分鐘後，於反應中加入飽和Na2 CO3 水溶液以使反應驟停。有機層經飽和NaHCO3 水溶液沖洗，接著乾燥(MgSO4 )、過濾、濃縮、及管柱層析純化。利用3：2 IH-EtOAc洗提管柱而得到碸標題化合物：RTA =3.90分鐘；m/z(ES+ )=412.0〔M+H〕+ 。當以1：9 MeOH-EtOAc洗提管柱時得到亞碸標題化合物，藉由將IH蒸氣擴散至所得化合物的EtOAc溶液中而進一步純化之。RTA =3.73分鐘；m/z(ES+ )=396.0〔M+H〕+ 。mCPBA (65% purity, 158 mg, 548 μmol) was added to (E)-N-(5-chlorothiazol-2-yl)-3-cyclopentyl-2-(5-methylthiopyridin-2-yl) A solution of acrylamide (Example 13, 200 mg, 525 μmol) in CH 2 Cl 2 (10 mL). The mixture was stirred at 20 ° C for 16 hours, then more mCPBA (65% purity, 53 mg, 184 μmol) was added. After 30 minutes, a saturated aqueous solution of Na 2 CO 3 was added to the reaction to quench the reaction. The organic layer was rinsed with saturated aqueous NaHCO 3, then dried (MgSO 4), filtered, concentrated, and purified by column chromatography. Using a 3: 2 IH-EtOAc sulfone column was eluted to give the title compound: RT A = 3.90 minutes; m / z (ES +) = 412.0 [M + H] +. When the column was eluted with 1:9 MeOH-EtOAc, the title compound was obtained from the title compound. RT A = 3.73 min; m/z (ESI + ) = 396.0 [M+H] + .

表9所列示的化合物係根據實例5所揭示之方法及併用實例45和46所揭示的方法而製備。The compounds listed in Table 9 were prepared according to the method disclosed in Example 5 and using the methods disclosed in Examples 45 and 46.

實例55Example 55

(E)-3-環戊基-2-(6-甲亞磺醯基吡啶-3-基)-N-噻唑-2-基丙烯醯胺(E)-3-cyclopentyl-2-(6-methylsulfinothrazin-3-yl)-N-thiazol-2-ylpropenylamine

在0℃下，將mCPBA(85%純度，64mg，318μmol)於CH2 Cl2 (1mL)所形成的溶液加至攪拌中之由(E)-3-環戊基-2-(6-甲硫基吡啶-3-基)-N-噻唑-2-基丙烯醯胺(實例5，110mg，318μmol)於CH2 Cl2 (5mL)所形成的溶液中，歷時5分鐘。在0℃下4.5小時後，反應混合物經EtOAc(40mL)稀釋。所得的溶液經H2 O-飽和NaHCO3 水溶液(1：1,2 x 20mL)和鹽水(20mL)沖洗，接著乾燥(MgSO4 )。過濾、蒸發溶劑和管柱層析(先EtOAc後THF)得標題化合物：RTA =3.32分鐘；m/z(ES+ )=362.1〔M+H〕+ 。Add a solution of mCPBA (85% purity, 64 mg, 318 μmol) in CH 2 Cl 2 (1 mL) at 0 ° C to (E)-3-cyclopentyl-2-(6-A) thio-3-yl) -N- thiazol-2-yl acrylamide (example 5,110mg, 318μmol) solution in CH 2 Cl 2 (5mL) is formed in 5 minutes. After 4.5 hours at 0&lt;0&gt;C, the reaction mixture was diluted with EtOAc EtOAc. The resulting solution was H 2 O- saturated aqueous NaHCO 3 (1: 1,2 x 20mL) ( 20mL) and rinse with brine, then dried (MgSO 4). Filtered and the solvent was evaporated and column chromatography (after the first EtOAc THF) to give the title compound: RT A = 3.32 minutes; m / z (ES +) = 362.1 [M + H] +.

表10列示根據實例55所揭示之方法而製得之化合物。Table 10 lists the compounds prepared according to the method disclosed in Example 55.

實例60Example 60

(E)-3-環戊基-2-(6-乙亞磺醯基吡啶-3-基)-N-(5-氟噻唑-2-基)丙烯醯胺(E)-3-Cyclopentyl-2-(6-ethionsulfonylpyridin-3-yl)-N-(5-fluorothiazol-2-yl)propenylamine

根據實例5所揭示之方法，令(E)-3-環戊基-2-(6-乙硫基吡啶-3-基)丙烯酸(製備例4，215mg，0.78mmol)與5-氟噻唑-2-基胺氫氯酸鹽(製備例21，240mg，1.55mmol)進行縮合，得(E)-3-環戊基-2-(6-乙硫基吡 啶-3-基)-N-(5-氟噻唑-2-基)丙烯醯胺：m/z(ES+ )=378.2〔M+H〕+ 。根據實例55所揭示之方法，氧化所得的硫醚(22mg,60μmol)，得標題化合物：RTA =3.50分鐘；m/z(ES+ )=394.2〔M+H〕+ 。(E)-3-Cyclopentyl-2-(6-ethylthiopyridin-3-yl)acrylic acid (Preparation Example 4, 215 mg, 0.78 mmol) and 5-fluorothiazole according to the method disclosed in Example 5. 2-Hydrylamine hydrochloride (Preparation 21, 240 mg, 1.55 mmol) was subjected to condensation to give (E)-3-cyclopentyl-2-(6-ethylthiopyridin-3-yl)-N- ( 5-fluorothiazol-2-yl)propenylamine: m/z (ES + ) = 378.2 [M+H] + . The disclosed method of Example 55, the resulting oxide sulfide (22mg, 60μmol), to give the title compound: RT A = 3.50 minutes; m / z (ES +) = 394.2 [M + H] +.

根據實例60所揭示之方法，製備表11所列示的化合物。The compounds listed in Table 11 were prepared according to the method disclosed in Example 60.

實例64Example 64

(E)-3-環戊基-2-(6-甲亞磺醯基吡啶-3-基)-N-(5-氯噻唑-2-基)丙烯醯胺(E)-3-Cyclopentyl-2-(6-methylsulfinothrazin-3-yl)-N-(5-chlorothiazol-2-yl)propenylamine

在0℃下，將oxone®(190 mg,0.98mmol)於H2 O(2mL)所形成的溶液加至攪拌中之由(E)-3-環戊基-2-(6-甲硫基吡啶-3-基)-N-(5-氯噻唑-2-基)丙烯醯胺(實例6，120 mg，0.32mmol)於THF-MeOH(1：1,6mL)所形成的溶液中。15分鐘後，加入飽和NaHCO3 水溶液(5mL)和10% Na2 S2 O3 水溶液(5mL)，接著混合物經EtOAc萃取(2 x 10mL)。合併的有機層經H2 O(10mL)和鹽水(10mL)沖洗、乾燥(Na2 SO4 )、過濾及在真空下濃縮。殘餘物經層析純化(EtOAc-n-C6 H14 ,2：1)得標題化合物：δH (CDCl3 )：1.40-1.62(m,4H),1.70-1.82(m,4H),2.27-2.42(m,1H),2.96(s,3H),7.19(d,1H),7.24(s,1H),7.86(dd,1H),8.14(d,1H),8.52(dd,1H),8.72(br s,1H)；m/z(APCI+ )=396,398〔M+H〕+ 。Add a solution of oxone® (190 mg, 0.98 mmol) in H 2 O (2 mL) to (E)-3-cyclopentyl-2-(6-methylthio) at 0 °C. Pyridin-3-yl)-N-(5-chlorothiazol-2-yl)propenylamine (Example 6, 120 mg, 0.32 mmol) in THF-MeOH (1:1, 6 mL). After 15 min, saturated aqueous NaHCO 3 (5mL) and 10% Na 2 S 2 O 3 solution (5mL), then mixture was extracted with EtOAc (2 x 10mL). The combined organic layers were dried over H 2 O (10mL) and brine (10 mL), dried (Na 2 SO 4), filtered and concentrated in vacuo. The residue was purified by chromatography (EtOAc-nC 6 H 14, 2: 1) to give the title compound: δ H (CDCl 3): 1.40-1.62 (m, 4H), 1.70-1.82 (m, 4H), 2.27-2.42 (m, 1H), 2.96 (s, 3H), 7.19 (d, 1H), 7.24 (s, 1H), 7.86 (dd, 1H), 8.14 (d, 1H), 8.52 (dd, 1H), 8.72 ( Br s,1H);m/z(APCI + )=396,398[M+H] + .

實例65Example 65

3-環戊基-2-(6-甲磺醯基吡啶-3-基)-N-噻唑-2-基丙醯胺3-cyclopentyl-2-(6-methylsulfonylpyridin-3-yl)-N-thiazol-2-ylpropanamide

(E)-3-環戊基-2-(6-甲磺醯基吡啶-3-基)-N-噻唑-2-基丙烯醯胺(實例35，500 mg，1.3mmol)、甲酸銨(500mg,7.9mmol)和10%披鈀碳(50% H2 O,500mg)於MeOH(20mL)所形成的混合物在80℃下攪拌20小時。在真空下除去溶劑，接著殘餘物經EtOAc稀釋及以寅氏鹽過濾。濃縮濾液後，再以EtOAc稀釋、以寅氏鹽過濾及濃縮。粗產物經管柱層析純化(EtOAc-n-C6 H14 ，3：7至1：1)得標題化合物：δH (CDCl3 )：1.05-1.22(m,2H),1.40-1.85(m,7H),1.95(dt,1H),2.29(dt,1H),3.21(s,3H),3.82(t,1H),7.09(d,1H),7.53(d,1H),8.06(d,2H),8.58(t,1H)；m/z(APCI+ )=380〔M+H〕+ 。(E)-3-Cyclopentyl-2-(6-methylsulfonylpyridin-3-yl)-N-thiazol-2-ylpropenylamine (Example 35, 500 mg, 1.3 mmol), ammonium formate ( the mixture 500mg, 7.9mmol) and 10% palladium on carbon (50% H 2 O, 500mg ) in MeOH (20mL) was stirred at 80 ℃ 20 hours. The solvent was removed in vacuo then the residue was purified eluting with EtOAc After concentrating the filtrate, it was diluted with EtOAc, filtered and evaporated. The crude product was purified by column chromatography (EtOAc-nC 6 H 14, 3: 7 to 1: 1) to give the title compound: δ H (CDCl 3): 1.05-1.22 (m, 2H), 1.40-1.85 (m, 7H ), 1.95 (dt, 1H), 2.29 (dt, 1H), 3.21 (s, 3H), 3.82 (t, 1H), 7.09 (d, 1H), 7.53 (d, 1H), 8.06 (d, 2H) , 8.58 (t, 1H); m/z (APCI + ) = 380 [M+H] + .

實例66Example 66

3-環戊基-2-(6-巰基吡啶-3-基)-N-噻唑-2-基丙醯胺3-cyclopentyl-2-(6-decylpyridin-3-yl)-N-thiazol-2-ylpropanamide

3-環戊基-2-(6-氟吡啶-3-基)-N-噻唑-2-基丙醯胺(實例14，350 mg，1.1mmol)和NaSMe(1.53g,22.0mmol)於無水且脫氣的DMSO(4mL)所形成的溶液在160℃(浴)攪拌1小時。冷卻後，混合物在EtOAc(50mL)和1M HCl(50mL)間分配。有機層經H2 O(20mL)和鹽水(50mL)沖洗。蒸發溶劑和使殘餘物再結晶(EtOAc- IH)，得標題化合物：RTA =3.24分鐘；m/z(ES+ )=334.2〔M+H〕+ 。3-cyclopentyl-2-(6-fluoropyridin-3-yl)-N-thiazol-2-ylpropionamide (Example 14, 350 mg, 1.1 mmol) and NaSMe (1.53 g, 22.0 mmol) The solution of degassed DMSO (4 mL) was stirred at 160 ° C (bath) for 1 hour. After cooling, the mixture was partitioned between EtOAc (EtOAc) The organic layer was dried over H 2 O (20mL) and brine (50mL) rinse. The solvent was evaporated and the residue was recrystallized (EtOAc- IH), to give the title compound: RT A = 3.24 minutes; m / z (ES +) = 334.2 [M + H] +.

實例67Example 67

3-環戊基-2-(6-甲亞磺醯基吡啶-3-基)-N-噻唑-2-基丙醯胺3-cyclopentyl-2-(6-methylsulfinothrazin-3-yl)-N-thiazol-2-ylpropanamide

步驟1：MeI(44μL之2.3M的無水DMF溶液，102μmol)和K2 CO3 (14 mg,102 μmol)加至攪拌中之由3-環戊基-2-(6-巰基吡啶-3-基)-N-噻唑-2-基丙醯胺(實例66，34mg，102μmol)於無水DMF(1mL)所形成的溶液中。16小時後，在低壓下蒸發除去溶劑，接著殘餘物於EtOAc(12mL)和H2 O(5mL)間分配。有機層經H2 O(5mL)和鹽水(5mL)沖洗，接著乾燥(MgSO4 )。溶液經過濾、通過短SiO2 柱、及蒸發，得3-環戊基-2-(6-甲硫基吡啶-3-基)-N-噻唑-2-基丙醯胺：m/z(ES+ )=348.2〔M+H〕+ 。步驟2：根據實例55所揭示之方法，氧化所得的硫醚(52 mg,150 μmol)，得標題化合物：RTA =3.17分鐘；m/z(ES+ )=364.2〔M+H〕+ 。Step 1: MeI (44 μL of 2.3 M in anhydrous DMF solution, 102 μmol) and K 2 CO 3 (14 mg, 102 μmol) were added to a stirred solution of 3-cyclopentyl-2-(6-mercaptopyridine-3- ))-N-thiazol-2-ylpropionamide (Example 66, 34 mg, 102 μmol) in a solution of anhydrous DMF (1 mL). After 16 hours, the solvent was removed under low pressure evaporation, then the residue in EtOAc (12mL) and distribution between H 2 O (5mL). The organic layer was dried over H 2 O (5mL) and brine (5mL) rinsed, then dried (MgSO 4). The solution is filtered, passed through a short SiO 2 column, and evaporated to give 3-cyclopentyl-2-(6-methylthiopyridin-3-yl)-N-thiazol-2-ylpropanamine: m/z ( ES + ) = 348.2 [M+H] + . Step 2: The resulting thioether (52 mg, 150 [mu]mol) was obtained according to the procedure of Example 55 to give the title compound: RT A = 3.17 min; m/z (ES + ) = 364.2 [M+H] + .

表12所列示的化合物係根據實例67所揭示之方法而製備。The compounds listed in Table 12 were prepared according to the method disclosed in Example 67.

實例70Example 70

3-{5-〔2-環戊基-1-(噻唑-2-基胺甲醯基)乙基〕吡啶-2-基硫基}丙酸3-{5-[2-cyclopentyl-1-(thiazol-2-ylaminecarbamimidyl)ethyl]pyridin-2-ylthio}propionic acid

根據實例67之步驟1所揭示之步驟，令3-環戊基-2-(6-巰基吡啶-3-基)-N-噻唑-2-基丙醯胺(實例66，100mg，300μmol)與3-碘丙基(60mg,300μmol)反應，得標題化合物：RTA =3.61分鐘；m/z(ES+ )=406.4〔M+H〕+ 。3-cyclopentyl-2-(6-decylpyridin-3-yl)-N-thiazol-2-ylpropionamide (Example 66, 100 mg, 300 μmol) was obtained according to the procedure of Step 1 of Example 67. 3-iodopropyl (60mg, 300μmol) reaction, to give the title compound: RT A = 3.61 minutes; m / z (ES +) = 406.4 [m + H] +.

實例71Example 71

3-{5-〔2-環戊基-1-(噻唑-2-基胺甲醯基)乙基〕吡啶-2-磺醯基}丙酸3-{5-[2-cyclopentyl-1-(thiazol-2-ylaminecarbamimidyl)ethyl]pyridine-2-sulfonyl}propionic acid

根據實例35所揭示之方法，氧化3-{5-〔2-環戊基-1-(噻唑-2-基胺甲醯基)乙基〕吡啶-2-基硫基}丙酸(實例70，49mg，121μmol)，得標題化合物：RTA =3.37分鐘；m/z(ES+ )=438.2〔M+H〕+ 。Oxidation of 3-{5-[2-cyclopentyl-1-(thiazol-2-ylaminecarbamimidyl)ethyl]pyridin-2-ylthio}propanoic acid according to the method disclosed in Example 35 (Example 70 The title compound: RT A = 3.37 min; m/z (ES + ) = 438.2 [M+H] + .

實例72Example 72

{5-〔2-環戊基-1-(噻唑-2-基胺甲醯基)乙基〕吡啶-2-基硫基}乙酸{5-[2-Cyclopentyl-1-(thiazol-2-ylaminecarbamimidyl)ethyl]pyridin-2-ylthio}acetic acid

3-環戊基-2-(6-巰基吡啶-3-基)-N-噻唑-2-基丙醯胺(實例66，50mg，150μmol)加至攪拌中之由NaH(12mg之60%礦油的分散液，300μmol)於無水DMF(0.8mL)所形成的溶液中。5分鐘後，加入由氯乙酸(14mg,150μmol)於無水DMF(0.4mL)所形成的溶液。反應混合物經攪拌15分鐘後，加入更多的NaH(10mg之60%礦油的分散液，250 μmol)和氯乙酸(14mg,150μmol)。15分鐘後，反應混合物於EtOAc(10mL)和飽和Na2 CO3 水溶液-H2 O(1：1,15mL)間分配。水層經2M HCl酸化至pH 2.5，接著所得的沉澱物經萃取至EtOAc(15mL)。EtOAc溶液經鹽水(5mL)沖洗、乾燥(MgSO4 )、過濾、濃縮、和再結晶(CH2 Cl2 -IH)，得標題化合物：RTA =3.52分鐘；m/z(ES+ )=392.2〔M+H〕+ 。3-cyclopentyl-2-(6-decylpyridin-3-yl)-N-thiazol-2-ylpropionamide (Example 66, 50 mg, 150 μmol) was added to a stirred NaH (12 mg of 60% ore) A dispersion of the oil, 300 μmol) in a solution of anhydrous DMF (0.8 mL). After 5 minutes, a solution of chloroacetic acid (14 mg, 150 [mu]mol) in anhydrous DMF (0.4 mL) was added. After the reaction mixture was stirred for 15 minutes, more NaH (10 mg of a dispersion of 60% mineral oil, 250 μmol) and chloroacetic acid (14 mg, 150 μmol) were added. After 15 minutes, the reaction mixture in EtOAc (10mL) and saturated aqueous Na 2 CO 3 -H 2 O: Room (1 1,15mL) allocation. The aqueous layer was acidified to pH 2.5 with 2M EtOAc then EtOAc (EtOAc) The EtOAc solution was brine (5mL), dried (MgSO 4), filtered, concentrated, and recrystallized (CH 2 Cl 2 -IH), to give the title compound: RT A = 3.52 minutes; m / z (ES +) = 392.2 [M+H] + .

實例73Example 73

{5-〔2-環戊基-1-(噻唑-2-基胺甲醯基)乙基〕吡啶-2-磺醯基}乙酸{5-[2-Cyclopentyl-1-(thiazol-2-ylaminemethanyl)ethyl]pyridine-2-sulfonyl}acetic acid

步驟1：根據實例72所揭示之步驟，以溴乙酸第三丁酯(55mg,283μmol)烷化3-環戊基-2-(6-巰基吡啶-3-基)-N-噻唑-2-基丙醯胺(實例66，94mg，283μmol)，得{5-〔2-環戊基-1-(噻唑-2-基胺甲醯基)乙基〕吡啶-2-基硫基}乙酸第三丁酯：m/z(ES+ )=448.3〔M+H〕+ 。步驟2：根據實例35所揭示之步驟，氧化所得的硫醚，得{5-〔2-環戊基-1-(噻唑-2-基胺甲醯基)乙基〕吡啶-2-磺醯基}乙酸第三丁酯：δH (CDCl3 )：1.05-1.20(m,2H),1.25(s,9H),1.45-1.85(m,7H),1.90-2.00(m,1H),2.30-2.40(m,1H),3.90-4.00(m,1H),4.30-4.45(m,2H),7.10(d,1H),7.55(d,1H),8.05(d,1H),8.10(dd,1H),8.70(d,1H)。步驟3：所得的化合物(48 mg,100 μmol)於CH2 Cl2 -TFA(1：3,4mL)所 形成的溶液在20℃下攪拌2小時。蒸發溶劑後，殘餘物經飽和NaHCO3 水溶液(5mL)處理。所得的溶液經2M HCl酸化至pH 2，接著混合物經EtOAc萃取(10mL+5mL)。有機層經濃縮及層析(MeOH-CH2 Cl2 -AcOH,2：18：1)得標題化合物：RTA =3.37分鐘；m/z(ES+ )=424.1〔M+H〕+ 。Step 1: alkylation of 3-cyclopentyl-2-(6-decylpyridin-3-yl)-N-thiazole-2- with butyl bromoacetate (55 mg, 283 μmol) according to the procedure of Example 72 Propionamide (Example 66, 94 mg, 283 μmol) gave {5-[2-cyclopentyl-1-(thiazol-2-ylaminecarbamimidyl)ethyl]pyridin-2-ylthio}acetic acid Tributyl ester: m/z (ES + ) = 448.3 [M+H] + . Step 2: According to the procedure disclosed in Example 35, the obtained thioether was oxidized to give {5-[2-cyclopentyl-1-(thiazol-2-ylaminecarbamoyl)ethyl]pyridine-2-sulfonium hydrazide. Tertiary butyl acetate: δ H (CDCl 3 ): 1.05-1.20 (m, 2H), 1.25 (s, 9H), 1.45-1.85 (m, 7H), 1.90-2.00 (m, 1H), 2.30 -2.40 (m, 1H), 3.90-4.00 (m, 1H), 4.30-4.45 (m, 2H), 7.10 (d, 1H), 7.55 (d, 1H), 8.05 (d, 1H), 8.10 (dd , 1H), 8.70 (d, 1H). Step 3: A solution of the obtained compound (48 mg, 100 μmol) in CH 2 Cl 2 -TFA (1:3, 4 mL) was stirred at 20 ° C for 2 hours. After evaporating the solvent, the residue (5mL) was treated with saturated aqueous NaHCO 3. The resulting solution was acidified to pH 2 with 2M EtOAc then EtOAc (EtOAc) The organic layer was concentrated and chromatographed (MeOH-CH 2 Cl 2 -AcOH , 2: 18: 1) to give the title compound: RT A = 3.37 minutes; m / z (ES +) = 424.1 [M + H] +.

實例74Example 74

{5-〔2-環戊基-1-(噻唑-2-基胺甲醯基)乙基〕吡啶-2-亞磺醯基}乙酸{5-[2-Cyclopentyl-1-(thiazol-2-ylaminecarbamimidyl)ethyl]pyridin-2-sulfinyl}acetic acid

根據實例55所揭示之方法，氧化{5-〔2-環戊基-1-(噻唑-2-基胺甲醯基)乙基〕吡啶-2-基硫基}乙酸第三丁酯(見實例73，61mg，136μmol)，得{5-〔2-環戊基-1-(噻唑-2-基胺甲醯基)乙基〕吡啶-2-亞磺醯基}乙酸第三丁酯：δH (CDCl3 )：1.10-1.25(m,2H),1.35(s,4.5H),1.4(s,4.5H),1.45-1.85(m,7H),1.90-2.00(m,1H),2.30-2.40(m,1H),3.70-3.80(m,1H),3.90-3.95(m,1H),4.00-4.05(m,1H),7.05(d,1H),7.50(d,1H),8.00-8.15(m,2H),8.60(m,1H)。根據實例73之步驟3所揭示之條件，除去第三丁基，得標題化合物：RTA =3.15分鐘；m/z(ES+ )=408.1〔M+H〕+ 。Oxidation of {5-[2-cyclopentyl-1-(thiazol-2-ylaminecarbamimido)ethyl]pyridin-2-ylthio}acetic acid tert-butyl ester according to the method disclosed in Example 55 (see Example 73, 61 mg, 136 [mu]mol) gave <RTIgt;5-[2-cyclopentyl-l-(thiazol-2-ylamine-carbamoyl)ethyl]pyridin-2-sulfinyl}acetic acid tert-butyl ester: δ H (CDCl 3 ): 1.10 - 1.25 (m, 2H), 1.35 (s, 4.5H), 1.4 (s, 4.5H), 1.45-1.85 (m, 7H), 1.90-2.00 (m, 1H), 2.30-2.40 (m, 1H), 3.70-3.80 (m, 1H), 3.90-3.95 (m, 1H), 4.00-4.05 (m, 1H), 7.05 (d, 1H), 7.50 (d, 1H), 8.00-8.15 (m, 2H), 8.60 (m, 1H). The title compound was obtained from the title compound: RT A = 3.15 min; m/z (ES + ) = 408.1 [M+H] + .

實例75Example 75

(E)-2-(6-胺基吡啶-3-基)-N-(5-氯噻唑-2-基)-3-環戊基丙烯醯胺(E)-2-(6-Aminopyridin-3-yl)-N-(5-chlorothiazol-2-yl)-3-cyclopentylpropenylamine

(E)-{5-〔1-(5-氯噻唑-2-基胺甲醯基)-2-環戊基乙烯基〕吡啶-2-基}胺基甲酸第三丁酯(製備例18，212mg，473μmol)於CH2 Cl2 (5mL)所形成的溶液在攪拌的情況下經TFA(5mL,65.1mmol)處理。2小時後，蒸發混合物至乾燥，接著加入EtOAc(60mL)。EtOAc溶液經H2 O-飽和NaHCO3 水溶液(1：1,20mL)和鹽水(20mL)沖洗，接著乾燥(MgSO4 )。過濾及蒸發溶劑得殘餘物，將之溶於最小量的Et2 O中，於Et2 O溶液加入IH以沉澱固體，收集固體及乾燥之，得標題化合物：RTA =3.07分鐘；m/z(ES+ )=349.2〔M+H〕+ 。(E)-{5-[1-(5-Chlorothiazol-2-ylaminecarbamimidyl)-2-cyclopentylvinyl]pyridin-2-yl}carbamic acid tert-butyl ester (Preparation Example 18 , 212mg, 473μmol) in a solution of CH 2 Cl 2 (5mL) is formed by a process TFA (5mL, 65.1mmol) under stirring. After 2 h, the mixture was evaporated to dry then EtOAc (EtOAc) The EtOAc solution was H 2 O- saturated aqueous NaHCO 3: (20mL) Rinse (1 1,20mL) and brine, then dried (MgSO 4). Filtered, and the solvent was evaporated to give a residue, dissolved in the minimum amount of Et 2 O, the Et 2 O was added to IH to precipitate a solid, the solid was collected and dried to give the title compound: RT A = 3.07 minutes; m / z (ES + ) = 349.2 [M+H] + .

根據實例75所揭示之步驟，製備表13所列示的化合物。The compounds listed in Table 13 were prepared according to the procedure disclosed in Example 75.

實例78Example 78

(E)-N-(5-氯噻唑-2-基)-3-環戊基-2-(6-甲磺醯基胺基吡啶-3-基)丙烯醯胺(E)-N-(5-chlorothiazol-2-yl)-3-cyclopentyl-2-(6-methylsulfonylaminopyridin-3-yl)propenylamine

(E)-2-(6-胺基吡啶-3-基)-N-(5-氯噻唑-2-基)-3-環戊基丙烯醯胺(實例75，50mg，143μmol)於無水CH2 Cl2 (3mL)所形成的溶液經吡啶(570μL,7.1mmol)和MsCl(170μL,2.2mmol)處理。在20℃下攪拌3天後，反應混合物經Et2 O(40mL)稀釋，接著以1M NaOH-飽和NaHCO3 水溶液(1：1,2 x 15mL)萃取。合併的水性萃取液經2M HCl中和，接著以EtOAc萃取(2 x 50mL)。合併的有機萃取液經鹽水(20mL)沖洗，接著乾燥( MgSO4 )。過濾、蒸發溶劑、和管柱層析(1：1 IH-EtOAc)，得標題化合物：RTA =3.73分鐘；m/z(ES+ )=427.2〔M+H〕+ 。(E)-2-(6-Aminopyridin-3-yl)-N-(5-chlorothiazol-2-yl)-3-cyclopentylpropenylamine (Example 75, 50 mg, 143 μmol) 2 Cl 2 (3mL) solution was formed by pyridine (570μL, 7.1mmol) and MsCl (170μL, 2.2mmol) process. Was stirred at 20 ℃ 3 days, the mixture was diluted with Et 2 O (40mL) The reaction, followed by saturated aqueous NaHCO 3 1M NaOH-: Extraction (1 1,2 x 15mL). The combined aqueous extracts were neutralized with 2M EtOAc then EtOAc (EtOAc) The combined organic extracts were dried with brine (20mL) rinsed, then dried (MgSO 4). Filtration and solvent evaporation, and column chromatography (1: 1 IH-EtOAc) , to give the title compound: RT A = 3.73 minutes; m / z (ES +) = 427.2 [M + H] +.

表14所列示的磺醯胺類化合物係根據實例78所揭示之方法由適當的胺基吡啶製得。The sulfonamide compounds listed in Table 14 were prepared according to the procedure disclosed in Example 78 from the appropriate aminopyridine.

活體外GK活性In vitro GK activity

使用與WO 00/58293相類似的方法，以G6PDH作為偶合酶，結合GST-GK製備G6P的作用與產製NADPH的作用而分析GK活性。GK activity was analyzed using a method similar to that of WO 00/58293, using G6PDH as a coupling enzyme, binding GST-GK to prepare G6P and producing NADPH.

GK分析係在30℃下於購自Costar的平底的96-孔分析盤中在最終培育體積為100μL的情況下進行。分析緩衝液含有：25mM Hepes緩衝液(pH 7.4)、12.5mM KCl、5mM D-Glc、5mM ATP、6.25mM NADP、25mM MgCl2 、1mM二硫蘇糖醇、測試化合物或5% DMSO、3.0單位/mLg6PDH、和0.4μL/mLgST-GK(得自人類肝臟GK )。ATP、G6PDH和NADP係購自Roche Diagnostics。其他的試劑是>98%純度及購自Kanto Chemicals。測試化合物係在加至無ATP之分析緩衝液之前溶於DMSO。此混合物在SPECTRAmax 250微盤光譜儀(Molecular Devices Coporation,Sunnyvale,CA)的溫控室中預培育10分鐘，接著藉由添加10μL ATP溶液加引發反應。GK analysis was performed at 30 ° C in a flat bottom 96-well assay plate purchased from Costar at a final incubation volume of 100 μL. Analytical buffer contains: 25 mM Hepes buffer (pH 7.4), 12.5 mM KCl, 5 mM D-Glc, 5 mM ATP, 6.25 mM NADP, 25 mM MgCl 2 , 1 mM dithiothreitol, test compound or 5% DMSO, 3.0 units /mLg6PDH, and 0.4 μL/mL gST-GK (from human liver GK). ATP, G6PDH and NADP are purchased from Roche Diagnostics. Other reagents were >98% pure and available from Kanto Chemicals. Test compounds were dissolved in DMSO prior to addition to assay buffer without ATP. This mixture was preincubated for 10 minutes in a temperature controlled chamber of a SPECTRAmax 250 microdisk spectrometer (Molecular Devices Coporation, Sunnyvale, CA), followed by initiation of the reaction by the addition of 10 μL of ATP solution.

反應開始後，在10分鐘的培育期間，監視340nm之光密度(OD)的增加以測量GK活性。加入足量的GST-GK以在10分鐘的培育期間內使含有5% DMSO但無測試化合物的盤孔的OD340 增加。初步的實驗證明GK反應在此反應期間呈線性關係，即使在可增加8倍GK活性之活化劑的存在下亦是如此。控制孔之GK活性與含有測試的GK活化劑的孔之GK活性相比較。計算可增加50%的GK活性(即FA1.5)之化合物濃度。GK活化劑在30 μM的情況下達到FA1.5。After the start of the reaction, an increase in optical density (OD) at 340 nm was monitored during 10 minutes of incubation to measure GK activity. Sufficient GST-GK was added to increase the OD 340 of wells containing 5% DMSO but no test compound over a 10 minute incubation period. Preliminary experiments have shown that the GK reaction is linear during this reaction, even in the presence of an activator that can increase GK activity by a factor of eight. The GK activity of the control wells was compared to the GK activity of the wells containing the tested GK activators. The concentration of the compound which increases the GK activity (i.e., FA 1.5) by 50% is calculated. GK activator at FA1.5 is achieved in the case of 30 μM.

上述實例1至80的化合物之EC50 的範圍為0.1至32.0 μM，而最大FA值係為1.7至6.7。The compounds of the above Examples 1 to 80 have an EC 50 ranging from 0.1 to 32.0 μM and a maximum FA value of from 1.7 to 6.7.

活體內GK活性In vivo GK activity

在18小時的斷食後，以50mg/公斤體重的劑量將GK活化劑經口灌食於C57BL/6J鼠。在投服後6小時的研究期間內分5次進行血液Glc的測量。After 18 hours of fasting, the GK activator was orally administered to C57BL/6J mice at a dose of 50 mg/kg body weight. Measurement of blood Glc was performed 5 times in a 6-hour study period after administration.

稱量老鼠(n=5)的體重並在經口投服之前斷食18小時。將GK活化劑溶於WO 00/58293所報導的Gelucire載劑(EtOH：Gelucire 44/14：PEG 400調至4：66：30 v/v/v)，濃度13.3mg/mL。各鼠係以每公斤體重7.5mL調合物的劑量經口投服至50mg/公斤的劑量。在即將投服之前，藉由剪下一小段動物的尾巴(<1 mm)並收集15μL的分析用血液而取得投服前(第0時間)的血液Glc讀數。在GK活化劑處理後，再於投服後的第1、2、4和6小時自相同尾巴的傷口取得血液Glc讀數。藉由比較在6小時時研究期間內之5隻經載劑處理的老鼠的平均血液Glc值與5隻經GK活化劑處理的老鼠的平均血液Glc值而解釋實驗結果。當化合物於2個連續分析時間點相較於載劑展現出統計學上顯著地降低血液Glc值時，此化合物被認為是活性的。The body weight of the mice (n=5) was weighed and fasted for 18 hours before oral administration. The GK activator was dissolved in the Gelucire carrier reported by WO 00/58293 (EtOH: Gelucire 44/14: PEG 400 adjusted to 4:66:30 v/v/v), concentration 13.3 mg/mL. Each mouse was orally administered to a dose of 50 mg/kg at a dose of 7.5 mL of the compound per kilogram of body weight. Blood Glc readings before administration (time 0) were obtained by cutting the tail of a small animal (<1 mm) and collecting 15 μL of blood for analysis immediately before delivery. Blood Glc readings were taken from wounds of the same tail at 1, 2, 4 and 6 hours after administration of the GK activator. The results were interpreted by comparing the mean blood Glc values of 5 vehicle-treated mice in the study period at 6 hours with the mean blood Glc values of 5 GK activator-treated mice. This compound is considered active when the compound exhibits a statistically significant decrease in blood Glc values at 2 consecutive analysis time points compared to the vehicle.

當根據上述的方法而經口投服時，數種上述的GK活化劑顯示出有力的活體內GK活化劑功效。Several of the above GK activators exhibited potent in vivo GK activator efficacy when orally administered according to the methods described above.

Claims (14)

一種如下式(I)所示之化合物 或其藥學上可接受之鹽或N-氧化物，其中：A1 、A2 、A3 、A4 和A5 中之一者是N，另一者是C-R5 ，另一者是C-R6 ，及另二者各自獨立地為N或CH；Q是C3-8 環烷基；T與相連結的-N=C-形成雜芳環，或雜環(其中N=C鍵是唯一的未飽和位置)；R1 和R2 各自獨立地為氫、鹵素、羥基、氰基、硝基、乙烯基、乙炔基、甲氧基、OCFn H3-n 、-NH2 、-NH(C1-4 烷基)、-N(C1-4 烷基)(C1-4 烷基)、CHO、或C1-2 烷基(任意地經1-5個各自獨立的鹵素、羥基、氰基、甲氧基、-NH2 、-NH(C1-2 烷基)、-NH(C1-2 烷基)(C1 -2 烷基)、SOCH3 或SO2 CH3 取代基所取代)；或R1 和R2 一起形成C3-8 碳環；或R1 和R2 一起為經由雙鍵而與環相連結之氧原子；R3 和R4 各自獨立地為氫、鹵素、OCFn H3-n 、甲氧基、 CO2 R77 、氰基、硝基、CHO、CONR99 R100 、CON(OCH3 )CH3 、或任意地經1-5個各自獨立的鹵素、羥基、氰基、甲氧基、-NHCO2 CH3 、或-NH2 、-NH(C1-2 烷基)、-NH(C1-2 烷基)(C1-2 烷基)取代基所取代之C1-2 烷基、或C3-7 環烷基；或R3 和R4 一起形成5-8員芳基或C3-8 碳環；R5 和R6 各自獨立地為氫、羥基、鹵素、氰基、硝基、CO2 R7 、CHO、COR8 、C(OH)R7 R8 、C(=NOR7 )R8 、CONR9 R10 、SR7 、SOR8 、SO2 R8 、SO2 NR9 R10 、CH2 NR9 R10 、NR9 R10 、NHSO2 R8 、N(C1-4 烷基)SO2 R8 、NHCOR7 、或C1-4 烷基、C2-4 烯基、C2-4 炔基、C1-4 烷氧基或芳基，其中各個基團任意地經1-6個各自獨立的鹵素、氰基、硝基、羥基、C1-2 烷氧基、-NH2 、-NH(C1-2 烷基)、-NH(C1-2 烷基)(C1-2 烷基)、C1-2 烷基、CFn H3-n 、芳基、-COC1-2 烷基、-CONH2 、-CONH(C1-2 烷基)、-CONH(C1-2 烷基)(C1-2 烷基)、SCH3 、SOCH3 、SO2 CH3 、或-SO2 NH2 、-SO2 NH(C1-2 烷基)、-SO2 NH(C1-2 烷基)(C1-2 烷基)取代基所取代；或R5 和R6 一起形成5-8員碳環；R7 和R77 各自獨立地為氫、或C1-4 烷基、C2-4 烯基、C2-4 炔基、C3-7 環烷基或芳基，其中各個基團任意地經1-6個各自獨立的鹵素、氰基、硝基、羥基、C1-2 烷氧基、-NH2 、-NH(C1-2 烷基)、-NH(C1-2 烷基)(C1-2 烷基)、C1-2 烷基、C3-7 環烷基、CFn H3-n 、芳基、CO2 H、-COC1-2 烷基、-CONH2 、-CONH(C1-2 烷基)、-CONH(C1-2 烷基)(C1-2 烷基)、SOCH3 、SO2 CH3 、或-SO2 NH2 、-SO2 NH(C1-2 烷基)、-SO2 NH(C1-2 烷基)(C1-2 烷基)取代基所取代；R8 是C1-4 烷基、C2-4 烯基、C2-4 炔基、C3-7 環烷基或芳基，其中各個基團任意地經1-6個各自獨立的鹵素、氰基、硝基、羥基、C1-2 烷氧基、-NH2 、-NH(C1-2 烷基)、-NH(C1-2 烷基)(C1-2 烷基)、C1-2 烷基、C3-7 環烷基、CFn H3-n 、芳基、CO2 H、-COC1-2 烷基、-CONH2 、-CONH(C1-2 烷基)、-CONH(C1-2 烷基)(C1-2 烷基)、SOCH3 、SO2 CH3 、或-SO2 NH2 、-SO2 NH(C1-2 烷基)、-SO2 NH(C1-2 烷基)(C1-2 烷基)取代基所取代；R9 、R10 、R99 、和R100 各自獨立地為氫、或C1-4 烷基、C3-7 環烷基或芳基，其中各個基團任意地經1-6個各自獨立的鹵素、氰基、硝基、羥基、C1-2 烷氧基、-NH2 、-NH(C1-2 烷基)、-NH(C1-2 烷基)(C1-2 烷基)、C1-2 烷基、C3-7 環烷基、CFn H3-n 、芳基、-COC1-2 烷基、-CONH2 、-CONH(C1-2 烷基)、-CONH(C1-2 烷基)(C1-2 烷基)、SOCH3 、SO2 CH3 、或-SO2 NH2 、-SO2 NH(C1-2 烷基)、-SO2 NH(C1-2 烷基)(C1-2 烷基)取代基所取代；n是1、2或3；m是0或1；其中虛線和實線一起形成任意的雙鍵，及△表示雙鍵具有(E)構型；及芳基表苯基或萘基；其中該雜環表示含有1或2個選自氧、硫及氮的雜原子之4至8員飽和環，且雜原子彼此不直接相連結，以及該 雜芳環表示含有1至4個選自氧、硫及氮的雜原子之5 或6 員雜芳環；及其先決條件是式(I)所示之化合物不為3-環戊基-2- 吡啶-4-基-N-噻唑-2-基丙醯胺。a compound of the following formula (I) Or a pharmaceutically acceptable salt or N-oxide thereof, wherein: one of A 1 , A 2 , A 3 , A 4 and A 5 is N, the other is CR 5 and the other is CR 6 And the other two are each independently N or CH; Q is a C 3-8 cycloalkyl group; T is bonded to the -N=C- to form a heteroaryl ring, or a heterocyclic ring (wherein N = C bond is unique) Unsaturated position); R 1 and R 2 are each independently hydrogen, halogen, hydroxy, cyano, nitro, vinyl, ethynyl, methoxy, OCF n H 3-n , -NH 2 , -NH ( C 1-4 alkyl), -N(C 1-4 alkyl)(C 1-4 alkyl), CHO, or C 1-2 alkyl (optionally 1-5 each independently halogen, hydroxy , cyano, methoxy, -NH 2 , -NH(C 1-2 alkyl), -NH(C 1-2 alkyl)(C 1 - 2 alkyl), SOCH 3 or SO 2 CH 3 substituted Substituted by a group; or R 1 and R 2 together form a C 3-8 carbocyclic ring; or R 1 and R 2 together are an oxygen atom bonded to the ring via a double bond; R 3 and R 4 are each independently hydrogen , halogen, OCF n H 3-n , methoxy, CO 2 R 77 , cyano, nitro, CHO, CONR 99 R 100 , CON(OCH 3 )CH 3 , or optionally 1-5 independently Halogen, hydroxy, cyano, methoxy, -NHCO 2 CH 3, or -NH 2, -NH (C 1-2 alkyl), - NH (C 1-2 alkyl) (C 1-2 alkyl) substituted with the group C 1-2 alkyl, or C 3-7 cycloalkyl; or R 3 and R 4 together form a 5-8 membered aryl or C 3-8 carbocyclic ring; R 5 and R 6 are each independently hydrogen, hydroxy, halogen, cyano, nitro , CO 2 R 7 , CHO, COR 8 , C(OH)R 7 R 8 , C(=NOR 7 )R 8 , CONR 9 R 10 , SR 7 , SOR 8 , SO 2 R 8 , SO 2 NR 9 R 10 , CH 2 NR 9 R 10 , NR 9 R 10 , NHSO 2 R 8 , N(C 1-4 alkyl)SO 2 R 8 , NHCOR 7 , or C 1-4 alkyl, C 2-4 alkenyl a C 2-4 alkynyl group, a C 1-4 alkoxy group or an aryl group, wherein each group is optionally subjected to 1 to 6 independently halogen, cyano, nitro, hydroxy, C 1-2 alkoxy groups. , -NH 2 , -NH(C 1-2 alkyl), -NH(C 1-2 alkyl)(C 1-2 alkyl), C 1-2 alkyl, CF n H 3-n , aromatic a group, -COC 1-2 alkyl, -CONH 2 , -CONH(C 1-2 alkyl), -CONH(C 1-2 alkyl)(C 1-2 alkyl), SCH 3 , SOCH 3 , Substituted with SO 2 CH 3 or -SO 2 NH 2 , -SO 2 NH(C 1-2 alkyl), -SO 2 NH(C 1-2 alkyl)(C 1-2 alkyl) substituent; Or R 5 and R 6 together form a 5-8 membered carbocyclic ring; R 7 and R 77 are each independently Hydrogen, or C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-7 cycloalkyl or aryl, wherein each group is optionally 1-6 independently halogen , cyano, nitro, hydroxy, C 1-2 alkoxy, -NH 2 , -NH(C 1-2 alkyl), -NH(C 1-2 alkyl)(C 1-2 alkyl) , C 1-2 alkyl, C 3-7 cycloalkyl, CF n H 3-n , aryl, CO 2 H, -COC 1-2 alkyl, -CONH 2 , -CONH (C 1-2 alkane , /CONH(C 1-2 alkyl)(C 1-2 alkyl), SOCH 3 , SO 2 CH 3 , or -SO 2 NH 2 , -SO 2 NH(C 1-2 alkyl), -SO 2 NH(C 1-2 alkyl)(C 1-2 alkyl) substituent substituted; R 8 is C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C a 3-7 cycloalkyl or aryl group, wherein each group is optionally subjected to 1 to 6 independently halogen, cyano, nitro, hydroxy, C 1-2 alkoxy, -NH 2 , -NH(C 1-2 alkyl), -NH(C 1-2 alkyl)(C 1-2 alkyl), C 1-2 alkyl, C 3-7 cycloalkyl, CF n H 3-n , aryl , CO 2 H, —COC 1-2 alkyl, —CONH 2 , —CONH(C 1-2 alkyl), —CONH(C 1-2 alkyl)(C 1-2 alkyl), SOCH 3 , SO 2 CH 3 , or -SO 2 NH 2 , -SO 2 NH(C 1-2 alkyl), -SO 2 NH(C 1-2 alkyl)(C 1-2 alkyl) substituent Substituting; R 9 , R 10 , R 99 , and R 100 are each independently hydrogen, or C 1-4 alkyl, C 3-7 cycloalkyl or aryl, wherein each group is optionally passed through 1-6 Independent halogen, cyano, nitro, hydroxy, C 1-2 alkoxy, -NH 2 , -NH(C 1-2 alkyl), -NH(C 1-2 alkyl) (C 1- 2 alkyl), C 1-2 alkyl, C 3-7 cycloalkyl, CF n H 3-n , aryl, -COC 1-2 alkyl, -CONH 2 , -CONH (C 1-2 alkane , /CONH(C 1-2 alkyl)(C 1-2 alkyl), SOCH 3 , SO 2 CH 3 , or -SO 2 NH 2 , -SO 2 NH(C 1-2 alkyl), -SO 2 NH(C 1-2 alkyl)(C 1-2 alkyl) substituent substituted; n is 1, 2 or 3; m is 0 or 1; wherein the dotted line and the solid line together form an arbitrary double bond And Δ indicate that the double bond has the (E) configuration; and the aryl group is phenyl or naphthyl; wherein the heterocyclic ring represents a 4 to 8 membered saturated ring containing 1 or 2 hetero atoms selected from oxygen, sulfur and nitrogen. And the heteroatoms are not directly bonded to each other, and the heteroaromatic ring represents a 5 or 6 membered heteroaryl ring containing 1 to 4 hetero atoms selected from oxygen, sulfur and nitrogen; and a prerequisite thereof is the formula (I) the compound is not shown for the 3-cyclopentyl-2 - -N- pyridin-4-yl-thiazol-2-yl propan Amides 如申請專利範圍第1項之化合物或其藥學上可接受之鹽或N-氧化物，其中：虛線和實線一起形成雙鍵；A3 是C-R5 ，A4 是C-R6 ，A1 、A2 和A5 中之一者是N，而另二者是CH。The compound of claim 1 or a pharmaceutically acceptable salt or N-oxide thereof, wherein: the dotted line and the solid line together form a double bond; A 3 is CR 5 , and A 4 is CR 6 , A 1 , A One of 2 and A 5 is N, and the other two are CH. 如申請專利範圍第1項之化合物或其藥學上可接受之鹽或N-氧化物，其中：虛線和實線一起形成雙鍵；A3 是C-R5 ，A4 是N，A1 、A2 和A5 中之一者是N，而另二者是CH。The compound of claim 1 or a pharmaceutically acceptable salt or N-oxide thereof, wherein: the dotted line and the solid line together form a double bond; A 3 is CR 5 , and A 4 is N, A 1 , A 2 One of A and A 5 is N, and the other two are CH. 如申請專利範圍第3項之化合物或其藥學上可接受之鹽或N-氧化物，其中Q是C3-8 環烷基。A compound according to claim 3, or a pharmaceutically acceptable salt or N-oxide thereof, wherein Q is a C 3-8 cycloalkyl group. 如申請專利範圍第1項之化合物或其藥學上可接受之鹽或N-氧化物，其中：虛線和實線一起形成單鍵；A3 是C-R5 ，A4 是C-R6 ，A1 、A2 和A5 中之一者是N，而另二者是CH。The compound of claim 1 or a pharmaceutically acceptable salt or N-oxide thereof, wherein: the dotted line and the solid line together form a single bond; A 3 is CR 5 , and A 4 is CR 6 , A 1 , A One of 2 and A 5 is N, and the other two are CH. 如申請專利範圍第1項之化合物或其藥學上可接受之鹽或N-氧化物，其中Q是環戊基或環己基。 The compound of claim 1 or a pharmaceutically acceptable salt or N-oxide thereof, wherein Q is cyclopentyl or cyclohexyl. 如申請專利範圍第1至6項中任一項之化合物或其藥學上 可接受之鹽或N-氧化物，其中下式所示之基團 為2-吡啶基、2-吡嗪基、2-嘧啶基、4-嘧啶基、3-(1H-吡唑基)、2-(1H-咪唑基)、5-〔1,2,4〕噻二唑基、2-〔1,3,4〕噻二唑基、2-(4,5-二氫噻唑基)、3-異噁唑基、2-噁唑基、或2-噻唑基。The compound of any one of claims 1 to 6 or a pharmaceutically acceptable salt or N-oxide thereof, wherein the group of the formula Is 2-pyridyl, 2-pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 3-(1H-pyrazolyl), 2-(1H-imidazolyl), 5-[1,2,4] Thiadiazolyl, 2-[1,3,4]thiadiazolyl, 2-(4,5-dihydrothiazolyl), 3-isoxazolyl, 2-oxazolyl, or 2-thiazolyl . 如申請專利範圍第1、5及6項中任一項之化合物或其藥學上可接受之鹽或N-氧化物，其中虛線和實線一起形成單鍵，及不對稱中心α之相對於醯胺羰基碳的絕對構型是(R)。 The compound of any one of claims 1, 5 and 6, or a pharmaceutically acceptable salt or N-oxide thereof, wherein the dotted line and the solid line together form a single bond, and the asymmetric center α is relative to 醯The absolute configuration of the amine carbonyl carbon is (R). 如申請專利範圍第1至6項中任一項之化合物或其藥學上可接受之鹽或N-氧化物，其中R3 是氫、鹵素、C1-2 烷基、或三氟甲基；及R4 是氫或甲基。The compound of any one of claims 1 to 6 or a pharmaceutically acceptable salt or N-oxide thereof, wherein R 3 is hydrogen, halogen, C 1-2 alkyl, or trifluoromethyl; And R 4 is hydrogen or methyl. 一種化合物，其係選自下列：2-(6-氯吡啶-3-基)-3-環戊基-N-噻唑-2-基丙醯胺；3-環戊基-2-(6-苯基吡啶-3-基)-N-噻唑-2-基丙醯胺；3-環戊基-2-吡啶-3-基-N-噻唑-2-基丙醯胺；(E)-3-環戊基-2-(6-甲硫基吡啶-3-基)-N-噻唑-2-基丙烯醯胺；(E)-N-(5-氯噻唑-2-基)-3-環戊基-2-(6-甲硫基吡啶-3-基)丙烯醯胺； (E)-3-環戊基-2-(6-乙硫基吡啶-3-基)-N-噻唑-2-基丙烯醯胺；(E)-N-(5-氯噻唑-2-基)-3-環戊基-2-(6-乙硫基吡啶-3-基)丙烯醯胺；(E)-3-環戊基-2-(5-甲硫基吡啶-2-基)-N-噻唑-2-基丙烯醯胺；(E)-N-(5-氯噻唑-2-基)-3-環戊基-2-(5-甲硫基吡啶-2-基)丙烯醯胺；3-環戊基-2-(6-氟吡啶-3-基)-N-噻唑-2-基丙醯胺；(E)-3-環戊基-2-(2-丙硫基嘧啶-5-基)-N-噻唑-2-基丙烯醯胺；N-(5-氯吡啶-2-基)-3-環戊基-2-(6-環丙烷磺醯基吡啶-3-基)丙醯胺；3-環戊基-2-(6-環丙烷磺醯基吡啶-3-基)-N-[1,2,4]噻二唑-5-基丙醯胺；3-環戊基-2-(6-環丙烷磺醯基吡啶-3-基)-N-[1,3,4]噻二唑-2-基丙醯胺；3-環戊基-2-(6-環丙烷磺醯基吡啶-3-基)-N-嘧啶-2-基丙醯胺；3-環戊基-2-(6-環丙烷磺醯基吡啶-3-基)-N-(4-甲基噁唑-2-基)丙醯胺；3-環戊基-2-(6-環丙烷磺醯基吡啶-3-基)-N-(4-甲基吡啶-2-基)丙醯胺；3-環戊基-2-(6-環丙烷磺醯基吡啶-3-基)-N-(6-甲基吡 啶-2-基)丙醯胺；3-環戊基-2-(6-環丙烷磺醯基吡啶-3-基)-N-異噁唑-3-基丙醯胺；3-環戊基-2-(6-環丙烷磺醯基吡啶-3-基)-N-(5-氟吡啶-2-基)丙醯胺；3-環戊基-2-(6-環丙烷磺醯基吡啶-3-基)-N-(1-甲基-1H-吡唑-3-基)丙醯胺；3-環戊基-2-(6-環丙烷磺醯基吡啶-3-基)-N-(5-甲基吡啶-2-基)丙醯胺；3-環戊基-2-(6-環丙烷磺醯基吡啶-3-基)-N-吡啶-2-基丙醯胺；N-苯並噻唑-2-基-3-環戊基-2-(6-環丙烷磺醯基吡啶-3-基)丙醯胺；3-環戊基-2-(6-環丙烷磺醯基吡啶-3-基)-N-吡嗪-2-基丙醯胺；N-(6-氯吡嗪-2-基)-3-環戊基-2-(6-環丙烷磺醯基吡啶-3-基)丙醯胺；3-環戊基-2-(6-環丙烷磺醯基吡啶-3-基)-N-嘧啶-4-基丙醯胺；3-環戊基-2-(6-環丙烷磺醯基吡啶-3-基)-N-(3-甲基-[1,2,4]噻二唑-5-基)丙醯胺；(E)-3-環戊基-2-(6-甲磺醯基吡啶-3-基)-N-噻唑-2-基丙烯醯胺；(E)-N-(5-氯噻唑-2-基)-3-環戊基-2-(6-甲磺醯基吡啶 -3-基)丙烯醯胺；(E)-3-環戊基-2-(6-乙磺醯基吡啶-3-基)-N-噻唑-2-基丙烯醯胺；(E)-N-(5-氯噻唑-2-基)-3-環戊基-2-(6-乙磺醯基吡啶-3-基)丙烯醯胺；(E)-3-環戊基-2-(5-甲磺醯基吡啶-2-基)-N-噻唑-2-基丙烯醯胺；(E)-N-(5-溴噻唑-2-基)-3-環戊基-2-(6-甲磺醯基吡啶-3-基)丙烯醯胺；(E)-3-環戊基-2-(6-環丙烷磺醯基吡啶-3-基)-N-噻唑-2-基丙烯醯胺；(E)-N-(5-氯噻唑-2-基)-3-環戊基-2-(6-環丙烷磺醯基吡啶-3-基)丙烯醯胺；(E)-3-環戊基-2-(6-環丙烷磺醯基吡啶-3-基)-N-(5-氟噻唑-2-基)丙烯醯胺；(E)-2-[3-環戊基-2-(6-環丙烷磺醯基吡啶-3-基)丙烯醯基胺基]噻唑-5-甲酸甲醯胺；(E)-N-(5-氯噻唑-2-基)-3-環戊基-2-(5-甲磺醯基吡啶-2-基)丙烯醯胺；(E)-N-(5-氯噻唑-2-基)-3-環戊基-2-(5-甲亞磺醯基吡啶-2-基)丙烯醯胺；(E)-2-[5-氯-6-(丙烷-1-磺醯基)吡啶-3-基]-3-環戊基-N-噻唑-2-基丙烯醯胺；(E)-2-[5-氯-6-(丙烷-1-亞磺醯基)吡啶-3-基]-3-環戊基 -N-噻唑-2-基丙烯醯胺；(E)-2-(5-氯-6-甲磺醯基吡啶-3-基)-3-環戊基-N-噻唑-2-基丙烯醯胺；(E)-2-(5-氯-6-甲亞磺醯基吡啶-3-基)-3-環戊基-N-噻唑-2-基丙烯醯胺；(E)-2-(5-氯-6-甲磺醯基吡啶-3-基)-N-(5-氯噻唑-2-基)-3-環戊基丙烯醯胺；(E)-2-(5-氯-6-甲亞磺醯基吡啶-3-基)-N-(5-氯噻唑-2-基)-3-環戊基丙烯醯胺；(E)-3-環戊基-N-(5-氟噻唑-2-基)-2-(6-甲磺醯基吡啶-3-基)丙烯醯胺；(E)-3-環戊基-N-(5-氟噻唑-2-基)-2-(6-甲亞磺醯基吡啶-3-基)丙烯醯胺；(E)-3-環戊基-2-(6-甲亞磺醯基吡啶-3-基)-N-噻唑-2-基丙烯醯胺；(E)-3-環戊基-2-(6-乙亞磺醯基吡啶-3-基)-N-噻唑-2-基丙烯醯胺；(E)-N-(5-氯噻唑-2-基)-3-環戊基-2-(6-乙亞磺醯基吡啶-3-基)丙烯醯胺；(E)-3-環戊基-2-(5-甲亞磺醯基吡啶-2-基)-N-噻唑-2-基丙烯醯胺；(E)-3-環戊基-2-[2-(丙烷-1-亞磺醯基)嘧啶-5-基]-N-噻唑-2-基丙烯醯胺；(E)-3-環戊基-2-(6-乙亞磺醯基吡啶-3-基)-N-(5-氟噻唑 -2-基)丙烯醯胺；(E)-3-環戊基-2-(6-環丙烷亞磺醯基吡啶-3-基)-N-噻唑-2-基丙烯醯胺；(E)-N-(5-氯噻唑-2-基)-3-環戊基-2-(6-環丙烷亞磺醯基吡啶-3-基)丙烯醯胺；(E)-3-環戊基-2-(6-環丙烷亞磺醯基吡啶-3-基)-N-(5-氟噻唑-2-基)丙烯醯胺；(E)-3-環戊基-2-(6-甲亞磺醯基吡啶-3-基)-N-(5-氯噻唑-2-基)丙烯醯胺；3-環戊基-2-(6-甲磺醯基吡啶-3-基)-N-噻唑-2-基丙醯胺；3-環戊基-2-(6-巰基吡啶-3-基)-N-噻唑-2-基丙醯胺；3-環戊基-2-(6-甲亞磺醯基吡啶-3-基)-N-噻唑-2-基丙醯胺；3-環戊基-2-(6-甲氧基甲亞磺醯基吡啶-3-基)-N-噻唑-2-基丙醯胺；3-環戊基-2-[6-(丙烷-2-亞磺醯基)吡啶-3-基]-N-噻唑-2-基丙醯胺；3-{5-[2-環戊基-1-(噻唑-2-基胺甲醯基)乙基]吡啶-2-基硫基}丙酸；3-{5-[2-環戊基-1-(噻唑-2-基胺甲醯基)乙基]吡啶-2-磺醯基}丙酸；{5-[2-環戊基-1-(噻唑-2-基胺甲醯基)乙基]吡啶-2-基硫基}乙酸； {5-[2-環戊基-1-(噻唑-2-基胺甲醯基)乙基]吡啶-2-磺醯基}乙酸；{5-[2-環戊基-1-(噻唑-2-基胺甲醯基)乙基]吡啶-2-亞磺醯基}乙酸；(E)-2-(6-胺基吡啶-3-基)-N-(5-氯噻唑-2-基)-3-環戊基丙烯醯胺；(E)-2-(6-胺基吡啶-3-基)-3-環戊基-N-噻唑-2-基丙烯醯胺；(E)-3-環戊基-2-(6-甲胺基吡啶-3-基)-N-噻唑-2-基丙烯醯胺；(E)-N-(5-氯噻唑-2-基)-3-環戊基-2-(6-甲磺醯基胺基吡啶-3-基)丙烯醯胺；(E)-3-環戊基-2-(6-甲磺醯基胺基吡啶-3-基)-N-噻唑-2-基丙烯醯胺；(E)-3-環戊基-2-[6-(甲磺醯基甲基胺基)吡啶-3-基]-N-噻唑-2-基丙烯醯胺；或其藥學上可接受之鹽或N-氧化物。 a compound selected from the group consisting of 2-(6-chloropyridin-3-yl)-3-cyclopentyl-N-thiazol-2-ylpropanamine; 3-cyclopentyl-2-(6- Phenylpyridin-3-yl)-N-thiazol-2-ylpropionamide; 3-cyclopentyl-2-pyridin-3-yl-N-thiazol-2-ylpropanamine; (E)-3 -cyclopentyl-2-(6-methylthiopyridin-3-yl)-N-thiazol-2-ylpropenylamine; (E)-N-(5-chlorothiazol-2-yl)-3- Cyclopentyl-2-(6-methylthiopyridin-3-yl)propenylamine; (E)-3-cyclopentyl-2-(6-ethylthiopyridin-3-yl)-N-thiazol-2-ylpropenylamine; (E)-N-(5-chlorothiazole-2- (3)-cyclopentyl-2-(6-ethylthiopyridin-3-yl)propenylamine; (E)-3-cyclopentyl-2-(5-methylthiopyridin-2-yl) -N-thiazol-2-ylpropenylamine; (E)-N-(5-chlorothiazol-2-yl)-3-cyclopentyl-2-(5-methylthiopyridin-2-yl) Acrylamide; 3-cyclopentyl-2-(6-fluoropyridin-3-yl)-N-thiazol-2-ylpropanamine; (E)-3-cyclopentyl-2-(2-propane Thiopyrimidin-5-yl)-N-thiazol-2-ylpropenylamine; N-(5-chloropyridin-2-yl)-3-cyclopentyl-2-(6-cyclopropanesulfonylpyridine 3-yl)propanamine; 3-cyclopentyl-2-(6-cyclopropanesulfonylpyridin-3-yl)-N-[1,2,4]thiadiazol-5-ylpropionate Amine; 3-cyclopentyl-2-(6-cyclopropanesulfonylpyridin-3-yl)-N-[1,3,4]thiadiazol-2-ylpropanamine; 3-cyclopentyl 2-(6-cyclopropanesulfonylpyridin-3-yl)-N-pyrimidin-2-ylpropionamide; 3-cyclopentyl-2-(6-cyclopropanesulfonylpyridin-3-yl) -N-(4-methyloxazol-2-yl)propanamide; 3-cyclopentyl-2-(6-cyclopropanesulfonylpyridin-3-yl)-N-(4-methyl Pyridin-2-yl)propanamine; 3-cyclopentyl-2-(6-cyclopropanesulfonylpyridin-3-yl)-N-(6-methylpyridyl Pyridin-2-yl)propanamine; 3-cyclopentyl-2-(6-cyclopropanesulfonylpyridin-3-yl)-N-isoxazole-3-ylpropanamine; 3-cyclopentyl 2-(6-cyclopropanesulfonylpyridin-3-yl)-N-(5-fluoropyridin-2-yl)propanamine; 3-cyclopentyl-2-(6-cyclopropanesulfonate) Pyridyl-3-yl)-N-(1-methyl-1H-pyrazol-3-yl)propanamide; 3-cyclopentyl-2-(6-cyclopropanesulfonylpyridin-3-yl) -N-(5-methylpyridin-2-yl)propanamide; 3-cyclopentyl-2-(6-cyclopropanesulfonylpyridin-3-yl)-N-pyridin-2-ylpropane Indoleamine; N-benzothiazol-2-yl-3-cyclopentyl-2-(6-cyclopropanesulfonylpyridin-3-yl)propanamine; 3-cyclopentyl-2-(6- Cyclopropanesulfonylpyridin-3-yl)-N-pyrazin-2-ylpropionamide; N-(6-chloropyrazin-2-yl)-3-cyclopentyl-2-(6-cyclo Propanesulfonylpyridin-3-yl)propanamine; 3-cyclopentyl-2-(6-cyclopropanesulfonylpyridin-3-yl)-N-pyrimidin-4-ylpropanamine; Cyclopentyl-2-(6-cyclopropanesulfonylpyridin-3-yl)-N-(3-methyl-[1,2,4]thiadiazol-5-yl)propanamine; (E --3-cyclopentyl-2-(6-methylsulfonylpyridin-3-yl)-N-thiazol-2-ylpropenylamine; (E)-N-(5-chlorothiazol-2-yl )-3-cyclopentyl-2-(6-methylsulfonylpyridine -3-yl) acrylamide; (E)-3-cyclopentyl-2-(6-ethanesulfonylpyridin-3-yl)-N-thiazol-2-ylpropenylamine; (E)- N-(5-chlorothiazol-2-yl)-3-cyclopentyl-2-(6-ethanesulfonylpyridin-3-yl)propenylamine; (E)-3-cyclopentyl-2- (5-Methanesulfonylpyridin-2-yl)-N-thiazol-2-ylpropenylamine; (E)-N-(5-bromothiazol-2-yl)-3-cyclopentyl-2- (6-Methanesulfonylpyridin-3-yl)propenylamine; (E)-3-Cyclopentyl-2-(6-cyclopropanesulfonylpyridin-3-yl)-N-thiazole-2- Acrylamide; (E)-N-(5-chlorothiazol-2-yl)-3-cyclopentyl-2-(6-cyclopropanesulfonylpyridin-3-yl)propenylamine; (E --3-cyclopentyl-2-(6-cyclopropanesulfonylpyridin-3-yl)-N-(5-fluorothiazol-2-yl)propenylamine; (E)-2-[3- Cyclopentyl-2-(6-cyclopropanesulfonylpyridin-3-yl)propenylamino]thiazol-5-carboxylic acid formamide; (E)-N-(5-chlorothiazol-2-yl --3-cyclopentyl-2-(5-methylsulfonylpyridin-2-yl)propenylamine; (E)-N-(5-chlorothiazol-2-yl)-3-cyclopentyl- 2-(5-methylsulfinylpyridin-2-yl)propenylamine; (E)-2-[5-chloro-6-(propan-1-sulfonyl)pyridin-3-yl]-3 -cyclopentyl-N-thiazol-2-ylpropenylamine; (E)-2-[5-chloro-6-(propane-1-sulfinyl) 3-yl] -3-cyclopentyl- -N-thiazol-2-ylpropenylamine; (E)-2-(5-chloro-6-methanesulfonylpyridin-3-yl)-3-cyclopentyl-N-thiazol-2-ylpropene Indoleamine; (E)-2-(5-chloro-6-methylsulfinylpyridin-3-yl)-3-cyclopentyl-N-thiazol-2-ylpropenylamine; (E)-2 -(5-chloro-6-methanesulfonylpyridin-3-yl)-N-(5-chlorothiazol-2-yl)-3-cyclopentylpropenylamine; (E)-2-(5- Chloro-6-methanesulfinylpyridin-3-yl)-N-(5-chlorothiazol-2-yl)-3-cyclopentylpropenylamine; (E)-3-cyclopentyl-N- (5-fluorothiazol-2-yl)-2-(6-methanesulfonylpyridin-3-yl)propenylamine; (E)-3-cyclopentyl-N-(5-fluorothiazole-2- ()-(6-methylsulfinylpyridin-3-yl)propenylamine; (E)-3-cyclopentyl-2-(6-methylsulfinylpyridin-3-yl)- N-thiazol-2-ylpropenylamine; (E)-3-cyclopentyl-2-(6-ethionsulfonylpyridin-3-yl)-N-thiazol-2-ylpropenylamine; E)-N-(5-chlorothiazol-2-yl)-3-cyclopentyl-2-(6-ethanesulfinylidenepyridin-3-yl)propenylamine; (E)-3-cyclopentyl 2-(5-methylsulfinothrazin-2-yl)-N-thiazol-2-ylpropenylamine; (E)-3-cyclopentyl-2-[2-(propane-1- Sulfosyl)pyrimidin-5-yl]-N-thiazol-2-ylpropenylamine; (E)-3-cyclopentyl-2-(6-ethanesulfinylpyridine) 3-yl)-N-(5-fluorothiazole -2-yl) acrylamide; (E)-3-cyclopentyl-2-(6-cyclopropanesulfinylidene-3-yl)-N-thiazol-2-ylpropenylamine; (E -N-(5-chlorothiazol-2-yl)-3-cyclopentyl-2-(6-cyclopropanesulfinylpyridin-3-yl)propenylamine; (E)-3-cyclopentyl 2-(6-cyclopropanesulfinylpyridin-3-yl)-N-(5-fluorothiazol-2-yl)propenylamine; (E)-3-cyclopentyl-2-(6 -methylsulfinylpyridin-3-yl)-N-(5-chlorothiazol-2-yl)propenylamine; 3-cyclopentyl-2-(6-methylsulfonylpyridin-3-yl) -N-thiazol-2-ylpropanamide; 3-cyclopentyl-2-(6-decylpyridin-3-yl)-N-thiazol-2-ylpropanamine; 3-cyclopentyl-2- (6-methylsulfinylpyridin-3-yl)-N-thiazol-2-ylpropanamine; 3-cyclopentyl-2-(6-methoxymethylsulfinylpyridin-3-yl) -N-thiazol-2-ylpropionamide; 3-cyclopentyl-2-[6-(propane-2-sulfinyl)pyridin-3-yl]-N-thiazol-2-ylpropanoid Amine; 3-{5-[2-cyclopentyl-1-(thiazol-2-ylaminecarbamimidyl)ethyl]pyridin-2-ylthio}propionic acid; 3-{5-[2-ring Pentyl-1-(thiazol-2-ylaminecarbamimidyl)ethyl]pyridine-2-sulfonyl}propionic acid; {5-[2-cyclopentyl-1-(thiazol-2-ylamine) Mercapto)ethyl]pyridin-2-ylthio}acetic acid; {5-[2-cyclopentyl-1-(thiazol-2-ylaminecarbamimidyl)ethyl]pyridine-2-sulfonyl}acetic acid; {5-[2-cyclopentyl-1-(thiazole) -2-ylaminocarbamimidyl)ethyl]pyridin-2-sulfinyl}acetic acid; (E)-2-(6-aminopyridin-3-yl)-N-(5-chlorothiazole-2 -yl)-3-cyclopentylpropenylamine; (E)-2-(6-aminopyridin-3-yl)-3-cyclopentyl-N-thiazol-2-ylpropenylamine; (E --3-cyclopentyl-2-(6-methylaminopyridin-3-yl)-N-thiazol-2-ylpropenylamine; (E)-N-(5-chlorothiazol-2-yl) 3-cyclopentyl-2-(6-methylsulfonylaminopyridin-3-yl)propenylamine; (E)-3-cyclopentyl-2-(6-methylsulfonylaminopyridine -3-yl)-N-thiazol-2-ylpropenylamine; (E)-3-cyclopentyl-2-[6-(methylsulfonylmethylamino)pyridin-3-yl]-N a thiazol-2-ylpropenylamine; or a pharmaceutically acceptable salt or N-oxide thereof. 一種藥學組成物，其包含如申請專利範圍第1至10項中任一項之化合物或其藥學上可接受之鹽或N-氧化物，及藥學上可接受之載體。 A pharmaceutical composition comprising a compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt or N-oxide thereof, and a pharmaceutically acceptable carrier. 如申請專利範圍第11項之藥學組成物，其係用於治療高血糖症或糖尿病。 A pharmaceutical composition according to claim 11 which is for the treatment of hyperglycemia or diabetes. 一種製備如下式(Ia)所示之化合物的方法， 該方法包含縮合下式(IV)所示之化合物： 與下式(V)所示之化合物之步驟： 其中A1 -A5 、Q、T、R1 -R4 、m和△係如申請專利範圍第1項所定義。A method of preparing a compound represented by the following formula (Ia), The method comprises condensing a compound of the formula (IV): Steps with a compound represented by the following formula (V): Wherein A 1 -A 5 , Q, T, R 1 -R 4 , m and Δ are as defined in the first item of the patent application. 一種製備如下式(Ib)所示之化合物的方法 該方法包含縮合下式(VIII)所示之化合物： 與下式(V)所示之化合物之步驟： 其中A1 -A5 、Q、T、R1 -R4 和m係如申請專利範圍第1項所定義。Method for preparing a compound represented by the following formula (Ib) The method comprises condensing a compound of the formula (VIII): Steps with a compound represented by the following formula (V): Wherein A 1 -A 5 , Q, T, R 1 -R 4 and m are as defined in the first item of the patent application.
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